Chemistry of Heterocyclic Compounds

vol.22

OxO- and thioxo-1,3-thiazines (review)

1-13
Mass-spectrometric study of the cyclization reactions of diazoketones. 8. 1-Diazo-3,4-epoxy-4-
arylbutan-2-ones
13-18
Synthesis of 2-, 6-, and 7-aminomethyl derivatives in the 4,5-dihydroxybenzofuran series
18-22
Conversion of trans, trans-1-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes into
hemidithioacetals and 4H-thiopyrans. Structure of trans, trans-1-mercapto-3-phenyl-5-(4-
methoxyphenyl)-2-thiabicyclo[4.4.0] dec-3-ene
23-28
Study of kinetics and mechanism of sulfonation of thiophene and its derivatives by complex
compounds of sulfuric anhydride
28-33
Synthesis of heterocyclic analogs of prostaglandins from pyrrole and indole
33-36
New synthesis of indole-7-carboxylic acid
36-37
Synthesis of heterocycles from 1,5-diketones. 3. Alicyclic 1,5-diketones in reaction with
phenylhydrazine
38-44
Synthesis of derivatives of 4-imino-2-amino-2-imidazoline. New example of a multicomponent
condensation involving isonitriles
45-51
New derivatives of imidazoline 3-oxide and thiazoline with 2,6-dialkylphenol fragments
52-56
Spectroscopic study of the structure of N-(2-benzimidazolyl)-O-methylcarbamate
57-63
Reactivity of methyl derivatives of nitrogenous heterocycles in vapor-phase catalytic oxidation
63-66
Synthesis and ring-chain isomerism of n-monosubstituted 4-benzoylnicotinamides and 3-
benzoylisonicotinamides
67-70
Acetals of lactams and acid amides. 46. Unusual reactions of -cyano--
dimethylaminocrotonamide with anthranilic acid derivatives
70-73
Synthesis of 5-oxoindeno[1,2-b]pyridinium salts
73-76
Azaindole derivatives. 67. Synthesis of N-substituted 1-benzyl-4-methyl-5-cyano-6-amino-7-
azaindoles
76-80
Synthesis and some reactions of 4-nitro derivatives of imidazo[4,5-c]pyridin-2-ones
80-85
Synthesis of N6-substituted adeninyl-9--D-glucofuranuronosides
85-88
Synthesis and properties of symm-triazine derivatives. 4. Synthesis of 2,4,6-trisubstituted symm-
triazines containing sterically-hindered phenol fragments
89-94
Structure and some properties of tetrazole 5-methylpyrimido[4,5-e]-[1,2,4]triazine-6,8-dione and
its azide in different phase states
95-100
10-Alkenylphenothiazines. 1. Synthesis and cis,trans-isomerization of 10-propenylphenothiazines
100-103
New type of recyclization of 2-benzopyrylium salts
104-105
Reaction of flavylium perchlorate with carbon monoxide
105
Unusual reaction of N,N-dimethylacetamide diethyl acetal with 2-aminomethylene-5,5-
dimethylcyclohexane-1,3-dione. Synthesis of coumarin and carbostyril derivatives
106-107
1-Thiocarbamoyl-5-oxy- and 5-thiosemicarbazido-2-pyrazolines
107-108
Methods for the synthesis of azoles containing indole substituents (review)
109-133
Quantum-chemical treatment of recyclization reactions. 9. Photoisomerization of five-membered
heterocycles
133-140
Synthesis of 5-substituted cyanofurans and their reaction with hydrazine
140-145
Chlorination of 1,3-dioxolan-4-ones
145-147
Reaction of 2-methyl-5,6-dihydro-2H-pyran with dichlorocarbene
147-148
Chemistry of isoflavone heteroanalogs. 11. Benzodioxane analogs of chalcone, flavone, and
isoflavone
149-154
An unusual product of the reaction of 1-phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-1-
propanone with hydrogen sulfide and acids: 2-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-1-
thiadecalin
155-161
Reactions of azirines with sulfur nucleophiles. 4. Treatment of 2H-azirine with
mercaptosubstituted acids. reactions of aziridinyl alkyl sulfides with carboxylic acids and acyl
chloride derivatives
161-166
New derivatives of meso-(tetra-4-pyridyl)porphine and their reactions
167-171
Tetracyanoethylation and fischer rearrangement of some 4-oxo-4,5,6,7-tetrahydroindoles
172-175
Chemistry of the pyrazolidines. 26. Alkylation of 4-benzyliden-1-phenyl-3.5-dioxopyrazolidines
176-180
Reaction of 4-aminoimadazo[4.5-c]pyridin-2-ones with -bromomethylketones
180-186
Effects of acids on orientation in the reaction of 5-formyl-4-(1-pyridino)azole 2-oxides with
aromatic amines
186-192
Reaction of pyrido[1,2-a]benzimidazole and tetrahydropyrido[1,2-a]benzimidazole with
acetylenedicarboxylic ester
192-194
Mass spectrometric study of the stereoisomers of 2-furyl- and 2-phenyldecahydro-4-quinolinone
and their tertiary alcohols
195-199
Arylidenehydrazono-2(4)-azafluorenes
200-205
Synthesis and dynamic stereochemistry of 1,5-disubstituted 2,3,4,5-tetrahydro-1H-1,5-
benzodiazepin-2-ones
206-210
Homolytic addition of 1,3-oxathiolane to unsaturated hydrocarbons
210-214
Effect of substituents on the relative stability of furoxan isomers
214-217
Mass spectra and 13C NMR spectra of the adducts of epoxyenamines with sulfene
217-221
Fragmentation of substituted 2-sila-1,3-dioxacycloalkanes under electron impact
221-224
Synthesis of 2-(diazomethyl)-3-methyl-5H-furan-4-one from 1,5-bis(diazo)-3-methylpentane-2,4-
dione
225
Thermal isomerization of -arylideneisochromenes into -naphthols
226
Addition of isocyanates and isothiocyanates to 2-amino-3-phenylcarbamoylazirines
227-228
First synthesis of ethylenebisporphyrins
228-229
Synthesis of N-heterocyclic analogues of 2,5-diaryloxazoles
229
Synthesis of 2-benzoyl(thenoyl)benzo-1,4-thiazines
230
Electrophilic heterocyclization of unsaturated sulfur and phosphorus compounds (review)
231-242
Hydrogenation of furfural on polymer-containing catalysts
243-246
Interaction of ethoxyacetaldehyde with 1,3-dicarbonyl compounds
247-250
Acid-base properties and stability of pyrylium polymethine dyes in chlorohydrocarbon solutions
250-253
Electrochemical reduction of N-vinylazoles
253-257
Studies of 1-azabicyclics. 23. Nitration of 1,2-dihydropyrrolizine and its homologs
257-261
Synthesis of derivatives of indole and quinoline by the intramolecular catalytic cyclization of
allylanilines
262-264
Nucleophilic substitution reactions in 4-halonitro-pyrazolecarboxylic acids
265-267
Reaction of 1,2-hydroxylaminooximes with 1,2-diketones. Conversion of 2-acyl-1-hydroxy-3-
imidazoline 3-oxides to pyrazine 1,4-dioxides
268-275
Studies of imidazo[1,2-a]benzimidazole derivatives. 21. Synthesis of haloketones in the
imidazo[1,2-a] benzimidazole series
275-282
Reaction of N-aminobenzimidazolium cations with aromatic aldehydes. Synthesis of 2,4-diaryl-as-
triazino[1,6-a] benzimidazoles
282-287
Formation of 4,5-dihydro-1,2,4-triazoles during rearrangement of O-acetyl derivatives of 1,2-
hydroxylaminohydrazones and thiosemicarbazones
287-291
Quantum-chemical interpretation of recyclization reactions. 10. Photoisomerization of six-
membered heterocycles
291-297
Reaction of 5-bromo-6-amino-3-(4-methylaminobutyl)pyridine with potassamide
297-300
Rearrangement of 2-hetarylalkylpyridinium salts
300-303
New method of synthesis of 3-alkyl-4-piperidones
304-306
Mass spectrometry of stereoisomeric 3-hydroxy-4-piperidones
306-310
Synthesis of 5-arylpyrimidine-2-carboxylic acids and the liquid-crystal characteristics of their aryl
esters
310-318
Reactions of azinium ions. 4. Reactions of quinoxalinium salts with nitroalkanes Single-stage
path to tetraazaheterocycles with bridged and framework structures
318-328
Preparation of some substituted 1,2,4-triazines
328-330
Purinenucleoside analogs. 2. 9-(1-Alkoxyethyl-1)-6-substituted purines
331-334
Configuration of 2-(4-pyridyl)-5-aryloxazole molecules in various states of aggregation
334-339
Macroheterocycles. 24. Synthesis of new derivatives of diaza-18-crown-6
340-342
Reaction of phthalimide with diethylene triamine and triethylene tetramine
343
5-Amino-6-mercaptopyrimidines in the synthesis of derivatives of 5-amino-1,2,3-thiadiazole
344-345
2-Selenoxoquinazolones-4, a new kind of quinazolone
345-346
Alkylation of 6-substituted purines in conditions of interphase catalysis
346-347
Synthesis of condensed tetrahydropteridines by the cyclization of the 8-ethylpteridinium cation
with dinucleophiles
348-349
Synthesis of 2,3-diphenyl-5,6-dihydro-1,3-oxazinium hexachloroantimonate from 2-phenyl-1,3-
dioxane
349-350
Acidic transformation of 2-(2-hydroxyphenylamino)-1,4-naphthoquinone-4-phenylimines into N-
phenylbenzo[a]-phenoxazimes
350-351
Synthesis of heterocycles on the basis of aliphatic nitro compounds (review)
353-370
Some reactions of 3,7-dimethyl-2,3-epoxyoctanal and its derivatives
370-372
Synthesis of the diastereomeric 2-aryl-1-cyclohexyl-3-(2,3-epoxypropionyl)aziridines
372-375
Quantum-chemical treatment of recyclization and cyclization reactions. 11. Formation of a
pyrylium ring
376-380
Synthesis of 4-methyl-2,3,4-trichlorotetrahydropyran and several features of the stereochemistry
of the nucleophilic substitution of the -chlorine atom
380-386
Structure of the products of the o-monoalkylation of pyrocatechol by -bromoketones
386-389
X-ray structural investigation of novel azabicyclic systems containing aziridine rings
390-393
New examples of the vinylation of NH-heterocycles with acetylene at atmospheric pressure in the
KOH-DMSO system
393-396
Synthesis of tetraphenylporphins with reactive groups in the benzene rings. 3. Use of
diazotization for the preparation of substituted tetraphenylporphins
397-401
Ethyl 1,4-dihydropyridinecarbodithioates and the electronic effects of sulfur-containing ester
substituents
401-410
Formation of a derivative of 3,3,5-tricarbonyl-1,2,3,4-tetrahydropyridine under the conditions of
the hantzsch synthesis
410-414
Synthesis and reactions of 8-benzylidene-2-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylic acid
arylamides
415-416
Preparation of derivatives of 1,2-dihydro- and 1,2,3,6-tetrahydropyrazinones from acylated 1,2-
hydroxylamino ketones
417-421
Synthesis of 1-alkyl(aralkyl)-4-acyl-2-piperazinones
421-424
Analogs of purine nucleosides. 3. Alkoxyalkylation of hypoxanthine by the silyl method
425-431
Alkyliminomalonic acid and 2-alkyloxaziridine-3, 3-dicarboxylic acid esters
431-437
Oxazolidines. 1. Basic catalytic disproportionation of cyclohexanospiro-2-oxazolidines: Synthesis
of N-substituted 4,5,6,7-tetrahydroindoles
437-439
Oxazolidines. 2. Synthesis of 2-methyloxazolidines by cyclization of vinyl ethers of 1, 2-amino
alcohols
440-442
Mass spectrometric study of 1,2,4- and 1,3,4-oxadiazoles containing indole substituents
442-446
NMR spectral study of the structure of 2-amino-4-thiazolinones
447-451
Synthesis of isomeric 4- and 5-hydroxylaminothiazolidin-2-thiones
451-455
Benzazolin-2-thiones in the michael reaction. 1. Reaction of benzothiazolin- and benzoxazolin-2-
thiones with acrylonitrile, acrylamide, and methylacrylate in the presence of acid catalysts
456-459
PMR study of the conformational behavior of 2,5,5-trisubstituted 1,3,2-dioxaborinanes
459-462
Synthesis of furan derivatives from 1,3-alkadiynes
463
A new reaction in the series of 4,5,5-trimethyl-3-butenolides
464
Addition of indole to fervenulin-3-one and its 4-N-oxide
465-466
New synthesis of pyrrolo[1,2-a] pyrrole derivatives
466-467
Homolytic alkylation of 2-methylquinoline by benzodioxolane and benzodioxane
467-468
Reaction of 4-methoxy(methylthio)-5-amino-6-mercaptopyrimidines with , -
dibromoacetophenone
468-469
New synthesis of 1-vinyl- and 1,3-divinyluracils
469-470
Reaction of 8-bromo-3-methylxanthine with amines in DMFA
470
Analogues of prostacyclin (PGI2) modified in the 2-oxabicyclo[3.3.0]octane fragment (review)
471-485
Reaction of 1-alkyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines with boron trifluoride etherate
in methanol
485-489
Formation of 2-phenyl--benzpyrone (flavone) in nucleophilic thiylation of 1-(2-hydroxyphenyl)-3-
phenylprop-1-yn-1-one by potassium p-thiocresolate
490-491
Synthesis of tetra(1,4-dithiacyclohexene)porphyrazine and its metal complexes
492-494
Asymmetrical alkylation of 1-[(s)--phenylethyl]-azethidinone-2
495-499
Azo coupling and aminomethylation of 2,5-diphenylpyrrole and its derivatives
499-503
Kinetics of the cycloaddition of maleic anhydride to arylaminomethylene derivatives of 3-methyl-1-
phenylpyrazole-5-thione
503-507
Recyclization of 1-amino-3.5-diaryl-2.6,6-tricyanocyclohexa-1,3,-dienes to pyridine derivatives
508-512
Electrochemical reduction of bipyridinium salts
513-516
Preparation and properties of betaines of 4-pyridyl-3,4-dihydropyridine-2-thiones(1H)
517-521
Acid deuterium exchange in methoxyquinolines and their N-oxides
522-529
-phenylisocinchomeronic and 4-azafluorenone 3-carboxylic acids
529-532
Reaction of 1-methyluracil with phenylbenzhydrazonoyl chloride
532-538
Reaction of diaroylethylenes with ortho-phenylenediamine and its derivatives
538-542
Nitroazines. 5. Use of the japp-klingemann reaction for the synthesis of nitrotriazines
543-546
Reaction of 3,4-diaminofurazan with carbonyl compounds and their metal complexes
546-549
Crown ethers bound to sulfanilamide preparations
549-551
2-Hydroxymethylamino-4-thiazolinone. Confirmation and chelate formation
551-557
Acid deuterium exchange in benzazoles
557-564
Benzazolin-2-thiones in the michael reaction. 2. Reaction of benzothiazolin- and benzoxazolin-2-
thiones with acrylonitrile, acrylamide, and methyl acrylate in the presence of basic catalysts
564-567
Heterocyclization of compounds containing diazo and cyano groups. 2. Synthesis and
recyclization of 4-substituted 5-amino-1,2,3-thiadiazoles
567-571
Divinyl sulfide. 15. Cycloaddition of divinyl sulfide and its 2-methyl derivatives to thiourea and N-
monoalkyl- and N-monoarylthioureas
572-577
Mass-spectrometric study of benzopyridosilaazepines and -azepinones
577-580
Electrochemical preparation of pyridinyl radicals, substituted by electron acceptors in the -
position
581-582
Synthesis of 4-aryl-5-thioxo-4,5-dihydroindeno[1,2-b]pyridines
582
Reaction of O-aryl-N-di(2-chloroethyl)amidoguanidyl phosphates with acetoacetic ester
583
Pyrimidinetetrasulfonic acid
584
Addition of trichloroacetonitrile to vinyltetrazoles
585
Effect of the acid-base properties of heteroaromatic compounds on their electrophilic substitution
reactions (review)
587-608
Condensed heterocycles. 45. Synthesis and structures of imines of 2-selenolo-3-benzo [b]
furanaldehyde and 3-selenolo-2-benzo [b] furanaldehyde and their derivatives
608-612
Condensed heterocycles. 46. Crystal structure of 3-mercapto-2-benzo[b]-furylidene-(p-
methylphenyl) amine
613-616
Mass-spectrometric behavior of benzo-substituted dibenzo-18-crown-6 ethers
616-619
Catalytic properties of rhodium hydridocarbonyl trithienyl-phosphine complexes in the
homogeneous hydrogenation and isomerization of unsaturated compounds
620-624
Reactions of aromatic and heteroaromatic compounds carrying electron-acceptor substituents.
26. Acylaminomethylation of 2-acylthiophenes, 2-thiophenecarboxylic acid, and its esters
625-629
Improved method for synthesis of substituted tetraphenylporphins
629-632
Tautomerism of azine derivatives. 11.14N-NMR and17O-NMR investigation of intrachelate
tautomerism of acylmethylpyridines
633-639
Condensation of 4-azafluorene with -butylene glycol and glycerin
640-642
Synthesis starting from 3-methyl-2-phenyl-5-(3-methyl-2-phenyl-3,4-dehydropiperidyl-6)pyridine.
2-phenyldinicotinic and 4-azafluorenone-2-carboxylic acids
642-646
Synthesis of methyl esters of 6-dialkylamino-2-(carbethoxy)-methylthiopyrimidine-4-carboxylic
acids
647-650
Synthesis of 2-aryl- and 2-hetaryloxazoles from the oxazolines and oxazolidines
650-653
Synthesis, structure, and spectral properties of some bioxazoles
654-663
Course of bromination of thiazole and 2-methylthiazole
663-666
Synthesis of macrocyclic compounds containing thiophene and thiazole nuclei
666-669
Synthesis and structure of methyl-substituted 1,3-Dioxa-2-Silacylohexanes
670-675
Synthesis of dibenzofuran and its nitro-substituted derivatives
676
Furo[2,3-c]pyrylium A new heteroaromatic system
677
Alkylation of furan and thiophene with tert-butanol in the presence of the strongly acid cation
exchanger amberlyst 15
678-679
New method of isolating N-substituted 3-aminomethylenethiol-4-en-2-ones
679
Synthesis of bis(o-xylylenedithio)tetrathiafulvalene
680
Reactions of copper and silver acetylides with hydrazone bromides A new route to 1,3,5-
substituted pyrazoles
681
New synthesisof imidazo[4,5-f]quinoline derivatives
682
Reaction of 2-aminobenzothiazoles with glycidyl phenyl ether
683
Ion-radical and redox transformations of cyclic acetals (review)
685-695
Effect of the heteroatom of a benzo[b]-annelated five-membered heteroring on the structure and
properties of an aminovinyl ketone fragment included in the ring
695-699
Condensation of 3-methyl-3-buten-1-ol with some ketones
700-702
Pyrylocyanines. 22. Styrils derived from methoxy-substituted 4-methylflavylium salts
703-707
Reactivity of cyclic sulfides in reactions with quinones
707-710
Preparation of spiroaziridinefluorene, spiroindoxyl-fluorene, and -aminopropionic acid ester with
a 4-azafluorene fragment
710-713
Mechanism of the Fischer indole synthesis. Quantum-chemical interpretation of the
rearrangement of substituted cyclohexanone arylhydrazones to tetrahydrocarbazoles
713-722
Thermal heterocyclization of methyl aryl ketazines. 2. Reactions of the tautomeric enehydrazine
form
723-732
Research on imidazo[1,2-a]benzimidazole derivatives. 22. Synthesis of 2,3-dihydroimidazo[1,2-
a]benzimidazoles starting from 2-imino-3-(2-hydroxyethyl)benzimidazolines
732-739
Heterocyclization of compounds containing diazo and cyano groups. 3. Two pathways in the
cyclization of 2-diazo-2-cyanoacetic acid derivatives under the influence of bases
740-745
Reactions of 4-nitro-1,2,3-triazole with alkylating agents and compounds with activated multiple
bonds
745-748
Chemistry of heterocyclic N-oxides and related compounds 13. Acylamination of pyridine N-oxide
by aniline, p-anisidine, and their N-p-tosyl derivatives
749-751
Synthesis of substituted 2-pyridones and 4-aza-3-fluoridones
751-754
Condensation of N-(piperidylidene-4)arylamines with acetylenedicarboxylic esters
755-758
Synthesis and luminescence of benzo[f]quinoline derivatives with fused alicyclic rings
759-762
Quantitative determination of the electronic effects of 3- and 4-pyridazinyl groups from NMR
spectral data for isomeric aminophenyl- and phenylpyridazines
763-770
Synthesis of condensed pyrazines from N-substituted amino-o-quinones and ethylenediamine
771-774
Chemical properties of ylidene derivatives of azines. 3. Synthesis and reactions of ylidene
derivatives of halopyrimidines
774-779
Free radicals in the perimidine series. 2-Tert-butylperimidyl radicals
780-782
Fluorine-containing azoles. 4. 2-Perfluoropolyoxaalkyl-substituted perimidines
783-785
Electronic structure and mass spectra of substituted hexahydro-1,3,5-triazine-2-thiones
786-790
Condensed imidazo-1,2,4-azines. 14. Synthesis and reactivity of 3-chlorine-substituted
imidazo[1,2-b]-1,2,4-triazines
791-795
Reaction of 2-alkylaminobenzothiazoles with acrylic acid
795-799
Investigation of nitrogen- and sulfur-containing heterocycles. 44. New heterocyclic systems.
Derivatives of imidazolidino-[3,2-f]pyrido[2,3-b]-and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-
thiazines. Synthesis and structure
800-805
Synthesis of bromo-substituted 2-formylpyrroles
806-807
Recyclization of 4-cyanobenzo[c]pyrylium salts upon reaction with hydrazine
807
1,1Azobenzimidazoles
808
Synthesis of benzopyrano[3,4-c]-and benzothiopyrano[3,4-c]-[2,1,3]selenadiazol-4-ones
809
Structures synthesis, and properties of 1,2,3-thiadiazoles (review)
811-827
Synthesis of acetylenic derivatives of 1,4-dioxane
828-829
Homolytic telomerization of vinyltrimethylsilane with 5,5-dimethyl-1,3-dioxane
830-834
Mechanism of amination of aziridines and oxiranes. 3. Quantum-chemical investigation of the
effects of specific solvation
834-839
Mechanism of amination of aziridines and oxiranes. 4. Quantum-chemical investigation of the
effect of the polar solvent
839-844
Crystal and molecular structure of 6-methyl-2,7-diphenyl-1,3-diformylindolizine
844-848
Mass-spectrometric behavior of isatin oximes
848-851
Reaction of 2,3,3-trimethyl-3H-indole salts with acrylamide. Synthesis of 1,2,3,4,10,10a-
hexahydropyrimido[1,2-a]indol-2-one derivatives
852-855
Formation of 2-imidazoline derivatives in the reaction of 1,2-hydroxyamino oximes with phenyl-
and methylglyoxal
856-860
The NMR spectra of cyclic nitrones. 3. Effect of protonation and a hydrogen bond on the chemical
shifts in the13c NMR spectra of derivatives of 3-imidazoline 3-oxide
861-868
Organolithium and organosodium compounds of n-substituted 2-alkylbenzimidazoles
868-872
Chemistry of 2-hetarylbenimidazoles. 7. Transformations of trans-1-methyl-2-[-(2-furyl)vinyl]
benzimidazole
872-875
Derivatives of imidazo[4,5-e]-2,1-benzisoxazole and synthesis of substituted benzimidazoles from
them
876-879
Tetrazoles. 21. Reaction of benzonitrile with salts of hydrazoic acid
880-883
Reaction of salts of nitroaminotetrazoles with alkyl iodides
883-886
Twofold reactivity of 1,2-disubstituted dihydro-n-heteroaromatic systems. 10. Synthesis and
aromatization of ferrocene-containing hantzsch esters
886-893
Synthesis and spectral characteristics of acenaphthene derivatives of benzo[f]quinoline
894-898
Three-dimensional structures of stereoisomers of 2-phenyl-4-ethynyldecahydro-4-quinolinol
899-902
Investigation of the acid- and base-induced transformations of nitrogen heterocycles by NMR
spectroscopy. 1. Substituted pyridines and pyrimidines
903-908
Acetals of lactams and acid amides. 47. Investigation of the behavior of substituted 6-(-
dimethylamino) vinyl-4-pyrimidinones in acidic media. Synthesis of 3-cyano-4-anilino-5-formyl-2-
pyridone and 3-chloro-4-cyanobenzo[b] [1,6]-naphthyridine
909-914
Synthesis and catalytic oxidation of 2,5-dimethylpyrazine
915-917
3-Aryl-1,2-dihydroquinoxalines
918-922
Reaction of 7-acylmethyl-8-bromo-3-methylxanthines with formamide
923-925
Reaction of 3-nitro- and 3,5-dinitro-derivatives of 2-pyridone with hydrazine hydrate
926
Formation of pyrimido[1,2-a]benzimidazoles in reaction of 1,2-diaminobenzimidazole with
chalcones
927
Direct introduction of azoloazine residues into resorcinol
928
1,2,3-Seleniumdiazolo[4,5-d]pyrimidine-5,7(4h,6h)dione A new condensed hetero system
929
Synthesis and properties of 1,6-dioxaspiro[4.4]nonane and its derivatives (review)
931-943
Synthesis and three-dimensional structures of 2-(2-furyl)-acrylonitriles
943-945
Conformations of isomeric 2,3,4-trisubstituted tetrahydrothiophenes
945-950
Synthesis and structure of derivatives of 7-aminobenzo[b]thiophene
951-953
13C and 15N NMR spectra of 2,3-substituted 2H-azirines
953-955
13C NMR spectra of N-substituted carbazoles. Transmission of the electronic effects of
substituents through the nitrogen atom to the carbazole ring
956-959
Nitration of tetrabenzoporphins
960-964
Electrochemical behavior of metal complexes of derivatives of dibenzo[c,j]dipyrazolo[3,4-f 3,4-
m][1,2,5,8,9,12]-hexaazacyclotetradecynes on a pyrographite electrode
965-970
Synthesis and structure of 1-benzoyl-2,5-dimethyl- and 1,2,5-trimethyl-4-arylpiperideins
970-976
Synthesis of stereoisomeric alkyl- and phenyl-substituted 5-cyanopiperidine-3,4-diols
976-980
Arylation, alkylation, reduction, and pyrolysis of 1h-1-methylindeno[2,1-b]pyridine
980-982
Investigation of stereoisomers of 4-alkenyl-trans-decahydroquinol-4-ols in mixtures by the method
of reaction chromato-mass spectrometry
983-985
Naphthyridines in hetarylation reactions
986-990
Synthesis and properties of derivatives of 1,4-dihydropyrimidine-5-carboxylic acid
990-994
Synthesis and mesomorphic properties of aryl 5-alkyl-(and alkoxy) pyrimidine-2-carboxylates
994-1001
Synthesis and spectral examination of the position of tautomeric equilibrium in 2-thioxo-4-
quinazolone
1001-1003
Diazabicycloalkanes with nitrogen atoms in nodal positions. 13. Reactions of benzo[b]-1,4-
diazabicyclo[2.2.2]octene with electrophiles
1004-1009
Cyclotrimerization of thiocyanic acid in organic solvents
1009-1010
Stereoisomerism in macrocyclic bis(piperidones)
1011-1016
Investigation of substituted 1,3-oxazolidines using 1H and 13C NMR spectroscopy
1017-1022
Synthesis and spectral and luminescent properties of 4-(5-aryloxazoyl-2)benzoic acids and their
derivatives
1022-1025
2-(4-Cyanophenyl)-5-aryloxazoles
1026-1027
Hetarylethylene derivatives of 2,5-diaryloxazoles and 2,5-diarloxadiazoles and their luminescence
and scintillation properties
1028-1031
Polynuclear heterocyclic compounds based on the adduct of o-cinnamoylbenzoic acid and
cyclohexanone
1031-1035
Optical and electrophysical properties of metal complexes of tetra(1,4-
dithiacyclohexeno)porphyrazine
1036-1039
Synthesis, structure, and transformations of 1-aza-3-oxa-7-thiabicyclo[3.4.0]nonan-2-one
1039-1044
Efficient method for the hydrolysis of 4-chlorotetrahydropyrans
1045
New reaction of malononitrile and arylidene- and 1-arylethylidenemalononitriles
1046-1047
1H-isobenzofurylium (phthalylium) salts (a review)
1049-1058
Mass spectrometric decomposition of -phenyloxiranecarboxylic esters
1058-1063
Photochemistry of unsaturated lactones. 2. Photoannelation of 2-acetyl-3,4,4-trimethyl-2-buten-4-
olide by terminal alkynes
1063-1068
The chemistry of 1,5-diketone derivatives. 2. Preparation of 2-hydroxy-1,3,5-triphenyl-1,5-
pentanedione and some heterocycle derivatives
1068-1071
2,2-Dimethyl-5-(5-r-2-furfurylidene)-1,3-dioxan-4,6-diones. 1. Synthesis, properties, and structure
1072-1075
Isomerization of 5-acyl-6-halo-1,6-diazabicyclo[3.1.0]hexanes, a case of inversion rather than 1,2-
acyl migration
1076-1079
Mass spectrometric study of ring-chain tautomers of 3-amino(hydroxy)pyrazolidines
1080-1083
Nitrosochlorination reaction of substituted imidazolin-2-ones
1084-1087
Mass-spectrometric study of the cyclization of diazo compounds. 9. 2-Diazo-2-cyanoacetamides
1087-1093
Synthesis and conversions of 2-aryl derivatives of s-triazolo[4,3-a]pyrimidine
1093-1096
Synthesis of acid-base transformations of 3-aroyl-6-methyl-2-oxopyridines
1097-1099
Synthesis and acid-base transformations of (4-styrylpyridinio)-alkanesulfonates
1099-1104
Acid hydrolysis of N-methyl derivatives of 4-phenyl-5-oxo-4,5-dehydroindeno[1,2-b]pyridine
1104-1107
1,2,5-Trimethyl-4-(p-hydroxyaryl)-3-tetrahydropyridines and their spatial structure
1107-1110
Synthesis of 1,5-methano-2-benzazocines from 3-hydroxy-1,3-dimethyl-6-phenyl-4-piperidone
1110-1113
Alkylation of quindoline and quindoline-11-carboxylic acid
1114-1117
Reaction of azinium cations. 5. Addition of water and methanol to 1,4-diazinium cations in the
presence of bases. equilibrium constants and PMR spectra of the mono- and diadducts
1118-1125
Heterocyclic analogs of pleiadiene. 59. Reaction of 1-acetonyl- and 1-phenacylperimidinium salts
with hydrazine and ammonium acetate
1126-1131
Reaction of vinyl ethers of the pyridine series with bromine and iodine
1132-1134
Structure of the alkaline salts of 2-phenyl- and 2-p-methoxyphenylimino-4-thiazolidinones
1134-1139
Synthesis and spectrometric investigation of the thioamides of thiazole- and benzothiazole-2-
carboxylic acids
1139-1144
Synthesis of substituted 1,3-thiazinoazoles
1145-1148
Synthesis and mass-spectrometric study of 2-amino- and 2-chloro-5-aryl-1,3,4-thiadiazoles
1148-1152
10-Alkenylphenothiazines. 2. Synthesis and mechanism of acidic hydrolysis of cis- and trans-10-
2-phenylvinyl)phenothiazines
1152-1157
Photodimerization of 2,6-diphenyl-4-(5-bromofuryl-2)-pyrylium and pyridinium perchlorates
1158
Formation of heterospirans, containing a -lactone ring, upon treatment of dialkylacetylcarbinols
with malonic ester
1159
Novel polyfunctional spiroheterocyclics based on acetylenic hydroxyacids
1160
Synthesis of benzothiazepines (review)
1161-1170
Reaction of furan compounds with hydrogen sulfide and aspects of its application
1170-1173
Synthesis and three-dimensional structure of 4-hydroxy-4-methyl-3-chloro-6-
alkyltetrahydropyrans
1174-1177
Alkylation of benzo- and dibenzocrown ethers by various alcohols
1178-1185
Synthesis and properties of bis(vinylenedithio)- and bis(dimethylvinylenedithio)tetrathiafulvalenes
1186-1189
5-Substituted 2-methyl- and 2-methyleneindolines
1189-1192
Heterogenous-catalytic synthesis of 2,3-dihydroselenophene and 3,4-dihydro-2H-selenopyran
1193-1195
Benzindoles. 24. Reduction of nitro-2,3-dimethyl[4,5]- and nitro-2,3-dimethyl[6,7]benzindoles
1195-1198
Synthesis of 1-substituted 1,2,3,9a-tetrahydro-9H-imidazo[1,2-a]indol-2-ones
1198-1202
Mass spectra of piperidine dicarboxylic acids and their esters
1203-1207
Conformation of the piperidine ring in isomeric 1,2,5-trimethyl-4-phenyl(triorganosilyl)piperidin-4-
ols from the PMR spectra
1208-1213
The 13C NMR spectra, isomerism, and conformational analysis of substituted piperidin-4-ones
1214-1225
Dual type of reactivity op 1,2-disubstituted dihydro-N-heteroaromatic systems. 11. Aromatization
of N-sulfonyl-1,2-dihydroquinolines and isoquinolines containing an -indolyl or pyrrolyl
substituent
1226-1228
Reaction of N-arylidene-2-naphthylamines with allylacetone
1229-1231
Synthesis of substituted 2- and 4-hydroxyaminopyrimidines
1232-1236
6-Aminopyrimidine 1-oxides. Acylation and methylation
1236-1241
Reactions of azinium cations. 6. N(1)-alkyl-1,2,4-triazinium salts. Reactions with indoles The
first case of the double addition of nucleophiles to a triazine ring
1242-1249
Nitroazines. 6. Direct introduction of indole residues into 6-nitroazolo[1,5-a]pyrimidines
1250-1255
Polarographic examination of 5-aryl-2-(2-thienyl)-oxazoles and -1,3,4-oxadiazoles
1255-1258
Conversion of 2-amino-5-R-phenyl-1,3,4-oxadiazoles into 3-R-phenyl-5-alkoxy-1,2,4-triazoles
1258-1261
Synthesis of arylazoles and their luminescent properties
1262-1266
1,4-Dihydrobenzothieno[3,2-b]pyridine-5,5-dioxides
1267-1271
Photochemical rearrangement of 4,5-ethylenedithio-1,3-dithiol-2-thione to 4,5-ethylenedithio-1,2-
dithiol-3-thione
1272
Stereospecificity of direct 13C-1H spin-spin coupling constants of vinylpyridines
1273-1274
Photochromic fulgides of the indole series
1274
Replacement of bromine by hydrogen in bromo derivatives of tetrahydropyrimido[4,5-
b][1,4]benzthiazine under conditions of electron-impact ionization
1275-1276
1-Tellurachromylium perchlorate
1276
Phosphorylated pyridines and their benzo-homologs (review)
1277-1291
Alkylation of -dicarbonyl compounds by 1,2,3-trihalopropanes as a method for the preparation of
-substituted furans
1291-1295
Pyrylocyanines. 23. 2-Pyrylocarbocyanines with substituents in hetero residues
1295-1300
Thermal hydrothiolysis of di(2-thienyl)sulfide in the gaseous and liquid phase
1301-1306
Structure of the intermediate particles in the radiolysis of indolinespiropyran
1307-1310
Indole derivatives. 128. Synthesis and properties of 5,6- and 4,5-ethylenedioxyindoles
1311-1315
Electronic and photoelectron spectra of amino-1-methylnitropyrazoles and their quantum-
chemical interpretation
1316-1321
Reactions of heterocyclic cations with n-containing nucleophiles. 15. Reaction of 2,6-
diphenylpyrylium perchlorate with semi- and thiosemicarbazides
1322-1326
Asymmetric synthesis and absolute configuration of 1--phenylethyl-2,5-dimethyl-4-piperidone
isomers
1327-1333
Synthesis of 2,3-polymethylenepyridines from 3-aminoacrolein and cyclic ketones
1334-1336
N-glycosides. 7. Synthesis of 4,5-anhydro-3-(2,2-O-isopropylidene--D-ribofuranosyl)-4-
hydroxyhexahydropyrimidine-2-thiones
1336-1341
Diazabicycloalkanes with nitrogen atoms in nodal positions. 14. Synthesis of dibenzo[1,2-b,e]-
1,4-diazabicyclo[2.2.2]octadienes containing a tertiary amino group in the aromatic ring
1342-1345
-Dimethylaminomethylene derivatives of succinimide and glutarimide in the Fischer reaction
1345-1349
Cyclizations with hydrazones of nitroglyoxalic acid. Synthesis and structure of tetrazolo[5,1-
b][1,2,4]triazines
1350-1354
Synthesis and properties of 1,4,9-triazaspiro[5,5]undecane and 3,7,11-triazaspiro[5,6]dodecane
1354-1357
Acid-base interaction of tetraazaporphin in organic solvents
1358-1362
Unusual reaction between 6H-6-oxo-5-haloanthra[1,9-cd]-isoxazoles and quinoline
1363-1366
Formation of derivatives of thiazoline by the reaction of thiourea with 2-bromo-3-aminopropionic
acid
1367-1369
Reaction of 2-thiopyrrolidones with monochloroacetic acid and its methyl ester
1370-1372
Condensed heterocyclic compounds containing a thiazole ring. 12. Derivatives of thiazolo[3,4-
b][1,2,4]triazine
1373-1376
OXO- AND THIOXO-I,3-THIAZINES (REVIEW)

G. A. Mironova, V. N. Kuklin, UDC 547.869.1(047)

E. N. Kirillova, and B. A. Ivin

Literature reports on the methods of synthesis, chemical properties, and tauto-

merism of oxo- and thioxo-l,3-thiazines have been summarized.

1,3-Thiazines, interest in which has increased steadily over the last decade, remain
relatively little-known compounds in comparison with pyrimidines and 1,3-oxazines. It has
nevertheless been established that a number of oxo- and thioxo-l,3-thiazines possess useful
properties, in particular high biological activity. The object of the present review is to
summarize the available information on the synthesis, chemical properties, and tautomerism
of 2-, 4-, and 6-oxo-l,3-thiazines, their sulfur analogs, and other derivatives.
It is preferable to divide the methods of preparation of these compounds into the four
general methods of synthesis of six-membered heterocycles, depending on the number of atoms
present in the fragments destined to form the ring [i]. Methods of synthesis which involve
modifications of compounds already containing the 1,3-tiazine ring will be considered in
the section devoted to the chemical properties of these compounds.

N C~ C N'~C"c NIC'C N/C"c N"C"c

] I I i I J [ I
Cxs/C C..S C C S C C"S C C S ''C
type A type B
(8+0) (s+x)

N/C'C N C--.C N/C C N C"C

I r l f i f I
C C- C C C S C C
~S S" r
type C type D
(4+~) (o+:0

(6 + O) CONDENSATION
Reactions of this type have been relatively little used for the synthesis of 2-, 4-,
and 6-oxo-l,3-thiazines. However, many reactions of types B-D occur via intermediates simi-
lar to those formed in type A reactions. The closure of six-membered fragments to form the
ring usually occurs by nucleophilic addition of nitrogen or sulfur to the carbonyl carbon
atom or the more reactive carbon of the protonated carbonyl group.
There have been no reports in the literature on the use of reactions of this type for
the synthesis of 2-oxo-l,3-thiazines, but there are a few examples of their use for the pre-
paration of 4- and 6-oxo-l,3-thiazines [2-5]. Condensation of the 2-thiocyanatocarbonyl
chlorides (I) in the presence of dry hydrogen chloride gives substituted 4-oxo-l,3-thiazines
(II) [2, 3]. The reaction must be carried out at O=C as a result of the high reactivity of
the carbonyl carbon. The reaction is assumed to proceed as follows [4]:

R ~. .SeN 2HCl ~i.. S>, ICI Cl- R S. ~.CI]c]" l~ - s. cl

"cii ~'~ ,cl[ ..'(:I ~- ....... |'--~,- I
c el / 2 c ~INH~ ! 9 R~/J" ./

II
1 RI=R2 II.CH:~: R I .R2=(_ r

Leningrad Institute for Pharmaceutical Chemistry, Leningrad 197022. Translated from

Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 3-16, January, 1986. Original article
submitted May 2, 1984.

0009-3122/86/2201-0001512.50 9 1986 Plenum Publishing Corporation 1

The condensation of the 3-thioureidobutyrate (ili) in methanolic sodium methoxide at 80~
has been used to obtain 6-oxo-l,3-thiazines [5]. The unusual nucleophilic attack on the car-
bonyl carbon by sulfur is explained by the authors [5] as being due to the formation of the
anion (IV) in an alkaline medium. In this case, the electron density at the sulfur atom must
be increased to a greater extent than that at the amino-group, while simultaneously the posi-
tive charge on the carbonyl carbon is reduced by conjugation. These factors result in the
preferential formation of the C-S bond.

0 O CH~
" r ~i I
CH3"C~CH't:--OC2H~'
I NaOCli4]_
I CH 3,
"r "
CH-I.-OC.~H~ Na+ N' "b~
,.
9 t I ---- [I /
HN..C.NH 2 N:. /~2 ,-b,,
9" - ~{'. ] NH~ 'S" '~O
II S' NH 2 J '

II[ IV

A general method for the synthesis of 2,4-dioxo-l,3-thiazines and their thio-analogs,

which permits the introduction of substituents into the 5- and 6-positions, is based on in-
tramolecular nucleophilic attack on the carbonyl group or the more reactive corresponding
enol ether by the sulfur atom in acyldithiourethanes [i, 6]. For example, acetoacetyldi-
thiourethane slowly cyclizes to2-ethylthio-4-oxo-6-methyl-l,3-thiazine on treatment with cold
concentrated sulfuric acid [6]. Reaction of the acyl chloride (V) with the S-ethyldithio-
carbamate (VI) affords the unstable acryloyldithiourethane (VII), which on cyclization gives
2-ethylthio-4-oxo-5-methyl-l,3-thiazine (VIII) [6].
O O

il + ml~cssc~H~ - - - - | li I , I
9 - [ 4'~11 ~c" [
.c Ic.~o s" "sc,,z~ ] s%.~
V VI L. " Vll / Vlll

The isomerization of 2-thio-4-oxo-6-methyl-l,3-oxazine to the more stable 2,4-dioxo-l,

3-thiazine on treatment with concentrated sulfuric acid [7] may be regarded as a reaction of
this type.

(5 + i) CONDENSATION
Type B reactions comprize the condensation of five- and one-membered fragments, in the
course of which bonds are formed between the heteroatoms and a carbon atom, or between two
carbon atoms. The five-membered fragment is frequently an acyl isothiocyanate [8, 9], an
unsaturated acid [10-13], or an acyldithiourethane, which condense readily with amines,
thiols [8], aromatic carboxylic acid derivatives [11-13], or orthoesters [i, 14]. The reac-
tion is normally carried out in aprotic nonPolar solvents in the presence of acetic anhydride
[14] or polyphosphate ester [11-13]. This type of condensation is not used for the prepara-
tion of 2-oxo-l,3-thiazines. An example of its use for the synthesis of 4-oxo-l,3-thiazines
is the reaction of 3-chloro-3-phenylpropenoyl isothiocyanate (IX) with amines to give the
substituted thioureas (X), which then cyclize to 2-alkylamino-4-oxo-l,3-thiazines (XI) [8].

/0 HNRIR 2 .~0
C H--C=CH C / . . . C H--C~--CH-C~"
. . . . . . . |fN I
6 5 CII "NCS 6 ,5 CII *'NHCSNR R ~ R1RZN / CsH5
IX X gI
R~ =H,Alk,Ar.; R2~AIk,Ar

The condensation of the 3-acylamino-2-butenoate (XII) with 2,4-bis(4-methoxyphenyl)-l,

3,2,4-dithiaphosphetane 2,4-disulfide (XIII) has been used to prepare the 2-substituted 6-
thio-4-methyl-l,3-thiazines (XIV) [I0]. In the first step, the 3-(2-thioacylamino)-2-buten-
oate (Xlla) is formed, and on boiling in xylene this cyclizes by nucleophilic addition of
the sulfur to the carbonyl carbon. Simultaneously, the oxygen atom at C(6) is replaced b y
sulfur.
 S
jS\ll
P-CH~OC.H~ - - P ~ ~P--C.H..-OCI.I.-p
" " - II--S . . . . cH~C:_: c
C113~C ~:CII-COOC21I~, S 3"111 - / t~C--OC2H s
RCONH" - ................................. NX\

XII
R'\
C--SI~

Xlla
B=Clia,CH(CH s)z,c(cll~) ~ coil s

Clt 3
XIY

This type of condensation is used rather more extensively for the synthesis of 2~4-di-
oxo-l,3-thiazines and their sulfur analogs, Condensation of the acyldithiourethanes (XV),
which contain a reactive methylene group, with the orthoesters (XVI) gives the intermediate
N-B-ethoxyacryloyldithiourethanes (SVII), which cyclize in the presence of acetic anhydride
to the corresponding 1,3-thiazines (SVIII) [i, 14]. Triethyl orthoformate is the most re-
active in the reaction. It appears that the use of triethyl orthoacetate or orthopropion-
ate increases the electron density at the electrophilic site, thus hindering the formation
of the C--S bond.

o o

~ OHC~.' ~ ~ s 2 9 1~:~ 'S""sC~H5

XV! XVll . XVIiI
R1 ~CN,COCH~; R2=H,CHs,CaH~.

The acyldithiourethanes (XIX), obtained by reacting the isothiocyanate (IX) with thiols,
cyclize to 2-alkylthio-4-oxo-6-phenyl-l,3-thiazines (XX) by intramolecular nucleophilic re-
placement of halogen by sulfur [8]. Reaction of the isothiocyanate (IX) with sodium hydro-
sulfide occurs via the unstable dithiocarbamate (XXI) to give 2-thio-4-oxo-6-phenyl-l,3-
thiazine (XXII) [8]. This compound (XXII) has previously been obtained from sodium hydro-
sulfide and 3-phenylpropionyl isocyanate [9].

0 0

HC I C ' - N t !

,>" co,,;,,
lX XT~ XX

Cl ...?N+ ~ ,C~
~S Coli 8
C6H5
x ~ r

R=C2H~,C3H?,CoHsCH 2

The condensation of substituted acrylamides (XXIII) with aromatic carboxylic acids has
been the subject of several studies [11-13]. Varying the reaction conditions and the reac-
tants affords differing reaction products. When benzoic acid or its anhydride i~ used, the
principal cyclization products are 6-thioxo-l,3-oxazines (XXIV), which isomerize quantita-
tively on heating in protic solvents to give the 6-oxo-l,3-thiazines (XXV) [12. The driving
force in this reaction is the greater stability of the 1,3-thiazine ring in comparison with
the 1,3-oxazine ring [7, 12]. It is noteworthy that condensation only occurs in the presence
of polyphosphate ester.

i 0 ~ir ~CII
NC NC II
(
r h c o , ~: l ~
i " R i '
"'l-
['.. "~'I ~'-H~
PhCOC|N" .CC
[]. . "INH
. z. . " ". ( p('!H'"5"
h ( T O ) 2 0. . . . . . (I IIN .E',)II- - .] "~" tlN
tlSCS ~ ' t'h " "' II~CS" :';H CII(.i5 .~ "" (I |eh 0 "" "'S Ph
~Xll[ X.XIV ~V
R:,;CH,(;ONtl 2
 (4 + 2) CONDENSATION
Type C reactions, which comprize the condensation of a four-membered unit (8-diimines,
8-iminopropionitriles, isothiocyanates, or thioacylketenes) with a two-membered unit contain-
ing a multiple bond, are quite widely used for the synthesis of oxo- and thioxo-l,3-thiazines.

1 ~ C .. /NHAr CS 2 ..-"
1 C ~NHAr \

~'\,, S

N' 'S

XXVIIItc ~ d

XXVI--XXVIII a Ar=p-OCH~C~H~, b, e Ar=C~H~, d Ar=p-CI-tsC~H~; a-d R~=C~H~;

a,e~d R~=C~I-t~, b R~=CH~

The condensation of 8-diimines [15] or ~-iminonitriles [16] with carbon disulfide has
been employed to obtain 2-thioxo-l,3-thiazines. In the case of the diimine (XXVI), nucleo-
philic addition of the diimine to the CS2 carbon first takes place. The subsequent course
of the reaction depends on the electronic effects of the substituents in (XXVI), Electron-
donating substituents R2 at the electrophilic center hinder the formation of the C--S bond,
and in this case the reaction products are the pyrimidines (XXVII). The absence of a sub-
stituent with a +M effect in the benzene ring attached to nitrogen results in a decrease in
the yields of pyrimidines (XXVlI), the thiazines (XXVlII) being formed in yields which are
largely independent of the type of substituent present [15].
The activating effect of the cyano-group in ~-imino-B-arylpropionitriles (XXIX) together
with basic catalysis favor the addition of sulfur to the methylene group. When the reaction
is carried out in dimethylformamide at 2~ addition of a further molecule of sulfur occurs
with the formation of 5-substituted-2,6-dioxo-4-aryl-l,3-thiazlnes (XXX) [16].

H
I
NH N.~ R .
.--~-'CH~CU
X~3X US2'~-CsHI
'ON"r-- E ' ~ S~

s
R=Ar~M~; RI=CN,CO2CH~ XXX

4-Oxo-l,3-thiazines are most frequently obtained by (4 + 2)-cycloaddition. Usually,

thioacyl isocyanates [17, 18] or isocyanates [18-20] are condensed with alkenes [17], al-
kynes [17], ketenimines [19], or phosphacumulidenes [18]. The reactions are normally carried
out in nonpolar aprotic solvents, the temperature used being dependent on the reactivity of
the reactants. The condensation of thiobenzoyl isocyanate (XEXI) with nucleophilic alkenes
and alkynes [17] has received especially close attention. The rate of this reaction is great-
er with alkynes than alkenes, and increases as the electron-donor properties of the substitu-
ents at the multiple bond of the nucleophile are increased.
O
CsHs__C_N~C= 0 NaCH(CN)C%C2H s , li 9 i ~o N
[r - ~" C'H'--C-:IO~C--CH'C~ --~" II II

-~.~c
o " - ~R ~ . . ~-.~, o ~ . o

N N

cs. ~ "s ~ c6~ ~ "s" "c6H5 c~H~ "s" "N(C2Rs)~

 The lower reactivity of the ketenimines (EXXII) in t h e i r reactions with isothiocyanates
(XXXIII) requires the use of more severe reaction conditions [9], The condensation is sen-
sitive to the electronic effects of the substituents. The yield of the 1,3-thiazinethione
(XXXIV) decreases as the electron density of the isothiocyanate (XXXIII) is increased, and
when electron-acceptor substituents are introduced into the keteneimines (XXXII).

S t~ -- . ~ 1
, II =
RIR=--~-C=C~.NR:s + ]~ 2,NC--NC8 CsHsCH
3- R42N/ ~ ' S ~ N R 3

X]ODI 13[XIII XX~V.

XXXIV a,b I~=R2=CHs, e RI=R~=C6Hs; a,b Ra=p.CH3CsH4,c RS=p.OCH3CsH4; a

R~=C~H~, b,c R4=i-CaHr

The cycloaddition of the isothiQcyanates (XXXV) to the phosphacumylidenes (XXXVI) af-

fords products with a zwitterionic structure (XXXVII) [18] in yields which are highly depend-
ent on steric factors (as the volume of R is increased, the yield of the thiazinethione
(XXXVII) decreases).

x
(Ph)3P
S
R--C--N--C~-~.g + (Ph)3--P--C=C=C-.~X
II
S S R
XXXV XXX'~ ]OtXVll
R=N(A.I.k)2; X=O,S,Nph

The four-membered unit can be thioacylketene (XXXVIII), which reacts with diisopropyl-
carbodiimide [ 2 1 ] .

f (Me)2HC% N ~ , - / R
Ph-- C--C..~-C=O I-C3H? --N~-C =-N-- C3ST-i
S (Me)2HC--N S 'Pb
XXXVIII R=CN,CO2C2H~

An interesting route to 4-oxo- or 4-thioxo-l,3-thiazines is by the reaction between 3-

substituted-2-oxo- or 2-thioxo-4-tosylimino-l,3-thiazetidines (XXXIX) and diethylaminopropyne
[22, 23]. Attack on the carbonyl or thiocarbonyl carbon by the ynamine appears to result in
recyclization of the four-membered to the six-membered ring.

X
R\ ~/CH 3
R N"C'~'S + CH3--CmC--N(C2Hm)2 ~ N [~
- - \CJl / TaN
~.~J \N(C2Hs)~
NTs
R=II.C~H~; X=O,S 9

The (4 + 2)-cycloaddition reaction has rarely been used to obtain 6-oxo-l,3-thiazines.

The only example known to the authors is the condensation of N-thioaroyl-N'N'-dimethylformi-
dines (XL) with ketches [24, 25]. Phenylketene is less reactive than its unsubstituted ana-
log.

~=c..(u,)2 R-c~c=o ---- 9 ]!

XL Ar '5 0
ll::.lt,l'rSl{~

Type C reactions have not been used for the preparation of 1,4-dioxo-l,3-thiazines.
They have, however, been used extensively in the synthesis of 4,6-dioxo-l,3-thiazines and
their sulfur analogs. The previously-mentioned isothiocyanate (XXXI) reacts with diethyl
sodiomalonate to give the straight-chain adduct (XLI), which cyclizes in the presence of c~-
pyridone to the 1,3-thiazine (XLII) [17].
 ,0
N,i /C02C2l[5
XXXI + NaC[4(CO~C~IIs)2 ...... ~m- C~Hb-CSNHCOCH(C02C,~H3) ~ . . . . -D- I1 ]I
CSI[~"~"'~S "~ " O H
XLI XLII

The rate of condensation with nucleophilic alkenes and alkynes increases when gem-electron-
donor substituents are present:

i
Ce~f~"' "~ S'
9

~R
T.
r
'='~
xxxx
,
CH3CmCOC~H5 ~ C6H 5 S 0 C 2H~t
110 e
R--OC2H~,SCH ~

The isothiocyanates (XXXIII) condense readily with reactive ketenes to give 5-substitu-
ted-2-alkylamino-4-thioxo-6-oxo-l,3-thiazines (XLIII) [19].
S

XXXIII + R~R2C--C-----O J~- R2

R42N ~S / ~'~0
R ! =R2=Ar;R4=Alk kqlII

One of the few examples of the condensation of a C3N fragment with the CS unit is the
reaction of 2-imino-4-oxothiazolidine l,l-dioxide (XLIV) with potassium tert-butoxide, car-
bon disulfide, and iodomethane in dimethyl-formamide solution [26].
0

~I RI SC 13
0 z "O
XMV R ~,R2::Ar XLV

(3 + 3) CONDENSATION
This reaction (type D) is that most frequently used for the preparation of the 1,3-thi-
azine ring. The most frequently-used method for the synthesis of oxo-l,3-thiazines is the
condensation of acetylenecarboxyli c acid derivatives with thioureas or dlthiocarbamic acid
derivatives, and for the preparation of 4,6-dioxo-l,3-thiazines, condensation of the appro-
priate thioamides with 'malonating' agents. Despite the extensive use of this type of syn-
thesis, there have been no reports of its use to prepare 2-oxo-l,3-thiazines or their thio-
analogs.
1,3-Thiazines with an oxo-group in the 4-position are formed by the condensation of B-
substituted acetylenecarboxylic acids (XLVI) with thiourea or its N-alkyl derivatives [27-36].

2 Jk R1
"'N"
1~
~
3
R=tl
C
II
NHR ~
I R ~=H
" -X
C-
I
R "..N + I -.i----- C + C ::S --~ S ---d~-
~C~ 3 RI/IN~/~'S X
R IN >" NR2R
XJ.NI XLVII XLVIII

RI=H, Alk,Ar; R2=H, Alk,At; R3=H, Alk; X=CO2CHs, Ar, 2-furyl

The mechanism of ring closure has unfortunately received little attention, and it is
not possible to provide an unambiguous explanation of the effects of substltuents on the
course of the reaction. The condensation is carried out in both protic and aprotic polar
solvents. It appears that initially ~-addition of the thiourea sulfur atom to the sp-hy-
bridized carbon takes place preferentially, and in several instances [35] the products of
such a reaction (XLVII) have been isolated. The NCS fragment can also be provided by 4-sub-
stituted thiosemicarbazides, which condense with acetylenedicarboxylic ester to give 2-imino-
3-amino-4-oxo-67alkoxycarbonyl-l,3-tbiazines [37]. The thiazine structure was assigned to
the product of the reaction of ethyl propiolate with thiobenzamide [38], but regrettably
these authors failed to provide any confirmation of this structure.
 1,3-Thiazines with an oxo- or thioxo-group in the 6-position have been obtained by con-
densing substituted thiobenzamideswitb cyanoacetlc acid in the presence of PC1, or POCIs [39,
40]. The introduction of electron-acceptor substituents into the thioamide, and electron-
donor substituents in the a - p o s i t i o n of the c y a n o a c e t i c a c i d , reduce the y i e l d s of c y c l i z a -
tion products.
NIl 2

ArCSNH 2 + CN--CHqCOOH ~-- ~-

E At" "" "co ~ " 0
R=H.AIk

Reaction of B,B-dichlorovinyl ketones (XLIX) with thioamides or thioureas affords 6-

thioxo-l, 3-thiazines [41-43]
R' t H N .3 ~ N R3
" C .>0
I
.tt~/C.~ ,CI ~i ~ R2 I C ~ C / S R2 ~ S .
C~-CI I el
C! S

XLIX L
Rr=ph, Alk; R2=CI, H; R3=NH2; NHAlk, NAlk2, Alk. Ar
2,4-Dioxo-l,3-thiazines and their sulfur analogs are formed by condensing dithiocarbamic
acid [i, 44, 45] or its N-alkyl derivatives [44, 46] with propiolic [i, 44, 46] or y-hydroxy-
tetrolic acid [45].
The condensation of dithiocarbamic acid derivatives with propiolic acid in the presence
of PCIs had been studied previously [46]. Subsequently, acetic anhydride with traces of sul-
furic acid was used in place of PCIs [i, 44], the yields of 1,3-thiazines being considerably
increased. The reaction proceeds via the formation of the product of the nucleophilic attack
on the ~-carbon by sulfur. In several cases these compounds (LI) could be isolated [46].
O
ii. <'~~176162 .-lit-. ~3
It'CtCCOORz .+ ~'biiiCSSil ._._~ ,, NltR" ..... ! i

LI LI,
RI=~H,Cit20[I; R2=II; R3;-iI,Alk

It is preferable to use the free acetylencarboxylic acids in this reaction, since the
use of esters results in the cyclization giving low yields and requiring more severe condi-
tions [i].
(3 + 3)-Cyclocondensation is most frequently used to obtain 2-substituted 4,6-dioxo-l,3,
thiazines. These methods are based on the reaction of thioamides with a variety of 'malonat-
ing' agents, namely, malonyl chloride, malonic acid, and carbon suboxide [47-67].
In a study of the condensation of thiobenzamides (LIII) with malonyl chloride, it was
suggested that initially the sulfur atom of the thioamide (LIII) was acylated to give the
intermediate (LV), which is either converted into the 4,6-dioxothiazine (LVI), and reacts
with a second molecule of the thioamide (LIII) [47].

N .!L..,
.rcsN~ 2 + cH..(cocl) 2 ..... Arc(=Ns.)~eOc.2coct ....... ~
MI! LV Ar ~ S
I L~,'I

LIII
ArCSNHCOCII2COCI ------,.... ArCSNHCOCH2CONHCSA~

It has been found that the dichloride (LIV) or carbon suboxide react with S-alkyldith-
iocarbamates (LVII) or thioacetamides to give both cyclic (VLIII) and straight-chain (LIX)
products [48-50].
~-_r176
LIX . LVI[ LVII[
 There have been several studies of the reaction of n~alonyi chloride (LIV) with alkane-
thiocarboxyllc acids or N-substituted thioamides to give 2-arylidene-or 2-alkyiidene-4,6-
dioxo-l,3-thiazines [51, 52].
,i~ O
hiV R~ N - ,\" ~:H,~
,R ~~zGHt-'SNH~" ....... ~ El , C - : : S'~3 ;'~i Clfz
O
Rl~ H,AIk: R :=:~lt~;Ar

Disubstituted maionyl dichlorides react with NNt-disubsLituted thioureas to give 3,5,5-

substituted 2-a!ky!imino-4,6-dioxo-l,3-thiazines [53, 54].
R3 , , O

R~ =Alk; R'?,t*,~D, lk ,A r

When O-alkylthiocarbamates react with the acid chloride (LIV), in addition to 2-alkoxy-
4,6-dioxo-l,3-thiazines there is also formed 2,4,6-trioxo-i,3-thiazine, apparently as a re-
sult of the reaction of the former with the hydrogen chloride liberated [55].
.OH OH

s --~:o s --~"o
Malonic acid and its derivatives react with thiobenzamides in the presence of condens-
ing agents (PCI3) to give 5-substituted-2-aryl-4,6-dioxo-l,3-thiazines [56]. A drawback of
this method is the partial resinification of the cyclization products. This reaction takes
place in acetic anhydride with O-ethyldithiocarbamates or N-acetylthiourea [56, 57], but in
this case further acylation of the 1,3-thiazines formed takes place to give the 4-acetoxy-
compounds [57].
A highly efficient 'malonating' agent is carbon suboxide, which reacts with thioamides
to give 2-substituted-4,6-dioxo,l,3-thiazines (LX) [57-60]. The reaction may be complicated
by the addition of C30= to the thiazine (LX) with the formation of hi- (LXI) and polycyclic
derivatives [57, 61].
OH X N O OH
X-CSNH 2 + C302 )=- J
X~- %o,._ TT-T
0 0
l ~X LXI

The reaction of carbon suboxide with N-acetylthiourea has received the closest attention.
It has been found that acylation reduces the electron density at one of the thiourea nitro-
gens, facilitating NS-cycloaddition of the carbon suboxide [49, 55, 57]. The use of thiourea
or N-arylthioureas results in the formation of 2-thiobarbituric acids [58, 62, 63]. Unsym-
metrical NN'-dialkyl(or aryl)thioureas are converted to 2-dialkylamino-4,6-dioxo-l,3-thia-
zones [63, 64].

CHEMICAL PROPERTIES
The chemical properties of oxo- and thioxo-l,3-thiazines have received much less atten-
tion than the condensation reactions used in their preparation. The majority of studies have
examined alkylation, acylation, and electrophilic and nucleophilic substitution. It is worthy
to note that several reactions have been used to modify compounds already containing the 1,3-
thizaine ring. For example, alkoxy-, alkylthio-, and alkylimino-l,3-thiazines are frequently
obtained by alkylating the appropriate thiazines with diazomethane [i, 6, 28, 45, 65], dimeth-
yl sulfate [i, 6, 41], or iodomethane [29, 41]. The use of dimethyl sulfate is complicated
by the possibility of the opening of the thiazine ring in the presence of caustic alkali.
Alkylation takes place both at the ring nitrogen [i, 6, 28] and at the nueleophilic centers
of the substituents [i, 29, 41, 45, 65]. Methylation of 2-substituted 4,6-dioxo-l,3-thiazines
w i t h diazomethane in ether affords only O-methylation products, which were originally regarded
as 6-methoxy-l,3-thiazines [60]. Subsequently, however, quantum-chemical calculations and the
~3C NMR spectra of *SN-phenyl-4,6-dioxo-l,3-thiazine and its O-methylation product showed that
the latter was 2-phenyl-4-methoxy-6-oxo-l,3-thiazine [68]. Acylation has been closely examined
in the case of 2-substituted-4,6-dioxo-l,3, thiazines (LX). The use of acetic anhydride gave
the O-acetyl derivatives [69]. Another method of preparation of O-acyl derivatives is by acyl-
ating the sodium salt of the thiazlne (LX) with aromatic carbonyl and sulfonyl halides [70,
71]. In addition to O-acylation, examples are known of the N-acylation of amino-groups in
the 2-position of the aminooxothiazines (XLVIII, L) [28, 35, 41].
The 1,3-thiazinediones (LX), which comprize a heteroaromatic system in which C(s) is ac-
tivated to electrophilic attack, react with great ease withelectrophilic reagents. For in-
stance, reaction with phenyldiazonium chloride gives 2-substituted-5-phenylazo-4-hydroxy-6-
oxo-l,3-thiazines [56, 65, 72]. Reaction of (LX) with disubstituted aminomethanols affords
the Mannich bases (LXII~ [73]. Nitration, halogenation, and sulfonation of 2-aryl-4,6-diox O-
1,3-thiazines, even under mild conditions with equimolar proportions of the reactants takes
place exclusively at C(s) of the thiazine ring [72]. Nitration has been effected in nitric
acid (d 1.42) in acetic acid in the presence of acetic anhydride, and halogenation with bro-
mine in organic solvents (preferably acetic acid), lodination has been accomplished only
with iodine chloride. When sulfonation of the thiazine (LX) was carried out with sulfuric
acid of SO~ in pyridine, no product could be isolated, However, sulfonation takes place
readily with SOa in dichloroethane.

I
OH q'J~|
I
N'"":::'~:',/CH:~NR:z N
I
":- '
NO~

9 .,v,~ ~OJ' "/x .....s ""o

I ! o,,

LXH ",'-'. 1 Br

~" C~ . IX
"':'
: .................. ""
3 I
01[ ~-- .d- X S "'0
.I . . . N:::N--Ph ~,, J) so,J!
N.

l~III

It is interesting that the nitration of 6-(2-furyl)-l,3-thiazines (XLVIII) takes place

in the s-position of the furan ring [35].
Reactions with nucleophilic reagents occupy an important place in studies of the chemi-
cal properties of oxo- and thioxo-l,3-thiazines. For example, the hydrolysis of 2-alkylimino-
[i, 34, 35] or 2-alkylthio-4-oxothiazines [i, 6] is frequently employed for the preparation
of 5- and 6-substituted-2,4-dioxo-l,3-thiazines~ The reaction is usually carried out with
acid catalysis [I]. In alkaline media, cleavage of the thiazine ring often takes place [72].
One of the most interesting of the chemical properties of substituted 2,4-dioxo-13,-thiazines
is their reaction with ammonia [6, 44] and primary amines [14, 44] when the thiazines are con-
verted into the corresponding pyrimidines. The first step in this reaction appears to be
cleavage of the ring by the nucleophile, and in several cases aeyclic reaction products (LXIV)
have been isolated [14].

q) 0

N ~ ' -

II " "
EtS "- "" S "" CH NIIR S ~" ~N"'
ux.]v I
R

Acyclic products have also been obtained in the reaction of 6-substituted 2-amino-4-oxo-
1,3-thiazines or the thiazines (LX) with secondary amines [28, 74-76]. It is interesting
that in the case of the thiazines (LX) the intermediate ammonium salts (LXV) have been iso-
lated, these undergoing cleavage on heating in organic solvents,

ItNR, N ~ I~
i,x: ---"" ]I I" ~"J . ~(' . - ....
. . X(::SNII~:Oe~.,('ONR,
r

J
1:-%

The reaction between 4,6-dioxo-l,3-thiazines and sodium a!koxides may follow two routes,
since 2-aryl-4,6-dioxo-l,3-thiazines form stable salts with sodium ethoxide [71], whereas 2-
alkylidiene-4,6-dioxo-l,3-thiazines rearrange to the piperidones [51].
 Nucleophilic replacement o~ the halogen atom in 2-chloro-4-oxo-l,3-thiazines (II) has
been examined using amines [3]. Depending on the amine taken and on the reaction conditions
either the 2-alkylaminothiazines are obtained, or acyclic compounds, but cleavage always pre-
cedes replacement [3].

o
Jl
RaRIN ~S #
L\"VI I.XVII

It has been shown to be possible to convert oxo-l,3-thiazines into their thioxo-analogs

by treatment with P~S~o [24, 25, 77]. The reverse transformation has been effected with mer-
curic acetate (ii), and in the case of the 6-thioxo-l,3-thizaine (L), the 6-oxo-compound is
obtained [41].
The structures of the reduction products of oxo-l,3-thiazines are dependent on the re-
action conditions. For example, when sodium borohydride is used only the C=N bond of the
thiazine (XXV) is reduced [12], whereas the catalytic hydrogenation of methyl 3-methyl-2-
imino-40oxo-l,3-thiazine-6-carboxylate gives N-methylsuceinimide [28],
Less general chemical properties are the conversion of the carboxamide group in (XXV)
(R = CONH=) into the nitrile by treatment with trimethylsilyl polyphosphate [78] and the di-
merization of 2-alkyl-6-methyl-4-oxo-l,3-thiazines on heating with a catalytic amount of tri-
fluoroacetic acid in dimethylformamide [79].
Oxo-l,3-thiazines are potentially tautomeric. It is unfortunate that up to the present
only the ~automerism of 2-substituted-4,6-dioxo-l,3-thiazines (LX) has been studied. These
thiazines can exist in at least four tautomeric forms (LEa-d).

N.--./" 011 / 0 ' 0

ix a Lx b LX'c LXd

On the basis of the IR, PMR, and UV spectra, Beilin et al., [60, 68] have shown that
when the substituent in the 2-position of the thiazine ring is varied, the structure of the
fl-dicarbonyl fragment also changes, in the opinion of these workers owing to the "differing
contributions of the substituent to the conjugation of the thiazine ring." For instance,
crystalline 2-(p-chlorophenyl)- and 2-phenyl-4,6-dioxo-l,3-thiazine were assigned a zwitter-
ionic structure (LXd) on the basis of the similarity of the IR spectra to the spectra o f
their salts, and the absence of absorption above 1600 cm -~. In solution~ these compounds
already exist in the enol forms (LXa) of (LXc), since their IR spectra correspond to that of
4-methoxy-2-phenyl-6-oxo-l,3-thiazine. The enol form was confirmed by the PMR spectra, since
in DMSO solution they showed signals for olefinic (5-H, ~ 5.4-5.8 ppm), hydroxylic (12.0-
12.6 ppm), and phenyl (7.5-8.3 ppm) protons. The spectra showed no signals for the methylene
group with 6 = 3.5 ppm, as observed for compounds with structure (LXb) and an olefinic proton
for the anionic form with 6 = 4.7 ppm such as is present in the spectra of the salts. In or-
der to determine the relative stabilities of the tautomers (LEa) and (LXb) s the atomization
energies of these forms of 2-phenyl-4-hydroxy-6-oxo-l,3-thiazine were calculated by the PPP
method in Dewar's o, ~-parameterization. It was found that the tautomer (LXa) was the more
stable. From the IR spectra of crystalline samples and of solutions, 2-alkylthio-4,6-dioxo-
1,3-thiazines were assigned the diketonic form (LXb)o 2-Methyl- and 2-alkoxy-4,6-dioxo-l,3-
thiazines display an interesting structural feature. The IR spectra of crystalline samples
of these compounds shown characteristic C=O absorption at 1650-1628 cm -~, showing that they
exist in the enol form. However, solutions of these compounds in DMSO solution (from their
IR and PMR spectra) contain both the keto- and enol-forms [60]. It is difficult to arrive .
at any conclusions concerning the structure of 2-amino-4,6-dioxo-l,3-thiazines in the ab-
sence of adequate spectral data. In the opinion of Baranova, Dashkevich, et al., [6].
63], the PMR spectra of these compounds in DMSO indicate the presence of two tautomeric forms
(enol and diketonic).

i0
 SUMMARY
This review has shown that the attention of workers has been concentrated for the most
part on the synthesis of 4-oxo-, 2,4-dioxo-, and 4,6-dioxo-l,3-thiazines. These compounds
are most commonly obtained by condensing acetylenecarboxylic acids with thioureas or dithi-
ocarbamic acids, or by reacting thioamides with malonic acid derivatives or carbon suboxide.
The chemical properties of this interesting group of heterocycles have received relatively
little attention, and it is not possible to arrive at any firm conclusions as to the effects
of variations in the ring heteroatoms on their chemical properties, and the position of these
compounds amongst their hetero-analogs. The available information does enable novel, pre-
viously inaccessible compounds to be prepared. It hardly needs to be mentioned that the 1,3-
thiazine ring is present in naturally-occurring biologically active compounds such as cephal-
osporins and antibiotics. Oxo-and thioxo-i,3,-thiazines possess properties which are valuable
from the practical point of view, such as antiinflammatory [54], analgetic [80], tranquiliz-
ing [81], antipyretic [39], diuretic [39, 70, 71], fungicidal [80], and antimicrobial [43]
activity.

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Publ. in Byull. Izobret., No. 4, 70 (1971).
51. J. C. Martin, K. C. Bronnock, and R. C. Menn, J. Org. Chem., 31, 2966 (1966).
52. W. Zankowska-Jasinka and J. Eiimes, Roczn. Chem., 50, 1059 (1976).
53. T. Zawisza, E. Wagner, J. Matczakova, andT. Jacobiec, Arch. Immunol. Ther. Exp., 26, 943
(1978).
54. T. Zawisza, J. Matczak, S. H. Kowalczyk-Bronisz, and T. Jacobiec, Arch. In~nunol. Ther.
Exp., 2_~9, 235 (1981).
55. L. I. Khirul'kova, V. G. Beilin, and L. B. Dashkevich, in: Results and Prospects in
the Search for New Drugs at the Leningrad Institute for Pharmeceutical Chemistry. Abstr.
Reports [in Russian], Leningrad (1979), p. 27.
56. E. Ziegler and E. Steiner, Monatsh. Chem., 95, 495 (1964).
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58. E. Ziegler and H. Biemann, Monatsh. Chem., 93, 34 (1962).
59. E. Ziegler and R. Wolf, Monatsh. Chem., 95, 1061 (1964).
60. V. G. Beilin, V. A. Gindin, E. N. Kirillova, and L. B. Dashkevich, Khim. Geterotsikl.
Soedin, No. 8, 1042 (1976).
61. N. A. Baranova, V. G. Beilin, L. B. Dashkevich, and L. I. Khitul'kova, in: Results and
Prospects in the Search for New Drugs at the Leningrad Institute for Pharmaceutical
Chemistry. Abstr. Reports [in Russian], Leningrad (1979), p. 28.
62. T. Kappe, G. Lang, and E. Ziegler, Naturforschung, 29B, 258 (1974).
63. L. B. Dashkevich and V. M. Siraya, Zh. Obshch. Khim., 32, 2330 (1960).
64. V. G. Beilin, V. A. Gindin, L. B. Dashkevich, V. N. Kuklin, and L. I. Khirul'kova, in:
Results and Prospects in the Search for New Drugs at the Leningrad Institute for Phar-
maceutical Chemistry. Abstr, Reports [in Russian], Leningrad (1979), p. 31.
65. E. Ziegler and E. Steiner, Monatsh. Chem., 95, 495 (1964).
66. J. C. Martin and R. N. Meen, US Pat. No 3 408 348; Chem. Abstr., 70, 11709 (1969),
67. J. C. Martin and K. C. Bronnock, US Pat. No. 3 373 159; Chem. Abstr., 69, 59254 (1968).
68, V. G. Beilin, V. A, Gindin, and B. Ya, Simkin, Khim. Geterotsikl. Soedin., No. 4, 481
(1979).
69. H. C. Scarborough and C. A. Hanning, US Pat, No 3 336 305; Chem. Abstr., 68, 12968 (1968).
70. V, G. Beilin, E. N. Kirillova, L. B. Dashkevich, A. A. Lebdev. and N. S. Ma!achevskaya,
Khim.-farm. Zh., No. i, 20 (1980).
71. V. G. Beilin, E. N. Kirillova, and L. B. Dashkevich, Inventor's Cert. (USSR) No. 596,583;
Publ. in Byull. Izobret., No. 9, 107 (1978).
72. V. G. Beilin, V. A. Gindin, V. N. Kuklin, and L. B. Dashkevich, Khim. Geterotsikl. Soe-
din., No. i, 44 (1979).
73. E. Ziegler and E. Kiesewetter, Monatsh. Chem., 96, 659 (1965).
74. L. M. Manoilova, E. N. Kirillova, V. G. Beilin, T. N. Zozulya, and L. B. Dashkevich,
Khim.-farm. Zh., No. i0, 89 (1976).
75. V. G. Beilin, E. N. Kirillova, and L. B. Dashkevich, Inventor's Cert. (USSR) No. 412,186;
Publ. in Byull Izobret., No. 3, 96 (1974).

12
76. V. G. Beilin, I. M. Ginzburg, E. N. Kirillova, and L. B. Dashkevich, Zh. Org. Khim., 13,
1333 (1977).
77. R. N. Warrener and E. N. Cain, Chem. Ind., No. 7, 591 (1982).
78. M. Yokoyama, S. Yoshida, and T. Imamoto, Synthesis, No. 7, 591 (1982).
79. Y. Yamamoto, S. Ohnishi, A. Moroi, and A. Yoshida, Chem. Commun., No. i, 56 (1983).
80. K. Tomito and T. Murakami, Jap. Pat. No. 7 920 504; Chem. Abstr., 91, 157 755 (1979).
81. H. M. Blather and G. Stevens, US Pat. No. 3 098 071; Chem. Abstr., 60, 1766 (1964).

MASS-SPECTROMETRIC STUDY OF THE CYCLIZATION REACTIONS OF DIAZOKETONES.

8.* I-DIAZO-3,4-EPOXY-4-ARYLBUTAN-2-ONES

A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, UDC 543.51:547.537'

T. P. Pokidova, V. G. Kartsev, and V. S. Petrosyan 284.4'235.2

An analysis of the mass spectra of l-diazo-3,4-epoxy-4-arylbutanones has shown

that the molecular ions of these compounds lose a molecule of nitrogen and that
the [M-- N2] + ions formed cyclize to form hydroxyfuran structures, whose fur-
ther fragmentation determines the whole picture of the dissociative ionization
of the compounds investigated under electron impact. The majority of the [M --
N2] + ions have the form of the cyclic intermediate formed in the first step of
the cyclization process. It cannot, however, be ruled out that a certain por-
tion of the [M -- N2] + ions are stabilized as a result of a Wolff rearrangement
and do not cyclize at all.

We previously [2] showed that under electron impact in the gaseous phase diazoketones
which contain a heteroatom or a heteroatomic grouping in their chain eliminate a nitrogen
molecule and cyclize to form heterocyclic systems owing to the practicable cooperation of the
heteroatom, rather than decompose according to a mechanism involving a Wolff rearrangement
[3, 4]. Since the action of acids on diazoketones in solutions produces similar products [5,
6], it was concluded that it would be possible to predict the direction of this reaction on
the basis of mass-spectrometric data. The results of the treatment of phthaloyldipeptide
derivatives of diazomethane with acidic reagents completely correspond to the predictions
made on the basis of the mass spectra of these compounds [2, 7].
Continuing this investigation, we studied the mass spectra of a series of arylepoxydia-
zoketones I, whose conversions in solutions were not previously investigated.

H I!

s2~ O R ~

sa-h
I a RI=H, b RI=CH3, c h RI=OCH3, d RI=NO2, e RI=F, f, g Rs=CI;
a--f R~=R3=H, g R2=}I, R~=D; h I{~=OCH:~,l~:'~=l!

The first step of the fragmentation of these compounds under electron impact, as would
be expected [I, 2], is the elimination of a nitrogen molecule. This results in the formation
of [M -- N2] + ions, whose structure makes it possible to draw a conclusion regarding the direc-
tion of the reactions of diazoketones with acidic reagents, which is the main goal of the
present work. The possible structures of the [M -- N2] + ions (see Scheme I) can be suggested
on the basis of the preceding investigations [i, 2] and the data in [3, 4].

*For report 7 see [i].

M. V. Lomonosov Moscow State University, Moscow 117234. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. i, pp. 17-22, January, 1986. Original article submitted Decem-
bet 4, 1984.

0009-3122/86/2201-0013512.50 9 1986 Plenum Publishing Corporation 13

 TABLE i. Intensities of the Peaks of the Characteristic Frag-
ment Ions in the Mass Spectra of Diazoketones I in the Total Ion
Current
,e,

Corn-
pond
M~ [M-N~I' F~ F'2 F3 F~ Fs F~ Flo 105169
i
!a -- 0,6 1,1 2,0 4,3 -- 3,5 0,9 3,2 : 7,0 0,5 7,1 21,6 6,0
lb 0,1 1,3 1,1 1,4 4,2 0,1 2,8 0,5 2,0 i 6,6 0,9 17,0 20,1 3,2
Ic 0,4 1,45 1,2 0,9 4,2 0,4 1,8 0,3 1,4 6,2 1,3 15,9 18,5 --
Id -- 4,0 0,3 1,1 1,5 0,7 1,4 3,5 0,7 -- 7,7 1,1 0,6
le 2,1 4,0 1,1 3,1 0,1 2,7 1,0 6,7 10,7 0,6 5,9 2,1 10,2
If ~ 0,5 0,5 0,4 1,6 - - 1,2 0,2 3,5 5,6 0,2 11,6 9,9 6,6
lg 0,4 0,8 0,4 1,1 4,6 0,4 1,3 0,7 1,0 3,6 0,8 15,8 5,7 0,8
lh 0,3 7,9 2,5 3,4 0,2 6,5 1,5 1,6 8,5 0,8 5,8 7,1 5,0

The ions of type A with a linear structure are unstable and are stabilized either as a
result of a Wolff rearrangement (ion B) or as a result of intramolecular cyclization (inter-
mediate D' and ions of type D). Ketene B can also cyclize to form ion C [8]. It should be
noted that both intramolecular cyclization and a Wolff rearrangement can take place simul-
taneously with the elimination of a molecule of nitrogen and can, in fact, initiate this pro-
cess.

Scheme i
]+"
H H H H
i I - I I
~_c<_pc_co CnN2 -N~ \ /
Ar --C--C--C0- CH +" Ar - - C ~ - - ~ C - - C H : C = 0
o o 0
M+ A B

A~ I IJ"
0 + ~C,~ 0 ~C / CIt
"CH "~0
II
/ D'
o
c
+"

Ar "/C~'o/CH2

D D

The molecular ions (M+ of compounds I, like M + of the previously studied diazoketones
[2], are unstable. The intensity of the peaks for M + does not exceed 0.5% of the total ion
current,* and the presence of electron-acceptor substituents in the benzene ring (NO~, F)
results in the complete disappearance of the peak of this ion. Nevertheless, the formation
of [M -- CHN ]+ fragments with an intensity of 0.1-0.2% and of [COCHN2] + which has a mass-to-
charge ratio equal to 69# (see Table i), proves that diazo compounds I form M +, i.e., ioni-
zation of the diazo compounds, rather than the products of their thermal decomposition, par-
ticularly the ketenes, occurs under the conditions of our experiment [3, 4].
An analysis of the fragmentation paths of the [M -- N=] + ions allows us to conclude that
they mainly have a cyclic structure (form D, see Scheme i). Some of the [M -- N ]+ ions de-
compose prior to the migration of the hydrogen ion (the D'-D transition) and the formation
of the hydroxyfuran pseudomolecular ion. Ion D can exist in two principal tautomeric forms:
a keto and an enol form. In the case of 4-isopropyl-3-hydroxy-4,5-dihydrofuran, the enol
form is predominant in the gaseous phase [9]; therefore, it may be postulated that in the
case of diazo compounds I, the majority of the ions of type D will have the enol form, since
additional stabilization of such a structure is caused by the formation of the aromatic furan
system.

*The fraction of the ions of a particular type in the total ion current is given in percent.
#The formation of this ion form M + in the case of compound I is confirmed by the peak of the
metastable ion with an apparent mass of 21.4. Here and in the following, the numbers char-
acterizing an ion determine the value of m/z.

14
 The main directions of the fragmentation of the [M-- Na] + ions of diazoketones I may be
represented by the general scheme

Scheme 2

A~"c~.TSa
09 ArCllO-]+ " [ M - N ~ -C01+'
Fs Fz o --2

_]+. ~ --cHco I I +'

Ar ~CII----CII ~ I ---C..~O J --I!.,CO "~" "~ CH~

-uco' j-'" ,c .' ..I o.~ ,c~ \ \

ArCtl2+ A~CH=CH --,~--- IM_N2 _CHO]+ ..... ~. Ar-C~C~ I+"

F8 F5 F6
(ArCO+)
I05

"The genetic relationship of these ions was not established.

The structures of ions F~, Fz, Fa, Fa, and F9 may be represented differently, if it is
postulated that the first step in the transformation of the [ M , N=] + ions is a Wolff rear-
rangement [3, 4]. However, other experimental findings attest to the fact that the majority
of the [M -- N=] ~ ions (and possibly all of them) are stabilized as a result of intramolecular
cyclization.
First, the Wolff rearrangement does not result in the destruction of the epoxy ring;
therefore, peaks of ions characteristic of the decomposition of aromatic epoxy compounds
should be observed in the mass spectra of diazoketones I. In the mass spectra of pheny!
epoxides the peaks of the ArCH + and ArC + ions have the maximum intensities [I0]. In the case
of diazoketones I, the peaks of these ions have intensities below 0.5%,* attesting to the
destruction of the epoxy ring in the initial steps of the fragmentation. On the other hand,
the peak of the ArCHO +" ions (F~o), which has the maximum intensity in the mass spectra of
the compounds investigated, is practically absent in the mass spectra of aryl epoxides [10]
and arylepoxyketones [ii]. The proves the impossibility of its formation from linear ions
A and B (see Scheme i), while the decomposition of intermediate D' with the formation of such
an ion is very favorable.
Second, the Wolff rearrangement does not account for the formation of ion F~ (see Scheme
2), while its appearance from intermediate D' as a result of the elimination of a COCHO par-
ticle or from ion Fa (elimination of a CO molecule) is not impeded. In addition, the forma-
tion of ions of type F6 as a result of the elimination of a COCH=O particle from the [M -- N=] "+
ion in one or two steps, as was observed in the mass spectra of 1,3-oxazin-5-ones [12] and
4,5-dihydro-3-oxofurans [9], confirms the cyclic structure of D for these ions.
Third, an additional mass-spectroscopic finding which confirms the cyclization of the
[M -- Na] + ion is the formation of the fragments of type FT. As a result of the attack of
the oxygen atom of the epoxy ring at the methine group, which bears a positive charge and a
free electron, the lone pair of the oxygen atom can form a bond either with the carbon atom
(the electrophilic center) (this results in the formation of intermediate D') or with the
acidic proton of the methine group with the subsequent cleavage of a C--C bond and the forma-
tion of fragment FT.

" c ~ ~ -%o Ar .
CH-- c~ Ar ~ C H ~ C H ~ + "
,.,+. . . . . . . \/
0:~ .' 0 O

*An e x c e p t i o n i s compound I e , f o r w h i c h t h e i n t e n s i t i e s of the peaks of these fragments are

5 . 5 and 4 . 5 % , r e s p e c t i v e l y . They a r e a l s o s u f f i c i e n t l y intense in the mass spectra of un-
substituted diazoketone I a ( 1 . 7 and 2.2%, r e s p e c t i v e l y ) .

15
 Electro1~-acceptor substituents in the aromatic ring increase the acidity of the methine
group. This is reflected in the increases in the relative intensities of the peaks of the
F7 ions in the mass spectra of compounds Id-f (see Table i).
In order to refine the fragmentation scheme, we synthesized compound Ig with deuteration
at the diazo group. The calculation of the intensities of the peaks in the mass spectrum of
this compound showed that the deuterium label is completely retained in ion FI, while 30% of
it is lost in F~. Therefore, the [M -- N2] + ions eliminate the benzyl hydrogen atom, and such
elimination can occur either from intermediate D' or from linear forms A and B of the [M -- N] +
ion [i0, ii].
The Fs ions apparently form along several paths. The successive elimination of a hydro-
gen atom and a molecule of CO from the [M -- N2] + ion does not result in the loss of the deu-
terium label. The elimination of an HCO" radical is the main process in the fragmentation of
furans [13, i4]. The fragmentation of diazoketone Ig according to such a mechanism should
result in the complete loss of the deuterium label in the case of the existence of ion D ex-
clusively in the enol form and in its partial loss when the keto form of this ion is present.
The partial loss of the deuterium label may also be the result of the elimination of a hydro-
gen atom from ion F2. It is not possible to evaluate the contribution of each of these paths
to the formation of ion F3; however, the experimental findings presented can be explained only
when the [M-- N2] + ions are assumed to have a cyclic structure. In this case, the structure
of fragment F~ can vary as a function of the mechanism for its formation and is, therefore,
not presented in the scheme.
It is known 14 that substituents in positions 2 and 5 of the furan ring (R) can result
in the appearance of an alternative direction of fragmentation~ An RCO" radical is eliminated
along with an HCO" radical. In the case of diazoketones I, position 5 in the furan ring
formed is occupied by an aryl substituent. The electronic properties of the substituents
in the benzene ring play an important role in the competitive elimination of the HCO' and
RCO" radicals. For example, in the mass spectra of compounds Ia-c with electron-donor sub-
stituents, the peak of the [M -- N2 -- RCO] ion is not observed at all. Electron-acceptor sub-
stituents (compounds Id-f) make this fragmentation path competitive. The mass spectra of
these compounds display peaks for the corresponding ion 55 with relative intensities equal
to 4.6, 1.0, and 1.0%, respectively. As was shown in [13, 14], this ion has a cyclic cyclo-
propane structure.
Tile cyclic structure of the [M --N2] + ions is also confirmed by the formation of the F~
fragments as a result of the elimination of a molecule of formaldehyde from the keto form of
ion D or an HCO" radical from ion F:.
Nevertheless, all the mass-spectrometric findings described do not allow us to completely
discount the possibility of a Wolff rearrangement; therefore, it should be assumed that the
formation of ketene ions of type B according to a mechanism involving a Wolff rearrangement
[3, 4] may be a process which competes with the intramolecular cyclization and takes place
for some of the [M-- N2] + ions.
Cleavage of the C(2)--C(s) bond in M + results in the formation of ions F9 and 69, and
the mass spectra of diazoketones I display peaks for both these ions (see Table i), i.e.,
these fragments have similar ionization energies [15, 16].
Substituents in the benzene ring do not alter the principal fragmentation paths. The
behavior of fluorinated derivative le is anomalous. The peaks of ions Fa and 69 have the
maximum intensities in the mass spectrum of this compound; the peaks of the ArCH +. and ArC +
fragments (5.5 and 4.1%), which are characteristic of the fragmentation of aryl epoxides
[i0], are also intense. The intensity of the peak of ion F7 is alsoincreased (see Table I).
Such a sharp increase in the number of ~ ions decomposing along paths not associated with
the initial formation of a furan ring indisputably reduces the proportion of [M -- N=] + ions
in form D to the total number of ionized molecules of this compound in comparison to the
other compounds of type I.

_/--CH--CH-
S \ /
0
CO- CH-X

I i X=~r z

16
 TABLE 2. Mass Spectra of Compounds la-i

Values of m/z:'~
Co m - (relative intensities of ion peaks as percentages of the maximum)
pound

|a 131 (19,4), 120 (15,0), 106 (36,2), 105 (100), 103 (16,3), 91 (32,2), 78
(12,5), 77 (54,0), 69 (30,1), 51 (25,0)
Ib 145 (21.3). 120 (84.2). 119 (I00), 117 (13.3), 105 (33,0), 92 (19.4), 91
(63,8), 69 (17.0), 65 (51,4). 41 (16.4)
Ic 161 (24.9), 159 (10,8), 137 (13,1), 136 (85.7). 135 (100). 121 (33.3), 91
(13.9), 78 (10.1), 77 (31,7), 51 (19,9)
Id 205 (51,6), 165 (45.7). 151 (lO0). 118 (33.8). 105 (70.4), 102 (37,3), 89
(38,3), 90 (36,9), 77 (36.9), 55 (59,6)
le 177 (40,3), 149 (30,8), 138 (66,7). 124 (55,0), 109 (100), 108 (61,8), 107
(33,0). 101 (49.0). 95 (68.9), 69 (95.5)
If 159 (30,5). 154 (28,2). 142 (62.9), 141 (80,t), 140 (100), 139 (85,0), 125
(48,1). 110 (27,6), 89 (43.4), 69 (67,1)
Ig't" 160 (14.2), 142 (30.4), 141 (43,2), 140 (87,8). 139 (100), 138 (27,0), 125
(33,1), 111 (21,6), 89 (28,3), 70 (14,8)
Ill 191 (28.9), 189 (15,9), 166 (100), 165 (36,4). 151 (23,0), 95 (23.8). 79
(13,4), 77 (21.9), 63 (11,3), 51 (16,7)
li 166 (91,9), 138 (29,5), 137 (39,6). 112 (68,4). 111 (83,2), I10 (26,2). 109
(76,5). 97 (I00), 69 (57.7), 65 (22,8)

i
*The i0 most intense peaks are given.
tThe spectrum was obtained on an MKh-1303 mass spectrometer.

The behavior of epoxythiophene li is similar to that of the compounds described. The

mass spectrum of this compound differs significantly from the spectrum of epoxyketone lli,
which has a similar structure [17], and all the fragments are described well by the general
scheme for the fragmentation of diazoketones I presented, i.e., in this case, too, the epoxy
ring opens and a cyclic furan ion forms.
Thus, an analysis of the mass spectra of diazoketones I showed that the M + ions of
these compounds lose a molecule of nitrogen and the [M -- N=] + ions formed undergo cyclization
with the formation of hydroxy furan structures, whose further fragmentation determines the
entire picture of the dissociative ionization of the compounds investigated under electron
impact. The majority of the [M -- N~] + ions have the form of the cyclic intermediate formed
in the first step of the cyclization process. It cannot, however, be ruled out that a cer-
tain portion of the [M -- N2] + ions are stabilized as a result of a Wolff rearrangement and
do not cyclize at all. On the basis of the investigation carried out, it may be postulated
that cyclic furan systems will form when the diazoketones studied are reacted with solutions
of acids. In the case of fluorinated derivative le, secondary reactions with the formation
of other products are possible.

EXPERIMENTAL
All the compounds investigated were synthesized at the Chernogolovka Branch of the In-
stitute of Chemical Physics of the Academy of Sciences of the USSR. The mass spectra of
diazoketones la-h were obtained on an LKB-2091 mass spectrometer (Sweden) with the use of a
system for the direct admission of the sample into the ion source. The temperature of the
samples was 60-140~ and the energy of the ionizing electrons was 70eV. The mass spectra
of compounds If and Ig were additionally recorded under identical conditions (the temperature
was 100~ and the energy of the ionizing electrons was 50 eV) on an MKh-1303 mass spectro-
meter with a similar admission system. The deuterated form of compound Ig was obtained by
holding diazoketone If in deuteromethanol (CD3OD) for 24 h with further evaporation of the
solvent and recrystallization of the deuterated derivative f~om deuteromethanol.

LITERATURE CITED
i. A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, V. G. Karsev, A. M. Sipyagin, and V.
S. Petrosyan, Khim. Geterotsikl. Soedin., No. 6, 788 (1985).
2. A. T. Lebedev. Dissertation for the Degree of Candidate of Chemical Sciences, M. V,
Lomonosov Moscow State Univeristy (MGU), Moscow (1982).
3. P. Kinson and B. Trost, Tetrah. Lett., 14, 1075 (1969).
4. K.-P. Zeller, H. Meier, and E. Muller, Tetrahedron, 28, 5831 (1972).
5. V. G. Kartsev and A. M. Sipyagin, Khim. Geterotsikl. Soedin., No. I0, 1324 (1980).
6. V. G. Kartsev, A. M. Sipyagin, N. F. Sepetov, and L. A. Sibel'dina, Khim. Geterotsikl.
Soedin., No. I0, 1327 (1980).
17
 7. A. T. Lebedev, P. A. Sharbatyan~ A. M. Sipyagin, V. G. Kartsev, and V. S. Petrosyan,
Khim. Geterotsikl. Soedin., No.5, 623 (1983).
8. K. K~gu, Helv. Chim. Acta, 24, 141 (1941).
9. M. Anteunis and M. Vandewall, Spectrochim. Acta, ~7A, 2119 (1971).
i0~ H. E. Audier, J. F. Dupin, M. Fetizon, and J. Hoppiliard, Tetrah. Lett., No. 19, 2077
(1966).
ii. S. Sasaki, H. Abe, and K. Nakanishi, Bull. Chem. Soc., Japan, 41, 522 (1968).
12. A. T. Lebedev, P. A. Sharbatyan, A. M. Sipyagin, V. G. Kartsev, and V. S. Petrosyan,
Khim. Geterotsikl. Soedin, No. i0, 1332 (1983).
13. R. I. Reed and W. K. Reed, J. Chem. Soc., 12, 5933 (1963).
14. K. Heyns, R. Stute, and H. Scharmann, Tetrahedron, 22, 2223 (1966).
15. D. P. Stevenson, Disc. Faraday Soc., i0, 35 (1951).
16. H. E. Audier, Org. Mass Spectrom., ~, 283 (1969).
17. F. P. Ballistreri, G. Musumara, and S. Occhipinti, Ann. Chim. (Rome), 71, 269 (1981).

SYNTHESIS OF 2-, 6-, AND 7-AMINOMETHYL DERIVATIVES

IN THE 4,5-DIHYDROXYBENZOFURAN SERIES

A. N. Grinev,* V. M. Lyubchanskaya, L. S. Sarkisova, UDC 547.728.1.07:

L. M. Alekseeva, and Yu. N. Sheinker 543.422.25

The 2-, 6-, and 7-aminomethyl derivatives have been synthesized from derivatives
of 4-hydroxy-5-methoxy- and 4-methoxy-4-hydroxybenzofuran. 2-Methyl-3-carbeth-
oxy-5-methoxy-7-dimethylaminomethylbenzofuran has been Converted into the 7-cyan-
omethyl derivative.

Aminomethyl derivatives of benzofuran are of definite interest in the area of the search
for drugs. One of them, viz., 2-phenyl-3-carbethoxy-4-dimethylaminomethyl-5-hydroxybenzofur-
an hydrochloride (phenykoberan), has found application in the practice of medicine [i]. We
recently synthesized derivatives of 4-hydroxy-5-methoxy- and 4-methoxy-5-hydroxybenzofuran
[2]. In the present work, we have used them as a basis for obtaining various, primarily the
2-, 6-, and 7-aminomethyl, derivatives.
The bromination of 2-methyl-3-carbethoxy-4-acetoxy-5-methoxybenzofuran (II) by N-bromo-
succinimide in the presence of benzoyl peroxide gives 2-bromomethyl derivative III, and 2-
dimethylaminomethyl-2-piperidinomethyl-, and 2-isopropylaminomethyl-4-hydroxy-5-methoxybenzo-
furan (IVa-c) are obtained by reacting the corresponding amines with III. When III is re-
acted with an excess of the amines, elimination of the acetyl group is observed along with
the replacement of bromine by the residue of the amine.
OH OCOCH3

%"~ Ao o J[ 'il
'%. / -.. ...~.
v 0 "CH~
I II
OCOCH3 OH

', CH3 C00C2H 5 HNRR I H3 C00C2H 5

~//" ~0 / ~ CH2Br ~//~ OA CH2NRR I

III IVa-s

IV a R=R'=CHa, b R-kRI=(CH2)~,c R=H, R~=CH(CH3)z

*Deceased.

S. Ordzhonikidze All-Union Scientific-Research Institute for Pharmeceutical Chemistry,

Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 23-27,
January, 1986. Original article submitted December 18, 1984.

18 0009-3122/86/2201-0018512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Carbon-13 Chemical Shifts of Compounds Va, Vlla, and
VIII

, ppm in CDCI3
Compound
C,2) I C,3) Ci3a) C~4) C(5) C(7) [ C(TR)

Va
Vlla
I
16~,6 I 108,8
161,5 I 109.4
113,8
119,0
138,9
139,7
143,0
147,5
1132
190,4
Ilia
105,4
I 147,7
147,5
VIll 162,6 109,1 113,6 143,! 140,6 112,9 119,2 149,6

The aminomethylation of 2-methyl-3-carbethoxy-4-hydroxy-5-methoxybenzofuran (I) by bis-

(dimethylamino)methane and a mixture of formalin with piperidine gives 7-aminomethyl deriva-
tives Va and b, and the aminomethylation of isomeric 2-methyl-3-carbethoxy-4-methoxy-5-hy-
droxybenzofuran (VI) by bis(dimethylamino)methane and dimorpholinomethane gives 6-aminomethyl
derivaties Vlla and b.

OH OCH~ OH

. ~[~ 0 -CH, R'RNCH~0 %CH~ Br TOLCI%

CH2NRR~ CH2N(CH~)2
va, b VIIa, b Vlll

Va, Vlla RffiRIfCH3; Vb R+RI=(CH2)~, VII bR+RJffi(CH2)20(CH2)2

In order to determine the positions of the substituents i n compounds Va, Vb, V I I a and
V I I b , we c o m p a r e d t h e Z3C s p e c t r a o f compounds Va and V l I a and t h e s p e c t r a o f V I I I , w h i c h
was p r e v i o u s l y o b t a i n e d i n [ 3 ] .
The s i g n a l s i n t h e X3C s p e c t r u m of u n s u b s t i t u t e d benzofuran for the C(3), C(3a), C(.),
C ( 5 ) , C ( s ) , and C(7) a t o m s and f o r t h e C ( a ) a n d C ( T a ) a t o m s a r e known t o be o b s e r v e d i n t h e
106-127 and 145-155 ppm r a n g e s , r e s p e c t i v e l y [4]. An e v a l u a t i o n o f t h e c h e m i c a l s h i f t s o f
the aromatic carbon atoms with the-use of the increments of the substituents f o r b e n z e n e [5]
r e v e a l s t h a t i n t h e s p e c t r u m o f V I I I t h e C ( . ) a n d C(5) s i g n a l s s h o u l d f a l l i n t h e w e a k e r - f i e l d
g r o u p a l o n g w i t h t h e s i g n a l s o f t h e C ( a ) a n d C(Ta) a t o m s . To a s s i g n t h e s i g n a l s h a v i n g s i m i -
l a r c h e m i c a l s h i f t s and t h e same m u l t i p l i c i t y , we a l s o t o o k i n t o a c c o u n t t h e d e p e n d e n c e o f
t h e v a l u e s o f t h e s p i n - - s p i n c o u p l i n g c o n s t a n t s o f t h e c a r b o n a t o m s of b e n z o f u r a n w i t h t h e p r o -
tons of the substituents on t h e number o f b o n d s [ 6 ] . On t h e b a s i s o f a l l t h e c o n s i d e r a t i o n s
just enumerated, the signals at 162.6 162.6 (q, 2Jc~2~' 2-CHa = 7.5 Hz, 109.1 (q, 37c~ 2CH , =
2.5 HZ), 112.9 (t, aJc(~a~.7-CH~ = 4.5 Hz) 119.2 (t, 2J~7 7-CH~ = 6 HZ), and 149.6 (t, 3Jci.~ 7CH~
=4.5) were assigned to the C(=), C(3 ), C(6); C(7), and C(7a) atoms, respectively.' It
should be noted that the spectrum ot compound VIII in CDCL3 displays additional splitting of
the signals of C(,) (2JG<~v4OH = 4 Hz), as well as of C(3a) and C(5) (3Jq~v4OH = S.[Cs;4OH
= 2.5 Hz), by the proton of the OH group, which participates in a chelating hydrogen bond
with the oxygen atom of the carbethoxy group at C(3) [3]. This splitting is absent in the
spectrum of VIII in CD3OD, where at singlet at 112.9, the signlet at 142.5, and the quartet
at 139.4 ppm (3Jcc~'~ocH~ = 4 HZ) belong to the C(3a), C(4), and C(5) atoms.
The spectrum of compound Va is similar in many ways to the spectrum of VIII. Here we
also observe additional splitting of the signals of the C(3a), C(,), and C(5) atoms due to
the proton of the hydroxyl group, which vanishes in the spectrum recorded in CD3OD. The
chemical shifts of the signals of most of the carbon atoms of the benzene fragment change
only slightly upon the transition from Va to VIII (Table i). The multiplicity*, of these
signals is consistent exclusively with placement of the aminomethyl group at C(7). The
signal of C(3a) is a singlet, the signal of C(,) is a doublet (fc~4~.6-H 8 HZ), the signal =

of C(~) is a quartet (~fC,~rSOCH~ = 4, =7C(~;O-H = 4 Hz), the signal of C(~) is a doublet of

triplets (~Jc~H = 158, ~Jq~l.;eH~ = 5 Hz), the signal of C(~) is a sextet (~7c,7
~ 7cu~ =

*The splitting of the signals in CD~OD is given.

19
4.5, ~]c,;~o.l~ = 1.5 Hz;, and the signal of C(~a) is a sextet (sJc(7=vG.~l= 11,5, ~]~(7~,,.7.cij~
4:5 Hz). The spectrum of compound VIIa differs significantly from the spectrum of
Va with respect to the values of the chemical shifts (Table i) and especially with respect
to the character of the multiplicity of the signals of the carbon atom of the benzene frag-
ment, ~ i c h can be unequivocally attributed only to the presence of an aminomethyl substiuent
iu position 6 in compound Vlla. The splitting of the signals of C(7) , C(~a), and C(s),
which are observed, respectively, in the form of a doublet (2]C(7~),7.H= 3 Hz) at 147.5, a
doublet (~Jc,3~v~.a 5.5 Hz) at 119, and a quartet
= (3/C(~),G-CH~4, = s/c<~>:H = 8 Hz) at
147.5 ppm, are the most characteristic from this point of view.
We also carried out the chloromethylation of 2-methyl-3-carbethoxy-4,5-dimethoxybenzo-
furan (IX) and obtained 7-chloromethylated derivative Vc and bis(benzofurnanyl)methane der-
ivative X. Demethylation of the methoxy group in position 4 by hydrogen chloride was ob-
served during the reaction.

OCII3
/
OCH3 OH CH~0 ~ _ .~COOC2H 5

z ""~''~Y-- i] ~ '" ~ ( H e l l o ) ' ~"~F:Y'~ ...... ,(~ '~ s

"-- O {-:It~ "~'i~ " 0 . . . . CH 3 CH 2

" (' k%,.~)~k . - {.>H:~CI , CH3

Oft z :-

CII30." , : ' . \ COOC21I 5 CHsO / "']~ C00C2H 5

1. CIl :~I
"CII 5 Va ....... =-~ - ~ V e X
; " 2. N a C N
CII2R

Vd, e vd R=o%iis;e R~CN

According to the literature data, the chloromethylation of derivatives of 4-methoxy-

and 5-methoxybenzofuran produces derivatives of bis(benzofuranyl)methane exclusively [7].
Compound Vc reacts with nucleophilic reagents, viz., ethanol and sodium cyanide. These
reactions result in the formation of 2-methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-ethoxymethyl-
benzofuran (Vd) and 2-methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-cyanomethylbenzofuran (Ve)
with high yields.
We also obtained 7-cyanomethylbenzofuran derivative Ve from 7-dimethylaminomethyl de-
rivative Va. Compound Va reacts with methyl iodide in dioxane to form a methiodide, which
is converted without isolation under the action of sodium cyanide into compound Ve.
The structures of the compounds synthesized were confirmed by the data from ~H NMR
spectra (Table 3).

EXPERIMENTAL
The ~H and :3C NMR spectra were obtained on Varian XL-200 and XL-100 spectrometers,
respectively, in CDCI3 with TMS as an internal reference. The course of the reaction was
monitored chromatographically on Silufol-254 plates in a 9:1 benzene'methanol system with
development in UV light.
The characteristics and yields of the compounds obtained are presented in Tables 1-3.
2-Methyl-3=carbethoxy-4-acetoxy75-methoxybenzof~ran (II~. A mixture of 2.5 g (I0 mmole)
of methoxybenzofuran I, I0 ml of acetic anhydride, and 0.01 ml of concentrated H2SO, was
heated at 60~ with stirring for 2.5 h. The reaction mixture was diluted by I00 ml of water,
and the precipitate was filtered out, washed with water, and dried. This gave 2.15 g (73.6%)
of II.
2-Bromomethyl-3-carbethoxy-4-acetoxy-5-methoxybenzofuran (III). A mixture of 5.45 g
(19 mmole) of acetoxybenzofuran II, 3.4 g (19 mmmole) of N-bromosuccinimide, ll ml of car-
bon tetrachloride, and i mg of benzoyl peroxide was boiled for i0 h. The hot reaction mix-
ture was filtered, the mother solution was evaporated to dryness, and the residue was re-
crystallized from ethanol. This gave 6.1 g (88%) of compound III.
2-Dimethylamingmethyl-3-carbethoxy-4-hydroxy-5-methoxybenzofuran (IVa). A solution of
1.85 g (5 m m o l e ) o f derivative III in 15 ml of dry benzene was given an addition of a solu-
tion of 0.68 g (15 nunole) of dimethylamine in i0 ml of benzene with stirring. The reaction

20
 TABLE 2. Characteristics of Compounds II, III, IVa-c, Va-e,
VZIa, Vllb, and X

Found, % Calculated, %
Com- mp/~ ~ Empirical Yield, %
pound formula l-
H [CI(Br) N c H [Cl(Br) N

II 129--131 61,9 5,5 C,5H1606 61,6 5,5 73,6

III 96--97 48,4 4,1 C~sHlsBrO6 48,5 4,1 '2~,5 88,0
IVa 170--173" 54,4 6,2 10,8 C,sH2oCINO5 54oE 6,1 '10,8 ~,2 51,0
IVb 181--1824 58,7 6,6 9,3 CIsH24CINOs 58,5 6,5 9.6 3,8 60,0
IVc 180--182 56,0 6,3 9,9 CIsH~2CINO5 55,9 6,4 10,3 4,0 45,0
Va 205---207 55,8 6,7 10,3 C,sH22CINO5 55,9 6,4 10,3 4,0 69,5
Vb 220--221: 59,7 6,9 9,4 CIgHmCINO~ 59,5 6,8 9,2 3,7 49,5
Vc 126--128 56,9 5,0 11,3 C14HIsCIOs 56,3 5,1 11,8 16,8
Vr 85--86 62,8 6,3 CisH2006 62,3 6,5 -- 87,5
Ve 174--176 52,3 5,3 C,sH,sNOs 62,3 5,2 ~,8 77,0
Vlla
Vllb
175--176~"
136--138
55,7
51,5
6,4
6,6
1;3 CI6H2~CINO6 55,9 6,4 10,,3 4,0 48,0
C,sH~3NO6 51,9 6,6 4,0 25,0
X 257--259 54,2 5,7 C2~H32Oto 54,4 6,0 18,5

*Compounds II, III, Va, Vb, and Vllb were recrystallized from
ethanol; IVa-c, Ve, and Vlla were recrystallized from acetone;
Vc and Vd were recrystallized from hexane; X was recrystallized
from ethyl acetate. Compounds IVa_c, Va, Vb, and Vlla were
characterized in the form of the hydrochlorides, and Vllb was
characterized in the form of the base.
~Decomposition.

TABLE 3. Proton Chemical Shifts of Compounds III, Vc, Vd, and

Ve

6 , ppm, in CDCI3
Com-
2-CH~, 7-H, 7-CH2CI. 7-CH2CN,
pound 2-CH2Br,S 3-COOC2Hs 5-OCH3, S 6.H 7-CH2OC2Hs

III 4,82 4,40 q 3,87 7,33 d, 7,10d (~rUao8 m.)

1,42 t
Vc 2,73 4,42 tq 3,92 6,94 s 4,79 s
1,45
Vd 2,70 4,42 q. 3,92 6,95 s 4,66 s 3,55q , 1,25t
1,44 t
Ve 2,72 4,42 q 3,92 6,92 s 3,87 s
1,45 t

mixture was left to stand for 24 h at 20=C and then washed with water (two 50-ml portions,
and the benzene) layer was separated, dried over magnesium sulfate, and evaporated to dryness.
The residue was dissolved in 20 ml of acetone and given an addition of concentrated hydro-
chloric acid to pH 3. The precipitate isolated was filtered, washed with acetone, and dried.
This gave 0.84 g (51%) of the hydrochloride of IVa.
Compounds IV and IVc were obtained in a similar manner.
2-Methyl-3-carbethoxy-4-hydroxy-t-methoxy-7-dimethylaminomethylbenzofuran (Va). A so-
lution of 15.0 g (60 mmole) of methoxybenzofuran I in 250 ml of dioxane was given an addition
of 24.5 g (240 mmole) of bis(dimethylamino)methane and boiled for 20 h. The reaction mixture
was diluted with 1 liter of water, and the precipitate formed was filtered out, washed with
water, dried, and recrystallized from acetone. The base obtained was dissolved in i00 ml
of acetone, and the pH was adjusted to 3 with concentrated hydrochloric acid. The precipi-
tate formed was filtered out, washed with acetone, and dried. This gave 14.3 g (69.5%) of
the hydrochloride of compound Va.
Compounds Vlla and Vllb were obtained in a similar manner from 2-methyl-3-carbethoxy-4-
hydroxy-5-methoxy-7-piperidinomethylbenzofuran (VI).
2-Methyl-3-carbethoxy-4-hydroxy-5-metboxv-7-piperidin0methylbenzofuran (Vb). A solution
of 2.75 g (llmmole) of compound I in 50 ml of dioxane was given an addition Of 1.72 g (21

21
mmole of piperidine and 0.7 ml of formalin and boiled for 25 h. The reaction mixture was
diluted with 200 ml of water, and the precipitate isolated was filtered out, washed with
water, and dried. The precipitate was dissolved in 20 ml of acetone, the pH was adjusted to
3 with concentrated hydrochloric acid, and the precipitated substance was filtered out, washed
with acetone, and dried. This gave 2.1 g (49.5%) of the hydrochloride of compound Vb.
2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-chloromethylbenzofuran (Vc) and Bis(2-methyl-
3-carbethoxy-4,5-dimethoxybenzofuran-7-yl)methane (X). A solution of 2.64 g (i0 rgnole) of
dimethoxybenzofuran IX in i0 ml of dry benzene was saturated with dry hydrogen chloride and
given an addition of 0.4 g (13 mmole) of paraformaldehyde at 5~ with stirring. The passage
of hydrogen chloride through the reaction mixture was continued for i h at 5-I0~ The pre-
cipitate formed was filtered out, washed with 30 ml of benzene, and dried. This gave 1.0 g
(18.5%) of compound X. The mother solution was washed with water (five i00 ml portions), and
the benzene layer was separated, dried, and evaporated to dryness. The residue was recrystal-
lized from hexane. This gave 0.5 g (16.8%) of Vc.
2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-ethoxymethylbenzofuran (Vd). A solution of
1.0 g (3 mmole) of chloromethyl derivative Vc in 30 ml of ethanol was boiled for 2 h. The
alcohol was evaporated to dryness, and the residue was recrystallized from hexane. This gave
0.9 g (87.5%) of Vd.
2-Methyl-3-carbethoxy-4-hydroxy-5-methoxy-7-cyanomethylbenzofuran (Ve). A. A solution
of 1.48 g (5 mmole of Vc in 30 ml of dioxane was given an addition of a solution of 0.245 g
(4 mmole) of sodium cyanide in 3 ml of water, and the mixture was boiled for 14 h. The re-
action solution was diluted with 200 ml of water, and the precipitate formed was filtered
out, washed with water, dried, and recrystallized from acetone. This gave 0.9 g (63%) of
compound Ve.
B. A solution of 6.6 g (21 mmole) of Va in 40 ml of dioxane was given an addition of
6.1 g (42 mmole) of methyl iodide with stirring. The precipitated methiodide was filtered
out, washed with dioxane, dissolved in 75 ml of dioxane, and given an addition of a solution
of 1.03 g (21 mmole) of sodium cyanide in 7.5 ml of water. The mixture was boiled for 3.5
h. Then the reaction mixture was diluted with water (300 ml), and the precipitate formed
was filtered out, washed with water, dried, and recrystallized from acetone. This gave 4.8
g (77%) of Ve. A mixed sample with the product obtained according to method A does not dis-
play any melting-point depression.

LITERATURE CITED
I. A . N . Grinev, A. A. Stolyarchuk, K. S. Shadurskii, N. I. Ivanova, N, K. Venevtseva, V.
I. Shevdov, V. K. Vasil'eva, and E. K. Panisheva, USSR Patent (Inventor's Certificate)
No. 530,683; Byul. Izobr., No. 37 (1976).
2. A . N . Grinev, L. S. Sarkisova, and V. M. Lyubchanskaya, Khim. Geterotsikl. Soedin., No.
i0, 1322 (1984).
3. A . N . Grinev, L. S. Sarkisova, V. M. Lyubchanskaya, Yu. N. Sheinker, and L. M. Alekseeva,
Khim. Geterotsikl. Soedin., No. 9, 1181 (1983).
4. P . D . Clark, Org. Magn. Reson., No. 8, 252 (1976).
5. G . C . Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemists,
Wiley-lnterscience, New York (1972).
6. P . F . Hansen, Progress in Nuclear Magnetic Resonance Spectroscopy, Vol. 14 (1981), p.
216.
7. R. Royer, J. Guillaumei, P. Demerseman, N. Platzer, and J.-P. Buisson, Bull. Soc. Chim.
France, No. Ii, 4201 (1972).

22
CONVERSION OF trans,trans-I-METHOXY-3,5-DIARYL-2-OXABICYCLO[4.4.0]DEC-
3-ENES INTO HEMIDITHIOACETALS AND 4H-THIOPYRANS.
STRUCTURE OF trans,trans-I-MERCAPTO-3-PHENYL-5-(4-METHOXYPHENYL)-2-
THIABICYCLO[4.4.0]DEC-3-ENE

S. K. Klimenko, T. I. Tyrina, N. N. Sorokin, UDC 547.81:543.422:

L. V. Vlasova, A. A. Shcherbakov, G. A. Aleksandrov, 548.737
Yu. T. Struchkov, and V. G. Kharchenko

The conversion of trans,trans-l-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes

into trans,trans-l-mercapto-3,5-diaryl-thiabicyclo[4.4.0]dec-3-enes or 2~4-diaryl-
5,6-tetramethylene-4H-thiopyrans, which takes place when hydrogen sulfide
is reacted with the acetals in acetic acid with the use of gaseous hydro-
gen chloride as a catalyst, has been described. A mechanism for the reaction has
been proposed. The structure and confirmations of the molecules have been deter-
mined by x-ray diffraction analysis and I~C NMR.

According to the data in [i], the reactions of 1,3-diaryl-3-(2-oxocyclohexyl)-l-propan-

ones with hydrogen sulfide in methanol in the presence of hydrogen chloride result in the
formation of either trans,trans-3,5-diaryl-2-thiabicyclo[4.4.0]dec-3-enes or trans,trans-
l-methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]dec-3-enes (I). In the latter case, an interaction with
one of thenucleophiles, i.e., with methanol, takes place. It was noted that the conversion of oxy-
gen analogs of I into sulfur analogs of type II is not observed in methanol. At the same
time, it is known that acetals are split under the action of hydrogen chloride. In this con-
text it seemed to be of interest to study the reactions of bicyclic acetals la-c with hydro-
gen sulfide and hydrogen chloride in a polar solvent.
For this purpose we studied the reactions of trans,trans-acetals la-c with hydrogen sul-
fide in acetic acid under the conditions of acid catalysis. It was established that the re-
action of hydrogen chloride with a suspension of trans,trans-acetals la-c in acetic acid
which had been saturated to the limit with hydrogen sulfide at I0-15~ results in the forma-
tion of trans,trans-hemithioacetals IVa and IVc. If the reaction mixture is subjected to
the simultaneous action of hydrogen sulfide and hydrogen chloride, 4H-thiopyrans lllb and
lllc are recovered as the reaction products. Thioacetals lla-c were not detected.
The openin~ of the acetal ring in compounds la-c should produce a carbonium ion (A),
which is structurally similar to the protonated form of 1,3-diaryl-3-(2-oxocyclohexyl)-l-
propanones. Since the equatorial attack of ions of such a type is sterically hindered, as
was shown in [i], the preferential axial attack of ion A should produce intermediate B. The
absence of trans,trans-thioacetals lla-c in the reaction products attests to the fact that
intermediate C with a configuration which is most favorable for the intramolecular interac-
tion of the mercapto group with the carbonyl group clearly does not form. The intramolecular
interaction of the mercapto and carbonyl groups which occupy axial and equatorial positions
in hemithioacetal B is impeded by the rigidity of the acyclic chain, and the formation of
cis,trans isomers of type II is also not observed. The elimination of methanol from intermed-
iate B gives carboniumion D and then either 4H-thiopyrans lllb and lllc, if the concentration
of hydrogen sulfide is small, of trans,trans-hemidithioacetals IVa and IVc via gem-dithiol E.

N. G. Chernyshevskii Saratov State University, Saratov 410601. Translated from K h i m i y a

Geterotsiklicheskikh Soedinenii, No. I, pp. 28-33, January, 1986. Original article submitted
August 2, 1984.

0009-3122/86/2201-0023512.50 9 1986 Plenum Publishing Corporation 23

 ~:[t + ......tI2S/ttC!.~ 0 <.~r..._ R
V
/_..-_ /_.#. /
0C}'I3 I 1 1It

la- C A
SH
. ~}~
/

H H '\" l " "'R

B C
0CH 3
CH3OH] IIa-C
+ .SH H~> ,,,R~

H (~H S R
D H+
lllb, c
I H.aS
~, ~ .,,,,R
' ~ .,,,,,,R
I

"~./* .' Z -H20 \S ~'R

SH" ~ .'
SFI
E IVa, C

a, cR=C611s, b R=CoH~OCI|3-4;a,b Rl=CoHa, c R~=C6H4OCHs-4

A necessary condition for the formation of gem-diothiolsof type E and then of trans,
trans compounds IVa and c as intermediates is the limiting saturation of the reaction mix-
ture at I0-15~ with hydrogen sulfide. When hydrogen sulfide and hydrogen chloride are sim-
ultaneously reacted with acetals Ib and Ic, the dissolution of the original compounds Ib and
Ic and the precipitation of 4H-thiopyrans lllb and c are observed after 30-40 min.
When there is a shortage of hydrogen sulfide in the mixture, ion A can be subjected to
the attack of another nucleophile, viz., water, which is evolved when 4H-thiopyrans of type
III are formed. This results in the formation of the products of the intramolecular cyclo-
dehydration of 1,5-diketones of type V, i.e., 2,4-diarylbicyclo[3.3.1]non-2-en-9-ones of
type VI.
The intramolecular cyclodehydration process E + IVa,c is stereospecific and results in
the formation of substances with a trans,trans configuration. The trans-diequatorial arrange-
ment of the interacting parts in gem-dithiol E is most favorable for cyclization.. This is
consistent with the results in [i].

" . . . . . . . . . . . . :g r
-CH~OH /" , ( ~'R '"R
V C VIc

When the experiment is conducted in the absence of acetic anhydride, a small quantity
(9.5%) of compound Vlc is recovered along with 4H-thiopyran lllc.
For the purpose of confirming the proposed mechanism for the conversion of trans,trans-
acetals of type I into hemidithioacetals of type IV, we determined the crystal and molecular
structure of l--mercapto-3-phenyl-5-(4-meth0xyphenyl)-2-thiabicyclo[4.4.0]dec-3-ene (IVc).
The crystals of compound IVc are monoclinic: a = 12.575(1), b = 10.2942(8), c = 16.425(1)
~, ~ = 115.71(1) ~ , V = 1915.7 ~3, M = 368, d c a l = 1.28 g/cm 3, z = 4, space group P2~/c, v(Cu
Ka) = 24.7 cm -~. The coordinates of the atoms are listed in Table i, and the equations of
t h e planar fragments in the molecule and the deviations of the atoms from them are given in
TabZe 2. The stereochemistry of the molecule with the principal bond lengths and bond ang-
les is shown in Fig. i, and the torsion angles are presented in Fig. 2.
The geometry of dihydrothiopyran ring A is close to that found in the molecules of
trans,trans--methxy-3-(4-methxypheny)-5-pheny-2-thiabicyc[4.4.]dec-3-ene [2] and cis-
3,5-diphenyl-2-thiabicyclo[4.4.0]decene-A ~'6 [3]. The geometry of the methoxy group is close

24
 /X'16(6 "

P117,9(3)

Fig. 1 Fig. 2
Fig. i. Bond lengths and bond angles in compound IVc. S(,)-C(,)= 1.835(4);
S(~)C(,)S(2) =108.6(2); S(,)C(~)C(,o) = 109.4(3); S(2)C(,)C(,o) = 105.6(3);
C(~)--C(6) = 1.546(6); S(,)C(~)C(6)= 112.7(3).
Fig. 2. Torsion angles in compound IVc.

to that found in the structure of 4-methoxybenzoic acid [4], where O-C(Me) = 1.443, O-C(Ph) =
1.360 A, and the C-O-~ angle is equal to 116.8 ~ . The length of the S(,)-C(,) bond in the mer-
capto group, which is equal to 1.835(4) ~, does not coincide with the standard value of 1.817(5)
[5].
The bicyclic system has trans annelation. Dihydrothiopyran ring A has a "half-chair"
conformation, the C(i) and C(,) atoms deviate in opposite directions from the planar S(2)C(3)-
C(~)C(5) fragment; cyclohexane ring B has a "chair" conformation. Phenyl rings C (in position
3) and D (in position 5) are planar. The dihedral angles between rings C and D and the planar
fragment of the heterocycle are 46.7 and 99.4 ~ , respectively. Phenyl substituent D is found
in a pseudoequatorial position.
l-Mercapto-3,5-diphenyl-2-thiabicyclo[4.4.0]dec-3-ene (IVa), like hemidithioacetal IVc,
has a trans,trans configuration, which was established on the basis of an analysis of their
'3C NMR spectra* (see Experimental section).
4H-Thiopyrans IIIb and IIlc were identified on the basis of the characteristic signals of
the vinyl and 4-H protons in the PMR spectra [6].

EXPERIMENTAL
The unit-cell parameters and the intensities of 1772 independent reflections with I > 30
were measured on a Hilger--Watts automatic four-circle diffractometer, which was controlled by
a PDP 8/1 computer, in Cu Ka radiation with a graphite monochromator, 0/20 scanning, and I <
e < 57 ~ . The structure was solved by the direct method according to the MULTAN program and--
re~ined by the least-squares method in the full-matrix anisotropic approximation. All the hy-
drogen atoms were revealed by a difference synthesis and taken into account in the concluding
steps of the refinement with fixed positional and thermal parameters (it was assumed that
Bis o = 5.0 ~2). The final values of the R factors were R = 0.0514 and Rw = 0.0641.

*A detailed discussion of the ~3C NMR spectra of hemidithioacetals of type IV and related he-
terocyclic systems will be presented in a separate report.

25
 TABLE i, Coord,ina~:es o f At:oms ( ~)

S(i) 4214 (I) 3376 (1) 8061 fl) FI/,q I 3187 3518 7729
Sc~ 5612 (i) 1777 tl) 9676 (1) 11(4~ 4195 3772 I0735
0 - 5 4 8 (2) 2234 3) 10602 (2) FI(81 2891 3689 9074
C(1) 4231 (3) 1866 13 8661 (2) |IIfll 3293 956 9267
C(s) 5319 (3) 2820 41 10409 (2) ||fT~ 1370 1435 8225
C~ 4245 (3) 3203 (41 10261 (3) |I ~7Q 1863 2401 7677
C(~ 3096 (3) 2903 (3] 9475 (2) ;l[~h 1308 442 6883
3167 (3) 1756 (3; 8893 (2) 2118 -383 7791
2023 (3) 1585 (4; 8042 (3) ;Iig~ 2988 1325 6831
C(e) 2050 (3) 445 (4) 7454 (2) 3137 -253 6898
C(9) 3097 (4) 547 (41 7225 fl(lO~ 4903 8O5 7907
C(~o) 4238 (3) 695 (3) ~]flo,) 4367 - I13 8451
C(,;~ 6393 (3) ]092 (3) 1126O (2) ll(12i 7490 3556 I0667
C(m) 7451 (3) ]445 (4) 11259 (3) 9200 3903 12027
8442 (4) 3648 (4) 12047 (3) llfI4~ 9114 3622 13453
Coo 8392 (4) ~491 (4) 12872 (3) /][iR~ 7298 3059 13470
C(~5) 7346 (4} H54 (4) 12881 (3) zL(f6) 5592 2685 12106
C~m) 6362!3) }945 (4) 12090 (3) H(,8) I075 4220 9067
C(17) 2129 t3) ~694 (3) i 9784 (2) H(191 -398 3941 9583
C(18) 1154 (3) L500 (4) i 9499 (3) H~21) 1409 796 II096
C(m) 291 (3) ;334 (4) 9789 (3) H ~22~ 2911 1123 I0607
C(~o) 368 (3) !331 (4) 10369 (2) HI~3~ -1389 Illl lllll
Cim) -1335 (3) 520 (4) 10667 (2) H (~B,) 56 1049 I1771
C(~2) 2210 (3) :715 (4) 10378 (2) -442 35O I0763
C(~) -596 (4) 123 (4) 11093 (3)

*The numbers of the H atoms coincide with the numbers of the

corresponding nonhydrogen atoms (with single and double prime
signs for the second and third H atoms), and the hydrogen atom
of the mercapto group is denoted by H(S ).

The *H and X3C NMR spectra were recorded on a Varian FT-80A spectrometer (80 MHz) with
HMDS (for XH) and CDCI3 (for '3C) as internal references. The course of the reactions was
monitored by TLC on Silufol UV-254 plates with a 6:1 hexane-ether mixture as the eluent.
The original acetals la-c were obtained in analogy to [7].
Conversion of trans,trans-l-Methoxy-3,5-diaryl-2-oxabicyclo[4.4.0]-dec-3-enes (la, c)
into trans,trans--Mercapt-3-pheny-5-(4-methxypheny)-2-thiabicyc[4.4.]de-3-ene (IVc)
and trans,trans-l-Mercapto-3,5-diphenyl-2-thiabicyclo[4.4.0]dec-3-ene (IVa). A suspension of
3.6 g (15 mmole) of acetal Ic in 40 ml of glacial acetic acid (with an addition of 2 ml of
acetic anhydride) is saturated with hydrogen sulfide for 1.5 h at !0-15~ and then with a
mixture of hydrogen sulfide and hydrogen Chloride for i h. After 0.5 h has elapsed from the
beginning of the passage of HCI, initial acetal Ic is dissolved, and crystallization of re-
action product IVc is observed. The mixture is left to stand for 17 h in a refrigerator,
and then compound IVc is filtered out, washed with water, and dried in air. This gives 2.05
g of hemidithioacetal IVc with Tm = 139.5-140.5 ~ (from petroleum ether). The mother solution
is poured onto ice, and another 1.5 g of IVc are recovered; the total yield is 94%. *SC NMR
spectrum (CDCI3): 57.32 (C(z)), 130.76 (C(s)), 123.09 (C(4)), 47.02 (C(5)), 49.56 (C(6)),
25.69 (C(7)), 27.13 (C(s)), 22.22 (C(9)), 40.98 (C(~o)), 139.06, 128.13, 126.32, 127.93 (phen-
yl), 134.96, 129.63, 113.83, 158.37 (p-methoxyphenyl), 55.03 ppm (the CHsO group in the aryl
radical at C(~)). In the case of the aromatic substituents, the signals of the quaternary,
ortho, meta, and para carbon atoms were given in that order. Found: C, 71.6; H, 6.9; S,
16.9%. Calculated for C==HzsOS=: C, 71.7; H, 6.6; S, 17.4%.
The treatment of 20 mmole of trans,trans acetal Ia according to the method just de-
scribed gives 5.9 g (87%) of hemidithioacetal IVa with Tm = I07-I09~ (from a 1:3 ethanol--
acetone mixture); according to the data in [8], Tm = I07-I09~ :3C NMR spectrum (CDCIs):
57.20 (C(:)), 130.82 (C(s)), 122.54 (C(4)), 47.72 (C(5)), 49.23 (C(6)), 22.50 (C(7)), 26.92
(C(s)), 22.06 (C(9)), 40.78 (C(xo)), 138.28, 128.26, 126.32, 127,87 (phenyl at C(s)), 142.88,
128.66, 128.04, 126.49 ppm (phenyl at C(5)).
Conversion of trans,trans-l-Methoxy-3-5-diaryl-2-oxabiqyclo[4.4.0]dec-3-enes (Ibp c)
into 2-(4-Methoxyphenyl)-4-phenyl-5,6-tetramethylene-4H-thiopyran (IIIb) and 2-Phenyl~4 -
(

26
 TABLE 2. Equations of the Planar Fragments in the Molecule
Ax + By + Cz = D* and Deviations of Atoms from Them in
0,352x + 0797y + 0,490z = - 5.503

S(2) C(3) C[4) C(5) C(D* C(6)* I S(1)*

Plane I - 0,003 0,009 - 0,009 0,004 0,450 -0,339 I 2,267
(ring A)

C(7)* C(1o)* I C(H)* I C~lT)* H(s)* H(6)* I

O:118x+ 0 , 8 2 7 y - 0:549z = - 5.781

c,,, c,o, ic., c,s, c,o, I c.o, ls,,,*l S/'-"* ICr H(6)*

- 0.261x + 0.9659 - 0.018z= 2.768

C(ll) C(121 I C1131 C~14) C(15) C1161 C131"~
Plane 3
(ring C)
--0,001 O,OOl I 0,003 -0,006 0,005 --0,002 --0,054
L
--0,169x--0.60gg- 0.756z= - 12,19
c )ic o) c,=,, i.c ),lo
Plane
4(ringD) 1o,oo6Io,oo2I-o,oosI o,oo6 0,002-0,009 i --0,012 10,022

1/2 1/3 1/4 2/3 2/4 3/4

Angles between 14,0 9 [ 46,7 99,4 39,0 95,6 121,9
planes in deg

*Atoms not involved in the calculation of the equations of the

corresponding planes.

methoxyphenyl)-5,6-tetramethTlene-4H-thiopyran (lllc). A suspension of 20 mmole of acetal

IB in 35 ml of glacial acetic acid with an addition of 2.5 ml of acetic anhydride is satur-
ated by a mixture of hydrogen sulfide and hydrogen chloride at I0-15~ After 0.5 h, dis-
solution of original acetal Ib is observed, and after 1.5 h the reaction mixture is poured
onto ice, and the precipitate formed is filtered out, washed with water, and dried in a
desiccator. The precipitate is dissolved in ether and filtered, and 4H-thiopyran lllb is
precipitated from the etheral extract by ethanol. The yield is 4.6 g (69%), and Tm = 107-
I08~ (ethanol--ether). PMR spectrum (CDCI~): 1.65-2.20 (8H, m, methylene protons), 3.68
(3H, s, CH30), 3.95 (IH, d, 4-H), 5.81 (IH, d, 4-H, 3Js,~ = 5.9 Hz), 6.69-7.20 ppm (9H, aro-
matic protons). Found: C, 79.3; H, 6.4; S, 9.6%. Calculated for C22H22OS: C, 79.0; H,
6.6; S, 9.6%.
4H-Thiopyran lllc is obtained in analogy to the method just described from 20 mmole of
acetal Ic. The yield is 4.8 g (72%), and T m = I19-120~ (ethanol--ether). PMR spectrum
(CDCI3): 1.61-2.20(8H, m, methylene protons), 3.67 (3H, s, CH30), 3.95 (IH, d, 4-H), 5.96
(IH, d, 3-H, 3J~,4 = 5.9 Hz), 6.72-7.40 ppm (9H, m, aromatic protons. Found: C, 78.9; H,
6.4; S, 9.6%. Calculated for C2=H22OS: C, 79.0; H, 6.6; S. 9.6%.
If the reaction is carried out in the absence of acetic anhydride, 0.6 ~ (9.5%) of 2-
phenyl-4-(4-methoxyphenyl)bicyclo[3.3.1]non-2-en-9-one (~Ic) with Tm = 174-1757 (ethanol)
is recovered from the residue which does not dissolve in ether. According to [9], Tm = 174-
175~ A mixed sample with a known preparation of the compound does not show melting-point
depression~

27
 LITERATURE CITED
I. S . K . Klimenko, T. I. Tyrina, T. V. Stolbova, N. N. Sorokin, and V. G. Kharchenko, Khim.
Geterotsikl. Soedin., No. 9, 1194 (1985).
2. S . V . Soboleva, O. A. D'yachenko, L. O. Atovmyan, V. G. Kharchenko, and S. K. Klimenko,
Zh. Strukt. Khim., 19, 499 (1978).
3. T . V . Stolbova, S. K. Klimenko, A. A. Shcherbakov, G. G. Aleksandrov, Yu. T. Struchkov~
and V. G. Kharchenko, Khim. Geterotsikl. Soedin., No. 8, 1056 (1980).
4. R . F . Bryan, J. Chem. Soc., B, No. 12, 1311 (1967).
5. L . E . Sutton, Tables of Interatomic Distances and Configuration in Molecules and Ions.
Supplement 1956-1959. Special Publication No. 18, The Chemical Society, London (1965).
6. I. Ya. Evtushenko, V. I. Ionin, S. K. Klimenko, and V. G. Kharchenko, Zh. Org. Khim.,
ii, 435 (1975).
7. L . V . V!asova, T. I. Tyrina, S. K. Klimenko, and V. G. Kharchenko, Khim. Geterotsikl.
Soedin., No. 4, 470 (1979).
8. I. Ya. Evtushenko, S. K. Klimenko, V. G. Kharchenko, and B. I. lonin, Zh. Org. Khim.,
13, 193 (1977).
9. J . R . Merchant, J~ B. Mehta, and V. B. Desai, Indian J. Chem., !, 561 (1965).

STUDY OF KINETICS AND MECHANISM OF SULFONATION OF THIOPHENE

AND ITS DERIVATIVES BY COMPLEX COMPOUNDS OF SULFURIC ANHYDRIDE

T. K. Shustareva, and V. E. Druzhinina UDC 541.127:547.732.07(088.8):

541.49:546.226.31

By quantitatively studying the sulfonation of thiophene and its homologs by com-

plexes of sulfuric anhydride with ethers, amides, and trialkyl phosphates it was
possible to determine kinetic and thermodynamic parameters of the process, to
propose a SE2 type reactionmechanism and also to reveal a quantitative depend-
ence of the rate constant of the sulfonation reaction of thiophene on the basic-
ity of the complex-forming agent: The sulfonating activity of the complexes
studied increases in the series ~ amides < trialkyl phosphates < ethers, which
is the reverse of the increase in the basicity series of a donor.

Despite the large amount of quantitative information of the electrophilic substitution

in the heteroaromatic ring [i, 2], no quantitative data are available in the literature*
on the sulfonation reaction of 5-membered heteroaromatic compounds, including thiophenes,
which are widely used in fine organic synthesis [3], and in particular for the preparation
of medicinal compounds, where thiophene sulfonic acid and its homologs are intermediate pro-
ducts in the synthesis of sulfamide and sulfanilamide derivatives [4, 5].
On the other hand, in recent years great attention has been paid to the study of the
structure and reactivity of complex compounds of S03, which are of interest as mild sulfona-
ting reagents for the sulfonation of acidophobic compounds (heterocyclic compounds, alcohols,
polysaccharides, steroids, etc) [6, 7].
Therefore, besides the study of kinetics and mechanism of sulfonation of thiophene and
its homologs, it was also of interest to study and quantitatively compare the reactivity of
complex compounds of SO3 with different organic donors.
*We have made a preliminary report on this problem in coauthorship with B. V. Passet in 1979
at the XVth Scientific Session of Chemistry and Technology of Organic Compounds and Sulfur-
Containing Oils in Ufa.

North-West Correspondence Polytechnical Institute, Leningrad 191041. Translated from

Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 34-39, January, 1986. Original article
submitted November 21, 1984.

28 0009-3122/86/2201-0028512.50 9 1986 Plenum Publishing Corporation

 9 C, mole/m3

3
3o Fig. I. Time-dependent change in con-
centrations of reaction compounds and
reaction products during sulfonation of
20 21` thiophene by a DMFA.SOs complex in a i,
2-dichloroethane medium at 20~ 30~
(2), 400C (3) and 50 ~ (4). 1-4) con-
1o , centration of sulfonic acid, I'-4') con-
centration of sulfonating agent.

0 I0 2o 30 c0 50 60 70 80 90 I00~, rain

In the present work, we quantitatively studied the sulfonation reaction of thiophene by

complexes of S03 with various organic donors: ethers [diethyl ether (E.S03), dioxane (DO.
S03), tetrahydrofuran (THF.S03)], amides [dimethylformamide (DMFA.S0s)], and trialkyl phos-
phates [tributyl phosphate (TBpoS03)], which are more active than the known agent [8, 9], the
pyridine.S03 complex (Py.S03). As the initial substrates, we chose thiophene, 2-methylthio-
phene (more active than thiophene), and 2-bromothiophene (less active in electrophilic sub-
stitution reactions).
Depending on the activity of the corresponding complexes and the reactivity of the het-
erocyclic compound, the sulfonation reaction is carried out in an inert solvent (l,2-dichlor-
oethane) or in the complex-forming agent medium.
In the benzene series, which is less active than thiophene, similar studies could not be
carried out, since the sulfonation of benzene proceeds very slowly (DO-SOs, THF.S03, TBP.S03),
or there is practically no reaction (DMFA.SOs).
In all the experiments, the change in the concentration of the initial sulfonation agent
(the SO3 complex) and the sulfonic acid formed in the reaction was quantitatively recorded by
the method of differential nonaqueous potentiometric titration of an aliquot portion by an
alcoholic solution of diphenylguanidine in mixed solvent medium (acetone--isopropanol--glycer-
in). It was thus possible to determine the overall amount of sulfonic acid and of the unre-
acted sulfonating agent for each experimental point over the whole kinetic curve. This amount
was the same and equal to the initial concentration of the complex or the corresponding thio-
phene, w h i c h p r o v e s t h e absence of stable by-products in analytically determinable amounts,
during the transformation of the heterocycle into a monosulfonic acid according to equation:

where D is a donor.
The UV spectra of the reaction mixture taken after the end of each experiment confirmed
the formation of monosulfonic acids only.
The nature of the kinetic curves obtained for the sulfonation reaction of thiophene and
its homologs was shown for the example of a sulfonation reaction of thiophene by the DMFA.SO~
complex at different temperatures (see Fig. i).
To determine the order of reaction with respect to the SOs complex, thiophene was sul-
fonated under pseudomonomolecular reaction conditions, i.e., at a considerable excess (>60:1)
of the heterocyclic compound with respect to the sulfonating agent (the SOs complex). The
experimental data thus obtained obey the kinetic equation for a pseudomonomolecular processes,
which shows a first order of the sulfonation reaction with respect to the SOs complex. As has
already been shown in [7, 10], the order of the reaction with respect to the substrate is also
equal to i.
As in the sulfonation of benzene homologs by SOs and its complexes [7, ii], during the
reaction of thiophene and its derivatives with complexes of SOs with different organic donors,

29
 and l~s Derivatives by Sulfurlc Anhydride Complexes

k'lOS~ 5~, mS/ k'lOS~5%, mS/

System T,~C kmole,sec System 7',"C kmole'sec
stage 1 ~ ;tage llstage Z
lhiophene and 5,495 0,330 Thiophene and 19,1c
Z'SOs, (i. -15 1,545
e~ner) 15,53 1,279 THF,SOs (in
37,85 4,141 DCE)
Thiophene and 2-Bromothiophene
DO'SO~(~n di- 314,3 ~6,48 I0 0,01
oxane) 17,87 1,551 and DMFA.S~ 50 2,13
29,17 2,657 (in- DCE), 60 5,7~
61,72 7,425
2-Bcomothiphene 70 14,6E
Thiophene and 93,77 3,59 and DO" S03 (in 30 6,58
TBP'SO S (in 155,2 7,285 dioxane)
DCE) ~63,0 ,9,60 2-Methylthio-
595,6 9,4 phene and DMFA, I0 ;0,53 4,285
Thiophene and
1053 ;6,9 SO 3 (im DCE)
0,106 0,008
DMFA.SO 3 '(in 1,789 0,183
DCE) 5,174 0,576
13,29 1,689
31,17 4,528
70,55 2,94

*In dichloroethane (DCE).

a stage which in general ends at 40-50% conversion of the initial reagents is first observed,
and then monosulfonic acids are further slowly formed, until a final yield of 85-100% is
reached (after 2-5 h). The fairly sharp change in the rate of sulfonation, leads us to as-
sume the existence of at least two sulfonating agents in the reaction mixture, of which one
should be considerably more active than the other.
For the reaction of each of the two sulfonating agents with one and the same substrate,
each has a characteristic rate, which is determined by means of a differential kinetic extra-
polation method, proposed in [12, 13], and successfully used previously for the determination
of the kinetic parameters of the sulfonation of benzene derivatives by complexes of SOs with
ethers [7]. By using this method fn the case of the sulfonation of thiophenes it is possible
to determine the values of kinetic parameters given in Table I.
In general, the sulfonation reaction of thiophenes comprises two stages. The first
stage is characterized by a rate constant kz, and the second by k=. Since slowing down of
the reaction rate begins after ~50% conversion of the initial compounds, it can be assumed
that in this case, a deactivation of the sulfonating complex by the sulfonic acid takes place
(see scheme).
According to the data in [7], and from our results it could be assumed that there exists
in the reaction mixture a complex of sulfonic acid with SOs, which is the presence of the
complex forming agent probably has the structure of Het,SOsH ... SOs ... D (Het is hetero-
cyclic radical), i.e., the donors in this case are the sulfonic acid formed during the reac-
tion and the complex forming agent (organic base) bound into a complex with SOs at the begin-
ning of the reaction. The formation of the intermediate complex as the result of the reac-
tion of the sulfonicacidwiththe SOs complex, and not with SOs itself is confirmed by the fact
that during the sulfonation in the complex forming agent medium, or in the presence of an ap-
preciable excess of the latter, when the dissociation of SOs complex is suppressed, there are
two sections on the anomorphosis of the kinetic dependence, as during the sulfonation by the
SOs complex in an inert solvent medium.
It is clear that the sulfonating activity of the intermediate complex is lower than
that of the D.SOs complex, which also leads to the slowing down of the rate of reaction.
To prove this supposition, the sulfonation of thiophene was carried out with a threefold
excess of D.SOs complex. In this case, the formation of the Het-SOsH ... SOs ... D complex
does not limit the rate of reaction, the sulfonating agent is the D,SOs complex, while the
reaction rate obeys a kinetic equation of the second order up to complete transformation of
the heterocycle into the sulfonic acid, i.e., the anamorphosis of the kinetic dependence is
in the form of a straight line. An excess of substrate does not lead to this result, i.e.,
in this case the anamorphosis of the kinetic dependence has two sections.

30
 Our data and the results
fect in sulfonation reactions
plexes [7], and also the fact
equation, lead us to conclude
accordance with a bimolecular
below):
of the other authors on the absence of a kinetic isotopic ef-
of aromatic compounds by sulfuric anhydride [Ii] or its com-
that stages 1 and 2 of the reaction obey a second order kinetic
that the sulfonation of thiophenes by SOs complexes proceeds in
electrophilic substitution mechanism of the SE2 type (see scheme

Scheme of reaction mechanism

+ Ds% ~ - ~ ~%'" D ~ ip~.~+//

S so~..D
Complex

e- complexSO~ ~s ~s%n

so..
o o--- 7~i__-~__ s%"'D~etc.
~'H "~S03H'-SOs'"D ,i

The first stage, limited by formation of a o-sulfonation complex, is concluded by the

formation of an intermediate complex Ret*SOsH ... SO3 ... D. At the second (slow) stage, as
the result of the interaction of the intermediate complex with the substrate with rate con-
stant k2, the further formation of the sulfonic acid takes place in a similar way.
It should be noted that when a sample is poured into water (to stop the reaction), the
intermediate complex formed in the reaction mixture immediately decomposes, and therefore,
the data of the material balance for the sulfonating agent at each point of the kinetic
curve indicate the absence of intermediate products.
The study of the influence of substituents at the 2-position of the heteroaromatic ring
on the rate of sulfonation in the thiophene series shows that in the case of substitution
into the 5-position, the log k, values satisfactorily correlate with Hammet's o n constants
in accordance with the equation (~ = 0.99):

Jgkt= -2.75-8.75o..
According to the value of the rate constant obtained p = --8.75, the increase in the el-
ectron denisty of the reaction center (electron-donor substituents) favors the acceleration
of the sulfonation reaction, while decrease in the electron density (electron-acceptor sub-
stituents) favors a decrease in the reaction rate. Thus, introduction of a methyl group in-
to the 2-position of thiophene considerably increases the rate of reaction at both the first
and second stages. For example, in the case of sulfonation by DMFA.SO3 complex at i0 ~ in
dichloroethane, the activity of thiophene at the first stage is -30 times lower than in the
case of 2-methylthiophene, but it is ~i00 times higher than in the case of 2-bromothiophene
(Table I).
The high value of O in absolute terms (8.75) indicates the great sensitivity of this
reaction to structural changes in the substrate molecule and the high polarity of the tran-
sition state of the sulfonation reaction that fully corresponds to the o-complex during el-
ectrophilic substitution. The determined value of 0 =--8.75 fully correlates with the con-
stants 0 of other electrophilic substitution reactions in the heteroaromatic ring [I, 2] and
of the sulfonation reaction of benzene homologs by sulfuric acid [i0], which proves a common
mechanism for the benzene and thiophene series.
The values of the kinetic and thermodynamic parameters that we calculated for the sul-
fonation process, confirm our supposition on the mechanism of this theoretically interesting
and practically important reaction (Table 2).
We carried out a comparative study of the reactivity of the complex SO3 compounds on
the example of the sulfonation of thiophene at --15~ in 1,2-dichloroethane. From the results
obtained (Table i), the SO3 complexes can be arranged into the following series according to
their sulfonating activity:
E.SO~ > DO.S03 > TBp.SO3 > THF.SO3 > DMFA-SO3,

31
 TABLE 2. Values of Kinetic and Thermodynamic Parameters of
Sulfonation of Thiophene Derivatives by Sulfuric Anhydride
Complexes

Stag_e_l Stage _ _
System AW ~ 5 ~ A S ~ 5 ~ K 0, m3/ A H ~ 5 ~ A S ~ 5 % K0, m 3 /
kJ/mol4 J/mole" k~ole" ~J/molel~egree /mole" kmole"see
|de~ree sec
Thiophene and E~SO3 61,94 60,67 5,62. I0'c 81,97 10,71 4,46.1012
(im ether)
Thiophene and DO-SO3 (in 56,02 83,40 7,46. lOs 76,89 32,11 3,53. ION
dioxane)
Thiophene and TBP,SO3 (in 26,72 157,0 1,08. 105 50,74 8%02 3,80. lOs
DCE) 1,64.1011
Thiophene and DMFA~SO 65,~J6 63,86 8,33. 109 78,75 3%05
(in DCE)
2-Bromothiophene and 85,89 31,24 4,46- 10"
D~A,SO 3 (in DCE)

which is the reverse of the relationship of the basicity series (pK~) of the complex-forming
agent [14]: E < DO < TBP < THF < DMFA, i.e., the lower the basicity, the higher is the sul-
fonating activity of the corresponding complexes. This dependence is expressed by correla-
tion equations (z = 0.99).

lgkl=O:35--1.11pK~;lgk2=- 0 , 7 0 - - 1 , 1 4 pK=.

Thus, the rate of sulfonation of thiophenes depends on the nucleophilicity of both the
substrate and the complex-forming agent.

EXPERIMENTAL
All the reagentsused in the investigation were thoroughly purified and dried. The char-
acteristics of the solvents, complex-forming agents and thiophenes corresponded to handbook
data.
Preparation of Solutions of Sulfuric Anhydride, Complex-Forming Agents and Substrates.
Sulfuric anahydride was obtained by conventional methods [8, 9] from 65% oleum. Before car-
rying out the experiment, a given amount of S03 was distilled at Tbp (44.8~ into a weighed
flask with 1,2-dichloroethane. The concentration of the solution was determined from the dif-
fernece in weights or by titration of aliquots with an alcoholic solution of diphenylguanidine.
The amounts of the complex-forming agent and the substrate required in the reaction were cal-
culated from the known concentration of SO3.
Method of Kinetic Investigations. A calculated amount of a solution of the complex-form-
ing agent in 1,2-dichloroethane is charged into a 150 cm 3 four-necked glass reactor with a
jacket, fitted with a thermometer, reflux condenser, a tube filled with P~Os, a sealed stir-
rer, and a sampler, and a calculated amount of SOs in l,2-dichloroethane at a known concentra-
tion is added by means of a hermetic microburette. After thermostating for 50-60 min, a sam-
ple (3-5 cm 3) is withdrawn from the reactor, and poured into 3-5 cm s of cold water. The mixture
is vigorously shaken. Then, an aliquot is withdrawn for analysis to determine the concentra-
tion of the corresponding complex. A c a l c u l a t e d amount of the substrate solution, thermostat-
ed at the same temperature is added to the reactor. The temperature is maintained with an
accuracy of 176 The number of samples withdrawn in the experiments is 14-17. The rela-
tive error of the determination of the concentration of the sulfonating agent and the sulfonic
acid is 0.1-3.0%.
For the determination of k, each experiment was repeated not less than 3 times, and the
mean value of k was found. The relative deviations from the mean value for k are -1-3%.
Finally, the values of k and the activation energies Ea were determined by the method of
least squares on an Odra-1204 compus

LITERATURE CITED
i. Dzh. Marino, Khim. Geterotsikl. Soedin., No. 5, 579 (1973).
2. A. N. Kost and V. A. Budylin, Zh. Vses. Khim. Ob-va, 22, 3151 (1977).
3. New Trends in Thiophene Chemistry [in Russian], Nauka, Moscow (1976), p. 424.

32
4. P. I. Buchin and A. E. Lipkin, T h i o p h e n e and Bithiophene Derivatives a s Prospective New
Group of Antiseptics [in Russian], Izd-vo Sarat. Un-ta (1974), p. 102,
5. G. A. Carter, G. W. Dawson, and J. L. Garraway, Pestic. Sci., ~, 43 (1975).
6. E. E. Gilbert, Sulfonatlon of Organic Compounds [Russian translation], Khimiya, Moscow
(1969), p. 416.
7. A. P. Mel'nik, B. V. Passer, and G. M. Gaevoi, in: Proceedings of VIIth International
Congress of Surface Active Agents, Vol. 1 [in Russian], Moscow (1976), p. 262.
8. A. P. Terent'ev and L. A. Kazitsyna, Zh. Obshch. Khim., 18, 723 (1948).
9. A. P. Terent'ev and G. M. Kadatskii, Zh. Obshch. Khim., 21, 1524 (1951).
i0. A. W. Kaanderp, H. Cerfontain, and F. L. Sixma, Rec. Tray. Chim., 81, 969 (1962).
ii. J. K. Bosscher and H. Cerfontain, Tetrahedron, 24, 6543 (1968).
12. S. Siggia and J. Hanna, Anal. Chem., 33, 896 (1961).
13. C. Reillej and L. Papa, Anal. Chem., 34, 801 (1962).
14. A. Gordon and R. Ford, Chemist's Guide [Russian translation], Mir, Moscow (1976), p. 541.

SYNTHESIS OF HETEROCYCLIC ANALOGS OF PROSTAGLANDINS

FROM PYRROLE AND INDOLE

V. A. Dombrovskii, E. V. Gracheva, UDC 547.741'754'295'361.07

and P. M. Kochergin

Heterocyclic analogs of prostaglandin, dl-2-(trans-3-hydroxyocten-lyl)-N-(6-eth-

oxycarbonylhexyl)pyrrole and -indole were obtained by the condensation of 2-for-
mylpyrrole and 2-formylindole with 2-oxoheptylidenetriphenylphosphorane, followed
by alkylation with ethyl 7-iodoheptanoate and reduction of the keto group by sod-
ium borohydride.

In recent years, studies on the preparation of prostaglandin analogs, which are synthe-
tically more accessible than the natural prostaglandins and have the same or comparable bio-
logical activity, received great impetus [i, 2]. Special attention is paid at present to the
synthesis of analogs of prostaglandins in which the cyclopentane ring is replaced by a nitro-
gen-containing heterocycle, for example, derivatives of indole, pyrrolidine, oxazole, and
others [i, 3-5]. This is mostly due to the fact that some of the azacyclic analogs of pro-
staglandin are strong inhibitors of the thrombocyte aggregation [6].
In search for new potential thrombocyte aggregation inhibitors, we were first to synthe-
aize dl-2-(trans-3-hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (la) and dl-2-(trans-
3-hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (Ib), in which the side chains corres-
pond to the side chains of natural prostaglandins. Commercially available 2-formylpyrrole
(lla) and 2-formylindole (lib) served as the starting materials for the synthesis of these
compounds. The synthesis of compounds la, b is shown by the following scheme:

RI ~ ~N" ~CHO I~~ "" " ' N ' / ~ C H = C | I C O - C ~ I I 1 1 - n

H 9 lI
lla.b Ilia, b
R~ R

R1/ -N / " CII=CtI-CO:CbH ~,~-n R1 "N

( ~C112)6~-C00C2iI~ ( ]CI|2)g-'COOC2I| 5
Iva,b la, b

I,ll a R~RI=}I; fi R4.RI=-CH=CH-~CII=CH --

All-Union Scientific-Research Institute of Technology of Blood Substitutes and Hormonal

Preparations, Moscow 109044. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i,
pp. 40-43, January, 1986. Original article submitted December 4, 1984.

0009-3122/86/2201-0033512.50 9 1986 Plenum Publishing Corporation 33

 The condensation of aldehydes ila, b by the Wlttig condensation with 2-oxoheptylidene-
triphenylphosphorane was carried out in carbon tetrachiorlde by boiling for several hours.
2-(trans-3-oxoocten-l-yl)pyrrole (Ilia) and -idole (lllb) thus obtained had the required E-
configuration of the double bond protons (the SSCC of olefinic protons is 16 Hz). Treatment
of ketones file, b by ethyl 7-1odoheptanoate in DMFA in the presence of NaH at 70-80~ leads
to 2-(trans-3-octoocten-l-yl)-N-(6-ethoxyearbonylhexyl)pyrrole (IVA) and -indole (IV5). Re-
duction of the carbonyl group in ketones IVa,b by sodium borohydride in 70% aqueous isopro-
panol at room temperature took place nonselectively, but without the side-processes of 1,4-
addition, and led to dl-la and lb. The individual compounds dl-la and -Ib were isolated
chromatographically on silica gel. Attempts to saponify the ester group in compounds la, b
by alkaline or acid hydrolysis led to resinification.
The structure of the intermediate and final compounds was confirmed by IR, ~3C NMR and
PMR spectroscopy. Some of the spectral characteristics of compounds Is, b, Ilia, b, IVa,b
are shown in Table i.
Thus, a simple, three-step synthesis of nitrogen-containing prostaglandin analogs has
been proposed, enabling obtention of dl-2-(trans-3-hydroxyocten-l-yl)-N)a(6-ethoxycarbonyl-
hexyl)pyrrole and dl-2-(trans-3-hydroxocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole, whose ac-
tivity in the thrombocyte inhibition test in a rabbit is equal to 40% of a standard (ara-
chidonic acid).

EXPERIMENTAL
The I R s p e c t r a w e r e r e c o r d e d on a UR-20 spectrometer, the PMR spectra of a BS-27 spec-
trometer (60 MHz) with reference to TMS as internal standard. The '3C NMR spectra were re-
corded on a Bruker WP-80DS spectrometer. A qualitative analysis of the mixtures was carried
out by TLC of Siiufoi UV-254 plates in the following systems of solvents: ethyl acetate--
hexane, 2:3 (system A), acetone--chloroform, 1:19 (system B), ethyl acetate--heptane, i:i (sys-
tem C). Brand LI00/160, 40/100 silica gel was used for column chromatography.
2v(trans-3-Oxooeten-l-yl)p~rrole (Ilia). A 0.42 g (4 mmole) portion of 2-formylpyrrole
was added with stfrring to a solution of 3 g (8 mmoles) of 2-oxo,heptylidenetriphenylphos-
phorane in 25 ml of CCI~. The reaction mixture was boiled for 6 h. The solvent was evapor-
ated, and the yellow oil obtained was dissolved in 5 ml of ethyl acetate, and the solution
was deposited on a column with silica gel (d 2.5 cm, I 20 cm) LI00/160, with elution by a
2:8 ethyl acetate--hexane mixture. The yield of ketone Ilia was 0.68 g (80%), mp 94-95~ Rf
0.63 (B).
2-(trans-3-Oxoocten-l-yl)indole (lllb) was obtained and isolated in the same way as com-
pound Ilia. A 0.2 g (18 mmole) portion of 2-formylindole was added to 1.4 g (3.7 mmoles) of
2-oxoheptylidenetriphenylphosphorane. After chromatographic purification, 0.37 g of ketone
lllb (88%) was obtained; mp 146-147~ RfI0.78 (B).
2-(trans-3-Oxoocten-l-yl)-N-(6-ethoxycarb@nylhexyl)pyrrole (IVa). A mixture of 0.i g
(4 mmoles) of NaH and 0.3 g (1.5 mmoles) of 2-(trans-3-oxoocten-l~yl)pyrrole in 5 ml of ab-
solute DMFA was stirred for 1 h at room temperature. A solution of 0.6 g (2 mmoles) of
ethyl 7-iodoheptanoate in 5 ml of absolute DMFA was added dropwise to the reaction mixture,
with stirring, for i h at 70-80~ followed by cooling, dilution with water, and acidifica-
tion with i N H2S0~ to pH 5. The aqueous solution was extracted with ether (5 x 50 ml), and
dried over Na2SO~. After distillation of the solvent, a yellow oil was obtained, which was
deposited on a column (d 2.5 cm, I 20 cm) with silica gel L40/100) with elution by a 2:8
ethyl acetate--hexane mixture. The yield of pure ketone was 0.51 g (94%), oil, Rf 0.73 (A).
2-(trans-3-Oxoocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (IVb) was obtained in a sim-
ilar way as compound IVa. A 0.6 g (2 mmole) portiona ofethylT-iodoheptanoatewasadded toe
mixture of 0.I g (4 mmoles) of NaH and 0.36 g (1.5 mmoles) of ketone lllb. After chromato-
graphic purification, 0.6 g of ketone IVb (77%) was obtailed. Oil, Rf 0.64 (B).
dl-2-(trans-3-Hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)pyrrole (la). A suspension
of 0.05 g (10.25 mmoles) of NaBH~ in 3 ml of water was added to a solution of 0.14 g (0.41
mmole) of 2-(trans-3-oxoocten-l-yl)-N-(ethoxycarbonylhexyl)pyrrole in 7 ml of 2-propanol,
and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted
with water, extracted by ethyl acetate (4 50 ml), the extract was washed with water, and
dried over Na2SO~. After a chromatographic purification on a column with silica gel (d 2.5

34
 TABLE i. Spectral Characteristics of Compounds la,b, Ilia,b, IVa,b
I IR spectrum,V , cm- ~ PMR s p e c t r u m , 6, ppta ( j , HZ), ~ Cilia
Compound CH-CH N--CH2 EH3 i n sid~
trans C=C c=o coo NH OH CH~CH OH CO~--CH2--CH3 CO--CH2 chain NH COOCHz--CHa

Ilia 975 16t0 1670 3290 6,8 d (IH); 5,8 d , d 2,60 t (2H) 0,90 t 8,70 s
(IH); I = 1 6 Hz
IIIb 960 1610 1650 3320 7,01 (IH); 6,85 d , d 2,65 t (2H) 0,93 t 8,20s
(IH); 1 = 1 6 Hz
IV a 970 1600 1680 1740 7,53 (IH); 6,35 (1H) 3,97 m (4H) 2,28 m (4H) 0,92 t 1,20 t (3H)
IVb 970 1600 1680 1740
la 96O 1650 1740 3200--3700 7,37 d (IH); 6,22 d,d 3,27 M (IH) 4,16m (4H) 2,28 t (2H) 0,86 t 1,22t (3H)
(IH)
lb 96O 1620 1740 3180--3600

ZSC ~ spectrum, 6 , ppm. i n CCI~

C(t) C~2) C(3) C(4~ C(5)' C(6)' C(7)"C(8)'C(22) I C(9) C(to) . C(H) Cil2) C(13)

I
IV b 14,33 59,71 172,38 41,97 24,70; 26,60; 28,70; 29,70; I 33,88 125,28 121,46 127,55 129,55
30,42
Ib 13,20 59,25 172,76 42,05 23,75; 25,75; 27,75; 29,03;[
I 33,21 119,88 118,69 120,42 120,88
30,76
I

t c(14)I C(l~)I c(m)I C(17)I C{,a)I c(19)I c(-oo) I C(21) I C(2a) I C{24) I c(25)

I 136,26 134,53 117,78 119,42 108,32 100,58 71,81 42,59 31,49 21,56 13,01

~o
~n
cm, ~ 25 cm) L40/IO0 with elution by a 1:19 acetone--chloroform mixture, 0.08 g (52%) of com-
pound la was isolated. Oil, Rf 0.78 (B).
dl-2-(trans-3-Hydroxyocten-l-yl)-N-(6-ethoxycarbonylhexyl)indole (Ib) was obtained and
isolated in the same way as la. A 0.i g (20 mmole) portion of NaBH~ and 20 ml of 70% 2-pro-
panoi were added to 0.32 g (0.8 mmole) of ketone IVb. After chromatographic purification,
0.18 g (56%) of compound Ib was obtained. Oil, Rf 0.73 (B).

LITERATURE CITED
i. E. I. Levkoeva and L. N. Yakhontov, Usp. Khim., 44, 1074 (1975).
2. V. A. Dombrovskii, D. Yu. Fonskii, V. A. Mironov, and P. M. Kochergin, Usp. Khim., 53,
689 (1984).
3. V. G. Avramenko, N. N. Levinova, V. D. Nazina, and N. I. Suvorov, Khim. Geterotsikl.
Soedin., No. 2, 204 (1975).
4. I. Barta, G. Ambrus, Gg. Horvath, M. Sdti, and P. S6har, Acta Chim. Sci. Hung., 98, 463
(1978).
5. G. Ambrus and I. Barta, Prostaglandins, i0, 661 (1975).
6. P. Parraclough, C. J. Harris, and A. G. Caldwell, U. K. Patent No. 2094793; Ref. Zh.
Khim., 12060P (1983).

NEW SYNTHESIS OF INDOLE-7-CARBOXYLIC ACID

V. I. Dulenko and Yu. A. Nikolyukin UDC 547.757.07

A new preparative method for the synthesis of indole-7-carboxylic acid has been
developed, consisting in reductive cyclization of ~-(dimethylamino)-3-carbo-
methoxy-2-nitrostyrene by the action of iron in acetic acid.

Indole-7-carboxylic acid is used in the synthesis of optical filter dyes, used for the
protection of an exposed light-sensitive material fogging during its treatment in light [i,
2]. The known methods for the preparation of this compound are multistep and proceed with a
low overall yield, which does not exceed 20% [3, 4].
In developing a new variant of the synthesis of indole-7-carboxylic acid [5], free of
the above drawbacks, we used the method of constructing the indole ring, consisting in a re-
ductive cyclization of B-(dialkylamino)-2-nitrostyrenes [6]. The latter compounds are most
conveniently obtained by the condensation of substituted o-nitrotoluenes with DMFA dialkyl
acetals [7]. In accordance with this, we selected 2-nitro-m-toluic acid (I) as the starting
compound.

+ (CH.~)='N-CH(OCI%)z J. Fe,Cl..I~COOH
..... ~7 ~-~" "
~'N% I1 NOz
COOt,I COOCH~ COOH

When acid I is heated with dimethyl acetal (II) in DMFA, an esterification of the car-
boxyl group takes place together with the formation of an enamine grouping. Reduction of
enamine III by iron in acetic acid gives methyl indole-7-carboxylate, which, without purifi-
cation, is hydrolyzed by boiling with an aqueous solution of sodium hydroxide. The overall
yield of indole-7-carboxylic acid is thus 60%.

Institute of Physical Organic Chemistry and Carbon Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedlnenii, No~ I~
pp. 44-45, January, 1986. Original article submitted December 4, 1984.

36 0009-3122/86/2201-0036512.50 9 1986 Plenum Publishing Corporation

 EXPERIMENTAL
The IR spectra were run in mineral oil on a UR-20 spectrophotometer.
B-(Dimethylamino)-3-carbomethoxy-2-nitrostyrene. A mixture of 9 g (0.05 mole) of 2-
nitro-m-toluic acid [8], 32.5 ml (0.25 mole) of DMFA dimethyl acetgl [9] and 50 ml of DMFA
is heated in an argon atmosphere to 130-140~ for 24 h. The red solution formed is evapor-
ated under vacuum, using an aspirator, and water is added to the residue. The precipitate
is filtered, washed with water, and dried. Yield, 9.3 g (74%), mp 131~ (from isopropano!).
IR spectrum: 1720 (C=O), 1635 (C=C), 1530, 1290 cm -~ (NO2). Found: C 57.4; H 5.8; N 11.2%.
C12HI~N=O~. Calculated: C 57.6; H 5.6; N 11.2%.
Indole-7-carboxylic acid. A mixture of 75 g of B-(diethylamino)-3-carbomethoxy-2-nit-
rostyrene, 180 g of iron powder, 800 ml of ethanol, and 80 ml of acetic acid is heated, with
vigorous stirring, on a water bath. When the temperature in the flask reaches 50~ the
bath is removed, and the mixture spontaneously heats up to 80~ This temperature is main-
tained by a cold water bath until the end of the exothermal reaction, after which the flask
contents are heated for another 30 min. The reaction mixture is cooled, 4.5 liters of water
are added, and the unreacted iron is filtered off. The residue on the filter is washed thor-
oughly with benzene, and the aqueous filtrate is extracted 3 times with benzene. The com-
bined organic extracts are washed with water and saturated sodium carbonate solution, and
dried over sodium sulfate. Benzene is distilled off, and a solution of 35 g of sodium hy-
droxidd in 310 ml of water is added to the residue. The mixture is boiled for 5.5 h, then
cooled, filtered, and acidified with hydrochloric acid to pH 2. The precipitate of indole-
7-carboxylic acid is filtered, washed with water, and dried. Yield 38.5 g (80%), mp 205-
206~ (from an ethanol-water mixture). IR spectrum: 3420 (N--H), 1670 cm -~ (C=O).

LITERATURE CITED
S. Bloom, A. Borror, and P. Hayffer, US Patent No. 4124592; Ref. Zh. Khim., 13N223P
(1979).
2. A. Borror, US Patent No. 3954799; Ref. Zh. Khim., 2N224P (1966); US Patent No. 3941807;
Ref. Zh. Khim., 23N238P (1976).
3. R. Ikan and E. Rapaport, Tetrahedron, 23, 3823 (1967).
4. H. Singer and W. Shiwe, J. Amer. Chem. Soc., 77, 5700 (1955).
5. Yu. A. Nikolyukin, Yu. A. Vasil'ev, A. V. Kazymov, K. M. Kirillova, V. N. Chepurko, and
V. I. Dulenko, Inventor's Certificate No. 1097619 (USSR~; published in Byul. Ozobr., No.
22, 76 (1984).
0 R. Clark and D. Repke, Heterocycles, 22, 195 (1984).
7. R. Abdulla and R. Brinkmeyer, Tetrahedron, 35, 1699 (1979).
8. E. M~ller, Bet., 42, 423 (1909).
9. H. Bredeck, G. Simchen, and S. Rebsdat, Chem. Ber., !0!, 41 (1968).

37
SYNTHESIS OF HETEROCYCLES FROM 1,5-DIKETONES.
3.* ALICYCLIC 1,5-DIKETONES IN REACTION WITH PHENYLHYDRAZINE

T. V. Moskovkina and M. N. Tilichenko UDC 547.594.3'556.8'759.3'

812.5'.816'835.9:543.422

8-R-7aH-5,6,7,8,9,10,11,12-Octahydroindolo[3.2.l-d,e]acridines, 1,2,3,4-tetra-
hydrocarbazole, 9-R-sym-octahydroacridines, and 9-R,10-phenyl-sym-octahydroac-
ridinium salts are formed by the action of phenyl-hydrazine on alkylidene-2,2'-
dicyclohexanone or the corresponding 8-R-tricyclo(7.3.1.02'7)tridecan-2-ol-13-
ones in an acid medium. Postulations were made for the paths of formation of
these compounds.
2,2-Dimethyl-3-oxa-4a-(2',2'-dimethyltetrahydropyran-4'-on-5'yl-methyl)-4aH-l,
2,3,4-tetrahydrocarbazole, 3,3,14,14-tetramethyl-2-oxa-ba,10b-(methanoxyisobu,
tane)-l,2,3,4,5a,10b,ll,lla-octahydroquinindoline.2,2-dimethyl-3-oxa-l,2,3.4 -
tetrahydrocarbazole and 3,3,6,6-tetramethyl-2,7-dioxa-sym-octahydroacridine were
obtained by the reaction of methylene-3,3'-di(6,6-dimethyltetrahydropyran-4-one)
with phenylhydrazine in acetic acid. The quinindoline structure was confirmed
by the synthesis of this compound from 2,2-dimethyi-3-oxa-4a-(2',2'-dimethyl-
tetrahydropyran-4'-on-5'-ylmethyl)-4aH-l,2,3,4-tetrahydrocarbazole by the ac-
tion of ammonia.

In a continuation [i, 2] of the study of the reaction of 1,5-diketones with phenylhydra-

zone, we studied the transformations taking place during the reaction of methylene-2-2'dicy-
clohexanone (I) with phenylhydrazine in the presence of acids. As the result, the previously
unknown heterocyclic compound, indoloacridine (Va), whose A, B, C, D rings are analogous to
the corresponding structural fragment of strychnine, and also the already known tetrahydro-
carbazole (VI), acridine (Villa) [3] and acridinium salt (iXa) [4] were isolated fmom the re-
action mixture. The. paths of the reaction of diketone I with phenylhydrazine are represented
by the scheme given below (following page).
The data obtained show that diketone I reacts with an equimolar amount of phenylhydra-
zine in acid medium with no clear-cut results - together with the indolization processes
(paths A, B) leading to indoloacridine Va and tetrahydrocarbazole VI, pyridination process
(path C) also takes place, as the result of which compounds Villa and IXa are formed.
Indoloacridine Va is formed as the result of the indolization of monohydrazone II with
the participation of the ~-CH2 group of the hydrazone fragment, followed by dehydration of
compound III. The appearance of tetrahydrocarbazole VI in the reaction mixture can be ex-
plained as occurring by splitting of a substituent from the position 4a of the intermediate
carbazolenine IV. A similar splitting was observed [5, 6] during the indolization of 2-R-
substituted derivatives of cyclohexanone.
The formation of acridine VIII is explainable b y t h e possible splitting of aniline from
the intermediate decahydroacridine VII. These data conform with previous reports on the re-
action of I with phenylhydrazine in the presence of CH3COOH and KBH~ [7]. The acridinium
salt IXa can be considered to be a product of the reaction of I with aniline, similarly to
that described in [4].

*For article 2, see [i].

Far East State University, Vladivostok 690600. Translated from Khimiya Geterotsiklich-
eskikh Soedinenii. No. i. pp. 46-52. January, 1986. Original article submitted December
26, 1984.

38 0009-3122/86/2201-0038512.50 ~ 1986 Plenum Publishing Corporation

 R R

~ ~5 .'

1 RffiH

I CetlsNHNII2 Ill V

I
NIIC,H~ IV Vl
II

\,
R R

NHC~II5 VIII a-d

VII +
R

o~ OH I
x a-d xla-d NHC~a5 [ ClO 4 -
IX'a
V~ X a R = H ; b R=CH3; c R=CeHs; d R=p.CH~O_C6H~

The structure of indoloacridine Va particularly follows from the analysis of its spec-
tral characteristics. Thus, in the mass spectrum, a peak of the molecular ion is observed
at m/z 263. In the IR spectrum, there is no absorption of the C=O and NH groups and absorp-
tion bands are observed at 1660 cm -x (C=C), while in the UV spectrum there is a long-wave
maximum at 312 nm, indicating a conjugation of the tetrahydrocarbazole ring with the C=C bond
(in the UV spectrum of tetrahydrocarbazole, a long-wave maximum is observed at 282 nm [5]).
The structure of other reaction products (VI, Vllla, IXa) was confirmed by comparison
with the corresponding standard samples (comparison of constants, spectra, mixed melting
point) [3-5].
It should be noted that the preparation of indoloacridine (Va) and its 8-R-substituted
derivatives (obtained from other alicyclic 1,5-diketones) proceeds in low yield and is im-
peded by the necessity for the chromatographic separation of the mixture of compounds ob-
tained. Another variant of the synthesis of indoloacridines that we have developed is to
some extent free of these drawbacks. It involves the use of tricyclohexanolones Xa-d as the
starting materials, which are the products of an intramolecular adolization of the corres-
ponding 1,5-diketones [8-10], During the reaction of compounds Xa-d with phenylhydrazine, we
obtained phenylhydrazones Xla-d in good yields. Heating of these compounds in concentrated
acetic acid led to the formation of indoloacridines Va-d, after which compounds Vb-d were
isolated by crystallization (Table i).
3,3'-Methylenedi(6,6-dimethyltetrahydropyran-4-one) (XII) [II] considerably differed in
its behavior in the reaction with phenylhydrazine in acetic acid from other alicyclic 1,5-
diketones. When the corresponding monophenylhydrazone XIII was treated with glacial acetic
acid at room temperature, we also obtained new heterocyclic compounds: 2,2-dimethyl-3-oxa-
4-a-(2',2'-dimethylpyran-4'~on-5'-ylmethyl)-4aH-l,2,3,4-tetrahydrocarbazole (XIV), 3,3,14,14-
tetramethy-2-xa-5a,b-(methanxyisbutane)-,2,3,4,5a,,,a-ctahydrquinindine (XV),
and 2,2,-dimethyl-3-oxa-l,2,3,4-tetrahydrocarbazole (XVI), as well as the known 3,3,6,6-tet-
ramethyl-2,7-dioxa-sym-octahydroacridine (XVII) [ii].

39
 o-"y"-~o
o
XqI

i CsHsNHNH2
lo ~'~._ 11 , 2 "~
0/'"7/~7/A" 0 H+ ,::~;"-I~" ~o,'~.~"'~..J~" o 0 / ~ - ~ - . . . . . . . "'~":.~

NItC6H5
XV XVI
Xlll

O~ -~ -.=.,.i "0

""J "~N

X",qI

Tile formation of compound XIV is explainable by the occurrence of indolization of mono-

phenylhydrazone XIII with the participation of a -CH group ~ with respect to the hydrazone
fragment. The absence in the reaction mixture of indolization products with the participa-
tion of the ~-CH= group clearly results from its being screened.
Compounds XV and XVI can be regarded as products of further transformations of carba-
zolenine XIV under the reaction conditions. 3-Oxatetrahydrocarbazole (XVI) was probably
formed by splitting a substituent from the 4a-position of compound XIV, while quinindoline
XV by the addition of NH3 to the C=N bond, followed by the closing of the six-membered ring
during the reaction of the carbonyl group and the NH2 group. It is known that indolenines
are capable of adding ammonia, amines, and phenylhydrazine at the C=N bond [12]. According
to the Fischer reaction mechanism, ammonia is liberated during the indolization of hydrazone
XIII.
We obtained confirmation for the formation of compound XV by this path by carrying out
the reaction XIV with ammonia in ethanol at room temperature. As the result, quinindoline
XI was obtained in a yield of 50%.
The structure of compound XIV is confirmed by the IR spectrum, with an absorption band
of the C=O group at 1713 cm -t. In the mass spectrum of this compound, a peak of a molecular
ion (m/z 341) and characteristic peaks of fragmentary ions with m/z 201 and 143 are present.
The latter indicate a splitting of a y-pyranonylmethyl fragment from the molecular ion, and
a molecule of acetone from the ion with m/z 201. In the PMR spectrum, signals of three iso-
lated methylene groups (AB system) and the CH=-'CH--CHa fragment were revealed by the spin-
decoupling and differential spectroscopy methods, as well as the signals of four aromatic
protons and four methyl groups. The C(~) methylene group protons appear as doublets at 4.0
and 3.11 ppm (J = 11.5 Hz). Irradiation of the signal at 4.0 ppm leads to degeneration of
the signal at 3.11 into a singlet. Similar experiments were carried out for signals of the
methylene group protons at C(t) (doublets at 3.01 and 2,69 ppmj J = 13.0 Hz) and at C(s)
(doublets at 2.28 and 2.10 ppm, J = 13.5 Hz). The CH=--CH--CH= fragment is revealed as a four-
proton multiplet at 3.25 ppm and one-proton multiplet at 1.55 ppm.
In the IR spectrum of quinindoline XV, there are absorption bands of NH and C=N groups
at 3370 and 1660 cm-t. In the mass spectrum, a peak of the molecular ion is observed with
m/z 340.
In the t3C NMR spectrum, in the absorption region of the aromatic carbon atoms (ii0-
128 ppm), there are four signals giving doublets under the off-resonance conditions. This
indicates the presence of a disubstituted phenyl ring in compound XV. Two other signals of
this ring are displayed as signlets at 130~0 and 164.4 ppm. The shift of one of these sig-
nals into a weak field shows that the'carbon atom is bound to the hetero atom. The signal
at 148.7 ppm (s) confirms the presence of the C=N fragment in the quinindoline structure.
The three singlet signals (72.7, 74.8, 80.5 ppm) indicate the presence of a further three
quaternary carbon atoms (C(3), C ( ~ ) , C(tsa)), having a hereto atom as one of the substitu-
ents. The signal at 42.2 ppm is characteristic of a quaternary alkyl-substituted carbon
atom (C(1ob)). In the spectrum, signals of carbon atoms belonging to four methyl groups

40
TABLE i. Characteristics of Phenylhydrazones of 8-R-Tricyclo(7.3.1.0a'7)tridecan-2-ol-13-ones (Xla-d) and 8-R-7aH-5,
6,7,8,9,10,11,12-Octahydroindolo[3.2.l-d, d,e]acridines (Va d)
UV spectrum '" Calculated
Foun~
Compound~ Mp~ ~ IR spectrtun, cm- i %"max( log Empirical formula [ !
c,% H,% N,% M c,% [ H,% N,%

132---133 1650 (C=N), 3000, 3342 (NH, OH) * 67,85 7 , 9 8 8,17 CmH26N~O"HCI 68.10 J 7,77 8,37 63
Hydrochloride XI~
several peaks 70
153--154 ]655 (C=~N), 3000--3400 (NH, OH) $, 68,60 8,30 7,83 CuoH28N~O"HCI 68.86 I 8,33 8,03
Hydrochleride XII
several Desks 80,20 I 8,0 7,40 374 78
XI c 158--159 1602 (C=N), 3330 (NH), 3600 (OH) i 80,0 8,40 7,90 I 374 C25H~oN~O
XId 159--160 1602 (C=N), 3440 (NH), 3580 (OH) 77,11 7,92 6,73 Z 404 C27I-I~N202 77.20 J 7,70 6,90 404 41
Va 1660 (C=C) 312 (4,24) 87,30 7,79 5,40 263 CtgH21N 87.60 ] 7,98 5,32 263 7(15)
Vb 99--100 1~0 (C=C) 314 (3,90) 86,92t 8,90 5,15 277 C20H=3N 86,60 [ 8,30 5,10 277 ;5
V c 160--161 165o (c=c) 318 (4,40) 88,06 7,62 4.10 339 C2sH=sN 88,5 [ 7,38 4,12 333 40
Vd 195--196 1655 (c=c) 318 (4,40) 84,78 7.75 3,75 369 C26H~zNO 84,55 [ 7,30 3,80 369 25

*V, Xla, R = H; b R = CHs; c R = C6H5; d R = p-CH30-C6H..

+The compounds were crystallized: Xla from a 1:3 ethanol--ethyl acetate mixture, Xlb from a 1:4 ethanol-ethyl acetate
mixture, Xlc, d from methanol, Vb, c from ethanol, Vd from ethyl acetate.
~The spectra were run in mineral oii.
~,4~ 23~5, 30.5~ ~ , 6 ppm) and live metilylene groups ~23.5, 42.5, 48.1, 66.4, 69.3 ppm)
are also observed.
In the PMR spectrum of compound XV, signals are observed of protons of four methyl
groups (1.16, 1.25, 1.29, 1.49 ppm), four protons of a disubstituted benzene ring,.6.7-7.1
ppm#, and a signal of an NH group proton (which disappears during a deutero exchange) at
4.37 ppm. The presence of three isolated methylene groups (at the 4, 12, 15-positions) was
revealed by double resonance. For the corresponding AB systems, the following chemical
shifts and SSCC were found: C~ (2H) A part 2.15, B 2.03 ppm (J = 13.5 Hz); C12 (2H) A 2.57,
B 3.37 ppm (J = 12.5 Hz); C:5 (2H) A 1.4, B 2.13 ppm (J = 14.5 Hz). There is also a CH2-CH--
CH2 fragment. The only nonaromatic methine proton is displayed as a multiplet at 2.38 ppm.
It interacts with two methylene groups. One of them at C ~ (2H) is represented by a doublet
of doublets at 1.83 ppm (J = 14; ii Hz) and a broadened doublet at 2.03 ppm (J = 14 Hz),
while the other at C= (2H) is in the form of a doublet of doublets at 3.95 ppm (J = 11.3;
7.5 Hz) and a broadened doublet at 3.46 ppm (J = 11.3 Hz).
The structure of 2,2'dimethyl-3-oxa-l,2,3,4-tetrahydrocarbazole (XVI) was confirmed by
elemental analysis, mass spectrum [a molecular ion is observed at m/z 201 and a fragmentary
ion at m/z 143, due to splitting of (CHs)2CO] and by IR spectrum (3473 cm -~, the NH group).

EXPERIMENTAL
The course of the reaction and the identification of individual compounds were control-
led by the TLC method [Silufol UV-254; petroleum ether-ethyl acetate 5:2 (system i, the spots
on the chromatograms were developed by iodine vapors]. The preparative TLC was carried on
plates (20 > 35 cm) with nonstationary A1203 layer (grade II of activity) in a i0:i petroleum
ether--ethyl acetate mixture (system 2) and in a 5-1 heptane--ethyl acetate mixture (system 3).
The IR spectra were obtained on a Specord IR-75 spectrophotometer (in CHCI3), the NMR
spectra (in CDCI3) on spectrometers Bruker WH-250 for IH, Bruker HX-90-E for 13C, at 250 and
22.63 MHz, respectively. The chemical shifts are given with reference to TMS. The mass spec-
tra were determined on LKV 9000 mass spectrometer at 70 eV, and the UV spectra on Specord UV-
vis in methanol.
The initial 1,5-diketones I, XII and ketones Xa-d were obtained by methods described in
[8-11, 13], respectively.
The characteristics of compounds Va-d and XIa-d are listed in Table i.
Reaction of Methylene-2,2'~Dicyclohexanone (I) with Phenylhydrazine~ A__~. A 5.18 g (48
mmole) portion of phenylhydrazine is added to a solution of i0 g (48 mmoles) of diketone I
in i00 ml of glacial acetic acid. The mixture heats up to 60~ and is left to stand for
24 h at room temperature. It is then diluted by 150 ml of water, and the oil that separates
is extracted by ether (3 30 ml). The extract is washed with water (2 30 ml) and a NA~C03
solution to a neutral reaction. The aqueous layer and the wash waters are combined. The
ether extract is dried over MgSO~, and evaporated to yield 3.2 g of reaction products. The
mixture is separated by preparative TLC in system 3. From the zone with Rf 0.74, 0.88 g (7%)
2O
of 7aH-5,6,7,8,9,10,11,12-octahydroindolo[3,2,l-d,3]acridine (Va), bp 167-1700C (i mm), n D
1.6319, is obtained.
From the zone with Rf 0.40, 0.58 g (7%) of tetrahydrocarbazole (VI), mp I14-I160C is iso-
lated; according to the data in [5], mp I15-I16~
The aqueous solution is made alkaline with potassium carbonate to pH 9. The oil that
separated is extracted by ether (3 25 ml). The extract is dried over MgSO~, the solvent
is distilled off to yield 6.5 g of a mixture of products, which are separated by distillation
2O
in vacuo. Two fractions are c o l l e c t e d : the first, aniline, i.I g, bp 48-500C (10 mm), n D
1.5863; the second, sym-octahydroacridine, 4.1 g, 46%, bp 151-153~ (5 mm), mp 72-73=C (pet-
roleum ether), according to the data in [3], mp 74~
B__~. A mixture of 6.2 g (30 mmoles) of diketone I and 4.3 g (30 mmoles) of phenylhydra-
zinc hydrochloride in 25 ml of dry dioxane is boiled for 6 h. When cool, the NH~CI precipi-
tate is filtered. Dioxane is evaporated, and the residue is dissolved in ether. The ether
solution is washed with a dilute hydrochloric acid, 1:3 (2 20 ml), and water to neutral
reaction. The aqueous layer is combined with wash waters (aqueous solution i). The ether
extract is dried over MgSO4 and ether is distilled to yield 2.3 g of a mixture of compounds
in the form of a partially crystallized mass. A 20 ml portion of petroleum is added, and

42
crystals of compound Vl are filtered, mp i15-i16~ From the filtrate, 0.3 g (3%) of indo-
loacridine Va and in addition, 0.2 g (3%) of tetrahydrocarbazole VI are obtained by prepara-
tive TLC.
The aqueous solution of I is made alkaline with sodium carbonate to pH 9. The oil that
is obtained is extracted by ether and separated from the equeous layer (aqueous solution 2).
The extract is evaporated to yield 3.5 g of a mixture of products, from which 2.2 g (40%) of
acridine Villa and 0.5 g of aniline are obtained, as described under A. Ammonium perchlor-
ate is added to aqueous solution 2, and the precipitate of N-phenyloctahydroacridinium per-
chlorate IXa is filtered. Yield l.l g (i0%), mp 198-199~ (from ethanol); according to the
data in [4], mp 199-200~
C. A 2 g portion of polyphosphoric acid is added to 2.08 g (i0 mmoles) of 2.08 g (i0
mmoles) of diketone I in l0 ml of absolute dioxane. A solution of 1.08 g (i0 mmoles) of
phenylhydrazine in 6 ml of dioxane is added, with stirring, to this mixture, which is then
stirred at room temperature for 6 h. Dioxane is evaporated, 50 ml of water are added to the
residue, and the oil is extracted by ether. From the extract, indoloacridine Va (0.13 g, 5%)
and tetrahydrocarbazole VI (0.2 g, 14%) are isolated, as described under A. From the aqueous
solution, compounds Villa (0.7 g, 35%) and IXa (0.2g, 5%) were isolated.
Phenylhydrazones of 8-R-Tricyclo(7.3.1.0217)tridecan-2-ol-13-ones (IXa-d). A 4.3 g (40
mmole) portion of phenylhydrazine is added to 40 mmoles of the corresponding ketone Xa-d in
150 ml of absolute benzene. The reaction mixture is boiled in a flask fitted with a Dean--
Stark trap up to the end of separation of water (5 h). Benzene is evaporated, and the resi-
due obtained in the form of a glass-like mass, crystallized under ethanol only in the case
of Xlc,d. Hydrazones Xla,b could not be crystallized and they were obtained as hydrochlor-
ides.
Transformation of Phenylhydrazones of 8-R-Tricyclo(7.3.1.0='7)tridecan-2-ol-13-ones
(Xla-d) by the Action of CH3COOH and Polyphosphoric Acid. A. A 20 g portion of polyphos-
phoric acid is added to 6.6 g (20 n~noles) of hydrochloride of phenylhydrazone Xla. The re-
action mixture is heated on a boiling water bath for 2 h, then cooled, and poured into 50 ml
of H20. The oil is extracted by ether (3 x 30 ml), the extract is washed with water to neu-
tral reaction, dried, and evaporated to yield 2.5 g of an oily product. From this product,
0.82 g (15%) of indoloacridine Va and l.l g (30%) of tetrahydrocarbazole VI are isolated by
preparative TLC. From the aqueous solution, I g (27%) of acridine Villa and 0.4 g (10%) of
acridinium salt IXa are isolated in a similar way as described above.
B_~. A corresponding phenylhydrazone Xlb-d (30 mmoles) is heated in CH3COOH for 2 h.
The hydrazone thus dissolves and a new crystalline precipitate separates. The mixture is
cooled, the precipitate is filtered, washed on the filter with CH3COOH (2 5 ml) and alco-
hol, and dried to yield indoloacridines Vb-d.
The mother liquor from the isolation of compounds Vb-d is neutralized with sodium car-
bonate to pH 7. The oily products are extracted by ether. After evaporation of ether, the
residue is separated by preparative TLC. Additional amounts of indoloacridine Vb-d and tet-
rahydrocarbazole VI (10-15%) are thus isolated. The aqueous layer is made alkaline with sod-
ium carbonate to pH 9 to give the corresponding acridines: 9-methyl-sym-octahydroacridine
(Vlllb 20%, 9-phenyl-sum-octahydroacridine (Vlllc) 22%, and 9-p-methoxyphenyl-sum-octahydro-
acridine (Vllld) 20%. Acridines Vlllb,c were identified by direct comparison with the cor-
responding samples [3]. Acridine Vllld has been prepared by us for the first time, mp 230-
231~ (from ethanol). IR spectrum: 1580, 1608 cm -I (vibrations of the aromatic ring).
Found: C 81.83; H 7.68; N 4.90%. M 293. C2oH23NO. Calculated: C 81.90; H 7.80; N 4.70%;
M 293.
3,3-Methylenedi(6,6-dimethyltetrahydropyran-4-one)monophenylhydrazone (XIII). A 16.1 g
(60 mmole) portion of diketone XII is dissolved in 40 ml of ethanol with heating and 6.5 g
(60 mmoles) of phenylhydrazine in 30 ml of ethanol are added to this solution in the course
of 2 h. The reaction mixture is heated for another hour, and left to stand at room tempera-
ture for 18 h. The precipitate is filtered, washed with ethanol (2 20 ml), and dried.
Yield, 4.3 g (20%) of hydrazone XIII, mp 142-143~ (from ethanol). IR spectrum~ 1705 (C=O),
3315 cm -I (NH). Found: C 69.97; H 8.41; N 7.73%; M 358. C21H3oN203. Calculated: C 70.39;
H 8.39; N 7.82%; M 358.
Transformation of 3,3'-Methylenedi(6,6-Dimethyltetrahydropyran-4-one)monophenylhydrazone
(XIII) by the Action of CH3COOH. A 7.16 g (20 mmole) portion of hydrazone XIII is dissolved

43
in JO mi of CH~CO{~H~ The reaction mixture is left to stand for 24 h, and then is diluted
by an equal volume of water, and neutralized by a Na=COs solution to pH 7. The reaction
products that separate are extracted by diethyl ~ther (4 50 ml). The extract is dried
over MgSO~, the ether is evaporated, and 30 ml of ethanol are added to the residue weighing
7 g. The precipitate is filtered to yield 1.8 g (26%) of quinindoline XV, mp. 174-176~
IR spectrum: 1660 (C=N), 3380 cm -~ (N--H). Found: C 74.27; H 8.47; N 8.21%; M 340. C2~H2s-
N=O2. Calculated: C 74.11; H 8.23; N 8.23%; M 340. The compounds remaining in the mother
liquor after the isolation of quinindoline XV, are separated by column chromatography: 5 g
of the mixture separated on a column (42 2.5 cm) with 300 g of silica gel 40/100 ;i. A
gradual elution is used (systems: petroleum ether--ethyl acetate, 6:1.3, 3:1, i:!, 0:I, 500
ml in each case and fractions of 50 ml are collected. The following compounds are isolated:
3-oxatetrahydrocarbazole (XVI) [0.56 g (14%), mp 150-160~ (petroleum ether). IR spectrum:
3473 cm -: (NH). Found: C 77.32; H 7.26; N 7.01%; M 201. CIsHIsNO. Calculated: C 77.61;
H 7.16; N 6.96%; M 201], 2,2-dimethyl-4a-(2',2'-dimethyltetrahydropyran-4'-on-5'-ylmethylo-
3-oxa-4~H-l,2,3,4-tetrahydrocarbazole (XIV) [0.8 g (12%), mp 161-1620C (ethanol). IR spec-
trum: 1713 cm -~ (C=O). Found: C 73.70; H 8.10; N 4.25%; M 341. C2~H=TNO3. Calculated:
C 73.90; H 7.91; N 4.10%; M 341], and 3,3,6,6-tetramethyl-2,7-dioxa-sym-octahydroacridine
(XVIII) [0.6 g (11%), mp I19-120~ (from petroleum ether), according to the data in [ii],
mp I18~ (from water)].
Preparation of Quinindoline XV from Compound XIV by the Action of Ammonia. A 2 ml por-
tion of 25% NH~OH is added to a solution of 0.7 g (2 mmoles) of compound XIV in I0 ml of
ethanol. The mixture is left to stand at room temperature for 5 h, then evaporated to half
its volume, and the precipitate that separates is filtered to yield 0.35 g (50%) of quinin-
doline XV, which was identified from TLC, IR spectrum and melting point of a previously iso-
lated sample.

LITERATURE CITED
i. T. 9. Moskovkina and M. N. Tilichenko, Khim. Geterotsikl. Soedin., No. 6, 821 (1983).
2. M. N. Tilichenko and T. V. Moskovkina, Khim. Geterotsikl. Soedin., No. 5, 645 (1976).
3. N. S. Berbulesku, G. Beditse, and M. N. Tilichenko, Zh. Obshch. Khim., 33, 645 (1963).
4. V. I. Vysotskii and M. N. Tilichenko, Khim. Geterotsikl. Soedin., No. 3, 376 (1971).
5. A. N. Kost, L. G. Yudin and Y. Ch'iu, Zh. Obshch. Khim., 34, 3444 (1964).
6. I. I. Grandberg, A. N. Kost, and L. S. Yaguzhinskii, Zh. Obshch. Khim., 30, 3108 (1960).
7. T. V. Moskovkina, V. A. Kaminskii, V. I. Vysotskii, and M. N. Tilichenko, Khim. Geter-
otsikl. Soedin., No. 6, 826 (1973).
8. M. N. Tilichenko, in: Yearbook of Saratov University [in Russian] (1954), p. 500.
9. V. Barbulescu, Rev. Chim., ~, 45 (1956).
i0. V. I. Vysotskii, N. V. Vershinina, and M. N. Tilichenko, Khim. Geterotsikl. Soedin.,
No. 7, 898 (1975).
li. M. N. Tilichenko, Izv. Vyssh. Uch. Zav., Khim. Khim. Teknol., ~, 96 (1961).
12. Heterocyclic Compounds [Russian translation], Vol. 3, R. Elderfield (ed.), Izd-vo Inostr.
Lit., Moscow (1954), p. 80.
13. M. N. Tilichenko and T. I. Akimova, Zh. Org. Khim., ~, 976 (1970).

44
SYNTHESIS OF DERIVATIVES OF 4-1MINO-2-AMINO-2-1MIDAZOLINE.
NEW EXAMPLE OF A MULTICOMPONENT CONDENSATION INVOLVING ISONITRILES

A. I. Polyakov, L. A. Medvedeva, O. A. D'yachenko, UDC 547.239'233.1'783'

A. B. Zolotoi, and L. O. Atovmyan 789.1:543.422'51

!sonitriles have been found to react with ketones and ammonium and methylammonium
thiocyanates in methanol or ethyleneglycol at 20~ to form derivatives of 4-imino-
2-amino-2-imidazoline and 2,4-diaminoimidazolium salts.

Ugi [i] has shown the possibility of preparing 2-thiohydantoin-4-imines by the conden-
sation of amines I and ketones II with isonitriles III and thiocyanic acid by the scheme

+
RIMH2 + R2-C0-R ~ + R4-N~C + I|SCN ~ ~ R v - N H .-C(RZR3)--C=~N'-R4 ] -~-------a"
I II If! IV NC3- -J
-- R 1 ~. /.R2

L ~CZ S~%'-N-"~N_LR~
H
VI

Upon using this reaction for the preparation of hydantoins VI with Rx = H and CH3j we
found an unusual multicomponent condensation leading to imidazole derivatives VII and VIII,
which were more complex than previously assumed [2].

I R2"C/R~ A IRZ" C ~'I~3

"'N" "CS-NH-R ~, R--.N/ -.CS_NI~R4
\ \
I + II + III + H$CN c-~ Ncs- _ =. f_--N
9 /! \\ - mCN
T '
J'"C / "NH E "r 1 .-*'N'-.c/C~.~. / R4
I R ~"/ \R 3 - R R2/-..R 3 ..--

VIIa-k vm a-k

The condensation products are, as a rule, imidazolium salts Vll, have strong IR bands
for the S-CEN group at 2030-2080 cm-* and give a positive test for the thiocyanate ion with
FeC13 solution.
Compounds such as VIIa and VIIe formed from acetone, p-tolylisonitrile and benzylisoni-
trile contain two molecules of bound HSCN, apparently as a result of the reaction 2 VII +
VII.HSCN + VIII. This is supported by the elemental analysis and IR spectral data (Table i).
The site of the addition of the second HSCN molecule could not be determined but is most
likely N(2) of the imidazole ring.
Imidazole derivatives VII and VIII are readily interconverted upon the corresponding
change in solution pH. Their structures were established finally only by x-ray diffraction
structural analysis. The x-ray diffraction structural data for model compounds VIIi and VIIIe
are given in Fig. 1 and in the Experimental.
Since the conditions for the reaction studied are identical to those for a well-investi-
gated four-component condensation, we assume, that differences in the reaction mechanism be-
tween them may arise only in the step involving stabilization of intermediates IV and V. As-
suming the formation of aziridinimine IX as an intermediate, the preparation of VII and VIII
may, in our opinion he explained by the following scheme:

#
All-Union Scientific-Research Institute for Chemical Means for the Protection of Plants,
Moscow 109088. Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow 117334.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 53-61, January, 1986. Ori-
ginal article submitted August 7, 1984; revision submitted January 22, 1985.

0009-3122/86/2201-0045512.50 9 1986 Plenum Publishing Corporation 45

 | }~', Nc:~" ' : R' ../C.,.~--R
W,V
9" ' " ' : ' " , >'--%_,: ,, : - '~%._,,. I'/:-~
SCN
IX

R ~ ,. ,,R'~ ,, " R2NI "r R~

" (: '' R ' "'~:/ rN__.~ ~' I
R*N,..C,C.;N L e~r I '-N" c r.'

_M//C ......S I I
.,C, N--R t ,<C .N r 1
X R'--N "/ "C~., --N;, :C..R, '

XI XI!

+H+ +IlSCN
.....
~ VIII ------~"

The reaction of thiazolidine X with IV or V may be presented analogously to the forma-

tion of VII and VIII.
The rate of consumption of X in the abovementioned reactions is apparently rather high
and, as a result, the corresponding 2,5-dilmino-l,3-thiazolidines are not found among the
products.
Thus, the key compound controlling the condensation is aziridinimine IX. Conformations
of the reaction site close to eclipsed must precede the formation of both IX and VI from in-
termediate IV or V. These conformations for IV and V may be represented along the C--N bond
as follows,

R I R2 R ~ R2
I ,
.... J_:: .L~

:~.::,jz r, c, C-: R
R4 / NR4 ,
IV V

The steric hindrance which is important for realization of the conformation leading to
the formation of aziridinimine IX is minimal for R* = H and CH3. Thus, the steric factor
apparently determines the nature of the reaction such that multicomponent condensation is
found upon slight repulsion between R*, R 2 and R 3, while four-component condensation is found
in the case of strong repulsion of these substituents.
The IR spectra of all imidazolium salts VII and imino-2-imidazolines VIII taken in KBr
pellets are in full accord with the x-ray diffraction structural data. An increase in the
intensity of the C=N band at 1620-1660 cm-* by almost a factor of 2 in going from VII to VIII
is characteristic for the IR spectra of these compounds. T h i s increase is probably a conse-
quence of the extension of the conjugation chain involving the two azomethlne groups.
This conclusion is in accord with the x-ray diffraction structural data. The delocali-
zation of the ~-electron density leads to the levelling out of the lengths of the C-N double
and single bonds (Fig. i).
The bond lengths found indicate a definite contribution, for example, of the following
resonance forms of imidazolium salts VII:

I
---NIl / ----" [ tl / "----" t I_ +/
N_ ~---N --N N --- " --

VIIa %'II b ~Ic

Special interest is found in the results of the spectral studies of solutions of these
two groups of compounds (Tables 1 and 2). This is related, especially for iminoimidazolines
VIII, to the expectation of a tautomeric equilibrium involving at least two forms; thioamide
(A) and thiolimide (B). The formation of tautomer VIIIB, although this form was not found
in the usual state for thioamides [3], might have been expected due to the possible stabili-
zation of the thiol form by the nitrogen atoms of the guanidine group.

46
 c :J it~ 84

$7 CI22)
C(23)

%
Vllle
Vllj " 9 $12 )

Fig. i. Structure of the products of the multicomponent condensation, imidazolium salt

Vllj and imino-2-imidazoline Vllle.

According to the spectral data, derivatives Vll in media of different polarity such as
CHCI3 and DMSO are virtually in a single tautomeric form A, containing an NH group in either
the free or bound state. The IR spectra of solutions of salts VII in CHCI3 do not contain
a band characteristic for the SH group.
We should note the absence of coupling of the NH-CH3 group protons in the PMR spectra
of Vlla, c, h-j, which indicates that the azomethine group nitrogen atom is also protonated
in solution.
The spectral data for iminoimidazolines VIII are rather complex in nature. Thus, the
IR spectra of Vllle, f, h, j in CHCI3 show weak bands for a bound SH group at 2400-2600 cm -~,
signals for a free NH group at 3440-3490 cm -I and lack the absorption characteristic for a
bound NH group.
Some support for the equilibrium proposed above for solutions of VIII was obtained in
the ~3C NMR spectrum of VIlli. In addition to the signals for the carbon atoms of the thio-
amide, guanidine and amidine groups at 203.9 and 170.2 (double signal), in contrast to salt
VIIi, there is a broad signal at 140.2 ppm for the base, which is apparently a result of the
overla p of the signal for the thiolimide group S - - ~ bond and of the aromatic carbon atoms.
To support this assignment, we studied the possibility of the synthesis of a model compound
with fixed tautomeric structure B. On the basis of elemental analysis and PMR spectral data,
the iodomethylate obtained from VIlli is a monoalkylated compound whose *SC NMR spectrum
lacks a thioamide group signal. Thee these findings indicate that reaction according to the
scheme

~C(S)NH_CH2C6H 5 - - -Cliff
-.~ ---C = N ~ - C H ~ s H s
I 'HI
~II j ~CH~

The s p e c t r u m h a s a s i g n a l a t 1 4 5 . 4 ppm a s s i g n e d t o t h e t h i o l i m i d e g r o u p . The somewhat

u p f i e l d s h i f t o f t h i s s i g n a l i s due t o t h e s a l t c h a r a c t e r o f t h i s compound.
The iodomethylate thereby obtained has a structure analogous to imidazolium salts VII.
As in compounds such as VII, it contains two similar NH--CH2 group doublets in the PMR spect-
rum (see Experimental) and two C=N bond signals in the ~3C NMR spectrum.

47
 ~1 I~1 I~1 ~~1~ i a~l
I I l,.,c~,.

zzzzzz~zzzz~zzz~z

~1 ~ I I~ ~ ~

,..M
I
I-4
I-4
I-4
:>

'1:1
Itl
.M
I
i-4
I-4 ~1 I I I I~1. I I I
:> r~

I.i
0
1.1-1

ol-4 .co
"el .co 00 r./3

I-.I o~c~ o~o ~ o o c~ ~ o

o
,-4
Itl

m
4.1

0 o
.r.t

48
 TABLE 2. PMR Spectra of Vll and Vlll

Compound Chemical shift, 6, ppm

VII a 1,31; 1,44; 1,62; 1,65 (4 4 s, CHs); 2.28~ 2,49 (d2 9s, Ar--CHs);
3,10 (6H, b r . s N--CH3); 6,97:7,13 (2 2 ,, C~'H~); 9,01; 10,28
(NH, b r . s )
VIII a 0,48; 1,24 (2 2 s, CHz); 1,44 (6H, b r . s CH3); 2,14; 2,36 (2
2 a N--CH3); 2,21 (6H, b r . s . Ar--CHs); 7,14 (8H, m, C6H~); 8,48 (NH,
br.s )
VII r 1,69 (20H, m-, cyclo-C6Hlo); 2,25 (6H, b r . s , Ar--CHz); 7,39 (8H, ra
C6H4); 7,87; 9,41; 10,90 (NH,b r . s j
VII h A t 250 Mtlz 1,43--2,26 (20H, M, cyclo-C~,H,o); 4,40; 4,75 {2X2H, 2 d.
CH_~N); 7,18; 7,27 (10H, m, CnH~); 7,80; 9,16; 10,05 (NH, b r . s )
VIII h ( At 250MHz ) 1.05--1.84 (20H. m, cyclo-C.H,o); 4,45; b4~ys(2X2H, 2 d,
CH=N); 7,21; 7,28 (10H, m C6H5)_; 6,32; 8,19; 9,56 (NH, )
VII i 1,91 (16H, m cyclo-CsH~); 3,13; 3,22 (2 2 s CH~--N); 4,36 (2tt, br.s.
, CH~--N); 4,73 (2H, d, CH.~--N); 7,15; 7,24 (2 2 s, C~Hs); 9,72;
10,02 (NH, b r . s )
V i l l i . {~(CDs)?CO] 1,72 (16H, n~ cyclo-CsHs);The NCBa :signals f a l l i n the region
of the solvent siBnals4,25; 4,33 (2}t, 2 d CH2N)j 4,42; 4,67 (2H. 2 s,
CHIN); 7,17 {10H, br.s CoHs);6.15;9,26 (NH, ~
v i i J 1,48--2,06 (20H,m. cyclo-C6H,o): 3,07; 3,26 (2X3H, 2 s, CHIN); 4,27 (2H,
b r . d . CH.~N); 4,70 (2H, d, CH.~N); 7,21 (10H, b r . s . C~Hs); 7,75; 9,72
(NH, or-s_L
ibr.d250 MHZ ) 1,13--2,41 (20H, r~ cyclo-CsH,o); 3,17; 3,32 (2 2s,
CH~--N); 4,37 (2H, br.d CH2N); 4,82 (2H, d, CH2N); 7,04--7,20 (10H,
m C6Hs); 9,68; 9,83 (NH, br. t )
(,HCL s a l t , 80~ 1,12~1,92 (20H, m cgclo-C~H~o); 3,07; 3,26 (2 s,
CHIN); 4,26 (2H, b r . d , CH2N); 4,70 (2H, d CH2N); 7,19 (10H, m,
C~H~); 9,96; 10,4 (NH b~.s )
VIII 1,61 (20H, m. cyclo-C~H,o); 1,88; 2,06 (2 2 sCHzN); 4,21; 4,27 (2>(2H,
2inCH~N); 7,12; 7,17 (10H, 2 s C6H~); 8,53 (NH, b r . s )
[in(CD~)~CO] 1,65 (20H, m cyclo-C6H,o); The NCHa s i g n a l s f a l l i n the
,~egionofLhesolventsignals4.77,;4,35 (2H, 2 d CH.~N); 4,50; 4,76 (2H,
2S, CHIN); 7,12; 7,16 (10H, 2s, C~H~); 8,62 (NH, b r . s )

The PMR spectra of solutions of Vlllg and VIlli in DMSO-d6 show a significant downfield
shift of the N--H and N-CH3 group signals in comparison with Vllg and VIIi. This difference
is attributed to the lack of the deshielding effect of the positive charge of the quanidine
fragment upon going to the free base. The broadening of the NH signals in the PMR spectra
of these compounds is also more pronounced relative to the salts, which complicates the de-
tection of the thiolimide group.
Imidazolidines VIII are stable upon heating, but gradually decompose upon heating at
reflux in water-ethanol solutions of KOH with~;the release of H=S and formation of unidenti-
fied compounds.
Upon brief heating at reflux in benzene or toluene, salt VII is converted to thiazoli-
dine XIII. On the whole, we propose the following scheme for this reaction:

I R2 ~ ~R:N--F.4

[ R~ /~ xN--R
VII ~ - Till --.,-e=,.- lq__,!. SI][ --r { {
I { R' -N-~ b,q' : R nN*"
+zC N~ 1 " -

H -S -C-=N

The conversion of VII to 2 XIII in the case of R ~ = p-CH3C6Ha proceeds more rapidly
than in the case of R 4 = CH=C6Hs. Thus, one of the steps of this conversion presumably in-
volves the thiolimide form, whose formation is especially facilitated in the case of R ~ =
p-CHsC6H4 by the conjugation of the aromatic ring electrons with the C----Nbond.
Pseudoanalogs of thiazolidinimines XIII, namely, iminothiohydantoins VI, were not found
among the reaction products.
A mass spectrometric study of Vlllh-j and Xllla showed that Villi and VIlli do not give
molecular ion peaks, even at 15 eV, while the (M + i) peak is present in these spectra. On

49
the other hand, the presence of peaks for the (M -- C2H4) and (M -- C2Hs) ions (487 and 486
for VIlli and 459 and 458 for Villi) in these spectra indicates their molecular mass (515
for VIlli and 487 for Villi) in accord with the structures p~oposed for these compounds on
the basis of the above results.
As expected, the mass spectra of these compounds have ion peaks* 91 (C6HbCH2 +) while
the (M + i) peaks are 3"5 times stronger at 15 eV than at 70 eV. In addition, Villi and
VIlli give strong peaks for ions 272 and 286 , which apparently, are formed as a result of
M -- [CH3--N-C(CH2)n-C-NHCH~C6Hb], where n = 4 and 5, respectively, for Vllli and VIlli. The
mass spectrum of Vlllh, in contrast to VIlli , contains not only an M+ peak (487) but also a
greater number of strong peaks for ions with high mass numbers. The effect of structure of
these similar compounds on the mass spectral intensity distribution clearly requires a sepa-
rate discussion.

EXPERIMENTAL
The IR spectra were taken on a Perkin-Elmer 457 spectrometer in KBr pellets and CHCIs
and CCI~ solutions. The PMR and '3C NMR spectra were taken on Bruker HX-90E (90MHz), Varian,
and WM-250 (250 MHz) spectrometers for solutions in (CDs)2SO with TMS as the internal stand-
ard. The mass spectra were taken on an LKB-2091 mass spectrometer at 70 eV.
The reaction course and compound purities were monitored by thin-layer chromatography
on Silufol UV-254 plates in 1:5 acetone--benzene and 1:2 acetone-hexane solvent systems.
The isoitriles were obtained according to ~gi [i]. The x-ray diffraction structural an-
alyses were carried out for monocrystals of Vllj and Vllle. The major crystallographic data
for Vllj, C32H~N6S2, M = 574.54 are a = 14.899(5), b = 18.875(8), c = 12.247(3) A, a = 90,
8 = 90, y = 65.23(2) ~ , V = 3127.22 ~3, deal c = 1.22 g/cm s, z = 4, space group P2,/b. The
major crystall~graphic data for Vllle, Cs,H4,NsS, M = 515.76 are a = 10.743(5), b = 11.185(6),
c = 12.052(3) A, a = 79.98(4), 8 = 80.88(3), y = 89.62(4) ~ V = 1407.77 ~a, d c a l c = 1.22 g/
cm ~, z = 2, space group PI. Sets of 2846 reflections for VIIi and 2914 reflections for Vllle
with I > 2o were measured on DAR-UM (for VIIi) and Syntex P1 (for Vllle) diffractometers. Ab-
sorption was not taken into account.
The structures were determined by the direct method according to Andrianov et al. [4].
The hydrogen atoms were localized from the R maps. The refinement was carried out by the
method of least squares in the full-ma~rixapproximation according to Andrianov et al. [4]
assuming anisotropy for the S, N, and C atoms and isotropy for the hydrogen atoms to R =
0.056-0.055. Molecular representations were obtained using the ELLIDS program [5].
Structural parameters for the hydrogen bonds: VIIi, bond lengths: N(4)...H(,)2.04 (3);
N(~)...N(~) 2.891 (3); N(,)...H(5) 1.93 (4); N(,)...N(,) 2.814 (4) ~; angle N(~)H(,)N(,) 156
(3), C(,)N(~)H(,) 99.3 (9),-C(~7)N(~)H(~) 146.7 (8), N(,)H(5)N(,) 146 (3), C(,,)N(,)H(,) 161
(i)~ VlIIe, N(~)...H(,) 1.92 (3);oN(4)...N(*) 2.809 (3); N(~)H(,)N(,) 160 (3); C(,)N(4)H(,)
103.7 (9); C(,7)N(4)H(,) 146.3 (9) 9 VII, Vlla, d-f, i-k R* = CH,, b, c, g, h R* = H; a, f
R 2 + R a = 2CH3, b, d, g, i R = + R a = (CH,)~, c, e, h, j, k R 2 + R = = (CH=)s, a-e R 4 = p-CH,-
C,H~, f-j R ~ = C6HbCH2, k R ~ = C2H,O,CCH2.
2-4-Diaminoimidazolium Derivatives Vlla, d-f, i-k. A sample of 0.01 mole isonitrile was
added dropwise with stirring to an equimolar mixture of 0.01 mole ketone, CHsNHa,HCl + KSCN
(NH~SCN was ~sed in the case of VIlb, c, g, h) in 8 ml ethyleneglycol or methanol at 20~
The reaction mixture was stirred for 6 h and left overnight to yield a single, chromatograph-
ically-pure product as lightly colored crystals, which were washed with hexane and dried. In
the preparation of VIld, the reaction mixture contained VIlld, which was isolated upon evap-
oration of the solution and lwashing of the residue with water (0.8 g).
The condensation with acetone and p-tolylisonitrile has several special features: only
Villa is formed in ethyleneglycol while both VIIa and VlIla are obtained in methanol. In the
latter case, 0.65 g VllIa in the precipitate was filtered off and VIIa was obtained by pre-
cipitation from water. This precipitate was extracted with three 20 ml portions of chloro-
form and the extract was dried over MgSO~. The solvent was evaporated and the precipitate
was filtered off and dried with 5 ml acetone and then hexane to yield 1.46 g (53%) Vlla. By
analogy, 1.53 g (55%) Vllf and 0.7 g VIllf were obtained in the reaction with benzylisonit-
rile in methanol.
9Here and subsequently, the ion peaks are given in units of m/z.

50
 These compounds are insoluble in water, benzene, ether, and most organic solvents but
are partially soluble in acetone, CHCI3, dimethylsulfoxide, and DMF. 13C NMR spectrum of
Vllj: 204.3 (C=S), 181.3 (guanidine C=N), 170.0 (amidine (C=N), 130.3 (SCN), 137.1, 136.8,
128.5, 128.2, 127.4, 126.9 (C6H5), 72,9, 72.0 (Cspiro), 48.7, 46.3 (N--CH2C6H~), 37.9, 36.8
(N--CH3), 34.7, 33.0, 24.6, 22.7, 21.9, 20.4 (cyclo-C~H1o).
2-Amino-4-imino-2-imidazoline Derivatives (Vllla-k (Table i). A sample of i0 ml 0.015
mmole 10% aqueous NaOH was added to a solution of 0.01 mmole VII in chloroform and stirred
for 0.5 h. The chloroform solution of VIII was separated, dried over Na2SO~ and evaporated.
These compounds are soluble in acetone, ethanol and chloroform.
~3C NMR spectrum of VIIi: 203.9 (C=S), 170.2 (double signal as a result of overlap of
the guanidine and amidine C=N signals), 140.1 br, 136.9, 127.9, 127.3, 127.1, 126.4, 125.9,
117.3 (C6H5), 68.3, 63.5 (Cspiro), 45.5, 45.1 (N--CH2C6Hs), 38.5, 38.1 (N-CH3), 35.6, 35.3,
31.4, 31.0, 27.7, 26.9, 24.8, 23.9, 22.2, 22.0, 21.8 (cyclo-C6H1o). Mass spectra*: Vlllh,
91 (98), 92 (9), 98 (i0), 107 (7),.215 (9), 245 (8), 257 (i00), 258 (19), 281 (91), 336 (19),
337 (56), 338 (20), 354 (9), 362 (17), 453 (301, 454 (10~,M + 487 (16); Villi, 65 (6), 68 (9),
91 (55), 92 (7), 96 (i0), 98 (14), 125 (5), 176 (7), 230 (21), 271 (141, 272 (i00), 273 (14),
380 (9), 381 (ii), (M + i) + 488 (13). VIlli, 34 (6), 68 (5), iii (14), 117 (16), 232 (5), 286
(100),365 (9), 405 (7), (M + i) + 516 (18).
The iodomethylate of VIIIj was obtained by treating VIIIj with a five-fold excess of
CH31 for 48 h. The product was obtained in 70% yield, mp 87~ Found: C, C, 58.2; H, 69;
N, i0.3; S, 4.9%. Calculated for C32H~INsS: C, 58.4; H, 6.7; N, 10.7; S, 4.9%. IR spect-
rum (KBr): 16.0, 1640 (C=N), 3160-3650 cm -~ (br. NH). PMR spectrum: 1.46-1.74 (20H, m, cy-
clo-C6HIo), 2.22 (3H, s, S-CHs), 3.24 (6H, br. s, NCH3), 4.29 (2H, d, (NHCH2), 4.68 (2H, br.
d, NHCH2), 7.13 (10H, br. s, C6H5), 9.62 ppm (NH, br. s). 13C NMR spectrum: 178.7 (quanidine
C=N), 166.0 (amidine C=N), 145.4 (S--C=N), 135.6, 134.6, 132.3, 129.4 (br. s), 121.8, 118.7
(hr. s, C6H5), 71.49, 71.24 (Cspiro), 37.4, 36.3 (NCHs), 32.8-20.47 (cyclo-C6H1o), 13.20,
12.95 ppm (SCHs).
1.3-Thiazolidin-5-imines (XXXa,e,j) were obtained from VIIa,e,j by heating at reflux
in 2% toluene solution. The reaction was monitored by thin-layer chromatography. Products
XIIIa and XIIIe were isolated from the oil obtained after solvent removal. XIIIa was dis-
solved in a minimum amount of acetone and separated by thin-layer chromatography using 1:3
acetone-benzene as eluent. XIIIe was obtained by crystallization of the oil from hexane.
Thiazolidinimine XIIIj was crystallized from toluene upon cooling.
Thiazolidinimine XIIIa was obtained in 65% yield, mp 185~ Found: N, 16.8; S, 13.3%.
Calculated for C13HITNsS: N, 17.0; S, 13.5%. Mass spectrum: 41 (7), 56 (i00), 57 (7), 65
(7), 70 (7), 91 (14), 116 (27), 118 (7), 132 (14), 159 (9), 173 (7), 232 (33), M + 247 (99).
IR spectrum (KBr): 1610, 1640 (C=N), 3435 cm -I (NH).
Thiazolidinimine XIIIe was obtained in 70% yield, mp 155~ Found: N, 14.8; S, 11.2%.
Calculated for C16H21N3S: N, 14.7; S, 11.2%. IR spectrum (KBr): 3415 (NH), 1695 cm -~ (br,
C=N). ~ C NMR spectrum, 179.2, 178.7 (NC=NH), 157.8, 157.3 (C=N--Ar), 145.8, 138.6, 136,3,
133.4, 131.6, 129.5, 120.8, 119.0 (C6H~), 70.1, 65.5 (Cspiro), 37.9, 37.1 (NCH3), 31.4-19.8
(cyclo-C6H~o, CH3--Ar).
Thiazolidinimine XIIIj was obtained in 100% yield, mp 205~ Found: C, 66.4; H, 7.4;
N, 14o4; S, 11.2%. Calculated for C16H2~N3S: C, 66.7; H, 7.3; N, 14.6; S, 11.2%. IR spect-
rum (KBr): 1585-1600 (C=C, C=N), 3420 cm -l (NH). PMR spectrum: 1.66 (1OH. m, cyclo-C6H~o),
3.01, 3.15 (3H, 2 s, CH3N), 4.29, 4.48 (2H, 2 s, CH=N), 7.03-7.14 (5H, 2 s, C6H5), 8.33 ppm
(NH, br. s). The ratio of the E and Z isomers was 1:5.

LITERATURE CITED
I. I. Ugi, Isonitrile Chemistry, Academic Press, New York (1971), p. 145.
2. I. Ugi, F. K. Rosendahl, and F. Bodesheim, Ann., 666, 54 (1963).
3. W. Walter and E. Schaumann, Chem. Ber., iO4, 3361 (1971).
4. V . I . Andrianov, D. Sh. Safina, and B. L. Tarnapol'skii, Rentgen-75. An Automatic Prog-
ram System for The Solution of Crystal Structures [in Russian], Div~son of the Institute
of Chemical Physics, Academy of Sciences of the USSR, Chernogolovka (1975), p. 82.
5. A . N . Chekhlov, Kristallografiya, 26, 596 (1981).
*Here and subsequently, the ion peaks with intensity greater than 5% of the strongest peak
are given; the intensities are given in parentheses.

51
NEW DERIVATIVES OF IMIDAZOLINE 3-OXIDE AND THIAZOLINE
WITH 2,6-DIALKYLPHENOL FRAGMENTS

T. F. Titova, A. P. Krysin, and V. V. Martin UDC 547.563.4:781.3'789.1:

541.124:678.048

(2,6-Dialkyl-4-hydroxyphenyl)-2-butanones and aminooxides were used to obtain the

corresponding 3-imidazoline 3-oxides. Nitrosylation of 3-imidazoline 3-oxide con-
taining a phenol substituent proceeds either at the imidazoline ring amino group
or at the phenol fragment. Intermolecular cyclization of (2,6-di-tert-butyl-4-
hydroxyphenyl)-2-butanone with sulfur and ammonia gave a 3-thiazoline as two dia'
stereomers.

A promising area of research in the chemistry of polymer stabilizers lies in the creation
of additives with a broad action range which protect the polymer from the action of light,
heat and atmospheric oxygen. The structure of such compounds consists, as a rule, of two
functional fragments, specifically, a sterically-hindered phenol and heterocycle such as pi-
per idine [i, 2]and hydantoin [3].
In the present work, we synthesized new imidazoline and thiazoline derivatives contain-
ing a phenol moiety. Interest in such heterocyclic compounds is related to the use of sever-
al 4-thiazolines as light stabilizers for polyolefins [4]. Compositions of 3-thiazolines and
thiurams act as thermal stabilizers [5], while benzimidazoline-2-thiones have been proposed
for use as oil and rubber antioxidants [6].
Imidazoline derivatives h a v e b e e n synthesized by the acid-catalyzed condensation of ke-
tones with aminooximes [7], while thiazoline derivatives have been prepared by the reaction
of ketones with sulfur and gaseous ammonia [8]. Readily available 4-(3,5-dialkyl-4-hydr0xy-
phenyl)-2-butanones I and II prepared by the alkylation of 2,6-dialkylphenols by methyl vinyl
ketone in the presence of bases [9] were used as the starting materials.
Heating butanones I and II with 3-amino-3-methyl-2-oximinobutane (III) and I with amino-
oxime IV in the presence of p-toluenesulfonic acid leads to the corresponding 3-imidazoline
3-oxides V-VII.
0It OII
~, / R~

R2 /Ott R 2 "~ ..O

-3~]~"--~:I N r --N R1
CH .--i-- C H 3 ; ~ -CH3 ----~/ +

! !
C~-O C~N--OH
[ Ill,IV Y,YI,YII I
CH~ CH 3
I,II VIII,IX

I, V, VII, IX R'=t-C4Hg; II, VI, VIII RI=CHz III, V, VI R2=CH~;

IV, VII R~=C6H5

The condensation of ketones I and II with aminooxime III proceeds rather smoothly to give
high yields of 3-imidazoline 3-oxides (~80%). The use of a 2.5-fold excess of aminooxime III
in the reaction with ketone II leads to a side reaction involving the formation of butanone
oxime VIII in 62% yield. A similar conversion was observed in the condensation of ketone I
with aminooxime IV; the yield of the product, oxime IX, was 5% in this case.

Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Academy of Sciences

of the USSR, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. I, pp. 62-67, January, 1986. Original article submitted October 31, 1984.

52 0009-3122/86/2201-0052512.50 9 1986 Plenum Publishing Corporation

 3-1midazoline3-oxidesreadily underg o nitrosylation [7] to give sterically-hindered
nitrosoamines, which have not been extensively studied. The reaction of V with NaNOa was
carried out in order to study the effect of the phenol substituent on the nucleophilic pro-
perties of 3-imidazolines.

OB
7 O
.... N
V"
"/"Nz ~'CIl:,CII~(( ~ ' ~ - - O H ....'-' +

NO2
X~ XlI

The PMR and elemental analysis data (Tables i and 2) permit the unequivocal assignment
of structure X to one of the reaction products. N-Nitroso compounds are known to exist in
solution as two stereomeric forms [7]. The signal for such forms XA and XB in the PMR spect-
rum were assigned taking account of the anisotropic effect of the N-nitroso group on the B-
methyl group protons [i0] of the imidazoline fragment and the aromatic ring protons.

11
~J~q/2
H ~ CH2CH2-~(/("
. . , \ . -"~')
j , --0H "~" CH2-C.H~( )f)--- OH

XA XB

In addition to substitution in the imidazoline ring, the phenol fragment in nitrosylated

leading to the formation of 4-nitro-2,6-di-tert-butylphenol (XI)and XII. The IR spectrum of
XII shows bands at 1680 and 1655 (C=O and C=C),, 1625 (heterocyclic nitrone ~ ) and 3610 cm-z
(OH). The PMR spectrum indicates cyclohexadiene and imidazoline 3-oxide fragments in XII
(Table i). Further proof for the structure was obtained in the Z3C NMR spectrum in CDCI3
which shows signals at 186.9 and 89.8 ppm related to the carbonyl carbon atom and carbon atom
attached to the OH group. Hence, XII was assigned the structure of 2,4,5,5-tetramethyl-2-[2-
(~-hydr~xy-3,5-di-tert-butylcyc~hexadien-2,5-~ny~)-~-ethy~]-3-imidaz~ine-3-~xide.
The formation of XI and XII may be represented by a scheme beginning with the attack of
the para positive relative to the benzene ring hydroxyl group by a nitrosium cation [ii] and
oxidation of intermediate XIII and quinonitrile XIV [12]. Due to its instability [13], XIV
is rapidly converted by two independent pathways. Pathway A involves the loss of an alkyl-
eneheterocyclic substituent from the geminal unit [14]. Pathway B involves substitution of
the nitro group by a hydroxy group and the formation of quinol XII [14, 15].
Thus, the presence of the 2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl fragment in the
structure of 3-imidazoline-3-oxide V sharply reduces the selectivity of the nitrosylation at
the amino group due to the appearance of an additional reaction site in the phenol substitu-
ent.

CII~r --01] ~ "N

HI / "CII~Ctf~
" \ ~ ' ~4~:=0H .....
V
"-. r r w o ~,o -
H
--A---~- Xl

XIII XIV
9 .__~o i~~
HO-

53
 The in~ermolecular cycllza~ion of ke~ones by the action of sulfur and a~unonia with the
formation of 3-thiazolines has been studied by Asinger [8], Various aliphat~c, alicyclic
and heterocyr ketones with at least one hydrogen atom in the ~-position relative to the
carhonyl group undergo this reaction, Such conversions for carbonyl derivatives of 2,6-
dialkylphenols have not been reported. We have prepared 3-thiazoline XVI by heating ketone
I with sulfur and gaseous ammonia for 7 h at 120~
Thiazoline XVI is a i:I mixture of diastereomers XVIA and XVIB wh:[ch may be separated
by crystallization. The iR spectra of these compounds show a band at 1660 cm -l (O,:N) char-
acteristic for thiazolines [16]. Further proof of the product structure was obtai~led from
the PMR and ,3 C NMR spectral data (Tables 2 and 3).

OH

S
;If
, ~,,~cH a s ;'"~crI 2' ,
CII-SII
]
C ==0
[
CH3
O~I
XY

Preliminary experiments of the compounds synthesized showed that some of them have both
thermal and light stabilizing action. The results of these tests will be published separately.

EXPERIMENTAL
The IR spectr 9 were taken on a UR-20 spectrometer in CCI~ and KBr pellets. The UV spec-
tra were taken on a Specord UV-VIS spectrometer in ethanol. The PMR spectra were taken on a
Varian A-56/60A spectrometer for V, VII, and IX in CCI~, for VI, X, and XII in CDCIs and for
VII in CD3OD. The *SC NMR spectra were taken in CDCI3 on Bruker HX-90 and WP-200SY at 22.63
MHz.
The yields, melting points and elemental analysis data for V-XII and XVl in Table 4.
2,4,5,5-Tetramethy~-2-[2-(3,5-di-tert-buty~-4-hydr~xypheny~)-~-ethy~]-3-imidaz~$ne 3-
oxide (V). A mixture of 29 g (105 mmoles) ketone I, 12 g (103 mmoles) aminooxime lll-and
0.05 g p-toluenesulfonic acid was heated in an argon stream for 2 h at 80~ and 8 h at 130~
The cooled glassy mass was treated with hexane. The precipitate was filtered off, washed
with hexane and dried to yield 31 g V.
2,4,5,5-Tetramethyl-2-[2-(3,5-dimethyl-4-bydroxyphenvl)-l-ethvl]-3-imidazoline 3-oxide
(Vl). A. A mixture of O. 3 g (1.56 mmole) ketone II, 0.177 g (1.53 mmoles) aminooxime III
and 1.5 mg p-toluenesulfonic acid was maintained in an argon stream for 2 h at 80~ and for
8 h at 130~ After cooling, the glassy mass was separated by column chromatography of sil-
ica gel with gradient elution using chloroform-ethanol to yield 0.076 g starting ketone II
and 0.346 g VI.
B__=Heating and subsequent treatment of a mixture of 5.5 g (29 mmoles) ketone II, 8.4 g
(72 mmoles) aminooxime III and 20 mg p-toluenesulfonic acid under the conditions described
in A gave 3.7 g 2-oximino-4-(3,5-dimethyl-4-hydroxyphenyl)butane (VIII) and 2.2 g imidazol-
ine 3-oxide VI.
2,5,5-Trimethy-4-pheny-2-[2-di-tert-buty-4-hydrxypheny--ethy]-3-imidazine 3-
oxide (VII) was obtained analogously under conditions described in procedure A from 5.52 g
(20 mmoles) ketone I, 3.5 g (19.7 mmoles) aminooxime IV and 15 mg p-toluenesulfonic acid.
Column chromatography gave 2.3 g starting ketone I, 0.3 g 2-oximino-4-(3,5-di-tert-butyl-4-
hydroxyphenyl~butane (IX), and 4 g 3-imidazoline 3-oxide VII.
Nitrosylation of 3-imidazoline 3-oxide (V). A sample of 62 ml 5% hydrochloric acid (pH
2-3) and 50 ml 10% aqueous NaNO2 was added to a solution of 11.5 g (30 m~oles) V in 200 ml
50% aqueous ethanol and maintained for 3 h at room temperature. The oil separated was ex-
tracted with chloroform, dried over MgSO~ and evaporated to give 12 g product, which was
subjected to column chromatography on silica gel with gradient elution using chloroform-
ethanol to give five fractions containing 0.5 g (7%) 4-nitro-2,6-di-tert-butylphenol XI '~

54
 TABLE i. Spectral Indices for V-X and Xll

IR spectrum, .cm~l UV spee- l PMR spectruma,6 , ppm

[solvent] trum, Xmax.
I [ CH3 CH~--CI-12 H&roi I OH

V 1610 [CCI,] (C=N); 228 (4,20) 1,2C 1,3~ 2,12C 6,7; 1,34i 4,99
3650 (OH) 278 (3,30) 1,26
VI 1655 [KBr] (C=N) 224,2 (4,23); 1,27 1,5J 2,28c 6,7~ 1,I( 6,27
277,8 (3,27) 1,30
VII 1540 [CCI,] (C=N); 284 (3,96) 1,57 1,4~ 2,28 c 6,86 1,3~ 4,96
3650 (OH) 1,54
VIII 1610 [KBr] (C=N) 281 (3,76) ! -- 2,52c 6,67 2,14
IX 1635 [KBr] (C=N); 278 (3,29) 2,55c 6,84 1,34 4,84
3635 (OH)
Xt 1625 [KBr] (C=N) 229 (4,32); 1,64 }(a) 2,o~ 2,54 7,00 1,39 5,14
~278 (3,41); 1,66 (b) (a)
304 (3,00) 1,89 (b) 1,7{~ 6,94
1,84 (a)
XII 1625 [CC14] (C=N); 233 (4,38) 1,32 1,51 1,77 6,56 1,17
1655 (C=C);
1680 (C=O);
3610 (OH)

ai.81 ppm for VIII and IX ( C H z ~ H ) . bSlight predominance

of the B form. CMultiplet center.

TABLE 2. Spectral Indices for XVIA and SVIB

~R spectrum, UV spec PMR spectrum (in CDCI3), ~, ppm

Com- ":m-I':[solvent] trum,
Ama~
pound
~
[ log !-C4H9
L ore 6-CH.. 17-CH2 10-CH2aI CH 8-CHa J9-CHa OH
I

XVIA 1660 [CHCI3] I278 (3,6O) 1,42 7,00;1 2,47b 12,04c 3,05 [4,58( 1,65 2,15 5,08;
(C=N); 5,12
3640 (OH)
XVI B 1660 [CCI4]
I
[278 (3,57) 1,42 6,94;I 2,39 b[2,04c 3,05 14,53c 1,42 2,!7 5,01;
(C=N); 7,00 [ 2,66c[ 5,08
3640 (OH) I
aMultiplet center (ABX system) for XVlA, JAB = 14, JAX = 4,
JBX = 12 Hz; for XVlB, JAB = 14, JAX = 4, JBX = 8 Hz.
bcenter of triplet of doublets, J = 12, J = 4 Hz. CMultiplet
center.

TABLE 3. Chemical Shifts (ppm) in the ~aC NMR Spectra of XVIA

and XVIB

Carbon atom XVIA XvIB Carbon atom XVIA XVIB

C(2) s, 89,1 s. 89,4 C(]2) q, 30,2 :q, 30,3

C(4) 168,2 s. 167,6 C (]') s, 129,3 s, 129,6
C~s) 65,0 q 65,2 C(w) s, 132,4 s, 131,1
C(6) b 46,4 t~ 46,8 C(2,6,) d, 124,7 d, 124,6
C~z) b 31,9 31,4 C (2",6") d, 125,2 d, 125,8
32,3 ~1 32,0 C (3',3",5t ~5") s, 135,7 $, 135,4
C(9~ qq, 18,3 9 18,3 C (~') s' 151,6 s, 151,6
Cr t, 41,2 g, 41,1 C (4") s' 152,4 s' 152,4
Coo s, 34,1 s, 34,2

(identified by comparison with the PMR and IR spectra of an authentic sample), 3.7 g 1-nitro-
so-2-[2-(3,5-di-tert-butyl-4-hydroxyphenvl)-l-ethyl]-3_imidazoline 3-oxide (X), 3.8 g 3-imi-
dazoline 3-oxide V, and 2.2 g 2,4,5,5-tetramethyl-2-[2-(l-hydroxy-3,5-di-tert-butylcylohex-
adien-2,5-onyl)-l-ethyl]-3-imidazoline 3-oxide (XII). X3C NMR spectrum: 186.2 (C(xs)),
176.3 (C(,)), 145.9 (C(~,,~6)), 142.4 (C(~a,~7)), 89.8 (C(x2)), 68.5 (C(2)), 61.6 (C(5)),
35.7 (C(x~)), 34.5 (C(~a)), 32.9 (C(xo)), 29.3 (C({9)), 28.0, 27.7 (C(s,9)), 26.3 (C(6)), 9.2
ppm (C(7)).

55
 TABLE 4. Indices for the Compounds Synthesized

Com- [~) ~ Found, % Chemical Calculated, % Yield, %

pound formula
C H N(S) c H N(S)
i

V 175--177 73,80 ' 10,3I 7,48 CzJ]3~N202 73,75 [0,23

7,48 78
VI 129--13s 70,39 9,07 9,62 C17112,;N~O2 70,31 ,(},02
9,64 76
VII 133--13~ 77,13 9,11 6,39 C~114(,N,2C)2 77,02 (,},23
6,41 47
VIII ~00--201 69,4,q 8,30 6,75 C,~lllTN()2 69,54 8,27
6,75 62
IX 126--128 74,23 10,00 4,80 C,~1-t2~)NO2 74,19 [0,03 4,80 5
X 159--161 68,57 9,53 10,41 C2~1t3,N~O2 68,55 9,57 10,41 30
XlI [62--t64 70,69 9,85 7,16 C,J~I3~N203 ,70,739,81 7,17 18
XVI.a [34--135 76,35 9,71 2,47 C36Hs~=NO2S 6,42 9,80 2,47 25
{5,64) (5,67)
XVI b 85--87 76,37 9,77 2,47 C3sHs~NO2S 76,42 9,80 2,47 25
(5,63) (5,67)

av, VII, IX, XVIA and XVIB were crystallized from hexane, VI,
VIII, X, and XII were crystallized from 1:2 ethyl acetate--
hexane, bRelative to the starting ketone.

2-4-Dimethy-2-[2-(3,5-ditert-buty-4-hydrxyheny)--ethy]-5-(3,5-di-tertbuty-4-
hydroxybenzyl)-3-thiazoline (XVI). A mixture of i0 g (36 mmoles) ketone I and 0.864 g (27
mmoles) sulfur was heated for 7 h at 120~ in a stream of ammonia. After cooling, the glas-
sy, dark red mass crystallized upon the addition of hexane to yield 5 g 3-thiazoline XVI as
diastereomers XVIA and XVIB. Three-fold washing with hot hexane gave 2.5 g of insoluble
diastereomer XVIA as a colorless precipitate. Evaporation of the filtrate gave 2.5 g color-
less diastereomer XVIB which turns pink upon exposure to light.

LITERATURE CITED
i. L. A. Skripko, Z. B. Popova, T. A. Pankova, V. M. Levin, E. N. Matveeva, E. V. Merkur'
eva, and E. I. Kirillova, USSR Inventor's Certificate; Byul. Izobr., No. 17, 87 (1980).
2. D. Randell and M. Smith, British Patent No. 1,395,159; Ref. Zh. Khim., 5N210 (1976).
3. US Patent No. 4,162,246; Ref. Zh. Khim., 3NI9OP (1980).
4. M. Bloom and G. Newland, US Patent No. 3,391,i06; Chem. Abstr., P36758S (1968).
5. C. Heuck, O. Mauz, and F. Rochlitz, West German Patent No. 1,096,599; Chem. Abstr.,
24116B (1961).
6. A. Amery, J. Crook, and V. Sharma, British Patent No. 1,363,233; Ref. Zh. Khim., 24N188
(1975).
7. V. V. Martin and L. B. Volodarskii, Khim. Geterotsikl. Soedin., No. i, 103 (1979).
8. K. V. Vatsuro and G. L. Mishchenko, Name Reactions in Organic Chemistry [in Russian],
Izd. Khimiya, Moscow (1976), p. 8.
9. T. F. Titova, A. P. Krysin, M. M. Shakirov, and V. I. Mamatyuk, Zh. Org., Khim., 20,
331 (1984).
i0. D, R. Battiste and J. G. Traynham, J. Org. Chem., 40, 1239 (1975).
ii. V. V. Ershov and G. A. Zlobina, Izv. Akad. Nauk SSSR, Ser. Khim., 2082 (1964).
12. R. Henry, J. Org. Chem., 23, 648 (1958).
13. V. V. Ershov, A. A. Volod'kin, and G. I. Bogdanov, Usp. Khim., 32, 154 (1963).
14. V. V. Ershov and G. A. Zlobina, Zh. Org. Khim., ii, 299 (1966).
15. K. Ley and E. Mfiller, Chem. Ber., 89, 1402 (1956).
16. L. Bellamy, The Infrared Spectra of Complex Molecules [Russian translation], Izd. Inostr.
Lit., Moscow (1963), p. 388.

56
SPECTROSCOPIC STUDY OF THE STRUCTURE OF
N-(2-BENZIMIDAZOLYL)-O-METHYLCARBAMATE

B. Eo Zaitsev, M. V. Palishkin, UDC 541.62:543.42:547,785.5

S. S. Kukalenko, and V. P. Brysova

X-ray electronic, IR, and electronic spectroscopy were used to determine that
N-(2-benzimidazolyl)-O-carbamate in the crystalline state and in organic sol-
vents exists predominantly in the benzimidazole carbamate form. The acid--base
characteristics of N-(2-benzimidazolyl)-O-methylcarbamate were evaluated. The
spectra of this compound were interpreted using quantum chemical calculations
and experimental data.

Benzimidazole derivatives have a set of biological properties which permit their use as
pesticides and drugs. N-(2-Benzimidazolyl)-O-methylcarbamate (BMC) occupies a special posi-
tion among these compounes [I, 2]. However, the structure and properties of this compound
have not been studied. In the present work, we carried out a detailed study of the structure
and physicochemical properties of BMC in the polycrystalline state and in various media.
The structure of BMC may be represented as tautomers I-III

~\ /c-oc~ 3 \ / - \

~-..o n H...o ~---o

i . ~F. III

Since monocrystals of BMC could not be grown, x-ray electronic spectra (XES), IR and UV spec-
tra as well as quantum chemical calculations were used to establish the predominant tautomer.
The x-ray electronic spectra were taken on a Kratos ES-100 spectrometer by pressing the
compound into a copper lattice. The Cls line at 285.0 eV obtained from the vapor of diffu-
sion oil condensed on the sample was used as the standard. Since the bond energy of the in-
ternal electrons in atoms within molecules depends on the electron density of their outer
shells, the XES method permits the qualitative differentiation Of the valence states of atoms
in molecules. Thus, one of the oxygen atoms is in a C=O double bond and the other is in an
OCH3 group. Of the three nitrogen atoms, one is a C=N double bond, and the other two have
three o-bonds and supply Pz electrons of the unshared pair to the ~-bond system. In struc-
ture II, both oxygen atoms are of the same bridging type while the three nitrogen atoms are
divided among two nitrogen atoms in double bonds and one atom supplying Pz electrons to the
T-system. In accord with the valence state types for the oxygen and nitrogen atoms in the
XES of tautomers I and III, we should expect the appearance of two Ols lines with i:i inten-
sity ratio and two Nls lines with 1:2 intensity ratio. In the XES of tautomer II, there
should be one Ols line and two Nls lines with inverse intensity relative to the intensity of
the Nls lines in tautomers I and III.
The XES of BMC shows two Ols lines with energies 531.4 and 533.2 eV and I.'i intensity
ratio (Table i). The assignments of these values to oxygen atom types were carried out using
literature data for the XES of compounds containing oxygen atoms of a determined type. Table
1 shows that the Ols bond energy of the oxygen atom within a double bond is 1.5-2 eV lower
than the Ols line for the oxygen atom in the bridging bond. Thus~ the BMC molecule has car-
bonyl and bridging oxygen atoms, which correspond to structures I and III and excludes struc-
ture II." The Ols values in the XES of BMC hydrochloride are higher by 0.3-0.5 eV (Fig. i).
The XES of BMC shows two Nls lines. The intensity of the line with higher energy is twice

P. Lumumba International Friendship University, Moscow 117923. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. i, pp. 68-74, January, 1986. Original article submitted
August 21, 1984, revision submitted December 28, 1984.

0009-3122/86/2201-0057512.50 9 1986 Plenum Publishing Corporation 57

 TABLE i. Bond Energies of Internal Electrons

Eb, eV
0Is NIs

Compound
.... OCII~, N~C

[" 0 ~ 0 -I 531,0 532,7

J
OCtt. N .... S
533,5 399,4
I "11 ~ [4]

531,4 533,2 398,5 400,2

..BHC. HCI 531,9 533,5 398,9 400,6
Benomil (V) 531,6 533,4 398,7 400,4

that of the low-energy line. According to XES data, the Nls bond energy in a,a'-dipyridine
is 399.1 eV [4], while for the Nls values for pyridines in the solid state lie in the range
from 388 to 399 eV [5]. In five-membered aromatic rings such as imidazole, the Nls line
atom of a double bond nitrogen atom is 399.1 eV and the corresponding value for a hydrogen
atom in p, ~-conjugation is 1.5 eV higher [6]. Finally, two Nls energies of 400.5 and 399.1
eV are observed in phthalocyanine for the eight nitrogen atoms with signal halfwidth d~/2 =
1.7 eV and 1:3 intensity ratio. The Nls value of 400.5 eV is related to the six "pyrroiic"
..

nitrogen atoms N while the value of 399.1 eV is related to two "pyridinic" nitrogen
/l\
atoms (N=C) [7]. Hence, the Nls energy of 400.2 eV in the XES of BMC was assigned to two
NH group nitrogen atoms and the line at 398.5 eV was assigned to the C==N bond nitrogen atom.
The Nls values in BMC.HCI are higher by 0.4 eV due to the induction effect of the proton.
The XES of benomil shows two Nls lines close to the Nls values in BMC (Table i) but with 1:3
intensity ratio.
Thus, the examination of the XES indicates that BMC in the crystalline state exists
predominantly as tautomer I or Ill.
Pariser--Parr--Pople quantum chemical calculations [8, 9] were carried out using a var-
iable ~ [10] according to the program of Kosobutskii [ii]. The energy characteristics of
tautomers I-III were calculated in order to determine the existence of tautomers in the gas
phase, the effect of the electrostatic interaction with the medium and evaluation of the con-
tribution of the ~- and o-energies to the total energy of BMC (Table 2). According to the
heats of atomization of tautomers I-III, these compounds have similar stability with some
preference for tautomer I in the gas phase due to the gain in H-bond energy in the tautomer
series 1-Ill. The similarity in the atomization energies of tautomers I and III and the en-
hanced solvation coefficient in tautomer III relative to I indicate that, the facile tauto-
merle transition between these forms is possible depending on the solvent.
The electronic absorption spectra were taken on Specord UV-VIS spectrometer in ethanol
and CHCI3. The electronic spectrum of BMC tautomer I has three absorption regions (Fig. 2).
According to the calculation, the first absorption region is related to the complex electron-
ir transition from the highest occupied molecular orbital (HOMO) ~n to the lowest unoccupied
molecular orbital (LUMO) ~m (41%), from ~n-~ to ~m (33%) and from ~n to ~m+1 (10%). The
transition is polarized at an angle of --13~ relative to the long molecular axis (x-axis).
The redistribution of H-charge in the molecule upon going from the ground state to the first
excited state indicates that the electron-donor fragment in this transition is the carbamate
group, while the electron-withdrawing fragment is the benzimidazole ring (Fig. 3). The ob-
served fine structure of the long-wavelength band with difference in frequency between the
components A~ = 800 cm-* is a consequence of electronic-vibrational transitions (Fig. 2).

58
 AI
I
1,2

7
--Z0~---Z;0
/\ -

~imEb,eV '?'-s!~--g3*3-g-3iEb, eV
0,8#.

0,4
I \EU~, ~il ,i

0
z,oz r :~98Eb, eV b3b 5a3 531 gb, eV 50 42 34 9.10 ~ c ~

Fig. 1 Fig. 2
Fig. i. X ray electronic spectra: a) Nls for BMC, b) Ols for BMC,
c) Nls for BMC-HCI and d) Ols for BMC-HCI.
Fig. 2. Electronic absorption spectra of BMC in ethanol (i) and of
BMC in alkaline ethanolic solutions (2-4).

TABLE 2. Energy Characteristics of Tautomers and lonic Forms

of BMC

",'-Bond O -Bond ne~t of ~olvation "

~nergy~, energy ~tomiza-~oefficient,
Compound ?~ ~ ev
EO , eV tion, L~4,~ M

I 23,92 49,26 I03.78 4,10

Ill 23,73 49,30 I03.62 4,70
II 23,50 49,27 I03.60 3,24
24,44 49,30 I08.67 4,38
J-:%
OH
IA 24.78 49,29 I08.77 5.17

The second n-electron transition is also complex: ~n + ~m (48%), ~n + ~m+, (19%), and
~n-~ + ~'m (17%) This transition is polarized by --32~ relative to the x-axis and is local-
ized predominantly in the benzimidazole system (C(I), C(~), C(5) and N(9) are electron-
withdrawing while C(a), C(a), C(6) and N(7) are electron donating). The band with two re-
solved vibrational components (Av = 950 cm-*) corresponds to this transition in the observed
spectrum.
The third complex electronic transition appears in the experimental spectrum as a shoul-
der kTabie 3) and is localized in the benzene ring (C(2) and C(3) are electron-withdrawing
and C(~) and C(6) are electron-donating) and in the carbamatoimidazole fragment (the imida-
zole ring is electron-donating and the carbamate group is electron-withdrawing).
The fourth transition is given in Table 3.
A bathochromic shift is observed in the spectra for BMC in alkaline ethanolic solutions
relative to the spectra in ethanol for all bands. The existence of isobestic points indi-
cates the existence of an ionized form of the molecule in solution (Fig. 2). According to
the calculation, the anionic form IIA of tautomer II is formed in alkaline solution (Table 3):

H / ." / C - - ,fJCH.3 , /
/ O- /

59
 %012 ,00~ ",3,~,~

-,oi~ -;,,~'~ "~","'r'~,~o~' 4,~' ,o~ /,27s

.Ie. ---I . ~%,/ 1,387 "~-" 18&

a -,o,, '~
, 0'8LAI ,
~%/%:,I
37 no I -,377

000 " " \ ' 6 ~" 004 /342

o.,,.. (.,"x,"':' A'/
j'
,od.... L:: x4. /Z"
9@ ' - - 4 Nx " ,,t@ . . . .
-IZ4 " 035 \x ~/
b " ,~B H (~ o L...li .............
%584 43 :.;3
C]II -

Fig. 3 Fig. 4
Fig. 3. Molecular diagrams of tautomer I: a) in the ground state,
and b) in the first excited state.
Fig. 4. Electronic absorption spectra for i) BMC in CHCI~; 2, 3) BMC
in CHCl~ after the passage of gaseous HCI; and 4) calculated spectrum
for protonated tautomer IA.

The long-wavelength band is attributed to the extent of 87% to the transition ~n(HOMO)
Tm(LUMO) and the intensity (f = 0.621) is 2.6 times greater than for the neutral form (f =
0.238). The calculated fneutr/fanion = 0.4 and experimental Cneutr/eanio n = 0.3 ratios for
the long-wavelength transitions are in satisfactory accord (Table 3). This transition is
polarized along the long molecular axis. The oxide anion is electron-donating while the
henzimidazole system is electron-withdrawing. The doublet nature of the band is due to the
appearance of vibrational structure in the electronic transition.
The spectra of the solutions of BMC in acidic ethanol media and in CHCI3 through which
gaseous HCI was introduced show that the BMC molecules are protonated as indicated by the ob-
servation of isosbestic points (Fig. 4). This protonation leads to a significant change in
the absorption spectrum (Table 3). The intensities of the bands at 212 and 228 nm undergo
inversion and a hypsochromic shift of 4 nm. T h e intensity of the 250/245 nm band is very re-
duced. According to the calculation, this band is shifted hypsochromically, which prevents
its observation due to overlap with the adjacent strong band. The long-wavelength band re-
tains its fine structure and undergoes hypsochromic shift by 4 nm. The calculated spectrum
of protonated tautomer IA is in satisfactory accord with the experimental spectrum (Fig. 4).

V2"b......~K
.

C--O~

The acidity and basicity constants of BMC in 50% ethanol were determined spectrophoto-
metrically using Na2B~O~,I0~20 (pH 9.18) and KH~PO~ (pH 6.86) buffer solutions, respectively.
The pK a value of 11,64 and pkb value of 5.60 fall withing the pK ranges for reported benzim-
idazole derivatives: pK a 13.2 and pKb 5.53 for benzimidazole and pK a 12.0 for 2-phenylbenz-
imidazole [12].
The IR absorption spectra were taken on a Specord IR-75 spectrometer. The IR spectrum
of BMC in vaseline oil at 3700-2100 cm -I shows a diffuse band with a set of maxima at 2555,
2675, 2755, and 2810 cm-* which we assigned to the stretching vibrations of the NH group
bound hy a strong intramolecular bond to the carbonyl group. This assignment is in accord
with the lack of this band in the IR spectra of polycrystalline benomil (Fig. 5) and in di-
lute solutions of BMC in CHC13. The band at 3330 cm-* is assigned to vibrations of the ex-
ocyclic NH bond forming strong intermolecular hydrogen bonds. The bands at 1640-1655 cm-*
were assigned to the C=O bonds since the vC==N band of benzimidazole is observed at 1620 cm-*
while the vC-_~ band of iminoesters are observed at 1615-1575 cm-* [13, 14]. The strong shift

60
 TABLE 3. Experimental and Calculated Absorption Spectra for
BMC Tautomer I in Ethanol (7 <_ pH < 7)

~max, rim Intensity Transition I

~olarization[ MKV eigen
Form of tautomer I exp "~]calc"'IExP 9, - direction9 I vectors
I' caxc. (~), deg.l

y pH----7 "
294' 278 5333,7 0,238 '-13 -0,64 (8--9);
7 287 14142,3 0,57 (7--9);
281 13360,9 0,32 (8--10)
276 11159,7
~',/5 "N C--OCH3 25O 249 9273,3 0,397 -32 0,69 (8--9);
6 9~]t I~//11 12 245 12520,7 0,43 (8--10);
-o
0,41 (7--9)
228 227 14318,8 0,308 10 0,59 (8--I0);
-0,54 (7--9);
0,42 (7--11)
212 197 23483,5 0,287 6O 0,79 (8--11);
--0,39 (7--9);
-0,27 (7--10)
y~ pH>7 304 301 18446,6 0,621 - 12 0,93 (8--9)
i ~(oc] 296 18203,9
26l 266 11650,5 0,140 -19 0,69 (8--10);
253 11407,8 0,46 (7--9);
0,35 (7--11)
II r 9~}1 J~111 12 "~ 226 237 66504,9 0,239 -64 0,59 (7--9);
0,54 (8--11);
-0,35 (8--1o);
.0,32 (7--10)
208 0,429 -41 0,76 (8--11);
--0,52 (7--9)
204 0,224 71 -0,60 (8--1o);
0,51 (6--9);
0,46 (7--11)
y~ pH<7 283 280 14508,9 0,339 9 -13 0,81 (8--9);
277 14508,9 -0,35 (7--11);
266 8816,9 -0,34 (7--9)
242 0,256 -35 0,57 (7--9);
0,50 (8--9);
0,41 (8--10);
0,38 (8--11)
225 231 21316,9 0,276 I0 -0,61 (7--9);
0,50 (8--10);
0,47 (7--11)
2O8 199 12276,8 0,083 -84 -0,62 (8--11);
0,57 (7--1o);
0,32 (7--9)

*Experimentally not distinguished since the solvent has strong

absorption in this region.
r by a broad band in the region 210-250 nm in the ex-
perimental spectrum.

of the vC= 0 band is a result of strong hydrogen bonding. The existence of a C=O bond in BMC
in the polycrystalline state is also indicated by the sharp bands at 1276 and 1292 (doublet)
and 1198 cm -x characteristic for vibrations of ester C-O--bonds [15, 16]. The low-intensity
band at 1712 cm -x in the IR spectrum of BMC is related to rotational isomer i':

~"" ----N O.::C_. 9

This hypothesis i s s u p p o r t e d b y ttle f i n d i n g o f a v e r y s t r o n g b a n d a t 1712 cm - x i n t h e

spectrum of benomil, The r e p l a c e m e n t of a hydrogen atom at the ring nitrogen a t o m by a n
amide group destroys the intramo]ecular hydrogen bond with the carbamate group in isomer I
and ]eads to the formation of a new bond:

61
 6O
&

2O

i 8O ~ Fig. 5. IR spectra in the crystalline

state and in vaseline oil for BMC (a),
BMC.HCI (b), and benomil (c),
~o 60

s0~ ~0
20
<0

w - - ~ - b.,< i _ , i ~-~ 0
20 16 12 B 6 37 33 29 25 21..l
"7,!O~' cIB

i
~:~
....
,~ . . . .
r, . ~ I 9
_:~
bl ,'~C
i l

)cll~

i iJ: o<:lI. "'~" ]I

O'.'(\N,+IJ~ ,'O tI. .C"-I"
I "N
('411~ . C4H~
IY "r

Since an eight-membered ring is formed in isomer IV, while a six-membered ring is formed in
V, the latter is favored energetically. This is in accord with the assignment of the band
at 1712 cm-* to the vibration for the free carbamate group of V since the vibrational fre-
quency of the free amide group does not exceed 1680 cm -I [15]. The ~NC=O frequency of the
amide group is strongly shifted toward lower values due to intramolecular hydrogen bonding
and is 1635 cm-Z.
The carbamate and am!de group C=O bands in the spectra of dilute solutions of benomil
in CCI~ are higher by 19 cm -I. The form and number of bands in the NH stretching band re-
gion in the spectra of benomil in vaseline oil and in CC14 solution are the same but are
shifted toward higher frequencies in solution by 20 cm -i. This behavior indicates that the
structures of the benzimidazole ring and the carbamate group in BMC and benomil are the same.
The IR spectra of BMC,HCI in the crystalline state shows a strong band at 1753 cm -~,
which was assigned to C=O group vibrations. The increase in vC==O relative to the frequency
of this band in BMC is attributed to a strong inductive effect. This is in accord with the
XES data which indicate that the energy of the C=O group increases upon protonation of BMC.

LITERATURE CITED
i. S. S. Kukalenko and E. A. Dvoichenkova, Khim. Sel'sk. Khoz., No. ii, 36 (1970).
2. G. P. Clemons and H. D. Sisler, Pesticide Biochem. Physiol,, ~, 32 (1971).
3. D. Clark, Proceedings of the Sixth Conference on Molecular Spectroscopy, Durham, 1976,
London (1977), p. 339.
4. B. E. Zaltsev, T. M. Ivanova, V. V. Davydov, and A. K, Molodkin, Zh, Neorg. Khim., 25~
No. Ii, 3031 (1977).
5. V, I. Nefedov, The Application of X-Ray Electronic Spectroscopy in Chemistry [in Rus-
sian], VINITI, Chemical Bond and Molecular Structure, Vol, i, Moscow (1973), p. 64.
6. Yu. A. Teterln, A. N. Baranov, V. M. Kulakov; L. N. Nikolenko, and N. S. Tolmacheva,
Koord. Khlm., ~, 1860 (1978).
7. M. Barker and D. T. Clark, Chem. Co~mun., 22, 24 (1970).
8. R. Pariser and R. G. Parr, J. Chem. Phys., 21, 466 (1953),
9. J. A, Pople, Trans. Faraday Soc., 49, 1375 (1953).
i0. K. Nishimoto and L. S. Forster, Theoret. Chim. Acta., ~, 407 (1965).
ii. V. A. Kosobutskii, Author's Abstract of Chemical Sciences Candidate's Dissertation, A l l -
Union Glass Research Institute, Vladimir (1974).

62
12. A. R. Katritsky (ed.), Physical Methods in Heterocyclic Chemistry [Russian translation],
Izd. Khimiya, Moscow--Leningrad (1966), p. 112.
13. K. J. Morgan, J. Chem. Soc., 2343 (1961).
14. B. Baccar, R. Mathis, A. Secches, J. Barrans, and F. Mathis, J. Mol. Struct., ~, Nos.
3-4, 369 (1971).
15. L. Bellamy, The Infrared Spectra of Complex Molecules, Izd. Inostr. Lit., Moscow (1963),
p. 275.
16. L. A. Kazitsina and N. B. Kupletskaya, The Application of UV, IR and N'MR Spectroscopy in
Organic Chemistry, Izd. Vyssh. Shkola, Moscow (1971), p. 122.

REACTIVITY OF METHYL DERIVATIVES OF NITROGENOUS HETEROCYCLES

IN VAPOR-PHASE CATALYTIC OXIDATION

L. Ya. Leitis, R. A. Skolmeistere, L. O. Golender, UDC 547.8:542.943.7

D. P. Yansone, P. A. Meksh, and M. V. Shimanskaya

A study has been made of the reactivity of methylpyridines, methylpyrazines,

and methylquinolines in oxidation in the vapor phase in the presence of B-VO
(P03)2. Relationships have been found between the overall reaction rates of
heterocyclic compounds and the charge on the ring nitrogen, and between the
partial oxidation rate and the charge on the ring carbon atom adjacent to the
methyl group. The partial oxidation rate of methylpyridines is given to a
first approximation by the Hammet-type expression InWa = --3.5 + 4.6 Eo, with
a correlation coefficient of 0.93.

The vapor phase oxidation of methylheterocycles with atmospheric oxygen over vanadium
catalysts forms the basis of the industrial production of heteryl aldehydes, which are inter-
mediates in the synthesis of biologically active compounds. In order to establish the most
important structural features governing the reactivity of heterocyclic compounds in oxidation,
and to obtain further information on the reaction mechanisms under comparable conditions, the
oxidation of representatives of three classes of nitrogen heterocycles has been studied, name-
ly pyridines, diazines, and quinolines. In the pulsed vapor-phase oxidation of these com-
pounds (Table i) in the presence of vanadyl ~-polyphosphate at 400~ the principal reaction
products are the monoa~dehyde and oxides of carbon. Under these conditions, 4-MP, 2,3-DMP,
2,5-DMP, 3,4-DMP, 2-MQ, and 4-MQ give predominantly the partial oxidation products, whereas
oxidation of 3-MP, 3,5-DMP, and DMPZ results in extensive oxidation. The rates of total and
partial oxidation W a of the remaining compounds are similar. Comparison of the total oxida-
tion rates (Wtot) of the pyridine bases shows that introduction of methyl substituents into
the pyridine ring increases the overall reaction rate, but there is not clear relationship
between the reactivity of the pyridines and the number of methyl groups present.
Under impulse conditions, the total conversion rate of monomethylpyridines and the
amounts of aldehydes formed on oxidation over B-VO(POs)2 decreases in the isomer sequence ~
4- > 2- > 3-, just as when vanadium oxide catalysts are used [i].
It is noteworthy that the sequence of reactivities of 2-, 3-, and 4-MP obtained under
conditions which restrict the occurrence of subsequent reactions is similar to the rate of
deuteration of the methyl groups in these compounds [2], and also to their reactivity in pro-
totropic reactions, for example with sodamide [3]. In the quinoline series, 4-MQ also under-
goes vapor phase oxidation more readily than 2-MQ both in total and partial oxidation (Table
i). These facts lead to the conclusion that the limiting step in the heterogeneous catalytic

Institute of Organic Chemistry, Academy of Sciences'of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 75-79, January, 1986.
Original article submitted May 7, 1985.

0009-3122/86/2201-0063512.50 9 1986 Plenum Publishing Corporation 63

 TABLE i. Rates and Selectlvity of Oxidation and Methylhetero-
cyclic Compounds over Vanadyl Polyphosphate

Con%"
pond 2 seC) I v i np ridineal-
Compound oxidized Idehy~es, %
J Wtot ~l J
I Pyridne (P).,
2-Methylpyridine (2-MP) 2,9
2 4,8 3,0 60
;3 3-Meuhylpyridine (3-MP) 3,0
4-Methylpyridin~ (4-MP) 0,3 8
4 5,0 3,:3
,5 2,3-Dime~ylpyridine (2,3-DHP) 3,9 3,2 81
6 2,4-Dimethylpyridine (2,4-DMP) 4,8 2,2 48
7 2,5-Dimethylpyridine (2,5-DMP) 3,9 1,7 44
8 2,6-Dimethylpyridine(2,6-DMP) 4,8 3,2 86
9 3,4-Dimethylpyridine (3,4-DMP) ,%6 3,7 65
I0 3~5-~imethylpyridine (b,5-DMP) 2,6 0,3 8
11 2,4,6-Trimethylpyridine(2,4,6-TMP) 3,7 1,8 47
12 2-Me~lyl-5-ethylpyridine(MEP) 3,0 1,6 56
13 Methylpyrazine (MP) 1,3 1,3 I O0
14 2,5-Dimethylpyrazine (DS~Z) 2,0 0,5 "~7
15 2-Hethylquinoline (Z-MQ) 2,4 2,1 89
16 4-Methylquinoline (4-~) 8,9 3,1 80

oxidation of nitrogen heterocycles has an ionic mechanism, and the rate of this step is de-
pendent on the mobility of hydrogen in the methyl group.
The variations in the reactivity of monomethylpyridines in vapor phase catalytic oxida-
tion are usually regarded as being due to the superimposition of r and inductive
effects. With methyl groups in the 3-position, there is no +M effect (the increased basic-
ity of pyridine consequent upon the introduction of a methyl group into this position is at-
tributed mainly to the +I effect), and the reactivity of 3-MP is similar to that of toluene.
However, in 2- and 4-MP conjugation is increased to such an extent that some authors have
assumed that the formation of quinoid structures is possible [3], the hydrogen of the methyl
group thereby becoming highly mobile. However, as a result of the high electronegative in-
ductive effect of the heteroatom at the 2-position, the shift in electron density at this
position is reduced, and reactivity of the 2-CH3 group is less than that of the 4-CH3 group.
Furthermore, according to nonempirical quantum chemical calculations [4], 2-MP should also
be more stable overall then 4-MP.
In the oxidation of di- and trimethylpyridines over a vanadium phosphate catalyst, this
sequence of reactivities of the methyl groups is maintained, i.e., the rates of conversion
of the CH3 group to CHO decrease in the sequence 4- > 2- and 6- > 3- and 5-. Similar behav-
ior has been found in the oxidation of pyridine bases over vanadium oxide catalysts [5].
Since, in nitrogen heterocycles, interaction with acidic sites on the catalyst surface
is most likely, to a first approximation it is desirable in assessing the effects of adsorp-
tive interactions on reactivity to compare the reactivities of these compounds with their
basicity.
An experimental measure of the basic properties of molecules in the vapor base is pro-
ton affinity (PA). However, the literature data on the PA of nitrogen heterocycles is high-
ly ambiguous [6, 7]. For example, even using the same method of measurement, for pyridine
the values vary from 908.7-943.0, and for 2-MP from 922.5-961.4 kJ/mole. We therefore re-
sorted to a theoretical measure of basicity, namely the value of the negative charge on the
nitrogen atom (qN), as calculated by the MO LCAO PPDP/2 method, which provides a good de-
scription of the electron density distribution in organic molecules [8].
For all the compounds examined, as qN is increased, the overall reaction rate increases
(Fig. i). For compounds 1-14, this relationship may be described by a trinomial equation,
with a correlation coefficient of 0.89:
lnWcot = -2,4-21.TqN+O.TEEs~
S=0.18; F=345,
where EEs ~ is the sum of the steric coefficients [9], which characterize steric hindrance in
the reaction of the N-heterocycle with the catalyst, involving the nitrogen atom. The points
for 2- and 4-MQ do not lie on this plot.

64
 1,8 In V~ot

1,5 9
1~" ~ 5 o16
1,0 I~ Wa
075
a "0" /
~'5~2"/ ~,
1,5 lnw,,
1,0
b
'Z 9/

IO/'
0 11 7
I(I 12"~ "3 7 12
-0,5 In Wa=3,0+0,9 tnqc(cH3)
o15 X 0
-1 - 0,5 r=0,93; S=q23; F=56,2
0
0,7 1~13 -1,0
,, L i X6 .... 3" /'~0 I i itrtqcccH3)
I 0,9 1,1 -5 -4 -3 -2
- 0,20 -0,16 -0,12 -0,08 O,5 0,7
Fig. 1 Fig. 2
Fig. i. Plot of Wto t against the charge on the nitrogen atom.
Fig. 2. Plots of inW a against the induction contant (a) and the charge on the carbon
adjacent to the methyl group (b).

As is well known, the heteroatom in pyridine may be regarded as a substituent introduced

into the benzene ring in place of the CH fragment. In this case, the rate of formation of
monoaldehydes in the oxidation of compounds 2-12 is satisfactorily approximated by a Hammet-
type equation with o-constants describing the electron-acceptor properties of the he teroatom
(Fig. 2a):

In W.= -3.5+4.6Eo; r=0.93; S=0.41.

In the case of 2,3- and 2,4-DMP, the sigma constants used were the sums ON2 + on-CH 3 and
(ON~ + On_CH3) , as in [ii].
Since these o-constants were calculated [12] from the rate of replacement of chlorine
by alkoxy-groups in pyridines, it may be that their use here indicates a similarity in the
transmission of electronic effects in nucleophilic substitution and in vapor-phase catalytic
oxidation at the stage of interaction with the catalyst.
From the values of the reaction constant s, obtained from the inWa-o plots, two conclu-
sions may be drawn with respect to the mechanism of the partial oxidation of methylhetero-
cycles: i) Oxidation of the CH3 group to CHO is a nucleophilic reaction, and 2) the surface
complex in the transition state is largely ionic in character.
These features of the mechanism of the oxidation of methylpyridines appear to hold true
both for vanadyl phosphate and vanadium-molybdenum oxide systems.
The description of oxidative reactions of other methylheterocycles in a single series
with methylpyridines by a Hammet-type equation has not so far been possible as a result of
the absence from the literature of o-constants which take fully into account electronic in-
teractions in these compounds.
The positive values of the parameter p obtained for the partial oxidation of methylpy-
ridines lead to the conclusion that the reaction proceeds the more readily as the electron
density at the ring carbon adjacent to the methyl group is reduced. It has in fact been
found that an adequately linear in Wa--ln qC(CH)s plot is obtained for methylpyridines (Fig.
2b).
Correlational analysis shows that the principal features determining the overall reac-
tivity of methylheterocycles in vapor-phase catalytic oxidation are the basic properties of
the heteroatom, and in partial oxidation to the aldehydes, tile most important factor is the
electron density at the ring carbon atom attached to the methyl group, which is dependent on
the electron-acceptor properties of the heteroatom.
Taking some diazines and quino]ines as examples, we have shown that the incorporation
of methylheterocyclic compounds of different types into an overall reaction series appears
to require the use of multifactorial correlational relationships which take into account the
basic properties and the structural features of the compounds to be oxidized, which have a
considerable influence on the mechanism of the oxidation reaction.

65
 Since such information is not atpresent available to us, a quantitative description of
the rates of catalytic oxidative reactions using the approaches developed here has been ob-
tained for pyridine derivatives only.

EXPERIMENTAL
Oxidations were carried out in a microreactor (3 ~:m ~ ].2 ~m) in the pulsed mode. The
catalyst volume was 0.5 ml, and the free volume of the reacLor was packed with quartz. The
preparation and properties of the catalyst have been described previously [13].*
The grain size of the catalyst and the inert packing w~th 0.25-0.5 mm. The impulse vol-
ume was 0.4 ~i, and the air flow 40 ml/min. The reaction products were analyzed chromato-
graphically on a column with a stationary phase containing 2.5% of Reoplex 400 and 10% SE-301
on Chromosorb W-AW (40-60 mesh), The column temperature was 120-160~
Before use, the compounds were dried over KOH and redistilled over CaH2. 2-MP, 4-MP,
and 1,6-DMP were first purified by crystallization of their complexes with Mn(CNS)2, CaCI2,
and urea, respectively.

LITERATURE CITED
i. L. Ya. Leitis, M. V. Shimanskaya, and V. A. Slavinskaya, Khim. Geterotsikl. Soedin., No.
6, 1061 (1968).
2. N. N. Zatsepina and I. F. Tupitsyn, Advances in Heterocyclic Chemistry [in Russian],
Zinatne, Riga (1976), p. 32.
3. H. C. Brown and W. A. Marphey, J. Amer. Chem. Soc., 73, 3308 (1951).
4. J. E. Del Bane, J. Amer. Chem. Soc., I01, 6184 (1979).
5. Yu. Sh. Gol'dberg and M. V. Shimanskaya, Izv. Akad. Nauk Latv. SSSR, Ser. Khim., No. 6,
731 (1977).
6. R. Welder and J. L. Franklin, J. Mass Spectrom. and Ion Physics, 36, 85 (1980).
7. D. H. Aue and M. T. Bowers, in: Gas-Phase Ion Chemistry, Vol. 2, M. T. Bowers (ed.),
Academic Press, New York (1979), p. 2.
8. G. Klopman and R. Ivens, in: Semiempirical Methods for the Calculation of Electronic
Structures [Russian translation], Mir, Moscow (1980), p. 47.
9. V. A. Pal'm, Fundamentals of the Quantitative Theory of Organic Reactions [in Russian],
Khimiya, Leningrad (1977).
lO. I. F. Tupitsyn, N. N. gatsepina, N, S. Kolodina, and A. A. Kane, Reakts. Sposob. Org.
Soedin., ~, 931 (1969).
Ii. N. N. Zatsepina, I. F. Tupitsyn, and A. V. Kirova, ibid., ~, 195 (1972).
12. M. Liveris and J. Miller, J. Chem. Soc., 3486 (1963).
13. R. A. Skolmeistere, L. Ya. Leitis, M. V. Shlmanskaya, Ya. Ya. Gedrovits, and Z. A. Kon-
stant, in: The Mechanisms of Organic Reactions. proceedings of the 3rd All-Union Con-
ference [in Russian], Novosibirsk, part 2, p. 1664 (1982).
*We thank our colleague at the Institute of Inorganic Chemistry of the Academy of Sciences of
the Latvian SSR u Ya, Gedrovits for the gift of catalyst samples.

66
SYNTHESIS AND RING-CHAIN ISOMERISM OF N-MONOSUBSTITUTED
4-BENZOYLNiCOTINAMIDES AND 3-BENZOYLISONICOTINAMIDES

R. E. Valter, and A. E. Batse, and M. V. Petrova UDC 541.62:547.824'826.1'298.1

4-Benzoylnicotinoyl and 3-benzoylisonicotinoyl chlorides have been found to ex-

ist in cyclic forms (3-chloro-3-phenyl-6(or 5)-azaphthalides), and their benzyl-
amides also occur as the cyclic forms (azaisoindolinones). The tert-butylamides
of both acids are obtained in the open amide forms. It has been shown by PMR
that N-tert-butyl-4-benzoylnicotinamide displays a greater tendency to undergo
closure of the isoindolinone ring (KT = 0.24 in CDsOD) than does N-tert-butyl-3-
benzoylisonicotinamide (KT = 0).

Ring-chain isomerism in 2-acylbenzoic acids has been the subject of thorough study [i],
but in the case of heterocyclic o-carboxylic acids this phenomenon has received little atten-
tion [2].
The object of this investigation was to synthesize and examine the ring-chain isomeric
interconversions of N-monosubstituted 4-benzoylnicotinamides and 3-benzoylisonicotin~mides,
and of their protonated forms. According to their IR spectra, both acids (I, III) resemble
2-aroylbenzoic acids [i] in the crystalline state, whereas in solution in dioxane they exist
in the open (ketocarboxylic) forms.

I I =--_ so=,,
Y COC~s Cell5 B O H C6H ~ "el
A
I-IV I-IV 'V.VI

, _ _

Y ~" Y .-.. N..

CeH s Oil A
VII=X ~-XIV X~-XIY

[, VII, XI X=N; II, V, VIII, XII X=N+H CI-; llI, IV, VI, IX, X, XIII, XIV X=CH;
I, II, V, VII, VIII, XI, XII Y=CH; III, VI, IX, XIII Y=N; IV, X, XIV Y=N+HCI -

Their hydrochlorides (II, IV) also possess the open structure, although in the IR spect-
rum of 3-benzoylisonicotinic acid hydrochloride (IV) there is weak absorption at 1805 cm -I,
indicating the presence of small amounts of the lactol form (IVB).
Treatment of the acids ( I ) a n d (III) with thionyl chloride affords the acid chlorides,
which exist in the cyclic chlorolactone form (V, VI), which is also characteristic of 2-
acylbenzoyl chlorides [i]. This is confirmed by the presence in their IR spectra of one,
and only one C=O band at -1800 cm -I. The chlorolactone (V~ was isolated as its hydrochlor L-
ide, and (VI) as the free base.
Acylation of benzylamine with the chlorolact0nes (V) and (Vl) gave the cyclic isomeric
amides (2-benzyl-3-hydroxy-3-phenyl-6-(or 5)-azaindolinones VII and IX), the IR spectra of
which showed broad OH absorption typical of intermolecularly associated hydroxyl groups (O--
H...O=C or O--H...N ) together with C=O absorption for the isoindolinone at 1703-1685 cm-*
(in Nujol). On passing from the crystalline state to the dioxane solution, there is a char-
acteristic shift in this absorption towards higher frequencies as a result of fission of the

A. Ya. Pel'she Polytechnic Institute, Riga 226355. Translated f r o m Khimiya Gerero-

tsiklicheskikh Soedinenii, No. i, pp. 80-83, January, 1986. Original article submitted
November 23, 1984.

0009-3122/86/2201-0067512.50 9 1986 Plenum Publishing Corporation 67

 x111

~k

Fig. i. IR spectra of crys-

talline N-tert-butylamides
W and their hydroch!orides.

O-H...O=C hydrogen bonds.

chlorides (Vlll, X).
I
700 1600 1500
#, cm'
The cyclic isoindolinone structure is retained in their hydro-

It is known [3] that cyclization of 2-acylbenzamides is prevented by the presence of a

tert-alkyl substituent on the nitrogen atom, and it has now been found that acylation of
tert-butylamine by the chlorolactones (V) and (VI) affords the N-tert-butylamides (XI) and
(XIII). Their IR spectra, obtained in Nujol, show absorption for N--H, C=O, amide-l, and
amide-ll. In the spectra obtained in dioxane solution, the absorption for the ketone C=O
and amide-I overlap, and a single band is seen at 1670 cm-*. This, together with the pre-
sence of the amide-ll band, confirms the open structure of amides (XI) and (XIII) in dioxane
solution.
The PMR spectrum of the amide (XI), obtained in CD3OD, shows two signals for the pro-
tons of the tert-butyl group (6 = 1.12, form A, and 1.43 ppm, form B), which is characteris-
tic of the ring-chain equilibrium XIA $ XIB [4]. The ratio of intensities gives the equili-
brium constant, K T = [XIB]/[XIA] = 0.24. In the PMR spectrum of the amide (XIII), there is
only one signal for the tert-butyl group at 1.13 ppm, confirming that this amide exists only
in the open form (XIIIA) in solution in CDsOD, within the limits of sensitivity of the PMR
method.
The same capacity to exist in the cyclic form is also seen in the crystalling hydro-
chlorides (XII) and (EIV). The IR spectrum of the hydrochloride (XIV), over the range 1800-
1480 cm -~, differs little from that of the base (XIII). The appearance of a low-intensity
band at 1698 cm-* (Fig. I) could be due to the presence of small amounts of the protonated
cyclic form (EIVB). The IR spectrum of the hydrochloride (XII) shows a strong, broad band
for the isoindolinone C = C at 1707 cm-*, and generally speaking the spectrum at 1800-1480 and
3600-2400 cm-* is similar to that of 2-benzyl-3-hydroxy-3-phenyl-6-azaindolinone (VIII), thus
confirming the cyclic structure of 2-tert-butyl-3-hydroxy-3-phenyl-6-azaindolinone hydrochlor-
ide (XIIB).
It has thus been shown, taking the N-tert-butylamides as examples, that 4-benzolnicotin-
amide shows a sreater tendency to exist in cyclic forms as a result of intramolecular addi-
tlon of the amide N--H to the C = O bond than does 3-benzoylisonicotinamlde. This behavior also
holds true for the hydrochlorides.

EXPERIMENTAL
IR spectra were obtained on IKS-14A and Specord 75-IR instruments, as suspensions in
Nujol and as solutions in dioxane (c = (2.5-5).10 -2 mole). PMR spectra were obtained on a
Tesla BS-487C (80 MHz) in solution in CD,OD at 25~
4-Benzolnicotinic acid (I) was obtained as described in [5], mp 215-219~ IR spectrum
(Nujol): 2400 (broad band, COOH), 1706 (COOH), 1669 (C=O), 1592, 1577, 1552; (dioxane):
1721 (COOH), 1680 (C=O), 1595, 1581, 1551 cm -~.

68
 Hydrochloride (II). To a solution of 0.i g of the acid (I) in 2 ml of anhydrous diox-
ane was added 5 ml of ether saturated with dry hydrogen chloride. There was obtained 0.i g
(86%) of colorless cyrstals, mp 238-242~ (decomposed) IR spectrum (Nujol): 3353, 3282,
3097, 2955, 2858, 2727 br. 2578 br., 2457 br., 1805, 1721, 1680, 1634, 1595 cm -z. Found:
C1 13.0%. C13HIoCINOs. Calculated: C1 13.4%. e

3-Benzoylisonicotinic acid (III) was obtained as described in [5], mp 272~ (decomposed).

IR spectrum (Nujol): 2417 (br., COOH), 1722 (COOH), 1670 (C=O), 1594, 1563; (dioxane): 1730
(COOH), 1676 (C=O), 1595, 1580, 1551 cm -~
Hydrochloride (IV) was obtained similarly to the above. IR spectrum (Nujol): 3369 br.,
3098, 3071, 2690, 2580, 2352 hr., 1722, 1677, 1635, 1588, 1507 cm -l. Found: C1 13.0%.
C~3HIoCINO3. Calculated: C1 13.4%.
3-Chloro-3-phenyl-6-azaphthalide Hydrochloride (V~. A solution of 0.46 g (2 mmole) of
the acid (I) and 1.4 ml (20 mmole) of thionyl chloride in 15 ml of benzene was boiled for 4
h. After 24 h, 0.51 g (90%) of colorless crystals of (V) were isolated, mp 171-173~ (de-
composed). IR spectrum (Nujol): 3095, 3066, 2869 br., 1814 (C---O), 1644, 1606, 1506 cm -~.
Found: C1 24.6%. C~3HgCI~NO2. Calculated: C1 25.1%.
3-Chloro-3-phenyl-5-azaphthalide (VI) was obtained as in the foregoing example, mp 174-
176~ IR spectrum (Nujol): 3044, 3017, 2698, 2931, 1799 (C=O), 1618, 1549 cm -I. Found:
C1 14.90%. C~3HeCINO2. Calculated: C1 14.43%.
2-Benzyl-3-hydroxy~3-phenyl-6-azaindolinone (VII). The hydrochloride (V) (2.5 mmole)
was suspended in i0 ml of dioxane, and added to a solution of 2.5 mmole of benzylamine and
5 mmole of triethylamine in 5 ml of dioxane. The mixture was kept for 12 h at 20~ then
diluted with i00 ml of water, the solution saturated with sodium chloride, and 0.74 g (94%)
of (VII) isolated, mp 183~ Two recrystallizations from ethanol gave 0.36 g (46%) of color-
less crystals, mp 205-206~ IR spectrum (Nujol): 3390, 3057 br., 2920, 2830 br., 1703 (C=
O), 1609; (dioxane): 1711 (C=O), 1603, 1409 cm -I. Found: C 76.1; H 5.3~ N 90%. C2oH~6N202.
Calculated: C 75.9; H 5.1; N 8.9%.
Compounds (IX), (XI), and (XIII) were obtained similarly from the chlorophthalides (V)
for (XI) and (VI) for (IX and XIII), and benzylamine for (IX) or tert-butylamine for (XI) and
(XIII with the addition of triethylamine.
HYdrochloride (VIII). To a solution of 0.14 g of the isoindolinone (VII) in 2.5 ml of
dioxane was added 15 ml of ether saturated with dry hydrogen chloride. There was obtained
0.16 g (100%) of colorless cyrstals of the hydrochloride (VIII), mp. 234-236~ (decomposed).
!R spectrum (Nujol): 3412 hr., 3051, 2584 br., 1716 (C=O), 1646, 1613, 1536 cm -~. Found:
C 69.3; H 5.1; C1 10.3; N 8.0%. C2oH~TCIN202. Calculated: C 68.1; H 4.9; C1 i0.0; N 7.9%.
Hydrochiorides (X), (XII), and (XIV) were obtained similarly.
2-Benzyl-3-hydroxy-3-phenyl-5-azaindolinone (IX). Yield 94%, mp 95-98~ After three-
fold recrystallization from benzene--hexane, mp I03-I06~ (decomposed). IR spectrum (Nujol):
3410 br., 3357 pl., 3157 br., 3067 sh., 2845, 1685 (C=O), 1591; (dioxane): 1714 (C=~O), 1590
cm -~. Found: C 75.3; H 5.1; N 8.3%: C2oHI6N202: Calculated: C 75.9; H 5.1; N 8.9%.
Hydrochloride CX). Mp 220-222~ (decomposed). IR spectrum (Nujol): 3352 hr., 3126,
3080, 3030, 2483 br., 1720 sh., 1706 (C=O), 1619 cm -2. Found: C 67.9; H 4.6; C1 10.9; N
8.0%. C2oHITCIN202. Calculated: C 68.1; H 4.9%; C1 I0.0; N 7.9%.
N-tert-Butyl-4-benzoylnicotinamide (XI). After two recrystallizations from benzene--
hexane, yield 36%, mp I19-i20~ IR spectrum (Nujol): 3269 (N--H), 3068, 2979, 1674 (C~O),
1632 (amide-I), 1596, 1581, 1556 (amide-II); (dioxane): 1671 (C=O + amide-l), 1594, 1581,
1552, 1531 cm -I (amide-II). Found: C 71.7; H 6.8; N 9.9%. C17HIsN202. Calculated: C
72.3; H 6.4; N 9.9%.
Hydrochloride (XII). Mp 224~ (decomposed). iR spectrum (Nu~ol): 3393, 3100, 3058,
2954, 2508 br., ]707 (C=O), 1643, !619, 1543 cm -~. Found: C 64.1; H 6.0; C! 11.4; N 8.7%.
C~TH~gCIN20=. Calculated: C 64.0; H 6.0; C1 ii.i; N 8.8%.
N-tert-Butyl-3-benzoylisonicotinamide (XIII). After two recrystallizations from ben-
zene--hexane, yield 56%, mp IIO-III~ IR spectrum (Nujol): 3390 (N--H), 3211 (N-H), 3066,
3043, 2989, 2968, 2931, 2902, 1671 (C=O), 1642 (amide-I, 1593, 1578, 1544 (amide-II); (diox-
ane): 1668 (C~O + amide-I), 1594, 1579, 1540 sh., 1529 cm -~ (amide-II). Found: C 71.6; H
6~6; N ]0.0%. C~THIsN202. Calculated: C 72.3; H 6.4; N 9.9%.

69
 Hydrochloride (XIV). Mp 220-222~ (decomposed). IR spectrum (Nujol): 3361 (O--H),
3096 (N-H), 3062, 2976, 2923, 2501 br., 1698 (isoindolinone C=O), 1668 (C=O + amide-I),
1657 sh., 1634, 1595, 1551 cm -~ (amide-II). Found: C 63.8; H 6.2; C1 11.3; N 8.7%. C~TH~9-
CINa02. Calculated: C 64.0; H 6.0; C1 ii.i; N 8.8%.

LITERATURE CITED
i. R . E . Valter, Ring-Chain Isomerism in Organic Chemistry [in Rusdian], Zinatne, Riga
(1978).
2. B. Paul and B. Korytnyk, J. Heterocyc. Chem., 13, 701 (1976).
3. G . A . Karlivan, R. E. Valter, and S. P. Valter, Zh. Org. Khim., 13, 805 (1977).
4. R . B . Kampare, R. ~. Valter, E. E. Liepin'sh, and G. A. Karlivan~-Izv. Akad. Nauk. Latv.
SSR, Ser. Khim., No. 2, 244 (1981).
5. A . A . Artamonov, T. Shneider, and N. V. Baranova, Khim. Geterotsikl. Soedin., No. 4,
514 (1980).

ACETALS OF LACTAMS AND ACID AMIDES.

46.* UNUSUAL REACTIONS OF ~-CYANO-B-DIMETHYLAMINOCROTONAMIDE
WITH ANTHRANILIC ACID DERIVATIVES

N. Z. Yalysheva, V. V. Chistyakov, and V. G. Granik UDC 547.391.3'398.1'583.5'

856.1'831:543.51'422

It has been shown that the reaction of the enaminoamide a-cyano-8-dimethylamino-

crotonamide with anthranilic acid and its ethyl ester unexpectedly gives quina-
zoline-2,4-dione and 2-methyl-3-cyano-4-quinolone, respectively. The structures
of the products were confirmed by their spectra and by direct synthesis.

It has been shown [2] that tertiary enaminoamides react with aromatic amines, the trans-
amination being best effected in acetic acid. For this reason, it was attempted to carry out
this reaction with ~-cyano-B-dimethylaminocrotonamide (I) and ethyl anthranilate (II) in or-
der to obtain the secondary N-arylenemonoamlde (III), which has a functional substituent (the
ethoxycarbonyl group) in the ortho-position in the benzene ring. The product obtained was
the compound (IV), the mass spectrum of which contained three main peaks%, viz., the molecu-
lar peak (162), 119 (M -- CONH) +, and 92, The IR spectrum of the compound showed absorption
at 1670 and 1700 cm -~ (CO), 3160 and 3250 cm -~ (NH). These findings, together with the ele-
mental analysis, lead to the conclusion that the reaction of (I) and (II) follows an unexpec-
ted route to give quinazoline-2,4-dione (IV). The structure of (IV) was confirmed by compar-
ison with an authentic sample synthesized by a literature method [3].

*For communication 45, see [i].

%Here and subsequently, the m/z values for the peaks are given (with the intensity relative
to the maximum ion peak, %, in parentheses.

S. 0rdzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,

Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. I, pp. 84-87,
January, 1986. Original article submitted November 27, 1984.

70 0009-3122/86/2201-0070512.50 9 1986 Plenum Publishing Corporation

 Me CONII 2 /.~.. .COOEL
,:::_.= ...../.t.. ~ "-'" " Me
. . . . ., ,.. J->. / CONII~
(Me).,N CN "'"-/ "N '~' " "
U "x'CN

.., cooer
ri/>] o
hie CN "/ "NIl.. "~ .
: + HN,'o ...................... &.~!
(Me)2N
)-~<, ,
l~ 11 " <>-"
,~.
i"
, :-:" 0
"N "
H
I), iv
NH 2 o

11 CN
"~~ q Oi~ O " Oil "
..... j. li .... ~ ...... I. )1 ...... ? il
M,a" " "[" " Me
CN
~~ ' ) ..... "~
CN
~~ 1CN '~ "~ "~'i
CN
''~ ~" T
CN
'~
v

The f o r m a t i o n o f the q u i n a z o l i n e d i o n e (IV) may be r a t i o n a l i z e d as follows. On h e a t i n g i n

acetic acid the enaminoamide (I) undergoes reversible c l e a v a g e o f HNCO, f o l l o w e d by c y c ! i z a -
tion. A s i m i l a r c l e a v a g e o f HNCO h a s b e e n p o s t u l a t e d p r e v i o u s l y i n t h e c a s e of N - c a r b a m o y l -
amidines [4]. Heating the enaminoamide (I) in acetic acid in the absence of ethyl anthrani-
l a t e ( I I ) a f f o r d s a complex mixture, from which 4 , 6 - d i m e n t y l - 5 - c y a n o - 2 - p y r i d o n e (V~ wa~ i s o -
lated [5]. The PMR s p e c t r u m o f t h i s compound (DMF-D6) showed s i g n a l s f o r t h e 4 - and 6 - m e t h -
y l g r o u p s a t 2 . 2 5 and 2 . 4 8 , r e s p e c t i v e l y , and s i g n a l s a t 6 . 1 2 (3-H) and 7.95 ppm (NH). The
mass spectrum of (V) contained a strong molecular ion peak at 148 (78). The principal mode
of mass spectral fragmentation was elimination of CO (as in unsubstituted u-pyridone) to
give a fragment of mass 120 (51), from which a hydrogen atom is eliminated to give a stable
fragment 119 (i00). The formation of the quinazolinedione (IV) and the pyridone (V) is
shown by the scheme above.
It is noteworthy that (V) was previously synthesized from 8-aminocrotononitrile [5].
The IR spectrum of (V) shows absorption at 720, 870, 1370, 1410, 1615, 1660, 2210, and 3400
cm -~, in full agreement with the data reported in [5]. The next step in this investigation
was to attempt to carry out the transamination reaction with anthranilic acid (VI) rather
than with ethyl anthranilate (II). Heating (I) and (VI) in acetic acid gave a complex mix-
ture (which contained no starting materials), from which it was possible to isolate 2-methyl-
3-cyano-4-quinolone (VII) [6] in low yield. The structure of the quinolone (VII) was con-
formed by its mass spectrum, in which the strongest peak was for the molecular ion, 184 (i00).
One of the main routes of mass spectrometric fragmentation, as in the case of unsubstituted
7-pyridone [7]) is elimination of carbon monoxide from M +" to give the indole ion-radical 156
(15), which in turn decomposes in the well-known way with loss of a hydrogen atom and HCN to
give the ion 128 (5). The spectrum also contains ion peaks at 130 (4), 129 (6), and 92 (ii).
The quinolone (VII) was also obtained by direct synthesis from a-ethoxycarbonyl-B-anilino-
crotononitrile (VIII) by the literature method [6]. The formation of the quinolone (VII) ap-
pears to be also due to the conversion of the enaminoamide (I) into fl-dimethylaminocrotono-
nitrile (IX), which then undergoes deamination to (X) and cyclization, since under these con-
ditions (heating in acetic acid) ~-cyano-fl-anilinocrotonamide (XI) does not cyclize to (VII).
A likely scheme for the formation of the latter is shown below.

~ COOH COOH CN
Me Me
,~.)~N J-.
/ ">11"
CN L ~ T
CONH a
(Me)2N /
T
"V
H
LX
CN + Lc )1
VI
......
.~.'"
L
t
H

X
J
/ IJ ~ CN I|2NOI~.
i~/":'-)'[ "" " , , / A (CH,COOH) ,} :~ ~. CN

"'" "" ~ ' N "Me ""~ "'N'" ''Me

I[ H
VII X[

According to this scheme, the B-monosubstituted enamine (IX) reacts with anthranilic
acid (VI). It was of interest to examine this reaction in another case, namely the reaction
of the acid (VI) with 8-aminocroton~c ester (XII). On heating these compounds in acetic acid,

71
a mixture of two compounds was obtained, which was separated by treatment with caustic alk-
ali. Using this method, it was possible to isolate the previously-described 2-methyl-4-
quinolone-3-carboxylic acid (XIII) [8] and the pyranoquinolone (XIV), into whicl~ it is sub-
sequently converted under these conditions. The mass spectrum of (XIII) contained a strong
peak for the molecular ion at 203 (75), and peaks for [M - CH3] + at 188 (i00), 120 (35), at-
tributed to the fragment H2NC6H~C~O +, 92 (C6H,NH= +, 25) and 77 (Ph+, 11). The (X!V) mole ~
cule is stable to electron impact. The spectrum shows a strong molecular ion peak, M+" 227
(81), [M-- CO] + 199 (I00), and probably [M -- CH~COCH3] + 170 (59). The IR spectrum of (XIV)
shows absorption at 3160 (NH), 1750 (lactone CO), and 1670 cm "t (quinolone CO), confirming
the presence of the pyran ring. The PMR spectrum in DMSO-D6 also corresponds to the proposed
structure, signals being present for CH3 at 2.61, CH at 6.26, and Ph at 7.21-8.10 ppm.

~.~ . o 9
L', 9 "cooI-t
[.. CtPOEt -~Nl:ia,-H20 ~ .-J" .' . . . .
'-" "~NH~ /
NH ~
"" /
i
" : " "N'"
1t
""Me "N" " ' ~
It
.Me
H
VI Xll Xlll XIV '

To conclude this investigation, it was found that when the enaminoamide (XV) (which does
not contain a CHa group in the ~-position of the enamine) reacts with ethyl anthranilate or
anthranilic acid, the normal transamination products (XVIa, b) are formed.

~COOR ~ (COOR
H
+ I
~"" ~NH2 NH2 "!'Nt~ "~ "N-
11
CH:=C""
~CONH z

ILVI XY .V,'~ a ~ : : - ~ t ; b g ~ H
II R = E t ; VI R = H

EXPERIMENTAL
Mass spectra were obtained on a Varian MAT-II2 spectrometer with direct introduction of
the sample into the ion source. The ionization chamber temperature was 180~ and the energy
of the ionizing electrons 70 eV. IR spectra were obtained on a Perkin-Elmer 457 in vaseline
oil.
quinazoline-2,4-dione (IV). A mixture of 1.53 g (I0 mmole) of the enamine (I) and 4.95
g (30 mmole) of the ester (II) in 15 ml of glacial acetic acid was boiled for 5 h, then
cooled, the solid filtered off, and washed with water and alcohol to give 0.9 g (50%) of (IV)
mp 350~ (from DMF). Found: C 59.0; H 4.1; N 17.4%. CaH6NaO~. Calculated: C 59.3; H 3.7;
N 17.3%.
4,6-Dimethyl-5-cyano-2-pyridone (V). A solution of 0.5 g (3.3 mmole) of the enamine
(I) in i0 ml of glacial acetic acid was boiled for 2.5 h, evaporated, filtered, and washed
wit b alcohol to give 0.05 g (10%) of (V), mp 294-2960C (from methanol) [5]. Found: C 64.8;
H 5~6; N 19.2%. CaHeN20. Calculated: C 64.9; H 5.4; N 18.9%.
2-Methyl-3-cyano-4-quinolone (VII). A mixture of i g (6.5 mmole) of the enamine (I)
and 2.74 g (20 mmole) of the acid (VI) in i0 ml of glacial acetic acid was boiled for 7 h.
The solid which separated was filtered off and washed with water and alcohol to give 0.i g
(8%) of (VII), mp 360-368~ (from DMF) [6]. Found: C 71.7; H 4,4; N 15.2%. CttHeN=O.
Calculated: C 71.9;H 4.3; N 15.5%.
2-Methyl-4-quinolone-3-carboxylic Acid (XVIII and 3-Methyl-!,2,5,10-tetrahydropyrano
[4,3-b]quinoline-l,lO-dione (XIV). A mixture of 1.26 g (i0 mmole) of 'the ester (XII) and
4.11 g (30 mmole) Of the acid (Vl) in i0 ml of glacial acetic acid was boiled for i0 h, eva-
porated, filtered, and washed with alcohol to give 0.32 g of a mixture of (XIII) and XIV).
The mixture was dissolved in 0.02 N NaOH, and the insoluble solid filtered off and washed
with water and alcohol to give 0.08 g (4%) of (XIV), mp 300~ (from DMF). Found: C 68.4;
H 3.8; N 5.9%. CIaH3NO3. Calculated: C 68.7; H 4,0; N. 6.2%.
The mother liquors were acidified with HCI to pH 3-4, and the solid which separated
was filtered off, and washed with water and alcohol to give 0.09 g (4%) of (XIII), rap 239-
243~ (from DMF)[8].

72
 ~-Cyano-~-(o-ethoxycarbonylphenyl)aminoacrylamide (XVIa). A mixture of 0.6 g (4.3
mmole) of the enamine (XV) and 2.5 g (15 mmole) of the ester (II) in i0 ml of glacial acetic
acid was boiled for 6 h, cooled, and the solid filtered off and washed with water and alco-
hol to give 0.24 g (19%) of (XVIa), mp 227-229~ (from DMF). M +" 259. Found: C 60.3; H
5.2; N 16.5%. C~HI3N30~. Calculated: C 60.2; H 5.0; N 16.2%.
a-Cyano-~-(o-carboxyphenyl)aminoacrylamide (XVIb). A mixture of 0.6 g (4.3 mmole) of
the enamine (XV) and 2 g (15 mmole) of the ester (II) in i0 ml of glacial acetic acid was
boiled for 6 h, cooled, and the solid filtered off and washed with water and alcohol to give
0.24 g (19%) of (XVIa), mp 227-229~ (from DMF). M +" 259. Found; C 57.0; H 3.9; N 18.1%.
Calculated: C 57.1; H 3.9; N 18.2%.

LITERATURE CITED
l~ L. V. Ershov and V. G. Granik, Khim. Geterotsikl. Soedin., No. 7, 929 (1985).
2. L. V. Ershov, S. S. Kiselev, and V. G. Granik, Khim. Geterotsikl. Soedin., No. 4, 538
(1984).
. Organic Synthesis, A. H. Blatt (ed.), Wiley, New York; Chapman and Hall, London (1946),
Coll. Vol. 2, p. 79.
. S. I. Kaimanakova, E. A. Kuleshova, N. P. Solov'eva, and V. G. Granik, Khim. Getero-
tsiklo Soedin.,No. Ii, 1553 (1982).
. K. Sato, M. Ohashi, T. Amakasu, and K. Takeda, Bull. Chem. Soc. Japan, 42, 2319 (1969).
6. R. J. Grout, B. M. Hynam, and M. W. Partridge, J. Chem. Soc., C, 1590 (1969).
7. G. Budzikevich, K. Djerassi, and D. Williams, Interpretation of the Mass Spectra of Or-
ganic Compounds [Russian translation], Mir, Moscow (1966).
. R. T. Coutts and D. G. Wiberley, J. Chem. Soc., No. 6, 2518 (1962).

SYNTHESIS OF 5-OXOINDENO[I,2-b]PYRIDINIUM SALTS

A. Z. Zandersons, V. K. Lusis, UDC 547.821.3'665.07

D. Kh. Mutsenietse, and G. Ya. Dubur

When N-methylated 4-aryl-5-oxo-4,5-dihydroindeno[l,2-b]pyridines are oxidized

with hydrogen peroxide in the presence of perchloric acid, in addition to the
formation of the indenopyridinium perchlorates, cleavage of the dihydropyri-
dine ring occurs, giving the 2-arylideneindan-l,3-dione.

We have previously converted the 1,4-dihydro-isomers of cyclic pyridine derivatives into

the corresponding 1,2-isomers by reducing pyridinium salts [i, 2]. Similar conversions of
polycyclic dihydropyridines such as dihydroindeno[l,2-b]pyridines have not been described.
The aim of this investigation was to develop methods for the synthesis of N-methyl-5-oxoin-
deno[l,2-b]pyridinium salts. The starting materials were 5-oxoindeno[l,2-b]pyridines (I) or
the N-methylated 5-oxo-4,5-dihydroindeno[l,2-b]pyridines (II) [3, 4]. In the case of pyr i-
dines (I), these were heated with methyl toluene-p-sulfonate or dimethyl sulfate. The use
of this classical method for the synthesis of the salts was restricted by preparative diffi-
culties, namely, resinification and the hygroscopicity of the products. When the salts (III)
were obtained as the monosulfates or tosylates, therefore, they were converted into the per-
chlorates by ion exchange by treatment with NaCIO4, since pyridinium perchlorates are read-
ily crystallizable compounds. A method used by us previously [I, 2] for the preparation of
pyridinium salts by the oxidation of N-methylated 1,4-dihydropyridines with hydrogen perox-
ide in the presence of perchloric acid was complicated in the indenopyridine series by the
occurrence of side reactions, i.e., in addition to salt formation, cleavage of the dihydro-

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp. 88-90. January, 1986.
Original article submitted December 3, 1984.

0009-3122/86/2201-0073512.50 9 1986 Plenum Publishing Corporation 73

 TABLE I. Properties of Indenopyridinium Perchlorates (III)

Found, % ~Iculated, %
:om- Np, ~ Empirical Yield; %
,ound
C H N
formula

Ilia 272--273 60,0 4,1 3,5 C2aH2oCINOz 60,3 4,4 3,1 55

lllb 210--213 58,8 4,5 3,1 C24H22CINO8 59,1 4,6 2,9 42
Illc 188--190 51,0 3,2 2,1 CmH,gBrCINO7 51,5 3,6 2,6 28
llld 237--240 54,5 3,8 5,.2 CmH I~C1N20~ 54,9 3,8 5,6 19
Ille 184--187 56,0 3,5 3,1 C23H19CI2NO7 56,1 3,9 2,9 27
Illf 230--232 54,5 3,5 3,0 C~4tt2oCIF~NO8 55,0 3,9 2,7 38
lllg 268--270 61,3 4,2 3,6 C~:Hz~ClNO~ 61,8 4,2 3,3 14
Illh 171--174 61,0 4,0 6,5 CmHIaCINaO5 61,4 3,7 6,8 48
llli 208~210 64,7 4,7 5,5 C~HmCIN~O~ 64,2 4,2 5,6 35

pyridine ring took place, which will be the subject of a further communication. Preparative-
ly, in addition to the salts (III), from the reaction mixture there were also isolated ti~e
acid hydrolysis products of (II) (in the case of (lla), 3%, (lib), 32%, and (llc), 10%). In
the oxidation of (lid), in addition to the expected 2-(p-nitrobenzylidene)indan-l,3-dione
(IVd) there was isolated 2-spiro-(2'-indan-l',3'-dione)-3-(4'-nitrophenyl)oxirane (V).
/ (I O Ar
II II ~Ar
~! "- I{ I1 ! .
V :} ....
<iT-" N' cl~_
i(. )i ti
N" CII~
t
II I
H:~%l ,
a-i I;113 c,O~
"HCI04 y] \" ,-4~ '
q,, ,

O s~r

0 / ~ ~O
o ,9
b _ / ~ ....... i,. j ; + i ~, ~; !. ~ ..:' . %;-::7---<( )? --N%
~"/ " " N" "" clI3 " ~' : : CH-Ar
i
IIIa-i Cl-la cPo. 0 V

II, llI a - f R=COOC2Hs, g R=COCH3, h R=CN, i R=CONHC6H~; a , g - - i Ar=C6H~,

b Ar=4-CH~OC6H4,c Ar=4-BrCeH4, d Ar=4-NO.~C6H4, e Ar=2-CIC6H4,f Ar=2-F2CHOC~H4

Clearly, the electron acceptor group in the 2-arylideneindan-l-3-dione activates the

>C=CH group, as a result of which addition of oxygen to this bond takes place under the
reaction conditions, giving the oxirane (V). The structure of (V) was confirmed by ~H and
ZaC NMR, IR, and mass spectroscopy, as well as by direct synthesis. It is noteworthy that
the synthesis of indan-l,3-dione derivatives of oxirane has hitherto been effected in basic
media only [5].
N-Methyl derivatives of 5-oxo-4,5-dihydroindeno[l,2-b]pyridine (II) are fairly readily
oxidized by atmospheric oxygen, since the salt (Ilia) was obtained in 55% yield on prolonged
boiling of (lla) in alcoholic solution acidified with HCIO4 (similarly, 28% of lllb was ob-
tained from lib). The 4-(p-nitrophenyl) derivative of the indenopyridine (lid) did not af-
ford the corresponding salt under these conditions, the reaction product being 2-(p-nitro-
benzylidene)indan-l,3-dione (IVd) (yields 40-60%).
The IR spectra of the 5-oxoindenopyridinium salts (III) show strong absorption for the
5-C0 group at 1735 cm-*. The absorption due to the CO at C(a) in the esters (Ilia-f) merges
with that for the 5-CO group, but in the 3-COCHa derivative (lllg) the absorption at 1712
cm-* is clearly separated. In the IR spectrum of (lllh), two amide bands are seen at 1694
and 1668 cm -I The type of anion in the salts (III) has no effect on these IR bands.

EXPERIMENTAL
PMR spectra were obtained on a Bruker WH-90 spectrometer in DMSO-D6, internal standard
TMS, and IR spectra on a PE 580 B. The compounds (II) were synthesized as described in [4].
The properties of the indenopyridinium perchlorates are given in Tables I and 2.
Synthesis of 1,2-Dimethyl-4-aryl-5-oxolndeno[l,2-b]pyridinium Salts (III). A. The in-
denopyridine (I) (i0 mmole) was heated with 2 ml of dimethyl sulfate (until a neutral reac-

74
 TABLE 2. PMR Spectra of 1,2-Dimethyl-4-aryl-5-oxoindeno[l,2-b]
pyridinium Perchlorates (III)

Compound 1-c[-I, 2-cH, iProtons at :.

(~3z~l (s,3m 3-. ,~-A~ ic(6,~_ c(9)
Ill a 4,47 2,84 0,86 ( t 31f}; 7,27--7,60 (m, 5H) 7,78--7,60 (m, 3H);
4,06 (q 2H) 8,32--8.52 (m, IH)
[IIb 4,51 2,88 ,,0l lq~ 3H}; 3,88 (s 3H); 7,79--8,10 (m, 3H);
4,19 ,2H) 7,12 (d 2H); 8,38--8,60 (m IH)
7,42 (d 2H)
IIIc 4,55 2,9l 0,93 (t 3H); 7,71 ~1,, 2H) 7,87--8,12 (r~ 3H)
4,12 !q, 2H} 8,36--8,61 (m, 3H)
IIId 4,52 2,90 0,99 (t 3H): 7,38 (d 2H); 17,87--8,09(m, 3H);
4,17 ~/q, 2H) 7,80 (,d, 2H) 18,42--8,58(m, 1H)
Ill e 4,55 2,94 0,89 ( t 3H); 7,18--7,71 (m, 4H) [7,83--8,09 (m, 3H);
,128 (o. 21]) ]8,42--8,60 (m, IH)
I!If 4,53 2,92 0,89 (~ 3H); 7,18 ('t; IH) /8,40--8,57 (m, IH)
4,10 (q, 2[t) IJh_ f=72,0 Hz] /
7,24--8,09 (m, 7H)
Illg 4,54 2,80 2,09 (s 3I-]) 7,31--7,68 (m, 5H) 7,83--8,03 (m, 3H);
8,40--8,58 (m, IH)
Illh 4,51 3,10 7,57 (s, 5H) 7,69--8,03 (m, 3H);
8,38--8,53 (ra, IH)
llli 4,62 2,94 7,49 ( s 5H): 7,07--7,43 (m, 5H) 7,84--8,31 (m, 3H);
10,79 (s IH) 8,44--8,60 (m, IH)

tion was obtained) for 6-8 h at 60-80~ The mixture was cooled, treated with ether, and
the solid separated and dissolved in the minimum amount of water. The aqueous solution was
saturated with NaCIO~, and the colorless or pale yellow indenopyridinium perchlorate which
separated was filtered off and recrystallized from propan-2-ol. Yield 35-60%. (In the case
of 1,2-dimethyl-3-acetyl-4-phenyl-5-oxoindeno[l,2-b]pyridinium monomethylsulfate, mp 250-
253~ yield 65%).
B. The indenopyridine (I) (3 mmole) and 1.5 g (8 mmole) of methyl toluene-p-sulfonate
were heated at 130-140~ for 12 h. The cooled reaction mixture was treated with dry dioxane,
filtered, and the tosylate recrystallized from chloroform-hexane. (In the case of 1,2-di-
methyl-3-cyano-4-phenyl-5-oxoindeno[l,2-b]pyridinium tosylate, mp 220-223~ yield 69%).
Exchange of the anion for CIO~- in the remaining tosylates was carried out by method A,
yields 40-65%.
C. The N-methyl compound (II) (i0 mmole) was boiled in 80 ml of ethanol with 20 mmole
of hydrogen peroxide (30% aqueous solution) and i0 mmole of perchloric acid (57% aqueous so-
lution) until the red color disappeared (1-4 h). The solvent was removed in vacuo, and the
residue cooled and treated with ether. The perchlorate (III) which separated was filtered
off and recrystallized. The ethereal solution was evaporated to give the 2-arylidene~ndan-
1,3-dione (IV), which was recrystallized from acetic acid. The compound (IVa) was identical
in its physicochemical properties with the authentic indan-l,3-dione derivative [6]. Follow-
ing oxidation of (Ild), the oxirane (V) was isolated from the ether solution (yield 35%).
2-Spiro-(2'-indan-l',3'-dione)-3-(4'-nitrophenyl)oxirane (V). 2-(4'-Nitrobenzylidene)-
indan-l,3-dione (2.8 g, i0 mmole) was boiled for 4 h in 50 ml of ethanol with 2.3 ml of 30%
H202 and 1.3 ml of 57% perchloric acid. The reaction mixture was diluted with water, and
the colorless solid which separated was filtered off and recrystallized from ethanol. The
yield of the oxirane (V) was 1.19 g (65%), mp 217-219~ IR spectrum: 1756, 1723 cm -I (CO).
PMR spectrum: 5.16 (s, IH, 3-H), 7.67-8.11 (m, 6H) and 8.33 ppm (d, 2H) -- aromatic protons.
~ C N~IR spectrum: 63.1 (C(~), 65.7 (C(2)), 192.1 (CO), 190.7 ppm (CO). Mass spectrum:
295 (6) [M] +', 278 (15) [M --)OH]+ , 182 (18) [M -- CO] + , 104 (i00). Found: C 64.9; H 3.2; N
4.5%. CI6HgN05. Calculated: C 65.1; H 3.1; N 4.7%; M 295.

LITERATURE CITED
i* D. Kh. Mutsenietse, V. K. Lusis, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., No. 9,
1225 (1982).
2. V. K. Lusis, A. Z. Zandersons, D. Kh. Mutsenietse, and G. Ya. Dubur, Khim. Geterotsikl.
Soedin., No. 4, 508 (1983).
3. V. Petrov, I. Saper, and B. Sturgeon, J. Chem. Soc., No. 9, 2134 (1949).
4. V. K. Lusis, D. Kh. Mutsenientse, A. Z. Zandersons, I. V. Mazheika, and G. Ya. Dubur,
Khim. Geterotsikl. Soedin., No. 3, 393 (1984).

75
5. M. Weigele, J. P. Tengi, S. De Bernado, R. Czajkowski, and W. Leimgruber, J. Org. Chem,,
41, 388 (1976).
6. A . K . Aren, B. ~. Arch, and G. Ya. Vanag, Dokl. Akad. Nauk SSSR, 13_55, 320 (1960).

AZAINDOLE DERIVATIVES.
67.* SYNTHESIS OF N-SUBSTITUTED
I-BENZYL-4-METHYL-5-CYANO-6-AMINO-7-AZAINDOLES

T. V. Sycheva, O. S. Anisimova, UDC 547.759:543.87:543.51

and L. N. Yakhontov

N-substituted l-benzyl-4-methyl-5-cyano-6-amino-7-azaindoles have been synthe-

sized from the respective l-benzyl-4-methyl-5-cyano-6-chloro(and 6-hydroxy)-7-
azaindoles. The effect of the 5-cyano group on the oxidation-reduction proces-
ses accompanying nucleophilic replacement of chlorine in 6-chloro-7-azaindoles
by primary and secondary amines has been considered. 7-Azaindoline compounds
were dehydrogenated by chloranil to N-substituted l-benzyl-4-methyl-5-cyano-6-
amino-7-azaindoles.

The selective effect of various 6-amino derivatives of l-benzyl-7-cyano-azaindoles on

central serotoninergic systems has been described in [2]. In order to broaden the study of
the antiserotonin effects of isomeric azaindoles it was of interest to obtain the hitherto
unknown 6-amino derivatives of l-benzyl-5-cyano-7-azaindoles (I). The starting material for
the synthesis of compounds la-g was l-benzyl-4-methyl-5-cyano-6-chloro-7-azaindoline (II)
[i].
We have shown [3, 4] that the nucleophilic replacement of chlorine at position 6 in the
7-azaindoline system is a serious problem. For these reactions in such a system, because of
the electron density distribution extremely severe conditions are needed, e.g., 6-chloro-7-
azaindolines that do not contain a r group react with amines only at temperatures of at
least 250~ , Under such severe conditions, normal nucleophilic replacement is accompanied by
redox processes, so that along with the 6-amino-7-azindolines there are formed the respective
6-amino-7~azaindoles and 7-azaindoles unsubstituted at position 6. The amounts of the latter
are determined by the nucleophilicity of the amine and the redox potential of the azoindoline
compound [3, 4].
The presence of a cyano group ortho to chlorine in l-benzyl-6-chloro-7-cyano-5-azaindol-
ine,/,~hich is distinguished b y a higher redox potential than would be expected, increased the
reactivity of the chlorine, and enabled it to undergo nucleophilic substitution by various
other amines at lower temperature (180-185 ~ without the occurrence of redox reactions [2].
An analogous effect of an ortho-cyano group was observed in our case. The chlorine in
compound II undergoes nucleophilic substitution with most primary and secondary aliphatic
and heterocyclic amines at 180-185 ~ to form N-substituted l-benzyl-4-methyl~5-cyano-6-amino-
7-azaindolines (IIIa-e) in high yield (77-87%). Only in the case of the sterically more
hindered di-n-butylamine is the substitution less complete (55%) under these conditions, and
about 35% of the starting chloroderivative II is recovered unchanged. With still weaker nu-
cleophiles -- aromatic amines of the aniline type -- compound II does not react at all, not
only at 180-185 ~ but is recovered practically unchanged even at 250 ~ Raising the temper-
ature to 280-290 ~ causes significant thermal decomposition of II. However with a stronger
nucleophile -- viz., hydrazine -- II reacts already at 110-120 ~ to form l-benzyl-4-methyl-5-
cyano-6-hydrazino-7-azaindoline (IV).
*For communication66, see [i].

S. Ordzhonokidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,

Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, pp, 91-96,
January, 1986. Original article submitted February 21, 1985.

76 0009-312286/2201-0076512.50 9 1986 Plenum Publishing Corporation

 1t 3 Ctlj

N C -.
7
'.. NC.
!
~-~
,7. .

0" " N N N
It ! E ~ "' I
C H ~C'6H ~ (ll.CeH ~
VI III
,r
Cli 3 CII~ 9 " CIt~E CIi3

NC ;~ NC. .~ I

H N ' " - e~. -- "'~- i" CI N N . "N ~ "~'N/ ' N " "N ~ "N
I I I 1~ I" I I
NH 2 Cii..Cr CH.2CJ|. a CIIZ(T6TT~ {!ti~C~II~
IV 11 1 V

I, III a) RR'N = morpholino; b) RR"N = piperidino; c) RR~N = pyrolidino;

d) RR'N = (C2H 5)2N- ; e) RR'N = n - C ~ H g N H ; f) RR'N = (n-C~Hg)2N_; g)
RR'N = CsH 5 CH2NH.

Moreover, in the reaction of chloroazaindoline II with benzylamine the previously noted

[5] lower redox potentials of 7-azaindoline compounds as compared with the 5-azindoline ana-
logs caused the formation not of 5-cyano-6-benzylamino-7-azaindoline derivative lllg, but of
the corresponding oxidized compound, viz., l-benzy!-4-methyl-5-cyano-6-benzylamino-7-azai n_
dole (Ig). In contrast to these previously described redox reactions between a 6-chloro-7-
azaindoline without a cyano group and an amine, where along with a 6-amino-7-azaindole an
azaindoline compound dehalogenated at position 6 is always obtained [3, 4], in the reaction
of compound II (5-cyano-6-chloro-7-azaindoline derivative) with benzylamine not even traces
of l-benzyl-4-methyl-5-cyano-7-azaindoline (V) could be detected in the reaction mixture.
The corresponding 6-benzylamino-7-azaindoline lllg was also entirely absent, but the amino-
azaindole Ig was separated in 81% yield. Evidently in this case the redox process is dif-
ferent from that previously observed [3, 4], and needs further intensive study.
In connection with publications on the direct replacement of the oxo group in azine sys-
tems by secondary amine residues [6, 7] we studied the analogous reaction as exemplified by
the reaction of l-benzyl-4-methyl-5-cyano-6-hydroxy-7-azaindoline (VI) with piperidine and
phosphorus pentoxide. The yield of the 5-cyano-6-piperidino-7-azaindoline compound lllb was
]0%; this is substantially lower than the overall conversion of VI to the aminoitrile lllb
via the corresponding 6-chloro derivative II. The 7-azaindoline compounds llla-f were de-
hydrogenated to the 7-azaindoies llla-f by chloranil in boiling xylene in 78-88% yield.
Study of these N-substituted compounds la-g* showed that only compound Id shows weak
central antiserotonin activity in 50 and i00 mg/kg doses (internal) in mouse tests, reducing
the number of head agitations caused by administration of 300 mg/kg of 5-hydroxytryptophane.
The mass spectra of compounds la-g and llla-f showed molecular ions, the mass numbers
of which confirmed the proposed structures. For all these compounds the most characteristic
decomposition is the formation of benzyl cation (m/z 91), to which the peak of maximum in-
tensity in the spectra of Ib-f and Ilia, c, e, f corresponds. The other decomposition route
of the molecular ions is the stepwise detachment of the RR'N substituent, as a result of
which the following ion peaks appear: [M-- CH=OH] +, [M -- C2H~OH]+, [M -- C3H50] + (la, Ilia);
[M -- C2H,] +, [M-- C4H,] + (Ib, lllb); [M-- C2H~] +, [M-- C,HT] + (Ic, lllc); IN-- CH,] +, [M --
C21I,]+, [M-- NC2H,] + (Id, llld); [M-- C3H7] +, [M-- C~Hg] + (le, f, llle, f).
The spectra of Ib, c and lllb, c in which NRR' are pyrolidine and piperidine residues,
show ion peaks with m/z 70 and 84 that correspond to fragments of the respective cyclic a-
mines.
The characteristic feature of the decomposition of the azaindoles la-f is a certain de-
crease in the peak intensity of the molecular ions as compared with the respective substi-
tuted azaindoline llla-f. The increase in peak intensity of benzyl cation observed here
causes the IM/ICHzC6H 5 ratio to decrease. These data, which are shown in Table i, show that
the N-benzyl group is easier to detach in the azaindole compounds I than in the azaindoline
compounds III.
*Carried out in the pharmacology laboratory of the All-Union Scientific-Research Institute
for Pharmaceutical Chemistry (Academician M. D. Mashkovskii, manager) by Canad. Med. Sci.
N. I. Andreeva, to whom the authors express sincerest thanks).

77
-,4
co

TABLE i. N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-azalndolines and Azaindoles

Com- [.t~_, ~ Found, % Empirical Calculated, % IR soectrum,[c{a_

1 ) Imax I
I UV spectrum,( Mass spectr~n
pound (solvent) formula ,,[ Inn l o g e Yield, %
i mlz
C H N C H N CN NH [ [ (intensity, %) IM/I CH~Cnl'I~
I
Ilia 136--137 ~2,7 5,2 17,0 C2oH=N40 72,3 6,0 16,9 2190 -- 335 (0,8), 334 (100), 303 (21), 162 81
(hexane- 255 (0,74), 289 (17), 277 (34),
benzene) 205 (0.79) 276 (21). 91 (62)
IIIb 85--86 T6,O 7,2 17,1 CmH24N4 75.9 7.2 16.9 2190 -- 339 (0,75), 332 (100), 303 (11). 430 87
312 (0,54), 277 (8), 276 (17),
(hexane) 257 (0.85) 91 (23). 84 (9)
IIIc 121--122 ~5,7 7,0 17,8 C2oH=N4 75,5 0,9 17,5 2180 -- 347 (0,8l). 318 (100), 290 (43). 100 76
hexane 296 (0.51), 289 (59). 275 (12).
244 (0.74), 263 (~ 91 (100),
240 (0,73) 70 (25)
IIId 75--76 ~5,2 7,6 17,8 C~oH24N4 75 7,5 17,5 2190 -- 346 (0,81), 320 (1O0), 305 (90), 250 81
(hexane) 297 (0.57), 291 (50). 277 (70),
258 (0,80), 91 (40)
24O (O,77)
Ilia 145--146 ~'5,0 7,7 17,5 C2oH24N4 75,0 7.5 17.5 2180 335O 347 (1,03), 32O (97), 291 (17), 97 86
hexane 292 (0,47), 278 (23), 277 (87),
benzene 247 (0.61) 263 (14), 91 (100)
Ill" f 39 40* 76.8 7,8 14,6 C24H32N4 76.6 8.5 14,9 2180 -- 348 (0.75), 376 (14), 334 (23), 14 55
298 (0,51), 333 (41), 319 (14),
259 (0,76) 291 (55), 277 (36),
91 (10o)
la 118--119 72,7 6,2 16,8 C2olqzoN40 72,3 6,0 16,9 2210 -- 334 (0,26), 332(100), 3Ol (23), 137 78
(hexane): 266 (I,20), 275 (42), 91 (73)
248 (I,27)
Ib 114--115 76,6 6,~ 16,9 C~tII~2N4 76,4 6,7 17,0 2210 -- 338 (0,25), 330 (31), 301 (12), 31 83
(hexane) 270 (I,II), 274 (7). 262 (7).
248 (I,10) 91 (100), 84 (27)
Ic !04--105 76,1 6,4 17,7 C2oH2oN4 76,0 6,3 17,7 2200 -- 3.58 (0,36), 316 (90), 287 (72), 90 88
hexane 270 (1,39). 273 (8), 261 (14),
244 (I,05) 91 (100), 77 (31)
Id 48--49 75,6 7,(: 17.5 C2oH2~N4 75,5 6,9 17,6 2200 -- 353 (0,29), 318 (19), 303 (38), 19 86
(hexane) 272 (1,28), 290 (19), 275 (17),
244 (I,07) 91 (100)
ie 98--99 75,4 6,8 17.6 C2oH.22N4 75,5 6,9 17,6 2190 3380 349 (0,41), 318 (25), 289 (17), 25 88
(hexane) 262 (I,36), 275 (6{}), 262 (13),
242 (I,08) 91 (100)
If 60--61" 77,1 8,(~ 14.9 C24H3oN4 77.0 8.0 15,0 2180 -- 354 (0,28), 374 (4), 331 (18), 86
272 (I,05), 289 (16), 275 (14),
244 (0,93) 91 (100)
Ig 186--187 78.4 5,7 15,7 C~3H2oN4 78,4 5.7 15,9 2200 3380 350 (0.38), 352 (100), 275 (11), 81
265 (1,01) 261 (20), 106 (22),
91 (65)

WPurified by chromatography,
 EXPERIMENTAL
Mass spectra were obtained on a Varian MAT-II2 instrument with direct introduction of
sample into the source. The energy of the ionizing electrons was 70 eV, the temperature of
the ionizing chamber was 180 ~ PMR spectra were obtained on a JNM-4H-IO0 instrument, with
TMS internal standard; IR spectra, on a Perkin-Elmer 457 spectrometer in mineral oil; UV
spectra, on a Carl Zeiss (Jena) Specord M-40 spectrophotometer in chloroform.
The properties of compounds la-g and llla-f are shown in Table I.
General Synthesis of N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-azaindolines
(Ilia-e). A mixture of 3 g (10.6 mmole) of azaindoline II and 15 ml of amine was heated in
a 55 ml steel autoclave for i0 h at 180-185 ~ The reaction product was treated with i00 ml
of water and 30 ml of 50% aqueous potassium hydroxide and extracted with chloroform. The
chloroform extract was dried with magnesium sulfate and evaporated in vacuum, and excess
amine was removed by addition of toluene and vacuum evaporation. The residue was recrystal-
lized from hexane or a 3:1 hexane--benzene mixture.
l-Benzyl-4-methyl-5-cyano-6-(di-n-butylamino)-7-azaindoline (lllf) is synthesized as
described in the preceding test. After removal of chloroform and excess di-n-butylamine the
residue was ground with hexane, and the residue of chloroazaindoline II was filtered off.
The material did not depress the melting point of an authentic sample, and has an identical
IR spectrum. The hexane filtrate was evaporated and the residue was placed on a column (d
30 mm, h 50 cm) with i00 g of 40/100 ~ silica gel. The column was washed with 200 ml of 9:1
hexane--benzene, then with 1.5 liters of 7:3 hexane--benzene which eluted 2.1 g (53%) of aza-
indoline lllf; then with 500 ml of i:i hexane--benzene which eluted 0.06 g of chlorozazindol-
ine !I. Total yield of II, 1.06 g (35.3%).
l-Benzyl-4-methyl-5-cyano-6-hydrazino-7-azaindoline (IV). To a solution of 3 g (Ii
mmole) of II in 45 ml of butanol at 110-112 ~ was added four i.I ml portions of hydrazine hy-
drate over i h. The reaction mixture was stirred at 110-112 ~ for i h and cooled to room
temperature. The precipitate was filtered off and washed with 40 ml of benzene. There was
obtained 1.3 g (44%) of IV. Colorless crystals, mp 256-257 ~ (from methanol). The material
was soluble in DMFA and hot alcohols; insoluble in water, acetone, ether. PMR spectrum in
DMSO D~: 2.33 (s, 3H, 4-CH3)~ 2.86 (t, 2H, 3-CH2)~ 3.44 (t, 2H, 2-CH2); 4.53 (s, 2H, CH2-
C~Hs); 4.68 (br. s., 2H, NH2NH); 7.25-7.35 (m, 5H, CH2C~Hs); 11.23 ppm (s, IH, NH2-NH. Mass
spectrum: 279 [M] +" (I00); 263 [M--NH2] + (9); 202 [M-- Ph] + (45); 91 [PhCH2] + (i00). Found:
C 68.6; H 6.3; N 24.7%: C~H27Ns. Calculated: C 68.8; H 6.1; N 25.1%.
l-Benzyl-4-methyl-5-cyano-6-piperidino-7-azaindoline (lllb). A mixture of 0.4 g (1.5
mmole) of hydroxyazaindoline VI, 0.21 g (1.5 mmole) of phosphorus pentoxide, and 2 ml of
piperidine was held for i0 h at 170-180 ~ in a steel autoclave. The reaction product was
treated with 50 ml of water and 20 ml of 50% potassium hydroxide solution, and extracted
with chloroform. The chloroform ~xtract was dried with magnesium sulfate and evaporated in
vacuum. The residue was treated with 40 ml of boiling benzene, and the residue thereof was
filtered off to give 0.22 g (55%) of starting VI. The benzene solution was evaporated and
the residue was recrystallized from 3:1 hexane--benzene. There was obtained 0.05 g (10%) of
lllb, which did not depress the melting point of an authentic sample obtained by the method
described above. Rf values of the two materials were identical in chloroform (0.66) and
benzene (0.13).
i-Benzy!-4-methyl-5-cyano-6-benzylamino-7-azaindole (Ig). A mixture of 1.7 g (6 mmo!e)
of compound II and 9 ml of benzylamine was stirred for i0 h at 180-185 ~ in a flask with a
reflux condenser. The cooled reaction mixture was treated with 50 ml of water and 20 ml
of 50% aqueous potassium hydroxide and extracted with chloroform. The chloroform extract
was dried with magnesium sulfate and evaporated in vaduum; excess benzylamine was removed by
addition of toluene and evaporation in vacuum. The residue was recrystallized from i:i hex-
ane--benzene. There was obtained 1.71 g (81%) of azalndole Ig.
General Method for Synthesizing N-Substituted l-Benzyl-4-methyl-5-cyano-6-amino-7-aza-
indoles (ia-e). A mixture of 6.5 mmole of azaindoline IIIa-f and an equal weight of chlora-
nil in 50 ml of xylene was boiled for 1.5 h. After cooling the xylene solution was washed
successively with 150 ml of 10% sodium hydroxide solution and three 150 ml portions of wa-
ter, dried with magnesium sulfate, and evaporated in vacuum. The residue was recrystallized
from hexane.

79
 l-Benzyl-4-me~hyl-5-cyano-6-(di-n-butylamino)-7-azaindole (If) was synthesized as de-
scribed in the preceding experiment. The residue after evaporation of xylene was placed on
a column (30 mm diameter, 20 cm high) with 90 g of 40/100 ~ silica gel. The column was
washed with 100 ml of hexane and 300 ml of 9:1 hexane-benzene, and 1.6 g of If was eluted.

LITERATURE CITED
l, T. V. Sycheva and L. N. Yakhontov, Khim. Geterotsikl. Soedin., No. I, 84 (1985).
2. V. A. Azimov, N. N. Bychikhina, A. I. Polezhaeva, M. D. Mashkovskii, and L. N. Yakhon-
toy, Khim.-farm. Zh., No. 5, 40 (1980).
3. L. N. Yakhontov, D. M. Krasnokutskaya, and A. N. Akalaev, Dokl. Akad. Nuak SSSR, 192,
119 (1970).
4. L. N. Yakhontov, D. M. Krasnokutskaya, A. N. Akalaev, I. N. Palant, and Yu. I. Vainsh-
rein, Khim, Geterotsikl. Soedin,, No. 6, 789 (1971).
5. I. N. Palant, Yu. I. Vainshtein, D. M, Krasnokutskaya, and L. N. Yakhontov, Khim. Geter-
otsikl. Soedin., No. 6, 773 (1973),
6. E. A. Arutinyan, V. I. Gunar, E. P. Gracheva, and S. I. Zav'yalov, Izv. Akad. Nauk SSSR,
Set. Khim., No. 2, 445 (1968).
7. E. A. Arutinyan, V. I. Gunar, and S, I. Zav'yalov, Izv. Akad. Nauk SSSR, Ser. Khim., No.
4, 953 (1970).

SYNTHESIS AND SOME REACTIONS OF 4-NITRO DERIVATIVES

OF IMIDAZO[4,5-e]PYRIDIN-2-ONES

Yu. M. Yutilov and I. A. Svertilova UDC 547.783'821:542.958.1:543.422.25

Imidazo[4,5-c]pyridine and its N-methyl derivatives do not undergo nitration,

but the 2-oxo derivatives of these compounds are easily nitrated when heated.
Some properties of the resulting 4-nitroimidazo[4,5-c]pyridin-2-ones have been
studied.

The introduction of a nitro group into the imidazo[4,5-c]pyridine molecule has not been
previously studied. However, work in this direction is of considerable importance in devel-
oping the chemistry of this heterocycle.
We have shown that imidazo[4,5-c]pyridine (I) and its i- and 3-methyl substituted deriv-
atives (II, III) are inert to nitrating mixtures. These compounds do not change when treated
with nitric acid or potassium nitrate in concentrated sulfuric acid and high-strength oleum
at temperatures up to 200 ~ The same result was obtained after heating the dinitrate of base
I with gaseous sulfur trioxide at I00 ~ For this reason it was of interest to carry out the
nitration of 2-oxo derivatives of compounds I-III, especially because with the analogous sub-
stituted imidazo[4,5-b]pyridines the strong activating effect of the oxo group appears in
this reaction [i].
Nitration of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (IVa) with nitrating mixture
proceeds at about i00 ~ to form the mononitro derivative in almost quantitative yield. For
example, the PMR spectrum of the product in CF3COOH solution (Table i) has two doublets of
aromatic protons (8.03 and 8.63 ppm), the spin--spin coupling constants (SSCC) of which, at
6.5 Hz, unambiguously demonstrate their vicinal location; this is possible only in 4-nitro-
1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Va). In the spectrum of 7-nitroimidazo[4,5-c]-
pyridin-2-one (VI) the pyridine ring protons do not show spin-spin coupling.

Institute of Physical Organic Chemistry and Coal Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
I, pp. 97-102, January, 1986. Original article submitted December i0, 1984.

80 0009-3122/86/2201-0080512.50 9 1986 Plenum Publishing Corporation

 TABLE i. PMR Spectra of N e w l y Synthesized Compounds
,,,,,

Com- Chmeical shift, 6 , ppm

SSCC,
pound So ivent Hz
C(? ) N- and O-alky!
C(4) C(6)
groups
va CF6COOH -- 8,63 (d, 1H) S,03 (d, 1H) ,/67=6,5
J DMSO .D6 -- 8,47 (d 1H) 7,87 (d., IH) Ja;=5,0
Vb CFaCOOH -- 8,73 ~d, IH) 7,97 3s Is, 3H, N~)--CHz)
(d,, IH) I67=5,4
DMPA - D r -- 8,19 (d, IH) 7,56 3,43 s. 3I-1, N(,)--CH3)
Id, I H) J67 =- 5,2
ve CFaCOOH -- 8,68 (d, IH) 8,t5 (d, 1H)4,02 (s, 3H, N(3)--CHa) ,/67=5,0
DMSO - D -- 8,08 (d,IN) 7,38 (d. 1H)3,33 (s, 3H, N~3~--CH3) J67=5,2
Vd CFaCOOH -- 8,63 ( d , 1H) 7,87 3,95 ,,,@,3H,
(d, 1}1) ,/67=6,3
Nr
3,77 is, 3H, N~I)--CtI3)
9 DMSO -D,3 -- 8,20 (d, ltI) 7,63 (d, I H) 3,42 ~ 3H, Joy=5,2
Nm--CHa);
3,38 s, 31-1, N(3)--CI-Ia)
w [5] CFaCOOH 9,40 ( , IH) 9,00 ts. IH) ,/4G~ 0
VII a CFaCOOH -- 7,86 d,
IH) 7,09 d, lit) ,/67 = 6,9
VII b CF3COOH -- 7,74 d,IH) !6,94 (d, IH) 3,60 r 3H, N,l)--CI-1a) ,/67= 7,0
VII c CFaCOOH -- 7,76 (d,
1H) 7,04 (d, 1}t) 3,87 (s, 3H, N,3i--CHz) ,/67=6,9
VII d CFaCOOH -- 7,78 (d.
IH) 7,03 (d, IH) 3,89 ~, 3H, 167=6,9
Nr
3,63 ~, 3H, N~I)--CH3)
VIII b CFaCOOH -- 8,02 (d, ltI) 7,34 (d, IH) 3,80 s , 3I-t, IG7=7,0
N,31--CHa) ;
1,65 {s, 3H,
N(I)--CHa) ;
4,49 ~S. 311, O--CH3)
VIII e CFaCOOH -- 7,98 (d, 1H) 7,31 (d, lit) 3.82 s. 3H, ,/67-- 7, l
N(3)--CH3); I<~ = 6,8
3,66 ts, 31-1,
N~--Clta);
4,76 ( q, 21t,
O- -CH~--);
1,70 {t 3II,C--CHa)
VIII d CFaCOOH -- 7,98td, 1H) 7,31 (d, Ill) ~,85 ~s 3H, JGr= 6,6
N(a~--CHa); ,/~ = 6,4
3,65 S~ 31-t, J~v = 7,4
N, ,~--CHa);
4,63 (t, 2H,
O--CH2--) ;
2,06 (m, 2H,
C--CIt~--C) ;
1,17 it, 3H, C--CI-{a)
VIII e CFaCOOH -- 8,01 (d, IH) 7,31 (d, lil) 3,77 s, 3H); ,/87=6,8
N,3~----CH~) ; 1~=5,6
3.60 (s, 3H, lv~ = 6,0
No )--s ;
4.67 I% 21-I,
O--CH2--) ;
2,13--1,40 (ra, 4H,
C---CH_~--CH2--C) ;
1,01 it, 3H, C--CHa)

Analogously to the formation of Vb, the 1-methyl derivative of base Iva also nitrates
(iVb) [2]. But the introduction of a nitro group into 3-methylimidazopyridin-2-one (IVc)
requires more severe conditions; the reaction goes at 125-130 ~ to give 4-nitro-l,3-dihydro-
2H-imidazo[4,5-c]pyridin-2-one (Vc) in good yield. The PMR spectra of Vb, c resemble that
of Va, and are distinguished from it by the N-methyl signals (Table i). It is important to
note that aside from the substances mentioned, no nitro derivatives of other structure could
be detected in the nitration products of bases IVa-c. All this indicates that the reaction
under consideration is highly selective. Of tile two free a-positions in the pyridine ring
of IVa-c, only C(,) undergoes attack by a nitrating agent. Even in the case of IVc, where
the N(3)-methyl group shields the reaction center, the 4-nitro derivative forms. Further
increase in the shielding effect of the N(3) substituent, e.g., in 3-ethylimidazo[4,5-c]-
pyridin-2-one (IVe), stops the reaction at position 4 completely, but it does not promote
the entrance of the nitro group at the other unoccupied e-position of the pyridine ring,
viz., at C(6).

81
 TABLE 2. 4-Substituted Imldazo[4,5-c]pyridin-2-ones
, i,,

I Cas

] C H
!

Va ,lO0 J 39,8 2,5 31,0 C~li~NoO~ 40.0, 2,2 3LJ 9~ (A).99 (B)
Vb 309--,3101 43,6 3,3 29,1 C~H~N4Os 43,3 3,1 28,9 9:3{A),96 (~)
Vc 274~275 [ 43,1 2,9 28,7 C71{eN4OII 43,3 3. I 28,9 77 [B)
Vd 225 46, I 4,0 27,1 Cal'lsN~Os 46,21 3.9 26,9 90(A),98{ )
Vlla 309--31( 47,8 3,9 37,2 C~I'IBN~O 48,0 4,0 :37,3 99,9 (B)
vIIb 360 50,9 5,2 33,8 Cyt'i~N40 51,2 4,9 34,1 99,9
VIIc 242--24~, 51,0 5,3 33,7 CrHaN40 51,2 4,9 34, l 9fi
Vlr" 240 53,8 5,8 31,1 Csl,i.iN40 53,9 5,7 31,4 92 (A),82 ( )
Villa 310--311 53,9 5,2 23,3 C~I-19N,~O2 53,6 5,1 23,5 80
VllIb 144-~145 55,9 5,8 21.7 C91'1,N302 55,9 5,7 21,8 99,9
Vllle 78--79 58,1 6,4 20,2 Clot-I~sNsO~ 58,0 6,3 20,3 95
Vllld 75--76 59,8 6,8 18.9 C.HIsNaO~ 59,7 6,8 19,0 94
VIIle 50--51 61,2 7,2 18.0 CI2H=rN~O~ 61,3 7,3 17,9 85

*Compounds Vlla,c recrystallized from water, Va from DMPA, Vb

from water or ethanol, Vc from nitromethane, Vd, Vlld from eth-
anol, Villa from water or nitromethane, Vlllb-e from hexane,
Vllb was reprecipitated from weak acid solution by ammonia.

The nitro compounds Va-c (Table 2) are high melting and insoluble in many solvents.
Since they are weak acids, however, they dissolve readily in aqueous alkali to give yellow
solutions. When such solutions are treated with dimethyl sulfate at room temperature, a
compound forms with mp 224-225 ~ in high yield that is insoluble in alkali but soluble in
alcohol; its PMR spectrum contains methyl signals (3.78 and 3.96 ppm in CF3COOH). This
material is also obtained with bases Vb, c are methylated with diazomethane in nitromethane
medium. We therefore assign this compound the structure of 4-nitro-l,3-dimethyl-l,3-dihy-
dro-2H-imidazo[4,5-c]pyridin-2-one (Vd).

1.. F. r ' -- N .R .yfi~. ......... N . R " 1- CtI=

.~" \, ___N ~

iv, a-e v a-d vlla-d VIII a-fi~

IV, V, VII a, h e R=H, b, d R=CHa; g b R'=H, e .d R'=CHo, e RI=C2Hb;

VIII aR=H, b R=CHa, e R=C2H6, dR=nCaHT, e R=n.C4H9

All the nitro compounds V are easily converted to the respective amines Vlla-d by such
reducing agents as iron, sodium sulfide, hydrazine, and hydroiodic acid. The two latter re-
agents give especially good results. Moreover when Va-d are reduced by hydrazine hydrate no
catalyst is needed and the amine yields approach quantitative [3].
4-Nitro-l,3-dimethylimidazo[4,5-c]pyridin-2-one, Vd, can replace the nitro group by a
hydroxy or alkoxy group, similar to what occurs with 2- and 4-nitropyridines [4], Such a
conversion is easily carried out by heating Vd with water or the appropriate alcohol in the
presence of alkali. The properties of the resulting 4-hydroxy- and 4-alkoxy-l,3,-dimethyl-
1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ones (VII) are shown in Table 2. In the PMR spectra
of bases VIIIb-e, besides the coublets of the aromatic protons at positions 6 and 7 and the
N-methyl singlets, the signals of the O-alkyl hydrogens also appear (Table I),

EXPERIMENTAL
PMR standards were obtained on Tesla BS-467 (60 MHz) and Varian XL-IO0/15 (I00 MHz) in-
struments; internal standard, TMS.
The properties of V, VII, and VIII are shown in Table 2.
Reaction of Nitrating Mixture with Imidazo[4,5-c]pyridine (I) [6] and Its i- and 3-
Methyl Derivatives (II, I!I ) [7]' A. A mixture of 0.36 g (3 mmole) of compound I, 2.1 g
of U=SO4 (d 1.86) and 0.6 g (9.5 mmole) of HNO~ (d 1.50) was heated in a sealed glass tube
at 170-180 ~ for 5 h. The contents of the tube were poured on ice and neutralized with po-

82
tassium hydroxide to pR 6-7. The colorless precipitate was filtered off, dried, and recyrs-
tallized from dioxane. There was isolated 0.3 g (85%) of the starting compound, mp 167-168 ~
B_~. A mixture of 2.38 g (20 mmole) of base I and 2.2 ml of HNOs (d 1.35) was evaporated
on a boiling water bath, and the residue was recrystallized from 2 N HNO,. There was ob-
tained 4.4 g (90%) of the dinitrate of I (prisms), mp 220-221 ~ (with decomposition). Found:
C 29.3; H 3.0; N 28.6%. C6HbN3.2HN03. Calculated: C 29.4; H 2.9; N 28.6%.
A mixture of 2.5 g (i0 mmole) of I dinitrate and 6 g of 60% oleum, prepared at 2-5 ~
was heated in a sealed tube at 100 ~ for 2 h. After cooling the contents of the tube were
poured on ice and neutralized to pH 6 with sodium carbonate solution. The precipitate was
filtered off, dried, and recrystallized from dioxane to give 0.8 g (67%) of imidazopyridine
I, mp 167-168 ~ The mother-salt solution was evaporated almost to dryness and washed with
boiling alcohol (3 20 ml). The aqueous alcohol solution was evaporated to dryness, the
residue was washed twice with hot alcohol, and the extract was evaporated. Recrystalliza-
tion from dioxane gave an additional 0.30g (25%)of I, mp 165-167 ~
C_:. Into the inner tube of a straight Liebig condenser held horizontal was placed 1 g
(4 mmole) of imidazo[4,5-c]pyridinium dinitrate, and gaseous sulfur trioxide was introduced
while water vapor at i00 ~ was passed through the jacket. After 2 h heating the tube contents
were dissolved in 5 ml of water, and the solution was neutralized to pH 6 and evaporated to
dryness. The solid residue was washed with alcohol (3 5 ml), the solution was evaporated
to dryness, and the residue was recrystallized from dioxane. There was obtained 0.44 g (94%)
of compound I, mp 168-169 ~ (according to [6], mp 169,170~
In all the experiments the isolated base samples did not depress the mp in a mixture
with an authentic sample of I.
The ability of 7-nitroimidazo[4,5-c]pyridine (IX) [8] and similar nitro compounds to
give an intense yellow color in alkaline medium was used for the qualitative detection of
small amounts of nitration products of compound I. In no test did alkalization of reaction
mixture, mother liquors, or unpurified unreacted I give a yellow color, or give reason to
speak of the presence of nitro compounds.
D. A mixture of 0.27 g (2 m/Role) of base If, 1.80 ml of H~SO~ (d 1.86), and 0.33 ml of
HNO3 (d 1.50) was heated in a sealed tube at 200 ~ for 4 h. After cooling the mixture was
poured on ice and made strongly alkaline with 40% sodium hydroxide solution. The oil that
separated crystallized when cooled. The precipitate was filtered off and dried. Reerys-
tallization from i:i benzene-hexane gave 0.22 g (81%) of starting compound II, mp 111-112 ~
(according to [7], mp 111.5-112.5~
Nitration of 3-methylimidazopyridine III was attempted under similar conditions. After
the mixture was heated, 88% of the starting compound was separated, mp 101-102 ~ (from ben-
zene) (according to [7], mp 101-101.5~
4-Nitro-3,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Va). A. To a solution of 2.0 g
(14.8 mmole) of base IVa [5] in 8 ml of concentrated H2SO~ was a-dded 1.50 g (14.8 mmole) of
potassium nitrate in 8 ml of concentrated H2SO~ with cooling in ice, and the mixture was
heated for 3 h at 100 ~ . The mixture was cooled, poured on ice, and neutralized with aqueous
ammonia. The precipitate was filtered off, washed with water and dried. Yield, 2.6 g.
B_z. To a solution of 60.0 g (440 mmole) of base IVa in 220 ml of concentrated H=SO~ was
added a mixture of 52 ml of HNO3 (d 1.50) and 52 ml of concentrated H2SO~ dropwise at 4-5 ~ .
After being held at room temperature for 0.5 h the reaction mixture was heated for 2 h in a
boiling water bath. The cooled mixture was poured on 1 kg of ice and neutralized with dry
ammonium carbonate, and finally w~th ammonia to pH 5. The precipitate was filtered off,
washed with cold water, and dried. Yield, 79.2 g,
4-Nitro-l-methyl- and 4-nitro-3-methvl-l,3,-dihydro-2H-imidazopyr2dines (Vb and Vc)
were obtained similarly, but in [5] compound IV was nitrated at 125-130 ~ .
4-Nitro-l,3,-dimethyl-l,3-dihYdro-2H-imidazo[4,5-c]pyridin-2-one (Vd). A. To a mix-
ture of 1.0 g (5.5 mmole) of compound Va and 0.8 g (14.3 mmole) of potassium hydroxide in
13.5 ml of water was added ].3 ml (13.4 mmole) of d:[methyl sulfate dropwise with vigorous
stirring, at such a rate that the temperature of the reaction mixture did not exceed 30-32 ~ .
After 10-15 m2n a precipitate formed. The mixture was stirred another 0.5 h at room temper-
ature, 1 ml of 8% KOH solution and 0.6 ml (6.2 mmole) of dimethyl sulfate were added, and

83
the mixture was kept for i h. Then another 1 ml of 8% KOH was added, and the mixture was
left overnight. The precipitate was filtered off, washed with water, and dried. Yield,
1.04 g.
B._.. To a suspension of 0.32 g (1.65 mmole) of compound Vb in a solution of 0.16 g (4.0
mmole) of NaOH in 30 ml of water was added 0.40 ml (4 mmole) of dimethyl sulfate dropwise
with stirring, After holding for 0.5 h, a solution of 0.2 g of sodium hydroxide in 2 ml of
water, and 0.40 ml of dimethyl sulfate were added and the mixture was left overnight. The
bright yellow precipitate was filtered off, washed with water, and dried. Yield, 0.!7 g
(50~).
C__~. Into a suspension of 0.20 g (i mmole) of compound Vb in 1.5 ml of nitromethane was
poured 1.2 ml of a 4% ether solution of diazomethane and the mixture was held for 1 day at
10-15 ~ . After the ether was distilled off the residue was recrystallized from alcohol.
Yield, 0.16 g (76%).
D. A suspension of 0.20 g (i mmole) of nitro compound Vc in 1 ml of nitromethane was
methylated with 1.3 ml of 4% ether solution of diazomethane as described in method C.
Yield, 0.18 g (84%).
Et To a solution of 0.40 g (2 mmole) of compound Vc in 4.2 ml of 6% NaOH solution was
added 0.65 ml (6.9 mmole) of dimethyl sulfate dropwise with stirring. After holding for i
h at room temperature, 1 ml of 8% NaOH was added and the mixture was stirred another 3 h.
The precipitate was filtered off, washed with 5% NaOH, and dried. Yield, 0.41 g. The mat-
erial did not depress the melting points of the methylation products obtained by the methods
described above.
4-Amino-l,3-dihydro-2HTimidazo[4,5-c]pyridin-2-0ne (VIIa). A. A solution of 0.50 g
(2.8 m_mole) of compound Va in a mixture of 4 ml of alcohol, 2 ml of water, and 5 drops of
concentrated HCI was heated to boiling; 1.0 g (18 mmole) of pulverized carbonyl iron was
added in portions with vigorous stirring, and the mixture was boiled for 6 h. The precipi-
tate was filtered off and washed with hot water (3 x 2 ml), and the filtrate was evaporated
to half its volume and alkalized with 20% NaOH solution. The precipitate was filtered off,
washed with water, and dried. Yield, 0.25 g (60%).
B. A mixture of 1.0 g (5.5 mmole) of Va, i0 ml of hydroiodic acid (d 1.7), and 1.0 g
(32 mmole) of red phosphorus was boiled for 4 h. The phosphorus was filtered off, and the
filtrate was evaporated to 1/3 its starting volume and alkalized with aqueous ammonia to pH
8. The precipitate was filtered off, washed with a minimal amount of cold water, and dried.
Yield, 0.75 g (91%).
C~ A mixture of 1.80 g of Va and i0 ml (200 mmole) of hydrazine hydrate was heated at
the boiling point for 2 h. The solution was evaporated to dryness and the residue was re-
crystallized from water. Yield, 1.50 g. This amine did not depress the melting point of
samples obtained by methods A and B.
4-Amino-l-methyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (VIIIB) was obtained hy
method C from 1.95 g (i0 mmole) of Vb and 15 ml (300 ml) of hydrazine hydrate. Yield, 1.64
g.
4-Amino-3-methyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (Vile) was obtained by
boiling a mixture of 1.95 g (i0 mmole) of Vc and 20 ml of hydrazine hydrate. Yield, 1.58 g.
4-Amino-l,3-dimethyl-l,3-dihydro-2H-imidazo 4,5-c pyridin-2-one (Vlld). A. It was ob-
tained similarly to amine VIIa by method C from 2.08 g (i0 mmole) of Vd and 15 ml of hydra-
zinc hydrate. Yield, 1.64 g.
B~. A mixture of 1.0 g (4.8 mole) of Vd, 20 ml of 45% hydroiodicacid, and 1.0 g (32
mmole) of red phosphorus was boiled for 4 h. The phosphorus was filtered off, and the fil-
trate was evaporated to 1/3 its original volume and alkalized with 20% NaOH solution. The
reaction product was extracted with chloroform (3 x 5 ml). Yield, 0.71 g.
4-Hydroxy-l,3-dimethyl-l,3-dihydro-2H-imidazp[4,57c]pyridin-2-one (VIIIa)~ A mixture
of 2.i g (10 mmole) of Vd and 70 ml of 5% NaOH solution was heated at the boiling point for
4 h. After cooling the solution was neutralized with concentrated HCI and evaporated to
dryness. The reaction product was extracted from the residue by methanol (3 8 ml) and
the solvent was evaporated. Yield, 1.54 g.

84
 4-Alkoxy-l,3-dimethyl-l,3-dihydro-2H-imidazo[4,5-c]pyridin-2-ones (Vlllb-e). To the
solution obtained by heating 0.15 mole of NaOH ~o~KOH)~ini.@-2.O mole of the appropriate
alcohol was added 0.I mole of Vd, and the mixture was boiled for 2-4 h. The sodium (or po-
tassium) nitrate precipitate was filtered off, excess alcohol was distilled from the filtrate
the reaction product was extracted with hot chloroform (50-60 ml) and the solvent was evapo-
rated.

LITERATURE CITED
i. R . M . Bystrova and Yu. M. Yutilov, Khim. Geterotsikl. Soedin., No. 2, 378 (1969).
2. Yu. M. Yutilov and I. A. Svertilova, Khim. Geterotsikl. Soedin., No. i, 138 (1973).
3. I . A . Svertilova and Yu. M. Yutilov, USSR Inventor's Certificate 521,277; Byull. Izo-
bret., No. 26, 80 (1976).
4. R . H . Mizzoni, in: Pyridine and Its Derivatives, E. Klingsbert (ed.), New York, London
(1961), Part 2, p. 479.
5. Yu. M. Yutilov and I. A. Svertilova, Khim. Geterotsikl. Soedin., No. 9, 1277 (1976).
6. Yu. M. Yutilov, A. G. Ignatenko, O. G. Eilazyan, and I. A. Svertilova, USSR Inventor's
Certificate 717,055; Byull. Izobret., No. 7, 121 (1980).
7. Y. Mizuno, M. Ikehara, T. Itoh, and K. Saito, J. Org. Chem., 28, 1837 (1963).
8. N . S . Miroshnichenko, I. G. Ryabokon', and A. V. Stetsenko, Ukr. Khim. Zh., 39, No. 4,
350 (1973).

SYNTHESIS OF N~-SUBSTITUTED ADENINYL-9-~-D-GLUCOFURANURONOSIDES

Yu. A. Maurin'sh, R. A. Pa~gle, UDC 547.857.7'483:

I. Ya. Zhola, and M. Yu. Lidak 577.113.3:631.8

N6-substituted adeninyl-9-~-D-glucofuranuronosides have been obtained by the conden-

sation of trimethylsilylated 6-aminopurines with 1,2,5-tri-O-acetyl-B-D-glucofur-
ano-6,3-1actone. The structure of the glucuronides was demonstrated by the UV,
IR 9 and PMR spectra.

For the synthesis of nucleosidic derivatives of kinetine (6-furfurylaminopurine) and

other 6-substituted adenines, mainly the amination of 6-chloro- and 6-methylmercaptopurine
nucleosides has been used [1-4]; only in individual cases [5] has glycosylation of a 6-sub-
stituted adenine with a carbohydrate fragment been used.
The purpose of the present work was to synthesize potential cytokinines in the 6-sub-
stituted adenine glucuronide series. Attempts to use l-(6-chloro- or 6-methylmercaptopurin-
yl-9)-~-D-glucofuranosides that we had previously synthesized [6] to obtain these compounds
were unsuccessful, due to the instability of the glycoside bond and the lactone ring under
the reaction conditions. We therefore synthesized the compounds by condensation of the tri-
methylsilyl derivatives of 6-methylamino- (IIa), 6-butylamino- (IIb), 6-cyclohexylamino-
(IIc), 6-benzylamino- (IId), 6-morpholino- (IIe), and 6-furfurylaminopurine (IIf) with 1,2,5-
tri-O-acetyl-~-D-glucofurano-6,3-1actone (III) [7] in 1,2-dichloroethane in the presence of
the condensing agent trimethylsilyltrifluoromethanesulfonic acid (TMS-TF), which is more re-
active than SnCI~ which we used previously [6, 8].
When the reaction was carried out at 80 ~ for 12 h (II:III:TMS-TF 1.1:1.0:1.2 moles), the
principal product was the Ng-~-D-glucofuranoside of N~-substituted purines (IVa-f). The TLC
data bear witness that other nucleosidic products are formed in the reaction (not more than

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006;
"Meristemnye Kul'tury" Agricultural Plant, Ogre 228300. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. i, pp. 103-106, January, 1986. Original article submitted
April 29, 1985.

0009-3122/86/2201-0085512.50 9 1986 Plenum Publishing Corporation 85

 TABLE I. Parameters of PMR S p e c t : r a o f Co.:~pound~ i V a ~
- ca~'mlc,'i" ...................

o. o . , otoo, I'-"1" P"I2

I
IVa 8,23, !6,34 6,13rid ' 0,7~ 3,8]5,4
8,15 i (311, (~.Xc), 2,97, m (3H
CI.I:~), ,,84, m (IH, lILt
IVb 8,20, ! 6,31 6,11 dd , 5,27 dd 'i5,13 5,8~] 2,1t,s (311, OAt), 2,06,s 4,0 l,O 3,414,8
836! (3H, OAc), 0,~8, t (3H,
EI I~), 1,37-- 1,70 (4H,
J
2CI12), 3,48, m (2H, CH,.,),
I L58, ra (Ill,tlil) i
IVe 8,21, 6,32 6,11 d 5,29dd e. 5; 5,91 2,12, s (3H, OAt), 2,09,s 3,8
o,l,., 0,78 3,4 4,8
8,17 i (3I'|, OAt), 1,17--1,95
(101 I, 5CH,.,), 4,13,m (lit,
CH),7,67, a ( l i i , Ill{)
IVd 8,20, 6,321(5,11 d 5,26 d 5,12 5,86 2,10, s(3li,-OAc), 2,07,s 4,0 ,L,O 3,6 5,0
8,18 I (3H, OAc), 4,74, m (2H.
CH.2), 7,24, m (5H, Ph).
,~,47, m (Ill. lilt)
IVO 8,28, 6,37 6,11 dd 5,2.9 d 5,17 5,84 ]2,!2, s (3H, OAc), 2,09.s 3,6 0,75 3,4 5,0
8,22 (3{I. OAt). 3,73, m (4]-t,
2CH.,), 4,22,m (4[{, 2CH2)
IVf 8,26, 6,33 6,13 dd 5,28 d 5,16 5,0012;10, s (3t[, OAc), 2,06,s 3,8 0,75 3,8 5,0
8,20 131i, OAc). 4,75, m (2H,
CI4!!), 6 26--6 38 (3H.
3CH). 7.5.t, t (IH. NH)

5-10% of the total); these could not be separated in pure form for identification. Appar-
ently they are isomers of nucleosides IVa-f. Furthermore, unreacted lactone III and 6-am-
inopurines la-f are left in the reaction mixture. Changing the proportions of reagents or
raising the reaction temperature to boiling did not increase the yield of nucleosides IVa-f.
The glucuronide of 6-dimethylaminopurine could not be synthesized by this method, because
the silyl derivative of 6-dimethylaminopurine does not react with lactone III even at the
boiling point of the solvent. Analytically pure samples of IVa-f were obtained by column
chromatography of the reaction products on silica gel.
The structure and configuration of the synthesized nucleosides were established on the
basis of spectral data.
The properties of the UV absorption spectra of the 6-aminopurine nucleosides IVa-f are
identical with those of the Ng-alkyl derivatives [9, I0] and the Ng-ribofuranosides [2-5,
ii, 12] of the related heterocyclic bases, and are significantly different from those of the
N7 derivatives [5, 13].
The IR spectra of IVa-f contain absorption bands at 1595-1615 (purine C=N), and in the
1800-1805 (7-1actone C=O) and 1750-1760 cm-* (acetate C=~) regions.

.'.co..--!"\o,. OAc n

N~'r------N

............. P"Ac 0
II sJi(cH=)
=
Za- f nL-
OA~
IVa-f

l-llI a R = N H C H a ; b r R = HNC~H's; c R = H N C e H x l i d R = HNCH2CeHs;

i R = morphlino - ; f R = furfurylamino -

The PMR spectral data (Table i) confirm the 8-anomeric configuration and the presence
of a hexafuranose ring in these compounds [14]. The spin-spin coupling constant (SSCC)
values of the carbohydrate protons of IVa-f (at least 6 Hz) are typical of furanose deriva-
tives. This enables us to confirm that during the glycosylation of the purine bases the

86
furanose form is not converted to pyranose. The SSCC value J,,~, = 3.6-4.0 Hz is evidence
for the 8-anomeric configuration of the lactones IVa-f.
Cytokinine properties were studied for IVd,f by the tissue culture method in synthetic
culture media, for the growth of plants from m eristem. The tests were carried out on the
growth of Dianthus from meristem in a modified culture medium. To compare the action of
glucuronides IVd and f, kinetin was added to the medium. The tests show that at concentra-
tions of 0.125 and 0.250 ml/g, IVd and IVf act approximately at the level of kinetine.
Another experiment was carried out to study lactones IVd,f as stimulators of sprout
formation in the growth of cuttings from meristem. In this case 6-benzylaminopurine (BAP)
was added to the culture medium to stimulate sprout formation. It was determined that the
activities of IVd and IVf are lower than that of BAP.

EXPERIMENTAL
UV spectra were recorded in methanol on a Spectromom-204 spectrophotometer; IR spectra
in mineral oil on a Perkin--Elmer spectrometer; PMR spectra in DMSO-D6 on a Bruker WH-90 in-
strument, with HMDS internal standard. Specific rotation w a s determined on a Perkin--Elmer
241 spectropolarimeter.
The course of the reaction and the identity of the reaction products were monitored
by TLC on Silufol-254plates in a 9:1 chloroform-methanol system. The chromatograms were
developed by spraying with a i:i mixture of 0.2% naphthoresocinol in ethanol and dilute
(I:i0) phosphoric acid followed by heating at 110-115 ~ for 15 min. Column chromatography
was carried out on a LKB (Switzerland) column (2.5 60 cm) with LI00/250 silica gel (Czech-
oslovak SSR).
6-Aminopurines la-f were synthesized by the procedures of [15, 16] from 6-chloropurine
or 6-methylmercaptopurine.
Silylation of 6-aminopurines la-f was carried out by boiling the purine in hexamethyl-
enedisilazane (20 ml per g of purine) (for Ib-d), with addition of 2 ml of trimethylchloro-
silane (for le, f) or 2 ml of pyridine (for la) until complete dissolution. The solution
was evaporated in vacuum, 20-30 ml of p-xylene was added, and the solution was again evapor-
ated. The silylated purines lla-f were used without further purification.
l-(6-Methylaminopurinyl-9)-2,5-di-O-acetyl-B-D-glucofuranurono-3,6-1actone (~ya). To a
solution of 1.48 g (6.71 mmole) of 9-trimethylsilyl-6-methylaminopurine (lla) in i00 ml of
1,2-dichloroethane was added 1.84 g (6.1 mmole) of lactone III and 1.71 g (1.38 ml; 7.32
mmole) of TMS-TF and the mixture was heated in an oil bath for 12 h at 80 ~ . After cooling
to 20 ~ the solution was poured into a vigorously stirred suspension of sodium bicarbonate
in 300 ml of chloroform and 50 ml of acetonitrile. The mixture was stirred for i h, the
precipitate was filtered off and washed with 2 i00 ml of chloroform, and the combined fil-
trates were evaporated in vacuum. The residue was dissolved in a minimal amount of chloro-
form, transferred to a column of i00 cm 3 of silica gel with chloroform, and eluted succes-
siveiy with 500 ml of chloroform and 300 ml each of 99:1 (by volume), 98:2, and 97:3 chloro-
form-ethanol, until all lactone IVa had come off the column. The fractions containing IVa
were combined and evaporated to dryness in vacuum. The yield of analytically pure IVa was
0.35 g (15%); mp 204-205; Rf 0.42;[~]D~U 89.2 ~ (c 0.56,DMFA). UV spectrum: %max 265 nm (log
4.24). Found: C 49.6; H 4.2; N 17.6%. CI~HITNsOT. Calculated: C 49.1; H 4.4; N 17.9%.
l-(6-Butylaminopurinyl-9)-2,5-di-O-acetyl-8-D-~glucofuranurono_3,6-1acton (IVb) was obtained
condensation of 9-trimethyl-silyi-6-butylaminopurine (lib) with lactone III, similarly to
IVa. After solvent was evaporated the residue was dissolved in 20 ml of chloroform, i0 cm 3
of silica gel was added, the mixture was evaporated to dryness and transferred with hexane
to a column of I00 cm 3 of silica gel. Material was eluted with 500 ml of hexane, then by
linear gradient elution with 500 ml each of hexane and ethyl acetate. The fractions con-
taining IVb were combined and evaporated. The yellow oily residue was dissolved in the min-
imal volume of chloroform and repeatedly chromatographed on a column of i00 cm s silica gel
with chloroform. Elution was carried out with chloroform. The fractions containing IVb
were evaporated to give a frothy residue. Yield, 17%; Rf 0.54; [a]D =~ 69.3 ~ (c 0.53, DMFA).
UV spectrum: Amax 267 nm (log c 4.21). Found: C 52.6; H 5.3; N 16.1%. C,gH23Ns07. Cal-
culated: C 52.6; H 5.4; N 16.2%.

87
 l-(6-Cyclohexylaminopuri~yl-9)-2,5-di-O-acetyl-8-D-glucofuranurono-6,3-1actone (!Vc) was
synthesized similarly to IVa from 9-trimethylsilyl-6-cyclohexylaminopurine (IIc) and lactone
2o
IIl, and was isolated similarly to glucuronide IVb. Yield, 39%, mp 175-177~ Rf 0.53; [aiD
77.1 ~ (c 0.54; DMFA). UV spectrum: Imax 267 nm (log e 4.30). Found: C 54.8; H 5.6; N
15.0%. C=IH25N~OT. Calculated: C 54.9; H 5.5; N 15.2%.
l-(6-Benzylaminopurinyl-9)-2,5-di-O-acetyl-8-D-glucofuranurono-6,3-1actone (IVd) was synthe-
sized from 9-trimethylsilyl-6-benzylaminopurine (IId) and lactone III and isolated similarly
to IVa. Yield, 41%; mp 11-113~ Rf 0.54; [a]D 2~ 70.2 ~ (c 0.56, DMFA). UV spectrum: Ima x
266 nm (log e 4.27). Found: C 56.7; H 4.4, N 14.8%. C22H2,NsOT. Calculated: C 56.5; H
4.5; N 15.0%.
l_(6_Morpholinopurinyl_9)_2,5~di-O-acetyl-8-D-glucofuranurono-6,3-1actone (IVe) was synthe-
sized and isolated similarly to IVa from 9-trimethylsilyl-6-morpholinopurine (lie) and lac-
tone III. Yield 26%. Mp 99-101~ Rf 0.56; [a]D 2~ 83.8 ~ (c 0.56, DMFA). UV spectrum: imax
277 nm (log e 4.28). Found: C 50.7; H 4.7; N 15.6%. CliH2,NsOs. Calculated: C 51.0; H
4.7; N 15.6%.
l-(6-Furfurylaminopurinyl-9)-2,5-di-O-acetyl-B-D-zlucofuranurono-6,3-1actone (IVf)was syn-
thesized similarly to IVa from 9-trimethylsilyl-6-furfurylaminopurine (llf) and lactone I!I,
and isolated similarly to IVb. Yield 23%; mp 175-176~ Rf 0.54; [a]D 2~ 85.0 ~ (c 0.40, DMFA).
UV spectrum: imax 266 nm (log e 4.26). Found: C 52.4; H 4.1; N 15.4%. C2oH,gNsO,. Calcu-
lated: C 52.5; H 4.2; N 15.3%.

LITERATURE CITED
i. A. Hampton, J. J. Biesele, A. E. Moore, and G. B. Brown, J. Amer. Chem. Soc., 78, 5695
(1956).
2. J. A. Johnson, J. J. Thomas, and H. J. Shaeffer, J. Amer. Chem. Soc., 80, 700 (1958).
3. M. Ikehara and H. Uno, Chem. Pharm. Bull., 13, 221 (1965).
oV
4. J. Zemllcka and F. Sorm, Coll., 30, 1880 (1965).
5. H. M. Kissman, C. Pidacks, and B. R. Baker, J. Amer. Chem. Soc., 77, 18 (1955).
6. J. A. Maurin~, R. A. Pa~gle, A. A. Zidermane, M. J. Lidaks, E. I. Kvasyuk, and I. A.
Mikhailopulo, Nucleosides and Nucleotides, ~, 147 (1984).
7. D. B. Davies, Studia Biophys., 55, 29 (1976).
8. M. K. Kilevitsa, Yu. A, Maurin'sh, R. A. Pa~gle, E. E. Liepin'sh, A. A. Zidermane, and
M. Yu. Lidak, Khim. Geterotsikl. Soedln., No. ii, 1532 (1981).
9. R. K. Robins and H. H. Lin, J. Amer. Chem. Soc., 79, 490 (1957).
i0. J. A. Montgomery and C. J. Temple, J. Amer. Chem. Soc., 79, 5238 (1957).
ii. H. M. Kissman and M. J. Weiss, J. Org. Chem., 21, 1053 (1956).
12. G. M. Blackburn and A. W. Johnson, J. Chem. Soc., No. Ii, 4347 (1960).
13. N. Prasad and R. K. Robins, J. Amer. Chem. Soc., 79, 6401 (1957).
14. A. A. Akhrem, V. A. Timoshchuk, L. N. Kulinkovich, and I. A. Mikhailopulo, Bioorg. Khim.,
~, 513 (1976).
15. J. W. Daly and B. E. Christensen, J. Org. Chem., 21, 177 (1956).
16. G. B. Elion, E. Burgi, and G. H. Hitchings, J. Amer. Chem. Sor 74, 411 (1952).

88
SYNTHESIS AND PROPERTIES OF symm-TRIAZINE DERIVATIVES.
4.* SYNTHESIS OF 2,4,6-TRIS~BSTITUTED symm-TRIAZINES
CONTAINING STERICALLY-HINDERED PHENOL FRAGMENTS

V. I. Kelarev, F. Laawad Yakhya, R. A. Karakhanov, UDC 547.491.07:543.422

A. F. Lunin, and O. V. Malova

2,4,6-Trisubstituted symm-triazines containing sterically-hindered phenol frag-

ments were synthesized by the cyclotrimerization of ethyl iminoesters. 2,4,6-
Trimercapto-symm-triazine derivatives containing shielded phenol residues may
be formed by the cyclotrimerization of the corresponding thiocyanates in acidic
medium.

The introduction of sterically-hindered phenol groups into symm-triazines permits the

preparation of antioxidants and thermal and light stabilizers for polymer materials and lub-
ricating oils [2-4]. In our previous work [5], we demonstrated the feasibility of preparing
such sym~-triazine derivatives by the reaction of chloro-symm-triazines with 4-hydroxy-3,5-di-
tert-butylaniline. In a continuation of this investigation, we synthesized 2,4,6-trisubsti-
tuted symm-triazines, in which shielded phenol fragments are attached to the heterocyclic
ring by means of C--C or C--S bonds.
Derivatives of symm-triazine may be obtained by the cyclotrimerization of the iminoes-
ters of carboxylic esters in the presence of their hydrochloride salts [6, 7] or other acid
agents [8, 9]. In the present work, we studiedthe use of this method for the preparative
synthesis of 2,4,6-trisubstituted summ-triazines containing 2,6-di-tert-butylphenol fragments
(VII) and (VIII).
Iminoesters V and VI required for the preparation of this type of heterocyclic compounds
were synthesized by the ordinary scheme from the corresponding nitriles I and II.
(~H2)~Ar

Ar--(CIIT)C~N C?'HsOtt"" NH'Itr .INH H N:~:'I~

- ........
Hc~ A~ - ~+ ,+.). Cc-+-oc...~. --- .c,'-^ ~ " ~':~';~" ':~;oco:o " I [
1-xt~-e mw. ~ v.vt,,-- c " ~,-~c. i "'N ff.H~) Ar
Vll--Vllle. - C
C(ClI~ s -C(('H.~)a
la.-.C)lllo- ~m42 .VIIa CAr +~
/z / Oil ; Ha C.IVa. ~Vla C.VIIIa CAI'==+ S --O11 ;

1 VI]I a , O; b .. I;C +~ .~
The hydrochtoride salts of ethyl iminoesters III and IV were prepared by the Pinner re-
action by passing dry HCI into a mixture of the corresponding nitrile I or II and absolute
ethanol in a suitable solvent. In the case of 4-hydroxy-3,5-di-tert-butylbenzonitrile (la),
the reaction was carried out in an excess of ethanol at I0-15~ with subsequent maintenance
of the reaction mixture for four days [I0]. The iminoester hydrochlorides lllb, lllc, and
IVa-c were formed in good yield upon carrying out the reaction at 0-5"C using equimolar
amounts of the corresponding nitrile and ethanol with subsequent maintenance of the reaction
mixture for 10-12 h at 20~ Iminoester salts III and IV are rather stable compounds and may
be stored for prolonged periods avoiding moisture.

*For communication 3, see [i].

I. M. Gubkin Moscow Petroleum Chemistry and Gas Industry Institute. Translated from ......
Khimiya Geterosiklicheskikh Soedinenii, No. i, pp. 107-113, January, 1986. Original article
submitted November 20, 1984.

0009-3122/86/2201-0089512.50 9 1986 Plenum Publishing Corporation 89

 TABLE i, Characteristic of Ethyl Im~noesters V, V~ and 'l'iies
Hydrochlortde Salts Iii and IV
~ , L : . . . . . . . . . . ~ .......... ~: . . . . . . . . . . . . . . . . . . . . .

~ ~ Found, ~ r
C Che~aical Yield, %
Corn-
pound

IIla 258~260 - ,- 65,3 8,9 4.(~1 1,5 1 CI71127NO,~. 1IC1 65,1 8,9 4,5 t,3 67
(260 [2H)
]V~ [54--155,5 O,42 73,5 9.8 5.2 1 .... CI,;It~TNO2 73.6 9,7 5,0 -- 89
172--174 {16,0O,l 4.2 1113) (iml I~,jNO2 9I ICI 55,9 9.2 4,3 0,8 74
Vb 80.--8 I 0,30 74,4 :J,9 5.0 I -- C,~I'12~NO~ 74,'2 0,0 4,8 -- 92
lllc 116--118 - - 86,6 9,3 :[.2 IlO, l C,ol'hlNO2" I ICI 86.8 9,4 4,1 0,4 93
Vc Macro 0,25 74,5 0,2 4,8 1 -- CI91"13INO:~ 74,7 0.2 4,6 -- 88
IVa 16,5.-166 -- 58,9 8.2 4,2 ii0,0 I CITI'I~TNO,.,S. 11C1 59,0 8,1 4,0 0,3 68
Via 133--135 0,67 66,2 8,6 4,31 -- CITH27NO2S 66,(] 8,7 4,5 -- 75
IVb 233--235 -- 60,0 8,3 4~0J10,2 I CLaI-I~oNO2S. HCI 50,1 8,3 3,9 9,9 76
V|b I05--I06,5 0,62 57,0 9,1 ~,5 - - C,~]-I~oNO2S ~6.9 9,0 4,3 -- 91
IVc 134.--136 -- 60,8 8,7 l~,91 ~,3 CmI-I3tNO2S. HCI 61.0 8,6 i3,7 9,5 86
Vlc Macro -~
"6"
0,51 57,7 CIgH~,NO2S 57,6 9,2 i4,2 - - 92
9 2 i4,4l -

*III and IV were purified by reprecipitation from glacial acetic

acid in dry ether, V and Via were purified by recrystallization
from aqueous ethanol, Vb, Vc, Vlb, and Vlc were purified by chro-
matography on alumina columns with elution by i0:i benzene--metha-
nol. Salts llla-c and IVa-c melted with decomposition.
tThin-layer chromatography on alumina with heptane eluent.
SnD 2~ 1.4864
Ethyl iminoester bases V and VI were obtained by treatment of suspensions of the imino-
ester salts in ether or methylene chloride at 0-5 ~ by 10% aqueous KOH or saturated aqueous
K2COa. However, heavy tar forumtion was noted using this method in the case of iminoesters
Vb and Via and thus, hydrochloride salts lllb and IVa were converted to the corresponding
iminoesters by treatment with triethylamine in dry ether.
The IR spectra of iminoester salts III and IV show strong bands at 1670-1655 cm-* char-
acteristic for C=N + stretching vibrations [i0, ii]. This band in the IR spectra of imino-
ester bases V and VI appear at lower frequencies (1635-1615 cm-'). The C=N+--H stretching vib-
rations in the spectra of salts III and IV are found at 3155-3100 cm -~, which is characteris-
tic for NH vibrations in imine salts [12]. T h e NH group vibrations in the IR spectra of im-
inoesters V and VI are seen as medium-intensity bands at 3370-3340 cm -~.
A study of the cyclotrimerization of ethyl iminoesters V and VI showed that these com-
pounds, with the exception of ethyl iminoester 4-hydroxy-3,5-di-tert-butylbenzoic acid (Va)
are smoothly converted to the corresponding 2,4,6-trisubstituted symm-triazines VII and VIII.
The cyclotrimerization of iminoesters Vb, Vc and Vla-c was carried out at 90-95~ for 20-25
h in the presence of iminoester hydrochlorides III and IV (3-5 mass % relative to iminoesters
V and Vl). The yields of symm-triazines Vllb, Vllc, and Vllla-c were 80-88% (Table 2).
The cyclotrimerization of iminoester Va proceeded with much more difficulty. Thus, 2,4,
6-tris(4-hydroxy-3,5-di-tert-butylphenyl)-symm-triazines (Vlla) was isolated in only 12%
yield after carrying out the reaction under the above conditions (90=C, 24 h) and the start-
ing iminoester Va was also isolated. Despite varying the reaction conditions by using other
acid catalysts, increasing the reaction time to I00 h and increasing the temperature to 120-
125*C, the yield of symm-triazine Vlla could not be markedly increased. We should note that
the major reaction products upon carrying out the cyclotrimerization of Va at 145-150~ for
15 h are 4-hydroxy-3,5-di-tert-butylbenzamide and nitrile In.
This difference in the behavior of iminoester Va is realted to the reduced reactivity of
the iminoester group as a consequence of its conjugation with the hydroxy group [i0]. In ad-
dition, the steric hindrance due to the tert-butyl groups in the vicinity of the reaction site
undoubtedly play a definite role.
Dexter et al., [13] have reported the preparation of symm-triazine Vlla by the direct
alkylation of 2,6,di-tert-butylphenol with cyanogen chloride (3:1 mole ratio) in the presence
of AICI3 in tetrachloroethylene. However, all our attempts to reproduce this procedure were
unsuccessful and only tar formation was noted; individual compounds could not be isolated.

90
 TABLE 2. Characteristics of 2,4,6-Trisubstituted symm-Triazines

77
919,11
,1
VII-VIII and X

Found, % Calculated, % Yield, %=~'/

Chemical (prepara-
~OIR- i~, ~ Ry.'~"
formula
potmd tive ree-
C H N s d H N S t.hod )

VII !' 310--3tl,5 0 92 78,0 CasH63N30~

~,0 B,3 -- -- 15 (A)
VII 161--162,5 0:54 78,6 C4sFI69N30~
9,4 15,0 78,8 9,4 5,7 84 (A)
VII 209--210 0,46 178,9 C511-ITsNaO3 178,8 9,6 5,4 ~z-,2 88(.A)
~,5 15,6
VIII 211--212 (I,42 [38,3 ',9 ]5,1 12,3
C4sI-I6aN303S3 58,4 8,0 5,3 81(A},
45(B),
67 (B)
VllI b 102--104 0,82 139,3 ~,8 i~,2 I 1,2 C48H~N303S3 1~9,4 8,3 5,0 11,5 80(A)
VIII c 57--59 0,66 170,0 8,7 5,0 10,9 CsII-175N303S3 170,1 86 4-8 I1,0 86(A)
X 195--196
( 197---198 [261)
0,50lB9,5
B,4 4,9 11,7 C481-1~9N303S3 [59,4 813 510 11,5 37(B,
69(B )

*The recrystallization solvents were aqueous DMF (Vlla and Vllb),

glacial acetic acid (Vllc), ethanol (Villa), aqueous ethanol
(VIII b and Vlllc), and i:i toluene--hexane (X).
*In 20:1 benzene-methanol.
SA) Cyclotrimerization of iminoesters, B) cyclotrimerization of
thiocyanates, C) convergent synthesis.

Martin et al, [14] have reported that 2,4,6-trialkyl- and 2,4,6-triarylthio-symm-tria-

zincs may be obtained by the cyclotrimerization of alkyl- and arylthiocyanates in the pres-
ence of acids. We attempted to use this method for the synthesis of derivatives of 2,4,6-
trimercapto-symm-triazine containing shielded phenol residues. Upon heating in DMF in the
presence of catalytic amounts of HaSO4, 4-hydroxy-3,5-di-tert-butylphenylthiocyanate (lla)
and 4-hydroxy-3,5-di-tert-butylbenzylthiocyanate (IX) were converted in good yield to the
corresponding symm-triazines Villa and X.

s(cn~)A,
li ~ N/
7 "N
lIa.IX Ar(C|I2) S N "~(C][.? Ar

VIIla.X

.... C(CII3} 5

IIa.VHIa,L':,X Ar . . . . . . f"(" ")")/-Oil ; IIu,VIHa i,-:O; IX,X .... l

c(ciI:) 3

In the present work, 2,4,6-trimercapto-symm-triazine derivatives Villa and X were also

obtained by convergent synthesis. The condensation of 4-mercapto-2,6-di-tert-butylphenol
with cyanogen chloride gave Villa, while X was obtained by the reaction of 2,4,6-trimercapto-
sym-triazine with 2,6-di-tert-butylphenol and formaldehyde.
I
The IR spectra of symm-triazines VII, VIII and X have a narrow band at 3650-3635 cm-
corresponding to the stretching vibrations of the nonassociated OH group in the hindred
phenols [15]. The spectra of these compounds show bands of different intensity characteris-
tic for the stretching and deformation bands of the symm-triazine ring (Table 3) [7, 16-18].
The bands at 885-880 and 825-820 cm -~ are characteristic for the 4-substituted benzene ring
while tile two bands at 1265-1210 cm-* are characteristic for the Ar--OH bonds [19].
The PMR spectra of s3~m-triazines VII, VIII and X show signals for the hydroxyl group
protons as singlets at 5.12-5.22 ppm, which is characteristic for sterically-hindered phenols
[20]. The signals for the tert-butyl group protons are seen as singlets at 1.62-1.75 ppm.
The aromatic ring protons give rise to singlets with intensity 2H at 7.14-7.30 ppm.

EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer as a suspension in vaseline oil (III
and IV), in CCI, (V and VI) or in KBr pellets (VII, VIII and X). The PMR spectra were taken
on a Tesla BS-487C spectrometer at 80 MHz using the 6 scale with HMDS as the internal stand-

91
 TABLE 3. Spectral Data for 2,4,6-Trisubstituted summ-Triazines
VII, VIII and X

IRspectrum, cm"I
'Vs' ~"a s triazine ring Vc-o PMR spectrum,~, ppm
G--H vibrations % 6~ 8a~
%'0-II (CHa,
C[la)
; V-rl ; f-
VII,

VII 1,72 (541t, a terl-C4H~); 3,56 (6H,

s CH,,); 5,12 (3tJ, a OH); 7,25 (5!t,
s, arom.protons )

VII ~ i,75 (541t, s lert-C4Ho); 4,46--4,68

(12}t, m CI-12--CH.~); 5,18 (3tl, s ,
OH); 7,28 (6H,s, arom.protons)
VIII,

VIII t,74 (54H, H lert-C41Ig); 4,22 (6H,

H CH2); 5,14 (3H, c, OH); 7,18 (6H,
s,, a r o m . protons)
VIII, 1,66 (54H, s, ferl-C4|tg); 4,58--4,74
(12H, m CH2--CH2); 5,22 (3H, s,
OH); 7,18 (6H, s. atom.protons)
1,62 (54H, s, tert-C4Hg); 4,42 (6H,
s, CH2'); 5.20 (3H, s OH); 7,14 (6H,
atom.protons)

*The PMR spectra of Vllb, Vllc and X were taken in DMSO-D6,

while the spectra of Vlllb and Vlllc were taken in deuterometh-
anol.
%~) In-plane ring deformation vibrations, ~) out-of plane ring
deformation vibrations.
SRing "breathing" bands.

ard. The reaction was monitored and the purity of the compounds obtained was checked by thin-
layter chromatography of Brockman grade II alumina with iodine vapor development or on Silufol
UV-254 plates with development in UV light.
4-Hydroxy-3,5-di-tert-butylbenzonitrile (la) [21] and 4-hydroxy-3,5-di-tert-butylphenyl-
acetonitrile (IV [22] as well as 4-hydroxy-3,5-di-tert-butylphenylthiocyanate (lla) [23] were
obtained according to published procedures.
~_(4_Hydr0xy_3,5_di_tert_butylphenyl)propionitrile (It). A sample of 14.8 g (279 mmoles)
freshly prepared acrylonltrile was added dropwise with stirring in an inert gas stream over
l0 mln to a mixture of 51.0 g (246 mmoles) 2,6-di-tert-butylphenol and 6.0 g (120 mmoles) KOH
in 150 ml dry DMSO. The reaction mixture was stirred for 8 h at 60-65~ and then DMSO and
unreacted 2,6-di-tert-butylphenol were removed at reduced pressure. A sample of 15 ml 15%
aqueous HCl was added to the residue and the organic layer was extrated with two 150 ml por-
tions of benzene. The benzene solution was washed with 150 ml waterj dried over CuSO, and
evaporated to dryness. The residue was crystallized from hexane to give 19.7 g (13%) nitrile
Ic, mp 110-112~ Rf 0.95 (20:1 benzene--ethanol), mp i13-114~ [24].
4_Cyanomethylthio_2,6_di-tert-but71phenol (llb~. A solution of 3.1 g (55 mmoles) KOH
in 45 ml absolute ethanol was added dropwise in an inert gas stream to a stirred solution of
12.9 g (50 mmoles) 4-mercapto-2,6-di-tert-butylphenol [25] in 35 ml absolute ethanol at 5-10~
The reaction mixture was stirred for 30 min at 5~ and then 7.75 g (50 mmoles) chloroacetoni-
trile was added dropwise in an inert gas stream at 5~ The mixture was stirred for 3 h at
65-70~ cooled to 10~ poured into 200 ml cold water, and acidified by dilute HCI to pH 6.5.
The organic layer was extracted with three 50 ml portions of ether. The extract was washed
with water, dried over CuSO,, and evaporated to dryness. The oil was crystallized from 20:1
hexane--benzene to give 6.57 g (51%) nitrile lib, rap 60.5-62~ Rf 0.18 (heptane). Found:
C 73.6;~H 7.0; N 4.4; S 10.0%. Calculated for CaoH2sNOS: C 73.8; H 7.1; N 4.3; S 9.8%.

92
 4-(B-Cyanoethyl)thio-2,6-di-tert-butylphenol(I~Ic). Three drops of concentrated aque-
ous KOH was added to a stirred solution of Ii.0 g (46 mmoles> 4-mercapto-2,6-di-tert-butyl -
phenol in 60 ml dioxane and then, 7.3 g (138 mmoles) acrylonitrile was added dropwise at 20-
25~ The reaction mixture was stirred at 70~ for 5 h, cooled to 20~ poured into 200 ml
cold water and neutralized with dilute hydrochloric acid to pH 7.0. The organic layers was
extracted with three 50-ml portions of ether. The extract was washed with water, dried over
CuSO~ and evaporated to dryness. The residue was crystallized from heptane to yield 10.9 g
(70%) nitrile llc, mp 97-990C, Rf 0.24 (heptane). Found: C 74.1; H 7.3; N 4.3; S 93%.
Calculated for C=~H25NOS: C 74.3; H 7.4; N 4.1; S 9.4%.
Hydrochloride Salt of the Ethyl Iminoester of 4-Hydroxy-3,5-di-tert-butylbenzoic Acid
(IIIa). A stream of dry HCI was passed for 2 h at I0-15~ through a stirred mixture of 4.6
g (12 mmoles) Ia in 40 ml absolute ethanol and 20 ml dry ether. The reaction mixture was
maintained for 72 h at 20~ and evaporated to dryness at reduced pressure. The residue was
treated with dry ether. The precipitate was filtered and dried in vacuum over KOH.
Hydrochloride Salts of Ethyl Iminoesters IIIb~ IIIc~ IVa-c. A stream of dry HCI was
passed for 1 h through a stirred mixture of i0 mmole nitrile Ib, Ic, IIa-c and 12 mmole ab-
solute ethanol in 30 ml dry ether at 0~ The reaction mixture was maintained for 4-5 h
at 200C and cooled to --15~ The hydrochloride precipitate of IIIb, IIIc, IVa-c was filter-
ed off and dried in vacuum over KOH (Table i).
Ethyl Iminoester of 4-Hydroxy-3,5-di-tert-butylphenylacetic Acid (Vb). A sample of
1.12 g (12 mmoles) triethylamine in i0 ml ether was added dropwise to a stirred suspension
of 3.27 g (i0 mmoles) hydrochloride IIIb in 120 ml dry ether at 0~ and stirred for 1 h at
O~ T h e precipitate was filtered off. The solvent was removed at a water pump and the
residue was subjected to chromatography on a 3.5 50 cm alumina column with i0:i benzene--
methanol as the eluent.
Ethyl iminoester Via was obtained analogously. The PMR spectrum of Via in deuterometh-
ano!: 1.34 (3H, t, CH~), 18.2 (18H, s, tert-C~Hg), 4.52 (2H, q, OCH2), 5.20 (IH, s, OH),
7.12 (2H, s, aromatic protons), 8.18 ppm (IH, s, NH).
Ethyl Iminoesters of Acids Va, Vc, VIb and Vlc. A sample of 35 ml 10% aqueous KOH was
added dropwise to a stirred suspension of 25 mmole ethyl iminoester hydrochloride IIa, IIIc,
IVb or IVc in 300 m! ether or methylene chloride at 0.5~ The ethereal layer was separated,
washed with 120 ml water and dried over CuSO~. The solvent was removed at a water pump.
The residue was either crystallized from aqueous ethanol (Va) or subjected to chromatography
on a 3.5 75 ml alumina column with I0:I benzene-methanol as eluent (Table i). PMR spectrum
of iminoester Vc (in CCI~): 1.22 (3H, t CH3), 1,66 (18H, s, tert-C~Hg), 4.24 (2H, q, OCH2),
4.48-4.72 (4H, m. CH2CH=), 5.65 (IH, s, OH), 7.34 (2H, s, aromatic protons), 8.12 ppm (IH,
s, NH).
2,4,6-Trisubstituted symm-T~iazines (Vlla-c, Villa-c). A mixture of 30 mmoles ethyl
iminoester Va-c or Vla'c and 3 mmoles of the corresponding iminoester hydrochloride was heat-
ed at 90-95~ for 20-25 h with protection from atmospheric moisture. The reaction mixture was
maintained for 1 h in vacuum created by a water pump on a steam bath. The residue was sub-
jected to chromatography on a 3.5 80 ml alumina column with 30:1 benzene-methanol as the
eluent (Table 2).
4-Hydroxy-3,5-di-tert-butylbenzylthiocyanate (IX). A solution of 34.3 g (135 mmoles)
4-hydroxy-3,5-di-tert-butylbenzyl chloride in 50~ml ethanol was added dropwise to a stirred
suspension of 19.4 g (200 mmoles) potassium thiocyanate in i00 ml ethanol. The reaction mix-
ture was heated at reflux with stirring for 2 h and then, 80-85 ml solvent was distilled off.
A sample of 150 ml cold water was added to the residue. The organic layer was extracted with
three 75 ml portions of ether. The extract was washed with i00 ml water, dried over CaCI2
and evaporated to dryness. The residue was crystallized from aqueous ethanol with activated
charcoal to yield 20.2 g (54%) thiocyanate IX, mp 42-43.5~ Rf 0.52 (20:1 benzene-methanol).
Found: C 69.2; H 8.2; N 4.9; S 11.7%. Calculated for C~6H=3NOS: C 69.3; H 8.3; N 5.0; S
]1.5%.
2,4,6-Tris(4-hydroxy-3,5-di-tert-butylphenylthio)-symm-triazine (VIIIa). B~ Five
drops of concentrated sulfuric acid was heated to a solution of 4.0 g (15 mmoles) thiocyan-
ate IIa in 15 ml dry DMF and heated at reflux for 8 h. The reaction mixture was cooled to
20~ and poured into !00 ml cold water. The dark oil isolated was extracted with I00 ml
ether. The extract was washed with 50 ml water, dried over CuSO~, and evaporated in vacuum.

93
The residue was subjected to chromatography on a 3.5 50 ml alumina column with 10:1 ben-
zene-methanol as eluent to yield 1.8 g (45%) symm-triazlne Villa, mp 210-2]I~ (from ethanol).
C__~. An ethanolic solution of potassium mercaptide obtained from 8.14 g (30 mmoles) 4-
mercRpto-2,6-di-tert-butylphenol and 1.68 g (30 mmoles) KOH in 30 ml absolute ethanol was
added dropwise to a solution of 1.84 g (i0 mmoles) cyanogen chloride in 25 ml acetone. The
reaction mixture was heated at reflux for 3 h, cooled to IO~ and the KCI formed was filter-
ed off. The filtrate was poured into 100 ml water. The organic layer was extracted with
three 50 ml portions of ether and dried over CuSO~. The solvent was distilled off and the
residue was crystallized from ethanol to yield 5.2 g (67%) symm-triazine VIIIa.
2,4,6-Tris(4THydroxy-3,5-di-tert-butylbenzylthio)-s,vmm-triazine(X ) . B~ This compound
was obtained by analogy to symm-triazine Villa from thiocyanate IX in 37% yield, mp 195-196~
C__z A solution of 27.8 (130 mmoles) 2,6-di-tert-butylphenol in 80 ml glacial acetic
acid was added with stirring to a suspension of 7.14 g (40 mmoles) 2,4,6-trimercapto-symm-
triazine and 7.25 paraformaldehyde in 30 ml glacial acetic acid, and then 13 ml 20% hydro-
chloric acid was added. The reaction mixture was stirred for 6 h at 45~ The precipitate
was filtered off, washed with 150 ml water and then with 100 ml 2:1 ethanol--acetone to yield
23.1 g (69.5%) symm-triazine X, mp 194-195~

LITERATURE CITED
i. V. I. Kelarev, A~mar Dibi, and A. F. Lunin, Khim. Geterotsikl. Soedin., No. ii, 1557
(1985).
2. H. Brunetti, West German Patent No. 2,155,453; Chem. Abstr., 77, 62782 (1972).
3. P. Klemehuk, US Patent No. 3, 81,006; Chem. Abstr., 81, 105575 (1974).
4. G. Gaspari, US Patent No. 4,038,197; Chem. Abstr., 88, 52833 (1978).
5. O. V. Malova, T. P. Vishnyakova, I. A. Golubeva, V. I. Kelarev, and A. F. Lunin, Khim.
Geterotsikl. Soedin., No. 12, 1678 (1984).
6. A. Ya. Yakubovich, E. L. Zaitseva, G. I. Braz, and V. P. Bazov, Khim. Obshch. Khim., 32,
3409 (1962).
7. V. I. Kelarev, Ammar Dibi, A. F. Lunin, R. L. Ushakova, A. I. Mikaya, N. V. Petrova,
and S. M.-G. Shvekhgeimer, Zh. Org. Khim., 19, 2401 (1983).
8. F. C. Schaefter and P. Grace, J. Org. Chem., 26, 2778 (1961).
9. V. G. Ostroverkhov, L. M. Goncharenko, and A. A. Kornienko, Ukr. Khim. Zh., 37, 1129
(1971).
I0. V. I. Kelarev, S. M.-G. Shvekhgeimer, V, N. Koshelev, A. F. Lunin, and G. A. Shvekhgei-
mer, Zh. Vses, Khim. Obshch. im. D. I. Mendeleeva, 27, 582 (1982).
ii. V. I. Kelarev and G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., No. 5, 645 (1980).
12. K. Nakanishi, IR Spectra and the Structure of Organic Compounds [Russian translation],
lzd. Mir, Moscow (1965), p. 46.
13. M. Dexter, B. Manor, and M. Knell, US Patent No. 3,905,939; Ref. Zh. Khim., 12NI82P
(1976).
14. D. Martin, M. Bauer, and V. A. Pankratov, Usp. Khim., 47, 1814 (1978).
15. V. V. Ershov, G. A. Nikiforov, and A. A. Volod'kin, Sterically-Hindered Phenols [in Rus-
sian], Izd. Khimiya, Moscow (1972), p. 38.
16. A. I. Finkel'shtein and E. N. Boitsov, Usp. Khim., 31, 1496 (1962).
17. V. E. Allenstein, W. Rodzum, and J. Weidhein, Z. Anorg. Chem., 53, 408 (1974).
18. A. R. Katritzky (ed.), Physical Methods in Heterocyclic Chemistry [Russian translation],
Izd, Mir, Moscow (1966), p. 594.
19. M. Avram and G. Hattescu, Infrared Spectroscopy, Wiley-lnterscience (1970), p. 527.
20. T. N. Pliev, Zh. Prikl. Spektroskopii, 13, 124 (1970).
21. L. A. Cohen, J. Org. Chem., 22, 1333 (1957).
22. V. V. Ershov and I. S. Belostotskaya, Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 376 (1965).
23. E. Muller, H. B. Stegmann, and K. Scheffler, Ann., 645, 79 (1961).
24. E. V. Glebova and T. P. Vishnyakova, Izv. VUZov. Khim. i Khim. Teknol., 20, 1076 (1977).
25. E. B. Hotelling, R. J. Windgassen, E. P. Previc, and M. B. Neuwort, J. Org. Chem., 24,
1598 (1959).
26. J. Grilles, US Patent No. 3,862,942; Ref. Zh. Khim., 22N243P (1975).

94
STRUCTURE AND SOME PROPERTIES OF TETRAZOLE 5-METHYLPYRIMIDO[4,5-e]-
[I,2,4]TRIAZINE-6,8-DIONE AND ITS AZIDE IN DIFFERENT PHASE STATES

N. A. Klyuev, G. G. Aleksandrov, Yu. A. Azev, UDC 539.26:547.859.2'866o796.1

E. O. Sidorov, and S. E. Esipov

The structure of the tetrazole, 5-methylpyrimido[4,5-e][l,2,4]triazine-6,8-dione

was established by x-ray structural analysis. The tautomeric equilibrium with
its azide isomer in solution was examined. The effect of bases on this equili-
brium was discovered. Analytical criteria were proposed which permit identifica-
tion of the tetrazole and the azlde forms in the gas phase.

The present study is a continuation of our previous work [1-3] on the physicochemical
properties of pyrimido-as-triazine antibiotics including rheumacine, fervenuline, and xantho-
tricine and their structural analogs [4-6] having antiviral activity [7].
In the present work, we established the nature of the ring fusion in the tetrazole, py-
rimido[4,5-e][l,2,4]triazine-6,8-dione (la or Ib) in the crystalline state and elucidated the
differences between the cyclic form (la or Ib) and its isomer (Ic) in the aizde form relate
to dissociative ionization upon electron impact. The structural results were compared for
isomers la-c (taking account of possible tautomerism) for different aggregate states.

0"" N ~ ' N "N 0 "N "N >:N 0 N N N-=N=rN

I I I I i
CHI CIII N :n-~:N CH 3
la I b IC

I n o u r p r e v i o u s w o r k , by a n a l o g y t o t h e s t u d i e s o f Messmer [8] and B o g a t s k i i [9] f o r t h e

c y c l i c f o r m , we a d o p t e d t h e a n g u l a r s t r u c t u r e (Ib) for both the crystalline and g a s e o u s s t a t e s
of this molecule. T h e r e i s no common o p i n i o n p r e s e n t l y i n t h e l i t e r a t u r e concerning the na-
ture of the cyclization of the 3-azido group in 1,2,4-triazine derivatives. Thus, x - r a y d i f -
fraction structural a n a l y s i s h a s shown t h a t t h e t e t r a z o l e isomer of 3-azido-5-p-chlorophenyl-
1,2,4-triazine exists in crystals as the linear analog, 5-p-chlorophenyltetrazolo[l,5-b]-l,2,
4-triazine [i0]. On the other hand, Messmer et al. [8] have shown that 3-azido derivitives
of benzotriazine cyclize in solution mainly to give the angular tetrazolo[5,l-c]benzo-as-tri-
azine and only a small amount of linear tetrazolo[l,5,-b]benzo-as-triazine is observed in
highly polar aprotic solutions. Recently, Nishigaki et al. [Ii] studied the UV spectra of
model azolopyrimidopyridazines and found that 3-azido-6,8-dimethylpyrimido[5,4-3][l,2,4]tri-
a zine-5,7-dione cycl izes to linear i, 3-dimethyl te trazolo [4,5-b ]pyrimido [5,4-e ]-a s-triazine-
2,4-dione but they did not present melting point or elemental analysis data for this compound.
In addition, no data were given on the state of the azido--tetrazole equilibrium for this iso-
mer pair or for the PMR and UV spectra of the azido derivative.
Thus, the lack of reliable data on th~ nature of the ring fusion of the tetrazole ring
in 1,2,4-triazines requires a special study in each specific case.
In order to determine the nature of the condensation of the tetrazole system in pyrimido-
[4,5-e][l,2,4]triazine-6,8-dione, we studied the molecular and crystal structure of this com-
pound by x-ray diffraction structural analysis and established that the tetrazole ring is
fused with the as-triazine ring at the C(~)--N(4) bond (structure la) and not at the C(~)--N(8)
bond (structure Ib, Fig. i). Dione la consists of three planar condensed heterocyclic rings,
namely, a uracil ring (A), as-triazine ring (B) and tetrazole ring (C, Table I), and has a

All-Union Scientific-Research Institute of Antibiotics, Moscow 113105. S. M. Kirov

Urals Polytechnical Institute, Sverdlovsk 620002. Translated from Khimiya Geterotsikliche-
skikh Soedinenii, No. i, pp. 114-120, January, 1986. Original article submitted November 20,
1984.

0009-3122/86/2201-0095512.50 9 1986 Plenum Publishing Corporation 95

 %~ 7~.--.:. ,~, ~ :L ~ BO }

,~%3,0L'3~
9 , co ~ ' ,
Fig. i. Bond lengths and angles in la~
:. _ +

-+ ,+

,,,,,,+-?:+.+

TABLE I. Coefficients of the Plane Equations Az + By + Cz --

D = 0 of Several Planar F~agments of la and Deviation of the
Atoms from These Planes, A

Plane Atoms

A N(u C(,) N~2) Ct2) C~3) 0,908 -0,0324 -0,4160 2,0077

- 0,002 --0,010 0,021--0,035 0,020
C(s) O*(1) 0*(2) C*(8)
-0,005-0,021-0,109 -0,043
0,91C -0,0017 -0,4126 2,2999
-0,010 0,001 0,006-0,010 0,0000,009
N(4) N(5~ Nt6) N(z) C(~) 0,907 0,0228 -0,4193 2,4839
-0,008 0,007 0,000-0,006 0,013
Nu) C(,) N(~) C(2) C~3, N~a) 0,90~ --0,0092 -0,4161 2,2103
0,028 0,001--0,001 --0,071 0,007 0,070
N(4) N(5) N(6) N(7) C(4) N(8)
0,011 0,038-0,007-0,047 -0,014 -0,004
C(s) O*(i) 0"(2) C*(m
0,016 0,000-0,170 0,020

*Atoms not included in the calculation of the corresponding plane.

Planes A, B, and C form the dihedral angles: A/B = 1.8; A/C =
3.2; B/C = 1.5 ~ .

highly compressed boat conformation. The plane of the central ring B forms dihedral angles
of 1.8 and 1.5 ~ with rings A and C, respectively.
The bond length distribution in Ia (Fig. i) indicates the electron delocalization usual
for such conjugated nitrogen-containing heterocycles: All the formal single C--N and N-N
bonds are shortened while the double bonds are extended relative to the standard values: C-N,
1.474| N--N, 1.451; N=-N, 1.25; C~N, 1.29 ~ [12].
Each molecule of la in the crystal participates in the formation of two intermolecular
hydrogen bonds: N(a)--H...O(a) (*/= -- x, i -- y, */s + z) and O(a)...H--N a (I/a -- x, i - y,
*/a + z) [N--H0.91(5);N.o.O, 2.819(7), H...O, 1.91(5) ~, <[N--H...O, 168(2)~ which leads
to the formation of spirals of la molecules about 2, axes parallel to the c-axis. The some-
what greater C(z)-O(a) bond length [1.219(7) ~] relative to C(,)-O(~) [1.186(8) ~] is a con-
sequence of the participation of O(a) in hydrogen bonding.
Crystalline azide and tetrazole isomers are sometimes capable of interconversion. Thus,
Messmer et al. [13] noted that solid 3-azidopyrido[2,3-3]-as-triazine spontaneously converts
to solid pyrido[2,3-3]tetrazole[5,l-e]-as-triazine. Equilibrium between these isomers is es-
tablished in dimethylsulfoxide solution. Irreversible conversion to the tetrazole isomer
occurs upon heating crystals of 3,3'-diazido-5,5'-bis-as-triazine [14]. The reverse process
of the conversion of solid tetrazole derivatives of quinazoline to azide derivatives has also
been noted [15]. A unique case of the conversion of the tetrazole isomer of naphthothiazole
upon heating to the aizde isomer and the reverse process upon cooling were noted by Postovskii
et al. [16].
96
 3 o.
/3max 9+o
100 93 la M
41
8O
6O
40 ]3 67 81 94 ] [ 192 l
2O 121 164 1
100(0) . . . . . . . ,, I,a ..lll ,I . , , ,,,.,. ,.... , , ~..-i .,l , . . . . ,...............

80
60 192
M+"
4O
2O
0
40 60 80 100 120 140 160 180 200 220
Fig. 2. Mass spectra of isomers Ia and Ic.

TABLE 2. Elemental Composition of Ions Indicated by the High-Resolution Mass Spectra of

Tetrazole (Ia) and Azide (Ic) of Pyrimido[4,5-e][l,2,4]triazine-6,8-dione and Their Met-
astable Ion Mass Spectra

Measured
Ion Calculated Mass spectra of metastable ions [de-
Ions
composition flecting voltage of the electrostatic
la 1C sector (E0 and El, V)]

M 220,0449 220,0462 C,;H4NsO2 220,0457

[ ( M - N~) +2HI +" 194,0538 C6fI6N602 194,0552
[ M - N21+" I{l},) 192,0388 192,0399 CstI4N~O~ 192.0395 506 (220)* +441 (191,7)
[(d},-N2) +21tl ~" 166,0455 C611sN402 166,0491 506 (192) - - +433 (164,3)
[ q h - N d +" (~.,) 164,0364 161,0351 C~I14N402 164,0351 --~-320 (121,4)
leD2-I!NCO] +" (OOa) 121,0290 121,0292 CslIaN30 121,0270 ---+248 (94,1)
[qba - I ICNp !)1,0174 94,0143 C4H2N~O 94,0167 5o5(~64) - - + 3 7 3 (121,1)
[ { P a - CO] ~" 93,0340 93,0333 C4H~N3 93,0326 504 (t21) - -+392 (94,1)
81,0308 CaI't3Na 81,0326 [--~387 (92,9)

*Parent peak (m/z).

#Calculated mass of the daughter ion (m/z).

Hence, prior to examining the analytical aspects of the mass spectrometric fragmentation of
isomers Ia and Ic, we must study the possible interconversion of these compounds in the gas
phase. Precedents exist for such isomerization [17, 18].
However, there are no isomerizational processes for azide Ic and tetrazole Ia under the
conditions of direct inlet to the ion source (150-170~ injector temperature) as indicated
by the different values of the IE a n d P E of the [M-- N2] + ions upon photoionization [3]~
This finding indicates definite differences in the nature of the fragmentation of isomers
Ia and Ic and requires detailed examination of their mass spectra (Fig. 2).
The fragmentation sequence of the molecular (M+) and major fragment ions for Ia and Ic
was established relative to the mass spectra of the metastable ions obtained in the secondary
fieldless space on a "reverse geometry" spectrometer (DADI/MIKES technique [19]). The ion
composition was found by high-resolution mass spectrometry (Table 2).
Figure 2 indicates that the major difference in the nature of the fragmentation of azide
Ic relative to tetrazole isomer la lies in the detection of ions with m/a 194 and 166 (the
difference in the ratio of the intensities of the peaks of ions M+/[M -- N2] + was discussed
in our previous work [3]). The appearance of these ions is probably not dictated by ion--
molecule reactions (1-10 -7 tort vacuum) although some workers have made such conclusions [20].
In our opinion, it is more realistic to assume the addition of a hydrogen atom to the nitrene

*The lack of interconversions upon heating crystals of I and Ic was indicated in a thermo-
gravimetric study. The DTA curves for each compound differ and there are no peaks for ther-
mal isomerization effects which should be observed in temperature ranges excluding change in
the sample mass (TG and DTG curves).

97
 TABLE 3 . Atomic Coordinates (xl0 ~, xl0 ~ for H) and Their
Anisotropic Temperature Factors T = exp[-i/4(B**h~a*~+.,.
+2B=~klb*c~)]
,,,i ,,,

Atom B. B=~ B~=

I
Oql) 1902 (5 7724 (3ti-2219 (6 5,2 (2: 3,8 (2) 3,8 (2 0,2 (2)',- 1,1 (21 0,8 (2)
O{2~ 2980 (5 4871 (311 1365 (ff 6,4 (2: 2,5 (2) 3,9 (2 o,1 (2}1-o,2 (2) 0,2 (2)
N,I} 2924 (5 8139 (4)1 448 (6', 4,0 (2 2,5 (2) 3,2 (2 0,2 (2)1 0,[ (2j 0,4 (2)
N{~ 2534 (5 6309 (4~1 -454 (71 3,6 (21 2,9 (2) 3J (2 0,0 (2)i-0,3 (2) -0,5 (2)
N~s) 4137 (5 6237 (4)1 3856 (6: 3,4 (2' 3,7 (2) 3,4 (2 0,4 (2)1-o,o (2) 02 (2)
N(4) 4558 (5 7010 (5)I 4995 {6] 3,1 (21 4,6 (3) 3,1 (21 0,4 (2)]-0,3 (21 0,2 (2)
N(5 5177 (61 6811 (5)I 6599(7) i 4,5 (3', 6,3 (3) 3,8 (31 0,0 (2)I-0,6 (3 o,7 (3)
N,~ 5391 (6' 7804 (5)] 7290(8) i 4,0 (31 6,8 (3) 4,4 (31 0,3 (3)]-0,3 (2! 1,9 (3)
N(7 4951 (if, 8605 (4)I 6190 (41 5,3 {3', 4,7 (3) 3,7 (31 03 (3) I o8(21 ' - 0 8 (3)
N~8 391l (51 8533 (4~1 3225 (7} 4,0 (2', 3,2 (2) 3,5 (31 03 (2)1-0,2 (2) I-<3 I2)
C(~ 2404 (61 7417 (5)1 -847 (8) 3,3 {3} 3,3 (3) 3,5 (3: 0,3 (2) I o,0 (2) o,o (2)
3oo8 (71 5850 (5}1 I079(8) 3,9 (3) 3,3. (3) 3,2 (31 o,3 (2)] 0,7 (3) o,o (2)
C~3 3898 (6) 5637 (4)1 2405 (8) 3,0 (3) 3,o (3) 3,0 (3~, 0,2 (2)1 0,3 (2) 0,2 (2)
C~4 4447 (71 8131 (5)I 4730 (8) i.l{3) 3,6 (3) 3,7 (31 0,4 (3)j 0,4 (3) -0,3 (3)
C~5 3495 (6} 7810 (4)1 2054 {8) 3,6 (3) '2,7 (2) 3,1 (3) 0,2 (2)I o,3 (2) -0,2 (2)
C~6 2794 (8) 9316 (5}1 78 (9) 5,9 (4) 2,8 (3) 5,0 (3) 0,6 (3L-0,8 (4) 0,3 (3)
HN<~ 241 (5) 586 14~I-142 (7) $
H(~2) 227 (5) 971 (4)1 107 (7)
H{~) 223 (5) 948 (5)1 -107 (7)
377 (5) 962 (4)1 --5 (7) $

~Value of B.

[17, 18, 21] formed exclusively from the azide form upon the loss of an N2 molecule as a re-
sult of thermolysis. This hypothesis is supported by the increase of the peak intensities
of the ions with m/z 192 and 194 over time and the lack of me(as(able transition from M + for
the ion with m/z (Table 2). The addition of hydrogen to the nitrene in this specific case
is apparently accomplished by migration of hydrogen atoms upon the thermal decomposition of
the dimeric or trimeric aggregate of Ic existing in the gas phase. The possible existence
of such aggregates was noted previously for derivatives of tetrazole [22] and pyrazole [23].
Thus, in azide Ic, the [M -- Na] + (~i) arises both due to dissociative ionization and
thermolysis leading finally to ionization of the nitrene and its amine addition product
[(M-- N=) + 2H] +. The formation of amines was observed in the thermolysis of tetrazoles [17].
The appearance of the other fragment ions is related to the decomposition of the ~ ion.
The #s ion and ions with m/z 94 and 93 (Table 2) arise as the result of one-, or two- and
three-step reactions. The metastable ion mass spectra obtained for isomers la and Ic coin-
cide fully, which proves the identity in structure and energy parameters (release of the same
kinetic energy) for ions ~,, ~=, and %3. The following decomposition scheme illustrates the
formation of the major ions:
o

-N2 ~HN ~ 2 ~ . ~ -N2'-HNCO'-HCN

M + (la,IO ----~ j ~i- |C4H2N20]+"
220 0 N N N +' ~ 94
l "" /
CIt3 ~ /-HCN
/
t _N2,_ItNco
:+'" "" L ~ --- I < +.;
i H
Ctt3 @~ 93
@2

These results indicate that la and Ic in the gas phase have structures analogous to
those in the crystalline state (Ic is apparently associated in pairs).
Information on the azide--tetrazole equilibrium in solution was obtained by PMR spectro-
scopy. Thus, the PMR spectrum of la in DMSO-d6 has two singlets with ~ 3.37 and 3.57 ppm
a n d a broad signal with 6 14.00 ppm. Upon the addition of a few drops of CF3COaH, the in-
tensity of the signal at 3.37 ppm increases and that of signal at 3.57 ppm decreases (the
signal at 14.00 ppm disappears). The downfield signal apparently is related to the NH group

98
proton in the uracil fragment, while the interconversion of the intensities of the signals
at 3.37 and 3.57 ppm upon acidification reflects the conversion Of the tetrazole isomer to
the azide isomer. Upon increasing the temperature of the solution of la, there is a shift
in the tautomeric equilibrium toward the azide. Thus, at 35~ we find 91% la and 9% Ic.
At 60~ we find 89% la and 11% Ic. At 100~ we find 77% la and 23% Ic, while at 140~
we find 67% la and 33% Ic. In aqueous solution, the equilibrium is shifted toward the azide;
at 35~ we find 32% la and 68% Ic. The tetrazole isomer predominantes in pyridine; at 35~
we find 65% la and 35% Ic. It is interesting that in the case of 3-azido-5,7-dimethylpyrimido-
[4,5-e][l,2,4]triazine-6,8-dione, the fraction of the tetrazole isomer [4] in pyridine is 15%
less than for the monomethyl derivative la. A significant shift in the Ic la equilibrium
toward tetrazole la (A = 15%) is also observed in aqeuous solution upon the addition of an
equimolar amount of sodium azide.
The azide--tetrazole equilibrium is established most slowly in dimethylsulfoxide solution
(4-5 h). PMR spectroscopy may be used to observe the formation of azide form Ic from an auth-
entic sample of linear tetrazole la. Since only signals for la and Ic are seen in the PMR
spectrum, we may conclude that angular tetrazole Ib does not exist in solution.

EXPERIMENTAL
The electron impact mass spectra were taken on a Varian MAT-311A mass spectrometer under
standard conditions with 70 eV ionization energy and 1.0 mA cathode emission current. The
accelerating voltage was 3 kV and the injector temperature was 150-170~ The high-resolution
mass spectra and the mass spectra of the metastable ions were measured on the same instrument.
The M/AM resolution was 15,000, PFC standard and 0.01 V error in the measurement of the peaks
on a digital voltmeter.
The x-ray diffraction structural analysis was carried out on a Syntex P1 four-circle dif-
fractometer using ~CuKa radiation, graphite monochromator, 8/2e scanning (2 ~ ~ 2e < 120~ A
total of 614 reflections with F 2 > 2o were recorded. The unit cell parameters of ~rthorhombic
crystals of la are a = 9.288(2), ~ = 12.254(3), c = 7.456(2) ~, d c a l c = 1.72 g/cm 3, z = 4,
space group P2,2,2~. The structure was solved by the direct method and refined by the method
of least squares in the anisotropic full-matrix approximation* to R = 0.049, Rw = 0.056. The
atomic coordinates and temperature factors are given in Table 3.
The thermal analysis was carried out on an MOM derivatograph under the conditions de-
scribed in our previous work [18].
The PMR spectra were taken on a Perkin--Elmer R-12B spectrometer at 60 MHz with TMS as the
internal standard using the 6 scale.

LITERATURE CITED
i. V. M. Adanin, S. E. Esipov, A. M. Zyakun, N. A. Klyuev, L. A. Saburova, and V. A. Bondar',
Khim. Geterotsikl. Soedin., No. 9, 1270 (1979).
2. V. M. Kazakova, S. E. Esipov, I. G. Makarov, N. E. Minina, and A. I. Chernyshev, in: Ab-
stracts of the All-Union Symposium on Magnetic Resonance in Biology and Medicine [in Rus-
sian], Moscow (1981), p. 16.
3. N. A. Klyuev, V. M. Adanin, I. Ya. Postovskii, and Yu. A. Azev, Khim. Geterotsikl. Soe-
din., No. 4, 547 (1983).
4. Yu. A. Azev, I. Ya. Postovskii, E. L. Pid~mskii, and A, F. Goleneva, Khim.-farm. Zh.,
14, 39 (1980).
5. Yu. A. Azev, N. N. Verreshchagin, I. Ya. Postovskii, E. L. Pid~mskii, and A. F. Goleneva,
Khim.-farm. Zh., 15, 50 (1981).
6. Yu. A. Azev, N. N. Verreshchagina, E. L. Pid4mskii, A. F. Goleneva, and G. A. Aleksand-
rova, Khim.-farm. Zh., 18, 573 (1984).
7. C. Kuechler, W. Kuech]er, and L. Heinisch, Arzneimit. Forsch., 16, 1122 (1966).
8. A. Messmer, G. Hajos, J. Tamas, and A. Nessmelyi, J. Org. Chem., 44, 1823 (1979).
9. A. V. Bogatskii, S. A. Andronati, Z. I. Zhilina, and N. I, Danilina, Zh. 0rg, Khim., 13,
]773 (1977).
i0. M. M. Goodman, J. L~ Atwood, R. Carlin, W. Hunter, and W. Paudler, J. 0rg. Chem., 41,
2860 (1976).
*Only the positional parameters were refined for the hydrogen atoms found in the difference
map with fixed Bis O = 5.0 A=.

99
ii. S. Nishigaki, M. Ichiba, and K. Senga, J. Org. Chem., 48, 1628 (1983).
12. Tables of Interatomic Distances and Configuration in Molecules and lons, Special Publi-
cation No. 18, London (1965).
13. A, Messmer, G. Hajos, P. Benko, and L. Benko, J. Heterocycl. Chem., i0, 575 (1973).
14. Yu. A. Azev and N. P. Lobanova, i n : Abstracts of the All-Union Conference on Aromatic
Nucleophilic Substitution [in Russian], Novosihirsk (1982), p. 85.
15. I. Ya. Postovskii and I. N. Goncharova, Zh. Obshch. Khim., 33, 2334 (1963).
16. I. Ya. Postovskii, G. N. Tyurenkova, and L. F. Lipatova, Dokl. Akad. Nauk SSSR, 179, I!I
(1968).
17. C. Wentrup, Tetradedron, 26, 4969 (1970).
18. Yu. V. Shurukhin, N. A. Klyuev, I. I. Gradnberg, and V. A. Konchits, Khim. Geterotsikl.
Soedin., No. 19, 1422 (1984).
19. N. A. Klyuev, E. N. Istratov, R. A. Khmel'nitskii, V. A. Zyrayanov, V. L. Rusinov, and
I. Ya. Postovskii, Zh. Org. Khim., 13, 2218 (1977).
20. D. M. Forkey and W. R. Carpenter, Org. Mass Spectrom., ~, 433 (1969).
21. c. Wentrup, A. Mmquestiau, and R. Flammang, Org. Mass Spectrom., 16, 115 (1981).
22. R. R. Fraser and G. K. E. Maque, J. Org. Chem., 34, 4118 (1969).
23. A. N. Kost and I. I. Grandberg, Advances in Heterocyclic Chemistry, Vol. 6, New York
(1966), p. 347.

10-ALKENYLPHENOTHIAZINES.
I. SYNTHESIS AND CIS,TRANS-ISOMERIZATION OF 10-PROPENYLPHENOTHIAZINES

V. A. Anfinogenov, O. A. Napilkova, E. E. Sirotkina, UDC 547.869.2:542.952.4:

V. D. Filimonov, and V. D. Ogorodnikov 541.634

A study was carried out on the isomerization of lO-allylphenothiazine (I)in

DMSO by the action of t-BuOK, KOH and NaOH. The isomerization proceeds stereo-
specifically at room temperature by the action of t-BuOK at an elevated temper-
ature by the action of KOH and NaOH to give cis-10-propenylphenothiazine (II).
The effect of the t-BuOK concentration, temperature and reaction time on the
isomeric composition of the 10-propenylphenothiazines formed was studied. Un-
der conditions of kinetic control, I gives II, which Isomerizes under the re-
action conditions to give an equilibrium mixture of cis- and trans-10-propenyl-
phenothiazine with 44-45% trans isomer III. The isomerization temperature has
virtually no effect on the II/III isomer ratio.

Of the N-akenylphenothiazines, only N-vinylphenothiazine has been studied in considerable

detail [1-3], while the homologs of this compodnd have not been described in the literature.
There has only been mention of 10-propenylphenothiazine obtained by the multistep procedure
in the proof of the structure of the product of the alkylation of phenothiazine by l-chloro-
2-dimethylaminopropane [4].
The base-catalyzed isomerization of N-allylamines is commonly employed in preparative or-
ganic chemistry to obtain N-allylamines [5] but this reaction has not been studied for thia-
zlnes.
In order to obtain lO-propenylphenothiazine, we studied the isomerization of 10-allyl-
phenothiazine (I) in DMSO by the action of t-BuOK, KOH and NaOH.

i. I. Polzunov Altai Polytechnical Institute, Barnaul 656099. Tomsk Institute of Petro-

leum Chemistry, Siberian Division, Academy of Sciences of the USSR, Tomsk 634055 and S. M.
Kirov Tomsk Polytechnical Institute, Tomsk 634004. Translated from Khimiya Geterotsikliches-
kikh Soedinenii, No. i, pp. 121-124, January, 1986. Original article submitted November 21,
1984.

I00 0009-3122/86/2201-0100512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Dependence of the
Composition of the Isomer
Mixture of Propenylpheno-
thiazines II/III on Time
and Temperature Upon the
Isomerizationofl([l]o =
Tempera:' II/III
ture, ~ Time, isomer
min ratio, %

5O 300 l oo/o
7O I0 84/16
60 69/3 l
180 62/38
300 61/39
10 77/23
120 59/41
300 56/44
100 10 71/29
180 56/44
300 57/43
150 10 60/40
180 54/46
300 54/46

*Here and subsequently,

0.717 N solution in
t-BuOH.
..... s \
i, i~ ~ '~ , /.. U. z~

"~" ~ " "N "

I i s ~ ! II
Cl~2Ci'Ia CH a C~-C~ . . . . .
ll" "H 11 ( . - - C ~ C l t a
I 11 1II

The isomerization both by the action of t-BuOK and KOH or NaOH gives the complete con-
version of phenothiazine I to a mixture of isomers II and III; other products were not de-
tected. In the presence of t-BuOK, the reaction rate reaches a maximum at a catalyst con-
centration of 0.15 mole/liter and the reaction is complete in this case in 15 min. The ef-
fect of the amount of catalyst on the time required for total conversion of phenothiazine I
at room temperature as determined by thin-layer chromatography is given below. The time for
total conversion is 4320, 75(65) and 15 min for 0.049, 0.083, and 0.15 mole/liter t-BuOK.
PMR spectroscopy at room temperature indicates that the reaction proceeds with high
steric specificity to form exclusively cis isomer II. This finding distinguishes this reac-
tion in the phenothiazine series from the isomerization of dialylallyamines [6] and 9-allyl-
carbazoles [7], in which the isomeric purity of the cis-isomers is not greater than 90%. As
shall be shown below, this is apparently related to the greater thermodynamic stability of cis-
isomer II relative to the trans isomer III.
The effect of temperature and reaction time on the ratio of isomers II and III was eval-
ulated relative to the integral intensities of the methyl group signals in the PMR spectra
(Table I). The trans isomer III appears in the reaction mixture at 70~ and its content after
5 h reaches 39%. A further increase in the reaction temperature to 150~ increases the con-
tent of III to 44-46%. The II ~ III equilibrium is reached 3-5 h after the onset of the iso-
merization and, within experimental error, temperature has virtually no effect on the equili-
brium constant (K) which was found to be 0.82 0.03 (AG,oo = 0.62 0.Ii kJ/mole). We note
that thin-layer chromatography indicates the absence of starting compound I in the reaction
solution. Under analogous conditions, pure cis isomer Ii gives a mixture of cis and trans
isomers II and III with approximately the same composition. Hence, under kinetically con-
trolled conditions, ally]phenothiazine forms II which isomerizes under the reaction conditions
to an equilibrium mixture of the cis and trans isomers, II and III.
The high thermodynamic stability of cis isomer II relative to trans isomer III distin-
guishes lO-propenylphenothiazine from previously studied 9-propenylcarbazoles, for which the
cis isomer is less stable than the trans isomer due to steric interaction of the methyl
group and the planar carbazole ring [7] Our results indicate that the steric interaction

i01
 TABLE 2. Conditions for the Preparation of cis-10-P~openyl-
phenothiazine II

l*,mole Catalyst(mole) Temperature, Time,t Yield

~ min % of II,

0,063 t-BuOK (1,6.10 -~) 25 15 89

0,0l t-BuOK (4,9 10-4) 50 I0
0,002 KOH (8,9.10 -~) 25 3600
0,002 KOH (8,9. l0 -4) I00 270
0,251 KOH (2.1.l0 -2) 60 30 68
0,013 NaOH (1,5.10 -2) 60 60 64

*5 ml DMSO per g I.
%Reaction time corresponding to complete conversion of I.

TABLE 3. Spectral Characteristics of 10-Propenylphenothiazines

PMR spectrum (CCl~)* IR spectrum ~, cm
Compound I' '"

II
III
[
H~

6,16,d
6,29,d
Chemical shifts,~, ppm t, j, Hz

5,6,m ],55.d
i

[ 7,0
I 1657
I
i

I 945
."I
5,6, m 1,68, d I 13,0 -- [ --

eFor compounds II and III, the SSCC are: J HB, CHs = 7.0, J
Ha, CHa = 1.5 ~z"
%The signals of the phenothiazine protons form a multiplet at
6.5-7.1 ppm.
%The IR spectrum of II is completely identical to the spectrum
of the mixture of II and III.

of the methyl group and the phenothiazine system in cis-i0-propenylphenothiazine is absent

or very weak compared to cis-9-propenylcarbazole.
This decrease in the steric strain in II is likely a consequence, firstly, of the non-
planar structure of the phenothiazine system [8] and the quasiaxial orientation of the sub-
stituent at the nitrogen atom (extra configuration [9]). It is quite obvious that the ster-
ic interaction in the extra configuration between the cis-methylgroup and the hydrogen atom
at C(,) of the nonplanar heterocyclic fragment in isomer II is less pronounced than in planar
cis-9-propenylcarbazole. Secondly, we should recall that the participation of the nitrogen
unshared electron pair in the extra configuration to the total z-electron conjugation is re-
duced [I0] and, thus, some twisting of the phenothiazine system in II about the C--N bond
leads to a significant suppression of p--, conjugation [7, ii].
The high thermodynamic stability of cis isomer II relative to the trans isomer of 10-
propenylphenothiazine permits us to categorize 10-propenylphenothiazlnes as "anomalous"
olefins, whose cls isomers are more stable than their trans isomers despite steric strain
[12-15]. Unfortunately, we are not able to give an unequivocal explanation for this inter-
esting finding.
This reaction is efficiently catalyzed by KOH and NaOH in DMSO. We should note that, in
contrast to t-BuOK, the isomerization of phenothiazine I in the presence of KOH and NaOH
proceeds stereospecifically both at room temperature and at IO0~ Although the catalytic
activity of KOH and NaOH is much less than that of t-BuOK (Table 2), these hydroxides are
conveniently used for the preparation of cis-10-propenylphenothiazine II to their availability
and ease in handling.
The structures of 10-propenylphenothiazines II and III were demonstrated using IR and
PMR spectroscopy. The spectral parameters are given in Table 3.

EXPERIMENTAL
The IR spectra were taken neat on a IKS-29 spectrometer. The PMR spectra were taken on
a BS-487C spectrometer in CCI~. In the study of the effect of the reaction conditions for

102
the isomerization of I on the ratio of isomers II and III, the spectra were taken in benzene.
Phenothiazine I was prepared according to the method of Simov and Kamenov [16].
cis-10,Propenylphenothiazine (II). A sample of 31 ml 0.51 N t-BuOK in t-BuOH was added
to a solution of 15 g (63 mmoles) 10-allylphenothiazine I in 75 ml dry DMSO and the mixture
was maintained at room temperature for 15 min. The reaction was monitored using thin-layer
chromatography on Silufol plates with 6:1 hexane-ether as the eluent. After the complete
conversion of I, the solution was poured into water. The precipitated oil was extracted with
benzene. The benzene layer was washed with water and dried over potassium carbonate. PMR
spectroscopy indicated that the solution contained cis isomer II. Vacuum distillation and
crystallization from ethanol give 13.4 g (89%) cis-lO-pr0penylphenothiazine as white needles
with mp 34-35~ bp 182-184~ (4 hPa). Found: C 75.4; H 5.3; N 6.0; S 13.2%. Calculated
for C:sHI3NS: C 75.2; H 5.4; N 5.9; S 13.4%.
Mixture of cis-10-propenylphenothiazine (II) and trans-lO-Propenylphenothiazine: (III).
A sample of 5 g (21 mmoles) I and 7 ml 0.69 N t-BuOK in t-BuOH in 25 ml dry DMSO was m a i n -
tained at 100~ for 1 h. T h e isolation of the products was carried out by analogy to the pre-
vious procedure. Vacuum distillation at 191-193~ (5-7 hPa) gave 3.9 g (78%) of a yellow
oil. PMR spectroscopy indicated that the mixture of isomers II and III was 54:46. Isomer
III could not be isolated from the mixture.
The reaction in the presence of KOH and NaOH was carried out by analogy to the above
procedure under the conditions indicated in Table 2. Samples of powdered KOH and NaOH were
used.

LITERATURE CITED
I. G. N. Kurov, L. I. Svyatkina, E. G. Pal'chuk, I. P. Naumova, and G. G. Skvortsova, Zh.
Obshch. Khim., 54, 178 (1984).
2. V. K. Turchaninov, A. G. Gorshkov, M. F. Larin, and G. G. Skvortsov, Vysokomol. Soedin.,
25A, 1892 (1983).
3. G. G. Skvortsova, M. F. Shostakovskii, and G. N. Kurov, Zh. Org. Khim., 8, 382 (1972).
4. P. Charpentier, Comptes Rendus, 225, 306 (1947).
5. M. Ju!ia, A. Schouteeten, and M. Bailerge, Tetrah. Lett., No. 38, 3433 (1974).
6. T. Sauer and H. Prahl, Chem. Ber., 102, 1917 (1969).
7. V. D. Filimonov, S. G. Gorbachev, and E. E. Sirotkina, Khim. Geterotsikl. Soedin., No.
3, 340 (1980).
8. I. I. H. McDowell, Acta Crystogr., 832, 5 (1976).
9. G. Fronsa, R. Mondelli, and G. Scapini, J. Magn. Reson., 23, 437 (1976).
i0. D. Simov, L. Kamenov, and S. Stoyanov, Khim. Geterotsikl. Soedin., No. 4, 497 (1973).
ii. V. D. Fi!imonov, V. A. Anfinogenov, and S. G. Gorbachev, Khim. Geterotsikl. Soedin., No.
12, 1640 (1982).
12. J. Huet, Tetrahedron, 34, 2473 (1978).
13. E. Tasinen and P. Liukas, Acta Chem. Scand., 28, 114 (1974).
14. V. A. Rodionov and V. D. Filimonov, Zh. Org. Khim., 18, 1094 (1982).
15. N. D. Epiotis, D. Bjorkquist, L. Bjorkquist, and S. Sarkanen, J. Am. Chem. Soc., 95,
7558 (1973).
16. D. Simov and L. Kamenov, Godishnik Sof. Univ., 60, 247 (1965/66).

103
 LETTERS TO THE EDITOR

NEW TYPE OF RECYCLIZATION OF 2-BENZOPYRYLIUM SALTS

V. G. Brovchenko and E, V. Kuznstsov UDC 547.812+546.137

Decarboxylation of monocyclic a-carboxy-substltuted pyrylium [i], pyridinium salts [2],

pyridine and its bezologs [3] proceeds with the retention of the heterocyclic structure.
We found that when heated with a twofold excess of morpholine in benzene for 2.5 h, l-
aryl-3-carboxy-2-benzopyrylium salts la, b convert into ketols llla, b. It is probable that
the formation of ketols Ilia, b takes place as the result of opening the heterocyclic ring
in adduct II, decarboxylatlon of the intermediate enamine, in a similar way as described in
[4], an attack by the anion formed on the benzophenone carbonyl group carbon atom, and sub-
sequent hydrolysis of the enamine.

CH30 ' //~, ~/-<~ ~COOH

9 -[- f :ooo,,
1

/11

tl i:"
0(:]]3 ocll.s OCII3
la,b II
a R=OClI~;bR=I! H
C 1I.sO -~ /~.. N" CH~O . . ,;.

, CII O" "):" " "~'~'OH

9 OCH3 OCll 3 _ Ilia ~ b ~

Ketols llla,b were isolated after column chromatography on aluminum oxide (eluent--chlor-
oform).
Ketol IIIa. mp 97-98~ (from benzene); yield 68%. IR spectrum (CHCI3): 35.25, 1755,
1590, 1240 cm-*. PMR spectrum (CDCI,): 3.70, quart., JAB = 5 Hz, CH2); 3.82 (s, 30CH3);
3.92 (s, 0CH3); 6.42-7.42 ppm (m, 5H); M + 344.
Ketol IIIb. mp 150-152~ (from benzene); yield 46%. IR spectrum (CHCI,): 3545, 1755,
1600, 1235 cm-*. PMR spectrum (CDCIs): 3.31 and 3.36 (Ch, 2s, CRy); 3.62 (s, OCH~); 3.72
(s, OCH,); 3.80 (s, OCK3); 6.52-7.20 ppm (m, 6H).
The initial, previously unknown salts la,b were obtained by the reaction of 3,4-dimeth-
oxyphenylpyruvic acid with veratraldehyde or anisaldehyde in polyphosphoric acid.
Salt la. mp 296~ (from acetic acid); yield 20%. IR spectrum: 3500, 1725, 1600, lllO
cm-*. PMR spectrum (CF3COOH): 3.55 (s, 30CHs); 3.80 (s, OCHa); 6.95 (d, IH); 7.30 (s, 2H),
7.50 (d, iH); 7.70 (s, IH); 8.20 ppm (s, IH).
Salt lb. mp 290-291~ yield 23%. IR spectrum: 3500, 1715, 1600, 1095 cm-*.
For all the compounds studied, the elemental analysis corresponds to the calculated val-
ues.

Scientific-Research Institute of Physical and Organic Chemistry of the M. A. Suslov

Rostov-on-Don State University, Rostov-on-Don 344090. Translated from Khimiya Geterotsikich-
eskikh Soedinenii, No~ i, pp. 125-126, January, 1986. Original article submitted July iO,
1985.

104 0009-3122/86/2201-0104512.50 9 1986 Plenum Publishing Corporation

 LITERATURE CITED
i. Yu. P. Andreichikov, N. V. Kholodova, and G. N. Dorofeenko, Dokl. Akad. Nauk SSSR, 236,
1364 (1977).
2. A . R . Katritzky, R. Awartani, and R. C. Patel, J. Org. Chem., 47, 498 (1982).
3. L. Pakett, Principles of Modern Chemistry of Heterocyclic Compounds [Russian translation],
Mir, Moscow (1971), p. 260.
4. J . K . Stamos, Tetrahedron Lett., 23, 459 (1982).

REACTION OF FLAVYLIUMPERCHLORATE WITH CARBON MONOXIDE

I. M. Gavrilyuk UDC 546.262:547.814

It is known that pyrylium and benzopyrylium salts, unsubstituted at the 4-position, react
with nucleophilic reagents, such as triphenylphosphine [i], or for example malonodinitrile in
the presence of triethylamine [2]. It could be expected that a similar reaction will proceed
also with carbon monoxide, although such examples were not reported in the literature. In
fact, it was found that when CO is passed for a long time into a hot solution of flavylium
perchlorate I in glacial acetic acid, a small amount of blue dye is formed. The latter was
isolated in individual state, and was identified as flavylomonomethinecyanine II, previously
described in [3] (6% after heating for 6 h and passing CO). T h e initial salt I, contaminated
by unidentified impurities, was also isolated from the reaction mixture.
The above described reaction is a new reaction in the series of pyrylium salts, a complex
redox process, whose mechanism is still unknown. However, it can possibly be stated that at
the first stage a nucleophilic addition of CO takes place at the 4-position of salt I, and the
following mechanism can be suggested for this reaction:

~ 5 clo4- %H5["c,~o,- c~.~ zo,

I

c'-o
-CO 2
! ~ t ~ ~ o
o J
| -HCIO 4

1 I 2clo~.- !
Cell~ Cell s _1 C6H5 C6H5
H

LITERATURE CITED
io S. V. Krivun, Dokl. Akad. Nauk SSSR, 182, 347 (1968).
2. F. Kr~nke and K. Dickore, Chem. Bet., 92, 46 (1959).
3. R. Wizinger and H. Tobel, Helv. Chim. Acta, 40, 1305 (1957).

" Institute!of Organic Chemistry of the Ukrainian $SR, Kiev, 252660. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. i, p. 126, January, 1986. Original article sub-
mitted April 15, 1985.

0009-3122/86/2201-0105512.50 9 1986 Plenum Publishing Corporation 105

UNUSUAL REACTION OF N,N-DIMETHYLACETAMIDE DIETHYL ACETAL WITH
2-AMINOMETHYLENE-5,5-DIMETHYLCYCLOHEXANE-I,3~DIONE.
SYNTHESIS OF COUMARIN AND CARBOSTYRIL DERIVATIVES

A. K. Shanazarov, V. V. Chistyakov, UDC 547.814:547.824

and V. G. Granik

It is known that amide acetals react with primary enamines to form enamidines [i]. In
contrast to this, we found that in the reaction of N,N-dimethylacetamide diethyl acetal (I)
with 2-aminomethylene-5,5-dimethylcyclohexane-l,3-dione (II) [2], unexpectedly, not the enam-
idinodiketone II is formed, but a mixture of l,l-bisdimethylamino-3-(2,6-dioxo-4,4-dimethyl)-
cyclohexylidene-l-propene (IV) and l-dimethylamino-l-(a-dimethylamino)ethylideneamino-3-(2,6-
dioxo-4,4-dimethyl)cyclohexylidene-l-propene (V), 3:7 (PMR spectrum) is obtained in an over-
all yield of 90%. Compounds IV and V were separated by fractional crystallization from ethyl
acetate. When the diene-diamine IV was boiled in a 10% aqueous HCI, 5-oxo-7,7-dimethyl-5,6,
7,8-tetrahydrocoumarin (IV) was obtained. Under the same comditions, amidine V, or a mixture
of compounds IV and V give a mixture of courmarin VI and 5-oxo-7,7-dimethyl-5,6,7,8-tetrahydro-
carbostyril (VII). The following compounds were synthesized: IV {yield 38%, mp 163~ (from
ethyl acetate). PMR spectrum (CDCI,): 1.05 (s, 6H, 4', 4'-CH,), 2.35 (s, 4H, 3',5'-CH2),
3.09 (s, 12H, I,I'-Me2N), 6.86 (d, IH, J = 14.7 Hz, 2CH), 7.92 ppm (d, iH, J = 14.7 Hz, 3-CH).
Mass spectrum, m/z: M +" 264, [M -- Me2N] + 220}, V {yield 9%, mp 183~ (from ethyl acetate).
PMR spectrum (CDCIs): 1.03 (s, 6H, 4',4'-CH3), 1.96 (s, 3H, a-CH3), 2.32 (s, 4H, 3',5'-CH2),
3.08 and 3.25 (two s, 3H, u-Me2N in each case), 3.16 (s, 6H, I-Me2N), 7.46 (d, IH, J = 14.4 Hz,
2-CH), 7.63 ppm (d, IH, J = 14.4 Hz, 3-C~). Mass spectrum, m/z: M +" 305, [M-- CH3] + 290;
[M--NMe2] + 261 and [M--NMe2 -- H -- CH3] ~245},VI {yield 96; (from IV), mp 88-900C (from hep-
tane), according to the data in [3], mp 89-92~ and VII {yield 45% (from V, together with
51% of VI), mp 276~ (from ethyl acetate) according to the data in [4], mp 276~

C!I 3
_

CH3~CH 3 + ~ 2' I 0E~ +

CH3" "C}I~ CH s" "CH 1
II ~ iV Y
A IHCI A IICI 0
N.~:_n<~Ctl3
.NMe2 %'I 0
0... 7'<. //0
CH~ + CH
CH 3 v "0 0 CH 3- v "N" "0
H
UI
The results of the elemental analysis of compounds IV and V for C, H, and N correspond
to the calculated data.
Information on the possible mechanism of this unexpected reaction and additional examples
will be submitted later on.

LITERATURE CITED
i. V. G. Granik, N. B. Marchenko, E, O. Sochneva, T. F. Vlasova, A. B. Grigor'ev, M. K.
Poliektov, and R. G. Glushkov, Khim. Geterotsikl. Soedin., No. ii, 1505 (1976).

S. Ordzhonikidze All-Union Scientific-Research Institute for Pharmaceutical Chemistry,

Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i, p. 127, Jan-
uary, 1986. Original article submitted August 20, 1985.

106 0009-3122/86/2201-0106512.50 9 1986 Plenum Publishing Corporation

 . A. Ya. Strakhov, D. V. Brutane, S. P. Valter, and M. T, Shul'tsa, Izv. Akad. Nuak Latv.
SSR, No. 2, 141 (1971).
3. J. H. Sellstedt, J. Org. Chem., 37, 1337 (1972).
4. A. Roegig, R. Manger, and S. Sch~del, Chem. Ber., iO, 2294 (1960).

I-THIOCARBAMOYL-5-OXY- AND 5-THIOSEMICARBAZIDO-2-PYRAZOLINES

K. N. Zelenin, A. B. Tomchin, UDC 547.772.2'497.1'422:04

O. V. Sol,d, and M. Yu. Malov

Products of the condensation of 1,3-diketones with thiosemicarbazide and its N3-substi -

tuted homologs in a 1:2 ratio have an antitumorigenic activity. These compounds I were as-
sumed to be bisthiosemicarbazones A [1-3], but their structure has not yet been studied.
We found that compounds I have actually a cyclic pyrazoline structure B, and not the
linear structure A. We shall add that also the condensation products of these reagents in a
ratio of i:i (II) are not monohydrazones A, as assumed in [3, 4], but the corresponding 5-
hydroxypyrazolines B.

It .^ R R

NNIIC.~N HIe T IlO" ~N

HA S ~ ::C- - N I I R I
lIB
-" R NNHCSNHR I

............. )~ N ' II
R ! I I N C S N I I N~II N ' - R~ HNC.~NHN
f" = I
S ~-~-C - .-NItR

IB IA

la-c, lla R = CH3, lib R = C6Hs; la, lib R I = H, Ib, lla R I = CH3, Ic R I = C2Hs.
Compound la [3]. PMR spectrum (Py-Ds): 1.58 (3H, t, J = 0.6 Hz, 3-CHs), 1.75 (3H, s,
5-CH3), 2.53 and 3.15 (AB system, JAB I = 18 Hz, j2 = 0.6 Hz, 2H, CH2), 7.30 (IH, s, NHa), 7.96,
8.20 (2H, s, CSNH2), 8.90, 9.17 (2H, s, CSNH2), 9.45 ppm (IH, s, NHB).
Derivative Ib [3]. PMR spectrum (CDCIs): 1.72 (3H, s, 5-CH3), 1.91 (3H, t, J = 0.6 Hz,
3-CH3), 2.58 and 2.92 (AB system, JAB x = 18 Hz, j2 = 0.6 Hz, 2H, CH2), 3.01 (3H, d, 5Hz, N--
CH3), 3.09 (3H, d, 5 Hz, N--CH3), b.65, 6.91 (2H, s, 2NH), 7.35 ppm (2H, m, 2NHCH3).
Compound Ic [3]. PMR spectrum (CDCI3): 1.15 (6H, t, J = 7 Hz, 2C=Hs), 1.73 (3H, s, 5-
CH3), 1.93 (3H, t, J = 0.8 Hz, 3-CH3), 2.61 and 2.91 (AB system, JAB ~ = 18 Hz, j2 = 0.8 Hz,
2H, CH2), 3.3-3.8 (4H, m, 2C2Hs), 6.61, 6.85 (2H, s, 2NH), 7.3 ppm (2H, m 2NHC2Hs). 13C NMR
spectrum (DMSO-D6): 14.5 and 14.6 (q, CH3CH2N), 15.9 (q, 3-CH3), 23.5 (q, 5-CHs), 37.7 (t,
CH3CH2N), 47.1 (t, 4-C), 84.6 (s, 5-C), 154.4 (s, C==N), 174.0 and 181.8 ppm (s, 2C==S).
Derivative lla was obtained by condensation of acetylacetone with N3-methylthiosemicar -
bazide in aqueous acetic acid. Mp 95-97~ PMR spectrum (CDCI3)" 1.87 (3H, s, 5-CH3), 1.94
(3H, t, JH--CH = i Hz, 2-CH3), 2.79 and 3.07 (AB system, JAB 2 = 18 Hz, J= = i Hz, 2H, CH2),
3.00 (3H, d, J = 4 Hz, NCH3), 6.30 (IH, s, OH), 7.25 (1H, m, NH). Foundi C 44.7; H 7.2; N
22.3%. CTH~3N~OS. Calculated: C 44.9; H 7.0; N 22.4%.
Compound llb [4]. PMR spectrum (DMSO-D6): 4.16 and 3.84 (AB system, J = 19 Hz, 2H, CH2),
6.80 (IH, s, OH), 7.5-8.2 (10H, m Harom) , 8.45, 8.65 ppm (2H, s, NH=). ~3C NMR spectrum
(DMSO-D6): 51.4 (4-CH2), 95.4 (5-C, 151.8 (C==N), 175.4 (C==S), 124.0-145.1 ppm (Carom' 8 sig-
nals) .

S. M. Kirov Military Medical Academy, Leningrad 194175. Translated ~rom Khimiya Geter-
otsiklicheskikh Soedinenii, No. i, p. 128, January, 1986. Original article submitted June
25, 1985.

0009-3122/86/2201-0107512.50 9 1986 Plenum Publishing Corporation 107

 Our data agree with those known on the structure of malonodialdehyde bisthiosemicarba-
zone [5]. The pyrazoline structure of the above described compounds is interesting in con-
nection with the search for antitumorigenic preparations, which in their activity sre not
inferior to bisthiosemicarbazones of 1,2- and 1,4-dioxo compounds [i],

LITERATURE CITED
i. V. C. Barry, M. L. Conalty, C. N. O'Callaghan, and D. Twomey, Proc. Roy. Irish Acad.,
65B, 309 (1967).
21 G. Losse, W. Hessler, and A. Berth, Chem. Bet., 91, 150 (1958).
3. C. N. O'Callaghan and D. Twomey, J. Chem. Soc., No. 22, 2400 (1967).
4. B. A. Gingras, T. Suprunchuk, and C. H. Bayley, Canad. J. Chem., 40, No. 6, 1053 (1962).
5. H. Buttkus and R. Bose, J. Org. Chem., 36, 3895 (1971).

108
METHODS FOR THE SYNTHESIS OF AZOLES CONTAINING INDOLE SUBSTITUENTS (REVIEW)

V. I. Kelarev and G. A. Shvekhgeimer UDC 547.751:547.77:324.7

A systematic review is given for advances in the synthesis of various azoles (im-
idazoles, oxazoles, thiazoles, pyrazoles, oxadiazoles, and triazoles) containing
indole fragments. A significant number of biologically active compounds have
been found among these bisheterocyclic compounds.

An enormous amount of experimental data has now accumulated in the literature on the syn-
thesis and application of heterocyclic compounds containing indole substituents. However,
only a few indolylazoles were very briefly considered among other bisheterocyclic compounds in
a single review [I].
In compiling this review of the literature data, we preferred to organize the subjects
not according to the indolylazole types but rather according to the means of their preparation
from specific classes of compounds. In our opinion, this approach to the systematization of
the vast literature data gives a clearer concept of the synthetic possibilities of the speci-
fic methods, which may be useful in selecting approaches for further studies on the prepara-
tion of new indolylazoles.
In the present review, we have limited ourselves to noncondensed indolylazoles, in which
the residues of the two heterocycles are joined either directly to each other or by carbon
chains.

i. PREPARATION OF INDOLYLAZOLES
BY THE FISCHER--ARBUZOV REACTION
The Fischer--Arbuzov reaction is the most general and common method for the synthesis of
indole derivatives. However, this method has not yet found extensive use for the synthesis
of indolylazoles since azole carbonyl derivatives and arylhydrazines containing azole residues
have generally been difficult to prepare.
The condensation of N(,)-hetaryl-4-methoxyphenylhydrazines with levulinic acidwas carried
out in order to synthesize structural analogs of the drug indomethacin, [l-(4-chlorobenzoyl)-
2-methyl-5-methoxyindolyl-3-acetic acid] [2, 3].

,- CH O ~ - - CHz-COOH

!
Hei

Het = 2-chlorothiazolyl-4-carbonyl, benzthiazolyl-2

The indomethacin analogs I synthesized display analgesic, anti-inflammatory and high fe-
ver-reducing activity.
The condensation of N(,)-aroyl-N(,)-(4-methoxyphenyl)hydrazines with 1,2-diphenyl-4-(3-
oxobutyl)-3,5-pyrazolinedione [4] or with <l-(2-oxopropyl)-2-methyl-4-nitroimidazoles [5-7]
was used to prepare another type of indomethacin analogs containing heterocyclic fragments
at C(3) of the indole ring.

I. M. Gubkin Moscow Institute of Petroleum Chemistry and Gas Industry, Moscow 117296.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 147-172, February, 1986.
Original article submitted January 4, 1984; revision submitted August 3, 1984.

0009-3122/86/2202-0109512.50 9 1986 Plenum Publishing Corporation 109

 CO-At CHj
CO,Ar
I!

n = i, Her = 1,2-diphenyl-3,5-pyrazolidinedione-4-yl; n = 0,
Her = 4-nitro-2-methy!-l-imidazolyl
Compounds containing high analgesic activity were found among indolylazoles If.
A patent has been issued for the preparation of 5-(indolyl-3-methyl)hydantoin (Ill) en-
tailing Fischer--Arbuzov cyclizatlon of the phenylhydrazone of ~-(5-hydantoyl)propionaldehyde
upon heating in hydrochloric acid [8].
0
~ . ---NH

0 ~ . ........
Nll

C6Hs_NII-N:CH-(CIL~)2 --. ~.N/~--O

II
H
III

Tatevosyan et al. [9, i0] synthesized indolybenzlmidazoles IV, which display strong an-
tiviral activity [ill, by heating 2-(3-oxobutyZ)- or 2-(4-oxopentyl)benzimidazoles with phen-
ylhydrazine in the presence of sulfuric acid.

IV CH3/ ~ N ~ ~ / J
H

R = H, alkyl; n = 0, i
2-Alkyl-3-(2-benzoxazolon-3-yl)indoles (V) were obtained in 65-70% yield upon heating
3- (2-oxopropyl)- or 3- (2-oxobutyl)-l, 3-benzoxazol-2-ones with phenylhydrazine in polyphos-
phoric acid [12].

R H
V

R = CHs, CaHs; R l = H, 5-CH3, 5-Ci, 6-SO2NH2

2-(l-Methyl-2-R-imidazol-5-yl)indoles (R = H, SC2H5) [13] and 2-(3-methylisothiazol-4-
yl)indole [14] were prepared by the cyclocondensation of l-methyl-2-R-5-acetylimidazoles and
3-methyl-4-acetylisothiazole with phenylhydrazines in the presence of zinc chloride. How-
ever, the yield of these indolylazoles did not exceed 25-40%.
The phenylhydrazones of 4- or 5-acetylthiazoles were converted by the Fischer-Arbuzov
reaction to indolythiazoles VI or VII, respectively [15]. High pesticide activity was n o t e d
for these compounds.

VI VII

R = H, CH3, Ph, COOH, COOC2Hs; R 1 = H, CHs

A patent was i s s u e d i n 1981 f o r the synthesis of 2-(5-R-3-R~-isoxazol-4-yl)indoles (R =
H, alkyl; R z = H, alkyl, aryl), which were obtained in high yield by the cyclization of 4-
aeetyl-5-R-3-RZ-isoxazole phenylhydrazone in polyphosphoric acid. These indole derivatives

ii0
are key compounds in the preparation of biologically active tryptamine analogs containing
isoxazole fragments.

2. PREPARATION OF INDOLYLAZOLES BY THE ALKYLATION

OR ACYLATION OF INDOLE AND ITS DERIVATIVES
l-(Imidazolinyl-2-methyl)indoles (VIII) are formed upon the alkylation of 2-arylindoles
by 2-chloromethylimidazoline in the presence of sodium hydride [17, 18].

-NaCl ~../'~.N/~-.Ar
~/~N H Ar H ! N--

N--...J
VIII H

R = H, CHs, C1; R x -- H, CHa; Ar = Ph) 4-ClC6H4, 4-CHs0CaHa

Hocker and Merten [19, 20] found that the alkylation of indole and 2-substituted indoles
by bis(l,3-diphenyl-2-imidazolidinylidene), which is a cyclic analog of tetraminoethylene,
proceeds at C(s) with the formation of 3-(1,3-diphenylimidazolidin-2-yl) indoles (IX).

~ sH5 COCH 3

9 N-,

H
ix_ x kl
R = H, CHs, Ph
Bergman [21] in an attempt to acylate indole with N-acetylimidazole in acetic anhydride
isolated the indole hetarylation product, 1,3-diacetyl-2-(indol-3-yl)-4-imidazoline (X) in-
stead of the expected N-acetylindole. This author considered that (X) is formed by electro-
philic attack at C(s) in indole by the 1,3-diacetylimidazolinium cation generated from N-ace-
tylimidazole. Also, heating indole with thiazole in acetic anhydride gave l-acetyl-2-(l-
acetylindol-3-yl)-4-thiazo!ine (Xl) [21].
D detailed study was carried out on the hetarylation of indoles not substituted at C(s)
by N-acylimidazolinium or N-acylhenzimidazolinium salts (XII) in situ. Sheinkman et al.
[22-24] reported that the reaction of indoles with imidazole or benzimidazole in the presence
of the acid chlorides or aliphatic, aromatic, or heterocyclic acids gave 3-(l,3-diacylimida-
zolin-2-yl)- or 3-(l,3-dfacylbenzimidazolin-2-yl)indoles (XII).

N" It;' i-. ~'Ol:

. COR

+ RCOCI - ~- , CI
I ;
i !
'N
i ("OR I~;'" " N
i.. (,OR
Xlll
XII

R = CHs, Ph, thienyl-2; R* = H, CHs; R ~ = H, CHs

The formation of salts Xll as intermediates was confirmed by the preparation of XIII un-
der analogous conditions using N-acylimidazoles instead of imldazole.
The benzoxazole fragment could not be introduced into the indole ring by the reaction
of indole with benzoxazole in the presence of acylating reagents in an inert solvent or by
using benzoxazole salts, which resulted only in N-acyl-o-aminophenols and tris(indol-3-yl)-
methane [25].
The reaction of indole with 4-ethoxymethylene-2-phenyl-5-oxazoline in acid medium gave
4-(indol-3-ylmethyl)-2-phenyl-5-oxazolone, which is an important intermediate in the synthe-
sis of tryptophan [26].

Iii
 Heating a mixture of indole or i~s derivatives not substituted at C(z) with 2-chioro-
ethyl Iso~hiocyanate in 1,2-dlmethoxyethane in the presence of sodium hydride at reflux gave
l-(Aa-thiazolin-2-yl)indoles (XZV), which are intermediates in the preparation of anti-in-
flammatory agents [27-30].

' " 1r " "R

" 1
S.+~ % N

XIV

R = H, thiazolyl-4; R z = H, (CHa)aNCHa; R a = H, CHaO, NOa

3. PREPARATION OF INDOLYLAZOLE$ FROM INDOLE C~BONYL DERIVATIVES

1,3-Disubstituted 2-(indol-3-yl)imidazolidlnes (XV) were synthesized by the cyclocon-
densation of l-acetyl-3-formyllndole with N,N'-dlarylethylenediamines with subsequent hydro-
lysis of the N-acetyl derivatives formed [31].

Ar Ar

< .:'+ . +

A ..o.o+ +"~"i"'.";- i ii Ii'~'i;m " ~i 'I , "~.m,~

ArlIN CI[ z N Ar ', "N" Ar
I 11
]
COCII3 ~,
(:(>r X','

Ar = Ph, 4-CHa0CeH4, 4-BrC6H~, C6HsCH2

3-Formylindole does not undergo this reaction, apparently due to insufficient electro-
philicity of the carbonyl group carbon atom. The introduction of electron-donor groups in
the benzene ring of the amines leads to increased yields of indolylimidazolidines XV. On
the other hand, electron-withdrawing substituents hinder the cyclocondensation. For example,
indolylimidazolidines could not be prepared from N,N'-di(4-nitrophenyl)- or N,N'-di(4-ethoxy-
carbonylphenyl)ethylenediamine.
3-Formylindole reacts readily with 2-mercaptoethylamine, which is a stronger nucleophile,
to give 2-(indol-3-yl)thiazolidine in high yield [32].
Heating Schiff bases XVI with acetic anhydride gives both acylation and cyclization to form
l-acetyl-2-(l-acetylindol-3-yl)oxazolidines (XVII) [33].

0--- P~

,.... , , _ + +

++

XWI
h + + +
+ , +

i
COCH 3

XVI1
oi!
R = H, CHs, C2H~, Ph, 4-CHsC6H~
The reaction of 3-formylindole hydrazones with 2,4-dinitrophenyl azide proceeds anomal-
ously with the formation of 2,5-disubstituted tetrazoles XVIII [34].

111
N ~ f~ ..... N Nh2
.... II + l
+~ ii-+ -i[ + [+~
~..~j .... L~. i[........+~
I + '~%
N" "r ~" ~:" N'
( I t J
R NO 2 R NO2
X"~'III

R = H, C6HsCH2; R ~ = Ph, 4-BrC6H~, 2,4-(NO2)=C6Ha, CONH=

4-(Indol-3-ylmethylene)-5-oxazolones (XIX), which are important intermediates in the
synthesis of tryptamine, tryptophan, and other biologically active indoles are readily formed

112
from 3-formylindole and N-acyl derivatives of glycine in the presence of potassium acetate
in acetic anhydride [35-38].

O,

H H
~X

R = H, COOCaHs; R x ffi CHs, Ph

The reaction of 3-formylindole with nitroacetate esters in the presence of sodium ace-
tate gives esters of the N-oxides of 4-(indol-3-yl)-3,5-dicarboxyisoxazolines (XXI) [39].
The extremely reactive nitroalkene X X w a s proposed as an intermediate, which rapidly reacts
with the starting nitroesters. The treatment of N-oxides XXI by aqueous ammonia gives the
diams of 4-(indol-3-yl)isoxazole-3,5-dicarboxylic acid (XXII).

1"-'*d--CliO + 02NCH2C00R ~ Ind--CH(OH)CH(NO2)COOR ~ Ind --CH:C--COOR -~---m.-

. -H20 I
N0 2

Ind C00R NH~_.Ind ~-~:--':- I~

02NCH2COOR ~02 "-~
--'- Ind--CtI-CH--COOB I
_lIND2
CONII2

CH(NO2)COOR ROOC H2NOC/k~N/0

O
X~ XXII

R = CHs, CeHsCHa; here and subsequently, Ind = 3-indolyl

4,5-Diaryl-2-(indol-3-yl)imidazoles were isolated in 60-67% yields as a result of the
cyclocondensation of 3-formylindole or its N-methyl derivative with aromatic a-diketones
[40, 41].
Indole aldehydes may undergo condensation with some azoles containing active methylene
or methyl groups. Thus, cyanine dyes XXIII were synthesized from substituted 3-formylin-
doles and the corresponding 2-alkylbenzazole salts. These dyes have been proposed for use
in photographic films [42-46].
.Y
X ...... 7

B" ~3 " R B-

XXIII
R, R x, R a, R s = H, alkyl, aryl; R ~ = H, CN; X = O, S, Se; Y =
CH, N; B - = I-, Ts-, ClO~-
Dyes obtained by the condensation of l-methyl-2-phenyl-3-formylindole with 3-substituted
derivatives of 5-pyrazolone and 5-isoxazolone have been used for the same purposes [47, 48].
IndolylmethyldenazolesXXIV which display strong anti-inflammatory action are formed by
the condensation of 3-formylindoles with derivatives of imidazolidine, isoxazoline, pyrazol-
ine, pyrazoline and thiazolidine containing the --CHaCO--group i ~ t h e ring [49-53].

(X h

I I
R R

X = --NH--CO-RNH--, --C(CHs) = N-O-, -CO--NPh--NR*--, --CRs = N--NRa-,

--NH--CO--S--; R, R*, R 2 = H, aryl~ R s = CHs, NHa
The Knoevenagel reaction of 3-acetylindole with 5-formyl-3-phenylisoxazoline gave the
corresponding ~,8-unsatumated ketone XXV [54].

113
 In6--CO-CH~ + OHC--- ~,. . ."HaO
.. ~ I~d- C0-CH=: C l l ~ 0 1 N
XXV
a,8-Unsaturated aldehydes and ketones, a-epoxyketones, 8-diketones, and a,8-diketoesters
of the indole series are convenient starting compounds for the synthesis of various indolyl-
pyrazoles.
Heating 8-(l-acetylindol-3-yl)acroleln (XXVI, R = Ar with hydrazine hydrate or phenyl-
hydrazine in acetic acid at reflux gave 1-substltuted 5-(l-acetylindol-3-yl)pyrazolines
(XXVII), which upon treatment with ethanolic alkali are converted to l-substituted 5-(indol-
3-yl)pyrazolines (XXVIII) [55].
The phenylhydrazone of 8-(indol-3-yl)acrolein (XXV, R = H) upon heating at reflux in
acetic acid is slowly cyclized to l-phenyl-5-(indol-3-yl)pyrazoline (XXVII, R: = Ph). The
phenylhydrazone of N-substituted aldehyde XXVI (R = Ac) undergoes more rapid cyclization un-
der the same conditions to give pyrazoline derivative XXVII (R = Ac, R: = Ph) and, upon de-
acylation, pyrazoline XXVIII (R = H, R ~ = Ph).
These authors consider that nucleophilic addition at the -CH=CH - double bond is diffi-
cult in ~-(indol-3-yl)acrolein due to the strong electron-donor effect of the indolyl group.
The introduction of an acetylgroup at N(z) in the indole system reduces the electron-donor
effect of the indole group and increases the reactivity of aldehyde XXVl (R = Ac) relative to
nucleophilic reagents.
Suvorov et al. [55] have proposed the following method for the synthesis of l-phenyl-5-
(indol-3-yl)pyrazole (XXIX).

] I n
COClI~ COCH a
~VI X~X

The reaction of l-(indol-3-yl)-3-aryl-3-propenones (XXX), which are the products of the

Knoevenagel reaction of 3-formylindole and methyl aryl ketones, with arylhydrazines lead to
the formation of 1,3-disubstituted 5-(indol-3-yl)pyrazolines (XXXI) [56-59].

//-~. ,~_..... /CHInCH-CO-At ~ ~ .- ] ~N..i~l ~Ar

H H
XX.-X XX~I
R=H, Ar
Indolypyrazolines EXXI have valuable properties and are central nervous system depres-
sants [57], anticonvulsants, monoamine oxidase inhibitors [58], and anti-inflammatory agents
[59]. These compounds also have strong luminescence both in the solid state and in solution
[561.
Indolylpyrazolines XXXIII which contain indolyl fragments at C(s) of the pyrazoline ring
were synthesized by heating l-(indol,3-yl)-3-aryl-l-propenones (XXXII) with a large excess of
hydrazine hydrate [60, 61].

Ind

Ind ~ CO-CH=CIt-A~ + N~lt4'tI~O .... !~ ~N~7s Ar

I
R
X.~XII .XD~XIII
R = H, Ac
Pyrazolines XXXIII w h i c h a r e n o t s u b s t i t u t e d at N(,) of the pyrazoline ring (R = H) a r e
rather unstable compounds which decompose upon purification. However, carrying out the re-
action in acetic acid leads to the formation of 1-acetyl derivatives of p y r a z o l i n e s XXX!II
(R = Ac) which are completely stable compounds [61].

114
 Unsaturated indole ketones may also be used to prepare indolylisoxazollnes. For exam-
ple, the heating Df ketones XXXWIth hydroxylamine gave 3-aryl-5-(indol-3-yl)isoxazollnes
(XXXIV) [62].

.At

Ind

Piozzi and Fuganti [60] studied the reaction of vinyl 3-indolyl ketone with hydroxylam-
ine to give 3-~indol-3-yl)isoxazoline and noted the inability to synthesize analogous isox-
azoline derivatives from l-(indol-3-yl)-3-phenyl-l-propenone (XXXll).lerivatives from l-(in-
dol-3-yl)-3-phenyl-l-propenone (XXXII),
Considerable interest is found in the reaction of indole ~-epoxyketones with hydrazine
hydrate, which, depending on the reaction conditions, leads to the formation of either 3-(in-
dol-3-yl)-4-hydroxy-5-arylpyrazolines (XXXV) [54, 63, 64] or 3-(indol-3-yl)-4-arylpyrazoles
(XXXVI, R = H) [60]. Pyrazolines XXXV are obtained upon carrying out the cyclocondensation
in alcohol using catalytic amounts of acetic acid, while pyrazoles XXXVI are obtained in eth-
er in the presence of BF3"0(CIHs),.

[rid ~I"

had 01f .~g~,'.. ~ "'N"

I} ' I N7114" 1f:~0 ;:--~.% ,{
CO CIi CII A r - -~
" " ~2~/A~,x x:kx v I
H

f" Ar
i
coil b
"%'<>{!'i l

R = H i Ph
Carrying out this reaction in acetic acid gives l-phenyl-3-(indol-3-yl)-5-arylpyrazoles
(XEXVII) [63, 64], while l-phenyl-3-(indol-3-yl)-4-arylpyrazoles (XXXVl, R = Ph) were ob-
tained in e:her in the presence of BF3 etherate [60]~
The reaction of ~-diketones XEXVIII with hydroxylamlne gave 3-aryliS-(indol-3-yl)isoxa-
zolines (XXXIX) [66], while the action of hydrazine hydrate or phenylhydrazine gave 3-aryl-5-
(indol-3-yl)pyrazoles (XL) [64, 67].

.At .At
........ hid C 0 Ctl ,CO A r I N
Ind ]C<XVlll hid N"

~D~LE XL
R=H, Ph
The ethyl ester of 4-(indol-3-yl)-2,4-butanedionoic acid (XLI) reacts with hydrazine
hydrate or phenylhydrazine in acetic acid to form the ethyl esters of l-R-5-(indol-3-yl)py-
razole-3-carboxylic acids (XLII), which were converted to l-R-5-(indol-3-yl)pyrazoles (XLIII)
upon subsequent hydrolysis to the acid and decarboxylation; these pyrazoles have high anti-
inflammatory activity [68, 69].

115
 ,COOC, LI,,
.... )I h
~" ,<,,,N,, N
lnd
i I
~,+,~,,~' R
ELl[ XLIII

Ind CO' f)H,~(IO9 COOC,!I] ~ : ,~'~t

coo('Jl:~

~0
[t)d '
XLIV

R=H, Ph

Treatment of 8-diketoester XLI with hydroxylamine in the presence of pyridine gives a

high yield of the ethyl ester of 5-(indol-3-yl)isoxazole-3-carboxylic acid (XLIV) [70]. An
interesting transformation occurs in the reaction of ester XLIV with hydrazine hydrate in
ethanol at reflux which gives the hydrazide of 5-(indol-3-yl)pyrazole-3-carboxylic acid.
Indole a-haloketones have been used in the synthesis of indolylimidazoles and indolyl-
thiazoles. Thus, heating 3-chloroacetylindole with a large excess of formamide gives 4(5)-
(indol-3-yl)imidazole [71], while heating with a stoichiometric amount of formamide and phos-
phorus pentasulfide gives 4-(indol-3-yl)thiazole [72]. Suvorov et al. [71] noted the inabil-
ity to extend this method for the preparation of indolylimidazoles from the amides of other
acids. For example, the reaction of 3-chloroacetyllndole with acetamide proceeds with heavy
tar formation and 2-methyl-4-(indol-3-yl)imldazole was isolated from the reaction mixture in
only a 4% yield.
The cyclocondensation of 3-chlbroacetylindoles with acid thioamides gives 2-substituted
4-(indol-3-yl)thiazoles (XLV) [14, 73], while this reaction with thiourea or N-substituted
thioureas gives 2-amino-4-(indol-3-yl)thiazoles (XLVI) or their N-substituted derivatives
[14, 72].
.,. ~ COCH.CI

"'~'/ ".'N'" ~'R ~'S"-"'R 1 - -" . . . . .

'~ N "~ ~ "~<." " N ~ R \s N~m2
II II H
XLV XLVl

R = H, CHs; R ~ = CHs, aryl, pyridyl-3! R 2 = H, CHs, NH2,

C(=NH)NHz
Significant interest is found in the condensation of 3-chloroacetylindoles with the func-
tional derivatives of several azoles in the synthesis of indolylazoles. For example, the re-
action of ~-chloroketones with 2-imidazolidinethione gives 5,6-dihydro-3-(2-R-indol-3-yl)-
thiazolo[3,2-a]imidazoles (XLVlI) while this reaction with 2-amino-Aa-thiazoline gives 2-
imino-3-[l-oxo-l-(2-R-indol-3-yl)ethyl]thiazolidines (XLVIII) [14].

H H It
~NI! XLVIII

R = H, CHs

Indolylthiazoles XLV-XLVIII have a broad range of pharmaceutical activity and are cen-
tralnervous system depressants, analgesics, and antibacterial agents as well as substances
used for lowering arterial pressure [14, 72, 73].
3-Aminoacetylindole hydrochloride was used in the synthesis of indolylimidazoles [71, 74].
The reaction of this hydrochloride with molten potassium thiocyanate gives a 16% yield of 5-
(indol-3-yl)-2-imidazolethione (XLIX). Heating this hydrochloride with an equivalent amount
of isothiocyanates gives 1-substituted 5-(indol-3-yl)-2-imidazolethiones (L) in 30-50% yield.
The desulfurization of 2-imidazolethiones XLIX and L by nancy nickel in ethanol leads to the
corresponding indolylimidazoles LI and LII which display tuberculostatic activity [71, 74].

116
 lnd Ind
KSCN NH
II J =- I r7
L N ~S
N
li It
lnd--I;0CH~.NHT. IICI XIJX LI
lnd Ind R
RNCS Ni N

It
L I.II

The antibiotic pimprinine was isolated from several natural products and identified in
1960 as 2-methyl-5-(indol-3-yl)oxazole (LIII) [75]. The structure of pimprinine was confirmed
by its synthesis from 3-aminoacetylindole hydrobromide [76-78].

9 1-Ac,aO + CsHsN CH3 D" C

2.POCIa "-~
it I H
C0CH3 LIII

In 1981, Houwing et al. [79, 80] reported the preparation of pimprinine analogs (LIV)
by the condensation of substituted 3-formylindoles with ~-tosylisocyanide or with dimethoxy-
N-tosylmethylimine; these analogs display antihistiminic activity [80].

R2 .

I~1 ~, CHO R~ It "N

+ Ts CH N ::C ~ ~
k . -" "N 1~'~ "P'" "- "
l.t R LIV

R ffiCHs,(CHs)2NCO; R x ffiH, CHsO, NO2; R a = H, CHs; R s ffiH,

CHsO
There has been a report of the use of l-acetylindoxyl (LV) as the starting agent for the
preparation of some indolylazoles. For example, the condensation of indoxyl LV with 1,2-
diphenyl-3,5-pyrazolidinedione gives a quantitative yield of I, 2-diphenyl-4- (1-acetylindol-3-
yl)-3,5-pyrazolidinedione (LVI) [81].
o~ -N C e H s
..~. .0 O~ C6H 5

I 0>" ~'C6115 !
COCI[~ CCCH3
LV Lvl

Heating carboethoxyisopropylidene hydrazone with l-acetylindoxyl in polyphosphoric acid

at 90~ gives intramolecular cyclizationwith the formation of 3-methyl-l-(l-acetylindol-3-
yl)-5-pyrazolinone [82].

4. PREPARATION OF INDOLYLAZOLES FROM INDOLE

CARBOXYLIC ACIDS AND THEIR FUNCTIONAL DERIVATIVES
Indole acids themselves have rarely been used for the preparation of indolylazoles until
recently. The condensation of derivatives of indol-3-ylacetic acids with o-phenylenediamine
leading to the corresponding 2-(indol-3-ylmethyl)benzimidazoles (IV) [9] has been described
in [9],

~ ,:. 11 ~
.~ CII COOII NH2~- . " ' k
. 4.~ H

" ~ ' / ' " ~z'"ctt~i} NI,, ": L. ~ IIN CH~

IV

R = H, C~H9

117
 The reaction was carried out by heating the corresponding acids with a large excess of
o-phenylenediamine in 4 N hydrochloric acid at reflux, However, the yields of indolylbenzim-
idazoles did not exceed 30%.
The reaction of ~-(indol-3-yl)alkanoie acids with tris(hydroxymethyl)methylamine gave
4-di(hydroxymethyl)-2-~-[(indol-3-yl)alkyl]-A'-oxazolines (LVII) [64].

Ind-(CH2)n-C00lI + NII2C(ClI20H)-~ ..... ~ Ind-(CII2),V-

N----~-CH20H
C}I20H
Lu
n=l-4
5-[a-(Indol-3-yl)ethyl]oxazole (LVIII) is an important intermediate in the synthesis of
the alkaloid, ellipticine, which stimulates brain activity and was prepared by the reaction
of the methyl ester of 2-(indol-3-yl)propionic acid with lithium methyl isocyanide at --50~
[83].

Ind-C[{(CII3)-COOCIl ~ + LiCII=N=C ~ Ind-'CH(CII'~).... "O 1

LVIII

Suvorov et al. [84] used the condensation of ethyl (indol-3-ylmethyl)malonate with hy-
drazobenzene in ethanol in the presence of sodium ethylate to obtain 1,2-dlphenyl-4-(indol-
3-ylmethyl)pyrazolidine-3,5-dione.
S-[~-Carbomethoxy-B-(indol-3-yl)ethyl]thiuroniumhydrobromide obtained from the methyl
ester of ~-bromo-8-(indol-3-yl)proplonic acid and thiourea is cycllzed upon heating in water
to give 5-(indol-3-ylmethyl)thiazolidine-2,4-dlonewhich has tuberculostatic activity [85].
Of all the functional derivatives of indolecarboxylic acids used as starting materials
in the preparation of indolylazoles, the nitriles of indole acids have been studied most ex-
tensively.
The hydrogenation of 3-indoly!acetonitriles or their N-acetyl derivatives over Raney
nickel in the presence of N,N'-diphenylethylenediamine leads to 1,3-diphenyl-2-(indol-3-yl-
methyl)imidazolidines (LIX) [86, 87].

~sH5
~\ c.~-cN Co%HN-~., H~ F" it- il~ ~_t
/ " C6HsHN-CH 2 Ni '~"
, ,J c' .o
I
LIX
R=H, Ac
Great interest has been found in the reaction of 3-indolylacetonitriles with ethylene-
diamine which gives indolylimidazoline s [88-94]. Thus, heating these nitriles with anhy-
drous ethylenediamine in the presence of sulfur compounds gives 2-(indol-3-ylmethyl)-A=-imi -
dazoles (LX). Hydrogen sulfide, carbon disulfide, phosphorus pentasulflde, aluminum sulfide
[88] and p-toluenesulfonic acid have been used as catalysts for this reaction [89, 94].

H H
LX
R : H, C1, Br, F, CHsO
Indolylimidazolines LX which may be formally considered as tryptamine derivatives have
various biological activities and are antidepressants, vasoconstrictors [91], repellants
[92], and serotonin antimetabolites [90].
Analogously, l-cyanomethyl-3-alkylindoles and ethylenediamine give 3-alkyl-l-(imidazol-
inyl-2-methyl~indoles (LXI), which display strong vasoconstrictor activity [93].

118
 CI{, ':/ ! ~"~" N
N ! It
1II H LXll

The cyclocondensation of indol-3-ylacetonitrile with B-mercaptoethylamine gives good

yield of 2-(indol-3-ylmethyl)-Al-thiazoline (LXII), which combines significant bacteriosta-
tic activity with low toxicity [95].
In the search for effective anti-inflammatory agents, a series of indomethacine analogs
LXIV has been prepared containing a tetrazole residue instead of the carboxyl group. The
synthesis of these compounds is carried out by the prolonged heating of 3-indolylacetic ac-
ids with sodium azide and aluminum chloride [96] or ammonium chloride [97] in DMF or THF.
These tetrazoles (LXIII) were subsequently acylated at the nitrogen a t o m of the indole frag-
ment in the presence of sodium hydride [97-100].

N -N N .....

~/ " N/
COCJ14CI
i).~ii IXIV

R = H, Cl, Br, CH30; R* ffi H, CHs

Of all the compounds synthesized, greatest activity was found for 5-(l-p-chlorobenzoyl-
indol-3-ylmethyl) tetrazole (LIV, R = R* = H) [97]. This compound also has antiserotonin and
antihistimine activities [98, i00].
The reaction of ethyl ester of 3-cyano-3-(indol-3-yl)propionic acid with sodium azide
and ammonium chloride gives the ester of 3-(tetrazol-5-yl)-3-(indol-3-yl)propionic a c i d (LXV),
which upon hydrazinolysis and subsequent Curtius rearrangement in the presence of ethanol is
converted to the corresponding urethane LXVI. Upon alkaline hydrolysis and decarboxylation,
LXVI gives 8-(tetrazol-5-yl)tryptamine (LXVlI) which displays antidepressant and hypotensive
activities [i01].

N N N ~ N -N

indl -C}I-CN -
N.N~
.' h)d I CH
[I i, 9
t:~ m.- l n ( ] '
9
t:H ,
]L hi
,:" - ~ h~d ! CH
[i
,.
INI
l i " N ] N - C2Hso 11
CH2COOC~II 5 }I i I{ I "N
H
. CII2COOC.2H5 (;[I,zNtICO0~2 H 5 "CO 7 CIt2NIt 2
I LK'r 12/', I L x~WII

Ind* = 4-chloroindol-3-yl, 4-chloro-5-methoxyindol-B-yl, 6-

chloro-5-me thoxyindo l-3-yl
N-Acetyl-~-cyano-8-carboethoxy-6-chlorotryptamine reacts with sodium azide in the pre-
sence of AICIs to give the corresponding tetrazole LXVIII, which upon alkaline hydrolysis is
converted to ~-(tetrazol-5-yl)-6-chlorotryptamine (LXIX) [102].

NHAa
NIIAe i N N N - N
N~'I~ , ~ ]I i! l)
1.d' e.T i: cN NtI~ r t ),,,l '.":<.;,"~ N ~ - t~,,,' e . , i H JP" N .~
COOCIH~ :i 1[ NI," 2 1{
COOC ,li >
L:.V[H ,>:,X
2nd ~ = 6-chioroindol-B-yl
Taborsky [103] obtained an unusual result upon the prolonged heating of indol-3-ylace-
tonitrile with anhydrous hydrazine (in 2:1 mole ratio), which yielded 4-amino-3,5-bis(indol-
3-ylme thyl) -i, 2,4-t riazole.
Indol-3-ylacetonitrile has been used in the Knoevenagel reaction with several hetero-
cyclic aldehydes to give trisubstituted ethylenes LXX [104].

119
 {~N
lnd*~ClI~*CN + [Iot,=(~llO ~ h~d {!~,C|I* llot

Bet = s 1-benzylimidazolin-2-yZ, 4-meth-

ylthiazol-2-yt
A convenient method f o r the p r e p a r a t i o n of indolyZoxadiazoles e n t a i l s ~he s
cycloaddition of indole nitriles with nitrile N-oxldes [105]. Thus, 3-cyanoindole, Indol-3-
ylacetonitrile and B-(indol-3-yl)propionitrile and aromatic nltrlle N-oxldes, generated ~n
s~r from the corresponding arylhydroxamic acid chlorides, gave 3-aryl-5-[(Indol-3-yl)alkyl]-
1,2,4-oxadiazoles (LXXI).

A~
i . l[Id ~-(CH~)n'~CN N 0~

,4.............................................................................
-HCI

n = 0, i, 2~ Ar = Ph, 4-OaNC6Hd, 4-ClCsHd, 3-CHsC6H~

Dyankova et el. [106, 107] have found that the best yleld of adducts LXXI is achieved
upon carrying out this reaction in the presence of boron trifluoride etherate, which enhances
the dipolarophilic activity of the nitrile group due to complexation. Oxadiazoles LXXI were
also obtained upon heating of these nltriles and arylhydroxamic acid chlorides in an inert
solvent for >48 h.
These authors [105-107] have noted that the yields of adducts LXEI synthesized by the
thermal condensation of nitriles with arylhydroxemic acid chlorldes are signlficantly higher
than in the reaction with nitrile N-oxldes.
Carboxylic acid iminoester hydrochlorides may be used as convenient starting materials
in the synthesis of various azoles. However~ only limited information is available on the
use of indole acid iminoester hydrochlorides for these purposes.
The condensation of indolylalkanoic acid imlnoester hydrochlorides with ethylenediamine
has been described [108-110]. This reaction proceeds rapidly under mild conditions and gives
a high yield of 2-substituted A2-imidazolines (LXXII).

R',
"r:<~.}1 .......I'",C[{R'(CH2).C"
" "oc~% l~- S)'~". . . . . . . . . . CIIR_(CII2)n_.~/~" I

Zl " -NIIdCt It
L~XII
R = H, Ph, 3-CHsOC~H~; R x = II, Clls; R 2 = H, CI, CHs0; n = 0, i
2-[B-(lndol-3-yl)phenethyl]-A2-1midazoline hydrochloride (LXXs163 R = Ph, R z = R 2 = H,
n = l) displays strong sympatholytic activity [108]. We should also note that 2-(indol-3-
yZalkyl)-AZ-imidazolines (LXXZZ, n = l) have recently been found to possess pronounced ra-
dioprotective activity [5, ii0].
Fel'dman e t a l . [111] have synthesized 5-imidazolones (LXXIIs which are unstable under
ordinary conditions, from the ethyl iminoester of 3-indolylacid and a-amino acids according
to the scheme:

Ind --CHI-C ~NH

~ + tI2N-CHR-COOH ........... ~
/~
Ind --CIIz-C~ NH
~2H50H
OC2H5 -C2}Is0|I NHCftRC00H HCI

.... ~ Ind ~-CIt2--c~NIt'HC1 0H~ N~ ~F ~0

~NIICHRC00C2H5 ~_C2Hs0H ~ Ind --CH2~ ~ '

12~III

R = H, i-CsH~, i-C4Hg, s-C4Hg~ indol-3-ylmethyl

In our previous work [112-116], we have shown that the cyclocondensation of carboxylic
acid iminoester hydrochlorides with 1,2-bifunctional compounds yields a large number of var-

120
ious azoles. Thus, the reactions of 3-indolecarboxylic and 3-indolylacetic a c i d ethyl hy-
drochlorides with N-monosubstituted ethylenediamines, monoethanolamine, o-phenylenediamine,
o-aminophenol, hydrazides, and acid amidoximes lead to the corresponding 2-substituted A=-
imidazolines (LXXIV, X = NR), A2-oxazolines (LXXIV, X = O), benzimldazoles (LXXV, X = NH),
benzoxazoles (LXXV, X = 0), 2,5-disubstituted 1,3,4-oxadiazoles (LXXVI), and 3,5-disubsti-
tuted ],2,4-oxadiazoles (LXXI).

I n d ' - ( C H 2 ) dX- f - ] | ~HXCH2CH2NH2 R1CONHNH2 N---N

- r------- Ji.
X--J ] Ind--(CH2).l" "~o~ --Ri

LXXIV "NH2 lad --(CH2)~--Cz~'0C2115

NH'HCI-~[ 2 ~NOH
R'-C~I~i2_ N ~/R"o

N--]~ ~ -:~ :~ o~
n = O, i; X = NH, NR, O; R = H, C6HsCHI, CHICH=CN, 2-thien-
ylmethyl; R z = H, CH3, Ph, 4-OiNC~H4, 4-CIC~H4, 5-nitro-2-
furyl, indol-3-yl, indol-3-ylmethyl; R= = CHs, CHIC1, Ph,
5-nitro-2-furyl
The use of indole acid thioamides for the preparation of indolylazoles has been indi-
cated only in a report of the cyclocondensation of l-methyl-2-indolcarboxylic and 3-indole-
carboxylic acid thioamides with halomethyl ketones to give 2-indolyl-4-substituted thiazoles
(LXXVII) [117, 118].

N ~
Ind1---c~S + R-C0-CH2X
NH2 -H20
-I~ IndI S
LXXVII

Ind I = l - m e t h y l i n d o l - 2 - y l ,i n d o l - 3 - y l , R = CH3, CHIC1, Ph,

4-CHsOC6H~, 2-thienyl, X = CI, Br
Indole acid hydrazides have found as yet only limited use for the preparation of 1,3,4-
oxadiazoles, 1,3,4-thiadiazoles, and 1,2,4-triazoles containing indole fragments.
Heating N-acyl derivatives of 2-indolecarboxylic acid hydrazides (LXXVIII) with POCI3
gave 2-substituted 5-(indol-2-yl)-l,3i4-oxadiazoles (LXXIX) [119, 120].

Rt R~

H H
LXXVII!
R = H, CH3, CHIC1, CHCI2; Ph; R' = H, C1
5-(Indol-2-yl)-l,3,4-oxadiazole (LXXIX, R = R z = H) was also synthesized by the reaction
of 2-indolecarboxylic acid hydrozide with ethyl orthoformate [119, 121]. Robba [119] and
Ainsworth [121] have noted that heating N-acyl derivatives LXXVll with phosphorus pentasul-
fide gives low yields of 2,5-disubstituted 1,3,4-thiadiazoles.
Hydrazides of substituted 2-indolylacetic acids upon treatment with cyanogen bromide in
an inert solvent give 2-amino-l,3,4-oxadiazoles (LXXX) [122].

R R
~'~ .__./"CH3 ~- /CH 3
- N---N

LXXX

Treatment of benzylidene derivatives of substituted 3-indolecarboxylic acid hydrazides

with bromine in the presence of sodium acetate in acetic acid or iron chloride in ethanol
gives a 38-40% yield of 2-phenyl-l,3,4-oxadiazoles (LXXXI) containing indole fragments at
C(,) [123].

121
 ....... N
R~O' 7 . . / , /CONHN=CHCeH" "'///'"I]...... i]/''''0''~-
C~H$

%-'""~'N....... cH~ I .......

R R'

R = H, C6HsCO; R I = H, CHs
Hiremath et al. [123] also showed that the reaction of 5-hydroxy-2-methylbenz[g]indole-
3-carboxylic acid (LXXXII) with carbon disulfide and base in ethanol gives the corresponding
1,3,4-oxazole-5-thione LXXXIII, which upon the action of formaldehyde and 2-aminothiazoles
is converted to Mannich bases LXXXIV, which display antimicrobic activity.

HNHet
I
N--NH N--N/CH2

~S H ~ ~N~ ~CH3 CH2-~-~O~ N ~'~CH~

T.XXX.II IXXXIII
Her ffi 4-phenylthiazol-2-yl, 4-ethyl-S-methylthiazol-2-yl,
benzthiazol-2-yl
Upon heating at reflux in alkaline solution, l-(2-methylindol-3-ylacetyl)-4-R-thiosemi-
carbazides (LXXXV) cyclize to give high yields of 4-R-3-(2-methylindol-3-ylmethyl)-l,2,4-
triazoline-5-thiones (LXXXVI) which are cardiac activity stimulators [124].

N--NH

CH~ -r L~N~CH 3 ~
LXXXV H
LXXXVl

R = CHs, CH2 : CH-CH~, Ph, 4-CIC~H,

Hiremath et al. [125] in 1981 reported the synthesis of various types of indolylazoles
using thiosemicarbazides LXXXVII. The oxidative cyclization of LXXXVII by iodine in an al-
kaline solution of potassium iodide gives N-substituted 2-amino-l,3,4-oxadiazoles (LXXXVIII).
Heating LXXXVll with orthophosphoric acid gives 40-45%yields of N-substituted 2-amino-l,3,4-
thiadiazoles (LXEXIX), while heating of this compoundwith aqueous alkali gives 4-R-I,2,4-
triazoline-5-thiones (XC);

H~PO4 ~ N--N
Ind 2 /~['S ~/~NHk
N.--N l. + KI | I.XXXlX
"~ --~" Ind :~'~CONHNHCSNHR
Ind2 / ~ O ~ N H R LXXXV]I
NaOH N--NH
Ind2 N S
R
XC
[nd 2 = 5-hydroxy-2-methylbenzo[g]indol-3-ylD R ffi C H s , Ph

Indolylisoxazolidines XCl are formed in 50-60% yield upon the treatment of potassium
salts of indol-3-ylalkylhydroxamic acids by 1-chloro-3-bromopropane in the presence of base
[1261.

Ind --(CH2)n-'C~NHOK+CI-(CH2)3-Br Na2CO~ CI CO"

Ind ~-( 12)n- / ~0"
n=l,3 XCI

The reaction of methyl thioesters of substituted indole-3-dithiocarboxylic acids with

aminoacetaldehyde diethylacetal has been used to prepare 3-(5-ethoxy-A2-thiazolin-2-yl)in -
doles (XCII) [127].

122
 J3C2H 5

~ ~
C~scH3 + 'H2NCHaCH(CCzHs)2
_._

XCII

R = H, CH,; R* = H, CH,, Ph
Tominada et al. [128] have described the preparation of indole derivatives of A~-imida -
zolines XCIV or Aa-oxazolines XCV from the iodomethylate of 1,2-dimethyl-3-indolcarboxylic
acid thiomorphilide (XCIII) and ethylenediamine or ethanolamine, respectively.
H

,%~~,,. "</ "iN" "CH~

/--.,, /C-----N 0 /,~. .,5C- -N
"~ .... +"
-
J -- < ~S~.+ \ ? . . . . . . .
"r "~'"

~>'~" "" " N'" " Cli~

I
CH3
XCV

However, the starting sulfur-containing compounds are not readily prepared due to dis-
advantages of the latter two synthetic methods.
Harris [129] has proposed using indol-3-yltrimethylthioformamidinium perchlorate (XCVI)
obtained from indole and chlorotrimethylthioformamidinium chloride as the key compound for
the synthesis of indolylazoles.

H
XC;I

Salt XCVI has high reactivity in reactions with bifunctional nucleophilic reagents and
thus various hetarylindoles may be prepared using this ~ompound [130].
N--N

N-q Ind S NH2

I n d -- // i .,=H~NCII?CH>XH ~ N H 2
XCVI
~x-J
X=O,S
.Ind

However, in using this method, we encounter great difficulties due to the extremely hy-
groscopicity and instability of the starting chlorotrimethylthioformamidinium chloride and
perchlorate, which require special care in their use.
Indole amino acids and hydroxyacids and their derivatives have also been used for the
synthesis of several types of indolylazoles.
Thus, tryptophan and ammonium thiocyanate in acetic anhydride gave l-acetyl-5-(indol-3-
ylmethyl)-2-thio-4-imidazolone [131, 132]. The use of phenyl isocyanate instead of ammonium
thiocyanate gives 3-phenyl-5-(indol-3-ylmethyl)-2-thio-4-imidazolone [133~ 134].
2-Methyl-4-(indol-3-ylmethylen)-5-oxazolone (XlX) was synthesized by the Bergman method
involving treatment of N-chloroacetyltryptophan by acetic anhydride in pyridine [37].
Oki and Nagasaka [135, 136] have synthesized 4-(l-acetylindol-3-ylmethyl)-2,5-oxasolid-
inedione which displays strong anti-inflammatory activity and is a central nervous system
stimulant by the action of phosgene on l-acetyltryptophan.

123
 Considerable interest is found in the method of Oikawa et el. [137, 138] for the pre-
paration of analogs of the pyrlmidine antibiotic, 2-methyl-5-(indol-3-yl)oxazole (LIII)
which entails the oxidation of the methyl ester of N-acyltryptophan by dichlorodicyanoben-
zoquinone in anhydrous TRF to give a high yield of 2-substltuted 4-carbomethoxy-5-(indol-3-
yl)oxazoles (XCVIZ).

0
CI. L~ CN CH,~OOC,.,...........
N
Ind CLT~Cli C,OOCIi.~ + ...... .........
NHCOR CI "~ "'CN Ind " "0 "R

o ,XCVll
R = CHs, Ph, 4-CHs0C,H4
The reaction of tryptophan amide with acetone gave 4-(indol-3-ylmethyl)-5-imino-2,2-
dimethyloxazolidine, which is converted upon hydrolysis to the corresponding 5-oxasolidinone,
which is an inhibitor of tyrosine and hlstldlne decarboxylases [139].
In 1960, Rao [140] isolated the antibiotic indolemycln from natural substances and iden-
tified it as 2-methylamino-5-[a-(indol-3-yl)ethyl]-4-oxazollnone. In 1963, this antibiotic
was prepared as a mixture of two isomers XCVIZI and XCIX by the scheme of Shach et al. [141].

II. .,,C00C2]IS
"~011

+ CH .--.,r.~-j.-~-CO0 CzH ~ ..... ~ N "' CH~ (CH3NH)'C=NH.,

H H

_NHCH~ CH~HN

-~ .....~ * H"I"

II H
XCVIII XCIX

In addition to indolemycin XCVIII itself, the condensation of the ethyl ester of a-hy-
droxy-B-(indol-3-yl)butyric acid (a-indolemycinic acid) with N,N'-dimethylguanidine gives
some amount of isoindolemycin XCIX as a result of the ready stereoisomerization of indole-
mycin under alkaline conditions [141].
Preobrazhenskaya et al. [142-144] have shown that, in addition to N,N'-dimethylguanidine,
N-methylthiourea may be used as the second component of the reaction for the preparation of
indolemycin.
The cyclocondensation of the esters of racemic indolemycinic acids with guanidine or
urea and several other compounds was studied in order to prepare indolemycin analogs and de-
termine their biological activity [145].
The reaction of indolymycinic acid esters with guanidine or thiourea gives a mixture of
racemic 2-amino-5-[a-(indol-3-yl)ethyl]-A2-oxazolin-4-ones (C) [145]. The condensation of
these esters with urea leads to a mixture of diastereomeric 5-[a-(indol-3-yl)ethyl]- A2-oxa -
zolidine-2,4-diones (CI), while this reaction with methyl isocyanate leads to diastereomeric
3-methyl-5-[u-(indol-3-yl)ethyl]-A2-oxazolidine-2,4.diones (CII), which are also formed upon
the methylation of 2,4-oxazolidinediones CI, which, in turn, may be obtained by the hydroly-
sis of 2-amino-A2-4-oxazolinones C [145].

I (H2N)2C=S Ind --C 0

I NIl 2
/CH~ [
CH~ C
_ _ -.-.N CH~NCO lnd --CIt-CH(OH)~OOC2H5
Ind --C
I 0 CH3
CH~
CII Ind -- CH 0--O
I
CH~ CI

124
 The methyl esters of racemic a-hydroxy-8-(indol-3-yl)propionic acids serve as starting
materials for the preparation of thiazoline analogs of indolemycin. Upon the action of meth-
anesulfonyl chloride, these esters are converted to O-mesylates CIII. The condensation of
CIII with thiourea or its derivatives gives a mixture of 2-imino-3-R-5-(indol-3-ylalkyl)-4-
thiazolinone (CIV) and 2-amino-5-(indol-3-ylalkyl)-A2-thiazolin-4-one (CV) [146-148].

Ind --CH-CH-COOC2H 5 + H2 NCSNHR~ .... ~ O NH _ _~_ N 0.. N

R O--S02CH 3 Ind --C S NIl Ind - C S NHR'

cm )
R R
I
ely CV
R, R* = H, CH3
Diastereomeric 2-methyl-5-[a-(indol-3-yl)ethyl]-~-thiazolin-4-ones (CV, R = R* = CH,)
and their derivatives obtained upon acylation of the indole ring at the nitrogen atom are
effective antiviral compounds [148].

5. SYNTHESIS OF INDOLYLAZOLES FROM INDOLE AMINES

The N-alkylation of azoles of indole Mannich bases, 3-(N,N-dimethylaminomethyl)indole
(gramine), 3-(N-piperidinomethyl)indole [149-151] and substituted gramines [152-154] has been
used rather commonly for the preparation of indolylazoles.
With the exception of benzimidazole, heterocyclic substrates are alkylated only in apro-
tic media such as upon heating in xylene at reflux [150, 151].

R
CVl

R, R* = H, alkyl, alkenyl, acyl, CtH~CH2; R 2 = H, alkyl,

alkoxy, HO, CF,, NH2; R 3 ffiCH3; R2' = (CH2)5 ; Her = imida-
zol-l-yl, pyrazol-l-yl, benzimidazol-l-yl, benztriazol-l-yl
It is noteworthy that in addition to the direct alkylation product in the alkylation of
indole by l-(N-piperidinomethyl)benzimidazole, namely, l-(indol-3-ylmethyl)benzimidazole
(CVI, R =R~ = R 2 = H), 3-(N-piperidinomethyl)indole is formed as the result of a transamination
reaction and benzimidazole is also obtained [149]. On the other hand, the action of indole
Mannich bases on azoles does not yield transamination products.
Greatest interest among indolylazoles CVI is found for substituted l-(indol-3-ylmethyl)-
imidazoles which may be used as drugs in cardiac disease, thromboses, and diabetes-related
vascular problems [153-156].
As noted above, the condensation of ethyl 3-indolylmethylmalonate with hydrazobenzene
leads to 1,2-diphenyl-4-(indol-3-ylmethyl)-3,5-pyrazolidinedione [84]. Subsequently, this
compound was obtained in higher yield by treating the sodium salt of 1,2-diphenyl-3,5-pyra-
zolidinedione by the methylsulfomethylate of gramine in DMF [157].

O~__N/Ce~5

Ind CH2"-NICH3) 3 "~" a~

,. -CH~OSO3Na
CH3OSO s O~ ~CeH s [

Vampilova [157] also indicated that the reaction of gramine itself with 1,2-diphenyl-3,
5-pyrazolidinedione gives exclusively the dialkylation product CVII. The dialkylation reac-
tion is facilitated by an increase in temperature to 160~ and the use of polar aprotic sol-
vents.
O C61L o~ N td~lt~

Ind- CH2N(CII3) 2 4 << I - + -- ,nd-CH2. / ]

O" Cell 5 0<" XC6115

CYI!

125
 The synthesis of 2-amino-4-(indol-3-ylmethyl)-Aa-thiazoline (CVlll) from a-chloromeChyl-
tryptamine hydrochloride and thiourea was carried out in a search for radioprotectlve indole
derivatives [158].

N ' ~ "~ll~
NH~' HCI CVlII

6. THE PREPARATION OF INDOLYLAZOLES FROM OTHER INDOLE DERIVATIVES

Presently, one of the most general methods for the synthesis of various heterocyclic
systems is the 1,3-dipolar cycloaddltion reaction. Despite extensive studies in this area,
the information of the participation of indole derivatives in these reactions has been lim-
ited. The use of indole acid nltriles as dipolarophiles in 1,3-dipolar cycloaddition with
nitrile N-oxides has already been discussed above [i05-i07].
Piozzi and Fuganti [60] have synthesized the corresponding indolylisoxazolines ClX and
CX in the reaction of vinyl 3-indolyl ketone or the ethyl ester of 8-(indol-3-yl)acrylic acid
with benzonitrile N-oxide.
,/CsH 5 C2H500C ~ ./Celts

Ind-"CO~ 0 I d'
r CX

Dyankova [106] has d e s c r i b e d the c y c l o c o n d e n s a t i o n of s e v e r a l s u b s t i t u t e d i n d o l e a l k e n e s

with aromatic n i t r i t e N-oxides to give 4 - s u b s t i t u t e d 3 - a r y l - 5 - ( i n d o l - 3 - y l ) - A 2 - i s o x a z o l i n e s
(CXI) in 17-53% yield.

Ar ~ ...... / R I
Ind'-CH=CRR I + [Ar,-C~N-*Ot D- ~1- [ ' ~ R
N~ 0/'~-..hl d

CXl

R = NO2, CN, COCHs; R I = H, COOCaHs; Ar = Ph, 4-O~NCsH~

A series of indolylisoxazolineswith interesting pharmacological properties was obtained
upon the introduction of the isoxazoline fragment into known indole drugs, namely, dimecar-
bine (5-hydroxy-3-ethoxycarbonyl-l,2-dimethylindole) and oxyfemedol (5-hydroxy-3-ethoxycar-
bonyl-l-phenyl-2-methylindole) [106, 159]. The alkylation of these derivatives at C(,)
yielded the corresponding allyl derivatives CXII. These dipolarophiles were used in the 1,3-
dipolar cycloaddition with aromatic nitrile N-oxides.

CH2~II:CH2 CIt2~Het
H0 I COOC2H5 HO ~" C0VC2H ~
HO.\s~___ [ ~ cOO%H~ " ~" , ....... , ~ [Ar-C~.N-PO] " ~ 2 "~I....... ' ] /

R R R
CXII CXIII

R = CHs, Ph; Ar ffi Ph, 4-02NC~H4, 4-ClC6H~| H e t = 3 - a r y l -

a~-isoxazolin-5-yl
The adducts synthesized in this reaction CXIII inhibit chollnesterase activity and act
as central nervous system stimulators and hypotensive agents.
The cyclocondensation of esters of u-nitro-~-(indol-3-yl)acrylic acid or 2-nitro-1-
phenyl-3-(indol-3-yi)-2-propen-l-one with sodium azide gives 4-substituted 5-(indol-3-yl)-
1,2,3-triazoles (CXIV) [160]. These authors also noted that the presence of electron-with-
drawin~ substituents in the indole ring (5-N02 or I-COCH3) enhances the reaction rate and
the presence of a methoxy group reduces the reaction rate.

126
 ROC~
I i

CXIV

R = CHs0, C2HsO, Ph; R* = H, COCHs; R ~ = H, CHs| R 3 = H, CHsO,

NO2
The 1,3-dipolar cycloaddition reaction of indole aldimines with aromatic nitrile N-ox-
ides was used to synthesize 4-alkyl-3-aryl-5-(indol-3-yl)-A2-oxadiazolines (CXV) [106].
These adducts display pronounced anti-inflammatory activity comparable to that of indometh-
acin.

r~
Ind-CH~-R [Ar-C~.N-~OJ ---~,11- "i-----

CXV

R = CHs, C2Hs, n-CsHT, i = CsHT; Ar = Ph, 4-02NC6H,, 4-C1C6H4

S i g n i f i c a n t i n t e r e s t i s found i n the 1 , 3 - d i p o l a r c y c l o a d d i t i o n i n v o l v i n g i n d o l e n i t r i l e
N-oxides [106, 161, 162]. These N-oxides are r e a d i l y formed i n the d e h y d r a t i o n of the c o r -
r e s p o n d i n g p r i m a r y n i t r o ~ompounds u s i n g p h e n y l i s o c y a n a t e i n the p r e s e n c e of t r i e t h y l a m i n e .
These r e a c t i o n s give good y i e l d s of 3 , 5 - d i s u b s t i t u t e d A 2 - i s o x a z o l i n e s CXVI, among which com-
pounds have been found w i t h a n t i b a c t e r i a l and a n t i f u n g a l a c t i v i t y .

Ar
f
I n d --CH-CHzNO 2 + R--CH:CH 2
%HsNCo md- C H ~
I
ar (CaHs)~N
N'-O./~'-R
c X~,-I

Ar = Ph, 3,4-(CHsO)2C~Hs; R = Ph, 4-CHsC6H., 4-pyridyl, CN,

C00CHs
N-(Indol-3-yl)alkylthiazolines (CXVII) displaying antiactinic activity were synthesized
by the reaction of 2-[ (indol-3-yl)alkylamino]ethanethiols with Rongalite (formaldehyde sod-
ium sulfoxylate) [163].

F--~--
, I ]
ind-,(CH2 ) _NHCH2CH2SH + HOCH2SO3Na ---.p ~d--(CH2)" - - N ~ / ~ S

CX~I

n=2-5
Zhungietu e t a l . [164-167] used i n d o l y l p y r i l i u m s a l t s f o r the s y n t h e s i s of i n d o l a z o l e s .
The r e a c t i o n of 2 , 6 - d i a r y l - 4 - ( 1 - R - i n d o l - 3 - y l ) p y r i l i u m p e r c h l o r a t e (CXVIII) with hydroxylamine
or p h e n y l h y d r a z i n e gave monooxime CXIX or monophenylhydrazone CXX, which upon h e a t i n g in a c e -
t i c a c i d c y c l i z e to give 5 - p h e n a c y l - 5 - ( 1 - R - i n d o l - 3 - y l ) - A 2 - i s o x a z o l i n e s (CXXI) or 5 - p h e n a c y l -
5 - ( 1 - R - i n d o l - 3 - y l ) - A 2 - p y r a z o l i n e s (CXXII). H e a t i n g CXXI or CXXII with a l k a l i in w a t e r - ~ t h -
anol a t r e f l u x gave 3 - a r y l - 5 - ( 1 - R - i n d o l - 3 - y l ) i s o x a z o l e s (XXXIX) or 1 - p h e n y l - 3 - a r y l - 5 - ( 1 - R -
i n d o l - 3 - y l ) p y r a z o l e s (LX), r e s p e c t i v e l y [164, 165].

127
 Ar

........ -ArCOCll~ / .N

XXXIX
Ax Ar
Indl._~x~ 0+ _ CX~X
CXX!
ClO~ Ar Ar
' ' ,l NHCsH~ Ar Ar

/~ ,N
OH . . . .
..........
-ArCOCH~ /~'N"
IIL
~"
CsH5 ma Csl[
I ~
Ar ~'-"0
C~ Ar
CXXI!
Ind ~ = l-methylindol-3-yl, l-benzylindol-3-yl; Ar = Ph, 4-CH~CIH.
Heating hydrazlne hydrate with 4-(l-methylindol-3-yl)flavinlum perchlorate gave 3-phen-
yl-5-(l-methylindol-3-yl)pyrazole (CXXIV) as the flnal product [166].

CsH 9
~CeH5 ._._J~_NHNH 2 CeH~ j.CsH 5

Ind ~ + ~ InclI ---(' 0 ~ ~'N/~" -CsH~OH I

CIO 4 -
/ /OH CXXIV

CXXIII ~._J/
In~ ~ = l-methylindolyl-3
Stupnikova et al. [168-170] have recently established that treatment of the iodomethyl-
ate of 4-(indol-3-yl)pyrimidine (CXXV) under mild conditions with ethanolic KOH gives a quan-
titative yield of the completely stable anhydrobase, l-methyl-4-(3-1ndolinylidene)-l,4-di-
hydropyrlmidlne (CXXVl).

H
CXXV CXXVI

This anhydrobase holds considerable interest as an intermediate in the synthesis of var-

ious heterocyclic indole derivatives including indolylazoles [168-171].
The treatment of CXXVI with hydrazine hydrate in ethanol gave 3(5)-(indol-3-yl)pyrazole
(XXIX), whose formation apparently proceeds by the following scheme [170].

NHNH2 NHNH 2

~ _._~ / , ~ / ~ N - - CH3

It

-CH~N=CHN_"2
11 ,,_/ H
XXlX

The reaction of CXXVI with hydroxylamine in acetonitrile gives a low yield of 3-(indol-
3-yl)isoxazole [171].
In conclusion, we note that two new indolylazoles were recently isolated from natural
substances, whose structures were established by chemical and spectral methods. One of these
compounds was identified as 2-imino-l,3-dimethyl-5-(indol-3-ylmethylene)-4-pyrazolidinone
(CXXVlI) [172], while the other was identified as 3-dimethylamino-5-(indol-3-ylcarbonyl)-l,
2,4-thiadiazole (CXXVIII) [173].

128
 , ~ -N(CH~)2

f lnd-CO' S

CH~ CXX~'II!
C~'VII

However, information on the synthesis of these compounds has not appeared in the liter-
a ture.

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QUANTUM-CHEMICAL TREATMENT OF RECYCLIZATION REACTIONS.

9.* PHOTOISOMERIZATION OF FIVE-MEMBERED HETEROCYCLES

Yu. B. Vysotskii and L. N. Sivyakova UDC 541.141:539.196:547.72'77'78

The pho~oisomerization of a number of five-membered heterocycles has been con-

sidered in the framework of the coupled variant of perturbation theory for a
one-electron transition density matrix in the n-electronic approximation of the
MO--LCAO-SCF method.

A method for describing photochemical reactions of the X type in Dougherty's terminology

[3], one of whose main steps is photoelectrocyclic contraction or ring formation, we developed
in [2]. In such reactions the energy of the light is utilized only for bringing the reactant
into an excited state and is not converted into the thermal energy needed for overcoming the
activation barrier, spent on light-induced electron transfer, etc. In this case, the reactiv-
ity is determined mainly by the changes in the electronic structure of the molecule upon ex-
citation and is, therefore, more easily subjected to quantum-chemical treatment.
Without dwelling in detail on the problem of using the index approach for the description
of the reactivity of molecules in electronically excite~ states (see, for example, [4, 5]), as
well as on the alternative method of correlation diagrams (see [3, 6-8], etc.) in the case of
electrocyclic reactions, we note only that expressions for the reactivity indices of such re-
actions, wfiich were obtained on the basis of the coupled variant of perturbation theory for a
transition density matrix in the PPP method [9], were presented in [2]. Here the perturbation
may be characterized as intramolecular coupling (see [3]), and the perturbation matrix is rep-
resented by the following matrix elements:

(H~)~= ( ~ 6 ~ + 6 ~ h ~ ) ~ . (1)
Then from the expression for the change in the n-electronic energy of the ground state in
first-order perturbation theory with respect to ASik

6Eih ~ = 2 P ~hA~ik (2)

it follows that in the ground state the bond orders between the not directly bonded atoms
Pik can serve as the reactivity indices in intramolecular recyclization and cyclization re-
actions.

*For report 8 see [i].

Institute of Physical Organic Chemistry and Carbon Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 3 4 0 1 1 4 . Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
2, pp. 173-180, February, 1986. Original article submitted July 31, 1984.

0009-3122/86/2202-0133512.50 9 1986 Plenum Publishing Corporation 133

 When a molecule undergoes a transition to an excited state, the change in the ~-elec-
tronic excitation energy in first-order perturbation theory with respect to ABik may be writ-
ten for the slnglet states in the form [9] (Eq. 15.88)

6Ei: = 2, Tr {Hm YD 2+ O (Yik) Y D~+ [ D, O (D) ] _ Y r~h} = 2 K~:A,~h, (3)

and for triplet transitions calculated in the Tamm-Dankov approximation, in a similar manner
we obtain
6E~,J= Tr {2ItmYD2+2G (r~h) YD2+ [O, O ( D ) ] _.YY~,, + [G ( D r ) , D]_.Yr = 2K~,TA,~m, (4)

where D is the unperturbed transition density matrix corresponding to the excited state un-
der consideration, Yik is the matrix of bond--bond mutual polarizabilities, which reflects
the change in the electronic structure in the ground state under the action of perturbation
(i), and supermatrix G describes the interelectronic interaction.
In [2] it was shown in the example of the photochemical ring-contraction reaction of
furan that the main contribution to the indices Kik is made by the changes in the long-range
bond orders AP*ik upon excitation of the molecule. The latter were used for the treatment
of photochemical, particularly, di-~-methane, rearrangements [10, ii]. The arguments in sup-
port of the use of AP*ik are based on the correspondence between these quantitites (see [ii])
and the location of the excitation energy in a molecule, its redistribution during a reaction,
and its conversion into the vibrational energy of the ground state. The bond orders in elec-
tronically excited states, which are generally calculated according to the HUckel method,
served as photoelectrocyclization indices in [12, 13]. Several quantities whichare directly
or indirectly related to them were used in [13-15]. The use of the sum of the free valences
of the positions at which cyclizatlon occurs, Mulliken populations~ including transition pop-
ulations, or localization energies ~of course, in a given excited state) as reactivity in-
dices is less substantiated and gives a poorer description than do AP*ik (see~ for example,
[16, 17]).
In the present work we examined the relationship between the indices Kik and the occur-
rence of the photoisomerization of several five-membered heterocycles in the PPP approxima-
tion.
i. Table 1 presents the indices for the four lowest singlet and triplet states of fur-
an, pyrrole, and thiophene. From the data presented it follows that the transition of a
molecule to the excited states is generally accompanied by weakening of the bonds between
the directly bonded atoms and strengthening of some of the bonds between the not chemically
bonded atoms. In the cases in which this strengthening (increase in the coefficients Kik)
is so great that the sum of the indices Pik and Kik becomes positive (see [2]), photoelectro-
cyclic contraction of the heterocycle, which is the first step in its further conversions,
should occur at positions i and k.
For example, from the data in Table 1 (see also [2]) it follows that the photorecycli-
zation of the furan molecule in the S, and T2 states should take place with the formation of
acylcyclopropene intermediate Ill, and in states $2 and T, it should involve the formation
of intermediate IIa followed by its isomerization to IIb, etc.
Scheme 1
L 2

s '>: ';: x ' 2 ,,

"o'( ". . . . . . . " . . . . . . "%o~ ' ' ...... "o~
I III i ~ + CO

,:-,.i:>--, "i,,
Ila II b II C II d

- . /
"o[ "O] o I

134
 The occurrence of a reaction along path a, especially in the T= state, has been thor-
oughly studied [6, 18-22]. Sensitization by mercury [Hg(SPz)] gives a steady yield of CO
and C3H4, which is large in comparison to the direct irradiation of furan. The latter find-
ing is consistent with the fact that K=,4 S < K=,4 T. There are still no experimental data on
the photoisomerization of furan in the $3 and Tz states (path b).
2. An analysis of the values of Kik for the pyrrole molecule (Table i) reveals that
in the Sx state, in contrast to the case of furan, isomerization should not occur owing to
the fact that IK=,4SI < [P=i4J and IK=,,Sl < IP=,sI. In the second triplet state iK=,4TI >
IP=,~I; however, the 2--3 (4--5) bonds are weaker than the 1--2 (i--5) bonds (see Table i). This
circumstance should result in the photolytic cleavage of these bonds with the evolution of
acetylene as the reaction product. In fact, when unsubstituted pyrrole was irradiated in the
gaseous phase (Sz), decomposition products, in particular, acetylene, were discovered [23].
It should, however, be stressed, that the presence of strong electron-donor or acceptor
substituents in a molecule can cause changes in the relationship between the Pik and the Kik
and, as a consequence, the corresponding photoisomerization [19, 22, 24]. In this case, the
direct participation of the atoms of functional groups, for example, of the nitro group [25],
in the isomerization process is possible. A radical mechanism with subsequent recombination
of the radicals has likewise not been ruled out [26].
According to the data from the calculation, the photoisomerization of pyrrole in the
second singlet and first triplet states should be similar to that of furan (path b).

Scheme 2
2 3 4
5
5
@ 3

I 5 _.

I x\C, /
9 "-3 4 . f,,~_ 2 ..J
1 \~ //
[, 4
Ya ~'b vc

(%)

"s~ S2(TI) * VI

,v -sit

fr i "2

st" \ sli

3. As follows from the data in Table i, the photoisomerization of the thiophene mole-
cule (IV) in the T= state should involve the formation of 1--3 and 2--4 (or i--4 and 3--5) bonds
(paths a and b in Scheme 2), i.e., the intermediate formation of a Weinberg zwitterionic tri-
cyclic intermediate [27]. A similar picture is also observed in the SI state. A structure
of type V implies the active participation of the d orbitals of the sulfur atom [18, 19, 22],
and, in fact, without consideration of the d orbitals the positive long-range orders of the
I--3 (i--4) bonds do not appear.
We note that, in contrast to the case of furan, cyclopropene was not discovered either
upon the direct irradiation (Sz state) or upon the sensitization (Tz) of thiophene vapor [28].
Finally, as follows from Table l, in the case of the S= and Ti states, recyclization
should involve the intermediate formation of a structure of type VI along path d in Scheme 2.

135
 TABLE i. Reactivity Indices in Photoisomerization Reactions
of Five-Membered lieterocycles

Compound State K*I,2 K2,3 K3,4 A'L,3 A'2,4 h'2 ,~

Furan So 0,442 0,763 0,5% 0,205 0,105 - 0,459

S, - 0,075 -- 0,386 -0,270 0,117 0,t31 0,254
$2 -- 0,205 - 0,205 0,070 0,058 0,032 0,864
Tt -0,187 -0,370 0,189 0,088 0,033 0,747
T~ -0,021 -0,474 -0,666 0,078 0,i70 0,16I
Pyrrole So 0,501 0,740 0,60.9 0,227 0,128 - 0,424
S, -O, lOI -0,354 -0,284 0,165 0,101 0,262
$2 -0,223 -0,314 0,091 0,071 0,036 0,849
T, - 0,196 - 0,356 0,107 0,090 0,024 0,757
T2 0,001 - 0,541 - 0,07 l 0,052 0,401 0,075
Thiophene So 0,627 0,715 0,635 0,315 0,028 - 0,400

St -0,101 -0,275 -0,211 0,344 0,001 0,348

$2 - 0,241 - 0,282 --0,180 0,122 0,011 0,732
Ti -0.243 9 0,102 0,112 0,003 0,736
7'2 -0,018 -0,070 -0,831 0,375 0,064 0,092

*The corresponding Pik are given for the ground state So.

TABLE 2. Reactivity Indices in Photoisomerization Reactions

of Azoles

Compound State A'*I,3 K,,4 /(2,4 K2,~ Ks~

Oxazole So -0,201 -0,184 -0,167 - 0,446 -0,108

S, 0,209 -0,008 0,460 0,365 -0,131
$2 -0,005 0,155 -0,111 0,713 0,280
TL 0,087 0,082 0,076 0,762 - 0,030

T~ 0,035 0.052 0.465 0,036 0,367

Imidazole So -0,223 -0,204 -0,188 -0,409 -O,131
S, 0,208 0,018 0,431 0,356 -O, IIO
S~ 9 0,007 0,175 -0.079 0,686 0,256
Tt 0,094 0,096 0.079 0,750 -0,025
T2 0.028 0.052 0,500 0,043 0,372
Thiazole So -0.312 - 0.274 --0,094 --0,4O0 --0,040
St 0,326 0.292 0.212 0,348 -- 0,056
$2 0,195 0.230 0,054 0,544 0,037
Tz 0,128 0,146 0,061 0,726 -0,050
T2 0,361 0,252 0,497 0,175 -0,175
Isodazole So -0.190 -0,240 -D,136 -0,390 " 0,051
St 0,26 I 0.158 0,257 0,489 - 0,478
-- 0,045 0.201 - 0,064 0,493 0,347
T, 0,086 0.184 0,070 0,763 -0,150
T2 0,059 0,176 0,302 0,039 0,II0
Pyrazole So --0,241 - 0,238 --0,179 --0,378 --0,014
St 0,358 0,208 0,189 0,352 --0,456
$2 --0,153 0,282 --0,024 0,559 0,355
Tt 0,092 0.058 0,180 0,758 - 0,064

T2 0,305 0,125 0,535 0,047 -0,102

Isothia- So -0,291 -0,350 -0,058 - 0.386 0,065
zole St 0,514 0,500 0,067 0,344 -0,3t0
$2 - 0,068 0,207 --0.107 0.672 0,201
T~ 0,070 0.196 0.055 0,742 - 0,080
T2 0,332 0,604 --0,127 0.144 -- 0,035

*The corresponding Pik are given for the So ground state.

There are still no experimental data on the reactions of thiophene derivatives in these
states. Nevertheless, in the case of the $I and T2 states, Scheme 2 is confirmed by all the
data available in the literature (see monographs [19, 22, 29] etc.).
4. Table 2 presents the indices Kik and Pik for photoisomerization reactions of azoles.
It is seen that the isoxazole molecule (VII) should readily isomerize to oxazole, the value
of Pik + Kik in the S, state being greater than 0 for both the 2--4 bond and for the 2--5 and
1--3 bonds. When the weakness of the i--2 bond is taken into account, this implies the pos-
sibility of the occurrence of a reaction both along the ring-openinE-contraction--formation

136
path and along the path of intramolecular cyclization with isomerization (with the intermed-
iate formation of IX and X) or isomerization with the formation of a zwitterionic tricyclic
intermediate. However, as follows from the calculation, the main reaction path should in-
volve the intermediate formation of azirine VIII (path b, Scheme 3).
Path b should also be predominant in the T2 state, although there is already another
isomerization path with cyclization at positions 3 and 5, which, incidentally, does not re-
sult in isomerization to oxazole.
Since the values of Pik + Kik for the S, state of molecule VII are significantly greater
than zero, the introduction of suhstituents should not alter the predominant direction of the
reaction. Experimental data confirming the conclusions drawn are found in monographs and re-
views [19, 22, 29, 30] and the literature cited therein.
The isomerization of isoxazole (VII) to oxazole (XI) is reversible, photoisomerization
through azirine intermediate VIII (Scheme 4, path a) being preferable for the oxazole mole-
cule in the S, and T2 states, according to the data from the calculation.
As is seen from Table 2, in contrast to the case of the $2 and T, states, bonding be-
tween positions 2 and 5 (the formation of intermediate Xlll) should not occur in this reac-
tion, in agreement with the data from the experiment and the nonempirical calculations with
consideration of the configuration interaction in [31]. In the second triplet state the re-
action can follow path b in Scheme 4 with the intermediate formation of XII.
The influence of the functional groups on lthe direction of the photoisomerization of ox-
azole is more pronounced than in the case of isoxazole, although the value of P2~ + Ka~ in
the S, state is fairly high. From the calculation in [22] it follows that the introduction
of phenyl and/or methyl groups into positions 2 and/or 5 of the oxazole ring results in in-
itial electrocyclization at positions 2-5 (intermediate XIII). it is curious that not only
substituents, but also the reaction conditions, particularly the solvent, have a significant
influence. For the experimental data on this reaction see [19, 22, 29, 30, etc.].
Scheme 3
%_._N 2 -, 5
);,
Oi OT O1

i,, ..~ . . . . %
"F--:r~"
.....
0

:_ J
IXa LX, b 'IX C md
a I $1{$2'T1)
. O

o'1 ~ s~(r2)
N'% ''~ -"; " o~
VII VIII

"1 '~ ('r:t)

Xa
i --~o
x~b
~/---~
xc xd

4/___N2 4 N Z /
2
o~ o %(

The photoisomerization of pyrazole XIV is distinguished from the isomerization of isox-

azole by the fact that in this case, according to the data in Table 2, electrocyclization at
positions 1 and 3 (intermediate XV), rather than at 2 and 4 (intermediate XVI), is predomin-
ant in the S, state, while the reaction should proceed predominantly by means of bonding be-
tween positions 2 and 4 in the T2 state. We stress that, although this mechanism differs
somewhat from that adopted in [22], it gives the same products, as is seen from Scheme 5.

137
 The photoisomerlzatlon paths of pyrazole in the S= and T, states are not presented in
the scheme, since there are no experimental data on these reactions. With respect to the
reverse isomerlzation of imidazole to pyrazole, it follows from the calculated data that it
should be completely analogous to the isomerization of oxazole.
Scheme 4

3
2 3 01
xx .... . b vm

i
c, s2(r,), ~
..........
"" ~
If
o~
~ ..N3

4 'o'i

7 .._N 3
2 ..... m.,,.
-- OI
9......... N
......
. . . . . . e,,.. # %,

5 4
F %__!.~

Scheme 5
3
---~?/N r=(s~) ~ N2
5 ab-
It 5 ~ 5 C~,~3
M Ht ~I
X]V X~

blS~(rD
'" ~' '~N"1 4" N2 3

2 It
L s ,j

L N2
-<>3 N~
4 __N? 4 5

1t 1t It

As was noted in [22], at the present time 95% of all the isomerization products of iso-
thiazole and thiazole in the lowest singlet state (see [19, 22, 29, 32, 33]) can be explained
either by a tricyclic zwitterionic mechanism or by an intramolecular cyclization-isomerization
mechanism. In the framework of the scheme developed here, this is manifested by the presence
of large positive values of Kik S for the 1--3, 1-4, and 2-4 positions of thiazole and isothia-
zole in the lowest singlet state (see Table 2). The possible photorecyclization paths of the
S, state of isothiazole (XVlI) under the assumption of a bicyclic transition complex are pre-
sented in Scheme 6. As we have already stated above, the predominance of a particular tran-
sition state is greatly dependent on the nature of the substituents and the reaction condi-
tions.

138
 Scheme 6

,, ~ 3 -N 2

~'~/:' s~(T2) sl
XWI[

bi ,N~(T2 )

4 --N ?

According to the calculated data, in the $2 and T, states this reaction should involve
bonding between positions 2 and 5. We note that the existence of large positive values of
K,,~ s for the S, state is also an indication of the possibility of the elimination of an HCN
fragment with the formation of a potentially antiaromatic C=H2S system. Photoreactions of
this type were studied in [34].

LITERATURE CITED
i. Yu. B. Vysotskii, B. P. Zemskii, T. V. Stupnikova, V. N. Kalafat, R. S. Sagitullin, and
B. P. Marshtupa, Khim. Geterotsikl. Soedin., No. 9, 1277 (1982).
2. Yu. B. Vysotskii and L. N. Sivyakova, Zh. Strukt. Khim., 21, 164 (1980).
3. M. J. S. Dewar and R. C. Dougherty, The PMO Theory of Organic Chemistry, Plenum Press,
New York (1975).
4. G. M. Zhidomirov, A. A. Bagatur'yants, and I. A. Abronin, Applied Quantum Chemistry [in
Russian], Khimiya, Moscow (1979).
5. R. Zagradnik and R. Polak, Zaklady Kvantove Chemie (Principles of Quantum Chemistry),
XNTL, Prague (1976).
6. J. A. Barltrop and J. D. Coyle, Excited States in Organic Chemistry, Wiley, London (1975).
7. J. Michl, in: Chemical Reactivity and Reaction Paths, G. Klopman (ed.), Wiley, New York
(1974), Chap. 8.
8. D. O. Cowan and R. L. Drisko, Elements of Organic Photochemistry, Plenum Press, New York--
London (1976).
9. M. M. Mestechkin, Density Matrix Method in Molecular Theory [in Russian], Naukova Dumka,
Kiev (1977).
i0. H. E. Zimmerman and T. R. Welter, J. Am. Chem. Soc., i00, 4131 (1978).
ii. H. E. Zimmerman and R. I. Pasteris, J. Org. Chem., 45, 4876 (1980).
12. E. E. Weltin, J. Am. Chem. Soc., 95, 7650 (1973).
13. C. Minor, P. Roland-Gosselin, and C. Thai, Tetrahedron, 36, 1209 (1980).
14. K. A. Muszkat, G. Seger, and S. Sharafi-Ozeri, J. Chem. Soc., Faraday II, No. 9, 1529
(1975).
15. S. El-Basil and R. Hilal, Bull. Chem. Soc. Japan, 51, 2749 (1978).
16. J. Sauer, U. Ladhoff, and H.-G. Henning, Ztschr. Chem., 16, 370 (1976).
17. M. Scholz, F. Dietz, and M. M~hlstadt, Usp. Khim., 38, 93 (1969); Z. Chem., 7, 329 (1967).
18. A. Lablache-Combier and M.-A. Remy, Bull. Soc. Chim. France, No. 2, 679 (197~).
19. A. Lablache-Combier, in: Photochemistry of Heterocyclic Compounds, O. Buchardt (ed.),
Interscience, New York--London-Sidney (1976), p. 123.
20. H. Hiraoka, J. Phys. Chem., 74, 574 (1970).
21. E. Poquet, A. Dardelog, and M. Chaillet, Tetrahedron, 32, 1729 (1976).
22. A. Padwa, in: Rearrangements in Ground and Excited States, Vol. 3, P. de Mayo (ed.),
Academic Press, New York (1980), p. 501.
23. E. C. Wu, J. Am. Chem. Soc., 93, 3432 (1971).
24. H. Hiraoka, Chem. Comm., No. 24, 1610 (1971).
25. R. Hunt and S. T. Ried, Chem. Comm., No. 22, 1576 (1970).
26. H. Hiraoka, Chem. Comm., No. 20, 1306 (1970).
27. H. Wynberg, R. M. Kellogg, H. van Driel, and G. E. Beekhuis, J. Am. Chem. Soc., 89,
3501 (1967).

139
28. H. A. Wiebe and J. Heicklen, Canad. J. Chem., 47, 2965 (1969).
29. H. C. Van der Plas, Ring Transformations of Heterocycles, Vol. i, Academic Press, London--
New York (1973).
30. S. T. Reid, Adv. Heterocycl. Chem., ii, i (1970).
31. H. Tanaka, T. Matsushita, and K. Nishimoto, J. Am. Chem. Soc., i05, 1753 (1983).
32. M. Kojima and M. Marda, Chem. Comm., No. 6, 386 (1970).
33. M. Ohashi, A. Jio, and T. Yonezawa, Chem. Comm., No. 8, 1148 (1970).
34. A. Krantz and J. Lanreni, J. Am. Chem. Soc., 99, 4842 (1977).

SYNTHESIS OF 5-SUBSTITUTED CYANOFURANS AND THEIR REACTION WITH HYDRAZINE

P. A. Pavlov and V. G. Kul'nevich UDC 547.72:543.422.25+547.792.1'

722.2+547.882'722.2

Based on the Schmidt reaction, a new method has been developed for the prepara-
tion of nitriles in furan series from the corresponding furfural derivatives.
Depending on conditions, the reaction of 5-substituted cyanofurans with hydra-
zinc leads to amidrazones, N-aminotriazoles, or 1,2,4,5-dihydrotetrazines.

The known methods for the preparation of cyanofurans from furancarboxaldehydes [1-6]
have several disadvantages: multiplicity of stages, difficulties related to the regeneration
of the reagents, limited number of suitable methods, because of scarcity of starting mater-
ials, as well as impossibility of their use for the preparation of individual compounds, for
example, 5-nitro-2-cyanofuran [5].
For this purpose we used the Schmidt reaction [7], considered to be unsuitable for the
preparation of nitriles of the furan series. Instead of sulfuric, phosphoric, hydrochloric
and other mineral acids, and also Lewis acids [7], we used 72% perchloric acid, with which it
was possible to avoid resinification of furancarboxaldehydes, but the yield of the nitrile did
not exceed 50%. When anhydrous magnesium perchlorate was introduced, it was possible to re-
duce the amount of perchloric acid to catalytic quantities, and thus the yield of products
I-XXI increased to 76-96%, while the time of the reaction was shortened.

S
R O C ~NH R ~* .... ~/ ~-- ~R
~NHNH2 H H
XXII,XXIII ~"VII - X ~

I, XXIV, XXVll R = H, II, XXV, XXVll R = CHs, III R = C6Hs, IV

R = --C -~ CC~Hb, V, XXII, XXVl, XXIX R = Br, VI R = I, VII, XXIII
R = NO2, VIII R = CH2CI, IX R = 4-C6H~NO~, X R = 4-OC6H~CHs, XI
R = OC6H4CI, XII R = SCHs, XIII R = SCHzCOOC2Hb, XIV R = 2,4-
SC~Ha(NOa)z, XV R = 5-thio-2-cyanofuran, XVl R = 5-thio-2-oxo-
furan, XWll R = S~-C,Hs, XVIII R = 3-S~-C,H4Br, XIX R = thio -

furo-5-yl, XX R -- SO2C6Hs, XXI R = 4-SO2C,H~CHs

Krasnodar Poiytechnical Institute, Krasnodar 350700. Translated from Khimiya G e t e r o -

tsiklicheskikhSoedinenii, No. 2, pp. 181-186, February, 1986. Original article submitted
July 13, 1984; revlsion submitted April 16, 1985.

140 0009-3122/86/2202-0140512.50 9 1986 Plenum Publishing Corporation

28. H. A. Wiebe and J. Heicklen, Canad. J. Chem., 47, 2965 (1969).
29. H. C. Van der Plas, Ring Transformations of Heterocycles, Vol. i, Academic Press, London--
New York (1973).
30. S. T. Reid, Adv. Heterocycl. Chem., ii, i (1970).
31. H. Tanaka, T. Matsushita, and K. Nishimoto, J. Am. Chem. Soc., i05, 1753 (1983).
32. M. Kojima and M. Marda, Chem. Comm., No. 6, 386 (1970).
33. M. Ohashi, A. Jio, and T. Yonezawa, Chem. Comm., No. 8, 1148 (1970).
34. A. Krantz and J. Lanreni, J. Am. Chem. Soc., 99, 4842 (1977).

SYNTHESIS OF 5-SUBSTITUTED CYANOFURANS AND THEIR REACTION WITH HYDRAZINE

P. A. Pavlov and V. G. Kul'nevich UDC 547.72:543.422.25+547.792.1'

722.2+547.882'722.2

Based on the Schmidt reaction, a new method has been developed for the prepara-
tion of nitriles in furan series from the corresponding furfural derivatives.
Depending on conditions, the reaction of 5-substituted cyanofurans with hydra-
zinc leads to amidrazones, N-aminotriazoles, or 1,2,4,5-dihydrotetrazines.

The known methods for the preparation of cyanofurans from furancarboxaldehydes [1-6]
have several disadvantages: multiplicity of stages, difficulties related to the regeneration
of the reagents, limited number of suitable methods, because of scarcity of starting mater-
ials, as well as impossibility of their use for the preparation of individual compounds, for
example, 5-nitro-2-cyanofuran [5].
For this purpose we used the Schmidt reaction [7], considered to be unsuitable for the
preparation of nitriles of the furan series. Instead of sulfuric, phosphoric, hydrochloric
and other mineral acids, and also Lewis acids [7], we used 72% perchloric acid, with which it
was possible to avoid resinification of furancarboxaldehydes, but the yield of the nitrile did
not exceed 50%. When anhydrous magnesium perchlorate was introduced, it was possible to re-
duce the amount of perchloric acid to catalytic quantities, and thus the yield of products
I-XXI increased to 76-96%, while the time of the reaction was shortened.

S
R O C ~NH R ~* .... ~/ ~-- ~R
~NHNH2 H H
XXII,XXIII ~"VII - X ~

I, XXIV, XXVll R = H, II, XXV, XXVll R = CHs, III R = C6Hs, IV

R = --C -~ CC~Hb, V, XXII, XXVl, XXIX R = Br, VI R = I, VII, XXIII
R = NO2, VIII R = CH2CI, IX R = 4-C6H~NO~, X R = 4-OC6H~CHs, XI
R = OC6H4CI, XII R = SCHs, XIII R = SCHzCOOC2Hb, XIV R = 2,4-
SC~Ha(NOa)z, XV R = 5-thio-2-cyanofuran, XVl R = 5-thio-2-oxo-
furan, XWll R = S~-C,Hs, XVIII R = 3-S~-C,H4Br, XIX R = thio -

furo-5-yl, XX R -- SO2C6Hs, XXI R = 4-SO2C,H~CHs

Krasnodar Poiytechnical Institute, Krasnodar 350700. Translated from Khimiya G e t e r o -

tsiklicheskikhSoedinenii, No. 2, pp. 181-186, February, 1986. Original article submitted
July 13, 1984; revlsion submitted April 16, 1985.

140 0009-3122/86/2202-0140512.50 9 1986 Plenum Publishing Corporation

 In the preparation of compounds X and XI, the use of perchloric acid as the catalyst led
to the resinification of the reaction mixture, but when HCIO4 was used in the form of diox-
anium perchlorate, they could be obtained in a yield of 69-76%. The characteristics of the
previously known compounds I-III, V, VII, IX, XX, XXI correspond to those described in [1-6],
but their yields are 10-15% higher, and the yield of 5-nitro-2-cyanofuran even increased from
50 to 92%.
In the IR spectra of the compounds synthesized, the characteristic absorption bands of
the stretching vibrations of the CN group are present in the region of 2244-2205 (I-XXI),
C=O at 1780-1680 cm -I (XIII-XIX) the COC grouping (X, XI) absorbs at 1260, 1230, and S02 at
1340, 1150, and 1130 cm -I (XX, XXI). Compounds IV, VIII, X-XIX were synthesized for the
first time, and their characteristics are given in Table i.
The reaction of different nitriles with hydrazine with the formation of amidrazones,
aminotriazoles, and tetrazines has been discussed fairly comprehensively in [8-10], but there
is no information on the reaction of furan nitriles.
Our studies showed that the direction of the reaction depends on the conditions under which
it is being carried out, while the stability of the desired end products depends on the nature of
the substituent at the 5-position of the furan ring (Table 2). The reaction of 5-bromo- and
5-nitrocyanofurans with an alcoholic solution of hydrazine leads to the corresponding amidra-
zones, and that 2-cyanofuran and 5-methyl-2-cyanofUran, to unstable products, which could not
be isolated.
Heating of 5-R-2-cyanofurans with an excess of hydrazine hydrate gave 4-amino-3,5-di(5-
R-2-furyl)-l,2,4-triazoles (XXIV-XXVI) in a high yield. In boiling alcohol in the presence
of sulfur, 3,6-di(5-R-2-furyl)-l,2-dihydro-l,2,4,5-tetrazines (XXVII-XXIX) are formed. 5-
Nitro-2-cyanofuran, which resinifies under the above conditions, is an exception.
In the IR spectra of triazoles XXIV-XXVI there are two stretching vibration absorption
bands at 3350-3325 and 3150 cm-* of the primary amino group, and two deformational vibration
bands at 1665-1645 and 1610 cm-*. The IR spectra of dehydrotetrazines XXVII-XXIX are char-
acterized by the presence of one single stretching vibration band of the secondary amino
group in the 3320-3330 cm-* region, and one deformational vibration band at 1740-1770 cm -I.
In the PMR spectra of compounds XXIV-XXIX, the signals of the NH and NH2 group protons
are recorded as a broadened singlet, which disappears during deuteration.
When 3,6-di(2-furyl)-l,2-dihydro-l,2,4,5-tetrazine (XXVII) is heated in pyridine in
the presence of copper sulfate, 3,6-di(2-furyl)-l,2,4,5-tetrazine (XXX) is formed in 81%
yield, while the corresponding 4-amino-3,5-di(2-furyl)-l,2,4-triazole (XXIV) is isolated un-
changed.

EXPERIMENTAL
The IR spectra were run on a UR-20 spectrophotometer in mineral oil. The PMR spectra
were recorded on a Tesla BS-467 spectrometer (60 MHz) for compounds I, II, V, VII, X, XI in
(CD3)2CO; for III-VI, VIII, IX, XII-XXI in CCI~, and for XXV and XXVIII in CDCI3, using
HMDS as internal standard. The spectra of the remaining compounds were recorded in DMSO-D6,
using t-BuOHas internal standard. The purity of the compounds synthesized was checked by
chromatography of Silufol in a 3:20 ethanol--toluene system.
The benzene solution of hydrazoic acid was in all cases prepared by the method described
in [7].
5-Substituted-2-cyanofurans (I-XXI). A 6.7 g (0.03 mole) portion of anhydrous magnesium
perchlorate is added to a mixture of 0.i mole of furancarboxaldehyde and 0.ii mmole of a ben-
zene solution of hydrazoic acid, and then 1.4 ml (0.01 mole) of 72% perchloric acid is added
dropwise, with stirring, at 35~ The rate of addition is controlled by the current of lib-
erated nitrogen, which should be rapid, but not violent. At the end of the evolution of nit-
rogen, the mixture is treated with water, the benzene layer is separated, washed once more
with water, and dried over sodium sulfate. Benzene is removed under reduced pressure, and
the residue is distilled in vacuo or recrystallized from alcohol. Compound XVI is recrystal-
lized from CCI~ and VII from a mixture of chloroform and cyclohexane.
Compounds X and XI are prepared in a similar way, but instead of perchloric acid, a
previously prepared dioxaniumperchlorate is used [5 ml of 1,4-dioxane and 1.4 ml (0.01 mole)
of 72% perchloric acid].

141
 TABLE i. Cyanofurans I-XXI

Com- oMPc[Bp]j PMR spectrum, ppm SSCC) Hz

pound" (Ira) .,,, d,,0 .....
8-H 4-H " R J R:' ,t R4 Ja4

7,82 d ),75 1,8

I 2,32 s
II 7,47 m.
I% 7,33 m
%
V:
Vl!
VII: 4,48 s
8,05 m

H'H" = I 0 , 0

7,03 ',
XI 6,97 (d, H');
7,27 (d, H") j.--,., i 9,0
XII 2,45 (s)
XIII 1,02 it, CH~);
4,08 (,q,, CH~O)
-I:
J CH,~CHa-- 7,0
3,51 (s, C H 2S)
XIV 7,60 O )
XV
XVI H
wt
H
f -- I --
! 'H'"N = 1,75
O It m J.H,. H =2,00
6,40 It, H'"); I.H... u = 5,50
6,10 (dd, H");
7,67 (dd , H')
XVII 7,68 (m)
XVIII 6,60 (m)
XlX ,,"
H~'H4' : 37
HJHs' = 2,0
I H~'H~'= 0,75

-j-
7,44 (d, H~');
6,55 (q , H4') ;
7,58 (d, 1{5')
XX ,7,55 (q. 7,85 (m)
an r i n g
tern pro-
H,,~H~ S02

XXI 7,51 ( q, 2,38 ~, CH3);

m ring 7,40 ~, H); =8,o
i~m pro- 7,85 (d, H)

Amidrazones XXlI, XXIII. A 0.5 ml (0.01 mole) portion of hydrazine hydrate is added to
a mixture of 0.01 mole of cyanofuran V, VII in 10 ml of alcohol. The mixture is stirred,
and left to stand overnight. The alcohol is distilled off under reduced pressure, and the
residue is recrystallized from CCl~ (XXiI) and CHCl, (XXIII).
4-Amino-3~5-di(5-K-2-furyl)-l,2,4-triazole (XXlV-XXVI). A mixture of 0.i mole of 5-R-
2-cyanofuran and 40 ml (0,8 mole) of hydrazine hydrate is boiled for 3 h in a nitrogen cur-
rent, then cooled, the crystals are filtered, washed with water and recrystallized from CHCI3,
3-6-Di(5-R-2-furyl)-l)2-dihydro-l)2,4,5-tetrazines (XXVII-XXIX). A mixture of 0.i
mole of 5-R-2-cyanofuran, 30 ml of ethanol, 30 ml (0.6 mole) of hydrazine hydrate

142
 Calculated, %
Found, % Empirical Yield, %
formula
S H N (2al)
H N (Hal)

34,5 %3 15,0 CsH3NO M,5 %3 5,0 -- 76

77,0 5,3 14,8 -- CsHsNO Z7,0 5,2 4,8 -- 82

70,0 8,3 -- C,,HzNO r8,0 f,2 8,3 -- 84

~0,2 3,5 7,1- -- C,3HzNO ~0,2 3,6 7,8 94
34,8 1,2 8,4 16.5) CsH~BrNO 34,8 I,l 8,3 16,5 78
27,3 ~,9 6,3 i7,7) CsH=INO .)7,4 %9 6,4 i7,7 85
43,5 1,4 20,3 -- CsH~N~O~ 13,5 1,4 !0,3 -- 92
50,6 2,7 9,8 ~5.2) C6H,CINO ~0,7 2,8 9,8 -)5,3 96
52,8 2,8 13,3 -- C,tH6N20~ i2,8 2,7 :3,3 -- 80

72,2 4,5 C,2HgNO2 72,4 4,5 7,0 -- 69

50,0 2,6 6,4 16.4) CItH,CINO2 60.0 2,7 6,4 16,4 76

51,7 3,5 10,0 23,0 CsHsNOS 51,8 3,6 [0,0 23,0 79

53,4 4,3 6,8 15,8 CgH~NO3S 53,4 4,4 6,9 15,8 78

45,3 1,7 14,4 10,9 C,,HsN3OsS 45,3 1,7 4,4 10,9 93

55,4 1,7 12,8 14,8 C,oH4N202S. 55,5 1,8 [2,9 14,8 92
52,1 2.3 6,7 15,4 CgHsNO.S 52,2 2,4 6,7 15,4 89

62,8 2,(. 6,1 13,9 C,~HTNO2S 62,9 3,0 6,1 14,0 90

46,7 1,~ 4,5 10,3 CI~HsBrNO~S 46,7 1,9 4,5 10,4 91
25,9: - 26,0)
54,7 2fi 6,4 14,5 C,oHsNO3S 54,7 2,3 6,4 14,6 90

58,4 2,4 6,0 13,6 C.HTNOsS 58,6 3,C 6,0 13,7 98

59,0 2,~ 5,7 13,0 Cj~H6NOaS 59,( 2,4 5,7 13,1 98

and 2 g of sulfur is boiled in a nitrogen current. After 2 h, crystals begin to sep-

arate. After heating for 1 more hour, the mixture is treated as described above. Compounds
XXVII, XXVIII are recrystallized from chloroform, XXIX from toluene.
3,6-Di(2-furyl)-l,2,4,5-tetrazine (XXX). A mixture of 1.92 g (0.01 mole) of 1,2,dihy-
drotetrazine XXVlI, 2.5 g (0.01 mole) of CuS04 and i0 ml of pyridine is heated with stir-
ring for 5 h at 50~ It is then cooled and filtered. The filtrate is poured into I00 ml
of ice water, the crystals are filtered with suction, washed with cold alcohol, and recrys-
tallized from CHCIa. The yield of compound XXX is 1.54 g (81%).

143
i-d
$-

TABLE 2. Characteristics of C o m p o u n d s Synthess

IR spectrum, cm-~ H~R spectrum Found
SSCC, Hz Empirica] Calculated, %
Com- .~ ! Yield, %
pound |'14
fgrmula
VNH 6N~I / NH R Hs . ]2,3 13,4 12,4 C N (Hal) C H N (Hal)

XXII 108 3500 1600 4,41 (1~r~) 6,33 (d,) 6,66 (d) -- 4,0 -- 29,4 2,8 20,5 CsH6BrNaO 29,4i 2.9 20.6 92
3300 (39,1) (39.2)
3200
XXIII '160 ~ 3555 1600 4,57 ( b r . s ) , 5,80 (d) 6,50 .~.) -- 4,0 -- 35,3 3,4 32,9 CsH6N403 35,3 3,5 32,9 89
3325 3,39 (br. s)
32O0
XXIV 240 3350 1645 5,10 ( b r . $) 6,70 ,~d) 5,55 ldd ) 6,]8 (d) 0,7 3,5 2,0 49,9 4,1 29,2 CsHsN402 50,0 4,2 29,2 87
XXV 242 3325 t665, 5,05 ( b r . s) 2,35 (CH~C) 6,08 (d) 7,03 (a) - - 3,9 - - 54,4 5,4 25,4 CIoH,2N402 54,5 5,5 25.5 90
3150 1610
XXVI 244: 3325 1665, 7,83 ( b r . s ) 5,66 (d) 6,11 (dl - - 3,8 -- 35,5 2f 20,5 8 5
CsHeBrN~O. 35,5 2,2 20.7
3180 1620 (29,5) (29,6)
XXVII 208 3330 1770 7 8 3 ~br.s) 6,66 (d) 5,50 ~dd ) 6,03 (d) 0,7 3,5 2,0 50,0 4,0 29,0 CsHsN40~ 50,0 4.2 29.2 88
XXVIII 189' 3320 1740 7,05 , Dr.s~ 2,26 (CHzC) 6,00 (d~ 6,55 (d) - - 4,0 -- 54.5 5,3 25,5 CIoHt2N40~ 54,5 5,5 25,5 87
XXIX 1255 3325 1760 7,91 (.hr. s) 5,6o ~d) 6.04 (d) - - 4,0 - - 35,3 2,1 20,6 CsH~BrN40 35,5 2,2 20,7 83
(29,3) (29,6)
XXX 195 1600 6,95 (@ 5,88 ( d d ) 6,54 (d) 0,9 3,8 2,5 50,3 3,0 29,4 CsH~N402 50,5 3,1 29,5 81

*With decomposition.
 LITERATURE CITED
i. A. L. Mndzhoyan, V. G. Afrikyan, and E. A Grigoryan, Dokl. Akad. Nauk Arm.SSR, 301 (1958).
2. G. Sosnovsky, J. A. Krogh, and S. G. Jmhofer, Synthesis, ~, 722 (1979).
3. P. Andove and A. Gaset, J. Chim., 237, 167 (1983).
4. A. P. Dunlop and F. N. Peters, The Furans, Reinhold Publ. Corp., New York (1953), p. 447.
5. Y. Kovac, Coll., 41, No. 6, 1692 (1976).
6. D. R. Shridhar, M. Ioglbhukta, and P. Gopalreddy, Indian. J. Chem. Sect..B, 1 9 No. 5, 386
(1980).
7. G. V. Wolf, in: Organic Reactions [Russian translation], Izd-vo Inostr. Lit. (1951), p.
291.
8. E. N. Zil'berman, Reactions of Nitriles [in Russian], Khimiya, Moscow (1972), p. 429.
9. Yu. P. Kitaev, and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974), p. 162.
i0. General Organic Chemistry, Vol. 8, D. Barton and W. D. Ollis (eds.), Nitrogen-Containing
Heterocycles, P. G. Simms (ed.), [Russian translations], Khimiya, Moscow (1985).

CHLORINATION OF 1,3-DIOXOLAN-4-ONES

V. R. Likhterov and V. S. ~tlis UDC 547.729.7:542.944

It is shown that the direction of chlorination of 1,3-dioxolan-4-ones in the pre-

sence of benzoyl peroxide is determined by the nature of the substituent at the
5-position of the ring. In this case a chloromethyl group, having a --I effect,
promotes a selective replacement of hydrogen at the 2-position, while a methyl
group mainly causes replacement of hydrogen at the 5-position.

The present work is devoted to the reaction of 1,3-dioxolan-4-ones with chlorine and aims
to establish the effect of the substituent at the 5-position of the ring on the direction of
chlorination.
5-Methyl- (I) and 5-chloromethyl-l,3-dioxolan-4-one'(II) underwent chlorination. Re-
placement of hydrogen by chlorine proceeds only at an increased temperature (80-I00~ and in
the presence of free-radical initiators. In the case of dioxolanone I on chlorination to an
increase in weight equal to the replacement of one atom %f hydrogen by chlorine, determination
of the composition of the reaction mixture was not achieved. In the second case chlorination
proceeds selectively and leads to 2-chloro-5-chloromethyl-l,3-dioxolan-4-one (III). This,
evidently, can be accounted for by the influence of the substituent with a --I effect, which to
a large extent lowers the reactivity of the C--H bond at the 5-position of the ring to attack
by an electrophilic chlorine radical.

C I C H 2 . ........ ..0
~:~'" C I C H 2 \. .0
'~ i c ~/r tlJ:%b
O. O O. /O

&
II
Ill

It was established (GLC) that the compound synthesized was a mixture of cis and trans
isomers; it showed thermal stability and was readily distilled, but was unstable on hydroly-
sis. Among the products of hydrolysis were identified 3-chloro-2-hydroxypropionic, formic,
and hydrochloric acids.

III - H--20~" C IC H ~ C H C O O H + HCO011 + HCl

-l
Oil

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 187-189, February,

1986. Original article submitted November 13, 1984; revision submitted February 26, 1985.

0009-3122/86/2202-0145512.50 9 1986 Plenum Publishing corporation 145

 It could be supposed that in the case of dioxolanone I, chlorine would, on the contrary,
replace hydrogen at the 5-position, forming a thermally unstable compound. For proof of this
hypothesis we chlorinated 5-methylene-l,3-dioxolan-4-one (IV). The reaction proceeded smooth-
ly at 0-5~ The 5-chloro-5-chloromethyl-lj3-dioxolan-4-one (V) obtained was a substance of
low thermal stability, and it was not possible for us to isolate it by vacuum distillation.

C! ~ 0
C H ~ O ._Cl---,
.2-~. CICt'2,'~--'-'~
O~.~/O 0~/~O
IV V

The dioxolanones III and V synthesized are isomers, being at the same time both lactones
and ~-chlorethers. It is well known that such compounds display exceptionally high reactiv-
ity in reactions with various nucleophilic reagents. We established that in the presence of
triethylamine as a base, in both cases splitting off of hydrogen chloride occurred and 2-
chloro-5-methylene-l,3-dioxolan-4-one (VI) and 5-chloromethylene-l,3-dioxolan-4-one (VII),
respectively, were obtained in high yield. ,.

4=

9 CH2.~ .O :~ CIHC ~ ~O
,H,~ .... ~ 5 ~ _ . . "l ..........~ .: "~--~S ~
O......0 0 ~,~.,0

C1
VI VII
The properties of the unsaturated compounds obtained were dependent on the nature of
the substituents at the 2- and 5-positlons. The first was a mobile, colorless liquid with
an odor similar to that of acid chlorides! it could be distilled under vacuum and hydrolyzed
with the formation of pyruvic, formic, andhydrochloric acids. The second was a stable,
crystalline substance. Their composition and structure were confirmed from the data of el-
emental analysis and IR spectroscopy.

EXPERIMENTAL
1R spectra were recorded on a UR-20 instrument using a thin film between KBr plates.
Chromatographic analysis was carried out on a Tsvet series chromatograph, with flame ioniza-
tion detector, and 3% neopentyl glycol succinate on cellite 545 as adsorbent. Dioxolanone I
was obtained according to a standard method [1].
.2-Chloro-5-chloromethyl-3-dioxolan-4-one (III). Into a reaction vessel fitted with
bubbler, thermometer, and reflux condenser with calcium chloride tube were inserted 136.5 g
(i mole)dioxolanone II [2] and 0.0014 g (0.001 wt. %)benzoyl peroxide; and this was heated
to 90-95~ Chlorine dried with sulfuric acid was passed through until there was a gain in
weight of 35 g and the mixture was distilled under vacuum, i0 g (7%) initial product was ob-
tained as well as 120 g (75% based on initial reactant) cis,trans-dioxolanone III, mp 57-58~
(1.33 hPa), nD 2~ 1.4680, d42~ 1.4740. IR spectrum: 1831 cm-* (C=O). Found: C 28.0; H 2.3;
C1 41.7%; MW 169. C~H~CI2Os. Calculated: C 27.5; H 2.3; Cl 42.0%; MW 171.
Hydrolysis of dioxolanone III was carried out on a boiling water bath, and after the
suspension was dissolved vacuum evaporation was carried out at 50~ The residue was 3-
chloro-2-hydroxypropionic acid, mp 77-78=C (from an ether-chloroform mixture), according to
[3]: rap 78-79~ A test mixture with a known sample melted without depression.
2-Chloro-5-methylene-l,3-dioxolan-4-one (VI). Into a reaction vessel fitted with stir-
rer, thermometer, dropping funnel, and reflux condenser with calcium chloride tube were in-
serted 20 g (0.118 mole) dioxolanone III, 50 ml ether, and free-radical polymerization inhib-
itors (p-methoxyphenol and phenothiazine); and at --5~ over the course of 0.5 h was added
dropwise a solution of 12 g (0.119 mole) triethylamine in 40 ml ether. Stirring was contin-
ued for a further 2 h at the temperature indicated. The triethylamine salt was filtered off,
the solvent was removed, and the residue was distilled under vacuum. 12.5 g (77%) was ob-
tained, mp 40~ (5.32 hPa), nD 2~ 1,4724, d~ 2~ 1.4579. IR spectrum: 1830 cm-* (C=O), 1680
cm -I (C=C). Found: C 35,5; H 2.3; Cl 26.4%; MW 135.0. C4H,CIO,. Calculated: C 35.7; H
2.2; C1 26.4%; MW 134.5. The product was easily hydrolyzed by water, undergoing quantitative
conversion to pyruvic acid (determined by polarography), formic and hydrochloric acids.

146
 5-Chloro-5-chloromethyl-3,3-dioxolan-4-one (V). Into a reaction vessel with stirrer,
thermometer, bubbler, and calcium chloride tube were inserted i0 g (0.i mole) of compound IV
[4], 20 ml carbon tetrachloride, and free-radical polymerization inhibitors. At--5~ 7.5 g
(0.107 mole) chlorine was passed in, and the mixture was maintained with stirring at room
temperature for 4 h. Completion of reaction was determined chromatographically according to
the disappearance of initial dioxolanone IV. The solvent was removed under vacuum, and 16.3
g (95%) crude dioxolanone V was obtained, which on heating decomposed with the formation of
tarry products. In a subsequent synthesis it was used without purification.
5-Chloromethylene-l,3-dioxolan-4-one (VII). Into a reaction vessel with stirrer, drop-
ping funnel, thermometer, and calcium chloride tube were inserted 10.6 g (0.105 mole) tri-
ethylamine and 20 ml benzene. At 20-250C a solution of 17.1 g (0.i mole) dioxolanone V in
30 ml benzene was further added. The mixture was maintained for 5 h; then triethylamine hy-
drochloride salt was filtered off, and the filtrate was washed successively with 5% solutions
of hydrochloric acid and sodium carbonate, and then with water. The solvent was removed,
and 9.5 g (71%) was obtained, mp 7.52-73.0~ (from an ether--n-hexane mixture in the presence
of grade A activated carbon). IR spectrum, 1817, 1805 cm-* (C=O), 1680 cm -2 (C=C). Found:
C 35.9; H 2.3; C1 26.5%; MW 138.5. C~HaCIO3. Calculated: C 35.7; H 2.2; C1 26.4%; MW 134.5.

LITERATURE CITED
i. P. Salomaa and S. Laiho, Acta Chem. Scand.~ 17, 103 (1963).
2. M . I . Khramushina, V. R. Likhterov, V. S. Etlis, and D. K. Chuprov, USSR Inventor's
CertificateNo. 609,290; Byull. Izobret., No. 6, 215 (1984).
3. E. Bear and H. Fischer, J. Biol. Chem., 180, 145 (1949).
4. V . R . Likhterov, V. S. Etlis, L. A. Balandina, and S. A. Arzhakov, USSR Inventor's Cer-
tificate No. 606,313; Byull. Izobret., No. 6, 215 (1984).

REACTION OF 2-METHYL-5,6-DIHYDRO-2H-PYRAN WITH DICHLOROCARBENE

U. G. Ibatullin, T. F. Petrushina, UDC 547.811.542.955:

R. R. Gataullin, and M. G. Safarov 543.422:541.634

Upon treatment of 2-methyl-5,6-dihydro-2H-pyran with dichlorocarbene there are

formed products of addition to the double bond a~d insertion at the C--H bond
giving cis- and trans-7,7-dichloro-2-methyl-3-oxabicyclo[4.1.0]heptane and 2-
dichloromethyl-2-methyl-5,6-dihydro-2H-pyran.

The reactionof dihalocarbenes with alkenes usually yields the corresponding adduct via
addition to the double bond (including 5- and 6-membered cyclic vinyl ethers [i, 2]).
We have found that three compounds are formed from 2-methyl-5,6-dihydro-2H-pyran (I) in
37% overall yield: cis- (III) and trans- (IV) 7,7-dichloro-2-methyl-3-oxabicyclo[4.1.0]-
heptane and 2-dichloromethyl-5,6-dihydro-2H-pyran (V) in the ratio 1.0:5.7:3.3.

i :'~- i~ i ~' ~ i I!
i
i c,~, I'~: CH~:l~
I:H~ t'H~
[ I!I,IV V

It can be proposed that the C--H insertion product appearing together with the adducts
III and IV is due to the allyl structure of I, the same course of reaction having earlier
been observed in the case of 2,5-dihydrofuran [3].

Bashkir State University, Ufa 450074. Translated from Khimiya Geterotsiklicheskikh

Soedinenii, No. 2, pp. 190-191, February, 1986. Original article submitted October 8, 1984;
revision submitted May 16, 1985.

0009-3122/86/2202-0147512.50 9 1986 Plenum Publishing Corporation 147

 TABLE i. Mass Spectra of the Products of Reaction of Di-
chlorocarbene with 2-Methyl-5,6-dlhydro-2H-pyran*
L , ,i , |,,, , i It, r HI 7

Compound m/z value (~ of maximum ion)

Ill 180 (0,3), 138 (5,8), 136 (9,8), 125 (I0,4), 124 (t6,2), 123 (16,5), 122 (265),
lC}3 (5,6), lOl (21,0), 97 (6,3), 89 (5,4.), 87 (18,7), 79 (6,6), 77 (7,0), 65
(20,8), 53 (5,0), 5l (9,6), 43 ([00,0), 4[ 12[,0)
IV 180 (0,2), 145 (6,6), 138 (19,5), 1'36 131,0), 125 (30,8)~ 124 (17,0). 1~3
(,16,5), 122 (24,4), 115 (6,3), 103 (10,5), ]01 (34,9), 89 (10,1), 87 (30,6),
79 (14,0), 77 (15,3), 71 (10,5), 65 (31,7), 53 (8,9), 51 (15,9), 43 (100,0),
4[ (30,9)
V 167 (3,2), ]65 (5,5), 98 (6,4), 97 (lOO,O), 79 (5,9), 77 (6,[), 65 16,0), ,53
(6,5), 43 157,7), 41 (19,4)

*Ion peaks greater than 5% given.

It is known, however, that another allyl isomer (4-methyl-5,6-dlhydro-2H-pyran (VI))

gives only the corresponding adduct in ~70% yield under the same conditions. I n all proba-
bility the different behavior of dihydropyrans I and VI is due to the high lability of the
2H in pyran I as well as the lower reactivity of the di-substituted double bond when com-
pared with the trisubstituted one in pyran VI.
The elemental composition of the mixture of IIl and IV agrees well with the empirical
formula CTH,oCI=O. In the PMR spectrum there are signals charaeterlstlc of the tetrahydro-
pyran ring together with signals for the protons of the double bond 15,81 ppm) and the di-
chloromethyl group (5.52 ppm). The'lll/V mixture contains 35% of oleflne (ozonolysls)
pointing to the dihydropyran V,
Compounds III and IV are extremely unstable towards electron impact (molecular ion In-
tensity 0,2-0.3%) and they break down by several routes. On the whole their mass spectra
are very similar. The spectrum of dihydropyran V is significantly simpler and markedly dif-
ferent from Ill and IV. The molecular ion is absent but there are fragments at M--CH= (m/z
165 and 167) and for CHCI= (m/z 83 and 85). The most intensive peak is seen for M-CHC1,
(m/z 97) (see Table 1).
In connection with the difficulty of separating III-V the stereochemlstrles are not es-
tablished. However, as is known for norbornene [5], dichlorocarbene adds to six-membered
olefines with a preferred formation of the trans isomer. Hence, in our case we can propose
that the predominant product is trans-7,7-dichloro-2-methyl-3-oxablcyclo[4.1.O]heptane (IV)

EXPERIMENTAL
GCMS analysis was carried out on a Finnegan-4021 instrument with glass capillary column
(30 m x 0.25 mm, SE-30) with temperature programming from 50 to 180~ (5~ at 68-70 eV
and a scan velocity of 1 spectrum/second. PMR spectra were recorded in a Tesla BS-467C (80
MHz) instrument in CC14. Double bond analysis was performed o n a n ADS-4M,
The reaction was carried out using the method [4] of generating diehlorocarbene from
CHCIs under phase transfer catalyticconditions to give an isomer mixture in 37% yield with
mp 97~ nD 2~ 1.5010. Found: C 46.2; H 5.2; C1 39.2%. C,H,oCI=O. Calculated: C 46.6; H
5.5; C1 39.2%.
When the system potassium tert-butylate/chloroform was used the yield of products fell
to 2%.

LITERATURE CITED
i. E.E. Schweizer and W. E. Parham, J. Amer. Chem. Soc., 82, 4085 11960).
2. J.C. Anderson and D. J. Lindsay, Tetrahedron, 20, 2021 11964).
3. J.C. Anderson and C. B. Reese, Chem. Ind., No. 3, 575 11963).
4. A.A. Gevorkyan, N. M. Khizantsyan, P. I. Kazaryan, and G. A. Panosyan, Khim. Getero-
tsikl Soedin., No. 2, 167 11981).
5. V. Kirmse, Chemistry of Carbenes [Russian translation], Mir, Moscow, 11966), p. 201.

148
CHEMISTRY OF ISOFLAVONE HETEROANALOGS.
ii.* BENZODIOXANE ANALOGS OF CHALCONE, FLAVONE, AND ISOFLAVONE

V, P. Khilya, A. Aitmambetov, A. V. Turov, UDC 547.814.5'841.07:

A. M. Kornilov, D. Litkei, and T. Patonai 543.422.25:615.272.4

Benzodioxane analogs of chalcones and their epoxides have been prepared. Dif-
ferent types of analogs of natural flavonolignan -- silibin -- have been synthe-
sized from these compounds. The PMR spectra of the new compounds and the re-
sults of the preliminary biological testings are reported and discussed.

A complex flavanoid (sibilin [2]) and its related compounds (for example, hydrocarplne [3]),
in which the chromone or chromanone nucleus is bound to 2,3-disubstituted 1,4-benzodioxane
have been isolated from different types of plant material. The structure of silibin has been
established and confirmed by synthesis [4-7].

/o..~H ~O~/CH20H

Of} 0 OH 0

Silibin Hydrocarpine
The increased interest in this group of compounds is due to their biological activity.
Thus, silihln has hepato-protectlve [2, 8], antiphalloidine [9], antiperoxide [i0] activi-
ties and inhibits prostaglandin synthetase [ii].
Natural sillblnhas a 3-hydroxy-3',4'-ethylenedioxyflavanoid structure. Hydrocarpine, which
has been isolated later [3], is a derivative of 2-(6-benzodioxan-l,4-yl)chromone and has a
similar structure. Since compounds of this type and those with other degrees of oxidation
have not yet been prepared, we decided to synthesize structurally more simple benzodioxane
analogs of isoflavones (VI) and flavones (VII) and to study their chemical and biological prop-
erties. The key materials for the synthesis of these 6ompounds were substituted 3,4-ethyl-
enedioxychalcones III and IV, obtained by an alkaline condensation of the corresponding o-
hydroxyacetophenones with 6-formyl-l,4-benzodioxane by a known method [12].
The benzodioxane analogs of chalcones III and IV are fairly high-melting crystalline sub-
stances with a yellow or orange color, which are readily soluble in organic solvents (Table
i). There are intense absorption bands in the 1636-1656 cm-* region in the IR spectra of
these compounds, corresponding to the stretching vibrations of the chalcone carbonyl group.
In the reaction of chalcones IV with hydrogen peroxide in an alkaline medium, epoxides
V are formed in good yields, which in contrast to the initial chalcones, are colorless crys-
talline substances, while stretching vibrations of the carhonyl in the molecules are shifted
to the 1664-1687 cm-* region

*For article i0, see [i].

T. G. Shevchenko Kiev State University, Kiev 252017. L. Koshut Debrecen University,

Hungarian People's Republic, Debrecen N-4010. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 2, pp. 192-198, February, 1986. Original article submitted January 14, 1985.

0009-3122/86/2202-0149512.50 9 1986 Plenum Publishing Corporation 149

 TABLE 2. Physicochemical Constants of BenzodloxaneAna!ogs
of Isoflavones and Flavones Via, d-ks Va, l
] !R spec-
3ore- rap,~ ~trum~ Foun.'d, % Empirical Calculated, ~ Yield

7.1, Ioo
~.C=O, " Formula
,o~d [cm. 1 C l'l Ital C H llal

VI a [96-- 197 1634 C,;H,204

vld 189.,~. 19(I 1638 C18H1404 73,5 I 42
V,e 192 :..,193 1634 C,sHi4Os 6a
\qf 168 169 1638 C,rH.Br04 69'7 I ~,3 37
VI g 171-172 1638 II,5 C,7H.CIO4 64,8 ] II,3 41
V Ih 209----21(I 1640 6,7 CtTHHFO4 6,8 43
Vii 205.---.21)6 1639 C,yH,604 74,0 I 61

Vlj 19(~.--197 1637 ClsHl405 57

VIk 189--19'0 1639 CmI-11404 45
VIIa 184-..185 1646 C,:H,=O4 52
VIIb 205---206 1646 10i8 C,TH,~Cl04
Vile 213.--214 165O I 1,3 C,rHhCD4 [ 6!
Vlkl 168-.-169 1644 Ci,H*~O4 55
vI[e 170---171 1643 C*,H,40~ 3!
VII f 239..- 240 1633 22,1 ClTH~tBrO4 43
VII g 22&.. 227 1641, I 1,5 C,rH.CIO4 50
1633
V [ l h 213214 1634, 6,8 C,rHnFO4 68
1630
VII i 207---208 1639 CmHI604 64
v!I j 194----,195 C,eHNO5 28
VII k 195--196 C,eH1404 64
VII 1 216-..217 9-O,3 C,7HIoC1204 95

*Compounds Via, i, j, k, and Vile were crystallized from an

ethyl acetate-petroleum ether mixture; VId and Vlla from an
alcohol-octane mixture; Vlf, g, and VIlc, i from alcohol; Vllf,
g, h, j-i from ethyl acetate; Vlld from aqueous alcohol.

isoflavones Vl are preferentially high-melting colorlesscrystalline substances. The

stretching vibrations of the carbonyl group in their molecules are present in the 1637-1650
cm-: region. The physical constants, spectral and analytical characteristics of compounds
VI, VII are listed in Table 2.
To confirm the structure and 9 the configuration of cha!coneslll, IV, epoxides
V, flavones VII and isoflavones VI we used the PMR method in the presence of a lanthanlde
shifting reagent (LSR), as well as the above indicated methods. In the spectra of chalcones
Ilia-l, the signal of the hydroxyl proton is observed in the weakest field (13.4-14.2 ppm).
The type of the functional groups located in the vicinity has only slight influence on the
position of this signal. In several cases, the signals of aromatic protons of these com-
pounds form an unresolved multiplet in the 7.0-8.3 ppm region, In all the compounds, there
is a somewhat detached signal of a proton aligned with the carbonyl group (see Table 3). The
chemical shift (CS) for this proton is 8-8.3 ppm. The signals of the aromatic protons of
the benzodioxane ring form a multiplet with a center at 7.52-7.57 ppm, while the methylene
group signals give a singlet at 4.52-4.54 ppm. Attempts to simplify the spectrum by means
of LSR, europium-III tris-l,l,l,2,2,3,3-heptafluoro-7,7-dlmehtyloctane-4,6-dlonate [Eu(fOd)s]
were unsuccessful, because of strong signal broadenings in the presence of LSR, which are
clearly due to the decomposition of the LSR by the action of strongly acidic phenol proton
of products IIIa-l.
The spectra of the benzyl derivatives IVa, d-i are also difficult to interpret. The
aromatic and olefinic protons give an unresolved multiplet in the 7-8 ppm region (see Table
3), but they can be simplified by the action of [Eu(fod),]. When this LSR is added, con-
siderable paramagnetic lanthanide-induced shifts (LIS) of the NMR signals are observed.
Thus, the highest LIS are characteristic for the methylene proton signals of the benzyl
group, signals of the olefinic protons and the signal of the aromatic proton located at the
o-position with respect to the carbonyl group (see Table 3). From the shift values it fol-
lows that the coordination of LSR is brought about at two centers: at the ether oxygen atom
of the O-benzyl and at the carbonyl group (cf. [15-17]). The benzodioxane ring oxygen atoms
do not participate in the complexation with LSR, as follows from the absence of noticeable

150
 TABLE i. Physicochemical Constants of Benzodioxane Analogs of
Chalcones and Epoxides lllaUl, IVa, d-l, Va, d-k

Calculated, %
Co~l- rap,~'C IR spec-' Found ~ Fapirical !Yield,
pound trum, I " formula
~0 C = O ~ c m - c H Hal C [ H Hal

Illa 126--12; 1638 72A 5,( - - Ct7Ht;O4 72,3 5,0 59

IIlb 172--1~ 1636 64,~ 4,~ 11,~ CjzH,3C104 64,5 4,1 II,2 25
IIIC 152--15~ 1642 64,~ 4,~ 11,,r CI7H],CIO4 64,5 4,1 11,2 97
Illd 127--12~ 1637 72,8 5,{ -- CIsHI~O4 72,9 5,4 8()
rile 140--141 1639 69,9 5,C C~sHlaO5 69,3 5,1 57
IIIf 140--141 1638 22,4 C17HI3BrO4 ~,l 96
IlI g 135--13~ 1638 64,7 4,3 i 1,~ CITH,3CIO~ 64,5 4,1 11,2 6O
lllh 173--174 1643 6,4 C~TH~FO; 6,3 78
/lli 145--14~ 1640 73,6 5,6 C,gH,~O~ 73,5 5,8 -- I 80
IIIj 80--81 69,5 5,3 -- CISHI~O~ 69,3 5,1 58
IIIK 138--!3~ 72,5 5,4 -- C18HlaO4 72,9 5,4 -- I 90
IILI 187--188 20,2 C~HmCI~O~ 20,2 85
1Va 111--112 1658 76,9 5,3 -- C,~H,oO~ 77,4 5,4 96
IV4 I10--111: 1659 78,1 5.9 -- C,~H=~O~ 77,7 5,7 83
IVe 113--115 1644 74,7 5,4 -- C=~H=~O~ 74,6 5,5 94
lVf 124--125 91648 18,0 C~H~oBrO4 17,8 I 96
IV, g 119--121~ 1645 70,5 4,7 8,9 C~4H~9CIO~ 70,8 4,7 8,7 95
IVh 118--119 1643 4,8 C~H,~FO~ 5,1 96
IVi 98--99 I 1649 77,6 6,1 -- C~6H2404 78,0 B,6 95
IVj 85--86 1648 74,6 5,5 -- C~sH~Os 74,6' 5,5 79
IVk 113--114 1645 77,9 5,7 1-6,0 C~H~O, 77,7 5.7 82
IV i 125--126 C~H,~CI~O~ 16,1 94
ya 120--121 1677 ?'4,4 5,3 -- C~H2oOs 74,2 5,2 82
143--144 1672 ?'4,5 5,5 -- C~H~Os 74,6 $,5 81
Vie 101--I02 1665 ?'1,8 5.3 lv~.9 C~sH~2Os T1,8 ~,3 72
y f 142--143 1682 C~,HI~BrOs 17,1 79
V g 147--149 1687 ~8,3 4,5 8,4 C~4HtgCIOs ~8,7 t,5 8,4 65
y h 142--143 1678 4,7 C~HIoFOs 4,7 8,t
vi. 134--135 1669 r5,3 5,6 -- C~H2405 ~5,0 87
V J: 129--130 1665 ~2.0 5,4 -- C~sH~O~ ~1,8 $,3 84
V k 120--121 1667 r4,4 5,7 ~- C~H~O~ q ,6 $,5 75

*Compounds Ilia, b and Vf, g, h were crystallized from an al-

cohol-ethyl acetate mixture; lllc, e, h from acetic acid; llld,
e, g, i, k, IVa-h, i, j, and Va, d, e, i-k from alcohol; lllj
from hexane; IVk from aqueous alcohol; IV1 from ethyl acetate.

0 ' 0
~ra-I ina-I

R2 OR + H/C .... ~ RI CH2C6H5

~'-~/~- ICH~ "~.2 ! ol o

l,ll R~ ~ ~ x ~ , ~ O/
I R=H; II R=CH2CsH ~
o Ira,d-1
RI I I{202/0}{-
R2 ~ 0 RI CH2C6H5

E3 C ~ CH~--~C 0

Vla,d-k II
o va,d-k
l'Vll a, c-k R* = H, b, 1 R* = CI; a, b, f-h, j-i R 2 = H, c
R = = CI, d, i R 2 = CH3, e R 2 OCH3; a-e R s = H, f R ~ = Br,
g, 1 R 3 = CI, h R 3 = F, i, k R 3 = CH3, j R s = OCH3
As the result of the rearrangement [13] of opoxides V under the influence of boron tri-
fluoride etherate, benzodioxane analogs of isoflavones VI were obtained in good yields.
Their isomers VII are formed from chalcones III by oxidative cyclization with selenium diox-
ide in amyl alcohol [14]. In contrast to the colored initial chalcones, flavones VII and

151
 TABLE 3. PMR Spectra* of Benzodioxane Analogs of Chalcones
Ilia, c-l, Ira, d-k and Their Epoxides Va, d-k

I [ Protons of t h e ~ diOxaale pax-t

, .... [ ' ......
I , o,,
S~ or --C--C~=CH ,L,
Z-OR, ~" 3-H 4-R 2 5-R ~ 6-H d). or
--C'CH- CH--, 7-, I-OCH~CH:O~,
5-,8.H S
s II x /
0 0 9 I
. y,,., .

Ilia 4,52
IIlc 4,54
llld 4,53
Ille 4,51
IIlf 9
IIIg 4,54
IIIh : 4,38
IIli 4,54
u)j 4,32
IIlk 4,33
fill 4,32
IVa 4,48
(o,o)
IXa 4.48
(0,3)
IVe 4,45
(0,2)
Iu 4,50
(0,2)
IVg 4,54
(o,0)
I~h 4,33
(o,3)
IVi 4,52
lo, i)
IVj 4.51
(o2)
lVk 4.45
(o,!)
va 4,r
Vd 4,,46
Ve 4A5
Vf 4,49
Vg 4,46
Vh 4,25
Vi 4,45
vj 4,47
Vk 4,37

*Units of measurement: 6, ppm; the values of the specific

LIS are given in brackets; absence of a letter, multlplet.
%CS of 2-OCHsC6Hs group protons.
%CS of 8-H proton.

LIS for the methylene proton signals of the benzodioxane ring. At a 0,2-0.3 molar ratio be-
tween LSR and the substrata, doublets of the two olefinic protons can beobserved separately
in the PMR spectra of products IVa, d-l. The SSCC [spin-spln coupling con~ant] for these
protons, equal to 15 Hz, indicates a trans structure of all the chalcones obtained.

In the PMR spectra of epoxides Va, d-k, the most characterlstleslgnals are the peaks
of methine protons of the oxirane ring in the form of doublets with a small SSCC (1-1.5 Hz).
One of the peaks is located at 4,55-4.70, and the other at 4,0-4.1 ppm. Changes in the na-
ture of the substituents in the molecules of the epoxides Va, d-k influence the disposition
of these signals in the spectrum very slightly (see Table 3). We assigned the signals of
oxirane protons on the basis of study of the interaction of LSR with compound Vl. The LIS
values found are shown in Table 3. It is seen that the maximal shifts are observed for sig-
nals of the epoxide ring protons, whereby one of the signals i$ shifted more strongly than
the other. At one side of the oxirane ring there is a carbonyl group~ which, as also the
epoxide oxygen atom, is capable of undergoing complexation with LSR. We therefore ascribed
the signal for which a higher value of LIS is observed, to the methine proton located in the

152
 TABLE 4. PMR Spectra* of Benzodioxane Analogs of Isoflav-
ones Vla,. d-k and Flavones Vlla, c-i

Compound[ Chromonerlng protons 8enzodioxane ring protons

I
s,I 5.
7-H
187, -OC~Ca20- ,
S
4

VIa 8,31 ~,04, dd : 7,2--7,7 7,2--7,7 7,2---7,7 6,9--7,2 4,29

Via'I" 7,95 B,29, dd 7,3--7,6 7,3--7,6 7,3--7,6 6,9--7,2 4,31
VId 8,34 7,94, d 6,7--7,4 2,49, s 6,T--7,4 6,7--7,4 4,25
vl d f 7,83 ~,09, d 6,7--7,4 2,48, s 6,7--7,4 6,7--7,4 4,27
VI e 8,25 7,94, d 6,7--7,2 3,92, s 6,7--7 o, 6,7--7,2 4,30
VI s 8,42 ~,13, d 7,88, dd 7,54,d , 6,8--7,2 4,32
VI g 8,50 B,03, d~ 7,77, s 7,77,s 6,8--7,3 4,34
VI 8,40 7,4--7,7 - - 7,4--7,7 7,4--7,7 6,7--7,2 4,31
w ~q" 7,91 3,04, s 2,42, s 2,42, s 6,9--7,3 6,9--7,3 4,32
VI' ].I. : 8,39 7,47 3,89, s 7,47 7,47 6,7--7,2 4,30
VI . 7,92 7,63, d 3,93, s 6,7--7,4 6,7---7,4 6,7--7,4 4,31
VI k 8,32 7 83 d 2,09, s 7,46, s 7,46, s 6,7---7, I 4,22
vL k f 7,87 S:O0: d_ 2,49, S 7,33, s 7,33, s 6,7--7,2 4,30
VII a 6,87' 05 d d 7,3--7,8 7,3--7,8 7,3---7,8 7,3--7,8 7,01 4,37
VII a% (6,71' dd 7,3--7,7 7,3--7,7 7,3--7,7 7,3--7,7 6,97 4,36
VII e 6,8oi 7,97, d 7,3--7,7 7,83, d 7,3--7,7 6,99 4,36
VII d 6,75' 7,88 d 7,3--7,7 2,49, s 7,3--7,7 7,3--7,7 6,97 4,36
VII ed-I- (6,591 7,97: d 7,0--7,4 2,51, s 7,0--7,4 ~,0--7,4 6,85 4,33
VII (6,79' 7,93 d 7,58 3,95, s 7,58 r,26, 0 7,00 4,37
Vll et (6,61', 7,36 3,92, s 7,36 i,8--7,1 6,8--7,1 4,36
Vlr ~-t (6,791 ~02 a -- 7,84, dd 7,60, d ',46 6,95 4,36
VI1 (6,65] ~,30, d 7,33, dd 7,2--7,5 ',2--7,5 6,94 4,33
VII (6,83; r,90, d 7,75, s 7,75, s ~,49 6,98 4,37
VII ~'!'. (6,66) ~,14, d 7,2--7,7 7,2--7,7 ',2--7,7 6,93 4,35
VII ~'l" (6,83) r,4--7,9 -- 7,4--7,9 7,4--7,9 ',4--7,9 6,98 4,35
VII (6,63) r,80 7,2--7,6 7,2--7,6 ',2--7,6 6,94 4,33
VII i (6,74) ~,74, s .>,38, .>,38, s 7,46 ',46 7,00 4,36
VII i S (6,66) ~,95, s .>,40, s ~,40, s 7,29, s ',37, dd 6,95 4,34
VII j (6,64) ',51, d 3,91, s 7,32, dd 7,28, d ',32 fi,91 4,33
VII k (6,77) ',79, d !,46, s 7,53 7,53 ',53 5,98 4,33
(6,66) ',96, d !,47, s ~,40 7,40 ',40 6,93 4,31
VII (7,82) 1,30, d -- 3,15, d ',82 7,20 4,53

*Absence of a letter) multiplet.

%The spectra of the compounds were measured in CDCIa, in
unmarked cases, the PMR spectra of the same compounds were
measured in DMSO-D6.
~The PMR spectrum was measured in CFaCOOH.

vicinity of the carbonyl group. The CS of signals of other protons of epoxides Va, d-k are
similar to the CS of the corresponding signals of chalcones IVa, d-k.
In the PMR spectra of isoflavones Vlaj d-k, the 2-H proton, located in the vicinity of
the heterocyclic oxygen atom, absorbs in the weakest field (8.2-8.4 ppm, in DMSO). The na-
ture of substituents R ~, R 2, and R a practically does not influence its CS. It is of interest
that when the spectra are run in deuterochloroform, the CS of the 2-H proton is located 0.5
ppm in a stronger field than when the spectra are run in a DMSO solution (see Table 4). It
is possible that this effect is caused by the stabilization of the bipolar form of the chrom-
one ring due to solvation by DMSO, and as a result, by a greater pramagnetic influence of
the heterocyclic oxygen atom on the position of the 2-H proton signal. The signal of the
5-H proton aligned with the carbonyl oxygen atom is present in a somewhat stronger field
(7.4-8.1 ppm). The signals of the remaining aromatic protons of compounds Via, d-k in most
cases form a multiplet in the 6.7-7.4 ppm region, from which signals corresponding to in-
dividual protons cannot be isolated. The signals of the methylene groups of the benzodiox-
ane ring appear in the form of a singlet at 4.2-4.35 ppm.
In the spectra of flavones Vlla-l, besides the signals of the chromone ring protons 3-H
and 5-H located at 6.5-6.9 and 7.7-5.9 ppm, respectively, the signal of the 8-H proton of the
benzodioxane ring is characteristic. It is located at 6.9-7.0 ppm and does not coincide with
the multiplet of the remaining protons. As in the case of 3-(6-benzodioxan-l,4-yl)chromones,
the signal of the methylene protons of the benzodioxane fragment is located at 4.3-4.4 ppm.
The results of biological tests showed that the compounds with flavone structure obtained
exhibited a weakly pronounced hepato-protective action, while compounds with an isoflavone

153
structure have an appreciable hypolipidemic activity, and in their pharmacological effect
are not inferior to the antlatherosclerotic preparation cetamlphen.

EXPERIMENTAL
The purity of the compounds was checked by TLC on Silufol UV-254 plates in a 9:1 benz-
ene-ethanol mixture. The IR spectra were run on a UR-20 spectrophotometer in potassium brom-
ide tablets. The PMR spectra were measured on a ZKR-60 spectrometer in CDCI~ with reference
to TMS (internal standard).
l%(2-Hydroxyphenyl)-3-(6-benzodioxan-l,4-yl)propenones (Ilia-l) and l-(2-Benzyloxyphen-
.yl)-3-(6-benzodioxan-l,4-yl)propenones (IVa~ d-l). A 20 mmole portion of 6-formyl-l,4-benz-
odioxane and 4.7 ml of a 50% solution of sodium hydroxide are added to a solution of 20
mmoles of the corresponding 2-hydroxy-l) or 2-benzyloxyacetophenone (II) in alcohol. The
reaction mixture is held at room temperature for 20-40 h. The precipitate is suspended in
water and the mixture is acidified with acetic acid to a neutral reaction. The product is
filtered, and crystallized from a suitable solvent.
l-(2-Benzyloxyphenyl)-3-(6-benzodioxan-l,4-yl)-2,3-epoxypropan-l-ones (Va, d-k). A 30
ml portion of 30% hydrogen peroxide and 30 ml of 2 N sodium hydroxide are added to a solution
of 6 mmoles of compound IVa, d-k in a minimal amount of a 15:4 acetone-methanol mixture. Af-
ter complete decoloration of the solution (12 h), the reaction mixture is diluted with water,
the precipitate that separates is filtered and crystallized.
3',4'-Ethylenedioxyisoflavones (Vla, d-k). A 0.6 ml portion of boron trifluoride ether-
ate is added to a solution of 3 mmoles of compound Va, d-k in 50 ml of absolute benzene, and
the mixture is boiled for 1-3.5 h (the end of the reaction is determined from the TLC data).
The solution is washed with water and benzene is evaporated under an aspirator. The precipi-
tate is crystallized from a suitable solvent.
3',4'-Ethylenedioxyflavones (VIIa-l). A 6.65 g (60 mmole) portion of a finely divided
selenium dioxide is added to a solution of 20 mmoles of IIa-1 in a minimal amount of a fresh-
ly distilled amyl alcohol, and the mixture is boiled for 18-50 h, with the course of the re-
action being controlled by TLC. Metallic seleniumis filtered off and amyl alcohol is evap-
orated under an aspirator. The residue is recrystallized several times from a suitable sol-
vent.

LITERATURE CITED
i. V. P. Khilya, M. Yu. Kornilov, N. V. Gorbulenko, G. M. Golubushina, E. N. Kovtun, N. V.
Kolotusha, and G. V. Panasenko, Khim. Geterotsikl. Soedin., No. ii, 1542 (1985).
2. A. Pelter and R. Hansel, Tetrahedron Lett., No. 25, 2911 (1968).
3. K. R. Rangenathan and T. R. Seshadri, Tetrahedron Lett., No. 36, 3481 (1973).
4. R. Hansel, J. Schulz, A. Pelter, and H. Rimpler, Tetrahedron Lett., No. 51, 44i7 (1969).
5. R. Hansel, J. Schulz, and A. Pelter, J. Chem. Soc. Chem. Commun., No. 3, 195 (1972).
6. L. Merlini, A. Zanarotti, A. Pelter, M. P. Rochefort, and R. Hansel, J. Chem. Soc.,
Perkin Trans., No. 3, 775 (1980).
7. A. Pelter and R. Hansel, Chem. Ber., 108, 790 (1975).
8. L. Cavallini and G. Lucchetti, Gazz. Med, Ital., 135, 365 (1976).
9. G. Vogel and W. Trost, Arzneim.-Forsch., 25, 392 (1975).
i0. L. Cavallini, A. Bindoli, and N. Siliprandi, Pharmacol. Res, Cormn., i0, 133 (1978).
ii. F. Fiebrich and H. Koch, Experientia, 35, 1550 (1979).
12. R. Bogn~r and Gy. Litkei, Acta Chim. Acad, Sci. Hung., 67, 83 (1971).
13. Gy. Litkei, R. Bogn~r, and Z. Dinya, Acta Chim. Acad. Sei. Hung., 71, 403 (1972).
14. H.S. Mahal, H. S. Rai,and K. Venkataraman, J. Chem. Soc., 866 (1935).
15. I. G. Marchenko, A. V, Turov~ and V. P. Khilya, Dokl. Akad. Nauk UkrSSR, Ser. B., No.
l, 43 (1979).
16. L. G. Grishko, A. V. Turov, M. G. Spasenov, and V. P. Khilya, Khim. Geterotsikl. Soedin.,
No. 9, 1202 (1981).
17. L. G. Grishko, A. V. Turov., I. A. Potrusaeva, and V. P. Khilya, Ukr. Khim. Zh., 49, 174
(1983).

154
AN UNUSUAL PRODUCT OF THE REACTION OF I-PHENYL-3-(3,4-DIMETHOXYPHENYL)-
3-(2-OXOCYCLOHEXYL)-I-PROPANONE WITH HYDROGEN SULFIDE AND ACIDS:
2a-PHENYL-2,4-ortho-(14,15-DIMETHOXYBENEO)-cls-I-THIADECALIN

S. K. Klimenko, T. I. Tyrina, UDC 547.81:543.422

N. N. Sorokin, and V. G. Kharchenko

The reaction of l-phenyl-3-(3,4,dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-propan-

one with hydrogen sulfide and acids gives an intramolecular rearrangement pro-
duct, 2u-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin in addition
to the usual products of disproportionation of intermediate 2-phenyl-4-(3,4rdi-
methoxyphenyl)-5,6-tetramethylene-4H-thiopyran, namely , 5,6-tetramethylenethio-
pyrilium salts and 2a-phenyl-4u-(3,4-dimethoxyphenyl)-cis-l-thiadecalin. The
configurational and conformational assignments for the sulfides, their sulfox-
ides, and sulfones were made by *SC NMR spectroscopy.

l-Aryl- and 1,3-diaryl-3-(2-oxocyclohexyl)-l-propanones are converted by the action of

hydrogen s u l f i d e i n acid media initially to the corresponding 5,6-polymethylene-4H-thiopyrans
[i], which then, by the action of a strong mineral or organic acid, undergo disproportiona-
tion to give 5,6-polymethylenethiopyrilium salts and 2-thiabicycloalkenes or 2-thiabicycloalkanes
[2-4].
We have studied the reaction of l-phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-
propanone (I) at room temperature with hydrogen sulfide and trifluoroacetic acid. In contrast
to other "seven-membered" 1,5-diketones, diketone I forms the tetracyclic intramolecular re-
arrangement product, 2a-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin (V) along
with the usual reaction products, namely, thiopyriliumtrifluoroacetate III and cis-l-thiade-

TABLE i. Conditions and Products of the Reactions of 1,5-

Diketone I with Hydrogen Sulfide and Acids
r ,,] .
Reaction conditions Reactionproducts Yield,g IV/V or Vl~V
starting acid solvent (rap, ~ sulfide ratios
compound (amount,ml) (amount,m in the mixtUreb
(mmoles)
I (30) CF3COOH III (166~-168) 7,0 (50)
(30) 1V 042.5--143,5)
v (180--181) !3,1 (28) 1:8
I (40) 70% HCI04 Ctt3COOH V (180--181)
(17,4) (75) VI (145---146) I 59 (40) 1:1
VII (183--184) 9,1 (49)
I (30) BF3 (30) CH3COOH V (180--181)
(7o) V1 (145--146) : 4,6 (44) 3:1
VIII (191--193) 5,8 (45)
1I (12) CFaCOOH tV (142,5--143,5
(30) V (180--181) 1,3 (29) 5:l
(III), VII (183--184)' 12,8 (52)

aproducts IV, Vl, and Vll were identified by mixing melting

points with authentic samples [2, 4, 5]. bThe sulfide ratio
in the:mixture was determined relative to the '3C NMR spec-
tra of the crude mixtures, eTrifluoroacetate III was con-
verted to perchlorate VII.

N. G. Chernyshevskii Saratov State University, Saratow410601. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 2, pp. 199-205, February, 1986. Original article sub-
mitred December i0, 1984.

0009-3122/86/2202-0155512.50 9 1986 Plenum Publishing Corporation 155

calin IV. The dimethoxyphenyl group in V is bound both to C(2) and C(4) of the heterocycle.
This led us also to study the reactions of 1,5-dlketone lwith hydrogen sulfide and 70% perchlo-
tic acid or boron trifluoride etherate. The experimental conditions and reaction products
are given in Table i. In both cases, tetracyclic product V was found in addition to the cor-
responding perchlorate or tetrafluoroborate VII and VIII and 2-thiabicyclo[4~
VI. All these compounds are given in Table 2. The configurational and conformationa! assign-
ments for IV-VI and IX-XII were carried out by laC NMR spectroscopy (Table 3). Sulfides V and
VI were oxidized by hydrogen peroxide to sulfoxides IX and X and sulfones XI and XII, respec-
tively.
CsH3(OMe) 2

V + I + VII(VIII)
(BF~) ~" / " ~ S ....."Ph
Ph Ph

I ] II VI

CsHs(OMe)2 CsHs(OMe)2 ,~./OMe

Ph
y-
Ill,VII,VIII IV
V
Me0,~ /0Me
15 ~4 ,

- ~3 r
10 f .....'X

6
V,IX,X IV.XI,XI~

III Y = CF~COO; VII Y = C104; VIII Y = BF~; IV, V X = S; IX,

XI X = SO; X, X I I X = S02
The formation of trifluoroacetate III and sulfide IV with cis,cis,cis configuration is
in accord with the usual concepts concerning the cyclization of 1,5-diketones and 4H-thiopy-
tans [i] and the mechanism for the disproportionation with acids [3] including the steric
specificity of hydride transfer in these systems [5]. Thus, we shall not treat these ques-
tions in the present work.
The sterically less hindered double bond (C(~)=C(s)) is initially protonated in the dis-
proportionation of condensed 4H-thiopyrans with acids [3]. Carbonium ion a which is generat-
ed in this step may be a hydride ion acceptor. The loss of a hydride ion from a second 5,6-
tetramethylene-4H-thiopyran molecule leads to reestablishment of the C(2)=C(3) double bond.
In our case, this ordinary process is accompanied by the reaction of the electrophilic site
in carbonium ion a with the dimethoxyphenyl group at C(~). Electrophilic substitution in
the aromatic ring apparently leads to intermediate XIII and then to product V due to the re-
duction of second double bond upon disproportionation.

GMe
~O~

/'- .I",.. if+ ~.~\ . . ; " \ .... ~ "~. ~(,>---OMe

"~/ " s / '"Ph

tI (o0 XIII

In our previous work [6], we have established that the heterocycle in 2,4-disubstituted
5,6-polymethylene-4H-thiopyrans is in boat form, while the substituent in the y-position is
pseudoaxial and, thus, close to C(2), which facilitates attack on C(a) upon formation of the
carbonium ion. The dimethoxyphenyl group itself is extremely active relative to electrophilic
attack, thereby facilitating its reaction with the carbonium site.

156
 TABLE 2. Characteristics of Compounds Obtained

Found, % Calculated
Chemical Yield,
&] rap, ~ IR spectrum, cm" i formula %
81 c H S C H S

III 166--168 [680--1660 (COO-), 1600, 63,1 5,2 6,9 C26H~31::304S 63,0 50--52
1585, 1525, 1495 (C=C),
1270, 1075 (C--O--C) I
V 180--181 1605, 1495 (C=C arom.i !75,2 7,4 8,7 C23H2802S 75,4 , 8,8 22
1265, 1070 (C--O--C)
VIII 191--193 1600, 1540, 1495 (C=C), 61,4 5,3 7,3 C23H23BF402S 61,4 [7,1 45
126% 1o3o (c--o--c),
1040 (BF4-)
1265, 1070 (C--O--C), i
IX 172--173 1600, 1500 (C=C ~.om~ 72,6 7,2 8,6 C23H28OaS 72,2 71
1045 (S--O)
X 221--222, 1600, 1500 (C=C arom. 69,5 !6,9 8,4 C2aH2oO4S 69,3 6,6 87
1300, 1130 (S--O), 1270,
1065 (C--O--C)
XI 156--158 1600, 1500 (C=C atom. 71,6 ,0 8,5 C23H28OaS 71,8 7,3 , 73
125o, 1o2o ( o - - o - - c ) ,
lO45 ( s - - o )

*The recrystallization solvents were i:I ethanol-acetone for

sulfide V and sulfone X and 2:1:0.5 hexane--ether--acetone for
sulfoxides IX and XI. Salts III and VIII were reprecipitated
from chloroform by the addition of ether.

The structure of tetracyclic sulfide V indicates that the reduction of the'angular dou-
ble bond as a result of protonation at C(~o) and transfer of a hydride ion from 5,6-tetra-
methylene-4H-thiopyran II to the carbonium site at C(9) proceeds by cis addition although
the approach of the hydride ion donor from the side of the condensed aromatic ring is ster-
ically hindered.*
The formation of t~iabicyclo[4.4.0]-A1'6-decene VI in addition to the intramolecular con-
densation product V in the reactions of 1,5-diketone I with hydrogen sulfide and perchloric
acid or boron trifluoride etherate supports our mechanism for the formation of V.
The reaction products did not contain 2a-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-trans-
l-thiadecalin or 28-phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-lrthiadecalin , which are iso-
mers of sulfide V.
Table 1 also gives the results of the disproportionation of thiopyran II in trifluoro-
acetic acid. The relative yield of tetracyclic sulfide V in this case is significantly lower
than in the reaction of 1,5-diketone I with H2S/CF3C02~. The higher yield of sulfide V in
this experiment indicates that the dimethoxyphenyl group apparently also reacts with carbon-
ium ions directly preceding the formation of 5,6-tetramethylene-4H-thiopyran II from the bi-
cyclic semithioacetal.
There have been reports of the intramolecular rearrangement of 9-benzyl-symm-octahydro-
thioxanthenes upon the action of hydrogen chloride, perchloric acid, and trifluoroacetic acid
to give 3,4-benzo-5,9-7,8-bis(tetramethylene)-6-thiabicyclo[3.3.1]-7-nonene as a result of
intramolecular electrophilic reaction of the benzyl group with the carbocation site with re-
duction of the double bond and formation of disproportionation products [7].
The formation of thiadecalin V in the reactions considered in the present work is the
first example of an intramolecular rearrangement during a disproportionation reaction. We
should note the finding that intermediate XIII is reduced in this reaction while the angular
double bond is retained in dihydro product VI.
The configurational and conformational assignments for 2~-phenyl-4u-(3,4-dimethoxyphenyl)-
cis-l-thiadecalin (IV) were carried out in our previous work [5]. The *SC--{H} and double het-
eronuclear resonance spectra permitted examination of the change in the multiplicity of two
signals in the rearrangement product V relative to thiadecaline IV. The aliphatic part of the
spectrum of V shows a singlet at 57.70 ppm while the aromatic part shows a singlet at 134.64
instead of doublets at 48.70 and 119.33 ppm in IV. These data indicate an intramolecular re-
action of a dimethoxyphenyl group with one of the u-carbon atoms of the heterocycle.

*Assuming that the transfer of the hydride ion from the donor molecule to the acceptor mole-
cule occurs in a ~imolecular complex.
157
oo

TABLE 3. "aC NMR Spectra of IV, V, and IX-XII, d, ppm

2-Ph 2,4-At or 4-Ar

Com- c,~ C(3) C(3) C(5) C(6) C(7) C(8) C(9) CHo) OCHa
pound c(~) II ortho meta para C(12) C(I~)
C(n) c.4) Ic~5) [c(~6)

V 57,70:s 39,20 57,50d 24,709 28,60 22,20 i 30,70 46,63,d 44,54, d 55,80 140,~7 127,71 127,71 126,60 136,64 134,64 104,84 148,321148,791107.28
(135}? (138) ~ (137)~
IX 70,43 s 35,46 49,92p 23,71 27,41 21,24 [ 27,27t 63,83,d 46,06, u 55,74 135,86 128,93 128,14 127,69 136,93 127,91 107,20 148,601149,331107,60
(130, (146)* (139)~,
X 75,78,s 35,08 51,61,d 23,33' 27,23 20,52:t I 19,54t 61,08, d 45,07, 55,85, 129r63 130,22 127,97 128,51 137,94 128,37 107,60 148,821150,241107,79
(13o) (133)* (138)* 55,76
C(I) C(6) C(5) c(,) Ic(,) It(,)

IV 48,70 33,50 48,20 21,10 126,50 19,20 i31,60 46,50 43,10 55,68, 142,29 127,12 128,23 126,93 136,88 119,33 110,86 148,481147,141111,20
55,59
XI 68,93 30,98 46,94 22,11 [ 25,93 20,86 [ 25,65 . 66,22 46,81 55,66, 136,77 128,62 128,13 128,05 134,25 118,29 110,76 148,45 148,53II 10.76
55,58
XII 67,39 31,02 46,67 21,12 /25,26 19,16 [ 23,12 60,72 44,94 55,78, 130,28 129,84 128,38 128,79 134,39 119,30 110,95 147,71 148,741110,95
55,67

*The XJc_ H coupling constants are given in parentheses. *Tentative signal assignment.
 TABLE 4. Difference in the Chemical Shifts of the y-Carbon
Atoms in Sulfoxides IX and XI and Sulfones X and XII Rela-
tive to the Corresponding Sulfides V and IV, ppm

Iv v
Atom
SO 802 SO SO~

-- 2,52 -2,48 --3,74 -4,12

t,~s) --5,95 -8,48 -- 3,43 -11,16
C([o) +3,61 + 1,84 + 1,52 +0,53

The complete interpretation of the '3C NMR spectrum of sulfide V became possible due to
analysis of two series of sulfide-sulfoxide--sulfone spectra for V, IX, X and IV, XI, XII tak-
ing account of the characteristic effects of the sulfinyl and sulfonyl groups in going from
sulfides to the corresponding sulfoxides and sulfones. Table 4 gives the y-effects of the SO
and SO= groups in IX-XII, which are in good accord with the data for thiadecaline derivatives
[i0]. The use of the SO and SOs group y-effects in IX-XII permitted the identification of
the signals for C(s), C(o), and C(,o). The C(e) signals in both series IV + XI + XII and V
IX + X are more shielded than the C(s) signals.
The signals for C(o) and C(zo) in sulfides IV and V (Table 3) do not differ significant-
ly, while the C(s) signal in V is shifted downfield by 5.7 ppm, perhaps as a consequence of
anisotropy of the condensed dimethoxyphenyl group and the presence of this atom in a five-
membered ring. Hence, we have assumed that the intramolecular cyclization proceeds at C(=).
The presence of an upfield signal at 22.20 ppm indicates cis ring fusion according to
the accepted criterion for condensed cyclohexanes [ii].
In addition, analysis of the theoretical Chemical shifts of the alicyclic carbon atoms
for conformations A and B or 2~-phenyl-cis-l-thiadecalin~[5] and the chemical shifts of C(5),
C(6), C(7), and C(e) in IV and V indicates that the cis-l-thiadecalin system is in conforma-
tion A in both IV and V (Table 5).
The orientation of the sulfinyl groups in IX and XI is equatorial. The '3C NMR spec-
tra of the sulfoxides and sulfones of 2-aryl- and 2,4-diaryl-cis-l-thiadecalins will be con-
sidered in a subsequent communication.

EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer ~n vaseline oil and hexachlorobuta-
diene. The *H and '3C NMR spectra were taken on a Varian FT-80A fourier-transform spectrom-
eter using HMDS (for *H) and CDCI3 solvent (for *SC) as internal standards. The 13C NMR
spectra were taken with broad-field suppression of the spin-spin coupling of the '3C and *H
nuclei with incomplete proton decoupling. The spectra for V, IX, and X were taken with gated
decoupling with retention of the *Jc-H values. The data of various workers [5, 8, 9] were
taken to calculate the chemical shifts of some alicyclic and aryl group carbon atoms with
subsequent comparison of the experimental and theoretical parameters.
The reaction course and product purity were monitored by thin-layer chromatography on
Silufol UV-254 plates with 6:1 hexane--ether as the eluent. Sulfides IV and V or V and VI
were separated by preparative column chromatography on alumina with hexane as the eluent.
The characteristics of the compounds synthesized for the first time are given in Tables
2 and 3.
Reaction of l-Phenyl-3-(3,4-dimethoxyphenyl)-3-(2-oxocyclohexyl)-l-propanone (I) with
~ydrogen Sulfide and Trifluoroacetic Acid. A sample of 30 ml absolute trifluoroacetic acid
was saturated with hydrogen sulfide for 1 h at 20-25~ A sample of 10.96 g (30 mmoles) di-
ketone I was added in portions over 1 h and saturation with hydrogen sulfide was continued
for an additional 3 h. The reaction mixture was maintained for three days until the inter-
mediate 4H-thiopyran had completely disappeared and then repeatedly extracted with a total
of 350 ml hexane. The extract was washed with water and dried over MgS04. Partial evapora-
tion of the hexane in vacuum gave crystallization of sulfide V, mp 180-181~ (from 1:2 etha-
nol--acetone) in 22% yield. Complete evaporation of the hexane from the residue gave a i:I

159
 TABLE 5. Comparison of Theoretical a and Experimental Chemical
Shifts of Alicyclic Carbon Atoms in IV and V, ppm
Configuratio~
Compound and confir- Nature of
[nation the data G{5) C~7) C(B)

2~ -phenyl-cis- cis-A calc. 24,40 26,69 2(I,88 31,86

l-thiadecalina cis-B talc. 34,22 19,61 . 28,28 27,34
IV cis-A exp. 21,10 26,50 19,20 31,60
V cis-A exp. 24,70 28,60 22,20 30,70

aData for the theoretical spectra of 2e-phenyl-cis-l-thiadeca-

fin from our previous work [5] are given for comparison.

mixture of sulfides IV and V in 6% yield. Trifluoroacetate II crystallized upon dilution of

the acid mother liquor of the reaction mixture by ether, mp 166-168~ (from chloroform-ether).
Reaction of 1,5-Diketone I with HTdrogen Sulfide and Boron Trifluoride Etherate. A sam-
ple of 70 ml glacial acetic acid was saturated with hydrogen sulfide for i h at 20~ and then
30 mmoles 1,5-diketone I was added in smallportlons along with the dropwise addition of 30 ml
boron trifluoride etherate over 1.5 h. The reaction mixture was maintained at room tempera-
ture for 72 h and diluted with 350 ml ether. Tetrafluoroborate VIII was filtered off, mp
191-193~ (from chloroform-ether) in 45% yield. The mother liquor was washed with water and
dried over MgS04. Removal of the solvent and chromatography permitted the separation of V
and Vl in 12 and 33% yield, respectively.
Reaction of l~5-Diketone I wit~ Hydrogen Sulfide and Perchloric Acid. The reaction was
carried out as in our previous work [2]. The experimental conditions and results a r e g i v e n
in Table i. Perchlorate VII and a mixture of sulfides V and VI were obtained.
2e-Phenyl-4e-(3,4-dimethoxyphenyl)-cis-l-thiadecalin 1-Oxide (XI). A sample of 0.6 g
(1.63 mmole) sulfide IV was dissolved in 21 ml glacial acetic acid and l.65 mmole 30% hydro-
gen peroxide was added dropwise. The mixture was left for 24 h at room temperature and then
poured onto chopped ice. Sulfoxide XI was filtered off.
2e-Phenyl-2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin 1-oxide (IX) was obtained
according to the procedure described above.
2u-Phenyl-4u-(3,4-dimethoxyphenyl)-cis-l-thiadecaline l,l-dioxide (Xil) and 2a-phenyl-
2,4-ortho-(14,15-dimethoxybenzo)-cis-l-thiadecalin l,l-dioxide (X) were obtained from the
corresponding sulfides by oxidation with excess hydrogen peroxide as described in our previ-
ous work [12]. Sulfone XII was obtained in 90% yield, mp 166-167=C (from ethanol). A mixed
probe of this sample with an authentic sample gave an undepressed melting point.

LITERATURE CITED
i. S. K. Klimenko, M. N. Berezhnaya, and V. G. Kharchenko, Zh. Org. Khim., i0, 2425 (1974).
2. S. K. Klimenko, T. V. Stolbova, M. N. Berezhnaya, N. S. Smirnova, I. Ya. Evtushenko, and
V. G. Kharchenko, Zh. Org. Khlm., iO, 1942 (1974).
3. T. V. Stolbova, S. K. Klimenko, and V. G. Kharchenk0, Zh. Org. Khim., 16, 178 (1980).
4. S. K. Klimenko, T. V. Stolbova, and V. G. Kharchenko, Khim. Geterotsikl. Soedin,, No.
i0, 1338 (1981).
5. S. K. Klimenko, T. V. Stolbova~ T. I. Tyrina, N. N. Sorokin, I. F. Leshcheva, N. M.
Sergeev, and V. G. Kharchenko, Khim. Geterotsikl. Soedin., No. 7, 898 (1984).
6. I. Ya. Evtushenko, S. K. Klimenk0, B. I. lonin, and V. G. Kharchenko, Zh. Org. Khim.,
ll, 2417 (1975).
7. A. A. Shcherbakov, G. G. Aleksandrov, Yu. T. Struchkov, and V. G. Kharchenko, Khim.
Geterotsikl. Soedin., No. ii, 1470 (1979).
8. R. Kh. Freidlina, V. I. Dostovalova, N. A. Kuz'mina, and E. C, Chukovskaya, Org. Magn.
Reson., 15, 133 (1981).
9. A. M. Krapivin and L. I. Perepelitchenko, Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 452
(1982).
i0. R. P. Rooney and S. A. Evans, J. Org. Chem., 45, 180 (1980).
ii. E. R. Eliel and F. W. Vierhapper, J. Org. Chem., 41, 199 (1976).

160
12. N. S. Smirnova, S. K. Klimenko, M. N. Berezhnaya, T. V. Stolbova, and V. G. Kharchenko,
Zh. 0rg. Khim., ii, 440 (1975).

REACTIONS OF AZIRINES WITH SULFUR NUCLEOPHILES.

4.* TREATMENT OF 2H-AZIRINE WITH MERCAPTOSUBSTITUTED ACIDS.
REACTIONS OF AZIRIDINYL ALKYL SULFIDES WITH CARBOXYLIC ACIDS
AND ACYL CHLORIDE DERIVATIVES

R. S. El'kinson and A. V. Eremeev UDC 547.717'279.104

Treatment of 2H-azirines with mercaptosubstituted acids and their derivatives

leads to B-ketoamides and 2-aziridinyl alkyl sulfides, respectively. 2-Aziri-
dinyl alkyl sulfides, in turn, react with carboxylic acids to give B-ketoamides
and substituted ethanethiol derivatives. Acylation of 2-aziridinyl alkyl sul-
fides with acyl halides generates a variety of products, depending on the reac-
tion conditions; either products derived from cleavage and isomerization of the
aziridinyl ring or (l-acylaziridinyl-2) alkyl sulfides are obtained.

Electrophilic addition of carboxylic acids to the C=N bond of 2H-azirines gives the cor-
responding B-ketoamides as a result of ~somerization and 1,2-cleavage of the aziridine ring
in the initially formed 2-acyloxyaziridine derivatives [2]. At the same time, 2,2-dimethyl-
3-phenylazirine (I) reacts with B-substituted ethanethiols to give a new type of functional
aziridine derivative, namely, aziridinyl alkyl sulfides [3].
It was of interest to us to study the reactions of azirine (I) with mercaptosubstituted
acids, i.e., bifunctional reagents which should be capable of entering into both nucleophilic
and electrophilic addition reactions to ~ bond of azirine (I). We have found that reaction
of azirine I with mercaptoacetic and mercaptopropionicacids occurs at the carboxyl group to
generate the corresponding u-(mercaptoacylamino)isobutyrophenones II and III:

Ce.Hs-~." -CH 3
~'~.~'-. CH 5 + [[S(CII2)COOH ....... C~IIsCOC(CkI5)2NHC0(CII2)sSH
N If,Ill
I

II n = i; III n = 2
The formation of products II and III from the reactions of azirine I with mercaptosub-
stutited acids should be anticipated based on a comparison of the ionization constants of
these acids (pKa 3.68; 10.40 and 4.32; 10.47, respectively) with those of unsubstituted car-
boxylic acids, which are known to react with 2H-azirines to give the corresponding B-ketoam-
ides.
In cases where protonation of azirine ring and subsequent nucleophilic addition of a
carboxylate anion are impossible, such as, for instance, during esterification or salt for-
mation, themercapto group of the carboxylic acid is the only reactive site, and as a result,
nucleophilic addition of the mercapto group to the C=N bond of azirine I occurs, and the cor-
respondin~ aziridinyl alkyl sulfides are formed, in analogy with the results reported in [3].
For instance, treatment of azirine I with the ethyl ester of mercaptoacetic acid for the sod-
ium salts of N-acetylcysteine or cysteine yields the aziridinyl alkyl sulfides IV-VI as the
only reaction products (Table i):

*For communication 3, see [i].

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 206-211, February, 1986.
Original article submitted November 30, 1984.

0009-3122/86/2202-0161512.50 9 1986 Plenum Publishing Corporation 161

CY~
tJ

TABLE 1. Physical Chemical Properties of Su.lfides IV-VI, XV-XVII, XIX, and XXI

Com- Found, % Calculated, %

pound IR spectrum, cm- 1 Molecular formula Yield, %
fl N
I S(Cl) 1t N S (Cl )

IV [68~9 1080, 1260, 1730, 3280 63.3 7,2 5,0 ii.8 C,4H ,,lqO2S' 63,4 7,2 5,3 12,1 72
(2,6 hPa)]
V 178--180 1410, 1560, 1650, 1690, 3250, 3300 54,3 5,6 8,7 9,4 C,sH,gNaN~OsS 54.5 5,8 8,5 9,7 57
VI 120--121 1600, 3200, 3260, 3350 54,1 5,7 9,9 10,9 C,aHjzNaN202S 54,2 5,9 9,7 11,1 51
XV 46---48 1640, 3300 63, I 7, I 5,5 11,9 C,4HvjNO2S 63,4 7,2 5,3 12,1 61
XVI 119--120 1650, 3350 69,6 6,1 4,5 9,6 C~gH~tNO2S 69.7 6.4 4,3 9,8 58
XVII 15---18 900, 980, 1430, 1650, 3330 65,2 6,6 5,3 11.3 C,sH,9NO2S 65,0 6.9 5.1 11.6 37
XIX 37--39 1050. 1250, 1640, 1720 62,4 6,5 4,4 t03 C u;H~ NOaS 62.5 6.8 4.5 10.4 45
XX! 183--185 825, 1540, t650, 2It0, 2210, 3300 49,6 6,3 8,4 9.3 C,4H2ICIN2OS. HC[ 49,9 6.5 8,3 9.5 64
(2o,9) (21,1)
 I

%19/'~-}
.6- ...... | IIRCII/CI[(NI1COCtI3.)COONa -\\',,

CSII5 CII3 C6II%>~. . . . ~/CH3

S~'~/'CHs /S" ~ .,, "-CH~ ,S'~/// CH.~
Ha HN CH2 HN ~H2 HN
COOC2H5 CII(NHCOCII3)COONa CII(NfI2)COONa
IV ~, VI
The azirldinyl alkyl sulfides were of considerable research interest, inasmuch as their
structural characteristics, namely, the presence of both aziridinyl and sulfide functional
groups, would seem to imply a wide spectrum of chemical reactivity, encompassing the chem-
istry of the aziridine ring as well as that of sulfides. We have therefore studied the re-
activity of these sulfides in reactions involving both retention and cleavage of the aziri-
dine ring, which are characteristic of aziridines. It is known, for example, that heteroly-
tic cleavage of the aziridlne ring occurs upon treatment with organic acids to give the cor-
responding 2-acyloxyethylamines [4]. However, our experiments concerning the reactions of
2-hydroxyethyl- and 2-dimethylaminoethylaziridinyl sulfides VII and VIII [3] with either sat-
urated or unsaturated carboxylic acids unexpectedly revealed some unusual product structures.
Instead of generating the expected 2-acyloxyethylamines, treatment of sulfides VII and VIII
with carboxylic acids led to the formation of the corresponding 8-ketoamides X-XIII and a
substituted ethanethiol derivative (Tables 2 and 3). 2-Alkoxyaziridines react in a similar
manner to aziridinyl alkyl sulfides with carboxylic acids. For instance, t r e a t m e n t of 2-
ethoxy-3,3-dimethyl-2-phenylaziridine (IX) [5] with carboxylic acids gave the same 8-keto-
amides as prepared above, and the compounds X-XIII were identical with respect to all physi-
cal chemical and spectral characteristics with these compounds. It should be noted, however,
that the reactions of aziridine IX with carboxylic acids require both longer reaction times
(6 h) and higher reaction temperatures (80=C) than the analogous reactions of sulfides VII
and VIII (3 h, 50 ~

RCH2CH2~q~CH3 R~C00H C6Hb~CH3

C6H5' N/ CH3 ":RCH2CHzS~- C6HsCOC(CH3)2NHCOR1 ~C2HsoHR1COOHC2H5~~ / ~CH~
H X-~II HN
3I,~II IX
Vll R = OH; VIII R = N ( C H s ) a ; X R* = C 6 H 5 ; X l R* = C 6 H ~ C H = CH;
R* = CeH=C-C; XIII R x = CHa,= CH
We cannot exclude the possibility that these reactions occur via intermediate 2-acyloxy-
ethylamines, since the rearrangement of 2-acyloxyethylamines to 2-hydroxyethylamides is known
[6]. One observation supporting this assumption is the fact that reaction of aziridine IX
with carboxylic acids requires harsher conditions than the analogous reactions of aziridinyl
alkyl sulfides; the sulfide group is, of course, a better leaving group than an alkoxy group.
It is known that acylation of aziridines with acyl halides to give N-acylaziridines oc-
curs only in the case of acceptor acids [7]. Treatment of the aziridinyl alkyl sulfides VII

TABLE 2. Physicochemical Properties of 8-Ketoamides X-Xlll

Com- / Found, % Molecular C,a l c . %

pound " rap, oC | R! IR spectrum, cm- i formula
0)
ther C H[N el.IN
X 153--155 0,71 1535, 1635, 1690, 3080, 76,2 6,3;5,4 CIzHITNO2 76,416,4 5,2 78
3250
XI 218--220 0,59 1540, 1620, 1655, 1680, 77,7 6,3 i4,9 CI9HIgNO2 77,816,5 4,8 56
3280 !
XII 118--120 0,75 1530, 1620, 1660, 1685, 78,1 5,6 4,7 CioHlTNO2 78,415,8 4,8 78
2210,3210,3315
XIII 158--160 0,44 1530, 1620, 1655, 1680, 71,7 6,6 6,3 CI~HIsNO2 71,915,9 6,41 53
3290, 3310

163
 TABLE 3. PHR Spectral Parameters of 8-Ketoamides X-Xll (CDCIs)

Com- ~, ppm
pound C0H~ C1% NH H.Rt (J, Hz)

X 7,91 (Ho); 7,11--7,33 (H., an~ 1,72 7,58 (H~), 7,11--7,33 (H.,and[.{~)*
Hp)
XI 7,93 (Ho); 7,4 (H.,andHv) 1,78 6,56 7,4 (C6H~); 6,25~'d6,51 (CH=CH,
16)
XII 7,89 .~[-Io); 7,11--,7,58 (Hr~and 1,71 7,02 7,1 I--7,58 (C6H~)t
H~)
XIII 7,91 (Ho); 7,42 (H,.andH~) 1,76 6,67 5,58 (CH; 5,4; 6,6), 6,r
(=CH2; 14,1; 5,4; 6,6)

*Multiplet, including both the aromatic ring proton signals and

the NH group signal.
tMultiplet consisting of all of the aromatic ring proton signals.

and ElY [3] with acyl halides in the presence of triethylamine readily gave the corresponding
N-acylaziridinyl alkyl sulfides XV-XVII (Tables 1 and4):

RCH2CII~S .CH3 RCII2CIt2S,. _ ...... _~CH3

%.(~:,+-)~"c% .el .- co.,~ I c,+

C(IR

X'V-.,X~'I! XVIII

9 R1COC1 =611; (C~Its)~N

C{CH3)2NH2'HCI RCH2CH2S ' CH RI C00CH2CH2S CH

........................... "" c H ~ \ / ~CH
C=H=
~~ SI , ~ / - 9 .R=OH
... C6['15/ ~ C INI 3 R=0H; (C2Hs)3N
" 6 5 \ N/ 3

H COR 1
X~ VII,XIV XIX

" RICOCII R=NH2. HCI CH3

CaHsC(Cl )C(CH3 )2NItCOR 1 H2_O_... C6HsCO~NIICOR

I 1 + IISCII2CH2R
!
SCI]2CII2R CH3
XXI

Vll R = OH; X I V R = NH2~ R* = CHs, C6H5, CH2 = CH

The rearrangement of N-acylaziridines in the presence of acid to give ring-enlarged pro-
ducts, namely, 2-oxazolines [8] is characteristic of N-acylaziridines; we have demonstrated this
reaction using sulfide XV, which gave the hydrochloride salt of 2,4,4-trimethyl-5-phenyl-5-
(2-hydroxyethylthio)-2-oxazoline XVlII.
When 1 mole of the aziridinyl alkyl sulfide VII was treated with 2 moles of acylating
agent in the presence of base, the hydroxy group of the sulfide also underwent acylation, and
the corresponding (l-acylaziridinyl-2-)-2-acylhydroxyethyl sulfide XIX was obtained.
In the absence of base the N-acylaziridines generated in these reactions undergo further
conversions involving ring opening and formation of B-halosubstituted N-acylethylamines [9].
Our experiments have shown, however, that, depending on the nature of the substituent in the
B-position to the sulfide group, a variety of products can be obtained from the reactions of
the aziridinyl alkyl sulfides VII and XlVwith acyl halides in the absence of base. For in-
stance, treatment of sulfide VII with acetyl chloride in the absence of base gave an almost
quantitative yield of a substituted 1,3-oxathiolane, which was isolated in the form of its
hydrochloride salt XX [i0]. Apparently, hydrogen chloride, which is generated in the begin-
ning of the reaction, induces heterolytic cleavage of the aziridine ring, which leads to in-
tramolecular rearrangement of sulfide VII to the 1,3-oxathiolane ring system, as has been
demonstrated previously [I0].
In contrast, workup of the hydrochloride salt of 2-aminoethyl aziridinyl sulfide XIV
with acetyl chloride under analogous reaction conditions generates the sulfide XXI; the struc-
ture of the latter was verified by spectroscopic analysis, as well as by hydrolysis to give
the known compounds [ii] ~-(acetylamino)isobutyrophenone and 2-aminoethanethioi hydrochloride.

164
 TABLE 4. PMR SpectralParameters o f Sulfides XV-XVII, XIX
(r
RCH2CII~S'~_ CH3

N
I ,
COR

8, ppm
tom- " R'
pound C6H5 CH~ CH2--S CH2--R Ha HRt (I, Hz)

XV OH CH3 7,49 (Ho); 7,29 0;62 and 2,44 3,49 2,88 2,02
(H,,,~ndH p) 1,56
XVI OH CsHs 7,99 (Ho); 7,29-- 0,78 and 2,58" 3,56 2,13 7,62 (Ho);
7,56 (H.,and Hp)* 1,73 - 7,29--7.56 (Hm
andHp )*
XVII OH CH2=CI-I 7,33 (Ho); 7,56 (Hr~ 0,71 and 2,51 3,40 2,51] 5,78 (CH; 3,44;
and Hp) 1,64 - 8,1); 6,17and
6,35 (=CH2;
7,92 (Ho); 7,48 18,1; 8,1; 3,44)
XIX CH3COO CHa (H~ and H~) 0,76 and 3,06 4,44 2,18 2,03
1,77

*Multiple, corresponding to all of the protons of the aro-

matic ring.

EXPERIMENTAL
IR spectra were recorded on a Perkin-Elmer 580B spectrophotometer using thin films. PMR
spectra were obtained on a Bruker WH-90 spectrometer using 5% solutions and TMS as internal
standard. Melting points of the compounds prepared in this paper were determined on a Boeth-
ius microheating apparatus.
2-(Mercaptoacetylamino)-2-methyl-l-phenylpropanone (II). A solution of 2.61 g (18 mmole)
of azirine I [5] in 20 ml of acetone was treated dropwise with 1.66 g (18 mmole) of mercapto-
acetic acid. The mixture was stirred 15 h at 70~ and the acetone was evaporated. The resi-
due was recrystallized from 1:3 chloroform--hexane. Yield 2 g (47%), mp 183-185~ Rf 0.18
(Silufol UV-254, ether). IR spectrum (nujol): 1550, 1645, 1690 (amide bands, C--O), 2500-2680
(SH), 3330 cm-* (NH)~ PMR spectrum (DMSO-D6): 8.57 (IH, s, N'H), 7.92 (2H, m, Ho), 7.46 (3H,
m, Hm, and Hp), 3.21 (2H, s, CH2). 1.46 ppm (6H, s, CH3). Found: C 60.4; H 6.0; N 5.7; S
13.4%. C,2H, sNO2S. Calculatedt C 60.7; H 6.3; N 5.9; S 13.5%.
2-(3-Mercaptopropionylamino)-2-methyl-l-phenyl-l-propanone (III). This was prepared in
an analogous manner; mp I18-120~C. IR spectrum (nujol): 1545, 1650, 1685 (amide I and II
b a n d s , CzO), 2530-2600 (SH), 3300 cm-* (Nil). PMR spectrum (DMSO-D6): 8.77 (IH, s, NH), 7.90
(2H, m, Ho), 7.46 (3H, m, Hm, and H p ), 2.89 (2H, m, 2-CH=) , 2.62 (3H, m, 3-CH2 and SH) , 1.46
ppm (6H, s, CH3). Found: C 61.9; H 6.7; N 5.3; S 12.5%. CI3HtTN02S. Calculated: C 62.2;
H 6.8; N 5.6; S 12.7%.
Ethyl (3,3-Dimethyl-2-phenylaziridinyl-2-thio)acetate (IV). A solution of 2.9 g (20
mmole) of azirine I in I0 ml of ethanol was treated dropwise with a solution of 2.5 g (20
mmole) of ethyl mercaptoacetate in i0 ml of ethanol. The reaction mixture was stirred 12 h
at 50~ the alcohol was evaporated, and the residue was distilled. Yield 3.8 g (72%); bp
68-69~ (2.6 hPa) PMR spectrum (CDCXs): 7.94 (2H, m, Ho), 7.39 (3H, m, H m and Hp), 4.21
(2H, q, O-CH2), 3158 (3H, s, S--CH= and NH), 1.29 (3H, t, CH3), 0.89 and 1.69 ppm (3H and 3H,
s, CH3).
Sodium 2-Acetylamino-3-(3,3-dimethyl-2-phenylaziridinyl-2-thio)propanoate (V). This
was prepared in a similar manner and was purified by washing twice with 20 ml of acetone.
PMR spectrum (D20): 7.34 (SH, 2, C6Hs), 4.33 (IH, t, J = 5 Hz, CH), 2.89 (2H, d, J = 5 Hz,
CH2), 2.03 (3H, s, CH3CO), 0.87 and 1.59 ppm (3H and 3H, s, CH3).
Sodium 2-Amino-3-(3,3-dimethyl-2-phenylaziridinyl-2-thio)propanoate (VI). This compound
was also prepared analogously to the manner described for compound (IV) and was purified by
recrystallization from a 1:3 chloroform--hexane mixture. PMR spectrum (CDCI3): 7.22 (5H, m,
C6H5), 3.26-2.71 (6H, m, S--CHa, CH, NH2 and NH), 0.83 and 1.53 ppm (3H and 3H, s, CH3).
The physicochemical properties of compounds IV-Vl are recorded in Table i.

165
 2-Benzoylamino-2-methyl'l-phenyl-l-propanone (X; Tables 2 and 3) A solution of 0.7 g
(3 mmole) of sulfide VII or VIII [3] in 30 ml of acetone was treated dropwise with a solution
of 0.37 g (3 mmole) of benzoic acid in i0 ml of acetone. The mixture was stirred 3 h at 50~
and the acetone was evaporated. The residue was recrystallized from 1:3 ethanol--ether. Yield
0.62 g (77.5%); mp 153-155~
Compounds XI-XIII were prepared in a similar manner (Tables 2 and 3).
l-(Acetyl-3,3-dimethyl-2-phenylaziridinyl-2)2- (hydroxyethyl) Sulfide (XV; Tables i and 4)~
A solution of 0.75 g (3.3 mmole) of sulfide VII and 0.34 g (3.3 mmole) of triethylamine in 20
ml of dry tetrahydrofuran was treated dropwise with a solution of 0.27 g (3.3 mmole) of acetyl
chloride in i0 ml of dry tetrahydrofuran. The mixture was stirred 3 h at 20~ and the triethyl-
ammonium chloride precipitate was removed by filtration. The filtrate was concentrated and the
residue was recrystallized from 1:3 ether-petroleum ether. Yield 0.53 g (60.9%); mp 46-48~
Sulfides XVI and XVII were obtained analogously (the latter was purified by recrystalliza-
tion from hexane).
2,4,4-Trimethyl-5-phenyl-5-(2-hydroxyethylthlo)-2-oxazoline Hydroch!oride (XVIII) o A so-
lution of 0.53 g (3 mmoles) of sulfide XV in i0 ml of acetone was treated dropwise with a solu-
tion of 0.Ii ml of concentrated hydrochloric acid in 5 ml of ethanol. The mixture was stirred
3 h at 20~ and the solvent was evaporated. The residue was recrystallized from 1:3 acetone--
ether. Yield 0.76 g (84.4%); mp i18-120~ IR spectrum (nujol): 1660 (C=~-~), 18i0 (imine
salt band), 2420 (ammonium band), 3300 cm-* (OK). PMR spectrum (DMSO-D~): 8.08 (2H, br s,
NH + and OK), 7.46 (5H, m, C~Hs), 3.33 (2E, t, O-CH2), 2.39 (SH, m, S-CH~ and 2-CH3), 0.78 and
1.64ppm (3Hand3H, s, 4.4-CH3). Found: C 55.5; H 6.4; N 4.3; S 10.8%. CI~HIgNO2S "HCI. Cal-
culated: C 55.7; H 6.6; N 4.6; S 10.6%.
(l-Acetyl-3,3-dimethyl-2-phenyla~iridinyl-2) 2-Acetoxyethyl Sulfide (XIX). This compound
was prepared similarly to compound XV. See Tables 1 and 4.
Hydrochloride Salt of (l-Chloro-2-acetylamino-2-methyl-l-phenylpropyl) 2-Aminoethyl Sul-
fide (XXI; Table i). A solution of 0.52 g (2 mmole) of sulfide XIV [3] in 20 ml of ethanol
was treated dropwise with a solution of 0.24 g (3 mmole) of acetyl chloride in l0 ml of ethanol.
The mixture was stirred i0 h at 20~ the alcohol was evaporated, and the residue was recrysta!-
lized from 1:3 alcohol--ether. Yield 0.43 g (64%); mp 183-185~ P~[R spectrum (DMSO-D6): 9.77
(IH, br s, NH), 8.94 (3H, br s, NHs+), 7.96 (2H, m, Ho), 7.55 (3H, m, E m and Hp), 3.56 (2H= t,
N--CH2), 3.29 (2H, t, S--CH2), 2.03 (3H, s, CH3CO), 1.76 ppm (6H, s, CH3).

LITERATURE CITED
i. R. S. El'kinson, A. V. Eremeev, Ya. Ya. Bleidelis, A. F. Mishnev, and S. V. Belyakov,
Khim. Geterotsikl. Soedin., No. 12, 1633 (1985).
2. A. V. Eremeev and R. S. El'kinson, Khim. Geterotsikl. Soedin,, No. 6, 736 (1984).
3. R. S. El'kinson, A. V. Eremeev, A. F. Mishnev, Ya. Ya. Bieidelis, and V. G. Semenikhina,
Khim. Geterotsikl. Soedin., No. I, 53 (1985).
4. J. Yukawa and S. Kimura, Patent No. 4,973 (Japan); Chem. Absto, 58, 1032 (1963).
5. R. F. Parcell, Chem. Ind., 33, 1396 (1963).
6. O. C. Dermer and G. E. Ham, Ethyleneimine and Other Aziridines, Academic Press, New York
(1969).
7. H. C. Brown and A. Tsukamoto, J. Am. Chem. Soc., 83, 2016 (i961).
8. H. W. Heine, M. E. Fetter, and E. M. Nicholson, J. Am. Chem. Soc., 81, 2202 (1959).
9. H. Bestian, Ann., 566, 210 (1950).
i0. R. S. El'kinson, A. V. Eremeev, and ~. ~. Liepin'sh, Khim. Geterotsikl. Soedin., No~ 5,
623 (1985). r

ii. A. Hassner, S. S. Burke, and I. Cheng-fan, J. Am. Chem. Soc., 97 , 4692 (1975).

166
NEW DERIVATIVES OF meso-(TETRA-4-PYRIDYL)PORPHINE AND THEIR REACTIONS

V. N. Madakyan, R. K. Kazaryan, Mo A. Khachatryan, UDC 547.979.733.07:

A. S. Stepanyan, T. S. Kurtikyan, and M. B. Ordyan 543.422

Some reactions of Co-meso(tetra-4-pyridyl)porphine were carried out, and a cyan-

opyridine complex was isolated. New water-soluble complexesbased on Co-meso-
(tetra-4-N-hydroxyethylpyridyl)porphine were obtained. Aliphatic, aromatic, and
heterocyclic amines were examined as ligands.

The effect of the structure and functional substituents of the porphyrine molecule on
its biological activity can be examined by studying a large number of different synthetic por-
phyrines.
The purpose of the present work is to synthesize some cyanamine cobalt complexes of meso-
(tetra-4-pyridyl)porphine (TPyP), a structural analog of vitamin B,2, and to prepare water-
soluble analogs of some previously described unsymmetric cobalt complexes [I]. Aliphatic,
aromatic, and heterocyclic amines were used as ligands on the central cobalt atom.
The reaction of a chlorofozmrnnethanol solution of CoTPyP (2) with 48% hydrobromic acid
gave meso-(tetra-4-pyridyl)porphinobromocobalt (III) (3) CoBrTPyP. Treatment of the latter
with cyclohexylamine gave the complex4, also obtained directly from CoTPyP in solution by
reaction with cyclohexylamine hydrobromide in cyclohexylamine [i].
Treatment of CoBrTPyP 3 or the complex 4 with excess KCN in methanol gave the complex 5,
in which cobalt is present as an anion. By refluxing in glacial acetic acid, followed by
chromatography on AI20~ (Brockmann activity grade II), the dicyano complex 5 was converted to
the monocyano derivative 6, which with pyridine gave a quantitative yield of the cyanopyridine
complex 7.
Attempts to synthesize the imidazole and benzimidazole cyano-derivatives of CoTPyP were
not successful; in neither case was the complex isolated.
The reaction of meso-(tetra-4-pyridyl)porphine (TPyP) i [3] with excess ethylene chloro-
hydrin gave the tetrachloride of meso-(tetra-4-N-hydroxyethylpyridyl)porphine (THEtPyP) (8)
in quantitative yield. The central cobalt atom was introduced by treating THEtPyP in aqueous
medium with a tenfold excess of cobalt chloride followed by concentrated hydrochloric acid;
the course of the reaction was monitored spectrophotometrically. The reaction of an aqueous
solution of the complex 9 with excess of the corresponding amine yielded the amino derivatives
10a-d.
All the compounds synthesized (8-10) were readily soluble in water at any pH.
In the infrared spectra of compounds 5-7, the cyano group absorbs in the region 2100-
2200 cm -I. The two cyano groups of complex 5 give rise to only one absorption band (at 2170
cm -I) indicating that they are equivalent. It can be assumed that both cyano groups are co-
ordinated to the cobalt atom and are situated symmetrically relative to the plane of the por-
phyrine molecule. This structure consists of two normal oscillations: inphase and antiphase.
These oscillations include the valency oscillations of the cyano group. Such a structure
is unique since only one of the oscillation, i.e. the antiphase oscillation, is IR-aetive.

Erevan State Medical Institute, Erevan 375025. Translated from Khimiya Geterotsikliche-
skikh Soedinenii, No. 2, pp. 212-216, February, 1986. Original article submitted January 23,
1985; revision submitted April 8, 1985.

0009-3122/86/2202-0167512.50 9 1986 Plenum Publishing Corporation 167

 CfI2CH201i
,~< c :

C ] " +/'t:'-::'x / NI'| N ,.[. /. " { k + C1

N. N
UOCU.,CH=
. .
,iN~ ,'~,
//
.-#'
\
~:.... ~i ; N-.
N" COfI.N .,.t ....... --. | ' f " :'=" N. IINI "[;r ,
" "":'=
C;I ~C.~zOH
"
9 '~ " "~" " ':':. ' 8
' t

N "~'~ %../' -" CltzCH20H ~,~. t

ieaA~.~
ne
/ i II / / / / l

.... '-<, /o._ 2 - \ :

.......

d + - J ...... 1 ;
N / I "N f ~'N:

.... N/Cq,N Br-

/ 3
/
4 //
CN

/~ N" I "N
CN .N
N..N,~.NI
.NIC ---.- N, .N
N;C~.~:~ ........ O
CN
5 8
Note. a~ n-butylamine, b) cyclohexylamine, c) piperidine, d) pyridine
Infrared spectral data and elemental analysis, show that the conversion of the complex 3
to the complex 5 is accompanied by the dehydrobromlnation of the peripheral pyridine groups,
so that in compound 5 the pyridine groups occur as free bases. Thus, in going from complex 3
to 5 there is a shift of the pyridine ring absorption band from 1640 to 1595 cm-*. Analogous
shifts in the absorption for the transition from a pyridine salt to a free base have been re-
ported in the literature [4].
In compound 6, stretching vibrations of the C-N group absorb at 2148 cm -~, while the free
C=_N- ion absorbs at 2080 cm -~ . An appreciable change in the frequency indicates that the cyano-
group is located in the inner sphere as in the complex 6, where the cyano group is covalently
bonded, and not in a structure with separated charges, as was proposed in [5] for etioporph-
r ine (cobalt) cyanide.
The infrared spectra of compounds 10a-d contain more absorption bands than that of the
complex 9; the frequencies of the additional bands are similar to the vibration frequencies of
the coordinated ligands (see Table i). It should be noted, however, that axial coordination
in the test compounds shows up less sharply in the infrared than in previously obtained com-
plexes of CoTPyP with a numher of amines [i]. This is to be expected, since the porphyrines
which we studied contain hydroxyethyl groups, the vibrations of which partially overlap the
region of absorption of the coordinated amines. Thus, some of the bands given in Table i, ap-
pear as shoulders on porphyrin absorption bands, and in several cases bands in the spectrum
of the complex are stronger and (or) half as wide as the corresponding bands in complex 9.
This is particularly the case for bands due to the stretching vibrations of the NH(NH~) group,
which indicate axial coordination. Bands corresponding to these vibrations, are small peaks
in the same region as the broad OH stretching absorption band with maximum at 3400 cm -~ . How-
ever, in all cases these bands are at lower frequencies than in the free amines. This pro-
vides evidence for ligand-coordination, since it is known [6] that the coordination of amines
is accompanied by a decrease in the frequency of the stretching vibrations of the N(NH2) groups.

168
 TABLE i. Aminoderivatives of meso-(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) Tetrachloride lOa-d

UV spectrum.X , nm Found, % Calculated, % Yield,

Coln- Empirical
pound Amine (~ -zo-~ F, IR s p e c t r u m , cm- 1 % I I
C It CI I formula II CI

10a Butylamine 436 (115), 548 (10,8), 575 V~ZI-L), 745, 1078 VtCN~, 1375, 56,7 1 4,8 16,0 I 11,4 C~2H5504CI~,CoN,j 56,4 5,0 16,1 11,4 93
585 sh (4,4) 1465 6(CH~ ' all:,), ' 2968 V,,,~(CH:,) ' 3200
Y (N H,.,)
I I
16b Cyclohexyl- 436 (114), 548 (10,3), 557 s h v~,~1.-To, 705, 898, 1385 5(Ci ), 57,5 5,2 15,8 ] 11,1 Cs4HszO4CIsCoN9 57.3 5,0 15,7 ql,l 91
amine 587 sh, (3,9) 2868 v,~ccH~) , 2945 V.~(CHA, 32',30
I
V.~(NH: ), 3300 %'"~(NHz)
16c Piperidine 439 (91,2), 552 (10,4), 555 V~--L), 1088 V~CN~, 1385 8(CH~) , 56,8 4,7 15,8 11,4 Cs3H,~O4CI.~CoN.a 56,9 4, 9 15.9 11,3 92
591 sh, (4,5) 1452 s h 8(dH~ ) , 2750, 2800, 2950
~'.S(CH:0 , 3200 VtNIt)
10d Pyridine 57,6 4,3 15,9 11,3 C~H4904CI~CoN9 57,2 4.4 16,0 11,3 93
440 (116), 562 (10,1), 696 pt~:u), 1440, 1598 vtcc~, [~cc.~
6Ol (4) i

*For complex 9 the corresponding bands were at 435, 546, and 584 nm, and at 412, 530, and 560 nm for Co(II)TPyP.
TWave numbers for bands not present in the spectrum of complex 9 are given.

O~
%0
 For the pyridine ligand, there is no N-H bond and this criterium cannot be used. How-
ever, two new bands at 696 and 1598 cm-* in the spectrum can reasonably be attributed to a
displacement of the ~*~b(CH), ~ea(CC), and 8(CCH) vibrations on coordination, In free pyri-
dine, the3e absorptions occur at 702 and 1580 cm-*; similar displacements have previously been
reported for pyridlne complexes [4].
The frequencies of the porphyrine ring vibrations change little on axial coordination.
The strongest bands from the macroring are at 800 and i000 cm-x, and are out-of-plane and in-
plane deformation vibrations of the pyrrole CH bonds [7], shifted by 6 cm-*. The greatest
shift is observed for the complex with pyridlne. Ultraviolet spectral data (see Table i) also
show the greatest bathochromic shift in the spectrum of the complex 10d. Apparently, increased
coordination of Co(Ill) with an aromatic system, which may also involve the dative component
of the metal-ligand bond, disturbs the electron system of the macrorlng more strongly, although
~udging from the small frequency shift, these disturbances are small.
The ultraviolet spectra of the compounds show a small bathochromic shift compared with
the complex 9 because of additional coordination. Examples of such bathochromic [8], and also
hypsochromic shifts [9] have been reported for absorption bands as a result of axial coordina-
tion.
Attempts were made to cleave the axial ligand from the complex at elevated temperatures
(70-80~ and reduced pressure (10-4 tort). The eliminated llgands were directly precipitated
onto a KBr substrate cooled with liquid nitrogen inside a vacuum cryostat, enabling the infra-
red spectra of the cleaved particles to be taken. In all cases they were found to be starting
amines, which, therefore, did not undergo any chemical change during the course of the reaction.

EXPERIMENTAL
Infrared spectra in the range 400-3600 cm -l were taken on a UR-20; samples were prepared
as KBr pellets or as suspensions in mineral oil. Ultraviolet spectra over the range 350-800
nm were obtained on a Specord UV-vis using anhydrous chloroform ~n a 4:1 mixture of chloroform
and methanol, or distilled water.
Chromatography was carried out on AlaO, (Brockman activity grade If).
Tetrahydrobromide of meso-(Tetra-4-pyridyl)porphinobromocobalt (llI) (3). To 4.25 g (6.28
mmoles) of CoTPyP (2) was added 500 ml of methanol, 500 ml of chloroform, and 12.5 ml of 48%
hydrobromic acid. The mixture was vigorously stirred at room temperature for 4 h. evapor-
ated to dryness, and the residue recrystallized from chloroform and ether, and dried for 1 h
in a vacuum desiccator at 40 ~ The violet crystals were carefully washed with dry ether and
dried in air to give 6.7 g (99%) of compound 3. Found: C 44.6; H 2.6; Br 37.2; N 10.0%.
CdoH~sBrsCoN,. Calculated: C 44.5; H 2.6: Br 37.1; N 10.4%.
Potassium Salt of meso-(Tetra-4-pyridyl)porphinodic[anobromocobalt (III) (5). A. To a
solution of 0.3 g (0.36 mmole) of the complex 4 in 300 ml of methanol was added 1.5 g (23
mmoles) of KCN. The reaction mixture was heated at 40~ with periodic stirring for 20 mln
and then allowed to stand overnight. A further 600 ml of chloroform was added, and after
3 h the mixture was chrommtographed on an A1203 column and evaporated to dryness. Recrys-
tallization from dry ether gave 0.13 g (48%) of 5, Rf 0.12 (AI~O3; chloroform-methanol, 5:3).
Found: C 65.5; H 2.9; N 18.5%. C~H2~CoKN,o. Calculated: C 65.8; H 3.1; N 18.3%.
B. To a solution of 0.3 g (0.28 mmole) of compound 3 in 200 ml of methanol was added 1.5
g (23 mmoles) of KCN. The reaction mixture was heated at 40~ for 0.5 h and 400 ml of
chloroform added. After standing overnight, the mixture was chromatographed on an A1203 col-
umn and then evaporated to dryness. T h e residue was recrystallized from dry ether to give 0.2
g (95%) of the salt, 5, Rf 0.12 (AlaO~; chloroform-methanol, 5:3). Found: C 65.8; H 3.0; N
18.4%. C~2EadCoKN,o. Calculated: C 65.8; H 3.1; N 18.3%.
meso-(Tetra-4-pyridyl)porphinocyanocobalt (III) (6). A solution of 0.15 g (0.17 mmole)
of the complex 5 in 50 ml of glacial acetic acid was refluxed for 0.5 h. When cool, the
reaction mixture was passed through an A120s column (chloroform-methanol 5:3). After evapor-
ation of the eluate, the residue was recrystalllzed from dry ether to give 0.i g (83%) of com-
pound 6, Rf 0.85 (Al~Os; chloroform-methanol, 5:3). Found: C 70.2| H 3.2; N 17.6%. Cd,H24-
CON,. Calculated: C 70.2; H 3.4; N 18.0%.
meso-(Tetra-4-pyridyl)porphinocyanopyridlnocobalt (III) (7). The complex 6 (0.05 g; 0,07
mmole) was dissolved in 20 ml of pyrldine by heating at 70~ for i0 min. The solution was

170
chromatographed on an Al2Os column and eluted with a chloroform-methanol-pyridlne (10:l:3)+mix-
ture. The eluate was evaporated to dryness and the residue recrystallized from dry ether to
+

give 0.055 g (99%) of the complex 7, Rf 0.75 (Alz 0 s,9 chloroform-methanol, 8:1) +Found: .C 70.9;
H 3.5; N 18.0%. C46H29CoN,o. Calculated: C 70.8; H 3.7; N 17.9%,
Tetrachloride of meso-(Tetra-4-N-hydroxyethylpyridyl)porphine (8). A mixture of 1 g (16
mmoles) of the TPyP i in I00 g (1.24 moles) of ethylenechlorhydrin was refluxed +for 2 h
(course of the reaction monitored by chromatography). The reaction mixture was evaporated to
dryness ~n Vucuo and the dry residue recrystallizedfrom ether. The crystalline material was
washed with chloroform and recrystallized from a mixture of water and propanol (i:i0)to give
1.5 g (99%). Found: C 61.0; H 4.9; CI 14.7; N 11.9%. C~,H~CI4N,04. Calculated: C 61.3;
H 4.9; C1 15.1; N 11.9%.
Tetrachloride of meso(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) (9). To
a solution of 8 g (8.5 mmoles) of compound 8 in 500 ml of distilled water was added 8 g (61
mmoles) of COC12 in i0 ml of distilled water. The solution was refluxed for 2 h with
simultaneous distillation of+water until the volume was reduced to i00 ml (course of reaction
was monitored spectrophotometrically). After the addition of 12 ml of concentrated HCI, the
reaction mixture was evaporated to dryness ~n vaouo, recrystallized from ether, washed with
9 acetone, and recrystallized from a mixture of water and ethanol (i:i0) to give 8.5 g (97%) of
the complex 9. Found: C 55.5; H 4.7; C1 17.4; N 10.8%. C~eH~4CIsCoN.O~ Calculated: C
55.8; H 4.3; CI 17.2; N 10.8%.
Aminoderivatives of meso-(Tetra-4-N-hydroxyethylpyridyl)porphinochlorocobalt (III) T e t r a -
chlori~e (10a-d, Table i). To a solution of 0.i mmole of compound 9 in i0 ml of distilled
water was added 0.4 mmole of the corresponding amine. After I0 minutes the reaction mixture
was evaporated to dryness, the dry residue recrystallized from absolute ether and then further
recrystallized from a mixture of water and the corresponding amine (i:i0). The crystalline
material was filtered off and washed with the corresponding amine and absolute ether.

LITERATURE CITED
i. V . N . Madakyan, R. K. Kazaryan, M. A. Khachatryan, T. S. Kurt~kyan, M. B. Ordyan, and N.
S. Enikolopyan, Khim. Geterotsikl. Soedin., No. I, 82 (1984).
2. E . B . Fleischer, Inorg. Chem., ~, 493 (1962).
3. S. Sugata, S. Yamanouchi, and Y. Matsushima, Chem. Pharm. Bull., 25, 884 (1977).
4. N . S . Gill, R. H. Nuttal, D. F. Scaife, and D. W. A. Sharp, J. Inorg. Nucl. Chem., 18, 79
(1961).
5. A . W . Johnson and J. T. Kay, J. Chem. Soc., No. 7, 2979 (1960).
6. K. Nakomoto, Infrared Spectra of Inorganic and Coordination Compounds [Russian transla-
tion], Mir, Moscow (1966).
7. G . P . Gurinovich, A. N. Sevchenko, and K. N. Solov'ev, Spectroscopy of Chlorophyll and Re-
lated Compounds [in Russian], Nauka i Tekhnika, Minsk (1968), p. 397.
8. D . V . Stynes, H. C. Stynes, and B. R. James, J. Amer. Chem. Soc., 95, 1786 (1973).
9. T . J . Bengelsdiyk and R. S. Drago, J. Amer. Chem. Soc., 97, 6466 (1975).

171
TETRACYANOETHYLATION AND FISCHER REARRANGEMENT
OF SOME 4-OXO-4,5,6,7-TETRAHYDROINDOLES

K. Dagher, P. B. Terent'ev, UDC 547.754.04'339.2:543.422

and N. S. Kulikov

The reaction of the 1,2-diaryl-4-oxo-4,5,6,7-tetrahydroindoles, and 3-methy[-4-

oxo-4,5,6,7-tetrahydroindole with tetracyanoethylene occurred at the 5 position
of the tetrahydroindole ring. A Fischer rearrangement of the phenylhydrazones
of these 4-oxotetrahydroindoles gave pyrrolo[2,3-c]carbazoles.

Pyrroles and indoles react readily with tetracyanoethylene (TCE) with electrophilic at-
tack by the latter at position 3 of the pyrrole ring [1-3]. However, it is known that TCE,
like acrylonitrile [4], can react with alicyclic ketones by the Michael reaction to give u-
tetracyanoethyl derivatives [5], while tetracyanoethane reacts with carbonyl compounds to form
furan derivatives [7].
In a continuation of work on the reactions of the 1,2-diaryl-4-oxo-4,5,6,7-tetrahydroin-
doles, which have both a pyrrole ring and an alicyclic ketone fragment [8, 9], we have studied
the reaction of the indoles la-f with TCE.
II
NC. ~,.CN O
NC ~N
NC / "CN ! .CN~ 'R~

O I" "'" " N "'R 2

I

~zN ~ /f ~ ~ R3 ...... ti6H~ lla- f

"" g i CsHsN21I 3, IICI. .... i It"

CI|~COOH i.... ii ........ i[ i
""//'"N" " R2 !
- R" 2

r '1 i
"'~'f;"" N.
", ] R~ ,oi 'X L, .R~
, il .tl "J II ....... II
" ' "N"'R z i <~ N " R2
L_ R .
]]10:t,d~ f~ g

g:R* = R s = H, R 2 = C,H5
It was found that by mild heating (40-60=C) in ethyl acetate solution, the reaction was
complete in two to four mi.nutes and gave 62-88% of the tetracyanoethyl-substituted indoles
lla-f, as white or light-colored crystals, which quickly darkened in air (Table I). When
heated to I00-150~ they decomposed, so that satisfactory elemental analysis data could not
be obtained.
Even on ionization by electron bombardment in the mass spectrometer, the molecular ion
(M+) of compounds lla-f* could not always be recorded, and only the use of field desorption
(FD) enabled their molecular weight to be established. Primary decay of the M + ion of com-
mA peak corresponding to [M--HCN]+ is observed in the region of greatest m/z values.

M. V. Lomonosov Moscow State University, Moscow 117234. LebaneseUniversity, Beirut,

Lebanon. Translated from Khimiya Geterotsiklichesklkh Soedinenii, No. 2, pp. 217-221, Feb-
ruary, 1986. Original article submitted February 15, 1985.

172 0009-3122/86/2202.0172512.50 9 1986 Plenum Publishing Corporation

 TABLE 1. Properties of 5 - T e t r a c y a n o ethyl-4-oxo-4,5,6,7-tetra-
hydroindoles lla-f

u tmethanol~-] IR spec-,j
[.~ I ~ "l tvam, cm'~l Mass spectrum,# m/z
(relative intensity, %)
u

LIa C8H5 248 (4,44), FD . 415 (23), 389 (32), 388 82

278 (4,23), (1oo)
474 (4,02)
lib 2-CHzC6Ii4 245 (4,32), 429 (78), 402 (38), 375 (20), 88
282 (4,35), 365 (33), 364 (100), 301 (100),
474 (4,44) 245 (55), 244 (60), 230 (44),
149 (84), 91 (25)
lic 3-C ['IaC,~]-I4 250 (4,60), 429 (25), 402 (100), 400 (50), 64
278 (4,38), 375 (85), 364 (100), 301 (50),
475 (4,52) 273 (37), 245 (40), 244 (42),
230 (37), 115 (37)
lid 4-CH3C~H4 217 (4,60), 402 # (5)~ 375 (9), 299 (16), 62
250 (4,60), 149 (]8), 145 (12), 135 (19),
472 (4,50) 131 (18), if5 (20), I07 (30),
105 (50), 91 (100)
lie 4-BrC~I-[4 248 (4,4t), 460'~(27), 439 (21), 365 (60), 62
286 (4,19), 363 (53), 244 (26), 165 (67),
468 (4,45) 149 (73), 121 (100), 119 (87),
{05 (80)
IIf 202 (4,22), 277 (23), 250 (15), 168 (10), 85
234 (4,30), 150 (10), 149 (20), 129 (14),
440 (4,38) 128 (100), III (20), 109 (15),
]05 (13), ]03 (100)

*lla-e R 2 = C6H5, R" = H; llf R 2 = H, R 3 = CH3.

tThe M + peak and the I0 most intense peaks are given. Ion peaks
for 79Br are given in italics.
~FD: 430 [M + i] + (15), 429 M + (19), 404 (10), 403 (16), 402
(i00), 400 (21).
*eFD: 493 (i00), 467 (28), 466 (25), 489 (59).

pounds lla-f occurs primarily by the successive elimination of two molecules of HCN, or with
the loss of a molecule of TCE or tetracyanoethane by a McLafferty rearrangement. This type of
decay indicates the presence of a tetracyanoethyl residue at position 5 of the heterocyclic
nucleus (ring system). This conclusion is supported by the fact that the 3-methyl-4-oxo-4,5,
6,7-tetrahydroindole If also reacts with TCE to give the tetracyanoethyl derivative of llf,
whereas when TCE is mixed with the previously reported 6,6-dimethyl substituted derivative of
these ketones [i0], the reaction does not take place, possibly because of steric hindrance,
and only starting compounds are isolated from the reaction mixtures.
In the UV spectra of compounds lla-f were observed two short-wave bands at 250 and 280
nm, characteristic of aryl pyrroles [I, ii], and one long-wave band at 468-475 nm, which is
probably due to the partially ionized particle formed by strong hydrogen bonding between the
acidic proton of the terminal dicyanomethyl group and the earbonyl oxygen atom. Consequently,
the C=O group stretching vibrations absorb at lower frequencies (1640-1645 cm-*) than those of
the ketones la-f (1660-1650 cm-*) [i0].
Conclusive proof of the position of the tetracyanoethyl group was obtained from an analy-
sis of the NMR spectra of compounds lid and e. In addition to a multiplet from the five pro-
tons of the 2-C6H~ group at 7.1-7.3 ppm and, partly superimposed on this, two 2-proton doub-
lets from the para-substituted l-phenyl residue at 7.2-7.7 ppm in the upfield region, there
was a singlet from the 3-H proton at 6.71-6.72 ppm, a three proton multiplet from the two pro-
tons of the methyl group (C(I))and one equatorial proton on the C(6) atom at 2.7-2.9 ppm and
a multiplet from one proton (6-Ha), centered at 3.30 ppm. Furthermore, in both PMR spectra
there was a sharp single-proton doublet of doublets from the 5-Ha proton, since the coupling
constants are 5 (axial-equatorial) and 15 Hz (axial-axial). These data confirm that the tet-
racyanoethyl residue in these compounds in on the 5-C atom and in the equatorial position.
It was found that the presence of methyl groups at position 6 of the 4-oxo-4,5,6,7-tetra-
hydroindole ring had a significant effect on reactivity, not only at position 5, but also at

173
 TABLE 2. Proper=ies of the Pyrrolocarbazoles lllc, d, f,
and g
. . . . . . . . . . . . . . . . .

p ~m
I t .o
111r I75~,~177 200 (4,22), 228 sh 3420 ;~72 (iO0), 371 (iT), 356 (i7), 9-54 34
(4,12), 248 (4,28), (20), 186 (rT), 17,q (~0), LTB(37),
253 (4,28), 29O 149 (33), III (33), I09 (30), I05
(4,19), 350 gh (2o)
(8,33), 432 (4,06)
IIld 220-~223 210 (4,33), 228 $h 3115 ;72 (I00), 371 ([2), 357 (5), 356 31
(4,19), 256 (4,40), [3), 254 (i?), 253 (9), 186 (12),
290 (4,28), 351 sh 49 (9), 105 (5), 91 (I00),77(3)
(3,37), 440 (3,08)
Ili f 240--242 202 (4,22), 229 3505 .~20 (100), 219 (82), 218 (36),205 21
(4,07), 255 (4,28),
295 (4,36), 328
(4,38)
3420
I(17), 191 (27), 190 (16), 179(II),
I78 (12), 165 (9), 164 (10), 152
(9)
Illg * 285--287 202 (4,40), 229 3460 282 (lO0), 281 (23), 280 (13), 254 55
(4,27), 256 (4,41), 3420 1(9), 253 (6) 179 (6) ]78
295 (4,45), 328 151 (7), 141 (20), 140 02) (8),
(4,26)

*The M + p e a k and the l0 most intense peaks are given.

#For the reacting ketone l.
~Found: C 84.9; H 5.0%. C2oH~N2. Calculated: C 85.1; H
5.0%.

the carbonyl group. Thus, compounds Ic, d, f, and g, which have no substituent at position 6,
when heated with phenylhydrazine hydrochloride, gave, apparently, normal hydrazones (confirmed
by the Fischer rearrangement to give the corresponding 1,2-dihydropyrrolo[2,3-c]carbazoles),
which are readily oxidized by atmospheric oxygen to the aromatic compounds lllc, d, f, g, iso-
lated in yields of 21-55%(Table 2). However, the reaction mixture always contains the start-
ing ketones, and the use of excess phenylhydrazone, or an increased reaction time does not in-
crease the yield of the final heterocyclic compounds III. Their UV spectra were very similar
to one another; in the IR spectra, there is an N--H stretching band at 3420-3415 cm -x, and in
the IR spectra of compounds !llf and g, an additional band at 3460-3505 cm -x. In the mass
spectra of the pyrrolocarbazoles III, there are strong peaks corresponding to M + and [M -- HI +
ions, which are typical for aryl- and methylindoles [ii].

O i- ]IN ' N -l', N 4-N

--~~.......... ' --Lc)~.-c113.. i i! I

~v;oo. ~c,L'"- ~-.~o >..... ,.. 9...
CH~ C611s
[
~ ' h call5 C6H5 ~ '-j IV ('6H5

Thus, 4-oxo-4,5,6,7-tetrahydroindoles can serve as suitable starting compounds for the

preparative single-stage synthesis of a number of pyrrolo[2,3-c]carbazoles. However, our at-
tempts to carry out an analogous Fischer rearrangement starting from 6,6-dimethyl-substituted
4-oxo-4,5,6,7-tetrahydroindoles were not successful. On prolonged heating in glacial acetic
acid, a mixture of phenylhydrazlne hydrochloride and 6,6-dimethyl-l, 2-diphenyl-4-oxo-4,5,6,7-
tetrahydroindole (Ig) gave an 88% yield (based on reacting ketone), of a yellow crystalline
material; in the UV, this material absorbed at 402 nm, and in the IR, there was a strong con-
jugated C=C stretching band, and a band at 1420 cm -~ which we attributed to the azo group. In
the mass spectrum of this compound was observed an M + peak with m/z 403; further decay of this
ion corresponds well with an enazo structure for IV (see reaction scheme), and leads to the
formation of [M-CH~] +, [M-CH~--C~HsN2] +, and [M-CHs--C6H~N~--H]+. The formation of
the enazo compound IV, instead of the usual Fischer rearrangement, is also apparently due to
steric factors, caused by the geminal methyl groups at the 6 position.

174
 EXPERIMENTAL
UV spectra were obtained on a Varian Cary (in methanol), IR spectra on a UR-20 (in mineral
oil), PMR spectra on a Varlan XL-100 (in deuterochloroform), using TMS as a standard. Mass
spectra were run on a Varian MAT-f12 at an ionization energy of 70 eV with direct introduction
of the compound into the ion source. Field desorptlon mass spectra were obtained on a Varlan
MAT-212, voltage of emitter 6 kV. Preparative chromatographic separation of the compounds was
carried out on Silufol UV-254 plates in ethyl acetate-hexane, 3:7; compounds were visualized
in UV light.
Characteristics of compounds lla-f and lllc, d, f, g are given in Tables 1 and 2.
5-Tetracyanoethyl-4-oxo-4,5,6,7-tetrahydroindoles (lla-f). To a solution of 0.7 mmoles
of the ketone I and 90 mg (0.7 mmole> of TCE in 15 ml of dry ethyl acetate was added 1 drop of
concentrated HCI, and the mixture stirred and heated on a water bath (40-45~ for 2-4 min.
The resulting solution was concentrated to 3-4 ml and the precipitate of II filtered off.
Pyrrolo[2,3-c]carbazoles (lllc, d, f, g). A solution of 0.3 m~mole of ketone I and 0.3
mmole of phenylhydrazine hydrochloride in 4 ml of glacial acetic acid was refluxed for 8 h,
poured onto 40 g of ice, and the precipitated material separated and washed with water followed
9 by 5% sodium hydroxide solution. After again washing with water, the produce was dried and
chromatographed, the bands with Rf 0.45-0.5 yielded the starting ketone, and bands with Rf
0.8-0.9, the pyrrolocarb@zole III. The latter was recrystallized from a mixture of ether and
hexane (i:i).
6,6-Dimethyl-l,2-diphenyl-4-phenylazo-6,7-dihydroindole (IV) was obtained analogously from
1 0 0 m g ( O . 3 2 ~ m o l e ) of ketone lh and 46 g (0.32 n~nole) of phenylhydrazine hydrochloride by re-
fluxing for i0 h. Bands with Rf 0.9 yielded 56mg (88%, based on the ketone) of the azo compound
IV, with mp 230-232 ~ (from a mixture of ether and hex~ne, I:I). UV spectrum, %max (log e): 250
(3.97); 296 (4.04), 402 nm (4.03). IR spectrum (CCI~): 1420 (~N==N), 1620 cm-* (~C=~). Mass
spectrum, m/z (%): 403 (33) M +, 402 (8), 388 (20), 298 (6), 283 (18), 180 (5), 165 (8), 149
(ll), 105 (38), 91 (70), 77 (i00).

LITERATURE CITED
1. R. I. Sunberg, The Chemistry of Indoles, Academic Press, New York (1970), p. 488.
2. W. E. Noland, W. C. Kuryla, and R. F. Lange, J. Am. Chemc_. Soc., 81, 6010 (1959).
3. Y. Shirota, S. Ezaki, S. Kusabayashi, and H. Mikawa, Bull Chem. Soc. Japan, 4 5 8 3 6 (1972).
4. A. P. Terent'ev and A. N. Kost, Reactions and Methods of Studying Organic Compounds [in
Russian], 2nd Edn., GNTI Chemical Literature, Moscow-Leningrad (1952), p. 47.
5. O. E. Nasakin, V. A. Kukhtin, G. I. Petrov, E. G. Nikolaev, V. V. Alekseev, and S. Yu.
Sil'vestrova, USSR Inventor's Cert. No. 759607; Byull. Izobr., No. 38, 38 (1980).
6. W. J. Middleton, R. E. Heckert, E. Z. Little, and C. G. Krespan, J. Am. Chem. Soc., 8~,
2783 (1958).
7. O. E. Nasakin, V. V. Alekseev, P. B. Terent'ev, A. Kh. Bulai, and V. A. Shmorgunov, Khim.
Geterotsikl. Soedin., No. 12, 1605 (1982).
8. K. Dagher, P. B. Terent'ev (Terentiev), Yu. G. Bundel, R. Hanna, and B. I. Maximov, J.
Heterocycl. Chem., 20, 989 (1983).
9. K. Dagher andP. B. Terent'ev, Khim. Geterotsikl. Soedin., 12, 1462 (1984).
i0. K. Dagher and P. B. Terent'ev (Terentiev), A. N. Kost, Yu. G. Bundel, B. I. Maxlmov, and
R. Hanna, J. Heterocycl. Chem., 19, 645 (1982).
il. R. A. Khmel'nitskii, Khim. Geterotsikl Soedin., No. 3, 291 (1984).

175
 CHEMISTRY OF THE PYRAZOLIDINES.
26.* ALKYLATION OF 4-BENZYLIDEN-1-PHENYL-3,5-DIOXOPYRAZOLIDINES

B. L. Moldarev, M. E. Aronzon, UDC 547.722.2'775'778'542.953

V. M. Adanin, and A. M. Zyakun

The reaction of 4-benzyliden-l-phenyl-3,5-dioxopyrazolidines with alkyl halides

in the presence of sodium alkoxide gave l-phenyl-2-alkyl-4-benzyliden- and l-
phenyl-2,4-dialkyl-4-(a-alkoxybenzyl)-3,4-dioxopyrazolines. The structures of
these compounds were confirmed by UV, IR, and PMR spectroscopy, and by mass-
spectrometry.

Previously, it was shown [ 2 ] that 4-benzyliden-l,2-diphenyl-3,5-dioxopyrazolidines react

with sodium alkoxides to give sodium salts of the 4-(a-alkoxybenzyl) compounds B, which do
not show the characteristic long-wave UV absorption bands present in the spectrum of A. The
enolates B react with methyl iodide to give 4-methyl derivatives C.

0:~,7-- N/Cells 0%,, ...C~:I{

s,. O~ N C~IIs
~,-~.~ j _A,~o~. X --~, ~.,. ~.~. , ...., "
- ~-?"-~"- I +- ........... A~-cH-\ I
0 "C6H5 O'" C~;IIs 0 ' Cell.~
A B C

It was of interest to perform this reaction with the 4-benzyliden-l-phenyl-3,5-dioxopy-

razolidines (la-c), since there are two possible reaction products -- the product of the reac-
tion with alkoxide, and the alkylation product.

0 ~ Cell 5 0 "

" '\k_"iY.,/ .'. N|] "" N

;" ".
O" O -- Na+
I a-c lla

0~ Call 5 0, 9 .Ceil 5

c,,j t
ORO.~X----N,.R
1 2 I ' ' ~---
/ , ~-~, -' N,
OR~/"-~'~L- ......... \___y Ob._.i~ RI
O- Na + R ~
va,b, c iv a ma-d

Ia-Va X = H, tb, lllb, Vb, e X = NO~; Ic, Illc, d X ffiOCHs;

Ilia-c, IVa, Va, b, e R l = CHs; Ilia, R x = C2H~; IVa, Va, b
R ~ = CHs; Ve R ~ = C2H5; Va, b, e R s = CHs
In the UV spectra of compounds la-c in alkaline ethanol, the position and intensity of
the long-wave band do not change significantly (experimental section). From this it can be
concluded that these compounds, unlike the 1,2-disubstituted analogs (A), react with sodium
alkoxide not as Lewis acids, but as Nil-acids, which form the enolates II. For compounds B,
as a result of bonding with the alkoxy-anion, the benzyl proton signal9 is shifted upfield to
5.2-5.4 ppm [2], however, in the PMR spectrum of compound la in CDsONa, there is no signal
in this region, confirming that the exocyclic double bond has been retained (Table i). In
the IR spectrum of compound lla, obtained by the reaction of la with sodium methoxide and
isolated by a precipitation with absolute ether, both the C=O absorption band at 1670 cm-* and
*For communication 25 see [I].
Leningrad Institute of Pharmaceutical Chemistry, Leningrad197022. Institute of Bio-
chemistry and Physiology of Microorganisms, Academy of Sciences of the USSR, Pushchino-on-Oka,
142292. Translated from Khimiya Geterosiklicheskikh Soedinenii, No. 2, pp. 222-226, February,
1986. Original article submitted February 26, 1985.

176 0009-3122/86/2202-0176512.50 ~ 1986 Plenum Publishing Corporation

 TABLE i. PMR Spectra of the Starting Compounds and Their
Alkylation Products

0 N--C~Hs -- C ~ I I 4 - - X , R' C~
(IH) I R2 R~
r~

la 7,11--7,78 (m 8H); 8,32--8,65 (q,2tt) 7,80 (~} ;

!7,93 {~'
It 7,11.--7,58 (m,3H); 8,21 (d,2tI, 17,81 (s);
7,71 (d 2 1 1 , J=8Hz}; 7,93 {s}
J = 4 Hz) . 18,45--8,76 {q, 2H)
It 7,20--7,68 (In, 5[-I) 6,94--7,17 (m 2tt); !7,79 (s};I
8,42--8,72 ( q2H); 7,92 (s)
3,81 (s 31t)
Ilia 7,01--7,48 (m, 8H); 7,98--8,45 ~a ,2H) 3,07 (s 3H) 7,82 (s)
I l l t 7,15--7,62 (m, 5H) 18,15--8,52 ( m .~'II); 3,18 (s, 3tt) 7,90(s)
(8,52-8,81 (-~2n} 7,94 (s)
lllc 7,22--7,65 (m, 5Hi 16,83--7,15 ( ~ 2H); 3,18 (s, 3H) 7,91(s)
18,63 (d, 2H, 7,95(s)
11=9 Hz);
[3,87 (~ 3H)
IVa 6,9--7,3 (m, 81-1); 7,3--7,58 ~n, 21t) 2,81 Is ,3H) 5,13 @) 3,23 ( s 3H)
Va 6,65--7,38 (m 10H) 2,83 {s, 3H) 4,33 (s, 3,16 (s 3H) 1,27 ~s,3H)
Vt 7,08--7,42 (m,5H) 7,42--7,68 (m 2H); 2,85 {s 3H) 4,55 (s) 3,18 (s 3H) 1,25 (s 3H)
8,02--8,32 (m, 2H)
vd 7,25--7,65 ~., 5H) 7,65--7,82 (m 21t}; 3,05 .s,, 3H) 4,65 (s) 3,28 (ra, 2H}; 1,21 (s, 3H}
8,15--8,42 (m, 21-t) 1,01 (Ill,3H)

*Spectrum of I was taken in DMSO, III-V in CDCI3.

the C=C band at 1625 cm -x are retained, in agreement with the proposed structure; in this it
differs from compound B. The dual character of the products of the reaction of la-c with sod-
ium alkoxide, and the previously reported [2] course of the alkylation of compound A indicates
that alkylation of compounds la-c with alkyl halides in the presence of excess sodium alkoxide
can occur at either the N or O atom.
The reaction with excess sodium alkoxide and alkyl halides was carried out with compound
la, (without a substituent at position 4), and also compounds with electron-acceptor (Ib) and
electron-donor (Ic) substituents. Under the conditions employed, the N-alkylation products
llla-d, and also the products of further alkylation of the latter, V, were obtained (Table 2).
No O-alkylation products could be detected.
The alkylation of compounds la-c occurs in a step-wise manner, as shown in the reaction
scheme; this was confirmed by the formation of compound IVa from the N-methyl derivative Ilia
and sodium methoxide, and by the formation of complete alkylation products Va and b from 4-
benzyliden- (Ilia) and 4-p-nitrobenzyliden- (lllb) derivatives from methyl iodide in the pre-
sence of sodium methoxide, and of the 4-methyl-4-(a-ethoxy-p-nitrobenzyl)- (Ve) derivative
from methyl iodide and sodium ethoxide.
Evidence for the structure proposed for III comes from infrared spectra, and also from
ultraviolet spectra, where the long-wave maxima of llla-d disappear on going from an acidic
to an alkaline medium. In the PMR spectra, signals from the benzylidene proton, and also sig-
nals from protons of the N-alkyl groups are observed (Table i).
Because of the asymmetry of the molecule, compounds I and III are obtained as mixtures of
Z- and E-isomers. This is confirmed by the presence of two spots with very similar Rf values
on thin-layer chromatograms of compounds la and b and Ilia and b, and also by the splitting of
the signal from the single benzylidene proton (Table i).
In the PMR spectrum of the intermediate IVa, the signal from the benzylidene proton,
which is bonded to the methoxy anion, is shifted from 7.82 to 5.13 ppm. At the same time, in
the IR spectrum, bands at 1785 and 1718 cm -I (C=O) or 1618 cm -l (C=C), which are present in
III, disappear, and are replaced by a strong enolate band at 1565 era-x [2]. From these data
we can definitely conclude that no O-alkylation products are present.
The IR spectra of the products of complete alkylation of V are similar to the spectra of
1,2,4,4-tetrasubstituted dioxopyrazolidines, which are in the fixed dioxo form [3], and con-
tain two strong bands at 1750-1740 cm -I and 1710-1700 cm -I, and no band at 1630-1618 cm -~. In
the UV spectra of compounds V, an absorption maximum occurs at 232-240 nm and is independent
of the pH of the medium; this also is characteristic for 1,2,4,4-tetrasubstituted derivatives

177
 TABLE 2. Alkyla~ion Products
m

i rap, ~ _~ ~pectrum,
~ Lirical
="
t (from ,; IR spectrum,
ethan~-i
max, nm (los
~), ethanol If~
Ilia (S, 1685 235 (4,01), 244 9,7 C17III4N~O.2 lO,l 40,2
152--153165116181718568(@, 1592, (3,95), 330 (4,24)
IIII~ 164--1651 ~5, 1730, 1693 (~, 260 (4,38), 324 13,0]C n'l lr.~N.~O4 13,C 36,0
I 1630, 1595, 1515 (4,15)
lllC 148-.-..149121 1620,1718'1682 ~ , 235 (4,35) sh 9,41C.JljsN2Or~ 9,1 16,2
1588, 1510 247 (4,40), ol4
(4,661, 379 (4,601
llId 142-'143l'1515851718' 1682, 1620, 252 (4,46~, 374 9,0 CjgII2oN20~ 8,7 15,0
(4,46)
IVa 1650, 1595, 1565 8,5 C,sHjTN203Na 8,4 I00,0
Va 113--114/t3 11750'5901710 (sj, 235 (4,04) 8,6 CmH2oN~O3 8,7 50,0
i
Vb 182~183 t !7 11748'5951710 ($, 240 (3 88) 11,3 C191{19N305 II,4 47,0
Ve 176--178t !9 1740, 1700, 1595 237 (4,15) 11,2 C'2(,H2,N~O5 II,0 19,4

*For compounds Ilia and b, ethyl acetate-heptane, i:i (after dry-

ing the chromatogram and repeatedly chromatographing in the same
solvent system, each spot gave two spots with the same Rf); for
lllc and d, ethyl acetate--heptane, 3:4; for Va, b, and e, ethyl
acetate--hexane, 1:7; Vb and c were chromatographically uniform
also in the systems: ethyl acetate--hexane, 1:2; chloroform--pet-
roleum ether, 5:1, benzene-chloroform, 1:3.
%Va. Pound: C 70.2; H 6.3%. Calculated: C 70.4; H 6.2%. Vb.
Pound: C 61.9; H 5.4%. Calculated: C 61.8; H 5.2%. Ve. Pound:
C 62.5; H 5.3%. Calculated: C 62.7; H 5.5%.

[3]. The PMR spectra of compounds V contains signals from the alkyl group protons and signals
from the single proton at the ~-carbon of the benzylidene residue.
Additional confirmation of the structures of compounds I, III, and V was obtained from
their mass spectra. For compounds la-c, the decay of the molecular ion under electron bom-
bardment is independent of the nature of the substituent in the para-position, and involves
the rearrangement of the molecular ion and the ejection of a CaHO2 (similar to the fragmenta-
tion of the benzylidene derivative of 1,2-diphenyl-3,5-dioxopyrazolidine [4]), and splitting
of the C--N and C-C bonds in the heterocyclic ring to form the X--C6H~-CH=CH-C-O + ion, which
then decays further with loss of the para-substituent. In the mass spectra of the monomethyl
derivatives (Ilia-c) (Table 3), the formation of the M -- CH3 fragment and the unchanged values
of the ketene fragments (la, Ilia m/z 130, Ib, lllb m/z 175, and Ic, lllc, llld m/z 160) in-
dicate that the CH3(C2Hb) group was joined to the nitrogen atom and did not affect the exo-
cyclic double bond. Additional evidence is the absence of an acyl ion from the spectra of
llla-d -- since the molecule does not contain a labile hydrogen atom (Nil), which in compounds
la-c migrates to C(4) with the formation of the X-C6H~--CH=CH-C--O+ ion.
The low intensity of the molecular ion peak of the final alkylation product V and the
+
formation of the X-C6H4-CH=OR fragment is consistent with the absence of conjugation between
the heterocyclic ring and the benzyl group as a result of the addition of the alkoxy group at
C=C.
The presence of two asymmetric carbon atoms in the product of complete alkylation V leads
to the formation of a mixture of isomers. Thus, Vb was isolated initially as a mixture of sub-
stances with a wide melting-point range (132-142~ Thin-layer chromatography gave two very
close spots; the PMR spectrum of this mixture had split signals from the N--CHs, O-CHa, and --CH
groups. After purification until chromatographically 9 the PMR spectrum of Vb (mp
182-183 ~ contained no split signals.

EXPERIMENTAL
IR spectra were obtained on UR-20 and Specord IR-75 spectrometers (mineral oil). UV spec-
tra were taken on SF-16 and SF-26 spectrometers using the following solvents: ethanol, ethanol

178
 TABLE 3. Mass Spectra of Compounds I, III, and V

Com- m/z (relative intensity, 96)*

pound

la 51 (181, 63 (6), 76 (10), 77 (41), 91 (6), 102 (421, 103 (16), 105 (6), 107
(7), 129 [9), 130 (51), 13l (44!, 132 (81, 134 (8), 158 (7), 173 (5), 187
(7), 195 (28), 196 (26), 263 (71, 264 (1(10, M.+)
lb 75 (10), 77 (371, 78 (6), 89 (6), 91 (5), 101 (161, 102 (6), 105 (8), 106
(6), 107 (71, 117 (6), 121 (51, 129 (8), 130 (61, 134 (161, 175 (22), 176
(171, 187 (6), 240 (161, 241 (14), 279 (5), 309 (100, M +)
Ic 51 (12~, ,57 (61, 63 (10), 77 (22),, 83 (21), 117 (22), 118 (,5), 121 (6), 132
(71, 133 (61, 134 (51, 145 (21), 147 (7), 160 (49), 161 (34), 22,5 (22), 226
(301, 227 (51, 2q4 (100, M+)
Ilia 51(171, 63(5), 77 (78), 78 (7), 91 (51, 102 (32), 105 (24), 121 (16), 130
(48), 131 (7), 201 (9), 209 (18), 263 (B), 278 (100, M +)
llib 51 (1,5~, 77 (791, 78 (61, 89 (5), 91 (,51, 101 (131, 105 (20), 119 (6-), 129
(6), 17'5 (241,201 (71, 254 (13), 323 (100, N[+)
Ille 51 (6), 77 (3,5), 83 (11), 105 (12), 117 (11), 145 (13), 160 ('55), 161 (8),
239 (7), 308 (100, M ~)
Itld 51 (81, 77 ('59), 78 (6), 83 (1,51, 105 (181, 117 (15), 135 (,5), 145 (15),
160 (,511, 161 (1,51, 162 (61, 204 (6), 22,5 (12), 279 (7), 2~ (181, 294 (191,
307 (48), 308 (15), 332 (100, M +)
Va 77 (14/, 8,':$ (61, 91 (61, 121 (1001, 122 (101, 324 (4, M+)
Vb 77 (10t, 83 (14), 120 (15), 166 (1001, 167 (9), 369 (5, M+)
Vc 77 (lq), 78 (6), 83 (20), 94 (5), 10'5 (6), 106 (91, 1'52 (75), 1,53 (61, 180
(loo), 181 (11), 383 (4, M~)

*Peaks with intensities greater than 4% are given.

containing 0.35% HCI, and 0.1% KOH in ethanol (concentration (I-4).i0 -5 mole/liter). PMR
spectra were recorded on Varian T-60 and Tesla BS-487 C instruments, internal standard HMDS.
Mass spectra were recorded on a LKB-2091 mass spectrometer with direct introduction of the
sample into the ion source, temperature of source 250 ~ , temperature of vaporization of sample
20-250 ~ ionization energy 70 eV.
Chromatography was carried out on Silufol UV-254 plates. Preparative chromatography for
the isolation of V was conducted using alumina activity II in a thin layer (4 ram) on plates
measuring 20 x 20 cm, solvent chloroform.
4-Benzyliden-l-phenyl-3,5-dioxopyrazolidines (la-c) were obtained in 50-56% yield by re-
fluxing ethanolic solutions of equimolar amounts of l-phenyl-3,5-dioxopyrazolidine and the
corresponding aldehyde for 2-3 h with subsequent recrystallization of the precipitated mater-
ial. la, mp 278=280 ~ with decomposition (from butanol). IR spectrum: 1713, 1683, 1663 (s),
1615, 1592 cm -~. UV spectrum, %max (log c): acidic ethanol, 249 (4.15), 325 (4.39); alkaline
ethanol, 232 (3.95), 270 (4.1), 312 (4.39). Found: N 10.6%. CI~HIaN~O2. Calculated: N
10.7%. Ib, mp 282-284 ~ with decompositon (from dioxane). IR spectrum: 1710, 1675 (s), 1620
(s), 1592 cm -l. UV spectrum, kma x (log E): acidic ethanol, 250 (4.14), 319 (4.10); alkaline
ethanol, 270 (4.30), 320 (4.05). Found: N 13.2%. Cx6N~xNsO~. Calculated: N 13.6%. Liter-
ature data [5], mp 280 ~ . Ic, mp 249-250 ~ (from aqueous DMFA). IR spectrum: 1705, 1675 (s),
1658 (s), 1590, 1572 cm -l. UV spectrum, %max (log g): acidic ethanol, 252 (4.33), 372 (4.54);
alkaline ethanol, 246 (4.33), 348 (4.37). Found: N 9.5%. C17H~4N203. Calculated: N 9.5%.
Literature data [6], mp 246~
Sodium Salt of l-Phenyl-4-benzyliden-3,5-dioxop~razolidine(lla). Absolute ether (50 ml)
was added to 0.264 g (i mmole) of compound la dissolved in a freshly-prepared solution of 0.046
g (2 mmoles) of sodium in i0 ml of absolute methanol. The product (0.26 g) was isolated as a
red material. IR spectrum: 1670, 1625, 1595, 1565 (s) cm -~.
l-Phenyl-2-alkyl-4-benzyliden-3,5-dioxopyrazolidine (III). Methyl (ethyl) iodide (300
mmoles) was added to a solution of 50 mmoles of compound la-c dissolved in a freshly prepared
solution of i0 mmoles of sodium in 50-100 ml of methanol. The mixture was left at 20 ~ , the
solution evaporated to half-volume, diluted twice with water, brought to pH 9 with 5% sodium
hydroxide solution, and exhaustively extracted with ether. Acidifying the aqueous solution
gave llla-d (Table 2).
Compound lllb, before evaporation gave 11.6% of Vb as a coloress crystalline substance.
Sodium Salt of l-Phenyl-2-methyl-4-(a-methoxybenzyl)-3~5-dioxopyrazolidine (IVa). Com-
pound Ilia (0.28 g, i ~mole) was dissolved in a freshly prepared solution of 0.046 g (2 m-
moles of sodium in i0 ml of absolute methanol. Addition of ether gave white, finely divided
cyrstals of IVa in quantitative yield.

179
 l-Phenyl-2'4-dlmethyl-4-(~-alkox~benzyl)-3,5-dloxopyrazolidine (V). A. The combined
e t h e r e x t r a c t s , o b t a i n e d during the s y n t h e s i s of compounds I l i a and b were d r i e d with sodium
s u l f a t e , f i l t e r e d , and e v a p o r a t e d to d r y n e s s , to a f f o r d a p a l e - y e l l o w o i l ( I l i a ) or p r e c i p i -
t a t e (lllb), from which after thin-layer chromatographic purification of alumin was obtained
a colorless oil <Ilia) or crystals (lllb), containing (TLC) two spots with very similar Rf
values. Further recrystalllzation from ethanol gave chromatographically homogeneous Va and
b. Pure Vb was also isolated during the synthesis of IIlb (see above).
B. Methyl iodide (0.24 mole) was added to a solution of 40 mmoles of compound Ilia or
b in a freshly prepared solution of 80 mmoles of sodium in 80 ml of absolute methanol (for
Ve, 170 ml of absolute ethanol). The mixture was left at 20 ~ for 96-120 h and worked up as
in the preparation of Ilia-d; compound V was isolated from the ether extract as described in
A. During the preparation of Vb, after extraction, an additional 22% of chromatographically
homogeneous Vb was isolated.
On acidifying the aqueous solutions, the starting materials Ilia and b were recovered.

LITERATURE CITED
i. B.L. Moldarev and M. E. Aronzon, Khim. Geterotsikl, Soedin., No. 6, 820 (1981).
2. B.L. Moldarev and M. E. Aronzon, Khlm. Geterotsikl. Soedln., No. 2, 224 (1974).
3. B.L. Moldarev and M. E. Aronzon, Khlm. Geterotsikl, Soedln., No. 2, 254 (1979),
4. A. Selva, A. Citterlo, and L. Merlinl, Org. Mass Spectrom., No. 10, 606 (1975).
5. A. Mustafa, A. Sammour, and M. Kira, Archly. Pharm., 298, 516 (1965).
6. Th. Asher, Bet., 39, 1018 (1897).

REACTION OF 4-AMINOIMADAZO[4.S-c]PYRIDIN-2-ONES WITH a'BROMOMETHYLKETONES

Yu. M. Yutilov and K. M. Khabarov UDC 547.783'822.7'284'233:543.422

The reactions of 4-amino derivatives of imidazo[4.5-c]pyridin-2-ones with a-

bromomethylketones have been studied. Depending on the nature of the reagents
and the reaction conditions, either 5-acylmethyi salts of the starting amine
or 2-substituted imidazo[4.5-c]imidazo[l,2-a]pyridin-8-ones can be obtained.
The latter compounds are also easily obtained by treatment of the 5-acylmethyl
salts with alkali.

The facile nitration of imidazo[4.5-c]pyridin-2-one in the 4-position has opened up many

new possibilities for the preparation of a wide variety of Substituted derivatives of this
compound [1-3]. Two of these new compounds which are of widespread interest are 4-amino-1-
methylimidazo[4.5-c]pyridin-2-one (Ib) and its 3-methyl congener (la). Previous work has es-
tablished that the base la can be readily alkylated at the nitrogen atom of the pyridine ring
upon treatment with alkyl halides [4]. In the present paper we report our results of the
study of the reactions of la and b with u-bromomethylketones (lib-h) and a-bromoacetaldehyde
(lie).
The addition of the allphatlc a-bromomethylketones lla-d to amine la occurs upon reflux
in alcoholic solution over 1-2 h and gives salts llla-d in hlghyleld (Table i). Clenuuenson
reduction of the acetonyl bromide Illb gives, after acidification of the reaction mixture
with hydrogen iodideD the iodide salt of 4-amlno-5-n-propyl-l,3-dlmethylimldazo[4.5-c]pyrld-
inlum-2-one (V), which has~een previously prepared form amlne la with n-propyl iodide [4].
This observation, coupled with the similarities in the UV spectra of the quaternary salts
llla-d (Table i), leads us to believe that reaction of amine la with the a-bromomethylketones
lla-d generates the 5-acylmethyl salts llla-d.
Institute of Physical Organic Chemistry and Petroleum Chemistry, Academy of Sciences of
the Ukrainian SSR, Donetsk, 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 2, pp. 227-232, February, 1986. Origlnal article submitted December 10, 1984.

180 0009-3122/86/2202-0180512.50 9 1986 Plenum Publishing Corporation

 /CII3 ..4-... CIl 3
I ____N/

0
NII2 CII3 R/
o,;/ iva-h

~ .~-( -%- --)N ~n ,- , r +

C~. ""~" N" 0 n - C,,II., "~/ aN/ O

f'! I +" I t
NIl2 CH 3 NH 2 CH3
R"C*~ llla-f
If, III, IV a R = H; b R = CHa; c R = C(CHa)a; d R = 2'-Ad; e
R = 3'4'-(CHaO)2C6Ha; f R = B-naphthyl; g R = C6Hs; h R = p -
NO2C6H4

Treatment of the acylmethyl salts llla-d with basic solutions releases the free bases
IVa-d. Compound IVa was shown to be identical to the dehydrogenation product of 8-oxo-7)9-
dimethyl-2)3-dihydroimidazo[4.5-c]imidazo[l.2-a]pyridine (VIIa), which was obtained via re-
action of chloride Via with thionyl chloride in refluxing DMF. In an analogous manner salt
IVb could be converted to the hydrochloride of VIIb. The IR spectra of compounds VIIa and b
do not contain absorption bands due to OH and NH2 groups, which are characteristic of the pre-
cursor salts Via and b (3260-3275 and 3370-3400 cm-*). The latter compounds are easily ob-
tained in high yields via reaction of amines Ia and b with ethylene chlorohydrin. Their IR
spectra are similar to that of iodide V.

+ II | I ......-..........
" R~
/ N \ -~-.~.-'% o ~ N;~..''~.'~'~ o " ~+ o
.' NH2 R
H0 Z t:' ~ "Vllla-e
VI a,b VIIa,b
VI, VII a R = CHa~ b R = H; VII a-d R = R 2 = H; e R = R 2 = CH3;
a R* = CHa, b R' = Ph; c R* = p-CHaOC,H~; d R* = 3,4-(CHsO) 2C,Hs;
eR* =H

Aromatic a-bromomethylketones lle and f also react with amine la to generate salts llle
and f, which can be converted to the tricyclic structural derivatives IVe and f upon treatment
with base. It was not possible, however, to isolate acylmethyl salts from the reaction of
amine Ia with the bromoketones IIIg and h. In these cases the 2-arylimidazo[4.5-c]imldazo-
[l.2-a]pyridines IVg and h were isolated directly, whereas half of the starting amine was con-
verted to the hydrobromide salt. If the reactions are carried out in refluxing DMF) the hy-
drobromide salts of imidazo[4.5-c]imidazo[l.2-a]pyridines, namely, VIIla-e, can be isolated
directly, without any intermediates, from the reactions of the amines Ia and b with equivalent
amounts of the u-bromomethylketones IIb, e, and g, p-methoxyphenacyl bromide, or u-bromopro-
pionaldehyde.
The structures of the imidazo[4.5-c]imidazo[l.2-a]pyridines IVa-h and VIIIa-e were con-
firmed on the basis of their spectral data. The IR spectra of the acylmethyl salts IIIa-f
(Table i) contain two carbonyl group stretching bands (1700-1715 and 1715-1730 cm-*)) as well
as N--H stretching bands (3270-3400 cm-~), whereas the spectra of the free bases IVa-h (Table
2) contain only one carbonyl group stretching frequency due to the C=O of the imidazole ring
at 1690-1720 cm-*. The PMR spectra of compounds IVb-h and VIIIa-d (Table 3) contain signals
due to the 3-H aromatic proton at 7.66-7.83 ppm in the case of an alkyl substituent in posi-
tion 2, and at 8.08-8.17 ppm in the case of an aryl substituent in the 2-position. The spec-
trum of compound Ira contains two doublets due to the vicinal protons of the imidazole ring
(2,3-H) at 7.83 and 8.00 ppm; the spin--spin coupling constant is 2.2 Hz) which is characteris-
tic of 2,3-unsubstituted imidazo[l.2-a]pyridines [5]. These data imply that both the bases
IVa-h as well as the hydrobromide salts VIIIa-e contain tricyclic aromatic structures. Methyl-
ation of compound VIIIa with dimethyl sulfate in basic solution gave compound IVb.
In order to verify the structures of the cyclization products arising from amines Ia and
b with u-bromomethylketones, an independent synthesis of a model compound, namely imidazo-
181
GO

TABLE i. Acylme t h y l S a l t s of 4-Amino-l, 3-dime thyXimida zo [ 4 . 5 - c ] p y r i d i n - 2 - o n e

rap, ~ ] IR spec- Found, % Calculated,

Com- Holecular formula Yield, % "
(from { t=rum, VC--0 I.~ Spectrl.mlf ~
pourtr
alcohol) I era-i (ig c) C H Br H Br

Ilia 263--264 1730, I715 229 (4,38), 254 (3,74), 293 39,4 4,7 ~6,8 18,3 C1o[-1rzBrN402 39,9 4,4 ~ ! 8,6 5.3
(3,95)
IIIb 281--283 1720, 1700 229 (4,36), 253 (3,74), 290 4"2,4 5,0 25,3 18,3 C,HIsBrN402 41.9 4,8 25,4 17,8 91
(3,86)
Itl c 280---28t 1"720, 1700 225 (4,71), 252 (3,73), 9_.92 47,1 5,7 21,9 15,4 C.t~H~IBrN40~ 47,1 5.9 22.4 15.7 66
(3,95)
III d 267--270 1725, 1700 229 (4,72), 272 (3,90), 291 54,9 6,4 17,9 13,1 C2,,I1~TBrN402 55.2 6,3 18,4 12.9 ~5
0,09)
IIIe 243--24,1 1715, 1700 | 49,8 5,3 18,0 1;3.0 C,aH~BrN40~ 49,4 4,8 ! 8.3 i_o.8 46
Illf 285--287 1725, 1705 54,4 5,0 17,4 12;7 C~oHI~BrN402. H._,O 53,9 4,8 17,9 12,6 59
 TABLE 2. Imidazo [4.5-c ] imidazo [I. 2-a ]pyridines

Com-
~o: C ]IR spect_r~, Found, % Molecular ICalc,. % [ ,,
pound
ethanol)I VC=O, cm C H N C H. N

IVa 222--224 1670, 1700 59,2 [4,9 C,oH,oN~O 59.4 5.0 27,7 66
IVb 229--230 1660, 1700 5f,815,7 25,6
27'3 C,r 61,1:5,6 25.9 73
IVc 224--225 1669, 1700 55,317,z 21,5 C,4H,sN40 55,17.0 21,7 68
IVd 285--287 !660, 16~p 71,717.5 16,9 C~oI-t2~N40 71,47,2 16.7 74
IVe 238--240 1660, 16.0 54,115,5116/1 C lstt ,sN~,O,~ 53,9'5,4 16.6 78
IVf 238--240 [1670, 1700 ~98,815,3 16,4 C=oHI~N40"Ha0 69,3 5,2 16,2 71
IVg 258--260 1670, 1690 59 315 1 21},0 C~GFII4N,10 69,1 5,1 20,1 58
IVh 350 11670, 1720 59 814,212!,g (:1,,11laNsO,~ 59.4 4,1 21,7 83
Villa 258---250J1660, 1700 422414,2119,'3 C,oHmN40 9 HBr 42,4 3,9 19,8 28
VlIlb 350 ]1660, 1690, 173( 52,1 I-'l-,O 1fi,4 ClsHI~N.~O9HBr 52,2 3,8 16,2 42
VIIIe 302--304~1670. 1705, 1730 48,4~4 7 .14,8 CIsHI,N402-IIBr. H~O 48,9 4.4 14,3 53
Vllld 342--343 1660, 1700, 1730 50,414:4114,0 C:rtII{~N4Os9}tBr 50,,I 4,2 13,8 46
VIII,o 218--219 -- 44,014,31 I8/ (2~HI.~N40 9HBr 44,5 4,4 18,9 32
X 271--273 50,714.312t,~ (';,~}IlaNsOa 59,4 4,1 21,7 35

*Compound IVa was crystallized out of water, and compounds

IVh and VIII out of DMF.

TABLE 3 . PMR specra of Imidazo[4.5-c]iidazo[l.2-a]pyridines

Corn- Chemical shift, 6, ppm

pound I
5,6-11" 2-R I[ 3-R N--CHa

IVa 7,48; 8,50 7.83; 8,00 3,70; 3,97

(2H, 2dh 1=2,2 Hz)
IVb 7,46; 8,41 2,64 (3H) 7,73 3,75; 4,05
IVc 7,42; 8,40 1,50 (9H) 7,70 3,70; 3.97
IVd 7,45; 8,40 1,91 (3H, CH); 7,66 3.70; 3,95
2,13 (12H, CH2)
IVe 8,55; 7,23--7,60 8,t0 3,75; 4,00--4,05 [9H,
[4H, m 5(6)-H and C6Ha] ra, (CH80)2,N--CH8]
1Vf 8,37; 7,27--7,90 8,08 3,60; 3,82
[8H, m, 5(6)-H andC~oHr]
IVg 8,55; 7,50--7,80 8,15 3.78; 4,05
[6fl,m, 5(6)-11 and C~Hs]
IVh 7,63; 8,02--8,73 3,78; 4,07
[6H,m, 5(6)-H, 3-Han~H4]
VIII a 7,42; 8,43 2,55 7,70 3,67
VIII b 8,57; 7,40--7,87 8,17 3,67
[6H, m , 5(6)-H, C6H5]
\ IIlC 7,42; 8,48 3,92 (CHaO); 8,07 3,63
7.10; 768
(2 d, I=8,51Hz ,,
C~,Hd
Vl]ld 8,50; 7.10 .7,55 8,10 3,73
[4}I. m 5(6)-Handc,H3];
e 4,05 (6H,two OC}Ia)
Vlll 7,62; 8,33 [ 7,67 2,68 (3H, s, 3,73; 4,03
CHa)
X 7,02 ar ; 8,07~8.60 I 7,80 3,58; 3,85
[5H, m,5 (6) -HandCdt4

*J = 7.0 Hz.
+J = 7.5 Hz.

[4.5-c]imidazo[l.2-a]pyridine X, with a p-nitrophenyl substituent in the 3-position, was car-

ried out; a mixture of the amine salt of la and p-nitrophenylbenzyl bromide was refluxed with
an excess of a formic acid-amyl formate mixture. The PMR spectrum of the resulting material,
3-(p-nitrophenyl)imidazo[4.5-c]imidazo[l.2-a]pyridine X, does not contain a methylene group
signal at 5.85 ppm, which is present in the spectrum of salt IX, but does contain a signal
for the 2-H proton at 8.47 ppm. A mixture of base X and its 2-isomer IVh exhibits a temper-
ature depression for a mixed melting point sample, which serves as further evidence of the
structures of the imidazo[4.5-c]imidazo[l.2-a]pyridines IVe-h and Vlllb-d, i.e., it confirms
the 2-position of the substituent groups.

183
 COOH
i
,.L
B~-r,"~'~ . . . . . N''cn~
il
I
1 ('II
I 9 N
~woot, ,,COOA. . . . ~ ............ N...I. %
N N ~t ~,
L..JJ ............. ....... ,:,,, 9 N "' ~ ' ' 0
',i iiN ,
CH~
"T" IX CH
NO 2 X X!

In analogy with the behavior described previously for imidazo[l.2-a]pyridine [6], the 3-
substituted imidazo [4.5-c]imidazo[l.2-a]pyridine derivatives Vllle and X also do not undergo
nitrogen coupling reactions, although the 2-methyl derivative IVb reacts with the diazonium
salt derived from p-aminobenzoic acid to give 8-oxo-2,7,9-trimethylimidazo[4.5-c]imidazo[l.2-
a]pyridine-3-azo-4'-benzoic acid (XI). The PMR spectrum of the azo compound XI does not con-
tain a signal due to the proton in the 3-position.

EXPERIMENTAL
IR spectra were recorded on a UR-20 spectrophotometer using vaseline mulls, and PMR spec-
tra were obtained on a Tesla BS-467C (60 MHz) spectrometer using solutions in trifluoroacetic
acid versus TMS as internal standard. UV spectra were taken on a Spectromom-204 spectrophoto-
meter for water solutions.
The properties of compounds III, IV, VIII, and X are summarized in Tables i and 2.
Acylmethyl Salts of 4-Amino-l,3-dimethy!imidazo[4.5-c]pyridin-2-one s (Ilia-f). A solu-
tion of 1.00 mmole of amine la and 1.10-1.15 mmole of ~-bromomethylketone lla-f in 6 ml of
ethanol was refluxed 2 h and then cooled. The precipitate was removed by filtration, washed
with acetone, and dried.
2-Substituted 8-Oxo-7,9-dimethylimidazo[4.5-c]imidazo[l.2-a]pyridines (IVg, h). A mixture
(or suspension) of i0 mmole of acylmethyl salt llla-f in 5 ml of water was treated with 3 ml
of a 45% aqueous NaOH solution and heated on a boiling water bath for 0.5 h. After cooling to
room temperature the precipitate was removed by filtration, washed with ice water, and dried.
2-Arylsubstituted 8-Oxo-7,9-dimethylimidazo[4.5-c]imidazo[l.2-a]pyridines (IVg, h). A
mixture of 1.12 mmole of amine la and 0.57 mmole of ~-bromomethylketone llg and h in 4 ml of
ethanol was refluxed 1 h. The precipitate was filtered, washed with water, and dried. Evap-
oration of the alcohol solvent and basificatlon of the residue yielded 0.09 g (0.51 mmole) of
recovered amine la.
4-Amino-5-n-propyl-l,3-dimethylimidazo[4.5-c]pyridinium-2-one Iodide (V). A. A mixture
of 0.18 g (i.01 mmole) of amine la, 0.35 g (0.20 ml, 2.03 m m o l e ) o f n-propyl iodide, and 3 ml
of DMF was refluxed for i h; the solvent was removed under aspirator vacuum, and the residue
was crystallized out of ethanol. Yield 0.18 g (51%), mp 262-264~ (from ethanol). UV spec-
trum, Imax (log s): 232 (4.70), 259 (3.62), 302 nm (3.76). Found: C 37.5; H 5.3; 1 36.6; N
16.0%. C**H,71N40. Calculated: C 37.9; H 4.9; 1 36.5; N 16.1%.
B. A mixture of 1.0 g of zinc powder, 0.i g of HgCla, and 0.05 ml of 36% HCI and 1.5 ml
of water was shaken, the aqueous layer was decanted, and 2.0 ml of 36% HCI, 1.0 ml of water,
and 0..50 g (1.59 mmole) of salt lllb was added; the mixture was refluxed 12 h, and then every
4 h 0.5 ml of 36% HCI was added. Themixture was evaporated to dryness and washed with ether
(3 x 8 ml); to the residue was added 2 ml of a 40% aqueous NaOH solution , and the precipitate
was filtered, dissolved in 1.5 ml of concentrated HI, evaporated to dryness again, and final-
ly crystallized from ethanol. Yield 0.22 g (40%), mp 262-263~ This material does not ex-
hibit a temperaturedepression in a mixed melting point determination with a sample from A.
4-Amino-5-(B-hYdroxyethyl)-l,3-dimethylimidazo[4.5-C]pyridinium-2-one Chloride (Via). A
solution of 0.99 g (5.56 m mole) of amine la in 1.80 g (1.50 ml, 22.3 =amole) ethylene chloro-
hydrin was heated at 160-170~ for i h. Excess ethylene chlorohydrin was evaporated under as-
pirator vacuum, and the residue was washed with hot isopropyl alcohol, followed by acetone,
and then dried. Yield 1.38 g (96%), mp 228-229~ (from ethanol). UV spectrum, Xma x (log E):
235 (4.74), 260 (3.61), 304 nm (3.92). Found: C 46.6; H 6.1; CI 13.9; N 21.7% C,oH, bCIN~O2.
Calculated: C 46.4; H 5.8; CI 13.7; N 21.7%.
4-Amino-5-(B-hydroxyethyl)-l-methylimidazo[4.5-c]pyridinium-2-one Chloride (Vlb). A sol-
ution of 1.20 g (7.32 mmoles) of amine Ib and 2.40 (35.70 mmoles) of ethylene chlorohydrin in

184
7 ml of DMF was refluxed for 1.5 h. After cooling the precipitate was removed by filtration,
washed with acetone, and dried. Yield 1.07 g (60%), mp 283-284~ (from DMF). UV spectrum,
lmax (log ~), 234 (4.82), 304 nm (4.12). Found: C 44.2! H 5.4! CI 14.1! N 22.9%. CgH, sCIN~02.
Calculated: C 44.2; H 5.4; C1 14.5; N 22.9%.
8-Oxo-7,9-dimethyl-2,3-dihydroimidazo[4.5-c]imidazo[l.2-a]pyridine (Vlla). A mixture of
1.29 g (5.0 mmole) of chloride Via and 0.50 ml (7.0 mmole) of thionyl chloride in 8 ml of DMF
was refluxed for 0.5 h. The solution was concentrated under vacuum to one-fourth of the ori-
ginal volume, cooled, and filtered to remove the hydrochloride Vlla. Yield i.i0 g (91%), mp
296-298~ (from ethanol). PMR spectrum: 3.60, 3.73 (2s, two N-CH3); 4.23, 4.83 (2 x 2H, 2t,
J2~ = 8.5 Hz, CH2CH2); 7.03, 7.90 ppm (2 IH, 2d, J56 = 7.0 Hz, 5,6-H). Found: C 49.9; H
5.5; C1 15.1; N 23.1%. C,oH,2N40"HCI. Calculated: C 49.9; H 5.4; C1 14.7; N 23.3%.
A solution of 0.28 g (1.16 mmole) of hydrochloride Vlla in 0.8 ml of water was treated
with 2 ml of a 45% aqueous NaOH solution; the resulting precipitate of base was removed by fil-
tration, washed with cold water, and dried. Yield 0.20 g (67%), mp 215-217~ (from ethanol).
IR spectrum (CHCI~): 1700 cm-* (C=O). UV spectrum, %max (log E): 238 (4.35), 264 (3.36),
315 nm (3.57). Found: N 21.5%. CIoH,2N~O.3H20. Calculated: N 21.7%.
8-Oxo-7-methyl-2~3-dihydroimidazo[4.5-c]imidazo[l.2ra]pyridine Hydrochloride (VIIb.HCI).
This compound was prepared from chloride Vlb in a manner analogous to that for hydrochloride
Vlla. Yield 93%, mp 262-264~ (from DMF). PMR spectrum: 3.60 (3H, s, N--CHs); 4.25, 4.87
(2 x 2H, 2t, J23 = 8.5 Hz, CH2CH2); 7.02, 7.92 ppm (2 Hz, CH2CH2); = 7.0 Hz, 5,6-H). Found:
C 41.3; H 5.7; C1 14.0; N 2 1 . 1 % . CgH, oN~O.HCI.2H~O. Calculated: C 44.2; H 5.4; CI 14.5;7-N
22.9%.
Dehydrogenation of 8-Oxo-7,9-dlmethyl-2,3-dihydroimidazo[4.5-c]imidazo[l.2-a]pyridine
(Vlla). A mixture of 0.51 g (1.97 mmole) of base Vlla and 0.21 g (1.32 mmole) of potassium
permanganate in 50 ml of acetone was refluxed for 1 hl The residue was removed by filtration
and washed with acetone, and the combined acetone solutions were evaporated and the residue
crystallized from water. Yield 0.42 g (83%), mp 222-224~ (from water). The sample did not
exhibit a melting point depression upon mixing with a sample of IVa.
Hydrobromides of 2-Substituted 8-Oxo-7-methylimidazo[4.5-c]imidazo[l.2-a]pyridines (Villa-
d). A mixture of 0.18 g (i.00 mmole) of amine Ib and 1.10-1.15 mmole of one of the ~-bromo-
methylketones lib, e, or g or p-methoxyphenacyl bromide in i0 ml of DMF was refluxed for 1.5
h. The mixture was cooled and the precipitate was filtered, washed with alcohol and ether,
and dried.
Hydrobromide of 8-Oxo-3.7,9-trimethylimidazo[4.5-c]imidazo[l.2-a]pyridine (Vile). This
Was prepared from amine la and ~-bromopropionaldehyde in a manner analogous to the procedure
used above for compounds Vllla-d.
Methylation of 8-Oxo-2,7-dimethylimidazo[4.5-c]imidazo[1.2-a]pTridine. A suspension of
0.20 g (0.71 mmole) of hydrobromiae Villa in a solution of 0.30 g (5.36 mmoles) of KOH in 4.5
ml of water was treated with 0.33 ml (3.50 mmoles) of dimethyl sulfate and the mixture was
maintained for 0.5 h, and then an additional 0.08 ml (0.85 mmole) of dimethyl sulfate in 2 ml
of 8.3% KOH solution was added; the mixture was then allowed to stand overnight. The precipi-
tate was removed by filtration, washed with water, and dried. Yield 0.I0 g (65%), mp 229-231~
(from alcohol). The substance is identical in all respects to a smple of IVb.
4-Amino-5-(p-nitrobenzyl)-l,3-dimethylimidazo[4.5-c]pyridinium-2-one Bromide (IX). A
mixture of 0.60 g (3.4 mmole) of amine la and 0.73 g (3.4 mmole) of p-nitrobenzyl bromide in
i0 ml of methanol was refluxed for 2 h. The solution was concentrated to */~ volume, cooled,
and the precipitate was filtered, washed with ether, and dried. Yield 1.02 g (77%), mp 296-
297~ (from methanol). PMR spectrum: 3.68, 3.97 (2s, two N--CH3); 5.85 (2H, s, N--CH2); 7.25,
8.07 (2 IH, 2d, Js6 = 7 0 Hz, 5,6-H); 7.50, 8.38 (2 x 2H, 2d, J2'3 = J 5'6 = 8.5 Hz, 2' 3'
5', 6'-H). Found: C 45.2; H 4.5; Br 20.3; N 17.8%. C,bH,6BrNb03. Calculated: C 45.7; H
4.1; Br 20.3; N 17.8%.
8-Oxo-3(p -nitrophenyl)-7,9-dimethylimidazo[4.5-c]imidazo[l.2-a]pyridine (X). A mixture
of 0.35 g (0.89 mmole) of bromide IX, 2.5 ml of 99% formic acid, and 2.5 ml of amyl formate
was heated at 170-!75~ for 2 h; the solvent was removed under vacuum and the residue was neu-
tralized with aqueous ammonia, washed with water, and crystallized from DMF. Yield 0.i0 g
(35~).

185
 8-Oxo-2,7,g-trtmethylSmid'azo[4.5-e]imidazo[1.2-a]p~ridine-3-azo-4'-benzotc Acld (Xl). A
solution of 0.12 g NaICOa in 5 ml of water was treated with 0,28 g (2.04 mmoles) of p-amlno-
benzoic acid, 0,15 g (2.17 mmoles) NaNOa, and 2 ml of water. The solution was then poured
onto a mixture of 2.5 g ice and 0.5 ml 36Z HCl and an alcohollc solution of 0.43 g (2.00 m-
moles) of compound IVb was added. After 15 min the resulting bright red precipitate was fil-
tered, washed with water and acetone, and dried. Yield 0.50 g (69Z), mp 348-350~ (from DMF).
Found: C 58.8; H 4.8; N 23.0X. ClaH~6N6Os. Calculated: C 59.3; H 4.4; N 23.1~.

LITERATURE CITED
1. Yu. M. Yutilov and I. A. Svertilova, Khim. Geterotsikl. Soedin., No. 1, 97 (1986).
2. Yu. M. Yutilov and I. A. Svertilova, Khim. Geterotsikl. Soedin., No. 1, 138 (1973).
3. I.A. Svertilova and Yu. M. Yutilov, USSR Inventor's Cert. No. 521,277| Byull. Izobr.,
No. 26, 80 (1976).
4. Yu. M. Yutilov, K. M. Khabarov D and I. A. Svertilova, VINITI, No. 4182-79, December 10,
1979.
5~ W.W. Paudler and H. L. Blewitt, J. Org. Chem., 31, 1295 (1966).
6. W.W. Paudler and H. L. Blewltt, J. Org. Chem., 30, 4081 (1965).

EFFECTS OF ACIDS ON ORIENTATIONINTHE REACTION OF

5-FORMYL-4-(I-PYRIDINO)AZOLE 2-OXIDES WITH AROMATIC AMINES

E. O. Kochkanyan, A. N. Zaritovsklij UDC 547.821.3'775'556.9'551:

A. B. Kruglova, and N. A. K l y u e v 543.422

Azole betaings containing viclnal formyl and pyridinium groups react with aro-
matic amines to glve, when protonated by weak or strong acids, azolldlne'2,4-
dione-5-aldehyde azomethlnes (1) or 4-aryllmlnoazolidin-2-ones (If), respective-
ly. Compound (1) is formed by the intramolecular migration of the oxygen in the
4-position of the azole, and (11) by decarbonylation of the original betalne.
The orientation in the reaction of dicentric nucleophiles (hydrazines and o-phen-
ylenediamine) is independent of the extent of protonatlon, giving betalne hydra-
zones and azolo[4,5-b]benzodiazepines, respectively. The PMRmass spectra of
the products are discussed.

The orientation of nuc!eophilic substitution in betaines, including nucleotides, dis-

plays special features as a result of the presence of charged centers, and it has received
little attention. Studies in this area could lead to an understanding of the processes oc-
curring in point mutations resulting from replacement of a pair of heterocyclic bases in nu-
cleotldes.
Azole betainealdehydes (I) may be regarded as systems with a masked electrophilic func-
tion resulting from theparticipation of the formyl group in delocalization of the negative
charge. This feature of betaines can, depending on the reaction medium, have a marked effect
on the orientation of nucleo philic substitution reactions, as a result of the selective sol-
vation of the solvent at the catlonoid or anionold moieties. We have previously reported
that mineral acid salts of betaines react with tertiary nitrogeneous bases [1] and triaryl-
phosphines [2] ~rlth replacement of one cation by another to give new betaine salts, and when
the betaines themselves react with annuonia or hydrogen sulfide trlcyclic systems are obtained.
We have not examined the reaction of betaines with nitrogeneous bases containing a primary

I n s t i t u t e of Physical Chemistry and Carbon Chemistry, Academy of Sciences of the Ukrain-

ian SSR, Donetsk~ 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp.
233-238, February, 1986. Original article submitted December 12, 1984; revision submitted
March 19, 1985.

186 0009-3122/86/2202-0186512.50 0 1986 Plenum Publishing Corporation

amino group, and the influence of the structure, the amine, and the reaction medium on t h e
orientation of the substitution.

<
Xk.2o
.I R
Ph r-
III ~X
R \,. N 0 k~7 t aHN.

Ph It 7 6
0 SP
0 ['h ~,
I i: a-d n a-d
Ph
IV

The betaines (I) react With anils in acetic acid when the molar ratio of reactants is i:i
to give azolidine-2,4-dione-5-aldehyde azomethines ( I I ) . Bearing in mind the alternative pos-
sibility of the formation of the isomeric 4-aryliminoazolidin-2-ones (III) by direct substi-
tution of the cation in the 4-position of the azole ring or of azolo[4,5-c]quinolines (IV),
hydrated with one molecule of/water, we examined the mass, PMR, and IR spectra of the products.
The molecular masses of the compounds (II) (R=H, p-NOi, m-CH,, and p-I) found by mass
spectrometry were in agreement with the calculated values for each of the azolidine-2,4-dione-
5-aldehyde azomethines. The mode of fragmentation of the molecular ion (M+) under electron
impact was fully in accordance with the proposed structures for the azomethines (II), and is
well described by the following scheme:
_ -- +

I /o "

"t, s .... (co~..mi .~~ , "+h _~. a.R] +

I I n' "~::;) I I ~'"V a \c::J

L 1--~ C I x2 ?xeII
d \"-J/' I + i /'- /i--2~ J~
%"~ + .... e C~NIi ' ff"C7 " k-~

u g ,.2::J

The PI~ s p e c t r a a l s o f u l l y confirmed the s t r u c t u r e s o f ( I I ) (Table 1 ) .

Let us consider the PMR spectrum of (IIe) (R = p-NOi) as an example. The broad singlet
at low field with 6 11.55 ppm is characteristic of the amino group. The protons of the N-
phenyl substituent are poorly resolved (multiplet at 6 7.45-7.65 ppm). The 3,7 and 4,6 pro-
tons of the p-nitrophenyl substituent give rise to two doublets at 7.35 and 8.17 ppm, J = i0
Hz. Protons I-H and 2-H form another system of signals appearing as two doublets with ~ 7.13
and 9.85 ppm, with J = 12 Hz. The integral plot gives the ratios of these signals as 1:5:2:2:1:1,
confirming the correctness of the assignment of the signals and of the structure as the azome-
thine (If).
The spectra of (Ia-d) (Table i) show superposition of the signal for the I-H proton and
the signals for the protons of the substituted ring on the resonance for the N-unsubstituted
benzene ring protons to give complex multiplets.
The IR spectra of (II) show absorption for two carbonyl groups and the associated amino-
group which, in conjunction with the results given above, unambiguously establishes their
structure as azolidine-2,4-dione-5-aldehyde azomethines.
In the reaction of the betaines (I) with o-aminobenzenesulfonic (orthanilic) acid in ace-
tic acid, elimination of the sulfo group occurs to give compounds which are identical with the
products of the condensation of the betaines with aniline, as shown by the absence of depres-
sion in the mixed melting point.
When the reaction of the betaines (I) with orthanilic acid was carried out in alcohol or
aqueous alcohol, a product was obtained which did not contain a sulfo group, and had empirical

187
O0
O0

TABLE i. PMR Spectral Data (in DMS0-D6) for Imidazolids Azomethines (IIa-e)

i . ~\.1r
l~h II 7- 6

. . . . . . . . . . . . . . . . . . . ~i~I ..... Shi~t~, ,S .p~,,'(J, ~.) ' .... "

ComPound }
8-{1 2.H C611s I-II 3 1-1 J I~-I1 5-1]
~-t[ I
la H 11,36, s ( 1 = 12) 9,32fl 6,88-- 7,64, m
I'D 4-[ 11,05, s (I= 12) 9,06,d 6,6--7,68, m
1C 4-CH~ 11,09, s (1=12) 9,25,d 2,06, s 6,8.--7,62, m
Id 2-COOH 11,55, s 9,o6,d ( I = t 2 ) 10,88, s 6,6--8,13, m
le 4-NO.~ 11,55, s 9,85 (J=12) 7,45--7,65, m, T,13, d (1=12) I 7.35,d (J=lo) } I 18A ,", d (i= ~o)
formula C,bH,~N30. Its PMR spectrum showed a multiplet at 6.14-7.10 ppm, and two singlets
at 4.71 and 10.31 ppm, which from their integral intensltles (i0~2,1) could be due to the res-
onance of the protons of two phenyl groups, a methylene, and an amino group. This was con-
flrraed by their IR spectra, which showed absorption for one carbonyl group at 1680 cm-*, and
for N--H and C-~ at 3280 and 1630 cm-*, respectively.
We therefore conclude that in alcoholic or aqueous alcoholic solution there is a change
in the orientation of the reaction of the betaines (I) with amines, the reaction involving
fission of a C--C bond* and cleavage of the formyl group with simultaneous nucleophilic re-
placementof the pyridine by the arylimino group to give l-phenyl-4-phenyliminoimidazolldln-2-
one (III), which was synthesized directly by the route shown below.
Elimination of the sulfo group under these relatively mild conditions is, in accordance
with literature reports [6], due in our opinion to the assistance of the betaine in the trans-
fer of a proton from the amino group of orthanilic acid to the carbon atom directly bonded to
the sulfonyl group. When an excess of the aromatic amine is used, the orientation of the re-
action changes the orientation of the nucleophilic substitution. For example, when the bet-
aines (I) react with a threefold excess of aniline in acetic acid, instead of the azomethines
(lI), (III) are obtained.
The stability to hydrolysis of the internuclear bond between the pyridine and imidazole
rings, which is unaffected by heating the betaines in water or aqueous acetic or mineral ac-
ids, together with the high rate of formation of the azomethines (II), lead to the conclusion
that replacement of pyridine by the oxygen atom when the reaction is carried out in acetic
acid, as is the case with triphenylphosphine [2], is a intramolecular process. This is quite
feasible when it is recalled that the oxygen atom of the formyl group in the betaines is ori-
ented with respect to the pyridinium cation as a result of electrostatic interaction to give
an intramolecular charge-transfer complex (CTC), such as we have reported previously [7]. On
this basis, attack of the amine on the carbonyl group enhances this interaction and the nucleo-
philic replacement of pyridine by the oxygen atom. This is also supported by the fact that the
color which develops in the reaction is not due to the intermediate formation of 4-pyridino-5-
formylazole-2-oxide azomethines, since a similar effect is seen in the reaction of the betaines
with N-methylaniline, leading to the formation of b-(N-methyl-N-phenylaminomethylidene)azoli-
dine-2,4-dione (V).
The above conclusions are supported by the observation that the reaction of betaines with
dicentric nucleophiles such as hydrazine and o-phenylenediamine, the two nucleophilic centers
of which compete with the oxygen atom in the formation of CTC with the pyridinium cation in
the transition state, lead to different products. For example, in the reaction of the betaines
(I) with a,u-methylphenylhydrazine, either in acetic acid or in alcoholic solution, the 5-
formyl-4-(l-pyridino)azole-2-oxide hydrazones (VI) are formed exclusively, i.e., when there
is no interaction between the betaine and the aromatic amine, no nucleophilic substitution by
oxygen is observed.
A similar situation occurs in the reactions of betaines with o-phenylenediamine in acetic
acid to give iH,10H-2-oxazolo[4,5-b]-l,5-benzdiazepines (VII). The structures of (V-VII) were
confirmed by their elemental analyses, IR, PMR, and mass spectra, and by direct synthesis.

~- N H
N N R N t~ti, ) 2 ........
L ; ;",- [ } iN l" 0
N Z "~\ -'" ! X=S N "~1 " '; X=N -Ph ~/~"N ""

l' S.~. t' X Ph

-0 ' "0 "
vI l VII

! f', [J N I i t ' H , II , :"-'" ~ b;}t z

.0 CI
IH'~ ,~ l-IN . . . . . ,~"
! ! c~t, |
li
~:/ q' "'i'---N" -C~II~ 0 " N'! "~ Cz HrcO
_

Ph II Ph
VL.!

*Fission of a C--C bond is typical of betaines or ylid systems in alcoholic and aprotic media,
but has not been observed in acetic acid [3-5].

189
 It m a y be assumed on the basis of these considerations that when an excess of aromatic
amine is used, and the reaction is carried out in acetic acid, by using competitive solvation
of the base by the pyridinium cation it is possible to achieve the result obtained in the re-
action of betaines with dicentric nucleophiles. This should result in reorientation of the
course of the reacgion to give, instead of the azomethines (If), the 4-arylimlnoazo-2-azolld-
ones (Ill), and this is found experimentally.
Returning to the examination of the reaction of betaines with anilines in acetic acid,
the following explanation of the reaction mechanism is proposed. The betaines (I) in acetic
acid are weakly protonated, the reaction merely amounting to solvation of the acid at the
anionic moiety of the betaine as a result of the formation of hydrogen bonds, since they crys-
tallize from acetic acid as the bases.
Consequently, the first step is attack of the amine on the aldehyde group of the betaine.
The reaction then proceeds by a concerted mechanism, with the acetic acid facilitating the
transfer of a proton from the ammonium group in the transition state on carbon C(s) of the
azole ring, thus facilitating the Intramolecular replacement of pyridlne by the oxygen of the
formyl group, as observed in the formation of four-membered rings in enamines

X~ N' "2h .... X=N-'Ph ~ "" " :/' ........ "O

I
"O/ I %'11
VI
"~'~"-, --Nit,

.O ,el
x,:~ .... # " .[m'~....... [(l.
/ L C'tl~
0 / / ~ " - N ..'' -:.'C .... N~._.C,fll5 0~z'lq ..... C'l~O
'I
Ph
I
1I
I
Ph
Viii

This mechanism is supported by the fact that addition of a mineral acid (HCI or H2S04) or
monochloroacegic acid (which are capable of protonating the betaine) to the reaction mixture
results in the formation of (IIl) rather than the azomethlnes (If), i,e., in the presence of
mineral acids, the relatively stable N-protonated form is produced, in which transformation of
carbon C(5) of the azole ring from the sp ~- to the sp'-hybridized state is rendered difficult.
This makes the intramolecular replacement of pyrldine by the oxygen atom less energetically
favorable, and assists the elimination of formanilide:
+

tl !l ,~ r,'-NH . , : % . ~ ...... I ,o- - . ~x

" t~ ...... ~'-----t~- ' li ii I Ii [-. ~-,- I - V
i/H
-~ 'N"~]- H~ 'N " i N:t..~ . ~ ~ L
[ I'! ti " I{C N "t..' i . O ""N"'''I[
va I I u l i I
t Ph ~'h j Ph -

EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument, in vaseline oil, and mass spectra on a
VarianMAT-311 spectrometer, ionizing electron energy 70 eV. The samples were introduced di-
rectly into the ion source of the mass spectrometer at a temperature of 100-150~ PMR spec-
tra were obtained on a Varlan XL-100, operating frequency I00 MHz, at a temperature of 30~
solvent deuterodimethyl sulfoxide, internal standard HMDS. UV spectra were obtained on an
SF-4 instrument, in methanol.
Azolidine'2,4-dione-5-aldehyde Azomethines (II). A mixture of i0 mmoles of the betaine
(la-d) and i0 mmoles of the aromatic amine was boiled in acetic acid for 20-30 min. The mix-
ture was then cooled, and the yellow crystalline powder which separated was filtered off.
(lla) (R = H), yield 76%, mp 257~ (from DMF). Found: C 68.8; H 4.8; N 15.3%. Ct,H,,N,O=.
Calculated: C 68.8; H 4.6; N 15.1%. (llb) IR = p-I), yield 63%, mp 265~ (from dioxane).
Found: C 47.6; H 2.8; 1 31.1; N 10.4%. C,6HI21Ns02. Calculated: C 47.4; H 2.9~ 1 31.3;
N 10.4%. (llc), yield 74%, mp 242~ (from toluene). Found: C 69.9| H 5.6; N 14.5%. C,7-
H, sNsOz. Calculated: C 69.6; H 5.1~ N 14.3%. (lid), yield 71%, mp 304-305~ (from nitroben-
zene). Found: C 63,5| H 4.2| N 13.2%: C,TH,3N30~. Calculated: C 63.2; H 4.0; N 13.0%.

190
(lle), yield 75%, mp 281~ (from dioxane). Found: C 59.3; H 3.8; N 17.4%. C~HI=N404. Cal-
culated: C 59.2; H 3.7; N 17.3%.
Reaction of Betaine (la) with Orthanilic Acid. The betaine (la) (2.65 g, I0 mmoles) was
dissolved in i0 ml of acetic acid, and 1.73 g (i0 mmoles) of orthanillc acid was added. The
mixture was boiled for 40-50 min, and the bright yellow solid which separated on cooling was
isolated to give 1.61 g (58%) of product, mp 257~ (from DMF). Melting point of a sample mixed
with azomethine (lla), 257~ ,.
l-Phenyl-4-phenyliminoimidazolidin-2-one (Ilia). A. The azomethine (la) (1.32 g, 5 m-
moles) was dissolved in a i:i mixture of methanol and water, and 0.86 g (5 mmoles) of orthan-
ilic acid added. The mixture was boiled for 50 min, and the solid which separated was filtered
off and washed with methanol to give 0.69 g (55%) of product, mp 295-296~ (sub., DMF).
Found: C 71.8; H 5.3; N 16.9%. C15H~sN30. Calculated: C 71.7; H 5.2; N 16.7%.
B. l-Phenyl-5-formyl-4-(l-pyridino)imidazole 2-oxide (la) (2.65 g, I0 mmoles) was dis-
solved in acetic acid, and boiled with a threefold excess of aniline for 5-10 mino The fine-
ly crystalline white solid which separated was filtered off and washed with methanol to give
2.2 g (90%) of product, mp 295-296~ (sub., DMF). Melting point of sample mixed with (Ilia),
295-296~ (sub.).
C. Equimolar amounts of 4-thiohydantoin and aniline hydrochloride were boiled in methanol
for 15-20 min. The solid which separated on cooling was filtered off and washed with methanol
to give 79% of product, mp 295-296~ (sub., DMF). Melting point of a sample mixed with (Ilia)
295-296~ (sub.).
l-Phenyl-5-(N-methyl- or N-phenylaminomethylidene)imidazolidine-2~4-dione (V). The be-
taine (2.65 g, i0 mmoles) was dissolved in acetic acid, and I.i ml (I0 m moles) of N-methyl-
aniline added. The mixture was boiled for 20-25 min, and cooled to give a bright yellow solid,
yield 1.77 g (61%), mp 283~ (DMF). IR spectrum: 1680 (C=O), 1720 (C=O), 3280 cm -I (N--H).
Found: C 69.4; H 5.2; N 14.3%. CITHIsN30=. Calculated: C 69.6; H 5.1; N 14.3%.
2__-Formyl-4-(l-pyridino)thiazole 2-Oxide u~u-Methylphenylhydrazone (VI). A mixture of
2.06 g (i0 mmoles) of 5-formyl-4-(l-pyridino)thiazole 2-oxide and 1.22 g (i0 mmoles) of u,a-
methylphenylhydrazine in i0 ml of acetic acid was heated for 5-10 min at 60~ The dark red
needles which separated were filtered off to give 2.08 g (67%) of product, mp 230~ (DMF).
PMR spectrum (DMSO-D6): 3.35 (3H, s, CH3), 7.27 (SH, m, C~Hs), 7.45 (IH, s, CH=N), 9.40 (2H,
+ + +
d, CsHsN), 8.75 (IH, t, CsHsN), 8.30 ppm (2H, t, CsHsN). Mass spectrum, m/z (peaks ~ 3% of
maximum): 50 (22), 51 (41), 52 (32), 56 (8), 60 (26), 63 (ii), 64 (i0), 65 (21), 67 (9), 70
(12), 77 (i0), 78 (55), 79 (i00), 80 (50), 91 (9), 92 (16), 93 (14), 104 (18), 105 (44), 106
(99), 107 (69), i08 (8), 133 (16), 134 (5), 144 (41), 158 (18), 159 (17), 177 (12), 204 (48),
205 (12), 250 (34), 251 (7), 310 (M+, 4). UV spectrum (in methanol), %max (log ~): 260 (4.1),
350 (4.5), 500 nm (3.5). Found: C 62.0; H 3.7; N 18.1; S 10.2%. C16HI~N~OS. Calculated:
C 61.9; H 3.9; N 18.1; S 10.3%.
iH,10H-2-Oxoimidazo[4,5-b]-l,5-benzodiazepine (VII). A. A mixture of 2.65 g (i0 n~noles)
of the betaine (I) and 1.08 g (i0 mmoles) of o-phenylenediamine in methanol with the addition
of a catalytic amount of hydrochloric acid was boiled for 20-30 min. The deep blue crystal,
line solid which separated was filtered off and washed with methanol to give 2.2 g (80%) of
product, mp 340~ (DMF). IR spectrum: 1630 (C=N), 1720 (C=O), 3260 cm -~ (N--H). Found: C
69.7; H 4.4; N 20.2%. CI~HI2N40. Calculated: C 69.5; H 4.3; N 20.2%.
B. A mixture of 8.9 g (40 mmoles) of l-phenyl-4-chloro-5-formylimidazolin-2-one (VIII)
and 0.48 g (60 mmoles) of o-phenylenediamine was boiled in 30 ml of ethanol for 20 min. The
solid which separated was filtered off andlwashed with ethanol to give 6.7 g (61%) of product,
mp 340~ (DMF). Melting point of a sample mixed with material obtained as in method A,
340~

LITERATURE CITED
i. R. O. Kochkanyan, N. V. Spitsyn, and S. N. Baranov, Khim. Geterotsikl. Soedin., No. 2,
272 (1983).
2. R. O. Kochkanyan, S. S. Lukanyuk, T. A. Dmitruk, and N. G. Korzenevskaya, Zh. Obshch.
Khim., 55, 155 (1985).
3. V. S. Garkusha-Bozhko, R. O. Kochkanyan, O. P. Shvaika, and S. N. Baranov, Khim. Getero-
tsikl. Soedin., No. 3, 372 (1976).

191
 4. H. W~tCman, P. SeuCel, and E. Zs Monatsh. Chem., 100, 1624 (1969).
5. H. Wittman, P. Beutel, and E. Ziegler, MonaCsh. Chem., 1619 (1969).
6. ~. E. Gilbert, The Sulfonation of Organic Compounds [Russian translation], Khlmiya, Mos-
cow (1969), p . 372.
7. R.O. Kochk~nyan, A. N. Zaritovskii, N. A. Klyusv, B. M. Zolotarev, and S. N. Baranov,
Khim. Geterotsikl. Soedin., No. 2, 255 (1978).

REACTION OF PYRIDO[I,2-a]BENZZMZDAZOLE AND

TETRAHYDROPYRZDO[I,2-a]BENZIMIDAZOLE WITH ACETYLENEDICARBOXYLIC ESTER

N. S. Prostakov, A. V. Varlamov, I. V. Shendrik, UDC 547.836.3;542.953:

A. P. Krapivko, and N. I. Golovtsov 543.422'25

Previously unknown polynuclear c o n d e n s e d systemswith bridgehead nitrogen atoms

have been obtained by treating acetylenedicarboxyllc ester with pyrido[l,2-a]-
benzimidazole and tetrahydropyrido[l,2-a]benzimidazole.

We have developed a convenient m e t h o d for the synthesis of pyrido[l,2-a]benzimidazole

(I) [i] allowing us to expand studies of its properties. With the aim of obtaining new poly-
nuclear condensed heterocycllc compounds with bridging nitrogen atoms we have turned to re-
actions of pyridobenzimidazole (I) (and the derived tetrahydropyrido[l,2-a]benzimidazole)
with acetylenedicarboxylic ester (ADCE),
Both of these compounds can be regarded as 1,2-disubstituted benzimidazoles. Thus their
reaction with ADCE can be the same as benzimidazole [2] but with the formation of more com-
plex heterocycles,
The reaction of pyrido[1,2-a]benzimidazole (1) with ADCE in benzene takes place quanti-
tatively at 20*C. In addition, adducts are formed with two and three molecules of ADCE and
are separated using column chromatography. The first of these is red, crystalline material

TABLE i. PMR Spectral Parameters for II, IV-Vl

Chemical shifts,% ~ ; ppm

C]I~O J, Hz
I I-H

I1 6,65 7,50 7,08 7,41 9,12 8,02 8,56 7,80 --- 3,26; 3,37; (1-2) 7,5; (1-3) 1,2;
! 3,488; 3,492 (I--4) 0,4; (P~--3) 7,5;
1 {2--4) 1,2; (3--4) 7,5;
(5--6) 6,0; (5--7) 1,4;
(5--8) 0,7; (6--7) 7,8;
(6 8) 1,5; (7--8) 8,0
V 6,69 i 7,03 7,03 6,69 3,67 201il,53 1,53 - - 3,71; 3,73;
3,78; 4,02
VI 6,90 7,]0 7,10 6,90 3,85 1,9.8 2,45 - - 5,4' 5,9 3,49; 3,65; 31,o n = 5
3,69; 3,82
IV 7,69j7,237,21 7,28 4,07 2,11 2,0213,09 - -

*For IV-Vl, the chemical shifts for the methylene protons

are assigned as the center of the corresponding multiplets.
%Benzene ring protons IH-4H, nitrogen ring protons 5H-8H,
1OH, IIH.

P. Lumumba People's Friendship University, Moscow, 117923. Translated from Khimiya Get-
erotsiklicheskikh Soedinenii, No. 2, pp. 239-241, February, 1986. Original article submitted
October 29, 1984; revision submitted March 26, 1985.

192 0009-3122/86/2202-0192512.50 9 1986 Plenum Publishing Corporation

whose color is apparently due to the poly-conjugated molecular system. The structure of this
material was shown by PMR spectroscopy to be 9,10,11,12-tetra(carbomethoxy)bis-pyrido[l,2-a:
2',l'-b]benzimidazole (II). Assignment of all of the PMR signals can be made for II by means
of double resonance and by comparison with the parameters for the starting pyridobenzimidazole
I [i] (Table l). The PMR spectrum of II shows two four-spin systems for the protons of t h e
dihydropyridine and the benzene fragments in the molecule with characteristic parameters. The
large increments for the chemical shifts of protons 1 and 3 to high field (1.26 and 0.42 ppm,
respectively, when compared with I [2]) are due to the change in hybridization of the imidazole
nitrogen atom from sp 2 in I to sp 3 in II. The presence of the quaternary carbon a t o m (C)aa in
!I) is shown by a XSC NMR signal at 6 79.5 ppm.
The second adduct (IIl), formed in significantly larger quantities, is a yellow crystal-
line material with PMR and ~3C NMR data in conflict with one another and not permitting an un-
equivocal structural assignment. Detailed NMR parameters for III will be reported after x-ray
inve s riga t ion.
The studied reaction occurs in two stages. Adduct II is initially formed and this re-
acts with a third molecule of ADCE to give III. Direct reaction of isolated II with ADCE gives
III in 90% yield.
6
/(2 7

cooc, .......... ,,,

"~" N~ "'v CII3OOC/ ~ / ~ C O O C H 3

C00CIt 3
I II

The a d d u c t s a r e a l s o p r o d u c e d from t h e r e a c t i o n o f t e t r a h y d r o p y r i d o [ 1 , 2 - a ] b e n z i m i d a z o l e
(IV) with ADCE. The basic product of the reaction (an analog of II) is the red, crystalline
5,6,7,8-tetrahydro-9, i0, ii, 12-tetra (carbomethoxy) bispyrido [i, 2-a: 2 ', l'-b] benzimidazoline (V).
In significantly smaller yield there is also obtained the yellow crystalline 5,5a,6,7,10,
ll-hexahydro-8,9, i0, ll-te tra (carbome thoxy) pyrido [1,2-a] azepino [2 ',! '-b ]benzimidazoline (VI).
" s
z--
4 5a/
9 "Y " l---N )

' ' !
.....
'.~/'
,I
" N" bw"
IL
2 % . > / .......N ~>~--COOCH m

, COOt II 5 CII300C 1~ F g " COOCtI 3

I COOCH3
IV V COOCI{3 VI

The molecule VI contains the fragment 9,10-dihydro-azepino[l,2-a]benzimidazole. Com-

pounds of this type, obtained by reaction of benzimidazoles with ADCE have been described
in [2].
A particular characteristic of the PMR spectrum of adduct VI is the presence of an iso-
lated system of two methine protons with 6 = 5.47 and 5.91 ppm for C(,o) andC(t,), respectively
(Table i). The small vicinal spin--spin coupling for these protons ( s j = 5 Hz) is apparently
due to the trans orientation of the carbomethoxy groups. It should also be mentioned that in
the adducts V and VI the four spin system for the benzene ring protons has degenerate charac-
ter on account of the virtual coincidence of IH with 4H and of 2H with 3H. The IH and 4H sig-
nals in V and VI are found at significantly higher field than those in IV, the highest shift
being observed for IH associated with the change in hybridization of the neighboring nitrogen
atom. The signals for the methylene protons of the piperidine related rings in V and VI occur
as complex multiplets.
The 13C NMR spectra of V and VI clearly show signals for the methylene carbon atoms of
the reduced heterocycles (corresponding to four and three carbons, respectively) as well as
the tertiary carbons C,o and C~,.

EXPERIMENTAL
PMR and '3C NMR spectra (internal standard TMS) were measured on Bruker superconducting
magnet instruments (WM-250 and WM-400) at 250 and 400 MHz for protons and 63 and 100.6 MHz
for carbons, respectively. UV spectra were obtained on a Specord UV-VlS using ethanol solvent
and IR spectra as KBr tablets. Mass spectra were run on a Varian MAT-44. Chromatography em-
ployed silica gel L 100/160 columns and applied layer Silufol grade UV 254 material.

193
 9,10,11,12-Tetra(carbomethoxy)bispyrido[l,2-a:2',l'-b]benzimidazoline (If). A solution
of I (0.4 g, 2.4 rauoles) and ADCE (! g, 7 mmoles) in benzene (20 ml) was allowed to stand at
20~ for 5 h. After evaporation of benzene the residue was chromatographed (30 1 cm column).
Initially, a mixture of ether and hexane (2:1) removed III (0.62 g, 44%) as yellow crystals
with mp 151~ (with decompositon, from ether). Rf 0.36 (ether). Found: C 58.9; H 4.5; N 4.8%;
M + 594. C2,H~,N20, 2. Calculated: C 58.6; H 4.4; N 4.7%; M 594.
Subsequently adduct !l (0.35 g, 33%) was eluted using ethyl acetate as red crystals, mp
171-172~ (from ethyl acetate). Rf 0.27 (mixture of ethyl acetate/alcohol, 3:1). *'C NMR
spectrum (DMSO-D,): 79.5 (C(sa~), 130.3 (C(,)), 145.5 ppm (C(s)); JCb, H-5 = 189 Hz. IR spec-
trum: 1750, 1720 cm -I (CO) J UV spectrum lma x (log e): 210 (4.40), 275 (4.05), 320 (4.00),
430 (3.80), 570 (sh) nm (3.20). Found: C 61.3; H 4.5; N 5.9%; M + 452. C=3H2oN=O,. Calcu-
lated: C 61.1; H 4.4; N 6.2%; M 452.
A solution of adduct II (0.i g, 0.22 mmole) and ADCE (0.03 g, 0.24 mmole) in benzene (ii
ml) was held for 2 h at 20~ The residue was chromatographed to give III (0.12 g, 91%) with
mp 150~ A mixed melting poins with the sample described above was not depressed.
5~6~7~8-Tetrahydr~-9~l~,l2-tetra(~arb~meth~xy)bis~yrid~[~2-a:2~-b]benzimidaz~ine
(V) and 5 ~ 5 a , 6 , 7 ~ l ~ l - H e x a h y d r ~ - 8 ~ 9 ~ - t e t r a ( c a r ~ m e t h ~ x y ) ~ y r i d ~ [ ~ 2 - a ~ - a z e ~ i n ~ [ 2 ~ - ~ ] -
benzimidazoline (VI). A solution of I V (0.86 g, 5 mmoles) and ADCE (1.5 g) in benzene (25 ml)
was stirred for 4 h at 20~ T h e reaction product was column chromatographed (30 1 cm col-
umn) using a mixture of ether and hexane (I:i) as eluent. Adduct V (0.98 g, 43%) was obtained
as red crystals with mp 176.5-178~ (ether) and Rf = 0.78(ether). iSCNMRspectrum(CDCls): 16.8
(C(,)); 21.9 (C(s)); 29.7 (C(,)); 43,3 (C(,)); 83.1 (C(ea)); 103.5 (C(da)); ll0.0 (C(4)); ili.4

(3 80). , 465 nm (3.80). Found: C 60.7; H 5.3; N 6.3%; M + 456. C2,H2aN=O,. Calculated: C
60.5; H 5.3; N 6.1%; M 456.
Following this was obtained the yellow crystalline VI (0.28 g, 12%) with mp 196-198~
(ether) and Rf = 0.3 (identical solvent system). UV spectrum lma x (log e): 219 (4.30); 260
(3.97); 307 "3.62); 460 nm (4.80). Found: C 60.7; H 5.4; N 6.1%, M + 456. C23H=aN~O,. Cal-
culated: C 60.5; H 5.3; N 6.1%: M 456.

LITERATURE CITED
i. N . S . Prostakov, A. V. Varlamov, I. V. Shendrik, B. N. Anisimov, A. P. Krapivko, S. Lav-
ani-Edogiaverie, and A. A. Fomichev, Khim. Geterotsikl. Soedin., No. i0, 1384 (1983).
2. R . M . Acheson, M. W. Foxton, P. I, Abbot, and K. P. Mills, J. Am. Chem. Soc. C, No. 4,
882 (1967).

194
MASS SPECTROMETRIC STUDY OF THE STEREOISOMERS OF 2-FURYL-
AND 2-PHENYLDECAHYDRO-4-QUINOLINONE AND THEIR TERTIARY ALCOHOLS

A. E. Lyuts, V. V. Zamkova, O. V. Agashkin, UDC 543.51:547.831

K. D. Praliev, O. T. Zhilkibaev, and M. Z. Esenalieva

A study was carried out on the major pathways for the decomposition of stereo-
isomers of 2-furyl- and 2-phenyldecahydro-4-quinolinone and their tertiary al-
cohol derivatives upon electron impact. The elemental composition of the char-
acteristic ions was determined by high-resolution mass spectrometry. The in-
troduction of a heavy substituent at C(2) leads to marked changes in the direc-
tions of the major fragmentation pathways of decahydroquinoline. The dependence
of the probability for the formation of characteristic ions on the molecular ge-
ometry in the stereoisomer series was demonstrated.

Mass spectrometry has found common use in the study of decahydroquinoline and its deriv-
atives. The major fragmentation pathways upon electron impact have been determined for de-
cahydroquinoline [i], the stereoisomers of 2-methyl- and 1,2-dimethyldecahydroquinoline [2,
3], 2-methyl- and 1,2-dimethyldecahydroquinolols [4], their benzoic esters [5], l-alkyl-2-
methyldecahydro-4-quinolol [6], stereoisomers of tertiary alcohols [7, 8], 2-methyl-4-chloro-
decahydroquinoline [6], and decahydro-4-quinolol N-oxides [i0]. The effect of molecular geom-
etry on decomposition has also been examined [2-9, ii]. The configuration at C(~) and C(4)
in the trans stereoisomers of 2-methyl- and l-alkyl-2-methyl-4-alkyldecahydro-4-quinolols
was determined using the ratio of the mass spectral intensities for the characteristic ions
[12-15].
We h a v e s t u d i e d the mass spectra of the following stereoisomers of 2-furyl- and 2-phen-
yldecahydro-4-quinolinones and the tertiary alcohol.derivatives I-XII:

n \x '~..... \ \

I,Vl ~::'0 R IX+VII ~0 VIII

III,IV,IX,X V,X] XII

I-V R = a-Fu, VI-XII R = Ph; III, IX R* = C~CH, R2 = OH, IV,

V, X-XII R* = OH, R 2 = CECH
We attempted to investigate the effect of the replacement of the methyl group at C(2) by
a furyl or phenyl group and of alteration in the molecular structure on the efficiences of
different fragmentation pathways.
The mass spectra of I-XII were studied for the first time. Tables 1 and 2 give the peak
intensities of the major ions in the total ion current scale, while Table 3 gives the elemen-
tal composition of several characteristic ions determined by high-resolution mass spectrometry.
The major fragmentation pathways of the molecular ions of these compounds are depicted in the

Institute of Chemical Sciences, Academy ofSciences of the Kazakh SSR, Alma-Ata, 480100. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 242-247, February, 1986. Orig-
inal article submitted December 27, 1984; revision submitted April 16, 1985.

0009-3122/86/2202-0195512.50 9 1986 Plenum Publishing Corporation 195

 TABLE i. Mass Spectra of l-V (peak intensities in % of Z a g )

Ions m/z I m/z III IV v

M+ 219 13,1 2,9 245 7,5 9,0 6,0

O1 218 1,2 1,3 244 1,7 1,8 1,5
[ M - OH]'+ 202 1,0 1,2 228 ' 2,2 3,7 2.9
[M- I I~O]) 227 0,6 3,3 2.4
190 : 1,4 " 1,7 216 1,0 1,0 0,9
% 176 10,8 0,0 202 2,2 2,4 3,1
O4 176 176 2,3 1,2 I,I
% 148 1,7 1,7
109 3,7 3,3 109 1,2 1,1 1,3
{I}8 c~6 13,8 0,4 96 21,5 0,I 17,3
{I}.q 94 6,2 7,9 94 2,4 2,3 3.0
81 2,3 2,1 81 2,8 2,6 2.9
(:l} it 67 1,6 1,5 67 1,4 1,3 1,5
65 1,6 1,8 65 1,2 1,2 1,3
55 1,9 2,2 55 1,0 0,7 (1,9
54 1,1 1,1 54 0,7 0,6 I 0,8
58 1,2 L3 53 1,5 1.4 t t,8
41 2,8 2,8 41 2,0 1.9 2.2
39 2,3 2,4 39 1,4 1.5 ] 1,7

scheme. Since the decomposition of the furyl and phenyl derivatives of decahydroquinoline is
similar, it was represented in a single scheme and the substituent at C(=) was given as R.
The molecular ion peak (M+) is one of the strongest in the mass spectra of I-XII. The
fraction for M + in the total ion current is an index of its stability. This fraction is high-
er for ketones relative to the corresponding alcohols, for the trans ketone isomers VI and
VII relative to the cis isomers (VIII), and for ketones with an equatorial substituent at
C(=) relative to an axial substituent. The stability of the molecular ion in the case of the
alcohols is higher for the cis isomer relative to the trans isomer and for the trans isomers
with an equatorial substltuent at C(=) relative to the epimar with an axial hydroxy group.
The low stability of E + in the case of alcohols V and XI may be related to a through-space in-
teraction of the axial substituents at C(=) and C(~).

R~ R2
9 "~

It ~z H H

O1 ~ -C2H5"-~

RI R2 R1 ~ I~21 r NIl

H 9 [I ......
=" I12N::CHR

. ~.. " ~ )~,- CH, = C I I _ ~ I ' .~

RI R2 "\ " ~ Og
CII2R
., ",. 010

g It
~+ 9s .

The strong ion peak [M -- 43] + in the mass spectra of the ketones is a composite peak and
is attributed to two ion types, namely, r and r (see Table 3). Ion r is characteristic for
the decomposition of previously studied derivatives of decahydroquinoline [1-9] and is formed
upon the fragmentation of the hydrocarbon ring. Ion r is formed upon bond breakage in the
piperidine ring. Such fragmentation is not characteristic for decahydroquinolines not sub-
stituted at C(4) [2] whose mass spectra do not display a peak for the analogous i0 n [M -- C=H~] +.
Ion r in the mass spectra of the alcohols makes a smaller contribution relative to ion ts,
while the total contribution of ions r and r to the total ion current for the alcohols is

196
 TABLE 2. Mass Spectra of Vl-Xll (peak intensities in % o f Zs,)

.Ions ralz VI VII VIII m/z IX X XI XII

M+ 29 .),4 2,2 11,0 255 L4 ~,4 7,0 9,7

28 1,2 1,5 1,2 254 L0 ~,I 1,7 1,3
[M-OH]+ 12 1,2 1,6 1,4 238 L5 3,5 3,2 3,7
[ M - H20]+ 237 ),8 1,8 1,5 0,8
O2 O0 1,7 2,3 2,4
O~ 86 2,1 2,6 13,1 212 3,7 4,1 5,6 9,9
04 86 186 .~,4 1,5 1,4 0,8
O5 58 1,9 1,9 2,9
O~ 52 1,4 1,9 1,2 178 1,4 1,5 1,8 1,0
O7 19 1,3 0,9 1,0 119 0,9 0,7 0,7 0,6
O~ 06 1,8 8,8 8,0 106 0,0 8,7 5,2 11,9
eP9 04 3,7 4,0 4,6 104 1,9 2,2 2,1 2,1
~bm 91 1,9 1,8 91 3,0 2,9 3,0 2,6
81 2,0 1,7
79 2,l 1,5 1,7 79 1,8 2,1 1,7 1,7
77 2,0 1,7 9,1 77 1,6 1,7 1,6 1,7
67 1,3 1,1 1,tl 67 1,2 1,2 1,9 0,8
55 1,a 1,3 1,3
54 I 1,1 O,c O,c
53 1,2 1,3 1,~ 1,4
41 2,0 1,8 1,c. 41 1,6 1,8 1,~ 1,4
39 i 1,0 0,9 1,~ 39 0,8 1,0 0,t 0,9

less than for the ketones. A clear dependences of the contribution of ion Cs to the total
ion current on molecular geometry is found in the mass spectra of the alcohols:i cis > trans,
Rex > Req, OHax > OHeq. The contribution of ion r also depends on the molecular geometry
and is greater for the trans isomers and for axial orientation of the hydroxyl group.
Ion r corresponds to the major peak in the mass spectra of alcohols III-V and IX-XII and
is one of the strongest peaks in the mass spectra of ketones I, II, and VI-VIII. These ions
are formed as a result of breakage of the C(2)-C(s) and C(9)--N bonds with rearrangement of the
hydrogen atom to the nitrogen atom and include the substituent R . The probability of the for-
mation of analogous ions With m/z 58 in the mass spectra of 1,2-dimethyldecahydroquinolines [2]
and their tertiary alcohols [7] is low, while the maximum peak in the mass spectrum of 1-math-
yl-2,6-diphenylpiperidine corresponds to the ion m/z 120 formed upon analogous decompositions
[16]. The high intensity of the peak of this ion in the mass spectra of the 2-furyl and 2-
phenyl derivatives relative to their methyl derivatives may be understood assuming that these
ions have two possible sites for charge localization, while the nitrogen atom is the only
charge localization site in the ion with m/z 58 for derivatives of 1,2-dimethyldecahydroquin-
oline [2, 7]. The intensity of the Cs ion peak depends on the molecular geometry. The prob-
ability of the formation of this ion is higher for trans isomers relative to cis isomarsl the
axial orientation of the furyl or phenyl group facilitates the formation of this ion. The
peak for this ion in the case of the trans alcohol isomers is higher for equatorial orienta-
tion of the hydroxyl group.
Ions ~9, whose appearance probability is much higher in the ketones (I, II, VI-VIII), do
not contain a nitrogen atom and are formed upon breakage of the C(2)--N and C(s)-C(~) bonds.
The intensity of the peak of this ion is higher in the case of the cis isomers (compare the
spectra data for VIII relative to VI and VII) and, in the case of the trans isomers, is high-
er for axial orientation of the substituent at C(2) (compare the data for II vs. I and for VII
vs. Vl), i.e., the intensity of the r ion peak for the ketones is inversely dependent on the
molecular geometry relative to the Cs ions. This may be understood considering that both
these peaks contain the substituent R and are formed upon competitive decomposition with bond
breakage at C(a).
Other ions which include the substituent R (r and r make an independent contribu-
tion to the total ion current and there is no clear dependence for the intensities oflthese
ion peaks on molecular geometry.
Decomposition with the loss of the methyl group at C(2) is characteristic for the frag-
mentation of 2-methyldecahydroquinoline and its derivatives [2-8]. The peaks of such ions 9
(~6) are seen in the mass spectra of phenyl derivatives VI-XII. The probability for the for-
mation of these ions does not show a clear dependence on the molecular geometry in the stereo-
isomer series.

197
 TABLE 3. Elemental Composition of the Characteristic Ions of
I, II, V, Vl and IX by High-Resolution Mass Spectrometry

I
Ion
Elemental compositioniRatio
.... t mass

I 190 CI,~HI~NO CnHI2NO~ I : 1 i \, 20(: C~al I)4NO

176 C,iI-ll4NO Cu, HIoNO~ ~:1 C]aiij~N : C j i ) ~ N O 2:1
103 C~Hr'NO C:J 1,,i N O
t6 Cs['I~NO 10~
f4 CaH~O I(14 C,di8 : CTI'I(IN 4:1
II t?0 CI2t'II~NO CIdlI~--NO.~ 3:4 91 C;i-b
CI iIti,iNO C iol-[ion O.~ 3:211 81 CJI~ : C51t,~O 5:1
I03 ! Cg'irNO 55 C4H7 : CaItaO 2:3
t.6
94
C~I':16NO : CsHIoN
Cg-I~O o:, II 54
43
C4i'1~ : CaH4N
Ca)'b : C~HsN : C~I-i:~O
2:1
1:2:
81 C~H0 : C~HsO 1:1[i :10
55 C4Hr : Caf'laO 2:g 41 CaI'l~ : CatIaN 10:1
CaH5 : C2HaN ~:111 238 CIrH~N
V CI~t'{I,~NO 212 Ct~I'II.1NO : CjsH,~N 10:l
~02 CI,~t'i~6NO :CI~HI:NO; 1:10tl 186 CI.~I'IICN
.09 C~Hr--NO 178 CIIHI6NO
,s C,~H~NO 106 C~H,~N
~4 C~H~N : C~H~O 1:5 104 C,dt8
C~H~ :CglrN :C~H~O 9i CTI'Ir
67 C,~Hr : C4H,~O 4:1
6~ CsH~
C4t-I~ :CaHO I:1
41 Ca)is : C2HaN 0:I

Let us examine some other ions which give weak peaks. Ion r is apparently formed upon
loss of a hydrogen atom as a result of the breakage of the ~-bond relative to the nitrogen
atom.
The [M -- 29] + peak in the mass spectra of phenyl derivatives VI-XII corresponds to one
#2 ion formed upon fragmentation of the hydrocarbon ring, while [M -- CH0] + ions also contri-
bute to this signal in the mass spectra of furyl derivatives I-V (see Table 3); these ions
are formed upon the decomposition of the furan ring. Ion #7 contains the nitrogen atom and
is obtained upon breakage of the piperidine ring. The peak for this ion is strongest in the
mass spectra of ketones I and II and is not diagnostlc for stereoisomer determination.
The peak for the [M -- OH] + ion is found in the spectra of all the compounds studied.
This ion is characteristic for the mass spectra of alcohols but it is not clear why the peaks
for this ion have comparable intensity in the spectra of the ketones and alcohols. This find-
ing may be related to stabilization of the enol form of ketones I, II, and VI-VIII, at least
in M +. In the case of the alcohols, we find that the [M--OH] + ion peak is higher for the
trans isomers with axial orientation of the hydroxyl group. The peak for the [M--H~O] + ion
in the mass spectra of the ketones is an order of magnitude less than for the alcohols.
Thus, we have established the characteristic pathways for the decomposition of 2-phenyl-
and 2-furyldecahydro-4~quinolinones and their tertiary alcohol derivatives upon electron im-
pact and studied the effect of ring fusion and the orientation of the substituents at C(2)
and C(4) on the fragmentation of these compounds. The introduction of substituents at C(2)
capable of participating in charge delocalization leads to the formation of ions due to spec-
ific fragmentationin addition to the fragmentation ions characteristic for 2-methyldecahydro-
quinoline and its derivatives.

EXPERIMENTAL
The syntheses of I-V were described in our previous work [17-19] and their structures
were demonstrated in our earlier communications [20, 21]. The syntheses and structures of Vl-
XII were described in our earlier work [22, 23].
The mass spectra were obtained on an MKh-1320 mass spectrometer with direct sample inlet
into the ion source. The ionization voltage was 70 V and the acceleration voltage was 2,5 kV.
The temperature of the ionization chamber was 100=C. The high-resolution mass spectra were
taken on the same spectrometer with M/(AM) = i0,000.

198
 LITERATURE CITED
i. C. K. Yu, D. Oldfield, and D. B. Maclean, Org. Mass Spectrom., ~, 147 (1970).
2. A. E. Lyuts, O. V. Agashkin, V. I. Artyukhin, G. S. Litvinenko, and D. V. Sokolov, Izv.
Akad. Nauk KazSSR, Ser. Khim., No. 2, 48 (1968).
3. A. E. Lyuts, O. V. Agashkin, V. I. Artyukhin, D. V. Sokolov, and G. S. Litvinenko, Izv,
Akad. Nauk KazSSR, Ser. Khim., No. i, 74 (1970).
4. A. E. Lyuts, O. V. Agashkin, D. V. Sokolov, V. I. Artyukhin, and G. S. Litvinenko, Izv.
Akad. Nauk KazSSR, Ser. Khim., No. i, 39 (1969).
5. A. E. Lyuts, O. V. Agashkin, D. V. Sokolov, K. I. Khludneva, T. T. Omarov, and G. S.
Litvinenko, Izv. Akad. Nauk KazSSR, Set. Khim., No. 2, 34 (1969).
6. N. Matamarov, O. V. Agashkin, A. E. Lyuts, K. I. Khludneva, D. V. Sokolov~ and G. S.
Litvinenko, Izv. Akad. Nauk KazSSR, Ser. Khim., No. I, 53 (1971).
7. N. Matamarov, A. E. Lyuts, K. D. Praliev, and D. V. Sokolov, Izv. Akad. Nauk KazSSR, Ser.
Khim., No. 5, 74 (1974).
8. N. S. Vul'fson, V. G. Zaikin, A. A. Bakaev, A. A. Akhrem, and L. I. Ukhova, Khim. Geter-
otsikl. Soedin., No. 7, 962 (1975).
9. N. Matamarov, A. E. Lyuts, O. V. Agashkin, V. I. Artyukhin, D. V. Sokolov, and G. S.
Litvinenko, Izv. Akad. Nauk KazSSR, Ser. Khim., No. 4, 80 (1971).
i0. V. G. Zaikin, A. A. Bakaev, N. S. Vul'fson (Wulfson), A. A. Akhrem, L. I. Ukhova, and N.
F. Marchenko, Org. Mass Spectrom., 12, 173 (1977).
ii. V. G. Zaikin and N. S. Vul'fson, Kh{-m-. Geterotsikl. Soedin., No. II, 1443 (1978).
12. V. I. Zaretskii, N. S. Vul'fson, V. G. Zaikin, A. A. Akhrem, L. I. Ukhova, and N. F.
Uskova, Izv. Akad. Nauk SSSR, Set. Khim., No. 9, 2164 (1968).
13. V. G. Zaikin, N. S. Vul'fson (Wulfson), V. I. Zaretskii, A. A. Bakaev, A. A. Akhrem, L.
I. Ukhova, and N. F. Uskova, Org. Mass Spectrom., ~, 1257 (1969).
14. N. S. Vul'fson, A. A. Bakaev, V. G. Zaikin, A. A~ Akhrem, L. I. Ukhova, and N. F. Mar-
chenko, Izv. Akad. Nauk SSSR, Ser. Khim., No. i, 209 (1972).
15. V. G. Zaikin, V. I. Smetanin, N. S. Vul'fson, A. A. Akhrem, L. I. Ukhova, and G. P.
Kukso, Izv. Akad. Nauk SSSR, Ser. Khim., No. 7, 1524 (1976).
16. A. I. Ermakov and Yu. N. Sheinker, Khim, Geterotsikl. Soedin., No. i, 65 (1981).
17. D. V. Sokolov, K. D. Praliev, B. T. Sydykov, V. I. Artyukhin, D. M. Manatauov, V. M.
Kurilenko, and Zh. N. Khlienko, Khim.-farm. Zh., iO, 30 (1976).
18. D. V. Sokolov, K. D. Praliev, and B. T. Sydykov, USSR Inventor's Certificate No. 485,112;
Byul. Izobr., No. 35, 64 (1975).
19. M. Z. Esenalieva, K. D. Praliev, and D. V. Sokolov, Izv. Akad. Nauk KazSSR, Ser. Khim.,
No. i, 61 (1984).
20. V. B. Rozhnov, L. P. Krasnomolova, K. D. Praliev, M. Z. Esenalieva, D. V. Sokolov, and
O. V. Agashkin, Zh. Fiz. Khim., 58, 240 (1984).
21. L. P. Krasnomolova, S. G. Klepikova, O. V. Agashkin, K. D. Praliev, M. Z. Esenalieva,
and S. A. Tarakov, Zh. Fiz. Fhim., 58, 2597 (1984).
22. O. T. Zhilkibaev, K. D. Praliev, V. B. Rozhnov, and D. V. Sokolov, Izv. Akad. Nauk Kaz-
SSR, Ser. Khim., No. 2, 81 (1984).
23. O. T. Zhilkibaev, K. D. Praliev, and D. V. Sokolov, Izv. Akad. Nauk KazSSR, Ser. Khim.,
No. 4, 57 (1985).

199
ARYLIDENEHYDRAZON0-2(4)-AZAFLUORENES

N. S. Prostakov, L. M. Kirillova, UDC 547.836:543.422

Hanna Bu Habib, and L. A. Murugova

Previously unknown unsymmetrical azines with arylidene and azafluorenylidene

fragments were obtained. Some of the geometric isomers of 3-methyl-9-benzyl-
idene(4-methoxybenzylldene)hydrazono-2-azafluorenes were isolated. The long-
wave absorption bands in the electronic spectra of these compounds were in-
terpreted on the basis of the experimental and calculated data (the PPP method).

In connection with the fact that azines containing the azafluorene fragment are unknown
we undertook the synthesis of a series of unsymmetrical arylidenehydrazonoazafluorenes. A-
zlnes III-Xll were obtained by the condensation of 3-methyl-2-azafluorenone hydrazone (I)
and also 4-azafluorenone hydrazone (II) [i] with benzaldehyde, anisaldehyde, salicylalde-
hyde, vanillaldehyde, and veratraldehyde.
Theoretically eight geometric isomers of the arylidenehydrazonoazafluorenes (four each
with the s-cisoid and s-transoi4 configurations) are possible. In practice, however, only
the last isomers can exist, i,e., two of them with the Z configuration of the arylldeneaza-
methine fragment in relation t o the nitrogen-containing ring and two with the E configuration.
By TLC it was established that two geometric isomers of the azines lll-V were present in
the obtained samples, but it was not possible to separate them by column chromatography. The
individual geometric isomers were isolated by fractional crystallization of the azine III
[(Ilia) mp 158-159~ (!llb) mp i07-108~ and the azine IV [(IVa) mp 134-136~ (IVb) mp
138-140~ The individual isomers of the azines III, IV have different colors and different
types of crystals| IIla~ IVa form yellow velvety flakes, and lllb, IVb form shiny orange
crystals.

N .-N}[ 2 N -N~:(1IAr
IJI II! Ell

I, III--VIt R=CHa, 2 a z a ; I I , VIII----XII R=H, 4-aza;Ill. VII1 Ar=C6IIg; IV, IX

Ar=p-CHaO~H4; V, X Ar=o-HOC6H4; VI, XI Ar=(p-OH)(m-CH~O)C6H3; VII, XII
At= "J,m- (CIi~O)~C~tI3

In the IR spectra of isomers Ilia, b in tablets with potassium bromide a difference is

observed in the region corresponding to the stretching vibrations of the C=C and C=N bonds
(Table i),* The bands at 1618, 1580, and 1500 cm-x in the spectrum of the isomer Ilia be-
long to the skeletal vibrations of the azafluorene fragment. In the spectrum of iosmer lllb,
in addition to the same absorption bands, there is a band of medium intensity at 1638 cm -I,
which is usually assigned to the stretching vibrations of highly perturbed C=N bonds of the
azine fragment [2].
In the IR spectra of compounds IV-XII (Table i) there is also an absorption band in the
region of 1633-1638 cm'*, on the basis of which it can be supposed that all these azines have
the same structure as the isomer IIIb.
A feature of the IR spectrum of the azine (V) is the presence of absorption bands in the
regions of 2600 and at -3100 cm-*, which can be explained by the coexistence of the conformers

*The authors express their gratitude to Doctor of Chemical Sciences B. E. Zaitsev for taking
part in the discussion of the IR and electronic absorption spectra of the compounds.

P. Lumumba People's FriendshipUniversity, Moscow, 117923. Translated from Khimiya Getero-

tsiklicheskikh Soedinenii, No, 2, pp. 248-253, February, 1986. Original article submitted
December 26, 1984,

200 0009-3122/86/2202-0200512.50 9 1986 Plenum Publishing Corporation

 TABLE i. IR Spectra of the Azines of Azafluorenes lll-Xll

Absorption bands, cm"I (in tablets with KBr)

Com-
pound* Ar C=C C--O
C = N
o -H Skeletal

Ilia C~H5 1618vs 1588 m,

1553m., t4s m
638 s 1612v~.15~0 m,
lllb C~H5 1565'r 1500 w
IV p-CH~OC~I-I4 .638 s 1617Ns 15~2 m, 1255vs., 1170v s
1570 vs, 1552 m,
1520'~ 1500 w
V o-HOC~H4 3400 m o
,6o8 s 1612vs, 1565 m,, 1260~s, 1165m
3120 m[ 1547m, 1506 w
3070 sb,
2600 mb,
(p-HO) (mLCt-130)--,C31: 3450m~ 636 s 1615vs, 15S8 s 1268 v s 1230 v$
VI 116~ ,~ l150s
2710 s, 1585s, 1570s
2570 s b , 1555.s, 15t3 vs 112~ ,i
2420 sb i
VII [pan-(CHaO)2--C~Ha 1638 m 1613vs, ISg0~h.
1555m ,1520vs
1280 vs i140 s ,
103t s

VIII C6}Is. 1638 s ! 1610m ,15Q0s,

1575s 1558m,
1500w
p- (CH~O)--C~H4 1639 s I 1615vs,15~Os, 1265 v s 1176 ~ts
1X
1600sh,1575m ,
1550m ,1525vs
3070 s b , 1633 s 1610vs, 1590s, 1310 vs, 1260 v s
o 1]O--C~H4
2740 s, 1575 m, 1550m
2620 sb
(p-HO) (m-CH~O)--C61-t~ 3100usb 1636 s I61~s.,i590s 130"~'% 1275 v s
XI 121t,"~ 1180 v s
1580sh,1560m
1523vs
XII o,m-(Ctt30),_,-- C~}13 1633 s" 160~s v 15GOs,
15716 1550m
.1273 vs, 1240 s
1170 m , l14fl v s
1520 vs 1030 vs

*Ilia, b, IV-Vll R = CHa, Vlll-Xll R = H.

A [ w i t h a strong intramolecular hydrogen bond (the band at 2600 cm-*)] and B (the bands at
-3100 cm-*).

~::' H R=uN. . tl
F ~
l ~ . 2: : x

.o-<,,X\ ,:,
L/
Y.. l
A B

For a more detailed investigation of the electronic structure of the azines III-XII we
used their electronic absorption spectra and quantum-chemical calculations.
The experimental data for azines lll-Xll(Table 2) indicate that the electronic absorp-
tion spectra are not a simple superimposition of two unconnected azafluorene (r and aryli-
denehydrazone (r systems. This becomes clear during comparisonwith the spectra of the in-
itial compounds, i.e., the hydrazones I and II, in which the long-wave maximum of the azafluor-
ene fragment undergoes of bathochromic shift to -320 nm (AI - 20 nm) on account of the auxo-
chromic effect of the =%N--NH= group. The introduction of the arylidenehydrazone group, how-
ever, leads to an even larger shift of the long-wave absorption band to 360 nm, which indi-
cates that the z-~ conjugation, which is only possible in the flat conformers, increases in
the investigated systems.
During the quantum-mechanical calculations we used the modified program in [3-5] with al-
lowance for the configurational interaction of 25 singly excited states, with variation in the
resonance integrals 8~v and bond lengths rpv, and with self-consistency in a linear relation-
ship to the bond orders PBv using the standard parameters for C, N, and O. T h e two-center
Coulombic intetrals Y~v were calculated by means of the Matago--Nishimoto formula [6].

201
 TABLE 2. Electronic Absorption Spectra of the Unsymmetrical A-
zincs of 3-Methyl-2-azafluorene Ill-VII and 4-Azafluorene VIII-
Xll (azafluorene =N-N=CH--Ar; for the R and Ar values, see Table i)
9~%ethanohrhx,~ dg e,) 9~:~ethanol + sulfuricr ).~,,~x
acid nm ([ge)
0 A B J C J ,,
A B C D

I
III 208 (4,70) 258 (4,6D),]340 (4,55) 388 sh i215 (,t,48) 1242 (4,53),] 295 (4,14) 368* (4,40)
220 ~h 264 (4,68} 1354 (4,571 (410) 380 (4,10)
(4'52 223 (4,59) 270(4,53) 1310(4,29)
IV 213 (5,17) 248 (4,54) ~ 367 (4,52) 237 (4,35), ] 235sh
273 (4,59) (4,43), .
330 (4,20) 403* (4,3t)
V 212 (4,61) 260 (4,65) 1340 (4,30) 378 (4,34) 217 (4,37) 242 (4,37), 297 (4,165, 400* (4,15)
220 (4,58) 263 (4'50) 1315324(4,32)(4'11)'

VI 2|6 (4,58) 260 (4,64) ]294 (3,045 390 (,I,435 2t2 (4,21) 270
233 (449) (4,26), 364 (3,615,
226 (4,55) (4,4~) 298
312 (4,251 424* (4,355
VII 216 (4,59) 260 (465) 1287 (4,07) 380 (4,445 207 (4,61) 233 (4,63) 272313(4,61),(4,45) 410' (4,38)
225 (4,57)
VIII 207 (4,525237 (4,54),[293 (4,34) 335 (4,44), 206 (4,58) 241 (4,54)]2938h 330 (4,36),
243 (4,55), 304 (4,38) 345 {~,47) (4,22), 345* (4,52)
2461 ~h 315 (4,40) 357 303 (4,32)
(4,5 [), (4,34)
264~;h
(4,3 ~)
IX 213 (4,505 246 (4,52), 300 (4,16) 367 (4,50) 212" 234* I 253 (4,48), 387* (4,45)
240 (4,53), 315 (4,14) (4,53), (4,50) 305 (4,27)
247 (4,52) 220 (4,67) 317 (4,805
217 (4,53) 267 (4,32) [310 (4,30) 340 (4.25), 217 (4,485236 (4,34), 329 (4,39) 390* (4,27)
227 (4,56) 375 (4,28) 253 (4,37)
240 (4,48) I
XI 212 ~4,47) 250 (4,38) ]287 (4,|65 384 (4,34), 212 (4,29), 280 (4,22) 323 (4,46) 412" (4,15)
227 (4,53) 500* (3,30) ]
32 (4,52) 2 7 7 3 2 4
XII 214 (4,56) 252 (4,47)~1287 (4,29), 387 (4,43) 212 (4,66), (4,44) (4,54) 395* (4,365
228 (4,60) 267 (4,38) 1313(4,19) 230(4,68)

~The bands disappear from the spectrum with the addition of

acid to the solution in ethanol.

During the calculations the =N-N = group was taken as structurally similar to the =CH-CH=
group. It was assumed that sp 2 hybridization is realized for the nitrogen atoms while the in-
teraction between the unshared electron pairs in the hybrid orbitals in the trans position to
each other can be disregarded. The ~ bonds are formed by overlap of the PZ atomic orbitals of
the nitrogen and carbon atoms. The calculations were made for the theoretically most probable
four Z and E isomers with the s-transoid configuration in relation to the N--N bond in azines
III and VIII not containing substituents in the arylidene fragment and, therefore, selected as
models. Since the calculated and experimental spectra of the two isomers differ little, dur-
ing the interpretation of the spectra and the electronic structure of these compounds we started
from the calculated data for one arbitrarily chosen isomer.
Experimentally, three absorption bands with the principal maxima in the regions of 210,
250, and 360 nm are mainly observed in the electronic absorption spectra of azines III and VIII.
On the slope of the long-wave absorption band it is possible to distinguish a shoulder with
lmax ~ 370 nm. From comparison of the experimental and calculated data and also analysis of
the configuration interaction matrix (CIM) it is possible to conclude that the long-wave ab-
sorption bands in the spectra of arylidenehydrazono-2(4)-azafluorenes III and VIII are formed
by the two so s * ~ * and so + s S ~ * electronic transitions. The first transition, polarized
along the y axis (the long axis of the molecule), is due to the extent of 98% to the transi-
tion of an electron from the highest occupied molecular orbital (HOMO) to the lowest unoccupied
molecular orbital (LUMO). The second transition, So + s2z~,, can also be considered a single-
electron transition with the major contribution from the Sm-, configuration (96%). This
transition is polarized along the x axis and" has an intensity and order of magnitude lower than
the so + s * ~ , transition.
Our calculated lma x values both for the first two electronic transitions and for the oth-
ers agree well with the experimental data. One of the possible reasons for the small quite

202
 TABLE 3. Total Charges, Eq(e), Calculated by the PPP Method,
the Change in Electron Density, Aq(e), at the Fragments, and
the Intramolecular Charge Transfer (ICT) (e) of Compounds III
and VIII
//-- ~. /,,~ /R

JJ

O) (~) (~) \_

Param- Fragments .Atom

)rind sn eters -- ICT
A B C D N(I ) N(~,) CH~,~I

Eq

I
III so 0,039 0,122 -0,013 0,044 l --0,16~ -0,188 0,161
S*l Eq 0,093 -0,054 0,018 0,105 [ -0,145 -0,119 0,099
Aq -o,oS4 0,176 - 0,031 - 0,061 I--0,02(] - 0,069 0,062 0,238 (e)
VIII so Eq 0,045 0,18o -0,076 0,043 /-0,166 -0,188 0,160
S*l Eq o,134 0,063 - 0,025 0,085/-o,193 -0,139 0,075
Aq - 0,089 0 , 1 2 0 - 0,051 -0,042 / 0,027 - 0,049 0,085 0,232 (e)

*A minu~ sign at Aq signifies a decrease in electron density

at the molecular fragment during the s sXn~, transition.

permissible increase in the Xmax ~alues of the so + s * ~ * transition compared with the experi-
mental Xma x values of the long-wave absorption band (A% = Xcalc -- %expt amounts to -20 nm) may
be conformational mobility of the investigated azines in the solutions.
Analysis of the molecular diagrams shows that the q-electron density in the ground state
of the molecules (so) is concentrated predominantly at the nitrogen atoms, and the nitrogen
of the azafluorene fragment (@~) has the largest ~ charge. The transition to the first sing-
let excited state (the so + s * ~ , transition) is accompanied by intramolecular charge trans-
fer (ICT) predominantly from the heteroatoms of the arylidenehydrazone group (@a) and the car-
bon atoms of fragments A and C to the atoms of the five-membered ring B. The ICT values for
this transition Aq are given in Table 3. For compound III compared with VIII the electron-
withdrawing characteristics of ring B are somewhat less clearly defined, since AqB for them
amounts to 73.8 and 51.7%, respectively. The methine carbon atom C(s), which is electron-
deficient in the so state of the molecules and for which Aq amounts to ~30%, also acts as an
electron acceptor. The donor is the benzene ring D.
The calculated values of the C==N and N-N bond lengths (1.30 and 1.35 ~, respectively)
agree satisfactorily with the data from electron diffraction in the gas phase for the planar
trans conformation of the acetaldehyde azine molecules, according to which rc==N = 1.27 and
rN-~I = 1 . 4 1 A [ 7 ] .

The introduction of electron-donating substituents (--OCHa and--OH) into the arylidene

fragment (compounds IV-VI, IX-XII) leads to a bathochromatic shift of the long-wave bands in
the electronic spectra by 20 nm (Table 2). This fact can be considered experimental evidence
for the existence of ~-~ conjugation. In addition, this is demonstrated by the spectral data
on the protonation of compounds III-XII (Table 2). With the addition of sulfuric acid to al-
cohol solutions of compounds III-XII, there is a bathochromic shift of the long-wave absorp-
tion bands by 20-30 nm in their spectra; the intensity of this band then decreases, and it
disappears. This process can be considered an equilibrium process, since isobestic points
are observed in the spectra. As known, a bathochromic shift in an acidic medium is typical
of ~-n * absorption bands. This is consistent with our calculated data and incidates that the
nitrogen atom of the azofluorene fragment is evidently protonated initially and the hydrazo
group is then protonated.
+
Quantum-chemical calculation of the electronic absorption spectra of the NH cations of
the azafluorenium fragments in compounds III and VIII in terms of the same PPP method showed
that the energy of the so s ~ , transitions does in fact increase the result of the increase
in the electronegativity of the heteroatom during protonation of the nitrogen and the associat-
ed relative approach of the HOMO and LUMO levels. The theoretical bathochromic shifts of the
long-wave absorption bands corresponding to these electronic transitions must amount to 30 and
40 nm for compounds III and VIII, respectively, which agrees qualitatively with the experi-
mentai data (Table 2).

203
 EXPERIMENTAL
The IR spectra were recorded in tablets with potassium bromide on a UR-20 instrument.
The electronic spectra were obtained on a Specord UV-vis spectrophotometer in 96% ethanol with
subsequent acidification by concentrated sulfuric acid. The concentration of the solutions
was varied in the range of 10-s-10 -5 M. The thickness of the quartz cuvette was 1.0 cm. The
absorbent for TLC was Silufol UV-254, and the eluant was ethyl acetate.
3-Methyl-9-benzylidenehydrazono-2-azaf!uorene (I!I) ~ A solution of 0.5 g (2.4 mmoles) of
hydrazone I, 0.5 g (5 mmoles) of benzaldehyde in 20 ml of ethanol, and 5 ml of benzene was
boiled for 1 h. After distillation of the solvents the residue was dissolved in chloroform
and deposited on aluminum oxide with ether as eluant to remove the benzoic acid. We obtained
0.32 g (46%) of a mixture of the isomers of the azine (III). Found %: C 80,7; H 5.1; N 14.0;
M + 297. CaoH, bN3. Calculated: C 80.8; H 5.1; N 14.1; M 297.
By fractional crystallization from hexane we obtained llla [orange crystals, mp 158-159~
Rf 0.52 (ethyl acetate)] and lllb [yellow needle crystals, mp I07-I08~ Rf 0.67 (ethyl ace-
tate)].
3-Methyl-9-(p-methoxybenzylidene)hydrazono-2-azafluorene (IV). A reaction mixture of 0.l
g (0.5 mmole) of hydrazone I, 0.2 g (1'5 mmoles) of anisaldehyde, 12 ml of ethanol, and 2 ml
of benzene was boiled for 3 h. After cooling I0 ml of heptane was added. The precipitate was
filtered off, washed with hexane, and dried. We obtained 0.12 g (73%) of a mixture of the
isomers of azine IV. Found %: C 76.9; H 5.3; N 12.9; M + 327. C=~H~TN30. Calculated: C
77.1; H 5,2; N 12.8; M 327.
By fractional crystallization from hexane we isolated yellow crystals [mp 134-136~ Rf
0.6 (ethyl acetate)] and then orange crystals [mp 138-140~ Rf 0.75 (ethyl acetate)]. A mixed
melting test with the two types of crystals melted at 135-139~
3-Methyl-9-(o-hydroxybenzylidene)hydrazono-2-azafluorene (V). A mixture of the isomers
of azine V was obtained similarly with a yield of 70% from hydrazone I and salicyladehyde; mp
143-145~ (from hexane), Rf 0.72 and 0.57 (ethyl acetate). Found %: C 76.4; H 4.9; N 13.6;
M + 313. C2oH~NsO. Calculated: C 76.7; H 4.8; N 13.4; M 313.
3-Methyl-9-(p-hydroxy-m-methoxybenzylidene)hydrazono-2-azafluorene (VI). A solution of
0.7 g (3.3 mmoles) of the hydrazone I and 0.56 g (3.7 mmoles) of vanillin in i0 ml of ethanol
was boiled for i0 h. The orange-red crystals which separated were recrystallized from a 5:1
mixture of n-butanol and chloroform. We obtained 1.0 g (90%) of azine VI; mp 208-210~ Found
%: C 73.6; H 5.2; N 12.5; M + 343. C21H~TN302. Calculated: C 73.5; H 4.9; N 12.2; M 343.
3-Methyl-9-(p,m-dimethoxybenzylidene)hydrazono-2-azafluorene (VII). In the reaction we
used 0.4 g (2 mmoles) of hydrazone i, 0.42 g (2.4 mmoles) of veratraldehyde, 20 ml of ethanol,
and i0 ml of benzene. The mixture was boiled for 30 h, and after cooling 15 ml of heptane was
added. The precipitated azine VII [0.55 g (81%)] was crystallized from heptane; mp 138-140~
Rf 0.75 (ethyl acetate). Found %: C 73.9; H 5.4; N 12.2; M + 357. C2zHIgNsO2. Calculated:
C 73.9; H 5.3; N 11.8; M 357.
9-Benzylidene-, 9-p-Methoxybenzylidene-, 9-o-Hydroxybenzylidene-, 9-p-Hydroxy-m-methoxy-
benzylidene-, and 9-m, p-Dimethoxybenzylidenehydrazono-4-azafluorenes (VIII)-(XII). The com-
pounds were obtained from hydrazone II and the respective aldehydes by similar methods and
with the reagents in the same molar ratios as in the syntheses of azines Ill-VII. Azine VIII
formed orange crystals; mp I04-I08~ (from heptane), yield 80%. Found %: C 80.5; H 4.8; N
14.9; M + 283; C19H~3N~. Calculated: C 80.6; H 4.6; N 14.8; M 283. Azine IX formed orange
crystals; mp 148-150~ (from heptane), Rf 0.71 (2:1 ethyl acetate--heptane), yield 84%. Found
%: C 76,4; H 4.8; N 13.6; M + 313. C2oHIbNsO. Calculated: C 76.7; H 4.8; N 13.4; M 313.
Azine X formed yellow crystals; mp 158-160~ (from heptane), yield 75%. Found %: C 76.3; H
4.5; N 13.8; M + 299. C19HI3NsO. Calculated: C 76.3; H 4.4; N 14.1; M 299. Azine XI formed
orange crystals; mp 211-212~ (5:1 butanol--chloroform), yield 72%. Found %: C 70.3; H 6.0;
N 11.5; M + 329. C~oH~sNsO~C=HbOH. Calculated: C 70.4; H 5.6; N 11.2; M 329. Azine XII
formed yellow-orange crystals; mp I15-I18~ (from heptane), yield 63%. Found %: C 73.5; H
4.9; N 12.2; M + 343. C21HITNs02. Calculated: C 73.7; H 4.9; N 12.3; M 343.

LITERATURE CITED
i. N. S. Prostakov, Hanna Bu Habib, L. M. Kirillova, O. I. Sorokin, and A. V. Varlamov, Khim.
Geterotsikl. Soedin., No. 7, 968 (1983).

204
2. Yu. P. K i t a e v and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974).
3. R. Pariser and R. C. Parr, J. Chem. Phys., 21, 466 (1953).
4. G. Pople, J. Chem. Phys., 21, 767 (1953).
5. G. Pople, Trans. Faraday Soc., 49, 1357 (1953).
6. T . G . Edwards and R. Grinter, Theor. Chim. Acta, 12, 387 (1968).
7. J . P . Ogilvie, S. J. Cyvin, and B. N. Cyvin, J. Mol. Struct., i~8, 285 (1973).

205
SYNTHESIS AND DYNAMIC STEREOCHEMISTRY OF 1,5-DISUBSTITUTED
2,3,4,5-TETRAHYDRO-IH-1,5-BENZODIAZEPIN-2-ONES

B. A. Puodzhyunaite, R. A. Yanchene, UDC 547.892:541.63'128:

Z. A. Stumbryavichyute, and P. P. Mikul'skls 543.422.25

The l-isopropyl and l-benzyl derivatives of 1,5-tetrahydrobenzodiazepin-2-one

were synthesized by alkylation under the conditions of phase-transfer cataly-
sis. The inversion of the heterocycle was studied by PMR spectroscopy, and
the free energies of activation were determined.

The stereochemical characteristics of somel,5-benzodiazepines and dihydro-l,5-benzodia-

zepin-2-ones have been studied before by a number of authors [1-3]. Here it was established
that the molecules of these compounds have the boat conformation, which inverts at various
rates depending on the temperature and on the structure of the substances. Tetrahydro-iH-
1,5-benzodiazepin-2-ones have been studied little in this respect.
In the present work We consider aspects of the synthesis, the dynamic stereochemistry,
and the conformational analysis of 1,5-disubstituted tetrahydrobenzodiazepin-2-ones, repre-
sented by the general formula I-III,

R
I
":-~ N CO

I ! ""
' " '<~
ell
N"" { II

l-Ill

la-c R = CH2C,Hb, R a = COCHs; a R z = H; b R* = CHa; c R x =

C6H5; f I R = CH(CHs)a, R* = R 2 = H, llla-g R = CH(CHs)2, R* = H;
a R ~ = COCHs) b R 2 = COCHzCI; c R ~ = CO(CH2)2CI; d R 2 = CO(CHz)s-
CI; e R 2 = CONH2; g R 2 = CHO
The l-alkyltetrahydro-l,5-benzodiazepin-2-ones were obtained for the first time by alkyl-
ation under conditions of phase-transfer catalysis in the benzene--50% aqueous sodium hydroxide
system in the presence of quaternary ammonium salts. Thus, the l-alkyl derivatives la-c were
synthesized by the reaction of the previously described 5-acetyl-4-methyl-5-acetyl, and 4-
phenyl-5-acetyl-2,3,4,5-tetrahydro-iH-l,5-benzodiazepin-2-ones (IV, V, VI) [5, 6] with benzyl
bromide. The above-mentioned method cannot be used for the production of compounds lllb-d, g
since the initial 5-substituted derivatives containing ~-halogenoacyl or formyl groups are
unstable under the conditions of phase-transfer catalysis. These compounds were obtained by
the following method. From 2,3,4,5-tetrahydro-iH-l,5-benzodiazepin-2-one (VII) [7] and iso-
propyl bromide under the conditions of phase-transfer catalysis, the l-isopropyl derivative
(II) is formed. Its acylation by the method in [4] by the appropriate agents gave compounds
lllb-d. The formy! derivative lllg was obtained by the reaction of II with a mixture of for-
mic acid and acetic anhydride. The carbamoyl derivative llle was obtained by the reaction of
the derivative II with sodium cyanate according to the method in [7].
Analysis of the data from the PMR spectra of compounds la and llla-e at the temperature
of the instrument showed that the signals for the methylene protons of the ethylene fragment

Institute of Biochemistry, Academy of Sciences of the Lithuanian SSR, Vil'nyus, 232021.

Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 254-258, February, 1986. Orig-
inal article submitted November 26, 1984; revision submitted February 12, 1985.

206 0009-3122/86/2202-0206512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Deriva t i v e s o f 2,3,4,5-Tetrahydro-iH-1,5-benzodia-
zepin-2-one (l-Ill)
m,
Com- Found, % Molecular Calculated, % [i~
pound rap, ~ formula Y Idl
c IHIC' N C I H C[ N
m
I

lb
Is 138--139 73,61 63 t 9,6 C lsH,sN202 73,51 6,2 -- 9,51 92
188---190 73,61 7,0 9.0 C,!~[I2oN~.O2 73,51 7,1 -- 9.01 72
Ic 201--2fl3 78,11 6,1 7,4 C24H22N202 77,81 6,0 -- 7,6192
II. 243 dec. 59,9 6,9 14,7 11,5 CE21-IIaN209HCI 59,91 7,1 14; l l,ti48
Ill a 123--125 68,5 7,2 11,5 Cldt 18N,'~O2 68,3 [ 7,4 11,4 [36
!Ilb 153--155 60,01 6,1 12,5 9,9 CI4HITCIN202 59,91 6,1 12J 9,91 60
111c 126--128 61,01 6,9 12,1 9.6 CIsH,gCIN202 6,., 6.5 ,2j 9.5 60
Illd 110~--112 62,4 7, I 11,6 9,1 CI6H2,C/N20~ 62,2 6,9 11,,~ 9,1 63
Ille 217--219 63,4 6,7 17.0 C,,~ItwNaO2 63,1I 6,91 - - 17,0 85
111g 102--104 67,4] 6,7 12,0 CI~H,~N202 67,2] 6,9 ] -- 12,11 61

*Compounds la-c, llla were recrystallized from a mixture of

benzene and hexane, lllb, g from a mixture of benzene and
ether, lllc, d from ether, llle from benzene, and the hydro-
chloride of II from absolute alcohol.

TABLE 2. Spectral Characteristics and Free Energy of Activa-

tion of the Derivatives Ilia-g, la
Chemical shifts,6, ppmat 3~~ in CDCl3
Com- A~max* Tc 9K
pound I-N--CH,
(C!I~)~C,d
septet
3-CH2jn 4-Cl 1:~, III kJ/mole

Ilia 1,12 4,70 2,4 3,39 28,7 373 79,0

1,42 4,78
llIb 1,14 4,66 2,4 3,49 26.7 374 79,5
1,44 4,80
IiIC 1,13 4,63 2,5 3,40 26,4 380 80,6
1,42 4,72
IIId 1.13 4,63 1.7--2,7 3,37 25,8 377 80,1
1,42 4,81
llle 1,10 4,63 2,4 3,39 27,3 350 74,1
1,42 4,80
Ill g 1,20. bd 4,60 2,49, t 3,0--4,8, bs 36,4 295 61,7
la 83,1 383 78,0

*For compounds llla-g the difference between the chemical

shifts of the protons of the geminal methyl groups in
CHCI2CHCI2, and for (la) the difference between the chemical
shifts of the methylene protons of the benzyl substituent in
DMSO-D6, JAB = 14.9 Hz.

of the heterocycle form an ABMX spin system (Tables 2 and 3). The difference between the chem-
ical shifts of the geminal protons at the C(3) atom of the heterocycle (the AB part) is small
and amounts to 0.1-0o2 ppm, whereas the signals for the geminal protons of the methylene group
at position 4 (the MX part) are observed in the downfield region and represent two multiplets
with A6 = 1.4 ppm. Such a large difference in the screening of the protons is evidently due
to the steric effect of the anisotropic carbonyl group of the substituent. In compounds llla-e
the geminal methyl groups in the l-isopropyl substituent are then equivalent, and two doublets
are observed with A6 = 0.3 ppm. In compounds la-c the geminal protons of the l-benzyl substi-
tuent are nonequivalent and form an AB spin system with A6 = 0.7-0.9 ppm. It should be noted
that for compound lllg, which contains a formyl group at position 5, the nature of the signals
for the methylene protons at positions 3 and 4 and the broadened doublet for the methyl pro-
tons show that the system is in a fairly labile state. Thus, comparison of the spectra of
compounds lllg with llla-e and la shows that the intramolecular mobility of the molecules is
substantially affected by the structure and the nature of the substituent at position 5, as
we have demonstrated for other 5-substituted derivatives of tetrahydro-l,5-benzodiazepin-2-
ones [8].
Investigation of the temperature dependence of the spectra of compounds la and llla-g
demonstrates the intramolecular mobility of the heterocycle. With increase in temperature the
signals for the protons of the methylene groups at the C(~) and C(4) atoms become broader and,

207
 TABLE 3. Parameters of the PMR Spectra of Compounds la-c in
DMS 0 -D,
Chemical shifts,'~, ppm, and ~S-CCi J, Hz (in DMSO-Ds)-
Observed
signals os la l,b [c
groups
3,t" 185~ 3.P ISY 34~ 185'

I -N---CII~ 4,62 ,t,07, s 4,62 ~1 4,71 4,68 4,77

5,51 5,37 5,14 5,43 5.20
9 = 14,9 21= 14,9
3-CI-I~ 2,43 " 2,43,t 2,12 I 2,15 2.82 [ 2.84
2,37 2,37 2,64 2.63
~l = 13,0 6.0 :q= 12,5; 6,5
~1= 13,0 ~l= 12,5
4-CH.~ 3,37 4,02, t
4,71
4-CH 5,03, m 5,00, m 6,01, m 6,03,m
4-CH~ 0.9o, d 0,98, d
CHACO 1,10 1,33,s 0,97, s 1,22, s 0,96, s 1,23, s

*Overlap with the solvent signals.

TABLE 4. Chemical Shifts and Spln--Spin Coupling Constants Cal-

culated for the Fragment of the Heterocycle CMSH4-CH * (H 2 or R t)
in the Molecules of Compounds (Ia-c) in CDCls

!Chemical shifts, .~' ppm .l SSCC, J, Hz

Com-
pound
13 14 ~3 24 t 34

.Ia
lb
Ic
5,28
6.23
I I
4,9,3 I 3,41 I 2,57
2,24
2,48 - 1 2 8
2,36
14,4
12,8
5,5
5,3
6,1
6,4 2,4 I --13,3
-12,7
-13,0
. . . . . .2,87
.... 2,71 i 12~5

passing through the coalescence points, are converted into triplets or broadened triplets, re-
spectively. The behavior of the signals for the protons of the substituents at position 1
is similar; the signals for the protons of the methyl groups in compounds IIIa-g here are con-
verted into ~ doublet, while the signals for the methylene protons of the benzyl substituent
in the derivative (la) are converted into a singlet. The free energies of activation were
determined at the coalescence temperature from the signals for the methylene protons at posi-
tion 4 of the heterocycle and the geminal methyl groups or methylene protons of the substi-
tuents at the first nitrogen atom on the basis of the approximate equations [9], The barriers
to inversion of the seven-membered ring for compounds IIIa, g, and Ia, determined from the sig-
nals of the methylene protons in the heterocycle, have the following values: AG # = 79.7 kJ/
mole (Av = 129.5 Hz, T c = 399 K), AG # = 61.5 kJ/mole (Av = 100.0 Hz, T c = 308 K), and
AG~ = 78.6 kJ/mole (Av = 123.1 Hz, T c = 393 K), respectively. The comparable values for the
free energies of activation~ obtained from the signals of the exocyclit (Table 2) and cyclic
protons for these compounds, give reason to suppose that the averaging of the signals of the
substituents takes place synchronously with the averaging of the signals for the protons of
the heterocycle and characterize the inversion of the molecules. A similar pattern has been
observed for the I-N derivatives of dihydro-l,5-benzodiazepin-2-ones [3] and dihydro-l,4-
benzodiazepin-2-ones [9, i0]. The authors of the last papers explained this by the fact that
the inversion of the nitrogen is a fast process compared with the inversion of the ring [3].
The dependence of the free energy of activation AG# on the nature of the substituent at
the nitrogen atom at position 5 is obvious (Table 2). The increase of 17.3 kJ/mole in AG#
for the N-acetyl derivative (Ilia) compared with the N-formyl derivative IIlg is probably due
to steric hindrances. The increase in the length of the alkyl chain of the acyl substituent
in compounds IIIb-d does not lead to significant changes in the size of the inversion barrier.
The dependence of the inversion rate of the heterocycle on the nature of the substituents
at position 4 was studied for the derivatives Ia-c (Table 3). The spectra of compounds Ib, c
at the instrument temperature contain signals for the methylene protons at the C(s) atom and
the methine protons at the C(~) atom, which form an ABX system. Whereas averaging of all the
signals for the nonequivalent protons was observed in compound Ia with increase in temperature,

208
in compounds Ib, c containing substituents at the C(4) atom of the heterocycle increase in
temperature to 1850C did not lead to broadening of the signals or to appreciable changes in
the chemical shifts and spin-spin coupling constants. This confirms that the presence of
bulky substituents (R * = CH3 and C~H3) prevents inversion of the heterocycle. A similar ef-
fect from the methyl substituent on the inversion rate has been observed in 7-chloro-3-methyl-
5-phenyl-2,3-dihydro-iH-l,4-benzodiazepine [Ii].
The values of the spin--spin coupling constants provide information on the positions of
the protons and the substituents at the C(3) and C(~) atoms of the heterocycle in the mole-
cules of compounds la-c. From comparison of the vicinal spin--spin coupling constants (Table
4) it is seen that in compounds Ib and Ic the substituents at the C(~) atom are in the pseudo-
quatorial position [12].
EXPERIMENTAL
The reactions and the purities of the compounds were monitored on Silufol UV-254 plates
in the 14:7:1.5 chloroform-ethyl acetate-methanol system. The PMR spectra were recorded on
a Hitachi R-22 spectrometer at 90 MHz with HMDS as internal standard. The temperature was
measured with an accuracy of 176 The calculations on the ABMX (la) and ABX (Ib, c) spin
systems were made by means of the LAOCN3 program [13].
The characteristics of compounds I-III are given in Table i.
l-Benzyl-5-acetyl-2,3,4,5-tetrahydro-iH-l,5-benzodiazepln-2Jone (la)~ To a mixture of
3.06 g (15 mmoles) of compound IV, i00 ml of benzene, 11.25 ml of a 50% aqueous solution of
sodium hydroxide, and 0.34 g (1.5 mmoles) of benzyltriethyla=monium chloride we added 5.13 g
(30 mmoles) of benzyl bromide. The mixture was boiled for 2 h with vigorous stirring. After
cooling the benzene layer was separated, washed with water'until the washing water was neutral,
and evaporated. The residue was recrystallized. Thederivatives Ib and Ic were obtained sim-
ilarly from V and VI, and Ilia was obtained from IV and isopropyl bromide, except that the
reaction mixture was boiled for 6 h.
l-lsopropyl-2,3,4-5-tetrahydro-IH-l,5-benzodiazepin-2-one (II). To a mixture of 6.4 g
(40 mmoles) of compound VII, 150 ml of benzene, 6D ml of a 50% aqueous solution of sodium hy ~
droxide, and 1.6 g (4 mmoles) of tetrabutylammonium bromide we added 19.68 g (160 mmoles) of
isopropyl bromide. The reaction was then continued as for compound Ilia. After evaporating
the solvent, we obtained the diazepinone II in the form of an iol, which we used in the sub-
sequent syntheses. Compound II was identified in the form of the hydrochloride, which was
isolated by saturating a solution of the base II in absolute ether with gaseous hydrogen chlor-
ide. After recrystallization we obtained 4.6 g (48%) of hydrochloride of II. PMR spectrum
(DMSO-D6): 1.12 (6H, d, CH3); 2.28 (2H, t, 3-CHz); 3.55 (2H, t, 4-CH=); 4.5 (IH, m, CH); 7.3-
7.7 ppm (4H, Ph).
l-lsopropyl-5-chloroacetyl-2.3,4,5-tetrahydro-iH-l,5-benzodiazepin-2-one (lllb). To a
solution of 2.04 g (i0 mmoles) of II and 0.79 g (i0 mmoles) of dry pyridine in 20 ml of ab-
solute benzene, while stirring and cooling to O~ we added a solution of i.i g (i0 mmoles)
of chloroacetyl chloride in i0 ml of absolute benzene over 20 min. The mixture was allowed
to heat to room temperature, kept at 50~ for 3 h, cooled, washed with acidic water and with
water, and evaporated. The residue was recrystallized.
Compounds lllc, d were obtained similarly from the diazepinone II and B-chloropropionyl
and y-chlorobutyryl chlorides.
l-isopropyl-5-carbamoyl-2,3,4,5-tetrahydro-IH-l,5-benzodiazepin-2-one (llle). To a mix-
ture of 2.4 g (i0 mmoles) of the hydrochloride of II and 1.3 g (20 rmmoles) of sodium cyanate
in 70 ml of absolute benzene, while stirring, we added 1.5 ml (20 mmoles) of trifluoroacetic
acid. After 0.5 h we added a further 0.65 g (i0 mmoles) of sodium cyanate and 0.75 ml (I0
mmoles) of trifluoroacetic acid. The same amount of the reagents was added again after 2.5
h. The mixture was heated to 60~ and kept at this temperature for 5 h. The benzene layer
was decanted, the oily precipitate was mixed with water, the mixture was neutralized with
potassium carbonate, and the product was extracted with chloroform. The extractwas evaporat-
ed, and the residue was recrystallized. We obtained 2.1 g of the derivative lllg.
l-lsopropyl-5-formyl-2,3,4,5-tetrahydro-iH-l,5-benzodiazepin-2-one (lllg). To 31 ml of
acetic anhydride we added 1.31 ml of 98% formic acid. The mixture was kept at 50~ for 2 h.
To the obtained mixture we added a solution of 6.12 g (30 mmoles) of the diazepinone II in 30
ml of absolute benzene. The mixture was kept at room temperature for 20 h, the solvent was
evaporated, and the residue was recrystallized. We obtained 4.2 g of lllg.

209
 LITERATURE CITED
i, A. Mannschrack, G. Rissman, F. Vogte, and D. Wild, Chem. Bar., !00, 335 (1967).
2. G. Vernin, H. Domloj, C. Metzger, J. Siv, A. Archavlls, and J. R. Llinas, Chem. Scripta,
15, 157 (1980).
3. R. Benossi, P. Lazzaretti, F. Taddei, D. Nardi, and A. Tajana, Org. Magn. Reson., 8,
387 (1976).
4, R. A. Balkyavichyute, B. A. Puodzhyunalte, and R. G. Lyutkene, in: Urgent Problems in
Experimental Chemotherapy Of Tumors, Chernogolovka (1980), p. 45.
5,. W. Ried and G. Urlass, Chem. Bar., 8_~6, ii01 (1953).
6, J. Krapcho and C. F. Turk, US Patent No. 3,321,468; Chem. Abst., 68, 21970 (1968).
7. R. A. Yanchene, B. A. Puodzhyunalte, and R. G. Lyutkene, Dep. VlNITI, NO. 6081-827 (1982).
8. B. Puodzhyunalte (Puodziunalte), R. Janciene, and Z. Stumbrevlciute, in: Topics in Chem-
istry of Heterocycllc of Compounds, Bratlslava (1981), p. 281.
P. Linscheid and J. M. Lehn, Bull Soc. Chim., France, No. 3, 992 (1967).
.

i0. L. Cazaux, Ch. Vidal, and M. Pasdeloup, Org. Magn. Reson., 21, 190 (1983).
ii. G. Romeo, M. C. Aversa, P. Giannetto, P. Ficarra, and M. G. Vigorita, Org. Magn. Reson.,
15, 33 (1981).
12. Z. Stumbrevi6iute, B. Puodzhyunalte (Puodzlunaite),
v. R. Janciene, and P. Mikulskis, in:
VIIlth Symposium on the Chemistry of ~eterocyclic Compounds and the VIth Symposium on
Nucleic Acid Components.
13. F. De Los de Tot, in: Computer Programs for Chemistry, New York (1968), p. 10.

HOMOLYTIC ADDITION OF 1,3-OXATHIOLANE TO UNSATURATED HYDROCARBONS

S. V. Nikolaeva, V. V. Zorin, UDC 543.51:541.63:547.787

S. S. glotskii, and D. L. Rakhmankulov

The homolytic addition of 1,3-oxathiolane to olefins takes place with the for-
mation of 2-substltuted 1,3-oxathiolanes and insignificant amounts of functional
derivatives of sulfides.

It is known that 1,3-dioxacycloalkanes add to olefins forming, in the general case, 2-

substituted dioxacycloalkanes and functional derivatives of esters [i, 2]. The reaction with
2-methyl-l,3-oxathiolane proceeds similarly [3]. In this paper, the direction of the homo-
lyric addition of 1,3-oxathiolane to unsaturated compounds has been studied in order to de-
termine the effect of the nature of the olefin on the course of the reaction.
We have established that, in contrast to 2-methyl-l,3-oxathiolane, the reaction of 1,3-
oxathiolane, I, with unsaturated compounds II-VI in the presence of tart-butyl peroxide at
140~ for one hour forms 2-substituted 1,3-oxathiolanes VlI-XI and the corresponding sulfides
Xl I-XVl.
[ ! ........ F--I .:!!x-:7!).,- 1........
I +x~_.. I ....
i
0 /S O~.S 0 /S -la O /S

I II ~1 ~ ,
la Ib n-.x,

(m-vl) + I
Hg , ~ H~'0 R~--CH-CH2R
"SCH~CH 2 "SCH2CH 3 -H' -C~" C2H~S .....-la---'~" I
Ic Id sc2~5
XII--XYI

II, VII, Xll R=COOCH,, III, VIII, XllI R=OC(O)CHs, IV, IX, XIu R=CN, V, X, XV
R=OC(O)H, VI, XI, XVI R=CH2CH2CH2CH3" II, VII, XII R*=COOCH3, III--VI,
VIII--X'I, XIII--XV RI=H
Ufa Petroleum Institute, Ufa 450062. Translated from Khimiya Geterotsiklicheskikh S0e-
dinenii, No. 2, pp. 259-263, February, 1986. Original article submitted December 3, 1984;
revision submitted March 12, 1985.

210 0009-3122/86/2202-0210512.50 9 1986 Plenum Publishing Corporation

 PMR Spectra and P h y s i c o c h e m i c a l Constants of the Products of H o m o l y t l c Addition
TABLE i.
Chemical shift, 6, ppm, fl:om HMDS in CCI=, J

Com- Formula o f compound bp, ~ (lmn) /'zD2O 9-1I;

2-H 3-H 4-H 5-H 6-H; 6'-H 7-H; 7"~H 8-H 9"-H
pound

5,32 d 2,82--3,01 m 3,60--3,75m ; 3,06--3,26 m 2,62--2,70 TM -- 3,14 S;

155 (7) 1,4920
VII 4,15--4,38 m 3,59 S.
o,,~ s
"~< 6 8 9
H': "CH-COOCH3
71 ~ 9'
CH2COOCH 3

1,4853 5,2--5~48 m 3,18--3,48 m 3,96--4,12 m 2,95--3,18 m 4,26--4,50 m 2,35 t~

12o (6)
VIII 4,18--4,5~
0 2.S
"~s 7 v~0
H" cn2ca2OC~H z

1,428825 5,5t t 3,18--3,51 ra 3,95--4,27 m 2,35--2,62 m 2,83 t

190 (7)
IX 4,50--4,79 m
0~2/S
6 7 8
R ' ~ ' ~ CH2CH2CN
1,4840 ~7 4,81--4,98 m 3,05 t 3,92--4,27 m; 2,48-~-2,60 m 3,52--3,70m 8,.~9 s --
87 (6)
I 4,27--4,58m
o 2 s
6 7 8~0
.-~'c.:n~oc<.
1,4686 4,90 t 2,89 m 3,63m ; 1,45 = 0,86 t
1t5--116 (10)
XI 4,22 m
o 2 s

1,4610 2,59 q 1 22 3,32--3,58 2,54 d 3,67 s ;

3 2 1 4 6 7 11o (I5)
XII CH.CH^S-CHCOOCH~ 3,71s
CH2COOCH 3

1,4610 "2,49 q 1,21 2,62 t 4,08 t 1,95 s

CU~CH=SCIL=Cli=OC "/>
48 (3)
XIII
86/4 !,4845 2,57 q 1.22 2,68t 2,73 t
XIV CH~CH:SCH=CH=CN 1,4593 2,50 q 0 87' 2,30t 2,23--2,53at 1,17 t
CH~CH~SC H.-4CH.-hCH3 170
XVI

t,J
k--=
I--=
 TABLE 2. ~SC-NMR Spectra of the Products o f the Homolytic
Addition of 1,3-Oxathiolane to Unsaturated Hydrocarbons
]

J~ I Chemical shift, ~ , ppm

C(s ) (C~e,)) C(91 (Co,) )

VII 85,96 d 32,23 t 72,36 47,77 d 32,68 t 171,7 52,17

86,60 d 32,04 t 171,0 52,49
171,4
VIII 84,27 d -- 36,57 t 71,85 33,59t 61,16 t 170,I s 21,49 q
IX 83,9 a -- 33,01 t 71,27 13,34t 31,53 t I09,5s
X 85,77~l, -- 33,9 t 70,88 37,7 t 60,14 t 169,0 d --
XI 87,45d. -- 33~27 t 71,65 37,34t 14,75 q
32,62t
30,03t
27,18t
23,43t
XII 36,70t .~6,21 51,59 d 41,88 170,4 s 52,49 q
171,4 52,10 q
XIII 26,53 t i5.4 30,55 t 63,88 169,8 ~ 20,97 q
XIV ~7,38 t 26101 31,91 t 26,74 I 11,76s

The formation of products VII-Xl apparently takes place via the formation of 1,3-oxathio-
lan-2-yl radicals la, which react with unsaturated compounds II-XI to give spin-adducts Ib and
then products VII-Xl.
The S-ethyl thioformate being formed by the isomerization of 1,3-oxathiolane [3] is known
[3,4] to give 2-(formylthiolethyl) radicals which participate in the formation of sulfides
XII-XVI.
The results obtained show that as the temperature rises from 130 to 150~ the yield of
cyclic adducts falls somewhat while that of the sulfides rises, Obviously, the activation en-
ergy for the rearrangementof 1,3-oxathiolan-2-yl radicals is somewhat higher than that for
their addition to the dimethyl maleate. This leads to an increased yield of sulfide IX ap-
pearing as a derivative of S-ethyl thioformate.
By comparing the ratio of yields of sulfides and 2-substituted 1,3-oxathiolanes for l-
hexene and other olefins containing polar groups, one can see that the fraction of sulfides
in the latter case is notably low. This is explained by the nucleophilic character of the
1,3-oxathiolan-2-yl radicals.
The addition to the double bond of olefins II-VI, which contain electron-acceptlng groups,
takes place significantly faster than the rearrangement in the formylthioethyl radicals,
[CH(O)SCH2~Ha]. This precludes the formation of an addition product of the latter with olefins
II-VI.

EXPERIMENTAL
The PMR spectra of substances VII-XVI were recorded on a Tesla BS-467 spectrometer with
a working frequency of 60 Ml{z, and the *sC-NMR on a Bruker WH-90 spectrometer with a working
frequency of 22.63 MHz. The quantitative analysis of the reaction mixtures was done on an
LKhM-8MD chromatograph with a thermal conductivity detector. The regime of the chromato-
graphic analysis: carrier gas helium; gas consumption rate 3.5 liters/hour; 3000 3mmcolumn;
SKTFT-50x 15% on chromaton N-AW-HMDS; temperature program 70 to 200~ at a rate of 4~
The experiments were run in glass ampoules. The ampoule was charged with 1,3-oxathiolane,
I, olefin II-VI, and TBP [tert-hutyl peroxide] in a molar ratio of I:(II-Vl):TBP = 10:3:0.3,
purged with argon, sealed, and then thermostated at 140~ for one hoqr. Substances VII-XI
were separated from the reaction mass by vacuum distillation and identified by the PMR and
~aC-NMR spectra (Table i-3).
Products XII-XVII were identified chromatographically by the identity of the reaction
times with those of known, synthesized samples.

212
TABLE 3. Composition of Products of the Homolytic Accion
of 1,3-Oxathiolane to Olefins (T 140~ molar ratio of I:
: II-VI:TBP = 10:3:0.3; reaction time 1 h)

Con- yield' of con-

Olefin v e t - ICom- Formula vetted o!e-
1 sion Inound Compound name
R CH.----CHR, % )fole-~ fin,
fin
COOClI~ 70* VII Dimethyl (1,3-oxa- 52 (69)*,
80 thiolan-2-yl )suc- O S (45)*
92 cinate H~COOCtI~
~cooc- 3
COOCh

XII Dimethyl (ethyi- C2Ilss-CHCOOCH~ 7 (6)*,

t~hio)succinate
i
CH2COOCH3 .(12)*

VIII 2- (2 '-Acetoxy-
cH--
2~CH-OC
/o ethyl )-1,3-oxa-
thiolane O_ S 0
~cs~
.>~caacR=OC~c. ~

XIII 2-Ethylthioethyl C2HsSCH2CH20C~cH~

acetate

2- (2 ' -Cyanoethyl)- 48
IX I ......... I
i,3-oxathiolane 0 ..S
II ''>~"CHzCII .CN

CH2=CHCN 2-Ethylthiopropio- r.2H~SCH~CH.~CN

XIV nitrile

:o 80 X 2- (2 '-Formyloxy- 59 84
C H2--=CH O C / ethyl )-i,3-oxa- 0 S
thiolane .><CH:H=OC~

O
XV Z-Ethylthioethyl C PIsSCM C H - O C ~
2 " 2 ,: "II
Formate
2-Hexyl-i,3-oxa-
XI thiolane [--1S
0
60

H~CeH13
CH:=CH-(CH~)3CH3 20 XV I Hexyl ethyl sul- C=HsSC,sH~a 22
fide
(VII 9
S-Octyl thio-
formate "SCsHI 4

*At 130~ reaction time 2 h.

%At 150~ reaction time 0.5 h.
Note. Asterisks as in Russian original; some Should probably
be daggers, and some other daggers are probably o m i t t e d --
Editor.

213
 LITERATURE CITED
i. D . L . Rakhmankulov, R. A. Karakhanov, S. S. Zlotskii, et al., Progress in Science and
Technology. The Technology of Organic Substances, Vol. 5, Progress in the Chemistry of
1,3-Dioxacyc!anes, [in Russian], GKNT VINITI, Moscow (1979), p. 288.
2. R. Lalande, B. Maillard, and M. Cazaux, Tetrahedron Lett., ~, 745 (1964).
3. V . V . gorin, A. V. Germash, S. V. Nikolaeva, S. S. Zlotskii, A. B. Terent'ev, and D. L.
Rakhmankulov, Zh. Obshch. Khim., 54, No. 5, 1152 (1984).
4. V . V . Zorin, S. V. Nikolaeva, S. S. Zlotskii, and D. L. Rakhmankulov, Zh. Obshch. Khim.,
54, 2401 (1984).

EFFECT OF SUBSTITUENTSON THE RELATIVE STABILITY OF FUROXAN ISOMERS

V. G. Andrianov, M. A. Shokhen, UDC 547.793.2'541.621.22'127.4:

A. V. Eremeev, and S. V. Barmina 530.145

The overall energy of isomers of substituted furoxans has been calculated using
the MINDO/3 method. Comparison with experimental results indicated that the
calculation correctly predicted the structure of the more stable isomer. Cor-
relation of the difference of the overall energy of the isomers (AE) with the
induction and resonance constants of the substituents, and comparison of the
values of AE calculated from the correlation equation with the experimental val-
ues have also been carried out.

At elevated temperatures unsyrmuetrically substituted furoxans are capable of mutual trans-

formation [I, 2] :

~---T ~ ...... ~.......ii

o~l'IxO/N k2 lq~ 0 . N-i 0

I I!

The relative stability of the isomers depends on the nature of the substituents R* and R ~.
However, the reasons for the stability of one isomer or the other are not clear and the lim-
ited amount of experimental material available does not allow a quantitative, nor even a
qualitative, correlation of the electronic effects of the substituents with the equilibrium
constants of the isomers.
In this connection, we have carried out calculations by the MINDO/3 method, using the
original program [3], of the difference in the overall energy of the isomers AE = Eli -- E1
of a series of furoxans with different substituents (Table i). In dealing with the geometry
of the furoxan ring, x-ray crystallographic data were used [4] and for the substituents R*
and R s, averaged geometrical parameters [5]. Comparison of the calculated difference in the
overall energy of the isomers with the experimentally determined values for the free energy
difference (AG) (Table i) indicates that the calculation correctly predicts the structure of
the isomer with the greater stability, although the difference is exaggerated for isomers
with cyano-group substituents. Therefore, calculation without optimization of the geometry
is satisfactory for an interpretation of the effect of substituents on the relative stability
of the.isomers.
In accordance with the principle of the linearity of free energies [6], the dependence
of the rate constant of the forward reaction on the induction (o~ and resonance (O~ con-

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 264-266, February, 1986.
Original article submitted November 23, 1984; revision submitted March 28, 1985.

214 0009-3122/86/2202-0214512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Calculated and Experimental Energy Differences for
Furoxan Isomers (kJ/mole)

R' R2 5E, AE, AOa Lit. ref.

quant,mech from eq. 2

CHa H -6,76 --9,61

C6Ha H 8,90 Ob
Coils CH3 18,51 -- 1 , 9 2 b
C~CH H - --0,39
NH2 l-t -- 37,83 -- 40,69
--C.
Ntt2 C6H5 -- 49,59
(CH3)2N C~H5 -- 65,78 -e-
OH H -53,17 -59,51
OCIt3 H - 45,88 --46,19
OCH3 CH3 -36,57 <-13d I0
OCH3 C6H5 --55,28 -c.. 11
OCd-t5 CH3 --31,73: e <--13 10
F H - 42,90 - - 38,27
CI CH~ --20,35 <--lO b 14
Cl Cd-h --38,87 ~.~ -- 8,2 f 15
Br C6H5 --39,54 ~<--5,8 f 15
CH3S CH~ - 2,20 --3,46 d 10
C6H5S CH3 --l,26 10
C6HsS C6tt~ --2,2 b 16
Ctt~SO2 CH3 -4,35 --2,63 d 10
CHO H 15,24 8,50
COCH~ CH3 -3,39 18,11 -0,8
COOCH~ H 5,75 7,23
COOCHs CH3 2,66 16.84
COOC~Hs CH3 16,84 - 0,73 10
CONH2 H 1,38 8,92g
CONf-I~ C1-t~ 3.67 18,53 g 2,69 10
C--=N CII~ I0,04 8,06 1,04 10
NO2 H --17,t8 - 16,24
_ c
NO2 CH~ -- 6,47 -- 6,63 10
NO2 Cdis --25,14 <-4,4 f 17

a) In cases where the absolute value of AG was not determined,

only its sign is given, b) Calculated from the equilibrium
constant, c) Equilibrium not fixed. Indicated that isomeri-
zation proceeds quantitatively, d) Experimental value deter-
mined for R I = OCaHs, SCaHs, or SOaCaHs, respectively, e) For
the group OC~Hs, Ol = 0.37 [12], OR =--0.36 [13]. f) Calcu-
lated from percentage isomer content, g) Calculated from orien-
tation for On = 0.20 and o I = 0.21 [12].

stants of the substituents R* and R 2 with allowance for their different positions on the ring
can be expressed by the equation

lg(k,/ko) =Ol~l~176 ,

where the constants 0x, 0a, 03, 0~, characterize the sensitivity of the position to the cor-
responding effect. Then the equation for the rate constant of the reverse reaction takes the
form
Ig(k2/ko) =p,om~176176176

Hence, the equilibrium constant K is equal to

Jg K = lg (k~/k2) = (0~ - v~) ( ~ o _ o,,~o) + (I,~-- v~) ( ~ o _ o,~o)

or in another form

- RT In K = AG = A H - TAS = p (~m ~ ~m ~ + P' (~i to - ox2~ (1)

The entropy difference AS could not be evaluated but, because in our case the forward and
reverse reactions are in fact the same process, and the differences are connected with the ar-
rangement of the substituents, which do not take direct part in the reaction, it seems valid
in this and similar cases to take AS = 0 so that the values of AG and All are determined only
by the difference in the internal energy AE of the isomers [18].

215
 The coefficients p and p' in Eq. (I) were determined by the least sequare method:

AE=80,1A~~ ~ (2)
(R=0,981; S=SA; r~=0,929; r~=0.501).
Comparison of the values of AE calculated from Eq. (2) with the experimental free energy
differences shows that Eq, (2) correctly predicts the greater stability of isomer II for R* =
NH2, (CH3)2N, CHsO, C6Hs0, CI, Br, CH3S, CHsSOa, NO2 and R = = CHs, C6H5, and the greater sta-
bility of isomer I for R I = CONH~ and CEN and R 2 = CHs. When R I = C6Hs, COCH3, CsH5 and C00C=Hs
andR 2 = CH3, the experimental results do not conform in sign to those calculated. It has been
suggested [2] that in the case of methylphenylfuroxans the equilibrium position is determined
not so much by electronic as by space effects. For furoxans with R ~ = COCH3, and C00C~H5 and
R a = CH3, the difference in the stability of the isomers is in general small (-0.8 and-0.73
kJ/mole) and dould be due to solvation effects.
In accordance with the signs of the coefficients of AO~ and AO~ in Eq. (2), +R and --I
effects of the substituted R ~ lead to greater stability of isomer II compared to isomer I and
conversely--R and +I effects of substituent R ~ lead to greater stability of isomer I. This
is shown by the observation that in the case of furoxans containing such groups as OR, NR2,
CI, Br (+R and --I substituents) the 4-substituted derivatives prove to be considerably more
stable than the 3-substituted. For --R and -I substituents (NO2, C00R, COR, CONH2, C5N, RS02),
i.e., when the effects are compensated, the difference in the stability of the isomers is us-
ually small.
The reason for the opposite action of induction and resonance effects becomes intelligible
if one takes into consideration the dual character of the N-oxide group as a substituent. On
the one hand, as a strong resonance electron donor it considerably increases the population of
the 2pz A0 of the, u-carbon atom in comparison with the B-carbon (the charges on the atoms are
shown with the 2pz A0 populations in brackets):

-~O.0~6 I | ~ I[ +0.126

-~~,oB2 ~u,. . . . {] LI

+o,,,~ N . O "N'~o"-a:.~, ~
- o.36a

Hence a +R effect of the substituted R ~ destabilizes isomer I and a--R effect stabilizes
it. On the other hand, the positively charged nitrogen atom of the N-oxide group is a strong
acceptor of o-electrons which is particularly clearly displayed in the increase of positive
charge on the hydrogen of the u-carbon. As a result of this, a +I effect in substituent R I
must stabilize isomer I, and a --I effect must destabilize it.

LITERATURE CITED
io L. I. Khmel'nitskii, S. S. Novikov, and T. I. Godovikova, Chemistry of Furoxans: Reac-
tions and Applications, Vol. 2 [in Russian], Nauka, Moscow (1983), p. 28.
2. A. Gasco and A. J. Boulton, Adv. Heterocycl, Chem., 29, p. 294 (1981).
3. R. C. Bingham, M. J. S. Dewar, and D. H. Lo, J. Am. Chem. Soc., 97, 1285, (1975).
4. M. Calleri, G. Chiari, A. C. Villa, A. G. Manfredotti, C. Guastini, and D. Viterbo, Acta
Crystallog., B33, 479 (1977).
5. J. A. Pople and M. Gordon, J. Am. Chem. Sot., 89, 4253 (1967).
6. V. A. Palm, Fundamentals of the Quantitative Theory of Organic Reactions [in Russian],
Khimiya, Leningrad (1977), p. 216,
7. R. Calvino, B. Ferrarotti, A. Gasco, A. Serafino, and E. Pelizzetti, Gazz. Chim. Ital.,
113, 811 (1983).
8. F~-B. Mallory and A. Cammarata, J. Am. Chem. Soc., 88, 61 (1966).
9. A. R. Gagneux and R. Meier, Helv. Chim, Acta, 53, 219 (1970).
I0. A. Gasco and A. J. Boulton, J. Chem. Soc., Perkin Trans. 2, No. 12, 1613 (1973).
ii. R. Calvino, A. Gasco, A. Serafino, and D. Viterbo, J. Chem. Soc., Perkin Trans. 2, No. 9,
1240 (1981).
12. R. W. Taft, E. Price, I. R. Fox, I. C. Lewis, K. K. Anderson,'and G. T. Davis, J. Am.
Chem. Soc., 85, 709 (1963).
13. R. T. C. Brownlee, R. E. J. Hutchinson, A. R. Katritzky, T. T. Tidewell, and R. D. Topsom,
J. Am. Chem. Soc., 90, 1757 (1968).
14. R. Calvino, A. Gasco-? E. Menziani, and A. Serafino, J. Heterocycl. Chem., 20, 783 (1983).

216
15. R. Calvino, A. Serafino, B. Ferrarotti, A. Gasco, and A. Sanfilippo, Arch. Pharm., 317,
695 (1984).
16. R. Calvino, V. Mortarini, A. Casco, A. Sanfilippo, and M. L. Ricciardi, Eur. J. Med.
Chem. Chem. Ther., 15, 485 (1980).
17. N. N. Mmkhova, I. V. Ovchinnikov, B. M; Khasanov, and L. I. Khmel'nitskii, Izv. Akad.
Nauk, Set. Khim., No. 3, 646 (1982).
18. M. Dewar and R. Doherty, Molecular Orbital Perturbation Theory in Organic Chemistry
[Russian translation], Mir, Moscow (1977), p. 171.

MASS SPECTRA AND ISC NMR SPECTRA OF THE ADD~JCTS

OF EPOXYENAMINES WITH SULFENE

G. I. Polozov, I. G. Tishchenko, UDC 543.51'422.25:547,592'

and V. P. Suboch 867.4'717'718

The behavior of the adducts of alicyclic epoxyenamines with sulfene under elec-
tron impact and also their ~3C NMR spectra were studied. The initial fragmenta-
tion of these compounds, which takes place with the ejection of sulfene, is ac-
companied by a specific hydrogen rearrangement of the molecularion. The degree
of substitution of the cyclohexane ring has a significant effect on the nature
of the subsequent dissociation, which leads tO extensive degradation of the oxi-
rane ring.

The readily occurring reaction of sulfene with alicyclic epoxyenamines leads to the for-
mation of aminoepoxythietane dioxides [i], which represent a new type of previously uninvesti-
gated heterocyclic system including three and four-membered heterocycles annellated with the
cyclohexane ring. It seemed of interest to determine which of the heterocycles would be de-
composed first by the action of electron impact and to trace the main directions in the mass-
spectrometric fragmentation of the compounds. In this connection in thepresent work we in-
vestigated the mass-spectrometric behavior of l-amino-8-oxa-3,thiatricyclo[5.2.0.OT'9]nonane
3,3-dioxides (I-VIII) bY means of the DADI technique and the high-resolution mass spectra and
studied their Z~C NMR spectra.

N x /-'\
. . . . " ,.--', v..e

CH"
3 [6 k~ 3S0 C[13~: ~
CHj "CH a "/
I-Vlll I~,X XI

I R=H, II--X R=CHa; I--IVRI=H. V--X R'=CH3; I, II, V, IX X=O, Ill, VII, X
X=CH2, IV, VIII X=(C}I=)2 (VI X = - )

The m o l e c u l a r i o n p e a k s (M+) i n t h e mass s p e c t r a o f a d d u c t s I - g i l l ( T a b l e i ) have low

intensity, w h i c h d e m o n s t r a t e s t h e low s t a b i l i t y of the molecules to e l e c t r o n impact. In the
general case the stability of M+ depends little on the nature of the amine substituent and
decreases with increase in the number of methyl groups at position 5 (Table 2) on account of
the appearance of new energetically favorable dissociation paths f o r M + on account of possi-
ble rearrangement.
The initial dissociation of M + is extremely similar to the previously investigated frag-
mentation of the cyclic adducts of sulfene and enamines [2-4], involving retro[2+2]-cleavage

Scientific-Research Institute of Physicochemical Problems, V. I. Lenin Belorussian State

University, Minsk 220080. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2,
pp. 267-271, February, 1986. Original article submitted October 19, 1984.

0009-3122/86/2202-0217512.50 9 1986 Plenum Publishing Corporation 217

 TABLE i. Mass S p e c t r a of Compounds l-Xl*
m,

Com- m/z values (relative intensity, %)

pound

273 ( l i ) , 195 (100), IO4 (95), 180 (45), 178 (34), 152 (11), 67 ( l i ) , 56
(12), 55 (20), 43 (37). 42 (11). 41 (31)
II 287 (23), 210 (ll), 209 (81), 208 (100), 195 (18), 194 (98), 193 (11), 182
(I1). 181 (38). 180 (14), 166 (14), 152 (11). 112 (13). 108 (16). 86 (21).
81 (14), 79 (16), 77 (14). 69 (14). 67 (29), 55 (32), 54 (15), 53 (16), 43
(63), 42 (23), 41 (57)
llI 285 (7), 207 (45), 206 (90), 193 (13), 192 (100), 190 (55), 188 (ll), 179
(15), 164 (23), 150 (11), 136 (12), 84 (33), 67 (12), 55 (21), 43 (29), 42
(13), 41 (41)
IV 299 (11), 221 (50), 220 (100), 206 (6~), 204 (32), 193 (12), 178 (12), 98
(II), 55 (17), 43 (20), 4l (23)
V 301 (6), 223 (43), 222 (79), 209 (25), 208 (100), 206 (16), 195 (36), 180
( I l L 112 (13), 93 (11), 91 (11), 86 (13), 8l (13), 79 (13), 77 (12), 67
(17), 56 (20), 55 (23), 53 (14), 43 (55), 42 (18), 41 (47)
VI 285 (4), 207 (30), 206 (54), 193 (19), 192 (lO0), 190 (16), 179 (20), 96
(II), 70 (22), 55 (17), 43 (22), 41 (24)
VII 299 (5). 221 (35). 220 (67), 207 (17), 206 (100)., 193 (25). 84 (t5), 55
(16). 43 (20), 42 (ll). 41 (24)
VIII 313 (5), 235 (29). 234 (69). 221 (17). 220 (100), 207 (20). 98 (13), 55
(21). 43 (17).41 (22)
IX 223 (33), 209 (30), 208 (100), 166 (ll), 165 (22), 114 (18), 112 (22). 93
(18), 79 (14), 77 (14), 70 (14), 56 (15), 55 (20), 43 (37),41 (55)
X 221 (16). 207 (13). 206 (100). 163 (11). 112 (11), I10 (15), 04 (33). 83
(30), 69 (28). 57 (11), 56 (11), 55 (17), 44 (12). 43 (16). 41 (55)
XI 245 (30), 167 (37), 166 (100). 165 (43). 152 (13), 138 (14). 136 (12). 122
(13). I09 (12), 108 (24), 95 (13). 94 (13), 86 (13), 81 (22). 79 (23), 7 7
(14),67 (20), 56 (15}. 55 (24), 54 (14), 53 (15), 42 (15), 41 (38)

*The peaks of M+ and of the ions with an intensity of more

than 10% of the maximum are given.

of the thietane ring and elimination of a molecule of sulfene or alkylsulfene. One of the
characteristic dissociation paths in compounds I-VIII is also realized with loss of sulfene and
the formation of the ~, ion (see the scheme), the fraction of which in the total ion current
is highest for compound (I) and decreases appreciably for the substituted derivatives II-VIII
(Table 2).
The main dissociation path for M + involves the formation of the stable fragment [M --
CH, SOa] + (the #2 ion); the probability of this process for compounds II-VIII is 1.2-2.4 times
larger than the probability o f the elimination of sulfene. We note that the formation of the
~ and ~2 ions is the result of independently occurring single-stage processes of the disso-
ciation of M+, since the metastable transition ~, --H. -~ ~i is not observed.
Scheme
F--\-W
o -I+ - - N x
9\\>.. +/---\

9R' > < R it'-'><-Xtu~

-~-- "%~_tx * i -CII2SO 2

-o,,. - _r (

% ~: " ~lJ--
"-,2"-
\-/
t
R

A characteristic feature in the mass spectra of the precursors of the adduces, i.e., the
epoxyenamines IX, X [5], is the absence of peaks for the [M -- H] + ions, and at the same time
the WMvalues of the latter are significantly higher (4.7 and 3.2%, respectively, Table i).

218
 TABLE 2. Intensities of the Peaks for the Characteristic
Ions in the Mass Spectra of Compounds I-VIII as Percentages
to the Total Ion Current (E~o, %)

Compound i~'i ~ % '~ ~* @s ~8

I 1,6 11,6 11,1 0,7 5,2 (qiq) 4,0 1,0 9

II 2,1 5,9 7,3 2,8 7,2 5,2 1,5
Ill 0,9 4,7 8,8 1,5 9,8 5,5 3,2
IV 2,1 7,7 15,5 1,9 9,9 4,9 1,7
V 0,8 4,7 7,8 3,6 9,9 1,6 1,3
VI 0,9 4,4 7,9 2,9 14,6 2,3 3,2
VII 1,1 5,4 10,3 3,9 15,4 1,2 2,3
VIII 0,8 4,7 11,2 3,2 16,2 I,! 2,1

The main peak in the mass spectra of these compounds is the peak for the [M-- CHs] + ion. On
the other hand, in the spectrum of the amino sulfone XI [6] the peak for the [M -- CH~S0=] + ion
is the maximum in intensity. These data indicate direct participation of the four-member het-
erocycle in the formation of the ions with structure r The most likely process is dissocia-
tion of M + by a mechanism of the McLafferty rearrangement type involving the mobile hydrogen
atoms of the s-methyl group in the nitrogen-containing heterocycle. This is typical of en-
amino ketones [7], 3-amiflo-l,2,4-triazine 1-oxides [8], and functionally substituted piperi-
dines [9]. According to the data from x-ray crystallographic analysis of the adduct of s u l -
fenewith E-l-dimethylamino-l-phenyl-l-propene [i0], the carbon atom of the N-methyl group lies
in the plane of the sulfonyl group and the nitrogen atom. Examination of molecular models of
adducts I-VIII demonstrates the steric proximity of the oxygen atom of the sulfonyl group and
the hydrogen atoms of the above-mentioned s-methylene group. Such molecular geometry undoubt-
edly promotes the migration of one of the hydrogen atoms to the sulfonyl group and subsequent
elimination of the CH2SOIH radical, which is realized through a cyclic transition state as a
result of a concerted process:

/" //
/ i
!~
It ~ .l ~ "~ N, X
C,~'. . . . . . . . '~....... / '"[ / R "~"" / % / +
N
O

II)
M+ 0

One of the characteristic fragmentation paths in the investigated compounds is the direct
formation of the [M -- C3H6S02]+ ion (~3) from M +. Its peak is particularly strong in the spec-
tra of adducts V-VIII. This ion is evidently formed through the simultaneous occurrence of
two processes, i.e., cleavage of the four-membered and nitrogen-containing rings with the e-
jection of sulfene and ethylene molecules, respectively. This suggesting is consistent with
the data on the fragmentation of the enamines of cyclanones and cycloamines [7], the mass spec-
tra of which contain a strong peak for the [M -- C2H4] + ion, formed as a result of the disso-
ciation of the nitrogen-containing ring. However, the peaks of the [M -- C2H4] + ions, which
would have the structure of the ~s ion, are absent in the spectra of epoxyenamines IX, X.
A characteristic dissociation path of M+ is also the elimination of a molecule of S02
with the subsequent ejection of a hydrogen atom. The spectra of all the compounds contain a
peak for the [M -- CH2SOH] + ion, and in the spectrum of compound I there is in addition a peak
for the [M -- OH] + ion; this is probably due to rearrangement processes in M +. The spectra of
adducts II-VIII always contain a peak for the [M -- CH3] + ion. The intensities of all the
above-mentioned peaks are low (less than 1% of the total ion current), and these paths are
consequently insignificant in the overall dissociation of M +.
The subsequent dissociation of the #i ion involves primarily the loss of the methyl group
and the formation of the [~1 -- CH3] + ions, which give a signal of high intensity (maximum for
compounds V-VIII). In the case of adduct I this process is evidently realized with the re-
moval of the methyl group from the oxirane ring and localization of the charge at the oxygen
atom (the ~'~ ion); for compounds II-VIII the removal of the methyl radical from position 5 is

219
 TABLE 3. Elemental Composition of the Ions in the Mass Spectra
of Compounds I and Vll

Elemental Accuratemass
IElementai Accurate mass
found I~ I
, ~~ lon composition lcalcu" , Ion composition~ za-T~lated
8 _lat~d ]8 ~,
]i

I M+ C,2}I,,NO,S 273,1025 273,10]6HVII M+ ClstI~NOaS 299,1547 299,1538

o. C,,H,,NO= 195,12771105,1258 Ci4112aNO 221,1803 221,1779
C.III~N02 194,12(15] 194,1180 ]l C,4I"122NO 220.1724 220,1700
OO~ C~H ,~NO~ 167,0955 I 167,0946 II Cj~lfl~NO 193,1471 193,1466
C.olI~NO~ 180,1049 ~ 180.1024 I] C;aH2oNO 206,1552 206,1544
O5 C.H~NO 178,1244J 178,1232 J]

TABLE 4. ~3C NMR Spectra of Compounds I-VIII, ppm

Compound c(t) c(~> c~4) c,5 ~ c~> c~7) C~9~

I 48.38 68,72 73,07 16,61 54,36 58,24

1I 48,92 68,88 79,75 30,ua 20,50 55,37 58,16
11I 49,23 69,66 80,22 30,13 22,36 55,13 58,39
IV 49,39 63,89 80,66 28,13 24,22 55,75 58,71
V
,Tv
51,71 66,47 82,16 34.71 23,12 57,93 58,01
Vl 49,46 63,36 82,62 30,36 27,10 58,39 59,48
VII 51.56 64,62 83,07 32,74 28,56 58.11 58,32
VIII 51,79 66,24 83,71 34,71 2~,04 58,47 59,17

most likely (the ~ ion). The maximum intensity of the peak for this ion is probably explained
by the ease of the elimination of the methyl group on account of its steric interaction with
the oxygen atom of the oxirane ring and the subsequent formation of a cyclic structure with
conjugated bonds and with stabilization of the charge at the nitrogen atom.
The subsequent dissociationpaths of the main fragment ions r162 largly characterize the
processes involved in the dissociation of the oxirane ring, which are accompanied by the elim-
ination of OH, CH3CO, and CHO radicals. The corresponding fragment ions and also the Cs and r
ions are capable of undergoing dehydrogenation processes. The elimination of the OH radical
from the r ion, which leads in the case of compounds I-IV to hlgh-intensity peaks for the Cs
ion (up to 5.5% of the total ion current) can also be explained by a characteristic rearrange-
ment with the participation of the oxirane oxygen atom and the ~-hydrogen atom of the nitrogen-
containing ring:

......
/
c.~"'"/~" ! ~ ' ~//" / -on'
........... ~./ \-/

For compounds V-VIII, which have two methyl substituents at the C(~) atom, the elimination
of the methyl group, which competes with the rearrangement, becomes the predominant process.
The peaks of all the remaining ions in the mass spectra have low intensity, and their fraction
in the total ion current is not greater than I-2%. Apart from the above-mentioned peaks, com-
mon peaks for the whole series of compounds are the strong peaks for ions with m/z 41, 43, 55,
67, 69, 77, 79, and 91 and also the r ion, which corresponds to the residue of the cyclic
amine.
The total fraction of M + and all the ions discussed above is greater than 40%, which in-
dicates a fairly high degree of selectivity in the dissociation of the compounds.
The high-resolution mass spectra of adducts I, VII (Table 3)confirm the elemental com-
positions of M+ and the main fragment ions. The paths presented in the Scheme and the order
of their formation follow from analysis of the DADI spectra of compounds I, III, VII.
Thus, the thietane dioxide and nitrogen containing rings in the investigated compounds
are cleaved with much greater probability than the oxirane ring, the dissociation of which is
due primarily to the possibility of a specific hydrogen rearrangement.
220
 In the '3C NMR spectra of adducts l-Vlll (Table 4), in addition to the downfield signals
characteristic of the carbon atoms of the thietane dioxide ring [3], in the regions of 54-59
and 58-60 ppm there are signals for the carbon atoms of the oxirane ring. The chemical shifts
of the C(,), C(~)-C(7) atoms are shifted appreciably downfield with increase in the number of
methyl groups at position 5.

EXPERIMENTAL
The mass spectra were obtained on a VarianMAT-311 instrument with direct injection of
the sample into the ion source at 70 eV and an ionization chamber temperature of 200~ The
:3C NMR spectra were recorded on a Jeol PS-100 spectrometer in deuterochloroform with HMDS as
internal standard under the conditions of full proton decoupling and single resonance.

LITERATURE CITED
i. I. G. Tishchenko, G. I. Polozov, and A. F. Abramov, Vestn. Belorus. Un-Ta, No. 2, 12
(1980).
2. B. Lamm, Acta Chem. Scand, Ser. B, 29, 332 (1975).
3. L. N. Koikov, P. B. Terent'ev and N. S. Kulikov, Zh. Org. Khim., 17, No. 5, 1087 (1981).
4. L. N. Koikov, P. B. Terent'ev, I. P. Gloriozov, V, N. Torocheshnikov, V. N. Baidin, and
Yu. G. Bundel', Khim. Geterotsikl. Soedin., No. 5, 643 (1983).
5. G. I. Polozov, I. G. Tishchenko, and A. F. Abramov, Zh. Org. Khim., 16, 765 (1980).
6. G. Stork and I. J. Borowitz, J. Am. Chem. Soc., 84, 313 (1962).
7. H. J. Jacobsen, S. O. Lawesson, J. T. B. Marshall, G. Schroll, and D. H. Williams, J.
Chem. Soc., No. 3, 940 (1966).
8. R. J. Radel, B. T. Keen, and W. W. Paudler, J. Heterocycl. Chem., 14, 1389 (1977).
9. A. I. Ermakov and Yu. N. Sheinker, Khim. Geterotsikl. Soedin., No. i, 65 (1981).
10. D. S. Yufin, Yu. T. Struchkov, L. N. Koikov, P. B. Terentev', and Yu. G. Bundel', Khim.
Geterotsikl. Soedin., No. 5, 651 (1983).

FRAGMENTATION OF SUBSTITUTED 2-SILA-I,3-DIOXACYCLOALKANES

UNDER ELECTRON IMPACT

R. S. Musavirov, I. A. Kondrat'eva, A. G. Kitov, UDC 621.384.8:547.1'128

E. P. Nedogrei, A. A. Kuz'michev, E. A. Kantor,
S. S. Zlot-skii, and D. L. Rakhmankulov

The mass spectrometric dissociation of 2-sila-l,3-dioxacycloalkanes takes place

mainly with loss of the substituent from position 2 of the heterocycle. The
fragment formed here eliminates the molecular of carbonyl compounds or alkenes.

The organosilicon analogs of cyclic acetals find use as water-repellant liquids [i]. The
methyl- and phenyl-substituted 1,3-dioxa-2-silacycloalkanes are used as components of lubri-
cants [2] and copolymers for most of the organosilicon polymers produced by modern industry
[3]. The aim of the present work was to study the mass spectra of substituted 2-sila-l,3-
dioxacyclohexanes I-IX and substituted 2-sila-l,3-dioxacyclopentanes X-XII:

UfaPetroleumlnstitute, Ufa 450062. Translated fromKhimiyaGeterotsiklicheskikh Soedinenii,

No. 2, pp. 272-275, February, 1986. Original article submittedApril 23, 1984;revision submit-
ted May 7, 1985.

0009-3122/86/2202-0221512.50 9 1986 Plenum Publishing Corporation 221

 CH 3
1 0-----" s /0 . . . . . CH3
R . / \ ~ . . I ~" ]?.
:si , t." . ,, ;',;i [
R2 " \0-'"' / "i~ ]~.... ~0 . . . .~. . . CII 3
R.s I;
CH3
I-- IX X-XJl

I, II, V-X, Xll R x CH3, Ill, IV, XI R I = C2H5; I, II, X R 2 =

=

CH3, III, IV, XI R 2 = C2Hs, V-IX, XII R = = C6H5; II, IV, VI, VII,
IX R 3 = CH3; VII, IX R 4 = CH3; 9 R 5 = R 6 = CH3; IX R 7 = CH3;
where not indicated, R = H
Earlier [4] we studied the main dissociation paths of 2,2-dimethyl-2-sila-l,3-dioxacyclo-
hexanes. In the present work we established the effect of substituents at the silicon atom
and also the size of the heterocycle on the stability of the molecular ions (M+) and analyzed
the general fragmentation pattern of these compounds under electron impact.
Analysis of the mass-spectrometric data (Tables 1 and 2) shows that the stability of M +
in the investigated 2-sila-l,3-dioxacycloalkanes I-XII corresponds to 0.8-8.8% of the total
ion current. An aromatic substituent at position 2 somewhat increases the stability of M + in
the 2-phenyl-substituted compounds V-IX, XII. A similar relationship was observed earlier [5,
6] during the discussion of t h e mass9 spectra of cyclic organosilicon compounds, and also in
2-aryl-l, 3-dioxacyclanes [7 ].
At the first stage in the dissociation of M + (Scheme) the R x(2) and R~(2)O particles are
eliminated with the formation of ions of the r and r types, respectively (Table 2). Simple
cleavage of the Si-R ~ (~) bond leads to the formation of ions which give a signal with maximum
intensity for all the compounds except VIII, IX, and XI. The preferential elimination of the
alkyl group from position 2 of the heterocycle has been mentioned for 1,3-dioxolanes and 1,3-
oxathiolanes [7] and also for silicon-containing heterocycles having two geminal substituents
at the silicon atom [8, 9]. The second process takes place with migration of the alkyl (or
aryl) group from position 2 of the heterocycle to the oxygen atom, and its probability is sig-
nificantly lower. The presence of two different substituents at the silicon atom in compounds
V-IX, XII gives rise to the simultaneous appearance of two ions of the r type. In the Scheme
and in Table 2 these alternative ions are marked by a subscript and a prime.
Analysis of the mass-spectral data makes it possible to isolate four main dissociation
paths for the r ion, leading to the formation ~of the r r r and r ions.

R2(1 ) S i --~O "~----- 0~. ./.O @6" r

r r z~.../ R M+~R ~ |*
/0 zO CH3
R R'--. /R R -CH ~" C H C ~ \C=O R /R
o--o\./ .~C~I12~ "~--(c).---~
" ""a '' ~ ~ H' c . 3~ ~(C).
R', " , "R - ~'-. +/~
\Z( o ..... o sl ---o
"Si I~P(1) ~"
R]2(') RI2(') '~'2' r
f
r r r ~1 |
/
" P I"
0 R20 ) _ Si.~OH
,) +/ ~/R l
~( --Si / "R HO"si+--R2(') "H
0 HO /
t
I r ~5' ~5
r r r ~4

R = H, CHs; n = 0, i
A characteristic feature of the investigated compounds is the elimination, by the frag-
ment ion r162 of a molecule of formaldehyde (the 4,6-unsubstituted compounds) or of mole-
cules of acetaldehyde (the 5,5-disubstituted compounds) and acetone (the 4,4-disubstituted
compounds) with the formation of a whole "family" of ions of the r type. Dissociation with
the elimination of the formaldehyde molecul~ predominates in these competing parallel proces-
ses, and the ketone molecule is eliminated least readily. A feature of the dissociation of
M + in compounds X-XII is the preferred elimination of the acetone molecule from the ion r162
It should he noted that in the majority of the spectra the r 1 6 2 transition is supported by

222
 TABLE i. Mass Spectra of Compounds I-XII*

Com- m/z value (peak intensity, % of maximum)

pound

[ 132 (5), l l 7 (lO0), lO1 (4), 87 (17), 75 ( l l ) , 61 (7), 59 (9), 43 (8), 31

(18), 45 (18)
II 146 (5), 131 (lO0), 103 (38), I01 (29), 87 (17), 77 (22), 75 (29), 45 (25),
43 (13), 28 (13)
If! 160 (10), 131 (100), 129 (2), 103 i l l ) , 101 (2), 91 (9), 89 (I), 75 (2), 73
(5), 45 (4)
IV 174 (7), .145 (100), 117 (14), 115 (12), 101 (5), 91 (7), 84 (82 , 45 (8), 32
(18), 28 (16)
V 194 (33), 179 (lO0), 146 (26), 133 (21), 131 (14), ll7 (93), 87 (31), 77
(7), 75 (21), 28 (21)
VI 208 (24), 193 (100), 163 (24)~ 139 (16), 137 (24), 130 (22), 121 (24), 116
(17), 105 (17), 77 (25)
VII 222 (27), 207 (I00), 177 (25), 165 (17), 139 (12), 137 (32), !29 (12), 105
(13), 77 (8), 45 (13)
VIII 222 (5), 207 (16), 137 (31), 105 (18), 77 (26), 51 (18), 45 (100), 43 (47),
41 (65), 39 (41)
IX 236 (6), 137 (23), 78 (31), 77 (53), 59(24), 46 (54), 44 (I00), 43 (62),
42 (92), 40 (46)
X 174 (52), 159 (100), 143 (10), 133 (18), 117 (24), 116 (65), 101 (24), 77
(24), 75 (43), 43 (29)
XI 202 (23), 173 (50), 91 (51), 85 (98), 59 (97), 57 (100), 45 (60), 43 (96),
41 (97), 31 (92)
XII 236 (45), 171 (75), 150 (IO0), 121 (88), 59 (96),58 (75), 44 (50), 43 (50),
51 (88), 30 (75)

*The ten strongest peaks are given.

TABLE 2. Peak Intensities of the Characteristic Ions for tom-

pounds I-XII (% of total ion current)
Com-
pound M.jol .Io,,I 1
q5 2 qb'~ cl~3 ep% r ca'4
. o loololoIo
I 2,0 40,0 -- 1,6 I -- 6,8 1,6 2,8 - - 3,61 - - , 4,4 ! - - i

II 1,2 24,0 - - 1,7 ] - - 6,9* -- 9,1 5,3 2,2 -- 2,41--,7,0;--

I
4,1
III 4,8 48,0 -- --- I 5,8 5,3 4,3 I,O I - - 2,4[--,0~5 --
IV 2,7 38,0 - - 0,8 -- 4,6 5,3 2,7 -- -- 1,11--,3,0 --
(1,9)
V 4,6 14,0 13,( 0,8 2,1 3,6 4,3 0,4 0 , 7 0,3 2,4 t 0,6 1,7 l,lll,Tll,l2,9
VI 4,3 18,0 1,~ 1,8 I 3,1 4,3 0,7 2,5 9,4! 2,9 4,5 1,4 1,4 4,319,914,3 0,2
! (2,0) (5,6
VII 6,5 24,0 0,~ 0,512,9 l,g
(0,2
3,41 0,2 2,~ 1,9 1,0 2,6 1,41--,7,7 0,2
VllI 0,9 2,7 0,]
0,5 -- I 0,7 0,5 I,O l 0,21 0,7 4,4 0,5 1,9 2,412,215,3 0,2
l i (0,3)
1X 0,8 ' 1,2 0,: 0,9 0,3 ' 1,4 0,5 0,41 0,4 0,8 6,9 0,3 2,1 0,913,113,0 0,0
(0,4) (0,5
X 8,8 17,0 - - 1,7 - - 3,9 4,1 . . . . . . 7,3 - -
XI 1,6 3 , 5 - - 04 - - 0,8 0,8 . . . . . . 0,4 - -
XII 3,6 2,7 8,( 118 1,4 i 0,9
i
0,5 o,61 9,6 -l ........ 1,7 1,5

*The component ions in relation to the substituents R ~ to RT;

the ions with the smallest m/z values are given in parentheses.
tThe [R2]+ ions make a contribution to the intensity of the
peaks for these ions.

the presence of peaks for metastable ions. The formation of cyclic ions like ions of the ~2
type (Scheme) was observed in [7] during examination of the dissociative ionization of sub-
stituted 1,3-dioxanes. Ring contraction as a result of fragmentation has been observed in the
mass spectra of silicon-containing heterocycles [5, 8, 9].
The r ions can then eliminate a molecule of the alkene and a molecule of the cycloalkene
(or alkyne) with the formation of the r and ~5 ions, respectively. Both these transitions are
confirmed by the presence of metastable ions in the spectra of the compounds.
There are at least three other paths for the dissociation of the r ion: i) An ion of the
r type is formed after the elimination of the alkene molecule. The appearance of such ions
has been observed before [i0] during the analysis of the mass spectra of diphenyldialkoxysilanes.

223
In the spectra of our investigated compounds these ions have appreciable intensity, and in
the 2-phenyl-substituted compounds V-IX, XII their intensity amounts to 32% on account of the
stabilizing effect of the phenyl substituent. 2) An ion of the #3 type, containing a four-
membered ring (three-membered in the case of 2-sila-l,3-dioxacyclopentanes) with three heter-
oatoms, is formed after the elimination of the molecule of the respective alkene from the
ion. The ~ ion can then, evidently, eliminate a molecule of the aldehyde or ketone, being
converted into the #~ ion (Scheme). 3) The elimination of the cycloalkene from the ~ ion is
confirmed by the presence of metastable peaks in the spectra. This process leads to the for-
mation of #~ ions.
Thus, considerable similarity is found in the fragmentation paths of 2-sila-l,3-dioxacy-
clohexanes I-IX and their five-membered analogs X-XII. In both cases the direction of disso-
ciation is determined by the nature of the substituent at the endocyclic silicon atom.

EXPERIMENTAL
Compounds I, III were synthesized by the method in [ii], and compounds II, IV-XII by the
method in [12]. The purity of the compounds (not lower than 98%) was monitored by GLC (3 m
3 mm column, SE-30 on Chromaton N-AB, column temperature 50-250~ programmed heating at 6
deg/min, helium, 2 liters/h). The mass spectra of compounds (I-XII) were recorded on an MI-
1201 instrument at 70 eV with an ionization chamber temperature of 70~ The samples were de-
livered to the source at room temperature through a probe connected to the tube by a fine
control valve.

LITERATURE CITED
i. J. Jack, British Patent No. 857153; Chem. Abst., 55, 18648 (1961~.
2. S.D.I. Brown,US Patent No. 3505378; Chem. Abst., 73, 5760 (1970).
3. M. G. Voronkov, V. G. Mileshkevich, and Yu. A. Yuzhelevskii, The Siloxane Bond [in Russian],
Nauka, Moscow (1976), p. 7,
4. R. S. Musavirov, I. A. Borisova, L. B. Gazizova, E. P. Nedogrei, S. S. Zlot-skii, and D. L.
Rakhmankulov, Zh. Obshch. Khim., 53, 1583 (1983).
5. V. Yu. Orlov, Usp. Khim., 42, 1184 (1973).
6. V. N. Bochkarev, T. L. Krasnova, and E. A. Chernyshev, Zh. Obshch. Khim., 4-2, 1339 (1972).
7. A. A. Polyakova and R. A. Khmel'nitskii, Mass Spectrometry in Organic Chemistry [in R u s -
sian], Khimiya, Leningrad (1972), p. 139.
8. V. N. Bochkarev, A. N. Polivanov, N. G. Komalenkova, S. A. Bashkirova, and E. A. Cherny-
shev, Zh. Obshch. Khim., 43, 2703 (1973).
9. V. N. Bochkarev, A.N. Polivanov, N. G. Komalenkova, S. A. Bashkirova, and E. A. Chernyshev,
Zh. Obshch. Khim., 43, 785 (1973).
i0. B. Y. K. Ho, L. Spialter, and L. D. Smithson, Org. Mass Spectrom., i0, 361 (1975).
ii. R. S. Musavirov, L. P. Lapuka, E. P. Nedogrei, V. I. Larionov, I. A. Kudashova, E. A.
Kantor, S. S. Zlot-skii, and D. L. Rakmankulov, Dokl. Akad. Nauk SSSR, 270, 616 (1983).
12. R. Calas and P. Nicov, Comp. Rend. Chemic Organosilicique, 249, i011 (1959).

224
LETTERS TO THE E D I T O R

SYNTHESIS OF 2-(DIAZOMETHYL)-3-METHYL-5H-FURAN-4-ONE
FROM 1,5-BIS(DIAZO)-3-METHYLPENTANE-2,4-DIONE

L. A. Tolochko, A. M. Sipyagin, and V. G. Kartsev UDC 547.722'235.42.07

In an investigation of acid reactions of bis(diazoacetyl)alkanes, we observed that un-

like the known representatives of the N2CHCO(CH=)nCOCHN2 series, where n # I [I], in the pres-
ence of acid agents (hydrogen chloride, acetic acid, and silica gel) diazo ketone I undergoes
intramolecular cyclization at the oxygen atom of one of the diazocarbonyl groups with the
formation of diazomethylfuranone II.

N2CHCOCHCOCHN~ - ~
i
i c% N2c c

I[

1,5-Bis(diazo)-3-methylpentane-2,4-dione (I) was obtained by the reaction of methylmal-

onic dichloride with diazomethane in 50% yield, mp 61-62~ (from an ether-hexane mixture).
Proton NMR spectrum (CDCIa), 5: 1.37 (3H, doublet, j = 7 Hz, CHs), 3.37 (IH, quartet, CH-
CHa), 5.49 ppm (211, singlet, CHa), IR spectrum, 2090 (N-N), 1600 mn -x (C=O). Uv spectrum
(ethanol): ~max 277 nm (log E 4.25).
2-(Diazomethyl)-3-methyl-5H-furan-4-one (II) was obtained from dlazo ketone I by passing
s through a column with silica gel L40/100~ in the benzene-ethyl acetate system. Melting
point 90-91~ (with decomposition, from ether). Proton NMR spectrum (CDCIs), 6: 1.62 (3H,
singlet, CH2), 4.51 (2H, singlet, (CH2), 5.08 ppm (i~, singlet, CH). IR spectrum (mineral
oil), v: 2080 (N-N), 1650 cm-* (C=O). UV spectrum (ethanol): Xmax 326 nm (log E 4.50).
The data of elemental analysis of compounds I and II correspond to the calculated data.
LITERATURE CITED
i. E. Fahr, Ann. Chem., 638, i (1960).

Branch Institute of Chemical Physics, Academy of Sciences of the USSR, Chernogolovka

142432. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, p." 276, February,
1986. Original article submitted August 23, 1985.

0009-3122/86/2202-0225.$12.50 9 1986 Plenum Publishing Corporation 225

THERMAL ISOMERIZATION OF u-ARYLIDENEISOCHROMENES INT0 ~-NAPHTHOLS

I. V. Korobka and E. V. Kuznetsov UDC 547.814.1.5'615.07:543.422

It was shown previously that a-arylideneisochromenes (I) are converted in acid nucleo-
philic media into u-naphthols (II) [i].
It has been discovered that such conversions are intramolecularly feasible on heating
melts of compound (la-c) at 220-250QC in a stream of argon for 40-60 min.
All the physicochemical characteristics of naphthols (lla-c) were in accordance with
those described in [1]. Their yields were reduced depending on the increase in size of sub-
stituents R and R'. Compounds, yield, Treac, and reaction time were (IIa), 95%, 220~ 40
min! (lib), 75%, 220~ 40 min; (llc), 25%, 250~ 60 m_in.

ii/ j i c o ......
X a";C L/---~,B 1 Xl a-c

I, II a, b R = CH3, c X = CsHs! a, c R* = H, b R* = 3,4-(0CHa)2

On thermolysis it is probable that fission of the O-C(a) bond in molecule (I), rotation
about the C(,)--nucleus bond, and formation of a new bond between C(a) and the 8-carbon atom
of the enol fragment occurs, i.e.) similar to the scheme for the thermal isomerization of an-
hydro-bases of the pyridine series considered on the basis of the calculated data of [2].

LITERATURE CITED
i. I. V. Korobka, I. V. Sherbakov, and E. V. Kuznetsov, Khim. Geterotsikl. Soedin., No. 9,
1184 (1982).
2. Yu. B. Vysotskii, B. P. Zemskii, T. V. Stupnikova, R. S. Sagitullin, A. N. Kost, and O.
P. Shvaika, Khim. Geterotsikl. Soedin., No. ii, 1496 (1979).

Scientific-Research Institute for Phyw and Organic Chemistry, M. A. Suslov Rostov

State University, Rostov-on-Don 344090. Translated from Khimiya Geterotsiklicheskikh Soed-
inenii, No. 2, pp. 276-277, February, 1986. Original article submitted April 15, 1985.

226 0009-3122/86/2202-0226512.50 9 1986 Plenum Publishing Corporation

ADDITION OF ISOCYANATES AND ISOTHIOCYANATES
TO 2-AMINO-3-PHENYLCARBAMOYLAZIRINES

A. V. Eremeev, I. P. Piskunova, UDC 547.717:546.268.2.6

and R. S. El'kinson

When investigating the addition of isocyanates and isothiocyanates to 2-amino-3-phenyl-

carbamoyl-l-azirine (I) in [i] we established that nitriles of N-acylaminomalonic acid (II,
ili) (60-70% yield) and 2,5-diaminothiazoles (V, VI) (-60% yield), respectively were formed.

C~ PhNHCOCHCN BF3"(C2H5)20 ~ PhNHCOCHCONH

2
H,II! NHCONHR H20 ~ NHCONHR

PhHNO~ NH2 RN=C=N PhHN0~ NH2

N ~ N~S
I NHR

II, V R = CHs; III, IV, VI R = C6Hs

The results of the experiments with isocyanates differed from the literature data as to
the final products of the reaction of isocyanates with 2-dialkylamino- and 2,3-alkylaryl-l-
azirines in which both imidazolidines, oxazolines, and acylamidines [2, 3], and substituted
perhydrothiazines, carbodiimides, zwitterionic i,i- and 1,2-adducts [4-7] were formed.
Compounds, yield, and mp were (II) 63%, 203~ (III), 70%, 243~ (V), 58%, 205~ (Vl),
60%, 176~
Bands were observed in the IR spectra (Nujol) of compounds (II) and (III) (mp 203~ and
243~ respectively) for the stretching vibrations of the C=O (1550-1680), C==N (2260), and
NH (3300, 3360 cm -~) groups. The data of the IR spectra of compounds (V) and (VI) (mp 205~
and 176~ respectively) indicated the presence of NH2 and NH (3280-3380) and also C=O (1540-
1670 cm -~) groups. In the PMR spectra (DMSO-D6) of amides (II) and (III) doublet signals
appeared for the protons of COCHNH (5.6 ppm, J = 8 Hz) and NHCH (7.6 ppm, J = 8 Hz) groups in
comparison with the spectrum of azirine (I). In the spectrum of amide (II) there were in ad-
dition signals of the protons of NHCHs (6.35 ppm, 1 H, br q and 2.6 ppm, 3H, d, J = 4 Hz).
Similar signals of protons of the NHCHs group (6.90 ppm, IH, br q, 2.90 ppm, 3H, d, J = 4 Hz)
were also observed in the PMR spectra of diaminothiazole (V). Signals were also recorded for
protons of NHPh at 9.1 ppm in the PMR spectra of compounds (III) and (VI). On comparing the
13C NMR spectra of amides (II) and (III) with the spectra of azirine (I), signals for the
carbon atom of a CEN bond at 117.1 ppm and for the carbon of a carbonyl group (156.9 ppm) ap-
peared, and in the analogous spectra of diaminothiazoles (V) and (Vl) there were signals for
the carbon atoms of a C=C bond at 120.6 and 146.6 ppm and of a C=N bond (150.4 ppm). The
structures of the nitriles of N-acylaminomalonic acids (II) and (III) were confirmed by hy-
drolysis of the latter under the action of boron trifluoride etherate to the amide (IV) known
from [i]. The data of elemental analysis corresponded to calculated values.

LITERATURE CITED
i. A. V. Eremeev, I. P. Piskunova, and R. S. El'kinson, Zh. Geterotsikl. Soedin., No. 9,
1202 (1985).
21 E. Schaumann and S. Grabley, Ann., No. I0, 1568 (1978).
3. E. Schaumann, S. Grabley, and G. Adiwidjaja, Ann., No. 12, 264 (1981).
4. G. Mukherjee-MUller, H. Heimgartner, and H. Schmid, Helv. Chim. Acta, 62, 1429 (1979).

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 277-27g, February, 1986.
Original article submitted April 5, 1985.

0009-3122/86/2202-0227512.50 9 1986 Plenum Publishing Corporation 227

 5. E. Schaumann, E. Kausch, and W. Walter, Chem. Ber., ii0, 820 (1977).
6. U. Schmid, H. Heimgartner, H. Schmid, and W. Oberhansli, Helv. Chim. Acta, 59, 2768
(1976).
7. U. Schmid, H. Heimgartner, and H. Schmid, Helv. Chim. Acta, 62, 160 (1979).

FIRST SYNTHESIS OF ETHYLENEBISPORPHYRINS

G. V. Ponomarev and A. M. Shul'ga UDC 547.749.07

The study of bisporphyrins is one of the main modern directions of the chemicaland phys-
icochemical investigations in the area of prophyrins. These compounds have proven to be con-
venient models for the clarification of processes of energy transfer in photosynthesis and
for the study of various catalytic systems (see review in [i]).
While studying the chemical properties of ethanebisporphyrins, the synthesis of which
will be described in a separate communication, we discovered that compounds (la-c) are con-
verted in acetic acid at 70~ after 20 min in a yield close to quantitative into new substan-
ces having significantly higher chromatographic mobilities on silica gel in comparison with
the initial porphyrins.
Analysis of PMR and mass spectral data of the isolated compounds made it possible unam-
biguously to ascribe to them the structure of the previously unknown ethylenebisporphyrins
(lla-c).

Rz R1 R2 R~

la- C.ll,a - c

Z A = CH~-CH2; ZI A = CH=CH; l, II a R z = Me, R ~ -- Et; b R I =

R ~ = Et; c R ~ = R 2 = Pr
There were intense peaks for the molecular ions in the electron impact mass spectra of
compounds (Ila-c) reaching i00% for the metal complexes which indicated their hish stability
in comparison with ethanebisporphyrins [m/z (relative intensity, % ) : lla 980 (p/r, 100), 492
(65), 490 (83), 488 (95), 478 (92); 11b, i092 (M+, 41), 560 (31), 558 (33), 548 (51), 546
(51), 534 (i00); llc 1316-1319 (i00), 672 (13), 658 (50), 646 (17)].
A singlet signal was observed in the PMR spectra of the ethylenebisporphyrins in the re-
gion of 8.5 ppm for the bridge protons which on protonation of the porphyrins is shifted to
the region of meso-proton signals. For example, the PMR spectrum of compound (lib) (CDCIs)
was 6 10.12 and 9.93 (4H and 2H, two s, meso-H), 8.56 (2H, s, CH=CH), 4.13, 4.11, 4.08, and
3.89 [(latter not resolved) all to a-CH2], 1.98, 1.96, 1.93, and 1.0 (all t, B-CH3), -2.72
ppm (s, NH); (CDCI3 + i% CF3COOH), 6. 1 0 . 2 6 (2H, s, CH=CH), 10.19 and 9.92 (4H and 2H, two
s, meso-H), --0.43 and--2.03 ppm (two s, NH).
The presence of an immensely broadened Soret band in the electronic spectra was a char-
acteristic of the ethylenebisporphyrins (lla-c). The band partially masked the four band
spectra in the visible spectrum, which is traditional for porphyrins, but a splitting of the

Institute of Biophysics, Ministry of Public Health of the USSR, Moscow 123182. Insti-
tute of Physics, Academy of Sciences of the Belorussian SSR, Minsk 220602. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 278-279, February, 1986. Original ar-
ticle submitted May 27, 1985.

228 0009-3122/86/2202-0228512.50 9 1986 Plenum Publishing Corporation

Sorer band into two components was observed in the spectra of the metal complexes, 406 and
419 nm for copper, 410 and 426 nm for zinc, and 405 and 415 nm for nickel complexes. On pro-
tonation of porphyrin free bases the spectrum acquired a pattern of ~he fluorene type. The
spectrum of compound (lib) in chloroform was %max, nm (e.10-s): 421 (240), 480 sh (32.8),
5i0 (30.6), 546 (12.4), 581 (12.7), 634 (4~8); on adding 1% CF3COOH, %max, nm (~-10-s): 402
(18.8), 508 (52.3), 770 (10.3).

LITERATURE CITED
i. D. Dolphin J. Hiom, and J. B. Paine III, Heterocycles, 16, 417 (1981).

SYNTHESIS OF N-HETEROCYCLIC ANALOGUES OF 2,5-DIARYLOXAZOLES

B. M. Krasovitskii, K. M. Dyumaev, L. Sh. Afanasiadi, UDC 547.787.3'832.5.07

I. N. Tur, A. A. Verezubova, and L. M. Ptyagina

2-Hetaryl-5-aryloxazoles are efficient luminophores. The method described for the syn-
thesis of 5-phenyl-2-(2-phenyl-4-quinolyl)oxazole (I) is a multistage, laborious technologi-
cal process which is accompanied by side reactions which lead to the formation of resinous
impurities [i]. The need to isolate the intermediate products and free them from these im-
purities substantially reduces the yield of the luminophore, and adversely affects its lum-
inescence.
We have synthesized (I) and other 2-(4-quinolyl)-5-aryloxazoles by the Robinson-Gabriel
reaction [3] in one step, by heating equimolar amounts of cinchoninic or 2-phenylcinchoninic
acid with m-aminoaryl methyl ketones in phosphoryl chloride under nitrogen at 125=C. Since
the phosphoryl chloride functions simultaneously as a solvent and a cyclohydrating agent,
there is no need to isolate the acid chloride or the amide. The use of an inert gas prevents
the formation of resinous products, and increases the yields and quality of the luminophore.
The method is also applicable to the synthesis of other carboxy-substituted nitrogen
heterocycles. For example, reaction of isonicotinic acid with ~-aminoacetophenone under these
conditions affords 2-(4-pyridyl)-5-phenyloxazole, and reaction of 2,2'-diquinolyl-4-carboxylic
acid with m-aminoacetophenone gives 2-(4-diquinolyl-2,2')-5-phenyloxazole.
5-Phenyl-2-(4-quinolyl)oxazole: yield 59%, mp 134-135=C (from heptane with alumina);
%max (e) absorption (in ethanol): 235 (30,300), 350 nm (15,900); %max fluorescence (in eth-
anol) 430 nm (n 0.52).
5-Phenyl-2-(2-phenyl-4-quinolyl)oxazole: yield 55%, mp 157-158~ (from heptane), as re-
ported in [I].
2-(2-2'-Diquinol-4-yl)-5-phenyloxazole: yield 60%, mp 218-219=C (from benzene--heptane,
1:2); %max (e) absorption (in ethanol): 260 (50,000), 330 nm (24,500; %max fluorescence (in
ethanol): 455 nm (n 0.46).
2-(4-Pyridyl)-5-phenyloxazole: yield 65%, mp 97-97.5~ [4].

LITERATURE CITED
io D. G. Ott, F. N. Hayes, E. Husbury, and V. N. Kerr, J. Amer. Chem. Soc., 79, 5448 (1957).
2. B. M. Krasovitskii, K. M. Dyumaev, L. Sh. Afanasiadi, I. N. Tur, A. A. Verezubova, and
L. M. Ptyagina, USSR Inventor's Cert. No. 1,109,402; Byull. Izobr., No. 31, 67 (1984).
3. R. Robinson, J. Chem. Soc., 95, 2167 (1909).
4. D. G. Ott, F. N. Hayes, and V. N. Kerr, J. Amer. Chem. Soc., 7_~8, 1941 (1956).

Monokristallreaktiv Scientific-Production Combine, Khar'kov 310141. Translated from

Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 279-280, February, 1986. Original ar-
ticle submitted July i0, 1985.

0009-3122/86/2202-0229512.50 9 1986 Plenum Publishing Corporation 229

 SYNTHESIS OF 2-BENZOYL(THENOYL)BENZO-I,4-THIAZINES

A. S. Nakhmanovich, T, E. Glotova, UDC 547.385.1'569.4'869.2.07

and G. G. Skvortsova*

Reaction of o,aminothiophenol with acetylenic ketones in methanol or glacial acetic acid

affords benzo-l,5-thlazepines [I]. Similar compounds have been obtained by reacting o-amino-
thiophenol with chalcone [2]. The reaction of terminal ~-acetylenic ketones with o-aminothio-
phenol in the presence of triethylamine yields 2-acylmethyl-4,5-benzothiazolines and 3-acyl-
vinyl-2-acylmethyl-4,5-benzothiazolines [3].
We have found that the reaction of a-acetylenic ketones (la-c) with o-aminothiophenol in
equimolar proportions in DMSO at 145-150~ gives 2-benzoyl(thenoyl)benzo-l,4-thiazines (Ilia-c).

R
J
/NH2 ~,
C'--'O

~ SH

NH~.'
]
C
+ 111
~
.,~ ~ /- .... S,. /COR /~.. SIt

I a-c II IH a-C

I, III a R = Ph, b, e R = C~HsS; a, b R ~ = H, c RI = Ph

By analogy with the findings reported in [4], it is assumed that under the reaction con-
ditions the o-aminothiophenol is readily oxidized to bis(o-aminophenyl)disulfide which reacts
with the acetylenic ketone (la-c) to give the intermediates (II). Intramolecular cyclization
of the latter with fission of the S--S bond on heating leads to the formation of the benzo-l,
4-thiazines llla-c.
(Illa): mp 241-242~ from a mixture of CHsCN and DMF, yield 60%. IR spectrum (KBr):
700 (C--S), 1520 (C=C), 1620 (C=O), 3290 cm -~ (NH). PMR spectrum (DMSO-D6), 6: 9.12 (IH, d,
Nil), 6.55-7.53 ppm (10H, m. arom protons, CH=). Mass spectrum, m/z: 253 (M+), 148, 105, 77.
(lllb): mp 237-283~ (from CHsCN), yield 62%. IR spectrum (KBr): 710 (C--S), 1545 (C=C),
1625 (C=O), 3240 cm -~ (Nil). PMR spectrum, 5: 9.28 (IH, d, NH), 6.61-7.88 ppm (8H, m, arom.
protons, C~HsS, CH=). Mass spectrum, mlz: 259 (M+), 148, iii, 108, 83.
(lllc): mp 165-166~ (from CHsCN--ether), yield 42%. IR spectrum (gBr): 715 (C--S), 1580
(C=C), 1620 (C=O), 3260 cm -: (NH). PMR spectrum, 5: 9.45 (IH, s, NH), 6.71-7.60 ppm (12H, m,
arom. protons, C4HsS).
The elemental analyses of these compounds corresponded to the calculated values.

LITERATURE CITED
i. W. Ried and E. K~nig, Liebigs Ann., ~55, 24 (1972).
2. W . D . Stephens and L. Field, J. Org. Chem., 24, 1576 (1959).
3. A . S . Nakhmanovioh, T. E. Glotova, G. G. Skvortsova, T. N. Komarova, V. I. Skorobogatova,
and Yu. A. Mansurov, Izv. Akad. Nauk SSSR, Ser. Khim., No. 6, 1371 (1982).
4. S. Miyano, N. Abe, K. Sumoto, and K. Teramoto, J. Chem. Sot., Perkin i, No, 6, 1146 (1976).

*Deceased.

Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR,
Irkutsk 664033. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2; pp. 280-281,
February, 1986. Original article submitted August 23, 1985.

230 0009-3122/86/2202-0230512.50 9 1986 Plenum Publishing Corporation

ELECTROPHILIC HETEROCYCLIZATION OF UNSATURATED SULFUR AND
PHOSPHORUS COMPOUNDS (REVIEW)

Yu. I. Gevaza and V. I. Staninets UDC 547.269'298.4'367.398.4'

341'732'738'77'789.04(047)

The literature on the electrophilic heterocyclization of unsaturated sulfur and

phosphorus compounds has been reviewed. The factors influencing the reactivity
of unsaturated compounds in such reactions are discussed, and data on the stereo-
chemistry of the addition are presented.

The electrophilic heterocyclization of unsaturated sulfur and phosphorus compounds as

a general method of synthesis of heterocycles [1-3] has been used successfully in the synthe-
sis of sulfur and phosphorus heterocycles. Some examples of the preparation of sulfur
heterocycles have been given in a review [4]. The electrophilic heterocyclization of non-
conjugated dienes has also been used to obtain these heterocycles [5].
We here discuss the electrophilic heterocyclization of unsaturated thiols, thiiranes,
sulfides, thioamides, thiourethanes, allenephosphonates and -phosphinates, butadiene-l,3-
diphosphonates, and buten-4-yl phosphates, by reaction with a variety of electrophiles, to
give heterocycles with one or more heter0atoms. The factors influencing the reactivity of
unsaturated compounds in this r e a c t i o n a r e discussed, and data on the stereochemistry of the
addition of electrophiles are presented~

ELECTROPHILIC HETEROCYCLIZATION OF UNSATURATED MERCAPTANS, SULFIDES,

DISULFIDES, AND THIIRANES

The electrophilic heterocyclization of unsaturated compounds in which the nucleophilic

group is a sulfide sulfur atom constitutes a convenient method for the preparation of
cyclic sulfonium salts.
For example, iodination [4] of the unsaturated sulfide (II) gives the salt (I). The
sulfonium salt (III) was also obtained from (II) by treatment with dimethyl(methylthio)
sulfonium fluoroborate [6]. But-3-enyl methyl sulfide (IV), when treated similarly, gave
the sulfonium salt (V).

/~--~ I'~"--2~--~--~S [(CH3)2S 2~ j

ICH2 I- l CH3SCH ~F.,-
CH 3 CH 3 CII~
I II II!

SCII 3 CH2C12,"
0 ~ ~ ~ ...
CH 9
,-
_
I BF 4
iv c~K-s~) BF,- CH 3
V

Bromination of methyl allyl sulfide (VI) gave quantitative yields of the sulfide (X).
Heating this sulfide (X) in CDCIs for 5 h afforded a mixture of sulfides (VIII) and (IX) in
a ratio of 82:18. The formation of the sulfide (X) may be rationalized by assuming that
the reaction proceeds via a thiiranium ion intermediate (IX), formed from the bromonium ion
( V I I ) [7]~

Institute of Organic Chemistry, Academy of Sciences of the Ukrainian SSR, Kiev 252660.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 291-302, March, 1986.
Original article submitted October 2, 1984.

0009-3122/86/2203-0231512.50 9 1986 Plenum Publishing Corporation 231

 + Br
Br~, CCt~. CH~$ ......... l~r l~r' ], Br

"r VII Viii

;I
i"' ...J,
./__2k ..~/..Br ........... Br Br
IX X

2-(Allylphenyl) methyl sulfide (Xl) reacts with iodine, phenylsulfenyl chloride, and
HBr [8] to give the salt (XII).

"~'" "S CH2X

I
XI XII CH3

XY=I~, PhSCI, HBr, X=I, phS, H; Y=I, CI, Br

The cyclic Z,E-thiacyclooct-4-enes (X!II)react with halogens and CFsSO3H [9] to give
cis-l-thiabicyclo[3.3.0]octanes (XIV) and (XV). E-Thiacyclononene is converted on treatment
with CF3SO3H into cis-thiabicyclo[4o3.0]nonane [i0].

CF~SO 3
XIV XIlI kT
X=CL Br" R=H. CH3

5-Methylthiocyclooctene (XVI) With RSCI gives the sulfonium salt (XIX) [ii, 12], and
with HX it affords a mixture of the sulfonium salts (XVII) and (XVII).

CH 3 CH 3
X-
X- ~ RSCI

"~- -'"" RS'" +

XVll XTI!I XVl XIX
X=CI. h F.=Fh, Me

4-Methylthiocyclohexene (XX) reacts with HI to give 7-methyl-7-thiabicyclo[2.2.1]heptane-

sulfonium iodide (XXI) [Ii] together with addition products of HI to the double bond (XXII).

~s/CH~
\ I-

.......... +
CHzC12

XX[ XXII

13-Thiabicyclo[S.2,1]tridec-5-ene (XXIII) on chlorination affords l-thioniatricyclo

[8.2.1.01'7]tridecane chloride (XXIV) [12]. Similarly, the sulfoxide obtained from the sul-
fide (XXIII) on treatment with bromine is converted into l-thioniaoxide-6-bromocyclo[8.2.
1.01'7]tridecane bromide [13].

-- CI-

- LA.._.)
XXIII :r

232
 On chlorination, the thiirane (XXV) gives five- and six-membered heterocycles (XXVI)
and (XXVII) [14].

CI CI +el
S
ggV XXVl XXVII

Similarly, halogenation of the cyclic thiiranes (XXVIII) and (XXX) affords the bicyclic
systems (XXIX)and (XXXI) [14-16],

"'X X~
XXVIII
X
XfCI. B r XXIX

9 ..x

~X ~ XAD~
X=CL B r . I

The thiaskeletal tricyclic systems (XXXIII) and (XXXV) were obtained by the heterocycliza-
tion of the thiirane (XXXII) [16] and norbornenethiols ~XXIV) [17, 18].

c-

X~OHI1

~ a-c XXXV

X~=Br~, PhSeCl; XXXIV a , c R' =H, b R' CN; a,b RZ=H, c R2~Ac

It interesting to note that bromination of the sulfide (XXXVI), in contrast to (XXXII),

affords the stable 2-methyl-6-thiatricyclo[3.2.1.1s'S]nonasulfonium bromide (XXXVII) [19].

CHCI3 Br"

X~*"V! XXX~!

On chlorination, the unsaturateddisulfides (XXXVIII) give the sulfenyl chlorides

(XXXIX), which then give rise to tetrahydrothiophens (XL) and tetrahydrothiopyrans (XLI).
The tetrahydrothiophens (XL)are the kinetically controlled reaction products. When the
reaction temperature is raised, they are converted into the thermodynamically-controlled
products (XLI) [20].

233
 (' I

X.w~XVIII
~
CH2C12

il"S
"=

......
I
Cl
*'X,'XIX
,
....

fisH, CH3
~S /

XL
"~'~- CI "~Sf

.......
.'~,)

Chlorination of the disulfide (XLII) gives the thianorbornane (XLIll) [21].

CH2 CH2 CHzCI2 ')" C1.

XLII XLIII

One method for the synthesis of thiaprostacyclins is heterocyclization of unsaturated

sulfur compounds. Reaction of the thiols and thioacetates (XLIV) with PhSeCl and iodine
[18, 22], or with phenylselenosuccin(or -phthal)imides [23, 24] affords the bicyclic systems
(XLV), for example:

9 PhSeCi D-
~ .." CH2C12 ~""

XLIV XLV
XLIV a , c RI= S , b , d R t =Ac; a ,b R2= Me, c)dR 2= - (CH2) zCOOMe

Pentene-4-thiol [25] and 2-allylpentane (and hexane-)thiols [26, 27] on treatment with
75% sulfuric acid give 2-methyltetrahydrothiophen, l-thiabicyclo[3.3.0]octane, and 2-methyl-
l-thiahydrindane respectively.
The 5Z- and 5E-thioacetates (XLVI), on iodination [28], phenylselenylchlorination [29],
and bromination with bromine or N-bromosuccinimide [30-31] are converted into the corresponding
thiaprostacyclins (XLVII) and XLVIII).

(CIt2)3C0zMe
,.' / (CH2)3C02Me
SR+ ( " ' " ...... ] " ' ' " X "- ~---~ "(XCH2)3CO2M`

OH OH OH
XLVI XLVll XLVIII
R=II, Bro IoAc; X=Br, I~SePh

The sulfinylallene (XLIX) reacts with bromine and PhSCI [32] to give the heterocycles
(La, b:, which contain two heteroatoms.

ph--s.9I"CII=C=-
0
/. ., _. .....
\ Brz(PhSCl~)
. . . . . . . . .
Ph--,~" ~

xux Ta.b
I a X = Y = B r ; b X=PhS, Y=CI

Similarly, iodination of sulfoxide (LI) affords the tricyclic heterocycle (LII) [33].

234
 I,I LIt

Electrophillc fragmentation-cyclization of the dial.lenyl sulfones (LIII) and the pro-

pargyl allensulfinates (LV) by treatment with bromine affords the a,B-unsaturatedy-sultones
(LIV) [34]:

0
o~ ~o o II

C
A
r%C
/~
~ +
MezC:CBrCItBr2
"~---'-- A
('-$ ["

LIII LIY I.V

On reaction with trichloro (or -fluoro)acetic acid, thethiaocids (LVI) give the y-dithio-
lactones (LVII) [35], and bromination of the propargyl trithiocarbonates (LVIII) affords
the 1,3-dithioles (LIX) [36].

LV'I LVII
LVI,LVIIR1,R2.R3=H,Me

Br S- - Br-
Me3C--S--CS-SCH2C~-CR ~ +i 1 Br
Me3CS" -S" >C~R
LV]li R=H, C6H5 LIX

Iodination and bromination of substituted allylxanthate and allyltrithiocarbonate esters

affords the 4,5-disubstituted 1,3-dithiol-2-ones and 1,3-dithiolan-2-thiones respectively
[37].
The ~ , y-unsaturated dithiocarbamates (LX) on bromination give quantitative yields of
the 2-dialkylamino-4-(2-bromoalkyl)-l,3-dithi01anium bromides (LXI) [38-40].

S Br2 ~ Br
I~~ %S CC14 Br-

Lxa-d LXIa-r I'/R2

LX, L X l a , b R I = H , c RI=Me, d R1=Ph;a,c,dR2=Me, bR2=Et

The vinyl NN-dimethyldithiocarbamates (LXII), on bromination, are converted into the

1,3-dithiolane-2-iminium salts (LXIII) [41, 42].

Br ~.
CIt2=CHSCSN(Me)z" ~ I----~-- Br-
LXII "S ~'~N+(Me)2
LXIII

Similarly, bromocyclization of l,l-dioxo-3-thiolen-3-yl NN-dialkyldithiocarbamates

(LXIV) gives rise to the 1,3-dithiolane-2-iminium salts (LXVa, b) [43].

S--CS-NRz
r-=---(
k.s ~
. . . . . . . . . .
cact~(clhco21t)
o~s
.I...... ~ . . +
Br ~
0 ~ "~ A'-S/"-~.NR2
0 ~" % 0
LXV
LKIV R=Me,Et

235
 On bromination i n CHiCle, the N-substituted methallylurethanes (LXVi) (X = O) afford
the 5-bromomeChyl-5-methyloxazolidln-2-ones (LXV~I) (X - 0), together wlth products of
addition of bromine t o the double bond(LXVI~) [44], Similar Froducts were obtained when the
me~hallylurethanes (LXVl) were reacted with sulfenyl chlorides [45]. The s
(LXVT) (X - S) are converted by bromination [46-48] or treatment with chlorine [49] into
2-bromomethyl- (LXVII) (X ~ S) and 2-chloromethylthiazolidin-2-ones respectively.
R
/ .[
Me\ [N'~ @x
Br: Me.]-~N~R
I ?e ~X
+ 9rCCBaNRC~
OEt CHzCI= ~"
91,CHa~'X ~C "~0 ! "Or-t,
CHaBr
LXVI LX",'I LXVIII

R'=H, Me, Et, t-Pr, Bu, Ph, CtHtt, CeHxs; X---O,S

Allylthioacetamides (LXIX), on brominatio~or iodination followed by hydrolysis of the

cyclization products (LXX), give substituted 7-halothiolactones (LXXI) [50]. The rate of
iodination of the thioamide (LXIX) is nearly twice as great as that of iodocyclization of the
appropriate amide.

I
x X
LXIX - LXX LX~C'
X=Br, I

The allylthioamides (LXXII) and (LXXIV) on halogenation are converted, depending on

their structure, either into thiazines (LXXIII) [51] or thiazolidines (LXXV) [52].

LX~I CHzC00H
X=CI,Br,I LXXIII
X HN-----~
(CH300C)2CHCS- - N I ~ -~(CH~OOC)2C~ S ~CH2X
LXLKIV X=Br, I LXXV

Allylthioureas [4, 53, 54], N-(cyclopenten-3-yl)- and N-(cyclohexen-3-yl)thioureas [55-

57] on bromination give the corresponding 2-amino-5-bromomethyl-2-thiazolines, 2-aminosub-
stituted 6-bromocyclopenta[2,3-d]thiazolines, and 7-bromohexahydrobenzothiazoles. Allyl-
thioureas also cyclize readily on treatment with acids [58, 59].
2-Diethylamino-5-iodomethyl-2-thiazoline (LXXVII) has been obtained by iodinating the
thiourea (LXXVI) with an iodine-pyridine complex [60].

~-~/NH-CS-NEt 2 H.2C~H~N]+NO~ --- CII21~-----~

LXXVI S~N
NEt2
IJO~WII

The iodocyclization of allyl- and propargylthioureas proceeds at approximately the same

rate [61].
4-Allylthiosemicarbazone (LXXVIII) on bromination is converted into the (5-bromomethyl-
2-thiazolin-2-yl)hydrazone (LXXIX) [62], and the thiosemicarbazide (LXXX) gives the 2,6-
disubstituted 1,3,4-thiadiazines (LXXXI) [63].

236
 Me COOH Me~c/COOH
~C / HN----- Br
~' ' L_ .... ~ " 'il- - q
H H
LXXVIII LXX1X

C H - - Crl Br 2 .~N i
R I /C}[ N~NHCSNHR 2 R 1 --CH S NHR2
I
Br
LXXX LXXXI
LXXX, LXX~ RI=Ph. R2=H; RI=ph, R2fCH2=C(Me)-CH2

The N-allyl-N-acylthiosemicarbazide(LXXXll), on treatment with bromine, gives 2-[(4,5-

diphenyl-l,2,4-triazol-3-yl)mercaptoacetylhydrazino]-5-bromomethyl-l,3-thiazole (LXXXIII)
[64], and 4-allyl-5-benzyl-l,2,4-triazoline-3-thione (LXXXIV) affords 2-bromomethyl-5-benzyl-
2,3-dihydro-l,3,4-thiazolo[2,l-b]triazolidine (LXXXV) [65].

N--N N
-----
fq N9 ' "IIBr
II II
p~N~SCH2CONHNHCSN~ Ph Nj SCtI2CONHNIpf'~-S/-V
[ l
Ph Ph
1200RI L.~CQI!

N~I~H
Br, N--N
~/~--N~-.S

LXX~r

3-Allyl-3,4-dihydro-2-mercaptopyrido[3,2-d]pyrimidin-4-one (LXXXVI) is converted on bro-

mination into 2-bromomethyl-2,3-dihydro-SH-pyrido[3,2-d]thiazolo[3,2-a]pyrimidin-5-one
(LXXXVI) [66], and 3-allylthiohydantoins (LXXXVIII) give 2,3,5,6-tetrahydro-2-bromomethyl-5-
oxoimidazo[2,l-b]thiazoles (LXXXIX) [67].

O 0

Br 2 ~" N
CH~COOH Br
H
L~LX~t'I LX:k.~WII

___~sN _ _ ~ o ~___~___~o

tI
L.~fXVIII LX~.LXLX
LXXXVIII, LXXXIX R=H, Me, Pr, i-Bu, CH2COOH

The thioazetidinones (XC) and (XCII) on iodination give the 3-iodo-3-methylcepham (XCI)
[68].

/ CH2OPh
N~x S PhOCIIzCONIt /S. . PhOCtI2CON~H S--Sg

Oy --" "~:'f 1I~ COOMe II/'~''COOMe

tl COOMe
XC XCI XCH
R= 2-benzothiazolyl

A novel method for the synthesis of five- and six-membered thiacycloalkanes is the
reaction of dimethyl(m-chloroa!kyl)alkenylsilanes (XCIll) with KSH in alcoholic solution.
The intermediate unstable thiols (XCIV) undergo intramolecular cyclization to give the hetero-
cycles (XCV) [69].

237
 l l e l l l ( CIIICIt~Ctll /CK~Clt~CHz /CH2~Cl~ Me
+ XSH Me;S1 ~ MelB! ~8
(Cil2)mCl "(c~),,,sn , ~(c 2d'~m
XCHI XCIV XCV

SYNTHESIS OF PHOSPHOROUS HETEROCYCLES BY THE ELECTROPHILIC HETEROCYCLIZATION

OF UNSATURATED ORGANOPHOSPHORUS COMPOUNDS

In 1975 A. A. Petrov et al. [70], in applying the electrophillcheteroeylization reaction

to unsaturated organophosphorus compounds, discovered a new route to phosphorus heterocycles.
The reactionof 3-methyl-l,2-butadienephosphonyl chloride (XCVl) with chlorine or bromine in
an inert solvent afforded quantitative yields of 2,2~2,4-tetrachloro- (XCVII, X = CI) or 2,2-
dichloro-2,4-dibromo-5,5-dimethyl-l,2-oxaphosphol-3-ene (XCVII, X = Br) [70].

0
XCVI
X=CL Br XCVII

In the chlorination of the acid chloride (XCVIII) it was found that the formation of
2,2,2,4-tetrahalo-l,2-oxaphospholenes (XCVII) occurred via the intermediate phosphonium salts
(XCIX) [71].

t ol ) u CI
~',ie (3. !-: :"-:~ t--Bu, !
L - B u " C :..: tl =:(, ..... - _ e . . ~ . ;* i Me -I. G =:C--C--CH2CI
9Cl,fl J i O rHzCl C l .. .P. .. 0 "';'"
" ' C I I ,CI '
CIzP=~O ' M"Le
" CI'"
XCVH! XCIX

Halocyclization of the dialkyl 1,2-alkadienephosphonates (C) affords 1,2-oxaphosphol-3-

enes (CI) [72-74].

O /X
(t~!0) I ' ;"" M,'. x~;,
Cll..C': C ... ~ O. I " [ Me + R1X
C R'O I` O, ~,R2
CI
R*=Me, El; R-~=Me, Et, i-Pr

The relative rates of reaction of iodine and interhalides with dialkyl 1,2-alka-
dienephosphonates decreases in the sequence CII > BrI > I2 [75]. The presence of hydroqui-
none has no effect on the rate of the reaction, and it was therefore concluded that the re-
action was an electrophilic one.
The allenephosphonic acids (CII) also react with Bra and Hg(OAc) 2 to give 1,2-oxaphos~
phole-3-enes (CIII) [76].

RI E

L l "'C~" C ~ C ~ 11 ........ O<,Js I

0
' {Oft). IIO......0 ~ ~I~.2
CII CIII

R=t.Bu; E=Br; HgOAc

Reaction of the allenephosphonates (CIVa-c) and the allenephosphinates (ClVd, e) with

RSCI and PhSeCI [77-80] has given the 4-alkyl (or-aryl)thio (or-seleno)-l,2-oxaphosphol-3-enes
(cv).
R I\. ..-+-ScPh R ~~ /SePh ] RI SePh
+

Y/l[ - O
i" ""
0 ~3 ND _j
cl~a -- e ~ CVa-e

C|V, C V a RI=I-Bu, b - e R t = H ; a R2=t-Bu, a R 3 = H , b , d , e R 2 = R S = M e , c R2=

=Ra=(CH2)s; a X=MeO, b,cX=EtO, d)e X=Ph; ~ eY=MeO, b,cY=EtO, d Y=OH

238
 1,2-Oxphosphol-3-enes are also obtained by hydrochlorinating dialkyl 1,2-alkadienephos-
phonates with gaseous HCI in inert solvents [81-83], and by reacting substituted propargyl
alcohols with phosphorus trihalides [84-86].
The bromination of a,a-dimethylpropargyl phenyl-y,y-dimethylallenephosphinate (CVI)
gives 4-bromo-5,5-dimethyl-2-phenyl-l,2-oxaphosphol-3-ene (CVII) in addition to fragmentation
products (CVIII) and (CIX) [34].

O~ Ph
0 Br CHBr=CBrCBrMe 2

_ ~ ~'/'" + cnix
Ill Me2C=CBrCliBr2
CVII CIX
C%1

Chlorination of dimethyl(3-methyl-l,2-butadienyl)phosphine oxide (CX) [87], or hydro-

chlorination [82], gives 4-chloro-2,2,5,5-tetramethyl-l,2-oxaphosphol-3-ene bromide (CXI).

CI Ct-
Me.. + / ' - ~ ~Me
M e 2 P . /CH:
~o C ~'CMe2 C12 ~" Me 1 P \0/~Me

CX CXI

On chlorination of dialkyl 2-chloro-3-methyl-l,3-butadienephosphonates (CXII), as in the

case of allenephosphonates, the principal pathway of the reaction is halocyclization, which
here leads to the formation of mixtures of the isomeric 2-phosphacyclohex-3-enes (CXIII) and
1,2-oxaphosphol-3-enes (CXIV) [88-90]. In the absence of substituents in positions I, 2,
or 3 of the alkadiene system, bromination affords only the products of addition of bromine
to the double bond [91].

CI CI

cRo)~ 0 ~ ~o"~P%__/<-. + ~o "%/"~.

CXII C~II CXIV
E = M e , Et

Halogenation of dialkyl 2-chloro-2-(l-cyclohexenyl)ethenephosphonates (CXV) gives the

six-membered, 1,2-oxaphosphorines (CXVI) only [92, 93].
CL
~CH:C~ "(1 " X~ " ..... [ ""

1~"~"" o i~- " ' "- m, l,

+ RCI
0 < 0

CX V CXVI
R=Me, Et, i-Pr, Bu; X = C I , Br

The chlorination of l-phenyl-2-chloro-3-methyl-l,3-butadienephosphonyl dichloride (CXVII)

and l-phenyl-4-chloro-3-methyl-l,2-butadienephosphonyl dichloride (CXVIII) results in the
formation of 2,2,2,4-tetrachloro-5-methyl-5-chloromethyl-l,2-oxaphosphol-3-ene (CXIX) [94].

{} cl
/
CI_P- C : : I: C - CH. ...... )
Ph CI
I
Ph Me I CL /~=\\ Me
CXVII
[ O "- CI
cl2~ c, = c =el c...cl. ..: .J
CXIX
0 Ph Me
CXVIII

239
 Halogenation of dialkyl 3-chloro-4-methyl-l,3-pentadiene-2-phosphonate (CXX) with a
tertiary carbon atom in the 4-position of the 1,3-alkadiene chain gives the 1,2-oxaphosphol-.
3-enes (CXXl) [95].

c~o),~,.o& o* % / " ~ .
c~ CXXl
R=Me--Bu; X=CI, Br

cis-2-1sopropenylcyclopropylphosphonates (CXXla-c) react with Br~ and HBr to give the

3,2Xb-oxaphosphabicyclo[3.1.0]hexan-2-ones (CXXlVa-c) [96]. The initially formed
phosphonium salts (CXXIIIa-e) are converted by the Arbuzov reaction into the final cycliza-
tion products. In the case of the salt (CXXIIId), in which this reaction is not possible,
the phosphonium salt is stable and could be isolated. The trans-isomers of (CXXII) react
with HBr to give the products of hydrolysis of the ester bond, but the stereoisomeric 2-
vinylcyclopropylphosphonates add Br2 and HBr at the double bond.

# ~ / \ ~ #. ~ . M , Br- 2 / \.M,

cxux cmxm cxmv

CXXil--CXXIVa,b Rl=OMe, % d R t = P h ; a p c R==OMe, h , dR2=Ph; E=Br, H

lodination of the buten-4-yl phosphates (CXXV) in acetonitrile affords the cyclic phos-
phates (CXXVI) [97]. Allyl phosphates fail to react with iodine under similar conditions~

- t IC' .. ../..1{3 1 l~A ~9C~"

0.. ~.0 -.9,------ [ O~+/O - 0.. /0
EtO/P~OEt [ EtO/P~OEt I 0 /P..
/ OE%
cn-v a- e " cxxvr a - e
CXIXV, CXXVI a~c,dR1=Me, b R1=pr, e R'=Et; a,h,d,eR2=H, c R2=Me; a - c , e
RZ=H, d R3=Me; a--d R4=H, e R4=M.e

OO-Dialkyl-S-allyl and OO-dialkyl-O-allyl thiophosphates [98] and substituted OO-dialkyl

2-propenylphosphonates [99] react with CI= and Br= to give the normal products of addition
of the halogen at the double bond.
The electrophilic heterocyclization of unsaturated sulfur and phosphorus compounds thus
makes it possible to obtain the corresponding heterocycles under mild conditions and in high
yields.

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241
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Khim., 50, 326 (1980).

242
HYDROGENATION OF FURFURAL ON POLYMER-CONTAINING CATALYSTS

E. A. Karakhanov, E. B. Neimerovets~ UDC 547.724.1:542.941.7:541.127.1

V. S. Pshezhetskii, and A. G. Dedov

The catalytic hydrogenation of furfural with molecular hydrogen has been investi-
gated under mild conditions i n t h e presence of metal complex catalysts with a
polymeric macroligando It has been shown that the reaction proceeds according
to a consecutive scheme with the formation of furfuryl and tetrahydrofurfuryl
alcohols. The kinetics of furfuralhydrogenation has been investigated and the
order of the reaction established; the rate constants of the first and second
stages have been determined. The influence of the solvent and of the metal-to-
polymer ratio on the furfural conversion have been investigated.

The hydrogenation of furfural, the main product of the processing of pentosan-containing

raw materials, is included in some industrial processes. At present, the development of
efficient catalysts which allow the hydrogenation of furfural under mild conditions is of
acute interest.
We have reported in [I] on the synthesis of catalysts which are active in the hydro-
genation of some aromatic and heterocyclic compounds under mild conditions. In the present
work we have investigated the hydrogenation of furfural in the presence of polymer-containing
metal complex catalysts at atmospheric pressure and 20-25~ The catalysts were complexes
of Pt, Pd, or Rh with polyacrylic acid (PAA), styrene copolymers with maleic acid (ST-MA),
and copolymers of methyl-methacrylate with maleie acid (MA-M~IA). The results are presented
in Tables 1-4.
In the hydrogenation of furfural the highest activity was shown by the rhodium catalysts.
The complexes of Pt and Pd were less active and stable. 9 On rhodium catalysts with macro-
ligands furfural was hydrogenated quantitatively to tetrahydrofurfuryl (THF) alcohol; furfuryl
alcohol was formed as an intermediate product of the hydrogenation. The character of the
kinetic curves of furfural hydrogenation (Fig. i) indicates a consecutive character of this
reaction:

~0~~ H2 ~-~ 2H2

The high number of conversions N,* reached in the hydrogenation of furfural, must be
pointed out. Thus, the number of conversions of the reaction at 25 ~ and a furfural concen~
tration of 0.9 mole/liter was ii0. The molar ratio substrate/catalyst was equal to 94 in
this case.
We have shown that a significant increase in the furfural concentration leads to a
decrease in the number of conversions (Table i); nevertheless, the catalyst works satis-
factorily and the conversion reaches 100%.
The polymer/metal ratio in the complexes also had an effect on the activity and selec-
tivity of the catalyst (Table 2). The data show that a decrease in the metal content of the
complex leads to a decrease in the furfural hydrogenation rate. When the metal content of
the catalyst is increased (up to 1-2 metal atoms per monomer unit), the conversion as a whole
increases, however the amount of pentanediol-l,5 in the reaction products increases sharply
(which is a product of furfural ring opening) and the stability of the catalytic system is
*N was calculated as the number of furfural molecules converted per metal atom in 1 h.

M. V. Lomonosov Moscow State University, Moscow 119899. Translated from KhimiyaGeterotsikli-

cheskikh Soedinenii, No. 3, pp. 303-307, March, 1986. Original article submitted January 29,
1985.

0009-3122/86/2203-0243512.50 9 1986 Plenum Publishing Corporation 243

 TABLE i. Influence of the Catalyst/Substrate Ratio on the
Conversion and Number of Conversions in the Hydrogenation of
Furfural on an ST-MA--Rh Catalyst (ST--MA 0.26 mmole, RhCIs,
4H=O 0.05 mmole, NaBH4 0.05 mmole, H=O 3 ml, i-PrOH 3 ml,
T = 25 ~ , P = 1 arm)

~/rfural c~ IIFurfural/RhCl
I s~' o.C~176 in Number of con-,
No. ~ration, mole/ 9 ~H 2 0 ratio h, % versions N, h -~
...... Iliter ....... I I
L

1 0,2 I 19 94 100
2 0,6 I 56 87 123
3 0,9 94 52 110
4 1.4 133 " 66 30

TABLE 2. Influence of Metal Content of Catalyst on the Hydro-

genation Rate and Conversion of Furfural (PAA 0.25 mmole,
amount of NaBH4 equimolar to RhCIs-4H=O; H20 3 ml, i-PrOH 3 ml,
furfural 6 mole; T = 20 ~ , P = 1 atm, reaction time 2 h)

Number of PA~ Initial H2ab- Reaction products, % 2onversion,

units per Rh sorption rate, f u r f u r a l l f u r f u r y l ! THF pentane- %
atom ml/min ~icohol lalcohol diol-l,5
i
20 12 12
10
5
4
2,5
17
23
24
34
88 ,2i ',
83
57
42
45
17
43
56
41
17
43
58
55
1,5 19 39 56 61
1 28 39 41 2o 100
0.5 15 4 17 71 96

TABLE 3. Influence of Solvent on the Hydrogenation Rate and

Conversion of Furfural (PAA 0.25 mmole, RhCIs.4H20 0.05 mmole,
NaBH4 0.05 mmole, furfural 6 mmole, total solvent volume 6 ml;
T = 20 ~ , P = 1 atm, reaction time 1 h)

Number of 3omposition of reactionmixture, % Coversion,

Solvent conversions furfuryl %
N, h -I THF
furfural alcohol alcohol

1t20-i-PrOH 44 45 55 45
(1:1)
1-t2()-- EiOH 31 40 59 6O
(1:1)
H20--.i-AmO H* 18 64 36 36
(1:1)
H20* 29 44 56 56

*Catalyst partly coagulated.

reduced. This is evidently due to the fact that in the case of a high rhodium content of
the catalyst a part of it does not react with the polymer but is present in the reaction
medium as black pigment; 5-10 monomer units per rhodium atom can be considered as the optimum
polymer/metal ratio.
The reaction order and the effective hydrogenation rate constants Kz and Ks were deter-
mined for a furfural concentration of 0.2 mmole/liter. It must be pointed out that pentanol-
1 was detected in the reaction products at a low furfural concentration. Its amount did not
exceed 5%; consequently, this reaction path was neglected in the calculations. The reaction
order n and the rate constant of furfural hydrogenation to furfuryl alcohol Kx were deter-

244
 TABLE 4. Hydrogenation of Furfural and Furfuryl Alcohol at
Different Initial Substrate Concentrations (polymers 0.25
mmole, RhCI3.4H20 0.05 mmole, NaBH4 0.05 mmole, H20 3 ml, i-
PeOH 3 ml, substrate 6 mmole; T = 25 ~ P = I atm)

IComposition o f Composition of
[ Ireaction mixture,
Catalyst Catalysts I ~ime,l- I-'~-'~-i'~- - - "
J Ileal Ico- alcohol
I l ~ot
PAA --Rh 0 14 86 MA -MMA--Rh 0
5 l~ 89 5 6
I0 92 2 10 12 2
15 92 5 20 19 2
25 90 9 30 35 4
35 I , 85 14 42 40 6
50 ~race. 73 27 55 47 7
PAA - R h 0 58 42 MA --MMA--Rh 0 100
5 56 44 5 87 13
13 32 66 10 78 22
21 23 74 17 61 39
31 16 81 27 51 49
46 8 87 37 39 61
73 3 90 48 22 78
PAA -Rh 0 100 S'['.~ MA--Rh 0 100
5 97 3 5 87 13
10 96 4 I0 80 20
16 92 8 21 65 35
25 87 13 31 53 47
36 82 18 41 41 59
PAA-t?h 0 100 ST--MA --Rh 0
5 97 3 5 10 4
I1 93 7 10 19 4.
16 90 10 24 32 4
26 81 17 2 34 43 4
36 78 2O ' 2 44 54 5
46 70 27 3 54 68 6

C, mole a

~,0 ,I 2 1.0

0,6

o,2
o
20 40 60 8fJ 2!) 40 9 ~0
t.rain

Fig. i. Kinetic hydrogenation curves of furfural on catalysts:

a) PAA-Rh; b) ST-MA-Rh (furfural concentration 0.2 mole/liter,
polymer/metal ratio in the catalysts 1:5); i) furfural; 2) fur-
furyl alcohol; 3) tetrahydrofurfuryl alcohol; 4) n-amyl alcohol.

mined graphically [2]: n = i, KI = 0.28 min -I for ST--MA--Rh and K2 = 0.22 min -~ for PAA--Rh.
K~ was also determined from the half-conversion period of the initial substance: in this
case Ka = 0.20 min -I for ST--MA--Rh and KI = 0.17 min -I for PAA-Rh.
By assuming that the stage of the hydrogenation of furfuryl alcohol to THF alcohol
represents a pseudo-first order reaction according to the equation K2 = (2.3/Tmax) long
(co/Cmax) where co is the initial furfural concentration, Cma x is the maximum concentration
of furfuryl alcohol, and Tma x is the time in which the maximum concentration is reached,
K2 was determined from the total kinetic curve; it was found to be 0.04 min -~ for ST--MA--Rh
and 0.01 min -I for PAA--Rh. These constants show that the complex ST--MA--Rh should be used
preferably for the production of THF alcohol and PAA--Rh for the production of furfuryl alcohol
which is formed on this catalyst with a high selectivity.

245
 The influence of the solvent on the hydrogenation of furfural in the presence of polymer-
containing metal complex catalysts has also been studied (Table 3). When the reaction was
performed in water, the conversion of furfural in 1 h was the same as that obtained in iso-
propanol/water and ethanol/water mixtures; however, the stability of the catalysts decreased.
When amyl alcohol is added, the conversion decreases, evidently due to disturbance of the
homogeneity of the system.
For comparison, the hydrogenation of furfuryl alcohol wasinvestigated under the same
conditions. A 100% conversion of the initial substance was also achieved in this case. It
was found that the hydrogenation rate of the aldehyde group of furfural and of the hetero-
cycle of furfuryl alcohol were similar on PAA-Rh and ST--MA--Rh, while on MA-MMA--Rh the hydro-
genation rate of furfuryl alcohol was higher than the hydrogenation rate of furfural (Table
4). On the other hand, in the hydrogenation of furfural the conversion of the main mass of
the furfuryl alcohol started when practically no furfural was left in the reaction mixture
(Fig. i). We have therefore investigated the simultaneous hydrogenation of furfural and
furfuryl alcohol at different initial concentrations of both substrates (Table 4). The data
show that small amounts of furfural (15%) inhibit the hydrogenation of furfuryl alcohol. At
similar quantities of furfural and furfuryl alcohol, furfural is hydrogenated first, practical-
ly completely suppressing the hydrogenation of furfuryl alcohol. Such an effect of furfural
is evidently due to competing complex formation Of lfurfural and furfuryl alcohol with the
catalytic center. It can be postulated that fu~fural is bonded more strongly to the rhodium
ion, primarily through the aldehyde group; in the case of furfuryl alcohol the q-electrons
of the heterocycle are the main contributors to the substrate/catalyst interaction, This
conclusion is in agreement with data on the homogeneousand heterogeneous H-D exchange of
furan compounds in the presence of catalysts based on metals of the VIII group [3, 4].

EXPERIMENTAL

The hydrogenation experiments were carried out in a "duck"-type static system with a
thermostated jacket. A weight of the polymer was placed in the reactor and dissolved in
distilled water; the solution was then treated with a weight of the metal salt (RhCI3,4H20,
K2PtCI~, K2PdCI~) and the alcohol component of the solvent. A quantity of sodium borohydride
was then added to the solution, equivalent to the amount of metal added. After addition of
the substrate the reactor was connected to the thermostat and shaken at a frequency of 400-
500 shakes/min. Hydrogen was supplied to the reactor from a gas buret.
The catalyst was separated from the reaction mixture by the addition of K2CO3. The re-
action products were analyzed by GLC on a Crom-5 chromatograph with flame ionization detec-
tor; the column was packed with 10% Carbowax 20 M o n Chromosorb W; column length 3.7 m,
internal diameter 3 mm. The standard deviation of the GLC results was less than 2%.

LITERATURE CITED
I

i. E. A. Karakhanov, A. S. Loktev, A. G. Dedov, Vo S. Pshezhetskii, and T. S. Lebedeva,

Dokl. Akad. Nauk SSSR, 275, 1098 (1984).
2. I. Vo Berezin and A. A. Klesov, Practical Course in Chemical and Fermentation Kinetics
[in Russian], Nauka, Moscow (1976), p. 6.
3. E. A. Karakhanov and A. G. Dedov, Khim. Geterotsiklo Soedino, No. 8, i011 (1982).
4. E. A. Karakhanov, A. G. Dedov, A. So Loktev, L. Vo Popov, Po A. Sharbatyan, and I. V.
Arkhangel'skii, Khim. Geterotsikl. Soedin., Noo 8, 1025 (1983).

246
INTERACTION OF ETHOXYACETALDEHYDE WITH 1,3-DICARBONYL
C@IPOUNDS

N. M. Tanchuk, M. M. Vartanyan, UDC 547.451.2'722.3:543.422.25

N. P. Karzhavina, ~. Ya. Knyazhanskii,
E. A. Runova, and E. A. Karakhanov

It has been established that on interaction,of ethoxyacetaldehyde with acetyl-

acetone, acetoaeetic ester, and benzoylacetone in the presence of piperidine
acetate, B,y-unsaturated compounds are formed,viz., 3-(2-ethoxy)vinyl substituted
acetylacetone, acetoacetie ester, and benzoylacetone. Methods are proposed for
the synthesis of 2,3,5-trisubstituted 4,5-dihydrofurans in the presence of tri-
fluoroacetic or acetic acids by the cylization of the linear condensation products.

The interaction of ethoxyacetaldehyde (I) with the 1,3-dicarbonyl compounds acetyl-

acetone (lla), acetoacetic ester (lib), and benzoylacetone (llc) has been investigated.
The general reaction scheme may be represented in the following manner.

0 0 [ 0 A ;
~[ H .< -E~--0
..............
" " - - -~,.. It[1t*.. j -___._
EtO/'~--0
R'7!{'~/-R -~ - l~to ~'I:" '" ..... =to/'~ "
!

R? O
I -0 i i I~ IIA '
-( \l{2

., . . .......... ,.,o" , "i: "" -0 , ' - - .! 0 "0 Ii 1"ll

1~" II c -L'-"}1 ~'

I
CH:~
Va-C vIa-c

]I--Via--eRI=CHa; aR2=CH~, bR~=OC2H~, cR2=Ph

On interaction of ethoxyacetaldehyde with equimolar quantities of diketones lla-c in

the presence of piperidine acetate as catalyst 8,y-unsaturated compounds IVa-c were formed
in place of the u,8-unsaturated products llla-c of a Knoevenagel condensation. The 3-(2-
ethoxy)vinylpenta-2,4-diene (IVa) obtained on reaction of ethoxyacetaldehyde with diketone
lla was practically completely in the enol form (Va) according to the data of PMR spectros-
copy. On interaction of ethoxyacetaldehyde with diketone lib not only was the appropriate
linear condensation product IVb formed, enolized to 45%, but also the cyclic isomer 2-
methyl--5-ethoxy-3-carbethoxy-4,5-dihydrofuran (Vlb), 9:1. The condensation product of
ethoxyacetaldehyde with benzoylacetone was the 8,y-unsaturated diketone (IVc, Vc) enolized
to 80 %. Analysis of the coupling constants of the protons of the AB system of the B,Y-
unsaturated adducts (JABa = 13.0; JABb = 12.5; JABc = 13.0 Hz) made it possible to assign
the structure of the Z-isomer to this compound both in the keto and in the enol form.
On interacting ethoxyacetaldehyde with a fourfold excess of acetoacetic ester a Michael
reaction occured following the Knoevenagel reaction and as a result a mixture of diastereo-
meric cyclohexanones VII 70:30 was formed the structure of which was confirmed by methods

H. V. Lomonosov Moscow State University, Moscowl19899. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 3, pp. 308-311, March, 1986. Original article submitted
February 15, 1985.

0009-3122/86/2203-O247512.50 9 1986 Plenum Publishing Corporation 247

 TABLE i. Properties of 2,3,5-Trisubstituted 4,5-Dihydrofurans

d,." iri a! L~lcu-

Compound }p~ t ppm lated, %
IID20 1 s, 250 MHz) M* _ _ ~ormula
c H c H
I
Via r8{2) ! 1,4810 5,46 (m,IH, X-H); 3,70 ( m 2H,I 170 63,5 ?,,4 ,%H170,~ 53,5 8,2
C.H, D-I-I); 2,80 (m, 2H, A-H,I
B.H); 2,17 (ti 3H, 2-CHa); 2,10/
(s,3Fl, CHaC=O); 1,17 (t 3H,|
OCIt.oCI-13) }
VIB 81 (2) 1,4633 5,52 (d..d IH, X-H); 3,80 ,m 20, 60,1 B,0 C l o H t o O 4 60,0 8,1
IH, C-H); 3,55 (ra IH, D.H);
3,49 (b 2H, CH20); 2,97(In~.
IH, A-H); 2,68 ~, 1H, B.H);
2,20 (q 3H, 2,CHa); !,30(t.
3H, CHaCH2C=O); 1,0 ( t 3H:
CHaCH20)
Vie+ VIc~ 133(2) 1,5550 VI e 7,41 (In, 5H, Ph); 5,58 23 72,4 B,8 CI4HIBOa 72,4 6,9
(d.d, IH, X-H); 3,88 (q, IH,
g-H); 3,84 (q. IH, D-HI; 3,22
(m, 1H, A-Hi; 2,91 (r~ IH,
B-H}; 1,87 ( t 3H, 2-CHa); 1,24
(t,3H, CHaCII2) "
VIev 7,56 ~1, 5H, Ph); 5,62
d.d, IH, X-H); 3,93 tq, 1H,
C-H}; 3,8g (q, lH. D-H); 3,29
(d, 1H, A-H); 2,94 (d, 1H,
B-H); 1,95 (s.3H, CHaC=O);
1,27 (t, 3H, CHaCH20)

*The spectrum of compound (Vla) was taken at 60 MHZo

of IR and XaC NMR spectroscopy. Similar conversion of Knoevenagel condensation products has
been observed for a series of monosaccharides in [i]o

9 OEt
{l:IJ~ O j O
o o L .
EtO / ~ " " + C-a -. / .... ~ gto
r
! nb c 3
OEt
mb
O CJt 3 O CH

A "" )l
-H~O EgO

ELO O VII
15

I~ 12 ~3 CH2
CIJ2OCII~CH 5 11 < 0

~'\\ /['I
?-~ II O
I ~:.2..~..d~

8 C .~..
/'-----~'X. Z..
C It
i901o ,~
OCH2CII ~ 0CIt2CH 3
VII (70%) VII~ {O0.%)

The cyclization has been investigated by us of the products of interaction of ethoxy-

acetaldehyde with diketones lla-cunder the action of acids. On heating a solution of the
linear adduct IVa in CC14 (70~ 7 h) in the presence of catalytic quantities of trifluoro-
acetic acid 2-methyl-5-ethoxy-3-acetyl-4,5-dihydrofuran (Via) was isolated in 85% yield.
From the mixture of condensation products (IVb-Vlb) 2-methyl-5-ethoxy-3-carbethoxy-4,5-dihydro-
furan (75%) was formed in the presence of acetic acid (70~ 2 h). The condensation product
of ethoxyacetaldehyde with diketone (llc) cyclized in the presence of trifluoroacetic acid
(70~ 2 h) to the corresponding dihydrofuran in 95% yield. Analysis of the PMR spectra
(250 MHz, CDCIa) of the dihydrofuran showed that it was a mixture of the two isomers (Vlc)
and (Vlcx) 2:1.

248
 II~ "H ~ I~,.0 B Io~0
IIA I{ C "s
l :~ 14 5i/ a
}I'
0 0 ('II~ 0 f)~ C6ll5
}~ }s Hu
ll' I IIb il' I" -
,~r . I
(:|13 ('113
VI C vIC

The formation of these two compounds is explained by the possibility of attack at the
carbon center of the vinyl ether both from the side of the benzoyl and from the side of the
acetyl group. Since arylacetones are enolized to a greater extent at the benzoyl group
than at the acetyl group more compound (VIc) is formed. The existence of two isomers was
confirmed by the data of ~3C NMR spectroscopy.

EXPERIMENTAL

The PMR spectra were obtained on Tesla BS-467 and Bruker WM-250 (60 and 25 MHz) in-
struments in 5-10% solutions in CCI~, C6D6, and CDCI3, the internal standard was HMDS. The
13C NMR spectra were obtained on a Bruker WM-250 instrument in C6D6. IR spectra were taken
on UR-20 and Specord-75 instruments ina thin film. Mass spectra were recorded on a Varian
CH-6 instrument by direct insertion of samples into the ion source, ionizing voltage was 70
eV. Analysis by GLC was carried out on a Khrom-4 instrument with a flame ionization de-
tector, column i000 4 mm, stationary phase 15% Tween on Chromaton, carrier gas nitrogen,
and analysis temperature 150~
The characteristics of compounds Vla-c are given in Table lo
Interaction of Ethoxyacetaldehyde with 1,3-Dicarbonyl Compounds (General Procedure).
The 1,3-dicarbonyl compound (0.5 mole) and a few drops ofpiperidine acetate catalyst were
added to a solution of ethoxyacetaldehyde (0.5 mole) in an organic solvent. The mixture was
left for 4 h in the dark. After removal of water the organic portion was dried over sodium
sulfate, the solvent distilled off, and the residue distilled in vacuum.
3-(2-Ethoxy)vinylpentane-2,4-dione (Va). Dione Va was obtained from compounds I and lla.
Yield was 28%, bp 74~ (2 mm), n~~ 1.4828. PMR spectrum (60 MHz, CCI~): 16.2 (s, i H, OH).
6.0 (d, A-H, JAB = 13.0 Hz), 5.15 (d, 1 H, B-H, JAB = 13.0 Hz), 3.74 (q, 2 H, OCH2, J = 7.0
Hz), 2.0 (s. 6 H, CH3C=O), 1.23 ppm (t, 3 H, CH3CH20, J = 7.0 Hz). IR spectrum: 2980,
1640, 1330, 1260 cm -I. Mass spectrum: M + 170.
3T(2-Ethoxyvinylbenzoy!acetone (Vc). A mixture of compounds IVc + Vc was obtained from
substances I and IIc. Yield was 53%, bp 136-137~ (2 mm , n =~ 1.5582. PMR spectrum (250
~mz, C6D6): ~ (IVc), 7.85 (m, 5 H, Ph), 6.71 (d, i H, A-H, JA~ = 13.0 Hz), 5.5 and 5.45 (d.d,
1 H, B-H, JAB " 13.0, JBX = 13.5 Hz), 4.1 (d, 1 H, X-H, JBX = 13.5 Hz), 3.33 (q, 2 H, CH20,
J = 7.0 Hz) 2.0 (d, 3 H, CHsC=O, J = 1 Hz), 0.96 ppm (t, 3 H, OI3CH20, J = 7.0 Hz); (Vc)
17.6 (s, 1 H, OH), 7.50 (m, 5 H, Ph), 6.67 (d, 1 H, A-H, JAB = 13.0 Hz), 5.83 (d, i H, B-H,
JAB 13.0 Hz), 3.32 (], 2 H, CH20, J = 7.0 Hz), 1.96 [d, 3 H, CHsC(OH)=C, J = 1.0 Hz], 0.91
ppm (t, 3 H, CH3CH20, J = 70 Hz). The ratio of IVc to Vc was 20:80. IR spectrum: 2980,
1635, 1600, 1350, 1240 cm -I. Mass spectrum: M + 232.
Interaction of Aldehyde (I) with Acetoacetic Ester. A mixture of isomers IVb + Vb +
VIb was obtained from compounds I and IIb. The yield of the mixture of isomers was 55%,
bp 98-I00~ (2 mm), nD ~I 1.4621. PMR spectrum (250 MHz, CDCI3): (IVb) 6.25 (d, 1 H, A-H,
JAB = 12.5 Hz), 5.02 and 4~ (d.d, 1 H, B-H, JAB = 12.5 Hz, JRX = 12.5 Hz), 3.99 (q, 2 H,
CH20C=O, J = 7.0 Hz), 3.74 (d, i H, X-H, JBX = 12.5 Hz), 3.49 (q, 2 H, CH20, J = 7.0 Hz)
1.0 ppm (t, 3 H, CH~CH=O, J = 7.0 Hz); (Vb) 13.42 (s, I H, OH), 6.22 (d, 1 H, A-H, JAB =
12.5 Hz), 5.3 (d, 1 H, B-H, JAB = 12.5 Hz, 3.97 (q, 2 H, CH20C=0, J = 7.0 Hz), 3.35 (q, 2 H,
CH20, J = 7.0 Hz), 1.89 (s, 3 H, CH3C=C), 1.15 (t, 3 H, CH30C=O, J = 7.0 Hz), 0.85 ppm (t,
3 H, CH3CH20, J = 7.0 Hz). The PMR spectrum of isomer VIb is given in Table i.
3-Methyl-5-ethoxymethyl-4-carbethoxycyclohex-2-enone (VII). Diketone IIb (130 g: 1
mole) and piperidine (6 drops) were added to compound I (22 g: 0.25 mole) in benzene (i00
ml). Compound VII (19.5 g: 0.08 mole) was obtained, yield was 32%, bp 130-131~ (2 mm),
nD 2 3 1.4788. 13 C
NMR spectrum (250 MHz, C6D6): (VII) 196.6 (s, C-l), 127.6 (d, C-2),
154.99 (m, C-3), 48.84 (d, C-4), 35.7 (d, C-5), 37.51 (t, C-6), 22.33 (q, C-7), 171.21 (s,
C-8), 71.45 (t, C-9), 14.5 (q, C-10), 60.71 (t, C-II), 66.07 (t, C-12), 13.74 ppm (q, C-13);

249
(VIIi) 197.5 (s, C-l), 128.01 (d, C-2), 155.97 (m, 0-3), 48.10 (d, C-4) 35.6 (d, C-5),
37.41 (t, C-6), 22.7 (q, C-7), 169.53 (s, C-8), 71,22 4t, C-9), 14.5 (q, C-10), 60-59 (t,
C-II), 66.07 (t, C-12) 13.74 ppm (q, C-13). IR spectrum: 1770, 1680, 1640 cm -~, M + 242.
2-Methyl-5-ethoxy-3-aeetyl-4~5-dihydrofuran (Via) (Table i). Trifluoroacetic acid
(0.5 ml) was added to compound Va (8.5 g: 0.05 mole) in dry CCIa (40 ml) and the mixture
stirred at 70~ for 7 h. The course of the reaction was checked by TLC (Silufol, hexane-
ether, 1:2). The reaction mixture was treated with saturated NaHCOs solution, the~solution
dried with sodium sulfate, and after distilling off the solvent the residue was distilled
in vacuum in a stream of nitrogen. Dihydrofuran (Via)47.2 g: 0.042 mole) was obtained in
85% yield.
2-Methyl-5-ethoxy-3-carbethoxy-4,5-dihydrofuran (Vlb). A c e t i c acid (4 ml) was added
to the mixture (i0 g: 0.05 mole) of c o m p o u n ~ i ~ - V I b in CCI~ 440 ml). The mixture was
stirred at 70~ for 2 h. After distillation dihydrofuran VIb (7.5 g: 0.038 mole) was
obtained, yield was 75%.
2-Methyl-5-ethoxy-3-benzoyl-4,5-dihydrofuran (VIc) and 2-Phenyl-5-ethoxy-3-acetyl-4~5-
dihydrofuran (VIcl). Trifluoroacetic acid 40.5 ml) was added to a mixture (4.2 g: 0.018
mole) of compounds IVc and Vc in CCI~ 420 ml), ithe'reaction mixture was stirred at 70~ for
2 h, and compounds ( V I c + VIcz) (4 g: 0.017 mole) were obtained. Yield was 95%. ~SC NMR
spectrum (250 MHz, C6D6): (Vlc) 113.88 (C-2); 166.5 (C-3); 28.86 (C-4); 105.26 (C-5);
37.83 (C-6); 127.7-130.83 (C-7); 64.33 (C-8); 15.01 4C-9); 201.2 (C-10); (Vlc~) 116.53 (C-2);
172.5 (C-3); 29.4 (C-4); 104.8 (C-5); 38.21 (C-6); 127.7-130.83 (C-7); 64.33 (C-S); 15.23
(C-9); 196.7 (C-10). IR spectrum: 3065, 1705, 1655, 1080 cm-*.

LITERATURE CITED

i. F. J. L. Herera, Mo V. Fernandes, and Ro Jo Segura, Carb. Res., 127, 217 (1980).

ACID--BASE PROPERTIES AND STABILITY OF PYRYLIUM POLYMETHINE

DYES IN CHLOROHYDROCARBON SOLUTIONS

L. S. Shishkanova, N. V. Timokhovich, UDC 547.812o5:541.651

and V. V. Yurchev

The reactions of pyrylocyanine dyes with aqueous alcoholic alkali and with acetic
acid have been studied. It has been shown that decoloration of such dyes in
chlorohydrocarbon solutions only occurred underthe action of alkali and was linked
with the formation of an intermediate acyclic form of the dye which was the addi-
tion product of hydroxyl ion at the ~ position of the pyrylium ring.

It is known from [i] that cyanine dyes are inclined to decoloration in solution both
under the action of acid and of alkali. The ease of carrying out the reaction leading to
decoloration may serve as a practical m e a s u r e o f the stability of cyanine dye molecules
in solution in organic solvents. Reactions of such type have not been adequately studied
for pyrylium polymethine dyes in spite of the urgency connected with the wise practical
application of these dyes for example as materials for quantum electronics in [2~ 3].
In the present w o r k t h e special features of the development of acid--base properties of
pyrylocyanine dyes in chlorohydrocarbon solutions has been considered. For this purpose the
behavior of pyryliumpolymethine dyes has been investigated in aqueous alcoholic alkali and
acetic acid using the example of 2-[7-(4,6-diphenyl-2H-pyran-2-ylidene)-4-chloro-3,5-tri-
methylene-l,3,5-heptatrienyl]-4,6-diphenylpyrylium perchlorate (dye PK-15) of [4] and several
of its derivatives. Methylene chloride and 1,2-dichloroethane served as solvents.

Scientific-Research Institute for Organic Intermediates and Dyes, Moscow 103787. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 312-314, March, 1986. Original
article submitted January 29, 1985.

250 0009-3122/86/2203-0250512.50 9 1986 Plenum Publishing Corporation

 .~ 60

i ~o~ 5
[,-i ~5 502

20 __. O] t
300 500 700 900 II00 A, rill;

Fig. i. Transmission spectra of PK-15 dye in methylene chloride

with added i0% (by vol.) 0.5 N aqueous alcoholic alkali: i)
freshly prepared solution; 2) after 0.5 h; 3) after 1.5 h; 4)
after 4 h; 5) after 20 h.

TABLE i. Characteristics of the Synthesized Compound

Electronic
Found, % Fapirieal Calculated,
%
Compound spectrum, IR spectrum, cm- z formula
C H C H

I (PK-I-=

Ill
1072 (4,78) 1110 .(CIO0; 1525 1610,
11640 (pyrylium c~tion) 72,0
520 (3,6I)[1190 (C--OH); 1495,
11590, 1635, 1685 (C=O)
4,8I
81,34 5,30
C44H34C]206

C44H3saIO3
72,4 i4,7
81,65 5,45
[[8], 3400 (hr. band,
[polyassociated OH)

An anomalous behavior was discovered for the pyryiocyanines in comparison with the salt-
form cyanine dyes. It turned out that they were not decolorized by acid and were decolorized
only under the action of alkali. Transmission spectra (TS) of dye PK-15 in methylene chloride
with addition of 10% (by vol.) 0.5 N aqueous alcoholic alkali, recorded at various time points,
are shown in Fig. 1 as an example. The changes of TS with time of a solution of PK-15 under
the action of alkali showed that decoloration of the solution proceeded in several stages.
In the initial step (during the first 1-2 h after adding alkali) a reduction in intensity of
the main absorption band (AB) of the dye at kma x 1072 nm (log r 4.78) occurred and linked with
it was a growth in intensity of absorption of the band with kmax 520 nm (log e 3.61). If
the solution of dye was acidified with acetic acid at this stage then the reverse reaction
began at once, proceeding with a significantly greater rate as indicated experimentally by the
observed restoration of the initial optical density at wavelength 1072 nm and a corresponding
(allowing for the difference in extinction) fall in intensity of the AB at % 520 nm in less
than i0 min.
After a greater duration (3-4 h) of the action of alkali on the initial solution irre-
versible conversions began, showing spectrally in a further fall of intensity of the main
AB and in a marked growth of the AB in the 360 nm region with a simultaneous reduction in
the intensity of the AB at 520 nm. After 20 h final destruction of the dye occurred which
was indicated by the complete disappearance of the AB in the neam IR region. The absorption
in the 230 nm region was sharply increased.
The observed difference in the TS of a solution of PK-15 dye under the action of alkali
and acid may be explained, from our point of view, if the specific nature of the properties
of the pyrylium ring are taken into consideration, i.e., the ability readily to add nucleo-
philic agents at the u position observed in [5, 6]. The following conversion scheme may be
proposed for the considered pyrylium polymethine dye.

251
 q
I i ' : 6H'~
..~. ........... f' .. o~ i "1 ..... I ~'~'"
C6IL~ 0' Cl.I:Cd ~ Cll CI[ O C~=II5 CbH 5 Cell ~
OH I
: (104- Ct CI
I ,~ lnax 107~I~11 /~"
,/
[I

j/

~6115 C6H5

~
~. li [ .... "L [ I!
C6II,." "~'0 C tk.
I CI[:-CII L'I "~"('I1 CI~ 0 '" C611,
o Oil t
C! ,,
iIi Am~ x 5~0 rlIII

Under the action of hydroxyl ion an unstable acyclic carbonyl form (III) (ACF) is formed
which is readily converted on acidification i n t o t h e initial form of the dye (I). Depending
on the extent of the accumulation of hydroxyl ions in solution a gradual accumulation of the
open form (III) occurs and subsequent destruction of it with the formation of unsaturated
ketones C6Hs-C(O)-CH =C(C6H~)--CIi----CHOH having two AB at 360 and 230 nm corresponding to
n + ~* and ~ + ~* transitions according to [7]. Evidently the reaction proposed above also
explains the stability in chlorohydrocarbon of the pyrylocyanine dyes.
For confirmation, form (III) mentioned above was isolated by us and characterized. It
is interesting to note that the formation of the ACF was observed by us directly in the actual
synthesis of dye PK-15 and its derivatives, but in the case of p-nitrophenyl substituted
derivatives of PK-15 only the open carbonyl form of the dye with kma x 520 nm was observed
under the action of a strong acceptor and not even traces of the form of the dye absorbing
in the near IR region were observed.
It may therefore be considered that decoloration of the pyrylium polymethine dyes in
solution in chlorohydrocarbons goes throughthe formation of an unstable acyclic form which
is the product of the addition of hydroxyl ion at the ~ position of a pyrylium ring of a dye
molecule.
The obtained results also proved t o b e extremely useful for clarifying possible routes
of photoconversion of pyrylocyanine molecules under the action of laser radiation. It was
established experimentally by us that on irradiation of solutions of dye PK-15 in chloro-
hydrocarbons with a neodymium laser of nanosecond duration the spectral manifestations of
the process of photodecolorization of such solutions were completely identical to the changes
in their transmission spectra described above under the action of hydroxyl ions. This
circumstance makes it possible to propose that the acid--base properties of molecules of
pyrylium polymethine dyes also play an important role in the process of photo-decolorization
of their solutions on resonance laser excitation.

EXPERIMENTAL

The electronic spectra of compounds were taken on an SF-8 spectrophotometer. IR spectra

were drawn on a UR-20 spectrophotometer in KBr disks.
Preparation of Acyclic Carbonyl Form (III) of the Dye. A solution of dye PK-15 in
methylene chloride was shaken w l t h 0 . 5 N aqueous alcoholic alkali, washed with water, dried
over CaCI=, and evaporated todryness. The dry residue was dissolved in methylene chloride
and was chromatographed on a column of A1203 in the same solvent. The open carbonyl form
(III) was eluted first. The spectral characteristics of this form and data of elemental
analysis are given in Table i.

LITERATURE CITED

I. A. I. Kiprianov, Color and Structure of Cyanine Dyes [in Russian], Naukova Dumka, Kiev
(1979). p. 501.
2. V. A. Babenko, G. G. Dyadyusha, M. A. Kudinova, V. I. Malyshev, et al., Kvant. Elektron.
(Moscow), i, 1796 (1980).
3. V. Korainsky, P. Qiu, W. Kaiser, B. Sens, and K. H. Drexhage,: Appl. Phys., B29, 15, (1982).
4. G. A. Reynolds and K. H. Drexhage, J. Org. Chem., 42, 885 (1977).

252
5. J. Joule and P. Smith, Basis of the Chemistry of Heterocyclic Compounds [Russian transla-
tion], Mir, Moscow (1975), p. 163.
6. I. V. Korobka, I. V. Shcherbakova~ and E. V. Kuznetsov, Khim. Geterotsikl. Soedin., No.
9, 1184 (1982).
7. L. A. Kazitsyna and N. B. Kupletskaya, The Application of UV, IR, NMR, and Mass Spectros-
copy in Organic Chemistry [in Russian], Izd-vo MGU, Moscow (1979), p. 20.
8. G. N. Dorofeenko, V. V. Mezheritskii, and A. L. Vasserman, Khim. Geterotsikl. Soedin.,
No. I, 37 (1974).

ELECTROCHEMICAL REDUCTION OF N-VINYLAZOLES

V. A. Lopyrev, T. G. Ermakova, UDC 543.253:547.77'791'792'796

T. N. Kashik, L. E. Protasova,
and T. I. Vakul'skaya

Classical polarography inaprotic solvents was used to study the reduction of N-

vinyl derivatives of pyrazole, imidazole, 1,2,3- and 1,2,4-triazoles, and tetra-
zole. The N-vinylazoles studied were reduced in acetonitrile by a one-electron
mechanism with subsequent dimerization of the radical-anions formed. The N-
vinyl derivatives of pyrazole, imidazole and tetrazole were reduced analogously
in DMF, while N-vinyltriazoles in DMF are reduced by a mixed mechanism with predom-
inant two-electron transfer. Possible schemes for the electrochemical reduction
of N-vinylazoles are discussed.

The study of the electrochemical initiation of the polymerization of vinyl monomers

requires knowledge of the primary electrochemical steps. The reduction of the vinyl group
in styrene and methyl methacrylate in DMF has been shown to occur by different mechanisms
[1-3]. Styrene is reduced in a single two-electron step, initiating polymerization by
dianions [i, 2], while methyl methacrylate accepts one electron under the same conditions
followed byradical-anion recombination [2, 3]. N-Vinylcarbazole under analogous conditions
gives one two-electron wave on the polarogram [4]. However, the nature of the solvent plays
a role in the reduction of N-vinyl-l,2,4-triazole [5]. The reduction in DMF proceeds
in a single two-electron step, while the depolarizer accepts only one electron in aceto-
nitrile i[5, 6]. Thus, the electrochemical reduction of even the same type of vinyl monomers
may proceed by different pathways.
In order to elucidate the common features and differences in the behavior of N-vinyla-
zoles, we studied the electrochemical reduction of N-vinyl derivatives of pyrazole, imidazole,
1,2,3- and 1,2,4-triazoles and tetrazole (II-IX) in aprotic solvents. For comparison, we
investigated N-vinylpyrrole I, tetrazole X and 5-vinyltetrazole XI. In order to exclude the
effect of impurities and water, the starting compounds and the solvents were subjected to
careful purification.

I I I I
CH:CH 2 CII:CH 2 CH~CH 2 CH:CH 2

I II III ~z

/~/ " --.--N

CHzC|| 2 CHzC~J 2 CHzCH 2

~,\ VI VII

r cnU_.c "N
]I 11
i
CH.CH 2 CH-CIt 2
Vlll IX X XI

Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR,
Irkutsk 664033. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 315-319,
l~rch, 1986. Original article submitted January 16, 1985.

0009-3122/86/2203-0253512.50 O 1986 Plenum Publishing Corporation 253

5. J. Joule and P. Smith, Basis of the Chemistry of Heterocyclic Compounds [Russian transla-
tion], Mir, Moscow (1975), p. 163.
6. I. V. Korobka, I. V. Shcherbakova~ and E. V. Kuznetsov, Khim. Geterotsikl. Soedin., No.
9, 1184 (1982).
7. L. A. Kazitsyna and N. B. Kupletskaya, The Application of UV, IR, NMR, and Mass Spectros-
copy in Organic Chemistry [in Russian], Izd-vo MGU, Moscow (1979), p. 20.
8. G. N. Dorofeenko, V. V. Mezheritskii, and A. L. Vasserman, Khim. Geterotsikl. Soedin.,
No. I, 37 (1974).

ELECTROCHEMICAL REDUCTION OF N-VINYLAZOLES

V. A. Lopyrev, T. G. Ermakova, UDC 543.253:547.77'791'792'796

T. N. Kashik, L. E. Protasova,
and T. I. Vakul'skaya

Classical polarography inaprotic solvents was used to study the reduction of N-

vinyl derivatives of pyrazole, imidazole, 1,2,3- and 1,2,4-triazoles, and tetra-
zole. The N-vinylazoles studied were reduced in acetonitrile by a one-electron
mechanism with subsequent dimerization of the radical-anions formed. The N-
vinyl derivatives of pyrazole, imidazole and tetrazole were reduced analogously
in DMF, while N-vinyltriazoles in DMF are reduced by a mixed mechanism with predom-
inant two-electron transfer. Possible schemes for the electrochemical reduction
of N-vinylazoles are discussed.

The study of the electrochemical initiation of the polymerization of vinyl monomers

requires knowledge of the primary electrochemical steps. The reduction of the vinyl group
in styrene and methyl methacrylate in DMF has been shown to occur by different mechanisms
[1-3]. Styrene is reduced in a single two-electron step, initiating polymerization by
dianions [i, 2], while methyl methacrylate accepts one electron under the same conditions
followed byradical-anion recombination [2, 3]. N-Vinylcarbazole under analogous conditions
gives one two-electron wave on the polarogram [4]. However, the nature of the solvent plays
a role in the reduction of N-vinyl-l,2,4-triazole [5]. The reduction in DMF proceeds
in a single two-electron step, while the depolarizer accepts only one electron in aceto-
nitrile i[5, 6]. Thus, the electrochemical reduction of even the same type of vinyl monomers
may proceed by different pathways.
In order to elucidate the common features and differences in the behavior of N-vinyla-
zoles, we studied the electrochemical reduction of N-vinyl derivatives of pyrazole, imidazole,
1,2,3- and 1,2,4-triazoles and tetrazole (II-IX) in aprotic solvents. For comparison, we
investigated N-vinylpyrrole I, tetrazole X and 5-vinyltetrazole XI. In order to exclude the
effect of impurities and water, the starting compounds and the solvents were subjected to
careful purification.

I I I I
CH:CH 2 CII:CH 2 CH~CH 2 CH:CH 2

I II III ~z

/~/ " --.--N

CHzC|| 2 CHzC~J 2 CHzCH 2

~,\ VI VII

r cnU_.c "N
]I 11
i
CH.CH 2 CH-CIt 2
Vlll IX X XI

Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR,
Irkutsk 664033. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 315-319,
l~rch, 1986. Original article submitted January 16, 1985.

0009-3122/86/2203-0253512.50 O 1986 Plenum Publishing Corporation 253

 TABLE i. Polarographic Characteristics and Diffusion Coef-
ficients of N-Vinylazoles

/) , I!1". L~,':, i, nb nC
Compound So iventa cm2/sec ~A

I DMF 8,39 3,(1) 2,6 1,01 0,99

I[ DMF 8,3 I 3,(o) 2,8 1,09 1,07
Ill DMF 8,16 3,(o) 2,4 0,93 0,92
I!V DMF 7,51 2,77 3,0( 1,17 1,20 ,
Acetonitrile 17,10 2,89 3,5~ 099 0,94
DMF 2,35 2,5z 0,99
Acetonitrile 2,45 3,3', 0,93
VI DMF ;7 2 2,75 4,4( 1,71 1,67
Acetonitrile 18,90 2,90 3,7( 0,96 0,93
VII DMF 8,40 2,71 ,I,3 ] 1,68 1,63
VIII DMF 7,56 2,10 4,4C 1,71 1,77
Acetonitrile 17,20 2,34 4,4! 1,16 l,I9
IX DMF 8,66 2,52 3,I,~ 1,21 1,16
Xd DMF 2,24 1,00
Xld 2,07 1,00
DMF

a 1 mmole/liter vinylazole concentration, 20~ b Calculated

relative to the first nitrobenzene wave. c Calculated accord-
ing to the Ilkovic equation. 6 Datafrom our previous work
[8].

-$ J2, V
2,8 Y]

2,7
/
2,6

2,5

2,4 v
9 ~
2,3 c n~ole/liter
0,5 1,0 1,5

Fig. i. Dependence of the halfwave potentials of V-VII

on the depolarizer concentration (c) in DMF.

,.. ~)J
13"/bliln Lg[i2%'Uli
~ ~,0d}]
1,0

.j _. 3 I

2 "-

_,,ol ,,o
1
Fig. 2. Graphic analysis of the polarogram of triazole
VI in DMF. Concentrations: i, 2) 0.Smmole/liter, 3, 4)
3 mmole/liter.

254
 2

"I
ig[i/(ilim - i)] L~L,'~!i.
.i -iJJ

E
2,O 3,O

Fig. 3 Fig. 4
Fig. 3. Polarograms of imidazole V inacetonitrile: i) c 0.9 mmole/liter,
2) 5 mmoles/liter. Instrumental sensitivity was 20 and 50 ~A, respectively.
Graphic analysis of the polarograms of imidazole V in acetonitrile (c 0.2
mmole/liter)=
We should note that pyrazole, imidazole, 1,2,3-triazole and 1,2,4-triazole and polaro-
graphically inactive, while tetrazole X, which has four ring nitrogen atoms, is reduced
somewhat more readily than its N-vinyl derivative IX (Table i). All the compounds studied
1-IX give one reduction wave in their polarograms at rather large negative potential values
(Table I). The halfwave potentials are shifted toward positive values with increasing number
of nitrogen atoms in the five-membered ring. The introduction of phenylene fragments also
causes an anodic shift of the potentials on the order of from 0.2 to 0.6 V. The halfwave
potentials in acetonitrile are shifted toward cathodic values relative to DMF by an average
0.2 V. Thus, in acetonitrile, only those vinylazoles, in which the number of nitrogen atoms
or sum of the nitrogen atoms and phenylene systems is at least three (IV-IX), are polaro-
graphically active.
For depolarizer concentrations from 0.2 to 2 n~noles/liter, the wave height is linearly
dependent on the concentration. The slope of the logarithmic dependence of the current on the
mercury column height is 0.5, while the temperature coefficient is 2.2% per degree, which
indicates the diffusional nature of the process. However, the reduction in DMF is irreversi-
ble since the slope determined for the dependence of log [i/(ilim -- i)] on the potential
E is 90-160 mV. The wave irreversibility is also indicated by the cathodic shift in the
E~/= values with increasing depolarizer concentration (Fig. I) [7]. In this case, we should
stress that while the halfwave potential shift for l-vinylnaphtho[2,3-d]imidazole (V) is
insignificant, it is 145 mV for l-vinyl-l,2,4-triazole (VI) and l-vinyl-l,2,3-triazole (VII).
At depolarizer concentrations a b o v e 2 mmole/liter, the polarograms do not give linear
Heyrovsky-llkovic or Koutecki--Hanusch plots (Fig. 2). At even higher concentrations of the
depolarizer, a clear doubling of the reduction wave is observed in the polarograms (Fig. 3).
Hence, N-vinylazoles have a tendency to adsorb on the cathode. In particular, at low
depolarizer concentrations, the values for the diffusional current activation [A log i/A
(i/T)].19.3 (on the order of i0 kJ) is in the range between 7.14 and 11.34 kJ, i.e., the
limiting currents are determined only by diffusion. On the other hand, in the case of de-
polarizer concentrations about 2 =~ole/liter, the activation energies determined from anal-
ogous relationships are'approximately 5 kJ, which indicates the superposition of adsorption
effects [9]. Thus, all the major measurements were carried out for depolarizer concentrations
not exceeding i mmole/liter.
The number of electrons determining the limiting current were calculated using the
llkovic equation and the diffusion coefficients and by comparison with freshly purified
nitrobenzene as a standard. The results obtained are given in Table I. In DMF, I-V and IX
are reduced by a one-electron mechanism. Upon the addition of a proton donor (phenol), a
virtual doubling of the limiting current is noted. The wave height for VI-VIII in DMF
corresponds to the transfer of more than one electron and falls short of the two-electron
level by only 20-30% (Table i). A two-electron wave is found upon the addition of phenol.

255
In acetonitrile, IV-VI and VIII accept one electron upon reduction (Table i) while the
reduction in the presence of phenol proceeds by a two-electron mechanism.
These results indicate the following conclusions. N-Vinylazoles are reduced under
classical polarography conditions by a one-electron mechanism to radical-anions. Lineariza-
tion of the curve in a plot of log[i2/s/(ilim-- i)] vs E for the one-electron waves obtained
in acetonitrile at low depolarizer concentrations (Fig. 4) indicates possible fast bimolec-
ular reactions of the primary radical-anions, which accounts for the irreversibility of the
reduction process and the absence of a radical-anion signal in the ESR spectra. The reduction
in the presence of proton donors proceeds by a two-electron mechanimn related to protonation
of the radical-anions and subsequent reduction of the vinyl group to give saturation of the
double bond by analogy to the reduction in aqueous media [6].

- X .........
X r " "~ X---X X--X
i It lJ,, I - +~ +2e.+2H

CII=CH:~ C:~I[5
X=COr N

In DMF, the compounds studied are reduced either by a one-electron mechanism (I-V, IX)
or by a mixed mechanism (Vl-VlII), when some of the molecules accept one electron, while
the remainder are reduced to dianions without intermediate protonation of the radical-anions.
This may be used to explain the finding that the number of electrons transferred to the
molecule upon the reduction of the compounds is 1.7-1,8. Since the reduction of all the
N-vinylpyrazoles was carried out under identical conditions~ these data may serve to indicate
that the electrochemical reduction in DMF proceeds without the participation of protons.
Furthermore, tetrazoleX and C-Vinyltetrazole XI are reduced by a one-electron mechanism
under the same conditions in DMF.
The proposed mixed reduction mechanism is apparentlycharacteristic only for N-vinyl-
triazoles in DMF. A simple calculation shows that, in this case, 7-8 of i0 depolarizer
molecules are reduced to dianions and only 2-3 are reduced to radical-anions which undergo
subsequent chemical reactions. However, a shift in the reduction mechanism is also charac-
teristic for N-vinyltriazoles in the presence of phenol.

EXPERIMENTAL

All the compounds studied were obtained by reported procedures and their physical
indices corresponded to literature values [10-16]. A sample of l-vinylpyrrole (I) was
kindly supplied by Dr. A. I. Mikhaleva. These samples were purified immediately before use.
The solvents were purified by modifications of the methods reported by Mann [17].
The polarograms were taken on an OH-f05 polarograph manufactured in Hungary and by an
LP-7 polarograph manufacturedin Czechoslovakia using 0.i mole/liter tetrabutylammonium
perchlorate as the base electrolyte relative to the saturated calomel electrode. The reduc-
tion was carried out on a dropping mercury electrode with an ordinary capillary (m = 1.47
mg/sec, t = 4.47 sec) and with induced dropping (m = 2.6 mg/sec, t = 0.25 sec). The w o r k i n g
depolarizer concentrations were in the range from 0.2 to 1.4 mmole/liter. The temperature
measurements were carried out in the range from 12 to 35nC. Freshly-distilled nitrobenzene
was used as the standard.
The diffusion coefficients were calculated using the Stokes--Einstein equation:

2.96.10 -7 9 I/s
D=
9~1" M l / 3

The value O 2o = 1.0857 for l-vinyl-l,2,4-triazole was determined pycnometrically. The p

values for the other compounds were taken from the literature [i0, ii, 14, 15, 18-20].

LITERATURE CITED

i. L. A. Korshikov, Ao P. Karpinets, and Vo D. Bezuglyi, Elecktrokhimiya, i0, 990 (1974).

2. V. D. Bezuglyi, A. P. Karpinets, and L. A. Korshikov, Elektrokhimiya, i__i, 1253 (1975).
3. G. S. Shapoval, T. E. Lipatova, and E. S. Shevchuk, Vysokomol. Soedin., 20__
A, 2104 (1978).

256
 4. V. D. Bezuglyi and Yu. Ponomarev, Zh. Anal. Khim., 20, 505 (1965).
5. T. G. Ermakova, A. I. Gritsa, N. M. Deriglazov, L. A. Tatarova, V. V. Keiko, T. I. Vakul'-
skaya, and V. A. Lopyrev, Khim. Geterotsikl. Soedin., No. 3, 408 (1980).
6. V. A. Lopyrev, T. N. Kashik, L. E. Protasova, T. G. Ermakova, and M. G. Voronkov, Vysoko-
mol. Soedin., 26B, 594 (1984).
7. C. Mann and K. Barnes, Electrochemical Reactions in Nonaqueous Systems [Russian transla-
tion], Izd. Khimiya, Moscow (1974), p. 15.
8. Vo N. Kizhnyaev, V. A. Kruglova, L. E. Protasova, G. V. Ratovskii , G. A. Gareev, and
L. I. Vereshchagin, Vysokomol. Soedin,, 28A, (1986) (in print).
9. S. G. Mairanovskii, Ya. P. Stradyn', and V. D. Bezuglyi, Polarography in Organic Chemistry
[in Russian], Izd. Khimiya, Moscow (1975), p. 68.
i0. I. P. Grandberg and G. I. Sharova, Khim. Geterotsikl. Soedin., No. 6, 1097 (1968).
ii. M. F. Shostakovskii, G. C. Skvortsova, N. P. Glazkova, and E. S. Domnina, Khim. Geterot-
sikl. Soedin., No. 9, 1279 (1981).
12. V. A. Lopyrev, N. P. Kuznetsova, G. F. Myachina, ad T. G. Ermakova, Khim. Geterotsikl.
Soedin., No. Ii, 1535 (1983).
13. L. Po Makhno, T. G. Ermakova, Eo S. Domnina, L. A. Tatarova, G. G. Skvortsova, and V. A.
Lopyrev, USSR Inventor's Certificate No. 464, 584; Byul. Izobr., No. 4, 66 (1975).
14. B. I. Mikhat'ev, G. V. Shatalov, and V. D. Galkin, i n : Monomers and High-Molecular-
Weight Compounds [in Russian], Voronezh (1973), p. 87.
15. G. Go Skvortsova, E. S. Domnina, No P. Glazkova, and L. P. Makhno, Abstracts of the
Third All-Union Conference on Acetylene Chemistry [in Russian], Izd. Nauka, Moscow
(1972), p. 115.
16. S. R. Buzilova, V. Mo Shul'gina, G. V. Sakovich, and L. I. Vereshchagin, Khim. Geterot-
sikl. Soedin., No. 9, 1279 (1981).
17. C. Mann, The Electrochemistry of Metals in Nonaqueous Solutions [Russian translation],
Izd. Mir, Moscow (1974), p. 17.
18. W. Reppe and Eo Keyssner, German Patent Noo 618, 120; Chem. Absto, 30, Ii0 (1936).
19o S. Trofimenko, J. Org. Chem., 24, 3459 (1970).
20. W. G. Finnegan and R. A. Henry, Jo Org. Chem., 2_~4, 1565 (1959).

STUDIES OF I-AZABICYCLICS.
23.* NITRATION OF 1,2-D!HYDROPYRROLIZINE AND ITS
HOMOLOGS

L. N. Astakhova, I. M. Skvortsov, UDC 547.759:542.958.1:541.621:543.422

L. V. Safonova, and V. I. Makukhina

Nitration of 1,2-dihydropyrrolizine and its homologs with a mixture of nitric acid

and acetic anhydride has been shown to give a mixture of 5-, 6-, and 7-nitro-l,2-
dihydropyrrolizines. The distribution of isomers with respect to the position of
alkyl substituents in the nonaromatic portion of the bicyclic is discussed.

Within the pyrrole series, the nitration of pyrrole, its homologs, and various derivatives
has been extensively studied [2-7]. 1,2-Dihydropyrrolizines are cyclic analogs of 1,2-di-
alkylpyrroles, and, in this regard, it would be interesting to study the behavior of compounds
I-V in nitration reactions~ We therefore decided, first of all, to determine the isomeric
distribution of mononitro-substituted 1,2-dihydropyrrolizines and homologs among the nitration
products; this knowledge is a prerequisite for a more general investigation of the effects of
structural factors on the positional selectivity of the reaction.

*For Communication 22, see [i].

N. G. Chernishevskii Saratov State University, Saratov 410601. Institute of Biochemistry
and Physiology of Bacteria and Microorganisms, Academy of Sciences of the USSR, Saratov 410015.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 320-324, March, 1986.
Original article submitted Feburary 18, 1985.

0009-3122/86/2203-0257512.50 9 1986 Plenum Publishing Corporation 257

 TABLE i. 5-N~ tro-I )2-Dihydropyrrolizines
i ,,,
i
COm= =p, o C I~ speot:~'tn Found) Molecular Calculatod,
pound ~fromp.ot~?, formula
s er~nQr) ~ ) 1~ ~ C H N C H N
I
,'~82 4,96 88,5 5,6 1.~),0 C~I~I~N,~O~ 55,3 I 5,8 18,4
V] I 47,0=47,5 353 4,20 ~,7,9 6,0 17,8 Cd~it)N~O~ 57,8 I 6,1 IB,9
VIII 82,0=88,5 354 438 88,0 6,0 16,8
X ~4,0 -=65.5 35,5 4,29 63,9 8,1 13,6 C,,I|,e~,,(),, {~%4 77 I:~ !')

TABLE 2. ~H-NMR Spectra of 5-, 6-, and 7-Nitro-l, 2-dihydro-

pyrrollzlnes*

6, ppmt J, Hz
Compound
5.H 6-H 7.H 5,6 5,7 6,7

VI 7,02 5,88 4)9

VII 6,95 5,82 4,2 $
VIII 7,02 5,83 4,8
X 6,99 5,81 ~t,1
XI 7,13 6,09 -- 1,2
XIII 7,28 6,19
XV 7,36 6,20 - - 1,5
XVI 6,42 6,26 3,0 --
XVI I [ 6,53 6,35 3,1
XX 6,49 6,47 3,6

*Values obtained from the spectra of pure compounds are shown

in italics; the remaining data was taken from the spectra of
isomeric mixtures.
+Chemical shifts (in ppm) for assigned signals of other pro-
tons are as follows: Vl (3-CH2 4.43); VII (3-HA 4.56, 3-HB
3.89, I-CH2 3.00, 2-CH 2.54, 2-CHs 1.28); VIII (3-CH 5.05,
3-CH3 1.41); XIII (3-CHs 1.47); XVIII (3-CHs 1.47). Here and
elsewhere the designation A refers to a proton located trans
to a methyl group, and B refers to a proton in the cis posi-
tion. In compounds XVI, XVlll, and XX the assignment of the
5-H and 6-H protons may be reversed.
SAbsolute values of other proton spin-spin couplin~ constants
in compound Vll: ~Jr-H, I-H 0.6, 2J3_HA , 3-HB 11.5, 33s-HA,
2-H 7.5, 3J3-HB, 2-H 6.3 Hz.

TABLE 3. Isomeric Distribution Data for the

Position of the Nitro Group in the Nitration
Products of 1,2-Dihydropyrrolizines
Isomeric position fraction for mixtures of
Starting 5-, 6-, and 7-nitro-l,2-dihydropyrrolizines,%
material
5 o 7

I 58-+2 15-+1 27--+1

II 57-+4 18 25_+.2
IV 5%+_3 15-~: 2 25~ 1
llI 43-+ 1 23 :~: 1 34_+_2
V 44+ 1 27-tl 29_+. 1

258
 I-.v vr .x x~..xv xx

t, VI, XI, XV! R = k ~ = H ; If, VII, XII, XVII R=CH~, RI=H; II1, VIII, XIII, XVIII
R=H, R~=CH~; IV, IX, XIV, XIX R=C2Hs, R'=H; V, X, XV, XX R=H, Rt=C(CH3}~

The nitration of 1,2-dihydropyrrolizines was carried out in a manner analogous to that

used for simple pyrroles [5], using a mixture of 94% nitric acid and acetic anhydride at
temperatures between --50 and --60~ In every case the reactions yielded a mixture of three
compounds, which were identified as 5-, 6-, and 7-nitro-l,2-dihydropyrrolizine isomers, as
well as a small amount of resinous material, which was not investigated.
The 5-nitro-l,2-dihydropyrrolizines VI-VIII and X were isolated by preparative column
chromatography on aluminum oxide (Table i) and were identified based on their UV and NMR
spectra. Ethanolic solutions of compounds VI-VIII and X exhibit absorption maxima (Xma x
352-355 nm) whose position and intensity (log E 4.20-4.96) are characteristic of pyrroles
containing a nitro group in the a-carbon position of the ring [4, 5]. The 6 and J values
of the 6-H and 7-H proton signals and corresponding spin-spin couplings (Table 2) in the
~H-NMR spectra of compounds VI-VIII and X are also characteristic of a-nitropyrroles [4, 5,
7].
The substitution pattern in the other isomers was interpreted on the basis of mixtures
of the 6- and 7-nitro-l,2-dihydropyrrolizines (XI, XVI and XIII, XVIII), which were isolated
from the nitration products of compounds I and III after preparative chromatography on
aluminum oxide. The UV spectra of mixtures of XI, XVI and XIII, XVIII have diffuse bands
in the absorption maxima region, which may be explained on the basis of overlap of the
absorptions of two compounds in each case. The spectral parameters of a mixture of XI and
XVI are Xmax 285 (log e 3.97) and 327 nm (log c 3.87), and of a mixture of XIII and XVIII,
%max 285 (log c 3.93) and 320-330 nm (logE 3.90). A similar absorption pattern has been
observed in the spectra of 3-nitropyrrole [4] and 2-methyl-3-nitropyrrole [5]. The IH-NMR
spectra of these mixtures and, in particular, their comparison with the ~H-NMR spectra of
3- or 4-nitropyrroles [4, 5, 7], provide unequivocal evidence for the assignment of the
6-position for the nitro group in compounds XI and XIII, and for the 7-position of the
nitro group in compounds XVI and XVlII (Table 2).
In order to determine the ratio of the observed isomeric nitro-l,2-dihydropyrrolizines,
we had to identify the peaks in the chromatograms of the reaction products after separation
on immobile phases of polyethylene glycol 20,000, 1,4-butanediol dinitrate, and lucoprene.
In all cases the first isomer to eluto from the column was that with the nitro group in the
5-position; this was verified by comparison of the retention times of the components of
the mixture with the retention times of reference compounds. The subsequent elution of
the isomers with nitro groups in the 6- and 7- positions was determined by comparing the
chromatograms and ~H-NMR spectra of binary mixtures of XI and XVI and XIII and XVIII; it
was found that the 7-nitro isomers eluted prior to the 6-nitro isomers. We are assuming
that this observed elution order for the 7- and 6-nitro-l,2-dihydropyrrolizines is also
applicable for other mixtures.
The isomeric distribution data for the nitro-l,2-dihydropyrrolizines was obtained from
a series of experiments involving four nitration runs for each of the compounds I-V and four
chromatographic measurements of the reaction products of each run of each experiment. The
statistical results of these data are presented in Table 3. The error values were calculated
based on 95% confidence.
As can be seen in Table 3, introduction of either a methyl or ethyl group in the second
position of 1,2-dihydropyrrolizine does not significantly change the isomeric distribution
ratio for the nitration products; this is due to the distance of these substituents from the
reactive sites. Replacement of a hydrogen atom in position 3 with a methyl group decreases
the fraction of isomer with a nitro group in the 5-position (compound III). This fact
indicates that the methyl group resUlts in partial blocking of the 5-positiono The results
obtained for the nitration of compound V with a tert-butyl group in the 3-position provide
conclusive evidence for the large steric effect exerted by a substituent in the 3-position
in deactivating position 5 of the dihydropyrrolizine system.

259
 The larger amount of the 7-nitro-l,2-dihydropyrrollzines formed relative to the amount
of the 6-nitro-l,2-dihydropyrrolizines is probably due to the influence of the aliphatic
chain attached to C(e), which acts as a first order eubstituent~
We have previously described the hydroxyethylation [8] and carboethoxymethylation [9]
of 1,2-dihydropyrrolizlnes, both of which also produce isomeric mixtures of substitution
products. In both of these reactions, as in the nitration reaction, the isomer with the
substituting group in the 5-position constitutes the largest product fraction. In contrast,
the ratio between the 6- and 7-isomers depends on the nature of the reaction. In this
regard, the nitration of 1,2-dihydropyrrolizinas displays the least amount of positional
selectivity.
The authors ackDowledge thegenerosity of K. Sh. Ovchinekii and N. N. Sorokin forobtaining:
the IH-NMR spectra.

EXPERIMENTAL

PMR spectra (of solutions in CCI~ at 0.18-0.3 mole/liter concentrations) were recorded on
BS-477 (60 MHz), Perkin-Elmer R-12 (60MHz), and Varian FT-80A spectrometers (resonance
conditions were locked versus deuteriumpresent in CD3COCDs as solvent additive). HMDS was
used as internal standard~ Chemical shifts are reported on the ~ scale relative to TMSo
UV spectra were obtained on an SF-4 spectrophotometer.
Chromatographic analysis of the nitration products of compounds I, III-V was carried out
on an LKhM-8MD chromatograph equippedwith a f l a m e ionization detector. The column was i
m long and 3 mm in diameter and was filled with 6% polyethylene glycol 20,000 on silylated
N-AW-HMDS chromaton (Chemapol, Czechoslavakia) (0~ mm). The column temperature was
185~ the rate of helium carrier gas flow was 70 ml/min. With the exception of compounds
X, XV, and XX, this immobile phase was able to separate completely all of the isomers in the
mixtures under investigation. 5-Nitro-l,2-dihydropyrrolizine (X) was completely separated
from its isomers XV and XX, which overlapped partially. Use of lucoprene a s t h e immobile
phase on the same support material led to complete separation of all of the isomeric mixtures.
The reaction products of compound II were analyzed on an LKhM-8MD chromatograph equipped
with a thermal conductivity detector. Poly-l,4-butanediol dinitrate (10%) served as the
immobile phase on the same support system described above. The column was 1.9 m long, 3 mm
inner diameter, and its temperature was 223~ the rate of hydrogen carrier gas flow was
ii0 ml/min.
The relative areas of the chromatographic peaks were used to calculate the weight con-
centrations of the individual components in the isomeric reaction mixtures.
Compounds I-V were prepared according to literature methods [10-13]. With regard to
some discrepancy in the literature concerning the index of refraction of 1,2-dihydropyrrolizine
(I) [i0, 14-16], this value has been determined to be nD 2~ = 1.5293 based on multiple
syntheses and index of refractionmeasurements. The average yield of compound (I) was 44%.
Nitration of 1,2-Dihydropyrrolizine (I). A solution of 2 g (19 mmoles) of compound I
i n 9.5 ml of acetic anhydride was stirred vigorously at --50 to--60~ and an already cooled
(about --40~ solutionof 1.5g (24mmoles) ofHNO3 (dl.50) and3.bmlace+ic anhydride was added
dropwise over a 40 min period. The reaction mixture was stirred at--60~ an additional hour
and cooling was discontinued. When the temperature of the reaction mixture reached O~ it
was poured onto ice. The dark oil which separated was extracted with ether (5 50 ml).
The combined ether extracts were washed with sodium hydroxide solution and dried over magnesium
sulfate. The ether was evaporated and 15 g of product was obtained as a viscous dark brown
oil, which crystallized upon cooling. The nitration experiment was repeated three times;
each experiment was analyzed by GLC four times in order to determine the concentrations of
isomers Vl, XI, and XVI in the product mixtures.
Nitration of 1,2-Dihydropyrrolizines II-V. These experimentsand analyses of the re-
action products were carried out in an analogous manner. The total preparative yield of all
of the isomeric nitrated 1,2-dihydropyrrolizine derivatives was about 50%.
5-Nitro-l,2-dihydropyrrolizine (VI). A 4-g mixture of isomers (VI) (58%), XI (15%) and
XVl (27%) was subjected to column (2.5 x 70 cm) chromatography on aluminum oxide with benzene
eluent. The separation was followed by TLC on an unmounted layer of activity II Al2Os.

260
Benzene was used as solvent and the separation was visualized using iodine and water vapor.
Under the TLC conditions selected isomer VI was well separated (Rf 0.37) from the others, but
isomers XI and XVI (Rf 0.23) could not be separated. Three fractions were obtained. The first
fraction consists of isomer VI and yielded 0.25 g (6%) of compound Vl, which was recrystalllzed
from petroleum ether to give yellow crystals, readily soluble in ether, acetone, carbon
tetrachloride, benzene, and ethyl acetate. The second fraction consisted of a mixture of
three isomers, Vl, XI, and XVI (0.9 g). The third fraction yielded 0.76 g of a mixture of
isomers XI and XVI as yellow-green crystals, which were readily soluble in the same solvents
as noted above for compound VI.
Compounds VII, VIII, and X were isolated in an analogous manner in yields of ii, 26. and
16%, respectively, from isomeric mixtures. In the last ease the eluent used was i:I (by
volume) benzene-hexane. We did not optimize the conditions for the preparative separation
of the isomeric mixtures.

LITERATURE CITED

i. O . A . Subbotin and I. M. Skvortsov, Khim. Geterotsikl. Soedin., No. 12, 1638 (1985).
2. R. A. Jones and G. P. Bean, The Chemistry of Pyrroles, Academic Press, London-New York--
San Francisco (1977), p. 122.
3. H. J. Anderson, Caned. J. Chem., 3_~5, 21 (1957).
4. K. J. Morgan and D. P. Morrey, Tetrahedron, 22, 57 (1966).
5. P. E. Sonnet, Heterocycl. Chem., ~, 399 (1970).
6. A. R. Cooksey, K. J. Morgan, and D. P. Morrey, Tetrahedron, 26, 5101 (1970).
7. L. Grehn, Chem. Scr., 13, No. 2-3, 67 (1978-79).
8. A. A. Ponomarev, I. M. Skvortsov, and V. M. Levln, Khim. Geterotsikl. Soedin., No. 10,
1339 (1970).
9. I . M . Skvortsov, S. A. Kolesnikov, Yu. Yu. Samitov, and G. D. Shcherbakova, Khim.
Geterotsikl. Soedin., No. 8, 1090 (1977).
i0. A. A. Ponomarev and I. M. Skvortsov, Zho Obshch. Khim., 3_22, 97 (1962).
ii. A. A. Ponomarev and V. M. Levln, Khimo Geterotsikl. Soedin., No. 5, 939 (1969).
12. A. A. Ponomarev, V. N. Dyukareva, and I. M. Skvortsov, Dokl. Akad. Nauk, 178, 893
(1968).
13. Io M. Skvortsov, I. V. Antipova, Yu. A. Pentin, Khoan' Tran Suan, and S. V. Vasil t-
kovskii, Khim. Geterotsikl. Soedlno, No. 8, 1087 (1975).
14. V. Carelli, M. Cardellini, and F. Morlacchi, Ann. Chim. (Rome), 53, 309 (1963); RZhKh,
10Zh218 (1964).
15. E. E. Schweizer and K. K. Light, J. Amer. Chem. Soc., 86, 2963 (1964).
16. J. Mo Patterson and J. Soedigdo, J. Org. Chem., 3_~2, 2969 (1967).

261
SYNTHESIS OF DERIVATIVES OF INDOLE AND QUINOLINE BY THE
INTRAMOLECULAR CATALYTIC CYCLIZATION OFALLYLANILINES

I~ B. Abdrakhmanov, A. G. Mustafin, UDC 547.551.2'753'831.2:541.128

G. A. Tolstikov, R. N. Fakhretdinov,
and U. M. Dzhemilev

An effective method for the isolation of 3-methyl-2-ethylindole and 2,4-dimethyl-

quin01ine by the intramolecular cyclization of N-(l-methyl-2-butenyl)- and 2-(1-
methyl-2-butenyl)anilines under the action of the catalyst PdCI2 (DMSO)n was
developed. The influence of the nature of the solvent, the temperature, and the
concentration of the catalyst on the Yield and the ratio of the reaction products
was investigated.

According to the data of the work [i], the application of complexes of transition metals
in the chemistry of heterocycles permitted the development of a series of original and prom-
ising methods for the synthesis of derivatives of indole and quinoline with the utilization
of compounds of Ni and Pd. Isoquinolines were obtainedby the intramolecular cyclization
of 2-allylbenzamides under the action of the catalytic system PdCI2(CH3CN)2--NaH, and 2-
alkylindoles were synthesized in sufficiently high yields from 2-allylanilines [2, 3]. By
analogy, 2-chloro-N-methyl-N-allylaniline is converted to 1,3-dimethylindole in the presence
of stoichiometric amounts of Ni(PPh3)~ [4].
Regrettably, the accomplishment of these reactions requires a large amount of the
catalyst or stoichiometric amounts of the complexesof the indicated metals.
With the object of the development of highly active complex catalysts permitting the
isolation of substituted indoles and quinolines from available allylanilines, we studied the
reaction of intramolecular cyclizationtaking, as an example,~N-(l-methyl-2-butenyl)aniline
(I) and 2-(l-methyl-2-butenyl)aniline (I!) with the participation of palladium salts in dif-
ferent solvents. Preliminary experiments showed that the most active of the tested complexes
of the transition metals (Fe, Co, Ni, and Pd) in the indicatedreaction are the catalysts
based on PdCI= modified by DMSO.
Thus, N-(l-methyl-2-butenyl)aniline (I), as a solution in nitrobenzene, gives a mixture
of 2-ethyl-3-methylindole (III> and 2,4-dimethylquinoline (IV) by t~e action of catalytic
amounts of the complex PdCI2--(DMSO)n at a temperature of 170~ in the course of 2 h; the
proportion and the yield of the products change noticeably with the nature of the solvent,
the reaction conditions, and the concentration of the catalyst.

I ' d - Ln

~,
l

II
-

Pd-Ln If- III

H
IV

Institute of Chemistry, Bashkir Branch, Academy of Sciences of the USSR, Ufa 450054.
Bashkir Agricultural Institute, Ufa 450089. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 325-327, March, 1986. Original article submitted May 24, 1984.

262 0009-3122/86/2203-0262512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Influence o f the Reaction Temperature on the Ratio
of the Products of the Intramolecular Cyclization of Compound
II*

I{Ratio of ~i...... of
Tj ~ ~tion,I T, OC T~ I V ) / ( I I I ) , ] Yi~ ld ,
(ivtiO)~nl),

140 79/21
150
160
61
,59
1 67/33
I 63/37
1go
200
0,5
0,3
67
79
63,5/36,5
56/44
170 81 I 46/54

*The reactlon conditions were as fo!lows: catalyst PdCl2

(DMSO)n, solvent nitrobenzene, and i0:i molar ratio of the
aniline !I to the catalyst,

TABLE 2. Influence of the Nature of the Compounds of the

Catalytic System on the Yield and Composition of the Products
of Cyclization of the Allylaniline II*
~posltxon oz rJle
9e a c t i o n ; r o d u c t s ,
Solvent Modifying T o t a l yield,
additive
IIl IV

Nitrobenzene 69 43 57
DMSO 30 58 42
Benzonitri!e 15 35 65
DMF
Nitrobenzene DMSO Tsrlaces
54 46
Benzonit~ile CH~CN 65 41 59
THF
DMF DMSO
Ni(acac)2
DMSO
68
15
I0
61
48
39
52
55 45

~Thereactlontemperature was 170~ the duration of the re-

action was 2 h.
tThe duration of the reaction was 1.5 h.

TABLE 3. Influence of the Con=entrationof the Catalyst on

the Yield and Ratio of the Products of the Intramolecular
Cyclization* of the Allylaniline II to the Compounds III
and IV

Molar r a t i o ' 0 f . . . . i Time ~ ~-I i

Conversion~ Yield, ~ Ratio of the products
(If) to the action, ~. . . . | (II!)/(IV}' ~ ,
catalyst . . . . . . . . . . . .
92 81 54/46
10:1
25:1
50; 1
I 2
2
I 82
68
76
49
60./40
66134
100:1 2 ' 22 20 78/22

*The reaction conditions were as follows: temperature 170~

solvent nitrobenzene, and catalyst PdCI2 (DMSO) n.

263
 As can be seen from Table i, the yield of the compounds llI and IV increases on raising
the reaction temperature, reaching ~80% at 200~ after 0.3 h. There is little change in the
ratio of the compounds III and IV with the condi=ions of the reaction. In passing from
nitrobenzene to DMSO and D ~ , the yield of the mixture of IIl and IV decreases from 69 to
15% (Table 2).
The concentration of the catalyst shows a significemt influence on the total yield of
the indole IIl and the quinoline IV and on their ratio. Tot example, the maximal yield of
the products of the intramolecular cyclization of the amiae I to the compounds Iii and IV
was obtained under the conditions of a (I0-25):i ratio of the amine to the catalyst, a
temperature of 170~ and the duration of 2 h.
Under analogous conditions, 2-(l-methyl-2-butmUyl)anlline (II), which is theproduct of
the Claisen rearrangement of compound I, is readil~ converted to a mixture of the indole III
and the quinoline (IV) in yields which are close to quantitative (Table 3). On the basis
of the experimental data, it was concluded that the rearrangement of the allylaniline I to
compound II proceeds initially in the conditions of our experiments; the intramolecular
cyclization of the latter under the action of c a t a l y t i c a ~ a c t l v e complexes of palladium
then also leads to the formation of the molecules of III and IV.
Therefore, the investigation of the intramoleeularcyclization of derivatives of N-
allyl- and 2-allylanilines by the action of homogeneous pelladlumcatalysts permitted the
development of an effective and promising route for the synthesis of substituted quinolines
and indoles which are not readily available.

EXPERIMENTAL

The IR spectra were taken on a UR-20 (film) instrummnt. The PMR spectra were taken on
a Tesla BS-487 (60 MHz) instrument in CC14 with an interna~ standard of TMS. The TLC and
column chromatography were performed on A l 2 0 3 o f t h ~ l l ~ . ~ e e of activity with the eluent
of benzene. The GLC analysiswasperformed on a L~hM-8~mhromatograph using a column 2700
by 3 m m w i t h 5% SE-30 on Chromaton N-AW-DMCS; the flow r~te of helium was 40 ml/min. The
initial substances were obtained according to the methodl o~ [5].
General Methods of Conducting the Experiment~ Into a finger-shaped autoclave (V = 17
cm 3) Were placed 0.i g (0.62 mmole) of compound I or II 8 ~ 0.062 m mole of the complex PdCI=-
Ln (Ln - DMSO, CH3CN, or DMF). We added 2 ml of the so~ve~t, bubbled the mixture through
with argon, and thermostatted it for the required time at the given temperature. The reaction
mixture was filtered through a layer of A1203, 33 by 150 I , eluting with benzene. The
eluent was then distilled, and the residue was analyzed by the method of GLC after first
adding thecalculated amount of hexadecane as the internal standard. The results of the
experiments are presented in Tables 1-3. Reaction products were separated by chromatography
on Al~O3.
3-Methyl-2-ethylindole (II!) ~ This had mp 66~ The IR spectrum had: 754 (Ar), 1380,
1470 (CH3), and 3396 cm-I (N-H). The PMR spectrum had 6 values of 1.05 (3H, triplet, CH3),
2,13 (3H, singlet, CH3), 2.48 (2H, quartet, CH2) , and 6~&@~7.50 ppm (4H, multiplet, ArH).
2,4-Dimethylquinoline (IV). This had nD 2~ 1,6030 ae~ bp ll0~ (2 m m). The IR spectrum:
860, 1600, 3040, 3070 (Ar), 1370, 1380, and 1460 cm "I (CH3). The PMR spectrum had ~ values
of 2.24 (3H, singlet, CH3), 2.42 (3H, singlet, CH3), 6.66 (i H, singlet, At--H), and 7.30-7.80
ppm (4H, multiplet, ArH).

LITERATURE CITED

i. S. L. Hegedus, F. G. Allen, J. J. Bozell, and L. E, Waterman, J. Amer. Chem. Sot., i00,

5800 (1978).
2. E. D. Korte, S. L. Hegedus, and K. R. Wirth, J. Org. C~sm., 42, 1329 (1977).
3. S . L . Hegedus, F. G. Allen, and L. E. Waterman, J, Amer. Chem. Sot., 98, 2674 (1976).
4. M. Mori and Y. Ban, Tetrahed. Lett., No. 21, 1803 (1976).
5. I. B. Abdrakhmanov, V. M. Sharafutdinov, I. A, Sagitdinov, and G. A. Tolstikov, Zh.
Org. Khim., 15, 2601 (1979).

264
NUCLEOPHILIC SUBSTITUTION REACTIONS IN 4-HALONITR0-
PYRAZOLECARBOXYLIC ACIDS

Yu. A. Manaev, V. P. Perevalov, UDC 547.776:542.944.6

M. A. Andreeva, and B. I* Stepanov

The reaction of 4-bromo-l-methyl-3-nitropyrazole-5- and 4-bromo-l-methy!-5-nitro-

pyrazole-3-carboxylic acids with arylamines in aqueous solution in the presence
of monovalent copper salts leads to the formation of 4-arylamino- and 4-hydroxy
substituted nitropyrazolecarboxylic acids.

Nucleophilic substitution reactions in the 4-halopyrazole series has not been adequately
studied. It is known that as a consequence of the high nucleophilicity of the 4 position of
the heterocycle, 4-halopyrazoles are extremelyinert in reactions of this sort [!]. Nucleo-
philic substitution of the halogen in these compounds is possible only if nitro groups are
present in neighboring positions of the pyrazole ring [2, 3] or if copper compounds are used
as a catalyst [4, 5].
The activating effect of a carboxyl group on the mobility of a halogen atom in 4-halo-
pyrazolecarboxylic acids in the presence of a copper catalyst was noted in [6] but a syste-
matic studyof such reactions was not carried out.
We have established [7] that the reaction of 4-halo-l-methyl-pyrazole-3- and 5-carboxylic
acids with aromatic amines in the presence of a copper catalyst leads to the formation of
4-arylamino substituted pyrazolesand is accompanied by reductive dehalogenation. In this
paper, we consider nucleophilic substitution reactions in the 4-halo-l-methylnitropyrazole-
carboxylic acid series.
The introduction of a nitro group in the 3 or 5 position of a molecule of 4-halo-l-methyl-
pyrazole-3- or -5-carboxylic acidsignificantly increases the rate of substitution of the
halogen atom in reactions of these compounds with aromatic amines. The reaction of 4-bromo-
l-methyl-5-nitropyrazole-3-carboxylic acid (I) and of 4-bromo-l-methyl-3-nitropyrazole-5-
carboxylic acid (II) with aniline takes place even at 60-70~ while the substitution of the
halogen atom in 4-bromopyrazolecarboxylic acids which do not contain nitro groups requires
prolonged heating at 100~ [7]. As in the case of 4-halopyrazolecarboxylic acids, nucleo-
philic substitution in compounds I and II occurs only in the presence of monovalent copper
salts, but no reductive dehalogenation is observed in this case. Divalent copper salts do
not posses any catalytic activity in this reaction.
In the reaction of compounds I and II with arylamines in aqueous solution, the replace-
ment of the halogen with a hydroxyl group was observed along with the formation of the 4-
arylamino substituted compound. This was not noted in the case of 4-halopyrazolecarboxylic
acids [7].

HOOC /Br HOOC NHCsH4R HOOC OH

N NO2 %N "NO 2
I ]
CH 3 CH 3 CH 3

I Ill a - c iv

HI a R = H ; b R = 2 - O C H 3 ; C R = 4 ~ N O 2

D. I. Mendeleev Chemical Technology Institute, Moscow 125820. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 3, pp. 328-330, March, 1986. Original article submitted
March 12, 1985.

0009-3122/86/2203-0265512.50 9 1986 Plenum Publishing Corporation 265

 TABLE i. Substituted l-Methylpyrazolecarboxylic Acids

PMR spectrum, ~, ppm Found, % Empirical;

T~,~ ~ N- I--~
formula Calculated96111
CtL~ other protons C H N C
i

l[Ia 190.--I 9 [ 4,21 7,29 (5H,m, atom.) 7,8 4,2 20,9 C liI-I/0N404 5@4 13,8 21,4 71
lllb 227--228 4,2( 3,76 (s,OCHa), 7,1 3,9 19,0 C12HI.oN40~ 49,3 14,1 19,2 80
6,62 (41.t,m,,atom .)
llIc 184--.186 4,2~ 6,93 (2H, d, 2'.H .~,8/2,6 20,0 CjIItgNsO~ 43,0 2,9 '19,8 56
and 6"H),
7,96 {2It, d, 3'-H
and 5'-H)
IV 135--137 4,0( :,9 2,7 22,3 CsHsN305 32,0 2,7 22,5 69
V 143--145 4,1z 7,12 (5H,re,atom,i ),5 4 1 21,2 CIIHjoN404 50,4 3,8 21,4 165
VI 183--184 4,0,r ~,2 217 22,1 CsHsN30.5 32,0 2,7 22,5 i5O
IX 215--216 4,1~ ,914,1/29,7 CsH~N404 82,4 3,7 30,1 84
X 156--158 4,21 3,17 (4H,m, CH2), ,6 4,6 !22,2 CgHI:~N405 42,0 5,0 21,8 77
(i~ 3,80 (4H, m, CH2)
DCI

*Compound lllb was crystallized from methanol, compound X

from water.

The amount of 4-hydroxy derivative, IV, obtained is determined by the ratio of the rates
of the two parallel reactions taking place and depends primarily on the basicity of the
aromatic amine in thereaetion (in the reaction of compound I with o-anisidine, the yield of
compound IV was 8%, and with p-nitroaniline, 24%); in the absence of an arylamine, the re-
action proceeds solely to the formation of the 4-hydroxy derivative.
The nonequivalency of the C(4)-C(5) and C 4 -C 3 bonds in the pyrazole ring [8] causes
the activation effect of the nitro group to differ In ) the B-nitro- and 5-nitro-4-halopyrazole-
carboxylic acids innucleophilic substitution reactions. This is most clearly shown in the
different reactivities of l-methyl-5-nitro-4-chloropyrazole-3rcarboxylic acid (VII) and
l-methyl-3-nitro-4-chloropyrazole-5-carboxylic acid (VIII). Thus, compound VII on boiling
with o-anisidine for 18 h gives 4-arylaminopyrazole lllb in 67% yield while acid VIII under
similar conditions does not react.
In distinction to the reactions of 4-halopyrazolecarboxylic acids with ammonia and
aliphatie amines, which lead to unsatisfactory results because of the high sensitivity of
the 4-amino derivatives being formed to atmospheric oxygen, when compound I reacts with
ammonia or morpholine, the corresponding 4-aminonitrosubstituted IX and X are obtained in
yields of 84% and 77%, respectively.

, "5. .oo~__j~2
Cu + .~N/~NO 2
I
CH 3
9 IXoX
IX R=H: X NRz=~ m o r p h o l i n e

EXPERDIENTAL

The PMR spectra were measured on a Tesla BS-497 instrument (i00 MHz, H ~ S internal
standard) in DMSO-D~. The mass spectra of compounds IV and VI were obtained on an MX-1309
instrument With an ionization potential of 70 eV and an ionization chamber temperature of
150~
The 4-halonitropyrazolecarboxylic acids I, II, VII, and VIII were obtained according
to [9].
The characteristics of compounds Ilia-c, IV-Vl, IX and X are given in Table i.
4-Arylamino-l-methyl-5-nitropyrazole-3-carboxylic Acids (Ilia-c). A mixture of 2.5 g
(0.01 mole) of acid I, 0.011 mole of the corresponding aniline, and 0.4 g CuBr are heated in

266
i00 ml of a 5% soda solution for 4 h at 60-70~ The reaction mixture is cooled and the
precipitate of copper salt of compound IV filtered off. The filtrate is acidified with HCI
and the precipitate filtered off and crystallized from 50% acetic acid. The 4-arylamino-
l-methyl-5-nitropyrazolecarboxylic acids llla-c were obtained analogously.
l-Methyl-3-nitro-4-phenylaminopyrazole-5-carboxylic acid (V) is obtained in the manner
described above from acid Ii and anoline at 7088 over a 6-h period. The product is
purified by reprecipitation withsubsequent crystallization.from i:i aqueous ethanol.
l-llethyl-4-hydroxy-5-nitropyrazole-3-carboxylic acid(IV). 2.5 g (0.01 mole) of com-
pound I and 0.4 g CuBr in 50 ml of 5% soda solution are heated at 80~ for 8 h, the mixture
is cooled, and the precipitate filtered off and dissolved in water with heating. This
solution is acidified to pH 4-5 by the addition of H=SO~ and the resulting precipitate is
filtered off and crystallized from water. Yield, 1.3 g. M + 187.
l-Methyl-4-hydroxy-3-nitropyrazole-5,carboxylic Acid (VI)is obtained in an analogous
way to compound IV.
4-Amino-l-methyl-5-nitropyrazole-3-carboxylic acid (IX). 2.5 g (0.01 mole) of acid I
and 0.4 g CuBr are heated in aquous a.....,onia
. 30 ml of 25% to IO0~ in an autoclave and kept
at this temperature for two hours, then cooled and evaporated down to a volume of i0 ml and
acidified with acetic acid to pH 4-5. The precipitate is fil~tered off and recrystallized
from acetic acid. Yield, 1.56 g.
l-Methyl-4-morpholino-5-nitropyrazolecarboxylic acid (X). 2.5 g (0.01 mole) of compound
I and 0.4 g CuBr in 50 ml of 30% aqueous morpholine solution are heated for two hours at
70~ cooled, acidified to pH 4-5 with acetic acid, and extracted with chloroform. After
distilling off the solvent, 1.98 g of compound X are obtained.

LITERATURE CITED

i. A. N. Kost and I. I. Grandberg, Advl. Heterocycl. Chem., 6, 347 (1966).

2. M. D. Coburn, J. Heterocycl. Chem., 8, 153 (1971).
3. C. G. Newton, W. D. Ollis, and D. E. Wright, J. Chem. Soc., Perkin i, 63 (1984).
4. R. G. Johnes, J. Amer. Chem. Soc., 71, 3994 (1949).
5. M. A. Khan and A. A. Pinto, J. Heterocycl. Chem., 18, 9 (1981).
6. S. F. Vasilevskii, E. M. Rubinshtein, and M. S. Shvartsberg, Izv. Akad. Nauk SSSR, Ser.
Khim., 1175 (1978).
7. Yu. A, Manaev, V. P. Perevalov, M. A. Andreeva, and B. I. Stepanov, Khim. Geterotsikl.
Soed., No. 8, 1123, (1984).
8. E. S. Krongaus, D. A. Bochvar, I. V. Stankevich, and V. V. Korshak, Dokl. Akad. Nauk SSSR,
Ser. Khim, 179, 94 (1968).
9. Yu. A. ~naev, M. A. Andreeva, V. P. Perevalov, and B. I. Stepanov, Zh. Org. Khim., 52,
2592 (1982).

267
REACTION OF 1,2-HYDROXYLAMINOOXIMES WITH 1,2-DIKETONES.
COI~ERSION OF 2-ACYL-I-HYDROXY-3-1MIDAZOLINE 3-OXIDES
TO PYRAZINE 1,4-DIOXIDES

L. N. Grigor'eva, A. Ya. Tikhonov UDC 547.288.4'781.3'861:543o422

S. A. Amitina, L. B. Volodarskii,
and I. K. Korobeinicheva

The reaction of acyclic primary and secondary 1,2-hydroxylaminooximes with ali-

phatic, alkylaromatic, and alkylheteroaromatic 1,2-diketones, depending on the
structure of the starting compounds and the reaction conditions, gives derivatives
of pyrazine 1,4-dioxide, 2-acyl-l-hydroxy-3-imidazoline 3-oxide, or mixtures
thereof~ 2-Acyl-l-hydroxy-3-imidazoline 3-oxides have been converted to pyrazine
1,4-dioxides.

It has previously been shown that when2-hydroxyamino-l-phenyl-l-propanone oxime (E

isomer) (Ih) reacts with biacetyl(IIa) inalcohol with heating, 2-acetyl-l-hydroxy-2-5,
dimethyl-4-phenyl-3-imidazoline 3-oxide (IIIh) [ l ] i s formed whereas condensation of alicyclic
1,2-hydroxylaminooximes with 1,2-diketones gives condensed pyrazine 1,4-dioxides [2, 3].
The present work considers the reaction of primary and secondary* acyclic 1,2-hydroxylamino-
oximes I with 1,2-diketones II in order to elucidate the factors that affect the course of
the condensation~

O~ R3 4
R I .~C .~NOH R3 ~ C:'0 H0~N~'C ~C ~I{
H R
H~ I + I ...... -"-
C R 4/C~)
RI .C.. /N~0 "'~---- R2 C--R ~
' R2 / "NItOH 11/C \R2
OH 0
la,c,d,g,h, ~,o lla,b,f,j,k
IIIa~ h-r

0
C~II~S= . .~ ; C41130: I "-., I" ~N~ , ~ 0 1

NO 2" " "" O 1 -~ ~ B

IVa-i, g,m, o,p

a,b,h-k) R I = P h ; c R I = C4H2NO3; d-g) R ~ = CHs; s R I = C4HsS; ~ o-r) R I = C4H30; a-f)

R 2 = H, g-r) R 2 = CH3, a,d, g,h, ~,o) R 3 = CH3; f,i,m,p) R 3 = Ph; j,n,q) R 3 = C~H3S, k, r)
9R 3 = C~H30; a,d,f-r) R 4 = CH3; b,c) R 3 + R ~ = (CH2)4o
In contrast to the secondary 1,2-hydroxylaminooxime Ih [i], condensation of the primary
2-hydroxyamino-l-phenylethanone oxime (E isomer)(Ia) with biacetyl in alcohol with heating
gives 2,3-dimethyl-5-phenylpyrazine 1,4-dioxide (IVa) in 72% yield, while 2-acetyl-l-hydroxy-
2-methyl-4-phenyl-3-imidazoline 3-oxide (Ilia) was isolated in only 3% yield. ~nen kept in
alcoholic solution at 20 ~ for 6 days compound IIIa is converted quantitatively to pyrazine
1,4-dioxide IVa. Condensation of other primary 1,2-hydroxylaminooximesIc, d with biacetyl

*For brevity, 1,2-hydroxylamino0ximes with a hydroxylamino group at the primary or secondary

carbons are degignated primary or secondary 1,2-hydroxylaminooximes.

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Novosibirsk 630090; Lenin Komsomol Novosibirsk State University, Novosibirsk 630090.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 331-338, March, 1986.
Original article submitted February 15, 1985.

268 0009-3122/86/2203-0268512.50 9 1986 Plenum Publishing Corporation

TABLE i. Spectral Properties of Synthesized 3-1midazoline 3-Oxides and Pyrazine 1,4-Dioxides

spectrum, A max~ IR spec- I spectrum, ppm ( J , H z ) ~

omp am (los ~) trum~ cm-1I R' R:' R'

III a 226 (4,03), 294 (4,22) 1720 ( C = O ) 7,4--7,6, m;8,2--8,4, m 4,49, s 2,31, s 1,78, s 4,49, s
IIii 235 (4,13), 248 (4,18) 1700 ( c = o ) 7,4--7,7, ca; 8,1--8,4, m 1,22, d (7,0) 7,4--7,7, m; 8,1--8,4, m 1,76, s 4,87, q (7,0)
1II J 227 (4,05), 300 (4,43) 1680 ( c = o ) 7 3--7,6, m~ 7,9--8,3, m 1,32, d (7,0) 7,21 d . d (4,0; 5,0): 1,76, s 4,82, q (7,0)
7,3--7,6, m; 7,9--8,3, m
111 k 226 (4,05), 292 (4,39) 16oo ( c = o ) 7,5--7,7, m ; 8,2--8,4, m 1,29, d (7,0) 6,77,d . .d (1,5; 3,8); 1,74, s 4,84, q ' (7,0)
7,5--7,7, m; 8,06, m (1,5)
III ~. 224 (4,03), 320 @20) " 1730 (C ==O) 7,24 d. d (3,0; 4,0); 1,50, d (6,5) 2,26, s 1,59, s 4,64. q ~6,5)
7,6--7,8, m
film 225 (4,8")), 250 (4,96), 1700 ( C = O ) 7,1--8,2, m 1,2~3,,i (7,0) 7,1--8,2, m 1,76, s 4,80, q (7,0)
320 (5,02)
llln 222 (4,06), 270 (4,11), 1670 (C==O) 7,1--7,3, m; 7,6--8,1, m 1,44,d (7,0) 7,1--7,3, m; 7,6--8,1, m 1,71, $ 4,70, q (7.0)
314 (4,18)
1Iio 307 (4,28) 1735 ( c : - o ) 6,70, d , d (2,0; 3,5); 7,79, m t,54,d (7,0); 1,59, d 7,0 2,19, ~ 2,24 s 1,60, $; 4,50, q (7,0);
1,69, 4.54, q (7,0)
IIIP 247 (4,14), 308 (4,34) 1635 ( c = o ) 6,76 d. d (2,0; 3,5); 1,39: :[:, d (7,0); 1,59, d 7,5--8,2,m 1,72 4,63, q (7,0)
7,5--8,2, m (7,0) 1,78, s
lllq 30.3 (4,34) 1660 ( c = o ) 6,72 d . d (1,8; 3,5); 1,37: * , d (7,0); 1,64, d 7,4--8,2, m 1,81 4,63, q (7,0)
7,4--8,2, m (7,0) 1,84, s
11 l r 304 (4,44) 1690 ( c = o ) 6,7--6,8, m; 7,73, d (3,5); 1,49, d (7 O) 6,7--6,8, m; 7,51, d(3,5): 1,67, s 4,58, q (7,0)
7,9--8,1, m 7,9--8, l, m
IVa 263 (4,56), 314 (4,21) 1360 7,4--7,9, m 8,40, s 2.52 2,52
IVc. 236 (4,20), 268 (4,11), 1350, 1360 7,4--8,0, m 8,66, s 1,87, 2,gO b r . s
318 (4.40). 344 (4,31)
['0
.,j
0

TABLE 1 (continued)
IVd 236 (4,45), 303 (4,35) 1345, 1355 2,51, c 8,50, 2,58 2,58
IVf 237 (4,22), 247 sh(4,04), 1310, 1355 2,53, c 8,62, s 7,4--7,8, m 2,29, s
309 (4,27)
IVh i241 (4,37), 2 5 0 s h ( 4 , 2 7 ) , 1320 7,46, m 2,22, ~ 2,52, s 2,56, s
308 (4,37)
IV i 238 (4,32), 260 (4,33), 1305, 1320 7,49, c 2,4t, s 7.49, s 2,41, S
316 (4,34)
IV s 241 (4,25), 267 (4,09), 1320 7,16, d : d (4,0; 5,2); 2,57, s 2,57, s 2,57. s
298 (4,39) 7,32, d~d (I,4; 4~0);
7,69, d , d ' {1,4; 5,2)
2,36, s
[Vm~ 241 (4,32), 303 (4,43) 1310, 1325 7,1--7,7, m 2,68, s 7,48, s
2.58, s
tVo 239 (4,16), 267 (4,21), 13i0, 1330 6;64, d. d ( 1,4; 4,0) ; 7,49, d 2,66, s 2,58, s
294 (4,45) (4,0); 7,67, d (1,4) 2,16, s
2,53, s 7,47, s
tVP 238 (4,18), 275 sh(4,24), t310 6,69, d. d (1,4; 4,0); 7,30, d
300 (4,41) (4;0); 7,95, d 0 , 4 )

*Compounds l!lo,p,q are mixtures of diastereomers.

tP~fR spectra of llli-r and IVc,p were recorded in (CD3)2S0; of Ilia, IVa, h in CDaOD; of IVd,f in D20; of
IVi,~,m,o in CDCIs. OH signals in spectra of llli, j, k, m, m, p, r appear at 9.36, 9.30, 9.17, 9.40,
9.26, 9.32, 9.03 ppm.
~Signals of the diastereomer of the predominant c o m p o u n d .
 TABLE 2. Properties of Synthesized Compounds

oC Found,
% , [Calculated, % Yield,%%%
Compound

IC 155--1561 36,2 3,5 2 0 , 6 1 - C6ttTN3Os 35.8 I 3,5 20,91 - - 49

Is AcOH 150--1511 43,7 5,8 11.41 13,1 C9HI4N204S 43.~ I 5,8 11.41 13,0 51
IO , AcOH 163--164147,3 6,4 1 2 , 5 1 - CgHI4N2Os 47.01 6,0 12,21- 60
ilia 142--1441 62,0 6,1 1 2 , 1 1 - CIzHI4N2Oa 61,51 6,0 12,01 - - 3
iIIi ]5]--152~ 70,1 5,7 9,31 CisHlsN~03 69.7 I 5,9 9.01 - - 77
nx~. 162--1641 62,4 5,4 9.41 11,21 C~sHjBN20~S 62,515,5 9.71 11,I 59
14()--|4~1 63,8 5,2 q.4, - - Cz~H~N204 64.01 6,4 9.3 t - - 80
Ill ~-
III~ 163--1641 51,8 5,3 I0,91 12,81
187--1;~91 60,1 5,4 8.81 9,7j
C.Hf4N20~S
CIsHI6N203S
,52.01 5,5
60.1 I 5,1
11.01 12,6l
u.;~l 9 6
57
69
Illm
IIIn 175--1761 52,2 4,4 8.71 19,91 CI4HI4N203S2 52,214,3 8 71 1~,9 47
IIio 1 3 4 - - 1 3 b l 56,2 5,9 11,41 - - C.,HI4N204 55.51 5,9 11.7 [ 48
IIIp 170--1721 64,2 5,5 9.41 - - C,~Hi6N204 64.01 5,4 9.3 I 83
iltq 151--1521 55,4 4,8 q.m 10,6 CI4HI4N20.IS 55.014,6 9,2 I IO~5 51
IIIr 132--1341 58,3 4,9 9.~ I - - CI4HI4N2Os 57.91 4,9 q 71 -- 73
IVO !4~--|4u~ 66,1 5,6 1 3 . 4 1 - C12HI2N20~ 66.71 5,6 13.01 72
IVc 206--2091 51,5 3,9 1 5 , 2 1 - CI2HHNaO~ 52,01 4,13 15,1[ Z I 71
IVd 136--1371 54,2 7,0 18,(51- , CTHIoN202 54.5 I6,5 18,2J -- I 82
IVf
IVb~
169--1701 66,9 5,6 12,91 - - I
184--1851 67,6 6,0 12.11 - - I
C,2HI~N~Oe
CIsHw4N20~
66.7 I 5,6
67.81 6,1
13,01
12,21
Z ] 60
14
IVX 185--1861 74,3 5,6 ~ 1 - - C~sH~6N~O~ 74.01 5,5 9.6t - - , 60
129--1301 56,7 5,t 12,01 13,4 CnH,~N~O~S 56.01 5,1 ll,81 t3,61 57
IV~
IVo
| 4 7 - - 1 4 ~ t 64,5 4,7 u-a, 10,6
124--1251 59,6 5,6 1 2 . 6 1 -
C~6H.~N~O~S
C.H~2N~O~
154.bl 4,7
60.01 5,5
u_4 J
12.71
10,71
--
38
31
Wp 151--1531 67,5 5,0 9.61 -- CI~HI~N=Oz 68.01 4,9 9.91 16

*Compounds IIio, p, q are i:i, 5:1, and 4:1 mixtures of dia-

stereomers.
tCompounds Ic, s o llli,j,k,m,p,q,r, and IVc, i,p were puri-
fied by crystallization from alcohol; l l l ~ n , o and IVf,h,s
from ethyl acetate; IVa,d from dioxane.
~Yields of pyrazine 1,4-dioxides obtained by condensation are
given.

lla, cyclohexanedione-l,2 (llb), and l-phenyl-l,2-propanone (llf) gave derivatives of pyrazine

1,4-dioxide, IVc-f (Tables i and 2). Possiblyderivatives of III are intermediates in these
cases.
It can be presumed that the pyrazine 1,4-dioxides IV and the 3-imidazoline 3-oxides III
form via the intermediate acyclic nitrone A [3]. Compound Ill in turn can be converted re-
versibly through nitrone A to dihydropyrazine B, which then dehydrates irreversibly to
pyrazine 1,4-dioxide IV.
In order to find the intermediates by PMR and UV spectroscopy we studied the reaction of
1,2-hydroxylaminooxime Id with biacetyl lla. The PMR spectrum of 0.5 M solution of Id and
biacetyl in CDaOD at 20 ~ , 3 min after preparation, showed (along with the spectra of the
starting compounds) a singlet at 1.41 ppm (see [I]) that can be assigned to the protons of
the methyl at position 2 of 2,3-imidazoline 3-oxide, llld. With time, signals appear at 2.40,
2.55, and 8.38 ppm that correspond to pyrazine 1,4-dioxide IVd (see Table i). The imidazoline:
pyrazine ratio was 4:1 after 20 min, 1:3 after 7 h, and after I day the reaction llld + IVd
was complete. The UV spectra of the reaction mixture obtained by pouring aliquots of 0.01 M
1,2-hydroxylaminooxime Id in alcohol into 0.4 M biacetyl in alcohol, recorded at 5 min inter-
vals (first spectrum obtained I min after mixing), show no absorption at 260-270 nm that
might be expected for acyclic nitrone A (cf. [4]). This seems to be evidence that nitrone
A is rapidly converted to III and IV. The UV maxima at 235 and 303 nm correspond to the
overlap of the absorption maxima of 3-imidazoline 3-oxide (%max ~ 235 nm, cf. [5]) and
pyrazine 1,4-dioxide (Xmax 236, 303 nm).
Thus in the study of the reaction of Id with lla by UV and PMR spectroscopy, only the
formation of llld was recorded, and this is converted relatively quickly to IVd. The relative-
ly greater stability of Ilia, which has aphenyl group at position 4, over that of llld is
apparently due to the conjugation of the benzene ring with the nitrone group (cf. [6]).

271
It should be noted that the relative stability of III should also depend on the ease of con-
version of the intermediate acyclic nitrone A to the pyrazine 1,4-dioxide IV.
In contrast to the secondary alkylaromatic !,2-hydroxylaminoo~Ime Ih the condensation of
the aliphatic 3-hydroxyamino-2-butanone oxime (Ig) with IIa gives the 2,3,5,6-tetramethyl 1,4-
dioxide (IVg) [7]. Study of the composition Of the products of the reaction of lh with
biacetyl when heated in alcohol showed that along with the diastereomeric 3-imidazoline 3-
oxides, IIIh (72% yield), pyrazine 1,4-dioxide IVh forms in 14% yield. When the reaction is
carried out with heating in an acetic acid--alcohol mixture the yield of IVh increases to 60%.
Condensation of the acetate salts of 2"hydroxyamino-l-(thienyl-2)-(I%) and 2-hydroxyamino-l-
(furyl-2)-(Io) l-propanone oximes with biacetyl in alcohol with heating gives the diastereo-
meric 3-imidazoline 3-oxides (IIIZ,o)*; when acetic acid is added, the predominant products
are the pyrazine 1,4-dioxides IVs along with a small amount of the 3-imidazoline 3-oxides
IIIl,o. From the data we can presume the conversion of the 3-imidazoline 3-oxides, IIIh,%,o,
to the pyrazine 1,4-dioxides IVh,%,o, by the action of acetic acid. Indeed upon prolonged
heating in alcoholic solution in the absence of acetic acid, 3-imidazoline 3-oxide IIIh was
separated unchanged. Only when heated in acetic-acid--alcohol mixture were IIIh,% converted
to IVh,~ in 57 and 34% yields, respectively.
Thus the 3-imidazoline 3-oxides IIIh, i with a methyl in position 5 of the imidazoline
ring are converted to the pyrazine 1,4-dioxides IVh,s under more severe conditions than the
3-imidazoline 3-oxide IIIa which has no substitue~t at position 5; this is evidently due to
the stabilizing effect of the methyl group in IIlh,Z [8].
In contrast to biacetyl, l-phenyl- and l-(heteroaryl-2)-l,2-propanediones (IIf,J,k) do
not react with the secondary 1,2-hydroxylaminooximes Ih, Z,o when heated in alcohol~ The
condensation could be carried out at room temperature b y the addition of acetic or tri-
fluoroacetic acid, to form 3-imidazoline 3-oxides llli,j,k,m,n,p,q,r.
The IR spectra of these compounds have the conjugated carbony! band at 1680-1700 cm-1;
in the PMR spectra the singlet in the 1.65-1.85 ppm region should be assigned to the protons
of the methyl group at position 2 of 3-imidazoline 3-oxide. From these data we can assign
the 3-imidazoline 3-oxides the structures of 2-benzoyl- (Illi,m,p), 2-(furoyl-2)-(Illk,r),
and 2-(thenoyl-2-(IIlj,n,q)3-imidazoline 3-oxides.* Thus the condensation of 1,2-hydroxyl-
aminooximes Ih, Z,O proceeds selectively at the acetyl group of the !-pheny!- or l-(hetero-
aryl-2)-l,2-propanediones IIf,j,k.
When the condensation of Ih,s with IIe is carried out at the boiling point of an
alcohol--acetic-acid mixture, a mixture of pyrazine 1,4-dioxides IVm,p and 3-imidazoline 3-
oxides IIIm,p or exclusively pyrazine 1,4-dioxide IVi. Under the same Conditions 3-imidazo-
line 3-oxide IIIm is converted to pyrazine 1,4-dioxide IVm in 34% yield; if trifluoroacetic
acid is used instead of acetic, the conversion of IIIi to IVi goes more smoothly, with 94%
yield.
The pyrazine 1,4-dioxides IVi,m obtained by condensation of 1,2-hydroxylaminooximes
Ih,Z with l-phenyl-l,2-propanedione (IIf), or by conversion of the 3-imidazoline 3-oxides
IIIi, m, areidentical in IR spectrum. Consequently the phenyl and heteroaryl groups of IVi,
m,p are located at positions 2 and 6 of the pyrazine ring. The pyrazine 1,4-dioxide IVi that
we isolated (with mp 185 ~ was isomerized to the previously described 3,6-dimethyl-2,5-di-
phenylpyrazine 1,4-dioxide (with mp 249 ~ [7]). Analogously pyrazine 1,4-dioxide IVf was
assigned the structure of 2,5-dimethyl-3-phenylpyrazine 1,4-dioxide [7].
Information on the synthesis of pyrazine 1,4-dioxide derivatives without usingoxidation
could not be found in the literature [9].
Thus condensation of primary 1,2-hydroxylaminooximes with 1,2-diketones inalcohol with
heating gives principally derivatives of pyrazine 1,4-dioxide. In the case of the secondary
alkylaromatic and alkylheteroaromatic 1,2-hydroxylaminooximes, condensation with biacetyl
forms predominantly derivatives of 2-acetyl-3-imidazoline 3-oxide. In the presence of acetic
acid the condensation of secondary alkylaromatic and alkylheteroaromatic 1,2-hydroxylamino-

*We did not separate or determine the configuration of the diastereomers.

272
oximes with biacetyl gives principally pyrazine 1,4-dioxides. The reaction of the secondary
alkylaromatic and alkylheteroaromatic 1,2-hydroxylaminooximes with l-phenyl- and l-(heteroaryl
2)-l,2-propanedione goes only in the presence of acetic or trifluoroacetic acid and at 20 ~
gives derivatives of 2-benzoyl- and 2-(heteroaroyl-2)-3-imidazoline 3-oxides; with heating
it gives pyrazine 1,4-dioxides. The 2-acyl-3-imidazoline 3 oxides are converted to pyrazine
1,4-dioxides by prolonged holding of the alcoholic solution, or by heating in the presence of
acetic acid.

EXPERIMENTAL

IR spectra were recorded in KBr on a UR-20 instrument; UV spectra in alcohol on a

Specord UV-VIS spectrometer. The condensation of 1,2-hydroxylaminooxime Id with biacetyl
in alcohol was studied by UV spectroscopy in a Beckman DU-8 spectrometer. PMR spectra were
recorded on a Varian A-56-60A instrument (60 ~ z ) f o r 7-10% solutions, with HMDS internal
standard. 1,2-Hydroxylaminooximes la,d,g,h were obtained according to [10-12].
The spectral properties of compounds III and IV are shown in Table i, and those of com-
pounds Ic,~,o in the Experimental section following. The physicochemical properties of Ic,
4,o,111, and IV are shown in Table 2.
Acetate Salt of 2-Hydroxylamino-l-(thienyl-2)-l-propanone Oxime (I~-AcoH). To a solu-
tion of hydroxylamine (obtained by neutralizing a solution of 69.5 g (I000 mmoles) of hydrox-
ylamine hydrGchloridein 250 ml of methanol with an equimolar amount of sodium methylate in
200 ml of methanol) are added 15 ml (250 mmoies) of acetic acid and 21.9 g (i00 mmoles) of
2-bromo-l-(thienyl-2)-l-propanone and the mixture is boiled for 4 h . The methanol is evap-
orated, 50 ml of water is added to the residue, the precipitate of ls is filtered off
and washed with water and ether. There is obtained 12.6 g Of l~-AcoH. UV spectrum, %m-x
270 nm (log ~ 4.13). PMR spectrum, 6 (in DMSO-D6): 1.27 (3H, d, J = 6.5 Hz, CH3), 1.8~
(3H, s, CH3), 4.19 (IH, q, J = 6.5 Hz, CH), 6.9-7.3; 7.6-7.8 ppm (5H, m, C4H3S, NH, OH).
Acetate Salt of 2-hydroxyamino-l-(furyl-2)-l-propanone oxime (lo~ was obtained
in analogous manner. UV spectrum, %max 266 nm (log s 4.26). P~m spectrum (in CD3OD):
1.37 (3H, d, J = 7.0 Hz, CH3), 1.96 (3H, s, CH3), 4.37 (IH, q, J = 7.0 Hz, 5), 6.55 (IH,
d.d, J = 1.8 and 3.5 Hz, 4-H), 7.44 (IH, d, J = 3.5 Hz, 3-H), 7.59 ppm (IH, d, J = 1.8 Hz,
5-H).
2-Hydroxyamino-l-(5-nitrofuryl-2)ethanone Oxime (Ic). To a solution of hydroxylamine
(obtained by neutralizing a solution of 3.80 g (60 mmoles) of hydroxylamine hydrochloride
in 30 ml of methanol with an equimolar amount of sodium methylate in 20 ml of methanol) was
added a solution of 1.20 g (6 mmoles) of 2-bromo-l-(5-nitrofuryl-2)ethanone oxime [13] in
40 ml of methanol at i0 ~ and the mixture was held for 0.5 h. The methanol was evaporated,
the residue was treated with water, and the precipitate was filtered off. It was mixed
with 3 ml of 3% hydrochloric acid and filtered. The filtrate was neutralized with 20%
potassium hydroxide solution, and the precipitate of compound Ic was filtered off, leaving
0.59 g. UV spectrum, Xma x nm (log E): 234 (3.91), 342 (4.13). PMR spectrum (in DMSO-D6):
3.87 (2H, s, CH2), 7.37 (IH, br. s, OH), 7.52 (IH, d, J = Hz, 3-H or 4-H) 7.76 (IH, d, J =
4.0 Hz, 3-H or 4-H), 12.41 ppm (IH, br.s, =NOH).
Condensation. of Primary 1,2-Hydroxylaminooximes Ia,c,d with 1,2-Diketones IIa,b,f. A
mixture of 6 mmoles of 1,2-hydroxylaminoo~ime and 7mmoles of 1,2-diketone in i0 ml of methanol
was boiled for 0.5-3.0 h (monitored by TLC). The methanol was evaporated and from the ether-
treated residue pyrazine 1,4-dioxides IVa,c-f were separated. From the filtrate after re-
moval of IVa there were separated by silica gel chromatography the 3-imidazoline 3-oxide IIIa
(ether eluent) and an additional amount of IVa (9:1 ether:methanol eluent). IVb was separated
by silica gel chromatography (ether eluent). The IR spectra of compounds !Vb,e were the
same as those of authentic samples [14, 15]. mp IVe 184-186 ~ (from alcohol), according to
[2], mp 180-181~ mp IVb 159-161 ~ (from alcohol), according to [3], mp 153~155~ mp IVf
169-170 ~ (from alcohol), according to [7], mp 165 ~ .
2~3~5,6-Tetramethylpyrazine 1,4-Dioxide (IVg). A solution of 1.04 g (8.8 mol~s) of 1,2-
hydroxylaminooxime Ig and 1.03 g (12 mmoles) of biacetyl in I0 ml of methanol was left at
20 ~ for 18 h. The methanol was evaporated. The residue was treated with an ether--ethyl-
acetate mixture to separate 1.08 g (73%) of IVg, mp 215-216~ according to [7], mp 220 ~ .

273
 Condensation of Secondary 1,2-Hydr@xYlaminooxi~es lh,~,o with Biacetyl. A. A solution
of i0 mmoles of i,2 hydroxylaminooxime lh or the acetate salts IE,o.AcCH and ii mmole of
biacetyl in i0 ml of alcohol was boiled for 4 h. The alcohol was evaporated. Treatment of
the residue separated the 3-imidazoline 3-oxides lllh,E,o. Silica gel chromatography of the
filtrate yielded additional lllh (ether eluent) and pyrazine 1,4-dioxide IVh (acetone eluent).
IR spectrum and mp of lllh were identical with those described in [i].
B. A solution of 5 mmole of lh or the acetate salts IE,o.AcOH and i0 mmoles of biacetyl
in a mixture of I0 ml of alcohol and 3 ml of acetic acid was boiled for 6 h, then evaporated.
Silica gel chromatography of the residue gave III~ (3%), IIio (3%), and the pyrazine 1,4-
dioxides IVh (59%), IV~ (57%), IVo (31%) (ether eluent).
Condensation of Secondary l~2-Hydroxylaminooximes l~h~E~o with l-phenyl-and l-(heteFo-
aryl-2)-l,2-propanediones llf,j,k. A. A solution of 4 mmoles of the acetate salt l~,o*AcOH
and 4 mmoles of l-phenyl- (llf) or l-(thienyl-2)-(llj) 1,2-propanedione in a mixture of 40 ml
of alcohol and 6 ml of acetic acid was left at 20 ~ for i day. T h e solvent was evaporated,
the residue was treated with ether, and the precipitate of 3-imidazoline 3-oxide lllm,n,p,q
was filtered off. The filtrate was evaporated, the residue was neutralized with sodium
hydroxide solution, and additional lllm,n,p,q was separated by chloroform extraction.
B. A solution of 5 mmoles of lh or the acetate salt lo.AcOH and 5 mmoles of l-phenyl-
(llf),l-(thienyl-2-)-(llj), or l-(furyl-2)- (Ilk) 1,2-propanedione in 20 ml of alcohol and
0.5 ml of trifluoroacetic acid was left at 20 ~ for 1-2 days (monitored by TLC). The alcohol
was evaporated, and treatment of the residue with ether gave llli,j,k,r.
C. A mixture of 3 mmoles of lh or IE,o.AcOH and 3 mmoles of l-phenyl-l,2-propanedione
(llf) in a mixture of 5 ml of alcohol and 5 ml of acetic acid was boiled for 2 h. The
solvent was evaporated, and the residue was diluted with 5 ml of water, neutralized with
sodium bicarbonate, and extracted with chloroform. The chloroform solution was washed with
water, dried with sodium sulfate, and evaporated. Silica gel chromatography of the residue
(ether eluent) separated 3-imidazoline 3-oxides lllm (3%) and lllp (9%), and pyrazine 1,4-
dioxides IVi (60%), IVm (38%), and IVp (16%).
Conversion of2-Acyl-l-hydroxy'3-imidazoline 3-Oxides llla,h,i,m to Pyrazine 1,4-Dioxides
IVa,h,i,m. A. A solution of 0.i0 g (0.42 mmole) of lla in 7 ml of alcohol was held at
room temperature for 6 days. The alcohol was evaporated, the residue was treated with ether,
and the precipitate of IVa was filtered off. Weight 0.075g (81%).
B. A mixture of 0.124 g (0.5 mmole) of lllh in 5 ml of alcohol and 0.03 ml of acetic
acid was boiled for 1.5 h. The solvent was evaporated and the residue Was treated with
ether. The precipitate of IVh was filtered off. Weight 0.06 g (57%).
C. A solution of 0.5 g (1.6 mmoles) of llli in 5 ml of alcohol and 0.5 ml of trifluoro-
acetic acid was boiled for 3 h, then evaporated. The residue was treated with ether, and the
precipitate of IVi was filtered off. Weight 0.44 g (94%).
D. A mixture of 0.32 g (i mmole) of lllm and 8 ml of acetic acid was boiled for 7 h.
The solvent was evaporated, 4 ml of water was added and the mixture was neutralized with
sodium bicarbonate and extracted with chloroform. The chloroform solution was washed with
water, dried with sodium sulfate, and evaporated. Silica gel chromatography of the residue
separated 0.01 g (33%) of IVm (ether eluent). Under the same conditions, from IIIE there
was obtained IV~ in 34% yield.

LITERATURE CITED

I. I. A. Grigor'ev, G. I. Shchukin, S. A, Dikanov, I. K. Kuznetsova, and L. B. Voiodarskii,

Izv. Akad, Nauk SSSR, Ser. Khim., No. 5, 1092 (1982).
2. L. Bo Volodarskii, S. A. Amitina, and N. V. Dulepova, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. 4, 904 (1979).
3. L. N. Grigor'eva, S. A. Amitina, and L. B. Volodarskii, Khim. Geterotsikl. Soedin., No.
i0, 1387 (i~83).
4. D. St. C. Black and A. B. Boscacci, Aus. J. Chem., 29, 2511 (1976).
5. S. A. Amitina and L. B. Volodarskii, Izv. Akad. Nauk SSSR, Ser. Khim., No. 9, 2135
(1976).
6. L. B. Volodarskii and A. Ya. Tikhonov, Zh. Org. Khim., 6, No. 2, 307 (1970).

274
 7. B. Klein and J. Berkowitz, J. Amer. Chem. Soc., 81, 5160 (1959).
8. R. E. Walter, Ring-Chain Isomerism in Organic Chemistry [Russian translation], Zinatne,
Riga (1978), p. 180.
9. G. B. Barlin, in: A. Weissberger and E. C. Taylor, editors, The Chemistry of Hetero-
cyclic Compounds, Vol. 41, Interscience, New York (1982), p. 59.
i0. A. Ya. Tikhonov and L. B. Volodarskii, USSR Inventor's certificate No. 977,453; Byull.
Izobret., No. 44, 93 (1982).
!I. Yu. G. Putsykin and L. B. Volodarskii, Izv. Akad. Nauk SSSR, Ser. Khim. Nauk, No. 6, I01
(1968).
12. L. B. Volodarskii, V. A. Koptyug, and A. N. Lysak, Zh. Org. Khim., 2, No. I, 114 (1966).
13. E. E. LiepinWsh, and N. O. Saldabol, Zh.- Org. Khim., 17, ~No. 3, 521 (1981).
14. V. A. Koptyug (editor), Atlas of Spectra of Aromatic and Heterocyclic Compounds fin
Russian], NovosibirskInst. Org. Chem., Siberian Br., Academy of Sci. USSR, Novosibirsk
(1978), No. 15, p. 146.
15. V. A. Koptyug (editor), Atlas of Spectra of Aromatic and Heterocyclic Compounds [in
Russian], Novosibirsk Inst. Org. Chem., Siberian Br., Academy of Sci. USSR, Novosibirsk
(1983), No. 26, p. Iii.

STUDIES OF IMIDAZO[I,2-a]BENZIMIDAZOLE DERIVATIVES.

21.* SYNTHESIS OF HALOKETONES IN THE D(IDAZO[I,2-a]
BENZ~IIDAZOLE SERIES

V. A. Anisimova, T. B. Korochina, UDC 547.785.5.04:542.944

N. I. Avdyunina, and A. M. Simonov

Methods for the synthesis of imidazo[i,2-a]benzimidazole haloketone derivatives

have been investigated. It has been found that ~-bromoketone derivatives of this
heterocycle can be prepared either by bromination of 3-acylimidazo[l,2-a]benz-
imidazoles with bromine in glacial acetic acid or by acylation of 3-unsubstituted
imidazo[l,2-a]benzimidazoles withhaloanhydride derivatives of ~-bromoalkanoic
acids. Treatment of imidazo[l,2-a]benzimidazoles with 3-chloropropionyl chloride
results in the formation of imidazo[l,2-a]benzimidazolyl-3-propionyl chloride and
bis(imidazo[l,2-a]benzimidazolyl)propan-3-one derivatives as side products. Re-
action of 2-phenylimidazo[l,2-a]benzimidazoles with 3-bromopropionic acid in poly-
phosphoric acid gives benzocyclohepten[5',6':4,5]imidazo[l,2-a]benzimidazole deriv-
atives.

Haloketones are widely used as synthons for the preparation of aminoalcohols, aminoke-
tones, and heterocyclic and other compounds. In order to expandthe synthetic possibilities for
the preparation of biologically active compounds in the imidazo[l,2-a]benzimidazole series,
we have been studying various methods for the preparation of haloketone derivatives of this
heterocyclic system.
One of the most common methods for the synthesis of ~-haloketones involves the direct
halogenation of ketones. All efforts to brominate ketones I directly failed, either with
N-bromosuccinimide in CC14, in the absence of a catalyst or in the presence of benzoyl per-
oxide, or with copper bromide in chloroform or chloroform-ethyl acetate mixtures. When
ketones I were treated with either dioxanedibromide in ether or with dioxane and bromine in
chloroform or methanol, only perbromides of the starting ketones were obtained; these per-
bromides decomposed upon extended refluxing in either water or alcohol, but did not generate
the bromoketones IIas expected (cf. [2, 3], for example).

*For Communication 20, see [i].

Scientific-Research Institute of Physical and Organic Chemistry, M. A. Suslov Rostov

State University, Rostov-on-Don 344090. Translated from Khimiya Geterotsiklicheskikh Soedine-
nii, No. 3, pp. 339-345, 1.~rgh, 1986. Original article submitted January 28, 1985.

0009-3122/86/2203-0275512.50 9 1986 Plenum Publishing Corporation 275

 TABLE i. Bromoketone Derivatives in the Imidazo[l,2-a]benzi-
midazole Series, IIa-h

I
Found, % [ Molecular Calculated, % Yield, %
Com- ~# ~
pound (dec.) C [HIBr N [ formula C [It Br [ N A B

II a 187-.-188 58,6 3,7 21.31 11,61 CIsI'{I4BrNaO 88,7 3,8 21,7 11,4 77 89--93*
lib 164--165 50,914,11 26,61 13,61 ClaHi2BrNaO 5o,r14,ol 26:1 ~3,rl 68 91--95"
1[c 59,5[4,3[ 20.91 11,21 CigHleBrNaO 59,7 [ 4,21 20,91 ] 1,o I 7o
lid 64,614.1[ 18.41 9.81 C=4Hf~BrNaO 64,9t4,11 18,01 9,5165
l i e 195--196 61,615,0[19,1110,01 C=IH2oBrNaO 61,5]4,9[ 19,5[ 10,2[ 82 9~
llf 52:614,4] 24.71 13.01 CI4HI~BrNaO 52,514,41 25,11 13,11 81'=
llg 60,0 4,1 [ 21,4 10,7 C,9l-llsBrNaO 59,7 4,2 20,9 11,0 ~,8 84*
11 h 137--138 61,4 5,0 19.3 10.4 C=iH2oBrNaO 61,5 4,9 19,5 10,2 -- 90

* ~ e n the acylation reactions werecarried out in benzene, the

yields of bromoketones lla, b, f, and g were 39, 46, 48, and
37%, respectively.

R2 . ~,. .~C0CH2R 4 C0CHBrR 4 COCBr2R ~

+ I.HBr
R~~ > . . N ~ N ~ . . R ~ c,,cooH ~N~..R~ 9 R3

la-g -~(e~c lla-h llla-h

l
# 2-3Br 2 \ x=B,c,
R2

N I

IIIa,b IVa-j
l--IVa'b,f,g R I= CHa, c,dRI= CH~C6Hs, e,j R l= C~Hs, h RI= C4Hg,andR i~ CaHT; a_ d
f_ iR~=H,e,fR~=CHa;a,d,e,g-j Ra=C6Hs, b',cRa=CHa; a-c R4=H, t~g R4=CHa

Treatment of ketones I with bromine in glacial acetic acid at room temperature also led
to the formation of perbromides; in refluxing acid, however, high yields of the bromoketones
II were produced (65-80%). The reactions are accompanied by the formation of small amounts
of the hydrobromides of I as well as of the dibromoketones III. The yields of dibromoketones
are increased to 50-89% when the amount of bromine used is increased to 2-3 moles.
The ~-bromoketones II can also be prepared directly by the alkylation of 3-unsubstituted
imidazo[1,2-a]benzimidazoles IV with haloanhydride derivatives of ~-bromoalkanoic acids.
The yields of II do not exceed 40-48% when the reactions are carried out in refluxing benzene,
since half of the starting material is consumed by reaction with the liberated HBr, and
the resulting hydrobromides cannot be acylated under these conditions. It was not possible
to increase the yield of bromoketones using anhydrous potassium hydroxide as an HBr scavenger,
and introductionof either triethylamine or pyridine to the reaction mixtures resulted in
considerable resinification. The yields of compounds II could be increased to 70-90% by
employing high boiling solvents such as toluene or xylene as the reaction medium. In re-
fluxing xylene it is possible to acylate not only the bases IV, but also their Salts; this
is especially convenient in cases where the precursorimidazo[l,2-a]benzimidazole is an oil
(for instance, compound IVh). The IR spectra of the bromoketones II, taken in Vaseline mulls,
exhibit C-Br stretches at 630-640, and C=0 absorption bands at 1630-1645 cm -z.
Haloacylation of compound IVa with 3-chloropropionyl chloride gave a mixture of two
compounds, one of which proved to be the chloroanhydride of imidazo[l,2-a]benzimidazolyl-3-
propionic acid'(Va) (yield about 80%, based on the corresponding acid), whereas the second
has been assigned the ketone structure Via. The IR spectrum of compound Via contains a
carbonyl group absorption band at 1620 cm -z. The PMR spectrum in CF3COOH shows two partially
overlapping three-proton singlets at 3.59 and 3.54 ppm, corresponding to the two N-CHa group
protons. Two slightly broadened signals at 3.22 and 2.65 ppm, with intensities corresponding

276
 TABLE 2. 13-Alkyl-6,7-dihydro-5-oxobenzocyclohept en[ 5 ', 6 ' : 4 , 5 ] i m i d a z o [ i, 2-a] b e n z i m l d a z o l e s
(IXa-e)
IR spec- Found, % Calcd. ," ,%
Com - I~tp~ ~ Ho lecular
spectrum in CDCI 3 9 6, ' M ~
pound (dec.) formula
ppm C H N c H N
chloroform

IXa 227--228 1682 3,62 (3H, s.. N--CHa), 3,15 301 75,8[ 4,6 14,2 ClgHlsN30 75,7 5,0 13,9
(4H, q, --CH2CH~--),
6,88--7,53 (8H, m., Arprotons)
ix b 206--207 1680 1,18 (3H, t , CH3), 3,15 (4H, 315 76,1 5,2 13,6 C20H~TN30 76,2 5,4 13,3
q , --CH2CH2--), 4,12 (2H,
q , N--C H3), 7,25 (8H, m, Ar
protonsJ.
IXc 153 1680 0,62 (3H, t , CH3), 1,62 (2H, 329 76,7 6,0 12,8 C21HIgN30 76,6 5,8 12,8
m, CHiCHi), 3,15 (4H, q, '
--CH2CH~--), 4,0 (2H,t ,
N--CH2).. 7,25 (8H, m, Ar "
protons )
IXd 150 1680 9,52 (3H, t, CH3), l,O (2H, 343 76,8 6,4 12,4 C2~H2,N~O 76,9 6,2 12,2
m., CHsCHs), 1,5 (2H, broad'
signal N--CH2Cfl2),
3,15 (4_H,q , --CH~CH2--),
4,0 (2H, t , N--CH2), 7,25
(8H,m, Arprotons ) .~
IX. e 221--222 1670 1,2 (3Ht t, CH2CH3), 2,06 343 76,9 6,3 12,5 CmH21N30 76,9 6,2 12,2
(6H, s,2CH3), 3,12 (4H, q ,
--CH2CH2--), 4,12 (2H, q ,
N--CH2), 7,06 (2H), 7,25--
7,35 (4H, Arprotons )

t~
to 2 protons apiece, may be attributed to protons in the ethylene bridge. The aromatic
protons (17H) appear as a complex multiplet at 6.92-7.23 ppm, while the signal due to the
ortho-proton of the phenyl substituent appears as a doublet at 8.12 ppm. The reactions of
other imidazo[l,2-a]benzimidazole derivatives IV proceed in an analogous manner.
The acyl halides V can be readily converted to the acids VII or amides VIII by treatment
with solutions of sodium bicarbonate and ammonia, respectively; these compounds are identical
to the derivatives prepared by substitution and addition reactions of compounds IV with
acrylic acid or acrylonitrile in polyphosphoric acid (PPA) [4, 5]. The IR spectra of the
chloroanhydrides V, taken in Vaseline mulls, contain strong absorption bands at 1790-1800
cm -I, corresponding to C=O stretching vibrations; these bands disappear upon conversion to
derivatives VII and VIII.

/ ,'CH2CH2COC1 CH2Clt2C0~

~/ Va,b,c Vla,e
H2CH2COOH ~ CH2CH2CONH
2

CeH5 : ~-~CH3
Vll a,e Villa

The identities of the substituent groups in com-

pounds Va, b, e are the same as those in the
precursor compounds IV.

In the first 10-15 min of the reactions of compounds IV with chloropropionyl chloride,
a large amount of precipitate, consisting of hydrochloride salts of IV, is deposited; this
fact, coupled with the absence of other imidazo[l,2-a]benzimidazole derivatives, leads us
to assume that the starting materials IV act as dehydrochlorinating agents (bases), resulting
in the conversion of chloropropionyl chloride to acryloyl chloride. The ease of addition
of the latter compound to imidazo[l,2-a]benzimidazole derivatives IV, or their salts, has
been demonstrated by independent syntheses. Reaction of compound V with a molecule of
imidazo[l,2-a]benzimidazole, which has not entered into an addition reaction (this is the
basis of the independent synthesis), or attack of the latter reagent by the two reactive
sites in acryloyl chloride (C(I) and C(3)) can generate ketone Vl. The yields of VI are low,
which indicates that the rate of the acyiation sequence is slow relative to the rate of the
addition reaction.
In the case Of 2-phenylsubstituted derivatives of IV, attempts to synthesize ~-haloketones
via reaction with 3-bromopropionic acid in PPA led to yellow colored substances which did
not contain bromine. The IR spectra of these materials, taken in chlDroform, displayed
characteristic bands at 1505, 1600, 1615, 1635 (C=C and C=N) and 1670-1685 cm -I (C=O)~ The
PMR spectra, taken in trifluoroacetic acid, exhibited in all cases a quartet at 3.15 ppm,
with an integrated intensity corresponding to 4 protons; this signal may be ascribed to the
--CH2--CH=-- group. Based on thisspectroscopic data, as well as elemental analysis, molecular
weight data (obtained by mass spectrometry), and comparison with compounds obtained upon
heating 2-phenylimidazo[l,2-a]benzimidazolyl-3-propionic acids in PPA at II0-120~ [5], the
compounds noted above have been assigned structures IX, i.e., benzocycloheptene[5',6':4,5]
imidazo[l,2-a]benzimidazole oxo derivatives.

-r,l o
IVa,e,h-j

vI, IVa-e

IX a-d R2=H, e R2=CHa; a RI=CHa, b;e., RI=C2H~, c RI=CaHT, d RI=C4H9

278
 Treatment of 2-phenylimidazo[l,2-a]benzimidazoles IV with 3-bromopropionic acid in PPA
results, first of all, in alkylation of the heterocyclic ring at position 3, followed by
intramolecular acylation of the ortho phenyl substituent in the 2-position. It was not
possible to isolate the intermediate acids VII, apparently because the rate of formation of
these acids under the reaction conditions is considerably slower than the rate of the sub-
sequent intramolecular cyclization. W h e n t h e analogous reaction was carried out with the
2-methyl substituted derivative IVb, 2,9-dimethylimidazo[l,2-a]benzimidazolyl-3-propionic
acid was isolated in low yield; this compound was unchanged by heating in PPA even u n d e r
much harsher reaction conditions (130-1500C).

EXPERIMENTAL

IR spectra were taken on a UR-20 spectrophotometer using either Vaseline mulls or

solutions in chloroform; PMR spectra were recorded on Tesla BS-467 (60 MHz) or Tesla BS-487
C (80 MHz) spectrometers using solutions in either deuterochloroform or trifluoroacetic acid
versus HMDS as internal standard. Molecular weights were determined by mass spectrometry
on an MU-1305 spectrometer at an ionizing current of 60 eV. The course of the reactions, as
well as purities of the products, were monitored by TLC on Kl2Os with chloroform or benzene
as eluent and visualization with iodine vapor in a moist cell.
9-Butyl-2-phenylimidazo[!,2-a]benzimidazole (IVh). A hot solution of 9.45 g ( 5 0 m moles)
of 2-amino-l-butylbenzimidazole in i00 ml of acetone"was treated with i0 g (50 mmoles) of
phenacyl bromide; the mixture was carefully stirred and allowed to stand at room temperature.
After I h the precipitate of 2-amino-l-butyl-3-phenacylbenzimidazole was removed by filtra-
tion and washed with acetone. Yield 18.1 g (93%). Snow-white crystals, mp 212-213~ (from
alcohol). IR spectrum: 1490, 1600 (C=C), 1670 (C=N), 1690 (C=O), 3160, 3300 cm -~ (NH~).
Found: C 58.7; H 5.8; Br 20.3; N 10.6%. C~gH21N30.HBr. Calculated: C 58.8; H 5.7; Br 20.6;
N 10.8%.
A mixture of 16.8 g (42 mmoles) of the above bromide, 8.9 g (84 mmoles) of sodium car-
bonate, i00 ml ethanol, and 50 ml water was refluxed for 4-5 h. The alcohol was evaporated,
and compound IVh was extracted from the residue with chloroform (3 x 15 ml). The extract
was dried over anhydrous sodium sulfate, solvent was evaporated, and 12.96 g (quantitative
yield) of compound IVh was obtained as a viscous yellow 0il, which was used without further
purification. If necessary, it could be purified by column chromatography on A1203 (benzene
eluent). IR spectrum: 1500, 1605, 1630 cm -~ (C=C, C=N). Found: C 78.7; H 6.5; N 14.7%.
C~gHIgN3. Calculated: C 78.9; H 6.6; N 14.5%. The hydrochlorides salt of IVh was prepared
by acidification of an ethanolic or acetone solution of the free base with conc. HCI. Snow-
white crystals, mp 207-208~ (from alcohol). Found: C 70.1; H 6.0; CI 10.5; N 12.8%.
C19HIgN3.HCI. Calculated: C 70.0; H 6.2; CI 10.9; N 12.6%.
9-Methyl-3-propionyl-2-phenylimidazo[l,2-a]benzimidazole (Ig). A mixture of 1.24 g
(5 mmoles) of compound IVg, i g fused sodium acetate, and 7 ml propionic anhydride was
refluxed i h, cooled, and poured into 30 ml of water. After decomposition of excess anhydride,
the mixture was neutralized with ammonia to pH 7-8 and extracted with chloroform (2 i0
ml). The latter was evaporated, and the residue was treated with i0 ml of ether. The pre-
cipitate was filtered and washed with ether. Yield 1.4 g (92.1%). Snow-white crystals, mp
145-146~ (from alcohol). IR spectrum: 1490, 1585, 1624 (C= C, C=N), 1646 cm-1(C=O). PMR
spectrum (80 MHz, CF3COOH): 0.67 (3H, t, C--CH~), 2.25 (2H, q, CH2), 3.62 (3H, s, N--CH3),
8.32 (IH, d and 7.25 ppm (8H, s, aromatic protons). Found: C 75.0; H 5.7; N 13.8%.
C~gHITNsO. Calculated: C 75.2; H 5.7; N 13.9%. Ketone Ig could also be prepared in 13%
yield by reaction of propionic acid (i0 mmole) with compound IVg (1.24 g, 5 mmole) in PPA
(12 h, ll0~
3-u-Bromoacylimidazo[l,2-a]benzimidazoles (lla-h~ Table i). A. A solution of i0 mmole
of the appropriate ketone la-h in 30 ml glacial acetic acid was heated to II0-I15~ stirred
vigorously, and a solution of 1.6 g (0.5 ml, i0 mmole) of bromine in 3 ml of glacial acetic
acid was added slowly, at such a rate that the solution decolorized immediately and bromine
did not accumulate in the reaction mixture. After addition was complete the mixture was
stirred an additional 5-10 min and then poured onto 150 ml of cold water. The resulting
precipitate was filtered, washed with water, and dried, then subjected to preliminary purifica-
tion through a small layer of A1203 (CHCI3 eluent); the light yellow fraction was collected
(Rf ~0.85-0.9)and crystallized from the solvent of choice: bromoketones lla, b from benzene,
lla,c,f-h from alcohol, lld,e from DMF. Recrystallization of compounds lla and b permitted
separation by crystallization from the corresponding dibromoketones.

279
 B. An energetically stirred solution of I0 mmole of compound IVa, b, e-h or a suspension
of the corresponding hydrochloride in 60 ml of absolute xylene was heated at 120-130~ and
treated with 20 m mole of bromoacetyl halide or 2-bromopropionic acid, and the reaction mix-
tures were stirred until the reactions were complete (TLC control). The reactiontime depends
primarily on the structure of the haloanhydride used. After being cooled, the mixture was
filtered to remove precipitate, which was washed with xylene and petroleum ether, dried in
air, and suspended in water for reaction with either sodium hydroxide solution or ammonia
to neutrality. The precipitate was separated, dried in air, and treated several times with
diethyl ether to remove traces of IV, then finally recrystallized from the appropriate
solvent.
3-Dibromoacetyl-9-methyl-2-phenylimidazo[l~2-a]benzimidazole (Ilia). A refluxing
solution of 2.89 g (I0 mmoles) of ketone la in 30 ml CH3COOH was treated dropwise with
stirring with 4.8 g (1.5 ml, 30 mmole) of bromine in 5 ml CH3COOH; the mixture was re-
fluxed an additional h, cooled, and poured onto i00 ml of water. The resulting precipitate
was filtered and washed with water. Yield 4 g (89%). Pale yellow crystals, mp 245.5~
(dec., from butanol). IR spectrum (CHCI3): 645 (CBr2), 1500, 1590, 1625 (C=C, C=N),
1645 cm-~(C=O). PMR spectrum (80 MHz, CF3COOH): 3.69 (3H, s, N--CH3), 5.7 (IH, s, CH),
8.25 (1H, d and 7.33 ppm (SH, s, aromatic protons). Found: C 48.5; H 2.8; Br 35.9; N 9.3%.
C~aHI3Br2N30. Calculated: C 48.4; H 2.9; Br 35.7; N 9.4%.
3-Dibromoacetyl-2,9-dimethylimidazo[l,2-a]benzimidazole (lllb), This was prepared
in 52% yield by bromination of ketone Ib (i0 mmole) with bromine (20 mmole) in refluxing
acetic acid. Pale yellow crystals mp 216-218~ (from butanol). IR spectrum (CHCI3):
645 (CBr2), 1510, 1595, 1620 (C=C, C=N), 1640 cm -~ (C=O). Found: C 40.1; H 2.9; Br 41.0;
N 10.8%. C~3H~IBr2N30. Calculated: C 40.5; H 2.9; Br 41.5; N 10.9%.
Reaction of 9-Methyl-2-phenylimidazo[l~2-albenzimidazole (IVa) with 3-Chloropropionyl
Chloride. A solution of 1.24 g (5 mmoles) of compound IVa in 25 ml of absolute xylene
was treated with stirring with i ml (about l0 mmoles) of chloropropionyl chloride and the
mixtures was refluxed for 2-3 h. The mixture was cooled and the precipitate of chioro-
anhydride hydrochloride Va was filtered and washed with petroleum ether until all traces
of chloropropionyl chloride had been removed. After drying the precipitate was suspended
in 20 ml of water, neutralized with sodium hydroxide solution to pH 7, and filtered again.
The dry solid was treated with i0 ml of CHCI3. The acid Vlla remained undissolved and was
separated and washed with CHCI3. Yield 1.28 g (80%) of VIIa, mp 271~ (dec., from D ~ ) .
IR spectrum (Vaseline mull): 1500, 1608, 1630 (C=C, C=N), 1690 (C=O), 920, 2400-2800 cm -I
(OH). PMR spectrum (60 MHz, CF3COOH): 3.62 (3H, s, N-CH3), 2.55 (2H, t, CH2), 3.25 (2H,
t, CH2) 7.15 ppm (9H, m, aromatic protons). Found: C 71.4; H 5.7; N 13.1%, C19HITN302.
Calculated: C 71.4; H 5.4; N 13.2%. The compound was identical in all respects to a
sample prepared earlier [5].
The residue which remained after evaporation of the chloroform solution after separa-
tion of acid VIIa was purified by chromatography on a 1.5 cm (diameter) by i0 cm (length)
column (AI=O3, CHCI3 eluent) to remove traces of the acid and then recrystallized from ethyl
acetate to give 0.19 g (13.9%) of ketone Via as snow-white crystals, mp 212-213~ (dec.).
Found: C 76.6; H 5.0; N 15.5%. C35H2sN60. Calculated: C 76.6; H 5.1; N 15.3%.
l~3-Bis(9-Methyl-2-phenylimidazo[l,2-a]benzimidazolyl-3)propan-3-one (Via) (Independent
Synthesis). A solution of 0.75 g (3 mmoles) of compound IVa in 15 ml of absolute xylene
was stirred vigorously at room temperature and 0.3 ml (3 mmoles) of freshly prepared
acryloyl chloride was added; the mixture was stirred until TLC indicated all of the starting
material IVa had been consumed (about 2 h). Another 1.5 g (6 mmoles) of IVa was added to
the reaction mixture, and the mixture was refluxed for 4 h. The mixture was cooled and
the precipitate was filtered and washed with 5 ml of benzene followed by petroleum ether
(2 5 ml). The precipitate was then treated at room temperature with i0 ml of CHCI3 and
the undissolved hydrochloride of IVa was separated by filtration. The chloroform solution
was passed through a layer of A1203 with CHCIs eluent, and the eluate was evaporated and
the residue crystallized from ethyl acetate. Yield 1.28 g (78%) of ketone Via, mp 212-213aC
(dec.), identic~l to the sample prepared as described above.
3-(6,7-Dimethyl-2-phenyl-9-ethylimidazo[l,2-a]benzimidazolyl-3)propanoic Acid (VIIe).
This was prepared in a manner analogous to acid VIIa by refluxing 1.45 g (5 mmoles) of
compound IVe with i0 mmole of chloropropionyl chloride in xylene for 4 h. Yield 1.37 g

280
(76.1%), mp 283~ (dec., from propanol). IR spectrum (Vaseline mull): 1500, 1610, 1630
(C=C, C=N), 1705 (C=O), 920, 2400-2800 cm-~(OH). PMR spectrum (80 MHz, CFsCOOH): 1.16
(3H, t, CH=CHs), 4.0 (2H, q, N-CH2), 2.08 (6H, s, 2 CHs), 2.55 (2H, t, CH~), 3.2 (2H, t, CH2),
7.13 ppm (TH, m, aromatic protons). Found: C 73.3; H 6.5; N 11.8%. C22H2sNS02. Calculated:
C 73.1; H 6.4; N 11.6%.
When 1.45 g (5 mmole) of IVe was heated with 0.7 ml (i0 mmoles)of acrylic acid in
25 ml of PPA (80~ 2 h), acid VIIe was obtained in 95% yield and was identical with respect
to mp and IR and PMII spectra to the sample prepared according to part A.
,3-Bis(6,7-dimethy-2-pheny-9-ethyimidaz[,2-a]benzimidazy-3)prpan-3-ne (Vie).
A. The chloroform solution which remained after separation of acid VIIe from the reaction
mixture of IVe and chloropropionyi chloride wasevaporated until 3-4 ml volume remained and
then passed through a layer of Al20s (CHCI3 eluent). The eluate was evaporated and the res-
idue was recrystallized from acetonitrile to give 0.24 g (15.2%) of ketone Vie as snow-white
fibrous crystals, mp 219-2200C (dec.). IR spectrum (Vaseline mull): 1620 cm -I (C=O).
Found: C 77.5; H 6.4; N 13.4%. C41H4oN~O. Calculated: C 77.8; H 6.4; N 13.3%.
In analogy with the method used for ketone Via, refluxing chloroanhydride Ve, pre-
pared from 0.72 g (2.5 mmoles) of IVe and 0.25 ml (2.5 B o l e s ) acryloyl chloride in 25 ml
xylene, with 1.44 g (5 mmoles) of compound IVe over 5 h gave 1.3 g (82.3%) of ketone Vie,
mp 219-220~ (dec.). A mixed melting point probe with a sample prepared from part A did not
exhibit a m p depression.
3-(2,9-Dimethylimidazo[l,2-a]benzimidazolyl-3)propanamid@ (Vlllb). The chloroanhy"
dride Vb precipitate, isolated by treatment of compound IVb with chloropropionyl chloride
in refluxing xylene, was treated with a 22% solution of NH4OH; the amide was separated, washed
with water, and crystallized from aqueous acetone. Yield 78% mp 234~ (deck. IR spectrum
(Vaseline mull): 1675 (C=O), 3160, 3370 cm -I (NH2). Found: C 65.4; H 6.5; N 21.9%.
C14H~N40. Calculated: C 65.6; H 6.3; N 21.9%.
A solution of 1.85 g (i0 mmoles) of compound IVb in 30 g PPA was heated to 125-130~
and 0.7 ml (i0 m moles) of acrylonitrile was added with stirring; the mixture was heated at
this temperature for 3 h, an additional 0.7 ml of acrylonitrile was added, and the mixture
was heated for 4 h. The mixture was cooled to 50-60~ and poured with vigorous agitation
into 60 ml of cold water. The resulting solution was carefully neutralized with 22% aqueous
ammonia to pH 7. After 30-40 min the precipitate was filtered and washed with water. Yield
2.4 g (93.8%), mp 234 ~ C(dec.).
3-Aky-6,7-dihydr-5-xbenzcychepten[5,6:4,5]imidaz[,2-a]benzimidazes (!Xa-e,
Table 2). A. A stirred mixture of 5 mmoles 9-alkyl-2-phenylimidazo[l,2-a]benzimidazole (IVa,
e, h-i), 1.53 g (i0 mmoles) bromopropionic acid, and 25 g PPA was heated for 3-4 at i00-i05~
and then at II0-120~ until the reaction was complete (3-4 h, TLC control). The mixture was
cooled to 40-500C and poured with vigorous agitation into 75-100 ml water; the mixture was
then basified to pH 8-9 with 22% NH~OH solution, and the resulting precipitate was filtered,
carefully washed with water, dried in air, and finally purified by recrystallization from
alcohol. Yield 90-95% of ketones IXa-e. Compounds IXa and IXc were identical to those
described in an earlier work [5].
A mixture of 0.72 g (2 m moles) of acid VIIe in i0 g PPA was maintained at 120-125~
for 1 h. The hot reaction mixture was poured into 40 ml of cold water, and ketone IX e
was separated and i s o l a t e d i n amanner analogous to that described in part A. Quantitative
yield.
A mixture consisting of 1.65 g (5 mmoles) of the hydrochloride of IVh, 0.7 ml (i0
mmoles) of acrylic acid, and 25 g PPA was stirred at 120-1250C for 3 h, and ketone IXd was
isolated from the reaction mixture as described in part A. It was purified by passage
through a layer of A1203 in chloroform solution, and then recrystallized from alcohol.
Yield 90%. The sample was identical with a sample prepared in part A.
3-(2~9-Dimethylimidazo[l,2-a]benzimidazolyl-3)propanoic Acid (VIIb). A mixture of
0.92 g (5 m moles) compound iVb, 1.53 g (I0 mmoles) 3-bromopropionic acid, and 15 g PPA was
stirred at I15-120~ for 28 h. The mixture was cooled and poured into 50 ml of water, then
neutralized with NH~OH to pH 7. The resulting oily material was separated and treated with
7 ml chloroform. The undissolved sample of acid VIIb was separated and crystallized from

281
DMF. Yield 0.18 g (15%), mp 250-251=C (dec.). Found: C 65.1; H 6.2; N 16.4%. C~H1sNsOa.
Calculated: C, 65.4; H 5.9; N 16.3%. The compound was identical to ~ha~ described in [5],

LITERATURE CITED

i. Yu. A. Zhdanov, G. V. Kovalav, V. A. Anisimova, A. A. Spasov, N. I. Avdyunina, V. G.

Alekseeva, E. A. Korol', I. L. Barchan, I. D. lonov, and V. V. Shaidrov, Khim-farm. Zh.,
No.4, 412 (1985).
2. K. W. Rosenmund and W. Kuhehenn, Chem. Berg, 56, 2042 (1923).
39 S . M . McElvain and L. R. Morris, J. Amer. ~ Chem. See., 74, 2659 (1952).
4. V. A. Anlslmova, L. I. Zhurkina, and N. K. Chub, USSR Inventor's Certificate No. 904, 296;
Byull. Izobr., No. 30 (1982).
5. V. A. Anisimova, L. I. Zhurklna, and N. K, Chub~ Khim. Geterotsikl. Soedin., No. 2,
271 (1983).

REACTION OF N-AMINOBENZIMIDAZOLIUM CATIONS WITH AROMATIC

ALDEHYDES. SYNTHESIS OF 2,4-DIARYL-as-TRIAZINO[I,6"a]
BENZIMIDAZOLES

V. V. Kuz'menko, T. A. Kuztmenko, UDC 547.785.5'873'571:542.953.4:543.422

and A. M. Simonov

On heating with aromatic or heteroaromatie aldehydes in polar aprotic solvents,

l-amino-3-alkylbenzimidazolium salts form 2,4-diaryl derivatives of a new hetero-
cyclic system of as-triazino[l,6-a]benzimidazole.

The reaction of l-amino-3-alkylbenzimidazolium salts (I) with aromatic aldehydes in an

alcoholic medium leads to the usual Schiff base analogs II i~ high yields [i]. We found
that in boiling DMFA, DMSO, orHMPTA, at 150~ this process is more complex in character and
is accompanied by the formation of 2,4-diaryl derivatives of a new heterocyclic system -- as-
triazino[l,6-a]henzimidazole (III). With ketones and 2-methyl derivatives of salts I, the
reaction does not proceed. According to our data, examples of this type of transformations
are not known for N-amino derivatives of heterocycles. The present work was undertaken to
establish the structure of compounds III and the factors influencing their formation (the
structural features of cations II, temperature conditions, basicity of medium).
Examination of the PMR spectra of the non-salt-like bright-yellow compounds, which we
isolated, showed clearly that at one of the reaction stages, salts I undergo dealkylation
(absence of signals in the absorption region of the aliphatic protons in the spectrum of
Ilia). Moreover, the more simple in character spectra of the model compounds lllb,c, obtained
from salts la,c with anisaldehyde, unequivocally indicated that compounds III include two
aldehydic residues in their composition. This was confirmed hy the data of the elemental
analysis and mass spectrometric determination of the molecular weight. In the PMR spectrum
of compound lllb two singlets of the methyl group are observed in the region of 3~ and
3.75 ppm, four doublets of the aromatic protons at 6.82, 6.90, 8~ and 9.0 ppm, with SSCC
(spin--spin coupling constant) of 9.0 Hz, which are assigned to ortho- and meta-protons of
two benzene rings, and also two multiplets of the benzimidazole ring protons in the region
of 7.35 and 7.90 ppm

Scientific-Research Institute of Physical and Organic Chemistry, M. A. Suslov Rostov

State University, Rostov-on-Don 344006. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 3, pp. 346-351, March, 1986. Original article submitted January 9, 1985.

282 0009-3122/86/2203-0282512.50 9 1986 Plenum Publishing Corporation

 TABLE i. l-Arylldeneamlno-3-alkylbenzimidazolium Iodides
IIa-i

Found, % Empirical Calculated, %

Corn- rap,* ~ Yield, %
formula
pound (dec.)
c H I N C H I N

lla 195--19{~ 49,4 4,1 34,8 11,7 C1sHI41N3 49,6 3,9 35,0 I 1,6 98
IIb 228--22g 48,9 4,3 32,2 10,5 CIsHI6INaO 48,9 4,1 32,3 10,7 97
.~.~.c 232--23~ 51,4 4,9 29,9 10,0 CzsH2olNaO 51,3 4,8 30,2 10,0 76
lid'[" 215--216 50,5 4,3 31,5 14,0 C17HtglN4 50,2 4,7 31.3 13,8 96
I~!e 218--219 49,5 4,6 35,0 11,3 C15HIelNa 49,3 4,4 34,8 I 1,5 85
IIt 191-192 45,6 4,0 34,3 11,2 Cl4HvtlNaO 45,8 3,9 34,6 11,4 82
233--234 60,0 4,1 27,3 9,1 C~I-IjsIN3 59.7 3,9 27,5 9,1 89
1ii 233--234 52,4 4,4 32,3 10,6 CI7HjsINa 52,2 4,6 32,5 10,7 87

*Compounds lla,e,g,i are crystallized from alcohol, llb,c

from butanol, lid from acetic acid, llh from DMFA.
%The compound was obtained in glacial acetic acid.

R 1. ..:5"- R R ~ . ... . 11 R1 ~?-

R2 "/
g,t /
9
"" N " I
- DMF - ~"
R2"
L'J: "" I I"
" I3 .
1~
.
"~
- Ar

I " 9t~Y ,-- N N

1 R * 1I " ~'Eh

R'. Y'"I NJ cno Ar Ill Ar

R z "~ "NIIN ~Cll?cr

glll

I-III a-d, f-i R = CH3, e R = C2Hs; a,b,d-h R I = R 2 = H, c, i R x = R 2 = C H a ; a,e,i Ar =

C~Hs, c.c Ar = D-CHsOC6H4, d Ar = p-(CHa)2NC~H4, f Ar = p-NOaC~H4, g Ar = 5-methylfuryl,
h Ar = 10-Cx4Hg.

However, experimental verification showed that increase in the amount of the aldehyde
introduced into the reaction up to 2 mmoles does not affect the yield of compounds III.
When the known aldimine II is heated in DMFA, it gradually transforms into compound III
(after 4 h, the yield of, for example, Ilia is 17%), i.e., the second aldehydic fragment
necessary for building the molecule of III is formed as the result of direct degradation of
aldimine II. Our assumption that the N--N bond is split was confirmed experimentally, when
deamination products of aldimines II, l-alkylbenzimidazoles, were isolated from the re-
action mixtSre.
The high lability of the N--N bond in the l-aminobenzimidazolium cations was already
previously observed during the thermal rearrangment of l-acylamino-3-alkylbenzimidazolium
salts into l-alkyl-2-acylaminobenzimidazoles [2]. Taking into account the data of the ele-
mental analysis and in analogy with this reaction, the structure of 2,3-diaryl-as-triazino
[2,3-a]benzimidazoles could be ascribed to compounds IIio However, 2,3-diphenyl-as-triazino
[2,3-a]benzimidazole, obtained by an independent method from 1,2-diaminobenzimidazole and
benzil [3], differs in its physicochemical characteristics from compound Ilia.
An important structural feature of N-aminobenzimidazolium cations is the high CH-acidity
of the meso-carbon atom of the heterocyclic ring. This feature imparts a unique imprint on
many reactions of N-aminobenzimidazoles, and has been more than once mentioned in our publica-
tions [4, 5]. There is no doubt that specifically in this case, together with the thermal
instability of the N--N bond in cations II, this factor plays a decisive role in the annelation
of the triazine ring. It can be assumed that the reactive yield IV formed during the de-
protonation of the C(~) atom, intermolecularly attacks the polarized C=N bond of the azo-
methine fragment with the formation of cation V. The cleavage of the N--N bond* in the latter

*If we assume the splitting of the N-N bond in aldimines II and the consequent formation of a
benzonitrile "cation," the existence of the latter in the presence of a base, as indicated
below, is not very probable.

283
leads to splitting off of a molecule of l-alkylbenzimidazole and intermediate Vl, which
cyclizes into a dihydride derivative VII, and aromatizes due to splitting off of an alkane
molecule to form triazinobenzimidazole III

011

N ,~, /' N

Ar Ar Ar N:~
.... 1V IV V
1
Ar
R t,~

. . )... ..... m,- III

- RII
R Dzl)t
N, NIl llN x N
Ii .... Ar
Ar _~
VI ~ [l

This scheme shows that the reaction should be activated in the presence of a base,
favoring the formation of ylide IV, However, on the other hand, it is known [I] that the
action of potassium carbonate on azomethine II in a DMFA solution, even at 50~ causes the
opening of the imidazole ring and leads to hydrazones VIII. We found that successful forma-
tion of triazinobenzimidazoles III depends on the temperature conditions of the reaction
and the basicity of the medium. Thus, in a boiling DMFA, but in the presence of the less
basic triethylamine, the yield of compounds III increases twofold, while hydrazones VIII are
almost not formed. However, in DMFA at 50~ Or in a boiling alcohol, even triethylamine
shifts the reaction totally in the direction of hydrazones VIII. Thus, DMFA plays in the
reaction its conventional role of a high boiling solvent with low solvating power.
In conclusion, we should note that the yield of triazinobenzimidazoles III increases
from 20 to 60% with increase in the acceptor properties of the substituent in the phenyl
ring of the aldehyde, which can readily be explained by the proposed reaction scheme.

EXPERIMENTAL

The IR spectra were run on a UR-10 spectrophotometer, and PMR spectra of a Tesla BS487
spectrometer, with HMDS used as an internal standard. The mass spectra were measured on a
VarianMAT-311A mass spectrometer with a direct introduction of the sample into the ionic
source, accelerating voltage of 3 kV, cathode emission current 300 ~A, ionizing voltage 70 eV.
General Hethod for the Preparation of l-Arylideneamino-3-alkylbenzimidazolium lodides
(II). Equimolecular amounts of l-amino-3-alkylbenzimidazolium iodides (I) and the correspond-
ing aldehydes in alcohol are boiled for 2-3 h. Salts II which separate on cooling are
separated and washed with alcohol. The physicochemical constants of iodides II are given
in Table I.
2,4-Diphenyl-as-triazino[l,6-a]benzimidazole (llla). A solution of 1.8 g (5 mmoles)
of salt lla in 7 ml of DMFA is boiled for 4 h. The solvent is distilled in vacuo, the res-
idue is treated with 20 ml of chloroform, and 0.3 g of l-methylbenzimidazole hydroiodide
is filtered. The latter is treated with a 22% solution of NH4OH, and extracted by chloro-
form, passed through a column with A1203 (chloroform) to yield 0.15 g (42%) of i methyibenz-
imidazole, mp 60-62~ hexane). According to data in [6], mp 60-61~ The chloroform
extract is passed through a column with A1203 (eluent benzene) to yield 0.i g (17%) of com-
pound Ilia. Yellow-green needles, mp 233-234~ (from butanol). PMR spectrum (CDCI3):
7.42 (SH, m~ aromatic protons); 8.1 (2H, m, aromatic protons); 8.33 (2H, q, 4-2VH), and 9.0
ppm (2H, q, 2-2'H). Found: C 78.2; H 4.1; N 17.5%. M + 322. C21HI4N~. Calculated: C
78.3; H 4.3; N 17.4%.
A solution of 0.9 g (2.5 mmoles) of iodide lla and 0.35 ml (2,5 mmoles) of triethyl-
amine (TEA) in 4 ml of DMFA is boiled for 2 h. The solution first becomes red, and the
the color gradually clears up. When cool, the precipitate is filtered and washed with alcohol.
Yield, 0.15 g (38%) yellow-green needles, mp 233-234~ (from butanol).
A solution of 1.37 g (5.0mmoles) of l-amino-3-ethylbenzimidazolium iodide and 0.5
ml (5.0 n~noles) of benzaldehyde in 8 ml of DMFA is boiled for 2.5 h. After cooling, the

284
yellow precipitate is separated and washed with alcohol. Yield, 0.i g (17%). Green-yellow
needles, mp 233-234~ (from butanol). The product does not depress the melting point of a
mixed probe with a sample from experiment A. The filtrate is evaporated in vacuo, and the
residue i s g r o u n d with alcohol. The precipitate of l-benzylideneamino-3-ethylbenzimidazolium
iodide is separated and washed with alcohol. Yield, 0.4 g (22%). Pale-yellow prisms, mp
218-219~ (dec. from alcohol). Found: C 49.1; H 4.7; 1 35.0; N 11.6%. C15HI61N3. Calcu-
lated: C 49.3; H 4.4; 1 34.8; N 11.5%.
2,4-Di(p-methoxyphenyl)-as-triazino[l~6-a]benzimidazole (lllb). A solution of 1.4
g (5.0 m moles) of salt Ib and 0.6 ml (5.0 m moles) of anisaldehyde in i0 ml of DMFA is boiled
for 3 h. After cooling, the precipitate is filtered and washed with alcohol. The precipitate
(0.5 g) is treated with 30 ml of hot chloroform to yield 0.3 g (15%) of iodide lib , pale-
yellow needles, mp 228-229~ (dec. from butanol). The chloroform extract is passed through a
column with AI=O3 (chloroform) collecting a yellow fraction. Yield 0.15 g (16%). Yellow-
green fibrous crystals, mp 201-202~ (from butanol). PMR spectrum (CDCI3): 3.7 (3H, s, OCHa),
3.75 (3H, s, OCH3); 6.82 (2H, d, J = 9.0 Hz, 4-3'H); 6.9 (2H, d, J = 9.0 Hz, 2-3'H); 7.35
(2H, m, aromatic protons); 7.9 (2H, m, aromatic protons); 8.23 (2H, d, J = 9.0 Hz, 4-2'H),
and 9.0 ppm (2H, d, J = 9.0 HZ, 2-2'H). Found: c 72.6; H 4.5; N 14.9%. M + 382. C23HIsN~O2.
Calculated: C 72.3; H 4,7; N 14.7%.
A solution of 0.5 g (1.3 mmoles) of salt lib in 3 ml of DMFA is boiled for 2 h.
When cool, 0.12 g (23%) of the initial salt is filtered, and the filtrate is diluted three
times its volume with water. The mixture is extracted by 15 ml of chloroform and the ex-
tract is purified chromatographically on A1203 (eluent chloroform), collecting the first
fraction. Yield, 0.05 g (20%). Yellow-green needles, mp 201-202~ (from butanol. No
depression of the melting point of a mixed probe with a sample from the preceding experiment
is observed.
2,4-Di(p-methoxyphenyl)-7,8-dimethyl-as-triazino[l,6-a]benzimidazole (lllc). A
solution of 1.5 g (3.6 mmoles) of iodide IIc and 0.7 ml (5.0 mmole) of TEA in 5 ml of DMFA
is boiled for 2 h, and after cooling, 0.13 g (18%) of compound IIIc is filtered. Yellow
prisms, mp 263-264~ (from butanol). PMR spectrum (CF3COOH): 2.18 [6H, s, 7,8-(CH~)2];
3.5 (3H, s, OCH3), 3.6 (3H, s, OCH3); 6.58 (2H, d, J = 9.0 Hz, 4-3'H); 6.8 (2H, d, J - 9.0
Hz, 2-3'H); 7.33 (IH, s, 6-H); 7.73 (IH, s, 9-H); 7.8 2H, d, 9~0 Hz, 4-2'H), and 8.0 ppm
(2H, d, J = 9.0 Hz, 2-2'H). Found: C 73.4; H 5.3; N 13.6%. M+ 410. C25H22N402. Calcu-
lated: C 73.2; H 5.4; N 13.7%.
The filtrate is diluted with 30 ml of water and extracted by 20 ml of chloroform. The
chloroform extract is passed through a column with A1203 (chloroform), collecting the first
fraction. The oily residue after the evaporation of chloroform is dissolved in i0 ml of
acetone, and treated with concentrated HCI to pH i. The precipitate is filtered, washed
with acetone~ and dissolved in 5 ml of water. The solution is neutralized by a 22% NH40H
solution, and the colorless precipitate is separated and washed with water. The yield of
1,5,6-trimethylbenzimidazole is 0.07 g (21%). Colorless needles, mp 145-147~ (from heptane).
PMR spectrum (CDCIs): 2.60 [6H, s, 5,6-(CHa)2]; 3.68 (3H, s, N-CH3); 7.10 (IH, s, 7-H);
7.50 (IH, s, 4-H), and 7.65 ppm (IH, s, 2-H). According to the data in [7], mp 142-143~
A solution of 1.5 g (5.0 mmoles) of salt Ic and 0.6 ml (5 mmoles) of anisaldehyde
in 4 ml of DMFA is boiled for 5 h . The mixture is cooled, and 0.65 g of a precipitate is
filtered. The latter is treated with 20 ml of chloroform, and 0.25 g (12%) of aldimine IIc
is separated. Cream-colored needles, mp 228-229~ (dec., from butanol), identical with an
authentic sample of IIc. The chloroform extract is passed through a column with A1203 and
eluted with chloroform. From the first fraction, 0.12 g of compound IIIc isolated. After
evaporation of DMFA and chromatography of the residue, additional 0.08 g of IIIc are ob-
tained. Overall yield 0.2 g (20%). Yellow prisms, mp 263-264~ (from butanol).
2,4-Di(p-dimethylaminophenyl)-as-triazino[l,6-a]benzimidazole (IIId). A solution of
2.8 g (7 mmoles) of salt IId and 1.0 ml (7.5 rmmoles) of TEA in i0 ml of DMFA is boiled for
2 h. After cooling, 0.35 g of orange precipitate is filtered off. Treatment of the filtrate
by water gives additional 0.06 g of the material. Overall yield, 0.41 g (29%). Orange
prisms, mp 225-226~ (from a mixture of butanol with DMFA). PMR spectrum (CF3COOH): 3.18
[12H, s, 2 N(CH3)2], 7.62 (4H, m, aromatic protons), 8.2 (4H, d, J = 8.0 Hz, 2,4-3'H), 8.5
ppm (4H, d, J = 8.0 Hz, 2,4-2'H). Found: C 73.5; H 5.9% N 20.8%. C25H2~N6. Calculated:
C 73.5; H 5.9; N 20.6%.

285
 2,4-Di(p-nitrophenyl)-as-triazino[l-6-a]benzimidazole (Illf). A mixture of 2.75 g (i0
mmoles) of salt la and 1.51 g (I0 mmoles) of p-nitrobenzaldehyde in I0 ml of DMFA is boiled
for 2 h. The precipitate that separated after cooling, is filtered and washed with alcohol.
Yield, 1.2 g (60%) Bright-yellow crystals, mp > 300~ (from DMFA). Found: C 61.4; H 3.1;
N 20.3%. C=IH~2N60~. Calculated: C 61.2; H 2.9; N 20.4%.
2,4-Di(5-methylfuryl)-as-triazino[l,6-a]benzimidazole (III$). A solution of 0.75 g
(2 mmoles) of salt llg and 0.35 ml (2.5 mmoles) of TEA in 3 ml of DMFA is boiled for 2 h.
After diluting the mixture with water, the product is extracted by 30 ml of benzene, and
then purified chromatographically on Al20s (eluent benzene). Yield, 0.2 g (60%). Orange
crystals, mp 216-217~ (from butanol). Found: C 68.9% H 4.3; N 16.9%. CI~HI4N~02. Calcu-
lated: C 69.1; H 4.2; N 17.0%.
2,4-Di(10-anthracenyl)-as-triazino[l,6-a]benzimidazole (lllh). A solution of 1.15 g
(2.5 mmole) of iodide llh and 0.35 ml (2.5 mmoles) of TEA in 4 ml of DMFA is boiled for 5 h.
After cooling, the solution is diluted twice its volume with water, and the precipitate that
separates is filtered. Yield, 0.4 g (61%). The product is purified on a column with Al=Os
(chloroform, collecting the first fraction. Orange prisms, mp > 310~ (from aqueous DMFA).
Found: C 85.2; H 4.4; N 10.7%. Cs~H~=N~. Calculated: C 85.1; H 4.2; N 10.7.
2,4-Diphenyl-7,8-dimethyl-as-triazino[l,6-a]benzimidazole (llli). A. A solution of
1.6 g (4 mmoles) of salt lli and 0.7 ml (5 mmoles) of TEA in 8 ml of DMFA is boiled for 2 h.
When cool, 0.25 g (30%) of compound llli is filtered. Bright-yellow needles, mp 235-236~
(from butanol). Found: C 78.7; H 5.0; N 15.8% M+ 350. C23H~,N~. Calculated: C 78.9;
H 5.1; N16.0%.
The filtrate is diluted with water (30 ml) and extracted with chloroform to yield 0.15 g
(44%) of 1,5,6-trimethylbenzimidazole.
B. A solution of 1.5 g (5 mmoles) of salt Ic and 0.5 ml (0.5 mmoles) of benzaldehyde
in 3 ml of DMFA is boiled for 3 h. When cool, 0.65 g of a material is filtered, which is
treated with 15 ml of chloroform to yield 0.3 g (15%) of salt lli, mp 231-232~ (dec. from
alcohol). No depression of a melting point of a mixed probe with an authentic sample was
observed. The chloroform extract is passed through a column with A1203 (chloroform), and,
first, a yellow fraction -- 0.2 g (20%) of compound Ilia-- is ~luted. Bright-yellow needles,
mp 235-236~ (from butanol). Further elution with chloroform gives 0.07 g (17%) of 1,5,6-
trimethylbenzimidazole. Weakly rose needles, mp 146-147~ (from heptane).
Benzylidene[o-(N,N-methyl, formyl)]aminophenylhydrazone (Villa). A. A mixture of 0.9
g (2.5 mmoles) of salt lla and 0.35 ml (2.5 =~oles) of TEA in 4 ml of DMFA is stirred for 2 h
at 50~ When cool, the solution is diluted thrice its volume with water, and the precipitate
that forms is separated and purified Chromatographically on a column with Al=Os (chloroform).
Yield 0.4 g (63%). Pale-rose prisms, mp 178-179~ (dec. from butanol), which corresponds
to the data in [i].
B. A mixture of 0.9 g (2.5 mmoles) of bait lla and 0.35 g (2.5 mmoles) of potassium
carbonate in 4 ml of DMFA is boiled for 2 h. The solution becomes first red, and after 50
min, the color clears up. After a threefold dilution with water, the material is extracted
by 20 ml of chloroform and purified as in the preceding experiment. Yield, 0.25 g (40%), mp
178-179~ (from alcohol).
C. A solution of 0.55 g (2 mmoles) of salt lla and 0.28 g (2 mmoles) of TEA in 8 ml of
alcohol is boiled for 6 h. After cooling, the precipitate formed is separated and washed with
alcohol. Yield, 0.3 g (60%). Weakly rose prisms, mp 177-178~ (from alcohol). N o depression
of melting point of a mixed probe with an authentic sample is observed,
p-Methoxybenzylidene[o-(N,N-methyl, formyl)]amino-4,5-dimethylphenylhydrazone (Vlllc).
A suspension of 0.42 g (i mmole) of salt llc and 0.2g (1.5 mmoles) of potassium carbonate in
i0 ml of Water is stirred for 5 min at 800C, whereby the form of the precipitate changes; it
is filtered and washed with water. Yield, 0.25 g (80%). Grayish needles, mp 175-176~C
(from alcohol). IR spectrum (CHCIs): 1670 (C=O), 3260 cm -I (N--H). Found: C 69.8; H 6.8;
N 13.7%. C18H~INsO=. Calculated: C 69.5; H 6.8; N 13.5%.
Benzylidene[o-N,N-methyl,formyl)]amino-4,5-dimethylphenylhydrazone (VIIIi). A suspension
of 1.0 g (2.5 =~oles) of salt lli and 0.5 g (3.6 mmoles) of potassium carbonate in i0 ml of
water is stirred at 80~ for i0 min. When cool, the precipitate is filtered and washed with
water. Yield, 0.7 g (quantitative). The material is purified chromatographically on a column

286
with A1203, collecting the first fraction. Weakly rose prisms, mp 174-175~ (from alcohol).
Found: C 72.4; H 7.1; N 1 5 . 0 % . CzTHgN30. Calculated: C 72.6; H 6.8; N 14.9%.

LITERATURE CITED

i. Y. Tamura, H. Hayashi, Y. Nishimura, and M. Ikeda, J. Heterocycl. Chem., 12, 225 (1975).
2. Y. Tamura, H. Hayashi, J. Minamika~ra, and M. Ikeda, J. Heterocycl. Chem., ii, 781 (1974).
3. A. V. Zeiger and M. M. Joullie, J. Org. Chem., 42, 542 (1977).
4. V. V. Kuz'menko, V. N. Komissarov, and A. M. S ~ n o v , Khim. Geterotsikl. Soedin., No. ii,
1497 (1981).
5. V. V. Kuz'menko, T. A. Kuz'menko, and A. M. Simonov, Khim. Geterotsikl. Soedin., No. 2,
25b (1983).
6. A. F. Pozharskii and A. M. Simonov, Zh. Obshch. Khim., 33, 179 (1963).
7. A . M . Simonov, A. F. Pozharskii , and V. M. Marianovskii, IndianJ. Chem., 5, 81 (1967).

FORMATION OF 4,5-DIHYDRO-I,2,4-TRIAZOLES DURING REARRANGEMENT

OF O-ACETYL DERIVATIVES OF 1,2-HYDROXYLAMINOHYDRAZONES AND
THIOSEMICARBAZONES

N. V. Belova, L. B. Volodarskii, UDC 547.288.3.4'792:543.422

and A. Ya. Tikhonov

Acylation of phenylhydrazone, semicarbazone, and thiosemicarbazones of 1,2-hydroxyl-

amino-ketones containing a hydroxylamine group at the tertiary carbon atom, by
acetic anhydride, leads to products of O-acylation at the hydroxylamine group,
which in alkali medium rearrange to form 4,5-dihydro-l,2,4-triazoles.

It has already been discovered that oximes of 1,2,(O-acylhydroxylamino)ketones, contain-

ing an acyloxyamino group at the tertiary carbon atom, split off a molecule of a carboxylic
acid by the action of alkali and rearrange into 4,5-dihydro-l,2,4-oxadiazoles [i].
In the present work, we have studied the action of alkali on the hydrazones of the same
1,2-hydroxylamino-ketones to verify the generality of the rearrangement discovered. From the
1,2-hydroxylamino-ketones la-c, we synthesized a phenylhydrazone lla, semicarbazone Ilia,
and thiosemicarbazones (IVa-c). Their acylation by acetic anhydride smoothly leads to O-
acetyl derivatives Va, Via, and Vlla-c, respectively.

CH CH 3 CH3
[ 3 R2NIiNII~ 1 [ ~ 1 [ OH-
R - - C - C -- N I I O I I " "::~"R - - C - - C - - N H O H R --C--C--NHOCCH. ~.~
[I I 2 II I 2 II I I[
O CH 3 R NHN CH~ R NHN CH3 0
la-c lla, Ilia, IVa-c Va, Via, Vlla-c
CH. Cll.~ H --]
i~ 3 ~ /~ R~ /N.. / C H 3 [ R~
'C~ NH-OAc ~ C "j------~. I NH

x Villa, IXa, Xla-c

a RI=ceHs; bRI=cH3; CR~=CH2CH3
[I, V, VJlI R2=CsHs; Ill, VI, IX R2=CONH2; IV, VII, XI R2=CSNH2

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of

the USSR, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
3, pp. 352-356, March, 1986. Original article submitted January 9, 1985.

0009-3122/86/2203-0287512.50 @ 1986 Plenum Publishing Corporation 287

 TABLE i. Spectral Characteristics of Compounds Synthesized
Ill-IX, XI
,,, , , ,,,,,,, ,,,, ,

IN speetrum
Com- (in XBr),cm-" ~a~, .P PMR spectrum, ppm
pound ( l o g ~)

llla 1685 (C=O) 234 sh(4,09) 1,22 (6I-I,s, CI-13); 7,1--7,6 (sH, m, C6H5)
IVa 2348h(4,10), 1,15 (6H, s)CHs); 7,1--7,4, 7,4--7,6 [6H,"m,C6H5
278 (4,40) NH(OH)]; 5,70, 7,80, 8,00, 8,45 (NH~, NH, OH)
IVc 274 (4,53) 0,99 (3H, t, ]=7,5 Ftt, CH3); 1,14 (6H, s ,;~CH3),
'2,47 (2H,q , ]=7,5 Fa, CH2); 6,94, 757, 8,13, 976
(NH2, NH, OH)
17311 ( c = o ) 271 (4,22), 1,25 (6H, s,CHD; 1,97 {3H, s, CH3); 7,0--7,5
295 (4,03) (10It, ra C6H.~); 7,74, 7,93 (Nit)
Via 1670, 1700, 225 sh(4,15) 1,27 (6H, s, CH3); 2,04 (3H, s, CH3); 7,1--7,3,
1750 (C=O) 7,4--7,6 (5H, m, C~H~) 9
Vlla ! '1730 (C=O) 236 (4,o8), 1,29 (6tt, s., CH3); 2,04 (3H, s , CH3); 7,1--7,3,
279 (4,36) 7,4--7,6 (5I-1, m, Cf,Hs)
Vllb 1730 (C=O) 232 (4,00), 1,27 (3H,S, CH3); 2,01 (3H, s, CH3); 2,07 (3H, s ,
273 (4,46) CH3); 7,84, 8,34, 10,34 (NH2, NH)
Vltc 172o ( c = o ) 2338h(3,98) 3,96 (3H, t, ] = 7,5 Ft~, CH~); 1,24 ( 6 H , s, CH3);
276 (4,44) 1,98 (3H, s, CH3); 2,51 (2H, q . , J=7,5 tiz, CHz);
7,54, 8,04, 8,20, 9,90 (NH~, NH)
Vllla 3330 (NH) 228 (4,29), 11,57 (6H, s,5,5--CH3); 7,2~7,5, 7,6--7,8. (10H, m,
263 sh(3,94}, 1,3-C6H5)
350 (4,08)
IXa 1660 (C=O), 232 (4,24), 1,61 (6H, s , 5,5-CH3); 6,01 (NH2); 7,4--7,6,
3200, 3380, 324 (3,~o) 7,6--7,9 (6I-1, m, 3-CsH5 II NH)
3520 (NH2,
NH)
X[a 3140, 3260, 235 (4,23), 1,94 (6H, & CH~); 7,4--7,6, 7,7--8,0 (5H, m C~Hs);
3380, 3440 342 (4,11) 7,30, 8,12, 8,32 (NHz NH)
(NH~, NH)
XI.t 3160,. 3270, 1238 (4,06), 1,90 (9H, s, 3,5,5-CHa); 7,17, 7,96 (NH2, NH)
3380 (NH2, 297 (4,18)
NH)
XI 3170,3280, 237 (4,07), 1,09 (3H, t , I=7,5 Hz, 3-CH2CH~); 2,19 (2H, q ,
3390 (NH2, 295 (4,18) ]=7,5Hz , 3-CH2CHs); 6,97, 7,64 (NH2, NH)
NH)

*UV spectrum of lla, %ma~, nm (log ~): 269 (4.26), 294 (4.00).
%The PMR spectra of IVa,c, Vllb,c, IXa, Xla-cwere recordedin
(CDs) 2SO, of Ilia, Via, Vlla in CD3OD, of Villa in CDCI3.

TABLE 2. Data of X3C NMR Spectra of Compounds III, IV, VII-IX,

X (in DMSO)

Conl-
pound
RI C~N A- CH,~ R2
I

IIIa 127,8, 129,1, 132,0 154,8 or 156,0 61,4 23,7 154,8 or 156,0
IVa 127,6, 129,3, 131,5 158,0 61,6 23,8 t77,8
Vlla* 127,5, 129,4, 131,2 155,7 61,7 24,0 178,1
VlIla 128,9, 129,1, 129,7 148,7 83,1 27,1 116,9, 120,1,
(in 125,8, 145,8
acetone) 148,7 or 154,9
IXa 125,9, 127,6, 128,4, 148,7 or 154,9 79,3 27,0
130,0
Xla 126,4, 128,4, 130,7 150,0 81,9 27,1 172,5
Xlb 11,4 150,8 80,9 26,8 171,5
Xlc 10,5. 19,1 155,2 80,9 26,8 171,8

*The signals for the acetoxyl group are observed at 19.1 (CH3)
and 169.9 ppm (C=O).

288
 TABLE 3. Characteristics of Compounds Synthesized If-IX, XI

Found, % Empirical Calculated, % Yield,

Com- oc formula
pound rap, %
H N S C H N

Ila 120--122 71,8 7,2 15,8 -- C,~H,gNsO 71,4 7,1 15,6 63

Ilia 145--146 I 55,5 7,2 23,2 Cl,IJl~N402 55,9 6,8 23,7 70
IVa 201--203[ 52,2 6,4 22,1 I~'/4 C,,I116N4OS 52,4 6,5 22,2 12,7 95
IVc 127--129[ 41,6 8,6 27,0 15.4 CTH,6N4OS 41,2 8,0 27,4 15,7 63
Va 95--97 ] 69,1 7,0 13,7 C,sH2,N~O2 69,4 6,8 13,5 70
Via 108--109J 55,8 6,5 19,9 C,sHIsN4Os 56,1 6,5 20,1 71
Vlla i68--170 I 52,9 6,1 19,2 10.6 C,3HIsN402S 53,0 6,1 19,1 98
126--128 41,1 6,5 23,9 13,6 CsH,6N402S, 41,4 6,9 24,1 13,8 78
120--122[ 43,3 7,5 22,5 13,1 CgHIsN402S 43,9 7,4 22,8 13,0 76
Villa 113--1151 76,4 6,6 16,5 CI~HIrN3 76,5 6,8 16,7 67
IXa 162--164 I 60,6 6,5 25,7 C.HI4N40 60,5 6,5 25,7 46
XIa 134--135J 56,4 6,1 23,7 13,,6 CHHI4N4S 56,4 6,0 23,9 59
Xlb 186--188 42,0 7,2 32,5 18,1 C6HI2N4S 41,8 7,0 32,6 18,6 30
Xlc 149--151 44.7 7.6 30.1 17,1 CTH,4N4S 45,1 7,5 30,1 17,2 71

*Compound la was crystallized from aqueous alcohol; Ilia and

IVa from alcohol; IVc and Xla,c from ethyl acetate, Villa from
hexane; Va, Via, and Vlla-c by reprecipitation from chloroform
by hexane; IXa and Xlb were purified chromatographically.

The presence of a stretching vibration band of the C-O bond in the 1720-1750 cm -I region
in the IR spectra of compounds Va, Via, and Vla-c (Table I) correlates with the fact that
they are products of acylation at the oxygen atom of the hydroxylamino group (cf. [I].
When the solution of O-acetyl derivative of phenylhydrazone Va in dioxane was treated
by aqueous sodium hydroxide, a solid crystalline product Villa was isolated in a ~70~ yield,
with an elemental composition (Table 3) corresponding to a split off of a molecule of acetic
acid from V a . In its IR spectrum in CC14, there is a band at 3380 cm -~ (NH), while the UV
s p e c t r u m is similar to the UV spectrum of the known 5,5-dimethyl-l,3,4-triphenyl-4,5-dihydro-
1,2,4-triazole [2]. These data, and also the signal at 83.1 ppm observed in the ISC NMR
spectrum (Table 2), characteristic for 4,5-dihydro-l,2,4-triazoles [3], permit us to ascribe
the structure of 5,5-dimethyl-l,3-diphenyl-4,5-dihydro-l,2,4-triazole to compound Villa.
Under similar conditions, the O-acetyl derivative of semicarbazone Via converts into
5,5-dimethyl-l-carbamoyl-3-phenyl-4,5-dihydro-l,2,4-triazole (IXa) (Table 1-3).
In a similar treatment of solutions of O-acetyl derivatives of thiosemicarbazones Vlla-c,
compounds Xla-c were isolated (Tables 1-3). In the IR spectrum of compound Xla (in CC14),
in addition to the band at 3380 cm -I, two bands are observed at 3240 and 352U cm -~, assign-
able to the stretching vibrations of the N--Hbonds. In the IR spectra of compounds Xla-c
(in KBr), an intense absorption band is observed in the 1340-1360 cm -~ region, which in its
position is similar to the C=S group vibration band in thioamides, thiosemicarbazides [4, 5],
and triazolinetriones [5], and is absent in the IR spectra of 4,5-dihydro-l,2,4-triazoles
Villa and IXa.
To explain the rearrangement, it can be assumed that initially compound X, containing
an aziridine ring is formed (cf. [6]), with subsequent cleavage of the C2-C 3 bond and the
formation of the R=N--~ bond.
It should be noted that the action of alkali on compounds Vlla-c leads in practically
all cases to the formation of deacylation products, namely, thiosemicarbazones IVa-c.
According to literature data, 4,5-dihydro-l,2,4-triazoles are formed during the condensation
of amidrazones with aldehydes and ketones [3, 7], or by cycloaddition of nitrilimines to
imine derivatives [8]. No information is available on 4,5-dihydro-l,2,4-triazoles Xa and
Xla-c, containing a carbamoyl or a thiocarbamoyl group as substituents.

EXPERIMENTAL

The IR spectra were recorded on a UR-20 spectrophotometer in KBr tablets or in a CCI~

solution, and the PMR spectra on a Varian A-56/60A spectrometer (60 MBz), using HMDS as
internal standard. The X3C N-MR spectra were r u n o n Bruker HX-90 (22.63 MHz) and Bruker WP-

289
200SY (50.3 MHz) spectrometers for i0-15% solutions. The UV spectra were run in alcohol on a
Specord UV-Vis spectrophotometer. The course of the reactions was controlled on Silufol UV-
254 plates, with development by UV light and iodine vapors.
The spectral characteristics of the compounds synthesized are given in Tables i and 2,
and the physicochemical characteristics in Table 3.
Phenylhydrazone of 2-Hydroxyamino-Z-methyl-l-phenyl-lrpropanone (lla). A 6.6 g (35
mmole) portion of compound la [9] in 60 ml of alcohol is added to a solution prepared by
adding I0 ml of 50% acetic acid to a mixture of 15 ml (153 mmoles) of phenylhydrazine and
132 ml of water. The reaction mixture is stirred to a complete dissolution of la, and then
for another 2 h. The precipitate is filtered, washed with water, and dried. Yield, 6.0 g
of hydrazone lla.
Semicarbazone of 2-hydfoxyamino-2-methyl-l-phenyl-l-propanone (Ilia). A mixture of 1.9
g (25 mmoles) of semicarbazide and 5.4 g (25 m m o l e s ) o f la hydrochloride in 40 ml of ethanol
is boiled for 2 h. The alcohol is evaporated, the residue is dissolved in 30 ml of water,
1.7 g (12.5 mmoles) of potassium carbonate are~added, and the mixture is extracted by ethyl
acetate. The ethyl acetate solution is dried over magnesium sulfate, and evaporated, Yield,
4.8 g of semicarbazone llla.
Thiosemicarbazone of 2-hydroxyamino-2-~ethyl-3-pentanone (IVc) is obtained in a similar
way from Ic hydrochloride [I0].
Thiosemicarbazone of 3-hydroxyamino-3-methyl-2-butanone (IVb) was obtained according
to [ii].
Thiosemicarbazone of 2-Hydroxyamino-2-methyl-l-phenyl-l-propanone (IVa). A mixture of
5.2 g (33 mmoles) of thiosemicarbazide and 7.1 g (33 mmoles) of la hydrochloride in 50 ml
of ethanol is boiled for i h. The alcohol is evaporated, and the residue is dissolved in 50
ml of water and 2.3 g ~16.5 mmoles) of potassium carbonate are added. The precipitate is
filtered and dried. Yield, 7.9 g of thiosemicarbazone IVa.
Phenylhydrazone of 2-acetoxyamino-2-methyl-l-phenyl-l-propanone (Va). A 0.4 ml (3.9
mmole) portion of acetic anhydride is added to a suspension of 1.0 g (3.7 mmoles) of lla in
20 ml of dry ether. The mixture is held up to the disappearance of phenylhydrazone lla
(TLC control). Ether is evaporated, and the residue is crystallized by grinding in petroleum
ether and filtered. Yield, 0.8 g of the acetyl derivative of Va.
Semicarbazone of 2-acetoxyamino-2-methyl-l-phenyl-l-propanone (Via) is obtained in a
similar way.
Thiosemicarbazone of 3-acetoxyamino-3-methyl-2-butanone (Vllb). ~ A 0.5 ml (5 mmole)
portion of acetic anhydride is added, with stirring, to a suspension of 0.9 g (5 mmoles) of
IVb in 25 ml of dry ether. After 4 h the precipitate is filtered and washed with ether.
Yield, 0.9 g of Vllb.
Thiosemicarbazones of 2-acetoxyamino-2-methyl-l-phenyl-l-propanone and 2-acetoxyamino-2-
methyl-3-pentanone (Vllc) are obtained in a similar way.
5,5-Dimethyl-l,3-diphenyl~4,5-dihydro-l,2,4-triazole (Villa). An 8 ml portion of i N
NaOH is added, with stirring, to a solution of 2.5 g (8 mmoles) of Va in 25 ml of dioxane
and the reaction mixture is held up to the disappearance of the initial Va (TLC control).
Dioxane is evaporated, 30 ml of water are added, and the mixture is extracted by chloroform.
The extract is dried over magnesium sulfate, evaporated, and the residue is crystallized
by grinding in hexane. Yield, 1.2 g.
5,5-Dimethyl-l-thiocarbamoyl-3-ethyl-4,5-dihYdro-l,2,4-triazole (Xlc) is obtained in a
similar way.
5~5-Dimethyl-l-thiocarbamoyl-3-phenyl-4,5-dihydro-l,2,4-triazole (XIa). A 7.5 ml portion
of 1 N NaOH is added, with stirring, to a solution of 2.2 g (7.5 mmoles) of VIIa in 22 ml
of dioxane, and the mixture is held up to the disappearance of VIIa (TLC control). Dioxane
is evaporated ~nd 30 ml of water and chloroform were added. The precipitate of thiosemi-
carbazone IVa, separating at the phase interface of chloroform and water, is filtered.
Yield, 0.34 g of IVa, The chloroform solution is separated, and the aqueous layer is ex-
tracted with chloroform. The combined chloroform solution is dried over magnesium sulfate,
and evaporated. Chromatography of the residue ona column with silica gel (eluent chloroform)
gives 0.9 g of XIa.

290
 Compounds IXa and Xlb are obtained in a similar way.

LITERATURE CITED

i. A. Ya. Tikhonov, N. V. Belova, L. B. Volodarskii, and Yu. V. Gatilov, Zh. Org. Khim.,
21, 196 (1985).
2. R. Huisgen, R. Grashey, R. Kunz, G. Wallbillich, andE. Aufderhaar, Chem. Ber., 98, 2174
(1965).
3. K. N. Zelenin, V. A. Khrustalev, and V. P. Sergutina, Zh. Org. Khim., 16, 942 (1980).
4. P . W . Sadler, J. Chem. Soc., No. 3, 957 (1961).
5. V. I. Kelarev, G. A. Shvekhgeimer, and L. F. Lunin, Khim. Geterotsikl. Soedin., No. 9,
1271 (1984).
6. D. A. Clark, C. A. Bunnel, and P. L. Fuchs, J. Amer. Chem. Soc., i00, 7777 (1978).
7. B. G. Bassar and F. V. Mathis, C. R. Acad. Sci., C, 258, 6470 (1964).
8. J. B. Polya, in: Comprehensive Heterocyclic Chemistry, Vo 5, A. R. Katritzky and C. W
Rees, editors, Pergamon Press, Oxford--New York--Toronto--Sydney--Paris--Frankfurt (1984),
p. 769.
9. L. B. Volodarskii and T. K. Sevastyanova, Zh. Org. Khim., ~, 1687 (1971).
i0. I. A. Grigor'ev, A. G. Druganov, and L. B. Volodarskii, Izv. Sib. Otd. Akad. Nauk SSSR,
Ser. Khim. Nauk, No. 9, 131 (1976).
ii. V. N. Kirichenko, S. V. Larionov, E. G. Boguslavskii, V. I. Lavrent'eva, and L. B.
Volodarskii, Zh. Neorg. Khim., 31, 835 (1986).

QUANTUM-CHEMICAL INTERPRETATION OF RECYCLIZATION REACTIONS.

I0.* PHOTOISOMERIZATION OF SIX-ME~ERED HETEROCYCLES

Yu. B. Vysotskii and L. No Sivyakova UDC 541.141:539.196:547.72'77'78

Singlet photoisomerizations of a number of six-membered heterocycles have been

described on the basis of the index approach in the framework of the coupled
variant of perturbation theory for a one-electron transition density matrix in
the Pariser--Parr--Pople method.

In the preceding investigations of this series we developed a quantum-chemical approach

to the description of the recyclization reactions of molecules with conjugate bonds on the
basis of the coupled variant of perturbation theory. In the case of dark reactions, the
orders of the bonds between not directly bonded atoms of the molecule Pik serve as the re-
activity indices. In the case of photochemical reactions of the X type in Dougherty's
terminology [2J, we obtained [3] more complicated expressions for the reactivity indices
Kik S,T, to which the main contribution is made by the changes in the long-range bond orders
upon excitation of the molecule. This approach was tested in the example of the photochemical
contraction reaction of the furan ring [3] and a number of photoisomerizations of five-mem-
bered heterocycles [i]. In the present work it was extended to the case of singlet photo-
isomerizations of six-membered heterocycles.
i. As follows from Table i, which presents the reactivity indices of singlet photoisom-
erization of zzines, the excitation of the pyridine molecule (I) results in a sharp increase
in the role of the nonclassical structures, particularly of Dewar azabenzene and azaprismane.
This is manifested by the presence of large positive values for K2,~ S and KI,~ S. At the same
time, the sum of these parameters in the first singlet state with the corresponding Pik is
close to zero. This is primarily an indication of the possible strong influence of the
substituents and even of the solvent on the nature of the transition state, and, in the final
*For Communication 9, see [i].
Institute of Physical Organic Chemistry and Carbon Chemistry, Academy of Sciences of
the Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 3, pp. 357-363, March, 1986. Original article submitted December 14, 1983; revision
submitted December 28, 1984.

0009-3122/86/2203-0291512.50 9 1986 Plenum Publishing Corporation 291

 TABLE i. Reactivity Indices of Singlet Photoisomerizations
of Azines Kik S
9" " -77 : --

Compound

Pyridine I--3 -0217 -0,022 0,028

I--4 -0,314 0,322 0,214
2--4 0,051 - 0,076 - 0.041
2--5 -0,338 0,335 0,355
2--6 -0268 0,I 13 0,050
3--5 -0,005 0,081 - 0,039
Pyridinium c a t i o n I--3 - 0,077 - 0,033 0,093
I--4 -0,252 0,238 0,25 l
2--4 0.206 - 0,254 - 0,224
2--5 -0,292 0,322 0,I 17
2--8 -0,279 9 0,408 0,221
3--5 0,055 0,187 -0,180
Pyridazine I--3 -0,082 0288 0,051
I--4 -0,311 0,319 0,183
I--5 0,035 - 0,082 - 0,009
3--5 0,043 -0,013 -0,038
3"6 9- 0,355 0,335 0,575
Pyrimidine I--3 -.0,034 - 0,037 0,091

I--,I -0,3[7 0,326 O, 199

I--5 - 0.022 0,055 - 0,043
2--4 -0,014 0,053 0,048
2--5 -0,341 0,331 0,519
4--6 0,104 -0,183 - 0 , I I0
Pyrazine I--3 0,033 -0,096 0,001
I--4 -0,297 0,307 0,070
2--5 - 0,352 0,360 0,454
2--6 -0,074 0,206 0,004

analysis, it points out the direction of the photoisomerization. In fact, from [4-7] it
follows that the photoisomerization of mono- and dimethylated pyridines in the first singlet
state cannot pass through an intermediate of the azaprismane type with an identical relative
arrangement of the atoms. Thus, while in the 2,3-dlmethylpyridine molecule an intermediate
azaprismane might be formed by the bonding Of atoms 2 and 6, i and 4, and 3 and 5, in the
2,6-dimethylpyridine molecule the isomerization products correspond to the possible formation
of a prismane with bonding between atoms I and 3, 2 and 5, and 4 and 6 [4, 7, 8].
The description of the photoisomerization products of other isomers of dimethylpyridine
requires the introduction of other intermediate states.
SCHEME i

6
9
/.

2
S~ 5@,
6
4

/
9 II

IV

6
) i ~
i
2

1 I
:0: 1
:9
I

292
 Nevertheless, the entire body of existing experimental findings (including those pre-
sented above) can be described with the aid of a bicyclic transition state based on Dewar
azabenzene II (see Scheme i). After the cleavage of the 1--2 or 1-6 bond, structure II isom-
erizes to bicycles III and IV, which, in turn, can be transformed into V or VI and then
into the photoisomerization products. According to the experiments in [5-7], it follows
from Scheme i that 2-methylpyridine and 4-methylpyridine, as well as 2,4-dimethylpyridine
and 2,6-dimethylpyridine, undergo interconversions. The irradiation of 3,4-dimethylpyridine
gives a mixture of the 2,3 and 2,5 isomers, and the irradiation of 2,3-dimethylpyridine and
3,5-dimethylpyridine do not undergo photoisomerization. We also note:that compound II was
isolated as an intermediate during the irradiation of pentafluoroethylpyridine [9] and that
structures of types III-VI are assumed to be transitional structures in the case of the
photohydrogenation of pyridine [4, i0].
We stress that Scheme i is based on the assumption that the initial cyclization of
pyridine occurs at positions i and 4. This assumption corresponds to t h e l a r g e positive
value of KI,~ S (see Table i), which is apparently enhanced to an even greater degree when
methyl groups are introduced into the molecule. As follows from Table i, the isomerization
of pyridine in the $2 state should involve the intermediate formation of a 2--5 bond.
2. Cyclization at positions 2 and 6 and at positions 3 and 5 is most probable for the
pyridinium cation in the first singlet state. This corresponds to the mechanism proposed
in [4, 7]

..... ~ - ------r N Cll.~

N
I t
CH~ CH~ OCH3

3. As follows from a comparison of the Kik S for the diazines (see Table i), in the
lowest singlet state the photoisomerization reactions should be most characteristic of the
pyrazine molecule (VII).

SCHEME 2
{ I
N.. N

t t t t
VIII X

5 6

T I

i
N N

6
.k'Ix 2

LX XIV i~'~/
=_li 84
6 --2J
XVI X"VII

{ { ,
I
1
N~ "~ N,.. a N~. N NT

5
:9 2
:9 3

293
In this case, bonding between atoms 2 and 6 or atoms 3 and 5 (paths a and b in Scheme 2) are
most advantageous for the $I state. All the numerous experimental data [4, 7, 8, ii, 12] con-
form to a scheme including the formation of blcycllc intermediates VIII and IX, which are
transformed in analogy to the five-membered heterocycles into structures X-XVII and then into
the photoisomerization products, viz., pyrimidines and trace amounts of pyridazines. As an
illustration we present only a few of the best known examples of such conversions:

CH 3 N
+ N

CH3 CH 3 CII 3 N
CH 3

Special mention should be made of the fact that one of the products of the last reaction
is 2,6-dimethylpyrimidine (see [8] and the literature cited therein), which conforms to
scheme 2, but was not presented in several reviews [12].
In constrast to the S, state, in the $2 state (see Table i) the pyrazine molecule should
be characterized by the appearance of 2-5 or 3--6 bonds (paths c and d in Scheme 2) with the
subsequent transformation of Dewar diazabenzenes XVIII and XIX into azaprismanes XX and XXI.
The opening of the latter (in analogy to prismane; see, for example, [4]) is followed by the
formation of the corresponding pyrlmidines. There are still no experimental data on the isom-
erization of pyrazine in the S2 state.
4. We shall not dwell on the photoisomerizations in the lowest singlet states of the
pyridazine and pyrimidine molecules that are less characteristic than those of pyrazine (com-
pare the values of the KikS). We shall only note that the mechanism proposed in [13] (see
also [4, 12]) for the photoisomerization of pyridazine (Scheme 3) does not contradict the
positiveness of the sum PI.~ + K~.~ calculated for this molecule (see Table I). In general,
we should again stress the strong dependence of this and other isomerizations with small
absolute values of Pik + Kik S on the nature and positions of the substituents and on the
solvent.

SCHEME 3

~ " ]

From Table 1 it is seen that the first step in the photoisomerizations in the pyridazine
molecule in the $2 state should be bonding between positions 3 and 6 and that the first step
for pyrimidine in the same state should De bonding between positions 2 a n d 5 .
5. In conclusion, we shall mention several photoisomerizations of pyran derivatives.
According to the theoretical data (P2.s =-0.290, K2.5 = 0.326, P2.6 = -0.324, K2.~ = O.431,
P3.5 = 0.061, Ks.5 = 0.202). The excitation of pyrylium cation XXII to the S2 state can
result in the rearragments shown in Scheme 4, a particular direction becoming the main direc-
tion, depending on the positions of the substituents and their character. For example, path
d is predominant in the case of 4-hydroxypyrylium cations, and practically all the presently
known photoisomerizations of these cations give isomers XXIII-XXVI (see [4, I~-18]). In

294
particular, products XXIV and XXV were isolated following the photoisomers of the 2,6-
dimethyl-4-hydroxypyrylium cation [4, 17] (2,4,6-trlmethylpyryllum perchlorate undergoes an
analogous photoisomerization [14]). With respect to products XXIII and KXVI, they were ob-
tained along with substituted furans as a result of the photoisomerization of the 2,3-dlmethyl-
4-hydroxypyrylium cation in concentrated sulfuric acid [18]. It has been suggested that
intermediate XXVII forms in the first step of this photoisomerization. Information on the
photoisomerizations of other derivatives of the 4-hydroxypyrylium cation which also conform
to Scheme 5 is given in [7, 16, 19].

SCHEME 4

XXVIII

,| 6 oC |
k I / "o~
--.. "o~ /
/ I/ D..2J./
"o~'l

" . ' ~

~ 2 6 2 4 3 3 2 5 6

~III XXIV ~LX'X

We note that the first step in the well-known photoisomerization of 4-pyrones to 2-pyrones
is presumably the formation of the corresponding hydroxy form, which is followed by its re-
cyclization according to Scheme 4 [15, 20-22]. In the case of the 2-hydroxypyrylium cation,
path b is predominant (see [15, 17]), and all the isomerization products have structure
XXVIII. Path a in Scheme 4 is not realized in any of the known photoisomerizations of the
derivatives of the pyrylium cation.
We stress that the "pericyclic" rearrangement of the transition states (see the schemes
in the present work and in [i]) has been thoroughly studied and is generally accepted for the
interpretation of both thermal and photochemical isomerizations [4, 20, 23].
The photoisomerization of 2-pyrone under the action of UV light to a B-lactone condensed
with a cyclobutene ring [5, 7, 8, ii, 24-26] is also in good agreement with the data from the
calculation in the framework of the approach developed. For example~ the maximum value of
Kik S corresponds to positions 3 and 6 and is equal to 0.440, which significantly exceeds the
absolute value of P3.6 = --0.311, and thus correctly describes this isomerization (the values
of the sum Pik + KikS for the other positions are small or negative).

SCHEME 5
') .0

fli~o "'2~o argon

go.

295
 It has not been ruled out in this connection that the photolsomerization of the 2-hydroxy-
pyrylium salts can occur with the preliminary formation of 2-pyrones and their further photo-
isomerization.
We note that in the ground state of 2-pyrone, as was noted above, Ps., < 0 and that
cyclization does not take place according to Scheme 5, since P~.s = 0.063 > 0. This, along
with the small values of the bond orders PI.2 (0,325) and P~.s (0.285), suggests the pos-
sibility of the thermal conversion of 2-pyrone into furan (see [ll]).

........ + CO

In the Sz state the 1--2 and 2-3 bonds are somewhat strengthened, although they remain
the weakest bonds, and the order of the 1-3 bond or, more precisely, the value of P,.3 + K1.s S
(0.063 --0.215 = - 0 . 1 5 2 ) b e c o m e s negative, forbidding this rearrangement.
The approach under consideration makes it possible to describe photoisomerizations in
cases in which the heteroatom is located outside of the ring. As an example, we mention the
following reaction [27]:

Cl '~ COOR
~-.-D- RO-
-CI- C -~-O _-.u-_~
ROH

Of course, the possibility that it takes place with the preliminary elimination of the
chlorine atom according to a radical (carbene) mechanism has not been ruled out, but the
presence of very large positive long-range bond orders such as P=.6 = 0.237 and the value
K=.6 S = 0.417 allow us to postulate photoelectrocyclization at positions 2 to 6 as the
first step in this rearrangement.
Thus, the index approach which has been developed for the quantum-chemical description
of recylization reactions may be useful for the interpretation not only of dark, but also
of some photochemical conversions.

LITERATURE CITED

i. Yu. B. Vysotskii and L. N. Sivyakova, Khim. Geterotsikl. Soedin., No. 2, 173 (1986).
2. M. J. S. Dewar and R. ~ Dougherty, The PMO Theory of Organic Chemistry, Plenum, New
York (1975).
3. Yu. B. Vysotskii and L, N. Sivyakova, Zh. Strukt. Khim., 21, 164 (1980).
4. J. A. Barltrop and J. D. Coyle, Excited States in Organic Chemistry, Wiley, New York
(1975).
5. S. T. Reid, Adv, Heterocycl. Chem., ii, i (1970)o
6. S. Caplain and A. Lablache-Combier, Chem. Comm., No. 19, 1247 (1970).
7. A. Lablache-Combier, in: O. Buchardt (editor),Photochemistry of Heterocyclic Com-
pounds, Interscience, New York--London--Sydney--Toronto (1976), p. 207.
8. E. MHller, Methoden der Organischen Chemic (Houben-Weyl). Photochemie, Georg Thieme,
Stuttgart (1975), Vol. i, p. 733; Vol, 2, p. 1675.
. H. G. Barlow, J. G. Dingwall, and R. N. Haszeldine, Chem. Comm., No. 22, 1580 (1970).
i0. K. E. Wilzbach and D. J. Rausch, J. Amer. Chem. Soc., 92, 2178 (1970).
ii, H. C. van der Plas, Ring Transformations of Heterocycles, Vol. 2, Academic Press,
New York (1973).
12. G. W. H. Cheeseman and E. S. G. Weerstink, Adv. Heterocycl. Chem., 14, 99 (1972).
13. D. W. Johnson, V. Austel, R. S. Feld, and D. M. Lemal, J. Amer. Chem. Soc., 92, 7505
(1970).
14. J. A. Barltrop, K. Dawes, A. S. Day, and J. H. Summers, Chemo Comm., No. 22, 1240 (1972).
15. J. A. Barltrop, J. C. Barrett, R. W. Carder, A. C. Day, J. R. Harding, W. E. Long,
and C. J. Samuel, J. Amer. Chem. Soc., i0!, 7510 (1979).
16. J. A. Barltrop, A. C. Day, and C. J. Samuel, J. Am. Chem. Soc., i01, 7521 (1979).
17. J. W. Pavlik and E. L. Clennan, J. Amer. Chem. Sot., 95, 1697 (1973).

296
18. J. W. Pavlik and Ao P. Spada, Tetrahedron Lett., No. 46, 4441 (1979).
19. J . W . Pavlik and R. M. Dunh, Tetrahedron Lett., No. 51, 5071 (1978).
20. R. F. Childs, Tetrahedron, 38, 567 (1982).
21. D. H. R. Barton and L. A. Hulshof, J. Chem. Soc., Perkin II, No. 9, iI0~ (1977).
22. J. A. Barltrop, A. C. Day, and C. J. Samuel, Chem. Comm., No, 17, 598 (1977).
23. A. Padwa, in: P. de Mayo (editor), Rearrangements in Ground and Excited States, Vol.
3, Academic Press, New York (1980), p. 501.
24. T. Bally and S. Masamune, Tetrahedron, 36, 343 (1980).
25. O. L. Chapman, C. L. Mclntosh. and J. Pacansky, J. Amero Chem. Soc., 95, 614 (1973).
26. N. P. Shusherina, Usp. Khim., 36, 437 (1967).
27. C. Guyon, P. Boule, and J. Lemaire, Tetrahedron Lett., 23, 1581 (1982).

R ~ C T I O N OF 5-BROMO-6-AMINO-3-(4-METHYLAMINOBUTYL)PYRIDINE
WITH POTASSAMIDE

V. G. Klimenko, A. M. Zhidkova, UDC 547.822.5'891.2'749.07

F. M. Stoyanovich, and V. G. Granik

It has been found that potassamide reacts with 5-bromo'6-amino-3-(4-methylamino-

butyl)pyridine to give a mixture of the starting material, 6-aminonicotine, and
l-methyl-8-amino-2,3,4,5-tetrahydro[4,3-b]azepine. Thelatter has been obtained
independently from l-methyl-9-cyano-2,3,4,5,7,8-hexahydropyrido[4,3-D]azepin-8-one.

It has previously been shown LI] that the reaction between potassamide and 5-bromo-2-
amino-3-(4-methylaminobutyl)pyridine (I) affords a mixture of 2-aminonicotine (II) and
l-methyl-6-amino-2,3,4,5-tetrahydropyrido[4,3-b]azepine (III). However, when the isomeric
5-bromo-6-amino-3-(4-methylaminobutyl)pyridine (.IV) was used i n t h i s reaction, no reliable
data could be obtained for the occurrence of similar heterocyclization reactions [i].
The aim of this investigation was to examine the reaction of the substituted pyridine
IV with potassamide, which, as in the case of compound I, could involve an intermediate 3,4-
dehydro-compound. The reaction of the pyridine IV with potassamide was carried out under the
conditions described in [i]. A mixture of compounds was obtained which proved extremely
difficult to separate, and it was not possible to obtain the components of the mixture in
the pure state. Consequently, in the initial stages of the investigation attempts were made
to synthesize independently l-methyl-8-amino-2,3,4,5-tetrahydropyrido[4,3-b]azepine (V),
which is presumed (by analogy with the findings in [I]) to be a product of the reaction of
the pyridine IV with KNH2. The bicycle V was synthesized as follows: condensation of N-
methylcaprolactam diethyl acetal VI with cyanoacetamide afforded the enaminoamide VII,
which was cyclized with dimethylformamide diethyl acetal to l-methyl-9-cyano-2,3,4,5,7,8-
hexahydropyrido[4,3-b]azepin-3-one (VIII) [2]. The latter was treated with phosphoryl
chloride in the presence of triethylamine hydrochloride (the use of NN-diethylaniline gave
much lower yields) to give high yields of the 8-chloro-compound IX, which was reacted with
ammonia to give l-methyl-8-amino-9-cyano-2,3,4,5-tetrahydropyrido[4,3-b]azepine (X). On
heating X with polyphosphoric acid, the cyano-group was hydrolyzed followed by decarboxyla-
tion to yield the bicycle V.

Novokuznetsk Scientific-Research Institute for Pharmaceutical Chemistry, Novokuznetsk

654034. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 364-367,
~ r c h , 1986. Original article submitted January 30, 1985.

0009-3122/86/2203-0297512.50 9 1986 Plenum Publishing Corporation 297

 TABLE 1, PMR Spectral Parameters of IV, V, XI, and t h e Mix-
t:ure of Products from the Reaction of IV with Potassamlde

Chemical shifts os protons, ppm

Compound
~,H 4,It I~oll N~,CI,I~ NII~ pro~oni!t

IV 7,74,7 d 7,19, d 2,32, 13,03,br

XI 7,86, m 7,36, m 6,3"~,m 2,06, 5,02, br 1,48--2,32,m,
2,83--3,13,m
V 7,55,s -- 559, s 2,8% s 4,31, br 1,68,m ; 2,57,t,
Mixture of 1~rod-
3,05,t
ucts from t~e re, 7,86 7,37 6,34
aqtlon of (IV) 7,75
w~n potassamide 7,51 5,76

TABLE 2. UV Spectra of IV, V, and Xl, and the Mixture of Prod-

ucts from the Reaction of IV with Potassamide

Maximum 1 Maxim~ 2 Minimum,

Compound ,,.,
~, rim
~,,nm D lg B

IV
XI , 239,1
230,I. I 0,23
0,30 I 4,18
4,05 312,i
302,8 o,0,08i i I 3,59
3,73 272,7
268,3
Mixture o~ products 230,4 0,54 4,43 287,0 0,17 3,94 261,0
from the reaction 235,2 0,69 310,6 0,29 272,7
of(IV) withpotas-
samiae

Br CHsHN%
KN}.I~,._

NH2~
IV IVa x[I

-i CH5 9" "] CI|3" N "

N "i

_ )% )l t
! ~'<" I II
N~N CH 3 "q'----'" l__ fIN" N CH~_j -- %-
XI Xla va

The IR spectrum (CCI~) of V contained bands at 980, 1030, ii00, 1240, 1450, 1490, 1550, 1600
(pyridine ring), 2825, 2835, 2910, 2960, 2980 (CH2 and CH3 groups), 3370 and 3470 cm -z (NH2).
The PMR spectrum (CDCI3) showed signals at 1.68 (4H, m, 3,4-CH2CH=), 2.57 (2H, m, 5-H), 3.05
(2H, m, 2-H), 2.80 (3H, s, N-CH3), 4.31 (2H, br. s~ disappeared on adding D20, NH2), 5.79
(IH, s, 9-H), and 7.55 ppm (IH, s, 6-H).
The mixture of compounds obtained from the reaction of IV with KNH2 was analyzed by
thin-layer and gas chromatography,and UV and PMR spectroscopy. Thin layer chromatography
showed that apart from the starting material IV, the mixture contained two compounds with the
same mobilities as 6-aminonicotine (XI) and the pyridinoazepine V respectively. GLC analysis
gave similar results.
The PMR spectra of the pure compounds IV, V, XI, and the mixture of these obtained by
reacting V with KNH2 were obtained (Table i). Examination of these spectra showed that in
addition to the starting material IV, the mixture contained the aminonicotine XI (doublet
at around 6.34 PPm) and the bicycle V (singlets at around 7.51 and 7.75 ppm). The successive

298
addition to the ampul containing the reaction mixture of authentic samples of V and XI re-
sulted in increases in the intensity of the appropriate peaks. No other reaction products
were observed. From the integral intensities in the PMR spectrum, the quantitative composition
of the reaction mixture was calculated for IV, Xi, and V (93, 3, and 4% respectively). The
yield of new reaction products based on starting material was 3.5% for XI and 5% for Vo
The UV spectra in 96% ethanol were also recorded for the same samples of IV, V, and XI
and the reaction mixture (Table 2). Examination of these spectra showed that using this
method it is also possible to calculate the amount of the bicycle V in the reaction mixture,
although the accuracy of this method is low. The analysis was carried out at 274 nm, the
amount of the bicycle V found by this method being substantially higher than that found by
PMR (<10%).
It has therefore been shown that the reaction of (IV) with potassamide in a boiling
mixture of benzene and ether affords the two cyclization products V and XI.

i i .........

"~N / \ 0C ,H{:, 'N ~<~CN L" N"" ~ ' ( " ~'~ 0

I i I i
CIIj CII~ Cll 3 CN
VI VII VIII

/--'x N

CH3 CN CH3 CN CH3

IX X V

It is assumed that both compounds are formed from a common intermediate, namely the
highly reactive 6-amino-3-(4-methylaminobutyl)-4,5-dehydropyridine (XII). Compound XI
appears to be formed as a result of the transfer of a hydride ion from the a-carbon atom of
the side chain to the 4,5-dehydro bond and nucleophilic attack of the terminal methylamide
anion on the a-carbon atom. Formation of V requires nucleophilic attack of the terminal
methylamide anion on the 4,5-dehydro bond (at the 4-position of the pyridine ring).

EXPERI~fENTAL

Pl~ spectra were obtained on a BS-497 instrument (I00 MHz) (Czech SSR) in CDCI3, internal
standard HMDS, IR spectra on a UR-20 spectrometer (East Germany) for the 3% solutions in CCI~,
and UV spectra on a Specord M40 spectrophotometer (East Germany) in 96% ethanol. TLC was
carried out on alumina in the system benzene-ethanol, 3:1 (the Rf values of IV, V, and XI
were 0.27, 0.64, and 0.82 respectively). GLC was carried out using an LKhM-7A chromatograph
(catharometer, column with PEGA/KhrR, temperature 185--215~
React!on of 5-Bromo-6-amino-3-(4ymethylaminobutyl)pyridine (IV) wit ~ P otassamide. To
0.2 mole of KNH2 (from 7.8 g of potassium and 300 ml of liquid ammonia) was added a solution
of 5.2 g (0.02 mole) of 5-bromo-6-amino-3-(4-methylaminobutyl)pyridine (IV) [i] in 250 ml of
dry benzene. The mixture was boiled for 2 h with stirring, then cooled, i00 ml of ethanol
added, and the solution filtered and evaporated to dryness. The residue was dissolved in
dilute HCI, and the acid was then neutralized and the:solution saturated with potassium
carbonate. The semicrystalline m a s s w a s extracted with acetone, and the extract filtered
and evaporated. The residue was boiled several times with benzene, and the solution treated
with activated charcoal and evaporated to dryness. The residue was a dark brown oil (4.3 g).
Analysis of the oil by PMR spectroscopy gave a IV:V:XI ratio of 93:4:3%.
l-Methy!-8-chloror9-cyano-2~3~4,5-tetrahydropyrido[4,3-b]azepine (IX). A mixture of
15.7 g (0.77 mole) of VIII in 80 mi of POCI3 and 8 g of triethylamine hydrochloride was boiled
for 1.5 h, the POCI3 distilled off under reduced pressure, and the residue treated with
chloroform followed by i N NaOH until the pH of the aqueous layer was 9-10. The layers
were then separated, the aqueous layer extracted with chloroform (3 20 ml), and the com-
bined extracts dried over Na=SO4, filtered, and evaporated to give 16.3 g of IX, yield 95%,
mp 88-89~ (from propan-2-ol). F o u n d : C 59.5; H 5.3; C1 16.0; N 19.1%. C11HI=CIN3. Cal-
culated: C 59.6; H 5.4; C1 16.0; N 19.0%.

299
 l-Methyl-8-amino-9-cyano-2~3,4~5-tetrahydropyrido[4~3-b]azepine (X). A mixture of 16.3
g (0.73 mole) of IX and 180 ml of an alcoholic solution of ammonia was heated ina bomb for
16 h at 200~ cooled, and 12 g of the amino-compound X filtered off, yield 81%, mp 200-201~
(from DMF). Found: C 65.0; H 7.2; N 28.0%. C21HI~N~. Calculated: C 65.4; H 6.9; N 27.7%.
1-Methyl-8-amino-2,3,4,5-tetrahydropyrldo[4,3-b]azepine (V). A solution of 4 g (0.02
mole) of the aminocyano-compound X was heated in 62 g of PPA at 160-170~ for 4 h, cooled,
poured into 250 ml of water, extracted with chloroform (4 50 ml), the combined extracts
dried over Na2SO~, filtered evaporated, and the residue triturated with heptane to give 2.7
g of V, yield 76%, mp 84-85~C (sublimation). Found: C 67.5; H 8.~; N 24.0%. C~oH2~N,.
Calculated: C 67.8; H 8.5; N 23.7%.

LITERATURE CITED

I. F . M . Stoyano~ich, V. G. Kllmenko, and Ya. L. GolVdfarb, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. ii, 2585 (1970).
2. V. G. Granik, N. B. Marchenko, T. F. Vlasova, and R. G. Glushkov, Khim. Geterotsikl.
Soedin., No. ii, 1509 (1976).

REARRANGEMENT OF 2-HETARYLALKYLPYRIDINIUM SALTS

Ao N. Rumyantsev, V. I. Terenin, UuC 547.821.3'822.8'724'733:543.422

and L. G. Yudin

The rearrangement of 2-thienyl-and 2-furylalkylpyrldinium salts to the correspond-

ing anilines by the action of methylammonium sulfites has been studied. It has
been shown that the rearrangement of these salts is accompanied in many cases by
the formation of phenols and dealkylation products. The influence of the length
of the alkyl chain between the heterocyclic rings on the ratio of the rearrangement
products has been investigated.

It has been demonstrated earlier that the quaternary salts of 2-(2-phenylethyl)pyridinium

are rearranged into 2-benzyl-N-alkylanilines under the action of aqueous solutions of alkyl-
ammonium sulfites [i]. It has also been found that under these conditions the 2-benzyl-
pyridinium salts are rearranged into o-alkylaminobiphenyls [2]. In the present work we have
investigated the rearrangement of pyridinium salts in which the pyridine ring is connected
to furan or thiophene in the s-position through one or two methylene groups. With this in
mind we have synthesized 2-(2-thienylethyl) ~ and 2-(2-furylethyl)pyridines (la,b) and ob-
tained their quaternary salts lla,b.
It has been found that, under the action of an aqueous solution of methylammonium sul-
fite (heating in a sealed ampul at 185~ the salt lla is rearranged with a yield of 80%
into 2-(2-thienylmethyl)-N-methylaniline (Ilia). The rearrangement of salt lib into 2-(2-
furylmethyl)-N-methylaniline was achieved with a yield of 40% when the reaction temperature
was reduced to 150 ~

CH3- ~'N/~'~CH21/ ~<N/ CH~ C6 "X /

~NACH=C~ ' x / ~ CH=C

I- I
la,b CH3 lla,b
I,II a x=s;bx-O

M. V. Lomonosov Moscow State University, Moscow. Translated from Khimiya Geterotsikli-

cheskikh Soedinenii, No. 3, pp. 368-371, March, 1986. Original article submitted January
15, 1985.

300 0009-3122/86/2203-0300512.50 9 1986 Plenum Publishing Corporation

 In both cases the rearrangement was accompanied by the simultaneous dealkylation of
the pyridine ring due to the attack of the nucleophilic reagent on the carbon atom of the
N-methyl group as this is usually the case in such systems.

.~i~.It/SO -*NH3CII3 H ~~<~.

/ SO 5NH3CII ~

(NH3CH,)2 SO, il ~ i " I ,~'" ' ~ .

lla-b ....... ' ........ ~ ri i]. ~, (
i "CII2CH2 ~ NH Ctl'CH2 X "~'CI)ff'X'X ""
r I i
Ia-b
CH ~ CII~ NHCH~ I I I a , b

The IR spectra of the obtained anilines Illa, b contain a valence oscillation band of
the NH group in the region of 3370 cm -z which is characteristic for aromatic amines. The
Pt~ spectra of compounds IIla, b show a singlet of the three protons of the methyl group in
the region 2.7-209, a singlet of the two protons of the methylene group in the region 4~
and a broadened sing of the proton of the NH group in the region 3.8 ppm. The mass
spectra* of compounds IIIa, b show maximum intensity peaks of the molecular ions 203 and 187
respectively that are equal to the molecular mass of these compounds. The main directions
for the decomposition of the molecular ions are by splitting off of a methyl radical or of
the entire aminomethyl group; this is evidently accompanied by cyclization of the radical
centers formed via the charged atom of the heterocycle. The M-CH3 ions further eliminate
NHX with the formation of a 141 fragment wilich is common to both compounds.

CH 2 X 141
H
NIICH~ "AtltC

In order to establish the effect of the length of the alkyl chain between the hetero-
cyclic rings on the direction of the reaction, we have studied the rearrangement of models
with one methylene unit. For this purpose we have prepared, starting from 2-cyanopyridine
and metalloorganic derivatives of thiophene and furan, 2-thienyl- and 2-furyl-2-pyridyl
ketones [3]; the latter were then reduced to the compounds Ic, d and converted by quaterniza-
tion with methyl iodide to the quaternary salts IIc, d.

~" ~'N CO ~ X '"

/
l~c_d cH~ IIc-d
l,lldx=s, Z=MgBr;dX=o. Z=L ~

The PMR spectra of the bases Ic, d are characterized by a singlet of the two protons
of the methylene group in the region 4~ ppm. The quaternization of compounds Ic,d was
performed in an argon atmosphere in a sealed ampul by heating on a water bath. The rearrange-
ment was carried out right after formation of the salts due to their instability. The re-
action of l-methyl-2-(2-thienylmethyl)pyridinium iodide with the methylammonium sulfite lead
to a rearrangement which gave 2-(2-thienyl)-N-methylaniline (IIIc); 2-(2-thienyl)phenol
(IVc) (25-30%) and 2-(2-thienylmethyl)pyridine (Ic) were also isolated from the reaction
mixture and identified. The formation of phenol in the rearrangement of salt IIc is evi-
dently due to the reduced rearrangement ability of the enamine fragment of the opened inter-
mediate, conjugated with the 5-membered heterocycle, in comparison with the enol form of
the molecule. Hydrolysis of the enamine fragment of the intermediate andsubsequent ring
formation lead to the formation of phenol IVc. The bases Ic, dare formed by nucleophilic
attack on the non-ring carbon atom linked to the heteroatom.
*Here and in the further text the values of m/z are given for the ion peaks; the intensities
in % of the maximum peak are given in brackets~ Ion peaks with intensities higher than 10%
are shown.

301
 The PMR spectrum of compound lllc contains a singlet of the three protons of the methyl
group in the region 2,8 and a singlet of the proton of the NH group in the region 4.2 ppm.
In distinction from compound lIIc the IR spectrum of compound IVc contains a valence oscilla-
tion band of the hydroxyl group in the region 3560 cm -~. A singlet of the proton of the
hydroxyl group in the region 5.6 ppm is present in the PMR spectrum of this compound.

11 , , , , SOaNll ~CIi'~,~ II SO ~NIIaCll,.

N CII~ "'X |1 '< j<~,<( I1

Nil X
i r
i CII ," CH .~
..A
IC-d tl,., , SO,NIl ~CII~

":: ' ' ".'" 0 '" llO "'CH' X'

011 NIICII s 111 c - d
re c'd

The reaction of l-methyl-2-(2-furylmethyl)pyrldinlum iodide with methylammonium sulfite

proceeds in the same way. GLC-mass spectrometry showed the presence of three substances in
the reaction mixture: 2-(2-furyl)-N-methylaniline (IIld), 2-(2-furyl)phenol (IVd), and 2-
(2-furylmethyl)pyridine (Id). In the mass spectra of the anilines IIIc,d the peaks of the
molecular ions 189 and 173 respectively show the maximum intensities; however, these com-
pounds are less resistent towards electron impact than compounds IIIa-c that contain amethyl-
ene bridge between the hetero- and the carbocycle and decompose with rupture of the hetero-
cycle. The thienyl derivative splits off a HS radical and the furyl derivative a HCO radical.
Thus, in the present work we have studied s the first time the enamine rearrangement
of hetarylalkylpyridinium salts, containing one or two methylene groups in the a-position to
the heter0cycle. It has been shown that 2-hetarylmethyl-N-methylanilines are the main prod-
uct of rearrangement of the hetarylethylpyridinium salts. The rearrangement of the 2-hetaryl-
methylpyridinium salts to the corresponding anilines is accompanied by a side reaction which
leads to the formation of phenols.

EXPERIMENTAL

The IR spectra were taken on an UR-20 (in Vaseline oil) and an IKS-22 spectrometer (as a
film); the PMRspectra were obtained on Varian T-60 and Tesla BS-497 spectrometers (working
frequency i00 MHz, internal standard TMS). The mass spectra were obtained on a MKh-1303
spectrometer with direct introduction of the sample into the ionization chamber with an
ionization energy of 50 eV. The GLC-mass spectra were taken on a Varian ~iAT-II2 chromato-
graph with a OV-17 column (~ = 1.8 m) and a Varian MAT-44 s chromatograph with an SE-54 capil-
lary column (l = 25 m). The progress of the reaction was controlled h y m e a n s of LKhM-3
chromatograph (model 3) with a SE-30 column (~ = 3 m), packed with N-AW.
2-(2-thienylethyl)pyridine (la)(yield 39%, mp 79-81 ~ from ethanol) and 2-(2-furylethyl)-
pyridine (Ib) (yield 43%, bp 99-101 ~ , i mm, nD~ ~~ 1.5132) were prepared according to [4] from
u-picoline and 2-carbethoxythiophene, and 2-carbethoxyfuran.
2-(2-Thienylmethyl)pyridine (Ic) was prepared in the same way as compound la from 2-
thienyl-2-pyridyl ketone, yield 80%, bp 258-260 ~ (i mm). PMR spectrum (CC14): 4.3 (2H, s,
CH~); 6,8-7.6 (6H, m, 3,4,5-H of thiophene, 3,4,5-H of pyridine); 8.4-8.6 ppm (IH, m, 6-H
of pyridine). Mass spectrum: 175 (I00), 129 (25), 97 (46), 78 (i0), 77 (ii). Found: C
68.2~ H 5.0; N 8.2%. C~oHgNS. Calculated: C 68.6i H 5.1; N 8.0%.
2-(2-Furylmethyl)pyr!dine (Id) is obtained in the same way as compound la from 2-furyl-
2-pyridyl ketone, yield 75%, bp 170-172 ~ (i mm). PMR spectrum (CCI~): 4.1 (2H, s, CH=),
6.0 (IH, m, 4-H of furane); 6.2 (IH, m, 3-H of furane); 6.8-7.8 (4H, m, 5-H of furane,
3,4,5-H of pyridine). Mass spectrum: 159(100), 130 (132), 81 (37), 78 (i0), 77 (12).
Found: C 74.5; H 5.8; N 9.0%. C~oHgNO. Calculated: C 74.8; H 5.6; N 8.8%.
l-Methyl-2-(2-thienylethyl)pyridinium Iodide (lla). A mixture of 0.55 g (3 mmoles) of
compound Ia and 1.4 g (i0 mmoles) methyl iodide is kept for 24 h at room temperature. The
precipitated salt is filtered off and washed with acetone. Yield 0.9 g (92%), mp 208-210 ~
(from acetone). Found I 38.6%. C~=H~INS. Calculated I 38.4%.
302
 l-Methyl-2-(2-furylethyl)pyrldinium Iodide (lib) is obtained in the same way as salt
IIa, starting from compound Ib; yield 80%. mp 203-204 ~ (from acetone). Found: I 40.6%,
CI=HI~INO. Calculated: ~ I 40.3%.
l-~ethvl-2-(2-thienylmethyl)pyridinium Iodide (IIc). A mixture of 0.18 g (i mmole)
of compound Ic and 0.5 g (3 mmoles) of methyl iodide is heated in a sealed ampul for 2 h in
an argon atmosphere at 100 ~ . The precipitate is recrystallized from acetone, yield 0.27 g
(85%), mp 140-142 ~ . Found: I 40.3%. C~IH~2iNSo Calculated: I 40.1%.
l-Methyl-2-(2-furY!methyl)pyridinium Iodide (IId) is obtained in the same way as salt
IIc starting from compound Id, yield 73%, mp 127-129 ~ (from acetone). Found: I 42.3%.
C11HI2INO. Calculated: 1 42.2%.
Rearrangement of l-Methyl-2-(2-thienylethyl)pyridinium Iodide (IIa). A mixture of
0.33 g (i mmole) of salt IIa, 2 ml of 50% aqueous solution of methylammonium sulfite and
2 ml of 25% aqueous methylamine is heated in a sealed ampul for 12 h at 185 ~ . After cooling
the reaction mixture is extracted with ether (3 X I0 ml), and dried with magnesium sulfate.
The ether is evaporated and the residue separated on a silica gel column (100 160 ~m) with
benzene as the eluent. Yield 2-(2-thienylmethyl)-N-methylaniline (IIIa) 0.15 g (75%), mp
47-48 ~ (from benzene). IR spectrum: 3420 cm -I (NH). PMR spectrum (CCId): 2.7 (3H, s,
CH~): 3.5 (IH, s, NH): 4.0 (2H, s, CH=): 6.5-7.8 ppm (7H, m, arom.). Mass spectrum:
203 (i00), 188 (46), 173 (57), 155 (21), 141 (28), 118 (45), 107 (49), 88 (12). Found:
C 70.5; H 6.6: N 7.0%. C12H,3NS. Calculated: C 70.8; H 6.4; N 6.9%. 2-(2-thienyl)-
pyridine (Ia) was separated with a yield of 5% besides substance Ilia, mp 79-81 ~ [4].
Rearrangement of l-Methyl-2-(2-furylethyl)pyridinium Iodide (IIb). As in the preceding
synthesis 0.32 g (i mmole) of salt IIb gave at 150 ~ after separation Of the reaction mixture
on a column: 0.08 g (44%) 2-(2-furylmethy!)-N-methylaniline (IIIb), mp 41-42 ~ (from hexane).
IR spectrum: 3380 cm -I (NH). PMR spectrum (CCId): 2.8 (3H, s, CHs); 3.6 (IH, s, NH);
3.85 (2H, s, CH2;)5.9-6.2 (2H, m, 3,4-H of furane); 6.5-7.7 ppm (5H, m, 5-H of furane, arom.).
Mass spectrum: 187 (i00), 186 (17), 172 (22), 157 (36), 144 (36), 141 (14), 131 (12), 118
(13), 91 (ii). Found: C 77.2; H 6.8; N 7.3%. C~2HI3NO. Calculated: C 77.0; H 7.0; N
7.5%. 2-(2-Furylethyl)pyridine (Ib) was separated with a yield of 4% besides compound IIIb,
nD 2~ 1.5132 [4].
Rearrangement of l-Methyl-2-(2-thienylmethyl)pyridinium Iodide (IIq~. As in the preced-
ing synthesis 0.32 g (i rmnole) of salt IIc gave after separation of the reaction mixture on
a column 0.12 g (60%) 2-(2-thienyl)-N-methylaniline (IIIc). IR spectrum: 3420 cm-1(NH).
PMR spectrum (CC14): 2.8 (3H, s, CH3); 4.3 (IH, s, NH); 6.5-7.6 ppm (7H, m, arom.). Mass
spectrum: 189 (i00), 156 (21), 154 (ii), 144 (12), 130 (23), 117 (45). The benzoyl deriva-
tive was prepared, mp 169-170 ~ (from ethanol). Found: C 73.3; H 4.9%. C17H~3NOS. Calcu-
lated: C 73.2; H 4.7%; 0.05 g (24%). 2-(2-tnienyl)phenol (IVc) was also obtained, mp 51-52 ~
(from ethanol). IR spectrum: 3560 cm-1(OH). P~fl~spectrum (CCI~): 5,6 (IH, s, OH); 6.8-7.5
ppm (7H, m, arom.). Mass spectrum: 176 (i00), 147 (21), 131 (25), 115 (16), 77 (12).
Found: C 68.4; H 4.6%. CIoHsOS. Calculated: C 68.2; H 4.5%; 2-(2-thienylmethyl)pyridine
(Ic) was also isolated, yield 3%, identical to the reference sample, besides compounds IIIc
and IVc.
Rearrangement of l-Methyl-2-(2-furylmethyl)~yridinium Iodide (IId). As in the preceding
synthesis, three substances were identified by GC-MS in the reaction mixture after rearrange-
ment of 0.3 g (I mmole) of salt IId: 2-(2-furyl)-N-methylaniline (IIId) (mass spectrum:
173 (i00), 172 (18), 144 (45), 143 (17), 130 (51), 117 (67), 115 (23), 103 (i0)); 2-(2-furyl)-
phenol (IVd) (mass spectrum: 160 (I00), 131 (36), 117 (24), 115 (21), 77 (i0)); and 2-(2-
furylmethyl)pyridine (Id) (mass spectrum: 159 (i00), 130 (32), 81 (37), 78 (i0), 77 (12)).

LITERATURE CITED

i. L. G. Yudin, A. N. Rumyantsev, R. S. Sagitullin, and A. N. Kost, Khim. Geterotsikl.

Soedin., No. I, 63 (1983).
2. A. N. Kost, R. S. Sagitullin, and A. A. Fadda, Khim. Geterotsikl. Soedin., No. i, 125
(1981).
3. R. I. Mohrbacher, V. Paragamian, E. L. Carson, B. M. Puma, C. R. Rasmussen, J. A. Meschino,
and G. J. Poos, J. Org. Chem., 3!i, 2155 (1966).
4. R. P. Zelinsky and M. Benilda, J. Amer. Chem. Soc., 73, 696 (1951).

303
 N~METHOD OF SYNTHESIS OF 3-ALKYL-4-PIPERIDONES

G. V. Grishina, V. M. Potapov, UDC 547.824'34:543.422

and S. A. Abdulganeeva

A new method is presented for the synthesis of 3-substituted 4-piperidones by alky-

lation of lithium derivatives of 4-(~-phenylethylimino) piperidines using alkyl
halides.

Racemic derSvatives of 3-substituted 4-piperidones possess analgesic and anaesthetic

properties [I, 2]. We have studied the possible synthesis of chlral members of this series
by asymmetric a-alkylation of the lithium salts of 4-piperidone imines ~analogous to known
derivatives of cycloalkanones [3, 4]).
The N-substituted 4-piperidone imines (la-c) were obtained in 70-90% yield by refluxing
4-piperidones with 1.2 equivalents of ( or (--) a-phenylethylamine in benzene and azeo-
tropic distillationof water, la-c are quite unstable compounds and sensitive to atmospheric
moisture. They may be stored for an extended period under an inert atmosphere in the cold.
Chromatography on silica gel caused decomposition to the starting materials. The structures
of la-c were confirmed by a C=N stretching band in the IR spectrum at 1670 cm-z and by signals
for the phenylethyl fragment in the PMR spectrum. Imines la-c were a-alkylated in conditions
analogous to those used for cyclohexanone imines [4].

C H , 9 , :H ('tflf~"
I

i
N

.. 2. t I 2 0 ,,
I'" " N"
I
N i ,
Ia-c lla-e
la, lla R=CH3, Ib,llb,cR=p-C4HgIc,lld,e R=CH(CH~)C~Hb;IIa,c,eRI=CH2CsH6,
b,d R,=CH3

Optimum yields of piperidones llb, d were achieved by metallation of imines Ib, d at

--20~ over i h with 1.5 equivalents of lithium amide followed by 3-4 equivalents of methyl
iodide at --70~ for 2-3.5 h. After decomposition of the reaction mixture with water of
hydrochloric acid the 3-substituted 4-piperidones were passed through a short silica gel
column. Benzyl piperidones (lla, c, e~ were obtained similarly in 52-60% yields. The PMR
spectrum of lid shows two doublets for the protons of the 3-methyl group at 0.93 and 0.98
ppm of equal integrated area Which points to the formation of a mixture of two diasteroiso-
mers in equal amounts. Introduction of the 3-benzyl group is confirmed in lla,c by the
appearance of two pheny! signals at 7.23 and 7.20 ppm respectively in their PMR spectra.
The presence of two phenyl proton signals at 7.17 and 7.27 ppm in the spectrum of 1-a-
phenylethyl-3-benzyl-4-piperidone also points to the formation of two pairs of diastereo-
isomers in equal amounts. Thus asymmetric alkylation of the lithium salts of piperidone
imines under the given conditions is not observed. However, the developed method of synthe-
sis of 3-alkyl substituted 4-piperidones by alkylation of lithium derivatives of 4-(~-phenyl-
ethylimino)piperidones can be recommended forsynthesizing3-substituted 4-piperidones which
are difficult to obtain by other routes.

-- M . V . Lomonosov State University, Moscow 117234. Translated from Khimiya Getero*

tsiklicheskikh Soedinenii, No. 3, pp. 372-374, March, 1986. Original article submitted
April 4, 1985,

304 0009-3122/86/2203-0304512.50 ~ 1986 Plenum Publishing Corporation

 TABLE i. Properties of I-R-3-R'-4-Piperidones (IIa-e)

" I rap, = C Pi__peridon____~e

pi_~crate___ss I IR PMR spectrum, :i
% Calculated,~pec- 6, ppm, (J, Hz),
"~ I
I found, _ Empirical[ % ~ m , 3-R' I~
.s (from
formula -C H I N ~f ,@

1
lla 0,5 175-- t52,8 4,6 t2,21 CmHETNO 9 52,8 4,7 ] 13,01 1720 7,23,s, 5H, C~H~ ~0
1765 9C~H3N~O7
I I b 0,5 153--155147,9 5,5 14.1 ] CIoHIgNO ' 48,2 5,6114,11 1720 3,92, d (6), 3H, 77
9C6H3N,307 l CH3
I
I I c 0,4 91--92 [56,1 5,5 11,8[ CI6H2sNO 9 55,7 5,5[11,8 1725 7,20,s, 5H, C~H~ 52
I 9C6H~N307
I I d 0,7 163--165153,1 5,2 12,61 CI4HIgNO 9 53,8 5,0 [ 12,6 1730 0,92, d (6), 0,97, d ~7
I 9C6H3N307 (6), 3H, CHa
I I e 0,7 155--157159,5 5,1 ll,01 C=oH23NO " 59,8 5,0 J 10,7 1730 7,17, s, 5H, C8H5 ~7
9C,~H:~N,,~O7

*lla) R = CH3; b,c) R = p-C~Hg, d,e) R = CH(CH3)C6Hs; a,c,e) R'=

CH2C6Hs; b, d) R' = CH~.
%Silufoi-254. lla in benzene:acetone (3:l):llb in benzene:
acetone:chloroform (6:2:1, saturated with ammonia); llc-e in
benzene:acetone (6:1).
fLit mp picrate = 169.5-171~ (from ethanol) [3].

EXPERIMENTAL

IR spectra were recorded on a UR-20 spectrometer as films in paraffin oil and PMR spectra
on a T-60 instrument in CDCI3.
4-Piperidone imines (Ia-c) were obtained by refluxing 4-piperidones with 1.25 equivalents
of u-phenylethylamine in absolute benzene (argon stream) using a Dean and Stark apparatus
with subsequent vacuum distillation.
Ia. Yield 90%, bp 148-149~ (7 mm), nD 2~ 1.5397. IR spectrum (film): 1670 cm-* (C=N).
PMR spectrum (CDCI3): 2.27 (3H, s, N-CH3), 2.47-2.53 (8H, m, piperidine ring protons), 1.45
(3H, d, J = 6.6 Hz, CHsCH), 4.72 (IH, q, J = 6.6 Hz, CH3CH), 7.37 ppm (5H, m, CHPh), Found:
C 77.2; H 9.2; N 12.6%. C14H2oN~. Calculated: C 77.7; H 9.3; N 13.0%.
lb. Yield 70%, bp I08-II0~ (I mm), n~ ~ 1.5251. IR spectrum (film): 1670 cm -I (C=N).
PMR spectrum (CDCI3): 0.9-1.5 and 2.2-2.6 (8H and 9H, two multiplets, piperdine ring and
n-butyl protons), 1.34 (3H, d, J = 6.6 Hz, CH3CH) 4.56 (IH, q, J = 6.6 Hz, CHPh), 7.1 ppm (5H,
s, CHPh). Found: C 79.1; H 10.2; N 10.4%. C17H26N2. Calculated: C 79.0; H i0.i; N 10.8%.
Ic. Yield 90%. IR spectrum (film): 1670 cm -I (C=N). PMR spectrum (CDCIs): 1.31
(3H, d, J = 6.6 Hz, I-CHPhCH3), 2.3-2.8 (8H, m, piperidine ring), 3.43 (IH, q, J = 6.6 Hz,
4-CHCH3Ph), 7.2 ppm (10H, s). Found: C 82.6; H 8.5; N 8.3%. C2~H2~N2. Calculated: C
82.3; H 8.6; N 9.1%. Analogously from (-) u-phenylethylamine (with [aid 2~ --41~ , no solvent)
there were obtained imines Ib with [~]D 2~ -42.5 ~ (c 1.4, benzene) and Ic with [a]D 2~ -49.1 ~
(c 9.2, benzene).
l-Methy!-3-benzyl-4-piperidone (IIa). l-Methyl-4- (~-phenylethylimino)piperidine (Ia,
0.54 g, 2.5 mmoles) in absolute THF (2.5 ml) at --23~ was added dropwise to a solution of
lithium diethylamide (previously prepared at --10~ from diethylamine (0.55 g, 7.5 mmoles)
in absolute THF (i0 ml) and an ethereal solution of methyl lithium (5.1 ml~ 7.5 mmoles,
1470 mmoles/liter). After one hour the reaction mixture was cooled to --75~ and benzyl
bromide (1.27 g, i0 mmoles) added dropwise. After holding for 1 h at --75~ the temperature
was slowly raised to 0~ Water (5 ml) was added and the product was extracted with ether
(i0 20 ml) and dried with 4A molecular sieve. Following removal of ether, the oil (2.3 g)
was column chromatographed on silica gel using benzene:acetone (5:1) as eluent. Combination
of the homogeneous chromatographic fractions gave l-methyl-3-benzyl-4-piperidone (IIa, 0.3 g,
60%) as a pale yellow oil.
Piperidones IIb-e were obtained similarly. The properties of all of the piperidones
IIa-e are presented in Table i.

305
 LITERATURE CITED

i. N. S. Prostakov and L. A. Gaivoronskaya, Usp. Khlm., 47, 829 (1978).

2. D. L. Larson and P. S. Portoghese, J. Med. Chem., 16, 195 (1973).
3. A. J. Meyers, O. R. Williams, G. W. Ericson, S. White, and M. Druelinger, J. Amer. Chem.
Sot., 103, 3081 (1981).
4. S. I. Hashimoto and Ko Koga, Tetrahedron Lett., 6, 573 (1978).
5. S.M. McElvain and M. D. Barnett, J. Amer. Chem. Soc., 78, 3140 (1956).

}lASS SPECTROMETRY OF STEREOISOMERIC 3-HYDROXY-4-PIPERIDONES

V. A. Mashenkov, A. P. Lugovskii, UDC 547.723:543.51

L. I. Krasovskaya, L. S. Stanishevskii,
and V. P. Suboch

The existence of several sites of charge localization upon the mass spectrometric
decomposition of stereoisomeric 3-hydroxy-4-piperidones leads to a large number of
fragmentation products both with retention and destruction of the piperidine ring.
Analysis of the mass spectra of the compounds studied showed that the appearance
of [M -- CO] + ion peaks for isomers with an axial hydroxyl group may serve as a
method for determining the configuration of the carbinol site of such cyclic struc-
tures.

A mass spectrometric study was carried out on the major characteristic pathways for the
decomposition of the molecular ions (M+) of stereoisomeric 3-hydroxy-4-piperidones in order
to establish correlations between the structure of these compounds and their mass spectra and
possible analytical applications. The mass spectra of the compounds studied are published
for the first time although Ermakov [i, 3, 4] and Bartanyan [2] have already discussed the
fragmentation of alkyl derivatives of 4-piperidone and 4-piperidol.
3-Hydroxy-4,piperidones (1)-(VIII) contain a tertiary nitrogen atom, carbonyl, hydroxyl
and phenyl groups, which may serve as positive charge localization sites in M +. Thus, these
mass spectra were interpreted assuming predominant charge localization on one of these sites.
The concept of charge localization on individual molecular sites is used in mass spectrometry
to explain pathways for the decomposition of organic compounds, including piperidine com-
pounds [1-6]. The decomposition of piperidones la, lib, Ilia, lllb and IVa was studied using
high-resolution mass spectrometry. T h e fragmentation sequence for several of these derivatives
was studied using metastable ions by the DADI method.

o%

OH CH 3
l'-;V a,V,VI l-lvb ,VlI,VJll

la,b,v Rt=H,IIa,b,llla,b~VII,VIII RI=CH3,1Va,b,VI RI=CH~Ph; la, b, lla, b, IVa, b

R2=H, Illa, b,V, VI R2=F, VII R~=CI-t3, VIII R2=CI

These compounds are characterized by an M + peak with intensity ~ I 0 % of the maximal peak
(Table i). Analysis of the mass spectra showed that two competing pathways obtain upon charge
localization in M + on the piperidine ring nitrogen atom (scheme i) involving both opening
and retention of the piperidine ring. One of the major decomposition processes of previously
studied derivatives of piperidine [1-4, 7] and 3,4-dihydroxypiperidines [6] containing a sub-
stituent in the s-position relative to the nitrogen atom is loss of this substituent. How-

V. I. Lenin Belorussian State University, Minsk 220080. Institute of Physics, Academy

of Sciences of the Belorussian SSR, Minsk 220602. Translated from Khimiya Geterotsikliches-
ikh Soedinenii, No. 3, pp. 375-379, March, 1986. Original article submitted March 23, 1984;
revision submitted April 29, 1985o

306 0009-3122/86/2203-0306512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Mass Spectra of I-VIII at 70 eV Electron Energy
(most intense peaks)

tom- m[z value (relative peak intensity as % of the strongest peak)

pound

la 205 (38), 188 (8), 187 (19), 177 (20), 162 (9). 134 (lO), 133 (21), 120
(14), 119 (62), I18 (100), !06 (49), 105 (67). 104 (80), 103 (19), 91 (42)
lb 205 (39), 188 (19), 187 (35), 162 (14). 134 (14), 133 (31). 120 (15), lI9
(81), lib (lO0), 106 (44), 105 (65), 104 (79). 103 (20), 91 (48)
IIa 219 (24), 202 (52), 201 (27), 191 (13), 176 (lO), 134 (19). 133 (68), 132
(100). 120 (8), 1t8 (27), 105 (68), 104 (32). 103 (26), 91 (36)
lib 219 (23), 202 (42), 201 (21), 176 (8), 134 (16), 133 (63), 132 (lO0), 120
(7), lib (21), 105 (65), 104 (23), 103 (20), 91 (37)
Ill a 237 (33), 220 (38). 219 (23), 209 (13), 104 (16), 152 (24), 151 (70), 150
(100). 138 (15). 136 (42), 123 (62). 122 (75), 121 (41), 109 (80) lOl (33)
lllb 237 (53), 220 (54), 219 (24), 194 (lO), 152 (25), 151 (87), 150 (lO0), 138
(9), 136 (25), 123 (54), 122 (32), 121 (19), 109 (60). lOl (17)
1Va 295 (li), 278 (59), 277 (22), 209 (28), 208 (37). 204 (75). 134 (12), 120
(75), 118 (78), 105 (62), 104 (33), 92 (33), 91 (100)
IVb 295 (ll), 278 (31), 277 (12), 209 (14), 208 (19), 204 (55), 133 (14), 120
(36), 118 (77), 105 (34), 104 (17), 92 (]7), 91 (100)
V 223 (45), 206 (12), 205 (19), 195 (14), 180 (24), 152 (17), 151 (29), 149
(32), 137 (52), 136 (94), 124 (45), 123 (46), 122 (lOO), 121 (29), 109 (84)
VI 313 (13), 296 (42}, 295 (18), 227 (23), 226 (17), 222 (69), 152 (17), 151
(35), 123 (39), 122 (31), 121 (19), 120 (90), 109 (77), 91 (lO0)
VII 233 (41), 216 (56), 215 (17), 190 (23), 148 (37), 147 (75), 146 (66), 132
(42), 119 (69), 118 (55), ll7 (40), lo5 (10o), 91 (~1)
VIII 255 (3o), 253 (83), 238 (39), 237 (30), 236 (91), 235 (39), 210 (22), 170
(17), 169 (48), 168 (91), 167 (96), 166 (lO0), 154 (24), 152 (30), 139
(78), 125 (91), 91 (57)

TABLE 2. Relative Intensities of Several Characteristic Frag-

ments in the Mass Spectra of 3-Hydroxy-4-piperidones in %
Relative to the Total Ion Current

Com-
pound 06 q)T ~)'ll

Ia 4,8 1,0 2,5 1,1 7,8 12,6 2,6 IO,O 8,4 10,0
Ib 4,4 2,2 1,6 912 11,5 3,6 9,1 7,5 9,1
IIa 2,6 5,7 1,I 7,4 10,9 7,4 2,9 7,3 3,5
lib 2,7 4,9 0,9 7,3 11,7 7,3 2,4 7,6 2,7
Ilia 2,7 3,1 1,3 5,7 8,2 5,7 3,4 5,1 6,1
IIIb 5,7 5,8 1,1 9,4 10,8 9,4 2,7 5,8 3,4
IVa 1,1 6,1 0,5 2,9 3,9 0,7 0,6 6,5 3,4
IVb 1,3 4,1 0,5 1,9 2,5 1,9 0,7 4,5 2,3
V 3,3 0,9 1,7 3,8 6,8 2,1 7,2 3,3 7,2
VI 1,3 4,1 0,5 2,2 1,7 3,3 0,4 3,8 3,0
VII 3,8 5,2 2,1 7,0 6,1 7,0 3,9 6,4 5,1

ever, the ~5 fragments formed in piperidones I-VIII as a result of this decomposition have
low or zero intensity. This behavior may be attributed to the significant contribution of
other decomposition pathways proceeding with ring opening and fragmentation of M + species,
the charge in which is localized on other sites. The loss of the substituent at the ring
nitrogen atom is clearly evident only for IV and VI which have an N-benzyl group. The mass
spectra of these compounds have strong ion peaks at 204 and 222* ([M -- CH2Ph] t, ~s) as well
as ~4 fragment peaks formed due to the loss of a water molecule from ~3 ions.
The decomposition of M + d u e to charge localization on the nitrogen atom proceeding with
ring opening is most characteristic for the compounds studied. The p e a k s f o r the correspond-
ing fragments are rather strong. The variety of the products of this fragmentation is
*Here and subsequently, the m/z value is used to characterize the ions.

307
apparently related to the possibility of ring opening with breakage of either the C(2)-C(s)
or C(s)-C(s) bonds with subsequent decomposition of the fragments formed, which may occur
with-hydrdgen atom migration. Thus, the appearance of the peaks for series of rearrangement
ions ~, - @s" and @zo - @zo" upon the decomposition of @7 ions is related to hydrogen atom
transfer to a charged fragment or neutral fragment. This is also true in the case of ions
@zs -- @ze" for IV and VI, which contain a benzyl group as the R ~ substituent; a phenyl
radical is eliminated from the benzyl group in ions @zo - @~o". The formation of the @7
fragment upon ring opening at the C(2)-- C(s) bond was indicated by the mass spectrum of
deuterated analogs of piperidone lllb contalhlng one or two deuterium atoms at C(s). The
peaks for ions 42 and 44 have elemental composition C2H~N and C=H~N, respectively and, thus,
they are also formed upon the decomposition of M + w i t h charge localization at the nitrogen
atom.

SCHEME i

0 0 0

CH~"I -R' CH~"I -H20 CH~y~

"~ H~ II
"-I~- ",PhR 2 "~,~.~'-~p hR z
R~I H H
MT
+ wR I

a,- CHz_~_N--~II.PhR z
I " " R PhR ~' ,~
CH~---.C--OH 07 +
I CH2-~=N---~CH'PhRZ
"2 -CRH20 R~=H I~
+ - +~CH_PhR 2 |
CH3~N~--CIt-PhR 2 CH2--N~
Cll R =CII.3, CII2Ph
,I,s I
cH 3 R R=H, Ph
. I + 2 -C~HTO:~,.. + +
CH.--C--C--CH~-N--CH-PhR
" H ~. ~ -Jl ~ RI-NH=CH.PhR 2 --~" CH~--NH':--CH'PhR~"
0 un K @1o @~s RI=cH2 Ph

l RI --N----CH'phR2 ~ +" 2
CH~---N----CH-PhR
-C~HgOZ' ~'o ~;8 R'=CH2Ph

+
R1 - - N ~ C - - P h R 2 "
"---'-'z~ +
CH3,----N== C - - P h R 2

@10 @16 RI =CI12Ph

Peaks for the [M -- OH] + and [M -- H20] + ions are virtually absent in the mass spectra of
previously studied piperidinediols [6] although such fragments are characteristic for cyclic
alcohols. Thus, the presence of strong peaks for the @z and @2 fragments (scheme 2) in the
mass spectra of piperidones I-VIII may be related to the formation of M +, in which the charge
is located on the carbonyl group oxygen atom. The decomposition of such M+proceeding with
ring opening apparently gives rearrangement ions @o and @'9 (confirmed by the mass spectra
of analogs of lllb deuterated at C(s) as well as @z4 (72), whose strong peak was found in the
spectra of all the compounds studied. The peak for a fragment with such composition was
found lacking in the mass spectra of previously studied piperidine derivatives.

SCHEME 2
O
C=--O+
CH -OH" s~'~
~h-c.~:=o* ---- .o" l I ~ c.
~.N/~.PhR2 ~-H/~'phR 2

~: ~ o *,

CHS~/C=C=0 +' PIeR 2

HO IRI
@I~ @2

308
 The high resolution mass spectra of the compounds studied show that a series of ions is
due to ions not containing heteroatoms. Ions ~i~ - ~ ", , ~Is and #' ~3 (scheme 3) are hydro-
carbon species and contain a phenyl group. These fragments and #,5 are apparently formed
from M + ions, i n w h i c h the charge is localized in the phenyl group. For compounds containing
an N-benzyl group, ion r is formed from both aryl substituents since fragment #~2 in the
case of VI gives two peaks. This occurs because the aromatic ring at C(~) contains a fluorine
atom. The mass spectra of III and vI-vIII which have F, C1 and CH3 substituents in the para
position of the phenyl ring were studied largely to confirm the peak assignments given.

SCHEME 3

CH/,..~ 9 ' " + 2

tC5115]+ --~-.-- [C7H7] ~ -,,~---- H0 [ j. +. ~ CH3"-CH:PhB
- .'"'/~' " N L " P h R 2 : " " l~ d~11'
9 ~'I~ 'l'Iz . 11 . . ...
,%
~- +" 2
M5 CH~---- C H - Ph~
[ 6H61 -",I---" [ C e H 6 R 2]

+ 2
[CoH%]+ ~ [C6HsR2] +' CHz=C----PhR

Interest was also found in the behavior of the peak for fragment #6 formed upon the loss
of a CO molecule from M + (Table 2). The intensity of this peak is significant (4-20%) only
for the stereoisomers with axial orientation of the hydroxyl group. The #6 fragment peak is
virtually absent (1<<'1%) for derivatives with an equatorial hydroxyl group. The lack of
peaks for [M -- CO] + ions for piperidones with an axial hydroxyl group is likely a consequence
of the formation of a rather strong 3e-OH...OC intramolecular hydrogen bond (Av = i00 cm-1).
This feature of the mass spectrometric behavior of steroisomeric 3-hydroxy-4-piperidones may
be used as a method of establishing the orientation of the hydroxyl group in this class of
compounds. We should note that identification of stereoisomeric 3-hydroxy-4-piperidones
is possible only by PMR spectroscopy since the hydroxyl group stretching bands in the IR
spectra of diluted solutions of both stereoisomers are virtually the same (OH...OC and OH...N)
[8]. The appearance of peaks for [M -- CO] + ions for 3a-hydroxy-4-piperidones may serve as
a mass spectrometric method for determining the configuration of the carbonyl site of such
cyclic structures.

EXPERIMENTAL

The mass spectra of l-Vlll were taken on a Varian MAT-311 A mass spectrometer with
direct sample inlet. The ionizing electron energy was 70 eV and the temperature of the
ion source was 20-100~ The precise ion masses were found relative to PFC at I0,000
resolution.
Samples of the compounds studied were obtained according to our previous procedures
[9, i0].

LITERATURE CITED

i. A. I. Ermakov, Yu. N. Sheinker, Zh. K. Torosyan, and V. A. Zamureenko, Khim. Geterot-

sikl. Soedin., No. 12, 1647 (1975).
2. R. S. Bartanyan and E. A. Mistryukov, Khim. Geterotsikl. Soedin., No. 4, 503 (1979).
3. A. I. Ermakov, Zh. K. Torosyan, and Yu. N. Sheinker, Khim. Geterotsiklo Soedin., No. 4,
507 (1979).
4. A. I. Ermakov and Yu. N. Sheinker, Khim. Geterotsikl. Soedin., No~ i, 65 (1981).
5. H. Budzikiewicz, C. Djerassi, and D. H. Williams, Mass Spectrometry of Organic Compounds,
Holden-Day (1967), p. 312.
6. V. A. Mashenkov, V. P. Suboch, L. S. Staneshevskii, and A. P. Lugovskii, Vestn. Belorussk.
Gos. Univ., Ser. 2, Dep. in VINITINo. 1981/82 (April 22, 1982), Ref. Zh. Khim., 15B128
Dep. (1982).

309
 7. R. A. Khmel'nitskii, N. A. Klyuev, S. B. Nikitina, and A. I. Vinogradova, Zh. Org. Khim.,
!, 391 (1971).
8. L. S. Staneshevskii, I. G. Tishchenko, Yu. V. Glazkov, and A. Ya. Guzikov, Zh. Prikl.
Spektrosk., 19, 123 (1973).
9. L. S. Staneshevskii, I. G. Tishehenko, and A. Ya. Guzikov. Zh. Org. Khim.. 7, 2612 (1971).
I0. L. S. Staneshevskii, I. G. Tishchenko, and A. M. Zvonok, Khim. Geterotskii. Soedin.,
No. 5, 670 (1975).

SYNTHESIS OF 5-ARYLPYRIMIDINE-2-CARBOXYLIC ACIDS AND THE

LIQUID-CRYSTAL CHARACTERISTICS OF THEIR ARYL ESTERS

M. A. Mikhaleva, G. A. Kolesnichenko, UDC 547.853.9'562.07:532.783

K. I. Rubina, Yu. Sh. Gol'dberg,
V. A. Savel'ev, L. Ya. Leitis, M. V.
Shimanskaya, and V. P. Mamaev

5-Arylpyrimidine-2-carboxylic acids were synthesized by the hydrolysis of 5-aryl-2-

cyanopyrimidines and the oxidation of 5-aryl-2-styrylpyrimidines under the condi-
tions of phase-transfer catalysis. The aryl esters of the acids were obtained,
and their liquid-crystal characteristics were studied. The p-substituted aryl
esters of 5-phenylpyrimidine-2-carboxylic acid do not exhibit mesomorphism, but the
introduction of a butyloxy group at the p position of the phenyl residue leads to
the appearance of nematic characteristics~ Aryl 5-phenylpyrimidinylearbonyloxy-
benzoates are nematic liquid crystals with a thermally stable meso phase and an
existence range of 50-80~

The pyrimidine analogs of biphenyls have been widely studied [3, 4] in connection with
advances in the study of cyanobiphenyls and the increased interest in liquid crystals with
positivedielectric anisotropy [i, 2]. An important position among the various types of
liquid-crystalline compoundsis occupied by the esters, but with the large number of re-
searches into liquid-crystalline aryl benzoates (e.g., [5-7]) the esters of heterocyclic
acids have hardly been studied at all; there are only data on the nematic characteristics
of the allyl esters of pyridine acids [8].
We have realized the synthesis of aryl pyrimidine-2-carboxylates, which are the analogs
of mesomorphous compounds of the aromatic series [9-11], and we investigated their liquid-
crystal characteristics. To obtain the acids I we used the traditional methods for synthesis
of pyrimidine-2-carboxylic acids [12], i.e., hydrolysis of the cyanopyrimidines (II) ob-
tained from the sulfones III and oxidation of styrylpyrimidines IV or methylpyrimidines
V. Here special attention was paid to the possibility of producing the pure product, which
is of primary significance during the synthesis of liquid-crystalline compounds.

SCHEME i

m a,b wa Va-c

R CN ~ .

~----' ~ - - N

u a-b la-c iv a - c

I-VI a R=H;b R=OCH~;CR=OCsH 9

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Novosibirsk 630090. Institute of Organic Synthesis, Academy of Sciences of the Latvian
SSR, Riga 226006. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 380-
388 March, 1986. Original article submitted February 12. 1985.

310 0009-3122/86/2203-0310512.50 O 1986 Plenum Publishing Corporation

 TABLE i. p-Substituted Phenyl Pyrimidine-2-ca~boxylates

Transition T, IR, spectnan, Found, % Molecular Calculated, I~

oC
Com-
pound
%Tt, ~, ~m -~ [, formula
Tis C H N

IX 208--21( -- 1775, 2230 76,4 ;,9c 1,1 C24HI~N302 76.~ 3,98 I 11, 61
XIIa 119--12f 1760 75,7 ;,3C 8,3 ~, C~2H22N202 76,: 6,36 8, [90
XlIl: 140--14~ 1760 72,8 ,,89 7.8(: CnH22N203 72,{ 6,O71 7,: 83
Xllc 1770, 2230 71,8 ,94 3,6 CtsH,IN~O2 712 3,66113.! 150
Xlld s '9 Tdg 45 1770, 2240 70,4 ,13 1,2 C22HzgN~O8 70,5 5.101111', 21
XIII," 80 1740, 1760 74,7 ,44 5,94 C29H26N204 74,; 5,581 6,( 59
XIIII: 15514523i27223~ 75 !740, 1760 72,5 24 6,0{ C29H26N20~ 72,1 5,40 5,~ '37
XIII e 45 1750, 1765, 71,6 ,62 9,8C C25HI~N~O4 71,~ 3,56 9,! 95
225 dacomp.
2235
X[V 270 1700, 1770 -- ~- 8,6~ CI~HI2N204 _ _ I 8,1 56
decomp. I

*Compound IX was crystallized from benzene, Xlla from hexane,

XIIb and XIIIa, b from ethanol, and XIIc, d and XIIIc from
ethyl acetate. Them is the temperature of the nematic meso-
phase, and Tis the temperature of the isotropic mesophase.
#AT is the existence range of the mesomorphous state.

The acid (la) was obtained with yields of 60-70% both by the hydrolysis of cyanopyrimidine
IIa and by the oxidation of styrylpyrimidine IVa under the conditions of phase-transfer
catalysis or of methylpyrimidine Va by selenium dioxide with prolonged boiling in pyridine.
In order to replace the toxic selenium dioxide we studied the possibility of synthesizing
the acids I from the derivatives V under the conditions of phase-transfer catalysis, the
effectiveness of which in oxidation reactions is well known [13]. The experiments showed
that the oxidation of Va by permanganate does not occur at room temperature in the two-phase
dichloroethane-water (benzene-water, o-dichlorobenzene-water) system in the pre~enge of
typical phase-transfer catalysts (18-crown-6, Bu3(C6HsCH2)N+CI -, Bu~N+Br-); when the
temperature was increased decomposition of the pyrimidine ring was observed, and only benzoic
acid was isolated from the reaction mixture. The oxidation of the pyrimidine V by atmospheric
oxygen in the presence of V-Mo--O catalyst (V:Mo, 3:1) and Pd-Cu-NaY zeolite at 400-440~
under pulsed conditions (4-methylpyrimidine is oxidized to 4-formylpyrimidine with high
selectivity under these conditions [14]) led to the formation of carbon oxides and resinous
products. Oxygen-containing organic compounds were not found in the reaction products.
During the production of the acid Ia from 2-bromomethyl derivative Via [15], according to
mass spectrometry, bromine-containing products were detected in the product as impurities.
Similarly, only p-methoxybenzoic acidis formed from methylpyrimidine Vb during oxidation
under the conditions of phase-transfer catalysis; it was possible to obtain the acid Ib by
the oxidation of styrylpyrimidine IVb in the two-phase benzene--aqueous potasssium permanganate
system in the presence of tributylbenzylammonium chloride. In the case of the butyloxyphenyl
derivatives IVc, Vc, however, oxidation under analogous conditions did not lead to the cor-
responding acid Ic as a result, evidently, of the oxidative elimination of the butyloxy group.
The hydrolysis of the cyanopyrimidine IIc gave a mixture of the acid Ic, its amide VIIc, and
2-hydroxy-5-(p-butyloxyphenyl)pyrimidine (VIIIc), the ratio of which depended on the hydrol-
ysis conditions. When 10-15% sodium hydroxide was used at a bath temperature of 90-I00~
hydrolysis only took place slowly (TLC), and the acid Ic and the amide VIIc were found in the
reaction mixture. If the temperature was increased to I00-120~ the initial cyano derivative
disappeared after 1 h, but the 2-hydroxy derivative VIIlc began to appear. During hydrolysis
at a bath temperature of 130~ the latter was the only reaction product. These compounds can-
not be separated by recrystallization and are difficult to separate by chromatography on
account of the similarity in their Rf values. The hydrolysis of the cyano derivative IIb
takes place similarly (according to IR spectroscopy and TLC).
From the acids Ia, c we than obtained their aryl esters in order to investigate their
mesomorphous characteristics. Various methods have been described for the production of the
aryl esters of carboxylic acids, but the most widespread method is the reaction of phenols
with acid chlorides [16]. Since the pyrimidine-2-carboxylic acids do not always form acid
chlorides readily [15], we checked the applicability of the carbodiimide method [17, 18]

311
and the method employing the trlphenylphosphlne-~arbon tetrachloride complex [19] for the
production of the aryl pyrimidine-2-carboxylates in the case of 4,6-dlphenylpyrlmidine-2-
carboxylic acid. The synthesis of the aryl esters of pyrimidinecarboxyllc acids has not
been described in the literature. There are only patent data on the production of p-nitro-
phenyl pyrimidine-5-carboxylate in the presence of dicyclohexylcarbodilmide (DCC) [20].
It was shown that, unlike pyrimidine-5-carboxylic acid [20], in reaction with p-cyano-
phenol in THF in the presence of DCC 4,6-diphenylpyrimldine-2-carboxylic acid forms a com-
pound which corresponds in its spectral characteristics to the ureide X and not the aryl
ester IX (Scheme 2).

SCHEME 2

%II s , %II 5

6H11
C~ H,~" ~ N / ~ ' C 0 0 1 1 CeH~ ~ " N / " C O S "
"" C O N H C ~ H 11

~176
~, 5
I C[~H5

\. ~-.."-/ CnlI ~.... N" ~(?ONI[C~I[ I

iX XI

Compounds of such a type are formed as a result of the rearrangement of the correspond-
ing O-acylisourea formed initially in the reactions with DCC [17]. During vacuum distillation
compound X was converted into the amide (XI). The p-cyanophenyl ester IX was obtained from
p-cyanophenol and 4,6-diphenylpyrimidine-2-carboxylic acid with a good yield by means of the
PPhs-CCI4 complex [19] and also by the traditional method through the acid chlorides [6].
We obtained the esters XII by the reaction of the acids I with p-substituted phenols
according to the method in [9] (scheme 3)~

SCHEME 3

Ia,c

--N ---

~-N ~--N '-----"

~v ~ x/i a-fl

N I

xIIIa-c
Xll XI[I a--c R=H,d RffiOC4H9; aRt=CbH,,, b RI=0CsH,,,c,dR"=CN

The esters XIII with two bridging groups were obtained by different methods [6, 16];
for R I = CsH~I and OCbHI, the synthesis was realized similarly to the previous synthesis from
the acid la and the aryl p-hydroxybenzoate [7], and in the case of R ~ = CN we first obtained
the carboxy ester XIV, which we then converted into the ester Xlllc through the acid chloride
by reaction with p-cyanophenol. The obtained esters XII and XIII were easy to isolate from
the reaction mixture and were purified well by recrystallization. Thin-layer chromatography
was only suitable for isolation or purification in the case of the esters not containing
CN groups. During chromatography on silica gel and elution with alcohol the latter were
converted into the corresponding ethyl esters.

312
 TABLE 2. 2,5-Disubstituted Pyrimidines
, , ,, ,
,, ,, , , , ,

Found, % Calculated, % Yield, %

Com- Trap. ~ M(Mealc) R/ Molecular
pound JR spectrum , v,cm-'
N(Br) formula C It N(Br)

la 223 200 0,2--0,3 1730 66,0 4,00 14,2 C,,HaN202 66,0 4,00 14,0 71
Ib 230--231 62,9 4,18 12,7 C,2HIoN203 62,6 4,38 12,2 42
Ic 170--1755' 272 0,50 1720 10,0 CI,~HmN~O3 10,3 61
lib 182--187 0,75 1260, 2250 67,9 4,30 20,0 CmHgN,~O 68,2 4,30 19,9 63
IIla 181--182 0,45 56,6 4,60 11,7 CIIH,oN202 56,5 4,30 11,9 30
Illb 184--185 0,65 1135, 1310 54,5 4,91 10.6 Ct2Hi2N2Oa 54,6 4,55 10,6 73
vb 137--138 O,35 72,2 5,83 14,0 CI2HI2N=O 72,0 6,00 14,0 83
V c 113--115 (1,35 74,8 7,45 11,4 Cml 1,8N20 74,4 7,44 11,6 95
VI a 163--165 404 0,90 32,4 1,72 6.80 C,,lbBr.sN2 33,0 1,61 6.49 68
subl. (59,0) (59,0)
Vile 150--160 % 271, 1322 0,52 1690,3200,3280 sh3400 C,s}laTN302
(271. 1321)
Vlllc 195--199 244 0,44 1680 b , r 69,5 6,71 11,5 C,411mN202 68,9 6,55 11,5 55 $

*Compounds la, b, Vlllc were crystallized from ethyl acetate, lib from a mixture of ethanol and carbon tetrachloride,
Ilia, b from ethanol, Vb from heptane, and Vc from methanol.
%After TLC.
,In the condensation reaction.

r
i-a
 Liquid-Crystalline Characteristics of Esters XII and XIII. The esters Xlla-c did not
exhibit mesomorphous characteristics even in the presence of the CN group (Xllc), although
the previously described benzene analogs of the esters Xllb, c, i.e., p-cyanophenyl [9]
and p-amyloxyphenyl [ii] biphenylcarboxylates, were nematic liquid crystals. As noticed
earlier for Schiff bases [21], ~he introduction of a pyrimidine ring in place of the benzene
ring in this case also to loss of the liquid-crystal characteristics. In the presence
of a substituent at the p position (the ester Xlld) the compound becomes mesomorphous, and a
nematic meso phase appears. In this case it is possible to draw an analogy both with the
appearance of nematic characteristics in biphenylcarboxylic esters [i0, ii] and in the
similarity in the clearing temperatures of their cyanophenyl esters [I0].
Similarly, diesters XIII are nematic liquid crystals (Table i). In compounds Xllla,
b the mesophase appears at lower temperatures than in the ester Xlld, while the cyano
derivative Xlllc is characterized by high-temperature transitions. The existence range of
the liquid-crystal state in these compounds amounts to 80~

EXPERIMENTAL

The IR spectra were recorded in tablets with potassium bromide on a UR-20 spectrometer.
The PMR spectra of compounds la, b, IVa-c were recorded on a Bruker WH-90/DS spectrometer in
chloroform with TMS as internal s t a n d a r d . The spectra of the other compounds were recorded
on a Varian A56/60 spectrometer in deuter0chloroform with HMDS as internal standard. The
molecular weights were determinedby massspectrometry on a high-resolution MS-902instrument.
The phase transition temperatureswere measured on a small-scale heater bench of the Boetius
type with an RNMK-0.5 visual facility. Thin-layer chromatography was performed in the 20:1
chloroform--alcohol system on Silufol UV-254 plates and silica gel L50/40.
The characteristics of the obtained compounds are given in Tables i and 2.
5-Phenylpyrimidine-2-carboxylic Acid (la). A. A suspension of 1.27 g (7 mmoles) of
the cyanopyrimidine lla in 25 ml of a 15% sodium hydroxide solution was boiled for 0.5 h
and cooled. The precipitate was filtered off and washed with chloroform and with alcohol.
The obtained salt was suspended in 30 ml of water and acidified to pH 2-3 with dilute
hydrochloric acid. The acid la was filtered off and dried in air. The yield was i g.

B. To a solution of 2.15 g (18.3 mmoles) of styrylpyrimidine IVa and 0.26 g (0.83 mmoles)
of tributylbenzylammonium chloride in 35 ml Of benzene, cooled to 15~ we added dropwise
a solution of 2.63 g (17 mmoles) of potassium permanganate in 55 ml of water at such a rate
that the temperature of the reaction mixture did not exceed 20~ The mixture was stirred
at 15-20~ for 0.5 h, the manganese dioxide was filtered off, the aqueous layer was separated
and acidified to pH 2-4, and the precipitated acid la was filtered off. The yield was 1.07
g (68%). PMR spectrum, 7.49-7.84 (m, 5H, Harom) , 9.16 ppm (s, 2H, 4,6-H of pyrimidine ring).
C. To a solution of 2.04 g (12 mmoles) of methylpyrimidine Va [22] in 25 ml of pyridine,
while boiling, we added 2g (18 mmoles) of selenium dioxide in small portions over 4 h. The
mixture was cooled, the precipitated selenium was filtered off, and the solvent was distilled.
The distillation residue was dissolved in 25 ml of 0.i N sodium hydroxide solution, filtered,
and acidified to pH 4 with hydrochloric acid. The precipitate was filtered off, and 0.91 g
(61%) of the acid la was obtained,
D. To a stirred solution of 1.5 g (3.6 mmoles) of tribromomethylpyrimidine Via in i0
ml of glacial acetic acid we added dropwise 5 ml of a 2 N aqueous solution of silver nitrate.
The mixture was heated in the dark for 1.5 h. The cooled suspension was treated with i ml
of 5 N hydrochloric acid. The precipitate was filtered off and washed with 50 ml of alcohol.
The alcohol filtrate was evaporated, and 0.64 g of the precipitate was obtained. It was
washed with ether and with methanol, sublimed at 150~ (I mm Hg), and recrystallized from
ethyl acetate. The acid la was obtained with a yield of 0.40 g (56%). The IR spectra of
the acids obtained by methods A and D were identical. The mass spectrum contained a line with
m/z 325, corresponding to the dibromomethyl derivative.
5-(p-Methyoxyphenyl)pyrimidine-2-carboxylic Acid (Ib). Compound Ib was obtained
similarly to la by method B from styrylpyrimidine IVb. P~fllspectrum: 3.44 (s, 3H, OCH3),
6.71-7.31 (m, 4H, Harom) , 8.62 ppm (s, 2H, 4,6-H of pyrimidine ring).

314
 5-(p-Butyloxyphenyl)pyrimidine-2-carboxylic Acid (Ic), 5-(p-Butoxyphenyl)-2-carbamoyl__-
pyrimidine (VIIc), and 2-Hydroxy-5-(p-butyloxyphenyl)pyrimidine ~IIIc). A suspension of
2 g (7.9 mmoles) of the cyanopyrimidine IIc [3] was heated and shaken with 50 ml of a 15%
solution of sodium hydroxide at 120~ for ! h. The mixture was cooled, and the precipitated
sodium salt was filtered off and washed with water and with alcohol. It was suspended in
30 ml of water and acidified to pH 2-3 with a 20% solution of hydrochloric acid. The pre-
cipitate was filtered off and washed with water and with alcohol. We obtained 2 g of a
mixture of the acid Ic, the amide VIIc, and the hydroxypyrimidine VIIIc. IR spectrum:
1610, 1630 sh, 1680, 1720 cm-I. Rf 0.40 (dark luminescence) 0.45-0.50 (two light spots).
The mixture was not separated during recrystallization from alcohol, ethyl acetate, or ben-
zene, or by reprecipitation by dissolution in alkali and careful acidification. By twofold
separation by preparative TLC we obtained 1.3 g of the acid Ic and a small amount of the
amide VIIc. The hydroxypyrimidine VIIIc was obtained with a yield of 0,i g; Rf 0.45, mp
199-200~ (from ethyl acetate). It was identical with an authentic sample in its IR spectrum.
2-Cyano-5-phenylpyrimidine (IIa). A suspension of 6.8 g (29 mmoles) of the pyrimidine
IIIa and 2.5 g (~9 mmoles) of potassium cyanide in 130 ml of N-methylpyrrolidone was stirred
at room temperature for 1 h, at 50~ for 2 h, and at 65~C for 4 h. The mixture was poured
into 40 ~ ml of water and extracted with ether (4 x i50 ml). The extract was washed with
300 ml of water, dried with magnesium sulfate, and evaporated. The yield of the cyano
derivative Ila was 3.7 g (70%); mp 128-129~ (from alcohol). Published data [23]: mp
129-130~
2-Cyano-5-(p-methoxyphenyl)pyrimidine (lib). To a solution of 8 g (36 mmoles) of the
pyrimidine IIIb in 200 ml of DMFA we added 2.34 g (36 mmoles) of potassium cyanide. The
mixture was heated at IO0~ for 3 h. A sample of the reaction mixture (i0 ml) was then
diluted with water (i:i). The precipitate was filtered off, dissolved in I0 ml of methylene
chloride, filtered, and evaporated. The product was recrystallized from a mixture of carbon
tetrachloride and alcohol, and 0oi g of the cyanopyrimidine IIb was obtained. PMR spectrum:
3.85 (s, 3H, CH3); 7.07 and 7.50 (d, 2H, J = 9 Hz,~ Harom) ; 9.00 ppm (s, 2H, 4,6-H of
pyrimidine ring).
The D ~ A was distilled from the remaining quantity of the reaction mixture. The res-
idue was extracted with methylene chloride (4 i00 ml), the extract was evaporated, and
6 g of a mixture containing two compounds with Rf 0.70 and 0.75 was obtained. A sample of
the mixture (0.76 g) was boiled with I0 ml of a 15% solution of sodium hydroxide. The un-
dissolved part was filtered off and recrystallized from alcohol, and 2-dimethylamino-5-
(p-methoxyphenyl)pyrimidine was obtained; mp 127-130~ The yield was 0.25 g (29%). PMR
spectrum: 3.12 (s, 6H, NCH3), 3~ (s, 3H, OCHs), 6.90 and 7.30 (d, 2H, J = 9 Hz, Harom) ,
8.43 ppm (s, 2H, 4,6-H of pyrimidine ring). Found %: C 67.9; H 6.45; N 18.4. CI~HIsN30.
Calculated %: C 68.1; H 6.55; N 18.3 .
2-Methylsulfonyl-5-phenylpyrimidine (IIIa). By stirring we dissolved 9.69 g (48 mmoles)
of 2-methylthio-5-phenylpyrimidine [22] in I00 ml of glacial acetic acid. The mixture was
heated to 60~ and 25 ml of 30% hydrogen peroxide was added drop by drop. The mixture was
heated for 6 h, the solution was poured into i00 ml of water, the precipitate was filtered
off and washed with 50 ml of 10% sodium bicarbonate solution and to a neutral reaction with
water, and 3.2 g of the pyrimidine IIIa was obtained.
2-Methylthio-5%(p-methoxyphenyl)pyrimidine. A mixutre of 30 g (90 mmoles) of 2-(p-
methoxyphenyl)-3-dimethylaminopropenylidenedimethylamine perchlorate [24] and 13.1 g (60
mmoles) of methylisothiourea sulfate in 150 ml of absolute pyridine was heated at 80~ for
6 h. The mixture was poured onto a mixture of 900 g of ice with ii0 ml of concentrated
sulfuric acid. The precipitate was filtered off, and 19.75 g (94%) of the product was ob-
tained; mp 79~ (from hexane). Found %: C 62.6; H 5.43; N 12.0. CI=HI2N20. Calculated %:
C 62.5;H 5.18; N 12.0.
2-Methylsulfonyl-5-(p-methoxyphenyl pyrimidine (IIIb). To a suspension of 10.58 g
(46 mmo~es) -~ ~ o - 5 - ( p ' m e t h o x y p h e n y l ) p y r i m i d i n e in 90 ml of glacial acetic acid
we added 23 ml of 30% hydrogen peroxide. The mixture was stirred at 50~ for 6 h and added
to 200 ml of water. The precipitate was filtered off, washed to a neutral reaction with I00
ml of 10% sodium bicarbonate solution and then with water, and dried. We obtained 8.8 g
of the pyrimidine IIIb.

315
 2-Styryl-5-phenylpyrimidine (IVa). A mixture of 17 g (i00 mmoles) of the pyrimidine
Va and 11.7 g (ii0 m moles) of benzaldehyde was stirred at 150-160~ for 4.5 h, cooled, and
dissolved in 50 ml of acetone. Water was added (i00 ml) until a precipitate separated. The
precipitate was filtered off and recrystalllzed from petroleum ether. The yield of styryl-
pyrimidine IVa was 18 g (70%); mp 143~ PMR spectrum: 7.15-8.16 (m, 12H, Hvlny I and Harm) '
8.90 ppm (s, 2H, 4,6-H of pyrim!dlne ring). The following two compounds were obtained
similarly.
2-StYrYl-5-(p-methoxyphenyl)pyrrimidine (IVb). The yield was 64% mp 166-168~ PMR
spectrum: 3.89 (s, 3H, OCH,), 6.96-8.02 (m, IIH, Hviny I and Harom ) 8.93 ppm (s, 2H, 4,6-H
of pyrimidine ring).
2-Styryl-5-(p-butyloxyphenyl)pyrimidine (IVc). The yield was 67%; mp 135-138~ PMR
spectrum: 1.00 (t, 3H, J = 6 Hz, CH3), 1.31-2.00 (m, 4H, CH=), 4.02 (t, 2H, J = 6 Hz, OCH2),
7.24 (q, A2B2, J = 8 Hz, 4H, Harom) , 8.78 ppm (s, 2H, 4,6-I{ of pyrimidine ring).
2-Methyl-5-(p-methoxyphenyl)pyrimidine (Vb) and 2-methyl-S-(p-butyloxyphenyl)pyrimidin ~
(Vq). The compounds were obtained by a method similar to that in [22].
2-Tribromomethyl-5,phenylpyrimidine (Via). To a boiling solution of ~.5 g (50 mmoles)
of the pyrimidine (Va) and 24.6 g (300 mmoles) of sodium acetate in 150 ml of glacial acetic
acid we added 24 g (150 m moles) of bromine in I0 ml of glacial acetic acid. The mixture was
stirred for 0.5 h and left over n i g h t . The precipitate was filtered off and washed with
100 ml of a saturated solution of sodium bicarbonate and with water. We obtained 12.15 g
of the pyrimidlne Via.
2-Hydroxy-5-(p-butyloxyphenyl)pyrimidine (VIIIc). To a mixture of 1.12 g (3 mmoles)
of 2-(p-butyloxyphenyl)-3-dimethylaminopropenylidenedimethylamine perchlorate [24] and
0.24 g (4 mmoles) of urea we added 5 ml of absolute methanol. The mixture was heated to
boiling, and a solution of sodium methoxide (from 0.16 g of metallic sodium and 3 ml of
methanol) was slowly added drop by drop. The mixture was heated for 3 h and cooled, and 50
ml of water and 5 ml of acetic acid were added. The product was rubbed until a uniform
suspension was obtained. The fine precipitate was filtered off and washed with water and
several times with ether. We obtained 0.4 g of the hydroxypyrimidine VIIIc.
p-Cyanophenyl 4,6-Diphenylpyrimidine-2-carboxylate (IX). A. A mixture of 2 g (7.25
mmoles) of 4,6-diphenylpyrimidine-2-carboxylic acid [25] and 14 ml of thionyl chloride in
150 ml of benzene was boiled in the presence of six drops of DMFA for 24 h. The mixture was
distilled to dryness, a further 30 ml of dry benzene was added, the mixture was again
distilled to dryness, and the residue was kept under vacuum (2.6-3.0 kPa) for 5-7 min. The
acid chloride was dissolved in 35 ml of pyridine, 0.86 g (7.2 m moles) of p-cyanophenol was
added, and the mixture was stirred at room temperature for five days. It was then poured
onto 150 g of ice with 35 ml of concentrated sulfuric acid. The precipitate was filtered
off and washed with water, alcohol, and ether, and 1.66 g of the ester IX was obtained.
B. A mixture of 2 g (7.25 mmoles) of the acid, 0.7 g (6 m moles) of p-cyanophenol, 1.9
g (7.2 mmoles) of triphenylphosphine, 0.73 g (7~ mmoles) of triethylamine, and i.i g (7.2
mmoles) of carbon tetrachloride in I0 ml of acetonitrile was stirred at room temperature
for 6 h. The precipitated ester IX was filtered off and washed with chloroform. The yield
was 1.5 g (66%); mp 208-209~ (from ethyl acetate).
N-Cyclohexy!-4,6-diphenylpyrimidine-2-carboxamide (XI). To a solution of 1 g (3.6 mmoles)
of 4,6-diphenylpyrimidine-2-carboxyllc acid and 0.96 g (7.2 mmoles) of p-cyanophenol in
50 ml of dry THF we added dropwise a solution of 1.5 g of DCC in 20 ml of dry THF. The
mixture was stirred at room temperature for 9 h and evaporated. The residue was rubbed with
15 ml of ether, and the ureide X was filtered off; mp 179-181~ (from ethyl acetate). IR
spectrum: 1640, 1680, 1705, 3290 cm -~. The ureide (X) was sublimed under vacuumat 150-160~
(2 mm Hg)~ and the amide (XI) was Obtained; mp 218-223~ IR spectrum, 1635, 3330 cm -~.
Found %: N 11.9; M 357. C2sH23N30. Calculated %: N 11.7; M. 357.
p-Cyanophenyl 5-Phenylpyrimidine-2-carboxylate (XIIc). A mixture of 1 g (5 mmoles) of
the acid Ia, 0.47 g (4.2 mmoles) of p-cyanophenol, 1.31 g (5 mmoles) of triphenylphosphine,
0.5 g (5 m moles) of triethylamine, and 0.77 g of carbon tetrachloride in 6.5 ml of acetonitrile
was stirred at room temperature for i0 h. The precipitate was filtered off and washed with
acetonitrile, and compound XIIc was obtained.

316
 p-Amylphenyl (Xlla) and p-amyloxyphenyl (XIIe) esters of the acid la were obtained
similarly.
p-Cyanopheny! 5,(p-ButyloxyphenYl)pyrimidine-2-carboxylate (Xlld). A mixture of 1.3
g (4.8 mmoles) of the acid Ic, 0.48 g (4 mmoles) of p-cyanophenol, 1.26 g (4.8 mmoles)
of triphenylphosphine, 0.47 ml (4.8 mmoles) of carbon tetrachloride, and 0.67 ml (4.8 mmoles)
of triethylamine was stirred on a magnetic stirrer for 6 h. The precipitate was filtered off
and washed with acetonitrile, heptane, and ether, and 0.9 g of the precipitate was obtained.
It was rubbed with 30-40 ml of benzene and filtered. The solution was evaporated, and 0.38
g of the ester Xlld was obtained. The product was purified by recrystallization from a i:i
mixture of benzene and petroleum ether and then from ethyl acetate. By purification by TLC
and elution with alcohol we only obtained the ethyl ester of the acid Ic, which was identical
with an authentic sample.
Ethyl 5-(p-Butyloxyphenyl)pyrimidine-2-carboxylate. A mixture of 0.13 g (0.48 mmoles)
of the acid Ic, 3 ml of alcohol, and three drops of concentrated hydrochloric acid was boiled
for 5 h and cooled. The precipitate was filtered off and washed with ether. The yield was
0.I g (70%); mp 150.5-151.5~ (from alcohol). IR spectrum: 1730 cm -I. Found %: C 68.1;
H 6.68; N. 9.39; M 300. C17H2oN203. Calculated %: C 68.1; H 6.66; N 9.33; M 300.
P-EthYl- and p-Ethoxyphenyl p-(5-Phenyl-2-pyrimidylcarbonyloxybenzoate (Xllla, b). We
mixed 2.4 mmoles of the acid la, 2 mmoles of p-ethyl- or p-ethoxyphenylp-hydroxybenzoate
[7], and 2.4 mmoles each of triphenylphosphine, carbon tetrachloride, and triethylamine. The
mixture was stirred at room temperature on a magnetic stirrer for 7-10 h. The precipitated
ester was filtered off and washed with hexane and with ether.
p-Cyanophenyl p-(5-Phenyl-2-pyrimidoylcarbonyloxy)benzoate (Xlllc). To a suspension of
0.64 g (2 mmoles) of the acid XIV in 20 ml of absolute benzene we added 3 ml of thionyl
chloride. The mixture was boiled for i0 h, and the benzene and thionyl chloride w e r e d i s -
tilled to dryness. To the residue we added i0 ml of benzene. The mixture was again distilled
to dryness, the residue was kept under vacuum (2.6-3.0 kPa) for 0.5 h, and 0.77 g of the acid
chloride XIV was obtained. IR spectrum: 1760 br, 1780 cm -I.
To a suspension of 0.75 g (2.22 mmoles) of the acid chloride in i0 ml of pyridine we
added 0.26 g (2.18 mmoles) of p-cyanophenol. The mixture was stirred at room temperature
for 4 h. The precipitate was filtered off, washed with i0 ml of 10% hydrochloric acid and
to a neutral reaction with water, and dried in air. We obtained 0.8 g of the ester Xlllc.
p-(5-Phenyl-2-pyrimidylcarbonyloxy)benzoic Acid (XIV). A mixture of 2 g (i0 mmoles)
of the acid la with 15 ml of thionyl chloride in i00 ml of absolute benzene with the addition
of i ml of DMFA was boiled for 15 ho The mixture was distilled to dryness, 50 ml of benzene
was added to the residue, and the mixture was again distilled to dryness. The residue (the
chloride of the acid la) crystallized in the form large needless. IR spectrum 1740 w, 1775
cm -I. To the acid chloride la we added 30 ml of dry pyridine and 0.7 g of p-hydroxybenzoic
acid. The reaction mixture was kept at room temperature for three dayso The precipitate
was filtered off, washed to a neutral reaction with water which had been acidified with
hydrochloric acid, and dried~ We obtained lo8 g of the acid XIVo

The authors express their gratitude to Mo Fo Grebenkin and V. To Lazareva for useful
discussion of the results~
LITERATURE CITED

io D. J. Byron, Do Lacey, and Ro Co Wilson, Mol. Cryst. Liqo Cryst., 62, 103 (1980)o
2. G. W. Gray: Jo Physo Collo, i, 337 (1975)o
3. Ho Zaschke, Zo Chemo, 17, 63 (1977)o
4. A. Boller, Mo Ceregetti-~Mo Schadt, and H. Scherrer, Molo Cryst. Liq. Crysto, 42, 215
(1977)o
5. M. Eo Neubert and L. To Carlino, Molo Cryst. Liq. Crysto, 59, 253 (1980).
60 Ho J. Deutscher9 Co Seidelo Mo Korber, and H. Schubert, Jo Pr. Chemo, 321, 47 (1979).
7. J. P. van Meter and Bo Ho Klanderman, Molo Cryst. Liqo Cryst., 22, 285 (1973).
8. A. I. Pavlyuchenko, No Io Smirnova, Eo Io Kovshev, Vo V. Titov, and K. M. Dyumaev,
USSR, Inventor's Certificate No. 681,056; Byul. Izpbro, No. 31 (1979), 94.
9o R. C. Maze and Ro M. Reynolds, U. So Patent No. 4,162,988; Chem. Abst. 92, 32031
(1980) o
10o L. A. K a r a m y s h e v a , Eo Io Kovshev, and Mo Io B a r n i k , Mol. C r y s t . L i q . C r y s t . , 37, 29
(1976).
317
ii. D. J. Byron, D. Lacey, and R. C. Wilson, Mol. Cryst. Liq. Cryst., 51, 265 (1979).
12. T. Sakamoto and H. Yamanaka, Heterocycles, 15, 583 (1981).
13. E. V. Dehmlowand S. S. Dehmlow, Phase Transfer Catalysis, Verlag Chemic, Weinheim,
(1980), p. 249.
14. I. G. lovel', M. V. Shimanskaya, and L. Ya. Margolis, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. i0, 2301 (1977).
15. W. K. Hagmann, F. Z. Basha, ~M. Hashimoto, R. B. Frye, S. Kojo, and S. M. Hecht~ J. Org.
Chem., 46, 1413 (1981).
16. S. Patai (editor), The Chemistry of Functional Groups. Suppl. A. The Chemistry of
Double-Bond Functional Groups, Interscience, New York (1977), p. 112.
17. M. Mikolajczyk and P. Kiebasinski, Tetrahedron, 37, 233 (1981).
18. A. Williams and J. T, Ibrahim, Chem. Rev., 81, 589 (1981).
19. S. Hashimoto and I. Furukawa, Bull. Chem. Soc. Japan. 54, 2227 (1981).
20. T. Y. Shen, U. S. Patent No. 3,316,267; Chem. Abst., 68, 95683 (1968).
21. M. A. Mikhaleva, V. T. Lazareva, M. F. Grebenkin, V. A. Savel'ev, and V. P. Mamaev,
Khim. Geterotsikl. Soedin., No. ii, 1545 (1982).
22. R. Mo Wagner and Ch. Jutz, Chemo Bet., i04, 2975 (1971).
23. S. G. Baram, O. P. Shkurko, and V. P. Mamaev, Izc. Akad. Nauk SSSR, Set. Khim., !985
No. 2, 299.
24. H. Zaschke, S. Arndt, V. Wagner, and Ho Z. Schubert, Chem., 17, 293 (1977).
25. V. P. Mamaev and V. P. Krivopalov, Khim. Geterotsiklo Soedin., No. i, 145 (1966).

REACTIONS OF AZINIUM IONS.

4.* REACTIONS OF QUINOXALINIUM SALTS WITH NITROALKANES -- SINGLE-STAGE
PATH TO TETRAAZAHETEROCYCLES WITH BRIDGED AND FRAMEWORK STRUCTURES

V. N. Charushin, D. M. Petrova, UDC 547.863.1.07:543.422.25:548.737

O. N. Chupakhin, E. O. Sidorov,
G. G. Aleksandrov, A. I. Chernyshev,
N. A. Klyuev, and N. N. 8orokin

The addition of the carbanions of nitroalkanes of N-alkylquinoxalinium salts in an

alcohol medium leads to dibenzo[d,k]-l,3,6,10-tetrasubstituted tricyclo[7.3.1.02'7] -
and tetracyclo[7.3.1.02'706'~3]tridecanes.

The reactions of azinium ions with the carbanions of nitroalkanes take place in various
ways. Thus, the N-methoxypyridinium ion adds nitroalkanes in the presence of sodium ethoxide
at position 2 with subsequent opening of the pyridine ring [2]. More complex transformations
were observed in the reaction of nitroalkanes with quaternary isoquinolinium salts, in which
complex polycyclic systems with a framework structure are formed as a result of thesuccessive
combination of two isoquinolinium molecules [3]. In the present work we give the results from
an investigation into the reactions of nitroalkanes with quaternary quinoxalinium salts,
which are susceptible (unlike other azinium ions) to the formation of products from the
diaddition of nucleophiles at positions 2 and 3 [4-7].
In fact, a common feature of the investigated transformations of quinoxalinium salts
under the influence of trinitroalkane anions is the formation of tetrahydroquinoxalines from
them as a result of the diaddition of the nucleophiles. However, the outcome of the reactions
depends on the nature of the reagents, the solvent, and also the base.
When dissolved in an excess of nitroethane in the presence of diethylamine, N-methyl-
quinoxalinium iodide (Ia) gives a high yield (87%) of the diaddition product II, melting at
*For Communication 3, see [i].

S. M. Kirov Ural Polytechnical Institute, Sverdlovsk 620002. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 3, pp. 389-399, March, 1986. Original article submitted
February 21, 19851

318 0009-3122/86/2203-0318512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Characteristics of the Tetrahydroquinoxalines II,
llla,d,e, and IX
..... i
} IR spec- I
I trum, !Massspectrum,m/z Found. % Molecular Calculated ~ I
(7>10%) formula
c[H N
i
II 196--1971339211508, 53,5 6,3 18,8 Cl3HtaN404 53,1 6,2 [ 19,0 86
I 11342
lIla 217--2181 -- 1510, 77 (I2), I31 (J2), 66,4 5,7 19,0 C2oH~rNsO2 60,, 5,81,9,3
340 145 (62), 185 (43), I
3t7 (100),363 09)
IIldl 176--178 -- ,[500, 77 (19), 130 (10), 66,7 6,3 19,4 C2,1-I2,~N502 66,8 6,1118,6 42
!345 131 (61),159 (100),
I60 (29), 185 (22),
331 (89), 332 (21),
377 (6)
llIe 158 -- 11507 77 (I1), 131 (35), 67,4 6,5 17,8 67,5 6,4117,9 44
1343 159 (82), 160 (12),
199 (44),345 (100)~
I
~ P i
i
346 (37), 391 (7) 1 ! "
iX 157 3392 1510, 77 (13), 102 (13), ,64,016,6 21,6 CmH26N602 64,C 6,6121,3 55
1350 I31 (12), 133 (2t),
145 (100),146 (17),
171 (43), 394 (2)
i 9 t I
196-197~ (Table i). The ZH NMR spectrum of II in deuterochloroform contains clear doublet
signals for the protons of the methyl groups of the two nitroethane residues at 1.53 and
1.57 ppm, a singlet for the N-methyl protons at 2.90 ppm, a broadened signal for the NH
proton at 5.82 ppm, and complex multiplets for the protons of the benzene ring (6.4-6.8 ppm,
4H) and the four methine protons in the region of 3.4-4.8 ppm. This part of the spectrum
becomes significantly simplier in the transition to the 2,3-deuterated analog of If, ob-
tained fromthe 2,3-2H-labeled quinoxalinium ion and nitroethane (see the experimental sec-
tion) and this confirms the structure of II.
The reaction of the cation Ia with nitroethane ethanol takes place differently. The
polycyclic compound III, melting at 217-218~ and having the molecular formula C2oH21N~O2
(according to mass spectrometry and elemental analysis), was isolated with a yield of 37%
as the main reaction product under these conditions. By using dimethylamine as base w e w e r e
able to increase the yield of III to 62% (see the experimental section). From the *H and
Z3C N~R spectra of III it follows that it contains two N-methyltetrahydroquinoxaline frag-
ments (singlets for the protons of the two N-methyl groups at 3.14 and 3.24 ppm, multiplets
for the eight protons of the two benzene rings in the region of 6.5-7.5 ppm) and one nitro-
ethane residue (a singlet for the methyl protons at 1.30 ppm) (Table 2). In view of the
hydrogenated structure of the pyrazine ring and also the absence of the absorption for NH
groups in the IR and ZH N-MR spectra it is possible to imagine three types of coupling of the
reagents corresponding to the above-mentioned molecular composition. They can be called the
2,3 (IIIa), 2,2 (IIIb), and 3,3 (IIIc) isomers, depending on which atoms of the pyrazine
ring are directly attached to the nitroethane fragment.
H H

+ C2HbN02 + HN(CzHs) 2 ---~-

I I- N CH(CH3)NO 2
CH3 Clt 3
Ia II

I C2HbOR

V< - . N / NO 2

CH~ CH 5 CH3
III a IIl b HI C

319
t~
tO
o

TABLE 2. aH and laC NMR Spectra of 8-N llla,d,e, and

IX in Deuterochloroform

P r o t o n c h e m i c a l . s h i f t ~ , ~, ppm (SStX~, Hz)

Com-
potlrtd 2-H 7-H 8-H 8-CH~ 9-FI t3-H K--R ]~i]hT~t;~]~ r i t~a~

Ilia 4,37, s 4,11, s 1,30, s 4,64, d 4,36, d 3,14. s {3H1. 6.5~7.4. m {SH]
(VgA3=2,7) 3,24, s {3HI
(t~:~ NCH.~i
IIld 4,25. S 4.00; bs. 4,40, b d , 4,60, dd 4.27, d 1,0--t.5, m {6HI. 6,5--7.3, m {SH]
(3Js,9=2,4; (319.n = 2,6) 3,3--3,8, m {4H}
3Jsz = 0,8) (two NC2HD
Hie 4,21, s 4,11, s 1,24, s 4,60, d 4,19, d i.0~1,4, s |6H), 6,5~L3, m (8tD
(~lo.ta=2.6) 3.4--3,7, s /414)
(two NC2Hs)
IX 4,78, d d 3,~ d , d 4,69. dd 4,45. d.d: 3,88. d 2,80; s {3H), 6,4~7.3. m |SH;
(af2,a = 1,6; (3J'7,a= I0,5) (318,o=2,7) (~1o n = 1,5) s I3Ht
3J'2.:= 4,5 ) ~ NCtI~|

Com- chemical shifts, ~ , pl~

pound
2-C 7-C ~-C : 8-CH~ 9-C I:14d. K -R ~ ~ Of"
ztazete r tn~
Ill a 64,6 80,9 06,2 18,0 66,0 81,9 37,8; 38,4 109,5, 113.4. 1|7~, li&::L 124,?.
( l l c . = 162) (I/CH = 157) ('Jc. = 150) Ilion = 1721 (two NCHz) 125,3. 125.8. 12"fs Ii2~.-[~ 13~_o4.
136.6. 141.9
llld 51,]* 79,8 88,5 63,8* 81,2 1 2 . 5 and t ~ . 3 ; i!2,0, 112.9. !17.9. Ii&{L 155~9.
1 3 . 9 and 4 5 . 6 125.91 126,9. 127.8o 131.1. 131.9.
134,2, 140,5
Ill e 64,2 77,8 c6,0 18,4 64,2 81,5 i 2 . 5 aml ~ . ~ ; 110,0, 112.6. 116.9. liT.5. 154.8.
(lJ'cH = 159) {'JCH = 152) (~lcu ==152) ( V c a = 181) 13.9 and h 5 . 5 19_5,6, 126.4. 127~. 130.0. 132~.
{tWo NC2HD 135,3, 140.7
lX 53,3 69,4* 88,3 61.7" 67.7 39.6:40.8 109,7, i13.4. 114J, 116,9: H S J ,
(two NCH,O; 119.5, 125,8, 125,9
41,9 N{CHs)~
~The assignment of the carbon atomsmarked by asterisks may be reversed.
~ Z Z ~ G ~ G ~ ~
~ # ~ . ~
0 ~I
9 &
fD 0 9
I'D
0 ~ 0 ~
0
rt
~.
m.
f~ m fD t't
f~ ~ . ~
fo I:~
~ m
E
~ ~ 0
0 N

g'og
t"l
0 0
~H
"0
0 Q

f~u

H o
I-4
&
m

v
f~

I
 C(7a)
C(s)
0,00
0,00
C..)
N,r)
-031'
0,00
C~1~)
C(4al
0,00
0,00
iccl:: i 0,00 N~I~) 0.05
-0,01 Cr -0,03
C~., 0,02
C(141 -O,Ol
0,00 CLra) 0,00 Ncs~ 0,00 ]Ct3~ 0,01 N,r, -0,81' N~r) 0,85*
C(to) -0,01 C~ttal 0,00 C~aa) 0,08* IC~4) 0,00 C~V2a) --0,05 C(o) -0,02
C(.) 0,01 N ,2 0,00 Cr -0,56' IC(4.1 -0,01 C~,,) 0,03 C(~l O,Ol
C(tl~*) 0,00 C~12,,) 0,12' N(13~ 0,00 "Ctl.) 0.01
Nita) -1,64'
C(,4) -1,32'
,,, ,,,,, ,,,,,
~gie,
Planes ~eg
Planes Angle, Planes Angle,
deg deg
AB 2,8 BC 44,3 CE 67,3
AC 42,0 BD 46,6 CF [05,3
AD 44,3 BE 95,3 DE 6fi.8
AE 92,6 BF 63,5 DF I08,8
AF 65,3 CD 2,5 EF [14.2

*Atoms not involved in the calculation of the equation for

the respective plane.

Since it proved impossible to determine the structure of the cyclization products III
unambiguously on the basis of the IH and 13C NMR data, we decided to use x-ray crystallographic
analysis for this purpose. By this method it was established that the product has the struc-
ture of 3,8,10-trimethyl-8-nitrodibenzo[d,k]-l,3,6,10-tetraazatetracyclo [7.3.1.02'706, 13] _
trideca-4,11-diene (Ilia) .%
The structure of the molecule of compound Ilia is shown in Fig. I, and the bond lengths
and bond angles are given in Table 3 and 4. The molecule contains six condensed rings A-F.
Both five-membered rings [imidazoline (E) and pyrrolidine (F)] have the envelope conformation
with
9
the NtT~
k ]
atom projecting from the planeo of the remaining four atoms of the
9 9
imidazoline
9
rlng E (C(ea3-C(z2a)--N(zs)-C(za)) by --0.81 A and from the plane of the pyrrolldlne rlng F
(C(z4)-C(~a)~C_
_ ()e-C(6a~) by 0.85 ~ (Fig. i). The six-membered tetrahydropyrazine rings. B
and C have a twisted h~if-chair conformation with the C(z2al and C(ea) atoms deviating from
the plane of the other four atoms of ring B by 0.12 and'--0.~l ~; for the C(~a) and C(,a) atoms
the deviations from the analogous plane of ring C amount to 0.08 and -0.56 A respectively
(Table 5). We not also that the sum of the bond angles at the nitrogen atoms N(7)(320.4 ~)
and N(z3) (335.5 ~ corresponds to pyramidal hybridization, whereas the configuration of the
other two nitrogen atoms in the six-membered rings B and C differs; the N(s) nitrogen atom has
the sum of the bond angles equal to 359.9 ~ , which corresponds to a planar trigonal hybridiza-
tion, while the N(12) nitrogen atom has 345.5 ~ (a flattened pyramidal configuration) (Table
4). The lengths of the C--N bonds with the N(s) and N(~=) atoms also differ; the N(s)--C
bonds are consistently shorter than the corr~s~onding-N(12)--C bonds (Table 3), but the main
bond lengths and bond angles in the molecule of the III as a whole agree well with standard
values [9].
The data from x-ray crystallographic analysis make it possible to assign the signals in
the ~H and laC NMR spectra of IIIa. Calculation of the vicinal constants between the protons

%For the preliminary communication, see [8].

322
 --NCH
8"H 9-H 7-H -~ICH 3

J
I - - I [ i I I
~,ppm 7 6 5 4 2

Fig. 2. The ~ H N M R spectrum in deuterochloroform for the reaction prod-

ucts IX obtained by the reaction of N'methylquinoxalinium iodide with
nitromethane and dimethylamine in ethanol.

of the bridgehead atoms in the pyrazine ring s by means of the Karplus-Conrow equation [i0]
showed that the experimental dihedral angles H--C(~a)--C(~2aI-H (76 ~ and H--C(5a)--C(14)--H (47 ~
must correspond to the 3J(H_H) , values of 0.2 an~ 3.2 ~z r~spectively. In fact, in the
IH NMR spectrum of IIIa in deuterochloroform the protons of one pyrazine ring (9-H and 13-H)
appear at 4.64 and 4.36 ppm in the form of two doublets with 3J91,~3 = 2.7 Hz, while the
methine protons of the second pyrazine ring appear as broadened singlets at 4.37 and 4.11
ppm (Table 2). Thus, the x-ray data make it possible to break the signals of the methine
protons down into two groups, i.e., 9-H, 13-H and 2-H, 7-H. An unambiguous assignment of the
signals for these protons in the IH NMR spectrum of IIIa Was made by comparison of the charac-
teristics of the IH and 13C N M R spectra, including allowance for the results from ex-
periments with selective decoupling of the interaction of the carbon-13 nuclei with
the individual protons. These experiments showed coupling between the proton with ~ = 4.11
ppm and the carbon atom with the following spectral characteristics: ~ = 80.9 ppm, ~J (C__H) =
157 Hz. Similarly it was established that the proton with ~ = 4.64 ppm is coupled with the
carbon atom which resonates at 66.0 ppm and has ~J(c--H) = 150 Hz. To judge from the ~J(c--H)
values, the signals at 80.9 and 66.0 ppm must be assigned to the resonance of carbon atoms
C( ~9- and C( )7, coupled to one nitrogen a t o m , since the signals for the other two brmdgehead"
carbon atoms [C(23 and Cry31] have larger spin--spin coupling constants through one bond
(C--H) (162 and 172 Hz), w~mch agrees with the arrangement of these CH groups between the
two nitrogen atoms. On the basis of the values 3J(H_-H) = 2.7 and ~J(c__H)= 150 Hz the signals
with shifts ~(IH) 4.64 and 6(z3C ) 66.0 ppm ~ere assigned to the H(gj and C 9 atoms, while
the signals with ~ ( ~H) 4.11 ~nd 6 ( ~3C) 80.9 ppm were assigned to ~h~ resonance
( ) of the HtTj
and C(7) atoms respectively. On account of the similar values of the chemical shifts fo~ hhe
2-H and 13-H protons selective decoupling from each of them was impossible, and the assign-
ment of the signals for the C(2) and C(~3) carbon atoms was therefore made with regard to the
following experimental data. First, the selective decoupling from the protons of the two
N-methyl groups with chemical shifts of ~ 3.14 and 3.24 ppm leads to narrowing of the signals
for the u-carbon atoms in the ~3C NMR spectrum at 64.6 and 66.0 ppm, which makes it possible
to assign the signal at ~ 64.6 ppm to the resonance of the C(2) carbon atom (since the signal
at 6 66.0 ppm had already been assigned to the C(9)carbon atom). Second, during selective
decoupling from the 9-H proton (6 4.64 ppm), in addition to the coalesence of the signals for
the C(p} carbon atom at 66.0 ppm into a singlet, narrowing was also observed in the lines for
the signals of the C ~ 3 ) carbon atom to a~clear doublet at 81,9 ppm on account of the removal
of the 2J(c(~3)-H(9)) coupling. Altogether these data make it possible to assign the signals
for the bridgehead carbon atoms and the protons attached to them in the ~H and 13C NMR spectra
of compound IIIa (Table 2).

323
 9 ,
TABLE 6. Atomlc Coordinates~x 10 4 , X 10 3 for the hydrogen
atoms) and the Temperature Factors B^. = 8~a(U~IUaiUa3)I/a
for Hydrogen Atoms (Bis o = 5.0 ~2) ( ~ e standard deviations
are given in parentheses)

Atom "x It eq

CII) 1599 (4} - 6 2 2 (2) 6',;64 (3) 4,1 (1)

C(la) 33;6 (4} --425 (2) 7233 (2) 3,2 (i/
C(21 ~89 15) -- 1266 (2) 7395 (3} 4.8 (I)
C13) 2186 (5} - 1715 (2) 8070 13} 4,9 {1)
C(41 3997 (5) - 1535 (2} 8351 (2) 4,1 (1)
C(4a} 4634 14) - 8 8 8 (2) 7q21 {2) 3,3 Ill
NI5) 6442 {3) --714 111 8161 (2) 3,6 {1}
C<r,:,) 7054 (4) 9- 2 7 (2) 7747 (2) 3,0 {I
Ci61 6979 {4) 752 121 8335 (2) 3,3 {1
C<6.,) 5819 (4) 1271 (2) 7511 (2) 3,0 (1
Niz} 6389 (3) 1o0o ( l } 6628 (21 2,8 (1
5389 14) 13,{}{} 12) 5732 (2) 2,8 11
C(8} 6189 (4} 1511 12) 4970 (2) 3,3 (I)
Ctm 52{~5 (5) 1917 (2) 4100 (2) 4,1 (1}
C(io) 3506 (5) 2187 (2) 4029 (2) 4,1 (1)
C~II) 2754 (4) 2668 (2) 4787 (2) 3,8 (l)
Cilia) 3642 (4) 1667 (2} 51161 (2) 3,0 {1)
N(t~) 2887 {3) 1564 (l) 6456 (2) 4,0 I l l
C( 1,28) 3862 (4) 1014 (2) 7204 (2) 3,1 (1)
N+I;)) 3994 13) 234 (1) 6760 (2) 2,9 (l)
C+l+) 5875 (4) 184 (2) 6715 (2) 2,8 111
NtIs} 8851 (4) 1120 (2) 8632 (2) 4,3 (2)
Oil) 10155 .(4) 702 (2) 8740 (2) 6,9 {2)
O,}} 8970 (4) 1800 (2) 8772 (3) 3,6 (2)
C, Is) 7725 (5) -I183 (2) 8872 (2) 4,7 {1)
C117 g36 (4) 1497 (2) 6215 (3) 4,9 (1)
C{18 6408 (5) 690 (2) 9283 (2) 4,8 {1)
H 77 -23 640
HI: -39 -141 713
It,,~ 175 --223 847
Ill< 505 --181 894
I{f5~ 84O --14 77O
H,6a 595 182 761
746 124 504
H{9 618 199 365
286 254 342
H, ll) 139 9 220 473
H{ t2a) 324 99 777
H,14) 6O2 -18 615
H+tm) 771 - 179 863
H( 162~ 75O - 107 957
H(I+~; 898 --95 894
Hi1711 67 141 690
Hill2) 46 103 566
HI 173} 26 2O4 588
H+lm) 527 41 913
HtI82} 620 123 957
H( *8~t 735 35 984

The ~roducts with framework structures llld, are formed in the reactions of N-ethylquin-.
oxalinium iodide lb with nitromethane and nitroethane in the presence of dimethylamine in
ethanol. This follows from comparison of the characteristics of their IH and ~3C NMR spectra
with the spectra of compound Ilia (Table 2). Substitution of the methyl group at the C(8).
carbon atom by a hydrogen atom leads to the result that the signal for the 9-H proton in the
~H NMR spectrum of compound llld appears as a doublet of doublets at 4.60 ppm on account of
interaction with the 13-H and 8-H protons. This provides a further argument in favor of
the assignments of the signals in the ~H NMR spectra for the series of compounds llla,d,e
(Table 2).
The structure of compounds llla,d,e also corresponds fully to the mass-spectrometric
data. In all cases the molecular ion peaks were recorded, although their intensities were
low (Table i). In the fragmentation schemesof the molecular ions it is possible clearly
to trace the processes of the removal of the nitro group and also the formation of the high-
intensity peaks of the quinoxalinium ions (Table i).

324
 From the established structure of compounds llla,d,e it follows that in the course of the
reaction the CH-active c e n t e r o f the nitroalkane adds at position 2 of one molecule of the
cations la,b and to the C(s) carbon atom of another quinoxalinium molecule. Since the addition
of the nitroalkane at position 3 can only be realized with the formation of an intermediate
having a 1,2-dihydroquinoxaline structure, the reaction mechanism can presumably be repre-
sented by the following scheme:

HN(CH~) z
+ R2CH2N02 + C2I|50H
iv.a,b
1"

la,b R1

c C2H50 / N /(
L..-':.N t
i
CflI50 "" N" " "~t "" " ' N " R 2 N0 2 l l )
~1 ], I.,
L. R R" ) l~' "
VII
v VI
R~ ) ..
/N \ \ , ,
/ / ' '\, ....
//
,~..~ N~. / NO 2

- tlli ---- "~f "N

viii llla,d,e
IO Ilia RI=CH~, Ib I I I d , e .RI=C2Hs; III a,e,lV4) R-~=CH~, IIld, IVa RZ=H

It is supposed that the two addition reactions of the carbanions of the nitroalkanes IVa,
b and the ethoxide ion to the quinoxalinium ions la,b, leading to two types of covalent
adducts (the C-adducts V and the O - a d d u c t s V l take placeconcurrently when the reaction is
carried out in an alcohol--base medium. We recently demonstrated the formation of the dihydro-
quinoxalines VI in an ethanol solution in the presence of bases by *H N MR spectroscopy [ii].
Extremely likely also is the reaction of the adducts V and VI, leading to the intermediate
VII, with subsequent intramolecular cyclizations to the polycyclic compounds llla,d,e
through the intermediates VIII. The presented mechanism makes it possible to explain the
formation of compounds llla,d,e in ethanol solutionby the participationof the covalent
adducts Vl of the cations la, b with ethanol in the cyclization and agrees well with the fact
that the reactions take place in a different direction in the absence of ethanol (see the
formation of compound II).
The direction of the cyclization of quinoxalinium salts with nitroalkanes does not
depend only on the nature of the solvento Smallest changes in the structure of the reagents
can lead to new types of reaction productso Thus, the cation la in reaction with nitro-
methane in ethanol in the presence of dimethylamine gives a 55% yield of the polycyclic
compound IX with a completely different structure compared with compound (Ilia) obtained
in the reaction with nitroethane under the same conditions. On the basis of the spectral
data (IHand 13C NMR spectra, mass spectra)the reaction product was assigned the structure
of $,~-dimethy~-~3-dimethy~amin~-8-nitr~dibenz~[d,k]-~,3,6,~-tetraazabicyc~[7.3.~.~ 2'7 ]
trideca-4,11-diene (IX) (Tables i and 2, Fig. 2).
In the tricyclic compound IX, unlike the tetracyclic product !lla,* the nitroalkane
residue was added to both tetrahydropyrazine rings at position 2, while one of the pyrazoline
rings has a free NH group, which shows up clearly in the IR spectra at 3392 cm-* and also
in the N}~ spectrum in deuterochloroform as a broadened signal at 4.08 ppm (Fig. 2). The
2-H proton also interacts with the NH proton and appears at 4.78 ppm in the form of a doublet
with 3J=,7 = 4.5 and aJ2,a = 1.6 Hz. It is easy to assign the remaining signals for the

*In both cases we are concerned with the skeleton of the molecules, disregarding the annel-
fated benzene rings.

325
 protons of the hydrogenated fragment of the molecule bysubsequent analysis of the coupling
between the methine protons. The 7-H, 8-H, and 9-H protons also appear in the form of
double doublets at 3,94, 4.69, and 4.45 ppm respectively, while the signal of the 13-H proton
appears as a doublet at 3.88 ppm with ~ J , ~ s = 1.5 Hz (TaBle 2~ Fig. 2).

!i!-j ji/j i .......

CtI~ NO 2 ('!I~

~ / N ~ '~ N(C.O~!

Clt.~
IX

It is logical to represent the formation of compound IX by a scheme involving the inter-

mediates X and XI. The change in the type of inclusion of the nitroalkane fragment in the
structure of the obtained polycyclic compound is evidentlv due to steric factors. In the
reaction of the cation la with nitromethana it is possible to suppose that the product from
simultaneous addition to two molecules of quinoxalinium at position 2 is formed (the inter-
mediate X), whereas in the reaction with nitroethane 2--2 addition is difficult on account
of steric hindrances on the part of the N-methyl groups, and a different type of coupling
with addition of the nltromethane at positions 2 and 3 is therefore realized.
The investigated reactions ofquinoxalinium salts with nitroalkanes demonstrate, on the
one hand, the complexity of their mechanism and the variety of chemical transformations and,
on the other, demonstrate the possibility Of a new approach to the synthesis of bridged
and framework tetraazapolycycloalkanes, based on simple single-stage methods and readily
available reagents,

EXPERIMENTAL

The ~ H N M R spectra in deuteroehloroform were recorded on Perkin-Elmer R-12B (60MHz)

and Bruker WH-90 (90 MHz) instruments~ith TMS as internal standard. The ~SC NMR spectra
were obtained on a Bruker WH-90 spectrometer at 22.62 MHz. The 13C chemical shifts were
measured with reference to the signal of the solvent deuterochlorofrom (~ 77.0 ppm) and
are given on the ~ scale. The ISC NMR spectrawere recorded both with full decoupling of
the spin-spin interaction between the protons and the carbons and without decoupling. For
compound Ilia experiments were also carried out on the ~sC NMR spectra with selective de-
coupling between the carbons and the individual groups of protons. The IR spectra in
Vaseline oil were obtained on a UR-20 spectrometer. The mass spectra were recorded on a
Varian MAT-311 A instrument with direct injection into the ion source (accelerating potential
3 kV, ionization energy 70 eV, cathode emission current i000 uA). The sample evaporation
temperature was 120-170 ~
The x-ray crystallographic analysis was performed on a Syntex PI diffractometer (lCuKu,
graphite monochromator, e/28 scan, 2100 reflections with F 2 ~ 3~). The crystals of (Ilia)
are monoclinic with the following unit cell ~arameters: a = 7.751(i), b = 17.159 (4), c =
13.855 (3) ~, 8 = 105.44 (2~ V = 1776 (6) A s , d a = 1.31 g/cm 3, z = 4, space group P21/c.
!c
The structure was interpreted by the dir~ctmetho~ and refined by the method of least squares
in anisotropic full-matrix approximation to R = 0.056 (Rw = 0.069.* The coordinates of the
atoms are given in Table 6, and the bond lengths and bond angles are given in Tables 3 and 4.
The equations for the planes of certain fragments of the molecules and the projection of the
atoms from these planes are given in Table 5.

*The position and temperature parameters r Le hydrogen atoms, revealed by thedifference

synthesis, were not refined.

326
 2,3-Di(l-nitroethyl)-l-methyl-l,2,3,4-tetrahydroquinoxaline (II) (Table i). A 2-g sample
(7 =~oles) of N-methylquinoxalinium iodide was suspended in 5.5 ml (20 mmoles) of nitroethane,
and 0.7 mi (7 mmoles) of diethylamine was added dropwise with stirring over 5-10 min until
the initial salt had completely dissolved. The reaction solution was a l l o w e d t o stand at
room temperature for 2-3 h, after which the bright-yellow crysdtalsof II were separated. The
yield was 1.85 g (86%); mp 196~ (from chloroform). IH NMR spectrum (in deuterochloroform),
~: 1.53 (CH3, d, CH3, J = 7 Hz), 1.57 (3H, d, CH3, J = 7 Hz), 2.90 (3H, s, NCH3), 3~
(4CH, m, which is transformed into two quarters with centers at 4.50 and 4.60 ppm in the spec-
trum of the 2,3-D2-deuterated derivative), 5.82 (IH, s, NH), 6.4-6.8 ppm (4H, m, protons of
benzene ring). Electronic spectrum (in ethanol), lma x (log ~): 222 (4.54), 260 (3.78),
3.10 nm (3.71).
3,8,~-Trimethy~-8-nitr~dibenz~[d,k]-~,3,6,~-tetraazatetra~c~[7.3.~.~2,7~6,13]trideca -
r,ll-diene (llla). A. To a mixture of 4 g (15 mmoles) of N-methylquinoxalinium iodide and
i.i ml (15 mmoles) ol nitroethane in 20 ml of ethanol at room temperature, while stirring,
we added dropwise 5 ml of a 25% solution Of dimethylamine in ethanol. A solution was formed,
and after 20-30 min light-yellow crystals of compound Ilia began to separate. After 1 h
the precipitate was separated and recrystallized from ethanol. The yield was 1.65 g (62%);
mp 217-218~ (from ethanol or acetone). If the crystals of Ilia did not separate from the
reaction solution, a few drops of water were added to isolate them, and the precipitate was
then separated and recrystallized twice from ethanol (the first time with charcoal).
B. To a mixture of i g (3.7 mm01es) of N-methylquinoxalinium iodide and 0.3 ml (3.8
mmoles) of nitroethane in 6 m of ethanol, while stirring , at room temperature we added 1.2
ml (12 mmoles) of diethylamine. A solution was formed and was left at room temperature
overnight. The precipitate was separated and recrystallized from acetone, giving 0.25 g
(37%) of yellowish prisms melting at 217-218~ The characteristics of the compounds Ilia
obtained by methods A (with dimethylamine) and B (with diethylamine) were fully identical
(Tables i and 2).
3,~-Diethy~-8-nitr~dibenz~[d,k]-~,3~6,~-tetraazatetracyc~[7.3.~.~2,7~6,13]trideca-4 -
ll-diene (IiId) (Tables 1 and 2). To a mixture of 1 g (3.5 mmoles of N-ethylquinoxalinium
iodide (Ib) and 0.23 ml (3.5 mmoles) of nitromethane in i0 ml of ethanol, while stirring,
we added dropwise at room temperature 1.7 ml of a 33% aqueous solution of dimethylamine.
The solution was left at room temperature for 3-4 h, after which the precipitate of compound
IIId was separated in the form of yellow crystals. We obtained 0.3 g (46%) ofthe compound;
mp 176-178~ (from ethanol).
3~8-Diethy~-8-methy~-8-nitr~dibenz~[d,k]-~3~6~-tetraazatetracyc~[7.3.~.~2~7~ 6'13]
trideca-4,11-diene (IIIe). To a mixture of 1 g (3.5 mmoles) of N-ethylquinoxalinium iodide,
0.26 ml (3.5 mmoles) of nitroethane in 6 ml of ethanol, and 1 ml of DMFA at room temperature
with stirring we added dropwise 4 ml of a 7% ethanol solution of dimethylamine. The reaction
solution was left at room temperature for 24 h, after which the crystals of IIIe were
separated. The yield was 0.3 g (44%); mp 158~ (from ethanol).
6-Dimethy-3-dimethyamin-8-nitrdienz[dk]-36-tetraazatricyc[7.3.. 2"7 ]
trideea-4,11-diene (IX) (Tables 1 and 2). To a mixture of 4 g (15 mmoles) of N-methylquinoxa-
linium iodide, 0.9 ml of nitromethane (15 mmoles) in 24 ml of ethanol, and 5 ml of DMFA, at
room temperature while stirring, we added 9 ml of a 7% ethanol solution of dimethylamine.
The solution was kept at room temperature for 2-3 h and then in the refrigerator overnight.
The precipitated compound IX was separatedand recrystallized from ethanol. The yield was
1.59 g (55%); mp 157~

LITERATURE CITED

io !. V. Kazantseva, V. N. Charushin, O. N. Chupakhin, A. I. Chernyshev, and S. E. Esipov,

Khim. Geterotsikl. Soedin., No. 9, 1257 (1985).
2. H. Takayama and T. Okamoto, Chem. Pharm. Bull., 26, 2422 (1978).
3., W. R. Schleigh, Tetrahedron Lett., iO, 1405 (1969-~.
4. G. W. H. Cheesman, and R. F. Cookson, Condensed Pyrazines, Vol. i and 2, Wiley, New
York (1979).
5. J . W . Bunting, and M. G. Meathrel, Canad. J. Chem., 50, 919 (1972).
6. V. N. Charushin and O. N. Chupakhin, Usp. Khim., 53,-~645 (1984).

327
 7. V. N. Charushin, M. G. Ponizovskii, and O. N. Chupakhln, Khim. Geterotsikl. Soedin.,
No. 8, i011 ( 1 9 8 5 ) .
8. O. N. Chupakhin, V. N. Charushin, G. M. Petrova, and G. G, Aleksandrov, (Alexandrov),
Tetrahedron Lett., 26, 515 (1985)o
9. L. E. Sutton (editor, Tables of Interatomic Distances and Configurations in Molecules
and Ions, Supplement 1956-1959, London (1965).
i0. H. Gunther, Introduction tO Course of NMR Spectroscopy [Russian translation], Mir, Moscow,
(1984), p. 122.
ii. V. N. Charushin. M. G. Ponizovskii, O. N. Chupakhin, E. O. Sidorov, and I. M. Sosonkin,
Khim. Geterotsikl. Soedin., No. 5, 669 (1985).

PREPARATION OF SOME SUBSTITUTED 1,2,4-TRIAZINES

L. M. Mironovich, V. K. Promonenkov, UDC 547.873:542.943

and V. P. Krysin

By nitrosating 6-R-l,2,4-triazine-3,5-diones(thiones) the corresponding 4-nitroso

derivatives are obtained. On reacting methyl iodide with 3-thio-4-nitroso-6-R-l,
2,4-triazin-5-ones their methyl analogs are obtained. The influence of structural
factors on the course of the reactions has been examined.

Interest in the chemistry of 1,2,4-triazines has been stimulated by the possibility of

obtaining compounds possessing biological activity. Certain 4-substituted 1,2,4-triazin-5-
ones [i], obtained bycondensation of ~-dicarbonyl compounds with thiocarbohydrazides [i, 2]
or of hydrazine with acylhydrazones of glyoxylic acid esters [3], have found application
as herbicides. Utilization of reactions for replacement of hydrogen in the triazine ring in
preparing 4-substituted 1,2,4-triazin-5-ones has been little investigated except for methyl-
ation of 1,2,4-triazine-3,5-diones (thiones) by various reagents [4].
The aim of the present work was to investigate the nitrosation of 1,2,4-triazine-3,5-
diones(thiones) for synthesis of the 4-nitroso derivatives.
TEe starting compounds -- 3-thio-6-tert-butyl-l,2,4-triazin-5-one (I), 3-thio-6-phenyl-l,
2,4-triazin-5-one (II), 6-phenyl-l,2,4-triazine-3,5-dione (III), and 6-phenyl-l,2,4-triazine-
3,5-dithione (IV) -- were synthesized according to [5, 6]. The products were identified from
the data of elemental analysis and IR spectroscopy.
On nitrosation of compounds I-IV with sodium nitrite in an acid medium, the 4-nitroso-
6-R-l,2,4-triazine-3,5-diones(thiones) (V-VIII) were obtained respectively.

~I X X X

N~,.f...
R H/~R NO,N~,~R NO,N~ R
H H
Ib-IVb Ia--Iva v-vm ix,x

I--III, V--VII, IX, X X=O, IV, VIII X=S; I, II, IV--VI, VIII Y=S, III, VII Y=O.
IX, X Y = ' S C H s ; I, V, IX R=-C(CHa)s, II--IV, VI--VIII, X R=-CsHs

Chernigov Filiate, Kiev polytechnical Institute, Chernigov 250027. All-Union Scientific-

Research Institute of PlantChemical Protection Agents, Moscow 109088. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 400-402, Harch, 1986. Original article
submitted December 4, 1984; revision submitted May 28, 1985.

328 0009-3122/86/2203-0328,$12.50 9 1986 Plenum Publishing Corporation

 TABLE i. Spectral Properties of Compounds V-X

Com- IRspeCtrum, cm "I PMR spectrum, ~, ppm

pound

V 1200 (C=S), 1675 (C=O), 1485 1,32 :$ C(CHa)3], 13--14 Is, SH

((N---N=O), 3408 (N2--H) (0,5H), s, NH (0,5H)]
VI 1185 (C==S), 1620 (C=O), 1500 7,27--7,78 (n~ At), 10,72--11,04 [&
(N--N=O), 3430 (N2--H) SH (0,5H),s, NH (0,5H)]
VII 1680, 1720 (C=O), 1490 (N--N=O) 7,38--7,78 (m, At), 12,2 ,s NH)
3410 (N2--H)
VIII 1190, 1240 (C=S), 1490 (N--N=O), 7,33--7,78 (m, Ar), 11,96--12,3 [s, SH
3415 (N2--H) (0,5H), ~ NH (0,5H)]
IX t680 (C=O), 1350 (CHa--S), 1480 1,28 [s,C(CHa)3], 2,47 (S,CH3S)
(N--N=O)
X 1620 ( C : O ) , 1355 (CHaS), 1495
(N- N=O)

TABLE 2. Properties of Compounds V-X

Com- Found, % Empirical Calculated,% Yield,

pound rap, ~ formula
decomp.)
c H N S C }{ N s I %
I

V 235--250 39,4 4,8 26,3 15,1 CrIImN402S 39,3 4,7 26,1 14,91 57
VI 183--210 46,2 2,5 2318 13,6 CgH,3N402S 46,t 2,6 23,9 13'716372
VII 238---252 49,8 2,8 25,5 -- Cg}IGN~Oa 49,6 2,7 25,7
VIII 168--186 43,1 2,4 22,5 25,7 CgH6N4OS2 43,2 2,4 22,4
IX 182--215 41,9 5,4 24,6 14.2 C~til2N40.~S 42,1 5,3 24,5 14,1 / 92
X 192--221 43,5 3,d 2218 13,1 C.JIsN40~S 48,4 3,3 22,6 12,9l 94

It is known [7] that in neutral and acid media the equilibrium la,b-IVa,b is strongly
displaced towards the a form. The nitrosation reaction i n t h i s case, like the nitrosation
of mixed amides, leads to the formation of N-nitrosamines. Derivation of 4-nitroso-6-R-l,2,
4-triazine-3,5-diones(thiones) (1-IV), and not a mixture of 4- and 2-nitroso-substituted
1,2,4-triazines, is evidently caused by the greater reactivity of the N-4 atom in the triazine
ring in combination with the kinetic control for product formation. Since the active
nitrosating agent (N203) is electrophilic, a greater reactivity is to be expected for the
nitrogen atom having a greater n-electron density value. Calculations of~-electron density
[8] show that for the N~ atom of 1,2,4-triazine-3,5-diones(thiones) this value is always
higher than that for the N2 atom in the triazone ring. Thus, the direction of substitution
in the triazine ring on nitrosation, under the experimental conditions adopted, corresponds
to the expected. The data from IR spectroscopy confirm the structure of the synthesized com-
pounds. In all the spectradistinctive absorption bands of b(N-N=O) at 1480-1580 cm -~ are
observed. In the spectrum of compound V the N4--H band at 3380 cm -~, which is present in
initial compound I, is absent, but the ~(N2--H) absorption band at 3408 cm -~ remains.
Assignment of the N4--H and N2--H absorption bands (Table i) was carried out in accordance with
the data in the literature for 1,2,4-triazine-3,5-diones(thiones) [9].
The causes of the stability of the substituents (especially sulfur) in 1,2,4-triazines
in the presence of the strong oxidizing agents HN02 and N203, present a certain interest. It
is possible that the acid medium, by further displacing the tautomeric equilibrium Ia,b--IVa,b
towards a, plays the role of protecting agent, owing to the lower susceptibility to oxida-
tion of thione groups in comparison with--SH groups and particularly--S- anions.
In view of the practical importance of 3-methylmercapto-4-substituted 6-R-l,2,4-triazin-
5-ones, we conducted the methylation of compounds V and VI using methyl iodide in an aqueous
alcoholic solution of alkali. Compounds IX and X obtained were, in fact, 3-methylmercapto-4-
nitroso-absorption bands of v(C=S) at 1185-1200 cm -~, which are present in the spectrum of
compounds V and VI, are absent, and v(CH3--S) absorption bands at 1350-1355 cm -I appear. The
N-CH3 absorption bands at 2800-2990 cm-i[9] are absent, and the N2H band, characteristic of

329
compounds V andVl, have disappeared. Unlike the methylation of 3-thio-6-R-l,2,4-triazin-5-
ones, which gives, under the experimental conditions adopted, a mixture of 3-methylmercapto
and N2-methyl derivatives (the small quantity of the 2-methyl derivative, determined by
P ~ , amounts to a few percent [i0]), the methylation of 3-thio-4-nitroso-6-R-l,2,4-triazin-
5-ones gives the 3-methylmercapto derivative of 1,2,4-triazine. The greater reactivity of
the --SH group compared to N2--H in the methylation reactions with CHsl in aqueous alcoholic
alkali can be explained by the greater nucleophilicity of the --S- anion, formed in an
alkali medium. This is confirmedby a comparison of nucleophilicity constants (nCH31) from
the Swain--Scott equation for compounds analogous with relation to S- and N--H. Thus, for
example, for C~HsS- ~3~n~=
T = 9.9, and for (C2Hs)3N n~H31 = 6.7 [ii]. The data from the PMR
spectrum of compound IX confirm the process of methylation on the thio group, as the signal
from the protons of the CH3--S group at 2.37 ppm is observed, and the signal from an N--CH3
group at 3.5-4 ppm is absent. The signals from the protons at 13-14 ppm, characteristic
of compound V, and having two different components, have disappeared. On increasing the
temperature of the run, a broadening of these lines occurs and at 50~ (in DMSO-d6) they
merge. In comparison with the methylation of 4-amino-3-thio-6-R-l,2,4-triazin-5-ones [I0],
the methylation of 4-nitroso-3-thio-6-R-l,2,4-triazin-5-ones is more selective, and there
are no by-products from methylation on the N2 atom in the triazine ring.

EXPERIMENTAL

IR spectra were obtained on a Specord IR-75 instrument using KBr pellets; PMR spectra
were obtained on a Tesla BS-487B instrument with working frequency 80 MHz in DMSO-ds with
internal standard TMS of HMDS. The properties of the compounds synthesized are presented
in Tables i and 2.
4-Nitroso-6-R-l,2,4-triazine-3,5-diqnes(thiones) (V-VIII). To a suspension of 0.05
mole initial 1,2,4-triazine in 50 ml 2 N HCI at 0~ and with stirring in such a manner that
the formation of nitrous gases was not observed (1.5-2 h). On completion of the addition
of NAN02 solution, the mixture was stirred for 15-20 min. The precipitate was filtered off,
washed with water to neutral pH, and dried in air. T h e product was purified by recrystalliza-
tion from acetone.
3-Methylthio-4-nitroso-6-R-l,2,4-triazin-5-ones (IX, X). 0.02 mole compound V (Vl)
was dissolved on stirring in 20 m ! o f an aqueous methanol solution of i N NaOH (methanol--
water i:i). To the solution at room temperature was added dropwise 0.02 mole CH31; the
mixture was stirred for 2-2.5 h and left overnight. The precipitate was filtered off and
dried in air. Theproduct was purified by recrystallization from 0.i N NaOH.

LITERATURE CITED

i. N. N. Mel'nikov, K. V. Novozhilov, and T. N. Pylova, Plant Chemical Protection Agents

[in Russian], Khimiya, Moscow (1980), p. 288.
2. A. Dornow, H. Menzel, and P. Marx, Chem. Ber., 97, 2173 (1964).
3. K. Dickore, W. Draber, and L. Eue, West German Patent No. 2,107,757; Ref. Zh. Khim.,
20420P (1981).
4. J. Daunis, G. Grunde, R. Jacouier, and P. Viallefont, Bull. Soc. Chim. France, No. 4,
1511 (1972).
5. D. Libermann and R. Jacouier, Bull. Soc. Chim. France, No. 2, 383 (1961).
6. J. Gut, M. Prystas, and J. Jonas, Coll., 26, 986 (1961).
7. H. Neuhoffer and P. Wiley (editors), TheChemistry of Heterocyclic Compounds, Vol. 33,
Interscience, New York-Chichester--Brisbane-Toronto (1978), p. 409.
8. J. Pitha and S. Vasickowa, Coll., 30, 1792 (1965).
9. M. Horak and J. Gut, Coll., 28, 3392 (1963).
i0. F. Ro Haglid, U. S. Patent No. 3,897,429; Ref. Zh. Khim., II0418P (1976).
Ii. F. Kerry and R.Sandberg, Fundamental Course in Organic Chemistry [Russian translation],
Vol. i, Khimiya, Moscow (1981), p. 188.

330
PURINENUCLEOSIDE ANALOGS.
2.* 9-(I-ALKOXYETHYL-I)-6-SUBSTITUTED PURINES

M. A. Madre, R. A. Zhuk UDC 547.857.2.7'371:542.953.1:543.422

and M. Yu. Lidak

Vinyl ethers react with 6-chloro- and 6-methylthiopurines in acid medium to give
9-(l-alkoxyethyl-l)-6-chloro- and 6-methylthiopurines. The 6-chloro compounds
were used to prepare 9-(l-alkoxyethyl-l)-6-mercaptopurines. All the synthesized
compounds proved to be inactive against lympholeucosis P 388, and Lewis carcinoma
grafted under kidney capsules in mice.

Many of the 9-substituted derivatives of 6-chloro-, 6-mercapto-, or 6-alkylthiopurines

are less effective antitumor agents than the parent purines from which they are derived;
however, in some cases they are superior to them in that they ~re more selective in their
action and less toxic [2, 3].
The 9-(tetrahydro-2gfuranyl)- and 9-(tetrahydro-2-pyranyl)-6-substitued purines a r e o f
this type, and are of special inerest, as they possess appreciable antitumor activity against
adenocarcinoma 755, and some other types of transplanted tumors in animals [2, 4-6].
No plausible explanation of the possible mechanism of biological action of the 6,9-
disubstituted purines exists in the literature. The possibility of enzymatic or chemical
dealkylation of these compounds does not necessarily explain their unique biochemical prop-
erties; someauthors suggest that the functional group at the 9 position can be replaced
by a sugar moiety, and this nucleoside analog can than take part in certain biochemical
reactions involving nucleosides [5, 7, 8].
It was also found that these compounds are highly lipohilic, which facilitates their
transport through the cell membrane [3, 5].
The present work involves the synthesis of some 9-(l-alkoxyethyl-l)-6-substituted purines,
i.e., compounds which are chemically similar to 9-(tetrahydro-2-furany!)purines, but differ
from them in a number of physicochemical characteristics. By analogy with the corresponding
pyrimidine derivatives, it can be expected that in the 9-(l-alkoxyethyl-l)-6-substituted
purines, the C--N bond will be more stable than in the corresponding tetrahydrofuran deriva-
tives [9], and that they will also be more lipophilic.
The reaction of purines with compounds containing polarized multiple bonds, such as
2,3-dihydrofuran, 2,3-dihydropyran, acrylonitrile, and others have been reported [4-6,10,ii].
For the synthesis of 9-(l-alkoxyethyl-i)-6-substituted purines, we studied the reaction of
purines with vinyl ethers, since of the methods available for alkylation, this method has
the advantage of being bothstereospecific and easy to carry out.
The reaction of 6-chloropurine (Ia) and 6-methylthiopurine (Ib) with vinylethyl (IIa)
and vinylbutyl (IIb) ethers in the presence of a catalytic amount of p-toluenesulfonic acid
gave 9-(l-ethoxyethyl-l)-6-chloro-(IIIa) and 6-methylthio- (IIIc) purine, and also 9-(1-
butoxyethyl-l)-6-chloro- (IIIb) and 6-methylthio- (IIId) purines.
The reaction was carried out at room temperature, and the yields of the alkylation prod-
ucts were high. moreover, in all cases (within the limits of accuracy of NMR) only one iso-
mer was formed.

*For Communication i, see [I].

Institute for Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 403-406, March, 1986.
Original article submitted May 27, 1985.

0009-3122/862203-0331512.50 9 1986 Plenum Publishing Corporation 331

 TABLE i. Chromatographic and Spectral Data for Compounds
llla-d and IVa and b

tom- It f* U~spectrum,
pound NMR spectrum, ~, ppm #
Amax, nm "
(~og ~)
i

Ilia 0,82 266 (4,01) 9.00 (IH, s . H~), 8,83 (IH, s. Hs), 6,11 u~ JIHrz
, Jq'
NCH), 3,49 {2H, m, OCH.,), 1,89 (3H, t~a)
1,14 (3H.t, CH~)
IIlb 0,89 266 (4,02) 9,01 (IH, s, H2), 8,83 (1H, s, It~.), 6,11 (IH, q ,
NCH), 3,45 12H, m, OCH,), ,92 (]14,d. CH~.), 1,37
(4H, m, CH2), 0,84 13H, m CH~)
IIIc 0.78 285 (423) 8,74 (1H, s, H.2), 8,18 (IH, s. 1ts), 5,9(.) (1II q ,
NCII), 3,44 (2H, m, OC[-I~), 2,74, 1,16 (3H, s .
CH~), 1,77 (3I"i,d , CII:I)
I51 d 0,87 285 (4,25) 8,74 (IH, S,H2), 8,06 (IH.m?l-I~), 5,97 (1H,q ,
NCH), 3,37 (2H. m, OCH~), 2,75, 0,86 (3H, S ,
CH~), 1,77 (3H, d, CH:0, 1,40 (4H, m CH~)
9 IVa r),59 325 (4,29) 8.46 (lH, s, H2). 8,29 ( ] H , s , H~), 5s (lH, q ,
NCH2), 3,40 (2H, m, OCH2), 1,77 (3It, d, L'H:J.
1,07 (3H, t, CH:0
IVb' ~),65 326 (4,36) 8.43 ( l I [ , s , H2), 8,20 (IH, s, Hs), 5.81 (Ill, qr
NCI{), 3,29 (2H, m, OCH~), t,73 (3It,d., CHa), 1,31
(4It, m, CH~), 0,78 (3H. m, CH~)

*Rf was obtained in system B for compounds Ilia-d, and in

system A for compounds IVa and b (see experimental section).
%Spectra of compounds Ilia and b and IVa and b were taken in
DMSO-D~, spectra of compounds lllc and d in CDCIa.

R1 R l

J,I
Ia,b llla-d CII
I3
Ia, lIIa, bRl=CI, I b , lIIc,d W=SCH:~; IIn, IIIa,.c R2=C2Hs, Ilb, IIIb,dR2=C4H9

It can be assumed that llla-d are 9-substituted isomers, since their absorption maxima
(Table i) at 266 rum for IIIa and b, and at 285 nm for IIIc and d correspond with the absorp-
tion maximum for 6,9-disubstituted purines but differ from those of the 6,7-disubstituted
purines (271 and 293 nm) [4].
During the course of the work, reports appeared in the literature 112-14] on the synthe-
sis of 9-(l-alkoxyethyl-l)purines and 9-(l-ethoxyethyl-l)-6-substituted purines, obtained
from the reaction of purines with l-chloroethylalkyl ethers in the presence of base. The
authors did not give yields of the reaction products, but noted that 7-substituted isomers
were formed as by-products [14].
The 6-chloropurine derivatives Ilia and b were used for the synthesis of the correspond-
ing 9- (l-alkoxyethyl-1)-6-mercap topurines.
Replacement of the halogen by a mercapto group in compounds IIIa and b using thiourea
in alcohol gave a single reaction product, 6-mercaptopurine, confirming that the C--N bond
was hydrolyzed under these conditions.
More sucessful was the use of a methanolic solution of sodium hydrogen sulfide to give
9-(l-ethoxyethyl-1)-6-mercaptopurine (IVa) and 9-(l-butoxyethyl-l)-6-mercaptopurlne (IVb).

llla,b NaS~ HN
5,~----N
!.0
HC" "'R
l
CH~
Ira, b
IV a R=C2Hs, b R=C4H9

332
 Structures and purity of all the compounds were confirmed from their physicochemicalL
constants (Table i).
An attempt was also made to synthesize the 9-(tetrahydro-2-methyl-2-furanyl) derivatives
of the 6-substituted purines (Via and b) by this method; however, the addition of la and b
acrosss the double bond of 2-methyl-4,5-dihydrofuran (V) in the presence of p-toluenesulfonic
acid or hydrogen chloride did not take place, probably because of steric hindrance.

R
I

la,b +
CH3/~ 0 \"r ~ Nf
V CII3" l

V/a,b
Vl ~ l~=CI, b R=SCH3

A study of the antitumor activity of compounds IIIa-d, and IVa and b established that
none of them were active against lympholeucosis P 388 or Lewis carcinoma grafted under kidney
capsules in mice.

EXPERIMENTAL

Ultraviolet spectra were run on a Unicam Sp-1800 spectrometer (in ethanol), NMR spectra
on a Bruker WH-90 (in DMSO-D6 or CHCI3), TMS was used as a reference. The purity of the com-
pounds was checked by TLC on Silufol UV-254 plates, using the solvent systems chloroform-
methanol, i0:i (A) and ethylacetate-acetic acid, 50:1 (B).
9-(l-Ethoxyethyl-l)-6-chloropurine (IIla). To a suspension of 2.0 g (13 mmoles) of
Ia in 30 ml of dry ethyl acetate was added i00 mg of p-to!uenesulfonic acid and 1.51 g (2.0
ml, 21 mmoles) of IIa. The reaction mixture was stirred at room temperature for 5 h, then
diluted with i00 ml of ethyl acetate, washed with 2 x 20 ml of 15% potassium carbonate, 30
ml of water, and dried with anhydrous sodium sulfate. The solvent was evaporated, giving
2.81 g (95.9%) of an oily substance, which was twice recrystallized from a mixture of diethyl
ether and petroleum ether to give 2.17 g (74%)of IIIa, mp 49~ Found: C 47.5; H 4.7;
N 24.8%. CgHIICIN~O. Calculated: 47.7; H 4.9; N 24.7%.
9-(l-ButoxYethyl-l)-6-chloropurine (IIIb) was synthesized by the method described above
from 2.0 g (13 mmoles) of Ia and 2.10 g (3.0 ml, 24 mmoles) of IIb. Two recrystallizations
from hexane gave 2.60 g (78.5%) of IIIb, mp < 30~ Found: C 52.2; H 6.1; N 21.7%.
C~IHIsCIN~O. Calculated: C 51.9; H 6.0; N 22.0%.
9-(l-Ethoxyethyl-l)-6-methylthiopurine (IIlc) was synthesized from 2.0 g ( 1 2 m moles) of
Ib and 1.87 g (2.5 ml, 26 mmoles) of IIa. The product was recrystallized from diethyl ether
containing hexane to give 2.26 g (79%) of IIIc, mp 68~ Found: C 50.5; H 5.8; N 23.3%.
C~oHI4N40S. Calculated: C 50.4; H 5.9; N 23.5%.
9-(l-Butoxyethyl-l)-6-methylthiopurine (IIId) was synthesized from 2.0 g (12 mmoles)
of Ib and 2.40 g (3.0 ml, 24 mmoles) of IIb. Two recrystallizations from hexane gave 2.38 g
(74.5%) of IIId, mp 33~ Found: C 53.9; H 6.7; N 20.7%. CI~HIsN~OS. Calculated: C 54.1;
H 6.8; N 21.0%.
9-(l-Ethoxyethyl-l)-6-mercaptopurine (IVa). To a solution of 2.27 g (i0 mmoles) of IIIa
in 20 ml of methanol was added 20 ml of 1 N sodium hydrogen sulfide in methanol, the mixture
refluxed for 30 min, and then filtered. The filtrate was neutralized with acetic acid, the
precipitated material filtered off, and precipitated from 1 N NaOH solution with acetic acid.
Recrystallization from ethanol gave 1.48 g (66%) of IVa, mp 202-204~ Found: C 48.3; H
5.4; N 25.2%. CgHI2N4OS. Calculated: C 48.2; H 5.4; N 25.0%.
9-(l-Butoxyethyl-l)-6-mercaptopurine (IVb) was synthesized from 2.55 g (i0 mmoles) of
IIIb by the method described above; 1.86 g (74~) of IVb with mp 182-184~ (decomp.) was
obtained. Found: C 52.6; H 6.5; N 22.1%. CI~H~6N4OS. Calculated: C 52.4; H 6.4; N 22.2%.

333
 LITERATURE CITED

i. M. A. Madre, R. A. Zhuk, and M. Yu. Lidak, Khim.-farm Zh., 19, 1371 (19855.
2. R. K. Robins, J. Med. Chem., ~, 186 (1964).
3. C. Temple, C. L, Kussner, and J. A. Montgomery, Cancer Res., ii, 41 (1968).
4. L. R. Lewis, F. H. Schneider, and R. K. Robins, J. Org. Chem., 26, 3837 (1961).
5. W. A. Bowles, F. H. Schneider, L. R. Lewis, and R. K. Robins, J. Med. Chem., 6, 471
(1963).
6. N. Nagasawa, I. Kumashlro, and T. Takenishi, J. Org. Chem., 31, 2685 (19665.
7. A. H. Chalmers, T. Burdorf, and A. W. Murray, Biochem. Pharm., 21, 2662 (1972).
8. S. Drake, R. L. Burns, and J. A. Nelson, Chem.-Biol. Interact. 41, 105 (19825.
9. R. A. Zhuk, M. Yu. Lidak, A. P. Gilev, A. A. Zidermane, A. S. Tseminya, and A. N.
Kozhukhov, Contemporary Problems in Experimental Tumor Chemotherapy, Vol. 2, [in
Russian], Chernogolovka, (19805, p. 40.
i0. B. R. Baker and P. M. Tanna, J. Org. Chem., 30, 2857 (1965).
ii. E. Pn Lira andC. W. Huffman, J. Org. Chem.& 3!, 2188 (1966).
12. H. L~nnberg, Acta Chem. Stand., A34, 703 (1980).
13. H. Lonnberg, P. Lehikoinen, and K, Neuvonen, Acta Chem. Stand., B35, 707 (1982).
14. H. Lonnberg, J. Lukkari, and P, Lehlkoinen, Acta Chem. Scand., B38, ~573 (19845.

CONFIGURATION OF 2-(4-PYRIDYL)-5-ARYLOXAZOLE MOLECULES

IN VARIOUS STATES OF AGGREGATION

P. B. Kurapov, N. A. Klyuev, UDC 541.65:543.51'422:547.787.1'829.04

L. Sh. Afanasiadi, I. N. Tur,
and I. I. Grandberg

The electronic absorption and emissionspectra in the crystals, solutions, vapor,

and ethanol-ether(77~ were investigated for the series of 2-(4-pyridyl)-5-
aryl-substituted oxazoles at various temperatures. The conjugation between the
rings of the system was investigated by mass spectrometry. The combination of
spectral data shows that the configurations of such molecules both in the ground
state and in the excited state depends Substantially on the state of aggregation
and on the temperature.

Earlier [1-3] we studied the effect of the state of aggregation and temperature on the
configuration and on the conjugation between the rings in heterosystems with structures of
the biphenyl type in the ground and excited states. Using a set of independent physical
methods (electronic and vibrational spectroscopy, dielectric constant measurement, mass
spectrometry, photoionization, and x-ray crystallography) andconsidering the reactivity
of such compounds, we came to the conclusion that the conjugation in this case does not
in fact depend on the angle of rotation (8) Of the rings forming the bis-system when 9 < 60 ~ ,
The aim of the present investigation was to examine the more complex system of 2-(4-
pyridyl)-5-aryloxazoles in terms of the above-mentioned problems. We undertook spectral-
luminescence and mass-spectrometrlc studies of the molecules of a series of 2-(4-pyridyl)-5-
aryloxazoles (I-IV) and of the model compound 2,5-diphenyloxazole (V).

l-V

l--IV X=N, V X=CH; I, V R=H, II R=CH~, III R=C1, IV R=OCH3 ,

K. A. Timiryazev Moscow Agricultural Academy, Moscow 127550. Monokristallreaktiv

Scientific-Production Association, Khar'kov 310141, Translated from Khimiya Geterotsikli-
cheskikh Soedinenii, No. 3, pp. 407-412, March, 1986. Original article submitted January
Ii, 1985; revision submitted May i0, 1985.

334 0009-3122/86/2203-0334512.50 9 1986 Plenum Publishing Corporation

TABLE i. Luminescence-Spectral Characteristics of 2-Pyridyl-
5-aryloxazoles I-V

I Electronicspectra ethanol-ether

Iabsorp-
~tion,
~emmax'l
crystal
emission V
1
era-
"~ ~
solution
~is~s
' max~ absorption Vmax ,
. ...... 'v_o,,, cm- 1 ;'~
vapor
iAbsorpti0n emission
Cm':t
Vmax,
matrixp 77~
.
Absorptio~
l~max, Cm--
emission
~)max~

8 , w, '~ cm- (f) i em-Z I c m -I

I 31300 24400
29400 @h 22200 ~ h )
(127) 31250 25300 (0,74) 33700
330O0 i29,
28100o t 33 oo
31100
27500
26300
30700 29~00
128900
II 29800 ( s h 25000 (129) 30600 24700 (0,61) 33900 28700 28400 26300
30700
28100 23800 32680 127600 29400 25600
.
27900 24300
IIl 33300 24100 (125) 31050 ]28900 31300 27500
27500 23300 ~ h ) 30~ 27800 29900 26300
28600 ~h) 28300 25000
IV 29400 28600 (149) 2~600 22700 (0,9.0) 30000 2~800 ( ~ ) .29w 25600'
27800 (sh 27500 28250 28400 24400
27000 (sh) 27000 23300
V -- 325O0 27400 (0.51) 34500 29400 34000 29000
30500 2870O (sh) 28100 32700 27600
28700 31950 26100
31150 25000
30500
29500

*The percentages in relation to 1,3,5-triphenylpyrazoline as

standard are given.

TABLE 2. Stokes' Shifts (Av) of

Compounds I-V

~ Magnitudeof Stokes'shift AV cm- I

Corny
pound ~thanol- crystal , solution in
~ther, 77~ 293~ . . ethanol,
! 293~
I 900 3400 6000
lI 1600 3100 5900
II! 800 3400 61 O0
IV 11O0 5000 5800
V 500 2600 51 O0

*For the vapor of compounds I-V Av =

0.

TABLE 3. Barriers to Internal

Rotation and Lifetimes of the
Conformers of Biphenyl at Vari-
ous Temperatures

[AE~ kcallmole
(according to
r,K ipublished data T,
I D]) sac

100 8,8 ~ lO~

300 5.4 ~ I0- ~u
343 3,1 ~ 10 -12
450 1,8 ~ 10 ''~

335
 wo~ I ,..,- U@ I

i/" ~ 0'I

I
,O :
' , H t~i

i ~.r4
'~! ~,
; i
II : ', f

O .tad
1 2 4 b

Fig. i. Cut-out form of the internal rotation potential func-

tion for the analogs of diphenyl in ground (So) and excited
(Sx) states.

TABLE 4. Mass Spectra of Compounds l - V

,, , ,

IM+ tl+ M" A B [B-H]+ M.2+

t g
I 223 (16) 222 (I00)194 (15)167 (71)166 (15)111 (II) 117 (121 105 (24) 77 (60) (17,8)
II 237 (17) 236 (100) 208 (11) 18[ (30)]180 (24)1118 (14) 117 (10) 118 (14) 91 (4~)j(18,3)
1141112 ~1113116 d
III 257(18) 12581 33Xl 1203111,I
IV 253 (17)]252 (100) 224 (10)1197 (16)116 (10)1126 (10) 1116 (10)1135 (19)1107 (10)1(17,2)
V 1222 (17)1221 (100)1193 (10)1!66 (151116~ (29)/110,5 (11 )1116 (18)1105 (17)1 77 (35)[(25,3)

*The intensities of the ions > 1 0 % of Jmax in the mass spec-

t r u m a r e given.

TABLE 5. Shift of the Emission Bands of Compounds I-V during

the Phase Transitions (in relation to the emission band of the
crystal)

~ ' - vo, ,cnl - I

Compound I~tt Op I" matrix solution vapor
(77 K) 1293K) t550 K)
I
0,00 I 1860 930 4760
1I -0,170 640 -310 3740
III 0,227 2150 900 4810
IV - 0,268 0 - 1660 3860

The spectroscopic investigations were carried out in various states of aggregation

(crystal,:solution, vapor, andethanol-ether matrix) (Table i). The structural changes do
not significantly affect the position and intensity of the short-wave absorption bands in the
UV spectra. We therefore restricted ourselves to discussion of the long-wave bands corre-
sponding to the conjugation and fluorescence, As seen from Table i, the position and form of
these bands i n t h e electronic spectra change during the phase transitions.
The absorption and emission bands of the crystals of compounds I-V are shifted toward
the red region compared with the solutions, and their vibrational structure appears in the
form of shoulders and inflections (Table i). Compound (l-V) luminesce well in the crystal

336
(Table i). The Stokes' shift (A~) amounts to 3000-5000 cm -I (Table 2). It is usually con-
sidered [4] that the presence of strong luminescence presupposes planarity in the excited
state of the molecules of I-V in the crystal, while a significant Stokes' shift indicates
a difference between the configurations of the ground and excited states.
In solution the position of the bands in the electronic spectra is intermediate between
the crystal and the vapor. The &w value is maximum for the investigated compounds, and they
fluoresce well in ethanol solution. The quantum yields of fluorescence (~f) amount to 0.5-
0.9. The fluorescence spectrum contains structure (Tables 1 and 2).
In the vapor at about 250~ the bands observed in the absorption and emission spectra
were shifted toward the blue region by 50-70 nm compared with the crystal and the solution,
and the form of the bands also changed. There was no Stokes' shift (Tables i and 2).
In the ethanol--ether matrix at 77aK the vibrational structure of the bands shows up
clearly in the electron absorption and emissio~ spectra of compounds l-V, and the bands for
compounds 1-IV are mirror-symmetric (Table I). In contrast to this the spectra of (V) are
devoid of mirror symmetry. The emission bands of the investigated molecules of I-V at 77~
are shifted toward the blue region compared with the spectra of the crystals and the solutions,
while the absorption bands conversely undergo a bath0chromic shift with decrease in tempera-
ture. The Av values for all the investigated compounds are small (500-1600 cm -I) (Table 2).
It is correct to discuss the obtained experimental data in terms of the potential func-
tions for internal rotation, i.e., the dependence of the energy of the molecule on the angle
of rotation of the rings (@). 2-(4-Pyridyl)-5-aryloxazoles can be regarded as conformational
analogs of biphenyl which only represent a system consisting of three independent tops having
two rotation axes and, accordingly, two angles of rotation for the nuclei e and 4.
Thus, whereas the potential function of internal rotation V(@) for a molecule of the
biphenyl type looks like a curve on a plane, the V(@,~) function looks like a potential sur-
face in three-dimensional space. However, there are no fundamental differences between
these two functions, and for simplicity and clarity in our subsequentdiscussions we therefore
restricted ourselves to discussion of one of them V(@).
According to Bellman's classification [5], the molecules of such a structure can be
divided arbitrarily into five classes according to t h e i r c o n f i g u r a t i o n s i n the ground and ex-
cited states. In Fig. i we have represented the internal rotation potential functions
(IRPF) for these five classes in cut-out form. It is seen that the molecules for which the
two states belonging to classes i and 2 respectively are simultaneously planar or nonplanar
have a small Stokes' shift. (The energies of the 0-0 transitions are similar). In these
cases the electronic absorption and emission spectra will be mirror-symmetric, since the
So and $I states have identical configurations. The deeper the potential well, the more
structure the electronic spectrum contains. With a deeper potential well the amplitude of
the torsional vibrations in the excited state decreases, and the probability on nonradiative
transitions is reduced. This is turn leads to an increase in the quantum yield of fluores-
cence. Consequently, compounds belonging to classes i and 3 must luminesce well, and
there will be clearly defined vibrational structure in their luminescence spectra, in con-
trast to compounds belonging to the second class, which as a rule do not luminesce. Com-
pounds belonging to classes 4 and 5 can be regarded as intermediate between classes 1-3.
By analyzing the position and the form of the bands in the electronic spectra of com-
pounds I-V (Table i), we came to the conclusion that the conformations of the ground and ex-
cited states show the maximum difference in ethanol solution and in the crystal; the $I state
is planar, while the So state is clearlynonplanar. Consequently, compounds I-V must be
assigned to class 3 in Bellman's classification (Fig. I), but the degree of nonplanarity will
differ for each investigated compound in the So state. In the vapor the configuration of
the molecules I-V is identical both in the ground state and in the excited state, and they
are both substantially nonplanar.
On the basis of published data [i] on the sizes of the barriers to internal rotation
we calculated the lifetimes of the conformers of biphenyl at various temperatures (T)
(Table 3). The T values given in Table 3 were determined by means of the formula taken from
[6], where A was taken as equal to 1014 sec-1:

J/'~=l~=Acxp( - AEIRT).

337
On the other hand, the lifetime of the excited state TR amounts to approximately i0-'-i0-~
sec [4, 7]. As follows from the data in Table 3, at low temperatures the lifetime of the
excited state of the molecules with structures of the biphenyl type (~R) is shorter than
the lifetime of the conformer (T), and such a molecule (being in the excited state) con-
sequently does not succeed in changing its conformation. At room temperature the r and TR
values are approximately the same, while at elevated temperatures in the excited state the
benzene rings can rotate several tens of times about the central bond during the lifetime
of the excited state (TR).
After analysis of the electronic spectra of compounds I-V it can be concluded that in
the $I state and 77~ the conformation of the molecules I-III does not succeed in changing,
and the fluorescence emission takes place from the non~quilibrium nonplanar vibrational
state. In contrast to this, in compound V at 77~ the conformation of the So and S~ states
is different, since the absorption and emission spectra are not mirror-symmetric. For
compound (IV) the position and the form of the emission bands in the crystal, solution, and
matrix at 77~ coincide. Consequently, i n t h e above-mentionedstates of aggregation the
molecule of IV is planar in the S ~ state.
While examining the electronic spectra of'compounds I-V (Table i) in the gas phase, we
concluded that the aromatic fragments of these molecules are in free rotation, and it can be
assumed that the conformations of the ground and excited states are identical. (This case
was not classified by Bellman.)
The maximum-intensity molecular ion peak is rec0rded in the mass spectra of compounds
l-V(Table 4). Dissociation processes involving the direct elimination of the aryl or
pyridine fragment from M + w e r e not observed. (This was demonstrated by recording the mass
spectra of the metastable ions by the DADI technique.)
Themass-spectrometric data (Table4) indicatesignificant conjugation between the rings
in the molecules of I V. Apart from the absence of cleavage of the bond between the rings,
the presence of conjugation in the system is confirmed by the high stability of the compounds
I-V to electron impact (WM lies in the range of 17-25% of the total ion current) and by the
significant intensity of the doubly charged molecular ion (M s+ ~ 10%) [2, 5].
In addition t o t h e above-mentioned ions, the following fragments were observed in the
mass spectra (Table 4): [M--COl + (A) (for compound I, found 194.0868, C13HIoN2, calculated
194.0843); [A-- HCN] + (B) (ifor I found 167.0744, CI=HgN, calculated 167.0735); [B --H]+ (for
I found 166.0646, C12HsN, calculated 166.0657); [M ~ RC6H~CO]+; [RC6H4CO] +. The ejection
of the CO particle from M+ presupposes migratio n of the aryl radical to position 4 of the
oxazole ring. The analogous process has been observed and discussed for 2-phenyl-substituted
indoles [8]. The appearance of the last two ions presupposes strong T-electronic inter-
action between the aryl and oxazole rings compared with the substituent at position 2.
The suggestions made on the basis of the mass spectra are closely confirmed during exam-
ination of the electronic effects of the substituents in the phenyl ring on the position
of the emission bands. Earlier, while studying the acid--base characteristics of compounds
1-IV, we established [9] that the pyridine ring behaves as a T-electron donor. The introduc-
tion of electron-donating substituents into the benzene ring must in turn increase the ~-
electron density in the region of the bonds between the rings, i.e., increase the conjugation
and promote stabilization of the planar conformer. The shifts of the emission bands in the
vapor, solution, and matrix in comparison with the crystal are given in Table 5. From this
table it follows that the magnitude of this shift correlates with the electronic character-
istics of the substituents in the benzene ring. The electron-donating groups -OCHs and CHs
reduce this quantity. This is particularly noticeable for the matrix and solution. In the
vapor this shift also changes in line with the electronic characteristics of the substituents,
but the effect of the substituents9 this case is not so substantial, since the effect of
the substituentsis 9 out in the vapor on account of free rotation of the rings.
Our study of the luminescence-spectral characteristics of compounds of the 2-(4-pyridyl)-
5-aryloxazole series has shown that the phase transitions and temperature changes are re-
flected significantly in the spectralcharacteristics and, consequently, affect the degree
of conjugation and theconformation in the investigated molecules.

338
 EXPERIMENTAL

The luminescence-spectral investlgationswere carried out on a Hitachi EPS-3T spectro-

photometer fitted with a G-3 fluorescence attachment. The spectrophotometer was provided
with special devices for recording the spectra of low-temperature matrices and vapor. The
absorption spectra of the crystals were obtained in tablets with potassium chloride. The
luminescence spectra of the crystals were obtained on apparatus consisting of a mlrror-type
ZMR~3 monochromator, an FEU-18 optical detector, and an M-95 mlcroammeter. The photo-
luminescence was excited with a SVDSh-500 lamp, from the spectrum of which the %exc 365 nm
line was isolated by means of a DRM-4 quartz monochromator. The absolute quantum yields of
fluoresence were determined by the method of equal absorption with 1,3,5-trlphenylpyrazoline
as standard. All the emission spectra were corrected wlthailowance for the sensitivity of
the FEU instrument. The low- and high-resolution mass spectra were obtained on a Varian
MAT-311A instrument. The recordingconditions were Standard: acceleratingpotential 3 kV;
cathode emission current 1000 ~A; ionizing potential 70 eV; evaporation temperature for
samples of (I-V) in the ion source froml40~ Compounds (I-V) were obtained by known methods
[9]. The purity of the compounds was monitored by chromatography.

LITERATURE CITED

i. P. B. Kurapov, N. A. Klyuev and V. I. Tyulin, Teor. Eksp. Khim. (1986), in press.

2. N. A. Klyuev, P. B. Kurapov, G. G. Aleksandrov, and I. I. Grandberg, Khim. Geterotsikl.
Soedin., No. 6, 775 (1982).
3. N. A. Klyuev, M. V. Povstyanoi, G. G. ' Aleksandrov, and V. P. Gumennyi, Khim. Geterotsikl.
Soedin., No. I, 88 (1983).
4. S. Parker, Photoluminescence of Solutions [Russian translation], Mir, Moscow (1972).
5. J. B. Berlman, J. Phys. Chem., 74, 3085 (1970).
6. V. G. Dashevskii, Conformation o-~Organic Molecules [in Russian], Khimiya, Moscow (1974),
p. 38.
7. R. G. Brown, N. Entwistle, J. D. Hepworth, K. W. Hodgson, and B. May, J. Phys. Chem., 86,
No. 13, 2418 (1982).
8. B. Robinson, Chem. Rev., 63, 373 (1963).
9. L. Sh. Afanasiadi, I. N. Tur, and P. B. Kurapov, Khim. Geterotsikl. Soedin., No. 4, 479
(1985).

339
b~CROHETEROCYCLES.
24.* SYNTHESIS OF NEW DERIVATIVES OF DIAZA-IS-CROWN-6

H. G. Luk'yanenko, R. G. Kostyanovskii, UDC 547.898:07

V. N. Pastushok, and A. V. Boga~skii t

New derivatives of dlaza-18-cr0wn-6 have been prepared by the aminomethylation of

N-alkylsulfonamldes under'the action of N,N'-bismethoxymethyldiaza-18-crown-6.

It is known that the complex-formlng and Ion-selectlve properties of crown ethers are
determined by their topology and by the nature of the reactive centers situated both in the
ring and in the side chains [2, 3]. Hence, modification of a macrocycle by the introduction
of functional substituents allows considerable variation in the complex-forming properties
to be achieved and is one of the major directions o f t he development of the chemistry of
macroheterocycles.
It has been shown previously that aza-crown ethers containing reactive secondary amino
groups enter readily into amlnomethylatlon reactions on C, O, and N atoms [4, 5]. The
present paper reportsthe results of a study of the amlnomethylatlon of N-alkylsulfonamides
by the action of N,N'-bismethoxymethyldiaza-18-crown-6 (I).

TsN ~'N N"" 'NTI TsN" 'N NT!

_\j Ph~SI' .. O\ ,..jO- Ph
IT Ill

~ o ~ T'NIICIIzPh'

/~ / 0 ~'t /'--O" 0~ llfe

I ....... ,, .~,o , ~ . - - "

". 0 /0 ..~ /1 0

/ /
Eto
>=o\.-0.\ , _ . . / o. ,Q=:.>
"'OEt CITzSO2NIlM~
IV i,.7 20".Ct;II~

r o/ Xo _-
/o / \ o.

~--~ CH2SOoN* ~N "NSO 2 .H 2---(--~

\ .tJ ~I / ', ~ \,.~_J

It has been established that as the size of the substituent on the nitrogen atom in the
sulfonamides increases, reaction becomes noticeablvmore difficult. Thus, whereas amino-
methylation of N-methyl-p-toluenesulfonamide by I proceeds at 20~ and of N-benzyl-p-toluene-
sulfonamide at 80~ reaction o~ N, tosyl-S-(--)-a-phenylethylamlne does not take place even
in benzene at boiling point.
*For Communication 23, see [i].
tDeeeased.
A. V. Bogatskii Physicochemical Institute, Academy of Sciences of the Ukrainian SSR,
Odessa 270080. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 413-415,
March 1986. Original article submitted December28, 1984.
340 0009-3122/86/2203-0340512.50 9 1986 Plenum Publishing Corporation
 TABLE i. Characteristics of Aza-Crow~ ethers II-V

Com- Found, % Empirical Calc. % Yield,

pound me. ~ forn~ula %
C I1 N C tt N

II oil 54,9 9,6 8,6 ] CaoHasNaOsS~ 5,t,8 7,4 8,5 98

III oil (32,1 6,7 7,,o C4.2I-I~,IN4OsS2 62,3 7,0 6,9 95
IV 7O--72 53,7 7,1 6,9 Cad~6N40,2S.2 54,0 7,0 7,0 87
V 9O 55,4 8,3 7,2 C~H64Nfl),oS2 56,6 8,3 7,2 87

TABLE 2. Spectral Characteristics of Crown Ethers II-V

Com- /
pound NHR in CDCh. & ppm V,Hz.I [ IR (CCh), v, cm "i spec.
M*
I

II 2,30 (61-t, s), ArCHa; 2,63 (6H, s), NCHa: 2,80 (8H, 1165 1350 (S02), 057
O,01), NCH2; 3.48 (16H, m), OCI-I~; 3,86 (4H, s), 16(10 (C=C),
NCt%N; 8,88 (4H, d[II,0]), ArH; 7,05 (4It, d ill.0]).[ 1040 ---3080
ArH ' (=C--H)
Ill 2,33 (6H, s), ArCHa: 2,63 (8II, t{5,8]), NCH~; 3,38 1165, 1350 (S%), 809
(16H:m), OCH2; 4,(13 (4H, s/, ArCI-1~; 4,36 (4H, s), 16oo ( c = c ) ,
NCH2N; 6,90 (14H, ra), ArH; 6,94 (4H, d[10,0]), ArH 3040--3080
(=C--H)
IV 0,90 (~;II,t[7,5]), CH~CIt~; 2,17 (6H, s), ARCH:,,; 2,60 I lfi5, 1350 (SO2), 801
(81f, t[5,7]), NCII2:3,33 (15H, m), OC112; 3,78 (41t,q IOOO (C=C},
U,5]), OCH2CIta; 3,93 (411, s COCH2; 3,97 (4H, s), 1700 (C=O),
NC|-I~N; 7,03 (4It, s[10,O]), ArH; 7,40 (4H, s.[10,0]), 3030---3080
ArH ( = C--H)

V* 0,85 ((ill. s), CH:~; 1,13 ((}H, s), CH:~; 1,63 (14H, m ;, i 165, 1340 (SO2), 777
(C|12)2CItCIIe; 2,52 (2H dig,a]), CH; 2,83 (8H, t 1750 (C=O)
{6.0]), NCI-1~; 2,88 (6H, s), NCHa; 3,22 (2H, d,~13,3]),
CH: 3.53 (16H, m), OCH2; 4,03 (4H. el), NCH2N

*[~]D = + 23"48~ (C 4.6, C=HsOH).

Analogous results were observed for the aminomethylation of ethyl esters of N-tosylgly-
cine and n-tosyl-a-alanine. This lends support to a hypothesis which we put forward earlier,
that spatial factors play an important part in t h e c o u r s e of aminomethylation reactions
based on macrocyclic N-methoxymethylamines [4, 5].
Aminomethylation of D-(+)-N-methyl-camphor-10-sulfonamide occurs in high yield. The
identity of the compounds prepared, II-V, was monitored by TLC and their composition and
structure were determined from the results of elemental analysis (Table i), and from their
N~R, IR, andmass spectra (Table 2).

EXPERIMENTAL

Plates coated with Silufol UV-254 were used for TLC, the eluant being selected according
to the properties of the compound under examination; iodine vapor was used for development.
NMR spectra wererun in 5-10% (by vol.) solution in CDCI3 on a Tesla BS 467 (Czechoslovakia)
instrument (60 MHz) using hexamethyldisiloxane as internal standard. Infrared spectra were
run on a Perkin-Elmer 580B (USA) instrument and the mass spectra on a Varian MAT-If2 spectrom-
eter with direct introduction of the sample and 70 eV ionizing electron energy.
N,N'-Bis(N-methyl-p-toluenesulfonamidomethyl)diaza-18-crown-6 (II). A mixture of 1.37
g (3.9 mmoles) crown ether I [4], 1.45 g (7.8 nm~oles)N-methyl-p-toluenesulfonamide and i0
ml dry benzene was held at 20~ for 2 ho The sQlution was filtered and the filtrate evaporated
yielding 2.52 g of compound II.
N,N'-Bis(n-benzyl-pTtoluenesu!fonamid0methYl)diaza-18-crown-6 (III) was prepared in a
similar way from 0.87 g (25 mmoles) crown ether I and 1.33 g (5 B o l e s ) N-benzyl-p-toluene-
sulfonamide at 80~ yielding 1.92 g of compound III.

341
 N,N'-Bis(N-tosylethoxycarbonylmethylamlnomethyl)diaza-18-crown-6 (IV) was prepared in
a similar way from 1.47 g (4.2 mmoles) crow~ ~ther I and 2.17 g (8.4 mmoles) ethyl ester of
N-tosylglycine at 20"C; the yield was 2.94 g of compound IV.
N,Nt-Bis-D-(+)-(N-methylcamphor-10-sulfonamidomethyl)dlazarlS-crown-6 (V) was similarly
prepared from 0,94 g (2.7 mmoles) crown ether I and 1.34 g (5.4 mmoles) D-(+)-N-methylcamphor-
10-sulfonamide to yield 1.85 g of compound V.

LITERATURE CITED

i. N. G. Luk'yanenko, A. V. Bogatskil, T. A. Voronina, N. Ya. Golovenko, T. L. Karaseva,

S. E. Timofeeva, S. S. Basok, V. N. Pastushok, T. L. Garibova, and R. G. Kostyanovskli,
Khim-farm. Zho, No. 6, 691 (1985).
2. J. S. Bradshaw and P. E. $tott, Tetrahedron, 36, 461 (1980).
3. E. Amble and J. Dale, Acta Chem. Scand., Set. B, 33, 698 (1979).
4. A. V. Bogatskii, N~ G. Luk'yanenko, V. N. Pastushok, and R. G. Kostyanovskii, Dokl. Akad.
Nauk SSSR, 265, 619 (1982).
5. A . V . Bogatskll, N. G. Luk'yanenko, V. N. Pastushok, and R. G. Kostyanovskii, Synthesis,
No. 12, 992 (1983).

342
LETTERS TO THE EDITOR

REACTION OF PHTHALIMIDE WITH DIETHYLENE TRIAMINE AND

TRIETHYLENE TETRAMINE
I
E. V. Ganin, Vo F. Makarov, UDC 547.584.07'415.5
and Vo Io Nikitin

It is known that both primary [i] and secondary [2] amines can react with the phthalimide
ring to form imides or amides, depending on the kind of substituents. To elucidate the be-
havior of the phthalimide ring in simultaneous reaction with primary and secondary amines,
wereacted phthalimide I with amines Ila,b. We found that when heated briefly to 190-220 ~
the imide ring of I reacts mainly with primary amino groups; this leads to their protection
in the presence of secondary amines, with the formation of the respective N,Nt-aminoethyl -
enediphthalimides llla,b.

L. '! NIl + |IdN k NII/n N|I2 -,. "~

0 0 0

1 IIa, b Illa, b
an=l~bn=2

Such a synthetic path to the diphthalimides llla, b is more stepwise than the one known
hitherto [3], viz., the reaction of potassium phthalimide with the respective dihaloderivatives
of the secondary amine.
A mixture of 0.2 mole of phthalimide I and 0.1 mole of amine IIa or IIb was heated
rapidly to 220 or 1950, respectively, held at that temperature until ammonia evolution is
finished, and crystallized. The individuality of the compounds was monitored by TLC (Silufol
UV-254; methanol-chloroform eluent 1:0-1:8; development in UV light and with ninhydrin).
There were obtained: bis(2-phthalimidoethyl)amine (IIIa), 85%yield, mp 178-180 ~ (from DMFA);
and N,N'-bis(2-phthalimidoethyl)ethylene diamine (IIlb), 65% yield, mp 153-154 ~ (from pro-
panol-2). Composition and structure of the synthesized imides were confirmed by elemental
composition and IR, PMR, and mass spectra.

LITERATURE CITED

I. F. S. Spring and J. C. Woods, Nature, 158, 754 (1946).

2. J. Sambeth and F. Grundschober, Angew. Chem., 77, 718 (1965).
3. F. G. ~ n n , J. Chem. Soc., No. 4, 461 (1934).

I. I. Mechnikov Odessa State University, Odessa 270000. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No, 3, p. 416, March, 1986. Originalarticle submitted
June 24, 1985.

0009-3122/86/2203-0343512.50 9 1986 Plenum Publishing Corporation 343

5-AMINO-6-MERCAPTOPYRIMIDINES IN THE SYNTHESIS OF
DERIVATIVES OF 5-AMINO-I,2,3-THIADIAZOLE

H. P. Nemeryuk, A. L. Sedov, UDC 547.854.1'794.3.07

and T, S. Safonova

It is known that substituted 5-amino-l,2,3-thiadiazoles can be obtained by the acid hy-

drolysis of certain pyrimido[5,4-d]-l,2,3-thia~iazoles [I], which are formed by the diazotiza-
tion of 5-amino-6-mercaptopyrimidines [i, 2],
We have found that diazotlzation of the stabilized thione forms of 5-amino-6-mercapto-
pyrimidones that have a substltuent at position 4 and lack mobile hydrogen atoms, gives 5-
amino-l,2,3-thiadiazole derivatives directly.
Thus, diazotization of 1-cyanoethyl-5-amino-4-chloro(methoxy)-l,6-dihydropyrimidinethiones-
6 (la,b) gives 5-amino-l,2,3-thiadiazoles (lla-c), that are substituted at position 4 with a
carbonitrile or methoxycarbonyl group~

,CN
N ............ I"
R [I 1~
N :" NIl, 1.1~C,1 ~ N I.,
' % ,- 'S N ( 0 1 { 0 ) C I I ~(!II~.CN

I ~. . CO~CH3
(~[I.~CI'[2CN ~ " .
la,b ii
S' ""N(R~ )CH; ('II,~('N
la R = Cl, b R = OCH3 ; lib RI = H, c R z = CHO IIb, c

At the same time, when 4-methoxy-5-amino-6-cyanoethylpyrimidine (III) stabilized in the

thiol form is diazotized, the 1,2,3-triazole derivative IV forms.

ClI
i
,/ ,,. ,NI[:~ fCO~CII~

N~ S - ~I[:~ ,II:~CN ~ N / " ' S --CII2-CII2CN

Ill IV

A similar conversion of pyrimidyl sulfides of analogous structure has been described

previously [3].
Compounds lla-c and IV are crystalline materials that arestable when stored. Following
are: compound, mp (~ yield (%): lla, 129-131 (from ethanol), 74; lib, 160-162 (from
ethanol), 47; IIc, i07-i08 (from methanol), 79; IV, 99-100 (from benzene--hexane mixture), 69.
The elementalcompositions of II and IV agree with the calculated values, and the IR,
PMR, and UV spectra confirm the proposed structures.

S. Ordzhonikidze All-Union Chemico-Pharmaceutical Scientific-Research Institute, Moscow

119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 416-417, March,
1986. Original article submitted June 12, 1985.

344 0009-3122/86/2203-0344512.50 9 1986 Plenum Publishing Corporation

 LITERATURE CITED

i. E. C. Taylor and E. E. Garcia, J. Org. Chem., 29, 2121 (1964).

2. W. E. Hymans, J. Heterocycl. Chem., 13, ~141 (1976)o
3. M. P. Nemeryuk , A. L. Sedov, I. Krzhepelka, and T. S. Safonova, Khim. Geterotsikl.
Soedin., No. i0, 1426 (1982).

2-SELENOXOQUINAZOLONES-4, A NEW KIND OF QUINAZOLONE

L. M. Yun and Kh. M. Shakhidoyatov UDC 547.856.1

No information has yet been published on quinazoline derivatives that contain such
heteroatoms as selenium, tellurium, etc., in position 2. Moreover~ quinazolines with these
substituents are of'great theoretical interest from the viewpoint of comparing their re-
activity with that of 2-oxo-, amino, or thioxoquinazolones-4. Furthermore~ these compounds
can be starting materials for the generation of a new heterocyclic system, viz., selenazo-
quinazoline.
On the basis of the nucleophilic substitution [I] of 2-methylthioquinazolone-4 (I) by
various amines we assumed that by means of this reaction a selenium atom could be introduced
at position 2 of the quinazoline ring, since when it is directly introduced into that position
(as, e.g., in the case of sulfur [2]) the expected results were not obtained.
We have shown that for compound I nucleophilic substitution by sodium selenide at the
moment it is formed [3] gives selenoxoquinazolone-4 (II), whereas 2-thloxoquinazolone-4
does not undergo this reaction.

.0 0

SCH~ Se
H

I I!

Alkylation of II with methyl iodide in alcoholic alkali gives, depending on proportions,

either 2-methylselenoquinazolone-4 (IV), or a mixture thereof with 3-metHyl-2-selenoquinazo-
lone-4 (V); alkylation with dibromoethane gives 2,3-dihydroselenazo[2,l-b]quinazolone-4 (VI).

O O
~# .Ny~\S,C,3
i!
[J .
[i ~-~ I
IV
O

,v i il <
II
V

Institute of Plant-Material Chemistry, Academy of Sciences of the Uzbek SSR, Tashkent

7[)0170. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 417-418, March,
1986. Original article submitted August 22, 1985.

0009-3122/86/2203-0345512.50 9 1986 Plenum Publishing Corporation 345

 2-Selenoxoquinazolone-4 (II). Yield 59%, R= 0.65 (silufol, 4:1 benzene-acetone), m p
245-247 ~ (from alcohol), M + 224/226. UV spectrum: 224, 318 (CzHsOH), 235,292 nm (C=HsOH +
KOH).
2-Methylseleno~ulnazolone-4~" (IV). Yield 62%, Rf0.82, mp 208-210 ~ (from alcohol), M+
238/240. PMR spectrum (CDCI3): 2.55 (SeCHs, s), 7.25-7.80 (6-, 7-, 8-H, m), 8.28 ppm
(5-H,d). UV spectrum: 225, 237, 279 nm (C2HsOH).
3-Methyl-2-methylselenoquinazolone-4 (V), Yield 16%. Rf 0.90, mp 78 ~ (from hexane),
M + 254/256. PMR spectrum (CDCIs): 2.55 (SeCHs, s), 3.55 (3-CHs, s), 7.37-7.70 (6-, 7-, 8-H,
m), 8.15-8.40 ppm (5"H, d). UV spectrum: 224, 237, 238 nm (C2HsOH).
2~3-Dihydroselenazo[2~l-b]quinazolone-4 (VI). Yield 52%, Rf 0.52, mp 141-142 ~ (from
3:2 alcohol-water), M+ 250/252. UV spectrum: 226, 286, 242 nm (C2H~OH).

LITERATURE CITED

I. M. Seth and N. M. Khanna, Indian J. Chemo, 14B, 536 (1976).

2. L. M. Yun, S. Yanglbaev, Kh. M. Shakhidoyatov, and Ch. Sh. Kadyrov, Khi. Geterotsikl.
Soedin., No. 2, 268 (1983).
3. M. Lath-Compere, A. Luxen, L. Christiaens, M. Guillaume, and M. Renson, J. Heterocycl.
Chem., 18, 343 (1981).

ALKYLATION OF 6-SUBST!TUTED PURINES IN CONDITIONS OF

INTERPHASE CATALYSIS

N. P. Ramzaeva, I. N. Goncharova, UDC 547.857.7:541.128.1

M. Yu. Lidak, Yu. Sh. Gol'dberg,
and M. V. Shimanskaya

Alkylation of the 6-substitutedpurin~s (la-c) in the presence of bases is usually

performed in dry bipolar aprotic solvents at 25-I000C in the course of 3-85 h; this leads
to the mixture of the N-9-, N-7-, and N-3-alkylation products [1-3]. It was recently shown
for adenine that the alkyiation proceeds by 75-92% at 20-800C in 8-12 h in the biphasic
system of the organic solvent and a i0-20% aqueous solution of NaOH (or without the solvent
with solid alkali) in the presence Of an interphase catalyst [4-6].
We established that theapplication of abiphasic system of the liquid--liquid or liquid--
solid type using 50% aqueous alkali or solid alkali is significantly more effective for the
alkylation of the purinesla-c. S u c h conditions increase the yield of the alkylpurines sub-
stantially with low duration of the reaction; the control of the course of the reaction is
also additionally greatly simplified byusing the liquid--liquid systems. The alkylation
can be considered as completed right after the disappearance of the suspension of the
sodium salt of the initial purine which is formed by its deprotonation at the interphase
boundary, and is solubilized in the organic phase with the aid of the interphase catalyst,
and is therefore gradually drawn into the alkylation reaction.

R R R R

N" CII~CelI5 NJ ~ - - - - - N
N - - ~ " ~ - ....... N C~HsCtt21]r (ll) N ~ "',: ..... N N ~# ":- ,

L'~N / ~ "~"N . . . . . "N 'N ~ ""

H i
C112C6H 5 CII CgH
la-c llla-c IVa-c
l,ltr- V a R::NHCII % H ~ . b R = e h c R:=SCII 3

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 419-420, ~rch, 1986.
Original article submitted September 19, 1985.

346 0009-3122/86/2203-0346512.50 9 1986 Plenum Publishing Corporation

 Thus, the purine la is alkylated with benzyl bromide II in the system CH2C12--50% NaOH
(system A) in the presence of Bu~NBr (i0 mole %) at 40~ in 5 min; the mixture of the alkyl-
purines Ilia and IVa, ~2:1 is formed in quantitative yield. On utilizing the more lipophilic
catalyst -- tetraoctylammmonium bromide, the reaction proceedsin 5 min at ~20~ On the
a!ky!ation of the purine la bY the alkyl halogenide II in the system of benzene--solid KOH
(18-crown-6, 60~ i h), the i:i mixture of the isomers Ilia and IVa is formed in quantitative
yield. On the alkylation of the purine (la) in the system of benzene--50% NaOH (system B)
using the interphase catalyst immobilized on an insoluble carrier -- the polymerically bound
hexyltributylphosphonium bromide -- the 5:4mixture of the isomers Ilia and Va is obtained
after i0 min at 40~ in a quantitative yield. This is the first example of the alkylation
of purines in the triphasic system of liquid--solid--liquid.
The alkylation of the purines Ib and Ic in the systems A and B leads to the mixture of
three isomers -- lllb,c, IVb,c, and Vc -- with a total yield greater than 95%. The purine Ib
with the system A, the catalyst Bu~NBr, the reaction temperature of 400C, and the time of
60 min gave the 3:1 mixture of III and IV. T h e purine Ib with the system B, the catalyst
(CsHIT)4NBr, the reaction temperature of 40~ and the time of i0 min gave the 3:2 mixture
of III and IV. The purine Ic with the system B, the catalyst (CeHIT)~NBr, the reaction
temperature of 60~ and the time of 5 min gave the 4:4:1 mixture of III, IV, and V.
The alkylation of the purines la-c does not proceed in the absence of a catalyst under
the conditions studied. The isomeric alkylpurines which are formed areseparated by the
method of preparative TLC in the i:i system of chloroform--ethyl acetate, and are identified
from the mps and the UV spectra, agreeing vith the literature data. When the purine la is
subjected to prolonged stirring in the system A (40~ 15 h) in the absence of the alkylating
agent, the solvent serves as the latter. Bis(6-benzylaminopurin-9-yl)methane is isolated
from the reaction mixture. The yield of the product is 30%; mp 228-230~ M + 462. The
PMR spectrum (DMSO-D6) was as follows: 4.73 (broad singlet, 4H, CH~Ph), 6.55 (singlet, 2H,
NCH2N), 7.33 (multiplet, 10H, C~Hs), 8.17 (singlet, 2H, 8-, 8'-H), and 8.22 ppm (singlet, 2-,
2'-H).

LITERATURE CITED

i. N. J. Leonard, K. L. Carraway, and J. P. Helgeson, J. Heterocycl. Chem., 2, 291 (1965).

2. J. A. Montgomery and C. J. Temple, J. Amer. Chem. Soc., 83, 630 (1961).
3. Z. Neiman and F. Bergmann, Israel J. Chem., 5, 243 (1967).
4. I. Sinkai, M. C. Vander Zvan, F. W. Hartner, R. A. Reamer, R. J. Tull, and L. M. Weinstock,
J. Heterocycl. Chem., 18, 197 (1981).
5. M. Hedayatullah, J. Heterocycl. Chem., 19, 249 (1982).
6. G. Bram and G. Decodts, Synthesis, No. 5, 543 (1985).

347
 SYNTHESIS OF CONDENSED TETRAHYDROPTERIDINES BY THE CYCLIZATION
OF THE S-ETHYLPTERIDINIUM CATION WITH DINUCLEOPHILES*

I. V. Kazantseva, V. G. Baklykov, UDC 547.859.07

V. N. Charushin, and O. N. Chupakhin

It waspreviously established in a series of published works that 1,4-diazinium cations

can produce polycyclic compounds in reactions with dinucleophiles; the very diverse five-
and six-membered nitrogen-,oxygen-~ and sulfur-contalning heterocycles are annelated to the
pyrazine fragment in these polycyclic compounds (see the reviews [2, 3]). The only example
of such a cyclization, which was described in pteridine series, is the formation of 5,5a,
8a,9-tetrahydrofuro[2,3-g]pteridines in the reaction of unsubstituted pteridine with 8-di-
carbonyl compounds showlngtheproperties of 1,3-C,O-dinucleophiles [4]. Information on the
reaction of pteridines with other types of dinucleophile is absent from the literature.
Attempts to cyclize N,C- and N,N-dinucleophiles with pteridines proved to be unsuccessful
[5].
In the present work, the possible participation of pteridines, activated by charge,
in cyclizations with dinucleophiles is reported. As a result of the reactions of 2-morpholino-
4-methyl-8-ethylpteridinium borofluoride (I) with phenylthiourea and N-(a-pyridyl)acetoaceta-
mide in ethanol at 20-30aC in the presence of triethylamine, the derivaaives of 5,5a,6,7,
8a,9-hexahydro-8H-imldazo[4,5-g] (II) and 5,5a,7,8,8a,9-hexahydro-6H-pyrrolo[2,3-g]pteridine
(III) were correspondingly obtained in high yields. The structure of the compounds II and
III was established by the comparison of thelr PMR spectra with the spectra of compounds of
a similar structure in the quinoxali~e series for which ~he detailed analysis was given in
the work [6].

CH~

N~c" ~, N -------- N'~'~v,~~, ', 1 ]

i~i J L ~ Jj+ -------~" ii i "
( f ~ " N/'~"~N ~ N/S~a'~'y'~ 0 / "N ~ ~N/A~ N~
0~ C2H5 COCII5 O~ CzH5 0 i C ~H%
III I II

The conversions found are the first case of the participation of pteridinium cations in
cyclizations with dinucleophiles, and they permit the accomplishment of the slngle-stage
synthesis of derivatives of the new heterocyc!ic systems: pyrrolo- and imidazo-pteridines.
Compound (II)~ The mp was 200-202~ the yield was 64%. The PMR spectrum (in CDCI~)
was as follows: 1.26 (3H, triplet, CHs), 1.74 (3H, singlet, CHs), 2.9-4.3 (2H, multiplet,
N-CH=), 3.72 (SH, multiplet, protons of the morpholine ring), 5.38 (IH, doublet, 8a-H,
3Jsa,ea ffi7.7 Hz), 5.82 (IH, double doublet, 5a-H, "J~,, a ffi3.5 Hz), 7.0-7.7 (5H, multiplet,
phenyi), and 8.05 ppm (IH, broad singlet, NH).
Compound (III). The mp was 149-150~ the yield was 79%. The PMR spectrum (in CDCI3)
was as follows: 1.19 (3H, triplet, CHs), 2.13 (3H, singlet, CH3), 2.54 (3H, singlet, COCHs)
3.0-4.3 (2H, multiplet, N-CHa), 3.71 (8H, multiplet~ protons of the morpholine ring), 4.01
(IH, doublet, 8-H, sJs,ea = 8.2 Hz), 4.75 (IN, multiplet, 8a-H), 5.25 (iN, broad singlet,

*Communication 20 in the series "Cyclizations of N-alkylazinium cations with bifunctional

nucleophi!es." For Communication 19, see [i].
S. M. Kirov Ural Polytechnical Institute, Sverdlovsk 620002. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 3, pp. 420-421, March, 1986. Original article submitted
June 17, 1985.

348 0009-3122/86/2203-0348512.50 ~ 1986 Plenum Publishing Corporation

NH), 5.58 (IH, double doublet, 5a-H, 3J5,s a = 2.9, 3Jba,sa = 5.7 Hz) and 6.9-8.6 ppm (4H,
multiplet, protons of the pyridine ring).
Satisfactory data of the elemental analysis were obtained for the compounds II and III.

LITERATURE CITED

1. D.S.Yufit, Yu. T. Struchkov, V. N. Drozd, V. G. Baklykov, V. N. Charushin, and O. N.

Chupakhin, KhimoGeterotsil. Soedin., No. i0, 1417 (1985).
2. V. N. Charushin and O. N. Chupakhin, Usp. Khim., No. i0, 1648 (1984).
3. V. N. Charushin, M. G. Ponizovskii, and O. N. Chupakhin, Khim. Geterotsikl. Soedin., No.
8, 1011 (1985).
4. A. Albert and N. Mizuno, J. Chem, Soc. Perkin I, No. 11, 1615 (1973).
5. V. N. Charushin, I. V. Kazantseva, and L . G . Egorova, in: Developments in the Chemistry
of Azines [in Russian], Sverdlovsk (1985), p. 146.
6. V. N. Charushin, A. I. Chernyshev, N. N. Sorokin, and O. N. Chupakhin, Org. Magn. Reson.,
22, 775 (1984).

SYNTHESIS OF 2,3-DIPHENYL-5,6-DIHYDRO-!,3-OXAZINIUM
HEXACHLOROANTIMONATE FROM2-PHENYL-I,3,DIOXANE

T. P. Kosulina, E. V. Gromachevskaya, UDC 547.867.07'841'546.845

and V. G. Kul'nevich

We have found a method for the synthesis of 1,3-oxazinium salts, taking as an example
the previously unknown 2,3-diphenyl'5,6-dihydro-l,3-oxazinium hexachloroantimonate (IV).
The main features of the proposed scheme are the acylation of 2-phenyl-l,3-dioxane (I) by
benzoyl chloride, the exchange reaction of chlorine for the amino group in the resulting
y-chloroester lla, and the subsequent acylation of compound III by benzoy! chloride in the
presence of SbCI~.
The secondary aminoalcohol V is formed on the alkaline hydrolysis of l-phenylamino-
3-benzoyloxypropane (III). Compound V also gives the salt IV by the action of benzoyl
chloride and SbCI5 in the ratio of 2:1.

PhNH~,.. [ ~
o~o 0
r
C1 0 NHPh
C-----O C=O
Ph
Ph ~ /' Ph
II ~o~,/" III
0"/
~"~ 1 PhCOC1 H20,0P-
' I
P ~ SbCl5 I

110 NHPh "~" " "Ph

|
; . Ph SbC16-
Y ....... IV

The structure and composition of the salt IV were confirmed by the data of IR spectros-
copy and elemental analysis, as well as by a chemical method. Hydrolysis of the salt IV
leads to the opening of the ring with the formation of the y-aminoester (III). The methods
of [i] and [2] were employed to obtain 2-phenyl-l,3-dioxane I and l-benzoyloxy-3-chloropro-
pane (II) respectively.

Krasnodar Polytechnical Institute, Krasnodar 350006. Translated from Khimiya Geterot-

sikiicheskikh Soedinenii, No. 3, p. 421, Harch, 1986. Original article submitted July 15,
1985.

0009-3122/86/2203-0349512.50 9 1986 Plenum Publishing Corporation 349

 l-Phenylamino-3-benzoyloxypropane (III). The yield was 51%; the bp was 201-203~ (S m m).
The IR spectrum: 3400, 3030, 1710, 1610, and 1590 cm "I.
3-Phenylaminopropanol (V). The yield was 72%; the bp was 151-1530C (8 mm). The IR
spectrum: 3560, 34a0, 3070, 3030, 1610, 1520, 1320, 1270, 1070, and 760 cm -I.
2,3-Diphenyl-5,67dihydr~176 um HeXach!0r~176 (!v). The yield was 62%;
the mp was I08-I09~ The IR spectrum: 3030, 1970 , 1600, 1550, 1490, and 1280 cm -~.
The contents of C, H, and N in III, IV, and V correspond to their calculated values.

LITERATURE CITED

i. N. P. Solov'eva, I. A. Terekhina, and A. G. Livshits, Maslo-zhirov. Prom. No. 6, 31

(1968).
2. T. P. Kosulina, E. V. Gromachevskaya, L. G. Malievskaya, and V. G. Kul'nevich, Manuscript
deposited in ONllTEkhim, Cherkassy (March 26, i984), No. 249, khp-D84.

ACIDIC TRANSFORMATIONOF 2-(2'HYDROXYPHENYLAMiNO)-I,4-

NAPHTHOQUINONE-4-PHENYLIMINES INTO N-PHENYLBENZO[a]-
PHENOXAZIMES

E. V. Tsoi, G. B. Afanas'eva, UDC 547.655.6'867.6.04

and O. N. Chupakhin

I t is known that in reactions of 1,4-naphthoquinone derivatives with o-aminophenols, not

only the usual aminoderivativesare formed, but also 5-benzo[a]phenoxazinones [i, 2]. Accord-
ing to the data in [i], the formation of the latter occurs as the result of substitution of
the nucleophi!ic residue in the primary amination product by excess of aminophenol. How-
ever, another mechanism has also beenpostulated, whereby the reaction proceeds via alternating
phenoxyquinones [2, 3].
We found that 2-(2-hydroxyphenylamino)-l,4-naphthoquinone-4-phenylimines (ilia-c) which
are the sole products of the amination of 1,4-naphthoquinone-4-phenylimine (I) by o-amino-
phenols (lla-c) in ethanol, on brief boiling in glacial acetic acid convert completely into
N-phenylbenzo[a]phenoxazimes (Va-c).

o 0

" IIa-c
~ H R .....a--

NPh NPh
! IIla-c
[ ~i', ', - NH2~/R

IV Va-c

II, II[, V a R = H , b R=CH~, c R=NO2

S. H. Kirov Ural Polytechnical Institute, Sverdlovsk 620002. Translated from Khimiya

Geterotsi~licheskikh Soedinenii, No. 3, p. 422, Harch, 1986. Original article submitted
June 17, 1985.

350 0009-3122/86/2203-0350512.50 9 1986 Plenum Publishing Corporation

 This transformation presupposes that an unusual acidic isomerization of compounds III
into phenoxyquinonimines IV occurs.
The structure of compounds III, V has been established from the data of the IR, UV, PMR
spectra. The structure of the condensation products V is confirmed by the synthesis of
compound Va from benzo[a]phenoxazine and aniline [4], and also by the hydrolysis of compounds
Va,b to the known 5-benzo[a]phenoxazinones [I].
Given are: mp, ~ yield, %: IIla, 212-214 (from ethanol), 87; IlIb, 206-208 (from
ethanol), 80; Illc, 250 (dec., from ethanol), 75; Va, 216-218 (from chloroform), 85; Vb,
225-227 (from ethyl acetate), 87, Vc, 268-270 (from ethyl acetate), 70.
The course of the reactions and the purity of the compounds obtained were monitored by
TLC. The elemental analysis results correspond to the calculated data.

LITERATURECITED

i. A. Butenandt, E. Bickert, and Wo Schafer, Anh, 632, 143 (1960).

2. N. Lo Agarwal and Wo Schafer, J. Orgo Chem., 45, ~ 2155 (1980).
3o N. L. Agarwal, S. Cloch, A. K. Tripathi, and C. K. Atal, Heterocycl, Chem., 2_~i, 509 (1984).
4. L. So Goldstein, Helv. Chim. Acta, 659 (1919).

351
SYNTHESIS OF HETEROCYCLES ON THE BASIS OF ALIPHATIC NITRO COMPOUNDS (REVIEW)

G. A. Shvekhgeimer, V. I. Zvolinskii, UDC 547.7/8;547.414.2'8

and K. I. Kobrakov

The data on the synthesis of nitrogenous heterocycles on the basis of mononitro-

alkanes, polynitroalkanes, and alkenes have been generalized in this review. Only
reactions in which the oxygen and nitrogen atoms of a nitro group appear in the
composition of the heterocycle formed have been considered.

Among the numerous chemical conversions of nitro compounds, the reactions which result
in the formation of heterocyclic structures occupy a fairly significant place. However, des-
pite the fact that the first reports of the synthesis of heterocycles from nitro compounds
date back to the end of the nineteenth century, only in the last 2-3 years have these reac-
tions come to be regarded as convenient general methods for obtaining nitrogen-containing
heterocycles rather than special cases in the chemistry of nitrocarbons.
The high and specific reactivity of aliphatic nitro compounds, their accessibility, and
the practically unrestricted possibilities for the variation of their structure make these
compounds some of the most convenient starting compounds for obtaining a broad spectrum of
heterocyclic compounds. Moreover, it should be noted that in a number of cases, aliphatic
nitro compounds are the only possible starting compounds for obtaining the desired heterocy-
clic compounds.
Out of the large variety of reactions of nitro compounds which give heterocycles, in the
present review we shall consider only conversions in which the nitrogen and oxygen atoms entel
the structure of a heterocycle. Our main attention will be focused on the work carried out i~
the period from 1960 to 1983. Unless it seemed necessary for some reason, the information on
the synthesis of furoxans from aliphatic nitro compounds will be omitted, since this question
was illuminated in a practically exhaustive manner in a recently published monograph [i]. We
shall likewise not consider the numerous reactions resulting in the formation of cyclic struc-
tures following the reduction of u-nitro carbonyl compounds (reductive cyclization), since
in this case, the cyclization is caused by the conversions of functional groups formed as a
result of the preliminary reduction of a nitro group.

MONONITROALKANES AND THEIR DERIVATIVES

In 1960 Mukaiyama and Hoshino discovered that the reactions of primary nitroalkanes with
phenyl isocyanate in the presence of catalytic amounts of tertiary amines gives disubstituted
furoxans, rather than the corresponding addition products, i.e., nitroanilides~ and proposed
the following scheme for the process [2, 3]:

Rt3N
RCH~NO v ~.'\ .m- ( R C l t N % ) ' - + R~NH+

(RCHN02) i.- C6tIsNCO - -J,,-'--(~u ON CH R ) - .,~ ~ CaH~NH C 9 O. (H R

-CO 2 ~ C I[~NCO
CaHsNIICOOIi - r 2 - ~ C6HsNIICONIIC6H 5
+
R R
R-- C ~N-~-O
R c~N-o lJ If
N'.o/N~k O
R ~ C H 3, C~H 5

When this reaction was carried out in the presenc e of alkenes, the corresponding isooxa-
zolines were obtained.
A. N. Kosygin Moscow Textile Institute, Moscow 117419. Translated from Khimiya Geter-
otsiklicheskikh Soedinenii, No. 4, pp. 435-452, April, 1986. Original article submitted March
12, 1984.

0009-3122/86/2204-0353512.50 9 1986 Plenum Publishing Corporation 353

 RCI'I~NO, ~ tTeli.~NCO r t;ll, t'HR' t~ !l 't I t'O., ~r t~l ~NItCONHt:s|~
N

RI ~!H~II{}O, t'tll,'

This synthesis method was subsequently used fairly widely by many investigators for ob-
taining various N-containing heterocycles [4-15]. Such methods were used, for example, to car-
ry out the synthesis of condensed heterocycles of the naphthoquinone series [4], cyclopentane-
isoxazole derivatives which can be used in the synthesis of prostglandins [5], ferrocene-con-
raining isoxazoles and isoxazolines [7, 8], oxo-l,2,3,5-oxathiadiazoles [ii], and indolyl-
substituted isoxazolines [14].
It is interesting that the use of nitromethane in these reactions resulted in the forma-
tion of products of the addition of more complicated nitrile N-oxide I (which is believed by
Paul and Tshelitcheff [16] to be formed as a result of the interaction of nitromethane with
phenyl isocyanate) to alkenes, rather than the expected isoxazolines without a substituent in
position 3:

....x/,. ~ ! IIC~N-~O 1 ........ .b,- / |

i
[ ....I N'"O " ) " R

C~I3NO
9 2" + CsHsNCO .. 0
Jl
0 C,IHsNH- {:
it CH2=CH-R 1~ ....... 1
........
~ C~,~NH..C C--~N.~-O .............~,.
... ~ j
I "0" ~'R

In the last few years it was shown that reagents such as carbodiimides [17], phosphoryl
chloride [18-20], acetic anhydride [18, 21, 22], trifluoroacetic anhydride [19], acetyl chlor-
ide [23-26], and benzoyl chloride [19] can be used instead of phenyl isocyanate.
In all these reactions the formation of the heterocycles upon the interaction of the
primary nitro compounds with the unsaturated compounds in the presence of phenyl isocyanate
or other reagents is usually viewed as the result of the cycloaddition of the nitrile N-oxides
formed from the aci form of the respective nitroalkanes under the action of these reagents to
the dipolarophiles present in the reaction mixture. It should, however, be noted that nitrile
N-oxides were not isolated in any of the investigations in this area and that no direct evi-
dence of their formation has been obtained.
It seems more likely that nitronic esters II, which can themselves act as 1,3-dipoles,
rather than nitrile N-oxides, form from primary nitro compounds.

RI o.~N,.o -
II
l
RI=C~HsNHCO, CHACO,C~HsNHC=NCsHs

Novikov et al. developed a convenient method for obtaining five-membered nitrogenous

heterocycles on the basis of primary nitroalkanes, which was subsequently used by many inves-
tigators. According to this method, nitroalkanes are converted under the action of diazometh-
ane [27-31], Lornblum' s reagent [32-35], alkyl halides [36] ~ trimethylchlorosilane [37-42],
or bis(trimethylsilyl)acetamide [37, 38] into the corresponding 0 esters, which react with
dipolarophiles according to a 1,3-dipolar cycloaddition scheme. In this case, the 0 esters
can either be isolated and then used or utilized in an Sn situ reaction:

Cl~i(Cll~) ~.0 Ct|2=CIiCN I ...... !

I~(71[2N02- - . . . . . . . . . . ~ Rt~}I:2:N ~OSi(CH3)3 (CH ~).~SiO ""N " 0 " * ' " C N

The mechanism of the cycloaddition of nitronic esters was thoroughly studied in [43-50].
The reaction of the O-methylnitroacetic ester with substituted alkynes has a peculiar
course: instead of the expected 1,3-dipolar cycloaddition products, i.e., isoxazolines, the
corresponding aziridines were isolated [51]:

354
 C~H.0COCH -~N "r + RC~CH ........ ~ 1~- - C -. "~'-_7-'-C02C2H
~ x0CH3 N 5
o I
OCH~

A way to obtain isoxazoline N-oxides from nitroalkanes and vinyloxosulfonium fluoborate

was recently described [52]:

RCH2N02 + 6H~?- --C]I:CIIC6H

[ [ 5 BF~ ...... 3~
89 v(cIt~)z .,]

The presence of other functional groups in the molecule of a nitroalkane expands the pos-
sibilities for the synthesis of heterocycles. For example, it was shown in [53-55] that y-
halonitroalkanes readily form cyclic nitronic esters III as a result of the intramolecular
nucleophilic attack of the carbon atom bonded to the halogen by the oxygen atom of the nitro
group. Esters of type III can then be subjected to a 1,3-dipolar cycloaddition reaction.

lk

NO z '0" "0" "D" "" R I

Ill

The synthesis of 3-nitroisoxazoline from the substituted propanes X(CH2)~Y (X = I, Br,

CI, NO2; Y = I, Br, CI) and KN02 or NAN02 was recently patented [56]. The reaction probably
takes place according to a scheme similar to that described above.
The sodium salts of the compounds of t h e a-bromophenylnitromethane series give isoxazo-
lines in the presence of dipolarophiles upon heating [57].

i- Hr "i " C :::C D-RC6t*4

p- IRCjIr " [ - Na ' 90 .100~ N ..J'7

NOz _! '0

Different heterocycles can be obtained from nitro ketones, depending on their structure,
as well as the reaction conditions. For example, disubstituted furoxans were synthesized by
reacting benzenesulfonic acid with a-nitro ketones [58].
a-Nitroacetophenone reacts in an acidic medium with isopropenyl acetate to form 3-benzoyl
5-methylisoxazole with a yield greater than 60% [59]. At the same time, the corresponding
isoxazole is obtained with a yield of only ~5% from a-nitroacetone under similar conditions.
Nelson, Karparian, and Trager suggested that ketene is initially formed from isopropenyl ace-
tate and then reacts with the nitro co~pound.

I coo. F ]

In the presence of acids, cyclic ~-nitro ketones can undergo a rearrangement with ring
expansion [60, 61]:
O O

t~-'x. ~ NO~ . \ ( ........ ]I OIl

"I "'- i

The reaction of ~-nitro ketones with o-aminothiophenols gives condensed S,N-containing

heterocycles [62, 63]:

355
 ..,.~....~S,..~>N--O~ :"~:i')' s~ 02NC"zC01r ~,,
~'~ " "hi " R " 9. . . . . . " N i l 0

3-Halo-4,5-disubstituted isoxazoles were obtained in [64] by heating B-nitro ketones with

concentrated hydrohalic acids. It was noted that the reaction takes place more readily with
HBr:

R~
R ~ O C H R , C.H z N O ~ .............
,. ~H.~,,. I[
R ' 3 I0I . . . . . . . " N

X=CI, Br

3-Halo-5-phenylisoxazoles (IV) form as a result of the reaction of phenyl B-nitrovinyl

ketone with gaseous hydrogen chloride or hydrogen bromide [65].

X
%H~COC~=CHN0z ~ CsHsCOCHX-C H~ HX
"oll CsHs.,.. .

X, ( ; I , Br N

In the opinion of Mack [66], y-nitro ketones interact with hydrazine according to a
scheme, which includes the intermediate formation of nltrile N-oxldes (V):

'. R I .~<,,.R;' R ~, R ?
-:" N--OH
R~ ..... C!H2NO, N,,II~,.. " '"r N.~O
R,! " < " C l l ,C(-)R ~ " )'
' I~ ~ "'N Nil;,
II
V

The synthesis of heterocycles from nitroalkanes and carbonyl compounds h a s b e e n described.

The reaction of nitromethane with cyclohexanone in the presence of pyrldine is somewhat unusu-
al in that the structure of the dispirane formed was established only many years after its
synthesis [67-69]:
N,,-OH

The reaction of nitromethane with cyclopentanone produces a similar structure [70].

Ethyl nitroacetate reacts with keto esters of the indole series in the presence of POCI3
to form isoxazolinylindoles [71].

~- . ./COCH.R' ~ \ .................. R ~

R R ~::C02CaH ~ R O

In a number of cases, the nitroalkenes formed as a result of the reaction of nitroalkanes

with carbonyl compounds undergo an additional reaction with another molecule of the nitroal-
kane, giving B-dinitro compounds, which are readily converted into heterocycles under the
conditions of the reaction. A number of investigators have suggested t h a t t h e intramolecular
cyclization occurs as a result of the nucleophilic replacement of one nitro group by the oxy-
gen atom of an ambidentate nitronate ion arising from another nitro group. The possibility of
the occurrence of such a reaction was pointed out by Kornblum [72]. The reaction of methyl
nitroacetate with aldehydes [73], which produces isoxazoline N-oxides Vl clearly takes place
according to the scheme

356
 CH502C /CH 11f ] CH302C )~T_ R
1 "'Y, "CHIN02 |
RCH0 + 2N0~CIt2C02CHs .....
/I :'-c%cH, I ----- o.N.o~co2ch~
. 0a ~0- J

vI

Nielsen and Archibald [74, 75] described the synthesis of 3,4,5-triphenylisoxazole from
benzaldehyde and phenylnitromethane in an alkaline medium. They believe that the reaction
involves the intermediate formation of 1,3-dinitro-l,2,3-triphenylpropane. Besides isoxazole,
3,4,5-triphenylisoxazoline forms with a small yield.
Several reports [76-79] of the synthesis of isoxazoles from nitroalkanes and ~,B-unsat-
urated ~-nitro esters have been published. The reaction clearly takes place according to a
scheme which includes the intermediate formation of dinitro derivative VII:

RCH=C(NO.)CO~C2H 5 N02CH2C02CzH5 R \ C H - - CI~C02C2H5

~ .CH NO~
i C2H502C "NO 2
VII
0
o o II
II R I C . H g N H --C ~.
NH-C. I C- -N|~C4H
...... ~,- I 'C -C H - C 9
c4t! II II .......""
.
Y NO~II l ~ CONHC4H9
1t0" 0

Ethyl nitroacetate reacts also with several azomethines to form disubstituted isoxazoles
Zen and Umezawa [78] suggested t h a t t h e reaction also involves the intermediate formation of
a dinitro derivative. An alternative scheme for the synthesis of an isoxazole ring from B-
dinitro compounds, which includes the intermediate formation of cyclic nitrone ester VIII,
was proposed in [79]:

J ? 1%.~ozc .R
C.2H ~'0 2C---CH-CII..CII.
I [ C0 2C.H.
~. J
NO 2 NO 2 ~ N02H _J 0A:N"o / " C02CzH 5
VIII

(;zHsoz(:- c
N
C~H~O.C - C-=:c - C- CO.C.,H~
- R NH-
-'2--J"-.D,.-
0
.
II
il
|
R

I- CH ~i c~

01t
~

[_ ~ .1

Such a course of the reaction is indirectly confirmed by the fact that in the case of
the reaction of ketoenamines with ethyl nitroacetate, intermediately formed nitronic ester IX
was isolated in the form of adducts with olefins [80, 81]

R2
I 3 VNo R2 1 _
[ 2 ~ H - C H : C -I
-;COR ~ N 0 2 C H"__2
C0 ~_~_
CH
R R N--CH=C--COE + N02CH2CO2CH~ ~ L C0~CH~

R2 R2
J I CO~CH.
R2CHCOR 3 R3COCH CO CH 3 RCOCH I ~
~o 2 I -m~o2 b--F: 2 CH~=CH-R" "~--- ~---~
~CH'C~-CHCO2CH.~ I | ~ ~ ~ | I |
cH.0~C t ~ ~ /N~ /,.. N J.. 4
" NO 2 CH302C 0 0 CH302C O / ~O "R
IX

When l-nitropropane was reacted with 2-nitro-l-butene, 3,5-diethylisoxazole, which prob-

ably forms as a result of the intramolecular cyclization of dinitroalkane, was isolated along
with the expected 3,5-dinitroheptane [82, 83].

357
 An unusual case of intramolecular heterocyclization with the participation of both oxy-
gen atoms of the nitro group was described in [84]:

CF~ c v ~ - c~ CF~--~N\
X o ,o
~io _ _ Ho c~z ~"-~-'>"~R'
E

The reaction of butylmagnesium bromide with nitromethane in the presence of styrene gives
isoxazolidine. It has been postulated [85] that the reaction involves the preliminary forma-
tion of nitrone X:

r. . . . ! Cti~=ClIC ~ [ ~
s ~Br + CH6NO2 ~" i cO I----
L ':."o ~ C,tIl~~ O" CC, U s

The reaction of l'chloro-l-nitrocycloalkanes with triphenylphosphine results in the form-

ation of lactams after a fairly complex series of conversions [86]:

CI 0
|t" H ) P /
I<%L '. . . . . . "' ~.-- ~ctb), , ]
"'- NOy "" --NH

N-cyclohexylcaprolactam (XI) was obtained as a result of the UV irradiation of nitrocy-

clohexane [87]:

) cyclohexane', , l . / -'---"-,~,o ,..-N=<, ./ ..-------

-,/ "..... Oil . . . . . ...........

O.

.... ~ .' ' ._Ni_ .i / ~ ---~- i .... N

Ell XI

In order to confirm such a course for the reaction, oxaziridine XII obtained by an in-
dependent method was converted practically quantitatively into N-cyclohexylcaprolactam under
irradiation [87].
The irradiation of a bicyclic nitroalkane results in ring expansion with the formation
of an hydroxylactam [88].

9 ' Clio... / C H ~

...... ~'.~\ hv .~ :-.!.

"-.~.~'l~ '~ C..IIsONa,C,~HsOII
" ~
".. ~'.~
"~N--~
i i :0
NO~ Q~

The reaction of nitroacetonitrile or methyl nitroacetate with l-bromo-l-nitroalkenes

produces 4-nitroisoxazoline N-oxides [89].

[
-O~N/O- " + 1- R R Tq R R I
NO 2 NaOH II
~C:=CHR + R~CII2N02
Br
- J L NO~ -u J

Novikov e t a l . [ 9 0 , 9 1 ] obtained derivatives of 2-hydroxy-4,5-dihydro-l,2,3-oxadiazole

as a result of the treatment of N-nitro amino compounds with bases.
A method -or the synthesis of 2,4,6-tricyanopyridine N-oxide on the basis of nitroaceto-
nitrile was proposed in [ 9 2 ] :

358
 C~N

c,2o n~ . ,o,
I~02CHiCmN ~ KN0zCHC-N HOCM~C--C~N - - 2 - - 4

N~C C~N

The reaction Na salts of secondary [93] or primary [94] nitroalkanes with diethylboron
halides results in the formation of dimeric esters XIII, which are converted upon storage into
2,5,5-triethyl-4-alkylidene-l,3-dioxa-4-aza-2,5-diboracyclopentanes:

_ (C.Hs).B--O

R/ --~-OB(C.Hs) ~ N__O /
XIII R--C--CH3

a-Nitro esters of carboxylic acids react with diethylboron chloride to form heterocyclic
compounds of hype XIV [95]:
R
x .q: "dN
oL~.o
172/t 5" C~,H.%
XIV

DINITROALKANES AND THEIR DERIVATIVES

Compounds containing the --C(NO2)2H grouping are converted fairly smoothly under the in-
fluence of various reagents into 3-nitroisoxazoline N-oxides, which are capable of undergoing
a 1,3-dipolar cycloaddition reaction.
3-Nitroisoxazoline N-oxides were obtained with good yields when potassium acetate was
reacted with y-bromodinitro compounds in [96-99]. Aqueous potassium hydroxide or potassium
methoxide can be used instead of potassium acetate [97]:

R R +. N ( I 2
i rli.r.oK. ;.
BrCH~-- CH-Cltt NO; ); . . . . ' . . . . . . l,,,,- : []
~l I "0 " N i(}

R = H , CH3, C~H~, RI=H; R--RI=--(CH2)~ - (n=3.4)

Alkoxylated and carboxylated 3-nitroisoxazolines have been obtained from the correspond-
ing ~,y-dibromo derivatives [i00]:

R !O NO .
BrC(N0212CH"CIIBrR KOH "i. . . . il
< i~'6i, ....
R /"O" NIo

R~}I, C02CIt ; R~=CIt~, C2tlL '

The reaction of the K salt of dinitromethane with chloroacetaldehyde results in the for-
mation of 4-hydroxy-3-nitroisoxazoline N-oxide [i01].
]" " K" 110, N0 2

: c.~o9~ i r:' + ,.a(:.~cHo . . . . . . cl~:.~c.o.(NO)~ I -- I II ------

1,,,, _J " 0 / N'io

NO2 ,
1tO. _.. ..... Oil " . .
RCH ~!;II~l... , -i(
<N
! "0 "'N" O / j 1t Rf
XV

The adducts of this N-oxide with a number of olefins (XV) are easily split under the ac-
tion of bases and converted into derivatives of 3-nitroisoxazoline.

359
 Compounds of the 3-nitroisoxazoline series have been obtained from the silver salts of
dinitromethane and l,l-dinitroethane when they are reacted with primary alkyl halides in the
presence of alkenes [102]:

R
. . . . . . . . . . N% .N%
RC(~%)'~Ag + +' R'l .....

CsH~..o.N.oR' . . . . . CeHs/~O/N
l""-'~"

The 0 ester formed from dinitromethane and trimethylchlorosilane readily undergo a 1,3-
dipolar cycloaddition reaction to form substituted isoxazolines [37].
The thermal decomposition of the potassium salt of phenyldinitromethane in the presence
of alkenes gives 3-phenyl-5-alkylisoxazolines [103, 104].
The synthesis of 2,4,6-trinitropyridine from 2,2-dinitroethanol was described in [105].

I,I,I-TRINITRO COMPOUNDS
Trinitromethane, like mono- and gem-dinitro compounds, reacts with diazomethane to form
an O-methyl ester, which is a reactive 1,3-dipole [27, 106, 107]:

NO 2

,c(N%)~ c,~,~._ ....o Rc~. .o~--~ . . . . . .

.......... {NO2)2C.-;-N. OCI|3 CIIxC~N'" 0 / ~ " R

Halotrinitromethanes react vigorously and sometimes explosively in an ethereal solution

with diazomethane at temperatures from --i0 to --15~ with the formation of 3-nitroisoxazoline
N-oxide as the main product [108]:

... , N O z

X~Cl, Br, I

The reactions of halotrinitromethanes with other diazo compounds of the aliphatic series
have a similar course [109]. In [ii0] it was postulated that the intermediates of the reac-
tion of halotrinitromethanes with diazomethane include halomethyl esters of nitronic acid.
Such a conclusion is supported by the isolation of the corresponding adduct when the reaction
is carried out in the presence of an active dipolarophile:

~IC(NO:~)3 + CH2N 2 ~--e, , .

lodotrinitromethane reacts with alkenes to form isoxazolidines. Some investigators con-

sider the first step of the reaction to be the alkylation of the anion of trinitromethane by
cations of the n-complex type (XVI). The formation of the heterocycle occurs as a result of
the reaction of iodoalkyl nitronate XVII with another molecule of the alkene [iii, 112]:

c=c~~ . .. -_. z

-" " "' " " " I ...... ------m-

:'I ~' . I ]
I,~02 X'V1 EVil

~.L...-- I N 1 1
0 \O--.C ~C-..[
i I

When bromotrinitromethane is reacted with cyclohexene, it forms 4,5-tetramethylene-3-

nitroisoxazoline N-oxide with a small yield, presumably according to the scheme [113]

360
 "-. NO . - -. NO 2
BrC(NO~)3 + <"---'~ _ .
~"~'"~0 ~ "0. ......Br L, ..-. 0 .N~to
'\
\, ,/

Vinyl- and allyltrimethylsilane can serve as alkenes in the reaction [114, 115]. It is
interesting that in the case of allyltrimethylsilane, the N-alkoxyisoxazolidine formed is un-
stable and undergoes 6-decomposition under the conditions of the reaction:

NO z NO_
E f
t- - t - -NOz - CItz = C I I - C H ~ .-

(CH3)3SiCH 2 ~ "'0 / " ' O - - C H CH2[ (C}I3)~SiCH 2 " " 0 ~0Si(CH3) 5

CH z S i(C H ~)3

Trinitroacetonitrile [116] and fluorotrinitromethane [117] react with alkenes according

to a similar scheme; however, under these conditions the nitro group participates in the
formation of the ion pair in these cases, and the reaction product is a cyano- or fluoroisox-
azolidine:

9 ?:c:=c~ "?
-~-NO 2:"C- - N v 0 I I --+'-
X" O -C--C--NO, - J N. I ]
L N% _/ I i o o--c--~:.--~,o.
X"= f'N. ~'

Dinitroisoxalidines of type XVIII have been obtained by reacting the silver salt of tri-
nitromethane with sec- and tert-alkyl halides. The heterocycles are adducts of the initially
formed nitronic esters with alkenes, which are obtained as a result of the dehydrohalogenatior
of the original alkyl halides. When a foreign dipolarophile is introduced into the reaction
sphere, the corresponding heterocycle (XIX) is recovered [118, 119]:

-HI

I ~R Noo
+ -- ~0 CH~~"~--C--CH 3 r----~- -N0~
AgCIN02)3+(CH312~ -I ~ (NO2}2C~NxocIcH~/~ /~-~ .I~
R [ ~ CH 3 0 "O--C(CH~) 2
R
XVIII R

N%
i CH2=CIICH20H m,. [- .... f--n%
~.~ N
IIOCH~ "0 / "OC(CII~) 2
r
XIX R

Trinitromethane, its silver salt, and its mercury salt form trimethylsilyl esters XX,
which readily undergo 1,3-dipolar cycloaddition; the 5-substituted 2-trimethylsiloxy-3,3-
dinitroisoxazolidines formed can be converted into 3-nitroisoxazolines [120-122]:

NO
i 2
~,0 -N02

The reaction of dilute mineral acids with l,l,l,3-tetranitroalkanes gives 3,5-dinitro-

isoxazoles [123].

TETRANITROMETHANE
In 1967 Perekalin and Altukhov [124] described the reaction bf tetranitromethane with
ethylene, which produces 3,3-dinitro-2-(2-nitroethoxy)isoxazolidine. In [125] the mechanism
of the reaction was discussed in the 9 of the interaction of tetranitromethane with

361
styrene, and the similarity of this reaction to the reaction between halotrinitromethanes and
alkenes was pointed out [iii]:

J II "
C(NO~)4 + CH2:=CIICsH~ ....~ (NO2)~'C'"NO2""~II ...."" (NO,~i.~C- H + .....,~.
(',II~ . C tl

NO.

" O--~H'CII2NOe J. N,
C~It~ C~t[~" " 0 " "O--CIt-CH2NOf
CJt b

Cyclohexene also reacts with tetranitromethane t o form t h e c o r r e s p o n d i n g gem-dinitrois-

oxazolidine [113].
The intermediate formation of the nitronic ester of trinitromethane XXI during the reac-
tion with cycloalkenes was demonstrated by isolating the corresponding cycloadduct when the
reaction was carried out in the presence of hexene [126]:

/ i '2 . . . . .

""-"/" 0 0 " "0 ''C4H 9

I C6H,o C~II,~

Adducts of tetranitromethane and cumulenes could not be isolated in [127]. When it is

reacted with conjugated dienes, the reaction has a course similar to that of the reaction
with alkenes [127, 128]. In this case, O esters are intermediately formed as a result of the
addition of tetranitromethane to the diene in positions i and 4 (butadiene) and positions i
and 2 (piperylene). 1,4-Addition takes place with isoprene, the nitro group being added in
position i. The nitronic ester formed (XXII) reacts nonselectively with a second molecUle of
isoprene, giving a mixture of two adducts:

CH
CtI2~---C--CH:CIt 2
C(NOz) 4 + CH/:=C--CH:CH 2 I(NO2)2c:=N D-
CI[3 I- "0"- CII2CII:~ - CII2N02 ]
Cll.~ -]
XD~II

N@~ NO)
I .... ~- ~N02 ,-. . . . . . NO~
- ~- Cll,.| | " ' ] CII3
" ~- N + .~. N. I
ci12-- CH ~O "O -- CH2-CH~
. -. CH2NO2 CH2~? / "O ~ "O--CIi~CH--C--CH2NO 2
CItj CH3

The unconjugated diene 1,5-hexadiene reacts with tetranitromethane to form a bicyclic

system as a result of the intramolecular cycloaddition of inits formed O ester XIII to
the second double bond [128]:

O~" ~ "-rC(N02)2 "S" "~[ ...... i

~CH2 I
{'(NO.,)q t I'.He::;CH(CH2)2CII=CH2--ap- CH Oi ~ l I ~_ NO2
CH CH ...~.~ .N ........~" "
~ ; l I ~ / " CIt2NO~ NOTCH~ "O" ~NO~
XXllI

In general, the reactions of tetranitromethane with alkenes can take place in two direc-
tions: addition at the double bond with the formation of tetranitroalkanes or O-alkylation
with the subsequent formation of a heterocycle. The influence of the electronic effects of the
substituents in the alkene molecule on the direction of the reaction was studied in [129].

362
 NITROALKENES AND THEIR DERIVATIVES

A number of examples of the readily occurring intramolecular heterocyclization of nitro-

alkenes as a result of the interaction of the nitro group with the double bond have been des-
cribed. For example, the formation of 4,4-di-tert-butyl-3-methyl-4H-l,2-oxazete N-oxide from
the corresponding nitroalkene takes place spontaneously [130]:

t -C~Ho

(t-C~Hg)~C=C(CH3)NO z --
*-c,n~-~---J- I-v-CH~
O---N~O

1,2-Oxazete N-oxides are also produced by the reactions of l,l-di-tert-butylallenes with

nitrogen tetroxide, which involve the intermediate formation of dinitroalkenes XXIV [131]:

R t--C4H 9 R

(t-CdH~/'2C ~C==CHR N20*I"" l

(t-C~IIs)2C c-'C--CH-NO 2 -----D- l - C d l l q - - ] | ........
][ ()IlNC~
-iTo~ I "
NO 2 O ....... N ~ 0

X.~IV

The formation of substituted 1,2-oxazete N-oxides XXV as intermediates was postulated in

the photochemical reaction of 8-nitrostyrenes [132]. The opening of the oxazete ring results
in the formation of an aldehyde and acetonitrile N-oxide, which is isolated in the form of an
adduct with methyl acrylate.

.N0~ h~' i- O ........ N-I~.0

p-xC6H4CH::C" "
CH 3
----" ~
i p- X%tl~,
;
i...... l_
I' CH3J . . . . . . . . . ."-

CH2=CIIC02CII~ CH~.... _ I
p--XCsH4CH0 + CHsC~N PO ..... "" il
N
0" "COzOh 3

Four-membered cyclic nitrones form when nitroalkenes are reacted with ynamines [133,
134]:

l~I ~./. N O 2
C 4 R ~ ~ _ - - - := N-t,~O
/'[[ + R . . . . :_~ --NR 2 .. . . . . . . R2.._j - _ _ _ [ _ . l ~ ~
R~ " "li
t).- ('-- NRda

Acidification of a salt of 2,3-di-tert-butyl-l,4-dinitro-2-butene produces 3a,6a-di-tert-

butyl-7,8-dihydroisoxazolo[5,4-d]isoxazole N-oxide with a good yield [135]

C(CHQ~
O\J/O"
(CH3)3C CH--N02 H / " N
" " "~C==C " ----.~,~ 04-N
N@=cli "c(c%)~ \, ./"

There is some indication that 3-nitroisoxazoline N-oxide forms from 4,4-dinitrobutenoic

acid [136].
The UV irradiation of nitrovinyl derivatives of indole and benzoruran produces structures
containing a 1,2-oxazine ring, generally with high yields [137]:
Oil

X=O, NH

~-Nitrostyrenes form indolones under the action of acetyl chloride in the presence of
ferric chloride [138-140]:
CH.CHNO~ - ~./~ /CI

R . . . . . . . :. . . . . . . . . . . . . ~ R-

. II

363
 An unusual path for the synthesis of indole derivatives from nitrostyrenes and isonitriles
has been described [141]:
OH
I
NO. , ' ,? ,..S .~R~
' I~'~-CH=C,.R +, k~'.--N~=c
"CONHR3

1,3-Cyclohexanedione reacts with nltrostyrene to form a heterocycle, for which various

structures have been proposed: either a cyclic nitronlc ester (n-hydroxy-4-phenyl-5,6,7,8-
tetrahydro-4H-l,2-benzoxazine-5-one) [142], or 4-phenyl-3,4,5,6,7,8-hexahydro-2H-l,2-benzo-
xazine-3,5-dione [143], or an N-hydroxylactam '(l-hydroxy-3-phenyl,2,3,4,5,6,7-hexahydroindole-
2,4-dione) [144].
A (4 + 2)-cyclgaddition reaction is characteristic of conjugated nltroalkenes. For exam-
ple, nitrostyrenes react with alkenes [145, 146] or enamines [147-149] according to such
schemes to form cyclic nitronlc esters.
C.H,.
. . . . . . .L. 9 / CII3
ii + C~|tsC||~C(C|[~}N0Z ....... I I
R ' CII )" I 0 " tO

When l-nitrocyclopentene is reacted with ynamines) it is converted into unstable cyclic

nitronic ester XXVI; the latter readily undergoes isomerization to isoxazolines XXVll and may
undergo 1,3-dipolar cycloaddition [150, 151]:
N
....... ~.c- '0 0 .
li /
-..a~- ! ~
0 CcHs
/..~ /N
{ ..... il + C~lf~--C--.C---N" ---- R~ jCOzCI[~
. ,j/ " ,. .... L.........]./ -=.r~\

, -..

I......l
X'XVI

The reaction of nitro-tert-butylaeetylene with ynamines, which involves the intermediate

formation of a stable nitrile N-oxide, has been described [152].

[i('H
0,C NO;! ' (t:H~),/'. (:=_~N),O
'CIIs),,CC~=I'Nf)..-i (CIJ[~ :~CCECN{,'|I,)2--s~ l '~ ".iii~:~it .... ' I! ......
t!c.,hc .... "N(C")2 ] ((:H~)~C" " CON(C.3) ~

(CI! ~)jC \
NO2CmCC(CII3)~ ][" "'I~ I:'=-:- ~ --cON(CH~)~
NO 2" OZ

The reaction of nitro-tert-butylacetylene with phenylhydrazine gives triazoline [i53]:

(CII~) C ,.
(CII3)sCC=-CNO 2 + IIzNNHC6H s .........
lb.
]I N/~O
N
' -s ".

I
C6H s

Derivatives of 3-nitroisoxazoline N-oxide have been obtained from some derivatives of

diazomethane and gem-dinitroalkenes [154, 155]:

..NO 2
R;s 2 + CHz=C(NOz'}z .....
R j''om %

364
 1,2-Dinitroalkenes react according to a similar scheme [156].
Unsaturated nitro esters react with bromine azide to form furoxans [157]:

NO;, R.~ /.C02C2H~

~__~,=CH. CO,C,H s + BrN3----z-- "[['--~

o~-N~o / N

A method for the synthesis of pyrazines from nitroalkenes according to the following
scheme was proposed in [158]:

R1 NO 2 R1 ~ N /R 2
,.jNo
2 "H
>%" - >i o
N.,
- ~o--7-1:0o 7 "
Ii i
"" . /l 2 . . . . N "
R" II

An u n u s u a l reaction takes p l a c e when a s a l t of bicyclic nitroalkene XXVIII i s a c i d i f i e d

[159] :

Cell,./*" O"" "'-.~ 0 N

::_ H<
..,// .~/ 6 5
04" N - - - O

XXVIII

The formation of five-membered O,N,P-cons heterocycles is a characteristic reaction

of various nitroalkenes with derivatives of trivalent phosphorus. For example, when esters of
unsaturated B-nitro acids are reacted with triethyl phosphite, a mixture of three- and five-
membered heterocycles forms [160, 161]:

+P(OC2Hs)~
+ I
~c.f?=,:m:%e:, ..... ~H:- I. -CH-%~:, .+_ff.?_%ff,2~ RCH2"-~ "-CH-CO2C2H5 ----re,-
NO 2 o~N..o - ok'N" 0 -

R C02C2H 5 RCH 2 C02C2H 5 RCH2 ~ ~C02C2H 5

___ v - 7 + 'r-'=-'-r: +
H O N o"P(0C~'H5)~ o k N " o '" (0C2H5)3
OH

The reaction of nitroalkenes with diphenylmethoxyphosphine, which gives the correspond-

ing heterocycles, has been studied in detail [162-165]:

C, ]l~
c.:, ir-I
RC(CII 5)=CIIN(12 t ? ! /. P(ICII~ ---~ i "R

Conjugated nitroalkenes react at positions i and 4 with C~HsP(OCH~)2 [166, 167], RP(OR)2
[168], P(OCH=CHaCI)3 [169], and P(OCHa)a [170] according to a similar scheme. The mechanism
of the reaction was considered in the example of the reaction of nitrostyrene with P(OCHa)s in
[171].
The material presented in this review demonstrates the great variety of the chemical con-
versions of nitro compounds which result in the formation of heterocyclic systems. It should
be noted that in a number of cases, the conversions take place according to the same pattern,
apparently according to similar mechanisms with the formation of heterocycles of similar
structure. For example, the reactions involving the cycloaddition of 1,3-dipoles formed from
nitro compounds and the intramolecular cyclizations occurring as a result of the attack of
an oxygen atom of a nitro group on an electron-deficient carbon atom may be among
such reactions which have become preparative methods for the synthesis of heterocycles. In
the latter case, various fragments of the molecule can act as the "leaving group" when the
ring is closed. It should be noted that a similar attack and the formation of a heterocycle
are not always accompanied by an elimination reaction. It is mor~ commonly clearly observed
in the formation of heterocycles as a result of the interaction of tri- and tetranitro deriva-
tives with alkenes. At the same time, in a whole series of cases, the type of conversion oc-

365
currlng upon heterocyelization does not fit any general scheme, and in some eases, the reac-
tions presented are still the only examples of the formation of the structure indicated. Ne-
ertheless, we felt it was necessary to present some experimental data of this kind without
further discussion, assuming that such material would be interesting and useful to chemists
becoming familiar with this area in organic chemistry.

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gorn, and A. N. Pudovik, Zh. Obshch. Khim., 51, 2137 (1981).
163. R. D. Gareev, T. M. Loginova, A. V. Ii'yasov, A. N. Ludovik, I. M. Shermergorn, Zh. Obshch
Khim., 51, 2626 (1981).
164. R. D. Gareev, A. V. Ii'yasov, Ya. A. Levin, E. I. Gol'dfarb, V. I. Morozov, I. M. Shermer
gorn, and A. N. Pudovik, Zh. Obshch. Khim., 52, 1278 (1982).
165. R. D. Gareev, A. N. Pudovik, and I. M. Shermergorn, Zh. Obshch. Khim., 5_~3, 38 (1983).
166. R. D. Gareev, G. M. Loginova and A. N. Pudovik, Zh. Obshch. Khim., 46, 1906 (1976).
167. R. D. Gareev, G. M. Loginova, Yu. Yu. Samitov, and A. N. Pudovik, Zh. Obshch. Khim., 47,
2663 (1977).
168. J. Galodan, R. North, A. Rowley, J. Chem. Res. (S), No. i, 1 (1976).

369
169. R. D. Gareev, T. M. Loginova, and A. N. Pudovik, Izv. Akad. Nauk SSSR, Set. Khim., No. 6,
1398 (1978).
170. R. D. Gareev, G. M. Loginova, and A. N. Pudovik, Zh. Obshch. Khim., 49, 25 (1979).
171. E. E. Borisova, R. D. Gareev, T. A. Guseva, A. M. Kozlov, and I. M. Shermergorn, Dokl.
Akad. Nauk SSSR, 226, 1330 (1978).

SOME REACTIONS OF 3,7-DIMETHYL-2,3-EPOXYOCTANAL AND

ITS DERIVATIVES

L. P. Glushko, V. N. Samsonova, UDC 547.382.2'39.84:542.422.25:541.128

L. A. Yanovskaya, and L. V. Dmitrikova

The oxide of citral (3,7-dimethyl-2,3-epoxioctanal) readily enters into the Knoeve-

nagel condensation with the formation of the corresponding epoxydienecarboxylic
acid. The epoxidation and addition of dichlorocarbene to similar epoxydienes proceeds
at the double bond which does not adjoin the epoxide ring. The condensation of the
acetal of citral oxide with ketones with the formation of 1,3-dioxolanes proceeds
with the participation of the epoxide ring.

We have previously studied several reactions of citral oxide: the Darzan reaction, the
Wittig reaction, acetalization, etc. [i]. Continuing the work in this field, we accomplished
the Knoevenagelcondensation of citral oxide (I) with ethyl cyanoacetate in the presence of
catalytic amounts of piperidine; the condensation only affects the carbonyl group. An attempt
to perform this reaction under the conditions of interphase catalysis (50% aqueous solution
of NaOH, TEBA) proved to be unsuccessful.

cN
ca~ c.~ I
(CH'~)2C~CH'"s ~~CH
"~' "N~___// CH0 CNCH2C00C~Hs~ (CH~)zC=CH~"CH~CH
~ ..~______/' CH~-C
/
"0'~ "0
I II

Absorption bands in the region of 1610 (C---C), 860, 1240 (epoxide ring), 2180 (CN), and
1730 cm -I (COOEt) were present in the IR spectrum of the resulting epoxydienic compound II.
In the PMR spectrum, the signal of the aldehyde proton disappears, and the signals of the ethyl
group appear; all the remaining signals are retained (see the Experimental section).
We performed the epoxidation of 6,10-dimethyl-5,6-epoxy-3-ethoxycarbonylundeca-3,9-dien-
2-one (III), an analog of the diene II, using monoperphthalic acid according to the method of
[2]. We performed the addition of dichlorocarbene to III using dichlorocarbene generated un-
der the conditions of interphase catalysis by the method of [2]. We previously synthesized
III by the condensation of citral oxide with acetoacetic ester. In both cases, the attack
only proceeds at the isolated double bond which does not adjoin the epoxide ring and the ac-
ceptor groupings, and possesses higher nucleophilicity. The formation of the respective com-
pounds IV and V is indicated by the disappearance of the signals of the vinyl group in the PMR
spectrum and the appearance of the signals of the new epoxide ring [2.16 ppm for IV] or the
dichlorocyclopropane ring [2.3 ppm for V], while the signals of all the remaining protons are
retained. (Formula, below table, following page.)
On the reaction of the acetal of citral oxide VI, which was obtained by the acetaliza-
tion of citral oxide with orthoformic ester according to [i], with ketones in the presence of
an acid catalyst, the opening of the epoxide ring occurs with the formation of the correspond-

Dnepropetrovsk State University, Dnepropetrovsk 320625. Translated from Khimiya Geter-

otsiklicheskikh Soedinenii, No. 4, pp. 453-455, April, 1986. Original article submitted No-
vember 27, 1984.

370 0009-3122/86/2204-0370512.50 9 1986 Plenum Publishing Corporation

 TABLE I
Pound, % Empirical la~d0 % old,
Compound bp,*, %; RD2~ formula
c H c H
I
Vlla 123--125 1,4782 67,5 10,5 C17H3204 68.0 10,7 [ 46
Vllb 126--130 1,4839 69,5 10,2 C19H3404 69,9 10.5 [ 44
NIIc 132--136 1,4828 70,5 10,0 C~oHa604 70.5 10,7 52

*Pressure 2 mm of Hg stem.

COCD"3
CH 5
(CIIs)'~C=CItCH.CH- - [ CH~CCOCH 3 (CH ~)., CII3 i
X / C00C.II5 ~ T-~ --T
~/
'. // COOC2H
~
0 0 0
11I "~\.,, IV

(CH-)2-.~__ .- CHzCH;~. i H~ CH::CCOCH 5

o ----:
\\ /
" "\7" -- "7
\, / I
C00C2H ~
CCI 2 "0'
V

ing 1,3-dioxolanes Vlla-c. The absorption bands characteristic of the epoxide ring were ab-
sent from the IR spectra of (VIIa-c).

Ctt 3
(CII3)~C=CtICllaCH~ ~-i CH(OC2-H5)2

O--.R/0
Vlla-c
~,*IIa R=C(CtI3)2; b IR=CI.CIIL,)4;C R=C(CH2) 5

EXPERIMENTAL
The IR spectra were taken on a UR-20 instrument (in CCI,). The PMR spectra were taken
on a Varian HA-100 spectrophotometer (for solutions in CC14); the internal standard was HMDS.
The UV spectra were taken on a Specord UV-vis instrument (in alcohol). The individuality of
the substance was verified by the method of thin layer chromatography on plates of Silufol
UV-254.
Ethyl 5~9-Dimethyl'4,5-epoxy-2-cyanodeca-2,8-dienoate .(II). To 1.68 g (0.01 mole) of
citral oxide I are added 1.13 g (0.01 mole) of ethyl cyanoacetate and 3 drops of freshly
distilled piperidine. The reaction mixture is left to stand for 5-6 days at room temperature.
It is dried with MgSO,. Compound II is isolated with a yield of 1.55 g (59%) by distilla-
tion; it has bp 136.5~ (1 mm) and nD 2~ = 1.4850. The UV spectrum, ~max (log E) is as fol-
lows: 245 nm (3.78). The PMR spectrum is as follows: 1.3 (6H, multiplet, 5-CH3, OCH=CH3),
1.54-1.60 (6H, double doublet, 9,10-CH3), 1.77-2.15 (4H, multiplet, 6,7-H), 2.67-3.09 (IH,
multiplet, 4-H, J = 8 Hz), 4.15-4.23 (2H, multiplet, OCH2CH3), 5.03 (IH, multiplet, 8-H),
and 7.21 ppm (IH, doublet, 3-H, J = 8 Hz). Found: C 68.4, H 8.0, and N 6.5%. C~sH2~NO3. Cal-
culated: C 68.5, H 8.0, and N 5.8%.
6,10-Dimethyi-5~6,9,10-diepoxy-3-ethoxycarbonylundec-3-en-2-one (IV). To the mixture of
5.6 g (0.02 mole) of 6,10-dimethyl-5,6-epoxy-3-ethoxycarbonylundeca-3,9-dien-2-one (III),
5.92 g (0.04 mole) of phthalic anhydride, and 0.06 g (0.01 mole) of urea in 20 ml of absolute
ether are added 1.36 g (0.04 mole) of 87-90% hydrogen peroxide dropwise, maintaining the temp-
erature at not greater than 20~ and with stirring. The reaction mixture is stirred at room
temperature; control of the course of the reaction is by thin layer chromatography. The res-
idue of phthalic acid is washed with ether and chloroform; the organic layer is washed with
a solution of NaHC03 and water, and is dried. Compound IV is isolated with a yield of 2.08 g
(50%); it has bp 142-145~ (I mm) ~:d ~ 2o ~485~.iTh:sU~ s~::tru~, ~ a x ( i ~ ~), is as fol-
lows: 220 (3.59) and 250 (3.52). T P sp tru "s ol s: .9- .44 ( H, multiplet,
6,10,11-CH~, OCH2CH3), 1.53-1.89 (4H, multiplet, 7,8-H), 2.16 (IH, multiplet, 9-H), 2.47 (3H,

371
singlet, l-H), 2.89-9.23 (1H, multiplet, 5-H), 4.05-4.26 (2H, multlplet, OCHaCH~), and 6.25
ppm (IH, doublet, 4-H). Found: C 64.2 and H 8.0%. C:6H2uOs. Calculated: C 64.7 and H 8.7%.
6,10-Dimethyl-5,6-epoxy,3-ethoxycarbonvi-9,10-dichloromethu (V3. The
solution of 5.6 g (0.02 mole) of compound III and 0.4 g of TEBA in 12.8 ml (0.16 mole) of
chloroform is cooled to 10~ and 24 ml of a 50% solution of NaOH together with 7 ml of meth-
ylene chloride are added with intense stirring. The mixture is kept for 3 h. It is extracted
with ether and chloroform and then dried. Compound V is isolated with a yield of 3.04 g (42%);
it has bp 144-147~ (i mm) and nD '~ 1.5293. T h e UV spectrum, Im (log r is as follows:
207 (4.32)and 265 nm (4.30). The PMR spectrum is as follows: 1.~-1.30 (12H, multiplet, 6,10,
II-CHs, OCH2CH3), 1.84-2.30 (5H, multiplet, 7,8-H, 9-H), 2.52 (3H, singlet, l-H), 3.12 (IH,
multiplet, 5-H), 4.04-4.26 (2H, multiplet, OCH~CH3), and 6.28-6.40 ppm (IH, multiplet, 4-H).
Found: C 57.0, H 6.5, and Cl 20.0%. C~7H~4C120~. Calculated: C 56.2, H 6.7, and C1 19.5%.
Dioxolanes Vlla-c. To the mixture of 0.6 g of anhydrous ferric chloride and 15 ml of
the ketone are added, with stirring, 5 g (0.021 mole) of the acetal of citral oxide VI. The
mixture is heated for 5 h at 45-50~ washed with a saturated solution of K2COs, extracted,
and dried. The dioxolanes Vlla-c are isolated by distillation. The constants of the dioxo-
lanes are presented in Table i.

LITERATURE CITED
i. L . P . Glushko, V. N. Samsonova, M. S. Malinovskii, and L. A. Yanovskaya, Izv. Akad. Nauk
SSSR, Set. Khim., No. 5, 1048 (1980).
2. M. Makosza, Naked Anions-Phase Transfer, in: Modern Synthetic Methods, Zurich (1976).
3. M. S. Malinovskii, L. P. Clushko, YU. Yu. Samitov, N. I. Pokhodenko, and T. M. Malinov-
skaya, Izv. Vyssh. Uchebn. Zaved., Khimiya i Khim. Tekhnologiya, No. 1, 89 (1971).

SYNTHESIS OF THE DIASTEREOMERIC 2-ARYL-I-CYCLOHEXYL-3-

(2,3-EPOXYPROPIONYL)AZIRIDINES

A. M' Zvonok, N. M. Kuz'menok, UDC 547.717.07

and L. S. Stanishevskii

The reaction of cinnamoyloxiranes with an iodine-cyclohexylamine complex in the pres-

ence of an excess of amine led to a mixture of the four diastereomeric epoxypropi-
onylaziridines the ratio of which depended on steric and electronic factors in the
substrate and reactants.

The interaction of 2-methyl-2,cinnamoyloxiranes with iodine-methyl- or iodine-ethylamine

complexes in aprotic solvents led to a mixture of the two diastereomeric trans-epoxypropionyl-
aziridines differing in configuration at the chiral center of the epoxide ring [I]. In a
continuation of the study of the influence of steric and electronic factors on the stereochem-
istry of the resulting epoxypropionylaziridines and with the aim of synthesizing new compounds
in this series, the interaction of substituted cinnamoyloxiranes with an iodine-cyclohexylamine
complex has been studied in the present work.
It has been established that in difference to the iodine--methyl- and iodine--ethylamine
complexes the reaction of epoxyenes Ia-g with the iodine-cyclohexylamine complex in benzene
orether led to a mixture of four or three diastereomeric l-cyclohexyl-2-aryl-3-(2,3-epoxypro-
pionyl)aziridines two of which had trans (I!a, b-VIIIa, b) and two (or one) cis configuration
of the aziridine ring (IXa, b-XIIIa, b, XIVb, XVb).

Scientific-Research Institute for Physicochemical Problems, V. I. Lenin Belorussian State

University, Minsk 220080. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4,
pp. 456-459, April, 1986. Original article submitted January 25, 1985.

372 0009-3122/86/2204-0372512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Physicochemical Characteristics of trans- and cis-
2-Aryl-l-cyclohexyl-3-(2,3-epoxypropionyl)aziridines IIa,b-
XIIIa,b, XIVb, XVb

Compound flap,9~C %Found N, Empirical formula Calculated,

N ok Yield, %

Ila 77--78 4.7 CI.~Hz~NO2 4,7 25

llb 67--68 4,5 21
llla 98--99 5,0 ClsH2aNO2 4,9 23
lllb 83--84 4,9 24
llVa 95--96 4,7 CjgH2aNO= 4,7 37
IV b 107--108 4,7 24
Va 121--122 5,0 C 18t-I~aNO2 4,9 43
Vb 111--112 4,0 28
IVIa 122--123 3,8 ClaHe~BrNO= 3,9 33
VIb I t9--120 3,8 23
VIIa 142--143 8,5 CI,sH:_~NzO~ ,3,5 14
Vllb 130--132 8,4 10
VIIIa 126--127 4,4 CI.~H2~NOs 4,4 30
VIIIb 111--113 4.4 28
IXa Oil 4,6 CI.qH2sNO2 4,7 6
IXb 78--79 4,7 8
Xa 113--114 4,8 CI~H~aNO= 4,9 13
Xb 93--94 4,9 14
xIa 114--116 4,5 CIgH~sNO~ 4,7 5
XIb 76--78 4,6 19
XII,a 99-- I O0 4,9 C~,H~aNOe 4,9 5
Xllb 93--94 4,8 20
xIIra 118--119 3,7 C~aH22BrNOa 3,9 14
XIIlb 108--1 lO 3,7 2O
Xl~Vb 127--128 8,4 CI~It22N204 8,5 38
XVb 99--100 4,4 CIgH~NOa 4,4 11

TABLE 2. Influence of Substituent at the a-Carbon Atom of

the Epoxy Ring (R 3) on the Ratio of Diastereomeric 2-Phenyl-
l-cyclohexyl-3-(2,3-epoxypropionyl)aziridines lla,b-Va,b,
IXa,b-Xlla,b

Com- Yield,_ %
_ atra___~
m btrans Yield, %
pound R' R~ R~
a b acis bcis Za s

II CHa CHa 4,2 2,6 31 29

IX CHa
lIl CH3. 23 24 1,8 1,7 36 38
X CHa 13 14
IV CHa CHa 24 7,4 1,3 42 43
XI CHa CHa 19
!V H CHa 28 8,6 1,4 48 48
Xll H H CHa 20

RJ H R3 H R~ H

~ ~ +2CeH~INH~ R1 Ar + R H

C6H11 C6H11

la-d Ar=C~Hs:e Ar=4-BrC6H4;f Ar=4-NO2C6H4; g-Ar=2-CHaOC~H4

The configuration of compounds lla,b-Xllla,b, XlVb, XVb was confirmed by data of IR and
PMR spectroscopy. Stretching vibrations of C=O groups of the trans isomers IIa, b-VIIIa,b
were observed in the region of 1690-1695 cm -I and of the cis isomers IXa, b-XIIIa,b, XIVb, XVb
at 1710-1715 cm -2 [2]. The vicinal protons of the aziridine ring of epoxypropionylaziridines
IIa,b, XIIIa,b, XIVb, XVb appeared in the PMR spectra as AB spin systems. The values of the
coupling constants of these protons were 2.7-3.0 Hz for the products of trans confirmation
IIa, b-VIIIa,b and 6.5-7.0 Hz for diastereomers of cis configuration IXa,b-XIIIa,b, XIVb, XVb
and correspond to constants for trans and cis acylaziridines known from [3].
The stereochemical relationships between the diastereomeric cis and trans aziridinyl-
epoxyketones were established when studying the isomerization of the latter. Thus isomeriza-
tion of compound Va in a methanol--DMSO mixture in the presence of sodium methylate led to the
formation of the cis isomer XIIa, i.e., compounds Va and XIIa and Vb and XIIb differ in the

373
 TABLE 3. ~nfluence of Substltuent in the Benzene Nucleus on
the Ratio of trans- and cls-Aziridines Va,b-VIlla,b, XTIa,b,
XI~a,b, XIVb, XVb

Va,b, Xllla,b
Via,b,Xllla,b
C,~lIi,
4,,BrC.H4
4.NOwC~H4
71 I 25
56
24
;~4
38
1,7
O,t~
Vlla,b,XlVb
Vllla,b,XVb 58 II 5,8

configuration of the s-carbon atom of the aziridine ring. On the basis of the difference in
the chemical shifts of the gem and vic protons of the aziridine and epoxide rings [i], and
also of the chemical shifts of the methyl group protons in compounds IIa,b-XlIIa,b, XIVb, XVb
by analogy with compounds Va,b and XlIa,b all the synthesized aziridinyl ketones were assigned
to group ~ or group b. The diastereomers belonging to group a differed from the diastereomers
of group b in the configuration at the center of chirality of the epoxy ring while the cis and
trans isomers of one group (a or b) had the opposite configuration at the ~-carbon atom of the
aziridlne ring. Isomerization of trans aziridinylepoxyketones IIb-Vb into the cis isomers IXb-
XIIb confirmed the configurational interrelation of the diastereomers.
The ratio of the diastereomeric aziridinylepoxyketones in the iodine-alkylamine-complex-
cinnamoyloxirane reaction fetermined from the PMR spectra of the reaction mixtures, are shown
in Tables 1-3. From these data and also from the results of [i] it follows that the amount of
the resulting diastereomers and their ratio depend on the size of the alkyl group of the amine,
the presence of a substituent at the s-carbon atom of the epoxy ring, and the character of the
substituent on the benzene ring. The observed ratio of products may be explained by considering
the structure of the transition complex and by using the data on the reaction mechanism from
[4]. In accordance with the mechanism of formation of 2-acylaziridines the stereochemistry of
the final product is determined by the iodlnation stage of the intermediate aminoenol with sub,
sequent stereospecific cyclization. The aminoenol may be found as a cyclic chelate complex the
iodination of which leads in the end to the trans-aziridine while iodination of the nonchelated
form of the aminoenol proceeds nonselectively. It follows from Table 2 that since the overall
yields of the resulting trans- and cis-isomers a and b are approximately equal in the majority
of cases (arran s + aci s = btran s + bcis) then addition of amines to the cinnamoyloxirane pro-
ceeds nonselectively. This means that the stereochemistry of the reaction products is deter-
mined at ths stage of iodination of the intermediate diastereomeric aminoenols a and b and
participation in the reaction of the chelated forms of the diastereomeric aminoenols, as might
have been expected, must increase the stereose!ectivity of the reaction.
Evidently, in the case of the iodine-methyl- and iodine-ethylamine complexes, a high de-
gree of chelate formation of the diastereomericaminoenols takes place, the attack of which from
the unhindered side led to trans-aziridinylepoxyketones in [i]. An increase in thedimensions
of the alkyl group in the case of the iodine-cyclohexylamine complex hinders the formation of
the cyclic chelate structure which leads to a mixture of trans- and cis-isomers IIa,b-XIIIa,b,
XIVb, XVb.
The observed selectivity of the formation of diastereomers IVa-VIIIa in relation to di-
astereomers IVb-VIIIb is probably linked with the influence of the substituent at the e-carbon
atom of the epoxide ring, which is particularly graPhically illustrated by the stereoselectiv-
ity of formation of trans isomers in relation to cis isomers between the diastereomeric pairs
(atrans/acis, btrans/bci s) for compounds IIa,b-Va,b, IXa,b-XIIa,b. In the absence of a sub-
stituent at the e-carbon atom of the oxirane ring the stereoselectivity of formation of
trans-aziridinylepoxyketones IIa and IIb, and IIIa and IIIb is close. On the other hand, the
diastereomeric aminoenol a of compounds IVa and Va is iodinated highly selectively almost ex-
clusively in the chelate form while iodination of aminoenols b occurs nonselectively, and is
probably linked with steric hindrance created by the e-methyl group in attack of the intermed-
iate aminoenol by the iodinating agent [i].
The character of the substituent in the benzene ring of the initial epoxyenone Id-g in-
fluences appreciably the ratio of transaziridinylepoxyketones Va,b-VIIIa,b and cis isomers
XIIa,b-XVb. It is evident from Table 3 that the introduction of an electron donating substi-

374
tuent favors the formation of trans-aziridinylepoxyketones Vllla,b. This may be linked with
the change in basicity of the amino group nitrogen in the intermediate diastereomeric amino-
enones. Electron accepting substituents reduce the nitrogen basicity so that nonchelated
conformations begin to play a guiding role.
Therefore a combination of steric and electronic factors in the substrate and reactant
determine the amount and the ratio of diastereomeric epoxypropionylaziridines obtained in the
reaction of epoxyenone--iodine--alkylamine complex.

EXPERIMENTAL
IR spectra of substances in CCI~ of concentration 10 -I mole/liter (layer thickness 0.01
cm) were taken on a Specord 75-IR spectrophotometer. PMR spectra sere measured on a Varian
HA-100D-15 spectrometer in benzene and CCI~, internal standard was HMDS.
2-Aryl~l-cyclohexyl-3-(2~3-epoxypropionyl)aziridines lla~b-Xllla~b~ XIVb~ XVb. Cyclo-
hexylamine (150 mmoles) was added dropwise slowly to a solution of cinnamoyloxirane la-g
(50 mmoles) and iodine (50 mmoles) in ether. The precipitated solid was filtered off, the
ether partially evaporated, the residue filtered through a layer of silica gel, hexane added,
and the mixture of diastereomeric epoxypropionylaziridines lla,b-Xllla,b, XIVb, XVb isolated.
Samples of compounds intended for analytical purposes were prepared by the chromatographic
resolution of the mixture of diastereomers on silica gel, eluent was a linear gradient of
petroleum ether-ether i:i. The cis,trans-isomers (lla,b-Xllla,b, XIVb, XVb were separated by
crystallization from alcohols.
Isomerization of 2-Phenyl-l-cyclohexyl-3-(2~3-epoxypropionyl)aziridinesllb-IVb, Va,b.
trans-Epoxypropionylaziridine llb-IVb, Va,b (i mmole) was dissolved in a mixture of methanol--
DMSO and potassium hydroxide (0.3 mmole) in methanol (i0 ml) was added. The course of the
isomerization was followed by TLC. AFter 5-24 h the reaction mixture was diluted with water
and extracted with benzene. The benzene was evaporated off and the PMR spectrum of the reac-
tion mixture was drawn. Signals of protons of the cis isomers IXb-Xlb, Xlla,b were separated
in the spectrum and were analyzed.

LITERATURE CITED
1. A. M. Zvonok, N. M. Kuz'menok, and L. S. Stanishevskii, Zh. Geterotsikl. Soedin., No. 7,
880 (1980).
2. P. Tarburton, L. J. Wolpa, R. K. Loerch, T. L. Folsom, and N. H. Cromwell, J. Hetero-
cycl. Chem., 14, 1203 (1977).
3. D. N. Nagel, P. B. Woller, and N. H. Cromwell, J. Org. Chem., 36, 3911 (1971).
4. P. L. Southwich and R. J. Shozda, J. Am. Chem. Soc., 82, 2888 (1960).

375
QUANTUM-CHEMICAL TREATMENT OF RECYCLIZATION AND CYCLIZATION REACTIONS.
ll.* FORMATION OF A PYRYLIUM RING

Yu. B. Vysotskii, B. P. Zemskii, UDC 547.812.04'441

E. A. Zemskaya, V. I. Dulenko,
L. V. Dulenko, E. V. Kuznetsov,
and G. N. Dorofeenko #

The formation of a pyrylium ring has been considered in the framework of a previ-
ously developed method for the quantum-chemical description of recyclization and
cyclization reactions. The influence of the condensation of glutaconic dialdehyde
and its protonated form with pyrrole, furan, thiophene, and benzene rings on this
reaction has been studied.

One of the general methods for the synthesis of a pyrylium ring is the acid dehydration of
unsaturated 1,5-dicarbonyl compounds [2, 3], particularly glutaconic dialdehyde (2-pentenedi-
al) [4]. Various 2-benzopyrylium salts have also been obtained from substituted o-acylphenyl-
acetones in this manner [5]. We also note that diketones which can serve as starting com-
pounds for the construction of a pyrylium ring can form during a reaction, for example, in the
case of the acid-catalyzed acylation of acetonyl derivatives of aromatic carbo- and heterocy-
cles, and can then be converted in sit,B into, say, 2-benzopyrylium [6], thienopyrylium [6-8],
pyrrolopyrylium [9, i0], and furopyrylium salts [ii, 12].
Since one of the stages in the quantum-chemical treatment of reeyclization reactions is
generally the description of the cyclization of the acyclic intermediate formed [13], it would
be interesting to use the method developed for the interpretation of reactionsresulting in
the formation of a pyrylium ring. We recall that in the framework of this plan the long-range
orders of bonds between atoms that are not directly bonded, whose positive values correspond
to intramolecular bonding and are a prerequisite for the formation of an aromatic cyclic prod-
uct, serve as the reactivity indices.
i. Table i presents the reactivity indices in the cyclization of the enol form of glut-
aconic dialdehyde (I) and its protonated form (II). For comparison, the table also presents
data from calculations~ of other neutral and charged 1,5-disubstituted pentadienes (Ill-VIII).
As is seen from the table (compare t~e ~ l u e ~ of PI~), the atoms supplying one electron to the
systemare a r r a n g e d i n the series N > 0 > C according to their tendency to participate in
ring closure under the condition that the second substituent Y is OH or NH2. It is also seen
that in the case of neutral systems, in accordance with HHckel's 4n + 2 rule, the atoms sup-
plying two ~ electrons to the system should predominantly form five-membered rings, while
those contributing one ~ electron predominantly form six-membered rings.
The structures presented in Table i can be obtained: i) by the protonation, deprotonation,
or tautomerization of acyclic compounds; 2) as intermediate structures during the recyclization
of heterocycles; 3) in condensation reactions, such as Hantzsch syntheses of heterocycles [14].
In addition, they simulate (in the framework of the q-electronic approximation) the transition

*For report i0 see [i].

#Deceased.
%The calculations were carried out in the framework of the PPP method according to the tech-
niques and with the parametrization in [13]. For the sake of simplicity, it was assumed that
the atoms in the molecules are located at the vertices of a regular heptagon and that all the
interatomic distances are equal to 140 p m .
Institute of Physical Organic Chemistry and Coal Chemistry, Academy of Sciences of the
Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
4, pp. 460-464, April, 1986. Original article submitted October 17, 1984; revision submitted
June 5, 1985.

376 0009-3122/86/2204-0376512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Reactivity Indices for the Cyclization of Gluta-
conic Dialdehyde (I) and Its Analogs
4

XY
i 7

Com- ]Charge '

pound x Y e,7 PI6 P~ P~r P~r

I OH 0 -0,0523i 0,1910 0,0858 0,0510 0,1520

II H OH +1 --0,0395 0,1164 0,0830 0,1164 0,0830
III CH~ NH~ 0 -0.0767 0,1491 0,0449 0,0213 0,1243
IV Clt2 OH 0 -0..0580 0,1517 0.0356 0,0135 0,0972
V O NH2 0 --0,1033 0,1590 010950 0,0888 0,1833
!VI NH OH 0 --0,1015 0,2217 0,0916 0,0479 0,1429
VII NH NH2 0 --0,1467 0,2209 0,1231 0,0850 0,1730
VIII NH NH -1 -0,2229 0,1017 0,2360 0,1017 0,2360

TABLE 2. Reactivity Indices for the Cyclization of Condensed

Derivatives of Glutaconic Dialdehyde
Y
X/ "\Z

0 H0
1 7

Compound PI: P16 Pl5 P2r Pn

IX CH CH NH --0,0652 0,1298 0,0490 0,0366 0,1020

X CH NH CH --0,0492 0,0930 0,0461 0,0287 0.0774
XI NH CH CH --0,0708 0,1400 0,0615 0,0433 0,1034
XII CH CH O -0,0677 0,1346 0,0524 0.0377 0,1061
Xlll
XIV
gH O
CH
CH
CH
-0,0456
-0,0736
0,0890
0,1452
0,0443
0,0650
0,0260
0,0443
0,0726
0,1084
X!V CH CH S -0,0639 0,1260 0,0579 0,0359 0,1011
XVI S CH --0,0516 0,1017 0,0481 0,0299 0,0820
XVII CH CH -0,0650 0,1278 0,0607 0,0369 0,1016
)0VIII CH CH=CH CH -0,0571 0,1124 0,0541 0,0325 0,0908

states of the corresponding cyclizations. For example, structure IV describes the intermed-

iate
I
:." OH
J
, etc. Similar intermediates can appear: i) as a result of the cleavage of
]I

bonds in seven-membered heterocycles; 2) as fragment ions in mass spectra; 3) during rearrange-

ments of six-membered and substituted five-membered heterocycles. Therefore, the data in Table
1 can be used for the interpretation of cyclization reactions and rearrangements of a fairly
extensive group of processes.
For example, compound III simulates one of the open forms appearing during the rearrange-
ment of picolines and anilines (see [15]). The data from the calculation of structure IV
demonstrate the possibility of the recyclization of the anhydro base 2-methylpyrylium to phen-
ol. In fact, such a reaction is widely known in a number of pyrylium salts (see, for example,
[4, 16]).
Structures V and VI are tautomeric forms, which simulate intermediates formed when pyryli-
um salts are reacted with ammonia (see reviews [4, 16-18]) or furfural is reacted with ammonia
(see [19]). The bond orders in these systems (see Table i) show that compound Vl should pre-
dominantly cyclize to form pyridine derivatives and that structure V should predominantly cy-
clize to form pyrrole derivatives. The experimental data provide evidence that the direction
of cyclization is greatly dependent on the reaction conditions and the presence of substitu-
ents. For example, the recyclization of 4-methylfurfural under the action of ammonia takes
place with the formation of pyridine derivatives, but if primary amines are used in this re-
action, N-substituted pyrroles are formed [19].

377
 Intermediates which simulate structures Vll and Vlll form as a result of rearrangements
of 1,2-diazepines after the cleavage of the N-N bonds. From the Bond orders presented in Ta-
ble i it follows that intermediate Vll should predominantly form pyrldlne derivatives and that
compound VIII should form pyrrole derivatives. Am analysis of the mutual atom-atom polariza-
bilitles reveals that the introduction of electron-acceptor groups into position 7 of compound
Vli results in an increase in the long-range order of the 2-7 bond and decreases in the other
bond orders (zT,~-, 9 ~0.038, ~,,2-, - 0.059, ~,,,.~ =-0.058, ~,,~-, --0.060). When elec-
tron-donor functional groups are introduced into position 4 or 6, the order of the i-6 bond
increases more strongly than do those of the remaining bonds Just enumerated. This can Be il-
lustrated by the recyclization of l-acyl-4-hydroxy-l,2-diazeplnes, which gives 2-acylamino-
5-hydroxypyridines [20].
Similarly, the introduction of acceptor substituents into positions 3, 5, or 7 of the
anion of 1,2-diazepine lowers the orders of the 1-5 and 3-7 bonds. In the framework of the
scheme developed, this should result in increases in the yields of the pyridine derivatives
with a corresponding decrease in the yield of the pyrroles upon the cyclization of structures
VIII. The data in [21] are consistent with these conclusions.
According to Table i, in the case of compound I, along with the large positive order of
the i-6 bond there is a large positive order for the 3-7 bond. This suggests the formation of
both pyrylium and furan rings upon the cyclization of structure I. Since a sufficiently large
positive residual z-electronic charge (+0.24) is localized in the z orbital of the oxygen
atom of the hydroxyl group of compound I, it may be assumed that this structure is close to
the structure usually considered as the intermediate in the recyelization of pyrylium salts to
furan derivatives (see, for example, [4, 16, 22]). The formation of pyrylium salts takes place
in an acidic medium; therefore, it would be very interesting to trace the influence of the
protonation of the oxygen atom in compound I on the long-range bond orders. The data from the
calculation of structure II (see Table i) show that both the 1-6 and 1-5 long-range bond or-
ders decrease upon protonation, but the order of the 1-6 bond remains greater than the order
of the 1-5 bond. In accordance with the experiment in [4], this results in the predominant
formation of a pyrylium ring in this reaction:

r -I

O
~- CIO 4- --' CIO 4

We note that in the present work we did not consider the addition of a proton to the
carbon atoms of structure I, which is possible along with the protonation of the oxygen atom,
since the description of the structures formed in that case is beyond the scope of the ~-elec-
tronic approximation.
2. Tables 2 and 3 present the reactivity indices in the cyclization reactions of gluta-
conic dialdehyde and its protonated form condensed with pyrrole (compounds IX-XI), furan
(XII-XIV), thiophene (XV-XVII), and benzene (XVIII) rings.
A comparison of these data with the corresponding indices for compounds I and II (Table
I) reveals that annelation reduces all the long-range bond orders presented and should, ap-
parently, hinder the formation of a pyrylium ring. At the same time, the greatest decrease
is observed for compounds X, XIII, and XVl, which correspond to annelation at the 3-4 bond
of the heterocycle, as well as for benzoglutaconic dialdehyde (XVIII), while the long-range
bond orders for the structures corresponding to annelation at the 2-3 (XI, XIV, and XVII) and
3-2 (IX, XII, and XV) bonds are close within each pair. This is consistent with the more dif-
ficult formation of heterocyclo[3,4-c]pyrylium salts in comparison to heterocyclo[2,3-c]- and
heterocyclo[3,2-c]pyrylium salts (see [6-12]~.
In the case of all the structures from IX to XVIII considered (see Table 2), the positive
long range bond orders decrease along the series: P:6 > P37 >> P~s > P27. This corresponds
to the predominant cyclization of these compounds between positions i and 6, i.e., the keto,
rather than the hydrox#l, oxygen atom shouid appear in the ring. This is also associated with
the occurrence of possible ring-chain tautomerism in theseries of compounds under investiga-
tion (see, for example, [23]).
As follows from the data in Table 2, the value of the long-range bond order P:6 is weak-
ly dependent on the type of heteroatom in the heterocycle. In cases in which the heteroatom

378
 TABLE 3. Influence of the Protonation of Condensed Deriva-
tives of Glutaconic Dialdehyde on the Reactivity Indices in
Cyclization Reactions
Y
X/ ""Z

"5F:?i"
oIt J/~
1 110
7

Compound x Y Z P J7 PJ~ Pl5 P~7 Ps~

IXa CH CH NH -0,0429 0,0995 0,0642 0,1015 0,0536

Xa CH -0,0347 0,0753 0,0625 0,0819 0,0405
Xla NH CH -0,0439 0,1009 0,0723 0,1041 0,0484
Xlla CH --0,0454 0,1089 0,0652 0,1132 0,0301
Xllla oCH ! CH --0,0329 0,0737 0,0623 0,0775 0,0402
XlVa CH -0,0448 0,1029 0,0744 0,1057 0,0528
XVa CH CH -0,0435 0,1000 0,0720 0,1028 0,0569
XVla CH S ]CH -0,0385 0,0876 0,0678 O,0911 0,0480
XVIIa S CH !CH -0,0416 0,0953 0,0713 0,0982 0,0539
XVllla CH CH~CH C H -0,0403 0,0921 0,0697 0,0951 0,0524

is located in the a position to the pyrylium ring being formed (structures IX, XI, XII, XIV,
XV, and XVII), furopyryiium salts should form most easily, and thienopyrylium salts should
form with greatest difficulty. When the heteroatom is located in the B position, the reverse
situation is observed.
As in the case of uncondensed systems I and II, the protonation of compounds IX-XVIII
results in decreases in the orders of the 1-6 and 3-7 bonds and a sharp increase in the order
of the 2-7 bond (Table 3). Here the following sequence of values of the positive long-range
bond orders is observed for all the condensed systems investigated from IXa to XVIIIa: Pa7
P16 >> Pls > PsT. The remaining laws governing cyclization are the same as in the case of
the unprotonated systems.
The closeness of the values of PaT and P16 in compounds IXa-XVIIIa attests to the fact
that, if the formation of a pyrylium salt involves the initial protonation of dicarbonyl com-
pounds I and IX-XVlII with subsequent cyclization, either of the oxygen atoms can enter the
ring with almost equal probability. If the formation of a pyrylium ring begins with the cy-
clization of compounds I and IX-XVIII, and then dehydration occurs under the action of an
acid, the oxygen atom of the acyl group should preferentially enter the ring, according to
the data in Tables I and 2. These conclusions can be tested on compounds with labeled oxygen
atoms.

LITERATURE CITED
I. Yu. B. Vysotskii and L. N. Sivyakova, Khim. Geterotsikl. Soedin., No. 3, 357 (1986).
2. R. L. Shriner, H. W. Johnston, and C. E. Kaslow, J. Org. Chem., 14, 204 (1949).
3. A. T. Balaban, W. Schroth, and G. Fisher, Adv. Heterocyc!. Chem., 12, 241 (1969).
4. G. N. Dorofeenko, E. N.Sadekova, and E. V. Kuznetsov, Preparative Chemistry of Pyrylium
Salts [in Russian], Izd-vo Rost. Univ., Rostov-on-Don (1972), p. 234.
5. M. Vajda, Acta Chim. Hung., 40, 295 (1964).
6. S. V. Krivun, V. I. Dulenko, L. V. Dulenko, and G. N. D0rofeenko, Dokl. Akad. Nauk SSSR,
169, 359 (1966).
7. L. V. Dulenko, G. N. Dorofeenko, S. N. Baranov, I. G. Katts, and V. I. Dulenko, Khim.
Geterotsikl. Soedin., No. 3, 320 (1971).
8. V. l.Dulenko and N. N. Alekseev, Khim. Geterotsikl. Soedin., No. 5, 631 (1975).
9. V. I. Dulenko, N. S. Semenov, and V. I. Rybachenko,nd S. N. Baranov, USSR Inventor's Certi-
ficate No. 382,619; Byul. Izobro, No. 23, 59 (1973).
i0. V. I. Dulenko, N. S. Semenov, and V. I. Rybachenko, USSR Inventor's Certificate No. 412,
763; Byul. Izobr., No. 2, 273 (1983).
ii. G. N. Dorofeenko and L. V. Dulenko, Khim. Geterotsikl. Soedin., No. 4, 417 (1969).
12. V. I. Dulenko, N. N.Alekseev, and M. V. Golyak, USSR Inventor's Certificate No. 717,056;
Byul. Izobr., No. 7, 122 (1980).
13. Yu. B. Vysotskii and B. P. Zemskii, Khim. Geterotsikl. Soedin., No. 7, 984 (1980).

379
14. K. V. Vatsuro and G. L. Mishchenko, Name Reactions in Organic Chemistry [in Russian],
Khimlya, Moscow (1976).
15. Yu. B. Vysotskii, B. P. Zemskii, T. V. Stupnikova, P. S. Sagitullin, A. N. Kost, and O. P.
Shvaika, Khim. Geterotsikl. Soedin., No. ii, 1496 (1979).
16. K. Dimroth and K. Wolf, in: W. Forst (editor), New Methods of Preparative Organic Chem-
istry, Vol. 3, Academic Press, New York (1964), p. 357.
17. A. Dinculescu, H. N. Kontrakis, and A. T, Balaban, Rev. Roum. Chim., 24, 439 (1979).
18. S. V. Krivun, O. F. Alferova, and S. V. Sayapina, Usp. Khim., 43, 1739 (1974).
19. H. C. van der Plas, Ring Transformation of Heterocycles, Vol. i, Academic Press, London--
New York (1973).
20. I. A. Moore, J. Org. Chem., 44, 2683 (1979).
21. R. R. Schmidt, Angew. Chem., 87, 603 (1975).
22. H. C. van der Plas, Ring Transformation of Heterocycles, Vol. 2, Academic Press, London--
New York (1973).
23. V. I. Minkin, L. P. Olekhnovich, and Yu. A. Zhdanov, Molecular Design of Tautomeric Sys-
tems, Izd-vo Rost. Univ., Rostov-on-Don (1977).

SYNTHESIS OF 4-METHYL-2,3,4-TRICHLOROTETRAHYDROPYRAN AND SEVERAL FEATURES

OF THE STEREOCHEMISTRY OF THE NUCLEOPHILIC SUBSTITUTION OF THE
s-CHLORINE ATOM

A. A. Gevorkyan, A. S. Arakelyan, UDC 547.811.07:542.944:541.621

and A. I. Dvoryanchikov

A convenient method has been developed for the synthesis of 4-methyl-2,3,4-trichlor-

otetrahydropyran by the chlorination of 4-methyl-4-chlorotetrahydropyran, 4-methyl-
5,6-dihydro-2H-pyran and its dichloride. A study was carried out on the reactions
of 4-methyl-2,3,4-trichlorotetrahydropyran with alcohols, with sodium thiocyanate
and Grignard reagents. PMR spectroscopy was used to study the stereochemistry of
4-methyl-2,3,4-trichlorotetrahydropyran and its derivatives, 2-substituted 4-methyl-
3,4-dichlorotetrahydropyrans. The dechlorination of these dichloro derivatives by
metallic sodium leads to 2,4-disubstituted 5,6-dihydro-2H-pyrans with high regio-
selectivity.

In recent years, 4-methyl-5,6-dihydropyran and 4-methyltetrahydropyran have become ob-

jects of intensive study [1-7] since, as industrial waste products, they are model molecules
of a large series of di" and tetrahydropyrans obtained from available petrochemical raw mate-
rials [8, 9].
This led to the development of methods for the Synthesis of citric acid [4], dehydro-
mevalolactone [6], and various isoprenoid synthones [i0].
In the course of these studies, we have found that the chlorination of 4-methyl-5,6-
dihydro-2H-pyran gives trichloride I (43%) containing an extremely active chlorine atom toward
amines. Trichloride I was also obtained i n t h e chlorination of the hydrochloride of 4-methyl-
5,6-dihydro-2H-pyran and 4-methylenetetrahydropyran (4-methyl-4-chlorotetrahydropyran (62%)
[7]) and the dichloride of 4-methyl-5,6-dihydro-2H-yran (4-methyl-3,4-dichlorotetrahydropyran
(66%). On the basis of the results of the chlorination of THF [ii], we may assume that the
chlorination of 4-methyl-4-chlorotetrahydropyran proceeds through the s-chlorination of the
tetrahydropyran, dehydrochlorination of the intermediate ~-chloroether to a dihydropyran and
the subsequent chlorine addition to this dihydropyran to give trichloride I. (Formula, top,
following page.)
PMR spectroscopy showed that the reaction gives a 4:1 mixture of isomeric trichlorides
(the methyl peaks were taken as diagnostic) with predominance Of the isomer with the downfield
Institute of Organic Chemistry, Academy of Sciences of the Armenian SSR, Erevan 375094,
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 465-471, April, 1986.
Original article submitted July 31, 1984; revision submitted July 16, 1985.

380 0009-3122/86/2204-0380512.50 9 1986 Plenum Publishing Corporation

 CH~
if, CII3." . El CI13,.~01 CI

"~'0" "l') " "O " ~CI

I CI

c. 3.:>i....
el cl cH:~)~.ci
.....
cl . ~
i __. ~!~_.__ ["
cH3:>~~cl
.
ci

CI " " O " -0" O \ ' 0 I ' "'CI

IA I

methyl group signal. In addition, a double resonance study reliably established that t h e two
v i c i n a l m e t h i n e p r o t o n s i n t h e PHR s p e c t r u m a p p e a r w i t h a c o u p l i n g c o n s t a n t o f 3 . 2 Hz. T h e s e
data and the finding that the vicinal diaxial proton coupling is 6-10 Hz [12] permits us to
exclude the structure of 4-methyl-2,4,5-trichlorotetrahydropyran (IA) in favor of 4-methyl-
2,3,4-trichlorotetrahydropyran (I) and give preference for structures Ia and Ib. Since the
minor component has an upfield methyl group and the conformational energy of chlorine is mark-
edly less than for the methyl group [13], isomer Ia must predominate in this mixture. Indeed,
comparison of the PMR spectra of model compounds, specifically, cis- and trans-3,4-dihydroxy-
4-methyltetrahydropyrans and their acetates [14] indicates that the equatorial methyl group
of the cis-isomer is a lower field than this group in the trans-isomer.

CI CH~ CH~ CI

</>-. ;,, - ;,, -.<-*.-,',,, ......

----.r <' 'r ~ <'' 'r
/
Cl li H Cl
xa I.' Ib Ib

Confirmation of the structure of the trichlorides was found in a study of the chemical
properties of I. Trichloride I reacts readily with Grignard reagents, alcohols and sodium
thiocyanate to form 2-alkyl- (or 2-aryl-), 2-alkoxy-, or 2-thiocyanato-4-methyl-3,4-dichloro-
tetrahydropyrans II in high yields (Table i). Products II under dechlorination upon reaction
with metals to form 2-substituted 5,6-dihydro-2H-pyrans identical (in the case of the alkyl
derivatives) to samples obtained in our previous work [15].
In addition to the proof of structure of trichloride I, this pathway for the preparation
of dihydropyrans is a very general and highly regioselective (>99%) method for the formation
of 2-substituted 5,6-dihydro-2H-pyrans (Table 2).

CH 3

IZ "O ~ Cl
-:= i) 0 Y "~

II a Y=C4Hg, b Y=i-CsHH, c Y=C~Hs, d Y=CH~CH--CH~, e Y=OCH3,

f Y=gC3HTO, g Y=i-Cs|-IHO,hY=SCN; M=Na, Zn

A study of the reaction of trichloride I with Grignard reagents revealed a very interest-
ing effect, namely, there is apparent retention of the configuration at the s-carbon atom in-
stead of the expected inversion at the reaction site as found for derivatives of cyclohexane
[16] and glucosyl halides [17], i.e., instead of local inversion at the reaction site, the
substitution is accompanied by complete inversion of the heterocycle analogous to that pro-
posed in the reaction of 2,3-dichlorotetrahydropyran with Grignard reagents [18]. The same
conclusion was drawn by comparing the integral intensities of the low and high field methyl
group signals of starting trichloride I and the products of its reactions with nucleophiles.
Indeed, if the substitution of the axial ~-chlorine atom by a nucleophile (studied in greatest
detail for CeHsMgX) occurred with local inversion, it would lead to a 2e-alkyl (or 2e-aryl)
derivative of II and, in the final analysis, to strengthening of the conformer with a 4e-
methyl group. However, the coupling constant of the vicinal methine protons in the PMR spec-
trum of the compound obtained is 9.5 Hz. This value indicates that, in contrast to expecta-
tion, the nucleophile apparently attacks for the same side from which the nueleophilic group
leaves. In our opinion, this is a consequence of an intramolecular reaction of the p electrons
of the B-chlorine atom with the reaction site leading to prevention of the direct attack of

381
the nucleophile at the ~-C-CI bond prior to the substitution. Then, the newly formed 2a-aryl
(or 2a-alkyl) group which has much higher sterlc requirements than the same substituents in
other positions of the tetrahydropyran ring [17] (inverse anomeric effect) causes the complete
inversion of the heterocycle.
+
C1 t l <.'t L'llt
//" .. ~.. ~J ICM I< ,'.; ..... i, 9 I ,+~
/ CI" . . . . CII, ("l ('1t! .......... ~ + E " " "CLI, +'-" II -"

0 '~, """ (} ~ t)"

9 I, u ~" r
('1 '(I ('1 II

The reaction with isomer Ib proceeds analogously.

This explanation is not in accord with the data given above for the substitution of glu-
cosy halides, which indicate that a ~-atom with p electrons such as oxygen is incapable of
retaining the configuration of the reaction site carbon atom. However, this contradiction is
only apparent. Oxygen and chlorine atoms behave differently as neighboring groups with p
electrons. Oxygen, which is one of the best p electron donors for the closure of five- and
six-membered rings, is completely inert in 1,3-interactions. On the other hand, chlorine atoms
may rather effectively act as p electron donors in 1,3-interactions [19].
The reaction of the trichloride with alcohols is also interesting. A mixture of two iso-
meric ethers is formed. These products differ both in the chemical shift of the 4-methyl group
protons and the coupling constants of the 2-H and 3-H vicinal atoms (2-4 and 6-10 Hz). This
apparently indicates the formation of isomer II with 2-,3-diaxial hydrogen atoms, i.e., the
replacement is again accompanied (although to a reduced extent) by inversion of entire ring.
However, we should note that while such inversion is entirely reasonable for derivatives of
II with 2a-alkyl and 2a-aryl substituents which display an inverse anomeric effect, it is far
from obvious for the 2a-alkoxy group with an anomeric effect. Hence, we considered data ob-
tained for the series of 6-methyl-l,3-dioxanes with 4-fluorinated methyl groups. The trifluor-
omethyl group in these molecules occupies an axial position due to the anomeric effect. The
same preference is found (although to a reduced extent) for the difluoromethyl group, while
the fluoromethyl group has equatorial orientation. The dipole-dipole interaction (anomeric
effect) presumably decreases in this series of fluoro derivatives and in the fluoromethyl
derivative, this interaction is insufficient for the suppression of steric hindrance [20].
It would appear that this behavior is analogous to that found in the series of alkoxy
derivatives II. The substitution initially proceeds as described above for Grignard reagents
and leads to the formation of isomers with 2a-alkoxy groups. Thus, since the conformational
energy of the anomeric effect of the alkoxy groups is significantly less than these values for
halogen atoms (for example, these values are 2.65 and 1.5 kcal/mole for the chlorine atom and
methoxy group, respectively). The effect of steric factors begins to become significant. In-
deed, we have noted that the fraction of the isomer with 2,3-diaxial hydrogen atoms increases
with increasing bulk of the alkyl group of the alcohol used. Thus, the isomer ratio is I:i
in the case of methanol, 1:3 in the case of 2-propanol and 1:4 in the case of isopentyl al-
cohol.

EXPERIMENTAL
The gas-liquid chromatographic analysis was carried out on an LKhM-80-1 chromatograph
using a katharometer detector, 40-60 ml/min helium gas flow rate, and a 2000 x 3 mm steel
column~packed with 15% Apiezon L on Chromaton NAW (0.20-0.25 mm) and a 3000 3 mm steel col-
umn:packed with 15% PEGA on Chromaton NAW (0.20-0.25 mm). The separation temperature was I00-
150~ The PMR spectra were taken on a Perkin--Elmer R-12B spectrometer at 60 MHz and on a
Tesla BS-497 spectrometer at i00 MHz in CC14 and CDCI~ with HMDS as the internal standard.
4-Methyl-2,3,4-trichlor0tetrahydrg~yran (I). A. A chlorine stream was passed with stir-
ring through 26.9 g (0.2 mole) 4-methyl-4-chlorotetrahydropyran at 35-40~ for 4 h. Distilla-
tion in vacuum gave 25..2 g (62%) trichloride I with bp 97-I00~ (3 mm), nD 2~ 1.5145, d~ 2~
1.3917. PMR spectrum (CDCI3): 6.06 (IH, d, J = 3.2 Hz, OCHCI), 4.26 (iH,d, J 3.2 Hz, CHCI),
3.94 (2H, m, CH20), 2.21 (2H, m, CH=), 1.82 ppm (3H, s, CH3). Pound: C, 35.2; H, 4.6; CI
51.9%. Calculated for C6H9C130: C 35.4; H 4.4; CI 52.3%.
B. An analogous procedure gave 17.2 g (43%) trichloride I from 19.6 g (0.2 mole) 4-
methyl-5,6-dihydro-2H-pyran.

382
 TABLE i. Some Characteristics of lla-g

~om- bp, ~3
ID2U Found, ok Chemical Calculated, %
pound ',pressure, J42o PMR spectrum, 6, ppm ~ield,
rim) brmula ok
IIm 21 H Cl
[la 98--i00 (3) 1,482s 1096 4,13 (IH, m, CHCI), 3,72 (3H,m, OCH2, OCH), 53,0 C,oH,sCI20 51
2,02 (2H,m, CH~), 1,69 (3H, s CH3), 1,32 (6H
m, CH~), 0,88 (3H, T, 1=5,3 HZ, CHa)
[Ib 102--105 (3) 1,481~ 0968 4,15 (IH, m, CHCI), 3,72 (3H, m OCH2and 55,3 CuH2oCI~O 59
OCH), 2,19 (2H, t , J~=5,3 Hz CH2), 1,68 (3H,
s CH:d, 1,32 (SH, m, CH2, CH), 0,83 J6H dl
/ -5,3 I ~ CH (CH~).o]
[1c 152--156 (3] 1,555~ 2402 7,51 (514, s, C6H0, 4,28 (2H, AIL, lAB=9,5 Hz, 58,3 C12HI4CIzO 60
CsH6CHandCHCI), 3,63 (2H, m, OCH2), 2,25
(2H, m, CH2), 1,97 (3H,s , CHa)
:Id 74--76 (2) 1,496C 1601 5,75 (IH, m, CH=C); 5,03 12H, m, C=CH2), 51,5 C9H,4C120 59
4,13 (IH, rrt, CHCI), 3,71 (3H, rrGOCH2and
OCH), 2,28 (4H, m,,CH2), 1,68 (3H s CH3)
lie 64--67 (3) 1,4860 2540 5,05 and 4,59(1H, d, 1=2,5 and J"6,7 Hz e-and 12,0 CrH,~ClaO2 62
a-C[tO), 4,23and 4,11 (tH, dp J=2,5 and
]=6,7Hz e-anda-CHCI), 3,83 .(2H, rr~ OCH2),
3,59 {3H, s, OCHa), 2,23 (2H, rn, CH~), 1~93and
1,84 (3H, s, CHa)
llf r0--72 (3) 1,4775 1772 4,89and4,39 (IlL d, J=3,3 t~ J,-.6,7 Hz e-and 47,3 C9HI6C1202 61
u-CHO), 3,92 (IH, m, CHCI), 3,62 (3H, m,
DCH2, OCH), 2,12 (2H, mp CH,2)_, 1,71 ~1 1,62
(3H, s.-, CH3), 1,16 and 1,0716H,d., J=2,6Hz,,
CIt (CH3)2]
Hg 93--95 (3) 1,4810 1342 ],83ana4,41 (IH, d, 1=2,6 and./=6,6 H~.. e-and 51,4 CnH2oC1202 65
~-CHO), 3,97 IIH, m, CHCI), 3,38 (4H, m,
DCH2), 2,11 (2H, m, CH~), 1,73 and 1,66 (3H,S ,
=[-13), 0,88 [6H, d, 1=6,6 Hz. CH(CH3)2]

LO
00
L~
O0

TABLE 2 . Some Characteristics o f llla-g

Found. % C alcttlated,
Com- bp, ~ hemical %
n D ~ll t14 ~"
pound (pmssure, PMR spectrum, 6, ppm Jformula
mm) C H C H

lIla. 73--75 (11) L4556 0,8794 5,21 (IH, m, =CH), 3,42 (3H, m OCH~and 77,81 11,5 Cf,HiaO. 77,9 11,7 78
OCH), 2,16 (2H, m, CH2), 1,66 (9H, m, CH2.
~C--CHa), 0,99 (3H, dist; t, CHa)
IIIb 81--83 (13) 1,4505 0,8639 5.25 (IH, m, =CH), 3,52 (3H, m, OCH2 a n d 78,3 11,6 CHH~oO 78,6 11,9 79
OCH), 2,03 (214, m, CHz), 1,45 (8H, ra CH2,
:=C-CHa), 0,83 [61-I,d., l = 6 H z . CH(Ot~)d
III~ 100--t03 (2) 1,5505 0,9080 ,7,19 (51-I,s, C6I-t~). 5,42 (IH. m CHCnHs)~ 4,93 82,6 82 CI~H,40 82,7 8,0 80
i(1ti, m =CH), 332 (2H, rq OCH~), 2,11 (2H,
m CH2), 1,68 (3H, br ~C--CH3)
III d 62--63 (12) 1,4675 0,8691 5,51 (4H, m ~CH, CH~CH2), 3,72 (3H, m 78,3 10,2 CgHNO 78,3 10,1 75
OCH2, OCH), 2,18 14H, t, I=6,9 Hz, CH~), - I

1,68 (3H,br, =C--CHs)

111 e 50--52 (12) 1,4555 0,9989 5,35 (1H, m, CHO), 4,78 (IH, m ~CH), 3,66 65,5 9,3 C~HI202 65,6i 9,4 74
12t-1, IIIOCH,,), 3,28 (3H,s , OCH:d, 2,11 (2H,
m CH~), 1,65 (3H,br, =C~CH3)
llIf 62--64 (12) 1,4540 0,9631 5,35 (lH, m, CHO), 4,78 llH, m, =CH), 3,66 69,1 lo,o C9H,602 69,2 10,2 76
(3H,m,OCH2andOCH) 2,11 12H m, CH.,} 1;6_8
(3H, br, =C--CH3), ljSandi,0~ I6H,-d: . _
=3,3 Hz, CHiCH3)2]
llIg 82--83 (13) 1,4525 0,8874 5,:]5 (IH, m, CHO), 4,78 (IH, m, ~CH), 3,59 71,6 10,7 C tlH~O2 71,7 10,9 81
(4H, m CH~O), 2,11 (2H, m, CH2), !,69 {3H,ht,
-~C--CH:0, 0,87 16H, d, I = 6 H z , CHICHa)2]
 C. Similarly, 26.8 g (66%) trichloride I was obtained from 26.7 g (0.2 mole) 4-methyl-
3,4-dichlorotetrahydropyran.
3,4-Dichloro-4-methyltetrahydropyran. A stream of 7.8 g (0.ii mole) chlorine was passed
through a mixture of 9.8 g (0.i mole) 4-methyl-5,6-dihydro,2H-pyran in 50 ml ethyl acetate at
f r o m - 6 5 to --70~ The reaction mixture was brought to room temperature. Ethyl acetate was
distilled off and vacuum distillation gave 9.2 g (54%) of a compound with bp 85-87~ (Ii mm),
nD =~ 1.4940, d~ 2~ 1.2609. PMR spectrum (CCI~): 4.28 (IH, t, J = 2.7 Hz, CHCI), 4.18 (2H, m,
OCH2), 3.72 (2H, m, OCH2), 2.05 (2H, m, CH2), 1.68 ppm (3H, s, CH3). Found: C, 42.2; H, 5.8;
CI, 42.3%. Calculated for C6HIOC120: C, 42.6; H 5.9; CI, 42.0%.
2~Alkyl-(or2-Aryl-)3,4-dich~oro-4-methyltetrahydropyran (IIa-d). A sample of 10.2 g (0.05
mole) trichloride I was added to the Grignard reagent obtained from 2.4 g (0.I mole) magnesium
and 0.i mole halide in i00 ml absolute ether at O~ The reaction mixture was then heated for
1 h at 32~ cooled to 0~ and decomposed with saturated aqueous annnonium chloride. The reac-
tion mixture was left for an additional 3 h. The ethereal solution was decanted from the pre-
cipitate and distilled in vacuum (Table i).
2-Alkoxy-3,4-dichl0r0-4-meth~itetrah~dropyran (IIe-$)~ A sample of 0.055 mole trichloride
I was added to a mixture of 30 ml alcohol and 0.i mole potassium carbonate at 50~ The mixtur
was heated at this temperature for 6 h and then treated with water and extracted with ether.
The ethereal extracts were combined, dried over CaCI2 and distilled (Table i).
3~4-Dichl~ro-4-methyl-2-thiocyanatotetrahydropyra n (ilh). A sample of 10.2 g (0.05 mole)
trichloride I was added to a mixture of 4.8 g (0.06 mole) sodium thiocyanate and 25 ml DMF at
25~ The mixture was brought to 40~ and stirred for 4 h. DMF was distilled off and the reac-
tion mass was washed with water and extracted With ether. The ethereal extract was dried over
CaCI2. Ether was removed and distillation gave 4.6 g (41%) of a compound with bp I12-I14~
(3 mm), nD 2~ 1.5440, d~ 2~ 1.3787. PMR spectrum (CCI~): 5.62 and 5.25 (IH, d, J = 2.7 and J =
8.7 Hz, e- and a-CHSCN), 4.02 (3H, m, CHCI and OCH2), 1.82 and 1.71 ppm (3H, s, CH3). Found:
C, 37.4; H 4.1; CI, 31.1; N, 6.4; S, 13~9%. Calculated for CTHgCI2NOS: C, 37.2; H, 4.0; CI,
31.4; N, 6.2; S, 14.1%.
2-Substituted 4-Methyl-5~6-dihydro-2H-pyran (Ilia-g). A sample of 0.i mole dichloride
lla-g) was added to a flask containing 0.25 mole metallic sodium in i00 ml absoluted ether.
The reaction mixture was stirred at 32~ for 15-20 h and then washed with water, extracted
with ether. The ethereal extracts were combined, dried over MgSO4 and distilled (Table 2).
B. Under analogous conditions, 0.25 mole zinc and 0.I mole dichloride II gave dihydro-
pyran llla-g. Gas-liquid chromatography indicated the formation of 3-10% isomeric 2-substitu-
ted 4-methyl-3,6-dihydro-2H-pyran.

LITERATURE CITED
i. A. A. Gevorkyan, S. M. Kosyan, Dzh. I. Gezalyan, Arm. Khim., Zh., 31, 430 (1978).
2. A. A. Gevorkyan, N. M. Khizantsyan, P. I. Kazaryan, and G. A. Panosyan, Khim. Geterotsikl
Soedin., No. 2, 167 (1981).
3. A. A. Gevorkyan, P. I. Kazaryan, N. M. Khizantsyan, A. S. Arakelyan, and G. A. Panosyan,
Khim. Geterotsikl. Soedin., NA, 8, 1025 (1981).
4. A. A. Gevorkyan, P. I. Kazaryan, M. S. Sargsyan, K. A. Petrosyan, and S. M. Mkrtumyan,
Khim. Geterotisikl. Soedin., No. 7, 891 (1983).
5. U. G. Ibatbllin, D. Ya. Mukhametova, S. A. Vasil'eva, R. F. Tolipov, L. V. Syurina, M. G.
Safarov, and S. R. Rafikov, Izv. Akad. Nauk SSSR, Ser. Khim., No. 9, 2114 (1982).
6. S. Kyo and A. Yasui, Japanese Patent No. 7,248-386; Chem. Abstr., 78, 97481 (1973).
7. A. A. Gevorkyan, A. S. Arakelyan, and N. M. Khizantsyan, Arm. Khim. Zh., 3_~I, 186 (1978).
8. A. A. Gevorkyan and A. S~ Arakelyan, Arm. Khim. Zh., 29, 1033 (1976).
9. A. A. Gevorkyan and G. G. Tokmadzhyan, Arm. Khim. Zh., 30, 165 (1977).
i0. A. A. Gevorkyan, P. I. Kazaryan, and N. M'. Khizantsyan, Arm. Khim. Zh., 34, 435 (1981).
ii. J Pichler, Coll. Czech. Chem. Commun., 39, 177 (1974).
12. C. B. Anderson and M. P. Geis, Tetrahedron, 31, 5207 (1975).
13. E. Eliel, N. Allinger, S. Angyal, and G. Morrison, Conformational Analysis [Russian trans
lation], Izd. Mir, Moscow (1969), ch. 7.
14. N. N. Khizantsyan, P. I. Kazaryan, and A. A. Gevorkyan, Arm.,Khim. Zh., 36, i01 (1983).
15. A. A. Gevorkyan, P. I. Kazaryan, O. V. Avakyan, and G. A. Panosyan, Arm. Khim. Zh., 37,
24 (1984).
16. J. B. Lambert, G. J. Putz, and C. E. Muxan, J. Am. Chem. Soc., 94, 5132 (1972).

385
17. N. K. Kochetkov and A. I. Usov (editors), General Organic Chemistry [in Russian], Vol. 2,
Izd. Khimiya, Moscow (1982), ch. 5.
18. B. A. Arbuzov, E. N. Klimovitskii, L. K. Yuldasheva, A. B. Remlzov, and A. V. Lygin, Izv.
Akad. Nauk SSSR, No. 2, 377 (1974).
19. G. A. Olah and J. M.Bollinger, J. Am. Chem. Soc., 89, 4744 (1967).
20. P. Dirinck and M. Ante~nis, Canad. J. Chem., 50, 412 (1972).

STRUCTURE OF THE PRODUCTS OF THE O-MONOALKYLATION OF PYROCATECHOL

BY ~-BROMOKETONES

I. B. Dzvinchuk, N. V. Kuznetsov, UDC 547.841'451:541.623:543.422.25

and M. O, Lozinskii

The reaction of pyrocatechol with ~-bromoketones in the presence of triethylamine

leads to the formation of o-hydroxyphenoxymethyl ketones or 2-hydroxy-2,3-dihydro-
1,4-benzodioxines. PMR spectroscopy revealed ring-chaln tautomerism of the products
obtained. The relative effect of structural factors on the stability of the ring
structure was evaluated.

The products of the monoalkylation of pyrocatechol I by chloroacetone [i] and phenyaeyl

bromide (2) were initially considered to be phenols III. Later spectroscopic studies showed
that both these compounds have cyclic structure IV, while their sodium derivatives exist a s
the open form III [3, 4]. There have also been reports of the preparation of the acyclic
structural analog of III (R = H, R x = COCH3) and its cyclic derivatives IV [R x = C(OCH3)2CH3
and C(OCH2)CH3] by an independent method [5, 6], No data have been given for the ketol--lactol
equilibrium of these compounds in solution. It was of interest to determine the preparative
range of this reaction in order to elucidate the capacity of its products to under ring--chain
transformations and establish the relationship of this capacity to the structure of these com-
pounds.
The reaction was carried out with a twofold excess of diphenol I relative to the alkylat-
ing component. Triethylamine was used as the base instead of the alkaline reagents previously
employed. These conditions permitted us to suppress side reactions such as O,O'-dialkylation,
oxidation, Favorskii rearrangement and dehydrobromination, simplify the synthesis procedure
and enhance the yield of the O-monoalkylation product. The reaction is rather general in na-
ture, encompassing ~-bromo derivatives of aromatic, heteroar0matic and aliphatic ketones with
both normal and branched hydrocarbon chains lla-h. The structure of the starting alkylation
agent has only a slight effect on the yield but determines the cyclic or acyclic structure of
the final product. Thus, the reaction with bromoketones lla-d leads to the formation of o-hy-
droxyphenoxymethyl ketones llla-d. The other bromoketones gave 2-hydroxy-2,3-dihydro-l,4-
benzodioxines IVe-h.

~:'~ \OH
OH N(CzHs) ~ m d
" " I i" OH + BrCR~CORI ...........

I .,~.. /0..,R

OH
we-h
Ila--~, 1Ha.-d, IVe..g R~H, lib, IVh R=CHa; I1, Ilia Rl=2,4.6-(CH~)aC61q~,b
Rl=2rthie.nyl, c Rl--2-fl~yt,,d RI=2,4,5-(CIt3)sC6tt.2 11, IVe RI=.C6H~, f Rt=I.C4H~,
g,h RL'=CH~

Institute of Organic Chemistry, Academy of Sciences of the Ukrainian SSR, Kiev 252660.
Translated from Khimiya Geterotsikhlicheskikh Soedinenii, No. 4, pp. 472-476, April, 1986.
Original article submitted November 6, 1984; revision submitted August 22, 1985.

386 0009-3122/86/2204-038651i.50 9 1986 Plenum Publishing Corporation

 TABLE i. Characteristics of Compounds Synthesized

Corn- mp (or bp), %:

pound ] [pressure, bYa]
[

Ilia (230--240) [20]~ 3540, sh 1715,

3380 1700, sh
75,6[ 6,7 CjrHj~Oa I75,5[ 6,7 53
lllb III,5--I12,5 3450, 1670 61,31 4,5 Cl2HjoOaS 61,5. I 4,3 79
3320 [(13,8: (13,7)
Illc 113--113,5 3400, 1680 65,91 4,5 CI2H~oO4 66,0 I 4,6 60
3340, sh I
IIId 83,5--84,5 3195 1670 75,31 6.7 C,THI~Oa 75,5t 6,7 76
IVe 1o9--11o,~ 3440 73,8[ 5,4 C.HmOa 73,7 ] 5,3 58
IVf 67--68,5 3505 68,91 7,5 Cl2tll60a 69,2 ] 7,7 70
lVg 98--99 3250 65,0i 6,2 CgHu,Oa 65,O [ 6,1 58
(130--137) 1201'' I

IM1 50--51 3435, 57,7] 7,1 CiiHl4Oa 68,0 I 7,3 53

(128--135) 12oi 3400 I

*lllb and IVg recrystallized from CC14; llc and lid, and IVe
recrystallized from benzene, IVf and IVh recrystallized from
hexane.
tnD 22 1.5692.
$MpI09.5-III~ (2.67 hPa) [4].
**Hp 100~ bp 135-145~ hPa) [4].
The structure of the alkylation products was found relative to the presence of absence
of the IR ~C=o band (the characteristics of IIl and IV) are given in Table I). We should
note that all the isolated reaction products do not give a positive test with ethanolic FeCI3
diagnostic for the phenol hydroxy group. A study of the PMR spectra of their solutions in
deuteroacetone established that previously described phenyl and methyl derivatives IVe and
IVg [4] exist in solution as a mixture of tautomeric ketol III and lactol (IV). The tendency
to undergo ring-chain tautomeric transformations for the newly obtained compounds varies in a
broad range. Within the limits of the PMR spectroscopic sensitivity, Ilia exists exclusively
in the ketol form, while IVh exists exclusively in the lactol form. The solutions of the re-
maining compounds displayed the ketol--lactol equilibrium III $ IV (the PMR spectral parameters
are gi-~en in Table 2).
We should note that the PMR spectrum of IVg in CDCI3 was given by Rosnati et al. [5].
Signals for protons of the C H ~ and C H 2 ~ groups m a y b e discerned along with the stronger
signals for the protons of the cyclic form. However, these authors did not consider the pro-
tons of the cyclic form. However, these authors did not consider the question of presence of
the acyclic ketol form lllg in solution. Nevertheless, the spectrum of IVg was given as evi-
dence for the acyclic structure of structural analog (R = H, R I = COCH3), in whose spectrum
the CH= group signal appears as a singlet. The assignment of structure III to this compound
raises doubt since the comparison of these spectra was carried out incorrectly. Only the dif-
ference in the multiplicity of the CHa group signals was taken into account while the simi-
larity of their chemical shifts was not considered. In our spectra, the signal for the dias-
tereotopic protons of the CH2 group of the cyclic form are not seen as a quartet for all these
compounds. This signal is not split for IVc apparently as a result of a coincidental isochron-
icity of the methylene group protons which leads to a degenerate AB system.
In our PMR spectra, the alkyl group protons of both tautomeric forms appear separately
and their assignment is not difficult. The tautomeric equilibrium constant K T (Table 2) was
found using the ratio of the integral intensities of the CHa group signals. Under our condi-
tigns, the tautomeric equilibrium of llla-d is shifted toward the open form, while it is
shifted toward the ring form for IVe-h.
The structural differences in the series of tautomeric systems llla-g are due only to
the nature of only the R I substituent. Steric hindrance by this substituent leads to destab-
ilization of the ring form. A decrease in the stability of the ring form also is encountered
upon substituting the aliphatic substituent by an aromatic or replacement of the aromatic sub-
stituent by a r-electron-rich heteroaromatic substituent. In this case, destabilization of
this form may be attributed to the gain in the energy of the ketol form due to conjugation
of the substituent with the C=O group and the decrease in the electron deficiency of the car-
bon atom of this group. This effect in heteroanalogs is even more pronounced as a consequence
of the mesomeric interaction of the heteroatoms of the thiophene and furan ring with the carb-

387
L~
GO
GO

TABLE 2. PMR Spectral Parameters of the Tautomeric Forms and Constants of the III ~ IV Equilibrium
C h e m i c a l shift, 6, ppm
Com- a r o m a t i c protom o f the pyi~-
HO =. [ lactol ] t
pound R catechol [ r a i m e n t
" ., t~itol [ ketol ]
lactol IV ,? ketol Ill lactol IV ketol HI l a c m l IV ketol Ill lactol lV

I _$
llla ; H 2,4,6- (CH3) 3C~H2 5,00,,, 2,10, s (2Ctt:0 7,73, s 6,65 6,~.~7, m ~0
I 2,t9, s (C1t3)
I 6,81, S (2H)
Illb i H 2-Thienyl 5,33, s 3,97; 7,t0--8,02, m _$ 7,99, $ fi,fi2, d 6,70--7,03,m 6,81 .In 0,274-0.01
4,22, q !1,6)
lllc i H 2-Furyl 5,22, s [ 4,16,s 6,37--7,82, m 8,02, s 6,53, s 6.6 I- -6,94. m 6,84.m 0.27___+0.0 I
llldi H 92,4,5- (CH3) 3Coll.', 5,29, $1 3,88; 2,18, s (2C1t3) 2,13, ss, 2.14, s, 8,05,s 6,00~ 6,63--6,95;m 6,80. m 0.3fi+_..0,02
4,14, q (1,2) 2,34, s (CH~) 2,39, (3CHs)
i 1 7,00, s, 6,90, =j
7,65, s (2H) 7,43,$ (2H)
IVr H C~H5 5,4 l,s [ 3,79; 7,29--7,42; 7,25--7,29; 7,89, S 6,14, d 6,55--6.88. m 6.~Lm 4.22___~0.14
4,07, q (15) 7,86--7,89, m 7,86--7,89
IVf H C(CH~)3 5,02, s1 3,92; 1,13, $ 1,05, s 7,92, S 5,16,d 6,60--6,92. m 653, m 7.72
4,16, q (1,2)
l~Vg ! H CHa 4,70, st 3,81 ; 2,13,s 1,45, S 8,11, s 5,71, d -$ 6.74. m 31,9__+i,2
L 3,98, q (0,9)
1Vh i CH3 CH~ 1,20, s; -$ 1,45, s -$ 5,45, $ 6,71, m
1,35, s

*For all the AB quartet systems, J = ii Hz; the J value (Hz) is given for the coupling between one of the protons of the
CHAH B group and the proton of the lactol OH group in parentheses.
%K T ~ 0 if the lactol form is not observed and K T > 99 if the ketol form is not observed.
*Signal not discerned.
onyl group. This interaction for the furyl derivative is less effective due to the great
electronegativity of the ring heteroatom (see the review by Joule and Smith [7], p. 214) and
the stability of the ring form for this derivative should likely be greater than for the thio-
phene analog. However, a difference between these compounds within the sensitivity range for
the method used to determine the tautomeric composition could not be detected. The substituent
at the C=O group in ketol--lactol systems with similar structure analogously affects the stab-
ility of the ring form (see the work of Valter [8], pp. 173, 177-178 and the later review by
Valter [9], pp. 1376-1383).
The shielding of the keto group in the a-position of the ring formed by methyl substitu-
ents usually leads to destabilization of the ring form [8, p. 181; 9, p. 1383]. However,
the introduction of methyl groups into a unit already containing a conformationally rigid
pyrocatechol fragment probably sharply limits the freeedom of rotation of the open form and
provides for spactial approximation of the C=O and HO groups. Such consequences in ring-chain
tautomeric systems lead to stabilization of the ring form [8, pp. 178-180; 9, pp. 1383-1392].
The electronic effect of the ethereal oxygen atom of ketol forms III on both reaction
sites apparently provides an additional contribution to stabilize the ring forms IV. The in-
ductive electron-withdrawing effect enhances the electron deficiency of the C---O carbon atom
and, thus, its tendency to add a phenol hydroxyl. The latter, in turn, should have a marked
tendency to add to a C=O group due to the mesomeric electron-donor effect of the ortho ether-
eal oxygen atom.
Thus, the products of the O-monoalkylation of pyrocatechol by a-bromoketones have a mark-
ed tendency to form the lactol structure. However, substituents which have a significant elec-
tron-donor or shielding effect on the C=O group may provide stabilization of the ketol form.
EXPERIMENTAL

The purity of III and IV was monitored by thin-layer chromatography on Silufol UV-254
plates using 2:1 chloroform--CCl~ as the eluent. The IR spectra were taken on a UR-20 spec-
trometer neat on KBr plates for Ilia and IVh and in KBr pellets for the other compounds. The
PMR spectra were taken on a Bruker WP-200 Fourier pulse spectrometer at 200 MHz in (CD3)2C0
with HMDS as the internal standard. The 0.3 mole/liter solutions were maintained at constant
25~ for 24 h prior to taking the spectra. The position of the tautomeric equilibrium did not
change upon maintenance up to 14 days. The K T equilibrium constants were calculated taking account
of the relative of the error inmeasurSng the integral intensities of the diagnostic signals.
o-Hydroxyphenoxymethyl Ketones III or 2-HydroxyF2,3-dihydro-l~4-benzodioxines IV (Table
i). A mixture of 22 g (0.2 mole) I, 0.I mole bromoketone II and 15.1 ml (0.ii mole) triethyl-
amine in 30 ml 2-propanol was heated at reflux using a condenser equipped with a liquid seal
for 2 h (i0 and 4 h for IIa and II h, respectively). The reaction mixture was cooled, diluted
with 50 ml water, acidified with 15 ml concentrated hydrochloric acid and left overnight. The
crystallized products were filtered off, washed with water and dried. Prior to distillation,
IVg and IVh were distilled in vacuum. The reaction mixture was extracted with i00 ml ether in
order to separate IIIa. The extract was washed with two lO0-ml portions of water. The reaction
product was extracted with three 50-ml portions of aqueous KOH. The alkaline solution was im-
mediately acidified with 40 ml concentrated hydrochloric acid. The oil separated was extracted
with i00 ml chloroform. The extract was washed with three 100-ml portions of water, dried
over calcium chloride and passed twice through a lO-cm alumina column using chloroform as the
eluent. The solvent was evaporated and the residue was distilled in vacuum.

LITERATURE CITED
i. C. Moureau, Bull. Sci. Chim. France, 21, No. 3, 291 (1898); Centralblatt, i, 679 (1898).
2. I. Lazannec, Bull. Soc. Chim. France, 5, No. 4, 509 (1909); Centralblatt, ii, 21 (1909).
3. G . B . Marini-Bettolo, R. Landy-Vittori, and L. Paolini, Gazz. Chim. Ital., 86, 1336 (1956
4. A . R . Katritzky, M. J. Sewell, R. D. Topsom, A. M. Monro, and G. W.Potter, Tetrahedron, 22,
931 (1966).
5. V. Rosnati, F. De Marchi, and D. Misiti~ Gazz. Chim. Ital., 94, 767 (1964).
6. A . M . Bianchi, V. Rosnati, A. Saba, F. Soccolini, and G. Lecchi, Gazz. Chim. Ital., 103,
79 (1973).
7. J. Joule and G. Smith, Fundamentals of Heterocyclic Chemistry [Russian translation],
Izc. Mir, Moscow (1975).
8. R . E . Valter, Ring-Chain Isomerism in Organic Chemistry [in Russian], Izd. Zinatne, Riga
9. R . E . Valter, Usp. Khim., 51, 1374 (1982).
389
X-RAY STRUCTURAL INVESTIGATION OF NOVEL AZABICYCLIC SYSTEMS
CONTAINING AZIRIDINE R I N G S

A. F. Mishniev, M. F. Bundule, Ya. Ya. UDC 548.737:547.717

Bleidelis, P. T. Trapentsier, I. Ya.
Kalvin'sh, and E. Ya. Lukevits

Successive conversion reactions of methyl aziridine-2-carboxylate have been used

to prepare novel azabicyclic derivatives, namely, 2-carbamoylmethyl-l,3-diazabi-
cyclo[3.1.0]hexan-4-one and 2,2-dimethyl-i,3,4-triazabicyclo[4.1.0]heptan-5-one,
whose structures were established unequivocally by x-ray structure analysis.

Derivatives of aziridine-2-carboyxlic acid are 0f interest both from a biological [1-3]

and chemical point of view [4, 5], since they may be regardedas analogs of naturally occur-
ring ~-amino acids. The presence of two reactive sites in these molecules opens up a wide
range of synthetic possibilities, among them the synthesis of novel bicyclic systems contain-
ing an aziridine ring and a bridging nitrogen atom. Only a few reports have appeared concern-
ing the preparation of these types of structures [6, 7], and only one report has dealt with
x-ray structure analysis for structure proof of a diazabicyclic derivative [8].
We have examined [5, 9] the feasibility of synthesizing novel heterocyclic systems con-
taining an aziridine fragment in two ways, by the reaction of the hydrazide of aziridine-2-
carboxylic acid with acetone, and by successive reactions of the methyl ester of azirldine-2-
carboxylic acid with methyl propiolate and ammonia:

<o,.=,, [
\ ...........
- -i _!c5!~c.?._ '.............. Nil
.... ~N'J- " / ~
9 ~i~ ~N/ N NIl
)<N',m,,
ii Ci[~ l" 'C l i 3 Cll ~'" "C}l:s
Ill IV
ItN " " " "4h,. 9. C O O C I 1 3 ......... 1>..0 - < ~
1

I
CH:CilCOOCH3 H/ "CIt~,CONH2
~7 .....
. j/\g_S

C0NIi~

V V[ VII

According to a published report [I0], the imine group in hydrazides is the most 9 reactive
site in hydrazide derivatives of acyclic amino acids; we have come to the opposite conclusion
on the basis of NMR spectral analysis, which showed that, for the reaction of hydrazide II
with acetone, only structure III, and not IV, is obtained [9]. In this reaction , then, the
carbonyl component reacts with the amine nitrogen atom of the hydrazide derivative. An x-ray
structural analysis was carried out on compound III in order to verify this conclusion. A
three-dimensional representation of a molecule of III, with atomic designations, hond length
values (A), and bond angles (degrees), is shown in Fig. i. The six-membered ring in III oc-
cupies a half-chair conformation. The deviations of atoms C(~) and N(3) from the average
plane of the remaining four atoms are 0.276 and 0.342 A, in opposite directions, respectively.
N(3) is bent away in the direction of C(7~ in the aziridine ring. The dihedral9 angle b e t w e e n
the three-membered ring and the average plane of the six-membered ring is 83.70. The endo"
cyclic bond angles around atoms N(1) and C(6~ in the six-membered ring are similar in value t o
the corresponding bond angles in non-condensed aziridine derivatives [ii, 12]. N(3) adopts
a pyramidal configuration, with the pyramid height equal to 0.673 A. The C(2)-N(I~ bond is
9 9 9 9 -
b e n t away from the plane of the azlrldlne rlng ( 9 )T by 59.0 o . The sum of the
~ ~ --
bond angles
around N(1) is 293.2 ~ . The geometric parameters of the cis-amide group in iII overlap those

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga, 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 477-480, April, 1986.
Original article submitted February 12, 1985.

390 0009-3122/86/2204-0390512.50 9 1986 Plenum Publishing Corporation

 \-,,1 T , '

" ~ ~" %.4/ "

1454 (5)'~.(i~.~<1,478(B)

Fig. i. Geometric parameters of a molecule

of III.

239t4)
-.L26,{3}
1342(4).,.,.,.,.,.,.,.,
.,~. "., \ ~'~'/
125,8(3}I
r"[07,4(~) 113,2(3)',~. Ill, 236(4)
1,485(5 \~,459t4)~ 121....
5(3)2i~122 2(3)
,0., . ,
10%4(2) ' k"(]}~ [57~,) /~i _ ',u,.~.. V "t.~lJ
I12.5(31C~ [3
,~1,..1484(4) // uJ.,z) ~.h.~rC.
~.~
1,485(4
L60,1(2)LN,, ,'{ ..... -
~ { 2 ) .... C,/.,-C,~r'N,,,
C~4cC(3FN(D 59,8(2}

C(4T'N[IFC(3 ) 60,1(2)

Fig. 2. Geometric parameters of a molecule of VI.

TABLE i. X--H-..Y Hydrogen Bond Parameters in

Structures III and VI

Stm~ure IAtomX [AtomY X 9 9 - Y, H 9 9 9 Y,

"A
AX--H 9 9 9 Y,

deg
III N(,~) 0 3.00 2,12 167,8
2.91 1,95 167,7
!VI N(~) O(,) 2.90 2,14 159,2
N(s) O(2, 2.93 2,05 173,2
N(2) N,,) 2.95 2,12 154,2

found in the cis-peptide bond in cyclic dipeptides [13]. The N(4)--C(5) bond [1.325(7) A] has
one and one-half bond character, whereas the other C--N bond is a single bond. In the crystal-
line state molecules of III are associated via a system of intermolecular hydrogen bonds, the
parameters of which are given in Table i.
The product of the reaction of aziridine-2,carboxylic acid hydrazide with acetone has
thus been shown to be 2,2-dimethyl-l,3,4-triazabicyclo[4.1.0]heptan-5-one.
We have also previously demonstrated that ammonia reacts readily with diester V [5]. N-MR
structure analysis of this reaction led to the conclusion that compound VI was formed as the
reaction product. X-ray structural analysis of this reaction product was carried out in order
to select unequivocally between the two structural possibilities, VI and V!I. A three-dimen-
sional representation, with atom designations, bond lengths (A), and bond angles (degrees) is
shown in Fig. 2. The five-membered ring present in molecule VI adopts an envelope conforma-
tion. The deviation of N(2) away from the strict planarity ( A) of the C(~)C(2)C(~)N(z~
fragment is 0.ii0 A in the direction of C(4) of the aziridine ring. The substituent a~tachld"
to C(~) occupies a pseudoequatorial orientation. The angle between the planar ( A) C(x)-

391
 TABLE 2 . Atomic Coordinates of Nonhydrogen Atoms in
Structures III and VI ( a)

Structure III StructureV1

atOffl y II tOrSI x y ]! ~"

i
Cfll 4229 17) 1872 (~)) 1562 (7) 9454 15) (695 (I) 7094 (2)
3780 (4) 3206 (6) 2674 (5) Ot'2J 7100 (5) o154(]i 19(5 (2)
C:(~l 5615 (6) 4120 (8) 3184 (7) 13864 {5)
C~s) 1150 (5) 4984 (6) ! 4538 (6) I lO0(2) I 4623(3)
CI~,) 0903 (5) 4850 {6) 19[l (5) 7401 17) 0780 (2) -0429(3)
Ccr) (}130 {5) :'~5(;4 (6) {)777 (fi) (:c Lj 11415 (6) O863 (2) 3600 (:3)
2255 (4) 3927 (6) : 0902 (4) 10585 (7) 147,1 (2) 5978 (3)
Ni3) 3067 (4) 2895 (6) 4876 (,i) (~) 13353 (7) 1616 (2) 5864 (3)
N,4) 2235 (4) 4041 (6) ! 5820 (4) ('(4~ 13723 (8) 2157(2) ] 4500 (4)
O 0452 (4) 5971 (6) 5445 (5) C.,) 10593 (7) 1109(2) I 1867(3)
8226 (6) 0+;34 (e) ] tl20 (3)

c ~ fragment and the average plane of the five-membered ring is 52.2 ~ . The crys-
tai-(~)C~6)O(2)N(o~structure2-p-bromphenyl-l,B-diazabicyclo[3.1;0]hexane has been studied [8]; in analogy
with compound VI, this molecule possesses condensed aziridine and imidazoline rings. The de-
viation of the aziridine ring from the average planarity of the five-membered ring is identi-
cal in the two structures, close to 75 ~ . The endocyclic bond angles around atoms N(1) and C(~)
in the five-membered ring are similar in values to those in corresponding bicyclic derivatives,
and are 7-12 ~ less than those in noncondensed aziridineoderivatives [ii, 12]. N(x) adopts a
pyramidal configuration with a pyramid height of 0.747 A. T h e C(1)-N(1) bond forms an angle
of 65.0 ~ with the plane of the aziridine ring (~'). The crystal packing of molecules of III
is stabilized by a system of three hydrogenbonds, whose parameters are given in Table i. The
other intermolecular contacts are within the sum of van der Waals radii of the respective
atoms i n c o n t a c t [14]. An interesting characteristic of these Structures is the involvement
of the aziridine ring nitrogen atom in intermolecular hydrogen bond formation.

EXPERIMENTAL

2,2-Dimethyl-l,3,4-triazabicyclo[4.1.0]heptan-5-one (III) was prepared according to [i0],

and 2-carbamoylmethyl-l,3-diazabicyclo[3.1.0]hexan-4-one (VI) according to [5].
X - ~ y Structural Analysis. Crystals of 2,2-dimethyl=l,3,4-triazabicyclo[4.1.0]heptan-5- ~
one (III) of composition C6H~:N30 were monoclinic: a = 6.681(1), b = 9.874(2), c = 5.731(1) A,
B = 100.04 ~ , V = 372.3(1) ~3 , M = 141,17, dcalc = 1.26 g/cm a, Z = 2, space group P2~, Fooo =
152.
Crystals of 2-carbamoylmethyl-l,3-diazabicyclo[3.1.0]hexan-4-one (VI) of composition Ca-
HgN302 were monoclinic: ~ = 5.235(1), b = 16.266(3), c = 8.448(1) ~, B = 98.50(2) ~ V = 711.5
(2) A 3, M = 155.16, d c a l c = 1.45 g/cm 3 Z = 4, space group P21/c Pooo = 328
The intensities of 561 independent reflections for compound III and iiii independent re-
flection for compound VI were measured on a Syntax P2~ diffractometer (CuK a irradiation,
graphite monochromator) using 0/20 scan method up to 2ema x = 150 ~ . The structures were solved
by direct methods using a MULTAN system XTL program and were refined by the method of least
squaresusing full matrix anisotropic approximations for the nonhydrogen atoms and isotropic
parameters for the hydrogen atoms; the positions of the hydrogen atoms were obtained by dif-
ference (Fourier) synthesis. The final R factors were 0.034 for ili and 0.047 for VI. The
atomic coordinates of the nonhydrogen atoms in compounds III and VI are given in Table 2.

LITERATURE CITED
i. I. Kalvins and E. B. Astapenok, Patent 860 239 (Belgium); Chem. Abst., 90, 30439 (1979).
2. U. Bicker and U. Hebold, IRCS Med. Sci.; Libr. Compend., 5, 428 (1977).
3. U. Bicker, Cancer Treatment Reports, 62, 1987 (1978).
4. P. T. Trapentsier, I. Ya. Kalvin'sh, E. E. Liepin'sh, and E. Ya. Lukevits, Khim. Geterot-
sikl. Soedin., No. 4, 481 (1983).
5. P. T. Trapentsier, I. Ya. Kalvin'sh, E. E. Liepin'sh, and E. Ya. Lukevits, Khim. Geterot-
sikl. Soedin., No. 3, 350 (1983).
6. S. A. Giller, A. V. Eremeev, I. Yu. Lidak, and V. A. Kholodnikov, Khim. Geterotsikl.
Soedin., No. 5, 607 (1971).

392
 7. H. Moureau, P. Chovin, and L. Petit, C. r., 243 , 910 (1956).
8. S. A. Giller, Ya. Ya. Bleidelis, A. A. Kemme, A. V. Eremeev, and V. A. Kholodnikov, Khim.
Geterotsikl. Soedin., No. 16, 411 (1975).
9, P. T. Trapentsier, I. Ya. Kalvin'sh, E. E. Liepin'sh, E. Ya. Lukevits, G. A. Bremanis,
and A. V. Eremeev, Khim. Geterotsikl. Soedin., No. 6, 774 (1985).
I0. P. S. Lobanov, A. N. Poltorak, and A. A. Potekhin, Zh. Org. Khim., 14, 1086 (1978).
ii. A. F. Mishniev, Ya. Ya. Bleidelis, A. V. Eremeev, F. D. Polyak, and B. S. Kataev, Zh.
Struk. Khim., 23, 86 (1982).
12. A. V. Eremeev, F. D. Polyak, A. F. Mishniev, Ya. Ya. Bleidelis, E. E. L1epln sh, Sh. S.
Nasibov, I. I. Chervin, and R. G. Kostyanovskii, Khim. Geterotsikl. Soedin., No. ii,
1495 (1982).
13. G. N. Tishchenko in: Itogi Nauku: Kristallokhimiya, Moscow (1979), Vol. 13, p. 189.
14. Yu. V. Zefirov and P. M. Zorkii, Zh. Strukt. Khim., 17, 994 (1976).

NEW EXAMPLES OF THE VINYLATION OF NH-HETEROCYCLES WITH ACETYLENE

AT ATMOSPHERIC PRESSURE IN THE KOH--DMSO SYSTEM

B. A. Trofimov, R. N. Nesterenko, UDC 547.749'734'759:542.953

A. I. Mikhaleva, A. B. Shapiro,
I. A. Aliev, I. V. Yakovleva, and
G. A. Kalabin

Vinylation of 2-hetarylpyrroles, 4,5-dihydrobenzo[g]indole, and 1,2,3,4-tetrahy-

dro-y-carbinols at atmospheric pressure in the superbasic system KOH--DMSO at I00-
120~ has given the corresponding N-vinyl derivatives in yields of 92-99%.

Until recently, the N-vinylation of heterocycles with acetylene was carried out under a
pressure of 20-40 atm at 160-200~ In view of the explosive hazards of this reaction, its
preparative use was extremely limited, and this has substantially retarded the development r
the chemistry of N-vinylheterocycles.
It has recently been shown that the superbasic KOH--DMSO catalytic system enables the
vinylation of alkyl- and arylpyrroles to be carried out at atmospheric pressure and tempera-
tures as low as 100-120 ~ (see [i] and the citations therein).
The object of this investigation was to assess to what extent this novel method was suit-
able for the synthesis of N-vinyl derivatives of other heterocycles.
The subjects chosen for study were the 2-hetarylpyrroles Ia, b, 4,5-dihydrobenzo[g]indole
(III), and the 1,2,3,4-tetrahydro-y-carbinols Va,b, 2-phenylpyrrole (Ic) being taken for com-
parison with the corresponding 2-furyl- (Ia) and 2-thienyl- (Ib) pyrroles.

R2 Me ~ f - - ~ H Me

. . ..... , // Me

I "N " X_~-~/ N

' l-lla-c R III,IV

V-VIs, b

la--c, III R=H, II~--c, IV R=CH=CH2; I, II a X=O, b X=S, e X=CH=CH; V~,b

RJ=H, Vh, bR~=CH=CH~; V, V i a R2=H, bR2=Me

The reaction was carried out in a glass flask with a stirrer. Acetylene was passed into
the reaction mixture at atmospheric pressure. When vinylating the 2-hetarylpyrroles Ia,b and
2-phenylpyrrole Ic, a fivefold exceys of KOH was employed. The progress of the reaction was
followed by GC. Chromatographically pure N-vinylpyrroles IIa,b were obtained by a single

Itkutsk Institute of Organic Chemistry, Siberian Section, Academy of Sciences of the

USSR, Irkutsk 664033. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp.
481-485, April, 1986. Original article submitted April ii, 1985.

0009-3122/86/2204-0393512.50 9 1986 Plenum Publishing Corporation 393

 TABLE i. Effect of Reaction Time and Temperature on the
Yields and Proportions of N-Vinylpyrroles lla-c
l Ratio (yield)of compounds,, %
Treatt,~ [ReacNon
I Ia .IIa (yield Ib :Hb (yield of Ic :Iic (yieldof
tLme, h of Ila} Hb) Ilc~

II0 3 28 : 72 49:51 50:50

II0 4 2:98 15:85
II0 4,5 Trace " 3:97 12:78
N 10o (98)
110 5 Tmce 5:95
,-,.10o (98,5)
II0 5,5 2:98
II0 6 Trace
,-- lOO (96)
120 23i57 38 : 62 24 : 76
120. 2 10:90 25 : 75 15:85
120 3 Trace 5:95 7:93
~100 I86)
120 4 Trace Trace
100 {82) 100 (87)

*Ratios were found by GC, and yields after distillation.

TABLE 2. Results of the Vinylation of Tetra-

hydro-y-carbolines Va,b (sevenfold molar ex-
cess of KOH)

Yield of N-vinyl derivative', %

T, ~ P 720 mm Hg Pinit 10-12 atm
Pmax 20-30 atsn
.... v'Ia' [ v,b via 'I vIb

Reaction time 6 h
95 93,7
100 97,5
120 92,5 99,0
Reaction time 3 h
100
II0 I ] 90,4 I 98,5
120 78,3 84,1

vacuum distillation of the crude product. Nearly quantitative yields (96-99%) were attained
at II0~ after 4-5-6 h (Table i). When the temPerature was raised to 120~ the time required
for vinylation was reduced by 1.5-2 h, but the yields of N-vinylpyrroles decreased by 9-16%
as a result of side reactions.
It is interesting that when an autoclave was used (initial pressure of acetylene 10-14
atm, maximum 20-30 atm, DMSO, threefold molar excess of KOH, 120~ the yields of N-vinylpyr-
roles IIa-c were only 80% as a result of resinification and the difficulty of workup of the
reaction mixture. Therefore, vinylation at atmospheric pressure is both safer and more effi-
cient.
From the data presented in Table i, the rate of vinylation of pyrroles increases in the
sequence Ic < Ib < Ia, which is the same as the order of increasing NH-acidity [I],* and con-
sequently, of decreasing nucleophilicity of their anions. Hence, this sequence of reactivity
of the pyrroles Ia-c is not in accordance with the nucleophilic nature of the reaction, al-
though it fully conforms withthe general behavior previously established by Skvortsova et al.
[2], that the rate of base-catalyzed additions to acetylene of structurally related azoles
increases as their acidity is increased. This contradiction is resolved when it is borne in
mind that the reaction involves ion pairs, rather than the free anions. In such a case, the
more 'acidic' azoles should form 'looser' ion pairs, and the introduction of acetylene at the
ionic bond ) N...K + is facilitated.

*Trofimov and Mikhaleva [i] do not report a value for the acidity of 2-(2-furyl)pyrrole, but
this can be calculated by the relationship they give between the pK a value and the inductive
constants of the substituents in the pyrrole ring.

394
 The same type of behavior is shown in the vinylation of 4,5-dihydrobenzo[g]indole (III),
which is less acidic than 2-phenylpyrrole (pK a values 22.2 and 21.6 [i]), and therefore adds
to acetylene less readily. In this case, in order to obtain the vinyl derivative IV in 97%
yield, it is necessary to carry out the reaction at 120~ for 8 h, adding the alkali (three-
fold molar excess) to the reaction mixture portionwise in order to avoid resinification.
Comparison of the results of the vinylation of the tetrahydro-y-carbinols Va,b at atmo-
spheric pressure and in an autoclave (T-ble 2) shows that in this case also, the use of com-
pressed acetylene at 95-ii0~ does not increase the yields of 9-vinylcarbinols Vla,b (within
the limits of error of measurement of and at 120~ the yields are even reduced by ~15%.
The reaction time here was only nominally reduced to 3 h, in view of the fact that cooling of
the autoclave required some days.
As will be seen from Table 2, the introduction of an additional methyl group into the
6-position of the carboline nucleus of (Vb) consistently, if only tO a small extent (4-8%)
increases the yields of the N-vinyl derivative (Vlb. Since this methylation must reduce
slightly the NH-acidity of the pyrrole moiety (as a result of the electron-donor effect of
the methyl group), it would be expected that in this case the relationship between the acidit3
of the NH-heterocycle and its tendency to undergo base-catalyzed vinylation. In our view, how-
ever, the available information is insufficient to confirm this assumption, since the yields
of Via and Vlb (the more so, since they are close to theoretical) do not provide, in the ab-
sence of quantitative measurements of the composition of the reaction mixture, a reliable
measure of reactivity. The difference in yields in this instance could be due to the differ-
ing stabilities of the starting materials Va,b and the products Vla,b under the reaction con-
ditions.
The NMR spectral parameters of the 9-vinylcarbinols Vla,b are given in Table 3. They were
assigned from known data for other N-vinylpyrroles [3].

EXPERIMENTAL
The reaction mixtures were analyzed by GC on an LKhM-8MD chromatograph (catharometer
detector, column 2.5 3 mm, 15% silicone DS-550 on Chromaton N-AW-DMCS, carrier gas helium)
and TLC on unbound layers of alumina (eluent, hexane--ethanol 5:1 and hexane-ether 3:1). The
IR spectra of the products were recorded on a UR-20 spectrometer as films. ZH and Z3C NMR
spectra were obtained on a Bruker WP-200 SY, and UV spectra on a Perkin-Elmer 402 (in ethan-
ol).
l-Vinyl-2-(2-furyl)pyrrole (IIa). In a round-bottomed flask fitted with a mechanical
stirrer, reflux condenser, thermometer, and an inlet tube for acetylene were placed 3.2 g (24
mmoles) of 2-(2-furylpyrrole) (Ia), 5.6 g (i00 n~noles) of finely ground KOH, and 30 ml of
DMSO. Acetylene was passed into the mixture at IO0~ and atmospheric pressure for 4.5 h, and
it was then diluted with water (1:2) extracted with ether, and the ether extracts washed with
water and dried over potassium carbonate. After removal of the solvent, the residue was frac-
tionated under reduced pressure to give 3.7 g (98%) of IIa, the constants of which agreed
with those given in [i].
l-Vinyl-2-(2-thienyl)pyrrole (IIb). From 3 g (20 mmoles) of 2-(2-thieny!)pyrrole (Ib),
5 g (90 mmoles) of KOH, and 30 ml of DMSO at II0~ for 5 h, the other conditions being as
described above, there was obtained 3.4 g (99%) of IIb, the constants of which were in agree-
ment with those given in [i].
l-Vinyl-2-phenylpyrrole (IIc) was obtained from 0.5 g (40 mmoles) of 2-phenylpyrrole
(Ic), 1 g (20 mmoles) KOH in i0 ml of DMSO at 120~ for 6 h, under the conditions described
above, yield 0.57 g (96%), constants as given in [1].
N-Vinyi-4,5-dihydrobenzo[g]indole (IV). From 1 g (6 mmoles) of 4,5-dihydrobenzo[g]indole
(III) in i0 ml of DMSO,with portionwise addition of 1 g (20 mmoles) of KOH (8 h, 120~ ther(
was obtained I.I g (97%) of the vinyl derivative IV, with constants as given in [i].
9-Vinyl-2,2,4,4-tetramethyl-l,2,3,4-tetrahydro-y-carboline (Via). In the glass apparatus
described above were placed 3 g (i0 mmoles) 2,2,4,4-tetramethyl-l,2,3,4-tetrahydro-y-carbo-
line (Va), 5 g (90 mmoles) of KOH, and 30 ml of DMSO. Acetylene was passed into the stirred
reaction mixture for 6 h at atmospheric pressure. The usual workup procedure (see above) gave
3.1 g (92%) of the vinylcarboline Via, a viscous liquid bp 172-174~ (3 mm) with a faint char-
acteristic odor, which crystallized readily, mp 65-67~ (ethanol-water, i:i). Found: C 80.1,
H 8.8, N 10.7%. C17H22N2. Calculated: C 80.3, H 8.7, N 11.0%.

395
 TABLE 3; Chemical Shifts in the zH and ~SC NMR Spec=~a
(ppm) of the 9-Vinylcarbinols Via (R = H) and Vlb (R =
CH~), 10% in CDCI~, 25~ THS
R~ Me~t~Me

~?;18
Numbering V[&
os nucleus
IH

37,3 2,64 37,2 2,53

50,7 50,7
1,56 1,54
51,5 51,5
120,4 7,58 123,0 7,36
6 121,6 7,25 129,6
7 119,7 7,25 l 19,7 7,02
8 II0,9 7,58 I I0,I 7,46
9
I0 132,5 132,5
II 117,8 117,4
12 126,3 126,5
13 136,5 134,8
14 30,8 127 30,7 1,26
15 31,5 I,58 31,9 1,58
16 129,6 7,00 129,7 6,98
17 I02,0 4,95 I01,i 4,89
5,24t 5,19~
7,25 21,6 2,46

*The numbering of the nucleus is shown in the structural

formula above.
+The chemical shifts of the protons in the trans- and cis-
positions to the nitrogen are given respectively, The coupling
constants of the protons of the vinyl moiety were 9.3 (cis-),
16.1 (trans-), and 0.7 Hz (gem-orientation).

9-Vinyl-2,2,4,4,6-Pentamethy!-l,2,3,4-tetrahydro-y-carboline (Vlb)2 F r o m 5.5 g (20 m-

moles) of Vl, 9.2 g (200 mmoles) of KOH and 60 ml of DMSO under the conditions of the preced-
ing experiment there was obtained 6 g (99%) of Vb, mp 163~ (i mm), mp 68-70~ (ethanol--water,
i:i). Found: C 80.7, H 9.2, N 10.4%. CIsH2~Nz. Calculated: C 80.6, H 9.0, N 10.4%.
The IR spectra of the 9-vinylcarbinols Vla,b contained absorptionbands 3040-3020, 1640
(CH==CH2), 2970, 2930, 2860, 1460 (CH3), 1610 (arom. ring), and 3420-3440 cm -I (associated NH).
The UV spectra (c 0.5 g/liter in ethanol) contained two strong bands at 205-220 and 252-258
nm. As in indole, the first of these comprises two superimposed bands, the second being due
to the N-vinyl substituent.

LITERATURE CITED
i. B . A . Trofimov and A. I. Mikhaleva, N-Vinylpyrroles [in Russian], Nauka, Novosibirsk
(1984), p. 260.
2. G . G . Skvortsova, E. S. Domnina, N. P. Glazkova, and L. P. Makhno, Proc. 3rd All-Union
Conf. on Acetylene Chemistry [in Russian], Nauka (1972), p. 115.
3. M . V . Sigalov, Diss. Cand. Chem. Sci., [in Russian], Irkutsk (1979), p. 116.

396
SYNTHESIS OF TETRAPHENYLPORPHINS WITH REACTIVE GROUPS
IN THE BENZENE RINGS.
3.* USE OF DIAZOTIZATION FOR THE PREPARATION OF SUBSTITUTED
TETRAPHENYLPORPHINS

A. S. Semeikin, O. I. Koifman, UDC 547.979'556.7.07:542.422

and B. D. Berezin

Diazotization of tetra(aminophenyl)porphins has been employed to obtain halo- and

hydroxy-tetraphenylporphins. Azo-coupling of tetra(diazophenyl)porphins has given
isomeric tetra[(p-hydroxyphenylazo)phenyl]porphins.

There is currently much interest in metalloporphins, the catalytic properties of which

are increasingly being utilized in a variety of important chemical processes. Of special sig-
nificance are tetraphenylporphins, which are readily obtained by the single-step condensation
of pyrrole with substituted benzaldehydes. The yields in this reaction, however, are highly
dependent on the substituents in the benzene ring of the benzaldehyde, ranging from 1 to 35%
[2, 3]. Since some benzaldehydes are difficult to obtain, difficulties were placed in the
way of the wider study and use of substituted tetraphenylporphins.
These difficulties can be surmounted by varying functional groups in tetraphenylporphins
which are obtained by condensation in high yields.
The aim of this investigation was to diazotize tetra(aminophenyl)porphins to give tetra-
(diazophenyl)porphins, followed by conversion to the substituted tetraphenylporphins I-XIII
(see below).
R1
/

Rz

Nz " "') " "R R ~ B

I--XIII
I RI=F; 11 R~=F; III R~=CI; IV Rz=CI; V RJ=Br; VI R2=Br; VII R'=l; VIII
R2=I; IX R~=OH; X R2=OH; Xl R=p-HOC6H4N=N; XII R'=n-HOC6H4N=N; XIII
R2=p -HOC6H4N= ~; nompecihed R,RI,R2= H

The starting tetra(aminophenyl)porphins are fairly readily obtainable by reduction of

the tetra(nitrophenyl)porphins [4, 5]. The latter were prepared in high yields by condensing
pyrrole with the appropriate nitrobenzaldehydes [4, 5]. (see Formula, below table, following
page.)
We have found that tetra(aminophenyl)porphins are readily diazotized with sodium nitrite
in aqueous solutions of mineral acids. The resulting diazonium salt solutions are relatively
stable, significant decomposition with evolution of nitrogen taking place only at tempera-
tures above 25~ The porphyrins were stable under the diazotization conditions, but on heat-
*For Communication 2, see [I].
Ivanovo Institute of Chemical Technology, Ivanovo 153460. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 486-490, April, 1986. Original article submitted
January 9, 1985.

0009-3122/86/2204-0397512.50 9 1986 Plenum Publishing Corporation 397

 TABLE i. Properties of Substituted Tetraphenylporphins I-
XIII
, ,, ,

Electronic ab~or}tion ~ e c - Calculated, o

O Rf*
I Found, %

O
._~
i
i I II II[ IV
Iore t c [ FI N c H N

I 0,57 (A)647 591 552 518 421 76.1 13,{ 7,9 C,4H26F4N4 77.0 3s 85 35
II'
t3,56
647
(3,86) (3,92) (4.37) (5,37)
591 552 517 421 76,4 35
r 77,0 3,~
~ (:5)
8.31 C,4H,~F4N 8,~ !(40)
(3,62 (3.85) (3,94) (4,30) (5,39)
III 0,35(A) 648 592 55O 515 421 70.4 3.~ 7.31 C~I~12d]14,~i~ 70,2 3,5 7,~ 52
('3,52 (&76) I (3,85) (4,29) (5,65)
IV 0,59 (A) 651 5931 551 517 422 69,8 3J! 7.6/C~H~CI4N~ 70,2 3,5 7,5 63
(3.65 (3,68)1 (4,10)l (4,34) (5,46)
V 0,64 (A) 650 541 549 515 421 57,2 3,1 6,41 C4~H~6Br~N~ 56,8 2,8 6,0 49,5
(3,76 (3,95)1 (4,24) (4,39) (5,74)
fVl 0,70 (A) 652 595 553 517 422 56,9 2,6 6,41 C~41t2~Br4N4 56,8 2,8 6,0 70
(3,74' (8,77)1 (3,97) (4.30)1 (5,69) I
vii 0,66(B) 653 593 552 518 423 146,4 2,1 5,2 I C44H~614N4 47,3 2,3 5,0 56
(3,72' (3.81)l (3,96) (4,33)1 (5.66)]
VIII 0,69 (B) 649 590 551 517 4z{ ~47,0 2,4 4,81 C~4H2~I~N~ 47,3 2,3 5,0 68
{3 82' (3,84)1 (4,07) (4,35) (5.70)1 !
IX 0,21 (C) 649 593 I 552 517 428 177,1 45 8,61 C,h~H,~oN404 77,9 4,5 8,3 63
(3,57' (3,72) (3,87) (4,26) (5.65)1
X 0,33 (D) 656 598 561 521 426 177,2 4,6 8,5 ] C44H~.N~O4 77,9 4,5 8,3 72
:3,81} (3,67)1 (4,11) (4,16) (5,6411
XI 0,17; 0,26 ] 656 599 561 526 436 174,9 4,1 5,0] C~aH4~NI~O~ 74,6 4,2 15,3 74
[3,95) I (4,06) (4,38) (5,36)1

590 553 517 428 175,2 3,9 5,81 C~sH;~N,~O~ 74,6 t,2 15,3 89
0,20 ~P ) ](3.91} C4,00)1 C4j5) (4,48) (5,72)l
XIIl 0,45(E) I 650 595 559 521 435 I 75,0 4,0 5,31C6BH46NI20r 74,6 1,2 15,3 98
I(4,0o) ',3,96)[ :4,35)! [4,39)I (5,54)1
*The chromato ;raphic s mtems are described in the experimen-
tal section.
TYields in the thermal decomposition of the diazonium fluoro-
borates given in brackets.
$Separates Into atropo-isomers. ~

N+

T::~ 84 ~F,. c.
"-Y -~,- N "~-( ~ . Cu2X2
A A N2 -- X=CI'Br ~" III-V1
f" "N..~/ I] -----=--.- va.vm
..:./ ,%.! H2o

.~ ~=
~=
"" "''~".. . . . .C61t50H
......
~ XI-XIII
NH 2

ing diazotized tetra-(2-aminophenyl)porphin it undergoes oxidation to non-porphin compounds.

Consequently, 2-substituted tetraphenylporphins are formed in low yields and with large amounts
of difficultly-separable impurities. However, the azo-coupling of diazotized tetra-(2-amino-
phenyl)porphin with phenol has been accomplished successfully in the cold to give 74% of the
azo-compound XIII. Diazotized tetra-(3- and 4-aminophenyl)porphins do not undergo oxidation,
and on heating they give the hydroxy-tetraphenylporphins X and IX. The latter are obtained by
condensing pyrrole with the appropriate benzaldehydes, in low yields [2]. Furthermore, tetra-
(diazophenyl)porphins may readily be converted into the halo-tetraphenylporphins I-VIII in
yields which are no lower, and in some instances higher, than when these are synthesized by
condensation. Of interest are tetra[(p-hydroxyphenylazo)phenyl]-orphins, which are obtained
readily by the azo-coupling of tetra(diazophenyl)porphins with phenol. In these compounds,
two chromophoric systems are present, namely the porphin and the azo-dye. Compounds XI-XIII
dissolve readily in alkalies to give orange-colored solutions. Reduction of XI-XIII with stan-
nous chloride in hydrochloric acid gives the starting tetra(aminophenyl)porphins. The yields
and some properties of the porphins obtained are shown in Table i.

398
 N
I I

L/
f
ii/t, /
i~

\ \k
.1'

, -- I
"\

,.~--%e:.., \ x:.>.
~'~--'--
400 500 600 700A,nm

Fig. i. Electronic absorption spectra of sol-

utions of porphins XIII ( ), XII (---),
and XI (--.--) in pyridine.

a
J

U.,...,--
I. I I

10 7 '~ ppm

i
/

Io 9 7 ~ppm

____t I

9 ~ 6 ~, ppm
F i g . . 2. PMR spectra of porphins: a) XII, b) XIII, and c)
XI in deuteroacetone.

Examination of the electronic absorption spectra of solutions of XI-XIII in pyridine

shows that the absorption of the 2- and 4-isomers is broadened and shifted bathchromically
as compared with that of the 3-isomer. This may be due to conjugation of the ~-system of the
azo-dye moiety with that of the porphyrin macrocycle. In the case of the 2-isomer this inter-
action appears to be steric in nature. This is confirmed by the PMR spectra in deuteroacetone.
In the case of the 2-isomer, there is a considerable shift of the signals for the B-protons
to high field (8.67 ppm) as compared with these signals for the 3- and 4-isomers (9.24 and
9.28 ppm). The broadening and splitting of the signals in the PMR spectrum of the 2-isomer
is apparently due to the presence of a mixture of atropo-isomers.

EXPERIMENTAL
Electronic spectra were recorded on a Specord UV-VIS spectrophotometer in pyridine, a n d
PMR spectra on a Tesla BS-497 in deuteroacetone, internal standard HMDS. The individuality ant
purity of the compounds were established by TLC on Silufol in the systems chloroform--hexane,
3:2 (A) and 2:1 (B), ether--benzene, 2:1 (C), acetone--hexane, 2:3 (E) and i:i (F).

399
 Tetra-(3%fluorophenyl)porphin (I). To a solution of 0.5 g (0.74 mmole) of tetra-(3-
aminophenyl)porphin in 40 ml o f ~ 0 % hydrofluoroboric acid was added with stirring and cooling
at 5~C dropwise a solution of 0.2 g (2,9 mmoles) of sodium nitrite in i ml of water. To the
resulting suspension of the diazonium fluoroborate was added with stirring a suspension of
freshly-prepared copper (i ~) in 10 ml of water. The mixture was stirred on the boiling water
bath until evolution of nitrogen ceased, and the solid was filtered off, washed with water,
and dried in air at 100=C. The porphyrin was extracted from the solid by boiling with 200 ml
of chloroform, and chromatographed on a column (4 40 cm) of trade III alumina with chloro-
form as eluent. The eluate was evaporated to 25 ml, and the porphyrin precipitated with 200
ml of methanol, filtered off, and dried in air at 100~ to give 0.18 g (35%) of produc=.
Tetra-(4-fluorophenyl)porphin (If) was obtained similarly from tetra-(4-aminophenyl)por-
phin, yield 0.2 g (40%).
Tetrar~3-chloropheny!)porPhin (llI). To a solution of 0.5 g (0,74 mole) of tetra-(3-
aminophenyl)porphin in a mixture of 5 ml of conc. HCI and 30 ml of water was added dropwise
with stirring and cooling at 5~ a solution of 0.2 g (2.9 mmoles) of sodium nitrite in 1 ml
of water. The resulting diazonlum salt solution was added all at once to a solution of 0.5 g
of cuprous chloride in 10 ml of conc. HCI. The mixture was heated on the boiling water bath
until evolution of nitrogen ceased, and the solid was then filtered off, washed with 100 ml
of 10% ammonia solution and water, and dried in air at 100~ The resulting porphyrin was
dissolved in 200 ml of chloroform at the boil, and chromatographed on a column (4 40 cm)
of grade III alumina with chloroform as eluent. The eluent was concentrated to 25 ml, and
the porphyrin precipitated with 200 ml of methanol, filtered off, and dried in air at 100~
to give 0.29 g (52%) of III.
Tetra-(4-chlorophenyl)porphin (IV) was obtained similarly, yield 0.35 g (63%).
Tetra-(3-brom0phenyl)porphin (V). To a solution of 0.5 g (0.74 mmole) of tetra-(3-ami-
nophenyl)porphin in a mixture of 5 ml of 48% hydrofluoroboric acid and 30 ml of water was added
dropwise with stirring and cooling at 5~ a solution of 0.2 g (2.9 mmoles) of sodium nitrite
in 1 ml of water. The resulting diazonium salt solution was added all at once to a solution
of 0.8 g of cuprous bromide in i0 ml of 48% hydrobromic acid. The mixture was heated on the
boiling water bath until evolution of nitrogen ceased, and the solid was filtered off, washed
with 100 ml of 10% ammonia and water, ald dried in air at 100~ The porphyrin was dissolved
in 200 ml of chloroform at the boil, and chromatographed on a column (4 40 cm) of grade llI
alumina with chloroform as eluent. The eluate was concentrated to 25 ml, and the porphyrin
precipitated with 200 ml of methanol, filtered off, and dried in air at 100~ to give 0.34 g
(49.5%) of V.
Tetra-(4-bromophenyl)porphin (VI) was obtained similarly from tetra-(4aminophenyl)porphin,
yield 0.48 g (70%).
Tetra-(3-iodophenyl)porphin (VII). To a Solution of 0.5 g (0.74 mmole) of tetra'(3-am-
inophenyl)porphin in a mixture of 5 ml of conc. H2SO~ and 30 ml of water was added dropwise
with stirring and cooling at 5~ a solution of 0.2 g (2.9 mmoles) of sodium nitrite in 1 ml
of water. The diazonium salt solution was added all at once to a solution of 1 g of potassium
iodide in i0 ml of water. The mixture was heated on the boiling water bath until evolution of
nitrogen ceased, and the solid was then filtered off, washed with I00 ml of 5% sodium hydroxide
and water, and dried in air at 100~ The resulting porphyrin was dissolved in 200 ml of
chloroform at the boil, and chromatographed on a column (4 40 cm) of grade III alumina,
eluent chloroform. The eluate was concentrated to 25 ml, and the porphyrin precipitated with
200 ml of methanol, filtered off, and dried in air at IO0~ to give 0.42 g (56%) of VII.
Tetra-(4,iodophenyl)porphin (VIII) was obtained similarly from tetra-(4-aminophenyl)por-
phin, yield 0.56 g (68%).
Tetra-(3-hydroxyphenyl)porphin (IX). To a solution of 0.5 g (0.74 mmole) of tetra-(3-
aminophenyl)porphin in a mixture of i0 ml of conc. sulfuric acid and 30 ml of water was added
dropwise with stirring and cooling at 5~ a solution of 0.2 g (2.9 mmoles) of sodium nitrite
in 1 ml of water. The resulting diazonium salt solution was heated on the boiling water bath
until evolution of nitrogen ceased, and the solid was filtered off, dissolved in 200 ml of 5%
sodium hydroxide, and filtered. The filtrate was neutralized with conc. HCI to pH 7, and the
porphyrin filtered off, washed with i00 ml of 10% ammonia and water, and dried in the vacuum
desiccator. For purification, the porphyrin was dissolved in 200 ml of boiling ether, and

400
chromatographed on a column (5 x 60 cm) of silica gel (L 100/250), eluent ether. The eluate
was concentrated to 25 ml, the porphyrin (IX) precipitated with hexane, filtered off, and
dried in air at room temperature to give 0.32 g (63%) of IX.
Tetra-(4-hydroxyphenyl)porphin (X) was obtained similarly from tetra-(4-aminophenyl)por-
phin, yield 0.36 g (72%).
Tetra[2-(p-hydroxyphenylazo)phenyl]porphin (XI). To a solution of 0.5 g (0.74 mmole) of
tetrai(2-aminophenyl)porphin in a mixture of 0.5 ml of conc. sulfuric acid and 30 ml of water
was added dropwise with stirring and cooling at 5~ a solution of 0.2 g (2.9 mmoles) of so-
diumnitrite in ! ml of water. The resulting diazonium salt solution was added dropwise to a
stirred solution of 0.3 g (3.2 mmole) of phenol and 1 g of KOH in i0 ml of water. The mixture
was diluted to 150 ml with water, and filtered. The filtrate was neutralized with conc. HCI
to pH 7, and the porphyrin filtered off, washed with i00 ml of 10% ammonia and water, and
dried in the vacuum desiccator. The porphyrin was purified by dissolving it in 200 ml of boil-
ing ether, and chromatography on a column (5 x 60 cm) of silica gel (L 100/250), eluent ether.
The eluate was concentrated to 25 ml, the porphyrin precipitated with hexane, filtered off,
and dried in air at room temperature to give 0.6 g (74%) of XI.
Tetra-[3-(p-Hydroxyphenylazo)phenyl]porphin (XII) was obtained similarly from tetra-(3-
aminophenyl)porphin, yield 0.72 g (89%), as was tetra-[4-(n-hydroxyphenylazo)phenyl)porphin
(XIII) from tetra-(4-aminophenyl)porphin, yield 0.78 g (98%).

LITERATURE CITED
i. A. S. Semeikin, O. I. Koifman, B.D. Berezin, and S. A. Syrbu, Khim. Geterotsikl. Soedin.,
No. I0, 1359 (1983).
2. A. Treibs and N. Haberle, Liebigs Ann. Chemie, 718, 183 (1968).
3. J. B. Kim, J. J. Leonard, and F. R. Longo, J. Amer. Chem. Soc., 94, 7868 (1973).
4. J. P. Collman, R. R. Gagne, T. R. Halbert, J.-C. Marchon, and C. A. Reed, J. Amer. Chem.
Soc., 95, 7868 (1973).
5. A. S. Semeikin, O. I. Koifman, and B. D. Berezin, Khim. Geterotsikl. Soedin., No. i0,
1354 (1982).

ETHYL 1,4-DIHYDROPYRIDINECARBODITHIOATES AND THE ELECTRONIC EFFECTS

OF SULFUR-CONTAINING ESTER SUBSTITUENTS

B. A. Vigante, Ya. Ya. Ozols, UDC 547.825'836.3,07:542.943.541.127.1:543.

M. I. Terekhova, E. S. Petrov, G. Ya. 422
Dubur, E. E. Liepin'sh , and G. I.
Rozentale

Methods have been developed for the synthesis of the ethyl esters of 2,6-dimethyl-
1,4-dihydropyridine-3,5-bis(carbodithioic) and 4-aryl-2-methyl-5-oxo-4,5-dihydro-
iH-indeno[l,2-b]pyridine-3-carbodithioic acids. From the physicochemical properties
(acid dissociation constants and electrochemical oxidation potentials of the 1,4-
dihydropyridines with sulfur-containing substituents in the B-positions, the elec-
tronic effects of these groups in the 1,4-dihydropyridine system have been deter-
mined. The inductive and resonance constants of these substituents in aromatic
compounds have been found by 13C and 1 9 F N M R spectroscopy.

Much attention has recently been devoted to 1,4-dihydropyridines (I,4-DHP) and hydrogena-
ted nitrogenous heterocycles, with their unique chemical properties [i, 2] and manifold bio-
logical activity [3].

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
L.Ya. Karpov Research Institute for Physical Chemistry, Moscow 107120. Translated from Khim-
iya Geterotsiklicheskikh Soedinenii, No. 4, pp. 491-500, April, 1986. Original article sub-
mitted August 29, 1984; revision submitted June 21, 1985.

0009-3122/86/2204-0401512.50 9 1986 Plenum Publishing Corporation 401

 In studying 1,4-DHP with sulfur-containing ester substituents in the B-positions, we set
ourselves the task of determining the electronic effects of these substituents. We have pre-
viously described [4-6] 1,4-DHP and dihydroindenopyridines with alkylthiocarbonyl, benzylthio-
carbonyl, and ethoxythiocarbonyl groups in the B-positi0ns (I, II X = 0, Y = S; X = S, Y = 0).
We here describe methods of synthesis and properties of 1,4-DHP and 4,5-dihydro-iH-indeno[l,2-
b]pyridine-5-ones bearing ethylthio(thiocarbonyl)substituents (I, II, X = Y = S) in the ~-
position.
0 C~H~R-p

CH~, H CH~ 1t CH
I I!

The key compound, ethyl acetodithioacetate (III) has been described in the literature
[7, 8], but in order to simplify~the synthesis and increase the yields we have developed a new
method for its synthesis, as follows:

" ~S /VsrI
CH3COCH~ + C2HsS-C,~ ~,~ CH~COCH=C~ S
SC2H~ CH=OCH2CH20CH
3 SC2tt5
III

Ethyl B-aminodithiocrotonate (IV) has been synthesized for the first time by reaction
of the dithioester III with ammonium acetate in the presence of acetic acid:

III CH3COONH4 C6H~, CH=C00H --- CH_C=CH_C~S

-H~0 [ SC2tl~
NHe

From monocyclic dithioesters of the 1,4-dihydropyridine series we have only been able
to obtain a 4-unsubstituted product (I R = H, X = Y = S) and a 4-p-nitrophenyl derivative
(I R = C6H~NO=-p, X = Y = S), which were synthesized by a modification of Hansch's method
[9]. The condensation of the dithioester III with other aromatic aldehydes in glacial acetic
acid was unsuccessful, since the prolonged heating required for cyclocondensation to 1,4-DHP
resulted in decomposition of the dithioester III.
Polycyclic 1,4-DHP with an (ethylthio)thiocarbonyl group in the 3-position (II X = Y = S)
were obtained from 2-arylideneindan-l,3-diones by two routes, either by boiling with the di-
thiocrotonic ester IV in acetic acid (method A), or by condensation with the dithio-ester III
in the presence of an excess of ammonium acetate (method B). Method B is preferred, substan-
tially higher yields of products being obtained.
The UV, IR, and PMR spectra of the products I and II (X = Y = S) (Table i) confirmed the
structures of these compounds. The UV spectra of the dithioesters (II = Y = S) the long-wave-
length maximum (Table i) undergoes a bathochromic shift by 20-40 nm in comparison with the
corresponding thiol and thione esters [4-6]. In the IR spectrum of the 1,4-DHP I (R = H,
H = Y = S), the only absorption present in the double bond region is seen at 1610 cm -~, as"
\ /
signed to the double j C ~ - C \ bonds of the dihydropyridine system. In the polycyclic dithioes-
ters (II, X = Y = S), in addition two bands are present for the cyclic benzoylene moiety of
the molecule, at around 1640 and 1670 cm -I (Table i).
In order to evaluate the electronic properties of the sulfur-containing ester groups,
the pK values (Table 2) of the 1,4-DHP with an (ethylthio)thiocarbonyl B-substituent were
found. For comparison, values were measured, previously determined values for known compounds
were used for thiolo (I, II, X = O, Y = S), thiono (I, II, X = S, Y = O) and oxygen esters
(I, II, X = Y = O) [4-6].
The pK values of compounds (I) and (II) were determined by the transmetallation method
in DMSO [i0], and for the dihydroindenopyridines (II) additionally by a spectrophotometric
method [ii] in 50% ethanol.
As will be seen from Table 2, replacement of an ether or carbonyl oxygen by sulfur in-
creases the acidity by practically the same amount (~1.2 pK units) in compounds with struc-

402
 TABLE i. Ethyl Esters of 2,6-Dimethyl-l,4-dihydropyridine-3,5-bis(carbodithionic) (I X = Y = S) and 2-Methyl-5-oxo-4,5-
dihydro-iH-indeno [i, 2-b]pyridine-3-carbodithionic) (II X = Y = S) Acids

]U'v" ~ e c - PIdR spectrum ~, ppm in DMSO-d 6. ) Found, % Calculated, %

IR spectrum, [trum, Xma x, Empi ~ic a l
I[ I Yi eld, qo
. Ig' v, cm "t Inm N-H,sl Harom. nm C H N S formula C IH N S
I

ld I-I 94 1610, 3365 207, 309, 500 1,18 3,13 2,27 3,76 9,27 48,9 6,2 4,3 40,0 C:aH,gNS4 49,216,0 4,4 40,4 35
In p-NO~C6114 111 1615, 3380 207, 310, 470 1,16 3,17 2,32 6,26 9,72 7,20--8,45 52,415,0 6,7 28,8 C tgH22N202S4 52,015,1 6,4 29,2 41
Ird H 200 1610,1620, 207, 232,262. 1,13 3,1l 2,18 5,04 10,15 7,10--7,70 76,4 4,9 3,5 16,7 C22HmNOS2 70,015,1 3,7 17,0 75 (A),
1640, 1670, 3200 320, 497 90 (B)
fig CHaO 183 1610, 1620, 207, 235, 262, 1,14 3,11 2,15 5,10 10,15 7,05--7,80 67,4 5,1 3,1 15,3 C23H2,NO2S2 67,815,2 3,4 15,7 68 (A),
1635, 1670, 3180 317, 496 84 (B)
IIi Br 195 1610, 1620, 207, 235,262, 1,13 3,11 2,13 4,96 I0,13 7,04--7,60 58,1 4,2 3,1 14,3 C~21-{18BrNOS2 57,9]4,0 3,1 14,1 55 (A),
1640, 1670, 3180 322, 495 75 (B)
Ill NO2 199 1610, 1620, 207, 231,266, 1,13 3,11 2,15 5,11 10,22 7,27--8,27 62,2 4,5 6,3 t4,9 C22HjsN2OaS2 62,5]4,3 6,6 15,2 71 (A),
1640, 1675, 3200 320 (ha.), 82 (B)
498 !

*--~full list of compounds is given in Table 3.

#The coupling constant with the ethyl group is 7.6 Hz.
$For the CH30 group, ~ 3.60 ppm, s.

o
Lo
 TABLE 2. Equilibrium Constants (Kaaui I) for t h e Reaction
-
of the 1,4-DHP (I), (V), and (Vl) and 4,5-Dihydroind 9 nopy-
ridines (II) with Potassium-Substituted Indicator Acids,
Long-Wave Absorption of Their Anions, and pK Values in
DMSO, together with the pK of (II) in 50% Ethanol

,me plr
Indicator (pK) K~qu~l kra&X,

la ~,-Methylim[ .dazols (I 9.9) 0,66~0,,1 475 2,64 20,I

fb ~-Phe.nylirai@zole (~18.1~ 2,4~0,3 522 1,60 17,7
Ic ~- MethVlitni a&zole'(l~,1) 6,5~-0,3 625 1,18 17,3
Id l,~,4-Tfiazols (18.@ 3,6=~0,4 70,5 2,76 14.8 w
]la 1,~,4-Triazole (15,4) 1,7~0,2 578 1,02 15.2 12,74
lib l,~,4-Trt azole'(15 ;4) 24,3~0;4 584 1,04 14,0 12,52
IIc 1,2,4-Tr~a~o~ (15.4) 20,7 1,2 620 1,20 14,0 12,52
lid Benztrlazole (12.6) 0,086 638 0,88 13,7 12,4
Benztriazole (12.6) 12,6
iII~ Benztriazole (12.6) 12,4
Benztriazole (12.6) II,7
V 1,2,4-.T~ azole (15.4) 0,06~0,01 435 1,04 16,7
VI 12.1~etnylimiaazole (19,9) 2,64-0,3 520 1,74 19.5

*A full list of compounds is given in Table 3.

ture II (lla-c), and by ~2.5 pK units in monocyclic 1,4-DHP (la-c). The twice greater value
of the change for compounds I is due to the fact that replacement of the oxygen atom by sulfur
occurs simultaneously in two groups. Measurement of the pK of the dihydroindenopyridines II
in ethanol gives closely concordant values for all the sulfur-containing substituents. It is
important to stress that there is a good qualitative agreement between the sequence of changes
in pK values of type II compounds in ethanol and in DMSO. The substantially lower differences
in the pK values obtained for dihydropyridoindenes in ethanol as compared with DMSO is due to
the leveling-out effect of the hydroxylated solvent [12]. The formation of a hydrogen bond
between the ethanol and the N-anlon stabilizes the latter, thereby increasing the strength of
the conjugate NH-acid. The greater the basicity of the anion, the greater is the stabilizing
effect of this specific solvation, and the greater is the decrease in the pK value in the hy-
droxylated solvent as compared with the aprotic solvent. Therefore, the range of acidity (pK
values) in alcohol for a series of NH-acids is usually smaller than in DMSO [12].
The introduction of (ethylthio)thiocarbonyl substituents into the B-position of 1,4-DHP
(Table 2, Id) results in an increase in acidity of 5.3 pK units. Hence, in the magnitude of
their effects on the acidity of 1,4-DHP these substituents can be arranged in the sequence:

~S
-C ~ ~ < -Ct ~ -C~ S < -C~
~0C2H5 SC2H5 ~ 0C2H5 'SC2H5

In type II structures, however, the (ethylthio)thiocarbonyl substituent increases acidity

in DMSO by only 1.5 pK units over the oxygen-containing ester, and by as little as 0.3 pK un-
its in comparison with the thiolo and thionoesters (Table 2, IIa-d). The comparatively small
differences in the pK values on varying the B-substituent in II is due to the fact that in the
indene moiety the whole of the B-aminovinylcarboline five-membered chain lies in one plane,
resulting in strong conjugation of the unshared electron pair of the nitrogen atom. On the
other hand, the effect of the non-fixed 6-substituent in II is to a large extent evened out,
since for steric reasons it must be largely withdrawn from conjugation. Replacement of the
ethoxycarbonyl group by the more highly electron-accepting nitrile group (in 2,6-dimethyl-3,5-
dicyano-l,4-DHP, (V)) increases acidity by 3.4 pK units, whereas the acetyl group in 3,5-di-
acetyl-2,6-dimethyl-l,4-DHP (VI) is similar in its effect on acidity to the ethoxycarbonyl
grouo (Table 2).
The increased acidifying effects of the ethoxythiocarbonyl and (ethylthio)thiocarbonyl
substituents is doubtless due to intramolecular interactions between these groups and the N-
anionic center, but it is difficult to arrive at an unambiguous interpretation of the effect.
It may be that it is due to participation of the 3d sulfur orbitals in stabilizing the N-anion,
but it is also possible that the ready polarizability of the sulfur atom is important [13].
The possible involvement of free 3d-orbitals of sulfur in charge delocalization at the N-anions

404
has been suggested to explain the enhanced acidity of N-phenylcarbamates on replacement of the
carbonyl oxygen by sulfur [14]. The participation of sulfur in the stabilization of carboan-
ions, or inclusion in conjugation of vacant 3d-orbitals of sulfur is well known in compounds
containing sulfonyl, sulfide, or thioamide groups [15-20]. At the same time, it should be
pointed out that the 1,4-DHP system is a very complex system for the unambiguous evlauation
of intramolecular interactions of the B-substituents examined here with the ~-electron system
of the ring, in view of the complex interactions of polar and steric factors.
According to the conclusions of Stradyn' et al. [21], the electron-acceptor strength of
B-substituents in 1,4-DHP and their electrochemical oxidation (EO) potentials vary in the sam~
way. Consequently, the EO potentials provide a measure of the electronic effects of these
sulfur-bearing ester substituents in the 1,4-dihydropyridine system. For this reason, we have
determined the potentials of a wide range of compounds and II (Table 3)~ The introduction of
a methyl or aryl substituent into the 4-position of 1,4-DHP (I) with sulfur-containing B-sub-
stituents resulted in an increase of 70-200 mV in the EO potentials (Table 3). A similar effect
has been observed in a series of oxygen analogs [22, 23]. There was no discussion of the mec~
anism of EO on 1,4-dihydropyridines in these reports. The problem has been considered in the
case of the simplest oxygen esters [23]. According to Vigante et al. [4], replacement of the
oxygen atom of an alkoxy-group in a single ester substituent by sulfur increases the EO poten-
tial (Ep) by 30-40 mV. The introduction of sulfur atoms in place of oxygen in both ester grour
doubles the effect [4] (Table 3), indicating that the (alkylthio)thiocarbonyl substituent has
a stronger electron-acceptor effect than its oxygen analog. Thiono- and dithio-esters of 1,4-
DHP (Table 3) are oxidized more readily than the carbonyl esters to the extent of 30-120 mV,
indicating that electron-acceptor effects of the groups in this reaction series are weaker th~
with the ethoxy-carbonyl substituent. In the indenodihydropyridines (II), differences in the
EO potentials depending on the nature of the B-substituent are less pronounced [6] (Table 3).
To summarize, from the results given in Table 3, the ester substituents may be arranged in
order of decreasing passivating effects on EO:

~. 0 ~S ~
--C ~ 0 > -C~ > --C~ ~ >~
~SC2H 5 "OC2H 5 XOC2II5 9 -C'~sc2H s

Hence, these results for acidity equilibria and EO give differing series of changes in
the electron-acceptor properties of ester substituents. The reason for this is concealed in
changes in the reaction center in these reaction series, since measurements of pK involve the
N-anion, whereas EO involves the initial removal of an electron to give the cation-radical
[23].
Finally, we measured the reactivity constants a T and ~ of the sulfur-containing ester
substituents for aromatic co m pounds, by 1 9 F and 1 3 C NMR
~
spectroscopy. For thls purpose, the
13C chemical shifts (CS) of substituted benzenes relative to unsubstituted benzene are norm-
ally used (method a) [24]:

o~ ~ -O~05A6C.~+O.O5A6Cp, (i)

01=0.42A6~,~+0.028A6Cp, (2)

t o g e t h e r w i t h t h e 19F CS o f p a r a - and m e t a - s u b s t i t u t e d fluorobenzenes [25, 26] r e l a t i v e to

f l u o r o b e n z e n e (method b ) :

A6F,~= -7.10o1+0.6, (3)

A6Fp-A6F,,= -29.5oR ~ (4)

o r a c o m b i n a t i o n o f t h e s e m e t h o d s [ 2 7 ] : ~ I was o b t a i n e d f r o m Eq. ( 3 ) , and e~ f r o m t h e 13C

c h e m i c a l s h i f t s f o r t h e p a r a - c a r b o n atom i n t h e s u b s t i t u t e d b e n z e n e a l l o w i n g f o r t h e s o l v e n t
(method c ) . F o r s o l u t i o n s o f t h e compounds i n d e u t e r o c h l o r o f o r m ,

o#~=O.O47A~C~_O.211o~. (5)

The ~3C and 19F CS found are given in Table 4. The values for o I and ~RO calculated by these
methods are reported in Table 5. There are some divergences between the values of o I and ~
obtained by different methods, although the general tendencies of'the changes as oxygen is
progressively replaced by sulfur persist. The greatest electron-acceptor properties are shown
by the (ethylthio)carbonyl substituent, largely on account of its inductive effect (oi), then

405
 TABLE 3. Half-Wave Potentials (E~/a) in the EO of 1,4-
Dihydropyridines (I) and 5-Oxo-4,5-dihydroindenopyridines
(II)
Com = COITI =
pound X Y t'~.,V pound R X Y &l~,V

Ia H 0 O 0,89 tla H I0 0 1,10

lb H 0 S 0,97 lib H 0 S 1,10
Ic H S 0 0,83 llC H [ S 0 1,08
id H S S 0,81 lid 1,07
le CH~ 0 0 0,96 lle CI laO O 1,15
If Ctla 0 S 1,08 llf Cl'I:sO O 1,05
tg CI-la S 0 0,93 CH~O IS S 1,12
Ih Cgq~ 0 0 1,08 Br 0 0 1,20
Ii C,M~ 0 S 1,1o lli Br [S S 1,09
S 0 0,98 NO2 'S
~ 0 t ,23
0 O 1,18 NO2 0 !,16
I! p-NO2C~M~ 0 S 1,20 ll~ NO2 , S S 1,t4
lm p-NO2C~It4 S O 1,06

follows oxygen analog, the ethoxycarbonyl group; the(ethylthio)thiocarbonyl and ethoxythio-

carbonyl groups display approximately the same electronic effects, the inductive effect being
greater in the (ethylthio)thiocarbonyl substituent, i.e., the NM R method gives the following
order of electron-acceptor properties for the ester groups:

_c>O O .S I.W
SC;,II~ :' -C[" > --C' ::, -C."
_, "OC~H s "SC2Ho: "OC211 s

Thus, the (ethylthio)carbonyl group in 1,4-DHP in all the reaction series (pK, EO, ox-
idation kinetics, and alkylation [4]) and in aromatic systems (NMR for laC and 19F nuclei) is
a stronger electron-acceptor substituent than its oxygen analog. The (ethylthio)carbonyl group
promotes reactions involving removal of a proton (pK), and retards reactions involving remov-
al of an electron (oxidation), which is in agreement with the values of its Hammet o-constanr
found by us previously [5] from ~ e experimental pK values of substituted benzoic acids [28,
30, 31]. It will be seen from these that the deciding factor in the total electron-acceptor
effect is the greater inductive effect of the (ethylthio)carbonyl group.
On the other hand, compounds containing thione sulfur in the B-substituent (-C ~ S
\ YC2Hs'
Y = O, S) behave differently, depending on the experimental subject (anionic and neutral forms
of 1,4-DHP or the aromatic system). When the thione group can participate in delocalization
of the negative charge (acid ionization), the ethoxythiocarbonyl and (ethylthio)thiocarbonyl
groups display stronger electron-acceptor properties than the ethoxycarbonyl group. However,
in reactions of 1,4-DHP not involving loss of a proton (in particular EO), and when the o-
constant is measured in aromatic systems, the (ethylthio)thiocarbonyl and ethioxythiocarbonyl
groups are weaker electron-acceptors than the ethoxycarbonyland (ethylthio)carbonyl groups.

EXPERIMENTAL
IR spectra were obtained on a UR-20 (in Nujol), electronic absorption spectra on a Spe-
cord UV-VIS spectrophotometer (in ethanol), and PMR spectra on a WH-90 spectrometer (90 Mllz)
in CDCI3 and DMSO-D6, internal standard TMS. IaC NMR spectra were obtained on a WH 90/DS
(22.63 MHz) (for the 10% solutions in CDCI3, internal standard TMS) at 35~ The accuracy of
measurement of the CS was ppm. !9F NMR spectra were obtained on a Perk R-12A
(10% solutions in CC14, temperature 36~ internal standard fluorobenzene. Accuracy of meas-
urement ppm). Melting points were determined on a Kofler block.
Ethyl Acetodithioacetate (III). To a suspension of 9.6 g (0.4 mole) of sodium hydride
in 200 ml of dry 1,2-dimethoxyethane was added slowly 33.3 g (200 mmoles) of SS-diethyl tri-
thiocarbonate under argon, with stirring at room temperature. After i h, 11.6 g (200 mmoles)
of thoroughly purified ~nd dried acetone was added dropwise. Stirring was continued for i h
at room temperature, then the mixture was boiled for 6 h on the water bath. The reaction mix-
ture, after cooling, was poured onto ice and acidified with cold i N hydrochloric acid. The
mixture was extracted with methylene chloride, the extract dried over anhydrous magnesium
sulfate, and distilled under reduced pressure to give 25.9 g (80%) of product, bp 120~ (15
mm Hg), the spectral properties and bp being in accordance with those reported previously [7,
8].

406
 3 2

TABLE 4. ~3C and 19F Chemical Shifts in Substituted Benzemes (VII)* . ~ x

Com- Cx
CH) C~2) C(3) C(4) C15) Cr .~6F
pound C~ CH: CH~

Vlla H --COOC:H~ 130,89 129,78 128,52 132,94 128,52 129,78 166,86 60,99 14,40
~S
Vllb H -C 138,92 128,97 128,26 132,77 128,26 128,97 211,80 68,63 13,81
~OC2H5
VIIc H 137,62 127,37 128,75 133,33 128,75 127,37 192,05 23,46 14,79
SC2H5

,'Vlld H -C~. S 145,58 127,06 128,49 132,35 128,49 127,06 225,74 31,55 12,32
sC2H 5
vile 4-F --COOC2H~ 127,35 132,45 115,68 166,17 115,68 132,45 165,76 61,22 14,40 6,24
(2,9)t (8,8) (22,1) (253,7) (22,1) (8,8)
~S
Vllf 4-F --C"-OC2H~ 135,15 131,42 115,20 166,10 115,20 131,42 209,98 68,73 13,78 5,90'
(2,9) (9,6) (22,1) (255,2) 122,1) (9,6)
4-F ~.O 133,85 129,90 115,84 166,11 115,84 129,90 190,68 14,79 7,18,
Vllg 23,62
-- C. SC2H$ (2,9) (9,6) 122,1) (254,4) 122,1) (9,6)
~'llh 4-F _C~ S 141,65 129,30 115,36 165,86 115,36 129,30 226,23 31,65 12,32 5,25
SC2H ~ (2,9) (8,8) 122,1) (254,4) 122,1) (8,8)
VIii 3-F --COOC~Hs 133,19 116,71 163,00 120,03 130,03 125,56 165,66 61,45 14,33 0,28,
H (7,4) (22,8) 1247,1) (22,1) 18,1) (2,9) (2,9)
VII/ 3-F 140,67 115,64 162,66 119,52 129,67 124,69 209,73 68,92 13,71 - 0,2ff
_c ~s (7,4) (24,3) (246,3) 122,1) (8,1) (2,9) (2,9)
9 "~oc2H s
Vllk 3-F 139,52 114,24 163,03 120,28 130,48 123,15 190,91 23,72 14,6~ 1,05
//0
(6,6) (22,8) (248,6) 121,3) (7,4) (2,9) (2,9)
~ C'SC:zH5
u 3-F 147,05 114,22 162,74 118,95 129,90 122,52 226,67 31,65 12,1 c 0,19
~.S
(5,t) (23,5) (247,1) (21,3) (8,1) (2,2) (2,2)
--C~sc2H5
Vllm F 124,24 130,24 115,57 162,29 0,00
(2,2) (7,4) (21,3) (245,6)

*The 13C CS for benzene is 128.38 ppm.

J'The 13C--~9F coupling constants (Hz) are given in brackets.

O
-,,,,d
 TABLE 5. o I and o Ro Values of Substituents

_C~- X

Method of calculation
Sub~titucnt a b c
Ol UR 0 O"I OR 6 OR0

9-:0
--C 0,19 0,92 0,12 0,22 0,19
OC2tt ~

-.C" 0,07 0,23 0,06 0,20 0,22

~SC2H 5

--C" 0,30 0,23 0,23 0,21 0,16

"SC2H 5

/~
.--C 0,16 0,2,0 0,11 0,17 0,16
"SC2H 5

*Literature values for the ethoxycarbonyl group: o 7 0.37 [28],

0.30 [29] (from the pK values of substituted benzoic acids),
0.ii (CC14), 0.35 (CF3COOH) [25] (from NMR on ~gF nuclei in
substituted benzenes); oRo 0.08 [28], 0.19 (CHCI3) [26]

Ethyl 8-Aminodithiocrotonate (IV)~ A mixture of 13 g (80 mmoles) of the dithioester III

and 17 g of ammonium acetate was boiled with stirring in 5 ml of glacial acetic acid and 90 ml
of dry benzene, in a Dean and Stark apparatus. Benzene (50 ml) was distilled off during 30
min. The remaining solution was washed with water, dried over anhydrous magnesium sulfate, and
fractionated under reduced pressure to give 8.5 g (65%) of an orange oil, bp 157~ (i0 mm).
PMR spectrum (DMSO-D6) 1.15 (3H, t, SCH2CH~, J = 7.6 Hz), 1.89 (3H, s, CH3CO), 3.45 (2H, q,
CH2, J = 7.6 Hz), 5.60 (IH, s, ==CH--), 8.76 (i H, s, N--H), 10.7 ppm (i H, s, N-H). Found: C
44.9; H 6.7; N 8.3; S 39.9%. Calculated: C 44.7; H 6.8; N 8.7; S 39.5%.
Diethyl 2,6-D1methyl-l,4-dlhydropyrldlne-3,5-bls(carbodlthl0ate~! (Id). A mixture of
3.3 g (20 mmoles) of the dithioester III, 0.7 g of urotropine, and 0.5 g of ammonium acetate
in 3 ml of glacial acetic acid was heated for i0 min on the water bath. After cooling, the
mixture was poured into water, extracted with ether, dried over anhydrous sodium sulfate, and
the solvent removed under reduced pressure. The residue was crystallized from methanol (deep
red crystals). Yield i.i g (35%) (Table I).
Diethyl 2,6-dimethyl-4-(4-nitrophenyl),l,4-dihydropyridine-3,5-bis(carbodithioate) (In).
The dithioester I!I (3.3 g; 20 mmoles) was heated on the water bath for 1 h with 1.4 g (i0 m-
moles) of p-nitrobenzaldehyde and 5 ml of glacial acetic acid. The cooled reaction mixture
was poured into water, extracted with ether, and dried over anhydrous magnesium sulfate. Af-
ter removal of the ether, the residue was chromatographed on a column of Brockman grade II
alumina, and eluted with a mixture of chloroform, hexane, and acetone (9:7:1). Crystallization
from methanol gave 1.8 g (41%) of In as deep red crystals (Table I).
General Method for the Preparation of Ethyl 4-Aryl-2-methylF5-oxo-4,5-dihydro-iH-indeno-
[l,2--b]pyridine-3-carbodithioates (lld,g,i,l). A. To a boiling solution of 5 mmoles of the
iLaryldeneindandione-l,3 in 20 ml of glacial acetic acid was added 0.81 g (5m moles) of the 6-
aminodithiocrotonate IV, and the mixture boiled for 5 min. Deep red crystals separated on
cooling, and these were crystallized from acetic acid (Table i).
B. The 2-arylideneindandione-l,3 (10m moles) and 3.3 g (20m moles) of ethyl acetodithioace-
tate III were boiled in 25 ml of acetic acid in the presence of 7.7 g (i00 mmoles) of ammonium
acetate for I0 min. After cooling, the mixture was diluted with water to 30 ml, and the red
solid which separated was filtered off and crystallized from acetic acid (Table i).
Synthesis of Esters and Sulfur-Containing Esters of Benzoic, p-Fluoro-, and m-Fluorobenz-
oic Acids (VIIi. Ethyl p-fluoro- (VIIe) and m-fluoro- ((VIii) benzoates were obtained by ster-
ifying the fluorobenzoic acids as described in [32]. The thiolo-esters of benzoic (Vilc) [33] and
p-fluorobenzoic (Vllg) acids were obtained by reacting the acid anhydrides with ethyl mercap-
tan in the presence of pyridine, as described in [33]. The above method was used to obtain
the novel thioethyl m-fluorobenzoate (Vllk), yield 69%, bp I15~ (i0 mm). PMR spectrum (CDCI3):

408
1.25 (3H, t, J = 7.6 Hz, CH3); 3.07 (2H, q, J = 7.6 Hz, CH2), 7.11-7.76 ppm (4H, m, arom.
protons).
The thiono-esters of benzoic (Vllb) [35], p-fluorobenzoic (Vllf), and m-fluorobenzoic
(VIIi) acids were obtained by direct thionylation of the esters of the acids with LawessSn's
reagent (molar proportions 1:1.2) in boiling toluene, as described in [36].
O-Ethyl p-Fluorothiobenzoate (Vllf). Yield 85%, bp 132~ (ii mm). PMR spectrum (CDCI3):
1.44 (3H, t, J = 7.6 Hz, CH2), 4.62 (2H, q, J = 7.6 Hz, CH2), 6.89-8.18 ppm (4H, m, arom. pro-
tons).
O-Ethyl m-Fluorothiobenzoate (VIIi). Yield 80%, bp 100~ (5 mm). PMR spectrum (CDCI3):
1.46 (3H, t, J = 7.6 Hz, CH3), 4.62 (2H, q, J = 7.6 Hz, CH2), 7.04-7.87 ppm (4H, m, arom.
protons).
Obtained similarly were ethyl dithiobenzoate (Vlld) [37] and the previously unknown ethyl
p-fluoro- (Vllh) and m-fluoro- (Vlll) dithiobenzoates, by boiling the thiolo-esters of benzo-
ic, p-fluoro- and m-fluorobenzoic acids in toluene with LawessSn's reagent [36] in a molar
ratio of 1:0.8.
Ethyl p-Fluorodithiobenzoate (Vllh). Yield 79%, bp 151~ (15 mm). PMR spectrum (CDCI3):
1.37 (3H, t, J = 7.6 Hz, CH3), 3.27 (2H, q, J = 7.6 Hz, CH2), 6.84-8.00 ppm (4H, arom. pro-
tons).
Ethyl m-Fluorodithiobenzoate (VlIT). Yield 75%, bp i37~ (5 mm). PMR spectrum (CDCI3):
1.40 (3H, t, J = 7.6 Hz, CH3), 3.31 (2H, q, J = 7.6 Hz, CH2), 7.07-7.67 ppm (4H, m, arom. pro-
tons).
The pK values in DMSO were measured by the transmetallation method, which is based on the
spectrophotometric determination of the concentration equilibrium constants for the reaction
of the 1,4-dihydropyridines with the alkali derivatives of indicators [I0]. The method for
the determination of the K^~.~I values in carefully purified DMSO in an all-brazed vacuum
apparatus was similar to that described previously [i0, 38]. The mean of four measurements
was taken, the pK values of the indicators being obtained from [38].
The ionization constant of (II) in 50% (vol.) ethanol was determined spectrophotometri-
cally [Ii], using the analytical wavelengths of the anion in the region of 600 nm.

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409
18. N. V. Kondratenko, V. l.Popov, A; A. Kolomeitsev, E. P, Saenko, V. V. Prezhdo, A. E. Kut-
skll, and L. M. Yagupol'skll, Zh. Org. Khlm., 16, 1215 (1980).
19. L. M. Yagupolskii, A. u ll'Ichenko, and V. N. Kondratenko, Usp. Khlm., 43, 64 (1974).
20. D. Cram, Fundamentals of the Chemistry of Carbanions [Russian translation], Mir, Moscow
(1967), p. 80.
21 9 Ya. P. Stradyn', Yu. T Beills, Ya R. Uldrikls, G. Ya. Dubur, A. E. Sausln' and B. S
. 0 , 9

Chekavlchus, Khim. Geterotslkl. S oedin., No. ii, 1525 (1975).

22. Ya. P. Stradyn', G. Ya. Dubur, Yu. I. Beills, Ya. R. Uldrikis, B. S. Chekavlchus, and
A. E. Sausin', Khim. Geterotsikl. Soedin., No. Ii, 1530 (1975).
23. V. P. Kadysh, Ya. V. 0gle, Ya. P. Stradyn', and G. Ya. Dubur, Izv. Akad. Nauk Lair. SSR,
Set. Khim., No. 5, 572 (1982).
24. V. I. Glukhikh and M. V. Voronkov, Dokl. Akad. Nauk SSSR, 248, 142 (1979),
25. R. W. Taft, E. Price, I. R. Fox, I. C. Levis, K. K. Andersen, and G. T. Davis, J. Amer.
Chem9 Soc., 855, 3146 (1963).
26. R. W9 Taft, E. Price, I. R. Fox, I. C. Levis, K. K. Andersen, and G. T. Davis, J. Amer.
Chem. Sot., 85, 709 (1963).
27. R. T. C. Brownlee and M. Sadek, Aust. J. Chem., 34, 1593 (1981).
28. K. Johnson, The Hammer Equation [Russian translation] , Mir, Moscow (1977), p. 27.
29. Yu. A. Zhdanov and V. I. Minkin, Correlational Analysis in Organlc Chemistry [in Rus-
sian], Izd-vo Rostov Un-ta, Rostov-on-Don (1966), p. 386.
30. D. H. McDaniel and H. C. Brown, J. Org. Chem., 75, 2267 (1953).
319 J. D. Roberts and W. T. Moreland, J. Amer. Chem. Soc., 75, 2267 (1953).
329 A. N. Kost (ed.), Laboratory Manual of General Organic Chemistry [in Russian], Mir, Mos-
cow (1965), p. 388.
33. H. Bohme and H. Schran, Chem. Bet., 82, 453 (1949).
34. A. Fosdlck and V. Barnes, J. Amer. Chem9 Soc., 67, 335 (1945).
359 H. Eilingsfield, M. Seefelder, and H. Weldinger, Chem9 Bet., 96, 2671 (1963).
36. B. S. Pedersen, S. Scheibye, K. Clasen, and S.-O. Lawess~n, Bull. Soc. Chlm. Beiges, 87,
293 (1978)9
37. J. Perregard, B. S. Pedersen, and S.-O. Lawessgn, Acta Chem. Scand., 31B, 460 (1977).
389 M. I. Terekhova, E. S. Petrov, E. M. Rokhlina, D. K. Kravtsov, and A. I. Shatenshtein,
Khim. Geterotsikl. Soedin., No. 8, 1106 (1979).

FORMATION OF A DERIVATIVE OF 3,3,5-TRICARBONYL-I,2,3,4-TETRAHYDROPYRIDINE

UNDER THE CONDITIONS OF THE HANTZSCH SYNTHESIS

B. S. Chekavichus, A. E. Sausin', UDC 547.827.07:543.422

R. M. Zolotoyabko, E. E. Liepin'sh,
I. B. Mazheika, and G. Ya. Dubur

An ester of p-nitrobenzoylacetic acid is cyclized under the action of hexamethyl-

enetetramine and ammonium acetate to 3,5-diethoxycarbonyl-3-p-nitrobenzoyl-6-p-
nitrophenyl-l,2,3,4-tetra-hydropyridine, the structure of which has been estab-
lished by NMR, UV, IR, and mass spectra and also by its chemical reactions.

Esters of B-ketocarboxylic acids form, in different variants of the Hantzsch synthesis,

1,4-dihydropyridines. Esters of benzoylacetic acid are not excluded in this respect, although
in general the reactions take place with some difficulty [i]. From an ester of p-nitrobenzoyl-
acetic acid, 4-substituted 1,4-dihydropyridines (I, R = p-NO2, R 2 -~ H) are obtained.
H R2 t

1~% , H 6 4

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 501-505, April, 1986.
Original article submitted February 12, 1985; revision submitted June 17, 1985.

410 0009-3122/86/2204-0410512.50 9 1986 Plenum Publishing Corporation

Esters of benzoyl and p-chlorobenzoylacetic acid form 4-unsubstituted 1,4-dihydropyridines
(I, R 2 = H) in reaction with hexamethylenetetramine (a source of formaldehyde and ammonia)
and ammonium acetate [i, 2]. However, from an ester of p-nitrobenzoylacetic acid under an-
alogous conditions compound II is unexpectedly obtained; this does not have the 1,4-dihydro-
pyridine structure. The long-wave maximum which is characteristic of the dihydropyridine sys-
tem is absent from the UV spectrum of this compound, but there is a maximum at 272 nm. High
resolution mass spectra gave for compound II an elemental composition for the group of atoms
CH20 greater than for the expected dihydropyridine. The IR spectrum gave evidence of the pres-
ence of a complex ether group at a saturated carbon atom (band at 1735 cm-1). A broad band
at 1690 cm -I could be due simultaneously to a ketone and a complex ether group at a C---C double
bond.
7 S g
~3 12 H H C00CH CH
CH3CHz00C ~ / ~__ -~

2 ~ CH C0ONH~ , ,1" ,o // 4"

k _- -/ N o - - 4 '~- ~_ = _~/ .......N
,[ / ~ ,, ~2 3
9 . ' k~ II ..~

COOC2H~ .,,,.- ~ '-~0 ~ COOC:~I:I5

C2HsOOC~ "-.../
~ J "C0_CsH4N02_p C2H'OOC'-/~'"'.[/ COOC2II5 C2H500C. / / ~ - /

NO p-I~0zC6114 6 4 z-P p-NOI~C(~H4 N OH

V In
IV

In order to establish the structure of compound II, IH and I~C NMR spectra were run, the
latter under conditions of full spin decoupling and without suppression of spin-spin coupling
(SSC) with the protons. The appearance of three different carbonyl groups in the ~3c spectrum
of compound II is characteristic, the resonance of C(~o) being easily identified according to
the characteristic chemical shift (195.0 ppm) and the SSC constant with the protons in posi-
tions 2 and 4 (=1.7 Hz).
A choice between the two remaining carbonyl carbon signals was made on the basis of their
SSC with the protons in positions 2 and 4. For carbon atom C(7) there is SSC with both groups
of proton s (1.4 and 1.2 Hz) while C ( ~ ) couples only with the protons at C(4) (~0.8 Hz).
Assignment of signals of atoms Cf2~ and C ( ~ does not give rise to doubt, on account of
their having direct SSC constants equal'to 145.2 Hz ~for C(2~) and 134.5 Hz (for C(~)). Fur-
thermore, atom C(2) additionally couplesqith the protons in position 4 (2.5 Hz) and also with
the proton of the NH group (3.4 Hz). For the signal corresponding to carbon C(~) only the SSC
constant with the protons in position 2 (3.7 Hz) is observed, and for C(3) SSC with the methyl-
ene protons in positions 2 and & is characteristic (3.1 Hz). The signal of atom C(s) is split
on account of interaction with the protons in position 4.
Assignment of the signals of the aromatic carbons and those of the ethyl groups was made
taking account of the data of [3].
In the 13C spectra of compound II, without suppression of SSC with protons, long-range
SSC constants are found between amine protons and all the nearby carbon atoms (2JHNc(2) = 3.4,
:JHNC(6) = 2.3, SJHNC(2)C(3 )= 3.4, 3JHNC(6)C(s)= 5.7, 3JHNC(6)C(~, ) = 2.3 Hz), which unequiv-
ocally support the proposed structure.
In connection with the presence of a tetrahydropyridine ring, a low intensity peak of a
molecular ion (M+, 4% of maximum) is observed in the mass spectrum of compound II, the elem-
ental Composition of which was determined at high resolution and corresponded to C24H23N309.
Decay of the molecular ion takes along certain principal rgutes (scheme i): i) formation of
intense even-electron ions [M -- COC6H4N02] + and NO2CsH4CO T as a result of rupture of the
C(m)--C(Io) bond (routes A, B); 2) formation of an odd-electron ion [M -- HOCOC2Hs] + , probably
arising from conversion of the tetrahydro- to the dihydro-form (route C).
The combination of spectral data demonstrates that compound II has the structure 3,5-
diethoxycarbonyl-3-p-nitrobenzoyl-6-p-nitrophenyl-l,2,3,4-tetrahydropyridine.
In the formation of the tetrahydropyridine II, in distinction from the Hantzsch synthesis
of 1,4-dihydropyridines, cyclization takes place not at the expense of a carbonyl group of one

411
 Scheme i

11 -~COC6"4No~=P - ~ II 11

=a,?(loo) "~ ~ol(~e)

Note. Here and below: value of m/e (intensity, %).

or another molecule of the p-nitrobenzoyl ester but by way of introducing a second molecule
of formaldehyde into the reaction which forms a bond with nitrogen and with the carbon of the
active methylene group of the 8-ketoester. 0nly isolated cases are observed where, in condi-
tions of the Hantzsch synthesis, the reaction proceeds in such a direction, and 1,2,3,4-tetra-
hydropyridines with geminal substituents in position 3 are obtained.
Thus, on heating S-aminocroUononitrile with hexamethylenetetramine in acetic acid with
hydrochloric acid added, one obtains the tetrahydropyridine VI [4].

o. %...,,,,,j~ ~ o~ .......i"
... ~'~

.R R
%'1 Vll VIII

Reaction of 3-amino(3-methylamino)-5,5-dimethylcyclohex-l-ene-2-one with formaldehyde in

dilute hydrochloric acid led to the spirocompound VII [5]. The similar spirocompound VIII was
formed by the reaction of 1,3-indandione with amines [6].
Sodium borohydride reduces the keto group in II to an alcohol without affecting the re-
maining part of the molecule. In the IR spectrum of the reduced compound III a band appears
characteristic of hydroxyl (3460 cm-: in Nujol, shifted to 3610 cm -I in chloroform solution)
and two doublets are observed in the proton NMR spectrum at ~ = 6.14 ppm (OH) and 4.99 ppm
(CH) with coupling constant J = 4.6 Hz.
It was net possible to prepare derivatives of the tetrahydropyridine II with reagents
on the carbonyl groups and this may possibly be connected with the spatially hindered posi-
tion of the geminal substituents. The action of oxidizing agents on the tetrahydropyridine II
led to unexpected results. Brief (5 min) heating of II with sodium nitrite in acetic acid led
to the formation of an N-nitrosoderivative. Bands for the stretching vibrations of the NH
group were absent from the IR spectrum of the N-nitroso compound IV but three carbonyl bands
were clearly defined at 1734, 1720, and 1700 cm -z. The proton and carbon-13 NMR spectra
showed little change compared with those of compound II: the signal for the protons of the
2-CH2 group in the proton spectrum was shifted downfield and in the carbon-13 spectrum there
was a large shift of C(5). More prolonged action of sodium nitrite in acetic acid on compound
II gave a mixture of the nitroso derivative IV and 2,6-di(p-nitrophenyl)-3,5-diethoxycarbonyl-
pyridine (V), isolated as an individual compound by the action of other oxidizing agents (se-
lenium dioxide in acetonitrile or chloranil in benzene) on the tetrahydropyridine II. The py-
ridine V was also formed during an attempt at the acid hydrolysis of the ester groups of II
with hydrochloric acid in acetone at elevated temperature.
In the mass spectrum of the pyridine V a more intense peak, M + (12% of maximum), than in
the spectrum of II is observed which ~robably arises from the aromatic pyridine system. The
main primary breakdown processes of M ~ are the formation of even-electron ions as a result of
separation of the radicals C2H50 and C2Hs (scheme 2), analogous to those observed in complex
esters of o-substituted benzoic acid.

412
 Scheme 2

C2H500C. f 7 ~
.,COOCzH~-] ~" . C2HoOOC / -. .COO+

p-NO2CBH4 "~N/~C6H4N0~-p
C23HlgN~O8 C21H14N308
M+ 4 s 5 ( i 2 ) 436(17o)

I -c2"5~ I -%a~
C2H500C. ~,,sC-~-O HOOC ~ /COO +
9 . ,.: ...... 378(9) ~ -" N 0 2 ~ .~sz(,z)
p'~NO2C~H~. [" N !1 CelI4NO2-p p-NO2C6H4 ~ ~N ~ "CsH4NO2- p
4zo(9) 4oa(tsj

The formation of the pyridine V proceeds, in all probability, in such a way that the
tetrahydropyridine ring of II is opened and a new cyclization into dihydropyridine takes place
(with separation of a molecule of formaldehyde) which is then oxidized to the pyridine V. The
unusually facile breaking of a C--C bond in tetrahydropyridine apparently results from the
presence of the two geminal electron-accepting substituents on the carbon atom in position 3.

EXPERIMENTAL
Infrared spectra were run on a UR-20 instrument in Nujol. Proton NMR spectra were ob-
tained using a Bruker WH-90 (in DMSO-d6 with TMS reference) and carbon-13 spectra on a Bruker
WM 360 in CDCI3 against cyclohexane. Mass spectra were run on an AEI MS-50 spectrometer, using
direct introduction of the sample into the ion source with the ionization chamber at 250~ for
compound II and 150~ for compound V, elemental composition was determined at a resolution
~60,000.
3,5-Diethxycarbny-3-p-nitrbenzy-6-p-nitrpheny-,2,3,4-tetrahydrpyridine (II).
The ethyl ester of p-nitrobenzoylacetic acid (1.19 g, 5 mmoles), hexamethylenetetramine (1.05
g, 7.5 mmoles), and ammonium acetate (0195 g, 12 mmoles) were heated at boiling point in eth-
anol for i0 min. After cooling, the precipitate was recrystallized from ethanol. Yield, 0.4
g, 32%. Mp. 167-168~ IR spectrum (in Nujol): 3320 (N--H), 1735 (C----O),1689 cm -I ( ~ ) (in
chloroform): 3430 ((N--H), 1735 (C=O), 1690 cm -I (C=O). ZH NMR: 8.4-7.3 (8H, m, arom.), 7.14
(!H, t, J = 3.6 Hz, N-H), 4.19 (2H, q, J = 6.8 Hz, OCH2CH3), 3.62 (2H, q, J = 7.0 Hz, OCH2-
L ~ ) , 3.63 (2H, q, J = 12.2 Hz, 2-CH2), 2.96 (2H, q, J = 16.2 Hz, 4-CH2), 1.12 (3H, t, J =
6.8 Hz, OCH2C~3), 0.68 ppm (3H, t, J = 7.0 Hz, O C H 2 ~ 3 ) . Z3C NMR 195.0 (C(xo)), 171.2 (C(7)),
167.4 (Cr ~), 152.0 (C(63), 150.7 (C(4'')), 148.6 (C(4,)), 145.6 (C(z')), 141~2 (C(~")),
130.1 (C(2")), 129.9 (C(2')), i ~ . 5 (C(3")), 123.9 (C(3,)), 95.8 (C(s)), 63.1 (C(~2)), 60.1,
C(8)), 56 (C(3)), 47.5 (C(2)), 30.7 (C(4)), 14.4 (C(9,13)). Mass s~ectra, m/z (%)*: 315 (15)
85 (13), 76 (13), 59 (ii), 44 (22). Found: C 57.5, H 4.6, N 8.1%; M ~ 497.3032. Calculated for
C24H23N309: C 58.0, H 4.6, N 8.4%, M 497.3015.
3-(~-Hydr~xy-p-nitr~benzy~;-3,5-dieth~xycarb~ny~-6-p-nitr~pheny~-~,2,3,4-tetrahydr~pyri-
dine (III). Tetrahydropyridine (0.25 g, 0.5, mmoles) was dissolved in 50 ml methanol, 3 drops
conc. hydrochloric acid added and then sodium borohydride (0.14 g, 2 m~oles) added in portions
at room temperature. The mixture was left to stand overnight. It was then poured into water
and the precipitate recrystallized from ethanol. Yield 0.I g, 40%. mp 191-193~ IR spectrum
(in Nujol): 3460 (OH), 3360 (N-H), 1710 (C----O), 1650 cm -I (C---O): (in chloroform): 3610 (OH),
3440 (N--H), 1728 ( ~ ) , 1690 (cm -I (C=O). Proton NMR: 8.2-7.2 (8H, m, arom.), 6.86 (IH, t,
N-H), 6.14 (IH, d, j = 4.6 Hz, OH), 4.99 (1H, d, J = 4.6 Hz CH), 4.02 (2H, q, J = 6.8 Hz,
OCH2CH3), 3.66 (2H, q, J = 7.0 Hz, OCB2CH3), 3.36 (2H, q, J = 12.6 Hz, 2-CH2), 2.60 (2H, q,
J = 12.4 Hz, 4-CH2), i.i0 (3H, t, J = 6.8 Hz, OCH2(~13), 0.7 ppm (3H, t, J = 7.0 Hz, OCH2CB3).
Found: C 55.4, H 4.8, N 8.7%. Calculated for C24H=sN3Og.H20: C 55.7, H 5.3, N 8.1%.
3,5-Diethxycarbny-3-p-nitrbenzy--nitrs-6-p-nitrpheny-,2,3,4-tetrahydrpyri-
dine (IVy. Tetrahydropyridine II (0.25 g, 0.5 mmole) was dissolved in i0 ml glacial acetic
acid and an e~cess of sodium nitrite (0.3 g) added in portions and boiled 5 min. The precip-
itated solid was recrystallized from ethanol. Yield 0.15 g (56%), mp 140~ Gave positive

*Ion peaks with intensities >10% are shown, not indicated in scheme i.

413
Liebermann reaction for nltroso group. IR spectrum (in Nujol): 1734 (C.---------------1720
-=O), (C~), 1700
cm "~ (C=O). Proton NMR: 8.4-7,5 (SH, m, arom.), 4.41 (2H, q, J = 12.4 Hz, 2-CH2), 4.21 (2H,
q, J = 6.8 Hz, O&~I~CH3), 3.82 (2H, q, J = 7.0 Hz, 0~2CHs), 3.33 (2H, q, J = 12.4 Hz, 4-CH2),
1.08 (3H, t, J = 6.8 Hz, O ~ C H s ) , 0.73 ppm (3H, t, J = 7.0 Hz, OCH2CHs). Carbon-13 NMR:
193.0 (C(~o)), 169.9 (C(~)), 165.9 (C(1!)), 148.8 (C(6)), 147.5 (C(~")), 145.8 (C(,')), 141.2
(C(I,)), 139.9 (C(~"~), 131.1 (Cc~')) , 130.3 (C(="~), 126.9 (C(s")5, 124.7 (C(3'~) , lll.l
(C(,)), 63.8 (C(~))~ 61.8 (C(8))~ 56~0 (C(,)), 44.8 (C(~)); 32.0 (C(~)), 14.2 (~(~i), 14.0
~3)). Found: C 54.8, H 4.4, N 10.7%. Calculated for C~4H22N40~o: C 54.8, H 4.2, N 10.6%.
3,5-Diethoxycarbonyl-2,6-di(p-nitr0Phenyl)pyridine (V). A. Tetrahydropyridine II (0.5 g,
i mmole) was dissolved in 20 ml acetone containing i ml conc. hydrochloric acid and heated i h
at bp. The solvent was distilled off and the residue treated with methanol and recrystallized
from ethanol. Yield 0.3 g (65~), mp 195~ IR spectrum (in chloroform) 1728 cm -~ (C-~).
Proton NMR: 8.61 (IH, s, 4-H), 8.4,7.7 (8H, m, arom.), 4.43 (4H, q, OCH=CH3), i.ii (6H, t,
OCH=CB,). Carbon-13 NMR: 166.4 (C(7)), 158.9 (C(=)), 149.2 (C(~')), 145.8 (C(~')), 141.9
(C(~), 130.7 (C(2')) , 126.7 (C(3)), 123.9 (C s')), 62.9 (C 8)), 14.3 (C(9)) Mass spectrum,
m/z ~%)*: 405 (9~, 376 (9), 345 (6), 330 (9),(129 (24), 115((18), 73 (71), 65 (47), 60 (i00),
41 (94). Found: C 59.4, H 4.4, N 9.0%. Calculated for C23HIgN306: C 59.4, H 4.2, N 8.9%.
B. A mixture of 0.i g (0.2 mmole) tetrahydropyridine II and 0.05 g (0.2 mmole) chloranil
was heated at bp for i h in i0 ml benzene. The solution was cooled and washed with cold 10%
NaOH and with water. It was then dried over anhyd, sodium sulfate and the benzene evaporated.
The residue was crystallized from petroleum ether. Yield 0.05 g (55%).
C. A mixture of 0.2 g (0.4 mmole) of tetrahydropyridine II and 0.55 g (5 mmole) selenium
dioxide was heated at bp for 2 h in acetonltrlle. The reaction mixture was poured into water
and the product recrystallized from ethanol. Yield 0.05 g (25%).

*lon peaks with intensities >5% are shown which are not shown in Scheme 2.

LITERATURE CITED
I. B.S. Chekavichus, A. E. Sausln', R. M. Zolotoyabko, and G. Ya. Dubur, Izv. Akad. Nauk
LatvSSR, Set. Khim., No. I, 77 (1985).
2. Ch. Pigerol, N. N. Chandavoine, and P. de Cointet de Fillain, W. Ger. Patent 2,844,782;
Chem. Abs., 91, 58137v (1979).
3. W. Bremser, B. Franke, and A. Wagner, Chemical Shift Range in Carbon-13 NMR Spectroscopy,
Verlag Chemie, Basel (1982), p. 59.
4. D. Hofmann, E. M. Kosower, and K. Wallenfels, J. Am. Chem. Soc., 83, 3314 (1961).
5. J . V . Greenhill, J. Chem. Soc,, No. 15, 2699 (1971).
6. H. M~hrle, S. D~rnbrack, and H. Novak, Monatsh. Chem., 112, 1417 (1981).
7. J. Martens, K. Praefcke, and H. Schwartz, Z. Naturforsch, Teil B, 30b, 259 (1975).

414
SYNTHESIS AND REACTIONS OF 8-BENZYLIDENE-2-METHYL-5,6,7,8-
TETRAHYDROQUINOLINE-3-CARBOXYLIC ACID ARYLAMIDES

V. I. Sigova and M. E. Konshin UDC 547.831.9'832.5:542.957.2:543.422

Arylamides of 8-benzylidene-2-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylic acid

were obtained by treating the ethyl ester with dimagnesylamines. An example is giv-
en of their conversion to 8-benzylidene-2-styryl-5,6,7,8-tetrahydroquinoline-3-
carboxylic acid anilides and subsequent cyclization to l'oxo-l,2,3,4,6,7,8,9-octa-
hydrobenzo[b]-l,6-naphthyridines.

We have previously [i] reported 2-styrylnicotinic acid amides and their conversion to 5-
oxo-5,6,7,8-tetrahydro-l,6-naphthyridines. In order to extend this work it was of interest to
synthesize 2-styryl-5,6,7,8-tetrahydroquinoline-3-carboxylic acid arylamides. With this in
mind, the chosen starting materials were ethyl 2-styryl-5,6,7,8-tetrahydroquinoline-3-carboxy-
late and dimagnesylamines. Attempts to synthesize the former were made by heating ethyl 2-
methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate and benzaldehyde in acetic anhydride using
the method previously described [2] for 2-(m-nitrosryrul)-5,6,7,8-tetrahydroquinoline-3-carb-
oxylic acid esters. The PMR spectrum of the reaction product showed signals as follows (d in
ppm): 1.17 (3H, carbethoxy CH3), 1.5 (2H, CH2 at position 6), 2.5 (4H, CH2 at 5 and 7), 2.8
(3H, CH3 at 2), 4.1 (carbethoxy CH=), and 7.6 (7H, benzene and pyridine rings and benzylidene
CH). Thus the compound obtained was ethyl 8-benzylidene-2-methyl-5,6,7,8-tetrahydroquinoline-
3-carboxylate (I).

I I I .__5+.,,:~H% . :~. . . . . R%..+m+,~gm-~

[ +] ! t N.~+t. ell ~ (CI-[+CO)~.O -+~" + ...... :...... --':-t~
. 9 H N" " ,+,+II 3

i'll('+ ll~,
! 0

i ; -+ . . . . pp~ ......
-+1 . +L. . . . oM+ [ . , - + + +,,
x'[i~ N "(H~ ' + ""'[I .... " N " CH-~7tIC'~,It a ""li "
('H( 6[~,, I-'HCr 1|,. I'llCF It ~
Ila e Ill. I%

Treatment of I with arylaminomagnesium halides gave 8-benzylidene-2-methyl,5,6,7,8-tetra-

hydroquinoline-3-carboxylic acid arylamides (lla-e) in 80-90% yields (Table I).
Compounds lla-e were colorless, crystalline materials soluble in hot alcohol and dimethyl
sulfoxide but insoluble in water and ether. The PMR spectrum of anilide lla showed the fol-
lowing signals (6 in ppm): 1.3 and 2.3 (6H, polymethylenes), 2.7 (3H, CHs), and 7.6 (12H, ben-
zene and pyridine rings and benzylidene CH). A low field signal was also observed at 10.7 ppm
due to the amido NH proton. The UV spectrum of lla showed band maxima at 230, 275 and 330 nm.
Heating arylamides lla,b with benzaldehyde in DMF in the presence of benzoylchloride gave
8-benzylidene-2-styryl-5,6,7,8-tetrahydroquinoline-3-carboxylic acid arylamides (llla,b). Ilia
underwent cyclization when heated with polyphosphoric acid (PPA) to give 6-benzylidene-l-oxo-
2,3-diphenyl-l,2,3,4,6,7,8,9-octahydrobenzo-[b]-l,6-naphthyridine (IV). The IR spectrum of IV
shows the presence of a ~ absorption band at 1650 cm -I and absence of the amide N-H b a n d
seen in the arylamide llla. The PMR spectrum of IV showed the following signals (8 in ppm):
1.85, 2.8 (6H, protons at C?, Cs and C9), 3.67 (2H, H--C4), 5.1 (IH, H-Ca), 8.0 (IH, H-CIo),
and a multiplet centered at 7.2 ppm (16H, protons of the aromatic rings and the benzylidene
CH).

Perm State Pharmaceutical Instiutte, Perm 614600. Translated from Khimiya Geterotsik-
licheskikh Soedinenii, No. 4, pp. 506-508. April, 1986. Original article submitted January
3, 1985.

0009-3122/86/2204-0415512.50 O 1986 Plenum Publishing Corporation 415

 TABLE i, 2-Methyl-8-benzylidene-5,6,7,8-tetrahydroquinoline-
3-carboxylic Acid Anilides (lla-e)

Com-I rap. *C .Found, % Empirical Calculated. % Yield,%

pound I R formula / Z ] ,(B,., ,
C H(Br) N
k
Ira H 209--210 80.01 6,2 7,9 C24H2~N=O I80,0 6,2 I 7,9 85
lib m-CH~ 200--201 81,3] 6.4 7,9 C2d~.~4N~O ] 81,5] 6,5 I 7,6 81
lie p-CH8 218-219,5 81,4] 6,5 7,6 CzM21N=O ]81,5 6,5 [ 7,t} 81)
lid p-CH~O 235--236 78,0 ] 6,6 7,5 C,,,,I~I~4N~O.. [ 7'8,1 [ 6,3 [ 7,3 !;0
lie p-Br 232--232,5 -- /(18,3) 6,7 Ca'H"BrN"O l - I(lSS~l 65 83

EXPERIMENTAL
IR spectra were recorded on a UR-20 instrument (GDR) in paraffin oil and PMR spectra
on an RYa-2310 (60 MHz) with HMDS as internal standard. UV spectra were obtained with an SF-
16 using ethanol solvent at concentrations of 10 -5 M.
Ethyl 8-benzylidene--2-methyi-5,6,7,8-tetrahydroquinoline-3-carboxylate (I). A mixture
of ethyl 2-methyl-5,6,7,8-tetrahydroquinoline-3-carboxylate [3] (1.4 g, 4.5 mmoles) and benz-
aldehyde (0.61 g, 5.8 mmoles) in acetic anhydride (i ml) were heated in a metal bath at 130~
for 3 h. After cooling the product was triturated with a small amount of ether, the precip-
itate filtered off and crystallized from ethanol. The yield was 0.84 g (60%) with mp 121-1220C.
Found: C 78.3; H 6.7; N 4.4%. C2oH2,N02. Calculated: C 78.2; H 6.8; N 4.6%.
8-Benzylidene-2-methyl-5,6,7,8ztetrahydroquin01ine-3-carboxylic acid Arylamides (!la-e~
Table i). Ethyl 8-benzylidene-2-methyl,5,6,7,8-tetrahydroquinoline-3-carboxylate (60 mmoles)
in anhydrous ether (20 ml) was added to the dimagnesylamine (previously prepared from the cor-
responding arylamine (90 mmoles) and ethylmagnesium bromide (180 mmoles) in ether). The mix-
ture was heated for 0.5 h and then decomposed using saturated ammonium chloride. The ether
layer was separated, steam distilled and the residue crystallized from ethanol.
8[Benzylidene-2-styryl-5,6,7,8-tetrahydroquinoline-3-carboxylic Acid Anilide (Ilia). A
solution containing lla (0.5 g, 1.4 mmoles), benzoyl chloride (0.3 g, 2.1 mmoles), freshly
distilled benzaldehyde (0.2 g, 1.8 mmoles) and DMF (5 ml) was heated for 16 h at 185-190~
Decomposition with conc. HCI and steam distillation yielded hydrolyzed benzoic acid and benz-
aldehyde and the residue in the distillation flask was recrystallized from ethanol. The yield
was 0.37 g (60%) with mp 255-257~ Found: C 84.1; H 6.0; N 6.2%. CaIH2~N20. Calculated:
C 84.2; H 5.9; N 6.1%. Compound lllb was obtained analogously in 52% yield, mp 228-230~
(ethanol). Found: C 84.3; H 6.0; N 6.1%. C32H28N20. Calculated: C 84.2; H 6.1; N 6.1%.
6-Benzy~idene-~-~x~-2,3-dipheny~-~,2,3,4,6,7,8,9-~ctahydr~benz~[b]-~,6-naphthyridine
(IV). A mixture of Ilia (0.12 g mm01e) and polyphosphoric acid (containing 80-84% P2Os) were
heated at 135~ for 3 h. The product was poured into iced water (30 ml), the acid layer neu-
tralized (Na2CO3) and the resulting solid crystallized from ethanol. The yield was 0.i g (90%)
with mp 178-180~ Found: C 84.3; H 5.7~ N 6.1%. CsIHa6N=O. Calculated: 84.2; H 5.9; N 6.3%.

LITERATURE CITED
1. V. I. Sigova and M. E' Konshin, Khim. Geterotsikl. Soedin., No. 6, 783 (1984).
2. U. Basu, Annalen, 530, 131 (1937).
3. W. Wunderlich, J. Prakt. Chem., 2, 302 (1955).

416
PREPARATION OF DERIVATIVES OF 1,2-DIHYDRO- AND 1,2,3,6-TETRAHYDRO-
PYRAZINONES FROM ACYLATED 1,2-HYDROXYLAMINO KETONES

T. I. Reznikova, A. Ya. Tikhonov, UDC 547.288.4'298.71'861.6

and L. B. Volodarskii

N-(2-Oxoalkyl)-2-chloroacetohydroxamic acids were obtained by acylation of 1,2-

hydroxylamino ketones with chloroacetyl chloride. Their reaction with urotropin
and sodium azide gives urotropinium salts and acetoxyhydroxamic acid azides, l-
Hydroxy-2-oxo-l,2,3,~-tetrahydropyrazines were obtained by treating N-(2-oxoal-
kyl)-2-chloroacetohydroxyamic acids with ammonia, and also by reacting the uro-
tropinium salts and azides of acetohydroxamic acids with hydrochloric acid and
triphenylphosphine, respectively. The reaction of N-(l-methyl-2-oxo-2-phenyl-
ethyl)-2-chloroacetohydroxamic acid with urotropin in an acid medium leads to
the formation of 6-methyl-2-oxo-5-phenyl-l,2-dihydropyrazine.

Acylation of 1,2-hydroxylaminooximes with a hydroxylamino group attached to a tertiary

carbon atom by ~-haloacid chlorides leads to N- and O-acylation products at the hydroxylamino
group, while treatment with bases of the N-acylation products -- N-(2-hydroximinoalkyl)-2-halo-
alkanohydroxamic acids -- depending on conditions, leads to l-hydroxy-2-oxo-l,2,3,6- or l-
hydroxy-2-oxo-l,2,5,6-tetrahydropyrazine 4-oxides [i]. In the present work, we examined the
acylation of 1,2-hydroxylamino ketones Ia'c with the hydroxylamino group attached to tertiary
(Ia, b) and secondary (Ic) carbon atoms, in order to obtain the N-acylation products -- N-(2-
oxoalkyl)-2-chloroacetohydroxamic acids II -- followed by their transformation into pyrazinone
derivatives which do not contain an N-oxide group. The pyrazine derivatives containing a hy-
droxamic acid fragment attract attention of research workers due to the biological activity
of compounds in this series [2].
Acylation of 1,2-hydroxylamino ketones la-c by chloroacetyl chloride in THF leads to N-
(2-oxoalkyl)-2-chloroacetohydroxamic acids IIa-c, in yields of 38-47%. During the acylation
of Ib, as well as IIb, 2-methyl-l-phenyl-2-chloroacetoxyamino-l-propanone (III), a product of
0-acylation of the hydroxylamino group, was also isolated in a yield of 40%. In the IR spectra
of hydroxamic acids IIa-c, absorption bands are observed in the 1630-1655 and 1680-1730 cm -I
regions (Table i), corresponding to the stretching vibrations of the C=O bond of the hydrox-
amic and ketonic groups, respectively. In the IR spectrum of the O-acylation product III (Ta-
ble i), besides the stretching vibration band of the conjugated C=O bond at 1690 cm -I, a band
at 1770 cm -I is also observed, corresponding to the stretching vibrations of the C---Obond of the
the chloroacetoxyamino group (cf. [i]).

CII.~ CH 3 CH 3
i I CICH ~COCI J
R --C--C--NIIOH .......... R I- -C ---(~-N C-CH~CI + C~H5 ~ --~" --NH 0 - C -~CH2CI
' ~ II , , H

la- C Ila-c lli

I, I1 a RI=R~=CH3; b R1=C~H~, R~=CH3; c R'=C6Hs, R2--H

Several methods are known for the cyclization of 2-haloacylamino ketone derivatives in-
cluding those using the substitution reaction of the chlorine atom by the amino- [3, 4], azido-
[5, 6], and hexamethyleneamino groups [7, 8]. During treatment of solutions of compounds IIa,
b in dioxane by an aqueous alcoholic solution of ammonia under the conditions of [4], l-hy-
droxy-2-oxo-l,2,3,6-tetrahydropyrazines (IVa,b) were obtained in yields of 8 and 17%, respec-
tively. Under similar conditions, chloroacetamide was obtained from IIc in a yield of 60%.

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Novosibirsk 630090. Novosibirsk Branch, All-Union Scientific-Research Institute of Chem-
ical Plant Protection Agents, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 4, pp. 509-513, April, 1986. Original article submitted January 17, 1985.

0009-3122/86/2204-0417512.50 9 1986 Plenum Publishing Corporation 417

 TABLE i. Spectral Characteristics of Compounds II~VI,
VIII
IUV spee-
Com- IR spectrum, I trum, PMR spectrum, ppm U, Hz)"
pound e m - I (in Kgr) [ ~-max,
nm (log r I@ I0 J CH, CH~ O H

lla 1635, 1655, 1730 ..... 2,02 s 1,34, s 4,37, s 9,23, s

(C=O)
llb 1630, 1680 (C~,O) 2,14 q,t,12) 7,3--,,7,6; 1,51, s 4,22,s 9,57, s
7,9--8,2, m
lie 163(}, 1650, 1700 244 {4,09) 7,5--7,7; 6,14,q I 1,57, d 4,37, s
(C=O) 7,,q--8, I, m (7,5) (7,5)
llI (B CCI,,) 1690, 246 {4.17) 7,2--7,6; 1,44, s 3,89, s
!1770 (C=:O) 7,8--8,2,m
I~Va 1680 (C----O) ' 2,07, t 1,51, s 4,19, s
(I,5) (1,5}
IVb 1660 (C=O) 235 p 7,39, s 1,42, s 4,44, s 9,71,
(~.60) bs
v a t 1660, 1730 (C=O) ,~ [ 2,23~ s 1,40, s 4,09,s
v b ? 1660, 1685 (C=-O) 242,,t,00) 7,4--7,7; 1,63, s 3,92, s
tV1 1700 (C=O)
I 7,9--8,1, m
257 (4,42) 1 7,31 ,s I 2,25, s 7,77,
V l l l a 1620, 1645, 1725 342 (4,04) I 1,98, s 1,24, S 4,02, s
(C=O), 2120, [
'2150 (N~) ' [
V l l l b 1630, 1695 IC=O), 1245 (4A7) 7,3--7,5; 1,44, s 3,97, s 10,34,s
2130 (N,~) 7,8---8,0, m
*The PMR spectra of IVb, VI, VIIIa,b were recorded in (CD3)2SO,
IIa,b in (CDs)2C0, IIc in CDCIs, Va,b in D20, III in CCI~, IVa
in CD3OD.
%In the PMR spectrum, the sighals of the urotropinium fragment
for Va are observed at: 4,65 (6H, s, CH2), 5.37 ppm (6H, s, CH2);
for Vb, 4.49 (6H, hr. s, CH2), 4.95 ppm (6H, s, CH2)
SA methine proton signal.

Data on the IR, UV, and PMR spectra of IVa,b derivatives (Table i) are in agreement with
the structure of l-hydroxy-2-oxo-l,2,3,6-tetrahydropyrazines. Thus, for example, in the PMR
spectrum, the spin-spin interaction (J = 1.5 Hz) between the methyl group protons in position
5 and methylene protons in position 3 of the heterocyclic ring in IVa is possible only for the
cyclic structure.
Because of the low yields of pyrazines IVa,b, which is possibly due to a cleavage of the
hydroxy-amide bond in compounds IIa,b during their tmeatment with ammonia, urotropin was used
as the aminating agent (cf. [7-9]). The reaction of compounds IIa,b with urotropin in aceto-
nitrile leads to urotropinium salts Va,b. which are readily soluble in water and polar organic
solvents. Treatment of salts Va,b with an alcoholic solution of hydrochloric acid gives IVa,b
in yields of i0 and 71%, respectively.

ca~ c H~
l + . (CH2)6N 4 NaN 3 i
]R~ .-C--C---N.-..C--CHSq~{CH,) 6 .4- . . . . . . I l a , b - ~ R ~ --C--C--N--C~-CHzN ~
il i i II " ~ !I [ l [I
O CH 3 OH O CI-" . : 0 CH 3 OH O

va,b ----~ '1,'1 Nrl~ ,x,) S J ~an aob

Ra N

c.,J i
C H 3" "N' \0
OH
wa,b

A urotropinium salt could not be obtained from compound IIc under the conditions described
above. At the same time, heating IIc with urotropin in the presence of hydrochloric acid leads
to 6-methyl-2-oxo-5-phenyl-l,2-dihydropyrazine (VI) [i0]. The reaction probably proceeds with
the formation of an intermediate tetrahydropyrazinone VII, whose dehydration under the reac-
tion conditions leads to VI. (Formula, following page, below table.)
The formation of pyrazinones IVa,b could be expected from 2-azidoacetohydroxamic acids
VIIIa,b (cf. [5, 6]), which were obtained by the reaction of IIa,b with sodium azide in DMFA.

418
 TABLE 2. Characteristics of Synthesized Compounds II-VI, VIII
L i

Gom- mp,* Found. ~ [ Empirical Calculated, %

pound "C I formula
C H CI N [ G H CI N

I
lla 135--137 43,6 6,4 19,0 ~[42 CrHt2CINOa 43,4 6,3 18,3 7,2
llb 145--147 56,4 5,7 14,0 C~Ffj4C NOa ~56,4 5,5 13,9 5,5
lie 54,9 4,9 14,6 5,7 I Cut-II2CINO,~ 54,7 5,0 14,7 5,8
III 56,2 5,5 14,2 5,3 I Cj~HI4CINOa 56,4 5,5 13,9 5,5
lVa 130--132 54,0 7,8 17,7 CzHI~N202 53,8 7,7 17,9
l!Vb 156--158 66,5 6,5 12,8 C~2H~4N202 66,0 6,5 12,8
Ve 190--192 46,2 7,4 172 21,2 ClaH_o4ClNsOa !46,8 7,3 1;,6 21,0
(dec)
\/a 162--164 54,1 6,7 8,6 17,2 I CjsH~CINsOa 154,6 6,6 9,0 17,7
(dec)
Vl' 252--254 71,5 5,4 15,t I C.HIoN20 I 71,0 5,4 15,1
~Vllla 109--111 41,5 5,8 28,0 CTHIgN4Oa '42,0 6,0 28,0
Vlllb 122--124 55,0 5,4 21,4 CI2HI4N4Oa 55,0 5,4 21,4
*Compounds [Ia from alcohol, IIb,c, IVa,b, VIIIa,b from ethyl
acetate, VI from methanol, Va,b reprecipitated from alcohol
by ether.

~ Z~176 L L . o
~!I Vl

Treatment of compounds VIIIa,b with triphenylphosphine in THF leads to IVa,b in yields of 79

and 53%, respectively.

EXPERIMENTAL
The IR spectra were run on a UR-20 spectrophotometer and the UV spectra on a Specord UV-
vis spectrometer in alcohol. The PMR spectra were recorded on a Varian A-56-60A spectrometer
with HMDS and tert-butanol (aqueous solutions) as internal standard. The IR and UV spectra
of compounds IIa-c, IVb, Va,b, and VI are given in [ii].
The characteristics of compounds synthesized are given in Tables 1 and 2.
N-(l,l-Dimethyl-2-oxo-2-phenylethyl)-2-chloroacetohydroxamic Acid (IIb) and 2-Methyl-l-
phenyl-2-chloroacetoxyamino-l-propan0ne (III). A solution of 4.7 ml (62 manoles) of chloro-
acetyl chloride in 45 ml of THF is added in the course of 30 min, with stirring and cooling
on an ice bath, to a solution of i0 g (56 mmoles) of Ib [12] and 9.4 ml (67 mmoles) of tri-
ethylamine in 170 ml of THF. The reaction mixture is stirred at room temperature for 2 h, and
filtered. The filtrate is evaporated and the residue is treated with ethyl acetate. The solu-
tion is washed with water, dried over magnesium sulfate, and evaporated. The residue is ground
in a mixture of ether and petroleum ether, and the precipitate is filtered. Yield: 6.7 g (47%)
of IIb. From the filtrate, by chromatography on silica gel (eluent, chloroform), 5.7 g (40%)
of III are isolated.
N-(l,l-Dimethyl-2-oxopropyl)-2-chloroacetohydroxamic acid (IIa) is obtained in a similar
way in a yield of 38% from 1,2-hydroxylamino ketone hydrochloride (Ia.HCI) [13], using a two-
fold excess of triethylamine.
N-(l-Methyl-2-oxo-2-phenylethyl)-2-chloroacetohydroxamic Acid (IIc). A 7.62 g portion
(55 mmoles) of K2COa and 20 ml of water are added to a solution of !0 g (61 mmoles) of Ic
[12] in 300 ml of ether, and then, with stirring and cooling, a solution of 4.6 ml (61 mmoles)
of chloroacetyl chloride in 40 ml of ether is added in the course of 1 h. The mixture is
stirred at room temperature for 1 h. The ether layer is separated, washed with 0.i N HCI, wa-
ter, dried over magnesium sulfate, and evaporate. The residue is ground in a mixture of ether
and hexane, and the precipitate is filtered to yield 6.20 g (42%) of IIc.
N-(l,l-Dimethyl-2-oxopropyl)-2-urotropinium-acetohydroxamic acid chloride (Va). Urotropin
(1.57 g, 11.2 mmoles) is added in portions to a solution of 1.8 g (9.3 mm01es) of IIa in 150
ml of dry acetonitrile, and the mixture is stirred for 20 h. The precipitate that separates
is filtered. Yield, 2.66 g (89%) of Va.

419
 N-(l,l-Dimethyl-2-oxo-2-phenylethyl)-2-urotropiniumacetohydroxamic Acid Chloride (Vb) is
obtained in a similar way, in a yield of 92%.
N-(l,l-Dimethyl-2-oxopropyl)-2-azidoacetohydroxamic Acid (Vllla). A mixture of 4.4 g
(23 mmoles) of lla and 1.62 g (25 mmoles) of sodium azide in 40 ml of dry DMFA is stirred at
room temperature for 24 h. The sodium chloride precipitate is filtered and DMFA is distilled
in vacuo. The residue is ground in ether, the precipitate is filtered to yield 2.20 g (50%)
of Villa.
N-(l,l-Dimethyl-2-oxo-2-phenylethyl)-2-azidoacetohydroxamic Acid (Vlllb). A mixture of
7.43 g (28 mmoles) of lib and 2.08 g (32 mmoles) of sodium azide in 50 mi of dry DMFA is
stirred for 24 h at room temperature. The sodium chloride precipitate is filtered and DMFA
is distilled in vacuo The residue is treated with ether, the ether solution is washed with
water, dried over magnesium sulfate, and evaporated. The residue is ground in ether, and the
precipitate is filtered. Yield, 4 g (53%) of Vlllb.
l-Hydroxy-5,6,6-trimethyl-2-oxo-l,2,3,6-tetrahydropyrazine (IVa). A. A solution of
3.9 ml of 25% aqueous ammonia in 5 ml of alcohol is added to a solution of 0.5 g (2.6 mmoles)
of lla in i0 ml of dioxane, and the mixture is left to stand for 3 days. The solvent is evap-
orated, and from the residue 0.03 g (8%) of IVa is isolated by chromatography on silica gel
(eluent, a 20:1 chloroform--alcohol mixture).
B. A solution of 0.3 g (0.9 mmole) of Va in i0 ml of ethanol and i0 ml of 0.i N HCI is
allowed to stand for 24 h. The solvent is evaporated and 0.02 g (10%) of IVa is isolated in a
similar way as in experiment A.
C. Triphenylphosphine (0.87 g, 3 . 3 m moles) is added in portions to a solution of 0.6 g
(3 mmoles) of Vllla in i0 ml of dry THF, and the mixture is allowed to stand for 24 h. The
solvent is evaporated and 0.37 g (79%) of IVa 'is isolated in a similar way as in experiment A.
l-Hydroxy-6,6-dimethyl-2-oxo-6-phenyl-l~2,3,6rtetrahydropyrazine (IVb). A. A solution
of 2.9 ml of 25% aqueous ammonia in 5 ml of alcohol is added to a solution of 0.50 g (1.9 m-
mole) of lib in i0 ml of dioxane, and the mixture is allowed to stand for 2 days. Alcohol and
dioxane are evaporated and the residue is treated by 3 ml of water, and extracted by ethyl ace-
tate. The ethyl acetate solution is dried over magnesium sulfate, evaporated, and the resi-
due is ground with ether. The precipitate is filtered to yield 0.07 g (17%) of IVb.
B. A solution of 7.65 g (19 mmoles) of Vb in i00 ml of ethanol and I00 ml of 0.i N HCI
is allowed to stand for 24 h. The alcohol is evaporated, and the precipitate that separates
from water is filtered to yield 2.5 g (59%) of IVb. An additional amount of 0.5 g (12%) of
IVb is isolated from the filtrate.
C. Compound IVb is obtained from azide Vlllb in a similar way as IVa by the method C,
yield 53%.
6-Methyl-2-oxo-5-phenyl-l,2-dihydropyrazine (VI). A solution of 0.5 g (2.1 mmoles) of llc,
1.6 ml of 2 N HCI and 0.5 g (3.6 mmoles) of urotropin in 7 ml of methanol is boiled for I0 h.
The precipitate that separates on cooling, is filtered to yield 0.14 g (36%) of VI.

LITERATURE CITED
i. A. Ya. Tikhonov, L. B. Volodarskii, and N. V. Belova, Khim. Geterotsikl. Soedin., No. i,
115 (1984).
2. G. W. H. Cheeseman and E. S. G. Werstiuk, in: Advances in Heterocyclic Chemistry, Vol.
14, A. R. Karitzky and A. J. Boulton, editors, Acad. Press, N.Y.-~ondon (1972), p. 99.
3. T. D. Harris, T. J. Reily, and J. A. DelPrincipe, J. Heterocycl. Chem., 18, 423 (1981).
4. K. Hirai, T. Ishiba, H. Sugimoto,and T. Fujishita, J. Org. Chem., 46, 4489 (1981).
5 J. Acrell, E. Galeazi, and J.Muchowski, Canad. J. Chem., 57, 2696 (1979).
6 R. J. Fryer, W. Leimgruber, and E. J. Trybulski, J. Med. Chem., __25, 1050 (1982).
7 K. Hirai, H. Sugimoto, andT. Ishiba, J. Org. tChem., 45, 253 (1980).
8 T. Kova~, B. Belin, T. Fajdiga, and VD Sunjic, J. He~eerocycl. Chem., 18, 59 (1981).
9 N. Blazevlc, D. Kolbah, B. Belin, V. Sunj IC , and F. Kaifez, Synthesis, No. 3, 161 (1979)
I0 G. Alvernhe, A. Laurent, and A. Masroua, Tetrahedron. Lett., No. ii, 1153 (1983).
ii Atlas of Spectra of Aromatic and Heterocyclic Compounds [in Russian], No. 26, V. A.
Koptyug, Editor, Izd-vo Novosibirsk. In-ta Organ. Khim., Sib. Otd. Akad. Nauk SSSR, Novo-
sibirsk (1983).

420
12. L. V. Volodarskii and T. K. Sevast'yanova, Zh. Org. Khim., ~, 1687 (1971).
13. T. K. Sevast'yanova and L. B. Volodarskii, Izv. Akad. Nauk SSSR, Ser. Khim., No. i0,
2339 (1972).

SYNTHESIS OF I-ALKYL(ARALKYL)-4-ACYL-2-PIPERAZINONES

Yu. S. Tsizin, N. L. Sergovskaya, UDC 547.861.6.07:542.953

and S. A. Chernyak

l-Alkyl(aralkyl)-4-acyl-2-piperazinones are formed in high yields during selective

acy!ation of N-monosubstituted ethylenediamines by benzoyl and cyclohexylcarbonyl
chlorides in the presence of pyridine hydrochloride and treatment of the reaction
products with chloroacetyl chloride in the presence of potassium tert-butylate.

Among 2-piperazinones, having different biological activities [1-3], the little inves-
tigated 4-acyl derivatives are of special interest, since the 4-acyl-2-piperazinone fragment
is included in the structure of a new anthelmintic prasiquantel (I) [4] with a broad spectrum
of activity. The aim of the present work was to find suitable method for the synthesis of
l-alkyl(aralkyl)-4-acyl-2-piperazinones (IIa-g). Compounds IIa-g were selected as the object
products, since they contain the same functional groups as prasiquantel, and have a similar
lyophilicity.
In the course of the investigation~ we studied schemes of synthesis of compound IIa-g,
based on the use of available N-monosubstituted ethylenediamines IIIa-c.

R~ RI
ill !I o Rz .
I
.N. //O R z ~.
I
NH
i [
r
i I
N
I
~N ~: -NH 2
..... CO ~OR 5
l na-h ]lla-C

l l a - c , f Ilia RI=PhCHe, IId,e Illb RI=PhCH~CH2, llfg, Illc Rt=Et; l l a - e , h

llla,bR~=l-l, llf,g, l l l e R~=Ph;lla,d,fR~=ph, b Ra=4-NOeC6H4, e , e , g R3=cyclohoxyl
h R3=CICH2

Taking compnund Ilia as an =xample, we first studied the variant of the synthesis of
2-piperazinones, which gives the formation of a hetero ring by the cyclization of the bis-
ch!oroacetyl derivative IV by the action of a strong base, and the subsequent elimination
of the chloroacetyl group.

~H2Ph ?H2Ph ~H2Ph

NCOCH.C! ~"N.~:O [/N:O
Ilia ~ ~/| ----a,- | .... ~ "HCI ~ Ha.b
k~NHCOCH~CI ~'N/ ~'N/
l H
COCH2C1
v," Ix$ vl

PhCH2NHCH2CH2NHCH2COO$1" .2 HCl
V

During the acylation of compound IIIa by chloroacetyl chloride, the derivative IV is ob-
tained in high yield. By the action of potassium tert-butylate, this converts into pipera-
zinone IIh in a yield of 37% only. Even mild acidic hydrolysis of compound IIh results not

E. I. Martsinovskii Institute of Medicinal Parasitology and Tropical Medicine, Moscow

119830. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 514-517, April,
1986. Original article submitted January 9, 1985.

0009-3122/86/2204-0421512.50 9 1986 Plenum Publishing Corporation 421

only in splitting of the chloroacetyl group, but also in opening of the piperazine ring. As
the result, amino acid V is formed~ which has been previously obtained by another method [5].
Because of this, specific methods were used for the removal of the chloroacetyl group: action
of o-phenylenediamine [6] or thiourea [7] on compound llh. In both cases pyrazinone VI was ob-
tained from compound llh in a yield not higher than 55-60%, since the isolation of the reac-
tion products is difficult, due to the presence of difficultly separable impurities. The acyl-
ation of compound llh by benzoyl of 4-nitrobenzoyl chloride'leads to compounds lla,b.
Better results were obtained by the alternative route also based on the use of substitu-
ted ethvlenediamines llla-c. The latter contain both a primary and secondary amino group, dif-
fering in the degree of steric hindrance. It could be assumed that the less hindered primary
amino group will be preferentially acylated. However, only in the case of compound lllc, where
the differences in the environment of the amino groups are in particular considerable, it is
possible under normal conditions (see the Experimental section) to acylate selectively the
primary group and to obtain compounds Vlla,b. N-Benzyl-N,N'-dibenzoylethylenediamine (VIII)
is formed under these conditions from equimolar amounts of ethylene-diamine Ilia and benzoyl
chloride, and ~50% of the initial compound Ilia, which does not enter the reaction, is left.
Monoaceylation of compounds llla,b could be accomplished using a method previously proposed
for l-aminomethyl-l,2,3,4-tetrahydroisoquinoline [8]. The reaction of ethylenediamines llla,b
with benzoyl or cyclohexylcarbonyl chloride in acetonitrile in the presence of pyridine hydro-
chloride leads to compounds Vllc-f in high yields

RI R~

llI a - c - - - - I , , - -
.., NH f. 2 I ]
---~-- iI;a)c= h
"'NHCOR~ , NHCOR

Vll a-f

- Vllla,bR'=Et, c,d RI=PhCH,2, e,f R~=PhCH2CI-I=; a,b R~=P~I, c-f R~=H; a,d,e
[~= Ph,b,c,f R ~= cyclohexyl

The secondary amino group becomes acylated by the action of chloroacetyl chloride on
acetylethylenediamines Vlla-f in the presence of potassium tert-butylate, and this is followed
by cyclization to give piperazinones lla,c-g. The 4-acyl-2-piperazinones lla-g thus synthe-
sized are colorless crystalline substances, an exception being compound llh, which is a vis-
cous liquid. The structure of the compounds was confirmed by elemental analysis and IR spec-
troscopy (Table i).
Thus, the selective acylation of N-monosubstituted ethylenediamines and subsequent reac-
tion with chloroacetyl chloride in the presence of potassium tert-butylate represents a con-
venient general method for the synthesis of 4-acyl-2-piperazinones.

EXPERIMENTAL
The IR spectra of the compounds synthesized were run on a UR-20 spectrophotometer in KBr
tablets. The course of the reactions and the purity of the products obtained controlled by
TLC on Silufol plates in 3:1 ether--acetone system.
Compounds llla,b were obtained from ethylenediamine and the corresponding aralkyl chlor-
ide by the method in [9], and compound lllc by reducing ~-ethylaminobenzylcyanide with lithi-
um aluminum hydride according to a method described in [i0].
N-Benzyl-N,N'-bis(chloroacetyl)ethylenediamine (IV). A solution of 15.5 ml (200 mmoles)
of chloroacetyl chloride in 10 ml of methylene chloride is added in the course of 20 min, at
0~ to a mixture of 13.5 g (90 mmoles) of compound Ilia and 30 g (280 mmoles) of Na2CO3 in
i00 ml of anhydrous methylene chloride. The mixture is stirred for another 40 min, the pre-
cipitate is filtered, and washed with i00 ml of methylene chloride. The filtrates are com-
bined and evaporated in vacuo. Yield, 25.2 g ~92%) of compound IV in the form of a pale-yellow
oil. IR spectrum: 3330 (NH), 1665 (CO), 1645 cm -I (sh, CO). Compound IV is used in the follow-
ing stage without additional purification.
l-Benzyl-4-chloroacetyl-2-piperazinone (llh). A solution of potassium tert-butylate, pre-
pared from 0.274 (7 mmoles) of potassium and i0 ml of tert-butanol, is added in the course of
20 min to a solution of 2.02 g (7 mmoles) of compound IV in 20 ml of anhydrous tert-butanol.
The mixture is stirred for another 20 min, i00 ml of water are added, and the mixture is ex-

422
 TABLE I. l-Alkyl ( a r a l k ~l)-4'acyl-2-piperazinones
at

Com- "C IR spectrum, Found. % Empirical Calculated,

% IYield,
pound mp,* c m - I UC0

!
IIa 101--t0211624, 1660 i 73,216,0[ 97 CIsHjsN~O2 73,5 6,21 9,5 71 (82)t
IIb 113--11411640, 1660 63,715 11 12:2 C18HIsN304 63,515,31 12,4 187
IIc 87=-88 I 1632 71,5t7,6 9,0 C~sH24N20~ 72,018,11 9,3 165
lid 80--82 I 1638, 1650 sh i 74,117,0 C~gH2oN202 74216,61 9,1 162
IIe t16--1181 1630, 1642 sh
Ilf
72,2,,1 ! g CjgHmN~O2 72,618,31 8,9 167
7~--74 I1635, 1660 74,216,9 9,0 C19H2oN202 74,016,6[ 9,1 166
IIg 152--15411630, 1655 br 72,318,21 9,0 C19H~N~O2 72,618,3] "8,9 164
IIh 1662 (13,7i CI3HIsCIN20~ ' (13,3) 135
*Com ~ouffds IIa,c were recrystallized from an acetone--petrole-
um ether mixture, IIb from alcohol, IId-g from an ethyl ace-
tate--hexane mixture.
tPrepared from compound VI and benzoyl chloride.

tracted by chloroform. The organic layer is separated, washed with water, 5% HCI, and water
again, and dried over MgSO4. The solvent is distilled off, and the residue is chromatographed
on a column with silica gel (eluent, chloroform) to yield 0.65 g (35%) of compound IIh.
N-(2-Benzylaminoethyl)glycine Dihydrochloride (V). A 1.03 g portion (3.9 mmoles) of
compound IIh is boiled for 1 h in i0 ml of dilute hydrochloric acid (I:i). The mixture is then
cooled and the precipitate filtered to yield 1.0 g (92%) of compound V. Colorless crystals,
mp 215-216~ [5].
l-Benzyl-2-piperazinone hydrochloride (VI). A. A mixture of 4.08 g (15.3 mmoles) of com-
pound IIh and 1.16 g (15.3 mmoles) of thiourea in 30 ml of alcohol is heated for 1 h at 60-
65~ and then boiled for 15 min. The solvent is distilled in vacuo, and 20 ml of water are
added to the residue. The mixture is boiled for 1.5 min, then cooled and the precipitate is
filtered. The filtrate is evaporated in vacuo, the residue is ground with acetone, and com-
pound VI is filtered. Yield, 1.91 g (55%), colorless crystals, mp I06-I07.5~ (alcohol--ether).
IR spectrum: 3300-3400 (br, NH), 1640 cm -I (CO). Found C1 15.8 N 12.1%. C11H~sCIN20. Calcu-
lated C1 15.6 N 12.4%.
B. A 9.87 g (37 mmoles) of compound IIh and 4.32 g (40 mmoles) of o-phenylenediamine are
boiled in a mixture of 20 ml of alcohol and 30 ml of water for 2 h. The solution is evaporated
in vacuo to 1/3 its volume, 50 ml of water are added, and the precipitate is filtered. The pre-
cipitate is washed with 15 ml of water, and the filtrates are combined. The aqueous solution
is evaporated in vacuo, the residue is ground with acetone and 5.0 g (60%) of compound VI are
filtered, and found to be identical with the product by method A.
4-Benzoyl- and 4-(4-Nitr0benzoyl)-l-benzyl-2-piperazinones (IIa,b). A 23 mmole portion
of the acyl chloride is added gradually at a temperature not higher than 20~ to a stirred
solution of 22 mmoles of compound VI and 44 mmoles of triethylamine in 50 ml of chloroform.
The mixture is stirred for 1 h, then washed with water, 5% hydrochloric acid, add water again,
and dried over MgSO4. The solvent is distilled off, and the residue is crystallized to yield
IIa,b.
!-Phenyl-N~-ethyl-N2-benzoyl(cyclohexylcarbonyl)ethylenediamines (Vlla,b). A 16 mmole
portion of Na2CO3 is added to a solution of 15 mmoles of compound IIIc in 25 ml of methylene
chloride, and then with stirring, a solution of 15 mmoles of acyl chloride in i0 ml of anhy-
drous methylene chloride is added gradually at a temperature not higher than 20~ At the end
of the addition, the mixture is stirred for another 30 min, and the precipitate is filtered.
The precipitate is washed with 25 ml of methylene chloride. The filtrates are combined and
evaporated in vacuo to yield compound VIIa [colorless crystals, mp 63-64~ (hexane). Found:
C 76.4; H 7.6; N 10.5%. C~7H2oN20. Calculated: C 76.1; H 7.5; N 10.4%] and VIIb [colorless
crystals, mp I03-I04~ (ethyl acetate--hexane). Found: C 74.3; H 9.2; N 10.3%. C~TH26N20.
Calculated: C 74.4; H 9.6; N 10.2%].
N-Benzyl-N,N'-dibenzovlethylenediamine (VIII) was obtained from ethylenediamine IIIa
and benzoyl chloride in a similar way as compounds VIIa,b. Yield 45%. Colorless crystals, mp
182-184~ (alcohol). IR spectrum: 3330 (NH), 1658 (CO), 1620 cm -~ (CO). Found: C 77.2; H 6.0;
N 8.2%. C=~Hz=N202. Calculated: C 77.1; H 6.2; N 7.8%.

423
 N-Benzyl-N'-cyclohexylcarbonylethylenediamine (Vllc). A solution of 4.4 ml (33 mmoles)
of cyclohexylcarbonyl chloride in 20 ml of anhydrous acetonitrile is added in the course of
i h to a solution of 4.5 g (30 mmoles) of compound llla in a mixture of 60 ml of acetonitrile,
2.66 ml (33 mmoles) of pyridine and 15 ml of 2 N HCI. At the end of the addition, the reaction
mixture is stirred for another 2 h, the solvent is distilled off in vacuo~ and to the residue
200 ml of ether are added, and the mixture is extracted with 60 ml of i N HCI. The acid ex-
tract is made alkaline with 30% NaOH to pH i0, and extracted by chloroform. The chloroform
solution is dried over Na2SO~, the solvent is distilled off, and the residue is crystallized
from an acetone-petroleum ether mixture. Yield, 6.2 g (79.5%) of colorless crystals, mp 56-
58~ IR spectrum: 3325 (NH), 1640 cm -I (CO). Found: N 10.8%. C16H2~N20. Calculated: N
10.8%.
Hydrochlorides of N-Benzyl(phenylethyl)-N'-benzoyl(cyclohexylcarbonyl)ethylenediamines
(Vlld-f) are obtained in a similar way as compound Vllc with the difference that at the end
of the reaction, 200 ml of ether is added to the mixture and the precipitates of hydrochlor-
ides of compounds Vlld-f are separate are filtered. [As in Russian original; there's probably
some HCI in the final ether solution -- Editor.]
Hydrochlprid e of Compound Vlld. Colorless crystals, mp 194-195~ (alcohol-ether). Found:
C112.5; N 10.0%. C16HITCIN20. Calculated: C112.3; N 9.7%.
Hydroqhl0ride of Compound Vile. Colorless crystals, mp 198-199~ (water). Found: C1
11.6; N 9.2%: C17H21CIN20. Calculated: C111.2; N 9.5%.
Hydrochl0ride of Compound Vllf. Colorless crystals, mp 230-231.5~ (alcohol-ether).
Found: C 65.9; H 8.8; CI Ii.i; N 9.4%. CI~H27CIN20. Calculated: C 65.7; H 8.8; C111.4; N
9.0%.
4-Acyl-2-piperazinones (lla~c-~) . A solution of 0.75 ml (i0 mmoles) of chloroacetyl
chloride in 12 ml of benzene is added at 20~ to a solution of i0 mmoles of compounds Vlla-f
(the compounds Vlld-f were isolated from the corresponding hydrochlorides)in 30 ml of anhy-
drous benzene, and then a solution of potassium tert-butylate (prepared from 20 mmoles of
potassium and 30 ml of anhydrous tert-butanol), is added. The reaction mixture is stirred for
i h, boiled for 3 h, cooled and poured into i00 ml of water. The organic layer is separated,
and the aqueous layer is extracted by chloroform. The extracts are combined, washed with wa-
ter, 5% HCI, and water again, and dried over Na2SO~. The solvent is distilled off in vacuo~
and the residue is crystallized to yield compound lla,c-g.

LITERATURE CITED
i. H. Zellner, US Patent No. 3935214; Chem. Abstr., 85, 214956 (1976).
2. Japanese Patent No. 80136280; Chem. Abstr., 94, 156968 (1981).
3. W. Zumma, et al., US Patent No. 4163849; Chem. Abstr., 92, 41986 (1980).
4. J. Seubert, R. Pohlke, and F. Loeblich, Experientia, 33, 1036 (1977).
5. G. Struve, C. Gazzola, and G. Kenyon, J. Org. Chem., 42, 3069 (1977).
6. R. Holler and A. Holler, J, Amer. Chem. Soc., 74, 3069 (1952).
7. M. Masaki, J. Amer. Chem. Soc., 90, 4508 (1968).
8. J. Seubert, German (West) Patent No. 2504250; Chem. Abstr., 8_55, 142999 (1976).
9. A. Frost and A. Carlson, J. Org. Chem., 24, 1581 (1959).
i0. A. P. Roszkowski, et al., German (West) Patent No. 2733698; Chem. Abstr., 88, 170144
(1978).

424
ANALOGS OF PURINE NUCLEOSIDES.
3.* ALKOXYALKYLATION OF HYPOXANTHINE BY THE SILYL METHOD

M. A. Madre, E. E.Liepin'sh, UDC 547.857.3'431.4:543.422

R. A. Zhuk, O. V. Sakhartova,
and M. Yu. Lidak

The reaction of bis(trimethylsilyl)hypoxanthine with methyl trichloromethyl ether

has been investigated, l-Methoxymethyl-, 7-methoxymethyl-, and 9-methoxymethyl-
hypoxanthine, as well as 1,7-, 1,9-, and 3,7-bismethoxymethylhypoxanthine, have
been isolated from the reaction mixture. The structures of the isomers have been
established on the basis of an analysis of their UV, IR, IH NMR, 13C NMR, and 15N
NMR spectra. The influence of the conditions under which the reaction is carried
out on the yield of the alkylation products and the isomeric composition of the
reaction mixture has been studied.

N-substituted derivatives of hypoxanthine are of interest both from a chemical and a bi-
ological point of view. It has been established that 9-(2-hydroxyalkyl)hypoxanthines, particu-
larly erythro-9-(2-hydroxy-3-nonyl)hypoxanthine both in the individual state and in a complex
with dimethylamino-2-propanol p-acetamidobenzoate, have antiviral, antileukotic, and immuno-
modulatory activity [2-4]. N-substituted hypoxanthines are also interesting objects for study-
ing the mechanism of action of enzymes for nucleic acid metabolism and synthesis [5, 6].
In this context the development of effective methods for the synthesis of compounds of
the class under consideration is a timely problem.
At the present time hypoxanthine derivatives are most often obtained from the correspond-
ing derivatives of other 6-substituted purines, i.e., by the chemical or enzymatic deamination
of N-substituted adenines [3, 7, 8] and by the alkaline or acid hydrolysis of 6-halo- [3, 9,
i0] or 6-alkoxypurines [i0]. These are usually complicated, multistep processes, which do not
always make it possible to obtain the desired products with a sufficiently high yield.
The alkylation of hypoxanthine is seldom used for the synthesis of its derivatives. The
methylation and benzylation of hypoxanthine by the corresponding alkyl halides produces a mix-
ture of different mono- and bis-substituted derivatives, the ratio between the products being
dependent on the structure of the alkylating agent, the pH of the reaction mixture, and the
conditions under which the reaction is carried out (the solvent, temperature, etc.) [11-15].
The possibility of the migration of substituents during the alkylation of hypoxanthine has
been demonstrated [16, 17].
The silyl alkylation method has not heretofore been used for the synthesis of nonglyco-
side derivatives of hypoxanthine; there are only data on the use of this method for obtaining
inosine and some of its analogs [18-23].
When most investigators used this method [18-20, 23], the corresponding 9-substituted
derivatives of hypoxanthine were isolated as the only product with a higher or lower yield;
however, the formation of a mixture of 7- and 9-substituted products with predominance of the
7-isomer was noted in some cases [21, 22].
Our work was devoted to an investigation of the silyl method for the alkylation of hy-
poxanthine for the purpose of using it for the synthesis of N-alkoxyalkylhypoxanthines.
The alkylation of a silyl derivative of hypoxanthine by compounds such as alkyl, 2-halo-
ethyl, and 2-acetoxyethyl halomethyl ether showed that a complex mixture of products forms

*For report 2, see [i].

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 518-524, April, 1986.
Original article submitted July 3, 1985.

0009-3122/86/2204-0425512.50 9 1986 Plenum Publishing Corporation 425

 TABLE i. UV and IR Spectra and Chromatographic Parameters
of Hypoxanthine Derivatives III-VIII
'UVspectrum, Xmax, nm iRspectmm, v, cm-t HPLC(reia'
Com- (tnchtoroform) ~vereten-
pound I
~t don voI-
pH 2 I pll 7 pll 12 NH G ~ (> C-~ O* umes)
I

III
IV
250 I 251 262
255
3488
3388
1708
1690
1708
1710
0,34
0,32
2,57
1,18
V
V1
255
255 256
263 3390
.....
1705
" ' '
1680
1700
0,81
0,62
1,00
1,65
IVII
VIII 263 266
252 253 253
266
1700
165O
0,71
0,47
2,00
4,36

*In liquid pet'rolatum.

TABLE 2. Proton Chemical Shifts (ppm) in the PMR Spectra of

Xanthine Derivatives Ill-VIII

Compound I~.Fl (S. lid 2-11 (S, 11t) NCIt..,O ($, 21I) C+II, (S, 311) Nil (S. III)

III
IV
8,32
825.
8,12
8,10
5,36
5.50
3,30
3 28
l1,98
12,,15
rV 8,42 8,02 5,66 3,27 12,46
VI 8,44 8,50 5,71, 5A1 3,30, 3,35
VII 8,31 8,50 5,54, 5.43 3,3 I, 3,35
Pr 8,43 8,50 5,71, 5.55

during the reaction. Therefore, as a model reaction of the process under consideration we
investigated the methoxymethylation of hypoxanthine by the silyl method.

N) I
~ f ~ )N
I
Si(CH3)3
+ CICItzOCH3
II

0 0 0 0
CH30CHz~-N~___ N ltN" , ~ - - N "~'[" .-CH2OCli3 CH3OC'~ A -CH2OCil
~

.i.9 H I
111 lV CHeocg3 V VI

0
CH3OCH2"~N- ~ . . ~ N
L2;
i I
CH2OCH~ CH20CH~ CH2OCH~
VII VIII IX
The reaction of bis(trimethylsilyl)hypoxanthine (I) with methyl chloromethyl ether (II)
gave a mixture of alkylation products. Their separation was carried out with the aid of frac-
tional crystallization and preparative column chromatography on silica gel. In this manner we
isolated i- (III), 9- (IV), and 7-methoxymethylhypoxanthine (V), as well as 1,7- (VI), 1,9-
(VII), and 3,7-bismethoxymethylhypoxanthine (VIII).
The determination of the individuality of the compounds obtainedwith the use of TLC is
complicated by the similarity between the Rf values of the isomers in different solvent sys-
tems; therefore, HPLC served as the main method of determination (Table i).

426
 The establishment of the structure of compounds Ill-VIII, i.e., the determination of the
position of the substituent in the purine ring, turned out to be a fairly complicated problem.
A back synthesis by means of the deamination of 9-methoxymethyladenine (IX) gave compound IV
and thereby proved that the structure corresponds to the 9-isomer. The structures of the re-
maining compounds synthesized were established on the basis of their UV, IR, and NMR spectra.
The UV spectra, which are usually used for the determination of the position of a sub-
stituent in a purine ring [24]2 was found to yield little information in this case due to
the similar values of the absorption maxima of the isomeric N-substituted hypoxanthines; how-
ever, a comparison of the spectra of isomers Ill-VIII (Table I) with the UV spectra of alkyl-
hypoxanthines demonstrated that compound V has an absorption maximum at 255 nm, which is char-
acteristic of the neutral molecules of 7-substituted hypoxanthines [24]. The UV spectrum of
compound III corresponds more closely to the structure of l-methylhypoxanthine than to 3-
methylhypoxanthine [24], and the spectra of isomers VI, VII, and VIII correspond to the spec-
tra of the 1,7-, 1.9, and 3,7-disubstituted hypoxanthines, respectively [12, 13, 24].
The vibrational frequency of the NH group of compound V in chloroform, i.e., 3390 cm -~
(Table 1), corresponds exactly to ~NH in 7-methylhypoxanthine [25], and the frequencies of
the ~NH (3438 cm -~) and ~C=O (1708 cm -~) vibrations of isomer II! are evidence in support of
the structure of l-methoxymethylhypoxanthine for this compound.
The structures of the alkylation products of hypoxanthine were unequivocally established
with the aid of IH, ~3C, and 15N NMR, as well as the 13C spectra without decoupling from the
protons and 13C spectra with selective suppression of individual IH signals (Tables 2-4). As
is seen from the data in Table 2, the IH chemical shifts provide little information to prove
the structures of the isomers. In the case of 1,7- and 3,7-disubstituted products VI and VIII,
an unequivocal assignment is totally impossible.
The ~3C NMR spectra proved to be far more informative. The presence of characteristic
values of the long-range ~3C--~H spin--spin interaction in the hypoxanthine ring (Table 3) makes
it possible to unequivocally assign all the ~3C signals. The site of substitution is also
proved by utilizing the long-range spin--spin coupling with the protons of the NCH2 group, as
was described in [26]. A difference in the spectral behavior of bis-substituted products VI
and VIII, whose ~H NMR spectra were identical, was thus detected.
The ~SN NMR spectra could also be obtained for some oflthe compounds (IV-VII), and the
I~N chemical shifts for all four nitrogen atoms of the purine ring could then be established
(Table 4). The changes in the 15N chemical shifts of hypoxanthine under the influence of the
substituents are similar to those found in methylated purines [27].
We next investigated the influence of the conditions for carrying out the methoxymethyla-
tion of hypoxanthine O n the regioselectivity and yield of the alkylation products, the iso-
meric composition of the mixtures obtained being determined by HPLC with the use of the prev-
iously isolated compounds Ill-VIII as markers.
When compounds I and !I were reacted in dichloroethane at room temperature, it was found
that the alkylation yield reaches 30%, of which ~75% is made up of 1-substituted isomer III,
and ~25% is made up of 9-substituted isomer IV. Traces of compounds V, VI, and VII (1-3%) were
also discovered among the alkylation products.
When the alkylation of I was carried out in the absence of a solvent at an elevated temp-
erature (at the fusion point), the extent of conversion of I amounted to 60%; however, the
isomeric composition of the reaction mixture changed significantly, i.e., the percentage of
disubstituted isomers VI and VII increased sharply (to 50% of the total yield of the alkyla-
tion products). The second half of the products was made up of 7- and 9-isomers V and IV in
a 1.5:1 ratio. Compound III was present only in trace amounts (<__2%).
A mixture of IV and V was obtained as the main alkylation product both when the reaction
was carried out in the presence of an equimolar quantity of triethylamine (IV:V = 1:5.5; the
yield was 10%) and when tin(IV) chloride in an amount equal to 1.5 eq was employed as a cat-
alyst (IV:V = 1:1.5). In the latter case, the yield of the alkylation reaction was high
(60%); however, the reaction mixture also contained VI and VII and an admixture of isomer III.
Since there are data [28] indicating that an excess of the silylating agent and the se-
condary silylation products influence the course of a glycosylation process, the reaction of
compounds I and II was also carried out without distilling off the excess of hexamethyldisil-
azine, which was employed as the silylation agent. The yield of the alkylation products did

427
 TABLE 3. :~C NMR Spectra of Compounds Ill-VIII

C h e m i c a l shifts, 6, ppm

Ctl., CH. C~2) CI~ C(5) C~) [ C(8)

[

111 75,84 56,24 147,64 152~9 18,12 154,81 141,11

IV 73,85 56,32 146,13 148,66 124,07 156,72 140,7;3
V 76,27 55,65 144,78 157,34 14,81 154,09 144,47
~VI 76,47 (N!~), 55,76 (Nal), 1147,99 156,94 114,13 153,60 145,42
75,76 (N(,>) 56,28 ( N I . )
VII 73,85 (NI...), 56,37, 56,37 149,01 148,00 123,33 156,11 141,34
76,03 (N~)
VIII 75,93 (N~)), 56,54 (NrTi), 148,64 144.65 113,62 161,92 143,22
78,28 (N,:.) r: ( (N,.~,)
,)5,8J
m m,,,
lSc-,H s p i n - s p i n coupling comtant,J~ Hz
.5 g~
s .,-
I I I J I .I J C(x)--CH 2
G G ~- v-

III* 207.4 210,7 5 5,1 C~2), 2.8 C~s)

IV 203,5 211,4 7,1 4,2 C(s,, 3.3 C~4)
V 205,7 211,8 3,3 7,2 4.1 13,3 0.8 4.6 Cis), 1,5 C(5>
IVI 208,3 212,4 4,0 6,2 3,9 12,9 1,1 5,0 C~21, 3.2 C(~),
4,6 CI~I, 3,3 C~5)
VII 208,6 214,4 813 6,0 11,2 4,6 0,9 2,9 C~4), 4,2 C~sl,
3,2 C(~), 5,3 C(2p
VIII 206,5 214,2 7,8 12,2 4,4 13,2 0,6 3,0 C~5t, 4,6 C~aI.
5,1 C(2), 3,6 Cr

*The signals from the C(,) and C(5) carbons are strongly broad-
ened, and the constants of the spin--spin interactions involv-
ing them could not be determined.

TABLE 4. Chemical Shifts of Nitrogen Atoms (ppm)

in the ~SN NMR Spectra of Compounds IV-VII

Compound N(I) N(s~ N~7) N(~)

Inosine* - 206.9 - 167,,I - 132,9 - 206,9

IV - 206.5 ~- 166.7 131.7 - 206,5
~V - .- 208,6 - 147,2 - 212,0 -- 129,2
VI - 197,5 - 145.4 -211,0 .... 129,0
VII - 195,l - 1752 - 130.7 - 208,[

*According to data in [29].

not decrease in this case (45-50%), and a mixture of the 7- and 9-isomers (V:IV = 1.5:1) was
also isolated as the main product of the reaction; however, disubstituted products VI and VII
and isomer VIII, which made up 5-10% of the total quantity of the alkylation products, were
obtained along with them.
Isomers Vl and VIII were found to be unstable compounds when they were isolated in their
pure forms. Under the conditions for obtaining the X3C and :SN spectra (broad-band suppres-
sion of the interaction with the protons, a temperature of the samples equal to 40~ and
dimethyl sulfoxide as the solvent) 1,7-dlsubstituted hypoxanthine VI was converted into an
equilibrium mixture of 1,7- and 1,9-isomers VI and VII, as follows from the data from the
~aC NMR spectra. Since an equilibrium mixture of VI and VII was also obtained in the case of
< =
samples containing >70% 1,9-bis-substituted product VII and__30% 1,7-disubstituted product VI,
it may be postulated that migration of the substituent between positions 7 and 9 of the purine
ring occurs in a dimethyl sulfoxide solution.
3,7-Bisubstituted hypoxanthine VIII was also converted into a mixture of 1,7 and 1.9
isomers VI and V I i u n d e r similar conditions; therefore, the kinetically more advantageous
substitution in position 3 turns out to be thermodynamically unadvantageous, and migration
of the substituent to position i of the purine ring occurs.

428
 The investigation which we carried out showed that the methoxymethylation of hypoxanthine
by the silyl method can be used when appropriate conditions for carrying out the reaction are
selected for the preparative synthesis of 1-, 7-, and 9-methoxymethylhypoxanthine, as well as
1,7- and 1,9-bismethoxymethylhypoxanthine.
The 7- and 9-monosubstituted reaction products and the disubstituted reaction products
were also isolated by us in the case of the alkylation of compound I by other e-halo ethers
(by alky! chloromethyl ethers and by 2-acetoxy- and 2-chloroethyl chloromethyl ether). More
detailed investigations of the influence of the alkylating agent on the regiospecificity and
the yield of the alkylation of hypoxanthine by the silyl method are being continued.

EXPERIMENTAL
The UV spectra were recorded on a Unicam-SP 1800 spectrophotometer, and the IR spectra
were recorded on a UR-20 instrument. The IH NMR spectra were obtained on a Bruker WH-90/DS
spectrometer (90 MHz) in DMSO-D 6 with TMS as an internal reference, the accuracy of the meas-
urements of the chemical shifts being ppm. The 13C and ~SN spectra were recorded on a
Bruker WM-360 spectrometer at 90.5 and 36.5 MHz, respectively. The chemical shifts in the ~ C
NMR spectra were measured relative to the signal of the solvent DMSO-D 6 and were recalculated
with respect to tetramethylsilane (~ = 39.6 ppm). The ~SN chemical shifts were measured rela-
tive to the external reference nitromethane. The accuracy of the measurement of the ~ C chem-
ical shifts was ppm, and that for the iSN chemical shifts was ppm. The accuracy
of the measurement of the 13C--~H spin--spin coupling constants was Hz. The purity of the
compounds obtained was monitored by TLD on Silufol UV-254 plates in a i0:i chloroform-methan-
ol solvent system. Silica Gel L 40/100 (from Czechoslovakia) was used for the preparative col-
umn chromatography. The separation of the isomers by HPLC was carried out on a Du Pont model
850 liquid chromatograph in a column measuring 4.6 130 mm filled with the sorbent Silasorb
C 18 4C (Czechoslovakia) with a particle diameter equal to 5 ~. A mixture of acetonitrile,
acetic acid, and a 0.02 M solution of sodium dodecylsulfonate in a 15:2.5:82.5 ratio served
as the mobile phase, and the time for an analysis w a s 5 min.
l-MethgxYmethylhypoxanthin e (III). A mixture of 5.0 g (37 mmoles) of hypoxanthine and
30 ml of hexamethyldisilazane is boiled until the hypoxanthine dissolves completely. The ex-
cess hexamethyldisilazane is distilled off in a vacuum, product I obtained is dissolved in
30 ml of dichloroethane, and 2.98 g (37 mmoles) of II are added. The solution is stirred at
room temperature for 5 days, cooled to 0~ and given an addition of 40 ml of ethanol. The
mixture is stirred at room temperature for I h and evaporated in a vacuum. The residue is ex-
tracted by 180 ml of a boiling 10:2 chloroform-~thanol mixture. The extract is evaporated,
and the residue is dissolved in chloroform (30 ml) with heating. The insoluble precipitate,
which consists mainly of product III, is filtered and recrystallized from ethanol. An addi-
tional quantity of III is isolated from the chloroform solution with the aid of column chrom-
atography on silica gel. Product III is eluted by a 2:1 chloroform-methanol mixture after
the separation of the fractions containing isomer IV.
The total yield of compound III was 1.49 g (22.5%), mp 205.5-206.5~ Found: C 46.7;
H 4.6; N 30.9%. Calculated for CTH~N402: C 46.7; H 4.5; N 31.1%.
9-Methoxymethylhypoxanthine (IV) and 7-Methoxymethylhypoxanthine (V). A. A 4.0-g portion
(29 mmoles) of hypoxanthine with 25 ml of hexamethyldisilazane is boiled until the hypoxan-
thine completely dissolves. The solution is given an addition of 20 ml of dichloroethane
and 2.34 g (29 mmoles) of II and storred at room temperature for 4 days. After cooling to ~0~
the reaction mixture is given an addition of 30 ml of ethanol, stirred for 1 h at room temp-
erature, and evaporated in a vacuum. The residue is extracted by 120 ml of a boiling 10:2
chloroform-methanol mixture, the extract is evaporated in a vacuum, and the residue is dis-
solved in chloroform (30 ml) with heating. The insoluble precipitate, which consists mainly
of product V, is filtered out and recrystallized from ethanol. An additional quantity of V,
as well as compound IV, are isolated from a chloroform solution by column chromatography on
silica gel. After the removal of disubstituted isomers VI-VIII by chloroform, IV and V are
eluted by a 20:1 chloroform-methanol mixture. This gives 1.15 g (22%) of V (mp 215-217~
Found: C 46.4;H 4.7;N 31.0%. Calculated for CTHsN40=: C 46.7; H 4.5; N 31.1%) and 0.80 g
(15.3%) of IV (Tm 205.5-207~ Found: C 46.9; H 4.7; N 31.2%. Calculated for CTHsN402: C
46.7; H 4.5; N 31.1%).
B. Silyl derivative I, which is obtained from 1.0 g (7.3 mmoles) of hypoxanthine, as
described in the synthesis of III, is dissolved in 50 ml of dichloroethane and given an addi-

429
tion of 0.59 g (7.3 mmoles) of II and a solution of 1.3 ml (ii mmoles) of tin(IV) chloride
in i0 ml of dichloroethane. The solution is stirred at room temperature for 24 h. Then it is
cooled to ~0~ given an addition of a mixture consisting of 25 ml of ethanol and 5 ml of tri-
ethylamine, stirred at room temperature for 1 h, and evaporated in a vacuum. The residue is
extracted by 55 ml of a boiling i0:i chloroform-~ethanol mixture. The extract is concentrated
to a minimal volume and introduced into a column with silica gel. After the removal of disub-
stituted isomers VI and VII by chloroform, compounds IV and.V are eluted by a 20:1 chloroform-
methanol mixture. This gives 0.41 g (31%) of V and 0.25 g (19%) of IV.
1,7-Bismethoxymethylhypoxanthine (Vl). Silyl derivative I, which is obtained from 5.0 g
(37 mmoles) of hypoxanthine as described in the synthesis of III, is given an addition of 2.98
g (37 mmoles) of II. The reaction mixture is held at II0-120~ for 45 min and then cooled to
~O~ and given an addition of 40 ml of ethanol. The mixture is stirred at room temperature for
1 h and evaporated in a vacuum," The residue is extracted by chloroform (100 ml), and the ex-
tract is concentrated to a minimal volume and introduced into a column with silica gel. Prod-
uct VI is eluted by chloroform after the separation of the fractions containing mainly up to
70%) product VII. Recrystallization from ethanol gives 1'16 g (14%) of isomer VI, mp I04~
Found: C 48.1; H 5.4; N 25.3%. Calculated for CgHz2N4Os: C 48.2; H 5.4; N 25.0%.
3,7-Bismethoxymethylhypoxanthine (VIII) is obtained with a 5-8% yield by separating the
chloroform extract obtained as described in the synthesis of compounds IV and V (method A) in
a column with silica gel. Isomer VIII is eluted by chloroform after the separation of the
fractions containing products VI and VII. Mp I10-III~ Found: C 48.5; H 5.5; N 24.9%. Cal-
culated for CgHz2N~O,: C 48.2; H 5.4; N 25.0%.

LITERATURE CITED
i. M. A. Madre, R. A. Zhuk, and M. Yu. Lida~, Khim. Geterosikl. Soedin., No. 3, 403 (1986).
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4. L. N. Simon, A. Giner-Sorolla, and A. Guttag, European Patent No. 36,077; Chem. Abstr.,
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5. J. R. Piper, A. G. Laseter, and J. A, Montgomery, J. Med. Chem., 2-3, 357 (1980).
6. J. R. Piper, A. G. Laseter, T. P. Johnston, and J. A. Montgomery, J. Med. Chem., 2-3,
1136 (1980).
7. M. J. Robins, P. W. Hatfield, J. Balzarini, and E. De Clercq, J. Med. Chem., 27, 1486
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(1982).
I0. K. K. Ogilvie and H. R. Hanna, Canad. J. Chem., 62, 2702 (1984).
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12. J. A. Montgomery and H. J. Thomas, J. Org. Chem., 28, 2304 (1963).
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(1966).
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16. J. A. Montgomery, H. J. Thomas, and K. Hewson, Chem. Ind., No. 37, 1596 (1965).
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19. Sankyo Co., Ltd., Netherlands Patent No. 6,510,323; Chem. Abstr., 65, 10652 (1966).
20. S. Suzaki, A. Yamazaki, A. Kamimura, K. Mitsugi, and I. Kumashiro, Chem. Pharm. Bull.,
18, 172 (1970).
21. V. Nelson, H. S. E1 Khadem, B. K. Whitten, and D. Sesselman, J. Med. Chem., 26, 1071
(1983).
22. V. Nelson and H. S. E1 Khadem, J. Med. Chem., 26, 1527 (1983).
23. E. Ya. Lukevits and A. E. Zablotskaya, Silyl Method for the Synthesis of Nucleosides
[in Russian], Zinatne, Riga (1985), p. 82.
24. J.H. Lister, in: D. J. Brown (editor), Fused Pyrimidines. Part 2. Purines, Interscience,
New York--London--Sydney--Toronto (1971), p. 482.
25. D. J. Brown and S. F. Mason, J. Chem. Soc., 2, 682 (1957).
26. B. L. Cline, P. E. Fagerness, R. P. Panzica, and L. B. Townsend, J. Chem. Soc., Perkin
II, No. ii, 1586 (1980).

430
27. M. Schumacher and H. Gfinther, Chem. Ber., 116, 200 (1983).
28. L. W. Dudycr and G. E. Wright, Nucleosides, Nucleotides, 3, 33 (1984).
29. V. Markovski, G. R. Sullivan, and J. D. Roberts, J. Am. Chem. Soc., 99, 714 (1977).

ALKYLIMINOMALONIC ACID AND 2-ALKYLOXAZIRIDINE-3,3-DICARBOXYLIC

ACID ESTERS*

A. V. Prosyanik, A. S. Moskalenko, UDC 547.717.04:541.632:543.422

J. Moretti, A. Forni, G. Torre,
and R. G. Kostyanovskii

2-Alkyloxaziridine-3,3-dicarboxylic acid esters have been obtained by oxidizing

alkylaminomalonic acid esters by monoperphthalic acid. The activation parameters
for the inversion of the nitrogen atom have been obtained for a number of alkyl-
iminomalonic acid and 2-alkyloxaziridine-3,3-dicarboxylic acid ester.

The introduction of geminal esteric groups in the a position to a configurationally sta-

ble nitrogen atom made it possible to develop a general method for the separation of l-alkoxy-
aziridine-2,2- [2]-, l-alkyldiaziridine-3,3- [3], and 2-alkoxyisoxazolidine-3,3-dicarboxylic
acid esters [4], which contain only a nitrogen chiral center, into antipodes. It would be of
interest to extend this method to other nitrogen-containing heterocycles, particularly to ox-
aziridines, whose chiral derivatives werepreviously obtained only by asymmetric reactions
involving the oxidation of imines [5]. However, oxaziridines with electron-acceptor function-
al groups on the C atom were not known until very recently. The report of the syntheses of 2-
phenyl-3,3-dibenzoyloxaziridine by the photoisomerization of N-phenyl-a,a-dibenzoylnitrone and
the oxidation of the anil of diphenyl triketone in [6] proved to be erroneous [7]. We devel-
oped methods for the synthesis of alkyliminoamlonates and the first oxaziridines with function-
al groups on the C atom. #
Alkyliminomalonates IIa-j were obtained on the basis of mono- and dibromomalonates ac-
cording to the schemes

II,NR I, / "C4}I~OCI
( ( H d . ) ( ' O ) I'Hl~h . . . . . . . . . . . " .... ~ (C H O C O ) j C H N H R ............ ~ (CIIjiCO):C=NR
- ~ { C.,tt:~) ~N lb 2. CH2N : nb

Rlf)lil~ Rlt/OC I~lfHiC

Ilz~,~l ~ . H2NR I~
(Ir ~ _ - CBr 2 ........ ""c:-.: N + ~'(::,--N. R
R2OOt - "" " CH _~ooL" / " cilaOtl('"
IIc-f IIIa-d z IIg-j F

l, ]l a R=CH3, b R=C2Hs; If,e, d, g, i R=i-C~HT, d, f , h , j R = t - C J ~ 9 ; c , d R'=CH~,

e, f, g h RI=C2Hs, i j RI=i-C:~H7 [II a, c , d RI=CH3, b R ~=C2H6; a R~=CH~, b , c
R2=C2H~; d R~=i-C:~H7

Imines IIa and b cannot be obtained by reacting n-alkylamines with dibromomalonic ester,
since exhaustive amidation is observed in this case [8]. It must be noted that imines IIa
and b, unlike the remaining imines, are unstable and polymerize completely during storage over
the course of 1 month.
When imines IIa-j are oxidized by monoperphthalic acid, they form the corresponding oxa-
ziridines IVa-j with good yields:

*Report 46 from a series entitled Asymmetric Nonbridging Nitrogen. For report 45 see [i].
+For the preliminary report see [8]~
F. E. Dzerzhinskii Dnepropetrovsk Chemical-Engineering Institute, Dnepropetrovsk 320640.
Institute of Organic Chemistry, Modena, Italy. Institute of Chemical Physics, Academy of Sci-
ences of the USSR, Moscow 117977. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 4, pp. 525-532, April, 1986. Original article submitted March 28, 1985.

0009-3122/86/2204-0431512.50 9 1986 Plenum Publishing Corporation 431

 :if +~ + f 0'= =~N

Iv, -f ~ IVg-j

IV a R=CH~, b R~C=H~, c, e, g. i [~=i.C+H?,d, f, E J Rm~oC+H~; a -dRI=CH~,

c ~hRI~C~H~, i, J Rh~i.CoH?

Oxaziridines IVc-J are thermally stable compounds, which can withstand many hours of
heating in toluene at ll0~ without showing signs of decomposition. At the same time, oxazlr-
idlnes IVa and b are restrlctedly stable during storage in the cold in solutions. Attempts to
concentrate the reaction solutions of oxaziridines IVa and b resulted in their decompositlon
with the formation of the corresponding aldehydes:

++ " ~ " w,b

Va R~H:bR~cH~
In this case, acetaldehyde was identified in the form of the 2,4-di~itrophenylhydrazone
(VI). Dimethyl imlnomalonate could not be isolated, apparently due to its polymerization un-
der the conditions of the reaction.
The oxidation of asymmetric imines Ilg-J produces a practically equilibrium mixture of
the Z and E isomers of oxazirldines IVg-J, which is not suitable for the determination of the
activation parameters for the inversion of the nitrogen atom. For the purpose of synthesizing
the individual E isomers of oxaziridines IVg and h, we investigated the deasymmetrization of
oxaziridines IVc and d in analogy to other heterocycles containing geminal esteric groups [2-4]:

IVc, d ~o,+,c,~o,, '~i ,.",.,o+~ IVg. h

O 9 9 .+ ,,

COOCH~ T< ~;

The saponification of oxaziridines IVc and 'd is trans-stereospecific, and the E configura-
tion is maintained during the further conversions.
The composition and structure of the compounds obtained were confirmed by elemental an-
alysis, as well as by the data from the IR aHd PMR spectra (Tables i and 2). The carbonyl
bands of the esteric groups in the IR spectra of imines lla-j and oxaziridines IVa-j were as-
signed in accordance with the 20-25-cm -~ displacement of the bands of the S-trans carbonyl
groups to lower frequencies in comparison to the S-cis carbonyl groups [9].
The signals of the protons of the esteric groups in the PMR spectra of imines lla-j in
benzene (Table i) were assigned on the basis of the fact that in the case of acetone N-propyl-
imine, the shift induced by an aromatic solvent is 0.28 ppm greater for the C-methyl group in
the cis position to the substituent on the nitrogen atom [i0]. The assignment was confirmed
by an analysis of the shifts induced by the aromatic solvent for the esteric groups in the Z
and E isomers of asymmetric imines llg-j with consideration of the fact that the E isomer is
predominant in the equilibrium due to the weak steric interaction of the substituent at the
nitrogen atom with a cis-oriented esteric group.
It should be noted that in the PMR spectra of imines lla-j in CC14 the protons of the
esteric groups are always equivalent, while in the case of acetone N-propylimine, a deshielding
influence of the lone pair of the nitrogen atom with respect to the cis substituent at the im-
ino carbon atom in comparison to the substituent on the N atom was noted [I0]. This fact is
apparently caused by the influence of the effective conformations of the esteric groups.
The proton signals of the esteric groups in the PMR spectra of oxaziridines IVa-j in CC14
(Table 2) were assigned on the basis of the shielding effect of the lone pair of the nitrogen
atom with respect to cis-oriented substituent, which was established by comparing the chemi-
cal shifts of the protons of the esteric groups in the Z and E isomers of oxaziridines IVg-j.
We determined the activation parameters of the thermal topomerization of imines lla-d
and the inversion of ~he nitrogen atom+in oxaziridines E-IVg and h (Table 3). The lowering of
the values of AG29s K ~ as the size of the substituent at the imino nitrogen atom is increased
is an indication of an inversion mechanism for the topomerization of imines lla-d. The high
barriers to the inversion of the nitrogen atom in the 2-alkyloxaziridine-3,3-dicarboxylic
acid esters attest to the possibility of the synthesis of chiral derivatives of oxaziridines.

432
 rABLE 2. Characteristics of 2-Alkyloxaziridines-3,3-dicarboxylic Acid Diesters IVa-j
roob::'
/['-
O"~..........JTN
~OOFI~ R

Equilibrium PMR spectrum (in CCh), &~, ppm

IR spectrum, content of ~ound: ~mpideal Calcu-
~]om- lated: Yield. %
pound 7D~ ~C=O, cm "I isomers, % R ~ormula
N,%
;. trans S- cis Ctl:, CH~ CH~, CI-t~
gila CH
lUl
'va '45 1760 .,8D 3,94 3,87
~0,25) (0,5i)) 5),56)
Vb '48 176g 1,25 2 91. 3,94 3,88
(0,24) {0,24) (0,51 ) I0,56)
Ve 1,4397 1766 1,12and1,25 2,42 3,91 3,85 6,81 CsHI3NO5 3,89 86
(0,17and0,16) --0,13) (o,51) 0,61 )
[!Vd 1,4504 1768 1,15 3,90 3,85 6,41 CoH ISNO5 3,44 89
(O,lO) (0,50) i0,63)
[Ve 1,4588 ;39 1758 1.14andl.27 2,40 1,38 4,3; 1,33 4,27 6,03 CIoI-I,TNOs ],05 90
(0,10and).15) -0,17) (0,51 ) o,31) :0,57) (0,42)
:'Vf 1,4441 '36 1760" 1,16 1,38 4,3: 1,33 4,28 5,64 C11HIgNO5 5,71 87
(o.I 1) 10,51 ) o,31) 10,59) (0,45)
:vg 1,4396 '39 1762 t8 52 1,13andl,26 2,40 t,39 4,3, 3,84 6,29 CgHIsNOs 5,44 91
( 0,08and0,12) i-O, JS) (0,48) 0,27) :0,58)
I, 13andl,26 2,40 3,90 1,34 4,29
(0 08andD 12) --0,18) (0,54) [0,62) (0,44)
!Vh 1,4481 1740 1763 J,8 52 1,16 1,39 4,31 3,85 ~,97 C,0H,7NOa 5,05 39
(0,11) (0,45) 0,26) i0,63)
1,16 3,90 [ ,33 4.29
(0,07) (o,5o) :0,6-t ) (0,49)
iv( ,4573 174:1 1766 48 52 l,l 4and1,27 2,40 1,33 5,1q 3,85 3,81 C,oHjTNO5 5,05 36
((I,10and),13) :-o,18) (0,34) 0,12) ~0,60)
I 14anal,27 2,40 3,90 1,30 5,05
((1:10and), 13) :-o,18) (0.54) :0,47) (o,16)
[~Vj ,4416 1743 1760 ~7 53 I,I 6 1,33 5,1! 3,85 ,67 CnHmNO~ 5,71 )3
(o,I J) (0,36) 0,12) Io,65)
1,16 3,90 1,30 5,03
(0.06) {0,52) 10,47) (0,17)

*The values of the shifts induced by the aromatic solvent are given in parentheses: JCHaCH2 = 7.0, J C H 3 C H = 6.0 Hz.
fad = 12.5, JHH = 13.5 Hz.

ta~
,.D"

TABLE i. Characteristics of Alkylamino- and Alkylminiomalonates la, Ib, and lla-j

R~OOC
"+C --"+lq
"R
R ~ O O / C+

IR spectrum, v, cm -1 Equilibrium PHR s p e c t r a ( i n C6Hs) , 6 :~

bp, *C "l Content of Found: C.alcu-
Empidcal lamd, Yield. %
Corn- 1 isomers, % R' N,% facmula
POund Hg)(mm ,,o~0 C = O C=O N. %
S-tram .S-cis cn:~, cH~.
CH~ CH Ctt CH:~

1736 1752 ~ 1381) 2,20 3,40 3,40 -- 8.60 C6H.NO+ 8.69 33

la 78 14)11.4342I -- 7,90 CrH,3NO4 8.00 35
Ib 70 (2)11,4311l 1739 1759 |389) 0,86 2,45 3,40 3.40
[725 1745 i658 3,25 3,37 3.40 -- 8,70 C+II~NO~ 8.80 77
ll'a 71 (3){1.44561
(0,25) (0,52) (0.49}
1724 t742 t656 1,05 3,45 3,37 3.40 -- 8.01 C~HnNO+ 8,09 81
11 b 84 (5){ t,44881 ( 0,52 ) (0.49}
I (0,25) (0,17)
1721 1744 1653 I,Oh 3,70 3,33 3,42 -- 7.4 I 7.48
llC 70 (2) I 1,4406l (-0,05) (0,561 (11,4 t )
! (o,14)
lldl" 72 (2) 1722 1745 1655 1,18 3,32 3,42 -- 6.91 ( ~ I ,~N()., 6.86 93
(0,10) (0,55) (o,45)
1723 1740 1654 1,09 8,70 0,81 3,93 0,92 4,03 l;,48 C,uH,~N()~ 6,.~i 78
11r 76 (I) 1.4362l [11,_29)
(o,12) (-o,o4) 10.53) (0.391 (O.42)
1718 1741 1660 1,23 0,81 3,90 0,91 4.02 5,85 CniI~N(h 6.11 87
Ill 80 (I) 1,44511 (0.531 (0.43} [0.28)
(0,06) (0.40)
llg 70 (2) 1,4392l 1723 1743 1655 48 52 I.I0 3,70 0.80 3,93 3,4O -- 6,79 C.JI~NO~ G.-~, 71
(0,1.{ } (--0.04) ( 0,54 | 10,38) (0,46)
t,!0 3,70 3.3! 0.92
(0,111 (--0,04) ( 0,55 ) (0.42) [0,781
Ilh 73 (2) 1,44031 1722 1739 1658 47 53 1,20 0.81 3,9l 3.43 6.4'7 C,~IIm:NO4 6.50 86
(0,09] (0.54) 10.4l) (0.451
1,23 3,33 0.90 4.42
+ (0,061 f0.55) ( 0.45 I [0,30|
1655 47 53 1,10 i70 0,92 5.09 3,38 6.39 C,oH~:NO, 6.50 66
[I~. 76 (2) 1.4377] 1726 1750
(o,J 11 (-o.o4) -(0,41 ) ( - 0.tin) (0,441
1,10 3,70 3,29 1,03 [.%181
(0,1 I1 (-0.04) (0,53) (028|
0,93 5,08 "1.39
0.15) 5.97 CnHv.N()~ 6.11 81
llJ 84 (2) 1,4395! 1722 174C 1659 46 54 1,22
(0,06', (0,39) (-- 0,05) (0.44)
1,25 3.29 0,95 5.17
(0.03: 10,5.1) 10.271 0.141

*The values of the chemical shifts induced by the aromatic solvent are given in parentheses: A6 = 6CCI~ -- ~C6H6; JCHzCII3 =
7.0, JCH3CH = 6.0 Hz.
imp 44~
 TABLE 3. Activation Parameters* for the Inversion of the
Nitrogen Atom in Imines lla-d (in 1,2-C6H4C12) and Oxazir-
idines IVg and h (in C6H6)
Corn- AGf ~, AG298 K ~
pound a~, Hz Tf,'~ K kf'$ sec'I kJ/mole kl/mole lg '~29sr:

IIa 1,6 435 3,55 J03,2 104,3 -- 5,49

IIb 2,2 429 4,90 100,6 101,7 --5,03
II c 4,0 435 8,90 99,9 101,0 --4,91
IId 4,8 372 10,80 84,4 85,0 --2,10
IVg 383 1,45. 10-~ 122,9 123,6 --8,87
(1,57. IO-4) 122,6 123,3 --8,81
IVh 353 6,13- 10-4 108,4 109,0 --6,31
(6,5l 9 I0 ~) 108,2 108,8 --6,13

*The values of the parameters at Tf were determined with the

use of the formulas k~ = ~*A~//2 [ii] and AGf = 4.576-Tf~
(10.319 + log Tf/kf~ ~[ii] under the assumptions that AS @ =
0 and AG=98 K = AGf # + R(Tf -- 298) [12]. The values of log
k298 K were calculated from Ey~ing's equation [ll] on the
basis of the values of &G29s K #.
#The temperature at which the E,Z isomerization was carried
out is given for compounds IVg and h.
Sin the case of compounds IVg and h, the rate constants of
the forward (reverse) inversion reaction were calculated by
the least-squares method from the kinetic data on the E,Z
isomerization.

EXPERIMENTAL
The IR spectra were obtained on a UR-20 spectrophotometer in microlayers (in CC14 in the
case of compounds lla and b and in a KBr tablet in the case of lid), and the PMR spectra were
recorded on an RYa-2305 spectrometer (60 ~ z ) with the use of 5 mole % solutions and with
HMDS as an internal reference.
The activation parameters for the inversion of the nitrogen atom were determined from
the temperature of fusion (Tf) of the protonsignals of the methoxycarbonyl groups in the PMR
spectra (imines lla-d) or on the basis of the data on the kinetics of the thermal E,Z isomer-
ization process (oxaziridines IVg and h). The isomerization kinetics were determined upon
heating in sealed evacuated ampuls by measuring the integrated intensities of the PMR signals
of the methoxycarbonyl groups. In the case of imines lla and b, which are unstable at high
temperatures, the value of Tf was determined after brief heating (i0 min) in a pickup heated
to Tf following the preliminary determination of T# in other experiments on other samples of
imines lla and b. The error in the determination o~ Tf was 176 and the error in the de-
termination of A~ was Hz. Thus, the errors in the determination of the activation pa-
rameters of inversion were sec -~ for kf, kJ/mole for AG #, and for log k29s K-
The characteristics of the compounds synthesized are presented in Tables 1-3.
Methyl Ethyl Malonate. A solution of 16 g (i00 mmoles) of malonic ester in 50 ml of ab-
solute ethanol is given an addition of a solution of 5.6 g (I00 mmoles) of KOH in i00 ml of
absolute ethanol, the mixture is held for 10 h, the ethanol is driven off, and the salt is
washed with I00 ml of ether and dissolved in 30 ml of H20, given an addition of i0 ml of 36%
hydrochloric acid, and extracted by ether (three 50-ml portions). The extract is given an
addition of an excess of a solution of diazomethane in ether, the mixture is held for 15 min,
the ether is distilled off, and the residue is vacuum-distilled. The yield is 13.6 g (93.5%),
bp 58~ (3 mm Hg), nD 2~ 1.4155. According to the data in [13], Tb 182~
Methyl Isopropyl Malonate. This compound is obtained in an analogous manner from diiso-
propyl malonate, but the reaction with KOH is carried out in tert-butanol. The yield is 81.5%,
bp 63~ (3 mm Hg), nD=~ 1.4145. Found: C 52.6; H 7.7%. Calculated for C7H1204: C 52.5; H 7.6%.
Dimethyl dibromomalonate (Ilia) is obtained according to [14]. The yield is 95%, mp
65~ According to the data in [14], mp 63-65~
Methyl ethyl dibromomalonate (lllc) [93% yield, Tb I08~ (2 mm Hg), nD 2~ 1.4393. Found:
C 23.8; H 2.8%. Calculated for C~HsBr20,: C 23.7; H 2.6%] and methyl isopropyl dibromomalon-

435
ate (llld) [94% yield, bp II0~ (2 mm Hg), nD =~ 1.4357. Found: C 25.6; H 3.2%. Calculated
for CTH~oBr204: C 26.4; H 3.2%] are obtained in a similar manner.
Dimethyl Ethylaminoma!onate (Ib). A solution of 4.5 g (i00 mmoles) of ethylamine and
i0.i g (i00 mmoles) of triethylamine in 150 ml of acetonitrile is given an addition of 21.0 g
(i00 mmole) of dimethyl bromomalonate, the mixture is stirred for 2 h, the acetonitrile is
distilled off, and the residue is extracted with 150 ml of absolute ether. The extract is
saturated with dry HCI, the precipitate formed is separated and dissolved in 20 ml of abso-
lute methanol, i0.i g (i00 mmoles) of triethylamine are added to the solution, the mixture
is stirred for 5 min, the methanol is distilled off under a vacuum, and the residue is ex-
tracted with ether (two lO0-ml portions). The ether is evaporated, the residue is vacuum-
distilled, and 6.1 g (35%) of amine Ib are obtained.
Compound la is obtained iN a similar manner.
Dimethyl Ethyliminomalonate (Ilb). A solution of 1.75 g (i0 mmole) of Ib in 30 ml of
asbolute ether at O~ is given an addition of 1.09 g (I0 mmoles) of tert-butyl hypochlorite
in 5 ml of absolute ether, the mixture is held for 5 min, and a solution of diazomethane is
added until the evolution of nitrogen ceases. The ether is distilled off, the residue is
vacuum-distilled, and 1.4 g of imine lib are obtained.
Compound lla is obtained in a similar manner.
Dimethyl tert-butyliminomalonate (lid) is obtained according to [8]. The yield is 93%.
Compounds llc and e-j are obtained in a similar manner.
Dimethyl 2-tert-Butyloxaziridine-3,3-dicarboxylate (IVd). A solution of 2.01 g (i0 m-
moles) of imine lid in 5 ml of ether is given an addition of an ethereal solution of monoper-
phthalic acid containing i0 mmoles of active oxygen, the mixture is held for 3 h and then
filtered, and the filtrate is washed with a 5% solution of Na2COs to pH 7 for the ethereal
solution and dried over Na~SO~. The ether is evaporated, and the residue is chromatographed
in a column (Silica Gel LI00/160 ~ with chloroform as the eluent). This gives 2.93 g (89%)
of oxaziridine IVd.
Oxaziridines IVa-c and e-j are obtained in a similar manner.
Aceta!dehyde 2,4-Dinitrophenylhydrazone(v!)_: The reaction mass remaining after the
thermolysis of oxaziridine IVb is treated in ~nalogy to [15]. This gives hydrazone Vl, mp
146 ~ . According to the data in [16], mp 147~
cis-Methyl trans-Ethyl 2-tert-Butyloxaziridine-3,3-Dicarboxylate (E-IVh). A solution
of 0.43 g (2 mmoles) of oxaziridine IVd in i0 ml of absolute methanol is given an addition
of a solution of 0.ii g (2 mmoles) of KOH in i0 ml of absolute methanol. The mixture is held
for 24 h, 0.34 g (2 mmoles) of p-toluenesulfonic acid in 5 ml of absolute methanol is added
at 0~ the mixture is stirred for 5 min, and a solution of diazoethane in ether is added
until the evolution of nitrogen ceases. The reaction mixture is held for i0 min, the solvents
are removed at a reduced pressure, the residue is extracted with ether (two 50-ml portions),
and the ether is evaporated. The product is chromatographed in a column (Silica Gel LI00/160~
with chloroform as the eluent). This gives 0.39 g (85%)of oxaziridine E-IVh.
Oxaziridine E-IVg is obtained in a similar manner.

LITERATURE CITED
i. G. V. Shustov, M. A. Shokhen, S. V. Barmina, A. V. Eremeev, and R. G. Kostyanovskii,
Dokl. Akad. Nauk SSSR, 287, 689 (1986).
2. R. G. Kostyanovskii and V. F. Rudchenko, Dokl. Akad. Nauk SSSR, 231, 878 (1976).
3. G. V. Shustov, O. A. D'yachenko, S. M. Aldoshin, A. B. Zolotoi, M.D. Isobaev, I. I. Cher-
vin, L. O. Atovmyan, and R. G. Kostyanovskii Dokl. Akad. Nauk SSSR, 231, 1174 (1976).
4. V. F. Rudchenko, O. A. D'yachenko, A. B. Zolotoi, L. O. Atovmyan, I. I. Chervin, and
R. G. Kostyanovskii (Kostyanovsky), Tetrahedron, 38, 961 (1982).
5. F. Montanari, J. Moretti, and G. Torre, Chem. Comm., No. 19, 1086 (1976).
6. M. L. Scheinbaum, Tetrahedron Lett., No. 48, 4221 (1969).
7. M. J. Haddadin, A. M. Kattan, and J. P. Freeman, J. Org. Chem., 47, 723 (1982).
8. A. V. Prosyanik, D. V. Fedoseenko, I. I. Chervin, Sh. S. Nasibov, and R. G. Kostyanov-
skii, Dokl. Akad. Nauk SSSR, 270, 337 (1983).

436
 9. A. I. Mishchenko, A. V. Prosyanik, A. P. Pleshkova, M. D. Isobaev, V. I. Markov, and
R. G. Kostyanovskii, Izv. Akad. Nauk SSSR, Ser. Khim., No. I, 139 (1979).
i0. T. Jonezava, J. Morishima, and K. Fukuta, Bull. Chem. Soc. Japan, 41, 2297 (1968).
ii. A. J. Gordon and R. A. Ford, A Chemist's Companion: A Handbook of Practical Data, Tech-
niques, and References, Wiley--Interscience, New York (1973).
12. J. S. Splitter and M. Calvin, Tetrah. Lett., No. 42, 411 (1973).
13. Societe Chimique des Usines du Rhone, German Patent No. 427,856; Beilstein, Vol. II, 2nd
Edn., Springer-Verlag, Berlin (1942), p. 523.
14. R. Wilstatter, Ber., 35, 1376 (1902).
15. Methoden der Organischen Chemie (Houben-Weyl), Vol. 10/3, Georg Thieme Verlag, Stuttgart,
(1965), p. 476.
16o A. Purgotti, Gazz. Chim. Ital., 24, 565 (1894).

OXAZOLIDINES.
i. BASIC CATALYTIC DISPROPORTIONATION OF CYCLOHEXANOSPIRO-
2-OXAZOLIDINES: SYNTHESIS OF N-SUBSTITUTED 4,5,6,7-TETRAHYDROINDOLES

B. F. Kukharev, V. K. Stankevich, UDC 547.787.3'752:543.422.25

and V. A. Kukhareva

It has been shown that the basic catalytic disproportionation of cyclohexanospiro-

2-oxazolidines in the presence of potassium hydroxide or sodium methylate leads to
N-substituted 4,5,6,7-tetrahydroindoles with a yield of up to 73%. The influence
of the character of substituents at the nitrogen atom of oxazolidine on the course
of the reaction has been established.

The cyclohexanospiro-2-oxazolidines disproportionate in the presence of potassium tert-

butylate to form tetrahydroindole derivatives with yields of up to 20% [I]. In order to de-
velop a procedure for the preparation of 1-substituted tetrahydroindoles from readily avail-
ably cyclohexanospiro-2-oxazolidines we have investigated the disproportionation of 3-(2-hy-
droxyethyl)-cyclohexanospiro-2-oxazolidine (I) under the influence of the hydroxides and al-
coholates (C,-C~) of potassium, sodium, lithium, calcium, barium, and aluminum. The highest
activity (at a high selectivity) was shown among the catalysts of this series by potassium
hydroxide and sodium metbylate, while the aluminum hydroxide and alcoholates did not catalyze
the process at all. The highest yields of l-(2-hydroxyethyl)-4,5,6,7-tetrahydroindole (IIa)
(63-73%) were obtained by refluxing 1 mole of oxazolidine I with 0.2-0.5 mole potassium hy-
droxide or sodium methylate. The duration of the reaction, determined by GLC from the time
required for the complete decomposition of the oxazolidine Ia, was 2.5-4 h.
The disproportionation of the oxazolidines Ib-m was also performed under the conditions
found.

1r T,'.1 . R2
r O- ]" ~...OH /^ ----. R'

i a-m IIa-m

L If a,k R (UI~(IH2()}I.b,m R=CFI:,. c R~ CII(~]J~)~. d R= C4Ho,t. e R=C4Hg-i.

f R=C~ll,,-u, g R=C~IIs. h R-CFI,~CsHs. i Ir162 [ I?=C[t~GIt(OH)CHa;
a - k R ' ~ [ I , l ,m R'=CII:~; a--i~l.mlU~: tt, k 1{~ = Ctl,,~

Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR,
Irkutsk 664033. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 533-535,
April, 1986. Original article submitted December 3, 1984.

0009-3122/86/2204-0437512.50 9 1986 Plenum Publishing Corporation 437

 TABLE i. Tetrahydroindoles la-m

und, 9o Em~trteal Calaulated, % Yield'

peundl {p=e,,ure, I",, "',"1
::7 r, [ : '0
. . . . . . . .

. I l '. )' .........

Ila 14,t-,.147 (5) I,(')~{'}1 i,5.li 5 7Z:I! !),:1 K7i Gi,,I I),,N! } 7~,n q,L 8,5 78
llb 108~104 {1i} 0,!)!)06 1,8~H7 71),;')I 9,6 I0,~ C!Jti:~N 8(},0
IIr 115~118 (20) 0,(D566 1,81 ;}8 81)~) 0s 8,8 {]i)It)?N 8.),9 10.5 ~.(~l 8(3
lid 114--117 (5) {},9,109 1,810(} 81,0 I0,5 8,0 ~;l:,ll!:)N ,~;I ,:q In,8 7.91 Ik2
Ile 116--118 (12) 0,94.14 I,fi08 I 81A 10,,q 7,S i GiL,IIi,,N ~,t,a / I(L8 73) 1 47
llf 110--119, (9) (},94(15 1,8{}{,_)7 81A l{J,(J 7,!i l t]i~ili,N st,;)] 10,8 7!)1 30
152~155 (8} 1,{}736 1,5!}60 88,4 7.6 7,i Ci)[/l~N 7.', ', 88
150~-152 {4) 1,0M8 1,5786 8,5,1 8,0 iL(I (;]l~>lli~,N S5,8| 8,1 6,6 i 43
lli 134,-137 (3) 1,0067 1,388(1 82,~; Io,5 7,o (] 1.1[l~j N 8t).7 ) I 0,,l (3,9] 41)
Ilk 150~158 {4). 1,0601 1,5;J{i{} 73,5 {)J} ?,i) C!ll[l:NO 78,7I ),6 7,81 ~" .}~)
Ill 133--134 (8) 1,0P, I 0 I ~957 74,9 C',l~t lioN(") 7'1,6 ] !),9 7.,~[ 68
Ilrn 113--116{15) 80,4 1(i,7 915 80,5 10,1
[38--a41 I (.Jtil['[ !t,N D,4 I 58

Besides the tetrahydroindoles lla-m, cyclohexanols and aminoalcohols are also formed in
the reaction with yields of 75-95%. The character of the substituent at the nitrogen atom of
the oxazolidine ring has an essential influence on the course of the process. Thus the time
required for the complete conversion (as controlled by GLC) of 3-methyl- (Ib), 3-benzyl- (Ih),
and 3-phenylcyclohexanospiro-2-oxazolidines (Ig) to the corresponding tetrahydroindoles in
the presence of 40 mole % of potassium hydroxide was 3,5,8, and 15 h, respectively; 3-acetyl-
cyclohexanospiro-2-oxazolidine could not be converted to the corresponding indole in the
presence of the above amount of catalyst even when heated at 250 ~ for 20 h. Attempts to dis-
proportionate cyclohexanospiro-2-oxazolidine and 5-methyleyclohexanospiro-2-oxazolidine, un-
substituted at the nitrogen atom, lead to their complete decomposition, accompanied by the
formation of cyclohexanol, ethanol- and propanolamines (respectively), and resin-like substan-
ces; only traces of the expected 4,5,6,7-tetrahydroindole and 3-methyl-4,5,6,7-tetrahydroin-
dole were detected. Such a strong difference in the behavior of the N-substituted and N-un-
substituted oxazolidines can only be attributed to the fact that the latter, inclining to
tautomerism, react not in the cyclic form but in the form of azomethyne alcohols instead.
Thus, the region in which the reaction of basic catalytic disproportionation proceeds
normally is limited on one side by the N-unsubstituted oxazolidines and on the other side by
oxazolidines containing a low-basicity, for instance, an amide nitrogen atom. Within this
region the reaction can be used successfully for the preparative synthesis of N-substituted
4,5,6,7-tetrahydroindoles.
The identity and structure of the synthesized tetrahydroindoles IIa-m have been confirmed
by GLC and IR and NMR spectroscopy. The physicochemical constants of the cyclohexanols and
aminoalcohols obtained in the reactions correspond to literature data.

EXPERIMENTAL
The cyclohexanospiro-2-oxazolidines used in the work were synthesized by the condensa-
tion of cyclohexanone and 2-methylcyclohexanone with aminoalcohols according to the procedure
given in [2]. The chromatographic analysis was performed on a LKhM-8MD chromatograph equipped
with a catharometer detector; the length of the column was 2 m, the diameter 3 m; the solid
phase was Chromaton N-AW-HMDS, the liquid phase 15% DS-550 siloxane oil; temperature program-
ming was used from i00 to 225~ at a rate of 4~ with helium as the carrier gas. The NMR
(PMR) spectra were taken on a BS-487B spectrometer (80 MHz). The compounds were investigated
as 10-% solutions in CC14 with HMDS as internal standard. The IR spectra were obtained on a
UR-20 spectrometer in the form of liquid films or KBr tablets.
General Procedure for the Disproportionationof Cyclohexanospiro-2-oxazolidines. A mix-
ture of 0.2 mole of oxazolidine la-m and 0.04-0.1 mole potassium hydroxide or sodium methylate
is brought to the boil. The initial boiling temperature (220~ ~ decreases gradually and
spontaneously to 150-260 ~ . Samples are taken periodically during the reaction (1-2 times per
hour) and analyzed by GLC. The reaction is continued until complete conversion of the oxa-
zolidine. The cooled reaction mixture is dissolved in 200 ml benzene and extracted with water
(3 50 ml); the extract is distilled in vacuum to separate cyclohexanol and the 4,5,6,7-
tetrahydroindoles. The aminoalcohols are isolated from the combined aqueous extracts. In the
disproportionation of oxazolidines Ig-i ethanolamines are formed which are poorly soluble in
water. The benzene solution of the reaction mixture is treated first with the calculated

438
 TABLE 2. Spectroscopic Characteristics of Tetrahydroindoles
la-m
PMR spectrum, ppm IR spectrum, v, em : r - - "
Com-
pound 2-H [ ~H I 7-H
4-H, 6-H
5.H, ] R
pyrrole_._~
tint, =CH I R
in m
I
Ila 5,65 2,41 In (NCH2CH20), 1490, 1570, 3440
s (OH) 1660 (OH)
lib 5,64 2,34 s (NCH,~) 1485, 1570
llc 5,77 2,50 m ~NCH), 1,29, a 1490, 1580,
~CCH3) 1650
lid 5,66 2,44 t (NCH~), 1,42-- 1485, 1620
In (CH~CH2), 0,90, t
llle 5,62 2,42 0d (NCII2), 1,40- 1500, 1590,
m (CCHC), (I,92, d 1640
,CCH3)
llf 5,67 2,42 In (NCtt), 1,55-- 1485, 1580,
(CCH2C), 1,30, d 1640
2H3), 0,77, 't
2CH~)
IIg 5,87 2,55 m (C6H~) 15001 1590

llh 5,80 2,35 s (NCH2), 7,14, m 1490, 1670 1590,

~) 1602
(C6H5)
lIi 5,65 2,49 in (NCH), 1,43-- 1480, 1662
In (CH~)5
Ilk 5,69 2,40 (NCH~CH.~O), 1492, 1560, 3450
2,57 (OH), 1,14, d 1642 (OH)
II.l -- 2,35 f~ (NCH2), 3,71,m 1520 3420
q), 3,40, s (OH); (OH)
s (C=CCH~), 1,20,
CCH.0
IIm - - 2,40 s (NCH3), 1,91, s 1530, 1590,
CCH3) 1630

*SSIC 2J23 = 2.9 0.i Hz in all compounds.

amount of i mole/liter hydrochloric acid and then extracted with water (3 50 ml); the ex-
tract is washed with i00 ml 1% sodium carbonate solution and distilled. The quantity of acid
is taken which is necessary to neutralize the catalyst and 0.i mole of the aminoalcohol formed.
The aminoalcohol is isolated from the combined extracts (after neutralization with potassium
hydroxide) by distillation in vacuum.

LITERATURE CITED
i. B. F. Kukharev and A. S. Atavin, Khim. Geterotsikl. Soedin., No. ii, 1580 (1973).
2. K. D. Petrov and G. I. Ostroumova, Khim. Geterotsikl. Soedin., No. 2, 204 (1967).

439
OXAZOLIDINES.
2.* SYNTHESIS OF 2-METHYLOXAZOLIDINES BY CYCLIZATION OF VINYL ETHERS
OF 1,2-AMINO ALCOHOLS

B. F. Kukharev, V. K. Stankevich, UDC 547.435'787:07:541.128

G. R. Klimenko, V. P. Terent'eva,
and V. A. Kukhareva

A study has been made of the catalytic activity of a number of proton acids and
Lewis acids, amongst which mercury salts were particularly active, in the cycliza-
tion of N-phenylethanolamine vinyl ether to 2-methyl-3-phenyloxazolidine. A meth-
od for the preparative synthesis of 2-methyloxazolidines has been developed.

Condensation of amino alcohols with carbonyl compounds is not very suitable for the syn-
thesis of 2,methyloxazolidines [2] since the aldehyde used readily undergoes self-condensa-
tion. Taking into account the future prospects for using oxazolidines [3], it is of interest
to search for new ways of synthesizing them.
It is known that by the action of proton acids N-acetylethanolamine vinyl ether is con-
verted quantitatively to 3-acetyl-2-methyloxazolidine [4], N-phenylethanolamine vinyl ether
forms 2-methyl-3-phenyloxazolidine with 13% yfeld [5], while the vinyl ethers of mono- and
diethanolamine are not cyclized at all [5, 6]. According to our data [7], they are all con-
verted to 2-methyloxazolidines by the action of palladium chloride.
With the aim of elucidating the possibilities of preparative synthesis, in the present
work the isomerization of N-phenylethanolamine r ether (la) on treatment with proton
acids and Lewis acids at concentrations up to 0.05 moles/liter in a solution of l-methyl-2-
pyrrolidone at 40~ was studied with the help of GLC. Under these conditions acetic acid,
SnCI~, salts of copper, zinc, cadmium, lead, and thallium did not bring about the cyclization
of ether la. In the presence of perfluoroacetic and p-toluenesulfonic acids and also SnCla,
together w i t h t h e formation Of 2-methyl-3-phenyloxazolidine (lla) the reaction mixture be-
comes tarry and the yield of oxazolidine lla does not exceed 65% for a 20-25% degree of con-
version of ether la. With an increase in conversion of ether la the yield of oxazolidine lla
falls to 10-15%. Silver nitrate, although causing ether la to cyclize, is rapidly deactivated,
being reduced to metallic silver. Only salts of mercury and palladium bring about a quanti-
tative conversion of la lla.
The catalytic rate constants of the first-order reaction were 1.24-10-", 7.5.10 -5 , and
2.81-10 -~ sec -I for mercuric acetate, mercuric chloride, and palladium chloride, respectively.

CH2:~-~CH- O- CtII,F"CHR' NHE ----~'~ i.......I

o ,N
la-j "I ....."r
CH%
isa-]

I, I l a R=C~Hs. b R=H, c R=CH2CH2OH. d R=CH=CH2OCH=CH2, e.i. j R=Ct-I~,

f R=CH~CH~CN, g R=CH~C6Hs,h R=CHaCO; a . i RI=H,j Rl=Cth; a.-d,f, iR~=H,
e R~=CH~OCH.~, J R:=CHo

For the preparative synthesis of 2-methyloxazolidines we proposed carrying out the cy-
clization of vinyl ethers of 1,2-amino alcohols in inert solvent media (diethyl ether, hexane,

*For Communication i, see [i].

Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR,
Irkutsk. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 536-538, April,
1986. Original article submitted January 23, 1985.

440 0009-3122/86/2204-0440512.50 9 1986 Plenum Publishing Corporation

 TABLE !. Oxazolidines IIa-j

Compound Data bp, r (mm) ,%:o (nD:,~) d : (tiT) Yield, %

lla
lib Ours 53--56 (60) 1,4345 0,9668 48
[91 50--60 (60) {1,4336) (0,9651)
IIc Ours 55--58 (2) 1.4680 1,0543 76
[91 69 (4,5) ll,4663)
lid Ours 78--80 (11) 1,4590 0,9855 98
[91 76--78 (9) (I,4552) (0,977)
lie 60--63 (15) 1,4332 0,9609 81
llf 91--93 (2,5) 1,4620 1,0215 9O
IIg Ours 106--I08 (4) 1,5203 1,0217 98
[1o] 190--195 (25)
lh Ours 105--108 (10) 1,4660 1,0810 99
[41 92 (4) 1,4670 1,087
lli Ours 106--108 (720) 1,4235 0,9046 86
[21 109 (758)
.J 50--52 (60) 1,4247 0,8864 76

benzene, etc.) in the presence of 0.2-0.5% mercuric acetate. Oxazolidines IIa, IIc-j were ob-
tained with yields from 76% to quantitative (Table i). Oxazolidines IIe and IIj were equi-
molecular mixtures of two and four stereoisomers, respectively.
On cyclization of monoethanolamine vinyl ether (Ib), 2-methyloxazolidine (yield 20%),
monoethanolamine, and N-ethylideneethanolamine vinyl ether (III) are formed. Such an outcome
can evidently be explained by the ability of oxazolidine IIb to tautomerize to azomethine B
[8]. Even by simply mixing ether Ib and oxazolidine IIb the following reaction occurs:

ib
|~- - | ~ ----.~- cN.r.H=NCN..CH.OM .......... ___~.. C H ~CI:[=NCII~CI!r0 C H = C H ~
0 /NH -'~- . . . . . . . .
, NJ] r'l! .'l ~ )}1
Ill
('J|~

a .b

Taking into account the reversibility of the reaction it is possible to increase the
yield of oxazolidine IIb to 48%, on conducting the cyclization of vinyl ether Ib in a monoeth-
anolamine medium.

EXPERIMENTAL
Chromatographic analysis was carried out on a LKhM-8MD instrument, with Catharometer de-
tector, column 2 m 3 mm, Chromatone N-AW-HMDS as solid phase, 15% polyethylene glycol 20,000
as liquid phase, thermostat temperature programmed from 50 to 170~ with a rate 4~ and
helium carrier gas. The initial ethers I were obtained according to methods [5, 6].
2-MethyI-3-phenyloxazolidine (lla). We boiled 16.32 g (0.i mole) N-phenylethanolamine
vinyl ether (ia), 0.08 g (0.28 mmole) mercuric acetate, and 20 ml diethyl ether under reflux
for 3 h with stirring. After removal of solvent by distillation at atmospheric pressure the
reaction mass crystallized out. 16.4 g (100%) oxazolidine IIa was obtained, with mp 55-60~
59.5-60~ (from diethyl ether); according to the data of [5], mp 58.5-59~
2-Methx!v3-cyanoethylox~zolidine (IIf). Welheatedl4.02 g N-cyanoethylethanolamine vinyl
ether (If), 0.07 g (0.24 mmole) mercuric acetate, and 35 ml benzene for 3 h at 70~ with
stirring. 12.67 g (90%) oxazolidine IIf was separated by vacuum distillation. Found: C 60.1;
H 8.9; N 19.9%. Mr D 37.03. CTHI=N20. Calculated: C 60.0; H 8.9; N 20.0%. Mr D 37.48.
Oxazolidines IIc-e, g-j. These were obtained in a similar manner. IIe. Found: C 57.6;
H 10.4; N 9.8%. Mr D 39.29. CvHIsNO 2. Calculated: C 57.9; H 10.4; N 9.6%. Mr D 39.42. IIj,
found: C 64.9; H 11.7; N 11.0%. Mr D 37.25. CTH, sNO. Calculated: C 65.1; H 11.7; N 10.8%. Mr D
37.63.
2-Methyloxazolidine (IIb) and N-Ethylideneethanolamine Vinyl Ether (III). 87 g (i000
mmoles) monoethanolamine vinyl ether (Ib), 0.43 g (1.5 mmoles) mercuric acetate, and i00 ml
hexane were heated for 4 h at 60~ with stirring. On distillation under vacuum on a rectifica-
tion column (20 theoretical plates), 17.4 g (20%) oxazolidine IIb [53-56~ (60 mm)], 26.1 g
2O
monoethanolamine, and 28.3 g vinyl ether III were separated. III: bp 74-75~ (i00 mm); n D

441
1.4405; d~ 2~ 0.8784. IR spectrum (thin layer): 1620 (C=C), 1660 ( ~ ) , 3100 cm -z (----C--H).PMR
spectrum (in CCI~): 7.53 (IH, q, N=CH), 6.32 (IH, q, OCH==C), 4.08 (IH, q, trans-C--CH), 3.87
(IH, q, cis-C--CH), 3.75 (2H, m, OCH2), 3.54 (2H, m, NCH2), 1.87 ppm (3H, d, CH3). Found: C
63.3; H 9.6; N 12.2%. Mr D 34.02. C~HIINO. Calculated: C 63.7; H 9.8; N 12.4%. Mr D 34.37.
On conducting the reaction in a similar manner in 200 ml monoethanolamine, 41.6 g (48%)
oxazolidine IIb was obtained.

LITERATURE CITED
i. B. F. Kukharev, V. K. Stankevich, and V. A, Kukhareva, Khim. Geterotsikl. Soedin., No.4,
533 (1986).
2. L. Knorr and H. Mattes, Ber., 34, 3484 (1901).
3. D. L. Rakhmankulov, V. V. "Zorin, F, N. Latypova, S. S. Zlotskii, and R. A. Karakhanov,
Khim. Geterotsikl. Soedin., No. 4, 435 (1982).
4. 0. A. Tarasova, B. A. Trofimov, M. L. Al'pert, N. I. Ivanova, S. V. Amosova, and M. G.
Voronkov, Zh. 0rg. Khim., 17, 2628 (1981).
5. M. F. Shostakovskii and I. A. Chekulaeva, Izv. Akad. Nauk SSSR, Otd. Khim. Nauk, 146
(1955).
6. M. F. Shostakovskii and I. A. Chekulaeva, Izv. Akad. Nauk SSSR, Otd. Khim. Nauk, iiii
(1954).
7. B. F. Kukharev, V. K.Stankevich, V. P. Terent'eva, and V. A. Kukhareva, Zh. Org. Khim.,
20, 1344 (1984).
8. E. D. Bergmann, Chem. Revs., 53, 309 (1953).
9. L. E. Conlon and W. A. Watanabe, US Patent No. 2817663; Chem. Abs., 52, 7363 (1958).
i0. N. Kh. Maksudov, M. M. Makhamatkhanov, A. Aripov, and Zh. Seitkasymov, Uz. Khim. Zh.,
No. 2, 70 (1978).

MASS SPECTROMETRIC STUDY OF 1,2,4- AND 1,3,4-OXADIAZOLES CONTAINING

INDOLE SUBSTITUENTS

R. L. Ushakova, A. I. Mikaya, UDC 543.51:547.793'752

V. G. Zaikin, V. l.Kelarev,
and G. A. Shveikhgeimer

1,2,4- and 1,3,4-Oxadiazoles containing indole substituents decompose upon electron

impact due to breakage of bonds in the oxadiazole ring. Skeletal rearrangements may
occur in the molecular ions of 2,5-diaryl-l,3,4-oxadiazoles due to migration of the
aryl groups.

There has recentlY been increasing interest in indole derivatives containing 1,2,4- and
1,3,4-oxadiazole fragments since compounds have been found among these bisheterocyclic systems
possessing a broad range of biological activity.
Extensive information is not available on the dissociative ionization of aryloxadiazoles
[1-6] upon electron impact and the possibility of the mass spectrometric differentiation of
substituted 1,2,4- and 1,3,4-oxadiazoles and of positional isomers has not been adequately
evaluated. In this regard, we studied the electron impact mass spectra of 1,2,4- (I-IV) and
1,3,4-oxadiazoles (V-X) containing a 3-indolyl or (3'-indolyl)methyl group as one of the sub-
stituents. We studied both common and specific pathways for the decomposition of these com-
pounds and elucidated diagnostic fragmentation patterns suitable for the differentiation of
isomers. The mass spectral data for 1,2,4-oxadiazoles I-IV at 70 eV ionizing electron energy
are given in Table I, while the corresponding data for V-X are given in Table 2.

I. M. Gubkin Moscow Institute for Petrochemistry and the Gas Industry, Moscow 117296.
A. V. Topchiev Institute of Petrochemical Synthesis, Academy of sciences of the USSR, Moscow
117912. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 539-543, April,
1986. Original article submitted December 18, 1984; revision submitted March 26, 1985.

442 0009-3122/86/2204-0442512.50 ~ 1986 Plenum Publishing Corporation

 l--Iv v-X (indolyl-3 ' )methyl

I. VII R'= indolyl-3, If, IV, VIII, X R'=C6HsI'.III. IX R'=n-NO2C6H,. V R'=H. VI

R'=CH2Ch I R-~=C6Hs, 11, 1II, V - - I X R~-~"indolyl-3,1 V', X R~=(,HH~IOJIH~I-3')MeTHJI

The mass spectra of oxadiazoles I-X display rather strong molecular ion peaks (M+) which
are sometimes accompanied by [M -- H] + ion peaks. The major processes for the decomposition of
M + of these compounds are related to the loss of the aryl substituent or breakage of the oxa-
diazole ring. The processes involving break age of the oxadiazole ring hold the greatest in-
terest relative to structural analysis since they are characteristic for the entire series of
compounds studied.
For 3,5-diaryl-l,2,4-oxadiazoles I-IV, among the most advantageous dissociative ioniza-
tion processes, we should note three major directions due to the process which is the reverse
of 1,3-dipolar addition: breakage of the O-C(5) and C(3)--N(~) (pathway A) and breakage of &-N
and N-C(s) bonds (B) or of the O-N and C(3)--N(~) bonds (C). As a result of the oxadiazole
ring by the first two pathways, the charge may be localized on both parts of the molecule. In
this case, the peaks for the ions formed have strong intensity in the spectra of I-IV.

[R2]+
IR~_C___N]~.' f

Ia-HCN]
A ~Nco
[RI]+
U
[R~CNO)+"
b ~ -~0 Ib .Co] +

[R' C] +
-s
A +'
___B__ c f
N
B
M +', I-D"

C
~R1LCmN]+'
e

The primary ions (a-e) undergo further decomposition through pathways typical for cyan-
ides and diazo compounds [7].
We should note that, despite the common nature of thedissociative ionization of 1,2,4-
oxadiazoles I-IV, the differences in the structural elements contribute to the form of the
mass spectrum. Thus, the presence of the (3'-indolyl)methyl substituent in IV suppresses t h e
decomposition due to breakage of the oxadiazole ring. Thms is a result of the favorable
"benzyl" cleavage leading to the maximum peak for the ion with m/z 130.* This ion most likely
has quinolinium structure [7]~ The maximum perks in the mass spectra of I and II correspond
to the [b -- NO] + (or [d -- N=] ) ions, while the major peak in the spectrum of II is due to
type-a ions. On the other hand, the peak for the type-b ion ([C6HsCNO] +) has greatest intens-
ity in the mass spectrum of 3,5-diphenyl-l,2,4-oxadiazole [4].
The M + ion for 1,3,4-oxadiazoles V-X, in contrast to the corresponding ions of the 1,2,4
analogs, decompose mainly along pathways A and B and also with the formation of aroyl ions.
In this case, the peaks with m/z 144 (type-g ions) are the maximum peaks in the spectra of
V-IX. The peaks with m/z 116 are apparently the result of the further decomposition of the
type-g ion through elimination of a CO molecule. The minor fragmentation for M + of V-X are
accompanied by the formation of arylnitrile radical-ions as a result of breakage of the O-C(s)

*The numbers given for the ions in the schemes are the corresponding m/z values.

443
TABLE i, Characterlstlc Ions in the Mass Spectra of 3,5-D1aryl-l,2,4-Oxadiazoles l-IV
m / z Values ( i n t e m i t y as % ? f the m a x i m u m peak)
Com-
pound
liq-- HI ~ {b.-HCN)+ [ b Ib-col' IR'CY .f

I 261 (12) 200 (3) 1o3 (38) 76 .(3) 158 (58) 130 .(14) 128 (lliO) !o5 (2o) 156 (74) 142 (7) 77 (8} ! 16 {2}
!1 261 (53) 260 (6) t42 ~100) l l 5 (7} 119 (28) 91 (3) 89 (6i ]44 (73) 117 (36) 9 103 (3) lift (62) 77 13)
[11 306 (72) t42 (75) 115 (34) 164 (14) 136 (4) 9 134 (100) 144 (68) 162 (28) lift (49)
IV 275 (17) 274 (3) 156 (22~ 129 (72) )19 (46) 91 (25) 89 (13) 158 (55) 117 (3) 103 (7) 130 (!00) 77 (15|
 TABLE 2. Mass Spectra Of Compounds

Com-*
pound
m/z Value (~) T

V I01 {27), I02 (28), I03 (29), 114 (8), 115 (23), 116 (33), 127 (5), 128
(37), 179 (52), 142 (13), 143 (lO), 144 (lO0), 185 (M+, 64)
VI I01 (10), 102 (7), 103 (7), 115 (13). 116 (~4), 128 (14), 142 (17), 143 (9),
144 {100). 198 (24), 233/235 {M~, 33/11)
VII 101 ( I l L 102 ( I l L 103 (12), 114 r 115 (10). 116 (33), 128 (15), 129
154). 142 (12). 143 (5), 144 (100). 243 (34), 244 (13). 300 (M +', 50)
VIII 105 (50), 115 (30). 116 {75). 117 (34). 118 (7). 142 (14), 143 (9), 144
(I00), 204 (15), 205 {9), 261 (M~', 23)
IX lOl (9), 102 (7), 103 {7), 104 (17), I05 (7), If5 (12), I16 (23), 120 (12),
128 {9), 199 (5), 142 (18). 143 (8). 144 (10(}), 150 (13), 204 (8), 276 (7),
305 (17), 306 iM~% 41)
X 103 126). 104 (9), 105 (27), 115 (6), 116 (12), 117 (10), 118 (5). 119 (6),
130 (lO0), 144 (32), 145 (13), 217 (6), 275 (M +', 42).

*2-(3'-indolyl)- (V), 2-chloromethyl-5-(3'-indolyl)- (VI),

2,5-bis(3'-indolyl)- (VII), 2-phenyl-5-(3'~indolyl) - (VIII),
2-(para-nitrophenyl)-5-(3'-indolyl)- (IX), 2-phenyl-5-[(3'-in-
dolyl)methyl]-l,3,4-oxadiazole (X).
tPeaks are given in the range from i00 to M + with intensity
>5%.

and N-N or O-C(2) and N--N bonds. When R ~ is not an aromatic substituent (V and VI), there are
no peaks in the spectra for [R~CO] + and [R~CN] +.

:%. B C +

H H
Ii ' g. 144 {100..~} 11
9 tl .....
'-C N/ 9 _+
t|
M +. V *' A
l.,J
H
142

Benzyl cleavage with the formation of the maximum peak for the (3'-indolyl)methyl cation
is the major fragmentation process for X upon electron impact. On the other hand, the decomp-
osition pathways noted for the other 1,3,4-oxadiazoles (V-IX) are less pronounced.
The most diagnostic pathway for the decomposition of M + of 1,3,4-oxadiazoles VII and
VIII which permits the reliable distinction of these compounds from other isomeric oxadiazoles
is related to a rearrangement process. This process may be a consequence of the initial migra-
tion of an aryl group to the carbon atom bearing the other aryl group and subsequent cleavage
of the oxadiazole ring:

I:
]rid
N-

"o"

M*
N-i +"

'At
N .....N
...... ({:-~'~':J'<;~d

A~=,~a (vm. %H5 (urn

-N 2. -co
--~'- +~'",.d
,.~r -!If_

~osivm~
I
---,.
t!
i , ~-4~ ~ll)
H "

H
i. ~o4 (vm)

The formation of type-h and type-i ions was noted for 2,5-diphenyl-l,3,4-oxadiazole [2].
A similar pathway for dissociative ionization was also found in the case of p-nitrophenyl der-
ivative IX. However, this pathway is obtained not in M + b u t rather in the [M - NO] ~ and [M - NO2] +

445
ions, resulting in the formation of ions with m/z 220, 219, 204 and 203, respectively. In go-
ing to X which contains a methylene unit between the oxadiazole ring and the indole system,
the N2CHO species is eliminated with the formation of h' ions after migration of the phenyl
group, while subsequent elimination of a hydrogen atom leads to a type-i' ion:

|! / N N I
+ HN ......
N

H M ~, X

-- N.~F.r

9 CH:C
{/i !' Jl ill ) ....
N'
" i II
i' II hi

We should note that the peaks for ions b-d, g, h, h', i,i', [RX]+ and [R2]+ are the most
important for the determination of the position of the aryl substituents and the nature of
the oxadiazole ring, This is wall illustrated in the ease of isomeric phenyl(indolyl)oxadiaz-
oles I, II and VIII. Thus, the finding of strong peaks of the [IndCNO]+(1958)and [IndCN=] +
(156) ions, on one hand, and [CsHsCO] + (105) ions, on the other, in the spectrum of 1,2,4-oxadiazole
I unequivocally proves the location of the indolyl group at C(a ) and of the phenyl group at C(s ) .
On the other hand, the spectrum of 3-phenyl-5-indolyl-l,2,4-oxadiazole II shows peaks for the
[C~HsCNO] + (119), [IndCO] + (144) and [C~HsCN2] + (117) ions indicating the opposite arrange-
ment of these substituents in the 1,2,4-oxadia~ole ring relative to isomer I. The mass spec-
trum of the third structural isomer VIII shows medium-intensity peaks for j (205) and i ions
(204), which permits the assignment of this compound to the 1,3,4-oxadiazole series.

EXPERIMENTAL
The 1,2,4-oxadiazole (I-IV) and 1,3,4-oxadiazole derivatives (V-X) were prepared in our
previous work [8]. The samples studied were crystalline substances with mp 159-161~ (I),
172-174~ (II), 242-244~ (III), 154-155~ (IV), 193-195~ (V), 202-204~ (Vl), 172-173~
(VII), 263-264~ (VIII), 302-304~ (IX), and iI0-!14~ (X).
The mass spectra were taken on an LKB-2091 mass spectrometer with direct sample inlet
into the ion source (70 eV ionizing electron voltage, 25 ~A emission current and 200~ ion
source temperature) with 90-150~ evaporation temperature for the samples.

LITERATURE CITED
lo Q. N. Porter and J. Baldas, The Mass Spectrum of Heterocyclic Compounds, Wiley-lntersci-
ence, New York (1971), p. 5 2 6
2. J. L. Cotter, J0 Chem. Soc., 5491 (1964).
3. A. Selva, J. F. Zerilli, B. Cavalleri, and G. G. Gallo, Org. Mass Spectrom., 6, 1347
(1972).
4. A. Selva, P. Tralda, L. F. Zerilli, and G. G. Gallo, Org. Mass Spectrom., ii, 217 (1976).
5. A. Selva, L. F. Zerilli, B. Cavalleri, and G. G. Gallo, Org. Mass Spectromo, 9, 558
(1974).
6. T. Tanako, V. E. Marquez, M. T. Di Parsia, and V. Suarez, Org. Mass Spectrom., 13, 236
(1978).
7. H. Budzikiewicz, C. Djerassi, and D. H. Williams, The Mass Spectrometry of Organic Com-
pounds, Holden-Day, San Francisco (1967).
8. V. I. Kelarev and G. A. Shvekhgeimer, Khim. Geterotsikl. Soedin., No. 3, 343 (1982).

446
NMR SPECTRAL STUDY OF THE STRUCTURE OF 2-AMINO-4-THIAZOLINONES

S. M. Ramsh, N. A. Smorygo, UDC 547.789.1.3:543,422.25:541.623

E. S. Khrabrova, and A. I. Ginak

As a consequence of partial double bond nature of the exocyelic C--N bond, 2-methyl-
amino-4-thiazolinone exists in DMSO-D 6 as a mixture of E and Z conformers of the
amino form with predominance of the sterically favored E conformer. 2-Phenylimino-
4-thiazolidinone in the same solvent exists as a mixture of the E and Z isomers
of the imino form.

The tautomerism of 2-methylamino-4-thiazolinone (I) was studied previously employing UV

spectroscopy [I]. The predominance of the amino form was concluded but experience in the
study of the structure of cyclic amidines by various spectral methods [2, 3] has indicated
the necessity of supporting this conclusion with NMR spectral data using model compounds II
and III. The conclusion of Sheinker et al. [4] that 2-phenylimino-4-thiazolidinone (IV) exists
as a mixture of the amino and imino tautomers raises doubt since the NMR spectra of IV were
not compared to the spectra of models V and VI. These circumstances led us to carry out a de-
tailed analysis of the IH and :~C NMR spectra of potentially tautomeric I and IV using the
NMR data for their metyylated derivatives II, III, V and VI~

3.03 ppm ~ _ _ _ ~ o _ . 9 . 5 0 ppm~ r

I
n z ~ ~ ppm cn,--o7 ppm
I-E I-Z

CII z
t R..~

I I I
CH3 CH3 CH3
l-Zsolv I-Z a I-Zsolv:~

N_____~O CH3x N _ ~ 0

I
R II,VI III,V
lI R=CH3; VI R=Ph; Ill R=H; V l~=Ph

H~

Hc..h.J~./H.~I_IN
. . . . _~0 _ HD J~. H~,

~" .~.,,v ~ 7.0 p p m ~nl~,~, ,--7.6 p.pm

[V-E IV-Z

The 13C NMR spectrum of I in DMSO-D 6 contains two sets of signals for the N-CHa group
and the C(2 ) and C(4) atoms (Table 4) (Table i). The signal for the C(5) atom is superimposed

Lensovet Leningrad Technological Institute, Leningrad, 198013. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 4, pp. 544-548, April, 1986. Original article submitted
December 8, 1984.

0009-3122/86,/2204-0447512.50 9 1986 Plenum Publishing Corporation 447

on the solvent signals and its minor component was not found. The downfleld methyl group car-
bon at 36.4 ppm* is approximately three stronger than the upfield signal at 35.3 ppm. The ad-
dition of D20 does not affect the spectral pattern. Comparison of the chemical shifts of I
and model compounds, 2-dimethylamino-4-thiazolinone (II) and 2-imino-3-methyl-4-thiazolldlnone
(III) gives convincing evidence in favor of the amino structure for 2-methylamino-4-thlazolln-
one (I). The doubling of the resonance signals arises due to hindered rotation about the
C(~)-N(~,) double bond [5] resulting in two conformations.'Topomerizatlon is found for !I
due to an analogous reason (Table 1).
The E conformer is sterically favored and predominates the equilibrium but the Z conform-
er is stabilized to some extent by specific solvatlon; the steric hindrance to such solvation
is greater for the E conformer, t The stabilization of the Z conformer by hydrogen bonding with
the solvent is indicated by the significant paramagnetlc shift of the minor NH proton signal
in the PMR spectrum of I by 0.4 ppm more than expected due to the different shielding by the
N(s) and S atom s (Fig. is). The ratio of the intensities of the signals at 9.50 and 9.11
ppm was equal to ~1:3.
The signal of the methyl protons in thoroughly dried DMSO-D s is complex in nature (Fig.
la) and analogous to that observed for 2-methylamino-5-benzylidene-4-thiazoline [6]. We as-
sume that the signal of the methyl protons of the E conformer are split by the slowly exchang-
ing NH protons with JHNCHs = 4.6 Hz and coupling is observed only for those molecules whose
NH protons do not participate in exchange processes caused by solvent impurities. The unsplit
signal of the CHs protons of the E conformer is found at 3.03 ppm. The NH protons of the Z
conformer exchange much more rapidly and do not split the signal of the methyl protons at 2.97
ppm. The greater rate of exchange of the H E protons is attributed to the capacity of the Z
form to undergo self-association with the ~ormation of I-Z2 dlmers and association with the
formation of solvated complexes I-Zsolv or I-Zsolv ~. The sterlc hindrance for solvation of the
NH group in the E form may play a role in the reduced rate of exchange of the H z proton in
this form as in the case of secondary amides [7]. The multiplet ~oalesces at about 65~
The methyl proton multiplet simplifies in most DMSO-D s by the action of impurities pres-
ent in the solvent which catalyze exchange and after isotope exchange with heavy water: the
doublet disappears and only the signals at 3.03 and 2.97 ppm remain (Fig. ib). The signal at
3.03 ppm related to the E conformer is approximately three times stronger than the signal at
2.97 ppm for the Z conformer. The position and relative intensity of the signals for the NH
protons in moist DMSO-D s are not altered but "the signal at 9.50 ppm is broadened.
The PMR spectrum of I taken with suppression of the HN--CHs doupling does not show a con-
centration dependence of the relative intensity of the doubled signals. Hence, in contrast to
the chloroform solution of an analogous oxazoline [8], the dimerization constant for the Z
conformer in I-Z.
The participation of the Z conformer in an exchange process, in which the E conformer does
not participate or participates to a much reduced extent, is indicated by the broadening of
the signal at 9.50 ppm until it almost completely disappears upon the addition of a drop of
acetic acid into a solution of I in dry DMSO-D6, while the signal at 9.11 ppm does not broad-
en in this case and the splitting of the methyl proton signal of the E conformer does not dis-
appear. This exchange apparently occurs in solvated complexes l-ZsolvOr I-Zsolv 2. Broadening
of the signal at 9.50 ppm is sometimes observed in dry DMSO-D e along with HN-CH3 coupling and
always in the ease of suppression of this coupling by rapid exchange of the NH protons of the
E conformer. The ratio of the intensities of the H E and H Z protons is independent of their
form.
Evidence for the existence of solvated complexes of the Z conformer with water is found
in the splitting of the water proton signal in the PMR spectrum of I taken in moist DMSO-D e
at 270 MHz. The weaker downfield signal at 3.38 ppm is related to protons of "excess" water
molecules outside the solvation shell of the Z conformer. Indeed, if H=O is now added (or the
solution is diluted) or D20 is added to the ampule, the downfield signal at 3.38 ppm (H20)
or 3.48 ppm (DHO) becomes stronger, demonstrating the saturation of the solvate by H=O or DHO
molecules. In light of the integral intensity, the solvate has dihydrate structure I-Zsolv ~.

~'rhe signals for Ct2~ and C(~) have low intensity.

*The significant positlve charge on N(=) also facilitates the participation of the Z form in
associative processes, while the positive charge on the sulfur atom is much less [5].

448
 -,~ ,- 3HN_CH;4,@Hz

;
b

a 4 3 2 8,.pprn

I ........
.L~_____-L .... I I ..... I J

10 9 8 7 6 5 4 3 2 ~, ppm
F i g . 1. PMR s p e c t r a o f 2 - m e t h y l a m i n o - 4 - t h i a z o l i n e ( I ) , . 80
MHz: ~) in dry DMSO-D and b) after isotope exchange with
D20.

TABLE I. Chemical Shifts in the 13C NMR Spectra, ppm

if,-
~Ieterocycle Substituent
Com-
pound phenyl
C4~) C(4) I C(5) me~yl
c, I r c~ic.
I i
I 189.0; 185,0 I 191,7; 191,31 44,5 36,4; 35,3
II 188,4 I 193,0 I 47,6 47,0; 45,7
111 164,5 I 179,0 I 39,3 33,8
IV 178,2; 176,1 [ 188,3 I 35,0

At this radio frequency, not only the methyl protons but also the methylene protons absorb as
doublets.
The dynamic NMR spectra taken at 80 MHz in the absence of spin-spin coupling permitted
us to determine the coalescence temperature for the signals of both the NH and CH3 protons,
which are 348 and 337 K, respectively. The temperature dependence of the line form is typ-
ical for bipositional exchange b~tween states with different occupancies. The activation pa-
rameters AGE+z # = 79.9 and AGF~+Z~ = 76.9 kJ/mole were determined at the coalescence tempera-
ture relative to the methyl proton signals* using the equations of Shanan-Atidi [9] and Gun-
ther [i0] and are approximate values since, in addition to the approximate nature of the
solution of the line form equation [9], the temperature dependence of the occupancies of the
exchanging states was not taken into account, # while the procedure for finding the coales-
cence temperature is complicated by the similarity of the chemical shifts and the unequal in-
tensities of the CH3 proton signals (Av = 4.8 Hz) [i0].
Khovratovich and Chizhevskaya [ii] proposed that 2-phenylimino-4-thiazolidinone (IV) in
the crystal state exists in the imino form but our studies [12] showed that this proposal is
incorrect. Since the amino form is stabilized by ~(2)-C~)=N(3)-C(~
"~ f~ ~- ~, conjugation, the compet-
ing p--~ conjugation should destabilize this form. On the other hand, ~ and ~--~ conjugation
stabilizes the imino form. In other words, a phenyl ring at the exocyclic nitrogen atom in-
creases the energy of the amino form and decreases the energy of the imino form of IV in the
case of a conformation relative to the N(2)--Ph bond favorable for the participation of the
phenyl ring in conjugation. An effect of the structural factor on the position of the tauto-
meric equilibrium should be expected in solutions, especially, in apolar, aprotic solvents,
in which stabilization is actually observed [4, 13]. The NMR data indicate that IV exists in
the imino form also in a dipolar, aprotic solvent, namely, DMSO-D 6.

*The chemical shifts and the line form of the NH protons depend not only on the rate of the
E $ Z exchange.
#Neglecting the enthalpy component (AS ~ = 0), we have kz E = kE , where K is the E 2 Z
equilibrium constant at 29~ (0.3), AG ~ s Z -- AGz+ E = 3 kJ/mole.

449
 0

7 6 8, ppm 8 7 6 ~,ppm
Fig. 2. PMR spectra of 2-phenylimino-3-methyl-4-thiazolid-
inone (V) (a) and 2-phenylimino-4-thiazolidinone (IV) (b) in
DMSO-D at I00 MHz.
6

The phenyl proton signals for 2-phenylimino-3-methyl-4-thiazolidinone (V) which is a

model for the imino form correspond to an AA'BB'C system (Fig. 2a). This compound exists ex-
clusively as the Z isomer due to steric hindrance between the methyl and phenyl groups [14].
Thus the signals of the CH2 and CH3 protons are unsplit. The PMR spectrum of this compound
in deuterochloroform is analogous.
The aromatic protons of 2-methylphenylamino-4-thiazolinone (VI) which is a model for the
amino form, in CDCI3 also give rise to a multiplet but the chemical shifts of the ortho, meta
and para protons differ not as significantly as in the imino form model V. Splitting of the
methyl proton signal is noted due to hindered rotation about the C(2)--N(=) bond. ~ In DMSO-Ds,
the aromatic signal coalesces into a broad peak but the methyl proton signal as previously
remains an asymmetric doublet. The relative intensities of the doublet components indicates
that the Z isomer predominates in DMSO-D6, while the E isomer predominates in CDCI3. The dif-
ference in the isomer content is apparently a consequence of specific solvation in chloroform
due to formation of an intermolecular hydrogen bond. A specific solvation polarizing VI en-
hances the partial positive charge on the exocyclic nitrogen atom, which leads to the observed
inequivalence of the ortho, meta and para protons of the phenyl ring.
The PMR spectrum of IV could not be taken in CDCIs due to poor solubility. In DMSO-D e,
the multiplet for the aromatic meta and para protons has the same form as in V, but the ortho
protons give rise to two unresolved multiplets. The multiplet centered at 8.0 ppm occupies the
same position relative to the meta and para protons as the ortho protons in the spectrum of
V (see Fig. 2a and 2b). This form of the specZrum is attributed to E-Z isomerization occurring
by inversion [4]. The aromatic proton signal is the superposition of AA'BB'C and DD'EE'F
systems with BB'C similar to EE'F. The isomers differ only in the signals of the AA' and DD'
ortho protons. The Z isomer is somewhat favored over the E isomer. The signal of the hetero-
cycle methylene protons is not split. The similar nature of the singals in the PMR spectra of
IV and the model imino form V indicates the imino structure of IV in DMSO-D 6. The chemical
shifts of the two isomers differ sufficiently so that this difference may be detected in the
13C NMR spectrum (Table I) only for C(2).

EXPERIMENTAL
The PMR spectra were taken on a Tesla BS-467 spectrometer at 60 MHz, RYa 2305 spectrome-
ter at 80 MHz and Bruker HX-270 and 270 MHz in DMSO-D 6 and CDCI~ with BMDS as the internal
standard. The sample of DMSO-D 6 was maintained for 24 h over 4-A molecular sieves and distilled
at 2-3 mm in a dry nitrogen stream.
2-Methylamino-4-thiazolinone (I). A sample of 2 ml 25% aqueous methylamine was added to
1.0 g (7 mmoles) 2-methylthio-4-thizzolinone in 15 ml ethanol. After 30 min, the precipitate
formed was filtered off and crystallized from water to give 0.72 g (78%) product, mp 197-198~
(196-199~ [15]). Found: C 21.8; S 24.6%. Calculated for C~H6N20S: N 21.5; S 24.6%.
Samples of II and III were obtained as in our previous work [16] while samples of IV-VI
were obtained by analogy to our previous procedure [13].

LITERATURE CITED
I. E. Akerblom, Acta Chem. Scand., 2_~i, 1437 (1967).
*The aromatic proton signal in this case should correspond to the superposition of AA'BB'C
and DD'EE'F systems [4] but these could not be resolved due to the approximation of these
signals.

450
 2. P. Sohar, G. Feher, and L. Toldy, Org. Magn. Reson., ii, 9 (1978).
3. G. Toth and A, Almasy, Org. Magn. Reson., 19, 219 (1982).
4. A. P. Engoyan, E. M. Peresleni, T. F. Vlasova, I. I. Chizhevskaya, and Yu. N. Sheinker,
Khim. Geterotsikl. Soedin., No. 2, 190 (1978).
5. Yu. G. Basova, Chemical Sciences Candidate's Dissertation, Leningrad (1980).
6. S. M. Ramsh, S. Yu. Solov'eva, and A. I. Ginak, Khim, Geterotsikl. Soedin., No. 6, 761
(1983).
7. C. L. Perrin, E. R. Johnston, C. R. Lollo, and P. A. Kobrin, J. Am. Chem. Soc., 103, 4691
(1981).
8. c. F. Howell, W. Fulmor, N. Q. Quinones, and R. A. Hardy, J. Org. Chem., 29, 370 (1964).
9. H. Shanan-Atidi and K. Bar-Eli, J. Phys. Chem., 74, 961 (1970).
i0. H. Gunther, Introduction to NMR Spectroscopy [Russian translation], Izd. Mir, Moscow
(1984), p. 262.
ii. N. N. Khovratovich and I. I. Chizhevskaya, Khim. Geterotsikl. Soedin., No. 4, 637 (1967).
12. S. M. Ramsh, N. A. Smorygo, and E. S. Khrabrova, Khim. Geterotsikl. Soedin., No. i, 32
(1985).
13. S. M. Ramsh, N. A. Smorygo, A. I. Ginak, and E. G. Sochilin, Zh. Org. Khim., 15, 1506
(1979).
14. A. P. Engoyan, T. F. Vlasova, Yu. N. Sheinker, and I. I. Chizhevskaya, Dokl. Akad. Nauk
SSSR, 209, 1099 (1973).
15. E. Akerblom, Acta Chem. Scand., 21, 843 (1967).
16. S. M. Ramsh, A. I. Ginak, N. A. Smorygo, Yu. G. Basova, and E. G. Sochilin, Zh. Org.
Khim., 14, 1327 (1978).

SYNTHESIS OF ISOMERIC 4- AND 5-HYDROXYLAMINOTHIAZOLIDIN-2-THIONES

T. I. Orlova, S. P. Epshtein, UDC 547.789.1'288.4'496.2.07:543.422

V. P. Tashchi, A. F. Rukasov,
L. Ya. Bogel'fer, and Yu. G. Putsykin

Isomeric 4- and 5-hydroxylaminothiazolidin-2-thiones were synthesized by the reac-

tion of 1,2-aminosubstituted oximes with CS2, and of dimeric olefin nitrosochlorides
with dithiocarbamate salts. These compounds react with aldehydes and ketones to
form the respective nitrones. In contrast to the 5-derivatives, the 4-hydroxylamino
derivatives hydrolyze to 4-hydorxythiazolidin-2-thiones.

We have previously reported the synthesis and reactivity of the 4-hydroxylaminoimidazol-

idin-2-ones [i, 2]. In continuation of our studies of heterocyclic systems that contain an
exocyclic hydroxylamino group we have obtained the hitherto unknown 4- and 5-hydroxylamino-
thiazolidin-2-thiones.
By the reaction of 1,2-aminosubstituted oximes la-e with CS2 we have synthesized the re-
spective 5-hydroxylaminothiabzlidin-2-thiones, lla-e. The N-(2-oximinoalkyl)dithiocarbamic
acids A were separated as the cyclic form B, but treatment of, e.g., llc with alkali by an-
alogy with the properties of the 5-hydroxythiazolidin-2-thiones [3] gave salt III of linear
structure. The 13C NMR spectrum of the latter in H=O is characterized by signals at 211.0
(C(1)-----S), 161.9 (C(2~---N), 61.8 (C(~)), 25.8 (C(4,5)), and ll.l ppm (C(6)). Neutralization ~
of the aqueous solution of III gives the starting hydroxylamine llc, while methylation is ac-
companied by formation of the linear ester IV; the 13C spectrum of the latter (DMSO) contains
signals at 196.4 (C(1)-----S),158.4 (C(2)=N), 61.5 (C()3 ), 25.5 (C(~,s)), 17.6 (S--CHj), and lO.O
ppm (C(6)). The locations of the carbon signals f o r compounds III and IV agree with the !3C
Nq~R spectra (C=S 193.5, ~ 153.5 ppm) for the authentic linear structure, viz., N,N-dimethyl-
S- (3-oximino-2-methylprop-2-yl) dithiocarbamate synthesized according to [6 ] .

All-Union Scientific-Research Institute for Protection of Plants, Moscow 109088. Trans-

lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 549-553, April, 1986. Original
article submitted January 30, 1985.

0009-3122/86/2204-0451512.50 9 1986 Plenum Publishing Corporation 451

 S

Ri
"~
}{' N"
. .._<':,,.. t ' ':'Nil . ,.ii
" ' I' N" 'i '~11
H
C ,R ~
i~ ]'. t' ::'R~' It'i it > t; 1~ IIIlilN. LI,,'.> '~N" ,R 3
. R' R"
la- e .~
t~ ~ ' " ~ "~I.G
.do~ .. B, IIa-d
S ","#
MON
II..
~I
c I r I,1, I ,~l'l,i
""~i 'IL +
4' .~ N :' ,~t~ , i' ~ N t 8Na
lt:ll,, C !, I(
~' "?if "ciq I.i!l13 C}I~
1%' I11

I, I I a , e R'=H, bic RI=CH,~, d RI 4. R~= ~C1t.0~; a-c,e R~,=P~=f;Itz; a,b,d R4=CI'I~,

C R4=I'|, e R~-----Oll

It is of interest to note that 1,2-aminoaldoximes I with bulky substituents (R ~ = iso-

C3H7, CsH::, CH2C6Hs) do not react with CS2 under these conditions.
The 4-hydroxylaminothiazolidin-2-thiones Vll were obtained by the reaction of the dimeric
nitrosochlorides V with dithiocarbamate salts. The linear s-(2-oximinoalkyl)dithiocarbamate
VI that is formed initially in this reaction was noted in the PMR spectrum (CDCIs) in the reac-
tion of potassium N-methyldithiocarbamate with 2-chloro-2-methylpropanal oxime (from the therm-
al conversion of nitrosochloride Va [4]). After the initial chlorooxlme disappeared from the
solution (as monitored by TLC), as the intensity of the signals of cyclic Vlla increased in
the spectrum, viz., 1.5, 1.6 (C(CH~)I, s); 3.5 (N-CHs, s); 4.6 ppm (CH, s), the intensities
of the characteristic signals of the corresponding linear form V simultaneously decreased,
viz., 1.6 (C(CHs)z, s); 3.2 (N-CHs), d, J = 4 Hz), 7.6 ppm (N=CH, s).
S S S
HON S H
~I II 4
~C.. iS CNHR
R R2/C~R~ CHz~ t t ' I CrI~
.. C ...... C =CH-C ...... C ".~' '
Vla,b Vlla-g cH~ x crlj CI|~
S
x /

,k~ N~OI
~/C,~ H ,- CI
R R~/C~R~
.12
~.__~_=,~
S

Ira.,i
S

I..R~ .......~"
.... CHT.~_ i..CH '
i !
< . R ' ~ .........
~...R~ ,"i~o--
CII~:"< ---'~CH 3 ]
Va-c \ .....J V l l l a - c ~e IX
Xl
V, V I a RI=H. b Rt=CHs, Vc RI+R~=(CH2)4; V, VI a,b R2=R3=CH3, Vc R~=H;
VI a R4=tert-C4H~, e R4=iso-C~H7; Vll~d', VIIIa-e Rl=lt, Vlle,fVllle RI=CHs,
VIIg Rt'+R2=(CH2)4; Vlla--f ', V I l l a - e , e R2=R3=CH3, Vllg R~=H; V l l a , o , g
VIIIa,eR4=CH3, VII, VIII b R4=CH2C6Hs, e R4=iso-C~HT; VIIe,fR4=H

It should be noted that in [5] the products of the reaction of Va,b and the N-methyldi-
thiocarbamate salts were mistakenly assigned a linear structure.
In contrast to the ~3C NbIR spectra of the linear compounds III and IV, the spectra of 5-
and 4-hydroxylaminothiazolidin-2-thiones II and VII (DMSO) show, instead of the ~ signals,
the C(5) or C(~) signals at 87-92 ppm, along with the general ~ signals for the linear and
cyclic structdr&s (194-197 ppm for II and VII).
With increase in bulk of'R ~ and R", e.g,, in compounds Via,b, cyclization to thiazolidin-
2-thiones VII does not take place, according to the IR and NMR spectra.
In acid solution compounds Va-c,e are converted to the respective 4-hydroxythiazolidin-
2-thiones Vllla-c,e. Their IR spectra (CC14) show valence vibration bands a t 3 5 6 0 cm-i (OH),
and the bands at 3400 and 3590-3600 cm -i (NHOH) observed for II and Vll are absent. The PMR
spectrum (DMSO-D6), e.g., that of the 4-hydroxy derivative Villa, shows two gem-dimethyl sing-
lets at 1.31 and 1.43, a singlet at 3.26 (N--CH3), and ~io doublets (J = 7 Hz) of the CHOH pro-
tons at 5.03 and 7.05 ppm.
In benzene in the presence of 4-toluenesulfonic acid, 3,4,5,5-tetramethylthiazolidine
Vllle loses water reversibly to form the 4-methylene derivative IX. Thus when its solution in
C6D~ is heated directly in the spectrometer monitor, as the intensity of the four CHa signals
weakens (at 0.86, 0.90, 0.95, and 2.92 ppm) there appear signals at 1.08 and 2.88 ppm (C(CH3)2

452
and N--CH3, respectively) and the signals of methylene protons in the form of an AB system
(3.78 and 3.80 ppm, J = 3 Hz).
In concentrated acid the 4-hydroxylamine derivative, like the corresponding 4-hydroxy-
thiazolidin-2-thione, is converted to X [3], while VIIg is converted to the 4-thiazolin-2-
thione XI.
In contrast to VII, the isomeric 5-hydroxylaminothiazolidin-2-thiones II do not undergo
appreciable hydrolysis in mine~:al acid solution. Neutralization of the hygroscopic salts
yields the initial hydroxylamines II.
Condensation of isomeric II and VII with 4-nitrobenzaldehyde gives the respective ni-
trones XII. The presence in the UV spectrum of XII of an intense absorption band at 346 nm
(log ~ 4.2) and reduction to the respective N,N-disubstituted hydroxylamines XIII confirm
the presence of the aryl nitrone group [7].

.'~ Y ~ ~'N a [ X "Y 3

HO/tN [ I R3 - - ~- p-NOzC6H4"-CH=N\ I I .R ~ p-NO2CsH~-CHe-N\ I ) II
, ..c--.c~ 2 ~ c . . . . . c...R z ~.'c--c~ z
R R R : R 11

lla,d VllC Xlla-c Xlll a - c

XII, Xlll a, b X=S, Y=NCH3, c X=iso-C3H~N, Y=S; ~ c RI=H, R2=R3=CH3,

b RJ'+R~=(CH2)4, R3=H
*Unclear in Russian original - Editor.

The P M R spectra of nitrones XII show the singlet of the azomethine proton in the 8.i-
8.7 ppm region, whereas compounds XIII are characterized by the methylene proton signals as
an AB system in the 4 ppm region (J = i5 Hz) and the OH signal at 7.1-7.9 ppm.

EXPERIMENTAL
IR spectra were recorded on a Perkin Elmer 457 instrument in KBr tablets and in CCI~ sol-
utions; UV spectra, on a Specord UV-vis instrument in ethanol. PMR spectra were obtained on

TABLE I. PMR Spectra of Compounds II, IV, VI, VII

Com-
pound Chemical shifts, ppm (SSCC, J) (NH and OH signals, broadened)
. . . . . . . . . . . . . ,

IIa 1,31, 1,39 [6H, s, C(CHs)~], 3,08 (3H, s, NCH3), 4,65 (IH, d, 7=9 Hz, CH),
6,23 (NH, d / = 9 H z ) , 7,65 (OH, s)
lib 1,20, 1,31, 1,40 (9H, s, CHz), 3,11 (3H, s, NCH31, 6,18 (NH, S }, 7,62 (OH, s)
llc 1,28, 1,43 (9H,s, CH~), 6,15 (NH. s), 7,65 (OH, s ), 9,90 (NH, s)
lid 1,08--2,32 [8H, m, (CH2)4], 3.18 t3H, s. NCH3), 4,01 (IH, m, CH), 6,03 (NH,
s), 7,72 (OH, sj
lie 1,30, 1,32 [6H, s., C(CH3)2], 4,95 (IH, d, y=6Hz., CH), 6,31 (NH, d, Y=6Fz),
7,86 (OH, sy, 10,5 (OH, s)
IV 1,62 16H, s, C(CH3)r 1,82 (3H, s, Cl-|~), 2,46 (3H, s, NCH~), 8,73 (NH, s),
9,68 (OH, s)
Via 1,50 [6H,s, C(CH~)2], 1,53 (9H, s, tert-C4Hg), 7,55 (IH, s CH=N), 8,19 (NH,
s), 10,3 (OH, s)
Vlb 1,20 d, 4,55 m (Y=7 Hz, iso-C3HT), 1,53 [6t-t, s, C(CH3)2], 8,20 (NH, s), 10,42
(OH, sj
Vlla 1,53, 1,55 [6H,s , C(CH3)21, 3,38 (3H, s, NCH3), 4,68 (IH, d, J=5 Hz, CH),
6,48 (H,d, g=SHz), 7,0 (OH,~.)
Vllb 1,24, 1,40 [6H, s, C(CH3)2], 4,20 (1H, s, CH), 4,46, 5,62 (2H, ABsystem,,
l=151rlz, CH~), 6,75 (NH, s), 7,31 (5H, m C6H~), 7,42 (OH, s)
VIIe 1,36, 1,52 [6H, s, C(CHa)2], 1,27 d, 1,50 d, 5,02m (J=5 Hz, iso-C3HT), 4,52
(1H, d, J=3Hz, CH), 6,26 (NH, s), 7,6[ (OH, s)
Vlld 1,38, 1,46 [6H, s, C(CH3)21, 4,23 (IH, d, J=6Hz, CH), 6,04 (NH, d, J=6Hr
7,46 (OH, s). 8,93 (NH, s)
VIle 1,40, 1,44, 1,46 (9H, s, CH3), 3,26 (3H, s, NCI.13), 6,26 (NH, s), 7,20 (OH, s)
Vl!f 1,31, 1,35, 1,43 (gH, s, CH,3), 5,96 (NH, s ), 7,46 (OH, s), 9,34 (NH, s)
Vllg 1,30--2,0 [8H, m, (CH2)4], 3,04 (3H,s, NCH:~), 4,20 (1H, s, CH), 6,73 (NH, s),
7,71 (OH, s)
*Spectra of compounds IV, Via,b, Villa were obtained in ace-
tone-D6; of VIIc, in DMSO-D~--benzene-D6 mixture; other com-
pounds, in DMSO-D6.

453
Varian FT-80A (80 MHz) and Bruker HX-90E (90 MHz)instruments; 13C N-MR spectra, on a Bruker
HX-90E instrument (22.625 MHz), TMS internal standard. The course of the reactions was moni-
tored on Silufol UV-254 sheets in i:i THF:hexane and 3:1 benzene:acetone systems.
The physicochemical and spectral properties of the synthesized compounds are shown in Ta-
bles I and 2.
The substituted aminooximes I and the dimeric nitrosocHlorides V were synthesized by the
procedures of [8].
5-Hydroxylaminothiazolidin-2-thione s (lla~d). A. To a solution of i0 mmoles of amino-
oxime la-c in 4 ml of DMFA or DMSO was added 17 mmoles of CS2. After i h the reaction mixture
was diluted with 50 ml of water and extracted (3 50 ml) with ether. The extracts were dried
over MgSO~ and evaporated, and ,the residue was treated with petroleum ether to yield compounds
lla-c.
B. A mixture of 20 mmoles of methylaminooxime Id and 30 mmoles of CS2 in i00 ml of ab-
solute alcohol was kept for 48 h. At the end of the reaction the solvent was evaporated and
the residue was reerystallized from benzene to give compound lid.
3-HydroxT-4,4-dimeth~l-5-hydroxylamlnothiazolidin-2-thione (lle). A mixture of ii mmoles
of hydroxylaminooxime le and 21 mmoles CS2 in 30 ml of aeetonitrile was held for 1 h at 60 ~ .
The solvent was evaporated and the residue was treated with acetone. Upon prolonged standing
at 5 ~ a precipitate formed, which was filtered off to give [N-(3-hydroxy-4,4-dimethylthiazoli-
din-2-thion-4-yl)-C-dimethyl] nitrone, XIV. IR spectrum (KBr): 1530, 1430, 1365, 1290, 1225,
1155, 1130, 1115, I010, 970, 920, 815, 780 cm -I. PMR spectrum (DMS0-D,): 1.28 (3H, s, CH3),
1.36 (3H, s, CH3), 1.96, 2.19 (two doublets of (CH3)2N), 5.92 (IH, s, CH). The material was
treated with 2 ml of cone. HCI and i mmole of nitrone XIV and heated to 50 ~ . After cooling,
the mixture was neutralized with dilute NaOH solution and extracted with ether. The extract
was dried over MgSO~ and evaporated, and the residue was treated with hexane, and filtered to
yield compound lid.
S-Methyl-N-(3-oximino-2,methylbut-2-yl) dithiocarbamate (IV)A To a solution of i0 mmoles
of llc and ii mmole of NaOH in 40 ml of water was added 12 mmoles of dimethyl sulfate gradual-
ly with vigorous stirring. The precipitate was filtered off after 1 h, washed with water, and
dried to give the methyl ester IV. IR spectrum (CCI~): 3590 (OH), 3380 (NH); in KBr: 1520,
1500, 1440, 1355, 1210, 1145, 1020, i000, 9554 945, 920, 760 cm -I.
N-Tert-butyl (or isopropyl)-S-[2-methyl-3-oximinopr0p-2-yl (or but-2yl)] Dithiocarbamates
(Via,b), 4-Hydroxylaminothiazolidin-2-thiones (Vlla-g). A mixture of equivalent amounts of
the respective dimeric nitrosochloride V and the dithiocarbamate9 salt was boiled in absolute
alcohol. At the end of the reaction (as monitored by TLC) the inorganic precipitate was fil-
tered off and the solvent was evaporated. The residue was recrystallized from benzene or al-
cohol. IR spectrum (KBr) of Via,b: 1520 cm -I (NHC=S). 13C NMR spectrum (DMSO) of Via: 191.6
(--C=S), 153.7 ppm (C=N); Vlb: 191.9 (C=S), 159.3 ppm (C----N).
Hydrolysis of 4-Hydr0xylaminothiaz01idin-2-thione s (V!la-c, e-g). A suspension of i0
mmoles of VII in i0 ml of cone. HCI or 50% H2SO~ was held at 50 ~ for 15 min. After neutraliza-
tion the reaction mixture was extracted with ether (3 30 ml). The extract was dried over
MgSO4 and evaporated, and the residue was treated with hexane to yield the respective 4-hy-
droxythiazolidin-2-thiones Vllla,c,e. In the case of Vlla the product that crystallized on
standing was treated with CC14 and filtered to yield Villa. In the case of Vllf the precip-
itate that formed in acid solution was filtered off, washed with water, and reprecipited from
acetone-petroleum ether mixture to give a 46% yield of 4-(5,5-dimethyl-2-thioxo-2-thiazolidin-
ylidenemethyl)-4,5,5-trimethylthiazolidin-2-thione X, mp 216-218 ~ (decomposition); according
to [3], mp 221 ~ (decomposition). The IR and PMR spectra agree with those published. In the
case of Vllg, the precipitate that formed in acid was filtered off, washed with water, and
dried to yield 4,5-tetramethylene-3-methyl-4-thiazolidin-2-thione XI. IR spectrum (KBr): 1640
cm -~ (C=C). PMR spectrum (acetone-De): 1.81-2.51 (SH, m, (CH2)~), 3.53 ppm (3H, s, CH3).
[N-(Thiazolidin-2-thion-5-y~.)- or [N-(Thi@zolidin-2-thion-4-yl)-C-(4-nitrophenyl)] Ni-
trones (XII). A mixture of equimolar a m o u n t s o f II or Vile with 4-nitrobenzaldehyde in benz-
ene was boiled with or without 4-toluenesulfonic acid, respectively, until the reaction was
finished (monitored by TLC). The solvent was evaporated and the residue was treated with ether
to yield compound XII.

454
 TABLE 2. Physicochemical Data for Compounds II, IV, VI-
VIII, XI-XIV

Com- [ * Pound % Empirical Calculated, %

pound rap, *C formula
H N s c H N s

IIa C6HmN2OS~ 6,3 14,6 84

lib CzH,4N2OS2 6,8 13,6 30
Ilc CsHI2N~OS2 6,3 14,6 45
Ild CsHI4N2OS2 6,5 12,8 67
IIe C6HioN~O2S2 5,2 14,4 60
IV CTH14N2OS2 6,8 13,6 50
Via CgHIsN2OS2 7,7 12,0 50
VIb CgHIsN=OS2 7,7 12,0 52
tVIla C6HmN~OS= 6,3 14,6 84
Vllb C,2HI6N2OS2 6,0 10,4 85
VIIc CsHmN2OS2 6,1 12,7 44
Vlld CsH,oN2OS2 5,7 15,7 92
YIIe CvHI4N~OS2 6,8 13.,6 50
VIlf CsHmN2OS2 6,3 14,6 ' 56
Vllg CsH14N~OS2 6,5 12,8 50
VIIIa CsH,iNOS2 6,3 7,9 4O
~VI I Ib C,2H,sNOS2 6,0 5,5 79
VIIlc CsH,6NOS2 7,4 6,8 90
VIIle CTH,3NOS2 7,4 7,3 70
XI CsH,jNS2 6,9 7,6 56
XIIa CmHisNaOaS2 4,7 12,9 50
XIIb CIsHIvNaO3S2 4,9 12,0 60
XIIc C,sHIgN303S2 5,3 13,4 45
XIIIa C,3HiTNaOaS2 5,2 12,6 55
XIII _b C,sHtgN303S2 5,4 11,9 44
XIIIe C,sH2,N30~S2 6,0 11,8 30
XIV CsH,4N202S2 5,0 11,9 66
~Compounds lie, Xlla,c and Xlllc melt with decomposition; ac-
cording to [9], for Villa mp 57o; according to [i0], for Vllle,
mp 68 ~ .

Reduction of Nitrones XII. To a suspension of 1 mmole of XII in a i:i alcohol--THF mixture

was added 5 mmole NaBH4 in portions. The mixture was neutralized with dilute hydrochloric acid
and extracted with ether (3 5 ml). The extracts were dried over MgSO4 and evaporated and the
residue was crystallized from a ether--hexane m i x t u r e t o yield compound XIII.

LITERATURE CITED
i. S. G. Simonova, S. P. Epshtein, Yu. G. Putsykin, and Yu~ A. Baskakov, Khim. Geterotsikl.
Soedin., No. 7, 980 (1980).
2. S. P. Epshtein, A. F. Rukasov, V. P. Tashchi, Yu. G. Putsykin, Yu. A. Baskakov, and T. G.
Simonova, Khim. Geterotsikl. Soedin., No. i, 82 (1983).
3. J. C, Jochims and A. Abu-Taha, Chem. Ber., 109, 139 (1976).
4. K. A. Ogloblin and V. P. Semenov, Zh. Obshch. Khim., 33, 888 (1963).
5. J~ Beger, C. Thielemann, and P. D. Thong, J. Pr. Chem., 321, 249 (1979).
6. L~ K. Payne and H. A. Stansbury, J. Agr. Food Chem., 14, 356 (1966).
7. J.Hamer and A. Macaluso, Chem. Rev., 6-4, 473 (1964).
8. J. Beger, T. T. Luong, C. Thielemann, and P. D. Thong, J. Pr. Chem., 320, 433 (1978).
9. R~ A. Bufford, F. Chanon, M. Chanon, and J. Metzger, Bull. Soc. Chim. France, No. 3, 971
(1973).
i0. M. Chanon and J. Metzger, Bull. Soc. Chim. France, No, 7, 2842 (1968).

455
BENZAZOLiN-2-THIONES IN TUE MICHAEL REACTION,
i, REACTION OF BENZOTHIAZOLIN- AND BENEOXAZOLIN-2-THIONES WiTH
ACRYLONITRILE, ACRYLAMIDE, AND METHYLACRYLATE IN THE PRESENCE
OF ACID CATALYSTS

K. V, Anan'eva and N. K. Rozhkov* UDC 547,339,1'371'398.1'787.3'789.6.04

The reaction of benzothiazolin- and benzooxazolin-2-thiones with acrylonitrile,

acrylamide, and methylacrylate under conditions of acid catalysis takes place at
the sulfur atom. The formation of minor amounts of N-derivatives is attributed
to isomerizatlon of the principal reaction products.

In continuation of our study of the behavior of benzoazolin-2-thlones in nucleophilic ad-

dition reactions [i] intended for the synthesis of potential pesticides, we have investigated
the effect of acid catalysts on the reactions of benzothiazolin- and benzoxazolin-2-thiones
(la, b) with acrylonitrile~ acrylamide, and methylacrylate (IIa-c).
It is known that benzothiazo!in- and benzoxazolin-2-thiones add acrylonitrile at the ni-
trogen atom in the presence of basic catalysts, i.e., under conditions of anion formation [2,
3]. Information about the reactions of benzazolin-2-thiones in acid medium is limited to a
report of the addition of benzimidazolin-2-thione to acryionitrile and unsaturated aldehydes
and ketones at the sulfur atom in the presenceof HCI [4, 5].
We used AICI, and H2SO~ as catalysts. To thlone I and AICI3 dissolved in chloroform was
added an equimolar amount of electrophile II and the mixture was stirred at 25-40 ~ for 1-48 h.
Product yields were determined by a procedure that combined thin layer chromatography and
spectroscopy (Experimental part). We isolated the S-derivatives, compounds IIa-f (Table i).

95::"" -- NIl N
~" + CH.;:~CIII( 9 "-- I1~
q" "~ X "':" ~; IIa - C E "~CII~CIf2R

la.b t,a-h
|a X=S. b X=O; l] a R=CN, b P=CONH,~,c R=COOC113; I]Ja,c.e~ X=S,
b~,f,hX=O; a,b R=CN, c,d R=CONH2, r R=COOCH3, g,h[~=s

The product yields are substantially affected by the amount of catalyst used. In the
absence of catalyst there is no reaction. The maximum yield is achieved in the presence of
1-2 moles of AICI3 at 40 ~ 9
When thione la is boiled with acrylonitrile in toluene in the presence of AICI3, along
with Ilia, the product of addition at sulfur (49%), the corresponding N-derivative, 3-(3-
benzothiazolinyl-2-thiono)propionitrile, IVa, is also formed in 25% yield. A test of the
stability of nitrile Ilia showed that after i h in toluene at ii0 ~ it is 15% isomerized to
IVa. Under the same conditions thione la reacts with amide lib only at the sulfur atom.
Replacement of AICI3 by H2S0~ does not affect the course of the reaction. The reaction
of thiones la,b with lla-c in the presence of H2SO~ in toluene at Ii0 ~ also forms the S-der-
ivatives (Table 2).

*Deceased.
Institute of the Chemistry of Plant Materials, Academy of Sciences of the Uzbek SSR,
Tashkent 700170. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 554-
557, April, 1986. Original article surbmitted February 13, 1985; revision submitted July 17,
1985.

456 0009-3122/86/2204-0456512.50 O 1986 Plenum Publishing Corporation

 Minor amounts of 3-(3-benzothiazolinyl-2'thiono)propionic acid IVg (1%) detected in the
products of the reaction of Ia and IIb are apparently formed by hydrolysis of 3-(3-benzothiaz-
olinyl-2-thiono)propionamide IVc. As established by a special experiment, the latter forms by
isomerization of amide IIIc. However, in the reaction of thione Ib with amide IIb no products
of reaction at nitrogen were found. A test of the stability of amide IIId under reaction con-
ditions showed that it is partially hydrolyzed to acid IIIh (15%), but isomerization to the N-
analog was not observed.

EXPERIMENTAL
IR spectra were obtained in KBr tablets on a UR-20 spectrophotometer; UV spectra, on a
Hitachi EPS-3T spectrophotometer; PMR spectra, on a Jeol C60-H instrument (TMS internal stand-
ard); mass spectra, on a MX-1303 instrument, identity and purity of synthesized compounds was
monitored by TLC on Silufol-254.
Reactions were carried out in absolute solvents (chloroform, toluene) in the presence of
catalyst (AICI3 or H2SO4) at constant temperature, with hydroquinone as polymerization inhibi-
tor. After cooling, the reaction mixture wa~ transferred to a volumetric flask (if heterogen-
eous, with the aid of a solvent). A sample removed by microsyringe was placed on a Silufol-
254 sheet and chromatographed in 14:2 benzene--acetone, 3:1 chroroform--benzene, 20:1 chloro-
form-ethanol, and 14:5:5 petroleum ether-chloroform-acetone. After development in the chroma-
toscope the bands with individual fractions were cut out, powdered, and extracted with ethyl
alcohol. Extract volume was carefully dispensed into volumetric flasks. Optical densities of
the solutions were measured on a SF-16 spectrophotometer. Product content (moles) was calcu-
lated by the formula:

x= (D" Vr. Ve. 10-3)/(E. Vs),

here D is optical density; E is extinction coefficient; V r is volume of reaction mixture trans-

ferred to volumetric flask; V s is volume of sample placed on sheet; V e is volume of extract.
3-(2-Benzothiazolylthio)propionitrile (IIIa). To a mixture of 0.84 g (5 mmoles) of thi-
one Ia and 1.4 g (i0 rmnoles) of AICI3 in 30 ml of dry chloroform was added 0.3 g (5 mmoles)
of acrylonitrile, and the mixture was heated under reflux at 40 ~ for 1 h. After the solvent
was removed, IIIa was extracted with cold hexane and finally purified by preparative separa-
tion on sheets with attached Si02 layer. Rf 0.8, (3:1 chloroform--benzene). There was separa-
ted 0.91 g (82%) of lemon-colored oil, n ~ ~ k,6539, IR spectrum (KBr): 2260 cm -I (CN). UV
spectrum (ethanol, c 0.012 mg/ml), %max (log c): 276 nm (4.08). PMR spectrum (CDCIs): 2.8
(2H, t, CH2R), 3.4 (2H, t, CH2S), 7.75-7.25 ppm (4H, m, Ar). Found: C 54.5; H 3.5; N 12.7%;
M 220. CIoHsN2S2. Calculated: C 54.4; H 3.6; N 12.7%; M 220.
3-(2-Benzoxazolylthio)propionitrile (IIIb) was obtained analogously in 85% yield as scaly
light cream-colored crystals, mp 43 ~ (from hexane). Rf 0.95 (20:1 chlorofornr-ethanol). IR spec-
trum (KBr): 2256 cm -I (CN). UV spectrum (ethanol , c 0.015 mg/ml), %max (log e): 287 (4.04),
280 nm (0.04). PMR spectrum (CDCI3): 3.0 (2H, t, CH2), 3.5 (2H, t, CH2S), 7.4 ppm (4H, m, Ar).
Found: C 58.6; H 3.9; N 13.5%; M 204. CIoHsN20S. Calculated: C 58.8; H 3.9; N 13.7%; M 204.
3-~2-Benzothiazolylthio)propionamide (IIIc). A mixture of 0.84 g (5 mmoles) of thione Ia
and 0.3 g (5 mmoles) of acrylonitrile in 20 ml of 80% H2SO~ was held at room temperature for
5 h, then poured on ice. The precipitate was separated and washed with 5% alkali solution and
water. There was separated 1.12 g (95%) of white needle-shaped crystals, mp 136 ~ (from aque-
ous alcohol). Rf 0.20 (20:1 chloroform--ethanol). IR spectrum (KBr): 3420-3210 (NH2), 1670
cm -I (CO). UV spectrum (ethanol~ c 0.015 mg/ml), %max (log e): 280 (4.14), 230 nm (4.35). PMR
spectrum (CF3COOH): 2.72 (2H, 6, CH2), 3.45 (2H, t, CH2S), 7.5 ppm (4H, m, Ar). Found: C 50.4;
H 4.1; N 11.7%. CIoHIoN20S2. Calculated: C 50.4; H 4.2; N 11.7%.
3-(2-Benzoxazolylthio)propionamide (IIId) was obtained analogously in 96% yield as white
crystals, mp 132 ~ (from aqueous alcohol). Rf 0.27 (20:1 chloroform-ethanol). IR spectrum
(KBr): 3420-3210 (NH2), 1670 cm -~ (CO). UV spectrum (ethanol, c 0.015 mg/ml), %max (log g):
287 (4.09), 279 (4.12), 250 nm (4.10). PMR spectrum (CF3COOH): 2.85 (2H, t, CH2), 3.65 (2H,
t, CH2S), 7.5 ppm (4H, m, Ar). Found: C 54.3; H 4.0; N 12.6%. CIoHIoN20=S. Calculated: C
54.0; H 4.0; N 1 2 . 6 %
Methyl 3-(2-Benzothiazolylthio)propionate (IIIe). A mixture of 0.84 g (5 mmoles) of thi-
one Ia and 0.43 g (5 mmoles) of methyl acrylate in 20 ml of 80% H2SO4 was held at room temp-
erature for 5 h. Then the mixture was treated analogously to the procedure for the separation

457
 TABLE i. Synthesis Conditions in Presence of AICI3 and
Yields of Compounds llla-h

Compound * r, oc Time, h A1Cls,

moles Yield, ~1o

lllb (llIcl 25 I 2 65,6 ( 1.2 )

25 24 2 .8:L7 (2,9)
25 48 2 89.9 [traces)
40 I 0.00 I 23,9 (I ,4)
40 I 0,5 68,5 (0,8}
40 1 I 71.9 ((),fi), (1,1)t"
40 1 2 82,5 (0,9)
40 I 3 27,6 (11,5)
40 5 2 92.6 (1.6)
IlIe 110 I I 48,0 (traces), (25.6)t'
I10 I 1 57,6
lllb (llld) 40 I 1 85,8 (traces)
40 I 2 80,2 (traces)
llld I lO 1 1 34,8
11I e (Illg 40 I 1 50.6 (4,1)
lllf (IIl~) ' 40 I 1 52,6 (10.4)

*Ilia (lllc) and lllb (llld) were obtained by reaction with

acrylonitrile; lllc and llld by reaction with acrylamide;
llle (l!Ig) and lllf (lllh) by reaction with methyl acrylate.
+Yield of 3-(3-benzothiazolinyl-2-thiono)propionitrile IVa.

TABLE 2. Synthesis Conditions in Presence of H2SO~ and

Yields of Compounds llla-h
Benzazolin- !Electro-
2-thione phile " Time, h I Yield, %

la lla
Ila
lib
'l
5
I
I
4,3 (llla), 52 (Iltcl, 7.I (III~)
6,5 (Ilia), 7,2 (IlIU), 18,5~IITg)
14,4 (lllo), 2,2 ( l l l g ) , 1,4T
llc 1 36,9 (Ille), 16,0 {lIlg)
lie 5 I 41,8 (llle), 26,9 ( l l l g )
Ib I la I 2,2 (lllb), ,5,7 (llld), 15,7 {lllh). 0,2~
Ila 5 f,6 (llld), 21,0 (lllh), 0,3~'o'..
lib 1 4,3 (llld), 3,6 (l[lh)
Ilc I 20,7 (I11f),-4,9 (lllh)
lie 5 28,2 (lilt), 9,4 (lllh)

*In toluene at ii0 ~.

#Yield of 3-(3-benzothiazolinyl-2-thiono)propionic acid.
~Yield of 3-(3-benzoxazolinyl-2-thiono)propionic acid.
**Probably should be labeled as # or $. The Russian has a
B - Editor.
of lllc. There was obtained 1.14 g (91%) of white crystals, mp 41 ~ (from hexane). Rf 0.50
(14:5:5 petroleum ether--chlorofornv-acetone). UV spectrum (ethanol, c 0.01 mg/ml), %max (log
c): 276 nm (4.06). Found: C 52.3; H 4.3; N 5.8%. C11HIINO2S2. Calculated: C 52.1; H 4.3;
N 5.5%.
Methyl 3-(2-benzoxazolylthio)propionate (lllf) was obtained analogously to ester llle in
85% yield. Mp 40 ~ (from hexane). Rf 0.57 (14:5:5 petroleum ether-chlorofornt-acetone). IR spec-
trum (KBr): 1760 cm -I (CO). UV spectrum (ethanol, c 0.014 mg/ml), %max (log E): 284 (4.08),
280 (4.08), 250 nm (4.06). PMR spectrum (CCI~): 2.7 (2H, t, CH2), 3.3 (2H, t, CH2S), 7.11 ppm
(4H, m, Ar). Found: C 55.4; H 4.5; N 5.8%; M 237. C11HIIN03S. C 55.7; H 4.6; N 5.9%; M 237.
3-(2-Benzothiazolylthio)propionic acid (lllg) was obtained by hydrolysis of Ilia, lllc,
or llle with hydrochloric acid in ~95% yield. Mp 148-149~ according to [6], mp 148-149 ~ . Rf
0.48 (14:2 benzene--acetone).
3-(2-Benzoxazolylthio)propionic acid (lllh) was obtained analogously to lllg in ~90%
yield. Mp 87-88 ~ (from water). Rf 0.44 (14:2 benzene--acetone). IR spectrum (KBr): 3000-2500
(COOH), 1710 cm -I (CO). UV spectrum (ethanol, c 0.006 mg/mi), %max (log ~): 287 (4.20), 280
(4.0), 250 nm (3.90). PMR spectrum CR3COOH): 2.20 (2H, t, CH~), 3.50 (2H, t, CH2S), 7.19-7.0
ppm (4H, m, Ar). Found: C 53.5; H 4.0; N 6.7%. C:oHgN03S. Calculated: C 53.8; H 4.0; N
6.3%.

458
 LITERATURE CITED
I. K . V . Anan'eva and N. K. Rozhkova, Uzb. Khim. Zh., No. 5, 56 (1973).
2. A . F . Halasa and G. Smith, J. Org. Chem., 36, 636 (1971).
3. V. Kalcheva and D. Dimov, Annual of the University of Sofiya, Khimfak [Chemistry Depart-
ment] 1969-1970 (1972), Vol. 64, p. 33.
4. G . F . Galenko, A. K. Bagrii, and P. M. Kochergin, Ukr. Khim. Zh., 41, 405 (1975).
5. G . F . Galenko, A. K. Bagrii, and P. M. Kochergin, Ukr. Khim. Zh., 41, 759 (1975).
6o J . E . Jansen and R. A. Mathes, U.S. Patent 2,483,416; Chem. Abstr., 44, 1544h (1950).

PMR STUDY OF THE CONPORMATIONAL BEHAVIOR OF 2,5,5-TRISUBSTITUTED

1,3,2-DIOXABORINANES

A. I. Gren', V. V. Kuznetsov, UDC 547.87'244:541.63:543.422.25

and K. S. Zakharov

The conformational behavior of 2,5,5-trisubstituted 1,3,2-dioxaborinanes was stud-

ied by PMR spectroscopy. Molecules with similar substituents at C(s) are in a
state of rapid ring inversion between two energetically equivalent forms. In the
case of different substituents, the inversion proceeds between energetically in-
equivalent states with a shift in the equilibrium toward one of them.

The conformational freatures of 1,3,2-dioxaborinanes are a function of their substitu-

tion, the nature of the substituents in the carbon part of the ring and p,p-conjugation at
the bororr-oxygen bond [1-5]. In the present work, we studied the effect of the nature of the
substituents at C(s) on the conformational behavior of 2,5,5-trisubstituted derivatives by
PMR spectroscopy.
All the compounds studied (I-XXIV) fall into three groups relative to their conformation-
al properties. The first group comprises compounds with substituents similar in nature and
bulk at C(5), which leads to ring inversion between two energetically equivalent forms which
is rapid on the NMR time scale (I-XIV, Table i). This is indicated by the singlet nature of
the signal for the ring methylene protons and the low-temperature PMR data. The magnitude of
the inversion barrier for 5,5-dialkyl- and 5,5-diallyl-l,3,2-dioxaborinanes could not be de-
termined due to the exceedingly low coalescence temperature (from --115 to --133~ for dimethyl
analogs according to Carton et al. [3]). The coalescence temperature is --83~ for 2-isopropyl-
5,5-dibenzyl-l,3,2-dioxaborinane corresponding to AG # = 9.7 kcal/mole, which hardly differs
from the analogous value for 5,5-disubstituted 1,3-dioxanes [6]. The nature of the signal for
the ring methylene protons at --100~ (Fig. la) indicates that cessation of ring inversion
leads to an undistorted form. The x-ray structural [7-10] and dipole measurement d a t [11-13]
indicate the predominance of a semiplanar or sofa form.
Analysis of the PMR spectra of analogs containing groups at C(s) differing in their bulk
and electronic properties shows rapid ringinversion between two energetically inequivalent
states. Compounds, for which the A9 value for the ring methylene protons at room temperature
for solutions in CC14 is not less than 0.09 ppm, belong to the second and third groups (the
A~ values for compounds in the first group do not exceed 0.02 ppm). In this case, the spectrum
of these protons for compounds in the second group (XV-XIX) is a multiplet consisting of five
lines with A~ value from 0.09 to 0.17 ppm (Fig. ib). With decreasing temperature, this multi-
p!et degenerates into an AB system which, however, may also be a consequence not only of hin-
drance to inversion but also to a change in the chemical shifts of the protons at C(4) and
C(6) with change in the temperature.
The signals for the ring methylene protons in the third group of compounds (XX-XXIV) at
room temperature correspond to a usual AB system (Fig. Ic) with A~ value in the range from
0.20 to 0.49 ppm (solutions in CCI~).
A. V. Bogatskii Physical Chemistry Institute, Academy of Sciences of the Ukrainian SSR,
Odessa 270080. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 558-561,
April, 1986. Original article submitted August i, 1985.

0009-3122/86/2204-0459512.50 9 1986 Plenum Publishing Corporation 459

 TABLE i. PMR Spectral Parameters for 2,5,5,-Trisubstituted
1,3,2-Dioxabor inanes

B1%,,, ~B,~B )

lla" "'1[~
...... = . . . . . . . ......................... .......

co - :: ........... i'pim "

pound Iv I,~ I ~ ~'/:~'

[i'l lib (") r') "" (: I1'~ I'IZ
O)
, c,,~, (:i,;, 3,6~ (m) 1,0, .....

II CI't~ CH.~ 3,44 ! ! I 0,86 9 -..

Il I (?,~H~ (:.,H.~ 3,86 . . . . . .
IIV CH~,,~,:CHCH~ C'i[~,~,(:I~CII,~ 3,90 ........
V C~It,~CH~ (:~H~(:H~ 3,66 . . . .
VI~ C~H~, C~Hs 4,47 . . . . . .
Vlff Cdt.~O C~,Hr>O 3,96 . . . . .
IVlll COOCH, COOCH:, 4,06/~t . . . . . .
1X COOC~H~ COOC~H~ 4,41 I : l -- --
X i-C~t'bO i-C~d'irO 3,56 -- --
XI COOCH:~ COOCI"I,~ 4,20 (S) --
XII CO()CI% COOCH~ ,t,21 ( s ) . . . . . .
XIII COOC~H~ COCH~ 4,21 (s) -- --
XIV CH2=,CHCH~ C~['IsCH~ 3,58 (s) -- --
~V CII.~ CHK) " 3,60 (m) 1,00 .--
XVI Cl-t~ CH~O 3,68 (m) 1,03 -.
XVII Ct'I3 i.C~Hz 3,60 (m) 0,81 --
XVlll CH:~ CH~=CHCH~ 3,50 (m) 0,78 --
XIX t-C~ltr CH~=CHCH,~ 3,67 (m) -- --
XX Cl=I~ CI-I,~OCH~ 3,75 (e) l 4,03 (e) 0,30 11,0
XXI CH~ C~Hr, 4,10 (e) 14,42 (e) 1,51 11,0
XXlI CHs C~H,O 3,97 (~a)]4,22 l : I 1,39 11,0
XXIII C~H~ CH:~OCH,~ 3,89 (e) I 4,10 --. 11,0
XXIIV Br NO.~ 4,15 (e) ] 4,64 (e) -- 12,0

9 I R ~ = OH; II--X, XIII--XV, XVII--XXIV, R ~ = i-C~H~; Xl R ~ =

C~H=; XII R = i-C,H,; XVl R ~ = C~H~0.
TThe spectrum was taken in benzene, while CCI~ was the solvent
for the other compounds.

TABLE 2. Temperature Dependence of the Difference in the

Chemical Shifts of the Protons of the AB Segment of the
PMR Spectra of Several 2,5,5-Trisubstituted 1,3,2-Dioxa-
borinanes
~, .../--o
., ...-i R - - C3[I7_ i
R" \- 6' "

R' t(~ Temperature, ~Au, Hz (for maxi-

*C .Xv.Hz mum temperature range)

C6HsCH~ C.HsCH.~ Room <.2,0 >11,8

- 100, 13,8
i-C~Hz CH~=CHCH2 Room 10,2 2,8
0 10,7
-50 11,8
-70 13,0
C~H5 CH3OCH2 Room 20,1 1,6
0 20.4
-20 20,6
-40 21,2
- 60 21,4
-80 21,7
Br NO~ Room 47,3 1.0
0 47,8
--2O 47,9
- 40 48,3
-60 48,3

The spectra of compounds in the second and third groups show a definite similarity due to
the presence of a prochiral center at the ring C(s) atom which gives rise to diastereotopic
CH2 protons at C(4) and C(6). However, there is also a significant difference between these

460
 a

HsC61IS, / ---O,
tI~Cd[oC ',X,..... ,../]B-C3H7-;:
- 1o o" c

20':'C
L

H2C=HC-H~C. F-O x
,B-CgHT-i
HTCg-i ~'--O"
-?C('C - ~

HB ElA

~'J~=-12[~

8r, ----0,
) '8-17.3H7-/
02N ,--~/

4 3 ' ~, ppm
Fig. i. PMR spectra for ring methylene protons of a) 5,5-
dibenzyl-2-isopropyl-l, 3,2-dioxaborinane, b) 5-allyl-5-iso-
propyl-l, 3,2-dioxaborinane, and c) 5-bromo-5-nitro-l, 3,2-
dioxaborinane.

two groups of compounds related to the different change in the internal shift between these
two protons with decreasing temperature evident upon comparing the low-temperaturespectra of
XIX, on one hand, with those for XXIII and XXIV, on the other (Table 2). The lower AA~ values
for XXIII and XXIV relative to XIX indicates a greater shift of the conformation equilibrium
toward one form at room temperature for compounds of the third group which is sufficient to
distinguish a predominant conformation by analogy to 5,5-disubstituted 1,3-dioxanes [6]. The
2JAB coupling constants for compounds in the third group do not differ from the 2JAB values
of the corresponding 1,3-dioxanes [14]. In our previous work [4], we noted similar nature
for the coupling in the carbon part of 1,3-dioxanes and 1,3,2-dioxaborinanes. Thus, this sim-
ilarity in the coupling constants indicates the lack of distortion in the carbon fragment of
XX-XXIV which exist in the predominant semiplanar conformational form.
The PMR data for compounds of the third group do not guarantee unequivocal conclusions
concerning the spatial orientation of the substituents at C(s) in the predominant conforma-
tion. The major reason for this lies in the considerable differences in the shielding constants
of the substituent protons due to interaction of these groups. In particular, the chemical
shift of the known equatorial methyl group in the spectrum of 2-isopropyl-5-methyl-l,3,2-di-
oxaborinane is 0.95 ppm (in CCI~) [4], while 6CH3 for XX-XXII varies from 0.30 to 1.51 ppm.
Thus, determination of the relative orientation of the methyl group on the basis of the
values is difficult. We may only note that the orientation o4 the nitro group in 5-bromo-2-
isopropyl-5-nitro-l,3,2-dioxaborinane is predominantly axial. This is indicated by the dipole
measurements for 5-alkyl-5-nitro-l,3,2-dioxaborinanes [ii, 12] and the nature of the PMR spec-
trum of 2-isopropyl-5-nitro-l,3,2-dioxaborinane [4].
Thus, the introduction of two substituents at C(s) in the 1,3,2-dioxaborinane ring leads
to the appearance of rapidly inverting systems with different extents of displacement of the
conformational equilibrium determined by the nature of the substituents at C(s).

461
 EXPERIMENTAL
The PMR spectra were taken on a BS-497 spectrometer at I00 MHz for 15% solutions of the
compounds studied in CCI~ and benzene with TMS as the internal standard. Freon-12 was used
for the low-temperature spectra of V and carbon disulfide was used for the low-temperature
spectra of XIX, XXII!, and XXIV . The inversion barrier was determined according to a standard
procedure [15] while the A~ value was determined from the experimental spectra according to
Emsley et al. [16].
2,5,5-Trisubstituted 1,3,2-dioxaborinanes I-XXIV were described in our previous work [17].

LITERATURE CITED
i. V. V. Kuznatsov, A. I. Gren', A. V. Bogatskii, S. P, Egorova, and V. I. Sidorov, Khim.
Geterotsikl. Soedin., No. i, 26 (1978).
2. F. Davis, I. Turchi, B. Maryanoff, and R. Hutchins, J. Org. Chem., 37, 1583 (1972).
3. D. Carton, A. Pontier, M. Ponet, J. Soulie, and P. Cadiot, Tetrahedron Lett., No. 28,
2333 (1975).
4. V. V. Kuznetsov, A. I. Gren', I. V. Petrovskii, and V. A. Antonovich, Manuscript Dep. v
VINITI, January 4, 1983, Nos. 89-83; Ref. Zh. Khim., 8B365 (1983).
5. A. I. Gren' and V. V, Kuznetsov, in: Questions in Stereochemistry [in Russian], No. 7,
Izd. Vischa Shkola, Kiev-Odessa (1978), p. 55.
6. W. J. Orville-Thomas (ed.),Internal Rotation in Molecules, Wiley-lnterscience, N. Y.
(1974).
7. S. Kuribayashi, Bull. Chem. Soc. Japan, 39, 2784 (1966).
8. S. Kuribayashi, Bull. Chem. Soc. Japan, 46, 1045 (1973).
9. H. Shimanouchi, N. Saito, and Y. Sasada, Bull Chem. Soc. Japan, 42, 1239 (1969).
I0. R. KSster and W. Dahlhoff, Liebigs Ann., ~o. i0, 1925 (1976).
ii. T. Urbanski, D. GHrne, R. Kolinski, H. Piotrowska, A. Jonczyk, B. Serafin, M. Szzetter-
Szmid, and M. Witanowski, in: Proceedings of the International Symposium on Nitro Com-
pounds, Warsaw (1963), p. 195.
12. T. Urbanski, J. Sci. Int. Res., 33, 124 (1974).
13. O. Exner and R. Rose, Collect. Czech. Chem. Commun., 39, 2234 (1974).
14. Yu. Yu. Samitov, Atlas of the NMR Spectra of Structural Isomers [in Russian], Vol. i,
Izd. Kazan. Univ., Kazan (1978), p. 326.
15. A. J. Gordon and R. A. Ford. Chemist's ~andbook: A Handbook of Practical Data, Tech-
niques, and References, Wiley-Interscience, N. Y. (1973).
16. J. Emsley, J, Finney, and L. Sutcliffe, High-Resolution NMR Spectroscopy, Vol. I, Per-
gamon Press, Elmsford, N. Y.
17. V. V. Kuznetsov, Manuscript Dep. v VINITI, OctoSer 14, 1983, Nos. 5646-83; Ref. Zh. Khim.,
5Zh343 (1984).

462
LETTERS TO THE EDITOR

SYNTHESIS OF FURAN DERIVATIVES FROM 1,3-ALKADIYNES

G. G. Melikyan, A. B. Sargsyan, UDC 547.317'724'727.07

and Sh. O. Badanyan

For the first time, we studied the reaction of the conjugated diacetylenes 1,3-hexadiyne,
1,3-butadiyne, and5-methyl-l,3-hexadiyn-5-ol with acetylacetone and acetoacetic ester in the
presence of the oxidative system manganese(III) acetate/copper(II) acetate. It was shown that
the reaction products are substituted 5-alkynyl- and 5-(5-furyl)furans. In particular, in the
reaction of i,3-hexadiyne with acetylacetone, 3-acetyl-5-(l-butynyl)-2-methylfuran (I) and 3-
acetyl-5-(3-acetyl-2-methyl-4-ethyl-5-furyl)-2-methylfuran (II) are formed in an equimolar
ratio in a total yield of 33%.
Compound I is obtained as a result of attack of the acetylacetonyl radical at the C(I)
atom of 1,3-hexadiyne with subsequent oxidative cyclization of the intermediate radical A in
the presence of copper(II) acetate. By a separate experiment, it was shown that under the re-
action conditions furan I is not converted to bifuryl II. Therefore, the formation of compound
II is apparently due to the attack Of the acetylacetonyl radical at the C(4) atom of 1,3-
hexadiyne, leading to the reactive intermediate B, which then gives reaction product II in the
reaction with a second mole of acetylacetone.
The reaction was carried out at 30~ in acetic acid with 1,3-hexadiyne--acetylacetone--
Mn(OAc)~--Cu(OAc)2 molar ratios of 1:8:4:4. Cyclization products I and II were isolated in the
individual state by column chromatography on silica gel, with hexane--ether (4:1) as the eluting
agent.
3-Acetyl-5-(l-butynyl)-2-methyifuran (I). Yield, 17%" nL~ n2~ 1.5380 (Silufol, hexane--
ether, i:i). IR spectrum (thin layer), ~: 3135 (C--H), 2240'(C------~C),1680 (C=O), 1595, 1555 cm -I
(furan ring). Proton NMR spectrum (CC14), 6 : 1 . 2 1 (3H, triplet, J = 7.6 Hz, CH3), 2.28 (3H,
singlet, CH3CO), 2.42 (2H, quartet, CH2), 2.52 (3H, singlet, 2-CH=), 6.59 ppm (IH, singlet,
4-H).
O

II

3-Acetyl-5-(3-acetyl-2-methy174-ethyl-5-furyl)-2-methylfura n (II). Yield, 16%; mp 105-

I06~ Rf 0.17 (Silufol, hexane--ether, i:I). IR spectrum (mineral oil), ~: 1678, 1660 (C=O),
1597, 1578, 1512 cm -~ (furan ring). Proton NMR spectrum (CCI~), 6 : 1 . 1 2 (3H, triplet, J = 7.5
Hz, CH3), 2.32 (3H, singlet, CH3CO), 2.36 (3H, singlet, CH3CO), 2.55 (3H, singlet, 2-CH3),
2.58 (3H, singlet, 2-CH3), 2.80 (2H, quartet, CH2), 6.59 ppm (IH, singlet, 4-H), M + 274.
The obtained compounds had satisfactory analytical characteristics.
The reactions proceed similarly in the case of acetoacetic ester and other diacetylenic
compounds.

Institute of Organic Chemistry, Academy of Sciences of the Armenian SSR, Erevan, 375094.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, p. 562, April, 1986. Original
article submitted August 22, 1985.

0009-3122/86/2204-0463512.50 9 1986 Plenum Publishing Corporation 463

A NEW REACTION IN THE SERIES OF 4,5,5-TRIMETHYL-AS-BUTENOLIDES

A. A. Avetisyan, A. A. Kagramanyan, UDC 547.724'339.07

and G. S, Melikyan

We found that the cyanethylation of the methyl group at the double bond takes place in
the reaction of 3-substituted 4,5,5-trimethyl-AS-butenolides (I) [i, 2] with an equimolar
amount of acrylonitrile in the presence of sodium methoxide with the formation of the corres-
ponding 4-(y-cyanopropyl)-5,5-dlmethyl-~S-butenolides in a yield of 85-90%. The reaction pro-
ceeds at a temperature of 50-60~ in the course of 2 h.

CH~.. .R CN-CHz-CH2-CH 2 R
CH3~O
CH 3" "o" 0
I a-c II a - c
la lie R=cNlbR=COCH 3 ;C R=COzCzH ~

This reaction is evidently a particular case of the Michael condensation by analogy with
the dimerization of piperitone [3].
Compound lla has mp 174-175~ The IR spectrum is as follows: 1760 (C=O) lactone),
2250 (C~N), and 1640 cm-* (C=C). Compound (~Ib) has mp 135-136~ The IR spectrum is as
follows: 1758 (C=O lactone), 1640 (C=C), and 1720 cm "I (COCH3). Compound (llc) has mp 143-
144~ The IR spectrum is as follows: 1760 (C=O lactone), 1640 (C=C), and 1730 cm-I (CO2-
C~Hs).
The compounds lib and llc were identified in the form of the 2,4-dinitrophenylhydrazones
and the phenylhydrazide correspondingly.
The signals of the methylene groups of the (CH2)sCN fragment are observable in the re-
gion of 2-3 ppm in the PMR spectra of compounds lla and lib.
The data of the elemental analysis correspond with the calculated data.

LITERATURE CITED
i. A . A . Avetisyan, A. A. Kagramanyan, and G. S. Melikyan, Arm. Khim. Zhur., 38, 335 (1985).
2. A.A. Avetisyan, S. G. Matsoyan, G. S, Melikyan, M. T. Dangyan, and Ts. A. Mangasaryan,
Zh. Org. Khim., ~, 967 (1971).
3. E.D. Bergman, D. Ginsburg, and R. Pappo, Organic Reactions [Russian translation], Vol.
i0, Publishing House of Foreign Literature, Moscow (1963), p. 220.

Erevan State University, Erevan 375049. Translated from Khimiya Geterotsiklicheskikh

Soedinenii, No. 4, p. 563, April, 1986. Original article submitted July 16, 1985.

464 0009-3122/86/2204-0464512.50 9 1986 Plenum Publishing Corporation

ADDITION OF INDOLE TO FERVENULIN-3-ONE AND ITS 4-N-OXIDE

Yu. A. Azev, E. O. Sidorov, UDC 547.859'873'753.07

and I. I. Mudretsova

On heating 2,3,5,6,7,8-hexahydro-6,8-dimethylpyrimido[5,4-e][l,2,4]triazine-3,5,7-trione
(fervenulin-3-one) (I) in ethanol in the presence of hydrochloric acid, it reacts with o-
p-enylenediamine with the formation of 8a-(3,4-diaminophenyl)fervenulin-3-one [i].
We also found that fervenulin-3-one reacts with the indoles lla,b in boiling butanol
in the absence of acid catalysis with the formation of the 8a-indolyl derivatives of 1,2,3,5,
6,7,8,8a-octahydro-6,8-dimethylpyrimido[5,4-e][l,2,4]triazine-3,5,7-trione (Ilia,b).

o o

"H~\N / [[ . ~.
N ,o R C~.N~N

0.7.~. N ,..NH fla,b o

t
CH;

IIa, IIIa R=H;bR=CH3 HN 'q..~

llla,b

To begin with, the magnitudes of the chemical shifts and the SSCCs of the protons of
the i- and 2-NH groups of the compounds Ilia (8.09 and 9.95 ppm, J = 1.7 Hz) and lllb) (8.18
and 10.08 ppm, J = 1.9 Hz), which are close to those of 8a-(3,4-diaminophenyl)fervenulin-3-
one (7.80 and 9.84 ppm, J = 1.9 Hz) [1], indicate the addition of indoles at the 8a position
of fervenulin-3-one.
The reaction of the fervenulin-3-one-4-oxides IVa,b with the indoles lla,b leads to the
8a-indolyl derivatives of 1,2,3,5,6,7,8,8a-octahydro-4-0xido-6,8-dimetbylpyrimido[5,4-e][l,2,
4]triazine-3,5,7-trione (Va-c) in boiling butanol in the course of 2-4 h.

0 0 0 0

CH ~ . L . ~ 0

CH 5

IVa-b R2
II
Va-d
II, IV a R = H , b R=CH3; V a RJ=R2=H; bRl=I-l, R2=CH:~; c R I = R2= C H ~

All the signals of the protons corresponding to the proposed structure are in the PMR
spectra of compounds Va-c. Thus, compound (Vc) has the following PMR spectrum (in DMSO-D6):
2.25 (singlet, CH3), 3.12 (singlet, N-CHa), 3.14 (singlet, N-CHa), 3.40 (singlet, N-CH3),
6.80-7.45 (multiplet, CH arom.), 9.65 (singlet, I-NH), and 11.41 ppm (broad singlet, NH). The
value of the CS of the C(sa) atom of compound (Va) in the C NMR spectrum comprmses 65.0 ppm;
3 . . . . 9 " 9
this is characteristic of sp -hybrldlzed 3unctzonal carbon atoms mn compounds wxth the annular
1,2,4-triazine ring [i]. The mass of compounds (Vb,c), determined by mass spectrometry, cor-
responds to the calculated value. In addition, compound llla is formed with a yield of 55-
60% on heating the product Va in ethanol in the presence of hydrochloric acid.

S. M. Kirov Urals Polytechnical Institute, Sverdlovsk 620002. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 4, pp. 563-564, April, 1986. Original article submitted
July 9, 1985.

0009-3122/86/2204-0465512.50 9 1986 Plenum Publishing Corporation 465

 The compounds are presented as follows [mp (~ yield (%), IR spectrum in mineral oil
(cm-Z)]: Ilia, 269-270, 70, 1668, 1678, 1694, 1738 (CO), 3120, 3236, 3310, 3356, 3425, and
3445 (NH); lllb, 214-215, 70, 1672, 1680, 1698, 1730 (CO), 3078, 3215, 3317, and 3346 (NH);
Va, 262-263, 80, 1670, 1683, 1697, 1710, 1740 (CO), 3122, 3245, 3330, and 3447 (NH); Vb, 221-
222, 85, 1684, 1694, 1705, 1733, (CO), 3110, 3205, 3390, 3475 (NH); Vc, 220-221, 75, 1670,
1680, 1690, 1708, 1741 (CO), 3180, 3325, 3375, and 3425 (NH).
The conversions described for fervenulin-3-one and its 4-N-oxide with indoles reveal
new routes for the modification of the pyrimidotriazine antibiotics and are of interest in the
consideration of the possible routes of transformation of these compounds in the living or-
ganism.

LITERATURE CITED
i. Yu. A. Azev, E. O. Sidorov, and I. I. Mudretsova, Khim. Geterotsikl. Soedin., No. 12,
1692 (1985).

NEW SYNTHESIS OF PYRROLO[I,2-a]PYRROLE DERIVATIVES

A. V. Kadushkin, T. V. Stezhko, UDC 547.744'759.5.07

and V. G. Granik

It is known that the reactivity of electron acceptor substituents in the B-position of

enamines is significantly lowered on account of the electron donor effect of the enamine am-
ino group [i].
Nonetheless, the enaminonitriles la-c (obtained by treating the diethylacetal of N-cyano-
methyl-2-pyrrolidone [2] with compounds possessing an active methylene unit) readily take part
in intramolecular Thorpe-Ziegler cyclization [3] to form pyrrolo[l,2-a]pyrroles (lla-c) under
mild conditions (ButOH, ButONa, 82~

CH2CN C}I2CN
NC ~NH2
Ia-c ITa-c
ImIIa R=COOC~H~;DR=CONH2;CR=CN
Moreover, cyclization of this type takes place even when only weakly basic agents like
DMF diethylacetal (III) are used. Further, the velocity for the closing of the pyrrole ring is
higher than the expected condensation at position 3 of the pyrrolidine ring. The result of the
reaction of Ic with III is thus the bicycle llc and the product of further condensation of the
latter with the acetal III (compound IV).

NMe2

,(c~: ~ iIa ber~ene 8"~ ,p- TIc +

CH~CN
9 Nc~N=CH.NMez
IV
Recorded compound, mp in ~ (crystallization solvent), yield, %: la, 196-198 (alcohol),
92; Ib, 97-98 (2-propanol), 68; Ic, 59-61 (2-propanol), 72; lla, >300 (DMFA), 94; llb, 246-247
(DMFA), 92; llc; >300 (DMFA), 44; IV, 178-180 (alcohol), 25.
Elementalanalytical data were in agreement with those calculated and the structures of
the synthesized compounds were shown by IR, PMR and mass spectroscopy.

S. Ordzhonikidze All-Union Scientific-Research Chemicopharmaceutical Institute, Moscow,

119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 564-565, April,
1986. Original article submitted November 26, 1985.

466 0009-3122/86/2204-0466512.50 9 9 Plenum Publishing Corporation

 LITERATURE CITED
i. S. Petersen, German Patent 863,056, Chem. Zentr., 8416 (1953).
2. T. V. Stezhko, V. G. Granik, R. G. Glushkov, L. F. Roshchina, A. I. Polezhaeva, and M. D.
Mashkovskii, Khim.-farm. Zh., No. 3, 290 (1984).
3. E. C. Taylor and A. McKillop, Advances in Organic Chemistry: Methods and Results. The
Chemistry of Cyclic Enaminonitriles and o-Aminonitriles, Vol. 7, Interscience, New York
(1976), p. i.

HOMOLYTIC ALKYLATION OF 2-METHYLQUINOLINE BY BENZODIOXOLANE

AND BENZODIOXANE

A. V. Sokolovskii, Yu. B. Ze!echonok, UDC 547.729.7'831.2'841.07

V. V. Zorin, S. S. Zlotskii, and
D. L. Rakhmankulov

Known methods for obtaining substituted benzodioxanes and benzodioxolanes from pyrocate-
chol differ little in efficiency [i, 2]. At the same time, compounds of this type possess a
wide spectrum of biological activity [3, 4].
In this connection we have investigated the possibility of obtaining substituents in the
hetero-fragments of benzodioxanes and benzodioxolanes by homoiytic alkylation of a heteroaryl
base using the readily available benzodioxane (I) and benzodioxolane (II).
Reaction of protonated 2-methylquinoline (III)with I or II is initiated by the redox
system (CH3)3COOH+FeSO 4 and yields, selectively, 4_(5,6-benzo-l,4-dioxan-2'yl)quinaldine (IV)or
4-(4,5-benzo-l,3-dioxolan-2-yl)quinaldine (V). The yields are 85 and 90%, respectively, and
are based on the amounts of reacted base (conversion of I I I = 70%).

-t-BuOH + F e S O 4

I Ill CH3j "IV

+ m- 0
0 /0 H ~Clt3 -t-Bu0H + FeS0 4 N~C~ ....
~

II TII CH3J V

The high yields and selectivity illustrate the synthetic importance of the reaction dis-
cussed.

EXPERIMENTAL
Tert-butylhydroperoxide was added dropwise over 30 min to an aqueous-DMSO solution of 2-
methylquinoline sulfate (0.02 mole), benzodioxacyclane I or II (0.04 mole), and FeS04 (0.01
mole) in a stream of argon. Compounds IV and V were separated using column chromatography
(A1203, hexane-ether, 5:1).
4-(5,6-Benzo-l,4-dioxan-2-yl)quinaldine (IV). nD 2~ 1.6155. PMR spectrum (CCI~, HMDS)
2.53 (3H, s, CH3), 3.58-3.86 (iN, m, CH2-O), 4.18-4.42 (IH, m, CH2--O), 5.40-5.60 (IH, m, CH--
0), 6.60-6.90 (4H, m, C6H~), 7.08-7.98 ppm (5H, m, Ar).
4-(4,5-Benzo-l,3-dioxalan-2-yl)quinaldine (V). Isolated in the form of a monohydrate
losing water at 85~ mp 87-89~ PMR spectrum (DMSO-d6, HMDS): 2.67 (3H, s, CHs), 2.81 (2H,

Ufa Petroleum Institute, Ufa 450062. Translated from Khimiya Geterotsiklicheskikh Soed-
inenii, No. 4, pp. 565-566, April, 1986. Original article submitted April i0, 1985; revision
submitted August 25, 1985.

0009-3122/86/2204-0467512.50 9 1986 Plenum Publishing Corporation 467

s, Hg0) , 6.85 (4H, s, C,H~), 7.38-8.18 ppm (6H, m, Ar + OCHO). Elemental analytical data was
in agreement with that calculated.

LITERATURE CITED
1. G. Sloof, Rec. Trav. Chim., 54, 995 (1935).
2. E. R. Cole, G. Crank, and H. T. Hai Minh, Austral. J. Chem., 33, 673 (1980).
3. R. L. Metcalf, Ann. Rev. Entomol., 12, 229 (1967).
4. S. Kuwatsuka in R. D. O'Brian (editor), Biochemical Toxicology of Insecticides, Academic
Press, New York (1970), p. 131.
. E. D. Laskina and T. A. Devitskaya, Zh. Prikl. Khim., No. 34, 2338 (1961).

REACTION OF 4-METHOXY(METHYLTHIO)-5-AMINO-6-MERCAPTOPYRIMIDINES
WITH e,~-DIBROMOACETOPHENONE

M. P. Nemeryuk, M. M. Likhovidova, UDC 547.854.83'869.2.07

I. D. Mitsev, and T. S. Safonova

It is known that reaction of 5-amino-6-mercaptopyrimidines with m-haloacetophenones gives

6-aryl-6-hydroxy-5H-6,7-dihydropyrimido[4,5-b][l,4]thiazines which are readily dehydrated to
6-aryl-7H-pyrimido[4,5-b][l,4]thiazines [i].
We have found that the reaction of 4-methoxy- and 4-methylthio-5-amino-6-mercaptopyrimi-
dines (la,b) with m,~-dibromoacetophenone (under conditions for the synthesis of 6-aryl-7H-
pyrimido[4,5-b][l,4]thiazines) unexpectedly produces 4,7-dimethoxy(dimethylthio)-Sa-phenyl-
pyrimido[4,5-b][l,4]thiazino[7,8-g]pyrimido[4,5-b][l,4]thiazines (Ilia,b) which represent a
new heterocycli c system.
The product expected was 6-aryl-7H-pyrimido[4,5-b][l,4]thiazine (IV) (substituted at the
7-position) but this was not formed in the reaction.
In the case of la and lla it was possible to separate the cyclic carbinol, Va, which is
postulated intermediate in this process. It may be converted to Ilia but not to IV.

R
~ N ~ [ NH2
SH + /~COCHBr2

Iv va HIa,b
a R=OCH3;DR=SCH~

Compounds llla,b and Va were crystalline materials, stable on standing.

Ilia: mp 243-245~ (DMFA-water), yield 66%
lllb: mp 253-254~ (DMFA-water), yield 64%
Va: mp 165-167~ (methanol), yield 80%
Elemental organic analytical data agreed with that calculated and IR, UV and PMR spectra
confirmed the structures proposed for llla,b and Va.

S. OrdzhonikidzeAll-Union Scientific-Research Chemic,pharmaceutical Institute, Moscow

119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 566-567, April,
1986. Original article submitted May 20, 1985.

468 0009-3122/86/2204-0468512.50 @ 1986 Plenum Publishing Corporation

 Benzo-analogs of the tetracyclic system llla,b have been obtained previously by reaction
of o-aminothiophenol with cyclohexanone [2].

LITERATURE CITED
i. T. S. Safonova and M. P. Nemeryuk, Khim. Geterotsikl. Soedin., No. 4, 735 (1968).
2. V. Carelli and P. Marchini, Int. J. Sulfur. Chem., Part A, ~, No. 4, 254 (1971); Chem.
Abstr., 77, 34462 (1972).

NEW SYNTHESIS OF I-VINYL- AND 1,3-DIVINYLURACILS

Z. V. Stepanova, G. G. Skvortsova,* UDC 547.854.4'314.2.07

V. K. Vorono~ and A. V. Afonin

It has previously been reported that 2-pyridone reacts with acetylene in the presence
of cadmium acetate preferentially forming 2-vinyloxypyridine, while vinylation proceeds at the
second reaction center, the nitrogen atom, in the presence of potassium hydroxide [I]. The
sensitivity of the pyrimidine ring to alkaline agents precludes the use of alkali metal hy-
droxides as catalysts during the vinylation of uracil. We have found that the reaction of ura-
cil with acetylene, catalyzed by cadmium acetate, leads in one step to the synthesis of N-
substituted mono- and divinyluracils. As products of the reaction, two compounds were isolated:
!-vinyluracil (I), mp 180~ and 1,3-divinyluracil (II), mp 60~ The process temperature con-
ditions were varied between 200-240~ and the yields of compounds I and II reached 20-43%.
The structure of compounds I and II was confirmed by the hydrogenation of the vinyl
groups, by IR and PMR spectra. The individuality of the compounds was confirmed by TLC on
aluminum oxide: Rf 0.155 (benzene-ethyl acetate-methanol, i:i:i) and 0.824 (benzene--ethyl ace-
tate, I:i) for compounds I and II, respectively. The physical constants of compound I obtained
by direct vinylation coincide with those for coNpound I obtained by a two-step method [2].

0 0 0 Hx.

N " O
H

HA HA
I I!

The position of the second vinyl group in divinyluracil was determined by the analysis
of P ~ spectra. The values of the vicinal SSCC in compound II (Jcis 9.0-9.2 and Jtrans 15.4-
16.0 Hz) indicate the presence of two vinyl groups joined to nitrogen atoms [3].
IR spectrum (with KBr): for compound I, 3100, 1635, 975 (CH=CH2), 1713, 1690 (C=O),
3160 cm -I (NH); for II, 3100, 1640, 975, 965 (CH=CH2), 1720, 1690 cm -I (-C=O). There is no
absorption in the 3380-3160 cm -~ region. PMR spectrum (CDCI3): for I, 4.95, 5.08, 7.18 (ABC
protons of the vinyl group, d.d. JAB = 2.2, JAC = 8.4., JBC = 16.4 Hz), 5.78 (SH, d) 7.46 (6H,
d, J56=8.0 Hz), 10.3 ppm (NH, br. s); for II, $.95, 5.06, 7.16, and 5.26, 5.87, 6.80 (ABC and
A'B'C' protons of the two vinyl groups, d.d. JAB 2.3, JA'B' = 0, JAC = 9.0, JA'C' = 9.2,
JBC = 15.6, JB'C' = 16.0 Hz), 5.79 (5-H, d), 7.40 (6-HJ, d, J56 = 8.0 Hz)0
The elemental analysis and molecular weights (mass spectrometrically) of uracils I and
II correspond to the calculated values.

*Deceased.
!rkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the USSR,
Irkutsk 664033. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 567-568,
April, 1986. Original article submitted July 15, 1985.

0009-3122/86/2204-0469512.50 9 1986 Plenum Publishing Corporation 469

 LITERATURE CITED
i. M.F. Shostakovskil, G. G. Skvortsova, S. M. Tyrine, Yu. L. Frolov, N. M. Deriglazov,
V. K. Voronov, and N. A. Ivanova, Dokl. Akad. Nauk 8SSR, 186, 620 (1969).
2. N. Ueda, K. Kondo, M. Kono, K. Takemoto, and M. Imoto, Makromol. Chem., 120, 13 (1968).
3. A . J . Gordon and R. A. Ford, Chemist's Guide: A Handbook of Practical Data, Techniques
and References, Wiley-lnterscience, N. Y. (1973).

REACTION OF 8-BROMO-3-METHYLXANTHINE WITH AMINES IN DMFA

N. I. Romanenko, N. A. Klyuev, UDC 547.857.4:07:543.51

B. A. Prilmenko, N. V. Fedulova,
and A. N. Stepanov

It is known [i, 2] that 8-aminoxanthines are formed when the corresponding 8-halo deriva-
tives are heated with amines in ethanol under pressure or in methoxyethanol.
We studied the reaction of 8-bromo-3-methylxanthine with primary and secondary amines in
DMFA. Instead of the expected 8-alkyl, dialkyl, cycloalkylamino-substituted 3-methylxanthlnes,
only one compound, 3-methyl-8-N,N-dlmethylaminoxanthine (I) was obtained and identified in
all cases.
As far as we know from the literature, no similar reactions, in which DMFA would compete
with strong nucleophiles in the nucleophillc substitution reactions are known. It is probable
that the mechanism of this reaction is as follows. A proton is split from the N(r atom by the
action of amine. The 8-bromo-3-methylxanthlnyllum anion formed adds to the carbonyl atom of
DMFA with Simultaneous elimination of dlmethylamide anion, which then plays the role of nucle-
ophile. Further, with the participation of an excess of the amine, a further elimination of
the N,-formyl group takes place.

0 0

CIt~ Ctl]
0

HN ~ ' " , , . . ~ N H

0 ~;;~'N/'" N"~ N--: .~

I I
CH~ CII3
I

A mixture of 0.i mole of 8-bromo-3-methylxanthine, 0.3 mole of benzylamine, cyclohexyl-

amine, monoethanolamine, n-hexylamine, N-benzylaminoethanol, or diethanolamine is boiled in
i00 ml of DMFA for 2-4 h. The mixture is cooled, washed with hot water, ammonia, water, and
dried. The precipitate is crystallized from glacial acetic acid. The yield of 3-methyl-8-
N,N-dimethylaminoxanthine (I) is 60-80%, mp >330~ PMR spectrum (DMSO, standard TMS): 3.015
[s, 6H, N(CH3)2] 3.297 (s, 3H, 3-CH3),II0.352 (s, IH, 7-H), 11.360 ppm (s, IH, l-H). Mass
spectrum (m/z): 210 (!0), 209 (i00) [M] ~ (determined 209.0878, calculated 209.0193 for CsHII-
N502), 194 (61) [M -- CH3] +, 180 (49) [M -- NCH3] + (determined 180.0627, calculated 180.0647
for CTHsN402), 166 (13) [M-- C2HsN] + and [M-- HNCO]+ (Ph) (determined 166.0501 and 166.0830,
calculated 166.0491 and 166.0854 for C~HsN402 and CTHIoN~O, respectively), 165 (15) [Ph -- HI +
(determined 165.0770, calculated 165.0776 for CTHgN40), 138 (18) [Ph -- CO]+, 137 (40) [(Ph --
H) -- CO] + , 124 (39) [(Ph -- CO -- CHs] +, iii (i0), 109 (14); 104.5 (12) [M] 2t, 68 (51), 53 (49).

LITERATURE CITED
i. F. F. Blocke and H. C. Godt, J. Amer. Chem. Soc., 76, 2835 (1954).
2. M. Gorczyca, A. Zeic, J. Krupinska, and R. Czarnecki, Ii Farmaco-Ed. Sci., 29, 802 (1974).
Zaporozhe Medicinal Institute, Zaporozhe 3 3 0 0 7 4 . Translated from Khimiya Geterotsiklich-
eskikh Soedinenii, No. 4, pp. 568-569, April, 1986. Original article submitted June 25,
1985.

470 0009-3122/86/2204-0470512.50 9 1986 Plenum Publishing Corporation

ANALOGUES OF PROSTACYCLIN (PGI2) MODIFIED
IN THE 2-OXABICYCLO[3.3.0]OCTANE FRAGMENT ~
(REVIEW)

Ya. F. Freimanis and K. Dikovskaya UDC 547.361'391'514'738'735'852.07(047)

A review is given of the synthetic analogs of the prostacyclins having greater

chemical and metabolic stability than prostacyclin itself. Possible routes for
synthesis are discussed.

Prostacyclin [synonyms: prostaglandin X (PGX), prostaglandin 12 (PCI2), and 6,9~-epoxy-

9-deoxyprostaglandin F2a] was discovered in 1976 [i]. This compound immediately caused great
interest, since it possessed the highest activity known at that time against the aggregation
of thrombocytes [2, 3]. The chemical structure of prostaglandin (i) was established by a
group of scientists under the direction of Johnson [4] in the same year, 1976. Immediately
after this, total chemical synthesis of this compound were performed independently in various
scientific centers of the world. The great interest of synthetic chemists in this problem is
shown by the fact that during the first seven months six different methods of obtaining PGI2
were reported [5-10].
(CH~,)~,COOR
4/
CH~
,fdH /
" o ~'~7. / oll
9 o

[ 10 14 i 16 18 20 ," "

9 / 13 ; I/ 19
6n o*~ oI1
1

In biological tests PGI2 is usually employed in the form of the readily water-soluble
sodium salt (i; R = Na). However, the probability of the development of medicinal prepara-
tions based on PGI2 remains extremely low, since the period of decomposition of aqueous solu-
tions of prostacyclin in the organism in 3-4 min [ii, 12] (or, according to [13, 14], -1o
min). This characteristic of substances of the type (i) is due mainly to the hydrolyclc
lability of the enol ether grouping of PGI2. As a result of this reaction, both 6n ~t2=o and
in u~uo, prostacyclin (I) always forms the same decomposition product -- 6-ketoprostaglandin
F, a (2) [14, 15]. Consequently, soon after the discovery of PGI= searches were begun for an-
alogs of it that would be distinguished by an increased chemical and metabolic stability [16]
with the retention of a high antithrombic activity that would be free from some side effects
of prostacyclin [17, 18].
A number of structural changes in the PGI2 molecule could, a priori, impart to it an in-
creased resistance to the action of the universal enzymes catabolizing all prostanoids (pro-
staglandin 13, 14-hydrogenase and prostaglandin 15-dehydrogenase, and also enzyme systems
causing the 8-oxidation of hydrocarbon residues). Such changes would include substitution
at the C(13), C(,~), C(,5), C(,6), C(2), and C(3) atoms, and, to a certain extent, also at
the C(,7),C(,2), and C(~) atoms. It is important to emphasize that the methods of synthesiz-
ing these atoms of PGI2 differ little from the methods of obtaining their prototype.

*This review is an expanded version of the plenary lecture of the authors at the 3rd All-
Union Conference on Synthetic and Applied Studies of Prostaglandins [in Russian], Ufa (1984).

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 579-595, May, 1986. Original
article submitted May 4, 1985.

0009-3122/86/2205-0471512.50 9 1986 Plenum Publishing Corporation 471

 The subject o~ the presen~ review is a consideration o~ modified p r o s t a c y c l i n s havlns
~he C-O bond os the b i c y c l t c system s t a b i l i z e d in some way, and also p r o s t a c y c l i n s the r e a c -
t i v i t y os which depends more on other structural ~rasment8 o~ the molecule than on the O-C-C
chain of atoms. We shall theregore conglder only those compounds in which the changes involve
the C(m)-C(LL) and 0 atoms of the tetrahydrofuran ring of the initial prostanoid, the hydrogen
atoms at C(s), C(~), and C(,o), and the chemical bonds of the b i c y c l i c system. The replacement
of the C(s)-C(e) double bond by an ordinary bond will be considered if it takes place as a
consequence of the migration of A s or is accompanied by a supplementary modification of other
c e n t e r s of the molecule. Change in the bonds of the C(~) atom will be r e f l e c t e d in individual
cases -when, a priori, they should have a substantial influence on the chemical properties of
the O-C-C structural fragment. On the basis of what has been said above, the chemically sig-
nificant region of structural modification of prostacyclin is outlined in formula (i).
In the preparation of this report, we have also used reviews published previously [16,
19, 22]| we assume that they succeeded in fully reflecting the situation with respect to pro-
stacyclin analogues up to and including 1984.

THE MOST IMPORTANT SYNTHETIC ANALOGUES OF PGIa.

SUBSTITUTION OF ATOMS ZN POSITIONS 5-11
Let us first consider PG1a analogues in which the oxygen atom has been replaced by a
methylene group -- so-called carbaprostacyclins. The first representative of them - 6a-
carbaprostacyclin la (3) [it has also been called carbacyclin, 6,9a-methanoprostaglandin Is,
6a-carbacyclin, and 9(O)-methanoprostacyclin] - was obtained in 1978.
At the end of the 70s, the interest of synthetic chemists in the preparation of PGIa
analogues contalnued to be very high: In the course of ten months, one and the same compound
(3) was obtained independently in six scientific centers [23-31]; for later work, see [32-36].
Below we also consider other carbacyclins (4-12).*
Carbacyclin (3) is characterized as a compound that is completely stable to hydrolysis
in vitro under conditions modeling physiological conditions [23, 27-31]| however, it has proved
to be as unstable metabollcally as natural PGIa [41]. Further modification of carbacyclin by
the introduction of fluorine atoms into the periphery of the molecule were obviously undertaken
with the aim of increasing the life of the carbacyclins in vivo, as well, (compounds (6) and
(7)). Unfortunately, there is still no information on their activity and metabolic stability.

:coo. 2
.~.COOR

8r e ~
~:_9 t
7 IOOR
5H 6H o. 6z4
3 R=C}I~.t4, Na 4 137| 5 [381
F F / (c4~o)
,n
~OOR ~OOR

9 9 % 9
~ RI HO"'~R 1
5a 6H o. 0H 9a,b![4s]
6 439] 7 [40J B 4421 9a n=1, bn=O

*Here and below in the formulas the substituent attached to the five-membered ring R* = 3(S)-
hydroxyoct-i(E)-enyl.

472
 Rooc.~./.:~[

l
6w os 6H 6~ HO'" ~ R 1

10 t441 LI I451 t 2 (46] t 3 {471 14 ,rl3J

Carbacyclins (4), (5), (8), and also (10-12) were synthesized as close structural ana-
logues of the prototype (3), Compounds (9a, b), (13), and (14), are already extremely remote
analogues of PGI2; for example, in the cyclopentanoindane (13), the ~-chain of a prostanoid
has been only formally replaced by a fragment with the Same number of carbo:r-c~bou bonds.
Thiaprostaglandin I= (15) was synthesized in 1977. This compound, and its analogues
(16-20), including some with a hydrogenated C(s)-C(,) bond, are still the only modified pro-
stacyclins in which the heteroatom can have different degrees of oxidation; furthermore, each
of the 9(0)-sulfoxa derivatives can exist in two epimeric forms, depending on the configura-
tion of the sulfoxide bond. The thiaprostacyclin (15) is completely stable in a neutral med-
ium and can be purified chromatographically on silica gel. This compound also possesses anti-
aggregation properties and its action is more prolonged than that of PGI2 [49].

( o l s -" ~. (o)ns9~ "-,: s"/ ~ . .

OH OH OH
15 - 17 I B- ~0 r. t IS?.Stq]

15 [49--54], 18 [52, 56] n=O; 16 [50, 51, 55], 19 [56] n = l ; 17 [50, 55], 20 [56] n = 2

For the 9(O)-aza analogues of PGI2 the problem of their structure is complicated further
by the fact that the five-membered he'terocycle can exist in the enamine (22a) or the imine
(22b) forms. Nevertheless, in the papers known to us only structure (22b) is found.
r/~'~COOR

! t ]

HN " 2 N ;* "% N /#"

/ \

zza 22b z 3 {59]

CooR [/ \cooR 9 CooR i cooR

;\
6H 6u ou 6n
~4-28 2 ? t59] 28 [6Z,631 ~ 9 t641

24 X~O, 25 X = S , 26 X=NR [16, 60, 61[

We may also mention compounds (30-37) in which two substitutions of atoms in the bicvclic
systems have now been made. These substances are only superficially similar to tile prostacy-
clins and, disregarding the principle of the construction of the octenol chain, the methods
for their production likewise differ from those customary in prostaglandin chemistry.

473
 ~ '~coos N~ coos ~"coos

s /x,.~

SO leSJ al [ee,eTl S~ laB]

; CO0~ "A'COOR <'~'COOCll~

i

. : o-'~-o

0 Oil OH
33, 34 37 [73] 35, 36

The aza analogues of the prostacyclins are more stable than PGI2 [60, 61]. Thus, the
stability of the ethyl ester of 5-aza-PGla (29: R = CaHb) is higher than that of the methyl
ester of PGI~ (i, R ffiCH~): It can be stored for several months at 4~ and the half-
decomposition time of its aqueous solutions at pH 7 ~s 33 h, while the PGIa ester at the phy-
siological pH is stable for only 4.5-6 h [12, 64].

HOMOPROSTACYCLINS AND THEIR HETEROANALOGUES

Some remote analogues of PGIa with a slx-membered ring in the place of one of the five-
membered rings in the blcyclic fragment have been mentioned above [compounds (ga, b) and (14)].
There are three types of "true" homoprostacyclinst with an additional methylene group between
C(6) and C(7) or the C(6~ and 9a (the ethereal oxygen atom) atoms or between the C(o) and 9a
atoms [compounds (38-42)].
1
9c O O R

f~rl ; j~,.,"" 5 0

HO
... . . . I
liO"
38 [7~d ~9 V75.76] 40 177,7B1

/R COOR
(\ COOR

ltO" ' " "" RI HO"

41 [793 4~ [44~

This group of compounds also contains the 2-nor-7-homo-9(O)-azaprostacyclin derivative

(43) and the 6,9-pyridazaprostacyclins (44). Analogues (39) and (40) do not contain the enol
ether structural fragment and are therefore more resistant to hydrolysis than PGI2. The py-
ridazines (44) are unstable in an alkaline medium, and with m-chloroperbenzoic acid they each
form two N-oxides the stability of which is considerably higher than that of the initial com-
pounds. They are stable in a neutral medium and possess interesting biological properties [38].

i I-
HO'" "R~ HO'" R~

43 C59] 4 4 [801

474
 DIHYDROPROSTACYCLINS I,
This name unites all those prostacyclin analogues in which the double r arbon-~arbon bond
has been eliminated from the C(s)--C(~) position. Such analogues may also contain another C=C
bond or a triple bond in place of the double bond [compounds of types (45)-(51)].

} 'C(tOR l COOR I C00R

- //~ j..

c} ./i o- .: o- ~.: o- ...:

6. 6H :
0II :
01{ :
O1{
46 [81,OZl 48 [O3J 47 [5,84] 48 [061 49 [88J

\coo. i-> cooR " coo,

q~.)N 0/\~. " SC611b -.~

OH 6H :
OH :
OH
50 [871 51 [85~ 62 [88-90; 53-56
53 [89, 90] X=B-SC6H~; 54 [89, 90] X=B-S(O)C6Hs; 55 [91] X=F; 56 [93] X=O,
57 ~1,92] X=Br;58191,99] X=C]
The 5 - and 7 - s u b s t i t u t e d prostanolds (52-58) are also known, t h e i r p r o t o t y p e b e i n g c o m -
pound ( 4 5 ) . These substances are frequently formed during the synthesis of the 5- or 7-sub-
stituted PGI='s.
Each of the analogues (45), (49), and (52-58) contains an enol ether grouping. There is
very little information on the hydrolytic stability of these compounds, concrete results hav-
ing been published only in relation to the analogue (52): Its biological activity is retained
under extremely severe conditions (pH 1.5, room temperature) for i h [88]. In the other cases
the authors state merely that the enol ether fragment can be subjected to hydrolysis but the
stability of the substances synthesized is higher than that of PGI= [61, 86, 93].

PROSTAGLANDINS 12 SUBSTITUTED IN THE

BICYCLIC FRAGMENT OR AT C(s) C(4)
The rate-determining stage of the hydrolysis of the enol ether group is its attack by a
HsO + ion [94, 95], and therefore any electron-accepting substituents adjacent to this group
should stabilize the molecule. We may mention first the PGI2 analogues (59-72), containing
electronegative systems in the C(7), C(e),C(s), and C(m) positions.

COOCH~ 9~" " ~ COOR ~COOR

- . O9 . O"
. ..9 ." "'.:"
:

-~y.- .,..dd
-~...--~.....-~..-' .~... . ~....
...... ~.~..'"-.R~

39 [92] 69-64 ~-87 6e m~,gaJ

475
 "11 o [I.... ''o 'I/
q"
.
"~'
:
:X '
: o"
' ."
q"
.
",:

~, ~.... I ,

; 61i . .,
oil : 611 x
O11
69, 7 0 71 [13j 7P. n ~ 0 - - 4 (JOl.-.lO3J 7il, 7 4

60 ~2] X=CN; 61 [91, 107], 67 [90], 70 [98], 74 [105] X=F; 62 [91] X=CI; 63
[88, 90] X=SC6Hs; 64 [88] X=S(O)CsHs: 65 [89, 90] X=~-OH; 66 ~9, 90] X=~-OOCCHs;
69 [20, 99], 73 [10~ X=H
The fluorinated analogue (74) contains the modifying atom in a position too remote for
it to be possible to expect an effect of it on the hydrolytic stability of the compounds in
relation to the O--C=C- fragment.
A series of amide derivatives of compound (61) is also known [106].
The stabilities of compounds (59)-(72) are substantially higher than that of their proto-
type PGI2. The half-decomposition period of 5(E)-chloro-PGI= (62) at pH 4.7 is 1.5 h, and
that of the 5(Z)-analogue under the same conditions is 8 h [92]. It can be seen that an im-
portant role is also played by the spatial position of the substituents at the C(5)=C(6) bond.
For comparison: The half-decomposition period of PGI2 at pH 5.98 is 22.4 seconds, and at pH
7.46 it is 10.5 min [14]. A phenylthio substituent has an even greater stabilizing effect:
for (63) TI/~ = 1.5 days (pH 7.4) [70], or 1 day at pH 1.5 [88]. A distinct stabilizing ef-
fect is also exerted by electron-repelling groups in position 7 of the prostacyclin system.
The period of half-decomposition of compound (65) at pH 4.7 is 3 h and that of the 7-fluoro
analogue (67) is 2.5 days [90]. Thanks to their stability, compounds (65) and (66) can be
purified by column chromatography on silica gel [89]. A special effect is exerted by the 7-
oxo group: In buffer solutions at pH 6.7 and 10.7 the prostacyclin analogue (68) does not
change in 26 days, and even at pH 2 the T,/2 value for this substance is 4 days [98]. How-
ever, its antiaggregation activity is 15 times smaller than that of natural PGI2.
Studies of stability by chemical methods and by biotesting have been described in detail
using the prostacyclin (71) as an example in [13]. Thus, if a solution of the sodium salt of
this compound is subjected successively to acidification, extraction, and chemical modifica-
tion, i.e., the procedure that normally precedes many methods for the qualitative determina-
tion of the prostanoids, the bulk of (71) remains unchanged, while natural PGI= decomposes
completely. The half-decomposition periods of the prostacyclins (71) and PGIa have been mea-
sured by the biotesting of solutions (i0-' M) in bicarbonate buffers (pH 7.4) at 37~ A
lowering of the bioresponse by 50% was observed for solutions of (71) after 24 h, and for
PGI2 after only i0 min [14].
Consequently, in order to find the optimum of the indices for the creation of a suffi-
ciently effective medical preparation -- for example, an antithrombic drug -- a compromise must
be found between the usually lower (by an order of magnitude and more) antithrombic activity
of PGI2 analogues and the substantially higher hydrolytic stability of these compounds as
compared with natural prostacyclin.

SOME FEATURES OF THE SYNTHESIS OF UNNATURAL PGI2 ANALOGUES

At the present time, a large amount of material has accumulated on methods of synthesiz-
ing prostacyclins. In the present review, we are able to dwell only on some of the, in our
view, most important principles of obtaining the desired compounds. We shall first consider
methods common for the synthesis of the most diverse groups of PGI2 analogues.

Nucleophilic Cyclization of PGF2u Derivatives

These include, as a rule, those methods of cyclization in which the actual closure of the
furan ring of the prostacyclin system is initiated by the action of a positively polarized
halogen atom or other grouping. This has led to the term "iodocyclization reaction"; it is
just this reaction that we used in the first syntheses of PGI2 and PGIs [82, 107]. A number
of substituted prostacyclins having two five-membered rings condensed in the usual manner
[20, 99, lO0, 104, 105, 108, 109 ], two types of homoprostacyclins (scheme I), and the tetra-
hydroprostacyclin (50) [87] have been obtained.

476
 Scheme 1
CO0CH~ (CH2)m-C0OCH '

9H
I2 0~ "(CH2)n 0 cHz)~

R'" R1 ."
R"" R1 R" R~
75 76 I , 3 0 . 73, 7 4

. / " .. COOCH3 , ~.-COOCH3

OH
.... o
....
] I
,,,, ~ /
." ~/~" C00CH3 K2CO 3 ....- ~

H0" .. ~.E1 HO" , , .R1 tiO" , " R~

78 4 t [79]
V7

1 R=OH, n=0, m=2 [82, 106J; 38 R=OH, n = l , m = l [74]; 73 R = H , n = 0 , m = 2 [104];

74 R = F , n=0, m = 2 [105]; D B U = 1,8-diazobicyclo[5.4.0]hndec-7-enc

T h e r e a c t i o n is usually initiated either by molecular iodine in the presence of carbonate

or by compounds containing a positively polarized bromine atom [5, 92]. The addition of a 9a-
hydroxy (or thiol, see below) group to the C=C double bond of the side chain takes place in
such a way that the oxygen (or sulfur) atom always attacks the C(6) atom, forming a new five-
membered heterocycle. This takes place correctly even in those cases where the double bond
in the initial prostaglandin has shifted into the C(6)--C(7) position (scheme 2) [57]. An ex-
ception is formed by cases of the heterocyclization of the methyl ester of 5-fluoro-PGF=~
(scheme i) in which the C(s) atom proves to be the most electrophilic, and a case in which
the formation of the furan ring is impossible in principle (scheme i, n = i).
Scheme 2

OH oH

?" i1, N - b r o m o - q" :~ H

. . . . . . ~ : " Br - ~ . . . . ~- 43, 56, tO3]
i )" succinimide / ~
CtI~C 3~;" ":~ ' ""
OCOCH3 ()C~CII.5 OCOCII
5
79 B0

In parallel with the 6B-substituted precursors of PGI2 (scheme I, variants with n = 0

and 2), the corresponding 6a-eplmers are also formed, and these, on dehydrohalogenation, give
~-dehydroprostacyclin Iz (type (47)) [22]. The key stage of the formation of the enol ether
or enethiol ether function in all cases is the trans-elimination of a hydrogen halide from the
adduct A (scheme 3). The stereochemical conditions necessary for this are usually fulfilled
in the case of the B-arrangement of the 6-substituent in the cyclization product (scheme i).
Scheme 3
H\ H Y R
9 --.:c c ' ~ R -- c = cI
'"" \X H
A
X = I , Br; Y = - O - , S

The halocyclization reaction can also be extended to the synthesis of the thiaprostacy-
clins (15) (scheme 4). In this case, the primary formation is assumed of the structural frag-
ment (81) in which the closure of the tetrahydrothiophene ring then takes place [49, 511.
Since the same thiaprostacyclin can be synthesized from the disulfide (83) (see scheme 4)
[52, 57], the hypothesis of the formation of an intermediate sulfenyl halide appears logical.

477
 Scheme 4

~" ~C00CH~
I~./X
S.H ~ ' v ~ -/c~ [.
X2 S ~
~" "" K.CO~
2 - --'~
5H 6H 6H
81 82

t
( .,, F ':'" ]

83 84
X=I, Br; ' here and below, THP = tetrahydropyran-2-yl

The thiol group proves to be so reactive that, for example, 9(O)-thia-5,6-dihydro-PGl2

(18) is formed under the conditions of simple acid catalysis [56]. The 4E, and 4Z-isomers
of 9-thio- and 9-acethylthio-PGFaa also cyclize in the presence of phenylselenyl chloride
with the formation of the 6-epimers of type (18) compounds containing phenylaelenyl groups,
in position 5 [50, 55].
Scheme 5

~COCH~ .~ ",-...., .COOCH 3 J.,.

/-/-%oo.
/ v S " ":.b,,

,,o.,
5R 5H oH
85 21 [58]

S COCH~ S/j --/ -'-~ c~ 176

: - .

~.."~ ~ .~/CO0CH~ K_zCO~

OR 6n OH
86 15 t54]

The nucleophilic cyclization of thiaprostaglandin derivatives containing a triple bond

in the a-chain deserves special attention. Both in this case and in the cyclization of the
corresponding 9-oxa prototype [ll0], it is just the five-membered heterocycle that is formed
(scheme 5).
Scheme 6
N N
+~ i11.,. 1,'-"/--~,
/~; COOCH~
/'- /CooCns--" -~.--<-"~ ~i
----l,- 23

HO"
& 6H oH
87 88

The production of 9-aza-PGl~ (23) [59] also falls within the general scheme of synthe-
sizing PGI= analogues by the nucleophilic heterocyclization method if the formation of the
pyrrolidine ring is regarded as a consequence of an attack on the C(6) atom of the u-chain of
the initial prostanoidby the negative end of the dipole of the azide fragment followed by
the elimination of a molecule of nitrogen (scheme 6).

478
Methods of Synthestzlng Homopr0stacyciins
We have already mentioned some syntheses of these compounds (scheme i). A homoprosta-
cyclin derivative [(42), scheme 7], used for the synthesis of the carbacyclln (i0), has also
been obtained by the iodocyclization method [ 4 4 ] .
Scheme 7

RO"""
~ V

.
i ~ I. 12, b a i e -.-

RO""'
~.~7~i~.i".
6R OR
89 4~

In the synthesis of 6,gu-methanoepoxyprostaglandins F2a (39) or 6,9a-methano-7~-homo-

prostaglandin 12 (9) the same principle is used as in the synthesis of many carbacyclins (see
below): First, bicyclic ketones are constructed - in the present case (90) and (91) with the
preformed m-chains of the prostanoid -- and from these the desired homoprostacyclins are ob-
tained by the traditional method using the Wittig reaction.

O
~ ~

90 OR OR
01

The 2-oxabicyclo[4.3.0]nonan-4-one system (90) was synthesized by cyclization with the

participation of the u-hydroxy group of the initial cyclopentanol and the thermal nucleophilic
atom of a vicinal a-propyl [75, 77, 78] or a-propenyl [76] substituent (scheme 8).
Scheme 8
Br ~CH3
~ ORi 0
~ 1. Nail, THF 0"/'~"
r Z ~ . 99

SiO2, CH2CI2 3. C~HsN.Cr0,~. HCI .L.....

92 90 94
R2=H, OR]; 9-BBN= 9-borabicyclo[3,3.1]nonane

Scheme 9 shows the synthesis of the bicyclo[4,3,0]nonan-3-one system (91). It makes use
of a comparatively rare method of alkylating a thioacetal carbon atom in the presence of lith-
ium diisopropylamide [43].
Scheme 9

S. S
1
C|I2Br S j" "" /--x~
9!

OR dR
95 96

Methods of SYnthesizing 9(O)-Carbaprostacyclin 12 and Its Analogues

The multiplicity of approaches to the synthesis of carbacyclins known at the present time
was developed with the aim of obtaining the prototype of this series of prostanoids -- 9(0)-
methanoprostacyclin (3) itself. As a rule, the key stage is the preparation of the bicyclo-
[3.3.0]octan-3-one synthons (97)-(99), onto the molecules of which are built the hydrocarbon
chains of a prostanoid in one sequence or the other (scheme I0, routes A and B). The majority

479
of authors, however, prefer Co synthesize carbacycllns by route A, and the originality of
each new method of obtaining compounds of type (3) resides mainly ~ust in the stage of form-
ing the intermediates -- the synthons (97)-(99).
Scheme i0

A A
[~, ~7, ~9, 3s,
9 CII0
6R
98

~ .CCORZ /"

[32,331
OR 2
CHzOH:
6R 5R ~
@7 IO0

Schemes ii and 12 show examples of the synthesis of the key synthons (97) and (98), and
scheme (13) the four main routes to the synthesis of synthon (99).
Scheme ii

0 I. ClSi(t-C4Hg)(CH3)2, /COOC~H5 0
0~. DMFA. imidazole A C2~I5~c ~
2. LICH2COOC~H ~ r q 9 [23] 0// ~ " "~"
~ ": "3. Ts011. to|uen~e " ~ -~"'" DB-'--'N. . . .
"~"--5!k.~ .OH 4. K2CO ~, CH~OH .OSi
~. oxidation
OCOR 0 0

101 102 103

I [32.361 i. NaBH4
2, Dabco i[33]
COOCH~ 3, CsHsCOCI

/
i~I" "~ COOCH5 ~..!3-~'.-3,6-l ~ "~]."\coocH~ 132,38J
~.- 97
I, Pa/c. H2
THPO'" .~- . . . .~.
"" ~o " J ~.o"~ Li "'-CH"COOCH3 THPO'"9 ....... l., ~ / 0.. ""'~~:6~S
2. t-C4H~OK
104 Si -- 105
~- 3. HMPA, 175 ~
DBN= 1.5-diazabicyclo[4.3.0]non-5-enr Dabco = 1,4-diazabicyclo[2o2o2]ocraiJr HMPA =
=: nexarnetnvtDnosvnoramide

Scheme 12

o F--I i
_.i o

1, NaOH, H20:~ 1. K2CO,

2.c~%. H~SO, C,~COC%COO%H~ 2.~ZD /~
108 3, I m C O h n CO
(Et2OCCH2CO2)2_ME2+ 107 ; " ~"
0 108
109 ,
\ [23,$9,27]
798
ImCOIm = carbonyldfimidazole;'MgD = 2- m e t h y l - 2- e t h y l - 1 , 3 - d i o x 0 i a n c

480
 Scheme 13

9 "-d'/"'h" ""-/"-/
9 " ;" 'V" "" :
II0 6Siq/-" 611 OR OR ~ OR
K
111 112 113
0
O.
; I~fll : [;~81

I14

S
115
CII:CII'CsH ~ 1.

COOCH3
/
/ ,0%%/ 1351

C() THPO"" ClIO

I]6 117

o L. o
\ / ,3.~, U. cH,c~176 ~35, ~ ":"
/
"" ..... ""/" " "-"'~" 'rHpo"" ,~....~-.. N. ........
-. . . . . , . -,N..~--V.~"I.......--..~
OTIIP d'rIzP OTHP OR dR
118 11@ 120

Scheme 14
0 Met X:'
i ] (AI/Hr
09 4 Crii]5 ~ C CIt:~ CI{~ C CII,.OI~ - h,-

IRI

X? X7 X'r X/

CI[7()R (;(}O1[
X'
X!
[}
- ?
/
: !
6R ~ 1")tl OH
;'L 6, ~

3 .X'=X'-'=H {.Met=A'lgBr): 6 X I, |1. X'l=V (A~.eI=MRBr): ~ X ' = F . X:'=[l b\hA= l.i)

According to scheme 9 (route A), the concluding stage in the majority of syntheses is
the Wittig reaction with the introduction of a carboxybutenyl residue. However, another he-
teroorganic synthesis, based on sulfoximides, is also used (scheme 14). Not only carbacyclin
(3) [28] but also its 5-fluoro analogue (8) [42] and its 2,2-difluoro analogue (6) [39] have
been obtained by this method.

MODIFICATION OF DERIVATIVES OF PGI2 AND OF ITS A6-1SOMER

The simplest method of synthesizing other prostacyclins from PGI2 or its 9(O)-thJa ana-
logues is the isomerization of the AS-bond, which takes place in methanol, in the presence of
an acid catalyst. During rearrangement, the molecule of prostacyclin (i) adds the elements
of methanol and the C(5)-C(6) bond, but in the following stage (thermolysis) these are elim-
inated again, now with the formation of the C(~)--C(7) double bond [81].

481
 ( 'VooR~ 'cooIf

X' ', X'

6)~ 6R oi~ fir

1, I5 r 4.~

1 [811,45181,82]X=O; 15[III].21[57.58]X=S
This reaction may also take place in the opposite direction (likewise through the addi-
tion-eliminationof a nucleophile -- in this case, water) when a fluorine or a chlorine atom
is present in position 5 of the initial A'-isomer; thus, the transformations of (55) and (58)
into (61) and (62) have been performed [91, 92].
The reduction of 9(O)-aza-6,9~-dehydro-PGI~ (23) leads to the two 6-epimers of compound
(27) [59]. A widely used method of modifying natural PGI2 is the addition of aprotic agents
to the C(,)--C(~) double bond. The adduct so obtained cannot be isolated and decomposed again
with the formation of a multiple bond in the C(s)6) or C(,,7) position, but now the prostanoid
molecule contains an electrophilic substit~ent (scheme 15). Together with compounds of types
(62), (63), (53), (57), and (58), the isomerization products s and (124) are sometimes formed.
~he use of benzeneaulfenylchloride as modifying agent and the isqmer_izat$onreactlon ~hat has
been mentioned permits the formation of 7-hydroxy-substituted prostacyclins (65) [89) 90], and
through them also the fluorinated prostacyclin (67) [90]. The chlorination of prostacyclin
(58) has led to the dichloro derivative (59) [92].
Scheme 15

9 " COOR

,Y
,/X --llX ~, "":
E Y ....... , , . . q
I)GI;, ....

OR OR 6R dR
l_
23 62, 63

,.,~J

."'COOR
ff/~C0OR
. Y
~. %"

1 \

6R 8R
53. 57. 58 5q. 12.1

52, 63 Y=SC6Hs [88--90]; 53 Y=O-SC6H~ [89, 90]; 57 Y=Br [91]; 58 [92], 62 [91], 124
Y=C1

It was mentioned at the very beginning of this review that in addition to those consid-
ered, another whole series of analogues and derivatives of prostacyclin retaining only a rough
superficial resemblance to it exists [16, 20]; there is also a group of prostacyclins modified
in the periphery of the molecule where the substituent no longer affects the chemical stabil-
ity of the enol ether grouping of PGI~. We have been able to discuss the chemical properties
of analogues of PGI~ and also their syntheses only in fragmentary fashion. Nevertheless, in
our opinion, the material considered in the present review gives a fairly complete idea of
the chemistry of the modified prostacyclins; by the methods that have been considered it is
also possible to obtain other, very different, substituted prostanoids, including those with
a modifying group in the periphery of the molecule. Already it is clear that the prostacy-
clins are extremely reactive compounds and their use as the starting materials for obtaining
new biologically active compounds of this series with greater efficiency and with a selective
action is only in its initial stage. Broad investigations in this respect taking into account
the accessibility of the chemical precursor of the prostacyclins (PGF2u, which can be obtained

482
by chemical synthesis) are extremely real and urgent at the present time. The authors hope
that this review -- the first in the domestic literature on this subject - will serve as a de-
finite stimulus to the development of broader investigations of the prostanoids in our country
in the very near future.

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REACTION OF I-ALKYL-2-ARYL-3-(2-METHYL-2,3-EPOXYPROPIONYL)AZIRIDINES
WITH BORON TRIFLUORIDE ETHERATE IN METHANOL

A. M. Zvonok, N. M. Kuz'menok, and I. G. Tishchenko UDC 547.422+547.717

The reaction of boron trifluoride etherate in methanol with trans-l-methyl(ethyl)-

or cis-l-cyclohexyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)aziridines leads to the
formation of the corresponding boron fluoride complexes on the nitrogen atom of
the aziridine ring. Reaction with trans-l-cyclohexyl-2-phenyl-3-(2-methyi-2,3-
epoxypropionyl)aziridines occurs with stereospecific opening of the aziridine ring
to give diastereomeric 2-methyl-5-methoxy-5Zphenyl-4-cyclohexylamino-l,2-epoxypen -
tan-3-ones, as well as products from the opening of the epoxide and aziridine
rings -- tetrahydrofuranones and tetrahydropyranones.

The presence of the epoxide and aziridine rings in the epoxypropionylaziridine molecules
makes it possible to compare their reactivity towards a number of reagents, it is known that
Lewis acids are widely used as catalysts in reactions of oxiranes and ethyleneimines with
nucleophilic reagents [i, 2]. In this connection, the conversions on treatment with boron
trifluoride etherate in methanol of the diastereomeric l-alkyl-2-aryl-3-epoxypropionylaziri-
dines synthesized previously [3] are studied in the present work.
It has been established that the nature of the proeucts formed is dependent on the size
of the alkyl substituent at the nitrogen atom of the aziridine ring, while in the case of

Scientific-Research Institute of Physicochemical Problems, V. I. Lenin Belorussian State

University, Minsk. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 596-
600, May, 1986. Original article submitted January 25, 1985.

0009-3122/86/2205-04855i2.50 9 1986 Plenum Publishing Corporation 485

 TABLE i. Physicochemical Properties of Compounds IV-VI,
Villa,b, a n d Xa, b, to XXa,b

Corn- Found, % Emplfleal Calculated *~o Yield,

pound nap,"C formula qo
G it N c II N

IV 125--126 54,5 5,4 4,7 C,sH~bNO~, BF:~ 54,8 5,3 4,9 61

V 117--118 47,2 4,4 8,3 Ct;~Ht4N204 9 BFa 47,3 4,3 8,5 52
VI 140--143 48,7 4,6 8,0 Cj,sI:lloN204' BFa 48,9 4,7 8,1 88
Villa
VIII b
145--146
139--140
61,2
61,1
5,4
6,6
4,0 }
4,0 Clslq~sNO2 ' BFs 61,2 6,6 4,0 85
95
Xa 189--190 59,2 7,0 3,5 } CloI"12zNO:, BVa 53
Xb 124.--125 59,2 7,0 3,5 59,2 7,1 3,6 39
XI 177--179 59,1 7,0 3,5 C i,.H27NOs' B F;.~ 59,2 7,1 3,6 38
XII 183--184 48,6 6,2 3,2 CjgH2sBrNOs 9BI'~ 48,9 6,1 3,0 46
Xllla
XIIIb
Oil
Oil
71,7
71,8 I
8,7
8,7
4,3
4,3 } CjoH2rNOs 71,9 8,6 4,4 99
99
XIV Oil 71,8 8,5 4,4 CIgH2rN03 71,9 8,6 4,4 90
XV 139--140 70,1 8,1 3,8 C21H=gNO4 70,2 8,2 3,9 56
XVI Oii , 71,8 8,5 4,5 CI.qH2rNO~ 71,9 8,6 4,4 26
XVII 116--I17 70,1 8,1 3.8 C~tI't~gNO4 70,2 8,2 3,9 74
XVIII 84--86 67,4' 7,6 5,5 C14H~oNO3 67,4 7,7 5,5 88
xIXa
xIXb
99--100
94--96
59,2!
59,2
7,0
7,0
,3,6
3,6 }CIoH2rNOs ' BF3 59,2 ] 7,1 3,6 29
38
xXa Oil 71,7 8,6 4,4 } Cj~I-I27NO~.~ 80
XX,b Oii 71,7 8,6 4,3 71,8 8,6 4,4 88

bulky substituents there is a dependency on the configuration of the epoxypropionylaziridines.

Thus, the trans-2-aryl-l-methyl(ethyl)-3-(2-methyl-2,3-epoxypropionyl)aziridines la, lib, and
Illa, react readily with boron trifluoride etherate in methanol to form complexes on the ni-
trogen atom of the aziridine ring, IV-Vl. On interaction of the cis-2-(2-methyl-2,3-epoxy-
propionyl)-3-phenyl-l-cyclohexylaziridines Vlla, b with boron trifluoride etherate, the ana-
logous boron trifluoride complexes Villa, b are isolated in quantitative yield.
Unlike the cis-aziridines Vlla, b the interaction of boron trifluoride etherate in meth-
anol with the trans-2-(2-methyl-2,3-epoxypropionyl)-3-phenyl-l-cyclohexylaziridines IXa, b
gives a mixture of boron trifluoride complexes formed as a result of opening of the aziridine
ring as well as both the epoxide and aziridine rings. In the case of the aziridinylepoxyke-
tone IXa, a mixture of 2-methyl-5-methoxy-5-phenyl-4-cyclohexylamino-l,2-epoxypentan-3-one-
boron trifluoride (Xa) and 2-methyl-2-methoxymethyl-5-phenyl-4-cyclohexylaminotetrahydrofuran-
3-one-boron trifluoride (XI) is formed in the ratio 5:4. Compound Xa is obtained as a result
of the stereospecific addition of methanol to the initially formed aziridinylepoxyketone-
boron trifluoride. Opening of the aziridine ring takes place from the B-carbon atom in the
aziridine ring, which is characteristic of reactions between aziridinylketones and nucleo-
philic reagents [4, 5]. Preservation of the epoxide ring in complex Xa is shown by reaction
of the latter with hydrobromic acid, leading to the formation of the bromohydrin XII. On
treatment with an alkaline solution the boron trifluoride complex Xa is converted to the cor-
responding unstable base Xllla.
Formation of the cyclohexylaminotetrahydrofuranone-boron trifluoride XI indicates that
in methanol as well as complex-formation on the nitrogen atom in the aziridine ring a com-
peting alcoholysis of the epoxide ring, catalyzed by boron trifluoride, occurs with subse-
quent stereospecific opening of the aziridine ring from the B-carbon atom. Treatment of the
boron trifluoride complex XI with an alkaline solution permits separation of the base XIV,
which is converted to the acetamide XV by the action of acetic anhydride.
The reaction of boron trifluoride etherate in methanol with the diastereomer IXb, which
differs from the trans-aziridinylepoxyketone IXa in the configuration of the chiral center of
the epoxide ring, gives the boron trifluoride complex Xb (the corresponding base is XIIIb)
which is a diastereomer of boron trifluoride complex Xa, and the cyclic compound XVl isolated
and characterized as a base. It transpires that compound XVI is 5-methyl-5-methoxy-2-phenyl-
3-cydlohexylaminotetrahydropyran-4-one, which is formed as a result of opening of the epoxide
ring, catalyzed by boron trifluoride, from the s-carbon atom and the subsequent cyclization
on the aziridine ring. The aminotetrahydropyran-4-one XVI is converted to the corresponding
acetamide XVII by reaction with acetic anhydride.
Analysis of the chemical shifts from the aminotetrahydrofuranone XIV and aminotetrahy-
dropyranone XVI and their acetamides XV and XVII~ as well as the magnitudes of Jvic and Jgem

486
and the data from the nuclear Overhauser effect make it possible for the right configurations
to be assigned unequivocally to the compounds just mentioned. Since on formation of the
aminotetrahydrofuranone XIV during the reaction the a- and a'-carbon atoms of the epoxide and
aziridine rings are unaffected, in the initial epoxypropionylazlrldlne IXa and R(S) configur-
ation of the chiral center of the epoxide ring is combined with an RR(SS) configuration of
the carbon atoms of the aziridine ring, while in the diastereomer IXb an R(S) configuration
of the chiral center of the epoxide ring conforms to an SS(RR) configuration of the aziridine
ring.

/C /CH-CH
BrCH~" 0H
[~C' NH'BF~"
[ "C~H. ~ ~0/ i ~N/ ~ HO 0 0 ~'BF3
0 * I
CeHII R R

Xll ~ I-IIl'vli~b'~~~
ab"3FBCHjOH
O(C2H5)2 Iv-vI'avbIll
x------C CH~CH ~ C e H s
CH3OCH2~. ' H H + \ / ~C/I ~Ar + C
CH!3~'~'~0/~,~C~H5 ~,,/ NH.BF3
m R
xa~,)~xab - OCH3 ._j

BF3"0(C2H5)2I I If0 BF3- 0(C2H5)211110~ i H0-

CStI~1 H
" O~ NHCeH1~ CH3 0~-.. ~H I
(~H30CHz . x----~ /CH-cH~OCH3
H ~'\
C6H5
c H c.-~..~0/A~.
HI sHs \,// "C,,1NHR "At C H ~ \
0 0 "0
XIV
xnm.hxvm.xxa,b OCH~
Ac20I Ac XVI
o T N~ IA%o
CHf'" ~0 ~\;~H5 6H5
AT

OCH3
ATII
I, IL IV, V, XVIII R=CH~, III, VI R=C=Hs, vIIa)--Xa, N XIlI~b, XIXa,b, xxa,b
R=C~HII; I, IN VII~b--Xa, b, XIIIab, XVIII, XIXa,N XX~b Ar=C~H~, II, IlI, V, VI
Ar=4-NO2C6H4
Thus, cyclization of the epoxypropionylaziridine I X a w i t h an RRR(SSS) r e l a t i v e configura-
tion of the chiral centers takes place as a result of opening of the epoxide ring from the ~-
carbon atom and gives the aminotetrahydrofuranone XIV, while cyclization of the diastereomer
IXb with an RSS(SRR) configuration occurs by ring-opening from the s-carbon atom and gives
the aminotetrahydropyranone XVI. Hence, the nature of the products formed is determined by
the regioselectivity in opening the opoxide ring, whith in turn depends on the relative con-
figuration of the a-carbon atom of the neighboring heterocycle. These results are in agree-
ment with the data obtained when studying the acetolysis of ketodiepoxides of a steroid ser-
ies [6] and also the acid hydrolysis of a,~,a',B'-diepoxyketones [7], and indicates that the
regioselectivity in opening the epoxide ring is determined by the configuration of the neigh-
boring three-membered ring irrespective of the nature of the heteroatom.
Reaction occurs on boiling N-methylaziridinylepoxyketone-boron trifluoride IV in methanol
for 5 min and gives the a-methylamino-B-methoxyketone XVIII. In the case of the cis-N-
cyclohexylaziridine-boron trlfluoride complexes Villa, b when boiled in methanol for 24 h a
complex mixture of reaction products is formed, from which the a-cyclohexylamino--8-methoxy-
ketone--boron trifluoride complexes XIXa, b are isolated with 30-38% yield and converted by the
usual method to the corresponding bases XXa, b.

EXPERIMENTAL
IR spectra of the compounds in CC14 with concentration 10 -I moles/liter (thickness of
layer 0.01 cm) and in KBr pellets were recorded on a Specord 75-IR spectrophotometer. PMR
spectra of solutions of the compounds in CD30D and CCI, were measured on a Tesla BS-467-A
spectrometer, the internal standard was HMDS.

487
 TABLE 2. IR and PMR Spectra of Compounds IV, Villa,b, and
Xa ,b XXa,b
Com- IR spectrum, u, crn'~; , PMR sp-ect-rumof complexes(in CDsoD) and
pound Cl,~ solutlon(KBr pel- ba~es (in CC1,O, ~5,,ppm (I, Hz)
tSI .......
IV (1705, C=O) 1,27, a (311); 2,44,$ (3tl); 2,60, d, 2,80, d (2t-I, 5,0);
4,30, d, 4,55, d (2H, 5,8); 7,35, s (51-1) . .
VIlla (1705, C=O) 1,30, s (3I'I); 1,00--2,10 rn (I1H); 2,80, a, 2,98, Cl
(2H, 5,0); 3,90,~. (2H); 7,24, s (5H)
VIllb 1,28, $ (3H); 1,10-.2,40, m (I1H); 3,06, d, 3,55,d
(2I-I, 5,0); 4,32, d., 4,56, d. (2H, 9,5); 7,30, s (5H)
Xa (1705, C=O; 1,27, s (3H); 0,9--2,20,m (~IH); 2,90, d, 3,10, d (2H,
3400, 3480, NH) 5,0); 3,30, s (3H); 3,93, d, 4,60, d (2H, 6,0); 7,40, s
(51-I)s
Xb 1,24, (3It); 0,6...-2,05,rn (IIH); 2,52, ~1 2,76, d (2H,
5,0) 3,00, s (3H); 4,20, d, 4,50, d (2H, 6,5); 7,30, s
(bH)
XI 1,I0, s (3H); 0,5--1,80, rn(llH); 3,22, d, 3,46, d (2H,
I0,0); 3,30, s (3H); 3,38, :s (2H); 7,32, m (bH)
X11 1,38, s (3H); 0,7--2,30, m (IIH); 3,26,s (3H); 3,48, d,
3,72, d (2H, 11,0); 5,07, d, 5,32, d (2I-I, 6,0); 7,40,s
(at)
X111a 1720, C=O; 1,37, s (3t-t); 0.8-....2,10, m (12H); 2,63, s (2H); 3,01,s
(3H); 3,56, d, 8,75, d (2H, 10,4); 7,20,m (5H)
X[[b 3320, 3380, NH 1,36, s (3H); 0,6---2,20, m (12H); 2,70,d., 3,26, d. (2H,
5,0); 2,91, s (3H); 3,36, d, 3,80, d (2H, 10,5); 7,15,s
(5t-1)
XIV 1760, C=O; 3300, 3370, 1,00, s (31-I); 0,45--2,40, m (12H); 3,30, d, 4,40, d.
NH (2H, 9,6); 3,30,s (3I-I); 3,35js~ (2H); 7,20,m (bH)
XV 1770, 1640, C=O 1,28, s (3H); 0,6--2,00,m (!IH); 2,00, s (3H); 3,20,
cl 5,20, d(2H, 9,0); 3,33, s (5H); 7,30, m (bH)
X~I 1728, C=O; 3360, NH 1,26, s (3H); 0,5--2,10,m (12H); 2.86.d, 4.26, d (2H,
8,0); 3,68, d, 4,12, d (2H, 9,0): 7,P.0.m (51-D
XV[ I 1730, 1640, C=O 1,38, s (31-I); 0,6--I,50,m (11H); 1,87, s (3H); 2,82,d,
4,80, d (2H, 7,6); 3,42, s (3H); 3~60, d 4,50, d (2H,
8,5); 7,12, $ (SHI
XVIII 1700, C=O; 3320, 3380, 1,42, s (31-I); 2,02, s (3H); 2,75, d, 3,24, d(2H, 5,0);
NH 3,02, s (3H); 3,28, d. 3,96, d (2H, 9.0); 7,20, s (6H)
XIXa 1,18,s (31-1); 0.6--2,10, m (llH); 3,15, d, 3,28, d (2H,
5,0); 3,16, s (3H); 4,18, d, 4,42, d(2H, 9,0); 7,26,m
(51-[)
XlXb 1,05,s~ (311);0,8--2,20,m(llH); 2,88, s (2H}; 3,20, s
(3H); 4,36,d, 4,60, d (2H, 7,0),7,35, s (5H)
XXa 1710, C=O; 3330, 3415, !,20, s (3H); 0,6--2,10, m ( t l H ) ; 2.36, s (2H); 3,16,
NH s (3H); 3,90, s (2H); 7,08, rn (bH)
XXb 1,35, s (3H); 0,6--2,10, rn (llH); 2,70,s (2H); 3,38,
d 4,44, d (2H, 3,5); 7,22, m(5H)

The properties of the compounds synthesized and their spectral data are given in Tables
1 and 2.
The synthesis and spectral properties of epoxypropionylaziridines I-III, Vlla, 5, and
IXa, b are described in [3, 8].
trans-l-Methyl(ethyl)- and cis-l-Cyclohexyl-2-aryl-3-(2-methyl-2,3-epoxypropionyl)
aziridine--Boron Trifluoride Complexes (IV-VI, Villa, b). I0 mmoles of aziridines I-III and
Vlla, b in I00 ml of methanol cooled to 0~ was mixed with ii mmoles of boron trifluoride
etherate. The reaction mixture was diluted with ether and after 2 h complexes IV-VI and Villa,
b were filtered off. The mixture was made alkaline with a solution of sodium carbonate and
aziridines IV-VI and Villa, b were extracted with ethers} their identity was confirmed from
their melting points and by TLC.
2-Methyl-5-methoxy-5-phenyl-4rcyclohexlamino-l~2-epoxypentan-3-one--Boron Trifluoride Com-
plexes (Xa. b), 2-Hethyl-2-methoxy-5-phenyl-4-cyclohexylaminotetrahydrofuran-3-one--Boron Tri-
fluoride (XI), and 5-Methyl-5-methoxy-2-phenyl-3-cyclohexylaminotetrahydropyran-4-one (XVI).
50 mmoles of aziridines IXa, b was dissolved in i00 ml of methanol, 55 mmoles of boron tri-
fluoride etherate was added, and the reaction mixture was kept for 12 h at 18-20~ The
methanol was partially evaporated on a film evaporator, and ether was added. Complexes Xa,
b crystallized out in the cold. The mother liquor was boiled off on a film evaporator, and
the residue was crystallized from a i:i0 methyl ethyl ketone--ether mixture, separating boron
trifluoride complex XI. After the crystals of Xb had been separated and the solvent evapor-
ated, a solution of sodium carbonate was added to the residue, which was then extracted with
ether, and the ether extract dried over sodium sulfate. The ether was evaporated and pyranone
XVI was separated by chromatography on a silica gel column, the eluent being a i:i ether--
hexane mixture.

488
 l-Bromo- 2-hydroxy-2-methyl-5-met hoxy-5-phenyl-4-cyclohexylaminopen tan-3-one--Boron Tri-
fluoride (XII). 5 mmoles of complex Xa was dissolved in 20 ml of acetic acid and 1 ml of 47%
hydrobromic acid was added. The crystals of compounds XII formed were filtered off and re-
crystallized from a methanol-methyl ethyl ketone mixture.
2-Methyl-5-methoxy-5-phenyl-4-cyclohexylamino-l, 2-epoxypentan-3-ones (Xllla, b) and 2-
Methyl-2-methoxy-5-phenyl-4-cyclohexylaminotetrahydrofuran-3-one (XIV). To 20 mmoles of boron
trifluoride complexes Xa, b and XI in 50 ml of water was added an aqueous solution of sodium
carbonate or alkali, and the mixture was extracted with ether. After drying the ether was
evaporated and compounds Xllla, b and XIV were separated in the form of oils.
2-Methyl-2-methoxymethyl-5-phenyl-4-cyclohexylacetaminotetrahydrofuran-3-one (XV) and 5-
Methyl-5-methoxy-2-phenyl-3-cyclohexylacetaminotetrahydropyran-4-one (XVII). i0 mmoles of
amines XIV and XVI in acetic anhydride was kept for i h at room temperature. The reaction
mixture was diluted with water, made alkaline with a solution of sodium carbonate, and ex-
tracted with ether. After partial removal of solvent acetamides XV and XVII w e r e crystallized
from an ether--hexane mixture.
2-Methyl-4-methylamino-5-methoxy-5-phenyl-l,2-epoxypentan-3-one (XVIII). 1.4 g (5 mmoles)
of complex IV was boiled in methanol for 5 min. The alcohol was evaporated and the residue
was made alkaline with an aqueous solution of sodium carbonate, extracted with ether, and the
ether extracts were dried over potassium carbonate. After partial removal of ether compound
XVIII crystallized out.
2-Methyl-5-methoxy-5-phenyl-4-cyclohexylamino-l, 2-epoxypentan-3-one--Boron Trifluoride
Complexes .(XlXa~
. . b)
. .and. Their
. . Corres~ondin$_Bases. (XXa, b) _" 3.53 g (iO mmoles) o~ complexes
ViIIa, D was boiled in methanol ior Z4 h. lhe solvent was evaporated and complexes XIXa, b
were crystallized from a 1:5 methyl ketone-ether mixture. Bases XXa, b were obtained from
complexes XIXa, b by the usual method.

LITERATURE CITED
I. P. A. Gembitskii, D. S. Zhuk, and V. A. Kargin, The Chemistry of Ethyleneimine [in Rus-
sian], Nauka, Moscow (1966).
2. L. Paquette, Fundamentals of the Current Chemistry of Heterocyclic Compounds [Russian
translation], Mir, Moscow (1971).
3. A. M. Zvonok, N. M. Kuz'menok, and L. S. Stanishevskii, Khim. Geterotsikl. Soedin., No.
7, 880 (1980).
4. I. G. Tishchenko, O. N. Bubel', and V. A. Konovalov, Khim. Geterotsikl. Soedin., No. i,
38 (1981).
5. I. G. Tishchenko, O. N. Bubel', and V. A. Konovalov, Khim. Geterotsikl. Soedin., No. 7,
936 (1981).
6. A. V. Kamernitskii, I. G. Reshetova, and K. Yu. Chernyuk, Izv. Akad. Nauk SSSR, Ser.
Khim., No. i, 134 (1978).
7. L. S. Stanishevskii, I. G. Tishchenko, A. M. Zvonok, and N. M. Kuz'menok, Khim. Geterot-
sikl. Soedin., No. i, 17 (1983).
8. A. M. Zvonok, N. M. Kuz'menok, and L. S. Stanishevskii, Khim. Geterotsikl. Soedin. No.
4, 456 (1986).

489
FORMATION OF 2-PHENYL-7-BENZPYRONE (FLAVONE) IN NUCLEOPHILIC THIYLATION OF
I-(2'-HYDROXYPHENYL)-3-PHENYLPROP-I-YN-I-ONE BY POTASSIUM p-THIOCRESOLATE

S. P. Korshunov, V. E. Statsyuk, UDC 547.385'569'814.5:

V. M. Kazantseva, and I. V. Bodrikov 541.63:543.422

The mechanism of formation of 2-phenyl-y-benzpyrone (flavone) in nucleophilic

thiylation of l-(2'hydroxyphenyl)-3-phenylprop-2-yn-l-one by potassium p-thio-
cresolate has been established by IR and PMR spectroscopy,

It has already been shown [i] that in the absence of catalysts, l-(2'hydroxyphenyl)-3-
phenylprop-2-yn-l-one I adds thiophenols to form the corresponding 8-arylthiovinyl ketones II.
However, when a similar reaction is carried out with the participation of potassium thiocre-
solate, besides the normal adduct II, a noticeable amount of flavone III is obtained. The
formation of this heterocyclic compound may proceed by one of the two most probable mechan-
isms. The first includes splitting of a proton from the hydroxyl group of the acetylenic ke-
tone I by external nucleophile (the thlolate anion), followed by attack of an internal nucleo-
phile (the phenolate anion) on the 8-acetylenic carbon atom. The second path comprises the
addition of the thiolate anion to the triple bond, followed by proton transfer from the hy-
droxylic group of the intermediate to the carbanion center (formation of adduct II). The sub-
sequent intramolecular substitution of the thioaryl fragment added by a phenoxyl group leads
to the formation of flavone III.
To determine the role of one or other product in the formation of flavone, we used IR
and PMR spectroscopy to study the transformation of the reaction products in the thiylation
of compound I by potassium thiocresolate in a CCI~ medium with an equimolar addition of 18-
crown-6-polyether at room temperature.
In the PMR spectrum of the acetylenic ketone I, the signal of the hydroxyl group proton
appears at i1.62 ppm, and the signals of the aromatic ring protons in the 6.9-7.7 ppm region.
In the PMR spectrum, as in [2], stretching vibrations of the triple bond appear in the 2220
cm-~ region and those of the carbonyl group at 1630 cm-~.
Immediately after the addition of an equimolar amount of 4-CHsPhSK to the solution of
compound I, proton signals appear in the PMR spectrum that are characteristic of the E- and
Z-isomers IIa and Ilb of arylthiovinyl ketone II [3]. In the spectrum there are singlets be-
longing to the protons of the methyl group of the CH3PhS fragment and the double bond of the
E-isomer at 2.38 and 6.6 ppm, respectively, and of the methyl group of the CH,PhS fragment
of the Z-isomer at 2.25 ppm. The signal of the vinyl proton of this isomer, as in all other
similar adducts with a Z-configuration [3], is superimposed on the signals of the aromatic
rings. The ratio of the integral intensities of the signals of the CHs group protons of the
adducts with the two configurations IIa and IIb is close to i~I. In the PMR spectrum of the
reaction mixture, the signal of the hydroxyl groupproton simultaneously disappears. The IR
spectrum of the reaction mixture corresponds well to the data of the PMR spectra. In the IR
spectrum, two stretching vibration bands of the carbonyl group of the isomers of the adduct
appear at 1668 and 1643 cm -~, and the absorption band corresponding to the stretching vibra-
tions of the C----Cbond at 2220 cm -I disappears. After the reaction mixture has been held for
24 h, the proton signals of the CH3 and--CH=C< fragments of the E-adduct (2.38 and 6.6 ppm)
completely disappear, the band at 1668 cm-* in the IR spectrum also disappears, and an intense
band in the 1680 cm-~ region appears that is characteristic of the stretching vibrations of
the flavone C=O group [3]. After the reaction mixture has been treated with hydrochloric
acid, almost equimolar amounts of Z-thiovinyl ketone IIb, flavone III and thiocresol could
be isolated.

Toliatti Polytechnical Institute~ Toliatti. Translated from Khimiya Geterotsikliches-

kikh Soedinenii, No. 5, pp. 601-602, May, 1986. Original article submitted February 15, 1985.

490 0009-3122/86/2205-0490512.50 9 1986 Plenum Publishing Corporation

 The above data thus show that the formation of flavone in the reaction of l-(2'-hydroxy-
phenyl)-3-phenylprop-2-yn-l-one with potassium p-thiocresolate proceeds according to the ad-
dition-substitution scheme:

I <~--//'l CHsPhSK

0 . . . . . OH 18-.Cr0WN -6
..............
J

O:- :C \ OK " --~ 0:" C OK ] -[< !k o, oK

C C .Ph C :- (7-" I ' h r 9 " O : Ph \C~C ~SPhCH3
H/ -- ~ S P h C I I 3 [ II "",~PhCIt z _ + II . . . . Ph
]Ia E - i s o m e r CHsPhSk II,l z-isomer

The process includes conjugated addition of a thiolate anion and hydroxyl group proton
to form 8-arylthiovinyl ketones lla, lib, followed by intramolecular substitution of the thio-
aryl group by a phenoxyl anion present in the trans-position with respect to the leaving group
of the adduct with the E-configuration. For the 8-adducts llb, in which the intramolecular
attack on the B-carbon atom by the phenoxyl anion is hindered, cyclization under these con-
ditions practically does not occur. A similar transformation of the E-isomer lla into flavone
is also observed when adduct lla is boiled with metallic potassium in toluene.

EXPERIMENTAL
The IR spectra were recorded on a UR-20 spectrophotometer and PMR spectra on a Tesla BS-
4870 spectrometer (80 MHz), using HMDS as an internal standard.
l-(2'-Hydroxyphenyl)-3-phenylprop-2-yn-l-one was prepared by organomagnesium synthesis
from phenylacetylene and salicylaldehyde, following by the oxidation of the acetylenic car-
binol obtained by active manganese dioxide in acetone [2]. p-Thiocresol was obtained by re-
duction of p-toluenesulfonyl chloride [4]. Immediately before the experiments, p-thiocresol
was distilled in a nitrogen atmosphere.
Reaction of l-(2'-Hydroxyphenyl)-3,phenylprop-27ynTl-on ~ with Potassium Thiocresolate.
A suspension of i.5 mm01es of potassium cresolate and 15 mmoles or 18-crown-6 ethel fn 5--ii
of CH2C12 was added dropwise at O~ to a solution of 1.5 mmoles of compound I in 20 ml of
methylene chloride. After 24 h, the solvent was evaporated, the mixture was treated with 20
ml of methanol with addition of a small amount of HCI, and the crystals of the Z-isomer of
Ilb were separated. Freezing of the mother liquor gave an additional amount of lib, and pre-
cipitation with water gave flavone III and thiocresol. The molar ratio of compounds IIb--III--
CHaPhSH was 1:0.9:0.85.
A similar result was obtained in the reaction of compound I with potassium thiocresolate
in absolute meEhanol.

LITERATURE CITED
i. V . E . Statsyuk, S. P. Korshunov, N. V. Korzhova, and I. V. Bodrikov, Zh. Org. Khim., i__5,
1998 (1979).
2. J. Okajima, J. Pharm. Soc. Japan, 80, 322 (1960).
3. V . E . Statsyuk, V. L. Krasnov, S. P. Korshunov, and I. V. Bodrikov, Zh. Org. Khim., 19,
468 (1983).
4. Weygand-Hilgetag, Experimental Methods in Organic Chemistry [Russian translation],
Khimiya, Moscow (1968), p. 944.

491
SYNTnE$%8 OF TETRA(I,4-D%TH~ACYCLOHEXENE)PORPHYRAZINE
AND ITS METAL COMPLEXES

G. P. ShaposhnlkovD V. P. Kullnlch, UDC 547.979.812'~541.49

and R. P. $mirnov

The syntheses o f tetra(l,4-dithiacyclohexene)porphyrazlne and its lithium salt,

obtained by reaction of 3,6-dithiahexene-l,2-dicarbonltrile with lithium amylase,
are described. A series of metal complexes of tetra(l,4-dithiacyclohexene)por-
phyrazine has been synthesized starting from 3,6-dithiacyclohexene-l,2-dicarbon-
itrile and the salts of the corresponding metals as well as from the free ligand
and metal chlorides.

Compounds including the tetraazaporphlne ring have found wide appllcatlon in the most
varied fields of science and technology, ~eing used as dyee~ organic semiconductors, catalysts,
e t c . [i-3].
The preparation of tetraazaporphines in which the pyrrole rings are condensed with heter-
ocycles is of definite interest. Literature data on compounds of this type are limited [4-6]
and an investigation of them would be of great interes in studying the effect of heterosub-
s=itution on physical chemical properties as well as because of the possibility of their
practical utilization.
In this paper, the syntheses of tetra(l,4-dithiacyclohexene)porphyrazine, HaTDTP (1),
and its metal complexes, Clo_aMTDTP (II-XVII) are described.

N :'~/ ':"N
.~ ? ~ .'\ d .s..
% ..........".i ;::/",,"

ILTDTP (I) CIo..2MTDTP (II--XVII)

II M=Cu 2+, I1[ M=Zn ='4", IV M = M g 2+, V -M=Cd 2F, VI M = F 24", Vll M=Co =+, Vlli
M=Ni =+, IX M=Pb 2+, X M = S n 2+, XI M = A P F, XII M=Ga 8+, XIII M=In3+,.XIV
M=Cr 3+, V M=Ge 4+, XVI M = S # +, XVII M=Zr *+

The syntheses of metal complexes II-XVII were carried out starting with 3,6-dithiacyclo-
hexene-l,2-dicarbonitrile (8VIII) and salts of the corresponding metals (acetates or chlor-
ides) in a melt or in boiling quinoline, (i) and (2), as well as by the reaction of the free
ligand with the metal chlorides (3)

i/ S ~.. CN +M(AcO)~
.............. II-X (1)
"S~ CN
XV'III

.............. ,,,' - XI

The central metal atoms in complexes with tri- and tetravalent metals have additional
chlorine ligands.

Ivanovo Chemical Technological Institute, Ivanovo. Translated from Khimiya Geterotsik-

licheskikh Soedinenii, No. 5, pp. 603-606, May, 1986. Original article submitted January 28,
1985.

492 0009-3122/86/2205-0492512.50 9 1986 Plenum Publishing Corporation

 ,,0- D

0,8 ,-~ Lo ~o

H~TDTP

0,4 Cl
/
Al TDTP
......

0,2- K.

350 400 soo 600 700 800 A, nm

Fig. i. Electronic spectra in ~-chloronaphthalene.

In carrying out the reaction in a melt, we heated the mixture of starting materials to
180~ after which the reaction mixture was observed to solidify and the temperature rose
spontaneously to 220~
We monitored the completion of complex formation in reaction (3) by comparing the elec-
tronic spectra of I and the reaction mixture. We ended the synthesis when the absorption
band at 625 nm, characteristic of starting compound I (Fig. i), disappeared from the spectrum
of the reaction mixture in ~-chloronapthalene.
In order to prepare H2TDTP (I), we synthesized its lithium complex (XIX) by reacting di-
nitrile XVIII with lithium amylate in boiling amyl alcohol:
~III CsHT 1 0 L i / C s H I 10tt H.S04
~X . . . . . L.---w.,.- I

When compound XIX is reprecipitated from concentrated sulfuric acid, it is completely

demetallated to form compound I.
We prepared the starting dinitrile, XVIII, by reacting the disodium salt of dimercapto-
maleindinitrile with dichloroethane in DMFA [i].
Compound I and its metal complexes were purified by washing with water and acetone in a
Soxhelet apparatus and then subliming out volatile impurities in vacuum (i0 -3 Pa) at 200-230~
For the stable metal complexes, II, VI-VIII, we also used reprecipitation from concentrated
sulfuric acid. This method could not be used successfully to purify complexes III-V because
they undergo demetallation. In the process of dissolution and subsequent reprecipitation from
concentrated sulfuric acid, the complexes of tri- and tetravalent metals (XI-XVIi) are found
to change into the corresponding hydroxy derivative:

xl- xvm ....... : ' -- mm .MTDTP

The individuality of the compounds synthesized was confirmed by elementary analysis and
electronic spectroscopy.
H2TDTP (I) and its metal complexes, II-XVil, appear as deeply colored, polycrystaliine
substances that do not melt on heating up to 500~ and do not sublime in vacuum. They are
difficultly soluble in organic solvents.

EXP ER IMENTAL
The electronic spectra of the compounds synthesized were taken in ~-chloronaphthalene on
a Specord UV-vis spectrophotometer at room temperature over a wavelength range of 330-760 nm.
The starting 3,6-dithiacyclohexene-l,2-dicarbonitrile was prepared according to [i].
Tetra(l,4-dithiacyclohexene)porphyrazine H2TDTP (I). Add 6.72 g (4 mmoles) of dinitri!e
k~Vllf' to a mixture of 1.88 g (20 mmoles) of lithium amylate and 150 m] of amyl alcohol, heat
to boiling (138-140~ and stir for 6 h. Cool the reaction mixture to room temperature and
dilute it with benzene to a i:i ratio. Filter off the precipitated solid, wash with benzene,
and dry at 100~ Then dissolve it in 200 ml of 18 M H2SO~ and pour the solution onto 400 g
of crushed ice. Filter off the precipitated f!ocs, wash with water until the washings are
neutral, and then with acetone in a Soxhelet apparatus. Dry at 100~ to obtain I in a 3.85 g
yield (57%) Found: C 43.2 H 2.8 N 16.5 S 38.2%. Calculated for C2~H~sNsSs: C 42.8,
H 2.5, N 16.7, S 38.0%.

493
 TABLE i, Yields and Elementary Analyses of Metal Complexes
o f Tetra(l,4-dithiacyclohexene)porphyazine, I I - X V Z I
m
I
Empirical ] Calculated,~o Yield,
I
formula [c,% H, % c ~ , ~ N
% %IS % M %

1
11139 J347 83 C=4HIsCuNsS8 [39,2 2,~ 15,2 34,81 8,7 62
Ii139420 54,343 89 C=4HisNsSsZn 139,112,r 15,2]34,7j 8,8 60
IV[41,6 2,5 16,0136,5 3,31 C~4HIsMgNsSs [41,4[ 22 16,1136,81 3,4 70
V[36,5 2,3 14,1132,5 4,51 C24HIsCdNsSa [36,7[ 2,C 14,3]32,7 4,3] 65
Yl ]39,1 2,4 15,8[34,9 7,9[ C24HIsFeNsSs [39,6 [ 2,2 15,4 [35,21 7,71 54
9 VII [39,6 2,1 15,4[34,8 8,21 C24HIoCoNsSs [39,4 [ 2,2 15,3 [35,0 l 8,II 63
'VIII [39,5 2,2 15,1 [35,1 8,0[ C=~HIoNsNiSa [39,4 [ 2,2 15,3135,01S,ll 68
IX [32,9 1,9 12,4[29,0 3,8[ C24H18NsPbSs [32,8 1,8 i2,7129,11 3,61 45
X [36,7 1,9 14,1132,1 5,2[ C24HIBNsSsSn /36,4 [ 2,0 14,2132,41 5,01 75
XI]39,4 2,1 4,6 15,3]34,7 3,91 C24HIsAICINsS8 [39,2[ 2,2 4,8 15,2134,9[ 3,7 83
XII]37,4 2,1 4,3 14,2~32,7 9,3[ C~4HIsCIOaNsS8 137,1[ 2,1 4,5 [4,4~32,9[ 9,0[ 53
XIII]35,2 2,0 4,2 13,0131,4 4,1J C24HIsCIInNsS8 [35,0[ 1,9 4,3 [3,6131,I[ 4,0] 61
XIY[37,9 2,3 4,5 14,6 33,41 7,21 C~HIeCICrNsS8 37,9[ 2,1 4,61 L4,8133,71 3,91 65
XV]35,1 2,2 8,5 13,6 31,31 9,21 C=4HIsCI2GeNsS8 35,3] 2,0 8,6] 3,7131,4[ 9,0 [ 45
XVI[33,2 1,8 8,0 13,2 29,9 3,91 C24HI6CI~N~SsSn 33,4 [ 1,9 8,1 3,0129,7[ 3,8 48
XVII [34,7 1,7 8,3 13,7 30,5 1,1[ C~4H~CI=NsS~Zr 34,5[ 1,9 s,5 3,4130,7 / 0,9 74

Chlorotetra(l,4-dithiacyclohexene)porphyrazinealuminum ClAITDTP (Xl). Add a mixture of

6.74 g (1 mmole) of I and 13.5 g (500 mmoles) of aluminum chloride to 150 ml of quinoline and
boil and vigorously stir for 8 h (235=C). Filter the hot reaction mixture and wash the pro - ~
cipitate on the filter with 200 ml of ethanol and then with water until chloride ion is ab-
sent from the filtrate. Purify further by extracting impurities with 200 ml of ethanol and
200 ml of acetone for 12 h in turn in a Soxhelet apparatus. Dry at 100~ to obtain complex Xl.
Metal Complexes of Tetra(l,4-dithiacyclohexene)poryphyrazine (If-X). Heat a finely ground
mixture of i0 mmoles of dinitrile XVIII and 5 mmoles of the appropriate metal acetate to 220~
and keep it for 30-40 min. Cool the reaction mixture to room temperature, powder it and pu ....
rify it by extraction with water and acetone for 12 h in turn in a Soxhelet apparatus. Dry at
100~ Complexes II and VI-VIII are further purified by reprecipitation from 18 M HaSOa.
XII-XlV. Mix a finely ground mixture of 5 mmoles of dinitrile XVIII and 22 mmoles of the
appropriate metal chloride with 50 ml of quinoline, heat it to boiling (235=C) and hold it
with stirring for 6 h. Cool the reaction mixture and dilute it with acetone to a i:I ratio.
Filter off the precipitate, wash it with water until chloride ion is absent from the filtrate,
then with 200 ml of acetone in a Soxhelet apparatus for 12 h. Dry at 100~
XV-XVII, Heat 20 mmoles of dinitrile XVlII (135~ and add I0 mmoles of the appropriate
metal chloride with stirring. Raise the temperature to 180~ after which the reaction mixture
spontaneously heats up to 220~ and solidifies. Cool the mass and powder it. In the case of
complexes XV and XVI, wash the product with 300 ml of 0.5 M HCl and then with water until
chloride ion is absent from the filtrate. Extract organic impurities by extraction in a Sox-
helet apparatus for i0 h with 200 ml of benzene and 200 ml of acetone in turn. In the case of
complex SVII, wash the product after the reaction mixture had cooled with acetone for 12 h in
a Soxhelet apparatus.
All of the metal complexes synthesized, II-XVII, are held in vacuum (10 -3 Pa) at 200-230~
for 2-4 h. The yields and elementary analyses are shown in Table I.

LITERATURE CITED
i. H . E . Simons, R. D. Vest, D. C. Blomstr6m, J. R. Roland, and T. L. Cairnsp J. Am. Chem.
Soc., 84, 4146 (1962).
2. C. Haman, J. Helm, and H. Burghard, Organic Conductors, Semiconductors Photoconductors
[in German], Akad. Ve=lag, Berlin (1980), p. 28.
3. M . R . Tarasevich and K. A. Radyushkina, Catalysis and Electrocatalysis with Metal Por-
phyrins [in Russian], Nauka, Moscow (1982), p. 5.
4. M . J . Danzig, C. Y. Liang, and E. Passiglia, J. Am. Chem. Soc., 85, 688 (1963).
5. M . G . Gal'pern and E. A. Luk'yanets, Zh. Obshch. Khim., 39, 25 (1969).
6. B . D . Berezin, V. N. Klyuev, and A. B. Korzhenevskii, Izv. Vuzov. Khim. Khim. Tekhnol.,
20, 357 (1977).

494
ASYMMETRICAL ALKYLATION OF I-[(s)-u-PHENYLETHYL]-AZETHIDINONE-2

N. N. Romanova, V. A. Budylin,* G. V. Grishina, UDC 547.718'466.3:541.632

V. M. Potapov, M. L. Demchuk, I. Yu. Sivkova,
and Yu. G. Bundel'

The methylation of the lithium derivative of azethidinone-2 which has a chiral

substituent at the nitrogen atom is asymmetrical and leads, with an optical yield
of 35%, to diastereomeric 3-methylated azethidinones-2. The reaction of these
compounds with Na in liquid ammonia gives enantiomeric 3-methylazethidinones
which confirms that an asymmetrical synthesis has taken place.

The ant action of natural ~-lactam antibiotics such as the penicillins, cephalo-
sporins, and monobactams is determined by the absolute configuration of the atoms C(3) and
C(4) of the G-lactam r i n g [i, 2]. Recently, the main method for the preparation of the syn-
thetic analogs of such biomolecules (the optically active B-lactams (azethidinones-2) with the
required absolute configuration of the asymmetric centers) can become asymmetrical synthesis.
The 3-substituted azethidinones-2 are usually obtained by the reaction of metal deriva-
tives of azethidinones-2 with different electrophiles [3, 4]. In [5] we have demonstrated
that the asymmetrical methylation of l-(~-phenylethyl)azethiadinone-2 (I) is possible in prin-
ciple. In order to elucidate the stereochemical rules governing the asymmetrical synthesis,
it was necessary to study the reactivity of the initial compound (
The reaction of ( I with the twofold excess of lithium diisopropylamide
in an argon atmosphere in THF, followed by the treatment of the lithium derivative with the
tenfold excess of heavy water, gives, according to mass-spectrometric data, a mixture of iso-
topomers II, III, and IV (route A) with the ratio 6:1:1. This indicates two directions of de-
protonation: via the Dositions C(3) and C(a) of the a-phenylethyl substituent at the nitrogen;
the main direction of the reaction is the formation of 3-monodeuterated azethidinone II.
/D D .D

w 5. o H--c-crI~ D --C --CH 3 D--C --CIt 3

//'b' I " I 1
C~H~ C6II5
N*~ ] ~ 3
A CStI5
II lII 1V

~CII~

I. ~O I "O
R *=:CH(CH3)CsH 5 R It ClI:( -C - ,~
~,)-Va (+_)- v b "c j i 5
(--)- v b (+_)-.vI
(-)-vt

The methylation of the lithium derivative of ( obtained in the reaction with two
equivalents of lithium am with a twofold excess of methyl iodide under the same conditions
leads to the formation of the diastereomeric pair ( b and the dimethylated azethidinone
( (route B) with the ratio 1:1.5 (preparative column chromatography). According to PMR
data, ( V represents a mixture of diastereomeric racemates ( (with a large
Rf value) and ( (with a smaller Rf value). The azethidinones ( and ( were sep-
arated by TLC on plates and isolated in the ratio 1:3.5. According to PMR data, the diastereo-
mer purity of the isolated diastereomers Va and Vb was better than 98%. It must be pointed
out that all physicochemical characteristics of the ( Va and Vb coincide with
*Deceased,

M. V. Lomonosov Moscow State University, Moscow. Translated from Khimiya Geterotsikli-

cheskikh Soedinenii, No. 5, pp. 607-611, May, 1986. Original article submitted March 25, 1985.

0009-3122/86/2205-0495512.50 9 1986 Plenum Publishing Corporation 495

 s 10~
~I0 ~b

9O

5O

,o
0 . . . . . . . .
- 10 200 22~,~2t,0

- 30

-=.,0

Fig. i. CD Spectra of Compounds Villa, b in m e t h a n o l .

the data given earlier in [6]; the predominant formation of one of the 3-methylated azethidi-
nones-2 (55% Vb) allows us to use this reaction for asymmetrical methylatlon.
In order to study the factors affecting the ratio of the diastereomers (f)-Va and (
we have varied the reaction conditions: the temperature, the duration of the reaction with
the metal and of the methylation, the polarity of the solvent, and the rat$o of the reactants.
Increasing the temperature of methylation (from -78 to-46 ~ and the duration of reactlonwith
the metal (5-60 min) and of methylation (30-60 min) did not increase significantly the optical
yield of the diastereomer ( Reducing the polarity of the solvent (THF--hexane mixture,
i:i) decreases the excess of the diastereomer ( to 42%. When the readtlon is performed
in an even less polar medium (THF--hexane, 1:5), no monomethylated azethldlnone V is f~rmed;
only dimethylated l-(~-methyl~,phenylethyl)-3-methylazethidinone-2 (VI) (yield 20%) and trl-
methylated 1-(~-msthyl-a-phenylethyl)-3,3-dimethylazethldinone-2 (Vll) (yield 15%) have been
isolated, the structure of which was confirmed by IR, PMR, and mass spectrometry.

O
CH~---?--CH3
CeH 5

Reducing the amount of lithium amlde to an azethidinone--amide molar ratio of 1:1.15 in-
creases the chemical yield of the monomethylated ( V (39%) as well as the dia-
stereomeric excess of ( (60%).
The variation of the methylation conditions has shown that the maximum excess of the di-
astereomeric racemate ( (60%) is formed in the reaction of l-(u-phenylethyl)azethldinone-
2 in THF with 1.15 equivalents of lithium dlisopropylamide at --78~ for 30 minp followed by
methylation with two moles of methyl iodide at the same temperature for 45 mln.
The methylation of the lithium derivative of the optically active l-[(s)-u-phenylethyl]-
azethidinone-2 under optimum conditions leads also to the predominant formation of the (--)-
azethidinone Vb with an optical yield of 35%.* Improved values have been obtained for the
specific rotation, somewhat different from those published in [6], for the isolated optically
active diastereomers of Va and Vb.
In order to establish the causes for the decrease in the optical yield in comparison
with the diastereomeric racemates~we have tested the stability of the individual diastereomer
*The configuration of the C(s) atoms in the compounds (--)-Va and (--)-Vb has not been estab-
lished and has been assigned arbitrarily on the basis of chromatographic mobility.

496
(--)-Vb. It was found that a mixture of diastereomers (--)-Va and (--)-Vb 1:5 is formed when
the lithium derivative of the individual isomer (--)-Vb, obtained under the usual conditions,
is decomposed with water. This result indicates that thediastereomer (--)-Vb is converted to
(--)-Va and requires a more detailed investigation.
Besides the optically active monomethylated diastereomers (--)-Va and (--)-Vb, a dimethyl-
ated optically active azethidinone (--)-Vl was isolated with a yield of 14%; during the reac-
tion methylation occured via the atoms C(3) and C(a) of the chiral substituent at the nitro-
gen, i.e., destruction of the center of asymmetry in the initial molecule. It can be assumed
that the retention of optical activity in the azethidinone (--)-VI indicates the sequence of
deprotonation: Removal of a proton and methylation first takes place at the C(3) atom, then
at the C(u) atom.
In order to confirm the asymmetrical synthesis in the methylation of the lithium deriva-
tive of (--)-azethidinone-l, the chiral u-phenylethyl substituent was removed from thenitrogen
in each of the diastereomers (--)-Va and (--)-Vb by the action of sodium in liquid ammonia,
since it was found [7] that under these conditions no change takes place in the absolute con-
figuration of the C(3) atom in the 8-1actams:
,~H
(-)-Va Na/NH3 " I ~CH~
HN
~0
(+)-villa

. ,,~CH 3
(_)_vb Na/NH3
ItN
"~0
(-)-~nb

Enantiomers of 3-methylazethidinone-2 (+)-Villa and (--)-Vlllb were obtained, having iden-

tical IR, PMR and mass spectra, but antipode CD curves.
Thus, an assymetrical synthesis has been proposed (optical yield 35%) of optically active
3-substituted azethidinones-2, representing chiral syntons for different transformations of the
~-lactam ring.

EXPERIMENTAL
The IR spectra were taken on an UR-20 spectrometer as a thin film, the PMR spectra on
Varian T-60 and XL-IO0 spectrometer in CC14 with TMS as the internal standard; the mass spec-
tra were obtained on an MX-1303 spectrometer at an energy of 50 eV,with direct introduction
of the substance in the ion source. The specific rotation and CD spectra were measured on a
Jasco J-20 instrument. The racemic l-(a-phenylethyl)azethidinone-2 (I) and its optically ac-
rive analog (--)-I with [u] D 2 0 --99 .40 (c = 0.i, CC14) were prepared by the procedure given in
[6]. The Rf values for the N-substituted azethidinones-2, which represented thin oils, were
calculated for the system benzene--ethyl acetate 2:1, on Silufol UV-254 sheets.
Deuteration of l-(~-Phenylethyl)azethidinone-2. A solution of 1 mmole lithium diisopro-
pylamide, prepared from 1 ml i.i N solution of butyllithium in hexane and 0.14 ml (i mmole)
diisopropylamine in 0.5 ml THF, was treated dropwise with a solution of 87.5 mg (0.5 mmole)
azethidinone ( in 5 ml THF at --78~ in a stream of argon and stirred for 5 min. 0.09 ml
(5 mmoles) D20 in 0.5 ml THF was added, followed by a saturated solution of ammonium chloride
in D20. The mixture was extracted with absolute ether and dried with magnesium sulfate. Af-
ter stripping of the ether the reaction mixture was investigated by mass spectrometry. It
was found to consist of a mixture of isotopomers II, III, and IV with the molecular ions M+
176, 177, 178, corresponding to the presence of one (55%), two (9%), and three (9%) deuterium
atoms in the molecule; the initial azethidinone I with M+ 175 was also present (27%).
Methylation of l-(u-Phenylethyl)azethidinone-2. A solution of 4 mmoles lithium diiso-
propylamide, prepared from 3.5 ml of a 1.14 N solution of n-butyllithium in hexane and 0.56
ml (4 mmoles) of a solution of diisopropylamine in 5 ml THF at --78~ , was treated dropwise in
a stream of argon with 350 mg (2 mmoles) azethidinone ( in 5 ml THF. The reaction mixture
acquired a yellow-brown color which disappeared after a few minutes. After 5 min 0.25 ml (4
mmoles) of methyl iodide in 5 ml THF was added. The reaction mixture was stirred at --78~ for
30 min and decomposed with 20 ml of a saturated ammonium chloride solution. It was then ex-
tracted with ether and dried with MgSO~. After removal of the ether the yellow oil was sepa-

497
rated on a column (Si02, L40/100; benzene-ethyl acetate, 2:1). Yield 51 mg of diastereomeric
racemate of 1-(~-phenylethyl)-3-methylazethidinone-2 ( Rf 0,32; 41 mg of a mixture of
diastereomers ( b, Rf 0.33 (I:i according to PMR); total yield of ( 20.5 mg (5%),
of ( 71.5 mg <19%); diastereomeric excess of ( 55%. Isolated 67 mg (16%) 1-(~-
methyl-~-phenylethyl)-3-methylazethidinone-2 (VI), Rf 0.47. IR spectrum: 1750 cm -~ (CO of
8-1actam). PMR spectrum: i.I (3H, d, CHs--C(s)); 1.5 (6H, s, 2CHs-C(~); 2.44 (IH, m, H--C(s));
2.86 (2H, m, CH2); 7.13ppm (bH, s, atom.) Found: C 76.5; H 8.5%; M~ 203. CIsH~TNO. Cal-
culated: C 76.8; H 8.4%; M 203.
B. A solution of 1.15 mmoles lithium diisopropylamide, obtained from 1.15 mmoles diiso-
propylamine in 5 ml THF and 1.2 ml 41.15 mmoles) 0.99 N hexane solution of butylllthium, w a s
treated in an atmosphere of argon at --78~ with 175 mg (i mmole) of azethidinone ( in 5 ml
THF. The reaction mixture was stirred at--46 ~ for 30 min. The usual decomposition of the
reaction mixture and chromatographic separation gave 20 mg (11%) ( 54.2 mg (29%) 4
(diastereomeric excess of (~)-Vb 46%), and 12.2 mg (6%) (
C_.:. A solution of 4 mmoles lithium diisopropylamide, prepared from 3.5 ml of a 1.14 N
solution of butyllithium in hexane and 0.56 ml (4 mmoles) of a solution of diisopropylamine
in 3.5 ml THF, was treated dropwise in a stream of argon with 350 mg (2 mmoles) azethidinone
( in 8.5 ml of a solvent mixture (hexane--THF i:i) and stirred for i h at -78 ~ . A solution
of 0.5 ml (8 mmoles) CHsl in 5 ml of the same solvent mixture was added and the reaction mix-
ture stirred for 1 h at the same temperature. The usual treatment of the reaction mixture
and chromatographic separation on a column gave 31 mg (8.2%) ( 60.4 mg (18.3%) (
(diastereomeric excess of ( 42%), 238 mg (6.7%) ( and 44.8 mg (12.8%) of the initial
azethidinone ( with Rf 0.35.
D_=. A solution of 4 mmoles lithium diisopropylamide, prepared from 3.5 ml 1.14 N solution
of butyllithium in hexane and 0.56 ml (4 mmoles) of a solution of diisopropylamine in a solvent
mixture of 1 ml THF and 1.5 ml hexane, was treated dropwise in a stream of argon at--78 = with
350 mg (2 mmoles) azethidinone ( in a mixture of i ml THF and 5 ml hexane and stirred at
--78~ for 1 h. A solution of 0.5 ml (8 mmoles) methyl iodide in 6 ml of a solvent mixture
(THF--hexane 1:5) was added, and the reaction mixture decomposed in the usual way after stirring
it at -78 ~ for i h. Separation on the chromatographic column gave 69 mg (20%) of azethidinone
( and 54 mg (15%) of ( with Rf 0.54. IR spectrum: 1760 cm -I (CO of 8-1actam).
PMR spectrum: 1.20 46H, s, 2CHsC(s)); 1.63 46H, s, 2CHs-C(~) ; 2.45 (2H, s, CH2); 7.25 ppm
(5H, s, arom.). Isolated 58.5 mg 417%) of initial azethidinone (
E__. 2.3 mmoles of lithium diisopropylamide, prepared from 2.3 mmoles diisopropylamine in
i0 ml THF and 2.4 ml (2.3 mmoles) 0.99 N hexane solution of butyllithium, was treated in an
argon atmosphere at --78~ dropwise with stirring on a magnetic stirrer with 350 mg (2 mmoles)
azethidinone ( in i0 ml THF.After 30 min, 4 mmoles CHsl in i0 ml THF was added dropw
the solution was stirred for 45 min at --78~ The usual treatment of the reaction mixture and
chromatographic separation on a column gave 14.7 mg (8%) ( 59 mg (31%) ( (diastereo-
meric excess 60%), and 15 mg (7%) (
F_u. Methylation of the optically active l-[(s)-u-phenylethyl]azethidinone-2 under the con-
ditions of the previous experiment gave 40.7 mg (33%) of the diastereomer 4--)-Va ([~]D 2~ 68.7 ~
[c = 2.5, CCLd)), 83.7 mg (68%) diastereomer (--)Vb ([~]D 2~ 120 ~ (c = 2.5, CCItt, optical yield
of (--)-Vb (35%)), and 57 mg (14%) of azethidinone (--)-Vl ([u]soo 2~ 71.1 ~ 4c = 0.19, CCId)).
IR spectrum: 1750 cm -I (CO of 8-1actam). PMR spectrum: 1.2 (3H, d, CH3--C(s))~ 1.6 (6H, s~ 2CHs--
C(u)), 2.44 (IH, m, 3-H); 2.90 (2H, m, CH2), 7.20 ppm (5H, s, arom.).
Isomerization of l-[(s)-~-Phenylethyl]-3-methylazethidinone (--)VB. A solution of 0.5
mmole lithium diisopropylamide, prepared from 0.5 ml i.i N solution of butyllithium in hexane
and 0.07 ml 40.5 mmole) diisopropylamine, in 0.5 ml THF was treated dropwise in a stream of
argon at --78~ by a solution of 94.5 mg (0.05 mmole) of the individual diastereomer (--)-Vb, and
after 5 min by I mmole water in 2.5 ml THF. The reaction mixture was stirred for 30 min at
--78~ treated with a saturated solution of ammonium chloride, extracted with ether, dried with
magnesium sulfate, and the ether stripped off. The obtained yellow oil was separated on a
column packed with silica gel (L40/IO0, benzene--ethyl acetate 2:1), and the chromatographically
uniform fractions evaporated. Yield 32.9 mg (--)-Vband 16.9 mg of a mixture of diastereomers
(--)-Va and (--)-Vb i:i (according to the PMR spectrum taken on an XL-100 spectrometer).
Enantiomers of 3-Methylazethidinone-2 z A solution of 50 mg (2 mmoles) metallic sodium
in i0 mi liquid ammonia was treated dropwise with a solution of 1.3 =~ole of azethidinone

498
(--)-Va in 3 ml absolute ether at --78~ The reaction mixture was stirred for 1.5 h. The ex-
cess sodium was decomposed with dry ammonium chloride and the reaction mixture allowed to
warm up to room temperature (until complete removal of ammonia); the residue was then extracted
with absolute ether. After stripping of the solvent the yellow oil was purified on a column
(Si02, L40/100, benzene-acetone i:i). Yield 42 mg (38%) (+)-Villa, Rf 0.48 (Silufol UV-254;
benzene--acetone i:i). IR spectrum: 1760 cm-* (CO of S-lactam). PMR spectrum: 1.30 (3H, d,
CHIC(3)); 2.90 (IH, m, ~-H; 3.08 (IH, m, 4-H)~ 39 (IH, M, 3-H). Mass spectrum: M + 85,
Mcalc 85; [~]so$~+54.1 ~ (c 0.17, CCI~). The analogous procedure gave from 1.3 mmoles (--)-Vb
43 mg (39%) (--)-VIIIb; the Rf value, IR and PMR spectra were identical to those of the com-
pound (+)-VIIIa, [a]soo2~ ~ (c 0.15, CCI~), however the course of the CD curve is anti-
podic (see Fig. i).

LITERATURE CITED
i. V . M . Giriyavallabhan, A~ K. Ganguly, S. W. McCombi, P. Pinto and R. Rizvy, Tetrahedron
Lett., No. 36, 3485 (1981).
2. C . M . Cimarusti, H. E. Applegate, H. W. Chang, D. M. Floyd, W. H. Koster, W. A. Slusar-
chyk, and M9 G. Young, J. Org. Chem., 47, 179 (1982).
3. T. Durst and M. J. LeBelle, Canad. J. Chem., 50, 3196 (1972).
4. H. Otto and R. Mayrhofer, Ann., ~, 1152 (1983).
5. N . N . Romanova, V. A. Budylin, G. V. Grishina, V. M. Potapov, and Yu. G9 Bundel', Khim.
Geterotsikl. Soedin., No. I, 134 (1985).
6. N . n . Romanova, V. A. Budylin, G. V. Grishina, V. M. Potapov, V. N. Torochesnikov, Ii. L.
Demchuk, and Yu G. Bundel' Khim. Geterotsikl Soedin., No 12, 1644 (1984)
9 , 9 9 9

7. S . T . Hodgson, D. M. Hollinshead, and S. V. Ley, Chem. Comm., No. 8, 494 (1984).

AZO COUPLING AND AMINOMETHYLATION OF 2,5-DIPHENYLPYRROLE AND ITS DERIVATIVES

A. N. Grinev,* M. V. Mezentseva, UDC 547.471

E. F. Kuleshova, and L9 M. Alekseeva

The azo coupling of 2,5-diphenylpyrrole with arenediazonium chlorides has given

previously unknown 3-arylazopyrroles and 4-phenylazo-3-phenylhydrazono-3H-pyrrole.
The methylation and reductive acetylation of the anylazo derivatives have led to
N-methylarylazo and acetylamino derivatives of 2,5-diphenylpyrrole. 3-Amino-2,
5-diphenylpyrrole has been obtained by the reduction of 3-p-chlorophenylazo-2,5-
diphenylpyrrole. The aminomethylation of 2,5-diphenylpyrrole and its derivatives
with bis(dialkylamino)methanes had led to aminomethyl derivatives.

Continuing investigations in the pyrrole series [i] with the aim of finding biologically
active compounds, we have studied the azo coupling of 2,5-diphenylpyrrole with aryldiazonium
chlorides. It has been established that, depending on the pH of the medium during azo coup-
ling, either monoarylazo- (Ia, b) or 4-phenylazo-3-phenylhydrazono-2,5-diphenyl-3H-pyrroles
(II) are formed. The methylation of compounds (Ia) and (II) takes place in each case at the
nitrogen atom of the pyrrole ring with the formation of compounds (Ic) and (III), respectively9

*Deceased.

S. Ordhonikidze All-Union Scientific-Research Institute of Pharmaceutical Chemistry,

Moscow. Translated from Khimiya Geterotslklicheskikh Soedinenii, No. 5. pp. 612-615, May,
1986. Original article submitted January 29, 1985.

0009-3122/86/2205-0499512.50 9 1986 Plenum Publishing Corporation 499

 /

Ph~N~p h 11

CH3 I aR=R~=H;DR=II, RI=CI;

I~ C R=CH3, RI=CI

The existence of compound (II) in the monophenylhydrazone form and not in the form of a
diphenylazo derivative was confirmed by a comparative analysis of the IR, UV, PMR, and mass
spectra of compounds (la), (II), and (III).
The IR spectrum of the arylazopyrrole (la) contains an absorption band of the NH group
of a pyrrole at 3180 cm -~, while in compound (II) this absorption band was detected neither
in paraffin oll nor in a tablet with KBr nor in CHCIs, while the absorption band at 3060 cm -~
observable in CCI~ can be assigned either to the stretching vibrations of a N'H group or to
the stretching vibrations of the CH groups of an aromatic ring. It was impossible to confirm
the structure of compound (I) unambiguously from its IR spectra.
In the PMR spectrum (DMSO-d~) of compound (II), in addition to the multiplet of 20 aro-
matic protons in the 7.41-7.92 ppm region of a broadened signal was observed at 15.8 ppm of
the proton of a NIl group, which disappeared when deuteromethanol was added. The strong down-
field shift or the signal of the Nll proton is apparently connected with the formation of an
intramolecular hydrogen bond, which is possible in the case of the anti-orientatlon of a sub-
stituent [2, 3].
As was to be expected [4, 5], in the UV spectra the long-wave absorption band at 480 ran
in compound (II) was shifted hypsochromically by 125 nm in the spectrum of compound (III).
The mass spectra of compounds (la), (II), and (III) had strong peaks of the molecular
ions (M+ 323, 427, and 441, respectively*). In the case of compounds (la) and (III) under the
action of electronimpact, the qbJectlon of the phenylazo group from M+ with the formation of
fragments 218 (85)~ and 336 (25), respectively, was observed. In the case of compound (III),
the formation of a fragment [PhCNCH~] +, 118 (99), was also observed. The spectrum of compound
(II) showed not only the elimination of a PhN= group from M + [ions at 322 (28)] but also the
ejection of a PhNH group with the formation of a stable ion at 335 (i00). Thus, a combina-
tion of the results of IR, UV, PMR, and mass spectroscopy confirms the structure of compound
(If).
On the reductive acetylation of compounds (Ib, c) and (II) with zinc in acetic acid in
the presence of acetic anhydride and sodium acetate at 50-60~ the acetylaminoderivative (IVa-
c) were obtained. The reduction of the arylazopyrrole (Ib) with sodium hydrosulfite, and also
with zinc dust in a i:i mixture of ethanol and acetic acid led to 3-amino-2,5-diphenylpyrrole
(IVd).
R~ NHR

p Ph PN H Ph

~a-d va-g

IVa--c R=COCH3;d R=H; ~,b,d RI=H,c R~=NHCOCH3; a,c, dE==H, b R2=CH3;

Va, f R=CH=N(CH3)=,b R = C~-pipe~dino, ~. ~, g R=C~-mo~holino, R=H; a,d
RI=CH2N(C2Hs)=, b R1=Cl~,piperidino, ~ R~= CH~-morpholino,~ f R I=
=N=N--CsH4CIp, g RI=NHCOCH3

We have shown that 3-arylazo- and 3-acetylamino-2,5-diphenylpyrroles take part in the

aminomethylation reaction when they are heated with diaminomethanes in dioxane, while 2,5-

*The numbers characterizing the ions show the m/z values.

~The intensities of the peaks in % with respect to the maximum peak are given in parentheses.

500
 TABLE 1. Characteristics of the Compounds Synthesized

;om- Found, % Calculated, % ,Yielc

,ound
T
mp'
* ~ Empirical formula "%
C H Cl N C H Cl N

Va 227--229[64,7 7,3[17,1 10,2 C22H27N3' 2HCI 65 7,2 17,4 10,3 43

Vb 184--186164,4 ]7,7113,3 ] 8,3 C28H35N3"2HCI--2H20 64,4 7,9 13,6 8,01 52
Vc 183--184174,717,61 - - [ 1 0 , 3 C26H3tN302 74,817,5 -- lO,11 60
Vd 19o-192173,817,4llO,5 j 8,1 CmH~4N2 9 HCI 173,917,4 10,41 8,11 40
Ve 200--202171,215,61 7,7]12,7 C~TH~sCIN40 ]71,0 ]5,5 7,7112,31 54
Vf 195--197 66,2 5,5[15,9[12,5; C25H23CIN49HCI [66,5 [5,4 15,7[12,4 40
Vg 239--240 73,4 6,7] -- I1,4 C23H25N302 173'6 ]6,7 -- 111,2 62

*Compounds (Va, b, f) were crystallized from methanol--

acetone-ether, (Vc, g) from methanol, and (Ve) from methanol--
DMFA (4:1).

diphenylpyrrole with a free position 3 is aminomethylated by these compounds only on heating

in acetic acid. In this way the aminomethyl derivatives (Va-g) were obtained.

EXPERIMENTAL
IR spectra were taken on a Perkin-Elmer instrument (Sweden) in paraffin oil, UV spectra
on an EPS-3 spectrometer (Japan) in ethanol, and PMR spectra on a Varian XL-IO0 spectrometer
with TMS as internal standard~ Mass spectra were obtained on a Varian MAT-f12 mass spectrom-
eter (FRG) with a system for the introduction of the sample directly into the ion source at
an energy of the ionizing electrons of 70 eV. The purity of the substances was checked by
TLC on Silufol UV-254 plates in the benzene--ethyl acetate (4:1) and chloroform systems, the
spots being revealed in UV light.
2,5-Diphenylpyrrole was obtained by the procedure of Overberger et al. [6].
2,5-Diphenyl-3-phenylazopyrrole (la). At from --5 to O~ with stirring a solution of
benzenediazonium chloride prepared in the usual way from 1.4 g (15 mmoles) of aniline, 4.95 ml
of concentrated hydrochloric acid, 16.5 ml of water, and 1.03 (15 mmoles) of sodium nitrite
that had then been neutralized with sodium acetate of pH 6.0 was added gradually to a solution
of 3.4 g (15 mmoles) of 2,5-diphenylpyrrole in 150 ml of methanol. The reaction mixture was
stirred at 0~ for 0.5 h. The precipitate that had deposited was filtered off, washed with
water, and dried. The yield of compound (la) was 2.23 g (45%), mp 149-149.5~ (benzene-
hexane). IR spectrum, cm-*: 3180 (NH), 1580, 1620 (C=C), 1400 (N==N). UV spectrum: %max, nm
(log e): 205 (4.58), 225 (4.30), 315 (4.77), 415 (4.24). PMR spectrum (CDCI3), ppm: 7.38-
7.94 (15 H, m, atom.); 7.0 (i H, d, 4-H, J,.4 = 3 Hz); 8.7 (i H, s, NH). Mass spectrum, m/z
(%): M + 323 CI00): 322 (68); 246 (15); 218 (85). Foundz C 81.7; H 5.5; N 13.0%. CaaH, TN3.
calculated: C 81.7; H 5.3; N 13.0%.
3-p-Chlorophenylazo-2,5-diphenylpyrrole (Ib). Compound (Ib) was obtained from 2,5-di-
phenylpyrrole and p-chloroaniline under the conditions for the synthesis of compound (la).
Yield 94%, mp 196-197~ (from methanol--DMFA). IR spectrum, cm-*: 3460 (NH), 1580, 1620 (C=C),
1400 (N=N). UV spectrum, %max, nm (log c): 205 (4.32), 232 (4.18), 260 (4.18), 316 (4.55), 430
(4.16). Found: C 74.1; H 4.4; C1 10.4; N 11.7%. Ca=H,6CINa. Calculated: C 73.8; H 4.5; Cl
i00; N 11.7%.
2,5-Diphenyl-4-phenylazo-3-phenylhydrazono-3H-pyrrole (II). At --5~ and pH 8-9 a solu-
tion of benzenediazonium chloride prepared in the usual way from 14.2 g (45 mmoles) of aniline,
I0 ml of concentrated hydrochloric acid, and 3.1 g (45 mmoles) of sodium nitrite that had then
been neutralized with sodium acetate to pH 3 was added gradually to a solution of 4.38 g (20
mmoles) of 2,5-diphenylpyrrole in 250 ml of methanol. The pH of the reaction mixture was kept
constant by the simultaneous addition of a saturated solution of sodium carbonate. Then the
reaction mixture was stirred at Ooc for I h. The precipitate was filtered off, washed with
water, dried, and chromatographed on a column of KSK silica gel (benzene, chloroform). Yield
6 g (70%), mp 240-241~ (decomp., methanol--DMFA). IR spectrum, cm-*: 3060 (NH). UV spectrum;
% max, nm (log ~): 200 (4.12), 235 sh. (3.95), 295 (4.19), 480 (3.98). PMR spectrum (DMSO-d6),
ppm: 7.41-7.92 (20 H, m, atom.) 15.8 (i H, br.s, NH). Mass spectrum, m/z (%): M ~ 427 (99);
426 (56); 350 (12); 335 (I00); 322 (28); 105 (22); 92 (32); 77 (17). Found: C 78.4; H 5.1,
N 16.7%. C28Ha,Ns. Calculated: C 78.4; H 5.0; N 16.4%.

501
 3-p-Chlorophenylazo-l-methyl-2,5-diphenylpyrrole (Ic). At 10~ a saturated solution of
2 g (50 mmoles) of caustic soda in water was added to a solution of 3.58 g (i0 mmoles) of
compound (Ib) in 50 ml of acetone. The reaction mixture was stirred for 5 mln, and then 2.53
g (20 mmoles) of dimethyl sulfate was added dropwise. After further stirring for 20 mln, the
mixture was poured into water. The precipitate was filtered off, washed with water, and dried.
Yield 2.65 g (71%); mp 172-174~ (from methanol-DMFA). UV spectrum, lma x, nm (log r 206
(4.12), 250 (3.91), 300 (4.07), 390 (3.89). Found: C 74.2; H 5.1; C1 9.8; N 11.3%. C=,H,aCINs.
Calculated: C 74.3; H 4.9; C1 9.5; N 11.3%.
l-Methyl-2,5-diphenyl-3,4-bisphenylazopyrrole (III)~ Compound (Ill) was obtained from (If)
under the conditions of the synthesis of compound (Ic) with a yield of 97%; mp 200-201~ (from
methanol). UV spectrum, lmax, nm (log c): 208 (4.54); 220 (shoulder) (4.33); 294 (4.46); 335
(4.27); PMR spectrum (CDCI,), ppm: 3.54 (3 H, s, H-CHs); 7.26-7.64 (18 H, m, arom.). Mass
spectrum, m/z (%): M ~ 441 (i00); 440 (18); 364 (65); 350 (4); 336 (25); 233 (23); 218 (i0);
77 (30). Found: C 78.6; H 5.1; N 15.6%. C=gH=sNs. Calculated: C 78.8; H 5.3; N 15.9%.
3-Acetylamino-2,5-diphenylpyrrole (IVa)~ With stirring, 9.18 g (90 mmoles) of acetic
anhydride and 3.44 g (42 mmoles) of fused sodium acetate, and then, in portions, 11.7 g (180
mmoles) of zinc dust were added to a suspension of 10.7 g (30 mmoles) of compound (Ib) in 80
ml of glacial acetic acid, the temperature of the reaction mixture being maintained at 50-53~
Then was stirred for 0.5 h, and the precipitate was filtered off and was washed with glacial
acetic acid, and the mother solution was poured into water. The precipitate that deposited
was filtered off, washed with water, and dried. The yield of compound (IVa) was 3.33 g (40%);
mp 171-172~ (from aqueous methanol). IR spectrum, cm-*: 3220, 3440 (NH), 1650 (C--O). UV
spectrum, lma x, nm (log ~): 205 (4.38), 232 (4.36), 325 (4.40). Mass spectrum, m/z (%): M +
276 (i00), 234 (80); 233 (38), 206 (7), 130 (10), 127 (i0), 105 (9), 103 (ii), 77 (12), 44
(16), 43 (12). Found: C 78.2; H 5.8; N 10.1%. C,sH~,N=O. Calculated: C 78.5; H 5.8; N
i0.0%.
3-Acetylamino-l-methyl-2~5-diphenylpyrrole (IVb)~. In a similar manner to the preceding
case, (IVb) was obtained from (Ic) with a yield of 62%, mp 78-79~ (from benzene--hexane). IR
spectrum, cm-1: 3230 (NH), 1650 (C=O). UV spectrum, %max, nm (log E): 209 (4.32), 305 (4.22),
Found: C 78.5; H 6.3; N 9.7%. C19H,sN=O. Calculated: C 78.6; H 6.2; N 9.6%.
3,4-Bisacetylamino-2,5-diphenTlpTrrole (IVc). The compound (IVc) was obtained with a
yield of 71% under the conditions for the synthesis of compound (IVa); mp 290-292?C (decomp.,
from methanol). IR spectrum, cm-*: 3220 (NH), 1650 (C=O). UV spectrum, %max, nm (log ~):
208 (4.37), 220 sh. (4.18), 313 (4.36). Mass spectrum, m/z (%): M + 333 (i00), 291 (67), 273
(80), 249 (32), 231 (22), 131 (30), 104 (27), 77 (21), 44 (39), 41 (48). Found: C 72.2; H
5.9; N 12.3%. C2oH~gN30. Calculated: C 72.0; H 5.7; N 12.6%.
3-Amino-2,5-diphenylpyrrole (IVd). A. To 65 ml of boiling water was added 8 g (40
mmoles) of sodium dithionite and then a bo-~ling solution of 3.58 g (i0 mmoles) of the aryl-
azopyrrole (lib) in 250 ml of ethanol. The reaction mixture was stirred for 1 h, filtered,
and poured into water. The precipitate was filtered off, yield 2.08 g (89%), mp 186-187~
(benzene). According to the literature [7], mp 186-187~
B. A solution of 25.2 g (140 mmoles) of sodium dithionite in 90 m~ of water was added to
a solu-~ion of 10.8 g (30 mmoles) of compound (lib) in 450 ml of glacial acetic acid at 70~
The reaction mixture was stirred for 0.5 h and was then poured into water and neutralized with
ammonia to pH 6. The precipitate was filtered off. Yield 6.2 g (88%), mp 186-187~ (benzene).
C. With stirring, 8.23 g (120 mmoles) of zinc dust was added to a suspension of 3.58 g
(i0 mm-oles) of compound (lib) in 300 ml of a i:i mixture of ethanol~and acetic acid. The re-
action mixture was stirred for i h, and then the precipitate was filtered off, and the filtrate
was alkalinized~with ammonia. The precipitate so formed was filtered off. Yield 1.87 g (80%),
mp 186-187~ (benzene).
Preparation of Dialkyiaminomethyl Derivatives of 2,5-Diphenylpyrrole (Va-g) (General
Procedure). A mixture of i0 mmoles of 2,5-diphenylpyrrole, the arylazopyrrole (Ib), or the
aminopyrrole (IVa) and 40 ml of dry dioxane ~ was boiled with 30 mmoles of a bis(dialkylamino)-
methane derivative for 5 h. The solvent and the excess of amine were distilled off in vacuum.
The residue was dissolved in absolute ether and was neutralized with an ethereal solution of
hydrogen chloride. Information on compounds (Va-g) is given in Table i.
mThe reaction of the 2,5-diphenylpyrrole was performed in acetic acid with heating in the
water bath.

502
 LITERATURE CITED
i. V . I . Shevdov, M. V. Mezentseva, and A. N. Grinev, Khim. Geteroesikl. Soedin., No. 9,
1217 (1975).
2. N . N . Suvorov, Sh. A. Samsoniya, L. A. Chilikhin,I. Sh. Chikvizidze, K. F. Turchin,
T. K. Efimova, L. A. Tret'yakova, and I. M. Gverdtsiteli, Khim. Geterotsikl. Soedin., No.
2, 217 (1978).
3. W . R . Brode, Y.H. Gould, and G. M. Wyman, J. Am. Chem. Sot., 74, 4641 (1952).
4. F. Ramirez and A. F. Kirby, J. Am. Chem. Sot., 76, 1037 (1954).
5. W . R . Brode, Y. H. Gould, and G. M. Wyman, J. Am. Chem. Sot., 75, 1856 (1953).
6. C . G . Overberger, M. Valentine, and Y.-P. Anselme, J. Am. Chem. Soc., 91, 687 (1969).
7. A. Kreutzberger and P. A. Kalter, J. Org. Chem., 26, 3790 (1961).

KINETICS OF THE CYCLOADDITION OF MALEIC ANHYDRIDE TO

ARYLAMINOMETHYLENE DERIVATIVES OF 3-METHYL-I-PHENYLPYRAZOLE-5-THIONE

I. Ya. Kvitko, I. I. Potanochkina, and L. A. Brindza UDC 547.775:541.127

A series of arylaminomethylene derivatives of 3-methyl-l-phenylpyrazole-5-one have

been synthesized, which take part in a cycloaddition reaction with maleic anhy-
dride. The kinetics of cycloaddition and the influence of the nature of substi-
tuents in the phenyl ring of the aminomethylene fragment, of the temperature, and
of the solvent on the course of the reaction have been studied.

The synthesis of 3-methyl-4-methylamino-5,6-dihydro-4H-thiopyrano [2,3-d] pyrazole-5,6-

dicarboxylic acids by the cycloaddition of maleic anhydride (MA) to 3-methyl--4-methylamino-
methylene-l-phenylpyrazole-5-thione has been described previously [i]. In order to elucidate
the mechanism of this reaction, a series of 3-methyl-l-phenyl-4-R-phenylaminomethylenepyrazole-
5-thiones (I-Xl) differing by the nature of the substituent in the phenyl ring has been ob-
tained by the reaction of 4-formyl-5-mercapto-3-methyl-l-phenylpyrazole with the correspond-
ing aromatic amines (Table i).
When solutions of the aminoethylene derivative (compounds (I-Xl)) were mixed with MA,
decoloration took place with the formation of a precipitate of the corresponding adduct:
NHC6H4R
+ i H
CH3..~___ _f/CII=NH-CslI4R CII 3 ..~/CttNIICaH4R tl. /CO CH CII I ~CO
JJ - ~ ~ . ~ o ~o ---- ,, It 61 o
~"N/"s - , H c N'~"5 q'co/
CsH~, CeH5 C6H5
1- X I XlI.XlII
Of the adduces, the products of the addition of MA to the thiones (Vl) and (Xl) -- (Xll)
and (XIII) --were isolated in the form of yellow crystalline substances. The IR spectrum of
compounds (XII) and (XIII) lacked the absorption band at 1650 cm-' characteristic for the
initial substances, and exhibited bands in the 1745-1730 and 3450-3470 cm -I regions (CO and
NH, respectively). In the PMR spectra in DMSO-d~, the signals of isolated protons (4.6, 4.2,
and 3.4 ppm) were assigned to the protons in positions 4, 6, and 5 of the thiopyran ring,
respectively. The signal of the proton of the Nil group fell into the region of aromatic pro-
tons, as could be judged from the appearance in the spectrum in the presence of trifluoro-
acetic acid of a greatly broadened signal at 8.2 ppm (as the result of a downfield shift).
The electronic absorption spectra in toluene of the products of MA to compounds (1)-(XI) each
had an absorption maximum at 320-330 nm and did not absorb in the 440-460 nm region.

Lensovet Leningrad Technological Institute. Translated from Khimiya Geterotsikliches-

kikh Soedinenii, No. 5, pp. 616-620, May, 1986. Original article submitted November 15, 1984;
revision submitted October i, 1985.

0009-3122/86/2205-0503512.50 9 1986 Plenum Publishing Corporation 503

kn
o
4>

TABLE I. Physicochemical and Spectral Properties of Arylaminoethylene Derivatives of 3-Methyl-l-phenylpyra-

zole-5-thione (I-Xl).
PMR spectrum, Calculated, %
Com- UV spectram, ppm Found, % Empirical
PKa
pound kmax" nm (loo c) formula
CH NH H N C H N

I p--N (CH3)2 187 460 (4,3), 8,10 15,00 13,16 68,1 6,0 16,6 9,5 CjgH~,N4S 67,8 6,0 16,7 9,5
385 (4,3)
II p-OCH3 153 435 (4,2), 7,99 15,10 12,47 66,8 5,4 13,1 9,8 CIsH,TN3OS 66,9 5,3 13,0 9,9
360 (4,5)
II1 p-CH3 183 435 (3,9), 8,05 14,90 12,60 70,5 5,6 13,5 10,4 CjsHjTN3S 70,3 5,5 13,7 10A
355 (4,3)
IV m-N (CH3)2 119 435 (4,1), 8,22 15,00 12,72 67,8 5,9 16,8 9,6 CvJ lx~N4S 67,9 6,0 16,7 9,5
348 (4,4) i
!V In-CH~ 105 435 (3,9), 8,13 15,00 12,45 70,5 5,7 13,8 10,2 CIsHITNaS 70,3 5.5 13,7 10,4
353 (4,3)
VI H 155 440 (3,9), 8,09 15,10 12,09 69,8 5,4 14,3 10,9 CITHxsN3S 69,6 5,1 14,3 10,9
355 (4,3)
VII m-OCH3 133 435 (4,0), 8,19 14,90 12,10 66,7 5,3 12,9 9,9 CIsHtTNaOS 66,9 5.3 13,0 9,9
355 (4,4)
VIII m.COOC=Hs 160 445 (3,9), 8,14 15,00 11,34 65,6 5,2 11,4 8,8 C~oHtgNaO2S 65,8 5,2 11,5 8,8
362 (4,4)
IX p-COOC2Hs 157 440 (3,7), 8,25 15,00 11,31 65,5 5,2 11,4 8,8 C2oHt9NaO2S 65,8 5,2 I 1,5 8,8
353 (4,2)
X m-NO2 190 445 (3,8), 8,80 15,10 10,59 60,2 4,2 16,6 9,4 CITH,4N402S 60,4 4.1 16,6 9,5
355 (4,4)
XI p-NO~ 208 460 (4,0), 8,30 15,00 10,36 59,8 4,2 16,4 9,7 C~I{14N402S 60,4 4,1 16,6 9,5
375 (4,5)

*Compounds (I) and (IX) were crystallized from toluene, (II), (II), (Vlll), (X), and (Xl) from benzene, and
(IV)-(VII) from ethanol.
 tg k s |

Fig. i. Correlation of the rate constants

of the cycloaddition of MA to arylamino-
methylene derivatives of pyrazolethione
with Hammett's G-constants of the substi-
tuents.

. . . . ~,oj , , , , ,

-1,0 -0,6 -0,2 q2 0,6 1,0~

TABLE 2. Second-Order Rate Constants and Thermodynamic

Parameters of the Activation of 3-Methyl-l-phenyl-4-R-
phenylaminomethylene pyrazole-5-thiones with MA in Toluene.

Com- k2 "I03,liter/(mole 9see) -As ~ , J/(mole-K) AH~ .

pounds
303 K 313 K 323 K 333 K 303 K 313 K 323 K aa3 K M/mole

I p--N (CHa)2 3,80 6,49 13,00 22,00 ] 128,5 129,9 129,5 130,1 49,22
II p-OCHa 2,00 3,74 6,80 10,90 ] 145,0 145,2 145,3 146,1 45,86
III p'CHa 1,55 3,03 6,151 8,28 ] 149,5 149,3 t48,4 150,6 45,12
IV m-N (CHa) 2 1,74 3,96 7,27 I 12,20 [ 140,9 139,6 139,8 140,4 47,45
V m-CHa 1,44 2,88 5,50 8,85 I 139 7 139,6 139,5 140,6 48,28
VI H 1,12 2,81 4,49 7,10 I 15317 I 151,3 152,4 153.2 44,68
IVII m-OCHa 1,30 2,80 4,97 8,87 ] 133,3 132,8 133,5 13319 50,49
VIII m,~COOC2Hs 1,34 2,50 5,48I 8,24 ~ 137,1 137,7 136,5 138,2 49,26
IX p-COOC=H5 1,20 2,30 5,00 7,70 1134,6 I 135,1 134,1 135,7 50,29
X m-NO~ 0,92 I 1,80 3,59 5,82 ] 139,9 140,1 139,7 140,8 49,36
XI p -NO2 0,81 1,56 3,221 4,76 I 146,7 146,8 146,1 147,7 47,62

The course of the re&ction can be affected by the electronic and steric properties of the
substituent in position i of the initial aminomethylene derivatives, and, to investigate this,
the phenol group was replaced by a methyl group and the resulting 1,3-dimethyl-4-phenylamino-
methylenepyrazole-5-thione (XIV) [2] was subjected to the cycloaddition reaction under similar
conditions. The adduct (XV) was isolated, and its PMR spectrum showed the signals of isolated
protons at 5.4, 4.4, and 3.4 ppm, assigned to the protons in positions 4, 6, and 5 of the
thiopyran ring, respectively. The IR spectrum of compound (XV) showed absorption bands at
1712 and 3010 cm -I (CO and NIl, respectively). The electronic absorption spectrum in ethanol
showed a shoulder at 240 nm.
The kinetics of the cycloaddition of MA to compounds (I)-(Xl) and (XIV) were studied spec-
trophotometrically in toluene at four temperatures in the range of 303-333 K. The concentra-
tion was varied within the range of 10-~-10 -3 M. i.e., in the region where the Bouguer--
Lambert--Beer law is obeyed. The measurements showed that the reaction had the first order
with respect to each reactant. The bulk of the investigation was performed with the use of a
50-fold excess of MA, i.e., under the conditions of a pseudo-first-order reaction. The re-
sults obtained were used to calculate the rate constants of the second-order reaction (Table
2).
It can be seen from the figures in Table 2 that the rate of the reaction rises with an
intensification of the electron-donating and falls with a rise in the electron-accepting pro-
perties of a substituent in the phenyl ring. However, the change in the rate constant of the
cycloaddition reaction on passing from a p-nitro to a p-dimethylamino groups is small (only
5-fold) Figure 1 shows the dependence of the rate of the reactions of the compounds studied
on Hammett's a-constant. The correlation coefficient is 9.97, O = --0.345, S = 0.122. (When
Hammett's a~ were used, the correlation coefficient was 0.95.) The negative value
of p shows the occurrence of the reaction in the diene-donor, dienophile--acceptor manner.
The low absolute value of O makes a mechanism with a zwitterionic intermediate unlikely. The
reaction most probably takes place as a concerted process [3]. Judging from the values ob-
tained (Table 3), the replacement of a phenyl group (Vl) by a methyl group (XIV) has no sub-

505
 TABLE 3. Second-Order Rate Constants and Thermodynamic
Parameters of Activation of the Cycloaddltion of MA to Com-
pounds (VI) and (XIV) in Various Solvents.

Cop- Solvent k~. 10~, 1~et/(rnole .see) =as ~ , J/(mole .K)

I
3!3 K 323 K | ~33K

VI Totuene 1,12 2,81 4,49 I 7,10 153,7 151,3 15Z4 153,2 44,68
VI Acetonltrile 5,16 8,71 12,50 21,95 l 156,1 155,2 158,0 157,5 [ 40,12
VI Dioxane 4,91 8,98 16,80 30,30 [ 132,4 132,9 132,9 133,0 [ 50,05
VI Chloroform 4,20 6,40 I0,55 2,13' I 163,2 164,3 164,5 163,9' 38,57
VI IDimethu 6,31 II,55 19,49 [32,34 [ 150,3 150,2 150,5 150,6 41,35
XIV [Dimethylacetamide, 6,33 12,36 19,08 ]32,39 /153,8 153,0 153,9 153,5 40,29

*At 293 K.

stantial influence on the activities of these compounds. For all the compounds studied a
linear dependence of log ks on I/T was observed. The correlation coefficienD is 0.99.
The thermodynamic activation parameters are characterized by large negative values of
the activation entropy and relatively small values of the activation enthalpy (Tables 2 and
3). For all the compounds differing by the substituent in the phenyl residue of the amino-
methylene group a linear dependence of A H o n AS~;is observed~ which shows the monotypical
nature of the reaction mechanism. High negative values of AS~ (from--30 t o - 4 0 e.u.) are
characteristic for a concerted mechanism, although they do not contradict a two-stage bio-
logical mechanism elther~ provided that the closure of the ring is rate-determlning [4].
We also studied the influence of the solvent on the rates of the cycloaddition of com-
pounds (l-Xl)and (XIV)to MA. As can be seen from Table 3D the influence of the solvent is
shown to a very slight degree. A tendency is observed to an increase in the rate of the re-
action with a rise in the basicity of the solvent~ which is apparently connected with the fact
that the initial compounds (I-XI) and (XIV) areweak acids and the anions formed from them in
basic solvents are more reactive than the neutral molecules. These facts are in harmony with
those given in the literature [5] explaining the effect of the solvent as the result of its
donor-acceptor interactions. The rise in the rate of cycloaddltion in chloroform (in compari-
son with its baslcity) is apparently connectedp as in [6]p with its capacity for giving hy-
drogen bonds with carbonyl-containlng compounds.
Thus, the study of kinetics has permitted the formation of derivatives of 3-methyl-l-
phenyl-4R-phenylamino-5,6-dihydro-4H-thiopyrano[2p3-d]pyrazole-5~6-dicarboxylic anhydride as
the result of addition by a concerted (or radlcal) mechanism.

EXPERIMENTAL
IR spectra were taken on a UR-20 instrument (in chloroform),UVspectra on a SF-8 spectro-
photometer (in toluene), and PMR spectra on a Varian-60 instrument (in DMSO) with TMS as in-
ternal standard.
3-Methyl-l-phenyl-4R-phenylaminomethylene Derivatives of Pyrazole-5-thione. A mixture of
30 mmoles of 5-chloro-4-formyl-3-methyl-l-phenylpyrazole in 150 ml of ethanol and lSOmmoles
of 50% KHS was boiled for 3 h [7].
The cooled reaction mixture was poured into 300 ml of HaO, the mixture was filtered, and
the filtrate was cooled to 5~ and was acidified with dilute HCI to pH 7. Then it was treated
with 90 mmole of the appropriate amine in the form of the base or in the form of a salt with
a mineral acid, the mixture was heated to 40~ and was kept there for 2 h, and the precipitate
that had deposited was filtered off, washed with water, and dried. The yields were 80-95%,
see Table i.
1,3-Dimethyl-4-phenylaminomethylenepyrazole-5-thione (XIV) was obtained as described in
[2].
3-Methy~-~-pheny~-4-pheny~amin~dihydr~thi~pyran~[2,3-d]pyraz~e-5,6-dicarb~xy~ic anhydride
(XII). After the addition of 0.18 g (0.6 mmo~f- 3-methyl-l-phenyl-4-phenylaminomethylene-
pyrazole-5-thione i n 15 mi o f a b s o l u t e t o l u e n e t o a s o l u t i o n o f 0 . 0 6 g ( 0 . 6 mmole) o f f r e s h l y
sublimed maleic anhydride in 12 ml of absolute toluene the reaction mixture was boiled for 30

506
 min. The excess of toluene was distilled off, and then petroleum ether was added to the re-
action mixture. The precipitate that deposited was filtered off and dried. Yield 0.19 g
(81%). mp 220-221~ (from ethanol). IR spectrum, cm-*: 1715 (CO). UV spectrum, Xmax, nm
(log r 325 (328). PMR spectrum, ppm: 4.6 (i H, 4-CH), 4.2 (i H, 6-CH), 3.4 (i H, 5-CH).
Found: C 65.4; H 4.6; N 10.4; S 8.0%. C2~H,,N,O~S. Calculated: C 65.3; H 4.5; N 10.4; S
7.9%.
3-Methy--pheny-4-(p-nitrphenyamin)-dihydrthiopyran[2,3-d]pyrazle-5,6-dicarbxyic
anhydride (XIII) was obtained in a similar manner to compound (II). Yield 80%. mp 135-136~
(from ethanol). IR spectrum, cm-*: 1730 (CO). UV spectrum, Xmax , nm (log ~): 330 (3.9).
PMR spectrum, ppm: 4.6 (i H, 4-CH), 4.2 (i H, 6-CH), 3.4 (i H, 5-CH). Found: C 58.7; H 4.1;
N 20.2; S 6.7%. C22HITN~O~S. Calculated: C 58.7; H 3.8; N 10.2; S 6.8%.
1,3-Dimethyl-4-phenylaminodihydrothiopyrano[2,3-d]pyrazole-5,6-dicarboxylic anhydride
(XV) was obtained in a similar manner to compound (XII). Yield 91%. mp 256-257~ ~from ethyl
acetate). IR spectrum, cm-1: 1712 (CO). UV spectrum (in ethanol), nm: 240 (sh;).PMR
spectrum, ppm: 5.4 (i H, 4-CH), 4.4 (i H, 6-CH), 3.4 (i H, 5-CH). Found: C 58.3; H 4.4; N
12.5%. C16H, sN~03S. Calculated: C 58.3; H 4.6; N 12.7%.
Acid--Base Properties of the Initial Compounds. Ionization constants were determined on
a EP-74 universal pH meter by the potentiometric method in 75% aqueous dioxane at IO~ The
ionization constants were calculated in [8].
Kinetics of the Cycloaddition of MA. The rate constants of the cycloaddition reaction
were determined spectrophotometrlcally from the change in the absorption of the reaction solu-
tions in a SF-4A spectrophotometer fitted with thermostable cells. The study was performed
in the region of the long-wave maximum (440-460 nm) of the initial arylaminomethylene deriva-
tives, where the adducts do not adsorb. The solvents used were purified by standard methods
[9]. The working concentrations of the solutions of the arylaminomethylene derivatives were
i0-~-i0 -~ M. The M A w a s purified by sublimation before each series of experiments. The re-
action was performed with a 70-fold excess of MA. The moment of mixing was taken as the start
of the reaction. The optical densities were measured after predetermined intervals of time.
The first-order rate constants were calculated (as the means of three experiments) from the
optical density figures, and from then the second-order rate constants and thermodynamic ac-
tivatlon parameterswere calculated by well-known formulas [4].

LITERATURE CITED
1. G. K. Lebedeva, I. Ya. Kvitko, and A. V. El'tsov, Khim. Geterotsikl. Soedin., No. 4, 527
(1979).
2. L. N. Kurkovskaya, N. N. Shapet'ko, I. Ya. Kvitko, Yu. N. Koshelev, and E. D. Samartseva,
Zh. Org. Khim., i0, 2210 (1974).
. A. S. Dneprovskii, and T. I. Temnikova, Theoretical Foundations of Organic Chemistry [in
Russian], Khimiya, Leningrad (1958), p. 258.
. R. W. Hoffmann, Anfkarung von Reaktionsmechanismen, Georg Thiene Verlag, Stuttgart (1977).
5. R. Haberfield and A. K. Ray, J. Org. Chem., 37, 3039 (1972).
6. V. D. Kiselev and A. I. Konovalov, Zh. Org. K ~ m . , i0, 6 (1974).
7. I. Ya. Kvitko and B. A. Porai-Koshits, Zh. Org. Khim., ~, 1685 (1969).
8. A. Albert and E. Sergeant, Ionization Constants of Acids and Bases, Methuen, London/Wiley,
New York (1964).
. A. Weissberger, E. Proskauer, J. A. Riddick, and E. Toops, Organic Solvents, 2nd Edn.,
Interscience, New York (1958).

507
RECYCLIZATION OF I-AMINO-3,5-DIARYL-2,6, 6-TRICYANOCYCLOHEXA-I,3,-DIENES
TO PYRIDINE DERIVATIVES

Yu. T. Abramenko, A. V. Ivashchenko, UDC 547.822'829.07'592.3:

K. A. Nogaeva, and Yu. A. Sharanin 543.422

The base-catalyzed recyclization of l-amino-3,5-diaryl-2,6,6-tricyanocyclohexa-

1,3-dienes to 2,4-diaryl-5-cyano-6-dicyanomethylene-l,2,3,6-tetrahydropyridines,
4,6-diaryl-3-cyano-2-dicyanomethylene-l,2-dihydropyridines, and 4,6-diaryl-3-
cyano-2-dicyanomethylpyridines has been investigated. The intermediate products
of this reaction - cis,trans-2-amino,4,6-diaryl-l,l,3-tricyanohexa-l,3,5-trienes -
have been isolated; on heating these are transformed reversibly into the initial
cyclohexadienes or they isomerize irreversibly into trans,trans-hexatrienes, while
in the presence of a base (piperidine, diethylamine, triethylamine, KOH), they
cyclize to form the above-mentionedpyridine derivatives.

It has been established previously that the products of the cross-dimerization of 3-aryl-
2-cyanobut-2-enonitriles (I) and of 3-aryl-2-cyanopropenonitriles (II) -- 1-amino-3,5-dlaryl-
2,6,6-tricyanocyclohexa-l,3-dienes (III) -- recyclize to form the pyridlne derivatives (Va-g)
[i, 2]. In the present investigation, this reaction has been studied in more detail.

NH 2 R~

.. - - - ~R 2
i ma-g aA ~va-e va-g cs
III--V a.,c,e Rl=CeHs, b RI=4.CICeH~, d Rr=4-CHsCeH~; a,b,d R2=C6Hs, c R2=
=4-CIC6H4, e R2=4-FCsH4; V f, g RI=4-CIC6H4; f R2=4-CIC~H4, g R2=4"FCeH4

We have shown that the thermally unstable cyclohexadienes (Ilia-g) [i] readily undergo an
electrocyclic transformation with the opening of the ring at the C(5)--C(6) bond and the for-
marion of the cis-hexatrienes (IVa-e).
In the PMR spectrum (acetone-d6) of the cyclohexadiene (Ilia), an AB system of protons
was observed with chemical shifts of 5.73 and 4.52 ppm and SSCC 3JAB = 4 Hz [i, 2]. Under
these conditions the protons of the cis-hexatriene (IVa) also formed an AB system, but with
signals at 7.36 and 6.65 ppm (SJAB = 16 Hz, Table i). The substantial difference between the
SSCCs of the protons of compounds (llla) and (IVa) has permitted their interconversion to be
recorded by the PMR method. For example, the heating in sealed tubes to 100~ of solutions
both of the cyclohexadiene (Ilia) and of the cis-hexatriene (IVa) led to the formation of mix-
tures of them in ratios of 1:5 (in deuteroacetone) and 2:3 (in deuterochloroform). It has
been established preparatively that the ratio of the concentrations of these compounds in
xylene is i:i (IO0~ Consequently, the position of the equilibrium (Ilia) ~ (IVa) depends
appreciably on the polarity of the medium. We may note that the electrocyclic transformations
of substituted cyclohexadienes and noncyclic hexatrienes have been widely studied and have
already become classical. The opening of the ring and cyclization on heating take place in
disrotatory fashion and reversibly [3], but they have not hitherto been observed in the en-
aminonitrile series.
The prolonged heating of xylene solutions both of the cyclohexadiene (Ilia) and of the
cis-hexatriene (IVa) at 100~ led to the formation of the stable trans-hexatriene (Via),
which no longer cyclized into the cyclohexadiene (Ilia). The invariability of the SSCCs of

Scientific-Research Institute of Organic Intermediates and Dyes, Moscow. Translated from

Khimiya Geterotsiklicheskikh Soedinenii, No. 5, PP. 621-625, May, 1986. Original article
submitted January 23, 1985; revision submitted July i, 1985.

508 0009-3122/86/2205-0508512.50 9 1986 Plenum Publishing Corporation

 TABLE 1. PMR Spectra (acetone-ds) of Com-
pounds (IVa-d) and (Via), ~, ppm

Com-
pound NH2 Ar,rn A--H,d B--H,d 'VAB'Hz

IVa 8,34; 8,10 7,40 7,36 , 6,65 16,0

I!Vb 8,38, .br.s 7,40 6,76 16,5
IVC 8,39, br.s. 7,40 6,70 16,0
IVd 8,22; 8,05 7,40 7,29 6,65 16,5
IVla 8,04, br.s 7,41 7,63 6,80 16,0

*Overlapping with the multiplet of the aro-

matic protons.

the A--H and the B--H protons as the result of the conversion of the triene (IVa) into (Vla) in-
dicated the isomerization of compound (IVa) relative to just the C(s)-C(~) double bond, since
the trans configuration of the C(s)-C(6) double bond was retained, and the presence of two
identical substituents (nitrile groups)-at the C(I) carbon atom excluded such a possibility
for the C(4)-C(2) double bond.

NIlo sN

IVa
Ilia ...... H ~ -~':/ii "CN ....
'+ =" / "CN
R ~ " " It

VI ~R R I=R~=CsH,~

The result of heating ethanol solutions of the trienes (IV) and (Vla) with an excess of
a base (diethylamine, piperidine, triethylamine, KOH) was the formation in high yields Of the
salts (Villa-g), which, under the action of acids, were converted reversibly into the corres-
ponding tetrahydropyridines (V). Compounds (Vllld-g) were also obtained at room temperature
by treating the cyclohexadienes (Ilia-g) with 2 N ethanolic KOH. The recrystallization of the
cyclohexadienes (III) into the tetrahydropyridines (V) apparently took place with the inter-
mediate formation of the hypothetical compounds (VII) which underwent electrocyclization to
compound (VIII) under the reaction conditions.

BH +
[ ~c~ :cN -1 R'
:. CN
Ill IV - ~ | ( Y ~{t" -B
NO./ I . . . . [' - ~

/ ". :._= II 1'- BH +

VI - - - - ..i~ CN
%11 "~qlta-~

VIII a--f RI=C6Hs, g RL=4-Ctt3C61t4: a--d,g R2=C6Hs, e R2=4-FC6H4, f R2=

=4-CIC6H4; a B-(C211s)3N, b B=(C2Hs)2NII, c B=.p~peridine, d - g , ~ = K O H

In the IR spectra of the tetrahydropyridines (Va-g) strong absorption bands in the 2220-
2190 cm -~ corresponded to conjugated nitrile groups. An absorption band at 3260 cm -~ was due
to the stretching vibrations of an NH group bound by a hydrogen bond. The formation of the
salts (VIII) led to a lowering of the frequency of the stretching vibrations of the nitrile
group to 2150-2000 cm -~ and to a broadening of these absorption bands. The absorption band
of the NH group was, as a rule, shifted into the region of higher frequencies (Table 2).
When xylene solutions of the cyclohexadienes (III) were heated to boiling for I h with
an excess of an organic base and were then cooled and were treated with concentrated hydro-
chloric acid, mixtures of the pyridines (IXa-e) and (Xa-e) were obtained. Their structures
were confirmed by spectral methods and by independent synthesis -- in particular, by the re-
action of 2-chloro-3-cyano-4,6-diphenylpyridine (Xla) with malonodinitrile in DMFA in the
presence of sodium hydride~

509
 TABLE 2. IR Spectra of Compounds (Va-g) and
(Villa-g)
Com- v, cm-I Com-
v, cm "I
pound
pound
NH CN NH CN

Va 3250 2220, 2200 VIIIa 3280 2180, 2140

~b 3270 2210, 2190 VIllb 3240 2200, 2170, 2140
Vc 3250 2210, 2190 VlIIC 3260 2200, 2180, 2140
Vd 3250 2220, 2220 V l l l d 3340 2200, 2160
Ve 3240 2210, 2190 Dlllle 3300 2200, 2160
wf 3260 2210, 2190 V I l l f 3300 2200, 216()
vg 3270 2220, 2200 VIIIg 3320 2200, 2150

R1 R1

HCI ~ ~ 7 CN
III IV
B
--~ VII 'VIII
~ CN ~---~-~ ~ c~

CN CN
~I a,b ,x a-e

IRI R1

R2 .- C1 9 _
-HCI
_ ~-R2/,iI
xia xa-8 cN

IX--XIIa, IX, X d e Rt=C~Hs, IX, X, XIIb RI=4-CHaC6H4, IX, Xc RI=4-CIC6H4;

IX, Xa--c, XIa, XIla, b R2=C~Hs, IX, Xd R~=4-FC~H4, e R2=4-CIC6H4; xIIa, b B=KOH

In the IR spectra of the majority of pyridines (IX) and (X), only weak broad absorption
bands were observed in the 3250-3220 cm -I region which it is difficult to assign unambiguously
to the vibrations of a NH group. An exception was the pyridine (IXb), in the IR spectrum of
which a strong absorption band was observed at 3350 cm -I corresponding to the stretching vi-
brations of a NH bond. In the Raman spectra of pyridines (IXa) and (Xa) absorption bands
were observed at (cm-I) 2260 (m.br.), 2220 (s), 2204 (m), and 2175 (s), which are character-
istic for conjugated and nonconjugated nitrile groups. The pyridines (IX) and (X) apparently
existed in solutions and crystallized from them as mixtures of the two forms [(IX) ~ (X)].
These compounds were also readily converted into the high-melting crystalline salts (XlIa, b)
in a 2 N ethanolic solution of KON.

EXPERIMENTAL
IR spectra were taken on UR-10 and Perkin-Elmer 457 instruments (in KBr tablets), a n d
Raman spectra on a Coderg T-800 instrument using the 5145 ~ green line of an argon laser for
excitation. Mass spectra were measured on a LKB-2091 instrument (under standard conditions).
PMR spectra were recorded on Tesla BS-4870 and Bruker XH-90E instruments (80 MHz and 90 MHz,
respectively) using 10% solutions in (CD3)2CO, with TMS as internal standard. Chromatograms
of solutions of the substances were obtained on Kavalier light-sensitive plates in acetone--
hexane (3:4) and tetrahydrofuran--hexane (2:1) solutions.
The characteristics of the compounds synthesized are given in Tables 1-3.
2-Amino-4,6-diaryl-l,l,3-tricyano-l,cis-3,trans-5-hexatrienes (IVa-e). A mixture of 0.01
mole of a cyclohexadiene (III) [i, 2] and 30 ml of xylene was heated to boiling. After i0
min~ a pale yellow precipitate deposited from the boiling solution, and this was filtered off
and washed with hot xylene and with hexane. In this way the analytically pure trienes
(IVa-e) were obtained with a yield of 50%. The initial compounds (III) remained in the mother
solutions. The solutions were boiled again for a few minutes, giving an additional 25-30%
of the trienes (IV) containing the trienes (VI) as an impurity.
2,4-Diaryl-5-cyano-6-dicYanomethylene-l,2,3,6-tetrahydropyridines (Va-g). A. & mixture
of 0.01 mole of a diene (Ill) and i0 ml of 2 N ethanolic KOH was heated to"boillng. After

510
 TABLE 3. Characteristics of the Compounds Synthesized

Com- Found. % Empirical Calculated,% Yield,

pound Tmp,* "C formula ~o
C H C H

IVa 205 78,4 4,1 17,1 C~lHI4N4 78,,' 4,4 17,4 50

IVb 218--220 70,9 3,9 15,8 C:II'{13CIN4 70,7 3,7 15,7 50
IVC 246 70,7 3,7 15,8 C2tHI3CIN4 70,7 3,7 15,7 50
l~d 215 78,2 5,0 16,7 i C=:HI6N4 78,6 4,8 16,7 i 50
INe 209--212 74,2 3,7 16,4 C21HI~FN4 74,1 3,9 16,5 l 50
Va 238--240 78,3 4,0 17,2 C2/HI4N4 78,2 4,4 17,4 76
Vb 199--200 70,7 3,7 15,5 CmHI~CIN4 70,7 3,7 15,7
VC 246--247 70,5 3,6 15,1 C~IHI3CIN4 70,7 3,7 15,7 57
~Vd 175--177 16,7 C22HIsN4 16,7 46
V,e 241--242 74,1 3,8 16,2 C22HI3FN4 74,1 3,9 16,5 86
vf 220--222 64,5 3,2 14,3 C~IHI~CI2N4 64,5 3,1 14,3 43
vg 226 67,2 3,5 15,1 C21HI2CIFN4 67,3 3,5 15,0 7O
,~la 219--22t 78,3 4,2 17,6 C21H,4N4 78,2 4,4 17,4 5O
Villa 127--130 76,1 6,6 16,3 C27H29N5 76,3 6,9 16,5 5O
VIIIb 147--149 75,8 6,2 17,6 C2~H2sN5 76,0 6,3 17,7 75
~VIII~ 151--152 76,6 6,2 17,3 C2sH23Ns 76,5 6,2 7,2 78
VIIId 181--184 67,8 4,5 13,7 C21HIbKN40 66,6 4,0 14,8 8O
VIIIe 175 C2jHI4FKN40 77
NIIIf 185 C21HI4CIKN40 78
vmg 202--204 68,3 4,1 15,5 C~2H,TKN40 67,4 3,8 14,3 62
IXb 251--253 16,9 C22HI4N4 16,8 48
Xa 252 17,1 C21HI~N4 17,5 40
X.e 25O 15,7 C21HuCIN4 15,8 48
Xd 243 16,6 C~jH.FN4 16,7 45
X,e 22O--222 15,8 C21HuCIN4 15,8 22
XIIa >300 15,6 C21H13KN40 14,9 82
XIlb >300 67,6 4,1 15,0 C22HI~I(N40 67,8 3,6 [4,4 78

*Compounds (IVa-e) were crystallized from xylene; (Va, c, e, g)

from chlorobenzene; (Vb, f) and (IXb) from acetic acid; (Vd)
from toluene; (Via) and (Xa, d, e) from nitromethane; (Vlla, d-
g) and (Xlla) from ethane [sic]; (Vlllb) from methanol; (Vlllc)
and (Xllb) from acetonitrile; and (Xc) from nitromethane--toluene.

5 min, it was cooled and was acidified with concentrated hydrochloric acid, and the precipitate
was filtered off and was washed successively with water, ethanol, and hexane to give one of the
pyridines (Va-g).
B__x. A mixture of 0.01 mole of a triene (IV) and 2 ml of diethylamine (or piperidine) in
10-15 ml of ethanol was heated to boiling for i0 min. Then it was cooled and was treated
with an excess of concentrated hydrochloric acid, and the resulting yellow precipitate was
filtered off and was washed by method A, giving the corresponding pyridine (Va-g).
C 2. A suspension of 0.01 mole of one of the salts (Villa-g) in i0 ml of ethanol was acid-
ified with hydrochloric acid. The corresponding pyridine (V) was obtained, and this was iso-
lated by method A. Mass spectrum of the pyridine (Va): 322 (34.0; M +),* 295 (7.0), 220 (18.0),
217 (6.0), 206 (11.5), 191 (8.0), 135 (6.5), 116 (67.0), 93 (6.0), 91 (i0.0), 83 (5.0) 81 (5.0),
78 (7.0) 77 (17.0) 71 (6.0) 69 (7.5) 57 (9.5), 55 (11.5)
2-Amino-l,l,3-tricyano-4,6-diphenyl-l,trans-3,trans-5-hexatriene (Via). A mixture of 0.01
mole of the diene (Ilia) and 30 ml of xylene was heated to boiling for 3 h and was cooled, and
the precipitate was filtered off and recrystallized from nitromethane. This gave the yellow
crystalline triene (Via).
Salts of 2,4-Diaryl-5-cyano-6-dicyanomethylene-l,2,3,6-tetrahydropyridines with Bases
(Villa-g). A. A mixture of 0.i mole of the triene (Via) and 2 ml of diethylamine, piperidine,
or triethyl~mine in 10-15 ml of ethanol was boiled for i0 min. Then it was cooled and the re-
sulting precipitate was filtered off, washed with ethanol and then with hexane, and recrystal-
lized from the appropriate solvent, giving the salt (Villa, b, or c).
B__=. A mixture of 0.01 mole of diene (III) in i0 ml of 2 N ethanolic KOH was boiled for 5-
i0 min. Then it was cooled and the resulting white precipitate was filtered off, washed with
2 N ethanolic KOH, and dried in vacuum. This gave the corresponding salt (Vllld-g), which

*Here and below the mass spectra are given the values of m/z (intensity in % relative to the
maximum ion peak).

511
it was difficult to recrystallize, and therefore in some cases, the characteristics of these
salts are given in Table 3 without their elementary analyses.
C__~. A mixture of 0.01 mole of a pyridine (V) and 10-15 ml of ethanol was boiled with an
excess of a base and, after cooling, the corresponding salt (Villa-g) was isolated by methods
A and B.
4~6-Diaryl-3-cyano-2-dicyanomethylpyridines (IX, Xa-e). A. A mixture of 0.0! mole of a
diene (III)and 20 ml of xylene was boiled for i0 min, and then 2 ml of triethylamine was
added and boiling was continued for another 1 h. The reaction mixture was cooled, the upper,
xylene, layer was decanted off, and the resinous precipitate was triturated in concentrated
hydrochloric acid until it solidified and was then filtered off. The residue was washed suc-
cessively with water, ethanol, and hexane and was recrystallized from a suitable solvent. The
pyridines (IX),and (Xa-e) were obtained in this way.
B. A mixture of i mmole of the pyridine (IXa), 2 mmoles of sodium hydride, and 2 mmoles
of malononitrile in i0 ml of absolute DMFA was stirred in a current of argon for i h. Then it
was heated to 100~ and was stirred at this temperature for another i h. The reaction mixture
was diluted with water and was treated with an excess of hydrochlorid acid and the resulting
precipitate was filtered off and washed with water, ethanol, and hexane and recrystallized
from nitromethane. This gave the pyridine (Xa) with a yield of 38%, mp 252~ Mass spectrum:
321 (i00), 320 (96; M+), 293 (i0.0), 294 (i0.0), 295 (i0.0), 266 (5.5), 255 (ii.0), 228 (7.0),
228 (14.0), 165 (5.0), 149 (9.0), 135 (9.0), 133 (12.5), 123 (i0.0), 119 (10.5), 105 (15.0),
94 (13.5), 90 (15.0), 83 (12.0), 81 (12.8), 79 (15.0), 77 (32.5), 69 (18.5), 68 (12.0), 55
(35.o).
Hydrates of the Potassium Salts (Xlla, b). With stirring 10 mmoles of one of the mix-
tures of the pyridines (IX, Xa, b) in 15-20 ml of 2 N ethanolic KOH was heated to 5oiling for
a few minutes. The bright orange coloration of the initial compounds disappeared almost in-
stantaneously and a light yellow precipitate was formed which was filtered off and was washed
with 2 N ethanolic KOH, with a small amount of ethanol, and with hexane. This gave the corres-
ponding salt (Xlla, b) crystallizing poorly from ethanol and acetonitrile.
We express our deep gratitude to Professor Yu. A. Baskakov and to A. F. Vasil'ev, Yu. G.
Putsykin, and E. B. Putsykina for assistance given in the investigation.

LITERATURE CITED
I. Yu. A. Sharanin, Yu. A. Baskakov, Yu. T. Abramenko, Yu. G. Putsykin, A. F. Vasil'ev, and
E. B. Nazarova, Zh. Org. Khim., 16, 2192 (1980).
2. Yu. T. Abramenko, Yu. A. Baskakov, Yu. A. Sharanin, N. A. Kiseleva, O. N. Vlasov, Yu. G.
Putsykin, and V. V. Negrebetskii, Zh. Vses. Khim. Obshch. im. D. I. Mendeleeva, 24, 409
(1979).
3. C . K . Ingold, Structure and Mechanism in Organic Chemistry, 2nd Edn., Cornell University
Press, Ithaca, New York (1969).

512
ELECTROCHEMICAL REDUCTION OF BIPYRIDINIUM SALTS

I. P. Krainov, S. F. Kramarenko, UDC 547.828

E. I. Dotsenko, A. A. Bumber,
E. S. Klimov, and O. Yu. Okhlobystin

The N,N'-aryl substituted bipyridinium perchlorates were studied by the methods

of cyclic voltamperometry and classical and commutated polarography in DMFA. It
was shown that cation-radicals, which are stable in an atmosphere of argon, are
formed at the first stage of reduction. The reversibility and the number of the
subsequent stages depend on the nature of the substituent at the nitrogen atom.
The formation of the bipyridinium cation-radicals was confirmed by the method of
EPR spectroscopy.

Bipyridinium salts (viologens) find application in the production of electrooptical de-

vices as the reversible component of spectroelectrooptical cells [i]. These organic salts
can exist in three oxidation-reduction states [2].

R-- --E ~ R-- --R ~ R-- --R

I-VIII

I R=C6H4--OCH3; II R=CsH4--CN; III R=CH3; IV R=C6H4CI; V R=C~H4--CO--OCH3;

VI R=C6Hs; VII R=CH=--Cr VIII R=CsH4Br

The object of the present work was the study of the reduction of viologens, the majority
of which have not previously been investigated, by the methods of classical and commutated
polarography, cyclic voltamperometry (CVA), and EPR spectroscopy.
The reduction of the compounds (1)-(VIII) (Table i) proceeds in two single-electron
stages by the scheme presented above. The presence of the commutated polarograms with the
potentials E,/2 close to the classical values testifies to the reversibility of the processes
in the first stage for all compounds.
The method of CVA confirms the results obtained on the platinum electrode (Table 2) and
indicates the relatively high stability of the cation-radicals formed.
The second stage of the reduction is not reversible in all cases. The corresponding
cathodic peak is quasi-reversible for compound (I); it is completely irreversible for compound
(V). Consequently, the reduced uncharged forms of (I) and (V) are unstable (Fig. i).
The benzylviologen (VII) is reduced in four stages, the first two of which are reversible
and single-electron, in contrast to the behavior of the compounds described. The third and
fourth stages of the reduction are almost completely irreversible (Fig. i); this is probably
on account of the rapid ensuing reactions involving the participation of the products of the
electrochemical reactions.
The reversibility of the first stage of the reduction of all of the viologens studied
shows little dependence on the presence of oxygen in the DMFA. This is expressed by the fact
that the values of the limiting currents of the commutated polarograms are practically un-
changed in the presence of oxygen in the air .(Table i). Consequently, the rate of the inter-
action of the bipyridiniumcation-radicals with oxygen cannot be high.
The existence of cation-radicals of the viologens studied was confirmed by EPR spectro-
scopy. The reduction of the benzylviologen (VII) on a zinc surface in DMF leads to the for-
mation of the EPR spectrum of the cation-radical (Fig. 2). The central portion of the spectrum

Scientific-Research Institute of the Chemistry of Free Radicals, K. L. Khetagurov Sverno-

Osetinsk State University, Ordzhonikidze. Translated from Khimiya Geterotsiklicheskikh Soe-
dinenii, No. 5, pp. 626-629, May, 1986. Original article submitted February 13, 1985; Re-
vision submitted June 26, 1985.

0009-3122/86/2205-0513512.50 O 1986 Plenum Publishing Corporation 513

 TABLE i. Yolarogzaphlc Behavior of the Bipyrldinium Per-
chlorates (Z)-(VllI) (E=/= is the half-wave potential, V;
i is the wave helghtj ~A; is thehelght of the commuteted
wave in the presence of oxygen in the air)

Classicalpolarography Commutat~d polatography

Compound
-gg~ t =Ei/~ I

l 0,25 0,89 0,44 0,34

0,56 1,00 0,60 0,40
II 0,16 0,78 0,23 0,39 0,40
0,34 0,97 0,38 0,31
Ill 0,47 1,0 0,50 0,46 0,38
0,80 0,90 0,82 0,40
IV 0,23 0,92 0,28 0,42 0,37
0,50 1,02 0,56 0,40
V* O, 14 0,86 O, 18 0,45 0,40
0,35 0,91
VI 0,23 0,88 0,25 0,43 0,39
o,44 1,o5 0,46 0,41
VII 0,26 0,80 0,28 0,52 0,40
0,53 0,75 0,60 0,40
0,95 2,0
1,29 4,2
VIII 0,18 0,81 0,22 0,38 0,30
0,44 1,0 0,54 0,35

*A third wave of reduction is observed with the maximum at

E,/a =-0.95 V.

TABLE 2. Characteristics of the Cyclic Voltamperograms of

the Bipyridlnium Perchlorates (1)-(VIII) on a Platinum Disk
Electrode (Ep is the potential of the peak, V; i is the
height of the peak, ~A)
Reduction Oxidation
Compound
-Ep -Ep

I 0,39 8,8 0,25 8,6

0,73 8,8 0,55 6,0
II 0,22 8,6 0,16 8,5
0,40 8,0 0,34 8,2
Ill 0,51 9,0 0,48 9,2
0,90 8,8 0,87 8,8
IV 0,30 10,2 0,26 lO,O
0,50 9,1 0,53 9,1
V 0,26 7,6 0,20 7,8
0,42 7,7
VI 0,24 9,0 0,18 9,4
0,50 9,0 0,45 9,0
VII 0,37 9,0 0,33 9,0
0,65 9,0 0,60 8,0
1,14 15,0
1,80 18,0
VIII 0,24 8,5 0,19 8,4
0,52 8,5 0,42 8,3

is shown in Fig. 2 (the outer components are not visible in the conditions of the scanning).
The hyperfine structure of this spectrum is practically the same as those obtained for the
bipyridinium cation-radicals previously. The changes in the values of the splitting constants
in the same solvent on varrying the substituents at the nitrogen atoms are not sharply char-
acterized; the multiplicity factor of the constants of the hyperfine splitting is a character-
istic feature of the EPR spectra in many cases [3-6]. It follows from the EPR spectrum that
the unpaired electron is delocalized over the entire cation-radical skeleton of the bipyridin-

514
 -0,42V
-0.2SV A T ^

i /-i=0-- I
+O~,,.,j/ -1,0 E,V
H

Fig. i Fig. 2
Fig. i. The cyclic voltamperogram of the compounds (V) and
(VII) and the polarogram of compound (IV) obtained after
the electrolysis at a controlled potential.
Fig. 2. The EPR spectrum of the cation-radical of the ben-
zylviologen (VII) in DMF at 25~

ium fragment and over the benzyl substituents at a nitrogen atom. The hyperfine structure of
the spectrum is determined by the interaction of the energy levels of the unpaired electron
with the two equivalent I~N nuclei (aN = 4.20e), the eight equivalent protons at the 2, 2',
6,'6~3, 3',5, 5'positions (aH = 1 . 4 0 e ) , and the two methylene groups (four equivalent protons)
of the N- and N'-benzyl substituents (aH= 2.80e). The splitting of the phenyl ends does not
appear under the conditions of the experiment; it introduces a contribution to the width of
the individual spectral line. The magnitude of the g-factor of the EPR signal is close to the
value for the free electron g = 2.0030.
The EPR spectra of the remaining compounds were obtained in the form of unresolved sing-
let lines under analogous conditions. The disappearance of the blue (green) color of the
cation-radicals is observed on opening the degassed ampuls in air; the intensity of the sig-
nal thereby abruptly decreases to zero in i-2 min.
The results of the electrolysis at a controlled potential for the first stage of reduc-
tion in an inert atmosphere are close to the data of the commutated polarography and EPR
spectroscopy; the main product of the electrolysis is the corresponding cation-radical (Table
3).
The number of electrons calculated by the Faraday formula is close to that determined
from the classical and commutated polarograms. The primary reduction product -- the cation-
radical -- is present in significant concentrations in the majority of cases on the classical
polarograms taken after the electrolysis (Fig. i, IV) t the anodic wave of its oxidation to
the initial dication is observable. At potentials which are more negative than the E~/2 of
the first and second stages of the reduction of the viologens (1)-(VIII), polarographic waves
pertaining to the products of the conversion of the cation-radicals to the corresponding bi-
pyridinium salt are observed. The formation of by-products (with the possible participation
of traces of oxygen in the argon) proceeds from the relatively slow reaction following the
transfer of the electron during the electrolysis (30 min).
The high degree of the reversibility of the oxidation-reduction processes, the relative
stability of the cation-radicals of the viologens, and their bright color permit the use of
electrolytes containing the viologens (1)-(VIII) in spectroelectrochemical cells. The record
of the composition is held up to 10 s cycles; erasure occurs at the working voltage of 0.8 V
and the current-density of 0.5 mA/cm 2 (ferrocene was employed as an anodic component).

515
 TABLE 3. Results o f the Electrolysis at a Controlled Poten-
tial of the First Wave of the Reduction of the Bipyridinium
Salts (E:/a is the half-wave potential, V; i is the limiting
current, ~A; n are the results of the calculation of the num-
ber of electrons according to the formula of Faraday)

"--'--'---~haraoteristict of the polaro~ rams taken after electrolysis

Compound ,,,, l .- - . . .
!
m w

I 1,02 0,40 0,57 0,42 0,83 0,80

II 1,14 I 0,14 1,40 0,33 1,42 0,78 0,42
IV 1,Ol I 0,16 1,60 0,,52 1,40 0,83 1,2
V 0,90 [ 0,17 l,O0 2,10 2,2
VI 0,82 I 0,26 1,40 o78 Go 1,84 1,8
VII 0,82 J 0,23 1,40 0,53 1,20 1,00 2,0

EXPERIMENTAL
The viologens (1)-(Vlll) were synthesized according to the methods of [7, 8]. The 0.i M
solution of tetraethylammonium perchlorate in DMFAwas utilized as the base electrolyte.
Electrolysis at a controlled potential was performed in a Lingane electrolyzer of total
volume 4 ml on platinum wire-gauze electrodes using a P5827 M potentiostat and stirring with
a magnetic stirrer in an atmosphere of argon. The time of the electrolysis was 30 mln. The
concentration of the viologen was 2,10 -s M. The amount of the electricity was determined by
weighing the chart paper under the current-time curve. The classical and cyclic polarograms
were plotted under the conditions described in [9].
The EPR spectra were taken in the vacuum of 10-' m m H g a t room temperature.
using a modified ~ - 1 3 0 1 spectrometer (the K-54 klystron with ~ 3.2 cm; the~resolution was 0.1
Oe).

LITERATURE CITED
le H. T. Van Dam and J. J. PonJee, J. Electrochem. Sot., 121, 1555 (1974).
2. C. L. Bird and A. T. Kuhn, Chem. Rev., i0, 49 (1981).
3. B. I. Shapiro, V. V. Minin, and Ya. K. Syrkin, Zh. Strukt. Khim., 14, 642 (1973).
4. J. C. Evans, A. G. Evans, and M. W. Baker, J. Am. Chem. Soc., 99, 5882 (1977).
5. J. C. Evans, M. H. Sorkhabi, and C. C. Rowlands, Tetrahedronp 38, 2581 (1982).
6. U. Prior, Free Radicals in Biology [Russian translatlon], Mir, Moscow (1979), p. 31.
7. J. G. Allen, British Patent No. 1, 399, 595, Ref. Zh. Khim., 3N246 {1976).
8. G. P. Klimisha, I. P. Krainov, E. G. Protsenko, and B. G. Distanov~ Khlm. Geterotsikl.
Soedin., No. 2, 264 (1979).
. A. A. Bumber, A. G. Milaev, and O. Yu. Okhlobystin, Zh. Obshch. Khim., 53, 606 (1983).

516
PREPARATION AND PROPERTIES OF BETAINES OF
4-PYRIDYL-3,4-DIHYDROPYRIDINE-2-THIONES(IH)

A. A. Krauze, E. E. Liepin'sh, UDC 547.825'821.3.07:543.422

Yu. E. Pelcher, Z. A. Kalme,
and G. Ya. Dubur

Condensation of 2-cyano-3-pyridylthioacrylamides with esters of acetoacetic or

B-aminocrotonic acids yields betaines of 3,5,6-substituted-4-pyridyl-3,4-
dihydropyridine-2-thiones(iH). The spectral characteristics of the betaines
have been examined and their ionization constants (pK) determined.

We have extended our studies in the area of 3,4-dihydropyridine-2-thiones(iH) [I, 2] by

preparing betaines of 6-methyl-5-alkoxycarbonyl-3-cyano-4-(3-pyridyl)- and -(4-pyridyl)-3,4-
dihydropyridine-2-thiones(iH) (Vl).
We used two routes to the betaines (VI): condensation of 2-cyano-3-pyridylthioacrylamides
II with acetoacetic esters I using piperidine as condensing agent, and condensation of the
thioamide II with esters of ~-aminocrotonic acid III.

PY t I PY PY

31 + H ~:Z_ X+ (CH~'2SO~
CH - NH~~S CH H S CH3" "N"
H -SCH5
I II IVa-r,Va-r VIHa-r
x
NaNO2
Ac0H
Py+H H 9 N~ ~
Py
R00CHI3~ + ~CN Ac0H ROOC~CN Y
C NH2 NH2 ~S CH~ / ~HN/"-~,S
III II 9 ~, VIa-r CH~ N
H -SCH3
XI Py
R00C~Ly CN ~ ROOC/~CN
CH3/ ~"N ~ S CH31 CH3/~'N~/~"SCH3.
H
IV-Dr: a, bR =CH~, c,d R = ~Hs; a, c Py = 8-pyndyl,b, d ~ = 4-py~dyl;IV a-d:
X = ~peridine,V a-d: X = Na
In the first route, pyridine salts of 6-methyl-5-alkoxycarbonyl-3-cyano-4-(3-pyridyl or
4-pyridyl)-3,4-dihydropyridine-2-thiones(1H) (IV) were i s o l a t e d a s i n t e r m e d i a t e p r o d u c t s .
A c i d i f i c a t i o n o f t h e s a l t s IV w i t h an e q u i m o l a r q u a n t i t y o f h y d r o c h l o r i c a c i d i n e t h a n o l y i e l d s
the betaines VI. In the second route, the betaines Vl are obtained by brief heating of the
initial components in acetic acid. In this case small amounts of the pyridine-2-thiones VII
are also obtained and if heating is prolonged these become the main products.
The betaines VI are clear yellow compounds (Table i). Compounds Vl differ from compounds
VII in their greater polarity (in TLC) and their increased solubility on passing from ethanol
to 50% ethanol.
With piperidine or caustic soda, the betaines Vl form piperidine or sodium salts of 3,4-
dihydropyridine-2-thiones(iH) (IV and V). The betaines VI are not oxidized by atmospheric

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 630-635, May, 1986. Original article
submitted March 12, 1985.

0009-3122/86/2205-0517512.50 9 1986 Plenum Publishing Corporation 517

 TABLE I. Characteristics of Compounds IV-IX

pound" rap, . . . . . . . . . . . . . . . . . . Empirical formula ..............

IVa 158--!60 61,2 a,6 14,6 8,7 C~H~NdO~S 61,3 6,6 15,01 8,6 93 87
IVb 173~175 61,1 5,4 14,9 8,5 C!gH~r 61,3 6,6 15,01 8,6 77 80
Ive 140~142 61,9 ~,6 14,3 8,6 C~oH~N~O~S 62,1 6,8 14,51 8,3 63 66
IVd 152~154 61,8 ~,7 14,3 8,7 C~oHssN,O~S 62,1 6,8 14,51 8,3 70 65
Va 198--200 54,1 3,9 13,0 10,2 C~dI-II~NaN~O.,S 54,4 3,9 13,6 10,4 92
~b >250 54,2 4,2 13,8 I0,9 CIdHI2NaN~O=S 54,4 3,9 13,6 10,4 81
Ve 195--197 55,1 ~,6 13,1 9,31 CI~HI4NaN~O2S 55,7i4,4 13,0 9,9 66
Vd 238--240 55,3 4,3 12,7 9,3] CI~HIdNaNaO=S 55,7 a a 13,0] 9,9 79
Via 186--188 58,2 ~,8 14,2 10,9[ Ct~HI~N~O2S 58,514.b 14,6{11,2 69 45
IVlb 218--220 58,3 4,5 14,6 10,8 ] CIdHI3N~O2S 58,514.~ 14,6 11,2 69 60
VIe 173--175 60,6 5,2 13,6 10,2 CI~HI~N302S 59,8 !5.0 13,9110,6 71 60
VId 181--183 60,1 5,2 14,1 10,1 CI~I'I16NaO2S 59,815,0 13,9 10,6 49 69
VIId 244--246 59,3 4,2 14,4 10,4 ] C~HIsN~O2S 60,214,4 14,0 10,7 29
IVIIIa 214--.215 59,6 5,0 13,6 10,8[ CIsHI6N~O2S 59,8 5,0 13,9 10,6 68
VIIIb 169--170 59,6 4,8 13,9 10,2 CI~H~sN30~S 59,8 5,0 13,9 10,6 70
VIII= 226--228 60,9 5,4 13,2 10,2 [ CleH17N30~S 60,9 5,4 13,3 10,9 70
VII1 d 148--150 60,4 5,4 12,9 10,2 CIoHITN~O~S 60,9 5,4 13,3 10,2 73
IXd 78--80 61,9 4,9 12,9 9,9 CI~HIbN~O2S 61,3 4,8 13,4 10,2 61 [52

*IVa, b, Va, b, Via, b, Villa, b: R = CH3. IVc, d, Vc, d,

Vlc, d, Vlld, Vlllc, d, IXd: R = CaHs. IVa, c, Va, c, Via,
c, Villa, c: Py = 3-pyridyl; IVb, d, Vb, d, Vlb, d, Vlld,
Vlllb, d~ IXd: Py = 4-pyridyl.
%Compounds IV-VI, VIII, IX recrystallized from ethanol, VII
from nitromethane; Vb, with decomp.

TABLE 2. IR and UV Spectra of Compounds IV-X

it

1t%spectra ~, era'*
Compound UV spectra,, ~, nm
C=O C~N N--H

IVa 1685 2172 3110, 3178, 3216 261, 306, 373 p.

llVb 1696 2177 3104, 3142, 3210 262, 308, 373 p.
I'qc 2691 2182 3112, 3158, 3190 261, 308, 373 p.
IVd 1694 2168 3140, 3175, 3255 258, 310, 375p.
IVa 1661 2181 3161, 3205, 3372 261, 308, 367p.
Vb 1674 2180 3165, 3205, 3390 259, 309, 370 p.
Vc 1659 2177 3158, 3205, 3360 260, 303, 368 p.
Vd 1652 2188 3156, 3192, 3375 258, 309, 372 p.
~VIa 1642 2178 3328 258, 310, 342 p.
Vlb 1712 2166 3200 258, 312, 340p.
VIe 1637 2177 3320 256, 314, 338p.
VId 1705 2176 3204 257, 313, 3 3 8 p
IVIIa 1712 2234 3180 247 p , 330, 410
VII! a: 1697 2194 3166 228, 270, 282 p., 358
~VIII b 1702 2194 3155 229, 280, 359
VIIIc 1705 2200 3110 232, 254 p., 286 P, 360
~?IIId 1700 2190 3160 227, 270, 358
IXd 1720 2226 216, 285, 326p.

oxygen on standing in solution, thus differing from the 4-aryl-substituted 3,4-dihydropyridine-

2-thiones(iH) which are comparatively easily oxidized to the corresponding pyridine-2-thiones-
(IH) [2].
The betaines Vl, like 4-aryl-3,4-dihydropyridine-2-thiones, are easily alkylated. The
best results are obtained by alkylation of the piperidine salts of IV with dimethylsulfate.
The 2-methylthio-l,4-dihydropyridines VIII which are obtained are oxidized to 2-methylthio-
pyridines IX; these can also be prepared by alkylation of the pyridine-2-thiones VII.
The betaine structure of compound VI is supported by the results of IR, and proton and
:3C NMR spectroscopy. The IR spectra (Table 2) show absorption bands for the stretching vi-
brations of ~ groups for the salts IV and V, and also, for the betaines Vl, bands at 2168-
2188 cm-*. Thus, the salts IV and V serve as model compounds for corroboration of the betaine
structure of compounds VI. In addition, in all the compounds IV-Vl there are absorption bands
for NH groups; this supports the formation of anions by loss of a proton from the tertiary car-
bon of the 3,4-dihydropyridine ring.

518
 TABLE 3. Proton NMR Spectra of Compounds IV-Vl and Vlll (in
DMSO-D~)*

Corn- Chemical shift, & ppm

pound 4-H 16-CH3 R--H Py--H I NH others

IVa 3,44 8,3 (2% 6'-H), 3,0 (a-CH2),

7,5--7,2 (4',5'H) 1,6 ([~,y-CH2)
l[Vb 3,44 8.4 (2'.6'H), 2,9 (~z-CH2),
7,06 (3'-, 5'-H) 1,6 (fLv-CH2)
IVc 3,82 (CH2), 8,3 (2'-, 6'-H), 2,9 ((z-CH2),
0,97 (CH3) 7,4--7,1 (4'-, 5'-H) 1,5 ([~,,u
5,4 (N+H2)
IVd 3,89 (CH2), 8,33 (2'-, 6'-H), 7,07 2,9 (a-CH2),
1,02 (CH3) (3'-, 5'-H) 1,5 ([3,y-CH2),
7,6 (N+H~)
Va 3,44 8,27 (2% 6'-H),
7,5--7,1 (4'-, 5'-H)
,%% 3,44 8,44 (2'-, 6'-H), 7,11
(3'-, 5'-H)
Vc 3,89 (CH2), 8,29 (2% 6'-H), 7,44
1,04 (CH3) (4'-H), 7,24 (5'-H)
tVd 3,89 (CH2): 8,38 (2(-, 6'-H), 7,04
1,04 (CHa) (3'-, 5'-H)
VI a 3,51 8,60 (6'-H),
8,49 (2'-H),
8,0--7,7 (4'-, 5'-H)
VIb 3,45 8,73 (2'-, 6'-H), 7,62

rYlc l 3,96 (CH~),

,[ 1,07 (CH3)
(3'-, 5'-H)
8,58 (6'-H),8,48
(2'-H), 8,0--7,5
(4'-, 5'-H)
VId / 3,90 (CH2), 8,73 (2'-, 6'-H), 7,61
11,03 (CH3) (3'-, 5'-H)
Villa 4,58 3,58 8,47 (2'-, 6'-H), 2,55 (S--CH3) "
7,64--7,33 (4'-, 5'-H)
VIIIb 4,74 3,66 8,57 (2'-, 6'-H), 7,22 2,48 (S--CH3)
(3'-, 4'-H)
IVIH c 4171 4,09 (CH2), 8,49 (2% 6'-H), 2,49 (S--CH3)
1,18 (CH~) 7,69--7,72 (4% 5'-H)
VIIId 4,49 3,92 (CH2), 8,51 (2% 6'-H), 2,46 (S--CH3)
1,02 (CI-I3) 7,13 (3'-, 5'-H)

*Spectrum NMR of compound Vlllb run in CDCI3.

The proton NMR spectra of the analogous 4-aryl-substituted 3,4-dihydropyridine-2-thiones

X [2] show signals for the 3-H and 4-H protons in the form of doublets, corresponding to two
stereoisomers. The spectra of the betaines VI and the salts IV and V show only a singlet for
the 4-H proton (Table 3). It should be noted that the signals of the 4-pyridyl radical pro-
tons of the betaine VI are shifted downfield in comparison with those of the salts IV and V,
which is further support for the betaine structure of compound VI.
In the carbon-13 spectra of betaines VId, and the corresponding Na salts Vd, the C(2)
signals are found at 167-164 ppm (Table 4). Comparison of these signals with the C(2) signals
from 4-aryl-3,4-dihydropyridines X (191.25 and 189.76, trans- and cis-isomers) [2] shows that
the signals from the betaine are shifted markedly downfield, which also precludes the presence
of a C==S group. On comparing the carbon-13 spectra of the betaines VId with those of the model
compounds V, VIII, and XI, prepared by acidification of VIIId (Table 4), it can be seen that
the chemical shifts of the carbons of the pyridine ring are close to those having aprotonated
nitrogen atom (compound XI), and the chemical shifts of the carbons of the dihydropyridine ring
are close to those in the sodium salt V.
Ionization constants (pK) were determined for the betaines VI and the corresponding 4-aryl
derivatives X [2] (Table 5). It has been shown that these compounds in 50% aqueous ethanol be-
have as acids of average strength. Examination of the ionization constants pK also provides
support for the betaine structure for compound VI. We used compounds VIII and X as model com-
pounds. On the strength of [3, 4, p. 21], we assigned the constants pK, (4.54 and 5.15) to

519
 TABLE 4. Carbon-13 NMR Spectra (in DMSO-D~) of Compounds
Vd, Vld, V l l l d , and XZ

4&H

150,6
VIC 1 ( ~ 97,(i]149,71 --, 112,~ 1 1 6 7 ~ ~ 2 5 , 3 14,~,I
)toad
I"""I t "~ I I I ~9,111~4
~Vlll 147AI87,~ 1 4 1 , z i l o o , ~ 1 ~ 4 ~ , 1 1 . ~ , , ~ i l l o , ~ , o l
I ' J23,~. 151,3
xi I 142,8

observed in e=essi b oadenln .

TABLE 5. Ionization Constant (pK) of Betaines VI, 1,4-

Dihydropyridlnes VIII, and 4-Aryl-3,4-dihydropyridlne-2-
=hiones X

Compound pK~ pK2

Vlc 4,54 2,17~0,08

VId 5,15 2,26
VIII= 3,18
VIIId 3,79
6-Methyl-4-phenyl- 5.-ethoxyoarbonyl-.3- cyano-3,4- 4,03
dihyaropyri~ine-2- tmone[[1H](Xa) [2]
6.MerhvI-4-[4'-nirrophenyU- 5-eth~xycarbonyl- 3- 3,29
eyano:.3,4-aihydropyridine-2- thione[1H] (X~) [2]

protonation of the 4-pyridyi radical and pKa (2.17 and 2.26) to detachment of a proton from
the 3,4-dihydropyridine-2-thione residue. It was shown that the pyrldine cation, as a strong
electron-acceptor, markedly increases the acid strength of compound Vl (for VId, pKa = 2.6;
for Xb, pKa = 3.29), but on the other hand, the anion increases the basic character of the
nucleophilic center in the 4-pyridyl radical (for VId, pK, = 5.15; for VIIId, pKI = 3.79).

EXPERIMENTAL
A Perkin-Elmer 580B spectrometer was used to obtain the infrared spectra (in nujol).
Ultraviolet spectra were run on a Specord UV-vis in ethanol. A WH 90/DC instrument (90 MHz)
was used for the proton NMR spectra, the internal standard being TMS~; carbon-13BNMR spectra
were run at 22.63 MBz with cyclohexane (6 = 27.44 ppm) as internal standard. The accuracy
of the reported chemical shifts was ppm for *H and ppm for ~SC. Ionization con-
stants were determined by potentiometric titration with a glass electrode [4, p. 108] in 50%
aqueous ethanol.
The main characteristics of the prepared compounds are set out in Tables 1-5.
piperidine Salt of 6-Methyl-5-alkoxycarbonyl-3-cyano-4-pyridyl-3,4-dihydropyridine-2-
thione(iH) (IV). A. A mixture of i0 mmoles acetoacetic ester I and i0 mmoles 2-cyano-3-
pyridylthioacrylamide II was heated and stirred at 50~ partially dissolved in 20 ml absolute
ethanol, 2 ml (25 mmoles) piperidine added, and the reaction mixture filtered hot. The filtrate
was cooled to O~ and the white, finely crystalline product filtered off and washed with cold
ethanol and ether. Yield 70-77% compound IV.
B__~. A mixture of 5 mmoles betaine VI and 0.5 ml (i0 mmoles) piperidine in i0 ml absolute
ethanol was stirred 15-30m in at room temperature and cooled to O*C. The reaction product was
filtered off and washed with cold ethanol. Yield 65-87% compound IV.
Sodium Salt of 6-Methyl-5-alkoxycarbonyl-3-cyano-4-pyridyl-3,4-dihydropyridine-2-thiones
(IH) (V). A mixture of 5 mmoles betaine Vl heated in 2 ml 3 N NaOH (6 mmoles) and 15 ml eth-
anol was filtered and cooled to 0~ The precipitated solid was filtered off and washed with
cold ethanol. Yield 66-92% compound V.
Betaines of 6-Methyl-5-alkoxycarbonyl-3-cyano-4-pyridyl-3,4-dihydropyridine-2-thiones(iH)
.(Vl). A. To 20 ml of 0.5 N hydrochloric acid in ethanol at 50-60~ i0 mmoles of the piperi-

520
dlne-salt IVwas added and dissolved with vigorous stirring. The solution was filtered hot,
cooled to 0~ and the precipitate filtered off and washed with cold ethanol and water. Yield
49-71% compound Vl.
B__=. A mixture of i0 mmoles of an ester of 8-aminocrotonic acid III and i0 mmoles 2-cyano-
3-pyridylthioacrylamide was heated on a water bath with 20 ml absolute ethanol and i0 ml gla-
clal acetic acid until dissolved~ filtered and cooled to 20~ A small amount of product VII
separated. The filtrate was cooled to 0~ and the precipitate filtered off and washed with
cold ethanol and water. Yield 45-69% compound VI.
6-Methyl-5-ethoxycarbonyl-3-cyano-4-(4-pyridyl)-pyridine-2-thione(iH) (Vlld). A mixture
of i0 mmoles of the ethyl ester of 8-aminocrotonic acid III, I0 mmoles 2-cyano-3-pyridylthio-
acrylamide II in 20 ml absolute ethanol, and i0 ml glacial acetic acid was heated 1 h on a water
bath and filtered. The filtrate was kept at 0~ for 24 h and the precipitate filtered off.
Yield 0.87 g (29%) compound Vlld.
2-Methythi-6-methy-5-akxyarny-3-cyan-4-(4-pyridy)-,4-dihydrpyridine (VIII).
A mixture of i0 mmoles freshly prepared piperidine salt IV and 1.2 ml (15 mmoles) dimethyl
sulfate in 20 ml absolute ethanol was stirred for i h at room temperature. The reaction mix-
ture was poured into water, ammonia added to pH 5-6 and the precipitate filtered off. Yield
68-73% compound VIII.
2-Methylthio-6-methyl-5-ethoxycarbonyl-3-cyano-4-(4-pyridyl)-pyridine (IX). A. A mix-
ture of 0.6 g (2 mmoles) ester VII and 0.3 ml (5 mmoles) methyl iodide in I0 ml 0.5% sodium
ethoxide was heated on a water bath for 5 min. The mixture was cooled, poured into ice-cold
water, acidified to pH 6-7 and the precipitate filtered off. Yield 0.45 g (61%) compound IXd.
Bz_. A mixture of 0.63 g (2 mmoles) 1,4-dihydropyridine VIII in 3 ml glacial acetic acid
was heated to 50-60~ and 0.35 g (5 mmoles) sodium nitrite added. The reaction mixture was
cooled, poured into ice-cold water, neutralized with ammonia and the precipitate filtered off.
Yield 0.33 g (52%) compound IX.

LITERATURE CITED
i. A. A. Krauze, Z. A. Kalme, Yu. E. Pelcher, E. E. Liepin'sh, I. V. Dipan, and G. Ya. Dub.r,
Khim. Geterotsikl. Soedin., No. ii,.1515 (1983).
2. A. A. Krauze, ~. ~. Liepin'sh, Yu. E+~ Pelcher, Z. A. Kalme, I. V. Dipan, and G. Ya. Dub.r,
Khim. Geterotsikl. Soedin., No. i, 95 (1985),,
3. N. Bjerrum, Z. Phys. Chem., i04, 147 (1923).
4. A. Albert and E. Sergeant, Ionization Constants of Acids and Bases [Russian translation],
Khimiya, Moscow (1964).

521
ACID DEUTERIUM EXCHANGE IN METHOXYQUINOLINES AND THEIR N-OXIDES

i. G. Tupitsyn, N. N. Zatsepina, UDC 547.831.7'111.02.2

A. I. Belyashova, and A. A. Kane

Kinetic studies of acid deuterium exchange have been carried out for a series of
isomeric 6-, 7-, and 8-methoxyquinolines and their N-oxides, in comparison with
the analogous carbocyclic compounds. It has been found that methoxyquinolines
are deuterated in the N-protonated form, whereas the N-oxides are reactive in
their neutral forms. In full agreement with data for the reactivity of these
heterocycies in nitration, quantum chemical calculations show that in exchange
in 6-methoxyquinoline and its N-oxide the preferred site for electrophilic at-
tack is the 5-position, and in the 7-isomers the 8-position is preferred. The
rate is lower in the 8-isomer, owing to the presence in the latter of intramole-
cular hydrogen bonding. The probable structure of the transition state in the
reaction is discussed.

In studying the reactivity of bicyclic heteroaromatic compounds, it is useful to have

available information on the rates of the simplest, least sterically hindered electrophilic
substitution reactions, namely acid-catalyzed protium-deuterium exchange of hydrogen atoms
directly bonded to the heteroaromatic ring (H--D exchange). In this connection,in order to es-
tablish those factors which determine reactivity it is important that all the kinetic data be
obtained under comparable conditions, and can be considered in terms of a single reaction se-
quence. However, at the present time comparisons of the rates of H-D exchange in the types
of compounds of interest to us (quinolines and their derivatives) with their carbocyclic ana-
logs (naphthalene and its derivatives) are virtually impossible as a result of the lack of
standardization in the determination of log K D values (the logarithm of the H--D exchange rate).
In fact, nitrogeneous heterocycles are capable of undergoing replacement of hydrogen by deuter-
ium in the heteroaromatic ring only under severe conditions (150-180~ reaction medium con-
centrated sulfuric acid [1-4]), whereas H--D exchange in most carbocyclic aromatic compounds
(naphthalene and its derivatives [5, 6] and complex condensed structures [7]) takes place at
a conveniently measurable rate in comparatively mild proton-donor media (anhydrous CF3COOH,
a moderately strong acid, or CF3COOH with the addition of either CHsCOOH, aqueous H2SO4, or
aqueous HCIO~), and at lower temperatures (0-70~
Consideration of currently accepted concepts of the mechanism of acid H--D exchange sug-
gests that this reaction should take place in nitrogeneous bicycles in the absence of concen-
trated sulfuric acid, if an electron-donor substituent [CH3, CI, OCH3, N(CH3)2] is introduced
into the benzene ring of the molecule (positions 5-8). Such a substituent, in creating excess
electron density at the ortho- and para-carbon atoms, should facilitate H--D exchange in com-
parison with the unsubstituted compounds. We found in preliminary experiments that when
CF3COOD with the addition of the strong acid DCIO4 was used as the reaction medium, the acti-
vating effects of CH3 and CI were insufficient to confer any appreciable activity on any of
the positions in the heteroaromatic nucleus. For example, 6-methyl, 5-chloro-, and 6-
chloroquinolines, dissolved in the system 92% CF3COOD-25% DCI04--5.5% D20, did not undergo H--D
exchange even after keeping for 8-10 h at 200~ In contrast, the introduction of such a
powerful ~-donor as the methoxy group into the 6-, 7-, or 8-position of the quinoline ring
results in an adequate activating effect, since the reaction of the isomeric methoxyquinolines
and their N-oxides takes place at a measurable rate in the temperature range 60-180~
The object of the present study was to obtain kinetic data for H--D exchange as a measure
of the relative reactivities of the different positions of the heteroaromatic ring in isomeric
methoxyquinolines and their N-oxides under conditions suitable for the measurement of differ-

State Institute of Applied Chemistry, Leningrad. Translated from Khimiya Geterotsikli-

cheskikh Soedinenii, No. 5, pp. 636-644, May, 1986. Original article submitted February 18,
1985.

522 0009-3122/86/2205-0522512.50 9 1986 Plenum Publishing Corporation

 TABLE 1 . Results of Experiments on Acid H--D Exchange in
Methoxyquinolines

Com-
pound* T, ~
Time, h ~ euterium.
Eidl, % K D 9 lOS, ~"

do d~ (d21 see -I

140 8 36,2 36,2 2,1

140 20 59,9 59,9 1,9
160 2 32,4 32,4 7,2
160 6 58,4 58,4 6,2
180 1 38,2 38,2 18
180 2 60,0 60,0 19
180 3 67,5 67,5 17
Ill 140 4 21,1 21,1 2,1
140 6 26,7 26,7 1,9
160 2 27,4 2714 5,8
160 3 38,9 38,9 6,2
180 1 39,5 39,5 19
180 2 60,1 60,1 19
180 3 62,6 62,6 14
V 160 6 11,5 5,85 0,42
160 9 18,8 10,2 0,38
160 12 20,8 9,45 0,32
180 9 19,0 (1,0) 10,4 0,48
180 12 25,2 12,6 0,44
2OO 4 62,8 (15,8) 47,2 7,1
2OO 6 62,1 (16,3) 47,7 4,9

*For compounds (I) and (III), the Zd i and K D values refer to

i
a single exchangeable atom in the molecule, and for (V) the
value K D refers to two exchangeable atoms (see text).
~In calculating K D from the first-order equation, the equil-
ibrium concentration of deuterium (~80 at.%) was taken into
account.

TABLE 2. Results of Experiments on Acid H--D Exchange in

Methoxyquinoline
Deuterium distribution, qJ
Compound T, ~ Time, h KD- lo~*,
do : [ sec -I

90 8 78,9 21,1 1,1

90 12 72,8 27,2 1,1
105 4 63,3 36,7 4,3
105 6 51,8 48,2 4,3
120 1 59,2 40,8 20
120 2 42,1 57,9 18
120 3 32,9 67,1 17
IV 90 6 83,1 16,9 1,1
95 4 70,6 29,4 3,2
95 6 66,2 33,8 2,5
110 2 61,2 38,8 9,2
110 6 ,37,6 62,4 7,0
120 1 48,2 51,8 29
120 2 34,8 65,2 23
VI 180 12 75,2 24,8 0,85
180 18 62,1 37,9 0,90
2OO 4 74,5 25,5 2,7
2OO 6 64,0 36,0 2,8

*Values of K D refer to a single exchangeable atom.

ences in reactivity in comparison with the analogous carbocyclic compounds. A wider range of
quinolines and their N-oxides was used here than in the only previously-published study [3].
In addition to the previously-studied [3] 6-methoxyquinoline (I), there were included 6-
methoxyquinoline N-oxide (II), 7-methoxyquinoline (III) and its N-oxide (IV), 8-methoxyquino-
line (V), and 4-methoxyquinoline N-oxide (VI).
The experimental conditions and results are shown in Tables i and 2. The rate constant
calculated from the first order equation (KD) was taken as a measure of reactivity.

523
 TABLE 3. Results of Calculations of Reactivity Indices for
H--D Exchange in Methoxyquinolines (PPDP/2 m e t h o d )
1r-electron charges on
Localization energy, eV atoms, e
Com- -IgK
pound Atom No. at 180~)
neutral N-proto- neutral N-proto-
molecule nateatorm molecule nated form

7,1563 +0,0027 -0,0362

14,1315 8,6962 -0,0558 -0,0195 3,74
13,2500 75163 -0,0253 +0,0690
13,7143 8,1503 - 0,0039 - 0,0483
Ill 7,,5603 -0,0278 -0,0683
7,7246 +0,0255 +0,0742
13,0360 8,3686 --0,0469 -0,0259
13,7688 8,7197 --0,0854 --0,1262 3,77
V 7,3282 -0,0586
8,5719 +0,0145 5,28
8,0638 +0,0379
l 8,1323 +0,0405

In order to explain the differences in reactivity in H--D exchange in (l-Vl), in parallel

with the experimental work model quantum chemical calculations were carried out for the neu-
tral molecules and for the nitrogen-protonated heterocyclic bases, and for all the possible C-
protonated forms (calculations for the N-protonated heterocycles (I), (III), and (IV) were
necessary since the reaction in question is carried out in a proton-donor solvent). The re-
sults of the PPDP/2 calculations are shown in Tables 3 and 4.
The following comments relating to the results obtained here are necessary:
i. If the temperature dependence of the H-D exchange rate constant is shown in the form
of the Arrhenius equation, it is easy to calculate the activation energy AE a and the activation
energy A s ~ f o r compounds (1)-(IV). The values of AE a and A S ~ calculated in this way are equal
to: AEa(1) =21,4, AEa(II) =26,4, AEa(Itl) = 19,9, AEa(IV) =34.3 kcal)m0ie AS~(1) -30,8 AS~(II) . . . . 10,9, AS~
(Ill) =,-33,8, AS~(IV)=9,9 e . u .
In principle, entropy of activation may be used to determine the chemical form of the re-
acting species if the criteria given in [8] are employed, according to which the value of AS ~
in the case of reactions of protonated molecules should be less than --20 eu, i.e., the theo-
retical value o f A S ~' for a chemical reaction involving two charged substrates. It will be
seen that the entropy of activation for H--D exchange in the N-oxides (II) and (IV) correspond
to the case of reaction of neutral molecules. The validity of this argument is to some ex-
tent confirmed by the results reported in [3, 4], o~tained from a study of the changes in the
rate constant of H--D exchange in (I) as a function H0 bf "~he acidity~of the medium (medium
aqueous sulfuric acid, function Ho varied from 0.3 t6'0"8)~.
It is interesting to compare the above conclusions as to the nature of the reacting
species with literature information for a typical electrophilic substitution reaction, namely
the nitration of quinoline and its N-oxide [9]. It follows from Tables 1 and 2 that H--D ex-
change in the N-oxides (II) and (IV) takes place 40-50 times faster than the same reaction in
the similarly substituted quinolinium salts (I) and (III). In contrast to this, the rate con-
stant for the nitration of quino!ine N-oxide is less than in'the case of the quinolinium ca-
tion (0.78.10 ~ and 1.67.104 liter-mole*sec-:, respectively [9]. It is evident that nitration
differs from H--D exchange in that quinoline N-oxide takes part in the first reaction in its
protonated form, the NOH+ group here functioning as a stronger deactivating electron-acceptor
than the NH+ group in the quinolinium cation.
2. As noted above, the H-D exchange reaction was carried out between a "light" substrate
and a mixture of deuterated acids, D2SO~ and 70% DCIO4 ("direct" H--D exchange). Since neither
:H NMR nor IR spectroscopy gave unambiguous information on the sites of entry of deuterium in-
to the condensed benzene ring, the directivity of isotope exchange was deduced indirectly.
Firstly, it was found that the value of the H-D exchange rate constant (KD) in compounds (I-
IV) did not change even when the extent of exchange was greatly increased (Tables 1 and 2).
This indicated that the reactivities of the different positions in the heteroaromatic ring
were markedly different.

524
 TABLE 4. Results of Calculations of Reactivity Indices for
H--D Exchange in Methoxyquinoline N-Oxides (PPDP/2 method)

Compound Atom No. Localization energy, ~r-Electron charges -tg 1%

eV on atoms, e (at 120~

II 14,0800 - 0,1348
14,1200 -0,0772
13,5827 -0,0877 3,92
12,9140 - 0,0480
12,6262 + 0,0341
IV 14,6093 -0,1164
13,1417 +0,0260
13,7500 -0,0026
13,1349 -0,0124
14,0251 --0,0458 3,66
VI 13,8610 --0,0973
12,7943 -- 0,0241
13,0875 --0,0104 6,5*
12,8519 + 0,0071

*Approximate value, calculated from kinetic data at 180 ~ and

200~

The selective nature of isotope exchange was supported by the appearance in the low-
voltage mass spectra of strong peaks for the molecular ions, with m/z 160 (Tables 1 and 2).*
Bearing in mind that these peaks are 1 amu greater than the low-intensity peaks for the non-
deuterated ions, it may be concluded that the hydrogen atoms in all the positions in molecules
(I)-(IV)save one are virtually non-enriched with deuterium, under conditions in which H--D ex-
change at one position has proceeded sufficiently far.
The partial rate factors for the individual positions in the heteroaromatic nucleus are
comparable with each other in their n-electron charges on the carbon atoms q~ (C i) ("static"
factor) and electron delocalization energies L e (Ci) ("dynamic" factor).
In the majority of calculations for (I) and (III), both theoretical measures of reactiv-
ity lead to the same predictions as to the sites of electrophilic attack (Table 3). An ex-
ception is the cation of (I), in which, notwithstanding the values of L e the atom in the 5-
position of the heteroaromatic nucleus, C(s) possesses greater n-electron density than C(3~.
Since, in assessing relative reactivities in aromatic substitution it is more correct to use
localization energies, it may be said that in (I), H--D exchange involves the atom in the 5-
position, whereas in (III) by far the greater part of the deuterium entering the molecule
should be found in the 8-position. This conclusion is in full agreement with the orientations
found for "elementary" electrophilic substitution reactions, since irrespective of its actual
nature the electron-donor substituent in the condensed benzene ring in quinoline (positions 6
or 7) invariably directs electrophilic reagents to positions 5 or 8 adjacent ot the existing
substituents [i0]. T h e fact that the reactivity of the 5-position in (I) is much greater than
t h o s e of positions 7 and 8 is supported by studies of the kinetics of the "inverse" exchange
(protodedeuterization) of (I) in sulfuric acid solution [3].
An unexpected finding is that in H--D exchange in the N-oxides (II) and (IV), according
to calculations of their L e and q~ values the most'reactive positions should be 2- and 4- in
the heteroaromatic ring (Table 4). This finding can be scarcely be regarded as in accordance
with fact, since in unsubstituted quinoline N-oxide and in some of its methoxy-derivatives
qualitative studies of the relative reactivities of different positions in these compounds
towards electrophilic substitution have shown that the methoxy-group has more powerful orient-
ing effect than the N-oxide grouping, and reaction therefore takes place in the ortho-position
to the methoxy-group [i0].
In all probability, these inadequacies in the quantum-chemical approach are due to de-
ficiencies in the PPDP/2 method of calculation, in which the interelectron repulsion integrals
with p-functions are replaced by integrals with spherically symmetrical s-functions. If this
artefact of the method is ignored, then it is found to give a completely realistic assessment

*In the N-oxides of the heterocycles studied here, electron impact results in cleavage of oxy-
gen from the heteroaromatic NO grouping with the formation of a molecular fragment with m/z
159, the peak for which is greatest in the spectra of nondeuterated samples.

525
of the relative reactivities of the different positions in the carboeycllc moiety of the N-
oxide ring. As in the case o~ the corresponding unoxidized heterocycles (I) and (III), when
a methoxy-group is present in the 6-positlon (compound II), according to calculations of the
values of L e and q~ H-~D exchange takes place preferentially in the 5-position [q~(C(s)) >
qz(C(7)) > q~(C(,)); Le(C(~)) > Le(C(,)) > Le(C(,)], and when this group is in the ;-position
<compound (IV), replacement in the 8-position predominantes [q~(C(,)) > qz(C(,)) > q~(C(~))i
Le(C(.)) > Le(C(~)) > Le(C(~))].
3. The relatively high positional selectivity shown by the H--D exchange reaction in (l-
IV) is not seen in this reaction in (V). Indeed, in contrast to the mass spectra of (l-IV),
in which the greatest peak is for the ion with m/z 160 corresponding to the monodeuterated
form, the spectrum of (V) following extensive H--D exchange (200~ shows not only an ion with
m/z 160, but also an ion with m/z 161, the relative intensities of these peaks corresponding
to randomization of the deuterium atoms between two positions in the heteroaromatic nucleus
(Table 1).
These considerations are supported by literature reports of the regiospecificity of el-
ectrophillc substitution reactions in 8-hydroxy- and 8-methoxyquinolines. Previous studies
[i0] of the orientation of the incoming reagent in electrophilic attack were carried out using
as an example the nitration of 8-hydroxyquinoline in strongly acidic media (mixture with con-
centrated sulfuric acid). No mono-nitro-compounds could be isolated from the products, only
5,7-dinitro-8-hydroxyquinoline being formed. Other electrophilic substitution reactions w h i c h
have been described include halogenation, sulfonation, and nitrosation, which take place pri-
marily in the 5-position of the quinoline nucleus, more severe conditions leading to the for w
marion of the 5,7-disubstituted derivatives [i0]. These findings suggest that in (V) also in
H--D exchange under acidic conditions two positions will potentially be the most reactive,
namely 5 and 7. This assumption is in qualitative agreement with the predictive calculations
of the localization energy Le indicating preferential isotope exchange in the 5-posltion (as
will be seen from Table 3, the values of L e in the formation of the ~-complex of the cation
of (V) with a proton increase in the sequence 6 < 7 < 5). Furtherfore, in this case there is
no correspondence between the "dynamic" and "static" reactivity indices. According to Me cal-
culations, the greatest ~-electron density will be found at the atoms in positions 3 and 5.
If one adheres to the view that the course of electrophilic attack is determined by the
reversible and limiting step of formation of a a-complex, then from what has been said it may
be concluded that the n-electron charges on the carbon atoms in (V) do not determine their re-
lative reactivities, redistribution of electron density and the consequent resonance stabili-
zation of the ~-complex in all likelihood having the greatest influence on changes in free
energy of activation in the H--D exchange reaction in (V).
4. Evaluations of comparative reactivity in this series of isomeric methoxyquinolines
from the localization energies at the most reactive carbon atom [C(s) in (I) and (V), and
C(,) in (III)] show that the rate of H--D exchange in the 6- and 7-isomers should be similar
in magnitude, but the relative reactivity of both heterocyeles should be greater than that of
the 8-isomer. Experiment has shown that the rate of H--D exchange in (I) differs little from
that in (III) Cat 160~ KD = (6-7)'10 s sec-~), whereas the rate of this reaction with the
isomer (V) is 15 times slower (at 160~ KD = 0.35.10 -s sec-*).
The decrease in the H--D exchange rate constant in the (V) cation may be explained by
steric interactions. The heteroatomic NH+ grouping in the peri-position to the methoxy-
substituent creates a barrier to pz-conjugation of the latter with delocalized ring n-electrons
in consequence of the formation of a strong intramolecular hydrogen bond between the oxygen
and cyclic nitrogen atoms. The occurrence of such interaction has been shown in spectral
studies of PKNH+ values in a series of isomeric methoxyquinolines [ii].
5. Although it is not possible from the results presented here to determine precisely
the ratios of the rates of H--D exchange at each ortho-position to the methoxy-group in single
molecules of (II-V;, we estimate it to be quite high, amounting to several logKD units (see
section 2). This confirms the hypothesis that the fixation of the double bonds in the
quinoline ring is responsible for its chemical behavior [12]. The great differences in the
reactivities of the ~- and 8-positions of the ring in (I-IV) is in general agreement with lit-
erature information on the orienting effect of the methoxy-substituent in acid T--H exchange
(protodetritiation) in a carbocyclic analog of the heterocycles studied here, namely 2-
methoxynaphthalene-a-T, and -8-T~ (VII). It was found that the rates of T--H exchange in (VII)
at the ~- and ~-positions were in the ratio 4.10S:l (70~ in anhydrous CF~COOH [5]).

526
 TABLE 5. Changes in the Rate Constant for the Acid H-D Ex-
change in Naphthalene and 2-Bromonapthalene with Respect to
the Composition of the Reaction Medium

Compound Temperature, Reaction

"C medium* z%. los, see - t - I g XD at 7o~

VIII 70 *1" A 2,6 4,6

B 2,2
B 7,2 3,1
IX 70 A 0,29 5,5
70 B 9,2 4,1
X** 70 A 0,32 5,5
40 B 0,62
50 B 2,3 (3,3)

*A is anhydrous CF3COOH, and B is 92% CFsCOOH + 2.5% HCIO4 +

5.5% HaO.
tAccording to [5], in protodetritiation K T = i.i*i0 -s sec -I.
SApproximate values for activation parameters, Ea = 25.3 kcal/
mole, log A 13.0.
**"Direct"H-q) exchange.

With respect to the construction of a general scale of electrophilic reactivities based

on the values of the H--D exchange rate constants in heteroaromatic bicycles and x-isoelectro-
nic systems without a heteroatom, it is necessary to bear in mind the difficulty due to the
immeasurably fast introduction of deuterium into the l-position of the napthalene ring in
(VII) even when extremely small amounts of the strong acid HCIO, (=0.001%) are added to the
CFaCOOH (after i0 min at --20~ one atom of hydrogen has been completely replaced by deuterium).
In order to obtain kinetic data for the heterocycles (I-IV) and for (VII) (together with other
substituted naphthalenes) in a single system, we had recourse to a factor describing the in-
crease in the rate of H--D exchange when anhydrous CFsCOOH is replaced by CF3COOH with added
CHI04 and H=O for related compounds of comparatively low reactivity, namely naphthalene-l-Dx
(VIII), naphthalene-2-D, (IX), and 2-bromonaphthalene (X). It was assumed thaL ~he conversion
factor for the rates to conditions chosen for the reaction retained its numerical value, and
was applicable to compound (VII).

It will be seen from Table 5, which gives a summary of the kinetic measurements in both
reaction media, that acid H--D exchange in CFsCOOD + DCIO, + D20 solution takes place 25-40
times more rapidly than in anhydrous CF3COOD. Bearing in mind that the rate constant for
"reverse" T--H exchange in (VII) is K T = 2.101 see -I at 70~ [5], we obtain the value K T = 6.102
sec -I for a medium which differs from that employed in [5] by the presence of added aqueous
DCIO4.
Table 6 presents kinetic data on H--D exchange in (I), (II) and (VII) in the form of com-
parable rate constants (70~ medium CFaCOOD + DCIO~ + D20); also shown are the rate constants
for the nitration of unsubstituted analogs of the compound under examination, namely naphtha-
lene, quinoline, and quinoline N-oxide. It will be seen from Table 6 that the deactivating
effects of the NH + and NOH + groups, shown by their "standard" nitration rate constants, al-
though very high (A log K D ~ 8.2-8.4) are nevertheless lower than in the H--D exchange reaction,
in which it is AlogKD~ 9-6- This difference in the ranges of logKDvalues may be explained as
follows. The reactivity of the unsubstituted compounds is determined by the relative stabil-
ity of the intermediate o-complex, whereas that of (I) and (II) towards H-D exchange (reaction
with more 'reactive' substrates) may be largely determinedby electron density transfer in the
transition state from the carbon atoms of the aromatic (heteroaromatic) ring to the lowest un-
occupied orbital of the electrophile. This unusual mechanism for H-q) exchange, involving as
it does partial transfer of electron density, may be responsible for the lac k of agreement be-
tween the increases in the rate constants for H--D exchange in the sequence NH + < NO < CH, and
the predictions of MO calculations using the localization energy L e as a measure of reactivity
(Table 6).
6. In addition to the N-oxides (II) and (IV), which contain a methoxy group in the ben-
zene moiety of the molecule, H-q) exchange has been studied in the N-oxide (VI), in which di-
rect conjugationbetween the methoxy group and the N-oxide group has a substantial effect on
electrophilic reactivity. We regard support for this view as being provided by the fact that

527
 TABLE 6. Logarithms of the Rate Constants for the Acid liD
Exchange and Nitration for Some Heteroaromatlc Bicycles,
a n d Calculated C-Protonation Energies

Compound IgKl)(?70~) [ g,,*,'eV Compound I r

I Ig #~
H-D exchange Nitration
2- Methoxynaphthalene 2,8 13,8022 Naphthalene 1,85
6-MethoxyquinoIine -6,8 8,6962 Qulnoline - 6,36
(14,1315)
6-MethoxyquinotlneN-oxlde - 6,5 ] :3,,~6'27 QulnoUne N-oxide -6,6

*For 6-methoxyqulnoline, L e values for the cationic form of

the heterocycle are given, with (in brackets) the unproton-
ated molecule.
%The logarithms of the "standard" nitration rate constants
are given (log Ka at 25~ and H 6.6 in aqueous sulfuric acid
[13]).

the rate of H--D exchange in (VI) is at least i000 times less than that in the most "reactive"
sites in (If) and (IV) (Table 2). It will be seen from Table 2 that the height of the peak
with m/z 160 corresponds to the presence of nearly 40% of the monodeuterated form in the mix-
ture of isotopic modifications, more highly-deuterated forms being absent. This indicates
that H--D exchange in (Vl) is a selective reaction (at 200~ We have at our disposal no
data for the unambiguous location of the site of entry of the deuterium into the heteroaro-
matic ring in (Vl). A definite argument for the assumption that the 3-position is more re-
active than the 2- and remaining positions in the N-oxide ring in (Vl) is provided by studies
of the nitration of 4-hydroxyquinoline N-oxlde, which have shown that the electrophile is pre-
ferentially oriented in the 3-position [i0]. This finding is not in accordance with the pre-
ferential formation of 2- and 5-deuterated forms predicted from the L e values.
More precise location of the site of entry of deuterium in the ring of (Vl) will require
further investigation.

EXPERIMENTAL
The mass spectra of the compounds were obtained on an MI-1309 instrument with direct in-
troduction of the sample into the ion source, ionizing electron energy 12-18 eV, sample heated
to 20-40~ (I, Ill-V) or 50-I00~ (II, Vl), emission current 0.4-0.5 mA.
Compounds (I), (III), and (V) were obtained by the methods reviewed in [14] (see also
[15]), and (II), (IV), and (VI) as described in [16]. The H--D exchange reaction was carried
out in sealed glass ampuls with metal sheathing. The thermostat accuracy was 176 . The
ratio of number of moles of the acid CF3COOD to the compound was 100-150. When the reaction
was complete, the mixture was poured into a 5% solution of sodium bicarbonate, the product ex-
tracted with chloroform, the chloroform solution dried (CaCO3), and the chloroform removed un-
der reduced pressure. The energy of activation AS~,(eu) was calculated from the equation

AS~ =4,5761g(A/T)-49.21.

In calculations for the neutral molecules and the cations by the PPDP/2 method, standard
geometry was assumed [17]. The model chosen for the G-complex was a molecular system in which
the ring geometry remained unchanged, and the geminal angle (the site of proton addition) had
the following geometric parameters: rCH = 1.08 ~, ZHCH ffi109 ~ projection of the CH bonds on
the plane of the ring coincident with the direction of the CH bonds in the original hetero-
cycle. Calculations were carried out on a'BESM-6 computer.

LITERATURE CITED
i. V. P. Lezina, A. U. Stepanyants, L. D. Smirnov, N. A. Andronova, and K. M. Dyumaev, Khim.
Geterotsikl. Soedin., No. 12, 1647 (1972).
2. U. Bressel, A. R. Katritzky, and R. J. Lea, J. Chem. Soc., B, No. 6, 4 (1971).
3. U. Bressel, A. R. Katritzky, and J. R. Lea, J. Chem. Soc., B, No. 6, Ii (1971).
4. A. Ei-Anani, J. Banger, G. Biandu, S. Clementi, D. Johnson, and A. R. Katritzky, J. Chem.
Soc., Perkin Trans. 2, No. 7, 1065 (1973).

528
 5. C. Eaborn and P. Golburn, J. Chem. Soc., B, No. i0, 1112 (1968).
6. A. P. Neary and R. Taylor, J. Chem. Soc., Perkin Trans. 2, No. 8, 1233 (1983).
7. A. Streitwieser, Jr., A. Lewis, J. Schwager, R. W. Fish, and S. Labana, J. Amer. Chem.
Soc., 92, 6525 (1970).
8. A. A. Frost and R. I. Pearson, Kinetics and Mechanism, New York (1953), p. 107.
9. J. T. Gleghorn, R. B. Moodie, K. Schofield, and M. J. Williamson, J. Chem. Soc., B, No.
3, 3i6 (1968).
i0. Zh. I. Aksel'rod and V. M. Berezovskii, Usp. Khim., 39, 1337 (1970).
ii. Z. P. Bruvers and I. B. Zuika, Khim. Geterotsikl. Soedin., No. 3, 387 (1980).
12. I. P. Bean, A. R. Katritzky, and A. Marzee, Bull. Acad. Polon. Sci., Ser. Sci. Chim., 16
(1968).
13. A. R. Katritzky, S. Clementi, K. Tarhan, and K. Okan, J. Chem. Soc., Perkin Trans. 2,
No. 14, 1624 (1975).
14. R. Elderfield (ed.), Heterocyclic Compounds [Russian translation], Vol. 4, Izd-vo
Inostr. Lit., Moscow (1955), p. 99.
15. B. I. Ardashev and V. I. Minkin, Zh. Prikl. Khim., 30, 1877 (1957).
16. E. Ochiai, Aromatic Amine Oxides, Academic Press, London--New York (1967).
17. J. A. Pople and M. Gordon, J. Amer. Chem. Soc., 89, 4253 (1967).

~-PHENYLISOCINCHOMERONIC AND 4-AZAFLUORENONE 3-CARBOXYLIC ACIDS

N. S. Prostakov, Sakha Shibu Rani, UDC 547.826.2'412.5'836.07

N. M. Mikhailova, and N. D. Sergeeva

3,6-Dimethyl-6-phenylpyridine, obtained on phenylation of 2,5-1utidine, has been

used in the synthesis of a-phenylisocinchomeronic acid, derivatives of it, and
also for the preparation of 4-azafluorenone 3-carboxylic acid. It was established
that 4-hydroxy-3,6-dimethyl-2-phenylpyridine was formed on phenylation of 2,5-
lutidine.

Pyridine bases containing methyl and phenyl substituents in the ring seemed of interest
for the preparation of phenyl substituted pyridine carboxylic acids and also of condensed
heterocyc!es. Compounds of such type are the subject of numerous investigations carried out
mainly with the aim of obtaining effective physiologically active compounds.
The initial subject of the present work was 3,6-dimethyl-2-phenylpyridine (I). Its pre-
paration from the oxime 5-hydroxy-2-methyl-i-phenylhexa-l,3-diene has been described in [i],
and also from 2,5-1utidine by a multistage synthesis in [2]. Various melting points were
cited in these studies for the picrate of (I) base, viz., 179-180~ in [i] and 134-135~ in
[2]. The data obtained by us corresponded to the second value.
Considering that the most convenient means of synthesizing 3-methyl-2-phenylpyridine (30%
yield) is the phenylation of B-picoiine from [3] we examined the possibility of obtaining py-
ridine [I) by this method. The reaction of 2,5-1utidine with phenyllithium was carried out
on gentle boiling in ether. 3,6-Dimethyl-2-phenylpyridine (I), formed in 21% yield, was char-
acterized as the picrate and iodomethylate. A special feature of its mass spectral fragmenta-
tion was the formation of a [M -- H] + ion peak of maximum intensity which confirmed the pres-
ence of the phenyl substituent in the ortho position relative to the nitrogen atom. The pres-
ence in the mass spectrum of peaks with m/z ]67 [M -- H -- CH3] + and 152 [M -- H -- CH3 -- CH3] +
confirmed the presence of two methyl groups. The high intensity of the ion peak with m/z 167
indicated that a methyl group was found in the ortho position relative to the nitrogen atom.

P. Lumumba Peoples' Friendship University, Moscow. Translated from Khimiya Geterotsik-

licheskikh Soedinenii, No. 5. pp. 645-648, May, ]986. Original article submitted March 12,
1985.

0009-i~122/86/~03-0529~12.50 9 1986 Plenum Publishing Corporation 529

 oil OCOCH~
(:ll, (:ll,, I r ( YI I ell

CH~"" " ~ : " C ) ~ " ""'N' " % H . C|! ~ ' ' C~H~ C H 3' "N" C~H~
! II Ill

The phenylatlon reaction of 2,5-1utidlne was accompanied by the formation of a signifi-

cant amount of resinous products partially reverting to the initial lutidine. From the resi-
due after distillation of (I) base, 4-hydroxy-3,6-dimethyl-2-phenylpyridine (II) was isolated
in insignificant yield, the structure of which was confirmed by data of elemental analysis,
IR, mass (presence of a molecular ion peak), and PMR spectra.
Confirmation of the structure of compound (If) was also provided by its conversion into
3,6-dimethyl-4-acetoxy-2-phenylpyridine (III). Evidently the hydroxy derivative (If) is
formed by the oxidation of (I) under the conditions of the experiment.
~-Phenylisocinchomeronic acid (IV) was obtained in moderate yield on oxidation of pyri-
dine (1) with potassium permanganate and was converted into the diacid chloride (V), dimor-
pholide (VI), and dimethyl ester (Vll). These derivatives of acid (IV) were subjected to a
study of their useful practical properties. On the other hand they served to confirm its
structure.

H O0 CJ ~ " NJ"~'~'~Ce H ~ , CtH s

IV V--VII
V R=C]; VI R=morpholinoVH R=OCH3

Searches for routes of obtaining azafluorenones containing functional substltuents have

been conducted in our laboratory, since they may be useful in synthetic and applied respects.
Pyridine (I) seemed of interest in this project. It was established that 3-methyl-4-
azafluorene (VIII) was obtained from it by the catalytic dehydrocycllzation method for meth-
ylphenyl substituted pyridines developed in our laboratory [4]. Compound (VIII) has active
methyl and methylene groups. However azafluorene (VII) was formed in a mixture with starting
pyridine (I), separable with difficulty, consequently when obtaining 4-azafluorenone 3-
carboxylic acid (XI) the mixture of compounds (I) and (VIII) was subjected to oxidation.
A more convenient method of obtaining ketoacid (IX) was the cyclodehydration of ~-
phenylisocinchomeronic acid (IV) with polyphosphoric acid. In this case acid (IX) was iso-
lated (80% yield) as high melting yellow crystals. A peak was present in its mass spectrum
at M + 225. The formation of a maximum intensity ion peak with m/z 181 [M -- CO2] + confirmed
the presence of a carboxyl group. Subsequent fragmentation of this ion was accompanied by
fission of the molecular ion of 4-azafluorenone [5].
.~. ..N . CH~ ~ -~ N~ CO011

VIII
IX IV X-XII

X R= OCH3; XI R=Ch XII R=morpholino

The methyl ester (X), a c i d c h l o r i d e (XI), and morpholide (Xll) were obtained from a c i d
(IX).

EXPERIMENTAL
Mass spectra were taken on a ME-1303 instrument with direct insertion of samples into
the ion source at an ionizing voltage of 70 eV and various temperatures of admission. PMR
spectra were obtained on a BS-467 (60 MHz) instrument (TMS was internal standard) and IR
spectra on a Specord UR-20 spectrometer.
3,6-Dimethyl-2-pheny!pyridine (I) and 4-Hydroxy-3,6-dimethyl-2-phenylpyridine (II). 2,
5-Lutidine (68.5 g: 0.64 mole) was added gradually to phenyllithium obtained from lithium
(9 g: 1.3 moles) and bromobenzene (i00 g: 0.64 mole) in ether (300 ml). The mixture was
stirred for 4 h with the ether boiling gently, then water (230 ml) was poured in. The ether
solution was dried over magnesium sulfate. On distilling the residue from the ether extract

530
the initial lutidine (18.5 g: 27%) was obtained also and pyridine (i) (18 g: 21% on the re-
acted lutidine) as a yellow liquid bp 130-139~ (5 mm). Found: N 7.5%. M + 183. CIsH,3N.
Calculated: N 7.6%. Picrate: mp 133-1340C (from acetone), lodomethylate: mp 187-1880C.
Found: N 3.8%. [M-- CH31] + 183. CIsH,3N.CH31. Calculated: N 4.3%.
The fraction with bp 198-2070C (5 mm) crystallized from heptane. Compound (II) (1.3 g:
1.4%) was isolated as colorless crystals, mp 222-223~ PMR spectrum (acetone-d6): 2.25 (s,
3 H, 3-CH3), 2.46 (s, 3 H, 6-CHs), 8.43 (s, 1 H, OH), 7.5 ppm (m, 6 H, 5-H and C6H5). IR
spectrum (in chloroform): 3600 cm -I (OH). Found: N 7.4%; M + 199. C13H,3NO. Calculated:
N 7.5%. Hydrochloride: mp 229-230~ (with decomposition, from alcohol). Found: 5.6%.
C13H~3NO.HCi. Calculated: N 5.9%.
4-Acetoxy-3,6-dimethyl-2-phenylpyridine (III) was obtained in 60% yield on boiling com-
pound (II) with acetic anhydride in benzene as colorless crystals of mp 78-79~ (from heptane).
Found: 5.4%; M + 241. CIsHIsNO2. Calculated: 5.8%.
~-Phenylisocinchomeronic Acid (IV). Potassium permanganate (23 g: 0.16 mole) was added
in portions to a suspension of pyridine (I) (4 g: 0.21 mole) in water (350 ml) at 100~ The
mixture was stirred for 8 h at 100=C. The manganese dioxide was filtered off and washed with
water. The combined aqueous filtrate was evaporated to 25 ml and treated with 18% hydro-
chloric acid to pH 5. The solid was filtered off, washed with water, and with ether. Acid
(IV) (1.3 g: 24%) was obtained as colorless crystals of mp 205-207~ IR spectrum: 3290
(OH), 1745 cm -I (CO) I M + 243. The value for the analysis of nitrogen content was underes-
timated by 1.2% in comparison with the calculated value.
~-Phenylisocinchomeronic acid diacid chloride (V) was obtained from acid (IV) and thionyl
chloride in 90% yield as pale orange crystals, mp I01-I03~ (from a heptane-ethyl acetate mix-
ture, i0:i). Found: N 4.9%; M + 281. C13HTCI=NO=. Calculated: N 5.1%.
~-Phenylisocinchomeronic acid dimorpholide (VI) was obtained from diacid chloride (V)
and morpholine in dioxan in 55% yield as yellow crystals of mp 162-163~ (from a heptane-
acetone mixture, 12:1). Found: N 10.9%; M + 381. C21H=3N304. Calculated: N 11.0%.
~-Phenylisocinchomeronic acid dimethy! ester (VII) was obtained by the esterification of
acid (IV) in the presence of sulfuric acid in 99% yield and had mp 91-92~ (from heptane).
IR spectrum: 1725 cm -I (CO). Found: C 66.6; H 4.9; N 5.3%; M+ 271. C15HI3NO~. Calculated:
C 66.6; H 4.8; N 5.2%
3-Methyl-4-azafluorene (VIII) was obtained by the dehydrocyclization of pyridine (I) (ii
g: 0.09 mole) in benzene (i00 ml) according to [4]. The temperature in the catalyst zone
was 540-560~ The gas (7.8 liters at 21~ 765 mm) was collected. On redistillation of the
condensate a fraction (9.8 g) of bp 120-1500C (4 mm) was collected. The picrate (1.3 g) of
azafluorene (VIII) was obtained from this fraction (5 g) and had mp 220-220.5~ (from acetone).
Found: N 13.7%. C13HI,N,C6H3N3OT. Calculated: N 13.7%.
4-Azafluorenone 3-Carboxylic Acid (IX). A. A mixture of acid (IV) (1.3 g: 0.005 mole)
and polyphosphoric acid (5 ml) was heated for 7 h at 190~ cooled, and poured into water
(120 ml). The solid was filtered off, washed with water, and dried in vacuum. Compound (IX)
(0.96 g: 80%) was obtained as bright yellow crystals of mp 238-239~ M + 225. The value for
analysis of nitrogen content was underestimated by 1.5% in comparison with the theoretical
value. IR spectrum: 3275 (OH), 1720 cm-: (CO).
B. Potassium permanganate (10.4 g: 0.07 mole) was added in portions with stirring to a
suspension of the mixture (4.5 g) of azafluorene (VIII) and pyridine (I) in water (300 ml) at
100~ The mixture was maintained at IO0~ for 2.5 h. Manganese dioxide was filtered off and
washed with water. The combined filtrate was extracted with hexane. Pyridine (I) (3.5 g)
was isolated from the hexane extract. The aqueous solution was evaporated to 20 ml and
treated with ]8% hydrochloric acid to pH 5. The precipitated solid was filtered off, washed
with water, and dried in va(~uum. Ketoacid (IX) (0.75 g: 6.2% on the azafluorene VIII con-
tained in the initial mixture) was obtained having mp 238-240~ A mixture of both samples
of acid (IX) melted with no depression of melting point.
4-Azafluorenone 3-carboxylic acid methyl ester (X) was obtained by esterification of (IX)
in the presence of sulfuric acid in 71% yield as pale yellow crystals of mp 191-192~ (from
heptane). IR spectrum: 1755, 1725 cm -: (CO). Found: C 70.1; H 3,8; N 5.5%; M + 239.
C,~HgNO3. Calculated: C 70,2; H 3.7; N 5.8%.

531
 4-kzafluorenone 3-carboxyllc acid chloride (XI) was obtalned ~rom acid (IX) and Chionyl
chlorlde in 90% yletd as yellow crystals os mp 247-248~ (from a heptane~acetone mixture, 5:1).
IR epactrum: 1773, 1730 cm "~ (CO). Found: N ~.3~," ~ 243. C~jH,C~NOn. Calculated: N 5.7~.
4-kzas 3-carboxymorpholide (XZ~) was obtained s acid chloride (Xl) and mot=
phollne in dloxan in 79% yield as yellow crystals o~ mp 138-140~ (from e heptane~acetone mix-
tu~e, i0:1). Found: N 9,1%| M + 294. CL,HL~N~Os. Calculated: N 9,S%.

LITERATURE CITED
M. G. As~ and M. T, Bogert, Rec, Tray, Chlm., 5~4, 917 (1935),
2. d. M. Bonnier and J. Court, Bull. Soc. Chim, France, No, I, 142 (1970),
3. R. A. Ambramovitch and E. S. Giam, Caned. J. Chem., 38, 761 (1960).
4. N. S. Prostakov, A. V. Varlamov, T. A. Vasil'evp O. G. Kesarev, and T. A. Urblna, ~im.
Geterotslkl. Soedin., No. i, 124 (1977).
. P. N. Zakharov, V. P. Zvolinskii, V. K. 5hevteov, V. G. Pleshakov, G. A. Vasil'ev, and
N. S. Prostakov, Khlm. Geterotslkl. Soedin., No. i, 89 (1979),

REACTION OF I-METHYLURACIL WITH PHENYLBENZHYDRAZONOYL CHLORIDE

N. B. Chernyshova and V. N. Shlbaev UDC 547.854.4:542.951.8

The ambideut anion of l-methyluracil gives with phenylbenzyhydrazonoyl chloride,

depending on the conditions, the N-acylatlon product (polar solvent, room temper-
ature), or the O-acylatlon product (nonpolar solvent, heating), which rearranges
to a cytosine derivative. Convenient methods have been developed for the prepar-
ation of 6-methyl-l,3-diphenyl-5,6-dihydro-5-oxopyrimido[4,3-c]triazolium chlor-
ide, a fluorescent derivative of l-methyluracil, from the N-acylation product,
and for the rapid base cleavage of the uracil ring under very mild conditions.

The search for new reactions of uracils suitable for the chemical modification of the
uracil ring under mild conditions is of great importance and potential for the modification
of nucleotldes and RNA. In contrast to the well-known alkylation of uracils, acylation has
been investigated only in isolated instances [1, 2]. The most suitable model compound for
such studies is l-methyluracil.
The aim of this investigation was to examine the reactions of l-methyluracil (1) with
phenylbenzyhydrazonoyl chloride (II) in the presence of bases. We have found that (II)
functions as an acylating agent, and depending on the reaction conditions, gives with (I) the
N-acylation products l-methyl-3-(N(z)-phenylbenzhydrazonoyl)uracil (III) and l-methyl-4-
(N(1)-benzoyl-N-phenylhydrazino)-iH-pyrimidin-2-one (IV), which is apparently formed by rear-
rangement of an O-acylated product of the uracil (I), which we have been unable to isolate.
O NNHPh

O
~L
.... Cl|~ IH
N~N~0 + phC=NNHPhcII
l3
CH n
1

CH3 -J 7CH3
IV

N. D. Zelinskii Institute of Organic Chemistry, Moscow. Translated from Khimiya Geterotsik-

lichesklkh Soedinenii, No. 5, pp. 649-655, May, 1986. Original article submitted July 25, 1985.

532 0009-3122/86/2205- 0532 $12.50 9 1986 Plenum Publishing Corporation

 TABLE i. PMR Spectra of the Compounds Obtained (6, ppm; J,
Hz)

Compound* ~-.. d ~)-u. d Clh, S NH, $ At, rn

I 5.74 7.74 3,45 9,0

Ill 5,79 7,82 3,35 10,0 6,88--7,6
IV 5 q') 7,81 3,30 11,54 7,22--7,98
V~t 7:i35 8,4(i 3,9 7,18--8,18
5,27 7,14 3,25 7,4--8,2

*Compounds (I), (llI), and (IV) recorded in DMSO-D6, (VII)

in D20/CD~O, and (X) in (CDa)=CO.
%Signals for the OEt group: 1.27 (3H, t); 4.2 ppm (2H, q).

When the sodium salt of (I) reacts with the chloride (II) in aqueous ethanol, (III) is
the main product (70% yield), together with -9% of (IV).
The IR spectrum of (III) is typical of 1,3-disubstituted uracils [3], showing absorption
at 1720 (C2=O), 1680 (C~=O), and 3355 cm -I (NH), the latter becoming more intense as the solu-
tion is diluted. The PMR spectrum of (III) contains signals for the 5-H and 6-H protons (AB
system, characteristic of the pyrimidine ring [4]), and in the ~aC NMR spectrum the signals
for C(5) and C(~) are clearly apparent (Tables 1 and 2) [5]. Comparison of the spectral re-
gion 140-165 ppm for (I) and (III) enables the singlet signals to be assigned to C(=), C(~),
and C(8). The molecular ion peak in the mass spectrum of (III) (m/z 320) corresponds to the
empirical formula of the structure given. The IR spectrum of (IV) is similar to those of cy-
tosine derivatives [3], with absorption at 1740 (C(2)= 0), 1642 (hydrazide C=O), and 3225 cm -~
(NH). The UV spectrum of (IV) in ethanol (%max 289 nm) is similar to that of N(~)-phenylcyto-
sine (Emax 293 nm [6]). The mass spectrum of (IV) contains the molecular ion peak (m/z 320)
together with peaks with m/z 201 and 119 corresponding to fission of the N--N bond, which is
typical of diaryl benzohydrazides [7]. The ion with m/z 201 corresponds in its mass to l-
methyl-N(~)-phenylcytosine, and the spectrum also contains a peak for the corresponding doubly-
charged ion with m/z 100.5. This peak is present also in the spectrum of l-methyl-N(~)-
phenylcytosine, specially synthesized by us by the method given in [6]. From the PMR and ~aC
N~R spectra (Tables i and 2), it may be concluded that the molecule contains the C(5)H=C(~)H -
grouping, three carbon atoms doubly bonded to the heteroatoms (C(=), C(~), and C(8)), aro-
matic rings, and the N-CH3 group.
The formation of two reaction products (III) and (IV) when l-methyluracil reacts with
phenylbenzhydrazonoyl chloride prompted us to examine the reaction conditions favoring the
formation of one or other of these products (Table 3).
When the sodium salt of (I) is reacted with (II) in DMF, the main product is (III). Sim-
ilar behavior is observed when the reaction is carried out in aqueous alcoholic sodium hy-
droxide. However, when triethylamine is used as the base the proportion of (IV) in the reac-
tion products increases, although the extent of reaction of the starting material (I) i s
small. On prolonged boiling in dry benzene, however, high yields of the pyrimidine (IV) were
obtained, no N-acylated product being obtained under these conditions.
It is assumed that (III) is formed by electrophilic attack of the chloride (II) on the
nitrogen atom of the ambident anion of l-methyluracil, and the formation of (IV) results from
rearrangement of the intermediate O-acylation product of the ambident anion. Similar O-acyl-
ation is well known in the reaction of (II) with phenols in the presence of triethylamine
[7-11]. The initially formed hydrazonate (V) then rearranges to N'N'-diphenylbenzohydrazide
(vl) :
+ PhOH --~ PhOC(Ph)=NNHPh ---~ PhCONHNPh 2
V

It is noteworthy that 1,3-dimethyluracil is recovered totally unchanged following heat-

ing for many hours with (II) in dry benzene with triethylamine, although it might be expected
that the 1,3-dipole formed under these conditions would undergo cycloaddition to the C(5)=C(6)
double bond in the uracil. The structures of (III) and (IV) were also confirmed by their
chemical reactions.

533
 TABLE 2. X=C NMR $ ,ectra of Corn ,ounds Obtained, ppm
Corn- [
pound c~=~,s ~m, A~

I 151,4 154,0 too,~ 146,6 35,2 -- u

Ill 149,7 161,7 [00,3 146.5 36,0 144,5 133,9; 128,9; 128,5; 127,75; 1242;
J19,8; ll&O
IV 155,5 164,5 91,2 148,7 37,0 165,3 142,1; 132,3; 1313; 1282; 128,6;
127,7; 125,3; 125,9
VII 151,O 148,8 90.4 149,5 39,5 144,6 134,85; 133,6; 132,5; 131,8; 129,55;
125,4; 123,95
X t 161,9 151,7 96,9 135,9 35,9 155,2 138,8; 132,2; 130,2; 130,05; 129,4;
127,1; 125,4
~The s o l v e n t s used were the same as for the PMR spectra.
t S i g n a l s f o r the OEt group: 63.2 (t); 14.7 ppm (q).

'~ 0 NNHPh

.i il. .I'h

.% I1 .~o. [I ~.1 + ,,,,

CH~
'<<c,.o
Ur X

On heating (III) with dilute hydrochloric acid in ethanol, it is converted almost quan-
titatively into crystalline 6-methyl-l,3-diphenyl-5,6-dihydro-5-oxopyrimido[4,3-c]triazolium
chloride (VII). The (VII) cation on paper electrophoresis moves to the cathode, has a UV
spectrum with characteristic long-wave absorption maxima (314 and 268 nm), has a deep blue
fluorescence (excitation Xmax 320 nm, emission kfmax 414 nm, relative quantum fluorescence
yield ~30%), and is similar in its properties to phenylimldazo[1,2-c]pyrimldines [12]. The
IR spectrum differs markedly at 1680-1800 cm'* from that of 1,3-disubstituted uracils, 5 u t
is similar to that of N(s)O(4~-ethylene-l-methyluracilium sulfonate [4]: there is no ab-
sorpr cm corresponding to C(~)_0, all the proton signals are shifted
to lower field in comparison with the origlnal (III), as would also be expected
for a heteronuclear cation (see [4]). The.*SC NMR spectrum (Table 2) is similar t o those
pyrimidines.
Unlike (III), (IV) is stable towards mild acid hydrolysis (2 N HC1, i h, 80~ and only
under more severe conditions (2 N HCl, 24 h 100~ does it decompose to (I), benzoic acid, and a
phenylhydrazine, identified as 1,3,5-triphenylpyrazoline following reaction with benzalaceto-
phenone.
Like 1,3-disubstituted uracils [13-15], on treatment with aqueous alkali (III) undergoes
extremely facile cleavage of the pyrimidine nucleus with the formation of a single product,
1,3-diphenyl(4H)-l,2,4-triazol-5-one (VIII), an authentic sample of which was obtained by
direct synthesis [16].
The mass spectrum of the triazoline (VIII) contains the molecular ion peak with m/z 237,
the principal breakdown route being cleavage of a molecule of HNCO to give an ion with m/z
194, this reaction being accompanied by a metastable transition with m*/z 159. Partial for-
matlon of the triazoline (VIII) from the uracil (III) takes place on drying in an oil-pump
vacuum at 60~ The triazoline (VIII) is also formed under the conditions of recording of
the mass spectrum, the ion with m/z 194 being the most intense peak in the spectrum, and a
metastable ion is also present corresponding to the transition m/z 237 194.
On heating the uracil (III) with ethanol in the presence of triethylamlne, in addition
to (VIII) (33%) there was also isolated (X) (52%). It would appear that intramolecular nucleo-
philic attack of the hydrazine nitrogen on C(~) of the uracil nucleus leads to the formation
of the intermediate (IX), which adds ethanol at the C(z)--N(s) bond of the pyrimidine ring to

534
 TABLE 3. Formation of Products of the Reaction of the Uracil
(I) with Chloride (II) (as % of (I))
Com- I ETO.. DMF. Nail, 20"C, Et O H + HzO,
EIaN, 20 ~
Benzene,EtzN.
boiledfor80 h
pound 1 N NaOH, 1 -1.Sh
I.~ h 40 tt

I I
III 16,0
70,0
17,7
65,7
66,4
28,1
12,5
IV 8,8 4,5 10,6 78,6

give (X). This compound was also formed in 79% yield on treatment of the salt (VII) with an
equimolar amount of alkali in aqueous alcohol, in addition to 5% of the starting material
(III). The hydroxyl ion attacks the (VII) cation at C(4) of the pyrimidine nucleus [4] to
give the same intermediate (IX), which adds a molecule of ethanol, or recyclizes to the
starting material (III).
The IR spectrum of (X) shows strong absorption at 1642 cm -: (characteristic of enamine
C==C [17]) and 1700 cm -I (ester carbonyl), but no absorption is seen in the NH or OH regions.
The PMR spectrum (Table I) shows signals for the NCH3 and EtO protons, aromatic protons, and
an AB system for the protons of the--CH=CH--N--fragment. The chemical shifts of the latter
(7.14 and 5.27 ppm, respectively) are similar to those of enamine protons [18-20], and the
coupling constant corresponds to the trans-configuration of the double bond, and hence in-
dicates opening of the pyrimidine ring. The ~3C NMR spectrum (Table 2) also corresponds to
structure (X). The most intense ion in the mass spectrum has m/z 91, typical of N-phenyl
compounds, the molecular ion (m/z 348, being98% of the maximum. The main course of break-
down is cleavage of the ethoxycarbonyl group, accompanied by the metastable transition m*/z
217 (calculated, 217.3) and loss of the ethoxy-group [21-23]. Cleavage of the heterocyclic
substituent from the molecular ion or from the fragment ion with m/z 276 gives an ion with
m/z 221, the mass of which is equal to the molecular mass of 3,5-diphenyltriazole, which then
loses the PhC=NNPh fragment with m/z 194. The UV spectrum of (X) is similar to those of 2-
substituted-3,5-diphenyl-l,2,4-triazoles [24]. This compound (X) remains unchanged on heat-
ing for i0 h in a mixture of ethanol and triethylamine (i.e., conditions used for its prepar-
ation from the uracil (III)), and gives ~o traces of the triazolone (VIII) (according to TLC),
and is therefore in all probability not an intermediate in the foramtion of the triazolone
(VIII) from the uracil (III), but rather a product of a parallel reaction.
The reactions described here enable uracil derivatives to be converted readily into com-
pounds which fluoresce strongly, and on the other hand it is possible to cleave the hetero-
cyclic nucleus rapidly under very mild conditions. Extension of these reactions to nucleo-
sides and their derivatives would appear to be quite feasible, and they are therefore of con-
siderable interest for the chemical modification of components of nucleic acids.

EXPERIMENTAL
IR spectra were obtained on UR-20 and Specord IR-75 instruments, UV spectra on a Specord
UV-vis, PMR spectra on a Bruker WM-250 or a Tesla BS-467, I~C NMR spectra on a Bruker WM-250
with selective proton decoupling,*mass spectra on a Varian CH-6, and the fluorescence spee-
trum~on an ELyumin 2M, solution concentration 2.5.10 -~ mole/liter (relative to fluorescein).
Electrophoresis was carried out in an 0.025 M pyridine acetate buffer at pH 4.5; 28 V/cm, 60
min. TLC was carried out on Merck F25~ plates, layer thickness 0.2 mm, in the systems:
ethyl acetate--acetone-water, 7:4:1 (A), benzene--ethyl acetate, 2:1 (B), and chloroform--
methanol--water, 60:25:4 (C), the compounds being visualized under UV and with iodine vapor.
Column chromatography was carried out on Silperl silica gel, 25-40 ~, the material to be
chromatographed being applied together with the adsorbent, l-Methyluracil (I) was obtained
as described in [25], mp 242~ (from absolute ethanol). Phenylbenzhydrazonyl chloride (II)
was obtained in 80% yield as described in [26], excess PC15 being destroyed with phenol fol-
lowed by methanol, the reaction mixture being cooled with dry ice in acetone, mp 127-128~
(from acetone-water). 1,3-Diphenyl(4H)-l,2,4-triazol-5-one (VIII) was obtained by fusing N'-
benzoyl-N-phenylhydrazine with urea at 200-210~ followed by column chromatography, yield 23%,
mp 229-230~ (from ethanol) [16], and 1,3,5-triphenylpyrazoline as described in [27], yield
98%, Rf 0.9 (benzene--heptane, 5:1).
*The authors are deeply indebted to M. I. Struchkova and A. S. Pashkov for the ~3C NMR spectra.

535
 l-Methyl-3-(phenylbenzhydrazonoyl)uracil (III) and 4-(N'-Benzoyl-N-phenTlhydrazino-l-
methTl-lH-pyrimidin-2-one (IV). A._. To a suspension of 63 mg of the uracil (1) (0.5 mmole)
in 2 ml of ethanol was added 0.5 ml of i N NaOH. To the homogeneous solution was added im-
mediately with stirring at room temperature a solution of 132 m E of the hydrazonoyl chloride
(II) (0.6 mmole) in 6 ml of ethanol, the mixture stirred for 1.5 h at 20~ and evaporated to
dryness. The residue was dissolved in the minimum amount of ethanol, and separated prepara-
tively on silica gel plates (layer thickness 2 mm, system A). The bands which absorbed UV
were eluted with ethanol, evaporated, and dried ~n uaouo for 48 h at 20~ to give 112.7 mg
(70%) of (III), Rf 0.58 (system A), dec. 100~ pale yellow film, purified by boiling with
activated charcoal in ethanol. IR spectrum (chloroform): 1600 (C=C), 1680 (C(~)=O), 1720
(C(2)=O), 3355 cm-* (NH). I[V spectrum (ethanol), lmax, nm (log s 340 (4.39), 282 (4.13),
240 (4.29). M a s s spectrum*, m/z (I, %): 320 (97), 276 (3.5), 237 (15), 194 (I00), 167 (22),
126 (6), 105 (32), 104 (31), 103 (18), 91 (91), 84 (32), 77 (72). Found: C 67.0; H 5.0;
N 17.8%. C,,H,~NdO2. Calculated: C 67.5; H 5.0; N 17.5%. There was obtained 14.1 mg (8.8%)
of (IV), Rf 0.3 (system A), purified by boiling with activated charcoal in ethanol, followed
by removal of the solvent and drying ~n u~duo to give an analytically pure sample as a film,
mp 214.5-215.5~ IR spectrum (KBr): 1740 (C(2)=O), 1642 (C=C), 3225 cm -I (NH). UV spectrum
(ethanol), lmmx, nm (log ~): 289 (4.0); pH 10 252 (4.06), 320 (4.01); pH 2 294 (3.94). Mass
spectrum, m/z (I, %): 320 (12), 277 (27), 276 (28), 227 (15), 201 (12), 200 (18), 194 (100),
172 (7), 167 (9), 157 (8), 105 (54), 104 (22), 91 (80), 77 (56). Found: C 67.3; H 5.2; N
17.4%. C~,H,,NdO~. Calculated: C 6 7 . 5 ; H 5.0; N 17.5%. Also obtained was I0 mg (10%) of
the original l-methyluracil.
B_=. The uracil (I) and the chloride (II) were first dried over P205 ~n uacuo for 48 h at
20~ To a solution of 252 mg of ( I ) , A 2 moles in 10-12 ml of dry DMF was added with stirring
70 mg of NaH (2.5 n~uoles, 80% suspension in mineral oil), the mixture stirred for 0.5 h at
20~ until evolution of hydrogen ceased, and to the resulting suspension was added all at
once with vigorous stirring a solution of 520 mg of (If) (2.2 mmoles) in i0 ml of DMFA. The
mixture darkened immediately, and was stirred for 1-1.5 h at 20~ the solvent removed under
reduced pressure to dryness, and the residue subjected to column chromatography. Elution was
carried out with benzene, benzene ethyl acetate (I:i), ethyl acetate, and system A to give
420 mg (65.7%) of the uracil (III), Rf 0.58, 70 mg (27.7%) of the uracil (I), Rf 0.4, and 31
mg (4.5%) of the pyrimidine (IV), Rf 0.3 (system A).
C__z. To a mixture of 194 mg (1.5 mmoles) of (I) and 711 mg (3 mmoles) of (II) previously
dried in an oil-pump vacuum over P20s (48 h, 20~ were added 80 ml of benzene and 5 ml of
EtsN. The mixture was boiled under reflux for 20-30 h, the solvent removed, and the residue
chromatographed on a column, eluting successively with benzene, benzene-ethyl acetate (i:i),
and system A to give 377.4 mg (78.6%) of (IV), Rf 0.3, and 24.5 mg (12.5%) of (I), Rf 0.4
(system A).
6-Methyl-l,3-diphenyl-5,6-dihydro-5-oxopyrimido[4,3-c]triazolium Chloride (VII). To a
solution of 280 mg (0.87 mmole) of~(lll) in i0 ml of ethanol was added 1.5 ml of 2 N HCI, and
the solution boiled under reflux on the water bath for 1 h. The solvent was then removed,
and the residue dried by evaporating with 3 x 5 ml of ethanol, finally in an oil-pump vacuum.
It was then dissolved in 15 ml of ethanol, and dry ether added until no more solid separated,
to give 294 mg (100%) of (VII), colorless crystals. A second reprecipitation gave 223 mg
(76%) of analytically pure material, Rf 0.33 (system C), mp 163 and 204-205~ IR spectrum
(KBr): 1750 (C(2)=0), 1620 (C=C), 1595 cm -I (C=N). UV spectrum (ethanol), Imax, nm (log e):
314 (4.07), 268 (4.12); fluorescence spectrum: excitation, Imax 320 nm, ~ fmax 414 nm, quan-
tum yield 30% (relative to fluorescein. Found: C 62.0; H 5.4; C1 9.8; N 14.9%. C,sH,bCIN~O.
C~sHbOH. Calculated: C 62.4; H 5.6; CI 9.2; N 14.6%.
Acid Hydrolysis of (IV). A mixture of 80 mg (0.25 mmole) of (IV), 2 ml of 2 N HCI, 1 ml
of ethanol, and 78 mg (0.37 mmole) of benzalacetophenone was heated in a sealed ampu for 24
h at 100~ then cooled, evaporated to dryness under reduced pressure, i ml of glacial acetic
acid added, and the mixture boiled under reflux for 1 h. The acetic acid was then distilled
off, and the residue chromatographed on a column. Elution with benzene-hexane (i0:i, then 5:1)
followed by benzene, benzene-eth-1 acetate (i:i), and system A gave 24.4 mg (30%) of starting
material (IV) [Rf 0.3 (system A)], ii.7 mg (54%) of (I) [Rf 0.4 (system A), mp 2420C], 13.3 mg
*Here and subsequently, I is given as a percentage of the strongest peak.
%Glassware was dried at 1700C and cooled in a desiccator over P205. Failure to observe
strictly anhydrous conditions reduces the yield of (IV) to 33-35%.

536
(63%) of benzoic acid [Rf 0.5 (benzene-ethyl acetate, i:i), mp 122~ and 8 mg (16%) of i,
3,5-triphenylpyrazoline [Rf 0.9 (benzene--heptane, 5:1)]. Mass spectrum, m/z (I, %): 1,3,5-
triphenylpyrazoline: 298 (i00), 296 (64), 221 (3), 194 (6), 149 (i0), 105 (i0), 91 (36), 77
(22); uracil (I): 126 (i00), 83 (76), 55 (63); benzoic acid: 122 (61), 105 (i00), 77 (78),
44 (68).
1,3-Diphenyl(4H)-l,2,4-triazol-5-one (VIII). To a solution of 80 mg (0.25 mmole) of (III)
in 2.25 ml of ethanol was added 0.5 ml (0.5 mmole) of i N NaOH, the mixture stirred for 0.5
h at 20~ 0.25 ml of 2 N HCI. added, and the solid filtered off, washed with water, dried,
and crystallized from ethanol to give 44.1 mg (74.5%) of the triazolone (VIII), mp 240~
spectrum, m/z (I, %): 237 (90), 118.5 (8), 105 (8), 103 (64), 91 (I00), 77 (72). This com-
pound (VIII) gave no depression of melting point with an authentic sample, and their IR spec-
tra were identical.
5-[2-(N-Methyl-N-ethoxycarbonylamino)vinyl]-l,3-diphenyl-l,2,4-triazole (X). A. To 300
mg (0.9 mmole) of (III) was added 20 ml of a mixture of Et3N and ethanol (i:i), and the mix-
ture boiled under reflux for 60 h, until the starting material (III) was no longer present
(TLC), and it was then evaporated, chromatographed on a column, and eluted with benzene-ethyl
acetate (continuous gradient) to give 70 mg (32.8%) of the triazolone (VIII),Rf 0.33 (system
B) and 162 mg (51.7%) of the triazole (X) (system B), colorless liquid, readily miscible with
organic solvents. IR spectrum (CC14): 1700 (C=O), 1642 (C=C), 1600 cm -I (C=N). UV spectrum
ethanol), %max: 257 nm. Mass spectrum, m/z (I, %): 348 (98), 303 (3), 275 (48), 221 (25),
194 (17), 91 (!00), 77 (13).
B. To a solution of 202 mg (0.6 mmole) of (VII) in 2 ml of water and 1 ml of ethanol
was added 0.6 ml of 1 N NaOH at 20~ After i0 min, the mixture was evaporated, 3 ml of water
added, and extracted with benzene (3 5 ml). The benzene extracts were combined, washed with
water (3 ml), evaporated, and dried in an oil-pump vacuum at 20~ to give 165.9 mg (79.4%) of
(X), Rf 0.6 (system B), identical with the material obtained in the previous perparation in
respect of its IR and mass spectra.

LITERATURE CITED
R. J. De Pasquale, Int. Eng. Chem., Prod. Res, Devel., 17, 278 (1978).
K. A. Cruickshank, J. Jiricny, and C. B. Reese, Tetrahedron Lett., No. 25, 681 (1984).
C. L. Angell, J. Chem. Soc., No. 2, 504 (1961).
D. Lipkin and E. G. Lovett, J. Org. Chem., 40, 1713 (1975).
G. W. H. Cheesman, C. J. Turner, and D. Brown, J, Org. Magn. Reson., 12, 212 (1979).
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8. A. J. Elliott, P. D. Callaghan, M. S. Gibson, and S. T. Nemeth, Canad. J. Chem., 53, 1484
(1975).
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No. 13, 689 (1971).
i0. A. F. Heagarty, J. A. Kearney, and F. L. Scott, J. Chem. Soc., Perkin 2, No. i0, 1422
(1973).
ii. A. F. Heagarty, J. A. Kearney, and F. L. Scott, Tetrahedron Lett., No. 31, 3211 (1972).
12. A. P. Rozjivin, A. A. Kost, and V. N. Shibaev, Studia Biophysica, 51, 291 (1975).
13. H. C. Van der Plas, Ring Transformation of Heterocycles, Vol. 2, Academic Press, London
(1973), p. 116.
14. E. G. Lovett and D. Lipkin, J. Org. Chem., 42, 2574 (1977).
15. E. G. Lovett and D. Lipkin, J. Org. Chem., _~, 1722 (1975).
16. T. Kametany, K. Sota, and M. Shio, J. Her. Chem., ~ 8 2 1 (1970).
17. P. W. Hicmott, Tetrahedron, 38, 3363 (1982).
i8. J. L. Ripoll, H. Lebrum, and A. Thuiller, Tetrahedron, 36, 2497 (1980).
!9. H. Ahlbrecht and W. Raab, Synthesis, No. 4, 320 (1983).
20. R. Knorr, P. Loew, and P. Hassel, Synthesis, No. I0, 785 (1983).
21. R. Stradi, P. Trimarco, and A. Vigevani, J. Chem. Soc., Perkin 2, No. i, i (1978).
22. M. Ahmed and P. W. Hickmott, J. Chem. Soc., Perkin 2, No. 6, 838 (1977).
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Soc., B, No. I0, 940 (1966).
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537
25. W. Szer and D. Shugar, in: Synthetic Procedures in Nucleic Acid Chemistry, Vol. i,
Interscl. Publ. (1968), p p . 61, ii0,
26. I. N. Zhmurova and V. G. Yurchenko, Zh, Obshch. Khim., 47, i010 (1977).
27. L. C. Raiford and R. H. Manley, J. Org. Chem., ~, 590 (1940).

REACTION OF DIAROYLETHYLENES WITH Ortho-PHENYLENEDIAMINE

AND ITS DERIVATIVES

V. D. Orlov, B. Insuasti, and S. M. Desenko UDC 547.553:1'572.6'

863.19.07:543.422

Derivatives of 1,2-dihydroquinoxaline were synthesized. The direction of the

reaction of unsymmetrical diaroylethylenes with o-phenylenediamine was shown by
chemical and spectral methods and the reaction mechanism was discussed,

A number of studies have been devoted to the reaction of o-phenylenediamine (PDA) with
dibenzoylethylene (DBE) [1-5] but only Bass et el. [5] convincingly demonstrated that the pro-
ducts formed upon heating PDA and DEE at reflux in glacial acetic acid are 1-(2-aminophenyl)-
2,5-dlphenylpyrrole, 2-phenylquinoxaline, and 2-phenacylidene-3-phenyl-l,2-dihydroqulnoxaline.
Brindra and LeGoff [2] and Trattner et al, [33 4] carried out the reaction under milder con-
ditions (in ethanol) and obtained only 2-phenylquinoxaline, while Bass et al. [5] subsequently
managed to isolate the intermediate of this synthesis, which was found to be 2-phenacyl-3-
phenyl-l,2-dihydroquinoxaline.
In the present communication, we studied the controlled formation of 1,2-dihydroquinoxa-
line in the reactions of derivatives of PDA and DEE.
Symmetrically substituted DBE (R2 = R s) and PDA even upon heating at reflux for I0 min in
methanol form the desired products I, III, Vl, VIII, and XI in good yields (Table i). Under
these conditions, the other diketones form dihydroquinoxalines only in trace amounts since
the secondary elimination of the acetophenone fragment leads to 2-arylquinoxalines as the
major reaction products. An exception was found for VII, which was obtained in 45% yield.
The same results are obtained when the reaction is carried out at room temperature. On the
other hand, stirring of benzene solutions of the starting compounds at 40-50~ for 3-4 h gave
dihydroquinoxalines I-XV in good yields, although the formation of small amounts of 2-
arylquinoxalines occurs under these conditions. This secondary reaction is especially pro-
nounced in the synthesis of IV and X.
M
R . ~ . ~ / . ~ . N...~. CH~C0 C6H4R2-4

R ' ~ NH2NH
+24R
-2CsH4COCH=CHCOC6H4R34
-
RI
I-X%'
I--XI R=H; XII--XV R=C1; I--XlII R~=H; XIu R~=CI; I R2=Ra=H 9 II R2=H,
R3=CH~; III R2=R3~CH~; IV R~=CI, RS=H; V R2=CI, R3=CH3; VI R~=R3=CI; Vll
R2=Br, R3=H; VIII R==R~=Br; IX R2=Br, R~=CHs; X R2=NO2, R3=H; XI R2=R ~=
=NO2; XII, XIV R2=R3=H~ XIII, XV R2=,R~=CH3

The formation of I-XV was shown by IR, UV, PMR, and mass spectroscopy and supported by the
nitrogen content determined. The purity of these compounds was also indicated by thin-layer
chromatography (see Tables 1-4). We should note that the formation of two isomeric structures
is possible in the reactions of unsymmetrical diaroylethylenes (R2 # R s) with PDA. Isomers
may also be obtained in the synthesis of XII-XV. Thus, an important problem was resolution of
the question of the direction of the synthesis of II, IV, V, VII, IX, X, and XII-XV.
A. M. Gor'kii Kharkov State University, Kharkov. Translated from Khimiya Geterotsikli-
cheskikhSoedinenii, No. 5 pp. 656-661, May, 1986. Original article submitted January 28,
revision submitted May 12, 1985.

538 0009-3122/86/2205-0538512.50 O 1986 Plenum Publishing Corporation

 TABLE i. Characteristics of I-XV
CaD I
:om- IR spectrum (KBr),cm-* Found Chemical CU = Yield,
rap, ~ !lated
ound N,~ formula %
u ~C=O ~NtI N, %

I 124 1607 1668, 3365 C~H~sN~O 61

1678
II 135 1607 1679 3305 C~HmN~O 51
III 136 1605 1663, 3370 C~FI~N~O 55
1654
IV 119 1605 1680 3364 C~HIrC1N20 50
V 130 I608 I655 3356 C23HIoC1N20 68
VI 122--123 1606 1656 3358 C2aHI6C12N20 75
VI1 I31 1607 1680 3389 C29HITBrN~O 60
VIII 134 1605 1652 3349 C~HI6Br~N~O 81
IX 137 1608 1657 3361 C~aH~gBrN~O 74
X 92--95 1608 1690 3383 C22HIzN~O3 69
(decomp.,
Xl 156 1604 1686 3339 C2~Hi6N4Os 74
XII 116--117 1598 1650, 3349 C22HIzCIN20 58
1658
XIII 143 1602 1654 3335 C24H2jCIN20 52
XIV 132--133 1598 1672 3377 C2sH~6CI2N20 51
XV 144 1602 1676, 3343 C24H~oCI2N20 5O
1658

*For I, III, VI, VIII and IX, the yield of the product ob-
tained according to method A is given while the yields of
the other compounds obtained by method B are indicated.

The IR spectra of I-XV clearly show bands for the N--H (3305-3379 cm-l), C----N(1598-1607 em-~),
and C=O bonds (1650-1690 cm-l). The slight sensitivity of these bands toward the electronic
effects of substituents R-R 3 hinders the use of the IR spectra for the identification of iso-
mers. Furthermore, the NH band in the IR spectra of I measured in CCI~ in the concentration
range from 10 -4 to 10 -2 mole/liter appears as a narrow peak with ~NH 3422 cm -I (Avl/2 = 27 cm -I)
independently of the concentration, which indicates the absence of hydrogen bonding between the
NH and C==O groups. The electronic absorption spectra of I-XV (Table 2) are a function of ~he
NC~H,N==C6H,R a chromophore group. A quantum mechanical analysis of this group was given in our
previous work [6]. A feature of these spectra is the marked bathochromic shift upon introduc-
tion of electron-withdrawing R s groups, which permits us to resolve the question of the direc-
tion of the formation of IV, VII, IX, and X by the comparison of their spectra with those of di-
hydroquinoxalines I, III, VI, VIII and IX, in which the structure is unequivocally determined
since R 2 = R s. In all cases, the carbonyl group of the aroyl fragment containing the stronger
electron-withdrawing substituent participates in the condensation with the amino group, i.e.D
the donor properties of R s are always greater than for R 2 in the dihydroquinoxalines obtained.
This conclusion was confirmed by analyzing the mass spectra of I-III and VII (Table 3).
In all cases, greatest intensity is found for the 2-(4-Ra-phenyl)quinoxaline radical-ion peak,
while the relative intensity of the molecular ion (M+) peak is less than 5% and decreases with
increasing sample inlet temperature.

N +
H 4" -4-R2 CeH4COCH~.
,.~. ~ . /j-~
"~' N C~HcR -4 ~ . - "'..N-f" Ct H4R3 ,4

Such fragmentation for II and VII permits the unequivocal identification of the position
of the fragments containing the R 2 and R s substituents in the dihydroquinoxaline bicyclic sys-
tem.
The elimination of acetophenones with the formation of 2-arylquinoxalines is also ob-
served upon heating methanolic solutions of I-XV with added mineral acids. This process (in
addition to oxidation to 2-phenacylidene-3-phenyl-l,2-dihydroquinoxalines [5]) also occurs
upon the storage of these extremely unstable compounds. Upon identifying the 4-R2-acetophenones
by their dinitrophenylhydrazones (DNPH) and the 2-arylquinoxalines by the comparison of their
properties with those of compounds obtained by convergent syntehsis from arylgloyoxals and PDA,
support was found for the conclusion concerning the structure of the dihydroquinoxalines with
R 2 ~ R s made on the basis of their UV and mass spectra.

539
 TABLE 2. Absorption and Luminescence Spectra of l-XV
lrnax' for absorption,nm (z. lO'S~ Areax for luminescence, nm
Compound
in methanol* in toluene [ in methanol in toluene

I 395 395 (5,96) 571 (7800) 516 (5940)

II 391 392 (6,44) 584 (8450) 499 (5470)
Ill 391 392 (6,87) 560 (7720) 520 (6280)
IV 392 395 (4,22) 560 (7650) 525 (6270)
V 397 397 (3,99) 555 (7170) 533 (6430)
VI 402 403 (5,00) 590 (7928) 535 (6122)
VII 394 396 (5,85) 575 (7990) 510 (5650)
VIII 403 403 (4,76) 593 (7950) 524 (5730)
IX 393 397 (6,97) 584 (8320) 535 (6500)
X 390 390 (9,02)
XI 446 443 (6,34)
Xll 400 397 (6,72) 584 (7880) 510 (5580)
XIII 392 390 (9,02) 553 (7430) 490 (5230)
XI)V 397 397 (7,19) 558 (7270) 518 (5880)
XV 397 397 (7,49) 545 (6840) 518 (5880)

*The determination of the molar extinction coefficients for

I-XV in methanol is complicated by the instability of these
compounds.

TABLE 3. Mass Spectra of I-III and VII

Corn- m/z value'(intensityof the ton peaksas %
pound of the maximum)

I 326 (1,2), 207 (22), 206 (I00), 205 (8), 180 (8), 179 (61), 178 (15), 152 (7),
105 (27), 104 (lO), 103 (25), I02 (8), 77 (36), 76 (55), 75 (15), 74 (6)
II 340 (1,4), 222 (13), 221 (87), 220 (I00), 219 (36), 207 (8), 205 (16), 194
(16), 193 (7), 192 (46), 179 (12), 178 (ll), 165 (24), 120 (54), I19 (19),
I16 (27), llO (32), I06 (12), lOS (99), I03 (19), I02 (13), 91 (44), 90 (22),
89 (27), 78 (39), 77 (98), 76 (72), 75 (23), 74 (17)
Ill 354 {1,8), 222 {15), 221 (76), 220 (lO0), 219 (54), 218 (6), 205 (21), 194
(25), 193 (82), 192 (87), 191 (13), 166 (lO), 165 (37), 135 (8), 134 (82), 120
(35), I19 (89), I18 (25), I16 (59), llO (12), I05 (13), I03 (35), I02 (24), 92
(50), 91 (97), 90 (70), 89 (89), 78 (16), 77 (68), 75 (44), 74 (23)
VII 208 (7), 207 (48), 206 (lO0), 205 (7), 2O0 (14), 198 (15), 185 (64), 183 (66),
180 (12), 179 (73), 178 (18), 157 (31), 153 (33), 152 (9), 151 (7), 149 (9),
I04 (14), 103 (29), I02 (ll), 89 (7), 78 (5), 77 (31), 76 (84), 75 (37)

*The M+ peaks and ion peaks with intensity greater than 5%

are given.

However, these methods do not answer the question of the direction of the reaction involv-
ing 4-chloro- and 3,5-dichloro PDA derivatives (XII-XV). A similar problem was encountered in
the chemistry of dihydrodiazepines and solved by a PMR spectral method [7]. The PMR spectra of
III, VIII and XII-XV in CDCIa (Table 4) display a septet and quartet for the CH2--CH group pro-
tons and a broad imine proton singlet. The signals of the 8-}{ proton are readily identified
in the aromatic proton region since they are shifted upfield by the effect of the electron-
donor ortho amino group and are not overlapped by the signals of the other aromatic protons.
The signals of this proton in the case of dihydroquinoxalines III and VIII (R = R* = H) are a
quartet with J = 8 Hz (ortho) and J = 2 Hz (meta). On the other hand, the 8-H signals for XII-
XV form a doublet with J = 2 Hz, which unequivocally indicates the presence of the chlorine
atom at C(7). Such a structure for XII-XV indicates that, of the possible isomers, that, in
which the less basic amino group adds at the double bond, is formed in the reactions of sub-
stituted o-phenylenediamines with diaroylethylenes.
The formation of heterocycles in the reactions of 1,2-diamines with a,8-unsaturated ke-
tones may be achieved by two pathways differing in the sequence of addition and condensation
[4, 8]. In the synthesis of I-XV, this can be illustrated by the following scheme:

540
 TABLE 4. PMR Spectra of III, VIII, and Xll-XV
6, ppm
Corn- I CH~*
pound CH, q HA, q ~I~), q NH, $ 8-I'I

ill 5,4t 3,58 2,83 4,78 6,54 (q, lortho : 8.Hz, Jmeta = 2 Hz)
VIII 5,35 3,53 2,76 4,75 6,51 (q, ]-o~tho = 8 Hz, Jmeta = 2 Hz)
Xl[ 5,46 3,56 2,9 I 4,93 6,50 ('d;, I = 2 Hz)
XIII 5,38 3,5 I 2,88 4,91 6,52 (d, I = 2 Hz)
X t~V 5,48 3,5(; 2,93 ,5,07 6,48 (d,l = 2 H z ~
XV 5,.13 3,18 2,88 5,1}3 6,44 (d,J=2Hz)

*The protons of the CHs-CH group form an ABX system with the
following coupling constants: JAB = 9, JAX = 5 and JBX =
1.5 Hz (for III, VIII and XII-XV).

F .. NH~ -- c'~ N /Cell4R~-~

s NH2 ~
ad I 'N" "CH2COC~H#R2-4~
"~ -NH z A _1 H

4 "'R3C6H4 b-- . N|I 2 ~ I'~ CH2COCsH4R3-4

C6114R~-4
L "'~" "N=:C- C~H4R'--4 ~ 4

The experimental data on the reactions involving unsymmetrical diarovlethvlenes indicate

that the addition of the diamine proceeds at the carbon atom of the diketone in the B-position
relative to the carbony] group of the aroyl moiety with the more electron-withdrawing substi-
tuent, i.e., the direction of this reaction is a function of the polarization of the C=C bond
in the starting diketone. This finding indicates that the formation of intermediate A is the
first step in the reaction studied.

in our previous work [8], we established that the sequence of addition and condensation
in such reactions may depend on the pH of the medium. Thus, we carried out the reaction for
two unsymmetrical diaroylethylenes (R 3 = H, R 2 = Br or NO=) in pure triethylamine and in meth-
anol solutions containing Et3N or HCI. The reaction course is not altered in basic media and
Vii and VIII are formed. On the other hand, the use of an acid catalytic agent led to the
formation of a mixture of the two possible 2-arylquinoxalines and the corresponding acetophe-
nones in approximately equal ratios. These results indicate that both isomeric dihydroquinox-
alines are formed in the acid-catalyzed reaction and, thus, the reaction under these conditions
loses its regioselectivity. In our opinion, this finding is a consequence of the competitive
reaction of PDA with the diketones through pathway b.

The dihydroquinoxalines synti~esized with the exception of the nitro derivatives X and XI
have pronounced fluorescence in solution (see Table 2). We should note that the fluorescence
spectra are much more sensitive to the solvent polarity than the absorption spectra. As a re-
sult, the Stokes shifts for the spectra taken in methanol are, on the average, 1800 cm -z higher
than the analogous values for the toluene solutions. This effect is characteristic for mole-
cules whose excited state is more polar than their ground state [9]. The very high Stokes
shifts observed in methanol solution also indicates a considerable specific interaction of the
protic solvent with the dihydroquinoxalJne molecules in their excited state.

EXPERIHENIAL
The IR spectra of I-XV were taken in KBr pellets on a Specord IR-75 spectrophotometer.
2'he electronic absorption spectra were taken on a Specord UV-vis spectrometer in methanol and
toluene at (3-4).i0 -S mole/!iter. The P"IR spectra were taken on a Varian XL-100 spectrometer
in CDC2~ with ]'MS as the iz~terna! standard. Tile fluorescence spectra were taken in methanol
and to]uene on a unit consisting of a monochromator from an SF-4 spectrophotometer, FEU-38
photodetector and DRSh-500 mercury lamp. The optical density at the excitation wavelength
did not exceed 0.2. The ma,,~s spectra were taken on a Varian MAT CH-6 spectrometer with direct
sample inlet into the ion source.

541
 The purity of I-XV and the composition of the reaction mixtures were monitored by thin-
layer chromatography on Silufol UV-254 plates with chloroform as the eluent.
2-Phenacyl-3-phenTl-l,2-dlhTdroqulnoxallne CI). A. A solutlon of 0.5 g (2.1 mmoles)
trans-dibenzoylethylene and 0.23 g (2.1 mmoles) o-phenylenedlamlne in 5 ml methanol was heated
at reflux for 15 min and then cooled. The y.ellow-orange crystalline precipitate was filtered
off to give 0.42 g (61%) I, mp 124QC (from hexane).
Products Ill, VI-VII~, and X~ were obtained by analogous procedures.
B. A sample of 0.46 g (4.2 mmoles) FDA was added to a solution of I g (4.2 mmoles) di-
benzoylethylene in 5 ml benzene and the mixture was stirred for 3-4 h at 40-50~ The solution
was cooled and filtered to gixe 0.75 g (57%) I , mp 124~
Products II-XV were obtained by analogous procedures (Table i).
2-Phenylquinoxaline. A solution of 0.3 g I in 10 ml methanol with 0.3 ml hydrochloric
acid was heated at reflux for 15 min, cooled to room temperature and added to a methanol solu-
tion of 0.5 g 2,4d-initrophenylhydrazine. The precipitate (0.18 g, 62%) is the NDPH of aceto-
phenone (compared with an authentic sample, mp 237~ Imax 337 nm in methanol~ and Rf 0.75). The
excess hydrazine was eliminated by the addition of acetone and the filtrate obtained by re-
moving the DNPH of acetone was neutralized with ammonia and diluted with 30-40 ml water. The
precipitated oily product was crystallized from hexane to give 0.1 g (53%) 2-phenylquinoxaline,
mp 76~ Imax 335 nm in methanol, Rf 0.6.
Reaction of l-(4-Bromophenyl)-4-phenyl-2-butene-l,4-dione with PDA under Acid Catalysis
Conditions. A solution of i g (3.2 mmoles) l-(4-bromophenyl)-4-phenyl-2-hutene-l,4-dlone and
0.35 g PDA in a mixture of 30 ml methanol and i ml hydrochloric acid was heated at reflux for
30 min. The reaction mixture was then divided into two equal portions. The first portion
was evaporated to i0 ml and cooled. Filtration gave 0.2 g (44%) 2-(4-bromophenyl)quinoxallne
with mp 141~ (from hexane). The filtrate was diluted with 20 ml water and left at room tem-
perature for 3-4 h and then 0.14 g (42%) 2-phenylquinoxaline with mp 76~ was filtered off.
The second portion of the reaction mixture was treated with a methanolic solution of 1 g 2,4-
dinitrophenylhydrazine and 0.25 g of a mixture of the dinitrophenylhydrazones of acetophenone,
and 4-bromoacetophenone were filtered off. These derivatives were identified relative to au-
~then=ic samples with R? 0.75 and 0.6, respectively.
The reaction with l-(4-nitrophenyl)-4-phenyl-2-butene-l,4-dione was carried out under an-
alogous conditions to give 40% 2-(4-nitrophenyl)quinoxaline (mp 187=C), 46% 2-phenylquinoxaline
(mp 76 ~ and a mixture of the dinitrophenylhydrazones of acetophenone (Rf 0.75) and 4-nitro-
acetophenone (Rf 0.5).

LITERATURE CITED
la M. I. Shevchuk, A. F. Tolochko, and A. V. Dombrovskii, Zh. Org. Khim., 6, 1108 (1970).
2. A. Brindra and E. LeGoff, Tetrahedron Lett., No. 16, 1523 (1974).
3. R. B. Trattner and H. D. Perlmutter, J. Heterocycl. Chem., ii, 89 ~1974).
4. H. D. Perlmutter and R. B. Trattner, J. Heterocycl. Chem., ii, 847 (1974).
5. R. G. Bass, D. D. Criston, H. K. Meltz, and A. F. Johnson, Tetrahedron Lett., No. 25, 2073
(1975).
. F. G. Yaremenko, V. D. Orlov, N. N. Kolos, and V. F. Lavrushin, Izv. Vuzov, Khim. Khim.
Tekhnol., 23, No. 7, 831 (1980).
. V. D. Orlov and S. M. Desenko, Khim. Geterotsikl. Soedin., No. 12, 1673 (1985).
8. V. D. Orlov and I. Z. Papiashvili, Khim. Geterotsikl. Soedin., No. 2, 261 (1985).
9. S. Parker, Solution Photoluminescence [Russian translation], Izd. Mir, Moscow (1972), p.
356.

542
NITROAZINES.
5.* USE OF THE JAPP--KLINGEMANN REACTION
FOR THE SYNTHESIS OF NITROTRIAZINES

V. L. Rusinov, T. L. Pilicheva, UDC 547.792.9'873.07:

O. N. Chupakhin, N. A. Klyuev, 543.422'51
and D. T. Allakhverdieva

Condensation of diazoles with ~-dicarbonyl nitro compounds (nitromalondialdehyde

and nitromalondiester) gives derivatives of azolo[5,l-c][l,2,4]triazine with a
nitro group in the triazine ring.

Cyc!ization of aliphatic nitro compounds is a basis for synthesis of nitrotriazines. It

has previously been shown that construction of the 1,2,4-triazine ring (containing a nitro
group) can be brought about by condensation of the ~-nitrocarbonyl compounds (nitroacetic
ester [2] or nitroacetonitrile [3]) with diazoles. The reaction proceeds via formation of
azolylhydrazones of nitroglyoxylic ester or nitrile. At the same time it is known that g l y -
oxal arylhydrazones and their derivatives may be readily obtained from B-dicarbonyl compounds
by the Japp--Klingemann reaction [4, 5]. This stimulated us to examine the use of the more
convenient and more stable B-dicarbonyl nitro products for the synthesis of azolo-annelated
nitrotriazines rather than the monocarbonyl analogs.

We have shown that the diazonium salts Ia-e (obtained from 3-carbethoxy-5-aminopyrazole
or 3-R-5-amino-l,2,4-triazole) react with nitromalondialdehyde (II) in acid medium to form
6-nitro-7-hydroxy-4,7-dihydroazolo[5,l-c][l,2,4]-triazines IIIa-e (see scheme).

CItO
I F o
HC_.NO 2 II "
N-- -NH NaNO~ ~ Nll + ~CH0 - - N . . . . . NH "C / N--" "N~ " ~ I / [

I a - e ~~176
HC-- NO 2
Na2C051 C00C2It~

i VII H :OR 1 II /0It

oli -] N__N
"~<
/ ~-"
Noo~ R +OH N__N>~N%
' N% II I H ~ II / 1!
N--N/~'~-S ! Na +
I i II R/~-x/J~-~ ~N ~2o R~"x(X'~"~: "N
~ ' H It
R/X'X@"" N/N VIa-e IIIa-e
VIIIb, c
a , b R = H , c R=Ctt3, d R (2~t-1~, e R=C()OC~H5; a X=CCOOC~Hs, b - - e X = N

In the IR spectra of IIIa-e there are observed bands corresponding to the symmetric
(1330-1350 cm -x) and asymmetric (1540-1590 cm -~) absorption modes of the nitro groups together
with a broad band (3100-3500 cm -~) which may be assigned to vibrations of the N--H and O--H
bonds. The mass spectra of tne nitrotriazines show a molecular ion peak (M+) and decomposi-
tion under electron impact conditions with ejection of OH' (ion F) and H=O (ion FI) (see Ex-
perimental section) thus pointing to the presence of a hydroxy group in the molecule. The
occurrence of nitro groups is confirmed by the characteristic processes [6] of sequential
elimination of NO" and CO as well as nitro groups from ions F and Fx. For IIIa, loss of the
nitro group occurs directly from ~ ~ Ions with m/z 68 and 67 point to the presence of a tri-

S. M. Kirov Ura! Polytechnic Institute, Sverdlovsk. Translated from Khimiya Getero-

tsiklicheskikh Soedinenii, No. 5, pp. 662-665, May, 1986. Original article submitted January
30, 1985+

0009-3122/86/2205-05435]+2.50 9 1986 Plenum Publishing Corporation 543

azole fragment in the molecule - the ion composition being supported by high resolution mass
spectral data. For llla-e the general position is the same but, along with formation of F,,
there are observed the fragments C2H4, 0C~H4, 0CaHj', and C00C2H4' fromM+andF~, which points
to a carbethoxy group in the molecule.
In their PMR spectra, compounds IIIa-e gave signals for the substituent protons in the
azole ring as well as two doublets for 7-H (7.00-7.90 ppm) and the O-H (8.15-8.30 ppm) with
a spln-spin coupling of 8 Hz. The inter-spln correlation of these protons was demonstrated
by double resonance and by addition of DaO which caused the signal near 8 ppm to disappear
and the doublet near 7 ppm to collapse to a slnglet.
The 1,2,4-triazoles IZIb-e could be formed as the [5,1-c] or the [4,5-c] isomer. Exper-
iments have shown [2, 3, 7] that the position of the triazole ring proton is an indication of
the nature of the ring fusion and occurs at 8.55ppmin7=oxo-4,7-dihydro-l,2,4-triazolo[5~l-c] -
[l,2j4]triazine, at 8.29 ppm in the 6-nitro derivative, and at 9.23 ppm in 7-oxo-4sT-dihydro-
1,2~4-triazolo[4jb-c][l,2,4]triazine. The chemlcal shift of the triazole proton in IIIb
(8.04 ppm) thus points to formation of the [5,1-c] isomer. The close similarity in the UV
spectra of triazines IIIb-d suggests condensation at the triazole N, atom in the reactions
of the substituted trlazoles Ic-e.
Cycllzation to azolo[5,l-c][1,2,4]triazines when Ia-e were treated with nltromalondialde-
hyde is difficult to envisage without the formation of the Japp--Klingemann nltroglyoxal hydra-
zone but it was not possible to separate this intermediate even upon carrying out the reaction
at-5~ Evidently, in the course of the reaction, the hydrazones IV very readily cyclize to
derivatives of 6-nltroazolo[5sl-c][l,2,4]triazine V. The increased ~-deflciency of V leads
to addition of water to form the sigma adducts, 6-nitro-7-hydroxy-4,7-dlhydroazolo[5,l-c]
[l~2,4]triazines IIIa-e, which were separated from the reaction mixture.
Heating the adducts III in methanol or ethanol causes substitution of hydroxy by alkoxy
graups with formation of Via-c, boiling of which with water regenerates the adducts (scheme).
The spectral data for VIa-c (see Experimental section) is in full agreement with their pro-
posed structures. In the IRe bands are produced corresponding to the nitro and the amino
groups. Fragmentation of the alkoxy adducts VIb, c under electron impact occurs with elimin-
ation of OC2Hs" (ion F) and HOCaHs (ion F,) and further decomposition analogous to IIIb, c.
The PMR spectra show signals for the azole part of the molecule: a singlet for 7-H (6.80-7.11
ppm) and signals for methoxy (Via) or ethoxy (VIb, c) groups.
Other 8-dicarbonyl nitro compounds react analogously to nitromalondialdehyde, e.g., the
nitromalondiester VII condenses with diazo-l,2,4-triazoles (Ib, c) in the presence of sodium
carbonate to give the sodium salts of 6-nitro-7-oxo-4,7-dihydro-l,2,4-triazolo[5,l-c][l,2,4]-
triazoles (Vlllb, c), identical to products obtained from diazo-l,2,4-triazoles Ib, c and ni-
troacetate [2].

EXPERIMENTAL
UV Spectra were recorded for aqueous solutions on a Specord UV-vis, IR spectra in paraf-
fin oil on a UR-20, and mass spectra on a Varian MAT-311A under standard working conditions
[3]. PMR spectra were measured on a Perkin-Elmer R-12B using DMSO-d6 solvent andwere refered
to HMDS as internal standard.
3-Carbethoxy-6-nitro-7-hydroxy-4,7-dihydropyrazolo[5~l-c][l~2~4]triazine (Ilia). A sol-
ution of sodium nitrite (0.8 g, ii mmoles) in water (5 ml) was added over 15 minutes to a
solution of 4-carbethoxy-5-aminopyrazole (1.55 g, I0 mmoles) in nitric acid (d 1.4, 1.6 ml)
and water (i0 ml) which had been cooled to 0~ After holding at this temperature for i0 min
and mixing with a solution of sodium nitromalondialdehyde monohydrate (1.57 g, i0 mmoles) in
water (7 ml), the product was stirred at 20~ for 3 h and filtered. The precipitated solid
(Ilia) was crystallized from water and dried zn uacuo at 100=C over P20s to give 2.3 g, 90%,
with mp 204-205~ UV spectrum, %max, log e: 218 (3.49), 238 (3.51), 370 nm (3.43). IR
spectrum: 1330, 1590~ (NO2), 1730 (C==O), 3100-3400 cm-* (NH, OH). Mass spectrum (ionization
temperature 120~ m/z (%)*: 46 (i0) [NO2] +, 53 (23), 65 (32) [C3H,N2] +, 66 (I0) [C3H2N2] +,
67 (20), 95 (21), 146 (56) [F~ -- OCzH5 -- NO~] +, 162 (56) [F, -- OC=H5 -- NO] + , 165 (74) [F~ --

*lons reported have intensities >i0% of the intensity of the maximum peak in the spectrum.

544
COOC2H~] +, 191 (ii) [F~ -- NO2] +, 192 (i00) [Fz -- OC2H5] +, 193 (66) [F~ -- OC2H~] +, 209 (58)
[M-- NO2] +, 210 (18) [M-- OC2Hs] +, 237 (43) [M-- H20] + (F~), 255 (47) M +. PMR spectrum: 1.30
(3H, t, CH3), 4.3 (2H, q, CH2), 6.90 (IH, s, 2-H), 7.98 (IH, d, 7-H), 8.10 (IH, d, OH), 12.7
ppm (IH, s, NH). Found: C 38.0; H 3.6; N 27.2%. CsHgNs05. Calculated: C 37.7; H 3.5; N
27.5%.
6-Nitro-7-hydroxy-4,7-dihydro-l,2,4-triazolo[5,l-c][l,2,4]triazine (IIIb) was obtained
analogously to IIIa in 90% yield with mp ~300~ UV spectrum, ~max (log e): 202 (3.5), 340
nm (3.84). IR spectrum: 1344, 1543 (NO2), 3150-3500 cm -~ (NH, OH). Mass spectrum (ioniza-
tion temperature i40~ m/z (%): 46.(15) IN02] +, 53 (90) [F3 -- HCN] +, 67 (i0) [C2H~N3] +, ]+
68 (29) [C2H2N2] +, 80 (18) [F2 -- N2H]* (F3), 109 (22) [F -- NO -- CO] + (F2), 120 (60) [F~ -- NO~
137 (I0) IF -- NO] + , 166 (i00) [M -- H20] + (F~), 167 (31) [M--OH] + (F), 184 (30) M +. PMR spec-
trum: 7.00 (IH, d, 7-H), 8.04 (IH, s, 2-H), 8.15 (IH, d, OH), 12.62 ppm (IH, s, NH). Found:
C 25.8; H 2.7; N 45.0%. C~H4N603. Calculated: C 26.]; H 2.2; N 45.2%.
2-Methyl-6-nitro-7-hydroxy-4,7-dihydro-l,2,4-triazolo[5,l-c][l,2,4]triazine (IIIc)ob-
tained as for IIIa in 80% yield with mp 280-282~ UV spectrum, ~max (log ~): 203 (3.34),
341 nm (3.90. IR spectrum: 1350, 1543 (NO2), 3050-3400 cm -~ (NH, OH). Mass spectrum (ioni-
zation temperature 130~ m/z (,~): 46 (i0) [NO=J + , 67 (91) [F3 -- HCN]+, [C2H~N3] +, 68 (14)
[C2H2N3] +, 94 (i~ [F2 -- NH] + (F3), 123 (ii) IF -- NO -- CO] + (F2), 134 (24) [Fx -- NO=] +, 150
(I0) IF-- NO] +, 180 (i00) [M-- HzO] + (F~), 181 (19) [M-- OH] + (F), 198 (20) M +. PMR Spectrum:
2.30 (3H, s, CH~), 7.10 (IH, d, 7-H), 8.30 (IH, d, OH), 12.60 ppm (iH, s, NH). Found: C
30.0; H 2.8; N 42.2%. CsH6NeO3. Calculated: C 30.3; H 3.0; N 42.4%.
2-Phenyl-6-nitro-7-hydroxy-4,7-dihydro-l,2,4-triazolo[5,l-c][l,2,4]triazine (IIId) was
obtained as for IiIa in 75% yield with mp 199-200~ UV spectrum, Ama x (log s): 204 (3.50),
256 (3.00), 340 nm (3.92). IR spectrum: 1340, 1540 (NO=), 3100-3400 cm-: (NH, Ok). PMR
spectrum: 7.10 (IH, d, 7-h), 7.50-8.00 (SH, m, C6H5), 8.20 (IH, d, OH), 12.65 ppm (IH, s, NH)
Found: C 45.7; H 3 .3~. CIoHsN603. Calculated: C 46.1; H 3.1%.
2-Carbeth~xy-6-nitr~-7-hydr~xy-4,7-dihydr~-~2,4-triaz~[5,~-c][~,2,4]triazine(~IIe) was
obtained analogously to IIla in 80% yield with mp >300~ IR spectrum: 1350, 1560 (NO2),
1730 (C=O), 3100-3400 cm -I (NH, OH). Mass spectrum (ionization temperature 120~ m/z (%):
46 (ii) [NOz] +, 53 (60), 67 (36) [CzH~N3] +, 68 (29) [C2H2N3] +, 120 (I0), 165 (12) [F~ --
COOC2H4 -- H20] +, 167 (52) [M -- C2H~ -- OH] + , 180 (2~ [M -- CH2H~ -- NO -- H20] +, 184 (26) [M --
COOC2H~] +, 193 (i00)[F~ -- OC~H5~ +, 198 (18) [M-- C=H~ -- NO] + , 211 (17) [M-- OC=Hs] +, 228 (i0)
[M -- CzH4] +, 238 (I0) [M -- H=O] (F~), 256 (i0) M +. PMR spectrum: 1.30 (3H, t, CHs), 4.25
(2H, q, CHz), 7.05 (IH, d, 7-H), 8.30 (1H, d, OH), 12.65 ppm (IH, s, NH). Found: C 33.1;
H 3.2; N 32.5%. CTHoN~O~. Calculated: C 32.8; H 3.1; N 32.8%.
3-Carbeth0xY-@-nitro-7-methoxy-4,7qdihydropyrazolo[5~l,c][l,2,4]triazine (Vla). The hy-
droxy~hdduct IIia (1.27 g, 5 mmoles) in methanol (20 ml) was refluxed for 5 min and evaporated
to dryness ~; ~,~u~ to give Via in quantitative yield, mp 155-156~C. IR spectrum: 1340,.1550
(NOz), 1680 (C~O), 3265 cm -~ (N--H). PMR spectrum: 1.30 (3H, t, CHs), 3.48 (3H, s, OCH~),
4.30 (2H, q, CH=), 6.80 (IH, s, 7-H), 8.05 (IH, s, 2-H), 12.95 ppm (IH, hr. s, NH). Found: C
39.8; H 4.3%. C~H~NsH~. Calculated: C 40.1; H 4.1%.
6-Nitro-7-ethoxy-4,77dihydro-l~2,4ntriazolo-[5,l-c][l~2~4]triazine (VIb). Refluxing of
IIIb (0.9 g, 5 mmoles) in ethanol (i0 ml) for 5min, cooling, and filtration gave VIb (0.75 g,
70,%) with mp 164-165~ IR spectrum: 1344, 1540 (NOz), 3122 cm -~ (NH). Mass spectrum (ion-
ization temperature 60~ 46 (i~ [NOz] +, 53 (80) [F~ -- HCN] +, 67 (IO)[CzHzNs] +, 68 (40)
[CzHzN~] +, 71 (64), 80 (29) IF -- NO -- CO -- HzO] + (Fs), 120 (33) [F~ -- NO=] +, 121 (71) [F --
NOz] +, 166 (88) [M -- HOC=H] + (F~), 167 (i00) [M -- OC=H~] + (F), 212 (13) M +. PMR spectrum:
1.10 (3H, t, CHs), 3.85 (2H, q, CH=), 6.95 (IH, s, 7-H), 8.04 (IH, s, 2-H), 12.60 ppm (IH, s,
NH). ~ound: C 34.0; H 4.0%. C~H~N~O~. Calculated: C 34.0; H 3.8%.
2-Methyl-6-nitro-7-ethoxy-4,7-dihydro-l,2,4-triazolo[5,l-c][l,2,4]triazine (VIc) was ob-
tained analogously toVIb in 75% yieldmp 230~ IRspectrum: 1344, 1556 (NOz), 3110cm -~ (NH).
Mass spectrum (ionization temperature 60~ 46 (15)[NO~]*, 67 (70) [F~ -- HCN]+,[C~H~N~] +,
68 (30) [C~H~;~] +, 94 (26) [F -- NO -- CO -- NH~] + (F~), 134 (i0) [F~--NO~] +, 135r (73) [F -- NO~] +
180 (86) [M -- HOC~H~] + (F~), 181 (I00) [M -- OC~H~] + (F), 226 (15) M +. spectrum: 1.08 (3H,
t, CH~), 2.3i (3H, s, CH~), 3.55 (2H, q, CH=), 7.11 (IH, s, 7-H), 12.60 ppm (IH, s, NH).
Found: C 36.9; H 4.5; N 37.7%. C~HzoN~O~. Calculated: C 37.2; H 4.5; N 37.2%.

545
 6-Nitro-7-oxo-4,7-dihydrg-l,2,4-triazoloIb,l-c][l,2,4]triazine , Sodium Salt <Vlllb). A
solution of the diazonium salt of 5-amino-l,2,4-trlazole (1,7 g, 20mmoles), nitromalonicdi-
ester (4.4 g, 20 mmoles) and NaaCO, (3.2 g) was mixed in ethanol (50%, 20 ml). Stirring for
1 h at 0~ and 2 h at 20~ and filtration gave triazine VIIIb (1,25 g, 60%) with mp >300~
(from [2], mp >300~
2-Methyl-6-nitro-7-oxo-4,7-dihydro-l,2,4-triazolo-[5,l-c][1,2,4]triazine, sodium salt
(VllIc) was obtained by the method described above in 55% yield with mp 282-284~ (from [2],
mp 282-284~

LITERATURE CITED
i. L. Kh. Baumane, R. A. Gavar, Ya. P. Stadyn', O. N. Chupakhin, V. L. Rusinov, and A. Yu.
Petrov, Khim. Geterotsikl. Soedin., No. 5, 689 (1985).
2. V . L . Rusinov, A. Yu. Petrov, and I. Ya. Postovskii, Khim. Geterotsikl. Soedin, No. 9,
1283 (1980).
3. V . L . Ruslnov, A. Yu. Petrov, O. N. Chupakhin, N. A. Klyuev, and G. G. Aleksandrov,
Khim. Geterotsikl. Soedin., No. 5, 682 (1985).
4. F . R . Japp and F. Klingemann, Chem. Ber., 20, 2942 (1887).
5. Yu. V. Maksimov, S. M. Kvitko, and V. V. Perekalin, Zh. Org. Khim., ~, 332 (1982).
6. R . A . Khmel'nitskii and P. B. Terent'ev, Usp. Khim., 48, 854 (1979).
7. J. Dannis and M. Follet, Bull. Soc. Chim. France, No. 7-8, i178 (1976).

REACTION OF 3,4-DIAMINOFURAZAN WITH CARBONYL

COMPOUNDS AND THEIR METAL COMPLEXES

I. S. Vasil'chenko, S. G. Kochin, UDC 547.793.2:542.953.2

V. A. Anisimova, L. I. Khmel'nitskii,
and A. D. Garnovskii

It is shown that when 3,4-diaminofuranzan reacts with formic acid under various condi-
tions there is, along with the mono- and diformylation, an intermolecular re-
action leading to a polymeric compound. The diamine under consideration forms
a monoazomethine with salicylaldehyde but a bis(azomethine) complex with the
salicylaldehydate of divalent nickel.

It is known that as a consequence of the extremely low basicity of the NH2 groups in
aminofurazans [i, 2], the latter have substantial difficulty in reacting with carbonyl-
containing compounds [i].
In the present paper, we report on an attempt to obtain imidazo[d,c]furazan (II) and
azomethines from 3,4-diaminofurazan (I) with salicylaldehyde (III). These products are of
interest as potentially biologically active substances [i] and as ligands for complex form-
ation [4].

M. A. Suslov Scientific-Research Institute of Physical and Organic Chemistry, Rostov

State University, Rostov-on-Don. N. D. Zelinskii Institute of Organic Chemistry, Academy of
Sciences of the USSR, Moscow. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
5, pp. 666-669, May, 1986. Original article submitted February 27, 1985,

546 0009-3122/86/2205-0546512.50 9 1986 Plenum Publishing Corporation

 N,..~ N

C=N. N=:(" x | 0 N /N ]
H " "[[....(" ~ L "o _j,,
II

\
1. HC00H + HC: NH2 NHCHO 0HCttN~., NHCHO

Nx O / N N-..o/N Nxo/N

I .... _ "~. - 0 ~\ IV V
/ -. -
/
,_HOC6Hr ~'-. /f ~'O~. 0 .'~]/~

H~ ~ - ~ ~'H
) Vll N~O/N N"o/N

When 3,4-diaminofurazan reacts with formic acid in the presence of a catalytic amount of
concentrated HCI or with an o-formic ester in acetic anhydride under the conditions usually
used for the annelation of an imidazol ring from ortho-diamines [5, 6], the bicyclic compound,
If, is not obtained; only mixtures of the mono- and diformyl derivatives, IV and V, respec-
tively, are formed. Carrying out the condensation of diamine I with HCOOH in polyphosphoric
acid (PPA) leads to high-melting polymers, probably having structure VI. The analogous poly-
mer VI was evolved when it was attempted to cyclize the monoformyl derivative, IV, to imidazo-
[d,c]furazan with PPA or by high-temperature dehydration. In addition to bands which are
characteristic of the furazan ring (-1620-1630 cm-1), carbonyl absorption bands appear in the
1690-1700 cm -I region of the IR spectra of compounds IV-VI; the azomethine group of polymer
VI absorbs at 1635 cm -I.
Consequently, even under rigorous conditions the cyclization takes place as an inter-
rather than an intramo!ecular process. In our opinion, this result is explained not only by
the low basicity of the amino groups in diaminofurazan I, but also by their spatial arrange-
ment which impedes the participation of both amine groupings in reactions with carbonyl com-
pounds to form five-membered heterocycles [i].
This conclusion is confirmed by the unusual reaction of diaminofurazan with salicylalde-
hyde. Unlike o-phenylenediamine [7], diamine I forms only monoazomethine VII with this alde-
hyde. Carrying out this condensation in the presence of HCI or ZnCI=, which is known [8] to
facilitate the formation of azomethines, still does not lead to the diazomethine. Therefore,
we carried out a template synthesis [9], introducing the nickel complex of salicylaldehyde
into the reaction with compound I. It turned out that as a result of this change (I VIII)~
both amino groups of 3,4-diaminofurazan react to form an innercomplex compound (ICC) that is
similar in properties to salicyliminato ICC's of aliphatic and aromatic diamines [7]. In the
IR spectrum of ICC VIII, one finds the total furazan and azomethine absorption at 1580-1630
cm -I and the absence of NH2 group frequencies. The complex is diamagnetic. The composition
and the properties adduced agree with structure VIII that we have proposed for the nickel ICC
being considered.

The participation of both amino groups of compound I in the synthesis of ICC VIII can be
explained by the activation of the carbonyl groups in the salicylaldehydate by the metal.
We note also that the formation of ICC VIII is facilitated by the chelate effect [I0] that
is responsible also for the formation of compound VIII from monoazomethine VII and nickel
acetate. Reaction VII ~ VIII obviously starts with the hydrolysis of monoazomethine VII un-
der the conditions of the synthesis to the diamine and aldehyde, followed by the formation of
nickel salicylaldehydate that then reacts with liberated diamine just as in the I ~ VIII
transformation.
Thus, the reaction of 3,4-diaminofurazan with carbonyl compounds is substantially activ-
ated by carrying out the reaction in a transition metal matrix.

547
 EXPERIMENTAL
The IR spectra of the samples were taken on e Specord-71 spectrometer in petrolatum.
The magnetic properties of the complex compounds were measured by the Faraday comparative
method at 293 K [ii].
3-Amino-drformy!aminoSurazaB (IV), Boll a solution of 1 g (I0 mmoles) of dlaminofurazan
I [3]" in 3 ml of concentrated HCOOH for 3 h and allow to stand at romm temperature. On
the following day, filter off the solid precipitating out when the reaction mixture is di-
luted twofold. Yield 0.89 g, mp 160-164~ Recrystalllze twice from ethanol to obtain
0.72 g of coarse, colorless crystals with mp 169-170~ IR spectrum: 1700 (CHO), 3075, 3195,
3375 cm'* (NHa). Found: C 28.0; H 3.1; N 44.1%. Calculated for C,H~N~O~: C 28.1; H 3.1;
N 48.8%.
3,4-Di(formylamino)furazan (V)' A. After separation of the monoformyl derivative, IV,
neutralize the formic acid solution with ammonia, evaporated to a small volume (~1.5 ml), and
filter off the solid that precipitates. Unite it with the residue after evaporation of the
alcoholic mother liquor remaining from the recrystallization of compound IV, and crystallize
from alcohol and acetonitrile to give 0.12 g of the diformyl derivative in the form of color-
less, needle-like crystals with mp 140~ IR spectrum, 1615-1620 (furazan ring), 3205 (NH),
1690 cm-* (CHO). Found: C 30.6; H 2.6; N 36.2%. Calculated for C~HdNdO,: C 30.8; H 2.6;
N 3.5%.
B. When diaminofurazan reacts with HCOOH in the presence of two drops of concentrated
HCl under the conditions stated above for the synthesis of the monoformyl derlvative, IV D
there first preclpitates from the reaction mixture a solid (0.2 g, mp 130-133~
primarily of the diformyl derivative, V, but when the filtrate, neutralized with ammonia, is
evaporated, compound IV is evolved (0.8 g, mp 160-163~ contaminated with dlformylamine V.
After subsequent recrystallization from the above-mentioned solvents, pure samples of com-
pounds IV (mp 169-170~ and V (mp 140~ are obtained.
C. Heat a mixture of 1 g (I0 mmoles) of 3,4-diaminofurazan, 5 ml of acetic anhydride,
and 5 ml of ethyl orthoformate for 5 h at the boiling point. After evaporation of the solu-
tion to 5 ml cool it, filter off the precipitate, and pass it through a layer of AI=03 (e~uent,
ethyl acetate) and recrystallize it from a large quantity (100 ml) of benzene or toluene.
mp 134-135~ (incipient liquifaction at I12~ From the elementary analysis, the precipitate
is a mixture of mono- and diformyl derivatives, IV and V, containing more than 50% of compound
V.
Polymer Vl. A. Pour i ml of 98% HCOOH with stirrin~ into a mixture of i g (i0 mmoles)
of diamine I and i0 g PPa, heat to 60-70~C, and continue to heat, gradual raising the temper-
ature. At 120~ the reaction mixture foams strongly. After holding the mixture at this
temperature for 1 h, cool it and pour it into water. Separate the solid which precipitates
and wash it with water, alcohol, and acetone -- to obtain 0.63 g of polymer in the form of a
yellow, finely crystalline substance, difficulty soluble in the majority of organic solvents
and water, mp >340~ IR spectrum: 1620 (furazan ring), 1635 (C=N, azomethine), 1700 (a
low-intensity band, C=O), 3325 cm-* (a broad band, NH). Found: C 31.4; H 2.5; N 55.2%.
Calculated for polymer VI with n = 10-20: C 32.1; H 2.4; N 51.6%.
B. Heat 0.64 g (5 mmoles) of 3-amino-4-formylamino furazan in a sealed tube in a sili-
cone oil bath. At 170-175~ a melt forms which foams violently when the bath temperature
is raised to 220-225~ forming the yellow, crystalline polymer. Digest it with alcohol,
then acetone. Yield 0.38 g, mp >340~ A similar polymer forms when monoformyl derivative
II is heated in PPA at 120-130~
3-Salicylideneamino-4-aminofurazan (VIII). Add 4.88 g (40 mmoles) of salicylaldehyde in
20 ml of ethanol to a solution of 2 g (20 mmoles) of 3,4-diaminofurazan, I, in 20 ml of the
same solvent. Boil the mixture 30 min, evaporate to a volume of 20 ml, cool, and filter off
the solid that has precipitated. Light yellow, needle-like crystals are obtained chromato-
graphically pure (silica gel) after recrystallization from toluene. Yield 75%, mp 191-192~
IR spectrum: 1620 (furazan ring), 1645 (C=N, azomethine), 3305, 3385 cm-* (NH2). Found: C
52.6; H 4.11; N 27.3%. Calculated for CgHsN~02: C 52.9; H 3.9; N 27.4%.
(3,4-Bissalicylideneaminofurazan)nickel (VIII). A. Add 2.44 g (20 mmoles) of salicyl-
aldehyde in i0 ml of methanol to a boiling solution of 2.48 g (i0 mmoles) of nickel acetate
tetrahydrate in 20 ml of the same solvent. Boil the solution for 20 min, during which time

548
the color characteristic of nickel salicyladehydrate appears. Then add in sequence 1.12 g
(20 mmoles) of KOH in 15 ml of methanol and 1 g (I0 mmoles) of 3,4-diaminofurazan in i0 ml
of methanol. After boiling the solution for i0 h, filter off the precipitated complex com-
pound, wash it repeatedly with hot methanol, and dry it in vacuum at 120~ Yield 2.95 g
(82%), black crystals with mp 350~ IR spectrum: 1615 (C=N, azomethine), 1630 cm-: (fur-
azan ring). Found: C 52.8; H 2.7; N 15:5; Ni 16.5%. Calculated for C~6HIoN~NiOs: C 52.6;
H 2.8; N 15.4; Ni 16.1%.
B. Dissolve 0.5 g (2.5 mmoles) of azomethine VII in 30 ml of methanol and add 0.26 g
(1.25 m-"moles) of nickel acetate tetrahydrate in i0 ml of the same solvent. After boiling
the solution for 4 h, filter off the black crystals, wash three times with methanol, and
dry in vacuum at 120~

LITERATURE CITED
i. V. G. Andrianov and A. V. Eremeev, Khim. Geterotsikl. Soed., No. 9, 1155 (1984).
2. I . V . Tselinskii, S. F. Mel'nikova, and S. N. Bergizov, Khim. Geterotsikl. Soed.,
No. 3, 321 (1981).
3. M. D. Coburn, Heterocycl. Chem., 5, 83 (1968).
4. A. D. Garnovskii, O. A. Osipov, L. I. Kuznetsova, and N. N. Bogdashev, Usp. Khim., 42,
177 (1973).
5. A. F. Pozharskii, A. D. Garnovskii, and A. M. Simonov, Usp. Khim., 35, 261 (1966).
6. R. J. Sundberg and R. B. Martin, Chem. Rev., 74, 471 (1974).
7. R. H. Holm. G. W. Everett, and A. Chakravorthy, Prog. Inorg. Chem., ~, 83 (1966).
8. G. Westphal and R. J. Schmidt, J. Prakt. Chem., 315, 791 (1973).
9. N. V. Gerbeleu, Reactions on Matrices [in Russian], Shtiintsa, Kishinev, 1980.
i0. K. B. Yatsimirskii, Teor. Eksp. Khim., 16, 34 (1980).
ii. V~ P. Kurbatov, A. V. Khokhlov, A. D. Garnovskii, O. A. Osipov, and L. A. Khulkhachieva,
Koord. Khim., ~, 351 (1979).

CROWN ETHERS BOUND TO SULFANILAMIDE PREPARATIONS

A. V. Bogatskii,* E. V. Ganin, V. F. Makarov, UDC 547.898:551.52'459.9.07

S. A. Kotlyar, and N. G. Luk'yanenko

Complexes with a 1:2 composition were obtained by the reaction of 8-crown-6

ethers with 4-aminobenzenesulfonamide and 4-aminobenzensulfoguanidine. Crown
ethers containing a sulfanilyl group were obtained in the reaction of azacrown
ethers with 4-acetylaminobenzenesulfonyl chloride.

Interest has recently arisen in crown ethers containing pharmacophoric groups [i, 2].
To change the hydrophilic-hydrophobic properties of sulfanilamide preparations (SFAP), we
carried out reaction of 4-aminobenzenesulfonamide, 4-aminobenzenesulfoguanidine, 2-(4-
aminobenzenesolfonamido)thiazole, 4-aminobenzenesulfonylurea, 2-(4-aminobenzenesulfonamido)-
4,6-dimethylpyridimidine, 2-(4-aminobenzenesulfonamido)-3-methoxypyrazine, 3-(4-aminobenzene-
sulfonamido)-6-methoxypyridazine, and 6-(4-aminobenzenesulfonamido)-2,4-dimethoxypyrimidine
with i5-~rown-5 and 18-crown-6 ethers in solvents that ensure the dissolution of the start-
ing materials. In the literature, spectral data are given on the complexation of 18-crown-
6 ethers with SFAP, including 3-(4-aminobenzenesulfonamido)-6-methoxypyradizine and 6-(4-
aminobenzenesuifononamido)-2,4-dimethoxypyrimidine [3], but preparatively, we succeeded only
*De~-ea~ed,

A. V. Bogatskii Physicochemical Institute, Academy of Sciences of the Ukrainian SSR,

Odessa. All-Union Scientific-Research am,i Planning Institute of Monomers, Tula. Trans-
lated from Khimiya Getero~siklicheskikh So~dinenii, No~ 5, pp. 670-671, May i, 1986. Orig-
inal article submitted March 19, 1985.

0009-3122/86/2205-05495!2.50 9 1986 Plenum Publishing Corporation 549

 TABLE i. Characteristics of Com ~ounds Synthesized
Com- IR spectrum, cm "l Found [Gal-
ou-
pound mp,' 'C R~ N,~ Empirical lated
,formula N, %
NH I SO2 COC

Ia 140--141 0,39t 3380 1310, 1155 III0 9,1 C~4t{40N4010S2 9,2

I.b 226--227 0,27t'J 34301 1150 II130 16,0 C26H44N80,oS.o 16,2 374 90
95
Ila 167--168 0,34 338011310, 115011095 7,6 Ci~H~oN206S 7,5 64
lib 107--108 0,29 3370 1310, 1150 1090 6,9 C,sl'tsoN2OvS 6,7 418 66
50
II c 150--151 0,39 3360 1300, I130 1080 I0,0 C241-I3GN4OsS2 9,8

*Compound la was crystallized from dioxane, Ib and lla, from

water, llb from benzene, llc from ethanol.
~The value of Rf is given for SFAP, since during the TLC
the complexes decompose and 18-crown-6 forms a loop.

in isolating the 18-crown-6-SFAP complexes with 1:2 composition only when 4-amlnobenzenesul-
fanomlde (Ia) and 4-amlnobenzenesulfoguanidine (Ib) were used. Complexes of 15-crown-5-
ethers with SFAP could not be preparatively isolated. For the same purpose, compounds IIa-c
were obtained from 4-aminobeenzenesulfonyl chloride and azacrown ethers.

IIa-c

II R=SO2CoH4NH2; a RI=O, n = l , m = 2 ; b RI=O, n=2, rn=2; c RI=NSO=C6HdNH2.

n=2, m=2
The reaction of compounds lla-c with 18-crown-6 ethers does not lead to the preparative
isolation of the complexes. This shows that for complexation with a crown ether it is appa-
rently essential that a sterically unhindered, weakly basic (sulfamide and or sulfoguanidine)
HaN groups be present in the molecule of SFAP.

EXPERIMENTAL
The IR spectra were recorded on a Perkin-Elmer 580B spectrophotometer in potassium brom-
ide tablets, and the PMR spectra were run on a Tesla BS-407 spectrometer. The mass spectra
were measured on a MAT-If2 mass spectrometer at an ionizing voltage of 70 eV with a direct
introduction of the sample into the source. The TLC was carried out on Silufol UV-254 plates,
for compounds I in a 1:3 methanol-chloroform system, and for compounds II in a 1:2 acetone-
benzene system, with development in UV light (extinction) and ninhydrine (red spots).
Complexes of 18-Crown-6 Ethers with SFAP (I) (Table 1). A 10-mmole portion of 18-crown-6
ether is added to a solution of i0 mmoles of 4-aminobenzenesulfamide in 20 ml of diozane or
4-aminobenzenesulfoguanidine in 200 ml of water at 100~ After cooling and evaporation of
the solutions, 1:2 complexes of 18-crown-6 with 4-aminobenzenesulfamide (la) and 18-crown-6
with 4-aminobenzenesulfoguanidine (Ib) crystallized. In the PMR spectra (CF~COOH) of compounds
I, the chemical shifts of the phenyl protons are 7.70-8.30 and of the oxymethylene protons
3.75-3.80 ppm.
Sulfanilyl-Containing Crown Ethers II (Table i). A solution of i0 mmoles of monoaza-15-
crown-5 or monoaza-18-crown-6 or 5 mmoles of diaza-18-crown-6 and 20 mmoles of triethylamine
in 30 ml of dloxane is added to a solution of i0 mmoles of 4-acetylaminobenzenesulfonyl chlor-
ide dissolved in 50 ml of dioxane. The mixture is allowed to stand for i h, then filtered,
and the filtrate is evaporated. The oil obtained is boiled for 5 min with i0 ml of 10% HCI,
and the solution is then neutralized with 30 mmoles of sodium carbonate, and the oily products
lla-c are crystallized to yield 1,4,7,10-tetraoxa-13-(sulfanil)azacyclopentadecane (lla), I,
4,7,10,13-pentaoxa-16-(sulfanil)azacyclooctadecane (lib) and 1,4,10,13-tetraoxa-7,16-(di-
sulfanil)diazacyclooctadecane (llc). In the PMR spectra of compounds lla, b (in CDCI3) and
llc (in CFsCOOOH), the chemical shifts of the phenyl group protons lie in the region of 6.47-
7.53 and 7.70-0.17 ppm, respectively, of the H2N groups at 4.12 (lla) and 4.17 (lib) ppm, of
CH20 groups at 3.60 (lla, b) and 3.93 (llc) ppm, of the CHmN at 3.17-3.33 (lla, b) and 3.57
(llc) ppm. The integral intensities of the groups of protons correspond to the formulas given.

550
 LITERATURE CITED
F. VSgtle and U. Elben, Chem. Ber., Iii, 1434 (1978).
2. U. Elben, H. Fuchs, K. Frensch, and F. VSgtle, Liebigs Ann. Chem., No. 8, 1102 (1979).
3. K. Takayama, N. Nambu, and T. Nagai, Chem. Pharm. Bull., 27, 715 (1979).

2-HYDROXYMETHYLAMINO-4-THIAZOLINONE.
CONFIRMATION AND CHELATE FORMATION

S. M. Ramsh UDC 547.789.1.3:541.62'572.54

In DMSO-d6 solution 2-hydroxymethylamino-4-thiazolinone, as well as its 5-methyl-

congener, exists in the form of E- and Z-conformers relative to the exocyclic ni-
trogen-carbon bond; for each of these conformers, furthermore, both a transoid
and cisoid orientation of the hydrogen and oxygen atoms, relative to the N-CH=
bond, are possible. The transoid form is able to form a chelate derivative with
intramolecular hydrogen bond formation. Both acids and bases catalyze transi-
tions among the "open" forms, although chelate formation is only acid-catalyzed.

Heating 37% aqueous formaldehyde with 2-amino-4-thiazolinone (Ia) in ethanol at 70~ re-
sults in the formation of an adduct, namely, a monohydroxymethyl derivative. Tertiary amines
accelerate the reaction, and hydroxymethylation occurs at room temperature in their presence.
The adduct does not melt, even upon heating to 250~ although its derivatograph (thermal
gravimetric analysis) indicates that it loses one molecule of formaldehyde in the 140-160~
temperature range. The adduct gives only one spot with thiazolinone Ia on TLC, and its UV
spectrum is identical [to that of thiazolinone Ia]. Because of its thermal lability, the
adduct does not exhibit a molecular ion (M+) peak in its mass spectrum, but does exhibit M +
peaks due to compound Ia and formaldehyde.
We have previously demonstrated [i] that, for the hydroxymethylation of mesomeric anions,
kinetic and thermodynamic regioselectivity overlap, as a result of which hydroxymethylation
occurs on the "harder" site of an ambident anion, which, in this case, is the exocyclic ni-
trogen atom [2]. Hydroxymethylation of the neutral molecule takes place only at elevated
temperatures, where addition to the carbonyl group carbon atom is reversible, and as a re-
sult, thermodynamic control of the product mixture leads to formation of the most stable hy-
droxymethylation derivative, whose structure in this case would correspond to the most stable
tautomer of la, the aminotautomer [2]. Thus, the adduct should exhibit the structure of the
2-hydroxymethyl derivative IIa, regardless of whether it is the anionic form or neutral Ia
which reacts. This expected hydroxymethylation pathway has been verified by NMR analysis of
compound IIa.

N ;7
o CII2fl
N .----~~

Nil, .% R IIOf;II~NII S R

Ia, b IIa, b
& Ir b R=~-II 3

PMR Spectra. The PMR spectrum of compound IIa in DMSO-d6 at an operating frequency of
270 MHz (Fig. la) is totally unexpected. It contains four signals due to the NH proton, one
of which, the most downfield, broadened one at about i0 ppm, cannot always be discerned;
there are also four triplets due to the hydroxyl proton, four multiplet signals arising from
the methylene protons of the hydroxymethy! group, and three signals due to the methylene pro-
tons attached to the heterocycle, C(5)H2. This type of PMR spectrum can be rationalized on

Lensovet Leningrad Technological Institute, Leningrad. Translated from Khimiya Get-

erotsiklicheskikh Soedinenii, No. 5, pp. 672-678, May, 1986. Original article submitted
February 13, 1985.

0009-3122/86/2205-0551512.50 9 1986 Plenum Publishing Corporation 551

 10 ~ 8 8, ppm ~ ~J~ NH J

9 S 5 /~ 8, ppm
Fig. I. PMR spectra of 2-hydroxymethylamino-4-thiazo-
linone (IIa): a) 270 MHZ, concentration 200 mmole/
liter; b) 90 MHz, concentration 45 mmole/liter.

the basis of the presence in solution of an equilibriummixture of conformers, lla-E" + lla-E'

ZZa-E ~ ZIa-Z ~ Ila-Z' ~ ZZa-Z". The equilibrium between the open forms, Ila-E ~ lla-Z, does
not differ from the conformational equilibrium for 2-methylamlno-4-thiazollnone [3], and may be
attributed to partial spa-hybrldlzation of the exoc y clic nitro g en atom N (a' ), Conformer Ila-E
is sterlcally the most favored isomer [at a concentration of 0.2 mole/llter, the ratio (ZIa-E +
I~a-E')/(ZZa-Z + IZa-Z') is about 3:1]; it gives rise to the very strong triplet at 9.69 ppm
for the NH group proton, which is deshielded by the oxygen atom in the cisoid orientation of
the hydrogen and hydroxyl groups relative to the N-CHa bond, and thus is shifted to lower field
relative to conformers IZa-E' and ZZa-E".* The HOCH2NH fragment of conformer Ila-E gives rise
to viclnal spln-spln coupling, with a constant of J = 7.3 Hz, of the hydroxyl and methylene
group protons, Just as is observed for all of the other isomeric forms, but also exhibits vic-
inal coupling due to the CH~--NH protons, with a spin-spin coupling constant J = 4.6 Hz; the
signals due to these protons thus appear as a multiplet centered at 4.78 ppm as a result of
overlap of two doublets, Splitting of the methyl group proton signal by the vicinal NH group
proton has been detected previously, in the case of the E-conformer of 2-methylamlno-4-thiazo-
linone [3]. A similar splitting pattern which is seen in secondary amides [4, 5], can be at-
tributed to rate retardation of exchange of the amlde proton as a consequence of partial pos-
itive charge on the nitrogen atom; in our case, suppression of the exchange rate is due not
only to the amide character of N(m'), but also to the steric requirements of the exchange
process.
The broadened signal at about i0 ppm and the triplet centered at 4.64 ppm correspond to
the NH and NCH2 group protons, respectively, in conformer IIa-Z. Just as was observed in the
case of the corresponding protons in the Z-conformer of 2-methylamino-4-thiazolinone, these
protons resonate either downfield (in the case of the NH proton) or upfield (in the case of
the NCH2 protons) relative to the same protons in the E-conformer [3]. The chemical shifts
of the methylene group protons in the heterocycle, C(5)H2, in both of the open conformers,
IIa-E and IIa-Z, are exactly the same as in 2-methylamino-4-thiazolinone [3], namely, 3.92
ppm for the E-conformer and 3.90 ppm for the Z-conformer. The triplets due to hydroxyl group
protons, at 6.24 (lla-E) and 6.27 ppm (lla-Z), are superimposed on one another.
Examination of Stuart--Dreiding molecular models reveals the possibility of chelate
structures, characterized by intramolecular hydrogen bonding, for IIa-E" and IIa-Z", without
any significant changes in either bond angles or bond lengths. From a stereochemical view-
point, chelate formation should be especially favorable in the case of an spS-hybridized
exocyclic nitrogen atom. CNDO calculations [6] of 2-amino-4-thiazolinone (Ia) give a popu-
lation density for the P~z orbital of N(2') of 1.757 (i.e., a ~-change of +0.243), which is
indicative of the significant sp 3 character of this'nitrogen atom. Three-dimensional models
also reveal that conformer IIa-E' can form a "cyclic" hydrate, which is facilitated by the
partial negative charge on N(3)I [2], and that the Z-conformer can exist in a chelate form,
IIa-Z', with CH20...S contact. The feasibility of the existence of form IIa-Z' is also sup-
ported by the calculated degree of ~=charge on the sulfur atom (+0.092) and by x-ray struc-
*The methylene protons of the hydroxymethyl groups in the chelate forms IId-E" and IIa-Z" also
experience downfield shifts for the same reason.

552
 TABLE i. ~3C-NMR Spectral Chemical Shifts for Compound lla

Assignment
6, ppm
a tom form

191,49 C(4) IIa-E'+IIa-E~,

191,03 C~4~ IIa-E
190,67 C(4) I Ia-Z + IIa-Zt+ I I a-Z"
186,59 IIa-Z+ IIa-Z'+IIa-Z"
184,91 CI2> IIa-E+ IIa-E'+IIa-E"
74,85 N--C IIa-Z+ IIa-Z'+ I Ia-Z"
71,1l N--C lla-E+lla-E'+IIa-E"
43,50 C(5) IIa-Z + lIa.Z" + IIa-Z"
42,41 C(s) IIa-E+ IIa-E'+Ila-E"

ture analysis of the almost isoteric compound, 2-amino-4-triazolinone-5-caboxylic acid [7]

(S-..0 distance, 2.96 A, compared to the sum of van der Waals raddi, 3.25 A).

H2C~N "- ...N~;

.. "~'" ~ .....

H [Ia-E" H H
k o ,

o ~-----~,~ / *~7-- -~

2 ~NAs -~. . . . . " o "~ ~NW's'" "'---

H It
I I a -E' IIa -E
o ~__~o
N-~-- - N ....f"
"-
"---- '+ J
m'~%~<'s"~ ....
"" "'N A s "--- <S . y
0/CH2 H~C~'o" HlC~ 0/H
I I
n IIa-z H IIa-Z' IIa-z"

Form I I a - E " i s c h a r a c t e r i z e d by a s t r o n g s i g n a l f o r t h e NH g r o u p p r o t o n a t 8 . 7 8 ppm a n d

by a d o u b l e t f o r t h e NCH= g r o u p p r o t o n s a t 5 . 0 2 ppm; f o r m I I a - Z " , o n t h e o t h e r h a n d , e x h i b i t s
t h e c o r r e s p o n d i n g s i g n a l s a t 9 . 0 0 ppm ( b r o a d s i g n a l ) and a t 4 . 8 6 ppm ( d o u b l e t ) . The c h e m i c a l
s h i f t s o f t h e NH g r o u p p r o t o n s i n t h e s e two f o r m s a r e v i r t u a l l y identical to the chemical
shift for 2-amino-4-thiazolinone (Ia), which is indicative of the absence of strain in the
chelate structures. The signals due to the methylene protons of the heterocycle overlap for
forms iIa-Z and IIa-Z", whereas the corresponding resonance for isomer IIa-E" occurs at 4.02
ppm. Upon protonation, i.e., complete transfer of a proton to N(3) [9], the C(s)H2 proton
signal is shifted downfleld [8]. At a concentration of 200 mmole/liter, the an~ounts of forms
Ila-Z and lla-Z', on one hand, and form IIa-Z", on the other hand, are approximately equival-
ent, while the ratio (Ila-E + IIa-E')/(IIa-E") is about 3:1.* Addition of DIO results in the
disappearance of the signal multiplicity for the NCH2 group protons,
Changes in the concentration of compound lla, within the range 0.9-620 mmole/liter, do
not affect the signal positions for the mobile (active) NH and OH group protons. As the con-
centration is lowered, however, the amount of the chelate forms decreases; at a concentration
of 0.9 mmole/liter, (Ila-E + !la-E')/(Ila-E") is about i0:i, and (IIa-Z + IIa-Z')/(IIa-Z '~)
is about 3:1, whereas the ratio of the "open" forms, (IIa-E + IIa-E'~/(IIa-Z + IIa-Z'), equals
about 2.7:1, which is almost unchanged. Decreasing the concentration of the chelate forms ap-
parently does not result in diminution of the intensity of the high field components of the
NH group proton signals. Thus, the (Ila-E + iIa-E')/(IIa-E") ratio changes from 3:1 to 5:1
a~ the concentration is lowered from 200 to 45 mmole/liter, but the intensity ratio for the
9.70 and 8.78 ppm signals remains unchanged at about 1.7 (see Fig. Ib). We attribute this
observation to preferred solvation of the open forms Ila-E' and IIa-Z' by residual water pre-
sent in the solvent, which is in excess compared to the small concentration of sample which
is present in solution; specific solvation of the hydroxyl groups in chelates IIa-E" and
]la-Z" facilitates their cleavage and transition to the "open" forms IIa-E' and IIa-Z', which
are characterized by transoid configurations of the kL-H and CHI--O bonds. The signals due to
*Estimated based on the relative signed intensities of the NCH2 group methylene protons.

553
 b a

A
1; ; 8 7 r ............. 3
,~, ppm

4 6,ppm & ppm

_ ..1 . . . . . . . . . . s_ . . . . .

lo 9 3 2 & ppm

I v

lO 9 7 6 4 3 2
~.ppm
Fig. 2. PMR spectra of 2-hydroxymethylamino-4-thiazolinone
lla: a) in purified and dried DMSO-d6, 60 MHz, concentra-
tion 60 mmole/liter; b) same sample, after addition of D20
to the sample tube, 270 MHz; c) same sample at 47~ d) same
sample at 83~ e) same sample at 92~ f) in DMSO-d6 in the
presence of catalytic amounts of acetic acid~ 60 MHz, concen-
tration 620 mole/liter , recorded immediately after dissolv-
ing (i), and 5 min after the first spectrum (2); g) same sam-
ple in the presence of catalytic amounts of dibutylaniline.

the OH and CH2 group protons overlap in both forms lla-E' and lla-E", and lla-Z' and lla-Z";
these compounds differ only in the NH group proton signals, which are the same in forms lla-
E' and lla-E", and lla-Z' and lla-Z". The equilibrium shifts which accompany change in the
concentration of lla in DMSO-d6 solution are thus due to varying amounts of different solvent

554
 1 9 8 7 6 5 4 2 8, ppm
Fig. 3. PMR spectra of 5-methyl-2-hydroxymethylamino-4-
thiazolinone (lib): a) in purified and dried DMS0-d6 at
60 M~z and a concentration of i00 mmole/liter; b) same
sample after addition of D20 to the sample tube.

complexes. Dimerization (self-association) schemes, although structurally possible for com-

pounds of similar structure [3], cannot explain th~bserved spectral changes, in particular,
the changes in signal intensities for the discrete forms of compound lla, which accompany
concentration variations.
At a lla concentration of 0.9 mmole/iiter, the amount of excess water (relative to the
amount of dissolved substrate), and the presence of very small amounts of acidic impurities
therein, suppresses spin-spin coupling of the CHm--OH group protons, although spin-spin coup-
ling of the CH2--NH group protons in form lla-E is retained. At this concentration, spin-
spin coupling of the CH2--NH group protons is also observed in form lla-Z" (6CH = 4.86 ppm, J =
4.9 Hz). Apparently, specific solvation of the N(3) atom (calculated charge, --0.535 [2]) by
excess water results in steric conditions which favor exchange processes for the NH group
proton in form lla-Z".
13C-NMR Spectra. The recorded ~3C-NMR spectra of compound lla allow us to rule out pro-
totropic tautomerism as the reason behind the complex PMR spectra; in particular, the C(2)
and C(~) signals are in the same position as for the amino tautomer [3]. The N-C and C(5)
methylene carbon atoms are sensitive to the E $ Z conformational equilibrium about the C(z)--
N(z,) bond (the intensity ratio of the weak field and high field signals is about 1:2), but
apparently are not sensitive to chelation or to the orientation about the CH2--N bond (see
Table I). The C(~) carbon atom is sensitive not only to the E + Z equilibrium, but also to
chelate formation and formation of isomer lla-E'.

Dynamics and Mechanism of Transitions. In several instances we observed PMR spectra of

compounds lla and lib in which the equilibria involving form II-E, on one side, and forms
II-E' and II-E", on the other side, had not yet been established. It appears that in high-
purity DMSO-d6, which does not contain acidic or basic impurities which can catalyze inter-
conversion about the N(z')--CHz bond (as might be expected, this is DMSO which is virtually
free of water), the rate of the II-E ~ II-E' transition is very low. The conversion barrier
is controlled by the degree of orbital overlap for the hydroxyl oxygen, C(=) carbon, and N(s)
nitrogen atoms in the case of the lie liE' equilibrium, and for the hydroxyl oxygen, C(2)
carbon, and S(~) sulfur atoms in the case of the IIZ ~ IIZ' equilibrium. Either protonation
of N(3) [9] or deprotonation of N(2') changes the hybridization of the nitrogen atoms in such
a way that the geometry of the amide fragment permits a decrease in the barrier for rotation
about the N(2')--CH2 bond. It is assumed that the degree of spm-hybridization of the N(2,)
nitrogen atom increases upon both protonation [9] and deprotonation (the calculated ~-6rders
for the N(2)--C(2) and N(3)-~(2) bonds in the 2-methylamino-4-thiazolinone anion are 0.726
and 0.523, respectively). Examination of Stuart--Dreiding molecular models also reveals that
rotation about the N(z')--CHz bond in the E-conformers is not hindered by sp2-hybridization of
the N(2,) atom, but is strained in the Z-conformers. We cannot propose any arguments to
account for the fact that the barrier for the IIZ IIZ' conversion is so much lower than
that for the liE liE' barrier, since we did not detect any catalytic effect which would in-
crease the rate of the IIZ IIZ' transition.

555
 Finallyj the rate of the uncatalyzed partial proton transfer for the lIE' ~ liE" con-
version is also iowD which may be explained in terms of hindered rotation about the CHa-O
bond as a result of overlap of the p-orbitals of the oxygen atom and both nitrogen atoms, as
well as by the characteristics of the proton transfer reaction [i0]. In any event, as can
be seen in the P~LR spectrum reproduced in Fig. 2a, the proton signals for form lla-E" at 5.02
and 4.02 ppm are just barely discernible, whereas the signal at 8,76 ppm is totally missing,
According to the relative intensities of the multiplet components for the N-CH~ group protons,
form lla-Z" is present in solution in equilibrium amounts. Addition of D20* to the sample
tube (Fig. 2b) or increasing the temperature (Fig. 2c) leads to an increase in the concentra-
tion of isomer Ila-E" up to its equilibrium value,~ although in the latter case, higher tem-
peratures are also accompanied by collapse of the spln-spln multiplets and coalescence of the
signals due to the "open" c0nformers, and by collapse of the doublet due to form IIa-Z" (Fig.
2d); still higher temperatures lead to collapse of the spln-spln doublet of form IIa-E". Cat-
alyticamounts of acetic acldimpurlty also increase the rate of both rotation and chelation, and
repeated extractions allowed us to follow the increase in the concentration of form lie-E" up
to its equilibrium value (Fig. 2f); the presence of acids increases the rate of exchange of
the hydroxylic protons and suppresses spln-spln interaction of the CH2-OH groups, while pre-
serving spln-spin coupling of the CHa-NH group protons.
In contrast, catalytic amounts of dibutylaniline accelerate proton exchange of the NH
groups, and thus suppress spin-spin coupling of the CHa-NH groups while retaining spin-spin
coupling of the CH2-OH groups (Fig. 2g), Spectrum 2g is characterized by the almost complete
disappearance of themethylene proton signals for form IIa-E" as well as by the intensity of
the signal at 8.76 ppm due to the NH group proton. This demonstrates that in the presence of
basic impurities the Ila-E ~ lla-E ~ conversion proceeds very rapidly, and equilibrium is
achieved between these two forms, whereas the rate of uncatalyzed chelation is very slow, and
as a result the Ila-E' ~ Ila-E" equilibrium is achieved at a much slower rate.
Analogous spectral results were obtained for 5-methyl-2-hydroxymethylamino-4-thiazolinone
(lib). As an example, in neutral DMSO-d~ which contains neither acidic nor basic impurities, form
lib-E" is scarcely detected (Fig. 3a) Just as was observed in the case of compound Ila, but
addition of DaO results in a significant incrdase in its concentration (Fig. 3b).

EXPERIMENTAL
PMR spectra sere recorded on Tesla BS-467 (60 MBz), Bruker HX-270 (270 MHz), and Bruker
KX-90 (90 MHz) spectrometers in DMSO-d6 solution versus HMDS as internal standard. DMSO was
purified as reported earlier [3]. The mass spectrum of compound lla was obtained on an MX-
1313 spectrometer using direct sample injection and an ionizing current of 70 eV at a source
temperature of 100=C. The derivatograph of compound lla was recorded on a derivatograph ap-
paratus of F. Paulik, I. Paulik, and L. Erdey "(Hungary).
2-Hydroxymethylamino-4-thiazolinone (lla). A mixture of 4.6 g (40 mmoles) of compounds
lla and 16 ml (200 mmoles) formalin in 30 ml of ethanol was stirred for 5 min at 70~ until
all of the starting material precipitate had dissolved. The resulting precipitate of lla
which was obtained after cooling the reaction mixture was washed with ethanol and crystallized
from idoxane. In the presence of equimolar amounts of either dimethylaniline or dibutylaniline
compound lla can be obtained at room temperature by stirring the reaction mixture for 30-40
min and filtering the resulting precipitate due to product. Yield 5.8 g (99%), mp 1600C.
IR spectrum (Vaseline oil): 3300 (OH), 3250 (NH), 1675 (C=O), 1550-1570 (C=N). UV spectrum
(in ethanol), %max, (log e): 220 (4.22), 250 nm (3.90). Found: N 18.9; S 21.3%. C~H6N2OaS.
Calculated: N 19.2; S 21.8%.
Compound llb was prepared in a similar manner from 5-methyl-2-amino-4-thiazolinone (Ib).
Yield 89%, mp 166~ IR spectrum (vaseline oil): 3290 (OH)', 3240 (NH), 1685 (C=O), 1550-1590
(C=N). UV spectrum (in ethanol), kma x (log ~)~ 221 (4.21),249 nm (3.88). Found: N 17.7;
S 19.8%. CbHsN202S. Calculated: N 17.5; S 20.0%.

*The accelerating effect of D20 can be attributed not only to an isotope effect ii , but also
to the fact that D20 contains an acidic impourty which catalyzes rotation and proton transfer.
tlncreasing the temperature also increases the concentration of the energetically unfavorable
form lla-E", which can be seen in Fig. 2c-f.

556
 LITERATURE CITED
i. S . M . Ramsh, S. Yu. Solov'eva, and A. I. Ginak, Khim. Geterotsikl. Soedin., No. 7, 928
(1983).
2. Yu. G. Basova, Candidate's Dissertation, Chemical Science, Leningrad (1980).
3. S. M. Ramsh, N. A. Smorygo, E. S. Khrabrova, and A. I. Ginak, Khim. Geterotsikl. Soedin.,
No. 4, 544 (1986).
4. R. Baibl, Interpretation of Nuclear Magnetic Resonance Spectra, Atomizdat, Moscow (1969)
p. 77.
5. A. I. Kol'tsov and G. M. Kheifets, Usp. Khim., 41, 875 (1972).
6. B. E. L'vovskii and G. B. Erusalimskii~ Koord. ~ i m . , ~, 1221 (1976).
7. V. Armithalingam and K. V. Muralidharan, Acta Cryst., 28B, 2417
8. S. M. Ramsh, n. A. Smorygo, and A. I. Ginak, Khim. Geterotsikl. Soedin., No. 8, 1066
(1984).
9. S. M. Ramsh, A. I. Ginak, N. A. Smorygo, Yu. G. Basova, and E. G. Sochilin, Zh. Org.
Khim., 14, 1327 (1978).
i0. I. P. Gregerov, V. K. Pogorelyi, and I. F. Franchuk, The Hydrogen Bond and Rapid Proton
Exchange [in Russian], Naukova Dumka, Kiev (1978), p. 204.
ii. R. V. Hoffmann, Mechanisms of Chemical Reactions [Russian translation], Khimiya, Moscow
(1979), p. 258.

ACID DEUTERIUM EXCHANGE IN BENZAZOLES

I. F. Tupitsyn, N. N. Zatsepina, UDC 547.72+546.11.02.2:541.127
A. I. Belyashova, and A. A. Kane

The kinetics of acid deuterium exchange in benzazoles carryingelectron-donor

substituents in the 5-, 6-, or 7-positions have been studied. Mass spectrometric
studies have shown that exchange in 5-methoxy-l,2-dimethylbenzimidazole takes
place exclusively at one position in the benzene ring, in 5-chloro-, 7-chloro-,
5-methoxy-2-methylbenzothiazole and 6-methoxy-2-methylbenzoxazole simultaneously
in two positions, and in 6-methoxy-2-methylbenzothiazole the hydrogen at all
three possible positions is exchangeable. Using quantum chemical reactivity
indices (CNDO/2) in dynamic and state approximations, the orientational features
of the reaction have been ascertained. The lack of agreement between the reac-
tivities of the most reactive sites to exchange in heteroaromatic bicycles of
similar structure and electrophilic localization energies is explained by dif-
ferences in the energy profile of the reaction.

Continuing studies of proton-deuterium exchange (H--D exchange) in bicyclic heteroaroma-

tic systems [I], we have measured the rate constants for the reactions of some substituted
benzazoles. The acid-initiated H--D exchange reaction in condensed five- and six-membered
aromatic heterocycles with two heteroatoms in the ring has received considerably less atten-
tion [2, 3] than, for example, in quinolines and isoquinolines [4-6], and no such studies
have been carried out in benzazoles. However, for the elucidation of factors governing
changes in electrophilic reactivity, such studies are of considerable interest for theoreti-
cal heterocyclic chemistry as a whole.
The n-electron deficient parent compounds of this series (benzothiazole N-methylbenzi-
midazole, and benzoxazole) appear to be totally inert to acid H--D exchange in the benzene
ring. In order to facilitate the occurrence of exchange reactions we introduced into the
benzene ring, as on a previous occasion [i], an activating substituent (chloro- or methoxy-)
in the 5-, 6-, or 7-position of the benzazole nucleus. In addition, in order to be able to

State Institute of Applied Chemistry, Leningrad. Translated from Khimiya Geterotsikli-

cheskikh Soedinenii, No. 5, pp. 679-687, May, 1986. Original article submitted February 18,
1985.

0009-3122/86/2205-0557512.50 9 1986 Plenum Publishing Corporation 557

 TABLE 1, Experlmental Results for Acid H--D Exchange in
Chlorobenzo thiazoles*

Time, Deuterium distribution,~]o

cpm-
pound
o~' h ~di, % h',~. ZOL,'?
sec-I

140 24 70 28,0 16.0 0,24

140 30 70,3 36,8 16,2 0,19
140 40 58,2 38,4 24,0 0~
160 6,0 78,6 21,4 I0,8 0,62
160 I0 65,7 30,7 18,9 0,68
160 16 54,4 39,5 25,8 0,61
180 2,0 56,6 36,5 25,2 4,8
180 6,0 29,9 46,9 (1,2) 47,4 4,3
200 1,0 34,0 45,9 (1.3) 43,8
I! 140 24 89,4 10,5 5,4 0,080
140 48 80,7 19,3 9,6 0,067
160 I0 60,3 33,8 22,8 0,84
160 16 47,3 41,5 32,1 0,80
160 20 41,0 44,7 36,6 0,76
180 6,0 54,3 39,0 26,1 1,6
180 8,0 40.8 44,2 (0,3) 37,2 1,9

*Zd i and K D values relate to the two replaceable atoms.

%In calculating K D from the first-order equation, allowance
was made for the equilibrium concentration of deuterium (88%).

compare the results of measurements of H-9 exchange in benzazoleswith those reported in [i]
for quinolines, the reaction medium employed was a mixture of CFsCOOD, DCIO~, and D20 in the
same molar proportions as in [i] (91.8 moles of CFsCOOD, 2.5 moles of DCI0~, and 5.7 moles
of DsO). Comparison with quinolines was necessary in order to obtain information on the
nature of changes in electronic interactions consequent upon replacement of a vinylene CH=CH
group in the conjugated blcycllc system by a sulfur or oxygen atom, or the NCH3 group.
The subjects of the study, experimental conditions, the isotopic composition of the
benzazoles following H--D exchange from mass spectrometric data, and the rate constants cal-
culated from the first order reaction equation are shown in Tables 1 and 2.
Since compounds deuterated in a given position in the heteroaromatic ring are extremely
difficult to obtain, we measured the H--D exchange rates in benzazoles of natural isotopic
composition with a deuterated solvent ("direct" exchange). These was no possibility of H--D
exchange in the 2-position in these compounds, since it was protected by the methyl group,
but the use of this method involved difficulties of interpretation as to which of the non-
equivalent sites in the condensed benzene ring was the most reactive.*
As a result of the inadequacy of chemical information on the orientation of electrophilic
reagents in the benzazole ring when activated by electron-donor substituents, we had recourse,
in analyzing the experimental findings for H--D exchange, to quantum chemical calculations of
reactivity indices: the ~-electron charge on the ring carbon atoms (qz(Ci)) and the electro-
philic localization energy Le(Ci). These indices were calculated by the standard PPDP/2 meth-
od. All calculations of the qz and L e values were carried out for compounds unsubstituted in
the 2-position by a methyl group, since in their ability to undergo electrophilic condensations
in the condensed benzene ring these compounds are similar to their 2-methyl derivatives (see,
e.g., [7]). The reactivity indices for these benzazoles in respect of H--D exchange are shown
in Tables 3 and 4.
The compounds under study were divided into two groups in accordance with the results ob-
tained: l) 5- and 7-chloro-2-methylbenzothiazoles (I) and (II), which have a lesser tendency
to undergo acid H--D exchanges since the unshared electron pairs of the chlorine participate
insufficiently effectively in the Pz conjugation with the n-electrons of the ring, and 2) 5-
and 6-methoxy-2-methylbenzothiazoles (III) and (IV), 1,2-dimethyl-5-methoxybenzimidazole (V),
and 2-methyl-6-methoxybenzoxazole (VI), in which as a result of stronger p~ conjugation the
heterocyclic system is less n-deficient and hence more reactive in H--D exchange.

*Attempts to identify directly the site of isotripie substitution by *H NMR and IR spectro-
scopy did not provide unambiguous information

558
 TABLE 2. Experimental Results for Acid H--D Exchange in
Methoxybenzazoles*

Corn- Time, h Deuterium distribution, qo

K D 9 105',t
pound T,~ Zidi, %
do d~ d2 d3 : see -1

tlI 90 16 67,8 3I,I I,I I6,5 0,43

95 12 55,7 43,8 0,5 22,5 0,69
95 16 51,1 41,5 7,4 28,4 0,68
95 24 29,5 52,2 18,3 44,3 0,82
110 8,0 10,3 46,8 42,9 66,2 5,0
110 12 8,3 42,4 49,3 70,5 3,8
110 20 7,4 39,6 53,0 73,0 2,5
120 1,9 66,0 3 t ,4 2,6 18,5 6,6
120 2,0 36,9 49,6 13,8 38,2 7,9
120 4,0 18,1 52,6 29,3 55,7 8,6
125 1,0 35,0 49,4 14,6 39,6 17
IV 120 30 58,6 37,1 4,3 22,9 0,4
140 6,0 61,4 32,5 6,1 22,5 1,5
140 lO 51,9 3%0 8,7 0,4 28,8 1,2
140 16 36,7 55,5 7,8 31,5 0,87
140 24 24,2 61,4 14,4 45,0 0,95
160 2,0 67,7 28,6 3,7 18,0 3,5
160 6,0 25,8 43,0 24,9 6," 37,2 [2,9]
160 8,0 14,3 39,9 33,4 12,~ 48,3 [3..2]
180 1,0 20,9 41,2 28,6 9,~ 42,3 [9_1]
VS . 50 lO 79,9 20,1 -- 20,1 0,82
50 16 73,1 26,9 -- 26,9 0,72
50 24 60,0 39,8 -- 39,8 0,80
60 4,0 76,3 23,7 -- 23,7 2,.5
60 8,0 60,7 39,3 -- 39,3 2,4
60 18 33,1 62,6 4,3 35,5
70 1,5 74,7 25,3 -- 25,3 7.6
70 2,0 67,8 31,9 0,3 32,4 7,3
7O 8,0 26,1 65,5 8,4
VI 120 4,0 72,3 23,7 4,0 16,2 1,5
120 6,0 66,9 30,0 3,1 18,0 1,1
120 7,5 61,2 33,7 5,1 22,0 1,1
140 l,O 70,2 26,5 3,3 16,6 6,1
140 2,0 47,9 42,4 9,7 31,0 6,3
140 4,0 28,6 50,9 20,6 46,0 5,4
160 32 28,7 48,4 22,9 47,2 23
160 1,13 8,7 41,4 49,4 0,~ 70,6 (16)
160 4,0 6,6 37,0 55,5 0,! 75,0 (15)

~The Edl and K D values for (III), (IV) (partially for the
i
latter), and (VI) relate to two exchangeable atoms, and in
(V) to a single atom.
%H--D exchange in (III), (IV), and (VI), the equilibrium
concentration of deuterium was 80%. The values of K D in
square brackets are for three exchangeable atoms.
~The activation parameters of the Arrhenius equation were
E = 23.6kcal/mole, log A = 10.5, and the logarithm of the
rate constant at 120aC IogKD = --2.6.

i. The total inactivity of 5- and 6-chloroquinolines in H--D exchange in CFaCOOD with

added aqueous DCIO~ has been demonstrated previously [i] (no H--D exchange occurs at T 200~
and heating for 8-10 h). In contrast, (I) and (II) undergo exchange quite extensively (by
40-50%) at 180~ (Table i). This difference in the behavior of heteroaromatic bicycles is
explicable in terms of a general increase in the z-electron density in the condensed benzene
ring in benzothiazole as compared with the benzene ring in quinoline.
The task of determining the orientation of the electrophilic reagent in H--D exchange in
isomers (I) and (II) was complicated by the fact that here isotope substitution takes place
in two positions in the benzene ring. In fact, to judge from the low-voltage mass spectra
of samples of (I) and (II) following the experiments (Table 1), the strongest molecular ion
peaks d~ and du (m/z 184 and 185) are one or two units stronger than the molecular ion peak
do corresponding to the nondeuterated compound, whereas when the extent of deuteration is
fairly high (180-200~ the isotopic forms dl and du are present in comparable concentrations
Consequently, the reactivities of each of the exchangeable Dositions in the rin~ in

559
 TABLE 3. Calculated Reactivity Indices for E--D Exchange
in Chlorobenzothiazoles (PPDP/2 method)

Corn- Atom Localization energy, eV [ ~r-electron charges on ,

atoms, e - l g KD
pound No. neutral N-protonated I1 neutral N-protonated a t 18o~
molecule form I molecule form

13,5024 8,3747 -- 0,0400 -- 0,0400 4,35

12,9689 8,1099 --0,0532 --0,0096
13,2534 - 0,0050 +0,0209
13,1920 8,1736 -- 0,0192 -0,0175 4,75
..J2,6254 7,8261 -0,0018 +0,0463
12,8055 8,0199 -0,0175 +0,0241

(I) and (II) may differ, but not to such an extent that H-q) exchange in each can be clearly
differentiated.
From the quantum chemical point of view, the directivity of the H--D exchange reaction
remains unclear in respect of which form, uncharged (neutral) species of the cyclic nitrogen-
protonated forms of these compounds are involved in the exchange reaction. For this reason,
calculations of the electrophilic localization energies in (I) and (II) were carried out in
two versions, in one of which ll--D exchange in the neutral molecule is considered, and in the
other, the benzothiazolium cations. Calculations of both types were carried out on the sp-
basis for the sulfur and chlorine atoms.
As will be seen from Table 3, protonation of (I) and (II) does not result in any changes
in the predicted orientation of the electrophilic agent. In both versions of the calculation,
position 4 has the lowest localization energy, follo@ed by position 6, where strictly speak-
ing attack of the deuteron should occur during H-D exchange in (I) and (II).
The calculated values for the ~-electron charges on the atoms both in the neurral mole-
cules and their N-protonated forms are in qualitative agreement with those predicted from the
reactivity indices: The L e for values positions 4 and 6 correspond to the most effective
~-charges.
In order to be able to relate the relative reactivities of different positions in the
carbocyclic ring of the benzothiazole nueleuswith the fine structure of the annelated rings,
we turned to the ~-isoelectronic analog of (I), 2-chloronaphthalene. The H--T exchange re-
action has been studied in detail [8] for the latter compound. In particular, it follows from
this study that the rate constant for the reaction with 2-chloronaphthalene-l-T is some 8-10
times greater than with 2-chloronaphthalene-T-3. It appears that approximately the same ratio
of KD(Ct~)) to KD(C(~)) is maintained in the benzazole analog of 2-chloronaphthalene, namely
(I). This is shown indirectly by the isotopic composition of samples of (I) following H--D
exchange carried out under conditions favoring low and high extents of deuteration. For ex-
ample, at 140~ for 24-30 h, when the rate of exchange of the less active position should not
be immeasurably great, the mass spectra contain a relatively strong dx peak (m/z 184), cor-
responding in all likelihoo4 to the 4-deuterated compound(1). Unde~ more sever~ conditions
(180-200~ as already indicated, a mixture of the dx and da forms is seen.
These findings therefore argue in favor of the absence of significant changes in the re-
lative reactivities when passing from the carbocycle to its benzothiazole analog, and also of
a marked shift of ~-electron density from the condensed benzene ring to the azole ring [in
contrast to (I) and (II), in i- and 2-chloronaphthalene the hydrogen atom undergoes exchange
in anhydrous CFaCOOH (an acid of "moderate" strength) even at 70~
2. From the point of view of elucidating the mechanism of the mutual effect of the
rings, of considerable value are quantitative data describing the ratios for the H-~ exchange
rate constants in separate positions in the benzene ring in methoxybenzothiazoles, benzimida-
zoles, and benzoxazoles. We did not have at our disposal entire series of isologous benza-
zoles with methoxy-substituents in the same position in the condensed benzene ring, and for
the comparison of relative reactivities we were obliged to study the kinetics of R--D exchange
in pairs of 5-substituted (III, V), 6-substituted (IV, Vl), and 5- and 6-methoxybenzothiazoles
(III, IV).
Consideration of mass spectral measurements for (III) (Table 2) shows that the rate of
H--D exchange in this compound is similar in the two positions of the benzene ring. It is

560
 TABLE 4. Calculated Reactivity Indices in H-D Exchange
for Methoxybenzazoles (PPDP/2 m e t h o d )
v-Electron chargeson
Com- A tom Localization energy atoms,
- l g KD
pound* No. neutral N-protonated neutral N- protonate d at,120 ~
molecule form molecule form

III 4 13,8570 8,8306 --0,0765 -0,0785 4,2

(13,7675) (-0,09~8)
6 13,3715 8,5311 -0,0614 -0,0Z89
(-0,0680)
7 13,3612 8,3815 +02069 +0~-296
(+0,0453)
IV 4 13,2824 8,0489 +0,0048 +0,0125
(13,1734) (-0,0082) (--0,0120)
5 12,4983 8,1125 -0,0511 --0,0077
(12,5712) (7,6506) (-0,0212) (+0,0350)
7 13,9065 9,0938 --0,0742 --0,0610
(13,8008) (8,9184) (--0,0395) (-0,0203) 5,6
V 4 13,5430 8,4654 - 0,0710 --0,0728 2,6
6 13,1540 8,2672 -0,0587 --0,0154
7 12,8847 7,8499 -0,0276 +0,0001
VI 4 13,0005 7,6775 -0,0042 +0,o012
5 13,2468 8,3525 --0,0556 --0,0090 4,9
7 13,0321 8,2515 -0,0830 --0,0735

*For (III) and (IV), calculations are given on the sp-

basis for the sulfur atom, calculated values on the spd-
basis being given in brackets.

assumed that as in (I), and for the same reason, isotope substitution takes place in positions
4 and 6. Calculations of Le and q~, carried out both on the sp- and the spd-basis for the
sulfur atom, confirm these conclusions as to the sites of initial attack.*
In contrast to (III), H--D exchange in (V) is highly selective; prolonged heating at 60-
70~ resulted in only one hydrogen being involved in H--D exchange (a strong peak with m/z 177
is seen in the mass spectrum). CNDO/2 calculations in this case also favor the preferential
orientation of the attacking electrophile in the 4-position, both from the localization ener-
gies and from the ~-electron charges (Table 4).
As will be seen from Table 2, the reactivities in H--D exchange of the most reactive po-
sition in (V) and (III) are in the ratio of nearly i0~'~i. Such a marked drop in reactivity
on passing from (V) to (III) is undoubtedly due to the relatively great n-deficiency of the
penzothiazole system, and the increased influx of T-electrons from the azole to the benzene
ring in the benzimidazole system. The latter is in accordance with the general chemistry of
benzimidazole, which is characterized by electrophilic rather than nucleophilic substitution
in the benzene ring.
The high positional selectivity of H--D exchange in (V) reflects the known naphthalene-
like bond localization in the benzimidazole nucleus. It is worth mentioning in passing that
the further loss of conjugation between the benzene and azole rings which appears to occur in
l-benzyl-5,6-dimethylbenzimidazole as a result of steric hindrance created by the adjacent
methyl groups favors even more strongly accelerated acid H--D exchange. In contrast to (V)
the exchange products of which contain predominantly monodeuterated compounds, samples of the
former compound contain mono-, di- and trideuterated compounds (at 140~ for 8 h, KD = 2.3.10 -~
see-l; mass distribution do 40.9; d I 37.8; d2 18.0; ds 3.3%).
Concluding the comparison of the results for (III) and (V), it may be concluded that
both the quantum chemical approaches used (dynamic and static) provide explanations of the
directivity of H--D exchange within a single molecule. Unfortunately, these approaches do
not provide information on the changes in the rate of the most "reactive" position depending
on the nature of the second heteroatom in the azole ring. It has in fact been found experi-

*Bearing in mind that all the methoxy-compounds (lll-Vl) possess basic properties, and that
H--D exchange takes place in a strongly proton-donating medium, we calculated, as in the case
of the chlorobenzothiazoles (I) and (II), the reactivity indices Le and q~ for the neutral
molecule and for the ring nitrogen-protonated form.

561
mentally that in (s the reaction proceeds at a measurable rate at temperatures 50-60~
higher than in the case of (V), whereas all our calculations predict that the anlogous ben-
zothiazole system should be more reactive. In our view, this discrepancy is due to the dif-
ferent energy profile of the reaction. It is considered to be likely that in the case of
(ZIZ) the relatively low rate of reaction is due to the formation of a stable o-complex
which requires high temperatures for its aromatization. On the other hand, in the case of
(V) a transition state wlth partial charge transfer is formed, the reason for the high re-
action rate being perhaps optimum coupling of ease of addition of a deuteron and elimination
of a proton at the intermediate stage.
Turning now to a consideration of the experimental findings for H-D exchange in the 6-
substituted benzazoles (IV) and (VI), the stepwise nature of the exchange reaction in (IV)
is noteworthy. As will be seen from Table 2, in the products of H--D exchange carried out un-
der relatively mild conditions (140~ 6-24 h), deuterium is distributed with nearly equal
probability between the two positions of the benzothiazole ring, whereas after more exten-
sive exchange under more severe conditios (160-180~ a mixture of three isotopic modifica-
tions (d,, d~, and de) is formed. This equalization of the reactivlties of the indJvldual
positions in the rir~, in our opinion, is evidence of the fact that (IV) is more highly aro-
matic than the other benzazoles studied.
Calculations of the reactivity indices for (IV) in two forms (nonprotonated and proton-
ated) and in two versions (sp and spd) lead to the conclusion that positions 7 and 4 are
relatively hlghly-activated towards H--D exchange, and that position 5 is very weakly activated.
This is not in accordance with our experimental findings of the small differences in reactivity
between positions 7, 4, and 5.
Attempts to obtain a monodeuterated product from H--D exchange with (VI) by carrying out
the reaction at low temperatures (120~ were unsuccessful (Table 2). As in the case of (IV),
two atoms in the condensed ring undergo exchange in CFsCOOD, but in this instance the third
hydrogen atom is not exchanged for deuterium even under the most severe conditions (160~ 4
h). The calculated localization energies show that in H-D exchange the electrophile must at-
tack (VI) predominantly in the 5-posltlon, i.e., the 8-1ike-position, rather than the u-
position as in (IV). On the other hand, calculations of w-electron charges appear to indicate
maximum attack in the 7-position. The directlvity of attack in the acid H--D exchange reaction
in (Vl) will require further investigation.
Before discussing the differences in reactivity in the isomeric methoxybenzothiazoles,
it is also worth pointing out that according to its calculated L e and qz values (IV) should
be more reactive in respect of acid H--D exchange than (Vl) (Table 4), but this is clearly not
in accordance with the experimental findings (Table 2).
Comparison of the rates of exchange in the isomers (III) and (IV) shows that the 5-
methoxy substituent is scarcely more effective than the 6-methoxy substituent. This appears
to be due to the fact that the methoxy-substituent in the 6-position of the benzothiazole
nucleus is conjugated with the nitrogen atom, resulting in an additional shift of z-electron
density from the annealated benzene ring to the heterocyclic part of the molecule (it is also
possible that the smaller activating effect of the 6-methoxy substituent is due not only to
its direct electronic effect~ but also to its ability to facilitate protonation of the pyri-
dine nitrogen, which in turn facilitates the reaction of (IV) with the electrophile as the
conjugate acid). In contrast, the 5-methoxy substituent, which is located meta to the nitro-
gen atom, exerts its T-donor influence to a greater extent on the nearest atom C(~), on which
a higher negative charge is concentrated. This modifies the z-electron charge on the most re-
active positions in (III) and (IV), but not their localization energies Le (Table 4).
In order to evaluate more fully the properties conferred on the isoelectric analogs of
6-methoxyisoquinoline by the second heteroatom, it was of interest to compare the observed
changes in the exchange capacity of (VII) and benzazoles (III) and (V) (formally obtained by
replacing the carbon-carbon double bond in (VII) bysulfur or NCHs) with theoretical assess-
ments of electrophilic reactivity in H--D exchange. Such comparisons were made with the local-
ization energies and the z-electron charges on C(s) in (VII) (the values of Le and q are given
in [I]), and C(~) in (III) and (V) (Table 4), these being the most active reaction sites in
these molecules. The rate constants KD show the following order of increasing reactivity:
(VII) < (III) < (V). According to their L e indices, these compounds are arranged in a differ-
ent sequence: (V) < (III) < (VII) (calculated values of L e for H--D exchange in the neutral
molecules). The relative reactivities of the same positions in (III), (V), and (VII) are

562
similarly not correlated with the T-electron charges on the atoms: (Vll) < (V) < (III). A
possible reason for these discrepancies is the structure of the transition state, intermediate
between a T-complex and the original reaction state (see above).
In order to provide a qualitative explanation of the observed changes in the reactivity
of the most reactive positions in the heteroaromatic ring in these compounds, we employed the
concepts of the valence scheme method. According to this, a measure of the relative stability
of the transition state in H--D exchange is provided by the humber of principal resonance struc-
tures, characterizing the extent of localization-delocalization of the T-electron in the
heterocycle.
The transition state in H--D exchange in (VII) is the system with the least delocalized
H-electron density, since this can be described by only one canonical formula (A), which re-
tains unchanged the arrangement of double bonds in the heteroaromatic nucleus; the other can-
onical form (B) has a quinoid structure, and its contribution to the resonance hybrid must be
considerably smaller.

1t ti
A B
The slightly greater T-electron delocalization in the transition state in liD exchange
in (III) may be due to the fact that here two energetically nonequivalent canonical forms (C)
and (D) are possible, which retain unchanged the T-system of the benzene ring.

II It
c D
Finally, the considerable stabilization of the transition state for tt D e x c h a n g e i n (V)
is the result of yet more delocalization of ~-electrons, due to the superimposition of two
energetically nearly equivalent resonance structures, (E) and (F):

CH3O~ .~. CII 3 CH30.~ ~ ' ~ " ~ /CH3

9 ("

CH~ CH3
E

It is worthy of mention that the above sequence of increasing reactivities of methoxy-

substituted heteroaromatic bicycles with respect to H--D exchange is also the sequence of de-
creasing CH-acidities of the methyl groups in quaternary salts of 2-methylquinoline and 2-
methylbenzazoles, obtained from base H--D exchange in aqueous media [9]. The interpretation
proposed by these workers [9] for the changes in CH-acidity is similar to that adopted here,
bearing in mind that those factors which promote stabilization of the transition state in
acid H--D exchange destabilize the transition state in base H--D exchange, and vice versa.

EXPERIMENTAL
The synthesis and purification of the compounds studied were carried out by standard
methods as described in [10-12]; see also reviews [13, 14]. Mass spectra were obtained on a
Soviet-made MI-1305 instrument with a modified system for introducing the sample directly
into the ion source, ionizing electron energy 14-16 for (1)-(IV) or 20 eV for (V). Cathode
emission current 0.45-0.50 mA. Inlet temperature 20~ Kinetic measurements of H--D ex-
change were carried out as described in [i]. CNDO/2 calculations were carried out using
previously described geometric parameters for the azole systems in their protonated forms
[!, 15]. The geometric parameters chosen for the substituents were standard [16].

LITERATURE CITED
1, I. F. Tupitsyn, N. N. Zatsepina, A. I. Belyashova, and A. A. Kane, Khim. Geterotsikl.
Soedin., No. 5, 636 (1986).
2. A. Ei-Anani, S. Clementi, A. R. Katritzky, and L. N. Yakhontov, J. Chem. Soc., Perkin
2, No. 7, 1072 (1973).

563
 3. S. Clementi, S. Lepri, G. Sebastiani, S. Gronowitz, C. Westerlund, and A. Hernfeldt, J.
Chem. Soc., Perkin 2, No. 9, 861 (1978).
4. U. Bressel, A. R. Katritzky, and J. R. Lea, Chem. Soc., B, No. 6, 4 (1971).
5. U. Bressel, A. R. Katritzky, and J. R. Lea, Chem. Sot,, B, No. 6, ii (1971).
6. V. P. Lezina, P. U. Stepanyants, L. D. Smirnov, N. A. Andronova, and K. M. Dyumaev,
Khim. Geterotsikl. Soedin., No. 12, 1647 (1972).
7. D. J. Evans, H. F. Thimm, and B. A. Coller, J. Chem. Soc,, Perkin 2, No. 9, 865 (1978).
8. C. Eaborn and P. Golburn, J. Chem. Sot., B, No. i0, 1112 (1968).
9. M. Bolga, A. Barab~s, V. D~nes, and F. Chiraleu, J. LaBel. Comp., 13, ii (1977).
I0. C. DiModica, E. Barni, and M. Delle, Gazz. Chim. Ital., 95_, 432 (1965).
ii. K. Tries and A. Wolter, Liebigs Ann., 527, 66 (1937).
12. Y. Mizumo and K. Adacbi, J. Pharm. Soc~Japan, 72, 745 (1952).
13. R. Elderfield (ed.), Heterocyclic Compounds [Russian translation], Vol. 5, Izd-vo
Inostr. Lit., Moscow (1961), p. 217.
14. P. N. Preston, Chem. Rev., 74, 279 (1974).
15. N. N. Zatsepina, I. F. Tupitsyn, A. A. Kane, and G. N. Sudakova, Khim. Geterotslkl.
Soedln., No. 9, 1192 (1977).
16. A. Gordon and R. Ford, Chemist's Companion [Russian translation], Mir, Moscow (1976).

BENZAZOLIN-2-THIONES IN THE MICHAEL REACTION.

2.* REACTION OF BENZOTHIAZOLIN- AND BENZOKAZOLIN-2-THIONES WITH
ACRYLONITRILE, ACRYLAMIDE, AND METHYL ACRYLATE IN THEPRESENCE
OF BASIC CATALYSTS

K. V. Anan'eva and N. K. Rozhkova% UDC 547.339.1'371'398.1'

787.3'789.6.04

Depending on the structure of the reagents and the kind of basic catalyst, the
addition of benzazolin-2-thiones to an activated double bond takes place at ei-
ther nitrogen or sulfur. Acrylonitrile, regardless of the catalyst, reacts at
the nitrogen atom. In the presence of sodiummethylate, addition to acrylamide
takes place only, and to methyl acrylate predominantly at nitrogen. In the pre-
sence of triethylamine, a mixture of compounds with a high content of S-derlva-
tives forms.

As is well known [2, 3], under conditions of basic catalysis azolin-2-thiones react as
ambidentate anions, and depending on conditions and reagent structure can give either S- or
N-derivatives. Thus benzothiazolin-2-thione reacts reacts with methacryloyl chloridein alkalin~
medium at the sulfur atom [4]. Addition of benzoxazolin-2-thione to methyl acrylate in the
presence of Triton B takes place at the nitrogen atom [5]. The products of the reaction of
benzothiazolin- and benzoxazolin-2-thiones with acrylonitrile in basic medium have been as-
signed the structures of both S-derivatives [6, 7] and N-derivatives [2, 5] by various authors.
In order to elucidate the dependence of the course of benzazolin-2-thione addition to an
activated double bond on reagent structure and kind of basic catalyst, we have studied the re-
actions of benzothiazolin- and benzoxazolin-2-thiones (la, b) with acrylonitrile (lla), acryl-
amide (lib) and methyl acrylate (llc) in the presence of triethylamine (TEA) and sodium meth-
ylate. The reaction was carried out at an equimolar ratio of reagents and catalyst in dry

*For i, see [i].

tDeceased.

Institute of the Chemistry of Plant Substances, Academy of Sciences of the Uzbek SSR,
Tashkent. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 688-690, May,
1986. Original article submitted February 13, 1985.

564 0009-3122/86/2205-0564512.50 9 1986 Plenum Publishing Corporation

 TABLm I. ~ynnnesls Conditions and Product Yields of Re-
action of Thiones Ia) b with Electrophiles IIa-c ~

Electro- Tim , Yield, %

p~le ,h reaetionprodue~ o f t a reaetionproduetsoflb

lla b 6,7 (lVa), 2,7 (l!V g) 6,3 (Wb), 1,00,Vd)

7,0 (IVa) 4,4 (IVb)
I la c 22,7 (1V~), 0,3 (Illc}, 1,0 (Illg) 27,8 (IVb), 1,3 (IIId), 2,6 (I~h)
40,0 (1Va), 0,8 (lllC), 0,7 (IIt g) 42,2 (tVb)
IIad 7,8 (IVa), 1,8 (Illg)
15,3 (IVa), 1,o (~i~)
IIbb 1,8 (IVc) 1,7 (1Vd) 0,7 (I~.t~
I Ib" 35,5 (IIib),6,7 (lVg) 31,9 (Illd), 5,1 (IVh)
Ucb 6,8 (IIle}, 13,8 (IVe), 5,7 (tVg) 17,3 (Wf), 2,3 (IVb)
3,3 (llle), 16,2 (I!Ve), 5,9 (1vg)
! I cc 63,7 (llle), 3,5 (IVe), 0,4 (II1 g,) 40,8 (IIIf), 17,5 (ItVf), 0,6 (lIIh~, 0,5
79,0 (Ille), 5,9 (We), 0,8 (Iltg) (tvb)
~Vc I9,0 (III g) 63,8 (IIbf), 27,3 (IVfj, 1,0 (IIIh), 0,5
O~:tO

*a) In toluene at ii0 0. b) In presence of equimolar amount

of sodium methylate, c) In presence of equimolar amount of
triethylamine, d) In presence of catalytic amount of tri-
ethylamine.

toluene at ii0 ~ for 1-5 h. Depending on the catalyst and the structure of the reagents, pro-
ducts of reaction at both sulfur (IIIa-f) and nitrogen (IVa-f) are formed (Table i). Fur-
thermore in each reaction, products were found that could not be identified.

+ CH2=CHR ~ I +
X S IIa-C SCH2CH2R S

m.b m a-f ,va-f

Ia X=S, b X=O; lIa R=CN, b R=CON~, c R=COOCHa; III, I V a . ~ e . g X = S ,
b, d, f, h X=O; a, b R=CN, ~ d R=CONH2, e, f R=COOCH3, g, hR=COOH

According to the distribution of electron d e n s i t y a t t h e B - c a r b o n o f t h e C=C b o n d [ 8 ] ,

acrylonitrile is the most electron-deficient; regardless of the kind of basic catalyst (TEA,
CH3ONa) or solvent (toluene, methanol), it reacts predominantly at the rigid basic center of
the ambifunctional anion, viz., the nitrogen atom. The kind of catalyst exerts a decisive
effect on the course of the reaction of benzazoline-2-thiones with the less rigid electro-
philes. According to the UV spectrum for compound Ia.TEA) kma x is 335 nm, i.e., access is
open to the soft reaction center, viz., the sulfur atom (for S-derivatives, kmax is 278
nm). For this reason, apparently, thiones Ia, b react with electrophiles IIb, c to form a
mixture of products with a high content of S-derivatives. For the sodium salt of thione la,
%max is 312 nm (for N-derivatives, 328 nm), and addition to amide IIb takes place only, and
to ester IIc predominantly, at the nitrogen atom.
Because of the thermal instability of the reaction products under the test conditions
it is not possible to relate the reactivity of the test electrophiles to the parameters that
characterize the double bond.
In order to determine the path by which the N-derivatives form, the possibility of S-
analog isomerization in the presence of sodium methylate and TEA was tested. When ester
IIIe was heated with TEA at ii0 ~ along with unchanged S-product, 9.7% of N-isomer IVe was
isolated. This permitted us to consider that some ester IVe formed when compounds Ia and
IIc react, as a result of isomerization of the main reaction product. In the other cases no
isomerization was observed, and consequently it can be concluded that direct N-alkylation
occurs along with S-alkylation.

In the reaction of thiones Ia, b with electrophiles IIa-c besides the principal products
the corresponding acids IIIg, h and IVg, h were separated. Two routes to their formation
can be presumed: hydrolysis of the reaction products, or initial hydrolysis of electrophiles
IIa-c to acrylic acid followed by reaction with la, b. The ability of IIIa-f and IVa-f to
hydrolyze under the reaction conditions, which we verified, permits us to consider the first
route as more likely. Furthermore when Ia, b react with acid V under the same conditions

565
(CH3ONa or TEA, ii0 ~ 5 h) only the S-derivatives IIlg, h form. This also confirms that in-
significant amounts of acids IVg, h form by hydrolysis of the products of the reaction of
IIIa-f with IVa-f.

EXPERIMENTAL
IR spectra were obtained in KBr tablets with a UR-20 spectrophotometer; UV spectra, on
a Hitachi EPS-3T spectrophotometer; mass spectra, on an MX-1303 instrument. The identity and
purity of the synthesized compounds were monitored by TLC on Silufol-254.
Product yields were calculated from the optical density of the alcohol extract of frac-
tions separated by TLC [1].
3-(3-Benzothiazolinyl-2-thiono)propionitrile (IVa). A mixture of 1.67 g (I0 mmoles) of
thione Ia, 0.5 g (i0 mmoles) of acrylonitrile, and 1 g (10 mmoles) of triethylamine (or 2.2
ml of a solution of sodium methylate in methyl alcohol (10 mmoles Na)) was boiled in dry tol-
uene. After 5 h the mixture was cooled and the solvent removed. The dry residue was
treated with 5% alkali solution, then with water, to give nitrile IVa in 40% yield, mp 162-
163 ~ (from alcohol); according to [2], mp 162-163 = . Rf 0.87 (14:5 benzene-acetone).
3-(3-Benzoxazolinyl-2-thiono)propionitrile (IVb) was obtained analogously to IVa in 42%
yield, mp 172-173~ according to [5], mp 173-174 ~ Rf 0.93 (20:1 chloroform-ethanol).
3-(3-BenzothlazolinTi-2-thiono>propionamlde (IVc). A mixture of 1.67 g (i0 mmoles) of
thione la, 0.7 g (i0 mmoles) of acrylamide, and 1 g (i0 mmoles) of triethylamine (or the same
amount of sodium methylate in methyl alcohol) was boiled in dry toluene for 1 h. The mixture
w a s treated just as for the separation of IVa. There was obtained 35% of amide IVc, with mp
224 ~ (from aqueous alcohol); according to [9], mp 224-225 ~ erroneously assigned the structure
of 3-(2-benzothiazolylthio)propionamide. Rf 0.14 (20:1 chloroform--ethanol). IR spectrum (KBr):
3420-3210 (NH2), 1680 cm -I (CO). UV spectrum (ethanol, c 0.014 mg/ml), Ama x 326 nm (log
4.40). Found: C 50.1; H 4.1; N 11.6%. C:oH~oNaOS2. Calculated: C 50.4; H 4.2; N 11.7%.
3-(3-Benzoxazolinyl-2-thiono)propionamide (IVd) was obtained analogously to IVc in 32%
yield, mp 196 ~ (from aqueous alcohol): according to [i0], mp 196 ~ . Rf 0.10 (20:1 chloroform-
ethanol).
Methyl 3-(3-benzothlazolinyl-2-thiono)propionate (lYe). A mixture of 1.67 g (i0 m~oles)
of thione la, 0.86 g (10 mmoles) of methyl acrylate, and 2.2 ml of a solutlon of sodium methyl-
ate in methyl alcohol (i0 mmoles Na) was boiled in dry toluene for 1 h. After removal of the
solvent the dry residue was treated with 5% alkali solution, then with water. The resulting
mixture of esters llle and IVe was treated with concentrated HC1. The insoluble residue was
filtered off and washed with water to give ester IVe in 14% yield, mp 86 ~ (from benzene).
Rf 0.43 (14:5 benzene-acetone). IR spectrum (KBr): 1730 cm-* (CO). UV spectrum (ethanol, c
0.007 mg/ml), ~max 328 nm (log e 4.33). Found: C 52.5; H 4.0; N 5.4%; M 253. C,~H**N02S2.
Calculated: C 52.1; H 4.3; N 5.5%; M 253.
After the removal of esters llle and IVe, when the alkaline solution was acidified, 3-
(3-benzothiazolinyl-2-thiono)propionic acid separated in 6% yield; it was purified on sheets
with attache= SiO2 layer, mp 161-162 ~ (from alcohol); according to [ii], mp 161-162 ~ . Rf
0.45 (14:5 benzene--acetone).
Methyl 3-(3-benzoxazolinyl-2-thiono)propionate (IVf) was obtained similarly to ester IVe
in 17% yield, mp 65~ according to [5], mp 64-65 ~ . Rf 0.54 (10:5 hexane--acetone).
3-(3-Benzoxazolinyl-2-thiono)propionic acid (IVh) was obtained similarly to acid IVg in
2% yield, mp 141 ~ (from alcohol); according to [i0], mp 140-142~ in [5], mp 189-192 ~ , the
constants for 3-(3-benzoxazolinyl-2-thiono)propionamide given incorrectly. Rf 0.49 (20:1
chloroform-ethanol).

LITERATURE CITED
i, K. V. Anan'eva and N. K. Rozhkova, Khim. Geterotsikl. Soedin., No. 4, 554 (1986).
2. A. F. Halasa and G. Smith, J. Org. Chem., 36, 636 (1971).
3. W. J. Humphlett, J. Heterocycl. Chem., ~, 387 (1968).
4. G. Sumrell, G. E. Ham, and E. D. Harnbaker, J. Am. Chem. Soc., 80, 2509 (1958).
5. V. Kalcheva and D. Dimov, Annual of Sofia University, 1969-1970, Vol. 64 (1972), p. 33.
6. B. Harman, US Patent 2,413,917; Chem. Abstr., 41, 2446 (1947).

566
 7. C. D. Hurd and L. J. Gershbein, J. Amer. Chem. Soc.! 69, 28 (1947).
8. G. Miyajima, K. Takahashi, and K. Nishimoto, Org. Magn. Reson., 6, 413 (1974).
9. J. J. Amico, J. Amer. Chem. Soc., 7__9, 5270 (1957).
i0. N. A. Aliev, R. Aflyatunova, and K. Giyasov, in: Fungicides [in Russian], Fan, Tash-
kent (1980), p. 53.
Ii. K. V. Anan'eva and N. K. Rozhkova, All-Union Institute of Scientific and Technical In-
formation, Academy of Sciences of the USSR, deposited paper No. 239-71; Ref. Zh. Khim.,
9Zh99 (1972).

HETEROCYCLIZATION OF COMPOUNDS CONTAINING DIAZO AND CYANO GROUPS.

2.* SYNTHESIS AND RECYCLIZATION OF 4-SUBSTITUTED 5-AMINO-I,2,3-THIADIAZOLES

Yu. M. Shafran, B. A. Bakulev, UDC 547.467.2'791.6'

V. S. Mokrushin, and G. I. Validuda 794.3'07

The reaction of carbonyl derivatives of diazoacetonitrile with hydrogen sulfide

in the presence of triethylamine yields 4-substituted 5-amino-l,2,3-triadiazoles.
Under analogous conditions, hydrogen selenide and ethyl mercaptan reduce the
starting diazo compounds to hydrazones. Thiadiazoles are recyclized to 4-sub-
stituted 5-mercapto-l,2,3-triazoles by the action of bases.

In our previous work [i], we showed that the reaction of carbonyl derivatives of diazo-
acetonitrile with hydrogen halides leads to the formation of 4-substituted 5-halo-iH-l,2,3-
triazoles. In the present communication, we studied the reactions of diazoacetonitriles
with hydrogen sulfide and hydrogen selenide in order to obtain 4-substituted 5-amino-l,2,3-
thiadiazoles, which are starting reagents for the preparation of various pesticides [2, 3]
and their selenium analogs.
Diazoacetonitrile and its alkyl and aryl derivatives react with hydrogen sulfide in the
presence of bases to form 5-amino-l,2,3-triadiazoles [4, 5]. In addition, the reaction of
carbonyl derivatives of diazomethane with hydrogen sulfide, depending on the substituents,
gives either thionylation of the carbonyl group with subsequent cyclization to 1,2,3-thiadia-
zole or reduction of the diazo compounds to hydrazones [6]. Thus, the formation of three
different products may be expected in the reaction of carbonyl derivatives of diazoacetoni-
trile with hydrogen sulfide.
However, the only products of the reaction of 2-diazo-2-cyanoethyl acetate (la), 2-
diazo-2-cyanoethylacetamide (Ib), 2-diazo-2-cyanoethyl-N-methylacetamide (Ic) and 2-diazo-
2-cyanoethylacetophenone (Id) with hydrogen sulfide in the presence of triethylamine were
4-substituted 5-amino-l,2,3-thiadiazoles (lla-d). The sturcture of thiadiazoles lla-d was
confirmed by IR, UV, and PMR spectroscopy and by the convergent synthesis of lla and lid
according to Goerdeler [7]. Thus, only the first of the three possible reaction pathways
obtains.
We should note that formation of 5-amino-l,2,3-thidiazoles in this reaction may proceed
by two different mechanisms, either through the ~-diazothioamide or through the ~-cyanothia-
diazene with subsequent cyclization of these kinetically unstable intermediates. In order
to distinguish between these two mechanisms, we carried out a comparative kinetic study of
the reactions of 2-diazo-2-cyanoacetamide Ib and a compound with similar electronic struc-
ture but incapable of reacting through the first mechanism with hydrogen sulfide. 2-Diazo-
malondiamide III was taken as this model.
*For i, see [i].

S. M. Kirov Urals Polytechnical Institute, Sverdlovsk. Translated from Khimiya Geter-

otsiklicheskikh Soedinenii, No. 5, pp. 691-696, May, 1986. Original article submitted De J
cember 26, 1984.

0009-3122/86/2205-0567512.50 9 1986 Plenum Publishing Corporation 567

 N 0,183~
\
C 0,1~57 0 -0,3505 ~,3021k ) "2985
\ /
90,I~I C - - C 0,3619
/ \
N 0,3557 N -0,2534 -0,6323 |C,0087 Fig. i. Calculation of the charge dis-
/
N -0,0611
J50,5524 .
tribution (a) and LUM0 coefficients (b)
of 2-dlazo-2-cyanoacetamlde.
a b
TABLE i. Pro)erties of the Compounds Synthesized

,Com- ,a er ~o~ Found, ~o Chemical Calculated, % Yield

pound rap.
A B c n N s formula %

IIa[ 125--126b 88 84 85 34,s 4,3 24,5 18,6

IIbl 178--179 c 681 63 73/25,1 2,9138,9 I22,5
CsHTN~O=S
C:J {4N4OS
34,7 4,1
25,012,8 38,9 [22,2 8l
Ilc[ 210162~ I --521777978130,4 3.9{35,3 I 20,3 C~H6N~OS 30,413,t~ 35,4 [20.3 30
ndl --120,61 15,6 CoHzN3OS 52,713,4 20,5[15,6 51
165--166 e 41 81 1,7144,6l 25,6 C3H2N4S 28,6 [1,6 44,4 J25,4 51
178 20 [ 58 57128,1 4,7 [42,9 I ~,5 CsHaN402 127,714,6 43 ! I -- 89
~Vml 207_2~ 87125,I 2,8139,01 C3H~N~OS 125,o 12,8 38,9 ]22,2 97
VIo i 202--204 90128,9 4,5 [33,9[ 19,1 CJ~N4OS [28,7[4,2
X0,5H~O
VIIbl 257--259 33 [ 64 71 [30,I 3,9[35,5[ 20.3 C4H6N4OS /30,4 13,8 35,4120,3IS~
'Vllf 172--175 31 ] 71' 60132,0 4,3134,51 18,7 CsHsN4OS 134,914,7 32,5/18,6164
Vll15 170--171 --]41 86 }32,4 3,8149,71
C3H4N40 la21p,6 50,0 ] -- !27
amp not corrected.~ lla-c, e, VlIb, f, and Vlllb were re-
crystallized from'water, Ild from CHCls--hexane, IVb, c
from ethanol, and IV was precipitated from 10 N citric
acid by the addition of sodium carbonate, bmp 126~
(subl.) [7]. cWithout decomposition, dmp 160~ [7].
emp 168-171~ (from CH3CN).

UV spectroscopy indicated that the time for 50% conversion of diazoamide Ib in the case
of 2.2.10 -~ mole/liter initial concentration in the presence of an equimolar amount of tri-
ethylamine and 4,10 -s mole/liter hydrogen sulfide in absolute ethanol is 9 min. The family
of kinetic curves transverses an isosbestic point, indicating that neither side-products nor
intermediates for formed during the reaction in any significant concentration. Under analo-
gous conditions, diazodiamide lII remains unchanged over two months.
NH2CSCHCN
NH2
V
I HNO

NCCR1N2 .._H2.~
S NH~'~C_CRI .....~ ~(" "RI
s~ II ..
la-d _ N2 ....... N~S - - I N H 2

[O11 I H2Se
(
NC~R1=NNH2 ,t u
N N /9 . "~SR 2 N~N-~ "SK
vmb,c H H
w*b,f wh, c
N2C(CONH2) 2 . . . . a.,.- NH2N=C(CONH2) ~
Ill IV

I, II aR~=COOEt, dR~=COPb; II e Rz=CN;I, I K V I - - V I I I b R*=CONH2, R~=-Me,

f R~=Et; I, I1, VI, VIII c R~=CONHMe
When the concentrations of the diazo compound and triethylamine are increased to 0.01
mole/liter, diazonitrile Ib reacts with hydrogen sulfide virtually instantaneously. On the
other hand, the reaction of diazodlamide III with excess hydrogen sulfide is complete only
after 22 h with the formation of only 2-hydrazonomalonodiamide (IV).
Such a sharp difference in the rates of the reactions of diazonitrile Ib and diazodia-
mide III with hydrogen sulfide may be attributed only to the formation of different inter-

568
 TABLE 2. Spectral Indices of Compounds Synthesized

Corn- IR spectrum (KBr), cm "t UV spectrum

(in water), t MRgpec m (in DMSO-d~),
pound
stretching deform. Xmax, nm (log ~)[ 5, ppm

Ila 3275, 3220, 315e 1530 (NH) 262 (3,90), 284 8,4 (2H, s, NH2), 4,45 (2H, q
(NH), 1690 (~h., 3,78) 1=7,8Hz, CH2), 1,36 (3H, t,
(co) I---7,8 Hz, CHs)
llb 3380,3305,3270, 1520 (NH) 260 (3,99), 291
3200 (NH), (3,89)
1675 (CO)
Ilc 3400, 3250 1515 (NH) 258 (3,35), 283 9,0 (1H, s, NH), 8,52 (2H, s,
(NH), 1645 (3,78) NHz), 2,96 (3H, d, I=6,0 Hg
(co) NHCH3)
lie 3420, 3320, 3220 1525 (NH) 247 (3,66), 292
(NH), 2250 (3,63)a
(CN)
IV 3475, 3390 275 (3,97)a
(NH), 1705
(co)
tVIb 3420, 3340 1565, 256 (4,03)
(NH), 1670 1530 (NH)
(co)
VIe 3240, 3155 1550 (NH) 258 (4,00) 8,95 (s, NH), 2.84 (s, NCH3),
(NH), 1650 775 (SH) 2,84 (d, J=7,3 H~ NHCHz)
(co)
Vllb 3385, 3285, 3235 1555 (NH) 233 (sh., 3,69), 7,63 (IH, s, NH), 7,40 (IH, s
(NH), 1675 263 (3,53)a NH), 2,49 (3H, s, SCH3)
(CO)
~VII 3390, 3290, 3235 1570 (NH) 233 (sh., 3,71), 8,3--7,1 (3H, NH), 3.04 (2H. q,
(NH), 1680 262 (3,69) J=7,2Hz. SCH2), 1,25 (3H, t,
(CO) 1=7,2 H~, CHa)
Vlllb 3400, 3345, 3240, 1520 (NH) 230 (3,64),
3160 (NH), 286 {4,09) a
2235 (CN),
1710 (CO)
VIIIc 3390, 3320, 3220 245 (sh, 3,69), 8,1 (1H, s, NH), 2,72 (3H, d ,
(NH), 2220 286 (4,02) 7=4,8 HZ NHCHa)
(CN)

aIn ethanol.

mediates (an ~-diazothioamide, which rapidly cyclizes to thiadiazole lib [8], and a thiadia-
zene, respectively) or a much greater rate for the cyclization of the thiadiazene than for
its decomposition to the hydrazone and sulfur. However, in this latter case, the thiadiazene
should accumulate in the solution. Thus, the reaction of diazonitriles I with hydrogen sul-
fide apparently proceed through the formation of ~-diazothioamides.
The conclusion of the reaction of hydrogen sulfide with diazonitrile I at the cyano group
requires further evidence, since there is not information in the literature on the direction
of the cyclization of the diazothioamides formed in this case which contain electron-with-
drawing substituents in the R-position (either at the sulfur atom or at the nitrogen atom of
the thioamide group). Experimental evidence was found in the reported generation of this
system upon the diazotrization of 2-amino-2-cyanothioacetamide (V). In our previous work
[9], we found that the only product of this reaction is 5-amino-l,2,3-thiadiazole-4-carbonit-
rile (Iie) which was identical to this compound synthesized previously by Volpp [2] by an in-
dependent method. Thus, a-diazothioamides may be found on the coordinate of the reaction of
diazonitriles I with hydrogen sulfide.
However, under more vigorous conditions, the a-diazothioamides formed upon heating thi-
adiazoles IIa-c at reflux in excess aqueous ammonia or methylamine cyclize to give isomeric
5-mercapto-iH-l,2,3-triazole-4-carboxamide (VIb) and the corresponding N-methylcarboxamide
(VIc), respectively. The recyclization of ester IIa is accompanied by the amidation of the
ester group. In contrast to the starting thiadiazoles II, mercaptotriazoles VIb and VIc
give a rapidly disappearing green-blue color with aqueous ferric chloride, indicating the
presence of a free mercapto group [I0]. In order to confirm the structure of mercaptotria-

569
zoles Vlb and Vlc, we carried out the alkylation of mercaptotriazole Vlb with methyl iodide
and ethyl iodide. The PMR signals for the methyl and methylene group protons in the products
5-methyl- (VIIb) and 5-ethylthio~-ZH-l,2,3-triazole-4-carboxamide (VIIf) are at 2.49 and 3.04
ppm, which is characteristic for alkylthio groups.
In order to address the second aspect of this work~ we studied the reaction of diazoni-
triles I with hydrogen selenide. However, in this case, we isolated pure compounds which, on
the basis of their IR spectra and elemental analysis, were identified as 2-hydrazono-2-
cyanoacetamide (VIlb) and the corresponding N-methylacetamide (VIIIc) instead of selenadia-
zoles. Under analogous conditions, diazonitrile Ia forms a mixture of strongly colored pro-
ducts which could not be separated due to their similar chromatographic mohilities. The
structures of hydrazones VI~Ib and VIIIc were indicated by their oxidation using lead tetra-
acetate to the starting diazo compounds Ib and Ic.
In an attempt to obtain 5-ethylthio-iH-l,2,3-triazole-4-carboxamide (VIIf) from diazo-
amide Ih, we found that this compound does not react with ethyl mercaptan upon heating at
reflux in chloroform. Heating of the reaction mixture at 1000C for 12 h in an autoclave leads
to a mixture of seven products as indicated by thin-layer chromatography. None of these com-
pounds corresponds in its chromatographic mobility with ethylmercaptotriazole VIIf or hydra-
zone Vlllb. On the other hand, diazoamide Ib reacts rapidly in ethanol with ethyl mercaptan
in the presence of triethylamine at room temperature but hydrazone VIIIb rather than triazole
VIIc is formed in this case.
We carried out quantum chemical calculations for the reactivity indices of 2-diazo-2-
cyanoacetamide (Ib) using the CNDO/2 approximation and the VIKING program set. The neutral
diazoamide molecule Ib was selected as the model since the UV and IR spectra of diazonitriles
Ib and Id remain unaltered upon the addition of triethylamine, whose role thus reduces to
anionic activation of the nucleophilic reagents.
These calculations account for the preference of the attack of hydrogen sulfide at the
nitrile carbon atom. In other cases, electrophilic attack at the diazo group is preferred,
leading to reduction to a hydrazone.
Thus, these experiments and quantum chemical calculations indicate the double reactivity
of carbonyl derivatives of diazoacetonitrile.

EXPERIMENTAL
The UV spectra were taken on a Beckman Model 26 spectrometer in water at pH 6.5-6.8 and
ethanol. The IR spectra were taken on UR-20, Specord IR-75, and Beckman IR-4260 spectro-
meters in KBr pellets. The PMR spectra were taken on a Perkin-Elmer R-12B spectrometer at 60
MHz in DMSO-d6 with HMDS as the internal standard. The reactions were monitored and purity
of the compounds separated was checked by thin-layer chromatography on Silufol UV-254 plates
using 9:1 chloroform-ethanol (A), 3:1 propanol--3 N ammonia (B) and 4:1:1:1 butanol--acetic
acid-water--ethyl acetate (C) as eluents. The diazo compounds were determined by the color
reaction of their chromatographic spots upon spraying the chromatograms with ethanolic m-
phenylenediamine.
The characteristics of the compounds synthesized are given in Tables 1 and 2.
5-Amino-l,2,3-thiadizaoles lla-d. Hydrogen sulfide was introduced into a solution of
5.56 g (40 mmoles) diazoester la or 4 mmoles diazo compounds Ib-d and an equimolar amount of
triethylamine in 500 ml chloroform at 20-25~ until diazo compounds la-d disappeared. The
reaction mixture was evaporated in vacuum to drMness, and the residue was crystallized to give
light yellow crystals.
2-Hydrazonomalonodiazmide (IV). Hydrogen sulfide was introduced into a solution of 0.3
g (2.34 mmoles) 2-diazomalondiamide (III) and 0.33 ml (2.34 mmoles) triethylamine in a mix-
ture of 180 ml chloroform and 40 ml ethanol at room temperature for 75 min. After 22 h, the
solvent was evaporated and the dry residue was treated with two 20-ml portions of ethanol.
Sulfur was filtered off and the filtrate was evaporated in vacuum to dryness. The residue
was reprecipitated from ethanol to give colorless needles.
5-Amino-l,2,3-thiadiazole-4-carbonitrile (lie). A sample of 20 ml ether was added to a
solution of 0.4 g (3.48 mmoles) amine V and 36 ml 2 N hydrochloric acid and then a solution
of 0.5 mg (5.79 mmoles) KN02 in 2 ml water was added with stirring at 0-2=C. The layers were
separated and the aqueous layer was extracted with five 20-ml portions of ether. The ethereal

570
extracts were combined land evaporated to dryness. The residue was crystallized to give light
yellow crystals.
5-Mercapto-iH-l,2,3-triazole-4-carboxamide (Vlb). A solution of 0.5 g (3.47 mmoles)
thiadiazole lib in 20 ml 25% aqueous ammonia was heated at reflux for 15 min. The solvent
was evaporated in vacuum to 50% volume and the pH was brought to 6 by the addition of sul-
furic acid. The solution was evaporated to dryness and the residue was crystallized to give
light yellow crystals.
5-Mercapto-iH-l,2,3-traizole-4-N-methylcarboxamide (Vie). A. A solution of 0.i g (0.63
mmole) thiadiazole llc in 5 ml 25% aqueous ammonia was heated at reflux for 15 min and treated
analogously to the procedure for Vlb to give colorless needles.
B. This product was obtained by analogy to method A from 0.6 g (3.46 mmoles) ester lla
and 15 ml 22% aqueous methylamine. The product was identical to that obtained by method A in
its IR spectrum and melting point.
5-Alkylthio-IH-l,2,3-triazole-4-earboxamides (Vllb)~ A sample of 6.6 mmoles methyl
iodide or ethyl iodide was added to a solution of 0.476 g (2.3 mmoles) diazoamide Ib
and 0.124 g (2.3 ~moles) sodium methylate in 8 ml methanol. After 15 min, the solvent was
evaporated in vacuum to dryness and the residue was crystallized to give light yellow crys-
tals.
2-Hydrazono-2"cyanoacetamide (Vlllb). A Hydrogen selenide was introduced into a
solution of 4 mmoles diaozamide Ib or Ic and an equimolar amount of triethylamine in
200 ml chloroform at 20-25~ until the complete disappearance of the diazo compound. The re-
action mixture was maintained for 2 h and amorphous selenium~as filtered off. The filtrate
was evaporated in vacuum to dryness and the residue was crystallized to give light yellow or
light brown crystals which darken over time in the air.
B. A sample of 0.60 ml (8 mmoles) ethyl mercaptan was added with stirring to a solutioD
of 4 mmoles diazoamide Ib or Ic and 0.14 ml (4 mmoles) triethylamine in i0 ml ethanol. The
solvent was evaporated in vacuum to dryness and the residue was crystallized. The products
obtained were identical in their IR spectra and melting points to the products obtained by
method A.
Oxidation of 2-Hydrazono-2-cyanoacetamides. Lead tetraacetate was added in small por-
tions to an aqueous solution of hydrazone Vllb or Vllc until a black precipitate began to
form. The reaction mixture was cooled and diazoamide lh or Ic was extracted with ether and
evaporated. The oxidation products were identical in their IR spectra and thin-layer chroma-
tographic behavior with diazo compounds Ib and Ic, respectively.

LITERATURE CITED
i. Yu. M. Shafran, V. A. Bakulyaev, V. S. Mokrushin, and S. G. Alekseev, Khim. Geterotsikl.
Soedin., No. 9, 1266 (1984).
2. G. P. Volpp and H. Dounchis, US Patent No. 3,723,448; Chem. Ahstr., 79, 5345 (1973).
3. H. Schultz and F. Arndt, West German Patent No. 2,214,632; Chem. Abstr., 80, 14931 (1974).
4. N. V. Konstantinova, USSR Inventor's Certificate No. 956,476; Byul. Izobr., No. 33 (1982).
5. M. Nakai, K. Harada, and Y. Mori, US Patent No. 4,269,982; Chem. Abstr., 95, 62231 (1981).
6. P. P. Norton and S. Shyam, J. Heterocycl. Chem., 12, 1191 (1975).
7. J. Goerdeler and G. Gnad, Chem. Bet., 99, 1618 (1966).
8. R. Huisgen, Khim. Geterotsikl. Soedin., No. 5, 579 (1981).
9. Yu. M. Shafran, V. A. Bakulev, V. S. Mokrushin, and P. N. Kondrat'ev, USSR Inventor's
Certificate No. 1,055,741; Byul. Izobr., No. 43 (1983).
i0. M. Regitz and A. Liedhegener, Ann., 7!O , 118 (1967).

571
DIVlNYL SULFIDE.
15.* CYCLOADDITION OF DIVINYL SULFIDE AND ITS 2-METHYL
DERIVATIVES TO THIOUREA AND N-MONOALKYL- AND N-MONOARYLTHIOUREAS

G. M. Gavrilova, S. V, Amosova, B. A. Trofimov, UDC 547.379'496.3'876:

E. I. Kositsyna, B. Z. Pertsikov, V. I. Gostevskaya, 542.953:543.422
G. K. Musorin, M. L. Al'pert, and N. M. Borodina

The heterocyclization of divinyl sulfide with N-monoalkyl- and N-monoarylthio-

ureas and 2-vinyl propen-l-yl sulfide and di(propen-l-yl) sulfide with thiourea
in the presence of equimolar amounts of inorganic acids leads to new nitrogen
heterocycles 2H,6H-2,6-dialkyl-4-alkylamino- and 2H,6H-2,6-dialkyl-4-imino-5-N-
phenyl-l,3,5-dithiazines in salt form. The action of bases on the diathiazine
salts gives the corresponding 1,3,5-dithiazines. These heterocycles were found
more sensitive to the action of nucleophiles causing ring opening than 1,3,5-
dithiazines unsubstituted at the nitrogen atom.

In our previous work [2], we showed that divinyl sulfide (I) and thiourea undergo pro-
tophilic cyclization in the presence of acids to form 2H,6H-2,6-dimethyl-4-amino-l,3,5-
dithiazinium salts. Divinyl sulfide derivatives with electron-withdrawing substituents
such as di(2-phenylvinyl) sulfide do not undergo this reaction.
In light of the protophilic nature of this heterocyclization, we would have expected
that the introduction of electron-donor substituents into the divinyl sulfide molecule would
facilitate this process. We checked this proposal for the case of the reactions of vinyl
propen-l-yl sulfide (II) and di(propen-l-yl) sulfide (III) with thiourea. Indeed, sulfides
II and III under the same conditions used for divinyl sulfide (50-55~ aqueous ethanol as
solvent and acid catalysis) readily cyclize with thiourea to form the corresponding dithia-
zinium salts IV or Va-h in 60-90% yield.

NHR N,II"I Nlla

F
H2t~C~s
)~.+ A- , .l~..t A-
HA s "NIl a n d / o r ~ "tin .
R~ ' / ~ S / ~ ~1{4 R3 "~ ' ~ ' / ~ ' R 4
I-Ill ~,'~-h vh

--- "t ~ i{4

=--- I A
R:~/~.S .4
C D E
r vii, a,b.r f.h
I R I =R2=~; " R I=H, R 2 = M o ; Ill R I=R2=Mc; B=KOH, Et3N

In the case of sulfide II, the formation of two structural isomers IVa and IVc or their
mixtures may be formed, in which R ~ = Et may be either at C(2) or C(6) of the diathiazine
ring (R = H).
Divinyl sulfide behaves analogously with N-monoalkyl and N-monoarylthioureas and two
structural isomers with the Alk and Ph substituent either at the exocyclic (IVe-h) or endo-
cyclic nitrogen (Ve-h, R 3 = R ~ = Me).

*For 14, see [i].

Irkutsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Irkutsk. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 697-703,
May, 1986. Original article submitted March 20, 1985.

572 0009-3122/86/2205-0572512.50 9 1986 Plenum Publishing Corporation

 . 3600 340U t/uu 1500 1700 1500 36UU J4UO ]/uo 150o l'lOu lbO0

CHCt3 ~CHC[ 3 ~ 1~[3r HCL3 3N Br

1640 1

'WI..~Z~.j ,8 t
"3445" 1630 ~ '~4 ']
I ~ Ii ] i_ ! L

16
1630 2 3422
i I ._J I I i I I I t I I ' I

3410 1518!
1634 3
__ L r,~ ~--L.__L I I 1~
3600 3400 1700 1500 1700 1500 3600 3400 1700 1500 1700 1500
~, crd -1
Fig. i. IR spectra of 2H,6H-2,6-dialkyl-4-alkylamino- and
2H,6H-2,6-dialkyl-4-imino-5-N-phenyl-l,3,5-diathiazines:
l) 2H,6H-2,6-dimethyl-4-amino-l,3,5-dithiazine, 2) dithia-
zine Vlla, 3) dithiazine Vllb, 4) dithiazine Vile, 5) dithi-
azine Vllf, 6) dithiazine Vlh (see Table i).

The physical constants and analytical data for the compounds synthesized are given in
Table i.
In addition ot the cyclization reaction, a side reaction involving the acid hydrolysis
of the starting divinyl sulfides I-III is observed (sulfides I-III are thus taken in slight
excess). Okuyama et al. [3] have reported that sulfides II and III are more stable toward
acid hydrolysis than divinyl sulfide which, under the conditions of the reaction studied,
partially undergoes hydrolytic cleavage to form H2S, acetaldehyde and 2,4,6-trimethyl-l,3,5-
trithiane [4].
Substituted divinyl sulfides II and III were used as isomer mixtures: 52% cis,cis and
48% trans,trans (II) and 40% cis,cis, 59% cis,trans, and i% trans,trans (III) (determined by
PMR spectroscopy). However, isomerically uniform dithiazinium salts IVa, b, e, f are obtained
in all likelihood as a result of their cyclization with thiourea. The conclusion that these
salts and their derived bases exist as single isomers is based on the lack of doubling of their
PMR signals. Evidence for this conclusion is also found in the data of Day et al. [5] on the
isomeric uniformity of dihydro-2,4,6-trimethyl-4H-l,3,5-dithiazone having only cis configura-
tion as indicated by Z3C NMR spectroscopy and x-ray diffraction analysis.
The action of KOH or Et3N on salts IVa, b, e, f, h gives 1,3,5-dithiazines Vlla, b, e, f
and Vlh (Table i) which, similarly to these salts, are probably formed as structural isomers
Vld, f, h and Vlla, b, e, f, h. The latter may exist as two tautomeric forms (D and E).
While the neutralization of 2H,6H-2,6-dimethyl-4-amino-l,3,5-dithazinium nitrate [2] by
0.5 N aqeuous KOH proceeds smoothly with the formation of the free base, in the case of salts
IVa-h, we must use weaker bases such as triethylamine in rigorously equimolar amounts since
the dithiazines obtained are even more sensitive to the action of nucleophiles than 2H,6H-2,
6-dimethyl-4-amino-l,3,5-dithiazine, which undergoes extensive decomposition by the action of
excess amine [6]. We should note that products are formed in the reaction of dithiazinium
salts IVa-h with triethylamine in water or nonabsolute solvents, whose IR spectra (for low
concentrations in CHCIs) show a strong band at 3505 cm -z which does not disappear upon dilu-
tion of the solutions studied. The appearance of this band may be explained by strong intra-
molecular hydrogen bonding in trace hydroxyl-containing compounds formed as a result of the
addition of water at the C==N bond of dithiazines Vlla-f and Vlh with subsequent decomposition
of the heterocycles. This band is lacking in the IR spectra of bases synthesized in dry sol-
vents. Oligomerization of the dithiazines with ring opening is also possible in aqueous sol-
vents. Thus, resins of various consistency are formed upon the preparation of dithiazine
Vllf in nonabsolute acetone; the PMR spectra of these resins show broad peaks characteristic
for oligomeric products at 1.18-1.55 (protons of three structurally inequivalent CH3 groups),

573
 TABLE i, 2H)6H-2,6-Dialkyl-4-alkyl- and 2H)6E-2,0-4-
Arylamlno-l,3,5-di~hazlnas and Their Salts

$L~ ~Ntt

Com-.l ., [ Found, % Calculated, % Yield,

Chemical
pound' Trap, ", ] formula
H(CI) N s c H(CI) N] s

IV'a 55=15, ~,(16,6) 13,1 30,61 CoHtaCIN~S2 -- (16,7) 13,2 30,1 84

I~ b 50~153 0,%0) 12,3 28,41 CTH,sCIN2S~ (15,6) 12,4 283 80
30,9 5,8 163 25.91 CsHtsN30~S2 30,1 5,5 17,61 26,7 62
c~8~IS: 33,1 6,1 16,5 28.51 CrHtsN30~S2 33,2 5,9 16,6 25,3 68
IVe -- 1(16,7) 12,6 29,51 C6H,aCIN2S2 -- (16,7) 13,9- 30,1 77
IVf 18--121 1(14,8) 12,7 27.91 CrHIsCIN=S~ (15,s) 12,4 28,3 94
Oil _~_ [ (ll,O) 8,9 20,51 CIsH=rCIN~S2 -- (1 L4) 9,0 20,6 90
Powdez (13,6) I0,3 23.51 C.HIsCIN2S2 -- (12,9) I0,2I 23,3 90
VIIa 0~i 4o.71 6,8 15,2 37,01 CsH,~N~S2 4S,9 6,9 15,9 36,4 68
Vllb 52--53 43,9[ 7,4 14,6 33,91 CrH,N~S2 44,2 7,4 14,7 33,7 94
Vile 95--96 40,81 6,9 16,0 36.5l CaHtsN2S2 40.9 6,9 15,9 36,4 66
VlId OIll 43,5 7,5 14,7 33.31 CrHI4N2S2 44,2 7,4 14,7 33,7 64
Vle Oil 56,0 6,2 12,0 20.41 CItHI4N2S2 55,4 5,9 II,8 26,9 96

*IVa-d, Vlla) b R = H, lYe) Vile R = Me, lVf) Vllf R = Et,

IVg R = octyl) IVh, Vlh R = Ph, IVa) c) e-h, Vlla) e, f, VIh
R 3 = Me, lVb, d, Vllb R s = Et, IVa-d, Vlla, b R ~ = Et, IVe-h
Vile, f, Vlh R ~ = Me, IVa, b, e-h A = CI, IVc, d A = NO,.
%Ira was crystallized from aqueous ethyl acetate, IVb from
ethanol, IVd, f from acetone, and Vllb, e from CCI~.

3.49 (N--CH2CH3 methylene protons), and 4.50 ppm (CHCHs methine protons). On the other hand,
the mass spectrum shows a molecular ion with m/z 191 corresponding to the mass of the monomer,
which indicates the presence of monomer molecules in the oligomer or depolymerization of the
oligomer upon electron impact. The IR spectrum of this sample also differs from that for the
same dithiazine synthesized in absolute ether (Fig. i).
In order to confirm the structures of dithiazines VIla-f and Vlh and study their tauto-
merit transformations, we investigated their IR spectra in chloroform, acetonitrile, and
KBr pellets (Fig. I). Conclusions regarding the structures of these compounds may be made by
comparing the NH stretching and deformation bands and double bond stretching bands.
Considerable difficulties arise in the IR spectra of such compounds since the character-
istic bands of amino and imino forms are found close to each other [7, 8]. Thus, we used the
IR and UV spectra of 2H,6H-2,6-dimethyl-4-amino-l,3,5-dithiazine (VIII) and its acyl deriva-
tives [8, 9], which are similar in structure and method of synthesis with the compounds
studied. The introduction of an ethyl group at C(2) or C(6) of the dithiazine ring (VIIa)
(the position of the substituent was not unequivocally indicated by the PMR spectrum) leads
to changes only in the NH2 stretching band region. Figure 1 shows that the spectrum of VIIa
has bands at 3388 and 3487 cm -t, and the band at 3487 cm-* is asymmetric while the band at 3388
cm -I has a pronounced shoulder at 3410 cm -I, which indicates the existence of an additional
two NH groups, apparently due to imino form E since these bands for VIII with amino structure
are symmetric (~s 3388 and ~as 3492 cm -I) [8]. Thus the bands for ~s 3388 and ~as 3487 cm -I
indicate the presence of amino form D. The band at ~3410 cm -~ may be assigned to stretching
vibrations of the ==NH group, while the absorption band of the secondary NH group (imino form
E) probably overlaps the band at 3487 cm-*.
The spectrum of dithiazine VIIb (R = H, R 3 = R ~ = Et) shows bands characteristic for im-
ino form E (in CHCIa solution) even in the double bond region as indicated by the weak band
at 1520 cm-* due to stretching vibrations of the exocyclic C==N group of the imino form [9-11].
In general, however, the IR spectrum of this compound indicates that it exists in amino form
D (Fig. i). The predominance of amino form D for VIib in CC14 is also indicated by its FMR spec-
trum, which shows a broad singlet for the NH2 group at 5.08 ppm with integral intensity cor-
responding to two protons.

574
 Fig. 2. UV spectra of 2H-6H-2,6-
dialkyl-4-alkylamino-l,3,5-dithiazines:
5I " "'""'"", X i) 2H,6H-2,6-dialkyl-4-amino-l,3,5-
dithiazine, 2) dithiazine Vlla, 3)
dithiazine VIIb, 4) dithiazine Vile,
5) dithiazine Vllf (See Table i).

200 220 240 260 ~

The IR spectrum of dithiazine Vile (R = R 3 = R ~ = Me) in KBr pellets shows a band at

1530 cm -~ which may be assigned, as in the case of Vllb, to the stretching vibrations of the
exocyclic C=N group of imino form E. In going from the crystal to solutions in chloroform
and acetonitrile, changes are encountered in the spectra of Vile: The band at 1530 cm -~ dis-
appears and a band appears at 1630 cm-* assigned to the ring ~ group [9, I0]. The only band
in the high-frequency region at 3445 cm -* may be due to vibrations of free NH in amino form D.
These results permit us to exclude the structure with substituent R = Me at the endocyclic
nitrogen atom Vie, since such a structure may exist only in imino form C and cannot take part
in tautomeric transformations.

The PMR spectrum of the CCI~ solution of Vile has only one sharp signal for the methyl
group protons at the nitrogen atom at 2.81 ppm. The single broad NH proton signal is at con-
siderably higher field (3.88 ppm) relative to dithiazine Vllb which does not have an electron-
donor alkyl substituent at the nitrogen atom. We should also note the significant chemical
inequivalence of the methine protons (see Experimental section). All these findings indicate
the existence of dithiazine Vile in CC14 solution predominantly in a m i n o f o r m D [12].
The presence of a more bulky substituent (R = Et, Vllf) at the nitrogen atom complicates
the IR spectrum of this compound at 1500-1600 cm-*. One broad band is found in the spectrum
for the compound in a KBr pellet; this band has several maxima. In chloroform solution, the
band at 1550 cm-* decreases markedly in intensity while the band at 1627 cm -~ becomes more
intense, which also indicates the presence of significant amounts of amino form D in this
dithiazine. The broader band at 3222 cm -* does not disappear with decreasing concentration
from 0.02 to 0.002 mole/liter. This behavior is likely the results of strong intermolecular
hydrogen bonding.

The IR spectrum of Vlh with an electron-withdrawing substituent (R = CsHs) both neat

(film upon evaporation of CHCI3) and in CHCI3 solution shows a strong band at 1518 cm-* and
a weak band at 1643 cm-*. The predominance of the imino form is also indicated by the band
at 3410 cm -~ (this band should be significantly higher for ArNHR [13]). The band at 3385
cm -~ may be assigned to an intramolecular hydrogen bond between the N}{ group and the benzene
ring. This type of hydrogen bonding is possible in a structure with an exocyclic C=N
bond.

~# N---If

In light of the IR data and the protophilic nature of the cyclization as well as the
more "acidic" properties of the hydrogen at a nitrogen atom adjacent to a phenyl ring than
for NH2 hydrogens in N-phenylthiourea, we may assume the formation of dithiazine Vlh in
imino form C.

575
 These conclusions concerning the structure and tautomerlsm os dithlazines Vile, 5, e, f,
h were supported by their UV spectra which show three bands (200-210, 210-230, and 240-260nm,
Fig. 2). In our previous work [9]m we showed tha~ the bands at 210-230 nm may be assigned to
amino form D while the bands at 240-260 nm may be assigned to Imlno form E.

EXPERIMENTAL
The PMR spectra of 10-20% solutions of IVa, b, e, f and Vile, b, e, f, h in CCI~ and
CDsOD were taken at room temperature on a Tesla BS-497-C spectrometer at i00 MHz with TMS as
the internal standard. The IR spectra were taken on a Specord 75-IR spectrometer in the range
from 700 to 3700 cm'* in KBr pellets, chloroform, and acetonitrile (c 0.2-0.002 mole/llter, J
0.4-2 cm). The UV spectra were taken in ethanol on a Specord-vis spectrophotometer.
A sample of di(propen-l-yl) sulfide was obtained according to our previous procedure [14].
Freshly distilled vinyl propen-l-yl sulfide (bp 38-40~ (53.3 hPa)) and di(propen-l-yl) sulfide
(bp 45~ (20 hPa)) were used in the reactions.
Monosubstituted N-alkyl and N-phenylthioureas were obtained according to standard pro-
cedures [15]. N-Methylthiourea, mp 119-121.5~ (from ethanol), i19-120.5~ (lit. value).
N-ethylthiourea, mp 103-I06~ 103-106~ (lit. value) . N-octylthiourea, mp 84-85~ (from
ethanol) (Found: C 57.5; H 10.7; N, 14.1; S, 16.9%. Calculated for CgH2oN2S: C57.4; H10.7;
N 14.9; S, 17%), mp 114 [16]. N-Phenylthiourea, mp 152-153~ (from ethano[!~, 152.5-153~ (lit.
value).
Reaction of Vinyl Fropen-l-yl Sulfide and Di(propen-l-yl) Sulfide with Thiourea in the
Presence of Acids (General Method). A sample of 8.3 g (Ii0 mmoles) thiourea and 80 ml alcohol
(ethanol or methanol) were added to a solution of ii0 mmoles acid in 20 ml water and stirred
for 0.5 h at 20~ The temperature was raised to 55~ and 14.7 g (130 mmoles) di(propen-l-yl)
sulfide was added. The mixture was stirred at 55~ for 6 h. Most of the solvent was removed
in vacuum. The crystalline precipitate (7.6 g) was separated. More crystals were obtained
upon letting the mother liquor stand. The reaction with HCI gave 12.2 g 2H,6H-2,6-diethyl-4-
amino-l,3,5-dlthiazinium chloride. PMR spectrum (CDsOD)~ 1.15,overlap of two triplets (6H,
CHCH2CHs), 2.03, overlap of two multiplets (4H, CH-CH2CHs), 5.05 ~, ppm, q formed by the
overlap of two triplets (2H, CH_CH2CH,).
The PMR spectra of the dithiazlnes studied and their salts feature overlap of signals in
the corresponding spectral regions due to the structural inequivalence of the methine, methyl-
ene and methyl protons of the XCHCH, and XCHC~Hs groups (X = N, S). In comparison with the
PMR spectra of the free bases, all the protons of the CH, CHs, and CzHs groups of the corres-
ponding salts are shifted downfield. The endocyclic nitrogen atom is the protonation site in
these heterocycles, which is in accord with our previous data [17] on the enhanced basicity
of this nitrogen atom in 2H,6H-2,6-dimethyl-4-amino-l,3,5-dithiazine.
The reactions of vinyl propen-l-yl sulfide with thiourea and divinyl sulfide with N-alkyl-
and N-phenylthiorueas were carried out by analogous procedures.
2H,6H-2,6-Diethyl-4-amino-l,3,5-dithiazine (Vllb)~ A sample of 1.83 g (18 mmoles) tri-
ethylamine in I0 ml ether was added with stirring to 4.1 g (18 mmoles) chloride IVb in 30 ml
ether. Stirring was continued for an additional 4 h at room temperature. Then, the precipi-
tate of N(C2H~)3.HCI was separated. Ether was removed in vacuum to give 3.2 g (94%) base Vllb.
PMR spectrum (solution of Vllb in CCId), 6: i.ii (m, 6H, C2CH3), 1.87 (m, 4H, CH2CH3), 4.48 (q,
2H, N XCHC2Hb, X = N and S), 5.08 ppm (br. s, 2H, NH2).
2H,6H-2,6-Dimethyl-4-methylamino-l,3,5-dithiazine (Vlle)z A sample of 56.4 ml 0.5 N
aqueous KOH (28 nunoles) was added with stirring to 6 g (28 mmoles) chloride IVe in 30 ml water.
Stirring was continued for 4 h at room temperature. The reaction mixture was extracted with
four 50-ml portions of ether. The solvent was removed in vacuum to give 3.3 g (66%) base Vile,
whichwas twice crystallized from CCI4 (Table i). PMR spectrum (CCI~), 6:1.52 (d, 6H, XCHCH3,
X = N and S), 2.82 (s, 3H, NHCH3), 3.88 (br. s, IH, NH), 4.41 (q, IH, SCH_.CH3), 4.66 ppm (q,
iH, NCH__CHs), ~JXCHCH3 = 6.5 Hz.
2H,6H-2,6-Dimethyl-4-ethylamino-l,3,5-dithiazine (Vllf)~ A sample of 1.3 g (13 mmoles)
triethylamine in 5 ml ether was added with stirring to 3 g (13 mmoles) chloride IVf in 30 ml
dry ether, and stirring was continued for 4 h at 20~ The N(C=H~)s.HCI precipitate was fil-
tered off and washed with ether. The solvent was removed in vacuum to give 1.6 g (64%) base
Vllf as a viscous oil.

576
 LITERATURE CITED
i. B. A. Trofimov, S. V. Amosova, V. V. Nosyreva, and M. G. Voronkov, Zh. Org. Khim., 21,
2324 (1985).
2. B. A. Trofimov, G. M. Gavrilova, G. A. Kalabin, V. V. Bairov, and S. V. Amosova, Khim.
Geterotsikl. Soedin., No. ii, 1466 (1979).
3. T. Okuyama, M. Nakada, and T. Fueno, Tetrahedron, 32, 2249 (1976).
4. G. M. Gavrilova, V. I. Gostevskaya, B. A. Trofimov, and S. V. Amosova, Zh. Org. Khim.,
18, 1843 (1982).
5. C. S. Day, T. I. Hansen, L. K. Keefer, J. Heterocycl. Chem., 19, 1301 (1982).
6. G . M . Cavrilova, B. A. Trofimov, V. I. Gostevskaya, and S. V. Amosova, Khim. Geterotsikl.
Soedin., No. 5, 652 (1982).
7. Yu. N. Sheinker and ~. M. Peresleni, Zh. Fiz., Khim., 36, 1705 (1962).
8. E. I. Kositsyna, B. A. Trofimov, G. M. Gavrilova, S. V. Amosova, and V. I. Gostevskaya,
Khim. Geterotsikl. Soedin., No. 8, 1050 (1981).
9. G. M. Gavrilova, ~. I. Kositsyna, B. A. Trofimov, V. I. Gostevskaya and S. V. Amosova,
Khim. Geterotsikl. Soedin., No. 5, 622 (1982).
i0. E. M. Peresleni, Yu. N. Sheinker, N. P. Zosimova, and Yu. I. Pomerantsev, Zh. Fiz. Khim.,
37, 2713 (1963).
ii. Zh. N. Fidler, E. F. Shibanova, P. V. Makerov, I. D. Kalikhman, A. M. Shulunova, G. I.
Sarapulova, L. V. Klyba, V. Yu. Vitkovskii, N. N. Chipanina, V. A. Lopyrev, and M. G.
Voronkov, Khim. Geterotsikl. Soedin, No. I0, 1414 (1980).
12. V. K. Voronov, B. A. Trofimov, G. M. Gavrilova, S. V. Amosova, and V. I. Gostevskaya,
Khim. Geterotsikl. Soedin., No. 4, 485 (1981).
13. K. Nakanishi, Infrared Spectra and the Structure of Organic Compounds [Russian trans-
lation], Izd. Mir, Moscow (1965), p. 45.
14. B. A. Trofimov, S. V. Amosova, G. K. Musorin, V. V. Nosyreva, and M. L. Al'pert, USSR
Inventor's Certificate No. 1,114,675) Byul. Izobr., No. 35, 59 (1984).
15. A. F. Plat~ (ed.), Handbook of Organic Preparations [in Russian], Izd. Inost. Let.,
Moscow, Vol. 3 (1952), pp. 301, 318 Vol. 4 , p. 512 (1953).
16. H. Jahn, Monatschr., ~, 165 (1882).
17. T. V. Kashik, G. V. Rassolova, G. M. Gavrilova, V. I. Gostevskaya, S.V. Amosova, and
B. A. Trofimov, Khim. Geterotsikl. Soedin., No. 3, 333 (1983).

MASS-SPECTROMETRIC STUDY OF BENZOPYRIDOSILAAZEPI~S AND -AZEPINONES

V. K. Shevtsov, A. V. Varlamov, S. G. Poshivalov, UDC 543.51:547.859.1'

L. A. Simonova, and N. S. Prostakov 128.7

The influence of various structural factors on the dissociative ionization of

benzopyridosilaazepines and -azepinones has been investigated. It has been
shown that the mass spectra can be used to identify isomeric benzopyridosila-
azepinones with respect to the position of the amide fragment in the central
heterocycle. The anomalously high intensity of the ion [M -- HI + in the mass
spectra of these compounds is attributed to fragmentation of the molecular
ions from the open form.

The dissociative ionization of benzo[b,f]silepines [I] (nitrogen-free analogs of the

substances investigated in the present article) has been reported earlier [i]. The mass-
spectrometric characteristics of polycyclic compounds which contain the silaazepine fragment
have so far not been studied. In the present work we have investigated fragmentation of the

P. Lumumba Peoples' Friendship University, Moscow. Translated from Khimiya Geterotsik-

licheskikh Soedinenii, No. 5, pp. 704-707, May, 1986. Original article submitted February
13, 1985.

0009-3122/86/2205-0577512.50 9 1986 Plenum Publishing Corporation 577

 TABLE I. Mass Spectra o~ Compounds l-V*
,,1,J , J ..... J . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . :

Corll-
pound m/z values (reIa~ve [nt~ml~ tn a]o)"r

! 241 (]a), 24O (5(;), ~;~,() (II), ~ 7 (6), '."~0 (20), 22,~ (I00), 223 (6), 210
(7), ')09 (,SL 1,08 (7), 197 (i~), IDfi (~2), [85 {~;3), 181 (14), 181 (49) 167
(7), 166 (7), 1(14 (r)), 1~;:) (~3), 1(1~ (,q), 149 (7), 14(i (7), 135 (5), 120 (7),
119 (6), 105 (8), 88 (6), .57 (13); %l"'~),--q~)/o
II 379 (;)2).;~78(98).377 (I0)."~01 (30).;~00(30),299 (I00).'27'2(I0).195
(8), 10,5 (6); W~," :!SQI)
Ill 2,5.5 (17), ~.54 (7!)), :Yi:i (I00), 240 (I0), 239 (48), 211 (13), 196 (43),
169 (6), 167 (5), !35 (6), II t) ()0); II",~,-14%
IIV 255 (9), ".5,1 (4!)), ~.53 (100), 252 (15), ~,IO (8), 239 (35), 211 (18), 196
(23), 134 (6),)'20 (5); I['~l ,12'~)
V 393 (:35), 3!)2 (I00), ;391 (!)I), 3!)0 (.5),377 (9), 376 (8), 317 (3), 316
(17), 315 (521, 314 (L)6), 313 (8), 28(,) (8), 288 (231, 287 (68), 286 (5),
273 (5), 272 (1(1), 271 (16), 270 (,~), 181 (10), 105 (10); W~r23%

*I) 5,5-Dimethyl-5-s i l a - 5 H , 10H, l l H - b e n z o [b ] p y r i d o [ 4 , 3 - e ] -

azepine; II) 3-methyl-5,5-diphenyl-5-sila-SH, 10H, llH-benzo-
[b]pyrido[4,3-e]azepine; llI) ll-oxo-5)5-dimethyl-5-sila-SH)
10H,llH-benzo[b]pyrido[4,3-e]azepine; IV) 10-oxo-5,5-dimethyl-
5-sila-5H, 10H, llH-benzo [e ]pyrido [3,4-b ]azepine; V) 3-methyl--
li-oxo-5,5-diphenyl-5-sila-SH, 1OH) llH-benzo [b ]pyrido [4,3-e ]-
azeplne and 3-methyl-10-oxo-5,5-diphenyl-5-sila-SH, 10H, IlH-
benzo [e ]pyrido [3,4-b ]azepine.
%Peaks with intensities >5% are shown.

first representatives of a new group of nitrigen heterocycles (benzopyridosilaazepines) under

the action of electron impact.*

N--X
N

I, III R=CH3, RI=tt; II, V R=C6Hs, RI=CH~; I, II X=CH~,III, V X=CO

The mass spectra of the investigated compounds are given in Table i. As expected [2],
the resistance to decomposition (WM) increases when the methyl group at the silicon atom is
replaced by a phenyl group. However, in distinction from the dihydrosilaazaanthracenes and
corresponding silaazaanthrones [3], WM changes little in the transition from the benzopyri-
dosilaazepines I, II to the benzopyridosilaazepinones Ill-V; this is evidently due to re-
tention of the noncoplanar character of the molecule in the transition from compounds I, III
to III-V.
The molecular ions (M+) of the silaazepines I, II decompose according to two routes
(Scheme l). The first route leads to the formation of ion peaks [M -- H] + with similar in-
tensities, due probably to the predominant splitting of a hydrogen atom from the methylene
group [4]. The second route of fragmentation of compounds I, II leads to the elimination
of the R substituent from the silicon atom, whereby in the case of the dimethyl-substituted
compound I the ion peak [M -- R] + has the maximum intensity.
The appearance of other fragment ions in the mass spectra of compounds I and II is due
to the decomposition of the ion [M -- R] +. The fragmentation of this ion is characterized by
the formation of the cation [M -- R -- H=] + (Scheme i; the process is confirmed by metastable
ions). In the mass spectrum of compound I the intensity of this ion peak is insignificant,
while in the spectrum of compound II its intensity is at a maximum (Table i). Both mass spec-
tra contain intensive peaks (-5%) of ions [M -- R -- H2] + with two charges which is character-
istic for aromatic polycyclic systems [5]. The mass spectra of the deutero-analogs of com-
pounds I and II show that the hydrogen molecule which is splitting off contains the hydrogen
atom of the NH group (the second hydrogen atom is due probably to the methylene group). All
this leads to the assumption that the ion [M -- R -- H=] +has the structure of the benzopyrido-
silaazepine cation (Scheme i). The higher peak intensity of this ion in the mass spectrum of
*The structure of compound IV is shown in Scheme 2 (two pages hence). Compound V is a mixture
of isomers (See Table i.

578
compound II in comparison with I is due to the stabilizing effect of the phenyl group caused
by its conjugation with the polycyclic system [2].
Scheme i
-~ +. R R
R\ /R I ~ I I+ I
<// ~ ~'/~'~'" --R "~"~ l / -CH2NH"

. I . /N *
N--C N-C
H i;'~z ~ d 'a
I t 9 6 (Z2)
I 240 (56)* I 2 2 5 (1O0) II 2 7 2 ( I 0 )
M+ II 3 7 8 ( 9 8 ) II 391 (;:~0)

"t : ....
R.~si.R R" R " ~ ~--,N

N~C N==C
H I [
tl tI tl
I 2~q9 ( 1 1 ) I 2Z:] (6) I 18I ( 4 9 )
]I 3"75' (1O) II Z99 ( I t ) 0 ) II 195 (5)

~(m/z values (% of maximum).

The second characteristic of the decomposition of the ion [M -- R] + is the formation of a
fragment that does not contain silicon, due to splitting of the particle SiRH (Scheme I).
This process is confirmed by metastable ions and by the measurment of the exact mass of this
ionn in the mass spectrum of compound I (measured 181.0763, theory 181.0764, empirical form-
ula Ct2HgN2). Since in the mass spectra of compounds I and II, deuterated at the imino group,
the ion peak [M -- R-- SiRH] + is shifted by one a.m. unit, it can be assumed that a hydrogen
from the methylene, not the imino group, migrates to the silicon atom. This process is ac-
companied by the formation of highly stable ions which evidently have the structure of 3,6-
phenanthroline with fully conjugated bonds (the latter assumption is confirmed by the presence
of peaks of the corresponding ions carrying two charges). Another route for the fragmentation
of the ion [M -- R] +, accompanied by narrowing of the central ring, is related to the elimina-
tion of the particle CH2NH (Scheme i).
The main decomposition routes that are characteristic for the azepines I and II occur
also in the fragmentation of the silaazepines III-V. Nevertheless, the replacement of the
methylene group in the seven-membered fragment of the molecule by a carbonyl group leads to
some specific fragmentation features. In particular, regardless of the absence of a methylene
group in the molecules of compounds Ill-V, the peak intensity of the ion [M -- H] + is much
higher than in the mass spectra of the silaazepines I and II. It must be pointed out that
high-intensity peaks of the ions [M -- H] + are not characteristic for the mass spectra of seven-
membered lactams condensed with an aromatic ring [6]. Naturally, it can therefore be assumed
that the moving force for the elimination of a hydrogen atom from M + of compounds III-V is
the high stability of the fragments [M-H] + formed. The anomalously high peak intensity of
the ions [M-H]+~n be explained by of lactams III-V from the open form of M +.
The existence of an open form of M ions was postulated to explain the mass-spectrometric
behavior of some oxygen- and silicon-containing polycyclic compounds [7]. In the ionization
of compounds III-V the positive charge can be localized at the amide nitrogen [8] as well as
a~ the oxygen a t o m ~ the earbonyl group [6]. In both cases the primary process in M + must bel
the rupture C the both cases the primary process in M+ must be the rupture of the bond bet-
ween the carbonyl carbon and the pyridine (compounds Ill,V) or phenyl (compound IV) ring
(~-rupture with respect to the heteroatom). In the open form of M + a separation into a
cationic and a radical fraction takes place [8]. The existence of M + of the lactams III-V
in an open form is confirmed by the elimination of a CONH particle already at the first stage
of the decomposition :Scheme'2, Table i). An analogous process which leads to narrowing
of the central ring is observed in the fragmentation of compounds I and II only at the stage
of the decomposition of the [M-- R] + ion (Scheme i).

The existence of M + of compounds III and IV in an open form is also confirmed by the
formation of the following characteristic fragments: Ions are formed in the mass spectrum
of compound III with m/z 119 and 135 which correspond to the rupture of the Si--Cphenyl bond;
ions with m/z 120 and 134 are formed in the mass spectrum of compound IV that correspond to

579
 Suhem~ 2

~e i ~1~ I "t' ~, ~.~i .' I ~" ~i ....~.~

II tl II Jl ~ 1|
M+~ 0 O

C ~0 CONH 9 ,...~ ~CONlt

~,Me "Ni Me J ~ . " . ,qi lit4 (8) J

1..... i,1 I.i LI L ,.t,

I it
"...... "~..J

2~t ilO0) (~ll (1#i) IO(t (~:;)

the rupture of the Si-Cpyrid bond .(measured 120.0322, theory 120.0323, empirical formula
C,H4NsO; measured 134,0547, theory 134.0549, empirical formula CsH1oSl; Scheme 2). These ion
pairs can be used to establish ~he different arrangement of the amide fragment between the
phenyl and pyridine rings.
Two routes are available for the formation of the [M - H] + ion from M + present in the
open form =. The first assumes elimination of a hydrogen atom from the imide group and is
based on the well-known fact that the fragment ion formed is stabilized by the isocyanate
group [6, 9]. The second route for the formation of a stable [M -- H] + ion is given by the
possibility of rotation in the ion M + around the Si-Cpyrl d bond (Scheme 2). Conformations
can be formed in which splitting of an aromatic hydrogen atom will be accompanied by closure
of a five-membered ring [i0]. The [M -- H] + ion formed has the stable structure of a silaaza-
fluorene cation, with an isocyanate group at the C(~) atomj protonated via the nitrogen atom.
Thus, the different mass-spectrometric behavior of silaazeplnes and silaazepinones is
due to the fact that fragmentation of the latter takes place predominantly in the open form
of the molecular ion with the destruction of the polycyclic system. In the fragmentation of
silaazepines the narrowing of the central seven-membered ring takes place only in the second
stage of the decomposition.

EXPERIMENTAL
The mass spectra of compounds l-V and of their deutero-analogs were recorded on an LKB-
9000 mass spectrometer at an ionizing potential of 70 V and a temperature of sample injection
into the ion source of 50 ~ . The accurate mass of the fragment ions was measured on an MS-30
instrument by the peak superposition method. Perfluorokerosene (PFK) was used as a standard.
Compounds I-V were synthesized by the procedure given in [ii]. Compounds I and II were deu-
terated in CH3ONa solution with a 10-fold excess of CD3OD by refluxing for 8 h. The purity
and identity of the compounds was checked by TLC and IR and PMR data.

LITERATURE CITED
i. J. R. Corey, M. Dueber, and M. Malaidza, J. Organomet. Chem., 36, 49 (1972).
2. A. A. Polyakova and R. A. Khmel'nitskii, Mass Spectrometry in Organic Chemistry [in Rus-
sian], Leningrad (1972), p. 368.
3. N.S. Prostakov, N. Saxena, P. I. Zakharov, and A. V. Varlamov, J. Organomet. Chem., 184 , 167 (1980).
4. K. Levsen, ~undamental Aspects of Organic Mass Spectrometry, Verlag Chemie, Weinhiem
(1978), p. 312.
5. F. McLafferty and M. Bursey, Chem. Comm., No. ii, 533 (1967).
6. P. B. Terent'ev, O. E. Vendrova, V. M. Dem'yanovich, L. D. Solov'eva, and V. M. Potapov,
Khim. Geterotsikl. Soedin., No. 9, 1236 (1983).
7. V. K. Shevtsov, A. V. Varlamov, Nazrul Islam, and N. S. Prostakov, Khim. Geterotsikl.
Soedin., No. 4, 534 (1985).
8. V. V. Takhistov, Practical Mass Spectrometry of Organic Compounds [in Russian], Izd-vo
LGU, Leningrad (1977), p. 119.
9. J. Moiler, G. Becher, C. Johse, and K. Lempert, Acta Chem. Scand., 27, 3647 (1973).
i0. C. W. Fong and C. R. Hameister, Org. Mass Spectrom., 13, 711 (1978).
ii. N. S. Prostakov, A. V. Varlamov, A. M. Kloehkov, and A. A. Fomichev, Khim. Geterotsikl.
Soedin., No. 12, 1669 (1983).

580
LETTERS TO THE EDITOR

ELECTROCHEMICAL PREPARATION OF PYRIDINYL RADICALS,

SUBSTITUTED BY ELECTRON ACCEPTORS IN THE B-POSITION

R. A. Gavar, L. Kh. Baumane, Ya. P. Stradyn', UDC 547.821.3~541.515'138.3:

V. K. Lusis, G. Ya. Duhur, and D. Kh. Mutsenietse 543~422.27

In the electrochemical oxidation of 1,2-dihydropyridines, containing electron~acceptor

substituents in positions 3 and 5, we have obtained relatively stable cation-radicals which
deprotonated and transformed into pyridinyl radicals [i]. However, under the conditions of
electrochemical generation at positive potentials the latter rapidly undergo further electro-
oxidation; as a result of this, the EPR spectra cannot be recorded. For the preparation and
study of pyridinyl radicals we have therefore used the opposite processes: electroreduction
in aprotic solvents (dimethylformamide, acetonitrile) of the corresponding pyridinium salts
of type I:

R4

RI=CHa, p-CHaC6H4, C6tts; Ra=Rs=COOC2.Hs, COCHa, CN; R4=H, CHa, C6H5, p-CHaC~H4
The first stage of the polarographic reduction of these compounds (Ex/a in the interval
from--0.6 to --i.i V against the saturated calomel electrode) is a one-electron process. The
reduction potentials as function of the nature of the substituents and their position in the
pyridinium ring are giv4n by the equations

El/2=O.82o+p (R4) -0.93 (B), r=0.999;

EI/:=I.11"2(~,,~(Ra,S)-l.85 (B), r=0.993.

Cyclic voltammetry on a mercury drop or on a graphite electrode showed that the rever-
silibity of this one-electron process also depends on the nature of the substituent and the
place of substitution by decreasing when the substituents R*, R 3 (RS), and R ~ decrease in
the following order:

p-CHaCsH4~C6Hs>>CHa ( for RI);

C6Hs~CHa~H (for R4);
COCHa>COOC2Hs>CN (for Ra, R~).

Electrochemical generation [2] at the potentials of the first polarographic wave leads
to the formation of pyridinyl radicals which are sufficiently stable for recording by EPR.
The stability of these radicals is due to the reversibility of the primary one-electron
process of electroreduction of the initial compounds. The EPR spectra of the pyridinyl rad-
icals have a complex hyperfine structure (HFS) which is difficult to interpret. For instance,
the HFS constants for the pyridinyl radical with the substituents R* = R ~ = C~H~, R 3'5 =
COOC2H5 have the following values (mT):

aN=%_ H =0.50_0,02; a~=0:33__0,01; %_H=0315_0,005;

ar~=0,145+--0,005; a:2_H:=0,074_0,005; a2_tt=0,04

Thus, at room temperature relatively stable pyridinyl radicals have been recorded, in
which the electron-acceptor substituent is not in the position 4 (in conjugation with the
nitrogen atom), but in the positions 3 and 5 of the pyridinium ring.

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 708-709, May, 1986. Original
article submitted November 13, 1985.

0009-3122/86/2205-0581512.50 9 1986 Plenum Publishing Corporation 581

 LITERATURE CITED
i. Ya. V. Ogle, L. Kh. Baumane, R. A. Gavar, V. P. Kadysh, Ya. P. Stradyn', V. K. Lusis,
D. Kh. Mutsenietse, and G. Ya. Dubur, Khim. Geterotsikl, Soedin., No. 5, 651 (1984).
2. Ya. P. Straydyn', R. A. Gavar, and L. Kh. Baumane, Izv. Akad. Nauk LatvSSR, No. 2, 73
(1986).

SYNTHESIS OF 4-ARYL-5-THIOXO-4,5-DIHYDROINDENO[I,2-b]PYRIDINES

V. K. Lusis, D. Kh. Mutsenietse, and G. Ya. Dubur UDC 547.836'665.07

We have found that 4-aryl-5-oxo-4,5-dihydroindeno[l,2-b]pyridines la-d react easily with

Lawessons's reagent (dimeric sulfide of p-methoxyphenylthionophosphine) to form the hitherto
unknown 5-thioxo-derivatives lla-d; they are not accessible via cyclocondensation [i] since
the corresponding thioketones of the indane series are not known so far.

S S
o il/ ~ s
~ ~ . ~ R I IH Ar I p-CH~,.OC~H4
--P'%s//P--
~ CsH4OCHb-P ["
l i I[a RI1 1

1 " L
t a-d R n a-d R

I, I! a--cR=H, dE=CH~: a, b, d RI=COOC2H~,c EI=CN; a, c, d Ar=CsHb, bar=

C6H4NO24
5 mmoles of ketone I and 1,01 g (2.5 m m o l e s ) o f Lawesson's reagent are refluxed in 250
ml dry benzene for 15-20 min (Ic for 40 min). The solvent is evaporated and the thioketones
II isolated by preparative TLC (L 40/100 silica gel, eluent chloroform--hexane--acetone 9:7:1)
or column chromatography [2] (L 100/160 silica gel, eluent first benzene then benzene-
acetonitrile i0:I). All compounds obtained are dark blue crystalline substances which ab-
sorb in the visible region of the spectrum around 370 and 580 nm.
2-Methyl-3-ethoxycarbonyl-4-phenyl-5-thioxo-IH-4,5-dihydro indeno [1,2-b ]pyridine (IIa).
Yield 55%, mp 158-160 ~ (from ethanol); IR spectrum (nujol): 3295 (NH), 1680 (C==O), 1218 cm-*
(C----S). PMR spectrum (CDCI3): 5.11 (s, IH, 4-H), 6.77 ppm (s, IH, NH). iSC NMR spectrum
(DMSO): 167.9 (C=O), 217.1 ppm (C=S). Mass spectrum: M % 361.1139. C22HIgN02S. Calculated:
M 361.1136.
In the same way were prepared the thioketones llb (mp 171-173 ~ from ethanol), llc (mp
182-184 ~ from chloroform, CN 2203 cm-1), and lid (mp 145 ~ from ethanol; signal of the N--CH3
group in the PMR spectrum (CDCI3) at 373 ppm).

LITERATURE CITED
i, V. Petrow, J. Saper, and B. Sturgeon, J. Chem. Soc., No. 9, 2134 (1949).
2. B. S. Pedersen, S. Scheibye, N. H. Nilsson, and S. O. Lawesson, Bull. Soc. Chim. Belges,
87, 223 (1978).

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, p. 709, May, 1986. Original
article submitted November i, 1985.

582 0009-3122/86/2205-0582512.50 9 1986 Plenum Publishing Corporation

REACTION OF O-ARYL-N-DI(2-CHLOROETHYL)AMIDOGUANIDYL
PHOSPHATES WITH ACETOACETIC ESTER

I. I. Kuz'menko UDC 547.497.1'118.5'859'892.07

We attempted to prepare phosphorylated aminopyrimidines I, containing an alkylating

group, to prove the influence of the bond between the phosphorus atom and the molecule of
the heterocycle on the antitumorigenic properties of compounds.
The phosphorylated aminopyrimidines I were synthesized by a method already described
[I], starting from O-aryl-N-di(2-ch!oroethyl)amidoguanidyl phosphates [2] and acetoacetic
ester.
However, in the reaction not only a pyrimidine ring is formed, but also a ring closure
by the chloroethyl group with one of the nitrogen heteroatoms takes place, leading to the
formation of substituted 1,2,3,4-tetrahydro-5H-2,1,3,6-pyrimidophosphotriazepin-2-ones (I).
0
N II IOColI4R

0 ~ 0 I
(NH2)2C: N_ ~!/'OC6H4R CHsCOCH2COOC2H
5
0
~'N(CHzCH2Cl)2 C2HsONa ~k FI OC.1t.R
CII3 N. Nil_ p / ~ 4

0
II

a R=H, b R=p-CH3,c ~ R=p-CI, d R=p-Br, ' e R=p-I,f R=p-F

A 10-mmole portion of O=phenylbis(2-chorethyl)amidoguanidyl phosphate [2] is added to

a sodium ethylate solution (prepared from 50 mmoles of sodium and i00 ml of ethanol), and
the mixture is heated to boiling. Then, 48 mmoles of acetoacetic ester are added, the mix-
ture is boiled for another 3 h, and the solvent is distilled in vaaao. The solid residue is
dissolved in 50 ml of water and the solution is acidified with 10% hydrochloric acid to an
acid reaction. The crystalline compound lla that separates is filtered, dried, and recrys-
tallized from benzene. Compounds llb-f are obtained in a similar way. Following are: compounds,
yield (%), mp (~ lla, 59, 155-157; lib, 72, 187-189; llc, 56, 200-201; lid, 31, 203-204;
lie, 56, 183-185; llf, 62, 192-194. Data of elemental analysis correspond to calculated data.
IR spectrum (KBr): 1700 (C=O), 1600 (pyrimidine ring), 1200 cm -I (P=O).

LITERATURE CITED
i. L . V . Rozvodovskaya, A. F. Gromov, and N. I. Mel'nikov, Zh. Obshch. Khim., 45, 2156
(1975).
2. I . I . Kuz'menko, Farm. Zh., No. 2, 71 (1985).

Kiev Scientific-Research Institute of Pharmacology and Toxicology, Ministry of Public

Health of the Ukrainian SSR, Kiev. Translated from Khimiya Geterotsiklicheskikh Soedinenii
No. 5, p. 710, May, 1986. Original article submitted July 2, 1985.

0009-3122/86/2205-0583512.50 9 1986 Plenum Publishing Corporation 583

PYRIMIDINETETKASULFONIC ACID

Yu. L. Yagupol'skii, M. T. Kolycheva, UDC 547.853'551.52

and V. M. Cherkasov

By reacting 2,4,6-trichloro-5-nitropyrimidine (I) with sodium sulfite, a derivative of

pyrmidine was obtained for the first time, in which the sulfo groups are attached to all the
carbon atoms of the heteroiyclic ring, i.e., a sodium salt of pyrimidinetetrasulfonic acid
(II).

i ,'l NOv SO ~Nll

I[ N
CI " N CI NaO ~:5 N ,~(~,Ne
! !!

A solution of 4.6 mmoles of pyrlmidine I in i0 ml of dioxane was added to a solution of

23 m moles of freshly prepared Na2SOa in 12 ml of water, and the mixture was stirred for 8 h.
The precipitate was filtered, and repreclpitated from water by alcohol. The yield of sodium
salt of tetrasulfopyrlmldine IIwas 16%. Found: C8.7; H0.9; N5.5; Na17.7%. C4N2Na~O~2S~.
2.5H20. Calculated: C 9.0; H 0.9; N 5.3; Na 17.3%
We could not increase the yield of salt II, since increase in the temperature or the
reaction time leads to precipitation of a mixture of products of hydrolysis of the sulfo
groups. After separation of compound II, a similar mixture precipitated from the mother li-
quo r on standing.
Sodium salt II is a white crystalline substance, which does not melt on heating to 300~
and is unstable in aqueous solutions. When AgNO, is added, the exchenge reactionproceeds
slowly, and a silver salt of pyrlmidinetetrasulfonic acid is formed in an overall yield of
not more than 19%.
In the IR spectra of the sodium and silver salts of the sulfopyrmiidine, very intense
vibrational bands appear at 1250 (Vas SO2) and 1065 (Vas SO=) cm-*. Several other weak bands
are also observed at 1645, 1515, 1465 cm-* that probably belong to stretching vibrations of
the pyrimidine ring.

Institute of Organic Chemistry, Academy of Sciences of the Ukrainian SSR, Kiev. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 710-711, May, 1986. Original
article submitted September 23, 1985.

584 0009-3122/86/2205-0584512.50 9 1986 Plenum Publishing Corporation

ADDITION OF TRICKLOROACETONITRILE TO VINYLTETRAZOLES

G. A. Shvekhgeimer, K. I. Kobrakov, UDC 547.464.4'796.1

O. G. Mityagina, V. K. Korolev,
and V. K. Promonenkov

The reaction of vinyltetratrazoles with trichloroacetonitrile has not yet been described,
We found that 5-vinyl-substituted i- and 2-methyltetrazoles (Ia, b) smoothly react with tri-
chloroacetonitrile (II) in the presence of copper-containing catalysts to form 2,2,4-trichloro-
4-tetrazolylbutyronitriles

R--CII=CII~ + CCA~CN .... ~ E - CHC1CHzCCI2CN

1,a, b 11 Ilia, b
I. l I I a R=l-methyltetrazolyl; bR=2-~methyltetrazolyl

The r e a c t i o n s were c a r r i e d o u t by h e a t i n g m i x t u r e s o f t h e c o m p o n e n t s i n t h e r a t i o o f I
t o I I from 1 : 1 . 5 to 1 : 5 a t 80-90~ f o r 2 h i n s e a l e d a m p u l s . Cuprous c h l o r i d e o r m e t a l l i c
c o p p e r i n an amount o f 5-10 mole % was u s e d a s c a t a l y s t . At t h e end o f t h e r e a c t i o n , e x c e s s
of nitrile I I was removed i n v a e u o . The r e s i d u e was t r e a t e d w i t h a b s o l u t e e t h e r , f i l t e r e d ,
and t h e e t h e r was e v a p o r a t e d . The c r y s t a l s t h a t s e p a r a t e d were c r y s t a l l i z e d from e t h a n o l .
2,2,4-Trichloro-4-(1-methyltetrazolyl)butyronitrile (Ilia). Y i e l d 86%, mp 75~ PMR
spectrum, 6:3.72 (2H, m, CHi), 4 . 1 7 ( 3 H , s , CH3), 5 . 4 3 ppm (1H, m, CH).
.2,2,4-Trichloro-4-(2-methyltetrazolyl)butyronitrile (Illb). Y i e l d 94%, mp 82~ PMR
s p e c t r u m , 6: 3 . 4 4 (2H, m, CHi), 4 . 3 0 (3H, s , CHs) 5 . 4 2 ppm (1H, m, CH).
The compounds o b t a i n e d have s a t i s f a c t o r y analytical characteristics.

A. N. Kosygin Moscow Textile Institute, Moscow. All-Union Scientific-Research Institute

of Chemical Plant Protection Agents, Moscow. Translated from Khimiya Geterotsiklicheskikh
Soedeninii, No. 5, p. 711, May 1986. Original article submitted October 22, 1985.

0009-3122/86/2205-0585512.50 9 1986 Plenum Publishing Corporation 585

EFFECTOF THE ACID-BASE PROPERTIES OF HETEROAROY~TIC
COMPOUNDS ON ~{EIR ELECTROPHILIC SUBSTITUTION REACTIONS (REVIEW)

L. I. Belen'kii UDC 547.562'72'732'771'787'789'796.04:543:87(047)

The effect of the properties of heteroaromatic compounds as acids and bases on their
behavior in electrophilic substitution reactions was examined. The established
peculiarities were compared with the behavior of functional compounds of the benzene
series. The specific characteristics of the mechanisms of electrophilic substitution
in the heteroaromatic series due to the acidic and basic properties of the hetero-
aromatic compounds are discussed.

This review is dedicated to the memory of Professor Yakov Lazarevich Gol'dfarb, in whose
research the problem of the effect of the acid-base properties of heterocycles on their re-
activities, primarily on the specificity of various substitution reactions, was one of the
major concerns. Gol'dfarb's contribution to the chemistry of thiophene, furan, and benzene
was particularly significant in this respect.
Individual problems related to the topic under discussion were not only the subject of
original papers but were also correlated in reviews; this makes it possible, where appropriate,
to condense the exposition in the present review. In addition, the problem as a whole has not
been duly reflected in monographs dealing with both aromatic substitution (for example, see
[I, 2]) and general problems in the chemistry of heterocycles, for which it is particularly
essential, although in a previously published book [3] this gap was partially bridged with
respect primarily to compounds of the pyridine series. Taking into account the information
stated above, we will begin our exposition with the general problems of the mechanisms of
electrophilic substitution in the aromatic series and the effect of the acid-base properties
of functional substituted benzenes on such reactions; this makes it possible to emphasize the
peculiarities of the behavior of heteroaromatic systems.
Electrophilic substitution is the most important and widely investigated class of reactions
in the aromatic and heteroaromatic series. ~reover, one cannot help being struck by the
fact that, despite the great diversity of substrates and reagents, virtually all electro-
philic substitution reactions are usually considered to be reactions that proceed via a single
mechanism, viz., through the intermediate formation of o complexes; the differences, for
example, between nitration and halogenation are basically reduced to the peculiarities of the
conditions for the generation of the electrophilic agent E +, which participates in the above-
mentioned single mechanism:
H ~
~! + E. . . . . ~ r t , E, . . . . . . . ArE (1)

This sort of treatment sheds no light on the problem regarding the steps of the reaction
that precede or accompany the formation of the ~ complex, which include reaction of the sub-
stratenot only with the electrophilicparticleE also with catalysts or condensing agents
that are usually present in the reaction mixture. We will not discuss here the problem of
the intermediate formation of ~ complexes and the role of one-electron transfer in electro-
philic substitution reactions. The task of this review includes an examination of the effect
of the reactions of aromatic and heteroaromatic substrates with protic and aprotic acids, in
which these substrates act as bases and are converted to nv or o complexes (in the latter
case, however, the complexes are not converted to the desired electrophilic substitution
products). Problems associated with the effect of the acidic properties of the substrates
on electrophilic substitution will also be discussed. This aspect is of substantial signifi-
cance not only within the framework of the "classical" mechanism described by Eq. (i) but

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow

117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 749-773, June,
1986. Original article submitted November i, 1985.

0009-3122/86/2206-0587512.50 9 1986 Plenum Publishing Corporation 587

takes on particular interest in connection with the fact that concepts regarding different
mechanisms of electrophilic aromatic substitution have recently emerged. These concepts are
formulated in the most general and precise form in [4], in which the possibilities of the
occurrence of electrophilic substitution reactions via concerted mechanism (2) and through a
carbanion (3) are examined:

Ar/ lI!,. -Null (2)

~lig ( N u ..... ~ ArE

Arl' ~ Ar-- -- ArE (3)

We do not know of cases in which a concerted mechanism for electrophilic substitution has
been rigorously proved. However, let us present a description of a similar process in which,
moreover, the acidic properties of the substrate play an essential role [5]:
IH

~ r
-HBr
H-'~Br

It might be assumed that electrophilic substitution reactions of activated heteroaromatic

compounds in which condensing agents are not used also proceed via a concerted reaction. A
vulnerable feature of this mechanism is the inevitable formation during the reaction of a
protic acid, which, if special measures are not taken, may serve as a catalyst.
The carbanionic mechanism is considerably more substantiated. Practically speaking, the
direct metallation of aromatic and heteroaromatic compounds, which is accompanied by treatment
of the reaction mixture with the electrophile, proceeds via this scheme. The similar bromi-
nation of 1,3,5-tribromobenzene with tert-butyl hypobromite in the presence of potassium
tert-butoxide is described in [4]. Specific variants of such processes, which include the
intermediate formation of relatively stable ylids, are known in the heteroaromatic series and
will be examined in a special section of this review.
i. Effect of the Acidic Properties of Aromatic Compounds
on Their Electrophilic Substitution Reactions

In addition to reactions that proceed via a carbanionic mechanism in which the CH acidity
of the substrate is manifested, numerous examples of electrophilic substitution in which NH
and OH acidities play a substantial role are known. This is the case of phenols, anilines,
and carboxylic acids. Data published up to 1970 were correlated in a previous review [6]. To
give a complete picture, some of these datawill be presented below; however, principal attention
will be directed to newer publications. The transformations that precede substitution itself
are far from being proven in all cases. In most cases one can arrive at a judgment regarding
them from indirect data, primarily from the preferred formation of ortho-substituted compounds.
The methods for the preparation of o-alkylphenols and o-alkylanilines by the action of
olefins on phenols and anilines in the presence of aluminum metal or aluminum phenoxide have
found substantial preparative value and use in industry [I, 6]. In particular, the method
is used for the synthesis of sterically hindered phenols that are used as antioxidants [7].

+ . y-
YH Y-'M~ Y .-M--..v Y" CH~ YH ~tI~ Y --AU~

.....
. .R.-.C.H.=.C H 2~ .... ~ H Phg|I +
("300 ~ -.\~ . . . . . ".. ....

Y = O , NII

It is possible that the thiylation of aluminum phenoxides by disulfides [8] and the
iodination of phenols in the presence of thallium acetate [9] proceed via a similar mechanism.

Oil r Oil

R [i <:[ 1.. .A1

....
(N2,,..................
lflO-150 ~ ~
R. . . . .
~i1 "[',OAe. 1~,
,,,- R
..v/5 g. RIRSR 1, A . .5~ fleOH "4":

588
 Cases of the primary ortho halogenation of phenols have been described in the literature;
intermediate replacement of the hydrogen of the hydroxy group by the halogen is assumed [6].
Data on the effect of the pH of the medium on the ratio of the products of the chlorination
of phenols by the action of sodium hypochlorite are in agreement with this assumption [i0]:
The ortho/para ratio increases sharply on passing from an acidic medium to an alkaline medium
(from 0.64 at pH 4 to 4.3 at pH i0). It is interesting to note that in the case of anisole a
change in the pH of the medium does not affect this ratio, which remains within the limits
0.63-0.66.
The intermediate formation of a product with replacement of a hydrogen atom of a functional
group, which then undergoes isomerization to an o-substituted product, was established by
means of the IR spectra for the chlorination of N-methylaniline by calcium hypochlorite (the
yields of the compounds formed are indicated under the formulas) [Ii]:
N lime M e . N/C1 NIIMe NilMe~
! I I el l
(10 min)~ I.~,~. - ~ ' h ~ -~ product
C1
g7% 3% 18"~

The formation of an o-nitro-substituted product by the action of nitrogen pentoxide

on biphenyl-2-carboxylic acid fits into the same scheme [12].

! .... I. . . . . ~1 I....
CoSll O~N__O .CO NO~ CCOTI

Reagents of a new type t h a t ensure selective ortho or para substitution of phenols, due,
in the opinion of the authors, to the formation with the substrate of an intermediate complex
in which the phenol acts both as a proton donor for a hydrogen bond and as a ~ donor, have
recently been proposed [:13-15]. 2,2,3,4,5,6- and 2,3,4,4,5,6-Hexachlorocyclohexadienones have
been proposed as chlorinating agents of this type. In particular, the first agent in the
chlorination of hydroquinone monomethyl ether gives compounds with a chlorine atom in the
ortho position relative to the OH and OMe groups in the ratio of 95:5. The same reagent gives
only p-chloroanisole i n the chlorination of anisole.

0 o ....:,I
9.-~ !1 + ~., .... 9 .- ~;_" ...... %~I,O,
cl " -! cI ! ~l ci
Cl (:1 ..J

Phenol is converted to o-nitrophenol with high selectivity by the action of mixed anhy-
drides of nitric and N-alkylpyridiniacarboxylic acids [15].

I
AIk

In the case of anisole and potassium phenoxide, in which the formation of a hydrogen bond
with the reagent is impossible, nitration proceeds unselectively.
2. Effect of the Prqperties of Aromatic Compounds as
Bases on Their Electrophilic Substitution
The presence in an aromatic compound of a functional group that has an unshared pair of
electrons creates the possibility of the formation of an nv complex with an aprotic acid or
protonation of this group under the influence of a protic acid; this leads to a pronounced
change in the orienting ability of the substituent. Thus the halogenation of aniline and
dimethylaniline leads only to o- and p-substituted products; however, the halogenation of com-
plexes of the same anilines with AICI3 gives %20% meta isomers, and 50-60% meta isomers are
+
formed in the case of the ammonium compounds PhNR2HA!CI4- [16]. The bromination of dimethyl-
aniline in sulfuric acid by bromine in the presence of silver sulfate gives a similar effect

589
[17]. The nitration of dimethylaniline in sulfuric acid is a convenient method for the'syn-
thesis of an m-nitro-substituted compound [18],
The situation is more complex in cases in which the onium grouping develops with the
participation of the attacking electrophile. For example, in the sulfonation of aniline the
slow step is the formation of the similar onium ion PhNHzSO3H, which then is rapidly converted
(inter- or intramolecularly) toproducts of sulfonation in the para and ortho positions but not
in the meta position [19]. The nitration of acetanilide and some of its m-substituted deriv-
atives with acetyl nitrate or nitronium tetrafluoroborate leads to a mixture of o- and p-nitro-
substituted products withasubstantialpreponderanceof the former [20]. In the opinion of
the authors, the reason for this is preceding coordination of NO2 + at the nitrogen or oxygen
atom of the amide group. The well-known instances of the selective formation of o-nitro-
substituted products in the nitration of anisole [21-23] and methyl phenylethyl ether [22, 24]
can also be explained by similar coordination of the nitronium cation at the ether oxygen
atom. Thus the intermediate formation of an onium center with the participation of a cation
reagent does not lead to a fundamental change in the orienting effect of activating substitu-
ents and can only increase the formation of o-substituted products.
Complexing or protonation at the functional group in the case of carbonyl compounds has
an extremely substantial effect on the specificity of substitution. It is well known that
replacement of the hydrogen atoms of the a-methylene group in the case of ketones (for example,
see [25, 26]) and, not infrequently, an aldehyde proton [27], is observed under ordinary con-
ditions in many electrophilic substitution reactions. However, various eleetrophilic substi-
tution reactions are directed to the meta position of the~aromatic ring when a strong aprotic
acid in amounts above the equimolar amount or excess protic acid is used. As examples of such
reactions, let us cite the chlorination and bromination of benzaldehyde and acetophenone in a
iarge excess (2.5 moles) of anhydrous AICI3 without a solvent [28, 29] or the bromination of
these compounds with i to 1.5 moles of AICI3 in a solvent [30].

= x

Bromination by the action of bromine in concentrated sulfuric acid in the presence of

Ag2S04 on benzaldehyde [31] and acetophenone [32] is also directed to the meta position.
Acetophenone in the form of a complex with A i C l 3 i s converted smoothly to m-(chloromethyl)-
acetophenone by the action of various reagents, viz., mono- [33] and bis(chloromethyl) [34]
ethers, as well as a mixture of paraformaldehyde with AICI3 [35].
An interesting example of the effect of protonation on the specificity of a reaction is
the electrophilic hydroxylation of benzaldehyde and acetophenone with 70% hydrogen peroxide in
HF-$bF5 super acid [36]. It is well known that in conditions under which complete protona-
tion of both components is not achieved, oxidation to benzoic acid and the Baeyer-Villiger
rearrangement to give the phenyl formate and phenyl acetate, respectively, occur [37].

O I~ + IH ~ IH 0

R R H
OH ----~

I n i n t e r p r e t i n g the unusual s p e c i f i c i t y of e l e c t r o p h i l i c s u b s t i t u t i o n r e a c t i o n s one

must s p e c i a l l y demonstrate that, complexes w i t h p r o t i c and a p r o t i c acids are a c t u a l l y formed
under the reaction conditions and that theproducts of their transformations differ from the
substances obtained from the corresponding aromatic compounds that are not tied up in com-
plexes. Such data are available for many of the examples examined above. In particular,
complexes of carbonyl compounds of the benzene series were identified in solutions by diverse
physical methods, including IR, UV, PMR, and 13C NMR spectroscopy [30, 38-42], as well as
calorimetry, dielectrometry, and cryoscopy [ 4 3 ] . At the same time, instances in which the
real transformations do not, it would seem, fit into an extremely plausible scheme are known.
Such "deviations" are known primarily for the halogenation and alkylation of phenols and ani-
lines, and they are due to the possibility of C protonation of the activated aromatic rin~ and
the associated reversibility of the indicated reactions, which is manifested even under
mild conditions. Thus the bromination of p-alkyl- and o,o-dialkyl-substituted phenols and
anisoles in a super acid medium proceeds in the meta position relative to the hydroxy or
methoxy group; this was explained by Jacquesi and co-workers [44] as being the result of

590
 protonation at the oxygen atom, as a consequence of which, the orienting effect of an oxygen-
containing substituent of the first order also changes. However, in actuality, as demon-
strated in [45] in the case of p-cresol, protonation is not directed to the oxygen atom but
rather to the carbon atom in the ortho position relative to the hydroxy group. Bromine also
enters the same position, but this is then followed by slower conversion of the kinetically
controlled product to the thermodynamically more favorable isomer, the amount of which in-
creases significantly when the reaction mixture is allowed to stand for a long time.
OH -- OH OH OH OH

Br 2
CF~SO~I! :~Br -- ~" " :~Br "'Br

Ma [. Me Me .j Me Me
I0 rain 40 : 60
> 2 0 h I0 : 90

Similar transformations are also known for aniline derivatives. In particular, the
transformations of o-bromo-N,N-dimethylaniline under the influence of HBr to dealkylation,
debromination, and isomerization products have been studied [46].

NMe~ +
N}|Me:, Me..N~.H
t /Br ~ . . zBr . .... Br

..ri!
NMe~ NMe~ NMe~ NMe~

0 -

Br
A study of the alkylation of anisole using various alkylating agents and catalysts [47]
under kinetic-control conditions (at a low temperature and a low catalyst concentration)
showed that o- and p-alky!-substituted products are formed in a ratio close to the statis-
tical value (2:1) and that the amount of meta isomers does not exceed 3%. Isomerization of
the substances is observed under more severe conditions; the amount of the ortho isomer de-
creases, and the amounts of the para and meta isomers increase. In the same study in the
case of the benzylmethylphenyloxonium ion generated at --90~ it was shown that initial attack
of the electrophile at the heteroatom of the functional group, in contrast to the prevailing
opinion, does not at all ensure the formation of o-substituted products: When the temperature
is increased, the indicated cation is converted exclusively to a product of intermolecular
transfer, viz., p-benzylanisole.
OMe + ~.~/OMe
11 .~_/... P h - - O - - t'tt:~ Ph ----m-
"- ~- CH 2ph Me phCH2 I% J

. Basicities of Heteroaromatic Compounds and Their Electrophilic Substitution Reactions

In the preceding section it was shown how the basic properties due to the presence in
the benzene ring of appropriate substituents lead to the formation of complexes with protic
and aprotic acids, a consequence of which is a change in the specificity of electrophilic
substitution as compared with the free bases. Similar effects, which are determined by
complexing at the functional group, are also manifested in the heteroaromatic series,
as will be stated below. However, in heterocycles even the first members of the series and
homologs are essentially functional compounds in which the ring heteroatom acts as a function.
It is therefore clear that phenomena similar to those described above are usually widespread
in the heteroaromatic series. Considering the enormous diversity of the types of hetero-
atomatic systems, one must sharply limit the subject of the discussion.
Principal attention will be focused on monocyclic five-membered heterocycles
with one heteroatom, compounds of the pyridine series, and azoles. We will not touch upon
condensed systems, since in them the peculiarities of theelectrophilic substitution reactions of
interest to us turn out to be either similar to those of monocyclic heterocycles or to those

591
of functional compounds of the benzene series. Oxygen and sulfur analogs of pyridine, viz.,
pyrylium and thiopyrylium cations, do not react with electrophilic agents. The reaction of
electrophilic agents with azines that contain severalnitrogenatoms, however, usually does
not lead to substitution products but rather to onium salts involving one or two nitrogen
atoms. Electrophilic substitution becomes possible only when activating substituents are
present in such compounds.
A t the same time, it must be pointed out that q-deficient di- and triazines under
certain conditions can act as electrophilic reagents with respect to various aromatic and
heteroaromaticcompounds. T h u s some halogen-substituted pyrimidines and sym-triazines,
w h i c h c a n be regarded as analogs of imido chlorides, undergo condensation with aromatic
compounds in the presence of Lewis acids [48-50].
el
J,
CI OH N" ":'N

L L , I;.
CI "OH

The conversion of azines to azinium cations by protonation, alkylation, or acylation

makes it possible to realize the so-called "hetarylation" of active aromatic and heteroaro-
matic compounds [51, 52]. N-Acyloxyazinium salts formed in the acylation of N-oxides can
also serve as hetarylating agents [53]. Hetarylation often proceeds under very mild con-
ditions. For example, pyrimidine, 5-methylpyrimidine, and the corresponding benzo-annelated
compounds react readily in trifluoroacetic acid with active aromatic and heteroaromatic com-
pounds to give aryl(hetaryl)dihydropyrimidines, which can be aromatized by the action of
potassium ferricyanide [54-56].
Ar
At". flI Ar. ~ I t
.R 9 f R HN'X. .R K.~F e l C N ~
~
'bl: "'N"" "<N"
II II
R=H. Me

The reaction of sym-triazine with aromatic compoundsinitiated by means of hydrogen

chloride, which can serve for the synthesis of aldehydes [57], evidently also has similar
character.

N/~N HCI
ArH ----.--m.- Ar-C -- ~" ARCH0
N Cl-"

Pyrylium [58, 59] and thiopyrylium cations [60] can also undergo hetarylation.
Turning now directly to the problem of the properties of heteroaromatic systems as sub-
strates in electrophilic substitution reactions, let us note that the heterocycles under dis-
cussion differ substantially from one another with respect to their strengths as
bases. The pKa values of a number of monocyclic compounds and some of their substituted
derivatives at 20-25~ in water or aqueous sulfuric acid, taken for 2,5-dimethylfuran,
2,5-dimethylthiophene and 2,5-dimethylpyrrole from [61], and for 2-acetylthiophene from [62]
~the remaining values are presented f r o m d a t a in [3, pp. 126, 127] and are supplemented and
partially corrected from the data in [63]), are presented in Fig. i. It is not
difficult to see that the differences in basicities exceed 17 orders of magnitude between the
strongest base (imidazole) and the weakest bases (furanand thiophene, for which data are
not available but which should be weaker bases than their 2,5-dimethyl-substituted derivatives)
It is apparent that such colossal differences in basicities also predetermine the extremely
different behavior of the examined systems with respect to protic and aprotic acids.
The protonation of heteroaromatic compounds or their complexing with a Lewis acid under
the reaction conditions leads to slowing down of electrophilic substitution; this is due to
two reasons: i) a decrease in the substrate concentration as a consequence of tying up of a
significant amount of the substrate in a deactivated complex with a protic or aprotic acid;
2) a sharp decrease in the reactivity of the substrate when it is completely converted to the
complex. Katritzky and co-workershave made comprehensive studies that make it possible in
many cases to draw conclusions as to the form (free base or conjugate acid) in which various
heteroaromatic compounds react. Criteria based on measurement of the reaction rate constants

592
 . . H [0-

..... c/.,~
1t H

H H

-)0 -5 0 5 p~

Fig. i. Ionization constants of the conjugate acids of hetero-

aromatic compounds.

at various acidities of the medium, determination of the activation parameters, and compari-
son of the observed rate with the reaction rate of a related compound known to exist in the
ionic form (for example, pyridine methiodide in a study of the reactions of pyridine in an
acidic medium) were developed [64]. The same group of researchers obtained comparable quanti-
tative data on the reactivities of heterocycles of various classes. Data extrapolated for
hydrogen isotope exchange in a moderately acidic medium (pD 0) at 100~ [65-67] are presented
in Fig. 2, and, in the case of "standardized" constants for nitration by nitric acid, scaled
for 25~ and Ho-6.6 (75% sulfuric acid) [68-72], are presented in Fig. 3. We will
subsequently use these data in an examination of various groups of heteroaromatic
compounds. Here, however, we will make some general comments. The differences in the rela-
tive reactivities of the heteroaromatic compounds as compared with benzene (Fig. 2) in the
case of hydrogen exchange reach 30 orders of magnitude; for the same compound in the form of
the neutral base and the conjugate acid these differences amount to 6-9 orders of magnitude.
It is important to note that 1,2-azoles (in the free base form) in the case of acid-catalyzed
hydrogen isotope exchange are more active than benzene and approach thiophene and N-methyl-
pyrrole in this respect, which differ substantially from pyridine. In a more acidic
medium (see the data on nitration in Fig. 3) the same 1,2-azoles are substantially
inferior in reactivity to not only thiophene but also to benzene; they are similar in activity
to deactivated acetophenone. Such differences can be explained by the fact that at H0--6.6
the substrates are almost completely protonated, and the true concentration of the free base
is very low. If the conjugate acid undergoes the reaction, the reaction rate again decreases
by several orders of magnitude, so that, with respect to their activity, the protonated forms
resemble nitrobenzene. T h e smaller range of differences (12 orders of magnitude) in the case
of nitration as compared with hydrogen isotope exchange is due to both the higher rate (and
the lower substrate selectivity) of nitration and t h e a b s e n c e of data for the "extreme"
members of the series, viz., the pyridinium ion and the protonated pyridine N-oxide, on the
one hand, and N-methylpyrrole, on the other.
An idea as to what relative activities various heteroaromatic compounds had in electro-
philic substitution reactions, if one could completely exclude their reaction with protic and
aprotic acids, was given by the results of experiments on the solvolysis of analogs of benzyl
halides and benzyl ethers, which were carried out in neutral media such as aqueous ethanol,
methanol, or acetone. It is assumed that the intermediates of such reactions resemble cationic
o complexes:

CRzX -- ----~,,=- CR z ....... ),,. CR2Y

In each case a linear correlation of the Hammett type with the utilization of electro-
philic substituent constants ~+ is observed when various substituents are introduced into the
benzene ring:

l gt~Ar/kVh = p" OA~+.

A similar correlation is also observed for heteroaromatic analogs; each heteroaromatic

residue can be characterized by a "substituent" constant that formally corresponds to replace-
ment of one or two vinylene groups in the phenyl residue by NH, O, S, or --N=CH--. Data on

593
 q) t7 1
3- 2- 3-2-

9 t

3-5- ',,-

,, [i
J._...=.._=_..J ~ . . . J _ , . a . i I I _
-15 -10 -5 0 5 10 15

F i g . 2. Logarithms of the f a c t o r s of the p a r t i a l r a t e s of

hydrogen i s o t o p e exchange i n h e t e r o a r o m t i c compounds (pD
0, 100~ The positions of the ring for which the partial
rate factors are presented are indicated under the formulas.

. 9 9 . / -,.

H H H H

[i,I: I ~"

NO~ Aa

o
- 10 - 5 0 lg k 2

Fig. 3. "Standardized" constants of nitration (kz ~ of some

het eroaromatic compounds by the action of HNO in sulfuric
acid (H0-6.6, 25~ The positions of the ring for which
the nitration rate constants are presented are indicated
under the formulas.

[!. i]
"s:'

H ~0 : " "~
9
,31
- 2- 4'-
1t
t _ . ~ _.J
4-(5-1 2-

1t

4-
I 1 ! ! ~ l i r _._....i_ i i i i i i ---L.
92,0 -1,0 0 1,0~

Fig. 4. The O~rCOnstants of some heteroaromatic com-

0
pounds for the solvolysis of heterocyclic analogs of
benzyl halides and benzyl ethers. The positions of the
heterocycle that are bonded with the side chain in the
heteroanalogs of compounds of the Ar--CRzX are indicated
under the formulas.
594
the ~ r values for various hetaryl systems obtained primarily by Noyce and co-workers [73-81],
as well as in [82-84], are presented in Fig. 4; the heterocycles are depicted above the O~r
values corresponding to'the ring positions that are most reactive in electrophilic substitution.
It is clearly seen in Fig. 4 that the heterocycles under discussion are distributed between
pyrrole and pyridine in two groups, in one of which imidazole and pyrazole are included along
with furan and thiophene, whereas the other is made up of other 1,2- and 1,3-azoles, the O~r
values of which are close to that of benzene ( ~ r ~ 0 for phenyl).

3.1. Five-Membered Heterocycles with One Heteroatom~ Furan, thiophene, pyrrole and their
homologs are not only the weakest bases of the heterocycles under consideration but also differ
fundamentally from pyridine and azoles with respect to the structure of the protonated part.
Five-membered heteroaromatic systems with one heteroatom are not protonated at the hetero-
atom but rather at the m-carbon atom; this was demonstrated clearly by physical methods,
primarily by means of PMR spectroscopy; it is important to note that in the case of pyrrole
[85-88] and thiophene [89-95], the resulting heteroarenium ions (o complexes), as a conse-
quence of the stabilizing effect of the heteroatom, are quite stable in acidic media at or-
dinary temperatures for the first members of the series, whereas in the case of furan they
are stable for the sterically hindered di- and trialkyl-substituted compounds [96-99].

Rz R~

1-?,~ / "2~" "|1

The well-known acidophohic character of five-membered heterocycles is due to the formation

of C-protonation products: Heteroarenium ions can act as electrophilic agents with respect to
free heteroaromatic molecules, which leads to products of acidic oligo- and polymerization,
which are often formed under the conditions of electrophilic substitution carried out in the
presence of protic and aprotic acids (see a previous review [i00] for a more detailed dis-
cussion). One should, however, bear in mind that oligomerization is often observed in the
presence of relatively small amounts of acid and that stable heteroarenium ions can be formed
in excess protic acid; the bonding in the form of this sort of ion may create a distorted idea
regarding the reactivity of the heteroaromatic compounds. In our opinion, the lower activity
of thiophene as compared with benzene in the case of alkylation in liquid hydrogen fluoride
observed in [i01] can be explained precisely by the formation of C-protonation products, which
are incapable of reacting with the electrophilic agent. Such complexes can develop under
electrophilic substitution conditions even without the addition of a protic acid from the
outside due to the protic acid liberated during the reaction if the aprotic acid used in an
equivalent amount forms a stable anion, as we observed in the acylation of thiophene and
its homologs by means of carboxylic acid chlorides in the presence of 1 mole of AICI3 [94],
in which case up to half of the substrate was found to be tied up in the form a a C-proto-
nation product and did not participate in the primary reaction.
2 C

R" " " S " "'R 1 R " S R1 + R " "~S'" 11

A1C14"
a R=RI=H; b R=~qe, R ' = H ; c R=RI=Me; R2=?,ie, CH2CI

Replacement of the aprotic acid, in this case for example, by stannic chloride, prevents
the formation of stable o complexes. However, when stabilizing substituents are present in
the substrate molecule, o complexes can also be formed in the presence of SnCI4 [93].
The formation of stable o complexes can also be used for preparative purposes. Thus it
makes it possible to avoid the production of di- and polyalkyl-substituted compounds if the
alkylation is carried out in the presence of an equivalent amount of AICI3 [102].
~K

[ + AlkCI + AICI3
Mk
," .c7

S "
H

II
Ei/ l-.
"~N / \H

AICI4- .~dC14"
I -H* i -It4
,-Alk

595
 Substituted thiophenium ions undergo disproportionation, the driving force of which is
conversion of the less stable cations to more stable cations. In the case of alkylmercapto-
substituted [92] and tert-alkyl-substituted compounds [94] these processes take place at a
quite high rate (after a few hours) even at room temperature. Compounds with secondary and
primary alkyl groups behave similarly, but their transformation proceeds very slowly or requires
heating [94, 95]. Disproportionatlon can serve for the preparative synthesis of 2,4-bis(alkyl-
mercapto)thiophenes [92] and 2,4-dialkylthiophenes [95] from the 2,5-substituted isomers and
also makes it possible to convert a mixture of 5- and 3-tert-butyl-2H-thiophenium ions formed
in the alkylation of thiophene by the method in [102] and containing ~15% of the 3-substituted
compound to practically pure 2-tert-butylthiophene [94]. The mechanism of the disproportion-
ation under discussion, which was examined in [92, 94, 95], is similar to the transformations
described above for the products of alkylation and halogenation of activated compounds of the
benzene series, viz., phenol and aniline derivatives [45-47]. Disproportionation is due to
the reversibility of the formation of ~ complexes and the possibility of transfer of the sub-
stituent split out in the form of an electrophilic particle to a free molecule that already
bears a substituent. The unsuccessful attempts to obtain alkylmercaptothiophenium ions by
the action of sulfenyl chlorides on thiophene in the presence of an equivalent amount of AICI3
[103] can be explained by the ease of splitting out and redistribution of the alkylmercapto
groups in the presence of AICI~ and also by oligomerization.
The well-known difficulties involved in the productionof 2-bromothiophene, which is
generally formed by bromination in a mixture with.2,5-dibromothiophene, are probably due to the
facile disproportionation of the intermediately formed c complexes. In this connection let
us note that our attempts to obtain bromothiophenium ions by the action of bromine on thio-
phene in the presence of AICI3 under conditions close to those described for alkylation [102]
were unsuccessful, and the deprotonation product contained significant amounts of 2,5-dibromo-
thiophene. It seems to us that the successful production of 2-bromothiophene by the action
of a bromide--bromate mixture on thiophene by the method in [104] is due to the fact that
ether, which ensures deprotonation of the resulting ~ complexes, w a s u s e d as the solvent.
Data indicating that 2,5-dibromo-2H-thiophenium ions are readily converted to 3,5-dibromo-
substituted compounds [105] are in agreement with the information stated above. Let
us also note that the diverse chloro-substituted thiophenium ions described in [106, 107],
which are generated by protonation of chlorothiophenes at--40~ to --70~ evidently undergo
rearrangement and (or)polymerization at temperatures above --30~ C , i.e., they behave like
2,5-bis(alkylthio)-2H-thiophenium ions (see [92]).
Thus, with respect to their behavior toward acids, the first members of the series of
five-membered heterocycles with one heteroatom resemble activated aromatic compounds, viz.,
phenols, anilines, and polyalkylbenzenes, To an even greater degree this pertains to pyr-
role, thiophene, and furan derivatives that have a substituent of the first type. Let us
note in this case that C protonation can also be observed for such derivatives of hetero-
cycles that have substituents that are the site of protonation in the case of the benzene
analogs. Thus C protonation of sulfides of the thiophene series was noted frequently above,
whereas, according to the data in [108, 109], alkyl phenyl sulfides are protonated at the
sulfide sulfur atom. Even when a strongly basic center such as an amine nitrogen atom is
present in the substituent, C protonation is observed for heteroaromatic compounds. This
occurs in the case of aminofurans [ii0], including those in which the nucleophilicity of
the ring is reduced by the presence of a negative substituent (CN) [Iii].
CN R CN

E" \0 ~NII 2

R=Me, Ph; I~ + R=(CH2) 4

It is appropriate here to note that anilines and diphenylamine form stable products of
protonation at the nitrogen atom [112]. Carbazole also behaves in the same way [113]. Stable
C-protonation products are observed only for 1,3,5-triaminobenzene [114] and 1,3,5-tris-
(dialkylamino)benzenes [115], which form ~ complexes that are stabilized by three amino
groups. It might be assumed that the discussed differencesbetween functional substituted
benzenes and their five-membered heterocyclic analogs are due to the lower aromatic character
of the latter; the energy expenditures associated with the loss of aromatic stabilization in
the formation of a heteroarenium ion are fully compensated by the gain due to charge de-
localization with participation of the multiple bond and the ring heteroatom, as well as the
suhstituents. If the amino group is not conjugated w i t h t h e heteroaromatic ring, protonation
and complexing with the Lewis acid are directed to the nitrogenatom. This circumstance can
be used for preparative purposes. Thus "blocking" of the amino group by means of AICI3 makes

596
it,possible to prevent both cleavage of 2-thenyl- and 2-furfurylaminesat the N--CHet bond and
N acylation in the case R = H []16].

AICI~
~X / ~CHzNR 2"A|CI 3 Ac/" "'X" ~ CHzNR2

a x : s . I~=11; b x=3, 1{ iie; c x: o, I{;:Me

I n p y r r o l e s , f u r a n s , and t h i o p h e n e s t h a t h a v e s e c o n d - o r d e r s u b s t i t u e n t s the basicity

center, as in the benzene analogs, is the substituent heteroatom. Exceptions are known only
for compounds that have additional substituents that increasethe electron density in the
heteroring, like the above-mentioned amino nitriles of the furan series[ill] or polyalkylated
carbonyl compounds of the pyrrole series [117, 118]. The effect of complexing and proto-
natio~ at the substituent heteroatom on electrophilic substitution reactions has been widely
studied for thiophene and furan derivatives, chiefly by Ya. L. Gol'dfarb and co-workers (see
the previous reviews [i00, 119, 120], as well as [121, Chap. l]) and by Anderson and co-workers
in the pyrrole series [122]. Here, one should recall only that for the first members of the
series in electrophilic substitution reactions the activity changes in the order pyrrole >>
furan > thiophene, whereas the selectivity (the w-B ratio) changes in the order furan>> thio-
p h e n e > pyrrole. The reasons for the disparity between the activity and selectivity series
were examined in [100]. It is important to bear in mind only the fact that the same orders
are also retained for substituted heterocycles. With respect to their behavior in reactions
with electrophilic agents, the B-substituted compounds, for which the m-orienting effect of
the substituent is in accord with the e-orienting effect of the heteroatom, are most similar
to the benzene analogs. A peculiarity that is due to the higher activity of the system is
the appreciable formation of other isomers, chiefly the 2,3-disubstituted compounds. In the
case of e-substituted compounds the orienting effects of the substituent and the heteroatom
do not coincide, and mixtures of 2,4- and 2,5-disubstituted compounds are often formed. If
complexing and protonation at the functional group are prevented (chiefly carbonyl-containing
substituents were studied), the reactionsare then directed exclusively to the 5 position for
furan derivatives and exclusively or primarily to the 5 position for thiophene derivatives.
Primarily 2,4-disubstituted compounds are formed in the ease of pyrrole derivatives. Con-
version of a free functional substituted compound to a complex with a protic or aprotic acid
markedly intensifies the electron-acceptor properties of the substituent (see [42] for
quantitative estimates of the o~ constants of various substituents modified by complexing
with AIX3). In conformity with the selectivity order presented above the complexing under
consideration makes it possible to readily suppress the o-orienting effect of the heteroatom
in the ease of pyrrole compounds and to obtain diverse 2,4-disubstituted pyrroles [122]. In
the case of thiophene derivatives the desired effect is achieved only for the strongest meta
orientators, viz., formyl and acetyl groups modified by complexing or protonation. In the
case of 2-(ethylsulfonyl)thiophene [123] and 2-cyanothiophene [124] complexing with AIX makes
it possible to obtain primarily 4-bromo-substituted products in bromination. Selectivity in
substitution is virtually absent in the case of the thiophene-2-carboxylic acid ester. Proto-
nation of the carbonyl group gives virtually the same results as conversion to a complex with
AIC13. When sulfuric acid, which evidently does not form a true protonated form as in the
case of HSbCI~, but rather a hydrogen-bonded complex, is used the selectivity is appreciably
lower. The corresponding data are presented in Tables i and 2. In the case of furan compounds
the o-orienting effect of the heteroatom cannot be overcome. Primarily 4-bromofurfural is
formed in the bromination of the complex of furfural with AICI3 [130].
3.2. Pyridine. Because of the deactivating effect of the pyridine nitrogen atom, electro-
philic substitution reactions proceed with great difficulty and are directed to the 3 position
of the heteroring. The unfavorability of the formation of 2- and 4-substituted compounds can
be explained by the instability of the corresponding ~ complexes because of the contribution of
structures with a positively charged divalent nitrogen atom.

EJ E

lJE II.
N" "H "N"

Protonation or complexing at the nitrogen atom substantially decreases the reactivity but
does not change the specificity of electrophilic substitution in the pyridine series. It is
easy to see that extremely unfavorable structures with a doubly charged trivalent nitrogen

597
 TABLE I. Specificity in the Electrophilic Substitution of
Complexes of Carbonyl Compounds of the Thiophene Series with
AICI3
E

'. 1r ..C: ~" , #" ' ' , C O g

II
O'AICI3

!Ratio of the
R E Reagent 2 , 4 and 2,5 Literature
isomers
H, Me Br Brs/AIClzin CIiCb, 99:1 [12~I
Me Br Brs in excess AICIs without a 99,5 : 0,5 [1261
solvent
Me CH3CO CH~Q.OC1 in excess A1Cls 94:6 [127l
wlthout a solvent
H, Me CH2CI (CICH2)20/AICI:~in CHCIs >99 : < I 1.1281
H, Me CH2CI (CHsO) x/AlCla in CHCIa >99 : < 1 [35]

TABLE 2. Specificity in the Electrophilic Substitution of

Complexes of Carbonyl Compounds of the Thiophene Series with
Protic Acids
E

E / ' ""S ~ ~ " C O R

H
O.liA n

Ratio of the
R An E Reagent 2,4 and 2,5 Literature
isomers

H SbCI6 Br Br2/AlClain CICH2CH2CI 98:2 [1241

Me SbC16 Br Br~/AICla in CICH~CHsCI 96:4 [1241
H SbCI~ NO2 NOs+BF4-in C[CH~CH2CJ 94:6 [411
Me SbC16 NO2 NOs+BFcin CICHsCHsCI 89: ll [41]
MeO SbCIs NO2 NOs+BF4-in CICH~CHsCI 59:41 [41]
H HSO4 NO~ KNO~ in excess HzSO4 75 : 25 [601
Me HSO4 NO= KNO:~ in excess HsSO4 90: lO [6oi
Me HS04 Br Br2 in excess HzSO4 75 : 25 [32]
H HSO4 CH.~CI (CICH2)20 in excessHS$04 67 : 33 [1291
Me HSO4 CH~CI (C CH2bO in excess H2SO4 80 : 20 [129]

atom make a contribution to charge delocalization in the a complexes that develop during
electrophilic attack at the 2 and 4 positions of the pyridinium ion. A different situation
occurs in the case of N-oxides. It is well known that pyridine N-oxides are nitrated in the
4 position by a mixture of nitric and sulfuric acids; this is explained by an increase in the
electron density in this position via a mesomeric mechanism [64, 131]. The bromination of
alkylpyridine and quinoline N-oxides, which is r e a l i z e d b y the action of bromine in acetic
acid in the presence of thallium triacetate [132], also proceeds in the 4 position. At the
same time, the sulfonation of pyridine N-oxide, which takes place in oleum, is directed to
the 3 position. This peculiarity is explained [64, 131] by the participation in the reaction
of protonated forms in which the orientation is similar to that examined above for the
pyridinium ion.
NO z

O' OH o-

The effect of the properties of diverse compounds of the pyridine series as bases on
their electrophilic substitution reactions, chiefly hydrogen isotope exchange and nitration,
was studied in detail by Katritzky and co-workers, and the corresponding data were correlated
in a review [64] and reflected rather fully in a monograph [3]. In this section we will
focus our attention on the halogenation of pyridines, which was virtually untouched upon in
a previous review [64]. The realization of such reactions is fraughtwith specific diffi-
culties: The protic or aprotic acids necessary for the generation of the electrophilic particle

598
ti~ up a pyridine molecule in a complex, which is deactivated with respect to electrophilic
attack to an even greater extent than the neutral molecule. Judging from the available data,
the electrophi!ic chlorination andbromination of the pyridinium ion could not be realized
at all. Thus Pearson and co-workers [133] carried out the chlorination of pyridine in excess
anhydrous AICI3 without a solvent at %100~ however, in this case approximately half of the
starting pyridine is tied up in the form of the hydrochloride and does not undergo substitution.

Bromination of pyridine under the indicated conditions does not proceed at all [133]. It
might be assumed that i n e x c e s s A i C ! 3 (2.5 moles) pyridine would be completely tied up in a
deactivated complex with AiCI~, which can be subjected to reaction with a more active
e!ectrophilic agent (Cl2 + AICIz) but not with a less active agent ~ (Br~ + AICI3). This point
of view is confirmed by the successful bromination of pyridine under similar conditions but
with the use of an equimolar or catalytic amount of AICI3, as well as other Lewis acids [134],
Some other unusual and by no means obvious methods for the bromination of pyridine t h a t
require clarification should be noted. The bromination of pyridine in oleum, which, in the
opinion of den Hertog and co-workers [135, 136] proceeds through a complex with S03 during
which SO~ also participates in the generation of an electrophilicparticle, has been described.

2 C~H~N + ~ S03 + BrZ ~ " ~ C~H4Nt]r + SO~ + HzSOr

The iodination of methylpyridines also proceeds under similar conditions; however, the
halogen is partially incorporated in the methyl group [137]o Methods for the bromination of
pyridine in thionyl chloride [138], as well as bromination and chlorination in phosphorus
oxychloride, sulfuryl chloride, and in a monochloride medium [139], which suggest the for-
mation of unchargedadducts of these compounds with pyridine [138], are also known.
3,~. Azoles~ Azoles constitute an extremely distinctive group of heteroaromatic com-
pounds, slnce in them one or several"pyridine" nitrogen atoms are combined with a hetero-
atom of the "pyrrole"type. In this connection an examination of azoles as ~-amphoteric
systems [3] that are capable of manifesting both q-donor and ~-acceptor properties seems
extremely felicitous. At the same time, the so-called ~ ~balance", i.e., the sum of the
calculated (by the Huckel method) ~ charges on the carbon atoms of the heteroring, which
was proposed in a book [3, p. 70] as an index of the m-donor or ~-acceptor character, clearly
does not suit this purpose. First of all, the magnitudes of the ~ charges depend substantial-
ly on the method of calculation and pertain in each case to the static state of the neutral
molecule, i.e., one can, by no means, disregardeither the mechanism or the conditions of
the reaction. In addition, the conclusions that one might have drawn on the basis of the
values under discussion contradict the experimental data in a :lumber of cases.
Thus the idea [3] that isothiazole, isoxazole, and oxazole have lower reactivities than
thiazole in electrophilic substitutionreactions clearly does not correspond to the available
data, particularly to the data presented in Fig. 4. Moreover, as we will demonstrate below,
oxazole in the form of the free base is evidently even more active than thiazo!e in such re-
actions. The deactivating effect of "pyridine" nitrogen atoms in triazoles and tetrazole
has also been clearly exaggerated.
In electrophilic substitution reactions that proceed via an addition--cleavage mechanism
the activities of the individual positions for 1,3-azoles change in the order 5- > 4->>2-, as
compared with 4- >>3- ~ 5 - for 1,2-azoles. The particular unfavorability of the formation of
2-substituted products in the case of 1,3-azoles and of 3- and 5-substituted products in the
case of 1,2-azoles is determined by the contribution of the boundary structures with a posi-
tively charged divalent nitroEen atom to the correspondingcationic ~ complexes.

599
 H"
:2"'X"" ....... ,J ""
/ "
-'-- L]
H

"X""

. --N ...... N
,q: ........... . i !F.. l jJ

[ '~
v" L "-'" ~xZ[< /...

X X

E .,~E

X i ,'~ X"

/
H X" H X

As i n t h e p y r i d i n e s e r i e s , c o m p l e x i n g w i t h p r o t i c o r a p r o t i c a c i d s d o e s n o t c h a n g e t h e
specificity of the electrophilic substitution of azoles but markedly decreases its rate. The
c o n v e r s i o n o f a z o l e s t o N - o x i d e s makes i t p o s s i b l e t o c h a n g e t h e s p e c i f i c i t y of substitution
[140, 141].
VO vO

I -'" " N O 2 " " "' N f l ~ 0 I ": N " NO 2

Me Me Me Me

The available data on the electrophilic substitution of azoles show that imidazole and
pyrazole -- pyrrole analogs -- are the most active compounds of this class. A comparison of
diazoles with respect to activity is hindered by the fact that imidazole is a considerably
stronger base than pyrazole (see Fig. i). In particular, imidazole in the case of nitration
with a mixture of nitric and sulfuric acids always u n d e r g o e s t h e reaction in the cationic
form, whereas pyrazole reacts in the c a t i o n i c f o r m only at a sulfuric acid concentration
above 90% [142]. O w i n g to the high activities and moderate strengths of pyrazoles as bases,
these compounds can even be a c y l a t e d v i a the Friedel--Crafts reaction; under standard con-
ditions, which require an equimolar amount of AICI3, the latter ties up pyrazole in a de-
activated complex. The reaction can be carried out in the presence of a catalytic amount of
sulfuric acid [143].

Ae

"~ / H2S0 4 ~. /

" I ' f
R R

The "activity orders" of azoles in electrophilicsubstitution reactions evidently, both

for 1,2- and 1,3-azoles, have the same form as for five-membered heterocycles with one hetero-
atom: N>> 0 > S (for the most active positions). Indeed, from the data for nitration (Fig. 3),
one can, to counterbalance the data from hydrogen isotope exchange (Fig. 2), draw the con-
clusion that isothiazole derivatives are somewhat more active than their oxygen analogs.
The v o l u m e o f literature data on electrophilic substitution in the oxazole, isothiazole,
isoxazole, and, to a lesser extent, thiazole series is relatively small. As a consequence
of this, as well as the severe conditions under which the reactions under discussion are often
carriedout, there is an opinion that the azoles mentioned above, particularly oxazole, undergo
electrophilic substitution with difficulty. In actuality, t h e r e i s no basis for this opinion,
and severe reaction conditions, particularly the use of protic and aprotic acids, in many cases
are not only unnecessary but also simply detrimental. A number of reactions of 1,3- and 1,2-
azoles that proceed under extremely mild conditions similar to those that are used for higher
active T-surplus heterocycles with one heteroatom are known. Thus thiazole [144] and4-met~yl-
2-phenylthiazole [145], as well asphenyloxazoles [146], are readily mercuratedby the action of

600
mercury acetate, and all of the free positions of the heteroring are substituted. Oxazole
and thiazole with both methyl and phenyl substituents are brominated without a catalyst in
benzene or chloroform under conditions that differ in no way from the conditions for the
bromination of their imidazole analog [147] i
i
~e - Me
. . . . . . . . . . . . . . . . . . .

lJ
X=NI[. O, S

The bromination (with bromine in the presence of pyridine) and nitration with nitric
acid in acetic acid have been described for a number of 4-aryl-2-chlorothiazoles, which give
the corresponding 5-substituted compounds in high yields [148]. Up until recently, the only
known instance of the nitration of an oxazole in the heteroring was the transformation of 2-
dimethylamino-4-phenyloxazole, as a result of which a nitro group is incorporated in both the
benzene and oxazole rings [149]. As we have shown, 2-phenyloxazole [150] and 2-phenyl-
thiazole [151] are brominated smoothly by bromine in benzene and are nitrated by N-nitro-
picolinium tetrafluoroborate or nitric acid in acetic anhydride, and 2,phenyloxazole even
undergoes Vilsmeier formylation; all of these reactions are directed to the 5 position of the
heteroring.

X=O, S; EmBr, NO 2 X~O. E::CHO

Taking into account the results of competitive nitration and the fact that 2-phenyl-
thiazole does not undergo formylation [151], it may be concluded that the oxazole ring is
more active than the thiazole ring in electrophilic substitution reactions.
The realization of bromination and nitration in sulfuric acid, i.e., under conditions
of protonation of the heterorings at the nitrogen atom, leads to substitution in the benzene
ring [150, 151].

~H
!J --
"" X /'~'Ph X k~/
X : S ; E = B r , NO 2 X = 0 : E=NO 2

Similar effects have been described for l-phenylpyrazole, which in sulfuric acid is
nitrated in the benzene ring [152], whereas it is nitrated in the heteroring in acetic anhy-
dride [153, 154].
If the substrate undergoes the reaction in the form of the free base, the reaction may
be directed to the heteroring, despite the fact that it is carried out in an acidic medium.
Precisely this case was described in [155] for the bromination in sulfuric acid of 3,5-di-
phenyloxazole, which is a very weak base (pKa--3.24); its transformation to an N-methyl-
isoxazolium ion leads to a product of bromination in the benzene ring.
Ph Br. Ph

Ph 0/ Ph

!
~- -i~ Ph - = II
........
'I+:CsH4Br-P

Ph "0 " Me Ph" ~0 / "M~

Triazoles and tetrazoles can undergo electrophilic substitution under conditions that
exclude complexing with protic and aprotic acids. Thus, 1,2,4-triazole and l-benzyl-l,2,4-
triazole undergo C hydroxymethylation under the influence of formalin [156]. The chlori-
nation, bromination, and iodination of 1,2,3-triazole and its i-, 2-, and 4-methyl-substituted
derivatives at the carbon atoms of the heteroring, which proceed under diverse conditions
[157, 158] including reactions in neutral solvents (CCI~, CHCI3), and require in the
case of 2-methyl-l,2,3-triazole the presence of a catalyst (iron filings-bromination)
or an oxidizing agent (HNO3-iodination) , have been described. Acetoxymercuration has
been described for l-phenyltetrazole [159]. Under very mild conditions (the action of

601
dimethylamine and formalin) l-methyltetrazole undergoes aminomethylation [160].

N ...... N CH~0 N ....... N

"' ~ ~N"
!L, ' t ; H ~NMe z

In an acidic medium, as in the case of other azoles, the triazole and tetrazole rings
are deactivated with respect to electrophilic substitution, and such reactions in the case of
aryl-substituted compounds are directed to the benzene ring [161-164]. The reactions of
N-substituted triazoles and tetrazole are complicated by tautomeric transformations and the
possibility of substitution at the nitrogen atom. The mechanisms of electrophilic substitution
reactions in many cases have specific peculiarities; these will b e examined in the next
section.
4. CH Acidity. NH Acidity. Ylid Mechanism for the
Electrophilic Substitution Of Heterocycles
If one examines the carbanionic mechanism of electrophilic substitution proposed in [4]
and depicted by Eq. (3) as applied to heteroaromatic compounds, it should be pointed out that
direct metallation (chiefly lithiation) and subsequent reaction with electrophiles of the re-
sulting carbanions or their ion pairs with metal cations are extremely characteristic for
these compounds. Such reactions proceed readily for furans, thiophenes, oxazoles, thiazoles,
and isothiazoles, as w e l l as N-alkyl- and N-arylpyrroles, imidazoles, and pyrazoles. High CH
acidities of the heteroaromatic systems (as compared with aromatic hydrocarbons) and the
coordinating effect o f the heteroatom (see [165], as well as [121, Chap. 2]) promote the occur-
rence of such reactions. With respect to direct metallation, within the framework of our re-
view we will restrict ourselves to the information stated above, since this reaction is usually
regarded not as electrophilic substitution but rather as a transformation of a special t y p e -
protophilic substitution. This approach is especially legitimate since the steps involving
metallation and reaction with the electrophile are never realized simultaneously, as occurs
in the case of the ylid mechanism examined at the end of this section.
The NH acidities may play a large role in the reactions of N-unsubstituted pyrroles,
imidazoles, pyrazoles, triazoles, and tetrazoles. In many cases the reactions with electro-
philes proceed through the corresponding anions; because of delocalization of the negative
charge, substitution may be directed to different nitrogen atoms ( i n the case of diazoles,
triazoles, and tetrazole), as well as to the carbon atoms. A general examination of the
mechanisms of such reactions was made in a monograph [3, Section 5.2]. Here, we will re-
strict ourselves to some specific examples.
One can arrive at a judgment regarding the possibilities of electrophilic substitution
at the nitrogen atom f r o m the formation of N-nitro derivatives in the action of nitric acid
in acetic anhydride (acetyl nitrate) on N-unsubstituted pyrazoles [166, 167] ; when the N-
nitro derivatives are heated, the nitro group migrates from the nitrogen atom to the carbon
atom [167]. Similar data are also available for the nitration of imidazole [168].
R R R

H I
R=H, Me NO 2

The formation of N-halo-substituted products was detected in reactions involving the

halogenation of 1,2,3-triazoles in a n a q u e o u s alkaline medium[158]. Similar observations
were made in the chlorination [169] and bromination [170-172] of 1,2,4-triazole and 3-methyl-
1,2,4-triazole. The role of NH acidity in electrophilie substitution reactions at the carbon
atom can be illustrated in the case of the well-known mechanism of the iodination of imi-
dazole with iodine in an aqueous solution of potassium iodide [173-175]. The reaction in-
cludes a number of steps, including dissociation of imidazole to give the anion, reaction of
the latter with an 12 molecule, which leads to an uncharged intermediate (the fast step),
and the rate-determining step, viz., deprotonation of this intermediate to give the iodo-
substituted anion.
__N +B(-BH ~) .. N

" I I I
H H

602
 The so-called ylid mechanism of electrophilic substitution is of specific interest for
the chemistry of heterocycles, particularly azoles. The principal features of this mechanism
were formulated during a study of hydrogen isotope exchange in azoles. The interest in such
transformations is associated with Breslow's idea [176] regarding the role of thiazolium
ylids in metabolism w i t h t h e participation of thiamine. The research in [176], in which the
ability of thiazolium salts to undergo exchange of the hydrogen atom in the 2 position under
very mild conditions was demonstrated, was followed by a number of publications devoted to the
study of hydrogen isotope exchange for diverse azoles and azolium salts [177-184]. For the
present reKiew it is important that the proton in the 2 position, which should be the least
active in ~ e case of the classical addition--cleavage mechanism, turns out to be the most
labile proton in 1,3-azoles over a wide range of pH values [177-180]; a marked acceleration
in the rate of exchange (by several orders of magnitude) is noted on passing from the azole
to the corresponding azolium salt [177]. The rates of exchange for 1,3-azolium salts are
several orders of magnitude higher than for the isomeric 1,2-azolium salts [181]. These
data are in agreement with the intermediate formation of azolium ylids in which the negative
charge is additionally stabilized by the adjacent heteroatom of the "pyrrole" type [180],
+ +
* D+ _ ~ RO- ND D*

" "" -'~-- H ~owly - X "D

The importance of the ylid mechanism not only for hydrogen isotope exchange but also for
other electrophilic substitution reactions in the azole series h a s become increasingly more
apparent in recent years. Thus N-substituted imidazoles are acylated very readily in the
presence of~-~riethylamine; it is assumed that the reaction proceeds through an ylid [185].
COR ~ +/COR 1

_ . CON 1
N C1
I t I t
R R R R

Thiazole [186], 4,5-dimethylthiazole, l-methoxymethyl-l,2,4-triazole, and 2-phenyl-l,3,4-

oxadiazole, as well as benzothiazole andbenzoxazole [187], undergo a similar transformation.
It might be assumed that the C acylation of 1,2,4-triazoles, which takes place in the absence
of an aliphatic tertiary amine at high temperature, also preceeds through an ylid [188].

N----N ArCOCI N----N N.... N

I I I
Ph Ph Ph
H=H, P h

A number of transformations of thiazoles [ 2 8 6 , 189] a n d o x a z o l e s [ 1 9 0 ] u n d e r t h e i n f l u -

e n c e o f some k e t e n e s h a v e b e e n d e s c r i b e d b y D o n d o n i a n d c o - w o r k e r s . It is assumed that the
ketenes activate the substrate molecule due to the intermediate formation of ylids, which
t h e n r e a c t w i t h a s e c o n d k e t e n e m o l e c u l e a t t h e C(2) atom, a f t e r which t r a n s f e r of the acyl
residue from the N atom to the 0 atom and the formation of a 2-acylthiazole or 2-acyloxazole
occur.
0
H
N CI2C=C=O
~ /C --CHCI 2
CI2C=C=O
-- ~- CI
X .2
X=$, 0

~---i~ 'OCOCHCI2 ~--N

ii im
~ X " "'COCHC12
Cl

The C(2) acylation of l-methylimidazole, as well as pyridine, which stipulates the

production of an azolium (or, correspondingly, pyridinium) salt, its conversion to an ylid,
and r e a r r a ~ e n t of the latter, was recently described [191]. A peculiarity of this
reaction i S ~ h e fact that it does not require stabilization of the ylid (pyridine also under-
goes this transformation) but is evidently restricted to sufficiently strong bases that are
capable of{forming onium salts of the type presented in the scheme given on the following page.

603
 I cl
OCOR

F +I . . . . . . ] "" I. HCI, H20 .

L ,
OCOR ....
J I
COR
X=NMe. "" CII=CII -

One cannot doubt that new possibilities of ylid substitution will be discovered in the
near future, since this mechanism, which takes advantage of both the basic and acidic proper-
ties of heteroaromatic systems, makes it possible to subject deactivated compounds to the
reaction and direct the entering substituent to the least active (in the case of ordinary
electrophilic substitution) position.

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CONDENSED HETEROCYCLES.
45.* SYNTHESIS AND STRUCTURES OF IMINES OF 2-SELENOLO-3-
BENZO[b]FURANALDEHYDE AND 3-SELENOLO-2-BENZO[b]FURANALDEHYDE
AND THEIR DERIVATIVES

V. P. Litvinov, V. A. Petukhov, UDC 547.728.2:542.945.24:543.422.25:548.737

V. Yu. Mortikov, and A. F. V a i s b u r g

A number of new selenolaldimines of benzo[b]furan were synthesized. It was estab-

lished that they exist in dipolar form with delocalized multiple bonds.

In a previous paper we described the synthesis os imines of 2-mercapto-3-benzo[b]furan-

aldehyde and 3-mercapto-2-benzo[b]furanaldehyde [i]. It was shown that a thione-enamine
tautomeric form with the contribution of a dipolar structure, as in the case of their benzo[b]-
thiophene analogs [2], was characteristic for them. In order to study the effect of the
nature of the exocyclic heteroatom on the structures and properties of aldimines of this
type we synthesized a number of isomeric selenolaldimines of benzo[h]furan.
Thus the reaction of 2-bromo-3-benzo[b]furanaldehyde (I) [3] or 3-chloro-2-benzo[b]furan-
aldehyde (II) [4] with sodium hydroselenide and the subsequent action of salts of primary
amines lead to the formation of 2-selenolo-3-benzo[b]furylideneamines III and 3-selenolo-2-
benzo[b]furylideneamines IV in high yields (Table i).
Like their sulfur analogs, selenolaldimines III are stable readily crystallized
substances, in contrast to selenolaldimines IV, which are unstable in solutions and therefore
cannot be purified by recrystallization and were characterized analytically. We established
*See [i] for communication 44.
N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow
117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 774-778, June,
1986. Original article submitted July 5, 1985.

608 0009-3122/86/2206-0608512.50 9 1986 Plenum Publishing Corporation

TABLE i. Selenolaldimines III,# Diselenides V, and Methyl-
selenolaldimine VI
=

Pound, % Empirical Calc., %

' "=1 mpff*C formula
~1 c H N se C H N Se .4

Ilia 187--192 60,7 4,3 5,0 26,6 CIsHuNOSe 60,0 3,7 4.7 26,3 70
IIIb 196--200 60,81 4,2 4,7 25,6[ C16HlaNOSe 61,11 4,2 4,5 25,11 78
IIIc 176--180 60,01 4,4 4,2 22,81 C16H,3NO~Se 58,21 4,0 4,2 23,9 I 79
IIId 190--194 61,41 4,4 4,5 24,7[ CIGHI3NOSe 61,I I 4,2 4,5 25,11 62
IIIe 169--172 62,11 3,7 4,2 23,21 CIrHIaNO2Se 62,61 4,0 4,3 24,2 I 71
IIIf 148--151 49,81 4,4 4,4 26,21 C13HI~NO3Se 50,31 4,2 4,6 25,5 I 25
Va 151--155 6O,91 4,8 4,8 26,11 CsoHzoN202Se2 60,21 3,4 4,7 26,4 I 31
'Vb 166--171,5 59,91 3,7 4,6 24,81 C32H24N202Se2 61,31 3,9 4,5 25,2 I 60
VC
Vd
169--172,5
128--131
57,41
60,51
3,7
3,8
4,4
4,6
23,7[
24,91
C32H24N204Se2
C32H24N202Se2
58,41 3,7
61,3 3,9
4,2
4,5
24,0 I
25,2 Io,
VI 70,5--71,5 61,5[ 4,3 4,6 24,9] CIsHIsNOSe 61,1 4,2 4,5 25,1 78

*Selenolaldimines IVa-f were obtained in 84, 91, 66, 79, 86,

and 81% yields, respectively, and decomposed when heated at
80-120~
#Solvents: benzene for Ilia-d, CHCIs for llle and Vc, CC14 for
lllf and Vb, methanol for Va, d, and ether for VI.
9FThe unrecrystallized stubstance.

TABLE 2. Spectral Characteristics of Seleno!aldimines III

and IV, Diselenides V, and Methylselenoaldimine VI
=~

IR spec- I PM-Rspectmm, (CDCls): 5, ppm, TMS

trum UV spectrum,~" nm
~= (KBr),* kmax' NH, br d =CH, d Harom, m C H 3, s
~ cm-1 [(log s) (J, Hz)

IIla 1644 478 (4,30), 333 (3,96), 297 14,14 8,71 (13,8) 7,53--7,17
(4,56), 263 (4,37)
IIIb !64~ 484 (4,37), 337 (3,97), 299 14, i5 8,67 (13,6) 7,48--7,16 2,38
(4,70), 266 (4,36)
IIlc 1651 478 (4,40), 340 (4,10), 299 14,18 8,59 (13,7) 7,47--6,93 3,85
(4,70), 270 (4,39)
IIId 1641 479 (4,24), 337 (3,88), 297 13,74 8,76 (13,4) 7,54--7,19 2,57
(4,62), 264 (4,46)
IIIe 1640 435 (3,95), 293 (4,11), 266 12,52 8,30 (13,6) 8,02--7,10
(sh) (3,90), 245 (4,02) (br.s)
IIIf 1642 435 (4,10), 292 (4,55), 266 12,31 8,26 (13,6) 7,33--7,08 1,34 t
(4,24), 217 (4,36) (br.s)
IVa 1641 548 (--), 385 (--), 312 (--) 15,05 8,53 (13,0) 8,03--7,60
IVb 1649 548 (--), 386 (--), 311 (-- 15,08 8,45 (13,0) 7,96--6,58 2,38
1Vc 1643 550 (--), 392 (--), 313 (--) 15,20 8,40 (13,4) 8,03--6,72 3,83
IVd 1634 543 (--), 387 (--), 303 (--) 14,47 8,61 (12,8) 8,03--7,18 2,55
IVe 1632 510 (--), 360 (--), 249 (--)
I v.f 1640 508 (--). 361 (--). 288 (--)
Va 1614 349 (sh.) (4,55), 318 (4,60), -- 8,00, s 7,72--6,82
239 (sh.) (4,42)
Vb 1616 363 (4,49), 316 (4.55), 244 -- 8,01, s 7,66--6,73 3,35
(4,33)
Vc 1612 382 (4,47), 315 (4,47), 250 --- 8,01, s 7,70--5,76 3,83
~h .) (4,29)
Vd 1612 360 (sh.) (4,29), 310 (4,47), -- 7,84, s 7,73--6,23 2,38
250 (sh.) (4,30) ~n CH2C12)
VI 1623 342 (4,28) -- 8,70, s 7,72--7,00 2,18

*These are VC=N~ bands for III and IV and vc=N bands for V and VI.
+The UV spectra were obtained in ethanol (III, V, and VI) and in
CHCIs (IV).
~A signal at 5.07 ppm (2H, d CH2) is present in the P~fi~ spectrum of
IIIe, and signals at 4.39-4.23 ppm (4H, m, 2CHe) are present in the
P~ spectrum of IIlf.

609
that the products of transformation of aldimines IV when they are dissolved in organic solvents
are bis(2-benzo[b]furylideneamino) 3,3'-diselenidesV* (Table i).

:, :
:CI ......
~el| [OJ .~r'; '" 1 ~--
Se .......
[
t 9 . g. NH a R
' ; " " '0 " r +Clio " " 0 C|t=NR "::": " CII:N
*, ira- f Va-d
/... .cao ;~::i C,,NR
~ q :'r ~1. . . . . . . I ' I ' NaSeH ' ..r.,

'%/ "O "Sell "qu/" 0" "CH:NC~H s

I ma- f vt
I C6}tsNH'z I CsHsNH2

CH:NC~H, r . CHO /:. ".. ./SeCH 3

" . . .
- - . . . . . . . . . I1
[- C I1 Nil -
"' 0 NHC61t s - '0" SegH.~ ":t, ' " 0 / "CLIO
IX VIII VII

a R=C6H~, b R=p-C6H4CH~, c R=p-C6H4OCHa, d R=o-C6H4CH3, e R=CH2COC6Hs,

f R=CH2CO2C2H~

Signals of protons at 7.8-8.0 ppm, which are characteristic for the protons of anazometh-
ine group, are present in the PMR spectra of diselenides V, and the IR spectra contain
absorption bands of a C = N group at 1610-1620 cm-X; the UV spectra of the diselenides are
similar to the spectrum of 3-methylseleno-2-benzo[b]furylidenephenylamine (VI) (Table 2) ob-
tained by the reaction of 3-methylseleno-2-benzo[b]furanaldehyde (VII)[5] with analine.
It should be noted that the reaction of 2-methylseleno-3-benzo[b]furanaldehyde (VIII)
(an isomer of aldehyde VII) [5] with aniline does not lead to 2-methylseleno-3-benzo[b]furyli-
denephenylamine (an isomer of imine VI). The reaction product is 2-phenylamino-3-benzo[b]-
furylidenephenylamine (IX), which is also formed by the action of aniline on 2-methylmercapto-
3-benzo[b]furanaldehyde [i] or on bromo aldehyde I.
In order to establish the structures of the isomeric selenolaldimines III and IV,
which may exist in various tautomeric forms, such as A, B, or C (the latter can be depicted
by boundary structure D) or an equilibrium mixture of them, we analyzed their PMR, UV, and IR
spectra.

//~___~./CH: N FR /R ,R ~ CH:N~B
+/R

III-A III-~ IIl-C III-D

Se-
I ]J t ----.-- ~ />Se

! "----- " +/H

IV-A IV-4~ Iv-C [v-D

Signals of two protons at 12.3-15.2 ppm in the form of a broad doublet and at 8.2-8.7
ppm in the form of a resolved doublet with spin-spin coupling constant (SSCC) J = 13-14 Hz
are present in the PMR spectra of selenolaldimines III and IV (Table 2) at weak field. This
character of the spectra may correspond to tautomeric form C or its boundary structure D,
and the indicated signals are related to the protons of the NH and CH groups, respectively.
ilowever, it is difficult to give preference to any of the structures, viz., C or D, on the
basis of the PMR spectra. To solve this problem we used UV spectroscopy.
A keto(thione)~-enamine tautomeric form of the C type has usually been ascribed to o-
hydroxy(mercapto)aldimines [4, 6], whereas a dipolar structure of the D type has been pro-
posed in the benzene and naphthalene series [7]. This was done on the basis of the similarity
between the UV spectra of the aldimines and the spectra of compounds that model one or another
tautomeric form. However, this method makes it possible only to reveal the similarity or
difference between the aldimines and the model compounds and does not always make it possible
to establish the structure of a molecule.

*We were unable to isolate the products of transformation of aldimines IVe and IVf.

610
 An intense long-wave band, the position of which is virtually independent of the temper-
ature and polarity of the solvent but changes as a function of the relative orientation of the
selenolo and azomethine groups relative to the ring oxygen atom and the character of the radi-
cal attached to the nitrogen atom (Table 2), is present in the UV spectra of selenolaldimines
III and IV. An increase in the pH of the medium leads to an ~i00 nm hypsochromic shift of
this band; the original character of the spectrum is restored when the solution is acidified,
and this indicates the existence of an acid-base equilibrium.
These changes in the UV spectra are in good agreement with dipolar structure D, in which,
upon the absorption of light, an electron migrates from the electron-donor Se- ion to the
electron-acceptor C = N + group. Thus an increase in the pH of the medium, which leads to de-
tachment of a proton from the nitrogen atom, decreases the electron-acceptor capacity of the
azomethine group in structure D, which should lead [7] and does lead to a short-wave shift of
the absorption bands in the UV spectra of aldimines III and IV. Quantum-chemical calculations
[6], which predict migration of an electron to the azomethine group in 3-mercapto-2-benzo[b]-
furylidene(thenylidene)amines, also constitute evidence in favor of structure D, which also
makes it possible to explain other changes in the UV spectra of aldimines III and IV. For
example, the bathochromic shift of the bands in the spectra of imines IV as compared with
the position of the bands in the spectra of III is due to the closer orientation of the
electron-donor ring oxygen atom to the C=N+ group in imines IV (in analogy with Woodward's
rule for ~,~-substituted, ~,B-unsaturated carbonyl compounds [8]). The observed hypsochromic
shift of the bands on passing from arylimines IIIa-d and IVa-d to alkylimines IIIe, f, and
IVe, f is associated with a decrease in the length of the conjugated system in the latter,
and the analogous shift of the bands in the UV spectra of the previously synthesized mercapto-
aldimines [i] is associated with the lower polarizability and the greater ionization potential
of the sulfur atom as compared with the selenium atom [9, i0].
It is difficult to explain the changes in the UV spectra of t h e a l d i m i n e s when alkali is
added starting from selenone enamine form C, in which, upon light absorption, an electronshould
migrate from the electron-donor amino group to the electron-acceptor selenone group, since in
t h i s case, first of all, the occurrence of any acid--base reaction leading ultimately to a
hypsochromic shift of the bands in the spectra of imines III and IV is hardly possible (as
a consequence of the low probability of detachment of a proton from the nitrogen atom) and,
second, even if detachment of a proton from the nitrogen atom were to occur, a bathochromic
shift of the bands, which contradicts the experimental results, would be observed in the UV
spectra of selenolaldimines III and IV as a consequence of an increase in the electron-donor
capacity of the amino group (--N--R).
Thus, on the basis of the data from the PMR and UV spectra it may be concluded that the
structures of selenolaldimines III and IV are described by dipolar structure D, which, with
allowance for delocalization of the electrons, can be represented in the form of mesomeric
structure E.

I , ILo :
m-E Xv--E

A band at 1632-1651 cm- , which can be ascribed to stretching vibrations of the C=N +
bond [2], is present in the IR spectra of imines III and IV; this is in agreement with struc-
tures III-E and IV-E. In addition, bands at 1691, 1753, 1690 , and 1729 cm -I, respectively,
which are due to stretching vibrations of the carbonyl groups of benzolymethyl and carbethoxy-
methyl residues, also appear in the IR spectra of imines IIIe-f and IVe-f. The other bands in
the IR spectra of III and IV do not contradict the data on their structures.

EXPERIMENTAL
The IR spectra of the compounds (KBr pellets) were recorded with a UR-20 spectrometer.
The UV spectra were obtained with a Specord UV-vis spectrophotometer. The PMR spectra of
solutions of the compounds in CDCI~ were recorded with Bruker WM-250 (250 MI{z) and Tesla BS-
467 (60 ~ z ) spectrometers with tetramethylsilane (TMS) as the internal standard. The course
of the reactions and the individuality of the compounds were monitored by means of thin-layer
chromatography (TLC) on Silufol UV-254 plates in CHCI3 or in a CHCl3--hexane system (I:i). The
physicochemical characteristics of the synthesized compounds are presented in Tables 1 and 2.

611
 2-Selenolo-3-benzo!b]furT!idengamines (Ilia-f) and 3-Selenolo-2-benzo[b]furylideneamines
(IVa-f), A soiution of 5.5 mmoie of aldehyde I or II in 20 m l o f methanol was added in an
argon atmosphere to a hot solution of 0.66 g (6.4 mmole) of NaSeH in 20 ml of anhydrous
ethanol, after which the mixture was refluxed for 20 min and then treated with 30 ml of water.
The mixture was cooled to 5~ and a threefold excess of the salt of the appropriate amine
(in the preparation of imines IIIa-d and IVa-d), 0.94 g (5.5 mmole) of ~-aminoacetophenone
hydrochloride (in the case of imines IIle and IVe), or 0.77 g (5.5 mmole) of glycine ethyl
ester hydrochloride (in the case of IIIf and IVf) in 30 ml of water was added. The mixture
was stirred for 30 min, after which it was diluted with I00 ml of water, and the resulting
precipitate was separated and dried over P2Os. Aldimines IIIa-f were recrystallized.
Bis(2-benzo[b]furylidenephenylamino) 3,3-Diselenide (Va). A 0.45 g (1.5 mmole) sample
of aldimine IVa was added to i00 mr" of methano!, and the mlxture was allowed to stand for 3
h. It was then heated and filtered, and the filtrate was allowed to stand at --15~ for 5
days. The resulting precipitate was separated.
Bis[2-benzo[b]furzlidene(p-meth/iphenyl)gmino ] Diselenide (Vb). A 0.47 g (1.5 mmole)
sample of aldimine IVb was added to 50 ml of CC14, and s mixture was allowed to stand for 3
h. It was then heated end filtered, and the filtrate was evaporated to 20 ml. The concen-
trate was cooled, and the resulting precipitate was separated.
Bis[2-benzo[b]furylidene(~-methoxyphenyl)amino ] 3,3'-Diselenide (Vc). This compound was
similarly obtainld (as in the case of Vb) from 0.50 g (1,5 mmole) of iline IVc in CHCI3.
Bis[2-benzo[b]furylidene(o-methylphenyl)amino] 3,3'-Diselenide (Vd). A 0.47 g (1.5 mmole)
sample of imine IVd was added to 50 ml of methanol, after which the mixture was allowed to
stand for 3 h. It was then cooled, and the resulting precipitate was separated.
3-Methylseleno-2-benzo[b]furylidenephenylamine (VI). A 0.46 ml (4.9 mmo!e) sample of
aniline was added to a solution of 0.82 g (3.4 mmole) of aldehyde VII in 50 ml of benzene, and
the mixture was refluxed for 2 h with a Dean--Stark adapter. It was then cooled, washed with
water, and dried with MgS04. The benzene was evaporated, and the residue was recrystallized
twice from ether.
2-Phenylamino-3,benzo[b]furylidenephenylamine (IX). A 0.9 ml (9.7 mmole) sample of
aniline was added to a solution of 1.59 g (6.7 mmole) of aldehyde VIII in 50 ml of benzene,
and the mixture was refluxed for 2 h with a Dean--Stark adapter. It was then evaporated, and
the residue was refluxed with 40 ml of ethanol. The mixture was cooled, and the resulting
precipitate was separated and recrystallized from propanol to give 0.91 g (43%) of amine
IX. A 0.21 g (30%) sample of amine IX, with mp 160-163~ was obtained when a mixture of
0.50 g (2.2 mmole) of bromo aldehyde I and 0.42 ml (4.4 mmole) aniline in 40 ml of ethanol
was refluxed for 40 min with subsequent similar workup of the reaction mixture. The results
of elementary analysis, the melting point, a n d t h e spectral characteristics of amine IX were
identical to the data in [i].

LITERATURE CITED
i. A. F. Vaisburg, V. Yu. Mortikov, and V. P. Litvinov, Khim. Geterotsikl. Soedin., No. 5,
598 (1985).
2. V. Yu. Mortikov, V. P. Litvinov, and Ya. L. Gol'dfarb, Khim. Geterotsikl. Soedin., No. 8,
1052 (1984).
3. V. P. Litvinov, V. Yu. Mortikov, and A. F. Vaisburg, Izv. Akad. Nauk SSSR, Set. Khim.,
No. 2, 477 (1984).
4. V. A. Bren', Zh. V. Bren', and V. I. Minkin, Khim. Geterotsikl. Soedin., No. 2, 154 (1973).
5. V. P. Litvinov, V. Yu. Mortikov, and A. F. Vaisburg, Khim. Geterotsikl. Soedin., No. 9,
11.77 (1984).
6. V. A. Bren', V. I. Usacheva, Zh. V. Bren', B. Ya. Simkin, and V. I. Minkin, K]Rim. Getero-
tsikl. Soedin., No. 5, 631 (1974).
7. R. N. Nurmukhameto~, O. I. Betin, and D. N. Shigorin, Dokl. Akad. NaukSSSR,_2300 , 146 (1976).
8. A. Stern and K. Timmons, Electronic Absorption Spectroscopy in Organic Chemistry [Russian
translation], Mir, Moscow(1974).
9. V. I. Vedeneev, L. V. Gurvich, V. N. Kondrat'ev, V. A. Medvedskii, and E. L. Frankevich,
Handbook of Energies Required for the Cleavage of Chemical Bonds, Ionization Potentials,
and Electron Affinities [in Russian], Izd~ Akad. Nauk SSSR, Moscow (1962).
i0. V. A. Petukhov, V. P. Litvinov, A. N. Sukiasyan, and Ya. L. Gol'dfarb, lzv. Akad. Nauk
SSSR, Ser. Khim.,No. 8, 1700 (1971).

612
CONDENSED HETEROCYCLES.
46*. CRYSTAL STRUCTURE OF 3-MERCAPTO-2-BENZO[b]-
FURYLIDENE-(p-METHYLPHENYL)AMINE

V. N. Nesterov, V. E. Shklover, UDC 547.728.2:542.945.24:543..422.25:548.737

Yu. T. Struchkov, V. P. Litvinov,
A. F. Vaisburg, and V. Yu. Mortikov

An x-ray structural examination of 3-mercapto-2-benzo[b]furylidene-(p-methyl-

phenyl)amine has been carried out. For the first time, the position of the bridge
hydrogen atom in a mercaptoaldimine containing the planar conjugated S=C--C=C--N
grouping closed by an intramolecular N--H...S hydrogen bond has been established.

The attention of investigators has in recent times been drawn towards o-hydroxy-, o-
mercapto-, and o-selenolaldiminesof the aromatic and heteroaromatic series (A):

X=U, S, 8 e

This is due primarily to their photochromic, thermochromic, complexing, luminescent,

and other properties of practical value [2-5]. For this reason, the structures of such com-
pounds, in particular the investigation of prototropic tautomerism, intramolecular hydrogen
bonding (X--H...N or X...H--N), etc., is of considerable interest.
Available spectral data provide evidence for the keto (thiono, or selenono)amine structure
(B) in these compounds [6, 7]. However, x-ray structural examination of 2-mercapto-3-
thenylidenecyclohexylamine (I), carried out at room temperature [8], has shown that the bond
lengths in the chelate ring are evened out, but the position of the bridge hydrogen atom was
not established, explained by theseworkers [8] as being due to the simultaneous presence
of both the thionoamide (B) and mercaptoimine (A) forms. Shortly after this, NMR and UV
spectroscopy was used to show the lack of correspondence between the structures of a l d i m i n e s
and that of (B), and the need to allow for the contribution of resonance form (C) to the
tautomeric form (B), such as occurs in the mesomeric structure (D) [9, i0].
In order to establish the position of the bridge hydrogen atom (whether attached to
sulfur or nitrogen), and to provide more definite information on the structure of ortho-
mercaptoaldimines, we have carried out a low-temperature x-ray structural study of 3-mercapto-
2-benzo[b]furylidene-(p-methylphenyl)amine (II).
Atom coordinates are given in Table i, and valence angles in Table 2. Figure 1 shows
a general view of the molecule of (II), with bond lengths.
The C ~ distance (1.697(2) A is close to that of the Csp2=S bond (1.610(9) ~ [Ii]), but
is shorter than the single Csp2-S bond (1.817 % [12]), which is in accordance with attachment
of the hydrogen atom to nitrogen rather than sulfur.

In the approximately planar fragment S=C(3)-C(2)=C(s)-N (in which the atoms do not devi-
ate from the mean plane by more than 0.013(2) A), conjugation is se~n, as sho~n by the de-
creased C(2)--C(3) and C(8)-~ bond lengths to 1.406(3) and 1.333(3) A (the standard C(sp2)-C(sp2 )
and C(sp2)-N bond lengths are 1.476 [13] and 1.426 (12) A [14]), and by the increased lengths
*For communication 45, see [I].
N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow
117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 779-782, June,
1986. Original article submitted July 5, 1985.

0009-3122/86/2206-0613512.50 9 1986 Plenum Publishing Corporation 613

 TABLE i. Atom Coordinates ( s for S atoms; ~ for O, N,
and C atoms, xl0 ~ for H atoms), and Isotropic Equivalent
Temperature Parameters for Nonhydrogen Atoms (isotropie
for H atoms)
~a~

. . . . . . . B eq and B,__(~ ~)
Atom x y z i~ ~so,

S -27631 (7) 69039 (5) 6750(3) 1,95(1)

O 1506(2) 7958 ( 1) -506(I) 1,9o(3)
N 12~(2) 5550(2) 867(I) 1,66(4)
694(3) 7198(2) 1o(1) t,55,(4)
C(s) -- 1278(3) 7539 (2) 85(1) 1,53(4)
C~) - 1702(3) 8563 (2) -422(]) 1,59(4)
Cr~b) 22(3) 878~ (2) -755(1) ~,68 (5)
- 3378(3) 9313(2) -611(1) 2,06(5)
-3242,(3) 10268 (2) -1114(1) 2,39(5)
- 1483(3) 10470(2) -1431(I) 2,46(6)
Cm 185(3) 9730(2) -1261(1) 2,28(5)
C~) 1902(3) 6298(2) 361(D 1,69(4)
C(9) 2317(3) 4602 (2) 127~(I) 1,60(5)
C(IO) 1399(3) 4028 (2) 1834(1) 2,00(5)
C(m 23~ (3) 3,113(;2) 2265 ( 1) 2,27 (5)
C(,~) 4323(3) 2749,(2) 215'7(1) 2,03(5)
C(m) 5204(3) 3332 (2) 1597(1) 2,00 (5)
C(m 4227(3) 4248(2) 1t59(1) 1,79(5)
5391 (4) 1739(2) 2619(I) 2,80(6)
H i (~) 569(2) ~(1) 2,8(5)
H(4) -457(3) 916(2) -41(1) 2,1 (4)
H(~ -440(3) 1078(2) -124(1) 1,8(4)
H(6) -143(3) I114(2) -176(1) 2,8(5)
H(z) 141 (3) 987(2) -147(1) 3,2(5)
1t(8) 330(3) 623(2) 28(1) 2,2(4)
H(m) 2(3) 43I (2) t9o(t) 2,7(5)
H~i~) I73 271 (2) 265(I) 2,7(5)
H()3) 653(3) 310(2) 150(I) 2,5 (5)
H(,4) 488 (3) 464(2) 79(1) 2,2(4)
H(m.n 680(4) 163(2) 253(1) 5,4(7~
H(m.~) 556 (4) 196(2) 311(1) 5,3 (7)
H(m.a) 475(4) 97(3) 255(2) 6,3(8)

TABLE 2. Valence Angles ~ (deg)

Angle ~ Angle ~o Angle o

105,2(1) C~4)C(s)C(~) 120,9(2) NC(91C~I4) 122,7(2)

111,5(2) C;~)C(~)C(7) 122,1 (2) C(~o~Cc9)Cr 119,8 (2)
OC(~C(~) t17,4(2) C(6~C,7)(]~2b) 116,1(2) C,9)C~m)C,Ii) 120,0(2)
t31,1 (2) II t23,2(2) 121,1 (2)
1o4,7(2) 1 Cc,.)C~2b)O 125,1 (2) C(mC~I2)C(13~ 117,8(2)
126,7(2) 111,6(2) 121,0(2)
128,6(2)] 121,0(2) Cfts)C(I~)C(m) 121,1 (2)
I07,0(2) C(s)NC(9) 127,5(2) C(12)C<m)C(m 12,1,8(2)
Cta)C(a#)C(4) 133,5 (2) C~8)NH 114(1) C(m)C(14)C(9) 119,5 (2)
119,5 (2) Cr 118(1)
C~,)C~4)C~) ~8,~(2) N('(,,~C(m) 117,5 (2)
o

of the C(2)=C(s) and ~(3~ = S bonds to 1.373 (3) and 1.697(2) A (the standard C(sp2 ) = C(sp2 ~
bond length is 1.333 A'[i3]). Theolength of the C = S b o n d i n (II) is the same as the mean value
of the C----Sbond length in (I) 1700 A (two symmetrically independent molecules). The bond length
distribution in the planar conjugated SCCCN grouping observed in (II) is also shown by (I).
The possibleinvolvement of the unshared electron pair of the n i t r o g e n a t o m in (II) in conju-
gation with the q-system of the C(2) = C(a) double bond is confirmed by its planar geometry
(the sum of the valence angles is 359.5~ The N-H...S hydrogen bond closes the S = C(3)--C(=)~
C(s)--N fragment into a six-membered ring [ ~ 0.88 (2), H...S 2.29 (2) ~, N-H...S 147(2)~
The distance between the N and S atoms in (ll) is 3.060(2) ~, and in (I) it is 3.005(7) ~,
which would also permit the presence of a hydrogen bond in the ring, although the position
of the hydrogen atom has not been established in this instance.

The O-C(2) andoO-C(2b) bond lengths in the furan moiety areodifferent. The O-C(2b) bond
length of 1.371(2) A is in agreement with the value of 1.368(5) A in furan [15], but the
O-C(2) bond length of 1.405(2) A is considerably greater than this. This difference appears
to be due to greater participation of the unshared electron pair of the oxygen atom in conju-
gation with the annelated benzene ring than with the S=C-C=C-~ grouping [16]. Indeed, the

614
 s

C(?) O C(141 ~C{13}

F i g . 1. S t r u c t u r e o f t h e .molecule o f ( I I ) . The
broken line shows the intramolecular hydrogen bond
N--H...S.

oxygen atom is coplanar with the benzene ring, favoring ~ conjugation, whereas it departs
from the plane of the S=C-C=C-Ngrouping by 0.046(1) A.
The C(9~...C(I~) benzene ring is virtually coplanar with the conjugated grouping
S=C(3)~C(~)~C(8)--,N [the C(8)NC(9)C(z0) torsion angle is 173.4(3)~ The N-C(9~ bond length
of 1.410(2) A is close to the standard value for the C(sp2)--N bondo(l.426(12) A [14].
In the crystal, intermolecular contacts C(3)...C(9) 3.399(3) A and C(9)...C(Is) 3.310(3)
are seen between the originalmolecule of (II) and the molecules derived from it by symmetry
transformations (~, 1 -- y, ~) and (i -- x, y + 1/2, 1/2 -- z) respectively, these being approxi-
mately twice the van der Waals radius of the carbon atom, 3.40 A - [17]. The planar molecules
of (II) form stacks along the b-axis with an interplanar distance of 3.60 ~.
These x-ray studies have therefore shown that the C=S bond is double, the hydrogen atom
is located at the nitrogen atom rather than sulfur, and the conjugation in the S=C--C=C--N
grouping shows that the molecular geometry is described by the mesomeric form (D).

EXPERIMENTAL
Compound (II) was obtained by successive treatment of 3-chloro-2-benzo[b]furfural with
sodiumhydrogen sulfide and p-toluidine hydrochloride, as described in [18].
o
The crystals of (II) were monoclinic: a = 6.775(4), b = 10.596(8), c = 18,396(14) A, 8 =
96.254(60) ; V = 1312.7(1.6) A 3, dca]c = 1.353 g/cm 3, z = 4, space group P2z/c. The cell
parameters and the intensities of 2242 independent reflections with I ~ 2~ were measured on a
Syntex R2~ automaticfour-circle diffractometer at --120~ (IMoK~, graphite monochromator,
e/2 scanning, 2 0 ~60~ The structure was calculated directly using the MULTAN program, all
the nonhydrogen atoms being visualized, and refined by full-matrix least squares in anisotropic
approximation for the nonhydrogen atoms. All the hydrogen atoms were visualized by difference
synthesis, and refined isotropically. The final values of the divergence factors were
R = 0.044 and RW = 0.045. All calculations were carried out on an Eclips S/200 computer
using INEXTL programs [19].

LITERATURE CITED
I. V. P. Litvinov, V. A. Petukhov, V. Yu. Mortikov, and A. F. Vaisburg, Khim. Geterotsikl.
Soedin., No. 6, 774 (1986).
2. L. A. Kazitsina, N. B. Kupletskaya, L. L. Polstyanko, B. S. Kilot', and A. P. Terent'ev,
Zh. Obshch. Khim., 31, 313 (1961).
3. W. F. Richey and R. S. Becher, J. Chem. Phys., 49, 2092 (1968).
4. V. I. ~ n k i n , L. P. Olekhnovich, L. E. Nivorozhkin, Yu. A. Zhdanov, and M. I. Knyazhanskii,
Zh. Org. Khim., 6, 348 (1970) o
5. V. P. Litvinov, Ya. L. Gol'dfarb, and E. G. Ostapenko, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. i0, 2279 (1974).
6. V. A. Bren', V. I. Usacheva, Zh. V. Bren', B. Ya. Simkin, and V. I. Minkin, Khim.
Geterotsikl. Soedin., No. 5, 631 (1974).
7. V. S. Bogdanov, M. A. Kalik, I. P. Yakovlev, and Ya. L. Gol'dfarb, Zh. Obshch. Khim., 40,
2102 (1970).
8. L. G. Kuz'mina, Yu. T. Struchkov, M. A. Kalik, and Ya. L. Gol'dfarb, Khim. Geterotsikl.
Soedin., No. 12, 1625 (1978).
9. R.N. Nurmukhametov, O. I. Betin, andD.N. Shigorin, Dokl. Akad. Nauk SSSR, 230, 146 (1976).
i0. L. N. Kurkovskaya, R. N. Nurmukhametov, and D. N. Shigorin, Zh. Strukt. Khim., 21, 61 (1980).
ii. H. W. Kroto and B. M. Landsberg, J. Mol. Spectr., 62, 346 (1976).

615
12. G. Pepe and M. Pierrot, Acta Cryst., B32, 1321 (1976).
13. A. I. Kitaigorodsky, Molecular Crystals and Molecules, Academic Press, New York (1973),
p. 431.
14. International Tables for X-Ray Crystallography, Kynoch Press, Birmingham (1968), Vol. 3,
p. 276.
15. R. Fourme, Acta Cryst., B28, 2984 (1972).
16. E. Ya. Lukevits (Ed.), Advances in Furan Chemistry [in Russian], Zinatne, Riga (1978),
p. 15.
17. A. Bondi, J. Phys. Chem., 70, 3006 (1966).
18. A. F. Vaisburg, V. Yu. Mortikov, and V. P. Litvinov, Khim. Geterotsikl. Soedin., No. 5,
598 (1985).
19. R. G. Gerr, A. I. Yanovskii, and Yu. T. Struchkov, Kristallografiya, 28, 1029 (1983).

MASS-SPECTROMETRIC BEHAVIOR OF BENZO-SUBSTITUTED

DIBENZO-18-CROWN-6 ETHERS

P. B. Terent'ev, V. A. Shmorgunov, UDC 547.898.07:543.51

A. V. Bogatskii, R. Donau,
E. I. Ivanov, and A. A. Polishchuk

It was shown that the intensity of the peak of the molecular ion in the mass spectra
of dibenzo-18-crown-6 derivatives depends to a marked extent on the electronic
properties of the substituents on the benzene ring. ~ragmentation of the substitu-
ents is ohserved after the decomposition of the polyether ring. This permits the
proposition that the preferred localization of the charge in the m o l e c u l a r i o n and
the fragment ions is on the oxygen-containing part of the molecule. The analysis of
the mass spectra of benzo-substituted crown ethers renders possible the determination
of substituents occurring in the aromatic part of the molecule and their sterie po-
sition.

Crown ethers and macrocyclie compoundssimilar t o t h e m have received a very widespread

attention in differing areas of orKanic and analytical chemistry in recent years. The di-
benzocrown ethers are especiallypromising since the introduction of different substituents
into the benzene ring and theirmodification in the prepared macrocyclic molecule permit the
variation in the properties of such compounds over a wide range [1-3].
The determination of the structure of the macrocycles obtained in this way often repre-
sents a difficult problem. In connection with this, the crown ethers and compounds structur-
ally similar to them have become the object of a series of mass spectrometric investigations
[4-7] in recent years.
However, the benzo-substituted crown ethers h a v e h e e n little studied by this method until
now. Therefore, we also undertook investigations of a series of substituted dibenzo-18-
crown-6 ethers containing electron-donor or electron-acceptor groups in t h e b e n z e n e nuclei,
as well as the heterocyclic ring of 2-methylimidazole and2-aminothiazole ring-fused to benzene.
A series of compounds was obtained in the form of two isomers differing in the syn or anti
disposition of the same substituents in the different benzene rings relative to each other.
The analysis of the mass spectra (Table i) permits it to be noted, first of all, that
the molecular ion M+ was registered in all cases; the intensity of the peak of the molecular
ion depends to a marked degree on the electronic properties of the R I and R 2 substituents. The
stability of the molecule (Table 2) to electron impact is higher in the case of electron-
donor substituents and lower in the case of electron-acceptor substituents or ring-fused
heterocyclic nuclei.

M. V. Lomonosov Moscow State University, Moscow 117234. A. V. Bogatskii Physicochemical

Institute, Odessa 2 7 0 0 8 0 . Translated from Khimiya Ges Soedinenii, No. 6, pp.
783-786, June, 1986. Original article submitted February 18, 1985.

616 0009-3122/86/2206-0616512.50 O 1986 Plenum Publishing Corporation

 The main decomposition of t h e M + of the compounds investigated proceeds by a scheme
characteristic of dialkyl andalkylaryl ethers and is associated with the cleavage of the
molecule by the route A with the formation of the Fz and F2 ions. Cleavage of the structure
by the routes B and C is only noted in the case of compounds containing amino groups as sub-
stituents. The intensity of the peak of the [M/2] + ion in the mass spectra of compounds (Ia,
b) reaches 1.2% of the complete ion current, whereas it does not exceed 0.3% in this case for
the [M -- F ]+ ion (route B). The [M/2] + ion probably exists mainly in the acyclic form since
it further readily eliminates the ~{', HzO, C2H2, C2H3", and CH2OH" fragments. The total in-
tensity of these ions (%Zs0) in the mass spectra of the compounds (Ia, b) comprises 1.75%.
The intensity of these ions is appreciably less in the mass spectra of the compounds (IIa, b)
and (IIIa, b) and it does not exceed 0.2-0.4%. Only the [ M / 2 - CHzCO] + ions are observed in the
mass spectra of compounds (IVa, b). The loss of the R I or R 2 substituents from the molecular
ions was noted for the decomposition of the nitro derivatives (IIIa, b) and (IVa, b), but the
intensity of the peaks of these ions was also low (0.8%).
The main part of the ions observed in the mass spectrum represents the F~ and F2 fragments
or the products of their subsequent decomposition (cf. the Scheme and Table 2). It is important
to note that the electronic properties of the R ~ and R 2 substituents have appreciable influence
on the stabilities of the M + and F~ ions, since the decrease of the +M-effect of the amino group
[compounds (IIa, b)], the introduction of the acceptor nitro group (IIIa, b), or the presence

I\ 3 +' 3 +"

I-IVa,b,V VI

j .........,.o__~ t-.H.O'
!
+ R1

F3 ~2 F4 P5 ~ I cH

l~'r F8 go F~
~ -CO

I::io

of both of these factors (IVa, b) abruptly lowers the value of WM and the intensity of the
peaks of the FI ions. It is interesting to note the increased stabilization of the Fz-F6 ions
on account of the elimination of the ketene molecule. It is also characteristic that the
fragmentation of the substituents is mainly only observed after the formation of the FI-F6
fragments (it is confirmed by the metastable ions); this permits the proposition that the
charge in the molecular ion and the fragment ions is mainly localized on the oxygen-containing
part of the molecule. Even in the case of the compounds (V) and (VI), which have the corres-
ponding fragments of aminobenzothiazole and methylbenzimidazole in the molecule, the cleavage
of these heterocyclic rings only proceeds at the third and fourth stages of the decomposition.

617
 TABLE i. Mass Spectra of the Crown Ethers (1)-(VI) (the
molecular ion peak and the ten most intense peaks are pre-
sented
J , ,,,,,,,,,,,.,,.,, u

Com-
pound m/z (relative intensity, %)

la 39O (41), |51 (|00), I50 (21), 136 (39), 125 (19), 124 (59), 96 (37), 95
(79), 80 (21), 79 (25), 67 (32)
Ib 390 (35), 15t (100), 136 (41), 125 (21), 124 (60), 122 (18), 96 (47), 95
(84), 80 (29), 79 (34), 67 (40)
474 (17), 193 (23), 178 (30), 152 (22), 151 (100), 136 (21), t24 (50), 96
(24), 95 (49), 80 (26), 79 (27)
lib 474 (17), 193 (28), 178 (33), 152 (23), 151 (100), 136 (23), 124 (45), 96
(2l), 95 (40), 80 (17), 79 (17)
Illa 480 (4), t96 (lO0), 181 (30), 166 (77), 151 (26), 150 (39), 124 (24), 120
(31), 107 (25), 95 (35), 94 (65)
lllb 480 (15), 196 (58), |8l (26), |51 (21), 150 (40), 124 (27), 123 (23), 95
(34), 94 (100), 80 (28), 78 (31)
IVa 564 (23), 197 (30),,196 (100), 192 (63) , 181 ( 4 1 ) , 15t ( 2 9 ) , 150 ( 4 9 ) , 124
(26); 95 (,27), 94 (77), 68 (54)
IVb 564 (14), 197 (34), 196 (lO0), 192 (28), 18l (42), 166 (33), 151 (4t), 150
(46), 135 (26), 124 (27), 95 (39)
V 504 (7), 208 (100), 193 (82), 182 (56), 181 (93), 153 (64), 152 (97), 124
(97), 124 (64), 95 (59), 94 (46), 82 (58)
VI 468 i l l ) , 191 (33), 190 (31), 175 (35), t64 (33), t63 (33), 134 (35), III
(38), 105 (lO0), 95 (15), 77 (60)

TABLE 2. Intensity of the Peaks of Some Characteristic lons in

the Mass Spectra of the Crown Ethers (1)-(VII) (rs0)

Com-
pound * R' R~ t~<~ ~t , F2 Fs

la NH~ H 62 12,0 0,7 4,8

lb NH2 H 5,0 I1,0 0,9 4,7
Ila NHCOCH,~ H 2,4 2,7 (l 1,6) 1,5 (2,5) 3,5 (2,5~
llb NHCOCHa H 2,3 3,2 (11,3) 1,6 (2,6) 3,7 (2,6)
Iila NH~ NO~ 1,2 4,0 0,5 1,8
IIIb NH~ NO,2 0,2 5,7 O,6 1,7
IVa NHCOCH3 NO~ 1,8 0,4 (6,2) - (: ,9 ) 0,5 (2,5)
IVb NHCOCHs NO2 0,7 0,3 (5,0) - (1,7) 0,5 (2,D
V 0,3 3,9 1,2 3,2
" ~ S "C ----N " /
I
NH 2

VI ""N)'IC=N"" 0,8 2,2 2,3 2,5

C{i"3

TABLE 2 (continued)
,,, ,,,, ,,, , ,,,

Com- F~ (FT=FIo) (F,'-F6')$ (FT'-FI~ I F : / I M

poundr P4 Fs

Ia 2,3 7,1 1,8 14,6 4,6 5,9 2,4

[b 2,4 6,8 2,1 16,2 4,8 3,4 2,8
lIa 0,5 (2,4) 0,5 (5,8) 0,4 (1,9) 1,5 (9,8) 52 ~,0 1,3
IIb 0,6 (5,1) 0,6 (2,1) 0,6 (1,7) 2,o (8,5) 5,6 5,2 1,6
IIIa 0,4 1,0 0,6 l,l 5,3 L2 3,8
IIlb 0,8 0,9 0,7 0,6 6,2 I1,0 24,6
tVa - (0,4) - (1,2) - (0,4) 0,4 9,6 8,0 (4,3 02
IVb - (0,4) - (1,o) - (o,6) 0,8 9,1 62 (6,9 0,4
V 2,2 3,6 1,2 8,8 4,0 9,8

VI 2,3 2,3 l,O 4,3 3,2 3,1

*Compounds (la)-(IVa) have the syn disposition of the R l and

R = radicals; compounds (Ib)-(IVb) have the anti disposition
of the R: and R 2 radicals.
tThe intensities of the peaks of the [Fi - CHACO] + ions are
given in brackets for the compounds (lla,b) and (IVa,b).
%The total intensity of the peaks of the fragment ions
formed as a result of the fragmentation determined by the
substituents.

618
 Therefore, the analysis of the mass spectra of benzo-substituted crown ethers permits the
confident determination of the character and structure of the substituents situated in the
aromatic part of the molecule. We will note thatthe mutual disposition of the R I (R 2) sub-
stituents in the macromolecule[syn in compounds (la)-(IVa) and anti in the cases of (Ib)-
(IVb)] also influences the probabilityof decomposition, b u t the mode by which this is achieved
is unclear. It follows from the data in Table 2 that the ratio JFI/JM+ is always somewhat
lower for the syn isomers than for the anti isomers; the introduction of the nitro group
causes this difference to become still more noticeable, i.e., the anti disposition of the
substituents makes M+ less stable and increases the probability of its decomposition with the
formation of the Fl ion. It is possible that this is associated with the trans ring-fused
interaction in the macrocycle.
Therefore, the comparison of the mass spectra of a pair of isomers evidently permits the
determination of the steric position of the substituents. However, it should be noted that
it is not possible to determine this from the mass spectrum of only one of the isomers.

LITERATURE CITED
i. A . V . Bogatskii, N. G. Luk'yanenko, Yu. A. Popkov, N. Yu. Nazarova, M. U. Mamina, and
Z. A. Chernotkach, Dokl. Akad. Nauk SSiR, 171, 630 (1983).
2. I.S. Markovich, N. A, Filigina, V. M. Dziomko, Yu. S. Ryabokobylko, G. M. Adamova, and
S~ L. Zelichenok, Khim. Geterotsikl. Soedin., No. 2, 185 (1983).
3. M . G . Voronkov, V. I. Knutov, and M. K. Butin, Khim. Geterotsikl~ Soedin., No. 2, 275
(1983).
4. R.R. Whitney and D. A. Jaeger, Org, Mass Spectrom., 15, 343 (1980).
5. R . A . Hancock, R. Walder, H. Weige!, V, Gold, and C. M. Sghibartz, Org. Mass Spectrom.,
18, 402 (1983).
6. ~. V. Ganin, B. V. Rozynov, V. F. Anikin, and G. L. Kamalov, Khim. Geterotsikl. Soedin.,
No. 8, 1048 (1984).
7. P. Traldi, U. Vettori, G. Podda, A. Maccioni, and L. Gorda, Org. Mass Spectrom., 18, 69
(1983).

619
CATALYTIC PROPERTIES OF RHODIUM HYDRIDOCARBONYL TRITHIENYL-
PHOSPHINE COMPLEXES IN THE HOMOGENEOUS HYDROGENATION AND
ISOMERiZATION OF UNSATURATED COMPOUNDS

A. A. Dudinov, Ya. L. Gol'dfarb,* UDC 541.128:547.732'128'718'197:543.422.25

E. F. Litvin, L. M. Kozlova,
and B. S. Bogdanov

Syntheses are reported for trithienylphosphine analogs of hydridocarbonyltris(tri-

phenylphosphine)rhodium(1) and the catalytic activity of these analogs in the
hydrogenation and isomerization of terminal olefins was demonstrated. The PMR
chemicalshifts and form of the signals of the hydride hydrogen atom of these
rhodium hydridocarbonyl complexes correlate with their catalytic properties in
homogeneous hydrogenation and isomerization.

In the case of the thiophene analog of the Wilkinson complex, we showed that the concept
of isosterism may serve as a criterion in the search for new catalysts for the homogeneous
hydrogenation of unsaturated compounds [I]. The term "isosterism" which was introduced by
Langmuir [2] implies the analogy of benzene and thiophene in this specific case [3] and the
steric and electronic analogy of triphenylphosphine and tri(thienyl-2)phosphine.
In the presentwork, we studied the catalytic properties of trithienylphosphine com-
plexes, namely, hydridocarbonyltris[tri(thienyl-2)phosphine]rhodium(1) (K-I catalyst) and
hydridocarbonyltris[tri(5-trimethylsilylthienyl-2)phosphine]rhodium(1) (I-II) which are iso-
steres of hydridocarbonyltris(triphenylphosphine)rhodium(1) (I-III) which is an efficient
catalyst for the homogeneous hydrogenation of olefins [4]. In our subsequent communication,
we used PMR spectroscopy to show the geometrical similarity of the structures of K,I and
K-Ill [5]. The homogeneous hydrogenation of allylbenzene was taken as a model reaction.
Hydridocarbonyl complexes K-I, K-II, and K-Ill and hydridocarbonyltris[tri(5-tert-
butylthienyl-2)phosphine]rhodium(1) (K-I~), which we specially synthesized for spectro-
scopic purposes, are highly soluble in benzene and chloroform but only moderately soluble
in ether. The presence of a tert-butyl or trimethylsilyl group at C(s) of the thiophene
ring markedly enhances the solubility of the complex. Light orange solutions are formed
upon dissolving these complexesin benzene not containing oxygen; this color does not change
u p o n t h e brief introduction of hydrogen and upon the addition of allylbenzene. Upon standing
for 72 h, benzene solutions of K-I with concent ration~.l.10 -2 mole/liter without access to
atmospheric oxygen turn from light orange to dark red, which indirectly indicates the de-
composition of catalyst K-I. Wilkinson et al. [6] have shown that the spontaneous decomposition

*Deceased.

TABLE i. Hydrogenation of Allylbenzene

. . . . . " ' cat'.~iyst con- V~p [mi H2. rain-:: "'i
Ca~lyst , cenrrafion,
...... mole/liter raole-l,, liter]_ . ~/~i8o*
!
K-I 3,8. I0 -s 260 I 1,6
K-If
K-Ill
3,6. I0 -s
4,5. I0 -a
320
490
I 2,3
3,2

*Vh/Vis o is the ratio of the rates of hydro-

genation and isomerization.

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences Of the USSR, Moscow

117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 787-792, June,
1986. Original article submitted October 29, 1985.

620 0009-3122/86/2206-0620512.50 9 1986 Plenum Publishing Corporation

 H2, ml ~ K-M
i30 . K-E
113

9O7o i- i

50
30
lO
10 30 50 70 90 110 130 150
t~ mi n
F i g . 1. K i n e t i c c u r v e s f o r t h e h y d r o g e n a t i o n
of allylbenzene in the presence of K-I, K-II,
and K-III.

~oo~% _
801\ _Tf 801\ 2

40 40

,oo o 20 40 60 80 100 120 20 40 60 80 100 120

Fig. 2. Dependence of the change in the catalysate compo-
sition over time: i) allylbenzene, 2) propylbenzene, and
3) cis- and trans-propenylbenzenes.

of complexlK-III occurs in benzene solution with the formation of catalytically inactive

compounds not containing hydridic hydrogen atoms. Upon storage of these complex in an argon
atmosphere at about 4~ their decomposition (darkening) is visible only after two weeks.
In their catalytic activity in the hydrogenation of allylbenzene and the nature of the
corresponding kinetic curves, these new catalysts are comparable with the triphenylphosphine
analog (see Fig. 1 and Table i). The activity of the complexes increases in the series K-I <
K-II < K-III. In all cases, the initial stage of the reaction (up to 20-40% allylbenzene
conversion) proceeds with zero-order kinetics relative to the substrate. Then, the hydro-
genation rate decreases and at allylbenzene conversion o f ~ 8 0 % (for K-III) and ~/60-70% (for
K-I and K-II), the reaction virtually is halted. The hydrogenation rate increases propor-
tionally to the catalyst concentration.
Analysis of the catalysate composition showed that in addition to hydrogenation, there
is also isomerization of the starting ~-olefin to its B-isomer and cis- and trans-propenyl-
benzene accumulate in the catalysate (see Fig. 2). The rate of hydrogenation of the B-iso-
mer is 1-1.5 times less than that of the starting olefin and this reaction is completed after
24 h. Similar results were obtained in the hydrogenation of l-pentene [4]. The initial
product of the isomerization is cis-2-pentene, which is converted to the thermodynamically
more stable trans isomer.
Figure 2 shows that the extent of isomerization of allylbenzene in the case of trithienyl-
phosphine complexes is 30-40%, while it is only 20% for the triphenylphosphine analog.
Thus, the new trithienylphosphine complexes differ from the triphenylphosphine analog in
their activity both in the addition of hydrogen to olefins and in the catalysis of C=C bond
migration. In our opinion, this difference should be attributed to the difference in the
stability of these complexes (extent of dissociation) and different electronegativity of the
hydride atoms of the hydridocarbonyl complexes.
In this regard, we studied the PMR spectra of the hydridic hydrogen atoms in K-I, K-II,
K-III and specially prepared K-IV. In contrast to K-III, whose hydridic hydrogen atom appears
at 25~ as a broad singlet at --9.67 ppm and at --30~ as a doublet of quartets, the hydridic
h y d r o g e n atoms of complexes K-I, K-II and K-IV appear even at 25~ as a well resolved doublet
of quartets (see Fig. 3 and Table 2) with 1:3:3:1 ratio for the intensities of the quartet
signals.

621
 TABLE 2. Spectral Indices for Rhodium Hydridocarbonyl Com-
plexes
IR s p e c t m m , T - " ~
Com- v, cm =I [ _ PMR spectrum
pound
,trot. n, HZ /Rh.-.P,HZ

K-! 1934~ -9,17 15,8 1,8-0,4 134

K-II 1938 -8,92 15,6 1,5---0,3 164
K-III 1930 -9,67 154
K-IV 1937 -9,10 14,7~0,7 0,8 134

The finding of distinctly resolved signals for the hydridic hydrogen atoms indicates high
configurational stability of the trithienylphosphine complexes K-I, K-II, and K-IV in compari-
son with K-III. Thus, broadening of the signal for the hydridic hydrogen atom (formation of
a singlet) for complex K-I occurs in CDCI3 and C6Ds at 52~ The resolved signal reappears
upon cooling of the sample to 25=C as a doublet of quartets.
We assume that the decrease in catalyst activity in going from K-III to K-I and K-II is
related to the configurational stability of the two latter complexes and, as a consequence, a
decrease in the concentration of L2Rh(CO)H species which are active intermediates in the hy-
drogenation reaction and are formed upon the dissociation of L3Rh(CO)H according to the
equation:
-L
LzRh(CO)H ~ -'4" L~Rh(CO)H + L
41,

(L=ligand)

Hence, t h e s p e c i f i c h y d r o g e n a t i o n a c t i v i t y in the case of complex K-III s h o u l d be g r e a t e s t as

found in our experiments (Table 1).
In the catalytic cycle for isomerization, the hydridic hydrogen atom of the intermediate
may add t o t h e s u b s t r a t e b o t h i n a c c o r d and c o u n t e r t o t h e M a r k o v n i k o v r u l e . Addition according
to the ~arkovnikov rule leads to the formation of the isomerization products while anti-
Markovnikov addition does not lead to the formation of isomerization products since the starting
a l l y l b e n z e n e i s o b t a i n e d upon r e d u c t i v e ~ - e l i m i n a t i o n ("empty cycle"). The d i r e c t i o n o f t h e
a d d i t i o n d e p e n d s on t h e c h a r g e on t h e h y d r o g e n a t o m [ 7 ] . An i n c r e a s e i n t h e n e g a t i v e c h a r g e
on t h e h y d r o g e n atom f a c i l i t a t e s anti-Markoamikov addition. Comparison of the chemical shifts
o f t h e h y d r i d i c h y d r o g e n a t o m s o f K - I , K - I I , K - I I Z and K - I V shows t h a t g r e a t e s t s h i e l d i n g i s
f o u n d f o r t h e h y d r o g e n atom i n K , Z I I ( s e e T a b l e 2 ) . Hence, anti-Markovnikov addition is most
favored in the case of complex K-III, i.e., the extent of isomerization in this case should be
minimal. In light of the isosteric nature of the trithienylphosphines and t r i p h e n y l p h o s p h i n e
( t h e v o l u m e s o f t h e t h i e n y l and p h e n y l g r o u p s a r e v i r t u a l l y t h e same [ 8 , 9 ] , w h i l e t h e s t e r i c
e f f e c t of t h e t h i o p h e n e r i n g s u b s t i t u e n t s s h o u l d n o t h a v e an e f f e c t due t o t h e i r c o n s i d e r a b l e
distance from the reaction site), the "electronegativity" of the hydrogenatom of the hydri-
docarbonyl complex is the factor determining the extent of isomerization of the unsaturated
compound. Of course, this only holds for the isomerization of the same alkene and for sterically
TABLE 3. Rhodium Hydridocarbonyl Trithienylphosphine Complexes

Found %
Compound Dec. T, ~C
H P Rh s (si)

>119 45,7 3,3 9,0 10,0

3Rh(CO)H

>165 47,5 6,3 5,4 5,9 17,6 (14,6)

>150 59,8 7'0 6,1 6,7 !9,4

622
unhindered hydridocarbonyl complexes.
B A
,. . . . u L. . . . .
/ Rh / / .h /
allylbensene co----L .~llylben- prop~nyl- co ........ L allylbenzene

R / i F1 r II
L~__ ~h"*~x, CHCH,t.Ph / ~"hx', ~HCH.,'Ph ./ Rh"...... CHCH3 ii H2

CO CH.z CO CHa H CHPh CO CHCIlaPB

|~ / ~
,"
''~!'I"2 ~'-,i ""(iHCH=,]Ph
' ' L j
i
,
l/ i ~.

c- o- j L J l..-....il..j L co _j
\.
/ L~
/
CH2/CHaCH2Ph
-..
L
:(,
,CH
Rh " //" Rh . / - "CH2Ph
c6 . . . . I, co . . . . . . L"

Thus, the PMR spectral data, specifically, the chemical shift of the hydridic hydrogen
atom and its lineshape, may be used to predict the catalytic properties of rhodium hydrido-
carbonyl complexes. Thus, the complexes with highest shielding 6Hr~--9.6 ppm of the hydridic
hydrogen atom with broad line shape (at room temperature) will probably have enhanced activity
in hydrogenation (with minimal isomerization), while complexes with relatively low chemical
shifts 6nr~--8.8 ppm for the hydridic hydrogen atom should be more active in the C = C b o n d
migration.

EXPERIMENTAL
The PMR spectra were taken on Bruker WM-250 and Bruker AM-300 spectrometers in CDCIs and
C6D6 with TMS as the internal standard. The IR spectra were taken on a Perkin--Elmer 577
spectrometer for Csl pellets and a UR-20 spectrometer for KBr pellets. The gas--liquid
chromatographic analysis was carried out on an LKhM-8MD chromatograph with a flame ionization
detector and nitrogen gas carrier using a I00 0.3 cm column packed with 10% PEGS on Chromatone
N-AW. The temperature for the onset of decomposition of the complexes was determined on a
Boetius microscopic block.
A sample of tri(thienyl-2)phosphine was obtained according to Issleib and Brack [i0], mp
of the sublimed product was 34-35~ Samples of tri(5-tert-butylthienyl-2)phosphine with mp
138.5-140.0~ (from ethanol) and tri(5-trimethylsilylthienyl-2)phosphine with mp 55-57~ (from
ethanol) were prepared according to our previous procedures [5]. Compelxes K-l, K-If, and K-Ill
were obtained by analogy to the method of Wilkinson et al. [Ii] while complex K-IV was ob-
tained by analogy to the method of Ahmad et al. [12]. The characteristics of complexes K-l,

Calculated %
C h e m i c a l formula
H ICh s (si)

CaiH2sOPaRhSu 45,7 2,9 9,6 10,6

C~H tooOPaR I1SuSi9 47,4 6,2 .5,7 6,3 17,8 05,6)

C73H~ooOP~RhS9 59,3 6,8 0,3 7,0 19,5

623
 J Rh tt
i. . . . . . . .
'~1 14.'

j
II
Th~R.~
//' ~h~',\.
Th~P ...... --[-----'-~PTh~
CO

I
Jl
-gJ?ppm
Fig. 3. PMR spectrum of hydrido-
carbonyltris[tri(thienyl-2)phos-
phine]rhodium(1) (hydridic region)
in CDCI3 at 25~

K-II and K-IV are given in Table 3.

Samples of allylbenzene and benzene were thoroughly dried, distilled in an argon stream
over metallic sodium, and stored in an argon atmosphere. The hydrogenation was carried out
using hydrogen purified to remove traces of oxygen.
Hydrogenation Procedure. A sample of the catalyst was i n t r o d u c e d i n t o a long-necked
hydrogenation flask and argoh was flushed through. A sample of 20-30 ml benzene flushed
previously with argon was introduced by means of a syringe. After thecatalyst was completely
dissolved, the argon was replaced by hydrogen, maintained for 2-4 min and i ml allylbenzene
was introduced by m e a n s o f a syringe. The hydrogenation was carried out at 20~ with vigorous
rocking (700 cycles per minute).

LITERATURE CITED
i. Ya. L. Gol'dfarb, E. I. Klabunovskii, A. A. Dudinov, L. N. Sukhobok, V. A. Pavlov, B. D.
Polkovnikov, and V. P. Litvinov, Izv. Akad. Nauk SSSR, Ser. Khim., No. 8, 1880 (1983).
2. I. Langmuir, J. Am. Chem. Soc., 41, 1543 (1919).
3. S. Gronowitz (editor), Thiophene and Its Derivatives, J. Wiley and Sons, New York (1985),
p. 354.
4. M. Yagupsky and G. Wilkinson, J. Chem. Soc., A, No. 6, 941 (1970).
5. Ya. L. Gol'dfarb, A. A. Dudinov, and V. S. Bogdanov, Izv. Akad. Nauk SSSR, Ser. Khim., No.
9 (1986).
6. M. Yagupsky, C. K. Brown, G. Yagupsky, and G. Wilkinson, J. Chem. Soc., A, No. 6, 937
(1970).
7. K. Masters, Homogeneous Catalysis by Transition Metals [Russian translation], Izd. Mir,
Moscow (1983), p. 83.
8. Ya. L. Gol'dfarb, A. A. Dudinov, V. P. Litvinov, D. S. Yufit, and Yu. T. Struchkov, Khim.
Geterotsikl. Soedin., No. i0, 1326 (1982).
9. G. Ferguson, R. McCrindle, A. J. McAlees, and M. Parvez, Acta Crystallogr., B39, 2679
(1982).
i0. K. Issleib and A. Brack, Z. Anorg. Chem., 292, 245 (1957).
ii. D. Evans, G. Yagupsky, and G. Wilkinson, J. Chem. Soc., A, No. ii, 2660 (1968).
12. N. Ahmad, S. D. Robinson, and M. F, Uttley, J. Chem. Soc., Dalton Trans., No. 13, 843
(1972).

624
 REACTIONS OF AROMATIC AND HETEROAROMATIC COMPOUNDS
CARRYING ELECTRON-ACCEPTOR SUBSTITUENTS.
26.* ACYLAMINOMETHYLATION OF 2-ACYLTHIOPHENES,
2-THIOPHENECARBOXYLIC ACID, #~D ITS ESTERS.

Ya. L. Gol'dfarb, t A. Po Yakubov, UDC 547.298.1'464.2'733.07:542.953.2

and L. I. Belen'kii

The reaction of 2-thiophene aldehyde, 2-acetylthiophene, 2-thiophene carboxylic

acid, and its methyl ester w i t h N-(hydroxymethyl)chloroacetamide in concentrated
sulfuric acid yields a mixture of 4- and 5-(N-chloroacetylamino)methyl derivatives,
the former being preferred.

As early as 1935 a paper [2] had appeared in which it was reported that when 2-thiophene
carboxylic acid (I) reacts with the N-(hydroxymethyl)amides of acetic and benzoic acids in
concentrated sulfuric acid the products are N-acylaminomethylated in position 4 of the thio-
phene ring. When one considers the powerful a-orientating effect of the hetero-atom, which
is clearly displayed in thiophene carrying acceptor substituents in position 2, such a direc-
tion of the oxidation is surprising. Hence in a well-known monograph on the chemistry of
thiophene [3] the quoted results of [2] were regarded with doubt and it was suggested that
the compounds obtained were in fact 2,5-disubstituted. This doubt was also shared by the
authors of a review on N-acylaminoalkylation reactions [4].
In a series of papers emanating from our laboratory (see the reviews [5] and [6]) it
was shown that conversion of certain thiophene carbonyl compounds into nv-complexes with
AICI3 or protonation at the carbonyl group markedly accentuated the electron-accepting
ability of the substituent and directed electrophilic attack onto the 4-position of the
thiophene ring. At the same time, while carrying out various electrophilic substitution
reactions of 2-thiophene aldehyde (II), 2-acetylthiophene (III) and the methyl ester of 2-
thiophene carboxylic acid (IV) in concentrated sulfuric acid, that is, in conditions close
to those of [2] for the acylaminomethylation of the acid (I), the ~-orientating effect of
the heteroatom was not completely overcome and in addition to the 2,4-substituted thiophenes
considerable quantities (i0 to 50%) of the 2,5-isomers were obtained [7-11]. It should be
noted that, in distinction from true protonation which is attained, for example, by the
action of HCI and SbCls in 1,2-dichloroethane and permits one to obtain, in the case of
bromination of the aldehyde II and the ketone III, 4-bromoderivatives containing respectively
2 and 4% of the 5-isomers [12], in sulfuric acid it seems that hydrogen bonded complexes are
formed [ii]. _Thus the formation of 4-acylamino-methyl derivatives as the sole products
when carrying out the reaction in concentrated sulfuric acid [2] gives rise to doubt, the
more so since the carboxyl group as a substituent has a lower electron-accepting ability than
formyl or acetyl.
The object of the present work was an investigation of the direction of acylaminomethyl-
a t i o n of a series of thiophene derivatives carrying electron-acceptor substituents: the acid I
and compounds II-IV. Because of the reactivity of the reagent and the possibility of deter-
mining the ratio of the isomers formed by PMR we used the example of N-chloroacetylamino-
methylation by the action of N-(hydroxymethyl)chloroacetamide in sulfuric acid.

*For Communication 25, see [i].

tDeceased.

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciencesof the USSR, Moscow

117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 793-797, june,
1986. Orig~inal article submitted January 24, 1986.

0009-3122/86/2206-0625512.50 9 1986 Plenum Publishing Corporation 625

 TABLE i. PMR Spectra of (N-Chloroacetylamlno)methyl-
Substituted 2-Thiophenecarboxyllc Acid, Its Ess 2-Thiophene-
aldehyde, and 2-Acetylthlophene
Chemical thift, 6, ppm,
Com"
pound CICH~ NCH~, NH
proton groups

ClIO CH:,CO COOCH

xI protons of thiophene ring

3-tt 4-14 ,5-H

V 4,10~ 4,45d 8,10 9 7,73d b.. 7,60d

broad
VI 4,10s 4,63d 8,10 7,60 7,0,5d
broad ~veflap
VII 4,08s 4,47d 7,15 ,88S 7,7 I, d ' 7,41
brosr broad
VIII 4,08 4,66d 7126 ,86s 7,64 d 6,98 d
broar
IX 4,08s 4,50d 7 55 9,83dj' 7,7,~d 7,63
b/6ac broad
X 4,08s 4.68d 7,56 9,80s 7,80'd 7,10d
broa,
XI 4,13s 4.46d 8,10 2.48S 7,79d 7,68 d
oroad
XII 4,1~ 4,62d 8,24 2,46 S 7,65d 7,C~4d
broad

*Spectra of compounds V, VI, XI, XII, run in (CD3)2C0, VII-X

in CDCI3.
#J(5-H, CHO) = 1 Hz (spectrum run on Bruker WM-250).

When we repeated the experiments described in [2], we obtained a mixture of 4- and 5-(N-
chloroaeetylamino)methyl-2-thiophenecarboxylic acids (V and VI respectively) in the ratio of
75:25 (by PMR). Oxidation of this mixture and subsequent treatment with diazomethane led to
a mixture of the methyl esters of 2,4- and 2,5-thiophenedicarboxylic acids in 75:25 ratio (by
GLC). This mixture of acids melted over a wide range of temperature (120-140~ and was iso-
lated in 83% yield. The substance described in [2] as the acid V had mp 153-156~ and was ob-
tained in 53% yield. Evidently a change in the ratio of the isomers in the mixture took place
on recrystallization but it is impossible to judge the purity of the acid isolated in [2] with-
out further information.
On amidoalkylation of the methyl ester IV we obtained a mixture of esters VII and VIII,
70:30 (by PMR). An attempt to increase the proportion of the 2,4-isomer VII by carrying out
the reaction not in sulfuric acid but in the presence of an excess of AICI3 (about 4 moles) was
unsuccessful: around 75% of the initial ester was recovered unchanged and around 10% of a 50:50
mixture of esters VII and VIII was formed. Assuming that in reacting with N-(hydroxymethyl)-
chloroaeetamide aluminum chloride can be partially irreversibly converted to hydrolysis products,
incapable of activating an electrophilic agent and of forming a complex with the ester IV, we
carried out the reaction of the same ester IV with N-(chloromethyl)chloroacetamide in the
presence of 4 moles AICI3. A mixture of esters VII and VIII was isolated in the ratio 85:15 and
in 10% yield but there was considerable tar formation and recovery of the initial ester IV
amounted to 20% in all. Because of this result we used only N-(hydroxymethyl)chloroacetamide
in sulfuric acid for subsequent amidomethylations.
YNHCH z
~.~ CICH2CONHCH2OH
D.- ~ 4- ~
COX ltzS04 COX I'NHCH COX
I-1%' V. %ql.LX. XI %q. Vlll. X. XII
Y=CICH2CO; I, V, VI X=OH; II, IX, X X=H; III, XI, XlI X=CH,; IV, VII, VIII
X = OCH3

The aldehyde II, reacted with N-(hydroxymethyl)chloroacetamide over a period of 3 h, gave

a 20% yield of a mixture of 4- and 5-(N-chloroacetylamino)methyl-2-thiophenealdehydes (IX and
X) in the ratio 93:7; around 50% of the aldehyde II was recovered. When the reaction time was
increased to 24 h, the same mixture was obtained in 32% yield but only 7% of the aldehyde II was
recovered. From the ketone I I I a mixture of the 4- and 5-derivatives (XI and XII) in 90:10
ratio was obtained in 25% yield after 3 h reaction, 45% of the ketone III being recovered. In-
creasing the reaction time to 28 h gave the same mixture in 46% yield but the recovery of the
ketone III was only 5%.

626
 The proportions of the 2,4- and 2,5-isomers was determined in each case from the proton
PMR spectrum. The signals were assigned on the basis of the values of their coupling constants:
For the 2,4-disubstituted derivatives J35 = 1.5 llz and for 2,5-disubstituted, J34 = 4 Hz. Values
of the chemical shift of the protons for compounds V-XII are given in Table i. In all cases,
J(NHCII2) = 6 Hz. Recrystallization of the mixtures of N-(chloroacetylamino)-derivatives in-
creased the concentration of the 2,4-isomer but isolation of this compound free from the 2,5 L
derivative was successful only in the case of the aldehydell. An individual sample of 5-(N-
chloroacetylamino)methyl-2-acetylthiophene (XII) was prepared By the action of chloroacetyl
chloride on 5-aminomethyl-2-acetylthiophene which we had prepared earlier [13].
The results which we have obtained for the direction of acylaminomethylation of compounds
I-IV in sulfuric acid are in agreement with the results for nitration, bromination and chloro-
methylation under similar conditions [7-11]. The ratio of 2,4- to 2,5-isomers corresponds to
the change in electron-acceptor properties in the sequence: CHO > CH3CO > COOCH3.

EXPERIMENTAL
Tesla BS-467 (60 MHz), Tes!a BS-497 (I00 MHz) and Bruker WM-250 C250 MHz) instruments
were used to obtain the PMR spectra; solvents were deuteroacetone or deuterochloroform and
TMS was used as the internal standard. Chromatographic analysis was carried out on a LKhM-SMD
chromatograph with a flame-ionization detector, nitrogen carrier gas, pyrex glass capillary
column 40 m x 0.25 mm, Carbowax 40M/KF, prepared according to the method of [14].
Chloroacetylaminomethylation o f 2 - T h i o p h e n e Carboxylic Acid (I). To a solution of 6.4 g
(50 r.nnole) acid I in 50 ml 92% H2S04 at 18-22~ 7.1 g (57 mmole) N-(hydroxymethyl)chloroaceta-
mide [15] was added in portions, stirred 3 h, the reaction mixture poured onto 300 g ice and
left to stand at 20~ for 20 h . The thickened oil was rubbed with a glass rod, filtered off
and washed on the filter with 2 x 25 ml water; it was dried in vacuum over conc. H2SO~. The
product (9.8 g, 83~) had mp 120-140~ and, from NMR data, was a mixture of 4- and 5-(N-chloro-
acetylamino)methyl-2-thiophene carboxyl%c acids (V and Vl) in the ratio 75:25. To 2 g (8.6
mmole) of the mixture of acids was added 8 ml cone. HCI and after boiling for 2.5 h the solu-
tion was then evaporated to dryness in vacuum (20 mm). The residue was dried in a vacuum
desiccator over KOH, dissolved in i00 m! water, and this solution was then added at 20~ to a
solution of 4.75 g (30 mmole) KMnO 4 and 2.6 g (40 mmole) KOH in 400 ml water; after 20 h 50
ml alcohol was added to reduce the excess KMnO~ and the ppt. of MnO 2 filtered off. The
filtrate was evaporated in vacuum, the residue dissolved in I00 mi water, the solution acidi-
fied with cone. HCI and the acid which separated filtered off (0.48 g, 33% yield). By the
action of an ether solution of diazomethane (from i g nitrosomethylurea), 109 mg of a mixture
of the dimethyl esters of 2,4- and 2,5-thiophenedicarboxylic acids (in the ratio 75:25 by GLC,
compared with reference compounds [16]) was obtained from 108 mg of the mixed acids.
Chloroacetylaminomethylation of the Methyl Ester of 2-Thiophene Carboxylic Acid (IV) in
Sulfuric Acid. To 40 ml conc. H 2 S ~ a t 0-5~ added 5.18 g (36 mmole) of the ester IV, and
5.2 g (42 mmole) N-(hydroxymethyl)chloroacetamide was added in portions. After stirring for
3 h at 20~ the reaction mixture was poured onto ice and extracted out with chloroform. The
extract was washed with water, saturated NaHCOs, again with water; distillation yielded 7.1 g
(80%) of a product with bp 195-198~ at 0.2 mm, mp 80-86~ which was shown by PMR to be a mix-
ture of 4- and 5-N-(chloroacetylamino)methyl-2-methoxycarbonylthiophenes (VII and VIII) in the
ratio 70:30. Recrystallized from methanol, the product had mp 86-97~ the ratio of VII:VIII
was 92:8 and elemental analysis gave the following results. Found: C 43.6, H 4.2, CI 14.3.
S 12.9%. Calculated, %: for C9HIoCIN03S. C 43.6, H 4.1, CI 14.3, S12.9%. In an analogous
experiment, it was found that increasing the reaction time to 3 days at 20~ reduced the
yield to 54%.
Chloroacetylaminomethylation of the Ester IV in Presence of AICI3. A. To a complex
prepared from 15.3 g (Ii5 m mole) anhydride AICI 3 and 4.1 g (28.8 mmole) of the ester IV,
4.07 g (33 mmole) N-(hydroxymethyl)chloroacetamide was added in portions at 50-60~ with
stirring. The mixture was stirred and heated to 70-80~ for i h and then, with external
cooling, it was decomposedwith ice-cold water and extracted with chloroform. The extract
was treated as in the preceding example and yielded 3 g (73%) unreacted ester IV and 0.95 g
(13%) of a substance shown by PMR to be a mixture of 4- and 5-(N-chloroacetylamino)methyl-
2-methoxycarbonylthiophenes (VII and VIII), ~ 50:50. In an analogous experiment, differing
in the use of 1,2-dichloroethane as solvent, after boiling the reaction mixture for 6 h
and treating it as before, a mixture of the esters VII and VIII in the r a t i o ~ 5 0 : 5 0 was ob-
tained in 8% yield together with 76% recovered ester IV.

627
 B. When the ester IV was reacted with N-(chloromethyl)chloracetamide [17] in the pres-
ence of 4 moles AICI3 in dichloroethane (2 days at 20~ 2 h at bp), considerable tar formation
was observed. Chromatographic purification on silica gel using chloroform as eluent resulted
in the isolation of the initial ester (~20% recovery) together with a mixture of acylamino-
methylation products VII-VIII, 85:15, in ~i0% yield.
Chloroacetylaminomethylation of 2-Thiophenealdehyde. To 50 ml conc. H2SO~ at 0-5~ 5.6
g (50 mmole) aldehyde II was added with stirring followed by 7.1 g (57m mole) N-(hydroxymethyl)
chloroacetamide in portions. The mixture was stirred 3 h at 20~ poured onto ice and ex-
tracted with chloroform (3 50 ml). The extract was w a s h e d w i t h water, saturated NaHC03, and
again with water, after which distillation yielded 2.9 g of the initial aldehyde (52% re-
covery) and a fraction [2.2 g, bp 200-225~ (0.3-1 mm) (partial decomposition), mp 64-70~
which was shown by PMR to be a m i x t u r e o f 4- and 5-(N-chloroacetylamino)methyl-2-thiophene-
aldehydes (IX and X) in the ratio 93:7, yield 20% on initial 11, 42% on II consumed. A
sample for analysis was prepared by recrystallization from a mixture of ethyl acetate and
hexane, mp 74-75=C; PMR showed this to be the pure 2,4-isomer IX. Found, %: C 43.9, H 3.5,
CI 16.2, S 14.6. Calculated, %: CsHsCINO2S. C 44.1, H 3.7, CI 16.3, S 14.7. In an analogous
experiment in which the reaction mixture was left for i day at 20~ a mixture of isomers IX
and X was obtained in 32% yield and 7% aldehyde II recovered.
Chloroacetylaminomethylation of 2-Acetylthiophene (III). To 57 ml conc. H2S04 at 5-I0~
7.3 g (57 mmole) ketone III was added f011owed by 8.3 g (67 mmole) N-(hydroxymethyl)chloro-
acetamide in portions. After stirring for 3 h at 20=C the mixture was poured onto 400 g
ice and extraced with 4 x 50 ml chloroform. The extract was washed with water, aqueous
KOH, and again with water; distillation yielded 3.2 g ketone III (44% recovery) and 3.3 g of
a material with bp 200-220~ at 0.2 mm, mp 65-80~ 9 which was shown by PMR to be a mixture of
4 - and5-(N-chloroacetylamino)methyl-2-acetylthiophenes (XI and XII) in the ratio 90:10. The
yield was 25% on the initial ketone III or 45% allowing for that recovered. A sample for
analysis was prepared by recrystallization from isopropanol, mp 84-86~ this proved to be
the 2,4-isomer XI with 3% of the 2,5-isomer XII as impurity. Found, %: C 46.3, H 4.5, C1 15.2,
S 13.6. Calculated, %: for CgHIoCINO2S. C 46.6, H 4.4, C1 15.3, S 13.8. In an analogous
experiment in which the mixture was reacted for 28 h at 200C the yield of mixed ketones XI
and XII was 46%, and 5% of the initial ketone III was recovered.
5-(N-Chloroacetylamino)methyl-2-Acetylthiophene (XII). To a solution of 0.3 g of the
hydrochloride of 5-aminomethyl-2-acetylthiophene [13] in 20 ml water cooled to 0=C, was added
3 ml chloroacetyl chloride and a solution of 5 g sodium acetate in 7 ml water. This was stirred
for 1 h, diluted with water and extracted with chloroform. T h e e x t r a c t was washed with i NHCI
water, 5% KOH, water, and the solvent evaporated off. Recrystallization of the residue (0.3 g,
83%) from isopropanol yielded the ketone XII, mp 95~98~ Found, %: C 47.1, H 4.6, CI 15.2,
S 13.7. C91110CI~NO2S. Calculated, %: C 46.7, H 4.4, CI 15.3, S 13.8.

LITERATURE CITED
i. L. I. Belen'kii, G. P. GromoVa, and Ya. L. Gol'dfarb, Khim. Geterotsikl. Soedin., No. 4,
472 (1980).
2. R. O'Cinneide, Proc. Roy. Irish Acad., Sect. B, 42, 359 (1935); Chem. Abs., 29, 7326
(1935).
3. H. D. Hartough, Thiophene and Its Derivatives, Interscience, New York (1952), pp. 253,
413.
4. H. E. Zaugg and W. B. Martin, "a-Amidoalkylations at Carbon," in: R. Adams, ed., Organic
Reactions, Vol. 14, Wiley, New York (1965), p. 56.
5. Ja. L. Gol'dfarb, Ju. B. Volkenstein, and L. I. Belen'kii, Angew. Chem., 80, 547 (1968).
6. L. I. Belen'kii, Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 344 (1975).
7. Ya. L. Gol'dfarb, E. I. Novikova, and L. I. Belen'kii, Izv. Akad. Nauk SSSR, Ser. Khim.
No. 6, 1233 (1971~.
8. L. I. Belen'kii, E. I. Novikova, I. A. D'yachenko, and Ya. L. Gol'dfarb, Zh. Org. Khim.,
7, 1736 (1971).
9. Ya. L. Gol'dfarb, E. I. Novikova, and L. I. Belen'kii, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. 12, 2841 (1973).
I0. L. I. Belen'kii, E. I. Novikova, and Ya. L. Gol'dfarb, Khim. Geterotsikl. Soedin., No. i0,
1353 (1971).
Ii. L. I. Belen'kii, I. B. Karmanova, E. I. Novikova, G. P. Gromova, Ya. L. Gol'dfarb, V. S.
Bogdanov, and L. V. Shmelev, Zh. Org. Khim., 9, 1499 (1973).

628
12. Ya. L. Gol'dfarb, G. P. Gromova, and L. I. Belen'kii, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. I0, 2275 (1974).
13. A. P. Yakubov, L. I. Belen'kii, and Ya. L. Gol'dfarb, Zh. Org. Khim., 7, 525 (1971).
14. Ri V. Golovnya, A. L. Samusenko, and E. A. Mistryukov, J. High Resoluti--on Chromatog.
Chromatogr. Commun., 2, 609 (1979).
15. A. Einhorn and T. Mauermayer,!Ann. 343, 282 (1905).
16. Ya. L. Gol'dfarb, A. P. Yakubov, a n d L . I. Belen'kii, Dokl. Akad. Nauk SSSR, 18__55,94
(1969).
17. M. Pianka and D. J. Polton, British Patent 917,924; Chem. Abs., 59, 1488 (1963).

IMPROVED METHOD FORSYNTHESIS OF SUBSTITUTED TETRAPHENYLPORPHINS

A. S. Semeikin, O. I. Koifman, UDC 547.979.733.07'571'74

and B. D. Berezin

Condensation of pyrrole with benzaldehydes in a mixture of xylene and chloroacetic

acid gives a series of substituted tetraphenylporphins with yields exceeding the
yields of porphyrins synthesized accordingto known preparative methods.

The development Of practicable methods for the synthesis of porphyrins having the most
varied properties and stable to the action of aggressive media and reagents is an urgent
necessity [i]. Included among such porphyrins are meso-tetraphenylporphins substituted in
the phenyl rings, w h i c h a r e obtained by a one-stage condensation of pyrrole with substituted
benzaldehydes.
R4 R2

l; I ,--Tj lJ ~J
r= ~ . y ' " - ~;~-.N-; "~ ...... - . ..~*,.,1~4 II R~=CHa; lII R2=Ctla; IV Ra=CHa; V R I=
,,>, > =OCHa; VI R2=OCtta; VII Ra=OCHa; VIII R~=F;
IX R~=F; X Ra=F; Xt R~=Cl; XtI R'2=C|;
XIII Ra=CI; XIV R1=Br; XV R~=Br; XVI Ra=Br;
r~ t.=g
~ \._.llr' XVI! R~=I; XVIII R==I, XlX Ra=l; XX R I = R = =
=CHa; XXI RI=Ra=CHa; XXlI Rt=R4=CHa;
XXlIt RI=RS=CHa; XXIV R~=Ra=CHa; XXV R~=
=R4=CHa; XXVI RI=R2=OCH3; XXVII R2=Ra=
R3 -.<.-"-,R1 ...... R~ - ".~J ",IR~
=OCHa; XXVIII R2q--Ra=OCH~O; XXIX R~=R~=
= t-Btl; Ra=OH; XXX R2=R4=CHa, Ra=OH;
not stated R ~, R2, Ra, R4, RS=H

The existing preparative methods for the synthesis of tetraphenylporphins have made it
possible for these porphyrins to be obtained with yields not usually exceeding 20-25% [2, 3].
The yield reaches 30-35% only when benzaldehydeswith certain electron-seeking substituents are
used in the condensation reaction [4, 5]. The best results are achieved when the condensation
is carried out in organic solvents containing an acid. A mixture of pyridine and acetic acid
(with bp 135~ [2] and propionic acid (bp 141~ [3] are the most suitable solvents. The use
of acetic acid (bp I18~ as solvent considerably slows down the rate of reaction in comparison
with the reaction in propionic acid (up to I0 h), while in butyric acid (bp 163~ porphyrins
are not formed [6]. The use of mixtures containing strong mineral acids as the medium for
conducting the condensationalso does not give positive results.
The yield of porphyrins in the condensation reaction decreases if there is water in the
reaction medium, whereas the addition to the reaction medium of weak dehydrating agents such
as acetic anhydride leads to some increase in yield [6].
The isolation of porphyrins that are very soluble in the reaction mixture and do not cry-
stallize after carryingiout the reaction is difficult. Methods of treating the reaction mass
under these conditions are protracted and complicated, and are accompanied by considerable
losses of porphyrins [2].
Ivanovo Chemical-Technological Institute, Ivanovo 153460. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 798-801, June, 1983. Original article submitted
January 3, 1985; revision submitted November 21, 1985.

0009-3122/86/2206-0629512.50 9 1986 Plenum Publishing Corporation 629

 1,0 D

/ . 9 ~.j
.r
,
Q '2

3O

20
,5 Io 15 20
Content of CICH2COOH, % 0
; 4 b %h
Fig. i Pig. 2
Fig. i. Dependence of yield of tetra(4-methoxyphenyl)porphin on concen-
tration of chloroacetic acid in the reaction mixture.
Fig. 2. Dependence of optical density of protonated tetra(4-methoxyphenyl)-
porphin (% 700 nm) on reaction time in a mixture of: I) 5% CICH2COOH +
isomeric xylenes; 2),5% CICH2COOH + toluene; 3) 5% CICH2COOH + benzene.

Based on w h a t h a s been saidabout conducting the condensation reaction, we chose a solvent

possessing the merits of the reaction media already known and lacking some of their inherent
shortcomings. Such a solvent turned out to be a mixture of isomeric xylenes (bp ~ 140~
with the addition of a strongly acid component with low volatility -- chloroacetic acid [7]. In
t h e course of condensation water separating out from the reaction mixture was removed. On
formations of porphyrins very soluble in the given reaction mixture, the latter were neutral-
ized with a solution of ammonia, and the organic layer after washing with water was chroma-
tographed on a suitable adsorbent. This considerably simplifies the more complex methods used
earlier for isolation and purification of such porphyrins [2].

TABLE I. Yield a n d Certain Properties of Tetraphenylporphins

Com- Electronic absorption spectra in pyridine, ),max, nm (log 8)

R!
pound
[ II III lV So r e t
m

I 646 (3,71 ) 591 (3,7I) 549 (3,96) 515 (4,27) 420 (5,73)
II 648 (3.54) 592 (3,73) 547 (3,76) 514 (4,29) 419 (5,64)
III 648 (3,71) 592 (3,67) 550 (3,89) 516 (4,21) 421 (5,64)
IV 652 (3,80) 595 (3,72) 554 (4,01) 517 (4,25) 422 (5,68)
V 648 (3,53) 590 (3,73) 546 (339) 513 (4,27) 420 (5,62)
VI 649 (3,73) 59l (3,74) 549 (3,86) 515 (4,28) 422 (5,66)
VII 651 (3,79) 595 (3,66) 556 (4,04) 518 (4,16) 424 (5,65)
VIII 653 (3,62) 593 (3,89) 546 (3,81) 512 (4,33) 419 (5,93)
IX 647 (3,56) 591 (3,86) 552 (3,92) 518 (4,37) 42l (5,37)
X 647 (3,62) 591 (3,85) 552 (3,94) 517 (4,30) 421 (5,39)
Xl 656 (3,54) 590 (3,89) 546 (3,74) 514 {4,38) 420 (5,20)
Xll 648 (3,52) 592 (3,76) 550 (3,85) 515 (4,29) 421 (5,65)
XIII 651 (3,65) 593 (3,68) 551 (4,1o) 517 (4,34) 422 (5,46)
XIIV 648 (4,09) 592 (4,33) 548 (4,26) 515 (4,69) 422 (5,99)
xv 650 (3,76) 591 (3,95) 549 (4,24) 515 0,3% 421 (5,74)
XV1 652 (3,74) 595 (3,77) 553 (3,97) 517 (4,30) 422 (5,69)
XVil 659 (3,58) 597 {3,98) 555 (3,91) 520 (4,46) 427 (5,76)
XVIII 653 (3,72) 593 (3,8t) 552 (3,96) 518 (4,33) 423 (5,66)
XIX 649 (3,82) 590 (3,84) 551 (4,07) 517 (4,35) 423 (5,7o)
XX 657 (3,84) 592 (3,8!) 547 (3,91) 515 (4,30) 420 (5,61)
XXl 650 (3,77) 592 (3,79) 548 (3,88) 516 (4,29) 422 (5,55)
XXII 651 (3,77) 592 (3,81) 548 (3,84) 516 (4,30) 420 (5,63)
XXIII 649 (3,75) 591 (3,73) 546 (3,76) 5t4 (4,18) 420 (5,43)
XXIV 651 (3,80) 595 (3,82) 555 (4,06) 518 (4,30) 424 (5,76)
XXV (;50 (3,80) 59~ (3,8]) 553 (4,01) 518 (4,29) 423 (5,74)
XXVI 653 (3,78) 590 (3,77) 545 (3,77) 513 (4,33) 420 (5,68)
XXVII 653 (3,80) 595 (3,72) 558 (4,05) 520 (4,22) 428 (5,58)
XX}VlII 652 {3,57) 594 (3,63) 557 (3,90) 520 (4,12) 428 (5,47)
XXlX 658 (4,17) 599 (3,94} 564 (4,39) 525 (4,35) 430 (5,86)
XXX 654 596 562 522 429

*Yield for condensation in a xylene--chloroacetic acid mixture

is given in brackets.
tFor condensation in a mixture of pyridine and acetic acid.

630
 We investigated the possibility of using a binary acid mixture of xylene-chloroacetic
acid for the synthesis of porphyrins on the model condensation of pyrro!e with anisaldehyde,
which results i n the formation of tetra(4-methoxyphenyl)porphin. This porphyrin is sparingly
soluble in a mixture of xylenes (1.3.10-4 moles/liter at 25~ which makes its isolation in
a pure form possible by filtration of the reaction mixture after it has been neutralized with
a solution of ammonia followed by washing of the precipitate of tetra(4-methoxyphenyl)porphin
with methanol.
The highest yield of porphyrin (42%) is observed when the reaction is carried out between
equimolar quantities of pyrrole and anisaldehyde in the xylene-chloroacetic acid mixture with
the content of the latter at ~5% (Fig. i) and for a reaction time of 1.5 h (Fig. 2). The
reaction was conducted with air bubbled through and water removed from the reaction mixture
with the aid of a Dean--Stark attachment.
When the synthesis of tetra(4-meth0xypheny!)porphin is carried out without removal of
water the yield decreases to 36%, and without bubbling air through it decreases to 34%. The
use of benzene or toluene instead ofxylene leads to a sharp increase in the reaction time
and a considerable decrease in the yield of porphyrin (Fig. 2). The use of isomeric xylenes
in the reaction does not affect the yield of porphyrin.
The proposed method was u s e d t o obtain a series of methyl- (II-IV, XX-XXV), methoxy-
(V-VII, XXVI-XXVIII), halogeno- (VIII-XIX), and hydroxy-(XXIX, XXX) substituted tetraphenyl-
porphins.
On separation of one or another porphyrins from the reaction mixture, specific proper-
ties determined by their differing solubilities in xylene are observed.

EXPERIMENTAL
Electronic absorptionspectra of the compounds were recorded in pyridine on a Specord
UV-Vis spectrophotometer. The identity of each compound obtained was established using TLC on
Silufol in the following systems: toluene-h~xane, i:i (A); chloroform (B); chloroform--hexane,
3:2 (C); chlorofor~exane, 2:1 (D); chloroform-hexane, i:I (E); and acetone--hexane, I:i (F).
Synthesized

Found, % i Empirical formula Calculated, %

Yield, %
C H N c H

C44HaoN4 43,0 (20,0)

C48Hs8N~ 20,0 01,5)
C~8HasN4 30,0 (16,0)
C48HasN4 39,0 (I 9,5)
C48HasN404 16,0 (9,0)
C4attaoN404 25,0 (14,0)
C4~HasN404 42,0 (20,0)
C44H~F4N4 24,0 (10,0)
C44H.~F4N4 102
C44H26F4N4 t 1,0 (5,0)
C44H2r 16,8 (3,3)
C44HaCI4N4 26,8 (17,0)
C,4H~CI4N4 34,6 (23,3)
C44t-I26Br4N4 13,o (2,5)
C44H26Br4N4 18,5
C44H=6Br4N4 19,0 (II,0)
C44H2~t4N4 14,7
C44H~I4N4 21,5
C44H~6 I4N4 15,5
Cs~H4oN4 102
Cs2H4oN4 20,0
(;s2H4~N4 17,0
Ca~H4oN4 0,6
Cs2H4~N4 12,5
Cs~H4~N4 29,0
Cs2H46N408 14,0
Cs~H4oN40~ 29,0
C~sllaoN4Os 23,0
CTd'194N40~ ar,o {1,o"I' )
('s2H.,~aN40.~ 11,5

(95:5); for comparison the yield in propionic acid

631
P r o p e r t i e s of the porphyrins obtained a r e given in Table i.
Synthesis of Substituted Tetraphenylporphins I-XXX (General Method). Into a 0.5 liter flask
with Dean--Stark attachmens 66nde6eer, dr6pping funnel, and air supply was inserted 300
ml of a mixture of isomeric xylenes and 16 g (5~) of chloroacetic acid. The contents of the
flask were heated to boiling point and with the constant passage of a flow of air a solution of
72 mmole of the appropriate substituted benzaldehyde and 5 ml (72 mmole) of pyrrole in 50 ml
of xylene was added through the dropping funnel over a period of 20 mln. The reaction mixture
was boiled for a further 1.5 h with air bubbled through. On coolins, the mixture obtained was
neutralized with a 25% solution of ammonia until the color changed from green to reddish brown,
and three methods of separation were then used depending on the solubility of the porphyrins
in xylene.
For isolation of the sparingly soluble porphyrins (VII, X, XXX), the mixture was filtered,
and the precipitate washed with methanol until the filtrate was colorless and then dried at
100~ The dried precipitate of porphyrin was dissolved in chloroform and chromatographed on
alumina or recrystallized from a chloroform-~ethanol mixture.
For isolation of the porphyrlns of medium solubility (III, IV, VIII, IX, XII, XIII, XV,
XVI, XVIII, XIX, XXIV, XXV, XXVII, XXVIII) the mixture was filtered and the filtrate washed
with water and chromatographed on alumina or silica gel. The precipitate was dissolved in
benzene and also chromatographed. The fractions containing reaction product were concen-
trated to a volume of 20 ml and the porphyrin was precipitated from the solution obtained by
adding 250 ml of methanol or hexane.
For isolation of the very soluble porphyrins (II, V, Xl, XIV, XVII, XX-XXIII) the organic
layer was washed with water and chromatographed on alumina or silica gel.

LITERATURE CITED
i. B. D. Berezin, Coordination Compounds of Porphyrins and Phthalocyanine [in Russian],
Nauka, Moscow (1978), p. 280.
. A. Treibs and N. Haberle, Liebigs Ann. Chem., 718, 183 (1968).
3. A. D. Adler, F. R. Longo, J. D. Finarelli, J. Goldmacher, J. Assour, and B. Korsakoff,
J. Org. Chem., 32, 476 (1967).
, N. Datta-Gupta and F. Bardos, J. Heterocycl. Chem., ~, 495 (1966).
5. F. R. Longo, M. G. Finarelli, and J. B. Kim. J. Heterocycl, Chem., 6, 927 (1969).
6. A. D. Adler, L. Sklar, and F. R. Longo, J. Heterocycl. Chem., ~, 667 (1968).
7. A. S. Semeikin, O. I. Koifman, and B. D. Berezin, USSR Inventor's Certificate No. 1,118,642;
Byull. Izobret., No. 38, 68 (1984).

632
TAUTOMERISM OF AZINE DERIVATIVES.
ii.* I~N-NMRAND Z?O-NMR INVESTIGATION OF
INTRACHELATE TAUTOMERISM OF ACYLMETHYLPYRIDINES

V. V. Lapachev, S. A. Stekhova, UDC 543.422.25:547.82.541.623

I. Ya. Mainagashev, M. A. Fedotov,
V. E. Khall, and V. P. Mamaev

Intrachelate[l, 5]-sigmatropic tautomerism in a series of acylmethylpyridines has

been studied by 14N- and I?O-NMR spectroscopy. Principles of tautomer modelling or
simulation have beenproposed and examined, nitrogen and oxygen chemical shift spectra
have been determined, and the accuracy of this method for the determination of tauto-
mer composition has been evaluated. The presence of acceptor (electron withdrawing)
substituents i n t h e acylmethyl side-chain fragment has been found to stabilize the
~{-tautomer.

We have previously studied [2, 3] tautomerism in pyrimidylmalonicand cyanoacetic esters.

Due to the low enolizability of the carboxyl groups in these classes of compounds, the enol
tautomer B is energetically inaccessible, and solutions of these compounds in CHCI3 and CC14
are characterized by equilibria of the type A~C.

A . t, o~./ B

H'"o//'R
x-~ C
l, VI R=CHa, I1 I~=C~Hs, III R=CFa, IV R=CH=CI, V R=CCla; I--V R~=H,
VI RI=CN

This type of tautomerism ([i, 3]-sigmatropic tautomerism [4]) is characterized by relatively

low rates of interconversion, since symmetry requirements render the intramolecular mechanism
of[l, 3]-sigmatropic proton t~ansfer improbable [5]. In the case of easily enolizable ketone
groups (R = CH3, C~Hs),[I, 5]-sigmatropic tautomerism of the type B$C becomes very rapid; in
contrast to [i, 3]-sigmatropic tautomerism, an intramolecular proton transfer mechanism has
been advanced for this process [intrachelate tautomerism).
This type of tautomeric equilibrium is of widespread importance in organic chemistry
(among enols of B-dicarbonylcompounds, Schiff bases, azo dyes containingortho-hydroxyphenyl
substituents, and enaminocarbonyl compounds, and others).
Interest in studies of intrachelate tautomerism has been stimulated not only by its
theoretical importance [6], but also by the feasibility of practical applications of tautomeric
chelated systems as light-stabilizers, complex-forming compounds, and photochromic systems.

*For communication i0, see [i].

Institute of Organic Chemistry, Siberian Branch, Academy of SciencesOf the USSR, Novo-
sibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 802-809,
June, 1986. Original article submitted March 22, 1985; revision submitted October 4, 1985.

0009-3122/86/2206-0633512.50 9 1986 Plenum Publishing Corporation 633

 a b

Fig. i. Structures of
chelate fragments: a)
iminoenol, and b)
enaminocarbonyl.

In addition, this type of tautome~ism has not been studied much in heterocyclic systems.
This is due mainly to the faster rate of intrachelate proton transfer in these derivatives,
which leads to signal coalescence of the exchanging nuclei and thus hinders the use of IH-
and ~3C-NMR spectroscopy for the determinationof tautomer composition. As a result, the
generally accepted method of analyzing tautomeric equilibria by NMR studies of model compounds
is of little utility for these systems, since their chemical shifts do not differ greatly.
Not surprisingly, therefore, the data available concerning the type B~C equilibria are in-
consistent, even in the case of a very simple model compound, such as acetonylpyridine I [7].
We have hypothesized that consideration of the NMII properties of the nitrogen and oxygen
atoms involvedin proton migration m ~ g h t y i e l d more useful information concerning the type
B~tC equilibria. The hybridization of these atoms changes during the course of tautomer
interconversions, and as a result, the differences in the chemical shift values of the ob-
served nuclei can reach i00 ppm and higher [8, 9]. This, in turn, permits semiquantitative
and even in some cases quantitativemeasurements of tautomer composition.
In the present paper we have used high field 14N- and I?O-NMR spectroscopy to study
intrachelate (B~C) tautomerism in acylmethylpyridinesI-VI, and have analyzed the effective-
ness of these methods for the study of rapid [i, 5]-sigmatropic tautomerism. Since the rates
of A~tB and A$-C tautomeric interconversions are slow on the N M R t i m e scale, the concentration of
A forms as well as the totalamount of B and C forms could be determined by PMR spectroscopy.
The ratios of B and C tautomers were evaluated based on the positionsof the nitrogen or oxygen
atom signals relative to those in model compounds.
Modelling Studies of the Spectral Characteristics of B and C Tautomers. In studies of
rapid tautomeric equilibria, the accuracy of equilibrium calculation~ depends to a large ex-
tent on the selection of model compounds. Analysis of literature data has established that
the magnitudes of the chemical shifts of nitrogen and oxygen atoms are very sensitive, as
might be expected, to conjugative effects as well as to hydrogen bonding [8-10]. For this
reason, we rejected the classical approach t o s e l e c t i n g tautomer form models (N- and O-
methyl derivatives)[Ii]. Instead, w e f o c u s e d on an approach to selecting model compounds
which preserved the structuralfeatures of the chelate fragment, namely, the enaminocarbonyl
group for type C tautomersand the iminoenol group for type B tautomers (Fig. 1). The peri-
pheral features surroundingthe chelate groups h a v e b e e n varied in such a w a y that one o f
the forms becomes energetically unfavorable and thus shifts the equilibrium for the model
compound almost entirely in favor o f o n e tautomeric form. This approach to model selection
is made possible by the fact that nitrogen and oxygen chemical shift values do not depend
to a large extent on the nature of their outer surroundings [8"10].
Cyanoacetic esters VII-X were selected as model compounds for 14N-NMRstudies of the
NH-tautomerso I~N- chemicalshiftcomparisons of compounds VII-XI revealed that the position
of the NH signal depended only weakly on structural changes in the molecular (A~ = ppm).
The similarities in thenitrogen shift values for azinylcyanoacetic~esters and 2-pyridQne
(XI) called our attention; we do not believethat these similarities are coincidental, b u t
rather, that they reflect the amide character of the NH groups in compounds VII-X and XI.
As a result, the two most important factors influencing chemical shifts, namely, con-
jugation of the carbonyl and amino groups, and hybrization state of the nucleus, are pre-
served in both cases (the enaminocarbonyl fragment in VII is a vinylog of the amide fragment
in XI).

634
 CN

"-. / , 0C2H5 . . 2H5 , 2H5 H

VII VIII IX X XI
5~%,ppm 215 230+3 ~20 230-+3 210u [ill

614N.pPlIl l l O i a ~ltl XII1 X]V

130 130

In selecting a model compound for the B tautomer, we considered that this form may be
regarded as a vinylog of 2-hydroxypyridine, and thus that, to a first approximation, the
i4N-NMR signals of the enol forms B of acylmethylpyridines can be modelled after the nitrogen
atom signal of 2-methoxypyridine XII.* The effect of intramolecular hydrogen bonding shifts
the nitrogen atom signal strongly upfield, by almost 20 ppm [9]. The nitrogen atom signals
of the e n o l f o r m s of acylmethylpyridines would thus b e e x p e c t e d to occur at approximately -130
ppm. This hypothesis is in excellent agreement with the spectral data for hydroxyphenylpyri-
midines XIII and XIV, which, in analogy with form B, possess iminoenol fragments.
In selecting model compounds for the i~_NMR spectra of the B forms, we considered com-
pounds XV-XVIII

O'-" / "[~ N t
il ,,i?.
XV R=CH3; XV[ R=C6H,~: XVII R=CF 3 NVIII
do, pplTl 124+-1 109-vi 96+-1 lt7~2

According to our previous work [12], the position of the signal due to the enol oxygen
atom in six-membered ring chelates depends only w e a k l y o n the basic portion of the molecule
which is involved in intramolecular hydrogen bond formation (A~ = ppm), but is more
noticeably affected by the presence of substituents attached to the enolizing carbonyl group.
For this reason, the enol tautomers can also be modelled using the enol forms of corresponding
$-ketoesters; thus, acetonylpyridine is modelled by acetoacetate ester XV, phenacylpyridine
by benzoylacetate ester XVI, etc. In this regard, we have found satisfactory agreement of
our spectral results with those of the model compound XVIII (compare with XVI), in which the
B~-C equilibrium is shifted almost entirely in favor of the enol form B [13].
The characteristics and extent of conjugative and intramolecular hydrogen bonding effects
on the chemical shift values of the carbonyl oxygen atoms can be evaluated in the series of
compounds XIX-XXI.

H CH3 % C N

9 0;:fl~-CH 3 ,.
X]X XX XXI XXII R=CH3(367 ppnq ) Vl
~=o.ppm sss uo] 48a [10] 420 xm~lm=cr .~.

Comparison of the spectral values in compounds XIX-XXI reveals that electron-donating

substituents and hydrogen bonding shift the signals upfield. Apparently, the signal of the
ylide tautomers of acylmethylpyridines is shifted toward higher field, as shown by the
i70-NMR chemical shift data for 2-cyanoacetonylpyridine VI and the acetonyl- and phenacyl-
quinolines XXII and XXIII. Accordin~ to their I~N-NMR spectra, these compounds exist almost
entirely in the form of their ylide tautomers (-6NH 199, 223, and 229 ppm, respectively). The
*The i4N-NMR chemical shifts of azines containing hydroxy groups are hard to measure, since
the equilibria involving these compounds are shifted primarily in favor of the oxo forms.
The use of methoxy derivatives is justified by comparison with the very small effect of
methylation on the i4N-NMR chemical shift values of hydroxyazines (g6 ~ 1 ppm) [ii].

635
 .o,~CH~ t. t%O.~CH
(8,C) s
.... ~ . . . . N~(B,C)

-so A
.......
~50~,,~ppm
L.-- ,__
y- o~L' p~,
c [10(B,C)

-.-c--: ......
JL
~. . . . . . . . . . . . : L - . . . . . . . t ..........
:B H'O'~' ['h D:' F'h
zoo ~o~ o %'o'ppm
Fig. 2. NMR spectra: a) cyanoacetonyl-
pyridine VI; b and c) phenaeylpyridine II.

ylide structure of the quinoline derivatives XXII and XXIII has been confirmed earlier based
on their UV and PMR spectroscopic data [14].
Based On the discussion above, we assumed a value of 352 21 ppm for the !70-NMR chemi-
cal shift of the NH-tautomer.
Accuracy of th e 14N-NMR and 170-NMR Methods for the Determination of the NH- and OH-
Tautomer Ratio. The use of 1 ~ N - a n a i?O-NMRmethods in tandem has allowed us to overcome the
limitations inherent in each method. The l~N-NMRmethod proved to be the more informative
means of analyzing mixtures containing a preponderance of the ylide tautomers, since the
signal due to the hq~ group is relatively narrow in these c a s e s a n d also characteristic in
comparison with the nitrogen a t o m s i g n a l in pyridine type compounds (Fig, 2 ) . The signal due
to the nitrogen nucleus broadens considerably as the B$C tautomer equilibrium is shifted in
favor of the enol form. For instance, the width of this signal in the spectrum of 2-cyano-
acetonylpyridine (Vl), which exists almost entirely in the ylide form, is 320 Hz, whereas the
half-width of the 2-phenacylpyridine signal, in which the B$C equilibrium is strongly displaced
in favor of the enol form, is much greater, wl/~ = 1300 Hz. In the case of compounds con-
taining significant contributions of the A and B tautomers in solution, the corresponding
broad signals sometimes overlap, which complicates determination of the chemical shift values.
For example, in the case of 2-phenacylpyridine, in which concentrations of the B and C forms
are comparable, the distance b e t w e e n t h e I~N-NMP. signals of the two forms is on the same
order as their line widths (Fig. 2). The deter~ination of the tautomer composition is even
more complicated in t h e c a s e of diazine derivatives, in which the spectra feature an additional
signal due to the second nitrogen atom in the ring. In order toovercome the difficulties dis-
cussed above, we considered it more expedient to utilize the !70-NMRmethod, in spite of its
greater experimental complexity. The use of 14N- and 170-NMR spectroscopy in tandem increases
the reliability of the results and decreases the probability of errors due to inadequate model
compounds in calculating the tautomer composition or in determining chemical shift values of
broad signals, etc. Error values in the tautomer composition results arising from inadequate
modelling of the compounds can be evaluated [15, 16] by differentiation of Eq. (!) with respect
to two variables, A6 B and A6 C

p= 6obs , - 6 C
6B_6 c , (1)

where 8obs is the experimentallydetermined chemical shift value and 6 B and 6C are the chemical
shift values of the model compounds.
OP OP
(2)
6B--6oh~ _~ _ 6obs--6C A ~
-~P= (6c_6B)~"~~ *' ( % _ ~ ) 2 ,

where A~B, C are the errors in modelling tautomers B a n d C, respectively.

636
 14

i[ i
F i g . 3. Dependence o f the
81 t10~wtg
L ~ > ~ ~ ~
absolute error in the tauto-
" mer composition measurements
61/ t ~; ~ of acylmethylpyridines "(by
m 49 j~. ~a 14N- and !70-NMI~) on the con-
. . . . . . ,~ centration of the C tautomer
~0 ~0 ~,o 7o ~0 in the mixture.
Concentration, %

TABLE i. I~N- and 170-NMR Spectral Characteristics

and Tautomer Composition for the Acylmethylpy-
ridines I-VI

CON- 14N-NMR spectrum I?O-NNhR spectrum

A/B/G"
pound chemicall chemical I
shiftT [ B/C:~ shiftt B/C $
I 130-+5 100/0(+- 10) 143-+3 92/8 ( 86:13:1
II 131 +-5 IO0/O(:k t0} )25-+3 90/t0 (+-5) 53:45:2
III 177-+3 45/55(-+8) 0:45:55
W 130-+5 I00]0 (----+--10) 160+-3 82/18(-+5) 28:59:13
V I94-+3 25/75(+-8) 0:25:75
VI 199-+ I 19/81 ( 356-+2 0/100(-+7) 0:19:81

*The concentrations of tautomers were calculated

from their 14N-, 170-, and IH-N%IR data; the lat-
ter data were also used to determine the A/(B +
C) ratio (accuracy
*Chemical shift data are reported only for those
nitrogen and oxygen atoms involved in proton
migration.
%Absolute errors are given in parentheses.

Analysis of Eq. (2) reveals that in the case of a predominance of the enol tautomer in a
mixture ( 6B-6obs ~ 0 ), the error in the tautomer concentration measurement will depend very
little on the accuracy of the model for the NIl-tautomer. In the case of an equilibrium
shifted in the reverse direction ( 6obs--6C~0 ), the error will depend only weakly on the
correctness of the OH-tautomer model compodnd. By inserting values of 6 B and 6 c i n Eq. (2), we
were able to calculate the errors inherent in the measurements o f t h e tautomeric composition
of acylmethylazines, as determined by 14N- and 170--~ spectroscopy (see Table l ) . We calcu-
lated AS values from the chemical shifts of model compounds by taking into account their
magnitude and corresponding Student coefficients for a 90% confidence limit [16]: for nitro-
gen atom signals, A6B N = A 6 ~ = ppm, and for the oxygen atom signals, A6B~ = =
i22 ppm. A graph showing the dependence of the error values on the tautomer composition is
given in Fig. 3, and indicatesthat the 14N-NMR method is more satisfactory in cases where
the ylide tautomer predominates (80% and higher), whereas in cases with an NH-tautomer concen-
tration from 0 to 80%, the 170-NMRmethod provides more accurate results.
We should point out that the accuracy of the I~N- and 170-NMR based determination of the
enol and ylide tautomer ratio was evaluated based on a wide range of compound types, and was
still relatively h i s h . For a narrower class of compounds, such as for instance phenacyl-
pyridines, the accuracy of the intrachelate equilibrium constant measurement approaches the
accuracy of PMRmeasurements made in a stationary (non-exchanging) system (5%), and can be
increased even further by more accurate modelling programs.
B~C Tautomeric Equilibrium of Acylmethylpyridines. Table i summarizes the I~N- and
I?O-NMIR spectral data for the acylmethylpyridines I-VI, and also gives the B/C tautomer
ratios which were calculated according to Eq. (i). As can be seen from the Table, there is
generally quite good agreement between the 14N- and 170-NMR results, which makes it p o s s i b l e
to assign the structures of acylmethylpyridines with a high degree of certainty and also to
resolve some of the contradictory literature data [7, 17-23].
Comparison of the 14N-NMR chemical shift data for acetonylpyridine (I) with that of model
compounds reveals that the B~C tautomer equilibrium is shifted almost entirely in favor of the
enol tautomer. The 170-NMR data (see also Table I), which is more accurate than the 14N-NMR

637
 method in cases involving a predominance of the enol tautomer, indicates that, in addition to
the A and B forms, the ylide tautomer C is also present, although in very small amounts (B/C =
92/8, see [17]). This result is also confirmed by UV spectroscopic analysis; the UV spectrum
of acetonylpyridine exhibits a weak long-wavelength absorbance band, Ima x 380 nm, corresponding
to the ylide tautomer (ef. [24]).
In the case of 2-phenacylpyridine (II), the 170-NMR data also indicates that the B~C
equilibrium is shiftedalmost completely in favor of the OH-tautomer (Table i). The 14N-NMR
signal due to the enol tautomer is located at--131 ppm, i.e., 20 ppm upfield relative to
methoxypyridine. This is consistent with the a s s u m p t i o n s w h i c h w e r e discussed above concerning
modelling of the enol form B.
It was anticipated that introduction of a CN group in the s-position of the side chain
to acetonyl- and phenacylpyridine would lead to an increase in the relative stability of the
C tautomer [2, 3]. Indeed, the strong downfield shift of the 170-NMR signal for compound
VI (60 356 ppm), relative to acetonylpyridine (60 142 ppm), is consistent with a preponder-
ance of the ylide tautomer C at equilibrium. Thel~N-N~,fl~data are also consistent with this
conclusion. Comparison of the !4N-NMR chemical shift value of cyanoacetonylpyridine (6N--199
ppm) with the chemical shift values of model compounds indicates quite clearly that the
equilibrium has been shifted strongly in the direction of the NH-tautomer. In summary,
therefore, both the X4N and 170-NMR results point to a predominance of the C tautomer in
~he B~C equilibrium of 2-cyanoacetonylpyridine (VI); as a consequence, some of the literature
data [21, 23] concerning tautomerism in cyanoacetonylpyridines requires some discussion and
refinement.
Based on a study of a series of acylmethylpyridines, Klose and Uhlemann [22] concluded
that trifluoroacetonylpyridine III exists entirely in the form of its enol tautomer B. Our
14N- and 170-NMR results, on the other hand, indicate quite clearly that the introduction of
acceptor (electron withdrawing) substituents in the B-position of the side chain (as for
instance, in the transition from acetonylpyridine to monochloro- trichloro-, and trifluoro-
acetonylpyridine) leads to significant destabilization of the keto form A (see Table), and
thus increases the concentration of the ylide tautomer; in the case of the trihalo derivatives
III and'V, the ylide tautomers are the major constituents (present at equilibrium). On the
basis of the results obtained for compounds I-VI, it is evident that the position of the B~C
intrachelate equilibrium is very sensitive to the nature of substituents located in the side
chain, and that an increase in the acceptor properties of the substituents favors the NH form C.
We have demonstrated that the application of 14N- and 170-NMRmethods in tandem can yield
a great deal of information in studies of [i, 5]-sigmatropic tautomerism, and were able to
resolve in this manner contradictory literature data concerning the structure of acylmethyl-
pyridines. Further applications of this procedure should be beneficial in establishing the
structures of a wider and more important class of heterocyclic derivatives. Analysis of the
accuracy of this approach revealed that 14N- and 170-NMR studies of [i, 5]-tautomeric systems
which involve changes in the hybridization of the nitrogen and oxygen atoms during the course
of tautomer interconversions can generate quantitative measures of the tautomer composition
ratios.

EXPERIMENTAL
Natural isotopic abundance I%N- and 170-NMR spectra were recorded on Bruker CXP-300 (Mechan-
isms of Catalytic Reactions ResearchLaboratory, A c a d e m y o f Sciences of the USSR) and Bruker WH-
400 (Bruker Laboratory, Rheinst~tten, FRG) spectrometers at operating frequencies of 40.67 and
54.23 (for oxygen) and 21.67 and 28.89 MHz (for nitrogen), respectively. The concentrations
of chloroform solutions were 10-20%; the temperature 300~ The rate of spectral acquisition
was 20-50 Hz, the number of spectral acquisitions i0 4 -I0 5 (for 1 % N) and i0 5 -I0 6 (for 1 7 O).
Chemical shifts are reported relative to external standards, nitromethane (14N), and HzO (170);
negative signs correspond to downfield shifts (deshielding).
Compounds I, II [17], V1 [23], VII [25], VIII [2], IX [26], X [27], XVII [28], XVIII [13],
XXiI, iandXXIII [29] were all prepared according to literature methods. The synthesis of hydroxy-
phenylazines XIII and XVI will be described separately.
Acylmethylpyridines III and IV. These were obtained via reaction of picolyllithium with
the et--~-T esters of trifluoroacetic and chloroacetic acids [30], respectively, and were puri-
fied by preparative TLC on silica gel using chloroform-ethyl acetate (2:1). The yellow zones
were collected; these gave strong blue color reactions with aqueous ethanolic FeCI 3. The

638
yield of pure trifluoroacetonylpyridine III was 30%, mp II0-I13~ (after evaporation and
drying in vacuo) [30]. The yield of purified ehloroacetonylpyridine IV was 35%, The sub-
stance was characterized immediately after purification by TLC (Silufol UV-254, ethyl ether,
Rf 0.7) and P>~ spectroscopy, although because of its instability during storage (it decom-
poses within 2-3 days), detailed characterization was not possible. 14N-NM~ spectra of IV
were recorded immediately after its purification by TLC. PMR spectrum (CDCI3): 13.31 [0.69 H,
br s, OH, NH (B, C)], 8.47-6.80 [4H, m, pyridine ring protons (A, B, C)], 5.52 [0.72 H, s,
--CH= (B, C)], 4.19 [0.56 H, s, CH2CI (A)], 4.00 [1.44 H, s, CH2CI (B, C)], 3.96 [0.56 H, CHz,
(A)].
2-Trichloroacet0nylpyridine (V). This was prepared analogously to [31]o A solution con-
taining i0 g (0.i mole) triethylamine and 2.8 g (0.03 mole) 2-methylpyridine in 40 ml benzene
was treated stepwise under an argon stream at 0~ with a solution of 18.2 g (0.i mole) of tri-
chloroacetic anhydride in i0 ml of benzene. The reaction m i x t u r e w a s stirred at room temper-
ature for 3 h, and, after removal of the triethylamine hydrochloride salt precipitate, the
benzene solution was evaporated. The residue was extracted with (3 20 ml) of boiling
petroleum ether. After cooling, the trichloroacetonyl derivative V fell out of solution as
yellow crystals. Yield 2.1 g (30%), mp 160-163~ (from petroleum ether). Found, %: C 40.2;
It 2.3; N 5.7. CBHGCI3NO. Calculated, %: C 40.3; H 2.5; N 5.9.
LITERATURE CITED
i. O. P. Petrenko, S. F. Bychkov, V. V. Lapachev, and V. P. Mamaev, Izv. Akad. Nauk SSSR,
Ser. Khim., No. 5, 1166 (1986).
2. V. V. Lapachev, O. A. Zagulyaeva, O. P. Petrenko, S. Fo Bychkov, and V. P. Mamaev, Khim.
Geterotsikl. Soedin., No. 6, 827 (1984).
3. V. P. Mamaev and V. V. Lapachev, Soviet Scientific Reviews (Chem. Rev.), Harwood Acad.
Publ. (1985), Vol. ~, p. I.
4. N. S. Zefirov and S. S. Trach, Zh. Org. Khim., 12, 697 (1976).
5. R. Woodward and R. Hoffman, Conservation of Orbital Symmetry [Russian translation], Mir,
Moscow (1971), p. 207.
6. P. S. Brown, J. Amer. Chem. Soc., 99, 5497 (1977).
7. R. Roussel, M. O. Guerreno, P. Spegt, and J. C. Galin, J. Heterocycl. Chem., 19, 785 (1982)o
8. W. G. Klemperer, Angew, Chem., Inter. Ed. Engl., 17, 246 (1978).
9. M. Witanowski, L. Stefaniak, and H. Januszewski, in: Nitrogen NMR (M. Witanowski and
G. A. Webb, eds.), Plenum Press, N.Y. (1976), p. 163.
10. T. Amour, M. Burgar, B. Valentine, and D. Fiat, Jo Amer. Chem. Soc., 103, 1128 (1981).
ii. L. Stefaniak, Tetrahedron, 32, 1065 (1976).
12. V. V. Lapachev, I. Ya. Mainagashev, S. A. Stekhova, M. A. Fedotov, V. P. Krivopalov, and
V. P. Mamaev, Zh. Org. Khim., in preparation.
13. O. A. Zagulyaeva and V. P. Mamaev, Izv. SOAkad. Nauk SSSR, Ser. Khim. Nauk, No. 5, 55 (1967).
14. R. Mondelli and L. Merlini, Tetrahedron, 22, 3253 (1966).
15. Handbook of Chemistry, B. F. Nikol'skii (editor), Goskhimizdat, Moscow (1962), Vol. l,p. 97.
16. A. N. Zaidel', Errors in Physical Measurements [in Russian], Nauka, Leningrad (1974).
17. R. P. Cassity, L. T. Taylor, and J. F. Wolfe, J. Org. Chem., 43, 2286 (1978).
18. K. R. Wurstharn and E. H. Sund, J. Heterocycl. Chem., 9, 25 (1972).
19. R. F. Branch, A. H. Beckett, and D. B. Cowell, Tetrahedron, 19, 401 (1963).
20. G. Klose and E. Uhlemann, Tetrahedron, 22, 1373 (1966).
21. M. L. Stein, F. Manna, and C. C. Lombardi, J. Heterocycl. Chem., 15, 1411 (1978).
22. G. Klose and E. Uhlemann, Nuclear Magnetic Resonance in Chemistry (B. Pesce, editor),
Academic Press,.New York (1965), p. 237.
23. C. D. Gutsche and H. W. Voges, J. Org. Chem., 32, 2685 (1967).
24. V. V. Lapachev, O. A. Zagulyaeva, andV. P. Mamaev, Khim. Geterotsikl. Soedin.,No.3, 395 (1977).
25. I. E. Douglass and I. M. Wesolosky, J. Org. Chem., 36, 1165 (1971).
26. O. A. Zagulyaeva, O. A. Grigorkina, V. I. Mamatyuk, and V. P. Mamaev, Khim, Geterotsikl.
Soedin., No. 3, 397 (1982).
27. V. V. Lapachev, O. A. Zagulyaeva, and V. P. Mamaev, Dokl. Akad. Nauk SSSR, 236, No. i,
113 (1977).
28. I. L. Knunyants and Go G. Yakobson (editors), Synthesis of Organofluorine Compounds [in
Russian], Khimiya, Moscow (1973), p. 60.
29. M. I. Weiss and C. R. Hauser, J. Amer. Chem. Soc., 71, 2023 (1949).
30. T. F. McGrath and R. Levine, J. Amer. Chem. Soc., 77, 3656 (1955).
31. L. P. Prikazchikova, B. M. Khutova, and E. A. Romanenko, Khim. Geterotsikl. Soedin., No.
9, 1256 (1978).

639
CONDENSATION OF 4-AZAFLUORENE WIll y-BUTYLENE GLYCOL AND GLYCERIN

N. S. Prostakov, V. P. Shalimov, UDC 547.424.23'426.1'828.07:542.953

Galo B. Montenegro Cordova and E. V. Kruglyak

1,4-Di(4-azafluoren-9-yl)butane and 9-(8-hydroxybutyl)-4-azafluorene were obtained

by condensing 4-azafluorene with y-butylene glycol. From the first of these products,
1,4-di(7-aza-3-oxo-l,2,3,10b-tetrahydrofluoranthen-10b-yl)butane was synthesized by
a series of successive transformations (cyanoethylation, hydrolysis, dehydrocycliza-
tion). In the condensation of 4-azafluorene with glycerin, 1,2,3-tri(4-azafluoren-
9~yl)propane was obtained.

In continuation of the work in [i] on the synthesis of heterocyclic compounds containing

two azafluorene fragments bound by a polymethylene chain, and also of9-w-hydroxyalkyl de-
rivatives of azafluorenes, we studied the condensation of 4-azafluorene (I) with y-butylene
glycol, which was carried out at 230~ in the presence of s o d i u m . From the reaction products,
two compounds were chromatographically isolated in more than 70% overall yield: 1,4-di(4-
azafluoren-9-yl)butane (II) and 9-(~-hydroxybutyl)-4-azafluorene (III). The second compound
quantitatively predominates. With increase in the amount of y-butylene glycol used in the
reaction, the yield of compound III increases and the yield of compound II decreases.
The chemical reactions of compounds II and III carried out serve as a proof for their
structure. The new compounds are also interesting as potentially biologically active compounds.
From alcohol III, 9-(~-chlorobutyl~)-4-azafluorene (IV) and 9-(~-phenylcarbamoyloxybutyl-
4-azafluorene) (V) were obtained in quantitative yields.
In the cyanoethylation of compound II carried out in the presence of an alcoholic so-
lution of ethoxytrimethylphenylammonium (the Rodionov catalyst, cR), a dinitrile, 1,4-di[9-
(B-cyanoethyl)-4-azafluoren-9-yl]butane (VI) was obtained, which was then converted into a
dibasic acid, !,4-di[9-(B-carboxyethyl)-4-azafluoren-9-yl]butane (VII).

I I ...... J I~I I[ il ....I I ii

~[" " (fTIz(CI]~,)~CD':, ~'" ']I }]" C.II2(CJl2)2(~Ilaf)} I
I I[ IJl

I
Ii l- rl ]:t
. . . . . . N

!,..j { ........ I---.,, jrl } i.] I.i i--I

9 ' "" ":'" " "' "'~"" ""' "' :" '1" "" "" 9 ~ """ I| ~"CHI(~;~I2) I

0"" "" V]!I "" ".'O VI.VII JV,V CIIzI

IV R=CI; V R=OCONHCsHs; VI RI=CN; VII RI=COOH

In intramolecular dehydrocyclization of the dibasic acid VII, carried out by the action
of polyphosphoric acid, 1,4-di(7-aza-3-oxo-l,2,3,10b-tetrahydrofluoranthen-10b-yl)butane
(VIII) was obtained in a yield of more than 20%. It was a light-yellow crystalline compound,
melting above 300~
A similar condensation of azafluorene I with glycerin was carried out.

P. Lumumba Peoples' Friendship University, Moscow 117923. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 6, pp. 810-812, June, 1986. Original article submitted
January 24, 1985.

640 0009-3122/86/2206-0640512.50 9 1986 Plenum Publishing Corporation

 I . _ ~ II Ct4, CM.-- CH 2

[1

I I "

IX

1,2,3-Tri(4-azafluoren-9-yl)propane (!X) was o b t a i n e d i n a y i e l d of 15%, and was i s o l a t e d

i n t h e form o f c o l o r l e s s h i g h - m e l t i n g c r y s t a l s .
The s t r u c t u r e o f t h e compounds s y n t h e s i z e d was c o n f i r m e d by s p e c t r a l and e l e m e n t a l
analysis data.

EXPERIMENTAL
The IR spectra of the compounds were run on a UR-20 spectrophotometer in KBr tablets.
The electronic absorption spectra were obtained on a Specord UV-VIS spectrophotometer in
ethanol. The course of the reactions, the individuality and the separation of the compounds
were controlled by TLC on aluminum oxide, grade II of activity. The molecular weights were
determined on a LKV-2091 chromato-mass-spectrometer.
1,4-Di(4-azafluoren-9-yl)butane (II) and 9-(~-hydroxybuty!)-4-azafluorene (IIl). A 0.58
g (25 mmoles) portion of sodium is dissolved in 1.62 g (18 mmoles) of 1,4-butanediol, 1 g
(5.9 mmoles) of azafluorene I is added, and the mixture is heated for 22 h at 230~ When
cool, 20 ml of water are added, and the mixture is extracted by chloroform. The residue after
the distillation of chloroform is chromatographed, using a 3:1 mixture of ether and hexane as
eluent. Yield, 0.51 g (22%) of compound II, mp 138-140~ (from hexane). IR spectrum: 3065,
3010 (Car--H), 2950, 2930, 2860 cm -l (Cal-~{). Found, %: C 86.7; H 5.9; N 7.0; M + 388.
C28H24Ne. Calculated, %: C86.6; H 6.1; N 7.2; M 388. The elution is then continued with
e t h e r . Yield 0.7 g (49%) of alcohol III, mp 123-124~ (from a 2:1 hexane--benzene mixture.
IR spectrum: 3225-3235 cm -I (OH). Found, %: C 80.6; H 7.1; N 5.8; M + 239. CI~HI?NO. Calcu-
lated, %: C 80.3; H 7.1; N 5.8; M 239.
97(6-Chlorobutyl)-4-azafluorene (IV). A solution of i0 ml of thionyl chloride in 5 ml
of benzene is gradually added to a solution of 0.4 g (1.6 mmole) of alcohol III in 20 ml of
anhydrous benzene. The mixture is heated at the boiling point for 5 h. After distillation of
benzene and excess thionyl chloride, 20 ml pf water and sodium carbonate are added to pH i0.
The reaction products are extracted by ether. Ether is distilled off and the residue is
passed through a chromatographic column (eluent, 3 : i m i x t u r e of ether and hexane). Yield,
0.35 g (81%) of chloride IV in the form of an oily, colorless compound, IR spectrum: 3060, 3030
(Car--H), 2999, 2950, 2870 cm -I (CaI--H). Found, %: N 5.4; M + 2 5 7 . CI~HI6CIN. Calculated, %:
N 5.4; M 257.
9-(~-Phenylcarbamoyloxbutyl)-4-azafluorene (V). A mixture of 0.2 g (0.8 mmole) of alco-
hol III and 0.2 g (1.6 mmole) of phenyl isocyanate in 20 ml of anhydrous benzene is heated
for 3 h at 60~ After the distillation of benzene, the residue is chromatographed, using a
3:1 mixture of benzene and hexane as eluent. Yield, 0.22 g (74%) of compound V in the form
of an oily colorless compound. Found: M + 358. C23H22N202. Calculated, %: M 358. Hydro-
chloride: mp 95-96~ Found, %: N 6.8. C23H22N202-HCI. Calculated, %: N 7.1.
1,4-Di[9(B-cyanoethyl)-4-azafluoren-9-yl)]butane (VI). In the reaction of 0.69 g (1.7
m m o l ~ of compound IY, 4.8 g (90 mmoles) of acrylonitrile, 0.i ml of cR and 30 ml of anhydrous
toluene are used. The mixture is stirred for 3 h at 60~ The toluene solution is shaken with
water and dried over potassium carbonate. After the distillation of the solvent and re-
crystallization, 0.64 g (73%) of compound VI is isolated, mp 214-215~ (from 1:3 hexane-
benzene mixture). IR spectrum: 3072 (Car--H), 2943, 2870 (CaI--H), 2254 cm -I (CN). UV spectrum,
Xma x (log a): 262 (4.26) ; 278 (4.14); 286 (4.29); 305 nm (4.44)~ Found, %: C 82.4; H 5.8;
Nll.5; M+494. Ca4H~0N4. Calculated, %: C 82.6; H 6.0; N 11.3; M 494.
1,4-Di[9-(B-carboxyethyl)-4-azafluoren-9-yl]butane (VII). A solution of 1.75 g (3.5 mmoies)
of dinitrile VI, 2.8 g (50 mmoles) of potassium hydroxide in 35 ml of ethanol is boiled for
18 h. The mixture is neutralized by 70% sulfuric acid to pH 7. The precipitate is washed
with water and dried. Yield i.i g (58%) of dibasic acid VII, mp 222-224~ IR spectrum: 3500
m, 3200, 2550 cm -I (OH in COOH). UV spectrum, %max (log s): 208 (4.68); 258 (4.24); 279
(4.08); 288 (4.28); 309 (4.51); 3.14 nm (4.54). Found, %: N 5.2; M + 532. Ca4H32N20~. Calcu-
lated, %: N 5.3; M 532.
641
 1,4-Di(7-aza-3-oxxo-l,2,3,10b-tetrahydr@f!uoranthen-10b-yl)butane(VIll). A mixture of
i g (1.88 mmole) of diaeid VII and 64 g of polyph0sphoric acid are allowed to stand for 2 h
at 160~ The reaction mixture is poured onto ice (150 g) and neutralized by ammonia. The
mixture is extracted by chloroform, and the extract is dried over potassium carbonate. After
the distillation of chloroform, the residue is chromatographed, using ethyl acetate as eluent.
Yield, 0.21 g (23%) of compound VIII, light-yellow crystals, mp 304-305=C (from a 1:2 benzene--
hexanemixture). IR spectrum: 2944, 2875 (Cal-~{), 1690 cm -I (CO). UV spectrum, ~max (log ~):
207 (4.69); 262 (4.48); 284 (4.14); 294 (4.25); 326 nm (4.19). Found, %: C 82.1; II 5.8;
N 5.3; M + 496. C3~HzsN202. Calculated, %: C 82.2; H 5.6; N 5.6; M 496.
1,2,3-Tri(4-azafluoren-9-yl)propane (IX)~ A 0.14 g portion (6 mmoles) of sodium is
dissolved in 3 g (32 mmoles) of glycerin, i g (5.9 mmoles) of azafluorene I are added, and
the mixture is heated for 24 hours at 230~ When cool, 20 ml of water are added, and the mixture
is extracted by chloroform. After distillation of chloroform, the residueis chromatographed,
using ether as eluent. Yield of compound IX 15%, mp 277-278~ (from a 2:1 hexane--benzene
mixture). IR spectrum: 3050 (C~r--H), 2910, 2860 (Cal--H), 1580 m, 1570 m, 1560 m, 1500 w
(C=C, skeleton), 1450, 1410 cm- (CaI--H), 740 cm -I (Car-~{). UV spectrum, %max (log ~): 200
(4.93); 255 (4.55); 282 (4.4); 288 (4.57); 314 nm (4.76). Found, %: C 86.5; H 5.4; N 7.9;
M + 539. C39HegN3. Calculated, %: C 86.3; H 5.3; N 7.7; M 539.

LITERATURE CITED
i. N. S. Prostakov, V. P. Shalimov, and Galo B. Montenegro Cordova, Khim. Geterotsikl.
Soedin., No. ii, 1525 (1984).

SYNTHESIS STARTING FROM 3-METHYL-2-PHENYL,5-(3-METHYL-2-

PHEIPfL-3,4-DEHYDROPIPERIDYL-6)PYRIDINE.
2-PHENYLDINICOTINIC AND 4-AZAFLUORENONE-2-CARBOXYLIC ACIDS

N. S. Prostakov, I. V. Eliseeva, UDC 547.829'826.2'836:543.422

H. Bu Habib,
/
L. M. Kirillova,
and A. E. Aliev

N-Methyl (ethyl, benzoyl, trifluoroacetyl)-substituted 3-methyl-2-phenyl-5-(3'-

methyl-2'-phenyl-3',4'-dehydropiperidyi-6')pyridines anddi(N-oxide) of the corre-
spondingly substituted ~,B-dipyridyl were prepared. A method for synthesizing 2-
phenyldinicotinic a c i d w a s developed. Cyclodehydration of thisacid gave 4-aza-
fluorenone-2-carboxylic acid. Transformations of this acid were carried out with
respect to two functional groups.

We used the structural analog of anabasine, 3-methyl-2-phenyl-5-(3'-methyl-2'-phenyl-3',4'-

dehydropiperidyl-6')pyridine ~ I ) , i n t h e syntheses of its derivatives, potentially physiolog-
ically active compounds, for the preparation of 2-phenyldinicotinic acid, and also for develop-
ing a new path for building up of a 4-azafluorene system.
The syntheses which we carried out served as an additional proof of the structure of ~-
dehydropiperidyl-B-pyridine I, described in [I]; its N-alkyl substituted derivatives were ob-
tained by two paths. 3-Methyl-2-phenyl-5-(l',3'-dimethy!-2'-phenyl-3',4'-dehydropiperidyl-6')
pyridine (II) was synthesized by the Leuckart method. The N-ethyl-substituted derivative III
was obtained by reducingthe analogous N-acetyl-substituted derivative IV with lithium aluminum
hydride [i].

P. Lumumba Peoples' Friendship University, Moscow 117923. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 6, pp. 813-817, June, 1986. Original article submitted
l~arch 12, 1985.

642 0009-3122/86/2206-0642512.50 9 1986 Plenum Publishing Corporation

 TABLE I. IR S ~ectra of N-Acyl-~-dehydropiperidyl-$- pyridine
, , ,,,

Frequencyof main bands,"~=~

COm-pound ""'....
[ R, C-F sttctchin~
C-Harom C-Halip h C=O vibrations (po~F-
sub~t.)
IV CH3 3065, 3035 3000--2870 1643
V C8H5 3063, 3032 2990--2850 1643
VI CFa 30....3040 3000--2850 1683--1702 1210--1226
Csp~t.)

/ I VII

. . . . . . . . , _ ./. .... ........ ,f'

....... , . o . . . .

IV-Vl Viii

[I R=CH3; Ill P=C2H~; IV RI=CHa; V R~=C6H~; VI RI=CF3

In the benzoylation of compound I according to Schotten-Baumann, 3-methyl-2-phenyl-5-(3'-

methyl-2'-phenyl-l'-benzoyl-3',4'-dehydropiperidyl-6')pyridine (V) is formed, and when treated
with trifluoroacetanhydride, N-trifluoroacetyl-substituted pyridine VI is obtained. The IR
spectra of compounds V and VI are similar to the IR spectrum of the N-acetyl derivative IV,
already obtained in [i] (Table I). The presence of split bands in the IR spectrum of derivative
VI indicates the presence of two rotation isomers, as revealed by means of a PMR spectrum for
compound IV [i]. For the trifluoro-substituted amide VI, the carbonyl group band is shifted
by 40-50 cm -I, compared to the shift of an analogous band of amides IV and V, which is charac-
teristic of these compounds [2].
As N-oxides of 2-alkylpyridines have different pesticidal activity [3], we synthesized the
di(N-oxide) VIII from 3-methyl-2-phenyl-5-(3'-methyl-2'-phenylpyridyl-6')pyridine (VII), already
obtained from the compound I in [i]. It is a high melting compound, which is practically in-
soluble in organic solvents.
From compound I, the previously unknown 2-phenyldinicotinic acid IX was obtained. De-
rivatives of this acid, being analogs of nicotinic acid, may be of a pharmacological interest,
while the acid itself can be used as a starting compound in the synthesis of substituted 4-
azafluorene.
In the oxidation of ~-dehydropiperidyl-B-pyridine I by potassium permanganate in water at
IO0~ acid IX is formed in a yield of less than 2%. Under these conditions, according to TLC
data, about 20% of the initial compound I converts into dipyridyl VII, while a considerable
part of the starting compound remains unchanged.
By oxidizing compound I under the same conditions and by adding a catalytic amount of acetone
(~0.6% of the volume of water), acid IX was iso!as in a yield of 74%, in the form of high-
melting crystals, which are insoluble in ether, ethyl acetate, chloroform, but are readily
soluble in alcohol and acetone.

643
 "N ' (',~lI< :N " "l,',lllf, f:~H~ "'N"
IX ~,1 XI

""/'~'11 ...... ' J coo. "J coo.

0
Xl|,'~lll XI",'
XII It: ll; XIH R "C:,II<

The d i b a s i c a c i d IX was i d e n t i f i e d by i t s h y d r o c h l o r i d e and d i m e t h y l e s t e r X. In the

r e a c t i o n of t h e l a t t e r w i t h h y d r a z i n e h y d r a t e , a c c o r d i n g t o t h e d a t a o f e l e m e n t a l a n a l y s i s and
m a s s - s p e c t r o m e t r i c a n a l y s i s , t h e r e a c t i o n p r o c e e d s a t one e s t e r g r o u p . Because of s t e r i c
h i n d r a n c e s by t h e p h e n y l . s u b s t i t u e n t a t t h e 2 - p o s i t i o n , i t can be assumed t h a t t h e r e a c t i o n
p r o c e e d s a t t h e e s t e r g r o u p a t t h e 5 - p o s i t i o n , and t h e compound o b t a i n e d i s a h y d r a z i d e o f
2-phenyl-3-methoxycarbonyl-5-pyridinecarboxylic acid (XI).
The s t r u c t u r e o f 2 - p h e n y l d i n i c o t o n i c a c i d IX p r e d e t e r m i n e s t h e p o s s i b l e s y n t h e s i s o f 4 -
azafluorenone-2-carboxylic acid (XII). I t i s i m p o r t a n t t h a t a f u n c t i o n a l l y s u b s t i t u t e d 4-
a z a f l u o r e n e c a n be o b t a i n e d by t h i s p a t h .
A z a f l u o r e n o n e c a r b o x y l i c a c i d X t I i s formed i n a N50% y i e l d i n t h e c y c l o d e h y d r a t i o n o f
a c i d IX, when t h e l a t t e r i s h e a t e d w i t h p o l y p h o s p h o r i c a c i d . A c i d X I I was i s o l a t e d i n t h e
form o f h i g h - m e l t i n g y e l l o w c r y s t a l s , w h i c h a r e p r a c t i c a l l y insoluble in organic solvents, a
characteristic property for these acids [4]. Esterification of a c i d X I I gave i t s e t h y l e s t e r
XIII.
The first representative of the hydroxy acids in the 4-azafluorene series, 9-hydroxy-2-
carboxy-4-azafluorene (XIV), is obtained by reducing compound XII by sodium borohydride.
Hydroxy acid XIV is readily oxidized in an aqueous medium in air into the initial keto acid
XII.
Thus, two paths of transition from B-picoline to compounds with a 4-azafluorene structure
have been developed. In the phenylation of B-picoline two main compounds are formed, 3-methyl-
2-phenylpyridine [5 ] and 3-methyl,2-phenyl-5- (3 '-methyl-2 '-phenyl-3 ', 4 '-dehydropiperidyl-6 ') -
pyridine (I) [i]. We converted the first of these compounds by catalytic dehydrocyclization
into 4-azafluorene [6], which was then oxidized to 4-azafluorenone. The second path for
building up the azafluorene system, i.e., the oxidation of compound I to acid IX and its
intramolecular cyclodehydration to azafluorenonecarboxylic acid has been described above.

EXPERIMENTAL
The IR spectra of compounds IV-VI, VIII, IX, and XIV were run on a Specord UR-75 spectro-
photometer in KBr tablets. The PMR spectra of compounds II, III, and XIII were recorded on
a Bruker WP-80 spectrometer (80 MHz) in CDCI3, and of compound X on a Tesla BS-487C spectro-
meter (60MHz) inCCl 4. The mass spectra were obtained on a Mx-i303 mass spectrometer with a
direct introduction of the sample into the ionic source at a ionization voltage of 70 V.
3-Methyl-2-phenyl-5-(l',3'-dimethyl-3',4'-dehydropiperidyl-6')pyridine (II)~ A solution
of i g (3 n~noles) of compound I and 4 ml of 40% formalin in 15 ml of formic acid is boiled for
i h (the end of the reaction is controlled according to TLC and cessation of gas evolution).
The reaction mixture is evaporated in vacuo to dryness. The residue (i g) is pruified on a
chromatographic column with aluminum oxide, using ether as eluent. Ether is distilled off, and
the oily residue is crystallized in 5 ml hexane. After prolonged standing at --5~ 0.48 g (45%)
of compound II separate, mp 127-128~ PMR spectrum: 1.36 (3H, s, 3'-CH3), 1.93 (3H, s, N-CH3),
2.36 (3H, s, 3-CH~), 2.38 (2H, m, 5'-CH2), 3.47 (IH, d.d, 6'-CHCsH4N), 3.66 (IH, s, 2'-CH-
(C~Hs)-), 5.61 (IH, s, 4'--CH~), 7.63 (IH, d, 4-H), 8.48 (IH, d,6-H), 7.3-7.5 ppm(10H, m,
aromatic protons). Found, %: C 8 4 . 5 ; H 7.2; N 7.7; M + 354. C25H26N2. Calculated, %: C 84.7;
H 7.3; N 7.9; M 354.
3-Methyl-2-phenyl-5-(3-methyl-l-ethyl-2-phenyl-3,4-dehydropiperidyl,6)pyridine (III).
Lithium aluminum hydride (i g, 28.6 mmoles) is added in portions in the course of 5 h to a
boiling solution of i g (2.6 mmoles) of acetyl derivative IV [i] in 40 ml of absolute

644
tetrahydrofuran. A 50 ml portion of water is added, and the mixture is filtered. The mother
liquor is extracted by three 2 0 m l portions ofchloroform. After the distillation of chloro-
form, the residue is dissolved in ether and passed through a chromatographic c o ! u m n w l t h
aluminum oxide. The eluent is distilled off and the oily residue is crystallized from 5 ml of
hexane. After standing for 12 h at --5~ 0.4 g (42%) of compound III separate, mp 97-99~
PMR spectrum: 0.77 (3H, t, N-CH2-CH3), 2.47 (2H, q, N-CH2-CH3), 1.39 (3H, s, 3'-CH3), 2.37
(3H, s, 3-CH3), 2.42 (2H, m, 5~-CH2), 3.86 (IH, d~d,6'-CHCsCH4N), 4.19 (IH, s, 2'-CH(C6Hs)-),
5.57 (IH, s, 4'--CH----),7~65 (IH, d, 4-H), 8.52 (IH, d, 6-H), 7.3-7.6 ppm (10H, m, aromatic
protons). Found, ~. ~" N 7.5%; M + 368 C2~HesN2. Calculated, %: N 7.6; M 368.
3-Methy~-2-pheny~-5-(3-methy~-2-pheny~-~-benz~y~-3,4-dehydr~piperidy~-6)pyridine (V).
A 6 g portion (4.1 mcnoles) of benzoyl chloride and i00 ml of a 10% solution of potassium
hydroxide are added with stirring to a solution of 2 g (5.9 mmoles) of compound I in 80 ml
of dry benzene. The mixture is stirred for 2 h, the benzene layer is separated, and benzene is
distilled off. The residue dissolved in a minimal amount of chloroform is deposited on
aluminum oxide (H 15 cm, d 4 c m ) a n d eluted with a i:I hexane-ether mixture. The eluent is
distilled off and the residue is crystallized from heptane. Yield, 1.7 g (65.4%) of colorless
crystals of compound V, mp 139.5-140~ Found, %: C 83.8; H 6.4; N 6.2. C~IH2sN20. C a l c u -
lated, %: C 83.8; H 6.3; N 6.3.
3-Methy-2-pheny-5-(3-methy-2-pheny--trifuracety-3,4-dehydrpiperidy-6)pyridine
(Vl). % mixture of I g (2~94 m m o l e s ) o f compound i and 0~82 ml (6 mmoles) of trif!uoroacetie
anhydride is boiled for 2 h. The excess anhydride is distilled off in vacuo at room temperature.
The residue is dissolved in a mixture of acetonewith chloroform, and the solution is deposited on
a chromatographic column with aluminum oxide (H 20 cm, d I cm). The elution is carried out
with chloroform. After the distillation of the eluent, the residue is crystallized from hep-
tane. Yield, 0.75 g (62.5%)of colorless crystals of compoundVl, mp !33-134~ Found, %:
C 71.5; H 5.5; N 6.4. C2GHe3F3N20. Calculated, %: C ~1.6; II 5.3; N 6.44
3-Methyl-2-phenyl-5-(3-methyl-2-phenylpyridyl-6)pyridine Di(N-oxide) (VIII), A solution
of 1 3 g (31w of dipyridyl VII [ l ] a n d 3 ml of 27% hydrogen peroxide in 45 ml of
glacial acetic acid is held at 90~ for i0 h. A I00 ml portion of water is added and the
mixture is left to stand for another 12 h. The precipitate is filtered to yield 1.02 g (73%)
of di(N-oxide) VIII, light cream-colored crystals, mp 3 2 7 = C ( f r o m a 1:2 acetic acid-water
mixture). IR spectrum: i283 cm -i (N-~O). Found, %: N 7.3; M+ 368. C24H20N202. Calculated,
%: N 7.6; M 368.
2-Phenyldinicotlnic Acid (IX). In the reaction 5 g (15 mmoles) of compound I, 750 ml of
water'and 5 ml of acetone are used7 The mixture is heated to boiling, and 47 g (300 m moles)
of potassium permanganate are a d d e d i n portions of 3-5 g in the course of 15 h, with vigorous
stirring. The last portion of the oxidizing agent deco!orizes a f t e r 5 h. Manganese dioxide
is filtered and washed ~ith i00 m l o f water. The aqueous solution is evaporated to a volume
of 150 m l . To the residual solution, 40 ml of chloroform are added, and then, with vigorous
stirring, 18% hydrochloric acid to pH 3. The precipitate that separates is filtered and
dried. Yield, 2.1 g of acid IX. By concentration of themother liquor, an additional 0~54 g of
compound is isolated(overall yield 74%). Acid IX -- colorless crystals, mp 269-273~ (from
water). IR spectrum: 2540 (br.), 1910 (br.), 1720, 1302-1264 c ~ i (split). Found, %: C 63~8;
H 4.1; M + 243. CI3H~NO4. Calculated, ~: C 64.2; H 3.7; M 243~
Hydrochloride of acid IX -- colorless crystals, mp 266-268~ (from alcohol). Found, %:
CI 12.5; N 4 . 8 . CI3HgNO4.HCI. Calculated, %: CI 12.7; N 5.0.
After evaporation of the chloroform mother liquid, 1.15 g of benzoic acid are isolated,
mp I18-122~ (from water).
2-Pheny!-3,5-di(methoxycarbonyl)pyridine (X). In the reaction 3~0 g (12.3 mmoles) of
acid IX, 20 ml of absolute methanol and 3 ml Of sulfuric acid are u s e d . The mixture is boiled
for 15 h, and after adding 50 ml of water, is neutralized by sodium carbonate to pH ~,9 and
extracted by ether. After distillation of ether, the residue is ehrom@tographed on aluminum
oxide, using ether as eluent. From 3.5 g of an oily substance remaining after the dis-
tillation of the eluent, after crystallization in 5 ml of hexane and prolonged standing at
--5=C, 2.68 g (80.2%) of diester X are obtained, colorless crystals, mp 50-50.50C (from hexane).
PMR spectrum: 3.7 (3H, s, CH3) , 3.98 (3H, s, CH3), 8~ (IH, d, J31 = 3 Hz, 4-H), 9.28 (I}I,
d, Jl3 = 3 Hz, 6-H), 7.26-7.66 ppm (5H, m, aromatic protons). Found, %: C 66.2; H 4.6; N 4.9;
M + 271. CIsHI~NO4~ Calculated, %: C 66.4; H 4.8; N 5.2; M 271.

645
 ~l-3-methoxycarbonyl-5-pyridinecarboxylic Acid Hydrazide (XI), A solution of 0.05
g (0,18 - ~ o ~ ~ T X and 0.5 m_ o~ ydrazine y ra~e in ~0 ml of ~hanol is boiled for
i h. A I0 ml portion of water is added. The mixture is allowed to stand for 3 days at--5~C
to yield 0,024 g (48%) of compound XI, pale-yellow crystals, mp 144-146~ (from 50% aqueous
ethanol). Found, %: N 15.4; M + 271. CI4HI~N~03. Calculated, %: N 15.5; M 271.
4-Azafluorenone-2-~lic Acid (XII). A mixture of 1 g (4.1 mmoles) of diaeid IX and
I0 ml of po!yphosphorlc acid is gradually heated to 100~ The homogeneous mixture is then
.held for i0 h ~at 210-250~C. ~ e n cool, the mixture is poured into 100ml of water. The pre-
cipitate (i.I g) is crystallized in 400 ml of 80% alcohol. Yield 0.44 g (47.8%) of compound
XII, greenlsh-yellow needle-like crystals, mp 305~ IR spectrum: 2500 (br,), 1910 (hr,), 1732-
1720 (split.), 1265 cm -I. Found, %: C 69,1; H 3,3; N 5.9; M 225. CI3H?N03. Calculated, %:
C 69.3; H 3.1; N 6.2; M 225.
2-Ethoxycarbonyl-4-azaf!uorenone (XIII). A. A mixture of 0.26 g (1.16 mmole) of acid
XII and 1.5 ml of sulfuric acid in 20 ml of absolute ethanol is boiled for 20 h. When cooi, the
mixture is poured into 40 ml of water to yield 0.19 g of ester XIII. The mother liquid is
neutralized with sodium carbonateto pH 7 to yield additional 0.031 g of compound XIII,
yellow needle-like crystals, mp 130-131~ (from petroleum ether). Overall yield 76%. PMR
spectrum: 1.44 (3H, t, CH3) , 4.45 (2H, q, CH2), 7,52 (IH, t, 7-H), 7.66 (!H, t, 6-H), 7.78 (IH,
d, 8-H), 7.93 (!H, d, 5-H), 8.45 (iH, d, l-H), 9.25 ppm (!H, d, 3-H). IR spectrum: 1725 (C=O),
1250, 1122-1138 cm-I (split.). Found, %: C 70.9; H 4.4; N 5.3; Me. 253. CIbHIIN03. Calcu-
lated,%: C 71.1; ff 4.4; N 5.5; M 253.
B. A mixture of 1.6 g (6.6 mmoles) of acid IX and 20 ml of polyphosphoric acid is held
for 15 h at 230-250~ When cool, the mixture is poured into 150 ml of water. The precipi-
tate that forms (2.6 g after drying) and 3 ml of sulfuric acid are boiled for 12 h in 65 m!
of absolute ethanol. The reaction mixture is poured into 200 ml of water, neutralized with
sodium carbonate to pH 9, and extracted by ether. After distillation of ether, the residue
is chromatographed (aluminum oxide, eluent, a i:I hexane-ether mixture) to yield I.i g (66%
based on acid IX used) of ester XIII, mp 130-131~ (from hexane).
9-1~ydroxy-2-carboxy-4-azaf!uorene (XIV). Sodium borohydride (i g) is added in 0.I g
portions, in the course of 3 h, to a vigorously stirred suspension of 0.14 g (0.6 m mole) of
acid XII in 15 ml of water. The mixture is then heated for 30 min at 70-80=C and 18% hydro-
chloric acid is added to pH 6. The~precipitate formed is washed on the filter to neutral
reaction with water. Yield, 0.088 g(63%) of hydroxy-acid XIV, pale-cream-colored crystals,
mp 235-237aC (from a 3:1 ethyl acetate-hexane mixture). IR spectrum: 3350 (OH), 2500-3080,
1700 (C=O), 1160, 935 cm -~. Found, %: N 5.9; M+ 227. C!~HgN03. Calculated, %: N6,2%; M227.

LITERATURE CITED
i. N. S. Prostakov, H. Bu Habib, V. A. Rezakov, A. A. Fomichev, L. M. Kiriilova, and V. K,
Shevtsov, Khim. Geterotsikl. Soedin., No. 8, 1115 (1984).
2, K. Nakanishi, Infrared Spectra and Structure of Organic Compounds [Russian translation],
Mir, Moscow (1965), p. 59.
3. G. V. Protopopova, A. F. Pavlenko, V. S. Petrenko, T. I. Cherepenko, G ~. V. Shurubura, and
V. P. Kukhar', AllUnionConference on Chemical Plant Protecting Agents. Section I.
Summaries of Lectures [in Russian], Ufa (1982), p. 35.
4. N. S. Prostakov, A. A. Obynochnyi, L.A. Gaivoronskaya, L. M. Kirillova, and V. P.
Zvolinskii, Khim. Geterotsikl. Soedin., No. 12, 1664 (1972).
5. R. A. Abramovitch, Giam Chao Seng, and A. D, Notation, Canad. J. Chem., 38, 761 (1960).
6. N. S. Prostakov, A. V~ Varlamov, G. A. Vasil'ev, O. G. Kesarev, and G. A. Urbina, Khim.
Geterotsikl. Soedin., No. i, 124 (1977).

646
SYNTHESIS OF METHYL ESTERS OF 6-DIALKYLAMINO-2-(CARBETHOXY)-
METHYLTHIOPYRIMIDINE-4-CARBOXYLIC ACIDS

S. P. Tumkyavichyus and P. I. Vainilavichyus UDC 547.854.07

A preparative method is proposed for the synthesis of methylesters of 6-dialkylamino-

2-(carbethoxy)methylthiopyrimidine-4-carboxylic acids form the butyl ester of orotic
acid.

2-Pyrimidylthioacetic acid derivatives, having an amino group in the4-position of the

pyrimidine ring and chlorine [i] or methyl [2] at position 6, possess hypolipidemic activity.
However, the dependence of this activity on the nature of the 6-substituent has been little
investigated. Hence we have studied methods of synthesis of methyl esters of 6-dialkyl-
amino-2(carbethoxy)methylthiopyrimidine-4-carboxylic acids (IVa-c) as part of our search for
compounds with novel biological activity. Incontrast to previously reported materials [3]
these have an electron acceptor ester group in the 6-position. These compounds are of inter-
est not only as potentially active substances but also in chemical terms. Because they can
react with nucleophiles at several active centers they serve as intermediates in the syn-
thesis of a variety of pyrimidine derivatives.

~OC4H 9 C00C4H9 COOCH3

L c~ 'N
(//~ NH POC15 I/ ~ " N R}I " ~ --~
O" "N O CI ~N CI "~
Ill II -~ e~ees~.( C ~ / ~ " |ll a-o

HSCII2COOC21|~ ~:;! N "~ ; "N

R :N / "'SCIt2COOC21t = (CII3)2N ~ " N "" (" 3)2

Iva-c v
III, IV a R= (CH3)2N, b R= piperidino c R= morpholino

Refluxing the butyl ester(I) with excess phosphorus oxychloride gave II which was treated
with equimolar amounts of secondary amines in methanol at 0~ (in the presence of anhydrous
sodium carbonate) to form the methyl esters of 6-dialkylamino-2-chloropyrimidine-4-carboxylic
acids (IIIa-c). The reaction course depends upon the reagent ratios. Use of excess dimethyl-
amine leads to substitution of both chlorine atoms in II with formation of the methyl ester
of 2,6-bis(dimethy!amino)pyrimidine-4-carboxylic acid (V). Such facile substitution of both
chlorines in II may be explained by the electron acceptor influence of the ester group in
position 4 of the pyrimidine ring.
On heating esters IIIa-c with ethyl thioglycolate in triethylamine there were formed
IVa-c respectively. The structures of compounds IVa-c were confirmed by elemental analytical
data (Table i) and by PMR spectra (Table 2) in which there were observed signals for the
ester group, the pyrimidine 5-proton, protons of the R substituent, and the characteristic
thiomethylene group at 4.18-4.30 ppm.
In view of the comparative ease of substituents of both chlorines in II by dimethylamine
there arose the need to show that the substitution in the pyrimidine ring of IIIa-c is at
the 6- and not the 2- position (despite literature data showing the predominance of 4- amino
derivative formation in reactions of 2,4-dichloropyrimidines with amines in polar solvents
[4, 5]).

V. Kapsukas State University, Vilnyus 232734. Translated from Khimiya Geterotsikliches-

kikh Soedinenii, No. 6, pp. 818-821, June, 1986. Original article submitted February 15,
1985.

0009-3122/86/2206-0647512.50 9 1986 Plenum Publishing Corporation 647

 TABLE I. Data for Compounds II, llla-c, IVa-e, V, VII, and
IX
,,,,,. ' ,,, ,,,

Corn- mp' or bp Found, % Empirical Calculated, %

Yield, %
pound (ram)ir~ 'C
N

11 177-I78 43,2 4,4 11,7 Cutl!oCI2N=O2 43,4 [ 4,1 11,3 83

(7)
Illa H17,5--138,5 44,9 4,8 19,6 CaHu,CIN~O2 [44,6 4,7 195 64
I I lb 88-89 51,3 5,6 16,I CIII'[~4CIN~O2i 51 7 5,5 m;4 59
l i l t 139,5-..,,140,5 46,7 4,5 IB,6 C ultt,~ClN:~Oa '46,6 4,7 16,3 91
IVa 93.-. 95 48,4 5,9 t 4,2 C~IIITNaO4S 48,2 5,7 14,0 80
IVb 87- 89 52,8 6,4 12,7 C,~It~INsO~S 53,1 6,2 ]2,4 45
I'Ve 126-- 127 49,5 5,7 12,2 CI~It,,~Na(.)~S 49,3 5,6 12,3 62
V 79--8 I 53,7 7,1 24,7 C,ot I,t~N40~ 53,6 7,2 25,0 80
VII t45,5--147,5 41,6 4,2 10,9 C~HwN~O~S 41,9 [ 3,9 10,9 65
IX 124--125 47,9 5,0 12,9 C,sH~rNsOsS 4 7 , 7 5,2 12,8 43 (h)
~3 (B)

*Compounds llla, b, V were crystallized from hexane; lllc,

IVa-c from ethanol; VII, IX from methanol.

TABLE 2. PMR Spectra of Compounds II, llla-c, IVa-c, V, VII,

and IX
. . . . t ,,,,,,,, ,, ,,, ,,,,,, ,,
Com-
pound PMR spectrum,6, ppm

II 1,04 (3H, t I = 5 Hz, CH~), 1,30--2,13 (4H, m, 2CH2), 4,58 (2H, t, 1=6 Hz,
OCH2), 836 (1lt, s, C~J)
llla 3,45 131-I,s, CHaN), 304 (3H, s, CHaN), 4,14 (3H, s, CHaO), 7,46 (IH, s , CH)
Illb 1,89 (6H, s, 3CII=), 3,75--4,35 (7H, m, 2CH2N+CHsO), 7,53 (IH, s, CH)
lllc 3,90~4,48 (11H, m, 2CH~N+2CHsO+CHaO), 7,58 (IH, s, CH)
tva 1,35 (3H, t, ,1=7 Hz CHa), 3,40 (6H, s, 2CH,~N), 4,08 (3H, s, CHaO), 4,18 (2H,
s, C[I~S), 4,35 (2Hfq; ,/=7Hz, CH~O), 6,90 (IH, s, CH)
IVb 1,35 (3H, t,. 1=6 l'lz CH3), t,83 (6H, s j 3CH2), 3,80 (4H, s, 2CHIN), 4,06
(5H, s, CH:~O+CH~S), 4,34 (2H, q J=6HZ, CH~O), 7,36 (IH, s, CH)
We 1,40 (3H, t, J=6Hz, CHa), 3,93--4,50 (15H,rr~ 2CH~N+3CH20+CHsO+CH~S),
7,41 (IH, s, CH)
V 3,25 (12H, ~ 4CH3N), 4,06 (3H, s, CHaO), 6,95 (IH, s, CH)
VII 3,93 (3H, s, CHaO), "4,13 (3H, s, CHaO), 4,26 (2H, s, CH2S), 7,34 (IH, $, CH)
IX .3,89 (3H, s, CHsO), 3,98--4,38 (13H, ~ 2CH=N+2CH20+CH2S+CHaO), 7,38
(1H, s, CH)

With this in mind we have studied other methods of preparing esters IV, e.g., the methyl
ester of 6-morpholino-2-(carbomethoxy)methylthiopyrimidine-4-carboxylic acid (IX).
Alkylation of the methyl ester of thioorotic acid (VI) using methyl chloroacetate in the
presence of sodium methoxide gave VII which was refluxed with phosphorus oxychloride to yield
the chloro derivative VIII. Without further purification this was then treated with an equi-
molar amount of morpholine to give IX. The spectral and physical properties of IX were
identical to those of the compound obtained by trans esterification of compound IVc.
(: O O C I I . COOCII,5
rI
1":r Nil (;If.'l[ COOCII, POC]3~.
I{
-. .... ' o; ' N
PI
HCII2COOCtl 3

%1 VII

t',OOC|T.~ t?OOCi{ ~

..... / mo pho, , ,'....._ Nj CIT.~ONa, CII~O~I

.............. IVc

(!l " " .' 3 2 '? ' I O "N " "' '" ~ClL,: CO~t.'H

VIII ~X

Thus the methyl esters of 6-dialkylamino-2-(carbalkoxy)methylthiopyrimidine-4-carboxylic

acids may be obtained by two alternative methods. Their synthesis from butyl orotate is to
be preferred because the starting ester(1) and all intermediate compounds are formed in
higher yields. Additionally the secondmethod has animportant drawback in that VIII

648
(evolved in the form of an oil) is difficult to purify by crystallization or by vacuum dis-
tillation.
A study of the hypolipidemic acs of the synthesized compounds was carried out in
the synthesis and medicinal studiesproblem solving laboratories of the V. Kapuskas State
University, Vilnyus, under the direction of V.-S. M. Rochka. This has shown that only the
methyl ester IIIc decreases the cholesterol level in rat blood serum by 14.3% when dosed at
200 mg/kg (LDs0 on oral administration greater that 2000 mg/kg). For this compound the
general lipids were reduced by 3.6% and triglycerides by 25% when compared with controls.

EXPERIMENTAL
Reaction following and compound purities were monitored by TLC on Silufol plates. PMR
Spectra were recorded on a Tesla BS 487 C (80 MHz) instrument at 33~ with CH3COOH solvent
and TMS internal standard.
Butyl orotate (I) was prepared from orotic acid using [6] and methyl thioorotate (VI)
from thioorotic acid [7] using [8].
The physicochemical and spectral characteristics of the synthesized compounds are given
in Tables i and 2.
Butyl Ester of 2,6-Dichloropyrimidine-4-carboxylic Acid (ii). A mixture of I (21.2 g,
i00 mmole) and phosphorus oxychloride (214 ml, 2340 mmole) were refluxed for 2 h. Excess
reagent was removed under reduced pressure and the residue was poured onto ice (150 g) and
extracted with ether (5 x 60 ml). The extracts were washed with water (3 x 60 ml) and held
over activated charcoal (15 min) with occasional shaking. The carbon was filtered off and
the extract dried (anhydrous magnesium sulfate), filtered, the solvent removed, and the
product vacuum distilled to give II.
Methyl Esters of 6-Dialkylamino-2-Chlorpyrimidine-4-carboxylic Acids (Ilia-c). The
appropriate dialkylamine (16 mm~ole) in absolute methanol (5 ml) was added dropwis&with
stirring to a mixture of II (4 g, 16 mmole), absolute methanol (60 ml) and anhydrous sodium
carbonate (3.2 g, 30 mmole). The reaction mixture was stirred at this temperature for 2 h
and allowed to stand overnight. 'l~e inorganic salt was then filtered off, the filtrate re-
duced to dryness at ~educed pressure, and the residue was recrystallized to give IIIa-c.
MethYl Esters of 6-Dialkylamino-2-(carbethoxy)methylthiopyrimidine-4-carboxylic Acids
(IVa-c). A mixture of IIIa-c (3.1 mmole), triethylamine (0.35 g, 3.4 mmole) and ethyl thio-
glycolate (0.37 g, 3.1 mmole) was held in water bath at II0~ for 2 h and then poured into
water (6 ml) and stirred thoroughly. In the case of IVc a precipitate was obtained Which
was filtered off and recrystallized. For IVa and b the aqueous solutionwas extracted with
ether (3 20 ml), the extracts washed with water (40 ml), dried (anhydrous magnesium sul-
fate), filtered, ether removed by distillation, and the residue crystallized.
Methyl ester of 2,6-bis(dimethylamino)pyrimidine-4,carboxylic Acid (V). Dbtained
analogously to IIIa-c using the butyl ester of 2,6-dichloropyrimidine-4-carbox#lic acid (II)
with a fivefold excess of dimethylamine. For isolation of V the inorganic salt was filtered
off, the filtrate concentrated at reduced pressure to one fifth volume, cooled to 0-5~ and the
solid filtered off and recrystallized.
Methyl Ester of 1,6-Dihydro-6-oxo-2-(carbethoxy)methylthiopyrimidine-4-carboxylic Acid
(VII). A solution of sodium methoxide (40 ml, i]25 N, in methanol) was added to a suspension
of VI (9.3 g, 50 mmole) in absolute methanol (120 ml). To this solution there was added drop-
wise with stirring methyl chloroacetate (5.4 g, 50 mmole) such that the temperature did not
exceed 30~ The mixture was stirred at room temperature for 1 h, refluxed for 4 h (to a
neutral reaction), filtered hot, the filtrate concentrated at reduced pressure to one third
volume, cooled to 0-5~ and the resultant solid filtered off and recrysta!lized to yield VII.
Mothy i Ester of 2-(carbomethoxy)methylthio-6-chloropyrimidine-4-carboxylic Acid (VIII).
A mixture of VII (4.0 g, 16 m m o l e ) a n d phosphorous 0xychloride (ii ml, 120 mmole) was re'
fluxed for 1.5 h. Excess reagent was distilled off under reduced pressure and the residue
poured onto ice (50 g). The solution obtained was extracted with ether (3 x 50 ml), dried
with anhydrous calcium chloride, filtered, and the ether distilled off to give VIII (4.0 g,
93%).

649
 Methyl Ester qf2-(Carbomethoxy)methylthi0-6-morpholinopyrimidine-4-carboxylir Acld (IX).
A. Anhydrous sodium carbonate (12.7 g, 120 rmmole) was added to a solution of crude VIII (ii.i
g, 40 mmole) in absolute methanol (60 ml). Morpholine (3.5 g, 40 mmole) was added dropwise
with stirring and the mixture obtained was stirred at room temperature for 4 h and allowed to
stand overnight. The solid product was filtered off and recrystallized to give IX.
B. Compound IVc (i g, 2.9 mmole) was added to a 0.035N solution of sodium methoxide (40
ml) and the mixture stirred for 3 h at room temperature until all of IVc had dissolved. The
solution was then concentrated at reduced pressure to one third volume, poured into water (30
ml), and neutralized with dilute hydrochloric acid ( 1 : 5 ) . The solid was filtered off and re-
crystallized to give IX.

LITERATURE CITED
i. A . A . Santilli, A. C. Scotese, and R. M. Tomarelli, US Patent 3,940,394; Ref. Zh. Khim.,
21090P (1976).
2. P . I . Vainilavichyus,M.-M. V. Burbulene, V. S. Lauchis, V.-S. M. Rochka, N.-D. I.
Lautsyuvene, and G. P. Polukordas, USSR Inventor's Cert. 791746, Byull. Izobr.,No. 48 (1980).
3, P. I. Vainilavichyus,M.-M. V. Burbulene, V.-S. M. Rochka, and N.-D. I. Lautsyuvene,
Khim.-Farm. Zh., No. 8, 35 (1982).
4. Vitayasat Vachanon Sukpracha, Science (Thailand), II, 22 (1957),Ref. Zh. Khim., 49542
(1959).
5. D . J . Brown, The Pyrimidines, Supplement I, Interscience, New York (1970), p. 129.
6. L . O . Ross, L. Goodman, and B. R. Baker, J. Org. Chem., 25, 1950 (1960).
7. UK Patent 820,147; Chem. Abstr., 54, 8867 (1960).
8. K . A . Chkhikvadze, N. E. Britikova, and O. Yu. Magidson, Zh. Obshch. Khim., 34, 161
(1964).

SYNTHESIS OF 2-ARYL- AND 2-HETARYLOXAZOLES FROM THE

OXAZOLINES AND OXAZOLIDINES

L. I. Belen'kii, M. A. Cheskis, U D C 547.786.37'787.37:542.943.7:541.128

and M. A. Ryashentseva

Treatment of 2-phenyl-, 2"(2-fury!)-, and 2-(2-thienyl)oxazolines with nickel peroxide

has been found to give, in addition to the dehydrogenation products (2-substituted
oxazoles), the fragmentation products (amides of benzoic, furan-2-carboxylic, and
thiophen-2-carboxylic acids). This fragmentation appears to give initially the nitriles,
which are then converted into the amides by the nickel peroxide. Catalytic dehydro-
genation of 2-phenyloxazolinegives low y i e l d s o f 2-phenyloxazole, the principal
product being benzonitriie. Treatment of the Schiff'sbases obtained from ethanolamine
and aldehydes (benzaldehyde, furfural, and thiophen-2-aldehyde) with nickel peroxide
gives trace amounts of the oxazoles, the principal produetsbeing the aldehydes, with
smaller amounts of the nitriles.

it has been s h o w n [ l ] t h a t l-pheny!oxazoline ( l a ) o n t r e a t m e n t with nickel peroxide is

converted to 2-phenyloxazole (IIa). We here describe ananalogoussyntheses of 2-(2-furyl)-
oxazole (IIb) and 2-(i-thienyl)oxazole (IIc). In all cases, although the oxazolines reacted
completely, the yields of oxazoles were around 50%o Attempts by us to carry out this dehydro-
genation with other oxidants (lead tetraacetate, pyridinium chlorochromate, sulfur, andN,N'-
bisbenzenesulfonyl-p-benzoquinoneimine) were successful. Further examination of the aromati-
zation of oxazolines showed that substantial amounts of the amides of the acids (III) [benzoic
acid (28%), furan-2-carboxylic (23%), and thiophen-2-carboxylic acid (45%)] remained adsorbed
on the nickel peroxide as by-products.

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow

117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 822-825, June,
1986. Original article suhmittedFebruary 15, 1985.

650 0009-3122/86/2206-0650512.50 9 1986 Plenum Publishing Corporation

 ]
. - .~,,. ~ ~{.. (:oNnz
O K" 0
! H HI

I--Ilia R=Ph, b R=2,-furyl, c R = 2 - t h i e n y l

We have now f o u n d t h a t 2 - p h e n y l o x a z o l e is converted into benzamide at a significant rate

on treatmentwith nickel peroxide. Hence, the amides formed under our conditions could arise
from the oxazoles rather than the oxazolines, and it was possible that fragmentation of the
oxazoles (or oxazolines) would not give rise directly to the amides, but rather to the nitriles,
which might then be converted into the amides. Gas-liquid chromatography in the early stages
of the reaction of oxazolines with nickel peroxide showed the presence of small amounts of
nitriles, which disappeared on longer contact of the reaction mixture with the nickel peroxide.
We have now shown, in separate experiments, that under the conditions used to aromatize the
oxazolines (boiling with nickel peroxide in benzene) benzonitrile is readily converted to
benzamide. In this connection it is noteworthy that the composition of the nickel peroxide
obtained f r o m n i c k e l sulfate and sodium hypochl0rite as described in [3] may be represented by
the formula NiO2.77H2.B5 [3], and this oxidant is a source of HO" radicals in aprotic
solvents. These radicals are able to detach hydrogen from the substrate and add at the free
valences to give new C--O bonds [3].
In a search for more selective methods for the preparation of 2-ary!oxazoles, we have
examined the catalytic dehydrogenation of 2-phenyloxazoline. This method was also found to
give benzonitrile, which was notconverted to benzamide under these conditions. Experiments
carried out at 400~ with an alumina--platinum catalyst gave complex mixtures containing no 2-
phenyloxazole (GLC), but small amounts of benzonitrile werefound. Clearer results were ob-
tained using a polyfunctional alumina--chromium--platinum catalyst containing rare-earth oxides,
used previously for the dehydrogenation of C(4)- and C(s)-hydrocarbons [4] and for their
heterocyclization with H2S [5]. The stability of this catalyst towards sulfur-containing [6]
and nitrogenous [7] heterocycles led us to its use for the dehydrogenation of 2-phenyloxazole.
It was shown to be possible in principle to obtain 2-phenyloxazole from 2"phenyloxazoline, but
the principal course of the reaction led to the formation of benzonitrile. At 450~ the
catalyzate contained 1 0 % o f 2-phenyloxazole, 45% of benzonit~ile, and 45% of unreacted 2-
phenyloxazoline.
We alsoexamined thearomatization of 2-phenyl-, 2-(2-furyl)-, and 2-(2-thienyl)oxazoli ....
dines (IV). It has been suggested (see, e.g., [8]') that such oxazolidines exist in tautomeric
equilibrium with the corresponding Schiff's bases (V), the equilibrium favoring the latter
[9]. Conversion of the Schiff'sbases obtained from aromatic aldehydes and o-aminophenol
into 2-arylbenzoxazolestakes place i n h i g h yields on treatment with a variety of oxidants,
notably lead tetraacetate [i0, ii] and nickel peroxide [12] even at ambient temperatures.
When we used the Schiff's bases (or oxazolidines), the yields of aryl- and hetaryloxazoles
obtained on treatment with nickel peroxide amounted to only a few percent, the principal
products being the aldehydes. Furthermore, the phenyl- and furyl-substituted compounds gave
small amounts of benzonitrile and 2-cyanofuran. Similar results were obtained when activated
manganese dioxide was used. The formation of aldehydes when Schiff's bases are oxidized with
lead tetraacetate is well k n o w n [ 1 3 ] , and the nitriles could be obtained by fragmentation of
the oxazoles or the intermediate oxazolines, as described above.

RCH=NfCH2)2Olt ~ . . . . + RCHO
R /""0 f' E ~O
V [%' It

lI, IV, V a R=Ph, b R ~ 2 - f u r y l , c R = 2 - t h i e n y l

EXPERIMENTAL
GLC analyses w e r e c a r r i e d out on an LKhM-80 chromatograph with a flame ionization de-
tector, carrier gas nitrogen, flow rate 20 ml/min, stainless steel columns: 2 mm x 2 m (5%
SE-30 on Chromaton N-AW-DMCS, temperature 165~ and 2 mm 1.5 m (15% Carbowax 20M on Chro-
maton N-AW-DMCS, temperature 185~ PMR spectra were obtained on a Tesla BS-467 radiospectro-
meter (60 MHz) in CCI 4 internal standard TMS.
2-Phenloxazole (lla)~ To a solution of 12 g (82 mmole) of (ia) in 60 ml of benzene was
added 78 g of nickel peroxide [2], and the mixture boiled with stirring for i h with periodic
removal of samples for GLC. In the sample removed after 30 min, in addition to the
651
 starting material (la) and 2-phenyloxazole (!la), traces of benzonitrile were present, but
these were not found in the subsequent sample. To the mixture was added i0 g of nickel perox-
ide, and the mixture boiled for i h (when starting material (la) was no longer present ac-
cording to GLC). The mixture was filtered, and the solid washed with benzene followed by
acetone. The combined benzene solution was evaporated and fractionally distilled to give 5.8
g (49%) of the oxazole (lla), bp 98-100~ (I0 nun) [lit. bp [I], 100~ (I0 mm)]. The acetone
solution, following removal of the acetone, gave 2.8 g (28%) of benzamide (Ilia), mp 126-127~
(lit. mp [14] 130~
2-(2-Furyl)oxazole (lib). From methyl furan-2-carboxylate and ethanolamine was obtained
94% of the N-(2-hydroxyethyl)amide, bp 176~ (1.6 mm), which on successive treatment with
thionyl chloride and KOH solution (as described in [1]) was converted into the oxazoline (Ib),
mp 77-79~ (95%) (lit. mp [15], 83~ To 11.4 g (84 mmole) of (Ib) in i00 ml of benzene was
added 66 g of nickel peroxide, and the mixture boiled with stirring for 2 h. The mixture was
worked up as described above. From the benzene extract there was obtained 5.0 g (44.5%) of
2-(2-furyl)oxazole (lib), mp 48-49~ PMR spectrum: furan ring protons 6.35 (q, 4-H), 6.87
(q, 3-H), 7.45 (br. 5-H); oxazole ring protons 7.7 (s, 4-H), 7.51 ppm (s, 5-H). Found, %:
N 10.3. CTHsNO2. Calculated,%: 10.4. From the acetone solution there was isolated 2.2 g
(23%) of the amide (lllb), mp 142-144~ (lit. mp [14], 143~
2-(2-Thienyl)oxazole(llc). From methyl thiophen-2-carboxylate there was obtained 96% of
the N-(2-hydroxyethyl)amide, bp 214~ (I mm), mp 88-90~ which was converted as for (la) [I]
i n t o the oxazoline (Ic) in quantitative yield, mp 58-59~ (lit. mp [16] 60~ From 4.1 g
(27 mmole) of (Ic) by treatment with 23 g of nickel peroxide under the conditions described
above there was obtained 1.9 g (46%) of the oxazole (llc), bp 105~ (I0 mm). PMR spectrum:
thiophen ring protons 6.98 (q, 4-II), 7.32 (q, 5-H), 7.51 ppm (q, 3-H); oxazole ring protons
7.08 (s, 4-H), 7.55 ppm (s, 5-H). Mp [17] 30~ From the acetone solution there was ob-
tained 1.54 g (45%) of the amide (lllc), mp 179-180~ (lit. mp [14], 180~
Reaction of 2"Phenyloxazole (lla) with Nickel Peroxide. To 0.48 g (3.3 mmole) of the
oxazole (lla) in 20 ml of benzene was added 7 g of nickel peroxide, and the mixture boiled with
stirring for 1 h. The mixture was filtered and the solid washed with benzene followed by
acetone. From the combined benzene washings following removal of the benzene there was ob-
tained 0.24 g (50% recovery) of (lla), and from the acetone solution 0.1 g (25.5%) of the
amide (Ilia).
Reaction of Benzonitrile:with Nickel Peroxide. To a solution of 0.5 g (4.5 mmole) of
benzonitrile in 25 ml of benzene was added 1 g of nickel peroxide, and the mixture boiled
with stirring for 5 min. The mixture was then filtered and the solid washed with benzene
followed by acetone. Evaporation of the acetone solution gave 0.3 g of benzamide (Ilia) (51%).
Catalytic Dehydrogenation of 2-Phenyloxazoline (la). The experiments were carried out in
a flow reactor in a stream of nitrogen over a c a t a l y s t of composition 5% Cr203, 5% of Polirit,
1% of K20, and 81% of u [18]. At 400~ a n d a flow rate of i h -z, the yield of liquid
catalyzate was 80%. When the flow rate was reduced to 0.5 h -I and the temperature raised to
450~ the liquid catalyzate (72%) contained (GLC) 4% of 2-phenyloxazole (lla), 90% of
benzonitrile, and 6% of starting material (la). When the flow rate was increased to i h -l,
the liquid catalyzate was found to contain 10% of the oxazole (lla), 45% of benzonitrile, and
45% of unreacted (la).
Reaction of 2-(N-Benzylidenamino)ethanol (Va) with Nickel Peroxide. T o a solution of 0.4
g (2 7 mmole) of Va, obtained as described in [9], in 25 ml of benzene was added 3 g of nickel
peroxide, and the mixture boiled with stirring for 0.5 h. The mixture was filtered, and the
solid washed with benzene followed by acetone. The combined benzene solutions were carefully evapor-
ated. The residue consistedof 0.14 g of amixture containing (GLC) the oxazole (lla), benzonitrile,
and benzaldehyde in proportions of 16:30:54, corresponding to yields of 8, 14, and 25%. The
acetone extract afforded 0.05 g (15.5%) of benzamide. When a solution of i g of (Va) in 40 ml
of benzene was boiled with 2 g of activated manganese dioxide for:20 min, the ratio of products
was 3:13:84.
Reaction of 2-[N-(2"Furfurylideneamino)]ethanol(Vb) with Nickel Peroxide. To a solution
of 2.4 g (1.73 mmo!e) of (Vb), obtained as described in [19], in 50 ml of benzene was added 5
g of nickel peroxide, and the mixture boiled with stirring for 5 min. The solid was filtered
off, a further 5 g of nickel peroxide added to the filtrate, the mixture again boiled for 5 min

652
and filtered, and the combined solids washed with benzene and acetone. The combinedbenzene
solutions were evaporated carefully under reduced pressure to give 0.32 g of solidcontaining,
according to GLC, the oxazole (IIb), furan-2-carbonitrile, and furfural in a ratio of 1:18:81
(yields 0.14, 4, and 16%). The acetone extract gave 0.09 g (5%) of the amide (IIIb).
Reaction of 2-[N-(2-Thienylideneamino)]ethano! (Vc) with Nickel Peroxide. To a solution
of 2 g (1.3 mmole) of (Vc), obtained as described in [20], in 50 ml of benzene was added 5 g of
nickel peroxide, the mixture stirred at room temperature for 5 h, 4 g of nickel peroxide
added, stirring continued for a further 5 h, and the mixture filtered. The solid was washed
with benzene, and the combined washings evaporated to give 0.28 g of solid which contained
(GLC) the oxazole (llc) and 2-thiophenaldehyde in a ratio of 14:86, yields 2 and 17% respective-
ly.

LITERATURE CITED
i. L. I. Belen'kii and M. A. Cheskis, Khim. Geterotsikl. Soedin., No. 7, 881 (1984).
2. K. Nakagawa, R. Konaka, and T. Nakata, J. Org. Chem., 27, 1597 (1962).
3. R. Konaka, S. Terabe$ and K. Kuruma, J. Org. Chem., 34, 1334 (1969).
4. M. A. Ryashentseva, Yu. A. Afanas'eva, and Kh. M. Minachev, Inventor's Cert. (USSR) No.
199 103 (1966); Byull. Izobret., No. 15, 21 (1967).
5. M. A. Ryashentseva, Kh. M~ Minachev, and E. P. Belanova, Inventor's Cert. (USSR), No. 527
430; Byull. Izobret., No. 33, 74 (1976).
6. V. B. Abramovich, M, A. Ryashentseva, Kh. M. Minachev, Yu. A. Afanas'eva, and M. D.
Pankratova, in: Heterogeneous Catalysis in the Preparation and Reactions of Heterocyclic
Compounds [in Russian], Zinatne, Riga (1971), p. 229.
7. M. A. Ryashentseva, Kh. M. Minachev, A. V. Varlamov, V. M. Polosin, and N. S. Prostakov,
Izv. Akad. Nauk SSSR, Ser. Khim., No. 8, 1905 (1984).
8. J. Cornforth, in: Heterocyclic Compounds (R. Elderfield, ed.) [Russian translation], Izd-vo
Inostrann. Lit., Moscow (1961), ~, p. 313,~
9. L. W. Daasch and U. E. Hanninen, J. Amer. Chem. Soc., 72, 3673 (1950).
i0. F. F. Stephens and J. D. Bower, J. Chem. Soc., No. 3, 2971 (1949).
ii. F. F. Stephens and J. D. Bower, J. Chem. Soc., No. 2, 1722 (1950).
12. K. Nakagawa, H. Onoue, and J. Sugita, Chem. Pharm. Bull., 12, 1135 (1964).
13. B. Rindone, E. Santaniello, and C. Scolastico, Tetrah. Lett., No. I, 19 (1972).
14. Dictionary of Organic Compounds [Russian translation], Izd-vo Inostrann. Lit., Moscow
(1949).
15. Farbwerke Hoechst, Pat. No. 955951 (BRD); Chem. Abstr., 53, 16152 (1959).
16. P. Y. Ferrini and A. Marxer, Angew. Chem., 75, 165 (1963).
17. P. Chauvin, J. Morel, and P. Pastour, Bull. Soc. Chim. France, Part 2, Nos. 9-10, 2079
(1974).
18. M. A. Ryashentseva, E. P. Belanova, and Kh. M. Minachev, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. 12, 2756 (1978).
19. T. F. West, J. Soc. Chem. Ind., 61, 158 (1942); Chem. Abstr., 37, 1396 (1943).
20. L. G. Angert, Ya. L. Gol'dfarb, G. I. Gorushkina, A. I. Zenchenko, A. S. Kuz'minskii, and
B. P. Fedorov, Zh. Prikl. Khim., 32, 408 (1959).

653
 SYNTHESIS, STRUCTURE, AND SPECTRAL PROPERTIES OF SOME BIOXAZOLES

L. I. Belen'kii, M. A. Cheskis, UDC 547.727'734'787.2.07:543.422:541.65

V. P. Zvolinskii, and A. E. Obukhov

Syntheses of systems containing two oxazole rings [2'-phenyl-, 2'-(2-furyl)-, and

2'-(2-thienyl)-2,5'-bioxazoles, and 2,2'-(2,5-furylene)bisoxazole] from aldehydes
obtained by formylating 2-phenyl-, 2-(2-furyl)-, and 2-(2-thienyl)oxazole have been
developed. Terephthalate and thiophen-2,5-dicarboxylate esters have been used to
obtain 2,2'-(l,4-phenylene)- and 2,2'-(2,5-thienylene)bisoxazoles. The PMR, UV, and
luminescence spectra of these systems have been examined, and quantum chemical calcu-
lations carried out in the PPP approximation.

We have previously [1, 2] developed syntheses of 2-phenyloxazole (la), 2-(2-furyl)oxazole

(Ib), and 2-(2-thienyl)oxazole (Ic) by aromatization of the oxazolines by treatment with
nickel peroxide. Some electrophilicsubstitution reactions of 2-phenyloxazole have been
studied [i, 3], and it has been shown that under conditions which do not permit protonation of
the nitrogen atom with consequent deactivation of the heterocycle the substituent enters in
the 5-position of the oxazole nucleus. The possibility of formylating the oxazole ring is
particularly attractive [i], since this would give a new C--C bond and introduce a functional
group capable of a wide range of subsequent reactions.
The aim of this investigation was to examine the formylation of the 2-hetaryloxazoles
(Ib) and (Ic), the conversion of the aldehydes so obtained and of the previously-synthesized
[i] 2-phenyloxazole-5-aldehyde (lla) into systems containing two oxazole rings, and a study
of the spectral properties of the latter.
The hetary!oxazoles (Ib, c) contain fragments of activated heteroaromatic compounds with
one heteroatom. For this reason it might be expected that the formyl group would enter,
either exclusively or predominantly, the furan (or thiophen) ring rather than the oxazole
ring. However, formylation of the thienyloxazole (Ic) gave 85% of a single compound, 2-(2-
thienyl)oxazole-5-aldehyde (llc), the structure of which was confirmed by its PMR spectrum,
which contained signals for three thiophen ring protons with typical coupling constants
(J34 3.7 and J45 5 Hz) in the aromatic region together with a singlet for the proton of the
oxazole ring and a singlet at lower field for the aldehyde proton (Table i). This finding is
understandable, bearing in mind that the systems under consideration (la-c), unlike their bi-
phenyl analogs, have two rings that are not equivalent, so that transfer of electron den-
sity to the oxazole moiety takes place. This follows from quantum chemical calcula-
tions for 2-phenyloxazole carried out in the valence approximation by the CNDO/2method [4].

TABLE i. PMR Spectra of Hetaryloxazolealdehydes (lib), (IIc),

and (III) (in deuteroacetone)
Chemical shifts, 5, ppm Coupling constant J, Hz
t ring thiophen !furan) ring
CHO 45 3'4' 3'5' 4'5'
~ [- 4-H 5-H 3'-H 4'-H $'-H
o

18,o,s
8.19s
III / 7.44d 8.17 d
7,85 m
7,40 d.d
7,31
7,25 d.d
6,79 d.d
7,62 d
7,85 m
--
9,80 s
7,94 d.d 9,86 S
9,78 s
--
0-~
3,7
3,76
3,76
O,*,9 t5,0
1,80
*As a result of the superimposition of the 3'-H and 5'-H signals,
it was not possible to measure the value of J3's'.

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences Of USSR, Moscow

117913. P : L u m u m b a People'S Friendship University, Moscow 117923. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 826-836, June, 1986. Original article submitted
November 22, 1985.
654 0009-3122/86/2206-0654512.50 9 1986 Plenum Publishing Corporation
 .) -0271
' 0,~,
,w~ -0273
' -
l),O0,~ -0 , : 8 6 909
L,005 0,017 N-- - k 0,06! N----~ 0,327
/O.
" N--
/
'
>

0 L2
' )'] "O,OI] 0,]28 .......... 0~3Z8 \ ......... : 0,3:{2
0.(~,q - g,(12'/ -0,0'/1 -(],!)~,::

Fig. 1. Distribution of w-electron density in 2-aryl- and

2-hetaryloxazoles (la-c).

TABLE 2. PMR Spectra of 2"Aryl- and 2-Hetaryloxazolines

Chemical sl~fts, 5, ppm
oxazoline o x a z o l e fing'l benzene, thiophen or furan
Compound Sol~nt ring* rln~
o-H m-H [ o-H
4-H 5-H 4'-H U-H (3-H) (4-H) ~ (5-H)'

.4,5-Dihydro-2- CC14 3,97 4,081 -- -- 7,76m 7,22m

phenyloxazole m
(2H) (3H)
4,5-Dihydro-2- CCI4 4,07 4,22 [ -- -- 7,49 d.d 6,97 d,d 7,35 d.d
(2- thi~enyl)ox-
azole~ I 6,87d 6,38 d.d 7,45 d
4.5-Dihydro-2- CDC% 4,10 420 t - - --
(2-furvl),ox- t

azolem*
Villa CDCI.~ 4,12 4,28 [ 7,52
t -- 8,20 m 7,55 m
| (2H) r
Vlllb* * CDCIa 4,14 4,29 i 7,65 -- 7,21 d 6,69 d.d [ 7,93 d
VlIlc'$ (CDa)iCO 4,07 4,36 7,80 -- 7,78d.d 7,20 d.d I 7,67 d.d
IX (;DCIa 4,19 4,3 [ 7,23 7.70 7,06s (2H)
Xa CDCIa 4,20 4,31 -- -- 7,97s (4H)
ge CDCI~ 4,20 4,33 -- -- 7,27 s (2H)

*Signals seen as partially overlapping multiplets, J45 ~ 7-8 Hz.

#Signals seen as singlets, splitting with J4s ~ 0.7 Hz not seen
in the spectra (60 MHz).
~In the thiophen ring J34~4. A ~ I . s J ~ 5 5 Hz.
**In the furan ring, J~3.5, 14~2.0 Hz.

Quantitative evaluation of the electron-acceptor capacity of the 2-oxazolyl residue in systems

(la-c) may be made from lJC NMR spectroscopic data for (ia) [4], from which it follows that
this residue functions as a substituent in the benzene ring with a Op+ value of 0.33, i.e.,
it is intermediate in its deactivating effect between the bromine atom (ap+ 0.23) and COOH
(Op+ 0.45).
We have here used the Pariser--Parr-~ople (PPP) method [5, 6] to calculate the distri-
bution of ~-electron density in the molecules (la-c). The results are shown in the molecular
diagrams (Fig. i). It will be seen that in 2-phenyl- and 2-(2-thienyl)oxazole sites with the
highest ~-electron density are the 5-positions of the oxazole ring, which is in accordance
with the directivity of formylation. Only in the case of 2-(2-furyl)oxazole (Ib) are the
free positions of the furan ring comparable in their ~-electron density to that at the 5-
position of the oxazole ring. This is in agreement with the results of the formylation of
(Ib), in which around 90% of a mixture of 2-(2-furyl)oxazole-5-aldehyde and the isomeric
2-(5-formyl-2-furyl)oxazole (III) is obtained in a ratio of 1:2 (according to GLC and PMR).
The isomers (lib) and (III) were separated by column chromatography on silica gel, and the
structures confirmed by PMR spectroscopy (Table i).

~X / ~O'" "'X' "o' "XCHO OHC~ O~ -O I

I fl-C lla-C III
I~ l l a X ~ c t t = c H ; b x.-o; C X=S

Oxidation of the aldehydes (lla, c) and (Ill) with Jones' reagent, and of (lib) with
silver oxide, proceeded smoothly to give the acids (IVa-c) and (VII). Reaction of the latter
with ethanolamine gave the N-(2-hydroxyethyl)amides, which were then normally without iso-
lation in the pure state reacted with thionyl chloride followed by potassium hydroxide to
give readily 4,5-dihydro-2'-phenyl- (Villa), 4,5-dihydro-2'-(2-furyl)- (Vlllb), 4,5-dihydro-
2'-thienyl)- (Vlllc), and 4,5-dihydro-2,2 '-(2,5-furylene)bisoxazole (IX).

655
 TABLE 3. PMR Spectra of Bioxazoles (Xla-c) and (Xlla-c)
I .........ch
....mi'cal
.....shifts, 6. ppm "
pound"
Com- oxazole
,I-II 5-t1
ri -'7L~ - -
4'-I1
benzene, furan, or thiophen ring
o-II {3-H) m-H (l-H) ] p.tt (5-H}

XIa 7,17s 7,51s 7,51s 8,12 m 7,40m (3II}

{2Jl)
XI b]~ 7.39d 8,37 d 7,85 s 7,27 d.d 6,74 d.d 7,88 d.d
XIc 7,41s 8,12s 7,8ls 7,85 d.d 7,27 d.d 7,79 d.d
Xlla 7,76s 8,17s -- 7,30s (411)
XIID'" 7,36 s 8,08 s 7,25s (211}
XII c 7,60 S 7,92 s 7,23 s ('2ti)

*Solvent for (Xla), CC14; for (Xlb, c) and (Xllb, c),(CD3)2CO;

and for (Xlla), CDCI3.
#In the spectrum (250 MHz), splitting of the oxazole ring protons
was seen (J45 = 0.7 Hz), and also of the furan ring protons J34 =
3.5, J35 = 0.7, J45 = 1.8 Hz.
~In the 60 MHz spectrum, the protons of the oxazole ring are seen
as broadened singlets, coupling constants in the thiophen ring:
Js4 = 3.5, J3s = 1.0, J4s = 5.0 Hz.
**In the oxazole ring J4s = 0.7 Hz.

"X 9 "''+'("}ll X" 0 "'~'OOM~ X" '--" '0" 'i'O " X'"-- "0"''" "'lJ
i
.B'a-c VLB.-C ]H H.'IIpCII;NII VIIIa'C

Ut~UC" 0 ~ EIOUC 0 O' ' "" " ...... '"

V VII IX

Similarly, dimethyl thiophen-2,5-dicarboxylate (obtained from adipic acid by a modifi-

cation of the standard methods [7, 8]) was converted via its N'(2-hydroxyethylamide) into the
bisoxazoline (Xc). However, the benzene analog (Xa) was obtained in low yields on successive
treatment of terephthalic acid NN'-bis-(2-hydroxyethyl)amide with thionyl chloride and po-
tassium hydroxide. This N-(2-hydroxyethyl)amide was therefore converted into the sulfate by
treatment with sulfuric acid, and this on treatment with sodium hydroxide gave (Xa).

HOCH~CH2NHOC .....X" ,~ CONHCH2CHzOH KOH

Xa-o

HO~5OCH~CH~NH0~ X "CONHCH~CH~O~O3H

The structures of the oxazolines (Vllla-c), (IX), and (Xa, c) followed from the methods
of synthesis and were in accordance with their PMR spectra (Table 2). In the same Table are
given for comparison the PMR spectra of 2-phenyl-, 2-(2-furyl)-, and 2-(2-thienyl)-oxazolines,
the preparation of which has been described previously [I, 2].
On treatment with nickel peroxide, the oxazolines (Villa-c) were converted into the
corresponding 2'-phenyl and 2'-hetaryl-2,5'-bioxazoles (Xla-c), and (Xa), (IX), and (Xc) into
p-phenylene-2,2'-bisoxazole, 2,5,furylene-2,2'-bisoxazole, and 2,5-thienylene-2,2'-bisoxazole
(XIIa-c) respectively. As i n t h e preparation of 2-aryl- and 2-hetaryloxazoles [2], the
corresponding carboxamides were obtained as by-products, but the yields of the required
compounds, particularly in the cases of the hisoaxazolines (Xa, c) and the furyl-substituted
oxazoline (VIIIb), were much lower than in the syntheses of the monooxazoles (Ia-c). The
PMR spectra of (XIa-c)and (XIIa-c) demonstrate their aromatic character and confirm their
structures (Table 3). The yields, melting points, and elemental analyses for (II-XII) are
given in Table 4.

656
 TABLE 4. Properties of the Compounds Obtained

Com-
pound rap, "C*
Found, ~o Empirical
formula
Calculamd % IYio,d---,
C H NIS) c H

IIa 72--74 85
lib 158--159 59,3 8,8 C~HsNOa 58,9 3 8,6 27
tic 110--112 53,4 8,1 C~H~NO~S 53,6 2, 7,8 85
(17,51 7,9
IIl 133--136 .... 8,6 C~HsNOa 58,9 3, 8,6 40
IVa 217--218 53,4 7,6 Cjc,H7NO3 63,5 3 7,4 77
l}Vb 242--243 53,7 7,9 Cd{sNO4 53,6 2 7,8 91
(decomp.)
IVc 245--250 49,7 7,1 CsHsNOaS 49,2 2, 7,2 " 78
(decomp.) (16,1) 6,4
V 229--231 53,3 7,6 C~HsNO~ 53,6 2 7,8 46
(deeomp.)
Vla 90--91 65,2 6,8 C11HgNO3 65,0 4 6,9 97
VIb 116--118 56,2 7,1 ~gHFN()4 56,0 3 7,3 91
Vie 108--109 51,7 6,8 C~J bNO3S 51,7 3 6,7 90
(15,2) 5,3
!VII 87--89 58,2 6,5 C.,H~NO4 58,0 4 6,8 66
Vllla 118--119 66,~ 4,6 12,8 C I2H!,,N20~ 67,3 13,1 I 91
VIIlb 138--139 59,6 3,7 13,1 CIoHaN2Oa 58,8 13,7 I 83
VIIIc 119--121 54,2 3,8 12,8 C,oHsN202S 54,5 12,7 i 62
14,4 (14,6) 9
IX 182--184 58,7 3,8 14,1 CjoHsN~O3 58,8 13,7 91
Xe 136--138 53,g 4,4 12,5 CIoHI/,N~O2S 54,0 12,6 90
14,2 (14,4
Xla 113--115 67,G ,3,6 13,7 CI~tIaN202 67,9 13,2 39
XIb 115--117 59.4 3,4 13,6 C.~H6N2Oa 59,4 t3,9 14
Xle 94--95 55,fi 2,7 13,0 C foHr,N202S 55,0 12,8 34
14,7 (14,7
Xlla 221--222 67,7 3,7 13,1 CI~H~N202 67,9 13,2 8
Xllb 177--179 59,4 3,3 13,6 CIsH6N202 59,4 13,9 26
XIIe 124--128 55,3 3,1. 13,1 CIoH6N202S 55,0 12,8 16
14,6 (14,7

*Compounds (lla), (VIIla, b), (IX), (Xc), and (Xlb, c) were

crystallized from hexane; (Ilb, c), (IIl), (Via-c), (VII),
(XIa), and (XIIb, e) from heptane; (VIIIc) from propan-2-ol,
and (XIIa) from ethanol.
#For elemental composition and empirical formula, see [2].

~qa-c
ix

"'X "O~
Xila-c

Examination of the UV absorption and fluorescence spectra for the bioxazoles (Xla-c) and
(XIIa-c) shows that these compounds absorb strongly and fluoresce efficiently in organic
solvents (Table 5). Their spectral properties have much in common, despite the fact that they
differ considerably in the positions of the absorption and fluorescence maxima. For instance,
in spectra of all the compounds the ~,~* bands predominate, which is typical of heteroaromatic
systems. The PMR data (Table 3) for these compounds (XIa-c) and (XIIa-c) show them to possess
a general aromatic T-system (for criteria of heteroaromaticity, see [9]). The absorption spec-
tra show that, in all instances, the most intense is the long-wavelength band. This band is the
widest, and is generally structureless; only in a few cases does vibrational structure appear.
The fluorescence spectrum is virtually a mirror image of the absorption spectrum.
When polar solvents are used instead of neutral solvents, the maxima of the long-wavelength
bands in the absorption spectra and the fluorescence band are shifted to longer wavelengths.
The effect of solvent on the position of the long-wavelength maximum is quite small, no greater
than 12 nm (Table 5). The fluorescence bands are shifted to longer wavelengths by between 2

657
 ..... +,J't (25%) .,~:

9 :--': -.,+--'. n u,+,t:, ',6., N -~!r,v,, I',g%l

"' ~%+' "~ "% 9 \ U 146

' ++ ":"' " ",b' '].6J'+i
'+~' u,b U,4~H* /O,Ut~U' ~" ',bl

"n,',~.,+: ,,:~++ ,'~+~, ,d,/',.L+ .- .\)jC+i

'+,~+,x~,+ I ~176 0,+gff
'I Jr (~u'Io: Y" :' o . ~ir "'K'% d,'+i,,
"--i;'?,7:,-'<~:,,u: u.~,.~,,.' "':'>"d.+ uS.-.+o I?(,,"~,+)
"U I/ ff,<tb ~.),O0()'tS/'PA ,~+~..

) _ .+J,II'!" ,,,,+ I0(~,' +;,',,'C+~,

..... ]C, 2' ? '~+ O,D,/'t
,~I,=+ + ,' OlB+,
( P?'~,,1 C,,Z71" N (; .qd~,~
++_ .. ' 5 ---
- 0 ,~l.:. . . if.i+-//+
. . . . . (I[I0 " + b(J!JlJ
.... ~
:, 0 5':~0 ' ,.+O0,;
"
L
....

"3+\-
/

'~,:~ (/~8%L,)
-

z --uu25
'+,ui+.++

"/~i+, . ,~,:.\ .....,. ~.;~...... -..(.',.++ (z~",,J

l;%+, -+.+>:>~>-+.~,+t.... .,".' '+ "t-~? .,+; -~+'.:::+--~

<=.'-,'.+ ' O . 4 ' -3 i;57 ,;l:,:+'
R,' ,.,/..-* (j>b~-,--" "+'
,:,~, ...... :~. u!~-, +::' "r~i:,_,,++" +,?+.
.... ~%~,:. . I,.,,.,,. Fo.~+ ~?* +
' q'' ++t': N~T~BL+ )OU5 + + ~--r

- "~ --P
U Z ~ J:~,~ b,'9,~
'-z++ 0 ::' ~ :b~,,,e,
... +,+
9-u u u u " ~ +'" +' C 3J --L'.+j -,~("

,/ )?{;,.. ( :,+,%.~ <+u+!"

, ':'. ~. " S \. - (k096
_,i('iil" ~ !' ~.~': ,, - qj,t I ~ ~ ~ 0 (J J'; ~
-';- - +~ l -+ : T ~ - _

9 . ,,> '
Z 'C. .,,, q

. v* + +~ ++
n t' -'.'~,q"'. ~. 04u]
' %>"+ Cc6 fl+)+ 02~ +
9 ;'-- -- - ' o
,- - u t t, + " ~")~ \ " );'8' N (17 "o1
2- = - : = -- j +~)t,' - ,:~.r+ -' <+ , , u.,<.,
~."'+" . l,+,-~, >.,'>:"~,u,: ,,,,,~ o:s~<t:!$
t';l , ',; !+,1),<, . ~ , "s~_uu~
.",' I ', ,' ,>-~-'.~ '._<, OIIl? / 0~X12

- uz?b ~. ;,,.." , x ,~, ,=, ~.

+ I ~ J't) (311
O.(J~3{ i),,+l G' 0 "-'Ij'~'J,f . . . . ~I'j-(]i~;,
,iOI)~ '.} J.+O

;t =-'"!+]J!
H(II H
S-.!'- ,!!'9_[
0,021~

Fig. 2. Distribution of ~-electron density and

The values of the +-charges in the ground state
the excited state S+~, (in the numerator). The
given in the ground and excited (indicated by
(%) are given above the rings.

and 22 nm. Consequently, the Stokes shift (Av = Vfluor -- Vabs) is dependent on the solvent
and on the compound; for spectra obtained in cyclohexane and alcohol, it varies from 34 to 80
nm. This dependence of the magnitude of the Stokes shift on solvent is apparently due to
changes in molecular configuration on excitation [i0]. The compounds examined here may exist
as several conformers, of which that which is the most stable in a given solvent predominates.
The tricyclic structure of (Xla-c) and (Xlla-c) is formed from a combination of one benzene,
furan, or thiophen ring with two oxazole rings, the three rings being either coplanar, or
rotated relative to each other.
In order to interpret the absorption and luminescence spectra, quantum chemical calcu-
lations of the electronic structures of (Xla-c) and (Xlla-c) were carried out using the PPP
method [5, 6]. The calculations were carried out for coplanar molecules with different
orientations of the rings relative to each other. The calculations showed that the conformation
shown in Fig. 2 is the most likely. Molecular diagrams of the distribution of n-electron
density both in the ground (S ~ and excited states ( S ~ * I) show that the nitrogen atom of the
oxazole ring carries a substantial negative charge, and may function as an electron-donor,
whereas the oxygen and s u l f u r a t o m s may function as strong and weak electron-aceeptors re-
spectively, the magnitude of the ~-eharges on these atoms varying little on excitation. It
is necessary to bear in mind that the,carbon atoms in the free positions of the oxazole rings

658
 : & 8 <k<>) (2(4 <~?)
t 2(: <Yo) - 0,2<~:# 0775 ~

/
-- 9:U71' j" l" . < ~ 0 I/ ~ iO1': __.: :2:,'J,:# f ' i '
0C92 1680
O,lOt.t 4< ,],lt)9 ~
~-- . (]i II/ ~ 5] : OiO0 ~
~ 0,0o0 ~ - n,ho,~

(48~
If//17~
------ %"
76~,] -~.0~I ~ %9h'~ (26 o)

/ ~ ,./>.U~ ",< :~>~ O,j:-Z ~ - -.~ y " ":<;L'.- ~

SO:O'~ :: --a a ~ ' / 0 11 'Z :I" __,~' ' )

0 Ui, ~ . / " -- .... :I~ ,,~Z+ )

,._._--~ ,~/_,.! :~ . uIU4< 060~*

- 0.26~ _0,02%~
I : ~o-..:>7
%(,k? / 5(P6)
I JIZ' #~1

i ~ I ~~) l ~ I I {) 00{) * I~ I I .' '' # I I I ] ' i I-- k +

-O,OX.: ~.% I " ..., . "<~ ~ " ",

t ],)~ 'i~" I $" ] ';:t~] I ,'
'~ (ill) lit) I "~ ''<" l$l I
'.
',600r N
j
~
:-'I"
N ')~'<" .~ >/~
'>
:(;:~Tu .:- ~-()~, u,;?c.

'q : . IJI(l {;'7

u{107

q-bond orders in bioxazoles (Xla-c) and (Xlla-c).

S o are given at the atoms (denominator), and for
q-bond orders for the intercyclic bonds are
an asterisk) states. Excitation localizations

(the 5-position) carry an appreciable negative charge (~0.i e), these charges being substan-
tially reduced on excitation when the ~-electron density is transferred to the disubstituted
oxazole ring and the benzene, furan, or thiophen moieties in the cases of structures (XIa-c),
or to the "central" benzene, furan, or thiophen ring in (XIIa-c). A measure of the consider-
able redistribution of electron density taking place at the atoms and fragments of the mole-
cules on excitation is provided by the magnitudes of the intramolecular charge transfer between
fragments of the molecules [ii, 12], the direction and magnitude of which depend on which ring
(benzene, furan, or thiophen) is present in the molecule. Intramolecular charge transfer is
greatest in the benzene ring and least in the thiophene ring.
In addition to changes in intramolecular charge transfer, both types of systems (XIa-c and
XIIa-c) show successive bathochromic and bathyfluoric shifts in the absorption and fluorescence
maxima, and decreased quantum yields in the series of molecules containing the benzene, furan,
and thiophen rings. It will be seen that excitation results in substantial changes in all the
bond orders, the order of the intercyclic C-C bonds being particularly strongly increased, and
this enables the molecule in its excited state S : ~ , (i.e., at the instant of emission of a
quantum of light) to be regarded as being more planar than in the ground state S O . The exci-
tation localization numbers indicate that approximately half of the excitation energy is local-
ized at the central fragment in (XIa-c) and (XIIa-c), through which charge transfer is also
effected. From the literature reports reviewed, in particular in [13], it may be assumed that

659
 TABLE 5. UV Absorption and Fluorescence Spectra of Bioxazoles

Gore- I Maximum, am Stokes shift, Relative quantum

pound I Solvent absorption fluoresenee v, nm yield,

Xla Cyelohexane 302 356 54 0,37

Ethanol 302 378 76 0,48
XIb Cyclohexane 3[0 360 50 0,35
Ethanol 314 367 53 0,36
XIc Gvelohexane 318 398 80 0,18
Ethanol 320 400 80 0,17
xIIa Cyclohexane 308 344 36 0,60
Et'hanol 309 350 41 0,71
XIIb Cyclohexane 318 358 40 0,42
Ethanol 321 353 42 0,63
XIIc Cxclohexanc 337 384 47 0,13
Ethanol 33.8 390 52 0,14

the introduction of chromophoric groups into the position of maximum localization of exci-
tation (the 5-position in these c o m p o u n d s ) w i l l provide compounds with useful optical proper-
ties. In order to predict reliably the spectral and luminescent properties of the molecules
discussed here, it will be necessary to examine the dependence of the orbital character
and the relative distributions of excited states on their electronic structure (spatial
structure and type of heteroatom) [14]. Such a study will form the subject of succeeding
communication~

EXPERIMENTAL
Theoretical calculations of electronic structure and the properties of the molecules in
q-electronic approximation were carried out by the PPP method [5, 6] using the Hinze-Jaffe
system of parameters [15]. Calculations were carried out using a program based on a modifi-
cation o f the PPP method which has been described previously [16]. The two-center coulombic
integrals y ~ were calculated from the Mataga--Nishimoto equation [17].
PMR spectra were obtained on Tesla BS-467 (60 MHz) and B r u k e r W M - 2 5 0 radiospectrometers
with TMS as internal standard. The solvents used are given in the footnotes to Tables 1-3.
The electronic absorption spectra of the compounds in solution were measured on a Specord
M-4030 spectrophotometer. The spectra were recorded at room temperature. The concentrations
of the solutions were varied between 10 -3 and i0 -s mole/liter. The accuracy of measurement of
the positions of the absorption maxima was not less than cm -z, of the optical density
and the molar extinction coefficient E~not less than depending primarily on errors in
the determination of the concentrations of the solutions. Absorption spectra were constructed
in the form of plots of the decimal molar extinction coefficient s against the frequency ~,cm -i
Fluorescence and excitation spectra were obtained on an SLM-4800S spectrofluorimeter(USA)
with two monochromators with holographic diffraction g r a t i n g s w i t h a linear dispersion of 2
nm/mm. Excitation was carried out with an Osram XBO-450 lamp (450 W). The spectra were re-
corded using a photomultiplier in two-channel mode. The spectra were recorded in the memory of
a microprocessor, and constructed using a graph-plotter in the form of plots of quantum intensity
against wavelength %, nm, or frequency, ~, cm -z. Fluorescence spectra were corrected on a
computer for the spectral characteristics of the photomultiplier used. The concentrations
of the solutions of the compounds under study were 10-5-10 -7 mole/liter. M e a s u r e m e n t of quantum
yields for the compounds was carried out in dilute solution by a comparative method, by compari-
son with the quantum yield of a standard. The standard employed was anthracene, the quantum
yield of which was taken to be ~ = 0.22, in a concentration not exceeding i0 -5 mole/liter [18,
19]. The errors in the measurement of quantum yields were not greater than 10%. For optical
measurements, a standard quartz cell with an optical path length of I0 mm was used.
Chromatographic analyses were carried out on an LKhM-80 chromatograph with a flame ioni-
zation detector, stainless steel column 2 mm 1.5 mm, 5% SE-30 on Chromaton N-AW-DMCS (A) or
2 m m 1.5 m, 15% Carbowax 20 M on Chromaton N-AW-DMCS (B), T 185~ carrier gas nitrogen, 20
ml/min.
The properties of compounds (II)-(XII) are given in Table 4.
2-Phenyloxazole-5-aldehyde (IIa). To 6 g (41 mmole) o f 2-phenyloxazole (In) in 20 ml of
DME was added dropwise with stirring at 0-5~ 8.5 ml of POCI3, and the mixture stirred at the
same temperature for a further i0 min, then for 7 h at 95~ The mixture was cooled, poured on

660
to ice, extracted with chloroform, the extract washed with water, and filtered through a
layer of silica gel L 40/100 approximately 5 cm thick. The residue after removal of the
chloroform contained (GLC, column A) 93% of the aldehyde (lla) and 7% of the oxazole (la).
Recrystallization from hexane gave 6.1 g (85%) of (l!a), mp 72-74~ (cf. [i]). On a pre-
vious occasion [i], more severe conditions during the workup of the reaction mixture gave a
yield of ~60% of (lla).
Formylation of 2-(2-Furyl)oxazole (Ib). The reaction was carried out as in the formy-
lation of (la), but the mixture was h - ~ f o r l . 5 h at 90~ until the starting material (Ib)
had disappeared (GLC, column B), and the cooled reaction mixture was neutralized with K2C03
solution~ From 4.6 g (34 mmole) of the oxazole (Ib) there was obtained 4.95 g (89%) of a
mixture of aldehydes (llb) and (III) in a ratio of 1:2 (GLC, column B, and PMR). Chroma-
tography on a column of silica gel L 40/100, eluent chloroform, gave 1.5 g of (llb) and 2.2 g
of (III).
2-(2-Thienyl)oxazole-5-aldehyde (IIc). The conditions used for the formylation of (Ic)
were similar to those described above for {he oxazole (Ia), except that the mixture was kept
for 5 h at 90~ From 4.8 g (30 m m o l e ) o f (Ic) there was obtained 4.85 g of (lie).
2-Phenyloxazole-5-carboxylic Acid (IVa). To a solution of 0.8 g (4.6 ~mole) of the al-
dehyde (IIa) in 7 ml of acetone was added at 5-I0~ a solution of 0.46 g of Cr03 in 1.5 ml
of water, followed by the dropwise addition of 0.35 ml of conc. sulfuric acid. The resulting
solution was stirred for 1 h at ~20~ then poured into water and extracted with ether.
Following washing with water and drying over MgSO~, the ether was removed to give 0~ g of
the acid (IVa). Acids (IVc) and (V) were obtained similarly.
2-(2-Furyl)o>azole-5-carboxylic Acid (IVb). To a solution of 1.65 g of silver nitrate
in 7 ml of water was added 0.75 g (4.6 mmole) o-~ the aldehyde (IIb) and 30 ml of dioxane,
followed by the dropwise addition with stirring of a solution of 0.8 g of NaOH in 20 ml of
water. The mixture was stirred for 2 h at ~20~ filtered, the solid washed with warm water,
and the combined aqueous dioxane solution acidified with hydrochloric acid and extracted with
ether. The ether extract was washed with water, dried over MgSO~, and the ether removed to
give 0.75 g of the acid (IVb).
Methyl 2-Phenyloxazole-5-carboxylate (Vla). To 2.5 g (13.2 mmole) of the acid (IVa) in
50 ml of methanol was added 0.5 ml of cone. sulfuric acid, and the mixture boiled for 6 h.
Excess methanol was distilled off slowly (over 2 h), and the residue poured into water,
extracted with ether, the extract washed with aqueous potassium carbonate, and dried over
MgS04. Removal of the ether gave 2.38 g of the ester (Via). Similarly obtained were the
methyl esters (Vlb, c) and the ethyl ester (VII).
4,5-Dihydro-2'-phenyl-2,5'-bioxazole (Villa). To 2 g (i0 mmole) of the ester (Via) was
added 5 ml of ethanolamine, and the mixture heated for 3 h at 150~ (in a bath). The methanol
was then distilled off, followed by excess ethanolamine (at 170~ 20 mm) (in a bath). To
the resulting N-(2-hydroxyethyl)amide of the acid (IVa) was added, after cooling and without
further purification, 8 ml of SOCIe, and the resulting solution was heated for i h at 60~
Excess SOC12 was distilled off at 60~ (20 mm), and to the solid residue was added 6 g of KOH
in i0 ml of water and i0 ml of benzene. The mixture was boiled with stirring for 2.5 h,
then cooled and e x t r a c t e d w i t h benzene. The benzene extract was washed with water, the benzene
removed, and the residue recrystallized from heptane to give 1.92 g of (Villa) (91%.yield). In
one experiment, the intermediate N-(2-hydroxyethyl)amide of 2-phenyloxazole-5-carboxylic acid
was isolated in quantitative yield, mp 149-150~ (from benzene). Found, %: C 61.9; H 5.2;
N 12.0. C~eHIeNzO3. Calculated, %: C 62.1; H 5.2; N 12.1.
Oxazolines (Vlllb, c) and (IX) were obtained similarly from the esters (Vlb, c) and (VII)
respectively, without isolation of the N-(2-hydroxyethyl)amides.
4,5,4',5'-Tetrahydro-2,2'-(l,4-phenylene)bisoxazole (Xa). To 20 g of ethanolamine was
added portionwise at 140-160~ 8 g (41 mmole) of dimethyl terephthalate, and the mixture kept
for 30 min at 150~ After cooling, the solid was filtered off, and washed with water and
chloroform to give 9.9 g (95%) of terephthalic acid bis~N-(2-hydroxyethyl)amide, which could
not be obtained in an analytically pure state. The bisamide (8.6 g) was added in small
portions with stirring to 8 g of cone. sulfuric acid, then cone. sulfuric acid (8 g ) was
added to the mixture with ice-cooling, and the resulting solution heated for 40 min at 140~
After cooling, 60 ml of absolute ethanol was added with cooling, and the mixture stirred for
i0 min at ~20~ The solid which separated was filtered off, and washed with two portion of

661
15 ml of absolute alcohol to give 10.5 g (71%) of the acid sulfate of terephthalic acid bis-
N-(2-hydroxyethyl)amide, mp 192-193~ which was dissolved without further purification in 100
ml of water. To this solution was added with stirring a cold solution of 50 g of NaOH in i00
ml of water, After keeping for 15 h at 20~ the resulting suspension was boiled with stir-
ring for 5 h, the solid filtered off, and washed with water to give 2.7 g (50%) of the bisox-
azole (Xa), mp 241-243~ (for lit. value, see [20]).
4,5,4',5'-Tetrahydro-2,2'-(2,5-thienylene)bisoxazole (Xc). To 15 g (103 mmole) of adipic
acid was added 80 ml Of SOCi= and i~8-~I of pyridin'e, and the resulting solution was boiled
for 24 h. Excess SOC12 was distilled off, the bath temperature being raised gradually from
130 to 155~ The residue was twice distilled in vacuo to give 13.1 g of thiophen-2,5-di-
carbonyl chloride, bp 150-152~ (Ii mm), mp 42-43~ yield 61% (lit. values see [7, 21]). To
4 g (19 mmole) of the diacid chloride was added 25 ml of methanol, the mixture becoming warm
and a solid separating. After keeping at room temperature for 20 min, the mixture was poured
into 300 ml of chilled water, extracted with ether, the extract washed with sodium carbonate
solution and water, dried over MgSO~, and evaporated to give 3.65 g of dimethyl thiophen-
2,4-dicarboxylate, mp 142-!46~ yield 95% (for lit. values, see [21]). To 4.6 g (23 mmole)
of this diester was added 8 ml of ethanolamine, methanol distilled off over 2.5 h, bath temper-
ature 135-140~ and the residue washed with water (2 x 20 ml), the solid being separated by
decantation. Filtration gave 4.16 g (73%) of thiophen-2,5-dicarboxylic acid bis-N-(2-hy-
droxyethy!)amide, mp 214-216~ Recrystallization from alcohol gave a solid mp 220-221~
Found, %: C 46.1; H 5.7; N 10.5; S 12.1. C~0HI4N20~S. Calculated, %: C 46.5; H 5.5; N 10.8;
S 12.4. Successive treatment of 4 g (13.5 mmole) of the bisamide with 35 ml of SOCIz and 20 g
of KOH in 40 ml of water as described above for (VIIIa) gave 3.11 g of the bisoxazoline (Xc).
2'-Ph__enyl-2,5-bioxazole (XIa). To a solution of 2.42 g (11.3 mmole) of the oxazoline
(VIIIa) in 80 ml of benzene was added I0 g of nickel peroxide [22], and the mixture boiled
with stirring for 1 h. A further 5 g of nickel peroxide was then added, and boiling continued
for 1 h (until starting material (VIIIa) was no longer present according to TLC on Silufol,
eluent chloroform). The mixture was filtered, the solid washed with benzene, and the com-
bined benzene solutions evaporated to give 0.94 g of the bioxazole (XIa) (Tables 3 and 4).
The solid nickel peroxide was washed with acetone, and removal of the acetone gave 0.15 g (7%)
of 2-phenyloxazole-5"carboxamide, mp 164-166~ (from chloroform). Found, %: N 14.9.
C!0HsNzO2. Calculated, %: N 14o9. P~R spectrum [(CD3)2CO]: 2.98 (s, 2H, h7{2), 7.50 (m, 3H,
m- and p-H of the benzene ring), 7.70 (s, IH, 4-H), 8.15 ppm (m, 2H, o-H).
2'-(2-Furyl)-2,5'-bioxazole (XIb). From 0.3 g (1.5 mmole) of the oxazoline (VIIIb) on
treatment with 3.5 g of nickel peroxide as described in the previous experiment there were
obtained 0.04 g of the bioxazole (XIb) (Tables 3 and 4), and 0.18 g (67%) of 2-(2-furyl)-
oxazole-5-carboxamide, mp 148-150~ (from benzene). Found, %: C 53.8; H 3.3; N 15.1.
CsH~N202. Calculated, %: C 53.9; H 3.4; N 15.7. PMR spectrum [(CD~)2CO]: 2.95 (s, 2H, NHz),
7.20(d.d., IH, 4'-H), 7.75 (d, IH, 3'-H), 7.92 (s, IH, oxazole 4-H), 7.97 ppm (d, IH, 5'-H,
J3' ' = 4 Hz, J~'5' = 2 Hz).
2'-(2-Thienyl)-2,5'-bioxazole (XIc). From 1.05 g (4.8 mmole) of the oxazoline (VIIIc)
on treatment with 7.3 g of nickel peroxide as described for the oxazole (XIa), there were ob-
tained 0.35 g of the bioxazole (XIc) (Tables 3 and 4) and 0.25 g (25%) of 2-(2-thienyl)-
oxazole-5-carboxamide, mp 144-145~ (from benzene). Found, %: N 14.3. CsHGNzOzS. Calcu-
lated, %: N 14.4. P~R spectrum [(CD3)2CO]: 2.99 (s, 2H, Nile), 7.25 (d.d., IH, 4'-H), 7.77
(s, IH, oxazole 4-H), 7.79 (d, IH, 3'-H), 7.88 ppm (d, IH, 5'-H, J3'4 = 3.6, J4'5 '= 5.0 H z ) .
1,4-Phenylene-2,2'-bisoxazole (XIIa). From 1.0 g (4.6 mmele) of the bisoxazole (Xa) and
9 g of nickel peroxide, as for (Xla), there was obtained 0.08 g of the oxazole (XIIa).
2,5-Furylene-2,2'-bisoxazole (XIIb). From 0.5 g (2.5 mmo!e) of the oxazoline (IX) and
4 g of nickel peroxide as described for (XIa), there was obtained 0.13 g of the bisoxazole
(XIIb).
2,5-Thienylene-2,2'-bisoxazole (XIIc). From 2.5 g (11.5 mmole) of the bisoxazoline (Xc)
and 30 g of nickel peroxide, as described for (XIa), there was obtained 0.39 g of the bisoxa-
zole (XIIc).

LITERATURE CITED
i. Lo I. Belen'kii and M. A. Cheskis, Khim. Geterotsikl. Soedin., No. 7, 881 (1984).
2. L. I. Belen'kii, M. A. Cheskis, and M. A. Ryashentseva, Khim. Geterotsikl. Soedin., No. 6,
822 (1986).

662
 3. L. I. Belen'kii, G. P. Gromova, M. A. Cheskis, and Ya. L. Gol'dfarb, Chemica Scripta,
25, 295 (1985).
4. L. I. Bel'enkii, V. S. Bogdanov, I. A. Abronin, G. P. Gromova, M. A. Cheskis, and R. Z.
Zakharyan, Chemica 8cripta, 25, 266 (1985).
5. R. Pariser and R. G. Parr, J. Chem. Phys., 21, 466 (!953),
6. G. A. Pople, Trans. Faraday Soc., 49, 1375 (1953).
7. S. Nakagawa, J. Okurama, F. Sakai, H. Hoshi, and T. Naito, Tetrahedron, Lett., No. 42,
3719 (1970).
8. East German Pat. No. 129,448; Chem. Abstr., 89, 75347 (1978).
9. A. F. Pozharskii, Khim. Geterotsikl. Soedin., No. 7, 867 (1985).
i0. R. N. Nurmukhametov, The Absorption and Luminescence of Aromatic Compounds [in Russian],
Khimiya, Moscow (1971).
ii. A. V. Luzanov, Teor. Eksp. Khim., 13, 579 (1977).
12. A. V. Luzanov and V. F. Pedash, Teoro Eksp. Khimo, 15, 436 (1979).
13. B. M. Krasovitskii and B. M. Bolotin, Organic Luminophores [in Russian], Khimiya, Moscow
(1984).
14. D. N. Shigorin, Zh. Fiz. Khim., 51, 1894 (1977).
15. I. Hinze and H. H. Jaffe, J. Amer. Chem. Soc., 84, 540 (1962).
16. V. P. Zvolinsky, G. I. Kagan, G. M. Kagan, M. E. Perelson, and Yu. N. Sheinker, Summaries
of Papers of Intern. Symp. on the Theory of Electronic Shells of Atoms and Molecules,
Vilnius (1969), p. 44.
17. K. Nishimoto and D. S. Forster, Theor. Chim. Acta, 4, 155 (1966).
18. I. N. Demas and G. A. Crosby, J. Phys. Chem., 75, 991 (1971).
19. A. S. Cherkasov, Zh. Fiz. Khim., 29, 2209 (1955).
20. Ger. Pat. No. 995951; Chem. Abstr., 53, 16152 (1959).
21. J. M. Griffing and L. F. Salisbury, J. Amer. Chem. Soc., 70, 3416 (1948).
22. K. Nakagawa, K. Konaka, and T. Nakata, J. Org. Chem., 27, 1597 (1962).

COURSE OF BROMINATION OF THIAZOLE AND 2-METHYLTHIAZOLE

Ya. L. Gol'dfarb~* G. P. Gromova, UDC 547.789.04:542.944.2:541.124:543.422

and L. I. Belen'kii

Bromination of thiazole by bromine in the presence of aluminum chloride in neutral

solvent or without solvent takes place at the 2-position. Such an orientation con-
tradicts the traditional addition-cleavage mechanism, and agrees with the y!id mecha-
nism of electrophilic substitution. 2-Methylthiazole brominates at the 5-position,
and the reaction is impeded in the presence of aluminum chloride; this is due to
heterocycle deactivation by comp!exation with the Lewis acid at the nitrogen atom.

We recently showed [i] that 2-phenylthiazole is smoothly brominated at the 5-position of

the thiazole ring by bromine in a neutral solvent (benzene or chloroform). 2-Phenylthiazole
can be considered as an analog of biphenylo As established by 13C NMR spectra and quantum chem-
ical calculations [2], already in the ground state there is a transfer of electron density from
the benzene ring to the thiazole; this is apparently the reason, to a substantial extent,
for the high reactivity of the thiazole ring in electrophilic substitution.
In the present work we have studied the bromination of unactivated unsubstituted thiazole
and of 2-methylthiazole. It is known that thiazole can not be brominated by bromine in a
neutral solvent: only the perbromide is formed [3]. We used conditions that had previously
permitted pyridine to be brominated [4], viz., the action of bromine in the presence of a
catalytic amount of AICI3 in carbon tetrachloride or without solvent. Here we obtained a small
yield of a mixture in which the main product, and also the only monobromothiazole, was 2-

*Deceased.
N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow
117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 837-840, June,
1986. Original article submitted February 3, 1986.

0009-3122/86/2206-0663512.50 9 1986 Plenum Publishing Corporation 663

 bromothiazole. Such a result was unexpected because for 1,3-azoles in electrophilic sub-
stitution by the addition-cleavage mechanism the relative reactivity of the positions changes
in the sequence 5 > 4 >>2. Furthermore, attack at C(2) is extremely unfavorable due to par-
ticipation in positive charge delocalization by limiting o-complex structures:

with a positively charged bivalent nitrogen [5, 6].

2-Bromothiazole formation can be explained if we assume that it occurs by the so-
called ylid mechanism of electrophilic substitution; in recent years this has been studied
quite widely for 1,3-azoles, in particular thiazole (see, e.g., [6-8]). This mechanism calls
for the initial formation of an azolium cation that easily cleaves a proton from the 2-
position to form an ylid, which in turn adds an electrophilic particle to become 2-substituted
(in the quaternized form). The possibility is not excluded that ylid formation promotes not
only quaternization but also complexation with aluminum chloride at nitrogen. In this con-
nection we point out that complexation with AICI3 and protonation at nitrogen lead to similar
changes in electron density distribution in the 2-methylthiazole molecule [2]. As regards
the bromination of thiazole the process can be described by the following scheme:

+ 9E + .E ~ E

9 "S "S "'S Br Br

E,~llr, l], AI CL,

We note that in all the cases of direct thiazole bromination previously described, the
only monobromide is 2-bromothiazole. It is difficult to decide about the mechanism of high-
temperature bromination [3] at 250,400 ~ in the vapor phase, but the bromination of N-bromo-
succinimide in CCI~, which gives ~i0% of 2-bromothiazole [9], probably follows the above
scheme. One of the reasons for the low yield under the conditions of [9] is, in our opinion,
the fact that at an equimolar ratio of reagents practically all the N-bromosuccinimide is
consumed in ylid formation, and no source of Br + is left in the reaction mixture. As we have
established, the yield can be approximately doubled by using a twofold molar amount of N-
bromosuccinimide. It should be noted that in all cases thiazole bromination is accompanied
by appreciable resinification.
In going from thiazole to 2-methylthiazole the possibility of substitution by the ylid
mechanism is naturally eliminated. In that case it is important to note that according to the
13C NMR spectra and quantum chemical calculations by the valence approximation of CNDO/2 [2]
the charge distribution over the heterocycle atoms in 2-methylthiazole is close to that found
for 2-phenylthiazole. In agreement with this finding are the data on bromination of 2-methyl-
thiazole by bromine in a chlorinated solvent in the presence of HBr as alkali acceptor, where
the yield of 5-bromo-2-methylthiazole reaches 48% [i0]. Without an alkali acceptor, as we
have sho%m, the yield is cut approximately in half. In the presence of an equimolar amount of
AICI3 the brominationyield falls even more substantially (to ~i0%). Approximately the same
yield as of 5-bromo-2-methylthiazole was also obtained in the bromination of N-bromosuccini-
mide, and in the reaction of bromine in acetic acid by the procedure of [ii].
Thus 2-methylthiazole (as probably other 2-alkylthiazoles) can be brominated under mild
conditions; but the presence of protonic or aprotic acids that form complexes at the nitrogen
atom sharply decreases the reactivity of the thiazole ring toward an electrophilic reagent.
In the case of unsubstituted thiazole even in the presence of a Lewis acid bromination takes
place at the 2-position, probably by the ylid mechanism.

EXPERIMENTAL
Chromatographic analysis was carried out on a LKhM-80 chromatograph with flame ionization~
detector, nitrogen carrier gas at 20 ml/min, 130-170 ~ stainless steel columns: A) 2 x 2000 mm
with 5% SE-30 on Chromatone N-AW-DMCS; B) 2 x 1500 mm with 15% Carbowax 20 M on Chromatone
N-AW-DMCS.
The starting compoundsand the reference bromothiazole samples were prepared by known
methods from 2-aminothiazole: thiazole by the method of [12], 2-methylthiazole by [13], 2-
bromothiazole by [14], 5-bromo-2-methylthiazole by [ii], 2,5-dibromothiazole by [12].

664
5-Bromothiazole was prepared by boiling 2,5-dibromothiazole with zinc in acetic acid, i n 3 5 %
yield, bp 65-68 ~ (17 mm), nD 2~ 1.5920, in agreement with [15].
Bromination of Thiazole in the Presence of AICI 3. A. To 5 g (60 mmole) of thiazole was
added 9.6 g (60 m mole) of bromine with vigorous stirring and cooling (0 to -10~ a solid
orange complex formed. After addition of 0.5 g (3.7 mmole) of anhydrous aluminum chloride
the mixture was heated at I00-150~ for 2.5 h; it became liquid and darkened. The mass that
solidified when cooled was treated with sodium hydroxide solution until alkaline and was
steam-distilled. The distillate was made alkaline to pH I0 and was extracted with e t h e r .
According to GLC the extract contained ~80% starting thiazole, ~i0% 2-bromothiazole, ~5%
2,5-dibromothiazole, and three unidentified compounds totaling ~5%. Thiazo!e, 0.93 g (18%
recovery) was separated by distillation.
B). To a solution of 1 g (12 mmole) of thiazole in 7 ml of CCI~ were added 0.I g (0~
nnnole) of anhydrous AICI3, then a solution of 1.92 g (12 mmole) of bromine in 3 ml of CCI~
dropwise. The mixture was heated for 2 h at 65-67~ an orange-bro~n resin deposited on the
wall of the flask. After cooling, the solution was separated and washed with water, dilute
NaOH solution, and again water. The solvent was removed. According to GLC with 2,3-1uti-
dine as internal standard, the residue contained 3.5 mg (0.08%)yield of 2-bromothiazole and
3.5 mg (0.12% yield) of 2,5-dibromothiazole. The resinous material was dissoved in conc.
NaOH and steam-distilledand the distillate was extractedwith ether. The extract contained,
by GLC, 0.26 g of thiazole (26% recovery) and traces of 2-bromothiazole.
Bromination of Thiazole with N-Bromosuccinimide. A. A mixture of 3 g (35.4 mmole) of
thiazole and 6.3 g (35,5 mmole) of N-bromosuccinimide in i0 ml of CCI~ was heated 45 min at
65-67~ After cooling the solution was decanted from the resin and washed with water, dilute
NaOH solution, and again water. According to GLC with 2,3-1utidine as internal standard the
solution contained 0.4 g of starting thiazole (13% recovery) and 0.6 g of 2-bromothiazole,
11% yield.
B). In an analogous experiment with twice the amount of N-bromosuccinimide the yield
of 2-bromothiazole was 23% and the thiazole recovery was 6%.
Bromination of 2-Methylthiazole. Am To a mixture of 0.5 g (5 mmole) of 2-methylthiazole
in 3 ml of CH2C12 was added a solution of 0.8 g (5 mmole) of bromine in 3 ml of CH2C12. The
mixture was stirred for 1 h a t 20~ then for 2 h during boiling, then left for 24 h at room
temperature. It was then washed with water, sodium carbonate solution, and again water. Ac-
cording to GLC the solution contained the starting 2-methylthiazole and 5-bromo2-methyl-
thiazole in 5:95 ratio, as well as ~1% of two unidentified substances. The residue after
evaporation of CH2C12 was boiled for 12 h with 5 ml of methyl iodide. Excess CH3I was
evaporated and the residue was washed with acetone. The acetone-insoluble part was crystal-
lized from water with carbon to give 0.36 g of 5-bromo-l,2-dimethylthiazolium iodide, mp
245 ~ (see [II]), 22% yield.
B) When bromination was carried out under the conditions of the preceding experiment
but in the presence of an equimolar amount of AICI3, a mixture was obtained (0.62 g) the
volatile components of which contained the starting 2-methylthiazole, 5-bromo-2-methylthiazole,
and unknown compounds in 4:90:6 ratio according to GLC. From this mixture there was obtained
0.14 g (8% yield) of 5-bromo-l,2-dimethylthiazolium idodide.
C) 2-Methylthiazole, 0.75 g (7.5mmole), and 1.5 g (8.4mmole) of N-bromosuccinimide in 8 m! of
CC14 were boiled for 3 h. After cooling the precipitate was filtered off, and the solution
was washed with dilute NaOH solution and water and evaporated. The residue (0.25 g) con-
tained, according to GLC, 2-methylthiazole and 5-bromo-2-methylthiazole in 55:45 ratio. The
residue was boiled for 12 h with 5 ml of CH3I to give 0.3 g of 5-bromo-l,2-dimethylthiazolium
iodide, 12% yield.

LITERATURE CITED
i. L. I. Belen'kii, G. P. Gromova, M. A. Cheskis, and Ya. Lo Gol'dfarb, Chem. Scripta, 25,
295 (1985).
2. L. I. Belen'kii, V. S. Bogdanov, I. A. Abronin, G. P. Gromova, M. A. Cheskis, and R. Z.
Zakharyan, Chem, Scripta, 25, 266 (1985).
3. J . P . Wibaut, Bero, 72, 1708 (1939).
4. R . E . Lokhov, S. S. Lokhova, N. M. Gaidarova, and L. I. Belen'kii, Khim. Geterotsikl~
Soedin., No. 9, 1236 (1981).

665
 5. M. M. Campbell, in: General Organic Chemistry [Russian translation], Vol. 9, Khimiya,
Moscow (1985), p. 443.
6. L. I. Be!en'kii, Khim. Geterotsikl. Soedin., No. 6, 749 (1986).
7. A. F. Pozharskii, Theoretical Foundations of Heteroeycle Chemistry [in Russian], Khimiya
Moscow (1985), p. 176.
8. A. Dondoni, Phosphorus and Sulfur, 24, 381 (1985).
9. B. M. Mikhailov and V. P. Bronovitskaya, Zh. Obshch. Khim., 27, 726 (1957).
i0. Japanese Patent 5734833; Ref. Zh. Khim., 15N, 213 (1984).
9 ii. K. Ganapathi and K. D. Kulkarni, Current Sci. (India), 21, 314 (1952); Ref. Zh. Khim.
46327 (1954).
12. P. Roussel and J. Metzger, Bull. Soc. Chim. France, Nos. 11-12, 2075 (1962).
13. P. E. Iversen and H. Lund, Acta Chem. Scand., 20, 2649 (1966).
14. Synthesis of Heterocyclic Compounds [in Russian], Coll. 9, Erevan (1972), p. 27.
15. H. Beyerman, P. Berben, and J. Bontekoe, Rec. Trav. Chim., 73, 325 (1954).

SYNTHESIS OF MACROCYCLIC COMPOUNDS CONTAINING THIOPHENE

AND THIAZOLE NUCLEI

Ya. L. Gol'dfarb,* E. A. Krasnyanskaya, UDC 547.736'789'898.07:542.944'953

A. A. Dudinov, and S~ Z. Taits

Macrocyclic ketones that contain a thiophene nucleus and have 14 or more carbon
atoms in the ring can form systems with a condensed thiazole ring, in high yield.

The introduction of a macrocyclic segment into a physiologically active molecule can

facilitate its directed transport through cell membranes t o t h e appropriate receptors.
Starting from this hypothesiswe undertook the synthesis of pyrazolone systems condensed with
a macrocycle [ i ] . The synthesis of macrocyclic compounds condensed with a thiazole ring has
also been demonstrated [2]. The present work is devoted to a detailed description of such
systems that are based on macrocyclic ketones.
The objective can be reached by various paths. If we arrange for quite simple syntheses
of macrocyclic ketones of formula I that contain a thiophene ring [3], it is natural to seek
a selective method for their halogenation ~ to the carbonyl group, and so convert them to
thiazoles by the classical method [4]:

I U fCH J._~-'" '

III
n=9, 10, 11

Macrocyclic ketones I (n = 9, ii) were obtained by intramolecular acylation of the acid

chlorides of long-chain ~-thienylalkanoic acids, using the high dilution technique [3]. [ll]-
e-Cyclothienone-I (I, n = i0) (for nomenclature of macrocyclic ketones containing a thiophene
ring, see [3]) was obtained by ketonic cleavage of 2-carbethoxy-5-(9-iodononyl)acetylthiophene
in methyl ethyl ketone in the presence of K2CO3 [5].
To develop the conditions for bromination of macrocyclic ketones at the ~-carbon atom,
5,ethyl-2-propiothienone (IV) was synthesized as model compound (in view of the quite limited
availability of ketones I). It was subjected to the action of various brominating agents:

*Deceased.

N. D. Zelinskii Institute of Organic ,Chemistry, Academy of Sciences of the USSR, Moscow

117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 841-844, June,
1986. Original article submitted February 13, 1986.

666 0009-3122/86/2206-0666512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Effect of Bromi- TABLE 2. Effect of Bromi-
nating Agent on Yield of nating Agents on Bromo-
Bromosubstituted Thiophenes cyclothienone Yield
Yield of reaction Yield of a-bromo-
Brominating product, % Brominating substituted cyelo-
agent agent n thienone II, %
V VI

CuBr2 72 CuBr~ 85
Br~/CCI4 88 CuBr2 92
N-Bromosuccinimide Br2/CCI4 83
Br2/CH3COOH Br2/CC14 87
Br2/AICIa -- 93 Br2~CH3COOH 65

CXI~ b 5 "(JOl-'2ll'o 17211~ "'S " C:I (1

CllBr
IV ., -. C113 /
CH~ / "~ / "--Ntla
VII

t: t"It~a S "COCjII,
J
Vl

The results of the bromination of IV are shown in Table i.

According to the PMR spectral data, in the case of bromoketoneV two thiophene ring protons
were clearly identified. In the case of bromoketone VI only one such proton was found. The
location of the bromine in the side chain was confirmed by the conversion of V to the substi-
tuted thiazole VII.
As the experimental data show, bromination without a catalyst is directed quite selective-
ly at the carbon that is in the m-position to the carbonyl group. As might be expected [6], the
addition of catalysts, viz., Lewis acids, changes the course of bromination to form the 4-
bromosubstituted thiophene VI. It might be assumed that these features are fully applicable
to macrocyclic ketones. Actually, with cyclothienones as examples it was shown that bromi-
nation at the e-carbon relative to carbonyl in macrocyclic ketones is quite selective and
takes place in high yield (see Table 2).
Condensation of the bromosubstituted macrocyclic ketones was carried out by boiling in
alcohols (methanol, ethanol). The resulting macrocyclic aminothiazoles III are quite mobile
oils with an unpleasant acrid odor, which are easily purified from resinous impurities by silica
gel chromatography. For analysis the solid acetyl derivatives or hydrohalide salts were used.
For all the cyclothienones the yields of condensed aminothiazoles were quite high, from 76 to
88%. This is evidence that this size of macrocycle (C14-CI~), even when it includes the"rigid"
thiophene group, does not hinder the formation of a condensed system, although the "rigid"
group is enlarged by the two carbon atoms conjugated with the ~-system of the thiophene ring.

EXPERIMENTAL
Bromination of 5-ethyl-2-propiothienone (IV). A. A mixture of 3.36 g (20 mmole) of IV
[7], 20 mi of ethyl acetate, 7.4 g (33.1 mmole) of finely ground anhydrous copper bromide, and
20 ml of chlor0form was boiled for 2.5 h. The dark green copper bromide color gradually dis-
appeared and a grayish white cuprous bromide precipitate, Cu2Br2, appeared. After stirring
for another i0 h the precipitate was filtered off and washed with chloroform. The combined
solutions were washed with water and dried. After removal of solvent, distillation yielded
0.46 g ofunreacted IV and 2.9g of 5-ethyl-(~-bromopropionyl)thiophene (V), bp 128-132~
mm), 72% yield. Found, %: C 43.4; H 4.4; Br 32.3; S 13.0. CgHIIBrOS. Calculated, %: C 43.7;
H 4.5; Br 32.2; S 13.0. The purity of IV and V was monitored by GLC on a LKhM-8MD instrument
with flame ionization detector, column 1 m x 2 mm with 2% OV-17 on Chromosorb (60-80 mesh),
nitrogen carrier gas, column temperature 190~
B. Analogously to the procedure of [8], to a solution of 5.04 g (30 mmole) of IV in 30
ml of CCI~ was added dropwise with stirring a solution of 5 g (31.3 mmole) of bromine in i0
ml of CC14 at such a rate that the solution was decolorized before the addition of the next
drop. The mixture was stirred for 1 h at 20~ and poured into aqueous NaHCO3 solution. The

667
organic portion was separated, washed with water, and dried with MgSO~. After removal of
solvent and distillation there was separated 6.55 g (88% yield) of bromoketone V, bp 120-122~
(0.16 mm), identical by GLC with the preparation obtained by method A.
C. As proposed in [6], to i0 g of AICI~ in 30 ml of CHCI 3 was added with stirring a
solution of 8.4 g (49.9 mmole) of IV in 5 ml of CHCI~ and 8 g (50 mmole) of bromine, and the
mixture was heated for 2 h until the bromine color disappeared. After cooling the reaction
mixture was poured on a mixture of ice and 15 ml of HCI, the organic layer was separated,
and the aqueous solution was repeatedly extracted with chloroform. The combined organic
solutions were washed with water and dried. Distillation gave 11.5 g (93% y i e l d ) o f 4-bromo-
5-ethyl-2-propiothienone (VI), bp i12-i14~ Found, %: C 44.4; H 4.4; Br 31.9;
S 12.8. CgHIIBrOS. Calculated, %: C 43.7; H 4.5; Br 32.2; S 13.0.
2-Bromo-[lO]-~-gyclothienone-i (II, n = 9). A. To a suspension of 4.7 g (21 mmole) of
finely ground copper bromide in l0 ml of ethyl acetate was added over 20 min with stirring
a solution of 2.92 g (12.3 mmole) of cyclothienone I (n = 9) in i0 ml of chloroform. After
0.5 h the color of the solution changed from black to bright green, and a grayish white
precipitate of Cu2Br2 formed. After heating for 3 h the precipitate was filtered off and
washed with chloroform. After removal of chloroform the residue was dissolved in ether, and
the ether solution was washed with water, sodium thiosulfate solution, and again water, and
dried with MgSO4. The residue after removal of the ether (3.7 g) was chromatographed on a
column with silica gel L 100/60 (.benzene eluent) to yield 3.23 g (85% yield) of 2-bromo-[10]-
e-cyclothienone-i (II, n = 9), which crystallized as long fan-shaped crystals, mp 58.5-59~
(from n-pentane). P ~ spictrum (CC14): 7.73 (IH, d, J = 4 Hz, thiophene), 6.89 (IH, d, J =
4 Hz, thiophene), 4.4-4.6 (IH, q, J = 6 Hz, CHBr), 2.9 (2H, m, CI__!{2C4H2S), 1.1-1.6 ppm (14H, m,
(CH2)7). Found, %: C 53.9; H 6.3; Br 25.5; S 10.2; M 315. CI4HIsBrOS. Calculated: C 53.3;
H 6.1; Br 25.4; S 10.2; M 315.
B. To a solution of 4.8 g (20.3 mmole) of cyclothienone I (n = 9) in 30 ml of CCI~ was
added with stirring at 20~ a solution of 4 g (25 mmole) of bromine in 12 ml of CCI~ over 3.5
h; there was violent evolution of HBr and loss of bromine color. The residue after removal
of CCI~ was dissolved in ether, and the ether solution was washed with sodium carbonate so-
lution, sodium thiosulfate solution, and water, and dried. The residue after removal of
ether (6.6 g of dark oil) was chromatographed on a column with silica gel (CH2C12 eluent)
and vacuum-distilled. There was obtained 5.25 g (83% yield) of 2-bromoeyclothienone II (n =
9), bp 180-186~ (0.09 mm), mp 58-59~ (from n-pentane), identical by TLC with the material
obtained by method (A).
2-Bromo-[ll]-~-cyclothienone-i (II, n = i0). A solution of 2.3 g (9.2 mmole) of [ll]-~-
cyclothienone (I, n = i0) in i0 ml of chloroform was added with stirring over 0.5 h to a
suspension of 2.85 g (12.8 mmole) of copper bromide in i0 ml of ethyl acetate. After HBr
evolution ceased, the mixture was heated for 4 h, and the grayish white cuprous bromide pre-
cipitate was filtered off and washed with chloroform. The combined chloroform solutions were
washed with~water and sodium carbonate solution and dried. The residue after removal of
chloroform was separated from the resin by chromatography on silica gel (CCI 4 eluent) and
vacuum distilled to yield 2.8 g (92%yield) of 2-bromo-[ll]-~-cyclothienone (II, n = i0),
bp174-175~ nmO. Found, %: C 54.7; H 6.6; Br 24.7; S 9.9%. C15H21BrOS. Calculated,
%: C 54.7; H 6.4; Br 24.3; S 9.7.
2-Bromo-[12]-e-cyclothienone-I (II, n = ii). To a solution of 4.6 g (17.7 mmole) of
[12]-~-cyclothienone (I, n = ii) in 20 ml of CC14 was added over 2 h a solution of 5.1 g
(32 mmole) of bromine in 22 ml of CCI%. The mixture was stirred for 1 h and treated with
water, and the organic layer was washed with water, sodium carbonate solution, and sodium
thiosulfate solution. The residue after removal of CC14 was chromatographed on a column of
silica gel (benzene eluent). There was obtained 6.4 g of crystalline bromination product,
which after recrystallization from hexane yielded 5.3 g (87% yield) of 2-bromo-[12]-~-cyclo-
thienone (I!, n = ii), mp79-79.50C. Found, %: Br 23.9; S i0.0; M 342. CI6Hz3BrOS. Calcu-
lated, %: Br 23.3; S 9.4; M 343.
2-Amino-[lO]-~-cyclothieno[l,2-d]thiazole (III, n = 9). A solution of 10.65 g (340
mmole) of 2-bromo-[lO]-~-cyelothienone (II, n = 9) in 40 ml of methanol was added to a
solution of 2.7 g (350 mmole) of thiourea in 20 ml of methanol and the mixture was boiled
for 6 h. When the resulting solution of aminothiazolium bromide III (n = 9) was cooled a
small amount of it (0.41 g)precipitated as crystals, mp126-127~ (from heptane). Found, %:
C 48.2; II 5.6; Br 21.0; N 7.0; S 17.3. C15HzIBrN2Sz. Calculated, T: C 48.2; H 5.6; Br 21.0;

668
N 7.5; S 17.2. The residue after removal of methanol was treated with 25 ml of 40% NaOH
solution andextracted with ether. After removal of ether and chromatography on silica gel
(benzene e!uent), free base III (n = 9) was separated as a bright y e l l o w o i l with an acrid
odor, 8.7 g (88% yield). IR spectrum (tablets with KBr): 1630 (NH2 of N-4C--NH2 group), 2850,
2830 cm -I [(CH2)8]. UV spectrum (inCHCI3), Imax (log e): 225 (8.6), 294 nm (4.8). PMR
spectrum (CDCI3): 7.0 (IH, d, J = 4 Hz, thiophene), 6.7 (IH, d, J = 4 Hz, thiophene), 5.1
(2H, m, NIl2), 2.9-2.7 (4H, m, CH2adjacent to heterocycle), 1.6-1.0 ppm [12H, m, (CH2)~].
Found, %: C 61.2; H 6.8; N 9.0; S 21.5%; M 292. CI~H20N2S 2. Calculated, %: C 61.6; H6.9;
N 9.6; S 21.9; M 292. From 0.9 g of thiazole III (n = 9) boiling with acetic anhydride
yielded the N-acetyl derivative, yield 0.6 g, mp 206-207~ (from i:I heptane--toluene) o
Found: C 61.0; H 6.6; N 8.4; S 19.0. C17H22N2S20. Calculated, %: C 61.0; H 6.6; N 8.4;
S 18.2.
2-Amino-[ll]-e-cyclothieno[l,2-d]thiazole (Ill, n = i0). To a solution of i g (12 mmole)
of thiourea in i0 ml of methanol was added a solution of 1.93 g (6 mmole) of 2-bromocyclo-
thienone II (n = i0) in 20 ml of methanol a n d t h e mixture was boiled for 5 h. After removal
of precipitated thiazolium bromide III (n = I0) (0.12 g, mp I12-I13~ the solvent was evapo-
rated, and the residue was treated with i0 ml of 40% NaOH and extracted with ether. There
was obtained 1.7 g of clear oil, which after chromatography on silica gel (benzene eluent)
yielded free base III (n = I0), 1.37 g yield, 76%. !R spectrum (in CHCI3): 1630 (N~=C--NH2),
2850, 2930 cm -I [(CH2)9]. From 0.4 g of aminothiazole III (n = i0) after treatment with
alcoholic HCI and evaporation there was obtained aminothiazole hydrochloride III (n = i0),
0.44 g yield (100%),mp 185~ (from heptane--toluene). Found, %: C 55.5; H 6.0; C1 10.5;
N 8.2; S i0.0. C16H23CIN2S2. Calculated, %: C 56.0; H 6.7; C1 10.4; N 8.2; S 10.4.
2-Amino[12]-~-cyclothieno[l,2-d]thiazole (IIl, n = ii). A solution of 3.46 g (i0 mmole)
of 2-bromo4[12]-e-cyclothienone II (n = ii) in 15 ml of ethanoi was added to a solution of
0.9 g (i0 mmole) of thiourea in 8 ml of ethanol and the mixture was heated for 6 h a t 70~ The
residue after removal of solvent was treated with 8 ml of conc. HBr and evaporated to dry-
ness. There was obtained 5.2 g of aminothiazole hydrobromide III (n = ii). Yield 97%, mp
122-124~ Found, %: C 49.8; H 6.0; Br 19.2; N 6.8; S 16.8. CITH2sBrN2S2.
Calculated, %: C 50.7; H 6.3; Br 19.9; N 7.0; S 16.0. Free base III (n = ii) separated as oil
after treatment of the main amount of III hydrobromide (n = ii) with 40% NaOH and extraction
with ether, 2.54 g (83% yield).
2TAmino-5-methyl-4-(2-ethy~thienyl-5)thiazole (VII). A mixture of 6.55 g (38 mmole) of
bromoketone V, 2 g (26 mmole) of thiourea, and 5.3 ml of water was boiled for 2 h; the two-
phase system became homogeneous after 20 min. The solution was cooled. The precipitate
was filtered off, recrystallized from water and dried to yield 5.79 g (64% yield) of 2-amino-
5-methyl-4(2-ethylthienyl-5)thiazole hydrobromide, mp 203.5-205.5~ Found, %: C 39.7; H 4.4;
Br 25.7; N 9.2; S 21.0. CIoHI3BrN2S2. Calculated, %: C 39.4; H 4.3; Br 25.8; N 9.2; S 21.0.

LITERATURE CITED
i. Ya. L. Gol'dfarb, S. Z. Taits, and E. A. Krasnyanskaya, Khim. Geterotsikl. Soedin., No.
7, 920 (1980).
2. S. Z. Taits, 6. A. Krasnyanskaya, and A. A. Dudinov, IX Internat. Symp. on Chem. of Org.
Sulfur Compounds, Summaries [in Russian], Zinatne, Riga (1980), p. iii.
3. Ya. L. Gol'dfarb, S. Z. Taits, and L. I. Belen'kii, Zh. Obshch. Khim., 29, 3546 (1959).
4. A. Hantzsch and V. Traumann, Ber., 21, 938 (1888).
5. Ya. L. Gol'dfarb, S. Z. Taits, and V. N. Bulgakova, Izv. Akad. Nauk SSSR, Ser. Khim., ~,
1299 (1963).
6. L. I. Belen'kii, G. P. Gromova, and Ya. L. Gol'dfarb, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. 6, 1228 (1971).
7. W. Steinkopf, Ann., 430, 78 (1929).
8. F. Kipnis, H. Soloway, and J. Ornfelt, J. Amer. Chem. Soc., 71, I0 (1949).

669
SYNTHESIS AND STRUCTURE OF METHYL-SUBSTITUTED 1,3-
DIOXA-2-SILACYLOHEXANES

R. S. Musavirov, E. P. Nedogrei, UDC 547.245'269.1'422'841.07:543.422.541.63

L. F. Lapuka, E. A. Kantor,
R. S. Sarmanaev, and D. L. Rakhmankulov

The reaction of dimethyl(diethylthio)silane with !,3-diols gave methyl-substituted

1,3-dioxa-2-silacyclohexanes. IH and 13C NMR spectroscopy were used to study the
configuration and predominant conformations of the compounds studied.

The cyclization of diols with various bifunctional compounds is the most common method
for the synthesis of 1,3-dioxa-2-silacyclohexanes [I-16].
The use of dihalosilanes [1-3] at temperatures not exceeding 50~ permits the preparation
of the silicon analogs of acetals in 50-80% yield. An advantage of this synthetic method lies
in the availability of the starting halosilanes. However, the need to remove the HCI formed
by the usual method of converting it to an amine hydrochloride somewhat reduces the preparative
value of this reaction. Interest is found in a method involving the substitution of the
arsenic atom by a silicon atom in 1,3-dioxa-2-arsocyclopentane by reaction with dimethyl-
dichlorosilane [4] which permitted the synthesis of previously unreported 1,2-dimethyl-l,3-
dioxa-2-silacyclopentane.
The removal of the alcohol or acetic acid formed from the reaction mixture and the shift
in the equilibrium upon using dialkoxysilanes [i, 5-9] and diacetoxysilanes [i0, ii] raises the
yield of cyclic ethers of dia!kylsilanediols to 80-90%. The reactions are usually carried out
in the presence of a solvent and acid or basic catalysts. The reaction temperature is dic-
tated by the need to remove volatile reaction products.
The high reactivity of silazanes permits carrying out the reaction most often without
solvent by the simple mixing of the reagents [12-16]. The mild reaction conditions permit
the synthesis of 1,3-dioxa-2-silacycloalkanes containing not only alkyl substituents but
also halogen atoms and alkoxy groups at the silicon atom.
The cleavage of linear or cyclic polydialkylsiloxanes [i] or silazanes [13] in the
presence of basic catalysts leads to cyclic esters of orthosilicic acid in 60-80% yield.
This method requires the continuous azeotropic distillation of the water formed from the re-
action mixture.
Diols, especially secondary and tertiary diols, are not readily available compounds
and, thus, methods which permit the synthesis of 1,3-dioxa-2-silacycloalkanes without the
use of diols hold definite interest. The use of cyclic aeetals instead of diols in the re-
action with dialkoxy- or diacetoxysilanes leads to cyclic esters of dialkylsilanediols [17,
18]. Diethylsilanes react with ~, B, y-hydroxyacids in the presence of colloidal nickel or
palladium to form 1,3-dioxa-2-silacycloalkanones in 60-70% yield [19-23]. The reaction of
1,2-dicarbonyl compounds with silylphosphine permits the synthesis of 1,3-di0xa-2-silacyclanes
containing phosphorus atoms [24]. Alcohols readily displace mercaptans in alkylthiosilanes
[25]. On the other hand, the reactions of dialkylthiosilanes with diols have not been de-
scribed.
In the present work, we studied the reaction of dimethyl(diethylthio)silane (I) with 1,3-
diols II-Vl which permits the synthesis of methyl-substituted 2,2-dimethyl-l,3-dioxa-2-
silacyclohexanes VII-XI (Table i).

Ufa Petroleum Institute, Ufa 450062. Translated fromKhimiya Geterotsiklicheskikh

Soedinenii, No. 6, pp. 845-851, June, 1986. Original article submitted Febru@ry 13, 1985.

670 0009-3122/86/2206-0670512.50 9 1986 Plenum Publishing Corporation

 TABLE i. Physicochemical Constants of Compounds Synthesized
VII-XI
Calculated, %
pound! M* (mmHg)['~D'~ ] d,~o C [ H c a l for- [-
H ,,,,[ Si

21,20 [CsHI~O2Si[45,42 9,15 [ 21,24

IVII1 14a 132 (754)1L416810,95321 49,301 9,60 19,20 }C~H,40~Sq49,27 9,64 ] 19,22
IXsx 160 139 (751)I 1,4'21310,94211 52,50 [ t0,10 17,50 [C&I~O2Si] 52.45 o,o6 t 17,05
I60 141 (753)[I,4~6910,97591 52,4O ;0,00 17,50 ICTHI~O~Sil52,45 10,06 t 17,54
XI 174 146 (755)[1,426310,9362[ 54,60 ll,lO 16,10 IC~H,sO2Si[54,62 11,13] 16,10

*Determined by mass spectrometry.

~" n~~ 1,4130 [1], 1,4118 [17], t,41~20 [2]; d4~ 0,970! [17], 0,9703 [2]; Tbp: 122
(763~ ~1], I23 (752) ~171, 121,7~ [2].
n~~ l~4272 [1], 1,4170 [43]; T.bp 144--145 (762) [I], 24--25 (5) ~ [43].

R4 R~ 1 5 R~ R3 2
. R R R
(CIt~);~Si(SC~Hs) ~ ~ R2 __--.~. RI + ~ C2HsSH
tt0 OH O\ ~0
I /Si ~I
II-Vt CH~ ~CH 3
VII-X1
II, VII R~=R2=I~'~=R4=R'~=II; III, VIII RI=CHa, R2=R3=R4=RS=H; IV, IX Rl=
=R2=CHa, R3=R4=Ra==tl; V, X R'=R2=R~'=:H, Ra=R4=CH3; VI, XI R'=W=Rs=CH3,
R3 - R~=t1

This reaction is not an equilibrium process and proceeds both with and without acid
catalysts such as H2SO~,SnCI 4, and p-toluenesulfonic acid (Table 2). The use of SnCI~ and p-toluene-
sulfonic acid at concentrations less than 0.01 mole/liter has virtually no effect on the yield
of dioxasilacyclohexane IX (Table 2). Increasing the concentration of SnCI4 or p-toluenesul-
fonic acid to 0.01 mole/liter or the use of H2S04 markedly reduces the yield of IX. The re-
action occurs instantaneously upon mixing of the reagents. An increase i n t h e temperature
increases the yield of 1,3-dioxa-2-silacyclohexanes such as XI having gem-dimethyl substituents
at the quaternary carbon atom in the ring. An increase in the temperature from 20 to 60~ in
the reaction of 1,3-propanediol with silane I leads to a reduction in the yield of VII from
58 to 10%. The temperature effect on the yield of the desired product is much less pronounced
upon using methyl-substituted propanediols III-V (Table 2).
Thus this reaction, in comparison with the reaction of diols with chlorosilanes [1-3],
alkoxysilanes [I, 5-9], and acetoxysilanes [i0, ii] or the cleavage of polyorgany!siloxanes
[i], proceeds under milder conditions s i m i l a r t o the reaction of diols with silazanes [12-16]
and gives 1,3-dioxa-2-silacyclohexanes in yields up to 76% (Table 2).
There have been only a few conformational studies of 1,3-dioxa-2-silacyclohexanes, and their
results have been contradictory [26-29]. Thus, for example, Albriktsen [28] and Voronkov [29]
concluded chair--chair conformational transitions on the basis of the averaged Z H N M R spectral
parameters of 2,2-dimethyl- and 2,2,5,5-tetramethyl-l,3-dioxa-2-silacyclohexanes, while Hellier
[27] indicated a significant contribution of flexible structures to the conformational equilib-
rium. Low-temperature measurement of IH NMR spectra of these compounds [28] showed a lower
inversion barrier than that for 1,3-dioxanes. For cyclic system having a silicon atom with
tetrahedral bond configuration [30], we should expect a stereochemical analogy with the corre-
sponding 1,3-dioxanes. 2-Alkoxy-2-sila-l,3-dioxacyclohexanes may be taken as an example. These
compounds, similar to 2-alkoxy-l,3-dioxanes, are found predominantly in their conformation with
axial orientation of the alkoxyl substituent [9].
We should note that the energy barriers in cyclohexanes and 1,3-dioxanes for chair--chair
interconversion are 1.2-2.0 times higher than in chair--twist interconversions [32, 33, 42].
The Si-O (1.66 ~ [31]) and Si-C (1.85 ~ [31]) bond lengths in organosilicon compounds
are greater than the lengths of the analogous C-O (1.44 ~ [12]) and C-C bonds (1.50
[32]) in their carbon analogs. Therefore, some levelling out of the rotational barriers is
possible in organosilicon compounds due to a diminution of steric hindrance. Thus, for
example, the energy barriers for chair--chair and chair--twist interconversions in l,l-dimethyl-
l-silacyclohexane are virtually identical (5.5 and 5.4 kcal/mole, respectively [33]).

671
 TABLE 2. Conditions and Results of the Reaction of D~methyl-
diethylthlosilane (I) wi~h 1,3-Diols (II-VI) in 1,4-D~oxane

, o~[dl01 taken at
Diol* o~ IT_~C Diol molelllmr
mole/liter
~'N=! 1 l! _

II ~VII 58 34 lO IV p-TSA 0,0! ]X [ 5'2

III VIII 36 32 1V p-TSA 0,04 IX t 32
IV IX 66 70 76 VI
~v X 4'2 42 42
IV I-I~SO~02 i [X 6 XI 52 66
IV SnCI~0,01 IX 48
*l,3-Propanediol (II), I, 3-butanediol (III), 3-methyl-l,3-
butanediol (IV), 2,2-dimethyl.l,3-propanediol (V), and 4-
methyl-2,4-pentanediol VI.
#2,2-D (VII), 2,2,4-tri-
methyl-l,3-dioxa-2-si!acyclohexane (VIII), 2,2,4,4-tetra-
methyl-l,3-dioxa-2-silacyclohexane (IX), 2,2,5,5-tetra-
methyl-l,3-dioxa-2-silacyclohexane (X), 2,2,4,4,6-penta-
methyl-l,3-dioxa-2-silacyclohexane (XI).

The IH and l~C NMR spectra of 2,2-dimethyl- (VII), 2,2,5,5- (X) and 2,2,4,4-tetramethyl-
1,3-dioxa-2-silacyclohexanes (IX) taken at room temperature indicate the stereochemical equiv-
alence of the geminal substituents in all the ring positions (Tables 3 and 4), which indicates
rapid ring inversion for these molecules on the NMR time scale. Thus, for example, the pro-
tons of the methyl groups at Si in VII give a ~H NMR signal at ~ 0.06 ppm. The protons
at C(4) and C(~) give rise to a triplet at ~3.98, while the protons at C(s) give a quintet at
61.78o The averaged vicinal spin--spin coupling constant for the protons of the carbon ring
segment is 6.2 Hz. As shown for several cis-l,4-substituted cyclohexanes [34], this behavior
is possible for molecules with rapidly inverting twist conformations.
An analogous conclusion was drawn by Hellier [27] in a conformational study of a series of
2,2-dimethyl-, 2,2-diphenyl-, 2-methyl-2-phenyl-l,3-dioxa-2-silacyclohexanes and their 5,5-
dimethyl derivatives. However, chair-chair inversion was indicated by other workers in de-
scribing the spectra of similar structures [28, 29]. The methyl protons of the gem-dimethyl
groups at Si and C(4) in the ring of IX give singlets at ~0.02 and 1.20 ppm, respectively.
The methylene protons at C(s) and C(6 ) give distorted triplets at ~1.66 and 3.96 ppm, re-
spectively; the middle line of these triplets is the superposition of five lines and its
amplitude is comparable to the two side lines. Analysis of the multiples according to second
order rules [35] gives the absolute sum of the averaged vicinalcoupling constants of the
methylene protons (II Hz) and the absolute difference of the geminal coupling constants of the
methylene protons at C(s) andC(s) (2.9 Hz). Assuming that the vicinal coupling constants
have the same signs, we expect that 3J6Ese + 3J~As a = 15.1Hz. In accord with Pihlaja and
Auras [36], such a value is characteristic for non-chairlike structures, while the analogous
sum of the coupling constants for chairlike 1,3-dioxanes does not exceed 14 Hz [32, 36-38]
(for the ideal 1,3-dioxane chair, 3JGE~e = 1.2 and 3J~As a = 12.4 Hz). Thus, the NMR spectra
of IX indicate rapid conversions of the following type:
CH 3

cI( "~0j~P" "-.(OH "HE "

HQ cH~ nA

Analogous structures were established for alkyl-substituted 1,3-dioxanes, in which 2,4-syn-

diaxial nonbonding interactions arepossible in the chair conformation betweenthe two alkyl
groups [32, 37, 38].
The PMRspectra of XI indicate the realization of a predominant conformation. The
proton at C(~) gives a multiplet at ~4.14 ppm with coupling constants 6.2, 4.8, and 8.8 Hz.
The splitting by 6.2 Hz is due to coupling of this proton with the protons of the methyl group
at C(G), While the two other coupling constants are due to the protons at C(s). The value
aJ~FH = 8.8 Hz is characteristic for trans orientation of the coupled protons [32, 38] and
corresponds to a dihedral angle e between the C--H bonds at C(5) and C(G) close to 180 ~ on the
Karplus curve. This permits assignment of pseudoaxial orientation for the proton at C(6) and,

672
TABLE 3. Chemical Shifts and Coupling Constants in the 1H NMR Spectra of 1,3-Dtoxa-2-sil-
acylohexanes (VII-XI)
' 6, p p m , ~ignai t y p e , Is H z ' '
Com-
pound ring protons subsfltuent p t o t o m
C(4 ) C(5 ) C(6 ) 2-CHs 4"CHs 5-CHa 6-CHs

VII 3,98 t 1,78q 3,98 t 0,06 s

s,/mj =6,2
3,97 t [26] 1,76 q [26] 3.97 t [261 0,09 s [261
~,~7 [28] 1,7 q [28] 3,9 t [28] o,o8 s [28t
~,u~ t [27] 1,81 q [27] 3,98t [27] - 0 , 2 s [27]
a/nn=5,4
27, 28]
J1m~=5,6 [37]
IX 1,66t 3,96 t 0,02 S 1,20 s
a/~Es~+ al6asa = 15,1
X 3,44 s 3,44 s 0,06 s 0,78
3,56 s [261 3,56 s ~261 0,09 s [26] 0,95 s [261 --
3,6 s [27] 3,6 s [271 0,2 s [271 0,95 s [27]
XI 1,48 Ha 4,14 HA 0,03 s 1,13s - - 1,08 d
1,41 He 3JsAse = 4,8 1,19 s aJCHa6A =6,2
2/s,5~= - 14,0 sJ6A~.= 8,8
aYsa6a=8,8 fc 6ACHa = 6.2
aJs~6a=4,8 1,05 d
VIII 3,90 HA 1,51 Ha 3.84 HA 0,03 S a] CHa4A = 6 , 5
s14.sa=9,6 1,22 He 3.79 HE 0,05 s
a]4.se=5,8 2Jsase= - 14,0 2JnAsE= -- 10,2
315a4A = 9,6 aJ6Asa= 9.6
aJsa6E = af5e4A = 5,8 a,,r6As~= aJsEs. = 5,8
3J~6E = 2,8 af6me = 2,8

TABLE 4. Chemical Shifts and IJc_ H Coupling Constants in the

13C NMR Spectra of 1,3-Dioxa-2-silacyclohexanes (VII-XI)
Com- 6. p p m . signal type. J, Hz
pound ring atoms substituent atoms
CI4 ) Ct5 ) CI61 2-CH~ 4-CHa 5-CHa 6-CHa

VII 58,6 t 35,1 1; -3,6 q

J = 142 J = 125 1=118
VIII 68,7 d 38.2 t 61,9 t -0,90 q 23,9 q
7= 139 J = 126 1 = 144 7=118 l = 125,5
-2,8 q
J=l18
IX 74,7 s 41,5 t 59,1t 0,3q 29,7 q
J = 125 7 = I44 7=117 J = 124
X 72,7 t 34,6 s 72,7 t -3,0 q 21,4 q
1 = 145 J = 145 ]=118 J = 125
XI 71,6 s 48,9 t 64,7 d 0.2 q 27,7q 24,4 q.
J=125 J = 125 7=118 J = 123 I= 126
1,0 q 32,7 q
J=l18 I=123

correspondingly, a pseudoequatorial orientation for the methyl substituent at C(6) (~ 1.06

ppm). The magnetic inequivalence of the protons at C(s) is 0.07 ppm.* The protons of the
methyl groups at Si give rise to a broadened singlet. The methyl groups at C(4) give singlets
with a chemical shift difference of 0.04 ppm. These spectral indices indicate that in solutions
of XI, the conformational equilibrium is shifted toward the predominant formation of the 2,5-
twist conformer:

6 ~..~cH~
(:H3. . "~- ~ ~ H A

et]3 ~0
HA

*The chemical shift difference for Ha and He at C(5) is 0.25-0.60 ppm in the chair confor-
mation of the 1,3-dioxane ring [32, 40, 41].

673
 2,2,4-Trimethyl-l,3-dioxa-2-silacyclohexane VIII gives a complex spectrum due to the
presence of two stereoisomers in 55:45 ratio.
Enrichment of the mixture with the more volatile component of VIII permitted interpre-
tation of the spectrum of this stereoisomero The methylene protons H A and HE at C(B) are
characterized by inversion of the nuclear magnetic shielding constants ~. The axial proton
has a greater chemical shift, probably as a result of the redistribution of electron density
in VIII upon the interaction of the unshared electron pairs of the oxygen atoms with the d
orbitals of the silicon atom. However, the geminal and vicinal coupling constants in VIII
are close to the typical values in 1,3-dioxanes [32, 38] with chair conformation. The
proton adjacent to the methyl group at C(4) gives rise to a signal at ~3.9 ppm with char-
acteristic vicinal constants 9.6 and 5.8 Hz due to coupling of the axial proton with the
methylene protons at C(s). Thus, the methyl group occupies the equatorial position at C(~).
The protons at C(s) have inversion to the Oa and Oe constants. Inversion of the shielding
constants at C(s) is typical for 1,3-heterocycles containing oxygen or nitrogen only in the
chair conformation [39]. Thus, these results indicate that the more volatile stereoisomer
is predominantly in the chair conformation.
The chemical and three-dimensional structures of these compounds were also supported by
their 13C NMR spectra. In the spectra of 2,2-dimethyl-2,2,4,4-, and 2,2,5,5-tetramethyl-l,3-
dioxa-2-silacyclohexanes with total proton decoupling, the signals of the methyl carbons of
the gem-dimethyl groups are singlets (Table 4), which, as in the PMR spectra, indicates
rapid ring inversion. In the case of XI, in which the equilibrium is enanchomeric, the
carbon atoms of each of the gem-dimethyl groups resonate at different fields. The chemical
shift difference of the carbon atoms of the methyl groups at C(~) (A~ = 5.0 ppm) is signifi-
cantly greater than that for the carbon atoms of the methyl groups at the ring silicon atom
(46 = 0.8 ppm).

EXPERIMENTAL
The IH NMR spectra of VII, IX-Xi in CC14 or in CC14 with 5% benzene or CHCI3 for VIII
were taken at 24~ on a Tesla BS-497 NMR spectrometer at I00 MHz. The 13C NMR spectra were
taken on a Bruker WH-90 spectrometer with and without s u p p r e s s i o n o f C - H coupling with
spectral width 6 kHz. Hexamethyldisiloxane was used as the internal standard.
The syntheses were carried out in a jacketed 6 cm 3 glass reactor with a device for the
removal of samples for chromatographic analysis. The temperature was maintained with an
ultrathermostat to 176 The calculated amounts of the reagents and solvent (l,4-dioxane)
were added to the reactor. The catalyst was added after the solution reached the required tempera-
ture and the reaction mass was maintained at this temperature for i0 min. The reaction was
stirred with a magnetic stirrer in order to obtain rapid homogenization of the catalyst.
The analysis of the starting and final products was carried out by gas-liquid chroma-
tography on an LKhM-8MD model 5 chromatograph using a katharometer detector and a 3 m x 3 mm
column packed with SE-30 on Chromatone N-AB (0.15-0.20 mm fraction). The column temperature
was 50-250~ The programming was accomplished at 6~ The helium gas flow rate was
2 liter/h.
The reaction products were fractionated by distillation and on a PAKhV-08 preparative
chromatograph using a 2 m x 9 mm column packed with 10% SE-30 on Chromatone N-AB (0.3-0.6
mm fraction) and helium as the gas carrier.
The physicochemical indices of VII-XI are given in Table i.

LITERATURE CITED
i. M. G. Voronkov and Yu. P. Romadan, Khim. Geterotsikl. Soedin., No. 6, 879 (1966).
2. Ro H. Krieble and C. A. Burkhard, J. Am. Chem. Soc., 69, No. ii, 2689 (1947).
3. Ro P. Narain and A. J. Kaur, Indian Chem. J., AIS, No. 6, 522 (1979).
4. F. Kober and J. Ruhlw, J. Organometall. Chem., i01, 57 (1976).
5. L. Wo Breed, W. J. Haggerty, and J. Harvey, J. Org. Chem., 25, No. i0, 556 (1960).
6. M. G. Voronkov, Yu. P. Romadan, Yu. P. Pestunovich, and I. B~. Mazheika, Khim.
Geterotsikl. Soedin., No. 6, 972 (1968).
7. R. P. Narain and A. J. Kaur, Indian Chem. J., AI6, No. 4, 355 (1978).
8. R. P. Narain and A. J. Kaur, Indian J. Chem. Soc., 154, 504 (1977).
9. V. I. Larionov, L. F. Lapuka, R. So Musavirov, S. S. Z!otskii, and D. L. Rakhmankulov,
Zh. Obshch. Khim., 52, 2280 (1982).

674
i0. M. G. Voronkov, V. P. Davydova, and B. N. Dolgov, Izv. Akad. Nauk SSSR, Otdel. Khim. Nauk
No. 6, 698 (1958).
Ii. V. P. Davydova and M. G. Voronkov, Zh. Obsheh. Khim., 288, 1979 (1958).
12. K, A. Andrianov, T. K. Dzhashiashvili, V. V. Astakhin, and G. N. Shumakova, Izv. Akad.
Nauk SSSR, Ser. Khim., No. 12, 2229 (1966).
13. L. Birkofer and O. Stuhl, J. Organometall. Chem., 187, 21 (1980).
14. L. Birkofer and O. Stuhl, J. Organometall. Chem., 164, 16 (1979).
15. L. Birkofer and O. Stuhl, J. Organometall. Chem., I~7, 16 (1979)~
16. R. S. Musavirov, L. F. Lapuka, E. P. Nedogrei, V. I. Larionov, i. A. Kudasheva, E. A.
Kantor, S. S. Zlotskii, and D. L. Rakhmmnkulov, Dokl. Akad. Nauk SSSR, 270, 616 (1983).
17. V. I. Larionov, R. S. Musaviron, E. A. Kantor, S. S. Zlotskii, D. L. Rakhmankulov, and
R. A. Karakhanov, Dokl. Akad. Nauk SSSR, 255, 255 (1980).
18. R. S. Musavirov, E. P. Nedogrei, S. S. Zlotskii, L. F. Lapuka, E. A. Kantor, and D. L.
Rakhmankulov, Zh. Obshch. Khim., 52, 921 (1982).
19. I. I. Lapkin, T. N. Povarnitsina, and T. Yu. Denisova, Zh. Obshch. Khim., 44, !23 (1974).
20. I. I. Lapkin, T. N. Povarnitsina, and T. Yu. Subocheva, USSR Inventor's Certificate No.
374314; Byul. Izobr., No. 15, 51 (1973).
21. I. I. Lapkin, T. N. Povarnitsina, and T. Yu. Denisova, Zh. Obshch. Khim., 42, 2032
(1972).
22. I. I. Lapkin, T. N. Povarnitsina, and V. V. Dvinskikh, Zh. Obshch. Khim., 48, 607 (1978).
23. I. I. Lapkin, T. N. Povarnitsina, and T. Yu. Subocheva, Zh. Obshch. Khim., 42, 399
(1972).
24. C. Couret, J. Satge, and F. Couret, J. Organometall. Chem., 57, 287 (1973).
25. S. N. Borisov, M. G. Voronkov~ and E. Ya. Lukevits, Organosil---icon Derivatives of Phos-
phorus and Sulfur [in Russian], Izd. Khimiya, Leningrad (1968), p. 292.
26. M. G. Voronkov, V. A. Petunovich, and Yu. P. Romadan, Khim. Geterotsikl. Soedin.~ No. i,
178 (1968).
27. D. G. Hellier, Chem. Ind., No. 41, 1323 (1970).
28. P. Albriktsen and S. Heggelund, Acta Chem. Scand., 28B, No. 5, 573 (1974).
29. L. K. Yudlasheva, R. P. Arsh~nova, Yu. Yu. Samitov, Yu. P. Romadan, and M. G. Voronkov,
Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 323 (1974).
30. F. Cotton and G. Wilkinson, Fundamentals of Inorganic Chemistry [Russian translation], Izd.
Mir, Moscow (1979), p. 220.
31. A. F. Skryshevskii, V. P. Klochkov, and Yu. V. Fasechnik, Zh. Strukt. Khim., 2, 140 (1961).
32. M. Anteunis, D. Tavernier, and F. Borremans, Heterocycles, 4, 293 (1976).
33. C. H. Bushweller, J. W. O'Nell, and H. S. Bilofsky, Tetrahedron, 27, 3065 (1971).
34. H. Booth, Tetrahedron Lett., No. 23, 1449 (1964).
35. J. Delmau and C. Barbier, J. Chem. Phys., 41, No. 4, I106 (1964).
36. K. Pihlaja and R. Auras, Acta Chem. Scand., 26, No. 3, 252 (1972).
37. K. Pihlaja and R. Auras, Acta Chem. Stand., 24---,531 (1970).
38. Yu. Yu. Samitov, Khim. Geterotsikl. Soedin., No. 12, 1587 (1978).
39. Yu. Yu. Samitov, Dokl. Akad. Nauk SSSR, 164, 347 (1965).
40. A. V. Bogatskii, Yu. Yu. Samitov, S. P. Egorova, T. A. Zakharchenko, Zh. Org. Khim., ~,
830 (1969).
41. J. Delmau and J. Duplan, Tetrahedron Lett., No. 6, 559 (1966); No. 24, 2693 (1966).
42. V. M. Gittins, E. Wynn-Jones, and R. F. ~ i t e , in: Internal Molecular Rotation [Russian
translation], Izd. Mir, Moscow (1977), p. 352.
43. N. Spassky, Comp. Rend. Chim. Org., No. 2, 2371 (1960).

675
LETTERS TO THE EDITOR

SYNTHESIS OF DIBENZOFURANAND ITS NITRO-SUBSTITUTED DERIVATIVES

Yu. V. Maevskii and G. I. Migachev UDC 547.728'621'07

The intramolecular nucleophilic substitution of the ortho-nitro group in 2'-nitro-2-

hydroxybiphenyl in the presence of alkali agents (KOH, NaH, t-BuOK) in polar aprotic solvents
(DMF, hexametapol, DMSO) leads to dibenzofuran. This reaction is a further example of the
intramolecular nucleophilic substitution of the ortho-nitro group in the biphenyl nucleus
[1, 2].
R3 ~ Rr

I a-f ua-f
I, I I b R~=NO2, c R2=NO~, d R3=NO~, e R4=N02, f R~=Rs=NO2; aU unspecified
R=H

The solution of 0.01 mole of 2'-nitro-2-hydroxybiphenyl (Ia-f) in 30-45 ml of the aprotic

solvent is stirred for 2-6 h in the presence of 0.02 mole of the alkali agent at a raised
temperature; the mixture is cooled and poured into dilute hydrochloric acid. The precipitate
crystals are filtered off and purified by chromatography on a column with alumina prior to
the isolation of the dibenzofurans (IIa-f).
The compounds are presented with the characteristics of reaction temperature (~ yield
(%, utilizing hexametapol or DMSO as the solvent and NaH as the alkali agent), and mp (~
(IIa), 125,130, 70, and 82-82.5 (from acetone); (IIb), 110-120, 72, and 138-138.5 (from
acetone); (IIc), 110-120, 75, and 182-183 (from ethanol); (IId), 110-120, 70, and 151.5-152
(from benzene); (lie), I00, 89, and 1.21-122 (from acetic acid); (IIf), 40-60, 83, and 327-
328 (from acetic acid).
The data of the elemental analysis of the compounds (IIa-f) correspond to the calculated
data. The individuality of the compounds was evaluated by the method of thin layer chroma-
tography on Silufol.

LITERATURE CITED
i. G. I. Migachev, A. M. Andrievskii, and L. V. Efimova, Khim. Geterotsikl. Soedin., No. 5,
703 (1977).
2. A. M. Andrievskii, A. N. Poplavskii, andK. M. Dyumaev, Zh. Vses. Khim. O-va., 26, i01 (1981).

Moscow Technological Institute of the Meat and Milk Industry, Moscow 109818. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, p. 852, June, 1986. Original
article submitted July 16, 1985. Revision submitted January i, 1986.

676 0009-3122/86/2206-0676512.50 9 1986 Plenum Publishing Corporation

FURO[2,3-c]PYRYLIUM -- A NEW HETEROAROMATiC SYSTEM

V. I. Dulenko and V. N. Voshchula UDC 547.728'816'828.07

Furo[2,3-b]pyrylium [i] and furo[3,2-c]pyrylium [2] salts are known. During the develop-
ment of the acid-catalyzed heterecyclization reaction [3], we synthesized previously unknown
furo[2,3-c]pyrylium salts. Thus, 5,7-dimethylfuro[2,3-c]pyrylium perchlorate (II) was iso-
lated in a yield of 65% by the acylation of 3-acetonylfuran (I) with the mixture of acetic
anhydride and 70% perchloric acid; (II) had the mp 155-157~ (with decomposition). The PMR
spectrum (CF3COOH) is given by the following ~ values: 3.0 (3H, singlet, 5-CH3), 3.2 (3H,
singlet, 7-CH3), 7.4 (IH, doublet, J = 2 Hz, 3-H), 8.0 (IH, singlet, 4-H), and 8.75 ppm (IH,
doublet, J = 2 Hz, 2-H). The initial 3-acetonylfuran was obtained from 3-bromofuran by the
method of [4]. O n the reaction of the salt (If) with ammonia, 5,7-dimethyifuro[2,3-c]pyri-
dine (III) is obtained.

/CH2CCCH 3 ,~-~ /eli 3

I U CH~ Ill CH~

LITERATURE CITED
I. J.-M. Mennier and P. Fournary, Bull. Soc. Chim. France, No. i0, 3343 (1971).
2. G . N . Dorofeenko and L. V. Dulenko, Khim. Geterotsikl. Soedin., No. 3, 417 (1969).
3. Ya. P. Stradyn', Khim. Geterotsikl. Soedin., No. i0, 1412 (1981).
4. T. Sugai, H. I~wa, T. Okazaki, S~ Akabushi, and S. Ikegami, Chem. Lett., No. 4, 597
(1982).

Institute of Physicoorganic Chemistry and Carbon Chemistry, Academy of Sciences of the

Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.
6, pp. 852-853, June, 1986. Original article submitted Dembember 2, 1985.

0009-3122/86/2206-0677512.50 9 1986 Plenum Publishing Corporation 677

 ALKYLATION OF FURAN AND THIOPHENE WITH tert~BUTANOL IN THE
PRESENCE OF THE STRONGLY ACID CATION EXCHANGER AMBERLYST 15

E. Ya. Lukevits, L. M. Ignatovieh, UDC 547.722'732.541.128

Yu. Sh. Gol'dberg, and M. V. Shimanskaya

The best of the presently known routes for the synthesis of 2-(tertbutyl)furan (I) is the
Friedel-Crafts alkylation of furan-2-carboxylic acid by tert-butyl chloride and the subsequent
decarboxy!ation of the resulting 5-(tert-butyl)furan-2-carboxylic acid in the presence of
quinoline and cupric oxide at a raised temperature [I]. We have established that the alkyl-
furan (I) can be obtained in one stage by the reaction of furan with tert-butanol in the
presence of the commercially available ("Fluka") strongly acid ion-exchange resin Amberlyst
15 (A 15) containing the SO3H function (4.6 mg-equivalents of SO3H groups in 1 g of resin;
the water content < 3%).*
The reaction can be accomplished in two variants. According to the first, A 15 (1.15
mmole based on the SO3H groups) is added to the solution of 1 mmole of tert-butanol in
excess furan; the resulting suspension is stirred at room temperature for 24 h. Compound
(I) is thereby formed in a yield of 80% based on tert-butanol.# Under analogous conditions,
compound (I) is alkylated to 2,5-di(tert-butyl)furan (II) with a yield of 75%. The tert-
butylation of thiophene does not proceed at room temperature, and the 3.5:1 mixture of
2- and 3-(tert-butyl)thiophene is formed in quantitative yield on heating the mixture of
thiophene with tert-butanol in the presence of A 15 (80~ 1 h).
In the second variant, the alkylation is performed in an inert solvent. For example,
the yield of the alkylfuran (I) comprises 90% in the alkylation of furan (0.3 M solution in
CCI~, a 1:1.5:2 molar ratio of furan--t-BuOH--A 15, 76~ microautoclave, 3 h). A tenfold ~
increase in the excess of the sulfo-cation exchanger, relative to the data ~resented above,
sharply accelerates the reaction, which stops after 3 0 min (~20~ and gives a 1:3.5 mixture
of the alkylfurans (1) and (II).
The method proposed for the tert-butylation is significantly simpler than that described
in the work [I] and permits selective monoalkylation, whereas the new recently proposed
variant of the alkylation of aromaticand heterocyclic compounds by tert-buty! bromide,
catalyzed by silica gel, only permits the isolation of the 2,5-di(tert-butyl) derivatives in
the case of furan and thiophene [5].
The tert-butylation reactiondoes not proceed with theutilization of the weakly acid
ion-exchange resin IRC-50 containing the COOH function. ~
Therefore, the described method of alkylation utilizing the sulfo-cation exchanger,
i n s o l u b l e i n the reantion medium, as the acid agent can evidently serve as an effective
alternative to the traditional Friedel-Crafts alkylation, which i s k n o w n [6, 7] to present
much difficulty in the case of five-membered heterocycles o w i n g t o the acidophobicity of
these compounds.

LITERATURE CITED
I~ J. Fitzpatrick, D. Milner, and P. ~ i t e , Synth. Comm., 12, 498 (1982).
2. L . T . Scott and I. O. Naples, Synthesis, No. 3, 209 (1973).
3. G . M . Coppo!a, Synthesis, No. 12, 1021 (1984).

For the utilization of AI5 as an acid agent in organic synthesis, see e.g., [2-4].
# T h e yield and the ratio of the reaction products were determined from GLC data.

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 853-854, June, 1986.
Original article submitted January i0, 1986.

678 0009-3122/86/2206-0678512.50 9 1986 Plenum Publishing Corporation

 . C. W. Jefford and G. Bernardinelli, Tetrahedron Lett., 26, 615 (1985).
5. Y. Kamitori, M. Hojo, R. Masuda, T. Izumi, and S. Tsukamoto, J. Org. Chem., 49, 4161
(1984).
6. S. H. Patinkin and B. S. Friedman, Friedel--Crafts and Related Reactions (ed. G. A. Olah),
Vol. 2, Interscience, New York (1964), p. 104.
7. C. C. Price, Organic Reactions, Vol. 3, New York, (1967), p. !.

NEW METHOD OF ISOLATING N-SUBSTITUTED 3-AMINOMETHYLENETHIOL-

4-EN-2-ONES

M. A. Kalik, Ya. L. Gol'dfarb, and M. M. Krayushkin UCD 547.733.04

The methods for the synthesis of the little-studied N-substituted 3-aminomethylenethiol-

4-en-2-ones (I) -- thiophene analogs of aromatic o-hydroxyazomethines -- are based on the appli-
cation of the not readily accessible and labile hydroxy and methoxy derivatives of thiophene
[1, 2].
We have found that the compounds (I) can be obtained in good yields (60-80%) by the re-
action of the corresponding N-substituted mercaptoaldimines (II) with mesitylnitrile oxide
(III) at 20~ for 20-30 min. The resulting oxyaldimines (la-c) and mesityl isothiocyanate
(IV) are separated by chromatography on silica gel utilizing hexane [for compound (IV)] and
CHCI3 [for the substances (I)] as the eluents.

I~'/'~S" ~S"" Ill J{ " s ~'-~-;,c,

0~ ~ A~

lla-C

CH N RI

----I~ I + AJ"--N:~(,'=S

R" "'S I O ~" IV

la-c

[, II a,b R=EL c R=OMe; a,c RI=cyclo-C6H1t, b RJ=~-CmH~; Ar=2,4.6-M%C6H2

The s t r u c t u r e and c o m p o s i t i o n o f t h e compounds o b t a i n e d were c o n f i r m e d by t h e d a t a o f
t h e e l e m e n t a l a n a l y s i s , IR, UV, PMR, and mass s p e c t r a . The o x y a l d i m i n e s ( I a , b) were i d e n t i -
c a l t o t h e s a m p l e s p r e v i o u s l y d e s c r i b e d by u s [2] a c c o r d i n g t o t h e mps and t h e s p e c t r a .
Compound ( I c ) , CI2HITN02S, had a y i e l d o f 70% and mp I 1 9 - 1 2 1 ~ (from a l c o h o l ) . The PHR
s p e c t r u m i n CDCI s was a s f o l l o w s : 3 . 7 5 (3H, s i n g l e t , OCH3), 5 . 3 8 (IH, s i n g l e t , 4-H), 7 . 0 0 (IH,
d o u b l e t , CH=N, JCH,NIi = 1 3 . 5 HZ), and 9 . 0 0 ppm (IH, b r o a d s i n g l e t , NH). The mass s p e c t r u m
(m/z, J, 7=) was as follows: 239 (I00) (M+), 224 (70), 157 (80), 142 (85), and 114 (20).
The conversion observed can be considered as the selective 1,3-dipolar cycloaddition of
the nitrile oxide (III) at the thiocarbonyl group of the mercaptoaldimine (II), and the
subsequent opening of the resulting oxathiazole ring with the accompanying migration of the
aryl residue to the nitrogen and the elimination of the isothiocyanate (IV) [3].

LITERATURE CITED
I. P. Demerseman, J. P. Lechartier, A. Cheutin, M. J. Desvoe, and P. Royer, Compt.
Rend., 254, 1652 (1962).
2. Ya. L. Gol'dfarb and M. A. Kalik, Khim. Geterotsikl. Soedin, No. 2, 178 (1971).
3. Ch. Grundmann and P. Grunanger, The Nitrile Oxides, Springer-Verlag, Berlin (1971), p.
122.

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow.

117913. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 854~855, June,
1986. Original article submitted February 3, 1986.

0009-3122/86/2206-0679512.50 9 1986 Plenum Publishing Corporation 679

SYN~IESIS OF BIS(o-XYLYLENEDITHIO)TETRATHIAFULVALENE

L. M. Gol'denberg and R. N. Lyubovskmya UDC 547.738'895:542.953.5.07

Radical-cation salts of tetrathiafulvalenes have the properties of metals and super-

conductors [i]. Condensed heterocyclic tetrathiafulvalenes with five-, six-, and seven-
membered dithiaheterocycles (I-III) have now been obtained:

BS ~A---$ S-~'~SR
l-lV
I R--R=CH~; 11 R-R=(CH2)~; III R--R=(Ctt2)s; IV R=Mo

The change of the geometry of the heterocycle condensed with the tetrathiafulvalene
system leads to a change of the type of intermolecular interactions in crystals of radical-
cation salts, which, in its turn, determines their electrophysical properties [2].
We obtained bis(o-xylylenedithio)tetrathiafulvalene (VII),tetrathiafulvalene with
condensed eight-membered dithiaheterocycles, by condensation of tetraethylammonium bis(2-
thioxo-l,3,-dithiolo-4,5-dithiolato)zincate (V) with o-xylene dibromide and subsequent di-
merization of the resulting dithiolo-2-thione VI [68% yield, mp 206-208~ (from dioxane).
IR spectrum (KBr): 1046 cm -I (C=S)] in trimethyl phosphite with boiling:

u V!

The yield of compound Vll was 50%, mp 270~ (with decomposition, from pyridine). IR
spectrum (KBr): 1625 (C=C), 753 cm" l ($2C=CS2). UV spectrum (l,l,2-trichloroethane), ~ x,
nm (log ~): 275 (4.04), 340 (4.09), 380 (3.70), 408 (3.11). Mass spectrum, m/z: 536 ( ~ 312,
224, 190.
The elemental analysis of compounds VI and VII corresponded to the calculated analysis.
In the series of compounds I-IV, with ring expansion (decrease of angular strain), hypo-
chromic shift of the long-wave absorption band occurred: 542 (I, CHzCI2 [3]), 467 (II), 400
(III), 378 pL (IV). Compound VII, with an eight-membered ring, occurs in this series between
compounds with six- and seven-membered rings. Such a shift of the absorption band indicates the
expansion of the highest occupied molecular orbital of the system, with a greater contribution
of sulfur atoms in the 4 and 5 positions, with the decrease in ring size [4, 5].

LITERATURE CITED
1. R. N. Lyubovskaya, Usp. Khim., 52, 1301 (1983).
2. R. Kato, A. Kobayashi, Y. Sasaki, and H. Kobayashi, Chem. Lett., No. 8, 993 (1984).
3. W. P. Krug, A. N. Bloch, T. O. Poehler, and D. O. Cowan, Ann. N.Y. Acad. Sci., 313, 366
(1978).
4. R. Kato, H. Kobayashi, A. Kobayashi, and Y. Sasaki, Chem. Lett., No. ii, 1693 (1984).
5. T. Mori, A. Kobayashi, Y. Sasaki, R. Kato, and H. Kobayashi, Chem. Lett., No. i0, 1335
(1984).
Branch Institute of Chemical Physics, Academy of Sciences of the USSR, Chernogolovka
142432. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 855-856, June,
1986. Original article submitted November 12, 1985.

680 0009-3122/86/2206-0680512.50 9 1986 Plenum Publishing Corporation

REACTIONS OF COPPER AND SILVER ACETYLIDES WITII I~DRAZONE
BROMIDES - - A NEW ROUTE TO 1,3,5-SUBSTITUTED PYRAZOLES

L. Yu. Ukhin, Zh. I. Orlova, UDC 547.314.13'556.9'778.4.07

and L. V. Belousova

W e h a v e found that substituted copper and silver acetylides (I) readily ethynylate
hydrazone bromides in refluxing acetonitrile.
For N-benzylidene-N'-p-nitrophenylhydrazone bromide (II) it has been shown that the
reaction product depends on the acetylenyl R substituent and can have both a cyclic (pyrazoles
III) and a linear (acetylenyl ketone hydrazone, IV) structure:

RC=-CM + C6HsCI~r=N~NH-.C~H4NO2-- P

/C6H5
KOH/DM$0 RC~C - C(CoHS):~N-NH- C6H4N0z- p
R=CeH5
R IV
t
CcH4NO2-p

Hydrazone IV may subsequentlybe quantitatively converted to pyrazole IIIb [i] by treat-

ment with KOH in DMSO at 60-80~ for several minutes.
A solution of the hydrazone bromide II (4 mmole) [2] and copper phenylacetylide (R =
CeH 6, 6 mmole) [3] in acetonitrile (20 ml) was refluxed for 0.5 h. The reaction mixture was
filtered hot and the filtrate cooled to give IV in 36% yield with mp 179-183=C (from octane)
and IfF 341. Use of the copper acetylide of propargyl alcohol (R = CH2OH) [3] under analogous
conditions (i h reflux) gave l(p-nitrophenyl)-3-phenyl-5-hydroxymethylpyrazole (IIIa) in a
33% yield with mp 132-137~ and M + 295.
The IR spectrum of hydrazone IV showed absorption bands at 2185 (C~C) and 3285 ( ~ I ) cm -I
which were absent in the spectra of the pyrazoles III. Elemental analytical data for all
compounds was in agreement with that calculated.

LITERATURE CITED
i. J. Elguero and R. Jacquier, Bull. Soc. Chim. France, No. 9, 2832 (1966).
2. F . L . Scott and J. B. Aylward, Tetrahedron Lett., No. 13, 841 (1965).
3. L. Yu. Ukhin, Candidate Dissertations, D. I. Mendeleev MKT Institute, Moscow (1968).

Scientific-Research Institute for Physical and Organic Chemistry, M. A. Suslov State

University, Rostov-on-Don, 344006. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 6, pp. 856-857, June, 1986. Original article submitted June 19, 1985; revision submitted
December 24, 1985.
0009-3122/86/2206-06812.50 9 1986 Plenum Publishing Corporation 681
NEW SYNTHESISOF IMIDAZ0[4,5-f]QUINOLINE DERIVATIVES

V. M, Pechenina, N. A. Mukhina, UDC 547.785.5'832.07

V. G. Klimenko, V, V. Chistyakov,
and V. G. Granlk

A method has been reported [i] for the synthesis of imidazo[4,5-f]quinolines by cycliza-
tion of 5(6)-aminobenzimidazole enamines(I) in the presence of polyphosphoric acid and phos-
phorus oxychloride. In particular the synthesis is recorded for compounds of the general
formula II.

X.. / X ~ Ir ~
:>~" .........M

% II

We have shown that enamines of 5-amino-4-benzoylbenzimidazole (III) c y c l l z e (with par-

ticipation of the benzoyl carbonyl group) upon heating with polyphosphoric acid to form com-
pounds with the structure IV.

coph [" l '~ ''P~

llla~b x IVa,b
a R1=Ph, R2=CH:~,X=COOEt; b RI=Ph, R~.=I|. X=COOEt

2-Methyl-3,9-diphenyl-8-carbethoxyimidazo[4,5-f]-quinoline (IVa) was obtained in 89%

yield with mp I17-I18~ Mass spectrum, m/z (relative intensity, %): M + 407 (100), [M-
C2H4] + 379 (28), [M-C2Hb] + 378 (71), [M-OC2Hs] + 362 (18), [M-COOC2H4] + 335 (14), [M-COOC2Hb] +
334 (28). PMR Spectrum (CF3COOH): 0.74 (t, CHs), 2.30 (s, 2-CH3), 3.95 (q, OCH2) , 7.34 (m,
Ar), 7.82 (d, 4(5)-H), 8.29 (d, 5(4)-H), 9.49 ppm (s, 7-H).
3,9-Diphenyl-8-carbethoxyimidazo[4,5-f]quinoline (IVb) was obtained in 91% yield with
mp 205~ Mass spectrum, m/z (relative intensity, %): M e 393 (62), [M-H]* 392 (I00), [M-
C=H4] + 365 (17), [M-C2Hb] + 364 (37), [M-OC=Hb] + 348 (8), [M-COOC=H~] + 321 (4), [M-COOC2Hb] +
320 (9). PMR Spectrum (CF3COOH): 0.70 (t, CH3), 3.92 (q, OCH=), 7.38 (m, Ar), 8.12 (d,
5(4)-H), 8.40 (d, 4(5)-H), 8.99 (s, 2-H), 9.53 ppm (s, 7-H).
The IR spectra (paraffin mull) of IVa and IVb showed absorption bands for the ester
carbony! groups (1695 and 1684 cm -I correspondingly) and the absence of an NH absorption
band.
Elemental analytical data for IVa, b was in agreement with that calculated.
LITERATURE CITED
i. K. Kigasawa, M. Hiragi, K. Wakisaka, S. Yosiga, and M. Kusama, Japanese Patent 5,528,920,
Ref. Zh. Khim., 40114 P (1981).

Chemico-Pharmaceutical Scientific-Research Institute, Novokuznetsk, 654034. Translated

from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 857-858, June, 1986. Original ar-
ticle submitted January 15, 1986.

682 0009-3122/86/2206-0682512.50 9 1986 Plenum Publishing Corporation

REACTION OF 2-AMINOBENZO~IIAZOLES WITH GLYCIDYL PHENYL ETIIER

L. P. Kosmacheva and R. F. Ambartsumova UDC 547.422'789.6.07

It has previously been shown [i, 2] that 2-aminobenzothiazole reacts with ethylene and
propylene oxides at the exocyclic amino group. By treating 2-aminobenzothiazo!es (Ib, c)with
glycidyl phenyl ether we have synthesized the products of addition at the endocyclic nitrogen
atom (IIb, c).

OH

=a-c ub-d
a R=H, b R=CH3, c R=C61q~, d R=CH~CH(OH)CH2OC6H5

In the case of Ia the product of diaddition (IId) was obtained. The isomeric amino
analog IIIb was obtained for comparison by reaction of 2-chlorobenzothiazole with N-methyl-y-
phenoxy-B-hydroxypropylamine. IIb and IIIb differed in melting point, RF value, and in
spectral characteristics.
In the IR spectra of benzothiazolines IIb-d there was observed an intense absorption band
for the exocyclic C=N bond at 1625-1630 cm -I. This band was absent in IIIb but an absorption
due to the endocyclic C = N b o n d w a s found at 1550 cm -l. In the PMR spectra of IIb and IIIb
(CDCI3 solvent) the protons of the NCH2 groups gave a signal in IIb (4.23 ppm) which was at
lower field than that for the amino isomer IIIb (3.86 ppm). In the spectrum of IIc this
signal was found at 4.35 ppm thus pointing to the imino structure.
Compound IIb, mp 91-92~ (benzene), yield 42%. Compound IIc, mp 123-124~ (ethanol),
yield 44%. Compound IId, mp I07-I08~ (benzene), yield 54%. Compound IIIb, mp 134-135 ~
(benzene/ethanol), yield 30%.
Elemental analytical data was in agreement with that calculated.

LITERATURE CITED
1. P. M. Downey, US Patent, 2642430; Chem. Abstr., 48, 4596 (1954).
2. R. Elderfield, ed., Heterocyclic Compounds [Russian translation], Vol. 5, Inostr. Lit.,
Moscow (1961), p. 470.

Institute for the Chemistry of Plant Substances, Uzbek Branch, Academy of Sciences of
the USSR, Tashkent, 700170. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6,
p. 858, June, 1986. Original article submitted July 8, 1985; revision submitted December 27,
1985.

0009-3122/86/2206-0683512.50 9 1986 Plenum Publishing Corporation 683

ION-RADICAL AND REDOX TRANSFORMATIONS OF CYCLIC
ACETALS (REVIEW)

D. L. Rakhmankulov, V. V. Zorin, and UDC 547.841:541.124.(047)

S. S. Zlot-skii

A review of research dealing with ion-radical and redox transformations of cyclic

acetals in the liquid phase is given.

Owing to their interesting physicochemical properties, high reactivities, and efficient

practical utilization, cyclic acetals have been of constant interest to researchers. The
problems involved in the synthesis and homo- and heterolytic reactions of compounds of this
class have been illuminated in detail in a number of monographs and review publications [1-7].
Their radical-chain isomerization to the corresponding esters, which, in a number of cases,
are difficult to obtain by different methods, have been found to be of value and interest for
preparative chemistry. The homolytlc halogenation and oxidation of cyclic acetals are of sub-
stantial value for organic sysnthesis. Diverse linear and cyclic dimeric and telomeric pro-
ducts that contain various functional groups can be obtained as a result of the radical addi-
tion of these compounds to carbon--carbon multiple bonds. Reviews [4-7] have been devoted to
the analysis and systematization of these data. However, a number of studies that open up
new synthetic possibilities associated with ion-radical and redox transformations of substi-
tuted 1,3-dioxacyclanes have been published in the last 5 yrs. In this connection, in the
present review we have summarized the principal methods and results of reactions of this
type in series of cyclic acetals.
Anion-Radical Transformations of Acetals
The possibility of the generation of anion radicals from acetals of nitroalkanols or
nitrobenzaldehydes was demonstrated in [8, 9]. In the reaction of 2-nitrophenyl-l,3-diheter-
ocycloalkanes I with the dipotassium salt of cyclooctatetraene in tetrahydrofuran (THF) at
20~ in an inert atmosphere, electron transfer from the cyclooctatetraene dianion to the ni-
tro group occurs, as a result of which the corresponding anion radicals la are formed.

I le.

R = 1,3- dioxan- 2- yl or substituted 1,3- dioxan- 2- yl, 1,3- dioxazin- 2- yl, 1,3- diisobutylimidazolidin-
2-yi, 1,3-oxathiolan-E-yl, and 1,3-dithiolan-2-yl.

The latter are readily recorded in the EPR spectra and display sufficient stability in
an inert atmosphere at -50~ to 40~ In all cases the yield of cyclooctatetraene is close
to quantitative, and this constitutes evidence for virtually complete conversion of starting
I to anion radicals la. In [8, 9] the effect of the 1,3-diheterocYcloalkyl substituent on
the q-electron system of the aromatic ring was judged from EPR, PMR, and mass-spectral data.
It was established that both in the base and the anion- and cation-radical states the intro-
duction of a 1,3-diheterocyeloalkyl substituent increases the hyperfine interaction (HFI)
constants aN, shifts the center of the multiplet of the aromatic ring protons to strong field,
and increases the intensity of the molecular ion in the mass spectra, in much the same way as
an amino group, in contrast to the acceptor effect of a nitro group, creates this effect.

Ufa Petroleum Institute, Ufa 450062. Translated from Khimiya Geterotsiklicheskikh Soed-
inenii, No. 7, pp. 867-877, July, 1986. Original article submitted April 23, 1984; revision
submitted December 16, 1985.

0009-3122/86/2207-0685512.50 9 1987 Plenum Publishing Corporation 685

 In contrast to aromatic substrates I, in the reaction of 5-alkyl-5-nitro-l,3-dihetero-
cycloalkanes II with the dlpotasslum salt of cyclooctatetraene in THF one observes in the
EPR spectra the presence of signals related to two paramagnetic particles: anion radicals
of 5-alkyl-5-nltro-l,3-dlheterocycloalkanes (aN = 25-27 0e) and nitroxyl radicals (aN = 11-14
0e), which, according to [i0], appear as a result of transformations of the initially formed
anion radicals [9, ii, 12].

R 1

~,.... .' .No

R1
('~:"i ...OH

. . . ... . ,. ,. %
.. f .... i ..-'-- L.,F.! .,
.><. ' *"I R
''Y
R
....I
R
II~t IIb It C
x---\ s' ~ / - - - x

i
O'

.d

Thus, in contrast t o aromatic anion radicals, allphatlc anion radicals IIa undergo fur-
ther transformations with splitting out of potassium nitrite. The development of nitroxyl
radlcals in the process was also established in [13], in which the reduction of 5-alkyl-5-ni-
tro-l,3-dloxanes with a solution of KOH in ethylene glycol was studied| 5-alkyl-l,3-dloxanes,
5-alkylldene-l,3-dloxanes, hydroxyacetaldehyde~ and potassium nitrite were obtained.

+ KNO 2 + HOCH2CHO
ol o] + xo. + "oc"2c%.o" ,eo-,~-* o~<o +
R~H R--H
R
ma-d Iva-d va-d
III.--.~V a R f H ; b R=CH3; c R=C2Hs; d R=C3H7

Mixtures of stereoisomeric 2,5-dialkyl-l,S-dioxanes IVb-d are formed in the case of 2-

substituted 5-nitro-l,3-dioxanes IIIb-d [13, 14]. The ratios of the yields of the isomers
do not depend on the three-dlmensional structure of the starting 1,3-dioxanes VI and VII,
evidently as a consequence of occurrence of the reaction through a step involving the forma-
tion of 2 , 5 - d i a l k y l - i m3-dioxa-5-cycloalkyl radicals [13, 14 ].

9 NO2

Ca 3 9 a~..~o-__./.--. (:H~

~Isa,b sxa,b
u a dffic,): bl,l~cs(clt~} 2

5-Alkyl-l,3-dlheterocycloalkanes Xla-e were obtained in 60-70% yields in the reduction

of Xa-e with sodium alkoxldes [14, 15].

~'~ -Y') e
" ~---x'. . . ~c.,oN.
. --v
.--(_~-R
xa-e xta-e

X; XI a R=CH3, b R=CH(CI-Is)2, c - e R'fH; a - d X=O, e X=NCH3; a,b Y=O,

e - e Y--NCH3

686
 The synthetic value of this reaction consists in the fact that the easily synthesized
nitro derivatives X can be converted in one step to the more difficult-to-obtain XI. The
latter, according to [16], are formed as a result of electron transfer from the alkoxide to
the nitro compound. Disproportionation of the resulting radicals in the "cage" leads to the
final products:

"R,.,~N0"~N.~" -1
X + RIcH2ONa ~.l,b- 4" R~CHzO' -----,'g,.-
i _NAN02

n .A XII

The reduction products are formed in part by detachment of hydrogen atoms by radicals
XII. This is indicated by the development of recombination products, vlz., 1,2-diols:

~ I + R1CH20H ~ ~ t R'CHOH ~ R'CH(OH)CH(0H)R 1

RICH20 4- R~CH~OH - ~ RICHzOH + R'CHOH

The lithium salt of 5-nitro-l,3-dioxane (Xlll) reacts with p-nitrobenzyl chloride in

dimethylformamlde (DMF) at O~ to give benzyl-l,3-dioxane (XVI) and 5,5'-bls(5-nitro-l,3-di-
oxanyl) (XVII) [17]. A signal related to anion radical XVc was recorded by EPR spectroscopy
of the reaction mixture [17]. The process is accelerated by UV irradiation and is retarded
in the presence of free-radical acceptors [17]; this is characteristic for anion-radical re-
actions that proceed via an SRN , mechanism [18]. The results made it possible to propose
the following scheme for the process [17]:

NO 2- Li ' NO:
N0~.
[/7"~'i/H 4"LiocI4~ [ / ~ , i/I:"{
-.-------a-- / + /9- 02NCsH4CH2CI + p - CICIIzCsH4Nb.,Li
O O CH30H O.~v/O 0../0

kqll ~ .'..",, .%TVa XVa

kWa ~ I/CI + D- 02NC~H4CH~'

XV

[-'Noz CH.zCoH4N%- ~] :
--~i
~ ] ,---o
* XV NOz..." ,. \
XIV x v b - - - ' - Li~: ..... "" ,\ /
1_ 0~./ ~ -XVa D.0zNCsH4CH2" \~---0
XTC X','I
0-~NO.
2 XIVa -:-'q~
/ /~--... ~, O
~, ,..
9 __/ ~ +
O NOz ~kk__O,
XVII

The formation of stereoisomers that differ with respect to the positions of the nitro
group and the nitrobenzyl substituent iS possible in the reaction of p-nitrobenzyl chloride
with the lithium salts (XVIII) of 2-substituted 5-nitro-l,3-dioxanes. However, the formation
of only an isomer with an axial nitro group was observed [17]. The stereospecificity of the
reaction is associated with the greater accessibility of the equatorial position in lithium
salts XVIII [17].

687
 !

NOe~'hl ~ m, /j.o ....../

xzx.a,b
! ~ ~.}I2CoH~N0~-p

llfflli & ,b

XVilI-XX a II~clls; b e~t;aU s xxa,,b,

The reaction of 2-bromo-2-nitropropane (XXZ) with s a l t XIV iu dimethyl sulfoxide (DMSO)

at 20~C gives dioxane XXIZ, bisdioxanyl XVZID and 2,3-ds (XXITI) [18].
The reaction i s accelerated by UV irradiation

(Cl.i:):r + (CH~)zCIINO2)ar + X~s

X~a

1
(cX~)26NO z + hti',r
xnb

and i s r e t a r d e d by e l e c t r o n a c c e p t o r s . The p r e s e n c e o f r e c o m b i n a t i o n p r o d u c t s ( d i n i t r o com-

pounds) in the r e a c t i o n m i x t u r e i n d i c a t e s the f o r m a t i o n of r a d i c a l s XlVa and XXIb d u r i n g the
reaction [18, 19].

xxlb+~ p--, .Who/ -, o-\.,~o~

,x~lI
Xpta * x ' ~ b . . - ~ - ~p~"lr

ax~b .... ,,,.. ( cR,~ I~C(NOz)C(NO~.)(CI-I~) a

XXII!

,',.'B'a ...... .,,.,.. XVI!

The reactions of individual stereoisomers of 5-bromo-5-nitro-l,3-dioxanes XXIV and XXV

with the lithium salt of 2-nitropropane in DMSO at 20~ proceed stereoselectively with the
primary formation of isomers XXVl with an axial nitro group [20]. It is interesting that the
stereochemical result of the reaction is independent of the three-dimensional structures of
the starting i, 3-dioxanes:

? ~ r NO2
/~C(CH.x)2NO 2
R...//o..~j R.../~o-~j
xxlvJa'b
,r ~ " h*+"~=C(cH~h ~ ~x,aa,,b
c(
~.CII3)2NOz
o ........ .7". N% /o .... ./-.No 2

xxva , b x~v-xx~l a R=CH.~.b R=CsHs xxvlla,b

Lithium salts (XIV) of 5-nitro-l.3-dioxanes can act as nucleophilic agents in reactions

with 5-bromo-5-nitro-l.3-dioxanes (XXVlII) [21. 22]. The reaction in DMSO leads to 5.5'-bis-
(5-nitro-l,3-dioxanyl) (XVlI) and 5,5'-bis(l,3-dioxanylidene) (XXIX).
The yields of XVII and XXlX depend on the ratios of the starting reagents. Thus the
selectivity with respect to bisdioxanyl XVlI increases with an increase in the concentration
of substrate XXVIII [21]. It is apparent that in many respects the process is similar to the

688
reaction of 2-bromo-2-nltropropane with the lithium salt of 5-nltro-l,3-dloxane.

Br ......NO,hi*

(i}
0..~/0

.'~Cv'lll XXVIIIw,
xxvql, ,..- .~Va + LiBr (~)

2 XlV~ ------~ " XVII (3)

/0 " \ :NO 2 + XXVIII
(4)
%.-'\_o>
X.~V]II~i

" o ....o

XXVlll I) - --?-.- (~)

XXVIIIa XXIX

Mixtures of stereoisomerlc 5,5'-bis(5-nltro-2-methyl-l,3-dloxanyls) and 5,5'-bls(2-methyl-

1,3-dloxanylidenes)(XXXII) are formed I n t h e reaction ofindlvldual 2-methyl-5-bromo-5-nitro-
1,3-dloxanes with lithium salts of 5-nltro-2-methyl-l,3-dioxanes in DMSO at 20~ [22]:

9 - N0 2

o ......
/~ :-__o//-.c,~

/ ~/ 2 9 0 6
CH~...~o--_.j '--.:/ ./ NO
.z
\ IClt
" o J
xXx, "":----~
\ .
......:~.......... /
---~//',
/ \ o
"% / \" """C"~ \ / "\ c,
I " /: \, NO~.~-//o---LX/
,o~._.<.I...,r : ........ Xxxll~'vz " N / /
CH~.~/7 o-.__~/ "%
et-- --0
\. i ,,
--/ -0

Primarily trans-stereoisomer XXXIa with a diaxlal orientation of the two nitro groups is
formed (in 52~ yield): The yield of cls-isomer XXXIb is considerably lower (15%). The stere-
ochemical result is independent of the three-dlmensional structures of the starting dloxanes;
this constitutes evidence in favor of an anlon-radical pathway for the formation of the final
products through a step involving 2-substituted 5-nitro-l,3-dioxa-5-cyclohexyl radicals.
The reaction of b-bromo-5-nitro-l,3-dioxanes XXVIII with sodium ethylmercaptide in DMSO
at 20~ leads to 5 , 5 ' - b i s ( 5 - n i t r o - l , 3 - d l o x a n y l ) ( X V I I ) , 5,5'-bis(l,3-dioxanylidene) (XXIX),
and diethyl disulfide; sodium bromide and nitrite are also produced [23]. The reaction is
also sensitive to UV irradiation and radlcal-reaction inhibltors; this made it possible to
propose the following scheme:
]~r. NO~ = N. ~
/ i

x~a. + N~SC2H~ .----,-. | ] + c~bs.

XXXIII O /O 2Q~XIIIa
XX3~II d
XXXHIa ---.-- XlVa + NaBr

XIYa - ----- XVII

2 XXXIHa ~ (CzHbS)2

689
 When in,us163 sodium athylmercaptlde is preeent, the reactlon s~ops a~ the step
InvolvlnE the s os dlnlt~oblsdlox&nyl XVZZ [23]. The lattQr, in the presence os ex-
cess ethylmercaptlde undergoes further transfon~ations to sire 5,St-bis(l,3-dioxanylidene)
(XXZX) [23].

xvv. c,..,.. ~-,.. \n_,,/~/'~~

-- "~: . x:m,,.

XYII~
XX'XIIT

The reaction of 5,5'-bis(5-nitro-l,3-dioxanyl) (XVII) with sodium methoxide in DMS0 at

20~ proceeds in a different direction and leads, when insufficient sodium methoxlde is pre-
sent, to 5-(5-nitro-l,3-dioxan-5-yl)-l,3-dioxane (XXXIV) and sodium methoxide and nitrite
[24, 25]. Further transformation of nitro olefln XXXIV to 5,5'-bls(1,3-dloxsne) (XXXV) oc-
curs in the presence of excess sodlummethoxlde. The reaction is accelerated under UV Irra-
dlatlon| this confirms the anlon-radlcal character of the process.

XXXIV

Reactions That Proceed through a Step Involving One-Electron Oxidation of 1,3-Diheterocyclo-

alkyl Radicals
The loss of an electron upon reaction with Fe(XIl) [33, 34] was found to be character-
istic for ibm 1,3-dihetero-2-cyclo-alkyl radicals that develop under the influence of redox
systems [26-32]. Thus 1,3-dioxolane (XXXVI) and 3-propyloxazolidine (XXXVII) are converted
to ethylene glycol monoformate (XXXVIII) and N-propyl-N-(2-ethoxyethyl)formamide (XXXIX) un-
der the influence of Fe(II) + H20~ + Fe(Ill) at 0-5~ in water. The formation of XXXVIII and
XXXIX includes a step involving one-electron oxidation of the 1,3-dioxa- or l-oxa-3-aza-2-
cyclopentyl radicals.

F.......
] + o,'. ...... - [.......3 .,. , : xxxvI.(x~,.)
Fe(nl)
....... j........I
O./X O ...X 0 ....+/X

XXXVI. XXXVII H H
x~(vI,L,xrcviia xxx~ b ,x:~IT.b
xx~qb(xxxvIIt~- "2---~
~ V-~ - - - - HCOXCH2CHzOI[
o X
"~OH X.'~D~VIII,.'k~=%IX
H
Xn'V'IC. X:k~VIIC

XXXVI, XXXVIII X = O ; XXXVII,XXXIX X=N--CaH7

N-(2-Acetoxyethyl)-N-butylformamlde (XLI, 60% yield) is formed in the reaction of 3-

butyl-l,3-oxazolidine (~) with the redox system in acetic acid, whereas N-butyl(2-chloro-
ethyl)formamlde (kill, 12% yield) is obtained along with N-butyl(2-hydroxyethyl)formamlde
(XLII, 45% yield) in a saturated aqueous solution of NaCI [34].

i ] F,,(.) + B2%" + Fe(m)

HCON(CcHg)CH2CH20CDCH ~
O~/N~4H 9 CH3COOH XLI

XL
\ HCON(C~Hg)CH2CH2OH
_. F e ( l l ) + H20 z + Fe(lII) m,,.. XLII

Naci, HzO HCON(C~H9)CH2CtleC1

XLIII

690
 Upon reaction with the Fe(ll) + H202 + Fe(lll) system in acetic acid 2-methyl-l,3-diox-
acyclanes XLIV give dlacetates XLV [35].

~..(,~) + ,,,ol + Vo(.,)

O. 0 CH~00H m,- CH3C00CH2(CII2).CH2OCOCH 3
y xLva~c
CH~
XUV~-C X~V, XLV a n;-o;b . ~ , l ; C n=2

Thus the nature of the nucleophillc particles present in solution determines the charac-
ter of the resulting products.
2-Ethoxyl-l,3-dioxolane (XLVI), which unexpectedly forms ethylene glycol monoformate
(XXXVIII) and acetic anhydride) reacts somewhat differently with the Fe(II) + H202 + Fe(III)
redox system [36]:

Fe(II) + Ha02 ----~-- Fe(IZl) + HO- + HO"

r------ 0 HO" ~--

' . . . . . . .'0 Fe(lll)
................ r----O Ha0

XLVI Xl,r XLVI b

. .........

I
XLHC 01I XLVI d X.'XX%III

Similarly, the reaction of 2-ethoxy-l,3-oxathlolane leads to 2-mercaptoethyl formate

[36]. One-electron oxidation of the monoalkoxyalkyl radicals is also the key step here.
Homolytic Replacement of a Hydrogen Atom in Protonated Hetero-aromatlc Bases by a 1,3-Dioxa-
cycloalkyl Residue
The nucleophilic properties of alkoxyalkyl and diakoxy-alkyl radicals have been used in
the alkylation of protonated heteraromatic bases by them [37-39]. The formation of products
of alkoxy- and dialkoxyalkylatlon of protonated hetetoaromatic bases proceeds with the par-
ticipation of cation radicals, it has been established [37] that 4-(2-quinoxalinyl)-l,3-
dioxolane (XLVIIi)Isformed selectively in the reactionof 1,3-dioxolane (XXXVI) with quino-
xaline ( X L V I I ) i n t h e presence~Of a source of tert,BuO" radicals, whereas 4- and 2-substituted
dioxolanes XLVIII and XLIX are formed slmultaneous!yunder the influence of "OH radicals.

I .... 1 :!n~t!~to~ I ........ I , I-:1

0 .0 o 0 0 0
!
~-x~q a xxxvl d
XXX%~.

) ' I I

1,4-Dioxane (L) reacts with the pyrazinium cation (LI) to give alkylation products LII
and LIII [37]:

.0 .o.
N
r .
{,+ il ' 9 I I "IW rl "" il .....
""N 0 0 . . .
H N
LI
l, !~ll 0 IJII

691
 A quantitative evaluation of the relative raactlvltias of 4-substltuted quinollnes LIV
in reactions with radicals generated from 1,4-dioxana demonstrated that electron-acceptor
substltuents promote an increase in the activity of the protonated base [37J, This depen-
dence of the reactlvltles is explained by the fact that the transition state in reactions
with nucelophillc 1,4-dloxanyl radicals is achieved m o r e rapidly in the case of heterocycles
that have greater electrophillcitles.

X
I

l 84184 I ..... Ii84 ,Iilj r,

o .... 9. . . . . . ' ....

uva-.f J.va.f 'o

LIV, LV a X=H; b X-OCH.~: c X-CH~;d X-CI; 9 X-COOC2H~; f X=CN

The reaction of 1,3-dloxolane with protonated quinaldlne (LVI) initiated by ROOH + Fe(ll)
systems [R - C(CHs) s, C6HsC(CHj)2] leads chiefly to 2-substituted dioxolane LVII (72-78%
yleld) and, to a lesser extent, to 4-substituted 1,3-dioxolane LVIII 412-14% yleld) [40J:

O-

0,..~ ,0 '.~,.]/

....., o - -c% ![
I!
LV~ LVII LVIII

On passing to t h e Fe(ll) + HaO2 system, which gives hydroxyl radicals, which are more
active and less selective than tert-BuO" and C6HsC(CHs)~O', the probabillty of the formation
of 1,3-dloxa-4-cyclopentyl radicals increases, as a result of which the ylelds of dloxolanes
LVll and LVIII are 40% and 35%, respectively. The yleld of the 2-substltuted 1,3-dloxolane
increases with an increase in the pH of the medium. The latter is associated with the fact
that more nonhydrolyzed Fe s+ ions than hydrolyzed Fe(OH) ~+ ions are present in the system at
low pH values, and the probabillty of one-electron oxidation - disappearance of the 1,3-dloxa-
2-cyclopentyl radicals (with their subsequent conversion to ethylene monoformate) -- is higher.
In contrast to 1,3-dloxolane, only 2-methyl-4-(1,3-oxathlolan-2-yl)quinoline (LX) is formed
in 90% yleld in the reaction of 1,3-oxathlolane (LIX) with protonated qulnaldine initiated
by the CIHsC(CHI)8OOH + Fe(ll) system [41]. The high selectivity of formation with respect
to 2-substltuted 1,3-oxathlolanes is due to the high selectivity of the formation of l-oxa-3-
thla-2-cyclopentyl radicals from l~3-oxathlolanes under the influence of oxygen-centered
radicals.

0I--7$
initiator
I 84 I + LVI
O..../S
~ C I I 3
LIX IX

The reaction of 1,3,5-trioxane (LXII) with protonated 4-methylqulnoline (LXI) has been
used as a method for the introduction of a formyl group into a heteroaromatic base [39].

H O.~ O
LXI LKII O.,.~..O

692
 The regiospeciflclty and stereospeclflcity of the reaction of protonated pyrldine with
1,3-dioxolanes have been studied [42], The four possible regiolsomers are formed when 1,3-
dioxolane is used. Primarily isomers LXIV and LXVI, which are derivatives of 1,3-dioxa-2-
cyclopentyl radicals, were obtained [42]~ The sum of the yields of isomers LXVI and LXV is
greater than the sum of the yields of LXVIand LXVII, which constitutes evidence for the
higher reactivity of t h e 4 position of the pyrldlnium cation with respect to nucleophilic
dioxolanyl radicals.

I i,A.'(:i ~'!" : A):I .4J.VI L~J~X lllX" I

""~
I..... A... + ! .....,...% + .+ -.---- +

~' "io t i

Only two isomers, viz., LXIX and LXX, which are derivatives of 2,2-dimethyl-l,3-dioxa-
4-cyclopentyl radicals, are formed in the case of 2,2-dimethyl-l,3-dioxolane (LXVIII).

0 CH~

LXm ~-~]. initiator ~ C HI ~ \ ]

~j1 /~CH~ o :.'o
CII3 CI1,~ N
l .X~q I I l ,XlX LXX

2-Methyl-2-ethyl-l,3-dioxolane (LXXI) can react with protonated pyridine to give two

regioisomers, each of which exists in the form of a pair of stereoisomers. It was estabished
that only trans-2-methyl-4-(4-pyridyl)-2-ethyl-l,3-dioxolane (LXXII) and trans-2-methyl-4-
(2-pyridyl)-2-ethyl-l,3-dioxolane (LXXIII) are formedunder the reaction conditions (0-5~
pH 4-5).

N /-~~

. C H ~ ~ ~'Cells
2H5 5
Lk'KI L'O~II LX~II

The formation of only trans isomers is associated with their greater thermodynamic sta-
bility as compared with the cis isomers, which are capable of epimerization under the reac-
tion conditions (pH<7) [43].
The results presented above make it possible to regard the ion-radical and redox trans-
formations of 1,3-dioxacyclanes as a highly effective method for their functionalization.
In virtually all cases these processes are realized under mild conditions and are distin-
guished by high yields and selectivity; this opens up possibilities for the substantial ex-
pansion of the synthetic chemistry of cyclic acetals.

LITERATURE CITED
i. Ro Elderfield (editor), Heterocyclic Compounds, Vol. 6, Wiley (1957)o
2. Jo Ap'ok, Mo Bartok, R. Ao Karakhanov, and M. I. Shuikin, Uspo Khim., 38, 72 (1969).
3o A. Vo Bogat-skii and N. L. Garkovik, Usp. Khim., 37, 581 (1968).
4. Do Lo Rakhmankulov, Ro A. Karakhanov, S. S. Zlot-skii, Eo A. Kantor, Uo Bo Imashev, and
Ao M. Syrkin, The Chemistry and Technology of 1,3-Dioxacyclanes. The Technology of
Organic Substances [in Russian], Vol. 5 (1979), p. 288~

693
 5. D. L. Rakhmankulov and S. So Zlot-skil, Khimo Geterotsiklo Soedino, No o 8, i011 (1977).
6~ D. L. Rakhmankulov, S. So Zlot-skll, Vo Vo Zorln, and Uo B. Imashev, Usp. Khimo, 50,
1463 (1981).
7. Do L. Rakhmankulov, V. Vo Zorin, F. No Latypova, So S. Zlot-skii, and Ro Ao Karakhanov,
Usp. Khim., 51, 1463 (1982).
8. Z. V. Todres, D. M. Kukovitskii, Vo V. Zorin, So So Zlot-skli, and Do Lo Rakhmankulov,
Izv. Akad. Nauk SSSR, Set. Khlm., No. 7, 1577 (1981).
9. Do M. Kukovltskil, Vo Vo Zorin, So So Zlot-skll, Do Lo Rakhmankulov, and Z. V. Todres,
Zho Org. Khlm., 19, 145 (1983)o
I0o A. Ko Hoffman and W. G. Hodson, Jo Am. Chemo Soco, 83, 4675 (1961)o
iio D. M. Kukovitskll, Z. Vo Todres, and Vo V. Zorln, Summaries of Papers on the Chemistry
and Technology of Acetals [in Russlan], Ufa (1980), p. 10.
12o D. M. Kukovitskil, Master's Dissertation, Ufa (1982)o
13. A. Lutko-Krasuska, H. Piotrovska, and To Urbanskl, Tetrahedron Lett., No. 14, 1243
(1979).
14. Vo V. Zorin, Do M. Kukovitskii, S. So Zlot-skii, Z. V. Todres, and D. L. Rakhmankulov,
Zho Org. Khimo, 21, 1790 (1985)o
15. Do Mo Kukovitskii, V. V. Zorin, So So Zlot-skii, Zo V. Todres, and D. L. Rakhmankulov,
Khimo Geterotsiklo Soedin., No. 6, 846 (1982).
16o Do Mo Kukovitskii, V. Vo Zorin, and Yuo Bo Zelechonok, Summaries of Papers on the Chem-
istry and Technology of Acetals and Their Heteroanalogs [in Russian], Ufa (1981), P. 102.
17o Vo Vo Zorin, D. Mo Kukovitskii, So S. Zlot-skii, Z. V. Todres, and D. Lo Rakhmankulov,
Zho Orgo Khimo, 19, 426 (1983)o
18. No Kornblum, Angew. Chem., 87, 879 (1975).
19. Vo Vo Zorin, Do Mo Kukovitskll, So S. Zlot-skii, Z. Vo Todres, and D. Lo Rakhmankulov,
Zho Orgo Khimo, 20, 864 (1984)o
20. V. Vo Zorin, D. Mo Kukovitskli, So So Zlot-skll, Z. Vo Todres, and D. L. Rakhmankulov,
Zh. Obshcho Khimo, 54, 828 (1984).
21. Vo Vo Zorln, Material from Papers on the Chemistry and Technology of Acetals and Their
Heteroanalogs [in Russian], Ufa (1982), po 27.
22. Vo Vo Zorln, D. Mo Kukovltskll, L. F. Lapuka, S. S. Zlot-skil, Z. V. Todres, and Do L~
Rakhmankulov, Zh. Orgo Khlmo, 19, 1753 (1983).
23. Vo Vo Zorin, Do Mo Kukovltskll, S. So Zlot-Skll, Z. Vo Todres, and D. L. Rakhmankulov,
Zh. Obshcho Khim., 53, 906 (~983)o
24. Vo Vo Zorln, D. Mo Kukovitskil, Zo Vo Todres, and Do L. Rakhmankulov, Zh. Orgo Khim.,
21, 463 (1985)o
250 Vo V. Zorin, Summaries of Papers on Organic Reagents and Articles of Domestic Chemistry
Based on Petrochemical Raw Material [in Russian], Ufa (1983), po 34~
26. A. Lo Bekwlth and Po Ko Tindal, Austo J~ Chem. 24_, 2099 (1971).
27~ A. I. Dobbs, Bo Co Gilbert, and Ro Oo Norman, J. Chemo Soc., A 9 No~ 1, 124 (1971)o
280 Vo V. Zorin, So So Zlot-skll, V. Fo Shuvalov, Ao Po Moravskli, Do L. Rakhmankulov, and
Ya. M~ Paushkin, DOklo Akad. Nauk SSSR, 236, 106 (1977)o
29. V. Vo Zorin, V. Fo Shuvalov, A. P. Moravskll, So S. Zlot-skii, and D. L. Rakhmankulov,
Zh~ Orgo Khimo, 15, 178 (1979).
30. Vo Vo Zorin, Vo Fo Shuvalov, Ao P. Moravskli, Uo B. Imashev, S. Mo Kalashnikov, So S.
Zlot-skii, and Do Lo Rakhmankulov, Doklo Akad. Nauk SSSR, 246, 1144 (1979)o
31o No Ao Batyrbaev, Vo Vo Zorin, Ao Po Mmravskii, Vo Fo Shuvalov, So S. Zlot-skii, and
Do Lo Rakhmankulov, Zho Obshcho Khim., 53, 416 (1983)o
32. Ao Ao Lapshova, Vo Vo Zorin, V. Fo Shuvalov, Ao Po Moravskii, S. S. Zlot-skii, and Do L.
Rakhmankulov, IZVo Akado Nauk SSSR, Sero Khimo, No~ 6, 1197 (1980)o
33~ Ao Ao Lapshova, Vo Vo Zorin, S. So Zlot-skii, and D. Lo Rakhmankulov, Zh. Org. Khim.,
16, 1341 (1980)o
34. Ao A. Lapshova, Vo Vo Zorin, So S. Zlot-skii, and Do L. Rakhmankulov, Khim. Geterotskiklo
Soedin., No. 3, 406 (1981)o
350 V. N. Trifonova, V. V. Zorin, S. S. Zlot-skll, and D. Lo Rakhmankulov, Zho Org. Khim.,
18, 1050 (1982)o
36. V. No Trifouova, V. Vo Zorin, S. S. Zlot-skli, and D. Lo Rakhmankulov, Zh. Orgo Khim~
19, 864 (1983).
370 F. Minichi, Curt. Chem. 62, 1 (1976)0
380 W. Buratti, G. P. Gardinl, Fo Minlchi, Fo Bertlni, R. Gall,, and M. Perhinunno, Tetra-
hedron, 27, 3655 (1971).
39. A. Porta and G. Sesana, Tetrahedron Letto, Noo 38, 3571 (1978).

694
40. V. V. Zorin, Yuo Bo Zelechonok, So So Zlot-skii, and D. Lo Rakhmankulov, Khim. Geterot-
sikl. Soedino, No. I, 1817 (1984) o
41o V. V. Zorin, Yu. B. Zelechonok, So So Zlot-skii, and Do Lo Rakhmankulov, Zho Orgo Khim.,
19, 1785 (1983).
42. V . V . Zorin, Yu. B. Zelechonok, So So Zlot-skii, and D. Lo Rakhmankulov, Zho Org. Khim.,
21, 193 (1985).
43. Yu. Yu. Samitov, Ao Vo B o g a t - s k i i , Ao Io G r e n ' , A. V. Agapov, and V. Po Kuzyakova, Zh.
Org. Khim., ~, 1975 (1969)o

EFFECT OF THE HETEROATOM OF A BENZO[b]-ANNELATED FIVE-MEMBERED

HETERORING ON THE STRUCTURE AND PROPERTIES OF AN AMINOVINYL
KETONE FRAGMENT INCLUDED IN THE RING

V. Ao Bren t UDC 547o728o2' 736' 753:541o6

An analysis of the results of theoretical and physicochemical studies of and x-ray

diffraction data for a series of aminovinyl ketones -- derivatives of hydroxy alde-
hydes of benzo[b]-annelated five-membered heterosystems -- is presented. In addition
to the peculiarities of the aminovinyl ketone fragment, the effect of the heteroatom
of the five-membered ring on the structure and properties of aminovinyl ketones,
which consists in direct electronic conjugation of the ring carbonyl group with the
heteroatom, was ascertained~

Studies carried out by means of electronic, IR, and PMR spectroscopy [i-3] and x-ray
diffraction analysis [4-6]have made it possible to establish and confirm, by means of the
results of quantum-chemical calculations [7], the preferableness of an aminovinyl ketone
structure (B) for the potentially tautomeric molecules of the I type in the solid phase and
in various solvents, regardless of the external conditions (temperature, irradiation). It
has also been shown that some types of aminovinyl ketones exist in solutions in the form of
two (E and Z) equilibrium forms [2, 8-10], and opinions regarding the preferableness of the
O---CR----CR--C}i=N~HRzwitter-ion structure in the aminovinyl ketone fragment have been expressed
[10-13] o

0,. 0
"'" ' - 9 H
i rl I -
!l , ...... : "" ""!I- - ;"
J""
N -R
"~"" ' X "'1'[1 ~ " " \ CIt R X II
F
N
i B,Z R H IB,E IC

9 oX ..... . . . . OZ.
:/~'~_j__.T/~
"~ 'ilI=" X' rl ('H ~ - - ......
~">". : ~'_~ ' % c u i N ' R ':
I~ ]D IE

In the present communication we attempted to evaluate the peculiarities of the structure

of compounds of the I type and their derivatives as a function of the properties of the
structural links, particularly the X group of the five-membered ring~ The IB molecules may
exist in the form of Z-IB and E-IB isomers [with an intramolecular hydrogen bond (IMHB)],
each of which, as a consequence of the effects of conjugation of the electron-acceptor car-
bonyl group, contains a certain degree of contribution of canonical forms D and Eo Struc-
ture D reflects ~ polarization in the tautomeric chain~ The contribution of the E form,
which corresponds to ~ interaction of the C----Oand X groups, will increase with an increase

Scientific-Research Institute of Physical and Organic Chemistry, Mo A. Suslov, Rostov

State University, Rostov-on-Don 344071. Translated from Khimiya Geterotsiklicheskikh Soed-
inenii, No. 7, pp, 878-882, July, 1986. Original article submitted April 8, 1985.

0009-3122/86/2207-0695512.50 9 1987 Plenum Publishing Corporation 695

 in the electron-<lonor character of the X group, evldeuts in the order CO<CH~<O<S<Se<NCH=. Elec-
tron shifts in c a n e D end E create excess negative charge on the oxygen carbonyl atom,
thereby promoting the formation of a strong ZMIIB as compared with kate form B, in which the
formation of a ring with an ZMHB is less likely, Let us note that hetarocycles that contain
S) Se) and NHe as the X group are aromatic. This should s t a b i l i z e the annelated q u a s i - a r o -
matic ring with 9 hydrogen bond.
It might be assumed that the influence of the corresponding electronic effects should
affect the actual bond lengths in the molecules, as well as the physicochemical properties
of the I systems= In order to detect this dependence we analyzed the structural and physico-
chemical characteristics of compounds that we have previously investigated~ The bond lengths
in the tautomerlc aminovlnyl ketone fragment, calculated for N-phenyl compounds ! (R = Ph)
by the Pariser-Parr--Pople (PPP) method within the Dewar ~, ~ parametrization [7], and the
corresponding data from x-ray diffraction analysis [4-6] are presented in Table io The
three-dimensional structures of the molecules are reflected in the writing of the formulas
(Table I). One may note that the calculated bond lengths do not convey the effect of the
X group~ On the other hand, the x-ray diffraction data provide evidence for the contribution
of conjugated structures D (Ill end V) and E (IV) to the distribution of the bonds; the domi-
nating role belongs to keto enemine form B. In fact, with the exception of the III molecule
(possibly as a consequence of the effect of nitrophenyl substituent R), the C=O bond is elon-
gated in IV and V as compared with II, which corresponds to its considerable polarization~
The carbonyl.group in II displays the greatest degree of double bond character. The dis-
tance between the Ct~ ~ and Ct~ ~ atoms is appreciably shorter in llI than in II and particular-
ly IV. The double Bg6d character of the exocyclic Cf3~=Cf4 ~ bond is most pronounced in II
and IV. The III molecules contain a stronger C(4)--Ni5i bdnf than II and IV structures.
Thus, in conformity with the electron-donor character of heteroatom X in the II-IV molecules,
the contribution of dipolar structures D and E increases~ This is the reason for the exis-
tence of the aminovinyl ketone fragment of IS in the Z configuration with an intermolecular
hydrogen bond and of the aminovinyl ketone fragments of Ill and IV in the E configuration
with an IMHB. Judging from the NHoooO,=C distances, all of the hydrogen bonds are quite
strong (Table i). The aminovinyl ketone of the indandione series (V) is an interesting
model that combines E- and Z-tautomeric chains in a single molecule. The O:i~=Ct9 ~ group is
,, ,!
included in a forcedly (for steric reasons) formed ring with an IMHB. It~6ond ~arameters
provide evidence for the evident contribution of dipolar form Do The other "free" C(6)=C(7 )
group has appreciably greater double bond character, and the C(6)=C(3 ) distance is 0.016 nm
longer than the C(2)-C(3 ) bond (Table i).
The above-noted structural peculiarities are reflected in the physicochemical properties
of the II-V molecules, as evidenced by the data presented in Table 2 for N-phenyl derivatives.
The constants for 2-(N-phenylaminomethylene)-indan-3-one (Vl), crystals of whidh have not
been subjected to x-ray diffraction analysis, are also included in Table 2. However, fol-
lowing the logic set forth above, in connection with the spS-hybridized X = CH2 group and
the absence of conjugation of the E type, one may propose for the VI molecules Z-keto enamine
structure B in the solid phase with a small contribution of the dipolar D form and with para-
meters close to those of benzofuran analog II. The frequencies of the stretching vibrations
of the bonds of the tautomeric frgment are a sensitive indicator of the fine structures of
the II-VI molecules. The conjugated bonds that mre not tied up in a ring wih an IMHB are
least polarized~ The high-frequency vibrations at 1715 and 1700 cm -x in the spectra of II
and V and, probably, VI (1695 cm -I) correspond to them~ Polarization of the orbitals in the
III-V molecules leads to a substantial decrease in the frequencies of the stretching vibra-
tions of the keto enamine fragment. Let us note that this effect is not a consequence of a
decrease in the strain of the five-membered ring in connection with an increase in the size
of the X groups, since, according to the data from x-ray diffraction analysis, the magnitude
of the ring angle at the carbonyl carbon atom does not vary over a wide range -- from 102.4 ~
in II to 108.9 ~ in III [4-6].
According to quantum-chemlcal calculations by the Pariser-Parr--Pople (PPP) method, the
long-wave band in the electronic absorption spectra of II-VI reflects redistribution of the

*The x-ray diffraction analysis was carried out by Lo Oo Atovmyan and S. M. Aldoshin (Branch
of the Institute of Chemical Physics, Academy of Sciences of the USSR, Chernogolovka)o

696
 TABLE i= Experimental and Calculated Bond Lengths of the Tau-
t0meric Fragments o f l l - V
Bond length,* nm f
.-
Compound
O~l)-C~m c(=,-c,=, J
H 9 ,'0(i )
I
0,1220 0,1458 0,1345 0,1358 0207
(0,1265) (0,1460) (0,1352) (0,1407)

II NHPh

I
0,1195 0,1452 0,I367 0,1342 0,195
(0,1264) (0,1465) (0,1351) (0,1413)

N%
1 _
~ 0 " . . i t 0,1248 0,1478 0,1353 0,1352 0,184
L~..l.--... + / ~ . 4 / N.
"~'~ ~N ~ ~CII "Ph
!
Ct13 N

1 -
0,1237 0,1439 0,1380 0,1328 0,208
(Ci~--C(a)
0,1224) 0,1455)
(0,1262) (0,1465) (0,1358) (0,1403)

*The calculated values are indicated in parentheses~ In the

case of III and V the values for molecules with unsubstituted
N-pheny94rings are presented~

charge from the aminomethylene part of the molecule to the electron-acceptor carbonyl
groups [7]. The effect of the X fragment, which consists in drawing together of the So and
Sz levels as its electron-donor character increases, is evident from the data in Table 2. A
bathochromic shift of the maximum of the long-wave band (A%max 150 nm) is noted on passing
from indandione molecules V (X = CO) to indole molecules IV (X = NCHa) through Vl, II, and
III; this is explained by an increase in the polarization of the systems.
The weak-field shift of the signals of the NH protons in the PMR spectra reflects the
considerable contribution of zwitter-ion form D, in contrast to the slightly polarized amino-
vinyl ketones, which have chemical shifts (CS) ~N~ 4-6 ppm [i]o Regardless of which form of
hydrogen bond predominates in solutions of I, th~-'strongest N H b o n d is noted in the II, V,
and VI molecules~ In direct relationship to this, the same amlnovinyl ketones with a very
slight contribution of dipolar form D have the lowest acidities (Table 2). All of the data
presented in Table 2 for VI make it possible to assume the real proposed structure, which
contains the least contribution of dipolar form D with a trans configuration of the amino-
vinyl ketone fragment in the solid phase.
In discussing the structure of systems I, we did not take into account the steric factors
of the X group, which should not be significant and may be reflected only in the stabilities
of the E and Z isomers in molecules of the IV type. An increase in the electron-donor char-
acter of the R group attached to the nitrogen atom in I leads to strengthening of the N--H
bond, a decrease in acidity [14], and an increase in the polarization of the C=O group.
Electron-accetor R groups increase the NH acidity and decrease theoverall effective negative
charge on the carbonyl fragment. Replacement of the exocyclic oxygen atom by sulfur leads
to aminovinyl thiones. Since a less electron-accepting (than C:-~O)but more polarizable
group arises in the molecules, the previous reasoning is also acceptable in this case. The
role of dipolar structures in aminovinyl thione molecules is significant. Evidence for this
is provided by the increased (as compared with ketones) acidities of the thiones [14J,
strengthening of the IMHB, the results of x-ray diffraction analysis [18], and other facts
[19]. The sulfur atom in the aminovinyl thione anion is a softer nucleophilic center than
the oxygen atom in amino ketones.

697
 TABLE 2, Physlcochemlcal Characteristics of II-VI
i i
v, cm 'i (In] ' 6+.~i(in pr~
Compound mineral
off) , [[ )'max,nm(~. I0-') DMSO),
ppm [14]
(in aceto-
nitfile) [14]

1715 [16] 417 (31,o) [16] 10,15 23,78

II [NHPh
o-..? 23,49
~ 1660 [151 445 (26,5) [15] 10,30

Ilia

1675 [17] 520 (25,4) [17] 10,0

I
IV CH~
07..H 1645 370 (36,9) [17] 11,10 23,21
1700 [17]

o Va

1695 [171 390 (30,3) [171 9,43 25,29

g "CH= "CH
t
NHPh

698
 Thus, in addition to other factors, the effect of heteroatom X of the five-membered
ring on the structure and properties of aminovinyl ketones of the I type was ascertained.

LITERATURE CITED
I. Ya. F. Frelmanis, The Chemistry of Enamino Ketones, Enamino Imlnes, and Enamino Thiones
[in Russian], Zinatne, Riga (1974).
2. Ya. L. Gol'dfarb (editor), New Directions in the Chemistry of Thiophene [in Russian],
Nauka, Moscow (1976), Chap. 3.
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Bren', Zh. Struk. Khim., 25, 136 (1984).
6. S. M. Aldoshin, L. O. Atovmyan, O. A. D'yachenko, V. I. Minkin, V. A. Bren', G. D.
Palui, and Zh. V. Bren', Zh. Struk. Khim., 25, 106 (1984).
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8. G. O. Dudek and O. P. Volpp, J. Am. Chem. Soc., 85, 2697 (1963).
9. W. Freyer, J. Prakt. Chem., 320, 508 (1978).
i0. I. Ya. Kvitko, Zh. Org. Khim., 15, 2590 (1979).
ii. L. N. Kurkovskaya, R. N. Nurmukhametov, and D. N. Shigorin, Zh. Strukt. Khim., 21, 61
(1980).
12. O. I. Betin and R. N. Nurmukhametov, in: Electronic Vibrational Spectra of Some Aromat-
ic Compounds [in Russian], Vol. 2, Smolensk (1978), p. 37.
13. V. I. Minkin, B. Ya. Simkin, L. P. Olekhnovich, and M. I. Knyazhanskii, Teor. Eksp.
Khim., 10, 668 (1974).
14. L. L. Popova, V. A. Bren', Z. V. Bren', and V. I. Minkin, Khim. Geterotsikl. Soedin.,
No. 3, 309 (1981).
15. V. A. Bren', V. I. Usacheva, and V. I. Minkin, Khim. Geterotsikl. Soedin., No. 7, 920
(1972).
16. V. A. Bren', Zh. V. Bren', and V. I. Minkin, Khim. Geterotsikl. Soedin., No. 2, 154
(1973).
17. Zh. V. Bren', V. A. Bren w, B. Ya. Simkin, and V. I. Minkin, Zh. Org. Khim., 13, 1723
(1977).
18. L. G. Kuz'mina, Yu. T. Struchkov, M. A. Kalik, and Ya. L. Gol'dfarb, Khim. Geterotsikl.
Soedin., No. 12, 1625 (1978).
19. V. Yu. Mortikov, V. P. Litvinov, and Ya. L. Gol'dfarb, Khim. Geterotsikl. Soedin.,
No. 8, 1052 (1984).

699
CONDENSATION OF 3-METHYL-3-BUTEN-I-OLW~TH S O ~ KETONES

U. G. Ibatullin, T. F. Petrushina, UDC 547,361'572'811.07:543.51

Z. Mo Nurtdlnova, Yu. No Popov, end M~ G~ Safarov

The reaction of 3-methyl-3-buten-l-ol with acetophenone and benzalacetone

affords a mixture of isomeric 2-methyl-2-aryldi- and tetrahydropyrans, the
composition of which was ascertatined by chromatography-mass spectromety,

A number of papers LI-4] have been devoted to the condensation of y-unsaturated alcohols
with carbonyl compounds in an acid medium, which, depending on the conditions, affords isomer-
ic dihydropyrans or tetrahydropyranols. In practically all cases, it was noted that aliphatic
ketones have lower reactivity than aldehydes, and the possibility of using aliphatic-aromatic
ketones was described with only one example in the reaction with 4-methyl-4-penten-2-ol (I)
[5]. However, this paper contains no data on the isomeric composition of the resulting dihy-
dropyrans, and, in addition, the very fact of the existence of the isomers is only assumed.
In the present investigation , we consider the effect of the structure of the ketones on
the course of the reaction with 3-methyl-3-buten-l-ol (II), and we studied the composition of
the products in detail.
It was ascertained that at room temperature in an aqueous sdlution of sulfuric acid and
with prolonged heating in hexane in the presence p-toluenesulfonic acid, the starting alcohol
II and acetophenone Ill remain practically unchanged. It was only possible to carry out the
reaction at a higher temperature in boiling octane (17Z) and cumene (40%), although even in
these cases a significant portion of the ketone remained unconverted:

+CHufR H., H~ + H.~

O
*~ ,n .=c.-5 v.,~. Vb,VIb Vc,Vlc
"IV R~ ~.~.C6H5

Previously, in the alcohol I-p-toluenesulfonic acid--ketone III system in boiling benzene,

Williams et al. [5] obtained 2,4,6-trimethyl-2-phenyl-3,6-dihydro-2H-pyran in-18% yield on
the basis of the starting ketone. According to the data of GLC analysis in our case, a mix-
ture of three products (Va-c) was formed.
The low reactivity of the ketones could be explained by the electronic or steric effects
of the substltuents at the carbonyl group.
We synthesized derivatives of acetophenone III with electron-acceptor substituents,
namely, e-bromoacetophenone VII and phenacylpyridinium bromide VIII. It was found that when
they were heated with alcohol II in hexane the reaction did not proceed. Under more severe
conditions (octane and toluene), there was significant reslnification of the reaction materi-
al. These facts indicate the predominant effect of steric factors. To confirm the obtained
results, we carried out experiments with anthraquinone end benzalacetone IV. In the first
case, we observed a situation identical to the condensation of alcohol II with compounds VII
and VIII, and when the phenyl substituent was removed from the reaction center (benzalacetone
IV) we obtained the target product (Via-c, also as a mixture of three isomers) in good yield

Bashkir State University, Ufa 450074. Translated from Khimiya Geterotsiklicheskikh

Soedinenii, No. 7, pp. 883-885, July, 1986. Original article submitted March 19, 1985.

700 0009-3122/86/2207-0700512.50 @ 1987 Plenum Publishing Corporation

 TABLE i. Chromatographic Mass Spectra of Compounds V-Vl
o~- o
Corn- , ,~ o I ~ -I Value of m / z (relative intensity, %)"
poundI ~ o ~..o~1
t u i~l, ~ ,~,~! ............
Vc 8 1757 43 (108), 67 (47), 88 (17), 77 (15), 105 (25), 121 (49), 160 (34),
t88 (8)
Va 14 1 7 5 7 43 (46), 77 (14), 105 (17), 111 (24), 173 (I00), 188 (5)
Vb 78 1800 43 (22), 67 (32), 68 (I08), 77 (17), 105 (48), 118 (15), 121 (37),
188 (3)
Vlc 47 2289 41 (14), 43 (61), 53 ('20), 67 (44), 77 (25), 91 (25), 103 (28),
115 (ll), 123 (17), 128 (25), 129 (38), 131 (94), 145 (71), 146
(13), 147 (45),185 (47), 199 (!08), 200 (12), 214 (63)
~la 15 2304 43 (21), 91 (15), 199 (100),200 (14), 214 (16)
Vlb 38 2340 43 (14), 68 (19), 91 (13), 103 (14), ll8 (15), 181 (I08), 145
(62), 146 (33), 171 (12), 214 (3)

*With the exception of molecular ions, the peaks of ions,

the peaks of ions with intensity >-10% are given.

(37%) with heating in benzene.

Since the components of the mixtures V and Vl could not be separated by the usual methods,
chromatography-mass spectrometry was used to identify them. The behavior of the cyclic ethers
isomeric with respect to the position of the double bond under the effect of electron impact
was specific. Previously this was shown for the case 2-alkyl (aryl)-4-methyl-5,6- and -3,6-
dihydro-2H- and 4-methylenetetrahydropyrans [6].
As is evident from the data of Table I, all the synthesized compounds had distinct molec-
ular ions with relative intensities from 3 to 65%. The most unambiguous spectra were charac-
teristic of isomers o f type aj in which the main direction of fragmentation was determined
by elimination of the substituent from the 2 position of the ring, with the methyl group be-
ing abstracted preferentially. To a lesser degree and only in the case of compound Via we
observed the formation of a fragment with m/z Ill [ M - R ] + . The isomers of type b underwent
cleavage by the mechanism of retro Diels--Alder decomposition (RDD). The most complex spectra
were observed in the fragmentation of compounds of type c, when several variants of the de-
composition occurred in parallel: at the O-C,., and C(5) C(4)('[M-C2H4] +) bonds in the frag-
mentation of compounds of type c, when C5H7+ ~o$ also formed in parallel:

CH~
F
J.
l"
i c~"L
CH~
oI>'" R Via 109
a) i " CH ~ . . . . . . . ~ / :
CtI,
4~O/l~ R
/ "~i
l A H~
"-.O-Y"~CH3

0 / /
VI 146 9
H3 CII ~ R ......... "'~ ~'P
+
s: ~-,] RDD
~ /CII3 43
~0 ~ R ~,lt, CIt~

701
 +
(tl(,

.......
o a ",%
ItO+ .R VC 121
I -C"II4 ~ " CH~ VIC 147

'~ .CN3 ...... a.- }l:,i

b'" "R ~ vx~ 186

From what has been described above, it follows that in the reaction of alcohol II with
ketones III and IV di- and methylenetetrahydropyrans isomeric with respect to the position
of the double bond were formed and could be identified unambiguously according to the mass
spectra.

EXPERIMENTAL
Chromatographic-mass-spectrometric analysis was carried out with a Finnlgan-4021 instru-
ment with a glass capillary column (30 m 0.25 mm). He carrier gas (i ml/min), SE-30 phase,
temperature-programming conditions (sec/min) from 50 to 180=C (further in the isotherm), and
ionization energy of 70 eVo
Proton NMR spectra were recorded on a Tesla BS-487-C instrument (80 MHz) in CCI~.
The reaction of alcohol II with the carbonyl compounds was carried out by the procedure
of [3].
We obtained compounds V [17% yield (octane, i0 h) and 40% yield (cumene, 8 h): bD 120-
126~ (5 gPa); n D m 1,5352; proton NMR spectrum (CC14):6.9--7,2(C6H5), 57 (CH=C(), 52 (CH2=C./), 3,9--3,2
(CH~--O), 2,5--I,9 (CH2), 1,6 (CHa), 1.25 ppm (CH~). Found: C 82.71; H 8.22%. C13H160 ~ Calculate~
C 82.98; H 8,51%] and VI [38% y i e l d ( b e n z e n e , i 0 h ) ; , ~ 1,5655 ; p r o t o n NMR s p e c t r u m (CCl+): 6,9
(C,Hs), 5.9 (CH=C<), 4.6 (CH,=C<). 3.8--33 (CH~--O). 2,3--1.9 (CH~). 1.6 (CH,), 1.2 ppm (CHs) ( t h e number of

protons is not indicated because the spectrum was recorded for a mixture of isomers)o Found:
C 8395; H 8.01% C~sHmO Calculated: C 8411; H 341% ]
Compound VII was synthesized by the method of [7], and VIII was synthesized by the pro-
cedure of [8]0
The reaction with alcohol II was carried out by the method of [3], but products of pyran
structure were not obtained~

LITERATURE CITED
lo Eo Hanshke, Chem. Bero, 88, 1053 (1955).
2. Ro Helin, R. Henry, and S. Gelin, C. R~ Acad. Sci., 273, 254 (1971)o
3. Ao Ao Gevorkyan, Ao So Arakelyan, and Po Io Kazaryan, Khimo Geterotsikl. Soedin., No~ 12,
1611 (1982)o
. A. A. Gevorkyan, A. S. Arakelyan, and N. M. Khizyantsyan, Arm. Khim. Zh., No. 9, 743
(1977).
, F. H. Williams, G. G. Ecke, and S, A. Ballard, J. Am. Chem. Soc., 72, 5738 (1950).
6. U. G. Ibatullin, Yu. N. Popov, I. R. Kleinos, and M. G. Safarov, Manuscript Deposited
at the Branch of the Scientific-Research Institute of Technicoeconomic Research of the
Ministry of the Chemical Industry of the USSR, July 24, 1984 [in Russian], No. 701
khp-D 84.
, Weygand-Hilgetag, Experimental Methods in Organic Chemistry [Russian translation],
Khimiya, Moscow (1969), p. 183.
8. N. A. Akmanova, R. F. Sagitdinova, R. F. Taipov, and V. P. Yur'ev, Zh. Org. Khim., 16,
2309 (1980).

702
PYRYLOCYANINES.
22.* STYRILS DERIVED FROM METHOXY-SUBSTITUTED
4-METHYLFLAVYLIUM SALTS

I. M. Gavrilyuk, A. A. Ishchenko, UDC 547.814.507:541.651:819.

M. A. Kudinova, and A. I. Tolmachev 45:543.422

Some methoxy-substituted styrils of the flavylium series have been synthesized. Sim-
ple HMO quantum chemical calculations have shown that the terminal rings in these
dyes are largely isolated in consequence of the low order of the C,,,--C, , bond.
The latter is responsible for and explains the unexpected effects ~)th$e6ositions
and widths of the absorption bands consequent upon the introduction of electron-
donor CH30 groups into the heterocyclic nucleus.

Pyrylocyanine dyes containing the p-dimethylaminophenyl residue have found extensive

practical application [2, 3]. For the goal-oriented synthesis of such compounds, it is nec-
essary to establish the relationship between the chemical structures of these compounds and
their spectral properties. Nevertheless, this relationship has so far been studied only with
respect to absorption maxima, and only for dyes in which the heterocyclic nuclei are highly
electron-donating [4-8] (Fo>45 = on a 90-degree scale [9]). The aim of this study was to
examine the influence of electron-donor substituents on the positions and shapes~ notably
the widths, of the absorption bands in styrils derived from weakly electron-donating (Fo<45 ~
hetero-residues, Thesubjects selected for study were styrils of the flavylium series, since
methods for the introduction of substituents into different positions have been well devel-
oped for this residue. It is noteworthy that substituted pyrylium and benzopyrylium styrils
have received little attention up to the present time.
Dyes (Ia-f) were obtained by condensing methoxy-substituted 4-methyl-flavylium salts
[i0, ii] with p-dimethylaminobenzaldehyde in acetic anhydride.

6
v{/ "5" " /;ff~" N{CH3)2
R

C104_

~/ a- f
4'
a,e R=6-OCH3, b , f R=7-OCH3; c RI=2'-OCH3, d - - f RI=4'-OCH3; not shown
R, R ' = H

*For Communication 21, see [i].

Institute of Organic Chemistry, Academy of Sciences of the Ukrainian SSR, Kiev 252660.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 886-890, July, 1986.
Original article submitted March 26, 1985.

0009-3122/86/2207-0703512.50 9 1987 Plenum Publishing Corporation 703

 In Table I, the spectral characteristics of solutions of thes~ dye~ in the ~eakl~" ~,~!ar
methylene chloride and the highly polar acetonitrile are compared. In vlcw of the great ~if.
ferences in the shapes of the bands for styrils and the parent dyes (in the present case,
flavylotrimethlnecyanlnes and Michler's hydrol), the deviation coefficient DM was calculated
from the mean positions of the bands rather than from their I values.
max
Comparison the the I values for dyes (la-f) and (I) (Table i) in the pair of solvents
max
shows that the introduction of the electron-donor methoxy group into any of the positions
tried in the heterocyclic nucleus results in a hypsochromic shift in the absorption maximum,
even when similar substitution in the flavylotrimethinecyanines results in a considerable
deepening in color [I0, ii]. Nor do the mean positions of the bands show any tendency to
deepening, except in the case of the 6-methoxystyril (la), the M'* value of which shows a
slight (~5 nm) bathochromic shift as compared with its unsubstituted analog. It is inter-
esting that the 4',7-dimethoxy-substituted dye (If) has approximately the same depth of col-
or as the 7-substituted compound, although in smymmetrical flavocarbocyanines the effect of
the 4'-methoxy group is clearly apparent [i0, ll].
We now consider the effects of methoxy-substituents in the heterocyclic residues of
styrils (Ia-f) on the breadth of the absorption bands. It will be seen from Table 1 that
the dyes obtained have narrower bands than the unsubstituted styril (I). The introduction
of a further methoxy-group into the oxygen-containing nucleus does not result in further nar-
rowing of the band, but rather results in a slight increase in o (dyes Ie and If). These
changes in the positions and breadths of the absorption bands in styrils (la-f) are unex~
pected. In fact, the CHsO group, by increasing the electron-donor capacity of the heterocy-
clic nucleus, modifies the electronic asymmetry of the dye molecule. An increase should re-
sult in a hysochromic shift and broadening of the band, and a decrease in the opposite changes
in these spectral features [12, 13]. None of these changes, as will be seen from Table i,
was seen in the present case.
The observed dis in the spectra of the substituted styrils (Ia-f) and the unsub-
stituted (I) cannot be due to differing extents of solvatlon of these compounds, since the
tendency to changes in ~ ax , M-*, and o from (I) to (la-f) are the same in methylene chloride
(low polarity) as in ace~onitrile (highly polar). In the latter, as would be expected from
its greater nucleophilicity and lower refractive index [14], the bands are only hypsochromi-
cally shifted, broaded, more symmetrical, flatter~ and more diffuse (lower values of Y~, Y2,
and F) than in the former solvent (Table I).
Additional information can be obtained by comparing the spectral effects caused by sub-
stituting CHsO groups into the nucleus of styril (I) with those observed when similar substi-
tution is carried out in the terminal nuclei of the symmetrical flavylotrimethinecyanine [10,
ii]. An examination of the differences in the shifts of the mean band positions AMs -I and
AMf -I for unsubstituted and substituted, respectively, styrils and flavylocarbocyanines (Table
i) shows that the introduction of the CH30 group into the same position in the hetero-residue
in which it causes a deepening of color in the flavylocarbocyanine results in an increase in
the hypsochromic shifts in the styrils (cf. the AMs -~ value for dye (Ib) and the corresponding
value of AMf-*), and in positions in which this group deepens the color of symmetrical dyes,
it decreases the bathochromic shift values in styrils, or even changes the sign of AMs -I to
positive (Table i). Quantum chemical calculations of the electron-donor ability of the term-
inal nuclei in the styril (I) by the simple HMO method give a Fo value of 24 ~ for the flaven-
ylidene residue, and of ii ~ for the p-dimethylaminophenyl residue. Bearing in mind the fact
that the CHsO group in any position of the flavylium residue increases its basicity [12],
the observed differences between AMs-* and AMf -I could be due to an increase in electronic
asymmetry. However, if an increase in this asymmetry were to play a major part in changes
in I and M-*, the methoxy-group in any position in the hetero-residue should enhance the
max
color. It will be seen from Table 1 that this does not occur. Consequently, the band shift
behavior is to a greater extent determined by changes in the effective length of the nucleus
than by increases in the electronic asymmetry of the dye. The nucleus also plays a more im-
portant part in changes in band width in these styrils. This is clearly apparent when the
os values of the dyes (I-If) are compared with those of the corresponding flavylotrimethine-
cyanines of [10s Ii] (Fig. I). This comparison shows that these values vary quite regularly.
The anomalous points corresponding to compounds substituted in the 2-phenyl ring may indicate
differing extents of conjugation of the 2'- and 4'-methoxy groups with the chromophore in

704
 TABLE I. Characteristics of the Long-Wavelength Absorption
Bands* of Solutions of Styrils (1) and (Ia-f)
Posi" i ~oI- [ ~=
[tion iM.1 ' AMc. 1 (~Mf-..~iDM,
)ye ~H,O vent~'} ~ : 1 ~ ~m ,[10,11]),nml nm i era_
j~' Y, V, F
g,o p i
I
I I
2
690
676
' 5,06 I664,4I
4,96 ] 649,7]
-- 6,5
5,1
1,02 l 997
1,04 11122
2,2 0,041
2,3 0,037
Ia 6 i" 692 5,101669,41 5,0(13,6) 4,7 1,071 918 2,4 0,036
2: 670 4,84 [654,4[ 4,7(12,6) 3,5 0,74 [I031 0,88 1,5 0,025
Ib 7 I 668 ' 5,04t649,8 I -- 14,6(-9,0) 6,4 0,99[ 950 0,82 1,9 0,021
! 646 4,941637,71 - 12,0(-9,1) 7,6 0,95 ] 1063 0,79 1,5 0,020
Ic 2' 11686 5,061665,41 1,o(4,5) 5,2 0,96 [ 924 1,04 2,1 0,034
2 664 4,99 ]652,2 I 2,5(4,1) 5,5 1,06 ] 1093 1,04 2,3 0,035
Id 4' I 682 5,1'71663,8I --0,6(19,3) 6,2 1,21 I 886 1,08 2,3 0,03~
2 666 5,01165~,81 3,1 (17,6) 9,4 1,0~ l I034 0,96 1,9 0,02~
le 6,4 1 684 5,13/665,21 0,8(29,6) 1,10[ 94o 1,12 2,7 0,035
2 666 4,97 [653,3[ 3,6(26,4) 6,0 0,9911081 1,07 2,7 0,03~
If 7,4 1 666 5,181646,0] -18,4(3,8) 1,08 [ 985 1,01 2,3 0,03~
. 645 4,961635,1 [ - 1 4 , 6 ( 5 , 3 ) + 2,2 0,99]Ib15 0,96 2,1 0,02~

eM-* is the mean position of the band measured by the method

of moments; f is the oscillator strength; ~ is the band width;
y, the asymmetry coefficient; y~ the excess coefficient; and
F is the fine structure constant.
% 1 denotes methylene chloride, and 2, acetonltrile.

OS~,,CDI"~ Ho 74"

lngn - .,6 6,L'

t -5"" e ~'
~0~3 H,, /_..
7.//,
9ZO~ / " ~ '
6 4; o fu0,11],crn-,
L___.L-- . . . . . . . . l,
750 850 950

Fig. i. Relationship between absorption band width in styrils

(I-If) and the corresponding flavylotrimethinecyanines '(~s):
black circles represent methylene chloride, and light circles,
acetonitrile.

symmetrical and nonsymmetrical dyes. It therefore follows from Fig. i that substituents
introduced into the heterocyclic nucleus of styril (I) influence the extent of vibronic in-
teractions to approximately the same extent as in symmetrical flavylocarbocyanines. In other
words, the substituent has a greater effect on changes in bond order on excitation in the
hereto-residue in styril (I) than in the polymethine chain. For example, when a methoxy
group is introduced into the 6-position of the styril (I), the Ap contribution of all the
bonds in the flavylium nucleus to the overall 8 value decreases by 2.6%, whereas the contri-
bution of all the remaining bonds remains virtually unchanged (~~0.005%).
Quantum chemical calculations for styrils (I) and (Ia), even with the same values for
the resonance integrals (flCC = l) for the bonds of the polymethine chain, suggest substantial
alternation in the orders of these bonds. For example, the orders of the T-bonds C(4)-~(~),
C(a)--C(fl), and C(8)--C(T) in the ground state in dye (I) have the values 0.5349, 0.7370, and
0.4844 respectively, and in (la) these values are 0.5344, 0.7374, and 0.4844 respectively.

705
 TABLE 2. Properties of Styrils (la-f)
mp*, Found, % .~mpiric al for, Calculated, % . . . . .
Dye
c H {OCFh) CI mUl~ C }-[ (OCHO C;i %
l& 225 (8,4) 7,0 C~eH.,~CINO~ (0,4) 7,4 7S
242 64,8 4,6 7~,A C~H,~4CINOe 84,8 5,0 7,4 80
801 (gA) 7,0 C26HI4CINOs (6,4) 7,4 74
I'1 ~49 (6,t) 7,l NO6
C2eH~4CI (8,4) 7,4 80
le, 239 83,2 5,3 6,9 C~H26CINO~ 83,3 5, I, 6,9 75
11 250 83,3 4,8 6,7 C~THs6CINO7 63,3 5,1 6,9 65

Dyes (Ic, e, f) from acetic anhydride, (la) from a mixture of

acetic and formic acids (9:1), (Ib) from a mixture of acetic
acid and acetic anhdyride (I:i), and (Id) from a mixture of
acetic and formic acids (3:2).

These alternations are even greater when the differences between these bonds are taken into
account. For instance, if~c~4~-q=l=~c~-c(~l =0.8~ and~c(~-c~= ].2~ the orders of the same bonds
in the styril (I) are 0.3896, 0.8602, and 0.3521, and in (la), 0.3893, 0.8604, and 0.3520.
These calculations show that the C(4)-C(~ ) bond approximates to a single one. Consequently,
the heterocycllc ring is to a large extent isolated from the rest of the cation. This iso-
lation also appears to result in spectral features resulting from substitution in the hereto-
residue in the styrll (I) being mainly governed by changes in the electronic characteristics
of the ring itself.
Further isolation of the terminal nuclei could result from rotation around the C(4)-C(~ )
bond. It may be pointed out immediately that conformational effects should not play an im-
portant part in differences between the unsubstituted styril (I) and its substituted deriva-
tives (Ia-f), since the fluorescence spectra of these dyes are mirror images of the absorp-
tion spectra, and are independent of the excitation wavelength.
To summarize, it may be concluded that in the molecule of the styrll (I) the terminal
nuclei, which are poor electron donors, are largely isolated as a result of the low order of
the C(4)-C(u ) bond, which results in and is the reason for the unexpected changes in the
positions and widths of the bands on introducing electron-donating CH30 groups into the het-
erocycllc nuclel.

EXPERIMENTAL
Absorption band moments were measured as in [i] from the absorption spectra obtained on
an SF-4A spectrophotometer. Quantum chemical calculations were carried out by the simple
HMO method with the set of parameters given in [15]. The methoxy group was modeled as in
[10]. The purities of the compounds were checked by TLC on Silufol UV-254 plates, with
nitromethane as eluent.
4-[l-(4-Dimethylamlnophenyl)-2-vinylJ-6-methoxyflavylium Perchlorate (la, Table 2). A
mixture of 0.i00 g (0.29 mmole) of 4-methyl-6-methoxyflavyllum perchlorate [9], 0.043 g (0.3
3 mmole) of p-dimethylaminobenzaldehdye, and 1.5 ml of distilled acetic anhydride was boiled
for 5 mln. After cooling, the solid dye was isolated by filtration.
4-[l-(4-Dimethylaminophenyl)-2-vlnyl]-7-methoxyflavylium (Ib), 4-[l-(4-dimethylamino-
phenyl)-2-vinyl]-2'-methoxyflavyllum (It), 4-[l-(4-dimethylaminophenyl)-2-vinylJ-4'-methoxy-
flavylium (Id), 4-[l-(4-dimethylamlnophenyl)-2-vinyl-4', 6-dimethoxyflavylium (le), and 4-
[l-(4-dimethylamlnophenyl)-2-vinyl]-4',7-dimethoxyflavyllum (If) perchlorates were obtained
as for (Ia) from the appropriate 4-methylflavylium salts [i0, ii].

LITERATURE CITED
. I. M. Gavrilyuk, A. A. Ishchenko, M. A. Kudlnova, and A. I. Tolmachev, Khim. Getrotsikl.
Soedln., No. 1, 44 (1985).

706
2. I. I. Boiko, T. N. Boiko, A. M. Bonch-Bruevich, T. A. Markina, T. K. Razumova, I. O.
Starobogatov, Opt. Spektr. 58, No. i, 56 (1985).
3. J. Williams and G. Reynolds, J. Appl. Phys., 39, 5327 (1968).
4. L. M. Yagupol'skii and A. I. Kiprianov, Zh. Obshch. Khim., 22, 2216 (1952).
5. L. M. Yagupol'skii and V. P. Nazaretyan, Ukr. Khim. Zh. No. 6, 617 (1967).
6. A. I. Kiprianov and F. A. Mikhailenko, Zh. Obshch. Khim., 31, 781 (1961).
7. V. I. Troitskaya, V. I. Popov, V. I. Rudyk, N. V. Kondratenko, and L. M. Yagupol'skii,
Ukr. Khim. Zh., No. ii, 1181 (1980).
8. V. I. Troitskaya, V. I. Rudyk, E. V. Konovalov, and L. M. Yagupol'skii, Zh. Org. Khim.,
I0, No. 7, 1524 (1974).
9. G--~G. Dyadyusha and A. D. Kachkovskii, Teor. Eksp. Khim., 15, 152 (1979).
lO. I. M. Gavrilyuk, A. A. Ishchenko, M. A. Kudinova, and A. I. Tolmachev, Khim. Geterotsikl.
Soedin., No. 3, 304 (1983).
ii. I. M. Gavrilyuk, M. A. Kudinova, A. A. Ishchenko, and A. I. Tolmachev, Dokl. Akad. Nauk
Ukr. SSR, Ser. B., No. 6, 28 (1983).
12. I . M . Gavrilyuk, A. A. Ishchenko, M. A. Kudinova, and A. I. Tolmachev, Khim. Geterotsikl.
Soedin., No. 9, 1189 (1983).
13. I. M. Gavrilyuk, A. A. Ishchenko, M. A. Mudinova, and A. I. Tolmachev, Ukr. Khim. Zh.,
No. i0, ii01 (1984).
14. N. A. Derevyanko, G. G. Dyadyusha, A. A. Ishchenko, and A. I. Tolmachev, Teor. Eksp.
Khim., 19, No. 2, 169 (1983).
15. T. Tani, J. Phot. Sci.~ 19, 161 (1971).

REACTIVITY OF CYCLIC SULFIDES IN REACTIONS WITH QUINONES

S. Khushvakhtova, V. S. Aksenov, L. Yu. Trusova, UDC 547.567:546.221

L. I. Perepelitchenko, and I. U. Numanov

Sulfonium salts are obtained by the reaction of cyclic sulfides with 1,4-benzoqui-
none and 5,8-quinolinedione in an acidic medium. It is shown by the method of con-
current reactions that the introduction of alkyl substituents into molecules of
thiacyclopentane and thiacyclohexane decreases the reactivity of the sulfides.
Quinolinedione is less reactive towards sulfides than is benzoquinone.

It is known [i, 2] that sulfides in an acidic medium react with quinolines, forming sul-
fonium salts. There is no information in the literature concerning the special behavior in
this reaction of quinones that contain a heterocyclic ring, expecially quinolinediones. Nor
is there any on the effect of the structure of the sulfides on ~ their reactivity. We were
interested in studying the behavior of cyclic sulfides analogous to the sulfides in the mid-
dle fraction of petroleum, in reactions with benzoquinone and 5,8-quinolinedione. To this
end we prepared sulfonium salts from sulfides IIa-j (see Table i) and also made quantitative
estimate of the reactivity of the sulfides by means of GLC. The composition and structure
of the salts were proven by elementary analysis and IR and PMR spectroscopy.
During this, it was found that a basic feature of the sulfonium salts formed in reac-
tions with 5,8-quinolinedione is that each molecule of the salt contains two anions of the
acid. In the PMR spectra of these salts, a shift of the protons of the nitrogen-containing
ring to weaker fields is observed, indicating the coordination of a second molecule of HCI
per nitrogen atom of the heterocycle. This probably explains the fact that these salts when
heated decompose at 150-180~ without melting. Physicochemical and spectroscopic methods
have so far been unable to show unambiguously whether position 6 or 7 is joined to the sul-
fur.

V. I. Nikitin Institute of Chemistry, Academy of Sciences of the Tadzhik SSR, Dushanbe

734063. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 891-894, July,
1986. Original article submitted May 28, 1985.

0009-3122/86/2207-0707512.50 9 1987 Plenum Publishing Corporation 707

 TABLE I, The Relatlve l~ac=ivltlom of tl'm Sulfldea
i i
tom- llrel In i=lctlon wlltil
Sulfida
~ii4-~n~oq~nono
.... i ,i
Ill Thiac~clo~entt~ 1 I
lib 0,70 0,07
IIr 1- Ethyli.h! icycto., l~rit ine 0,40
.~-P.,ropylt .ru..acyc~opentine 0/27 O,f~
lie '~..v~nyimi~cyc~opentane 0,08 0,02
IH cis- ~,4-D imethElthticyclohexine 0,52 0,27
uam- ~,4-Dime~hylthiacyclolmx~ne 0,36 0,18
cis- ~-Me~h~l-4.pen~ylcyclohexane 0,47 0,29
IIt ulm- S- Methyl-4-pentylcyclothiihexan~ 0,27 0,23
li! Col~centrite of =tetroleum sulfidel 0,25 0,17
Tboil ~1i)-~0 13

0
, :-i R
+ ~I ~ + I~IE'I - ---.i-.

0 fill
lie 'j lll,d,b
0
IIIII 1
,i, ,'t '" R i I~IICI ....... Ci-

0 I1CI 01l
ab lllc-j
Earlier [3], we investigated the reaction of cyclic sulfides with quinoid-type compounds
by measurin 8 the redox potentials of the reaction medium. This method, however, gave only
an approximate, qualltatlve estimation of the activity of the sulfides. In the present work,
we used the method of concurrent reactions to estimate the relative reactlvitles quantitative,
ly. The behavior of sulfides of the thlacyclopentane series was investigated along with a
concentrate of petroleum sulfides in reactions with 1,4-benzoquinone and 5,8-quinolinedlone.
It follows from the results of the measurements, shown in Table i, that unsubstituted thia-
cyclopentane has the highest reactivity. The introduction of methyl or other alkyl groups
into the mnlecule reduces the activity of the sulfide. Apparently steric hindrance plays a
decisive role because the extent of the reduction in reactivity is directly related to the
size of the substitutent in the position a to the sulfur. In this process it has not been
posslble to observe any marked inductive, electron donor effect of the alkyl substituents
accelerating the reaction. The least reactive is 2-phenylthiacyclopentane. In this case,
apparently, the sterlc effect of the phenyl group further decreases the nucleophilicity of
the sulfur atom because of the conjugation with the phenyl nucleus.
The introduction of a substituent in the 3-position, further removed from the sulfur ~
atom, does not lead to a substantial change in the .activity. Characteristically, the cis-
dialkylthiacyclohexanes have a higher reactivity than the trans-isomers. This can also be
explained by the greater accessibility of the sulfur atom in the cis-isomers to attack by
the bulky quinone molecule.
Along with the individual sulfides, we submitted to the investigation a fraction (Tboll
210-250~ of sulfide concentrate isolated by sulfuric acid extraction from the prebitulllinous
fraction of a collection of southern Tadjik petroleum. From elementary analysis, the frac-
tion contains 14% sulfur, which, for MW 200, means that the fraction of sulfur compounds in
the concentrate comes to 85%. The concentrate consisted basically of mono- and bicyclic
saturated sulfides. It was shown by desulfurizatlon on Raney nickel in the vaporizer of a
chromatograph that the concentrate contained primarily cyclic sulfides having alkyl substi-
tuents in the a-position to the sulfur. This apparently explains why the concentrate
investigated showed a reactivity close to that of compounds having steric hindrance at the
sulfur atom.
Comparing the order of activity of the sulfides in reactions with 1,4-benzoquinone and

708
 TABLE 2

C01TI - Initial Tmp, Found, %

pound conl-
pounds Acid (,~bpj' C H S

III a Ia+Ila HCI 119'* 13,1 C,oHl3C1SO2 I 13,8

Illb Ia+Ilb HC1 80 12,1 C.HtsCISO2 12,9
llIc Ib+lla HCI (155) 48,0 4,8 CI3H,4NCISO2"HCI [ 48,9 4,7
llld I b+ lib HCI (16o) 9,6 CI4HI6NCISO2.HCI I 9,6
life I b + II d HCI (16o) 54,8 6,3 Ct6H2oNCISO~-HCI ] 55,2 6,0
llIf Ib+Ilk HCI (16o) 7,9 C19H2~NCISOe-HCI ] 7,9
Illg Ib+lla H2SO4 (18o) 34,8 4,3 ClsHisNS206"H2SO4] 35,2 3,8
lllh Ib+ lib H2SO4 (170) 90,0 CI4HIzNS~O6.H2SOAI 2t,0
III i Ib~IIk H2SO4 (190) 17,6 CIgH27N$206. H~SO4I 18,3
I +lla HN03 (160) 42,3 4,l 8,0 C,3H,4N2SOs.HNO3 {41,8 4,0 8,6

*Ilk - - 4-pentylcyclothiahexane.
tTmp 119 ~ [i].

5,8-quinolinedione, one can see that the dpactivating effect of substituents in the thiacyc-
lanes appears more clearly in the second case. According to the electronic theory of organic
reactions, this is evidence of the lesser reactivity of 5,8-quinolinedione compared to 1,4-
benzoquinone.

EXPERImeNTAL
Synthesis of Sulfonium Salts. To a solution of i0 mmoles of 1,4-benzoquinone or 5,8-
quinolinedione and I0 mmoles of the sulfide in 15 ml of acetone at 0 to ~20C, we added, with
stirring, a solution of acid (12 mmolps for 1,4-benzoquinone and 24 mmoles for 5,8-quinoline-
dione) in 5 ml of acetone, We used concentrated hydrochloric, concentrated nitric acid, or
sulfuric acid diluted to 70% concentration with water. The salt precipitating out was fil-
tered off, washed with cold acetone, dried, and analyzed. Yield, 50-80%. Elementary anal-
yses and melting or decomposition points of some of the salts are shown in Table 2.
Procedure for the Concurrent Reactions and Calculation of Kre I. To run the concurrent
reactions, we placed two or three sulfides in a 25-mi, two-necked flask with a stirrer and
dropping funnel attached. The total amount of the sulfides came to 2.5 mmole. We added an
inert compound (standard) and 5 ml of acetone. As standards, we used the hydrocarbons hep-
tane, nonane, or decane. We then added 1.25 mmoles of 1,4-benzoquinone or 5,8-quinolinedine,
cooled the mixture to a temperature of 0 to -20C, and added 1.25 mmoles of concentrated HCI
dropwise with stirring. We stirred at this temperature until the reaction was complete (30-
40 min). We analyzed the mixture before ann after the reaction in a Khrom-5 chromatograph;
carrier gas, nitrogen; flame ionization detector; glass column, 2.5 m ~ 3 mm with SE-30 or
OV-17 5% silicone on Chromaton. The immobile phase, thermostat temperature, and carrier gas
flow rate depended on the specific mixture and were chosen to give the optimum separation of
the sulfides and standard in the time of the analysis (10-15 min). We did not raise the
temperature of the evaporator above 130=C in order to avoid decomposition of the salts which
starts above 150=C, evolving volatile products (see Table 2). We determined the area of the
peaks with an IT-2 electronic integrator (Czechoslovakia). In the investigation of the con-
centrate of petroleum sulfides, we used the sum of the areas of all the peaks of the com-
pounds entering into the concentrate in the calculations.
We based the calculations of the relative rates of reaction on Eq. (i), which takes the
form of Eq. (2) for analyses by GLC:

lg[C~]o-lglCl] (l)
Krel= Ig[C~l]o- IglC~r]'
lg (St/Sst) o - Ig (St/Sst)
Krel~ l g ( S i j S s t ) o - l g ( S i/Sst ) '
(2)

where K el is the ratio of the rate constant for the reaction of sulfide I to the rate con-
stant t~e for reaction of sulfide II, [CI]0 and [CII] 0 are the concentrations of sulfides I

709
 and II before the reaction; [C I] and [CTT] are the concentrations of sulfides I and II after
the reaction; ($1/Sst)0 and (Sll/Sst) 0 ~ e the ratios of the areas of the chror~:~rnphic
peaks of sulfide I to the standard and of sulfide II to the standard before the ~e~:~tion; a~d
(SI/Sst) and (Sll/Sst) are the ratios of the areas of the chromatographic peaks of sulfide I
to the standard and of sulfide II to the standard after the reaction.
Equation (2) is correct provided that the ratios [CI]/[SI/Sst) and [CII]/(SII/Sst)
remain constant quantities over the range of concentrations studied. To fulfill this condi-
tion, we chose the concentrations of the reactants so that, in the GLC analyses, the peaks
of the sulfides and the standard were comparable in area both before and after the reaction.
To estimate the reproducibility of the determination of Krel, we carried out several experi-
ments to determine the relative activities of the same palrs of sulfides. In this way, we
found that the error in the chromatographic results was no more than 2%, and in the value of
Krel, from 5 to 1 0 % .

LITERATURE CITED

I, H. Bosshard, Helv. Chim. Acta, 55, 32 (1972).

2. E. N. Karaulova, T. A. Bardina, N. P. Volynskii, G. D. Gal'pern. I. N. Degtyarova,
L. R. Barykina, N. L. Lutoshkina, and Yu. T. Struchkov, Zh. Orgo Khim , 20, 797 (1984).
. S. Khushvakhtova and I. U. Numanov, Dokl. Akad. Nauk Tadzh. SSR, 23, 717 (1980).

PREPARATION OF SPIROAZIRIDINEFLUORENE, SPIROINDOXYL-

FLUORENE, AND B-AMINOPROPIONIC ACID ESTER WITH A
4-AZAFLUORENE F R A G ~ N T

N. S. Prostakov, L. A. Gaivoronskaya, S. K, Sarkar, UDC 547.828'678.3'755'

V. F. Zakharov, and N. M. Durbazheva 466.2.07:543.42

It has been established that the reaction of 9-(p-methoxyphenylimino)fluorene with

dichlorocarbene (conditions of phase-transfer catalysis) proceeds in two directions --
the formation of spiroaziridinefluorene and of spiroindoxylf!uorene, the structure
of which has been demonstrated. Opening of the aziridine ring of spiroaziridine-
fluorene has been accomplished. From the analagous azamethine, 4-aza-fluorene, an
ester of N-substituted 8-aminopropionic acid with a 4-azafluorene fragment was ob-
tained by alkylation of its dianion with methyl chloroacetate.

The cycloaddition of carbenes to imines is widely used as a contemporary preparative

method for the synthesis of aziridines [iJ. There is no published information on the prepa-
ration of spiro compounds containing aziridine fragments from a series of fluorene imines
by such a method. We have carried out a study of the compounds which are formed by the reac-
tion of 9-(p-methoxyphenylimino)fluorene (I) with dichlorocarbene under phase-transfer catal-
ysis conditions [2] using triethylbenzylammonium chloride (TEBA) as catalyst. The reaction
does not proceed in only one direction. The main product is 3',3'-dichloro-l'-(p-methoxy-
phenyl)spiro-[aziridine-2',9-fluorene] (II) (75% yield). In addition to this, a compound
with the composition C21H~bNO2 is obtained in 10% yield; spectroscopic data indicate that
this is 5'-methoxyspiro[indoxyl-2',9-fluorene] (III). The structure of compound II is con-
firmed by carbon-13 NMR studies carried out during the present work. On heating the spiro-
aziridinefluorene II with ethanol (rectified spirit), opening of the aziridine ring occurs.
In this way, 9-chloro-9-(N-p-methoxyphenylcarbamoyl)fluorene (IV) is obtained in quantitative

Patrice Lumumba Peoples' University, Moscow 117293. Translated from Khimiya Geterotsik-
licheskikh Soedinenii, No. 7, pp. 895-897, July, 1986. Original article submitted February
27, 1985.

710 0009-3122/86/2207-0710512.50 9 1987 Plenum Publishing Corporation

yield. An analogous conversion of aziridines has been described in [i].

N--C6H~OCH.~- p
C!
II llI,V
\\ ?,

..... N~

I Z=CR; Vl Z=N; III R=H; V R=CH~CO

In the IR spectrum of compound III (KBr) there is an intense band at 1720 cm-~ corre-
sponding to the carbonyl group and a broad, very intense band at 3270 cm-* of the NH group of
the indoxyl fragment; bands at 3180 (broad) and 3425 cm-* (narrow) (chloroform solution) cor-
respond to associated and free secondary amine groups. All the signals of the carbon-13 NMR
spectrum of compound III have been assigned; the signal at 64,6 ppm corresponds to the spiro-
carbon.
The structure of the spirocompound III was further confirmed by x-ray photoelectron spec-
troscopy; a signal Nls = 400.1 eV corresponds to a nitrogen atom of pyrrole type. A symmet-
rical signal with band halfwidth = 3.2 eV resulting from the overlapping of signals from two
oxygen atoms in qualitative splitting gives two values for 0 is at 534.0 and 532.6 eV which
are assigned respectively to the oxygens of the methoxy and carboxy groups [4].
Confirmation of the presence of a secondary NH group in the spirocompound III is pro-
vided by its conversion into 5'-methoxy-l',acetylspiro-[indoxyl-2'9-fluorene ] ( V ) .
The formation of an indoxyl structure in the reaction under study is somewhat unexpected,
there having been no analogous examples up to now. It could be conjectured that in proceed-
ing in this direction the reaction of the imine I with dichlorocarbene takes place via an
electrophilic addition of dichlorocarbene at the o-position to the imino group of the methoxy-
substituted Benzene ring. Aromatization of the 1,3-dipole thus formed accompanied by migra-
tion of the proton to the nitrogen atom leads to a zwitterion which, in its turn, is cyclized
and after hydrolysis of the gem-dihalide is converted into the spiroindoxylflorene III.

:CCh
I1 i,~- ----~ III

+t Jl " il y',!
I . ./ "'-GCH3 " </" \Os

The study of the transformations of azomethines was also directed to the alkylation of
9-(p-methoxyphenylimino)-4-azafluorene (VI) with the object of preparing an ester of 8-amino-
propionic acid containing an azafluorene fragment.
The dianion which if formed from the azomethine VI by reaction with solidum was alkylated
with methyl chloroacetate. Under appropriate reaction conditions (absence of moisture and
oxygen, --50uC during the alkylation [5]), 9-(p-methoxyphenylamino)-9-(carbonylmethoxymethyl)-
4-azafluorene (VII) was obtained in 22% yield.
The compounds reported in the present communication were prepared for evaluation as
physiologically active substances.

EXPERIMENTAL
Proton and carbon-13 NMR spectra were run on a Bruker WP-80 instrument in CDCI3 using
TMS as reference. Photoelectron spectra were run on an ES-200 spectrometer from Kratos
(England). A Specord UR-20 instrument was used for IR spectra with KBr, NaCI, and LiF prisms,

711
the sampl~ b~ing in thQ form of KBr dlsc~. UV ~pectra wer~ obtained on a 8peco~d UV-Vis
spectrophotometer in chloroform solution. ~ s s spectra were run on an ~X-1303 instrument
with direct injection of the samples into the ion source and an ionization ~otenLL~d of 70 eV,
3 ',3' -Dichloro-l'- (p-me thoxyphenyl) spiro [aziridlne-2 ', 9-fluorene ] (II) and 5 ~:~<:ohc.y
spiro[indoxyl-2',9-fluorene] (liT). To a solution of 1.3 g (4.56 mm--~e) ~ the azomethlne I
and 0.09 g (0.4 mmole) TEBA in 15 ml chloroform, 5 ml of a 50% solution of NaOH heated to
60~ was added with vigorous stirring. This was stirred for 0.5 h at 40~ Water at 0~
(20 ml) and chloroform (30 ml) were added and the chloroform solution dried over MgSO~. The
chloroform was removed under reduced pressure without heating. The residue was chromato-
graphed onan aluminum oxide column 46 cm by 2.3 cm; a 2:1 mixture of petroleum ether and
ether was used to elute 1.26 g (75%) compound II, yellow crystals, mp I14-I15~ (from ether).
Carbon-13 spectrum: 55.79 (OCH,), 139.19, 122.51, 114.26, 157.99 (respectively C(~'), C(2')
and C(6,) , C(3,) and C(s,) , C(,) of--NC,HdOCHs-p, 147.50 (CC12), 74.76 (C-spiro), 125.33,
120.60, 130.47, 128.67 (doubled signals C(~)--C(~) and C(5)-C(8), 144.86 and 140.20 ppm (re-
spectively doubled signals of C(ea) and C(ga) , C(~a) and C(~b). UV spectra, %max (ige): 208
(4.46), 240 (4.50), 278 (4.04) 338 nm (inflection) (2.60). Found: C 68.6, H 4.1, CI 19.3,
N 3.8%; ~+ 367. Calc. for C2,H,bCI2NO; C 68.7, H 4.1, CI 19.1, N 3.8%; M 367. Ethanol was
then used to elute 0.13 g (10%) compound III, colorless crystals, mp 230-232~ (from ethanol).
Carbon-13 spectrum: 129.26, 127.56, 128.04 120.08 (respectively doubled signals of C(,)--
C(~) and C(s)--C(e)), 145.50 and 141.66 (respectively doubled signals of C(ea) and C(~a), C(~a)
and C(~b)), 64.16 (C-spiro), 136.68, 109.98, 155.28, 110.23, 113.63, 132.34 (respectively
C(,a) , C( ,)-~(,), C(T,a)) , 176.66 (C(,), 55.17 ppm (C-methoxy). Proton NMR spectrum:
8.90 broad (s, IH, N-H), 7.85-6.85 (m, H(arom.)), 6.24 (d, IH, 4'-H), 3.60 ppm (s, 3H, OCHs).
UV spectrum, %max (Ige): 214 (4.78), 233 (4.44), 266 (4.55), 297 (3.92), 308 nm (4.00).
Found: C 81.1, H 4.5, N 4.3%; M + 313. Calc. for C2,H,sNO~: C 80.5, H 4.8, N 4.5%; M 313.
9-Chloro-9-(N-v-methoxyphenylcarbamoyl)fluorene (IV). A solution of 0.22 g (0.6 mmole)
spiroaziridinefluorene II in 5 ml ethanol (rectified spirit) was heated at bp for 6 h. The
residue after evaporation of the alcohol was recrystallized from I:i benzene-petroleum ether.
Compound IV (0.17 g, 81%) was obtained as colorless crystals, mp 137-138~ Proton NMR spec-
trum: 7.90 (broad, s, IH, N-H), 7.80-7.20 (m, H(arom.)), 7.28 and 6.90 (two d, system AA'BB',
4H, p-C,H~), 3.75 ppm (s, 3H, OCHs). IR spectrum: 3410 (N--H), 1683 (C=O), 1255 (C-O), 752
and 632 cm-2 (C-CI). Pound: N 3.8%; M + 349. Calc for C2,H,6CINO2: N 4.0%; M 349.
5'-Methoxy-l'-acetylspiro[Indoxyl-2',9-fluorene] (V). A solution of 0.31 g (i mmole)
compound IIl and 5.4 g (52.5 mmoie) acetic anhydride in 20 ml dry benzene was heated at bp for
2 h. After removing the solvent the residue was recrystallized from benzene yielding 0.2 g
(56%) compound V, mp 211-213~ Proton NMR spectrum: 8.25 (d, IH, 7'-H), 7.86-6.80 (m,
H(arom.)), 6.19 (d, IH, 4'-H), 3.60 (s, 3H, OCH3), 2.60 ppm (s, 3H, COCH~). IR spectrum:
1750 (C3'=O), 1707 (CHsCON<), 1271 cm'1 (C-O). Found: N 3.8%; M+ 355. Calc. ~for C=sH~o
NO~: N 4.0%; M 355.
9-(p-Methoxyphenylamino)-9-(carbonylmethoxymethyl)-4-azafluorene (VII). A solution of
2.86 g (lO mmole) azomethine VI in 75 ml THP (distilled over lithium aluminum hydride) and
0.5 g (20 mmole) finely divided sodium was heated at bp for 3 h with vigorous stirring in an
atmosphere of dry, oxthen-free nitrogen. To the resulting balck-colored mixture, 3.7 g (15
n~nole) methyl chloroacetate was added at --50~ and stirred for 0.5 h. Methanol (15 ml) was
then added, the solvent distilled off and the residue extracted with boiling benzene (eight
I0 ml portions). The solution was concentrated to 20 ml and passed through a layer of alu-
minum oxide (h = 5 cm, d = 3 cm). The benzene was distilled off and the residue (1.47 g)
recrystallized from i00 ml ether. The yield of the aminoester VII was 0.8 g (22%); mp i36-
137~ (from 1:5 benzene/hexane). Proton NMR secptrum: 8.55 (d.d, IH, 3-H), 7.70-7.10 (m,
H(arom.)), 6.40 and 6.05 (two d, system AA'BB'; 4H, p-C,H~), 5.70 (broad, s, 1H, N-H), 3.67
and 3.55 (s, 3H, two CH~O), 2.92 and 2.67 (system AB, 2H, CH~). IR spectrum: 3382 (free
N-H), 1725 (C=O), 1250 cm-~ (C--O). Pound: C 75.6, H 5.9, N 6.9%; M+ 360. Calc for C~=H~o.
N~Os.~/=C,H~: C 75.3, H 5.8, N 7.0; M 399.

712
 LITERATURE CITED
I. R. R. Kostikov, A. F. Khlebnikov, and K. A. Ogloblin, Zh. Org. Khim., ~, 2346 (1973).
2. D. J. Sikkema, E. Molenaar, and D. B. von Guldener, Recl. Trav. Chim. Pays-Bas, 95,
154 (1976).
3. S. K. Sarkar and L. A. Gaivoronskaya, paper deposited at VINITI, No. 12, p. 99, No. 1290
(1984).
4. V. I. Nefedov, Applications of X-Ray Electron Spectroscopy in Chemistry, Series: Chem-
ical Bonds and Molecular Structure [in Russian], VINITI, Vol. i, pp. 33, 52 (1973).
5. J. G. Smith and D. Veach, Can. J. Chem., 44, 2245 (1966).

MECHANISM OF THE FISCHER INDOLE SYNTHESIS.

QUANTUM-CHEMICAL INTERPRETATION OF THE REARRANGEMENT
OF SUBSTITUTED CYCLOHEXANONE ARYLHYDRAZONES TO
TETRAHYDROCARBAZOLES

Yu. B. Vysotskii, N. M. Przheval'skii, B. P. Zemskii, UDC 54 7. 751:541:127

I. I. Grandberg, and L. Yu. Kostromina

Calculations of a number of model structures within the scheme of the Fishcer in-
dole synthesis were m a d e o n the basis of a bonding variant of perturbation theory
in the self-consistent-field (SCF) MO LCAO method. A quantum-chemical interpre-
tation of the effect of substituents on the course of the thermal process is given.
The kinetics of the thermal and acid-catalyzed indolization of substituted cyclo-
hexanone arylhydrazones to tetrahydrocarbazoles were studied by spectrophotometry.
It was shown that the experimental data are in satisfactory agreement with the
calculated values. It was concluded that a concerted mechanism (a [3,3]-sigma-
tropic shift) for the step involving the formation of a carbon-carbon bond in the
Fischer reaction is preferred.

The mechanism of the Fischer indole synthesis continues to attract the interest of chem-
ists [1-7]. To ascertain the details of this mechanism :SN [8] and *SC N ~ [9] spectroscopy,
mass spectrometry [i0], and kinetic investigations [6, ii] have been used in recent years.
However, some aspects of this reaction, viz., the effect of electronic factors on the rate
of the process, the ratios of the resulting isomers, and the hydrazone-enehydrazine tauto-
merism, continue to remain unclear.
We assumed that a quantum-chemical investigation of the Fisccher reaction, in conjunc-
tion with kinetic and other experimental data, might give additional information with re-
spect to these questions.
The calculations were made on the basis of a bonding variant of perturbation theory in
the self-consistent-field (SCF) ~ LCAO method (for example, see [12]). The indicated ap-
proach has been previously used to interpret the mechanisms of a number of processes [13]
and to predict [14] the subsequently experimentally confirm [15] the effect of substituents
on the recyclization of heterocyclic anhydro bases.
In the present study, as in [16], this approach was used to examine the step involving
the formation of a C--C bond in the Fischer synthesis of indoles, which reduced to description
of the interaction of the unbonded (or weakly bonded) ~-electron systems of II-V (Scheme i).

K. A. Timiryazev Moscow Agricultural Academy, Moscow 127550. Translated from F~imiya

Geterotsiklicheskikh Soedinenii, No. 7, pp. 898-907, July, 1986. Original article submitted
April 29, 1985.

0009-3122/86/2207-0713512.50 9 1987 Plenum Publishing Corporation 713

 TABLE i. Reactivity Indexes in t h e Fischer Indole Synthesis
L---
React-
ivity
~x
I III
indexes' '--II Iv .~eac tivi ty ll!
indexes*

P~ 0,050 0,012 -0,037 0 ~,iz -0,042 - 0,045 -0,042 -0,039

P~ -0,082 0,006 0,094 0 n~,~s -0,019 -0,012 -0,013 -0,016
P~ -0,035 0,367 0,392 0 nl~,~ 0,042 0,028 0,033 0,033
0,028 0,026 0,025 0,028 K~,~a 0,240 0-~33 I 0,233
~13,13 0,126 0,145 0,t24 0,125 K~,~s
KI~,~,~
0,238
0,534
~61 I 0,231
0,502
~45,45 0,174 0,142 0,137 0,173

For structures If-V, R = R ~ ~ R ~ = R s = R ~ -- H.

Scheme I

R I R~ R4

R~

" L
III

'[througha
".~"~"N--N ~ " a ~ '"; .... N-.N "R V- R4
~numSerof steps
a (a) . .R 4
| |l
.. R ~ ]~ ~-
R RI~
v
u

R = R I = R a = R s = R~ = H D d o n o r or acceptor group

Transition state III of the concerted process was calculated as a 10-center i0 n-electron
system isoconjugated with respect to cinnollne, and transition state V of the stepwise sys-
tem was calculated as interacting azabenzyl and azaallyl systems (Scheme 1) (see [6, 17]).
The results of quantum-chemical calculation of structures II-V are presented in Table 1
(only the variant of the thermal process is examined).
The basis for regarding structure II as two unbonded interacting ~ systems is (Table i)
the smallness of the 1--2 bond order (which is equal to zero in structure V). Thls~ on the
one hand~ constitutes evidence for the lability of this bond (its cleavage during the reac-
tion) and, on the other~ for the necessity to take into account second-order (with respect
to AB~ k) perturbation theory; if only one bond is formed (or cleaved) in the reactions~ the
self-polarlzabillties of this bond serve as the reactivity index~ whereas the stabilization
energy AE, determined as the sum (difference) of the bond--bond self- and mutual polarizabil-
ities, serves as the reactivity index if several bonds are involved. Thus, in analogy with
[16], in which this approach was used to interpret the mechanism of the diene synthesis,
cleavage of the 1--2 bond and the formation of the 4--5 bond can be described by the K~a,4,
index

A~ --~K12,45(~=f=) 2 _ (~12,12 "~-~45,45- 2~12,45) (A~ =~=)2

Similarly, the Kxa, ls,~s index is associated with the stabilization energy of the con-
certed process involving cleavage of the 1-2 bond and the formation of 4--5 and 1--3 bonds.
In addition to the orders of the cleaved and newly formed bonds, the bond--bond self- and
mutual p~larizabilities and reactivity indexes of the concerted reactions are presented in
Table i.

The numbering of the atoms in Scheme i (which is the same for all If-V) and in Table I does
not correspond to IUPAC nomenclature and was adopted only for convenience in the discussion.

714
 TABLE 2. Effect .of Substltuents on the Reactivity Indexes in
the Fischer Indole Synthesis*

~0 4

7 H

Reac-:tivity I-- Substituent position (|)

indexes 1 1 2 1 3 1 4 1 5 1 7 18191,0
"a" indexes
xs,m ] --0,0145 --0,0151 0 0070 0,0099 0,0030 0,00401--0,0003[ 0,0019]-0,0010
rU'~3 1 0,0155 0,01.50-0,0048 -0,0301 0,0045 0,0009-0,0004 0,0023 0,0019
0xj,4s 0,0082 0,0077 0,0078 0,0011 -0,0034 0,0017-0,0006 0,0003 0,0015
" b " indexes
~U,~2,m -0,0160 -0.01661 0,0088 0,0174[ 0,00341 0,0044[-0,00031 0,0022[-0.0012
:~j,~s,~s -0,0491 0,00901-0.0219-0,0032[-0,0084[-0,0007-0,0008 [ 0,0040]-0,0038
~t~.4~,4~ -0,0014 -0,00761 0.0038-0,01941-0,01121 0,00011-0,01001-0,0027 ] 0,0176
~J,J2,m 0,0152 0.0147]-0,0056-0,03171 0,00521 0,0014[-0,00041 0,00271 0,0020
r~,~2,45 0,0086 0,00811-0,0089-0,00041-0,00361 0,00231-020071 0,0005] 0.0020
:tj.ls.45 -0,0204 0,00451 0,0092-0,00391 0,00471-0,00361 000081-000101-0,0026
"c" indexes
AK~245 I -0,0346I-0,04041 0,0304 0,00121-0,0006 -0,0003-0,0089-0,0015 0,0124
AK~.I~,j3 [ -0,0955 -0,0370 -0,0019 0,0776-0,0154 0,0009 0,0013-0,0072 -0.0090
AKj.l~,lz,,s -0,1549 -0.0518 0,0381 0,0512-0.0100 -0,0074 -0,0057 -0,0089 -0,0006

In t h e c a s e o f d o n o r s Ac~ < 0, w h e r e a s Ac~ > 0 f o r a c c e p t o r s .

It is apparent from Table i that in II, despite the negativity P45(0) = -0.035, there
is a maximum self-polarizability ~45,~s = 0.174 eV -I, which, by virtue of the smallness of
the IP45(o) I modulus, means the possibility of ring closing in these positions. A similar
conclusion is also valid for structure V. After the formation of this bond and cleavage of
the 1--2 bond (see structures III and V, respectively) the 1--3 bond order becomes positive,
which, together with the sufficiently large values ~,a,ls = 0.145 and 0.124 eV -I, indicates
the subsequent formation of an indole ring.
An analysis of the bond--bond mutual polarizabilities in II also confirms this conclusion,
since, as follows from Table i, weakening of the 1--2 bond will lead to strengthening of the
4--5 bond, and, on the other hand, strengthening of the 4--5 bond will lead to weakening of
the 1--2 bond. A similar conclusion can be drawn on the basis of the data in Table 1 also for
structures III-V, It is apparent that in all of the examined structures strengthening of the
4--5 bond and weakening of the 1--2 bond lead to strengthening of the 1--3 bond, which should be
formed in the subsequent steps.
Thus an examination of the indexes in Table 1 makes it possible to draw the general con-
clusion that a concerted process involving cleavage of the N--N bond and the formation of a
C-C bond (pathway a) is somewhat more preferable than reaction via pathway b.
It is apparent that the results of the calculation correctly reflect the available ex-
perimental data [1-5], although they do not make it possible to draw a definite conclusion
regarding the mechanism of the ll->IV transformation.
In the description of the effect of substituents on the direction of the reaction under
consideration, in addition to the changes under the influence of substituents, which are .
characterized by scalar values AaR and bond orders APik = E~/ihAaRi, one must also take into
9 3 . . . . 1
account the changes in the bond-bond self- and mutual polarlzab111tles Anjmmq=~-~nLi~ ~IAc~Rj
Thus, in addition to the atom--bond mutual polarizabilities ~j,ik(the "a" indexes), the
~J,ik,pq indexes (the "b" indexes) and, in the case of a concerted process, the AK.3,ik,pq
indexes (the "c" indexes) should also act as characteristics of the effect of substituents
on the reaction under consideration. All of these values for II are presented in Table 2.

715
 TABLE 3. Kinetic and Thermodynam$c Parameters of the Fischer
Reaction for Cyclohexanone Arylhydrazones Xa-g
Hy- Reacfibnrzte constants,K.10s I Thermodynamic
Reaction dra- ............ sec-1 %ccelera-___parameters.

=I . .
~ik
. . . .
15o~
. .
1'lo~ 3;~~
. . . .
I
.
1~~ nu ~
. . . . . . .
o , 0 .tm0O,~.
~o~ tor, f 2 kcal/t
e I
As ~ eu

Ethyleneglycolsolvent
Thermal Xa 177,8 125,9[ 79,4 50.II31.6l 7,1 14,1 --38,3
Xb 41,7 22,4 14,1 7.2: 4.~1 0,6 17,7 --32,7
Xc 25,1 14,11 7,9 ..... '2.5~ 0,4 1 17,2 --35,2
Xd 43,7 25,0] 15,4 ~..~l 5.6l 0,9 1,7--2,3 15,8 -37,2/:0,3
Xe 12,6 6,3] 3.5 :.~: 0.9[ 0,1 0,5--0,3 19,6 --31,0
Xf 50,1 28,3[ 17,8 10.21 6.31 1,0 2,0--2,5 15,0 --39,1~0,2
Xg 17,8 8,9~ 5,C =.:~; :.=; 0,1 0,7--0,3 20,5 --27,7
X h" 35,5! 20,9 13.01 1,2 16,8 --34,2/:0,8
Acid-catal- Xa 28.21398.1 [89,1 13,2 -35,5~0,4
yzed, [60~)
Xb 141,5 79.2 50,21 7,9 15,8 -32,4/:0,5
H2SO4, XC 159,5 101,01 56,2 31.61 19.01 2,5 t 16~5 -33,2
2 moles'~ Xd 416,9 281,8~199,5 141.31 97.31 29,2 2,6--11,7 1t,5 --42,8/:0,4
Xe 141,4 82,41 44,7 25.1[ I4.H 2,0 0,9--0,8 17,3 --31,5
Xh I 5 8 1 100.OI 56,21 10,0 15,9 -32,6/:0,8

Decane solvent
Xc 31,5
I[L_~, 16,3 10,9
45,7 26,7 16,7 13,91 9 I I ,8 1 15,8
17,2 I -35,4/:0,2
-32,3

Cyclohexanone N-me thylphenylhydrazone [11].

%The number of moles of the acid per mole of the hydrazone.

Their analysis shows that the introduction of electron-donor groups ( ~ < 0) in the i and
/or 2 positions in enehydrazine II should, according to the "a" and "b" indexes, hinder the
Fischer reaction; for example, according to the "a" indexes, this should strengthen the 1--2
bond and weaken the 4--5 and 1--3 bonds. Moreover, it follows from the 5Kj,ik,p q values that
these substituents should very markedly accelerate a concerted process (see the "c" indexes);
the introduction of donors in the 1 position is apparently more effective than introduction
in the 2 position. The effect of electron-acceptor groups is just the opposite.
The experimental data (see, for example, [18, 19]), like the results of our kinetic
studies (see below), are in agreement with the latter assertion and thereby, within the frame-
work of the adopted theoretical approach, constitute evidence in favor of a converted mecha-
nism.
It follows from Table 2 that even within first-order (with respect to ASik) perturbation
theory the introduction of donors in the 3 and/or 4 positions leads to strengthening of the
4--5 and 1--3 bonds and weakening of the 1--2 bond (see the "a" indexes), which accelerates
Fischer indollzation. Similar conclusions can also be drawn with respect to the "b" indexes,
while the indexes of the concerted mechanism indicate just the opposite; of course, in this
case we are not taking steric factors into account. Experimental data [20, 21] show that the
indolization of a-methylcyclohexanone phenylhydrazone [I, R = R I = H; R 3 + R 3 = (CHz)~],
which leads to the formation of a mixture of indolenine and tetrahydrocarbazole, is faster
by a factor of nine than in the case of the unsubstituted compound.*
The calculated data on o-substituted benzene rings relative to the hydrazine fragment
(Table 2) with respect to all three indexes predict that the introduction of donor groups
should facilitate the Fischer reaction; for example, with respect to the "b" indexes, 7.
],12'12
> O, ~j,13, 13 < O, and wj,4s < O, i.e., the 1--2 bond is weakened, whereas the 1--3 and 4--5 bonds
are strengthened. In addition, it follows from the calculation that an o-donor substituent
increases the reactivity of precisely this center, whereas an acceptor substituent directs
the reaction to the free ortho position. These data are confirmed by the results obtained

The reaction was carried out in an acidic medium; the rate was measured from the amount of
ammonia liberated.

716
 TABLE 4. Physicochemical Characteristics of Cyclohexanone
. Arylhydrazones X and Tetrahydrocarbazoles XII and XIII

mp,~" ~ Pound, % Calc.,% Yield,

Compound rap,* Empirical R/ f0
[literature] formula
TIT
Xa Oil 77,7 9.4 CI~H~N~ 77,7 9,3 0,42 75
El) Oil 66,0 7.4 C13HITCtN~ 66,~ 7,~ 0,53 98
Xc 75"76 : 75--76 [111 92
Xd Oil CI3HIsN2 0,65 93
0il 65,0 6,6 CI2H15CIN~ 65,0 6,8 0,74 87
76,7 8,8 CI3HIsN2 77,1 8,9 0,67 86
Xg ~--87 65,2 6,9 CI~H~sCIN2 65,0 6,8 0,75 9t
Xlla 89--90 89--90 [36] 94
xllb 51--52 C~H,4CIN 75 o;1 84
XIIe 116--1t7 116~117 [37]
XlId+XlIld 82--92 82--90 [38] 72
XItI,d t29~130 130 [23]
XIIe+XlI! e 170~175 79
XIIIe 179~180 178--179 [39]
179--180 [40]
XII f 143~144 145--146 137] 92
141--142 [41]
XtI g 146---t47 146--147 [37] 90

The compounds were crystallized: Xc from 80% methanol, X~

and Xllf from hexane, Xlla,b, Xlld + Xllld, Xllld, Xlle +
Xllle, Xllle, and Xllg from methanol, and XIIc from 60%
ethanol.
~The compounds were crystallized: Xllc and Xlld + Xllld from
ethanol--water, Xllld and Xllf by the method in [37], and Xllg
from methanol.

in [21], in which it was shown that the rearrangement of hydrazone I [R = 5-CH3, R I = H, R 3

+ R ~ = (CH2)4] is faster by a factor of 1.9 than that of the unsubstituted analog and leads
to the formation of 8-methyl-l,2,3,4-tetrahydrocarbazole. In addition, the above-presented
quantum-chemical calculations (without allowance for steric factors) are in agreement with
numerous examples of ipso substitution in the 5 (ortho) position of the benzene ring (the
"anomalous" Fischer reaction [22]).
In the case of m-substituted hydrazine II a donor substituent in the 8 position strength-
ens the 4--5 bond to a greater extent than a similar substituent in the I0 position (compare
the ~. and AK. indexes in Table 2). Thus reacs in the para position relative to this sub-
stitu~nt is e~ergically more favorable, whereas in the case of acceptor groups reaction in
the ortho position with respect to it is energically more favorable, i.e., the ratio of the
resulting isomeric 6- and 4-substituted indoles should be greater than unity if R is a donor
and less than unity if R is an acceptor; this is confirmed by the data in [i, 5, 23].
Finally, if a donor substituent is located in the 9 position, it should, with respect
to all of the reactivity indexes, promote the II->VI cyclization; on the whole, this effect
is more pronounced than the effect of similar groups located in the meta position but weaker
than in the case of the ortho isomers (compare the K. values in Table 2). Acceptors
], 12, ~ 3 , 4 s
should hinder the II+VI transformation. In principle, these data are in agreement with the
literature data [l, 3, 5] on the reactivities of p-substituted arylhydrazones in the Fischer
reaction.
An analysis of the atonr-atom mutual polarizabilities ~ik makes it possible to describe,
within the framework of the developed approach, the effect of substituents on the shift of
the hydrazone 1 2 enehydrazine II tautomeric equilibrium. For the quantitative characteriza-
tion of this process we selected the difference in the residual n-electron charges in the 4

and 2 positions the anion , f ~ 5~~ ~ , which, in the unsubstituted structure, is q~ --q= =

(-0.4483)- (-0.5299) = 0,0816. The positiveness of this value denotes greater negativity
of the nitrogen atom, i.e., a greater probability of attachment of a proton to it as compared
with the C4 center and, ultimately, a shift in the equilibrium to favor the II form. The dif-

717
 TABLE 5. Spectral Characteristics of Cyclohexanone Arylhydra-
zones Xa-g
.........i u V ,p~C- ~ i.........................
i .................... ' - .......... " ...............
.......
Com-[trum (ethyl-]IRspectrum [
poundlene glycol),I(N=N, N--C), I PMR ~.cttum 6 ,~-m
Ik am ~, cm" I

Xa 253 I4,t3), 1510, I~0, w(. 1,68and~,46 (10H, met ~) 2,27 {3H, s, p-C}-]~),
295 (3,59) 2.97 ~3}t.s , N~ CH~), 0.75 (H~, H~. d, ,/~,~=l~,~-~
~o8,6 HZ), 7,06 (H~, H~, d~/t:=l~,~=8,6 Hz)
Xb 2~0 a,J7), 1510,1610, wt, 1,69and2A8 (10H, met), ~98 (3H,s, N~CH0,
290 (332) 6,77 (H~, Hs, d, l~,~,fs,~ 9,2 t'u), 7,19 (H~I Hs,
d, I~,3~15,s--9,2 Hz)
Xc 275 (3,89)
Xd 278 (4,10) 1300,1620, Wt- 132and2,30 (10H, m e r ), 2,36 (3H, s. m-CH~),
7,15~7,52 (4H,m, arom. NH)
Xe 278 (4,09) 1500,1610, wt 1.64and2,32 (10H, m o t ) , 6,65~-7,41 (4H, m,
atom, NH)
Xf 278 (4,02) 15t0,1620,wt . 1,74and2,33 (10H, m e ':), 2,39 (3H, s, p-CH3),
7,08--7,70 {4H, m, atom. NH)
Xg 280 (4.34) 1500,1600,~KBr 1,63aRd2.28(10H, tact,), 6,88 (H~. Ha d, I~.~,=
~./5.~=8,8 Hz), 7,1[ (H2, H~,d,, lz~=l~.~=8,SHz)

The abbreviation "mcr" stands for multlplet of the cyclo-

hexane ring.

ferences in the corresponding polarizEbilities A(q~ -- q=) = (z~ -- ~j.)A~R, where j is the
position of substitution, will, of course, be an index of the effect ~f substituents on this
equilibrium.

Calculation gives the following values for these differences: I) 0.0116, 3) -0.0176,
4) 0.1858, 5) -0.0066, 7) -0.0013, 8) 0.0018, 9) -0.0104, i0) -0.0089~ It is apparent from
the data presented above that the maximum sensitivity to substltuents corresponds to the 4
position, the introduction of acceptor groups (As > 0)in which should lead, according to what
was indicated above, to a shift of the equilibrium to favor the enehydrazine. This corre-
sponds to the available experimental data on hydrazone-enehydrazine tautomerism [24, 25].
The effect of donors is just the opposite: It hinders the formation of structure II, al-
though, as noted above, it also promotes cyclization.
These groups in the I and 8 positions should have a considerably smaller effect but in
the same direction, whereas they should have the opposite effect in the remaining positions
of the benzene ring. When one compares the calculated coefficients in the 5 and 7 positions,
one sees that the introduction of donor groups in the 5 position promotes a shift of the equi
librium to favor the enehydrazine to a greater extent than introduction in the 7 position,
which also corresponds to strengthening of the 4--5 and 1--3 bonds (see above). The opposite
conclusion can be drawn also with respect to the mete positions of the benzene r i n g - donors
in the 8 position apparently will hinder the I+II transition but donors in the 10 position
will facilitate it, i.e., in the latter case the effect of substituents on the I and II+
VI transformations is just the opposite.
Let us emphasize that the scheme for the~ description of the effect of substituents was
based only on quantum-chemical calculation of structure II, whereas it is possible that the
effects of substituents in III-V may also be different. Let us once again also note that we
have examined only thermal and not catalytic processes. Interaction of the groups present,
which also should be examined within second-order (with respect to A~R) perturbation theory
and may be comparable in magnitude to the effects described by the Zik,pq values, was not
taken into account in the calculation. All of these questions were left outside of the pre-
sent examination.
In order to experimentally verify the results of the quantum-chemical calculations and
as a continuation of previously begun investigations [6, Ii] we studied the thermal and acid-
catalyzed rearrangement of a number of m- and p-substituted cyclohexanone arylhydrazones
Xa-g to tetrahydrocarbazoles XIla-g + XIIId,e (Scheme 2).

718
 TABLE 6. Spectral Characteristics of Tetrahydrocarbazoles
XIIa-g
j

Compound UV st)ectrum (ethy-

lene glycol),kmax,nm PMR spectrum, 6, ppm

XIIa 235 (4,52), 293 (3,86), t,89and2,70 (8H,andmcr), 2,45 (3H, s, 6-CH3),
298 sh (3,83) 3,59 (3H,s , N--CH3), 6,96 (7-H, d.d, 17,s=8,2,
I~,7=1,2 Hz); 7,14 (8-H,d, JT,8=82Hz), 7,25
(5-H, d, 15.7=1,2 nz)
XIlb 239 (4,61), 294 (3,83), 1,89.and.2,69 (8H, mcr :), 3,59 (3H, s, N---CHa),
300s~. (3,82) 7,02--7,20 (7.H,m and '8-H), 7,42 (5-H,Sl)
XIIc 230 (4,61), 285 (4,13),
292 sh. (4,08)
XIId+XIIId 233 (4,40), 282 (3,93), 1,87and2,64 (H, mcr ), 2,43 (6H,d.O.7-CH3,
295sh. (3,90) 5-CHa), 6,95--7,37 (H, r~.aromO, 7,87andT,91
(2H, br s.,, NH)
XlIe+XIIIe 238 (4,50), 287 (3,74),
296s~. (3,70)
XIIIe 238 (4,48), 288 (3,74), 1,88 and 2,68 (8H, mcr ), 7,02 (6-H, d~ d, 1~.~=
295 sh. (3,70) =9,0, ./8,8=2,4Hz), 7,24 (8-H,d, 16.8=2,4 Hz),
7,34 (5-H, d, J~,6=9,0 Hz), 7,60 (NH, brs )
xIIf 233 (4,50), 287 (3,98), 1,91 and 2,72 (8H, mcr ), 2,46 (3I-I, s, 6-CH~),
298 sh. (3,90) .694 (7H, d;d., /za=8,8, Js,7=l,3tiZ), 7,19 (a-H,
a', 17.8=8,8tlz), '7,26 (5-H,d, ./5,?=l,3t-iz), 7,6
(NH br.s) d
XIIg 238 (4,58), 292 (3,97), 1,89and2,67(8H, mcr), 7,04 (7-H, .d, 17.8=
299 Hz. (3,93) =8,6 and, ]s,7=2,0Hz ), 7,17 (8.H, d, 17.s=
=8,6 Hz), 7,42 (5-H, d,'15,7= 2,0 Hz), 7,65 (NH.
br.s)

Scheme 2

NH .
N--N---'--O
R] , R
,, N-
RI, .. ,,N - - N
vna.g vma,b IXa-g xa-g
[ #=H

m a-g xu a-g xmd,e

VII, IX--XIa,fR=p-CH3, b,g R=p-Cl, c R = H , d R=m-CH3, e R=m-CI;abR'=CH~,
e--~ RI'=H; VIII a R=p-CH3, b R=p-CI, a.,b RI=CH3; X I I a , f R=6-CH3, b,g R=6-CI,
c R=H, d R=5"CH~, e R=5"CI, a , b R I = C H 3 , c - g RI'=H; Xlll d R=7-CH~, e
R=7-CI; d,e RI=H

Arylhydrazones X were synthesized from the corresponding anilines Vlla-g through hydra-
zines IXa-g. The kinetics of the rearrangement of hydrazones Xa-g to tetrahydrocarbazoles
Xlla-g + Xllld,e were studied by spectrophotometry in ethylene glycol (also in decane for Xc
and Xd) at various temperatures. The kinetic parameters for the indolization of hydrazones
Xa-g, which is a first-order reaction, are presented in Table 3.
It follows from the data in Table 3 that over the investigated temperature range the
conversion of hydrazones X to carbazoles XII + XIII is virtually independent of the nature
of the solvent [for example, at 1500C the rate constants (K'I0 s, sec -~) for the thermal re-
arrangement of hydrazone Xd in ethylene glycol and decane are 43.7 and 45.7, respectively].
On the other hand, electronic factors and the acidity of the medium have a substantial
effect on the course of the process.
A donor substituent (the CHs group) in the meta or para position of the benzene ring
increases the rate of thermal rearrangement of hydrazones Xd and Xf as compared with unsub-
stituted hydrazone Xc (acceleration factors f are, respectively, 1.7 and 2.0), whereas hydra-
zones Xe and Xg (R = Cz) react more slowly (f = 0.5 and 0.7).
A Similar pattern is observed for hydrazones Xa,b. These results correspond to the re-
sults of the quantum-chemical calculations. The latter are also confirmed by kinetic data

719
obtained in a study of the Indollutlon of m-substltuted cyclohexanone N-me=hylphenylhydra-
nones [11].
The rates of thermal rearrangement of m- and p-substltuted cyclohexanone arylhydrazones
are close (compare, for example, Xe and X8, and Zd and Xf), although a somewhat greater rate
is always observed for the pare isomers in accordance with the theoretical calculation.
~ m substltuant attached to the nitrogen atom has an appreciable effect on the indoli-
zatlon of hydrazones X. It is apparent from Table 3 and the data in [II] that N-unsubstltuted
arylhydrazones undergo the thermal Fischer reaction more slowly than the corresponding u-N-
methylphenylhydrazones Xa,b. For example, the rate constants (K.10 s, sec -~) for the rear-
rangement (ethylene glycol, II0~ of hydrazones Xf and Xa (R = p-CH~) are, respectively,
6.3 and 31.6 (Table 3), as compared with 0.9 (Table 3) and 2.8 Ill] for hydrazones Xe (R =
m-CHs) and cyclohexanone N-methyl-N-(m-chlorophenyl)hydrazone. These results confirm the
conclusions of the quantum-chemlcal calculations and are in agreement with the literature
data (see above).
Thus electron-donor substituents in both the aromatic ring and attached to the nitrogen
atom increase the rate of the thermal Fischer reaction. Moreover, it must be noted that the
maximum differences in the rates of thermal rearrangement observed for hydrazones Xe (R =
m-Cl, R* -- H) and Xa (R = p-CHs, R* = CHs) are 70 (at 80eC) and 35 and 28 (at II0~ and 120~
respectively). In addition, in all cases the entropies of activation of the process have
rather high negative values (Table 3).
The latter two conclusions, in conjunction with the kinetic and calculated data on the
effect of substituents attached to the nitrogen atom, constitute evidence in favor of a con-
certed mechanism for the formation of a carbon--carbon bond in the Fischer reaction.
A 10-fold to 30-fold acceleration as compared with the thermal reaction is observed in
the acid-catalyzed indollzatlon of hydrazones X (Table 3). For example, at 80~ the rate
constant for the rearrangement of hydrazone Xd in the presence of sulfuric acid in ethylene
glycol is 29.2, as compared with 0.9 for the thermal process.
Similar acceleration has also been noted for cyclohexanone N-methylphenylhydrazones
[ii]. %~%e effect of substituents in the aryl ring and attached to the nitrogen atom on the
acid-catalyzed rearrangement of hydrazones X coincides with that observed for the thermal
reaction, viz., electron-donor groups accelerate the process, and electron-acceptor groups
retard it (compare the rate constants for hydrazones Xd and Xe with that for unsubstituted
hydrazone Xc, Table 3).
In this connection, the results of quantum-chemical calculations of the thermal rear-
rangement of arylhydrazones can in some measure also be used to interpret the acid-catalyzed
reaction, although this is not completely justified from the point of view of quantum chemis-
try.
Thus the calculations showed that the method that we developed can be successfully used
for the quantum-chemical interpretation of Fischer Indolization. On the whole, the experi-
mental data confirmed the theoretically predicted effect of electronic factors on the rate
of rearrangement of arylhydrazones and the ratios of the resulting indoles.

EXPERDiEN TAL
The PMR spectra of solutions of the compounds in CDCIs were recorded with a Bruker WH
spectrometer (90 MHz). The IR spectra were recorded with a Jasco IR-S spectrometer. The
UV spectra were obtained with a Hitachi EPS-3T spectrophotometer. Thin-layer chromatography
(TLC) was carried out on Silufol UV-254 plates in a benzene--ether system (5 :i) %~ith iodine
as the developer. The kinetic data were obtained by spectrophotometry with the spectrophoto-
meter indicated above by the method in [6]. The purity of the starting amines was monitored
by gas-liquid chromatography (GLC).
N-Methyl-p-toluidine (VIIa). This compound, with bp 209-210~ (bp 209-211~ [28]), was
obtained from p-toluidine by methylation with dimethyl sulfate by the method in [26, 27].

720
 N-Me~hyl,P-chloroaniline (Vlib). This compound, with bp 239-240~ (bp 239-240~ [29]),
was similarly obtained from p-c-hior0anillne.
N-Methyl-N-nitroso-p-toluldlne (Villa). This compound, with mp 50-51~ [from ethyl
acetate--hexane (I:i0)] Imp 5i-52.5~ (from ethanol with ether)] and Rf 0.76, was obtained
in 88% yield from 30 g (0.25 mole) of amine Vlla by the method in [30].
N-Methyl-N-nltroso-p-chloroanillne (VllIb). This compound, with mp 50-510C [from ethyl
acetate-hexane (I:I0)] Imp 51~ [32] and 44'46aC [33]] and ~ 0.71, +was similarly obtained
in 72% yield from 35 g (0.25 mole) of amine VlIb.
N-Methyl-N-(p-tolyl)- (IXa) and N-Methyl-N-(p-chlorophenyl)hydrazine (IXb). These com-
pounds were obtained by reduction of 0.015 mole of nitroso c0mpounds VIIIa and VIIIb, re-
spectively, with a titanium reagent by the method in [34]. Compound IXa was obtained in 90%
yield and had Rf 0.20 and bp 95-96~ (4 ram*). Compound I~b was obtained in 96% yield and
had Rf 0.27 and bp 93-95~ (6 mm).
The constants of arylhydrazones IXa and IXb were in agreement with the data in [31, 35].
m-Tolyl- (IXd), m-Chlorophenyl- (IXe), p-Tolyl- (IXf), and p-Chlorophenylhydrazine (IXg).
These compounds were obtained by the general method for the synthesis of arylhydrazines by
diazotization of 0.2 mole of the corresponding amine V!Id-g with NaNO= and subsequent reduc-
tion of the diazo compound with SnCI2"2H20 and decomposition of the complex with 20% NaOH.
The constants of ary!hydrazines IXd-g were in agreement with the literature data.
N-Methyl-N-(p-tolyl)" (Xa), N-Methyl-N'(p-chlorophenyl)- (Xb), Phenyl- (Xc), N-(m-Tolyl)-
(Xd), N-(m-Chlorophenyl)- (Xe), N - ( p - T o l y l ) - ~ , and N-(p-Chlorophenyl)hydrazone (Xg) of
Cyclohexanone L These compounds were obtained fr0m 0.01 mole of the corresponding arylhydra-
zine IXa-g by the method in [ii]. The constants and yields of arylhydrazones Xa-g, as well
as their spectral characteristics, are presented in Tables 4 and 5.
6,9-Dimethyl- (Xlla), 6-Chloro-9-methyl- (Xllb), 6-Methyl- (Xllf), and 6-Chloro-l,2,3,4-
tetrahydrocarbazole (Xllg), Mixture of 5- and 7-Methyl-l,2,3,4-tetrahydrocarbazole (Xlld +
Xllld), and Mixture of 5- and 7-Chloro-l,2,3,4-tetrahydrocarbazole (Xlle + Xllle). These
compounds were obtained from 0.01 mole of the a r y l h y d r a z i n ~ ~ d L g , respectively) and
cyclohexanone by the method in [II].
7-Methyl- (Xllld) and 7-Chloro-l,2,3,4-tetrahydrocarbazole (Xllle). These compounds
were obtain-ed By repeated crystaliization from methanol of the mixtures of carbazoles Xlld +
Xllld and Xlle + Xllle.
The constants, yields, and spectral characteristics of the tetrahydrocarbazoles are pre-
sented in Tables 4 and 6.

LITERATURE CITED
I. H. Robinson, Usp. Khim., 40, 1434 (1971).
2. Yu. P. Kitaev and T. V. Troepol'skaya, Khim. Geterotslkl. Soedin., No. 8, i011 (1978).
3. I. I. Grandberg and V. I. Sorokin, Usp. Khim., 43, 266 (1974).
4. I. I. Grandberg, Zh. Org. Khim., 19, 2439 (1983).
5. B. Robinson, The Fischer Indole Synthesis, Wiley Interscience, New York (1982).
6. N. M. Przheval'skii, M. E. Kletskii, I. I. Grandberg, and L. Yu. Kostromina, Khim.
Geterotslkl. Soedin., No. 6, 779 (1985).
7. H. Heimgartner, H. J. Hansen, and H. Schmid, in: Iminium Salts in Organic Chemistry,
Wiley, New York (1979), p. 655.
8. A. W. Douglas, J. Am. Chem. Soc., I01, 5676 (1979).
9. A. W. Douglas, J. Am. Chem. Soc., i00, 6463 (1978).
i0. G. L. Glish and R. G. Cooks, J. Am. Chem. Soc., i00, 6720 (1978).
ii. N. M. Przheval'skii, L. Yu. Kostromina, and I. I. Grandberg, Khim. Geterotsikl. Soedin.,
No. 9, 1207 (1985).
12. M. M. Mestechkin, The Density-Matrix ~ethod in Molecular Theory [in Russian], Naukova
Dumka, Kiev (1977), p. 352.
13. Yu. B. Vysotskii and B. P. Zemskii, Khim. Geterotsikl. Soedin., No. 7, 984 (1980).
14. Yu. B. Vysotskii, B. P. Zemskii, T. V. Stupnikova, R. S. Sagitullin, A. N. Kost, and
O. P. Shvaika, Khim. Geterotsikl. Soedin., No. ii, 1496 (1979).
Here and subsequently, the pressure is given in millimeters of mercury.

721
15. Yu. B. Vysotskii, B. P. Zemskii, T. V. Stupnikova, V. N. Kalafat, R. S. Sagitullin, and
V. P. Marshtupa, Khim. Geterotsikl. Soedin., No. 9, 1277 (1982).
16. M. V. Bazilevskii, The Molecular Orbital Method and the Reactivities of 0rgan~c Mole-
cules [in Russian], Khimiya, Moscow (1969), p. 304.
17. S. Jolidon and H. J. Hansen, Helv. Chim. Acta, 60, 978 (1977).
18. P. Schiess and E. Sendi, Helv. Chim. Acta, 61, 1364 (1978).
19. R.N. Elgersma, "Einige aspekten van de indolsynthes volgens Fischer," Dissertation,
Rotterdam (1969).
20. K. H. Pausacker and C. I. Schubert, J. Chem. Soc., No. 7, 1814 (1950).
21. S. McLean and R. I. Reed, J. Chem. Soc., Part 3, 2519 (1955).
22. H. Ishil, Acc. Chem. Res., 14, 275 (1981).
23. Khim. Geterotsikl. Soedln., No. i, 58 (1971).
24. H. Albrecht, Tetrahedron Left., 545 (1971).
25. B. A. Shainyan and A. N. Mirskova, Usp. Khim., 48, 201 (1979).
26. Houben-Weyl, Methoden der organlschen Chemie, Vol. 4, Book i, Georg Thieme Verlag,
Stuttgart.
27. D. Biggs and W. D. H. Lyn, J. Chem. Soc., Perkin 2, No. 6, 691 (1976).
28. H. Decker and P. Becket, Ann. Chem., No. 395, 362 (1913).
29. F. D. Chattaway and K. J. P. Orton, J. Chem. ROc., Part i, No. 79, 461 (1901).
30. R. O. Matevosyan, N. Ya. Postovskii, and A. K. Chirkov, Zh. Obshch. Khim., 29, 858
(1959).
31. I. I. Grandberg and S. N. Dashkevich, Khim. Geterotsikl. Soedin., No. 3, 342 (1971).
32. F. Koch, Ber., No. 20, 2460 (1887).
33. A. N. Frolov, O. V. Kul'bitskaya, and A. V. El'tsov, Zh. Org. Khim., 15, 2118 (1979).
34. J. D. Entwistle, R. A. W. Johnstone, and A. H. Wilby, Tetrahedron, 38, 419 (1982).
35. A. Chattier, Gazz. Chim. Ital., No. 461, 367 (1916).
36. K. H. Bloss and C. E. Timberlake, J. Org. Chem., 28, 267 (1963).
37. E. Campaigne and R. D. Lake, J. Org. Chem., 24, 479 (1959).
38. V. F. Martynov, Zh. Obshch. Khim., 27, 1191 ~957).
39. N. M. Przheval'skii, I. I. Grandberg, N. A. Klyuev, and A. B. Belikov, Khlm. Geterotsikl.
Soedin., No. i0, 1349 (1978).
40. N. Campbell and E. B. McCall, J. Chem. Soc., No. I0, 2870 (1950).
41. N. A. Jones and M. L. Tomlinson, J. Chem. Soc., Part 4, 4114 (1953).

722
THERMAL HETEROCYCLIZATION OF M E a L ARYL KETAZlNES.
,
2. REACTIONS OF TBE TAUTOMERIC ENE~YDRAZINE FORM

Yu. V. Shurukhln, N. A. Kl~aev, and UDC 547.772,2T892'288.3:

I. I. Grandberg 543.51:541.11

Over the temperature range 220-280~ the thermal reactions of methyl arylketa-
zines (Ar = C6H5-, 4-CH~C~H-, 4-CH~OCsH~-, and ~-naphthyl-)proceedwiththeir
cyclization to give pyrazoline and benzodiazepine derivatives. With an increase
in temperature to 320-350~ the subsequent transformations of these compounds lead
to the formation of substituted pyrazoles, l-methyl'l,2-diarylcyclopropanes
isomeric olefins, low-molecular-weight aromatic hydrocarbons, and isoquino-
lines.

The present communication is a continuation of a series of publications [1-3] involving

the experimental verification of the possibilities of the mass-spectrometric prediction of
the thermal reactions of organic compounds. Considering the fact that thermolysls and mass-
spectrometric fragmentation proceed with the formation of products with the same elementary
compositions, the peculiarities of the dissociative ionization of methyl aryl ketazines make
it possible to assume their cycllzation under thermolysis conditions to give derivatives of
pyridazlne, pyrazole, phthalazlne, benzodiazepine, and indazole [1,4]. We have previously
shown [I] that over the temperature range 150-350~ the thermal transformations of azines
I-IV are represented by reactions of the dlenehydrazlne tautomer, the initial step of which
is the formation of substituted pyrroles and pyridazines.

I Ar=C~Hs, It Ar=4-CHaC~H~, III Ar=4-CHaOC6H4, IV Ar==-naphthyl

The appearance of new compounds in the compositions of the pyrolyzates of ketazines 1-IV
is observed over a narrower temperaturerange (220-350~ Among them we identified pyrazo-
lines (1.18, 1.15), pyrazoles (I.ii, I, Ill, IV.12, 1.23), cyclopropanes (I, II.14), the iso-
meric olefins (I, II.10), cyclopropanes (I, 11.16), aromatic hydrocarbons (I-IV.I-7, I, 11.8
9, I, 11.13), and, as an individual group of products, N-methylbenzodiazepines (I, II, IV.22)
and isoquinoles (1.17, 1.19, I, II, IV.20, 1.21; see Table l).t~ The experimental method
was previously described in [I]. The enumerated compounds were identified primarily by
comparison of their chromatographic and mass-spectrometric characteristics with those of
standards [1-3,5].
The principles of formation of the compositions of the products established in the
course of analysis of pyrolyzate samples selected at various temperatures over the range 220-
350=C reveal two consecutive reactives that determine the formation of all of the enumerated
products. Since the established structures of these compounds are explained by known reac-

*See [I] for Communication i.

%The order of numbering of the compounds corresponds to the sequence of their appearance in
the compositions of the pyrolyzate s with an increase in the temperature.

K. A. Timiryazev Moscow Agricultural Academy, Moscow 127550. Translated from E.himlya

Geterotsiklicheskikh Soedinenii, No. 7, pp. 908-917, July, 1986. Original article submitted
February 13, 1985.

0009-3122/86/2207-0723512.50 9 1987 Plenum Publishing Corporation 723

tions of hydrazones [5], we link their formation with the reactivity of the enehydrazine,
one of the possible tautomeric forms o f methyl aryl ketazines.
The formation of a pyrazollne (I.18), which provides the basis for a whole group of
compounds observed in the compositions of the pyrolyzates, is associated with the existence
of the enehydrazlne tautomer (Scheme I). Similar transformations of hydrazones under the
influence of catalysts (carboxyllc and mineral acids, Lewis acids, bases, and alkyl halldes)
or upon heating are well known [6, 7]. They also are not excluded for azines [8-12].
Because of the differences in the experimental conditions, the concepts regarding the
mechanism of the formation of pyrazollnes are not unambigous. The reaction schemes proposed
by various authors in most cases reflect the nature of the catalyst; the temperature is re-
garded as a condition that is necessary to maintain the hlgh rate of the process. Neverthe-
less, a number of publications contain conclusions regarding the sysnchronous character of
the investigated reaction, classifying it as thermal disrotatory cyclization [13-15].
Thus the isomerlzatlon of methyl aryl ketazlnes to pyrazolines contradicts neither the
chemical properties of these compounds nor the experimental conditions or the theoretical
assumptions, and the very possibility of the subsequent tautomerlc transformation to a dlene-
hydrazine is demonstrated convincingly by the "pyrrole" cycllzatlon that occurs [I].
Scheme 1

.,-Ar
[ ........ I',..,
('tt~ {" . Ar " ~-~"~'~ At/" ;'N" Nil
l,l i - CII~
lJ
~e N . j~.rS-,~.-,. Ar~ N
H
I,Ill,IV,1L}
I-B' / N'~NX~' I XAr .At
LIB ~]

If

Ar Ar Ar Ar I
"X.X. ~ j~,~ t.ILI4 Ctt 3
1,23

Ar CH 3
Ar~ ~CH 3 I
.C----C x CtI~CHCH2CH2Ar ~Ar
!
CH~' Ar l,ll.13 Ar
I,ILIO I.I1,16

CII. CH~ cH 3
l-.,v, l- v l , I I 8,9

The formation of pyrazoline 1.18 as an intermediate was previously proposed in the syn-
thesis of geometrical isomers of 1,2-diarylcyclopropanes in the thermolysis of methyl aryl
ketazines in the presence of bases [16-18]. The reaction scheme proposed by the authors thus
also finds experimental confirmation under uncatalyzed thermolysis conditions, and this pro-
vides a basis for linking the origin of the trans-l,2-diarylcyclopropanes (I, II.14) with
the thermal decomposition of pyrazollne 1.18 (Scheme i). A great deal of evidence for the
formation of cycloalkanes upon heating cyclic azo compounds [18-21], including cyclopropanes
from pyrazolines [8], confirms this conclusion.
Our experimental conditions and those described in [16-17] differ, and this is reflected
in the compositions of the products: instead of cis- and trans-cyclopropanes, which are the

724
 TABLE i. Products of the Thermolysis of Methyl Aryl Ketazlnes l-lV

IExit Amt.e Elemem~ry Lit.

oomz ]time, Mass spectrum* Mineas
po una ]rain % composi, data
tion ,
-i 11'"'_~ "3 6 7

ArH hydrocarbom

50 (16), 51 (18), 52 (18),76 (5), 77 (14), 78 (I00) 78,0470 C6H~ [3o1

1I 3,1 50 (8). 51 (14), 63 (9), 91 (I00), 92 (60) 92,0628 C7H8 [30]
lII 2,4 65 (61), 78 (56), 79 (ll), 93 (II), I08 (I00) 108,0576 C7H80 [30]
IV 1,6 iTrace ~ 52 (5), 65 (18), 102 (7), I03 (5), 127 (10), 128 (lO0) 128,0623 CIoHs [3o]

ArCH s hydrocarbons

I 3,2 Trace~ 50 (6), 51 (13), 63 (I0), 65 (20), 91 (I00), 92 (60) 92,0624 C7H8 [30]
II 6,1 ITrace~ 65 (I0), 77 (15), 79 (II). 91 (I00), 105 (24), 106 (50) 106,0771 CsHI~ [3o1
Ili 58 (96), 65 (23), 66 (19), 77 (38), 79 (31), 82 (42), 91 (23), 94 (77), 107 (35), 121 (46), 122 (I00) 122,0732 CsHloO [301
IV 4,0 rac 115 (20), 139 (10), 141 (78), 142 (100) 142,0783 CIoH,, [30]

ArC~H~ hydrocarbons

l 5,8 1,7 5l (20), 65 (14), 91 (I00), 92 (8), 106 (28) t06,0776 CsHlo " [30]
II 9,2 1,0 63 (6), 65 (10), 77 (15), 79 (15), 91 (13), 105 (100), 120 (25) 120,0939 C9H~2 [30]
IIl 6,4 3.2 65 (7), 77 (15), 91 (11), 121 (100), 122 (12). 136 (28) 136,0886 CgHlaO [30]
tV 6,4 1,0 115 (13), 141 (100), 142 (12), 155 (5). 156 (52) 156,0937 Cx2Ht~ [30]

ArCH---CH~ hydrocarbons

I 51 (78), 77 (33), 78 (53), I03 (46). 104 (I00) 104,0625 CsHs [3oi
I1 10,0 1,0 51 (16),63 (13), 65 (12),91 (33), I03 (12). ll5 (30), ll7 (91), I18 (100) I18,0783 C~H,o [3oi
III 7,2 0,7 65 (27), 77 (23),91 (47), 107 (14), 108 (15), 119 (48), 134 (100)
IV
68,11I8,
7,6 Traces 127 (35), 128 (55), 153 (78), 154 (I00)
134,0732
154,0782
C9HIOO
C,2Hlo

",-d
PO
L/1
tO

TABLE i (continued)

Exit Amt.. Elementary Lit.

Corn- time, o./o Mass spectrum * M~neas compo~- data
pound min tion
4 5 6 7
1 2 3

AtCH(CHs)z hydrocarbons

I 8,1 1,7 51 (13), 77 (13), 91 (5), 105 (I00), I06 (9), 120 (26) 120,0940 C,sHzz [301
II 11,3 0,8 91 (23), 103 (4), 115 (6), 119 (100), 120 (10), 134 (28) 134,1098 cioal4 [30]
9 11I 7,6 2,0 65 (6), 77 (8), 105 (19), 135 (100), 136 (8), 150 (24) 150,1046 C,oHz,O [30]
IV 8,6 1,0 101 (15), 127 (15), 141 (8), 155 (100), 170 (25) 170,1095 CzaH~4

A rCsI-I
I hydrocazbom

I 9,1 traced 78 (9), 91 (I00), 92 (I0), 105 (5), 120 (20) 120,0938 C~H~z [30]
II 12,3 rrace~ 57 (18), 77 (24), 79 (10), 91 (9), 105 (I00), 106 (II), 134 (13) 134,1097 Cldll4
llI (17), 91 (9), 107 (88), 121 (100), 122 (29), 150 (15) 150,1044 C,oHm0
IV 9,48'4rr09e~ 77
I15 (33), 141 (100), 142 (12), 155 (7), 170 (23) 170,1096 C~aH~4

A~(CHs)=CHz hydrocarbons
I 9,6 2,0 ,'",5~0(28)'57 (25), 58 (11), 58,5 (10), 77 (25), 78 (37), 91 (22), 103 (57), 115 (19), 117 (63), 118 118,0784 CgH,o [30]
II 12,9 1,0 91 (22), 115 (27), 116 (9), 117 (100), 131 (21), 132 (63) 132,0940 C,oH,,
Iit 9,6 1,0 77 (16), 79 (10), 103 (8), 105 (11), 106 (8), 133 (68), 148 (100) 148,0889 C,oH~O
IV I0,I 1,2 76 (I0), 83 (50), 85 (61), 151 (I0), 153 (I00), 167 (32), 168 (52) 168,0937 C,3H,4

ArCH(CHs)C~H E hydrocarbons

II 15,8 r 77 (19), 90 (11), 91 (36), 105 (13), 116 (15), 117 (31),
+ +,.+,+. +,. +.oo,.,+ + +. +, t 148,1253
++ ! CHH~n r
120 (9), 133 (100), 148 (11)

ArC(CHs)=CHCH s hydrocarbons

I T r aC e$ 91 (29), 103 (24), 115 (37), 117 (I00), 118 (44), 131 (17), 132 (48)
II 15,811,6Traeesl 91 (62), 92 (31), 115 (47), 116 (25), 117 (71), 119 (16), 128 (10), 129 (13), 131 (100), 132 (12), 146,1097 CIsHI4
134 (5), 146 (87)
'+i ++ I"
 TABLE 1 (continued)

~~ aime, Mass spectrum* Elernent~

Milleas
composi- ]data
tion [
'"I ~1 2 4 .... 5. . . .

Ar(CHs)C----CAr(CHs) hydrocarbom

I ['27,6 2,0 (3).7~3

~36)'78 (13),91 (68), 105 (98), '15 (100), 116 (2'), 129 (26),t30 (37), 165 (21), 178 (40), 179 208,1250 CmH,,
193 (77), 194 (25), 207 (29), 208 (75)
II 31,4 1;0 .770)(15)' 91 (24), t05 (34), t15 (16), 117 (13), 129 (100), 130 (13), 144 (9), 206 (18), 221
(5 236,1566 CmH~
236 (34)
I 5-Arylpyrazoles

I [27,9 ~races I 51 (16), 63 (9), 77 (17), 80 (ll), 90 (14), 115 (25), 117 (16), 143 (14), 144 (100) ] 144,0687 [ CHsN~ ] [31]
3- Methyl- 5- arylpyrazoles

I 29~6 Trace t 77 (35), 78 (12), 89 (12), 90 (lO), 91 (72), I03 (II), 104 (16), IOS (48), Ii5 (25), 117 (ll), I18 158,0845 CmHIoN2 [311
(32), I19 (40), 128 (ll), 129 (14), 130 (12), 157 (34), 158 (lO0)
Ill 27,o27,3 65 (lO), 77 (ll), 91 (7), 94 (77, 121 (19), 145 (44), 158 (I0), 173 (75), 174 (lO), 188 (I00) 188,0950 CltH,mN~O
IV I15 (67, 127 (If), 141 (13), 147 (12),153 (25), 155 (29), 165 (18), 167 (14), 178 (18), 179 (207, 208,1001 Cl~HI2N2
180 (18), 207 (78), 208 (I00)
1,,3rDiarylbutanes

I 29,9 ITrace,~ 77 (32), 91 (64), 92 (31), 105 (69), ll5 (72), 119 (16), 128 (ll), 129 (26), 130 (64), 131 (16), 210,t410 Cic,Hm
165 (13), 178 (37), 179 (20), 193 (100), 194 (14), 207 (15), 208 (75), 209 (147, 210 (46)
II 34,0 [Traces 77 (21), 91 (39), 105 (49), 115 (217, ll9 (50), 129 (I00), 143 (27), 144 (26), 206 (ll), 221 238,1720 ClsH~
{66), 222 (167, 236 (43), 238 (20)

trans-l-Methyt-l,2-diarylcyctopropanes
I 30,2 ] 3,0 77 (23), 91 (46), 103 (14), 105 (23), I15 (I00), 129 (22), 130 (28), 131 (I0), 178 (28), 179 (18), 208,1254 CI6H16 [16]
194 (64), 207 (13), 208 (64)
II 34!6 1,4 77 (18), 91 (33), 105 (41), 117 (19), 119 (7), 129 (100), 143 (23), 144 (16), 206 (197, 221 (100), 236,!566 C18H2o [16]
222 (25), 236 (45)

",,4
t'J
bJ
O0

TABLE i (continued)

C ]Exit [Amt. FAe~rmntary[ Lit.

~ itimr I,# Mass s p e c n m m 9 M}ne~ composi- [data
pouna rain [co tion ]
7 -W--j'-7"- 7 iT
3,5-Diary1.~-pyrazolines

I I 31,1 kraces[ 77 (34), 79 (25), 91 (40), 103 (20), 106 (26), !15 (25). 116 (10), 118 (21), 119 (18), 13t
1 ,,t, 144 (9). 180 (9). 193 (8). 194 (8), 222 (14)
, ,,,, , ,, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

l-Methyl-l'2-diavfl-AZ-cyclopropenes
!
77 (38), 91 (87), I02 (19), 103 (20), 115 (20), 127 (23), 128 (45), 129 (24), 178 (8), 191 (77), ] 206,1095
205 (19), 206 (100)
II ,, 33,4 ~races I 77 (ll), 91 (47). 105 (51), 115 (31), 129 (18), 132 (43), 204 (12), 219 (72), 233 (20), 234 (I00[ 234,t409 I t 1
1,2 ,3.4- Tet~ahydtoisoquiaolinr

77 (27), 91 (100), 105 (25), 115 (17), 117 (13), 118 (40), 132 (99), 133 ( n )
..... , . . . . . . . . . . . r,,, .......

3- Methyl- 3,5- diatylpyrazolines

IT [[ 35.1. . . _. . . 0,8 i 77 (51), 91 (44), 103 (17). 104 (ll), 105 (79), 118 (18), 119 (32). 120 (22), 131 (29), 132 (t00),
I I 236,1316
I ] t33 (18), 193 {22), 220 (11), 221 (17), 236 (26) I I '311 ....

3- Aryl- 1 .~,3,4- tetrahydtoiso quinolines

. . . . . . . . . . . . . . . . . . . i i
1- Methyl- 3- aryldihydroisoquinolincs

t 36,3 3,5 77 (54), 78 (11), 91 (16), 104 (24), 105 (24), I15 (34), 117 (t3), 130 (12), 144 (12), 206 (tl), 221,1207 Ct~HzsN 132]
220 (100), 221 (51)
iI 40,9 2.0 9t (31), 105 (ll), 115 (14), 117 (26), 1t8 (!9), t19 (13), t31 (lt), 234 (22), 235 (33), 248 (100), 249,15t8 C~8H~gN
249 (34)
IV 28,2 1,0 127 (35), 152 (lO0), 153 (92), 167 (15), 168 (37), 279 (27), 280 (17), 306 (35), 320 (40), 321 (45) 321,1520 Cu4H19N
 !
4

TABLE I (continued)
9 J L~,,. L ,,, ,,

k Mass spectrum* ~. ~hleas [ comp0si -~ ]data

t io. ! "

. . . . . . . . . ~ . . . . . . . . .. :L22!'.'.2:! . . . . . ~ -

3-Arylisoquinolines

37,8 I 1,5 [ 77 (20), t01,5 (ll), 102 (52), 102,5 (23), 117 (11), 176 (15), 203 (14), 204 (68), 205 (100) 205,0831 CmH,~N
,, , , ,. . . . . . . . . . . . . ,,

1,3-Dimethyl- 4- aryl- 4,5- benzo[d]diazepines

i 39,7 4,2 77 (67), 91 (14), 95,5 (22), 102 (29), loa (22), 105 (76), t08,5 (53), 109 (16), 109,5 (32), 115 248,1315 C17HI~N~ [33]
(36), 116 (15), 144 (86), 218 (17), 219 (54), 220 (47), 233 (21),247 (10), 248 (50)
II 43,8 1,5 91 (30), ll5 (17), ll7 (19), ll8 (20), 119 (69), 158 (71), 159 (ll), 246 (22), 247 (100), 248 (25), 276,1625 CIgH~oN2
261 (ll), 276 (34)
IV 35,1 5,5 127 (51), 152 (22), 153 (28), 165 (20), 168 (17), 304 (t9), 305 (16), 319 (100), 320 (67), 333 (26), 348,1627 C~H20N~
348 (32)

3- Methyl- 4,5-diarylpyrazole~
C,~H14N~ [ [31]
' , ,, ,

The peaks of ions with intensities of 5% are presented.

tTne position of the aouble bona was not established.

t ~
principal productl in t ~ publiihod experiments, we obee~e the fo~'~ion of only tr~ns-
cyclopropanee (%, ~%.14), the isomeric olefine (%, %LI0), cyclopropanes (T, I~,16)~ and a
large group of aromatic hydrocarbonJ (Scheme 1, Table 1).
The gormation of cyclopropanes via Scheme 1 is confirmed by independent investigations
of the thermolysis of cis-,and trans-l-methyl-I,2-diphenylcyclopropanes and a mixture of
these geometrical isoners.
The decomposition of the ~ - t a u t o m e r i c form of pyrazolLne to nitrogen and cyclopropane
is not the only reaction. Au independent pathway in the decomposition of pyrazoline, which
is evidently determined by another tautomeric form, i s the elimination of hydrocarbons (CH~
or ArH) and the for~ntlon of, respectively, 3-methyl-$-aryl- or 3,5-ciarylpyrazoles (~cheme
1). Subsequent hydrogenation, radical substitution, and N-methylation oZ these compounds
lead to the actual composltlons of the products. The enumerated processes are observed at
high temperatures and do not exclude the possibility of an alternative origin of products of
the pyrazole series. In this connection, it should be noted that numerous studies of the
thermolysis of azlnes [23-z6] explain the formatlon of pyrazoles by means of radical reac-
tion s 9
Scheme 2
H

CH~
l-IV

,...J..,.,~,
I"--,,I
. :,.N', -i':"'-:9
fIN ~ "CH~

I:i I
..,--,2'
..',,,:oN NR2 HN~.C XCH 3

I,ILIV,22

i CH3

LI7 1,19 CII3 1.21

I ,I|,IV.20

Above we examined the thermal reactions of methyl aryl ketazines, the initial step of
which is isomerization of the tautomerlc enehydrazine form to a pyrazoline. An alternative
direction of cyclization of the enehydraziue leads to the formation of a benzodiazepine
(Scheme 2). The chemical transformations of this compound in the ensuing steps are deter-
mined by either dehydrogenation and N-methylation or by decomposition with the elimination
of a molecule of ammonia and the formation of isoqulnolines. The indicated reactions t~ke
place at high temperatures at which radical processes make an appreciable contribution to
the formation of the compositions of the products. This hinders the identification of some
of the products indicated in Scheme 2.
In its general features, the proposed scheme resembles the peculiarities of the forma-
tion of products of the pyrrole and pyridazine series [i]. As an additional argument in
substantiation of this sequence of reactions one should point out examples of the synthesis
of benzodiazepines and isoquinolines from hydrazones [6], as well as direct evidence for
thermal transformations of benzodiazepines to isoquinolines with the elimination of a mole-
cule of NH, [27-29].
*The results of this research are being prepared for publication.
730
 EXPERII4ENT~I
The synthesis and principal physlcochemical characteristics of methyl aryl ketazines
I-IV are described in [16].
The thermolysis was carried out under conditions of linear raising of the temperature.
The starting compounds were heated in a sealed glass ampul from 20~ to 350~ at a constant
rate of 5~
The temperature range of 220-350~ which corresponds to the examined reactions, was
determined beforehand by derivatographic analysis (see [i]).
~le structural identification and quantitative analysis of the thermolysis products
(Table I) were carried out with a Varian MAT-311 mass spectrometer (USA) with the aid of low-
and high-resolution mass spectrometry [AM/M 15000, polyphosphoric acid (PPA) standard] and
gas-liquid chromatographic mass spectrometry. The ionizing-electron energy was 70 eV, the
cathode emission current was 1 mA, the accelerating voltage was 3 kV, the ion-source temper-
ature was 150~ and the amplifier voltage was 2 hV. ~ e chromatograph was a varian Aero-
graph 3700 (USA), and the capillary column was an Aerograph OV-101 (USA) with a length of 25
m and an inner diameter of 0.25 mm; the injector temperature :was 300~ The rate of heating
of the column over the ranges 40-Z40~ (for I), 40-260~ (Ii), and 60-260"C (III, IV) was
5~ the times of the initial and final isothermal periods were 3 and 30 min, respective-
ly, and the carrier gas was helium (1.5 ml/min).
The relative percentage of the thermolysis products were evaluated from the readings of
an 1-02 digital integrator (USSR) assuming equal sensitivity coefficients for all of the py-
rolyzate components being separated.
The structures of the compounds indicated in Table 1 were confirmed by reference sub-
stances (by comparison of the exit times and the mass spectra) and/or by the mass spectra
published in the cited literature.

LITERATURE CITED
i. Yu. V. Shurukhin, N. A. Klyuev, and I. I. Grandberg, Zh. Org. Khim., 21, 2057 (1985;.
2. N. A. Klyuev, Yu. V. Shurukhin, V. A. Konchits, I. I. Grandberg, V. L. Rusinov, V. A.
Zyryanov, and I. Ya. Postovskii, Khim. Geterotsikl. Soedin., No. 2, 265 (1980).
3. Yu. V. Shurukhin, N. A. Klyuev, I. I. Grandberg, and V. A. Konchits, Khim. Geterotsikl.
Soedin., No. I0, 1422 (1984).
4. N. A. Klyuev, A. B. Belikov, I. I. Grandberg, Yu. V. Shurukhin, and I. K. Yakushchenko,
Izv. Mosk. Sel'skokhoz. Akad. Timiryazeva, No. 2, 159 (1980).
5. N. A. Klyuev, I. I. Grandberg, L, B. Dmitriev, and Yu. A. Larshin, Zh. Org. Khim., 15,
2274 (1979).
6. Yu. P. Kitaev and B. I. Buzykin, Hydrazones [in Russian], Nauka, Moscow (1974).
7. A. N. Kost and I. I. Grandberg, Usp. Khim., 28, 921 (1959)o
8. C. H. Stapfer and R. W. D'Andrea, J. Heterocycl. Chem., 7, 651 (1970).
9. K. B. Slean and N. Rabjohn, J. Heterocycl. Chem., ~, 127~ (1970).
i0. A. N. Kost, I. I. Grandberg, and ~. A. Golubeva, Zh. Obshch. Khim., 26, 2604 (1956).
ii. A. N. Kost, I. I. Grandberg, and E. B. Evreinova, Zh. Obshch. Khim., 28, 512 (1958).
12. N. A. Tupikina, L. K. Suvorov, L. I. Zamyshlyaeva, and L. K. Sidorova, Izv. VUZov.
Khim. Tekhnol., 18, 68 (1975).
13. T. Gilcnrist and R. C. Storr, Organic Reactions and Orbital Symmetry, Cambridge Univer-
sity Press (1972).
14. J. Elquero, R. Jacquir, and C. Marzin, Bull. Soc. Chim. (Paris), No. ii, 4119 (1970).
15. H. D. Hause, Modern Synthetic Reactions, W. A. Benjamin, Inc. (1972), p. 138.
16. I. D. Yakushchenko, Master's Dissertation, Moscow (1980).
17. i. Io Grandberg, I. K. Yakushchenko, and L. B. Dmitriev, Zh. Org. Knim., 15, 89 (1979).
18. I. I. Grandberg, I. K. Yakushchenko, and L. B. Dmltriev, Izv. Mosk. Sel'skokhoz. Akad.
Timiryazeva, No. 4, 170 (1979).
19. P. S. Engel, R. A. Hayes, Z. Keifer, S. Szilaqui, and J. W. Timberlake, J. Am. Chem.
Soc., i00, i~76 (1978).
20. P. B. Dervan and T. Uyehara, J. Am. Cbem. Soc., 98, 126Z (1976).
21. R. C. Neuman and C. T. Berge, Tetrahedron Left., No. 20, 1709 (1978).
22. N. J. Turro, Lin Kou-Chang, W. Cherry, Liw Jong-Min, and B. Jacobson, Tetrahedron Lett.,
6, 555 (1978).
23. O. Tsuge, M. Tashira, and K. Hokama, Kogyo Kagaku Zasshi, 7-1, 1203 (1968).
731
24. 0, Tausa, K, Hokama) and H, Watanaba, 3. Phar~. Sac, Jpn. 8%9, 783 ~969),
25. O, Tsusa) K, Kakama) and M, Koga, 3. Pha~m. Sac. Jpn, 89, 7-~9 (196~),
26. 0. Tsuga, K, Hokama) and H. Watanaba, Kcsya Kagaku Zamshl) ?2, 1107 ~1968).
27. T. Tsuchlya) H. Sawanlshl, M. Enkaku, and T. Hi,el, Cham. Pha~n. Bull., 29, 1539 (1981)
28. A. Mango Vega) M. T. Martlnes) J. A. Palop) d. M. Marco) and E. Faraandez-Alvarez, J.
Heterocycl. Chem., 18) 889 (1981).
29. H. C. Van dar Plea) Ring Transfoz~atlons of Haterocycles, Vol. 2, Academic Press (1979),
p. 289.
30. E. Stenhagan) S. Abrahamsson) and F~ W. McLafferty, Atlas of Mass Spectral Data) Vols.
i-3, Intersclence. (1969).
31, A, P. Krasnoshchsk, Master's Dissertation, Moscow (1968),
32. A. A. Polyakova and R. A. Khmel)nitskll, Mass Spectrometry in Organic Chemistry [in Rus-
sian], Khimiya) Leningrad (1972).
33. R. P. Ryan, W. C. Lobeck) C. M. Combs, and Wu Yea-Hoe) Tetrahedron) 27, 23z5 (1971)o

RESEARCH ON IMIDAZO[1,2-a]BENZI~IDAZOLE DERIVATIVES.

22.* SYNTHESIS OF 2,3-DIHYDROIMIDAZO[1,2-a]BENZLMIDAZOLES
STARTING FROM 2-1MINO-3-(2-HYDROXYETHYL)BENZIM~DAZOLINES

V. A. Anlslmova) M. V. Levchenko) and UDC 547.785.5.07:543,422

A. F. Pozharskii

A 8-ellminatlon reaction with the formation of 2-imino-3-vinylbenzimldazolines

occurs simultaneously with intramolecular alkylation and the formation of an
imidazoline ring in the action of alcoholic alkali on 2-imino-3-(2-chloroethyl)
benzimldazollnes. The thermolysis of 3-chlorethyl-substituted imines without
a solvent or in an inert solvent leads exclusively to 2,3-dlhydroimidazo[1,2-a]
benzlmidazoles. An attempt to obtain the latter directly from 2-imino-3-(2-hy-
droxyethyl)benzimldazolines by the action of a mixture of thionyl chloride and
acetic anhydride on them also leads to ambiguous results.

One of the most widely spread methods for the formation of a condensed imidazoline ring
in systems with a bridged nitrogen atom consists in the successive action of thionyl chloride
and alcoholic alkali on N-8-hydroxyethyl-substituted nitrogen heterocycles in which there is
an amino group in the ~ position relative to the heteroring nitrogen atom [2,3]. This meth-
od was used in 1967 to obtain 9-ethyl-2,3-dlhydrolmldazo[1)2-a]benzimldazole, the first re-
presentative of this hydrogenated system [4,5]. However, it does notalways givegood re-
sults) and the yields of 9-benzyl- [6] and 9-phenyl-substituted compounds [7] synthesized
via a similar scheme were only 27% and 36%) respectively. We turned to an investigation of
this reaction in order to establish the reasons for the low yields of 2)3-dihydroimidazo-
[l,2-a]benzimidazoles and to find more acceptable cyclization conditions, especially since
little study has been devoted to the chemical and, particularly, pharmacological properties
of this heterosystem [6, 7].

See [I] for communication 21.

Scientific-Research Institute of Physical and Organic Chemistry, M. A. Suslov Rostov

State University, Rostov-on-Don 344090. Translated from Khimiya Geterotsiklicheskikh Soed-
inenii, No. 7, pp. 918-925, July, 1986. Original article submitted April 3) 1985.

732 0009-3122/86/2207-0732512.50 9 1987 Plenum Publishing Corporation

 TABLE i. 2-1mino-3-(2-hydroxyethyl)benzlmidazolines III

Found, % Empirical for- Calc.. a/o

Corn- rap,* ~C Yield, %
pound mula
C H CI N C H CI N

III a 271--272 52,6 6,2 15,4 18,7 C,oHIaNaO"HCI 57,7 6,2 15,6 18.5 88--96
III~-I t33--134 62,9[ 6,61 -- 22,1 CmH,aNaO 62,8 6,8 - - 2210
II1D 230 231 17,5 CnHIbNaO' HCt 54,7 6,7 14,71 17,4 91,7
IIIc
(230--231. [121)
254--255
(263--264 [6])
% ~176
i:i 13,8 C,sH,TNaO.HCI 63,2 6,0 ll,7J 13,8
I
(75 [12])
94--96
(68 [6])
IIld 233,5--234,5 62,11 5,6 12,f 14,6 CI6HIsNaO'HCI 62,2 6,6 12,2114, 9 ;t
life 280--281 63,2J 6,1 ] ll,e 14,0 C16HjvNaO"HCI 63,2 6,0 11,7 13,8
IIle-I 153--154 72,1J 6,4 -- 15,7 CI6H,rNaO 71,9 6,4 - - 15,7
IIIf 293 54,5 6,5 15,1 17,2 C,IH,bNaO. HCI 54,7 6,7 14,7 17,4 90,8
IIIf-I 132--133 64,5 7,4 - - 20,6 CuHl~NaO 64,4 7,4 - - 20,5

The hydrochlorides were recrystallized: llla-d from alco-

hol, llle from water, and lllf from 90% alcohol. The imine
bases were reerystallized: llla-I from benzene, llle-I from
isooctane, and lllf-I from ethyl acetate. Compounds llla,d,f
melted with decomposition.
+According to [7], the yield of the corresponding bromidewas 53%.

" , ~ - - - ~'N CICH2CH~OI{

C CH"CH(OH)RI 5"- CI{2CIICIR
il I! ........... -'--"-
~'~'/'"~" N/ NH'HCI " N NH
R // R
Ia-d m a-f 0"r n-a-f

/ ]//" i&
~
~ H ~ N H . H B r
NzCH2CORI

~N ""N /
/CH:CIIRI

" HH
.///if'x

~
---N

11" F %
" R
I I
R R R
II.a,b va-f ~aa-f
I a R=CHa, b R=C2H~, c R=CH2C~Hb, d R=CsHb; II a,b R=CHa; a RI = C6Hs,
b R~=CHa; III--VI a,e,fR=CHa, b R=C2Hs, c R=CH2C6Hb, d R=CsHs; a-d R'=H,
e RI=C6Hs, f RI=CHa

Starting 3-(2-hydroxyethyl)-2-iminobenzimidazolines III were obtained by hydroxyethy-

lation of amines I by means of ethylene chlorohydrin or by reduction of 3-acylmethyl-2-imino-
benzimidazolines II with sodium borohydride. It is more convenient to carry out the hydrox-
yethylation by fusing the starting reagents or by refluxing them in dimethylformamide (DMF)
or xylene. This makes it possible to significantly reduce the reaction time as compared with
the time described in [4-7] and, in some cases, to increase the yields of imino alcohols III.
The chlorination of the latter proceeds successfully under milder conditions than those de-
scribed in [4-7], viz., by the action of thionyl chloride in chloroform or benzene. The re-
sulting chloro-substituted IV were isolated in high yields in the form of the hydrochlorides
and were then converted to the bases by treatment with a solution of ammonia.
The action of alkali on salts IV under the conditions proposed in [4-7] gives mixtures
of two compounds, one of which is three-ring base VI; vinyl-substituted structure V was as-
signed to the second compound, which was identical to the first with respect to the results
of elementary analysis, on the basis of the IR and NMR spectra. An absorption band of a
free NH group at 3355-3360 cm -I is observed in the IR spectra of imines V; an absorption
band at 1660 cm-*, which can be ascribed to the absorption of an exocyclic C_--C bond, appears
in addition to a band at 1630-1640 cm -I, which is characteristic for the absorption of a
--C=N group in imines with a similar structure. In the PMR spectra of Va-d signals of the B-
cis and B-trans protons of a vinyl group appear in the form of doublets because of the small
degree of geminal coupling of these protons; the 8-trans proton (8 - 5.2-5.5 ppm) is de-
shielded by the heteroring by ~ 35-40 Hz as compared with the 8-cis proton (~ ~ 4.87-5.07

733
 TABLE 2. 2-Lmino-3- (2-chloroethyl) benzimidazolines IV and
Their Hydrochlorides

Com" Found, % Empirical C~.lc., % IYield

pound mp,* formula
C H c, N c I,. Ic, IN ]%
[V~,HCI 49,01 28,5
5,3 17,3 C,rlH,=CIN.~'HCI 48.8 5,3 28,8 17,1 95,9
IV~ 57,I[ 16.8
5,9 20.3 CInHI=CIN3 57,3 5,8 16,9 20,0 --
[V:b HCI 50,7 J 27,0
5,6 15,9 C11Ht4CIN.vHCI 50,8 5,8 27,3 16,1 100
IVb 59,0 [ 15,6
6,4 18,9 C.HI4CIN~ 59.1 6,3 15,8 18,1
]~e, HCI 59,5 [ 22,3
5,5 13.2 CIeHtsCIN:~'HCI 59,7 5.3 22,0 13,0 I00
IVe 67,3] 12,8
5,8 14,5 CI6HteCIN,~ 67,8 5,6 12,4 14,7
IV d HC[ 58,81 5,0 23,3 13.5 C15HI4CINs'HCI 58,3 4,9 23,0 13,6 I00
IVd 66,2l 5,0 16,7 15,5 CIsl'I14CIN~ 66,3 5,2 16.9 15,4
IVe.HC[ 59,8 [ 5,3 22,3 13,0 CL6HIsC[N~'HC[ 59,7 5,3 2210 13,0 9~,8
lye 67,01 6,[ 12,2 14,9 CIeHI~CINs 673 5,9 12,4 14,7 --
IVf .HC[ 51,1[ 5,7 27,5 16,0 CIiHI4CIN~'HC[ 50,8 5,8 27,3 16,1 97
58,8 i 6,3 16,3 18,5 CIIHHCIN3 59,1 6,3 15.8 18,8 - -

...,,, ,

The hydrochlorides were recrystalllzed: those of IVa,c,e

from alcohol, those of IVb,f from alcohol-ether, and that
of IVd from acetone-ether. Base IVa was recrystallized from
petroleum ether, and bases IVb-f were purified by chromatog-
raphy. Salts IVc.HCl, IVd.HCI, IVe-HCI, and IVf.HCI melted
with decomposition.

ppm). The signal of the proton of the --CB= group is deshielded to an even greater extent and
appears together with the aromatic protons in the form of a multiplet with the appropriate
integral intensity at 6.65-7.2 ppm. The broad singlet of one proton unit at 4.53-4.75 ppm
can be assigned to the signal of the proton of the NH group. In the PMR spectrum of Ve the
signal of this proton is found at 4.97 ppm| however, the signals of the aromatic and vinyl
protons (IIH) appear in the form of a poorly resolved multiplet at 6.77-7.31 ppm. The signals
of the vinyl protons of Vf are observed at 3.9-4.3 ppm, and the methyl group of the propenyl
substituent gives a doublet signal at 1.5 ppm.
Thus two reactions, viz., intramolecu!ar alkylation, which leads to the formation of an
imidazoline ring, and 8 elimination, which leads to vinyl-substituted V, are realized simul-
taneously under these conditions. Vinyl-substituted V are not intermediates in the synthesis
of Vl under the selected conditions. However, in the case of prolonged refluxing (30-40 h)
in concentrated HBr they undergo cyclization to VI derivatives in ~ 45-50% yields.
In a more detailed investigation of the behavior of chloro imines IV under alkaline
conditions we were able to establish that elimination proceeds in high yields under very
mild conditions, viz., at room temperature with an equimolar amount of alkali, which serves
as an HCI acceptor. However, refluxing the reaction solutions leads to mixtures of V and
Vl; the yields of dihydroimidazo[l,2-a]benzimidazoles VI increase in some cases on passing
from methanol, which serves as the reaction solvent, to ethanol and butanol. This fact, as
well as the instability of chloro imine bases IV during storage, led to the idea of the pos-
sibility of the occurrence of thermal cyclization in this series.
In fact, when chloro imines IV are maintained briefly at 5-I0~ above their melting
points, they undergo cyclization to hydrochlorides VI in virtually quantitative yields. The
cyclization also proceeds similarly in inert solvents; for faster reactions the solvent
should be selected in such a way that its boiling point is close to (or, better yet, some-
what higher than) the melting point of the starting imine. Steric factors, viz., the pre-
sence of phenyl or methyl groups in the chloroethyl grouping, do not affect the cyclization
(compare with [8]). The characteristic absorption bands of NH and ~ groups that are ob-
served in the spectra of the chloro imines at 3350-3360 and 1635-1640 cm-~, respectively,
vanish in the IR spectra of VI, but absorption bands at 1660-1665 cm-~, which are related to
the absorption of the endocyclic ~ bond of the 2,3-dihydroimidazo[l,2-a]benzimidazole ring,
appear. In the PMR spectra of Vla-d recorded in deuterochloroform the four protons of the
external imidazoline ring appear in the form of two symmetrical triplets at 3.55-3.9 and
4.05-4.3 ppm (an AA'BB' system); this is probably associated with the presence in this ring
of two types of nitrogen atoms. In the spectra of these compounds or their salts recorded in

734
 TABLE 3.. 3-Vinyl,2-iminobenzimidazoline s V

Corn- Found, %. Czlc., % Yield,

pound mp, "~C i " [ N[ Empirical formula
C [(tlal)
1
Va 62--63 626 67 1221 CIoH1~N3H20 62,8[ 6,9 220 96
V a,,H 220 570 60 [202 CloHi1N3"HC1 57,3! 5,8 20,0 --
(16,7)1 (t6,9)
V a-P 240 47,5 3,7 121,tl CIoHHN3"C~H3N307 4781 35 209 --
Vb 58--59 70,4 6,8 22,61 CuHi3N3 70,61 70 224 92
Vb-H 212--213 49,0 5,4 15,91 CI1H13N~"HBr 49,31 5,2 15,7 --
(29,5) (29,8)
Vb-P 199 48,8 4,0 19,9l CuH~aN~-CnH~N~O~ 490[ 39 202 --
Vc 95--96 76,8 62 f 7'1
5:6 Ct~HI~N~ 77,11 6,I 16,9 90
Vd Macao 765 180 Ct~HiaNa 76,61 5,6 17,8 97
Vd-H 205--206 42 1351 Ci3H~aNa-HBr 57,ot 4,4 t3,3 --
57,1 (25'0) i 17,0 (z5a)
Ve 154 Cl~Hl~Na , , 1 61 168 89
Vf 49--50 77,0
70,5 6,0
7,2 t 22,2 CnHIaNa 7061 70 224 95
V f-H 228--229 64,5 (154,3)16,3 CllHiaNa. HC1 6471 55 162
(13,7)

The compounds were purified: hydrohalides Va-H and Vf-H

from alcohol with ether, Vb-H from alcohol, and Vd-H from
alcohol, and Vd-H from acetone with ether; picrates Va-P
and Vb-P from acetic acid; bases Vb,c,e from ethyl acetate
and Va,d,f by chromatography. Compounds Va-H, Va-P, Vb-H,
Vb-P i and Vd-H melted with decomposition.

trifluoroacetlc acid the ethylene protons appear in the form of a four-proton singlet at
3.2-3.3 ppm (an A~ system).
We used the thermal cyciization method for the synthesis of the most diverse 2,3-di-
hydroimidazo[l,2-a]benzimidazole derivatives, including those substituted in the 2 posi-
tion and in the benzene ring [9]. The yields in most cases were close to quantitative.
Lower yields (70-84%) were obtained in the cyclization of hydrochlorides IV in inert sol-
vents in the presence of anhydrous potassium carbonate or sodium carbonate, in which case
the reaction proceeds considerably more slowly. When triethylamine is used as the HCI
acceptor, the yields decrease to an even greater extent because of resinification of the
reaction masses.
In an attempt to arrive at VI directly from hydroxy imines III by the simultaneous
action on them of thionyl chloride and acetic anhydride, as in the imidazo[2,l-b]thiazole
series [I0,ii], we obtained mixtures of VI-VIII.

OCOCH~
..~ cH:mom~' ~,>____N>CH:tHR' ~ : ~ : ~ C m '

I I I
CH~ CH 3 CH 3

'!-'L~o
"'--.~,. ~ SOCI2
cH2COC~H ~ 9 ~. . . . CII~COC~H~ ~'~ CH~CH(OH)C6H 5

";~" " " N : "%'NCOCH 3 --zl "N- "NCOCH 3

I i
CH 3 CH 3 CH3
I2( X XI
",qL'Vtll~. R" =H,b ~' ---C'~H,

The structures of VII and VIII were proved by independent syntheses. Chloro acetyl-
imines VIII are intermediates in the synthesis of VI; this is confirmed by their conver-
sion to Vl when the time of this reaction is increased. The quantitative ratios of VI
and VII depend on many factors (for example, on the amount of thionyl chloride and the
way it is introduced into the reaction, the reaction conditions, etc.) and are not very
reproducible. We were unable to select conditions that would completely exclude the for-

735
 TABLE 4 . 2,3-Dihydroimldazo[l,2-a]benzlm_idazoles V l
Corn- Found, % _ . Calc +%
~C ~:mpiricalIbr- "
pound mpl
G H Hal N ~[ 1Tlula C H Hal N

Via | 68 69,1 6,3 -- 24,5 i CioH.N.~ 69,3 6,4 -- 24,3

Via-Ill 276--277 57,0 6,0 16.7 20+2 'CIoHuN3.HCI 57,3 5,8 16,0 20,0
vIb | Oil 70,3 7,2 -- 22,2 CIIH~3Na 70,6 7,0 -- 22,4
vIb-l~ 256 .,_ 59,0 6,5 15,6 18,8 C.HtaNa'HC1 59,1 6,3 15,8 18,8
VIb-PI 268--268,5 ]: 49,2 4,0 -- 20,0 C HI3N3"C6H3NzO7 49,0 3,9 -- 20,2
VIe I Oil 76,9 6,3 -- 16,5 Ct6HmNa 77,1 6,1 -- 16,8
VIe-HI, 257--258 67,1 5,6 12,2 14,7 Ct6H15N3.HC1 67,3 5,6 12,4 14,7
(262--264 [61)
Vlc.-P 203,5--204 55,2 4,0! -- 17,7 Cj6HmN3"C~H3N307 55,2 3,8 -- 17,6
(204--206 [6])
Vld 115--116 76.6 5.5 -- 17.6 CIsHI3N3 76.6 5.6 -- 17.8
vId4-1! 226--227 57.2 4.41 25.0 13.5 CIsH,~N3-HBr 57.0 4.4 25.3 13.3
9 Vie H[. (225--228 [71)
258 67,3 5,8 12,7 14,9 C16HmN3-HCI 67,3 5,6 12,4 14,7
Vlf (258 [131)
121--122 70,3 6,8 -- 22,5 C,iH,3N3 70,6 710 -- 22,4
V/f-H! 275--276 58,9 6 4 15,5 19,0 CtIHmN~.HC1 59,0 15,9 18,8
Hydrohalides VIa-H--VIf-H were purified b y recrystallization
from alcohol, picrates Vlb-P and VIc-P were purified by re-
crystallization from glacial acetic acid, bases VIf,d were
purified by recrystalllzatlon from ethyl acetate, Via was
purified by recrystalllzatlon from benzene, and VIb,c were
purified by chromatography. All of the hydrohalldes and
picrates melted wlth decomposition.
~According to the data in [5], this compound had mp 267-268,
265-268, and 263-2660C (dec.).

marion of Vll. However, the successive action on hydroxy imines III of excess thionyl chlo-
ride and acetic anhydride without isolation of intermediate chloro imine IV leads to the
formation of three-ring product VI in high yield.
The absorption bands of NH and OH groups vanish in the IR spectra of VII and VIII; the
band of carbonyl absorption of the NCOCHa group is shifted significantly to the low-frequency
side and appears at 1535-1550 cm-*. This fact, as well as the absence of the absorption at
1630-1640 cm-* that is characteristic for the stretching vibrations of the C=N bond of imine
bases III and IV, indicates a decrease in the multiplicities of the O=0 and C=N bonds in
these compounds. On passing to the hydrochlorides of VII and VIII the double bond character
of the 0=0 groups increases, and its absorption is observed at 1725-1755 cm-*.

EXPERIMENTAL
The IR spectra of chloroform solutions of bases III-XI and mineral oil suspensions of
their salts were recorded with a UR-20 spectrometer. The PMR spectra of solutions in deuter-
ochloroform and trifluoroacetic acid were obtained with a Tesla BS-487 C spectrometer (80MHz)
with hexamethyldisiloxane (HMDS) as the internal standard. The course of the reaction and
the purity of the compounds obtained were monitored by thin-layer chromatography (TLC) on
aluminum oxide with elution by chloroform or benzene and development with iodine vapors in a
moist chamber.
l-R-3-(2-Hydroxyethyl)-2-iminobenzimidazoline Hydrochlorides IIIa-d (Table i). A) A
mixture of 10 mmole of amine Ia-d and 2.5-3 ml of freshly distilled ethylene chlorohydrin
was heated at 130-135~ for 30-40 min, after which the melt was cooled and triturated with
10 ml of ether. Precipitated salts IIIa-d were removed by filtration, washed with ether a n d
acetone, and crystallized from alcohol.
B) A solution of i0 m mole of amine Ia-d and 0.8-0.9 ml (a 10-20% excess) of ethylene
chlorohydrin in 4-5 ml of dry DMFA was refluxed for 0.5-1 h, after which it was cooled. Pre-
cipitated salts IIIa-d were removed by filtration and washed with ether and acetone.
The reaction time was 1-2 h when the process was carried out in absolute xylene.
2-Imino-l-methyl-3-(2-hydroxyethyl)benzimidazoline. A 0.46-g (2 mmole) sample of salt
IIIa was treated with 5 ml of 40% NaOH solution, and the liberated oil was extracted with

736
hot benzene. The benzene was evaporated, and the residue was triturated with petroleum
ether to give 0.39 g of the imine in the form of snow-white crystals (Table i). IR spectrum:
1500, 1610 (C---C);1630 (C=N); 3380 (NH); 3100-3300 cm-* (OH, broad band).
2-1mino-l-methyly3-(2-hydroxyl-2-phenylethyl)benzimidazoline Hydrochloride (llle). A
0.4-g (i0 mmole) sample of sodium borohydride was added in small portions at room temperature
to a stirred suspension of 2.7 g (i0 mmole) of imine lla or the corresponding amount of its
hydrobromide in 40 ml of methanol. At the end of the addition (~20-30 min), the resulting
solution was stirred for another 2-3 h, and the excess borohydride was decomposed by acidi-
fication of the solution with 10% HCI solution to pH 2-3. The methanol was evaporated, and
the residue was treated with 20 ml of cold water. The undissolved hydrochloride llle was
removed by filtration and washed with water to give 2.85 g of product. Information on llle,
imino alcohol lllf, which was similarly obtained from 3-acetonyl-2-imino-l-methylbenzimidazo-
line hydrobromide (lib), and the corresponding bases is presented in Table I. The absorption
band of a C=O group that appears in the IR spectra of the starting imines at 1690-1695 cm-*
vanished in the IR spectra of the salts obtained. The IR spectra of imine bases llle,f,
which were liberated by treatment of the corresponding salts with 22% NH4OH, contained bands
at 1635 ( ~ ) , 3375 (NH), and 3150-3300 cm-* (OH).
2-Imino-l-R-3-(2-chloroethyl)benzimidazollnes IVa-f (Table 2). A l-ml sample of freshly
distilled thionyl chloride was added to a suspension of i0 mmole of hydrochloride IIIa-f in
10-15 ml of dry chloroform or benzene, and the mixture was refluxed for 1-2 h. It was then
cooled, and the precipitated hydrochloride of IV was removed by filtration and washed with
petroleum ether. If no precipitate was formed from the cooled solution, the solution was
evaporated, and the residue was treated several times with petroleum ether until crystalli-
zation was complete. The yields of the hydrochlorides of IVa-f were close to quantitative.
Chloro imine bases IVa-f were isolated in quantitative yields by treating the salts with
22% NH4OH in the cold. The liberated imine was removed by filtration or extracted with some
solvent (chloroform, benzene, or ethyl acetate). The melting points of bases IVa-f were
determined by placing a capillary tube containing the substance in a heated device for deter-
mination of the melting point.
3-Vinyl-2-imino-l-R-benzimidazolines Va-f (Table 3). A mixture of 5 mmole of the hydro-
chloride of IVa-f and 10 ml of a 5% solution of NaOH in alcohol (or the corresponding amount
of sodium ethoxide) was maintained at room temperature until the reaction was complete. The
NaCI was separated, the alcohol was evaporated, and the residue was purified by recrystalli-
zation from ethyl acetate or by means of column chromatography (A1203, elution with chloro-
form),
k~en the reaction solutions were heated, the yields of imines V decreased due to the
formation of VI. Imines Va-f are snow-white low-melting crystals or oils, which were con-
verted to salts by dissolving them in acetone and adding the corresponding acid to the solu-
tions up to pH 2-3.
2,3-Dihydroimidazo[ip2-a]benzimidazoles VIa-f (Table 4). A) Imines IVa-f were maintained
at 5-15~ above their melting points until the resulting melts crystallized completely (-5-
20 min). The melts were then cooled and crystallized from suitable solvents to give the pro-
ducts in 93-97% yields.
B) A 2-mmole sample of chloro imine IVa-f was refluxed in 5-7 ml of absolute xylene,
toluene, octane, benzene, or ethyl acetate for 20-60 min, during which the completion of the
reaction was followed by means of TLC (the starting imines had ~ ~ 0.15-0.2, and the final
three-ring products had Rf - 0.3-0.4). The mixtures were then cooled, and the precipitated
hydrochiorides of VIa-f were removed by filtration and washed with the appropriate solvent
and ether. The yields were quantitative.
C) A 2-mmo!e sample of imine IVa,d,f was refluxed in 5 ml of water for 20-30 min (with
monitoring by TLC), after which the solution was cooled and made alkaline to pH 8-9 with am-
monium hydroxide. Imidazobenzimidazoles VIa,d,f were extracted with chloroform. The yields
were quantitative.
D) A solution of 0.84 g (4 mmole) of chloro imine IVa in 15 ml of acetic anhydride was
refluxed for 1 h, after which it was cooled and poured into 50 ml of water, and the aqueous
mixture was neutralized to pH 7-8 with sodium carbonate. The liberated oil was extracted
with chloroform and purified by column chromatography to give 0.62 g (90%) of a colorless

737
oil The oil cryetallized when it was triturated with petroleum Q~har ~o 8ire a p~oduc~
wit:h mp 68'C.
Compound Vle was also obtained in 8.~% yield when the hyd~ochior~L+ ~ o '~ ~V~ ~.,~, ~~,~!~ed
for 2 h in acetic anhydride.
E) A mixture of 2 m o l e of the salt of imine IVa,e and 8-i0 mmoi~ o~ finely 8 ~ o u ~ an~
hydrous potassium c a r b o n a t e o r s o d i u m c a r b o n a t e i n 10 ml o f a b s o l u t e b e n z e n e , t o l u e n e , o r
xylene was refluxed until the reaction was complete (5-7 h), after which the mixture was
filtered, and the solvent was evaporated from the filtrate. The residue was purified by
chromatography. The y i e l d s r a n g e d f r o m 70~ t o 84~..
2-Acetylimino-l-meth~l-3-phenacylbenzimidazoline (X)o A 1,14-g (4 mmole) sample of
imine IX was maintained in 15 ml of acetic anhydride at room temperature until the solid had
dissolved completely (-24 h). The solution was diluted with 50 ml of water, and, after de-
composition of the excess acetic anhydride, the mixture was neutralized to pH 7-8 with sodium
carbonate. The resulting precipita~ was removed by filtration, washed thoroughly with water,
air dried, and crystallized from alcohol t o give 0.9 g (75~) of silky fibrous crystals with
mp 179-180~ IR spectrum: 1545, 1705 cm-L (C=O), Found: C 70.2; H 56; N 13,9% C,gH,TN~O,,
Calculated: C 70,3; H 5,6; N J3,7% . The hydrochloride of X, with mp 210-211~ (from alcohol),
was obtained by acidification of an alcohol solution of the base to pH 2-3 with concentrated
HCI. IR spectrum: 1700, 1728 (O-O); 3250-3400 cm -L (NH). Found: C 62.7; H 5.2;Cl 100; N IZ4%.
H~TN~O~,HC], C a l c u l a t e d : C 62.9; H 5,3; CI 103; N I~,20/0 .
2-Acetyllmino-l-methyl-3-(2-hydroxy-2-phen~lethyl)-benzimidazoline (XI). A 0.2-g sample
of NaBH~ was added in small portions with stirrlng to a suspension of 7 n~n01e of imine X in
30 ml of methanol, after which the mixture was stirred at room temperature for 3-4 h, The
solution was acidified carefully to pH 1-2 with concentrated HCI, the methanol was evaporated,
and the residue was treated with I0 ml of water. The hydrochloride of XI, which was only
slightly soluble in water, was removed by filtration and washed with water to give 1.39 g
(80.2%) of snow-white needles with mp 217-218~ (from alcohol). IR spectrum: 1725 (O=O);
3200, 3370 cm-~ (OH, NH). Found: C 6S,4;H 5,3;CI 10.1;N 12.2%, C,~H,~N~O~.HCI. Calculated: C 62.5;
H 5,5; CI I0,3',N 12,2% .
The salt obtained was treated with NH~OH, and the mixture was extracted with chloroform.
The chloroform was evaporated, the residue was triturated with petroleum ether until it crys-
tallized from acetone to give a product with mp 156-157~ IR spectrum: 1545 ( ~ ) , 3150-
3300 cm -~ (broad OH band). Found.~ C 69.9; H 6,0;N 13.7%. C,aH,sNaO~ . Calcu:lated: C 69,9;H 6,2;
N ~3,6%.
2-Acetylimlno-l-methyl-3-(2-phenyl-2-chloroethy!)-benzimldazoline (Vlllb). A 0.4-ml
sample of SOCl~ was added dropwlse to a suspension of 0.9 g (2.5 mmole) of the hydrochloride
of XI in 10 ml of dry CHCIs, after which the mixture was stirred until the solid had dissolved
completely, and the solution was allowed to stand at room temperature for 24 h. The solvent
was evaporated to give 0.95 g of white crystals of the hydrochloride of Vlllb with mp 197-
198~ (dec., from alcohol with ether). IR spectrum: 1720 cm-, (C=O). Found: c 591; H 53;
Cl 19.2; N 11,6%. C,8H~8CIN~O.HCI. C a l c u l a t e d : C 59,3; H 5.3; CI 19,5; N 11,5% . Base V l l l b was o b -
t a i n e d b y t r e a t m e n t o f t h e s a l t w i t h 10% Nll~OII and had mp 142~ ( d e c . , f r o m a c e t o n e ) . IR
spectrum: 1555 cm- z ( ~ ) . Found; C 65.8; H 5.7; CI I0.5; N 12,9%. C,8H~8CIN~O. C a l c u l a t e d : C66.0;
H 5,5; Ct lO,8; N 12,8%.
Compound Vlllb was also obtained by acylation of imine IVe with acetic anhydride at
room temperature and by brief refluxing of llle with excess [I: (7-10)] SOCI~ in (CHACO)~0.
2-Acetylimino-3-(2-acetoxy-2-phenylethyl)-l-methyl-benzimidazoline (Vllb). A mixture
of 0.6 g (2 mmole) of hydrochloride llle, 0.5 g of fused sodium acetate, and 6 ml of (CHACO)~O
was refluxed for 2 h, after which it was cooled and poured into 20 ml of cold water. The
aqueous mixture was neutralized with NaHCOs, and the precipitate was removed by filtration,
washed with water, dried, and crystallized from benzene-petroleum ether to give 0.62 g (88.6%)
of colorless plates with mp 131~ IR spectrum: 1550, 1740 cm-x ( ~ ) . Found: C 68,2; H 6,1;
N 122% C=0H=,N~O~. Calculated: C 683; 11 6.0; N 12,0%. The hydrochloride of Vllb was isolated d
by acidification of an acetone solution of the base with concentrated lqCl and had mp 208-
209~ (from alcohol), IR spectrum: 1735, 1755 cm-x (C=O). Found: c hiE; H 5Y; C! 90; N I0,9%,
C.~0H=~N~O~.Calculated: C 6L9; H 57; CI 92; N !0,8% .

738
 Compound VIIb was also obtained in a mixture with Vie when hydroxy imine llle was re-
fluxed with excess SOC12 in (CHsC0)=O for 2-3 h.
2-Acetylimino-3-(2-acetoxyethyl)-l-methylbenziimdazoline (Vlla). A 0.68-g (2 mmole)
sample of hydrochloride llla was refiuxed in 5 ml of (CHACO)20 for 2-2.5 h, after which the
mixture was diluted with water. The aqueous mixture was neutralized to pH 7-8 with sodium
carbonate and extracted with chloroform. The CHCIs was evaporated, and the residual oil
crystallized slowly on standing to give 0.78 g (94%) of a product with mp 92-93=C (from ethyl
acetate). IR spectrum: 1545, 1740 cm -~ (C=O). PMR spectrum: 1.88 (3H, s, NCOCHs), 2.13
(3H, s, OCOCHs), 3.47 (3H, s, NCH3), 4.79 (4H, s, CH=CH2), and 7.15 ppm (4H, s, aromatic
protons). Found: C 61,1; H 6,2; N 15,3% C,4H,TN~O3. Calculated: C 61,0; H 6,2; N t 5 , 3 % .
Compound Vlla was also obtained in a mixture with Via and Villa when salt Ilia was re-
fluxed with SOC12 and (CHsCO)20.
2-Acetylimino-l-methyl-3-chloroethylbenzimidazollne (VIIIa). This compound was obtained
in the form of a colorless oil by acylation 0f Im IVa with acetic anhydride at room tem-
perature or by refluxing alcohol IIIa with SOC12 and (CH3CO)20. The hydrochiorlde was iso-
lated by acidification of an acetone solution of the oll with an ether solution of HCI to
pH 1-2 and had mp 257-258~ (dec., from alcohol with ether). IR spectrum: 1740 cm-x (C..--O).
Found: C 49,9; H 5,5; C1 24,2; N 14,5% Cj~HI4CIN30:HCI. Calculated: C 50,0;H 53; C1 24,6;N 14,6%

LITERATURE C I T E D
!. V. A. Anisimova, T. B. Korochina, N. I. Avdyunina, and A. M. Simonova, Khim. Geterotsikl.
Soedln., No. 3, 339 (1986).
2. W. L. Mosby, "Heterocyclic systems with Bridgehead nitrogen atoms," in: The Chemistry
of Heterocyclie Compounds, Interscience, New York (1961).
3o A. Weissberger and E. C. Taylor (editors), Special Topics in }leterocyclic Chemistry,
Intersclence, New York--London (1977).
4. A. M. Simonov and P. M. Kochergin, Khim. Geterotsikl. Soedin., No. 2, 316 (1965).
5. P. M. Kochergln, Khim. Geterotsikl. Soedin., Collective Vol. 1 (1967), p. 137.
6. R. I. North and A. R. Day, J. Heterocycl. Chem., 6, No. 5, 655 (1969).
7. A. C. White and R. M. Black, British Patent No. 1476949; Ref. Zh, Khim., 60157P (1977).
8. V. P. Kruglenko and M. V. Povstyanoi, Khim,-farm. Zh., No. 7, 61 (1979).
9. V. A. Anisimova, M. V. Levchenko, and A. F. Pozharskii, USSR Inventor's Certificate
No. 952848; Byull. Izobr., No. 31, 127 (1982).
i0. Chimetron S. a. r. i., French Patent No. 1488268; Chem. Abstr., 69, 59243 (1968).
ii. Chimetron S. a. r. i., French Patent No. 1488270; Chem. Abstr., 6_~9, 59248 (1968).
12. Yu. M. Yutilov, V. A. Anlsimova, and A. M. Simonov, Khim. Geterotsikl. Soedin., No. 3
416 (1965).
13. V. A. Anisimova, A. M. Simonov, and T. A. Borisova, Khim. Geterotsikl. Soedin., No. 6,
791 (1973).

739
HETEROCYCLIZATION OF COMPOUNDS CONTAINING DIAZ0 AND CYANO GROUPS.
3.* TWO PATHWAYS IN THE CYCLIZATION OF 2-DIAZO-2-CYANOACETIC
ACID DERIVATIVES UNDER THE INFLUENCE OF BASES

Yu, M. Shafran, V. A. Bakulev, V. S. Mokrushln, UDC 547.467.2' 791.3.4

S. G. Alekseev, A. T. Lebedev, and P. A. Sharbatyan

1,2,3-Triazol-5-olates are formed in the reaction of diazomalonodiamide and 2-

diazo-2-cyanoacetic acid amide and N-methylamide with sodium ethoxide, triethyl-
amine, and annnonia. The products of the reaction of 2-diazo-2-cyanoacetamide
with primary amines are mixtures of 4-cyano-l,2,3-triazol-5-olates and 5-amino-
l-alkyl-l,2,3-triazole-4-carboxamides.

In a previous communication [i] we showed that diazoacetonitrile derivatives, including

2-diazo-2-cyanoacetamide (la), 2-diazo-2-cyanoacetic acid N-methylamide (Ib), and ethyl 2-
diazo-2-cyanoacetate (la), react with hydrogen sulfide, hydrogen selenide, and ethanethiol
~t either the cyano or diazo group, depending on the '%ardness" of the nucleophile. One
should expect that, when '%arder" nucleophiles are introduced into the reaction, it would
proceed via two pathways: at the cyano group and at the even '%arder"center of diazoamides
la,b, viz., the hydrogen atom of the amide function,

Capable of reacting via the first pathway are sodium alkoxides, annnonia, and primary
amines, the addition of which to the cyano group of la-c may lead to the formation of a-diazo
imine system A, which undergoes rapid cyclizatio~ to 1,2,3-triazoles [2]~ In the case of
primary amines the initially formed ~-diazo-N-alkyla~dines can undergo cyclization at either
of the two nitrogen atoms of the amidine group~
Attack by nucleophillc reagents at the amide function (the second pathway) may lead to
a-diazoimidolates B, which undergo cyclization tO 4-cyano-l,2,3-triazol-S-olateso
The subject of the present research was a study of the relative reactivities of the
nitrogen, carbon, and hydrogen atoms, respectively, of the dlazo, cyano, and amido groups of
2-diazo-2-cyanoacetic acid derivatives with respect to alkoxides, ammonia, and aliphatic
amines.
We selected 2-diazomalonodlamide (II) as a compound that models 2-diazo-2-cyanoacetic
acid amides la,b but does not contain a cyano group. Ammonium 4-carbamoyl-iH-l,2,3-triazol-
5-olate (IIIa) and methylammonlum 4-carbamoyl-IH-!,2,3-triazol-5-olate (IIlb) were obtained
in thereaction of II with ammonia and methylamlneo A band of stretching vibrations of a
diazo group is absent in the IR spectra oftriazolates IIIa,b, and a band of stretching vi-
brations of an amide carbonyl group is observed (Table 3). In the PMR spectrum of llIb,
just as in the PMR spectrum of methylammonium trifluoroacetate in d~-DMSO, the signal of the
protons of the methyl group appears in the form of a slnglet at 2.4 ppm, which is in agree-
ment with the salt nature of amides IIIa,bo A molecular-lon peak (M+) is absent in the mass
spectrum of triazolate IIIb (Table 2), and an intense signal of [M--31] + pseudomolecular
ions is observed~ These ions correspond to 5-hydroxy-iH-l,2,3-triazole-4-carboxamlde (IV),
which is formed as a result of the elimination of methylamine from the M + ions in the ion
source. At the same time, triazolates IIIa,b do not undergo thermal decomposition, as evi-
denced by the substantial difference in the melting points of triazoles IIIa,b and IVo

See [i] for communication 2.

S. M. Kirov Ural Polytechnic Institute, Sverdlovsk 620002. Translated from Khimiya

Geterotsiklicheskikh Soedlnenii, Noo 7, pp. 926-93!, July, 1986. Original article submitted
April ii, 1985.

740 0009-3122/86/2207-0740512.50 9 1987 Plenum Publishing Corporation

 T~LE i, Conditions and Products of the Reactions of Diazo
Compounds l a - c a n d t I w ~ h Bases
i

No. Diazo oom-[! Solvent Reac~on 1_ . . . .

pound Ba~e time, mtn ~riazolates Amillo-
----- - [ tria~ot~s

.I- ~t , - NH~ H~o 210 ma. (~4) (o)

2 , HuNMe H~O 50 Hib (Sg) (0)
HzNMe EtOH 4320 II]b (75) CO)
4 Ia ' ElONa EtOH 8 va (84) (o)
5 NHa H~O 20 Vb (83) (07
6 NHs EIOH 150 Vb (82) (0)
7 H~NMe H~O 5 Vc (0) VIIa (70)
8 H~NMe EtOH 5
9 H~NE/ H~O 5 Va (59) Vllb (4)
:0 H~NEt EtOH 5 %.d (83) VIIb (16)
It >Ib EtONa EtOH ]5 v~a (89) (o)
:2 NEh EtOH 85 VIb (92) (0)
13 NH~ rhO 990 VIC (79) (0)
14 NHs EtOH "19 ViC (83) (0)
t5 H~NMe H~O 5 V~d (897 (o)
t6 H~NMe EtOH 5 Vld (92) (0)
17 H~NEt H~O 5 VIe (8~) Co)
t8 H~NEt EtOH 5 vt ~ (93) (o)
19 Ic" H~NEt EtOH 5 -- X (5)

TABLE 2. Pro turtles of the Synthesized Compounds

*~ mp,*
(dee.)~C ' ( t e l a t,i v e i n t e m i t y ) ,Il -c T Ilia) , 'mul~ [ N
(Nal

Ilia 199--2oo 24,7 4,7 i48,3 C~HTN~O~ 4,8 48,2

IIIbi 167' 12s (too), 7~ (40),54 30,I 5,8 i44,4
t
C4H~O~ 5,7 44,0
i (wi~hvu~d~c.
~Jl(}7), 44 (62) J

~v 190--191,5 9 t~28 (100), 71 C33), 54 27,93,343,7; C~H4N40= 32 43,7

(19~--i9.2 I3])I(14
[3]' ), 44 (607
Va 298 24,0 2,2 i37,6 i C~HN~NaO-H 2,0 37,3
220 9 UIo 000), 58 (9), 53 25,3 5,0 48,9 C3H~NsO-H2C 4,8 48,3
t(34), 38 (6)
Ve p l 0 (]00), 88 (]3), 53 35,3 5,3 50,9 C4HTNsO 5,0 49,6
t(39), 38 (7)
Vd 37,7 6,0 43,7, C~H~N~O-O,5 6,t 42~6
37~ 32,6 2,0 (15,9 CtH~N4NaO 2,1 :(15.7)
vie 206--206.5- 124 (100),67 (70), 58382 5,3 50J C~HzN~O 5,0 49,6
!(19), 53 (94)
I17--123 124 (100), 67 (6t), 58 38,5 5,9 44,8 C~H~NsO 5,8 453
ithomdec.) 21), 53 (85)
l~
VIe 3--117 42,9 6,7 41,4 C~HnN~O 6,6 41,4
~ithoutd~c,)
VII~ t--243 i t41 (100), 86 (22)~ 70 33,8 5J 50,0 C4H~N~O 5,0 49,6
243 [41) 09), 4 5 0 5 ) i
VIII: 6--206.5 it55 C28). 55 (3D, 45 39j 5,0 44,7 C~H~N~O 5,8 45,1
i(209--210 [4])i.(80 ), 44 (100) . !
VllI i156 [110 (t00), 58 (9), 53, 29,8 2,0 47,I C~HN40-0,5 t 2,3 47,1
.1(~4), 38 (67 !
LX t48 1124'(100), 67 (63), 58i38,6 3,5 45,2 C~H~N40 3,2 45,1
l(~7), 53 (84) ~i
X 8,5 30,4 6,630,4
1(3~), i% ooo7 ] i
The melting points were not corrected.
*The four most intense signals are presented.

Hydroxytrlazole IV was obtained preparatively by acidiflcatlon of an aqueous solution of

trlaz01ate llla. With respect to its melting point, triazole IV synthesized in this w a y w a s
identical to an authentic sample [3]. The chromatographic mobilities of hydroxytriazole IV
and triazolates l!la,b coincide in systems of solvents that contain a base or an acid as a
comsequence of hydrolysis of salts llla,b.

741
 O O
O
':c ,=('., c:
0 I[,NR 1
"='-".......
f
= 0
c-r
O

i N
....... !I I
Nt|
'
~.)
.....
~ ......
~
1
ii
N|~
"

I1
111~a
,b }|
IV

R~
%vy va .d.vla e vnux
,.0 . "c!"o

A
,o '~" vii a , b o

N2 "'N " Nil, "N ' Nt||~, )

ls't.
3;

+ +
Va Via X + = N a + ; V l b X+=HNEt3; Vb--d, V I e - - e X + = H a N R ' ; lII.a, Vb, V i e R"=H;
1II% r e , Vial, V l t a R1=Me; Vd Vie, VItb R ' = E t ; Va--d, VIII R~=H; V i a - - e , IX
R~=Me

Thus in a model experiment it was shown that ammonia and aliphatic amines do not react
at the diazo group but rather attack the hydrogen atom in 2-diazoacetic acid amides, which
leads to their cyclization to l)2,3-triazol-5-olates.
In a study of the reaction of diazo amides la,b with ethanol solutions of sodium ethox-
ide, triethylamine, and ammonia, a s well as with ammonium hydroxide, and of diazo methy-
lamide Ib with methylamine and ethylamine in water and ethanol it was observed that these
reactions proceed in the same way as the model reaction and that their only products are 4-
cyano-iH- (Va)b) and-l-methyl-l,2,3-triazol-S-olates (Via-e) of the corresponding cations.
However, another mechanism, which consists in the addition of the amines to the cya~o group,
is also realized in the reaction of dlazo amide la with raethylamine and ethylamine) and 5-
amino-l-alkyl-l)2,3-triazole-4-carboxamides Vlla,b are formed along with triazolates Vc,d in
this case.
With respect to the character of the IR) mass, and PMR spectra, as well as the chroma-
tographic mobillties in a thin layer, triazolates Va-d and Vla-e are similar to salts llla,bo
5-Hydroxy-IH- (VIII) and-l-methyl-l)2)3-triazole-4-carbonitrile (IX)) respectively, were
obtained in the acidification of Vb and Vlb. The singlet from the protons of the 1-methyl
group in the PMR spectrum of hydroxytriazole IX is shifted ~ 0.4 p p m to weaker field as com-
pared with the corresponding signal in the spectra of salts VZa-e (Table 3). The same shift
of the singlet of the methyl group is also observed in the recording of the PMR spectra of
Vla-e in d6-DMSO after the addition of trifluoroacetic acid to the spectrometer cell. The
weak-field shift of the signal from the protons of the methyl group is due to weakening0f
their shielding as a result of a decrease in the negative charge on both the oxygen atom and
in the 1,2,3-triazole ring as a whole on passing from triazolates VIa-e to hydroxytrlazo!e
IX.
The structure of aminotriazoles VIIa,b was confirmed by data from IR, PMR) and mass
spectroscopy, as well as by coincidence of the melting points of Vlla)b with the melting
points of genuine samples [4].
Amidation of one ester group with subsequent ring closure of the e-diazo amide$ ~O the
corresponding 1,2)3-triazol-5-olates occurs in the reaction of dimethyl d i a z o m a l o n a t e w i t h
primary amines [5]. However, mixtures of compounds that could not be separated into com-
ponents because of the closeness of their Rf values were obtained in the case of treatment
of ethyl 2-diazo-2-cyanoacetate (Ic) with aqueous solutions of methylamine and ethylamine)
as well as with an ethanol solution of methylamine. The individual compounds could be iso-
lated only from the mixture obtained in the reaction of diazo ester Ic with an ethanol solu-
tion of ethylamine. The ethyl 5 - a m i n o - l - e t h y l - l ) 2 , 3 - t r i a z o l e - 4 - c a r b o x y l a t e (X) structure
was assigned to it on the basis of spectral data. The retention of an ethoxycarbonyl group
in triazole X in the presence of excess ethylamine is in agreement with the previously noted

742
 TABLE 3. Spectral Characteristics of the Synthesized Com-
pounds
[IR spectrum (KBr)~ UV spectrum (in water),
PMR spectrum (in dC
I'~:~ I: crn-I k max, nrn (log s )
DMSO), 6, ppm

,n'l
IIIb
.... I 3393
3425
222 (3,78), 265 (3,98)
222 (3,80), 265 (4,00) 7,60 (2H, s, NH2); 6,55
(1H, s ~NH; 2,40 (3H, s,
Me)
IV 3460 223 (3,76), 268 (3,95)
Va 3340 219 (3,86), 259 (3,89)
Vb-',~ 219 (3,96), 258 (3,91)
Vc 219 (4,00), 258 (3,93) 2,38 (3H, s, Me)
Vd 2840 (vcH) 218 (4,08), 258 (4,06) 2,82 (2H, q, 2=72 Hz~
CH2); 1,12 (3H, t, 3"=7,2
Hz Me)
Via 218 (3,70), 262 (3,68)* 3,35 (3H, s,-Me)
VIb 3310~ 220 (3,87), 262 (3,87)* 3,40 (3H, ~,.N--Me); 3,09
(6H, g , ./=7,2 ~ CH,~);
1,20 (9H, t, 1=7,2 tim,
C--Me)
VIC~ 218 (3,64), 262 (3,67)* 7,18 (ill, s, N--H); 3,36
(3H, s, Me)
vid 219 (3,86), 262 (3,90)* 3,36 (3H, s, N~I)--Me) ; 2,40
(3H, s, N--Me)
vie 219 (3,69), 261 (3,74)* 3,31 (3H, s, Nt~)--Me); 2,82
(2H, KS, I=7,2 HZ CH2};
1,10 (3H, t4, I=7,2 Hz,
C--Me)
vIIa 3300, 3430 223 (3,89), 257 (3,87) 7,43 (2H, ~,, CO--NH2);
3,80 (3H, s, Me)
VIIb 3410, 3440 228 (3,79), 258 (3,83)* 7,2 (2H, s, CO--NH2); 6,24
(2H, s, C~s)--NH2); 4,15
(2H, q, I=7,2 Hz, CH2);
1,30 (3H, t, I%7,2 Hz, Me)
VIII 223 (3,76), 268 (3,95)
IX 219 (3,68), 261 (3,71)* 3,72 (3H, $, Me)
X 3485 230 (3,93), 261 (4,01) 6,63 (2H, s, NH2); 4,37
(2H, q, I=7,2 Hz. CH2);
4,28 (2H, q , I=?,5 Hz
CH2); 1,34 (3H, t, I=7,5
Hz, Me); 1,31 (3H, t,
I=7,2 Hz, Me)

In ethanol.
tThin layers.

[6] fact of the lower activity of ethylamine as compared with methylamine in reactions invol-
ving the amidation of esters of heterocyclic carboxylic acids.
The following principles were observed in an analysis of the compositions of the products
of the reaction of diazo amides la,b and II with bases (Table i). On passing from ammonia to
primary amines the reaction rate increases; this is associated with an increase in the nucleo-
philicity of the reagent. Aminotriazoles were obtained only in the reaction of diazo amide
la with primary amines. The methyl group in diazo methylamide Ib increases the electron-
donor character of the amide function, which increases the rate of the competing process,
viz., reaction of the amide and electron-acceptor diazo fragments. The same factor directs
the cyclization of a-diazo-N-alkylamidines A exclusively to the alkylated nitrogen atom,
which leads to the formation of 5-amino-l-alkyltriazoles Vlla,b and X.
Thus all of the bases investigated in this research react with the amide group of diazo
amides la,b and II. Primary amines also attack the cyano group of diazo nitriles la-c; the
products of these reactions are 1,2,3-triazol-5-olates and 5-aminol-l-alkyl-l,2,3-triazoles.
The bases used in the present research do not involve the diazo group of la-c and II.

EXPERIMENTAL
The IR spectra of KBr pellets of the compounds were recorded with UR-20 and Specord IR-
75 spectrometers. The UV spectra of solutions in water (pH 6.5-6.8) and ethanol were recorded
with a Beckmann Model 26 spectrophotometer. The PMR spectra of solutions in d6-DMSO were ob-
tained with a Perkin-Elmer Rl2Bspectrometer (60 MHz) with hexamethyldisiloxane (HMDS) as the
internal standard. The mass spectra were recorded with an MAT-311A mass spectrometer with

743
direct introduction of the samples into the ion source at a sample temperature of 20~ (lllb,
IV, Vb,c, Vlc,d, VIII, and IX) and also with an MKh-1303 sp~.tromet)e=~~
..... with a s ~ m for di-
rect introduction of the samples at a sample temperature of 100~ (Vlla,b and X)~ The course
of the reactions, the compositions of the reaction mlxtures, and the purity of the synthe-
sized compounds were monitored by means of thin-layer chromatography (TLC) on Silufol UV-254
plates in the following systems: chloroform-ethanol (9:1) (A), propanol--3 N ammonium hydro-
xide (3:1) (B), and butanol-water-acetic acld-ethyl acetate (4:1:1:1) (C). The chromatograms
were developed in UV light; the diazo compounds were determined from the color reaction of
the chromatographic spots after spraying the chromatograms with an ethanol solution of m-
phenylenediamine, and the hydroxytrlazole derivatives were determined from the red-brown co-
loration wlth an aqueous solution of iron(Ill) chloride.
The properties of the synthesized compounds are presented in Tables 2 and 3.
Cyclimationof la-c and II. A 2.72-mmole sample of the diazo compound was added with
stirring at 0~ to 0.9 ml of an 8 N solution of the base. At the end of the reaction, the
solvent was removed by vacuum evaporation to dryness. Chromatographically homogeneous pro-
ducts were obtained in experiments Nos. i-7 and I1-18 (Table i). Amides llla,b were crystal-
lized from water-ethanol-ether to give fine colorless crystals. Triazolates Va,b were re-
precipitated from solutions in ethanol by means of ether, and aminotriazole Vlla was crystal-
limed from water. After purification, salts Va,b were obtained in the form of colorless hy-
groscopic powders, and trlazole Vlla was obtained in the form of colorless lamellar crystals.
l-Methyltriamolates Vla-e were purified by reprecipltation from absolute ethanol-ether. Com-
pound Vlb was obtained in the form of a light-brown oil, while the remaining triazolates Via,
c-e were fine, colorless, hygroscopic crystals. Mixtures of substances were obtained in ex-
periments Nos. 8-i0 and 19. Separation of the mixtures obtained in experiments Nos. 8-10
was carried out by means of column chromatography on 40/100 ~ silica gel. The composition of
the eluent was changed from chloroform-ethanol (9:1) to pure ethanol.
5-Amlno-l-alky!-l,2s3-triazole-4-carboxamides VlIa,b. These compounds were detected in
the eluate with the composition chloroform-ethanol (3:1). After crystallization from etha-
nol--chloroform--hexane, VIIa,b were obtained in the form of colorless lamellar crystals. The
TLC data for Vlla were as follows: Rf 0.13 (A), 0.35 (B)~ and 0.38 (C). The TLC data for
VIIb were as follows: Rf 0.20 (A), 0.65 (B), and 0.61 (C).
4TCyano-iH-Is2,3-triazol-5-o!ates Vc,d. These compounds were isolated from the eluate
.............

with the composition chloroform-ethanol (1:2). Fine colorless crystals were obtained after
repreclpiatlon from ethanol-ether.
5-Hydroxy-l,2A3-trlazoles IV~ VIII, and IX. Sulfuric acid diluted with water in a ratio
of l:l by volume was added up to pH 5-4 to a solution of 3.63 mmole of trlazolates IIa, VD,
and VIb in 7 ml of water, after which the reac=ion mixture was cooled to 0~ The method
used to isolate hydroxytriazoles IV, VIII, and IX was due to their solubility in water. The
precipitated carboxamlde IV was removed by filtration, washed with cold water, and crystal-
lized from water to give fine colorless crystals. With respect to the TLC data, hydroxytri-
azole IV coincided with trlazolates IIIa,b: Rf 0.24 (B) and 0.59 (C). Water-soluble car-
bonitriles VIII and IX were extracted with ether (five 20-ml portions). The ether was re-
moved by distillations and the residue was repreclpitated from water-ethanol-ether to give
colorless fluffy crystals. With respect to its chromatographic mobility, hydroxytriazole
VIII coincided with salts Va-d: Rf 0.52 (B) and 0.66 (C). With respect to its chromatogra-~ ~
phlc mobility, hydroxytriazole IX coincided with triazolates Via-e: Rf 0.58 (B) and 0.34
(O.
Ethyl 5-AminoTl-ethyl-l)2,3-triazole-4-carboxylate (X)~ This compound was obtained by
the general cyclization method(experiment No. 19 in Table I). The residue after evapora-
tion of the solvent was treated with ether (four 30-ml protlons). The ether was removed by
distillation, and the residue was repreclpitated from absolute ethanol--heptane to give light-
red crystals. The TLC data were as follows: Rf 0.56 (A),0.74 (B), and 0.76 (C).

LITERATURE CITED
I. Yu. M. Shafran, V. A. Bakulev, V. S. Mokrushin, and G. I. Vallduda, Khim. Getrotsikl.
Soedin., No. 5, 691 (1986).
2. R. Huisgen, Khim. Geterotslkl. Soedln., No. 5, 579 (1981).

744
3. J . T . Witko~sky, R. K. Robins, and F, A. Lehmkuhl, US Patent No. 3948885; Ref. Zh.
Khim., I0145P (1977).
4. A. Dornow and J. Helberg, Chem. Bet., 93, 2001 (1960).
5. P. Murray-Rust, J. McManus, S. P. Lennon, A. E. A, Porter, and J. A. Rechke, J. Chem.
Sot., Perkin Trans. i, No. 4, 713 (1984).
6. R. Buchmann, P. He~steLn, and J. Wells, J. Med. Chem., 117, 1168 (1974).

REACTIONS OF 4-NITRO-I,2,3-TRIAZOLE WITH ALKYLATING AGENTS

AND COMPOUNDS WITH ACTIVATED MULTIPLE BONDS

L. I. Vereshchagin, N. I. Kuznetsova, L, P. Kirillova, UDC 547.791.1.07

V. V. Shcherbakov, G. T. Sukhanov, and G. A. Gareev

When 4-nitro-l,2,3-triazole is alkylated, a mixture of N,- and N2-isomers is

formed, with the latter usually predominating. The same behavior is also ob-
served in addition reactions of 4-nitrotriazole to activated multiple bonds.

Electrophilic substitution reactions in a number of vicinal triazoleshave been studied

very insufficiently. Thus, on alkylation of mono-and di-substituted 1,2,3-triazoles, a mix-
ture of all three isomers [I], the 1,4- and 2,4-isomers with one of them predominating [2-5],
as well as only the N, or N~ alkylation products [2, 3, 5] were obtained. Not only the na-
ture of the substitutent in the ring but also the reaction conditions have a given orienting
effect on the direction ofa~tack of the e!ectrophile. It is shown, for example [5], that
reaction of unsubstituted 1,2,3-triazole with picryl fluoride under conditions of basis catal-
ysis leads to the formation of 2-picryltriazole, while without catalyst l-picryltriazole is
formed. As far as 4-nitrotriazole is concerned, it is known [5] that when it is alkylated
with picryl fluoride in DMF only l-picryl-4-nitrotriazole is obtained.
In order to elucidate the orienting role of the nitro group, the alkylation of 4-nitro-
1,2,3-triazole (I) with various alkylating agents has been examined. Owing to the fact that
triazole I has three potential reaction centers, the formation of all three alkyltriazoles
is possible. The interaction of the Na salt of I with alkyl halides (II) and dimethyl sul-
fate was studied in acetone at 25~ It transpired that in all cases a mixture of two iso-
meric products -- I-R- and 2-R-4-nitrotriazoles (III and IV)with the N2-isomer often predomi-
nating -- was formed. The absence of the 1,5-isomer may be explained by steric factors and
also the negative inductive effect of the nitro group, lowering the nucleophilicty of the
neighboring nitrogen atom.

NO~ :.NO z

9; N O 1 R . . . . 'N'> ~N wN

a i (r m~ , rw
9 I

II~IV
R=C6HsCH=; g R-qE~HsCOCH2; lla X=,I b-e, g X=Br;e, X=CI

Institute of Petrochemical and Coal Chemicals Synthesis, A. A. Zhdanov Irkutsk State

University, Angarsk 665813. Translated from Khimiya Geterotsiklicheskikh Soedlnenii, No. 7,
pp. 932-935, July, 1986. Original article submitted March 12, 1985; revision submitted Octo-
ber 9, 1985.

0009-3122/86/2207-0745512.50 9 1987 Plenum Publishing Corporation 745

 TABLE i. Alkylatlon P r o d u c t s of 1,2,3-Trlazole (I) in Acetone
at 25=C

products Ireae-I c
m~
H u-.[ ~mpirioal
formuli
I C....................
H N lll+IV Isome~ isomer
L_!_ _
1lla+ IVa.a ~8,9 I 3,0 44,0 C~H4N4OI 28,i 3,I 43,7 9O 40 60
IIla+IVa~ 241 28,31 3,3 43,6 CaH~N~O= 28,1 3,1 43,7 94 40 60
lllb+ IVb 24 33,8t 4,4 39,8 C4H6N40= 23,5 4,2 39,,4 85 40 60
IIIc+IVc 1,56 39,2] 4,9 36,3 CsH~N402 38,5 5,1 35,9 70 45 55
II|d+Wd 156 38,91 5,3 35,4 CsHmN40~ 38,5 5,1 35,9 20 30 70
Ille+lVeq 24 35,7) 4,0 ~8,5 C~HaN404 36,0 4,0 28,0 57 67 33
lIle+IVe(i 120 36,3] 3,7 28,7 C~H~N404 36,0 4,0 25,0 50 70 30
l I l f + l V f 204 53,9] 4,1 26,3 CoHsN~O2 52,0 3,9 27,5 87 65 35
l l l g + I V g 24 51,81 3,7 23,8 CtoHsN40, 51,7 3,5 24,1 80 33 67

a II=CH,I. b II= (CH.~)~SO+ c II=C~HsO2CCH2Br. d IIfC~HsO~CCH2CI.

TABLE 2. PMRSpectra of Alkylation Products (III + IV)

........... 6,, ppm "

Mixtureof NI-isomr N2'isomer aR (III+IVL,ppm
~ome~
m (s) ~ (s)
I ....

llla+IVa 8,40 8.12 4,15 s; 4AOs

lllb+IVb 8.73 8A5 3,47 t; 1,51 m
IIlc+ I~, c 8,9~2 8,1~ 4,59 t; 2,07--1,97m; 0,96 r; 0,94 t
Illd+lVd 8,42 8,17 5,49 s; 4,92m; 1,69d.; 1,65d
llle + IV e 8,95 8,41 5,38s; 5,30s; 4,13 q 1,26 t
III f+IVf 8,00 7,87 7,35--7,14m 4,58 s; ~,66 s
lltg+t\.g %09 8,54 8,18--7,55m; 6,37 s

In order to elucidate the influence of the nature of solvent on the rates of reaction
and ratio of isomersD the alkylation of the Na salt of I with methyl iodide in the absence
of acetone was conducted in DMF t DMSO, MeOH, and EtOH. If this reaction takes 1 h in acetone
(Table I), then it takes 2 h in DMSO, 3 h in DMF, 30 h in MeOH, and 48 h in EtOH. The ratio
of isomers in fact changes very little.
In a number of works information is given about the migration of substituents in vicinal
triazoles from the 1-position to the 2-position of the heterocycle [6, 7]. Experiments have
shown that on standing mixture Ilia + IVa at room temperature without solvent for 2 years the
proportion of Na-isomer increased from 60 to 74%, while on maintaining this same mixture at
120~ in DMSO for 8 h, there was an increase of 4-5%. An experiment, specially set in an
ampul used for NMR spectroscopy, on the methylation of I with methyl iodide showed that even
in the first moment of reaction the N~- and Na-isomers are formed simultaneously in the ratio
2:3, which remains practically unchanged during the reaction.
Separation of the isomeric reaction products III and IV, with the exception of 1(2)-
methyl- (Ilia + IVa) and l(2)-ethylnitrotriazoles (lllb + IVb) (see experimental section),
was not achieved. Thus, fractional crystallization does nn t give positive results owing to
their solubility being the same, while fractionation by vacuum distillation is complicated
by the cl~seness of their boiling points and by partial isomerization and thermal decomposi-
tion.
Identification and determination of the ratio of isomers in the mixture of alkylation
products was conducted with the help of PMRspectroscopy from the position and intensity of
the signal from the proton at Cs in the heterocycle. It is known [8] that this signal in
l-R-nitrotriazole occurs at lower field than the corresponding signal in the N=-isomer.
Thus, in alkylation reactions of triazole ! the 1,4- and 2,4-isomers are formed, more
often with the latter predominating. The inductive and shielding effects of the nitro group
hinder attack by the electrophile on the 3-position of the heterocycle.

746
 Table 3. Special Properties of Addition Products Va,b-Vlla,b

Ulxtum ~rnixmm, % l- -" -~ ~ ~ ~ /

of l------T---~l------r----- I IR spectrum,
isomers ! Nv [ No- [. N,- [ Nz- 6R i cm-I
. . . . . . . . . Iisomer'sorher r'osome ~some~ ......
: sor, _ I . . . . . . . . . . .

va+~b 5 95 9t2 8,48 5,94 ~ 3,6I--3,32m, 1,53--I1109--t230, ]535~

(ti#~ . ' f,37r~; t,37--t,20m, 0,82t l t ~
catalyst)
Va+Vb 4 86 9,12 8,46 6,06 q, 5,94q, 3,67--3,29m,[II00--t230, I535,
(without. 1,56--1,39m-, 1,39-~1,16m ,] I565
catalyst) 0,84 t I
Vt~+Vlb 5 55 9,I2 8,52 4,97 t , 4,95t, 3,34 t, 3,31 t 11530, 1540, 1560~
|2260
Vila+VIIb ;9 61 9,06 8,5t 8,14--7,33 m, 6,73 d, 630d ,~1600, 16II, i678
9 ~,63 d, 5~59d 1

Analogous behavior is also observed in addition reactions of triazole I to multiple bonds.

Thus, addition of I to vinyl butyl either proceeds smoothly both in the presence of a catal-
ytic quantity of orthophosphoric acid and without it, that is to say, nitrotriazole itself
catalyzes this reaction. In both cases a mixture of l(2)-(!-butoxyethyl)-4-nitrotriazoles
(Va + Vb) is formed. Without the catalyst the ratio of NI- to Na-isomers is 126, and with
the addition of catalyst the ratio is I:19.

HsPO4 N~w-NxeHO~ u N--N/N

NO NO e
CH2=CHCN~ ~ +
KOH N~ ..N. N.~N.,.N
N CH~CH2CN
14
vi~ C~CH2CN
NO V~b /NO2

N CH=CHCOPh N
cli~CI|COPh

In the addition reactions of I to acryionitrile and benzoylacetylene in the presence of

bases, mixtures of l(2)-cyanoethyl-4-nitrotriazoles (Via + Vlb) and l-phenyl-3-[4-nitro-
l(2)-triazolyl]propen-l-ones (Vlla + VIIb) are formed. The structures of the addition pro-
ducts V-VII were confirmed by IR and PMR spectroscopy (Table 3). The quantity of isomers in
the mixture and their ratio were determined from the presence and intensity in the PMR spectra
of two signals in the regions 9.06-9.12 and 8~46-8.52 ppm from the ring protons at C5 in the
heterocyele. The proton signal at lower field, as in the case of alkylation, was assigned to
the N,-isomer.

EXPERIMENTAL
PMR spectra were recorded on Varian XL-!00/12 (I00.i MHz) and Bruker ~T-200-34 (200.13
~ z ) spectrometers. The accuracy of chemical shift measurema~./%t was i 0.02 ppm. IR spectra
were recorded on a UR-20 instrument in petrolatum oil, as a thin layer of pure samples and
in carbon tetrachlorlde. The course of the reactions was monitored by TLC on plates with
Al2Os in an ether~exane (3:1) system and on Silufol plates in an ether-petroleum ether (321)
system. 4-Nitro-l,2,3-triazole was obtained according to the method in [9].
General Method for Alkylation of Triazole I. To a suspension of 5 mmole (0.68 g) of
the Na salt of I in I0 ml of acetone was added"6~mmole of alkylating agent If, and the mix-
ture was stirred at 25~ (monitoring on Silufol plates). The time of reaction for every
specific case is given in Table I, The precipitate inorganic salt was filtered off, the
filtrate was evaporated, and the residue wa~ recrystallized from aqueous alcohol and dis~
tilled under vacuum. The ratio of isomers was determined both in the reaction mass and

747
 after isolation and purification of the mixture of isomers. Mixtures of alkylation p~oducts
IIIa-g + IVa-g were obtained, the properties of which are given in Tables i and 2. Isomers
IIIa and IVa were separated by chromatography on an AlzOs plate (standard activity II), the
eluent was ether-petroleum e~her (3:1); Ilia: mp 122-123~ IVa: mp 92-94aC. Isomers lllb
and IVb were separated by vacuum distillation; IIlb: bp 57-60eC (3 mm); IVb was isolated by
recrystallization of the indigo-colored residue from aqueous alcohol, mp 48-61~ Separation
of the remaining isomer mixtures was not achieved.
l(2)-(l-Butoxyethyl)-4-nitrotriazoles (Va + Vb). To a suspension of 6 mmole (0.? g) of
triazole I in I0 ml of chloroform was added 6 mmole (0.6 g) of vinyl butyl ether and I drop
of orthophosphoric acid at 25~ The reaction mixture was stirred while boiling for 8 h,
then washed with a 5% solution of sodium carbonate and dried over MgSO~. The solvent was
distilled off and the residue was distilled under vacuum, bp 71-80~ (3 mm), yield 63%.
Found: C 44.6; H 6.6; N 25.8%. CeH~,N~Os. Calculated: C 44.8; H 6.5; N 26.2%.
l(2)-Cyanoethyl-4-nitro-l,2,3-triazoles (Via + Vlb). To a solution of 6 mmole (0.7 g)
of triazole I in i0 ml of acrylonitrile at room temperature was added 0.6 mmole (0.03 g) of
anhydrous KOH, and the mixture was stirred at 30-40~ for 7 h. The excess acrylonitrile was
distilled off and the residue, a mixture of isomers Via and Vlb, was recrystallized from
aqueous alcohol. Yield 78%. Found: C 36.5; H 3.2; N 42.2%. CsHsNsOz. Calculated: C 35.9;
H 3.0; N 41.9%.
IEphenyl-3-[4-nitro-l(2)-triazolyl]propen-l-ones (Vlla + Vllb). To a suspension of 8
mmole (I g) of triazole I in I0 ml of dichlorethane was added 8 mmole (1.6 g) of benzoylace-
tylene and 2-3 drops of triethylamine. The reaction mass stirred at 80~ until the benzoyl-
acetylene had disappeared (monitored on AlaOs plates). The solvent was distilled off and
the residue was recrystallized from acetone. The yield of the mixture of isomers Vlla and
Vllb was 94%. Found: C 54.5; H 3.3; N 22.1%. C::HsN40~. Calculated: C 54.1: H 3.3; N
22.3%.

LITERATURE CITED
i. G. Keller, J. P. Fleury, W. Anschuts, and M. Regitz, Bull. Soc. Chin. Fr., No. 5-6, 1219
(1975).
2. L. Tanaka and S. L. Miller, Tetrahedron, 29, 3285 (1973).
3. K. Khuseinov, G. V. Shatalov, and O. Voischcheva, Paper deposited at VINITI, No. 3307-75.
4. H. Hober, Lieb. Ann., No. 707, 147 (1967).
5. P . N . Neuman, J. Heterocycl. Chem., 8, 51 (1971).
6. P. Jakman, G. L'Able, and G. Stemts, Tetrahedron Lett., No. 60, 5225 (1970).
7. L. Birkofer and P. Wegner, Chem. Bet., i00, 3485 (1967).
8. M . A . Khan and B. M. Lynch, J. Meterocycl. Chem., ~, 1237 (1970).
9. T.E. Eagles, M. A. Khan, and B. M. Lynch, Org. Prep. Proced., 2, 117 (1970).

748
CHEMISTRY OF HETEROCYCLIC N-OXIDES AND RELATED COMPOUNDS
13 . ACYLAMINATION OF PYRIDINE N-OXIDE BY ANILINE, p-ANISIDINE,
AND THEIR N-p-TOSYL DERIVATIVES

Yu. V. Kurbatov and M. A. Solekhova UDC 547.821.3.07:542.958.3

Acylamination of pyridine N-oxide by aniline, p-anisidine, and their tosyl deriva-

tives was carried out in an alkaline medium in the presence of p-tosyl chloride.
The reaction proceeds selectively with the formation of the corresponding 2-(N-
p-tosyl)anilino- and 2-p-(N-p-tosyl)anisidino-pyridines. The reaction products
were converted by acid hydrolysis into the corresponding 2-anilinopyridines.

We have previously described [2] the reaction of reductive acylamination of pyridine

N-oxide (I) by aniline II in the presence of p-tosyl chloride (III). The reaction takes 3
h, proceeds in an alkaline medium at room temperature, and leads to the formation of 2-(N-p-
tosyl)anilino-pyridine (IV) in a yield of 41%. The acrylamination reaction proceeds accord-
ing to the scheme

-, III ~ .... ,. CI-

0- [_ T8
I

C6H~NH 2 + T~CI --m,~ C6HsNHTs + HCI

II V

fi Cl- + C,H,.NH-T~ - - - - - - - ~ + 'rs--0H + HGI

I
OT~ . C6H5

Ts = p - C H 3 - C6H4 - SO2 - IV

This path of the reaction with the participation of p-tosylanilide (V) is confirmed by
the results of the acylamination of pyridine N-oxide by amide V, proceeding under the same
conditions in the presence of p-tosyl chloride, with a high yield of compound IV [3]. When
p-anisidine (VI) was used for the acylamination of N-oxide I, 2-p-(N-p-tosyl)anisidino-pyri-
dine (VII) was obtained in a yield of 67%.

/ " "-'~ '~" TsCI, K0H

~//J + NH2~_~/~ 0CH~ Ts0H- J~ N J - \ N _ _ ~ 0CH~
F
O- T~

For communication 12, see [I].

A. Navoi Samarkand State University, Samarkand703004. Translated from Khimiya Geterot-

siklicheskikh Soedinenii, No. 7, pp. 936-938, July, 1986. Original article submitted March
20, 1985.

0009-3122/86/2207-0749512.50 9 1987 Plenum Publishing Corporation 749

 The use of the knowa p-(N-p-tosyl)anisidlne (VIII) as the acylating agent also leads to
the formation of compoMnd VII in a yield of 74%.

The structure of compounds IV and VI~ was confirmed by acid hydrolysis to the correspond-
ing 2-anilinopyridine s.
As the above described acylamination reactions are selective, they can be proposed as a
convenient method for the synthesls of 2-acylamino-pyridines. Compound Vll can serve as an
intermediate in the sysnthesis of the pharmacological preparation "Allergil."

EXPERIMENTAL
The course of the reaction and the individual state of the compounds obtained were con-
trolled by TLC on aluminum oxide grade II o~ activity, in a chloroform--benzene-alcohol system,
11:4:1 (using iodine vapors as a developer, system A) and by chromatography on paper No. 2
(Rapid, produced in GDR) in a butanol-hydrochloric acic~-water system, 5:7:14 (using Dragen-
dorff reagent as a developer).
Reaction of N-oxide I with amine II. A solution of 1 g (10.5 mmoles) of N-oxide I, 0.9
g (i0 mmoles) of amine II and 4,7 g (25 mmoles) of compound III in 50 ml of chloroform is
shaken with L.6 g (40 mmoles) of 10% solution of sodium hydroxide for 3 h at room temperature.
The aqueous layer is separated and extracted by chloroform. The combined chloroform solutions
are dried over sodium sulfate, the solvent is distilled off, and an oily residue is obtained
containing besides the desived end product, also unreacted N-oxide (RfA 0.7, RfB 0.5) and p-
tosyl chloride. The residue is washed consecutively with ether, water, and alcbhol to yield
1.34 g (41%) of compound IV, mp 151uC (from alcohol), RfA 0.9, RfB 0.97. Found: N 8.9%.
C~aHI,N~O~S. Calculated: N 8.6%.
Reaction Of N-oxide I with amide V. Asolution of 0.5 g (5 mmoles) of N-oxide I, 1.28
g (5 ~ m i d e V, and i.14 g (6 mm0ies) of compound Ill in 30 ml of chloroform is shaken
with 1o14 g (28 mmoles) of a 10% solution of sodium hydroxide at room temperature for 2 h.
The aqueous layer is separated, extracted by chloroform, and the combined chloroform solutions
are dried over sodium sulfate. The solvent is distilled off to yield a semicrystalline mass
containing~ besides the desired and product, also small amounts of unreacted N-oxide I (RfA
O. 7~ Rf~ 0.5) and p-tosyl chloride. This mixture is washed with hexane to yield i. 26 g
(74%) o~ compound IV~ mp 151~C (from alcohol), RfA 0.9, RfB 0.97.
Reaction of N-oxide I with amine VI. A solution of 1 g (i0 mmoles) of N-oxlde I, 1.2 g
(i0 ~ e s ) 0f amine Vi~ and 5.] g (30 mmoles) of compound Ill in 60 ml of chloroform is
shaken with 2.4 g (40 mmoles) of a 10% solution of potassium hydroxide for 4 h at room tem-
perature. The aqueous layer is separated, extracted by chloroform, and the combined chloro-
form solutions are dried over sodium sulfate. The solvent is distilled off, and-the residue,
containing besides the desired end product, also small amounts of unreacted oxide (RfA 0.7,
RfB 0~5), is washed with water to yield 2.5 g (67%) of compound VII, mp 125~ (from alcohol),
RfA 0.9, RfB I. Found: N 8.0%. C,,ff,,N=O,S. Calculated: N 7.9%.
Reaction of N-oxide I with amide VIii. A solution of 1 g of N-oxide I, 1.23 g (4 mmoles)
of amide VIII~ and ).7 g (3 mmoies)of comp0und III in 60 m! of chloroform is shaken with
2.24 g (40 mmoles) of a 10% solution of potassium hydroxide at room temperature for 2 h. The
aqueous layer is separated and extracted by chloroform. The combined chloroform solutions
are dried over sodium sulfate, and the solvent is distilled. A residue forms, containing
besides the desired end product, also N-oxide I (RfA 0.7, Rf~ 0.5), and compound llI is
washed consecutively by ether and alcohol. Yield, [.g2 g (7~%) of compou~nd VII, mp 125-126~
(from alcohol)~ RfA 0.9, RfB I.
Acid Hydrolysis of Compound IV. A 1 g portion (30 mmoles) of compound IV is dissolved
in 1 5 ~ m ~ f concentrated hydrochloric acid, and the mixture is boiled for 12 h. The reaction

750
mixture is distilled to dryness, the residue is dissolved in water, the solution is made
alkaline with potassium carbonate to pH 8-9, and steam-distilled. The distillate, containing
the crystalline product, is extracted by ether. The solvent is distilled to yield,0.45 g
(87%) of 2-anilinopyridine, mp 106-107~ according to the data in [5], mp I06-108~
Acid Hydrolysis of Compound VII. A i g portion (28 mmoles) of compound VII is dissolved
in 5mT~ofconcentratedhydrOchlori~--acid, and the solution is boiled for 34 h. The reaction
mixture is evaporated ts dryness, and the residue is dissolved in water, alkaline with potas-
sium carbonate to pH 8-9, and extracted by ether. The ether is distilled off and tke residue
is treated with benzene. After distillation of benzene, 2-p-anisidinopyridine (IX) is ob-
tained in a yield of 0.40 g (73%), ~ mp 85"~7~ (from petroleum ether), according to the data
in [6], mp 85~

LITERATURE CITED
A. S. Kurbatova and Yu. V. Kurbatov, Khim. Geterotsikl. Soedin., No. 2, 249 (1983)~
2. Yu. V. Kurbatov and M. A. Solekhova, Zh. Organ. Khim., 19, 662 (1983).
3. Yu. V. Kurbatov and M. A. Solekhova, Khim. Geterotsikl. Soedin., No. 9, IZ78 (1982).
4. Organic Chemical Drugs and Their Synonyms [in German], Berlin (1961), p. 606.
5. R. A. Abramovitch and G. M. Singer, J. Am. Chem. Soc., 91, 5672 (1961).
6. O. Fischer, Chem. Ber., 35, 3674 (1902).

SYNTHESIS OF SUBSTITUTED 2-PYRIDONES AND 4-AZA-3-FLUORIDONES

N. S. Prostakov, Saha Shibu Rani, N. M. Mikhai!ova, UDC 547. 823' 836:543.51

V. K. Shevtsov, and N. D. Sergeeva

Substituted N-methyl-2-pyridones and N-methyl-4-aza-3-fluoridones, a previously

unknown group of heterocyclic compounds, were obtained by oxidation of 3-methyl-
2-phenylpyridine, 3-methyl-2-phenyl-5-(3'-methyl-Z'-phenylpyridin-6'-yl)pyridine
iodomethylates, as well as of 4-aza-fluorenes substituted at the 9-position.

For the syn.thesis of 4-aza-3-fluoridones we used 4-azafluorene, which is obtained by

catalytic dehydrocyclization of 3-methyl-2-phenyl-pyridine [i]. It was found that in the
synthesis of this pyridine base by phenylation of B-picoline [2], 3-methyl-2~phenyl-5-(3 '-
methy!-2'-phenyl-3',4'-dehydropiperidin-6'-yl)pyridine is formed in relatively appreciable
amounts; the compound readily converts into a similarly substituted ~,~-dipyridyl [3].
Having at our disposal practical methods for the preparation of these two pyridine bases,
as well as of 4-azafluorene, we turned our attention to the synthesis of new substitutd 2-
pyridones and previously unknown 4-aza-J-fluoridones. They are formed by oxidation under
alkaline conditions of iodomethylates of the corresponding bases.

CH~ CH~
L1H tLIV (:H~

For the oxidation of 3-methyl-2-phenylpyridine iodomethylate (I), we used potassium

hexacyanoferrate (Fe3+). Irrespective of the time of reaction, l,b-dimethyl-6-phenyl-2-pyri-
done (II) is formed in a yield of -20%; a considerable amount of the starting salt is reco~
vered unchanged.

Patrice Lumumba Peoples' Friendship University, Moscow 117923. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 939-942, July, 1986. Original article submitted
March 12, 1985.

0009-3122/86/2207-0751512.50 9 1987 Plenum Publishing Corporation 751

 SaneM i

%ITs,, (ill
(,'Hj I~'
, ~' r ' ~.,~

~lJ# A
M ~' 3,00 (100~) CH~
'
~ (r~)
~ (~) ~CO
..........
~ (s~)
. I ~.~,.%,

N C~N~

Is?

Under similar conditions, from 3-methyl-2-phenyl-5-(3'-methyl-2'-phenyl-2'-pyrldin-6-yl)

pyridine diiodomethylate (llI), s
pyridone (IV~ was obtained in a yield of 25%. In its mass spectrum, the peak of the molecular
ion M + (366) has the highest intensity. The formation of the highly intense peak of the
[M--H]+ ion (365.67%) is characteristic of the fragmentation of dipyridyls [4J, The presence
of two methyl groups in the molecule is confirmed by the formation of characteristic frag-
ments [M-CH,] + (351.23%) and [M--CH,,-CHs] + (33b.20%), whs the relatively high intensity of
the peaks of these ions indirectly indleates the ortho-position of the methyl and phenyl sub-
stltuents. The presence of a keto group in the moelcule is manifested at the second stage
of the fragmentation (Scheme l).
The characteristic feature of the fragmenaation of pyridone IV is splitting of the inter-
nuclear O-C bond between the rings. The charge is thus completely localized on the oxygenless
fragment of the molecule (ion 168.8%), which further decomposes similarly to phenylpyridines
[5].
For the synthesis of 4-aza-3-fluorldones we usedquaternary salts of 4-azafluorenes sub-
stituted at the C(9 ~ atom. The oxidation of 4-aza-florenone iodomethylate (V) was carried
out by atmospherld 6xygen in an aqueous potassium hydroxide solution. 9-0xo-4-methyl-4-aza-
3-fluoridone (Vl) was formedin relatively low yield and, similarly as the above mentioned
pyridones, was isolated in the form of colored crystals. Its structure was confirmed by
PMR and IR spectra and elemental analysis.

\ N ~ 0

o o

In the mass spectrum (scheme 2) of azafluoridone Vl, peak M + (211) has the mximum inten-
sity. The presence of a peak of the [M--HI+ ion with in appreciable intensity is possibly due
to the elimination of a hydrogen atom as the result of cleavage of the B-bond in the methyl
substituent [6]. The formation of intense ions 183 and 155 confirms the presence of two oxo
groups. The splitting of the hydrogen cyanide molecule, characteristic for nitrogen-contain-
ing heterocyclic molecules, is observed at the secondary stages of the fragmentation of M +.
This fact, as well as the absence of a peak of the [M--CH3]+ ion, may serve as an indirect
confirmation of the presence of the N-methylamide fragment in the molecule

In the text and in the schemes, the numbers characterizing the ion represent the m/z value.

752
 Scheme 2

. <.__ ,< , II ......... [ ]

~ "It .........
-, , M ~ ;~II, ( t o o ? g ) k~II) ( 1 2 . ~ )

" I -'11' ~'~ - HCN

1,5~ ( 1 1 % ) ...... ~- 1~8 ( 1 ~ )
el-,*.

4-Aza-3-fluoridones containing a tertiary alcoholic group at the 9-position were obtained

in a similar way. During the oxidation of 9-methyl-4-aza-fluoren-9-ol iodomethylate (VII),
9-hydroxy-4,9-dimethyl-4-aza-3-fluoridone (VIII) was obtained in a 21% yield.

N I-

"% -~:_ " , . -.~. . j ",.

]to .... R HO ~ "R

VIi,IX,XI VIII,X,Xti

VII, VIII R=CH3; IX, X R=P-CHsOC604; XI, Xll R=P-C2HsOCsH~

In the case of the oxidation of quaternary salts of similar alcohols with aryl substi-
tuents at the 9-position, 4-aza-3-fluoridones are formed in yields of >40%. From salts IX
and XI, 9-hydroxy-4-methyl-9-(p-methoxy-phenyl)-(X) and (p-ethoxyphenyl)-(Xll) 4-aza-3-fluo-
ridones were obtained. They are yellow high-melting crystalline substances.

EXPERIMENTAL
The mass spectra were obtained on MX-1303 mass spectrometer, fitted with a system for
a direct introduction of the sample into the ion source, at a ionizing voltage of 70 eV and
input temperature o~ 40uC. The IR spectra were recorded on a Specord UR-20 spectrophotometer~
The PMR spectra were obtained on a BF-467 spectrometer (60 MHz, internal standard TMS). The
chromatography was carried out on aluminum oxide, grade II of activity.
1,5-DimethTi-6-phenyl-2-pyridone (II). A solution of i0 g (32 mmoles) of potassium
ferrocyanide (Fe +3) and 4 g (80 mmoles) of sodium hydroxide in 50 ml of water is gradually
added, with stirring and cooling, to a suspension of 5 g (16 mmoles) ot quaternary salt I
(mp 170-172~ in 30 mi of water. The dark brown mixture is stirred for 4 h at 20~ and
then saturated with potassium carbonate. The reaction products are extracted by chloroform,
and the extract is dried over magnesium sulfate. After the dist of chloroform, 20
ml of acetone are added to the residue (3 g), and 2.7 g (54%) of the initial salt I are fil+
tered. Acetone is distilled from the mother liquor. The residue is chromatographed using
successively hexane--ether mixtures in ratios 3:1, 2:1, and i:I. From the last eluate, 0.Z7
g (19.6%) of pyridone II is isolated, yellow crystals, mp I14-I15~ (from heptane). IR
spectrum: 1610 cm -I (CO). Found: N 7.1%; M + 199. CI~HIsNO. Calculated: N 7.3%; M 199.
1,5-Dimethyl-6-phenyl-(3'-methyl-2'phenylpryldin-6'-yl)-2-pyrldone (IV). In the reac-
tion, 1.26 g (2 mmoles) of salt III, 7.9 g (26 mmoles) of potassium ferr0cyanide, 1.5 g
(20r~noles) of potassium hydroxide, and 50 ml of water are used. The mixture is stirred for
24 h. The precipitate is filtered, washed with water, and dried to yield 0.52 g of the
initial salt III. From the mother ligquor, the products are extracted by ether. After the

753
distillation o~ ethe~ 0.11 g (25~) of pyridono ~V is obtained, ora~Se c~ys~als, mp 178-179~
(from hep~ane), ~R spectrum: 1642 C~-* (C0), PMR spec~um (CDC!~): 1,83 (3H, ~ 5-C~)|
2,40 (3H, s, 3-~,)) 3,30 (3H, s, )~CM,), 7.1-?,8 (llH, m, 5-M and 2.C,~s); 8,37 (I~, 8, 4-~);
8.5 ppm (IS, d, j " 8.0 H~, 4-H), ~ound| N 7,2%| M + 366, C~sH~NaO, Calculatedl N 7,6%;
M 366.
9-0xo-4-mechyl-4-aza-3-fluorldone (VI). A suspension of 0,5 8 (1.5 mmoles) o~ qua=cheery
salt V In 40 ml of a ~5% aqueous solutlonof potassium hydroxide is s~Irred for 2 h at 20"C.
From an ether extract of the reaction products, 0,05 g (15.6%) of the pyrldone VI is isolated,
fish= 5town crystals, mp 195-196"C (f~om heptane). PMR spectrum (CDCI,): 3.95 (3H, e, NCH,),
6.45 (IHj d, $:= 9.2 Hz, 2-H), 7.60 (IH, d, J = 9.1 Hz, l-H), 7.4-7.7 ppm (4H, m 5,6,7,8-H).
IR spectrum: 1710 and 1685 cm-~ (CO). Found: C 73.9~ H 4,5; N 6.6%. C,,H~NO,. Calculated:
C 73.9; H 4.3; N 6.6%,
9-Hydroxy-4,9-dlmethyl-4-aza-3-fluoridone (VIII). A mlxture of 1.3 g (3 mmoles) of salt
VII (mp 227-228~C), 6,5 8(200 mmoies) Of potassium ferrocyanide~ 1.3 g (200 mmoles) of po-
~asslum hydroxide, and ii0 ml of water is stirred for 8 h. The desired end product is Iso-
lated by extraction with ether. Yield 0.17 g (20.9%) of pyridone VIII, yellow crystals, mp
183-184~ (from heptane). PMR spectrum (CDCl,): 1.41 (3H, s, 9-CH,), 3.50 (3H, s, 4-CH,),
3.83 (IH, hr. s, OH), 6.15 (IH, d, J = 9,0 Hz, 2-H), 7.37 (IH, d, J = 9.0 Hz, l-H), 7.3-7.9
(4H, mr 5,6,7,8-H). IR spectrum: 1665 (CO), 3318 cm-* (OH). Found: N 5.9; M + 227.
C~H~,NO~. Calculated: N 6.2%; M 227.
9-11ydroxy-4-methyl-9-(p-methoxyphenyl- and (p-ethoxyphenyl)-4-aza-3-fluoridones (X and
Xll) are obtained in a similar way from salts IX and Xl, in a yield of 47 and 40%, respec-
tively. Compound X. Yellow crystals, mp 214-215~ (from a heptane--acetone mixture, I0:I).
IR spectrum: 1650 (CO), 3285 cm-* (OH). Found: N 4.2%; M + 319. C~oH~TNOs. Calculated:
N 4.4%~ M 319. Compound XII. Yellow crystals., mp 201-202~ (from heptane). IR spectrum:
1650 (CO), 3300 cm-~ (OH). Foundz N 4.4%; M + 333. C,,HI,NO,. Calcul~ted: N 4.2%; M 333.

LITERATURE CITED
I. N.S. Prostakov, A. V. Varlamov, G. A. Vasil'ev, O. G. Kesarev, and G. A. Urbina, Khim.
Geterotsikl. Soedin., No. I, 124 (19775.
2. R.A. Ambramovitch and E. S. Glare, Can. J. Chem., 38, 761 (19605.
3. N.S. Prostakov, C. Bey Habib, A. A. Rezakov, A. A. Fomichev, L. M. Kirillova, and
V. K. Shevtsov, Ehim. Geterotsikl. Soedin., No. 8, 1115 (19845.
4. R.A. Khmel'nltskii, N. A. Klyuev, and P. B. Terent'ev, Zh. Org. Khim., No. 7, 395
(1971)o
5. P.B. Terent'ev~R.A. Khmel'nltskil, andI. S. Khromov, Zh. Org. Khim., No.6~606 (1970).
6. P.I. Zakharov, V. P. Zvollnskli, V. K. Shevtsov, V. G. Pleashakov, T. S. Seitembetov,
A. V. Varlamov, G. A. Vasil'ev, and N. S, Prostakov, Khim. Geterotsikl. Soedin., No. I,
89 (1979).

754
CONDENSATION OF N-(PIPERIDYLIDENE-4)ARYLAMINES WITH
ACETYLENEDICARBOXYLIC ESTERS

Vo V. Kuznetsov, L. A. Gaivor0nskaya, UDC 547:823'834.1:543.42

L. A. Murugova, and N. S. Prostakov

The substituted piperidines, N-(piperidin-3-en-4-yl)-N-(1,2-dimethoxycarbonyl-

etheno) arylamine and l-ary1-3,4,5,6-tetramethoxycarbonyl-l, 2-dihydrospiro [cyclo-
[pyridine-2,4'-piperidine], were synthesized by the condensation of acetylene-
dicarboxylic ester with an azomethine, obtained from a y-piperidone. It was
found that the amounts of I:i and 1:2 addition compounds obtained depends on
the ratio of starting reagents. Compounds isomeric at the vinyl group were
examined in the case of one of the I:i addition compounds. N-(l,2,5-trimethyl-
piperidin-4-yl)-N-(l,2-dimethoxycarbonyletheno)aniline was prepared by two
methods.

The reaction of a N-(cyclohexylidene)arylamine with acetylenedicarboxylic ester (ADCE)

proceeds with the addition of one molecule of ADCE to give a I:I addition compound, N-~yclo-
hexen-l-yl)-N-(l,2-dimethoxycarbonyletheno)arylamine, o r by the addition of two molecules to
give a 1:2 addition compound, l-aryl-3,4, 5,6-tetramethoxycarbonyl-l,2-dihydrospiro[cyclo-
hexane-l', 2-pyridine] [I]. Two examples of analogous condensations of ADCE with azomethines
obtained from y-piperidones have been reported [2].
Since this reaction offers a promising method for obtaining new spiranes with two nitro-
gen-containing six-membered rings, we undertook to synthesize new compounds of this series
and to examine their isomers. The starting azomethines, N-(l,2,5-trimethylpiperidylidene-4)-
p-anisidine (i), N-(l-methylpiperidylidene-4)-p-toluidine (IV), and N-(l-benzyl-2,5-dimethyl-
piperidylidne-4)aniline (VII) were~ prepared as described in [3].

COOCI[~
CN3OOc ~ COOC}L
p-R~C~I[4 ~N/C~-CI{ COOCR
!
R~
i >~.l
N"
Cr
'R"
i'%1
N Na
t
~e
IK, Vt

I
C06Ctt 3
I
CglIg.N ~C :~CIICOOC~ 1
N N}{

N" "CII~
1
C~ 3 Cl{3
I, IV, Vlt X Xl

I~IV, IX R"=CH~, VII, Vltta, b R~--CH,~CGHs; I--IlI, VII--IX R==R~-:-CHs, IV--VI

R~=R'~H; l ~ I l I R~=-OCH~, 1V--Vt R4---C}-Ia,VII--IX R4=H

Patrice Lumumba Peoples' Friendship University, Moscow 117923. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 943-946, July, 1986. Original article submitted
February 27, 1985.

0009-3122/86/2207-0755512.509 1987 Plenum Publishing Corporation 755

 Equlmolar quantities of the azomethlnes I or IV and ADCE gave both i:i and 1;2 addition
compounds: N- (i, 2,5-t rime thylplperldin-3-en-4-yl)-N- (i, 2-dime thoxycarbonyle theno)-p-anisidine
(II) and i' '2',5~-trimethy~-~-p-anisy~-3,4,5,6-tetrameth~xycarb~ny~-~'~-dihydr~spir~[pyridine-
2,4 '-pipe ridlne ] (IIZ), N- (1-me thylp Iperidin-3-en-4-yl) -N- (I, 2-dlme thoxycarbonyle theno )-p-
toluldine (V), and 1 '-me thyl-l-p-tolyl-3,4 j5,6-tetrame thoxycarbonyl-I, 2-dihydrosplro [pyridlne-
2,4'-plperldine](Vl), In both cases the i:i addition compounds predominate (compounds I~ and
V). However, using a 1:2 ratio of the starting reagents, azomethlne and ADCE, gives an ap-
preciable amount of the spiro compound (for example, in the synthesis of compound VZ),
Spectral data confirmed the presence of the dlmethoxycarbonylvlnyl group and the A m-
piperldlne system in compounds II and V. The NMR spectra showed signals at 5.71 ppm (s, IH)
due to the vinyl proton, and at 4.93 ppm (m, IH) and 5.25 ppm (m, IH) due to the proton at
position 3 of the piperidina ring. Protons of the ester group gave rise to signals at 3.76
ppm (s, 3H) and 3.7 ppm (s, 3H), 3.72 ppm (s, 3H) and 3.51 ppm (s, 3H), and 6OCHs(compound
IX) at 3.35 ppm. In the infrared spectrum the unsaturated bonds absorb at 1460 and 1510-1610
(compound II), 1390, 1445, 1520, and 1590-1610 cm-~ (compound V), and the ester group absorbs
at 1710-1740 (C=O) and at 1040 o 1175-1290 (C-O)(compound II), 1705-1730 (C=O) and 1140-1275
cm-1 (0-0) (compound V).
Thln-layer chromatography data showed that compounds II and V were present in two iso-
meric forms, which dlffered considerably in chromatographic mobility. The two isomers of
N- (l-benzyl-2,5-dlmethylplperldin-3-en-4-yl)-N- (I, 2-dime thoxycarbonyle theno) an iline (VIII) --
the trans isomer Vllla (an oily material) and the cls isomer Vlllb (crystals rap, 126-128~
~- ',were isolated by chromatography. The configuration of these isomers was determined from
the position of the vinyl proton signal in the NMR spectrum (5.92 ppm for Villa and 4.89 ppm
for Vlllb); these were compared with data in [i]. The proton at position 3 of the piperidine
ring in these isomers gave rise to signals at 5.10 (m, IH) and 5.47 ppm (d, IH) respectively.
The presence of the four methoxycarbonyl groups in the spiro compounds formed by the
condensation of ADCE with azomethines was confirmed by measuring the total intensity for
the se groups for i ', 2 ', 5 '-t rimethyl-l-p-tolyl-3,4,5,6-re tramethoxycarbonyl-i, 2-dihydrospiro-
[pyridine-2,4'-piperidine] [2]. Burzhen~s method and Ramsey's formula [4] were employed for
the c~Iculations. The area under the absorption curve was calculated using Simpson's formu-
la. Peak absorptions were within 20-80%; peak intensities were expressed in practical units
(moles/liter.cm2) -L. The diester l-morpholino-2,3-dimethoxycarbonylcycloctadiene-l,3 was
used as a standard. The intensity of both diester O=O bands at 1697 and 1720 cm -~ was A =
5.1 x i0 ~ for each band; the total intensity consequently is 10.2 I04. Intensities for
analogous bands in the infrared spectrum of the above spirane were: for the band ~CO 1745
cm -~, A = 12.1 I04 and for vCO 1706 cm-x, A = 10.28 x i04. The sum EA = 22.38 x I0 ~, i.e.,
it is approximately twice for the standard diester, thus confirming the presence of four
methoxycarbonyl groups in the 1:2 addition compounds.
The double bond of the piperidine ring of N-(l,2,5-trimethylpiperidin-3-en-4-yl)-N-(l,2-
dimethoxycarbonyletheno)anillne (IX) [2].was selectively reduced with sodium borohydride to
give a mixtures of isomers of N-(l,2,5-trimethylpiperidln-4-yl)-N-(l,2-dimethoxycarbonyl-
etheno)aniline (Xi). One of the isomers of this tertiary amine was obtained by the condensa-
tion of ADCE with the ~-isomer of 1,2,5-trimethyl-4-phenylaminopiperidine (X) [5].
EXPERIMENTAL
Infrared spectra were recorded on Specord IR-75 and UR-20 instruments using KBr, NaCI,
and LiF prisms; samples were prepared as KBr pellets or thin films between KBr plates. NMR
spectra were measured on a Tesla BS-487c (60 MHz), solvent- CDCI3, internal Standard -- TMS.
Mass-spectra were taken on MX-1303 and LKB-900 instruments using an ionization potential of
70 eV. Column and thin-layer chromatography were carried out on aluminum oxide activity II.
N- (i, 2,5-Trimethylpiperidylidene-4)-p-anisidine (I), N- (l-methylpiperidylidene-4)-p-
toluidine (IV), and N-(l-benzyl-2,5-dimethylpiperidylidene-4)aniline (VII) were obtained in
yields of 50, 45, and 46% respectively. Physical data were as follows: Azomethine I, bp
162-165 = (3 ms), n~ ~ 1.5510. IR spectrum (film): 1690 cm -~ (C=N). Picrate mp 165-167 ~ . ~-
(from alcohol). Found: N 14.5%. C~=H22N20-C6HsNsOT. Calculated: N 14.7%, Azomethinelte,
IV, bp 129-131 = (1.5 nnn), n~ I 1.5519. IR spectrum (film) : 1663 cm -I ( ~ o . Picrate,

756
mp 171 ~ (decomp., from alcohol). Found: ~ N 16.1%. C~H~,N~'C~H~N~O~. Calculated: N 16.4%.
Azomethine VII, bp 182-186 ~ (1.5 mm), n~ ~ i~5747. IR spectrum (film): 1680 cm -~ (C-----N). Pic-
rate, mp 145-145.5 ~ (from alcohol) Found: N 13.6%. C=oH~N~ C,H~ ~O~. Calculated: N
13.3%.
N-(~,2,5-Trimethy~piperidin-3-en-4-y~)-N-(~2-dimeth~x[~arb~ny~ethen~)-p-anisidine (II)
and ~ 5 ~ - s -
piperidine] (!ii). A soiuti0n of 4-~2 g (i7 ~ ) o f azomethine I and 2.66 g ( 1 7 ~ of
ADCE i n 2 5 ml of dry methylene chloride was maintained at 1-3 ~ for 24 h, The solvent was
then distilled and the residue (6.8 g) chromatographed (h = 75 cm, d = 3 cm). Elution with
ether gave 2.3 g (35%) of an orange oil which was a mixture of cis- and trans-isomers of
compound II with Rf values of 0.60 and 0.65 (I:I mixture of ethyl acetate and hexane), Found:
N 6.9%; M + 388. C=,H~N~O~. Calculated: N 7.2%; M 388. Oxalate, mp 159-162 ~ (from alco-
hol). Found: N 6.0%. C~:H~N~O~'C2H~O~. Calculated: N 5.8%. Elution with ethyl acetate
gave 1.38 g of an oil which crystmllized from a i0:i mixture of heptane and ethyl acetate
to give 0.18 g (2.6%) of compound ili, as a bright-orange amorphous powder with mp 86-88 ~
and Rf 0.33 (same system). IR spectrum (KBr): 2795 (N-CH~), 1755 and 1710 (C=O)~ 1590 and 1520 (C--~),
1252 and 1165 cm -~ (C-O). Found: C 61.6; H 6.2; N 5.2%; M + 530. C=~Hs~N=O~. Calculated:
C 61.6; H 6.4; N 5.3%; M 530.
N-(l-Methylpiperidin-3-en-4-yl)-N-(l,2-dimethoxycarbonyletheno)-p-toluidine (V) and l'-
methyl-l-p-tolyl-3,4,5,6-tetramethoxycarbonyl-l,2-dih~ridine-2,4~peridine~).
A. The reaction was carried out with 1.64 g (8.1 mmole) of imine IV, 1.2 g (8.4 mmole7 of
ADCE, and 25 ml of methylene chloride. The reaction products were chromatographed (h = 52
cm, d = 3 cm). Elution with a 1:20 mixture of ethyl acetate and hexane gave 1.4 g (40%) of a
mixture of isomers of compound V as a bright-orange oil with Rf values 0.5 and 0.52 (1:2 ethyl
acetate and hexane). Found: N ~ 6 % ; M + 3 4 4 , C~gN=~N20~. Calculated. N 8o1%; M 344. Diiodomethy-
late, mp 137-142 ~ (from acetone). Found: N 4.7%. C:gH2~N2Od~2CH~L Calculated: N 4.5%.
Elutionwith ethyl acetate gave 0.2g (7%) of compound VI as a yellow amorphous powder withmp 102-
!06~ (from 4:1 heptane and ethyl acetate), and Rf 0~13 (same system)~ NMR spectrum: 7.20-
6.95 (m, 4H, aromatic protons), 3.90-3.55 (12H, 4COOCH3), 3.43 (s, 3H, p-CH~), 2.45 (N-CH~),
2.60-2.18 ppm (m, 6H, CH~-piperidine). !R spectrum (KBr): 1760 and 1710 ( ~ O ) , 1 5 9 0 and
1520 (C==C),1220-1270 and 1160 cm -~ (C-O). Found: N 5.6%; M + 486. C2sH~oN~O~. Calculated:
N 5~8%; M 486.
B. A solution of 2.3 g (I0 mmole) of azomethine IV and 3.25 g (20 nim,ole) of ADCE in 25
ml of absolute ether was maintained at I-3~ for 48 ho Filtration of the powdery precipitate
gave 1.38 g (20%) of compound Vl with mp i00-I05~ admixture with a sample of A gave no melt-
ing point depression~ The mother liquors were chromatographed to yield 0.7 g (13%) of com-
pound V and 0.65 g (12g) of compound VI in a total yield of 32~oo
trans- and cis-lsomers of N-(l-benzyl-2,5-dimethylpyridin-3-en-4-yl)-N-(l,2-dimethoxy-
carbonyletheno)aniline (Villa and b). The reaction was carried out under the same conditions
as used previously with 0.85 g (3 mmole) of azomethlne VII, 0~ g (3 mmole) of ADCE, and 15
ml of methylene chloride~ Elution of the mixture with a 1:20 ethyl acetate-hexane mixture
yielded 0.41 g (31.5%) of the trans-isomer Villa, an orange oil with Rf 0~ (1:4 ethyl ace-
tate-hexane). NMR spectrum: 7~176 (m, IOH~ aromatic protons), 5~92 (s, IH, ~ C H - C O O C N ~ ) ,
510 (m, IH, A~-H-piperidine), 3.73 and 3~ (s, 3H, COOCH~), 2.46 (AB, 2H, N--CH~--), I~25-
0.86 ppm (m, 10H, CH--, CH2--, CH~--piperidine)~ IR spectrum (film): 1730 and 1715 (C=O)
1590 and 1490 (C=C),1260, 1222 and 1180 cm -: (C-O)o Found: N 6o3%; M + 434~ C~6H3oN20~.
Calculated: N 6~ ~" M 4340 Diiodomethylate, mp 139-142 ~ (from acetone) o Found: N 3o8%~
C=~H3oN20~o2CH~L Calculated: N 3~176 Elution with i:i0 ethyl acetate-hexane yielded 0~04
g (3~ of the cis-isomer VIIIB, as colorless crystals with mp 126-128 ~ (from petroleum
ether, bp 40-70=), Rf 0.50 (same solvent system)~ NMR spectrum: 7~ (s, 10H, aromatic
protons), 5~ (d, IH, A~-H--piperidine), 4~ (s, IH, -C==CH-COOCHs), 3o81 and 3~ (s, 3H,
COOCH3), 2~ (AB, 2H, N--CH~--), 1o27-0o96 ppm (m, 10H, CH--, CH=--, CH~--piperidine)o IR spec-
trum (KBr): 1750 and 1710 (C=O),1585 and 1500 (C=C), 1280-1140 cm -~ (C-O}. Found: N 6.2%;
M + 434~ C=6H=oN=O~o Calculated: N 6~ M 434=
N-(l,2,5-Trimethylpiperidin-4-yl)-N-(!,2-dimethoxycarbonyletheno)aniline (X!)o A. To
4 g ~ ) of sodium borohydride in 15 ml of methanol with vigorous mixing was gradually

757
added a solution of 1.3 g (4 mmole) of compound IX in 5 ml of methanol. This was refluxed
for 5 h, 50 ml of water added, and heating was continued for 2 h. The solution was evaporated
to 30 ml. The reaction products were extracted with ether and dried over magnesium sulfate
to yield 0.8 (61.5%) of compound XI (mixture of isomers), as a powder with mp 55-65 ~ (from
heptane), and Rf values 0.71, 0.65, and 0.32 (ether). IR spectrum (KBr); 2800 (N-CHs), 1760
and 1708 (C==O),1610, 1590 and 1512 (C=C),1170, 1085 and 1065 cm-* (C-O). Found: N 7.7%;
M + 360. CaDH~gNzO4. Calculated: N 7.8%; M 360.
B. Solutlons of 0.25 g (1.15 mmole) of the f-lsomer of compound X in 10 ml of methylene
chlorlde and 0.16 g (1.12 mmole) ADCE in 5 ml of methylene chloride were cooled to 0 ~ and
combined. The mixture was refluxed for 40 h, the solvent evaporated, and the residue (0.4 g)
chromatographed (h = 70 cm, d -- 2 cm, eluent 1-20 ethyl acetate-hexane) to yleld 0.07 g of
the starting compound X and 0.08 g (24% based on amine X) of compound Xl, mp 89-93 ~ (from
heptane), with Rf 0.71 (ether). NMR spectrum: 7.26-7.05 (m, 5H, aromatic protons), 4.80
(s, IH, -C==CH-COOCHs),3.65 and 3.55 (s, 3H, COOCHs), 2.20 (s, 3H, N--CH,), 1.38-0.90 ppm
(m, CH-, CH2--, CH,--piperidine). IR spectrum (KBr): 2790 (N--CHs), 1763 and 1712 (C=O), 1578
(C-----C),1578 (C=C), 1222, 1155 and 1130 cm'* (C-O). Found: N 7.5%; M + 360. C2oH2sH204.
Calculated: N 7.8%; M 360.
C. When the reaction was carried out in methanol (refluxed 24 h), compound XI was ob-
tained in 55% yield.
LITERATURE CITED
i. N . S . Prostakov, L. A. Galvoronskaya, V. Fo Zakharov, V. V. Kuznetsov, S. K. Das, and
A. E. Alley, Khlm. Geterotslkl. Soedln., No. 8, 366 (1984).
2. V.V. Kuznetsov, S. K. Das, L. A. Gaivoronskaya, V. F. Zakharov, and N. S. Prostakov,
paper deposited at VINITI, No. 12, p. 98; No. 1269 (1984).
3. I.N. Nazarov, N. S. Prostakov, N. N. Mikheeva, and V. N. Dobrynln, Izv. Vyssh. Uchebn.
Zaved., Khlm. Khim. Tekhnol., No. 5, 726 (1959).
4. D.A. Ramsey, J. Am. Chem. Soc., 74, No. i, 72 (1952).
5. N.S. Prostakov, A. A. Fomlchev, L. A. Gaivoronskli, N. I. Golovtsov, and S. K. Das,
Khlm. Geterotslkl. Soedin., No. ii, 1512 (1982).

758
SYNTHESIS AND LUMINESCENCE OF BENZO[f]QUINOLINE
DERIVATIVES WITH FUSED ALICYCLIC RINGS

N. S. Kozlov, S. V. Mikhalevskaya, UDC 547.836.7.07:535.372

L. F. Gladchenko, and V. A. Serzhanina

Cyclic ketones react with N-(2-naphthyl)formimidoyl-4-pyridine in refluxing aii-

phatic alcohol to form 1,2-(l',2'-cycloalkylene)-3-(4-pyridyl)benzo[f]quinolines.
Under mild conditions, cyclopentanone and cyclohexanone gave dihydrobenzo[f]quino-
line derivatives -- 1,2-(l',2'-cycloalkylene)-3-(4-pyridyl)-3,4-dihydrobenzo[f]-
quinolines, whereas cycloheptanone gave an aminoketone -- 2-[(4-pyridyl)(2-naph-
thylamino)methyl]cycloheptanone.

Derivatives of benzo[f]quinoline containing 1,2-fused alicyclic rings fluoresce strongly

[i]. As part of an investigation of this type of luminophore, the 1,2-cycloalkylene deri-
vatives of benzo[f]quinoline (III-V) were prepared by reacting N-(2-naphthyl)formimidoyl-4-
pyridine (I) with a cyclic ketone (II) in the presence of mineral acid; the luminescent pro-
perties (absorption spectra, fluorescence, fluorescence quantum yield) of these derivatives
was examined.

/7
.-S- ",- N tli ,,
a[ " " ~ , ~ 0 ~ (CIi2} ~

I i IIa "-C

.,@ CIt 2 ) 9 (c~2)

i
NIl- --CII- - ~ / ' ~ ) N
~-,z-%~ j . ......,
J i \\ ,:
1. 1% L IN

. (gu..~)~.
", 5
[ I! ,
lilt ",,,a.. C l~.,b
a a =,'-.);b n~, a : c a = ~

On refluxing the starting compounds in an aliphatic (C2--C4) alcohol for times ranging
from 15 min to 2 h, all the ketones (cyclopentanone, cyclohexanone, and cycloheptanone) gave
the corresponding benzo[f]quinolines -- 1,2-(l',2'-cycloalkylene)-3-(4-pyridyl)benzo[f]quino-
line (Va-c). Under mild conditions (50 ~ 30 min to 1 h reaction time), cyclopentanone and
cyclohexanone formed dihydroderivatives -- 1,2(l',2'-cycloalkylene)-3-(4-pyridyl)-3,4-dihydro-
benzo[f]quinoline (IVa and b), and cycloheptanone gave the aminoketone IIIc -- 2-[(4-pyridyl)-
(2-naphthylaminomethyl]cyclopheptanone (Table i). The structures of these compounds were
confirmed by spectral data and also by the conversion of the intermediates IIIc and IVa and
b to the corresponding benzo[f]quinoline Va-c by refluxing in alcohol in the presence of a
catalyst and an oxidizing agent.
Bands at 3380, 1690, and 3300 cm -I in the infrared spectra of the aminoketone III and
the dihydrobenzo[f]quinolines IV, and stretching and deformation vibrations from the benzo[f]-
quinoline ring in the spectrum of compound V [2], confirmed the structures of these compounds.
Mass-spectral data on the benzo[f]quinolines V showed that these compounds were stable to the
action of electron bombardment. The strongest peak was that of the molecular ion M+; there

Institute of Physical Organic Chemistry, Academy of Sciences of the Be!orussian SSSR,

Minsk 220603. Belorussian Polytechnic Institute, Minsk 220027. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 947-950, July, 1986. Original article submitted
April 15, 1985.

0009-3122/86/2207-0759512.50 9 1987 Plenum Publishing Corporation 759

 TABLE I. Phyaicochemical Da=a

Com-
pound .I I m,m:tm,, :m" . . . . 11
I
IIIo 4 146--14813880(~su), 1525(8~u), 80,~ 71 8,( C~H~N~O 80,2 7,0 8,1 44,0
1690{v~o)
IVa 2 230--232 3ZOO(v~.), IB25(6N.) 84.2 6,4 9,( C~,H~N~ 84,5 6,1 9,4 13,4
IVb a 1236-238 3SOO(v~.), 152a(a..) 84,B 6,6 8,~ C~H~oN~ 84,6 6,5 9,0 21,2
V. 2 170~172 3050, 3030(v~, ,aror&); 85,0 5,fl0,4C~H~N~ 85,1 5,4 9,~ 27,0
]2060, 2ab0(vcN,Ji t600,
1560, 1485, 1448(~r
835. 760 (6e. shoulder.)
vb 3 162~163 3060, 3030(~;c~ atom.); 84,915,fi C~2H~N~ 85,1 5,9 9,0 95J
~960, 2860(VcH~ ); 1600,
1St;0, 1480, ]435(v~.~);
B3~5,760(6ca should,~r,)
Vc 4 176~177 3060, 3010(vau arora);, 85,0 C2sH~0N~ 85,2 6,2 8,6 26,7
2920, 2860(vcH~); 1600,
1560, 1480, 1440(vc.c);
83S, 760(6c~ shoulder.)

*Compounds lllc and Va-c were recrystallized from Isopro-

panol, and IVa and b from a mixture of Isopropanol and
toluene.

was also an (M -- H) + peak. In the mass spectra of the dihydro derivatives of benzo(f)quino-
l i n e IV along with the molecular ion peak M+ there are low-lntensity peaks (M -- 2H) +, formed
as a result of aromatization of the dihydro derivatives IV a and b to the corresponding
benzo(f) quinolines V a and b by the action of electron bombardment. In the mass spectrum
of Iv a there is also the peak

......
I(M
L

The ultraviolet spectra of the benzo [f]quinolines V exhibit three bands, due to electron
transitions in the benzene and pyridine rings: hlgh-intenslty S-bands (258-269 nm; log
4.39-4.61), p-(293-325 nm; log E 4.19-3.12) and ~-bands with weak vibrational structures
(335-344 and 350-358 nm; log ~ 3.30-3.57 and 3.34-3.62 nm). Comparison of the absorption
spectrum of compound V with the spectrum of 1,2-(l'2'-cycloalkylene)-3-arylbenzo[f]quinoline
[i] showed that the introduction of a pyrldyl group at position 3 led to a bathochromic
shift of the 8- and p-bands, and a hyperchromic effect for the 8-bands. Compound V fluo-
resces in the UV (390-400 nm); the Stokes shift is 40-50 nm. The fluorescence spectra of
V are structureless in the solvent used, except that in benzene, compound Va, which has a
five-membered alicyclic ring, gives rise to two maxima (Table 2). The fluorescence quantum
yields are low and range from 3-17%. The decrease in the fluorescence quantum yield in com-
parison with compounds such as 1,2-(l',2'-cycloalkylene)-3-arylbenzo[f]qulnoline [i] is ap-
parently due to destruction of the coplanarity of the benzo[f]quinoline molecule when the
phenyl group at 3 position is replaced by a pyridyl group. Benzo[f]quinoline has the highest
quantum yield; this compound has a strained five-membered ring -- the four carbon atoms are
in one plane, producing the maximum hyperconjugation effect. In the less strained six- and
seven-membered rings (compounds Vb and c) the steric effect, which increases with ring size,
becomes more important [3]. The position of the fluorescence band shows a weak dependence
on the nature of the solvent, indicating the stability of the dipole moment of the molecule
on excitation [4]. The maximum fluorescence quantum yield (17%) was observed with ethanol
where hydrogen bonding between the nitrogen atom and the solvent reduces the influence of the
free electrons in the n-electron cloud and consequently also the probability of interconver-
sion [5].
On going to the partially hydrogenated derivatives of benzo[f]quinoline, the unshared
electrons on the nitrogen atom are lost to the conjugation system, and this shows up in the
luminescent properties of these compounds (Table 2). The absorption spectra of compounds
IVa and b are analogous to those of 2-naphthylamine and contain bands corresponding to n-m*

760
 TABLE 2. Luminescence Data for Benzo [f]quinoline Derivatives

. . . . . nuore.~c~nee, ~max (}"i %)

Com- Absorption (ethanol),
pound Xmax, nm(log g),
benzene ethanol DMSO

IVa 2 257 (4,64), 303 (3,87), 315 428 (25) 440 (4) 448 (42)
(3,78), 370 (3,63)
[Vb 3 257 (4,70), 298 (3,96), 310 408,425 (25) did not 437 (36)
(3,8S), 370 (3,65) luminesce
V~ 2 269 (4,53), 293 (4,19), 3,44 378,394 (ll) 39b (17) 395 (15)
(3,49), 358 (3,51)
Vb 3 258 (4,39), 322 (3,12), 335 390 (3) 400 (7) 400 (5)
(3,30), 350 (3,34)
Vc 4 267 (4,61), 325 (3,36), 340 '390 (5) 400 (6) 400 (lo)
(3,57}, 355 (3,62)

type transitions; there is a bathochromic shift compared with bands of 2-naphthylamine [6].
The dihydro derivatives IVa and b luminesce fairly strongly in aprotic solvents (25-42% in
benzene and DMSO), but show almost no luminescence in ethanolic solution. Quenching of the
fluorescence in ethanol is apparently due to the protonation of the nitrogen atom of the
pyridine ring. This is supported by the observation that there is no significant change in
the position of the fluorescence bands (425-440 nm) on going from aprotic to protic solvents.
The higher luminescence quantum yield in DMSO compared with benzene can be explained by the
increase in viscosity of the solvent, which helps to stabilize the fluorescing molecule [7].

EXPERIMENTAL
Infrared spectra were taken on a UR-20 instrument; samples were measured in KBr pellets,
Uv spectra were measured on a Specord UV-vis; samples were dissolved in ehtanol (10-4 mole/
liter). Mass spectra were recorded on a Varian MAT-311 with direct introduction of the sam-
ple into the ion source at an ionization energy of 70 V. Vaporization temperature was
I00-180~ Fluorescence spectra and the absolute fluorescence quantum yields were measured
on an SLM-4800 spectrofluorimeter. Excitation of fluorescence was carried out at a wave-
length of 350rim, the long-wave absorption region for the solutions examined. The absolute
fluorescence quantum yield was calculated by the relative method. The solvents used were
dry ethanol, benzene, and DMSO. A solution of 3-amino-N-methylthalimide in absolute ethanol
was used as a standard. The compounds were examined by TLC on Silufol UV-254 plates (eluent,
carbon tetrachloride-ethanol--acetic acid, i0:i:i; visualization in UV light).
N-(2-Naphthyl)formimidoyl-4-pyridine (I) was prepared by the method given in [8].
1,2-(l',2'-Cyclohexylene)-3-(4-pyridyl)-3,4-dihydrobenzo[f]quinoline (IVb) and 1,2-
(l',2'-cyclohexylene)-3-(4-pyridyl)benzo[f]quinoiine (Vb). A mixture of ~.32 g ( 1 0 - - ~ e ) of
compound I, 1.47g (15 mmole) of cyclohexanone, 20 ml of isopropanol, and i0 drops of concen-
trated HCI was heated at 50 ~ for 1 h, then at 80-85 ~ for a further 1 h. The mixture was
cooled and the precipitated material was filtered off, neutralized with 25% ammonium hydrox--
ide, and washed with water until the washings were neutral. Recrystallization from a l:l
mixture of isopropanol and toluene gave 0.66 g (21.2%) of compound IVb. The mother liquors
were partially evaporated, and the precipitate filtered and worked up as for IVb to give 0.8 g
(25.8%) of compound Vb (from isopropanol). Compounds IVa and Va and b were obtained in the
same way.
2-[(4-Pyridyl)(2-naphthylamino)methyl]cycloheptanone (IIIc). A mixture of 2.32 g (i0
ramole) of compound I, 1.4 g (12.5 mmole) of cycloheptanone, 20 ml of isopropanol~ and 16
drops of concentrated HCI was heated at 50~ for 1 h. After evaporation of the solvent, the
residue was treated with 50 ml of ether to extract tarry material, neutralized with 25% am-
monium hydroxide, and washed with water until the washings gave a neutral reaction to give
0.76 g (44%) of compound IIIc (from isopropanol).
Cyclization of 2-[(4-pyridyl)(2-naphthylamino)methyl]cycloheptanone. A mixture of 1.0 g
(2.9 mmole) of compound IIIc, 1 ml of boron trifluoride etherate, and 20 ml of dry benzene
was heated for 1 h on a boiling water bath. After cooling, the tarry materials was separated
and treated with 25% ammonium hydroxide, and then washed with water until the washings were
neutral; yield 0.65 g (69.1%) of compound Vc (from isopropanol) o

761
 Cyclization of 1,2-(l'~2'-cyclohexylen)-3-(4-pyrldyl)-3,4-dihydrobenzo[f]quinoline. A
mixture of 1.0 g (3.2 mmole) of compound IIib, 20 ml of Isopropanol, 10 drops of concentrated
HCl, and i ml of nitrobenzene was heated in sealed tube for 1 h at 150~ The mixture was
cooled, and the precipitate which separated filtered, neutralized with 25% ammonium hydroxide,
and washed with water until the washings gave a neutral reaction. A yield of 0.9 g (87.2%)
of compound Vb was obtained.

LITERATURE CITED
i. N.S. Koslov, V. A. Serzhanina, G. V. Vorob'eva, R. D. Sauts, and L. F. Gladchenko, Dokl.
Akad. Nauk BSSR, 22, No. lO, 910 (1978).
2. N.S. Koslov, V. V. Misenzhnikov, and M. S. Gaisinovich, Khim. Geteroslkl. Soedin., No.
3, 467 (1965).
3. K. Blaga, O. Chervinka, and Ya. Kovar, Fundamentals of Stereochemlstry and Conformatlonal
Analysis [in Russian], Leningrad, (1974), p. 192.
4. N.G. Bakhshlev, Opt. Spektrosk., 13, 43 (1962).
5. V.L. Ermolaev and I. I. Kotlyar, Opt. Spektrosk., ~, 353 (1960).
6. G.F. Bol'shakov, V. F. Vatago, and F. B. Agrest, Ultraviolet Spectra of Heterocyclic
Compounds [in Russian], Khlmlya, Leningrad (1969), p. 41.
7. N.S. Kozlov, L. F. Gladchenko, V. A. Serzhanina, G. S. Shmanal, I. P. Stremok, G. P.
Korotyshova, and R. D. Sauts, Khim. Geterosikl. Soedln., NO. 4, 511 (1978).
8. N.S. Kozlov, S. V. Mikhalevskaya, V. A. Serzhanina, and R. D. Sauts, Dokl. Akad. Nauk
BSSR, 28, No. 9, 810 (1984).

762
QUANTITATIVE DETERMINATION OF THE ELECTRONIC EFFECTS
OF 3- AND 4-PYRIDAZINYL GROUPS FROM NMR SPECTRAL DATA
FOR ISOMERIC AMINOPHENYL- AND PHENYLPYRIDAZINES

O. P. Shkurko, S. A. Kuznetsov, A. Yu. Denisov, UDC 541.62:543.422.25:

and V. P. Mamaev 547.852.2.07

The previously unknown aminophenylpyridazines were synthesized. The inductive and

resonance constants of 3- and 4-pyridazinyl groups were calculated on the basis of
*H and iSC NMR spectral data for isomeric aminophenyl- and phenylpyridazines in
dimethyl sulfoxide (DMSO).

Information regarding the electronic effects of 3- and 4-pyridazinyl groups is not avail-
able [i]; this is associated with the inaccessibility of the compounds and with the restric-
tions imposed by the methods for the determination of reactivity constants on the selection
of model compounds. Nevertheless, a knowledge of such constants is useful not only in the
prediction of the properties of compounds of the pyridazine series but is also of interest
from a theoretical point of view.
Pyridazinyl groups occupy a special position in series of azinyl groups, since the ni-
trogen atoms in them are bonded directly to one another, which leads to appreciabl@ alterna-
tion in the lengths [2] and orders [3, 4] of the ~ bonds and to a decrease in the degree of
delocalization of the ~ electrons in the ring [5].
In analogy with other azinyl groups, o n e s h o u l d expect the manifestation of electron-
acceptor properties by pyridazinyl groups; this is confirmed qualitatively by some spectral
data. Thus, increased (as compared with the benzene analogs) frequencies of the N-H and C--O
stretching vibrations were recorded in the IR spectra of amino- [6] and formylpyridazines
[7, 8]. An examination of the effect of various azinyi groups on the NH acidities of amino
azines [9], as well as on the CH acidities of methyl azines [i0] and acetyl azines [9], makes
it possible to qualitatively determine the locations of pyridazinyl groups in series of such
substituents. With respect to the ability to stabilize nitrogen and carbon anions, the 4-
pyridazinyl group is close to the 4-pyrimidinyl group, whereas the 3-pyridazinyl group is
close to the somewhat less electron-accepting 2- and 5-pyrimidinyl groups.
In the present research we determined the set of ~ constants of 3- and 4-pyridazinyl
groups on the basis of :~C N ~ spectral data for 3- (Ia) and 4-phenylpyridazine (IIa) and
PMR spectral data for four isomeric m- and p-aminophenylpyridazines (Ib,c and IIb,c). Only
the two phenylpyridazines [ii, 12] and 3-(p-aminophenyl)pyridazine (Ic) [13] have been de-
scribed.
We selected the scheme of synthesis that is usually employed in the preparation of 3-
substituted pyridazines starting from aroylpropionic acids IIIa,d,e [14]. The chlorine atom
was removed from 3-aryl-6-chloropyridazines VIa,d,e by catalytic hydrogenation in the pre-
sence of palladium on carbon. In the case of nitrophenyl derivative VId reductive dehalo-
genation was accompanied by reduction of the nitro group to give 3-(m-aminophenyl)pyridazine
(Ib).
In the reduction of p-isomer Vie the resulting p-aminophenyl group appreciably retards
the subsequent removal of a chlorine atom, and, despite an increase in the time and tempera-
ture, a small amount of chloro derivative VII was isolated from the products of reduction
along with aminophenyl derivative Ic.* In addition to a broad signal of protons of an amino
*The melting point of Ic differs markedly from the data in [13].

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7,
pp. 951-958, July, 1986. Original article submitted March 18, 1985.

0009-3122/86/2207-0763512.50 9 1987 Plenum Publishing Corporation 763

 group and two doublet signals of aroma=It protons os a p-substituted phenyl group (see Table
i), two doublets wi~h J - 9.0 Hz, whiah is characteristic ~o~ spln-~pln coupling coupling
of 4-H and 5-H p~otons of the pyridaslne ring [15]~ are present in the P~R spectrum of VII.

XV&,~,e ....." V~,,d,e

I, Itt--Vt a X f H , b X=m.NH,,* X=p-NHl, d X=m.NO~, e X=p-NO2

Isomeric 4-amlnophenylpyridazines IXb,c were obtained from nitrophenylsuccinic acids

VIlld,e as in the scheme in [11] for the synthesis of 4-phenylpyridazine (lla). In its last
step we noted stepwlse reductive dehalogenation of 4-nitrophenyl-3t6-dlchloropyridazines
Xlld,e. The chlorine atom adjacent to the aryl group was removed with difficulty; this led
to the production of, in addition to amlnophenylpyrldazlnes lib,c, certain amounts of 4-amino-
phenyl-3-chloropyridazines X!XZb,c. In addition to broad signals of the protons of the amino
group, two doublets, one of them at weak field with characteristic constant sJs,6 = 5.0 Hz
[15], were recorded in their PMR spectre (see Table I). The presence of a chlorine atom in
the 3 position of the pyrldazlne ring is confirmed by the correspondence of the 5-H and 6-H
chemical shifts in the PMR spectra of XIIIb,c with the values calculated via an additive
scheme from the spectra of 3-chloropyridazlne and 4-aminophenyl derivatives !Ib,c.
In the reductlve dehalogenatlon of XIIa we also recorded the formation of 4-phenyl-3-
chloropyridazine (Xllla) as an intermediate. Under conditions of Incomplete dehalogenation
of XIla with the absorption of an equlmolar amount of hydrogen we isolated lla and XIIIa in
a ratio of 1.2:1. As in the spectra of XIIIb,c discussed above, two doublets with sJs,6 =
5.0 Hz are observed in the PME spectrum of X~IIa.
COO}t XCoH4.., . _ , # 0 X%H, . .,. ........
,,~.0
XCeH,CHCH~COOH '---- {7~.O[ ....~,. ~ O~
VIII a ~d,~ ~ o

c/.,x [~."~"'xi]" ./~c'H'x

iX a,d,e
/
xa,d,r

L*N/N Cl / " "' 0

H
ha. c / xlr a,dtr Xla,d,e
CslI4X C~II4NH~-P

L'~N/N C1
xm a-C XI! C

II, VIII--XIII a X = H , b X=m-NH~,c X=p-NH2, d X=m-NO2 e X=p-NO2

The chemical shifts (CS) and spin-spin coupling constants(SSCC) of lb,c and llb,c
(Table I) correspond to the data in [16, 17]. The :3C NMR spectra were recorded for phenyl-
pyridazines la and lla (Table 2). The assignment of the signals to the carbon atoms of the
phenyl groups was made in analogy ~Ith the assignment in the spectra of phenylpyridines [18]
and phenylpyrimidines [19] with allowance for the relative intensities of the signals. The
remaining signals were assigned to the carbon atoms of the pyridazine ring on the basis of
quantitative data on the effect of a phenyl group as a substituent on the *SC CS in the ben-
zene and pyridine rings in the case of phenylpyridines [18]. For comparison, the *SC CS of
unsubstituted pyridazine, which we determined for a dilute solution in DMSO, are presented
in Table 2.
The ~I and ~ o constantSstarting
for the pyridazinylm_groUpSp_carbonaS
substituentsAwereatoms
(6 calculated in
accordance with [~9] from the CS of the and L and &~pU ) of
764
 TABLE i. PMR Spectra of Arylpyridazines I, II, VII, XIIc, and XIII in DMSO

Chemical shift,* ppm

Compound SubstitUents in the pyr- A6NH= % AS"NH=~
;idazine ring ~-H (dd), 4- H 5-H 6-H Ar NH2

Ia 3-C6Hs 8,20 dd 7,79 ,dd 9,26 dd 7,50--7,67m ; 8,10--8,32 m

3- (m-H2NCsH4) 7,72 dd 9,16 dd 6,63--7,50 m 5,25 -0,35 - -
0,32
Ib 7,98 dd
7,62 dd. 9,05 dd 6,74 d,; 7,92 d 5,53 - 0,63, --0,61
Ic 3- (p-H2NC6H4) 7,98 dd
IIa 4-C6Hs 9,68 8,00 dd 9,33dd 7,44--7,69m ; 7,7%-8,07 m
9,30 dd 6,67--7,38 m 5,31 -0,41 - - 0,38
llb 4- (m-H2NC6H4) 9,56 7,85 dd:
IIc 4- (p-H~NC~H4) 9,52 7,78 dd 9,09 dd 6,73 d; 7,67 d 5,64 --0,74 --0,72
VII 6-CI-3- (p-H2NC6H4) 8,0.~. 7,80 d 6,7.2 d; 7,88 d 5,66
Xllc 3,6-Di-CL4 - (p-H2NC6H4) 7,89s 6,71 d; 7,40 d 5,75
Xllla 3-Cl-4-C~H~ 7,83d 9,34 d 7,57 s
XIIIb 3-CI-4- (m-H~NC6H4) 7,71d 9,26 6,56--7,32m 5,30
XIII c 3-C1-4- (p-H~NC6H,) 7,69 d 9,19 d 6,72 d; 7,36 d 5,63

*In the pyridazine ring sJ~.5 = 8.3-9.0, s J 5 , 6 = 4 . 5 - 5 . 5 , ~ J a,s = 2.4-2.7, ~J~.~ = 1.5, and 3Ja.6 = 1.2-1.5 Hz. In the
p-disubstituted benzene ring sj = 8.5-9.0Hz.
%Relative to the signal of aniline in DMSO (4.90 ppm), the negative values correspond to a shift to weak field.
SWith allowance for the magnetic anisotropy of the pyridazine ring.

",4
0%
Ln
 TABLE 2. ~aC NMR Spectra of Pyridazine and Phenylpyridazines
la and Ila in DMSO
. . . . . . . . . . - ................

g;:;_ =,,-7 o;,; ......o,

'I~ 1t58,561124,18t1~7,5411,50.511136,221126,891129,02
1:~_0..0.;%6[
~[ 1 1,6210,46tl,52
,,. i,a,9,3,,it3r,O~1133,161lZl,al 113S,871127,1011'.'9,:~3130,0'~ 0,0:21 1,6=I o,rr[t,~2

~Relatlve to the signal of benzene in DMSO (128.41 ppm).

%With allowance for the magnetic anisotropy of the pyri-
dizaine ring.

TABLE 3. ~ Constants of Pyridazinyl Groups

Group -PMR ' llSCNMR I . . . . . . . . . .

AV. I I JI 01~ '~

..............

0.18 I 0,04 ] 0,30 ] 0,28 I 0,48

~ r ~'n,

.....
r

4-Pyridazinyl 0,21 0,27 0,24 0,02 0,35 0,36 0,59

the phenyl groups in the *SC NMR spectra of phenylpyridazines la and lla (Table 2) determined
relative to the signal of benzene (128.41 ppm) with allowance for corrections for the diamag-
netic anisotropy of the pyrldazlne ring.
The ~I and ~R constants were calculated in accordance with [20] on the basis of the CS
of the protons of the amino group in the PMR spectra of aminophenylpyridazlnes Ib and Ic, as
well as lib and llc, reckoned relative to the signal of the protons of the amino group of
aniline (4.90 ppm) with allowance for corrections for the diamagnetic anisotropy of the pyr-
idazine ring.
The contribution of the "ring current" induced in the benzene ring by the magnetic field
to the CS of the resonating ring as a function of the coordinates of the latter relative to
the center of the benzene ring was previously calculated in [21]. These data can also be
used in the case of six-membered nitrogen heterocycles under the condition that, if the geo-
metrical parameters of the heteroring differ little from the benzene parameters, the ~-elec-
tron structure undergoes little perturbation when a nitrogen heteroatom is introduced into
it. Such assumptions were previously made with respect to pyridine [18] and pyrimidine [20].
On the basis of calculations of the anisotropy of the diamagnetic susceptibilities of six-
membered nitrogen heterocycles [22], it might be assumed that the corrections for the mag-
netic anisotropy of pyridazinyl groups would differ by no more than 10% of the values pre-
viously estimated for the phenyl group. However, with allowance for the certain certain de-
gree of decrease in the bond lengthsin substituted pyridazines as compared with the benzene
analogs this difference will be even less appreciable, and this makes it possible to use in
this case corrections of 0.15 ppm for the m-carbon atoms (Cm), 0.i0 ppm for the p-carbon
atoms (Cp), 0.03 ppm for the m-amino groups, and 0.02 ppm for the p-amino groups.
The 6 constants of the pyridazlnyl groups calculated from the corresponding equations
are presented in Table 3. Whereas for the 3-pyrldazinyl group the induction constants de-
termined by the two methods coincide completely, they differ for the 4-pyridazinyl group.
The reason for this difference may consist in conferring the same status to the ~R and ~
constants, which is valid only to a rough approximation. Nevertheless, the average GI
value for the 4-pyridazinyl group (0.24) is comparable to the corresponding constant of the
4-pyridyl group (0.21 [18]).
As expected, the 4-pyridazlnyl group displays a stronger resonance effect than the 3-pyr-
idazinyl group; the D R constants for the two groups are approximately averages between the
constants of 2- and 4-pyridyl and pyrimidinyl groups. This can be stated to an equal degree
with respect to the generalized ~p Hammett constants.

766
 TABLE 4. Characteristics of Arylpyridazines I, If, Ve, Vle,
VII) XId, XIId, and XIII
,, ,L, ,,,,,,

Com- rap, ') ~E UV spectrum, Found, % Empirical C alc.,,% ~.

Xmax (log e) ~1 formula l-----r----~
pound N N ,,,

ia 102--I0t ~,I, (4,.8), 276, 38

m2.-i():~ sh (a,8t)
ll)l
ia:)-i4() 238 (,l,:q), 263, 70,5 .3,171 24,9 Cf,,H~Na 7O,? 5,30 24,5 50
sh (4,02), 323
(3, II )
lc 173--174 2;~8, sh (3,97), 70,0 95,:J t I 24.2 C~'01l,~Na 7021 $jJO 2,1,5 6,3
146-,~.147 ;)If) (1,:JO)
f!:q
fI~ 8~.5--87 22-I. sh f4,02). l 9!
86--86,5 t'qO ~4,26)
[2q
lib 138,:;--140,:, 226, sh t4,t8), 692 5,:~01 24,6] C v:H~Na 702 5,30 2.1,5 1,3
~'d:; cI,251, 267,
(4,1ti), 333
(3.40)
IIc 2l;3--2t.t 240 (4,05), 350 70,2 520 I 24J] CIeH~N~ 702 5,30 245 21
(4,301
284---28~; 55,1 :;,62 t 1%6 ] r ~eH,NaO:. 35.3 3.25 D,-i 80
Vie 289---29 t 51,0 2A01 17.9 C~cHoCINaO.~ 5!.0 2,57 17,S 95
i5,1 ~l 15.1 ',
VII d 166---168 58.6 4,091 20.51 C,,Jf~CIN~ 58,4 o.."q'_ 20,4 10
XId ::12()---321 3,121 18,11 Ctt,HrNs04 ,51.5 3,[1:1 18.0 60
.Mid 182,:;-- 1S3,5 44,2 1.9ll 15.4 ] Cv.,H.,Ct~Nf): 44,,5 1,87 15s 9(1
:o, 4 tI 26.3
.\l!!a tlO--lfl 14,7 1 C+~HrCIN+,
63,1 3..',-1 t 63,0 3,70 1t.7 ]6
X!l!b f49--.-150 56A 3,8'2 t 58,4 3.92 20,4 4
kllIc i39--I00 58,5 s,ga I ~0,7 { C~eH3C!N~ 58,4 3,92 20,4 22

*The compounds were crystallized: Ib and Ve from ethanol,

and Xlllbfrom acetone (with decomposition); Ve~ Vie, and
Xld in capillaries.

EXPERIMENTAL
The UV spectra of solutions of the compounds in ethanol were recorded with a Specord
UV-vis spectrophotometer. The PMR spectra of 0.5 M solutions of the compounds i n D M S O were
recorded with a Varian A-56/60-A spectrometer (60 MHz) with the 13C--H satellite of DM$O [221
Hz from the signal of tetramethylsilane (TMS)] as the internal standard. The ~aC N~R spec-
tra were recorded with a Bruker WP-200-SY spectrometer (50.33 MHz) under pulse conditions;
the pulse width was 20 psec, the lag between pulses was i0 sec, the scanning width was i0
kHz, and the digital resolution was 0.6 Hz.
The characteristics and the results of elementary analysis of the synthesized compounds
are presented in Table 4.
3q(pFNitrophenyl)-6z0xo-l,6-dihYdropyridazine(Ve). A solution of 5.8 g (55 mmole) of
hydrazine hydrochloride in 55 ml of 1 N KOH was added to a heated (to 90~ solution of 11.2
g (50 mmole) of p-nitrobenzoylpropionic acid (IIIe) in 50 ml of 1 N KOH, and the mixture was
refluxed for 2 h. It was then cooled, and the resulting red-brown precipitate of 3-(p-nitro-
pheny!)-6-oxo-l,4,5,6-tetrahydropyridazine (IVe) was separated) washed with water~ and dried.
An additional amount of IVe was obtained from the filtrate after treatment with acetic acid
and trituration of the liberated oily product with acetic acid. The overall yield of IVe,
with mp 228-231~ was 4.7 g (45%).
A solution of 3.5 g (22 mmole) of bromine in 5 ml of acetic acid was added dropwise
with stirring at 70~ to a saturated solution of 4.4 g (20 mmole) of lYe in acetic acid) and
the mixture was heated with stirring for another hour. It was then cooled, and the precipi-
tate was separated and washed with acetic acid and ether to give 4.85 g (80%) of the hydro-
bromide of Ve. This product was recrystallized successively from acetic acid and ethanol to
give greenish-yellow crystals of Ve.
3-(p-Nitrophenyl)-6-chloropyridazine (Vie). A mixture of 5.8 g (27 mmole) of Ve, 20 ml
of POCls, and 2 ml of N,N-dimethylaniline was heated at 130~ for 7 h, after which the ex-

767
 cess POOls was removed by vacuum distillation, and the residue was decomposed with lee. The
aqueous mixture was neutralized with NaHCO,, and the precipitate was separated and washed
with water and CHCIs, For analysis, the product was crystallized successively from mono~lyme
and DMSO and sublimed ~n va~o.
3-Phen~l-6-chloro~_yridazine (VZa) and 3-(m-Nitrophenyl)~6-chloropyridazine (Vld). These
compounds were obtained by a method s ~ m i ~ to that used to prepare Vle. Their constants
corresponded to those presented in Ill, 14].
3-Phen[l~yridazine (Is). A mixture of 3.81 g (20 mmole) of Via, 1.65 g (20 mmole) of
sodium acetate, and 0.1 g of 10% palladium on carbon in 15 ml of ethanol was hydrogenated
with hydrogen at atmospheric pressure. After hydrogen absorption had ceased, the mixture
was filtered, the filtrate was evaporated, and the residue was crystallized from petroleum
ether and sublimed in vac~o.
3-(m-Aminophenyl)pyridazine (Ib). A mixture of 0.59 g (2.5 mmole) of Vld, 0.25 g (3
mmole) of sodium acetate, 0.2 g of 10~ palladium on carbon, 20 ml of ethanol, and l0 ml of
acetic acid was hydrogenated with hydrogen at 40~ Upon completion of hydrogen absorption
the mixture was filtered, the filtrate was evaporated, and the residue was treated with
Na2COs solution. The mixture was then extracted with CHCIs, and the extract was dried and
evaporated. The residue was crystallized from benzene and sublimed in vacuo.
3_C~(-Aminophenyl)pyridazine (Ic) and 3-(p-Aminophenyl)-6-chloropyridazine (VII). A mix-
ture of 1.18 g (5 mmole) of Vie, 0.5 g (6 mmole) of sodium acetate, 0.3 g of 10% palladium
on carbon, 30 ml of ethanol, and I0 ml of acetic acid was hydrogenated with hydrogen at 50~
After hydrogen absorption had ceased, the mixture was filtered, and the filtrate was evapor-
ated ~n vacuo. The residue was treated with KzCOs solution, and the mixture was extracted
with CHClso The extract was evaporated to give a mixture of products, which were separated
by thin-layer chromatography (TLC) on silica gel with the addition of a luminophore and ethyl
acetate-CHCl, (i:i) as the mobile phase. The zones were detected in UV light. The lower
zone was collected and eluted with ethanol, and the eluate was evaporated. The residue was
crystallized from benzene with activated charcoal and sublimed at 160~ (0.2 mm) to give Ic.
Compound VII was obtained from the upper zone after elution with ethanol, evaporation
of the eluate, crystallizatio n of the residue from benzene, and sublimation at 160~ (0.2 mm).
m-Nitrophenylsuccinic Anhydride (IXd). A mixture of 4.3 g (18 mmole) of m-nitrophenyl-
succinic acid (VIIId)~ 20 ml of acetyl chloride, and 2 ml of thionyl chloride was refluxed
until HCi evolution ceased, after which it was evaporated in vacuo, and the residue was
sublimed at !80~185~ (4 mm) and crystallized from benzene-CCl4 (1:3) to give 3.8 g (95%) of
IXd with m, I09-III~ Found: C 54.6; H 3.18; N 6.21%. C~oHTN05. Calculated: C 54.3;
H 3.19; N 6.33%.
m-Nitrophenylmaleic Anhydride (Xd). A mixture of 4.8 g (22 mmole) of IXd, 7.7 g (43
mmole) of N-bromosuecinimide, 0.i g of benzoyl peroxide, and i00 ml of dry CCI4 was refluxed
for 26 h with periodic removal by distillation of the bromine accumulated in the reaction
mixture. The mixture was then evaporated, and the residue was extracted several times with
boiling benzene. The extract was cooled, the suceinimide was separated, and the filtrate
was evaporated. The residue was triturated with dry acetone and squeezed dry on the filter
to give 1.8 g (38) of Xd with m, 158-159~ (from acetone). Found: C 55.1; H 2.53; N 6.37%.
C~oHsN05. Calculated: C 54.8; H 2.30; N 6.39%.
4-(m-Nitrophenyl)-3,6-dioxo-l,2,3,6-tetrahydropyridazine (XId). A solution of 1.75 g
(8 mmo!e) of Xd in 15 ml of dry monoglyme was added in small portions to a refluxing solution
of 1.26 g (12 mmole) of hydrazine hydrate in 40 ml of water, and the resulting suspension
was refluxed for 3 h. It was then cooled, and the precipitate was separated, washed with
water, and dried. For analysis, the product was crystallized from ethanol and sublimed in
vacuo.
4-(m-Nitrophenyl)-3,6-diehloropyridazine (Xlld). A mixture of 1.12 g (5 mmole) of Xld
and 5--~of POCI3 was refluxed for i h, after which the excess POCI3 was removed by vacuum
distillation, and the residue was treated with ice. The precipitate was separated, washed
with water, dried, crystallized from benzene-isooetane (i:I), and sublimed at 150-160~ (4
mm).

768
 4-Phenyl-3,6-dichloropyrldazine (XI!a) and 4-(p-Nitrophenyl)-3,6-dichloropyrldazine
(Xlle~mp0unds were obtained by a method similar to that ised~to prepare Xlid.
Their constants corresponded to the data in [12, 23].
4-Phenylpyridazlne (Ila). A mixture of 3,9 g (17 mmole) of XIIa, 2.7 g (34 mmole) of
sodium acetate, 0.5 g of 10% palladium on carbon, and 50 ml of ethanol was hydrogenated with
hydrogen at 40~ At the end of the hydrogenation, the temperature was raised to 60~ and
the mixture was filtered. The filtrate was evaporated, and the residue was extracted with
CHCIs. The extract was passed through a layer of Al2Os and evaporated to dryness, and the
residue was sublimed ~n pacuo.
4-Phenyl-3-chloropyrldazine (XIIla). A mixture of 0.3 g (1.3 mmole) of XIIa, 0.11 g
(1.3 mmole) of sodium acetate, 0.05 g of 10% palladium on carbon, and i0 ml of ethanol was
hydrogenated with hydrogen at room temperature. After an equimolar amount of hydrogen had
been absorbed, the mixture was filtered, and the filtrate was evaporated. The resulting
mixture of products (IIa, XIIIa, and traces of XIIa) was separated by TLC on silica gel with
the addition of a luminophore and CHCls-ethanol (100:1.5) as the mobile phase; the zones were
detected in UV light. The product was eluted from the middle zone with ethanol, and the
eluate was evaporated. The residue was crystallized from hexane and sublimed ~n uaeuo to
give XIIIa.
The product was eluted from the lower zone on the TLC plate with ethanol, the eluate
was evaporated, and the residue was crystallized from hexane and sublimed ~n u ~ s o to give
0.03 g (19%) of IIa with mp 86-87~
4-(m-Amlnophenyl)pyridazlne (IIb) and 4-(m-Aminophenyl)-3-chloropyridazine (XIIIb). A
mixture of 1.2 g (4.4 mmole) of Xlld, 0.75 g (9 mmole) of sodium acetate, 0.3 g of 10%
palladium on carbon, 40 ml of ethanol, and 40 ml of acetic acid was hydrogenated with hydrogen
at 40~ with periodic heating of the mixture to 60~ After hydrogen absorption had ceased,
the suspension was filtered, and the filtrate was evaporated. The residue was treated with
K2COs solution and extracted with CHCIs. The extract was evaporated, and the mixture of
products was separated on silica gel as described above with diethyl ether as the mobile
phase. The product was eluted from the lower zone with ethanol, the eluate was evaporated
to dryness, and the residue was dissolved in the minimum amount of acetone and precipitated
with ether. The precipitate was separated, crystallized from acetonitrile, and sublimed at
130-140~ (0.2 mm) to give IIb.
The product was eluted from the middle zone with ethanol, the eluate was evaporated,
and the residue was crystallized from CHCI3. For analysis, the product was sublimed at
150-160~ (0.05 mm) and crystallized from acetone to give XIIIb.
4-(p-Amlnophenyl)pyridazlne (IIc). A mixture of 1.35 g (5 mmole) of Xl!e, 0.5 g (6
mmole) of sodium acetate, 0.3 g of 10% palladium on carbon, 40 ml of ethanol, and 40 ml of
acetic acid was hydrogenated with hydrogen at 40~ with periodic heating of the mixture to
60~ The mixture was then filtered, the filtrate was evaporated, and the residue was treated
with K=COs solution. The mixture was extracted with CHCIs, the extract was evaporated, and
the residue was washed with the minimum amount of acetonltrile. It was then crystallized
from acetonitrile and sublimed at 160-170~ (4 mm).
4-(___p-Aminophenyl)-3-chlorop_yridazine (Xlllc) and 4-(p-Aminophenyl)-3,6-dichloropyridazine
(XIlc). A 0.3 g (i.i mmole) sample of Xlle was hydrogenated with hydrogen at ~ under the
conditions of the preceding experiment. After 4.5 mmole of hydrogen had been absorbed, the
mixture was filtered, and the filtrate was worked up as in the preceding experiment. The re-
sulting mixture of products was separated by TLC on silica gel with the addition of a lumino-
phore and diethyl ether as the mobile phase; the zones were detected in L~ light. Elution
of the upper zone with ethanol, evaporation of the eluate, and crystallization of the residue
from benzene gave 0.05 g (19%) of XIIc; the p-nitrobenzoyl derivative had mp 268-272~ (in a
capillary) (mp 259-264~ [23]).
Elution of the middle zone on the TLC plate with ethanol, evaporation of the eluate~ and
crystallization of the residue from acetonitrile and sublimation ~n u~cuo gave XIllc.
Workup of the lower zone on the TLC plate by the same method gave 0.03 g (16%) of l!c
with mp 208-210~

769
 LITERATURE CITED
i. A. P. Pozharekii, Khim. Geterotsikl. Soedin., No. 9, 1155 (1979).
2. A. Almenningen, G. BJoernsen, T. Ottersen, R. Selp, and T. G. Strand, Acta Chem. Scand.,
A, 31, 63 (1977).
3. R. J. Pugmire and D. M. Grant, J. Am. Chem, Soc., 90, 597 (1968).
4. T. TsuJimoto, C. Kobayaehi, T. Nomura, M. lifuru, and Y. Sasaki, Chem. Pharm. Bull., 2_.[7,
2105 (1979).
5. T. Jacobs, in: Heterocyclic Compounds, Elderfield, ed., Vol. 6, Wiley (1957).
6. Y. Nitre, R. Tomii, and F. Yoneda, Chem. Pharm. Bull., ii, 744 (1963).
7. G. Heinisch and A. Mayrhofer, Monatsh. Chem., 108, 213~w
8. G. Heinisch, E. Luszczak, and M. Pailer, Monarch. Chem., !04, 1372 (1973).
9. M. I. Terekhova, E. S. Petrov, M. A. Mikhaleva, 0. P. Shkurko, V. P. Mamaev, and A. I.
Shatenshtein, Zh. Org. Khim., 18, 9 (1982).
i0. M. I. Terekhova, ~. S. Petrov,-~. P. Shkurko, M. A. Mikhaleva, V. P. Mamaev, and A. I.
Shatenshtein, Zh. Org. Khim., 19, 465 (1983).
ii. S. Gabriel and J. Colman, Chem. Bet., 32, 395 (1899).
12. J. Levisalles, Bull. Soc. Chlm. F-~., No. 7, 1004 (1957).
13. Yu. S. Shabarov, N. I. Vaeil'ev, and R. Ya. Levina, Zh. Obshch. Khim., 31, 2482 (1961).
14. E. A. Steck, R. P. Brundage, and L. T. Fletcher, J. Heterocycl. Chem., 12, 1009 (1975).
15. V . M . S . Gil and A. J. L. Pinto, Mol. Phys., 16, 623 (1969).
16. K. Tori and M. Ogata, Chem. Pharm. Bull., 12, 272 (1964).
17. T. TsuJimoto, T. Nomura, M. lifuru, and Y. Sasaki, Chem. Pharm. Bull., 27, 1169 (1979).
18. O. P, Shkurko, S. G. Baram, and V. P. Mamaev, Khim. Geterotsikl. Soedin., No. 1, 6~
(1983).
19. S. G. Baram, O. P. Shkurko, and V. P. Memaev, Izv. Sibirsk. Otd. Akad. Nauk SSSR, Ser.
Khlm. Nauk, No. 4, 135 (1982).
20. O, P. Shkurko and V. P. Mamaev, Zh. Org. Khim., 15, 1737 (1979)
21. C. W. Halgh and R. B. Mallion, Org. Magn. Reson.~-~, 203 (1972)~
22. M. H. Palmer and R. H. Findlay, Tetrahedron Lett., No. 3, 253 (1974).
23. G. Klahre and K, Seitz, Swiss Patent No. 478212; Ref. Zh. Khim., 13N318P (1970),
24. R. S~oermer and H. Fincke, Chem. Bet., 42, 3115 (1909).

770
SYNTHESIS OF CONDENSED FYKAZINES FROM N-SUBSTITUTED
AMINO-o-QUINONES AND ETHYLENEDIAMINE

S. A. Chernyak and Yu. S. Tsizin UDC 547.567.3'863.07

The reaction of N-monosubstituted and N,N-disubstituted amino-o-quinones with ethyl-

enediamine, which leads to condensed pyrazine derivatives, was studied.

A widely known method for the synthesis of quinoxalines and other condensed heterocycles
that contain a pyrazine ring is the reaction of the corresponding o-diamines with 1,2-diketones
[i]. However, another pathway based on the reaction of o-quinones with ethylenediamines is
also possible. The development of this method may be of practical interest, since presently
many derivatives of o-quinones, particularly N-substituted amino-o-quinones, are readily
accessible [2, 3].
0 O O 0
)LF "
"r I. mj 1,,(1
! !
L) ~tN~N z )4 N PL~
]
0 1 lt,-Vl VII }'Ill

It, VI NRIR r morpholyl,llI R~ ----Ph, I\; R'=Et~NCtt~CHe, V R'=4-HO--3-Et2NCH,)C~Ha;

III--V R~=lf; I i - - V X=CIt, Vi X = N

Only individual references to the condensation of o-quinones with ethylene diamines are
available [4, 5], and this reaction has not been studied systematically. The present research
is devoted to a study of the reaction of ethylenediamine with a number of carbocyclic (I-V)
and heterocyclic (VI-VIII) amino-o-quinones. The condensation of the accessible products of
oxidative amination, viz., dialkylamino-o-quinones I, II, and V-VIII [2, 6], was initially
studied. It was established that ethylenediamine reacts readily with these compounds at room
temperature. In all cases the principal reaction products are aromatic condensed heterocy-
cles. 6,7-Di-morpholino- (IX), 6-morpholinobenzo[f]- (X), 6-morpholino-pyrido[2,3-f]- (XI),
6,8-dipiperidinopyrido[3,4-f]- (XII), and 6-piperidino-7-phenyl-8-methyl-9-ethoxycarbonyl-
pyrrolo[2,3-f]quinoxaiine (XIII) were obtained in this way. The formation of coproducts was
also detected in the reaction of o-quinones with ethylenediamine. Most of them were excep-
tionally labile, but in the case of quinone I we were able to isolate, in addition to quin-
oxaline IX, XIV, which was additionally characterized in the form of diacetyl derivative XV.
The formation of XIV makes it possible to propose that this tetrahydroquinoxaline is
formed jointly with IX as a result of disproportionation of the primary product of condensa-
tion of quinone I with ethylenediamine (XVI). The less stable tetrahydroderivatives are evi-
dently oxidized again by air oxidation or by the startie~ quinone, as a result of which a
single product is formed

0 N
. Q l~ j
/ \ -. ..... I.. N1 I
O N N X N
\.... / ~ltlR2

IX X.XLXVIIs

E. I. Martsinovskii Institute of Parasitology and Tropical Medicine, Ministry of Public

Health of the USSR, Moscow 119830. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 7, pp. 959-962, July, 1986. Original article submitted February 9, 1985; revision sub-
mitted August I, 1985.

0009-3122/86/2207-0771512.50 9 1987 Plenum Publishing Corporation 771

 X, Xl NRtR2=, pipettdyl, xvII=XIX RI.H, XVII R ~ P h , XVIII R~Bt=NCH~CH~,
XIX R=~4-HO=3-EtsNCHiCH~; X, XViI=XIX X,-CH, XI X~N; XIV R~-H, XV R~Ae

I t i s n o t e w o r t h y that s u b s t i t u t i o n of the dialkylemino group is not observed during the

reaction, although this reaction proceeds very readily when monofunctional primary amines are
used [7]. This fact indicates that the rate of formation of the XVI type significantly ex-
ceeds the rate of transamlnatlon

\ =I o
0 N N o= L!

oF , II
NR
XX

It was subsequently established that N-monosubstituted amino-o-quinones (ZII-V) also

undergo condensation with ethylenediamine; the formation of benzo[2,3-f]quinoxalines (XVII-
XlX) proceeds under more severe conditions than the formation of IX-XIII. The reaction takes 1
place only at elevated temperatures, and the yields of products are appreciably lower. In
our opinion, this difference is explained by the ability of monosubstituted amino-o-quinones
to undergo deprotonation in basic media [8]. The formation of the XX anion is also a factor
that hinders the course of the condensation. The development of a deep coloration at the
start of the reaction, which gradually vanishes during the reaction, also constitutes evi-
dence in favor of this opinion.
Thus we have shown that the condensation of o-quinones with ethylenediamine can be used
in the synthesis of condensed heterocycles that contain apyrazine fragment. It is important
that qulnoxalines that contain substituents that are characteristic for a number of medicinal
preparations (for example, XVIII and XIX) can be obtained by this method.

EXPERIMENTAL
The IR spectra of KBr pellets of the compounds were recorded with a UR-20 spectrometer.
The PMR spectra of solutions in CDCls were recorded with a Tesla BS-467 spectrometer (60 MHz)
with tetramethylsilane (TMS) as the internal standard. The mass spectra were obtained with
a Varian MAT-I12 spectrometer (70 eV). The course of the reactions and the individually of
the compounds obtained weremonltored by thin-layer chromatography (TLC) on Silufol plates in
TABLE I. Characteristics of the Compounds Obtained

3om- mp,* %; Found,% Calc., % Yield.%

.. Empirical (isolation
~oundJ formula
c H N c H N method)

IX 210--211 64,0 6,6 18,5 C j6H,2oN402 64,0 6,7 18,7 42

X 171--173 72,6 6,0. 15,4 C16HtsN30 72,4 5,7 15,8 97 (A)
Xl 150~152 67,5 5,6 20,6 CIsHI4N40 67,7 5,3 21,0 68 (A)
XII 184--185 72,7 7,0 20,4 C21H25Ns 72,6 7,3 20,2 75 ~A)
XIII 150--151 72,4 6,0 13,2 C2sH=6N402 72,4 6,3 13,5 64 (B)
XIV 223--224 63,2 8,1 C 16H2aN402 63,1 8,0 -- 35
XV 194--196 61,6 7,0 1~,0 C~oH2~N404 61,8 7,3 14,4 78
XVII 163--165 80,0 5,1 15,7 CI~H~3N3~" 79,7 4,8 15,5 37
XNIII 2t0--211 55,0 6,1 14,6 CIsH24N404S 55, l 6,2 14,3 35
XIX 181--182 59,0 5,4 12,3 C=3H24N40~S 58,7 5,6 12,0 30

*The compounds were recrystallized: IX, XII, and XVIII from

ethyl acetate, X, XI, XIV, and XVII from ethanol, XIII from
benzene, XV from benzene-hexane, and XIX from ethanol--ether.
fir spectrum: 3300 cm -z (broad, NH).

772
a chloroform-methanol system (i0:i). Preparative TLC was carried out on plates with a loose
layer of L 40/100 silica gel in a chloroform-methanol system (i0:i).
Quinones i, II, and VI-VIII were synthesized by oxidative amination [6]. Compounds III
and IV were obtained by catalytic transamination of quinone II [9].
The characteristics of the synthesized compounds are presented in Table i.
4-(4-Hydroxy-3-diethylaminomethylphenyl)amino-l,2-naphthoquinone (V). This compound was
synthesized in 72% yield from II and 4-hydroxy-3-diethylaminomethylaniline by the method in
[9]. The dark-violet crystals had mp 209-210~ (chloroform-hexane). C 72.3; H 6.1; N 7.9%.
C21H=2N203. Calculated: C 72.0; H 6.3; N 8.0%.
Compound IX and 6~7-Dimorpholino-l,2,3,4-tetrahydroquinoxaline (XIV). A 0.6-ml (6
mmole) sample of ethylenediamine was added to a stirred suspension of 0.55 g (2 mmole) of
quinone I in 6 ml of methanol, after which the mixture was stirred for 2 h. Water was then
added, and the resulting precipitate was removed by filtration and crystallized twice from
alcohol to give quinoxaline IX. PMR spectrum, ~: 2.82 (m, 8H, ~-CH2), 3.42 (m, 8H, B-CH2),
6.88 (s, 2H, 5-H, 8-H), and 8,08 ppm (s, 2-H, 3-H). The mother liquors were combined, the
solvent was removed by distillation, and the residue was crystallized three times from ethyl
acetate to give XIVo IR spectrum, cm-1: 3360, 3330 (NH). Mass spectrum, m/z: M + 304.
1,4-Diacetyl-6,7-dimorph01ino-l,2,3,4-tetrahydro-quinoxaline (XV)._A 0.63-mi sample
of triethylamine was added to a solution of 0.45 g (1.5 mmole) of XIV in 5 ml of chloroform,
0.32 ml (4.5 mmole) of acetyl chloride was added dropwise, and the mixture was stirred for
i h. The resulting solution was washed successively with water, 5% hydrochloric acid, and
water and dried with MgSO4. The solvents were removed by distillation, and the residue was
chromatographed to give XV. IR spectrum, cm-~: 1663 (CO). PMR spectrum, ~: 2.23 (s, 6H,
CH3CO), 3.12 (m, 8H, ~CH2), 3.81 (m, 12H, ~-CH2, 2-H, 3-H), and 6.71 ppm (m, 2H, 5-H , 8-H).
Reaction of Dialkylamino-o-quinones II, III, VII, and VIII with Ethylenediamine. The
reaction was carried out by the method described above for quinone I. The reaction products
were isolated by one of the methods presented below.
A) Water was added to the reaction mixture, and the resulting precipitate was removed
by filtration washed with water, dried, and crystallized. PMR spectrum of XII, ~: 1.14 (m,
12H, B,y-CH=), 2.56 (m, 4H, ~-CH2), 3.16 (m, 4H, ~-CH=), 6.44[s, III, 7(5)-H], 6.64 Is, IH,
5(%)-H], 7.96 (m, 2H, 2-H, 3-H), and 9.54 ppm (s, IH, IO-H).
B) The reaction mixture was dissolved in chloroform, and the solution was washed with
5% HCI and water and dried with MgS04. The solvent was removed by distillation, and the
residue was chromatographed on plates with silica gel to isolate the product. IR spectrum
of XIII: 1725 cm -I (CO). Mass spectrum, m/z: M + 414.
Reaction of Quinones lll-V with Ethylenediamine. A mixture of 2 mmole of quinone ili
(or IV or V) and 6 mmole of ethylenediamine was refluxed in 6 ml of methanol for 3 ho For
the isolation of IX, 15 ml of water was added to the reaction mixture, and the resulting pre-
cipitate was removed by filtration, washed with water, and dried. In the case of XVIII and
XIX the mixture was dissolved in chloroform, and the chloroform solution was washed with
water and dried. The solvent was removed by distillation, and XV!II and XIX were isolated
from the residue in the form of the sulfates.

LITEP~TURE CITED
i. V. N; Ivanskii, The Chemistry of Heterocyclic Compounds [in Russian], Vysshaya Shkola,
Moscow (1978), p. 345.
2. Yu. S. Tsizin, Khim. Geterotsikl. Soedin., No. 9, 1155 (1978) o
3. W. Brackmann and E. Havinga, Recl. Tray. Chim., 74, 937 (i955).
4. L . C . March and M. M. Joullie, J. Heterocycl. Chem., 7, 39 (1970).
5. H.-J. Kallmayer and H. Seyfang, Arch. Pharm., 316, 283 (1983).
6. Yu. S. Tsizin, Doctoral Dissertation, D. I. Mendeleev Moscow Institute of Chemical
Technology, Moscow (1977).
7. F . J . Bullock, J. F. Tweedie, D. D. McRitchie, and M. A. Tucker, J. Med. Chem., 13, No.
i , 97 (1970).

773
 8. L.F. Fics~r and M. Fieser, Advanced Organic Chemistry, Reinhold Publishing Corporation,
N e w Y o r k (1961).
9. Yu. S. Tsizin and S. A. Chernyak, USSR Inventor's Certificate No. 857112; Byull. Izobr.,
No. 31, lll (1981).

CHEMICAL PROPERTIES OF YLIDENE DERIVATIVES OF AZ!NES.

3*. SYNTHESIS AND REACTIONS OF YLIDENE DERIVATIVES
OF HALOPYRIMIDINES

O. A. Zagulyaeva, I. V. Semushkina, UDC 547.853:541.623:542.953.5

and V. P. Mamaev

Some dihydropyrimidines have been obtained which contain a cyanoacetic ester or mal-
ononitrile residue and chlorine in positions, 2, 4, and 6. The reactions of these
compounds with nucleophiles has been examined.

Continuing an investigation of methods of synthesis and chemical reactions of substi-

tuted ylidene derivatives of pyrimidine, we have examined the reaction of the dichloropyr-
imidines (la-c) with the sodium salts of cyanoacetic ester and malononitrile in aprotic
bipolar solvents, and some further reactions of the products. Replacement of one chlorine
atom by a cyanoacetic ester residue occurs with (la-c) to give the sodium salts of esters
(lla-c). The solvents used for the stable 4-chloro-derivative (lla) may be DMSO or other
aprotic bipolar solvents, but in the ease of unstable pyrimidines such as (lib), dimethoxy
ethanes with the addition of DMF was employed. We have described the synthesis of the 4-
chloro-compound (lla) previously [2], but the spectral properties and some further reactions
of this compound are described here.

c~ " ~c, b ~ o H,
9 /~N I. NaCH{CN)C00C^Hs , ~ N "'{I 6/~" N/H'"O
11 | ..........."~ II [ + -' "lJ"oc~H~
l~~ ./q..N/~..~R~ 2, Nu R ~ ./<.,.N/~..R 2 CI CN
la-C lla-j Ill
i, II a RI=CI, b RI=H, cRI=C6Hs; a R2=H, b, c ~=CI; II d RI=N(CHs)2, e RI=
=NCsHlo, f RI=NHNH2, g R!=H,h--] RI=C6H6;d--fR~=H, g, i R~=NCsHm, h R2=
=N(CH3)s, j R~=NHNH2; Nu=NH(CH~)~, NHCsHIo, NH2NH~

We have failed to observe replacement of a second chlorine atom by the cyanoacetic ester
residue in pyrimidines (la-c), even in the presence of a large excess of sodiocyanoacetic
ester, apparently as a result of the considerable deactivation of the chlorine in the sodium
salts of (lla-c). For example, we were unable to replace the chlorine atom in (lla-c) by an
alkoxy group on treatment with sodium alkoxides, this treatment also resulting, according to
the UV spectra, in ionization. If, however, no ionization takes place, such as in the N-meth-
ylation product of (lla) (IV), obtained as described in [i], the pyrimidine (IV) reacts with
sodium ethoxide under mild conditions to give the ethoxy-compound (Va).

*For communication 2, see [I].

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7,
pp. 963-969, July, 1986. Original article submitted March 22, 1985.

774 0009-3122/86/2207-0774512.50 9 1987 Plenum Publishing Corporation

 . N C ~ C I C00C2Hs N C ~ C/C00C2Hs

I I
CH~ CH~
IV Va-C

V a R=OC2Hs; b R=N(CHs)2; C R=NCsHlo; Nu=C~HsONa, NH(CH3)2, NHCsHIo

Replacement of one of the chlorines in 2,4-dlchloropyrlmidine (Ib) and its 6-phenyl

derivative (Ic) can give two isomeric products by the replacement of the chlorine in the 2-
or 4-position. We have determined the proportions of these isomers in the reaction of 2,4-
dichloropyrimidine (Ib) with sodlocyanoacetic ester in dlmethoxyethane. According to TLC,
the reaction mixture following neutralization contains the two isomeric products (lib) and
(III), which were separated on a silica gel column in the pure state.
The IR, UV, and PMR spectra of (lla-c) and (III) (Tables 2 and 3) show that in the solid
state and in solution in solvents of low polarity these compounds exist in the ylidene tauto-
meric form with an intramolecular hydrogen bond, as shown by the presence in the IR spectrum
of absorption for the carbonyl group chelated by an intramolecular hydrogen bond at < 1700
cm-I and very strong 9CEN absorption at 2200-2210 cm -I, in the UV spectra of a long-wave-
length absorption maximum with ~ > 320 nm, and in the PMR spectrum of signals for the NH...O
protons at ~ 13 ppm.
The greatest difference between the isomeric compounds (lib) and (III) is seen in the
PMR spectra in the region of signals for the heteromatic protons. In the case of (lib), the
signals for 5- and 6-H are seen as two doublets at 6.98 and 7.82 ppm. The structure of pure
(III) confirms that in CDCI3 it has the tautomerlc structure (IliA), the possible ylidene
tautomer (IIIB) being virtually absent, since the signal for 5-H is seen as a doublet at
6.53 ppm, and that for 6-H is further split by the adjacent NH group with a J6-hq4 value simi-
lar to that of Js-6, appearing as a triplet at 7.72 ppm (cf. [3]). The ratio of isomers
(llb)/(lll), as found by PMR, is ~7:1.
Cl

CN CN
mA ,~

Hence, the preferred product in the reaction of 2,4-dichloropyrimidine with sodiocyano-

acetic ester, as in the reaction with amines in polar solvents [4], is the product of replace-
ment of the 4-chlorine atom. It is known [5] that the introduction of weak donor substi-
tuents into the 6-position does not affect the selectivity of substitution of the chlorine
atoms in 2,4-dichloro-pyrimidines in polar solvents. Therefore, by analogy with the results
obtained in the reaction of (Ib) with sodiocyanoacetic ester, we assign the structure (l!c)
to the monosubstitution product of 6-phenyl-2,4-dichloropyrimidine (Ic). The instability of
ylidene derivatives of 2-chloropyrimidines is noteworthy, especially that of (llb). Its
preparation required milder reaction conditions (see Experimental), and on standing in air
for a few days it was almost completely converted into a chlorine-free compound.
In the reaction of the chloro-compounds (lla-c) with amines and hydrazine, it would be
expected, firstly, that nucleophilic replacement of halogens as in vinyl substitution in
halo-derivatives of ylidenemalononitriles [6] would occur, and secondly, reaction of the nucleo-
philes with the ester group side chain and the exocyclic C = C bond. In fact, in the chloro-
derivatives (lla-c) chlorine was replaced quantitatively by dimethylamino-, piperidino-, or
hydrazino-groups on heating in ethanol or DMF with the appropriate nucleophile. Comparing
the reaction conditions and the time required for 50% reaction of these compounds with other
substituted chloropyrimidines [7], it will be seen that they are similar to the nucleophilic
substitution conditions for chloropyrimidines containing weakly-donating alkyl substltuents.
The ester groups in (lla-c) do not react with amines or hydrazine as a result of deactivation
due to conjugation of the carbonyl group in COOC2Hs with the hTH group in the 8-aminocarbonyl
system (cf. [8]). The influence of the intramolecular CO...NH hydrogen bonding appears to

775
 TABLg, Proper=les of ~yri~i~ines (ll-X)

lib I46.-150 47,6 3,85 18,4 16,: C~H~CIN~O~ 18,6 15,7

Hc I60---~t63 59,9 4,12 13,9 1,1,,8 C~Ht~CIN~O~ ~ _ 13,9 1 t,7
lid 149~153 54,5 6,27 23,2 C,,II~N~Ov 0,5 ~ 0 23,0
IIe 149~15l 61,4 6,59 20,5 , C~H~N~O~ 20,4
IIf 230--233 48,8 5,04 3~,0 C~H,~N~O~ 31,7:
lI g 149--15t 61,2 6,69 20,6 C~H~sN~O~ ~0,4
216--22l 65,4 5,98 18,3 , C~H~sN~O~ 18,0
~2.5--230
decog~ .
69,0 6,38 16,4 C~H~N~O~ 16~0 i

lit 255(deco P.) 61,0 2~9~ 23,4i C,sH,sNsOs 23,61

lit t,85--192 47,8 ,8,8] 16.1 CgH~CIN~O~ :8,6i I5,7
tV 260--262 49,7 4,20 17,5] 14,7 C~oH1aCIN30~ 17,5 ]
Va 1931--194 57,9 620 ~7,oi CmH:sN~O~ t6,8
vb 203~203 58,0 6,85 23,01 22,6
Vc 205--207 63,0 7,18 19,3i C:sH~N~O~ 19,4
Vt 230--235 61,5 2,74 21,61 f4,t I C~HzCIN~ 22,0 Ii9
VII 238--244 55,4 5,04 39,51 39G
VIII 240--249 71,I 5,67 ~3,01 C~sH~rN~ 23,1
IXa 218--220 37,6 2,45 ]6,31 C~H~BrN~O~ 16,4 (3t,2)
Xa 205--208 46,0 5,04 :6,21 C~H~BrN~O~ 16,4 (22,5)
Xb t85--189 47,8 5,41 15,6 ! C~H:~BrN~O~ l&8 (22,4)

TABLE 2, UV Spectra of (II-X)

kma x, nm (Igs) in Compound kma x, nm fig ~) in

Compound ethanol
ethanol

lla 3i0 (4,30), 350 pl, (3,92) III 306 (4,46),380 (3,38)
II aNa salt 325 (4,15) IV 354 (4A9)
lib 340 (4,25) Va 348 (4,~)
llC 234 , (~,o8), 300 (4,~?), Vb 27~ (3,83),366 (4,58)
3,76 (4,18) Vc 276 (3,86), 368 (4,66)
l l c Na salt 23~ (4,27), 263 (4,1t), 310 VI 260 (4,24), 315 (4,37), 367
(4,17), 364 (4,08) (4,09)
Ild 253 (424), 275 (4,20), 333 VII 52 (4,36), 350 (4,22)
(4,68) VIII 247 (4,43), 288 (4,23), 387
lle 256 (4,23), 278 (4j9), 336 (4,3s)
(4,6]) iXa 807 (4,6~) 398 (3,46)
lit" 253 (4,tl), 328 (4,59) IXb 303 (4 78), 390 (3,60)
276 (4,04), 367 (4,39) Xa 233 {4:19), 314 (4,60)
280 (4,48), 395 (4,35) xb 233 (4,12), 315 (4,54)
I1~ 281 (4,20), 397 (4,30) Xc 235 (4,08), 314 (4,46)
Itj 282 (4,54), 394 (4,45)

be small, since the N-methyl derivative (IV) displays similar properties, affording products
of the replacement of chlorine (%rb, c) without reaction of the ester group in the side chain.
Under our reaction conditions, in the case of (IIa-c) TLC failed to reveal the presence
of other products such as those of reaction of the nucleophiles at the external C==Cbond, the
reactivity of which is less than that of other ylidenemalonotriles [9].
The elemental composition and structures of the pyrimidines (Ild.j) and (Va-c) were con-
firmed by analysis and their spectral properties (Tables 1-3). According to the LW~ IR, and
PMR spectra, (IId-j) exist in the ylidene tautomeric form with intramolecular hydrogen bonding~
as in the original chloro-compounds (IIa-c).
Reaction of the dichioropyrlmldine (Ic) with sodiomalonitrile also affords the product
of substitution of a single chlorine atom, this probably possessing, by analogy with (lib,
c) the ylidene structure (VIA++VIB). The spectral data obtained for this compound do not
enable a further chloice to be made between these two tautomeric forms.

~NH

.... ....

rill viA vIB "~II

776
TABLE 3. PMR Spectra of (II-X)
Com- Solvent Chemical shifts, 6 , ,pro (I, Hz)
pound I' 2-H [4-H or 6-H] 5-H and Ar
C~2CH3", crt'tc n'*' Other protons

l.Ia CDCIo 8,12, br. s 7,13, S 4,2~ 1,32 13,8 (br.. s, NH)
llb CDCIa 17,82, d] (6,0) 6,98, d (6,0) 4,3~ 1,35 13,9 ( b}. s, NH)
Ile CDCI3 7,28, s ; 7,38--7,60; 4,2~ 1,28 13,7 ( bro s, NH)
7,88--8,06, m
lid CDCla 7,97, d (4,0) 5,84, s 4,t~ 1,22 3,101% N(CH3)2]; 10,5 (NH)
IIe CDCI3 7,95, d 5,96,s 4,1~ 1,,25 1,65 and 3,60 (m, NCsHto); 13,80 (br.. s, NH)
(4,0)
llf CDCIa-- 8,22, s 6,25, s 4,18 1,28 8,98 and 4,56 (s, NHNH2); 12,90 (br . s, NH)
DMSO-D 6
llg CDCI3 [7,85, d] 6,30, d 4~25 1,33 1,70and 3,68 (m, NCsHto); 1.3,63 (br .s, NH)
(6,0) (6,0)
Ilh CDCIz 6,75, d; 7,30--7,5~; 4,20 1,30 3,23 [s, N(CH3)2]; 10,25 (br. s, NH)
(1,3) 7,92--8,08, m
IIi CDCI~ 6,75, s ; 7,30--8,I0,m 4,20 1,30 1,68 and 3,70 (m,NCsHlo); 13,50 (br.. s, NH)
gJ DMSO-D 6 6,55, s ; 7,30--8.15, m 4,15 L20 3,35 and 9,65 (s, NH2NH~)
II1 CDCI3 [7,~, t] 6,53, d 4,25 1,30 13,10 (hr.. s, NH)
(6,5; 6,5) (6,5)
IV CDCI3 8,15, s 8,05, s 4~25 1,32 3,70 (s, N--CHz)
DMSO-D 6 8,50, s 8,00, s 4,10 1,,20 3,70 (s ~q--CH~)
Va CDCIa 8,52, s 7,45, s 4,15 1,30 1,48 t a n d ' 4 , 2 8 q (OC.,Hs*); 3,62 (s, N--CH~)
vb CDCIz 8,28, s 7,52, s 4,15 1,28 2,85 [s, N(CHD~]i'3;65 (s, N--CI-Ia)
ve CDCIs-- 8,22, s 7,55, s 4.1'8 1,30 1,65 and 3,02 ( ~ NCsHIo); 3,58 (s, N--CH~)
DMSO-D 6
VI CDCIa 6,78, s ; 7,35--7,90,m
q
VII DMSO-D 6 7,19,s ; 7,37--7,41; 5,44 (br.. s, NH2 aad NH); 7,51 (t, NHNH2)
8,07z-8,12,m
V~II. DMSO-D 6 6,29, s ; 7,32--7,62, m --! 1,63 and 3,67 (m,NCsHto); 10,87 (br..s, NH)
IxaT CDCIs [7,88, d ; 8,64, d ] 3,82 (s, OCH3); 13,83 (br. s, Nil)
(3,0) (3,o) +
Xa DMSO-D 6 [8,27, s ] 3,44 (s, OCH3); 1,59and 3,02 (br. to. H2NC~HIo); 3,96
+
(hr.. m, H2NCsHIo) +
xb DMSO=D 6 [8,25, s] 3,92 1,15 6,50--7,50 (br.. rn, H2NC~Hto); 1,59aid 3,02 (br,. m ,
+
H2NCsHlo)
Xc DMSO-D 6 [8,34, s ] 1,01 t~21

*J values z 7.0-7.5 Hz.

%For PMR spectrum of (IXb), see [3],
 Reaction of (Vl) with hydrazlne also takes place a= the tautomeric side chain, as de-
scribed for pyrldines and pyrldazlnes [10, ii]. The product obtained (VII) contalns a hy-
dramino-group and a dlamlnopyrazole subs~ituent. The spectral properties of this compound
are in good agreement with those reported previously [ii, 12]. In the reaction of (VI) with
piperldlne, only one chlorine atom is replaced to give the plperldlno-compound (VIII).
In the reaction of 5-bromo derivatives of dlhydro-2-pyrimldinylidenecyanoacetlc esters
(IXa, b) with amines such as dimethylamlne and plperidlne in nonpolar solvents at room tem-
perature, salts are obtained. The piperldinlum salts (Xa, b) are stable to recrystalllzation
from anhydrous ethanol and DMF. The structure of (Xa, b) are confirmed by comparing their
IR, UV, and PMR spectra with those of the salt obtained from (IXb) by treatment with alcoholic
sodium hydroxide (Tables 2, 3). On heating (IXa, b) with piperidine in DMF, resinification
occurs,

11 NH__CsH,O ,--

I t
CN CN M+
z~a,b X,a-C

IX, X a R=CH~, b R=C2Hb; M+=H2NCbHIo; Xe R=C2H~;M+=Na +

EXPERIMENTAL
IR spectra were obtained on a UR-20 spectrophotometer in KBr disks; UV spectra on a
Specord UV-VIS (sample concentration 10 -~ mole/liter) in ethanol; and PMR spectra on a Varian
A-56/60 instrument for 7-10% solutions, and a Bruker HX-90 (sample concentration 3-7%) in the
impulse mode followed by Fourier transformation.
The course of the reactions and the purities of the products were followed by TLC on
Silufol UV-254 plates in the solvent system chloroform-ethanol, I0:I, visualized in UV. The
properties of the compounds obtained are given in Tables 1-3.
2,4-Dichloropyrimidine (Ib) was obtained as described in [3], 6-phenyl-2,4-dichloropy-
rimidine (Ic) as described in [14], 4-chloro-l,6-dlhydro-6-pyrimidlnylidenecyanoacetlc ester
(lla) as described in [2], and 5-bromo-l,2-dihydro-2-pyrimidinylideneoyanoacetic ester (IXb)
as described in [3].
Reaction of 2,4-Dichlo~opyrimidine (Ib) with Sodiocyanoacetic Ester. To a suspension
of 3.3 g ~ mm6ie~ ~ a 50% dispersion ofN a H on oii i n 3 O m i of dimeth0xyethane and 2 ml
of D~F was added gradually, dropwlse, 7.5 ml (70 mmole) of ethyl cyanoacetate followed after
0,5 h by 3.7 g (25 mmole) of (Ib). The mixture was stirred until (Ib) was no longer present
(TLC, % 16-18 h) at room temperature. After removal of the dimethoxyethane under reduced pres-
sure on a rotary evaporator, the oily residue was treated with 5 ml of acetic acid and 3-5
drops of conc. hydrochloric acid, to give a thick yellow suspension. This was filtered, and
the solid washed on the filter with 50 ml of water and 2 ml of ethanol to give 3.8 g (68%)
of product, mp 140-145@C. TLC showed the presence of two spots, one with Rf 0.3 (bright
yellow), and the other with Rf 0.7 (graylsh-violet). After separation on a column (30 x 500
mm) of silica gel L 100/160 (Chemapol), elutlon with a mixture of chloroform and ethanol
(10:l), and recrystallization from ethanol there were obtained 2.5 g (45%) of greenish-white
lib) and 0.63 g (11%) of bright yellow (III).
2-Chloro-4-phenyl-l,6-dlhydro-6-pyrimldinylldenecyanoacetic ester (IIc) was obtained
similarly to (lib), from (!c) and sodiocyanoacetic ester in DMF, yield 70%.
4-Chloro-l-methy!-l,6-dihydro-6-pyrimidinylidenecyanoacetic ester (IV) was obtained by
methylating the sodium salt (IIa) with dimethyl sulfate in DMF, as described in [i] for
N-methylation, yield 85%.
Reaction of (IIa-c) and (IV) with Amines and Hydrazine Hydrate. A mixture of 5 mmole
of the ch!oropyrlmidine (IIa-c) or (IV) in 3-5 ml of DMF with i0 mmole of the amine or hy-
drazine hydrate was warmed to 50-80~ until the starting material was no longer present (TLC)
(~ 2-51h). The DMF was then removed under reduced pressure on a rotary evaporator, the re-
sidue treated with i0 ml of water, and the resulting solid filtered off, washed with 2 30 ml
of water until neutral, dried, and recrystallized from ethanol (yield 60-80%).

778
 Reaction of (lla-c) and (IV) with Sodium Ethoxide. To a solution of sodium ethoxide in
ethanol [from 0.2 g (9 mmole) of sodium in 8 ml of ethanol] was added 5 mmole of (lla-c) or
(IV) at room temperature, and the mixture stirred for 24 h. After removal of the ethanol,
the solid residue was treated with 5 ml of water and neutralized with aqueous HCI (i:i) to
pH 7, and the solid filtered off. Compounds (lla-c) were recovered unchanged, but (IV) gave
80% of the pyrimidine (Va).
2-Chloro-4-phenyl-l,6-dihydro-6-pyrimidinylidenemalononitrile (V!) was obtained as for
(lib), from (Ic) and sodiomalononitrile in DMF, yield 87%.
6-(3',5'-Diamino-4'-pyrazolyl)-2-hydrazino-4-phenylpyrimidine (VII). A mixture of 6 g
(24 mmole) of (Vl), 8 g (200 mmole) of hydrazine hydrate, and 90 ml of ethanol was heated
at 90=C for 18 h. After removal of the ethanol, the solid residue was treated with !0 ml of
water, and the solid filtered off, washed with 3 x 20 ml of water, and dried to give 3 g
(44%) of (VII).
2-Piperidino-4-phenyl-l,6-dihydro-6-pyrimidinylidenemalononitrile (VIII). A mixture of
2.9 g (i0 mmole) of (VI) and 1.7 g (20 m mole) of piperidine in 50 ml of ethanol was heated
at 90~ until the starting material (VI) was no longer present (~ 8h). The product (VIII)
was isolated as described for (VII), yield 2.9 g (86%).
The methyl ester (IXa) was obtained as for (IXb), from 5-bromo-2-chloro-pyrimidine and
methyl cyanoacetate, yield 80%.
PiPeridinium Salt of 5-Bromo-l,2-dihydro,2-pyrimidinylidenecyanoacetic Ester (X5). Pi-
peridine (I ml, i0 mmole) was added to 0.27 g (i mmole) of (IXb), and the mixture stirred for
i0 min at room temperature. It was then diluted with 20 ml of dry light petroleum, and the
solid which separated was filtered off, washed with 20 ml of dry light petroleum, and dried
to give 0.31 g (86%) of (Xb). When (IXb) was reacted with an equimolar amount of piperidine
in chloroform or dimethoxyethane, the Yield of (Xb) was 70%. When (IXb) was heated in di-
methoxyethane or DMF, it resinified.
The Piperidinium salt of (Xa) was obtained as for (Xb), from the ester (IXa) and piperi-
dine, yield 90%.
Sodium Salt of Ethyl 5-Bromo-l,2-dihydro-2-p~rimidinyl_idenecyanoacetate (Xc) ~.....
To a solu-
tion of 0.27 g (i mmole) of (IXb) in i0 ml of ethanol was added a solution of 0.04 g (I mmoie)
of NaOH in i0 ml of ethanol. The mixture was cooled, and the solid which separated was fil-
tered off an recrystallized from ethanol to give 0.25 g (80%) of (Xc).

LITERATURE CITED
i. O. A. Zagulyaeva, O. A. Grigorkina, V. I. Mamatyuk, and V. P. Mamaev, Khim. Geterotsikl|
Soedin~ No. ii, 1537 (1984).
2. O. A. Zagulyaeva, O. A. Grigorkina, V. I. Mamatyuk, and V. P. Mamaev, Khim. Geterotsiklo
Soedin., No. 3, 397 (1982).
3. V. V. Lapachev, O. A. Zagulyaeva, O. P. Petrenko, S. F. Bychkov, and V. P. Mamaev, Khim.
Geterotsikl. Soedin., No. 6, 827 (1984).
4. O. A. Zagulyaeva, N. V. Bukhatkina, and V. P. Mamaev, Zh. Org. Khim., 14, 409 (1978).
5. Vachanon Sukpracha and Vitayasat, Science (Thailand); i_~i, No. i0, 22 (1957); Ref. Zh~
Khim., No. 14, 49542 (1959).
6. Z. Rappoport and R. Ta-Shma, J. Chem. Soc., B, No. 5, 871 (1971) o
7. V. P. Mamaev, O. A. Zagulyaeva, S. M. Shein, A. I. Svets, and V. P. Krivopa!ov, Reakts.
Sposobn. Org. Soedin., 5, 824 (1968).
8. B. S. Chekavichus, A. ~. Sausin', and G. Ya. Dubur, Khim. Geterotsikl. Soedin., No~ 8,
1072 (1982).
9. S. Patai and Z. Rappoport, J. Chem. Soc., No. 2, 383 (1962).
i0. J. A. Daboun, S. E. Abdou, and M. M. Khader, Arch. Pharm., No. 6, 564 (1983).
ii. M. Drobnic-Kosorok, K. Jerneje-Pfundner, J. Peternel, B. Stanovnik, and M. Tisler, Jo
Heterocycl. Chem., 1__3, 1279 (1976).
12. G. Zvilichovsky and M. David, J. Chem. Soc., Perkin Trans I, No. i, Ii (1983).
13. G . M . Kosolapoff and C. H. Roy, J. Org. Chem., 26, 1895 (1961).
14. T. Matsukawa and B. Ohta, J. Pharm. Soc. Jpn., 70, 134 (1950); Chem. Abstr., 4_~4, 5886
(1950).

779
FREE RADICALS IN THE PERIMIDINE SERIES.
2-TERT-BUTYLPERIMIDYL RADICALS

V. Kh. Sabanov, E. S. Klimov, I. V. Bogdanova UDC 547.856.7

E. P. Trub, N. T. Berberova, and O. Yu. Okhloblstin 541.138
543.422.27

Electrochemical and EPR methods have been applied to a study of perlmidyl free
radicals containing a bulky tert-butyl substituent in the 2-position. A stepwise
mechanism is proposed for the dehydrogenation of 1,3-dimethy!-2-tert-butyl-2,3-
dihydroperimidine; the mechanism involves formation of a cation-radical from the
substrate in the first step. Shielding of the nitrogen atoms seems to be an im-
portant factor in increasing the stability of free perimidyl radicals.

The anion-radlcal of l-methylperimldine is a known derivative in the perimidine series

[!]. Several perimidlnes have been studied in the crystalline state By EPR and have given
EPR signals of ~ 7 0 e width [2].
Reduction of heteroaromatic cations which are not sterically hindered generally leads to
rapid dimerization of the intermediate free radicals which are formed (cf, [3]). For this
reason, it was of interest to us to study perimidines containing tert-butyl groups, which
block the potential reactive site, in the 2-position.
2-tert-Butylperimidlne (~) was prepared from 1,8-dlaminonaphthalene and trimethylacetyl
chloride in 74% yield; 1,8-di(pivaloylamino)naphthalene was obtained as a side product in 14%
yield:

Reaction of tert-butylmagnesium chloride with 1,3-dimethylperimidinium iodide gave 1,3-

dimethyl-2-tert-butyl-2,3-dihydroperlmidine (II), which was further reacted to give 1,3-di-
methyl-2-tert-butylperimidinlum iodide (III):

. . . . . ~, CH 3 ~H _ .... CH 3

:.----=-.( ~ !) + (cH.)J.:.~gC:L .... -,-- '\.=~.\. ;~ ".~,- .....

. ~...

~' 9

Assuming that dehydrogenation of the 2H-perimidine II can not take place via a synchro-
nous mechanism, i.e., by a one-event transfer (cf. [4]), we have studied the electrochemical
oxidation of II and have also attempted to isolate and identify its corresponding cation rad-
ical, formed during chemical oxidation, by EPR, as has been done previously in the case of
4H-pyrans [5, 6].
Two oxidation waves were obtained during the oxidation of dihydroperimidine II on a sta-
tionary platinum electrode in anhydrous dimethylformamide.

Sclentific-Research Institute of the Chemistry of Free Radicals, K. L. Khetagurov Severo-

Osetinsk University~ Ordzhonikidze 362040. Scientific-Research Institute of Physical and Or-
ganic Chemistry, M. A. Suslov Rostov University, Rostov-Don 344090. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 7, pp. 970-972, July, 1986. Original article submitted
March 3, 1985. Revised article submitted June 17, 1985.

780 0009-3122/86/2207-0780512.50 9 1987 Plenum Publishing Corporation

 H

Fig. I. EPR spectrum of 1,3-dimethyl-2-tert-butyl-

perimldyl radical in DMF at 25~

The first wave is a one-electron wave which is partially reversible (E = 0.73 V) relative
to silver chloride electrode (e = 0.67), and corresponds to formation ~ the unstable cation-
radical IV. Its subsequent fragmentation can be followed by cyclic voltemmetry: it loses a
proton and generates the cation III, which was identified by addition of an authentic sample
(-E a = 1.72 V). Electrochemical dehydrogenation of II apparently proceeds according to the
scheme -e, -H +, -e:

+" ~ - - \ CI}~3

IV
CIl 3 i V

The second irreversible, two-electron wave which is observed during oxidation of compound
II is probably due to decomposition of the molecule (Epa = 1.32 V).
The cation radical IV could also be formed during chemical oxidation of dihydroperimidine
II with aluminum chloride in nitrohenzene; in this case an unresolved singlet of width AH = 30
Oe was detected by EPR. Reduction of the cation III with zinc metal in DMF or oxidation of
the dihydroperimidine II with silver oxide in the same solvent both led to the same perimidyl
free radical, namely V; its spectrum is shown in Fig. i. Analysis of the hyperfine structure
of this spectrum yielded the following values of the hyperfine splitting constants: aNx'S =
aHx'S-CHs = 4 . 2 0 e ; aH = 1 , 4 0 e (for the proton in the naphthyl fragment).
Oxidation of dihydroperimidine II with 3,5-di-tert-butyl-l,2-benzoquinone did not permit
us to trap either the cation radical stage IV or the free radical V, although even in this
circumstance the presence of one-electron transfer was established without doubt by the obser-
vation of the EPR signal for the well-known o-semiquinolate radical [7], (doublet, a H = 2.5
Oe).
Oxidation of perimidine I with lead dioxide in benzene gave rise to a signal for the un-
stable 2-tert-butylperimidyl radical, whose spectrum was interpreted in a manner similar to
that described above: a~ 1's = 4 . 2 0 e ; a~ = 1 . 4 0 e (for the naphthyl fragment proton), Elec-
trochemical oxidation of~perimidine I occurred as a one-electron, incompletely reversible
wave, E = 0.64 V; decomposition of the molecule was observed beginning at a potential of
pa
E = 1.24 V.
pa
The relatively low stability of the 2-tert-butylperimidyl radical is probably related
to the relatively high spin density on the unhindered nitrogen atom.

EXPERIMENTAL
EPR spectra were recorded on a modified RE-1301 radiospectrometer under vacuum (5'10 -4 mm);
PMR spectra were obtained on a Tesla BS-487-C spectrometer (80 MHz) versus HY~S is internal
standard. Electrochemical experiments were carried out on a P-5827-M potentiostat with a
trigonal impulse generator [8] in a three-electrode cell. The anode consisted of a Pt needle,
with auxiliary Pt spiral electrode, and a silver chloride reference electrode separated by a
waterproof membrane. DMF was used as solvent and was purified according to a general proce-
dure [9]; 0.i M lithium perchlorate was used as background electrolyte and the working depo-
larizer concentration was 5"i0 -s mole/liter.

781
 2-uert-ButylperSmi~i~9 (I) and 1,8-Di( ivaloylamlno)n22hthalene. A solution of 8 g
(50 ~nole) of 1 , 8 - d i a m l n o n a p h ~ ~ ~ w a s ~-~dwith stirring with 8.5 g
(70m mole) of trlmethylacetyl chloride; a colorless, voluminous precipitate was obtained,
The mixture was heated on a water bath for 0.5 h with continued stirring; the residue rema~-
ing after removal of the benzene was worked up with I00 mi of boiling water. The aqueous
solution was filtered to remove insoluble material, cooled, and neutralized with 25% aqueous
ammonia to ~H 8, The resulting precipitate was recrystallized from toluene. Yield of com-
pound I, 8.2 g (74%); coarse yellow-green crystals, mp 155~ IR spectrum: 3400 cm-* (Nl4).
PMR spectrum (in DMSO-D~): 1,28 t (t-C4Hg), 5.28 (NH), 8.62 ppm (Harom). Found: C 80.2;
H 7,3; N 12.2%. C~sHI~N2. Calcd.: C 80.3; H 7.1; N 12.5%.
The solid which was not soluble in water was recrystallized from toluene. Yield of 1,8-
di(pivaloylamino)naphthalene, 1.2 g (14%); colorless needles, mp 274~ IR spectrum (vase~
line mull): 3300, 3370 (NH), 550, 1670 cm-* (amide group). Found: C 73.2; H 8.1; N 8.4%,
C2oH2~N202. Calcd.: C 73.6; H 8.0; N 8.6%.
l~3-dimethyl-2-tert-butyl-2,3-dihydroperimidine (II). An ethereal solution of tert-
butylmagnesium chioride (40 mmole) was treated with st~rring with 6.48 g (20 mmole) of pow-
dered 1,3-dimethylperimldlnium iodide [i0]. The mixture was stirred under reflux until it
was completely decolorized (2 h), and was then decomposed by the addition of saturated am-
monium chloride solution; the ether extracts were dried over sodium sulfate. Yield of com-
pound II, 4.8 g (94%); colorless crystals, mp 144~ (from ethanol). PMR spectrum (in ace-
tone-D2): 1.25 (t-C~Hg), 2.95 (CHs), 6.52, 7.12 ppm (Harom). Found: C 80.2; H 8.5; N 111%.
C~TH2zN2. Calcd.: C 80.3; H 8.7; N 11.0%.
!,3,Dimethyl-2-tert-butzlperimidiniumIodide (III). A mixture of 2.5 g (i0 mmole) of
dihydroperlmidine II in 20 ml of ethanol ~as treated with a solution of 2.5 g of 12 in 20
ml of ethanol. After 10 min the mixture was worked up with Na2S2Os and the precipitate was
recrystallized from water to give yellow crystals, rap 259-260~ with a yield of 3.5 g (92%).
PMR spectrum (in acetone-D6): 1.26 (t-C4Hg), 3.52 (CH3), 7.2, 7.60 ppm (Harom). Found:
C 53.4; H 5.6; N 7.5, I 33.5%. C~TH221N2. Calcd.: C 53.6; H 5.5; N 7.3; I 33.4%.

LITERATURE CITED
i. L. P. Smirnova, A. F. Pozharskii, O, Yu. Okhlobystin, and B. A. Terror, Khim. Geterot-
sikl. Soedin., No. 6, 875 (1977).
2. A. F. Pozharskii, I. S. Kashparov, P. Dzh. Kholls, and V. G. Zaletov, Khim. Geterotsikl.
Soedin., No. 4, 543 (1971).
3. A. S. Morkovnik and O. Yu. Okhlobystin, Khim. Gaterotsikl. Soedin., No. 8, i011 (1980).
4. N. T. Berberova and O. Yu. Okhlobystin, Khim. Geterotsikl. Soedin., No. 8, i011 (1984).
5. N. T. Berberova, A. A. Bumber, M. V. Nekhoroshev, V. B. Panov, and O. Yu. Okhlobystin,
Dokl. Akad. Nauk, 246, i08 (1979).
6. V. A. Samarskii, M. V. Nekhoroshev, V. D. Pokhodenko, and O. Yu. Oklobystin, Zh. Org.
Khim., 15, iii0 (1979).
7. J. J. Conradi and C. A. Maclaren J. Am. Chem. Soc., 82, 4745 (1960).
8. G. E. Troshin, Fo S. Lakomov, and I, M. Sosonkin, Elektrokhimiya, 17, 891 (1981).
9. Ya. M. Kolotyrkin (editor), Electrochemistry of Metals in Nonaqueous Solutions [in Rus-
sian], Mir, Moscow (1974), p. 24.
i0. A. F. Pozharskii and I. S. Kashparov, Khim. Geterotsikl. Soedin., No. i, i01 (1970).

782
FLUORINE-CONTAINING AZOLES.
4. 2-PERFLUOROPOLYOXAALKYL-SUBSTITUTED PERIMIDINES

V. G. Poludnenko, O. B. Didinskaya, and A. F. Pozharskii UDC 547.856.7'412.722:

542.945.24

The reaction of 1,8-naphthylenediamine with perfluoropolyoxaalkanoy! fluorides

and m-fluorosulfonylperfluropolyoxaalkanoyl fluorides yielded 2-perfluoropoly-
oxaalkyl-substituted perimidines. Their basicity and sulfonation by sulfuric
acid were studied.

Perimidines containing a perfluorlnated substituent at the two position have been very
little studied. The first examples of them were obtained comparatively recently by the re-
action of 1,8-naphthylenediamine with trifluoroacetic anhydride or the acid chlorides of per-
fluorinated carboxyl~c acids [2]. The introduction of a perfluorinated substituent leads to
a significant change in the chemical properties of the perimidine ring, and to the appear-
ance of insecticidal and acaricidal activity in the compounds [3]. Very effective antistatic
agents were observed among them [4].
We investigated the possible isolation of perimidine derivatives with a higher 2-per-
fluoropolyoxaalkyl substituent from 1,8-naphthylenediamine and the acid fluorides (I) and
(II) of perfluorocarboxylic acids. It was established that 1,8-naphthylenediamine reacts
with the e-fluorosulfonylperfluoropolyoxaalkanoyl fluorides (la-c) and the perfluoropolyoxa-
alkanoyl fluorides (lla-c) in the medium of boiling absolute diethyl ether with the formation
of the 2-(~-fluorosulfonylperfluoropolyoxaalkyl)perimidines (Ilia-c) or the 2-perfluoropoly-
oxaalkylperimidines (IVa-c) as the main products respectively with yields of 79-96%.

R c;2cF2o(c~cr~o)o?Fco;
CF 3 CF~
/NH
/
(
\
~NH
2
-
40 ~
~-
~ N
I
~
\
~\}--CF(OCF
/ I
CF) OCF~CF -I~
21 ~ . 2

la-c, lla-c
llla-c,IVa-c
I, III R=FSO2; I4 IV R=CF~; a n=0, b n = l , c n=2

In contrast to the reaction of 1,8-naphthylenediamine with trifluoroacetic anhydride,

the acid chlorides [2], and the acid bromides of fluoroacetic acids [5], the formation of
the N,N'-diacyl derivatives of 1,8-naphthylenediamine is not observed in the given case.
This can be explained by the larger steric hindrances with the entry of the second bulky ~-
fluorosulfonylperfluoropolyoxaalkyl or perfluoropolyoxaalkyl substituent into the 1,8-naph-
thylenediamine molecule. The absence of monoacyl derivatives in the reaction products in-
dicates the case of their cyclization in the experimental conditions.
Since the reaction of 1,8-naphthylenediamine with the acid fluorides (la-c) and (lla-c)
proceeds very regiospecifically, the perimidines (Ilia-c) and (IVa-c), which were isolated
directly from the reaction mass, were chromatographically pure. They are readily identified
by the doublet of the bands of stretching vibrations of the C=~ and ~ bonds in the region

For communication 3, see [i].

Borislav Branch, State Scientific-research and Design Inss of the Chlorine Indus-
try, Borislav 293760. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp.
973-975, July, 1986. Original article submitted March 10, 1985. Revision submitted August
7, 1985.

0009-3122/86/2207-0783512.50 9 1987 Plenum Publishing Corporation 783

 TABLE 1. Physicochemical Characteristics of =he Pe~imidines (111) a n d (ZV)

Corn- [ . .. ^ , lg spectrum, v, om "~ Pound EmoiRc~l f~r= Cal. Y~ald,

pound i'raP' ~C Color ~f ~="~ /
chloroform Idr ~(in CCh) . . . . . . . . . . . . . . C, go ~.~.,
'"'" ~ ~cula-
!ec=. ~o
"
................ ~n IL ~'.~7__I
| ~k_l_s
| ~'~........................................................ ~ , . ~ - .......
I

Ilia [ 89~90 Orange 0,98 3,3l 3435{ 1640[ 1600[1465 38,4 C,,H,F,N=O~S 38,6 88
lllb I Oil Red 0,91 3,18 84301 16d51 1600i 1468 34.5 C,~H~F,~N~O~S 34,2 92
lllc I Otl D~tk-red 0,84 3440 1 16~5 1 1605 1 1470 31,8 C~H~FaN~OsS 31,6 96
IV =~ I 8 5 - - ~ 6 ~ng= 0,95 3T;~ ~5,5)164o)16oo 4~,8 C.H,a,~=O ~,5 55
~vb I o ~ 0,95 3440l 1643 1605[ 36,1 C~H~FI~N=O~ 35,4 79
Dark-red 0,90 3;9 84401 1640 16001 34,1 C~aH~F~N~Os 33,7 91

The value of the pKa of the compounds (IIlc) and (IVb) was not measured.

TABLE 2. Characteristics of the Sulfonlc Acids (v) and (VD

~ m p t r i c a l iculated Yield,%

Va 7A 75 40~1660 10601 1445] 33,4 C mHTFaO~N=S= 33,0 93

~4-- I~5--Fo65 I06511460130,1 C IsHTFIsOgN=S= 29,8 89
~ 0 6 7 1 ] 0 0 ?011460128,3 C21HTF=IOL~N2S= 27,9 94
Via 82--841640--1655 I? ~ ~ C16HTFklOdN=S 36.1 90
Vlb 53--~4 ]640--1670 I0751 -- 132,2 C,~OTF~70,N=S 32,1 95
VIo 51--52 1640--1670 1065 1 -- [ 28,0 C~,H:F=~O~N=S 28,4 88

of 1590-1650 cm-~ (Table 1), which is characteristic of 2-substituted perimidines [6]. The
presence of the absorption hand of the FSO= group at 1465-1470 cm -~ [7] in the IR spectra of
the products of the reaction of 1,8-naphthylenedlamine with the m-fluorosulfonylperfluoro-
polyoxaalkanoyl fluorides (Ia-c) indicates that the reaction proceeds exclusively at the
fluorocarbonyl group of the compounds (la-c).
The introduction of the 2-(m-fluorosulfonylperfluoropolyoxaalkyl) or 2-perfluoropolyoxa-
alkyl substituents into the molecule of the perlmldine of yellow color leads to the deepening
of the color of the individual compounds to orange and dark-red. We determined the values of
the pK a of some of the synthesized perimidines by the method of potentiometric titration in
a 30% (vol.) aqueous ethanol solution at 220C (Table i). For comparison, the value of the
baslcity of the unsubstltuted perimidine was measured under the same conditions; it was equal
to 5.91. As was to be expected, the introduction of the 4-fluorosulfonylperfluoro-2-methyl-
3-oxabutyl radical at the two position of perimidine [compound (Ilia)] produces a decrease
of 2.6 in the basicity. The replacement of the CFs group by the SO2F group has practically
no effect on the basicity [compounds (Ilia) and (IVa)].
As in the case of the 2-difluoromethyl-, 2-trifluoromethyl-, and 2-perfluorohexylperi-
midines [8, 9], the sulfonation of the perimidine derivatives (III) and (IV) already proceeds
exceptionally readily at the temperature of 100C. On the basis of the data of the work [3])
it can be assumed that the sulfonation reaction proceeds at the position six (seven). The
yields of the monosulfonic acids (V) and (VI) reach 85-93%.

___~=so,.,. -~ s'-~--'~>-~
m,-c.~=-c io-i~~ ~x__~ c t [
CF~ CF~

Va-c, VI a-c
III,V R=F50=; IV, VI N=CF3;a n=0, b n=1, c n=2

The absorption bands of the sulfonyl group occur in the region of 1040-1060 cm -z in the
IR spectra of the sulfonic acids (V) and (Vl) in mineral oil. The sulfonic acids obtained
exist in the form of crystal hydrates and probably as the internal salts; this is indicated
by the presence of the band at 1640-1670 cm-~. which is characteristic of the stretching vib-
rations of the CaN bonds in the perimidinium cations, in the IR spectra.

784
 EXPERIMENTAL
The IR spectra were taken on a UR-20 spectrometer. The TLC was performed on aluminum
oxide of IV degree of activity in chloroform. The pK a values were determined according to
[i0].
The characteristics of the compounds (Ill)-(Vl) are presented in the Tables 1 and 2.
2-(~-Fluorosulfonylperfluoropolyoxaalkyl)perlmldlnes (IIla-c) and 2-Perfluoropolyoxa-
alkylperlmidines (IVa-c). To the solution of 0.79 g (5 m m 0 1 e ) ~ 8 - n a p h t h y l e n e d i a m l n e in
20 ml of absolute diethyl ether are added 5 mmole of the ~-fluorosulfonylperfluoropolyoxa-
alkanoyl fluorlde (la-c) or the perfluoropolyoxaalkanoyl fluorlde (Ila-c) with intense stir-
ring, at such a rate as to ensure the uniform boiling of the reaction mass. The mixture is
maintained at 40~ for 30 mln, and filtered. The filtrate is rapidly treated with 20-30 ml
of a 5% aqueous solution of NH4OH. The ether layer is separated. The chromatographically
pure product, which is well sublimated ~n vacuoj is obtained after the evaporation of the
solvent.
2-~-Fluorosulfonylperfluoropolyoxaalkyl)perimidine-6(7)-sulfonicacids (Va-c) and 2-(Per-
fluorop01yoxaalky!)perimidine-6(7)-sulfonic acids (Via-c). To i0 ml of concentrated sulfuric
acid (d~ 2~ 1.82) are gradually added 3.2 mmole of the 2-(~-fluorosulfonylperfluoropolyoxa-
alkyl)perimldlne (Ilia-c) or the 2-perfluoropolyoxaalkylperimidine (IVa-c) at the temperature
of I0-15@C. The dark-red solution obtained is stirred at room temperature for I0 mln. Then,
the reaction mass is poured onto 20 g of crushed ice with stirring. The dark-red precipitate
is filtered off; it is dried at 35-40~ (2 r~n of Hg stem) and recrystallized from alcohol.

LITERATURE CITED
i. V. G. Poludnenko, O. B. Didinskaya, and A. F. Pozharskii, Khim. Geterotsikl. Soedin.,
No. 4, 524 (1984).
2. A. F. Pozharskii, G. G. Yurchuk, and L. L. Gervits, Khim. Geterotsikl. Soedin., No. 3,
413 (1979).
3. G. G. Yurchuk, Dissertation, Candidate of Chemical Sciences, Rostov-on-Don (1981).
4. Yu. I. Vasilenok, V.N. Lagunova, A. F. Pozharskii, O. M. Bagrova, and G. G. Yurchuk,
Inventorts Certificate No. 789,562 (USSR); Byull. Izobr., No. 47, 112 (1980).
5. G. G. Yurchuk and A. F. Pozharskli, Khlm. Geterotsikl. Soedin., No. 8, 1106 (1981).
6. V. I. Minkin, Yu. A. Zhdanov, I. D. Sadekov, O. A. Raevskii, and A. Do Garnovskii,
Khim. Geterotsikl. Soedin., No. 6, ii00 (1967).
7. K. Kimoto, H. Miyauchi, J. Ohmura, M. Ebisawa, and T. Hane, Patent No. 8,017,838
(Japan); Chem. Abstr., 93, 27443 (1980).
8. A. F. Pozharskii, I. V. Borovlev, G. G. Yurchuk, O. M. Bagrova, Yu. I. Vasilenok, and
V. N. Lagunova, Khlm. Ceterotsikl. Soedin., No. 4, 550 (1980).
9. A. F. Pozharskii, V. V. Kuz'menko, V. N. Koroleva, and G. G. Yurchuk, Khim. Geterotsikl.
Soedin., No. 5, 691 (1980).
i0. D. J. Raliger and M. M. Joullie, J. Org. Chem., 29, 476 (1964).

785
ELECTRONIC STRUCTURE ANDMASS SPECTRA OF SUBSTITUTED
HEXAHYDRO-I,3,5-TRIAZlNE-2-THIONES

O. S. Zakharova, A. S. Moskovkin, UDC 539.194:543.51:547.491

V. V. Kravchenko, and K. I. Petrov

The electron density in the molecules of substituted hexahydro-l,3,5-triazlne-2-

thiones was calculated by the LCAO-MO SCF method in the MINDO/3 approximation.
The mass spectra of substituted 5-methylhexahydro-l,3,5-triazine-2-thiones were
studied, and a fragmentation scheme for the compounds is proposed.

The reactivity of substituted hexahydro-l,3,5-triazine-2-thiones, which have found wide

use as herbicides [i] and as accelerators for the sulfur and nonsulfur vulcanization of diene
rubbers [2], is determined not only by the presence of nucleophilic sulfur atoms in their
molecules but also by ~the nature of the substituents at the nitrogen atoms of the triazine
ring [2]. However, in spite of the practical importance of these compounds, published data
on their structure are extremely limited. The crystal and molecular structures have been
determined only for 1,3,5-trinitrohexahydro-l,3,5-triazine [3] and a compound related to the
triazines and containing a thioamide group, i.e., hexahydropyrimidine-2-thione [4]. In addi-
tion, the mass spectra of symmetrically substituted hexahydro-l,3,5-triazines have mostly
been described in the literature.
In order to determine the effect of the sulfur atom of the thioamide group and also the
nature of the substituent at the nitrogen atoms on the distribution of charges and on the
nature of dissociation under electron impact we studied the mass spectra of substituted hexa-
hydro-l,3,5-triazine-2-thiones (II, IV-VIII) and undertook a calculation for the model sys-
tems (I-IV) by the LCAO-MO SCF method in the MINDO/3 approximation [8].

R3

H6" [ I "If 4

S
I-Nil

], II RI=H, III, IV, VII RI=CH3, V RL=C2Hs, VI, VIII RI=C6Hs; l--IIl, VI R-~=H,
IV R~=CHs, V R2=C2H~, VII, VIII R~=C6H6; I R3=H, II--VIII R3=CH~

Since the molecular and crystal structures were not known for any of the investigated
compounds (I-VIII), for the quantum-chemical calculation we used a model constructed on the
basis of a comparison of the known structures of related compounds, i.e., 1,3,5-trinitrohexa-
hydro-l,3,5-triazine (IX) [3], hexahydropyrimidine-2-thione (X) [4], and thiourea (XI) [9].
In the molecule of (IX) the triazine ring has a configuration reminiscent of the chair con-
formation of cyclohexane [3]. The presence of the thiosm~de group in the molecule of (X)
leads to a ring configuration corresponding to a half-chalr, since the thioamide group devi-
ates slightly from the plane in which the C(6)N(1)C(2)N(s)C(4),atoms lie. This agrees well with
the results from work [9] on the molecular structure of (XI). The idealized model of the
saturated triazine ring was therefore selected in the following way. The C(6),N(~), C(2),
N(3), C(4), and S atoms lie in one plane, and the N C ) atom projects from it. The model mole-
cules have sy~netry described by the C S point group~- The bond lengths and bond angles for
the model compounds (I-IV), taken from [3, 4], have the following values:

M. V. Lomonosov Moscow Institute of Fine Chemical Technology, Moscow 119435. Translated

from Khimiya Geterotsiklichesklkh Soedinenii, No. 7, pp. 976-980, July, 1986. Original arti-
cle submitted March 12, 1985.

786
0009-3122/86/2207-0786512,'50 9 1987 Plenum Publishing Corporation
 TABLE I. The Distribution of the Charge at
the Atoms in the Molecules of (I-IV), au

Atom I Ii lII IV

S -0,5700 --0,5633 --0,5731 --0,5818

N(2) 0,4699 0,4662 0,4541 0,4426
N(u --0,1920 -0,1766 -0,1528 --0,1547
N(3} --0,1920 -0,1766 -0,1786 --0,1547
C~4) 0,2583 0,2601 0,2581 0,2594
CI6) 0,2583 0,2601 0,2617 0,2594
Nts) --0,2388 --0,2~53 --0,2270 --0,2286
CMe~ 0,1800 0,1790 0,f781
C~'te~ 0,1541 0,1534
C l',~e= 0,1534
0]248 0S311
H(2> 0,1248 0,1311 0,1278
Ht4) -0,0316 --0,0348 - 0,0360 - 0,0373
H~) ~o,o3t6 -0,0348 - 0,0364 --0,0373
Hr -0,0383 -0,0666 - 0,0679 -0,0696
H~6~ -0,0383 --0,0666 - 0,0686 --0,0696
H(5) 0,0967
H Me~ -0,0458 - 0,0469 -0,0479
HM~: -0,0282 -- 0,0202 -0,0212
H ~',e.~ -0,0282 -0,0202 -0,0212
H Me~ -0,0146 -0,0159
H ~e~ -0,0258 -0,0273
H Me~ 0,0332 0,03t9
HMe~ -0,0159
H ,'r --0,0273
H Me= 0,0319

rC~N,=:I,334; r c ~ s = l . 7 2 2 ; rC~N=l,452; rcoa~=l.454; rN%M~=l.47 [10]; "rNH=

=1,00; ~ H = 1 - 0 9 A ; /-.SC2N1=l19,Z5; /__NIC~N3='t20.50; Z-C2N~C6=
=122.40; /_.NIC6Ns=109.30; / C 4 N s C 6 = 1 1 4 . 8 1 ; /--'C2NiH~=/--HtN1C6=
='118.80; A-NIC6H'6=/--~NICsH"s=t09.35; /__H'sC6Hs=/__H%CsNs=109.35;
Z ~~, 6~6
~ H ~6 = , 1 0 , 1 2 ; ziC6N6H5 = 1 1 7 - 9 0 ~
For the methyl groups all the angles were taken as tetrahedral. When the hydrogen atoms are
substituted by methyl groups, the corresponding bond angles remain unchanged. The calculation
was made for the closed electron shells with participation of the s and p orbitals for the C,
N, and S atoms and the s orbitals for the H atoms,
As a result of the calculation we obtained the distribution of the charges in compounds
(1-IV) (Table i), the energies of the molecular orbitals, the dipole moments, and the enthal-
pies of formation (Table 2). (The energies are only given for the last occupied MO.) From
Table I it is seen that the maximum negative charge in the molecules of (1-IV) is concentrated
at the sulfur atom and increases with increase in the number of electron-donating substituents
at the nitrogen atoms at positions I and 3 of the ring. The last occupied orbital in the
molecules of (I-IV) is of the same type as the nonbonding orbitals of the sulfur atom, The
first ionization potential of these compounds must therefore be of the n type, and the tran-
sition to the ionized state will lead to a decrease in the negative charge at the sulfur atom.
An analogous conclusion about the localization of the charge at the sulfur atom of the thio-
carbonyl group was reached during study of the photoelectron spectra of thiazolidine-2-thiones
[Ill. The introduction of substltuents at the nitrogen atoms in the molecules of (I) leads
to a decrease in the stability of compounds (II-IV), as indicated by the increase in their
enthalples of formation and also by the increase in the antibonding character of the last
occupied orbital, which shows up as some decrease in the coefficients at the Px atomic orbit-
als of the sulfur atoms in the breakdown of the MO (Table I). The increase in the antibond-
ing character of the last occupied MO with increase in the number of electron-donating groups
at the nitrogen atoms leads to a decrease in the stability of the molecules to electron im-
pact in the translt from (II) to (IV).
According to [5-7], the intensity of the peak for the M + ion in the mass spectra of most
of the derivatives of hexahydro-l,3,5-triazine, recorded with 70-eV ionizing electrons, is not
greater than 3%. In addition, while recording the mass spectra of compounds of this type,
Schumacher and Taubenest [5] came up against a number of difficulties due to thermal decom-
position of the compounds before the spectra were recorded. The mass spectra of compounds

787
 TABLE 2. The Energy and the Form of the Last Occupied MO, the
Dipole MomentD and the Enthalpy of Formation of Compounds (I-IV)
Corn- a,v,
pound ~.eV ~-~c~hx~* .u,D k e a l / m o l e

I -8,252 0,969Pxs -O,092(sNj - SN~ ) +0,091 (PXN, --PXN, ) - 7,302 - 15,832

--0,090(PYH,-- PY I-I,~)
1I --8,323 --0,968Px+O,O92(~,--SN~)--O,O94(pxN,--PXNs) + 7,943 1,150
+0,091 (PYH,- Prelim)
1II --8,074 -.0,951Pxs --O,087Pzc~-O,137Pzc, +0,104SliMe~ 7,764 19,644
IV -7,843 0,941PXs+0 131 (pzc, -pzc~ ) -0,103 (st~y,e2-- 7,596 32,260
--SliMe~)

XAi/X represents the type of basis AO, A represents the type

of atom, and i represents the number of the atom.

TABLE 3. The Mass Spectra of Compounds (IL IV--VIII )*

Com- m / z values (relative intensity, %)

pound
II 131 (100), 89 (21), 88 (48), 60 (62), 53 (21), 45 (19), 44 (92), 43 (40),
42 (82), 30 (51), 28 (61)
IV 159 (100), 116 (20), 73 (49), 72 (26), 57 (56), 45 (15), 44 (94), 43 (92),
42 (77), 41 (14), 28 (35)
V 187 (100), 144 (45), 129 (35), 103 (28), 87 (67), 72 (24). 59 (27). 58 (77),
57 (93), 44 (25), 42 (76)
VI 207 (56), 164 (24), 135 (79), 119 (75), 118 (91), 105 (32), 91 (82), 77
(100), 64 (63), 51 (49), 42 (73)
VII 221 (17), 136 (16), 135 (100), 105 (13), 103 (tO), 77 (74), 51 (,28), 50
(ll), 43 (33), 42 (59), 41 (12)
VIII 283 (I0), 135 (77), 105 (I00), 104 (45). 77 (93), 51 (34), 50 (12), 44
(18), 43 (35), 42 (45), 41 (13)

The H+ and the I0 s t r o n g e s t i o n p e a k s a r e g i v e n .

( q I , I V - - V I I I ) (Table 3) were therefore recorded with 20-eV electrons with the inlet system
at room temperature.
Analysis of the obtained data (Table 4) in comparison with published data [5] shows that
the introduction of the thiocarbonyl group into the hexahydrothiazine ring appreciably sta-
bilizes the M + ion. Thus, the intensity of the peak for the M~ ion in the spectrum of 1,3,5-
trlmethylhexadhydro-l,3,5-thiazine is 9.8% [5], while the peak of the analogous ion in the
spectrum of its 2-thioxo derivative (II) has the maximum intensity. The stability of the
molecules of compounds ( II, IV--VIII ) to electron impact decreases with increase in the chain
length of the a!kyl substituent at the nitrogen atoms and with substitution of the alkyl group
by a phenyl group (Table 4).

The dissociation of M+ ion in compounds ( II, IV--VIII ) (see the scheme) takes place
both in directions independent of the presence of the thiocarbonyl group in the ring and in
directions determined by the latter. The r fragment [produced by the removal of a neutral
molecule containing the N . . nitrogen atom] and the ~2--~4, ~7 fragments are removed by
the mechanism proposed fo~S~he dissociation of the M + ion in symmetrically substituted hexa-
hydrotriazines [5]. This is favored by the practically identical intensity of the peaks for
the ~i--~4, ~7 fragments in the spectra of (I) and 1,3,5-trimethyl-hexahydro-l,3,5-tria-
zine [5]. In addition to a cyclic structure the #, fragment may have an open structure, from
which the #s fragments are formed as a result of migrations of the hydrogen atoms and removal
of the nitrogen-containing molecule; the composition of the ~s fragments was established by
means of the high-resolution mass spectra of compounds (IV, V). The peak for the analogous
ion [C3HgN]+ with m/z 59 and a relative intensity of 37% is present in the spectrum of the
trimethyl-substituted triazine [5]. Further dissociation of the ~5 fragment with the loss
of the sulfur atom leads in the spectra of compounds (IV-VI)to the appearance of the peaks
for the ts fragments, which according to the high-resolution mass spectra contain one nitro-
gen atom. Thus, the fact that the peak for the ion with m/z 57 is absent in the spectrum of

788
 TABLE 4. The Peak Intensities of the Characteristic Fragment
Ions fn the Mass Spectra of Compounds ( If, Iv-viii )
,,,,, , , , ........ ,,,, - : ~ _ _

Corll- Peak intensities of ions as percentages of total ion current

pound
M* (Ilz~) r % [R~]

II i8,1 7,0 7,5 2,6 8,9 12,1 9,1"

tV 17,9 3,1 14,3 13,9 I 1,7 L',7 11,7 7,4
V 13,6 5,3 83 10,9 2,0 3,3 0,4 8,9 1,5 2,8
VI 6,2 2,5 0,6 - 3,2 1,6 7,7 7,4 8,0 I0,t
VII 3,7 1,1 0,6 2,6 1,7 11,9 20,I 14,8
VIII 1,8 -- 1,3 14,8 6,6 6,6 11,4 I3,8

The [Oo+H]. f ragmen t

# N---. -I+" + "~"r~2

S/.~ ..... ~N,,R~ "'----~" R' I N ~ N ' R 2
,.d r S
/" -C2HsN I
CH 3

R " "~C "R \N~ N

//
N S S
:,I* II,IV~VH[ I i

+
" R~--N~I~C}I2 S=CH.-NR2-CH3~
+"
S=('=N N ~q ~-"

I -.(R2--(!}{ ,) I '
I

"1,9

-IICN 4- +
[R?]+ --I........... R 2- N ~ C I [ CII2=N=CIL2

the trimethyl-substituted triazine "[5], i.e., the analog of the r ion, makes it possible to
suppose that the N(s ) atom is not involved in the formation of the r fragment.
The presence of the thiocarbonyl group in compounds ( If, IV--VIII ) leads to the appear-
ance in their spectra of peaks for the Cs fragments, which according to the high-resolutlon
mass spectra contain nitrogen and sulfur atoms, and to the absence of peaks for the isobaric
[ R N H C H 2 N H C H 3 ] +, fragments typical of the spectra of symmetrically substituted hexahydro-
trlazines [5]~ In addition to the peaks shown in the scheme, the spectra of compounds
( VI--VIII ) contain peaks for phenyl-containlng ions with m/z 118 and 77, while the spectrum
of (VI) contains peaks for ions with m/z 91, 65, and 64. (According to the high-resolution
spectra, the latter is a doublet for [CsH4]+/[C4H2N]+ l:] , while the ion with m/z 91
contains one nitrogen atom.)

EXPERIMENTAL
The mass spectra were obtained on a Varian MAT-731 instrument with direct injection of
the sample into the ion source (accelerating potential 3 kV, cathode emission current 300 ~A,
ionization potential 20 eV, inlet system temperature 25-35~ The high-resolution mass
spectra were obtained on the same instrument under similar conditions with perfluorokerosene
as standard. The resolution was M/AM=f0000 .
The MINDO/3 calculations were carried out on an EC-1960 Computer using the program in
[8].
The synthesis of compounds (If, IV--Vl]I ) was described in Ill.

789
 LITEP~TURE CITED
i~ U. S~ Patent No, 3505057; Chem~ Abstr,, 72, 132790 (1971).
2. M. M. Donskaya and ~. I. Orldunov, Kauchuk P~zlna, No, 6t 25 (1980).
3. C. S. Chol and E. Pr~nce~ Acta C r y s t a l l o s r , 2~8B, 2857 (1972),
4. H. W. Dias and M. R. Truter, Acta, Crystallosr., i_~7, 937 (1964).
5'. E. Schumacher and R. Taubenest, Rely. Chlm. Acta~ 4~9, 1439 (1966).
g, S, Bulusut T. Axenrod, and G.W.A. Milne, Ors. Mass Spectrum., ~, 13 (1970).
7. R. A. Corral and O. O. Orazl, Ors. Mass Spectrom., i~i, 1221 (1976).
8, M.J.S. Dewar t QCPE Prosram 277, University of Indiana.
9. M. R. Truter, Acta Crystallogr, 22, 556 (1967).
10. S. Jumet-Delcrolx, Acta Crystallogr, 29B, 977 (1973).
ii. C. Guimon, G. Pfister-Guillozo, M. Arbelot, and M~ Chanon, Tetrahedron, 30, 3831 (1974).

790
CONDENSED IMIDAZO-I,2,4-AZINES.
14. * SYNTHESIS AND REACTIVI'IX OF 3-CHLORINE-SUBSTITUTED
IMIDAZO[I,2-b]-I,2,4-TRIAZI~S

V. P. Kruglenko, A. A. Timoshin, UDC 547.785'873.07:542.

N. A. Klyuev, E. V. Logachev, 944'958.3:543.87
and M. V. Povstyanoi

When boiled with phosphorus pentachloride in phosphorus oxychloride, 2-methyl-6-

phenyl-imidazo[l,2-b]l,2,4-triazin-4H-3-one gives a mixture of mono- and dichloro
derivatives, whereas the action of thionyl chloride in chloroform with a cataly-
tic amount of DMFA gives only the monosubstituted product 2-methyl-3-chloro-6-
phenylimidazo[l,2-b]-l,2,4-triazine. The reactivity of the 3-chloro derivatives
of imidazo[l,2-b]-l,2,4-triazine in reactions with diethylamine, piperidine,
morpholine, aniline, hydrazine hydrate and thiourea was investigated.

According to the data from spectral analysis of imidazo[l,2-b]-l,2,4-triazines

(imitrines) [2,3], their laser characteristics are due to the electronic characteristics of
the substituents in the imidazole fragment of the molecule (at positions 6 and 7). While
continuing a series of researches into the chemical and laser characteristics of substituted
imidazo[l,2-b]-l,2,4-triazines, we realized the synthesis of new imitrines ~cith a variable
substitutent in the triazine part of the molecule.
Earlier we reported on the synthesis of 2-methyl-3-chloro-6-phenylimidazo[l,2-b]-l,2,4-
triazine (lla) by the action of a mixture of phosphorus oxychloride and phosphorus penta-
chloride on 2-methyl-6-phenylimidazo[l,2-b]-l,2,4-triazin-4H-3-one (la) [4].
CH N , R N Cl

0 / __. ~ Cl " N . . . . N" \,___./

i
CHar N p ~5H ~ M B R ~ ~ CH~. ~

tlS Cl "'~ ~N `'+ tN \~__., R2 1 N '~'V ~ (

V 6 llsi,b g ~o ~V

il R=H; b R = P h

Chromatographic analysis of the reaction mixture obtained by this method (method A) by

GLC showed that the previously described reaction does not take place in a well-defined
manner but leads to the formation of two final products. In order to established the struc-
tures of the individual components of the mixture we used chromato-mass spectrometry (CMS)
with a high-resolution mass spectrometer. The individual components of the mixture were
identified on the basis of an analysis of the mass spectra, recorded repeatedly at the maxima
of the chromatographic peaks, By CMS it was established that the first chromatographic peak
(~min = 10'20", yield 87%), corresponds to the monochloro derivative (IIa), In its mass
spectrum (Table I) the molecular ion peaks (M+) 244/246+ were recorded with an intensity
ratio of 3:1. This indicates the presence of one chlorine atom in the molecule. According
to high-resolution mass spectrometry, the peak of the I,~ ion for (IIa) corresponds to the

For Communication 13, see [I].

#The numbers ehamacterizin~ the ions denote the m/z values.
Kherson Industrial Institute, Knerson3Z5008. Translated from Khimiya Geterotsiklicbes-
kikh Soedinenii, No. 7, pp. 981-985, July, 1986. Original article submitted March 19~ 1985.

0009-3122/86/2207-0791512.50 9 1987 Plenum Publishing Corporation 791

 TABLE i. The Mass Spectra* of Compounds (lla, b, IVc, d)

Com- m/m values (relativeimensi~y,~0)

pound

Ila 246 (33), 245 (12), 244 (I00), 205 (9), 203 (29), 169 (7), 168 (67), 141
(~,8), 129 (7), 116 (IS), 115 (22), 114 (~4), I04 (IS), I03 (18), I02 (I0),
a9 (49), 88 (~4), ~8 ,(9), 77 (is), ~ (is), 63 (~s), 62 (l~), si (~3),
llb
(15), 192 (14), 178 (13), 166 (7), 165 (32), 141 (IlL If5 (19), 114 (14),
103 (IO), 89 (26), 77 (17), 76 (14), 63 (8), 51 (5)
III 28~ (lO), 280 (57), 278 (lO0), 241 (4), 239 (25), 237 (36), 204 (8), 202
(27), 177 (5), 175 (15), 152 (4), 150 (20), 148 (16), 138 (7), 136 (21),
t15 (12), 102 (lO), lO! (18), 88 (13), 77 (lO), 63 (13), 51 (18), 50 (13)
IVc 370 (32), 369 (lO0), 368 (13), 329 (13), 328 (59), 260 (19), 259 (12), 244
(I0), 178 (6), 165 (14),r 129 (15), I04 (18), ]03 (32), 89 (13), 84 (9), 77
(]o), 66 (]2)
IVd 372 (33), 371 (ZOO), 33l (8), 330 (35), 260 ([5), :259 (18), ~44 (10), 178
(9), 165 (17), 129 (12), 104 (1.0), 103 (31), 89 (14), 86 (8), 77 (15),
66 (23)

*The peeks of ions with intensities of ~ 3% of the

maximum are given.
molecular formula CI~HgN~ssCI (found 244.0513; calculated 244.0515). The initial stage in
the fragmentation of M + for compound (lla) under electron impact coincides with the general
scheme for the dissociation of M+ in imidazo[l,2-b]-l,2,4-triazines [3] and involves destruc-
tion of the triazine fragment with the elimination of the CHsCH particle (the ~ ion, found
203.0205; C:oH~NsSSCl; calculated 203.0250) and subsequent elimination of a chlorine atom
(the ~ ion, 168). The %1 ion subsequently loses two HCN molecules (for the [#~--HCN]+ ion,
found 141.0495, calculated 141.0452; for the [~I--HCN, -HCN] + ion, found 114.0389, calculated
114.0343). The appearance of the 116 and 115 ions is due to the cleavage of the imidazole
ring of the molecule. The fragments which form probably have azarine radical-cation and
cation structures (found 116.0498 and 115.0391, CeH6N and CeHsN, calculated 116.0500 and
115.0421 respectively) and, together with the [C6HsC-CH] + ion (found 102.0469, calculated
102.0471), demonstrate the absence of a chlorine atom at position 7 in compound (lla).
At the maximum of the second chromatographic peak (Tmin = 13'10", yield 13%) we obtained
the mass spectrum of (III); the intensity ratios of the M+278/280/282 peaks were 9:6:1,
which indicates the presence of two chlorine atoms in the molecule, i.e., the product (III)
is dichloro-substituted 2-methyl-6-phenylimidazo[l,2-b]-l,2,4-triazine. This is confirmed
by high-resolution mass spectrometry, according to which the 278 ion corresponds to the
molecular formula C~2HsN4ssCI2 (found Z78.01~4, calculated 278.0126). The fragmentation
path of M + in compound (III) is similar to that examined above for the monochloro-substituted
compound (lla) (Table i); the elimination of the CH3CN particle from M + is observed (the
ion s 237/239/241) with subsequent removal of the chlorine atom (~ I ion, 202/204). Then as in the
case of compound (lla), successive elimination of two molecules of HCN takes place from the ~ ion
(175/177 and 148/150). Such an analogy in the dissociative ionization path indicates that one of
the chlorine atoms is at position 3 of the bicyclic compound. The appearance of the [C~H=C-CCI] +
(136/138) and [C6H~C=CCI-N] + (150/152) ions in the mass spectrum indicates that the second
chlorine atom is at position 7 (found 136o0066 and 152o0069, C6HsssCI and CsHsN37CI, 136.0079
and 152.0081 respectively).
The PMR spectrum of the isolated mixture of chlorination products (lla, III) contains
signals for the following protons: 2.19 (3H, s, CHs); 7o38-7.91 (5H, m, atom.); 8.28 ppm
(IH, s, CH of imidazole) and does not contain signals for the protons of an AB system; this
rules out the presence ot the product chlorinated at the C ( ~ ) atom in the mixture [5]0
The IR spectra of the bicyclic compounds (lla, III), unlike those of the initial com-
pound, do not contain absorption bands for the carbonyl (vC=O 1700-1700 cm -~) and imino
(~NH 3110--3180 cm -~) groups.
It is interesting to note that brief boiling of the imidazotriazin-3-one (Ia) with
thionyl chloride in chloroform in the presence of catalytic amounts of DMFA (method B)
leads to the exclusive formation Of the monochloro derivative (IIa).

792
 TABLE 2. The Characteristics of the Synthesized Substances
, , . . ................

Corn- Trap, ei$ I Pound,% Molecularhalculated,%1 9

pound' R' } R~ tr I-U-UT i N 5Y ~
Ib 307--308 0,15 71,8 4,4 18,7 CIsH|4N40 ]71.5] 4,7 I8.5, 94
lib 246--2'48 0J4 67,3 4,0 17,4 CIsHI~C1N4{67,4[ 4,1 17.5I 93
1Va t61--163 0,70 73,9 6,3 ! 9,6 C~Hz3N~ ~73,91 6,5 t9.61 60
I'vb 156--157 0,41 69,2 6,4 23,7IC~rH~gNs I69,61 6,5i 23.9I 79
IVc --CHa (CH2)aCH~-- 219--220} 0,71 74,7 6,5 19,t Q~aFI~aNa 174,8I 6,3] 19.0t 58
17Vd --CH~CH~--O--CHaCHa-- 239--2401 0,68 71,3 6,2 t8,9tC~2H~NsO }71,t] 5,7 18.91 61
IVe C6I-I~ H 231--232~ 0,63 71,4 4,7 23,lIC18HIsN~ /71,71 5,0 ~3.21 56
ivf NHa H 227.--229I 0,17 60,0 5,1 34,8~C~HI2N6 ~60,0/ 5,0 35.01 62
wg NH~ H 247--248 0,3t 68,5 4,8 26,5IC~sHioN8 I68,3] 5,1 ~6.6! 48
Va 288--290I 0,74 59,1 4,5 22,9/C~HIoN4S I59,5] 4,2123.11 75
vb 286--28'7] 0,64 67,7 4,9 17.6|Ci8Hi4N4S t67,9[ 4,4 17.61 69

*Compounds (Ib, lib, IVa, c, d, g, Vb) R = C~Hb; (IVb, e,

f, Va), R = H.
#The compounds were recrystallized: (Ib, Va, b) from
DMFA; (IIb, IVc, d) from methanol; (IVa) from aqueous
methanol; (Vb, f, g) from dioxane; (IVe) from aqueous
DMFA.
$Silufol UV-54 plates, eluat isopropanol for (IVb, e) and a 2:1
mixture of toluene and isopropanol for the remaining compounds.

During the chlorination of 2-methyl-6,7-diphenylimidazo[l,2-b]-l,Z,4-triazinone (Ib) by

method A only the monochloro derivative (lib) was isolated. In the mass spectrum of (I15)
we detected a doublet of strong peaks for M+ 320/322 (signal ratio 3:1), corresponding to
its molecular mass with the allowance for. the chlorine isotopes. With the introduction of a
second bulky substituent (R=C6Cs) the fragmentation path for W ~ o f compound (lib) changes
greatly in connection with the preference for the dissociation processes due to the ortho
effect [6]. Thus, the appearance of peaks 243/245 (3:1) in the mass spectrum is due to the
elimination of the phenyl group, while the peaks for the 217/219 ions are due to the elimina-
tion of the benzonitrile fragment (Table I). The ions of the 1,2-dipheny!aeetylene (178)
and fluorene (165) structures confirm the ortho arrangement of the phenyl groups and indicate
that the chlorine atom is not present in these substituents.
In connection with the electron deficiency at the C(s) atom in the imidazotriazines
(lla, b)* the chlorine atom at this position can be expected to have significant mobility.
In order to confirm this conclusion experimentally we studied the behavior of compounds
(lla, b) in reactions with nucleophilic reagents. It was found that the boiling of 3-chloro-
imidazotriazines (lla, b) in an excess of diethylamine, piperidine, morpholine, aniline~
and hydrazine hydrate leads to the formation of the corresponding derivatives of imidazo[i~
2-b]-l,2,4-triazine (IVa-g) (Table 2).
In the mass spectra of compunds (IVc, d) we recorded the peaks for M + 369 and 371, res-
pectively (Table i). At the first stage of the dissociation of M+ the CHsCN particle is
eliminated (the r ion). At the same time the other nitrile residue is eliminated from the
triazine part of the molecule (with the formation of the common [M -- RIR~N~N] (259) ion).
Most of the remaining fragment ions in the mass spectra of the imidazotriazines (IVc, d)
are due to the dissociation of the imidazole part of the molecule (the 178, 165, 129, 103,
77).
In the IR spectra of the bicyclic compounds (IVf) and (IVg) the hydrazine group is
characterized by two broad absorption bands in the region of 3230-3310 cm -:.
When the 3-chlorine-substituted compounds (lla, b) were heated with thiourea in dioxane,
the corresponding thio analogs (Va, b) were obtained. The latter are formed readily during
the direct thionylation of the initial imidazotriazin-3-ones (la, b) by the action of phos-
phorus pentasulfide in pyridine (see the scheme).

The charge at the C(a) atom, calculated by the Hfickel method, amounts to +0.102 and +0.189
respectively.

793
 The obtained compounds (I~-V) e x h i b i t luminescence (~maz 47~532 rim) and are capable
of generating laser radiation during excitation ~y =he third aud ~ourtn harmonics of =he
neodymium laser in the 485--593 nm band. The Imldazotrlazlnes (Ira) exhibit =he highest
senerating efficiency ~22~),

EXPERIMENTAL
The ~R spectra of the compounds were measured in dlozane end in tablets wlth potassium
bromide on a UR-20 speetrophotometer. The PMR spectra of 10% solutions of the reaction mix-
ture of (lea) and (Ill) in DMSO-d6 were obtained on a Bruker WH-90 instrument with TMS as
internal standard.
The GLC and mass-spectral investlgatlons were carried out on LKB-2091 instrument at 70 eV
with a cathode emission current of 300 ~A and an acceleratin 8 potential of 3 kV. A packed
column was used for the separation of the reaction products (lea, Ill) (Z = 2m, d - 2 mm,
liquid phase OV-lOl). The chromatograph injector temperature was 300~ and the column
temperature was 250~ (isothermal). The hlgh-resolution mass spectra were obtained on a
Varian MAT-311 instrument with resolution M/AM = 15,000 and with PPA as standard.
The quantum-chemical calculations for compounds (lea, b) were performed out in the
Huckel approximation. The coulomb and resonance integrals were taken from [9]. Compound
(la) was obtained by the method in [i0], and imidazotriazin-3-one (Ib) was obtained for
the first time by a similar method.
The characteristics of the synthesized compounds are given in Table 2.
Chlorination of Compounds (la, b). A. The chlorination of (Ia, b) was realized by the
method in [4]. Starting from imidazotriazin-3-one (la), we obtained a mixture of compounds
(lea) and (Ill). From compound (Ib) we obtained the individual 2-methyl-3-chloro-6,7-dlphenyl-
imidazo[l,Z-bJ-l,2,4-trlazine (lib).
B. A mixture of 0.01 mole of the respective imidazotriazin-3-one (la, b), 11.9 g (0.I
mole) of thlonyl chloride, and 5-7 drops of DMFA in I00 ml of chloroform was boiled for 2 h.
The mixture was filtered out, and the precipitate was washed with cold ethyl acetate and
dried. The yields of (lie, b)were 65 and 73% respectively.
Synthesis of Compounds (IVa-g). A mixture of 0.i mole of 3-chloroimidazo-l,2,4-trlazlne
(IIa) or (Iib) and 1 mole of the corresponding amine or hydrazine hydrate was belled for 4-6 h.
The mixture was cooled, and the precipitate was filtered off, washed with ether, and dried.
3-Mercapto-Substituted Imidazo [l,2-b]-l,2,4-triazine (Va, b)__A. Amixture of 0.005 m o l e
of 3-chloro-imldazotriazine (Ila) or (Ilb) and 0.015 mole of thiourea in 50 ml of propyl
alcohol was boiled for 6 h. The reaction mass was cooled, and the precipitate was filtered
off and washed with water. The yields of (Va, b) were 63 and 58% respectively.
B. A mixture of 0.01 mole of (Ia) or (Ib) and 0.02 mole of phosphorus pentasulfide
was boiled for 4 h. The mixture was cooled, poured onto ice, and left at 0~ for 4 h. The
Precipitate was filtered off, washed with water, and dried.

LITERATURE CITED
i. V . P . Kruglenko, V. P. Gnidets, N. A. Klyuev, E. V. Logachev, M. A. Klykov, and M. V.
Povstyanoi, Kh. Geterotsikl. Soedin., No. i0, 1402 (1985).
2. V . S . Zuev, L. A. Komel'kova, V. P. Kruglenko, O. A. Logunov, M. V. Povstyanoi,
A. V. Startsev, Yu. Yu. Stoilov, and A. A. Timoshin, Kvantovaya Elektron., ii, 393
(1984).
3. M . V . Povstyanoi, V. P. Kruglenko, A. A. Timoshin, N. A. Klyuev, I. I. Grandberg,
and Yu. Yu. Stoilov, Izv. Timiryazevsk. S-kh-Akad., No. 5, 155 (1984).
4. M . V . Povstyanoi, V. A. Grin', V. P. Kruglenko, and S. S. Stoyanovich, Zh. Org. Khim.,
15, 1991 (1979).
5. Yu. V. Strokin, B. A. Priimenko, A. K. Sheinkman, and N. A. Klyuev, Khim. Geterotsikl.
Soedin., No. i0, 1404 (1979).
6. R . A . Khmel'nitskii, Khim. Geterotsikl. Soedin., No. 3, 291 (1974).

*The lasar characteristics of compounds (II-V) are discussed in detail in [7, 8].

794
 7. L. A. Komel'kova, V. P. Kruglenko, O. A. Logunov, M. V. Povstyanoi, A. V. Startsev,
Yu. Yu. Stoilov, and A. A. Timoshin, Kvantovaya ~lektron., i0, 876 (1983).
8. V. S. Zuev, V. P. Kruglenko, O. A. Logunov, A. V. Startsev, and Yu. Yu. Stoilov,
Kvantovaya Elektron., 8, 1567 (1981).
9. A. Streitwieser, Molecular Orbital Theory for Organic Chemists, Wiley, New York (1961).
i0. J. Lalezari and Y. Levy, J. Heterocycl. Chem., Ii, 327 (1974).

REACTION OF 2-ALKYLAMINOBENZOTHIAZOLES WITH ACRYLIC ACID

V. A. Saprykina, R. F. Ambartsumova, UDC 547.789.6.07:543.422

and N. K. Rozhkova

The behavior of 2-alkylaminobenzothiazoles in the reaction with acrylic acid was

studied and it was shown that under kinetically controlled conditions, the reaction
proceeds at the endocyclic nitrogen atom of the ambifunctional system. The forma-
tion of amino-isomers is controlled thermodynamically.

The addition of 2-alkylamlnobenzothiazoles to reagents containing carbon-carbon multiple

bonds has not yet been investigated. There are only a few reports on the reaction of un-
substituted 2-aminobenzothiazole with acetylenecarboxylic acid esters [1-5], leading to the
formation of condensed addition products at the endocyclic nitrogen atom of the hetero-sys-
tem. At the same time, in addition to pyrimidobenzothiazoles, the authors of [3] isolated
an adduct with an amino structure, i.e., an addition product at the exocyclic nitrogen atom.
To synthesize potential pesticides, and to examine the paths and conditions of the reac-
tion of 2-aminobenzothiazoles with activated alkenes, we studied the reaction of compounds
la-d with acrylic acid. The reaction was carried out in aprotic solvents (acetone, toluene)
in the temperature range from 30 to II0~

' ~f~\ - -N /"~- -~. N ' ~ C H z C I I z C O ~ /%-'C" ...... N +

$" NHR S "NR ~

I a-d 11 a - d w a-d

+ rT;"'" " "NCHs ",

t I
R g
rVa-d
I - r v a R=.CB~, b F m C 2 ~ 5, C R ":C3H7, dR= C4g ,

The ratio of yields of compounds lla-d-IVa-d depends on the temperature (Table I). At
30 and 56~ 2-alkylimino-3-(2-carboxyethyl)benzothiazolines (lla-d), products of addition
of acrylic acid to the endocyclic nitrogen of the heterocycle, become predominant. The
isomeric amino analogs llla-d are not formed in appreciable amounts. Increase in the tem-
perature to II0~ leads to a sharp increase in the yield of 2-[N-alkyl-N-[2-carboxyethyl)
aminojbenzothiazoles (Ilia-d). Under the same conditions, benzothiazolylamides of 3-(2-
benzothiazolyl)propionic acids (IVa-d) are formed in low yields. The alkyl substituent
in compounds la-d does not influence the path of the reaction, but the overall yield of
the products somewhat decreases with the elongation of the chain. The predominant formation
of compounds llla-d at II0~ (Table i) is probably the result of isomerizatlon of the imino
analogs lla-d under the reaction conditions. We shall discuss this fact in a future article.
The structure of the synthesized compunds was established by using IR, UV, and PMR
spectroscopy methods (Table 4), and mass spectrometry (Tables 2 and 3), and was also
confirmed by elemental analysis data (Table 5) and alternative synthesis.

Institute of Chemistry of Plant Materials. Academy of Sciences of the Uzbek SSR, Tash-
kent 700170. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 986-991,
July, 1986. Original article submitted March 12, 1985.

0009-3122/86/22070795512.50 9 1987 Plenum Publishing Corporation 795

 TABLE i, C e n d i ~ i o n m o~ P r @ p a r a t i o n a n d u 1 6 3
o f Produc~s o f A 1 k y l a ~ i o n Reaction of Compoundn
Xa-d

COm- Yield ~ = ~ ~
pou~ Tme, Iv
I 11 1 1H I
lJ 30 +00' 80
58 I0 =
110 83 8
Ib 30 1800 89 5 <!
66
l lO 7i 12
Ic 30 1800 49
58
llO 8 11
ld 30 1800 32
56 <1
110 5 7

*At a 1:2 ratio between 2-alkylaminobenzo-

tnlazole and acrylic acid.

TABLE 2. Mass Numbers (m/z) and Relative Intensities of Frag-

ments (%) in Spectra of Compounds lla-d and llla-d

pound
J ~176
M, [M-C~HsCOOH+ [M-CH2COOH]+ !I[M_CH:COOItl,M-C~H~COOH]' Olher Hagments

lh 23~ (43) 164 (100) 177 (5) 20 191 (25), 177 (5), 163 (25),
150 (5),136 (45),135 (34)
llb 250 (6) 177 (I00) 191 (2) 50 205 (5),164 (9),163 (61),
150 (79), 136 (42), 135
(12)
Ilc 264 (2) 192 (58) 205 (0,3) 193 177 (14), 164 (17), 163
(100), 150 (60), 136 (21),
135 (7)
IM 278 (23) 206 (73) 219 (0,3) 243 235 (100), 191 (7), 177
(20), 164 (26), 163 (87),
150 (82), 136 (20), 135
03)
III~ 236 (100 164 (63) 177 (53) I 191 (21), 163 (25), 150
(ll), 136 (53), 135 (21)
IIIb 250 (31) 177 (49) 191 (49) I 205 (15), 177 (49), 163
(lO0), 164 (7), 150 (14),
136 (30), 135 (19)
IIld 264 (31) 192 (45) 205 (5) 9 177 (20), 164 (16), 163
(I00), ISO (60), 136 (22),
135 (11)
Illd 278 (26) 206 (24). 219 (1) 24 177 (21), 164 (18), 163
(lO0), 150 (40), 136 (27),
135 (12)
It is known that the alkylation of 2-aminobenzothiazoles by alklyl halides, including
halocarboxylic acids, in a neutral medium takes place at the endocyclic nitrogen atom [6].
Thus, in the reaction of benzothiazole la with 8-bromopropionic acid, carboxyethylbenzo-
thiazoline lla, identical to the above described compound lla, is formed.
The amino-isomer Ilia was obtained by the saponification of 2-[N-methyl-N-(2-methyoxy-
carbonylethyl)amino]benzothiazole [7]. It should be noted that an imino structure has been
erroneously ascribed previously [8] to compound Ilia.
The alternative synthesis of compounds IVa and IVd has been carried out by acylation
of heterocyclic amines la and Id by acids Ilia and llld, respectively.
In the IR spectra of the reaction products, intense stretching vibration hands of
carboxylic (1705-1740 cm-*, compounds II, Ilia-d) and amide groups (1660-1680 cm-*,
compounds IVa-d) were recorded. Still more intense bands characterize the vibration of
the C ~ N bonds, whereby the absorption of the exocyclic azomethine bond is observed in
the higher frequency region (1605-1640 cm-*), than that of the endocyclic azomethine
bond (1540-1560 cm -~ (Table 4).

796
 TABLE 3. Mass Spectra of Compotmds IVa-d
,

Com- Values of m/z (relative intemity, %)

pound Type of rupture Othex fragments
M+
A~ A.~ B
IV. 382 (27) 163 (27) 219 (t00) 177 (91) 19t (36) I89 (30), I64 (64), 150 (9),
136 (45), 135 (27)
IV 4to (41) 177 (35) 233 (58) 191 (65) 205 (41) 203 (35), 178 (76), 164 (18),
163 (100), 150 (65), 136
(70), 135 (24)
IV 438 (1 t ) 19~ (46) 247 (I00) 205 (1t) 2t9 (8) 217 (23), 164 (t9), 163 (57),
t50 (68), t36 (32), 135 (2)
IV 466 (22) 205 (66) 261 (I00) 2t9 (51) 233 (68) 231 (78), 206 (66), t92 (32),
178 (17), 163 (86), 150 (68),
136 (29), t,35 (92)

T.ABLE 4 . S p e c t r a Characteristics of Compounds II-IVa-d

...... ,, , .,,0,,

Corn- UV spectrum, kmax,

I lit spectrum.,]
u, era -I HvlRspectrum, 6, ppm(CFsCOOH)
pound I nm(l~ ~
"Ethanol o,IN.HCI C=O C=N N--CH~ CHACO c~ C~ Aromatic
protons
(others)
tla 223 (4,44) 223 (4,33) I720 t620 4,20 (T 2H) 2,79 (~ 2H) 2,88 (d, 3H) 6,95--7,55
264 (3,97) 256 (4,04) (M,4H)
281 (3,70) 28I (3,98)
306 (3,59) 290 (4,02)
IIb 223 (4,26) 223 (4,19) 1720 t630 4,t5 (T,2H) 2,7i (2: 2H) 1,o5 (q?,3H) 6,95--7,50
264 (3,80) 256 (3,82) 3,0--3,4 (M,4H)
281 (3,57) 280 (3,74) (M 2H)
290 (3,52) 289 (3,78)
306 (3~39)
tId 222 (4,39) 219 (4,34) 1710 I640 4,20 (T 2H) 2,80 (T 2H) 1,25--1,75 0,65 (T.,3H) 6.95--7,60
263 (3,94) 258 (3,9I) 2,90--3.35 (M,2H) (M,4H)
28l (3,79) 281 (3,89) (~,2H)
290 (3,8t) 290 (3,9t)
306 (3,37)
lid 222 (4,47) 215 (4,30) 1605 4,18 (~ 2H) 2,76 (T, 2H) 0,85--1,60 0,56 (T,3H) 7,00--7,50
265 (4,0I) 258 (3,89) 2,95--3,35 IM,4H) (M,4H)
283 (3,84) 280 (3,86) "(Iv~2H)
290 (3,82) 290 (3,89)
305 (3,65)
tIIa 227 (4,50) 215 (4,47) 3,62 (T, 2H) 2,62 (T, 2H) 3,05 (S, 3H) 6,85--7,30
274 (4,23) 262 (4,10) (M,4H)
305 (3,65) 280 (4,04)
296 (4,08)
lllb 226 (4,59) 220 (4,43) 3,72 (T, 2H) 2,69 0",2'H) 1,08 (T,3H) 7,00--7,50
275 (4,31) 265 (4,12) 3,30--3,67 (M,4H) ,
302 (4,01) 282 (4,08) (~ 2H)
291 (4,10)
lllc 227 (4,39) 220 (4,30) 3,72 (T~ 2H) 2,67 (T 2H) 1,15--1,82 0,65 (T,3H) 6,95--7,50
275 (4,13) 265 (4,00) 3,05--3,50 (M,2H) (M,4H)
302 (3,83) 282 (3,98) (M, 2H)
-99I(4,00)
IIId 227 (4,27) 220 (4,14) 3,70 (% 2H) 2,68 (T,2H) 1,15--t,65 0,70 (% 3H) 6,90--7,40
275 (4,00)
302 (3,52)
265
283
(3,84)
(3,81)
3,15---3,45 (M,4H) (M,4H)
(M 2H)
290 (3,85)
tVa 223 210 (4,55) 3,75 ~r, 2H) 3,08 (T 2H) 3,10 (s, 3H) 6,70--7,35
273 259 (4,I8) 3,52 (st 3H) (M, 8H)
309 28t (4,12)
289 (4,13)
I~Vb 224 (4,56) 2t0 (4,53) 3 80--4,15 3 05--3,65 t,i7 (T,3H) 7,00--7,80
278 {4,36) 259 (427) iT, 4H) iM 2m (U, 8H)
301 (4,12) 281 (4,t0) 3,05--3,65
289 (4,10) (~ 2H)
IVc 227 (4,53) 212 (4,54) 3,70--4,I 0 3,t0--3,50 t,42---1,70 0,68 7,05--7,65
279 (4,29) 260 (4,22) (hi 4H) ~ 2H) (M, 4H) (2?, 6H) (M, 8H)
302 (4,11) 282 (4,14) 3,10--3,50
290 (4,12) (,M 2H)
IVd 224 (4,54) 2!0 (4,57) ,65 (T 2H) 2,90--3,50 1,00--1,25 0,52 6,90--7,40
278 (4,37) 260 (4,32) 2,90--3,50 (M 2H) (~ 8H) (2?, 3H) (~i, 8H)
301 (4,18) 28t (4,13) (~ 2H) 0,65 (T.3H)
289 (4,13)

797
 In the UV spectra in ethanol, =he Imino isomers lla-d display a finer structure than
the amino compounds llla-d and IVa-d. On transition from alcoholic solutions to 0.i N
hydrochloric acid, =he spectra of =he ~wo =ypes of isomers average out (Table 4).
In the PMR spectra, the CS values of the CHa group protons a= =he endocyclic nitrogen
atom are shifted to the weaker field (4.15-4.20 ppm, compounds lla-d), compared with CS
of the same pro=ons at the axocyclic nitrogen atom (3.05-3.72 ppm, compounds Ilia-d; see
Table 4).
We have previously developed in association wi=h Ya. V. Rashkes [7, 9, I0] a method
for the identification of amino- and imino-lsomers in the series of 2-aminobenzothiazoles,
using mass spectrometery. The most important indication distinguishing these groups of
compounds is the distribution of intensities of ions formed as a result of ~ and ~-ruptures
(with respect to the heterocycle) of the alkyl chain. The above characteristics were
applied in the present work to confirm the structure of compounds lla-d-IVa-d (Tables 2, 3).
The great prevalence of the [M-- CzH3COOH] + ions and the low (or completely absent) peaks of
the characteristic [M -- CH2COOH] + ions indicate the presence of imino compounds lla-d. Sharp
decrease in ratio I[M - C~HsCOOH]+/I[M -- CH2COOH] + (Table 2) is characteristic for amino-
benzothiazoles llla-d. The peaks of the molecular ions in the mass spectra of lla-d are
less intense than the corresponding peaks in the spectra of the amino isomers llla-d,
since a decrease in the degree of aromatization destabilizes the molecular ion. The dif-
ficulties in the interpretation of the spectra of compounds lld and llld due to the elonga-
tion of the readily decomposing alkyl substituent should be noted.
Compounds IVa-d decompose similarly to the fragmentation of both 2-alkylaminobenzo-
thiazoles [7] and 2-acylaminobenzothiazoles [9] (Table 3). The conversion of the carboxylic
group in compounds llla-d into an amide group (compounds IVa-d), in general, decreases the
stability of the molecule to electron impact. In the mass spectra of amides IVa-d, a
successive splitting of the molecular ion according to type A, B, C is observed, the dominat-
ing fragmentation process being the e-rupture (type A).

A~ B C~ A~

~2 ('2 AZ
IV a-d

Taking compound IVd as an example and using high resolution mass spectrometry, it was
shown that in the compounds studied the rupture of the CH=--CO bond leads to the appearance
of two types of fragmentary ions in the spectrum. The determination of the elemental com-
position of the ion with m/z 233 made it possible to establish the empirical formula
C~3H~TN=S (type Ca). However, only 60% of the ions with mass number 231 (CIsH,sN=S composi-
tion) have been formed by this path. The remaining 40% of the ions were formed as the
result of type C2 fragmentation (C,2H**N2OS composition).

EXPERIMENTAL
The iR spectra were recorded in KBr tablets on a UR-20 spectrophotometer; the UV spectra,
on a Hitachi EPS-3T spectrometer; and the PMR spectra, on a Jeol C-60 HL spectrometer,
using TMS as internal standard. The mass spectra of compounds lla-d-IVa-d were run on an
MX-1303 mass spectrometer (direct introduction of the sample), at the temperature of the
input tube of I00-120~ and ionizing voltage of 40 eV. The summary spectra of compounds
!Vc-d and the elemental eompositions of the ions were determined on a MX-1310 apparatus,
at the temperature of t~e direct introduction system of the sample of I00-130~ ionizing
voltage of 50 eV, usii~ [~erfluorokerosene as a reference substance.
The compounds obtained were separated by preparative column chromatography, using
silica gel L 100/160 as sorbent, and elutlng the products successively with benzene and
ethanol. The purity of the compounds obtained was controlled on Silufol UV-254 plates.
Reaction of 2-alky_laminobenzothiazoles with Acrylic Acid. A mixture of i0 mmoles of
acrylic acid and 5 mmoles of the corresponding heterocyclic amine is held in i0 ml of a
solvent (acetone or toluene) at the corresponding temperature (Table I). After evaporation

798
 TABLE 5. Characteristics of Synthesized Compounds
Com- F6und_, % Empirical Calculated, %,i .......
l
,

pound rap, *C I "~%' formula C H N S

I
IIa 147--14~1 0,41 55,7 5,1 I I1,81 13,4 C11HI~N20eS 55,9 5,1 11,9 13,6
Ilb 110---1111 0,46 57,8 5,8 [ ll,1 ] 12,6 CIeHI4NeO2S 57,6 5,6 11,2 12,8
Ii~ 122--1231 0,50 59,1 6,2 10,5 [ 12,0 CI~Ht6N~O~S 59,0 6,1 10,6 12,1
Ild ~H~--iI~I 0,61 60,2 6,3 10,0 1 1 , 2 C14HmN~O~S 60,4 6,5 10,I 11,5
IIIa 167--1681 0,20 55,6 5,0 11,8 1 3 , 4 CI~HI2N2OeS 55,9 5,1 tl,9 13,6
IIIb 129--1301 0,31 57,4 5,6 11,2{ t3,5 CIeH~4N202S 57,6 5,6 11,2 13,6
III c 89--9~ t0,45 59,3 6,0 10,6[ 12,2 C~3HmN202S 59,0 6,1 10,6 12,1
Itld 9ti---_qY I 0,39 60,0 6,4 10,0] 11,1 Cv~HmN20~S 60,4 6,5 10,1 11,5
l'Va 209--2101 0,52 59,6 4,7 14,8 [ 16,8 C19HIsN40S2 59,7 4,7 14,6 16,8
1Vb 107--1081 0,64 61,3 5,2 13,61 155 C21H22N~OS~ 61,4 5,4 13,7 15,6
IVc ~--9~ i 0,83 63,2 6,0 12,7[ 14,3 C~3H~N4OS2 63,0 6,0 12,8 14,6
,IVd 105--~071 0,8w 64,0 6,3 11,9] 13,6 C~HaoN4OS~ 64,3 6,5 12,0 13,7

*For compounds Ia-d in a 2:1 ethanol-water mixture; for IIla-d

and IVa-d in a 4:1 benzene--acetone mixture.
of the solvent, the residue is chromatographed on a column with silica gel. Compounds IIa-d
and IIIa-d are recrystallized from ethanol and compounds IVa-d, from benzene. The charac-
teristics of the synthesized compounds are listed in Table 5.
2-Methylimino-3%(2-carboxyethyl)benzothiazo!in e (ila). A 1.52 g portion (I0 mmoles)
of 3-bromopropionic acid is added to a solution of 0.82 g (5 mmoles) of compound Ia in 15 ml
of acetone, and the mixture is boiled for I0 h. The solvent is evaporated, and the residue
is treated by water, with heating, then cooled, and triethylamine is added to pH 60 Unreacted
initial amine is extracted by benzene. The aqueous solution is evaporated to dryness, and
residue is crystallized from absolute ethanol to yield 0.34 g (41%) of compound Ia. The
compound does not depress the melting point in a mixture with compound lie, obtained by
reacting amine Ia with acrylic acid.
2-[NT(2,Carboxyeth[l)-N-methylamino]benzothiazole (IIIa). A 0.i g portion (0.4 mmole)
of 2-[N-methyl-N-(2-methoxycarbonylethyl)amino]benzothiazole [7] is dissolved in 1.5 ml of
ethanol, 1 ml of concentrated hydrochloric acid is added, and the solution is boiled for 3 h.
The reaction mixture is evaporated to dryness, the residue is treated with 5 ml of a saturated
solution of sodium carbonate, the mixture is filtered, and the product is isolated by neutral-
ization of the filtrate with 10% hydrochloric acid. Yield, 0.04 g (43%). The reaction
product does not depress the melting point in a mixture with compound !Ila~ obtained from
amine Ia and acrylic acid.
N-Alkyl-N-(2-benzothiazolyl)amides of 3-[N-alkyl-N-(2-henzothiazolyl)-amino]propionic
acids (iVa, d). An equimolar mixture of aminobenzene la or Id and amino acid IIIa or I!Id
is boiled in toluene for 20 h. The solvent is removed, and the residue is extracted by
hot hexane. Hexane is evaporated, and the dry residue is washed with dilute hydro-
chloric acid and recrystallized from benzene. Yields, 21 (iVa) and 15% (IVd). The compounds
do not depress melting points in a mixtures with samples of IVa and IVd obtained in a
reaction of amines Ia and Id with acrylic acid.

LITERATURE CITED
i. D. W. Dunwell and D. Evans, J. Chem. Soc., No. !I, 2094 (1971).
2. H. Ogura, M. Kowano, and T. Itch, Chem. Pharm. Bull., 21, 2019 (1973).
3. H. Reimlinger, M. A. Peiren, and R. Merenyi, Chem. Bet., 108, 3894 (1975).
4. H. N. AI-Yallo and M. A. Muniem, J. Heterocycl. Chem., 15, 849 (1978).
5. J. J. Wade, R. F. Hegel, and C. B. Toso, J. Org. Chem., 44, 1811 (1979).
6. Y. Matsunaga and S. Takagi, Yakugaku Zasshi, 88, 1003 (1968); Chem. Abstr., 70, 19971
(1969).
7. Ya. V. Rashkes, R. F. Ambartsumova, V. A. Saprykina, and N. K. Rozhkova, Zh. Org. Khim.,
~, 1981 (1978).
8. N. K. Rozhkova and V~ A. Saprykina, Uzb. Khim. Zh., No. 3, 60 (1974).
9. Ya. V. Rashkes, R. F. Ambartsumova, V. A. Saprykina, and N. K. Rozhkova, Zh. Org. Khim.,
16, 1744 (1980).
10. Ya. V. Rashkes, R. F. Ambartsumova, V. A. Saprykina, and N. K. Rozhkova, Zh. Org. Khim.,
17, 614 (1981).

799
INVESTIGATION OF NITROGEN- AND SULFUR-CONTAINING HETEROCYCLES.
44. * NEW HETEROCYCLIC SYSTEMS. DERIVATIVES OF IMIDAZOLIDINO-
[3,2-f]PYRIDO[2,3-b]-AND IMIDAZOLIDINO[3,2-f]PYRIMIDO[4,5-b]-
1,4-THIAZINES. SYNTHESIS AND STRUCTURE

L. G. Levkovskaya, :. E. Mamaeva, L. A. Serochkina, UDC 747.781.3'783'836.3'

and T. S. Safonava 869.2~176

New representatives of heterocyclic systems, imidazolidino[3,2-f]-pyrido-[2,3-b]-

and imidazolidino[3,2-f]pyrimido[4,5-b]-l,4-thiazines, have been obtained. Inter-
mediate compounds of 5N-oxalamides-6-hydroxy-7H-pyrido[2,3-b]-l,4-thiazine have
been isolated and characterized. Amides of N-(pyridyl-3)- and N-(pyrimidyl-5)-
oxaminic acids have been obtained.

We have previously reported [2] that interaction of o-aminomercapto derivatives of pyr-

idine and pyrimidine with esters of 8-halogeno-e,y-dlketoacids results in formation of
derivatives of oxazolidino[3,2-f]pyrldo[2,3-b]-l,4-thiazines (I, II). However, in the case
of 2-mercapto-3-amino-6-chloropyrldlne and esters of 8-1sovalerylpyruvic acids the reaction
is arrested at the stage of formation of the corresponding esters of N-(pyridyl-3) oxaminic
acid (IIIa, b).
As a continuation of these studies we have investigated the chemical properties and
transformationsof compounds I-III under the action of nucleophilic agents. It has been
foundthat compounds I and II react extremely easily with ammonia and amines. Depending
on the reaction conditions~ the reaction proceeds either with retention of the tricyclic
system~ or with the ring opening of the oxazolldlne cycle only, or with the opening of
both oxazolidine and thiazine cycles at the C(a)-O and N(s~-Cr bonds. Thus, according
to [3], interaction of Ia-d and II with ammonium acetate'in g~a6ial acetic acid at 80-I00~
gives rise to derivatives of new heterocyclic systems, imidazolino[3,2-f]pyrido-[2,3-b]-
1,4-thiazine (VII a-d) and imidazolino [3,2-f]pyrimido[4,5-b]-l,4-thiazine (VII g, Table i).

I O~ ~0 O~ C C xO

/7---[
I ~NH2
X~/~,. N. /0 .......... ~ - - . . . . . . . ~ /'- ,N 0tl --a,-

",,.,\, 1 s
R "bN S ::I

oo~x'~," la-d,ll ',,\.\ iv a-e

c: / ,x

"@ 0 0 0 RI 0 0 R~ 0 0
, } | ~. /i~llC--C-- OC~H s A t~n~-- Cm X/S~. /NIIC - C R
~L, ':- ~H r~'~ " Y'"r "

R" ":N'" " S "

vii a-g .I a-d Va_l v] a-c
Ia--d, Va.~-f,h--k, VIb, VIIa--f X=CH, R=CI, R:=H; ti, VgtL, Via, VtIg. X=N,
R=H; RJ,~OCHa, R2=C~H~, Ia, llte, IVa, Va,C,i, Vlla R~=CHa; Ib, IVb, Vbd, Vllb,
R2=C~H.:.; [~ Ill& IVc, Ve,f,k Vile R2=C3HT; Ilia, Vd,t~ VII R2=C6Hs; I@ VII d,
R~=n.C4H~c illb, Vile R2=t-C,Hg; Va--d Ra=H; Ve~f Vlti, c R~=NHCH2C~Hs; V h - k t
R3= rnorpholyl;Vg, Via R3= H

*For communication 43, see [I].

S. Ordzhonikidze All-Union Scientific-Research Institute of Pharmaceutical Chemistry,

Moscow 119815. Translated from Khimiya Geterotsiklicheskikh Soedininii, No. 7, pp. 992-
997, July, 1986. Original article submitted February 18, 1986; revision submitted June 19, 1985.

800 0009~3122/86/2207-O800512.50 O 1987 Plenum Publishing Corporation

 TABLE i. Characterization of Compounds IVa-c, Va-l, Via,b, and VIIa-g
,,,, ,,,, ,,,,,j ,,,,,,, ,

Com- ~o~n~
pound rap*. 'E: gf (sys- t- M01eculaz formula .....I Yield.
tem) .... c ,,, c! N S t~ C -' H CI N s %
IV~ 287--289 0,51 (a) 41,5 3.4 12,3 14,7 11,4 CmHmCIN~OaS 41,7 3,5 12,3 14,6 11.1 1 93
IV b 262--264 43~8 4,2 11,8 14,4 I0.~ C . H,2CIN~OaS 43,8 4.0 1 t,8 13,9 10,6! 81
IX;c 247--~49 0,5 (a) 45,5 4,4 11.8 13,5 10,2 C12H,4CINzOsS 45.6 4.4 11,3 13,3 10,I! 9O
Va 208--210 41,4 3.5 12,3 14,5 11,3 C,oHmCIN~O~S 41.7 3.5 12,4 lq,6 11)1 ] 71
Vb 207--209 0,5 (a) 43,8 3.9 1t,3 13,9 10,6 CItHmCINzO~S 43,8 4.0 11,8 13,9 10.6i 75
Vc 193--194 45,5 4.6 tl.5 13,2 103 C~H~,CINaO~,S 45,6 4,4 II,3 13,3 lO,1] 94
Vd 228--230 0,6 (a) 5,1,6 3~5 10,3 I 11,8 9,~ CmHI2CINzOaS 51,5 3~4 10,2 12,0 9J i .0.5
Ve 189--190 54,1 4,2 8,7 11,1 : - - C,THI6CINzOsS 54,0 4,2 9,3 II,I 8,5J 61
vf 179--181 55~9 4,6 8,9 1,0,4 7,6 CmH~CIN~OsS 56,2 4,9 8,7 i0,3 7,9 81
Vg 196--197 0,67 (b) 44,3 4.7 18,91 10,8 C n HI,IN,tO4S 44,3 4,7 -- 18,8 10,7 88,6
Vh 145--147 54,4 4.3 8,3 9.8! 7,4 CIoHiaCIN~O4S 54,3 4.3 8,5 10,0 7,6] 96
Vi 105--107 47,0 4.5 10.0 1 t,7 I 9.3 C,4H~6CINzO4S 47.0 4.5 9.9 11,7 8,9, 80--8:~
vJ 133--135 46,2 4,6 9.3 10,8i 8,4 CisHIaC1N304S 46,5 4,6 9,2 10,8 8,2 1 78
Vk 113--115 49,8 5,2 9,0 10.7 8,4 C,~H:oCINsO4S 49,8 5,2 9,2 10,9 8.3 t 93
V1 13'0--131 48,5 5,3 14,3 i 8,9 C,~H2oN4OsS 48,9 5,5 -- 15,2 8.f 89
Via 214--215 43,0 4,2 .)8,4! CvHsN40~ 42,9 4,1 -- 28,6 72
Vlb 212--214 57,8 4,0 14,7] Cl4Hl2CINaO2 58.0 4,1 1:4,5 71
VH a 298--300 0~&5(a) 44,4 3.0 13.5 15,3 ] 11.7 CmHsCIN30~S it4,5 3,0 13,2 15,6 1:1,91 96---98
Vllb 263--264 0,39(a) 46,3 3,6 12,7 14,9 11,4 CuHmCIN302S 46,6 3,5 12.5 14.8 11,3 91 --98
VIIc 250--251 0,39 (~) 48,4 4,0 13,8 14,4 10.8 C mHtaCIN,OzS 48,4 4,0 11.9 14,1 10,7 90
VII d 262--264 0,44 (a) 50~4 4,5 11,7 1~,7 10.2 CtzH~4CIN,O~S 50,1 4,5 t 1,4 13,5 10,3 88
Vile 249,--250 5O,I 4.8 11,3 13,6 10,3 CI~H14CINzO2S 50,1 ~,5 I 1,4 13~5 10,3 96
vIIf >30O 54,1 3,0 10,7 12,4 9,7 CmHIoCINaO~S 54,3 3,0 10,7 12,7 9,6 72--93
Vllg 249--241 O,5(b) 47,2 4,5 20,0 11,I CuHI~N~OzS 47,1 4,3 20,0 11,4 69--79

*Recrystallization of compounds IVa-c, Va,d,f,h,i,k, Vlb, Vlla-d,g from ethanol, Vb,c,e from a 1:2 mixture
ethanol--DMF, VIIf from a 2:0,5 mixture of ethanol--DMF, Vj from a i0:I mixture of ethanol--DMF, V1 from water,
Vg from aqueous ethanol, 3:1, and Via from ethyl ace,tete.

OO
O
k-a
 TABLE 2. Spectral Charac~arSza~toa o~ Compo~n,l$

~~ "'H [ ten ] Of Of ~ '~mtX' am (in C~mN) '

" I ' I=mtd=v ~etonel tlo=~)

1740
ivb 344O 1730~
I760
0,78 (CH~O~, t ), i,98 (CHICH~
q), 3,52 if.OH=, ~)
lye: 3440 1670, 0,79, 1,30, 1,98 @rotor~ofC~H~),
1720
v a ~380 3~ 1880--
3300 18~0
V b 3390 3295, 1670 225 9,99 (CHiCHi, 't), 2,66 (CHiCHi,
3~10 ~,), ~,07 (S:=C.H=, ~), 8,1~8,B8
(Ntl,~, broaa s),- 10,27 (NH,
bmacl,)
Vr 3400 3300, 1860~
3200 1870
Vd 3400 3310, 1860-- ~45
3290 1680 0,84)
Vr 33OO 1670 23o
0,98)
vf ~29~ 1660, 282
1700
Vg 3440- 3280, 1885 0,95 (CHsCH~.t ), 2,~3 (CHsCH~
3310 3250 9q), 3,76 (OCIis, s), 4,13
(S~CH~, s), 8,63 (2-CH--, $),
9,23 (NH~,s), I,I,49 (NH)
3~20 1690 304 4,71 (S--CH~, s), 3,76, 4,26
(p~otousof the mornhollae ring).
7,01, 7,1, 8,15, 8,20 (p~o-
tom of the pyri~n~ ring).
7,54 (p[otomor ~ . ~
Vi 3250 1650, 2,23 (CHa, s), 3,45~ 3,98 (pro-
1680 totl~ of the morphnline ~ln~L
4,1 (S~CH~,s), 7,2}, 7,91
(protom of the pyridine ritsg)
V] 3310 1680
~k 3310 1640, 302 0,94, 1,67, 2,66 ( Dtoto~
1680 C~H~), 4.0I (S--CH~, s3. 3,75,
4.26 (protom of the mo~pholine
rin~). 7.02. 8,14 (p~otom 9
oft~epyridine ring)
v l 3250 1650~ 0,96 (CH~CH3.T), '2,51 (CHiCHi,
1685 q). 3,79 (OCH~. s), 4,17
(S~CH2, s ), 8,46 (2-CH, s )
V i a 3440, 3290, 1670 3,79 (OCtt~, ~), 8,65 (2-CH, ~),
3360 3260 9,61 (6-C[-I, s)
V[bi 3290- 1660--
3300 1670
vH~ 3260- 1740. ~08 (4,07), 244 1,67 (3a-CH~, s}, 8,44 (4.CH,,
3300 1780 423), 310 (3,90) .q)
3270 1720~ t08 (4,06), 244
(4,2(), 310 (3,88)
0,78 (CHiCH3, t ), 2,00 (CHiCHi,
q), 3,54 (4-CH~, q )
1760
VH.C 3080-- 1740-- 206 (4,0t), 244 0,79. 1,30. 1,98 (protons Of CsHT).
3100 1760 (4,20), 3tO (3,88) 3,52 (4-CH~. q)
Vlld 3060-- 1740,
3120 1760
vile ~030 1750. 240 (4,241, 300
) 760-- (3,90)
1770
VII f 3250 1740--
1770
VI1 g 3020 1745~ 0,82 (CH~CHu t), 1,41 (CHiCHi,
1775 q), 3,6, 3,66 (4-CH,~, ~o d,),
'3,99 (OCH~, s), 8,57 {2.CH, s )

*IR spectrum of compound IVa vOH 3530, IVb and VIe vOH 3540 cm -~.
tNMR spectra of Ib were taken in DMSO-d, Vh-k in CDCI3, and Vi
in CD3OD~

802
 It has been shown that the transformation to compounds Vlle,f can be realized using the
reaction of esters o{ N-(pyridyl-3)oxamic acid llla,b with ammonia under the above-mentioned
conditions. During the reaction of compounds Ia-c with ammonia in glacial acetic acid or
its mixture with benzene, the intermediate compounds 5N-oxalimides of 6-hydroxy-TH pyrido[2,3,
-b]-l,4-thiazine (IVa-c) were isolated. Compounds IVa,b were transformed into tricyclic
compounds VIIa,b by dehydration over P205.
Contrary to compounds Ia-c, the treatment of oxazolidino[3,2-f]pyrimido[4,5-b]-l,4-
thiazine (II) with ammonia, under the conditions described above, leads exclusively to the
formation of imidazolidino[3,2-f]pyrimido[4,5-b]-l,4-thiazine (VIlg).
Interaction of compounds I-III with a 25% aqueous ammonia, as well as with primary
aliphatic and secondary cyclic amines (benzylamine and morpholine), gives good yields of
amides of N-(pyridyl-3)- and N-(pyrlmidyl-5)oxaminic acids (Va-Z).
We established the identity of amides Vi,k obtained by us from esters IIIc,d and from
the cyclic oxazolidino[3,2-f] derivatives Ia,d.
We demonstrated that heating of amides Vg and Vd in glacial acetic acid or with POCI3
leads to imidazolidino[3,2-f]pyrimido- and pyrido-l,4-thiazines (VIlg,f). Cyclization of
amide Vg was also observed upon boiling it with an alcoholic HCI solution. However, the
yield of compound VIIg did not exceed 28%.
During the reductive desulfurization of amides Vf and Vg in alcohol with Raney nickel
amides of N-(pyridyl-3)- and N-(pyrimidyl-5)oxaminic acids (Via,b) are formed, similarly as
in [4].
The structure of synthesized compounds was confirmed by physicochemical methods such as
IR, UV, N-MR, and mass spectroscopy.
The IR spectra of compounds VIIa-g exhibit absorption bands of the NH group in the region
3030-3290 cm-* and the CO groups in the region of 1730-1780 cm -~ (Table 2). The structure of
compounds IVa-c and VIIa-g was unequivocally established by its NMR spectrum. In these com-
pounds the signal of the protons of the 7-CH= group (IVb,e) and of the 4-CH2 group (VIIa-c,g),
due to the presence of the asymmetric carbon atom in the 6 and 3a positions, show up as two
doublets with constant of the geminal interaction IHH = 12 Hz, contrary to compounds of the
opened structure Vb,g in which the signal of the SCH2 group protons appears as a singlet.
The mass spectra of imidazolidino[3,2-f]-pyrido- and pyrimido-l,4-thlazines VIIb,g show
peaks of molecular ions M + with mass numbers 283 and 280, respectively (calculated for the
35CI isotope). The fragmentation of M + proceeds similarly with the stepwise loss of NHCO
and CO molecules from the imidazolidine ring. One should point out that the most convenient
first step of the fragmentation of M + of compounds VIIb,g, as oppossed to the previously
studied oxazolidino [3,2-f]-derivatives, consists in elimination of the ethyl group in the
position with respect to the nitrogen atoms of the imidazolidine ring. Consequently, in
the spectra of compounds VlIb,g the peaks of ions [M-C2Hb] + (40 and 19)*, M-C2Hs-CO] + (21 and
26), and [M-C2Hs, -CO,-NHCO] + (48 and 22) have higher intensities then peaks of ions [M-NHCO] +
(4 and 8) and [M-CO,-NHCO] + (16).

EXPERIMENTAL
IR spectra of the synthesized compounds were recorded on a Perkin-Elmer 599 instrument
(in paraffin oil), and UV spectra on a Perkin-Elmer 575 spectrophotometer (in alcohol). NMR
spectra were measured on JNM-4H (i00 MHz and Varlan XL-100 instruments using TMS as an inter-
nal standard. T h e purity of compounds was confirmed by thin layer chromatography on $ilufol
UV-254 plates in the following systems: benzne--ethyl acetate--ethanol !7:5:2 (a) and 5:5:1.5
(b). The chromatograms were visualized in UV light. Electron impact mass spectra were
obtained on a Varian MAT-II2 mass spectrometer by the method of direct insertion of the
sample in the ion source.

The numbers in parentheses represent the intensities of ion peaks in percent with respect
to the maximal peak,

803
 Amides of N-[2-acylmethylthio)-6-chloropyridyl-3]oxaminic Acid (Va-f,h-k). A. A sus-
pension of 2 ~ o Y e s o f - Y ~ 3 a - ( a l k y l ~ ~ - b J - l , 4 -
thlazines ~a-c in I0 ml of 25% aqueous ammonia was stirred for 2-3 h at 18-20 o . The precip-
itated solid was filtered off, washed with water, and dried to give amides Va-c. Under
analogous conditions the reaction of 2 mmoles of oxazolidino[3,2-fJpyrido-l,4-thiazines la-c
with 3 mmoles of benzylamine or morpholine in 15-20 ml of ethanol produced compounds Ve,f,i-k.
B. The ethyl ester of the corresponding N-[2-acylmethylthio)-6-chloropyridyl-3]oxaminic
acid (IIIa,c,d)(2mmole) was stirred with 2.5-3 mmole of morpholine in 15-20 ml of ethanol.
The precipitate was filtered off, washed with water and ether, and then dried to give com-
pounds Vh,i,j. A sample of 8.0 g (26 mmole) of compound IIIa was treated with 25% aqueous
ammonia under conditions described for method A to yield amide Yd.
The identity of amides Vi,k obtained according to methods A and B was confirmed by
comparing their analytical and spectral characteristics.
Amides of N-(4-Methoxy-6-propionylmethylthio)pyrimidyl-5-oxaminic Acid (Vg,l)o To a
suspension of 0.83 g (2.83 mmole) of compound II in 50 ml of alcohol 5 ml of 25% aqueous
ammonia was added. The substance dissolved and after 10 min a solid precipitated. The
reaction mixture was stirred for additional 30 min at 18-20~ The precipitate was filtered
off, washed with water, and dried to give substance Vg. Amide VZ was obtained from 0.7 g
(2.5 mmole) of compound II and 0.21 (2.5 mmole) of morpholine in 30-40 ml of ethanol.
Amide of N-(4-Methoxypyrimidyl-5)-oxaminic Acid (Via). A mixture of 0.74 g (2.48 mmole)
of compound Vg and 6.0 g of Raney nickel in 40 ml of ethanol was refluxed for 5 h with
vigorous stirring. The catalyst was filtered off, additionally extracted with 20 ml of
boiling alcohol, and filtered again. The alcohol filtrates were combined and evaporated
under vacuum to dryness to yield amide Via.
N-Benzylamide-6-chloropyridyl-3)-oxaminic Acids (VIb) and N-Benzylamide of Pyridyl-3-
oxaminic Acid (Vie). These were obtained from 0.3 g (0.7 mmole) of compound Ve, 3.0 g of
Raney nickel in 20 ml of boiling ethanol during 4 h. The hot solution was filtered. ~le
precipitate was washed twice with I0 ml of hot ethanol. The filtrate and washings were
combined and concentrated to 1/3 of the original volume. The precipitate was filtered and
dried to give compound VIb. After removal of compound VIb the filtrate was evaporated to
dryness; then 5 ml of water was added, and the solid was filtered off and dried to give
0.05 g (27%) of compound Vlc, mp 167-168~ (form alcohol). The identity of compound VIc was
proved by comparison of its analytical and spectral characteristics with the sample obtained
previously [$].
2-Chloro-5N-oxalimides of 6-Hydroxy-6-alkyl-7H-pyrido[2,3-b]-l,4-thiazine (IVa-c)o
Gaseous ammonia was buubled through a suspension of 2 mmoles of compounds Ia-c in i0 ml of
glacial CHsCOOHo The reaction mixture warmed up to 100~ and solidified~ It was kept for
3 h at 18-20~ and then diluted with 20 ml of water. The precipitate was filtered off,
washed with water, and dried to give compounds IVa-c.
l~2-Dioxo-3a-ethyl-9-methoxy-4H-imidazolino[3,2-f]pyrimido[4,5-b]-l,4 -thiazine (Vllg).
A. A solution of 0.35 g (1.25 mmole) of compound II and 1.8 g (23,2 mmole) of CHsCOONH4 in
15 ml of glacial acetic acid was heated for 2 h at 80~ The reaction mixture was poured in
30 ml of water, neutralized with ammonia, evaporated to 15 ml s and cooled with ice-water; the
precipitated product was filtered off to give compound VIIg. Mass spectrum, m/z (%): 281
(17), 280 (100), 265 (9), 251 (19), 237 (8), 230 (4), 223 (26), 219 (5), 209 (16), 208 (13),
197 (30), 194 (21), 183 (13), 1 8 2 (10), 181 (13), 180 (22), 169 (15), 164 (1), 163 (9), 156
(12), 154 (i0), 137 (ii), 131 (12), 121 (9), 119 (15), 113 (Ii), 81 (i0), 69 (75), 56 (23).
B. Gaseous ammonia was bubbled during 0.5 h through a suspension of 0.2 g (0.73 mmole)
of compound Vg in 10 ml ~f glacial acetic acid. The mixture was kept for 2 h at 20~ and
dil~ted with 20 ml of water. The precipitate was filtered off to give compound VIIg.
C. Thiazine VII was also obtained from 0.5g (1.78 mmole) of compnund II in i0 ml of
glacial CHsCOOH under conditions employed in method B.
D. A mixture of 0.43 g (1.45 mmole) of compound Vg, 20 ml of ethanol, and 1 ml of
alcoholic HCI was refluxed for 8 h. The precipitate was filtered off and dried to yield
0.06 g (28~ of thiazine VIlg. The filtrate gives 0.19 g of the starting amide Vg.

804
,3-Dixo-3a-(araky)-7-chr-4H-imidazidin[32-f]pyrid[23-b]-4-thiazine (Vlla-f).
A. Thiazlnes VIlas o b t a l u e d ~ r ~ ~ 3 m moles of 1,2-dioxo-3a-(alkyl)-7-chloroxaz0ildin6
[3,2-f]pyrldo[2,3-b]-l,4-thlazines la-d, 2.0 S of ammonium acetate in i0 ml of glacial acetic
acid, or its mlcture with benzene under conditions analogous to those employed for obtaining
compound VIIg (method A) with the only difference that the solutions were refluxed for 5 h.
Mass spectrum of compound VIIB, m/z (%): 285 (40), 283 (I00), 270 (8), 268 (16), 256 (15),
254 (40), 240 (4), 228 (i0), 227 (8), 226 (21), 214 (8), 213 (8), 212 (16), 211 (10), 200 (17),
199 (13), 197 (22), 185 (23), 183 (48), 172 (8), 171 (7), 167 (8), 166 (7), 165 (6), 135 (10),
119 (8), 103 (8), 69 (12), 64 (6), 56 (12), 55 (9).
Bo Compounds VIIa,b were obtained by dehydration of 0~ mmole of compounds IVa,b
during 3 days under vacuum on heating over P2Os (heating agent water).
Co Compounds VIIe,f were obtained from 1.5 mmole of the ethyl ester of the correspond-
ing N-[2-acylmethylthio-6-chloropyridyl-3]oxaminic acids (IIa,b) in i0 ml of glacial acetic
acid under conditions analogous to the synthesis of compound VIIg (method B)o
Do A sample of 7o75 g (22~ mmole) of compound Vd in 15 ml of POCI~ was refluxed for
15-20 mln. The reaction mixture waspoured on ice~ The precipitate was filtered off,
washed with water to neutrality, and dried to give compound VIIf.

LITERATURE CITED
i, N. Jo Traven' and T. S. Safonova, Khimo Geterotsiklo Soedino, Noo 2, 241 (1985)o
2. L. G. Levkovskaya, I. E. Mamaeva, O. S. Anisimiva, and T. S. Safonova, Khimo Geterotsikl.
Soedino, No. 2, 250 (1979)o
o T. S. Safonova, L. G. Levkovskya, I. E. Mamaeva, and L. A. Blokhina, Inventor's
Certificate Noo 586, 642 (USSR); Byullo Izobro, Noo 37, 270 (1982)o
. L. G. Levkovskya and T. So Safonova, Khimo Geterotsiklo Soedino, NOo 5, 676 (1973).

805
LETTERS TO THE EDITOR

SYNTHESIS OF BROMO-SUBSTITUTED 2-FORMYLPYRROLES

V. A. Dombrovskil, E~ V. Gracheva, UDC 547.7.29.96

E. P~ Prokof'ev, E. E. Lavut,
and P~ M. Kochergin

Information regarding substitution reactions in the 2-formylpyrrole series is virtually

confined to data on the introduction of an isochlorosulfonylisocyanato [sic] group in the 4
position of the pyrrole ring, which gives the product in low yield [I]. We have found that
the bromination of 2-formylpyrrole (I) with dioxane dibromide at 5~ in the presence of the
calculated amount of concentrated alkali leads, depending on the way in which the reaction
mixture is worked up, to 4-bromo-2-formylpyrrole (II) or 4,5-dibromo-2-formylpyrrole (III).

Br Br

~N" ~CHO CHO Br "CHO

H H H
I I! I;I

The positions of the bromine atoms in the compounds obtained were established by ~H and
~3C NMR spectroscopy and by comparison of the spectra with one another and with the spectra
of 2-formylpyrrole. Data on the chemical shifts (0S) in the *H and ~SC NMR spectra for
unsubstituted pyrrole were taken into account [2]. A coupling of 1.4 Hz, which was assigned,
taking into account the data for aldehyde I, to the ~Jss coupling, is observed between the
two ring protons of II, and~ on the basis of this, it was concluded that the bromine atom is
located in the 4 position. Taking into account the effect of the electronegative nitrogen
atom, one of the ~JCH constants in the spectra of the ring carbon atoms of I and II (182
and 187 Hz, respectively), which is substantially greater than the other, was assigned to
C(s )-H coupling. The absence of this coupling in the case of III makes it possible to
conclude that the second bromine atom is located in the 5 position. The observed changes
in the ~SC C$ are in good agreement with the conclusions drawn. The *Sc NMR spectrum of the
reaction mixture showns the presence of at least four compounds and does not contradict the
assumption of the presence of I-I~I in the mixture.
4-Br6mo-2-formylpyrrole (II) t A solution of 16 g (0.i mole) of bromine in 160 ml of
dioxane was added with vigorous stirring in the course of 2 h at 5~ to a mixture of 0.I
mole of 2-formylpyrrole, 30 ml of dioxane, and 5.6 g of KOH in ~0 ml of H20, after which
the mixture was filtered. The filtrate was shaken with 15 ml of 40% KOH, and the solvents
were removed by distillation. The residue was diluted with water, and the aqueous mixture
was extracted with ether. The solvent was removed by distillation, and the resulting oil
was poured into water. The precipitate was removed by filtration to give 3.3 g (20%) of
aldehyde II with mp 122-123~ (from ethyl acetate-hexane, 1:9). PMR spectrum (CD3OD), ~:
9.31 (CHO), 7.05 (5-H), and 6.88 ppm (3-H); ~J3s = 1.4, 5J~_H, CH----O= i Hz. 13C NMR spectrum
(CD~OD), 6:180,5 (C=O), 134.5 [C(2~], 127.7 [C(s)], 122.5 [C(3)J, and 99.2 ppm [C(~)],
~JCHO = 173, IJc(~) H = i87, IJc(3)H'= 173, 3Jc(3),5_ H = 6, 2J~(4),3- or 5-H = 5, and
3j = 7 Hz.
C(5),3-H

4,5-Dibromo-2-formyipyrrole (III). This compound was obtained in the same way as II.
After completion of the reaction, the mixture was filtered, the filtrate was poured into
water, and the resulting precipitate was removed by filtration to give 6 g (20%) of aldehyde
III with mp 154-155~ [from ethyl acetate--hexane (1:9)]. 13C NMR spectrum (CD3OD), 6:
179.5 (CO), 135.2 [C(2)], 123.2 [C(s)], 113.3 [C(,)], and 101.9 ppm [C(4)]; ~JCHO = 175,

- - A l l - U n i o n Scientific-Research Institute of the Technoiogy of Blood Substitutes and

Hormonal Preparations, Moscow 109044. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 7, pp. 998-999, July, 1986. Original article submitted October 22, 1985.

806 0009-3122/86/2207-0806512.50 @ 1987 Plenum Publishing Corporation

*Jc ( 3 )H = 176, sJCO,~-H = 2 ' and ~Jc(s), ~-H = 9 Hz. The results of elementary analysis of II

and III were in agreement with the calculated values.

2-Formylpyrrole (I). PMR spectrum (CD,OD), 6:9.33 (CHO), 7.05 (5-H), 6.88 (3-H), and
6.18 ppm (4-H); aj ,~ _ 3.6, "J~5 = 2.4, ~J as = 1.4, 5Js-H.CH 0 = I Hz. IaC NMR spectrum
(CDaOD), 6 : 1 8 0 . 8 (CO), 134.2 [C(=)], 128.3 [C(5)], 122.~ [C(3)], and 111.9 ppm [C(~)];
:JCHO = 170, *Jc(s)H = 182, *JC(a)H = 168 , ij C(4) H = 170, ~Jc(5), a_H = 4 , 3j C(a), ~_H = 6,

2Jc(~),~- or s-H = 7.5, 2j C(4),s- or a-H = 3.5, 2Jc(5),~_ H = 8, and sJC(s),a_H = 8 HZ.

LITERATURE CITED
. C. Eo Loader and H. J. Anderson, Can. J. Chem., 59, 2673 (1981).
2. A. Gordon and R. Ford, The Chemist's Companion, Wiley (1973).

RECYCLIZATION OF 4-CYANOBENZO[c]PYRYLIUM SALTS UPON

REACTION WITH HYDRAZlNE

Yu. A. Nikolyukin, L. V. Dulenko, UDC 547.814'833'779

and V. I. Dulenko

In a study of the reaction of benzo[c]pyrylium salt I with hydrazine we observed that

the previously undescribed 5-methyl-7,8-dimethoxy-l-phenylpyrazolo[5,4-c]isoquinoline (II)
is formed in 40% ySeld as a result of the reaction. The conversion of perchlorate I to pyr-
azoloisoquinoline "II evidently includes the formation of intermediate 5-aminopyrazole
derivative III.

CB30, .~P" c..2o I

C6H~ N2H,- CH 3 ~. ~ .... N ]r H

CH~ ~ CH~ _j CM~

I ;i! I!

Pyrylium Salt I. This salt, with mp 210-212~ (dec.), was obtained by treatment of
~-benzoylhomoveratronitrile with acetic anhydride in the presence of an equimolar amount of
perchloric acid. IR spectrum (in Nujol): Ii00 (CI04"), 16~5 (pyrylium cation), and 2250 cm -~
(CsN). PMR spectrum (60 MHz, CFsCOOH), 6: 3.20 (3H, s, CH3), 3.97 (3H, s, OCH3), 4.13
(3H, s, OCHa), 7.30 (5H, s, C6Hs), and 7.67 and 7.80 ppm (each IH, s, 5- and 7-H).
Compound lit This compound had mp 272-273~ (from xylene). IR spectrum (in Nujol):
1620 cm -~ (ring C=N). PMR spectrum (60 MHz, CFsCOOH), 6: 3.23 (3H, s, CH3), 3.80 (3H,
s, OCH~), 4.07 (3H, s, OCHa), and 7.67 ppm (7H, s, Harom).
The results of elementary analysis of ~he compounds were in agreement with the calculated
values.

Institute of Physical Organic Chemistry and Coal Chemistry, Academy of Sciences of the
b~rainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklieheskikh Soedinenii,
No. 7, p. 999, July, 1986. Original article submitted November 25, 1985.

0009-3122/86/2207-0807512.50 9 1987 Plenum Publishing Corporation 807

I,I'AZOBENZlMIDAZOLES

I. M. Nanavyan, A. F. Pozharskii, UDC 547.785.5:542.943

and V. V. Kuz'menko

l,l'-Azobenzimidazoles, formally related to the class of tetrazenes, were unknown until

recently. It is true that English workers [lJ in 1973 obtained salts of l,l'azobenzimidazoles
from salts of l-amino-3-methylbenzlmldazoles using bromino water, but it has not so far proved
possible to prepare the base compounds by oxidation of l-aminobenzimidazoles with, e.g., mer-
curic oxide [2]. We have now shown that l,l'-azobenzimidazoles IIa-e are almost always form-
ed when l-aminobenzimldazoles Ia-e are oxidized with a small excess of lead tetraacetate in
methylene chloride.

~N ~ ~R :",.~" ' .~ " R/" "IN R

I
NH a " " - H r._ H.._. -~
la-f IIa-e Ule,f
I--Ill a" R=H;b R=CH3;r R=CI: dR=N(CH~)2; e R=NHCH~; f R=NH2

The best results were obtained for oxidation of l-amino-2-methyl- and l-amino-2-chloro-
benzimidazole (Ib,c) which gave the tetrazenes llb,c in 43 and 58% yields with mp 260-262
and 238-239~ respectively (all melting points were determined in sealed capillaries). Oxida-
tion of the unsubstituted amine Ia gave IIa in only 5% yield (mp 261-263~ the basic product
of the reaction being the previously reported [3] l-acetylbenzimidazole (mp I13~ ~C=O
1745 cm-*). Production of tetrazenes IId,e from Id,e was accompanied by significant tarring,
the yields being 4-5% with respective melting points of 173-174~ (from benzene/hexane) and
120~ (separated chromatographically because recrystallization proved impossible). The oxida-
tion of le also yielded 7.5% of 3-methylamino-lt2,4-benzotrlazine (IIIe, mp 189-190@C, from
benzene~methanol). It is interesting that oxidation of 1,2-diaminobenzlmidazole (If), accord-
ing to [4J and confirmed by us, leads only to 3-amlnobenzotrlazine (IIlf) in yields approaching
65-80 %.
Bromine water may also be used as oxidant, giving even better results in certain cases.
Addition of bromine water to a solution of amine la containing sodium carbonate leads to a
25% yield of tetrazene Ila.
The structures of the tetrazenes lla-e were determined from IR, UV, PMR, and mass spec-
troscopic data and by elemental analysis, l,l'-Azobenzimidazoles were colorless (lla,b) or
slightly yellow (llc-e) substances, decomposing with ignition in a burner flame. Compounds
lla-c were extremely stable on storing and could be recrystallized from DMF or acetic acid
without noticeable decomposition. Tetrazenes lld,e were less stable.

LITERATURE CITED
i. E . E . Glover, K. T. Rowbottom, and D. C. Bishop, J. Chem. Soc., Perkin Trans. I, No. 8,
842 (1973).
2. J. De Mendoza, C. Millan, and P. Rull, J. Chem. Soc., Perkin Trans. I, No. 2, 403 (1981).
3. H . A . Staab, Chem, Ber., 90, 1320 (1957).
4. A . V . Zeiger and M. M. Joullie, J. Org. Chem., 42, 542 (1977).

I. M. Manavyan, A. F. Pozharskii, and V. V. Kuz'menko, M. A. Suslov State University,

Rostov-on-Don 344006. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp.
999-1001, July, 1986. Original article submitted February 6, 1986.

808 0009-3122/86/2207-0808512.50 @ 1987 Plenum Publishing Corporation

SYNTHESIS OF BENZOPYRANO[3,4-c]-ANDBENZOTHIOPYRANO[3,4-c]-
[2,1,3]SELENADIAZOL-4-ONES

V. L. Saval'ev, O. L. Samsonova, UDC 547.814.07'794.3'818o5.04

and L. D. Smirnov

In continuation of our work on the synthesis of new condensed systems based on 3,4-
difunctlonally substituted eoumarins and thiocoumarlns (e,g., [1,2] and references therein)
we have treated 3,4-dlamlnocoumarin (I) and 3,4-dlamlnothiocoumarin (II) with hydroselenlc
acid. Treatment of dioxane solutions of I and llwith aqueous N2SeO3 readily gives IH-[I]-
benzopyrano[3,4-c][2,1,3]selenadiazol-4-one (III, 90%, mp 236-2380C, from 1:3 benzene:
isopropanol) and iH[l]-benzothiopyrano[3,4-c][2,1,3]-selenadiazol-4-one (IV, 85%, mp 223-
225~ from 1:3 benzene:alcohol) -- the first representatives of selenadiazoles in the coumarin
and thiocoumarin series.
The systems obtained may prove of interest in studying their chemical and physic,-
chemical properties and in relation to the search for novel physic,logically active compounds.
Elemental analytical data and molecular weights (determined mass spectrometrically)
were in agreement with those calculated.

~z N--Se

2 H2Se03=_

I. I I I~IY
Io lII X=O; ZI. IV X--S

LITERATURE CITED
l. V. L. Savel'ev, A. V. Makarov, and V. A. Zagorevskii, Khim. Geterotsikl. Soedin., No. 6,
845 (1983).
2. V. L. Savel'ev, N. T~ Pryanishnikova, V. A~ Zagorevskii, I~ V. Chernyakova, O. S. Artomova,
V. V. Shavyrina, and L. I. Malysheva, Khim. Farm. Zh., No. 6, 697 (1983).

Scientific-Research Institute of Pharmacology, Academy of Medical Sciences of the USSR,

Moscow, 125315. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1000-
1001, July, 1986. Original article submitted November 10, 1985.

0009-3122/86/2207-0809512.50 9 1987 Plenum Publishing Corporation 809

STRUCTURES SYNTHESIS, ANDPROPERTIES OF 1,2,3-THIADIAZOLES
(REVIEW)

V. A. Bakulev and V. S. Mokrushin UDC 547.794.3(047)

Methods of synthesis and the physical, chemical, and biological properties of

1,2,3-thiadiazoles are systematized.

1,2,3-Thiadiazoles were first described by Pechman at the end of the last century [I],
and a little later by Wolf [2]. The reports of these authors were for a long time the only
ones in this area. At the beginning of the 1960's, with the appearance of modern methods
of analysis of organic compounds and new approaches to the construction of heterocyclic
systems utilizing pericyclic reactions, the chemistry of 1,2,3-thiadiazoles received a
powerfu~ stimulus to its development. A large number of new 1,2,3-thiadiazoles were synthe-
sized containing a wide variety of substituents. It was observed that these compounds,
in contrast to 1,3,4- and 1,2,5-thiadiazoles, being crypto-diazo compounds, readily re-
arrange, and are converted by thermal and light energy into organic compounds of diverse
structure [3-6]. In the last decade, compounds have been obtained which display high
biological activity. Such a compound, produced on the industrial scale, is thidazuron,
l-phenyl-3-(l,2,3-thiadiazol-5-yl)urea, a defoliant for fine fibered cotton. Much work is
currently in hand on the synthesis of analogs o f t h l s compound with a view to finding more
active pesticides.
1,2,3-Thiadiazole and its derivatives therefore comprise a class of compounds with
interesting properties, and the chemistry of this heterocycle is a rapidly extending, growing
and independent branch of the chemistry of heterocyclic compounds. There are, however,
no reviews in the literature devoted soleiyto 1,2,3-thiadiazoles.~In reviews describing the
properties of thiadiazoles in general, information on 1,2,3-thiadi~zoles is either obsolescent
[6], or is highly condensed and far from complete [3-5].
The present review surveys and systematizes information on the synthesis and properties
of 1,2,3-thiadiazoles which has for the most part appeared over the last 10-15years. Of
the earlier publications, only those which have fundamental significance for the chemistry of
1,2,3-thiadiazoles are included.

i. NOMENCLATURE, STRUCTURE, AND PHYSICOCHEMICAL PROPERTIES

In IUPAC nomenclature, the numbering of the atoms in the 1,2,3-thiadiazole ring is as

follows:

3N r

Stiefvater [7] has examined the microwave spectrum of 1,2,3-thiadiazole, and determined
the angles and bond lengths in'the gaseous state. X-ray diffraction studies of the struc-
tures of a number of 1,2,3-thiadiazoles have Seen carried out [8-12], including some with
zwitterionic structure [9-12]. It was shown thas the heteroatoms and carbon atoms lie in
one plane, and the e-~ and N-S bond lengths are 0.169 nm, typical of heterocycles with 3p~-
2p~conjugation.
Chemical shifts in the laC NMR spectra of 1,2,3-thiadiazole and its derivatives have
been reported [13-16] (Table I). Comparison of these values with those for carbon in

S. M. Kirov Ural Polytechnic institute, Sverdlovsk 620002. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 8, pp 1011-1028, August, 1986. Original article sub-
mlttedApril 15, 1985; revislon~submitted December 2, 1985.

0009-3122/86/2208-0811512.50 @ 1987 Plenum Publishing Corporation 811

 TABLE.I. Structural a n d Spectral Characteristics
of 1,2,3-Thiadiazole

Bond Valence z 3C .~g',IR J

leng~h~ angles, ( c f . ['tS]) ( c f . [18l)
(cf. [71) ~eg (~f. [7])
|
a 0,16971 cz 9,2,91 147,3 I 135,8, 8,8 8,8
b 0,12897 111,21
c 0,13662 y 113,95
d 0,13686
e 0,16888
6 114,15
lO7,79 I
imidazole, 1,2,3-triazole, thiophene, furan, and thiazole shows them to be shifted to lower
field by 10-20 ppm [17]. The chemical shifts of the protons in thiadiazole are also shifted
to lower field as compared with the signals for the protons in other five-membered aromatic
heterocycles [11, 18]. These observations show that 1,2,3-thiadiazoles are ~-deficient.
Mass spectral studies have shown that fragmentation takes place exclusively with the
loss of a molecule of nitrogen. Depending on the substitutents, either a thioketal A or
a cation-radical B is formed [19-21].

-N 2

BR ""c =c-s'q T 4'ii

'TR
S~R ~ S
R
A B

The photoelectronic [22],magnetic circular dichroism (MCD) [23], and NQR spectra on t4N
nuclei [24] have been studied. Quantum chemical calculations of the IN, NQR, and MCD spectra
have been carried out for thiadiazoles, and it has been found that the ab initio method gives
good values for the ionization constants and splitting constants in the NQR spectra, and the
PPP method for transitions in the electronic and MCD spectra [22-24].

2. SYNTHESIS OF 1,2,3-THIADIAZOLES

Methods of synthesis of 1,2,3-thiadiazoles may be arbitrarily divided into four groups:

i) Cycloaddition of diazoalkanes to compounds containing the C=S bond; 2) Heterocyclization
of 2-diazothiones; 3) Reaction of hydrazones with thionyl chloride; and 4) Other methods.
2. i. Cycloaddition of Diazoalkanes to Compounds with C=S Bonds
Reaction of diazoalkanes with chlorodithioformates, carbon disulfide, and thiophosgene
gives mixtures of 1,2,3- a n d 1,3,4-thiadi~zoles [25.'28].

CH3OCO(CH2)3-S-C-CI + CH2N2 ~
SI1 ~S / ' ~SAIk "s s~tk

.COaC2Hs
e*-c-c*ll '" c 2 u ' ~ --" * [1 II
S 0 "S ~ ~Cl el w ~ " S J ' ~ ' C O . , C 2 H s ,

It is interesting that ethyl chlorodithioformate gives preferentially the 1,3,4-thiadia-

zole on reaction with ethyl diazoacetate in the presence of triethylamine, and the 1,2,3-
thiadiazole in reactions with its mercury salt [25].
N --- N

9 ~ I CZII~3" "S/~'COzCzR~
+ /
S

N~S/ ~SCzH 5
812
 It appears that the 1,2,3-and 1,3,4-thiadiazoles are formed by different mechanisms:
1,3,4-thiadiazoles by cycloaddition of the diazo compound followed by elimination of hydrogen
chloride, and 1,2,3-thiadiazoles principally by acylation of the diazo compound followed
by cyclization of the resulting diazothione.

I N--N
[_ct s a

-HCI
n--c--C*ll + RI--CH=N2 ~-~ I
S N2 N~S J ~ - R
S

In contrast to the examples given above, the thioester (I) and thioketenes (II) react
with diazoalkanes to give exclusively 1,2,3-thiadiazoles [29, 30].

C2H~,O~CH(CH~)C0OC."Rt:5 + CHzN:, _o=H,o,, m,-

..... I-I
N..
S $ CH(CH~)COOC~H~
I
R~ R~ ~ + ~R3

Isothiocyanates react with diazoalkanes to give 5-amino-l,2,3-thiadiazoles. This

reaction was first described by Pechman [i] with phenyl isothiocyanate and diazomethane,
and has been subsequently extended to a variety of isothiocyanas and diazoelkanes [31-
481.
RI
RNCS + RICH=N z ~ ~--~
N~R

Kinetic studies have shown that the reactivities of isothiocyanates and diazoalkanes
decrease in the following sequence [48]:
R I=PhCO>C2HsO=C>p-NO2Ph>m,o,!o-CIPh>CH2=CH-;
R = I-I > C H 2 = C H - > C 2 H 5 0 2 C - > P h C O .

In addition to the formation of thiadiazoles, decomposition of the diazo compounds

occurs followed by reaction of the resulting carbenes with the starting materials and prod-
ucts. The yields obtained im these syntheses are therefore low, being with few exceptions
in the range 30-70Z. Introduction of electron-acceptor substitutents into the isothiocyanate
increases the yields of thiadiazoles. If the changes in yield are equated with the rate
of the main reaction, this observation is in accordance with excitation theory calculations
[49-51].
This method enables 5-amino-l,2,3-thiadiazoles with a variety of substituents in the 4-
position to be obtained, but in view of the great explosive hazards attending the use of
diazo compounds, its synthetic potential and practical value are limited.
2.2. Heterocyclization of 2-Diazothiones
Cyclization of e-diazothioketones or e-diazothioamides affords exclusively 1,2,3-thia-
diazoles. This system contains six ~-electrons, and its conversion into the thiadiazole
encounters a low energy barrier whether by electrocyclization (a) [52], or like the cycliza-
tion of azidoazomethine to tetrazole [53] without rotation around the C=S bond (b).

f I
~ .,,m-~ "C/_ ..~.

aand b

813
 This method was used to synthesize condensed benzo[d], pyrimido[4,5-d]- [54], and
amino- [55-57] and carbonyl-substituted [58, 59] 1,2,3-thiadiazoles.
Diazothlones, which are compounds of low stability, cyclize to 1,2,3-thiadiazoles under
the conditions of their preparation. The existence of these compounds has been shown by
the isolation of the complex of 2-diazobenzenethione with iron nonacarbonyl, obtained by
reacting benzo[d]-l,2,3-~hiadiazole with Fe3(CO)9 [60].
i

Diazothiones may be generated by introducing the diazo group into compounds containing
the carbon-sulfur double bond, constructing a CffiSgroup in a diazo compound, or by the simul-
taneous introduction into organic compounds of diazo and thione groups.
2.2.1. Introduction of the DiazoGroup into Th$ones. Diazotization of aliphatic, aro-
matic, or heterocyclic 2-aminothiones gives 1,2,3-thiadiazoles, apparently via the inter-
mediate dlazochlones (IIl) [54, 58, 59]. The formation of 1,2,3-chiadiazoles by this
method requires the presence of substituents in the thionemolecule which stabilize the
diazo compound. For example, Shafran et al. [58] were unable to obtain 5-amino-l,2,3-
thiadiazoles by diazotizing 2-aminothioacetamide (IV).

~7 7 o

c, t
H

NaNO: " ~ S - ~ Clf

r~c-cu(~2)-cs~ 2
HCl NH

H:-ca:csm~z ~,.. ~---'7

I
IV "5: "" IWI{2

When thioketones containing acidic methylene protons are reacted with tosyl azide,
the diazo function is also introduced into the molecule [61-63]. The resulting diazothiones
rapidly cyclize to 1,2,3-thiadiazoles; With the thioamides (V), 5-amino-l,2,3-thiadiazoles
are obtained [61, 62, 64, 65].

itJ
_COlt
I~OCII2Cb'R' '"T~ ~1-~
N~,S~ R ' s

T~ ~ - ' - ~ R1
RCH2CSNH~1 -
v NIIR

R=CN, COFh, ~.~ jJ, COCII:,. C00CzH.~; R'--nH. At; TolImp-CH~-CsH4-S0 z-

C Q 5

2.2.2. Introduction of the C=S Bond int 9 Diazo Compounds. The introduction of the C=S
bond into diazo compounds is severely restricted by the lability of the diazo compounds.
The conversion of ketonic and amide groups with sulfurizing agents has been described [59,
66-68], together with the reaction of ~-diazonitriles with hydrogen sulfide [55-57, 69] and
the cleavage of thioesters [70].

814
 Reaction of the acyldiazoalkanes (VI) with ammonium sulfide affords 4-carbonyl deriva-
tives of 1,2,3-thiadiazole [59, 66].

N2 . ~COg..$1 ' N/NIl2

~ ~" ~c/C~c/R
tl I[ a~ II Jl
0 0 0 0

It has been reported [59] that in the case of ~ ' = i ~ instead of thiadiazoles, the

hydrazone (VII), a reduction product of the diazo compound, is formed. Other types of
sulf~rizing agent have been used. For example, reaction of the diazoketones (VIII) with
p~Sld or Lawesson's reagent gives naphtho[2,3-d]-l,2,3-thiadiazole [67, 68].

5~ / S /PhOCll~
N2 CH3OPh ~'S / ~S ~-
0
VIii

It is reasonable to assume that ~-diazothioamides are intermediates in the reaction

of diazoacetonitriles (IX) with hydrogen sulfide, leading finally to the formation of 5-
amino-l,2,3-thiadiazoles. It is interesting that this reaction was described for different
compounds independently and almost simultaneously by Konstantinova [55], Shafran [56], and
Nakai [57].
~-c-~,, ---51- ~.--~ R
N2 NII2
TX
E=IL Alk~ At. C00C~H,3. COPh. CONHz. CONHCH;I

When the aminobenzo[d]thiazoles (X) are diazotized, the thiazole ring is opened. As
in the preceding reactions, it is likely that a diazothione is formed as an intermediate,
this then cyclizing to the thiadiazole.

, |R" ~ -s L R~/Y's"
NH2 L Nz .~ NHa
X

Diazotization of 4-aminobenzothiazoles (XI) followed by treatment with thiourea affords

4-carbonyl derivatives of 1,2,3-thiadiazole. This reaction probably proceeds via the
following mechanism [71, 72]r

R I~X2 R ~"

~S" "ll

H ~ N H~ NH ~ C0R

S--C E N2 .J ~S / ~H
2
R=H. CH~

2.2.3.~ Simultaneous Introduction of Diazo and Thione Groups into Organic Compounds.
This method includes opening of the 1,2,3-thiadiazole and -triazole rings, and the reaction
of chloral tosylhydrazone with sodium sulfide.

815
 On heating with acids, 5-mercapto-l,2,3-triazoles (XII) rearrange to 5-amino-l,2,3-
thiadiazoles [31, 65, 73-80] (see also section 3.2)

511 "I"-- Sw "~N2 ~,~S/_~NHR I

~rl R----H,AIM.At. COOAIM.COF'h; F?=H, AIk; ~v

It has been found that l-aryltriazoles rearrange more easily than the l-alkyl compounds,
and that l-benzy~5-mercapto-l,2,3-triazole does not rearrange at all. In neutral solvents,
or on fusion, 1,2,3-triazolo-[4,5-b]pyridlne-4-thiones rearrange to 1,2,3-thiadiazolo[4,5-
c]pyridines [75-77]. Replacement of the hydrogen in the l-position of the triazole ring by
the ribose residue results in considerable acceleration of recyclization.

S NH~

[ H
R
R=H. ~-D-ribof,m:anosyl

The introduction into the 5-position of 1,2,3-thiadiazole of a diazo-methyl group

results in its conversion into the isomeric thiadiazole (XIII) [81},. A similar reaction
has been described for condensed thiadiazoles (XIV) [82].

~I----~ ~ N,S~Mz N-S ~k'C_4OOCzK l

H" s ~ CH:N--NRTo8 ~2
XIII
B R~

"--"" il

~2 N~ N2
XlV

The reaction of the chloral hydrazone (XV) with sodium sulfide also apparently gives
the diazothione, which cyclizes to 5-mercapto-l,2,3-thiadiazole [83].

Tos- NH-N=CH-CCI~ LN2 S Nm~

XV N~sf "~N~

2.3. Reaction o f H ydrazones with Thion.71 Ch!or!de

The most widely used method for the preparation of 1,2,3-thiadiazoles is by reacting
hydrazones (XVI) with thionyl chloride [59, 84-i05]. The yields in these syntheses are 30 ~
80Y0. The following reaction mechanism is based on the isolation of intermediates and on
kinetic studies [105].

H Ii R~/"Sl R2
o II

RffiH, Alk, CH.~Ph, Ar, OAr: R'=H, CI, Alk, Ph, COOH; --R--R'--ffi--(CH----CH).--
--N(R)--CON(R)--CO--; R~=COOC2H~, CONH2, Tos

It has been shown that the reaction of the aryl derivatives (XVI) with thionyl chloride
is regioselective [88], whereas alkyl derivatives give a mixture of isomeric thiadiazoles
[13].

816
 N.~ NHR2 -'~ R2ItN. N

~CH~ ~ /CH~ ~

R' " ~S " "P,

It has been shown to be possible'to use $2CI 2 or SC12 in this reaction in place of
thionyi chloride [92, 103, 104], but the yields of thiadiazoles are substantially reduced.
The synthesis of thiadiazoles from hydrazones and thionyl chloride cannot :be Tused
when amino, mercapto, hydroxy, or other groups capable of reacting with thionyl
chloride are present. It has been found [59] that the hydrazone (XVII), which contains a
carboxyl group, gives in addition to the thiadiazole (XVIII), the oxadiazine (XIX), which is
an intramolecular cyclization product.

R --CH2- ~ --COOH ....... R - C H 2 - ~ --CCgM

N -- N
C2H.~C~ ~HN / ~NHCOOC?Hs
X'-/111t XVII
H
i ~ ~ ~ ..~o
!
cox I! 1

N~S~ ~R 0
XVIII ~[X
XNII-XIX X = ? l . OH; R = A l k , Ar

Since it has been shown [14, 85] that the Z-isomer is involved in cyclization, this
method would be expected to be capable ~ extension to compounds containing reactive groups,
but which are E-isomers.
2.4. Other Methods
The transformation of 1,3,4-thladiaz~n-2-ones in the presence of tert-butyl hypochlorite
gives 1,2,3-thiadiazoles in yields of 35"85Z. The authors have suggested the following
mechanism [106]:
~-Cl* ~'~ -CI ~ Ar ....~N..N H .0

Ar ~ ~Cl Az ..
At. ~ _ : ~ N .~-CI~" "~rv-----N ~,- --N

H~'J~..S/N~COOH -H R / \s/N~cooII -ilCl p / ~.s.~N

R=H. Alk

2,7-Dihyd@o-3,6-diphenyl-l,4,5-thiadiazepine on treatment with bromine is converted

into a mixture of thiophens and 4-phenyl-l,2,3-thiadiazole [107]. It is interesting that
treatment wi~h chlorine gives the thiidiazole only.
Fh rh /r'~
J. J~ ~rz --
9 - CH~OH --
}][ 1|

Reaction of N4~i0 with acetylene derivatives gives a mixture of thiadiazoles containing

9% of the 1,2,3-thiadiazole (XX) [i08].

R R~ M~SI ~R ~

817
 The information considered in this section leads to the conclusion that the best methods
for the synthesis of 1,2,3-thiadiazoles are the reaction of hydrazones with thionyl chloride
and the heterocyclization of d~azothioketones and diazothioamides.

3. CHEMICAL PROPERTIES

1,2,3-Thiadiazole undergoes reactions characteristic of other five-membered heterocycles.

For example, boilin E 1,2,3-thiadiazole with D20 in the presence of NaOD results in replace-
ment of the hydrogen in the 5-position of the rin E by deuterium [109], the hydrogen in the
4-position remainin E unchanged.

N~S/~ H NaOD N~S~ ~D

Similarly, alkoxy and methylthio groups, together with halogen atoms in the 5-position 9
are readily replaced by C-, S-, and N-nucleophiles [87, 96, 110-114]. The possibility of
nucleophilic substitution in the 4-position has not been studied.
Bromination of alkylated 1,2,3-thiadiazoles with N-bromosuccinimide results in replace-
ment of a hydrogen in the side chain. In the case of monoalkyl derivatives, the ring hydrogen
is not replaced [85, 115].
CH~R _CHB~R
~ NBS N--~"
.0y - .oJo
As NMR spectroscopy shows (see section i), the 1,2,3-thiadiazole ring is ~-deficient.
This l~rgely determines'its chemical behavior. Acylation of 5-amino-l,2,3-thiadiazoles re-
quires severe conditions, and the reaction with nitrous acid affords N-nitrosoamines (XXI)
rather than the diazonium salts [31, 116]. In addition, 1,2,3-thiadiazoles are not known
to undergo electrophilic replacement of ring hydrogen. An exception is the zwitterionic
3-phenyl-l,2,3-thiadiazol-4:o~ate (XXII). As a result of the influence of the ionized
hydroxy group, the hydrogen in the 5-position of the ring becomes labile. This compound
reacts with~i:t~i~ acid, and undergoes Mannich eminomethylation and Vilsmeier formylation
[116].

" R R

N~$ ~ N H C g R ' ~J NH2 HCI N ~S ~ NHNO

X~

/ N"s/~ N%

~S..~-..~CHO -- POCI~

~ " S " / ~ " CH2N(CH,,)z

In consequence of the electron-acceptor properties of the ring, 5-methyl-l,2,3-~hiadia-

zole functions as a CH-acid, and reacts readily with alkyl nitrites to give 5-hydroxyimino-
methyl-l,2,3=thiadiAzole [117].

i .0 I!
NOH

The alkylation [ii, 31, 113, 114, 116, 118], acylation ~Ii, 31, 114, 116, i18, 119] and
oxidation by peracids [14, 120] of 1,2,3-thiadiazoles have been reported. There has been
a report [31] of the alkylation of 5-acylamino-l,2,3-thiadiazoles by trimethyloxonium tetra-
fluoroborate in the 2-position of the ring. However, the proof given of the structure of the
product (XXIII) is unreliable. It was later shown that alkylation with dimethyl sulfate
gives the 1-methyl derivative (XXIV) [ii], and diazomethane affords a mixture of thiadiazoles
(XXIII-XXV) [Ii, 116].
818
 R~

R_C6 N ~ - ~ N C O R

N-S- -NHCOR ~" $/'~"" NCOR

R~ R~:
+ ~ +
CH3/N NCOR N--COR
l
)~III XA'7 CH3
R'

N"S" "F. o~r~--s/"-R o~S.o R

1,2,3-Thiadiazones are unique in their ease of decomposition by bases, transformations

into other heterocycles, and their photo- and thermochemical decomposition.
3.1. Reactions With Bases and A c i d s
Treatment of 4-phenyl-l,2,3-thiadiazole with phenyllithium gives the thiadiazolyllithium
(XXVI). Replacement of phenyllithium by potassium tert-butoxide or'KOH, however, gives
the potassium salt of mercaptoacetylene [121, 122]. Treatment with carbon disulfide with
heating or in the presence of bases results in the conversion of 1,2,3-thiadiazoles into 1,3-
dfthiolanes [122, 123].

/Ph
ph--C-------C--SK ~ II/Ph
~S / Li

N -M z S

The 1,2,3-thiadiazole ring is more stable to acids than to bases. For example, on
boiling 1,2,3-thiadiazolo[4,5-d}pyrimidines with aqueous hydrochloric acid, opening of the
pyrimidine ring occurs [124]. The resulting 5-amino-l,2,3-thiadiazone (XXVI~) is not con-
verted into 5-mercapto-l,2,3-triazole on treatment with acids [31], although ~his con-
version does take place on treatment with bases.
~CH 3

U It - --

3.2. Photo- (and Thermo-)chemical Reactions

The photolysis of 1,2,3-thiadiazoles has been reported in several communications
[125-132], in which it was shown that the photochemical decomposition of 1,2,3-thiadiazoles
gives thiofulvenes (XXIX), thioanthrenes (XXX), thiophens (XXXI), and 1,2,5-trithiepins
(xxxii) (Pig. 1)o
The irradiation of thiadiazoles condensed with polyene rings gives rise to by-products.
The effect of ring size on the course of the reaction has been examined, and it was found
that as the ring size increased there was a tendency for sulfur to be eliminated and for
dimerization to occur [128]. The formation of such a "rich" mixture of products in the
photochemical degradation of thiadiazoles is explained by secondary reactions between the
biradical (XXVIII), the thiirene (XXXV), and the thioketene (XXXIII) [128-135]. The
formation of thiirenes in the photolysis of thiadiazole and its derivatives has been demon-
strated by IR spectroscopy [136, 137]. These findings were confirmed in [i09], which may
be regarded as a model of chemical experimental methodology. These workers not only con-
firmed the formation of the thioketene (XXXIII) and ethynyl mercaptan (XXXIV) when thiadia-
zole was irradiated with ultraviolet light in an argon matrix, but they also showed in ex-
periments with XSC and 2H tagged thiadiazoles that both the biradical (XXVIII) and the
thlirene (XXXV) lay on the reaction coordinate. It was shown conclusively that (XXXIII)
and (XXXIV) are formed by two routes (a and b, Fig. I). The thioketene (XXXIII) is formed

819
 o
h' \ ~ R a k~ /ItI
RI--C=C- R ~ H--C--~C--SH - - - - - ~ R' ~R
H" "'S ''- ~'R I S S

~' R' ~ ~i'- / ~ s

N---~ h=, ~'1" h.-.,,, a' "c - s -a~k B I .. II
R

~-~

R I~ S _ RI RI S~ R~ R1
S R

:XXK ~ :ECUl

Fig. i. Photochemical and thermal decomposition of 1,2,3-thladlazoles.

preferentially by route b, and ethynyl mercaptan ( X X X I V ) b y route a.

Photolysis of thiadiazoles in the presence of acetylenes results in 1,3-dipolar cyclo-
addition, with the formation of thiophenes (XXXVI) [109, 138, 139].
Thiadiazole 2-N-oxide, on irradiation with visible light, isomerizes to the 3-N-oxide,
but on irradiation with UV it decomposes [14, 131, 140, 141].
Thermolysis of 1,2,3-thiadiazoles leads to the formation of the ~hioketenes (XXXIII).
Their formation has been established by flash thermolysis [1427:'1"43], chemically [128], and
by photoelectronic spectroscopy [144].
The thioketenes formed by photolysis or thermolysis of thiadiazoles are converted in
the presence of amines into the thioamides ( ~ I ) , and in the presence of alcohols, into
thioesters (XXXVIII) [121, 131, 135]o
There is, unfortunately, no information in the literature on the photo- or thermochemical
degradation of thiadiazoles containing amino, mercapto, or hydroxy groups in the 4- or 5-
positions of the ring. Such studies would be of practical value, since such compounds are
intermediates in the synthesis of thiadiazoles with useful properties. The only publication
in this area is a study of the stability of 5-chloro-, 5Jamino -, and 5~acetamido-l,2,3 -
thiadiazoles to mechanical treatment [145], in which it was shown that unlike the 5-acetamido =
compounds, 5-chloro- and 5-amino-l,2,3-thiadiazoles decompose explosively at high pressures.
3.3. Transformation into Other Heterocycles.
On treatment with bases, 5-amino-l,2,3-thiadiazoles rearrange to 5-mercapto-l,2,3-
triazoles [31, 119, 145-148]. This reaction is reversible. Either by treatment with acids
[65] or on heating in high-boiling solvents~ 5-mercapto-l,2,3-t=iazoles are converted into
5-amino-l~2,3-thiadiazoles (see also Section 2.2). Electron-acceptor substituents accelerate
both the forward and reverse reactions. Kinetic studies of the conversion of 5-amino-~,2,3-
thiadiazoles into 5-mercapto-lj2,3-tniazoles show that there is a good correlation between
the rate constant and the Hammer constant [149]o It has been shown that 5-glycosylamino-,
5-ureido-, and 5-acetamido-l,2~5-thiadiazoles "are not converted into triazoles [18, 31].
On the other hand, 1-glycosylated 1,2,3-triazolo[4,5-b]pyridine~4-thiones rearrange con-
siderably faster than the unsubstituted compounds [73]. These findings lead to the con-
clusion that of the two isomeric rings, the more stable is the ring with a bulky substituent
in the side chain. The intermediate in this reaction is the diazothione (XXXIX), which,
depending on the substituents and the reaction medium, cyclizes to the thiadiazole or the ....
triazole.

=:ax ~'
RI=H, ~ 3 ' ~ : R'=H, ~ . C00C2H5~ C ~ h

820
 The ease of fission of the N-S bond is one of the main reasons for the conversion of
1,2,3-thiadiazoles into other heterocycles. For example, d%@zotization of substituted
7-aminobenzo[d]-l,2,3-thiadiazoles followed by reduction with hypophosphorous acid or re-
placement by chlorine by the Sandmeyer reaction gives, generally speaking, both the normal
product (XL) and the rearranged product (XLI) [82]. Bulky substituents in the 6-p0sition
favor the rearrangement. It remains unclear, however, whether rearrangement is possible in
the unsubstituted compounds.
y Y x

~lli ' cl ci
XL

The introduction into the 5-position of the 1,2,3-thiadiazole ring of a diazomethyl

group or an azido group also results in recyclization to the isomeric thiadiazole and thia-
triazole respectively [81, 150].

i M~c-c-z
II II N.j
N~s Iti
J f kl/! "*~

_ . .

II II
N1

N~S/ "Z--
I

Z=CH. N
In principle, the reaction could follow three routes, either stepwise via the inter-
mediate diazothione (XLII) or thiadiazolo[l,5-d]thiadi(or tri)azoles, or as a concerted
reaction.. This rearrangement takes place only when an electron-acceptor substituent is
present in the 4-position of the ring.
Benzo[d]-~,2,3-thiadiazole reacts with sulfur to give benzopentathiepin [151], which
on treatment with alkenes or alkynes in the presence of organic peroxides, which are
radical sources, are converted into benzo[d]thiophens [152]. The isolation of the dithian-
thre~m (XLIII) as a by-p=oduct indicates that the biradical (XLIV) is involved in the re-
action.

.~. ..s-s\
_,__
~'~// " s " s -- s /

/2~SIN S" (>C=C<)

v S v
XLUl

4. PRACTICAL APPLICATIONS

1,2,3-Thiadiazoles show a wide spectrum of physiological and biological activity.

They display pesticidal [153-184], antiinflanmmtory [182], hypotensive [183], antibacterial
[184-191], antiallergic [192-194], antitumor [195], and antihelmintic [196] activity. Com-
pounds of this type inhibit enzymes such as monoamine oxidase [182, 197], phenylethanolamine

821
N-methyltransferase [198], and adenosine kinase [199]. The inhibition of 8-adrenoreceptors
by 1,2,3-thiadiazole derivatives [200], and the use of these compounds for the removal of
stones from the bladder [201]~%ave been described.
The greatest attention has been paid to the pesticidal properties of 5-ureido-, 5-
thioureido-, 5-alkoxycarbonylamino-, and 5-acylamino-l,2;3-thiadiazoles. These compounds
include herbicides [95, i02, 104, 118, 153-163], growth regulants [95, 154, 164], fungicides
[155, 165, 166-173], and defoliants [96, 97, 157, 158, 175-180].
At the present time, l-phenyl-3-(l,2,3-thiadiazol-5-yl)urea (dropp, defolite, thidia-
zuron) is used in the field as a defoliant for fine-fibered cotton [202, 203]. The effects
of thidiazuron on fish and rats have been studied [204-208], and it was shown that the com-
pound decomposed in the bodies of the ani~als, the products being excreted in the urine
[208]. The great advantage of thidiazuron overother defoliants is its low toxicity and
rapid breakdown to harmless compounds in the soil and under the influence of microorganisms
[209, 210]. Its defoliant activity is due to the inhibition of photosynthesis [211].
Thidiazuron has been found to possess high cytokinin activity [211-215]. There has been shown
to be a relationship between its defoliant effects and the liberation of ethylene by the
leaves of the treated cotton [216]. The effects of thidiazuron are enhanced by a variety of
organic and inorganic compounds [217-233].

CONCLUSION
This review shows the scientific and practical importance of the study of the properties
of 1,2,3-thiadiazoles. The ease of rupture of the C-N and N-S bonds is the reason for the
high reactivity of the ring in photo- (~nd thermo-)chemical breakdown and transformations
into other heterocycles. In turn, the ease of breakdown of the 1,2,3-thiadiazole ring to
compounds of lowmolecular weight favors the use of its derivatives as pesticides of low
toxicity.
In spite of the considerable advances made during the last decade, little attention
has been paid to nucleophilic and electrophilic substitution of the ring hydrogen atoms,
the limits to the extension of the recyclization reaction are unclear, the photo- (and
thermo-)chemical breakdown of compounds containing labile groups has nc~ been examined,
and all the methods used for the preparation of 1,2,3-thiadiazoles have considerable
technological deficiescies.
Without question, solution of these problems will result in the coming decades in the
discovery of novel chemical reactions of 1,2,3-thiadiazole, and its derivatives, in con-
sequence of the lability of the ring to chemical, thermal, and light energy, and will find
new applications in the fields of technology and biology.

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825
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826
210. M. Klehr and I. I. Pilmann, Pestic. Sci., 14, 359 (1983).
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827
SYNTHEBIS OF ACETYLENIC DERIVATIVES OF 1,4-DIOXANE

S. G. Grigoryan, K. G. Avetisyan, UDC 547.841.07'366:541.128

A. M. Arzumanyan, A. A. Mkrtchyan,
and A. A. Matnishyan
Cyclic ketals - 2,5-dimethyl-2,5-bis (4-penten-2-ynyloxy)-l,4-dioxane and 2,5-di-
methyl-2,5-bis(3-phenyl-2-propynyloxy)-l,4-dioxane - were isolated in the reaction
of proparEyl alcohol with vinyl, and phenylethynylcarbinols in the.presence of
H&K>-BF~.~(CIH~)~ catalytic system.

It has already been shown that, dependins on the temperature and solvent, the exothermic
reaction of propargyl alcohol by the action of the HgO-BF~.O(CiHs)2 catalytic system leads
preferentially to a tetramer - 2,5-dimethyl-2,5-bis(2-propynyloxy)-1,4-dloxane -- or a polymer
with a system of conjuEated bonds [I~. Under similar conditions, the nonterminal a-acetylenic
alcohols -vinylethynylcarbinol and phenylethynylcarbinol - form exclusively polyconjugated
polymers, while in the presence of propargyl alcohol, they can form 1,4-dioxane derivatives
2,5-dimethyl-2,5-bis-(4-penten-2-ynyloxy)-l,4-dioxane (I) and 2,5-dimethyl-
2,5-bis (5-phenyl-2-propynyloxy )- I, 4-dioxane (II ), respect ively:

RClC--r
,, "~rit \ O--CHzC~CE

! R-CH,--CM--; I! R=C~H,

I n the PMR spectra of the co=pounds obtained, t h e r e are s i g n a l s of a x i a l and e q u a t o r i a l

protons (H a, H e) of the Cit1 Eroup of the 1,4-dioxane ring (the AB spin system), and in the
IR spectra, the absorption bands of the -C-CHgroup in the 300 and 2120 cm "~ region are absent~
while absorption bands of the disubstituted acetylenic group in the 2240 cm -~ region are
present. The above spectral data indicate the participation of only terminal acetylenic
bonds in the mercury-catalyzed reaction of the electrophilic addition of the alcohol, leading
to the formation of cyclic ketals I and II by the mechanism previously described in [i].
By special experiments, the possibility was also shown of transetherification of the cyclic
ketals by the acetylenic alcohol, whereby hydroxyacetone is formed, a product of hydrolysis
of the cyclic ketals. A hydroxyacetone was also observed in the transformation products of
the reaction studied. Compound I polymerizes at 80-90~ in the presence of benzoyl peroxide,
forming cross-linked polymers containing conjugation blocks in the main chain and dioxane
rings as cross-links. Compound II does not polymerize thermally.

EXPERIMENTAL

A freshly distilled propargyl alcohol with nD z~ 1.4320 was used. Vinyle~h~nylcarbinol

[2], phenylethynylcarbinol [3], and 2,5-dimethyl-2,5-bis(2-propynyloxy)-l,4-dioxane [i]
were obtained by known methods. The IR spectra of the samples were run on a UR-20 spectro |
photometer in KBr tablets, while the PMR spectra were recorded on a "Varian 60A" spectro-
meter (60 MHz) in CDCI~ with HMDS as an internal standard. The GLC analysis was carried out
on a LKhM-8MD apparatus using a heat conductivity detector, a 2000 x 0.4 mm column, 5%
Apiezon on WvAW chromosorb, carrier gas helium, 60-80 ml/min, column temperature 160~ and
evaporator temperature 215"C. The TLC analysis was canried out on $ilu~ol UV-154 plates,
usinE an 8:5 hexene-~ther mixture as the mobile phase and iodine vapor as a developer~
215-DimethTi-2,5-bis~47penten-27vnvloxy)l,4-dioxane (I>. A mixture of 5.5 g (i00 mmoles)
of propargyl alcohol, 8.2 E (I00 mmoles) of vinylethynylcarbinol, a n d 0 . Z g (0~9 mmole) of
HgO and 14 ml of benzene was cooled to--5"C. A 0.1 ml portion (0.S m mole) BF3.0(C2Hs) 2 was

Armenian Branch, All-Union Scientific-Research Institute of Chemical Reagents and Ultra-

pure Chemical Substances, Erevan, 375005. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. 8, pp. 1029-1030, AuEust, 1986. OriEinal article submitted December 3~ 1984;
revision submitted April 15i 1985.

828 000973122/86/2208-0828512.50 9 1987 Plenum Publishing Corporation

added and the mixture was stirred for 8 h at 20~ It was then neutralized by dry K2COs,
and, after distilling benzene, cooled at 0-5"C for 24 h. The crystals that separated were
filtered. Yield, 4.8 g (35%), mp 87~ (from ethanol), Rf 0.52~ IR spectrum: 1020, 1045,
1080, 1140, 1190 (the 1,4-dioxane ring and the C-O-C-O-C group), 910, 950, 1610, 3065
(-CHfCH2 conjug.), 2240 cm -I (-C~C-). PMR spectrum: 1.23 (6H, s, CH3); 3.68 and 3.47 ppm
(2H a, m, 2H e, J = 11.8 Hz, ring CH~). Found: C 69.6; H 7.6%. C1eH200,. Calculated:
C 69.5; H 7.3%.
2,5-Dimethyl-2,5-bis(3-phenyl-2-propynyloxy)-l,4-dioxane (II). A mixture of 5.6 g
(100 ,,noles) of propargyl alcohol, 13.2 g (i00 mmoles) of phenylethynylcarbinol, 0.5 g
(2.3 mmoles) of HgO, and 0.2 ml (1.6 mmoles) of BFs.O(C2Hs) 2 was stirred at 45-50~ for 12 h,
and then cooled for 0-5~ for 24 h. T h e crystals that separated were filtered, Yield,
7.5 g (40%), mp 158-159~ (from 3:1 ethanol-benzene mixture), Rf 0.64. IR spectrum: 1040,
1080, 1135, 1190 (the 1,4-dioxane ring and the C-O-C-O-C group), 700, 770, 1450, 1595,
3035 (-CeHs) , 2220, 2260 cm -z (-C~C-). PMR spectrum: 1.25 (6H, s, CHs) , 3.40and 3.70 (2Ha,
m, 2He, J = I0.0 Hz, ring CHz) , 4.20 (4H, s, OCH2) , 7.0-7.2 (10H, m, C&Hs). Found: C 76.6;
H 6.5%. Calculated: C 76.6; H 6.4%.
Transetherification. A mixture of 2.05 g (9 ,moles) of 2,5-dimethyl-2,5-bis(2-propynyl-
oxy)-l,4-dioxane, 4.0 g (3 mmoles) of phenylethynylcarbinol in I0 ml of dioxane was heated
at 500C for 5 h in the presence of 0.01 ml (0.81 m o l e ) of BFs.O(C2Hs)2. The reaction
mixture was cooled at 0-5~ for i0 h, and the crystals that separated were filtered. Yield
2.4 g of compound II, mp 158~ (from 3:1 ethanol-benzene mixture). Hydroxyacetone [4] was
detected i n t h e mother liquid by GLC (yield, 14%).

LITERATURE CITED

i. A. A. Matnishyan, S. G. Grigoryan, G. A. Panosyan, A. V. Arutyunyan, M. M. Davtyan, M.

K. Mardoyan, and V. N. Nikogosov, Aru. Khim. Zh., 37, 233 (1984).
2. S. G. Grigoryan, A. M. Arzumanyan, A. A. Matnishyan, and S. G. Matsoyan, Arm. Khim.
Z h . , 36, 243 (1983).
3. S. G. G r i g o r y a n , K. 'G. A v e t i s y a n , M. K. Mardoyan, and A. A. Matnishyan, Reagents and
U l t r a p u r e S u b s t a n c e s [ i n R u s s i a n ] , No. 1, (1982), p. 30.
4. W. R~ppe, L i e b . Ann., 596, 61 (1955).

829
H(AMOLYTIC TELOMF/{IZATION OF VINYLTRIMETHYLSILANE WITH
5,5-DIMETHYL-I,3-DIOXANE

R. M. Makaeva, S. A. Bochkor, UDC 547.841:541.63:543.422.25:542.952.6

R. S. Musavirov, S. D. Badmaeva,
E. A. Kantor, A. B. Terent'ev,
and Do L. Rakhmankulov

The homolytic telomerization of vinyltrimethylsilane by 5,5-dimethyl-l,3-dioxane

follows three principal routes, with the formation of 2- and 4-substituted 5,5-
dimethyl-l,3-dioxanes and a formate ester. The rings in the reaction products
(2-trimethylsilylethyl-and'4-trimethylsilylethyl-5,5-dimethyl~l,3-dioxane)
exist in the chair conformation. The substituents in the 2- and 4-positions
of the dioxane ring occupy equatorial positions.

The telomerization of 1,3-dioxanes with ethylene and propylene is a convenient method

for the preparation of telomers containing acetal and ester groupings [ i - 3 ] . Continuing
studies of the telomerization of olefins by acetals, we have examined the homolytic telo-
merization of vinyltrimethylsilane (VTMS) with 5,5mdimethyl~l,3-dioxane (DMD)o The use of
VTMS in homolytic reactions is of interest, both from the point of view of extending the
range of monomers studied, and of establishing the special features of the reactions related
to the nature of this monomer.
Examination of the composition of the reaction mixture and the structures of the pro-
ducts showed that the reaction follows three main pathways to give the 2- and 4-derivatives
of DMD 0Dn 2 and Dn ") respectively, and the formate ester (E,):

n C'H2=CHSI(CH~).,
OvO
H~

n
CH
oyo
tCH~CHSi(CH3)3].H
~IC00Cll;.C(C~~)~CH~(CH2~HS|(CH3)3],'II
-- ~0Bbez of mon1~me~units in telo~

Compounds in which n = 1 (Dl ~, Dz z, and El) were isolated in the pure state from the
reaction products. The structures and preferred conformations of these compounds were
established from their IH and IsC NMR spectra (Tables 1 and 2). In the 13C NMR spectrum of
Dl ~, in addition to signals with chemical shifts similar to those of DMD, there were present
a doublet (87.3 ppm), two triplets (23.1 and 13.0 ppm), and a quadruplet (-1.6 ppm), cor-
responding to the ring methine group (C(~)), and the methylene and methyl groups of silicon-
containing substituent. The compound DI 2 contains the methine acetal fragment O-CH-O (103.3
ppm) and the CH2CH2Si(CH3) s grouping. In the laC spectrum of E l, signals are present which
are characteristic of the HCO2CH2- ester grouping (159.2; 70.9 ppm) and for the CH2Si(CH3)~
group (17.4 and -1.6 ppm) (Table I). In addition to the adducts described above, a telomer
with two monomer units was isolated, possessing the neopentyl 3,5-bistrimethylsilylvalerate

Ufa Petroleum Institute, Ufa 450062. Translated from Khimiya Geter0tsiklicheskikh

Soedinenii, No. 8, pp. 1031-1035, August, 1986. Original article submitted April 2, 1985.

830 0009/3122/86/2208-083~$12.50 @ 1987 Plenum Publishing Corporation

TABLE I. ZaC NMR Spectral Data and Elemental Analyses for Products (Dz 2, Dz ~, Ez, and F) of the Telomerization of VTMS with
5,5-Dimethyl-l,3-dioxane

Chemical shifts,. 6 , ppm " Found, % Calculated,

CIhCILSiICIID:~
Compound n D21'
> CO~ --CII~O >CLIO - >C< >C(CIID~ ::-CH,';i; SI C II I SI
ICII~)'JSII- I --CI-I:~-- CII2Si

I I
D20CH2C
1 (CHz) ~CH2OCHCH2CH2Si (CH3) 3 103,33 76.68 29,86 21,88e, --1,74 28.90 10.04 1,4390 61,2 11,4 13,4 61.0 11,2 13,0
23,06a
I
.4 (~CH2OCH2C(CHa)2CHCH2CH2Si (CHa)~
D1 93,92 78.06 87.28 33,37 18,53e, --1,61 23,09 12.94 61,5 1 !.4 13,3 61.0 11,2 13,0
21,85a
a
El HCO2CH2C (CII3)~CII2CH2CH2Si(CI-13) 159,2U :70,90 33.70 24,21 -i,60 17.92, 17.41 61,3 11.3 12,5 61,0 11,2 13,(1
43,24
O
Ii
F1C (CH3)~CHzOCCH2CHCHsCH.~Si (CH3)a 172.41 172.89 31.22 26,61 --1,80. 23,91 15.50, ! .4452 60,9 !!,7 18,2 60.7 II,5 17.7
I --2,30 25.40
Si(CH3)3

TABLE 2. PMR Spectrum of 2-Trimethylsilyl- and 4 - T r i m e t h y l s i l y l - 5 , 5 - d i m e t h y l - l , 3 - d i o x a n e (Dz 2 and DI ~)

Chemical shifts of protons, ~, ppm Couvltn~ C o n s t a n t , Hz

ring substituents -
I
Compound 2 tlEE,
II AB ~lac ~]HCFI.~ Ulgc ~'! 14ACIt~a
5.CH~a 5-CIt~e CHz IC|I:Si Si(CrlD,
@ o e a e

,,,~ ?o
(ClI3)3SiCH2CH2 --~'~ 4,59 5.06 3,05 -- 3,25 3.51 ,04 1,71 1,36 0,36 -- 0,01 --I 1,2 -5.8 3,2 -- 1.2 -0,6

[o ,i t, -o
Ctl 3
H^ ~a
,15 0,67 1,53 - 10,8 - 1,3 -0,6
"~~"i" ""?/'"CIIzCII,,,SI(CII3)J 4,21 -- 3.50 3 28 3,50 3,28 0,55 -- 0,01 5.0 --

[o llt, ---.
'~ C|li3
 TABLE 3. Radical Telomerization of VTMS with 5,5-Dimethyl-
1,3-dioxane (DMD) [Time 2 h, T 140~ tert-Butyl Peroxide
(TBP) I ~ . %]
Amount ) Initialratio Conversion, Mean ratio Amomr uf products,
mmole of VTMS--DMD, of V'D4S-- - mole~.
moles DMD, moles
!VTMS DMD DI = IDI~ E l F
I
0,7 I 14,2 0.02 0,03 49 14 17 20
1,4 } 13,7 O,lO 93 0,05 44 17 12 27
2,4 11.8 0,20 99* 12 O,ll 46 18 15 21
2,7 9,I 0,30 92* 0,17 38 19 12 31

~5 wt Z TBP.

structure (F). We assume that this is formed by a route involving 1,5-hydrogen shift followed
by ring opening.

c.~><~cs3 c.~,J~
t-5 H D/4D. (CH~)3c_cH2_oco_
CI[=CHCH=CH=Si(CII~)~
o..-'~ = o o ~ ~i(c,%),

CH2CHCHzCH2Si(CH3)3
/t(cR3)3

In the z3C NMR spectrum, the CO 2 group resonates at 172.4 ppm. Also characteristic are
the signals for OCH 2 (72.9 ppm) and CH-Si (25.4 ppm). The signals for the Si(CHs)a group
are strong (-1.8 and -2.3 ppm) (Table i).
The formation of the products described above (DI 2 and E I) is in all likelihood due to
the formation of a radical from DMD by removal of hydrogen from the ring carbon C(2 ), such
as i~ typical of radical-initiated reactions of 1,3-dioxanes [1-3]. The presence or Dn" in
the reaction products is somewhatunexpected. It may be that the occurrence of the reaction
is due to the high nucleophilicity and steric hindrance of the growing radicals of the
-CH2CH~i(CHa) 3 type, in which the reaction center is adjacent to the trimethylsilyl group.
At the chain transfer step, these radicals attack not only the 2-position of the ring, at
which the most easily cleaved C-H bond is present, but also the less nucleophilic and more
sterically hindered 4-position, i.e., polar and steric factors play an important part in
determining the course of the attack.
When the reaction was carried out with the ratio of VTMS to DMD changed by a factor of
six (Table 3), behavior was seen which is characteristic of competing reactions involving
dioxanyl radicals. Increasing the concentration of the monomer resulted in an increase in
the amounts both of higher telomers, and the relative proportion of cyclic to straight chain
compounds in the reaction mixture.
The preferred conformations of DI ~ and DI 2 were established from their PMR spectra
(Table 2). In the case of DI ~ , the methylene protons at the acetal atom of the ring res-
onated at lowest field, giving rise to an AB quadruplet with a geminal constant of -5.8
Hz. The signals for the equatorial protons at C(= ) (5.06 ppm) were broadened by stereo-
specific remote spin coupling (RSC) with the equatorial proton at C(s ) (~JEe = 1.2 Hz). The
magnetic nonequivalence of the protons in the second position of the ring was 0.47 ppm.
In accordance with reported data [4, 7], this indicates the preferred chair conformation of
the 1,3-dioxane ring. Additional proof is provided by the symmetry of the spectra of the :
methylene protons at C(e), in the form of a quadruplet, typical of 1,3-dioxanes with the chair
conformation, with 2JAE = -11.2 Hz and ~ 6 ~ = 0.26 ppm [5| Bearing in mind the stereo-
specificity observed in the RSC spectrum, the high-field component of the quadruplet (3.25
ppm) was attributed to H A resonance (~JHA CHs = -0.6 Hz)~ and the low-field component to
resonance of the equatorial proton H E (4~Ee = -1o2 H z ) . T h e location of the CH2CH2Si(CH3)3
group at C(~) can be established from the angular correlation of the RSC between the protons
of the 4- and 6-positions of the ring. If the interaction through the four bonds between
these protons occurs in a planar W-type zigzag fragment (equatorial-equatorial), the value of
~3EB~ will be greater'than in equatorial-axial interaction of the protons at C(~) and C(e).

832
Hence, if the proton at C(~) is in the equatorial position, the signal for the equatorial
proton at C (:e)will show adaitional multiplicity of broadening with ~JEE' = 0.8 + 1.5 Hz
[10].
It is difficult to discern such broadening in this spectrum, since the equatorial
proton at C(e ) experiences RSC with the equatorial proton at C (2) 9 However, the INDOR
method reveals the absence of interaction between the proton at C(~) and the equatorial
proton at C( )e, enabling the proton at C(4) to be assigned ~ the axial orientation, and the
CH~CH2Si(CHs) s group accordingly the equatorial orientation. The methyl groups at C(s )
resonated as two singlets. The signal which is broadened by RSC with the axial protons at
C(~,s) resonating at lower field (1.04 ppm), is assigned to the axial methyl group. RSC
is shown by the differing halfwidths of the signals for the methyl groups, 0.6 Hz, and
the type of interaction was shown by a homonuclear IH -- {CH3} INDOR experiment. In the 1,3-
dioxane molecule, DI ~ possesses an asymmetric carbon (C(,)), resulting in the loss of
magnetic ~equivalence of the adjacent groups of methylene protons, ~ Consequently, the protons
of the CH 2 groups in the substituent resonate as multiplets (0.36 and 1.36 ppm) of type AA z
(XXI). The methylene protons of the carbon atom directly bonded to the dioxane ring are
further split (SJHACH2 = 3.2 Hz), owing to vicinal interactions with the axial proton at
C (4). The findings establish that 5,5-dimethyl-4-trimethyl-silylethyl-l,3-dioxane (Dz 4)
exists preferentially in the chair conformation, the substituent in the 4-position of" the
ring being equatorially oriented.
In the PMR spectrum of 5,5-dimethyl-2-trimethylsilylethyl-l,3-dioxane (DI2), the acetal;.
proton resonates at lowest field, as a triplet at 4.21 ppm (Table 2). Its chemical shift
enables it, tb~be assigned to the axial position, and accordingly the substituent is equa-
torially oriented. The protons in the equivalent positions at C ~ ) and C(e) give a charac-
teristic AB system quadruplet with a geminal coupling constant JAg = -10.8 Hz, indicating
a shift in the conformational equilibrium towards the preferred chair conformation. The
relative nonequivalence of protons H A and HE, 0.2 ppm, is also characteristic of 1,3-
dioxanes in the chair conformation [5-10]. Bearing in mind the stereospecificity observed
in RSC spectra [4], the high-filled component of the quadruplet (3.28 ppm) is assigned to H E
resonance (~JEE' - - 1 . 3 Hz), and the low-field component (3.50 ppm) to H~ resonance '
(~JH_ACHsa = -0.6 ~ ) It may therefore be concluded that the dioxane DI z exists preferentially
in the chair conformation, the substituent on the second carbon atom of the ring having the
equatorial orientation.

EXPERIMENTAL
ZH and Z3C NMR spectra were obtained in a CC14 solution on a Tesla BS-567 spectrometer (Czech-
slovakia).
Analytical experiments were carried out in 4 ml glass ampuls. The experimental conditions
and the results of GLC analyses are given in Table 3.
Telomerization of VTMS wit h 5~5-dimethyl-l,3-dioxane. Preparative experiments were
carried out in glass ampuls, charged with ii g of DMD (95.5 mmole), 1.9 g of VTMS (19.2 mmole),
and 0.55 g of TBP. Six preparative experiments were carried out, the products combined, and
the starting materials distilled off. The residue was fractionated in vacuo. The conversion
of DMD was 127.. Preparative chromatography of the fraction bp 72-I00"C (3 mm HE) gave I~ g
of Dz 2, 0.6 g of Dl ~, and 0.5 g of El.
The fraction bp I00-140~ (3 n~m Hg) similarly gave compound F in a yield of 0.9 g.

LITERATURE CITED

i. D. L. Rakhmankulov, R. A. Karakhanov, S. S. Zlotskii, E. A. Kantor, U. B. Imashev, and

A. M. Syrkin, Itogi Nauki i Tekhniki. Tekhnologiya Organicheskikh Veshchestv (Progress
in Science and Technology. The Technology of Organic Compounds), VINITI, Moscow (1979),
p. 157.
2. V. V. Zorin, S. S. Zlotskii, and D. L. Rakhmankulov, Zh. Org. Khim., 12, 2472 (1976).
3. O. G. Safiev, D. E. Kruglov, Yu. N. Popov, S. S. Zlotskii, and D. L. Ra---khmankulov, Zh.
Org. Khim., 2_~0, I096 (1984).
A, K.-Pihlaja and P. Ayras, Acta Chem. Scand., 24, No. 2, 531 (1970).
5. Mo Anteunis, D. Javermier, and F. Borrem~ns, Heterocycles, ~, 293 (1976)o
6. Yu. Yu. Samitov, Khim. Geterotsikl. Soedin., No. 12, 1587 (1978).

833
 7. A. V. Bogatskii, Yu. Yu. Samitov, S. P. Egorov, and T. A. Zakharchenko, Zh. OrE. Khim.,
~, 830 (1969).
8. N . S. Z e f i r o v a n d I . V. K a z i m i r c h i k , Usp. Khim., 43, 252 (1974).
9. A. I . Gren t, S. G. Soboleva, and G. R. T a n t s y u r a , i n : T o p i c s i n S t e r e o c h e m i s t r y [ i n
R u s s i a n ] , Vishcha S h k o l a , Kiev (1971), p. 52.
10. J. P. S t o d d a r t , S t e r e o c h e m i s t r y of C a r b o h y d r a t e s , Wiley "(1971).

MECHANISM OF AMINATION OF AZIRIDINES AND OXIRANES.

3. QUANTUM-CHEMICAL INVESTIGATION OF THE EFFECTS OF
SPECIFIC SOLVATION

S. G. Koldobskii, 6. F. Tereshchenko, UDC 547.717:541.124

V. A. Bobylev, and A. R. Dalin

The characteristics of the associates formed by the aziridine and ethylene oxide
molecules in protic solvents were studied by the nonempirical SCF MO-LCAO quantum-
chemical method in the STO-3G basis set. It was shown that the main reacting
particles in the acid-catalyzed 8mmonolysis reactions are ethylene oxide-an~nonium
cation and protonated aziridine-solvent complexes.

It is known that unactivated aziridine (I) and oxirane (II) have low reactivity in the
nucleophilic addition of ammonia [3]. The reaction is accelerated appreciably with catalysis
by acids and ammonium salts [4]. It is usually considered that under the conditions of acid
catalysis the protonated forms of aziridine and ethylene oxide (III, IV) enter into reaction
with the ammonia at the controlling stage [5].

N 0 NH 2 OH
H
I I1 II1 IV

However, the formation of a whole series of associates, including the molecules of the
three-membered rings, the proton, and the solvent molecules, is possible in the aqueous
ammonia solutions in which these processes are usually realized [6]. The question of the
reactivity of the above-mentioned intermediate products remains open. In view of the great
theoretical and practical significance of these processes and also of the complexity of the
experimental investigation of their kinetics, in the present work we attempted to calculate
the reactivity of the complexes of aziridine and ethylene oxide with the solvent under the
conditions of acid catalysis.
We undertook nonempirical calculations using the minimal basis set of the STO-3G
orbitals. The calculations in the minimal basis set make it possible to describe satis-
factorily the stabilization arising through the hydrogen bond, although they appreciably
overestimate its energy. The complexes which can be formed by aziridine and ethylene oxide
with the proton and with one water-or "ammonia molecule were considered. By the calculations
in the STO-3G basis set we discovered the stable complexes (V-VIII). (In the structural
formulas of the complexes the proton attached both to the molecule of the three-membered
ring and to the solvent molecule was considered to "belong" to the heteroatom from which it
was separated by the shortest distance.)
CH.--CH 2 CH2--CH 2 CH2--CH 2 C~2~CH2
~ ~u "<V --- +

HNHo-. O H 2 HNH... N H 3 OH-," O H z 0.. oH N H ~

V Vl Vll VIII

State Institute of Applied Chemistry, Leningrad. Translated from Khimiya Geterotsikliche-

skikh Soedinenii, No. 8, pp. 1036-1041, August, 1986. Original article submitted June 4,
1985.

~ 0009-3122/86/2208-0834512.50 O 1987 Plenum Publishing Corporation

 TABLE I. The Energy Charac-
teristics of theComplexes,
Determined by the STO-3G
Method

Com- Total Heat of com-

plex forma-
pound energy, <tion, .kJ /,
au mole

V -206,8474 - 141,9
VI -187.3484 - 172,1
VII -226,3466 --216,0
VIII -206,8529 - 146,1
XIV -281,8503 --239,1"
XV -242,8444 --278,9*

*The heat of formation of

the complex from the mole-
cule of the three-membered
ring and the two isolated
solvent molecules.

TABLE 2 . The Geometric Characteristics of the Three-Membered

Rings (I-IV) and the Complexes (V-VIII, XIV, XV) According to
Data from STO-3G Calculations*
Structural ~ e r s $
a b c l Id e g ~ V 6 e ~ 'v

I 1,491 1,482 1,042

I
150,01 56,3 t56,4
I [ 1,084 57,857,31110'3
II11,0881 1,483 1,433 155,31 57,3 155,3
III[1,091 1,493 1,509 1,037 1,037 159,41 58,1 159,4 58,11123,6 123,6
IV[I,095 1,490 1,49~ ),999 160,21 57,6 163,7 58,7 ] i ~7,8
Vl1,088 1,490 1,494 [,148 1,033 1,28t 0,983 158,2[ 58,0 156,3 57,6 [125,0 ll9,1 118,2 105,4
v111,o87 1,491 1,489 1,210 l ,O33 1,297 1,032 157,7[ 57,8 155,3 57,5 ]127,0 117,6 112,3
vI I/ 1,o9 l 1,486 1,455 I,!52 1,174 0,983 157,7] 57,7 161,I 58,2 ] 123,0 I15,7 1067
VI I I[ 1,090 1,486 1,44{] 1,245 1,183 1.034 156,91 57,6 159.8 57,9 [ 127,7 111,4
X IV[ 1,086 1,490 1,484 1,096 1,096 1,392 0,982 156,11 57,6 156,1 57,6 ] 121,6 121,6 121.8 104,2
XV] 1,086 1,490 1,480 1,112 I,ll2 1,469 1,031 155,6 ] 57,5 155,6 57,51121,1 121,l 113,1

*The designation of the parameters are given in Figs. 1 and 2;

bond lengths, ~; angles, deg.
%The data on the STO-3G calculations of the structures of (I, II,
IV) were taken from [8, 9].
$The parameters = and 8 relate to the C-H bonds on the same side
of the plane of the ring as the heteroatom-hydrogen bond [in the
molecules of (I, IV)] or as the solvent molecule [in complexes
(V-VIII)].

Energy minima corresponding to the aziridine-hydroxonium cation (IX), ethylene oxide-

hydroxonium ion (X), aziridine-ammonium ion (XI), and protonated ethylene oxide-ammonia
(XII) complexes were not found. The STO-3G calculations cannot, of course, be used as the
basis for conclusions about the absence of the above-mentioned complexes in the gas phase.
At the same time it should be noted that the stable complex (H2OH...NHs) +, which is to some
degree the analog of systems (IX, XII), was not found during quantum-chemical investigation
of the ammonia-proton-water system, using a two-exponent basis set [7]. In solutions, how,
ever, compounds (IX-XII) may also exist in addition to the complexes (V-VIII), since the
solvation may increase their stability. The results from calculations on the parameters of
the molecules of (I-IV) and of the complexes (V-VIII) are given in Figs. 1 and 2 and Tables
1 and 2o According to the calculated data, the principal geometric characteristics of the
three-membered rings in the complexes (V-VIII) occupy an intermediate position between
the corresponding values for the protonated and unprotonated forms of aziridine and ethylene
oxides. The reactivity of the complexes (V-VIII) must also, therefore, be lower than in

835
 TABLE 3. The Charges on the
Methylene Groups in Compounds
I-VIII, XIV, XV, Determined by
the STO-3G Method, and the Po-
tential Barriers for Their Re~
actions with Ammonia
E... l.J/mole
CON- calculated
pound qCH2* d e t e r m i n e d 'by means
by of Eq. (7)
~Nnn/
I 0,0727 198,9 11,2] 194,1
I! 0,1038 167,9 [1, 21 166,3
Ill 0,3364 66,2 [I, 21 52,4
IV 0,3969 34,8 38,8
V 0,2581 77,3
VI 0,2296 87,5 11,21 89,0
VII 0,2817 68,7
VIII 0,2436 72,0 [I, 21 83.0
XIV 0,2192 93,8
XV 0,1911 107,8

*In electron charge units.

~ g H

H l-lq'r"~x~H

H
~-N
H

Fig. 1 ~ig. 2
Fig. I. The conformations of the complexes, calculated by the STO-3G method.
Fig. 2. The common fragment of the three-membered rings in the complexes.

compounds (III, IV) but higher than in the rings (I, II). The calculated heats of stabiliza-
tion of the complexes vary appreciably in the series of (V-VIII) but are large in all
cases.
Earlier we reported the results from MINDO/3 calculations on the gas reactions (i-6) of
compounds (I-IV) and also the protonated aziridine-ammonia (VI) and ethylene oxide--ammonium
ion (VIII) complexes with ammonia [I, 2]:

siow fast
I+NH~ - -,-6-NHCH2CH2NH3*+-----~NH2CH2CH2NH-
~, (i)
9 .. . _ slow 8 0+ fast
IL+NH3-------~ -OCH2CH2NH~ ~---*HOCH2CH2NH~, (2)
III+NH~------ ~NH2CH2CH2NH3+, (3)
IV+NH3 -- , ~HOCH2CH2NH~+, (4)
- NIt:;
VI + NH3 ~NH2CH2CH~NH~+, (s)
- NH3 (6)
V I I I + N H3-----------"HOCH2CH2NH3
The structural parameters of the associates (VI, VIII) obtained by the MINDO/3 method
are similar to the data from calculations in the STO-3G basis set. It is known, however,
that in a number of cases the MINDO/3 method describes the hydrogen bond unsat~sfactorily
[i0]. As a result the method proved unsuitable for calculation of the characteristics of
the transition states in the reactions of the complexes (V, VII) with ammonia. The results
from calculations with the STO-3G basis set were therefore used duringassessment of the re-
activity of these and certain other associates.

836
 The Mulliken charges at the carbon atoms of the three-membered rings and the total
charges on the methylene groups in them (aC and aCH 2 respectively), determined by the STO-3G
method, vary significantly in the series of s y s t ~ s (I-VIII) and can be used as reactivity
indices. We examined the relationships between the charges qc/or qCH~ for compounds I-IV,
VI, VIII and the potential barriers (E a) for the amination of these sgstems (1)-(6), cal-
culated by the MINDO/3 method. The size of the potential barrier for reaction (4) given
here (Table 3) differs somewhat from the value reported earlier [2], since the parameters
for the transition state of (XIII) in this process were ~efined in the present work (see
the section on the computation procedures).
A good linear a c e a correlation was not obtained for the six reactions given above
(correlation coefficient r = -0.83), but a satisfactory qcH2 - E a was obse~r (r = -0.96).
Thus, it was possible to obtain an approximate estimate of the potential barriers for the
amination reactions from the charges on the methylene groups of the substrates. For this
purpose we used the empirically selected linear correlation between the charges qCH2 and
the logarithms of the potential barriers (r = -0.98):

E,=exp (-.4,9692qcH,+5,6298), (7)

From Table 3 it is seen that the values of the potential barriers calculated by means
of Eq. (7) are fairly close to the values obtained by direct calculation. This shows that
the equation is suitable for determining the reactivity of the investigated systems.
According to the data in Table 3, all four complexes (V-VIII) exhibit fairly high reactivity
in reactions with ammonia. Moreover, ammonolysis is possible in the (IX-XII) systems, which
(as mentioned above) may also be present in the solutions. In order to solve the question as
to which of the associates are the main participants in the reaction it is necessary to
determine their relative concentrations in the solution. Since the free energy of reaction
(8) in aqueous solution amounts to -52.3 kJ/mole [ii] and since the basicities of oxirane
and water are close, it must be supposed that the concentrations of the hydroxonium ion
end also of the protonated ethylene oxide in the aqueous ammonia solutions are negligibly
small compared with the concentration of the ammonium ion.

"3~ + s~ --" ~' + K2~ (8)

The c o n c e n t r a t i o n s o f t h e a s s o c i a t e s ( V I I , X, X I I ) must be c o r r e s p o n d i n g l y small in
comparison w i t h t h e complex ( V I I I ) . S i n c e t h e d i f f e r e n c e in t h e r e a c t i v i t i e s o f t h e f i v e
complexes i s n o t v e r y l a r g e [ c f . t h e Ea v a l u e s f o r t h e r e a c t i o n s o f t h e a s s o c i a t e s (VII) and
(VIII) with ~onia, Table 3 ] , t h e main r e a g e n t in t h e a m i n a t i o n o f e t h y l e n e o x i d e under
r e a l c o n d i t i o n s i s in a l l p r o b a b i l i t y t h e e t h y l e n e o x i d e ~ o n i u m ion complex ( V I I I ) .
It is'more difficult to make analogous estimates for the reactions with aziridine. On
account of the low concentration of the hydroxonium ion the amount of particles (IX) in the
solution is undoubtedly negligibly small compared:with the complexes (V, VI, XI), the
concentrations of which are clearly similar i n o r d e r of magnitude. Since the pK a values
for the conjugate acids in water are somewhat higher for ammonia than for aziridine (9.3
[12] and 8.0 [3]), it can be supposed that the concentration of the ammonium ion-'aziridine
complex (XI) in the aqueous ammonia solution is higher then the concentration of the associate
(VI), while the latter in turn clearly exceeds the concentration of the complex (V) [since,
according to data in Table i, the heat of stabilization of the complex (VI) is larger in
absolute value than that of system (V)]. At the same time the reactivity in amination re-
actions decreases in the following order (Table 3): V > VI > XI. In our opinion, the main
reacting particles in the reactions of aziridine with ammonia are the associates (VI, V),
formed by the protonated aziridine with a solvent molecule, since they are present in the
solution in sufficient quantities, and their reactivity must be perceptibly higher than that
of the complex of aziridine w i t h t h e ammonium ion (XI)o
It must also be borne in mind that the protonated aziridine is capable of forming
at least two hydrogen bonds with the solvent molecules. In the present work we considered
two'such complexes (XIV, XV) (Figs. 1 and 2, Tables 1 and 2).

~'~./ - \V
~f~U 9 " 9 IINR 9 9 9 OH 2 N I I ~ ~ 9 9 Ii N I l " 9 Nil.,

~V XV

837
 Their reactivity is somewhat lower than that of the associates with one solvent molecule
(Table 3). Without calculating the free energies of complex formation it is difficult to
conclude which of the complexes (with[.one or two solvent molecules) is present in the solu-
tion in sufficient quantities. In any case, complex formation with one solvent molecule
already satisfies the capacity of the protonated aziridine to act as a hydrogen bond donor
to a significant degree.
The foregoing shows that the following can act as reacting particles in acid-catalyzed
liquid-phase amination reactions: i) The protonated molecules of the three-membered rings
attached to solvent molecules by strong hydrogen bonds; 2) the molecules of the three-
membered rings included in the first solvate shell of ammonium or hydroxonium ions. In
the latter case the transfer of the proton to the ring heteroatom, the formation of the
carbon atom-nucleophile bond, and the opening of the r i n g t a k e place synchronously. The
above-mentioned processes correspond to two types of acid catalysis, where the first type is
more effective than the second. The second type of catalysis can be realized if the con-
centration of associates of the first type in the solution is negligibly small. As shown
above, the reaction with aziridine is catalyzed by a mechanism of the first type, while the
reaction with ethylene oxide is catalyzed by a mechanism of the second type. Generally
speaking, acid catalysis can be realized even if the molecule of the ring enters the second
or third solvate shell of NH4 + or HsO +, since in this case synchronous transfer of the
proton along the chain is possible. However, since elongation of the chain leads to a rapid
increase in the energy expenditures [13], this mode of catalysis probably does not play a
significant role.

COMPUTATION PROCEDURES

The nonempirical calculations were performed by means of the GAUSSIAN-70 program [14].
During the calculations the optimization of the structure was considered complete if the
decrease in the calculated total energy of the system in the next cycle of optimization of
the geometric parameters was not greater than 5.10 "s au. During the calculation of the
characteristics of the complexes V-VIII, XIV, XV certain limitations were imposed on their
geometric structure. It was assumed that the heteroatoms of the solvent molecules and all
the atoms of the apical groups of the rings lie in the bisecting plane of the angle @ (Fig.
i). The angle ~ was taken as equal to 180 ~ . For each complex it was assumed that the
lengths of all the C-~ bonds, all the angles ~, and the lengths of all the N-~ or 0-~ bonds
in the solvent molecules were identical. It was also assumed that the ammonia molecules
in the domplexes'retain the locai symmetry axis. During calculation of the structures of
the complexes containing two solvent molecules it was assumed that e = ~, d ffi e, and NIH I
(or OIH I) = N2H 2 (or O=H 2) = f. The calculations showed that the str~ctures of all the com-
plexes have a plane of symmetry. One conformer was found for each of the associates V-
VIII, XV, and three conformers for the complex (XIV). The characteristics of the most stable
of the latter are given in Figs. 1 and 2 and in Tables 1 and 2.
The MINDO/3 calculations on reaction (4) were carried out in the reaction coordinate
mode by a procedure similar to that described in [2]. The obtained structure of (XIII)
was identified as the transition state. (The Hessian for this structure had only one
negative eigenvalue.) To identify the transition state we used a program written by V.
A. Pichko (Rostov State University).
The structure of (XIII) differs little from that reported earlier [2], but its NH s
group is rotated by 60 ~ in relation to the local rotation axis. The calculated enthalpy
of formation for the transition compound (XIII) is 610.8 kJ/mole.
The authors are grateful to M. V. Bazilevskii for discussing the results.

LITERATURE CITED

i. S. G. Koldobskii, V. A. Bobylev, G. F. Tereshchenko, and Yu. V. Puzanov, Zh. Obshch.

Khim., 53, 2356 (1983).
2. A. Yu. Shibaev, N. V. Astrat'eva, and G. F. Tereshchenko, Zh. Obshch. Khim., 54, 2744
(1984).
3. A. J . Lowe, D. B u t l e r , and E. M. Mead, B r i t i s h P a t e n t No. 760215; Chem. A b s . , 5!1, 10564
(1957).

838
 N. N. Lebedev and M. M. Smirnova, Kinet. Eat., 6, 457 (1965).
J. T. Smith, Polyme 5, 2, 95 (1961).
Kh. A. Arutyunyan, E. ~. Dzhavadyan, A. O. Topoyan, S. P. Davtyan, B. A. Rozenberg,
and N. S. Enikolopyan, Zh. Fiz. 1(him., 50, 2016 (1976).
7. S. Scheiner and L. B. Harding, J. Phys. Chem., 87, 1145 (1983),
8. W. A. Lathan, L. Radom, P. C. Hariharan, W. J. Hehre,. and J. A. Pople, Top. Curt.
Chem., 40, i (1973).
9. R. H. Nobes, W. R. Rodwell, W. J. Bouma, and L. Radom, J. Am. Chem. Soc., 103, 1913
(1981).
i0. T. J. Zielinsky, D. L. Breen, and R. Rein, J. Am. Chem. Soc., I00, 6266 (1978).
ii. D. H. Aue, H. M. Webb, and M. T.Bowers, J. Am. Chem. Soc., 98, 318 (1976).
12. A. Gordon and R. Ford, Chamist's Companion, Wiley-Interscience (1973).
13. S. Scheiner, J. Am. Chem. Soc., 103, 315 (1981).
14. W. J. Hehre, W. A. Lathan, R. D~-tchfield, M. D. Newton, and J. A. Pople, QCPE, Catalogn
11, Program 236 (1973).

MECHANISM OF AMINATIONOF AZIRIDINES AND OXIRANES.

4.~ QUANTUM-CHEMICAL INVESTIGATION OF THE EFFECT OF
THE POLAR SOLVENT

So G. Koldobskii, G. F. Tereshchenko, UDC 547.71~:541.124'12.038.2

V. A. Bobylev, and A. R. Dalin

The effect of nonspecific solvation on the mechanism of the amination of'three-mem-

bered rings was investigated by the MINDO/3 quantum-chemical method and by the sol-'
vatonmodel.

The energy of nonspecific solvation is determined pr~m-rily byelectrostatic interactions

between the self and inducedcharges of the solvate and the solvent. Interactions of this
type can be calculated by means of the solvation model of Germer [2], in which the solvent
is modelled by a set of point charges (solvatons) surrounding the dissolved molecule, and it
is assumed that each atomic center of the molecule induces one solvaton with a charge
having a sign opposite to the charge of'the a t o m . We used the version of the solvaton model
proposed in [3]. This model, realized within the framework of the CNDO/2 method, was
calibrated for a set of neutral and positively charged molecules similar in structure to the
calculated syst~m~ (see the computation procedure section). Since the protonated aziridine-
ammonia (I) and ethylene oxide - ammonium ion (II) complexes are some of the most likely partic-
ipants in amination reactions, calculation of the energy parameters of the reactions of these
associates with ~-~onia (1,2) with allowance for electrostatic solvation makes it possible
at a qualitative level to study the effect of both general end specific solvation effects.

H~... ~Bt~ 0 . . ~ H~',IH 3

! II
I + NH 3 - NHzCH2CEL~NH3 ~ (1)
" + NIl, ------~----~=,- ROCH~,CI~=NH~ ~" (z)
Here the specific solvation is taken into account by MINDO/3 calculation in the super-
molecule approach through inclusion of the solvent molecule in the reaction system, and the
heats of interaction of the solvate with the polar solvent medium are calculated by means
*For Communication 3, see [i].
State Institute of Applied Chemistry, Leningrad. Translated from Ehimiya Geterotsiklir
cheskikh Soedinenii, No. 8, pp. 1042-1047, August, 1986. Original article submitted June
4, 1985.

nflflO-"41")'9/~/'9-)ng_t%Q':toel,') =n ~ 1QR7 Pl...,.,,, =,,z.1~,,~.~.. ,- . . . . . . . ~__ ,...

 TABLE I. The Energy Characteris-
tics of Reactions (1-8) in t h e
Gas Phase and in Solution, Deter-
mined by the MINDO/3 Method and
the Solvaton_Mddel [2]

Reaction
! E~z, A H c, ,Q,P,
[,~..i k.J/mole kJ/,~ole kJ~'mole
1 87,5 [5, 6l 5,4 93,0
2 72,o [5, 6l 0,8 72,9
3 198,9 [5, 6] --116,4 82,5
4 167,9 [5, 61 --141,1 26,8
5 66,2", [5, 6] 13,4 79,6
130,2T' [5, 6] 3,8 ! 34,0
6 34,8" {l] --8,0 26,8
100,5T- 23,9 124,4
7 188,8 -56,5 132,3
8 138,6 --46,5 92,1

~Rear nucleophilic attack.

tFrontal nucleophilic attack.

of the solvaton model. The potential barrier for the liquid-phase reaction (Ea~) is deter-
mined as the sum of the potential barrier in the gas phase and the AHC value (the difference
between the calculated heats of solvation of the transition state and the reagents). During
the calculations it was assumed that the structures of the stable compounds and transition
states do not change in the Iransition from the gas phase to the solution. Published data
[4] indicate that this assumption is valid on the whole for reactions (i) and (2). From
Table i it is seen that electrostatic solvation retards reactions (i) and (2) little.
According to the obtained results, specific interactions with the protic solvent have a
larger effect on the rate of the acid-catalyzed amination reactions than the polar medium.
The obtained values for the potential barriers (93.0 and 72.9 kJ/mole) are close to the ex-
perimental activation energies of the single kinetically investigated reaction of aziridine
with a nitrogen-containin 8 nucleophile, ioeo, the polymerization of aziridine (52.8 - 81.6
kJ/mole [7]) and the reaction of ethylene oxide with ammonia in aqueous solution (51.1 kJ/
mole [ 8 ] ) .
The s o l v a t o n model was a l s o u s e d t o i n v e s t i g a t e t h e e f f e c t o f a p o l a r s o l v e n t on t h e
r a t i o between t h e v a r i o u s mechanisms o f t h e a m i n a t i o n r e a c t i o n s . The f o l l o w i n g were con-
sidered: 1) R e a c t i o n s (3) an~ ( 4 ) , which model t h e a m i n a t i o n p r o c e s s e s i n t h e a b s e n c e o f
a c i d c a t a l y s i s ; 2) r e a c t i o n s which model t h e n u c l e o p h i l i c o p e n i n g of the rings under the
c o n d i t i o n s o f c a t a l y s i s by a c i d s and t a k e p l a c e b o t h by a b i m o l e c u l a r A2 mechanism ( 5 , 5)
and by a monomolecular A1 mechanism ( 7 , 8 ) .

II~C- - C H 2
\/ NH~ ----~" NH2CH~CH2NH ~ (3)
N
ii
Ill
"IaC~--~CK2
NH~ ~ HOCH2CH2NH 2 (4,)
0
IV

+ NH3 ~ NH2CH2CH2NH~ (6)

NIt 2
V
H~C ~ C H 2
" \ + NH~ ~ HOCI[~CH2NH~+ (6)
OIl

9 +NH 3
H2C - - C H 2 slow
\ .... .~ N,H2CH~CH2~ fast NH2CH2CH2NH~ +
~K2
+NH~
9 H ~ C\-\ -. C
H2 S l O9W . L- HOCH2Clt2 fast = HOCH2C~I~
OH

840
 For reactions (5) and (6) we considered the cases where the ammonia approaches the sub-
strate from the side of the C - C ( r e a r nucleophilic attack) and from the side of the carbon-
heteroatom (frontal nucleophilic attack) bonds. T h e characteristics of the transition
states for the majority of the reactions listed above in the gas phase had been calculated
before [i, 5, 6]. The results from MINDO/3 calculations for the gas-phase reactions (6)
(for the case of frontal nucleophilic attack), (7), and (8) are given in the present work.
The structural parameters of the transition state (VII) corresponding to frontal
addition of ammonia to the molecule of the protonated oxirane are given in Fig. i. Its
characteristics are similar to the data obtained for the corresponding reaction with pro-
tonated aziridine. The potential barrier in this case is also appreciably higher than for
rear addition (Table i).
During investigation of the gas-phase reactions (7) and (8) we considered the possible
products from monomolecular opening of the protonated rings. The MINDO/3 calculation re-
vealed two stable conformers NHzCH2CH2 + (VIII, IX) and one conformer HOCH2CH2 + (X) (Fig. 2).
The geometric parameters of conformer (X) were close to the data from nonempirical calcu-
lation on the 4-31G basis set [9]. At the same time calculation of the characteristics
of the NH2CH=CH2 + cation in this basis set [i0] indicated the presence of only one conformer
with a structure intermediate between structures (VIII, IX). The procedure for the calcu-
lations in the reaction coordinate mode wasunsuitable for determination of the saddle
points in reactions (7, 8). To determine the structural and energy characteristics of the
transition states for these processes we therefore made the assumption that all the geometric
parameters of the reaction systems vary synchronously on the reaction path in the transition
from the initial to the final compounds. According to this shheme,~theLtransition states
correspond to degrees of transformation where the curve for the dependence of the energy of
the system on the degree of transformation passes through a maximum. (In"the course of the
reaction = changes from 0 to i). The method is quite suitable for the production of
qualitatively correct conclusions and has been used successfully for the solution of analogous
problems in nonempirical calculations [9, 10]. During determination of the characteristics
of the transition state (XI) for the controlling stage of reaction (7) it was assumed that
its product is the conformer (IX). (The choice is substantiated in the computation procedure
section). The structure (XI) is close to structure (IX) (= = 0.85). The transition state
(XII) in reaction (8) is significantly less product-like (~ = 0.65).

yo
9
H~ __ ~
H~ OH

Fig. I. The geometric structure of the transition state

in reaction (6) (frontal nucleophilic attack), determined
by the MINDO/3 method. Here and subsequently the numbers
along the bonds are the bond lengths (~).

kl ? ~'~ ~ 113,5

H
a b

Fig. 2. Yhe structures of the conformers, determined by the MINDO/3 method:

a) NH2CHaCH2+; b) HOCHaCH=+o

8 4 1
 TABLE 2.

Structure AHf.

VII 676,6
VIII 893, t
IX 893,9
X 716,0
XI 901,0
XII 754,1

TABLE 3. Comparison of the Calculated and

Experimental Heats of Solvation of the Mole-
cules

NH4 + ] 644,4] 452,21 386,5 l 334,1 I 296,0 I 267,5 351,7

(CH3)~NH [ 16,3[ 276,8[ 100,9 [ 46,1 [ 25,1 I 15,9 53,2
r I 671'61 "8'~ 326,2 1268,81 236,61 215,6 291,8
~Calculated by the MINDO/3 method.
SHeets Of hydration [15 ].

TABLE 4.
j i i i i

~tructure -Hso l v , Structu~ -Hsolv,

kJ/mole kJ/mole

I 288,9 XII 367,2

II 337,5 XIII 303,6
III 22,6 XIV 356,7
IV 44,4 XV 159,1
V 283,9 XVI 205,6
VI 307,3 XVII 289,0
VII 317,0 XVIII 298,5
XI 338,7 XIX 335,4

The heats of electrostatic solvation of the reagents and the transition states for
reactions (3-8) were calculated by the solvaton method. The results from the calculations
(Table i) make it possible to conclude that the effects of the polar solvents on the acid-
catalyzed bimolecular reaction of the rings with the =,-,onia, on the one hand, and on the
reactions taking place without catalysis, ~ the other, are qualitatively different in
character. The solvent significantly stabilizes the highly polar transition states in re-
actions (3, 4) and changes the energy characteristics of the catalytic processes (5, 6)
fairly little. The values obtained for the potential barriers of the liquid-phase re-
actions with unprotonated aziridines and ethylene oxide are undoubtedly low. This result
can be explained both by the characteristics of the Germer model, which is insufficiently
reliable for the calculation of solvation in uncharged systems, and by the fact that the
MINDO/3 calculations ~ould give values too low for the activation energies of the gaseous
reactions. It is clear, however~ that the solvaton model describes the effect of the polar
solvent on the processes correctly in qualitative respects. According to the calculated
data, the potential barriers of the uncatalyzed reactions in t h e g a s phase are approximately
100-130 kJ/mole higher than for reactions (5, 6), which take place with inversion of the
configuration, i.e., the gas-phase reactions (3, 4) must be practically unobservable. At
the same time the reaction of substituted oxiranes with amines in the absence of acid
catalysis in solutioR was investigated experimentally [11]. This showed a marked reduction
of the break in rates between the catalyzed and uncatalyzed reactions in the transition
from the gas phase to the solution, and this is fully consistent with the results from the

842
present work. The calculated difference between the potential barriers of reactions (3)
and (4) in the liquid phase (55 kJ/mole) is very large. Thus, according to the calculated
data, the reactivity of the unprotonated aziridine is significantly lower than that of
ethylene oxide. This result is consistent with the experimental data; the reaction of
aziridine with ammonia hardly takes place at all without catalysis [12].
It is known that in some cases acid-catalyzed amination reactions take place with
partial retention of the configuration at the reaction center [12, 13]. This is usually
explained by a contribution from the A1 mechanism. In fact, according to the data in
Table i, electrostatic solvation appreciably accelerates reactions (7, 8). It seems to us
that the retention of the configuration may be due also to the realization of frontal
addition of the nucleophile by the A2 mechanism. The values obtained for the potential
barriers of the liquid-phase reactions with frontal attack are approximately the same as
the barriers in reactions (7, 8). It should also be borne in mind that the present calcu-
lation does not take account of specific solvation effects, which may be extremely signif-
icant for the given processes. The possibility that bimolecular reactions with retention
of the configuration do take place in certain cases must not, therefore, be ruled out.

COMPUTATION PROCEDURES

The MINDO/3 calculations were made with full optimization of all the geometric parameters
of the systems. The search for the saddle points on the potential energy-surface for the
reaction (6) was made in the reaction coordinate mode. The condition for localization of
the saddle point was reversion to zero in the standard gradient of the potential energy
function of the system and change in the sign of the component of the gradient along the
reaction coordinate during passage through this point. As reaction coordinate we used the
C(1)N(I ) distance. The obtained structure (VII) was identified as the transition state.
(The Hessian for this structure had one negative eigenvalue}. We used the program written
by V. A. Pichko (of Rostov State University) for the identification of the transition states.
For the NHzCH2CH~ + 6atiDn we found.two conformers (VIII, IX) (Fig. 2a). The MINDO/3
calculation of the transformation of the conformer (VIII) into the protonated aziridine
[14] showed the presence of a fairly significant potential barrier (38 kJ/mole). This result
does not agree well with the data from ab initio calculation [I0], according to which the
activation barrier amounts to about 10 kJ/mole, while the structure o f the transition state
is close to the structure of the open NH2CH2CH= T cation. In the present work we considered
the reaction of conformer (IX) [the reverse of reaction (7)], the heat of formation of which
is only 0.8 kJ/mole higher than the heat of formation of structure (VIII). The value ob-
tained for the potential barrier (7.1 kJ/mole) was appreciably lower than for the reaction
involving the conformer (VIII). The enthalpy of formation (~Hf) of the systems examined in
the present work, calculated by the MINDO/3 method, are given in Table 2.
For the calculations by means of the solvaton model [3] it was necessary to select
a value for the parameter r (the distance between the solvaton and the atom to which it
"belongs"). The heats of solvation were calculated for a set of neutral and positively
charged molecules structurally similar to the investigated systems. If r = 1.2 ~ (Table
3), the calculated heats of solvation (Hsolv) are close to the experimental values, and we
therefore used this value for r in the subsequent calculations. The heats of electrostatic
solvation were calculated by means of the structural parameters of the systems, determined
by the MINDO/3 method. The obtained Hsolv values are given in Table 4. [The numbers
(XIII-XIX) correspond to the transition states in reactions (1-4) and (5) for rear and
frontal nucleophilic attack and (6) for rear nucleophilic attack.]
The authors are grateful to M. V. Bazilevskii, I. A. Abronin and L. G. Gorb for dis-
cussion of the results.

LITERATURE CITED

9. S. G. Koldobskii, G. F. Tereshchenko, V. A. Bobylev, and A. R. Dalln, Khim. Geterotsikl.

Soedin., No. 8, 1036 (1986).
2. Ho Ao Germer, Theor. Chim. Acta, 34, 145 (1974).
3. L. G. Gorb, I. A. Abronin, N. V. Kharchevnikova, and G. M. Zhidomirov, Zh. Fiz. Khim., 58,
9 (1984).

843
 4. K. C. Westaway, Can. J. Chem., 56, 2691 (1978).
5. S. G. Koldobskii, V. A. Bobylev, G. F. Tereshchenko, and Yu. V. Puzanov, Zh. Obshch.
Khim., 53, 2356 (1983).
6. A. Yu. Sh~baev, N. V. A s t r a t ' e v a , and G. F. Tereshchenko, Zh. Obshch. Khim., 54, 2744
(1984).
7. D. S. Zhuk, Paper deposited at VINITI, No. 709-81Dep.
8. P. Ferrero, F. Berbe, and I. R. Flamme, Bullo Soc. Chim. Belg., 56, 349 (1947).
9. A. C. Hopkinson, M. H. Lien, I. G. Crizmadia, and K. Yates, Theor. Chim. Acta, 47, 97
(1978).
10. A. C. Hopkinson, M. H. L i e n , I . G. Crizmadia, and K. Y a t e s , Theor. Chim. Acta, 55, 1
(1980).
11. Kh. A. Arutyunyan, A. O. Topoyan, S. P. Davtyan, and N. S. Enikolopyan, Dokl. Akad.
Nauk SSSR, 214, 832 (1974).
12. P. A. G e m b i t s k i i , D. S. Zhuk, and V. A. Kargin, Chemistry o f E t h y l e n e Imine [ i n
Russian}, Nauka, Moscow (1966), p.256.
13. R. G h i r a r d e l l i and H. J . Lucas, J . Am. Chem. S o c . , 79, 734 (1957).
14. L . M . Timofeeva and V. G. Avakyan, I z v . Akad. Nauk SSSR, S e r . Khim., 1557 (1980).
15. D. H. Aue, H. M. Webb, and M. T. Bowers, J . Am. Chem. S o c . , 98, 318 (1976).

CRYSTAL AND MOLECULAR STRUCTURE OF 6-METHYL-2,7-DIPHENYL-I,3-

DIFORMYLINDOLIZINE

D. S. Yufit, Yu. ~. Struchkov, UDC 5 4 8 . 7 3 7 : 5 4 7 . 7 5 9 . 1

N. S. Prostakov, and V. I. Kuznetsov

An x-ray crystallographic investigation was made of 6-methyl-2,7-diphenyl-l,3-

diformylindolizine, obtained by the formylation of 6-methyl-2,7-diphenylindol-
izineo The effect of various carbonyl-containing substituents at positions
I and 3 on the geometry of the indolizine ring in the structually investigated
indolizine derivatives is discussed.

6-Methyl-2,7-diphenyl-l,3-diformylindolizine (I) was obtained by the formylation of

6-methyl-2,7-diphenylindolizine by the Vilsmeier reaction.

CHO
I

In view of the electrophilic character of this reaction it could be expected that

formylation would take place at positions 1 and 3 of the indolizine ring. In order to
obtain conclusive evidence for the structure of (I) we undertook its x-ray crystallographic
investigation.
The general appearance of the molecule of (I), the numbering of the atoms, the bond
lengths, and the bond angles are shown in Fig. i. The five- and six-membered mings of the
indolizine system in the molecule of (I) are planar within the limits of 0.012(8) and 0.025
(8) ~ respectively. The dihedral angle between the planes of the rings is 3.5 ~ while the
maximum deviation of the atoms from the mean-square plane of the whole bicyclic system
amounts to only 0.051 (8) ~ (for the C(6 ) atom). Subsequently, therefore, we will consider
the orientation of the substituents in relation to this plane , drawn through all the indol-
izine rings as a whole.

A. N. Nesmeyanov Institute of Heteroorganic Compounds, Moscow. Translated from

Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1048-1051, August, 1986. Original
article submitted April 15, 1985.

844 0009-3122/86/2208-0844512.50 @ 1987 Plenum P u b l i s h i n g C o r p o r a t i o n

 TABLE I. The Bond Lengths in the Bicyclic Ring of the Indol-
izine Derivatives
'7 8 ~q I

Refer-
Co~-
pound ~
I--2 :~--3 ~-N~i) INt4)-5 5--6 0-,;-7 7--8 f s~9 9--I en~e
I
Present
I 1,41 ! 1,40i 1,42 !,38 1,37 I;42 1,37 1,40 1,43 1,39 work

11 "I' 1,420 1,393 1,397 1,385 1,373 1,402 1,3481 1,42 1,369 1,410! [I]
1,426 1,384 1.407 1,382'~ 1,365 t.41~1 1,367/ 1.393[ 1.375 1.410
IV4" 1,395 tA01 t ,4 t 4 1,368 1,3601 1,404 i,359[ 1,4371 1.374 1.388 [4]
1,402 1,385 1,414 1,368 1,353 1,404 1,354/ 1,4311 1,378 1,394
V 1,427 1,376 1,384 1,369 I~ 1,425 1,355/ 1,421/ 1,354 1,422 [31
VI 1,427 1,390 1,352 1.395 1,346 1,402 1,381/ 1,42l[ 1,375 1,419
VII 1,44 1,37 1,41 1,38 1,40 1,41 1,39 [ 1.4~ / 1,34 1,42
VIII 1,44 1,37 1,38 1,43 1,40 1,41 1,34/ 1,4t 11,37 1,42

e(IV) is di(2,8-diphenyl-3-indolizinyl)disulfide, (V) is 2-

phenyl-6-nitroindolizine, (VI) is 2-phenyl-8-nitroindolizine,
(VII) is 2-phenyl-5-butylemino-8-nitroindolizine, and (VIII)
is 2-phenyl-5-piperidino-8-nitroindolizine.
~Contains two indolizine rings in the molecule.

)123,2r~
~
- 24"~'--I~2(I) -//" ~'~ <"It- /7 ~ ~"' - w "~'~
~ ~ ~ ';8,,,,~" ~ ~ ~ ~.'~\~T.~

9 , >; ~ ".'a>, it

Fig. i. The data from x-ray crystallographic analYsis; the bond lengths
and bond angles in the molecule of (I).
Among the few structurally investigated derivatives of indolizine there are only two
compounds with carbonyl-containing (benzoyl) substituents, i.e., l,l-bis(5-methyl-2-phenyl-
l-benzoyl-3-indolizinyl)ethylene (II) [i] and l-(2-pyridyl)-3-benzoyl-6-bromoindolizine (III)
[2]. Both papers consider the contribution to the geometry of the molecules from forms with
separation of charges, which for indolizine (I) can be represented, for example, in the
following way:

-0 " I { o~I!
4 c

On the basis of the chemical and spectral data it was supposed that the molecule of
(III) exists predominantly in the bipolar form (B, C), but the-x-ray crystallographic data
obtained in [2] cannot, in our opinion, provide reliable evidence for this ~roposal on
account of their insufficiently high accuracy. (The errors amount to 0.05. A in the deter-
mination of the bond lengths and 3 ~ in the bond angles. ) These data will not therefore be
used in the subsequent discussion.
845
 TABLE 2 . The Coordinates of the Nonhydro-
gen Atoms (x 104) and Their Equivalent Isotropic
Temperature Factors (A 2)

eq
Atom x y z B'soz

O(i) 6421(6) 457(4) 521(5) 4,5(2)

O(2) 4901(7) 4829(4) 2055(5) 5,3(2)
N(4~ 4933(7) 2190(4) 592(6) 9,7(2)
5534(8) 33o1(5) 1876(7) 2,7 (3)
C<=~ 6260(8) 2499(6) 2236(7) 2,8(3)
C(3) 5927(8) 1810(6) 1442(7) 2,6(3)
C~s~ 4199(9) 1759(5) -326(7) 3j (3)
3251(8) 9240(6) -I042(7) 3,0(3)
C(r) 3062 (8) 3182(6) --869(7) 2,6(3)
C(8~ 3763(8) 3593(5) 71(7) 2,8(3)
C~e) 4698(8) 3095(6) 829(7) 2,7 (3)
C~~0~ 6596(8) 959(6) 1341(8) 3,3(3)
Cd,, 5558(9) 4167(6) 2448(8) 3,9(3)
C~) 2143(9) 3736(6) -1682(9) 3,4 (3)
ioo5(11) 4155(6) -1333(7) 3,8(3)
Cn4~ 96(9) 4683(6) --2083(I0) 4,7(4)
Qm 356(12) 4794(7) -3155(10) 5,0(4)
C(,,) 1509(13) 4385(7) -3520(8) 5,2(4)
C(m 2380(9) 3852(6) -2783(9) 4,0{3)
C(~e) 7210(9) 2380(6) 3300(7) 3,0(3)
C(1~) 7020(8) 1631(6) 3992(8) 3,5 (3)
C(~o~ 7883(10) 1524(6) 5023(9) 4,5(4)
C~m) 8923(12) 2138(8) 5351(9) 5,4(4)
C(=) 9114(10) 2872(7) 4662(10) 5,6(4)
C~) 8261(9) 2996(6) 3609(8) 3,8(3)
C(=4) 2379(8) 1716(6) -2023(7) 4,1 (3)

TABLE 3. The Coordinates of the Hydrogen

Atoms (~i0 3)

Atom x y z Atom g z

H(5) 440 101 --50 H{ig) 618 I12 374

H~s~ 357 433 26 H~) 778 92 557
H(to) 735 72 208 962 206 617
H~,,) 620 425 329 990 341 496
H(I~) 79 407 --45 849 355 301
H(t4) -82 503 - 180 H(2~d) 253 100 - 1 9 8
H(t+) -36 521 -377 H(24.2) 250 200 -275
169 451 -442 H124.3) 127 183 -210
Him 325 351 - 308

Substitution of the benzoyl groups in the molecule of (II) by the more electronegative
aldehyde groups in the indolizine (I) should lead to shortening of the C(I ) - C(tz) and C(3 )-
C(t0) bonds on account of the larger contribution from forms B and C. It can evidently
be considered that such a tendency is observed within the accuracy limits in the determination
of the geometric parameters for the molecule of (I). In fact, the average length of the C(in=
dolizine)--C(benzoyl) bond in (II) amounts to 1.460 ~, whereas thd lengths of the C(l~- C(is )
and C( )3 - C( 0)x bonds in the molecule of (I) are 1.43(1) and 1.44(1) ~. Unfortunately, un-
substztuted indolizine has not been investigated structurally. (An attempt to obtain its
single crystals proved unsuccessful [3]). For this reason it is impossible to determine
what changes occur in the geometry of the indolizine ring with the introducton of the
carbonyl-containing substituents at positions 1 and 3. As seen from Table I~ which gives
the bond lengths in the bicyclic rings of the structurally investigated indolizine deriv-
a-tives, the lengths of the respective bonds in the various molecules vary greatly ~eog., for
the N(~)- C(3 ) distance, from 1.35 to 1.42 ~). Compounds (I-VIII) differ greatly in the
number, position, and nature of the substituents in the indolizine ring. However, it can be
seen that some shortening of the C(a ) -C(9 ) and N(~) - ~ 9 ) bonds and elongation of the
C(1)-C(e ) bond are observed in the indolizine (I) compared with the molecules of (V-VIII)
ndt'containing substituents at positions 1 and 3. T h i s is due to the contribution from the
forms w~th separation of the charges.

846
 In the molecule of (III), where there is no substituent at position 2 of the indolizine
ring, the carbonyl group lies in the plane of this ring. In (II) the planes of carbonyl
groups at positions i are rotated in relation to the planes of the indolizine systems by 17
and 37". This is probably due to intramolecular contacts between the substituents at
positions 1 and 2. In the investigated molecule of (I), compared with the molecule of (II),
the bulky benzoyl group at position 1 is substituted by an aldehyde group, the plane of
which forms a dihedral angle of 5.0 ~ [smeller than in the molecule of (II)] with the plane
of the bicyclic system. The angle formed by the plane of the second aldehyde group at
position 3 amounts to 14.7". The different orientations of the aldehyde groups in the mole-
cule of (I) are evidently determined by the asymmetry of the indolizine ring [in particular,
by the inequality of the angles C(z)C(9)C(s ) 134.4 (8) ~ and C(a)N(~)C(s ) 128.2 (7)~ on
account of which even with larger'rotation of the 3-aldehyde group the 0(I ) ... C(~) 2.98 (i)
distance remains smaller than 0(2)?..C(, ) 3.07 (I) ~. In addition, the steric interactions be-
tween the substituents at positions i, 2, and 3 in the molecule of (I) lead to an increase
in the C(2)C(I)C(11) 128.1 (8) and in the C(2)C(a)C(10) angle to 12.8 (8) ~ compared with the
theoretical value of 126" and to rotation of the plane of the phenyl ring at position 2 by
48.4 ~ in relation to the plane of the indolizine system. The plane of the other phenyl sub-
stituent forms a dihedral angle of 61.3" with the plane of the indolizine ring.

EXPERIMENTAL

The PMR spectrum was obtained on a Tesla BS-487 spectrometer at 80 MHz in deuterochloro-
form with TMS as internal standard. The IR spectrum was recorded in tablets with potassium
bromide on a UR-20 instrument. The UV spectrum was recorded in chloroform on a Specord
UV-vis instrument. The mass spectrum was measured on a MX-1303 mass spectrometer at 70 V.
The crystals of the indolizine (I) C23HI?NO 2 are monoclinic; a = 9.8831 (6), b = 14.692
(i), c = 11.972(1) ~, 8 = 98.373(6)", Z = 4 (at 20"C), space group P 2 J c . The unit cell
parameters and the intensities of 1779 unique reflections, 1009 of which with I ~ 2c were
used in the calculitions, were measured on a Hilger-Watts automatic four-circle diffract,m-
eter (ACuKa, graphite monochromator, 8/28 scan,.8 ~ 66"). The structure was interpreted
by the direct method by MULTAN program and refined by the full-matrix method of least
squares in anisotropic approximation for the nonhydrogen atoms. The hydrogen atoms of the
methyl group were revealed from a difference synthesis, and the remaining hydrogen atoms
were placed at the calculated positions; all the hydrogen athens were included in the calcu-
lation with fixed position and temperature parameters (Bis O = 6 ~2). The final values of
the divergence factors were R = 0.069 and R w = 0.064. All the calculations were made
on an Eclipse 5/200 computer by means of the INEXTL programs [5].
The coordinates of the nonhydrogen atoms are given in Table 2, and the coordinates of
the hydrogen atoms are given in Table 3.
6TMethyl'2,7-diphenyl-l~3"diformylindolizine. To i.i ml (12 mmole) of phosphorus
oxychloride at room temperature we added 5 ml of DMFA. We then gradually added a solution
of 1.4 g (5 mmole) of 6-methyl-2,7-diphenylindolizine [6] in i0 ml of DMFA. The mixture
was stirred at room temperature for 40 min, at 45-50"C for 1 h, and at 80"C for 2 h. It
was then poured onto ice and neutralized with a 50Z solution of potassium carbonate. ~he
precipitate was filtered off, washed with water, and dried. We isolated 0.76 g (50Z) of
6-methyl-2,7-diphenyl-l,3-diformylin~lizine; mp 192-194~ (from isopropyl alcohol).
PMR spectrum: 9.82 (2H, s, 3-CHO, 5H); 9.64 (IH, s, I-CHO); 8.50 (IH, s, 8-H); 2.36 ppm
(3H, s, 6-CH3). IR spectrum: 1655 cm "I (vC=O). UV spectrum, Ama x (log e): 246 (4.37);
278 (4.60); 294 (4.42); 302 (4.40); 362 nm (4.42). Found Z: C 81.5; H 5.1; N ~ . 3 ; M +
339. CzaH17NO2t Calculated ~: C 81.4; H 5.0; N 4.1~.

LITERATURE CITED

i. E. Oeser,'Chem. Bet.,.105, 2351 (1972).

2. L. A. Aslanov, V. M. Ion,v, I. S. Akhmed, Farag, V. A. Tafeenko, S. M. Vinogradova,
A. N. Kost, and P. B. Terent'ev, Zh. Strukt. Khim., 17, 746 (1976).
3. V. A. Tafeenko and L. A. Aslanov, Zh. Strukt. Khim., 21, 69 (1980).
4. D. S. Yufit and Yu. T. Struchkov, Izv. Akad. Nauk SSSR, Set. Khim., No. 12, 2724 (1985).

847
 0 R. G. Gerr, A. I. Yanovskii, and Y u . T . Struchkov, Kristallografiya, 28, 1029 (1983).
6. N. S. Prostakov, L 9 A. Gaivoronskaya, KamaraHaiga Sarata Hokhomon, V. P. Zvolinskii,
A. A. Savina, Munzer Makhsida, and Viktor Ugo Opasko Karrasko, Khim. Geterotsikl.
Soedin., No. 4, 506 (1976).

MASS-SPECTROMETRIC BEHAVIOR OF ISATIN 0XIMES

P. B. Terent'ev, L. I. Mazhilis, UDC 543.51:547.'756

A. G. Kalandarishvili, and A. P. Stankyavichus

On the basis of an analysis of the mass spectra of a large series of benzo-substi-

tuted isatin oximes it is shown that their molecular ions undergo type II Beck-
mann rearrangment ~o the corresponding o-N-carboxyaminobenzonitriles.

It is known that, like many benzolactams [I], oxindole under electron impact loses a
molecule of CO with the formation of an ion that has a structure similar to that of a 2-
methyl nitrene, since its subsequent fragmentation coincides with the fragmentation of the
[M - N2] + ion of a 2-methyl azide [2]. The fragmentation of the molecular ion (M+) of
isatin is also determined by primary elimination of a molecule of CO, chiefly from the 2
position [3-5]. The same primary fragmentation process (the loss of CO) is also character-
istic for the H + ions of 3-aryl-iminoisatins [5] and isatin 3-thiosemicarbazones [6]. Up
until now, the mass-spectrometric behavior of isatin-3-oximes has not been investigated,
even though it is known that such 3-hydroxyiminolactams may exist in several tautomeric
forms [7], and thermal type II Beckmarm rearrangement, which takes place at temperatures
above 200~ [8-11] in vacuo [19] and l e a d s t o o-aminobenzonitriles, has been observed for
isatin oximes. Since transformations of M + i o n s that are similar to certain reactions of
the same compounds in the condensed phase are frequently observed under the conditions of
mass-spectrometric experiments [12-15], we studied the behavior of a series of isa~in 3-
oximes I-XII under electron impact.

Rz R[~ c ~ N l~

R-""~")'~!I.1.....
- --~--~ "~
_.~.__ R~"~/J"~
@~C O 0 ~
,r"<'~- "N)"~o ,,~'

i
!*o i o~ I.H
-.:o #
" R2 .2 R2 , R~ T*'
R" ~ i c'N- R R ~ . r. ~-. ' ~ . j C ~'N'] " "~
-~o "-~-:,[ i !i , tl
R4 ;=CO * ~" "/A''TJ'J~N R4 I ~ . . - ~ . N = C = O ' NH
R 4 "'~"~t-""""

FI F3 F2 F~
-HCN i "CO -HCN
) )
-'HCN
F6 Fs .... F? Fs
An M + peak, the intensity of which (Table 2) depends to a considerable degree on the
character of the substituent and its position in the benzene ring, is observed in the mass

Kaunas Hedical Institute, Kaunas 233007_ H. V. Lomonosov Moscow State University,

Moscow 117234. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1052-
1055, August, 1986. Original article submitted April 25, 1985.

848
0009-3122/86/2208-0848512.50 @ 1987 Plenum Publishing Corporation
 TABLE i. Mass Spectra of I-XIII

Corn- rap, ~ Mass spectra,-~m/z

p6und (relative intensity, ~)

I 224 162 (31), 145 (12), 144 (20), 132 (i2), 118 (I00), I17
(14), 116 (7), 91 (40), 90 (13), 64 {14), 63 (13)
II 191--193 176 (87), 159 (29), 158 (28), 132 (36), 131 (I00), 130
(20), 129 (17), I04 (16), I03 (37), 77 (16), 63 {I0)
II-D 189--190 179 (I00), 162 (40), 160 (64), 135 (34), 134 (62), 133
(34), 118 (24), 107 (30), I06 (28), 91 (20), 78 (26)
Ill 220 176 (59), 169 (30), 158 (100), 131 (36), 130 (28), I16
(26), 115 (43), 105 (36), 104 (69), 89 (26), 78 (39)
IV 243,5 176 (43), 159 ( l l ) , 158 (12), 132 (55), 131 (lO0), 130 (5),
105 (3), 104 (8), 103 (2), 77 (7), 51 (4)
V 229 176 (9), 159 (4), 158 (3), 132 (lO0), 131 (75), 130 (4), 105
(3), 104 (9), 103 (2), 78 (4), 77 (9)
VI 242--243 176 (I00), 159 (31), 158 (15), 132 (II), 131 (52), 129 (11),
104 (I0), 103 (18), 89 (15), 78 (15), 77 (I0)
VII >260 240 t' (7), 222 t (15), 196t (21), 146 (19), 115 (17), 105
(26), t04 (lO0), 91 (18), 90 (24), 77 (27), 63 (17)
VIII .... 185 212 (2), 194 (10), 169 (lO), 168 (lO0), 141 (7), 140 (17),
132 (2), 131 (3), 114 (6), 113 (3), 91 (2)
IX 202--204 216 (55), 200 (43), I19 (91), 198 (100). 197 (35), 171 (36),
139 ( l l ) , If4 (6), 97 (5), 83 {5), 63 (5)
X 225--227 212 (0,5), 194 (64), 168 (I00), 166 (7), 141 (4), 140 ([4),
139 (II), If4 (6), 97 (5), 83 (5), 63 (5)
XI >300 216 {47), 199 (21), 198 (55), 172 (39), 171 (28), 170 (I00),
169 (55), 155 (25), 144 (25), 115 (24), 91 (22)
XII 245--247 216 (100), 199 (36), 198 (50), 188 (50), 172 (27)~ 171 (40),
170 (60), 156 (24), 144 (38), 116 (22), 115 (22)
XIII 175--175,5 176 (100), 145 (29), 144 (10), 118 (29), 117 (49), 116 (6),
102 ( l l ) , 90 (22), 76 (6), 64 (6), 63 (8)

~The molecular-ion peak arid the I0 most intense peaks are

~resented.
%Ions that contain the VgBr isotope.

spectra of all of the investigated compounds. The most stable M + ions were those of
1-methyl-, 5-methyl-, and 7"methylisatin-3-oximes (II, IV, VI) and 5,6-tetramethyleneisatin-
3-oxime (XII), i.e., compounds in which a substituent with a + I effect is located in the
ortho or para pesition relative to the heteroring nitrogen atom. The introduction of a
methyl group in the 4 position (III) or 6 position (V) of the benzene part of the molecule
and of a bromine atom in the 5 position (VII) or benzo-annelation in the 4,5 (VII) or 6,7
(X) positions leads to a sharp decrease in WM; in contrast to the data in [16], aromatization
of IX and XI (conversion to benzo derivatives VIII and X) makes the molecules less resistant
to electron impact. All of these facts suggested that, as a result of ionization, the
heterocyclic ring of isatin is destroyed, and the M + ion undergoes isomerization (rearrange-
ment) to the acyclic form of the corresponding o-N-hydroxycarbonylaminobenzonitrile.
Isomerization takes place precisely in the M + ion and is not the result of thermal action
prior to ionization, since the temperatures at which the mass spectra were recorded did not
exceed I00-120~ The occurrence in the M + ions of a type II Beckmann rearrangement is also
indicated by the character of their fragmentation. Thus the peaks of [ M - CO] ~ ions, which
are characteristic for isatins and their 3-oximes [2-5], as well as peaks of [H - NO] + or
[M - N H O H ] + ions, which are typical for the mass spectra of oximes, particularly the oximes
of tetralone and other cyclic ketones [16-18], are absent in all of the mass spectra. At
the same time, the M + ions of I-XII readily eliminate OH (FI), H20 (F2) , and, successively,
OH and CO particles (Fa) , as well as C02 (F4) (see the scheme); the formation of Fl, Fa, F~,
and F 6 ions is generally confirmed by metastable transitions. In addition, the elementary
compositions of the FI-F7 ions in the mass spectra of III and VI were established by the
accurate determination of the masses of these ions (Table 3).
Shifts of the mass numbers of the FI, Fa, and F4 ions (3 amu) and of the F 2 ion (2
amu) were observed in the mass spectrum of 3-hydroxyimino-l-trideuteromethyloxindole (II-
D3); this demonstrates the participation of the 1-methyl hydrogen atoms in the loss of water
by the molecular ion, i.e., it also confirms the noncyclic form of t h e M + ion. In complete
conformity with the fragmentation scheme, shifts of the masses of the Fl, Fa, and F~ ions
(i amu)hand the F~ ion (2 amu) were observed in the mass spectrum of I-D2, which contains
deuterium atoms in the hydroxy group and attached to the nitrogen atom; the mass numbers
of the F2, Fs, Fs, and F7 ions did not change.

849
 TABLE 2 . Intensities of the Principal Characteristic Ions in
the Mass Spectra of Oximes I-XII (X Xss)

E R' Rs F= F~ F5
O
CO
~r
R2 R~
.z~, i rl F~ Fs F7 FS

H 10,3 13,9 6,4 4,3 31,2 2,2 1,2 4,1 12,5

I1 H H H 22,2 6,9 6,7 24,1 6,2 4,8 8,8 3,8 1,7
IIII CH3 H H 7,7 2,1 I 1,4 4,0 2.3 3,2 ] ,3 7,9 4,0
IVvHH/CH~HCH~ H H
H
18,8 4,5
4,2 1,6
4,8
I,I
41,6
33,0
22,8 1,8 i,1
43,9 1,9 0,8
3,2
4,0
1,2
1,3
1,0
VI H H 27.0 7,2 3,3 12,J 2.6 1,8 4,1 2,3
VII H Br HH 3,6 0,5 8,1 10,8 6,9=~.[.
VIII - - ( C H ) 4 - - 1,4 6,0 62,1 4,1
6,9 9,~ 10,5 r,8 2,3 10,5 35 2,-7
XII
x:p, I"--i-- g
x,
(C "I2),--
t),-- 0,4
9,6 2,6"
16,5 4,9 ~ .
28,6
I0,I
6,8 5,4
43,0 3,0 4"~
7,0 18,0
3,7 8,1 5,2
4,5_
1,9
1,9

~For I and III-XII, R z = H; for II, R z = CHa.

tThe F~ ion initially loses a Br atom [m[z i17(3.0Z)] and
then a molecule of HCN.
r addition, an [ H - CzH~] + ion (6o8Z) is observed.

TABLE 3. High-Resolution Mass Spectra

of III and VI
r e , J, _

Calr o
Found Ion :ompositiO,fi
l~mld

VI 159~542 l CgHTN~ 159,0558

III 158,0455 CgHsN~ 158,0480
VI 158,0456 F~ C,H~N~9 15&0480
III 132,0668 F4 C,H,N= 132,0687
VI 132;0676 F'4 CaH,N~ 132,0687
III 131,0595 F3 CaHTN~ 131,0578
VI 131,0591 CsHTN2 131,0578
III 129,0454 [z,Z ~ CsHsN~ 129~458
+
-CHOI
111 105,0523 Fs CzHTN 105,0578
III 104,0502 Fa C~H~N 104,0500
VI 104,0504 F6 CIH~N 104,0500
VI I03,0429 Fz CTHbN I03,0426

The mass spectrum of the thermally stable 3-methoxy-iminooxindole (XIII), which we

synthesized, showed that, in addition to a m a x i m u m M + peak and an intense [M - OCHs] +
ion peak (145), ~ peaks of [M C HNCO] + (133) e and [M - OCH3 - HCN] + (118) ~ ions are observed
in it (see Table i), the 145 118 + 27 transition is confirmed by the metastable ion with
an apparent mass of 96.0 (calculated value 96.0), which can be possible only in the case of
a cyclic lactam form of t h e M + ion of XIII.
Thus an analysis of the mass-spectrometric behavior of isatin oximes makes it possible
to establish a similarity in their mass-spectrometric and thermal behavior.
As we were putting this paper into its final form, we became aware of a communication
[19] in which the mass spectrum of isatin-3-oxime (I) was briefly described. However, the
presented hypothetical fragmentation scheme was not ~onfirmed by more thorough investigations
(high-resolution spectra and metastable ions) and therefore evidently cannot lay claim to
serious validity. At the same time~ an analysis of the ions presented in this paper does
not contradict our proposed rearrangement of the molecular ion~

EXPERIMENTAL

The mass spect=a were recorded with MKh-1303 and MAT-II2 spectrometers with direct
introduction of the substances into the ion source at ionization energies of 50 and 70 eV~
Thehigh-resolution mass spectra were obtained with an MAT-311 spectrometer by the peak-
coincidence method.
~These are the m/z values.

850
 The synthesis of the isatin oximes was accomplished by the methods in [9-11]; the con-
stants of the compounds obtained are presented in Table i. Compound II-D3 was synthe.sized
in analogy with the method in [10,18], and XIII was synthesized in analogy with the method
in [20]. Deuterium derivative I-D= was obtained by threefold dissolving of I in CH3OD
with successive evaporation of the solutions in vacuo. According to the mass spectrum, the
product contained 89Z and ii~, respectively, of the di- and monodeuterated analogs.
The authors thank N. A. Klyuev for his assistance in recording the high-resolution
mass spectra.

LITERATURE CITED

i. P. B. Terent'ev, O. Vendrova, V. M. Dem'yanovich, L. D. Solov'eva, and V. M. Potapov,

Khim. Geterotsikl. Soedin., No. I, 1236 (1983).
2. R. F. C. Brown and M. Butcher, Aust. J. Chem., 25, 149 (1972).
3. M. Butcher, Org. Mass Spectrum., ~, 759 (1971).
4. Kh. Sh. Khariton, G. I. Zhungietu, M~ A. Rekhter, B. T. Oloi, and N. I. Chmykhova, Khim.
Geterotsikl. Soedin., No. 7, 957 (1975),
5. N. P. Peer and R. I. Barbuch, Org. Mass Spectrom., 19, 171 (1984).
6. Kh. Sh. K11ariton, M. A. Rekhter, G. I. Zhungietu, N. I. Chmykhova, and B. T. Oloi, Khim.
Geterotsikl. Soedin., No. i, 75 (1979).
7. T. J. Schwan and H. A. Burch, J. Heterocycl. Chem., 20, 239 (1983).
8. G. I. Zhungietu and M. A. Rekhter, Isatin and Its Derivatives [in Russian], Shtiintsa,
Kishinev (1977), p. 228.
9. W. Borsche, H. Weissmann, and A. Fritzsche, Chem. Bet., 57, 1149 (1924).
I0. G. R. Bedford and M. W. Partidge, J. Chem. Soc., No. 4, 1633 (1959).
ii. J. Faust, J. Prakt. Chem., 319, 365 (1977).
12. P. B. Terent'ev (Terentiev), A. N. Kost, and J. Lange, Org. Mass Spectrcm., 2, 1022
(1974).
13. M. M. Green, T e t r a h e d r o n , 36, 2687 (1980).
14. I. Stach, R. Herzschuh, S. Leistner, and H. Wagner, Khim. Geterotsikl. Soedin., No. 3,
329 (1983)o
15. R. K. M. R. Kallary and P. L. M. Rao, Org. Mass Spectrom., 12, 411 (1977).
16. K. Dagher, P. B. Terent'ev (Terentiev), Yu. G. Bundel' (Bundel), R. Hanna, and B. I.
Maksimov (Maximov), J. Heterocycl. Chem., 20, 989 (1983).
17. H. F. Grutzmacher and C. Rommer, Org. Mass Spectrom., 17, 318 (1982).
18. O. M. Radul, G. I. Zhungietu, M. A. Rekhter, and S. M. Bukhanyuk, Khim Geterosikl.
Soedin., No. 3, 353 (1983).
19. I. V. Shantsevoi, in: Science in Pharmaceutical Practice [in Russian], Shtiintsa,
Kishinev (1984), p. 45.
20. F. J. Villani, R. F. Tavares, and C. A. Ellis, J. Pharm. Sci., 58, 138 (1961).

851
REACTION OF 2,3,3-TRIMETHYL-3H-INDOLE SALTS WITH ACRYLAMIDE.
SYNTHESIS OF 1,2,3,4,10,10a-HEXAHYDROPYRIMIDO[1,2-a]INDOL-2-
ONE DERIVATIVES

A. A. Shachkus and R. Yu. Degutite UDC 547.752:547.853

Methyl derivatives of pyrimido[l,2-a]indol-2-one were obtained by the reaction of

2,3,3-trimethyl-3H-indole salts with acrylamide in a proton-containing solvent.
The products were condensed with aromatic aldehydes. The interconversion of
pyrimido[l,2-a]indol~2-ones and 1-(2-carbamoylethyl)-3H-indoliumsalts under the
influence of acids end bases was studied.

It is known that 2,3,3-trimeghyl-3H-indole salts canreact with a, ~-unsaturated

carbonyl-containing compounds, particularly with methyl vinyl ketone [1, 2]. In the present
research we investigated the reaction of hydrohalides Ia-d with arylamide. We found that
pyrimido[1,2-a]indol-2-one derivatives (IIIa, b) are formed when mixtures of the reagents
in a proton-containing solvent are heated with subsequent treatment of adducts IIa-d with
a base. The addition of acrylamide to salts Ia-d proceeds most smoothly in acetic acid.
When the reaction is carried out in ethylene glycol or diethylene glycol, ethanol, or water,
the yields of IIIa, b are lower by a factor of 2-2.5 and amount to 25-30Z.

R.,,~c}I 3 R.,...4"-,. ...,:H~ +liX R . ~ cH~\ Cii3

I! X- X- CH.CII.CONH 2
! a-d " " o
lla-@ llI

l - - l l l a R=H, X=CI; b R=CHa, X=CI: c R=H, X=Br; d R=CH3, X-Br; e R=H,

X=CIO~

The structures of IIIa, b were confirmed by means of spectral investigations. An

absorption band at 1655 cm -I, which is due to a carbonyl group, and a band at 3180-3190 cm -I,
which corresponds to stretching vibrations of the N-H bond, are observed in their IR spectra.
Characteristic signals in the I H N H R spectra are three singlets of protons of the 10,10,10a-
methyl groups at 1.10-1.52 ppm. In addition to a molecular~ion peak, peaks of ions 215 and
200, ~ the formation of which is associated with splitting out of methyl groups, and
signals of ions with 187 ([M -NHCO]~) and 173 ([M -NHCOCH2]+), which characterize f~ag-
mentation of the hexahydropyrimidine ring, are present in the mass spectrum of IIIa. The
presence of ions with 144, 142, 131, and 130 is typical for the mass spectra of indole
derivatives [3].
Under the influence of acids, IIIa, b undergo decyclization and are converted to 1-(2-
carbamoylethyl)-3H-indolium salts. Thus perchlorate IIe was obtained by reaction of IIIa
with perchloric acid. Absorption bands that are characteristic for primary amines [4] are
present in its IR spectrum: 1690 (C = 0), 3190 (NH), and 3445cm "I (NH). Starting compound IIIa
is formed when it is treated with bases.
Compounds IIIa, b undergo condensation with aromatic aldehydes in acetic acid in the
presence of acetic anhydride. The resulting salts IVa-g (X = CHsCOO) undergo cyclization to

*The numbers that characterize the ions are the m/z values.
A. Snechkus Kaunas Polytechnical Institute, Kaunas 233006. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 8, pp. 1056-1059, August, 1985. Original article
submitted May 21, 1985.

852 0009-3122/86/2208-0852512-50 @ 1987 Plenum Publishin~ Corporation

 TABLE 1. 10a-Styrylpyrimido[l,2-a]indol-2-ones(Va-g)
i~p ) ~ Found, Calc.,
Com- (t'~om ] Empirical
pound alcohol) N- formula Yield, %
c N
(llal) C [! (Hal)

Va 237--238 76,4 7,7 11,5 C:3H_.:N30 76,4 7,5 11,6 91

Vb 200--201 77,0 8,1 11,1 C~Ha,NsO 77,1 8.0 10,8 93
Vc 238--239 76,7 8,0 t 1,0 C_~4H,_)~N30 76,8 7.8 1t,2 85
Vd 200--201 75,9 7,0 7,9 75,8 7,0 8,0 56
Ve 235--236 71,6 6,1 7,9 C.~,I-I_~iCIN~O 71,5 6.0 7,9 52
(10,0) " (10,0)
Vf 233--234 63,7 5,3 6,9 C2,H~iBrN~O 63,5 5,3 7, I 74
(t9,9) (20,I)
Vg 201--202 79,0 7,2 8,6 C~,H.~.~N~O 7~,2 7,0 8,8 65

TABLE 2 . IH NMR Spectra of 10a-Styrylpyrimido[l,2-a]indol-

2-ones(Va-g)
Com- ZH ~ spectrum, ppm ( i n CDCI3)
pound
I0,10-CH3 CH2CH~(m) CHarom.vinyl, R, R I (except for
(two ~) (m)" aromatic protons}
Va 1,20; 1,33 1,90--3,92 6,10--7,46 2,06 (6H,s, N,N-CH3)
Vb 1,19; 1,33 1,82--4,00 6,10--7,46 1,15 (6H, t, 2XCH2CH~)
3,39 (4H, q, 2XCH.~CH~)
1,19; 1,32 1,85--4,05 6,10--7,45 2.31 (3H, s , 8-CH3)
1,19; 1,34 1,93--4,10 6,18--7,46 3.84 (3H,s~OCH~)
vl. 1,18; 1,34 1,93---4,00 ' 6,30--7,43
1,18; 1,34 1,93-.4,00 6,31 --7,55
V8. 1,20; 1,34 1,80--3,98 6,31 --7,52

10a-styrylpyrimido[l,2-a]indol-2-ones Va-g under the influence of bases.

~ ' ~ c ~ . _ < J - ~ _ R, :' v -~- "Na

x- i

~a-g v a-g
IV, V a R=H, RI=N(CH3)2; b R=H, R'=N(C2H,)2 c R=CHs, Ri=N(CH,)2 d R=H,
Ri'=OCH3; e R=H, RI=CI; f , R = H , Ri=Br; g R = R I = H ; X= anion-

Compounds Va-c were previously obtained by the reaction of 2-(p-dialkylaminostyryl)-3,

3-dimethyl-3H-indoles with acrylamide [5]. However, the yields and constants of these
compounds were not presented. When we attempted to reproduce the indicated method for the
synthesis of Va, we found that the substance obtained does not have a distinct melting point
and contains considerable amounts of impurities. From this mixture, by crystallization from
acetone or ethanol) we were able to isolate Va in no more than 25% yield. However, the
synthesis of 10a-(p-dialkylaminostyryl)pyrimido[l,2-a]indol-2-ones by condensation of
pyrimidoindoles IIIa, b with aromatic aldehydes makes it possible to significantly raise
the yields of the corresponding styryl derivatives (based on 2,3,3-trimethyl-3H-indole)
and to decrease the consumption of acrylamide by a factor of five to six [6]. With the
same success in the synthesis of Va, f we also used perchlorate IIe) which reacts smoothly
with p-dimethylamino- and p-bromobenzaldehyde in acetic acid.
Absorption bands that are characteristic for carbonyl and ethylene groups, respectively,
at 1650-1670 and 1643-1647 cm -l are observed in the IR spectra of Va-g. The absorption hand
at 3210-3250 cm -z is related to stretching vibrations of the ~ bond. Two singlets of
diastereotopicgeminal methyl groups at 1o18-1.34 ppm are isolated in the IH NMR spectra of
Va-g. The vicinal spin-spin coupling constants (SSCC) of the protons of the ethylene group
are 16.0-17.0 Hz and attest to their trans orientation [7].

853
 Protic acids promote conversion of the 10a-styrrylpyrimidoindol-2-ones to the colored
fo.-m of salts IVa- g. In the IH NMR spectrum of Va in CFsCOOH the signals of the protons of
+
the methylene groups appear at 2.80-3.05 (CH2CO) and 4.55-4.88 ppm (NCH 2) and vir{ually
coincide with the positions of the corresponding signals of perchlorate IIe; this Confirms
opening o f t h e hexahydropyrimidine ring.

EXPERIMENTAL

The IR spectra of KBr pellets of the compounds were recorded with a Perkin-Elmer
spectrometer. The I H N M R spectra were obtained with Varian XL-100 and XL-200 spectrometers
with hexamethyldisiloxane (HMDS) as the internal standard. T~e I S C N M R spectrum was re-
corded with a Tesla BS-567 spectrometer (25.14 MHz). The assignment of the signals was made
on the basis of the results of the application of various pulsemethods for recording the
spectra [8] and the data in [9, i0]. The mass spectra were obtained with an LKB-9000
spectrometer (70 V). The course of the reactions and the individuality of the compounds
were monitored by means of thin-layer chromatography (TLC) on Silufol UV-254 plates.
10,10,10a-Trimethylrl,2,3,4,10,10a-hexahydropyrimido[l,2-a]indol-2-one (IIIa). A )
A solution of 19.57 g (0.i mole) of 2,3,3-trimethyl-3H-indole hydrochloride and 7.82 g
(0.ii mole) of acrylamide in 40 ml of acetic acid was heated at 100oC for 1 h, after which
the mi~xture was poured into water. The aqueous mixture was made alkaline with potassium
hydroxide solution and extracted with ether. The solvent was removed by distillation,
and the residue was crystallized from ethanol to give 16.2 g (70Z) of a product with mp
172-173~ I H N M R spectrum (CDCIs): i. Ii (3H, s, 10-OHs), 1.32 (3H, s, 10-CH3) 1.51 (3H,
s~ 10a-CHs), 2.00-2.75 (2H, m, CH2CO), 3.29-3.90 (2H, m, N-CH2)9 and 6.50-7.15 ppm (5H, m, - ~
aromatic, NH). 13C NMR (CDCIa): 19.8 (CH,), 21.1 (CH,), 26.4 (CH,), 27.2 [C(3)], 36.8
[C~)], 47.9 [C 10], 84.2 [C(10a)], i08.7 [C(6)], "120.2 and 122.3 [C(,)] and C(9)]~, 127.4
[C(7)I, 138.3 [C(,a)],147.0 ICe,a)] , and 169.6 ppm [C(2)]. Found: C 73.1; H 7.6; N 12.1Z.
CI~HIgN20. Calculated: C 73.0; H. 7.9; N 12.2%
B) A solution of 12.0 S (0.05 mole) of 2,3,3-trimethyl-3H-indole and 3.91 g (0.055
mole) of acry]mmide in 30 ml of acetic acid was heated at 100~ for 2 h, after Which the
mixture was poured into water. The aqueous mixture was made alkaline with sodium hydroxide
solution and extracted with ether. The solvent was removed by distil~ation, and the res-
idue was crystallized from ethanol to give 7.3 g (63Z) of product.
8,10,10,10a-Tetramethyl-l,2,3~4~10~10a-hexahydrop.yrimido[l~2-aJind01-2-one (IIIb).
A) This compound was obtained'in analogy to IIIa (method A) from 10.49 g (0.05 mole) of
2,3,3,5-tetramethyl-3H-indole and 3.91 g (0.055 mole) of acrylamide. The yield of product
with mp 176-1770C (from ethanol) was 8.05 g (66Z)o PMR spectrum (CDCIs): 1.12 (3H, s,
10-CH3), 1.33 (3H, s, 10-CH3), 1.51 (3H, s, 10a-CH~), 1.98-2.81 (2H, m, CH2CO), 2.28 (3H,
broad s, 8-CHs), 3.28-3.95 (2H, m, NCH2), 6.32 (IH, broad s, NH), 6.56 (IH, d, J = 8.0 Hz,
6-H), 6.86~6.90 (IH, m, 9-H), and 6.91-7.05 ppm (IH, m, 7-H). Found: C 73.6; H 8.2;
N ll.6Z. CI~H20N20. Calculated: C 73~ H 8.2f N II.SZ.
B) This compound was obtained in analogy to IIIa (method B) from 5.08 g (0.02 mole)
of 2,3,3,5-tetramethyl-3H-indole and 1.56 g (0.022 mole) of acrylamide. The yield was 2.9
g (59Z).
l-(2-Carbamoylethyl)-2t3t3-trimethy!-3H-indolium Perchlorate (lie). A solution of
2.3 g (0o01 mole) of pyrimido[l,2-a]indol-2-one in 20 m l o f ethanol was neutralized with
60Z perchloric acid, after which the mixture wascooled, and the precipitated substance
was removed by filtration and racrystallized from ethanol to give 2.0 g (61Z) of a product
with mp 147-148~ PMR spectrum (CF3COOH): 1.25 (6H, s, 3~3-CH3), 2.57 (3H, s, 2~CH3),
2.79 (2H, t, J = 6.5 Hz, CH2CO), 4~ (2H, t, J = 6~ Hz, NCH2), and 7o23-~.45 ppm (4H,
m, aromatic protons). Found: C1 10.5; N 8.2Z. CI~HzgCIN2Os. Calculated: C1 i0.7; N
8.5Z.
8-R-~0~0-Dimeth7~-~a-(4-R1-st7r~)-~2~3~4,~0a-hexah7dr~Pyrimid~[~2-a]ind~-2-~nes
V (Tables 1 and 2). A) A solution of 0.02 mole of IIIa, b and 0.02 mole of the corresponding
aromatic aldehyde in a mixture of 20 ml of acetic acid and 2 ml of acetic anhydride was
heated at 1000C for 1,3 h, after which the mixture was poured into water. The aqueous
mixture was made alkaline with potassium hydroxide solution, and the precipitated substance
was removed by filtration, ~ried, and crystallized from ethanol or acetone.

854
 B) A mixture of 0.01 mole of perchlorate lie and 0.01 mole of the corresponding aro-
matic aldehyde in i0 ml of acetic acid was heated at 100=C for 2 h, after which the reaction
mixture was worked up ae in the example described above. This method was used to obtain
styryl derivatives Va (82% yield) and Vf (72% yield).

LITERATURE CITED

I. T. Kurahashi, Sh. Maeda, and H. Yamaga, Japanese Patent Application No. 79127433; Chem.
Abstr., 92, 112256 (1980).
2. D. D. Chapman, J. K. Elwood, D. W. Heseltine, H. M. Hess, and D. W. Kurtz, J. Org. Chem.,
42, 2474 (1977).
3. R. A. Khmel'nitskii, Khim. Geterotsikl. Soedin., No. 3, 291 (1974).
4. G. Sokrates, Infrared Characteristic Group Frequencies, Wiley, New York (1980), p. I.
5. H. Psaar, West German Patent Application No. 2510238; Ref. Zh. Khim., 17N 268P
(1977).
6. A. A. Shachkus, A. V. Vannikov, A. D. Grishina, A. Yu. Kryukov, R. Yu. Degutite, and Yu.
I. Kozhenyauskaite, USSR Inventor's Certificate No. 1101442; Byull. Izobret., No. 25,
57 (1984).
7. B. I . I o n i n , B. A. Ershov, and A. I . K o l ' t s o v , NMR S p e c t r o s c o p y i n Organic C h e m i s t r y
[ i n R u s s i a n ] , Khimiya, L e n i n g r a d (1983), p. 159.
8. P. T r s k a , V. S k l e n a r , and M. Hajek, Chem. L i s t y , 77, 874 (1983).
9. W. Grahn, L i e b i g s Ann. Chem., No. 1, 107 (1981).
10. H . - I . Teuber, J. Hohn, and A. Gholami, Chem. B e r . , 116, 1309 (1983).

855
FORMATION OF 2-IMIDAZOLINE DERIVATIVES IN THE REACTION OF
1,2-HYDROXYAMINO OXIMES WITH PHENYL- AND METHYLGLYOXAL

N. V. Dulepova, D . G . Mazhukin, UDC 547.288.4'781.3:543.422

A. Ya. Tikhonov, and L. B. Volodarskii

2-Acyl-4-hydroxy-2-imidazoline 3-oxide derivatives were obtained by the reaction

of 1,2-hydroxyamino oximes with a hydroxyamino group attached to a tertiary
carbon atom with phenyl- andmethylglyoxal.

In a previous study of the reaction of 1,2-hydroxyamino oximes with hydroxyamino group

attached to a tertiary carbon atom it was shown that the reaction of acyclic 1,2-hydroxy-
amino oximes Ia, b with diacetyl leads to 2-acetyl-3-imidazoline 3-oxides [I], whereas the
reaction of both alicyclic 1,2-hydroxyamino oxime Id and acyclicl,2-hydroxyamino oxime Ic
with an aldoxime group with 1,2-dicarbonyl compounds leads to 2,3-dihydropyrazine 1,4-
dioxide derivatives [2, 3]. In the present research we studied the reaction of the same
1,2-hydroxyamino oximes la-d with phenyl- and methylglyoxal.
The reaction of Ia-d with phenylglyoxal hydrate in tetrahydrofuran at 20~ for 8-18
days or by refluxing for 2-6 h led to IIa-d (Table I), the compositions of which correspond
to products of condensation with splitting out of a molecule of water. The IR spectra of
KBr pellets of IIa-d (Table 2) contain intense bands at 1610-1620 and 1665-1675 cm -l, whereas
the IR spectra of I% solutions in CHCI s contain bands at -3410 and at 3575-3590 cm -I, which
made it possible to assume the presence of C=N, C=O, NHp and OH bonds. Compounds IIa-d
have similar UV spectra with n m x i m at 256-257 and 320-322 nm (Table 2); th~s constitutes
evidence for the presence of the sam~ chromophore system. These data, as well as data
from the PMR and ISC NMR spectra (Table 2), m d e it possible to assign the 2-benzoyl-4-
hydroxy-5,5-dimethyl-4R~-2-imidazoline 3-oxide structure to IIa-c and the 2-benzoyl-3a-
hydroxy-7a-methyl-3a,4,5,6,7,Ta-hexahydro-iH-benzimidazole 3-oxide structure to IIdo The
most characteristic signals in the PMR spectrum of IIc are doublets of methylidyne and
hydroxy protons at 5.01 and 5.78 ppm, respectively (Table 2); only a singlet of a methylidyne
proton is observed when deuteromethanol is added to the solution. The spectral data
(Table 2) make it possible to assume the absence of tautomeric .equilibria between IIa-d
and their possible N-hydroxy forms (see [4, 5]).
To ascertain the schemes of the formation of IIa-d we conducted a study on the isola-
tion of intermediates. When we decreased the time of the reaction of Ib with phenylglyoxal
hydrate to 18,h at 20~ we obtained a compound, to which we assigned the N~(2-hydroximino-

ctl. CIT,.3 I~' ... ..... N.~,O

, I ~ C,.H~COCH(OH)/ I 1
R --C--C--NHOtl - ' -- R --C--C--N=CItCOC~L'~ .... R2...~~LI[
fl I )j iz ~,
lION R2 HON R 0 C I I -- C O-N-
C6H~/'"/<"
I a-d Ill b, c I
OH
Iv h

OH
RI "~I.... N vO

CH.~ N COCe|[~. CH,3 "N "COC61I~,

H
va~b n a-d
I--V aRt=C~Hs; bR'=CH3; c R'=H: a-c R2=CH3:d R'+R2=(CH~)4

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Acadeany of Sciences of the

USSR, Novosibirsk 630090. Lenin KomsoE~l Novosibirsk State Uni~rsity, Novosibirsk 630090.
Translated from Khimiya C~terotsiklicheskikh Soedinenii, No. 8, pp. 1060-1064, August, 1986.
Original article submittedMay 20, 1985.

856 0009-3122/86/2208-0856512.500 1987 Plenum Publishing Corporation

 TABLE i. Characteristics of the Compounds Obtained

Com- Found, % talc., %

form~lia Yield,
pound
C H c H

II 146--147 69,6 5,8 9,0 C lsI't LsN2Oa 69,7 5,9 9,0 83

II 139--141 63,1 6,3 11,2 C,3t-[,6N2Oa 62,9 6,5 II,3 45
II 161--163 61,5 5,9 I 1,9 Cl~[-l;4N,2Oa 61,5 6,0 12,0 12
II 164--166 66,2 6,2 10,1 C,~H,sN~,Oa 65,7 6,6 10,2 80
Ill 133--134 62,9 6,3 11,3 C,aH,6N~Oa 62,9 6,5 II,3 65
ill 148--150 61,9 6,0 12,0 C,:~H,4N'2Oa 61,5 6,0 12,0 72
IV 140--145 62,9 6,4 11,1 CLaHIGN.~Oa 62,9 6,5 11,3 94
V 138--142 74,5 5,7 9,5 C,sl-l,eN.~02 74,0 5,5 9,6 68
VI 214--215 63,0 6,2 11,0 Ct,',H~6N=Oa 62,9 6,5 11,3 70
VI 96--99 51,9 7,5 15,0 Cs!-I,4N2Oa 51,6 7,6 15,0 42
Vl 142--143 56,6 7,7 12,7 C|oHtsN~.Oa 56,6 7,6 13,2 49

eThe compounds were crystallized: IIa, d, Va, and Via, b,

d from alcohol, IIb from ethyl acetate, IIc from toluene,
and IIIb, c from acetone.

l,l-dimethylpropyl)-a-benzoylnitrone structure (lllb) on the basis of spectral data and the

results of elementary analysis. Under similar conditions we obtained a-benzoylnitrone IIIc
from Ic. Intense bands at 1525-1530 and 1665 cm -I, which correspond to stretching vibrations
of conjugated nitrone and carbonyl groups [6], are observed in the IR spectra of IIIb, c.
Compound IIIb is unstable, and in solution it undergoes quantitative conversion to 2-
benzoyl-4-hydroxy-4,5,5-trimethyl-2-imidazolin-3-oxide (IIb).
The addition of catalytic amounts of p-toluenesulfonic acid to a solution of =-benzoyl-
nitrone IIIb in alcohol led to 2-benzoyl-l-hydroxy-4,5,5-trimethyl-3-imidazoline 3-oxide
(IVb), which is isomeric in composition to IIIb. The UV spectrum of IVb (Table 2) is the
superimposition of the absorptions of two chromophore systems, viz., benzoyl and alkylnitrone
systems. A quartet of a methylidyne proton (2-H) at 6.17 ppm and a doublet of protons of a
methyl group (4-CH 3) ab 2.10 ppm, which is due to long-range spin-spin coupling, is observed
in the PMR spectrum of IVb; this is possible only for a cyclic structure. 3-Imidazoline
3-oxide IVb is a less stable compound than its acyclic isomer =-benzoylnitrone IIIb. 2-
Imidazoline IIb is formed quantitatively when IVb is heated in alcohol or when a solution in
chloroform is maintained in the presence of aluminum oxide at 200C. 4H-Imidazole Vb, the
subsequent covalent addition to which of a molecule of water [7, 8] leads to 2-imidazoline
IIb, is evidently formed in the dehydration of IVb. In fact, maintenance of solutions of :
IIIb and IVb in tetrahydrofuran at 20"C leads to an intermediate [monitoring by thin-layer
chromatography (TLC)], which is converted to 2-imidazoline IIb and is most likely 4H-
imidazole Vb; however, we were unable to isolate the latter. Intermediate 4H-imidazole Va
was isolated in the reaction of Ia with phenylglyoxal hydrate at 20~ for 30 h. The
greater stability of 4H-imidazole Va as compared with 4H-imidazole Vb can be explained by
conjugation of the phenyl group in the 5 position with the imidazole ring, which stabilizes
the diazadiene structure of 4H-imidazole Va. Maintenance of a solution of Va in tetrahydro-
furan in the presence of catalytic amounts of p-toluenesulfonic acid for 24 h at 20~ leads
smoothly to the product of covalent hydration of 4H-imidaz~le Va, viz., 2-benzuyl-4-hydroxy-
5,5-dimethyl-4-phenyl-2-imidazoline 3-oxide (IIa) (see [7, 8]).
The reaction of Ia, b, d:with methylglyoxal gives 2-acetyl-2-'imidazolines Via, b, d,
the spectral characteristics of which are similar to the spectral characteristics of IIa-d
(Tablei2). Bands.at 3410 and 3570-3585 cm -I, which correspond to stretching vibrations of
NH and OH bonds, respectively, are observed in the IR specta (1% solutions in CHCI a) of
Via, c, d.
oH
R~ ~ so
CH~COCHO R;~ ,,N
Ja,b,d - cH~/~NAc~ ~
H
~a~b,d

Thus in the case of the reaction of 1,2-hydroxyamino oximes with a hydroxyamino

group attached to a tertiary carbon atom with phenylglyoxal hydrate it was shown that the

857
O0
Ln
O0

TABLE 2. Spectral Characteristics of II-VI

IR spectrum, cm-1 OV spectrum, ~'max*

Compound (in ~ r ) nm ( l o g r
PHR spectrump~ ppm

lla 1620, 1670, 3376, 3415 267 (4,02), 322 sh (3,32) 1.07 (3H. so 5-CH3); 1.37 (3it.s. 5-CH3); 3.14 OH.s. 4-OH); 5.87 (IH.
bro s~ NH); 7.2--7.8. 8.1--8.4 (10H. m. 2-COC8H5. 4-C8H5)
lib !(i15, 1665, 3365, 3420 256 (4,02), 321 sh (3,31) 1.21 (3H.s. 5-CHa); 1.36 (3H. s. 5-CH~); i.46 (3H. s 4-CHa); 6.13 (IH.
s. 4-OH); 6.17 (IH. b r . s , NH); 7.2--7.7. 8.0--8.2 (5H. m. 2-cOC6H5)
llc 1610, 1665, 3385 256 (4,03), 321 sh (3,34) 1.20 (3H. s. 5-CHa); i.29 (3H. s. 6-CH~); 5.01 (IH. d~/=5.0 Hz. 4-H).
5.78 (IH. d. I=5.0 Hz. 4-OH); 6.27 (IH. b r . s , NH); 7.2--7.7. 8.0--8.2
(5H. m. 2-COC6HD
lid 1620, 1675, 3325. 3390 256 (4,00), 324 (3,30) i.31 (3H.s. 7a-CH3). 1.4--2.2 (SH.m. CH2); 3.14 (IH.s. 3a OH); 5.70
(IH, b r . s . NH); 7.2--7.7. 8.0--8.5 (SH.m. 2-COCsHs)
l|lb 1530. 1665, 3355 259 (3,94), 312 (4,15) i.81 (6H. s. CHa); 1.96 (3H.s. CH3); 7.8--8.1. 8.2--8.4 (SH. m. CoHs);
8.60 (IH, s, CH)
lllc 1525, 1665, 3370 259 (3,90), 308 (4,17) 1.79 (6H. s. CH~); 7.7--8.0. 8.1--8.4 (SH. m. CoH~); 8.00 (IH. s. CH);
8,48 (IH, s~CH)
1Vb 1625, 1695, 3205 245 (4,35) 1,17 (3H, s, 5-CHa); !.38 (3H, s, 5-CH3); 2,10 (3H,d,, I = i , 5 ttZ, 4-CH~);
6,17 (IH, q, 1=1,5 HZp 2-H); 7,4--7,7, 8,0--8,2 (5H, m, 2-COC~H~)
Va 1680 241 sh (4,16), 261 (4,24), 1,80 (6H, s, 4,4-CH~); 7,4--7,7, 7,9--8,1, 8,4--8,7 (10H, m, 2-COC6H~,
313 sh (4,00), 339 (4,06) 6-C6H~)
Via 1630, 1710, 3340 291 (3,62) 0,96 (3H, s , 5-CH:~); 1.27 (3H.s. 5-CH3); 2.40 (3H.s, 2-COCHj); 3.20
OH.s. 4OH); 5.64 (1tt. br. s. NH); 7.2--7.7 (SH. m. 4-C~H~)
Vlb 1630, 1700, 3280, 3390 292 (3,54) 1,10 (3H, s, 5-CH3); 1,26 (3H, s, 5-CH~); 1,50 (3H, s., 4-CH3); 2,36 (3t1,
s, 2-COCH3); 3,36 (IH, s, 4-OH); 5,46 (IH. br.,s. NH)
Vld 1635, 1720, 3375, 3420 294 (3,46) 1,32 (3H, s, ?a-CH3); !,4--2,1 (SH, m, CH=); 2,41 (3H, s, 2-COCH3);
3,19 (IH, s, 3a-OH); 5,44 (IH, br.s, NH)

*The PMR spectra of the compounds were recorded in various solvents: lla, d and Via, b, d in CDCI 3, lllb, c
and IVb in CDsOD, llb,c in (CD~)2CO, and Va in CCI~. IaCNMR spectrum (6, ppm) of lib in DMSO: 21.0,
23.1, 25.7 (4,5,5-CHs); 53.1 [C(s)], 96.5 [C(~)]; 128.0,130.4, 133.1, 135.6 (C~Hs); 148.5.[C(2)]; 187.6
(C=0). lSC NMR s p e c t r u m ( ~ , ppm) o f V i a i n DMSO: 2 3 . 8 , 2 5 ~ 2 6 . 7 (2-COCH3, 5 , 5 - C H a ) ; 5 4 . 3 [ C ( s ) ] ;
98.0 [C(~)]; 128.3, 128.7, 129.0, 140.0 (CsHs); 148.0 [C(2)]; 194.0 (C=0).
formation of 2-acyl-4-hydroxy-2-imidazoline 3-oxides occurs through intermediate l-hydroxy-
3-imidazoline 3-oxides. These hydroxides are readilydehydrated with the formation of 4H-
imidazoles, the covalent addition to which of a molecule of water gives 2-acyl-4-hydroxy-2-
imidazoline 3-oxides.

EXPERIMENTAL

The IR spectra of KBr pellets or solutions of the compounds in chloroform were re-
corded with a UR-20 spectrometer. The [IV spectra of solutions of the compounds in alcohol
were obtained with a Specord UV-vis spectrophotometer. The PMR spectra were recorded
with a Varian A-56/60A spectrometer (60 MHz) with hexamethyldisiloxane (HMDS) as the internal
standard. The I~C NMR spectra were recorded with a Brucker HX-90 spectrometer (22.63 MHz).
The course of the reactions was monitored by TLC (Silufol UV-254) with development with UV
light and iodine vapors. 1,2-Hydroxyamino oximes Ia-d produced by the Novosibirsk Institute
of Organic Chemistry, Siberian Branch of the Academy of Sciences of the USSR, were used.
N-(2-Hydroximino-l,l-dimethylpropyl~-~-benzoylnitrone (IIIb). A 6.6 g (50-r~nole)
sample of Ib was added to a solution of 7.6 g (50 m o l e ) of phenylglyoxal hydrate in 60
ml of tetrahydrofuran, after which the mixture was maintained at 20~ for 18 h. The
yellow crystals were removed by filtration to give 5.35 g of IIIb. An additional 2.64 g
of the substance was obtained from the filtrate by evaporation and treatment with ether.
N-(2-Hydroximino-l,l-dimethylethyl)-=-benzoylnitrone (IIIc). A solution of 3.04 g
(20 mmole) of phenylglyoxal hydrate in 8 ml of alcohol was added with stirring to a solution
of 2.36 g (20 mmole)'of Ic in 25 ml of water, after which the mixture was stirred at 20~ for
17 h. The resulting precipitate was removed by filtration. The yield was 3.50 g.
2"Benzoyl-l-hydroxy-4,5,5-trimethyl-3-imidazoline 3-Oxide (IVb). A) A 0.04 g (0.2
m o l e ) sample of p-toluenesulfonic acid was added to a suspension of 1 . 0 ~ (4 mmole) of IIIb
in 20 ml of alcohol, and the mixture was stirred for 5 min. The unchange~.nitrone IIIb
was removed by filtration, and the filtrate was evaporated. The residue was treated with
5 ml of ethyl acetate, and the precipitate was removed by filtration. The yield was
0.94 g.
B) A solution of 0.i g (0.4 mmole) of nitrone IIIb in 5 ml of tetrahydrofuran was main-
tained at 20~ for 2 days, after which the resulting precipitate was removed by filtration.
The yield was 0.03 g (30Z).
2"Benzoyl'4~4-dimethyl-5-phenyl-4H-imidazole 1-Oxide (Va). A 0.51-g (2.62 mmole) sample
of Ia was added to a solution of 0.39 g (2.62 mmole) of phenylglyoxal hydrate in 5 ml of
tetrahydrofuran. After 24 h, the solution was evaporated, and the residue was treated with
ethyl acetate. The ethyl acetate solution was washed with water, dried with magnesium
sulfate, and evaporated.= The residue was treated with ether, and the precipitate was removed
by filtration. The yield was 0.52 g.
2-Benz~ 3-Oxide (II). A) A 0.51 g
(2.62 mmole) sample of Ia was added to a solution of 0.39 g (2.62 mmole) of phenylglyoxal
hydrate in 3 ml of tetrahydrofuran. After 8 days, the solution was evaporated, and the
residue was treated with ethyl acetate. The ethyl acetate solution was washed with water,
dried with magnesium sulfate, and evaporated. The residue was treated with ether, and the
precipitate was removed by filtration. The yield was 0.68 g.
B) A 0.5 ml sample of water and 0.01 g (0.05 mmole) of p-toluenesulfonic acid were
added to a solution of 0.I g (0.34 mmole) of 4H-imidazole Va in 3 ml of tetrahydrofuran.
After 24 h, the solution was evaporated, the residue was treated with ether, and the
precipitate was removed by filtration. The yield was 0.08 g (75Z)..
2-Benzoyl-4-hydroxy-4,5,5-trimethyl-2-imidazoline 3 Oxide (IIb). A) This compound was
obtained from Ib in 45Z yield in analogy to the preparation of oxide IIa by method A; the
reaction time was ii days.
B) A solution of 1.0 g (4.1 mmole) of IIIb in 5 ml of tetrahydrofuran was maintained
at 20~ for 12 days, after which it was evaporated. The residue, was_treated with ether,
and the precipitate was removed by filtration. The yield was 0.7 g (70Z).
C) A 0.2 g (0~8 mmole) sample of IVb was added with stirring to a suspension of 5 g of
aluminum oxide in 20 ml of chloroform, and the mixture wa~ maintained at 20~ for 2.5 h.

859
The aluminum oxide was removed by filtration and washed with methanol, and the combined
filtrates were evaporated. The residue was treated with petroleum ethez--ether (3:1),
and the precipitate was removed by filtration. The yield was 0.08 g (40Z).
2-Benzoyl-4-hvdroxy-5,5-dimethyl-2-imidazolin-3-Oxide (IIc). This compound was obtained
in 12% yield from Ic in analogy to the method used to prepare oxide IIa by method A; the
reaction time was 18 days. The product was isolated by treatment with ether and subsequent
cooling.
2-Benzoyl-3a-hydroxy-Ta-methyl-3a,4,5,6,7,7a-hexa-hydro-iH-benzimidazole 3-Oxide (IId).
A solution of 1.52 g (I0 mmole) of phenylglyoxal hydrate in 20 ml of tetrahydrofuran was
added to a solution of 2.18 g (10 mmole) of the acetate of Id in 30 ml of tetrahydrofuran,
and the mixture was refluxed for 3 h. The solution was evaporated, the residue was treated
with ethyl acetate, and the precipitate was removed by filtration to give 2.20 g of oxide IId.
Oxides IIa-c were similarly obtained fTom the corresponding oximes Ia, c and the acetate
of oxime Ib by refluxing in tetrahydrofuran for 6h, 2.5 h, and 30 min, respectively.
2-Acetyl-4-hydroxv-5,5-dimethyl-4-phenyl-2-imidazolin-3-Oxide (Via). . A solution of
2.16 g (30 mmole) onmethylglyoxal in 5 ml of tetrahydrofuran was added to a solution of 5.82
g (30 mmole) of oxime Ia in 25 ml of tetrahydrofuran, and the mixture was refluxed for 4 h.
It was then cooled, and the resulting precipitate was removed by filtration. The yield
was 3.1 g. An additional 2.12 g of product was obtained from the filtrate after evaporation
and subsequent chromatography with acolumnpacked with silica gel (elution with chloroforn~).
~-Acetyl-4-hydroxy-4,bFb-trimethyl-2-imidazQline 3-Oxide (VIb). A solution of 2.7 g
(37 mmole) of methylglyoxal in 15 ml of tetrahydrofuran was added to a solution of 3~ g (20
mmole) of the acetate of oxime Ib in 10 ml of tetrahydrofuran, after which the mixture was
refluxed for 6 h. The solution was evaporated, and the residue was chromatographed with a
column packed with silica Eel (elution with chloroform). The y~eld was 1.63 g.
2-Acetyl'3a-hydroxy-Ta-methyl-3a~4,5~6,7,?amhexa-hydro-iH-benzimidazo! e 3 Oxide (Vld)o
A solution of 1.0 g (14 mmole) of methylglyoxal in i0 ml of tetrahydrofuran was added to a
solution of 1.42 g (9 mmole) of oxime Id in 5 ml of tetrahydrofuran, and the mixture was
maintained at 20"C for 24 h. The solution was evaporated, and the residue waschromatographed
with a column packed with silica Eel (elution with chloroform). The yield was 0.88 g.

LITERATURE CITED

i. S. A. Amitina and L. B. Volodarskii, Izv. Akad. Nauk SSSR, Sero Khim., No. 9, 2135 (1976)o
2. L. B. Volodarskiikii, S. A. Amitina, and N. V. Dulepova, Izv. Akad. Nauk SSSR, Set.
Khim., No. 4, 904 (1979).
3. Lo B. Volodarskii, L. N. Grigor'eva, and A. Ya. Tikhonov, Khim. Geterotsikl. Soedin.,
No. i0, 1414 (1983).
4. V. S. Kobrin and L. B. Volodarskii, Khim. Geterotsikl. Soedin. No. ii, 1557 (1976).
5. H. Letau, Chem., 10, 211 (1970).
6. I. A. Grigor'ev, G. I. Shchukin, A. G. Druganov, and L. B. Volodarskii, Izv. Sibirsk.
Otdo Akad. Nauk SSSR, Set. Khim. Nauk, No. 2,80 (1979~.
7. M Casey, C. J. Moody, and C. W. Rees, J, Chem. Soc., Chem. Commun., No. 19, 1082
(1983).
8. L. B. Volodarskii, L. A. Fust, and V. S. Kobrin, Khim. Geterotsikl. Soedin., No. 9,
1246 (1972).

860
THE NMR SPECTRA OF CYCLIC NITRONES.
3:* EFFECT OF PROTONATION AND A HYDROGEN BOND ON THE CHEMICAL
SHIFTS IN THE I~C NMR SPECTRA OF DERIVATIVES OF 3-1MIDAZOLINE
3-OXIDE

I. A. Grigor'ev, V. I. Mamatyuk, UDC 543.422.25+547.781.3

G. I. Shchukin, V. V. Martin and
L. B. Volodarskii

The effect of solvents on the 13C NMR spectra of the cyclic nitrones of 3-
imidazoline 3-oxide derivatives was studied. It was shown that in solvents
capable of forming hydrogen bonds with the N-oxide group the signal for the
nitrone carbon atom is shifted downfield by 1.5-2.5 ppm for solutions in
chloroform and 5-9 ppm for solutions in methanol. The size of the shift depends
on the substituent at position 1 of the imidazoline ring and decreases with in-
crease in its accepting character. Analogous effects are observed during the
formation 4f an intramolecular hydrogen bond with the oxygen atom of the nitrone
group. During protonation of the nitrone group the downfield shift of the signal
for the nitrone carbon atom amounts to 30-39 ppm.

In [I, 2] the characteristic region of the chemical shifts of the nitrone carbon
atoms in the 13C NMR spectra of 3-imidazoline 3-oxide derivatives was established. The
effect of substituents at positions i-5 on the electron density distribution in the ground
state of the molecules was also studied. The high sensitivity of the chemical shifts in the
13C NMR spectra to change in the nature of the solvents is well known for compounds con-
taining groups capable of effective solvation by one or the other solvent [3]. The ability
to form hydrogen bonds not only with protic solvents [4] but also with chloroform was
established for nitrones on the basis of IR spectroscopy, whereas there are hardly any
published data on the effect of solvents and of a hydrogen bond on the 13C NMR spectra of
nitrones, i
In the 1 3 C N M R spectra o{ the majority of compounds containing a C=N group (imines,
oximes etc.) the formation of a hydrogen bond and protonation lead to a downfield shift of
the signal for the carbon atom of the C=N group, but the opposite effect is observed in
certain cases, e.g., for pyridine derivatives [6]. In order to investigate the tendency for
the chemical shift to change during the formation of a hydrogen bond with the oxygen atom
of the nitrone group we undertook a quantum-chemical calculation of the change in the charges
and the associated change in the chemical shifts during the formation of a hydrogen bond
with one (B, C) and two (D) molecules of methanol in the model nitrone A (Table i). In
the scheme we give the calculated values of the change in chemical shift during the forma-
tion of a hydrogen bond according to the formula A6 = f'AQ, where f = 220 (for Qa+~) and 160
(for Q~) ppm/e (of. [i, 2]). According to these data a downfield shift of 3-4.5 ppm for
the nitrone carbon atom can be expected during the formation of a hydrogen bond with one
molecule of methanol and 6-8 ppm with two molecules of methanol.

CH~OH% CH30H"
H ..~0 o. 9HOCH3 H~N/~0 H~. ..e.O-. 9 HOCB.~

A B C D
for Q~+.~ A8=3.4ppm A~=.3?ppm ~=5~8 ppm
~or Q:, -%{}=:t.3ppm A6=45 ppm A6=7.9 ppm
9 For Con~nunication 2, see [i].
m,

Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of the

USSR, Novosibirsk. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp.
1065-1072, August , 1986. Original article submitted March 26, 1985.

0009-3122/86/2208-0861S12.50 ~ lqR7 P1~.,,m P,,hl~h4.o m. . . . . . . ~ Q.~

 TABLE i. Data from Quantum-Chemical Calculation of the
Total (Qo+~.10 a) and ~ Charges (Q~.I0 a) (in parentheses)

pound.
N(3) C(2) C(.5) Ntl)
I
N-CH= 4-CI-I)

A -36(-88)
+258(+893) -4o6(-8o5)
B w -21,(-61)
+ 254 ( + 886) -407(--825)
C -22(-6o) +254(+885) -408(-826)
D w - 10(-38) +250(+878) --407(--840)
Ib CH. +56(-40) +167(+781) --478(--827) + 208 +99 -2O,5 +80 -34
If NO, + h7(--92) +204(+829) --447(--796) +212 + 149 - 188 -30
VIII b CH, +48(+24) + 150(+748) --469(--870) +,21fi + 101 -205 +80
VIIlb c~ + 18(-73) + 190(+814) --460(--81,1) +20fi + 102 -204 +80
IXb C R +239(+280) +39(+500) --163(-972) +23'~ +112 - 196 +78 --75
IXs NCt. +229(+272) +80(+546) --143(--966) +22~ +139 --77
XIb CH~ +73(--38) + 176(+758) --423(--815) +20.= +85 +71 -36
XIIlb c ~ +259(+282) +46(+490) --119(-970) +23~= + 104 Z66 +58 -75

TABLE 2. The laC NMR Spectra of 4-Methyl- and 4-Phenyl-l-

R-2,2,5,5-tetremethyl-3-imidazoline 3-Oxides (I) II) in DMSO
r
C(4) C(2) Ctb) Or p~" 2.5-(CHub CII
pound Ci/,e,,

la H 142,6 87.2 61',0 8,8 2,7,4

[a H I,t2,0" 87.5 61,2 9.0 27,9. 27,7 N
(',x~Cc;14)
Ib CH, 1,42,1 88.3 6~9 8,6 23,6, 23.0 263
Ib CH, 141,4 88J 63.2 9.0 24,9* 233 2LI
( i n CCI4)
lc OH 142,2 90.0 66.4 8,9 23,8. 23.4
ld OCH3 141.4 99,1 67.0 8,7 64.4
le NO 139.6 89,2 67.2 8.5 26.8. 22.0
140.0 88,6 67.8 7,8 21.4
If NO= ! 40.6 89,.6 68.3 8.8 22,8, 21,8 I - -
Ila H 140.4 87.7 6h.8 128.6 1.27.3 128,6 129.0 2~.4. 27.6
lib ~CH3 140.5 89.0 63.6 1.28,1 127.5 128,1 129,2 24,3, 23,9 26,5
Ilc OH. 139.8 89,5 65,9 127,2 126.9 127,6 128,8 24,4, 23,7
lid OCH3 139,8 90.5 67.6 128,2 127.7 128,2 129.5 64.6
Ile NO 137.9 89,7 67.9 126,5 128.1 128,5 130,3 28.7, 22,2
138.8 89,2 68.7 125,8 27,6, 22,6

~They appear in the form of a broad signal [I]).

In the present work we studied the laC NMR spectra of 4-methyl- and 4-phenyl-l-R-2~2,5,5-
tetra-methyl-3-imidazoline 3-oxides (I, II) in a series of solvents (carbon tetrachloride,
DMSO, chloroform, methanol, trifluoroacetic acid, sulfuric acid, chlorosulfonic acid) in
order to establish the scale and the direction of the changes in the chemical shift of the
laC carbon during the formation of the hydrogen bond and also during the protonation of the
nitrone and other groups. In addition, we considered the possibility of using ZaC
spectroscopy of nitrones to establish the presence of an intramolecular hydrogen bond with
the oxygen atom of the nitrone group.
In Table 2 we give data from the lac NMR spectra of 4-methyl- and 4-phenyl-l,R-2,2,5,5-
tetramethyl-3-imidazoline 3-oxides (I, II).in DMSO. In Table 3 we give the changes in
the chemical shifts with replacement of the solvents in relation to the values of the
chemical shifts in DMSO. In order to compare the scale of the relative changes in the
chemical shifts in relation to the nature of the solvent in Table 4 we give the changes in the
chemical shifts for the 3-imidazoline derivatives (III) and (IV) not containing the N-oxide
oxygen. It can be seen that the observed changes for compounds (III) and (IV) during
protonation and the formation of the hydrogen bond agree on the whole with existing data
on other types of imines [6].

c~n. rc~U csss..

~ w"o .cH~ N %H. _ _ N
>C< -.r=. .
) l I l
R R 01I OH

Ia-f IIa-e IIIc IVc

a R - H . b R-CH3. e R - O H . d RfOCH3, e R f N O . s R=NO.,

862
 TABLE 3. The Effectof Hydrogen Bonds and Protonation on the
Chemical Shifts of the Carbon Atoms in l-R-4-Methyl- and I-R-
4-Phenyl-2,2,5,5-tetramethyl'3-imidazoline 3-Oxides (Ia-f~
and (IIa-e)

a6C~-~C (sDlvent) -6c,(~4S0), ppm

Compound Soivent
C~4) C(2) C(51 !Ctpso
]a CHCI.~
CH3OH
CFzCOOH
H:SO,
Ib CHCI3
CH3OH
CF~COOH
(XIIIb) H,SO4
Ic CH3OH
CFzCOOH
(XllIe) H2S04
Id CHCI3
CH~OH
CF3COOH
( x m d) H2SO~
CHCI3
CH3OH
CFaCOOH

CHC[3
CH30H
CF3COOH
(IXf) H2SO4
Ila CHCI3 -0,1
CH3OH ' 1,5
CF~COOH 4,0
(XWa) H2SO4 4,1
llb CHCI3 0,3
CH3OH 1,4
CF3COOH 3,5
(XlVb) H2S04 4,1
II c CF3COOH 4,0
H2SO4 4,3
(XlVc) HSO~C/ 4,4
IId CHCI3 0.2
CH3OH 2,1
(Xd) CF3COOH 3,4
(XIVd) H2SO4 4,1
IIe CHCI,~ 0
CH3OH 1,2
CFaCOOH 2,8

From the data in Table 3 it is seen that replacement of the solvents leads to appreciable
changes in the spectra of compounds (I) and (II), and the signals of all the carbon atoms
undergo changes. The smallest differences are observed between the chemical shifts of com-
pounds (la, b) in carbon tetrachlorideand DMSO solutions, i.e., in solvents which differ radically
in polarity but are not proton donors. In the transition to solvents capable of forming a h y d r o g e n
bond with the nitrone group, however, the changes in the chemical shifts become more significant.
Even in the transition from DMSO to chloroform a downfield shift of 1.5-2.5 ppm is observed for the
C(~) signal for all the investigated nitrones. This is clearly due to the formation of a weak
hydrogen bond between the chloroform and the N-oxide oxygen atom, which was established
earlier by IR spectroscopy [5]. In contrast to this, in the spectra of the corresponding
derivatives (lllc) and (IVc) having an Imine group the position of the C(~) signal remains
practically unchanged in the transition from DMSO to chloroform. In the spectra of methanol
solutions of the nitrones (I) and (II) a downfield shift of the C(~)signal by 8.7-5.6 ppm

863
 TABLE 4. The Effect of Hydrogen Bonds and Protonation on
the Chemical Shifts of the Carbon Atoms in l-hydroxy-4-methyl-
and l-Hydroxy-4--.-:Phenyl-2,2,5)5-tetramethyl-3-imidazolines
(IIIc, IVc)
a6c.~Sc.isolvent) "-6c~(DMSO), p ~
CON-
pound)'~ Solvent
C(4) C(2) C(5) cortho Cmer.a
Illc CHCI3 -0,I 0,4 0,5 --0,7
CH3OH 4,! 0.8 1,5 --0,I
IVc CHCI3 0.2 0,9 1,0 --0,7 -0,8 - - 1,2 -l,l
CH3OH 4,5 I,I 1,8 0,9 0,6 0,4 0,7
HSO~CI 8,2 6,9 14,I - I 1,4 5;,6 5,4 13,I

~Compounds (IIIc) and (IVc) are unstable in trifluoroacetic

acid solutions.
%For compound (IIIc), 4-CH a.

(I) and 7.8-5.0 ppm (II) is observed, whereas the analogous changes for the imines (IIIc)
and (IVc) have half the value (Table 4). According to the data from quantum-chemical
calculation, the major contribution to the change in the chemical shift of C(~) in the
transition from solutions in DMSO to solutions in methanol comes from hydrogen bonds between
the N-oxide group and two molecules of methylene (structure D). The signals of the C(2 )
and C (s) atoms and the signals of the carbon atoms of the phenyl ring in the spectra of com-
pounds [II) also undergo a downfield shift of 1-2 ppmo
Both for 4-methylo and for 4-phenyl-3-imidazoline 3-oxides (I, II) the substituent R
has an appreciable effect on the strength of the hydrogen bond between the nitrone group
and the methanol, as seen in the relative chemical shift A6~o Whereas an approximately
identical effect from the hydrogen bond is observed for. campounds (Ia-d) and (IIa-d) (7.8-
8.7 and 7.1-7.6 ppm respectively), increase in the electron-withdrawing character of
the substituent R in the l-nitroso derivatives (Ie) and (IIe) and the 1-nitro derivative
(If) leads to a decrease of 2-3 ppm in the A6~ value. Increase in the accepting character
of the substituent at position 4, e.go, transition to the 4-methoxycarbonyl derivative
(Vb), also leads to a decrease in'the relative chemical shift due to the hydrogen bond
(Table 5).
The presence of the intramolecular hydrogen bond in the 4-carboxy derivatives (V[b, f)
[7] shows up as a downfield shift of 4.3 and 4.4 ppm in the C(~) signal compared with the
signals of the corresponding esters (Vb, f). In this case the effect of the substituent R
on the A6 C value is not observed by virtue of the fact that this substituent affects both
the basicity of the nitrone group and the acidity of the COOH group. On the other hand,
increase in the accepting effect of the substituent R in the transition from (VIb) to (VIf)
leads to a decrease in the basicity of the nitrone group, while the acidity of the CO0}{ group,
on the other hand, increases [7], and the two effects (which influence the strength of the
hydrogen bond in opposite directions) are mutually compensated~ According to the quantum-
chemical calculation (Table i), the formation of the intramolecular hydrogen bond in com-
pound (VIIIb), i.e., the transition from (VIII'h) to (VIIIb), should lead to a downfield
shift of 6-7 ppm in the C(~)siEnal, which agrees satisfactorily with the experimental
data (Table-5). In the 4-hydroxymethyl derivatives (VIIIb, f) the effect of the substituent
R on theacidity of the hydroxy group is significantly smaller, and the difference in the
strength of the hydrogen bond is consequently determined mainly by the basiclty of the nitrone
group. As a result the value of A6~ = 6~ (VIII)-- 6~VII) for the 1-nitro derivative (VIIIf)
is 1 ppm smaller than for the 1-methyl derivative (VIIIb).
Compounds (VIIIb, f) proved convenient subjects for comparison of the results from
analysis of the iSC NMR spectra with the conclusions obtained on the basis of analysis of
their IR spectra. In the IR spectrum of (VIIIb) in carbon tetrachloride the intramolecular
hydrogen bond between the hydroxy group and the nitrone group appears as a broad band
centered at 3300 cm -I, whereas the analogous band in the IR spectrum of (VIIIf) is observed
at 3375 cm -I . The shift of the band for the intramolecular hydrogen bond between the OH
group and the nitrone group in the IR spectrum of (VIIIb) toward the lonEwave region by 75
cm -I compared with the analogous band in the spectrum of (VIIIf) indicates (with identical

864
 TABLE 5. The Data from the I%C NMR Spectra of Compounds (Vb,
f-VIIIb, f) in chloroform

COm- c t4) * C(5) (21[,: CO

pound Cc2) OCH~ ] 2,5.~L'11.04 C~

vb
Vbt
Vlb
Vf
\:Lf
135,6
137,6
t39.7 (4,I)
L32,5
136.9 (4,4)
93.0
93.8
9,2.3
93.4
93,0
63,4
64,2
63,6
68.0
69,1
159.6
160,0
158.0
158.0
156,3
iiii 23,8
23.9
23.3. 23,8
23,5, 22,9
23,5. 23,0
26,4
26,3
25.8

VII b 143,7 S9.5 63,3 58,7 63,6 23,6. 23.3 26.4

VIII b L47,7 (4,0) 89.8 63,2 55,2 23.7. 23,5 26,8
VII~ / 141,5 90,8 68,7 5~,4 63,8 23.3. 22,6
VIII 144,5 (3,0) 90,8 68,0 54.3 23,2. 22,7
~l"ne difference in the chemical shifts is given in paren-
theses: 8~(VI)-84(V)H 8~(VIII)-8~(VII).
%In CHsOH.
geometry in the chelate ring) a stronger hydrogen bond in (VIIIb), and this agrees with the
NMR data.

OCH~ 0--}r OCh, G --H.. H~

,o o=< d,, - ,o %

I I I 1 I
R R R R R
b,f 'b~f vxzb~f vm b',f vm b , f

In the derivatives of 3-imidazoline 3-oxide there are two groups capable of protonation;
depending on the substituent at N ~) and on the strength of the acid, protonation can
either occur only at the nitrone group or at the N 6) atom with the formation of the cations
(IX, X) and (XI, XII), or exhaustive protonation can occur with the formation of the
dications (XIII) and (XIV).
Table 1 gives calculated data for all three cases of protonation in the 4-methyl
derivatives of (I), i.e., (IX]), f), (XIb), and (XIIIb). According to these data, protonation
of the nitrone group must be accompanied by a considerable downfield shift of the C(,)
signal: A6 4 = 40-46 ppm.

cH~.\ +/oH CH_ o CH +/0H

R
IX ~ Xlll

C6H~ +/OH C6H~ 0 C6H~, +/OH

R
X XII X~

In concentrated sulfuric acid solutions (H 0 = -ii) the 3-imidazoline 3-oxide derivatives

(Ia-d) and (IIa-d) are protonated both at the nitrone and at the amino and hydroxylamino
groups with the formation of the corresponding dications (XIIIa-d) and (XIVa-d). With
increase in the acidity of the medium in the transition to solutions in chlorosulfonic acid
(H 0 = -13) there are hardly any changes in the spectra of compounds (IIc) in comparison with
the spectrum in concentrated sulfuric acid. This confirms the exhaustive protonation of
compounds (I) and (II) in these acids with the formation of the dications (XIII) and (XIV).
If the l-nitroso derivatives (Ie) and (IIe) are dissolved in concentrated sulfuric acid,
the nitroso group is rapidly removed, as shown by the identity of the spectra obtained here
with the spectra of (XIIIa) and (XIVa). The removal of the nitro group when (if) is dis-
solved in sulfuric acid takes place fairly slowly (several hours), and the signals of both
the dication (XIIIa) and the cation (IXf) are observed in the spectrum.

865
 During the protonation of thenitrone group the C( @ signal undergoes a downfield shift of
36-39 and 30-31 ppm both in the spectra of the dications (XIIIa-d) and (XIVa-d) and in the
spectrum of the cation (IXf); this is approximately four times larger than the analogous
effect in the protonation of the imino group (Table 4 and published data [611. During
the protonation of the 3-imidazoline 3-oxide ring only in the nitro group in the l-nitro
derivative (if), i.e., during the formation of the cation (IXf), the C(z ) and C(s ) signals
are shifted downfield by 4.7 and 5.4 ppm respectively, whereas protonation of the amino and
hydroxylamino groups in parallel with the nitrone group with the formation of the dications
(XIIIa-d) and (XIVa-d) leads to an additional downfield shift of these signals to 6-10 and
12-15 ppm.
The protonation of the tertiary amino group and also of the hydroxylamino group leads
to the appearance of magnetic nonequivalence in the gem-CH a groups at positions 2 and 5,
which appear in the form of four different signals in the spectra of (XIVb-d): 24.2, 22.6,
21.6 and 20.2 (XIVc); 23.9, 22~6, 21.6 and 20.~ (XIVc); 25.7, 24.6, 22.5 and 21.0 (XIVd).
The signals of the H-CH s and >NH-OCH s groups undergo a downfield shift of the 6 and 4 ppm.
The signals for the methyl groups at position 4 undergo a shift of the same magnitude and
direction during protonation of the nitrone group. The nature,of the change in the chemical
shifts of the carbon atoms of the aromatic ring during the protonation of the ~-phenylnitrone
group is similar to that in protonated ~-phenylimines (Table 4, cf. [6]); the Cipso signal
is shifted upfield by 7-8 ppm, whereas the signals of the ortho-, meta-, and para-carbon
atoms are shifted downfield, while the largest shift is found in the signals for the
carbon atom at the para position and the smallest is found in the signals of the carbon
atoms at the meta position: A6para > A6ortho > A6meta"
With decrease in the acidity of the medium, i.e., in the transition to solutions in
trifluoroacetic acid (H 0 = -3.3), the effect of the solvent and the chemical shift of the
carbon atoms in (I) and (II) is more complex in nature~ This is due to the fact that in this
case, in contrast to the solutions in concentrated sulfuric acid and chlorosulfonic acid,
exhaustive protonation of the 3-imidazoline 3-oxide ring does not occur, and one of the
functional groups is protonated (fully or partially), depending on the ratio of the basicities
of the two groups (the nitrone or the N(I ) atom). Thus, in the case of the amines (Ia, b)
and (IIa, b) e and the hydroxylemines (Ic) and (IIc) protonation takes place at the amino
and hydroxylamino groups more basic than the nitrone groups. This is favoredlbyhhe high
valuesffor hhe[downfield shifts of the C(2 ) and, particularly, C(s ) signals. The magnitude
of the downfield shift of the C(4) signal in these cases and also in (Ie, f) and (IIe)
indicates partial protonation of the nitrone group.
In compounds (Id) and (IId), in accordance with the known fact the basicity of hydroxyl-
amines decreases during successive substitution with alkyl groups [8], the basicity of
the hydroxylamino group becomes lower than in the hydroxylamines (Ic) and (IIc). As a result
protonation of the nitrone group becomes predominant~ The absence of protonation of the
hydroxylamino group in (Id) and (IId) in trifluoroacetic acid is demonstrated by the type of
signal for the gem-CH s groups, which [as in "inert" solvents (DMSO, chloroform, and
methanol)] also appear in the form of a broad signal [i], and also by the smaller value for
the downfield shift of the C (s) signal compared with the spectra of (Ia-c) and (IIa-c).
The downfield shift of the C(~) signal in the spectra of solutions of (Id) and (IId) in
trifluoroacetic acid becomes close to the g6~ value obtained with full protonation of the
nitrone group in solutions in strong acids. The direction of the changes in the chemical
shifts of the carbon atoms of the phenyl ring in the spectra of the ~-phenyl nitrones in
trifluoroacetic acid remains the same as in the solutions in concentrated sulfuric acid,
whereas the magnitude of the changes in the Cipso and Cpara atoms most sensitive to pro-
tonation is 1.5-2 times smaller.

EXPERIMENTAL

The 13C NMR spectra were recorded on a Bruker Physik AG HX-90spectrometer at 22.63
MHz. For the measurements we used 10-15~ solutions of the compounds in the respective

~The pK a values for the protonation of the amino groups in (lla) and (lib) in water at 25"G
are 2.06 and 2.25 respectively (measured by K. A. Udachin, Institute of Inorganic Chemistry
Suveruab Branch, Academy of Sciences of the USSR).

866
solvents. To stabilize the resonance conditions at the deuterium nuclei for the spectra in
D[4SO, chloroform, and methanol we added 10Z of the respective deute=ated solvent; for the
solutions in trifluoroacetic acid, sulfuric acid, and chlorosulfonic acid we used an external
standard (in a capillary, 3 mm in external diameter, containing a I:i mixture of deutero-
acetone and TMS), The chemical shifts for the solutions in DHSO, chloroform, methanol,
and trifluoroacetic acid were measured with reference to TMS as internal standard; for the
solutions in sulfuric acid and chlorosulfonic acid they were measured with reference to an
external standard with correction for the difference in the volume susceptibilities (A6x~ =
0.7 and 0.3 ppm respectively). The quantum-chemical calculations were performed by the
CNDO/2 method Without optimization of the geometry b~ m e a n s o f the set of VIKING programs
(the ~ Kaboratory, Moscow State University) on a BESM-6 computer. The geometric param-
eters of the nitrone group in the model compounds (A-D) and also the geometry of the imidazo-
lines (I, VIII, IX, XI, XIII) Mere taken from x-ray crystallographic data for 3-imidazoline
3-oxides [9, i0], and the parameters of the substituents were taken from [II]. During the
calculation of the complexes of the model nitrone with methanol (B-D) the~O...HO distance
was taken as 1.7 ~.
Compounds (I-IV) were obtained by the methods in [i]. The l-R-A-hydroxymethyl-2,2,5,5-
tetramethyl-3-imidazoline 3-oxides (VIIIb, f) were synthesized according to the following
scheme:

/O--COCH~ .,.0 --H ..

C"2"r 0 CH2 ~,D CH2 ~'~M~

t CK.,CN I I
}: R E
x~ b , f XVh , f ~s

The'l-R-4-acetoxymethyl-2,2,5,5-tetramethyl-3-imidazoline 3-oxides (XVb, f) were

synthesized from l-R-4-bromomethyl-2,2,5,5-tetramethyl-3-imidazoline 3-oxides(XVIb, f) [i]
by reaction with potassium acetate in acetonitrile in the presence of 18-crown-6-ether by the
method in [12].
~-R-45Hydrox.ymethyl-2,2,5,5-tetramethy173-!midazolin-3-Oxides (VIIIb, f). To a
solution of 4 mmole of the acetoxy derivative (XVb, f) in 20 ml of alcohol we added 0.5 ml
of hydrazine hydrate. The solution was left for 5 h, the solvent was evaporated, 10
ml of water was added to the residue, and the mixture was extracted with chloroform. The
extract was dried with calcium chloride and filtered. The residue was chromatographed on
a column of silica gel with chloroform as eluant. The yield of (VIIIb) was 40% (an oil).
Found ~: N 13.7. CsHIsN20 =. Calculated %: N 14.0. The yield of (VIIIf) was 35%;i mp
135-137~ Foufld %: C 44.1; H 6.9; N 19.1. CsHIsN~O 4. Calculated %: C 44.2; H 6.9; N
19.4.
ITR-47Hethox~methyl-2~2,5~5-tetramethyl-3-imidazoline 3-Oxides (VIIb~ f). To a solution
of sodium methoxide in methanol (from i0 mmole of sodium in 20 ml of methanol) we added
4 mmole of the bromine derivative (XVIb, f). The mixture was left at room temperature until
the initial compound had disappeared (monitored by TLC on Silufol UV-254, Rf of initial
compound 0.4, Rf of product 0.3 in chloroform). The methanol was evaporated, the residue
was dissolved in i0 ml of water, the solution was extracted with chloroform, the extract
was dried with calcium chloride and filtered, and the chloroform was evaporated. The
residue was chromatographed on a column of silica gel with chloroform as eluant. The yield
of (VIIb) was 70% (an oil). Found Z: N 9.6. C~0H20N=O2. Calculated %: N 10.0. The
yield of (VIIf) was 65% (an oil). Found %: N 18.0. CgHITN~O~. Calculated %: N 18.2.

LITERATURE CITED

I. I. A. Grigor'ev, G. I. Shchukin, V. V. Martin, and V. I. Mamatyuk, Khim. Getero~sikl.

Soedin., No. 2, 252 (1985).
2. I. A. Grigor'ev, ~. V. Martin, G. I. Shchukin, V. I. Mamatyuk, andL. B. Volodarskii, Khim.
Geterotsikl. Soedin., No. 2, 247 (1985).
3. G. C. Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemists,
Wiley-Interscience (1972).

867
 4. M. M= Mitasov, A. Grlgor'ev, G. I. Shchukin, I. K. Korobeinicheva, and L~ B.
Volodarskii, Izv. Sib. Otd. Akad. Nauk SSSR, No. 2, 112 (1978).
5. A. R. Forrester and R. H. Tomson, Spectrochim. Acta, 19, 1481 (1963).
6. M. Allen and J. D. Roberts, Can. J. Chem., 59, 451 ( I ~ 1 )
7. G. I. Shchukin, I. A. Grigor'ev, K. A. Udachin, I. K. Korobeinicheva, and L. B.
Volodarskii, Izv. Akad. NaukSSSR, No. 12, 2694 (1984).
8. A. Albert and E. Serjeant, Ionization Constants of Acids and Bases, Wiley (1962).
9. A. A. Shevyrev, G. S. Belikova, L. B. Volodarskii, and V. I. Simonov, Kristallografiya,
24, 787 (1979).
i0. Yu. V. Gatilov, M. M. Mitasov, I. A. Grigor'ev, and L. B. Volodarskii, Zh. Strukt.
Khim., 2_3, 9 1 ( 1 9 8 2 ) .
11. H. M. Niemege, T e t r a h e d r o n , 33, 1364 (1977).
12. I . A. G r i g o r ' e v , V. V. M a r t i n , G. I . Shchu~in, and L. B. V o l o d a r s k i i , I z v . Al~d. Nauk
SSSR. S e t . Khs No. 12, 2711 (1979).

ORGANOLITBIUMAND ORGANOSODIUM COMPOUNDS OF N-SUBSTITUTED

2-ALKYLBENZIMIDAZOLES

B. A. Tertov, Yu. G. Bogachev, UDC 547.785.5'253.1:542.957

Yu. V. Koshchienko, G . M . Suvorova,
E. B~ Tsupak, N. K. Chub,
and S~ F. Breus

Organolithium and organosodlum compounds of 1,2-dimethyl-, 1-methyl-2-ethyl - ,

1-methyl-2-propyl-, and l-phenyl-2-methylbenzimidazole, containing the metal
in the alky group at position C(2), were obtained by metallation. It was
found that metallatlon can be complicated by the addition of the metalling re-
agent at the C=N bond of the heterocycleo It was shown that the obtained or-
ganometallic compounds can be used for the synthesis of various derivatives of
benzimidazole o

It is known that 2-alkylbenzimidazoles are converted into 1-1ithio-2-1ithioalkylbenzi-

midazoles by the action of butyllithium [i]. In the present work we describe the metallation
of N-substituted 2-alkylbenzimidazoles and some transformations of the obtained organo-
metallic compounds.
Using butyl- and phenyllithium as metallating reagents, we established that the organo-
lithium compounds of N-substituted 2-alkylbenzimidazoles are formed with very low yields
at the metallation temperature used for 2-alkylbenzimidazoles (-0QC), except in the case of
2-1ithiomethyl-l-phenylbenzimidazole. Calculation of the energies of deprotonation (AE =
~ etCH2-EHetCHs) of 1,2-dimethyl- and 1-phenyl-2-methylbenzimidazole by the CNDO/2 method
] showed that the latter is a stronger CH acid. The difference in the deprotonation
energies of these compounds is 0.12 eV.* With such a difference, calculated by the CNDO/2
method, the rate constants for deuteroexchange of the methyl derivatives of the azoles,
which characterize the kinetic CH acidity, may differ by more than an order of magnitude
[3].
After hydrolysis of the products from the reaction of phenyllithium with 1,2-dimethyl-
benzimidazole in the hydrolysis product we found acetophenone and N-methyl-o-phenylenedia-
mine, which are clearly formed according to the following scheme:
.U ~,/ Nl|z

CR~ CH 3

~The calculation was performed with the standard bond lengths. A "planar model was used for
the carbanion.
M. A, Susiov Rostov State University. Scientific-Research Institute of Physical a n d
Organic Chemistzy, Rostov-on-Don. Translated from Khimiya Geterotsiklicheskikh Soedinenii~
No. 8, pp. 1073-1077~ August, 1986. Original article submitted May 4D 1985.

868 0009-3122/86/2208-0868812.50 9 1987 Plenum Publlshln= CorDoratlon

 TABLE i. Results from the Synthesis of the Organolithium and
Organosodium Compounds of N-Substituted 2-Alkylbenzimidazoles

o Metalling ?vroc ~ ~ o~YIeld .~ Metaliing ,= ~

%
reagent
fg
la C4HgLi 0 lla 3 Ib C,oHs:.-Na + 0 lid 80
Ia C4HgLi --78 lJa 56 IC C4HgLi 0 lie 2
la C6HsLi 0 lla 2 Ic C4HgLi 78 IIe 8
la C.~HsLi --78 Ira 47 Ic CIoHs; Li+ IIe 91
la CloHs~--Li
+ 0 Iia 96 Ic CloH8~ Na + IIf 82
la CLoHs"Na+ 0 lib 95 Id C4HgLi fig 38
Ib C~H~Li 0 lie 4 Id C4HgLi 78 II g 73
Ib C~H~Li -78 llc 5 I.d C~HsLi 0 II g 79
Ib C~HsLi 0 II.c 3 Id C~HsLi 78 II g 90
Ib C~HsLi --78 II.c 48 Id CloHs- Li+ 0 II g 39
Ib C~oH~--Li+ 0 IIc 94 Id CloHs~"Na + 0 II h 57

~The yields of the carbinols (III) are given.

Thus, during the metallation of the N-substituted 2-alkylbenzimidazole addition of the

metallating reagent to the heterocyclic ring takes place in addition to substitution of the
hydrogen atom in the C(2 )- alkyl group by the metal. The ratio of the rates of metallation
and addition of the metallatin g reagent to the cyclic C=N bond, on which the final result
depends, can be affected not only by the CH acidity but also by other factors. Thus, for
example, decrease in the temperature of the process to -78~ led to a considerable increase
in the yields of some organolithium compounds of N-substituted 2-alkylbenzimidazoles. In
all probability, this results from the fact that in these cases the rates of addition of the
metallating reagents to the C=N bond decrease more quickly with decrease in temperature
than the rate~ of metallation. If butyl- and phenyllithium are replaced by lithionaphthalene,
metallation becomes practically the only process for 1,2-dimethyl-, l-methyl-2-ethyl-, and
l-methyl-2-propylbenzimidazole. Good results were obtained during the metallation of
1,2-dialkylbenzimidazoles with sodionaphthalene. I t is not impossible, however, that the
mechanism of the metallation of N-substituted 2-alkylbenzimidazoles with normal metallating
reagents and with the adducts of naphthalene with alkali metals differs. (In any case the
reaction can take place through the intermediate formation of the radical-anions of the
substrate.) ;
The above-mentioned methods were used to synthesize the following organolithium and
organosodium compounds of N-substituted 2-alkylbenzimidazoles:

R B M

I, a-d n a-h
la-c R=CH3. d R=C4Hs;a, d 9R I =H, b RI=CH3. c RI=C2Hb; Ila-f R=CHs. g h
R=C6Hs;a, b, g, hR'=H,c, d R'=CH3. e, fR'=C~H~;a, c, e, gM=Li:b, d, f, h
M=Na; RaM=C~HgLi. C6HsLi,CIoHg'-Li+, C,0Hg"-Na+, NH2Na

The transformations of compounds (II) given below confirm their structure and also
illustrate the possibilities for the synthesis of benzimidazole derivatives from them.
l-Methyl-2-(2,2-diphenyl-2-hydroxyethyl)benzimidazole (IIIa) was also obtained from
l-methyl-2-chloromethyl-benzimidazole and dilithiobenzophenone. In the PMR spectrum of
l-methyl-2-(l-methyl-2,2-diphenyl-2-hydroxyethyl)benzimidazole (IIIb) in chloroform there
are signals in the regions of 1.15 (d, C-CHs) , 1.95 (s, OH), 3.52 (s, N-CHs) , 4.06 (q, C-H)
6.6-7.6 ppm (m, aromatic protons), which correspond to the assigned structure. The I R
spectra of l-methyl-2-nitromethyl- and l-phenyl-2-nitromethylbenzimidazoles (Via, b),
which contain absorption bands at i010, 1060, 1160 (CffiNO2H), 3225, 3310 cm -l (OH) respective-
ly, indicate that these compounds exist in the aci-nitro forms. The IR spectra of (IVa, Va)
and of authentic samples were identical.

869
 N" "Cll- C-(CsH5) z ~'~-'" "N ~CII-ClI-Ar
RI Oll ArC~:~ R O11

m a-d ~..~o ....... .- ~v a - ~

~ .-._.."uN0
J
~"~, N
', li ii ~, I it ,,~

R R

v a~b vta,b

III a - c R=CH3, d R=CsHs; add RI-H, b RI=CH3, c R'=C2Hs; IV a - e R=CH3,

a , b R ' = H , c , d,RI=CH3, e,R'=C.~Hs;a, C,Ar==CoHs, b, d, eAr=CH3OCeH4; V a, b
R=CH3, R'=H; a R==CH3, b R==C=Hs; VI a R=CH3, b R=CeHs; a, b R'=H

EXPERIMENTAL

The IR spectra were recorded in Vaseline oil on a UR-~0 instrument. The PMR spectrum
was obtained on a Tesla BS-487C spectrometer at 80 MHz with HMDS as internal standard.
The N-substituted 2-alkylbenzimidazoles were obtained by the.methods in [4-7].
Action of Phenyllithium on l~Z-Dimethylbenzimidazole. To phenyllithium, obtained from
0.9 g (130 mmole) of lithium ~nd 10o2 g (65 ,mole) of bromobenzene in 20 ml of ether,
we added a solution of 4 g (27 mmole) of Ij2-dimethylbenzimidazole in 20 ml of absolute
toluene~ The mixture was stirred at 20-25~ for 4 h. We then added 20 ml of water, separated
the organic layer, and distilled the ether and toluene. The remaining oil was boiled
for I h with 30 ml of 5Z hydrochloric acid. The mixture was cooled and treated with 25 ml
of ether. After distillation of the ether from the organic layer the residue was dissolved
in 3 ml of alcohol~ and an alcohol solution of 2,4-dinitrophenylhydrazine was added to the
solution. The melting point of the separated crystals was 238-239~ which corresponds to
acetophenone 2,4-dinitrophenylhydrazone. The obtained substance did not give a melting
point depression with an authentic sample. N-Methyl-o-phenylenediamine~ present in the
hydrochloric acid solution, was converted by the action of formic acid into l-methylbenzimid-
azole, which was identified as the picrate; mp 246-247~ (from water) [8].
Meta!lation O f N-Substituted 2-A1kylbenzimidazoles with Butyl- and Phenyllithium. To
butyl- or phenyllithium, obtained from 0.3 g (43.4 mmole) of lithium and 21.7 mmole of butyl
bromide or bromobenzene in 15 ml of ether~ at 0~ or -78~ we added over 20 min a solution
of i0 n~ole of the N-substituted 2-alkylbenzimidazole in i0 ml of THF. The reaction was
continued for i h~ To determine the yields of the organollthium compounds we treated them
with a solution of 4.19 g (23 mmole) of benzophenone in i0 ml of THF. The temperature was
brought to 25~ and the mixture was kept for 2 h. At the end of the reaction we added 15
ml of water. The organic layer was separated and shaken with 20 ml of 15Z hydrochloric acid~
Compounds (III) were precipitated from the hydrochloric acid extract with a 10Z solution of
ammonia, filtered, washed with i0 ml of water, and dried -. The results are given in Table i.
Metallation of N-Substituted 2-A!kylbenzimidazoles with Lithi 0- and Sodionaphthalene.
To lithio- or sodionaphthalene, obtained from 28 mmole of lithium or sodium and 3.5 g (28
mmole) of naphthalene in 20 ml of THe, over 20 min at 0"C we added 14 mmole of the N-sub-
stituted 2-alkylbenzimidazole in 10 ml of THFo The reaction was continued for a further 15
min. We then added 5.47 g (30 mmole) of benzophenone in I0 ml of THF. The temperature was
brought to 25~ and after 2 hthe mixture was treated with 10 ml of water. The THF was dis-
tilled, and the residue was shaken with 20 ml of ether and 20 ml of 15Z hydrochloric acid. Compounds
(III) were isolated from the hydrochloric acid extract by the method described above (Table i).
l-Hethyl-2-(2,2-diphenyl-2-hydroxyethyl)benzimidazole (Ilia). A solution of 2.5 g
(13.8 mmole) of benzophenone in 10 ml of THF Was added a t 0 ~ to lithionapthalene [from 0.2
g (28.8 mmole) of lithium and 5.7 g (28.8 mmole) of naphthalene] in 25 ml of THF. To the
obtained dilithiobenzophenone we then added over 15 min 2.5 g (13.8 mmole).of l-methyl-2-

870
 TABLE 2. Characteristics of Compounds (III, IV)
, i

Found, Calc., %
Com- Molecular Yield,%%
pound rap, ~
formula
c H N c H

Iila 194--195 80,4 6,4 8,8 C2=H20N~O 80,5 6,1 8,5

IIlb 168--169 80,7 6,4 8,1 C23H.~N20 80,7 6,5 8,2
IIIc 162--163 80,8 6,~ 8,0 C.~4H_~4N.~O 80,9 6,8 7,9
IIId 193--194 83,4 5,7 7,4 C~rH~..,N~.O 83,0 5,7 7,2
IVa 181--182 76,2 6,6 11,3 CI~HmN=O 76.2 6,4 11,1 64
IVb 182--183 72,0 6,6 9,6 C,THlaN~O~ 72,3 6,4 9,9 52
IVC 176--177 76,8 7,1 10.6 CI~'H,sN20 76,6 6,8 10,5 66
IVd 149--150 73,2 7,0 9,5 CIsH2oN20~ 73,0 6,8 9,5 89
IVe 174--175 73,8 7.2 9,2 C~gH~2N~O2 73,5 7,1 9,0 93

*Compounds (Ilia, c, IVa-c) were recrystallized from alcohol,

(IIlb,d) from benzene, and (IVd, e) from ethyl acetate.
%The yields of compounds (Ilia-d) are given in Table I.

chloromethylbenzimidazole in 15 ml of THF. After the treatment of the reaction mixture

described above we obtained 2.2 g (49%) of (Ilia); mp192-193~ (from benzene). A mixed
melting test with compound (IIIa) obtained by the previous method did not give a melting
point depression. The IR spectra of the two samples were identical.
l-Methyl-2-(2-aryl-2-hydnoxyalkyl)henzimidazoles (IV). To a solution of the organo-
lithium or organosodium compound (II) (from i0 nlmole of the N-substituted 2-alkylbenzimida-
zole, 20 mmole of the alkali metal, and 20 mmole of napthalene) in 23 ml of THF at 0~ we
~dded 25 mmole of the aromatic aldehyde in 10 ml of THF= Th~ m~iture was stirred for i h
30 min, and compounds (IV) were isolated by the method described for the carbinols (III).
The benzimidazoles(IVa,c) were" obtained from the organolithium compounds (IIa,c). The
benzimidazoles (IVb,d,e) were obtained from the organosodium compounds (IIb,d,f) (Table
2).
l-Methyl-2-ethylbenzimidazole (Va). To l-methyl-2-sodiomethylbenzimidazole [from
1.46 g (i0 mmole) of 1,2-dimethylbenzimidazole] in 23 ml of THF we added 3.14 g (22 mmole)
of methyl iodide. The mixture was stirred at -15~ for i h 30 min and at 50"C for 30 min.
We than added 10 ml of water, separated the organic layer, and treated it with 20 ml of
15% hydrochloric acid. The hydrochloric acid extract was washed with ether and neutralized
to pH 7-8 with 25% ammonia. The crystals were filtered off, and dried. The yield was I.i g
(69%); mp 55"C (from aqueous alcohol). Published data [5]: rap 55~
l-Methyl-2-propylbenzimidazole (Vb). The compound was synthesized similarly. From
1.46 g (i0 mmole) of 1,2-dimethylbenzimidazole and 3.43 g (22 mmole) of ethyl iodide we
obtained 1.0 g (58%) of (Vb); mp 58-59~ (from petroleum ether). Published data [6]: mp
59~
l-Methyl-2-nitromethylbenzimidazole (Via). To a suspension of sodium amide [obtained
from 1.57 g (65 mmole) of sodium in i00 ml of liquid ~..,onia] we added 3.65 g (25 mmole)
of 1,2-~imethylbenzimidazole. The mixture was stirred for 30 min, 8.4 g (80 mmole) of
propyl nitrate was added drop by drop, the mixture was stirred for a further 30 min, and
i00 ml of absolute ether was added in one portion. After evaporation of the ~,..onia the
sodium salt of (Via) was filtered off and washed with cold absolute alcohol (4 x I0 ml).
The l-methyl-2-nitr0methylbenzimidazole was isolated by acidification of the aqueous solu-
tion of the salt (Via) to pH 6-7 with acetic acid. The yield was 1.6 g (33%); mp 147~
(yellowish prisms from alcohol). Found %: C 56.1; H 4.8; N 22.1. CgHgN~O 2. Calculated
%: C 56.5; H 4.7; N 22.0.
l-Phenyl-2-nitromethylbenzimidazole (Vlb). The compound was obtained similarly to
(Via) with a 34% yield; mp 126-127~ (from alcohol). Found %: C 66.1; H.4.4; N 16.7.
C14HIIN302. Calculated %: C 66.4; H 4.3; N 16.6.

LITERATURE CITED

i. J. V. Hay, D. E. Portlock, and J. F. Wolfe, J. Org. Chem., 38, 4379 (1973).

2. J. A. Pople and D. L. Beveridge, Approximate Molecular Orbital Theory, McGraw-Hill,
New York (1970).

871
 3. N. N. Zatsepina, I. F. Tupitsyn, A. A. Kane, and G. N. Sudakova, Khim. Geterotsikl.
Soedin., No. 9, 1192 (1977).
4. M. T. Le Bris, H. Wahl, and T. Jambu, Bull. Soc. Chim. Ft., No. 2, 343 (1959).
5. R. M. Acheson, M. W. Foxton, P. J. Abbot, and K. R. Mills, J. Chem. Soc., C, No. 9, 882
(1967).
6. M. Le Guyader and D. Peltier, Bull. Soc. Chim. Fr., No. 8, 2695 (1966).
7. M. A. Phillips, J. Chem. Soc., 2820 (1925).
8. Dictionary of Organic Compounds [Russian translation] Vol. 2, IL, Moscow (1949), p. 630.

CHEMISTRY OF 2-HETARYLBENIMIDAZOLES.
7. ~ TRANSFORMATIONS OF TRANS-I-METHYL-2-[8-(2'-FURYL)VINYL]
BENZIMIDAZOLE

M. M. El'chaninov, V. M. Stoyanov, UDC 547.785.5'727:542.944'958.1:543.422.25

A. M. Simonov, and B. Ya. Simkin

Electrophilic substitution reactions in the furylvinylbenzimidazole series were

studied. In nitration, sulfonation, bromination, acylation, formylation, and
hydroxymethylation reactions, the substituent enters at the ~-position of the
furan ring. The presence of a vinylene group reduces the influence of the benzi-
midazole fragment on the furan ring, and therefore the reactions in the latter
proceed considerably more rapidly and under milder conditions than in the case
of furylbenzimidazole. Calculated data are given for the w-electronic density
on the carbon atoms of furyl-vinylbenzimidazole, obtained by the CNDOmethod.

The nitration and acetylation of the furan ring in l-alkyl-2-[8-(2'-furyl)-vinyl]

benzimidazole have already been studied in [2].
It was of interest to examine the behavior of l-methyl-2~'[8-(2'-furyl)-vinyl] benzimida-
zole (II) in other electrophilic substitution reactions, and to compare the reactivity of
the furan ring linked directly or through a vinylenegroup to the benzimidazole radical.
For this purpose, we carried out several reactions, as shown in the following scheme:

9 I "</ "N" "CH----CHI'0"

I
COB
CR 3
va-c ~ u vla-d

~-OJ" S%lt+ ~'~COCH~,

9 III sv

V a X=Br. b X=CH2OH, c X=NO~; VI aR=H, b R=C~Hs, c R=CH2CeHs. flR=C~H~

The sulfonation of l-methyl-2-(2'efuryl)benzimidazole (I) was previously carried out by

the action of concentrated sulfuric and polyphosphoric acids at 120"C [3]. Under these conditions,
compound II undergoes a complete resinification. We therefore carried out its sulfonation

*For Communication 6, see [i].

M. A. Suslov Rostov State University, Rostov-on-Don 344006. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 8, pp. 1078-1081, August, 1986. Original article
submitted April 25, 1985.

872 0009-3122/86/2208-0872512.50 O 1987 Plenum Publishing Corporation

 TABLE I. Characteristics o f Synthesized Compounds

rap, *C' [IRspec- Found, Calc., IYield,

, Corn- i truth ' Empirical
pound I(methan~ era"J- fcr~ula
C H H N
......

Ill 292--293 55.7 4.1 8.9 C,4HI2N204S !55.3 4.0 9.2 51

(from H20)
Va 128--129 55.4 4.1 9.5 Ct4Ht~BrN20 55.5 3.7 9.2 58
(~25 [6])
Vb 192--193 3240 71,2 5,1 II.3 CIsHI~N202 70.9 5.5 l 1.0 83
Vc 211--212 1350 62.9 3.8 15.7 C14H,N303 62.5 4.1 15.6 77
Via 177--178 ,1680 71.3 5.2 I0.9 CmHt~N202 71.4 4.8 ll.l 64
Vlb 190--191 1670 73.1 5.5 9.8 CtrH.6N20~ 72,8 5.6 10.0 33
VIr 154--155 1680 76.9 5.0 8.5 C~HmN~O2 77.2 5.3 8.2 54
Vld 163--164 1660 77.1 4.7 8.3 C21HI~N~O~ 76.8 4,9 8.5 47

under milder conditions: by the action of sulfuric acid in acetic anhydride at 0~ Thus,
the 5'-sulfo-derivative III was obtained in a yield of 51% with an admixture of an acetyl-
ation product IV.
The bromination of benzimidazole II proceeds in acetic acid at room temperature,
while compound I is brominated only at 80~ In both cases, bromine enters at the 5'-
position of the furan ring. In the PMR spectrum of the bromine derivative Va, as well
as the methyl group signals and the aromatic protons multiplet, there are doublets at
6.1 and 6.4 ppm, belonging to the 4-H' and 3-H' protons of the furan ring, and also doublet
signals at 6.6 and 7.15 ppm with J = 16 Hz of the vinylene group protons. The entry of
bromine only into the 5'-position of the furan ring has been proved by an alternate synthe-
sis - - condensation of 1,2-dimethylbenzimidazole with 5-bromofurfural in acetic anhydride.
The synthesis of 5'-hydroxymethyl- and 5'-nitro-derivatives (Vb,c) proceeds much more
rapidly (30 min) than the formation of analogous derivatives of I (6 and 2 h, respectively).
Compound Vc was obtained by an alternate synthesis by substituting a nitro group for
bromine under the Zincke' conditions.
In contrast with t h e c a s e of furylbenzimidazole I, the formylation of compound II pro-
ceeds smoothly, and high yields can be obtained according to Vilsmeier, while the action
of urotropin in polyphosphoric acid at 70~ (2 h) leads to the formation of a sparingly"
soluble polymer, mp > 300=C. Acylation of compound II by the action of carboxylic acids in
the presence of polyphosphoric acid also proceeds under mild conditions (50-60"C, 1 h)
with the formation of 5'-acyl derivatives Vlc-d, while with compound I they were obtained
after 6-I0 h at 110-1500C.
The steric structure of l-methyl-2-[~-(2'furyl)vinyl]benzimidazole (II) and its sub--
stitution products was established by the PMR spectroscopy method. Thus, in the spectrum of
compound II, the signals of the vinyl protons are represented by two doublets with centers
at 6.52-6.65 and 7.20 ppm; in the last doublet, one of the components overlaps with aromatic
proton signals. The spin-spin coupling constaflt is J = 16 Hz, which corresponds to the trans-
orientation of the substituents at the double bond. The PMR spectra of 5'-bromo-, 5t-nitro -,
5'-hydroxymethyl- and 5'-sulfo-substituted derivatives (Va-c, IIl) follow a similar pattern.
For the 5t-benzoyl derivative VId, the vinyl proton signals overlap to a large extent
with the aromatic proton signals; but~ be assumed that doublets with centers at 7;10
and 7.40 ppm with constant J = 8-10 Hz correspond to the vinyl protons. This indicates a
cis-configuration of this compound. At the same time, the presence in the spectrum of this
derivative of certain additional signals (for example at 7.50 and 7.15 ppm), appearing in
the form of a certain distortion of the form of the lines (a "shoulder" on the signal) leads
us to assume the presence of an admixture of a trans isomer. The spectra of other 5'-acyl
derivatives (Via-c) follow.a similar pattern.
In the spectra of all the compounds studied there are signals of the N-CH a group at
3.6-3.8 ppm, the furan ring protons at 6.15 and 6.5 ppm, and the aromatic protons at 7.2-7.3
ppm.

873
 Comparison of the behavior of furylbenzimidazole I and furylvinylbenzimidazole II in
the electrophilic substitution reactions shows that they form derivatives 5'-substituted
in the furan ring, but the transformations of compound II proceed more rapidly and under
milder conditions than those of compound I. The inclusion of the vinylene group between
the rings possibly ~eads to lessening of the influence of the benzimidazole radical on the
furan ring. Calculated data on the electron density on the carbon atoms of compound I [4]
and II by the CNDO method confirm this supposition.

o02
00301L-. 9II
- ' q
II-%o,'~-,.o,o~7 II
2---CH~CH----~
II
~ +o,oo~
~ ' ~ N ~ +0,2s'~ o ~' " O ~
o. H .O~ +O~O53
+0,08~

Thus, the overall ~-charge on the furan ring of furylbenzimidazole is equal to +0.043,
while on the furan ring in compound II, it is almost half that value (+0.025).

EXPERIMENTAL

The IR spectra were gun on a UR-20 spectrophotometer in chloroform, and the PMR
spectra - on a Tesla BS-487 spectrometer, using HMDS as internal standard. The MO were
calculated by the CNDO method, whose details and parameters are described in [5].
The characteristics of the synthesized compounds are given in Table I,
l-Methyl-2-[~ T(5'-sulfo-2'-furyl)vlnyl]benzimidazole (III). A solution of 2.94 g (30
mmoles) of sulfuric acid (d 1.84) in i0 ml of acetic anhydrideis added with vigorous
stirring at 0~ and in the course of 1 h to a solution of 2.24 g (10 mmoles) of compound II
in i0 ml of acetic anhydride. The sulfonic acid precipitate that separates is filtered and
washed with a small amount of water.
l-Methyl-2-[~-(5'-acetyl-2',furyl)vinyllbenzimidazole (IV) is formed as a byproduct
in the synthesis of compound III. The mother liquor obtained from the filtration of sul-
fonic acid III, is cautiously neutralized by a concentrated solution of ammonia to pH 7o
The acetylation product is extracted by 50 ml of benzene, chromatographed on a column (h
20 cm, d 3 cm) with 80 g of aluminum oxide, and eluted with benzene. Yield, 0.56 g (21%),
mp 167-168~ (from methanol). According to the data in [2], mp 164-165~ IR spectrum:
1680 cm -l (CO). Found: N 10.7%. CIeHI,N=O z. -.
Calculated:
t
N 10.5%.
l-~ethyl-2-1~-(5'bromo-2'-bromo-2'-furyl)vinyllbenzimidazole (Va). A, A solution
of 3.2 g (20 mmoles) of bromine in i 0 ml of acetic acid is gradually added at 20=C, with
vigorous stirring, to a solution of 2.24 g (I0 mmoles) of compound II in 20 ml of glacial
acetic acid. The reaction mixture is left to stand for i h, and the precipitate of the
hydrobromide of compound Va is filtered. The base is obtained by the action 6f i00 ml
of 10% ammonia solution on the hydrobromide.
B. A mixture of 1.46 g (10 mmoles) of 1,2-dimethylbenzimidazole and 1.75 g (10 mmoles)
of 5-bromofurfural in 10 ml of a freshly distilled acetic anhydride is; heated for 20 h at
140~ The reaction mixture is then diluted with 100 ml of water, and the solution is
neutralized by concentrated ammonia to pH 7-8. The reaction product that separates is ex-
tracted by benzene (2 x 50 ml) and chromatographed on a column (h 20 cm, d 3 cm) with i00 g
of aluminum oxide, and eluted with benzene. Yield, 1o7 g (55%). The compounds obtained
by methods A and B are identical, as confirmed by a mixed melting point test.
l-MethylT2-~-(5'-hydroxymethyl-2'-furyl)vinyl]benzimidazole (Vb). A mixture of 2.24 g
(I0 mmoles) of compound II, 1.15 g (13 mmoles) of paraform, and I0 ml or hydrochloric acid
(d 1.19) is heated for 30 min at 50-60=C, then cooled to 20~ and cautiously neutralized by
a 10% sodium hydroxide solution to pH 7-8. The reaction product is extracted by 50 ml of
chloroform, chromatographed on a column (h 20 cm, d 2.5 cm) with 70 g of aluminum oxide,
and eluted with chlorform.
1-Methyl-2-1~-(5'-nitro-2'-furyl)vinyl]benzimidazole <Vc). A. A solution of 1.89 g
(30 mmoles) of nitric acid (d 1.5) in 10 ml of acetic acid is added dropwise, with vigorous
stirring, at 0~ and in the course of 1 h, to a solution of 2.24 g (10 mmoles) of zompound

874
II in 10 ml of a freshly distilled acetic anhydride. The reaction mixture is then poured into
100 ml of ice water, neutralized with a I0% solution of ammonia to pH 7-8, and the product is
isolated in a similar way as in the case of compound Va. Yield, 1.3 g (88%), mp 211-212QC.
B. A 1.5 g portion (5 mmoles) of compound Va is dissolved in 15 ml of acetic acid and
1.04 g (15 n,noles) of sodium nitrate are added to this solution. The mixture is boiled for
1 h, then cooled, poured into 50 ml of water, and the product is isolated as described in
experiment A. The compounds obtained by methods A and B are identical, as confirmed by a
mixed melting point test. Compound Vc has been previously obtained by condensation of 1,2-
dimethylbenzimidazole with 5-nitrofurfural [7], mp 210-211~
l-Methyl-2-[~-(5'-formyl-2'-furyl)vinyl~benzimidazole (Via). A 2.24 g portion (i0 mmoles)
of compound II is dissolved in 4.38 g (60 mmoles) of dimethylformamide. The mixture is
cooled to @~ and 9.21 g (60 rmmoles) of phosphorus oxychloride are added dropwise at a
temperature not higher than 10"C. The mixture is then stirred for 10 min at 0"C and then for
2 h at 80"C. The reaction mixture is then poured into 100 ml of water. The mixture is
cautiously neutralized by a concentrated solution of ammonia to pH 7-8, and aldehyde Via is
isolated in a similar way as in the case of compound Va.
l-Methyl-2-[B-(5'-acyl-2'-furyl)vinyllbenzimidaz01es (Vie, d). A mixture of 2.24 g (i0
mmoles) of compound II and 30 mmoles of the corresponding carboxylic acid in 40 g of poly-
phosphoric acid is stirred for 1 h at 50-60~ The reaction product is isolated in the same
way as in the case of compound Va.
The authors wish to express their gratitude to Yu. N. Sheinker for help in the inter-
pretation of the PMR spectra.

LITERATURE CITED

i. M. M. El'chaninov, N. N. Magdesieva, A. M. Simonov, and N. G. Chovnikova, Khim. Geterotsiklo

Soedin., No. 11, 1531 (1983).
2. L. Ya. Bakhmet and F. T. Pozharskii, No. 6, 832 (1970).
3. M. M. El'chaninov, L. Ya. Oleinikova, and A. M. Simonov, Khim. Geterotsikl Soedin., No. 8,
1047 (1979).
4. M. M. El'chaninov, A. M. Simonov, .and B. Ya. Simkin, Khim. Geterotsikl. Soedin., No. 8,
1089 (198Z).
5. V. I. Minkin, B. Ya. Simkin, L. P. Olekhnovich, and M. I. Knyazhanskii, Teort. Eksp. Khim.,
10, 668 (1974).
6. F. T. Pozharskii, V. Ts. Bukhaeva, k. M. Simonov, L. Ym. Bakhmet, and O. M. kleksan'yan,
Khim. Geterotsikl. Soedin., No. 2, 325 (1969).
7. Dainippon Pharmaceutical Co., Ltd., French Patent No. 2583; Chem., Abstr., 61, 13319
(1964).

875
DERIVATIVES OF IMIDAZO[4,5-e]-2,I-BENZISOXAZOLE AND SYNTHESIS
OF SUBSTITUTED BENZIMIDAZOLES FROM THEM

V. M. Pechenina, N. A. Mukhina, UDC 547.785.5'786.3.07:543.422

V. G. Klimenko, and V. G. Granik

A series of imidazo[4,5-e]-2,l-benzisoxazole derivatives was synthesized by re-

acting benzyl cyanide with 1,2-disubstituted 5-nitrobenzimidazoles; their re-
duction gave 1,2-disubstituted 4-benzoyl-5-aminobenzimidazoles. Acylation,
oximation, and diazotization reactions with subsequent replacement of the diazo
group by iodine were investigated. In the reaction with DMFA diethyl acetal,
amidines were obtained, whose cyclization by the action of a,~onla~leads to
imidazo[4,5-f]quinazoline derivatives.

The reaction of nitrobenzene with benzyl cyanide (I) leads to a compound with a quinoid
structure II [i], at the same time, in the reaction of p-halonitrobenzenes with compound I,
substituted anthranils III are obtained [2, 3].

X
. Fh
0
I
~XffiCl,Br -

X
. Ph~2~
Xffi;/
C~

m N
1[

A similar reaction w i t h t h e participation of nitro derivatives of heteroaromatic com-

pounds has not yet been described in the literature, and the aim of the present work was
to study this reaction on the example of'l,2-disubstituted 5-nitrobenzimidazoles IVa-d~
In,analogy with the nitrobenzene derivatives, the reaction of compounds IVa-d could lead
to o-cyanomethylenequinone oximes of types V, VI or anthranils of types VII, VIII.

Pb.

.o-N ?-l"

~I Ph R~
v %q VH %'I|[

In the reaction of nitrobenzimidazoles IV with compound I in methanol in the presence

of an excess of sodium hydroxide, compounds were obtained in good yields, which" according
to the elemental analysis data correspond to structures VII and VIII. In their IR spectra,
absorption bands of the cyano and hydroxy groups were absent, which also excluded the
structures of oximes V, VI. The choice between structures VII and VIII could easily be
made from the PMR spectra: The doublet signals in the 7-8 ppm region with SSCC 9-10 Hz,
corresponding to the aromatic protons in the 7- and 8-positions, unequivocally indicated
structure VIII.
Thus, as the result of reaction of substitutednitrobenzimidazoles IVa-d with nitrile I,
derivatives of a new heterocyclic s y s t e m - imidazo[4,5-e]-2,l-benzisoxazoles (VIIIa-d) -
are formed. They may serve as suitable starting compounds for the synthesis of new benzi-
midazole derivatives, and also of condensed systems, containing a benzimidazole fragment.

Novokuznetsk Scientific-Research Institute of Pharmaceutical Chemistry, Novokuznetsk,

Kemerov district 654034. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8 ,
pp. 1082-1085, August, 1986. Original article submitted~

876 0009-3122/g6/2208-0876512.50 O 1987 Plenum Publishing Corporation

 TABLE 1. Characteristics of Synthesized Compounds

Col~- Trap,oC~ Found, Calc.. % Yiel,

pound Empirical %
formula C H N
C [t (H~al) (Hal)

Vill a 182--18,t C:,.tH~.~NaO ' 78

V l l l b 186,5--187 C=oHtaNaO 70
VIIIc 168--169 C,~H,aNaO= 84
Vllld 189--190 CIrri tsNaO-2 80
IXa 175--177 CmH,rNaO 89
IXb 161--162 C=oH~NsO 89
IXc 166--168 C~H~N~O 78
IXd 212--213 CtrHt~NaO~ 70
Xa 210---212 CmHsrNaOs 83
Xb 201--203 C=aH~NsO~ 75
Xc 146--148 C~,H~sNaOa 58
196--198 C=aH~aC1NaO2 62

Xe, 220--222 C~Ht~NsO~ 78

XIa 270--271,5 88
XIb 255--256 85
Xlla 232,5--234 C=IHt~IN=O 50
XIV~ 238--240 C24H~.N~O 74
xIvb 158--160 C~3H=oN40 " 62
XIVc 197--199 Ct.~H2oN40_~ 83
XIVd 202--203 C.~oH.~2N~O~ 85
XVa 193--195 C~H~sN4 "1" 50
XVb 228--230 C21H,~N~ 43
xvc 178--t79 C~rHt~N~O 45

*Compound VIIla was crystallized from a mixture of benzene

and ethanol; Vlllb-d, IXa-d, Xa-e - from ethanol, Xla, Xlla
from DMFA; Xib - from a mixture of DMFA and water; XIVa, b
XVa-c - from absolute ethanol, XIVc, d - from a mixture of
absolute alcohol and toluene.
tFound: M + 336. Calculated: M 336.

Thus, by the reduction Of the tricyclic nompounds Vllla-d by hydrazine hydrate in the presence
of Raney nickel, o-amino-ketones IXa-d were synthesized in high yields. Reduction of
compounds VIII and IX can be also effected by means of iron in acetic acid, but this method
is less convenient, and amino ketones are formed in lower yields. Various benzimidazole
derivatives were synthesized from amino-ketones IXa-d; their acylation gave a series of
5-acyl-amino derivative Xa-d, oximation of ketones IXa led to the corresponding oximes Xla,
b, and by diazolization of compound Ixa, followed by treatment with potassium iodide, 4-
benzoyl-5-iodobenzimidazole (Xlla) was synthesized.

O /Ph COPh COPk

rVa_ d VIIIa-d "/ IXa-d x a-e

/ N /Ph
CPh COFh l': COPh :':
I ~ k. MezN-CH=N ~ N J~

na,b .'ma x~'a-d xv a,c

IV, VIII, IX a R=Me, RI=ph; b R = H , R r = p h ; X R=Me, R l = P h : a R2=3,4,5.
(MeO)zC6H2, b R2=Ph: e R2=PhOCH2, d Ra=CH2CI, e .R2=Me; XI, XII, XIV, XV
c R = H , Rt=CH2CH2OH; d R=CHa, RJ=CH2CH2 OH

R77
 The presence of keto and amino groups at the ortho-positions of compounds IXa-d ensures
the possibility of the preparation from them of condensed tricyclic systems. As an
example, a reaction of amino-ketones lEa-d with DH~A diethyl acetal (XIII) was carried out~
as the result of which formamidines XIVa-d were obtained. Imidazo[4,5-f]quinazolines (XVa-c)
were synthesized by heating amidines XIVa-c with an alcoholic solution of ammonia in a bomb.

In the IR spectra of quinazolines XV, the absorption bands of an aromatic keto group
characteristic for the initial formamidines XIVa-c are absent, and in the PHR spectra, the
signals of N,N-dimethyl groups are absent. At the same time, in the PMR spectra of com-
pounds XV in DM~A-Dv, besides the signals of aromatic protons of the condensed benzene
ring, phenyl and benzoyl substituents in the 1- and 4-positions (in the 7.5-8+5 ppm
region) and signals of the CHs group (2.19 ppm for compound XVa) and the CH2CH20H group
(3.86 t CH2; 4.49, t, OCH2; 4.80, OH, for XVc), signals are observed of 6-H protons at
the 2-position of the pyrimidine ring at 9.24 (XVa), 9.30 (XVb) and 9.25 ppm (XVc), which
corresponds to the data in [4~ for the quinazoline ring protons. In the mass spectrum of
the tricyclic compound XVa, the peak of the molecular ion M + 336 is the most intense.
Thus, with the method that we developed an approach can be made to the synthesis of
previously unobtainable benzimidazole derivatives, which may serve, in particular, a s
starting compounds in the preparation of new condensed heterocycles.

EXPERIMENTAL

The IR spectra were run on an UR-20 spectrophotometer in KBr tablets, and the PMR
spectra on a Tesla BS-497 spectrometer (100 HHz), using HMDS as internal standard. The
mass spectrum was measured on a Varian HAT-112 spectrometer. The melting points were
determined on a Boetius apparatus. The individual state of the compounds obtained was verified
by chromatography in a thin layer (SilufoltrV-254).
The characteristics of synthesized compounds are given in Table 1.
3~6-Diphenyl-5-methylimidazql4~5-el-2~l-benzisoxazole (VIIIa). A 15.44 g (60 meoles)
portion of compound IVa and 21.08 (180 moles) of nltrile I are added at 60~ to a solution
of 96.0 g (2400 mmoles) of sodium hydroxide in 500 ml of methanol. The solution is brought
to boiling, held for 5 h, and cooled to 20~ After 500 ml of water have been added, the
precipitate is filtered, washed with water to pH 7, and then with alcohol. Yield 15.21 g.
Co~pounds VllIb-d are obtained in a similar way.
l-Phenyl-2-methyl-4-benzoy!-5-aminobenzimidazole (IXa). A i0% Raney nickel catalyst
is added to a suspensior~ of 12.5 g (38.5 mmoles) of compound VIIIa in 140 ml of ethanol.
The mixute is heated to boiling, and 35 ml of hydrazine hydrate are added dropwise in the
course of 1 h~ The mixture is boiled for 4 h, activated charcoal is added, boiling is
continued for i0 min, and the carbon is removed by filtration. When cool the precipitate
is filtered, washed with cold ethanol, and dried, +Yield, 11.16 g. Compounds IXb-d are
obtained in a similar way.
l-Phenyl-2-methTi-4-benzou (Xa). A 4.24 g
portion (40 mmoles) of finely ground sodium carbonate is added to a suspension of 6.54 g
(20 mmoles) of ketone IXa in 50 ml of methanol acetate. Then, 6 g (26 m o l e s ) of trimethoxybenzoyl
chloride in 30 ml of benzene are added dropwise at 20~ in the ~ourse of 30 min, and the mix-
ture is left to stand for 8 h. The precipitate is filtered, washed with water,~and+dried~
Yield, 8.65 g. Compounds Xb-e are obtained in a similar way.
l-Phenyl-2-methyl-4-benzoTi-5-aminobenzimidazo!e oxime (XIa). A 3.15 g portion (45 mmoles)
of hydroxylamine hydrochloride is added co a solution of 4.08 g ( 1 5 mmoles) of ketone IXa
in 30 ml of pyridine, the mixture is brought to boiling and held for 3 h. It is then cooled
to 20~ 100 ml of water are added, and the precipitate is filtered, washed with water, acidified
with HCI, and dried. Yield, 3.52 g, Compound XIb is obtained in a similar way.
l-Phenyl-Z-methyl-4-benzoyl-5-iodobenzimidazole (XIIa). A 5.2 ml portion of concentrated
HCI is added to a solution of 6.54 g 420 m o l e s ) of compound IXa in 50 ml of acetic acid. The
mixture is cooled 6o 6~ and a solution of 1.38 g (20 mmoles) sodium nihrite, in 10 ml of water
is added dropwide very slowly (in the course of 1 h to i h 30 min). The mixture is left to
stand for 1 h and then the diazonium salt is added Co a solution of 3.32 g (20 mmoles) of
potassium iodide in 10 ml of water, cooled to 50C. The ev01utionof nitrogen is complete

878
after 3 h, and towards the end of the holding time, the mixture is heated to 30-35~
The precipitate is filtered and washed with ethanol. Yield, 4.38 g.
l-Phenyl-2-methyl-4-benzoyl-5-dimethylaminomethyleneamin0benzimidazole (XIVa). A 6 ml
portion (40 nm~oles) of a 70% DMFA diethyl acetal is added in the course of 4 h, at the
boiling point, to a suspension of 6.54 g (20 mmoles) of ketone IXa in 20 ml of toluene. The
reaction mixture is cooled, filtered (in the case of compound XIVb, evaporated), and the
product is washed with a small amount of absolute ethanol. Yield, 5.67 g. Compounds XIVb-d
are obtained in a similar way.

4,7-Diphenyl-6-methylimidazo[4-5-f]quinazoline (XVa). A mixture of 4 g (ii mmoles)

of compound XIVa and ~O ml O t a 10Z alCOhOliC solution of ammonia is heated for 12-15 h in a
bomb at 140-145~ and at a pressure of 13-15 arm. The reaction mixture is cooled and
evaporated. The residue is treated with 10 ml of absolute ethanol and filtered. Yield,
1.42 g (40Z). Compounds XVb,c are obtained in a similar way.

LITERATURE CITED

i. R. B. Davis, L. C. Pizzini, and J. D. BeniEni, J. Am. Chem. Soc., 82, 2913 (1960).
2. K. H. Wunsch and S. I. Boulton, Adv. Heterocycl. Chem., 8, 277 (1967).
3. R. B. Davis and L. C. Pizzini, J. Org. Chem., 24, 1884 (1960).
4. Pretsch, Clerc, Seibl, and Simon, Tables for Structure Determination of Organic Compounds
by Spectroscopic Methods [in German], Springer Verlag, Berlin, Heidelberg, New York
(1976).

879
 TETRAZOLES.
21. * REACTION OF BENZONITRILE WITH SALTS OF HYDRAZOIC ACID

I. E. Titova, V. S. Poplavskii, 9 UDC 547.796.1.07

G. I. Koldobskii, V. A. Ostrovskii,
V. D. Nikolaev, and G. B. Erusalimskii

The reaction of benzonitrile with the ammonium, alkyl-, dialkyl-, and trialkyl-
ammonium salts of hydrazoic acid in DM~ at 100oC produces 5-phenyltetrazole.
The yield of 5-phenyltetrazole is practically independent of the structure of
the ammonium cation. Under the same conditions, the tetraalkylammonium salts
of hydrazoic acid do not react with benzonitrile. It was proposed that the forma-
tion of 5-substituted tetrazoles from nitriles and the salts of hydrazoic acid
proceeds by the mechanism of 1,3-dipolar cycloaddition.

The main method for the isolation of 5-aryltetrazoles is the reaction of substituted
benzonitriles with the salts of hydrazoic acid in DM~ [2]. This method, which was proposed
in 1958 [3], has not undergone any changes up to the present time. In the majority of
cases, ammonium azide is utilized for this purpose; it is obtained in situ as the result
of the exchange reaction of sodium azide with ammonium chloride. However, there are no
data to confirm the reaction mechanism proposed in the work [3], and there is no reliable
information on the effectiveness,of other salts of hydrazoic acid in this reaction.
in connection with this, the reaction of benzonitrile with salts of hydrazoic acid
containing ammonium cations of varying structure was studied in the present work. The
salts of hydrazoic acid, which are required for this, were obtained in situ by the exchange
reaction of sodium azide with the corresponding a,,,onium salts. We carried out the reaction
in DMF at 100~ for 5 h.
1.G ~ t ~ N 3 -
2. H ~ C6HSk NR
C,SsCN _-- II 1 ,.-
N~N~N
Cat=NI~, CH~NHs, (CH3)2NH2, (C2Hs)~NH2, (C4H~)2NH2, (C2H~)sNH

Under these conditions, 5-phenyltetrazole is formed with a yield of 71-77%; the struc-
ture of the ammonium cation does not show an appreciable influence on the yield of 5-
phenyltetrazole. An exception to this is ammonium azide, for which the yield of 5-phenyl-
tetrazole comprises 60%; this is evidently associated with the specific properties of this
salt, which readily volatilizes from the solution in DMF [4]. At the same time, 5-pheny !-
tetrazole is not generally formed when carrying out the reaction with sodium azide or the
tetramethyl- and tetrabutyle~,onium azides. These results can be explained on the basis
of the following considerations.
It is assumed that the azidoazomethine, which cyclizes to the tetrazole, is formed as
a result of the attack of the carbon atom of the nitrile group by the azide ion in the
first stage of the reaction of nitriles with salts of hydrazoic acid [2]. In one of the
first works concerned with the isolation of 5-substituted tetrazoles from nitriles and the
ammonium salts of hydrazoic acid, it was proposed that the coordination of the protonic acid,
which is represented by the ammonium cation, at the nitrogen atom of the nitrile group
assits theaddition o f the azide ion [3]~ No evidence to confirm the correctness of this
hypothesis was presented~ Nevertheless sucha mechanism for the formation of 5-substituted
tetrazoles from nitriles has become generally accepted inrecent years. However, the

~For Communication 20, see [i].

Lensovet Leningrad Technological Institute, Leningrad 198013. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 8, pp. 1086-1089, August, 1986. Original article
submitted May 23, 1985.

880 0009-3122/86/2208-0880512.50 @ 1987 Plenum Publishing C o r p o r a t i o n

 assumption of the coordination of the nitriles with protonic acids in the solution of DMF
gives rise to serious objections. It is difficult to admit that the protonic acids will
associate with the nitriles and not with DMF, which possesses significantly higher donor
capacity than the nitriles, under these conditions [5].
The mostprobable alternative may be the formation of the 5-substituted tetrazoles b y
the mechanism of 1,3-dipolar cycloaddition. The choice of one of the possible variants
was made on the basis of the detailed examination of the data obtained in the study of the
reaction of benzonitrile with the known dimethylanunonium and tetramethylammonium azides,
and with sodium azide in the presence of dibenzo-18-crown-6 and monobenzo-15-crown-5 in
DMF. We prepared dimethyla,,,onium azide (I) by mixing the benzene solutions of dimethyla-
mine and hydrazoic acid. We obtained tetramethylawanonium azide by the addition of an
aqueous solution of tetramethylammonium hydroxide to a chloroform solution of hydrazoic acid.
It is known that the tetraalkylammonium azides have an ionic structure [4]. In contrast
to quaternary ammonium salts, dimethylammonium azide, obtained as described above, is
evidently the complex (CH3)2HN...HN a in which the coordination is realized on account of
the hydrogen bond. In fact, the formation of the salt can only proceed in the benzene solu-
tion on account of the dipole-dipole interaction of the reagents, since hydrazoic acid
does not dissociate in benzene. Such a conclusion follows from the consideration of the
NMR spectra of both salts in DMF-D e. The chemical shifts of the methyl protons of the
tetramethylarmnonium and dimethyla,~monium azides are equal to 3.15 and 2.75 ppm respectively;
this is characteristic of the salts of amines and neutral compounds [6]. On the solution
of dimethylammonium azide in DM_F, the following equilibria, which are dependent on the
concentration of the salt, are possible:

(CH3)~HN..-SN~ = (Cng=NMFN3- ~ (r 2 N~- (I)

The equilibrium (i) is-displaced in favor of the complex (CH3)zHN...HN 3 at the 0 . 1 M

concentration of the salt; it is displaced in favor of the free ions on decreasing the con-
centration of the salt to 0.001M. This is confirmed by the data obtained in the study of
the electric conductivity of dimethla~monium azide in DM~. According to these data, the
dissociation constant (KD) of the salt at 25~ is equal to 6.29.10 -s. It should be n o t e d
that the formation of the complex of the type indicated is not something unusual. It is
well known that amines form stable H-bonded complexes with carboxylic acids and phenols -
without the transfer of the proton of the type B..oHa [7].
At the following stage of the work the IR spectra of benzonitrile in DMF and of the
solutions of benzonitrile in DMI~ with the varying content of (CH3)2HN...HN 3 (I) were studied.
The compound (I) was practically not ionized in solution at the concentration of 0.3 M; it
was almost half-ionlzed at the concentration of 0.04 M. It is known that a change of the
intensity of the shift of the band of the stretching vibration of C E N is observed in the
IR spectrum of the nitrile on the coordination of nltriles with proton-donor reagents
[8]. However, changes in the position and intensity of the absorption baud of the
C ~ N group (2232 cm -I) do not occur on the addition of compound (I) to the solu-
tion of benzonitrile in DMF. On this basis, it can be assumed that the reaction of
nitriles with the ammonium salts of hydrazoic acid proceeds as an uncatalyzed process,
whereby the formation of the azidoazomethiue is evidently accomplished as a result
of the addition of the azide ion to the nonactivated nitrile group. In this case, the
effective course of the reaction, with other conditions being equal, should be determined
by the concentration of the azide ion in the reaction solution and the character of its
solvation. Consequently, the best results can be expected on performing the reaction with
tetramethylammonium azide or sodium azide in the presence of crown ethers in solvents such
as DMI~. However, 5-phenyltetrazole is not generally formed by the heating of the indicated
salts with benzonitrile in DMF. At the same time, the yield of 5-phenyltetrazole comprises
75% for the reaction of benzonitrile with dimethylammonium azide. These results become
understandable if it is assumed that the formation of the 5-substituted tetrazoles from
nitriles and the ammonium salts of hydrazoic acid proceeds by the mechanism of 1,3-dipolar
cycloaddition, where the complex of hydrazoic acid with the amine serves as the 1,3-dipole:

881
 F R"C~N 1
RCN + (CH3).HN...HNS . . . . . . I(CH~)~HN... IIN-,,N,N- t - -
./
R... + R
.___ 17r~-,
~'N%(c"~)~ 4 II4"X- " ~ : NH
N'- ;~ ~" di 1 + NH2(CH~)~X
N~N~N

The data obained in the present work on the study of the reaction of benzonitrile with
other ammonium salts of hydrazoic acid conform oompletely with such a mechanism for the
formation of the 5-substituted tetrazoles. However, the final judgment on the mechanism of
the formation of 5-substituted tetrazoles can only be made after studying the kinetics of
this reaction.

EXPERIMENTAL

The IR spectra of benzonitrile in DMF and the solutions of benzonitrile and dimethyl-
ammonium azide in DMF were taken on a UR-20 instrument in cells of NaCI with the thickness
of the layer of 0.07-0.39 mm; the concentration of the reagents was 0.1-0.01M. The NMR
spectra were recorded on a Perkin-Elmer R-12 (60 MHz) spectrometer in DMF-D6. The internal
standard was HMDS; the concentration of the reagents was 0.1 M.
The electric conductivity of dimethylammonium azide was measured with the aid of the
E8-2 capacitance bridge in a thermostated ( 0.1~ enclosed cell of capacity 15 cm a having
the horizontal disposition of the electrodes~ made of unblackened platinum, of area 1 cm 2.
The cell constant, which was determined by aqueous solutions of KCI, was equal to 0.261 (25
0.1~ The conductometric measurements were performed with the relative accuracy of 0.25%~
Treatment of the experimental data was accomplished with the application of an algorithm and
the block scheme presented in the works [9, 10]. The DMF was purified by known methods [II];
the degree of purity was controlled by the method of GLC, and from the value of the specific
electric conductivity (~ = 3.5.10 -v R-1.cm'l).
Freshly distilled DMF was applied for the measurements.
Dimethylammonium Azide (I). To the solution of 8.3 g (180 mmole) of dimethylamine in
150 ml of benzene, which was obtained by the multiple extraction of a 33Z aqueous solution
of dimethylamine with drying over magnesium sulfate, were added 150 ml (180 mmole) of a 6%
solution of hydrazoic acid in benzene with slow stirring at 20"C [12]. The precipitated
dimethylammonium azide was separated from the benzene solution and dried in a vacuum desic-
cator over phosphorus pentoxide and paraffin. The yield was 75% after vacuum sublimation
(10 mm~ 40~ The IR spectrum (thin layer) was as follows: 2960, 2870, 1470, and 1380
(CHa); 2470, 1610 (NH2); 2040 cm -I (Na')o The PMR spectrum (in DM~-D6) was as follows:
6.90 (2H, singlet, NH 2) and 2~ ppm (6H, singlet, CHs). Found: C 26.9, H 10.4, and N 64.9%~
C2HsN~. Calculated: C 27.3, H 9.1, and N 63.6%.
T etramethylammonium Azide. To the solution of 6 g (66 mmole) of tetramethylammonium
hydroxide in 200 ml of water at 20~ were added, with slow stirring, 55 ml (66 mm61e) of a 6%
chloroform solution of hydrazoic acid; the mixture was stirred for a further 30 min. The
aqueous layer was separated; the water was removed at 40~ in vacuo, and the residue was
recrystallized from methanol. The yield was 60%~ The IR spectrum (thin layer) was as
follows: 3030, 1500, and 1410 (CH~); 2020 cm -l (Na-). The PMR spectrum (in DMF-D 6) was
as follows: 3.15 ppm (12/{, singlet, CHa). Found: C 41.0, H 10.2, and N 47.8%. C~HI2N~.
Calculated: C 41.4, H 10.4, and N 48.3%.
5-Phenyltetrazole. To the solution of 10.3 g (100 mmole) of benzonitrile in 50 ml of
DMF were added 7.8 g (120 mmole) of sodium azide and 6.4 g (120 mmole) of ammonium chloride,*
and the mixture was stirred for 5 h at 1000C. The sodium chloride was filtered off, and DMF
was removed in vacuo. The solid residue was dissolved in i00 ml of water; it was acidified
with concentrated HCI to pH < 2. The 5~phenyl~etrazole was filtered off. By analogy, the
reaction of benzonitrile with the known prepared salts of hydrazoic acid and with sodium

eThe other alkylammonium salts were utilized analogously~

882
azide was performed in the presence of crown ethers. The yield of 5-phenyltetrazole was
determined with the accuracy of 3%. In all cases, 5-phenyltetrazole had the character-
istics corresponding to the data of [3].

LITERATURE CITED

i. T. F. Osipova, G. I. Koldobskii, V. A. Ostrovskii, and Yu. E. Myznikov, Khim. Getero-

sikl. Soedin., No. 6, 841 (1985).
2. G. I. Koldobskii, V. A. Ostrovskii, and V. S. Poplavskii, Khim. Geterotsikl. Soedin.,
No. 10, 1299 (1981).
3. W. G. Finnegan, R. A. Henry, and R. Lofquist, J. Am. Chem. Soc., 80, 3908 (1958).
4. A. M. Goluba, Kh. Kelera, and V. V. Skopenko, The Chemistry of Pseudohalogenides [in
Russian], Vishcha Shkola, Kiev (1981), p. 23.
5. M. Szware, Ions and Ion pairs in Organic Reactions Reactions, Wiley (1972).
6. B. I. Ionin, B. A. Ershov, and A. I. Kol'tsov, NMR Spectroscopy in Organic Chemistry
[in Russian], Khimiya, Leningrad (1983), p. 139.
7. R. Bell, The Proton in Chemistry, Chapman and Hall (1973).
8. A. Smit, Applied IR spectroscopy [Russian translation], Mir, Moscow (1982), p. 168.
9. V . M . Tsentovskii and V. S. Tsentovskaya, ~lektrokhimiya, 8, 1636 (1972).
i0. V. P. Barabanov, V. M. Tsentovskll, and V. S. Tsentovskaya, Elektrokhimiya, iO, 432
(1974).
ii. Ya. M. Kolotyrkin (editor), The Electrochemistry of Metals in Nonaqueous Solutions
[Russian translation], Mir, Moscow (1974), p. 27.
12. G. Wolf, Organic Reactions [-Russian translation], Vol. 3, Inostr. Lit., Moscow (1951),
, p. 293.

REACTION OF SALTS OF NITROAMINOTETRAZOLES WITH ALKYL IODIDES

A. G. Mayants and V. V. Erina UDC 547.795.1

The reaction of salts of 5-nitroaminotetrazole, I- and 2-methyl-5-nitroaminotetra-

zole, and2-ethyl-5-nitroaminotetrazole with alkyl iodides is studied. It is
established that salts of 2-methyl- and 2-ethyl-5-nitroaminotetrazole are alkylated
at the nitroamine group while salts of l-methyl-5-nitroaminotetrazole are alkylated
at the second nitrogen atom of the tetrazole fragment with the subsequent splitting
off of the methyl group at the 1-position of the tetrazole r~ng and further
alkylation of the nitroamine group. It is shown that salts of 5-nitroamino-
tetrazole are initally alkylated at the second nitrogen atom of the tetrazole
fragment and then at the nitroamine group. It is hypothesized that the initial
alkylation of salts of l-methyl-5-nitroaminotetrazole and 5-nitroaminotetrazole
at the second nitrogen atom of the tetrazole fragment results from their nitro-
imino tautomeric form.

The preparation of dialkyl derivatives of 5-nitroaminotetrazole, I-III, by the reaction

of salts of 5-nitroaminotetrazole with methyl iodide (I), the alkylation of 5-nitroamino-
tetrazole with diazomethane-(I), and the nitration of the corresponding dialkyl derivatives
of 5-aminotetrazole (I-III), was described earlier [1].

~H~ R
I
/ N--NO 2 N --NO 2

C~3-"N'~ N~ N N%N~N

I 9 II,IU
II RfCH3; Ill RfCzlt ~

V. V. Ku~byshev Polytechnic Institute, Kuibyshev 443010. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 8, pp. 1090-1093, August, 1986. Original article
submitted February 26, 1985; revision submitted October 14, 1985.

0009-3122/86/2208-0883512.50 O 1987 Plenum Publishing Corporation 883

 In the present work, we have investigated the possibility of obtaining dialkyl deriv-
atives o f the tautomeric form o f 5-ni~roamlnotetrazole, 5-nitroamlnotetrazollne (IV, V), by
the reaction of salts of nitroeminotetrazoles with alkyl iodides in aqueous media. It is
known [2] that some nitroaminotetrazoles are present in aqueous solutions in the tautomeric,
nitroiminotetrazoline form.
Alkylation products I and YI-VIII containing the alkyl group at the 2-position of the
tetrazole fragment were unexpectedly obtained as the products of the reaction of the ammonium
salt of l-methyl-5-nitroaminotetrazole with ethyl and methyl iodides in aqueous acetone
solution. Thiscan be explained by the formation in the reaction of the expected dialkyl
derivatives of nitroiminotetrazoline (IV and V) which are apparently unstable compounds and
decompose with the splitting off of the methyl group at the l-position of the tetrazole
ring and the addition of an alkyl group to the nitroimine fragment according~o the scheme:

r// Pd "'~--SO2 ~OOR

c:,. "N
-.-.o2 9 I .
N-N~N IL/N,N~ m J -Cll3 R..N .N~ N R/N.N.: -N
NH~ ~ ,.
IV, V I, Vl VII. VII1

I. |%'.VII R:cll~;%'.%1. VIH R--'C~I!

5

If alkylation of the salt of l-methyl-5-nitroaminotetrazole took place at the nitroamino

group, then compound II would have to have been formed, but this is not found among the
reaction products.
In order to identify compounds I and VI-VIII obtained from the salt o f l-methyl-5-
nitroaminotetrazole, we synthesized them by alkylating salts of 2-alkyl-5-nitroaminotetrazole
in aqueous acetone solution with ethyl and methyl iodide according to the scheme:
L ".
ii z
I . ..~v ~
NNOz-~H4" RZI . /N--N',OR2

r ~.. R' ~.~N R' "N'N"~'

I, ~I VII, VIII.
I, ~I[ R 1 ~lt~'~C}l~; VI, Viii II 1 : ll~zCil'I:

The mixture of isomers VI and VIII was separated by means of preparative chromatography.
To isolate individual compounds I and VI, we treated the corresponding mixture of N- and
O-isomers, I, VII and VI, VIII, with 40Z HzS04 until the O-isomers were decomposed [3].
We identified the isomeric compositions through a comparison of the IR spectra, the
refractive indices n D and the Rf constants, and the retention times in GLC. It turned
out that the reactions of the salts of i- and 2-methyl-5-nitroaminotetrazole with methyl
iodide gave the same compound (the Rf values and retention times for the corresponding
N- and O-isomerswere the same and the indices of refraction and the IR spectra of the
isolated N-isomers were the same). At the same time, the refractive indices of the N-
isomers were the same as the refractive index of I, obtained by the authors of [l]. Con-
sequently, the structure of the N-isomers being formed.corresponds'tO I, so that the
structure of the O-isomers must obviously correspond to VIi. In a similar way, using
TLC, the refractive indices, the IR spectra, and elementary analyses, it was shown that
the reaction of salts of 1-methyl- and 2-ethyl-5-nitroaminotetrazole with ethyl iodide
formed, correspondingly, the same diethyl derivatives of 5-nitroaminotetrazole (N- and
O-isomers). This shows unambiguously that the methyl group is split off during the alkyla-
tion of salts of l-methyl-5-nitroaminotetrazole. Consequently, the structure of the N-
isomer corresponds to the product alkylated at the second nitrogen atom of the terazole
fragment, i.e., to VI, and the structure of the O-isomer corresponds to VIIIo
Mixtures of N- and O-isomers I, VII and VI, VIII, respectively, were also obtained
in the reaction of dianunonium and disodium salts of 5-nitroaminotetrazole with ethyl
and methyl iodide. On the basis of the data concerning the nitro~mine tautomeric form of
5-nitroaminotetrazole in aqueous solutions [2], we hypothesized that the alkylation of
salts of 5-nitroaminotetrazole, as well as of salts of 1-methyl-5-nitroaminotetrazole,
may take place initially at the second nitrogen atom of the tetrazole ring. To test this

884
hypothesis, the alkylation of the disodium salt of 5-nitroaminotetrazole was carried out
with ethyl iodide, as a result of which it was possible to isolate the monoalkylation
product, the sodium salt of ethyl-5-nitroamiaotetrazole. To answer the question of the
location of the ethyl group (the primary nitroamine, 2-ethyl-5-nitroemino-tetrazole or the
secondary nitroamine, 5-(N-ethyl-N-nitroamino)-tetrazole), the polarographic reduction of
the salt in alkaline medium was studied. It is known [4] that primary aromatic nitroamines,
2-ethyl-5-nitroaminotetrazole among them [5], are polarographically inactive in alkaline
medium; secondary aromatic nitroamines, however, are reduced in alkaline medium [6]. The
ethyl-5-nitroaminotetrazole salt isolated proved to be polarographically inactive in alkaline
medium, indicating the structure to be 2-ethyl-5-nitroaminotetrazole. The same was indicated
by a comparison of the UV spectra of the isolated compound and authentic 2-ethyl-5-nitro-
aminotetrazole [2]. Consequently, the reaction of salts of 5-nitroaminotetrazole with alkyl
iodides proceeds according to the scheme:

f.NNO2- M +
RI N~ RI
I I ~ ! + v'llorvI
N~N~N R.-N~N~N
i Vll B=CH~. W. V ~ R~C~H5 M + ~ N a ~. NB4~

EXPERIMENTAL

Reaction of salts of alkyl-5-nitroaminotetrazole with Alkyl Iodides. A 0.2 mole portion

of methyl or ethyl iodide is added to a solution of 0.1 mole Of the appropriate nitroamino-
tetrazole salt in 50% aqueous acetone (modulus i0). The reaction mass is held under reflux
with stirring at 40"C (for methyl iodide) or 60"C (for ethyl iodide) for 20 h. Then 0.i
mole of the alkyl iodide is added to the flask and the mixture held for another 10 h under
the same conditions. The acetone and excess alkyl iodide are then removed from the reaction
mixture, the reaction product is extracted with ether (4 40), and the extract passed
through a column of AI20 s and dried over MgSO~. After the ether has been distilled off and the
product pumped down at 40"C to a residual pressure of 5-10 mm HE, a mixture of isomers I and
VII (40%) or VI and VIII (25%) is obtained. I, VII, Found: C 22.9%; H 3.7%; N 53.2%.
Calculated for C~HeNeO2[ C 22.8%; H 3.8%; N 53.1%. VI and VIII, Found: C 32.4%; H 5.5%; N
44.8%. Calculated for CsHz0Ne02: C 32.2%; H 5.4%; N ~5.1%.
Isolation of 2-methyl-5-(N-methyl-N-nitroamlno)tetrazole (I) from a Mixture of Isomers
I and VII; Isolation of 2-ethyl-5-(N-ethyl-N-nitroam~no)tetrazole (VI) from a Mixture of
Isomers VI and VIII. A small quantity of the mixture of isomers (or ethanolic solution of
the mixture) is added to 40% H2SO ~ and held at 20-40~ until the O-isomers, VII or VIII,
are decomposed (the purity of the I or VI remaining in solution is monitored by TLC). The
I or VI is then extracted with ether, and the extract passed through a column of AI20 ~ and
dried over MgSO~. After the ether is removed and the product pumped down at 48~C to.a
residual pressure of 5-10 ~n Hg, separate I or VI is obtained. I. IR spectrum: 1295,
1580 cm -l (N-NO%). Found: C 22.9%; H 3.9%; N 53.1%. Calculated for C3HeNeO=: C 22.8%;
H 3.8%; N 53.1%. Vl. IR spectrum: 1288, 1580 cm? l (N-NO=). Found: C 32.3%; H 5.3%;
N 45.0%. Calculated for CsHIoNsO=: C 32.2%; H 5~4%i N 45.1%.
Separation of a Mixture of Isomers VI and VIII. "The mixture of VI and VIII is dissolved
in 6 volumes of eluent (benzene/hexane/diethyl ether, 11:3:1) and poured into a column
previously filled with eluent and L 100/400 grade silica gel. Eluent is gradually added
dropwise to the column and samples are withdrawn which are analyzed by TLC for the product
content. After pure eluent, VI is washed from the column and then with pure eluent again.
To recover VIII, the column is plushed with ether. Pure VI and VIII are obtained after
the solutions are dried over MgSO~; then the solvent removed and the products pumped down.
Found: C 32.1%; H 5.3%; N 45.2%. Calculated for CsH10NeO=: C 32.2%; H 5.4%; N 45.1%.
IR spectrum Vl: 1288, 1580 cm -l (N-NO=).
We investigated the products of the reaction of salts of i- and 2-methyl-5-nitroamino-
tetrazole and salts of 5-nitroaminotetrazole with methyl iodide by means of TLC (Silufol
plates, 11:3:1 benzene/hexane/ether eluent, developed in iodine vapor), GLC (on a
Tsvet-i instrument, katharometer detector, OV-17 phase on shimolite, carrier gas helium).
We determined the refractive indices of the individual N-isomers of I and measured the
IR spectra. The characteristics were the same for all of the samples: Rf 1 0.44; Rf VII

885
0.17; retention time for I, 105 sec at 50QC, for VII, 180 sec atl05"C; lRspectra ofl, identical;
refractive index of I, nD2~ (from data in [i]~ nD 2~ is 1.5052).
We investigated the products of the reaction of salts of l-methyl-~and 2-ethyl-5-nitro-
aminotetrazole and salts of 5-nitroamlnotetrazole with ethyl iodide by means of TLC (Silufol
plates, 11:3:1 benzene/hexane/ether eluent, developed in iodine vapor). We measured the IR
spectra and determined the refractive indices of the individual N-isomers of VI. The
characteristics of all of the samples were the same: Rf VI 0.64; IR spectrum of VI identical,
refractive index of VI, nD 2~ 1.4890.

LITERATURE CITED

i. W. P. Norris and R. A. Henry; J. Or E . Chem., 29, 650 (1964).

2. A. G. Mayants, S. S. Gordeichuk, V. A. Shlyapochnikov, T. V. Gordeichuk, and V. P. Gorelik,
Khim. Geterotsikl. Soedin., No. ii, 1569 (1984).
3. H. Feuer (editor), Chemistry of the Nitro and Nitroso Groups, Wiley (1969).
4. E. Laviron, P. Fournari, and J. Greusard, Bull. Soc. Chim. Ft., No. 4, 1255 (1967).
5. A. G. Mayants, S. S. Gordeichuk, and S. M. Muratov in: VII All-Union Conference on
Polarog=aphy. S[m~ary Reports. [in Russian], Nauka, Moscow (1978), p. 22.
6. E. Laviron and P. Fournari, Bull. Soc. Chim. Ft., No. 2, 518 (1966).

TWOFOLD REACTIVITY OF 1,2-DISUBSTITUTED DIHYDRO-N-HETEROAROMATIC

SYSTEMS.
i0o ~ SYNTHESIS AND AROMATIZATION OF FERROCENE-~ONTAINING HANTZSCH
ESTERS

A. K. Sheinkman, E. Yu. Nesterova, UDC 547.827'172:543.87:541.124

G. N. Yashchenko, and A. I. Chernyshev

l-Ferrocenylphenyl-4-aryl(furyl)-2,6-dimethyl-3,5-diethoxycarbonyl- 1,4-dihydro-
pyridines and 4-ferrocenyl-2,6-dimethyl-3,5-diethoxycarbonyl-l,4-dihydropyridines
(Hantzsch esters) have been prepared, and their reactions with triphenylcarbenium
and l-oxo-2,2,6,6-tetramethyl-piperidinium perchlorate salts have been studied.
Treatment with triphenylmethyl perchlorate results in oxidation of the ferrocenyl
substituent to the ferrocenium cation, whereas treatment with the oxoammonium
cation results in aromatization and the formation of salts containing a pyridinium
cation and a neutral ferrocene ring~ A 4-ferrocenyl-containing Hantzsch ester
which was unsubstituted at the nitrogen atom constituted a single exception to
this trend; it could be aromatized only upon treatment with sulfur.

The twofold reactivity of 1,2(4)-disubstituted 1,2(4)-dihydrohetero-aromatic compounds

with respect to aromatization reagents has been described previously [2~, and.was found to
depend on the relationship between the electrophilicity and oxidizing ability of the aromatiz-
ing agent. Strong oxidizing agents with weak electrophilic characteristics, such as l-oxo-
2,2,6,6-tetramethylpiperidinium perchlorate [2], direct the reaction along the oxidative
pathway, leading to loss of hydrogen and preservation of the =-substituent [3-5], whereas
strong electrophiles which are not strong oxidizing agents, such as triphenylcarbenium per-
chlorate, direct the reaction along an electrophilic pathway, resulting in cleavage of anion-
stabilizing substituent groups, such as indole or CH-acids [2].
It was therefore of interest to us to examine the reactivity of these two cations on
ferrocenyl-containing Hantzsch esters, since it is well known that aromatization of ferrocenyl ~
containing Yanov o-complexes [6] or 1,4-dihydropyridines [7] involves preliminary oxidation

~For Communication 9, see [i].

Dnepropetrovskii Institus of Civil Engineering, Dnepropetrovsk. Translated from

Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1094-1101, August, 1986o Original
article submitted May 5, 1985.

886 0009-3122/86/2208-0886512.50 @ 1987 Plenum Publ{shing Corporation

 TABLE i. Properties of Newly Synthesized Substances

COla- oC Found, Molecular Calc., %

pound formula Yield, %
H c H N

[a 212--213 CasHa~FeN:O6 75
Ib 174--174,5 Ca~HasFeN=O6 , 28
Ic 223--225 CasHasFeN=O~ 72
Id 166--166,5 CaaHaaFeNO~ 50
le 155--t56 Ca6HasFeNO5 27
II 210--212 C~aH=rFeNO~ 80
fly 142--143 C2~HmFeNO4 82
l~,a 241--242 C~aHIsFeN202 97
IVb ll8--119 C2aH~sFeN202 93
IVC 144--145 C.~HIsFeN~r 98
IVd 148--149 C~IHIrFeNO 77
IVe 189--190 C24H21FeNO 88
IVf 268--270 C2aHIgFeNO 83
IVg 213--214 Co.~H24FeN2 90
IXa 204--205 CasHa4CIFeN20~o 50
IXb 196--197 CasHa(CIFeN=O~o 47
IXd 217--218 CaaHa~ClFeNOo 50
IX e 197--198 Ca.H~CIFeNO. 45
X 194--195 C=~H=~CIFeNO~ 50
XI 217--219 C~,H=~CIFeNO~ 65
XII 93--94 C~aH=~FeNO~ 20

*Compounds la-e were crystallized from propanol, compound II,

from benzene.

of the ferrocenyl substituent to a ferrocenium cation, which is not susceptible to cleavage,

and which also, because of its strongly electron-withdrawing character, inhibits loss of
hydrogen from geminal positions relative to it, whether by an ionic or SET mechanism. It
would therefore seem likely that aromatizing agents which induce aromatization by an ionic
mechanism involving cleavage of a substituent would not be effective in the case of the
Hantzsch esters. In order to verify this hypothesis, we have investigated the reactivity
of both triphenylcarbenium and l-oxo-2,2,6,6-tetramethylpiperidinium perchlorates with
ferrocenyl-containing Hantzsch esters, namely, 1-p-ferrocenylphenyl-4-aryl(furyl)-2,6-
dimethyl-3,5~diethoxycarbonyl-1,4-dihydropyridines (Ia-e), and 4-ferrocenyl-2,6-dimethyl-3,
5-diethoxycarbonyl-l,4-dihydropyridines (II, III).
Compounds Ia~e were prepared according to a known method [8~ by treatment of ferrocenyl-
phenylamine with aromatic and heterocyclic aldehydes and acetoacetic ester. This synthesis .
is conveniently carried out in two stages: the first stage involves formation of the cor-
responding azomethines IVa-g, which are formed in excellent yield in the reactions of p-
ferrocenylphenylamine with aldehydes containing both electron donating as well as electron
withdrawing substituents (Table 1 ) , and the second stage involves condensation of ~the azo-
methines containing electron withdrawing substituents with acetoacetic ester to give N-p-
ferrocenylphenyl-substituted Hantzsch esters Ia-e (Table I). Electron donating substituents
on the aldehyde component of the azomethine inhibit this second reaction stage.

COOCzH5 El gc H. Fc

. . . . . CH. "N" "CH. C H , / ~ , ~ N / ~ . , , ~ CH, ~ Fc N-~CH-R

~3 ~~ ~ II ~ [
!a-e u ca, IVa-g

Fe =Fc

a R=p-NO~C~H4--; b R=moNO2C6H4--; c R=o-NO:C6H4--; d R = 2 - f u r y l - ; e R=

=p-CHaOC6H4--; f R=p-HOC6H~--; g R=p-(CHa):NC~H4--

887
OO
O0
O0

TABLE 2. Spectral Characteristics o f Compounds I - I I I , and I X - X I I

PHR spectrumL ' 5 , ppm, (BHSO-Ds)

'~ Fe I5 4* Tr spectrum~ ~ w).x)
3,5 COOC,:IIs N--/~, IR spectrum) V max) cm - 1
Zfi-C, FI ~ .tl I I~=H. 4R ~, run ( l o g E ) I% absorption),-i-n the
Compound
(S Jill) (8) R=CII,. regions 1800~!500 and
III) R=Pi~ =Ra-o
CIti I CII~ 3600-3300 cm -I
l~iltl)[tq. 41ti ,_,l i) (.s.: 5H)

la 2.06 7,23 (d 2fl).7.59 (d)2H). 210 (4.83), 247 (4,49), 288 1700 (851. 1640 (501. 1580
7,67 (d. 2H)~.23 (d, 2H) (4,41}, 330 sh (3,5), 472 (2,04) 147). 1527 (71)
Ib 2,07 7,25 (d, 2H),3.16 (d)lH). 211 (4,66), 248 (4,62), 276 [700 1821. 1695 1351. 1650
7,69 {d. 2H) 7.6--8.1 (4,49). 340 (3,98), 460 (3,0) (66). 1587 ((~). 153~ (85)
(mp3H)
[c 84 1,96 7.32 (r 2H). 7.37--7.87 212 (4,651, 247 (4,53), 287 1700 (921. 1550 (67). 1585
7.69 (d 2H) (m, 4H) (4.35). 330 sh (4.0). 465 (3.17) (70). 15!5 1~51. 1530 l~0)
Id 2,04 7.16 (d. 2H), 6,01 (d~lH), 212 (4,54), 247 (4,4), 286 1695 4361. 16~5 1641. 1610
7,65 ~1. 2H) 6,34 {q) IFi) (4.27). 345 (4.1). 468 (3.11) (49). 1585 (621. 1525. 1510
7,53 (q,, IH) (55)
le 2,02 ],87 (d, ~H)), 7.66 (d)2H), 212 (4,8), 250 (4,7), 287 14,61, 1695 476), 164L~ 158), 1579
L22 (d, 7,18 (d~2H) 350 (4.02); 462 12,3) (57). 1523 (56)
3,73 (s, 3H)
ll 2,5~2 .),87 (,s IH) 211 (4,52), 240 (4,36). 280 3440 (82), 3:~5 (42), 171J0
r,inCDCla) (4.0). 337 13.9). 456 (2.5) 190), 1655 (921
ill 2,36 3.14 (s 3Hi 209 (4.6). 241 (4.3). 267 (4.1). 1680 (93). 1610 n~. 178).
338 (3,8), 458 (2.7) 1585 (55)
IXa 2.47 8,49 (d.,2H). 7,64 lds2l-|} 210 (4,9), 252 sh. (4,5), 286 1720 1731. 150, (:B). 1510
(in ~ ) 7,64 (d, 2H) 7,94 {d~2H (4,7), 472 42,8) (60)
Ixb 2,47 7.94 (d.2H). 8.52 (d,IH) 207 14.8). 251 (4.5). 275 (4.7). IZ36 186). 1825 15-t). 1523
(in DH$O) 7.61 (d. 2H) 8.15 isslH} 335 sh (3.81. 467 (2.8) (65)
7.89 (ms 2H)
lYd 2.36 7,63 (a, 2H), ~,92 (q), |H), 207 (4,6), 248 (4,1), 287 (3,9), 1737 (82). 1515 1531. 1575
7,89 (~, 2H). 7,18 (d~llt), 357 (4,4), 472 (3,8) (581. 1525 4441
" 8.27 ld, IH)
IXe 2.41 7.92 (d. 2H). 7.28 "id.2H), 210 (4,7), 250 sh (4,5). 287 1738 (841. 1624 (741. 1533
7,66 (d, 2H).,7,23 (d~21t). (4,3), 356 (4,1), 480 (3.4) (55)
X 2,65 3,97 Is, 3H)#.1385 ls,3H) 2l O (4151, 288 (4,3), 316 (4,2), 1735 (82). 1384 1751. 1542
9 438 (3,71. 568 (3.5) (44)
Xl 2,36 7.48 (d,211).[2.61 {s,3H).:209 (4.7). 250 sh (4.61. 281 1650 (63). 157{} (3~). 1529
7,87 (d) 2H) ] 7,92 (s,~-F[-) .(4,8), 352 sh (3.6), 464 (3,1) (58)
XII 2,41 207 (4,4). 284 (4,0), 361 13,1), 1727 (851. 1595 (31). 1550
I 473 (2,7) (57)
I
 ~
I i i
'%!
i//it',. / I
7 r
5
KiA
[- <

f: i,~ "J !i\\,) <..< i)

t',X
!
"eL,It:
, 11-- , , .L_,,~.._~._._
300 4OO 500 70O A,nm 200 2~ 300 ~.00 500 700 A, nm

Fig. 1 Fig. 2
Fig. i. Electronic absorption spectrum (in CHaCN). Aromatization of l-p-
ferrocenylphenyl:2,6~dimethyl-3,5-diethoxycarbonyl-4-p-nitrophenyl-l,4-di-
hydropyridine (Ia) with l-oxo-2,2,6,6-tetramethylpiperidinium perchlorate
(VIII). i) Immediately after mixing of the reagents (Va); 2) after 45 min;
3) after 1 h and 30 min (IXa); 4) dication (XVIIIa); 5) ferrocenium perchlorate
(in 0.I N H2SO~).
FiE. 2~ Elehtronic absorption spectrum (in CH3CN). Aromatization of 4-ferro-
cenyl-l,2,6-trimethyl-3,5-diethoxycarbonylpyridine (III) with i-oxo-2,2,6,6 -
tetramethylpiperidinium perchlorate (VIII). i) Immediately after mixing of
the reagents (VII); 2) after 18 h; 3) after 46 h; 4) after 82 h (X); 5) dica-
tion XIX.

We have found that the Hantzsch ester II, obtained according to [9], can be easily
alkylated at the nitrogen atom with either methyl iodide or dimethyl sulfate under phase
transfer conditions with an equimolar amount of triethylbenzylammonium chloride (TEBAC) in
benzine-50Z NaOH s give compound III:

- H Pc R Pc
C2H~OOC.../,"~..jCOOC2H5 C2HsOOC~COOC2H~
tl II + (c~:):o, c,..t~o~ ..o~
CH~/'"~'/"'CH~ T~AC CH 3- "N- "CH 3

II Clt~
m

This newly discovered alkylation method is of preparative interest since it is well

documented that Hantzsch esters containing 3,5-diethoxycarbonyl groups undergo alkylation
at nitrogen with great difficulty and then only in the presence of strong bases, such as
sodium hydride [i0].
The UV, IR, and PMR spectra of the newly synthesized compounds I-III are fully consistent
with their proposed structures (Table 2). The electronic spectra of compounds la-e differ
from the spectra of N-substituted Hantzsch esters with analogous substituents [ii] only by
the presence of absorption bands due to the ferrocenyl ring at 330-350 nm and 460-470 nm.
The IR spectra of these compounds contain a set of intense bands in the 1500-1700 cm -l
region, which is characteristic of mixed ester functional groups, and also bands at 3100,
lll0, and 830 cm -l, which can be assigned to ferrocene-group absorptions [12].
Treatment of compounds I-III with triphenylmethyl perchlorate in acetonitrile resulted
in the formation of the 1,4-dihydropyridines V-VII, in which the ferrocene rings have been
oxidized to the ferrocenium cation stage:

889
 H. Fc + H .F 9
C!!3.~ /,COOC2Hs C2HsOOC~COOC2H 5 C2H500C~~ / C 0 0 C 2 H 5

i! Ii

ClO4- CH3" -COOCzH

s Ci04 C~3 ClO 4-
v a-e vl ~I:

We were unsuccessful in achieving aromatization of these substances using triphenyl-

methyl perchlorate, despite many attempts. The electronic spectra of compounds V-VII
formed in the above reactions are missing the bands in the visible region corresponding
to absorption by the ferrocene ring, and contain a new absorption maximumwhich is charac-
teristic of the ferrocenium cation (Figs. 1 end 2). The only salts which we were able to
isolate in the crystalline state corresponded to compounds VI end VII; the IR spectra of
these compounds were practically identical with those of the starting materials, namely
compounds II and III, with the exception of the appearance of a band due to the perchlorate
anion at 1100 cm "I, whereas their PMR spectra proved to be unresolvable as a consequence
of the presence of the paramagnetic ferrocenium cation. Salts VI and VII could be easily
reduced to their dihydropyridine precursors II and III with solutions of base or ammonia; this
is a well known [13] reaction of the ferrocenium cation. Salts Va-e were found to exist in
acetonitrile solution for a short time, although attempted isolation resulted in decomposition
and formation of iron salts.
Treatment of compounds I-III with 2,2,6,6-tetramethyl-l-oxopiperidinium perchlorate
(VIII) resulted in a variety of reaction paths: reactions involving compounds Ia-e and III
resulted in formation of the corresponding pyridinium salts IXa-e and X, whereas in the case
of compound II, containing an unsubstituted nitrogen atom, aromatization did not occur, and
salt VI was isolated:

It _
0 C]O~ CH~ CIO~.-
~ll IXa--e CIO,- X

The UV spectra of the pyridinium salts IXa-e differ from those of the dihydropyridine
precursors Ia-e with respect to the extinction coefficient of the absorption band at 250 nm,
which fs significantly "reduced (Table 2).
The structures of salts IX were confirmed by comparison of their spectral characteris-
itcs with those of salt XI, whose structure is known, and which was prepared by the re-
action of p-ferrocenylphenylamine with 2,4,6-trimethylpyrilium perchlorate:

L'H3

Y9

(;104-- XI

It was found that these salts exhibit UV absorption maxima at the same wavelength
(Table 2).
The PMR spectra of salts IXa-e do not contain signals due to the proton in the 4-position,
and the signals of the 2,6-methyl groups are shifted downfield (relative to their precursors>,
just as was found in the case of the PMR spectrum of XI, which further confirms their
structure (Table 2).
We note that, in contrast to the behavior of dihydropyridine derivative Ill, the
Hantzsch ester II containing an unsubstituted NH group could only be aromatized in the
presence of elemental sulfur, resulting in the formation of-4-ferrocenyl-2,6-dimethyl-3,5-
diethoxycarbonylpyridine (XII).

890
 V~
.,

ii -~- S CH~ NAcH3

Spectrophotometric study of the aromatization reactions of dihydropyridines I-III

revealed that preliminary oxidation of the ferrocene group to a ferrocenium cation occurred
in all cases to give the salts V-VII, and that the pyridinium portio n of the spectra did not
change at all during this stage; this indicates that intramolecular oxidation of dihydro-
pyridine rings by means of the fervocenium cations was not taking place. Further reaction
apparently involves oxidation of the dihydropyridine ring by means of excess perchlorate
salt VIII to give the dication diradical species XIII, which loses a proton and undergoes ~
either intramolecular or intermolecular [14] oxidation by the ferrocenium cation to generate
the final product of the reaction, compound IX:

CH3." /COOC~l 5 ClI3~._ /.COOC.H s

H -H

~-- >=/.. ". ~-- ~__

CH 3" "C00C2H ~ CH~ C00CzH ~
~II .%~"

Aromatization of the Hantzsch ester III occurs in an analogous manner. The presence of
an intramoleeular oxidation-reduction sequence ~n this reaction is supported by the observa-
tion that the UV spectrum of salt X, in addition to exhibiting a hypsochromic shift of the
ferrocene absorption at 438 nm, also displays a new maximum at 568 run, which can be assigned
to a charge transfer transition between the ferrocene group and the pyridinium ring (Fig.
2).
Fc "~
H FC t
C=H~00C~. COOt=IXs C- IlsO0 C.,.~,~,.../C OOC=Hs
@V~I
Ill ' :-- Vll

cH~ cH~
X~ XV[

A similar reaction pathway for aromatization of all of-the compounds I-III is reasonable
in light of the recently published data [15] concerning the mechanism of dehydrogenation of
a-hydrogen containing substituted ferrocenes using triphenylmethyi perchlorate.
Another reaction pathway involving intermediate formation of the dications XVII and
XVIII is possible; these dications would be expected to form in cases where oxidation of the
cation-biradicals XIV and XVI takes place not via the ferrocenium cations, but rather as
a consequence of the presence of excess oxoammonium salt VIII. The reaction products IX
and X could then be formed as a result of partial reduction of the dications XVII and XVIII
by means of either the starting materials I, III or the reaction media.

Fe~
CH-- .C00CZH 5
c:H:,ooc. ~1,...~/cooczH 5

C H 3 ) ~ ! ~ " CI13
XV'Ir CH 3
XVIII

_p
The authors of a study of the aromatization of ferrocene-containing anionic a-complexes
of trinitrobenzene [6] have postulated an analogous mechanistic path; they assumed that
reduction of the (initially) formed ferrocenium cation occurs by means of the u-complex
precursor. Spectrophotometric monitoring of our reactions indicated that the ferrocene
rings in the starting materials underwent oxidation immediately after mixing of the reagents
(Fig. 1, 2). Treatment of the salts IXa-e and X with equimolar amounts of the oxidant
VIII resulted in the formation of dications of strunture XVIII and XIX, according to their.
UV spectra; the dications proved to be unstable in air, but in acetonitrile solutions
these materials did not undergo reduction by the medium to give the salts IX and X even after
extended storage (Figs. i, 2).
 We have found that aromatization of ferrocene-cDntaining Hantzsch esters occurs via
an SET mechanism; the first step of the reaction involves oxidation of the ferrocenyl
fragment, and the probability of formation of the final reaction product depends on the
oxidizing ability of the aromatizing agent.

EXPERIMENTAL

IR spectra were recorded on a Specord 75-IR spectrophotometer using KBr pellets, UV

spectra were obtained on a SpecordUV-VIS spectrophotometer in acetonltrile solutions, and
PMR spectra were taken on a Bruker WH-90 spectrometer with HMDS as internal standard.
Sample puuities and the extent of reactions were followed by TLC analysis on Silufol UV-254
plates using chloroform-hexane--acetone (9:7:2) and iodine visualization. The properties of .
the newly synthesized compounds are reported in Tables 1 and 2.
p-Ferrocenylphenylamine was prepared according to [16], 2-formylferrocene according
to [17].

@-FerroEenylphenylazomethines IVa-g (General Method). A solution of I0 mmole of

p-ferrocenylphenylamine and i0 mmole of the appropriate aldehyde in 20 ml of ethanol was
refluxed for 1-2 h, cooled, and the precipitate was filtered and recrystallized from ethanol~
~-p-Ferr~ceny~pheny~-4-ary~(fury~)-2t6-dimethy~-3~5-dieth~xycarb~ny~-~t4-dihydr~pyridines
(la-e). These are prepared according to [8] by reaction of azomethines IVa-e with acetoacetic
ester. 4-Ferrocenyl-2~6-dimethy!-3~5-diethoxycarbonyl-lt4-dihydropyridine (II). This com-
pound was obtained according to method [9] by reaction of'2-formylferrocene with ethyl 6-
aminocrotonate in the presence of ammonium carbonate.
l~2~6-Trimethyi-4-ferrocenyl-3,5-diethoxycarbonyl-l,4-dihydroDyridine (III). A solu-
tion of i g (2 mmole) of compound II in 40 ml of benzene was treated with 0.46 g (2 n~nole)
of TEBAC, 15 ml of a 50% aqueous solution of NaOH, and 0.8 g (4 mmole) of dimethyl sdlfate.
The mixture was stirred for 2 h at 50-60~ and then an additional hour at room temperature;
the layers were then separated and the benzene layer was washed with saturated KCI solution,
water, and finally dried over MgSO~. The solvent was evaporated and the residue was recry-
stallizedfrom propanol. Yield, 0.81 g (82%), mp 142-1430C. Alkylation of compound II with
methyl iodide proceeded in an analogous manner. In that case the yield after 12 h reaction
time (heating and stirring) was 35%.
l-p-Ferrocen~iphenyl-4-aryl(furyl)-2~6-dimethyl-3~5-diethoxycarbonylpyridinium Per-
chlorate s (IXa-e)~ General Method. A solution of 0.24 mmole of oxidant VIII in 5 m l of dry
acetonitrile under an argon atmosphere was treated with 0.16 mmole of compound Ia-e and
stirred for i h to 1 h and 30 min at 20~ The reaction mixture was diluted with 150 ml of
dry ether, and the resulting precipitate of salt IXa-e was filtered and recrystallized from
dry methanol.
p-Ferrocenylphenyl-2,4~6-trimethylpyridinium Perchlorate (XI). A mixture of 0.4 g (1.8
mmole) of 2,4,6-trimethylpyrilium perchlorate and I g (3.6m mole) of p-ferrocenylphenylamine
in 20 ml of ethanol was refluxed for 1 h, cooled, and diluted with 50 ml of ether; the
resulting precipitate was filtered and recrystallized from propanol.
4-Ferrocenyl-l~2,6-Trimethyl-3~5-dieth0xycarbonylDyridinium Perchl0rate (X). A solu-
tion Of 0.ii g (0'44 mmole) of oxidant VIII in 3 ml of dry aces under argon was
treated with 0.i g (0.22 mmole) of compound III. The solution was heated to 50~ stirred
for 30 min, and then maintained at room temperature an additional hour prior to dilution with
i00 ml of dry ether; the resulting precipitate was filtered and recrystallized from dry
methanol.
4-Ferr0cenyl-2t6-dimethyl-3~5?diethoxycarbonylpyridine (XII) A mixture of 0.5 g
(1.2 mmole) of compound II and 0.12 g (3.6 mmole) of elemental sulfur was fused at 190-210~
and stirred (at this temperature) for 45 min, then cooled to room temperature and extracted
with petroleum ether. After. solvent removal and column chromatography on silica gel (with
chloroform-hexane--acetone (9:7:2) eluent) pyridine XII was isolated and subsequently re-
crystallized from methanol.
2,6-Dimethyl-3rS-diethoxycarbony!-l,4-dihydropyridine-4-ferrocenium Perchlorate (VI).
A solution of 0.15 g (0.44 mmole) of triphenylmethyl perchlorate in 3 ml dry acetonitrile
was treated with 0.19 g (0.44 mmole) of dihydropyridine II and stirred for 30 min; the

892
solution was filtered and 75 ml of dry ether was added. The resulting green crystals
were twice reprecipitated from acetonitrile with ether. Yield, 0.15 g (63%), flash
point 185-187"C. IR spectrum: 730 s, 810 m, 1020 m, 1100 vs, 1210 s, 1288 m, 1310 m,
1370 m, 1450 w, 1490 s, 1645 m, 1680 vs, 1700 s, 2940 w, 3110 m, 3430 s cm -l. UV spectrum,
Ima x (log E): 208 (4.4), 240 (4.3), 277 (3.8), 333 (3.5), and 644 nm (2.1).
l~2~6-Trimethyl-3,5-diethoxycarbonyl-l~4-dihydropyridine-4-ferrocenium Perchlorate
(VII). This was prepared in an analogous manner to that described above for compound VI
from 0.I g (0.22 n~nole) of compound III and 0.075 g (0.22 mmole) of triphenylmethyl
perchlorate. Yield, 0.06 g (50%), flash point I15-I16~ IR spectrum: 810 m, 970 w, i010
m, 1106 vs, 1207s, 1265 m, 1375 m, 1487 s 1545 m, 1585 s, 1647 m, 1700 vs, 2946 w, 3010 w cm -l UV
spectrum, 94 x (log E): 210 ( 4 , 5 ) , 242 ( 4 . 4 ) , 336 ( 4 . 0 ) , and 660 nm ( 2 . 9 ) .
Elemental analyses of compounds VI and VII could not be obtained due to their severe
detonating capacity.

LITERATURE CITED
I. Kh. Ya. LoDatinskaya, N. A. Klyuev, and A. K. Sheinkman, Khim, Geterotsikl. Soedin.,
No. ii, 1551 (1985~.
2. T. V. Stupnikova, Z. M. Skorobogatova, and A. K. Sheinkman, Khim. Geterotsikl. Soedin.,
No. 7, 946 (1979).
3. A. K. Sheinkman, V. A. Golubev, G. G. Vdovkina, and T. S. Chmilenko, Zh. Org. Khim.,
19, 2218 (1983).
4. T. V. Stupnikova, Z. M. Skorobogatova, A. K. Sheinkman, and V. A. Golubev, Dokl. Akad.
Nauk SSSR, Ser. B, No. 2, 144 (1978).
5. Z. M. Skorobogatova, V. A. Golubev, and A. K. Sheinkman, Khim. Geterotsikl. Khim.,
No. i, 78 (1981).
6. Mo I. Kalinkin, G. D. Kolomnikova, V. E. Puzanov, M. M. Gol'din, Z. N. Parnes, and
D. N. Kursanov, Izv. Akad. Nauk SSSR, Ser. Khim~ No. 8, 1852 (1977).
7. I. Omote, T. Komatsu,R. Kobayashi, and N. Sugiyams, Tetrahedron Lett., No. i, 93
(197~).
8. A. E. Sausin', B. S. Chekavichus, V. K. Lusis, and G. Ya. Dubir, Khim. Geterotsikl.
Soedin., No. 4, 493 (1980).
9. A~ E. Agronomov and Yu. S. Shabarov, in: Laboratory Methods inthe Organic Practicum
[inRussian], Khimiya, Moscow (1974), p. 212.
10. A. ~. Sausin', V. K. Lusis, G. Ya. Dubir, and Yu. I. Beilis, Khim. Geterotsikl. Soedin.,
No. II, 1508 (1978).
ii. I. Kuthan and A. Kurfurst, Ind. Eng. Chem. Prod. Res. Dev., 21, 191 (1982).
12. E. G. Perevalova, M. D. Reshetova, and K. I. Grandberg, in: M'--ethodsof Organometallic
Chemistry. Organoiron Compounds. Ferrocene, [in Russian] Nauka, Moscow (1983), p. 26.
13. Lo G. Abakumova, G. A. Abakumov, and R. A. Razuvaev, Dokl. Akad. Nauk SSSR, 220, 1317
(1975). "'
14. Ya. V. Ogle, Ya. P. Stradyn' and G. Ya. Dubir, Khim. Geterotsikl. Soedin. No. 9
1963 ( 1 9 8 0 ) . ' ' '

15. V. I. Boev and A. V. Dombrovskii, Charge Transfer Complexes, in: Ion-Radical Salts [in
Russian], Chernogolovka (1984), p. 133.
16. Ao N. Nesmeyanov, E. P. Perevalova, R. V. Golovnya, and L. S. Shilovtseva, Dokl. Akad.
Nauk, Set. Khim., 102, 535 (1955).
17. A- I. Titov, E. S. Lisitsina, and M. R. Shemtova, Dokl. Akad. Nauk., !30, 341 (1960).

8q~
SYNTHESIS AND SPECTRAL CHARACTERISTICS OF ACENAPHTHENE
DERIVATIVES OF BENZO[f]QUINOLINE

N. S. Kozlov, G. S. Shmanai, UDC 547.832.678.2:543.422'51

and Dang Ny Tai

The catalytic interaction of 5-acetylacenaphthene with arylidene-2-naphthylamines

leads to the formation of adducts to the C=N bond (aminoketones) or l-(5-acenaph-
thenyl)-3-aryl-(heteroaryl)benzo[f]qulnollnes. In several instances they are
accompanied by 1-(5-acenaphthenyl)-3-R-2-propen-l-ones or N-substituted 2-naphthyl-
amines. The ratio of the products depends on the condensation conditions and the
structure of the starting azomethine. Using the 3-(p-fluoropheny!)-substituted
derivative as an example, it has been shown that in the absence of dihydrogenating
agents ~-aminoketones undergo dehydrocyclization with formation of benzoquino-
lines and 1,2,3,4-tetrahydroquinolines.

Interest in the synthesis and properties of benzo[f]quinoline derivatives has been

occasioned by the possibilityof using them as complexing agents and biologically active
substances [i-3]. Condensation of 5-acetylnaphthene (I) with arylidene-2-naphthylamines or
with 6-[N-(2-naphthyl)-formylimidoyl]quinoline (II a-g) in ethanol in the presence of an
acidic catalyst allowed us to realize the synthesis of l-(5-acenaphthenyl)-3-aryl-3-(2-
naphthylamino)propan-l-one (IIIa) and l-(5-acenaphthenyl)-3-aryl(heteroaryl)benzo[f]quino-
lines (IV a-g).

--i O- CH3 +
~ 9
'~
N 7-"CII-R
~0 ~ Vla

iia-g
i'
100 ~, Ilia
H ~ ~\,,

~ NH-CH2-R
~ CO-CH=CH-R

iVa-g v c,g vl f~g

II--VI a R=4-FC,H4, b R~CeHs, c R-4-CICsH4, d R=4-BrC4H4. e R=4-CHsOC6H4,

f R=4"NO~C6H4, g R=6-quinolyl

8-Aminoketone IIIa, which is the first intermediate in the synthesis of benzoquinolines~

was obtained at room temperature. The heterocyclization of the adduct takes place during
condensation in the boiling solvent to yield up to 50% of benzo[f]quinolines IV (Table l).
The hydrogen generated during this process is partially consumed for hydrogenation of the
azomethine to give N-substituted 2-naphthylamines (V)o The target products are also
accompanied by ~,~-unsaturated ketones of the acenaphthene series (VI). In the case of
fluoro- and nitrobenzylidene-2-naphthylamines and 6-quinoline azomethine and in the presence

Institute of Physical Organic Chemistry, Academy of Sciences of the Belorussian SSR,

Minsk 220603. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. ii02-iI06~
August, 1986. Original ars submitted May 12, 1985.

894 -0009-3122/86/2208-0894512.50O 1987 Plenum Publishing Corporation

 TABLE i. Characteristics of l-(5-Acenaphthenyl)-3-arYl
(heteroaryl)benzo [f ]quinolines IVa-g

Found talc.
Co~l- mp, oC
~"
Molecular Yield
pound %
C,% ft. % N, % M+ formula C. % II, % N. % M

IVa 206--207 ; 3,4 425 C3tH2oFN 3,3 425 40

l~v.b 178--179 3,7 407 C31H2,N 5~2 3,4 407 26
IVc 256--257 84,5 4,8 3,2 441 C3,H2oCIN 84,3 4,5 3,2 441 49
IVd 265--266 3,0 486 C3tH2oBrNq 2,9 486 46
IVe 240--241 8 .2 5; 3,0 487 Ca2H2,NO J,9 5"~ 3,2 437 25
I%,f 309--310 82,4 4,7 6,0 452 C31H2oN202 82,3 4,4 6,2 452 9
IVg 230--231 89,3 5,1 5,9 458 Cz4H22N.~ 89,1 4,8 6,1 458 27

*Solvents for recrystallization: for IVa,f - dioxane, for

IVb-e, g -- benzene.
tFound: Br 16.3%. Calc: Br 16.4%.

of hydrochloric acid as catalyst, they are the predominant reaction products.

Formation of propen-l-ones (VI a,f,g) is possible as a result of hydrolytic cleavage
of 8-aminoketones. The ease of elimination of the amine can be explained by formation of
the energetically favorable conjugated electron system in the propenone molecule. In
order to suppress this competitive reversible process we added to the reaction mixture an
equimolar amount of 2-naphthylamine in the form of its hydrochloride. This allowed us to
lower the yield of the 6-quinolyl-substituted propenone VI E from 60 to 4%.
In the case of fluoro- and nitrophenyl derivatives Via,f, the effect of 2-naphthylamine
hydrochloride has not been detected. Moreover, it has been found that upon refluxing of 8-
aminoketone IIIa for 3 h in the presence of hydrochloric acid only benzoquinoline IVa and
its 1,2,3,4-tetrahydro derivative (VII) were formed; the cleavage products of aminoketone
have not been detected. This indicates that =,~-unsaturated ketones with electron-withdrawing
substituents (Via,f) constitute products of the aldol condensation of 5-acetylacenaphthene
with the aldehydes formed during the hydrolysis of azomethines in the acidic medium.
Formation of tetrahydrobenzoquinoline VII, along with heteroaromatic compound IVa, should
be explained by the disproportionation of the product of dehydrocyclization of the amino-
ketone, 3,4-dihydrobenzoquinoline (DH), in the absence of a dehydrogenating agent. This is
in accord with the available literature data [4, 5].

It"
Ilia --re.-
-H20

Dtt Vl|
Iv, a

The structure of the obtained compounds was proven by IR, UV, PMR, and mass spectra,
as well as by elemental analysis (Tables 1 and 2). Thus, the IR spectra of synthesized
products contain absorption bands of C-C and Cad bonds of the aromatic rings in the region
of 1600-1590 and 3100-3000 cm -I. The methylene groups of the acenaphthene substituent
give an absorption band at 2930 can-z. The spectrum of compound IIIa has strong bands of the
stretching vibrations of the CO and NH groups. These bands are absent in the spectra of the
final reaction products, benzo[f]quinolines IVa-g. IR spectrum of the tetrahydro derivative
VII manifests absorption of the NH group.
The mass spectrum of aminoketone IIIa contains besides the molecular ion (M+) intensive
peaks of the CI2HeCO +, [Cz2HeCOCHa]+ [C12H9]+, [Cz0HTNH2] +, ions and the peak of the maximal
intensity corresponds to the [CIoHTN = CHR] + .ion.

895
 TABLE 2. PMR Spectra of l-(5-Acenaphthenyl)-3-aryl(hetero-
aryl)benzo[f]quinolines IVb-g (CDCIs solutions)
~r a~

7" N 2"

7 6

3"- H

i
i
~Vb~ 7,87t 8,19[ 8,00l 7,8017,34]6,931 7.60 3,55 7,28
(6,8)
7,21 t 7,10 8,21 7,41tt
' I (9,2)l (9,2)l (7,8)1 I I (8,8) (8,4) ~6,8)
lye 7,841 8,17l 8,O2l 7,8~17,3916,97l 7,59 3,55 7,45d 7,4g 7,32 7,08 7,47 8,18m
; [ (9.2){ (9.2) I (7,8)1 I I (8,8) (6,9) (6,9) (6,9) (7,5)" , (8,4)
IVd ,7,86t 8,181 8o21 7,8717,4116,97l 7.60 3,57 7,46cl 7,50 7,33 7,27t 7,I0 7,63 8,20m
i (9.3)l (9.3)1 (7,8)1 I I (8,9) (6,9) (6,9) (6,9) (8,4)
IVY.i- 17,811 8,161 8,o81 7.82i7,3516,95t 7.58 3,5.~ ?,44d 7,48 7,29 7,13 7,02 8,18m
I (9,3)1 (9,3)1 (7,7)l ] I (8.7) (6,8) (6,8) (6,8) (7,6) (8,4)
IVf 7,94t 8,20f 8,08[ 7,8817,3717,00~ 7,63 3,57 7,47 7,51 7,33 7,26m 7,08 8,37 8,43m
l(9,2)1(9,2)1 (7,8)1 I I (8,8) (6.8) (6,8) (8,5)
IVg :l: 18,02l 8,18l 8,01l 7,8317,3816,951 7,64 3,51 7,43d 7,49 7,29 7,23 t 7,12
; 1(9'2)1(9'2)[(7'7)[ [ I (8'8) (6,8) (6,8) (6,7) (7,6) (8,4)

~3'-H, 4'-H, and 4"-H protons give a multiplet centered at 6

7 . 4 6 ppm ( 3 H ) .
%Signal of the methoxy group: 3 . 8 8 ppm (3H, s , CHs).
r of the protons of the quinolinyl substituent: 8.90
(IH d of d, 2"-H)~ 8.65 (IH, d, 8"-H); 8o63'(IH, s, 5"-H); 8.23
(2H, m, 4"-H, 7"-H)'; and 7.36 ppm (IH, m, 3"-H).

In mass spectra of l-(5-acenaphthenyl)-3-R-benzo[f]quinolines IVa-g t h e M + p e a k s are

of highest intensity. There are also less intensive peaks indicating fragmentation of the
para substituents in the phenyl ring, and peaks o f [ M - R] + ions. UV spectra of compounds
IVa-g are similar to the spectra of l-aryl-3-R derivatives of this series [6, 7]. They
represent a system of three absorption bands: ~ (253-270 nm), p (283-289 nm), and a (317-
370 nm). The vibrational structure of the e-band is somewhat smoothened.
PMR spectrum of benzoquinoline IVe has a singlet of the methoxy group protons at 6
3.88 ppm, a multiplet at 3.50-3.60 ppm formed by the methylene protons of the acenaphthene
'ring, and signals of the aromatic protons in the region 6.95-8.18 ppm (16 H). The presence
of the only singlet in this region at 7.81 ppm and two doublets at 8.08 and 8.16 (J = 9.3
Hz) resulting from the resonance of 6-H and 5-H protons indicates the 1,3-disubstituted
angular structure of the benzoquinoline ring. The two doublets at 7.58 (J = 8.7 Hz), 7.82
ppm (J = 7.7 Hz) and two multiplets centered at 6.95 and 7.35 ppm were assigned to the signals
of 10-H, 7-H, 9-H, and 8-H protons, respectively. The protons of p-substituted phenyl ring
form two symmetric multiplets at 7.02 (2"-H, 6"-H) and 8.18 ppm (3"-H, 5"-H). The 3'-H
and 4'-H protons of the acenaphthene ring give two doublets with 6 7.44 and 7.48 ppm (J = 6.8
Hz). They 7'-H proton forms a triplet centered at 7.24 ppm which interacts with doublets at
7.13 (8'-H, J = 8.4 Hz) and 7.29 ppm (6'-H, J = 6.8 Hz)~ Other acenaphthene derivatives
of benzo[f]quinoline have analogous spectra and, consequently, also analogous structure
(Table 2)~
In the PMR spectrum of tetrahydrobenzoquinoline VII, besides a complex multiplet of aromatic
protons in the region.of6.96-8.25 ppm and two multiplets centered at 3.33 and 3.35, formed
by the methylene protons of the acenaphthene substituent, there are in the strong field
signals of five additional protons. The aliphatic protons of the hydrogenated benzoquino-
line ring give four multiplets centered at 2.25, 2.82, 3.58, and 4.47 ppm. A broad singlet
at 5.45 ppm is attributed to resonance of the amino proton.

Rq6
 The structure of tetrahydro derivative VII is confirmed by its mass spectrum, which
shows intensive M + peaks (maximum) and [M-H] +, as well as peaks of the fragments formed
as a result of elimination of the acenaphthene and fluorophenyl substituents. Cleavage
of the hydrogenated heterocycle leads to the formation of C12HeCH 2, [CHI2HgCH=CH2] +" ,
FCsH4CH2 + and [FCsH~CH=CH2] +" ions. The intensity of the secondary ions is low.

Mass spectra of the secondary amines Vc,g and propenones Vla,f,g exhibit peaks of the
molecular ion and a number of fragments confirming the structure of these substances.

EXPERIMENTAL

IR spectra were taken on a DR 20 spectrophotometer in KBr pellets. UV spectra were

recorded on a Specord UV-vis instrument in ethanol. PMRspectra were taken on a Varian
MAT-311 instrument with direct insertion of the substance into the ion source with the
ionizin E electrons enery of 70 eV. The purity of individual compounds was controlled by TLC
on alumina (II activity grade) in benzene. The plates were stained with iodine.
l-(5-Acenaphthenyl)-3-(p-fluorophenyl)-3-(2-naphthylamino)propan-l-one (IIIa) and l-(5-
acenaphthenyl)-3-(p-fluorophenyl)-2-propen-l-one (Via). To a solution of 1o0 g (5 mmole) of
5-acetylacenaphthene (I) in i0 ml of ethanol was added a solution of 1.25 g (5 mmole) of
azomethine IIa in 40 ml of ethanol and 0.9 g (5 mmole) of 2-naphthylamine hydrochloride.
The mixture was left for 7 days at room temperature. The precipitate was filtered off,
neutralized with NH~OH, washed with aqueous ethanol, with ether, and then air dried.
Yield of aminoketone IIIa was 0.55 g (25%), mp 175-176~ (ethanol-benzene, i:i). IR spectrum:
1650 (CO), 3380 cm-* (NH). Mass spectrum,*m/z (intensity, %): 445 (2), 250 (38), 249 (i00),
248 (75), 196 (90),'182 (20), 181 (96), 153 (37), 152 (30), 143 (36), 127 (25). Found:
N3.0%, M + 445. C~H2~FNO. Calculated: N 3.1%, M 445. The mother and ether solutions
were evaporated to 10 ml to obtain 0.6 g (40%)of propenone Via. mp 96-97~ (hexane). IR
spectrum: 1655 cm -I (CO)o Mass spectrum, m/z (%): 302 (100), 273, 274, 207, 181, 153,
152, 149, 86, 57, 56. C21HIsFO. Calculated: M 302.
1 - (5-Acenaphthenyl) - 3- (6- quino lyl )benzo[ f Iquino line (IV~ ), N- (6-Quino lyl-methyl )-2-
naphthylamine (V~). and(l-(5-Acenaphthenyl)-3-(6-quinolyl)-2-propen-l-one (rig). A mixture
of 1 g (5 mmo!e) of compound I, 1.41 g (5 mmole) of azomethine IIg, 0.9 g. (5
mmole) of 2-naphthylamine hydrochloride, 30 ml of ethanol, and drops of nitrobenzene
were refluxed for 3 h. After 24 h the crystals were separated and worked up as described for
compounds IIIa and Via, washed with ether and ethanol (5 5 ml), and recrystallized from
benzene to give benzoquinoline IVg. The benzene filtrate was diluted with ether (I:i) to
yield 0.07 g (4%) of propenone VIg. mp 158-160~ (benzene). IR spectrum: 1655 cm -l (CO).
Mass spectrum, m/z (%): 335 (97), 334 (61), 307 (44), 306 (55), 207 (42), 182 (51), 181 (62),
167 (59), 153 (97), 152 (100), 127 (50). Found: C 85.7; H 6.6; N 4.0%; M + 335. C24H~TNO.
Calculated: C 85.9; H 6.3; N 4.2%; M 335. From the mother and-~icohol-ether solution
0.15 g (10%) of amine Vg was isolated, mp 148-149~ (ethanol). IR spectrum: 3420 cm -l
(NH)~ Found: C 84.1; H 5.9; N 9.7%; M + 2 8 4 . C20HI6N2. Calculated: C 84.5; H 5.6;
N 9.9%; M 284.
1-(5-Acenaphthenyl)-3-(p-nitrophenyl)benzo[flquinoline (IVf) and l-(5-acenaphthenyl)-3-
(p-nitrophenyl)-2-pro~en-l-one(VIf), were obtained analogously. From the precipitate was
washed out 0.9 g (55%) of propenone VIfo mp 175-176~ (acetone). IR spectrum: 1658 (CO),
1520, 1343 cm -z (NO~). Mass spectrum, m/z (%): 330, (39), 329 (100), 301 (35), 207 (13),
182 (16), 181 (91), 154 (18), 153 (78), 152 (70) 151 (21), 141 (18). Found: C 76.8; H 5.1~
N4.0%; M + 329. C21HzsNO 3. Calculated C 76.6; H 4.9; N 4.2%; M 329. The precipitate,
benzoquinoline IVf, which is insoluble in alcohol, was recrystallized from dioxane~
Using conc. HCI as catalyst (5 drops) under analogous conditions benzoquinolines IVb-e
and N-(p-chlorobenzyl)-2-naphthylamine (Vc) were obtained. Yield of amine Vc 0.14 g (ii%),
mp I04-I05~ (ethanol), M + 267 [8]. Propenones VIf,g under these conditions were obtained
with 62 and 60% yield, respectively.
*The molecular ion peak and i0 most intensive peaks are reported here and in the following
procedures.

897
 Heterocyclization of l-(5-Acenaphthenyl)-3-(p-fluorophenyl)-3-(2-naphthylamino)propan?
1-one (Ilia). To a solution of 1 nmlole of compound IIIa in I0 ml of ethanol was added 5
drops of conc. HCI. The mixture was refluxed for 3 h, cooled and worked up as described
for compounds IIIa and Via. The precipitate was separated, worked up, and recrystallized
from benzene to yield 0.17 g (42%) of l-(5-acenaphthenyl)-3-(p-fluorophenyl)-l,2,3,4-
tetrahydrobenzo[f]quinoline (VII). mp 226-227"C (benzene). IR spectrum: 3420 cm -z (NH).
NMR spectrum : 2.25 (IH, m, 2-H); 2.82 (IH, m, 2-H), 3.33, 3.35 (2 x 2H, m, I'-H, 2'-H);
3.58 (IH, m, I-H); 4.47 (IH, m, 3-H); 5.45 (hr. s, NH); 6~ ppm (15H, m, aromatic
protons). Mass spectrum, m/z (%): 430, 429 (i00), 428, 328, 320, 306, 304, 276, 274, 262,
250. Found: N 3.1%; M + 429. C~IH2~FN. Calculated: N 3.3%; M 429. After evaporation of
the mother liquor benzoquinoline IVa was obtained~ It was washed with alcohol and ether,
and recrystallized from dioxane. NMR spectrum: 3.51 (4H, m, I'-H, 2'-H), 6.93-8.19 ppm
(16H, m, aromatic protons).

LITERATURE CITED

i. A. P. Adamovich, M. Vildenkhain, A. A. Verezubova, and A. L. Gershuns, Izv. Vyssh. Uchebn.

Zaved., Khim, Khim. Tekhnol., 19, 1527 (1975).
2. W. -S. Chen, G. H. Cocolas, C. G. Cavalito, and K. G. Chai, J. Med. Chem., 20, 1616
(1977).
3. N. S. Kozlov, I. G. Shcherbak, O. D. Zhikhareva, F. A. Tugusheva, G. S. Shmanai, A. I.
Kulikova, V. A. Serzhanina, L. A. Romanchuk, Ro D. Sauts, and K. N. Kovalevich, Izv.
Akad. Nauk BSSR, Ser. Khim. Nauk, No. I, 74 (1982).
4. F. Andreani, R. Andrisano, G. Salvadory, and M. Tramontini, J. Chem. Soc., C, No. 5,
I007 (1971).
5. V. N. Gogte, M. A. Salama, and B. D. Tilak, Tetrahedron, 26, 173 (1970).
6. N. S. Kozlov, L. F. Gladchenko, V. A. Serzhanina, G. V. Vorob'eva, O. D. Zhikhareva, G.
S. Shmanai, and R. D. Sauts, Khim. Geterotsiklo Soedin., No. 9, 1237 (1977).
7. N. S. Kozlov, G. S~ Shmanai, and L. F. Gladchenko, Izv. Akad. Nauk BSSR, Ser. Khim. Nauk,
No. I, 52 (1983).!
8. N. S. Kozlov, O. Do Zhikhareva, E. I. Andreeva, N. G. Rozhkova, and S. S. Kuk.alenko,
Izv. Akad. Nauk BSSR, Set. Khim. Nauk, No. 2, 59 (1985).

898
THREE-DIMENSIONAL STRUCTURES OF STEREOISOMERS OF 2-PHENYL-
4-ETHYNYLDECAHYDRO-4-QUINOLINOL

S. G. Klepikova, L. P. Krasnomolova, UDC 547.831.3:541.63:543.422

O. V. Agashkin, O. T. Zhilkibaev,
K. D. Praliev, and D. V. Sokolov

The three-dimensional structures of four stereoisomers of 2-phenyl-4-ethynyldeca-

hydro-4-quinolinol were determined by PMR and IR spectroscopy. The IR spectra
of axial alcohols with an axial ~ substituent provide evidence for the existence
of two equilibrium forms in solution.

Four stereoisomers of 2-phenyl-4-ethynyldecahydro-4-quinolinol (I-IV) were isolated

in the ethynylation of the = and V forms of 2-phenyldecahydro-4-quinolinone [i]. The con-
figurations of the starting amino ketones consist of trans-fused rings with an axial phenyl
group for the = form and an equatorial phenyl group for the y form ~2].
In establishing the structures of the alcohols one must know the orientations of the
substituents attached to the C(2 ) and C(~) atoms as well as the way in which the rings are
fused. The orientation of the phenyl group was determined from the vicinal spin-spin
coupling constants (SSCC) of the 2-H and 3-H protons. The orientations of the substituents
attached to the C(4) atom in the epimeric pair of alcohols I and II were established from
the frequency of the stretching vibrations of the OH group [3] and the position of the signal
of the proton of the ethynyl group [4]. In alcohols III and IV the orientation of the
hydroxy group was found from the change in the chemical shifts of the protons of the piper-
idine ring when chloroform was replaced by pyridine [5, 6]. The ring fusion was determined
from a n analysis of the spin-spin coupling (SSC) of the angular protons with the adjacent
protons.
The PMR and IR spectra of I-IV are presented in Table i. The signal of the 2-H proton
in the spectra of all of the alcohols is located separately from the other signals, and this
makes it possible to easily determine the vicinal constants, from the values of which one
can form a judgment regarding the orientation of the substituent attached to C(2 ) atom.
The results obtained indicate an equatorial orientation of the phenyi group in alcohols I,
II, and IV and an axial orientation of the phenyl group in alcohol III.

~. _ ~. ~ ~"~,._i~, "~ ~"-~ o

z o~ n ~cH m ~

All of the alcohols except IV retain the conformations of the starting ketones. This
is confirmed by the fact that in the spectra of trans-fused decahydroquinolinols I-III the
signal of the 9-H proton is observed in the form of a triplet (i0.0 Hz) of doublets (-3.5 Hz).
The multiplet of the proton in the spectrum of alcohol IV is a doublet (12.0 Hz) of triplets
(4.0 Hz). The existence of one large constant corresponding to coupling of the trans-

Institute of Chemical Sciences, Academy of Sciences of the Kazakh SSR, Alma-Ata 480100.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1107-1110, August 1986.
Original article submitted May 15, 1985.

0009-3122/86/2208-0899512.50 0 1987 Plenum Publishing Corporation 899

 TABLE i. PMR and IR Spectra of I-IV
r ,

SoIveBt 2-H 3.11a 3-H, C~CH 9-H Ph 3.Ha [3. He

]3"He ] CIII-1 "

(CDa)~C----OI 4,05 ] 1,90 [ 2,07 ] 2,74 I 2,78 7,28 , II,0 3,1~ 13,0
CsD~N ] 4,23 i 2,(}8 ] 2,,19 ] 3,37 ] -- 7,26 II,5 2,6 12'5 3618 {16)
(CD3)~C----O| 3.99 ] 1.64 ] 2.97 ] 2,96 ] 2.61 7.28 11.5 2,(; 12.5
I CsDsN [ 4.29 ] 2.46 [ 2.95 ] 3,17 ] 3,16 -- 6,2 2.2 14,0
CDCI3
A~ t[ 4,23
0.06 [] 2,35
0,11 ]] 2,70
0,2,) [I 2,35
0,82 [] 0,31
2,8,5 7,27 6,0 2,2 I[ 14,5 3616 3588 (16)
128)
IVC~D.~ 14,47 [ 2,08, 2,19, 2.71 [3,15 .~,7 4-~ ] ] (25)
CDCI~ [ 4,25 ] 2.00 | 2,00 ] 2,35 , 3,11 7;7 I 7,0 ] 7,0 " 13-~-,5 3616
A6 I 0,22 / 0,08 / 0,19 ]0,36 10,04 -- --

oriented 9-H and 8-H a protons and of two identical constants (4.0 Hz) indicating coupling
of the 9-H and 8-H e and 9-H and 18-H~protons in the gauche frapents means that the 9-H
proton in IV is axially oriented with respect to the carbocycle and equator!ally oriented
with respect to the heteroring. The 10-H proton should consequently be equator!ally
oriented relative to the carbocycle and axially oriented relative to the heteroring.
The constants that we found provide evidence for cis fusion of the rings in IV. The correct-
ness of the assignment of the multiplet to the 9-H proton is confirmed by the fact that in
the spectrum of alcohol IV it is located at weak field as compared with the other signals,
except for the signals of the 2-H and phenyl ring protons, as well as by the. fact that in
t h e c a s e of protonation of this alcohol this multiplet and the quartet of the 2-H proton
experience the greatest weak-field shifts.
Thus alcohol III with an unchanged configuration is formed from trans-2-phenyldecahydro-
4-quinolinone, which has an axial phenyl group. The formation of cis-alcohol IV from the u
ketone is evidently explained by its isomerization to the B ketone with cis fusion of the
rings (see the scheme) under strongly alkaline ethynylation conditions.
The vicinal constants that we found indicate that alcohols I and II obtained from the
y-keto amine differ only with respect to the orientation of the substituents attached to the
C(4 ) atom. The orientation was determined by using the following rules for the epimeric
pair of alcohols: the frequency of the stretching vibrations of an axial OH group is 2-7 cm -I
higher than that of an equatorial OH group [3], and the proton of an axial ethynyl group
resonates at weaker field by 0ol-0.2 ppm as compared with the proton of an equatorial "
ethynyl group [4]. The differences in the frequencies of the vibrations of the OH group
and the chemical shifts of the ethynyl protons make it possible to conclude that the OH group
in alcohol I is axial~ whereas the OH group in alcohol II is equatorial.
The determination of the orientation of the hydroxy group in alcohols III and IV,
which are not an epimeric pair, was made from the change in the chemical shifts of the 2-H
and 3-H protons when the solvent was replaced. It i s k n o w n that in the case of an axial
orientation of the OH group the deshielding of the axial 2-H proton by pyridine relative
to chloroform is 0.2-0.4 ppm. The deshielding of the 3-H proton vicinally oriented relative
to the hydroxy group is greater, the smaller the dihedral angle between them. The changes
observed in the PMR spectra when the solvent is replaced are due to anisotropy of the magnetic
susceptibility of the pyridine ring, which is oriented in a definite way relative to the
dissolved alcohol molecule as a consequence of the formation of an OH...N intermolecular
hydrogen bond [5, 6]. On the basis of these indications and the A6 values (Table i) it may
be concluded that the OH group in alcohols III and IV is axially oriented.
The signal of the 9-H proton should experience the same changes as the signal of the
2-H proton when CDCIa is replaced by CsDsN under the condition that both protons have the
same orientation relative to the plane of the piper!dine ring. In fact, the axial 9-H
proton in III, like the 2-H proton in IV, experiences significant deshielding, while de-
shielding of the equatorial 9-H proton in IV, like the 2-H proton in III, is not very large.
This method of determining the orientation of the hydroxy group could not be applied to
alcohols I and II because of their limited solubility in chloroform.

900
 We obtained additional information regarding the orientation of the OH group, its
interaction, and the existence of rotational isomers in solution by studying the IR spectra
of these compounds and drawing upon the literature data. One narrow absorption band,
which is characteristic for a free hydroxy group, is observed in the spectra of dilute
solutions of alcohols I and II in CCI~ in the OH region. In addition to this band, the
spectra of alcohols III and IV contain an additional band, which appears in the form of a
shoulder in the spectrum of III, whereas in the spectrumof IV it merges with.theprincipal
band to form a slightly broadened band with one maximum. The appearance of a second band
constitutes evidence that two equilibrium forms exist in solution; their relative amounts
do not depend on the concentration but are determined by intramolecular forces and the
nature of the solvent.
The same thing was observed in a study of the three-dimensional structures of the
stereoisomers of 2-(2-furyl)-4-ethynyldecahydro-4-quinolinol (V) and its N-methyl derivative
(VI), as well as l-methyl-2-(2-furyl)-4-ethynyl-6-phenyl-4-piperidinol [7]. Two
absorption bands, which are 45 cm -I apart, are observed in the spectra of these alcohols
with diaxially oriented OH and furyl groups. The half width of the additional band is 38
cm -I, while the half width of the band of a free hydroxy group is 16 cm -l. The relative
intensities of these bands do not change upon dilution of the solution but depend on the
substituents in the molecules and the solvent. Thus the intensity of the additional band
increases sharply in the spectrum of N-methyl derivative VI. As compared with CC14,
chloroform stabilizes the form responsible for the low-frequency absorption. On the basis
of these data it was assumed that the additional band arises as a result of the formation
of an intramolecular hydrogen bond between the OH group and the ether oxygen atom of the
furyl group.
An explanation of the appearance of two or several bands in the VOH region in the
spectra of dilute solutuions of the alcohols is given in the literature. For example, the
complex absorption in the spectrum of the 8 isomer of l-benzyl-4-methyl-3-phenyl-3-piperidinol
is ascribed to stretching vibrations of an OH group included in intramolecular interaction
with the unshared pair of electrons of the nitrogen atom (broad band at 3480 cm -l) and the
electrons of the phenyl ring (narrow band at 3600 cm -I) [8]. The complex band, the half
width of which does not exceed 30 cm -I, in the spectra of axial and equatorial tertiary
cyclohexanols [9, I0] is associated with the phenomenon of retarded rotation of the hydroxy
group about the C-O bond. It was shown that the absorption depends on the presence of alkyl
substituents in the ~, 6, and y positions and their orientation~ To determine the number of
rotational isomers and their percentages the complex band was separated into components;
it was assumed that the molar absorption coefficients were the same for the three possible
rotamers. It was found that only two rotamers can exist in solutions of axial alcohols
with an axial ~ substitutent.
Thus taking into account the possibility of retarded rotation of the OH group about the
C-O bond and its participation in the formation of relatively weak intramolecular hydrogen
bonds with the heteroatoms or ~ systems, one can understand the complex character of the ab-
sorption of the OH group in the IR spectra of alcohols III and IV and compounds that we have
previously studied [7].
The two partially overlapped bands at 3616 (&v$ = 16 cm -z) and 3588 cm -I (&v89 = 28
cm -l) in the spectrum of III, in which the hydroxy ~nd phenyl groups are axial, can be
ascribed to the absorption of a free OH group and an associated OH group included in an
intramolecular hydrogen bond with the ~ electrons of the phenyl ring. The simultaneous
presence of two bands indicates that the energy of formation of this bond is insufficient
for the realization in solution of one rotational isomer. Let us note that the half width
of the absorption band of the associated hydroxy group is greater than the half width of
the absorption band of the free hydroxy group and that its shift relative to the unassociated
hydroxy group is 28 cm -l
The symmetrical band with one maximum at 3616 cm -I (&v89 = 25 cm -l) in the spectrum of
cis-fused alcohol IV with an axial OH group and an axial C(s)--C(8) bond relative to the
plane of the piperidine ring can be thought of as the superimposition of two closely
located bands with &v! = 16 cm -I. Their appearance is due to the absorption of an un-
associated OH group i~ two nonequivalent rotamers. The nonequivalence arises as a result of
the presence in the V position of an axial C(0 ) - C(8)bond of the carbocycle.

901
 The two bands in the VOH region in the spectra of axial alcohols with an axial furyl
substituent in the y position can be ascribed to the existence in solution of two rotamers,
one of which is stabilized by an intramolecular hydrogen bond of the OH...O type. In this
case the shift of the low-frequency band_and its half width are greater than for the OH group
included in a bond of the OH...~ type.
Consequently, certain rotamers of the three that are possible as a result of the
action of intramolecular forces and the effect of the solvent are realized in each specific
case. In ascertaining the reasons for the complex absorption in the VOH region it is de-
sirable to bring in not only the frequencies of the stretching vibrations of the OH group
but also the half widths of the bands, since intramolecular interactions of the hydrogen
bond type lead to broadening of the bands.

EXPERIMENTAL

The PMR spectra were obtained with a Tesla BS-487C spectrometer (80 MHz). The assign-
ment of the signals was made by means of spin decoupling. The IR spectra of dilute solutions
of the alcohols (c 5-I0-3-I'i0 -~ mole/liter) in CCI~ were recorded with a UR-20 spectrom-
eter in the VOH region.

LITERATURE CITED

I. Oo T. Zhilkibaev, in: Youth and Scientific-Technical Progress. Sun,naries of Papers

Presented at the Conference of Young Scientists of the Academy of Sciences of the Kazakh
SSR, Alma-Ata [in Russian], Nauka (1986), p. 26.
2. Oo T. Zhilkibaev, K. D. Praliev, V. B. Rozhnov, and D. V. Sokolov, Izv. Akado Nauk Kaz.
SSR, Sero Khimo, No. 2, 81 (1984).
3. E. L. Eliel, N. Allinger, So J. Angyal, and T. Morrison, Conformational Analysis,
Wiley (1965).
4. Ao P. Logunov, L. P. Krasnomolova, Yu. G. Bosyakov, O. V. Agashkin, and B. M. Butin,
Izv~ Akado Nauk Kaz. SSR, Sero Khim., No. 3, 55 (19810.
5. P. V. Demarco, E. Farkas, D. Doddrell, B. L. Mylari, and E. Wenkert, J. Am. Chem. Soc.,
90, 5480 (1968).
6. L. P. l~casnomolova, S. G. Klepikova, Oo V. Agashkin, E. D. Praliev, M. Z. Esenalieva,
and S. A. Tarakov, Zh. Fiz. Ehim., 58, Noo 10, 2957 (1984).
7. Oo V. Agashkin, S. G. Klepikova, L. P. Erasnomolova, K. D. Praliev, V. E. Yu. T. M.
Mukhametkaliev, M. E. Eskairov, and D. Vo Sokolov, Izv. Akad. Nauk Kaz. SSR, Ser.
Khim., No. i, 73 (1985).
8. M~ A. Iorio, P. Ciuffa, and G. Damia, Tetrahedron, 26, 5519 (1970).
9. I. H. van der Maas and E. T. G~ Lutz, Spectrochim. Acta, 38A, 927 (1982).
i0. E. T. G. Lutz, and I. H. van der Maas, Spectrochim. Acta, 37A, 693 (1981).

902
INVESTIGATION OF THE ACID- AND BASE-INDUCED TRANSFORMATIONS
OF NITROGEN HETEROCYCLESBY NMR SPECTROSCOPY.
I. SUBSTITUTED PYRIDINES AND PYRIMIDINES

V. P. Lezina, M. M. Kozlova, UDC 543,422.25:547.821'823:541.65

S. B. Gashev, A. U. Stepanyants,
and L. D. Smirnov

The principles of the changes in the chemical shifts of the protons of substituted
pyridines, pyrimidines, 3-hydroxypridines, and 5-hydroxypyrimidines as a function
of the basicity of the medium were investigated. The ionization constants and the
possible forms of existence of the molecules were determined. The character of
the effect of substituents (alkyl and hydroxy groups) on the basicities of the in-
vestigated compounds was ascertained. A spectral parameter that correlates satis-
factorily with the pK a values is proposed.

Continuing our investigation of the physicochemical properties of nitrogen heterocycles

[i-3], we studied acid- and base-induced transformations in the pyridine and pyrimidine
series. As the subjects of our investigation we selected pyridine (I), 3-hydroxypyridine (II)
pyrimidine (III), 5-hydroxypyrimidine (IV), and their methyl derivatives.

a N " "

R= nI ~ R'
*, II ~I, IV

I--IV a R'~R2=-RS=H; b R'=CHa, R2=Ra=H; I c R,=Ra=CHs, R2=H; II CRS=CH~,

RX=R2=H: d RI=R2=CHa, R~=H; eRI=R~=Ra=CHa; Ill c RI=R~=RS=CH~; IVc
RI=R~=CHa, Ra==H; d R'=R~=Ra---CHa; I, Ill X=H, II, IV X=OH

Depending on the pH of the medium, I-IV can exist in cationic (C) and neutral (N) forms. _
Ionization of the OH group in azines II and IV under alkaline conditions leads to the
formation of an anionic (A) form. In addition, the presence of a hydroxy group in the ring
does not exclude the formation of a dipolar form [I, 3]. In strongly acidic media (the H 0
region) III and IV are present in the form of dications (DC).

--H -H ~ -H'
DC
+H" .I~+ +H"

pKJ pK2
Up until now, virtually no information on the acid-base equilibria of methyl-substituted
II and IV in aqueous media has been available. In the present research we examined the
dependences of the chemical shifts (CS) of the ring protons and the protons of the CH a
groups on the pH values of aqueous solutions (D20/D2SO~) and, for III and IV, on the H 0
vaSues of the media. This made it possible to estimate the ionization constants (pK~',
pKa l, and PKa2), the CS of the protons of various forms (6DC , 6C, ~N, and 6A) , and the
limits of their transition (Table i). A comparison of the character of the dependences of
the CS of the protons on the acidity of the medium for azines I-IV, as well as an analysis
of the relative changes in the CS (&6DC_C, A6C_N, and A6N_A) , the spin-spin coupling con-
stants (SSCC) of the ring protons, and the CS of the methyl groups on passing from the N to
the C or A form of the molecule, enabled us to ascertain the character of the effect of

Scientific-Research Institute of Pharmacology, Academy of Medical Sciences of the

USSR, Moscow 125315. Institute of Chemical Physics, Academy of Sciences of the USSR,
Moscow 117977. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. IIii-
1117, August, 1986. Original article submitted April 23, 1985.

0009-3122/86/2208-0903512.50 0 1987 Plenum Publishing Corporation 903

0

rit'~
(~ ~-~

9 ~ n = ==

o~.~
o~|
I-

I,(
0

~.~
u) (~ (A
r+ ck
oooooooooooooooooooooooooooooooooooooooooooooooooo .

~ ~ ~ ~
H.~M
0
I I I I I

O~
H.
t::J ~-
0
e 0
C~
0
|
 s,+l / Z,+H

6,4f

I I , I ,..---t I i, -----J - -

-6 -4 -2 2 4 6 8 10 pH

Fig. I. Dependences of the chemical shifts (CS) of the

protons of 2-methyl-3-hydroxypyridine (0) and 4-methyl-
5-hydroxypyrimidine (O) on the acidity of the medium.

substituents (OH, CHs) on the parameters of the NMR spectra and the basicity of the nitrogen
atom. Characteristic dependences of the CS on the acidity of the medium for IIb and IVb
are presented in Fig. 1 as an illustration. The presence of a plateau on the curves
indicates the sequence of the formation of the A, N, and C forms, as well as the DC form for
IVb.
The addition of a proton to the nitrogen atom in pyridine leads to greater deshielding
of the protons in the 8 or 7 positions as compared with the ~ protons [4]. The methyl sub-
stituent in Ib does not violate the indicated principle and shifts all of the proton signals
to strong field. The average change A6C_ N for the ~ protons of Ia and Ib is ~ 0.30 ppm, as
compared with 0.33 ppm for the CH 3 protons. The CH 3 group increases the basicity of the
nitrogen atom by more than 0.5 PKaunits. As compared with pyridine, the degree of deshielding
of the ~ protons in 3-hydroxypyridine increases (~6C_N -m 0.43 ppm), whereas the degree of .
deshielding of both the ~ and ~ protons decreases. An analysis of the data presented in
Table 1 shows that 3-hydroxypyridine is a weaker base than pyridine (ApK_ I = 0.6). Methyl
substituents have a substantial effect on the basicity of the nitrogen a~om of 3-hydroxy-
pyridine. Thus on passing from IIa to the mono- and then to the disubstituted derivative
the PKa I value increases by 0.7 and 1.3 pK a units. A comparison of the experimental PKa l
values for 3-hydroxypyridine derivatives with the charges on the nitrogen atom previously
calculated by the MO LCAO method [5] led to a satisfactory correlation. It should be noted
t h a t the PKa I value remains virtually unchanged on passing from IIb to IIc and from IId to
IIe; this is also confirmed by calculation of the q-electron densities. We observed that
the contribution of the 2-CH s and 6-CH 3 groups to the CS of the 4-H and 5-H protons of IId is
additive. The average change A6C_ N (0.20 ppm) for the protons of the CH 3 groups of azines
IIb-e is smaller than in the case of Ib (0.33 ppm).
The introduction of a second electronegative nitrogen atom in the ring leads to marked
deshielding of all of the ring positions of pyrimldine and 5-hydroxypyrimidine, as a. c~n-.
sequence of which the signals of their protons are situated at weaker field as compared
with the corresponding signals of pyridine and 3-hydroxypyridine. The basicity of the compound
also decreases with an increase in the number of nitrogen atoms. Thus, for example, the
PKa I value of pyrimidine is smaller by more than four orders of magnitude than the PKa I value
of pyridine, and protonation of the second nitrogen atom of pyrimidine occurs when H 0 < 6.
It should be noted that the basicity of 5-hydroxypyrimidine is higher than that-of pyrimidine.
As in the case of pyridine derivatives, methyl substituents increase the shielding of the
protons and the basicity of the pyrimidine ring. Whereas in the case of 3-hydroxypyridine
a linear relationship between the PKa I value and the number of CH 3 groups in the ring is
observed only in the case of mono- and disubstitution, for 5-hydroxypyrimidine this propor-
tionality is observed for mono-, di-, and trimethyl derivatives; the PKa I value for IVd
is two orders of magnitude higher than for 5-hydroxypyrimidine. Protonation of pyrimidine
and 5-hydroxypyrimidine leads to greater deshielding of the protons in the 8 position relative
to the cationoid center as compared with the ~ protons [4]. In fact~ in derivatives III
and IV the d6C_ N values for the 5-H proton are higher than for the 2-H and 6-H protons.

905
An analysis of the experimental data showed that in the case of primary protonation the
the signals of the a protons of III and IV experience similar shifts to weak field (by 0.48
ppm on average), i.e., the degree of deshielding is higher than in pyridine derivatives.
Protonation of Ib and IIIb gives rise to approximately identical changes in the CS of the
protons of the CH~ groups (0.33 ppm), while the shift of the signals of the CH~ groups in
IVb-d is substantially greater than in the case of IIb-e and increases with an increase in
the number of methyl groups in the ring. As in the case of derivatives of pyridine and
3-hydroxypyridine, an increase in the constants of spin-spin coupling between the a and
protons, as well as the meta protons through the nitrogen atom, is observed in the pro-
tonation of pyrimidine. Thus, whereas Js~ = 5.0 Hz and J26 ~ 0 Hz in the spectrum of the
neutral IIIa molecule, in the spectrum of the monocation Js~ increases b9 0+6 Hz, and J2B
increases by 0.4 Hz.
The presence of two protonation centers is characteristic for pyrimidine, 5-hydroxy-
pyrimidine, and their methyl derivatives. In the case of symmetrically substituted pyrim-
idines the N(I ) and N(s ) atoms are equivalent, and primary protonation can occur at either
of the atoms. The introduction of a methyl substituent in the 4 position of pyrimidine
leads to the development of asymmetry of the molecule and a change in the basicities of
the nitrogen atoms to different degrees, and~ consequently, the nitrogen atom with the greater
basicity is protonated initially in this case. We found that it was possible to establish
the center of primary protonation of IIIb and IVb on the basis of an analysis of the param-
eters of the IH and ISC NMR spectra. In the protonation of pyridine and 3-hydroxypyridine
the changes in the CS of the protons int the B and y positions with respect to the cationoid center
are greater than for the a protons: the signals of the 2-Hand 6-H protons experience similar
shifts to wemk libido In the case of IIIb the A~C-N values fort he 2-H and 6-H protons are also
close; this provides a basis for the assumption that primary protonation is realized at the
N (I) atom. The addition of a proton to the N(s) atom should have led to a considerably
greater shift of the 6-H signal (the y position relative to the cationoid center) as
compared with the 2-H signal, but this is not observed experimentally. A comparison of the
spectral parameters of the neutral (N) and cationic (C) forms of IIIb shows that the position
of the cationoid center can also be established from the change in constants of spin-spin
coupling of the meta protons through the nitrogen atom~ In the spectrum of the N form of
IIIb the J2s constant is close to zero, and the signals of the 2-H and 6-H protons are
doublets (J2s = 1.0 and Js6 = 5~ Hz). In the spectrum of the monocation of IIIb the
signals of the indicated protons take on quartet structure with additional constant J26 =
0.8 Hz; this constitutes evidence for the addition of a proton to the N(l ) atom [6]. An
increase in other SSCC (J~s = 1.2 and Jss = 6.0 Hz) is also observed for the C form. It
should be noted that the A6C_ N values of the signals of the protons of the methyl groups
are virtually the same for 2-methyl- and 4-methylpyridine, and the A6C_ N values of the methyl
groups therefore cannot serve as a criterion for evaluating the site of protonation. In
the case of IVb the changes in the CS of the 2-H and 6-H protons in the process of primary
protonation are close, and this also constitutes evidence that it is realized at the N(I )
atom. Finally, the change in the parameters of the I~C NMR spectra of the investigated IIIb
and IVb molecules in the N, C, and DC forms is graphic evidence~that primary protonation is
realized at the ~ i ) atom. Thus, in conformity with the principles previously established
in [7], in the la~ spectrum of the monocation of IIIb the signals of the C (~} and C(s)
(the a-carbon atoms with respect to the protonation center) are shifted by 5.91 and 1.73
ppm to strong field as compared with the corresponding signals of the neutral molecule, while
the signals of the C(w) and C(s ) atoms, which are remote from the protonation center, are
shifted by 4.40 and 1.83 ppm to weak field. An analysis of the spectra of the N and C forms
of IIIb also shows a characteristic decrease in the SJcu}1~ value through the protonated N(I )
atoms: sJc H decreases from 8.54 to 8+00 Hz, and sJC , decrease from 10o99 to 8.50 Hz. Simi-
9 2 2 2~6
lar prlnciples also are manifested in the I~C ~MR spectra of IVb in the N, C, and DC forms.
In derivatives of pyrimidine and 5-hydroxypyrimidine protonation of one of the nitrogen
atoms significantly decreases the basicity of the second nitrogen atom, as a result of which
the DC form develops in the region H 0 < 3; a further shift of the signals of the protons to
weak field is observed. The SSCC also increase in the process of formation of the DC form.
Thus Js~ = 6.0 and J2~ = 0.8 Hz for pyrimidine; Js6 = 6.8 and J2~ = 2.0 Hz for IIIb. The
effect of deshielding of the 2-H proton in the step involving secondary protonation (0.50
ppm) is similar to the change in shielding on passing t o t h e monocation; however, the changes
in the CS of the 6-H, 5-H, and CHs protons are considerably smeller than those observed for
primary protonation. As expected, methyl substituents increase the shielding of al] of

906
the protons of the DC form. The basicities of IIIb and IVb increase to a greater degree
than for the C form. Thus on passing from mono- to trisubstituted 5-hydroxypyrimidine
the PK~ value increases by two orders of magnitude, as compared with 1.3 orders of magnitude
in the step involving the monocation.
In the region of high pH values 3-hydroxypyridine and 5-hydroxypyrimidine can exist
in the anionic (A) form. For 3-hydroxypyridine ionization of the OH group is accompanied
by an increase in the electron density on all of the carbon atoms and, consequently, by
a shift in the signals of the protons to strong field. The average changes A6N_ A in the
CS in the process of ionization for the protons in the 4, 6, and 2 positions are,
respectively, 0.39, 0.25, and 0.03 ppm. Calculation of the ~-electron densities of 3-
hydroxypyridine also showed that the change in the charge on the C(2 ) atom on passing
from the N to the A form is substantially lower than on the C(~)and C(6) atoms [5]. In
5-hydroxypyrimidine derivatives the changes in the CS of all of the ring protons are similar
and average 0.38 ppm, as compared with 0.09 ppm for the protons of the CH s groups. The
methyl groups in IIb-e and IVb-d increase the basicities and shift the signals of the pro-
tons to strong field. We found that the contribution of CH 3 groups to the CS of the 4-H and
5-H protons of IId and the 2-H proton of IVc is additive. The ionization constant of the
OH group (pK~) for'3-hydroxypyridine is almost two orders of magnitude greater than for
5-hydroxypyridine, i.e., the detachment of a proton in 3-hydroxypyridine should occur in a
more alkaline medium. Correlations between the pK~ values and the w-electron densities on
the oxygen atom, as well as the number of CH a groups in the ring, were uncovered from an
analysis of the data obtained for 3-hydroxypyridine derivatives. Methyl groups have a
greater effect on the pK~ values in 3-hydroxypyridine derivatives than in 5-hydroxypyrimidine
derivatives.
On the basis of the results of an investigation of the acid- and base-induced trans-
formations of azines I-IV and an analysis of the parameters of the I H N M R spectra we propose
spectral parameter ZA6C_N, viz., the overall change in the CS of the ring protons upon pro-
tonation, which correlates satisfactorily- with the calculated oK
= aI values 9 By means of the
following equations one can estimate the pK~ values for derivatives I-IV starting from N~4R
data:
p K ~ = - 1.19EA6c-~ -t-8.83;

p K ~ = - 1,16~Vk~c--N +7.23;

pK)= - 1 . 5 2 Z A 5 c ~ + 4 . 5 8 ;

p K ~ = -- 1 , 4 5 v ~ 6 c - ~ + 3 . 8 0 (r=0.99)

The linearity of the dependences provides evidence that parameter Z~6C. N can serve as a
characteristic of the change in the electronic structures of the investigated molecules.
The ZA6C_ N values decrease on passing from the unsubstituted compounds t o t h e methyl-sub-
stituted derivatives. The Ea6C_ N values are, respectively, 1.99, 1.43, 0.88, and 0.33
ppm and 1.38, 0.91, 0.48, and 0.0 ppm for 3-hydroxypyridine and 5-hydroxypyrimidine and
their mono-, di-, and trimethyl derivatives. The contribution of CH 3 groups to ZA6C_ N
is additive, and the change in the parameter upon the introduction of each group is 0.55
and 0.h8 ppm for derivatives II and IV. It should be noted that the overall change in
the shielding of the ring protons on passing from neutral to acidic media for 5-hydroxy-
pyrimidine is smaller than for 3-hydroxypyridine. A similar dependence is observed when
one compares E~6C_ N for Ia, Ib, and Ic (2.78, 2.29, and 1.69 ppm) and for IIIa, IIIb, and
IIIc (2.19, 1.58, and 0.61 ppm). The smaller ZASc_ N values for 3-hydroxypyridine and 5 s
hydroxypyridine are evidently due to the electron-donor properties of the OH group in
conjugation with an aromatic ring. The following equations were derived for I-IV for the
description of the relationship between EA6C_ N and the number (n) of CH 3 groups in the
ring:

E~6C-R ------ 0,54n + 2.80;

VA6c-. = -- 0.55n + 1.98;
_v:~SC~,R= -- 0.52n + 2 . 1 5 ;
vAbC.qj = -- 0.46n + 1.38 (r=0.99)

907
 A satisfactory correlation between pK~ (or the number of CHs groups in the ring) and
the overall change ZA6N_ A in the CS of the protons in the process of ionization was obtained
only for 5-hydroxypyrimidine derivatives.
In a comparison of the CS of the ring protons and the protons of the CH 3 groups of
azines I - I V w e esZablished a linear correlation between the CS of the protons of the N and
C, C and DC, and N and A forms. The existence of linear dependences of this sort constitutes
evidence for an identical effect of protonation of the nitrogen atom or ionization o f
the OH group on the CS in the investigated series of nitrogen heterocycles. In the series of
azines I-IV, 6N = 0.95~ C - 0.16; in the series III and IV, 5 C = 0.956DC - 0.05; in the
series II and IV, 6N = 1.03 6A + 0.06. In all cases one observes high correlation co-
efficients (r - 0.99), and the standard deviation does not exceed the error in the deter-
mination of the CS. We observed linear relationships between the pK~ and pK~ values in
the 3-hydroxypyridine and 5-hydroxypyrimidine series. Similar relatmonships are observed
between both the pK~ values of derivatives of the indicated compounds. We also established
a correlation between the experimental ZA6C_ N values for derivatives I, II and III, IV,
which is described by the equation

EL%6C--N (I, II) ffi 1.14EA6c---N (llI, IV) +0.39.

EXPERIMENTAL
Compounds I-IV were synthesized and purified by the methods in [8, 9]. The acidity
was varied over the range pH 0-10 by the addition of small amounts of D2SO ~ or NaOD to
a solution of the investigated substance in D20. The pH values of the solutions were
measured with a pH-121 pH meter with an ~SL-63-07 glass electrode with an accuracy of
pH units. Solutions of II and IV with definite H 0 values were prepared in accordance
with the data in [10]. The IH NMR spectra were recorded with a Varian HA-100 spectrom-
eter at 26~ The accuracy in the measurement of the CS was 0.02 ppm. The method of
calculation of the ionization constants from the dependence of the chemical shifts of the
protons on the pH of the medium and the reliability of the utilization of the NMR method
for estimation of the pK a values were examined in [I]. The accuracy in the estimation
of the ionization constants was no less than 0.1 pK a units, and the correspondence with
the data available in the literature was no less than 0~ pK a units. The zsC NMR spectra
were recorded with Bruker M-400 Spectrometer under Fourier-transformation conditions with
complete suppression of the protons and also without suppression of IsC-IH coupling, e The
samples were prepared in the form of 0.2 M (for ZH NMR) and 0.8 M (for 13C NMR) solutions;
the internal standard was tert-butyl alcohol.

*The authors thank I. I. Chervin for recording the ISC NMR spectra.

LITERATURE CITED

I. V. P. Lezina, A. U. Stepanyants, N. I. Golovkina, and L. D. Smirnov, Izv. Akad~ Nauk

SSSR, Set. Khim., No. 1, 98 (1980).
2. V. P. Lezina, L. V. Shirokova, M. M. Borunov, A. U. Stepanyants, and L. D. Smirnov,
Izv. Akad. Nauk SSSR, Set. Khim., No. 4, 753 (1981).
3. V. P. Lezina, M. M. Borunov, S. B. Gasher, and L. D. Smirnov, Izv. Akad. Nauk SSSR,
Set. Khim., No. i, 40 (1983).
4. V. M. S. Gil and J. N. Murrel, Trans. Faraday Soc., 60, 248 (1964).
5. V. P. Lezina, V. F. Bystrov, L. D. Smirnov, and K. M. Dyumaev, Teor. Eksp. Khim., !
281 (1965).
6. J. B. Merry and J. Ho Goldstein, J. Am. Chem. Soc., 8_88, 5560 (1966).
7. J. Riand, J~ Chem. Soc., Chem. Commun., No. i, 105 (1983).
8. J. H. Chesterfield, J. F. W. McOmie, and M. S. Tute, J. Chem. Soc., No. ii, 4590 (1960).
9. R. Muller and Ho Plieninger, Chem. Ber., 9__2, 3009 (1959).
i0. C. D. Johnson, N. R. Katritzky, and S. A. Shapiro, J. Am. Chem. Soc., 9__1, 6654 (1969).

908
ACETALS OF LACTAMS AND ACID AMIDES.
47.* INVESTIGATION OF THE BEHAVIOR OF SUBSTITUTED 6-(8-
DIMETHYLAMINO)VINYL-4-PYRIMIDINONES IN ACIDIC MEDIA.
SYNTHESIS OF 3-CYANO-4-ANILINO-5-FORMYL-2-PYRIDONE AND 3-
CHLORO-4-CYANOBENZO[D][I,6]-NAPHTHYRIDINE

N. Z. Yalysheva, N. P. Solov'eva, UDC 547.854.04'824'834.2:543.422

V. V. Chistyakov, Yu. N. Sheinker,
and V. G. Granik

The hydrolysis of 1-substituted 5-cyano-6-(8-dimethylamino)vinyl-4-pyrimidinones

in acidic media was studied. It was shown that the l-benzyl derivative is converted
to a mixture of e-cyano-8-benzylamino-crotonamide and 3-cyano- and 3-carbamido-4-
benzyl-amino-2-pyridones. The principal product in the hydrolysis of the l-phenyl
derivative is 3-cyano-4-anilino-5-formyl-2-pyridone. Cyclization of the latter by
heating in phosphorus oxychloride leads to 3-chloro-4-cyanobenzo[b][l, 6]naphthyr
idine.

It has been previously established that 1-substituted 5-cyano-6-(8-dimethylamino)-

vinyl-4-pyrimidinones, which are formed in the reaction of secondary enamino amides with
dimethylformamide diethylacetal, are readily hydrolyzed in alkaline media with opening of the
pyrimidine ring and subsequent recyclization to 2-pyridone derivatives [2, 3]. In contrast
to its behavior in an alkaline medium, in acids at room temperature the pyrimidine ring is
quite stable, and cyclization with the participation of the enamino and cyano groups takes
place under these conditions [2,4]. Thus pyridopyrimidine derivative II was isolated when
l-benzyl-5-cyano-6-(8-dimethylamino)vinyl-4-pyrimidinone (Ia) was treated with hydrochloric
acid at 20~ [4]. When we carried out this reaction with moderate heating (60-65~ we
obtained a mixture of substances, from which we were able to isolate in individual form 3-
carbamido-4-benzyl-amino-2-pyridone (III), which was identical to a sample obtained by a
previously described method [4]. In the mixture we also detected, by means of mass spectrom-
etry (the mass spectrum of the mixture was compared with the spectra of pure samples obtained
by the method in [3]), 3-cyano-4-benzylamino-2-pyridone (IV) [M+ 225 (36),# [PhCH2] + 91
(i00), and [PhCH 2 - C2H2] + 65 (9)] and e-cyano-8-benzylaminocrotonamide (V) [M+ 215 (37),
[M - OH] + 198 (16), [M - OH - NCN] + 171 (16), [PhCH2]~ 91 (i00), and 65 (13)]. The forma-
tion of the principal product of this reaction (III) could have been due to hydrolysis of
the cyano group in IV. However, it was found that cyanopyridone IV remains unchanged when
it is maintained under these conditions, and it may be assumed that amide III develops via
cleavage of the pyrimidine ring of intermediate pyridopyrimidine II. Enamino acid V is
formed as a result of opening of the pyrimidine ring and splitting out of the enamino
grouping in starting pyrimidinone Ia.
One might have expected that replacement of the benzyl substituent by a phenyl sub-
stituent in the 1 position of the pyrimidine ring would not change the fundamental scheme
of hydrolysis in an acidic medium. However, two substances were isolated when a solution
of l-phenyl-5-cyano-6-(8-dimethylamino)vinyl-4-pyrimidinone (Ib) was heated in 0.1 N HCI
at 60-65~ The minor component, which was obtained in ~10Z yield, was 3-carbamido-4-
anilino-2-pyridone (VI). An intense molecular-ion peak (M +) at 229 (54) is observed in its
mass spectrum.

*See [i] for Communication 46.

there and subsequently, the m/z values are given for the ions, and the relative intensities
in percent are given in parentheses.
S. OrdzhonikidzeAll-Union Scientific-Research Institute of Pharmaceutical Chemistry,
Moscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1118-
1123, August, 1986. Original article submitted May 21, 1985.

0009-3122/86/2208-0909512.50 @ 1987 Plenum Publishing Corporation 909

 N(Me);~
j6"
O 6,~Y F N(Me)2
l, C H 2 . , . . ~ CN
IS ! _Me2NCHO PhCll2H N / ~ .
"
/.cN
...". ~N.-,'%O 'HCOO~'- I ~ /CN
i PhCII2HN / " ~ ! CONH,
la
L C~ A , V -
I H~(tlzO)
"'-25,,,
--/;" Nil
i II ' (II.,O) ,-'#/:~"NIl % i~'4"" Nil
l "" ....# - I I
-.,.~ II " ( II,O ) -
PhCH2H N/" "Ii :'I} - phCH2H N / >-[ - O
CIJNII 2 CN
II III IV

The maximally intense peak belongs to the [M - OH] + ion at 212. Subsequent elimination
of a molecule of water and a molecule of CO gives peaks at 194 (25) and 184 (21), respec-
tively. A Ph + peak at 77 (33) is also observed. To confirm the structure of VI we investi-
gated its PMR spectrum simultaneously with the spectrum of known amide III (see Table I).
The spectra of pyridones III and VI are quite similar; a characteristic feature is the pres ~
ence of twe doublet signals of protons in the 5 and 6 positions of the pyridone rings,
which are found at 6.0 and -7.3 ppm for VI and at 5.93 and -7.3 ppm for III. A peculiarity
of the PMR spectra is the presence of signals of four labile protons; by means of hhe method
of decoupling of the signals we were able t o m a k e reliable assignments of the signals to
certain NH groups. Thus we established that the strongest-field signals are the signals
of the B-H protons, which do not participate in the formation of a hydrogen bond (7~ ppm
for III and -7~ ppm for V I); in the spectra they are represented by doublets due to spin-
spin coupling with the adjacent A-H protons (2JAB = 4.5 Hz for III and 4.3 Hz for VI)o
The adjacent NH protons are observed at rather weak field, viz., at 9.91 ppm (VI) and 9.84
ppm (III); this makes it possible to propose that they participate in hydrogen bonding with
the pyridone carbonyl group. The signals of the protons of the ring Nil groups are observed
in the form of either a doublet (for III, 10.99 ppm, aJNH 6-H = 4 Hz) or a markedly broadened
singlet (for VI, 11o21 ppm) due to spin-spin coupling wis adjacent 6-H proton. Finally,
the signals of the 4-RNH groups are represented in the spectra either in the form of a rather
narrow singlet (for VI, 12.67 ppm) or in the form of a triplet (for III, 11.14 ppm, aJNH,CH2 =
5.9 Hz). This weak-field position of the signals constitutes evidence for a strong intra-
molecular hydrogen bond of the chelate type. All of the data presented indicate the pre-
sence in III and VI of two rather strong intramolecular hydrogen bonds.

""
H 9O/~L,.NI H~, Ph'N 0 Ph~N / C~

llI ,VI VII VIII

Ill R=PbCI[2; VI R=PL

According to the results of elementary analysis, the principal substance obtained by

treatment of pyrimidinone Ib with acid could have two-ring structure VII or the structure
of hydroxymethylene derivative VIII.
Structure VII can be rejected starting from the data from the IR spectrum, in which
an absorption band of a cyano group at 2202 cm -I is observed~ The PMR spectrum of IX is
not in agreement with either structure VII or structure VIII. Two singletsat 9.60 ppm
(IH) and 8.42 ppm (IH), two broad signals at 12.42 ppm (IH) and 10.60 ppm (IH), and a
multiplet of benzene ring protons centered at 7.4 ppm (5H) are present in the spectrum.
From its position, the signal at 9.6 ppm can be ascribed to an aldehyde proton, and the two
broad signals can be ascribed to labile protons of NH or OH groups. It should be noted
that the corresponding arylhydrazone was obtained from IX when it was heated with p-nitro-
phenylhydrazine; this also confirmed the presence of an aldehyde function in this compound.

QII%
 TABLE I. Chemical Shifts of the Protons of
III, Vl, IX, and X (6, ppm) *

tOM- l i Ii
pound 5.1f I L;-ll [ I'laldl .I.I~NH CH=
I
A-,, I"",

I"
IIl 10,:)q 5.q3 ~ 7,301 -- 11,14~* 9.84 [ 7,07 ~.5ot
\,[ 11~21 6,()0 I~ 7,3Ol [12,67 9,91 7,3
IX IO,60 [ 8,42 I 9,60 112,42
X 11,35 1 7'3~ 19,40
*In the 1HNMR spectra the aromatic protons
form a multiplet at 7.2-7.5 ppm.
%The signal of the CH= groups has the form
of a doublet, whereas the N(~')H signal is
a triplet [SJCH2N(~,)H = 5.9 Hz].

TABLE 2 . Chemical Shifts of the zSC Atoms of IX and X (6 iSC,

ppm)
,,,,,
Com -
pound JC,2;=O C 3) C------~.N

IX
X 16!,7 80,5 118,0 158,5 94,9 138,7 -- 137,9 124,0 128,9 125,5

The most valuable information regarding the structure of IX was obtained from the iSC
NMR spectra (Table 2). A characteristic peculiarity of the spectrum is the presence of a
signal at 190.7 ppm, which is converted to a doublet under conditions of recording the
spectrum with partial suppression of the protons; this made it possible to unambiguously
ascribe this signal to the carbon atom of an aldehyde group. An additional confirmation
of this assignment of the signal is the existence of a geminal spin-spin coupling constant
(SSCC) for this signal (2JH,CO C = 24 Hz) in the isC NMR spectrum recorded under conditions
without suppressions of the protons. A second characteristic peculiarity of the spectrum
is the rather weak-field signal of the heteroaromatic carbon atom bonded directly to a
hydrogen atom (CH, 152.6 ppm). In addition to the above-described signals in the spectrum
of the compound obtained, one can isolate signals of a carbonyl (pyridone) carbon atom at
161.4 ppm and a carbon atom of a CN group at 113.9 ppm. The assignment of all of the
signals was made by comparison of the spectrum of IX with the spectrum of a model compound,
viz., 3-cyano-4-anilino-2-pyridone (X) (see Table 2). The ZsC NMR spectra of the investi-
gated (IX) and model (X) compounds are quite similar; the only exception is that the 5
position of the model compound is not substituted [C(s ) 94.9 ppm], whereas the signal of the
carbon atom of this CH group was absent in the spectrum of IX; however, a signal of a
quaternary heteroaromatlc carbon atom at 107.4 ppm and, as we have already pointed out, a
signal of an aldehyde carbon atom at 190.7 ppm were observed.
In addition to a maximally intense molecular-ion peak (M+) at 239, the mass spectrum
of aldehyde IX contains an intense [M - H] + ion peak at 238 (80). Elimination of a formyl
group from M + gives an ion peak at 210 (47). A Ph + ion peak at 77 (20) is also 6bserved in
thespectrum. Thus an unusual and unexpected rearrangement with the formation of 3-cyano-4-
anilino-5-formyl-2-pyridone (IX) occurs when pyrimidinone Ib is heated in an acidic medium.
"'(~')2
OhC -. 2~ ,
'~ IN it,! : "'" NH ~r
~a ' ~ 6,J C5 ~ ~ :;~I" :0 i.~.[/
; I ~i ti Pht|N 0
. ~' ..[. ~ (.'N CONH 2
7
Ib L~ ~q

It should be noted that the hydrolysis of 4-pyrimidinones under these conditions

depends on the character of the substituent in the 1 position and that when a benzyl group
is present in this position, as in Ia, substances with different structures (III-V, see

911
above) are formed. This difference in the behavior of 4-pyrimidinones Ia, b could be due to
a difference in the site of protonation of their enamine fragments. However, a study of the
PMRspectra of Ia, b in acetic, deuteroacetic, trifluoroacetic, and deuterotrifluoroacetic
acids did not reveal substantial differences in their behavior with respect to the protonating
agents used. *
The fundamental difference in the cleavage of the pyrimidine ring and the subsequent
recyclizations depending on the substituents may also be due to different pathways of this
cleavage in connection with different degrees of stabilization of the transition states by
aryl or alkyl groupings. Proceeding from this, the following scheme for the processes
described above can be proposed:

N(U,)~ N(W,) 2
N(M,) 2
I'
R"N~"
:
%:] "
CN
-. . ,,,,.
E J
N ' " ':'<c I
.CN R=PhCH~=.

N <'0 H'" ""N" ":'O CHO CONHz

tl XIH
a,b ~..;e~... "
x,
t H*(H20)
+
i//~NH
N:i ,cl :r '-i,r ,~_~o
N RHN / 0
i, ! ~ /x .~.b
PhHti ":"i"'-'0 P h H N " "'<'i, "0 CN
IV,X
CN CN
~[I X%'I

According to this scheme,% ring cleavage mey proceed via two pathways - with cleavage
of the N(I ) - C(2)bond (pathway A) or the N(s)-- C(2)bond (pathway B). The realization
of one or the other pathway depends on the substituent attached the N(1) atom. It might
be assumed that the formation of two types of compounds (XIV and XV) can occur in the rate-
determining step:
(M| o~{
: ,N(M,)=
,
~ "%~,. A s /"

CN HO~ CH CN
IC,' .'(IV

iH~(II20) I II '(H20)

The presence of an N-alkyl radical stabilizes structure XIV due to a positive inductive
effect, whereas, on the other hand, an aryl substituent destabilizes this structure. Prob-
ably as a consequence of this, pathway B with the formation of initially XIII and then
pyridone IV is characteristic for N-benzyl derivative Ia. At the same time, the reaction
for N-phenylpyrimidinone Ib is directed via pathway A with the formation of cation XV,

*In both cases (la, b) N protonation is evidently observed: the signals of the protons
attached to the C(~') = C(s") bond of the side chain are shifted to weak field, and new signals
(for example, of a CHz group, as would have occurred in the case of C protonation) do not
appear in the spectra. IH NMR spectra (CHsCOOD): 8.28 (6''-H), 4.73 (6'-H) (la); 8.25
(6''-H), 4.33 (6'-H) (Ib); (CFsCOOD): 8.79 (6"-H), 5.40 (6'-H) (Ia); 8.67 (6"-H), 4.85
ppm (6'-H) (Ib).
%A pathway involving the formation of pyridopyrimidines of the II type and their Cleavage
to III and VI was not taken into account in the scheme. Protonation of the enamine fragment
is also disregarded, since this is not essential for an examination of the synthesis of
IX and the differences between hydrolytic cleavage of the ring in pyrimidinones la, b.

01P
after which the imide carbon.atom; which bears a partial positive charge, attacks the 8
position of the enamine fragment, in which the electron density is increased due to con-
jugation with the dimethylamino group (it is assumed that the process takes place with
the participation of the unprotonated form of the enamine); cyclization with the formation
of inmlonium cation XVI with subsequent hydrolysis to aldehyde IX occurs in'this case.
The unexpected formation of formylpyridine IX opens up significant possibilities
from the point of view of the synthesis of heterocyclic compounds on the basis of it. In
particular, it was established that cyclization with the formation of 3-chloro-4-cyanobenzo
[b][1,6]naphthyridine (XVII) takes place when a solution of IX in phosphorus oxychloride is
heated in the presence of triethylamine hydrochloride. Signals at 9.83 ppm(l-H) and 9.68
ppm (10-H) are the most characteristic signals in the IH NMR spectrum of XVII. The signal
at 9.68 ppm is broadened somewhat due to coupling with the proton in the 6 position (8.40
ppm). In the mass spectrum of three-ring compound XVII the maximally intense peak belongs
to the molecular ion (M+) at 239, which contains one chlorine atom. The primary act of
fragmentation is the elimination of halogenwith the formation of a fragment peak at 204
(19)o Ions at 177 (20) and 150 (9) are formed by the successive detachment of two mole-
cules of HCN. The peak at 153 (which does not contain CI) probably beongs to the [M -
(NC-C=CCI + H)] + fragment (12).

CI-IO

CN X~[ CN
LK

EXPERIMENTAL

The mass spectra were record with a VarianMAT-ll2 spectrometer with direct introduction of
the samples into the ion source; the temperature of the ionization chamber was 180~ and the ion-
izing-electron energy was 70 eV. The IHNMRspectra were recorded with a VarianXL-200 spectrometer,
and the 13C NMR spectra were obtained with a VarianXL-100 spectrometer; the solvent was
ds-DMSO, and the internal standard was tetramethylsilane (TMS). The IR spectra of mineral
oil suspensions of the compounds were recorded with a Perkin-Elmer 457 spectrometer.
l-Benzyl-5-cyano-6-(~-dimethylamino)vinyl-4-pyrimidinone (Ia). This compound was
previously synthesized in [3]. IH NMR spectrum (in CDCI3): 4.46 (6'-H, d, 3J6,s,, = 12.8
Hz), 8.05 (d, 6''-H), 8.09 (2-H), 5.11 (s, CH2) , and 2.84 (s) and 3.01 ppm (s) (Me2N).
iSC NMR spectrum (in CDCIs): 154.3" [C(=)], 167.5 (C=0), 82.9 [C(s)], 118.8 (CN), 156.6
[C(6)], 82.8 [C(6,)], 152.2" [C(6,,)], -39 [CHs)2N],% 53.1 ~ (CH2) , 135.4 [C(=)], 126.3
[C(~)], 128.6 [C(~)], and 127.6 ppm [C(6)].
l-phenyl-5-cyano-6-(~-dimethylamino)vinyl-4-pyrimidinone (Ib). This compound was
previously synthesized in [5]. IH NMR spectrum: 4.05 (d, 6'-H, sJ6,8, , = 13 Hz), 7.87
(d, 6''-H), 8.40 (2-H), and 3.06 and 2.56 ppm (Me2N). ZSC NMR spectrum: 152.7" [C(=)],
167o5 (C=O), 82.2 [C(s)], 118.7 (CN), 160.0 [C(61], 83.7 [C(,')], 151.5"~C(6.)], 138.0
[C(~)], 127.5 [C(B)], 129.7 [C(y)], 129.7 [C(~)] and 39 ppm [(CHs)2N].%
3-Carbemido-4-(N-benzylamino)-2-pyridone (III). A 1 g (3.6 mmole) sample of pyrim-
idinone Ia was heated in 20 ml of 1 N HCI at 60~ for 5 h, after which the resulting
precipitate was removed by filtration and washed with water to give 0.03 g of a crude
substance, the principal constituent of which, according to the mass spectroscopic data,
was IV with M + 225. IR spectrum: 3280, 3140 (NH), 2200 (C~N), 1640, 1620 cm -z (C=O).
The aqueous mother liquor was made alkaline to pH 9-10 with 40% NaOH, and the resulting

*The direct SSCC iJl3c, H were taken into account for the C(=) and C(6,, ) atoms in the assign-
ment of the signals: 6 154.3 ppm, Ja_z3c, H = 206 Hz (2-C); ~ 152.2 ppm, IJ6"-I3C,H = 166
Hz [C(6,,)]. The assignment of the signals in the spectrum of Ib was also accomplished sim-
ilarly.

tThe signal of the carbon atom is'broadened markedly.

913
 B

precipitate was removed by filtration and washed with water to give 0.13 g of a crude
substance with molecular-ion peaks MI + 215 (V) and M = + 2 4 3 (III). Allowing theaqueous
mother liquor to stand at 20~ for 12 h precipitated 0.21 g (24%) of III with M+ 243 (35)
and [M - OH] + 226 (100) and peaks at 197 (75), 169 (65), 91 (90), 65 (25); the product
had rap 253-254~ (from DMF; 253-254"C [4]). Found: C 64.3; H 5.6; N 17.8%. CzsHI~N30 =.
Calculated: C 64.2; H 5.4; N 17.3%.
3-Cyano-4-(N-phenylamino)-5Tf0rmyl-2-pyridone (IX). A 5-g (20 mmole) sample of pyrim-
idinone Ib was~ dissolved in 100 ml of i N HCl, and the solution was heated at 65~ for 5 h.
The precipitate was removed by filtration and washed.with water to give 3 g (67%) of IX
with mp 280QC [dec., from DMF-water (2:1)] and M~. 239. IR spectrum: 3260, 3180 (NH), 2200 . ~
(CmN), 1690, 1650, 1630 cm -l (C=O). Found 65.3; H 3.6; N 17.5%. CIsHgNsO 2. Calculated:
C 65.3; H 3.8; N 17.6%.
The p-nitrophenylhydrazone was obtained in 58% yield by heating I X w i t h p-nitrophenyl-
hydrazine in alcohol; the product had M + 374 and mp 314-316"C (from DMF). Found: N 22.1%.
CIgHI~N~O s. Calculated: N 22.5%. The aqueous mother liquor after isolation of IX was
made alkaline to pH 9-10 with 40% NaOH, and the resulting precipitate was removed by
filtration and washed with water to give 0.36 g (8.4%) of VI with mp 280-283=C [DMF-MeOH
(2:1)] and M + 229. IR spectrum: 3300, 3110 (NH), 1650, 1600 on "I (C=O). Found:
C 63.1; H 4.8; N 18.4%. Cl2H1zNs02. Calculated: 62.9; H 4.8; N 18.3%.
3-Chloro-4-cyanobenzolb]~l,61napthyridine (XVII). A mixture of 1 g (4 n~nole) of IX with
0.4 g (2.9 mmole) of triethylamine hydrochloride was refluxed in 12 ml of POCI s for i h,
after which the resulting yellow precipitate was removed by filtration and washed with
methanol and water to give 0.5 g of XVII with M+ 239~ The mother liquor was poured into
150 ml of water with ice, and the resulting precipitate was removed by filtration and
washed with water to give another 0.4 g of XVII for an overall yield of 90%; the product
had mp 300~ (dec., from DMF). IR spectrum: 2220 (CmN), 1630, 1610 cm -l (CfN). Z H N M R
spectrum: 8.17 and 7.85 (7-H, 8-H), 8o31 and 8.40 (6-H, 9-H), 9.68 (10-H), and 9.83 ppm
(l-H). Found: C 65.5; H 2.0; C1 14.8; N 17.2%. CI~H6CIN 3. Calculated: C 65.1; H 2.5;
C1 14.8; N 17.5%.

LITERATURE CITED

I. N. Z. Yalysheva, V. V. Chistyakov, and V. G. Granik, Khim. Geterotsikl. Soedin., No. i,

84 (1986).
2. Vo G. Granik, A. M. Zhidkova, and R. A. Dubinskii, Khim. Geterotsikl. Soedin., No. 4,
518 (1982).
3. Vo G. Granik and S. I. Kaimanakova, Khim. Geterotsikl. Soedin., No. 6, 816 (1983).
4. V. G. Granik, S. I. Grizik, S. So Kiselev, V. V. Chistyakov, O. S. Anisimova, and N. P.
Solov'eva, Khim. Geterotsikl. Soedin., No. 4, 532 (1984).
5. V. A. Azimov, V. G. Granik, S. I. Grizik, L. V. Ershov, N. I. Smetskaya, S. D.
Yuzhakov, M. D. Mashkovskii, and L. N. Yakhontov, Khim-farm. Zh., No. 8, 947 (1985).

914
 SYNTHESIS AND CATALYTIC OXIDATION OF 2,5-DIMETHYLPYRAZINE

V. V. Kastron, I. G. Iovel', UDC 541.128.13:547.861.2

I. P. Skrastyn'sh, Yu. Sh. Gol'dberg,
M. V. Shimanskaya and G. Ya. Dubur

The classical method for obtaining 2,5-dimethylpyrazine by cyclization of amino-

acetone has been improved by use of ammonium persulfate in place of mercuric
chloride in the stage of catalytic oxidation of 2,5-dimethyldihydropyrazine.
Catalytic vapor phase oxidation of 2,5-dimethylpyrazine gave 5-methylpyrazine-2-
aldehyde and pyrazine-2,5-dialdehyde.

5-Hethylpyrazine-2-aldehyde (I) and pyrazine-2,5-dialdehyde (II) are starting materials

for synthesis of bioactive substances, [1-3] butsatisfactory methods for their preparation
are not available. Thus aldehyde II (as the bisphenylhydrazone) is obtained in only 12Z
yield by a four-stage synthesis from 2,5-dimethylpyrazine [4].
We propose a single-stage method for synthesis of pyrazine aldehydes I and II by cata-
lytic vapor phase oxidation of 2,5-dimethylpyrazine (III): using atmospheric oxygen with
vanadium-molybdenum oxide catalysts [5]. In this connection an improvement of the literature
methods for synthesis of III was needed. The most widely reported procedure is the self
condensation of u-aminoacetone to 2,5-dimethyldihydropyrazine which can then be oxidized
to the desired product [6], usually using mercuric chloride [7 8] or hydrogen peroxide
[9]:

NaOH
cl[~coc//~ C~BvONO c~3Cocll--t~o~ ~ SnCl:~ Ca~C~CH2NH2,HCl =.
HCI

~C0CB2NE~ to H/I~c~ / ~ c'h

9 CHjCOCH21~z C Cll~ N'
HI

With the aim of excluding toxic reagents and of increasing the yield of III we have
studied the use of compounds possessinga higher oxidation potential than HgCI 2 (see Table
1).
The maximum yield of III was found when ammonium persulfate, which has the highest
standard oxidation potential (+2.01 V, [i0]) of all the compounds studied in the given re-
action, was used as the oxidant. The yield of III (Table I) was determined by GLC analysis
of the products of oxidation of 2,5-dimethyldihydropyrazine following steam distillation.
Various solvents were checked for extraction of III from the distillate (ethe~, chloro-
form, benzene), but the best results were obtained with methylene chloride (98-99Z recovery
of III from the distillate).

Pyrazine III underwent oxidation by atmospheric oxygen at raised temperature in the

presence of vanadium-molybdenum oxide catalysts. Optimum conditions were established using
a microcatalytic reactor (volume 1 ml). The products were prepared in a flowthrough reactor
(volume 25 ml). A pulsed microcatalytic method with chromatographic analysis was used to
study the effects of temperature (300-450oC), contact time (0.05-0.30 sec), and atom V:Mo
catalyst ratio on the oxidation of III. The procedure was analogous to that described in
[ii], the catalysts being vanadium and molybdenum oxides and their mixtures (Table 2). The
physicochemical characteristics of the catalysts are given in [12].
.. -- . .

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga, 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1124-1126, August 1986
Original article submitted May 6, 1985. ' "

0009/3122/86/2208-0915512.50 @ 1987 Plenum Publishlng Corporation 915

 TABLE i. Dependence of
Yield of 2,5-Dimethylpyr-
azine (III) on Oxidant
(based on Acetone oxime)
I
Oxidant Yield of llI,%

FeCI3 96H~O 31
CuC[2-}-KI 20
HgCI~ 47
KMnO~ 24
H=O2 30
(NH02S2Os 56

TABLE 2 . Catalytic Oxidation of 2,5-Dimethylpyrazine

on re__D__
(% molar) ] atom Contact Conver- passed converted
-----7----[ ratio T, ~ time, S s i o n , % - - - - - -
v:Mo
I I! l I [[
~ m I
100 0 36O 0,I .09
4O0 0,I 16
400 0,3 13
42O 0,1 12
445 0,I 9
6O 40 36O 0,I 18
33,3 66.7 3O0 0,I II 41
335 0,I 2S 35
360 0,I 2S 46
405 0.1 23 28
14 86 360 0,I 15 44
8 92 360 0,I 13 19
0 I00 4OO 0,1 13
4OO 0,3 8

Under the studied conditions the degree of conversion of pyrazinelll amounted to 40-
90%. The partial oxidation products were the pyrazine aldehydes I and II which were
formed in approximately equal amounts. Their total yield reazhed 48 mole % (based on
pyrazine III passed through) with selectivity up to 96% (based on converted pyrazine).
Pyrazine-2-aldehyde was also formed in small quantities (up to 5Z). The optimal conditions
for formation of aldehydes I and II were a temperature of 335-360~ and contact time of
0.1 sec. Under milder conditions the conversion of III was small, and increasing the tem-
perature a~d contact.tLdm.led~ of higher oxidation products (CO, C02, NO, NO2).
Optimal yields of aldehydes I and II were achieved using equal (ionic) quantities of V and
Mo catalysts (Table 2).
For the aldehyde preparation a catalyst was prepared by application of the active
phase of the determined composition onto corundum (an inert carrier with a small specific
surface area of less than 0.i m2/g). The following results were obtained under optimal
conditions (see experimental): 56% conversion of starting pyrazine; 21 and 10% yields
respectively of aldehydes I and II.

EXPERIMENTAL

GLC analysis was carried out on a Chrom-4 instrument with flame ionization detector using
a glass column (2.4 m 3 mm) filled with 10% silicone elastomer E-301 a n d 2 . 5 % Reoplex-400
on chromosorb W-AW (60-80 mesh). The carrier gas was helium or air (60 ml/min) and the
operating temperature 120-150~ PMR Spectra were taken on a Bruker WH-90/DS (90 "MHz)
instrument and mass spectra on a Kratos MS-25 (70 eV) chromatography-mass spectrometer and
on an MS-50 (70 eV) mass spectrometer.

916
 2~5-Dimethylpyrazine. Acetone oxime (17.4 g, 0.2 mole) was added in small portions
to a mixture of stannous chloride (90 g, 0.4 mole) and conc. HCI (130 ml). The reaction
flask was cooled with iced water, and water (200 ml), NaOH (25Z, 380 ml), and ammonium
persulfate (64 g, 0.28 mole) were added in turn. After standing for 2 h it was steam distilled
to give 250 ml of distillate which was extracted with methylene chloride (4 150 m l ) .
The extracts were dried (anhydrous sodium sulfate) and evaporated in vacuo. Distillation
at normal pressure gave a fraction boiling at 153-156~ (lit. bp 153.5-155~ [8]). Yield
6.65 g (56%). PMR Spectrum (CDCI~, TMS): 2.50 (s, 6H, CH~), 8.25 ppm (s, 2H, ring
protons). Mass spectrum, m/z (peak intensity, %): 108 (M+, 60), 81 (12), 42 (i00), 41
(27).
5-Methylpyrazine-2-aldehyde and Pyrazine-2t5-dialdehyde. A flowthrough catalytic re-
actor was charged with 15 ml of catalyst consisting of a mixture of V20 s and MoO 3 (V:Mo -
i:i) loaded at 10% level on corundum granules of diameter -5 nun. A stream of air (40 liter/
h) was passed through, the catalyst heated to 360~ and a 5% aqueous solution of pyrazine III
was introduced (72 ml/h) with a peristaltic pump. (The reaction mixture was diluted with
water to suppress heating of the catalyst due to the exothermic reaction.) At the reactor
exit the organic reaction products and water were condensed in an ice-cooled trap. The
experiment was continued for 6 h and 380 ml of catalyzate was collected. The organic
materials were extracted with ether with GLC monitoring of the completeness of the extrac-
tion. The extracts were dried (anhydrous magnesium sulfate), the ether removed, and the
residue vacuum distilled. The f fraction (i0 g, bp 20-250C, 1 mm Hg) was pyrazine III
which was returned to the oxidation process. The second fraction (4.5 g, bp 38-40~ 1 mm)
was aldehyde I (mp I0-15~ n~ ~ 1.536). PMR Spectrum (CDCI3, TMS): 2.69 (s, 3H, CH~), 8.60
(s, IH, ring proton), 9.04 (s, IH, ring proton), i0.ii ppm (s, IH, CHO). Mass spectrum
(peak intensity, %): 122 (M+, i00), 94 (66), 93 (33), 67 (43), 66 (41), 53 (40), 52 (33)
42 (47), 40 (42).
Recrystallization of the residue from dioxane gave aldehyde II (2 g, mp 96-98~ mp of
bisphenylhydrazone 265=C, lit. mp 266"C [4]). PMR Spectrum (DMSO-d6): 9.25 (s, 2H, ring
protons), 10.53 ppm (s, 2H, CHO). Mass spectrum, m/z (peak intensity, %): 136(M+, 96),
108 (67),80 (13), 79 (23), 54 (13), 53 (75), 52 (100).

LITERATURE CITED

I. M. P. Mertes and A. J. Liu, J. Med. Chem., 13, 77 (1970).

2. F. C. Novello, German Patent 2313636, Chem. Abstr., 79, 146566 (1973)o
3. F. C. Novello, US Patent 3951966, Chem. Abstr., 85, 33092 (1976).
4. Wo Ried and R. M. Gross, Chem. Bet., 90, 2646 (1957).
5. Io G. Iovel' and M. V. Shimanskaya, USSR Patent 777028; Byull. Izobr., 41, 88 (1980).
6. L. Paqiuette, Principles of Modern Heterocyclic Chemistry, Benjamin-Cun~nings (1968).
7. S. Gabriel and G. Pinkus, Chem. Bet., 26, 2197 (1893).
8. H. J. X. Mager and W. Berends, Recl. Trav. Chim., 77, 827 (1958).
9. G. T. Newbold and J. S. Spring, J. Chem. Soc., 373-[1947).
i0. Handbook of Chemistry, [in Russina], Vol. 3, Khimiya, Moscow (1964), p. 750.
II. I. G. Iovel', M. V. Shimanskaya, and L. Ya. Margolis, Izv. Akad. Nauk SSSR, Set. Khim.,
No.. 10, 2301 (1977).
12. I. G. Iovel' and M. V. Shimanskaya, Izv. Akad. Nauk Latv. SSSR, Set. Khim., No. 6,
718 (1982).

917
3-ARYL-I,2-DIHYDROQUINOXALINES

N. N. Kolos, B. Insuasti, UDC 547.863.13.04:541.651:543.422

Kh. Kiroga, and V. D. Orlov

The reaction between o-phenylenediamine and its 4-chioro- and 3,5-dichloro-

derivatives and 4-substituted ~-bromoacetophenones gives 1,2-dihydroquinoxalines.
It has been found that the preferred course of the reaction under basic catalytic
conditions involves the more basic of the amino groups of the diamine in condensation
with the keto group. Anomalies have been found in thespectral-luminescent prop-
~'erties of "the dihydroquinoxalines, owing to specific interactions with protic
solvents.

1,2-Dihydroquinoxalines comprise a little-known group of compounds, probably owing to

their high tendency to undergo oxidation [I]. The synthesis of a number of aryl derivatives
of this heterocycle has been described [4-6], and the spectral and chemical properties of
some compounds have been reported [2].
The object of the present study was to synthesize and examine some 3-aryl-l,2-dihydro-
quinoxalines. The compounds were obtained by reacting o-phenylenediamine and its 4-chloro- and
3,5-dichloro-derivatives with p-substituted ~-bromoacetophenones in methanol, with anhydrous
sodium acetate as catalyst, in an inert gas medium provided by CO 2 or methane.

z'
//. .

Va-h~qb ~c,e,g,h
-llBr, -li20 X ~ VIII.b, C, e,h . Rz

z-m ~a-h
\

1
VIl'b,c,e,g,h;:IXb,e,f,h
I, V R f R t = H ; II, VI, VII RfC1, Rt'fH; III, VIII, IX R f R t f C I ; IV--IX a R2=H,
b R2=CH~, c R2fOCH3,d R2fOC2H,, e R2=C6Hs, s R2=CI, g R~=Br, h R2= NO,

The compounds obtained (V-IX) were identified by IR, PMR, and UV spectroscopy, and by
elemental analysis (Tables 1 and 2). The ~C= N values were little influenced by the substit-
uents R 2 introduced into the aromatic ring, exceptions being (Vh-IXh) as a result of the
considerable electron-acceptor influence of the nitro group. In the PMR spectra, singlets
for the CHz protons, a broadened signal for the imino group, and signals for the 6-, 7-,
and 8-protons of the annelated aromatic ring are readily identified. The UV absorption
spectra of the dihydroquinoxalines (V-IX) are typical of compounds the basic chromophoric
system of which is the fragment o-N-C6H~-N=C-CsH~R [7], characterized by the presence in
the near [IV of three of four clearly apparent bands, the intensities of which decrease
regularly as the wavelength increases.
Compounds (V-IX) are oxidized to the quinoxalines extremely rapidly, especially in
solution. This tendency to aromatization is in some cases so pronounced that, for instance,
the sole products of the reaction of the diamines (II) and (III) with ~-bromoacetophenone
(IVa) are the quinoxalines. For this reason, the dihydroquinoxalines were stored in sealed
ampuls under C02, and the preparation of these compounds for study was preferably carried

A. Mo Gor'kii Kharkov State University, Khar'kov 310077. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. 8, pp. 1127-1132, August, 1986. Original article
submitted April 23, 1985.

918 0009-3122/86/2208-0918512.50 @ 1987 Plenum Publishing Corporation

 TABLE I. 3-Aryl-l,2-dlhydroquinoxalines (V-IX)

fir speCtrum, cm- 1 6 Values, ppmb,c (in CdCla)

Compound Found, Calcu-
Trap, ~ or~la
fpirical lated, Yield, %
VII~N V,N II If! :.' C ! I " 11 7"r|l ~':1
I Nt%
~a 121 t22 d 1615 3376 3,9o 4A7 6,73m 6,97N 6,58q 13.5 CNH,~N2 13.5 55
Vb 125- 127 16t)8 3381 3,9o 4,:lq 6.72m 6.96n 6,49q 12.5 C,sHI4N2 12.6
VC 138-- 13sd 1606 3355 3,93 4.4q 6.~2m 7,08g 6,61 q 1 i.8 CIsHNN~) I 1.8 66
vd 147 149 I (io6 3385 3.9 I 4.28 6.8! m 7.ll51 6.53q 11.2 Cidli6NsO 11.2 66
ve 123--124 1612 3:171 3.92 4.51 6.79 m 7,ll I 6.60q 9.9 C~0H 16N~ 9.9 7(i
vf 137--138 I (i116 3353 3.86 4.4,1 6.75m 7,01u 6,59q 11.6 C.H.CIN2 I 1.5
vg 139--141d 1606 3377 3,88 4 ,.lJl 6,75m 7,00u 6.52q 9.7 C.H.BrN2 9.8 81
Xh 163 -- 165d 1598 3361 3,97 4,46 6.75m 7,00 r, 6.56q 16.7 Ct4H.N302 lfi.6 91
\'l b {6r,) 4,46 6.73m 6_55d
\.'11b 140) 114--116 ! 6O6 3103 3,9~ fi ,5OCl I 1,0 CIsHI~CIN2 I 0,9 52
4,46 6.73q 6,98r
VIC (6{~) 4,33 6.82q ti+47a
VII c Ih~) 109-- I.I I ! 6O6 3383 3,96 4.35 6,93r 6,47d 10,4 CFJt j3CIN20 10,3 55
v i e (60) 16(;6 3363 3.97 4.48 6.74 q 6,54d
V i l e (4o) 8 I--83(dec011p. : 4,48 6,99r 6,49d 8.7 C~oll ~5CIN2 8,8 65
VI g (65) 104 . - 106 ; 1606 3379 3,96 4,43 6,74q 6,54d 8.8
VIIR 135) 4,43 7,00 c, 6,50d CI4H ioBrCIN2 8,7 6'.~
V l h (551 132--134 1596 4.51 6.76q 6.57d
V[Ih (45t 3391 4,05 4.51 7,04q 6,52d, 14.7 Q4HIoCINaO2 1 |,6 81
VIIIb, IXb 126--128 16O I 3327 4.03 9.7 C,stll2CI~N2 9,6 40
VlllC# IXc 118--120 16O6 3409 4,05 8.7 CIsH,~CI2N20 8,7 48
Ville (100) 89,(dec0mP.) 16O6 3425 4.0Y 4.42 6.74d , 6,68 d 8,0 Q~H~4Ch,N2 7,9 58
IXe {0)
\ ' l i f t 056) 140--142 1616 34(17 4,(~0 4.32 6.76d i 6,33 d 8.9 CI4tlmClaN2 9.0 6d
IX f(34) 4.4l 7,04 d a
V l l l h (63) 1596 3405 3,99 4.50 6,godl 6,44d 12.9 CHHaoCI2N30~ 12,8 74
IXh (37) 172--174
4,62

aThe figure in brackets indicates the amount of the isomer inmixtures of (VI) with (VIII) and (VII) with (IX),
Z. bType of spectrum: d - doublet ( d 1 w i t h J = 2 Hz., d 2 w i t h J = 8 H z ) , m - s e x t e t , cSignals identi-
fied, 5-H, 5 = 7.37 q (Vc), 7.27 q (Vh), and 7.28 dl (VII). dAccording t o [ 2 ] , mp ( V a ) 1 4 1 - 1 4 2 ~ (Vc)
138-139~ (Vg) 138-139~ (Vh) 144-146~

M~
 TABLE 2 . Absorption and Luminescence Spectra of (V)-(IX)

labSmax'ra (E -'I0"3) , nm (Stokes .hilt, era. )

Cospound
in methanol in metN--I in toluene

Va 392 (3,6), 292 D1.,258 (19.8) 60r (8870) 514 (606o)

Vb 389 (4,7), 292p1'., 267 (23,6) 593 (8840) 5o9 (6130)
Vc 388 (6,1), 297 (13,9), 277 (20,8) 466 (4300) 539 (7420)
Vd 388 (6,5), 306 (15,4), 279 (22,2) 494 (5530) 5t3 (6480)
Ve 427 (8,6), 301 (22,9), 259 (26,8) 467 (2000) 530 (6130)
Vf 405 (4,5), 294~1., 265 (24,0) 606 (8200) 529 (6100)
vg 405 (4.9), 296"(10.3), 270 (26,0) 617 (8500) 547 (6720)
Vha 448 (4,9), 304 (11,2), 282 (17,0)
VIb, VIIb 391 (4,7), 304 (8,4). 270 (23,0) 573 (8100) 510 (5580)
VIe,VIle 39o (6,2), 308 (14,7), 286 (27,2) 475 (4600) 485 (5090)
Vie,Vile 406 (5,9L 309 (21,4). 286 (27,2) 473 (35O0) 543 (6270)
VIR, VIIg 406 (4,1), 307p1.~268 (26,7) 596 (7850) 550 (6510)
VIh,VIIha 455 (4.7), 305 (10,8). 286 (19,7)
VIIIb,IXb 392 (6,6), 305 (9.4), 274 (24,2) 559 (7600) 503 (5500)
VIIIc.IXc 385 (9,2), 312 (14,5). 286 (22.0) 485 (5300) 546 (7460)
VIIIe,IXe i398 (7,5), 312 (21.5), 287 (27.8) 489 (4700) 525 (6140)
VllIf,IXf _ 1410 (3,9), 302 (8,7), 265 (23,7) 600 (7700) 532 (5530)
V I I I h IX h a 438 (3,3), 344 (7,6), 286 (16,0)

aDid not fluoresce.

out in an inert atmosphere. Even under these conditions, however, it was not possible to
obtain the PMR specta of (VllIb), (IXb), (VIIlc), or (IXc) (Table I).
According to the literature [5], the introduction of substituents R 2 has little effect
on the rates of either step (substitution and condensation) in the formation of dihydroquinox =
alines. In fact, under the same synthetic conditions (concentrations of reactant and
catalyst, temperature, and reaction time) the variation of yields of the dihydroquinoxalines
is slight. Nevertheless, there is a tendency for the reaction rate to increase a s t h e elec-
tron-acceptor properties of R 2 are increased~ For example, (Vh) is obtained in a yield of
91% after 10-15 min. Introduction of chlorine atoms into the o-phenylenediamine molecule
reduces the reaction rate and the yields of the products (VI-IX). This is in accordance
with a report [8] of the influence of substituents on the rate of bimolecular substitution.
It is noteworthy that in the reaction of substituted ~-bromoacetophenones with 4-chloro-
and 3,5-dichloro-l,2-diaminobenzenes, two isomeric products could be formed: 7- or 6-
chloro- and 5,7- or 6,8-dichloro-3-aryl-l,2-dihydroquinoxalines (VI-IX). It will be seen from
Tables i and 2 that substituents R and R l have little influence on the IR and UV spectra of
dihydroquinoxalines, and it is therefore not possible to use them to locate the positions of
the chlorine atoms. Checks for the purity of the compounds by TLC were in this instance
also unreliable in view of the rapid oxidizability of (VI-IX). The isomeric composition
of the compounds could only be resolved by PMR spectrometry.
In the PMR spectra, the signal for the proton in the 8-position of the bicycle is shifted
to higher field than any of the other aromatic protons as a result of the influence of the
electron-donor imino group, and is readily identified. The signal for this proton consists
of a doublet with a coupling constant (J) of 2 Hz (meta-constant [9]) for 7-chloro- ( V I ) a n d
8 Hz (ortho-c0nstant [9]) for the 6-chloro isomers (VII); the weak para-interaction with
the 5-proton of the bicycle was not seen in these spectra. In the PMR spectra of (VIII),
the doublet for the 8-proton (J = 2 Hz) is retained, whereas in the isomeric compounds (IX)
this proton is totally absent. As will be seen from Table 1, the chemical shifts of the 6-
and 7-protons are also highly characteristic, and provide further confirmation of the correct-
hess of this assignment of the signals to these isomers. The effectiveness of such a
spectral analysis of the isomeric composition of heterocycles derived from o-phenylenediamine
has been demonstrated in the case of 2,3-dihydro-IH-l,5-benzodiazepines [i0]~
Having obtained the integral spectra of the relevant protons, we estimated the amounts
of each isomer in the mixtures (VI)-(VII) and (VIII)-(IX) (Table I). It was found that the
~-bromoacetophenones (IV) react with the diamine (II) to give mixtures of the isomers (VI)-
(VII) in a ratio of 3:2 (on average), and with diamine (Ill) to give mixtures of (VIII) and
(IX) (Vlll predominating), or the pure compounds, for instance (Vllle) (for the reasons

920
given above, it was not possible to determine the composition of mixtures (VIIIb)-(IXb)
and (VIIIc)-(IXc)). The ratios of the isomers (VI) and (VII) indicate that there is little
difference in the basicities of the amino groups in the diamine (II). Introduction of a
second halogen atom (diamine III) increases this difference. The results obtained show that
under basic catalytic conditions, the more basic amino group is preferentially involved in
the formation of the azomethine bond, i.e., in the condensation reaction.
These results are in accordance with the findings of, Kano et al. [ii], who examined the
reactions of a number of substituted o-phenylenediamines, including diamine (II), with
~-methylsulfinylacetophenone. In this reaction, 6- and 7-chloro-2-phenylquinoxalines (the
intermediate dihydroquinoxalines were not isolated) were formed in a ratio of 1:3. When
the 4-methoxy- and 4-nitro-derivatives of the diamine (I) were used in this reaction, only
one of the possible isomeric phenylquinoxalines was obtained (the 7-methoxy- and 6-nitro-
2-phenylquinoxaline, respectively), i.e., the more basic amino group is involved in re-
placement of the methylsulfinyl group. It should be noted that Kano et al. [II] used
acidic catalysis, and therefore the difference in the course of the reaction of u-methyl-
sulfinylacetophenone and (IV) with diamines is to be expected in view of the change in
the acidity of the medium.
A very important property of the dihydroquinoxalines obtained is their fluorescence
(with the exception of (Vh-IXh), which contain a nitro-group, Table 2). It has been shown
[7] by quantum chemical calculations of the electronic spectra of molecules containing the
N-arylidene-ortho-phenylenediamine chromophore that the long-wavelength absorption band may
be correlated with the one-electron transition 0 ~ I, localized at this chromophore. This
transition is accompanied by transfer of electron density from the amino (or imino) group
to the azomethine bond, as shown by the effects of the substituent R 2, which are seen
clearly in the experimental spectra of (V)-(IX). Thus, the introduction of electron-
acceptor groups R 2 (CI, Br, NO 2) favors this transfer. The incorporation of the chromophore
system into the flattened'dihydroquinoxaline ring also results in the absorption of (V)-(IX)
being strong as compared with their p, ~-analogs (azirinoquinoxalines and dihydrobenzodia-
zepines [7]), and in the occurrence of fluorescence.
In examining the fluoresence and absorption spectra, obtained in methanol solution
(Table 2), attention is drawn to their differing sensitivity to the electronic character of
R 2, in consequence of which the Stokes shift varies from anomalously high (-8800 cm -l) to
extremely low values (2000 cm-Z'f~r (Ve)). When the spectra were obtained in toluene, these
anomalies were not seen, leading to the conclusion that the spectral behavior of the dihydro-
quinoxalines in methanol is due to solvation by the solvent. It is known [12] that if the
excited state of a molecule is considerably more polar than the ground state, then an increase
in the polarity of the solvent will stabilize the excited state to a greater extent than
the ground state. Stabilization of the excited state will also facilitate specific inter-
actions with the protic solvent.
Stabilization of the excited state in dihydroquinoxalines may occur as follows:

"'"CCH~ 2 ~ H.'" ~ / R 2

R RI N
H'.. H--OCH 3

Electron-donor substituents R 2 destabilize form B, resulting in a considerable hypso-

fluoric effect in the polar solvent, whereas when R 2 is an electron acceptor group, the
opposite effect operates. Stabilization of structure B is much less in toluene than in
methanol, and hence the effect of R 2 on fluorescence lmax is largely evened out.
Worthy of special note is the fact that in carrying out the spectral measurements the
stability of the quinoxalines to oxidation was very different in toluene and methanol. The
spectra of (V-IX) in methanol remained virtually unchanged over periods of weeks, whereas
the measurements in toluene required the prior deoxygenation of the solvent and rapid
scanning.

921
 EXPERIMENTAL

The IR specta of (V)-(IX) were obtained in KBr disks on a Specord IR-75 spectrometer,
electronic absorption spectra in methanol and toluene at concentrations of (2-3)'i0 "s mole/
liter on a Specord UV-VIS spectrophotometer, and fluorescence spectra in the same solvents
using an apparatus consisting of the monochromator from an SF-4A spectrophotometer, an
F~U-38 radiation detector, and a DRSh-500 mercury lamp as light source. The spectra obtained
were corrected for the spectral sensitivity of the apparatus. The optical density at the
excitation wavelength was not greater than 0.2. PMR spectra were obtained on Tesla BS-
2487-B (80) and Varian XL-100 instruments, with TMS as internal standard.
3-Phenyl-!,2-dihydr0quinoxaline <Va). A mixture of I.i 8 (i0 m o l e ) of o-phenylenedia-
mine, 2~ g (I0 n~mole) of ~-bromoacetophenone, and 0.83 g (i0 mmole) of sodium acetate in
50 ml of methanol was boiled under reflux for 2 h, while passing a stream of methane or carbon
dioxide continuously through the solution. Inorganic salts were then removed by filtration,
and the filtrate cooled in a chamber filled with carbon dioxide, which was also used to
filter off the crystals of (Va) which separated, yield 1.14 g (55Z), mp 121-122~ ( f r o m
methanol).
Dihydroquinoxalines (V)-(IX) were obtained similarly, except that for (Vh)-(IXh) the
reflux time was shortened to 20 min.

LITERATURE CITED

I. I. Pratt, in: Heterocyclic Compounds, R. Elderfield, ed., Vol. 6, Wiley(1957).

2. J. Figueras, J. Org. Chem., 31, 803 (1966).
3. So Bodforss, Lieb. Ann., 633, 67 (1960).
4. D.M. Aleksandrova, L. I. Kolotova, and L. Ya. Kheifets, Zh. Org. Khim., 2, 2107 (1973)o
5. D. M~ Aleksandrova, L. I. Kolotova, and B. G. Distanov, Zh. Org. Khim., 13, 112 (1977).
6. Do M. Aleksandrova, L. I. Kolotova, N. A. Lapteva, and B~ G. Distanov, Zh. Org. Khim.,
14, 2433 (1978).
7. F. G. Yar~nenko, V. D. Orlov, N. N. Kolos, and V. F. Lavrushin, Izv. Vyssh. Uchebn.
Zaved., Khim. Khim. Tekhnol., 23, 831 (1980).
8. A~ S. Dneprovskii and T. Io Temnikova, Theoretical Fundamentals of Organic Chemistry
[in Russian], Khimiya, Leningrad (1979).
9. A. Zhunke, Nuclear Magnetic Resonance in Organic Chemistry [Russian translation], Mir,
; Moscow (1974).
I0. V. D. Orlov and S. M. Desenko, Khim. Geterotsikl. Soedin., No. 12, 1683 (1985).
ii. S. Kano, S. Shibuya, and Y. Yuasa, J. Heterocycl. Chem., 17, 1559 (1980).
12. J. Barltrop and J. Coyle, Excited States in Organic Chemistry, Wiley (1975).

922
REACTION OF 7 - A C Y L M E T H Y L - 8 - B R O M O - 3 - M E T H Y I ~ I N E S WITH
FORMAMIDE

N. I. Romanenko, A. A. Klyuev, UDC 547.859.785.5.07:543.51

I. V. Fedulova, B. A. Priimenko,
S. N. Garn~ash, A. Yu Chervinskii,
and A. N. Stepanov

A method has been developed for the synthesis of imidazo[l,2-f]xanthines and

oxazolo[2,3-f]xanthine by the reaction of 7-acylmethyl-8-bromoxanthines with
formamide.

In continuation of the investigations of synthesis in the series of annelated xanthine

and purine derivatives [1-3], we studied the reaction of 7-acylmethyl-8-bromo-3-methylxan-
thines (Ia-d) with formamide. Ketones Ia-d were obtained by reacting the potassium salt of
8-bromo-3-methylxanthine [4] with the corresponding e-bromoketones in DMFA, in analogy to
[1].
0 0 |(

UN
"~___s ~ B ~ - c a - c -1~ "N Z ~'r . . . . :~ " ~I

0:,~ ~ N -""- N ~/"" B~. D~._A O~/'N" N Br

/ ~Jt l ,
xa~d
[ICONH O
0 i,
!i .q
tin i N ...... ,
tiN ...... N" q
N
N N R1
0"-' " N" N "N- - -It
'li .
u.a-d

0
J).,
O ' N" N O "'C~II~NO2-D
I H ;
CH 3 CH~ III

Ia' IIa R=R'fCH~; Ib R=H, RI=C~H4NO~-p; I c II6 RfH, RI=C~H~CI-p; Id II c

R=H, Rm=C6H4Br-p

In the IR spectra of ketones la-d, there are stretching vibration bands of the carbonyl
groups in the 1680-1700 cm -l. In the PMR spectrum of 3-methyl-7-p-chlorophenacyl-8-bromo-
3-methylxanthine (Ic), the following proton signals were recorded (ppm): 3.20 - NCH 3 (s,
3H), 5.53 - NTCH 2 (s, 2H), an AB system with a center at 7.33 - CHarom (q, 4H).
It is known [5] that heating of formamide with halides leads to the formation of either
formylamines or formates, while with hydroxy- or haloketones, formamide forms imidazoles.
It was therefore of interest to study the reaction of ketones Ia-d with form~gxaide, as the
result of which heteroannelated derivatives of xanthine with one of the above indicated
structures could theoretically be formed (see scheme).
We found that, depending on the substituents in the side chain, the reaction of
ketones Ia-d proceeds in two directions only. A brief boiling of 3-methyl-7-(l-methyl-2-
oxo-l-propyl), 7-p-chlorophenacyl-, and 7-p-bromophenacyl-8-bromoxanthines (Ia,c,d) in
excess of formamide leads to substituted imidazo[l,2-f]xanthines (IIa-c). The PMiRspectrum
of 1,6,7-trimethylamidazo[l,2-f]xanthine (IIa) is characterized by the presence of three

Zaporozh'e Medical Institute, Zaporozh'e 330074. Translated Khimiya Geterotsikliches-

kikh Soedinenii, No. 8, pp. 1133-1135, August, 1986. Original article submitted May 4,
1985.

0009-3122/86/2208-0923512.50 @1987 Plenum Publishing Corporation 923

 TABLE I. Characteristics of Synthesized Compounds
I
Com- Found, % Empirical Calculated, % .[ Yield,
11~, ~ formula
pound C H N C H N I
[a 233--235 38,3 3,4 17,5 CIoH.BrN4Oz 38,1 3,5 17,8 41
[b 281--282 41,3 2,4 17,3 Ci4HioBrN6Os 41,2 2,4 17,2 88
Ic 290--292 42,3 2,8 14,3 C,~HtoBrCIN403 42,3 2,5 14,1 89
Id 304--305 38,2 2,4 12,4 Ci4HtoBr2N4Oa 38,0 2,3 12,7 76
lla >330 51,3 4,7 30,0 CloHliNsO2 51,5 4,6 30,0 52
lib >330 53,5 3,0 '~22,6 C~,H,uCIN~.O2 53,3 3,2 22,2 71
I[c >330 46,9 3,0 19,3 Cl~H,oBrNsO~ 46,7 2,8 19,4 75
III >330 50,9 3,2 21,7' CNHgN~Os 51,4 2,8 21,4 69

TABLE 2. Mass Spectra of Synthesized Compounds ,~r

Compound Mass spectrum, m/z (intensity, %)

tla 53 (20),67 (16),73 (8), 82 (12),95 (I0), 120 (lO), 135 (18), 161 (40),
162 (24),163 (10), 189 (I0), 190 (18), 232 (7), 233 (100), 234 (12)
lib ~3 (33), 75 (20), 82 (23), 91 (10), I01 (15), 127 (17), 138 (10), 182
(12), 208 (I0), 217 (24), 219 (8), 243 (55), 244 (44), 246 (40), 247 (16),
272 {55), 273 (13), 274 (19), 315 (100), 316 {17), 317 (33)
IIe 43 (26), 70 (12), 75 (16), 76 (I0), 82 (17), 91 (20), I00 (I0), I01 (14),
107 (i.l), 127 (22), 182 (18), 194 (10), 208 (13), 261 (13), 263 (i3), 287
(35), 288 (25), 289 (41), 290 (25), 316 (32), 317 (13), 318 (32), 359
(98), 360 (18), 361 (100), 362 (17)
III 56 (13), 73 (10), 83 (12), 89 (19), I01 (10), 117 (11), 147 (8), 150 (9),
209 (18), 210 (10), 256 (7), 281 (8), 284 (10), 297 (21), 327 (100), 328
(17)

,Given are ion peaks with intensity of ~ 7%. Evaporation

temperature of the sample 240~ (for (IIa) and 3000C for(II
b, c, III)).

narrow singlets with an intensity ratio of i:i:I at 3.27 (NICHa), 2o17 (CeCH~) and 1.9 ppm
(CvCHs). In the mass spectrum of imidazoxanthine(lla), a peak of M + w i t h m/z 233 is recorded,
which corresponds to the calculated molecular weight. The presence of an isotopic peak
with m[z 234 and intensity of 12.8% corresponds to the empirical formul~ of the molecule
Cl0HlINsO=. The high stability to electron impact (WM = 18%) confirms the cyclic character
of imidazo [l,2-f]xanthine (lla). The dissociation of M + can be represented by the
following ions (m/z): [M -- HI + - 232 (a B-dissociation leading to widening of ~he imidazole
ring),[M - NCHO] + - 190 (retrodienic dissociation of the uracil fragment of the molecule),
[M - H N C O ) - CO] + - 162 and [(M - HCNO) - CO - HCN] + - 135 (ions confirming the structure
of the uracil part of the molecule) [6], [ ( M - H N C O ) - H ] + - 189, [(M - H N C O ) - COH]+ - 161,
[(M - HCO) - CO - H C N - CHa] + - 120 (ions confirming the presence of the imidazole fragment
in the molecule of lla). The mass spectra of imidazoxanthines lla-c are given in Table 2.
Under similar conditions, the reaction of 3-methyl-7-p-nitrophenyl-8-bromoxanthine
(Ib) with formamide results in the formation of 2-p-nitrophenyl-6H-8-methyloxazole [2,3-f]-
xanthine (III), which is a representative of a new heteroaromatic system. In the PMR
spectrum of oxazole III there are two singlets at 3.27 - NsCHa (3H) and 7.67 ppm - CaH (IH).
The proton signals of para-substituted phenyl ring are represented by an A B s with
a center at 7.61 ppm (4H). The mass spectrum of oxazole III has a peak of M +ystem with m/z
327. According to high-resolution mass spectrometry data, the empirical for~mla of the
molecule is CI~HgNsO s (determined 327.0675, calculated, 327.0655)~ With the introduction
of the nitro group and in the presence of an oxazole ring, the character of the fragmenta-
tion of compound III changes substantially in comparison with the case of compounds IIa-c:
fragmentary ions with m/z 297 and 281 are observed, characterizing a nitro group in the
molecule. The oxazole ring (an e-substitution in it) is confirmed by the presence of an
ion with m / z 1 5 0 - [ C O -- CsH4 - NO2] +. In the mass spectrum of III there are also ions
characterizing the uracil fragment of the m o l e c u l e ( T a b l e 2).
All the above data serve to confirm the structure of the compounds obtained.

924
 EXPERIMENTAL

The IR spectra were recorded on an UR-20 spectrophotometer in mineral oil. The PMR
spectra were run on a "Tesla BS-467" spectrometer (60 MHz) in CFsCOOH, using HMDS as internal
standard. The mass spectra were taken on a "Varian MAT-311A" mass spectrometer with a direct
introduction of the sample into the ionic source. Standard measuring conditions were
employed: accelerating voltage 3 kW, cathode emission current 30 ~A, ionizing voltage 70 V.
The characteristics of compounds Ia-d, IIa-c and IIl are given in Table i.
3-Methyl-7-acylmethyl-8-bromoxanthines (Ia-d). A mixture of 2.83 g (10 mmoles) of
potassium salt 3-methyl-8-bromoxanthine [4] and ii mmoles of the corresponding bromoketone _
in 30 ml or DMFA is boiled for 1 h to i h 30 min, then cooled to 20~ and diluted with
water to i00 ml. The precipitate is filtered, washed with i00 ml of acetone and crystallized
from DMFA.
Derivatives of imidazoll,2-f]xanthine (IIa-c). A mixture of 0.01 mole of ketone Ia, Ic,
or Id is boiled for 15 min with 30 ml of formamide, and then cooled to 20~ The precipitate
is filtered, washed with 200 ml of water and 100 ml of acetone, and crystallized from DMSO.
2-p-Nitrophenyl-6H-8-methyloxazolo[2,3-f]xanthine (IIl) was obtained in a similar way
as IIa-c by reacting 3-methyl-7-p-nitro-8-bromoxanthine (Ib) with formamide.

LITERATURE CITED

I. B. A. Priimenko, S. N. Garmash, N. I. Romanenko, N. A. Klyuev, and A. K. Sheinkman,

Khim. Geterotsikl. Soedin., No. 8, 1125 (1980).
2. Bo A. Priimenko, N. I. Romanenko, So N. Garmash, N. I. Gnatov, and A. K. Sheinkman,
Khim. Geterotsikl. Soedin., No. 5, 623 (1980).
3. S. N. Garmash, B. A. Priimenko, N. A. Klyuev, N. I. Romanenko, and A. K. Sheinkman,
Khim. Geterotsikl. Soedin., No. 3, 407 (1984).
4. B. A. Priimenko, N. I. Romanenko, N. A. Klyuev, I. V. Fedulova, N. I. Gnatov, and S. N.
Garmash, Khim. Geterotsikl. Soedin., No. 8, 1129 (1984).
5. A. Fieser and M. Fieser, Reagents for Organic Synthesis, Wiley (1967).
6. Yu~ V. Strokin, I. A. Krasovskii, A. K. Sheinkman, N. A. Klyuev, and R~ I. Sinitsina,
Khim. Geterotsikl. Soedin., No. 9, 1267 (1981).

925
LETTF~RS T O THE EDITOR

REACTION OF 3-NITRO- AND 3,5-DINITRO-DERIVATIVES OF 2-

P Y R I DONEWITHHYD R A Z I N E H Y D R A T E

Yu. M. Yutilov and N. N. Smolyar UDC 547.82.5.7.77.7:546.171:542.953

Recyclization of 5-nitro-2-pyridone on heating it with hydrazine hydrate leads to the

formation of a pyrazole derivative with the same number of carbon atoms as in the starting
compound [i]. The methine C(s ) atom of pyridone is thus reduced to methylene and together
with the carbonyl C(2 ) atom is displaced to the side chain.
In the course of further investigations, it was shown that in contrast to the 5-nitro
isomer, 3-nitro-2-pyridone (Ia) converts, on heating (90-95~ with an excess of hydrazine
hydrate (20 mmoles per m~nole of Ia) for 7 h, into an unsubstituted pyrazole IIa in a yield
of 74Z (mp 69~ according to [2], mp 69-70"C). As well as pyrazole, a carbodihydrazide
was isolated from the reaction mixture (yield 75%, mp 154~ These data show that the
formation of pyrazole involves splitting of the C(2)-C(3)-C(~ ) bonds of pyridone.
Under similar conditions, 4-nitropyrazole (lib) was obtained from 3,5-dinltro-2-pyri-
done (Ib) and hydrazine hydrate in a 87Z yield (mp 162~ according to the data in [3],
mp 161~

++,
'-.,.NIN
tl II
a,b a X=mbX=NO2 n a,b

Compounds IIa, b were identified with authentic samples by the absence of depression
of the melting points of mixed samples and by their of IR and PMR spectra.

LITERATURE CITED

i. Yu. M. Yutilov and N. N. Smolyar, Khim. Geterotsikl. Soedin., No. 12, 1686 (1985).
2. H. Pechmann, Bet., 31, 2950 (1898).
3. K. C. Chang, M. R. Grinlnett , D. D. Ward, and R. T.. Weavers, Aust. J. Chem., 32, 1727
(1979).

Institute of Physical Organic Chemistryand Carbon Chemistry, Academy of Sciences of

the Ukrainian SSR, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii~
No. 8, p. 1136, August, 1986. Original article submitted December Z, 1985.

926 0009_3122/86/2208_0926512.50 9 1987 Plenum Publishing Corporation

FORMATION OF PYRIMIDO[I,2-a]BENZIMIDAZOLES IN REACTION OF
1,2-DIAMINOBENZIMIDAZOLE WITH CHALCONES

V. D. Orlov, S. M. Desenko, UDC 547.785.5

V. P. Kruglenko, V. P. Gnidets,
N. A. Klyuev, and M. V. Povstyanoi

The cyclocondensation of 2-aminobenzimidazole with 1,3-diketones is a known method

for the synthesis of 2,4-disubstituted pyrimido[l,2-a]benzimidazoles [I]. We found that 2,4-
diaryl-substituted derivatives of this bicyclic compound I-III are formed by boiling solutions
of 1,2-diaminobenzimidazole and 1,3-diarylpropenones in DMFA for 8 h. The reaction is accom-
panied by elimination of an amino group from the diamine in the 1-position in the form of
ammonia:
C.sH4B-4'
~0~
~'--NA + 4-RC~H4CfI:CHCOC6HsR-
4
N|[ 2
i
~H 2

Compound I: R = H, yield 52Z, mp 314~ (according to the data in [i], 312-315~ ~C=N
(KBr) 1624 cm-1; kma x (r 343 (16.8), 390 nm (5.5).
Compound II: R = CI, yield 44Z, mp 302-304~ ~C= N (KBr) 1624 cm-1; kmax (e'10-a):
346 (18.0), 390 nm (5.6).
Compound III: R = Br, yield 55Z, mp 298-299~ ~C= N 1624 cm-l; kmax (g'I0"3): 345
(19.1), 390 nm (5.7).
The data of the elemental analysis and mass-spectral determination of the molecular
weight of compounds I-III obtained correspond to the calculated values.

LITERATURE CITED

i. W. Ried and W. Muller, J. Prakt. Chem., 8, 132 (1959).

A. M. Gorkii Kharkov State University, Kharkov 310077. Kherson Industrial Institute,

Kherson 325008. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8. pp. i136-
1137, August, 1986. Original article submitted January 15, 1986.

0009-3122/86/2208-0927512.50 @ 1987 Plenum Publishing Corporation 927

DIRECT INTRODUCTION OF AZOLOAZINE RESIDUES INTO RESORCINOL

V. L. Rusinov, T. L. Pilicheva, UDC 547.565.2'792.9'859.3.04

A. V. Myasnikov, N. A. Klyuev,
and O. N. Chupakhin

The reaction of azoloazines with phenols has already been described. In [i], an
azoloazine- 3-cyano-6,7-dicarbethoxypyrazolo[l,5-a]pyrimidine - is used in the form of a
quaternary salt. As the result, benzofuran or cyclohexadienylidene derivatives are formed,
end not addition products of phenols, as should have been expected.
We succeeded in carrying out a direct hetarylation of resorcinol by azoloazines Ia-d
without converting them into the cationic form. When a mixture of azoloazines Ia-d end
resorcinol is boiled in butanol, 6-nitro-4,7-dihydro-7-(2,4-dihydroxyphenyl)azolo[ 1,5-a]
pyrimidines (IIa-c) and 6-nitro-4,7-dihydro-7-(2,4-dihydroxyphenyl)azolo[5,l-c] [1,2,4]
triazine (IId), retaining the resorcinol fragment in unchanged state, are formed in a 40-
60% yield.

OH Ho~oH

"'X//k~N~IY OH ~X--'NI
H
Ia-d ,I a-d
I.IIa X-N. bX-CNO2, c,d x-CCOOC~.H,;a-c Y-CH. dY.N

The molecular weight, determined mass spectrometrically, end the results of the ele-
mental analysis of the synthesized compounds correspond to the calculated values. The IR
and PMR spectra of adducts IIa-d confirm the proposed structure. Compound IIa, mp 260~
yield 58%; compound IIh, mp 300~ yield 60%; compound IIc, mp 246"C, yield 55%; compound
IId, mp 200-202~ yield 41%.
In the IR spectra of compounds obtained, the nitro group absorbs at 1550, 1340 cm -I,
the NH group of the azine fragment - at the 3300 cm "z region; and OH - at 3450 cm -l. In
the mass spectra fragmentary ions with m/z ii0 and [M - ii0] + are recorded, corresponding
to the resorcinol and hetaryl residues.
In a typical PMR spectrum (DMSO-D6, TMS) there are characteristic one-proton
singlets at 6.65 (7-H), 7.78 (2-H), 8.40 (5-H), 12.60 (4-H), 9.40, 9.60 ppm (OH) and
doublets at 6.20 (2'-H, J2',~' = 3 Hz), 7.12 (5'-H, Js,~, = 9 Hz), as well as a doublet of
doublets at 6.20 (4'-H, J~,5, = 9 Hz).

LITERATURE CITED

i. T. Kurihara and K. Nasu, Chem. Pharm. Bull., 30, 2723 (1982).

S. M. Kirov Ural Polytechnic Institute, Sverdlovsk 620002. Translated from Khimiya

Geterotsikls Soedinenii, No. 8, pp. I137-i138, August, 1986. Original article
submitted March 14, 1986.

928 0009-3122/86/2208-0928512.50 @ 1987 Plenum Publishing Corporation

1,2,3-SELENIUMDIAZOLO[4,5-d]PYRIMIDINE-5,7(4H,6H)DIONE - A
NEW CONDENSED H~TERO SYSTEM

~. I. Ivanov, A. A. Yavolovskii, UDC 547.859.1

V. V. Danilin, A. E. Tkach,
and R. Yu. Ivanova

We have found that the reaction of 6-hydrazinouracil (la) with selenous acid in an
ethanol-water medium, carried out at room temperature for 30 min, leads to compound IIa.

o d
H
N~NHNHz HzSe03 / / II~
0
H "--."%
ta

R
xlb

In the cyclization of 5-hydrazinouracil (Ib) under similar conditions, a strong re-

sinification of the reaction mixture is observed, from which the expected isomer IIb could
not be isolated.
Compound IIa: yield 61Z, mp > 300~ Mass spectrum: m/z 217 (M+). UV spectrum:
Amax 205 (~ 7200), 266 nm (e 11320). IR spectrum: 3320 (NH), 1708 cm -I (C=O). The data
of the elemental analysis correspond to the calculated results.

A. V. Bogatskii Physicochemical Institute, Academy of Sciences of the Ukrainian SSR,

Odessa, 270080. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, p. 1138,
August, 1986. Original article submitted March 14, 1986.

0009-3122/86/2208-0929512.50 9 1987 Plenum Publishing Corporation 929

SYNTHESIS AND PROPERTIES OF 1,6-DIOXASPIRO[4.4]NONANE
AND ITS DERIVATIVES (REVIEW)

L. Yu. Brezhnev, M. M. Vartanyan, T. Yu. Solov'eva, UDC 547.642'722.

V~ A. Zefirova, N~ P. Karzhavina, aSd R. A. Karakhanov 3'728.3.07(047)

Data on methods of synthesis and the chemical properties of 1,6-dioxaspiro-

[4.4]nonane and its derivatives are correlated.

In recent years, the chemistry of spiro compounds has undergone intensive development.
A particularly large number of studies dealing with the isolation of spiroketal structures
from natural sources and the establishment of their stereochemistry by modern spectral
methods have been published, and original methods for the synthesis of natural spiroketals
have been proposed. It has been shown that they have a broad spectrum of biological activity.
Thus, natural spiroketals display antibiotic, anti-anaphylactic [i], antlphlogistic [2], and
antispasmolytic [3] activity. In addi=ion, they are used as catalysts in the manufacture
of polymers [4], as attractants for bark beetles [5], and to accelerate processes involved
in the combustion of solid rocket fuel [6]. Despite the great interest of chemists in such
compounds and the constantly increasing number of publications in this area, there is only
one review on 1,6-dioxaspiro[4.4]nonanes, which was published in 1959 [7]. Our review encom-
passes the literature up to 1984.

I. METHODS OF PREPARATION

i.i. Synthesis from Aliphatic Compounds and from y-Lactones

1,6-Dioxaspiro[4.4]nonane and its dimethyl and diethyl homologs were first obtained by
Fittig [8, 9] starting from lactones of y-hydroxy carboxylic acids. The synthesis of these
compounds included the condenstation of two molecules of the lactone in the presence of so-
dium ethoxide to give a dilactone, conversion of the latter to the sodium salt of a spiroketal
acid by heating with a concentrated solution of sodium hydroxide, and decarboxylation of the
resulting acid by refluxing with water or a dilute mineral acid:
O

R ~...o. ~ O ....... k .. . . . Oi \ ~ - . . . . . R ~ "O L---] I

R

/
COOl[

R=H. CH~. CzH s

The yields of the dimethyl- and diethylspiroketal reached 80%, whereas the unsubstituted
spiroketal was obtained in lower yield as a consequence of partial cleavage of the 5utyrolac-
tone and the formation of a hydroxybutyrlc acid salt. A spiroketal from butyrolactone and
its dimethyl derivative from valerolactone were synthesized 10 years later by the same method
(in the presence of diethylzinc) [i0]. This method was also used for the preparation of
spiroketals from u-substituted y-lactones [Ii].
Volhard [12] proposed a new method for the preparation of such structures starting from
aliphatic y,y'-dihydroxy ketones. He obtained diallylacetone dihydrobromide from diallylace-
tone by the action of hydrobromic acid, and 2,7-dimethyl-l,6-dioxaspiro[4.4]nonane was iso-
lated by refluxing it with potassium carbonate solution:

N. D. Zelinskii Institute of Organic Chemistry, Academy of Sciences of the USSR, Moscow

117913. Translated from Khimiya Geterotsiklichesklkh Soedinenii, No. 9, pp. 1155-1168,
September, 1986. Original article submitted August 22, 1985.

0009-3122/86/2209-0931512.50 0 1987 Plenum Publishing Corporation 931

 /(CH2)2CH=CH2 liBr 0 :C/(CII2)zCHBrCH3
~(CH2)2CH=CH2 \(CH2)~CHBrCH~

K.zCO3J--H20 -~~ :-C/(CH2)2CH(~

[ " 0
.(CH2)2CH(OH)CH,I CH ,<...0:~_~
---- i | 0 T CH,

A method for the preparation of spiroketals from keto dicarboxylic acid diesters was
later developed [13] :

C2H$O2C(CH2)2-C0-(C~2)2C02C2H5.. (CH20H)2~
-~ 0 IC----'-~
I --4.-
I 2 0 0 -
\C.I
C~HsO2C(CH2)2/ ~(CH2)2CO~C2Hs
II
:_ -(CH20tl)2
LIAIH. I I ..... H+ =- ~--~ .0.
/0 0
~C
HOCH2(CH~)2/ "(CHz)2CH20H
IU W

A simple method for the preparation of substituted spirononanes on the basis of acetone
dimethylhydrazone and oxiranes was proposed in 1983 [14, 15]:
0 0
S--N(CH,), / \ . N--N(C%)z / \ ~' .-
Bul/ - J~IR B,,u. HOA~
CH CH., CH~
Of/
N--N(CII))z
RI ~ j i ~ R H* 0 R
OH OH R~

R. R I =A1k

T h e one-step synthesis of spiroketals by oxidation of heptane-l,7-diol with lead tetra-

acetate in refluxing benzene in the presence of calcium carbonate was realized in 1965-1969
[16, 17]. However, because of the difficulties involved in the isolation of the spiroketals
from the mixture of oxidation products, the yields of the desired products were less than
30%. The enantioselective synthesis of chalcogran from D-glucose [18, 19], as well as from
the (S)-(--)-bromo epoxide [20], was accomplished by cyclization of the dihydroxy ketone.
Unsaturated spiroketals that are present in products of plant origin [21, 22, 24-28] were
synthesized by cyclization of alkenyl dihydroxy ketones [21-23]:
HCOOC2Hs
(CH~)2C(OH)C-~CH + C2Hb-%fgBr ~--- (CH3)2C(OII)C=CCtI(0H)C~CC(CH~)2OH~

9 H2' P d / B a S 0 4 (CH3)2C(OII)CH=CIICH(OII)CH=CHC(CII~)~:Oll WnOz~,..

The structure of the principal aggregation-sex pheromone which is produced by male

bark beetles of the species P~tyogen~8 c;~do~rphu8 was recently established [5]. This
pheromone was isolated and identified as a mixture of isomers of 2-ethyl-l,6-dioxaspiro-
[4.4]nonane (V) and was named chalcogran. The high biological activity of chalcogran as an
attractant for'hark beetles which feed on the Norwegian spruce was confirmed by field tests
[5, 29]. A number of syntheses of chalcogran have been described [18-20, 23, 30-39]. A pre-
parative method for the synthesis of chalcogran and its homologs based on the reaction of
lithium salts of protected alkynols with equimolar amounts of lactones and subsequent hydro-
genation, acid-catalyzed hydrolysis, and cyClization can be considered to be extremely effi-
cient [37, 40, 41]:

R~O

932
 A series of homologs of chalcogran was obtained in rather high yields by this method.
The synthesis of 2,2,7,7-tetramethyl-l,6-dioxaspiro[4.4]non-3-ene, which was obtained in
42% yield from y,~-dimethyl-y-butyrolactone and the lithium salt of the tetrahydropyranyl
ether of 2-methyl-3-butyn-2-ol with subsequent hydrogenation over Pd/CaCOs, was presented
in [23]. 7-Methyl-l,6-dioxaspiro[4.4]nonanylacetic (exogonic) acid and its methyl ester
(28% yield) were obtained by the same method from the lithium salt of (carboxymethyl)-y-
butyrolactone.
A model synthesis of enol ethers of spiroketals [43-47] on the basis of 2-hydroxytetra-
hydrofuran via the following scheme was developed to confirm the structures of a large group
of polyyne compounds [42-79] from natural sources:

HO.~--
~ , + HCmCC:.C-IA ~ HC_~CC~.CCH(OH}(CH:).CHnOM

t_~.AJHt KOM, 8 r -
e HC~CCB=CHCH(OH)({H:~z~-Hz~ ~'- ~tCmC"H=s ---"-"

CH3(CmC)z~H CH3(C~C)3CH=L~ICHiOH)(CHz)zCHzOH ~ Cli2(C=C)3CH=CIi-CO'-(CHz)aCHzOH ----gm-

CH~(C~C)$CH=CI$- ~ CH~(C~C)z-CH~ ~ 0
BO

A method for the preparation of spiroketals by incramolecular cyc!ization of a hemiace-

tal through selenium-containing derivatives was proposed in [80] :

ph~e'..s~ .... !.,--~ H2/'~i

i.... ~ .(CHz~zCH=CHCH 3 ~--am. V
'..o..<.o.
ZmBr2 ' 0 :<\ | -SePh
0 :., <,CH3

Spiroketal structures, together with condensed structures, were obtained in the oxidative
addition to butadiene of acetopropyl alcohol or dihydro-~-methylfuran under the influence of
the Mn(OAc)~-Cu(OAc)= oxidizing system [81]:

: ~ . ! -i .... ' .E~

J[ - o,, 4 < o !"o" "ii " "'o :",~

CII~ ('[Ia
OF + ~5.~..,.r M n (IIl)-Cu (It)/<"

,r . . . . . ~ .... ...... .% H
,,,5< / :..o...,<,,~-,, .. , .
"o '\o/~...~" F. " \o'~"
An original method for the synthesis Of spiroketal IV from ethyl 3-cyclopropyl-3-oxo-
propionate in 58% yield was proposed in 1956 [82]:

0 I J IV
COCH2COaC2H~ NaOC2H5 ~.,,..0

The Va, b (2R,bRS) and Vc, d (2S,bRS) diastereomers of chalcogran were obtained as the
key products by alkylation of the dianion of e-acetyl-y-butyrolactone with optically active
epoxybutanes [30, 31, 83]:

q
o : F Va.b
-----m- +
0 Vc,d

1.2. Synthesis from Tetrahydrofuran Derivatives

A method based on Diels-Alder condenstation between 2-methylenetetrahydrofuran and
acrolein with subsequent oxidation of the resulting spiroketal VI to the corresponding car-
boxy aldehyde VII has proved to be quite successful [34, 38]:

933
 CH2
Vl
~ CHO

Vll

{C6Its)3P--CH2~-- ~ H2/Ni--
78~. 89% -- Y

The previously unknown substituted 1,6-dioxaspiro[4.4]non-2-enes were obtained by con-

densation" of tetrahydrofurfural with acetylacetone and acetoacetic ester [84, 85]:

~
OR I --;-1 ]

. 0 CH:.,.,,CORI .. . ,. . CORgi

: _ 9- -- ~
" . COR : " ,

~ O ~ R ~ a R--RI=CH3; b R=OC2HB. RI=CH3

The maximum yield (65%) was achieved when a mixed catalyst, viz., piperidine or 8-ala-
nine with acetic acid, was used. Similar compounds in even higher yields (up to 70%) were
obtained [86, 87] by thermal isomerization of propargyl esters of the tetrahydrofuran series.
The reaction was carried out on quartz in a flow-type reactor at 500at in an inert gas stream.
It was shown that both acetates and benzoates in the vapor phase undergo isomerization to
substituted 1,6-dioxaspiro[4.4]non-2-enes:
R~ COR 2 R1 COR =

C~--C ~.CR 2 R3 R2
I
OCOR ~
R'=H, CH3; R2=CH3, C~Hg,C6H~; R~=CH3, C6H~

Tetrahydrofuran alcohols Vlll were the key compounds for the synthesis of chalcogran pro-
posed by Torgov and coworkers [88]. The yield of chalcogran from VIII was 57%.

CH30---
-- %,

~=H. A=

1.3. Synthesis from Furan Compounds

1.3.1. CatalYtic Hydrogenation. 1,6-Dioxaspiro[4.4]nonane (IV) was detected for the
first time in the products of hydrogenation of furylacrolein in 1934 [89, 90]. Hydrogenation
was carried out on Raney nickel at 160~ and atmospheric pressure, and the yield of the spiro-
ketal did not exceed 33%. It was later established [91] that 1,6-dioxaspiro[4.4]nonane and
its 2,methyl homolog are formed in better yields (38-54%) in the hydrogenation of l-furyl-3-
propanol and 1-furyl-3-butanol over nickel on kieselguhr than in the case of hydrogenation
of the corresponding unsaturated furan oxo compounds under the same conditions.
The formation of 2-methyl- and 2-(=-furylethyl)-l,6-dioxaspiro[4.4]nonane was noted in
[92] in the hydrogenation of furfurylideneacetone and difurfurylideneacetone with a copper-
chromium catalyst; the yields of splroketals ranged from 15 to 25%. A number of homologs of
1,6-dioxaspiro[4.4]nonane were isolated in 30-40% yields in the hydrogenation of furan un-
saturated alcohols in the liquid phase on a Raney nickel--aluminum catalyst [93-95]~ 3-Methyl-
and 3-ethyl-l,6-dioxaspiro[4.4]nonanes were obtained in 12-20% yields from the products of
hydrogenation of e-alkyl-8-furylacroleins on a copper--aluminum catalyst. The following reac-
tion mechanism was proposed in a study of the formation of spiroketal structures [91, 96, 97]:

R=AI]~

934
 The experimental data on the formation of spirans in higher yields in the hydrogenation
of furan alcohols than in the hydrogenation of aldehydes and ketones served as a basis for
this assumption. In addition, the scheme of the formation of acetopropyl alcohol in the
hydrogenation-hydration of 2-methylfuran proposed in [98] was taken into account. Ponomarev
ec al. synthesized 1,6-dioxaspiro[4.4]nonane derivatives by hydrogenation of various furan
alcohols [7, 96, 97, 99-109]. It was established that, like primary and secondary furan
alcohols that contain a hydroxy group attached to the third carbon atom of the side chain
(y-furylalkanols), tertiary y-furylalkanols undergo cyclization with the formation of gem-
disubstiCuted spiroketais in 20-78% yields when they are hydrogenated in the presence of
nickel catalysts. The authors showed that the formation of homologs of 1,6-dioxaspiro[4.4]-
nonane depends on the structure of the starting alcohol and the nature of the catalyst [104].
The following dependence of the yields of spiroketals in the hydrogenation of y-furylalkanols
on the nature of the catalyst was observed: nickel on kieselguhr >5% Ru/C > Raney nickel.
The structure of the side chain of the furan alcohol has an even greater effect on the yields
of these products. The yields of 1,6-dioxaspiro[4.4]nonane homologs from tertiary y-furyl-
alkanols are higher than those from secondary y-furylalkanols; however, bulky subsCitu-
ants attached to the third carbon atom in the side chain hinder cyclization, and the
spiroketal is formed in 4% yield. The yields of 1,6-dioxaspiro-[4.4]nonane homologs
increase significantly in the hydrogenation of tertiary y-furylalkanois with aikyl
substituents attached to the first (from the ring) carbon atom of the side chain; in
a number of cases the spiroketals are the chief reaction products. It has been assumed
[104] that the presence of a branched side chain attached to the first (from the furan ring)
carbon atom, by hindering hydrogenation of the double bond between the ring Ca and Ca atoms,
creates favorable conditions for the formation of the intermediate 4,5-dihydrofuran compound
that is necessary for the subsequent cyclization.
The catalytic hydrogenation of furan compounds has been successfully used for the syn-
thesis of a number of natural spiroketals. Thus, Dedek et al. [ii0, iii] were able to
accomplish the synthesis of exogonic acid by hydrogenation of isopropyl 5-(3-hydroxybutyl)-2-
furylacetate over Raney nickel (160~ 7MPa) with subsequent alkaline saponification:
H2/N i
-- ~ I I / 0 ~/CH2COOCH(CH3)2
CH3CH(0H)(CH2) 2 //~" 0 / ~ CH2C0 0CH( CH~ )z CH3~O/~_~

NIOH

CH 3 O

Among the numerous methods for the synthesis of chalcogran and its analogs, the hydro-
genation of furan compounds under mild conditions (at room temperature and atmospheric pres-
sure) over 10% Pd/C can also be considered to be quite successful [32]. The yields (20-53%)
vary as a function of the substituents.

" =~- l / 0 R2
C-~-C--CHE ;~ R' /
R ~R" I
OH R~/ %R 3

1.3.2. Electrolytic Alkoxylation of yTFurylalkanols and y-Carbonyl-Containing Furan-

Compounds ,. On the basis of the Ciauson-Kaas method, Ponomarev et al. [112-118] developed a
new method for the preparation of ~,6-dioxaspiro compounds by electrolytic alkoxylation of
y-furylalkanols. The authors started from the assumption that, because of the spatial close-
ness of the hydroxy group in the side chain to the furan ring in such alcohols, in addition
to alkoxylation, intramolecular cyclization is extremely likely:

l IO R
~L TR
~0" ~CH~CHz CHaO" 0 ~ R

R, RT=Alk

It was established that primary, secondary, and tertiary y-furylalkanols are converted
to the corresponding 2-methoxy-l,6-dioxaspiro[4.4]non-3-ene derivatives in the case of elec-
trolysis of solutions of them in methanol [i14-i16]. The yields reached 76% of the theoreti-
cal values. In a study of the alkoxylation conditions it was shown [i17] that the presence
of a methyl group in the 5 position of the furan ring in the alcohols does not have an appre-

935
ciable effect on the formation of 2-methyl-2-methoxy-l,6-dioxaspiro[4.4]non-3-enes and that
an accumulation of alkyl groups in the aliphatic chain, particularly the presence of a gem-
dimethyl group attached to the first (from the furan ring) carbon atom of the side chain,
significantly facilitates cyclization under electrolysis conditions. The yields of polyalkyl-
substituted 2-methoxy-l,6-dioxaspiro[4.4]non-3-enes reached 95%. Similarly, a number of 2-
ethoxyspirononenes were obtained in 76-83% yields in the electrolysis of solutions of primary,
secondary, and tertiary y-furylalkanols in ethanol IllS]. Makrushina and Shulyakovskaya stud-
ied the electrolytic alkoxylation of y-carbonyl-containing furan compounds [119, 120]. It was
shown th@t under electrolysis conditions aldehydes'and ketones of the furan series behave
differently. The electrolytic methoxylation of furan aldehydes led to 2,7-dimethoxy-l,6-
dioxaspiro[4.4]non-3-enes in 72-75% yields.

R~(CH2)2CH O (NH4Br)CH~OHIc
|=" R ~----~
r OCH3 ] ~ R~OyOCH~
L~H~O~'~O/~CH2CH2CH(OH)OCH~ CH~O O ~._.~
R=ll.CH5
The authors assume that the hemiacetal of the furan aldehyde is formed as an interme-
diate during the reaction. The electrolytic methoxylation of furan ketones led to 2,5-
dimethoxy-2,5-dihydrofuryl-3-butanones; the formation of spiro compounds was not observed.
In addition to the electrolytic alkoxylation of furan compounds, chemical alkoxylation,
which has been successfully used to prove the structures of natural spiroketals isolated
from various higher plants, has been used for the synthesis of 1,6-dioxaspiro compounds [44,
47]. Chemical alkoxylation has also been used for the synthesis of enol ethers of spiro-
ketals that have sulfur-containing groups as an additional function [45].
A photooxidative analog of the Clauson-Kaas reaction was proposed in 1982 [121] for
the conversion of furan compounds to alkoxydihydrofurans. A mixture of diastereomers of
2-meChoxy-l, 6-dioxaspiro [4.4]non-3-enes, which are structural units for many natural com-
pounds, was obtained from 4-(2-furyl)-2-butanol in good yield.
OH

R=H, CH~

2. PROPERTIES OF 1,6-DIOEASPIRO[4.4]NONANE AND ITS DERIVATIVES

With respect to their chemical structures, 1,6-dioxaspiro[4.4]nonane (IV) and its homo-
logs are intramolecular cyclic spiroketals of y,y'-dihydroxy ketones. 1,6-Dioxaspiro[4.4]-
nonane is a molecule that has activity without the presence of an asymmetric atom. The five-
membered rings of spiroketal IV lie in mutually perpendicular planes, and the relative orien-
tation of the oxygen atoms in the rings (to the right and left of the spiral) is responsible
for the existence of optical antipodes; this was confirmed experimentally by the asymmetric
synthesis of optical antipodes by hydrogenation of furylacrolein over nickel applied to
an optically active support (d- and l-quartz) [122-123] and l-(2-furyl)-3-butanol over Raney
nickel modified by D-tartaric acid [124].
It has been established [8, ii, 12, 90, 91, 125] that 1,6-dioxaspiro[4.4]nonane and its
alkyl derivatives react with concentrated hydrohalic acids to give dihalides, which are
readily hydrolyzed to dihydroxy ketones; the latter are converted to the starting spiro-
ketala as a result of spontaneous intramolecular cyclization to the starting spiroketals:

R ~ E 1 + ~HBr ~ RCHBr(CHz)2CO(CHz)aCHBrP.
~

Ketone IX was obtained in 43% yield by acetylation of spiroketal IV with acetic anhy-
dride. Acetylation of the same compound with acetyl chloride led to l-acetoxy-7-chloro-4-
heptanone (X) in 62% yield [126]. Products of acidolysis of spiroketal IV by organic acids
(HX) were isolated in quite good yields and were characterized.

936
 .(CH2)3OAe Ac~O AcCl /(CH2)3OAe +H~
O=C~ ~ - ~ ~ O=C~ ; ~ ~ O=C I(C~z)3~
9(CH2}~0Ae (CHz)~Cl ~(CH2)3X
X
X=HCO0, CHsCOO, CICH2CO0
The experimental facts under consideration are in good agreement with the general mech-
anism of acidic hydrolysis of acetals. Like ordinary ketals, spiroketals with saturated
carbon bonds are characterized by stability in alkaline media [8]. As regards the carbonyl
derivatives of 1,6-dioxaspiro[4.4]non-2-enes, heating to 45~ with 15% sodium hydroxide
solution led to 2-(2-hydroxyethyl)-3-methyl-2-cyclo-l-pentenone in quantitative yield [84]:
cc :,H~ 0

OH-

Butyrolactone was obtained in the oxidation of 1,6-dioxaspiro[4.4]nonane with nitric

acid, whereas oxidation of the simplest spiroketal with potassium permanganate in an aqueous
medium led to succinic acid in good yield [7]. Spiroketals are quite active reducing agents.
They react with an an~oniacal solution of silver oxide with gentle heating to give a silver
mirror [7].
When a solution of spiroketal IV in benzene is refluxed with powdered sodium, it is
reduced to the y-tetrahydrofurylalkanol in 48% yield [126]. Hydrogenolysis of saturated
spiroketals was detected under severe hydrogenation conditions. Thus, spiroketal IV at
2000C and 10-20 MPa undergoes partial reduction in the presence of nickel on kieselguhr to
give tetrahydrofurylpropanol in 39% yield [89]. 2-Methyl-l,6-dioxaspiro[4.4]nonane forms a
mixture of octane-l,4,7-triol (47.8%) and tetrahydrofuryl-3-butanol (18.2%) when it is hydro-
genated under pressure (20 MPa, 200~ nickel on a zeolite) in the presence of water and a
small amount of formic acid. In the presence of copper--chromium catalyst under the same con-
ditions 56.2% octane-l,4,7-triol and 16.2% tetrahydrofuryl-3-butanol are formed [127].
The hydrogenation of polyalkyl-substituted 2-methoxy- and 2,7-dimethoxy-l,6-dioxaspiro-
[4.4]non-3-enes in the presence of heterogeneous and homogeneous rhodium catalysts has been
investigated [3, I14-120]. The hydrogenation of unsaturated spiroketals XI under pressure
of i0 MPa at room temperature in the presence of Raney nickel led to the corresponding me-
thoxyspiroketals XII in 70-89% yields. Not only reduction Of the ring double bond but also
splitting out of the methoxy group to give saturated spiroketals XIII (54-69% yields) were
observed at a high temperature (IO0~ [118-120].

R' CII~O~ ~O: ~ _ ~ ' R ' Cl,30''O/~_~'R '

XIII XI XII
R. R~ =Alk

The hydrogenation of spiro-3-nonene derivatives that contain not only a methoxy group
but also a methyl group in the 2 position leads, even at room temperature in the presence of
Raney nickel, to a mixture of products [1!7]:

R. R' =AIk

The corresponding saturated 2-methoxy-l,6-dioxaspiro[4.4]nonanes were obtained in quanti-

tative yields in the hydrogenation of polyalkyl-substituted 2-methoxy-l,6-dioxaspiro[4.4]non-
3-enes under mild conditions in the presence of homogeneous catalysts based on rhodium com-
plexes. Splitting out of the methoxy group was not observed. A catalyst based on a complex
of rhodium with fluorescein was found to be the most effective [3].
It is known [128] that 2- and 3-methyl-l,6-dioxaspiro[4.4]nonanes in the vapor phase on
platinized carbon at 300-320~ undergo the following transformations:

937
 l , z ~ ~,~ ic~/o ,~ ---'-- c-c0-(c)4-c + c--CLCO--(C)s-c

x
/ - - _ _

2-ootanone

r-~
: iC"
9 " " 'a~' " % ~" C-~o.'~ ! --~,','- C-C-CO-C.C-C

CII~ L , i - -
/-~o.-\ C ....
C C

It should b e noted that, in addition to the final reaction products, viz., aliphatic
ketones and diketones, intermediates, viz., tetrahydrofuran homologs and a tetrahydrofuran
ketone, were isolated. The behavior of the simplest spiroketal (IV) in the vapor phase on
pumice and various forms of Si02 at 340-360~ has been examined. Spiroketal IV remains un-
changed on pumice, whereas when silicon dioxide is used, IV undergoes partial conversion to
8- (tetrahydro-2-furyl) propionaldehyde and 3- (4,5-dihydro-2-furyl) -l-propanol [129 ].
Pyrrolizidine (XIV) (6% yield) was isolated when spiroketal IV was treated with an equi-
molar mixture of concentrated formic acid with f0rmamide. The same compound was obtained in
higher overall yield (36%) by a three-step synthesis through oxime XV with subsequent hydro-
genation on Adams' catalyst and treatment of the resulting amino diol XVI with hydrobromic
acid [126]:

NIIzOH 9 /(CH2)~OH HZ/Pt02 .(CHz)~0H KSr ~ N

IV --------H0N =C (CH2)~01~ ---NHz--CH.(CH2)~0H

HC00H. H C O N H 2

N-Substituted l-(2-pyrrolyl)-3-alkanols were obtained in 42-98% yields in the reaction

of 2-methoxy-l,6-dioxaspiro[4.4]nonanes XII with primary amines [130].

~I + H2NR 2 ~ m~"~CH2CHz
CRRIOH
#

3,5-Dimethyl-4-(5-hydroxy-2-oxopentyl)-N-phenylpyrazole phenylhydrazone was obtained

in 42% yield as a result of the reaction of spiroketal XVII with phenylhydrazine at room
temperature [84] :
~COCH 3

PhNHMH2_ H0
CHs " -- N N
FhNH CR 5 N
r
xvii Ph

In [131-139] it was shown that the bromination of 1,6-dioxaspiro[4.4]nonane with dioxane

dibromide takes place in the 4 and 9 positions. It was subsequently observed that mono- and
dibromo derivatives of the spiroketal are also formed in rather good yields (58-78%) upon
reaction with bromine in the presence of calcium carbonate [134]. Instead of the expected
spirononenes XIX, (hydroxyalkyl)furans XX were isolated in the dehydrobromination of mono-
bromo-substituted spiroketals XVIIIa-c [134, 135].
~Br -I

R
OH
l%q~ a- c kqx

)D~ X'VIIIa R=R'=rob R=H.R'=CH=;CRfR'=CH=

938
 The only reaction products in the dehydrobromination of monobromo derivatives of 1,6-
dioxaspiro[4.4]nonanes with several alkyl substituents were the corresponding spirononenes
[i35]. Their yields reached 83%. The peculiarities of the chemical structures (internal
two-ring ketals) of 1,6-dioxaspiro[4.4]nonane derivatives have also been reflected in the
reaction of monobromo-substituted 1,6-dioxaspiro[4.4]nonanes with sodium metal. The expected
3-(4,5-dihydro-2-furyl)propanol could be isolated in 70% yield only in the case of the simples
bromospiron, viz., 4-bromo-l,6-dioxaspiro[4.4]nonane (XVIIIa) [136].

~---~ 0 RZ Na H 0

l~I / J ' ~ O / ~ R ~ R ~~ CHRSCHR4CRJRZONa

R3 / ~R 4

Kx1!

In the action of sodium on monobromo-substituted 1,6-dioxaspiro[4.4]nonanes with several

alkyl substituents the principal reaction products were the corresponding spiroketals XXII
(60-70% yields). It was assumed that they are formed from intermediate (dihydrofuryl)alka-
nolsXXI, traces of which were detected in the reaction products by means of IR spectroscopy.
Under the conditions of the Grignard reaction in the case of equimolar amounts of the
reagents or an excess of the organomagnesium compound [137] 1,6-dioxaspiro[4.4]nonane (IV)
and its 2-methyl homolog react only with one molecule of RMgX to give the corresponding 3-
(2-R-tetrahydro-2-furyl)propanols [138]. The reactivities of the spiroketals in the reac-
tion with Grignard reagents depend on the nature of the substituents. Thus, for example,
when a methoxycarbonyl group was present, cleavage of the acetal bond of spiroketal XXIII was
not observed, and tertiary alcohol XXIV was isolated in 72% yield [139]:
OOCH~ .C(CsHs)2 OH
CsHs'~gS=-----

XXH! )D[IV

Methoxy-substituted 1,6-dioxaspiro[4.4]non-3-enes have been used as dienophiles in the

diene synthesis. The reaction of 2-methoxy-7-methyl-l,6-dioxaspiro[4.4]non-3-ene with var-
ious dienes in absolute toluene at 130-160~ was realized. The yields of adducts ranged
from 20 to 48% [140].

~o~ ~ :c"~ + ~ ~ ~ o\ c,~

c~,o ~._7 c.,o/<,,o~ _ _ ~ ""

Using dimethyl sulfoxide, which is known for its high isomerizing ability, as the sol-
vent, Karakhanov et al. [84] were able to obtain 2-methyl-3-acetyl-5-(3-hydroxypropyl)furan
from spiroketal XVII by refluxing in an inert gas atmosphere.
It was recently shown that 1,6-dioxaspiro[4.4]nonane (IV) reacts with ferrocene in the
presence of Lewis acids [141]. The pathway of this acid-catalyzed reaction depends on the
nature of the catalyst. When boron trifluoride etherate or aluminum chloride was used as
the catalyst, the reaction proceeded with the formation of 2-ferrocenyl-2-(3-hydroxypropyl)-
tetrahydrofuran (XXV) (55-89% yields). The authors feel that diol XXVI is formed only at
the end of the process, when the reaction mixture is treated with ice water, as a consequence
of reaction of the principal product (XXV) with the hydrochloric acid liberated in the hydro-
lysis of AICI,. The reaction with ferrocene in the presence of trifluoroacetic acid led to
a mixture of ferrocene derivatives. The isolated ferrocene derivatives are used as components
for the direct introduction of ferrocenyl groups into polyurethane systems and as catalysts
for the acceleration of the combustion of solid rocket fuel [6].

939
 i. AIC[~ [ ~ F-c + Fc-~(CIt2)30H
IV + FcH 2. H20 <~.O1 <~(CH2~OH CIICHzCII20H
I ~'~%" X.'XVI
CFjCOOH

Fc (CH~),Ot[ fro(eli2), , I
,L-k'V"+ .~[XVI ~C ~ "- + -~C(Fc) i (Csli,)~F'e
Fo~ "(CH~hOH [ ~o(c:. ), ~ ]

Fo= CsHsFeCsH ~

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940
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SYNTHESIS AND THREE-DIMENSIONAL STRUCTURES OF 2-(2-FURYL)-

ACRYLONITRILES

V. G. Kul'nevich, P. A. Pavlov, and G. D. Krapivin I/DC 547.722.321.1.239.2

543.422.254.6

Conditions for carrying out the Schmidt reaction that make it possible to ob-
tain 8-(2-furyl)acrylonitriles in high yields were found. It was shown by PMR
and IR spectroscopy that the furylacrylonitriles obtained have an E-s-cis con-
figuration.

In a previous communication [I] we described the conditions for the synthesis of 2-

cyanofurans from the corresponding 2-formylfurans via the Schmid~ reaction. These conditions
were found to be unsuitable for the synthesis of furylacrylonitriles IIa-h from furylacro-
leins Ia-h because of pronounced resinification of the reaction mixtures. One can, however,
avoid resinification if dioxonium perchlorate is introduced into the reaction mixture in-
stead of HCIO~.
O
RI C RI CN

R/---o
~a-h na-h
R=H, C H y C6H 5, ~.4.S-CsH2C| 3, NO2; RI=H, CH 3

According to PMR data, starting furylacroleins I have an E configuration [2, 3]. We

were interested in the peculiarities of the three-dimensional structures of the resulting
ni~riles IIa-h (Table i).
The Ha K~ spin-spin coupling constants (SSCC), which are 15.0-17.0 Hz (when R ~ = H) and
1.4-2.0 Hz (when R ~ = CH3) (Table 2), constitute evidence for a trans orientation of these
groups relative to the exocyclic double bond in IIa-h. Their IR spectra contain an absorp-

Krasnodar Polytechnical Institute, Krasnodar 350006. Translated from Khimiya Geterot-

siklicheskikh Soedinenii, No. 9, pp. 1169-1171, September, 1986. Original article submitted
May 27, 1985.

0009-3122/86/2209-0943512.50 9 1987 Plenum Publishing Corporation 943

 TABLE i. Characteristics of 8-(2-Furyl)acrylonitriies lla-h
Com- bp (rnm) Found, ~/o Empirical Calc., % Yield,
pound [mp], "C !
formula c H N %
C H I N

IIa [34] 71,2 4.4 11,8 CTH~NO 70,6 4,2 I 1,8 75

Itb~ 95 (5) 72,85 5,5 10,7 CnHTNO 72,2 5,3 10,5 84
Ecu 94 (5) 72,8 5,6 10,7 C~H~NO 72,2 5,3 10,5 74
lidc 112 (5) 73.9 6,4 9,6 CgHgNO 73,5 6,1 9,5 78
lie [711 80,6 4,8 7,7 C~FIgNO 80,0 6,1 7,7 86
Ilf [1381 81,0 5,4 6,7 CI4HuNO 80,4 5,3 6,7 85
18Ol 51,7 1,9 4,7 CIaH~CINO 52,0 2,0 4,6 88
1121 51,2 2,4 16,5 C;H4N2Oa 51,2 2,4. 16,6 95

aData: dlzo 1.1898 and nD ~~ 1,6036. bDaca: d2o ~ 1.1734

and nD a~ 1.5665. CData: d~o ~ 1.1611 and nD a~ 1.5710.

TABLE 2. Spectral Characteristics of the 8-(2-Furyl)acrylo-

nitriles
.m UV spec7 IR spec- SSCC, Hz
e~ trum (eth- tram, PMR spectrum, ppm
p,," anoD, ,cm-t ....
t )-max, nm" CN C=C
! s
,e others
HA 14B R ]CHa I~

o., jo.3,17.o,1
,., .oo
,Clog e;) ,, I
I It H 300 (4,32) 2220J1620, 3,6 Jwn R = 1,8
968 Jri.IBHa ~--"1,0
lib H 303 (4,43) 222011620, 3,(~ .I'FInR= 1,9
971
JrHBHa=1,0
IIc CH 312 (4,40) 2210[1625,! 3,6 J'HBHa= 1,0
] 969
lid CH 305 (4,48) 22oo1162o,! 3,6 ./HBHa = 1,0
lie C61- 237 (4,50)
f 9681
220011620~
| 970"]
7,1617,5511:6,815,68 4,( ]HBHa =0,9

Ill C~I- 230 (4,46),

351 (4,80)
220011610,
[ 967! , oli ii 4,6 J'HBHa = 1,0

fig CeI
2,41
209 (4.31),
318 (4,41)
222011620 LT,ool,,,,,2,0 JHBHa = 1,0
lib NC 344 (4,34) 222711620, I 4,0 ,/HBH~' = 0 , 9
[97o
*For lla, c, e, g, h, R l = H; R l = CHs for lib, d, f.
tion band of CH deformation vibrations of the trans form of the exocyclic double bond (967-
970 era-~).
A constant of ultra long-range spin-spin coupling between the lib and Ha protons (JHaHB =
1.0 Hz) is observed in the PMR spectra for the entire series of furylacrylonitriles II. The
intensity of this coupling constitutes evidence [4, 5] for a W-shaped orientation of the
bonds between the HB and Ha atoms. An s-cis configuration of the furan ring and the exo-
cyclic double bond corresponds t o this coupling [6, 7].
Of the other properties of the furylacrylonitrile system let us note the significant
effect of substituents on the positions of the chemical shifts in the PMR spectra. Methyl
groups (substituent R ~) in the side chain of II have a large shielding effect on the Ha pro-
ton. Donors in the 5 position of the furan ring shield the HB and R x = H protons to the
greatest degree. A phony1 substituent in the 5 position of the furan ring has a stronger
deshielding effect on the furan ring than a nitro group (TaBle 1, lie, h). The 2,4,6-tri-
chlorophenyl ring shields the furylacrylic system to a considerably lesser extent (Table i,
lle, g) than the phenyl ring, apparently because o f "twisting away" of the trichlorophenyl
ring from the plane of the furan r i n g . This is also confirmed by the hypsochromic shift of
the long-wave absorption band in the electronic spectrum of llg as compared with the absorp-
tion band of phenyl derivatives IZe, f. Other characteristics that confirm the structure
of II are presented in Tables 1 and 2.

EXP EEIMENTAL
The PMR spectra of solutions o f the compounds in CCI~ were recorded with a Tesla BS-467
spectrometer (60 MHz) at 25~ with hexamethyldisiloxane (HMDS)as the internal standard.

944
The IR spectra of thin films (lib-d) and mineral oil suspensions were recorded with a UR-20
spectrometer. The electronic spectra of solutions in ethanol were recorded with a Specord
UV-vis spectrophotometer. Benzene solutions of hydrazoic acid were prepared by the method
in [8].
2-(2-Furyl)acrylonitriles IIa-h. A 6.7 g (0.03 mole) sample of anhydrous magnesium
perchlorate was added to 0.1 mole of the corresponding furylacrolein and 0.11 mole of a
benzene solution of hydrazoic acid, after which 0.01 mole of dioxonium perchlorate [5 ml
of 1,4-dioxane and 0.01 mole (1.4 ml) of 72% HCIO~ at 35~ (ice bath)] was added dropwise
with stirring. The rate of dropwise addition was monitored with respect to the stream of
evolved nitrogen, which should be rapid but not too vigorous. When nitrogen evolution
ceased (after 1-1.5 h), the mixture was treated wi~h water, and the benzene layer was separ-
ated, washed with water, and dried with Na2SO~. The benzene was removed by distillation at
reduced pressure, and the residue was distilled in vacuo. Compounds IIe-h were recrystal-
lized from ethanol.

LITERATURE CITED
, P. A. Pavlov and V. G. Kul'nevich, Khim. Geterotsikl. Soedin., No. 2, 181 (1986).
2. A. A. Ponomarev, Syntheses and Reactions of Furan Substances [in Russian], Izd. Sara-
tovsk. Univ., Saratov (1960), p. 48.
. A. Jurasek and Martnov, Zaklady Organickej Syntesy, Prague (1975).
4. J. L. Emsley, J. Feeney, and L. H. Sutcliffe, High-Resolution NMR Spectroscopy, Pergamon
Oxford (1965), Vol. i.
. M. Dandarova, J. Kovac, D. Vegh, and V. Zvak, Coll. Czech. Chem. Commun., 47, 3412
(1982).
. A. Arcoria, F. A. Bottino, and D. J. Sciotto, J. Heterocycl. Chem., 14, 1353 (1977).
7. S. Fisichela, G. Mineri, G. Scarlata, and D. Sciotto, Tetrahedron, 31, 1557 (1975).
8. K. V. Wolf, in: Organic Reactions [Russian translation], Collective Vol. 3, Izd.
Inostr. Lit., Moscow (1956), p. 291.

CONFORMATIONS OF ISOMERIC 2,3,4-TRISUBSTITUTED

TETRABYDROTHIOPHENES

T. M. Filippova, B. D. Lavrukhin, S. D. Mikhno, UDC 547.732:543.422.25:

A. P. Kharchevnikov, I. G. Suchkova, N. S. Kulachkina, 541.621.2
and V. M. Berezovskii*

The conformations of a number of isomeric 2,3,4-trisubstituted tetrahydro-

thiophenes were determined by means of angular and temperature dependences of
the vicinal proton-proton spin-spin coupling constants (SSCC).

It has previously been shown that differences in the '3C chemical shifts (CS) of isomer-
ic 2,3,4-trisubstituted tetrahydrothiophenes can be used to determine the structures of the
individual isomers and to analyze a mixture of isomers [i]. In the present research we stud-
ied the conformations of isomeric 2,3,4-trisubstituted tetrahydrothiophenes I-IV,
RIHN
p
~s "~ (CH2)~COOCH~

I R=OH, RI=COC6Hs; II R = O H , RI=CONH2; III R = O H , RI=H-HCI; IV

P~=NHCONH.~, R]=CONH2; a 4-r, 3-l, 2-t; b 4-r, 3-t, 2-c; e 4-r, 3-c, 2-c:d 4-r, 3-c, 9-t

*Deceased.
Vitaminy Scientific-Industrial Union, Moscow 117246. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. 9, pp. 1172-1177, September, 1986. Original article submitted
May 28, 1985.

0009-3122/86/2209-0945512.50 9 1987 Plenum Publishing Corporation 945

 TABLE i. Vicinal Spin-Spin Coupling Constants
(aJ) and Differences in the Frequencies of the
Most Closely Situated 5-H' and 5-H" Signals
(A6sH',sH") for Solutions of the Isomeric I-IV
in Deuteropyridine
Com- " ~], H Z
pound A55H', 31V'
2H. 3H '] 3H, 4H 4H, 5H" 4H, 5H"

la 4,0 4,0 5,7 3,2 41,4

Ila 3,6 3,6 5,2 2,2 61,2
Ilia 5,9 5,9 5,8 5,9 13,0
IVa 6,0 4,4, 30,6
Ib 7,2 9,2 22,2
T'.b 718 7,8 6,7 8,5 31,2
Hlb 9,2 9,2 7,2 10,4 37,2
[Vb 8,5 8,5 6,4 8,5 24,6
Ic 3,3 3,3 8,0 10,3 1,0
llc 3,2 3,2 E14-~=17,6 0
~TIc 3,4 3,3 7,2 I I0,5 28,4
Id 2,o 3,9 Z/4_s= 16,4 9,6
lid 3,8 3,8 Z14-5 = 14,3 8,4
llId 3,9 3,9 6,2 I 7,8 37,2

A reliable method for the determination of conformations in solution is an analysis of

the vicinal proton-proton spin-spin coupling constants (SSCC) by means of their angular de-
pendence [2]. These values for the isomers of I-IV [i, 3-6] are presented in Table i.
The spectra of Ia-c and IIIa-d were calculated by means of the ITRCALL iteration program
in order to determine the true SSCC. The spectra of five-spin systems (the 2-H, 3-H, 4-H,
5-H', and 5-H" protons) were calculated in each case. The effect of the proton attached to
the nitrogen atom and the protons of the closest (to the ring) methylene group of the side
chain on the parameters was not taken into account because of the great difference in their
chemical shifts (A6 is no less than 300 Hz vis-a-vis the maximum J value of 12 Hz). The
magnitude of the correction of the constant depends on the difference in the chemical shifts
of the most closely situated 5-H' and 5-H" signals in the spectra. When A6sH',sH" = 1 Hz,
the maximum correction for J~HbH' and JaH'bH" reaches 3.5 Hz and does not exceed 0.i Hz when
A6sH',bH" ~ 10 Hz, i.e., it lies within the limits of the experimental accuracy. Consequentl}
when A6sH', 5H" > 10 Hz it is not necessary to calculate the spectrum in order to refine the
values of the vicinal constants, as, for example, for isomers a and b of the investigated
compounds. For most isomers c and d A6sH',sH" < i0 Hz (Table I). In this case, a conforma-
tional examination was made primarily for those compounds whose spectra were calculated (Ic,
IIIc, d). For the remaining compounds (Id, IIc, d) we used the experimentally found, to a
first approximation, sums of the vicinal constants with respect to the 4--5 bond, which remain
unchanged in the calculation of the spectra.
Because of the complexity of the subjects of the investigation, a massive complex of
experimental and computational investigations, including temperature measurements of the
constants and processing of them, is required to determine the types of conformations of the
five-mem~ered saturated rings and their relative percentages [7]. The procedure can be sim-
plified considerably if the compound exists primarily in one conformation. In this case,
the following can be used: a) direct calculation of the torsion angles of the molecule and
determination from them of the type of conformation [8]; b) calculation of the constants for
all possible conformations and selection of the preferred conformation when its constants
coincide with the experimental data. We used the latter method because of its descriptive-
ness and the possibility of the subsequent use of the results of calculation of the constants
of the various conformations of the five-membered ring(see scheme on following page).
The complete cycle of pseudorotation of the five-membered ring includes 20 conformations
with a symmetrical skeleton (the substituents were not taken into account in determining the
symmetry): i0 envelope conformations (CS) and i0 half-chair conformations (Ca) (see the
scheme) [9, i0]. Each conformation is characterized by phase angle A. The phase angle of
the complete pseudorotation cycle was assumed to be 720 ~ [ii]. The C2 and CS conformations
alternate in this chain. The phase angles of adjacent conformations along the cycle differ
by 36 ~ 9 To calculate the vicinal constants of the various conformers we formulated pseudo-
rotation cycles for each of isomers a-d. As the starting conformations (with A = 0 ~ we

946
 .Z
R' H N ~ \ \ Z Z Z / ~ NHR ! S ...... ""

,..X= 0 ~ A=3G ~ A=720 A=.~OB 0

R R S,, S.~Z R S

/ ~"NHP -e--- r / ,,, ! -' __ / Z /

Z ....~ 5 ----z, "NHR ~ \,~/~ NHF
A=252 ~ An216 ~ A= i 8 0 ~ A= 144 ~
i
R ~ R R R
! i
, _ " ' z /-T'--- s
---tin'- ~ / f

A=288 o NHR: NHR~

&=324o NHR : t'=396 ~

z z T

; - ~ ~ :'~ ~ ' / -,.~--- 5

S/~----~ NHR ' ""S / NtIR" \i , /~-R ~\//
A=540 a ~:50.io NHR i
A=.t66o "=43'~~ NHR'

Z T Z Z
Z
/\, ~ R
R~.//
. --D- , ,"'"NIIR" ~ .~-----7"-----~S ~ R tIN'/ i
""~-- / \ S - R fIN" R" " R ~j~- S
R~HN" "\ /
S A=fiOl~
A=fi76 ~ h=(~12 ~ A=648 ~
Z =(CH: } ~Ct~OCI-f~

selected the C= conformations with an equatorial orientation of the substituent attached t o

the C(,) atom at the site of maximum puckered character (see Table 2). The pseudorotation
cycle for isomer a is shown in the scheme. The pseudorotation cycles for isomers b-d can be
obtained from this scheme after appropriate replacement of the configuration of the substi-
tuents attached to the C(=) and C(a) atoms.
An interrelationship between the dihedral angles of the five-membered ring and the type
of conformation was previously found in [8]. By means of these data and the Karplus equation
[2] we calculated the vicinal constants for 20 possible conformations of each of the four con-
figurations (a-d) of 2,3,4-trisubstituted tetrahydrothiophene. In the calculations the con-
stant in the Karplus equation was varied from 8 to 12 Hz, i.e., the entire range of possible
jo values was used. It was assumed that jzso = 1.35 jo [12]. The maximum torsion angle
(~max) in the ring was selected as being equal to 50 ~ which is close to the theoretically
calculated [9, lO] and experimentally found [ill values for the C2 and CS conformations of
the five-membered ring. The results of the calculations are presented in Table 2. In using
Table 2 one should take into account the fact that the existence of the five-membered ring
in a single conformation is unlikely because of the low conformational energies. Therefore,
even in the case of a significant percentage of one of the conformations, there is a contri-
bution of other forms. It was shown that equilibrium between two conformations, the phase
angies of which differ by 360 ~ (invert conformations), is characteristic for substituted
saturated five-membered rings Ill, 13]. The cis constants in such conformations are identical,
whereas the trans constants differ significantly [13]. The contribution of the invert con-
formation with a lower percentage will therefore lead to a change in the trans constants
but will not affect the c constants. It hence follows that preference must be given to
the cis constants in the selection of the conformation.
A comparison of the experimental (Table l) and calculated (Table 2) vicinal constants
makes it possible to select the conformation with A = 684 ~ as the primary conformation for
isomers b-d:

a ~ b R d

947
kO
42-
0o

TABLE 2. Calculated =JHCCH Values for the Conformations of Isomers a-d of 2,3,4-Trisubstituted Tetrahydro-
thiophenes

" "~CHztaCO~ICtl ~ "

"R A=O a N(
~=~176a ,x=o" b &=o~ ~ e e d

Isomer a Isomer b Isomer c Isomer d

~i~O . . . . . . .

.~ , J'211.31[ J311. 41[ "/411.51|' Jill. 51t" J21[, 3ll ~3ll. ~lli 1411[. 511r " 411. 61[" 12II. 3H 1311, 41[ /,ill, 511[' J41l. 511" J21l. 31! "/31I, 4[[ J41|, 51[ r )411. 5[1 ~"

/ I
I 4,4--6,7 10,5--15,714,4--6,7 9,8--14,7 9,8--14,7 0.5-- i 5,714,4--6,7 9~8-- 14,714,4--6,7 3,3--5,0 1,4--6,7 L8--14,7 0,300,5 3,3--5,0 i,4--6,7 9,8--14,7
2 6,0--9,0 10,5 -- 15,713,3--5,0 0,5-- 15.7] 8,1--12.2 i 0,5-- 15,713.3--5,0 0, 5 -- ! 5,716,0--9,0 13,3~5 0 ],3--5,0 ),5--15,7[ 3,3--5,0 L3--5,0 10,5--15,7
3 7,4--11, 9,8-- 14,7[3,3 --5,0 0,5--15,7 t 5,6--8,5 1 9.8-- 14,713,3--5.0 0,5--15,7[7,4~1 1J t,4--6,7 t,3--5.0 ),5--15,7 I 0,6--1,0 [4.4--6,7 t,3--5,0 10,5--15,7
4 8,0--12, 8.1 -- 12,2[3.3--5,0 0,5--15,7 I 2,7--4,2 ] 8. I --12,213,3--5,0 0,5-- 15,7[8,0~ 12J fi 0--9 0 1,3--5,0 ),5--15,7 I 2,7--4,2 16,0--9,0 1,3--5,0 10,5--15,7
5 7,4--1 l, 5,6--8 5 14,4--6, 7 9,8--14,7 t 0,6~-I,0 5,6--8.5 ]4,4--6.7 9,8--14,717,4~1 I,( i1,4--1 l. t,4--6,7 ),8--14,7 I 5,6--8,5 17.4--11,' L4--6.7 9,8--14,7
6 6,0 --9,0 2 , 7 ~ ' 2 ]6,0--9,0 8,1 --12,~ 2,7--4,2 ]6.0--9,0 8, I -- 12,216,0~9,0 ~,0--12, ~,0--9,0 3,1--12,2] 8,1--12, [8,0--12; i,0--9,0 8,1--12,2
7 4,4 --6,7 0 6--1 '0 V,4--1 I,t 5.6--8.5~ 0,3--0,5 I 0.6--1,0 ~7.4--1 !,0 5.6--8,5 [4,4--6,7 I[,4~11,1 1,4--l[,( ~,6--8,5 1 9,8--14, 17,4--11, ~,4--1 I, 5,6--8,5
~! 3,3--5,0 ' 0 ' [8,0--12,1 2,7---4,2/ 0,9--1.4 I 0 [8.0--12,0 2,7--4.2 [3,3~5,0 1,0--9,0 ~,O--12J 2,7--4,2 i 0,5--15, [6,0--9,0 %0--12, i 2,7--4,2
3,3 --5,0 0,3--0,5 [7,4--I 1,, ~176 / o,9-1.4 I 0.3--0,5 [7,4--11,0 0,6--1,0 [3,3--5,0 [t,4--6,7 1,4--1 lJ 3,601,0 0,5--15, [4,4--6,7 T,4--1 !, i o,6-1,o
10 ~ 3,3--5,0 0,9--1,4 [6,0--9,0 0,9--1,4 1 0,9--1,4 [fi,0--9.0 t~,3--5.00 [3,3~5,0 5,0--9,0 0,5--15, 13,3--5,0 3,0--9,0 0
11 4,4--6,7 0,9--l,4 [4,4--6,7 0,3 ~0,5 I 0,30---0,5 0,9--1,4 ]4,4--6,7 0,3--0.5 ~4,4--6,7 p,3--5,0 t,4--6,7 3,3--0,5 9,8--14, 13,3--5,0 t,4--6,7 0,3--0,5
12 6,0--9,0 0,9--1,4 ]3,3--5,0 0,9--1.4~ 0,9--1,4 ]3.3--5.0
0.9--1.4 [6,0--9,0 13,3--5,0 3,3--5,0 3,9--1,4 ' 8,1--12, [3,3--5,0 3,3--5,0 0,9-- 1,4
13 7,4--11, 0,3--0,5 [3,3--5,0 0.9--1.41 0,6 -- 1,0 0,3-0,~ 13,3-5.0 o 9-1, 417, 4-1 l,, [4,4~6.7 3,3--5,0 3,9--1,4 5.6--8,~ [4,4--6,7 3,3--5.0 0,9--1,4
14 8,0--12, 0 13,3--5,0 0.9--1.4 2,7--4,2 0 13,3--fi,O 019--1,4 [8,0--12J [6,0--9.(] 3,3--5,0 ~),9--1,4 2.7--4,~ [6,0--9,0 3,3--5,0 0,9--1,4
15 7,4--1 i, 0,6--1,0 [4,4--6,7 0,30--0,5 5,6--8,5 0.6--1.0 14.4-6,7 0,3---0,5 [7,4~11,1 [7,4--11, 4,4--6,7 0,300.5 0,6~-1 ,C ]7,4--11, t,4--6,7 0,3--0,5
16 6,0--9,0 2,7--4,2 [6,0--9,0 8,1 --12,2 2,7--4.2 0.0--9.0 0 |6,0--9,0 [8.0--12. 6,0--9,0 ]8,0--12. 3,0--9.0 0
17 4,4--6,7 5,6--8,5 [7,4--1 I, 0,6~1,0 9,8--14.7 5.6--8,5 ]7,4--11 ,C 0,6--1,0 ]4,4~6,7 J7,4--1 I, 7,4--11, 0,6--1.0 0,3--O,fi 17,4--11, 7.4--11. 0,6--1,0
18 3,3~5,U 8.1--12,_~18,0--12, 2,7--4,2 10,5~15,7 8,1--12,218,0--12,s 2,7--4,2 13,3~5,o p,o-9,C 8,o-12, 2,7--4,2 0,9-- 1.4 [6,0~9,0 3.0-- 12, 2,7--4,2
19 3,3--5,C 9,8--14,;17,4--11. 5.6--8,5 i0,5--15,7 9,8--14,717,4--11,C 5,6-8,5/3,3--5,o 14,4--6,7 7,4--1 I,' 5.6--8.5 0,9--1,4 [4,4--6,7 7,4--1 i, 5,6--8,5
20 3,3--5,C ! 0,5--15,;16,0--9,0 8,1 --12,2 i0,5--15,7 l0,5-- 15,71~,0--9,0 8,1 -- 12,213,3~5 0 p,3--5,C 6,0--9,0 811-- 12,2 0,9--1,4 13,3--5,0 5,0--9,0 8, I --12,2
i
 !7,8!

14,6
9,6'
Fig. i. Temperature dependences of J~H,=H'
8,8i ' ~ ~ b 5 (0), J~H,bH"(O)~, and the sum of J2H,3H and
J J3H,~H (X).
8.0., . . . . 2 ~'b

1 [ 7 T
T,"C

The experimental values of all of the cis vicinal SSCC (J2H,~H' J3H,~H = 3.2-3.4 Hz for
isomers c, and J3H,~H = 3.8-3.9 Hz for isomers d; Table i) and the sums of the vicinal -on-
stants with respect to the 4--5 bond (ZJ~-, = 14.0-18.3 Hz; Table i) are within the limits of
the ranges of constants calculated for isomers b-d in this conformation (3.3-5.0 Hz for J2H,~H
and JsH,~H of isomers c and J3H,~H of isomers d; 14.1-21.1 Hz for EJ~-s of isomers b-d; Table
2). The experimental values of the trans vicinal constants for isomers b (J2H,3H and J3H,~H =
7.8-9.2 Hz; Table i) are somewhat smaller than the calculated values (10.5-15.7 Hz; Table 2),
whereas in the case of isomers d (J2H,3H = 2.0-3.9 Hz; Table i) they are greater than the cal-
culated values (0.9-1.4 Hz; Table 2). The observed deviations of the trans constants can be
explained by the 10-20% contribution of conformations with A = 324 = . The increase in these
deviations with an increase in the temperature (Fig. i, curves 3-8) confirms this, since the
percentage of the energically less favorable conformation (with A = 324 ~ increases with an
increase in the temperature. As expected, the cis vicinal constants (Fig. I, curves 1 and
2) remain virtually unchanged when the temperature is changed.
Of the compounds of the a group, only lla has a preferred conformation. It is inter-
mediate between conformations with a symmetrical skeleton -- 324 = < A < 360 = (see the scheme).
A conformation with 684 = < A < 720 = (0 ~ is in equilibrium with it. Its percentage is 15-25%.
In the case of la, Ilia, and IVa one cannot select a preferred conformation from Table 2.
The populations of the conformations are evidently equalized to a significant degree. The
experimental data correspond to an equilibrium of the conformations that are similar to the
conformations of lla: with A = 360 = and A = 720 ~ for Ilia, and with 324 ~ < A < 360 = and
684 = < A < 720 ~ (0 0) for la and IVa (see the scheme). For compounds of the a group the per-
centages of the conformations with A = 684-720 = increase in the order lla < la < IVa < llla.
For llla the percentage of this conformation is 50-60%.
It is interesting to compare the conformational state of 2,3,4-trisubstituted tetra-
hydrothiophenes and the previously studied [7] 3,4-disubstituted tetrahydrothiophenes and to
trace the effect of the substituent attached to the C(~) atom. For isomers b one observes a
shift of the conformational equilibrium to favor a conformation with A = 684 = as compared with
the trans-3,4 derivatives [7], in which the populations of the conformations are equalized.
R

. ..... s/

,.,=684o ( CN~}4COOCH~,

This is explained by an energically unfavorable 1,3-diaxial interation in the conforma-

tion with A = 324 ~ which is absent in trans-3,4-disubstituted tetrahydrothiophenes. An un-
favorable 1,3-diaxial interaction also develops in isomers r in the conformation with A =
324 ~ , but ~his does not lead to a substantial increase in the percentage of the conformer
with A = 684 ~ , since it is the preferred conformation in the case of cis-3,4-disubstituted

949
tetrahydrothiophenes. In a and d, in the conformations of which a 1,3-diaxial interaction
does not develop, a substituent attached to the C(2) atom has virtually no effect on the
conformational state. The latter result is in agreement with the well-known fact that the
r energies of substituents of cyclopentane are small as compared with cyclo-
hexane [14]. In addition, the substituent attached to the C(2) atom in the conformations
of the investigated compounds is not located at the site of maximum puckered character, where
=he difference between the axial and equatorial orientations is maximal.

EXPERIMENTAL
The vicinal $$CC were obtained with Bruker WP-80 (80 MHz), Wm-250 (250.13 MHz), and WP-
200 (200.i3 MHz) spectrometers [i, 3-6]. The temperature dependences of the vicinal constants
were measured with a WP-200 spectrometer. Traces of oxygen were removed from the samples by
bubbling argon through them. The pulse time was 3 ~sec (30=C). A computer memory of 32 K/
i000 Hz was used. The solvent was CsDsN. The temperature at each point was determined from
the dependence of standard samples, viz., ethylene glycol (for high temperatures) and methanol
(for low temperatures).

LITERATURE CITED
i. T. M. Filippova, S. D. Mikhno, I. G. Suchkova, N. S. Kulachkina, and V. M. Berezovskii,
Khim. Geterotsikl. Soedin., No. 7, 908 (1983).
2. M. Karplus, J. Am. Chem. Soc., 85, 2870 (1963).
3. S. D. Mikhno, T. M. Filippova, N. S. Kulachkina, T. N. Polyanskaya, I. M. Kustanovlch,
and V. M. Berezovskii, Khim. Geterotsikl. Soedin., No. 7, 897 (1972).
4. S. D. Mikhno, T. M. Filippova, N. S. Kulachkina, I. G. Suchkova, and V. M. Berezovskii,
Khim. Geterotsikl. Soedin., No. 5, 616 (1980).
5. S. D. Mikhno, T. M. Filippova, N. S. Kulachkina, I. G. $uchkova, and V. M. Berezovskii,
Khim. Geterotsikl. Soedin., No. 4, 459 (1976).
6. S. D. Mikhno, T. M, Filippova, N, S. Kulachkina, I. G. Suchkova, and V. M. Berezovskii,
Zh. Org. Khim., 14, 1706 (1978).
7. B. D. Lavrukhin, T. M. Filippova, and E. I. Fedin, Org. Math. Reson., ~, 368 (1974).
8. R. J. Abraham and K. H. McLauchlan, Mol. Phys., ~, 513 (1962).
9. J. B. Hendrickson, J. Am. Chem. Soc., 85, 4059 (1963).
10. K. S. Pitzer and W. E. Donath, J. Am. Chem. Sot., 81, 3213 (1959).
ii. C. Altona, H. J. Geise, and C. Romars, Tetrahedron, 24, 13 (1968).
12. S. Strenhell, Quart. Rev., 23, 236 (1969).
13. T. M. Filippova, B. D. Lavrukhin, and I. K. Shmyrev, Org. Magn. Resort., ~, 92 (1974).
14, E. L. Elial, N. Allinger, S. J. Angyal, and G. Morrison, Conformationa2 Analysis, Wiley
(1965).

950
SYNTHESIS AND STRUCTURE OF DERIVATIVES
OF 7-AMINOBENZO[b]THIOPHENE

A. N. Grinev,* I. A. Kharizomenova, M. V. Kapustina) UDC 547.736.07:543.422

YU. N. Sheinker, L. M. Alekseeva, N. M. Rubtsov,
and E. F. Kuleshova

Oximes of 2-acylamino-3-ethoxycarbonyl-7-oxo-4)5)6,7-tetrahydrobenzo[b]thio-
phenes have been prepared. A method for the synthesis of derivatives of 7-
aminobenzo[b]thiophene is proposed and the hydrolysis of the compounds pre-
pared has been studied.

Derivatives of 7-oxo-4,5,6,7-tetrahydrobenzo[b]thiophene (la-d) [i] readily form oximes

IIa-d in 50-64% yield. In the IR spectra of oximes IIa-d broad absorption bands are observed
in the 3200 cm -~ region) evidently due to OH and NH groups participating in the formation of
hydrogen bonds. Aromatization of the oximes IIa-c by the action of pyridine, acetyl chlo-
ride and acetic anhydride leads to the 7-diacetylaminobenzo[b]thiophenes (IIla-c). The struc-
ture of the compounds prepared was proved by PMR and IR spectroscopy. In the PMR spectrum
of the compound Ilia the following signals were observed in the aromatic proton region: 4-H,
8.35 (d, J,s = 7.5 Hz), 5-H, 7.52 (t, J,, = J,, = 7.5 Hz), 6-H, 7.12 ppm (d, Js6 = 7.5 Hz).
To establish the positions of the monoacetylamino- and diacetylamino-groups comparative IR
spectra of compound IIIa were run in concentrated and dilute solution in CCI,. The absence
of any shift in the NH band (3240 cm-*) for 4 and 0.02% solutions of IIIa proves that intra-
molecular hydrogen bonding is present. Hence, the monoacetylamino group is situated at posi-
tion 2 and is bonded by intramolecular hydrogen bonding with the CO of the ester grouping
and the diacetylamino group is at position 7. The acid and alkaline hydrolysis of compounds
IIIa-c was studied. The 2,7-bis-acetylamino derivatives IVa, c were isolated by action
of dilute acetic acid on benzo[b]thiophenes Ilia, c. 7-Acetylaminobenzo[b]thiophene IVb
was prepared by alkaline hydrolysis of compound IXIb. In the IR spectrum of the benzo-
[b]thiophene IVa, run in concentrated and dilute CCI, solution, a band at 3240 cm -x,
characteristic of an NH group bonded by intramolecular hydrogen bonds, was observed together
with a band due to free NH at 3420 cm-~. Such spectra of derivative IVa are indicative of
the hydrolysis of one of the acetyl groups of the diacetylamino substituent at position 7.
i ~ / COcC2H5 / ~-~ / COOC2Hs ~/.~_ ~ COOC2Hs

H II - - - - -

it
0 NOH N(COCH3) 2
I.-d IIa- d . "" Illa-,C
//
J

COOC2Hs
-

~'/~" S "2"" NIt 2 i

I ! t
NHCOCH3 NHCOCH~ NHCOCH5

l-IV * R t =NHCOCII2; b R' =NIICOC~Hb; C R' =NHCOC~H5; I - I I d R' =ff

Alkaline hydrolysis of compound Ilia leads to the amino derivative V. In the IR spectrum
of compound V, run as a mull in Nujol, NH2 bands were observed at 3280 and 3400 cm-i and the
band due to NH at 3240 cm-* was retained. To prove the position of the amino group, deamina-
tion was carried out by the diazo-method. The PMR spectrum of compound VI thus obtained,
besides signals for 4-H, 5-H, and 6-H protons at 8.40 (d, J,s = 7.5 Hz), 7.49 (5, d,, = Jb, =
7.5 Hz), and 7.70 (d, J,, = 7.5 Hz), respectively, there was a singlet 2-H proton signal at
8.54 ppm.
*Deceased.
S. Ordzhonikidze All-Union Chemical and Pharmaceutical Research Institute, Moscow
119815. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1178-1180,
September, 1986. Original article submitted June 27, 1985.

0009-3122/86/2209-0951~12.50 ~ 1987 Plenum Publishing Corporation 951

 TABLE i. Characteristics of Compounds Prepared

:oml rap, "C* Found, % Empirical

formula
talc.. %
I
~oundi C H N 84 S C I H N s >.

lib 227--228 60,5 5,2 %8 9,1 C~sHI~N.~O4S 60,3 5,1 7,8 8,9 I 47,4
llc 219--220 53,9 6,0 9,0 10,7 CI~HIsN204S 54.2 5,8 9,0 I0,3 64,5
lid 143--144 55,4 5,7 6,3 13,5 CIIHi3NO3S 55,2 5,5 5,9 13,4 ] 51,3
IIlb 234--235 62,4 4,6 6,7 7,5 C2uH2oN2OsS 62,2 4,7 6,6 7,5 [ 61,3
lllc 199--200 57,0 4,9 7,1 8,4 CI*H2oN~OsS 57,4 5,3 7,4
IVc 211--212 57,6 5,6 8,3 9,5 Ci6HIsN.~O4S 57,5 5,4 8,4 66,0

*Compound lib was recrystallized from 2:1 methanol-dioxane;

IId from 80% aqueous EtOH; IIIb, c and IVc from dioxane.

EXPERIMENTAL
PMK spectra were run on a Varian XL-200 instrument; TMS was used as reference standard.
A Perkin-Elmer 599 spectrophotometer was used for the infrared spectra; samples were examined
as Nujol mulls or in CCI~ solution. The molecular weight of the compounds prepared was de-
termined by mass spectrometry on a Varian MAT-II2 instrument with direct introduction of the
sample into the ion source, The ionization energy was 70 eV.
Characteristics of the compounds prepared are set out in Table i.
Oxime of 2-Acetylamino-3-ethoxycarbonyl-7-Oxo-4,5~6,7,te;rahTdr0beDz0[b]thigphen 9 (lla).
To a solution of 14 g (50 mmole) compound Ia in I00 ml dry pyridine was added 4.2 g (60 mmole~
hydroxylamine hydrochloride. The reaction mixture was kept at 20~ for 48 h. It was poured
into water and the precipitate filtered off and recrystallized from 2:1 methanol--dioxane.
Yield 9.8 g (55.2%), mp 226-227~ IR spectrum, cm-~: 1675 (CO), 3200 (OH). Found, %:
C 52.6, H 5.4, N 9.2, S 10.8; M + 296. C13Hi,NaO~S. Calculated, %: C 52.7, H 5.4, N 9,4,
S 10.8; M 296.
2-Acetylamino-7-diacetylamino-3-ethoxycarbonylbenzo[b]thiophene (IIIa). To a suspen-
sion of 2.96 g (i0 mmole) compound IIa in 6 ml acetic anhydride and 0.8 ml (i0 mmole) dry
pyridine was added a mixture of 0.9 ml (12 mmole) acetyl chloride and 4 ml acetic anhydride.
The reaction mixture was boiled for 1 h, cooled, and the precipitated solid filtered off
and washed with alcohol. Yield 1.81 g (50.0%), mp 181.5-182.5"C (i:i dioxane alcohol). 1R
spectrum, cm-~: 1670, 1690, 1710 (CO); 3240 (NH). PMR spectrum, ppm (in CDCI,): 12.0
(sir. s, NH), 8.35 (d, J = 7.5 Hz, 4-H), 7.52 (t, J~5 = Jb, = 7.5 Hz, 5-H), 7.12 (d, Jb, =
7.5 Hz, 6-H), 1.52, 4.51 (t, q. COOCaH,), 2.33, 2.35 (s, NHCOCH,, s, 6-H, N(COCH3) ).
Found, %: C 56.3, H 5.2, N 7.8, S 9.3; M + 362. C~,H~,N20,S. Calculated, %: C 56.~, H 5.0,
N 7.7, S 8.8; M 362.
2,7-Diacetylamino-3-ethoxycarbon[ibenzo[b]thiophene (IVa). A reaction mixture compris-
ing 7 g (195 mmole) compound Ilia, 56 ml acetic acid, and 14 ml water was heated to boiling
for 2 h, cooled, and the precipitate filtered off and washed with methanol. Yield 5.8 g
(93.8%), mp 241-242~ (dioxane). IR spectrum, om-~: 1660, 1700 (CO), 3240 (N-H). Found, %:
C 56.5, H 5.0, N 8.4, S 9.8; M ~ 320. C~bH~,NaO~S. Calculated, %: C 56.2, H 5.0, N 8.7,
S 10.0; M 320.
7-Acetylamino-2-benzoylamino-3-eth0xTcarbonylbenzo[b]thiophene (IVb).. To a suspension
of 2 g (47 mmole) compound IIIc in 5 ml dioxan and i0 ml alcohol was added a solution of 0.5
g (12.5 mmole) NaOH in 3 ml water and the mixture stirred for 1 1/2 h at 20~ and then filter~
The filtrate was poured into water and the precipitated solid filtered off. Yield 0.82 g
(45.5%, mp 258-259~ (from dioxane). IR spectrum, cm-l: 1660 (CO), 3240 (NH). Found, %:
C 62.9, H 4.8, N. 7.5, S 8.3; M + 382. CaoH:.N20~S. Calculated, %: C 62.8, H 4.7, N 7.3,
S 8.4; M 382.
2-Amino-7-acetylamino-3-ethoxycarbonylbenzo[b]thiovhene (V). To a suspension of 18 g
(50 mmole) compound Ilia in 30 ml dioxan and 50 ml methanol was added a solution of 5 g
(125 mmole) NaOH in 15 ml water and the mixture stirred for 30 min. It was then diluted
with water and the precipitated solid filtered off. Yield 11.4 g (82.5%), mp 222-223~ (from
EtOH). IR spectrum, cm-~: 1630, 1670 (CO); 3240 (NH); 3280, 3400 (N}{z). Found, %: C 56.0,
K 5.0, N 10.3, S 11.5; M + 278. C,3H~NaO,S. Calculated, %: C 56.1, H 5.1, N 10.1, S i1.5;
M 278.

952
 7-Acetylamino-3-ethoxycarbonylbenzo[b]thiophene (VI). To a suspension of 3 g (ii mmole)
compound V in 60 ml dioxane, 40ml EtOH and 9 ml concentrated H C I , cooled to --10~ was
added a solution of 2 g (29 mmole) sodium nitrite in 6 ml water, maintaining the reaction
mixture at --10~ and holding it as this temperature for a further 20 min. The diazo solu-
tion was then added to a solution of 0.05 g Copper acetate in 25 ml EtOH and the mixture
held at 70~ for 30 min and then poured into water. The solution was extracted with CHCI3,
the chloroform evaporated, alcohol added to the residue and the solid filtered off. Yield
1 g (35.2%), mp 194-195~ (from EtOH). IR spectrum, cm-:: 1645, 1710 (CO); 3240 (NH).
PMRspectrum (in acetone-d6), ppm: 9.26 (str. s, NH), 8.55 (s, 2-CH), 8.40 (d, J~s = 7.5
Hz, 4-CH), 7.70 (sir. d, J45 = 7.5 Hz, 6-H), 7.49=(t, Jds = Js6 = 7.5 Hz, 5-H) 4 . 3 ~ 1.70
(t, d, COOCH2CH3), 2.20 (sir. s, COCH3). Found, %: C 59.2, H 5.0, N 5.2, S 12.3; 263.
C:sH:3NOsS. Calculated, %: C 59.3, H 5.0, N 5.3, S 12.2; M 263.

LITERATURE CITED
i. I. A. Kharizomenova, M. V. Kapustina, A. N. Grinev, Yu. N. Sheinker, L. M. Alekseeva,
and E. F. Kuleshova, Khim. Geterotsikl. Soedin., No. 12, 1626 (1984).

13C AND ~bN NMR SPECTRA OF 2,3-SUBSTITUTED 2H-AZIRINES

E. E. Liepin'sh, R. S. El'kinson, I. P. Piskunova, UDC 547.717:543.422.25

and A. V. Eremeev

The :3C and ~bN NMR spectra of a series of 2,3-substituted 2H-azirines have
been studied. The ~SN chemical shift for the nitrogen in the azirine ring is
found at much higher field than in acyclic imines with a considerable elec-
tronic effect for the substituents on the double bond. Cooperative sterir and
electronic effects associated with substituents on the unsaturated carbon atom
of the ring were found to influence the shielding of the ~SC and ~SN nuclei.
Reaction constants have been calculated for 2-alkyl(aryl)-3-phenylazirines.
It has been shown that the azirine ring has a powerful --I effect (when compared
with the phenyl ring) that exceeds the analogous value for the cyano group.

The ~3C and ~SN NMR spectra of a series of 2,3-substituted 2H-azirines have been exam-
ined in order to study the factors influencing ~3C and ~SN nuclear shielding in 2H-azirines
and the effect of the azirine ring on adjacent bonds.
The ~3C and ~bN NMR spectral parameters are given in Tables 1 and 2. In the literature
[I, 2] only the ~3C spectra of II and III have been reported and our results are in good
agreement. Assignment of '3C signals were carried out using long range ~3C--~H spin-spin
coupling constants as described in [2].
The :bN signal for the nitrogen of the azirine ring was shifted to high field of the
cyclic analogues of azirines-- the imines [3, 4]. This is apparently due to sterie strain in
the three membered ring. Analogous shifts have been reported [5] for aziridines when com-
pared with acyclic amines. High field shifts for the azirines (-40-50 ppm) were larger than
for the aziridines (~35-45 ppm) [5]. This is possibly connected with the higher ring strain
at the nitrogen atom in the azirines than the aziridines. ~bN chemical shifts (CS) depend
significantly on the properties of the substituents on the double bond, the basic influence
on this shift being the mesomeric effect. This is a consequence of the correlation of ~SN
CS with the reaction constants for the 3-substituents. The ~bN resonance was shifted to
higher field with increasing donor ability of this substituent (COOEr < Ph < NH2) and is in
agreement with observations on imines [3, 4]. The effect of the C2 substituent on the ~bN
shift was also observed. Notable symbate shifts for both ~bN and C3 resonances were observed
Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1181-1183, September,
1986. Original article submitted June 28, 1985.

0009-3122/86/2209-0953512.50 9 1987 Plenum Publishing Corporation 953

 TABLE i. t=N NMR Spectral Data for Azirines l-Vll
R1 Ra

tom- tSN chemical shift, ppm t/tSN.iH,Hz

pound" R' R~
NH) N(R ~) N(R::) N(R') N(R ~)

[[10| CHa JCH~[ C6Hs - 83,5

II [Ill ]CH~
I[I [I I] [C6Hs
]i I C6H5
C~Ha - 104,3
- 98,0

[121 CaH~ COOC2Hs - 63,2

I~; [131 [C6H,NHCO NH, - 200,0 - ~'49,8 - 3-~9,8 92,3
- 199,7 -250,7 -319.9 89.9 91,7
VII 113 4-CHaOCaH4NHCO NH~ - 199,9 - 252,2 -319,9 90,1 91,3
*Synthetic method in brackets.

TABLE 2. taC NMR Spectra of Azirines l-Vll

=(3 chemical shift." ppm
om-
~ad tI~sC2.H,H~ Solvem
CtR,) C (R 3)
C(2) Ct3) Hz

25,04 ~26,58 (c~), CDCI3

132,95 (Cp),
129,64 (C,.),
129,38 (Co)
19.22 126.32 (Cr 186,5 CDCI3
132,99 (Cp),
129,58 (C.,),
129,44 (Co)
Ill 141,73 (C~), 124,80 (Cr 186,9 CDC13
127,67 ( C p ) [33.73 (Cp),
128,96 (C,.). 130,35 (CoL
126,75 (Co) 129,90 (Cm)
IV 139,29 (C~), 159,34 (CO). 185,7 CDCI3
128,63 (Cp), 63,87 (CHD,
129.07 (C.,), /4,41 (CH3)
127.14 (Co)
V 170.23 (CO), 180,0 DMSO
139,20 (C=),
128.21 (C,,,),
1 [9,33 (Co),
123,29 (Cp)
VI 171.06 (CO). 180,1 DMSO
137,75 (C~),
130.16 (C.,),
120,35 (Co),
133,21 (C~),
21,47 (C 3)
VII 170,91 (CO), 178,5 DMS@
133,57 (C~),
121,97 (Cm),
115,02 (C~),
156,45 (Co),
56,23 (OCH3)

*For compound I C(R 2) = 25.04.

with a change in the substituent at position 2. Evidently, the joint influence of steric
and electronic effects for these substituents is common to both nuclei but the sensitivity
of the *sN CS is some 1.5 times greater than the *SC CS. This is less than in the 2-substitu-
ted aziridines [6] where the ~=N resonance is 2.7 times more sensitive than the ~aCa signal.
The strong shielding of the azirine *SN nucleus in the 3-amino derivatives V-VII might
also have been due to an increased contribution from the tautomeric structure A.

N
H
A

However, in the *bN spectra obtained with proton spin-spin coupling, the signal for
the amino group was a clear triplet with a coupling of -91-92 Hz (Table i) making such an

954
 TABLE 3

A~rine oR

0,08 0,69
c.~ \//
N

0,08 0,66
N

0,10 0,78
w \//
N

explanation unlikely. This spin-spin coupling is characteristic of an sp 2 hybridized planar

nitrogen atom; a contribution from structure A would be expected to decrease it. Increasing
acceptor property in the 4-substituent of the phenyl ring (compounds V-VII) led to an increase
in both the *J~3ca H in the ring and xJxSNH in the amino group. This points to greater conju-
gation of the amino group with the C-~ bond when the acceptor strength of the 2-substituent
is increased. The XbN CS of the amino group showed a low sensitivity to this change of conju-
gation whereas the XSN shift of the amido nitrogen atom proved to be fairly sensitive to sub-
stituent change in the phenyl ring. In future work, it is proposed to carry out quantitative
analysis of this relationship with the use of an extended series of substituted 3-aminoazir-
ines.
The XSC CS of the carbon atomS of the 3-phenyl ring in I-III have been used to calculate
the reaction constant of 2-substituted azirine rings according to [7] (Table 3).
In relation to a phenyl ring the 3-azirinyl group behaves as a powerful acceptor. In-
deed, the inductive effect of the 3-azirinyl fragment exceeds such strong accep=ors as the
cyano group (oR = 0.56, OR = 0.13 [8]).

EXPERIMENTAL
:3C and :bN NMR spectra were obtained on WH90/DS (22.63 MHz) and WM 360 (36.5 HMz) in-
struments, respectively. For ~SC the internal standard was TMS and the precision of measure-
ment ppm whereas nitromethane was used for ~SN with a precision of ppm. The pulse
angle was ~30 ~ with pulse intervals of 4 sec for carbon and 15 sec for nitrogen. About i000
pulses were accumulated for carbon and ~ 2000 for nitrogen. :3C--:H Spin-spin couplings were measure
from proton coupled spectra with a precision of Hz. l~N--iH Spin-spin couplings were ob-
tained from the :bN spectra using polarization transfer from protons (the INEPT method [9])
with a precision of Hz. Solutions were -10% for :SC and ~50% for :SN.

LITERATURE CITED
i. V. Nair, Org. Magn. Resonance, ~, 483 (1974).
2. K. Isomura, H. Taniguchi, M. Mischima, M. Fujio, and I. Tsuno, Org. Magn. Resonance, ~,
559 (1977).
3. P. W. Westerman, R. E. Botto, and J. D. Roberts, J. Org. Chem., 43, 2590 (1978).
4. N. Naulet and F. G. Martin, Tetrahedron Lett., No. 10, 1493 (1979).
5. K. Crimaldi and R. L. Lichter, J. Org. Chem., 45, 1277 (1980).
6. E. ~. Liepin'sh, I. Ya. Kalvin'sh, and P. T. Trapentsier, Khim. Geterotsikl. Soedin.,
No. 9, 1231 (1981).
7. W. J. Hehre, R. W. Taft, and R. D. Topsom, Progress in Physical Organic Chemistry,
Vol. 12, 1976, p. 476.
8. O. Exner, in: N. B. Chapman and J. Shorter (eds.), Correlation Analysis in Chemistry,
Plenum Press, 1978, p. 509.
9. G. A. Morris and R. Fruman, J. Am. Chem. Soc., lOl, 760 (1979).
i0. R. F. Parcell, Chemistry and Industry, No. 33, 1396 (1963).
ii. V. Nair, J. Org. Chem., 33, 2121 (1968).
12. H. Hemetsberger, D. Knitell, and H. Weidman, Monatsch. Chem., 10!, 161 (1970).
13. A. V. Eremeev, I. P. Piskunova, and R. S. El'kinson, Khim. Geterotsikl. Soedin., No. 9,
1202 (1985).

955
:3C NMR SPECTRA OF N-SUBSTITUTED CARBAZOLES. TRANSMISSION
OF THE ELECTRONIC EFFECTS OF SUBSTITUENTS THROUGH THE
NITROGEN ATOM TO THE CARBAZOLE RING

V: D. Filimonov, T. A. Filippova, V. P. Lopatinskii, UDC 547.759.32:543.422.25

M. M. Sukhoroslova, and N. V. Stepanov

The effect of substituents attached to the nitrogen atom on the :3C NMR chemi-
cal shifts was determined for a series of 9-substituted carbazoles. Correla-
tion relationships between the inductive and resonance constants of the sub-
stituenCs and the chemical shifts of the carbon atoms were obtained. It was
shown that carbazole derivatives are similar to anilines with respect to the
conductivity of electronic effects through the nitrogen atom to the carbazole
ring.

In [i], by means of ISC NMR spectroscopy, we estimated the degree of transmission of

electronic effects of substituents from one phenylene ring of 3-substituted 9-methylcarbazoles
to the other; it was found chat the nature of the substituencs in the 3 position has virtually
no effect on the chemical shifts (CS) of the methyl groups in the I~C NMR spectra~ In the
present research, we attempted to determine if the effects of substituents are transmitted
through the nitrogen atom to the carbazole ring and, if so, the way in which this occurs.
The ~SC NMR spectra of 9-substituted carbazoles Ia-m with substituents that differ with
respect to their electronic and steric characteristics were recorded.

~'~'-~/~"
N " ~:~
X
la-m

~a X=H: b X=CH~: o X=C2Hs; d X=p-C3HT; e X=iso-C~H.; f X=~C~Ho;

X=iso-C~Ho;h X=~CsH ; i X=CH=OH; j X=C6Hs; k X=HCO: I X=COCH3;
m X=COCF3

The NMR spectra of 10% solutions of la-m in CDCI~ were recorded. The assignment of the
signals was made on the basis of known data on the ~SC NMR spectra of carbazoles [2].
An analysis of the data obtained (Table i) shows that varying substituents X gives rise
to an appreciable change in the chemical shifts of the C(3) atoms (the range of change in
the chemical shifts of the methyl groups in 3-substituted 9-methylcarbazoles is only 0.8 ppm
[i], i.e., transmission of the effect of the substituents from the 3 position through the
nitrogen atom formally does not occur, but reverse transmission of the substituent effects
is extremely appreciable. In addition to the C(a) position (the para position relative to
the nitrogen atom), subscituents X have the strongest effect on the chemical shifts of the
C(~) atoms (the range of changes is 8.0 ppm) and C(~a) atoms (4.7 ppm), which are in ortho
positions relative to the nitrogen atom. Minimal changes in the chemical shifts are observed
for the C(2) (2.2 ppm) and C(~) (0.6 ppm) atoms -- the meta positions -- and for the C(,a)
atoms (3.3 ppm). In these respects, the changes in the chemical shifts of the carbon atoms
in r Ia-m are subject to the same principles as in monosubstituted benzenes. Sub-
stituents have the strongest effect on the ~Co and ~Cp values of the atoms but not on the
6Cm values [3].
To evaluate mechanisms for the transmission of the effects of substituents X to the
carbazole ring it is important to compare the character of the changes in the chemical shifts
of atoms of the same type, viz., C(~) and C(~a) and C(2) and C(~). It follows from Fig. 1

S. M. K.irov Tomsk Polytechnical Institute, Tomsk 634004. Translated from Khimiya Geter-
otsiklicheskikh Soedinenii, No. 9, pp. 1184-1188, September, 1986. Original article submitte
June 18, 1985.

956 0009-3122/86/2209-0956512.50 0 1987 Plenum Publishing Corporation

 TABLE i. C NMR Chemical Shifts (6, ppm) of
N-Substituted Carbazoles la-m in CDCI3

Com- Cr~ C'2~ C~3) C[4} C(ga) C(4a)

pound (C~8}) (Q7}} (C~) {C{s) ) (C{8a))
(C{4b})

[a 10.49 124.98 I8,18 119,53 139,55 123,28

Ib 38,10 125.2I I8,33 119,68 140,37 122,07
Ic 08.25 125,44 I8,56 120,06 139,55 122,45
Id 08,32 125,21 18,26 119,68 139,92 122,07
le 39,89 125,29 18,49 120,13 139,25 123,04
If 38,40 125,40 18.41 119,83 139,99 122,22
38,63 i25,51 18186 120,06 I40,22 122,52
98,43 125,38 18,47 119,80 139,89 122,10
Ii 99,07 t25,21 19,01 I19,53 139,39 t22,44
Ij 99,45 125,73 19,68 119,90 140,34 122,82
Ik 16,47 127,15 24,24 120,06 137,09 125,73
I; 16,02 127,I5 ~3,49 119,68 138,35 126,10
Im 16,09 125,36 27,67 I19,83 137,38 126,77

TABLE 2 . Parameters of Regression Equations A~Ci = a + 0~

and ASCi = a + Pl~l + OROR o (&dCi = 8Ci X - 6cH) of N-Substl-
tuted Carbazoles la-m

Com- C{ i) Cor'~t.ant
pound 9R
.~I

1 C~z a> --0,67 10,21 0,933 1,48

2 C(l op + --0,12 7,61 0,965 0,95
3 C(I Grn~ -- 0,88 13,27 0,937 1,44
4 C{I ~o 0,33 19,58 0,969 1,01
5 Ctl {~I' an~ 0,57 2,95 22,0~ 0,9716 1,09
6 C(~ {~p -- 0,42 5,53 0,972 0,50
7 C{~ (rp+ --0,04 4,31 0,973 0,51
8 C{~ O'm --0,52 7,13 0,970 0,52
9 C{~ O'i, ga o 0,84 1,24 9,1{ 0,9743 0,54
I0 C(2} u~ 0,39 3,67 0,964 0,29
11 C(2] 020 + 0,64 2,16 m 0.822 0,58
12 C(2} O'm 0,32 4,77 0,971 0,25
13 C{2~ ~I 0,19 8,21 9,926 0,42
14 C{~} 0"1i", {Ya~ 0,36 5,68 2,06 3,9433 0,43
15 C(3) o'~} 0,84 10,51 0,989 0,58
16 C~8) {yp+ 1,65 7,86 3,942 1,41
17 C a) O'm 0,62 13,68 3,995 0,39
18 C,a crI 0,46 20,12 3,974 0,90
19 C{a,, 0"i, aa ~ 0,89 13,53 7,05 %9884 0,68

that in the case of great "sensitivity" of the C(~) atoms to the effect of substituents X
a good linear relationship with slope p = 0.51 (r = 0.987) exists between the C(:) and C(.a)
chemical shifts. The twofold intensification of the effects of the substituents on the C(~)
atom is, in all likelihood, determined primarily by the relative closeness of the C(:) atoms
and substituents X and by the effect of the latter on shielding of the C(:) atoms through
space. At the same time, one might have expected that, because of their close location,
additional effects of steric compression by substituents X would influence the change in the
chemical shifts of the C(:) atoms, in contrast to the C(.a) atoms. According to x-ray dif-
fraction data, steric reciprocal influence of substituents X and C(~)--X groups is manifested
even in the case of 9-methylcarbazole (Ib) [4]. However, there is no relationship whatsoever
between the chemical shifts of the C(~) atoms and E s or other steric constants in the series
of 9-alkyl-substituted carbazoles Ib-h, which have substituents that differ relatively mark-
edly with respect to their steric characteristics. The independence of the chemical shifts
of the C(x) atoms on the volume of substituents X is evidently the result of a certain con-
stant contribution of steric compression to shielding of these atoms.
We were unable to establish a satisfactory relationship between the changes in the
chemical shifts of the C(~) and C(~) atoms (meta position); this is evidently determined by
the narrow range of changes in the 8C(~a ) values (0.6 ppm).
We used the relative chemical shifts ~SCi = 5Ci X -- dcH for a quantitative evaluation of
Lhe effect of substituents in carbazoles la-m on the chemical shifts of the carbon atoms
(Table 2).

957
 61
'58C~.4a/
4

-I
3
2
1

0
/ I

-2
t

-1
I

0
, T

2
,,i

3
r

4
i

5
l ,,

6&8C(11
~I
013
o
o,2r
o,11-C H ~ O H /
~ Hco
cocH~

0 1 2 3 4 5 6 7 8 9A8C(3)
Fig. i Fig. 2
Fig. I. Interrelationship between the chemical shifts of
the C(~a) and C(I) atoms.
Fig. 2. Dependence of the chemical shifts of the C(s) atoms
on the inductive constants of the substituents.

The changes in the chemical Shifts of the C(~) and C(~a) atoms are described satisfac-
torily by correlation Eqs. (1)-(9) (Table 2); correlation relationships of the best quality
are obtained when the OR o constants are used for the A6C(~I values and the A~p + constants
are used for the A6C(~a) values [Eqs. (4) and (7), respedtlvely], and this constitutes a
significant difference between carbazoles and monosubstituted benzenes, for which simple
linear dependences of the chemical shifts of the C o atoms on the electronic effects of sub-
stituents are not observed [5].
Because of the narrow range of the change in the chemical shifts of the C(~) atoms, it
is impossible to statistically reliably evaluate the quantitative influence of the electronic
effects of substituents X on them. At the same time, the A6C(=) values change in a regular
manner under the influence of substituents X [Eqs. (10)-(14)]; correlation relationships of
the best quality were obtained when the am constants of substituents X were used in this
case. It would seem that there is nothing unusual in this, since the C(=) atoms are meta-
oriented relative to the nitrogen atom of carbazoles la-m. However, the best dependences
of the A6C(s) values (para position) are also observed for the Sm and Ol constants of sub-
stituents X [Eqs. (17) and (18)]. At the same time, it is known that the changes in the
chemical shifts of the Cp atoms in monosubstituted benzenes are described most satisfactorily
b y m e a n s o f the ap+ constants of the substituents [2]. A natural question arises -- is the de-
pendence of the A6C(s) values on the inductive effects of the substituents determined only
by the specific characteristics of the heterocyclic structure of carbazoles? The result ob-
tained formally indicates that the nitrogen atom in carbazole isolates the ring from the
effect of direct polar conjugation of substituents X.
N-Substituted anilines may be noncyclic analogues of carbazoles la-m.

X--NH~
IIa-f
II a X = H ; b X=CHa; e X=NH2;d X=C4H~; e X=COCHa, f X=C2Ha

An analysis of the literature data from the ~3C NMR spectra of N-substituted anilines
IIa-f shows that the effect of substituents on the change in the chemical shifts of the Cp
atoms is also determined by the inductive properties of substituenCs X [the compound number
and the ~Cp value (ppm) are given]: lla 118.35 [6]; IIb 117.07 [6]; IIc 119.15 [6]; IIe
123.10 [7]; IId 120.91 [6]; IIf 117.12 [6]; p = 19.95; r = 0.956. However, this does not
mean that only the inductive effects of substituents X are transmitted through the nitrogen
atom in anilines lla-f. The dependence presented for anilines is part of a general principle
for anilines X=NC,Hs that shows that there is a linear interrelationship between the ~I con-
stants of the X groups and the ~R o constants of the X=N fragments [6]. Taking into account
the fact that, for example, completely distinct mesomeric reciprocal influences of the carbon
atoms of the carbazole ring and the ~ bond are observed in the :~C NMR spectra of 9-alkenyl-
carbazoles [8, 9], one can completely validly assume that the relationships between the A~C(=I
values and the a I constants found in the case of carbazoles Ia-m are also the result of sym-
batic changes in the inductive constants of substituents X and the resonance effects of the

958
~N--X.
// fragments 9 From this point of view, carbazoles la-m do not differ qualita=ively
from anilines. However, the fundamental difference in the effect of radicals X on the change
in the chemical shifts of the C(3) atoms in carbazoles Ia-m and N-substituted anilines is
manifested in the fact that alkyl substituents, which are weak electron donors when they are
a=tached to the nitrogen atom, nevertheless give rise to deshielding of the C(s) atoms in the
~3C NMR spectra (Table i). Figure 2 graphically shows that the points for alkylcarbazoles
Ib-h, but not the point for carbazole (Ia), deviate from the general regression line. This
deshielding of the C(s) atoms, which are free from steric effects, under the influence of
alkyl groups is also not in agreement with nonempirical quantum-chemical calculations, which
show that the increase in the electron density on the C(3) atom of 9-methylcarbazole (Ib) is
comparable to that observed for carbazole (Ia) [i0].
It is important to note that the order of the increase in the shielding of the tertiary
carbon atoms of the carbazole rings, viz., ~C(2) < 6C(~) < 6C(3) < 6C(~), which coincides
with the order of the increase in the electron densities on these atoms in carbazole (Ia)
[ii], is disrupted for carbazole Im, which has a strong electron-acceptor COCF3 substituent.
In this case, the C(:) and C(,) atoms prove to be more shielded than the C(2) and C(3) atoms:
6C(3) < 6C(2) < 6C(4) < 6C(,). This provides a basis for the assumption that the regiospeci-
ficity of attack by the electrophile may change from the usually observed 1 and 3 positions
of carbazole in electrophilic substitution reactions of 9-X-carbazoles with strong electron-
acceptor substituents. This conclusion is also confirmed by the results obtained in [12], in
which it was shown that 2,7-dinitro-9-trifluoroacetylcarbazole is formed in the nitration of
carbazole Im.
It has been previously established [13, 14] that a rectilinear dependence of the ioniza-
tion potentials on the inductive constants of substituents in the 9 position of the carbazole
molecule exists. The observed dependence of the chemical shifts of the C(s) atoms in N-sub-
stituted carbazole on the inductive constants of the substituents, together with the data in
[13, 14], can be used for the qualitative evaluation of the ionization potentials from the
chemical shifts of the carbon atoms.

EXPERIMENTAL
The ~ C N'MR spectra were recorded with a BS-567A spectrometer (25.142 MHz) and ampuls
with a diameter of i0 mm; the reproducibility was no less than 0.05 ppm. The chemical shifts
were measured relative to the central peak of the signal of CDCI~ (76.9 ppm).
Carbazoles la-m were synthesized by known methods.
The authors thank N. V. Moskalev for providing them with a sample of carbazole Im.

LITERATURE CITED
i. V. D. Filimonov, T. A. Filippova, V. P. Lopatinskii, and M. M. Sukhoroslova, Khim.
Geterotsikl. Soedin., No. 2, 204 (1984).
2. J. Girand and C. Marzin, 0rg. Magn. Reson., 12, 647 (1979).
3. G. C. Levy and G. L. Nelson, Carbon-13 Nuclear Magnetic Resonance for Organic Chemists,
New York (1972), p. 107.
4. E. G. Popova and L. A. Chetkina, Zh. Struk. Khim., 20, 665 (1979).
5. D. F. Ewing, in: Correlation Analysis in Chemistry. Recent Advances, N. Chapman and
J. Shorter (eds.), Plenum Press, New York-London (1978), p. 357.
6. V. I. Glukhikh and M. G. Voronkov , Dokl. Akad. Nauk SSSR, 548, 142 (1979).
7. J. B. Stothers, Carbon-13 NMR Spectroscopy, Academic Press, New York--London (1972),
p. 192.
8. V. D. Filimonov, V. A. Anfinogenov, and S. G. Gorbachev, Khim. Geterotsikl. Soedin.,
No. 12, 1640 (1982).
9. V. D. Filimonov, V. A. Anfinogenov, and E. E. Sirotkina, Zh. Org. Khim., 1__4, 2607 (1978).
i0. D. Murk, L. E. Nitzsche, and R. E. Christoffersen, J. Am. Chem. Soc., i00, 1371 (1978).
li. A. F. Pozharskii, Khim. Geterotsikl. Soedin., No. 6, 723 (1977).
12. N. V. Moskalev, in: Young Scientists and Specialists -- The National Economy [in Russian]
Tomsk (1983), p. 112.
13. E. E. Sirotkina, I. L. Gaibel', V. I. Malkova, and V. D. Filimonov, Zh. Obsch. Khim.,
5_q, 1589 (1980).
14. E. E. Sirotkina, I. L. Filimonova, V. N. Trushnikov, and V. D. Filimonov, Izv. Akad.
Nauk SSSR, Ser. Khim., No. I, 90 (1985).

959
NITRATION OF TETRABENZOPORPHINS

V. N. Kopranenkov, E.A. Makarova, and E. A. Luk'yanets UDC 547.979.733:542.958.

1'941:541.422

Zinc meso-trinitrotetrabenzoporphin and zinc meso-tetranitrotetrabenzoporphin

were obtained by nitration of zinc tetrabenzoporphin and its tert-butyl-sub-
stituted analog with a mixture of nitric and acetic acids. A demetallated
compound is formed in 88% yield when zinc meso-tetranitrotetrabenzoporphin is
treated with HCI in acetic acid, a~d reduction of the nitro groups to amino
groups occurs when it is treated with tin in acetic acid.

Electrophilic substitution reactions in the macrocycle are some of the possible methods
for the synthesis of substituted tetrabenzoporphins (TBP) [1-4]. In our opinion, nitration
is of greatest interest, since nitro compounds make it possible to proceed to TBP derivatives
with various functional substituents. Information on the nitration of TBP is limited to ni-
tration of its cadmium complex with a nitrating mixture at 0~ Under the conditions of this
reaction, the complex undergoes demetallation to give a monosubstitution product, presumably
3-nitro-TBP, in 23% yield [4], in which, however, the position of the nitro group was not
rigorously proved. It, therefore, seemed of interest to find conditions for the nitration
of TBP with retention of the central metal atom, to increase the degree of nitration, and to
establish the site at which the nitro groups are incorporated.
We selected the zinc complex (I) of TBP and its tetra-4-tert-butyl-substituted analog
(II) [5] as the subjects of our investigation. A mixture of nitro compounds is formed in
33% yield when I is treated with nitric acid in trifluoroacetic and acetic acids at 25~
By preparative separation of this mixture on Silufol plates we were able to isolate two frac-
tions, the first of which was the zinc complex (III) of meso-tetranitro-TBP.
R

I-X R

I. III R=H, II, IV--X R=t-Bu, I, II, VI R1=R2=H, III, IV, VII Rz---RZ=NO~, V
RI=NO2, R2=H, VIII Rt=R2=NH~, IX RI=R2=AcNH, X RZ=R~=CLTH~CONH; I--V,
VIII--X M=Zn,u VII M=2H

Two signals of benzene ring protons with 6 9.33 (3-H and 6-H) and 8.09 ppm (4-H and 5-H),
which are shifted 0.60 and 0.25 ppm, respectively, to stronger field as compared with I [6],
are observed in the PMR spectrum* of this compound (Fig. i) in the weak-field region. Each
of the signals is a quartet with spin-spin coupling constants (SSCC) J o = 6 Hz and Jm = 3 Hz.
Signals of protons of methine bridges are absent in the spectrum of III. Three signals of
protons of methine bridges with 6 11.39, 11.41, and i1.49 ppm with an integral intensity
ratio of 4:3:1, respectively, and four signals of benzene ring protons with ~ 8.15, 9.33,
9.43, and 9.85 ppm, the first of which coincides with the signal of I, and the last of which
coincides with the signal of III, are observed in the PMR spectrum of the second fraction.

*The authors thank T. A. Babushkina (Institute of Biophysics, Ministry of Public Health of

the USSR) for recording the PMR spectrum of Ill and assisting in its interpretation.
Scientific-Research Institute of Organic Intermediates and Dyes, Moscow 103787. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1189-1193, September, 1986.
Original article submitted May 28, 1985.

960 0009-3122/86/2209-0960512.50 9 1987 Plenum Publishing Corporation

 < 3-H 6-H
5-H
~ II
t-Bu

i t p i , t
!0,0 9,5 910 8,5 <o $, ppm %s %0 a.5 ~.s ~. ppm

Fig. i Fig. 2

O 0
1,0 I,o b

0,8 I" -- 0,~

0,6 vJJ

I
0,4 I ;-q 0,4

0,2 ! I o,2
u
500 600 700 A. nm 500 600 700 ,t, n m
Fig. 3
Fig. i. PMR spectrum (250 MHz) of III in CsDsN.
Fig. 2. PMR spectrum (360 MHz) of IV in CsDsN.
Fig. 3. Electronic absorption spectra: a) IV, VII, and
VIII (in chloroform); b) VII and H2-TBP (in DMSO).

The integral intensity ratio of the protons of the methine bridges and the benzene rings is
1:14. The PMR spectral data and the results of elementary analysis make it possible to
assume that the second fraction is a mixture of mono-, di-, and tri-meso-nitro-substituted
zinc complexes of TBP.
Products with a higher degree of substitution are not formed, probably as a consequence
of the deactivating effect of the nitro groups already incorporated with respect to electro-
philic substitution. An increase in the nitric acid concentration or the reaction time
leads to a decrease in the yields of nitration products because Of destruction of the macro-
cycle.
The increased solubility of zinc complex II in acetic acid made it possible to avoid
the addition to the reaction mixture of trifluoroacetic acid, in the presence of which pro-
tonation and oxidation of the macrocycle are observed. A mixture of the zinc meso-tetrani-
trotetrakis(4-tert-butylbenzo)porphin (IV) (60% yield) and zinc meso-trinitrotetrakis(4-
tert-butylbenzo) porphin (V) (6% yield) was formed in the nitration of II with nitric acid in
acetic acid for 1 h at 25~ After chromatographic purification and separation on aluminum
oxide, we isolated IV and V in the form of monosolvates with pyridine. Bands of stretching
vibrations of a nitro group at 1363 (sym) and 1522 cm -~ (asym) are present in the IR spectrum
of a KBr pellet of IV. Four resonance regions with centers at d 1.66, 8.18, 9.28, and 9.43
ppm, which are related to the protons of tert-butyl groups and benzene rings in the 5, 6,
and 3 positions, respectively, are observed in the PMR spectrum of this compound (Fig. 2),
and signals of protons of methine bridges are absent.
As in the case of I, an increase in the nitric acid concentration or the reaction time
does not lead to products with a greater degree of substitution.

961
 TABLE i. Electronic Absorption Spectra of III-V and VII-X
in Chloroform

Corn- ': ) ' m a x ' nm (log r [relative intensity]

pound

IIl 640 [l,Ol 585 [0,13l 432 [2,6t] 410sh [I,02]

IV 646 (5,08) 596 (4,17) 436 (5,41) 412 sh {4,80)
V 644 (5,o8) 590 (4,18) 434 {5,40) 410 sh (4,81)
VII 688 {4,75); 632 (4,803; 582 (4,24) 428 (5,22) 400 sh (4,89)
624 (4.82): 618 (4,83)
VIII 652 [I,0] 6oo [o,281 476 [2,84]; 430 [0,88]
456 [3,74]
IX 648 (5,17) 594 (4,22) 436 (5,65) 410 (4,95)
X 650 (5,iS) 596 (4,33) 422 (5,61) 414 (4,88)

Nitro compound IV is formed in the nitration of II with nitronium tetrafluoroborate in

sulfolane; however, its yield is only ~2% as a consequence of pronounced destruction of the
macrocycle. It should be noted that only monosubstitution products are formed in high yields
in the nitration of metal complexes of phthalocyanine under similar conditions [7].
Attempts to nitrate demetallated Vl with nitric acid in acetic acid were unsuccessful,
since protonation, which deactivates electrophilic substitution in the macrocycle, occurs
under these conditions, meso-Tetranitrotetrakis(4-tert-butylbenzo)porphin (VII) was obtained
only by demetallation of zinc complex IV by passing a stream of hydrogen chloride through a
solution of the complex in acetic acid.
Attempts to reduce zinc complex IV by refluxing with stannous chloride in concentrated
hydrochloric acid with and without ether, sodium borohydride, and sodium hydrosulfite in
aqueous alkaline solution, as well as by hydrogenation in the presence of Pd/C in alcohol,
were unsuccessful. Only by reduction of IV with tin metal in refluxing acetic acid were we
able to obtain zinc meso-tetraaminotetrakis(4-tert-butylbenzo)porphin (Vlll), which we could
not isolate in analytically pure form in sufficient amounts because of its lability during
chromatographic purification. Compound VIII was characterized in the form of zinc meso-
tetra-N-acetamido- (IX) and zinc meso-tetra-N-stearylaminotetrakis(4-tert-butylbenzo)porphin
(X), which were obtained by refluxing amino compound VIII for i h in acetyl chloride or a
benzene solution of stearyl chloride; the yields were 78 and 40%, respectively, based on
nitro compound IV.
The electronic absorption spectra of solutions of the synthesized III-V and VlI-X at
220-800 nm were recorded (Table i). As in the case of the unsubstituted compounds, the
presence of two groups of bands, viz,, Q and B [8], is noted in their electronic absorption
spectra, i.e., the character of the spectrum does not change substantially in the case of
nitro and amino substitution. However, in contrast to phthalocyanines and porphyrazines [9,
i0], for which nitro substitution has virtually no effect on the positions of the absorption
bands, in the case of TBP we noted a bathochromic shift (up to ~25 nm) simultaneously of the
Q and B bands both for zinc complexes III-V and for demetallated compound VII. An even great-
er hathochromic shift of the corresponding bands is observed in the case of amino (VIII) and
N-acyl (IX, X) derivatives.
A characteristic property of nitro-substituted TBP is their increased, as compared with
other known TBP, resistance to oxidizing agents in solutions and particularly on sorbents
(aluminum oxide, silica gel). One should note the increased acidity of the N--H protons of
VII, which readily forms a dianion even when it is dissolved in DMSO, whereas the addition
of an alkali is required for the formation of a dianion in the same solvent in the case of
II.

EXPERIMENTAL
The electronic absorption spectra of chloroform solutions (lO-S-10 -4 m) were measured
with a Hitachi-356 spectrophotometer. The IR spectra (KBr pellets) were recorded with a
UR-20 spectrometer. The PMR spectra were obtained with Bruker WM-250 (250 HMz) and Bruker
WM-360 (360 MHz) spectrometers in deuteropyridlne with tetramethylsilane (TMS) as the internal
standard. Activity II aluminum oxide was used for the chromatographic purification and mon-
itoring of the individuality of the synthesized compounds. Compound III was isolated pre-
paratively on Silufol UV-254 plates.

962
 Zinc meso-Tetranitrotetrabenzoporphin (III). A 10-ml sample of a 5% solution of nitric
acid in acetic acid was added with stirring to a solution of 0.06 g (0.14 mmole) of I in a
mixture of 20 ml of trifluoroacetic acid and 30 ml of acetic acid, after which the mixture
was maintained at 25~ for 1 h and then poured into 250 ml of water. The resulting precipi-
tate was removed by filtration, washed successively on the filter with i00 ml of water, 50
mi of 5% sodium hydroxide solution, and i00 ml of water, and dried at 25~ for 12 h. The
residue was dissolved in 5 ml of pyrldine, and the solution was transferred to a chromato-
graphic column (3 40 cm) packed with aluminum oxide and eluted with chloroform-pyridine
(4:1). Repeated chromatography [chloroform--benzene (2:1)] and evaporation of the solvent
gave 0.03 g (33%) of a mixture of nitro products containing an average of three nitro groups.
Found, %: C 61.9, H 3.2, N 14.3. C36HITNTO~.C,HsN. Calculated, %: C 62.5, H 2.8, N 14.2.
Preparative separation of the mixture on i0 Silufol UV-254 plates (20 20 cm) with elution
by benzene gave 15 mg (17%) of III with Rf 0.65 (Silufol, benzene).
Zinc meso-Tetranitro- and meso-Trinitrotetrakis(4-tert-butylbenzo)porphin (IV, V). A
50-ml sample of a 5% solution of nitric acid in acetic acid was added in portions in the
course of 5 min with stirring to a solution of 0.25 g (0.31 mmole) of II [5] in 300 ml of
acetic acid, after which the mixture was maintained at 20~ for 1 h and then poured into 500
ml of water. The resulting precipitate was removed by filtration, washed on the filter with
200 ml of water, and dried. The residue was dissolved in i0 ml of pyridine--benzene (1:50),
and the solution was transferred to a chromatographic column packed with aluminum oxide and
eluted with the same mixture. The green fraction was collected to give 0.25 g of a substance
which, according to the results of thin-layer chromatography (TLC) [ethyl acetate--hexane
(1:2)], was a mixture of two compounds. The first fraction [0.20 g (60%)] was IV with Rf
0.70 [A1203, ethyl acetate-hexane (1:2)]. Found, %: C 65.1, H 5.1, N 12.0. Cs~H~sNsOa"
C~HsN. Calculated, %: C 64.7, H 5.1, N 11.9. The second fraction [0.02 g (6%)] was V with
Rf 0.5. Found, %: C 67.8, H 6.2, N 10.9. Cs2H~gNTO~.CsHsN. Calculated, %: C 67.6, H 5.4,
N Ii.0.
meso-Tetranitrotetrakis(4-tert-butylbenzo)porphin (VII). A stream of hydrogen chloride
was passed through a solution of 0.3 g (0.31 mmole) of IV in 300 ml of glacial acetic acid
for 30 min at 25~ after which the mixture was diluted with 500 ml of water, and the result-
ing precipitate was removed by filtration, washed on the filter with 250 ml of water, and
air dried. It was then dissolved in i0 ml of benzene, and the solution was transferred to
a chromatographic column packed with aluminum oxide and eluted with benzene--hexane (I:i) to
give 0.23 g (88%) of VII with Rf 0.41. Found, %: C 68.6, H 5.7, N 12.2. C52H52Ns08. Cal-
culated, %: C 68.3, H 5.5, N 12.3.
Zinc meso-Tetra-N-acetamidotetrakis(4-tert-butylbenzo)porphin (IX). A 2-g (16.9 mmole)
sample of granulated tin was added to a so!u=ion of 0.07 g (0.72 mmole) of IV in 50 mi of
glacial acetic acid, and the reaction mixture was then cooled and filtered. The filtrate
was diluted with I00 ml of water, and the resulting precipitate was separated by filtration
and air dried to give 56 mg of crude VIII, which was dissolved in 15 ml of acetyl chloride.
The mixture was refluxed for i h, the excess acetyl chloride was removed by distillation,
and the residue was dissolved in 5 ml of chloroform. The solution was transferred to a
chromatographic column (3 30 cm) packed with aluminum oxide and eluted with chloroform.
The solvent was removed to give 53 mg (78%) of IX with Rf 0.19 (AI20~, chloroform). IR
spectrum (KBr): 1690 (NHCO), 2870-2960 (C-H), and 3400 cm -~ (N--H). Found, %: C 70.5,
H 6.4. C6oH~NeO~. Calculated, %: C 70,2, H 6.3.
Zinc meso-Tetra-N-stearylaminotetrakis(4-tert-butylbenzo)porphin (X). A 6-g (20 mmole)
sample of stearyl chloride was added to a solution of 0.20 g of amino compound VIII, ob-
tained from 0.25 g (0.26 mmole) of nitro compound IV, in 50 ml of benzene, and the mixture
was refluxed for 1 h. The benzene was removed by distillation, and the residue was purified
by preparative TLC on a loose layer of aluminum oxide on six plates (15 20 cm) with col-
lection of the fraction with Rf 0.21 (chloroform) to give 0.18 g (40%) of X. IR spectrum
(KBr): 1670 (NHCO), 2855-2960 (C--H), and 3395 cm -: (N-H). Found, %: N 5.1. C:~H:29NsOa.
Calculated, %: N 5.8.

LITERATURE CITED
i. R. P. Linstead and F. T. Weiss, J. Chem. S,c., No. Ii, 2975 (1950).
2. B. D. Berezin, T. I. Potapova, and M. V. Plat.nova, Izv. Vuzov. Khim. Khim. Tekhnol.,
24, 160 (1981).

963
 3. R. A. Petrova, T. I. Potapova, B. D. Berezin, S. V. Kharitonov, and Z. V. Kharitonova,
Izv. Vuzov. Khim. Khim. Tekhnol., 27, 1304 (1984).
4. B. D. Berezin, I. K. Barvinskaya, and L. I. Sharova, Izv. Vuzov. Khim. Khim. Tekhnol.,
23, 161 (1980).
5. V. N. Kopranenkov, E. A. Tarkhanova, and E. A. Luk'yanets, Zh. Org. Khim., 1__5, 642
(1979).
6. K. N. Solov'ev, V. A. Mashenkov, A. T. Gradyushko, A. E. Turkova, and V. P. Lezina,
Zh. Prikl. Spektrosk., 13, 339 (1970).
7. M. Hgdayatullah , Compt. Rend., 296, 621 (1983).
8. G. P. Gurinovich, A. N. Sevchenko, and K. N. Solov'ev, Spectroscopy of Chlorophyll and
Related Compounds [in Russian], Nauka i Tekhnika, Minsk (1968).
9. S. A. Mikhalenko and E. A. Luk'yanets, Zh. Org. Khim., ll, 2216 (1975).
10. V. N. Kopranenkov, I. D. Mundshtukova, E. A. Makarova, and E. A. Luk'yanets, in: Sum-
maries of Papers Presented at the 4th All-Union Conference on the Chemistry and Appli-
cation of Porphyrins [in Russian], Erevan (1984), p. 34.

964
ELECTROCHEMICAL BEHAVIOR OF METAL COMPLEXES OF DERIVATIVES
OF DIBENZO[c,j]DIPYRAZOLO[3,4-f:3',4'-m][I,2,5,8,9,12]-
HEXAAZACYCLOTETRADECYNES ON A PYROGRAPHITE ELECTRODE

S. B. Orlov, R. O. Kalninya, and V. M. Dziomko UDC 541.138:547.779'898'

The electrochemical behavior in the adsorbed state (on a pyrographite electrode)

of metal complexes of a number of derivatives of dibenzo[c,j]dipyrazolo[3,4-f:
3',4'-m][l,2,5,8,9,12]hexaazacyclotetradecynates was studied by cyclic voltam-
merry. The determining role of the nature of the side groups of the complex
on the character of its electrochemical behavior on the electrode surface was
noted. The reversible redox transitions observed on the potentiodynamic curves
were ascribed to reduction and oxidation of the aza groups of the complexes.
The irreversible redox processes were ascribed to reduction of the side groups
of the complex, which is accompanied by attachment to the electrode surface,
and to their oxidative destruction.

Metal complexes of highly conjugated nitrogen macroheterocyclic compounds are of inter-

est in connection with their manifestation of catalytic activity in redox reactions in both
homogeneous and heterogeneous catalysis. A rather large volume of data on the use of elec-
trodes surface-modified by such complexes for the electrocatalysis of a number of important
redox reactions has been accumulated in the literature [i]. In the synthesis of new classes
of macroheterocyclic compounds important information can be obtained by drawing upon a num-
ber of electrochemical methods, particularly the cyclic potentiodynamic method, which makes
it possible to investigate the electrochemical behavior of complexes on the electrode sur-
face and the electrocatalytlc activity of such systems.
N
H Me~--P~"
/IN~ N% ' ,, " Pr
O=C\ H I

o kt._Jt rc' l
t

X I-IX
I, IV, V I - - V I I I M ~ + = N i ; I I M2+=Pd; III M2+=Co; V, IX M2+=Cu; I RLR2=H: II--VI
t~'=NO2; II--V R2=NO=;VII RI=NH2; VI, VII R2=NH2; VIII ~ = R = = N H A c IX mixture
R I, R2=NH2, R~=NH=, R~=NO2; X - - binuelear Cu ~ complex

In =he present research, we investigated the electrochemical behavior in the adsorbed

state (on =he electrode) of complexes (I-VIII) of a number of derivatives of dibenzo[c,j]-
dipyrazolo[3,4-f:3',4'-m][l,2,5,8,9,12]hexaazacyclotetradecynates, binuclear copper complex
X, and triazepine XI.
It was shown that complexes II-V applied to the surface of a pyrographite electrode
exist primarily in an electrochemically inactive state; the potentiodynamic curves over the

A. N. Frumkin Institute of Electrochemistry, Moscow 117071. All-Union Scientific-Re-

search Institute of Chemical Reagents and Ultrapure Chemical Substances, Moscow 107370.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1194-1199, September,
1986. Original article submitted May 4, 1985; revision submitted October 4, 1985.

0009-3122/86/2209-0965512.50 ~ 1987 Plenum Publishing Corporation 965

 -I6 ::-
I
-8-

i .F'-",. //
i\\/
8 i 3 ~l
E,V ~-- r r
i
110 TO,O 0,21 -O,Z

Fig. 1 Fig. 2
Fig. i. Potentiodynamic curves of a pyrographite electrode
modified by complex V (5.10-' mole) at various potential am-
plitudes (the dotted curve pertains to the unmodified elec-
trode): 1-4) successive change in the potential range of
the electrode modified by the complex (phosphate buffer solu-
tion, pH 7.5, v = 0.i V/set).
Fig. 2. Potentiodynamic curves of a pyrographite electrode
modified with triazepine derivative XI (the designations are
the same as in Fig. i).

range of potentials 0.8-0.3 V virtually coincide with the background curves (Fig. i, dotted
line and curve i). However, when the sweep amplitude is increased to the cathode side, the
existence of a cathode process leading to the appearance of reversible maxima II (E'c2 =
0.52 V and E'as = 0.55 V for complex V) can be detected. The cathode process at potentials
below 0.2 V is displayed on the first part of the curve in the form of maxima I and III, the
potentials of which are presented in Table i. With a further increase in the sweep ampli-
tude to the cathode side up to -0,2 V (up to the start of maximum III) maxima II are shifted
somewhat to the anode side, and yet another maximum appears at potentials of 0.65/0.70 V. It
is interesting that the electrochemical behavior of triazepine derivative XI (which contains
the same functional groups but does not contain a metal ion) is qualitatively similar to that
of metal complexes II-V (Fig. 3). This constitutes evidence that the metal ion does not par-
ticipate directly in the redox processes; however, the metal ion does have a substantial
effect on the redox processes of the complexes to which maxima I correspond, in that it dis-
rupts their reversibility (Figs. 2 and 3) and causes a shift in the potentials of cathode
maxima I to the cathode side. With respect to their stabilizing effect on the oxidized form,
the metal ions can be arranged in the order Ni 2+ > Cu 2+ > Co 2+ " Pd 2+ (Table i), which is
similar to the order of the change in magnitude of the negative charge of the porphyrin ring
[2]. Anode polarization of the electrodes modified by complexes II-V up to potentials more
positive than 1.0 V entails irreversible oxidation, which is evidently accompanied by de-
sorption of the complex. This is indicated by the fact that the corresponding anode maximum
(Fig. i, curves 3' and 4) can be detected only on the first part of the curve. Let us note
that maintaining the electrode modified by the complex, which exists in an electrochemically
inactive state (it does not undergo strong cathode polarization), at anode potentials of
1.2 V does not cause its destruction (desorption).
Complexes VI and IX, which have one nitro group and one amino group, behave similarly;
however, their oxidation does not lead to desorption (Fig. 3). Complex VII, which contains
two side amino groups, behaves differently. It is adsorbed on the surface immediately in
an electrochemically active state, as evidenced by the appearance of maxima on the potentio-
dynamic curve at 0.60/0.76 V even at a sweep amplitude of 0.9-0.4 V. Considerably more pro-
found (than for complexes I-V) cathode polarization up to potentials of --0.2 V is required
for conversion of complex VIII, which contains partially acylated side amino groups, to an
electrochemically active state. In general, binuclear complex X behaves like complexes II-
VI and VIII. The only difference consists in the fact that in the case of complex X anode

966
 -16

~8

op

8 ~ 5 ~ / Fig. 3. Potentiodynamic curves of a

._./3 pyrographite electrode modified by com-
plex VII (the designations are the same
~6 i~ as in Fig. i).

r i , --/ r ~ T ;
~,2 o,~ o,4 o,o E,V

maximum I at 1.23 V appears not only on the single potentiodynamic curve but also on the
cyclic potentiodynamic curve.
It follows from the data obtained that the nature of the side groups has the determining
effect on the electrochemical behavior of the complexes. 0 n e m i g h t assume that initially,
when it is applied to the electrode surface, the complex that has two side amino groups is
adsorbed flatly on the electrode surface due to the fact that in this case the conjugated
macrocyclic system has strongly expressed regions of negative charge under and above the
plane of the complex molecule because of the strong ~-donor character of the amino groups
(O_NH2i = 0.13; O_NH2r =--0.79) [3]; the amino groups, which are close to the electrode sur-
face, can react with the surface oxygen-containing groups, thereby forming amide bonds. A
complex that does not have side amino groups or has only one amino group, because of the
absence of a region of negative charge under the macrocyclic ring (O-N02 i = 0.63; O-N02 r =
0.15) [3], is oriented primarily at such a large angle to the electrode surface that direct
exchange of electrons between the molecule and the electrode surface is hindered and cannot
occur with either the central metal atom or with the conjugated ~-electron system of the
macrocyclic ligand. Partial ~-electron character of the amide bond theoretically should
lead to electron pairing between the amide groups and the aromatic system and, as a conse-
quence, with the entire conjugated ~-electron system, thereby causing charge transfer through
the amide bridge. However, a comparison of the properties of complexes that contain various
combinations of side nitrogen-containing groups (complexes VI, IX and V, VII) provides evi-
dence that this mechanism of electron transfer, as in [4], is not realized.
The conversion of complexes that contain side nitro groups to an electrochemically
active state can be explained by assuming that a shift of the electrode potential to the
cathode side may cause reorientation of a molecule bearing a partially positive charge; in
this case the angle between the plane of the molecule and the electrode surface decreases,
and the possibility of exchange of electrons between the complex molecule and the electrode
surface arises. If this orientation cannot be fixed by covalent bonds, a shift of the elec-
trode potential to the anode side again leads to reorientation of the molecule and its con-
version to an electrochemically inactive state. This is observed in the case of complex I,
which does not have side groups. Maximum II on the potentiodynamic curve is noted for this
complex only for the first pulses after prior cathode polarization up to -0.3 V. When the
sweep amplitude is decreased, the maximum slowly disappears and can be obtained again after
repolarization at a negative potential. This phenomenon can be observed repeatedly. If
reorientation of the molecule is accompanied by reduction of the side nitro groups with the
formation of amino groups, which are capable of chemical reaction with the surface groups
of pyrographite, the planar orientation is retained over a rather broad range of potentials;
the complex acquires the possibility of exchanging electrons with the electrode in this
case (complexes II-VI). Maximum I for complexes II-VI can then be explained by reductive
attachment of the nitro groups to the electrode surface. This attachment should be realized
simultaneously through both amino groups in this case. This is indicated by the difference
in the behavior of the diamino complex of nickel (VII) and the dinitro and nitro amino com-
plexes of nickel (IV, VI). The considerably more pronounced cathode polarization that is
required for conversion of the complex to an electrochemically active state when R: R 2 =
hq~Ac (complex VIII, Table i) can be explained within the framework of this assumption by the

967
 TABLE i. Potentials of the Maxima on the Potentiodynamic
Curves of a Pyrographite Electrode Modified by Complexes
I-XI
Com- Sweep in- E%3 Com- i Sweep in-
plex terval. V E;:, %2 (E*a~) E'a2 ptex tervai, V E'o: (E%0 E'a2

!0,90--0,00 V! 0,90--0,40 0.60 0,76

0,90--0,30 0,61 0,73. Vlla 0,90--0,40
0,86 0,90--0,30 0,57,
0,90--0,40 0.61 0.73, 0,69,
0,90 0,48 0,55
1.40--0, I0
II 0,90--0,25
0,90--0,10 O,IC 0.56 0,60 VIIE 0,90--0.20 0,32 0,37
0,90--0,15 0,I0 0.53 3,10 0,60 1 , 4 0 - - 0 , i0 0,68 0,76,
0,32 0,37
III 0,90--0.05
0,90--0,05 0,10 0,50 0,601 "II] 0,90--0, [0
0,90--0,20 0,10 0,73, ),24 0,77 ~0,90--0,20 0,57 0.80
0,48 3,60 0,90--0,30 0,57 0,80,
1,40--0,20 1,t5 0,65
IV 0,90--0.25 0,57 ,t5,
0,90--0.15 0,52 3,55 0.95,
0,90--0,20 0,04 0,65, ),13 3.70 0,80,
0,52 3,60 0,65
V 0.90--0.25 IX 0,90--0.I0
0,90--0,00 ),00 ).48 ) 54 I,I0--0,20 -0,2 0,60 0,75
0,90--0,20 ),00 ),63, - 1,35 )165 II
),45 X 0.90---0.10
0,90--0,05 0.48 0,56
VI 0,90--0.I 0
0,90--0,05 k47
-!1
),53 I
1,40--0,05 0,48 (t,23) 0.56
0,90--0.20 L45 ),54 II XI 0.90--0,40
1,35--0,10 ).67, 0,90--0.25 0.31 3,65 (0~21 D.73
L77, i 0,90--0,10 0.3; 3,65, 0.I7 0,73
~,45! 1,55
3,60; (0,42)

fact that either splitting out or rotation of the acetyl group, which exerts steric hindrance
to a planar orientation of the complex, is required.
The redox process in the region of maxima II evidently corresponds to reversible reduc-
tion of the aza groups of the complex. The shift of the potentials of the maxima to the
anode side and the appearance of additional maxima lla with retention, for a number of com-
plexes, of the amount of electricity corresponding to a redox process in the region of max-
imum II (Fig. i) constitute evidence that the aza groups exist in an energically nonequiva-
lent state with respect to electron transfer from the electrode surface and vice versa.
The presence on the surface of aggregated particles, the formation of which is highly likely
in the method used to apply the complex, may serve as an alternative explanation for the
appearance of maximum lla and the shift, in a number of cases, of maximum II. One also can-
not exclude the possibility that maxima II and lla (or one of them) are related to redox
transformations of the central metal atom, as observed, for example, in the case of many por-
phyrin complexes [1]. However, the close locations of the potentials of maxima II on the
potentiodynamic curves obtained on electrodes modified by complexes of different metals and
by the triazepine make this assumption unlikely.
The conclusions presented above are confirmed by the data presented by Sharp [4], who
demonstrated in the case of two isomers the existence of a reversible redox process in the
modification of the carbon surface by l-amino-9,10-anthraquinone, which is capable of orient-
ing itself parallel to the electrode surface, and the absence of pronounced redox processes
in modification of the surface by 2-amino-9,10-anthraquinone, which is not capable of this
orientation.
In the case of complex VII we compared the electrochemical behavior as a function of
the method of modification of the electrode surface. We used intermediate treatment of the
electrode with thionyl chloride with subsequent application of complex VII at room tempera-
ture (complex VIIa) and at 390 K (complex VIIb). We showed that the temperature at which
modification is carried out is of great significance. Complex VIIa, in contrast to complex
VII, initially exists in an electrochemically inactive state. Polarization of this electrode
at the cathode potentials makes it possible to convert the complex to an electrochemically
active state: two cathode and two anode maxima (0.57/0.69 and 0.48/0.55 V), which vanish in
the case of anode polarization at 1.2 V, are observed on the potentiodynamic curve. This
character of the electrochemical behavior, which coincides qualitatively with the behavior

968
of complexes II-V, constitutes evidence that chemical attachment of the complex under the
given conditions occurred only via one of the side amino groups. The shift of the potentials
of maxima II for complex Vlla, as compared with complex VII, to the cathode side indicates
that under these modification conditions the amino group may react not only with a surface
acid chloride group but also partially with the //~/C--CIgroup. This gives rise to redistribu-
tion of the electron density in such a way (by increasing the effective charge density of tNe
conjugated system) that the oxidized form of the complex is stabilized. Anode polarization
leads to cleavage of the bond and causes desorption of the complex, as in the case of complex-
es II-V.
Complex VIIb, attachment of which was realized at 390 K, behaves differently. On the
very first part of the curve one can detect reversible maxima at potentials of 0.32/0.37 V.
It might be assumed that in this case the reaction of the side amino groups proceeds prefer-
ably with the surface ~C--C1 and C--OH groups and i s r e a l i z e d for both side groups,
which gives rise to a stronger (as compared with Vlla) shift of maxima II to the cathode side.
In contrast to Vlla, anode polarization of the electrode does not lead to disappearance of
these maxima even in the case of prolonged maintenance at a potential of 1.4 V. A reversible
maximum at 0.68/0.76 V, which is close to maximum II of complex VII (Table i), additionally
appears in this case; this may be associated with migration of the bridge bond to a surface
carboxylate group.
Thus, the electrochemical properties of the complexes of the investigated series depend
substantially on the presence of side groups and their nature, as well as on the method used
to apply complexes containing R ~, R 2 = NH 2 to the electrode surface. These factors determine
the possibility and conditions for conversion of the complex to an electrochemically active
state as a result of fixing the necessary orientation of the complex on the surface. Chemi-
cal and electrochemical methods for modification of the electrode surface lead to the forma-
tion of rather stable electrochemically active coatinEs over the range of potentials deter-
mined by the nature of the bonds of the side substituents of the investigated complexes with
surface groups of pyrographite and the nature of the central metal ion.

EXPERIMENTAL
Complex I was synthesized by the method in [5], macrocyclic compounds II-IX were obtainec
by the method in [6], and triazepine derivative XI was synthesized by the method in [7].
The pyrographite electrode (a new one for each experiment) in the form of a 5 i0 mm
plate obtained by spallation was purified by refluxing in alkali for 15 min with subsequent
repeated refluxing in twice-distilled water. It was then activated by cathode-anode polari-
zation over the range--0.2 to 1.4 V. A solution of the complex in acetone (5,10-~ mole) was
applied to the electrode surface, and the electrode was dried at room temperature. Chemical
modification of the surface was carried out as follows. The pyrographite electrodes, which
were previously purified by refluxing in alkali, were acylated in SOC12 at the boiling point
for 2 h. After drying in a vacuum desiccator over H2SO~ for 12 h, the electrodes were trans-
ferred to a solution of the diamino complex of Ni (complex VII) in dimethylformamide (DMFA),
in which the C1 atoms of the surface groups of the modified pyrographite electrode were re-
placed by amino groups of the complex. Modification by the complex was carried out for 4 h
at 300 K (complex Vlla) and 390 K (complex Vllb), after which the electrodes were washed
thoroughly with benzene and chloroform and refluxed in methanol for 5 h.
The measurements were made in a phosphate-alkali buffer solution (~ = 0.15, pH 7.5).
The buffer solution was prepared from twice-distilled water, very pure-grade NaOH, and re-
crystallized KH=PO~.
The electrochemical measurements were made by imposition of potentiodynamic triangular
pulses [8] with the aid of a potentiodynamic device developed in the A. N. Frumkin Institute
of Electrochemistry, Academy of Sciences of the USSR, in a three-electrode glass cell with
separated eleztrode spaces at a potential imposition rate of 0.i V/sec. All of the potential~
were reduced relative to the potential of a hydrogen electrode in the same solution.

LITERATURE CITED
i. M. R. Tarasevich and K. A. Radyushkina, Catalysis and Electrocatalysis by Metal Por-
phyrins [in Russian], Nauka, Moscow (1982).

969
2. M. Zerner and M. Gouterman, Theor. Chim. Acta (Berlin), ~, No, i, 44 (1966).
3. P. Politzer, L. Abrahamsen,'and P. Sjoberg, J. Am. Chem. Sot., i06 , 855 (1984).
4. M. Sharp, Electrochim. Acre, 23, 287 (1978).
5. V . M . Dziomko, L. G. Fedosyuk, K. A. Dunaevskaya, Yu. S. Ryabokobylko, A. V. Kessenikh,
R. V. Poponova, and R. S. Kuzanyan, Khim. Geterotsikl. Soedin., No. 9, 1258 (1979).
6. V . M . Dziomko, R. O. Kalninya, Yu. S. Ryabokobylko, G. M. Adamova, R. V. Poponova, and
M. Z. Gurevich, Khim. Geterotsikl. Soedin., No. i, 106 (1984)~
7. V . M . Dziomko, R. O. Kalninya, Yu. S. Ryabokobylko, G. M. Adamova, R. V. Poponova, and
T. ~. Chernyshova, Khim. Geterotsikl. Soedin., No. 8, 1136 (1984).
8. F . G . Will and C. A. Knorr, Z. Elektrochemie, 64, 258 (1960).

SYNTHESIS AND STRUCTURE OF 1-BENZOYL-2,5-DIMETHYL-

AND 1,2,5-TRIMETHYL-4-ARYLPIPERIDEINS

T. N. Borisova, N. D. Sergeeva, A. A. Espenbetov, UDC 547.823.548.737:

D. S. Yufit, A. V. Varlamov, I. V. Eliseeva, 543.422.25
and N. S. Prostakov

Isomeric l-benzoyl-2,5-dimethyl-A'-piperidein and l-benzoyl-2,5-dimethyl-A ~-

piperidein were prepared from disubstituted y-piperidols and were hydroxylated
with osmium tetroxide. The isomeric 1,2,5-trimethyl-4-(p-nitrophenyl)-A 3- and
-A~-piperideins were obtained from trisubstituted 7-piperidols.

Some piperideins are known to exhibit physiological activity; a related compound, the
alkaloid phecolin, for example, is used in medicine. In our laboratory, piperideins, pre-
pared by the dehydration of disubstituted and trisubstituted y-piperidols, are intermediates
in the synthesis of pyridine bases [i, 2]. However, very little is known about the structure
(position of the double bond) of these piperideins.
We have synthesized a number of piperideins in order to determine their structure and
to study their biological action. A mixture of isomeric substituted y-piperidols, obtained
by benzoylation of a mixture of the isomers of 2,5-dimethylpiperidin-4-ol, was used for the
synthesis. At this stage in the synthesis of 1-benzoyl-2,5-dimethylpiperidin-4-ol (I), we
obtained information on the spatial structure of one of its isomers, isolated as a crystal-
line material with mp 131-133~ Its configuration and conformation were determined by ~H
and :3C NMR, and also by x-ray structural analysis.
The ~H NMR spectrum showed a quadruplet with coupling constant 3.5 Hz (Hsa,~ = J3e,~ =
J~,~) for the proton at the 4-position. This, together with the absence of large (>3 Hz)
coupling constants for the 6a and 6e protons allows the substituents at C(~) and C(5) to be
assigned axial positions. The coupling constants for the C(2) proton (J3a,2 = 6.4 Hz and
J3e,= = 2.7 Hz) are considerably lower than typical values, such as those for 2,6-diphenyl-
and dimethyl-derivatives of piperidol-4 with equatorially disposed substituents [3]. This
agrees with the report [4] that in 1-benzoyl-2-methyl- and l-benzoyl-cis-2,6-dimethylpiperi-
dines, the methyl groups occupy axial positions due to spatial overlap of the 2e-methyl and
phenyl groups on rotation around the hu-C amide bond. Thus, all three substituents have the
axial orientation and compound I has the configuration 4r-OH, 2c-CHs, 5t-CHs.
The :3C NMR spectra of compound I confirm this conclusion. The difference between ex-
perimentally obtained 8e and the theoretically expected 6 t values for the piperidine ring
carbon atoms are as follows:

P. Lumumba People's Friendship University, Moscow i17923. A. N. Nesmayanov Institute

of Heteroorganic Compounds, Academy of Sciences of the USSR, Moscow 117312. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1200-1206, September, 1986. Orig-
inal article submitted May 28, 1985.

970 ~0009-3122/86/2209-0970512.50 9 1987 Plenum Publishing Corporation

 c(a) c(,) C(~) c(,) c(~)
9 6e 41.3 32.2 69.9 35.9 40.2
6t 37.8 30.5 64.8 32.3 37.8
(calculated using increments for 2a- and 5a-CH3 [5] and 4a-OH [6]).
6e--6t 3.5 1.7 5.1 3.6 2.4
The differences are within acceptable limits, since the calculation of 6t did not take
into account interaction between pairs of substituents [7].
The spatial structure of this isomer of I (Fig. i) was determined by x-ray structural
analysis; the piperidine ring has a distorted chair conformation.
The nitrogen and carbon atoms deviated from the C(2)C(3)C(5)C(6) plane by 0.621(3)
and 0.622(4) A (probable error 0.028(4) A). The dihedral angles between the C(a)C(3)C(5)C(6)
plane and the C(2)NC(,) and C(a)C(4)C(5) planes are 52.1 and 46.7 ~ . The hydroxyl group and
the C(a) methyl group are in the trans position relative to the C(5) methyl group.
o
The amide fragment C(9)C(~)O(~)N is planar to within 0.003(3) A. The phenyl substituent
is tilted from its plane by 58.4 = . The nitrogen atom has virtually plane trigonal coordina-
tion (sum of the bond angles is 359.1~ The length of the N--2-Csp bond is 1.357(4) A and
indicates conjugation between the unshared electron pair on the nitrogen atom and the carbonyl
~roup oxygen atom (in the absence of conjugation, the length of the N--2-Csp bond is 1.425(5)
A [8]) T~oe C(~)==O(1) bond length is 1.240(4) A, greater than both the reported value
(1.215i5) Ao[9]), and the corresponding value for N-benzoyl-l-2~methyldecahydroquinoline-4-
one (1.230 A [i0]) and N-benzoyl-2,6-dimethylpiperidine (1.219 A [ii]); apparently this is
due both to its participation in conjugation with the unshared electron pair on the nitrogen
atom and to the formation of a stable intermolecular hydrogen bond O(a)H...O(~)==C(~). Because
of such bonds, in the crystalline form, molecules of compound I are linked to form an endless
chain algng the axis O(2)--H 0.80(4), O(a)...O(~)(x, 1 / 2 - y, --1/2 + z) 2.72(4), H...O(:)
1.94(4) A, angles O(a)HO(~) 164.2(4), C(~)O(~)H 133.3(4) ~ .
Apparently, the isomer of piperidol I which we isolated was formed from the isomer of
2,5-dimethylpiperidin-4-ol with substituents in the equatorial position, and, by analogy with
the corresponding piperidone [12], an axial unshared electron pair on the nitrogen atom.
Benzoylation of this piperidol should take place in the axial region. Subsequent compression
of the amide nitrogen atom as a result of conjugation of its unshared electron pair with the
carbonyl oxygen atom causes an inversion of the piperidone ring.
Isomers of piperidol I were converted to piperideins by treating them with thionyl chlor-
ide or phosphorous tribromide in benzene and the reaction products were separated by chromatog-
raphy on aluminum oxide, to give the isomeric piperideins II and III. The structures of
l-benzoyl-2,5-dimethyl-AS-piperidein I! and l-benzoyl-2,5-dimethyl-A~-piperidein III were
studied by PMR. The position of the double bond in the piperidein II was shown by the pre-
sence of doublets corresponding to the C(2) and C(5) methyl groups at 1.24 ppm (J = 7 Hz),
and at 1.0 ppm (J = 7 Hz), respectively, and multiplets at 5.6 ppm due to the olefinic protons
at C(~) and C(4). The spectrum of piperidein III contained a singlet due to the methyl group
at the double bond (1.65 ppm) and a doublet from the methyl group at the C(=) atom (1.24 ppm,
J = 6.5 Hz).

lltl

| ~ '. { --,,..

" N" " ' ~ CI-I 3 "'~N ~ "'~" CI:[ 3 %" N" "~'~ CH 3
i I :
COC6H5 COC6H 5 COC~[I~
II ~. Ill

t ,
0ll OH
I
CH3~.. / - ~ . . / - OH HO I

"'" N " " ' " C H 3 " " N */'~" C I I 3

1 !
COCBH 5 ~ COCBH 5
IV v

971
 _..Hto2~

(~ ;~L(~l~ 3, ' ,"" L; , , .

r C " :7
C,6C:f : C ~ ;",!~;J~ "~ ?~

C~ ~ . '~:L~ ~ c~
(, _~ ~ t.,~,~ -~
9 ~ C ~ C,~,~,~ ~'~,-
(6) 5L_.5;
'~' ~ic;

,;r'?~, . :,-~-D;: ~ " : : ~ ' 1 % ~ . ~ .... ~ ~

:'~'~t~'?[%~ ' ~ " ~:2"Z-2~ ~ C,,NC,61154(31 Fig. i. Molecular geometry of compound I.

C -v-'~ "~ '. ~r~A', O....C.,C,,u,.~(m .

='~C4,..~4-L .:,.~.t...)0,,~ C. IC'.:,C,,,, :4/.~3)

Additional information on the structure of piperideins II and III was obtained from
their hydroxylation with osmium tetroxide. The piperidein a-glycols obtained are themselves
of considerable interest. Oxidation of the mixture of piperideins containing an excess of
the A~-isomer III gave l-benzoyl-2,5-dimethyl-4,5-dihydroxypiperidein V, and oxidation of
the piperidein II gave l-benzoyl-2,5-dimethyl-3,4-dihydroxypiperidein (IV). The coupling
constants (J = i1.2 and 5.4 Hz) of the 4-H proton in the NMR spectrum of the piperidol V in-
dicates that it is in the axial position, Thus, since hydroxylation using osmium tetroxide
gives the cis-glycol, it can be assumed that in the diol V, the OH group at O(s) is axial,
and the methyl group equatorial.
It has been reported that some of the y-nitrophenylsubstituted piperidines are effective
narcotic antagonists [13]. As we had available y-phenylsubstituted piperidines, we used
them to synthesize the nitro compounds. As starting materials we used a mixture of the iso-
mers of 1,2,5-trimethyl-4-phenylpiperidol-4 (VI) and its propionate VII, and also the y-iso-
mer of 2,5-dimethyl-4-phenylpiperidin-4-ol (VIII), Nitration was carried out with a nitrating
agent in methylene chloride at --5~ In all cases, nitration of the phenyl ring occurred
only in the p-position and was accompanied by the formation of a piperidein.*

i02 IH2
O~
( ()
Clls"~LCH3 CH~ ~.CI[ 3

~CHj
CH~ Cl{3
IX .Xl XI!

VI, VII W = C H a ; VIII R t = H ; VI, VIII R~=OH; VII R2=OCOC2Hs

From the mixture of isomers of piperidol VI and its ester Vll was obtained a mixture of
1,2,5-trimer/ayl-4-(p-nitrophenyl)-A3- and A~-piperideins (IXa, b). The position of the
double bond in the piperidein IXa was shown by the presence of an olefinic proton signal
(narrow multiplet centered at 5.76 ppm), and two doublets from the methyl group at positions
C(a) and C(5) (1.22 ppm, J = 6.3 Hz and 0.90 ppm, J = 7 Hz, respectively). In the spectrum
of the isomer IXb, the methyl group at the double bond gives rise to a broad singlet at 1.58
ppm and the C(a) methyl group a doublet at 1.14 ppm (J = 6 Hz). The position and multipli-
city of the remaining signals in the spectrum correspond with the structure IX.
N% ~Hz JHI

CH3".r~>: ~ CH ~ X - r / / ' ~ CIt3" / " ' ~ , ,

~ N "" ~'" CH~ "~'N ~ CH 3 "'" N / ~ " CH 3

I I i
CH 3 CH 3 CH 3
1X XI Xll

*As in Russian original. The schemes shown here and below appear to be identical -- Publisher.

972
 Using analogous conditions, the piperidol VIII gave 2,5-dimethyl-4-(p-nitrophenyl)piper-
~dein-A ~ (X). The position of the double bond is confirmed by NMR spectral data; a broad
singiet from the methyl group at the double bond at 1.55 ppm and a doublet (1.2ppm, J = 6.5
Hz) from the methyl group at the C(=) position. With the y-isomer of piperidol VIII, the
hydroxyl group and the methyl group at the C(5) position are in the cis-position. Therefore,
trans-dehydration of this alcohol should lead to the piperidein X.
To prepare samples for a study of physiological activity, the nitro derivative IX was
converted first to 1,2,5-trimethyl-4-(p-aminophenyl)piperidein (XI), and then to 1,2,5-tri-
methyi-4~(p-hydroxyphenyl)piperidein (XII). From the mixture of isomeric piperideins XI and
XII, the corresponding A3-piperideins were separated chromatographically; the structures of
these compounds were confirmed by NMR.

EXPERIMENTAL
:H and :3C NMR spectra were taken on a Bruker WP-80 instrument, using CDCI3 as solvent
and TMS as internal standard. IR spectra of the compounds in KBr pellets were taken on a
UR-20.

o
Crystals of piperidol I were monoclinic: a = 7.3303(4), b = 11.0425(3), c = 16.193(1)
A. ~ = 90.156(5) ~ , Y = 1310.7(1) ~3, Z = 4, dcaic = 1.18 g/cm 3, space group P2~/c. Cell
parameters and intensities of 1688 independent reflections with F 2 ~ 2~ were measured on a
Hilger-Watts four-circle diffractometer (%Cu K~ graphite monochromator, e -- 28 scanning, e
66~ The structure was obtained by the direct method using ~ L T A N and was refined by the
full-matrix least squares method, at first in isotropic and then in anisotropic approximation.
All the hydrogen atoms which were located with difference synthesis were included in refine-
ment with fixed isotropic temperature factors (Biso = 6 A). The final R-factor was 0.063
(Rw = 0.076). Calculations were carried out on an EVM Eclipse S/200 with INEXTL [12]. Col-
umn and thin-layer chromatography were carried out on aluminum oxide (Brockman activity 2).
l-Benzoxi-2,5-dimethylpiperidin-l-ol (I). To a solution of 19 g (150 mmole) of 2,5-
dimethylpiperidin-4-ol and 7.8 g (200 mmoles) of sodium hydroxide in 60 ml of water was slow-
ly added 21 g (150 mmole) of freshly prepared benzoyl chloride; after 4 h, the reaction pro-
duct was extracted with ether, and dried with sodium sulfate. The ether extract was concen-
trated to a volume of i00 ml. On cooling, 6.4 g of crystals with mp 118-130 ~ were isolated
and were refluxed for 4 h in 50 ml of absolute ether. The insoluble material (1.3 g) was
one of the isomers of piperidol, mp 131-133~ IR-spectrum 3600 (free OH), 3400 (assoc. OH),
1610 cm -: (CO). NMR spectrum: 7.35 (s, 5H, COC6H5); 4.42 (a, d, IH, J = 6.4 and 2.7 Hz, 2-H);
3.77 (a, IH, J = 3.5 Hz, 4-H); 3.60 (m, 2H, 6-H); 2.4 (s, IH, OH); 1.4-2.1 ~, 3H, 3-H, 5-H);
1.39 (d, 3H, J = 6.5 Hz, 2-CH~); 0.96 ppm (d, 3H, J = 6.5 Hz, 5-CH~). Found, %: C 72.2,
H 8.3, N 5.8; M+ 223. C:~H~gNO2. Calculated, %: C 72.1, H 8.2, N 6.6; M 233. Total yield
of mixture of isomeric piperidols I was 180 g (53%).
l-Benzoyl-2,5-dimethylpiperidein-A 3 (II) and -A 4 (III). A. With mixing and cooling, a
solution of 7 g (60 mmole) of thionyl chloride in 5 ml of benzene was added to a solution of
5 g (20 mmole) of piperidol I (mixture of isomers) in 20 ml of benzene. The reaction mixture
was maintained at 20~ for i h and at 8 0 ~ a further hour. The excess thionyl chloride and
benzene were distilled off. The residue was treated with 5% sodium carbonate, the reaction
products were extracted with ether, and the extract dried over magnesium sulfate. The resi-
due (2.7 g) from the ether extract was chromatographed on a column (h = 30 cm, d = 2.3 cm,
eluant -- 5:1 hexane and ethyl acetate) to afford 2.5 g (47%) of piperidein II, a yellow oil
with Rf 0.42 (1:3 ethyl acetate-hexane). IR spectrum: 1650 (N--COC6Hs), 1600 cm -~ (C-~).
NMR spectrum: 5.4-5.9 (m, 2H, 3-H, 4-H); 4.8 (br. s, IH, 2-H); 3.7 (br. s, IH, 6e-H); 3.22
(d, d, IH, J = --13.0, 3.5 Hz, 6a-H); 2.20 (m, IH, 5-H); 1.24 (d, 3H, J = 7 Hz, 2-CHs); 1.0
ppm (d, 3H, J = 7 Hz, 5-CH3). Found, %: C 78.4, H 7.6, N 6.3; M + 215. CI~H~TNO. Calcu-
lated, %: C 78.1, H 7.9, N 6.5; M 215.
B. A mixture of 2.7 g (12 mmole) of alcohol I, 3.3 g (12 mmole) of phosphorus tribro-
mide and 130 ml of benzene was refluxed for 3 h, and then poured into 50 ml of water. The
benzene layer was separated, and the product was extracted from the aqueous layer with ben-
zene. The combined extracts were dried with magnesium sulfate. The residue, after evapora-
tion of the benzene, was chromatographed on a column (h = 20 cm, d = 2.3 cm, eluant -- 5:1
hexane and ethyl acetate). The first fraction contained 0.4 g (i6%) of piperidein II, an
oil with Rf 0.42 (1:3 ethyl acetate--hexane) and the next fraction gave 0.6 g (2.4%) of pip-
eridein III, an oil with Rf 0.5 (1:3 ethyl acetate--hexane). IR spectrum: 1650 (N-COC~Hs),

973
 TABLE i. Coordinates of the Atoms (xl0 ~, for H atoms xl0 ~)

Atom x y z Atom H x g z

O{i} ;oo~(4) 2206(3) 7683~2) [-L 02: 10I(5) 330(3) 383(3)

O~21 !086(4) 3323(3) a~~ 282(5) 241(4) 662(2)
N 314(4) 3113($) 646912) II,3~ 158(5) 106(3) 573(3)
C,t) -99(5) 2786(3) 7255(2) H/,- 316(5) 186(3) 515{3)
2134(5) 2834(4) 6132(2) H, ~i" 45(5) 152(3) 435(3)
1912(6) 1942(4) 5415(2) -222(5) 302(3) 480(3)
Ct4} 462(6) 2292(4) 478t (2) -43(5) 444(4) 557(2)
-1333(5) 259t(4) 5t92(2) -222(5) 37213) 613(3)
C(6) -1037(5) 3547(3) 5865(2) 443(5) 387(3) 5~8(3)
C,7} 3158{5) 3~95(4) 590I(3) 253(5) 453(4) 555(2)
-2315(6) 1467(4) 5531(3) 344(5) 440(4) 632(21
C{9) --1892(5) 3142(3) 7607(2) -256(5) 84(4) 508(3)
C{ lol -:3020(5) 2234(4) 7924~2) tL/,' -t8o(5) 109(3) 596{2)
--4647(5) 2544(5) ~283i3) -359(5) I63(3) 575(3)
C( Jk~l -5179(5) 3728(4) 8356(3) If, s -267(5) 128(3) 846(3)
C, L3; -~039(6) ,UJI5(4} 8069(3} It ~,, -535(5) 193(3) 846(3}
-2H8(5) 4339{3) 7681(2) H, i,. -632(5) 397(3) 855(2)
--!38i5) 531(4) 810{2)
-16~(5) 488(3) 751(2)

TABLE 2 . Torsion Angles r (deg) in I

Angle T, de- Angle T, de-

grees grees

C(,}--N--C,2)--C(~} 115,7(5) --57,0(4)

C(,--N--C(:>--C {~) -I18,2{5) 69,1 (4)
C(~)--N--C(~,~--C{a - 54,0 (4) C~s}--C,s}--N--C,2; 59,7(4)
C(~)--N--C(=~--C~} 72,1 (5) C,s)--C~6,--N--C{. - t09,5(5)
48,7(4) C~61--N--C~I,--O{. 165,5(5)
C(r)--C(~)--C(~}--C{~) --75,7(5) -15A(4)
C~>--C(~--C{,)--O(~} 70,3 (4) C(2~--N--C{D--OcD - 3,3 ( 4 )
--50,6(4) C~2~--N--C~ ~--C9 176,1(5)
--67,5(4) -56,0(4)
C(a)--C(~}--C(~}--C(6~ 53,1 (4) N--C~,~--C,9,--C(,o> 124,6 (5)
O(~}--C(4)--Ct~)--C(s} 167,1 (6) O(,}--C(,I--Co)--C,.14~ 119,4(5)
-72,3(5) -60,1 (4)

1600 cm -: (C,=C). NMR spectrum: 5.45 (n, M, IH, 4-H); 2.3-1.7 (m, 2H, 3a-H, 3e-H); 1.65
(br. s, 3H, 5-CH3); 1.24 ppm (d, 3H, J = 6.5Hz, 2-CHa). Found, %: C 77.8, H 7.9, N 6.3;
M + 215. CI~H:TNO. Calculated, %: C 78.1, H 7.9, N 6.5; M 215.
l-Benzoyl-2,5-dimethyl-3,4-dihydroxypiperidine (IV). A solution of 1 g (4.6 mmole) of
piperidein II and 1.17 g (4.7 mmole) of osmium tetroxide in 25 ml of freshly prepared pyri-
dine was kept at 20 ~ for 2 h and a solution of 15 g of sodium bisulfite in 20 ml of pyridine
added. After 1 h, the reaction products were extracted with chloroform, and the extract
dried with sodium sulfate. The chloroform was removed, leaving a tarry residue from which
the diol was extracted with ether to give 0.25 g (21%) of colorless crystals mp II0-I13~
(from ethyl acetate). IR spectrum: 3600 (free OH), 3400 and 3200 cm -~ (assoc. OH). NMR
spectrum: 7.36 (s, 5H, COC6H5); 4.5 (hr. q, IH, J = 7 Hz, 2-H); 4.0 (hr. d, IH, J =--13.5
Hz, 6e-H); 3.70 and 3.95 (m, 2H, 3-H, 4-H); 3.13 (d, d, IH, J =--13.5 Hz, 3.3 Hz, 6a-H);
2.95 (hr. s, 2H, 3-OH, 4-OH); 1.17 (d, 3H, J = 7.0 Hz, 2-CHa); 1.05 ppm (d, 3H, J = 7.0 Hz,
5-CH3). Found, %: C 67.7, H 7.4, N 5.9; M + 249. C:~H2oN03. Calculated, %: C 67.5, H 7.6,
N 5.6; M 249.
l-Benzoyl-2~5-dimethyl-4,5-dihydroxypiperidine (V). Using the same conditions as in
the previous synthesis, 0.86 g (4 mmole) of a mixture 0f piperideins II and III, containing
a larger amount of isomer III, 1.04 g (4.1 mmoles) of osmium tetroxide and 15 ml of pyridine.
Yielded 0.22 g (22%) of the glycol V, mp 141-143~ (from ethyl acetate). IR spectrum: 3630
(free OH), 3400 and 3200 cm -~ (assoc. OH). NMKspectrum: 7.35 (s, 5H, COC~Hs); 4.8-3.8 (br.
m, 2H, 2e-H, 6e-H); 3.65 (d, d, d, IH, J = 11o2, 8.5, 5.4 Hz, 4-H); 2.90 (IH, d, J = --14.4
Hz, 6a-H); 2.8 (s, IH, 5-OH); 2.37 (d, IH, J = 8.5 Hz, 4-OH); 1.25 (d, 3H, J - 7 Hz. 2-CH3);
1.27 (s, 3H, 5-CH3); 1.45-2.1 ppm (m, 2H, 3-H). Found, %: C 67.3, H 7.4, N 5.4; M + 249.
C:4H=oNO3. Calculated, %: C 67.5, H 7.6, N 5.6; M 249.

974
 1,2,5-Trimethyl-4-(p-nitrophenyl)piperidein (IX). A. To a solution of 7.5"g (34 mmole)
of piperidol VI in 50 ml of methylene chloride at --5 ~ , with vigorous stirring was added 32.13
g (330 mmole) of sulfuric acid (d 1.7), followed by 2.14 g (34 mmole) of nitric acid (d 1.5).
The reaction mixture was held at this temperature for i h, poured onto ice and neutralized
with sodium hydroxide solution. The reaction products were extracted with chloroform and
dried with sodium sulfate. Evaporation of the chloroform afforded 7.76 g (84%) of the nitro
derivative IX (mixture of isomeric piperideins) as a yellow oily substance; I g of the piper-
idein mixture was separated chromatographically (h = 20 cm, d = 2.0 cm, eluant -- 1:6 ethyl
acetate ~nd heptane). The first fraction yielded 0.3 g ( 3 0 % ) o f piperidein-A s (IXa), Rf
0.43 (1:4 ethyl acetate~eptane), the second fraction gave 0.7 g (70%) of the piperidein-& ~
(IXb), Rf 0.24 (1:4 ethyl acetate--heptane). IR spectrum: 1520 and 1350 cm -~ (NO=). NMR
spectrum: isomer IXa: 8.18 (d, 2H, J = 8.5 Hz, aryl o-proton); 7.44 (d, 2H, J = 8.5 Hz,
aryl m-proton); 5.76 (m, IH, 3-H); 3.3-1.8 (m, 4H, 2-H, 5-H, 6-H); 2.46 (s, 3H, N-CHs); 0.9
(d, 3H, 5-CHs); 1.22 ppm (d, 3H, 2-CHs); isomer IXb: 3.26-3.08 (m, 2-H, 6-H); 2.3-2.6 (m,
3H, 2-H, 3-H); 1.58 (s, 3H, 5-CH3); i.ii ppm (d, 3H, J = 6 Hz, 2-CHs). Picrate of mixed
piperideins -- mp 178-180 ~ (from alcohol). Found, %: N 14.8; M + 246. C~HITN=O2.C~H3Ns07.
Calculated, %: N 14.7; M 246.
B. Using the same method as in A, 2.6 g (10 mmole) of the hydrochloride VII, 25 ml of
methylene chloride, 8.55 g (87 mmole) of sulfuric acid and 0.54 g (8.7 mmole) of nitric acid
gave 1.5 g (61%) of a mixture of isomers of compound IX. There was no depression of melting
point on admixture with a sample prepared in A.
2,5-Dimethyl-4-(p-nitr0phenyl)piperidein-A ~ (X). Using the same method, 0.75 g (3.7
mmoleY'of piperidol VIII gave 0.45 g (58%) of compound X as a yellow oil. IR spectrum:
1510, 1356 (NO2) and 3350-3310 cm-~ (NH). NMR spectrum: 8.27 (d, 2H, J = 8.5 Hz, aryl o-
proton); 7.28 (d, 2H, J = 8.5 Hz, aryl m-proton); 1.55 (s, 3H, 5-CHs); 1.20 (d, 3H, 2-CH~);
3.42 (m, 2H, 6-H); 2.15 (m, 2H, 3-H); 3.0 (m, IH, 2-H); 2.75 ppm (s, IH, N-H). Fumarate of
compound X-- mp 191-192~ (from alcohol). Found, %: C 58.4, H 6.0, N. 8.4; M + 232. C17H2o
N20. Calculated, %: C 58.7, H 5.7, N 8.0; M 232.
1,2,5-Trimethyl-4-(p-aminophenyl)piperidein-A 3 (XI). A mixture of 1.2 g (43 mmole) of
the hydrochloride of IX, 22 ml of concentrated HzSO~ and 1.22 g (130 =~ole) of metallic tin
was heated at 65~ until the tin had completely dissolved. The reaction mixture was cooled,
and treated with sodium carbonate until strongly alkaline. Evaporation of the chloroform
afforded 0.2 g (16%) of compound XI, as an oil with Rf 0.12 (i:i ethyl acetate--heptane).
IR spectrum: 3450 and 3350 cm -~ (N-H). NMR spectrum: 7.03 (d, 2H, J = 8 Hz, aryl m-proton);
6.57 (d, 2H, J = 8 Hz, aryl o-proton); 3.65 (m, 2H, NH2); 3.3-1.8 (m, 4H, 6-H, 5-H, 2-H);
5.50 (m, IH, 3-H); 1.15 (d, 3H, J = 6.5 Hz, 2-CH3); 0.85 (d, 3H, J = 6.5 Hz, 5-CH3); 2.33
ppm (s, 3H, N-CHs). Found, %: C 77.6, H 9.0, N. 11.7; M + 216. C:~H=oN2. Calculated, %:
C 77.8, H 9.3, N 12.1; M 216.
1,2,5-Trimethyl-4T(p-hydroxyphenyl)piperidein-A 3 (XII). To a solution of 1.8 g (8 m m o l e
of piperidein XI in 4.6 ml (24 mmole) of 18% HCI at 5~ was added 3.3 ml of 2 M sodium nitrate
The excess nitric acid was neutralized with urea (negative reaction to congo). The reaction
mixture was heated on a boiling water bath until no more nitrogen was evolved, saturated with
sodium carbonate, and extracted with ether. The ether extract was dried over magnesium sul-
fate. The ether was removed and the residue chromatographed on a column (h = 25 cm, d = 2
cm, eluant -- 2:1 hexane and ether) to give 0.4 g (22%) of compound XII, an oil with Rf 0.05
(1:2 ethyl acetate--hexane). IR spectrum: 3600 cm -~ (free OH). NMR spectrum: 8.2 (s, IH,
OH); 5.6 (m, IH, 3-H); 2.48 (s, 3H, N-CHs); 1.8-3.3 (m, 5H, 6-H, 2-H, 3-H, 5-H); 1.30 (d, 3H,
J = 7.0 Hz, 2-CHs); 0.92 ppm (d, 3H, J = 6.5 Hz, 5-CHs). Found, %: C 77.0, H 8.5, N 6.2;
M+ 217. C,~HIgNO. Calculated, %: C 77.4, H 8.8, N 6.5; M 217.
In conclusion, the authors would like to thank Yu. T. Struchkov and N. I. Lebedev for
carrying out the x-ray structural study.

LITERATURE CITED
i. N. S. Prostakov and L. A. Gaivoronskaya, Zh. Org. Khim., 32, 76 (1962).
2. N. S. Prostakov, L. A. Gaivoronskaya, N. M. Mikhailova, and L. M. Kirillova, Zh. Org.
Khim., 31, 2573 (1963).
3. C. J. Chen and R. J. W. LeFevre, J. Chem. Soc., 3467 (1965).
4. R. A. Johnson, J. Org. Chem., 33, No. 9, 3627 (1968).

975
 5. E. L. Eliel, D. Kandasamy, YenChen-Yu, Hargrave, J. Am. Chem. Soc., 192 , No. ii, 3698 (1980)
6. O. A. Subbotin and N. M. Sergeyev, Anal. Chem., 48, 545 (1976).
7. O. A. Subbotin, N. M. Sergeev, and N.G. Nikishova, Zh. Org. Khim., 20, 1024 (1984).
8. R . W . Alder, N. C. Goode, T~ Y. King, I. M. Mellor, and B. W. Miller, Chem. Comm., 173
(1976).
9. Tables of Interatomic Distances and Configuration in Molecules and Ions, L. E. Sutton
(ed.), The Chemical Society, Special Publication 18, London (1968).
i0. G. S. Litvinenko, A. L. Espenbetov, and Yu. T. Struchkov, Izv. Akad. Nauk Kazakh SSR,
Ser$ Khim., No. 5, 63 (1982).
ii. E. Arte, J. Feneau-Dupont, J. P. Declerg, G. Germain, and M. Van Meersch, Cryst. Struct.
Commun., ~, 773 (1977).
12. R. G. Gerr, A. I. Yanovskii, and Yu. T. Struchkov, Kristallografiya, No. 5, 1029 (1983).
13. K~gi and M. Miescher, Helv. Chem. Acta, 52, 2481 (1979).

SYNTHESIS OF STEREOISOMERIC ALKYL- AND PHENYL-SUBSTITUTED

5-CYANOPIPERIDINE-3,4-DIOLS

V. I. Tyvorskli, I. G. Tishchenko, and A. S. Kukharev UDC 547.823.07:541.63

e-Hydroxy-8-[N-(2-cyanoethyl)amino]ketones were obtained by the reaction of

methyl- and phenyl-substituted 2-acyloxiranes with 3-alkylaminopropionitriles.
Treatment of the products with sodium tert-butoxide gave stereoisomeric 5e-
cyanopiperidine-3,4-diols, the three-dimensional structures of which were es-
tablished by means of spectral data, as well as by means of isomerization and
oxidation with periodic acid.

The development of new methods for the synthesis of functionally substituted piperidine-
3,4-diols is of considerable interest, since some natural compounds such as the alkaloid
fagomine [i], as well as substances that have antihypoxia and surface-anesthetic activity
[2], belong to this group of piperidine derivatives. Alkyl- and aryl-substituted piperidine-
3,4-diols are generally obtained by hydroxylation of the corresponding tetrahydropyridines
[3-6], by reduction of 3-hydroxy-4-piperidones [2, 7-9], or by reaction of the latter with
organometallic compounds [i0]. We have previously demonstrated [ii] the possibility of the
synthesis of isomeric 1,3,4-trimethyl-5-cyanopiperidine-3,4-diols via intramolecular cycliza-
tion of hydroxy derivatives of 8-aminoethyl ketones containing a 8-cyanoethyl group attached
to the nitrogen atom [12].
In the present research, we studied the reaction of a number of methyl- and phenyl-
substituted 2-acyloxiranes with 3-alkylaminopropionitriles, as a result of which we obtained
the corresponding e-hydroxy-~-[N-(2-cyanoethyl)amino]ketones Ia-d in 76-96% yields. We found
that acyloxiranes that contain substituents in the methylene link do not undergo this trans-
formation, in conformity with the established regioselectivity of the process. Because of
their tendency to undergo isomerization in the presence of bases, unsubstituted acyloxiranes
(R ~ = H) also form virtually no adducts with alkylaminopropionitriles(see scheme on follow-
ing page).
The IR spectra of la-d contain an absorption band at 3400-3470 cm-~ due to a hydroxy
group involved in an intramolecular hydrogen bond with the nitrogen atom of the amino group,
as well as an absorption band of a nitrile group at 2240 cm-~. A band of carbonyl absorption
of the acetyl group of la, b is observed at 1710 cm-~, and a band of the benzoyl group of
amino ketones Ic, d is observed at 1680-1690 cm-L. The PMR spectra also confirm the struc-
ture of la-d; in particular, a quartet of diastereotopic protons of an N-CH2 group with

V. I. Lenin Belorussian State Univeristy, Minsk 220080. Translated from Khimiya Geter-
otsiklicheskikh Soedinenii, No. 9, pp. 1207-1211, September, 1986. Original article sub-
mitted June 17, 1985.

976 0009-3122/86/2209-0976512.50 ~ 1987 Plenum Publishing Corporation

 OH
CH.~COR2
0
/ \\ 1 R3NHCH2CH2CN R3 ---N~ RI (CH3)aCONI

COR2 ~CH2CII2CN
:a-d
OH OH R2
' I
CN ~#'- 2 - CN ' CN i
//~'~~ ~R +
R~ /

OH OH
a a,c,d ma-d IVa-c
I--IV a Rt=R2=R3=CHa; b RI=R2=CH3, ~a=C2Hs; C ~I=~a=CH3, ~2=C6H~;
d ~1=~2=C6H5, ~=CH3

geminal spin-spin coupling constant (SSCC) J = 13-14 Hz is present at 2.4-3.6 ppm, which
indicates opening of the ring of the starting acyloxiranes by the aminopropionitrile at the
unsubstituted methylene link.
In the presence of sodium tert-butoxide cyano ketones, la-d undergo cyclization to
methyl- and phenyl-substituted 5-cyanopiperidine-3,4,-diols II-IV with the participation of
the caronyl group and the cyanoethyl fragment, which, under the influence of a base, gener-
ates a carbanion, as we established in [ii] and Unkovskii et el. established in the case of
the deoxy analogs of la-d [12]. Since two new asymmetric centers develop as a result of the
cyclization, one should have expected the formation of mixtures of stereoisomeric cyclic
products. In fact, from cyano ketones la-c under the indicated conditions we obtained mix-
tures (63-73% overall yields) of 5e-cyanopiperidine-3a,4a-diols lla-c, 5e-cyanopiperidine-
3e,4a-diols llla-c, and 5e-cyanopiperidine-3a,4e-diols IVa-c, which were separated by means
of column chromatrography. In the mixtures of isomeric piperidinediols lla-c--IVa-c, which
are present in the scheme in the order of the decrease in their chromatographic mobility,
cis isomers llla-c and IVa-c predominate significantly. 3,4-Dimethyl-l-ethyl-5e-cyanopiper-
idine-3a,4a-diol (lib), which was detected in trace amounts in the reaction mixture by thin-
layer chromatrography (TLC), could not be isolated in the individual state. On the other
hand, a mixture of diphenyl-substituted piperidine-3a,4a-diol and piperidine-3e,4a-diol lid
and llld, in which trans isomer lld predominates, is formed in 86% yield as a result of the
cyclization of Id; this may be associated with the more favorable equatorial orientation of
both phenyl groups in =his isomer.
It should be noted that the ratios of isomers llla-c and IVa-c may depend on the length
of time that the reaction mixture is allowed to stand. Thus, we showed that 3a,4e-diol IVa,
the axial orientation of the 3-OH group in which is probably a consequence of an intramolecu-
!ar hydrogen bond between the hydroxy group and the nitrogen atom in the cyclized In, is con-
verted to an equilibrium mixture of diols Ilia and IVa in a ratio of 1:2 upon prolonged con-
tact with sodium tert-butoxide. Similar treatment of individual isomer llla leads to a mix-
ture of llla and IVa with a similar composition. The equilibrium may be established via ring
inversion and epimerization with respect to the CHCEN fragment.
The structures of piperidinediols II-IV were confirmed by the results of elementary and
spectral analysis, as well as by the results of oxidation of a number of the diols with per-
iodic acid.
The IR spectra contain absorption bands of hydroxy groups at 3425-3605 cm-t and of a
nitrile group at 2240 cm-~, and the band of carbonyl absorption that is characteristic for
the spectra of la-d is absent. A comparison of the spectra of dilute solutions of isomeric
diols lla, c, d and IVa-c shows that the bands at 3425-3485 cm-: correspond to an axial 3-OH
group included in an intramolecular hydrogen bond with the nitrogen atom of the piperidine
ring. The absorption bands at 3520-3566 cm-~ in the IR spectra of 3e,4a-diols llla-d are
due to intramolecularly bonded hydroxy groups, whereas in the spectra of 3a,4e-diols IVa-c
they belong to an equatorial 4-OH group that is linked intramolecularly by a hydrogen bond
with the oxygen atom of the axial 3-OH group. An absorption band of an axial 4-OH group
linked by a weak intramolecular hydrogen bond with the equatorial cyano group also appears
in the spectra of 3a,4a-diols lla, c, d and 3e-4a-diols Ilia, b at 3565-3575 cm-t, or a band
of a free 4-OH group at 3600-3605 cm-~ is observed.
A characteristic feature of the PMR spectra of II-IV is a quartet of the 5-H proton,
which is deshielded under the influence of the adjacent cyano group, at 3.06-4.61 ppm. The
width of this signal, viz., 15-16 Hz, indicates an axial orientation of the 5-H atom and,

977
-.4
00

~ABLE I. Characteristics of the Compounds Obtained

bp Found, % 3alc., %
~om- (pres- Empiricat
pound sure, R; a VtHI, ?MR spectrum, 6, ppm (J, Hz)
hPa) ~m -t
[ormula
or mp, C l| N Lj 11 N
oC

la 12312)b 3,170 1,20 (311, s, 3.Clla); 2,20 1311, s, COCIIj); 2,25 [311. s NCII:~); 2,30 gvl Ij6N._,O~ 91
(,ttl, m, Cll,,CIb); 2,4,1and2,78 (211, rid,, J : 1 3 , NCII2), 5,74 (IH, S
lb I I~1,,) e 3155 0.93 (3H.t, J.-7, l; Clla); 1,117 1311, s, 3-Cl1~);2.09 1311. S . COCH,~) ; LSMI,~N~O~ 88
2,70 (411, m Cll,,Clt~); 2,4~and2,78 (2t1, dd 9 f---13, NCH~); 2,68
q , J 7, cr 3,85 ( I l l / s , OI1)
1C O~1 0,76 3t25 1,3a (311, s, 2-C11:0; 2.17 1311, s, NCI-I~); 2,25--2,92: i t l l , m, Ct I:,CIt:,) ; gjd t l~N'.,O', 96
3,30 (211, dd, 1~1,4, NCH~); 4,20 (lit, s, OH); 7,29--7,53 (3H, r
8 (}5--8 20 (211, m...'aromatic protons) , " "
kl ~2 3.1(10 2,18 (311, s, ~C11;~}I 2,27--2,80 (4t1, m CII:CIt:I; 2,49 an, C,H,,oN~O~ 75
12t{, d d , ./=13, NCH..0; 4,83 till, Z; OH); 7,10-- 7.56 (81|.m)and7.77
(2t-1, m. 'aromatic protom) "
Ila 153 3,69 3605, 1,27 (31t, s, CH~); 1,56 (3H,'s, CII~); 2,06 (3t% ~. NCI-1;;); 2.28 all 8
3490 (21i, d d , ,/=11, 2-1-1); 2,36--2,80 (211, m, 6-I-1); 3.40 (1tt. q. 1~..~
1,~..~,,=.5, 5-111; 4,83 (2tt,br.s , 2 O11)
I l i:aa 104 3,56 3505, 1,35 131-1, s, CH~); IA8 (31I, s, C|l;,); 2,05 1311, s, NCII:~); 2.38ala C91I~N~O~ 27
3575. 12H, d d , J=10, 2-t1); 2,48--2,74 (211, m 6-1t); 3,06 (IH, q. l~,~
3525 ./~,~,,=5, 5-tl); 5,34 (2H, b~.s , 2 O11)
lVa 95 3,19 3520, 1,22 (3H, s, CH:0; 1,34 13t-1, s, Cll:d; 2,05 131t, ~, NCII:(I; 2,12--2,3 28
3.170 m, 2-H., 6-H.); 2.47 (lit. q, /gem=12, Jz...,,=l,5, 2-11,.); 2,66and 2,78
do,, , 1~,,,~,,=1,5, Js,~,:'l, 6 - I L ) ; 3,44 (11I, q , ,1,s,6~=4, 5-111; 5,'hi
./~,..=ll, s. OI1); 5.72 ( l l l , s', O111
lllb Oil :},52 31i05, 0,t~3 (311, t. 1 - 7 , I;-CII;,); 1,28 1311, s, CII~); L,12 1311. s, CIl:d; 223 30
3575, q, .1=7. r 2,34 -2,72 (411, m, 2-and6-11); 2,97 (111, q, l.a
C,ollisN.~O~
1530 ,l~,,~,.- ,I.5, 5-111; 5,58 121I, br.s , 2 O111
IVb 911 ),29 ~525, 0,h3 (311. t , J -7, [$('ll:d; 125 (311, s, 131:0; 1,37 1311, s, C I I ; 0 ; 2.11 43
Yi~;0 1211, n~ 2-and611,,); 2,28 (211. q , 1 - 7 , a-CliD; 2,6,t (111, q , Jge
J~,. .... 1,5, 2-11,,}; 2,87and2,98 (t|1, m, L_,,..,.... 1,5. L~.,..--,I, 0-11,.); 3',5:
q, J~,,~,,,-ll, L,,~.,=4. 5111; 5,38 (211,br.s. . , 2 O11)
lie 145 0,81 ~6(}0, 1,30 131t, s, CII:~); 2,07 (311, s, NCII:0; 2,36a.nd 3.18 1211, dd., 7
$440 2-111; 2,75-2,87 (211, m, 6-II); 3,57 (1t1, q,
5,56 1211, bs 2 OII)
[l;cc 184 0,58 ~560 1,21 (311, s, CIl~); 2,12 (3H, s, NCII:,}; 2,52and 2,79 (211, d~!., ,t9
2-I1); 2,64--2,92 (21I, m, 6-11); 4,62 (1H, t, 1 - 8 . 5-11); 5,g|andS,48 i
2 OlD
IVc 189 0,23 3533, 1,26 (3ti, s , CII:~); 2,14 (311, ~, NCII:~); 2,28-- 2,96 (41I, Ill. 2-an, I1
3435 3.82 (1tl, q, 1.~.,.:12, 15,6,,~:4,5, 5-H); 5,82 (2tl, br.s , 2 OH)
lld 149 0,57 3565, 2,33 1311, s, CH:,); 2,65and3,62 121I, d d , J = l l , 2-11); 2,87--3,29 ( 57
3425 5-11); 4,62 (11t, q 1~,,.=10, 1.~,...~5.5, 5-1t); 5,80 (21l, hr,.s.. 2 2MI=oN.~O2
I H~c
c 178 0,42 3566 2,31) (311, s., CII,); 3 , 1 0 ~ d , 2 5 (211, d d . 1=12. 211); 3,hi (211, 29
5-11); 4,03 (111, q 1.,~,.:10, 1~,,~,,:-:5,5, 511); 5,82 121I, bt,s , 2 O1[)

aOn Al2Oa with elution by ether--hexane 14:11 (Ic, lid, llld), ether--hexane 17:11 [llc-IVc), and ethyl--isopropyl
~icohol (30:11 (lla; Ilia, b; IVa, b). bnDa~ 1.4620. cnDa~ 1.4612.
consequently, an equatorial orienta{ion of the cyano group. For some of the phenyl-substitu-
ted piperidinediols (llc, lllc) the constants of spin-spin coupling of the 5-H proton with
the protons of the 6-CH2 group have close values; this constitutes evidence for distortion
of the chair conformation.
As expected, diaxial diols II are oxidized very slowly by periodic acid as compared
with isomers III and IV; this is characteristic fo@ cyclic vicinal glycols with a trans
orientation of the hydroxy groups [13].

EXPERIMENTAL
The IR spectra of solutions of the substances in CCI~ (0.001 M) were recorded with a
Specord 75 IR spectrometer. The PMR spectra of solutions in CCI~ (Ib-d) or pyridine (la,
!I-IV) were obtained with a Varian HA-100 spectrometer (I00 MHz) with hexamethyldisiloxane
(HMDS) as the internal standard. The compositions of the reaction mixtures and the purity
of the compounds obtained were monitored by TLC on activity II AIa03 in ether--hexane or
ether-isopropyl alcohol systems with development by iodine vapors.
The acyloxiranes were obtained by oxidation of the corresponding unsaturated ketones
with alkaline hydrogen peroxide [14].
The characteristics of the synthesized compounds are presented in Table i.
4-[N-Alkyl-N-(2-cyanoethyl)amino]-3-hydroxy-3-methyl-2-butanones (la, b), 2-Hydroxy-2-
m_ethyl-3-[N-methyl-N-(2-cyanoethyl)amino]-l-phenyl-l-propanone (It), and 2-Hydroxy-3-[N-methyi
N-(2-cyanoethyl)amino]-l,2-diphenyl-l-propanone (Id). A solution"of 0.05 mole of the corre-
sponding acyloxirane and 0.05 mole of the 3-alkylaminopropionitrile in 30 ml of isopropyl
alcohol was refluxed for 10-15 h, after which the alcohol was removed at reduced pressure,
and the residue was distilled in vacuo (la, b) or crystallized from hexane-isopropyl alcohol
(I0:i) (Id). Compound Ic was isolated in the form of a viscous uncrystallizable oil by
chromatography of the residue with a column packed with AI=03 by elution with ether-hexane
(4:1).
Methyl- and Phenyl-Substituted l-Alkyl-5-cyanopiperidine-3,4-diols (IIa, c, d; IIa-d;
IVa-c). A solution of 0.03 mole of cyano ketone Ia-d in 25 ml of dimethoxymethane was added
dropwise at 18-20~ to a stirred suspension of 0.04 mole of sodium tert-butoxide in I00 ml
of dry dimethoxymethane, after which stirring was continued for 10-12 h. The reaction mix-
ture was then neutralized with 0.04 mole of glacial CH3COOH, and the dimethoxymethane was
evaporated at reduced pressure. The residue was treated with 20 ml of water, and the aqueous
mixture was extracted with chloroform. After removal of the chloroform, the residue was
chromatographed with a column packed with AI=O3 by elution with ether-isopropyl alcohol (30:1
(IIa; IIIa, b; IVa, b), ether-hexane (7:1) (IIc-IVc), or ether-hexane (4:1) (IId, IIId).
After removal of the solvents, individual piperidinediols II-IV were crystallized from hexane-
isopropyl alcohol (I0:i).
Isomerization of Piperidine-3a,4e-diol (IVa). A 1.8-g (0.01 mole) sample of IVa was
added to a suspension of sodium tert-butoxide, obtained from 0.35 g (0.015 mole) of sodium,
in dry dimethoxymethane, after which the reaction mixture was stirred for 48 h and worked up
as described above. After removal of the CHCI3, the residue was chromatographed with a col-
umn packed with A1203 by elution with ether--isopropyl alcohol (30:1) to give 0.53 g (29%) of
llla and 1.12 g (62%) of IVa. According to data from the PMR spectrum of the mixture ob-
tained, the ratio of llla and IVa was 35:65.
Oxidation of Piperidinediols II-IV by Periodic Acid. This reaction was carried out by
means of a standard solution of this oxidizing agent in glacial CH~COOH. The percentage of
the oxidized vicinal diol was determined by the method in [15]. In the course of the 30 min
necessary for the oxidation of cis-diols Ilia and IVa at 65~ trans-diol lla underwent 5-8%
oxidation under the same conditions. Similarly, at 60~ cis-diols lllc and IVc were oxidized
hy periodic acid in 3 h, whereas trans isomer llc underwent 1-3% oxidation during this time.

LITERATURE CITED
,
M. Koyama and S. Sakamura, Agric. Biol. Chem., 38, iiii (1974).
2. T. Yu. ll'yuchenok, M. N. Romanchak, A. M. Zvonok, I. G. Tishchenko, L. S. Stanishevskii
L. M. Frigidova, Yu. V. Zav'yalov, K. S. Shadurskii, Z. B. Berezovskii, A. S. gakharev-
skii, and A. V. Miklevich, Khim.-farm. Zh., No. 12, 40 (1978).

979
 3. T. N. Maksimova, V. B. Mochalin, and V. B. Unkovskii, Khim. Geterotsikl. Soedin., No. 6,
783 (1980).
4. V. Petrov and O. Stephenson, J. Pharm. Pharmacol., 14, 306, 522 (1962); Chem. Abstr.,
58, 501, 6829 (1963).
5. R. E. Lyle and W. E. Krueger, J. Org. Chem., 30, 394 (1965).
6. J. E. Saavedra, J. Org. Chem., 44,-4516 (1979).
7. N. Bregant, J, Janculev, and S. Ghyczy, Ark. Kemi, 27, 189 (1955); Chem. Abstr., 50,
12043 (1956).
8. L. S. Stanishevskii, I. G. Tishchenko, A. Ya. Guzikov, A. M. Zvonok, and L. A. Khil'mano
vich, Zh. Org. Khim., ll, 643 (1975).
9. A . M . Zvonok, A. P. Lugovskii, and L. S. Stanishevskii, Vestnik Belorussk. Gosudarstv.
Univ., Set. 2, No. l, 66 (1983).
10. A. M. Zvonok, A. P. Lugovskii, V. A. Mashenkov, and L. S. Stanishevskii, Zh. Org. Khim.,
~_88, 2108 (1982).
ii. V. I. Tyvorskii, L. S. Stanishevskii, and I. G. Tishchenko, Khim. Geterotsikl. Soedin.,
No. 3, 404 (1981).
12. E. T. Golovin, E. P. Badosov, A. P. Nikiforova, A. B. Khasirdzhev, and B. V. Unkovskii,
Zh. Org. Khim., 10, 1265 (1974).
13. E. L. Eliel, N. Allinger, S. J. Angyal, and G. Morrison, Conformational Analysis, Wiley
(1965).
14. V. I. Tyvorskii and I. G. Tishchenko, All-Union Institute of Scientific and Technical
Information Deposited Paper No. 5797-81 Dep.; Ref. Zh. Khim., llZhl91 (1982).
15. S. Siggia and J. G. Hanna, Quantitative Organic Analysis via Functional Groups [Russian
translation], Khimiya, Moscow (1983), p. 41.

ARYLATION, ALKYLATION, REDUCTION, AND PYROLYSIS

OF IH-I-METHYLINDENO[2,I-b]PYRIDINE

A. T. Soldatenkov, M. V. Bagdadi, V. O. Fedorov, UDC 547.665'828:542.953.5'941:

and N. S. Prostakov 543.422

Nucleophilic substitution (phenylation with phenyl lithium) of iH-l-methylin-

deno[2,l-b]pyridine occurred at the C(2) and C(~) positions, and electrophilic
substitution (methylation and benzylation with halogen derivatives) at C(,).
Reduction of the starting anhydrobases gave l-methyl-l,2,3,9a-tetrahydro-l-
azafluorene, and pyrolysis gave l-azafluorene and l-azafluorenone.

In a continuation of our work on NH-indenopyridines [i, 2], we have studied the pyroly-
sis, reduction, and substitution reactions of some anhydrobases such as iH-l-methylindeno 2,
l-b pyridine (I).
According to quantum mechanical calculations [3], nucleophilic substitution of the in-
denopyridine I should occur at positions C(~) and C(2). Arylation of compound I with phenyl
lithium gave iH-l-methyl-2-phenyl- and 4-phenylindeno[2,1-b]pyridine (II and III) in approxi-
mately equal amounts. A small amount of a crystalline substance, which, from mass-spectral
data was assigned the structure iH-l-methyl-2,4-diphenylindeno[2,l-b]pyridine was also ob-
tained. In the PMR spectra of the anhydrobase II, the 4-H proton signal is further downfield
and has a greater coupling constant (8.14 ppm, J3,~ = 7.1 Hz) compared with the 2-H proton
of its isomer III (7.71 ppm, J2,~ = 6.7 Hz); this is characteristic for anhydrobases of this
type [2]. The long-wave absorption maximum in the UV spectrum of compound II undergoes a
hathochromic shift (608 am) compared with that of compound III (590 nm).

P. Lumumba People's Friendship University, Moscow 117923. Translated from Khimiya

GeterotsiklicheskiP.h Soedinenii, No. 9, pp. 1212-1214, September, 1986. Original article
submitted May 15, 1985.

980 0009-3122/86/2209-0980512.50 ~ 1987 Plenum Publishing Corporation

 R2
!

/ I i ,. I
"~ CH 3

~,v / i "\. [l,III

zl---a "I H
CH~ O
~I VII VIII

II RI=C6Hs, R2=H; Ill Rm=H, R2=C6Hs; IV R=CH3; V R=C6HaCH2

Electrophilic substitution -- treatment of indenopyridine I with methyl iodide or benzyl

chloride, gave, respectively, the hydroiodide of compound IV and the hydrochloride of com-
pound V, which were then converted to iH-l,9-dimethylindeno[2,l-b]pyridine (IV) and IH-I-
methyl-9-benzylindeno[2,l-b]pyridine (V). The hydrochloride of the anhydrobase V was iso-
lated as high-melting, intensely-colored crystals. The structure of this salt was confirmed
by PMR, where in addition to singlets from the methylene and methyl group (at 3.8 and 4.6
ppm), signals from the dihydropyridine ring protons are seen (ABC system). The free anhydro-
bases IV and V are deep-violet crystalline substances.
Thus, nucleophilic arylation of indenopyridine anhydrobases took place at positions C(a)
and C(~) of the n'deficient nitrogen-containing ring, and alkylation with alkyl halides re-
sulted in electrophilic substitution at position C(9) of the ~-excessive five-membered ring.
Reduction of compound I with sodium borohydride gave l-methyi-l,2,3,9a-tetrahydro-l-
azafluorene (VI). Earlier, we obtained this compound by reduction of l-azafluorene iodomethy-
late with sodium borohydride [4].
Pyrolysis of the anhydrobase I at 650 ~ gave i-azafluorene VII in up to 50% yield, while
pyrolysis in air at 300 ~ gave l-azafluorenone VIII in ~18% yield.

EXPERIMENTAL
PMR spectra (internal standard -- TMS) were recorded on a BS-497 spectrometer (i00 Hz).
Mass spectra were obtained on an MX-1303 instrument at 70 eV with direct introduction to
source. UV spectra were taken on a Hitachi spectrophotometer (in ethanol).
iH-i-Methyl-2-phenyl-, 4-phenylindeno[2,l-b]pyridines (II, III). To a solution of
phenyllithium, prepared from 0.13 g (0.19 mmole) of lithium and 1.3 g (8.3 mmole) of bromo-
benzene in 75 ml of ether, was slowly added a solution of 1 g (5.5 mmole) of indenopyridine
I in 75 ml of ether. The mixture was stirred for i h, then poured into 150 ml of water.
The ether layer was dried over magnesium sulfate. The residue (1.5 g), after removal of the
ether, was chromatographed on aluminum oxide (H 24 cm, d i.i cm, eluant -- a i:i mixture of
ether and hexane). The first fraction contained 0.15 g (11%) of compound III, as deep-violet
crystals, mp 94-95 ~ (from ether and hexane), Rf 0.62. PMR, spectrum (acetone-D6): 7.71 (d,
J2,3 = 6.7 Hz, 2-H); 6.35 (d, J~,2 = 6.7 Hz, 3-H); 6.65 (t, J = 7.5 Hz, 5-H); 6.19 (s, 9-H);
7.58-6.98 (m, arom. protons); 4.01 ppm (s, I-CH3). UV spectrum, %max (log ~): 300 (4.3),
335 sh. (3.90), 480 sh. (3.14), 590 nm (3.50). Mass-spectrum, m/z, %: 257 (i00),
256 (5), 242 (19), 183 (29), 105 (36), 77 (29). Found, %: C 88.4, H 5.1, N 5.7. CzgH:,N.
Calculated, %: C 88.7, H 5.8, N. 5.5; M 257.
The second fraction contained 0.14 g (10%) of compound II, as deep-violet crystals, mp
76-77 ~ , Rf 0.29. PMR spectrum (acetone-D6): 8.14 (d, J~,s = 7.1 Hz, 4-H); 7.74-6.70 (m,
atom. protons); 6.42 (d, J~,3 = 7.1 Hz, 3-H); 6.21 (s, 9-H); 3.54 ppm (s, I-CH3). UV spec-
trum, Xmax (log ~): 308 (4.54), 350 (4.0), 480-570 (3.1), 608 nm (3.23). Mass spectrum,
m/z, %: 257 (40), 256 (16), 242 (2.5), 182 (26), 154 (52), 105 (i00), 77 (73). Found, %:
C88.4, H 6.0, N 5.4. C:gHzsN. Calculated, %: C 88.7, H 5.8, N 5.5; M 257.
Finally, the column was washed with ether to give 8 mg of deep violet crystals, mp 99-
103 ~ Mass spectrum: M + 333. C25HzgN. Calculated %: M 333.
iH-l~9-Dimethylindeno[2,l-b]pyridine (IV). A solution of 0.5 g (2.7 mmole) of the
indenopyridine I and 1.5 ml (24 mmole) of CH31 in 25 ml of acetone was refluxed for 3 h.

981
 The precipitate (0.21 g) was separated, dissolved in water, and treated with a 20% potassium
hydroxide solution to give 60 mg (11%) of the indenopyridine IV, as dark-vlolet crystals,
mp 160-162 ~ . UV spectrum, Imax (log e): 485 sh. (2.71), 585 nm (3.36). Mass spectrum,
m/z, %: 195 (36), 194 (33), 182 (0), 181 (75), 180 (36), 179 (45), 166 (54), 142 (i00), 139
(32), 127 (60). Found, %: N 7.4. C ~ H , s N . Calculated, %: N 7.2; M 195.
iH-i-Methyl-9-benzylindeno[2,l-b]pyridine (V). A solution of 0.5 g (2.8 mmole) of com-
pound I and 0.5 g (4 mmole) of benzyl chloride in 30 ml of benzene was allowed to stand for
7 days at room temperature. The material which precipitated was filtered, washed with ben-
zene, and then with ether to yield 0.2 g (23%) of the hydrochloride of compound V, black
crystals, mp 187-189 ~ PMR spectrum (DMSO-D~): 3.8 (s, 2H, CH2); 4.6 (s, 3H, CH3); 6.63
(t, IH, 3-H); 7.0-7.6 (m, atom. protons); 8.38 (d, J2,s = 6.6 Hz, 2-H); 8.69 (d, J~,~ = 7.6
Hz, 4-H); 9.00 ppm (s, IH, HCI). Found, %: N 4.6. C2oH~TN,HCIo Calculated, %: N 4.6.
Treatment of the hydrochloride with alkali gave compound V, as deep-violet crystals, mp 122-
125 ~ Mass spectrum, m/z, %: 271(i), 256 (i00), 254 (42),182 (80), 181 (90), 91 (65), 77
(45). Found, %: N 5.4. C2oH~TN. Calculated, %: N 5.8; M 271.
l-Methyl-l,2,3,9a-tetrahydro-l-azaflu0rene ' (Vl). To a solution of 1 g (5.5 mmole) of
the indenopyridine I in 50 ml of methanol with vigorous mixing was slowly added 0.4 g (ii
mmole) of sodium borohydride. The mixture was refluxed for 1 h and 30 ml of water added.
The reaction product was extracted with benzene to give 0.44 g (43%) of compound Vl, mp
50-51 ~ [4].
Pyrolysis of iH-i-Methylindeno[2,l-b]pyridine. A flow-through quartz reactor, filled
with ground quartz, was heated to 650 ~ and purged with nitrogen; through this was passed a
solution of 0.5 g (2.8 mmole) of indenopyridine I. The condensate, after evaporation of the
benzene gave 0.4 g of crystals, which were chromatographed on aluminum oxide (eluant i:I
ether-hexane). First was eluted 0.i g of diphenyl, followed by 0.25 g (50%) of l-azafluorene
VII, mp 84 ~ [5].
In an analogous experiment at 300 ~ in the presence of air, 1.3 g (7 mmole) of indenopyri-
dine I gave 0.14 g (17.5%) of l-azafluorenone VIII, mp 127-128 ~ [5], 0,36 g of starting mate-
rial (I) and 0.25 g of a mixture of compound I and l-azafluorenone VIII in a ratio of i:i,
which were separated by chromatography.

LITERATURE CITED
i. N . S . Prostakov, A. T. Soldatenkov, V. O. Fedorov, S. Mobio, and M. A. Galiullin, Khim.
Geterosiklo Soedin., No. ii, 1511 (1980).
2. N . S . Prostakov, A. T. Soldatenkov, M. V. Bagdadi, A. A. Fomichev, and N. I. Golovtsov,
Khim. Geterosikl. Soedin., No. 9, 1238 (1982).
3. R. Borsdorf, J. Pr. Chemo, 32, 211 (1966).
4. N . S . Prostakov, Ao T. Soldatenkov, V. O. Fedorov, A. I. Semikopnyi, I. A. Sytinskii,
M. M. Borisov, and T. P. Mufazalova, Khim.-farm., Zh., No. 8, 67 (1981).
5. N . S . Prostakov, A. T. Soldatenkov, and V. O. Fedorov, Khim. Geterosiklo Soedin., No. 8,
ii01 (1979).

982
INVESTIGATION OF STEREOISOMERS OF 4-ALKENYL-trans-
DECAHYDROQUINOL-4-OLS IN MIXTURES BY THE METHOD
OF REACTION CHROMATO-MASS SPECTROMETRY*

A~ I. Mikaya, V. G. Zaikin, R. L. Ushakova, UDC 543.51:547.831.3:541.634

L. I. Ukhova, and N. F. Marchenko

The mass spectra of the appropriate 4-ethyl derivatives, which provide the de-
termination of the configuration of the 4 position in the initial aicohols, are
registered in the chromato-mass spectrometric investigation of mixtures of the
stereoisomeric 4-vinyl-trans-decahydroquinol-4-ols using a microreactor for
hydrogenation; the microreactor is placed before or after the chromatographic
column.

The principle possibility for the application of electron-impact mass spectrometry (El)
in the determination of the configuration of the 2 and 4 positions in substituted 4-alkyl-
trans-decahydroquinol-4-ols was previously [2] shown on a large number of examples. In this
case, the utilization of the high stereospecificity of reactions of the cleavage of the alkyl
substituents from the indicated positions was proposed for the stereochemical assignments.
At the same time, it was established that it does not seem possible to determine the config-
uration of the 4 position in 4-alkenyl-trans-decahydroquinol-4-ols by the direct mass-spec-
trometric investigation due to the disadvantageous breaking of the C--Cviny I bond by the El;
this problem can be solved by the preliminary hydrogenation of the samples to their saturated
analogues. It is al interest to accomplish the hydrogenation reaction directly in the inlet
system of the instrument during the process of CMS. It was shown in the work [3] that the
method of CMS can be successfully utilized for the analysis of mixtures of the stereoisomers
of 4-alkyl-trans-decahydroquinol-4-ols in spite of the fairly drastic conditions of the ex-
periment. In the present work, the possible utilization of pre- and post-column hydrogena-
tion directly in the instrument was studied to determine the configuration of the 4-alkenyl-
trans-decahydroquinol-4-ols contained in the mixtures. Mixtures of the stereoisomers of the
4-vinyl-trans-decahydroquinol-4-ols (I), (II) and (III), (IV), of known stereochemistry [2],
were taken for the investigation; they were obtained from the corresponding trans-decahydro-
quinol-4-ones by the Norman reaction.
The work was carried out on an LKB-2091 instrument (energy of the ionizing electrons 70
eV, emission current 50 uA, temperature of the ionization chamber and the molecular separa-
tor 250~ In the chromatographic part, we utilized a quartz capillary c o l u m n 2 5 m 0.26mm
with the stationary liquid phase of Carbowax 20 M (the gas carrier and gas reagent was hydro-
gen; the division of flowwas 1:30; the temperature of the inlet block was 300~ the tempera-
ture was programmed from 40 to 200~ at a rate of 8~
We utilized 1.5% Pd/porous glass (diameter of the granules -0.3 mm) as the catalyst for
the hydrogenation. It was placed in the microreactor, previously described [4], between the
glass plugs. Special experiments using the hydrogenation microreactor between the inlet
block and the chromatography column with the individual compounds (1)-(V) showed that the
core of the catalyst of the diameter 2 mm and the height 20 mm guaranteed the quantitative
hydrogenation of up to 0.i Dg of the individual vinyl alcohol to the 4-ethyl analog at a
temperature of 150-200~ The isomerization, hydrogenolysis, or dehydration of the compounds
investigated was not thereby noted.

*Communication 13 of the series "Reaction chromato-mass spectrometry." For Communication 12,

see [I].
A. V. Topchiev Institute of Petrochemical Synthesis, Academy of Sciences of the USSR,
Moscow 117912; Institute of Bioorganic Chemistry, Academy of Sciences of the Belorussian
SSR, Minsk 220600. Translated from Khimiya Geterotsiklicheskikh Soedinenii, NO. 9, pp. 1215-
1217, September, 1986. Original article submitted May 27, 1985.

0009-3122/86/2209-0983512.50 9 1987 Plenum Publishing Corporation 983

 I

Fig. i. Chromatograms of the mixtures of

the stereoisomers of l-ethyl-4-vinyldecahy-
b
droquinol-4-ols (a) and l-ethyl-2-methyl-4-
vinyldecahydroquinol-4-ols (b) registered
using the hydrogenation microreactor (170~
placed between the column and the mass
c_, spectrometer.

:; !7 15 rain

In the investigations on the development of the method of reaction CMS [5], we paid
special attention to the utilization of microreaction systems situated between the chromatog-
raphy column and the mass spectrometer. The advantage of such a disposition of the micro-
reactor is the fact that each component eluted from the column undergoes chemical reaction
in the given case, whereby the registered chromatogram corresponds to that of the initial
mixture; the mass spectra correspond to the conversion products. We also utilized such a
disposition of the hydrogenation microreactor in the present investigation.
Two artificial mixtures were prepared with the following ratios of the components:
(I):(II) ~ i:1.5 and (III):(IV):(V) ~ 1.5:4:1. The fact that the ionization profiles of the
stereoisomers are close, and that the ratio of the areas of the chromatographic bands is
equal to the mass and molar ratio of the stereoisomers, was utilized for the assignment of
the chromatographic bands to a specific compound. The chromatograms of both the mixtures
of the stereoisomers are presented in Fig. i; they represent the recording of the change of
the full ion current in the process of the entry of the substances into the ionization cham-
ber of the mass spectrometer, and are registered on passing the components through the by-
pass or the hydrogenation microreactor. It was established that the presence of the hydro-
genation microreactor with the amount of the catalyst indicated above has practically no
influence on the times of outflow of the components, and does not impair the chromatrographic
separation which is obtained using the capillary column. At the same time, the registered
mass spectra correspond completely with the spectra of the 4-ethyl analogs (la)-(Va); this
indicates the quantitative hydrogenation of the vinyl alcohols (1)-(V) with the retention of
configuration.
R R~ I~z RJ

C~fl 5 C~H~
I.II [a,llll

R2
R' ~. R3
F
1 J~" I Pd p
, + I] 2 --
"N" CII 3 ~ "XCH3
: I
C2H~ C2H ~
III - V llla-Va

I R=OI{, R'=CI-I=CH2; II R=CH=CH2, RI=OH; la R2=OH, R2=C2Hb; Ila RI=C~Hs,

R3=OH: [II 2a-C[%; R=OH, R'=CH=CH2; IV 2e-CH~; R=OH, R*=CH=CH.~; V
2e-CH~; R=CH=CH2, RI=OH; Ilia 2a-CH3; R2=OH, R3=C.~Hs; IVa 2e-CH~; R2=OH,
R~=C~H~; Va 2e-CH~; R2=C~H~,, Ra=OH

984
 TABLE I. Ratio of the In-
tensities of the Peaks of
the Characteristic Ions
Corn- [I[M--CHs]+/ I[Ivl-- C2Hi]+/
poundII~'" I['M]+.
MS IRCMS

la -- -- 5,00 [ 5,10
lIa 6,30 6,30
Ilia 675 6,0-0 5,30 5,15
[Va 3 , 9 6 3,85 3,64 3,75
Va 3,24 3,10 8,46 9,00

As was noted above, the determination of the configuration of the 2 and 4 positions in
the 2-methyl-4-ethyldecahydroquinol-4-ols was based on the high stereospecificity of the
cleavage reactions of the alkyl substituents from these positions. In this case, the ratios
of the intensities of the peaks of the [M -- CH3] + (elimination of the 2-CHa group) and the
[M -- C2H,] + (elimination of the 4-ethyl, but not the N-ethyl group [6]) ions to the intensity
of the peak of the molecular ion were utilized; these ratios were always higher for the com-
pounds with axial alkyl groups by comparison with their equatorial analogues. The values of
the ratios of the intensities of the peaks of the ions, namely I [ M _ CHa]e/I[M] ~ and I[M--
C2Hs]+/I[M] +, are presented in Table i; they were obtained by using the direct introduction
of the individual substances (la)-(Va) into the ion source on the one hand (MS), and by using
the gas-chromatographic introduction of the mixture of alcohols (1)-(V) with the passage of
the components of the mixture through the hydrogenation microreactor (RCMS), under the con-
ditions described, on the other hand. As can be seen from Table I, these values, which were
obtained under different experimental conditions, are fairly close; the character of their
change in the transition from one stereoisomer to the other is preserved. The fact that the
ratios of the intensities of the peaks of the ions, namely I[M-- C2H,]+/I[M] +, are signifi-
cantly higher in the mass spectra of the compounds (lla) and (Va) than in the spectra of the
stereoisomers (la) and (IVa) correspondingly shows that the first have the axial, and the
second have the equatorial, ethyl groups. This result, in its turn, permits the assignment
of the axial orientation of the 4-vinyl group in the compounds (II) and (V), and the equato-
rial orientation in the compounds (I) and (IV).
Therefore, the utilization of hydrogenation in the admission system of the chroma=o-mass
spectrometer facilitates the mass-spectrometric differentiation of the stereoisomers with
unsaturated substituents in the decahydroquinoline series. The proposed method does not re-
quire the additional outlay of work and time on the isolation, separation, and hydrogenation
of the stereoisomers.

LITERATURE CITED
i. A . I . Mikaya, T. P. Popova, V. G. Zaikin, V. E. Shiryaeva, L. S. Glebov, G. A. Kliger,
A. V. Antonova, and N. S. Prostakov, J. High Res. Chromatogr. Chromatogr. Commun., in
press.
2. V . G . Zaikin and N. S. Vul'fson, Khim. Geterotsikl. Soedin., No. ii, 1443 (1978).
3. V. G . Zaikin, V. I. Smetanin, N. S. Vul'fson, A. A. Skhrem, and L. I. Ukhova, Khim.
Geterotsikl. Soedin., No. ii, 1537 (1976).
4. V . I . Smetanin, A. I. Mikaya, and V. G. Zaikin, Zavod. Lab., 49, No. I0, 24 (1983).
5. A . I . Mikaya, V. I. Smetanin, and V. G. Zaikin, Izv. Akad. Nauk SSSR, Ser. Khim.,
No. i0, 2270 (1982).
6. N . S . Vul'fson, V. G. Zaikin, A. A. Bakaev, A. A. Akhrem, and L. I. Ukhova, Khim.
Geterotsikl. Soedin., No. 7, 962 (1975).

985
NAPHTHYRIDINES IN HETARYLATION REACTIONS*

A. K. Sheinkman, T. N. Nezdiiminoga, T. S. Chmilenko, UDC 547.834.2'753.07:

and N. A. Klyuev 542.422.25'51

The reaction of indole (2-methylindole) with 1,5-, 1,6-, and 1,8-naphthyri-

dines at 20"C, in the presence of benzoyl chloride, leads to the preferential
formation of dihydro structures with one indolyl substituent at the a-position
to the hetero atom. With increase in temperature, dibenzoyl and monobenzoyl
tetrahydro-substituted naphthyridines with two indolyl residues in both pyri-
dine rings are formed besides the above compounds.

Hetarylation of organic compounds by azines or azoles in the presence of acylating

agents takes place in three stages: formation of N-acyl heteroaromatic cations, addition of
nucleophiles to them in situ, and aromatization of the N-acyl =(y)-substituted dihydrohetero-
aromatic compounds formed [2]. The rate of the first stage is higher, the higher is the
basicity of the heterocycle. The higher the basicity, the higher is the current concentratio~
of the N-acyl cations, and hence, the higher is the rate of nucleophilic addition to them.
However, with increase in the basicity of the heterocycle, the electrophilicity of its cation
decreases, which affects the decrease in the rate of nucleophilic addition. Aromatization
becomes more difficult at higher electrophilicity of the heteroaromatic cations thus formed,
in other words, at lower basicity of the corresponding heterocycles [3]. Therefore, when
the reactions are carried out under standard conditions, there is sometimes an increase in
the yields of the hetarylation products with increase in the basicity of the heterocycle [4],
and sometimes the yields decrease a little, but nevertheless remain fairly high even in the
case of weakly basic heterocycles such as 1,4-diazines [5]. It was interesting to study the
behavior of different naphthyridines [6] in this reaction [6].

pK, 2.91 3.39 3.78

It is known that in the presence of benzoyl chloride, 1,8- and 1,6-naphthyridines add
KCN to form the so-called Reissert compounds [7-10]. For the least basic 1,5-naphthyridine,
no such reaction is known, and there are no known cases of the addition of other nucleophiles
to naphthyridines [6-11].
We studied the reaction of 1,5-, 1,6-, and 1,8-naphthyridines with indole and 2-methylin-
dole in the presence of benzoyl chloride in toluene and DMFA at different temperatures and
ratios of the reagents. It was found that in toluene at 20~ the usual hetarylation products
I-III are obtained, and when the reaction is carried out under standard conditions, the yields
of products are approximately the same as in the reaction with quinoline and isoquinoline [4],
although the basicity of naphthyridine is 2.5 pK units, lower.

9 , "2"S
I H l l a , b II ~
[! ~ R=tI ba=CIl3

*Preliminary communication, see [i].

The Dnepropetrovsk Construction Engineering Institute, Dnepropetrovsk 320060. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1218-1222, September, 1986.
Original article submitted May 28, 1985.

986 0009-3122/86/2209-0986512.50 ~ 1987 Plenum Publishing Corporation

 TABLE i. Physicochemical Characteristics of Compounds Syn-
thesized
IR spectrum, cm-I Found, % Calculated,
:om- mp,* "C R/ Empirical
~o~Dd formula i
~. O Z C H N C I{ N

t
i
I 204--205 0,78 3380 1650 1550 78,3 4,4 1,6 C23HITN30 78,6 4,8 !]2.0
llaq" " 178--t79 0,51 3370 1660 1570179,0 4,7 1,5 C~H,TN30
78.6 4,8 ~12,0
IIb 261--262 0,64 3380 1660 1570/79,2 4,9 1,2 C24HmN30
78.9 5,2 l 1,5
ili 191--t92 0,64 3360 1670 1550{78,1 5,0 .~,I C2~HITN30
78.6 4,8 12.0
Va 289--290 0,39 3390 3320 1650 ~79,8 5,1 .~,IC3,H2~N40 79,5 5,1 12.0
Vb 240--241 0,60 3390 3290 1640 179,4 5,2 ),9 C33H2~N40 79,8 5,6 II,2
VI 278--279 0,53 3325 1645 ]79,5 5,2 ),4 C3sH2sN402 79,7 4,9 9,8
VII 194--195 0,24 3380 3270 [79,2 5,5 5,3 C:4H~oN4 79,1 5,5 15,4
VIII 185--t86 0,09 3420 3380 r9,5 5,9 5,4 C~H~oN, 79,1 5,5 15,4
IXa :1:" 271--272 0,07 3400 3380 ~79,2 5,1 L8 C~H~N~ 79,1 5,5 15.4
[Xb 209--210 0,25 3390 3340 ]79,3 6,0 t6 C~H~N~ 79,6 6,1 14,3
X** 204--205 3,16 3440 3345 178,8 5,4 5,0 C~4H~oN4 79,1 5,5 15,4

*Compounds lla, X were recrystallized from acetonitrile, llb

from DMFA, VIII, IXb from methanol, and the remaining com-
pounds from propanol.
fPMR spectrum: 10.90 (s, NH), 8.33-6.95 (13H, m, atom.), 7.07
(IH, dd, J = 7.4 Hz, 4-H), 5.73 (IH, dd, 3-H), 5.07 (IH, d,
J = 5.6 Hz, 2-H).
?#PMR spectrum: 10.82 (2H, d, NH), 7.75-6.74 (16H, m, naph-
thyridine and indoie ring protons), 4.94, 4.71 (2H, dd, J =
2.6 and 10.3 Hz, dd, J = 6.7 and 11.9 Hz, 3-H).
**PMR spectrum: 10.84 (2H, d, NH); 7.73-6.79 (16H, m, naph-
thyridine and indole ring protons); 4.60, 4.46 (2H, t, J = 4.7
Hz, J = 4.5 Hz, 3-H).

Compounds I-III were obtained at the boiling point of toluene, and in the reaction with
1,5-naphthyridine, ~-di-(3-indolyl)ethyl-o-benzanilide (IV) is also formed, while in the reac-
tion with 1,8-naphthyridine, l-benzoyl-2,7-di-(3-indolyl)-l,2,7,8-tetrahydro-l,8-naphthyridine
(V), 1,8-dibenzoyl-2,7-di-(3-indolyl)-l,2,7,8-tetrahydro-l,8-naphthyridine (Vl), and 2,7-di-
(3-indolyl)-l,2,7,8-tetrahydro-l,8-naphthyridine (VII) are obtained:

PhOC
H H H
IV Va,b

%1~"~ J I
phoc 'I6oph ~ N ~
H H H H
V'I VII

v a R=H.b R = C H 3

In the reaction with 1,8-naphthyridine in DMFA at 20~ the same compounds I, V-VII are
formed as in toluene, but at the boiling point the ratio of their yields changes: the amount
of compound VII increases from 5 to 83%, and that of compound V decreases from 15 to 5%, while
the dibenzoyl derivative VI and compound I were not detected in the reaction mixture. In the
reaction with 1,6-naphthyridine in DMFA at 20~ and at the boiling point, compound III is
not formed, but 2,5-di-(3-indolyl)-l,2,5,6-tetrahydro-l,6-naphthyridine (VIII) is. The behav-
ior of 1,5-naphthyridine in DMFA was found to be somewhat unusual. Two isomeric compounds
IX and X could be isolated from the reaction mixture in a ratio of 4:3, with a molecular
weight of 364 and an empirical formula of C2~H2oN~. The possible structures of these com-
pounds are represented by the following formulas:
H H H Ind [! H ~ ~ K ~nd

H ~nd H H H" "H H

A B C I=d D

987
 TABLE 2. Mass Spectra of Compounds I-III, V-X
Mass spectrum, m / z (relative 'intensity, %)

<
=
O
'7 7 '7 9

1 351 (12) 246 (!00) 130 (24) 17 (121 16 (2) 105 (33)
lla 351 (6) 246 (100) ]3o (4) 1 17 (39) 16 (3) 105 (70)
l i b 365 (12)
IIr 351 (t3)
260 (40)
246 (I00)
130 (29)
130 (24)
# (24)
(12) 105 (100)
16 (7) 105 (99)
Va~ 468 (7) 063 (29) 247 (ll) 246 (27) 17 (10( ) 16 (14) [05 (52)
Vb, 496 i21) 391 (I00) 261 (17) 260 (64) ]! (38) io5 (48)
VI 572 (8) 467 (8}%' t, (i9} I6 (3) I05 (ioo)
VII 364 (12) 247 (87) 246 (lO0) 17 (25) 16 (6)
VIII 364(18) 247 (95) 246 (I00) 17 (311 16 (6)
IXa 364 (91) 247 (80) 246 (I00) 17 (48) 16 (9)
IXb 392 (22) 261 (97) 1260 (100) 31 (74)
X 364 (48) 247 (I00) [2~6 (99) It7 (74) 16 (15)

*For compounds lib, Vb, IXb, Ind = 2-methylindole.

%The following peaks are in the mass spectrum: M -- 2COPh+
363 (7); M-- 2COPh-- Ind + 246 (30); M-- 2COPh-- Ind --H +
245 (17); M-- 2COPh-- 21nd + 130 (i0).

TABLE 3. Reaction Conditions and Yields of Hetarylation

Products of Indole
Reaction conditions
Eluent for chro-
Starring Reaction pro- matographyand
~,9o"
naphthyridine .,,~ e . r duct (yield, separation or re-
~ ~ solvent T. :C %) action products

~ a0' =0 . . , o
a-

=2 o~
1,6-Naph- 1* Toluene 25, bp lli (91) Ether -- chloroform-
thyridiffe 1 DMFA 25, bp VIII (90) hexane--alcohol
30:10:5:1
I.8-Naphthyd- 1 T oluene 25 [ (57) As above
dine 1 Toluene bp I (17), v (15),
C25~ (DMgA) Vl (9), v i i (5)
bp. l DM/'A v (5), v u (83)
1,5-Naph- 25 1 T o luene II (55)
thyridine bp l Toluene u (68) Ether--chloroform-
DMFA bp I IX (4o), x (30) hexane;8: 1 :1
ratio of reagents, the yield of reaction prod-
ucts was the same.

Aromatization of isomers IX and X by chloranil leads to one and the same compound Xl,
which indicates that the position of the indolyl substituent is identical in the two isomers,
and hence structures A and C or B and D are possible. We assigned the structures by analysis
of their PMR spectra. In the spectra, the most characteristic feature is the difference in
the multiplicity of signals in 4.4-5.0 ppm region. For compound IX there are in this region
two doublets of doublets with centers at 4.94 and 4.71 ppm and SSCC J = 2.6 and 10.3 Hz for
one of the isomers, and 6.7 and 11.9 Hz for the other, with an overall intensity of 2H. The
multiplicity and SSCC indicate that these signals can be assigned to 3-H protons of structures
A or B, while their overall intensity and absence of changes in multiplicity when double
resonance is superimposed on each of them indicate the presence of two conformers. In the
spectrum of compound X there are two triplets at 4.60 and 4.46 ppm with SSCC of 4.7 and 4.5
Hz, respectively, with an overall intensity of 2H. Structure D presumes the presence of two
triplets with an overall intensity of 4H for NH and 3-H protons. Therefore, the observed
overall intensity of triplets and absence of changes in addition of D20 show that it is pos-
sible to assign the signals to the resonance of 3-H protons of structure C, 2,6-di-(3-indolyl)-
1,4,5,8-tetrahydro-l,5-naphthyridine, and their independence of one another (according to the

988
double resonance data) shows that in this case also we can assume the existence of two con-
formers. A partner in the pair to this compound is 2,6-di-(3-indolyl)-l,2,5,6-tetrahydro-
1,5-naphthyridine, A.

VIII H II

H I~ H

X tt Xl It
a I~=H.bR=CH~

The PMR spectra of the remaining compounds also confirm the ~-disposition of the indolyl
substituent. For compound lla, the relative disposition of the 2-H, 3-H and 4-H protons is
at 5.07, 5.73, and 7.07 ppm, respectively, and the SSCC J = 5.6 and 7.4 Hz are similar to
those for 1,2-dihydroquinoline structures with an ~-substituent [12, 13]. Thus, the ~- and
not the y-position in the naphthyridine cation is subjected to the nucleophilic attack, which
agrees with all the above cases [6-11].
In the IR spectra of the compounds obtained there are absorption bands of the NH groups
of indole and dihydronaphthyridine rings, carbonyl group, and C=N double bonds (Table i).
The fragmentation of the molecular ions of compounds I-X is characteristic of these compounds
and analogous to the fragmentation of N-benzoyl-2-(3-indolyl)-l,2-dihydrobenzopyridine deriv-
atives by the action of an electron impact [14]. Besides molecular ions, ions of benzoyl
(m/z 105) and indole (m/z 117) fragments are observed in the mass spectrum. They are formed
as the result of cleavage of the amide and internuclear C--C bonds, which are not labile in
the molecule (Table 2).

EXPERIMENTAL
The IR spectra were run on a Specord IR-75 spectrophotometer, and the mass spectra on a
Varian MAT-3!1 spectrometer with a direct introduction system of the samples into the ionic
source, energy of ionizing electrons 70 eV, temperature of the ionization chamber I00-300~
The PMR spectra were recorded on a Bruker WH-90 spectrometer in DMSO-D6.
Typical Procedure for Hetarylation of Indole. A mixture of 0.65 g (5 mmoles) of naph-
thyr~dine, benzoyl chloride and indole in 15 m! of a solvent is stirred for 3-5 h, and then
poured into a dilute ammonia solution. The precipitate is filtered and washed with water.
The reaction products are separated by chromatography on aluminum oxide (Tables 1-3).
In the reaction with 1,5-naphthyridine, compound IV is obtained as a byproduct, yield
27%, mp 210-21i~ [15] (from propanol). Found, %: C 82.0, H 5.4, N i0.I. C3:H25N~O. Cal-
culated, %: C 81.8, H 5.5, N 9.2.
fi~6-Di-(3-indolyl)-l,5-naphthyridine (XI). A mixture of 0.18 g (0.5 mmole) of 2,6-
di-(3-indolyl)-l,2,5,6-tetrahydro-l,5-naphthyridine and 0.25 g (i mmole) of ehloranil in
15 ml of benzene is boiled to a complete dissolution of the materials. The reaction is
treated with alkali, the solvent is evaporated, and the precipitate is recrystallized from
propanol. Yield 51%, mp 183-185"C~ Mass spectra, m/z, %: 360 (i00), 359 (34), 358 (50),
246 (7), 245 (19), 244 (20), 218 (13), 180 (27), 179.5 (30), 179 (12), 166 (5), 165.5 (i0),
165 (5). Found, %: C 79.6, H 4.5, N 15.9. C=~H~6N~. Calculated, %: C 80.0, H 4.4, N 15.6.

LITERATURE CITED
i. A. K. Sheinkman, T. S. Chmilenko, and T. N. Nezdiiminoga, Khim. Geterotsiki. Soedin.,
No. 5, 706 (1983).
2. A. K. Sheinkman, Khim. Geterotsikl. Soedin., No. I, 3 (1974).
3. A. K. Sheinkman, Izv. Sib. Otd. Akad. Nauk SSSR, No. 4, Iii (1983).
4. V. Dobenek and H. Goltzsche, Chem. Ber., 95, 1484 (1962).
5. A. K. Sheinkman, Kh. Ya. Lopatinskaya, N. A. Klyuev, and Zh. K. Torosyan, Khim. Geterot-
sikl. Soedin., No. 2, 234 (1980).

989
 6. W. W. Paudler and T. S. Kress, Adv. Heterocycl. Chem., ii, 123 (1970).
7. V. Kobayashi, I. Kumadaki, and H. Sato, Chem. Pharm. Bull., 17, 2614 (1969).
8. I. Takeuchi and I. Hamada, Chem. Pharm. Bull., 24, 1813 (1976).
9. Y. Hamada and R. Shigemura, J. Pharm. Soc. Japan, 99, 982 (1979).
i0. F. D. Popp, Heterocycles, 14, 1033 (1980).
ii. W. W. Paudler and R. M. Sheets, Adv. Heterocycl. Chem., 33, 147 (1980).
12. E. O. Sidorov, A. I. Matern, and O. N. Chupakhin, Zh, Org. Khim., 17, 418 (1981).
13. K. U. Duehardt and F. Krohnke, Chem. Ber., ii0, 2669 (1977).
14. N. A. Klyuev, G. A. Mal'tseva, R. A. Khmel'nitskii, A. K. Sheinkman, A, A, Deikalo,
and ~. V. Stupnikova, Izv. Timiryaz. 8el'skokh. Akad., No. 3, 200 (1974).
15. A. K. Sheinkman, A. N. Kost, S. G. Potashnikova, A. O. Ginzburg, and S. N. Baranov,
Khim. Geterotsikl. Soedin., No. 5, 648 (1971).

SYNTHESIS AND PROPERTIES OF DERIVATIVES

OF 1,4-DIHYDROPYRIMIDINE-5-CARBOXYLIC ACID

E. L. Khanina, D. Kh. Mutsenietse, V. P. Kadysh, UDC 547.853.5'855.3.04:

and G. Ya. Dubur 542.942.3

1,4-Dihydropyrimidines were synthesized by reductive dethionation of the cor-

responding 2-thiono-4-aryl-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid de-
rivatives, and some of their properties were studied.

1,4-Dihydropyrimidines are 3-aza analogs of 1,4-dihydropyridines, which attracted atten-

tion because of their broad spectrum of biological action. However, until now, there are no
suitable methods available for the synthesis of 1,4-dihydropyrimidines, and only individual
representatives of this class are known. The synthesis of derivatives of 1,4-dihydropyrimi-
dine by intramolecular rearrangement of 1,2,3,4-tetrahydropyrimidine-2-thiones [i, 2]
is not very promising, since it is complicated by splitting of the pyrimidine ring
and recyclization into 1,3-thiazine derivatives. This method is also unsuitable for synthe-
sizing 2-unsubstituted 1,4-dihydropyrimidines. The existence of l-N-unsubstituted dihydro-
pyrimidines in the form of 1,4-dihydro isomer has been strictly proved only in separate cases
[3] because of tautomeric transitions [4]. In 1983 [5, 6], 1-substituted 4-methyl-l,4-dihy-
dropyrimidines were synthesized by reductive dethionatlon of pyrimidine-2-thiones over a
Raney nickel catalyst. We used this method for synthesizing 4-aryl derivatives of 1-substitut-
ed 1,4-dihydro-l,2,3,4-tetrahydropyrimidine-5-carboxylic acid, which have so far been un-
known. The reductive dethionation of 2-thiono-l,2,3,4-tetrahydropyrimidine-5-carboxylic
acid derivatives (I) which we synthesized was carried out in acetone and methanol. The reac-
tion is complicated by side-processes. In the reduction of the bromo derivative Ib, debrom-
ination takes place, and the reaction product is 1,4-diphenyl-l,4-dihydropyrimidine (lla).
In the reduction of a methoxy derivative Id in methanol, a mixture of dihydropyrimidine lid
and tetrahydropyrimidine IV is formed (in a 1:3 ratio, according to liquid chromatography
data), and the main product of the reduction of the nitro derivative llc is tetrahydropyrimi-
dine III. Reduction of 1,2,3,4-tetrahydropyrimldine-2-thiones over Raney nickel in a hydro-
gen atmosphere (p = i arm, T = 60~ does not lead to increase in the yield of II (see scheme
on following page).
The synthesis of lla by reductive splitting of 1,4-diphenyl-2-methylthio-5-ethoxy-6-
methyl-l,4-dihydropyrimidine (V) is not explicitly preferential, since the starting compound
V was obtained by alkylation of la. We took compounds lla, e as an example, and showed that
derivatives of 1,4-dihydropyrimidine-5-carboxylic acid have characteristic chemical proper-
ties. The ester grouping in lla is readily hydrolyzed in an alkaline medium to 1,4-dipheny!-

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1223-1227, September,
1986. Original article submitted May 27, 1985.

990 0009-3122/86/2209-0990512.50 ~ 1987 Plenum Publishing Corporation

 TABLE i. PKR Spectra of Compounds la-g in DMSO-D~ (ppm)
dOIIl- 6-cN 4-H 8-H
pound 5-R: I-R I 4-Ar

Ia 1,02 (t,3It); 3,98 (q2H) 1,96 7.34 (br.s , 10It) 5.22 9.90 4,00
Ib 1,06 {t, 3H}; 4.02 {eu2H) 1.97 7,04--7,42 (m 7H) 5.21 999 4,00
7,58 {d, 2I-I}
~c 1,06 {t, 3H) ; 4,01 (q2H) 2,00 7,06--7.44 7,59 {d, 2H} 5,3.t 10.02 4.00
{raSH} 8,24 (d, 2H)
Id 1,04 (t, 3H); 3,95 (q 2H) 1,93 7,00--7,44 (ra 7H) 5,[2 9.81 4,00
3.65 {s 3H},
i6,87 {d, 2H)
le 7,16 ( br.s ', 2H) 1,72 [ 7,40 (br,s t0H} 5,26 9.60 3,50
If 1,80 7,16--/.56 (m 10H} 5.20 i0,04 3,00
Ig 1,16 (L 3H); 4.09 (q2H) 2,44 3,47 (s,38) 7.13--7,42 5,21 9,84 4,50
{rn 5H}

TABLE 2. PMR Spectra of Compounds lla, d-g in DMSO-D6 (ppm)

Com- 6-Ct~]4-H t
pound (s, BHI(S. tH ) 2-I1 ! R~ i 4-Ar 5-R:

IIa 2,06 5,56 7,17--7,61 fm IIH) l,I3{t 3H);4.13(d 2H}

lid 2,04 5,5l 7,13--7,62 (m 8H) I 1.18(t 3H);4,04(d, 2H)
l t 6"88 (d'2H)
3,73 (~ 3H} /
!ie 2.10 5,51 7,14--%60 {m IIH) 3,2i {br.s ,2It)
iif
iig
1,87
2,34
5,33
5,40
7,22--7,71 {m I IH)
7,12{~ 1H}I3.11 (s 3H) I7.20{s,5H)| l,O6{t 3H);B,g6(q2H)
1
vi 2,07 5.58 7,18--7,64 (m llH) ] 12,0 s Ill}

R R R

~h [HI , I
t 2 ~
HN~.r~ Raney Ni [" R2 /~ .C00C2H5

S ~'~ N//'~CH3 ~'- N / % ' - CH 3 R1 //~'N~CH3

CsH5
la-g II a~d-g In,Iv

C{~H~ C6H5
/%.../~COOCzH~ I COOH
.~.....~
~'~ lla ~---~
A N/~'CHa
CHaS ~ N ---"%.CHa
I 1
C6H5 %H~
V VI

If ------ llf ---- L'e

I, I I a , d-g R=H, b P=Br, d R=NO=, f R=OCH3: a--d Rl=C6Hs, g RI=CH3: a - f ,
g W=COOC2Hs, e R2=CONH2. f R~=CN; III R=NOa, R*=H; IV R=OCHa. RI=OH
6-methyl-l,4-dihydropyrimidine-5-carboxylic acid (VI), while the amide of this acid (IIe)
reacts with phosphorus oxychloride to form 1,4-diphenyl-6-methyl-l,4-dihydropyrimidine-5-
carbonitrile (IIf).
The structure of the synthesized compounds was confirmed by the sum total of the data
of the spectral methods of investigation. In the PMR spectrum (Tables I, 2) of 1-methyl
derivative llg, the signals of 2-H and 4-H protons appear in the form of four sharp singlets,
and for 1,4-diaryl derivatives II, the 2-H proton signal and the mu!tiplets of aromatic pro-
tons are superimposed. This character and disposition of the signals show that the alterna-
tive forms of the dihydro structure for II can be excluded. The mass spectra of all compounds
II are characterized by a medium-intensity molecular ion peak and a parallel splitting of
substituents from the pyrimidine ring (Table 3). It is also characteristic that no splitting
of the I-N substituent is observed. In the IR spectra of 5-ethyoxycarbonyl derivatives I and
II the absorption frequency of the CO group is decreased to 1690 cm -~, which is characteris-
tic of the Nu-C.---C--COsystems. Compounds II are more stable to oxidation than the known S-
methyl- and 4-unsubstituted 1,4-dihydropyrimidines [6]. In electrochemical oxidation on a
rotating disk electrode, compounds II giv~ only one-electron irreversible waves in the poten-
tial range of 0.7-i.0 V (E~/= for lla 0.98, lid 0.92, lie 0.84, and llf 1.04), which is

991
 TABLE 3. Characteristic Ions in Mass Spectra of 1,4-Dihydro-
pyrimidines lla, d-g
Corn- - I i rn/z values (intensity, %)
pound
,'~-*' I [M--Ill" I {M--CH=]" [M-Celt4r] {,M.-R:]" other ions
1 [
IIa 320(13) 319 (5) 305 (17) 243 (100) 247 (21) : 291 (39) [M--C~H5]+, 275 (5)
[3~--OC2H~]+
lid 350(28) 1349 (16) 335 (13) 277 (33) 321 (100) [bl--C2Ha] +*,
I 305 (7) [St--OCaHs]*
lie 291 (17) 1290(19) 276 (67) (100} 247 t22)
lif 273 {36) 1272 (19) 258 (2) {1oo)
Ilg 258(16} 1257(7) 243 (18) {100} 185 {381 229 (60) [M--C.,Iis] ~,
213 (13) [M--OC:Hs]-
J

*The composition of the ion was determined by high resolution

321.1215, calculated 321.1239; a me(as(able transition with
m/z 350 ~ m/z 321 has been found.

TABLE 4. Characteristics of Compounds Synthesized la-g, lla,

d-g, III-VI

=
Calculated,
g rap, ~ IR s p e c - U 2 ~ , p e c- I Found, % Empirical % "O
tram, kmax, nm formula "o
.$
E cm-!
O (Iog~) j c , ,~ 'C H N
O V.
Ia 1700,3170 305 (4.17) [ C2ol4~oX2OeS 70
!b 1695,3180 308 (4,23) iC~oH,gBrN2OaS 66
lc 1695,3340 298 (4,16) iC2oH,.:N304S 76
ld 1702,3185 307 (4,06) C=iH~2N2OaS 9{1
Ie 1675.3170 291 (4,13) C,~HIrNaOS 87
3350
If 1695,2205, 303 (4,26) C,8H~sNaS 79
3150
Jg 1640,1705, 305 (4,24) ClslI:sN202S 83
3200
lla 1695 247 (3.94), C:oI-I2oN202 67
315 (3,74)
lid 1690 223* (4.04). Call 1:2X203 37
252* (3,79),
310 (3.68)
16~5.3150. 264 (4,27) C!~lt17XaO 65
3370 OO
)If 1675,2198 247 (3.98), C!sH:sNa
292 (3,74) 56
Ilg 1660,1700 :227* (4,07), CIsHI~X202
i323 (3,76) 61
II[ 1675,3195 238* (4,06). C o01tmNaO4"
307 (4,09) 50
ix" 1683,3312 [223 (4.08), C:J-I:~N,~O4
309 (4,211
V 16~0,1715 i248" (4,15), C=:H::N202S 54
1314 (3.49)
VI 1695,3360 313 (3,581 Ct~HIaN.~Oa

*Shoulder.

comparable with the values of potentials of 4-aryl derivatives of 1,4-dihydropyridine-3,5-

dicarbonitriles [7]. The introduction of a carbamoyl grouping instead of ethoxycarbonyl
(compounds lla, e) shifts the value of the electrooxidation potential into a less anodic
region and introduction of the nitrile group (llf) shifts this potential into a more anodic
region.

EXPERIMENTAL
The PMR spectra were run on a Bruker WH-90 spectrometer in DMSO-D6, using TMS as inter-
nal standard; the IR spectra were taken on a Perkin-Elmer 580 spectrophotometer in mineral
oil, the UV spectra, on a Specord M-40 spectrophotometer in ethanol at a concentration of
5'10 -5 mole/liter, and the mass spectra on an AEI MS-50 mass spectrometer with a direct
introduction of the sample into an ionic source at 70 eV. The resolution in determination

992
of the elemental composition of the ions was 60,000. The metastable transitions were found
by scanning the accelerating resolution. The electrooxidation potentials were determined by
the method in [8]. The characteristics of the compounds synthesized are given in Tables 1-4.
1,2,3,4-Tetrahydropyrimidine-2-thiones (Ia-e, g) were obtained by the Biginelli conden-
sation from ethyl ester or amide of acetoacetic acid, an aromatic aldehyde and N-
methyl- or N-phenylthiourea in an acid medium by the method described in [9, i0].
1,4-Diphenyl-2-thiono-6-methyl-l,2,3,4-tetrahydropyrimidine-5-carbonitrile (If). A mix-
ture of 2~0 g (6.2 mmoles) of compound Ie and 30 ml of POCI3 is boiled for 30 min, and the
solution is evaporated in vacuo. The residue is washed with water to a neutral reaction and
crystallized from alcoa01'
1,4-Diphenyl-5-ethoxycarbonyl-6-methyl-l,4-dihydropyrimidine (IIa). A 1.0 g portion
(2.5 mmoles) of compound Ia is dissolved in 30 ml of acetone, ~3 g of Raney nickel are added,
and the mixture is boiled for 2 h. It is then cooled, filtered, and the residue on the fil-
ter is washed with acetone. The combined filtrate is evaporated in vacuo. The oil formed
is crystallized from hexane. Compounds IId-g are obtained in similar way.
1,4-Diphenyl-2-methylthio-5-ethoxycarbonyl-6-methyl-l,4-dihydropyrimidine (V). A 0.66
g portion (5 mmoles) of methyl iodide is added to 1.6 g (4.5 mmoles) of compound Ia in 50 ml
of acetone, and the mixture is allowed to stand overnight. The crystals formed are filtered
to give the hydroiodide salt of V; mp 154-156~ yield 90%. The salt obtained is dissolved
with heating in 50 ml of acetone, a 10% aqueous solution of ammonia is added to decolorize
the yellow solution, which is then evaporated. The residue is crystallized from alcohol.
PMR spectrum: 1.07 (t, 3H, OCH2CH~): 1.93 (s, 3H, 6-CH~); 2.07 (s, 3H, SCH3); 3.98 (q, 2H,
OCH=CH3); 5.18 (d, IH, 4-H); 7.16-7.53 ppm (m, 10H, i- and 4-C6H5).
-Pheny-4-(p-nitrpheny)-5-ethxycarbny-6-methy-,2,3,4-tetrahydrpyrimidine (III)
and -pheny-2-hydrxy-4-(p-methxypheny)-5-ethxyarbny-6-methy-,2,3,4-tetrahydrpyri-
midine (IV) were obtained by boiling 2.5 mmoles of compound IIc or IId with 6 g Raney nickel
in 50 ml of methanol, as described above. The residue obtained after evaporation is crystal-
lized from a mixture of benzene with hexane. Compound III, PMR spectrum (CDCI3): 1.18 (t,
3H, OCH2CH3); 3.71 (s, 2H, 2-CH2); 4.09 (q, 2H, OCH2CH~); 5.31 (d, IH, 4-H); J3H-~H = 3.00
Hz; 6.60 (d, 2H, 4-Ar); 7.11 (d, 2H, 4-Ar); 7.28-7.46 (m, 5H, I-C6H5); 7.60 ppm (d, IH, NH).
Mass spectrum[ 367 (61) [M] +., 366 (ii) [M-- HI +, 338 (61) [M-- C2H5] +, 307 (61) [M-- CH3 --
OC2H5] +., 294 (i00) [M -- CO2C2H5] +, 279 (24) [M-- C H 3 C02C2H5] +, 275 (39) [M -- CH3 -- C~Hs] +"
Compound IV, PMR spectrum: 0.91 (t, 3H, OCH2CH3); 2.22 (s, 3H, 6-CH3); 3.71 (s, 3H, OCHs);
3.93 (q, 2H, OCH2CH3); 6.16 (d, IH, 4-H); J3H-~H = 9.50 Hz; 6.82 (d, 2H, 4-Ar); 7.04-7.50
(m, 7H, I-C~Hs and 4-Ar); 8.18 (d, IH, 2-H); J2H-3H = 1.00 Hz; 8.36 (m, IH, NH); 11.08 ppm
(s, IH, 2-OH). Mass spectrum: 368 (3) [M]+., 322 (i00) [M-- C2HsOH] +', 297 (27) [M --
C2HsOH - CO] +. , 276 (5) [M-- C=HsOH -- CO -- H=O] +', 205 (51).
-

1,4-Diphenyl-6-methyl-l,4-dihydropyrimidine-5-carbonitrile (IIf). A mixture of 0.4 g

(1.5 mmole) of compound IIe with 15 ml of POCI3 is heated to boiling and then allowed to
stand for 2 h at 20~ It is then evaporated in vacuo, and the residue is washed with water
and recrystallized from alcohol. Yield 0.25 g (70%).
!,4-Diphenyl-6-me=hyl-l,4-dihydropyrimidine-5-carboxylic acid (VI). A mixture of 0.i
mmole of IIa with 0.2 mmoie of KOH in 50% ethanol is boiled for 30 min. Alcohol is evaporated
and the residue is neutralized with dilute HCI, the precipitate is ground with hexane, and
recrystallized from methanol. Mass spectrum: 248 (32) [M -- C02] +', 247 (71) [M -- CO= -- H] +,
233 (!00) [M -- C02 -- CH3] +, 171 (52) [M-- CO= -- C~Hs] +'.

LITERATURE CITED
!. L. A. Ignatova, S. V. Baranov, and B. V. Unkovskii, in: Reactivity of Azines, Summary
of Lectures [in Russian], Novosibirsk (1979), p. 93.
2. B. V. Unkovskii, L. A. Ignatova, P. L. Ovechkin, and L. I. Vinogradova, Khim. Geterot-
sikl. Soedin., No. 12, 1690 (1970).
3. A. Weis and F. Frolov, Chem. Communs, No. 12, 89 (1982).
4. A. L. Weis, Tetrahedron Lett., 23, 449 (1982).
5. C. Kashima, M. Shimitzu, A. Katoh, and Y. Omote, J. Chem. Soc., Perkin i, No. 8, 1799
(1983).
6. C. Kashima, M. Shimitzu, A. Katoh, and Y. Omote, Tetrahedron L e t t . , 24, 209 (1983).

993
 7. Ya. P. Stradyn', G. Ya. Dubur, Yu. I. Beilis, Ya. R. Uldrikis, and A. F. Korotokova,
Khim. Geterotsikl. Soed., No. i, 84 (1972).
8. V. P. Kadysh, Ya. P. Stradyn', E. L. Khanina, G. Ya. Dubur, and D. Kh. Mutsenietse, Khim.
Geterotsikl. Soedin., No. i, 117 (1985).
9. K. Folkers, H. J. Harwood, and T. B. Johnson, J. Am. Chem. Soc., 54, 3751 (1932).
i0. G. Ya. Dubur and E. L. Khanina, Khim. Geterotsikl. Soedin., No. 2, 220 (1976).

SYNTHESIS AND MESOMORPHIC PROPERTIES OF ARYL 5-ALKYL-

(AND ALKOXY) PYRIMIDINE-2-CARBOXYLATES

M. A. Mikhaleva, V. A. Savel'ev, A. I. Pavlyuchenko, UDC 547.562'853.9:532.783

M. F. Grebenkin, and V. P. Mamaev

Some aryl 5-alkyl(and alkoxy)pyrimidine-2-carboxylates (I) and 5-alkylpyrimidin-

oyloxybenzoates (II) have been obtained. It has been found the former do not
display mesomorphism, but the latter are nematic liquid crystals with a range
over which the mesophase exists of 50-90~ The transition to the liquid crys-
tal state in these compounds takes place at approximately the same temperatures
as in their benzene analogues, but the thermal stability of the mesophase is
somewhat less. Cyano-derivatives of pyrimidine effectively increase the value
of the dielectric anisotropy of the matrix mixture, but they have a marked
effect on its clarification temperature.

It has been shown that substituted aryl 5-arylpyrimidine-2-carboxy!ates and pyrimidin-

oyloxybenzoates possess liquid crystal properties, forming a nematic phase [i]. However,
the presence of a 5-aryl group in the pyrimidine ring results in high-melting and sparingly
soluble compounds, presenting obstacles to their study. It would be expected that aryl 5-
alkylpyrimidine-2-carboxylates would possess liquid crystal properties with lower mesophase
temperatures.
We here report the preparation and study of the aryl 5-alkyl(and alkoxy)pyrimidine-2-
carboxylates (I) and (II), which are analogues of the extensively studied arylbenzoates [2-5].
The starting 5-substituted pyrimidine-2-carboxylic acids (Ilia, b) were obtained by
hydrolyzing the cyanopyrimidines (IV), which are readily accessible by introducing the cyano-
group into the sulfones (V). Attempts to utilize information on the oxidation of 5-alkyl-2-
methylpyrimidines [6] for the preparation of 5-heptylpyrimidine-2-carboxylic acid (lllb)
from 5-heptyl-2-methylpyrimidine (Vlb) were unpromising, the yields of the acid (lllb) being
very small (see scheme on following page).
A frequently employed route to 2,5-disubstituted pyrimidines (including the mercapto-
derivatives (VII, VIII)) [7, 8] makes use of various acrolein derivatives [9-11] (such as
(IX) and (X)), obtained by a multistage synthesis from the acetals (IX) via the vinyl ethers
(XII) and tetraethoxypropanes (XIII). This laborious route can be shortened by preparing the
acroleins (X) directly from the acetals (XI), as described in [12].
5-Pentyloxypyrimidine-2-carboxylic acid (lllc) was obtained by a convenient route for
the preparation of 5-alkoxypyrimidines (from the 4-hydroxypyrimidines).
Acids (llla-c) were converted into their aryl esters (la-d) and (lla-d) as described
in [i].
Liquid Crystal Properties of (I) and (II). The p-cyanophenyl esters (la) and (Ic)
and the hexyloxyphenyl ester (Id) did not display mesomorphism, in contrast to their benzene
Novosibirsk Institute of Organic Chemistry, Siberian Branch, Academy of Sciences of
the USSR, Novosibirsk 630090; Research Institute for Organic Intermediates and Dyes, Moscow
103787. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1228-1235, Septem-
ber, 1986. Original article submitted June 12, 1985; revision submitted September 30, 1985.

994 0009-3122/86/2209-0994512.50 9 1987 Plenum Publishing Lorporation

 gCRaut{(OCeH~) ~ 9~,- RCB=UHOC_II~ ---~-- Rs J.~)-l" , -~- R( .CPOC=~ 3
ma,b ~mb x~b ~xa,b

cl~_N ~ /.CHO N --N

/f

' '~'~- N xa.b ~C4/. '\-'~:

x---N ~ "---N
VIIIa-c Va-c ~a-c x~a-c

la-d **a-d
Ta,b R=CrH~, c,d R=OC~H!I: a,cRI=CN, b R'=COOH, d RI=OC6HI~: I]a R=CsH,,,
b~ R=CTH15;a,~ RI=CsH~, b R'=CN, d RI=OCsHI~; III--XI a R=C~Hj~, b
R=C;HI~, c R=OCsHII
a n a l o g u e s , which a r e n e m a t i c l i q u i d crystals [2, 3 ] . The p y r i d i n e a n a l o g u e of t h e e s t e r ( I c ) i s
m o n o t r o p i c a l l y nematic [13].
The d i e s t e r s (IIa-d) display liquid crystal properties, t he range of e x i s t e n c e of th e
nematic mesophase in (lla, c, d) being ~50~ and in the cyano-compound (llb), 90~ As
compared with the analogous esters of 5-phenylpyrimidine-2-carboxylic acid [i], the esters
(II), as expected, have substantially lower temperatures of transition to the liquid crys-
tal state (by 50-I00=C), the range in general being maintained.
Comparison of the properties of diesters of p-alkylbenzoic acids [4, 5] with those of
the diesters (II) shows that the latter have a less thermally stable mesophase, but the
transition to the nematic state takes place at approximately the same temperature.
Although the Schiff's bases of 2-substituted-5-aminopyrimidines are more prone to dis-
play smectic properties than benzylideneanilines [14], esters of pyrimidine acids (see [i]
and, for example, esters (lib, c)), unlike aryl benzoates [4, 5], do not form a smectic
mesophase.
Dielectric Properties of Pyrimidine Derivatives. The dielectric properties of (la),
(IVb), and (XV) (the latter was obtained as described in [15]), which contain the pyrimidine
moiety, were examined in connection with their molecular structure. For each pyrimidine
derivative, an aromatic compound of analogous structure was selected in order that the effects
of replacing the benzene ring by the pyrimidine ring on the dielectric properties could be
found. It has previously been shown that the dipole moment of the pyrimidine ring, directed
along the longer axis of the molecule, has a considerable effect on the dielectric properties,
with a considerable increase in dielectric anisotropy [14].
The measurements were made, as described in [14], with a mixture of the pyrimidine and
a weakly polar liquid crystal matrix (a mixture of azoxy-compounds A [16]), since the com-
pounds (la), (IVb), and (XV) do not themselves possess liquid crystal properties. No calcu-
lations of the effective values of the dielectric constants from the data for the mixtures
of pyrimidine and matrix A by the additivity rule were carried out for (la), (IVb), and
(XV), since the experimental concentration dependence of the clarification temperature (Tcl)
revealed highly nonadditive behavior, having a clearly apparent minimum or maximum, indicat-
ing strong specific interactions of the molecules of these compounds with the weakly polar
matrix [17, 18]. The concentration of the cyano-compounds in the matrix was kept low (I0
and 20 wt. %) in order to avoid association effects resulting from the strong intermolecular
interactions of the strongly and weakly polar components of the mixture [17, 18] and the
cyano-derivatives themselves [19], and in order that the clarification temperature should
remain in a range convenient for measurement. Comparisons of the values of the dielectric
constants were carried out at the same relative temperatures ~.
The compound selected for comparison with the pyrimidine (la) (p-cyanophenyl p-heptyl-
benzoate (XIV)) has a nematic phase range of 43-56~ [3] and high dielectric anisotropy
( ~ = +20.7 at 35~ and was successfully used to increase the dielectric anisotropy of the
mixtures used in the indicator technique. It will be seen from Table 2 that the compound

995
 TABLE I. Aryl 5-Alkyl(and alkoxy)pyrimidine-2-carboxylates
(Ia, c, d) and (IIa-d)
:om-
ound Tffamition,"!(I~r), v,
Tner~ Tiso 'Icm-1
fIR specrzum Found, % Empirical
formula
Calculated, %

c I H Ix c I r{ I x
Ia 91--92 1770, 2230 70,6 6.77 13,0 C=oH:lNaO2 70.7 6,50 13,0 42
Ic 113~114 65A 5,40 13,6 C~rH,rNaO3 65,6 5.50 !3,5 26
ld 68,3 7,94 T.2 C221-I3oN20~ 68,4 7,82 7,2, 64
lla 137--145 73,2 6,88 5,81 73,0 &96 6,0! 40
lib 112 o01 I740, 1760, 70,9 5,57 9,7; C_~6H~sNaO4 7[)14 5,64 9,4~ 68
2230
Ila 91 I48--149 1730, 1760 74,1 7,38 5,6 CaoH3sN~O4 73.8 7,37 5,7. 50
lid 102 152--156 1740, 1765 71,3 7119 5,8 C>H3~N20~ 71,4 7,14 5,5: ]6
(CHCIa)

~Compounds (la) and (lld) were crystallized from alcohol,

(Ic) and (Id) fromhexane, (lla) and (llc) from aqueous alco-
hol, (lib) from a i:I mixture of ethyl acetate and hexane.
Tnem is the temperature of the nematic mesophase, and Tiso
the temperature of the isotropic mesophase.

TABLE 2. Dielectric Properties of Mixtures*

[~ at Tcl'
Compound 125"C ~ itC ~I I ~ [ ~'e

- 0,35
t

+3,73
lit CTHI5~)-- C O O ~ CN +7.07

+2,35
XlV CTH~s~COO--~ "CN +4,80

+4,10
XV C~HoO
~ ~ -CN + 8,09

+ 2.24
XVI C4HeO
~ cN +4,71

+3,30
,vb -c" + 6,50

XVII C 6 1 i 1 3 0 - ~ - - - CN +2,40
+ 4,6

XV1H C . l l o - - ~ - - - CN +0,6

*c is the concentration Of the cyano-derivative in the mix-

ture A (wt. %): Tel is the temperature of clarification of
the mixture; T is the relative temperature, r = (Tiso +
273~ + 273~ Ar = EpF - ~ where ~II and ~i are the
dielectric constants of the compounds, measured in directions
parallel and perpendicular to the director of the liquid crystal.

SMixture A, 2:1.

996
(Ia), as compared with the analogous compound (XIV), increases the dielectric anisotropy of
the mixture much more effectively (by a factor of more than 1.5). A drawback of (Ia), how-
ever, is that it considerably reduces the clarification temperature of the mixture, and can
only be used in low concentrations.
The benzene analogue of (XV) is 4,4'-butoxycyanobiphenyl (XVI), which has Tmp 78~ and
Tcl 75.5 ~ (monotropic liquid crystals [20]), which is used extensively in liquid crystal
mixtures for electrooptical equipment. As in the previous case, the pyrimidine (XV) increases
the &g value of the mixture to a much greater extent than its benzene analogue (XVI) (by a fac-
tor of ~2). A characteristic feature of this pair of compounds is that they increase, rath-
er than reduce, the Tcl of the mixture, this effect not being due to the high Tcl of the
cyano-compounds themselves, but to the nature of the phase diagram for such systems, mixtures
of alkoxy-cyano derivatives with weakly polar liquid crystal matrices usually having a maxi-
mum on the concentration--Tcl plots and an induced smectic phase being present. These features
are clearly apparent in these compounds.
Studies of mixtures of matrix A with monocyclic cyano-compounds (IVb, XVII [21], and
XVIII [22]) also provide reliable evidence of the effectiveness of pyrimidines as compared
with their phenyl and cyclohexyl analogues as additives which increase the dielectric anisotropy
of mixtures. The be values for mixtures were found to be sufficiently high, despite the fact
that the degree of ordering of monocyclic compounds in a liquid crystal matrix must be low.
Table 2 shows the values of the dielectric constants for the cyano-compounds themselves (IVb,
XVII, and XVIII), which confirm that the pyrimidines possess high dipole moments corresponding
to the dipole moment of the cyano-group, which also favors their use for increasing the &e
values of mixtures. However, the Tcl values of the mixtures were found to be unsatisfactor-
iiy low, since the monocyclic cyano-compounds themselves are not liquid crystals.
The &a value for the ester (It), calculated as described in [14], was found to be +44
(for a 10% solution in mixture A). The analogous derivative of pyridine-2-carboxylic acid,
which is a monotropic liquid crystal, had As = +25 [13].

EXPERIMENTAL
IR spectra were obtained on a UR-20 spectrometer, and PMR spectra on a Varian A56/60A,
internal standard HMDS. Molecular masses were measured by mass spectrometry on a high-resolu-
tion MS 902 instrument. Phase transition temperatures were measured on a miniature Boetius
hot plate with an RN~"~K-0.5 direct-reading apparatus. TLC was carried out on Silufol UV-254
plates in chloroform.
The characteristics of the compound prepared are given in Table 1-3.
p-Cyanophenyi 5-Heptylpyrimidine-2-carboxylate (ia)~ A mixture of 1.8 g (8 mmole) of
the acid (IIIb), 0.7 g (6 mmole) of triphenyiphosphine, 0.8 g (8 mmole) of triethylamine,
and 1.2 g of CCI~ in i0 ml of acetonitrile was stirred for 8 h at 20~ The mixture was
then filtered, the acetonitrile distilled off on a rotary evaporator, and the residue ex-
tracted with boiling hexane (5 40 ml). The solid which remained after the residue cooled
was dissolved in 50 ml of ether, filtered, the ether distilled off, and the residue recrys-
tallized twice from alcohol to give 0.5 g of the ester (Ia). The hexane and ether solutions
were evaporated, combined with the ether-insoluble residue, and submitted to the same se-
quence of operations to give a further 0.3 g of the ester, overall yield 0.8 g.
~-Cyanophenyl 5-Pentyloxypyrimidine-2-carboxylate (Ic). In an analogous way to the
preparation of 5-methoxypyrimidines as described in [23], there was obtained from methyl
pentyloxyacetate and thiourea 65% of 5-pentyloxy-2-mercapto-4-hydroxypyrimidine, mp 220-
230~ Methylation of this with dimethyl sulfate in NaOH gave the S-Me derivative in 81%
y~eld, mp I03-II0~ The latter was converted without further purification into the chloro-
derivative by boiling with POCI3 (yield 56%, bp 147~ mm), which was then reduced with zinc
in methanol in the presence of NaOH to give the pyrimidine (VIIIc) (yield 75%, mp 145~ mm).
This (VIIIc) was oxidized with hypochlorite as described in [24] to give 5-pentyloxy-2-
methylsulfonylpyrimidine (Vc) in 60% yield, mp 80-83~ Treatment of the latter with NaCN
in DMSO gave 5-pentyloxy-2-cyanopyrimidine (IVc), yield 86%, which on hydrolysis with 10%
NaOH gave 82% of the carboxylic acid (IIlc), mp 132-136~ (from benzene).
A mixture of 2.1 g (i0 mmole) of the acid (IIIc) and 4.8 g (0.04 mole) of thionyl chlo-
ride was boiled for 8 h. Excess thionyl chloride was distilled off under a water pump vacuum,
and the residue treated with 50 ml of dry benzene, 1.19 g (i0 mmole) of p-cyanophenol, and

997
 TABLE 3. 2,5-Disubstituted Pyrimidines (Ill-VIII)
Found, % Calculated, %
: o m - mp, e ~ or Empirical
R/
~ound bp, "C (ram formula
Hg) C [I N C I~ N
>-

IIlb 41--43 .>22 ),5 t 59,3 8,I0 11,5 C~2HEsN202X 60.0 8,30 1!,6 63
xH20
IVb ~30 (2) ~03 0,6C 71,4 8,60 C,~HtTNa 7O,9 8.40] 71
Va 50--51,5 0.30 52.7 6,90 12,4 C,oHv~N202S 526 70ol f-,a 60
Vb 44--46 0.3(] 56,1 7,80 11,0 C,oH~oN~OoS" 563 7.8oi o,9 73
\Ii~ 126--128 (6) 97, 75,4 10,5 75.0 0,4 I !5
\lib 175--180 070 62,8 8,60 137,3 CuH,sN2S 62,9 8,60 1~-,3 80
\'Ilia 126--128 (1) <6 8,3o t3.8 C!oH ,aN~S 61,2 8,20 14,3 80
VIIIb 128--131 (1} 0,65 $4,4 8,60 13,0 Clotl~oN~S 64.3 8,90 12.3 78

*Crystallization solvents: (lllb), ethyl acetate; (Va, b),

light petroleum; and (VIIb) alcohol.
*In the system chloroform--ethanol (20:1).
$ Contains an impurity with m/z 171.

2 g (20 mmoie) of triethylamine, and the mixture boiled for 4 h. After cooling, the solid
was filtered off, and the organic layer evaporated under a water pump vacuum to give 0.8 g
of the ester (Ic).
Similarly, from (IIIc) and p-hexylphenol there was obtained the ester (Id), which was
purified by chromatography in benzene on alumina.
p-Cyanophenyl p-(5-Heptylpyrimidinoyl-2-oxy)benzoate (IIb). A mixture of 1.35 g (6.1
mmole) of the acid (IIIb), 3 ml of thionyl chloride, 5 ml of dry benzene, and 5 drops of DMF
was boiled for 38 h (followed by TLC). Thionyl chloride and benzene were then removed under
a water pump vacuum, the residue treated with 5 ml of dry benzene, and again evaporated to
dryness at the water pump, to give a dark-colored liquid residue of the acid chloride of
(Illb). IR spectrum (CHCI3): 1785 cm -~. To this was added 0.84 g (6.1 mmole) of p-hydroxy-
benzoic acid in 6 ml of pyridine, and the mixture stirred with a magnetic stirrer for two
days. The solid was filtered off, washed with water acidified to pH 2-3 (2 15 ml) to re-
move traces of pyridine, and dried in air to give 0.8 g (38%) of the carboxyester (Ib), mp
182-187~ IR spectrum (KBr): 1695, 1770 cm -x. To a suspension of 0.68 g (2 mmole) of the
acid (Ib) in 20 ml of dry benzene was added 3 ml of thionyl chloride, and the mixture boiled
for 5 h. The benzene was distilled off at the water pump, and the residue treated with 0.23
g (1.9 mmole) of p-cyanophenol in i0 ml of dry pyridine. The mixture was stirred at 20~
for two days, poured into a mixture of I00 g of ice and 30 m! of 3 N HCI, and the precipitat-
ed ester (IIb) filtered off. Recrystallization from a mixture of ethyl acetate and hexane,
i:i, followed by ethyl acetate with the addition of activated charcoal, gave 0.6 g of the
ester (IIb).
p-Pentylphenyl p-(5-Heptylpyrimidinoyl-2-oxy)benzoate (IIc). A mixture of 0.4 g (1.8
mmole) of the acid (IIIb), 0.4 g (1.4 mmole) of p-pentylphenyl p'-hydroxybenzoate, 0,47 g
(1.8 mmole) of triphenylphosphine, 0.28 g (1.8 mmole) of CCI~, and 0.18 g (1.8 mmole) of
triethylamine in 2,5 ml of acetonitrile was stirred for 8-10 h at 20~ The actonitrile was
distilled off in a rotary evaporator, and the residue extracted with boiling hexane (5 20
ml), cooled, and the solid filtered off to give 0.4 g of the ester (llc);
Similarly obtained were p-pentylphenyl p-(5-pentylpyrimidinoyl-2-oxy)benzoate (lla) and
p-pentyloxyphenyl p-(5-heptylpyrimidinoyl-2-oxy)benzoate (lid).
5-Pentylpyrimidine-2-carboxylic Acid (Ilia). A mixture of 8.43 g (37 mmole) of the pyri-
midine (Va) and 2.86 g (44 mmole) of KCN in 200 ml of DMFA was heated for 5 h at IO0~ The
DMFAwas distilled off at the water pump, the residue extracted with chloroform (3 i00 m l ) ,
and the chloroform removed in a rotary evaporator to give the cyanopyrimidine (IVa) as a
dark-colored liquid, which was purified by distillation into a flanged attachment at 120-130~
(2 mm), Rf 0.70. IR spectrum (CHCI~): 2250 cm-I (CN). To this cyano-derivative (IVa) was
added 80 ml of 2N NaOH, and the mixture was boiled for 6 h, cooled, acidified to pH 2-3 ~ith
20% HCI, and the acid (Ilia) filtered off. Yield 5.38 g (75%), mp 84-87~ (from ethyl ace-
tate). According to [6], mp 86-87~

998
 5-Heptylpyrimidine-2-carboxylic Acid (lllb). A. A mixture of 13.6 g (6.7 mmole) of
the cyanopyrimidine (IVb) and 130 ml of 2N NaOH was boiled for 8 h, cooled to 5-I0~ acidi-
fied with 20% HCI to pH 2-3, and the resulting suspension extracted with benzene (3 I00 ml).
The extract was dried over MgSO~, and the benzene distilled off at the water pump to give Ii
g of a residue which crystallized on trituration with ethyl acetate. The acid (IIIb) was
filtered off and air-dried.
B. The methylpyrimidine (VIb) (4.12 g, 21.4 mmole) was dissolved in 40 ml of pyridine,
the solution heated to II0~ and 3.5 g (31 mmole) of selenium dioxide added in three por-
tions at 2 h intervals, with stirring. Heating and stirring were continued for three days.
The precipitated selenium was then filtered off, and the filtrate diluted with i00 ml of
chloroform, washed with water acidified to pH 2-3 with HCI (3 50 ml), dried over MgSO~,
and evaporated at the water pump. The oily residue (mostly unreacted (VIb)) partially crys-
tallized on standing in air for 10-12 h. The solid was filtered off, and washed with 2-5
ml of CCI~ to give 0.75 g (15%) of product. IR spectrum (KBr): 1730 cm -:. Found: M 222.136
C~=HIsN202. Calculated: M 222.1368.
5-Heptyl-2-cyanopyrimidine (IVb). A mixture of 20.7 g (80 mmole) of the pyrimidine (Vb)
and 6.3 g (97 mmole) of KCN in 500 ml of DMFA was stirred at 100~ for 5 h. The DMFAwas dis-
tilled off at the water pump, and the residue extracted with methylene chloride (3 i00 ml).
Removal of the solvent gave 13.6 g of a liquid residue, which was purified by passing it
through a column of silica gel in chloroform followed by distillation into a flanged attach-
ment. Yield 11.6 g. IR Spectrum (CHCI3): 2250 cm-: (CN w).
5-Heptyl-2-methylsulfonylpyrimidine (Vb). A solution of 21.6 g (96 rmmole) of the pyri-
midine (VIIIb) and 50 m! (480 mmole) of 30% H202 in 250 ml of glacial acetic acid was stirred
at 70~ for 8 h. The mixture was cooled, poured into 800 ml of water, neutralized with solid
NaHC03, extracted with chloroform (3 150 ml), the extract washed with water until neutral,
dried over MgSO~, and distilled on the rotary evaporator, yield 18.5 g. PMR spectrum (in
CCI~): 0.82-1.22 (m, C7H15); 3.17 (s, 3H, CH3); 8.65 ppm (s, 2H, 4- and 6-H of pyrimidine
ring).
5-Pentyl-2-methylsulfonylpyrimidine (Va) was obtained similarly. IR spectrum (CCI~):
1140, 1330, 1410 cm -I.
2-Methyl-5-heptylpyrimidine (VIb). A mixture of 76 g (385 mmole) of the acrolein (IXb),
36.4 g (385 mmole) of acetamidine hydrochloride, and 250 m! of alcohol was heated to the boil,
and a solution of CH3ONa, obtained from 16.7 g (730 mmole) of metallic sodium in 150 ml of
absolute methanol, was added dropwise with stirring. The mixture was then boiled for 3 h,
the alcohol distilled off at the water pump, and the residue treated with 450 ml of 10% NaOH.
The mixture was extracted with chloroform (8 50 ml), and the extract washed with water un-
til neutral, dried over MgSO~, and the chloroform removed in a rotary evaporator. The resi-
due was fractionated in an oil-pum p vacuum to give 44 g of a mixture, bp 95-II0~ (2 mm).
Repeated fractionation separated the mixture into fractions with bp 95-I15~ (7 mm) (contain-
ing, in addition to the main product (VIb), an unidentified impurity with m/z 171) and 120-
135~ (6 mm). The latter was redistilled to give 10.9 g of the methylpyrimidine (VIb). PMR
spectrum (in the pure state): 0.83-1.27 (m, C6H:s), 2.43 and 2.50 (t and s, 5H, 2-CH3 and
CH2), 8.55 ppm (s, 2H, 4, 6H of the pyrimidine ring).
5-Heptyl-2-mercaptopyrimidine (VIIb). A. To a boiling mixture of 34.5 g (175 mmole)
of the acrolein (Xb) and 13.3 g (175 mmole) of thiourea in 150 ml of absolute alcohol was
added over 1.5 h a solution of 9.4 g of sodium methoxide in I00 ml of absolute alcohol. The
mixture was boiled with stirring for 8 h, tooled, and poured into 800 ml of 30% acetic acid.
The yellow solid which separated was filtered off, washed with 10% NaHCOs (3 50 ml) and
water until neutral, and air-dried. Yield 28.8 g.
B. From the acrolein (Xb) and thiourea, as described in [7], yield 51%, mp 175-180~
(from alcohol).
5-Pentyl-2-mercaptopyrimidine (VIIa) was obtained by method A, from acrolein (Xa), in
62% yield, mp 190-195~ (from alcohol). According to [8], mp 195-196~
5-Heptyl-2-methylmercaptopyrimidine (VIIIb). To a suspension of 34 g (162 mmole) of
the pyrimidine (VIIb) in 160 ml of IN NaOH was added dropwise with stirring at 20~ ml
(320 mmole) of methyl iodide. The mixture was stirred for 5 h, extracted with chloroform
(3 50 ml), dried over MgSO~, the chloroform removed at the water pump, and She residue

999
distilled under an oil pump vacuum. Yield 28,5 g. PMR spectrum (CCI~): 0.82-1.22 (m, 15H,
C7H~5), 2.40 (s, 3H, SCH3), 8.17 ppm (s, 2H, 4, 6H of the pyrimidine ring).
5-Pentyl-2-methYlmercaptopyrimidine (Vllla) was obtained similarly, from (Vlla).
2-Pentyl-3-ethoxyacrolein (IXa) was obtained as described in [9], yield 82%, bp 132-
135~ (15 ran). According to [9], bp 127-128~ (12 mm).
~-Heptylvinyl Ethyl Ether (Xllb). Obtained in 87% yield from pelargonaldehyde acetal
(Xlb) [ll] as described in [25], yield 87%, bp 84-85~ (12 ram), nD 2~ 1.4310. Found, %:
C 77.4, H 13.0. C~H220. Calculated, %: C 77.6, H 13.0.
2-Heptyl-l,l,3,3-tetraethoxypropane (XIIIb) was obtained from (XIIb) as described in
[26], yield 67%, np 137-!39~ (4 mm), nD 2~ 1.4282. Found, %: C 67.7, H 12.0. C:sH~80~.
Calculated, %: C 67.9, H 12.0.
2-Heptyl-3-ethoxyacrolein (IXb) was obtained from the tetraethoxypropane (XIIIb) as
described in [27], yield 70%, bp 130-138~ (4 mm), IR spectrum (CCI~): 1650, 1685, 1730
cm -: PMR spectrum (CCI~): 1.22 (m, CH3, CH2--C), 2.14 (m, CH2--C-~), 3.38 (m, CH2), 4.24
(q. OCH2), 7.0 (s, --CH~), 9.1 ppm (s, CHO). An analytically pure sample was not obtained.
2-Pentyl-3-dimethylaminoacrolein (Xa). Enanthaldehyde diethyl acetal (XIa) was ob-
tained in 65% yield, bp 84-87~ (i0 mm), from heptyl bromide and orthoformic ester as de-
scribed in [28]. This was reacted with the POCI3--DMFA complex as described in [12] to give
the acrolein (Xa) in 48% yield, bp 166-171~ (5 mm). According to [i0], bp I00-I05=C
(0.I mm).
2-Heptyl-3-dimethylaminoacrole!n (Xb) was obtained as described in [12] from pelargon-
aldehyde acetal (Xlb) in 82% yield, bp 135-140~ (0.5 mm), nD 2~ 1.5220. According to [ii],
bp 122~ (0.01 mm), nD 2~ 1.5239.

LITERATURE CITED
i. M. A. Mikhaleva, G. A. Kolesnichenko, K. I. Rubina, Yu. Sh. Gol'dberg, V. A. Savel'ev,
L. Ya. Leitis, M. V. Shimanskaya, and V. P. Mamaev, Khim. Geterotsikl. Soedin., No. 3,
380 (1986).
2. M. E. Neubert and L. T. Carlino, Mol. Cryst. Liq. Cryst., 59, 253 (1980).
3. V. V. Titov, E. I. Kovshev, A. I. Pavluchenko, V. T. Lazareva, and M. G. Grebenkin,
J. Phys., 36, CI, 387 (1975).
4. J. P. Van Meter and A. K. Seidel, J. Org. Chem., 40, 2998 (1975).
5 J . P . Van Meter, R. T. Klingbiel, and O. J. Genova, Solid State Commun., 16, 315 (1975).
6 H. Yamanaka, M. Mizugaki, M. Sagi, and K. Edo, Heterocycles, 12, 1323 (1979).
7 R. Kruse and E. Breitmaier, Chem. Ztg., i0! , 305 (1977).
8 L. Rylski, F. Sorm, and Z. Arnold, Collect. Czech. Chem. Commun., 24, 1667 (1959).
9 E. Breitmaier and S. Gassenmann, Chem. Ber., 104, 665 (1971).
i0 Z. Arnold and F. Sorm, Collect. Czech. Chem. Commun., 22, 452 (1958).
ii H. Bredereck, H. Herlinger, and J. Renner, Chem. Ber., 93, 230 (1960).
12 D.H.R. Barton, G. Dressaire, B. J. Willis, A. G. M. Barrett, and M. Pfeffer, J. Chem.
Soc., Perkin i, No. 3, 665 (1982).
13. A. I. Pavlyuchenko, N. I. Smirnova, E. I. Kovshev, V. V. Titov, and K. M. Dyumaev,
Author's Cert. (USSR), No. 681,056; Byull. Izobret., No. 31, 94 (1979).
14. M. A. Mikhaleva, V. T. Lazareva, M. F. Grebenkin, V. A. Savel'ev, and V. P. Mamaev,
Khim. Geterotsikl. Soedin., No. ii, 1545 (1982).
15. H. Zaschke, Z. Chem., 17, 63 (1977).
16. M. I. Barnik, V. V. Belyaev, M. F. Grebenkin, V. G. Rumyantsev, V. A. Seliverstov,
V. A. Tsvetkov, and N. M. Shtykov, Kristallografiya, 23, 805 (1978).
17. G. A. Beresnev and M. F. Grebenkin, Kristailografiya, 28, 998 (1983).
18. V. V. Belyaev and M. F. Grebenkin, Kristallografiya, 29, 815 (1984).
19. W. H. De Jeu, Phil. Trans. Roy. Soc., London, A309, 217 (1983).
20. G. W. Gray, J. Phys., 36, CI, 337 (1975).
21. M . W . Partridge, J. Chem. Soc., No. ii, 3043 (1949).
22. Jap., Application No. 92,789; Chem. Abs., 96, 77607 (1982).
23. Z. Budesinsky J. Prikryl, and E. Svatek, Collect. Czech. Commun., 29, 2980 (1964).
24. Z. Budesinsky,V. Bydzovsky,J. Kopecky, Svab, andJ. Vavrina, Cesk. Farm.,iO, 241 (1961).
25. M. G. Voronkov, Zh. Obshch. Khim., 20, 2060 (1950).
*Obtained from I. A. Nizovaya.

i000
26. V. T. Klimko and A. P. Skoldinov, Zh. Obshch. Khim., 29, 4027 (1959).
27. R. R~egg, H. Lindlar, M. Montavon, G. Saucy, S. Schaeren, U. Schwieter, and O. Isler,
Helv. Chim. Acta, 42, 847 (1959).
28. J. N. Zaganiaris, Berichte, 71, 2002 (1938).

SYNTHESIS AND SPECTRAL EXAMINATION OF THE POSITION

OF TAUTOMERIC EQUILIBRIUM IN 2-THIOXO-4-QUINAZOLONE

L. M. Yun, S. Yangibaev, Kh. M. Shakhidoyatov, UDC 547.856.1.07:543.422.6:

V. Ya. Alekseeva, and K. A. V'yunov 541.623

2-Thioxo-4-quinazolone and its derivatives mono- and dimethylated at ring atoms

N(:) and N(a) and the exocyclic sulfur have been synthesized. Using model com-
pounds, UV spectroscopy has been used to show that 2-thioxo-4-quinazolone exists
in the thioketo-form, no appreciable amounts of the thiol or enol isomers being
present.

2-Thioxo-4-quinazolones display biological activity, and are therefore of practical

importance [i, 2]. These compounds are also of interest from the theoretical point of view,
since they could exist in a variety of tautomeric forms. No studies of the position of the
prototropic equilibrium in thioxoquinoxalines have been carried out, as a result of the non-
availability of a complete set of methylated models, the electronic structures of which re-
duplicate the structures of the probable tautomeric forms.
We have examined the alkylation of 2-thioxo-4-quinazolone (Ia) with methyl tosylate in
dimethyl formamide, which gives a mixture of compounds alkyiated at N(:) (Ib), N(a) (Ic), and
the exocyclic sulfur (IIa), the last product predominating in the reaction mixture [3]. The
separation of the mixture of isomeric compounds (Ib), (Ic), and (IIa) was difficult, and we
were able to separate preparatively only (IIa), the model compounds (Ib) and (Ic) being ob-
tained by fusing 1-methyl- and 3-methyl-4-quinazolones with sulfur [4]. The course of alkyla-
tion was established from the PMR spectra, in which 2-methylthio-4-quinazolone (IIa) gives
rise to a singlet signal for the methylene protons at 2.58 ppm, whereas (Ib) and (Ic) give
signals for methyl protons at 3.70 and 3.35 ppm, respectively.
When monomethylated 2-thioxo-4-quinazolones (Ib) and (IIa) were methylated with methyl
iodide in alcoholic alkali, dialkyl derivatives (IIb) and (III) were isolated. Compound (Id)
was obtained by condensing N-methylanthranilic acid with methyl isothiocyanate.
0 0 0

la-d lla, b m
Ia R=RL=H;b R=H, RI=CHa;e R=CHa, R'~=H;d R=RT=CHa: II a R=H, R~=CHa;
b R=RL=CHa

The UV spectrum of (la) contained two bands at 218 and 292 nm, due to z + 7" transitions
in the amide and thioamide groupings, respectively. Maxima similar in intensity and position
are seen in the spectra of (Ib-d), the carbonyl and thiocarbonyl groups in which are unchanged
as compared with (la).

Leningrad Lensovet Institute of Technology, Leningrad 198013, and the Institute for the
Chemistry of Plant Compounds, Academy of Sciences of the Uzbek SSR, Tashkent 700170. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1236-1238, September, 1986.
Original article submitted June 17, 1985; revision submitted November 6, 1985.

0009-3122/86/2209-1001512.50 ~ 1987 Plenum Publishing Corporation I001

 TABLE i. 2-Thioxo-4-quinazolone (la) and Its Methylated
Analogs (Ib-lll)
UV spectrum, krnax' Calculated, %
nm (log ~.) - - , .... Found, % Empirical
O mp, "C f

Is formula
o I c:H,,o,, cdG'~+ I c ,* C t-I N S
t

Ia 208--300[ 218 (4,17) 224 (4,07) ;153,8i 3,2 13,8118,01

I Cg-I$%OS 53,7 3,4 I5,7 I7,9
292 (427) 299 (4,05)
Ib 239--240[ 220 (4,05) 225 (4,I4}; 56,41 4,3 14,4 16,71C~HsN.,OS 56.2 4.2 1!46 16,6
291 (4,19] 279 ~4,23}
Ic 259--2601219 (4,14): 223 (4,31]: 56,5t 4,4 14,5 I6,4ICgH~N2OS 5 6 . 2 4,2 14,6 ~6,6
29t (4,22) 268 (3,64)
Id 175--176I 219 {4,55) -- 58,0 { 4,9 14,0 15,7]C~c,H~,N:OS 58.2 4,8 13.6 15,5
292 (3,74)
Ila 210 ! 232 (4.12) 2~0 (4,:4); 56.5i 4,31 14,6 16,8l C:.HsY,".oOS 56,2 4,2 14,6 16,6
275 (3,87} 285 (3,85)
lib 78--79 !232 (4.17) - 58,-I i 4,61 13,7 i5.41C~,,H:0NaOS
- 58,2 i 4,8 13,6 155
280 (3,86~
III 159--1601203 (4,12) ; -- 58,4( 4,0 13,8115,61 C~H~c,N2OS ,58'2 ,1,8 }13,6115,5
1254 (4,16)
i

' I

When the exocycllc sulfur atom is alkylated (lla), the UV spectrum shows a bathochromic
shift of the first maximum, by ii nm (%max 232 nm), and a hypsochromic shift of the second
maximum by 16 nm. Similar changes in the bands for ~ + ~* transitions are seen in 2-thiohy-
dantoins, which incorporate the grouping --(O)CNHC(S)NH-- which is also present in 2-thioxo-4-
quinazolone [5]. In the formation of the S-methylated derivative of (llb), it is theoreti-
cally possible for two types of C=N bonds to be formed, involving atoms N(~) and N(a ). Com-
parison of the UV spectra of 1,3- and 2,3-dimethyl derivatives (Id) and (lib) shows that the
positions of the maxima are identical and the intensities of the bands similar for (lla, b),
indicating the formation on alkylation of a compound with a nonconjugated system of ~ and
C==N bonds. The conjugated grouping O=C--N3==C(SR) results in a more complex spectrum (III),
since a new band appears with a lower intensity and an absorption maximum at 315 nm, appar-
ently corresponding to ~ + 7" transitions in the thiocarbonyl group [5].
In the spectrum of the monoanion of (la), two absorption bands are seen at 224 and 299
nm, i.e., the maxima are shifted bathochromically with respect to their positions in the
neutral molecule. This is due to charge delocalization occurring in the (la) anion, the
possibility of such a process having been demonstrated by IR spectroscopy in thioamides [6].
This charge delocalization takes place for the most part in the thioamide group, and there-
fore the positions of the absorption maxima in the spectra of the monoanions of (la) and (Ib)
change over the range 280-300 nm, and the electronic structure of the anion approximates in
the limiting case to that of (III). When a proton is detached from N(~) (compounds Ib and
lla), delocalization of charge takes place in the heterocyclic moiety ot the molecule
5==C~2!~N(I~=~C~6~ , the latter being conjugated with the aromatic nucleus. This is the reason
for the appearance of absorption with a maximum at 307 nm in the spectrum of the anion of
(Za).
Examination of the UV spectra shows that dissociation of the 2-thioxo-4-quinazolone
molecule begins with the cleavage of a proton from N(a), the basicity of which is evidently
higher than that of N(:), The compounds (I) exist in the thioketo-form. The hydrogen atoms
are located at the ring N(:) and N(3) atoms, as confirmed by the spectra of the model com-
pounds (Ib) and (Ic). No appreciable amounts of the thiol form are present in solution,
since migration of a proton to the exocyclic sulfur would result in a bathochromic shift
of the first maximum in the region 215-225 ram, and a hypsochromic shift in the region 285-
295 nm, such as occurs in the spectrum of the 2-methyl compound (lla).

EXPERIMENTAL
UV spectra were obtained on a Hitachi EPS-3T in alcohol (c 10-4-10 -5 M), and PMR spectra
on a JNM-4H-100 instrument in CDCIs and CF3COOH, internal standard TMS (6 scale). Compounds
(I-III) were purified by recrystallization from alcohol, hexane, and acetic acid, and their
purities were established by thin-layer chromatography on Silufol UV-254 in the systems ben-
zene--acetone (4:1) or chloroform-methanol (15:1).
2-Thioxo-4-quinazolone (la) was obtained by fusing 4-quinolone with sulfur [4].

1002
 l-Methyl-2-thioxo-4-quinazolone (Ib). l-Methyl-4-quinazolone (0.13 g, 0.8 mmole) was
fused with sulfur (0.2 g, 6 mmole) at 220-230~ for 20 min. The mixture was then cooled,
dissolved in i00 ml of 2 N sodium hydroxide, and excess sulfur filtered off. The filtrate
was neutralized with dilute (I:i) acetic acid to pH 6.8. The solid which separated was fil-
tered off, washed with I00 m! of water, and dried to give 0.13 g (84%) of product. IR spec-
trum: 3200, 3090 (h~), 1695 cm-: (C=O).
3-Methyl-2-thioxo,4-quinazolone (Ic) was obtained similarly.
2-Methyl-2-thioxo-4-quinazolone (IIa). To a suspension of 3.56 g (20 mmole) of (Ia)
in i00 m~ of alcohol was added a solution of 1.12 g (20 mmole) of potassium hydroxide in 20
ml of alcohol. To the resulting solution of the salt was added 2.84 g (20 mmole) of methyl
iodide. The mixture was boiled for 6 h, cooled, and the crystals which separated were twice
recrystallized from alcohol to give 0.89 g (23%) of product. IR spectrum: 3170 (NH), 1680
(C---O), 1585 cm-~ (C---N).
1,3-Dimethyl-2-thioxo-47quinazolone (Id). To a solution of i.i g (7 mmole) of N-methyl-
anthrani!ic acid in i0 ml of acetic acid was added 0.5 g (7 mmole) of methyl isothiocyanate.
The mixture was kept for 2 h at IO0~ cooled, and the crystals which separated filtered
off and recrystallized from alcohol. Yield 0.46 g (33%). IR spectrum: 1680 cm -~ (C=:O).
P}~ spectrum (CF3COOH): 3.50 (3H, s, N(3)CH3); 3.72 (3H, s, N(~)CH3); 6.9-9.88 ppm (4H, m,
C6H.).
2,3-Dimethyl-2-thioxo-4-quinazolone (IIb). A mixture of 0.96 g (5 mmole) of (IIa),
0.71 g (5 mmole) of methyl iodide, and 0.28 g (5 mmole) of KOH in 50 ml of anhydrous methanol
was boiled for 4 h. The solvent was distilled off, and the residue washed with water, dried,
and twice recrystal!ized to give 0.75 g (77%) of product. IR spectrum: 1685 (C.---O),1620
cm -~ (C~').

1,2-Dimethyl-2-thioxo-4-quinazolone (III!. To 1.7 g (5 m~ole) of the potassium salt of

(Ib) in 20 ml of anhydrous methanol was added 0.71 g (5 mmoie) of methyl iodide, and the
mixture kept for 3 h at 50~ The solvent was distilled off, and the solid residue separated
on a chromatrographic column (3 x i00 cm) packed with grade II alumina, eluted successively
with hexane and a mixture of hexane and chloroform (i:i). Yield 0.06 g (6%) of 1,3-dimethy!-
2-thioxo-4-quinazolone (Id) and 0.9 g (87%) of (III). IR spectrum: 1645 (C----O),1605 cm-:
(C=N). PMR spectrum (CF3COOH): 2.18 (3H, s, SCH~); 3.71 (3H, s, H(:)CH~); 7.35 ppm (4H, m,
C6H,).

LITERATURE CITED
l, N. B. Das and A. S. Mittra, J. Indian Chem. Soc., 56, 398 (1979).
2. H. K. Misra and A. K. SenGupto, Pest. Sci., 13, 177 (1982).
3. Kh. M. Shakhidoyatov, S. Yangibaev, L. M. Yun, and Ch. Sh. Kadyrov, Zh. Prikl. Spektrosk.
No. i, 112 (1982).
4. L. M. Yun, S. Yangibaev, Kh. M. Shakhidoyatov, and Ch. Sh. Kadyrov, Khim. Geterotsikl.
So,din., No. 2, 268 (1983).
. K. A. Byunov, A. I. Ginak, and E. C. Sochilin, Zh. Prikl. Spektrosk., 16, 1037 (1972).
6. K. A. Byunov, A. I. Ginak, and E. G. Sochi!in, Zh. Prikl. Spektrosk., 25, 866 (1976).

1003
DIAZABICYCLOALKANES WITH NITROGEN ATOMS IN NODAL POSITIONS.
13.* REACTIONS OF BENZO[b]-I,4-DIAZABICYCLO[2.2.2]OCTENE
WITH ELECTROPHILES

A. A. Gall' and G. V. Shishkin UDC 547.863.13'542.944.2'958.1:

54.422

The reactions of electrophiles with benzo[b]-l,4-diazabicyclo[2.2.2]octene have

been examined. Electrophilic substitution is found to take place in the aromat
ic ring under severe conditions, in the case of halogenation giving high yields.
The structures of the electrophilic substitution products indicate that the
heteroatoms have a m-directing influence.

It is known [2, 3] that benzo[b]quinuclidine is deactivated to a considerable extent

toward electrophilic substitution as a result of the absence of conjugation between the free
electron pair on the nitrogen and the q-electrons of the benzene ring. Benzo[b]-l,4-diazabi-
cycio[2.2.2]octene (I) contains two nitrogen atoms in nodal positions, and consequently, elec-
trophilic substitution in the benzene ring should be even more strongly hindered. However,
bearing in mind the attractiveness of this approach to the synthesis of benzo[b]-l,4-diazabi-
cyclo[2.2.2]octenes substituted in the benzene ring, we have examined the behavior of (I)
toward some electrophiles.
Treatment of the base (I) in acetonitrile with nitronium fluoroborate results in an
exothermic reaction, probably as a result of the formation of an N-nitronium complex, from
which the original (I) can be recovered. When the mixture is boiled with an excess of nitro-
nium f!uoroborate, extensive decomposition occurs, probably as a result of oxidative cleavage
of the heterocycle. Compound (I) did not undergo sulfonation on boiling in chlorosuifuric
acid, although benzo[b]quinuclidine reacts at 50~ [2]. No sulfonation took place on heating
in sulfuric acid and oleum at 200~ for several hours, but no appreciable decomposition of
(I) took place, suggesting the use of this medium for a study of the effects of other elec-
trophiles.
Treatment of a solution of (I) in sulfuric acid with nitric acid at 130~ gave a mixture
from which a low yield of a nitro-compound was isolated. From its mass and PM~ spectra, this
was assigned the structure 4'-nitrobenzo[l',2'-b]-l,4-diazabicyclo[2.2.2]octene (II).
H H+
~/~,-~ N+ .N

~'3~N
H
+ ZHSO,- NO 2 ~N+"
H
ZHSO,-

l II

The highest yields of (II) were obtained using a mixture of 93% sulfuric and 99% nitric
acids. This composition of the nitrating mixture results in the greatest rate of nitration
in numerous benzene derivatives [4]. Under these conditions, after heating for several hours,
a product was isolated which, according to microcolumn liquid chromatography, consisted
mainly of (I) and (II) in a ratio of 5:1. Further heating did not result in the accumulation
of the nitro-compound (II) in the mixture, and the total amount of product isolated decreased,
possible owing to cleavage of the heterocycle under the reaction conditions. For this reason,
it was desirable to stop the reaction at an early stage, and isolate the nitro-compound to-
gether with substantial amounts of unreacted (I). The separation of the nitration product
from the starting material was difficult, since they crystallize in equimolar ratio, as shown
by liquid chromatography, PM~ and IR spectroscopy. The co-crystallizate obtained can be

*For Communication 12, see [i].

Novosibirsk Institute of Bioorganic Chemistry, Siberian Branch, Academy of Sciences of
the USSR, Novosibirsk 630090. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 9, pp. 1239-1245, September, 1986. Original article submitted June I, 1985.

1004 0009-3122/86/2209-1004512.50 9 1987 Plenum Publishing Corporation

 TABLE i. Benzo[b]-l,4-diazabicyclo[2.2.2]octenes
IR spectmln, cm -1 ] --Found C~lculated

Corn- mp.* ~ stretehin~ vibrations "t [ d.eformational Empirical Ic '

'R 1
[ vlDrations . M (mass formula Yield.:l: %
pound Br (1). % 11, % N, % (I),
Br % 31
II, %[ N, % % spec%
I [ arom c.
IC- .N I C---tI (&tom C--It) Cilz C--,I" l t.rum)
I
I9 Br~l 195 0[10 1048 2961 1477, 845 794 37,3 3,8 8,7 49,9 C~II,eN~. Br2 37,5 3,8 8,8 49,9 88
1.2Iz 158--160 0,08 1040 2942 1463 833 824,787, 758 18,0 1,7 3,9 (76,3) C,,d 112N~. 9 21a 18,0 1,8 ,1,2 (76,0) 97
I . I I [ 87--112 0,13; 1048 (30t3), 2972, 2951, 1479, 820 802, 785,750 55,3 6,1 9, 1 C,ol lf2N2. 65,7 6,3 19,2 13
I 0,17 2886 9C.,14.NaO2
|I' 115--117 0,17 1048 (3020), 298I, 2954, !1,t75,820 802,748 58,9 5,4 2~U~ 205 Cml l, ~NaO2" 58,5 5,4 '20,5 2O5 60
2886
0,19 051 (3062), 297t!, ~3 ' I,,5 1478, 813 900, 84t 50, I 1,6 1,9 33,0 238 "!.10 (: j(,lI~,BrN~ 50,2 91,6 I1,7 33,4 23~ 240 37 (A),
llli 117--121 0 (B)
2881
IV 234-.235 0,21 1041 I (3(}64), 2971, 29,13, !1456,811 864,822 37,6 49,8 ~16 318, (" ml l,dlr~N2 37,8 3,2 8,8 316, 318 47 ~A),
2885 320 320 14(B)
V 185--192 0,43 1042 ] (3050), 2968, 29.t0, !1,t53,833 8(38 :10,3 '~ 7,3 60,6 395 398 C,.1 b,B r:~N._, 30,3 2,3 7,1 60,4 396 398 4 (A),
2877 26 (B)
Vl 224- 225 0,73 1050 [ 2953, 2882 [I,159, 835 - 25,.I 1,9 5, I (i6,8 17'1 ,176, C.,I I~Br4N~ 25,2 1,7 5,9 67,2 "174 t76 5 {A),
Ii 478 478 53 (B)
V l l 160 .161 0,16 1045 ] (3630), 2960, 2940, 1473, 827 893,807 ,l 1,6 3,9 .%9 (44,3) 286 Cjoll,,1Na 42,0 3,9 (.),8 {44,4) 286 35
2876 I
Vlll 177--180 0,22 1048 [ (3043), 2963, 2950, !455,817 855,832 29,5 2,3 7.{} 0;1,2) 412 Cmllwl2N2 29,21 2,4 6,8 (61,6) 412 67
2880
IX 17(`1--181 0,50 1054 I (3061), 2980, 2950, I-t63,834 850 21,9 I ,(i 5,o (70,7) 538 Cud l:daN2 22,3 1,7 5,2 (7<8) 538
2887
X 220-.221 0,87 104212938, 2872 [1453, 828 -- - 18,5 1,1 ] 3,! (76,6) (i6.1 Cud I~I4N~ 18,1 1,2 ,1,2 (76,5) 6(H 0,4
I

*Compounds l-Bra, 1-212, and (Vlll-X) with decomposition; 1.21a and (IV-Vl) in a capillary.
#For (I-II) and (II), VN_ O 1529 cm -l.
S The yield of (I~ is calculated on (I) consumed.

0
0
 TABLE 2. PMR Spectra of Benzo[b]-l,4,-diazabicyclo[2.2.2]oc-
tenes Substituted in the Aromatic Ring* 6, ppm
PMR Spec=a in neutral media PMR Spectra in acid media* 9 .,.._ ppm
~om- aromatic protons ethylene
aromatic protons ethylene
ound O, Hz) bridge (J, Hz) bridge 3'-H 6'-H ~'-H
protons protons
3'-H I,;-H I 5'-H (sym.m) 3'-H J 6'-~I J 5'-H Oym.m)~!

I1 7.88d 8,32d 7.83d 8,44 dd 3 , 2 - - 4 , 0

7,35r 8,~ dd 2.5--3,5 0,44 0,48 0,24
(2,6) (815) 1
III (2[~[d (8[~[d 7/ dd 2,4--3,2 7,688 7,50d 7,73d 3, I --3,9 [3,40 0,45 0,29
(2,3) 1(8,1) i (8,0) 1(8,0)
IV 7,448 2.4--3,2 7.90 s J -- 3, ! --3,9 0.44 --
V 7,52 s 2,4--3,3 _8,o48_ I -- 3, i --4,o 0,52
VI I 2,5--3,3 2.7--3,5
VII 777d 673d 7.( dd 2,4--3,2 7,88 s 7.37d 7,92d 3,0--3,8 071 1074 0,2--9
(~,9) t(8,1) 1(7,4) ](7,4)
VitI 7,66 s 2,4-3,2 8,O7s I -- 3.0 --3,9 0,41
IX 7,78 s 2,4--3,2 3, l --4,0 0,48
X -- [/ -- 2,4--3,1 o,5--3,3
l
*Spectra taken at 90 ~ in DMFA-D:7, ratios of signal in-
tensities agree with the proposed structures.
**Acidity was attained by adding CF3COOH to 3%; further
increase in acid concentration did not lead to a change in
in CS.
***Downfield shift of the aromatic protons during protonation
of the nitrogen atom.

separated by preparative TLC. Losses on purification reduce the overall yield to 1.5, or 8%
calculated on the (I) reacted.
The reaction of (I) with bromine or iodine affords the molecular complexes l*Br2 and
1.212, which on heating to 150~ did not give ring-halogenated products, in accordance with
an earlier report [2].
We have been able to brominate (I) using dibromocyanuric acid in oleum [5, 6]. When
this reaction was carried out at 130~ a mixture of bromination products of benzo[b]-l,4-
diazabicyclo[2.2.2]octene (III-VI) was obtained, the relative amounts of which were depen-
dent on the amount of brominating agent and the reaction time. The principal components of
these mixtures were readily separable by crystallization, and the residual mixture could
be separated chromatographically. The use of an equivalent amount of dibromoisocyanuric
acid resulted in the preferential formation of the dibromo compound (IV), and the use of two
equivalents gave mostly the exhaustive bromination product (VI). The mono- and tribromo
compounds (III) and (V) were isolated as minor components from the reaction mixture by TLC.
Bromination was not complicated by side reactions, and the'overall yield of bromination prod-
ucts reached 93%.
Examination of the structures of the compounds showed that bromination initially takes
place in the position meta- to the heteroatom, but this does not deactivate the aromatic
ring to further electrophilic substitution. This results in the successive substitution,
initially in the other meta-position to the nitrogen atom, and subsequently, to successive
substitution in the ortho-positions.
X X

I III,VII PC,VII1 V,IX X

III-VI X = B r ; v!I-.X X=I VI,X

The use of a powerful iodinating agent, namely iodine in oleum at 150=C, also results
in successive substitution in the aromatic ring of benzo[~]-l,4-diazabicyclo[2.2,2]octene.
As in bromination, monosubstitution by iodine does not decrease the ability of the aromatic
ring to undergo further substitution. Consequently, the diiodo compound (VIII) is formed.
For this reason, in order to obtain sufficient amounts of the mono-iodo compound (VII) it
is necessary to use a twofold deficiency of iodine, and to separate the mixture of (I) and

1006
(VII) obtained by preparative TLC. Further substitution in the free positions in (VII) takes
place with great difficulty, and even when an excess of iodine was used the tri- and tetraiodo
compounds (IX and X) were obtained in low yields. All the iodination products were separable
by preparative TLC.
In the mass spectra of (II-X) (Table i), in addition to the molecular ion, peaks were
present for the fragments [M-- 28] +. , corresponding to cleavage of the ethylene bridges. The
molecular ions for the bromination products of (I) were seen as groups of peaks, the positions
and intensities of which were in accordance with the amounts and natural content of 7~Br and
8:Br isotSpes in the molecule.
In the IR spectra of the benzo[b]-l,4-diazabicyclo[2.2.2]octene derivatives, vibrations
were present characteristic of the diazabicyclo[2.2.2]octane fragment [7], manifested as the
strongest absorption bands at 2981-2876 and 1054-1040 cm -~ (C--N stretching and skeletal vibra-
tions of the 1,4-diazabicyclo[2.2.2]octane fragment) and at 1479-1453 and 845-811 cm -: (defor-
mational vibrations of the CH2 group). In addition, in compounds containing aromatic protons,
weaker signals were seen at 3064-3013 and 900-748 cm -: corresponding to stretching and defor-
mational vibrations of the aromatic ring C--H.
In the PMR spectra of (II-X) (Table 2), symmetrical multiplets were present in 2.4-3.5
ppm, corresponding to the eight protons of the ethylene bridges. The signals were shifted
by 0.2-0.7 ppm to lower field when the nitrogens were protonated by adding trifluoroacetic
acid. The signals for the aromatic protons in (II), (III), and (VII) corresponded to 1',2',
4'-trisubstitution in the benzene ring, the 5' and 6' protons having coupling constants of
8.1-8.5 Hz, and those in positions 3' and 5', of 1.9-2.6 Hz, characteristic of ortho- and
meta-positions for the protons, respectively. When the nitrogens were protonated, the sig-
nals for the aromatic protons were shifted to lower field. For the 3' and 6' (protons, in
the ortho-positions to the protonation center, this shift was -0.5 ppm, which is greater by
a factor of two than the shifts for the signals for the meta-located 5' protons. Similar
observations have been made by Mikhlina et al. [2] in a study of the structures of substitu-
ted benzo[b]quinuclidines. Hence, a comparison of the PMR spectra in neutral and acidic
media is a satisfactorily general method for establishing the positions of substituents in
the aromatic ring in these heterocyclic systems.
The signals for the aromatic protons in (IV), (V), (VIII), and (IX) are seen as singlets
at 7.44-7.78 ppm, which in acidic media are shifted to lower field by 0.41-0.52 ppm. A shift
of this magnitude is characteristic only of protons ortho- to nitrogen, confirming the postu-
lated structures. Study of the nature of the ~SC--H satellites in the PMR spectra at 200 MHz
for (IV) and (VIII) shows that the coupling constants for the aromatic protons in these com-
pounds approaches zero, in agreement with the relative para-disposition of the protons in the
aromatic ring.

EXPERIMENTAL
The IR spectra of the compounds were obtained on a UR-20 instrument in KBr disks, and
UV spectra on a Specord UV-VIS in pentane. PMR spectra were obtained on Bruker HX-90 and
WP-200 s, y spectrometers, internal standard TMS, 6 scale. Mass spectra were obtained on a
Finnigan MAT-8200. The quantitative compositions of the reaction mixtures were measured by
reversed-phase chromatography (LC) on Lichrosorb RP-18 as carrier, particle size 5 ~m, diam-
eter of micro-column 2 mm, height 50 mm, on a Milikhrom chromatograph, eluent 0.i M acetate
buffer (pH 5.0) in 60% methanol. Preparative chromatography was carried out on thin layers
of silica gel on 35 70 cm plates in the system chloroform--ethanol, 20:1, the compounds
being eluted from the silica gel with a mixture of chloroform and methanol (5:1). TLC was
carried out on Silufol b~-254 plates in the system chloroform-ethanol (20:1). Compounds
(II-VIII) were sublimed in vacuo at I00-170~ (0.i mm).
Benzo[b]-l,4-diazabicyclo[2.2.2]octene (I) was obtained as described in [8]. To prevent
a violent reaction when dissolving in acids, the (I) was used in a coarsely crystalline state.
Complex of Benzo[b]-l,4-diazabicyclo[2.2.2]octene with Bromine (I.Br=). This was ob-
tained by treating a solution of 0.2 g (1.25 mmole) of (I) in 8 ml of ether with 0.2 g (1.25
mmole) of bromine over ten minutes with sitrring. The solid was filtered off, washed with
ether, and dried in vacuo to give 0.35 g of a yellow solid. PMR spectrum (90MHz, inDMFA-DT):
7.53 (4H, s, arom. protons), 3.8-3.0 ppm (8H, sym. m., CH2).

1007
 Complex of Benzo[b]-l,4-diazabicyclo[2.2.2]octene with Iodine (1.212). This was ob-
tained by mixing solutions of 0.32 g (2 mmole) of (i) in 30 ml of ether and 1.02 g (4 mmole)
of iodine in 20 ml of ether. The mixture was kept for 12 h, then filtered, washed with ether,
and dried in vacuo. Yield 1.3 g of a reddish-orange solid. PMR spectrum (90 MHz, inDMFA-DT):
7.55 (4H, s, arom. protons), 4.0-3.1 ppm (8H, sym. m., CH2).
Cocrystallizate of Benzo[b]-l,4-diazabicyclo[2.2.2]octene and 4'-Nitrobenzo[i'2'-b]-l,4-
diazabicyclo[2.2.2]octene (l.II). To 160 ml of 93% sulfuric acid (d 1.83) frozen in liquid
nitrogen was added 64 g (0.4 mole) of (I), and the mixture stirred with gradual heating to
IO0~ until all the base had dissolved. To the solution initially, and after I, 2, and 3 h
with heating at 130~ were added with care and stirring 15 ml portions of fuming nitric acid
(d 1.51). After fJm,r h had elapsed, the mixture was cooled, carefully poured into an equal
volume of water, and air blown through to remove oxides of nitrogen. The mixture was then
neutralized with 700 ml of 25% ammonia with stirring and constant cooling to O~ the ammonia
being carefully introduced through a capillary immersed in the reaction mixture. The nitra-
tion products and unreacted base were extracted with 4 300 ml of ether, and the extract
dried over MgSO~ and evaporated to dryness. The solid residue was boiled for several minutes
with 40 ml of acetone, gradually cooled to 15~ filtered, and the crystalline solids washed
three times on the filter with 12 ml portions of acetone to give 51.5 g of the starting mate-
rial (I), mp 126-129~ containing, according to TLC, a small amount (0.8%) of the nitro-com-
pound (II). The nitration product separated as a cocrystallizate with the starting material
on evaporation of the mother liquors, and was recrystallized from 120 ml of light petroleum
(bp 70-I00~ to give 3.66 g of a yellow crystalline solid. PMR spectrum (90 MHz, in CDCI~):
8.18 (IH, d.d, 5'-H arom.); 8.03 (IH, d, J = 2,6 Hz, 3'-H arom.); 7.32 (IH, d, J = 8.5 Hz,
6'-H atom.), 7.23 (4H, s, arom. protons), 3.5-2.5 ppm (16H, m, CH2). Evaporation of the
mother liquors gave 2.0 g of (I), mp 126-129~
4'-Nitrobenzo[l',2'-b]-l,4-diazabicyclo[2.2.2]octene (II) was separated by TLC from
1.2 g of the cocrystallizate (I.II). The fraction with Rf 0.2-0.4 gave 0.5 g of (I), mp 127-
129~ Compound (Ii) was extracted from the fraction with Rf 0.4-0.5, and recrystallized from
light petroleum (bp 70-I00~ yield 0.4 g, as a yellow crystalline solid in the form of need-
les. UV spectrum %max, nm (log s): 216 (4.02), 263 (3.98).
4'Bromo, 4',5'-Dibromo, 3',4',5'-Tribromo-, and 3',4',5',6'-Tetrabromobenzo[l',2'-b]-l,4-
d iazabicyclo[2,2.2]octene (III-VI). A. To 20 ml of oleum (d 1.91) frozen in liquid nitrogen
was added 1.28 g (8 mmole) of (I), and the mixture gradually heated to 70~ until all the
base had dissolved. To this solution was added with stirring in small portions 2.4 g (8.4
mmole) of dibromoisocyanuric acid. The mixture was maintained at 130-140~ on an oil bath
for 6 h. Water (20 ml) was then added with cooling to 0~ with constant stirring, followed
by the careful addition of 25% ammonia (i00 ml), through a capillary immersed in the reaction
mixture. The bromination products were extracted with 5 i00 ml of ether, the extract dried
over MgSO~, and evaporated to dryness. The resulting mixture of bromides (2.5 g) was dis-
solved in the minimum amount(~150 ml) of boiling light petroleum (bp 70-I00~ and cooled
whereupon the major part of (IV) crystallized as prisms (i.0 g). The mother liquors were
evaporated, and the residue separated by TLC and recrystallized from light petroleum (bp 70-
100~ Compounds (III-VI) were extracted from the fractions with Rf 0.4-0.5, 0.5-0.6, 0.6-
0.7, and 0.7-0.8 (Table i).
B. All operations were carried out as in method A, with 4.8 g (16.7 mmole) of dibro-
moisocyanuric acid, and the reaction mixture was kept for 12 h. The bromination products
(3.5 g) were dissolved in the minimum amount (-350 ml) of boiling light petroleum (bp 70-
IO0~ Crystallization gave 1.7 g of (VI). The remaining compounds were extracted from
the mother liquors by TLC.
4'-lodobenzo[l'~2'-b]-ip4-diazabicyclo[2.2.2]octene (VII).. To a solution of 1.28 g
(8 mmole) of (I) in i0 ml of 24% oleum, prepared as described above, was added with stirring
0.51 g (2 mmole) of iodine. The mixture was kept at 140~ on the oil bath for 4 h, then i0
ml of water was added with constant stirring and cooling to 0~ followed by 50 ml of 25%
ammonia, carefully introduced through a capillary immersed in the reaction mixture. The
iodination product together with unreacted (I) were extracted with 3 80 ml of ether, and
the extract dried over MgSO~ and evaporated to dryness. The resulting mixture was separated
by TLC. The fraction with Rf 0.2-0.3 gave 0.87 g of (I), mp 127-129~ From the fraction
with Rf 0.3-0.4, following recrystallization from light petroleum(bp 70-I00~ there was
obtained 0.4 g of (VII) as colorless needles.

1008
 4',5'-Diiodo, 3',4',5'-Triiodo-, and 3'~4',5',6'-Tetraiodobenzo[l'~2'-b]-l~4-diazabicy-
clo[2.2.2]octene (VIII-X). To a solution of 0.64 g (4 mmole) of (I) in i0 ml of 24% oleum
was added with stirring 3.0 g (11.8 mmole) of iodine, and the mixture kept at i50~ for 3 h.
The preparation of the solution and its neutralization were carried out as described above.
Excess iodine was removed by adding 3 g of Na2S203.5H=O, the mixture stirred for 5 min until
decolorized, and diluted with i00 ml of water. The iodination products were filtered off,
washed with 30 ml of 3% Na2S20~ solution followed by water, and dried in vacuo to give 1.43
g of a mixture consisting principally of (VIII-X). This was separated by TLC, and the sepa-
rate compDnents recrystallized from a mixture of chloroform and light petroleum (bp 70-I00~
Compounds (VIII-X) were extracted from the fractions with Rf 0.4-0.5, 0.5-0.6, and 0.8-0.9.

LITERATURE CITED
I. V . I . Vysochin and G. V. Shishkin, Khim. Geterotsikl. Soedin., No. 5, 664 (1985).
2. E . E . Mikhlina, A. D. Yanina, L. M. Alekseeva, K. F. Turchin, Yu. N. Sheinker, L. N.
Yakhonotov, R. F. Dyuk, A. Ya. Richard, and A. R. Katritskii (Katritzky), Khim. Geter-
otsikl. Soedin., No. 3, 385 (1971).
3. R . P . Duke, R. A. Y. Jones, A. T. Katritzky, E. E. Mikhlina, A. D. Yanina, L. M.
Alekseeva, K. F. Turchin, Yu. N. Sheinker, and L. N. Yakhontov, Tetrahed. Lett., No. 21,
1809 (1970).
4. K. Schofield, in: Aromatic Nitration, Cambridge (1980), pp. 30, 157.
5. W. Gottardi, Monatsh. Chem., 99, 815 (1968).
6. W. Gottardi, Monatsh. Chem., !00, 42 (1969).
7. M. P, Marzocchi, G. Sbrana, and G. Zerbi, J. Am. Chem. Soc., 87, 1429 (1965).
8. G . V . Shishkin and A. A. Gall'j Khim. Geterotsikl. Soedin., No. 6, 827 (1980).

CYCLOTRIMERIZATION OF THIOCYANIC ACID IN ORGANIC SOLVENTS

A. G. Rybin, E. N. Zii'berman, I. V. Etlis, UDC 547.491.8.07'268.5:

and G. N. Chervyakova 542.952

Thiocyanic acid in organic solvents (i-PrOH Bu20, AcOH, dioxane) trimerizes to

form 1,3,5-trimercapto-sym-triazine.

When thiocyanic acid (TCA) is heated in aqueous medium, the formation of 5-amino-l,2,4-
dithiazol-3-thione (I) takes place and hydrogen cyanide is evolved [i]. The purpose of our
work was to study the conversion of TCA organic solvents.
We carried out the reaction in i-PrOH, AcOH, Bu20, and dioxane. As starting material,
we used the pyridinium salt of TCA, which is readily soluble in organic solvents. Heating
the solution of pyridinium thiocyanate in organic solvent in the presence of sulfuric acid
led to the formation of a yellow powder (II). The UV spectra of products obtained in differ-
ent solvents were identical and differed from the UV spectrum of compound I. Material II
did not melt up to 300~ dissolved readily in sulfolane and pyridine but poorly in dioxane
and benzene. The compound was soluble in aqueous solutions of inorganic acids and bases.
The IR spectrum of the compound contained absorption bands characteristic of the triazine
ring: 680, 1020, 1400 (C--N), 840, 920, and 1570 (--C=N) as well as absorption bands in the
1315 cm-: region (S-~N). The molecular mass of the compound, 177, was determined from an
analysis of the mass spectrum. The data listed, the P~IR spectrum, and also the elementary
analysis of the compound indicate that under our experimental conditions, TCA undergoes a
cyclotrimerization to form 1,3,5-trimercapto-sym-triazine, II. This conclusion was confirmed
by a reverse synthesis [2].

Dzerzhinskii Branch of the A. A. Zhdanov Gor'kovskii Polytechnical Institute, Dzerzhinsk

606026. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1246-1247, Sep-
tember, 1986. Original article submitted June 4, 1985.

0009-3122/86/2209-1009512.50 9 1987 Plenum Publishing Corporation 1009

 The formation of compound I from TCA in water and compound II from TCA in organic
solvents can be explained on the basis of HSAB principles, according to which soft,
weakly solvated reaction centers are more reactive in highly polar solvants, whereas
hard, strongly solvated centers become more reactive as the polarity of the medium
decreases. In water, the reactive center of TCA at the sulfur atom is more nucleophilic
than the reactive center at the nitrogen atom but the reaction center at the nitrogen atom
is more nucleophilic in organic solvents of low polarity. Accordingly, the condensation of
TCA in water and its cyclotrimerization in organic solvents apparently take place in the
following manner:
HSCN
!
sH
. -'6 0"11 , i
+HNCS N/C.~NH :
[HN=C(SII)SCN] [HN=C(SH)NCS] [I
C
HS ~ " N : C : S
I +HSCN !
1 )
H
I~ HN~c/Nxc .SH- HN~ N.~I/ SH NH 2~[/N. ~>S S!l
L

I i I -HCN--
k IIS SCN S --S S ---S
t

EXPERIMENTAL
We took the IR spectrum on a UR-20 spectrometer, the UV spectra on an SF-26 instrument,
and the PMR spectra on a Tesla BS-487c (80 MHz) instrument. We used CsDsN as a solvent (HMDS
internal standard). We carried out the mass spectroscopic analysis on an MK 12-01 instrument.
Pyridinium Thiocyanate. We added 75 ml of water to a mixture of 29.4 g (0.3 mole) of
potassium thiocyanate and 33.9 g (0.3 mole) of pyridinium chloride and heated it to boiling.
The reaction mass was then evaporated down at 20~ We dissolved the residue in acetone and
filtered off the potassium chloride. From the filtrate, we precipitated pyridinium thiocyan-
ate with ether (i:i by volume). Yield 38.6 g (95%), Tmp IO0~
1,3,5-Trimercapto-sym-triazine (II). Over a period of 8 min we added a mixture of con-
centrated H2SO~ and 5 ml of isopropyl alcohol to a solution of i0 g (0.07 mole) of pyridinium
thiocyanate in 15 ml of isopropyl alcohol heated to 90~ We heated the reaction mixture at
this temperature for I h 30 min with stirring under reflux. From the cooled reaction mixture
we separated the precipitate, washed it with water and dried it. Yield 0.8 g (19%). PMR
spectrum: 4.50 ppm (w, SH). Found, %: C 19.8, H 1.3, N 23.6, S 55.1. C3H~N~Sa. Calculat-
ed, %: C 19.9, H 1.7, N 23.7, S 54.2. The synthesis was carried out in a similar way in the
other solvents. Yields of triazine II were 5% (AcOH), 22% (Bu20), and 29% (dioxane).

LITERATURE CITED
11 Ch. L. Melamed and G. A. Blok, Kauch. Rezin., No. 8, i0 (1969).
2. E. Smolin and L. Rapaport, s-Triazines and Derivatives, Interscience, New York (1959),
p. 106.
. H. E. Williams, Cyanogen Compounds, Chemical Publishing Co., New York (1948), p. 261.

i010
STEREOISOMERISM IN MACROCYCLIC BIS(PIPERiDONES)

A. M. Belostotskii and A. B. Shapiro UDC 547.823'898:542.953.2:

541.634:543.422

The reaction of a polysubstituted 3,5-dimethylene-4-piperidone with aliphatic

diamines leads to macrocyclic products, namely, 3,3',5,5'-di(methylaminoalkyl-
aminomethyl)-bridged bis(piperidones). The latter compounds are formed as mix-
tures of cis,trans-isomers, and isolated in the form of cis,cis-isomers.
~3C-NMR spectral analysis has shown that these compounds also exhibit charac-
teristic syn-anti isomerism associated with the relative orientation of the
3,5-substituents on opposite piperidone rings.

It has previously been shown that reaction of piperidone I with primary amines leads to
the formation not only of the products of addition of the amine to the C=C bond, but also to
the formation of cleavage products of the piperidone ring [i]. In light of the unusual be-
havior of polysubstituted 4-piperidones, the addition of amines to piperidone I was subjected
to further study.
Reactions of the dimethylene ketone I with a!iphatic diamines lia-e were carried out
under high dilution conditions in order to avoid the formation of linear oligomers, and led
to the formation of the first type of compounds in quantitative yields. The structures of
these compounds were elucidated on the basis of their IR, mass, and :H- and :~C-h2~R spectra,
as well as by elemental analysis (Tables 1-3). The functional similarity between the dimeric
macrocyc!ic structure III and the monomeric bicyclic structure Q makes it difficult to dis-
tinguish between these two products, both of which result from one reaction pathway, namely,
addition of the amine to the double bond without ring opening.
H H H

I ==~-e IIla-e q

The formation of a mixture of compounds is deduced from PMR spectral evidence, which
shows, for each reaction product, two pairs of signals for the gem-dimethyl groups; these
signals have varying intensities, but exhibit constant predominance of one compound each in
the n = 2-6 series, which gives rise to the central pair of singlets. Those compounds which
were present in the greatest amounts could be isolated in 15-30% yields, and were shown by
:H- and ~ C - N ~ to be homogeneous to within 90-i00% (based on the integrated intensities of
the s-methyl group signals in the PMR spectra).
Based on mass spectral evidence, the isolated compounds were assigned the macrocyclic
structure III (Table 2). One characteristic feature of the mass spectra is that the proton-
ated molecular ion peak (M + H) + is either very small, or not detectable at all, whereas the
ion peak corresponding to half its mass is relatively intense. Nevertheless, any assumptions
concerning the formation of compounds of structure Q in mixtures with the corresponding macro-
cycles III, even in mass spectroscopically detectable amounts, appear to be groundless. Thus,
the spectrum of a completely acylated derivative of Ilia (Ac20, 20~ 4 days), which was not
subjected to any special purification prior to conversion, showed an intense peak for the
molecular ion (M + H) + of the macrocyc!io tetraamide. The presence of two signals for the
carbonyl carbon atoms in the :3C-NMR spectra also corroborates the macrocyclic structure for
compound Ilia (Table 3).
The highest homolog llle differs from the lower members of the series llla-d in its
fragmentation pattern; the latter compounds are characterized by thermal decomposition "and
Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1248-1254, September, 1986. Original
article submitted May 27, 1985.

0009-3122/86/2209-1011512.50 9 1987 Plenum Publishing Corporation I011

 TABLE I. Macrocyclic Bis(piperidones) llla-e and IV
IR spec- PMRa spectrum, 6
:om- lrum. c m "1 Found, Molecula i Cole., %
ound mp, ~ ppr~ formula
I

NH [ C=O (CH~)a [NCHa I(CHJ c I H ,!N c I H .!..N

tltli 131--132 ~290 1705 0,98; 1,16 2,26 -- 86,1 .1,0 16,6 C~H~N~O: ]6,4 0.7 16,6
IIIa b 119--120 0,77; o,98; 2,26; ~6,2 0,8 16,6 C~H~4N~O2 36,4 0,7 16,6
1,16; 1,37 2,30
IIIb. 132--133 ;300 [700 0,95; 1,13 2,24 1,56 57,3 0,6 15,6 C~oH~NaO~ $7.5 0,9 15,7
IIIb b 0,75; 0,95; 2,24; 1,56
1,13; 1,32 2,31
IIIc. 117--118 ~300 1705 0194; 1,11 2,23 t ,4C 58,1 0.9 14,9 C~;H~2NsO: 38,4 1,0 14,9
IIIe l: 0,73; 0,94; 2.23; 1,4C
1,11; 1,32 2,30
IIId 125--126 ~300_. 1705 0,97; t,16 2,27 1,32 58,9 1.2 14.1 -;9,1 1.2 142
llldb 0,75; 0,97; 2,27; 1,32
1,16 - - o 2,34
llIe, 115--116 ~300 1700 0,97; 1115 2,26 1,33 59,6 1,5 13,5 39,g 1,3 13,6
u,73; 0,97; 2,26; 1,33 i
1,15; - - r ' 2,32
IVb >200 1710 0,75; 0,80; 2,16; -33,6] 8,9 12,1 54,( 9.2 12.5
(dec.) 1640 1,34; 1,54 2,23
a m id~
aThe N--CH2 and CH protons give rise to overlapping multiplets
in the region 2.3-3.5 ppm. bFor a mixture of isomers (without
a superscript, for the cis,cis-isomer). CThe signal is hidden
behind signals due to other groups.

TABLE 2. Chemical Ionization Mass Spectra of Macrocyclic Bis-

(piperidones) llla-e and the Tetraacetyl Derivative of Piperi-
done Ilia (cis,cis-isomer) a
Conl-
pound m / e (relatiVe intensity, %)b

IIIa 507 (0.I), 449 (0,1), 447 (0,8), 391 (0,3), 345 (0,6), 305 (0,2), 279 (0.2).
268 (0,3). 254 (11,0), 235 (1,1), 223 (20,8), 194 (100,0)
IIIb 535 (0,1), 461 (0,8), 391 (0,4), 280 (0,3), 268 (l,fi), 239 (2,1), 222 (1,5),
220 (1,1), 194 (100,0)
IIIc 563 (0,04), 475 (0,4), 391 (0.1), 294 (0,1), 282 (2,9), 251 (3,9), 211 (2,5),
194 (100.0)
llId 391 (0,8), 290 (0,7), 265 (1,3), 225 (I,0), 194 (I00,0)
file 563 (I,0), 549 (1,2), 535 (2,0), 533 (I,I), 521 (I,5), 507 (2,6), 493 (I,6),
479 (1,7), 451 (1.3), 411 (1,2), 401 (1,2), 391 (3.4), 383 (2,8), 369 (3,6),
313 (1,8), 265 (1,4), 257 (5,7). 239 (3,6), 194 (100,0)
Ac4-IIIa 675 (16,1), 531 (0,1). 340 (1,4), 338 (5,3). 289 (1,0), 213 (1,0), 194 (15,5),
183 (3,0), 168 (1,4), 165 (1,9), 145 (100,0)

a ~ s peaks having mass greater than M/2 + H are given, along

with all lower mass peaks having intensities greater than i%
(with the maximum peak assigned 100%). The reagent gas was
NH~ for bis(piperidones) Ilia-e, and isobutane for Ac~-llla.
bThe ion peak corresponding to thermal decomposition of macro-
cycles Ilia-c, with loss of one molecule of the starting dia-
mine, is italicized, whereas the ion peak [M/2 + H] + is written
in boldface type.

loss of the starting diamine, whereas piperidone llle undergoes decomposition of the hexa-
methylene chain and elimination of the central methylene units (apparently in the form of
olefins having 4, 5, and 6 atoms). This also gives rise to the formation in the mass spec-
tra of relatively intense high molecular ions [M + H -- (CHa)n] +. If one assumes that the
protonated molecular ion (M + H) + is instead the peak with half the mass, 310 (corresponding
to the hypothetical structure Q), then the mass spectrum should also contain fragment ion
peaks resulting from similar decomposition of the hexamethylene chain in bicyclic Q. The
absence of these peaks establishes the unitary nature of the ion, and also establishes the
dimer structure llle. Yhe macrocyclic structures of the lowest (n = 2) and highest (n = 6)
homologs have thus been proven, and allow us to conclude that the mass spectra of the other
members of the series (n = 3-5) also describe macrocyclic bis(piperidones) of structure
lllb-d.
Compounds having the structure described in III can exhibit two types of three dimen-
sional isomerism (Scheme I): cis,trans isomerism, corresponding to the relative orientations
1012
 T ~ L E 3. ~SC-h~ Spectra of Macrocyclic Bis(piperidones)
IIIa-e
Theoretical
Chemical shift, pprn. multiplicity at partial UC-{*H} decoupling sum Z of
groups of
(theoretical number of groups of chemically nonequivalent carbon chemically
atoms for the eis,cis-, ets,trans-, and tram,tram-isomersr) nonequi-
valent ear-
Com- bon atoms
for each
pound isomer

, 4 ,sotl / - II - I I

iii!tiiiiil
23,06,1 60,94s ] 213,86[ iJ612s 16
(4,8,4 (2,4,2)] (2,4,2). I (2,2,2)l(2,4,,) (2,4.2) ] / E I
26,55
23,26 :[,
q 61'31s i 58,72 d I 213,60147,05 ~ 48,05t130,71t ] -- ] [
{4,8,4 I {2,,42)i (2,4,2) I {2,2,2)t{2,4,5 ) {2,4,2) ](2,2,2) [ t~813o ~8
26,07 q, 60,67s 58,23 d ] 212,99[47,29 t 50,16t128,04t[ -- ] [
22,86 q
, ] (4,8,4 [ (2,4,2)1 (2,4,2) [ (2 2.2)](2A,~) 12,4.2) [f2A,2) [ [18]32 18
ilId ]28,18q I 26,14 q, 49,42 t13h,29t/24,93t] t
1(22~ 22,76q
(4,8,4 / (2,4,21 t2,4,2}1 f2,2,2}1{2,4,, t2,4,2)](2A.2)l'2,2,2)/2~ i~0
26,37, 50,40 p'),45 t27,81 t /
22,92
~/|f2,2,2) ] (4,8,4 [ (2,4.2)[ /2421[ 12.2,2)H2,4.~ ( ..... )/(_,4,_) | {_,4,_1 | 2o] ~6
049 O ,2* "O O" . Q

49.73 / l | /
30,19 16331~160'60~210;4014T,08 4~.26 i l I /
26,44
23,33,
23,13
16,60,
16,47

aIncluding syn-anti isomerism, bMixture of the cis,cis-iso-

mer of IIIa and the corresponding cis,trans-isomer (only an-
cillary signals are given, i.e., signals of the cis,trans-
isomer). CTentative assignment.

of the 3,5-substituents in each piperidone ring (cis-cis-, cis-trans-, and trans-trans-iso-

mers) and also isomers corresponding to different relative orientations (syn vs anti) of
these substituents on opposing piperidone rings. This type of stereoisomerism is character-
istic of systems composed of two noncondensed saturated six-membered rings, such as perhydro-
anthracene or perhydrophenanthrene. In the case of the bis(piperidones) of type III, it has
been found that the independent conformmtional mobility of the terminal rings and of the
central chain in the macrocycle does not lead to interconversion of the syn- and anti-isomers;
the relative orientations of the Z substituents on the two different rings do not change upon
ring inversion. This indicates that both the cis-cis- and trans-trans-isomers of III can
each give rise to two isomers of the syn-anti-type. In the case of the cis-trans-isomers
two groups of conformers can be distinguished, and cannot be interconverted by ring inversion
into conformers of the other group, but rather are related to them as optical antipodes (pairs
from each group). The relative orientation of substituents of the two rings are identical in
each enantiomeric pair, i.e., the cis-trans-isomer is a cis-anti-~rans-isomer.
It is obvious that cis-trans-isomers should differ more in their physical chemical pro-
perties than should syn-anti pairs of isomers, since in the case of the latter isomers, each
of the piperidone residues in one isomer differ from the same piperidone ring of its isomer
only in. terms of the three dimensional arrangement of the distant piperidone ring. As the
size of the central macrocycle increases, the similarity in the properties of the syn-anti
isomers also increases.
Because of the different internal symmetries of the possible conformers, the cis-cis-
and trans-trans-isomers of III differ from the cis-trans-isomer in the absolute number of
groups of structurally nonequivalent atoms of one type, and thus in the number of lines ex-
pected in their theoretical :~C-hX~R spectra (see Scheme 1 and Table 3). The number of groups

1013
 Scheme I
'

:'++"?-
:'~,,<S~. / >~ . -,
i e ~ illt I

. M ~ I +Z~~e Me 0 Me

(/~,,.!)z
~e ..~
+j - :
(
-'.+.+ ?, + ' m+/ :(0
+m+,:'.,++
= +=+ , +/ Me
,+
' N I M e /,' M~
+ :" /
"'W\ d F "Z--
~e lJ M e

,~ ~ /
,Z l'p," I" /
- - M,; +t+/

,h: .~,. ,.;9 ~., , / ~: ~) ~'.. (!~

~+'ed~~e ~. Me , N : Me !( "Z ~' ' " N ~ '

Stereoisomerism and conformational transitions in type III

bis(piperidones): i) cis-cis-isomer (a, syn-isomer; b, anti-
isomer); 2) cis-trans-isomer (A and A', enantiomers); 3)
trans-trans-isomer (a, syn-isomer; b, anti-isomer). Three
dimensionally equivalent structures are denoted by asterisks
(* or ~*).

of atoms of one type is equal to the number of groups of atoms of each type which cannot be
interconverted by positional exchange (considering only conformational changes associated
with inversion of the six-membered rings). In the case of the cis-cis- and trans-trans-
isomers, degeneracy of the conformational transitions and internal symmetry of the conformers
leads to equivalency of all of the carbon atoms of one type in each isomer (with the excep-
tion of the geminal carbon atoms of the ~-methyl groups); at the same time, however, all of
the conformers of the cis-trans-isomer are structurally (three-dimensionally) different and
do not possess any symmetry elements. As a consequence, the cis-cis- and trans-trans-isomers
have the same number of groups of chemically nonequivalent carbon atoms (both of each type
and the total number), whereas the cis-trans-isomer has almost twice as many such groups.
The number of signals, 9, 9, 9, I0 and i0, respectively, in the :3C-NMR spectra of the
isolated isomers of IIIa-e does not allow us to assign signals to each of the isomers in the
cis-trans-series of III. At the same time, however, the presence of two signals for the
carbonyl group carbon atoms, of approximately equal intensity, in the spectrum of isomer Ilia
indicates that the latter (isolated isomer) consists of a mixture of the cis-syn-cis- and
cis-anti-cis-isomers in about equal ratios. The absence of double signals for the other
types of carbon atoms in the spectrum of bis(piperidone) Ilia, as well as the absence of
corresponding doubling of any of the signals in the spectra of the higher homologs lllb-e
can be explained in terms of the above-mentioned similarity of the syn- and anti-isomers,
which increases as the relative separation of the two six-membered rings increases. In these
cases one observes degeneracy of the signals for carbon atoms of one type in isomeric pairs,
and only the most proximate carbonyl groups of the syn- and anti-isomers of the lowest homo-
log llla exhibit their nonequivalence by Z~C-NMR spectroscopy.
The z3C-NMR spectrum of the product mixture resulting from the reaction of piperidone
I with diamine lla, after recrystallization from hexane, contains, in addition to the sig-
nals of isomer Ilia, a series of new signals which can be assigned to the cis-trans-isomer
of structure III. For each signal of a group of chemically equivalent carbon atoms in "com-
pound Ilia (with the exception of the C=O and N-Me groups), one detects four additional sig-
nals of lesser intensity, two of which have very similar chemical shift values to the predom-
inant isomer Ilia, and two of which have very different (chemical shift) values (see Table 3).

1014
The number of groups of chemically nonequivalent carbon atoms in the cis-trans-isomer of III
thus overlaps the number of auxiliary signals observed in the experimental spectrum (auxiliary
relative to the signals of isomer IIIa). One can further assume, that the first pair of sig-
nals corresponds to one piperidone ring having the same configuration of substituents as both
the piperidone rings of IIIa (cis- or trans-), and that the second pair of signals can be
attributed to the piperidone residue having the opposite configuration (trans- or cis-). The
mutual assignment of several signals of similar chemical shift values is simplified by the
relative intensity differences of these signals. The absolute assignment of the two weak-
field pai~s of signals (of four) to either the C(3,5) or C(2,s) atoms is not significant.
The three dimensional nonequivalence of the two piperidone rings is also supported by
the presence of two different signals for the carbonyl group carbon atoms. The signal of one
of the N--Me groups is apparently hidden under the signal due to the ring having the same con-
figuration on bis(piperidone) IIIa. The alternative signal assignment for the new signals,
i.e., to the cis- or trans-isomers of structure Q, can be ruled out, since a mixture of the
latter should lead to half the number of lines actually observed in the spectrum. For the
same reasons, assumptions concerning the presence of yet another isomer in the mixture, this
one with substituent configurations opposite that of isomer IIIa, either separately or togeth-
er with isomers of Q, can also be precluded, since they do not agree with the number of auxil-
iary signals; the assignment of the latter (auxiliary signals) to the cis-trans-isomer should
therefore be regarded as unambiguous (taking into account also the results of elemental anal-
ysis).
The chemical shift values of the carbon atoms of the piperidone rings were calculated
using the incremental values for methyl substituents [2], and the chemical shift value of l-
methyl-4-piperidone as a starting point [3]. The calculated chemical shift values for the
C(2,~) atoms of 1,2,2,3,5,6,6-heptamethyl-4-piperidone (61.7 ppm for the cis-isomer and 61.5
ppm for the trans-isomer) are very similar to the chemical shift values observed experiment-
ally in the spectrum of the cis-trans-isomer of III. The corresponding calculated values
for the chemical shifts of the C(3,5) atoms (56.9 ppm for the cis-isomer and 54.3 ppm for
the trans-isomer) were not detected in the spectrum of the trans-isomer. This demonstrates,
above all, that the chair-like conformation of the six-membered rings is partially distorted,
and to a greater extent for the trans-ring (the polysubstituted N-oxide piperidone ring which
occurs in the composition of formone derivatives also exhibits a twisted chair conformation
[4]). At the same time, one of the Z substituents of the trans-ring in the cis-trans-isomer
of III may not be purely axial, and thus may not confer the same y-gauche effect relative to
the chemical shift value of the corresponding C(s) or C(5) atom of the ring (in contrast to
3,5-dimethylpiperidine [2]). In such a case, the upfield shift of the signals due to one
pair of C(3,s) atoms in the cis-trans-isomer of III relative to the second pair of C(3,5)
atoms would not automatically mean that the first pair belongs to the ring having trans-con-
figuration. The difference in chemical shift values between the downfield pair of C(3,s)
atoms in tile cis-trans-isomer of III and the calculated chemical shift values for analogous
atoms in a ring having a cis-configuration is not large, on the order of 2-2.5 ppm, and is
even less (1.3-1.8 ppm) in the case of isomers of IIIa-e. This difference can be ascribed
to a partially twisted ring conformation, as well as to inadequate modelling of the unknown
incremental value of the alkylaminomethyl group by the known increment of a methyl group.
If one also takes into account the similarity in chemical shift values for the C(:,) carbon
atoms of isomers IIIa-e with the chemical shifts of the downfield pair of signals for the
corresponding atoms in the cis-trans-isomer of III, i.e., those with 3,5-diequatorial sub-
stituents, then the assignment of isomers IIIa-e to the cis-cis series can be made with a
higher degree of confidence.
This simplifies the cis-trans-assignment in 1,2,2,6,6-pentamethyl-3,5-dialkylaminomethyl-
4-piperidones. Since the o-methyl group signals in the PMR spectra of these compounds are
characteristic of cis- and trans-isomers ([i] and Table i), one can assume that the central
pair of methyl signals, with chemical shift differences of less than 0.25 ppm, corresponds
to the cis-configuration of 3,5-substituents, and the difference of greater than 0.5 ppm for
the pair of terminal singlets corresponds to the trans-configuration. The observed results
confirm the isomeric assignment made for similar compounds, which was concluded earlier based
on stereochemical considerations [I].
Acy!ation of the isolated mixture of cis-cis- and trans-trans-isomers of structure III
leads to a mixture of isomers of tetraamide IV, with the same ratio as in the precursor iso-
mers (based on integrated intensities of the gem-dimethyl group signals in their PMR spectra).

1015
 A~
H H I Ac
I

/ A~ . 0 ' ,I
-.~ r-~---cJ O---~- N-- ~ --p~ ~,~ O~ N--

H lr I A~-

The conversion of the amino functional groups to amide linkages removes the problem
associated with the characteristic chemical shift values of the proton signals due to the ~-
methyl groups in rings having the cis- and trans-configuration. Simultaneous shielding of
one pair of methyl groups and deshielding of the other pair of methyl groups in the cis-piper-
idinyl residue (A~ = 0.66 ppm) is the same as in the trans-substituted ring (A6 = 0.73 ppm).

EXPERIMENTAL
PMR spectra were recorded on a Varian T-60 spectrometer (in CDCI3 versus HMDS); 1 3 C - N ~
spectra were obtained on a Bruker WH-250 spectrometer (in CDCI3 versus TMS). IR spectra were
obtained on a Perkin-Elmer 580B spectrophotometer using Vaseline mulls, and mass spectra were
taken on a Finnigan 4201 spectrometer (chemical ionization with NHa or iso-BuH, 0.4 torr,
i00 eV, rate of sample heating 100~
,,2,2,2,2,6,6,6,6-Decamethy-cis-cis-3,3,5,5-di(methyaminakyaminmethy)-
4,4'-bis(piperidones) (Ilia-e). To 500 ml of benzene was added simultaneously over 15 h a
solution of i0 mmole of dimethylketone I in 50 ml benzene and a solution of i0 mmole of
diamine lla-e in 50 ml of alcohol; the mixture was then allowed to stand for 12 h. The resi-
due after evaporation was treated with i0 ml of cyclohexane for i0 days at 20~ and the un-
dissolved portion (bispiperidones Ilia-e) were removed by filtration. Recrystallization of
the residue from hexane after evaporation of the reaction mixture resulted in a mixture of
the cis-cis- and cis-trans-isomers of structure llla.
~,~,2,2,2~,2~,6,6,6~,6~-Decamethy~-3,3~,5,5~-di[N,N-diacety~(m-ethy~amin~ethy~amin~-
methyi)]-4,4'-bis(piperidone) (mixture of cis-cis and cis-trans-isomers) (IV). A mixture of
the cis-cis isomer Ilia and the corresponding cis-trans-isomer'(10 mmole~ was allowed to
stand in excess Ac20 for 4-5 days; after evaporation an aqueous NaOH solution (pH i0-ii) was
added, and the mixture was extracted with chloroform (3 15 ml) and then dried over CaCIa.
The mixture was subjected to chromatography on neutral A1203 (activity II) (Pharmacia SR 25/
45 column, supported in chloroform, eluted with chloroform); the fractions corresponding to
absorption peaks at 260 nm were then evaporated to give 8 mmole of the tetraamide IV (80%
yield).

LITERATURE CITED
1, A. M. Belostotskii and A. B. Shapiro, Khim. Geterotsikl. Soedin., No. 7, 937 (1984).
2. E. F. Eliel and K. M. Pitrusiewicz, Topics in Carbon-13 NMR Spectroscopy, Vol. 3 (1979),
p. 171.
, A. J. Jones and M. M. A. Hassan, J. Org. Chem., 37, 2332 (1972).
4. A. B. Shapiro and V. I. Suskina, Izv. Akad. Nauk SSSR, Ser. Khim., No. 2, 414 (1985).

1016
IhWESTIGATION OF SS~STITUTED 1,3-OXAZOLIDINES
USING :H AND :~C NMR SPECTROSCOPY

F. A. Alimirzoev, V. P. Lezina, and A. U. Stepanyants UDC 547.787:543.422.25:

541.65

The characteristics of the :H and ~SC NMR spectra of 1,3-oxazoiidines with sub-
stituents in the 2-, 3-, and 5-positions have been studied. The relation of
the spectral characteristics to the structure and configuration of the compounds
has been examined, and information on the transmission of the substituent effect
through the atoms of nitrogen and oxygen has been obtained.

i, 3-Oxazolidines, nitrogen-containing analogs of f ive-membered cyclic acetals, which are

widely used in organic synthesis, form part of the structure of biologically active and medicinal
compounds, and serve as convenient models for studying complex natural products containing
the 1,3-oxazolidine fragment. Information about the structure and physicochemical properties
of these compounds can also be used to determine the effect of their structural features on
biological activity.
At the present time, there is fairly detailed coverage of the structure and analysis of
the spectral characteristics of 1,3-dioxanes [i, 2], 1,3-dioxacyclanes and their sulfur-con-
taining analogs [3-5], while data concerning 1,3-oxazolidines is extremely sparse [6]. It
was therefore of interest to examine the ~MR spectra of 1,3-oxazolidines with a wide range
of substituents in order to obtain information about their structure and the transmission of
the substituent effect through the nitrogen and oxygen atoms, and also to determine and clas-
sify their spectral characteristics.
In the present work the ~H and :SC N21R spectra of 23 1,3-oxazolidines with subscituents
at the 2-, 3-, and 5-positions of the ring have been analyzed:
R=

O~ 2 5N~
R ~ ~R= R

|-XAUII

1. I--VI R=C6Hs, RI=R3=H, I R2=H, II R2=CH(CH3)e, III R~=C6Hs, IV Re=

=p-(CH3)2NC6H4. V R'~=p-CH3OC6H4, VI R~ 2. VII--XII R=C~HT,
I~3=H, VII RI=R2=H, VIII I~I=H, R2=C2Hs, IX R~=H, R'~=CH(CH3)2, X R~=H,
R~=C6Hs. XI PJ=R~-=cycIo-iCH~)4, XII W='R2=cyclo-(CH2)5~ 3, XIII--XVII R=i-C4H.~,
Rt=R3=H, XIII R~=H. XIV R2=CH3, XV R2=CzH6, XVI R2=CH(CH~)_~, XVII 17~=C6H5;
4. XVIII, XIX R=cb'clo-C6Hil, RI=R3=H, XVIII R:=H, XIX R2=CH(CH3).~: 5. XX
R=C2Hs, RI=R~=R~=H; 6. XXI--XXt!I R=C6H~, I~!=H, R3=CH3, XXI R2=H, XXIIa, b
R2=C~Hs, XXIIIa, b R~=CH(CH~)~

Identification of the signals and the characteristics of the :H and ~SC NMR spectra,
obtained experimentally and with the help of computer analysis, are given in Tables 1-5 and
on Figs. 1 and 2. The type of multiplicity of the methylene protons at the 4- and 5-positions
(A2B2 system) in compounds I, VII, XIII, and XX (Tables i and 2) indicates that these com-
pounds undergo a rapid pseudorotation. Verification of assignment of the signals from the
5-CH2 and 4-CHz groups can be provided by the spectrum of compound XXI, in which the protons
at C(~) and C(s) give a sharp spectrum of type AMX, which lays the foundation for an unequivo-
cal determination of the distinctive region of their chemical shifts.
Introduction of an alkyl or aryl substituent into the 2-position leads to a nonequiva-
fence of the methylene protons of the ring, the spectrum of which comprises an ABCD spin
system in the region 2.8-4.0 ppm. Analysis of this system was carried out by studying the
spectra recorded at high frequencies with the inclusion of computer analysis and double

Institute of Chemical Physics, Academy of Sciences of the USSR, Moscow 117977. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1255-1260, September, 1986.
Original article submitted April 23, 1985.

0009-3122/86/2209-1017512.50 9 1987 Plenum Publishing Corporation 1017

 He, /HA
a Ho't--lt~
O ..,.,...t',~-P~
'Fh I

All/ ,lT %
,

,v lij
,,%,J "' ~"
!i

' !~[.-J'bL,.

J ' < L ...... Fig. i. Experimental and theoretical ~H

NMR spectra of 2,3-diphenyl-l,3-oxazoli-
c H~IHc H~ H,4 dine: a) at i00 MHz; b) at 294 MHz; c)
calculated for a four-spin system ABCD
on BESM-22.

3,95 3,89 3,54 333

8, ppm

resonance experiments (Fig. ib, 2a, Tables i-3). A complete interpretation of the spectra
of oxazolidines I-XXIII makes it possible to assess the transmission of the substituent
effect through the nitrogen and oxygen atoms.
Analysis of the data in Tables I and 2 shows that introduction of a substituent into
the 2-position leads to a considerably greater displacement downfield of the signals from
the protons at C ( ~ ) than for those at C(5); in other words, the transmission of the substit-
uent effect through the nitrogen atom is stronger than through the oxygen atom and is vir-
tually independent of the nature of the substituent in the series of compounds investigated.
The nature of the substituent on the C(2) carbon atom has virtually no effect on the position
of the signals from the protons of the N-phenyl ring.
As was to be expected [7], the methyl protons of compound II are magnetically nonequiva-
lent (AS = 1.17 ppm), which is due to the asymmetry of the C(2) atom, in other words, to the
presence of a chiral center at the B-position.

TABLE i. Characteristics of IH NMR Spectra of N-Phenyl-l,3-

oxazolidines Found Experimentally (recorded at 294 MHz) and
Theoretically by Computer Calculation of a Four-Spin System
of Type ABCD (in brackets)
.~ Chemical shifts of ring pro- Chemical
== tons. 6, ppm shifts of sub- Absolute values of spin-spin
stitue~ntpro-! couplingconssntsof ringprotons,
~
-- ~-H , 4-H I 5-H tons. o. ppm I rtz
~ A--H B--H C--H D--H R~ 2lAB ~TAC 3TAD a]BC 3$BD ~/CD
I 4,58 3.08 3,08 3,85 3,85 6,25,
7,02,
6,56
II 4(81 3,23 3,35 3,'75 3.93 6,38, 2,05, 8,18 7,15 5,9'2 3.27 7,77 8.36
3,301 3,45 3,86: 4,01 7,15, 0,58, (8,161 (7,141 (5,92] (3,26) (7,75~ (8.36)
6,68 0,76
III 5,69 3,23 3,45 3.78 3,83 6,32, 7,22 8,18 6,53 6,51 5.51i 7,16 8,38
3,37' 3,54 3,89 3,95 6,89, (7,99) (6,53) (6,531 (5,55)! (7,14) (8,36)
6,55
IV 5,64 3,22 3,48 3,73 3,7a 6,35, 6,5, 7,96 6,51 6,51 5,531 7,14 8.36
3,34' 3,52 3,86 3.91 7,0 7,11 (7,97) (6,53) (6,53] (5,55) (7,14), (8,36)
6,57 ,2,8
V 5,67 326 3,46 3,81 3,85 6,31, 6,71, 3,16 7,16 5,90 3,27 I 7.73 8,36
3,32} 3,51' 3,87 3,94 6,99, 7,21 (8,t61 (7,14) (5,92) (3,26) I(7,75): (8,26)
~.55 3,55
VI 5,42 3.27 3,43 3,78 3.82 6,30, 7,38- 8,t7 7,15 5,95 3,28 7,75 8,36
3,33~ 3,53 3,89 3 93 6,97, 7,74 (3,t6) (7,14) (5,921 (3,26) (7,74) (8,36)
6,58

1018
 ~r .H,~ H' . ,
" H,~/C~H~_ CH _CH' .
u'-x~'~ ~-.C' - CH2 CH~
H" "cFj-,:.; . .--. ~;
," ,*, H. -~5)~ ? ~,'*t, " ]

i 2 2 ~:;pprn
q:,, CCL.;

ill i!t!, ...........

JJU ..._%,did'3
,I,!1
: L,,I.1,
,~i"i
!, b
I
, ! :t
90 80 ?0 50 56 ~9 29 20 X 0

Fig. 2. Assignment of signals in the NMR spec-

tra of 2-ethyl-3-n-butyl-l,3-oxazolidine: a)
ZH N-MR spectrum at 360 MHz; b) ~3C NMR spectra
with complete and partial decoupling from protons
at 90.55 MHz.

TABLE 2. ZH NMR Chemical Shifts of Substituted 1,3-Oxazoli-

dines
Ring protons, 6, ppm Substimenm, 5~ l ~ m
COITI- 4-H 5-H
pound I 2-H R2

A--H B--H C--H D--H

VII 4,16 2,84 2,84 3 , 6 7 3,67 0,88, 1,45, 2,41

VIII 3'92 2,48 3.2 3,82 3,82 0,89, 1,49, 2,21, 2,53 0,89, t,42, 1,54
IX 3,72 2,46 3109 3,68 3,72 0,87, 1,44, 2,22, 2,46 0,82, 0,86, 1,59
X 4,72 2,54 3123 3,9 3,93 0,83, 1,43. 1,48, 2,19, 7,23, 7,29, 7,38
2,4 I
Xl 2,8 2,8 3,71 3,7t 0,84, 1,30, 2,3t 1,3--1,8
XII 2,8 2,8 3,7 3,7 0,83, 1,32, 2,3 1,2--i ,75
XIIt 4,05 2,75 2,75 3,58 3,58 0,87, 1,57, 2,18
XIV 3,92 2,55 3,14 3,83 3,88 0,85, 0,88, 1,63, 2,03, I,I4
2,18
XV 3,85 2,4 3,11 3,74 3,74 0,85, 0,88, 1.63, 2,06, 0,86, 1,39, 1,51
2,18
XVI 4,87 2,36 3,04 3 , 6 3 3,68 0,83, 0,88, 1,59, 2,05, 0,80, 0.85, 1,18
2,18
XVII 4,68 2,44 3,13 3,81 3,88 0,84, 0,87, 1,58, 2,04, 7,0S. 7.14. 7,29
2,1
XVIII 4,16 2,78 2,78 3,74 3,74 1,0--2,0
XIX 4.06 2,84 2.94 3157 3,62 1,0--2,0 0,77, 0,84, 2,32
XX 4,04 2,73 2.73 3,54 3,54 0,98, 2,43

Analysis of the characteristics of the spectra in the series of 1,3-oxazolidines with

different substituents on the nitrogen atom shows that in comparison with compound XX the
signals from the methylene protons of compounds I, VII, XIII, and XVIII are shifted to lower
field, while the magnitude of change in chemical shift is virtually identical for the 4-H
and 5-H protons and increases in the series of compounds indicated. We should mention that
the signal from the 2-H proton, whose downfield shift increases in the series i-C~Hg, C3H7,
cyclo-C~Hzz, C~H5 (XIII, VII, XVilI, I), is very sensitive to the nature of the substituent
on the nitrogen atom.

1019
 TABLE 3. Spin-Spin Coupling Constants
of Ring Protons of Substituted 1,3-Oxa-
zolidines J, Hz
Com-
pound ~]AB a/AC ~]BC ] a]BD ' 2..rCD

VIII g,5 6,o 6,0 7,4

IX 9,9 7,0 7,2 5,1 I 6,0
6,0 7,2 7,5
X 9,0 7,2 7,3 3,6 .7,2 7,8
XtV 9,2 7,0 7,0 4,0 7,0. 7,-8
XV 9,5 7,0 7,0 5,0 6,5 8,0
XVI 9,0 6,5 7,2 4,5 5,4 8,0
XVII 9,0 7,1 7,4 3,6 7,2 7,8

TABLE 4. *~C NMR Chemical Shifts of Substituted 1,3-Oxazoli-

dines
Ring carbon atoms,
Com- 6. ppm Substituent~, 6, ppm
pound
c,,=, I C., I c(5, j Rs R', R~

! 143,67, 110,43, 127,12,

115,24
II 144,36, 111,27, 127,04, 29,43, 13,43, 16,3
115,27
III 144,39, 111,44, 127,36, 138.46, 126,55, 125,62,
116,1 126.55
IV 143,83, 110,05, 126,74, 148.72, 125,96, 111,05,
115,25 125,96
V 143,9, t11,06, 126,9, 147,4, 126,28. 111.76,
115.41 130,16, 52,66
VI 143.67, 111.27, 127.21, }43.67, 130,0l, 127,21.
116,42 126,67, 122,63
VII 54,27. 20,68, 9.8
VIII 53,44, 20,59, 9,86 24,94, 6.57
IX 54,5, 20,86, 9,9 29.99, 14,27, I6.95
X 52,38, 20,24, 9.75 138.53, 126,18, 125,78,
125,78
XI 47,32, 20,78, 9,9
XII 47,95, 20,95, 9,8 30,95, 21,53, 24,11
XItI 6t,74, 26,96, 19,1
XIV 59,62, 26,1. 18.36, 19,1 18.01
XV 60,09, 26,27, 18,64, 19,1 24,96, 6.51
XVI 61.5, 26,45, 18,79, 19.34 29.97, 17.16, 14,05
XVII 58,62, 26,1, 18,64, 19,18 139,46, 127,03, 126,65,
125.65
XVIII 58,94, 30,54, 23,07, 24,54
XIX 59,1. 31,06, 24,05, 24,62 28,62, 17,17, I5,14
XX 50,25, 12,58
XXI 143,71, 127,1I, 110,22, 16,7
115,24
XXIIa 145.15, 128.22, 116,02, 16,85 24,4, I0,21
i 11 ! ,44
XXIIb 146.05, 128,22, 116,t8, [6,33 24,65, 6,62
112,06
XXlIIa 145,15, 128,22, 116,41. [6,31 28,19. i6,0, 12,5
I12,13
XXIIlb 146,05, 128,22, 115,95, [6,78 30,6, 17,52, 13,9
t13,t3

The isopropyl group in compounds II, XVl, and XlX, and the aryl groups in oxazolidines
III, VI, and XVll give rise to a shift of the signal from the 2-H proton downfield, this
effect being most clearly marked in the case of the ortho-nitrophenyl substituent (Vl), for
which, by analogy with 1,3-dioxanes [6], the formation of an intramolecular hydrogen bond
is to be expected.
Comparison of the carbon spectra of compounds I-VI (Table 4) shows that the type of sub-
stituent on the C(a) carbon atom has a considerable influence on the magnitudes of the chemi-
cal shifts of t3 C nuclei in the oxazolidine ring and has no effect on the position of t3C
signals from the substituents on the nitrogen atom. For oxazolidines II, IX, and XVI, a mag-
netic nonequivalence of the carbon nuclei in the isopropyl group is displayed (A6 = 2.03-3.11
ppm), resulting from the chirality of C(2),

1020
 TABLE 5. Characteristics of :H NMR Spectra of 5-Methyl-N-
phenyl-l,3-oxazolidines
Chemical sl2ifts Chemical shifts of sub- Spin-spin coupling Spin-spin coup lin
ot protons, o, stituents, 6, ppm constants o~ nng constants oi SUD-
~ .pprn )rotons, J, Hz stituents, J, Hz
X--H Rz a/3/X lf4"CH~ groups
D
xxi 3,3 4.1811,27 6,28, 7,05, 8,0 7,5 6,0 6,0 10,2, 6,0
, 6,59
3,92 11,29 7,13, 6,65, 1,79, 0,99 8,2 9,02 5,74 5,74 7,79 7,5
6,43 2,0'
4,33 11.26 7,1, 6,62, 1,66, 0,91 8,61 7,79 6,15 ~,15 7,0, 5,33,
6,4 1,85
3,94 1t,27 6,49, 7,t3, 2.24, 1,03, 8,2 9,02 5,74 5,74 6,0, 2,05
6,64 0.88
4,3511,2 2,12, 1,02, 2,12, 1.02. 8,61 7,79 6,15 6,15 6,5, 3,28
6,59 0.77

Compounds XXIIa, b and XXIIIa, b (Tables 4 and 5) are mixtures of diastereomers. The
signals from the cis- and trans-forms have been identified from their spectra and their per-
centage composition in the mixtures was determined. Determination of configuration from the
~H NMR spectra was carried out on the basis of examining the difference in chemical shifts
of the ring protons of the two isomers and studying the values of the geminal and vicinal
spin-spin coupling constants with application of the criteria given in [8]. In this work,
it was shown that spin-spin coupling constants of geminal protons at C(~) for trans-isomers
of substituted 1,3-oxathiolanes are slightly greater than those for cis-isomers (typical
values are about 10.2 Hz and 9.8 Hz), whereas the vicinal constant of cis-isomers is consid-
erably greater than that for trans-isomers (i0.0 Hz and 6.0 Hz, respectively).
In our case, examination of the data in Table 5 shows that using these criteria the
cis-configuration should be assigned to compounds XXIIa and XXIIIa, and the trans-configura-
tion to compounds XXIIb and XXIIIb. The fact that in accordance with the data of [8] all
signals from the ring protons of the cis-isomer are displaced to higher field in comparison
with the signals from the trans-isomer serves as an additional criterion for such an assign-
ment. On the basis of the identification carried out and examination of the integral inten-
sities of the signals in the spectrum, it was shown that the ratio of cis- to trans-isomers
for both pairs of compounds was 55:45, which was used as a basis for identifying the lines
of the cis- and trans-isomers in the ~3C NMR spectra of compounds XXIIa, b and XXIIIa, b
(Table 4).
Analysis of the characteristics displayed in the :3C NMR spectra shows that the chemi-
cal shift of the signal from the methyl carbon at C(5) hardly varies for the cis- and trans-
isomers, whereas the chemical shifts of C(2) and the substituent carbon atoms of the cis-iso-
mer correspond to considerably lower field values. The chemical shifts of the carbons of
the N-phenyl substituent for both isomers are alike, which suggests the same orientation of
the lone pair. Thus, the values of the chemical shifts of C(=) and the carbon atoms of the
substituent at the 2-position can be used to identify the cis- and trans-isomers from the
:3C NMR spectra.

EXPERIMENTAL
XH NMR spectra were recorded at frequencies of i00, 294, and 360 MHz (Varian HA-IO0,
OIKhF, and Bruker WH-360 spectrometers); X~C NMR spectra were recorded at 25.15 and 90.55
MHz (Jeol PFT-100 and Bruker WH-360). For interpretation of complex multiplets in the ~H
NMR spectra, double proton-proton resonance was used. The series of ~3C NMR spectra was
recorded under conditions of partial proton decoupling (Fig. 2b). The samples comprised
10-15% solutions in CCI~. The internal standard was HMDS (A6HMDS-TMS is 0.05 ppm for :H
and 1.94 ppm for :3C).
Calculation of the four-spin proton system of the oxazolidine ring was carried out at
the Branch of the Institute of Chemical Physics, Academy of Sciences of the USSR on a BESM-
22 computer using a program developed for analysis of complex high-resolution NrMR spectra
[9].

1021
 The authors are sincerely grateful to G. V. Lagodzinskaya, ~. B. Fel'dman, and N. F.
Sepetov for their assistance in the work, and to S. S. Zlotskii and V. V. Zorin for making
available research items and for useful discussions.

LITERATURE CITED
i. D. Taverier and M. Anteunis, Tetrahedron, 27, 1677 (1971).
2. V . P . Lezina, A. U. Stepanyants, F. A. Alimirzoev, S. S. Zlotskii, and D. L. Rakhmanku-
lov, Izv. Akad. Nauk SSSR, Ser. Khim., No. 4, 792 (1976).
3. M. Goodman and F. Morehouse, Organic Molecules in Action, Gordon (1973).
4. E. Eliel, Angew. Chem., 24, 779 (1972).
5. M. Anteunis, Heterocycles, ~, 293 (1976).
6. F . A . Alimirzoev, A. A. Lapshova, V. V. Zorin, A. U. Stepanyants, V. P. Lezina, F. N.
Latypova, S, S. Zlotskii, and D. L. Rakhmankulov, Zh. Prikl. Khim., No. 4, 911 (1980).
7. M. Van Gorcom and G. E. Hall, Quart. Rev., 22, 14 (1968).
8. R. Keskinen, A. Nikkila, and K. Pihlaja, Tetrahedron, 28, 3943 (1972).
9. G . V . Lagodzinskaya and A. A. Fomichev, Zh. Strukt. Khim., 8, 695 (1967).

SYNTHESIS AN~ SPECTRAL AND LUMINESCENT PROPERTIES

OF 4-(5-ARYLOXAZOYL-2)BENZOIC ACIDS AND THEIR DERIVATIVES

B. M. Krasovitskii, V. M. Shershukov, and V. L. Volkov UDC 547.787.2.07'584'572:

535.37:541.651

Condensation of acid chloride of monomethyl terephtalate with w-aminomethyl-

arylketones and subsequent cyclodehydration of the resulting amides in sulfuric
acid or phosphorus oxychloride give rise to methyl 4-(5-aryloxazolyl-2)benzoates
which led to the corresponding acids, acid chlorides, and amides. The effect
of electron-withdrawing groups on the spectral and luminescent properties, as
well as on the stability of substituted 2,5-diaryloxazoles toward UV irradiation
has been investigated.

As a continuation of our studies [i-3], we have investigated the effect of structural

transformations related to the replacement of the hydrogen atom in the aldehyde group by a
hydroxyl, methoxyl, or amino group, or a chlorine atom on the spectral and luminescent proper-
ties of substituted 2,5-diaryloxazoles. From acid chloride of monomethyl terephthalate [4]
and m-aminomethylarylketones, we obtained in the Robinson--Gabriel reaction methyl 4-(5-ary!-
oxazolyl-2)benzoates (II), and then by their hydrolysis, the corresponding carboxylic acids
(I). From the latter, we obtained their acid chlorides (III) and amides (IV) (Table i).
__~
CH~90C COCI
~-co-c.~N~
" ~ ~ --CO-CH~N~=O
~ -- CG3CH
3
_
_Hz~

na-g la-g

~.~ }.--CGC1 > '/ "}>-'- CONH2

lli a - c , e - g Ira-c, e-g

I--IV a Ar=C~Hs; b Ar=4-CH3--C4H4; c Ar=4-CHaO--C6H~; d Ar=4-(CH~)=N--C~H~;
e Ar=4-C1--C~H4; f Ar=4-C6H~--C6H4; g Ar=I--CIoH7

Scientific-Industrial Association "Monokristallreaktiv" ("Single Crystal Reagent"),

Khar'kov 310141. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1261-
1264, September, 1986. Original article submitted May 27, 1985.

1022 0009-3122/86/2209-1022512.50 O 1987 Plenum Publishing Corporation

 TABLE i. Physicochemical Properties of Com-
pounds I-IV

C Ol TI- Found 9Empiricalfor- ICalc. Yield,

pound Mp, ~C N,%
mula " l N, % %

247--248 5,2 CI6HnNO3 5,3 93

Ib 257--258 5,2 CITHI3NO3 5,0 80
I.c 259--260 4,9 CITHI3NO~ 4,8 81
ld 222--223 8,8 CIsHi6N~O3 9,1 70
Ie 269--270 4,8 CI6HIoCINO3 4,7 71
Lf 301--302 4,2 C~2H~sNO3 4,1 78
tg 239--240 4.6 C~oHIaNO3 4,4 89
IIa I70--17t 5,2 ClrHlaNO3 5,0 83
limb t54--155 5,0 C18HIsNO3 4,8 92
155--156 4,7 CIsHIsNO4 4,5 89
118--119 8,5 CIQHIsN203 8,7 47
I I,e 193--194 4,6 CIvHI2C1NO3 4,5 96
IIf 210--211 4,1 CnH17NOa 4.2 92
IIg 117--118 4,4 C21HlsNOa 4.5 95
IIla 156--157 5,0 CI6HmC1NO~ 4,9 96
IVb 226--227 0,8 Cj~HI2N202 10,6 95
IVc 252--253 0,2 CITHI4N20~ lO, I I 96
IVd 234--235 9,7 CIrH14N203 9;5 7_o
IV.e 250--251 4,8 CI~HuCIN~O~ 4,7 95
IVf 284--285 8,5 C~Hi~N~O~ 8,2 70
IVg 231--232 9,1 8,9 80

TABLE 2. Spectral and Luminescent Characteristics of Compounds

I-V in Toluene
Absorption Luminescence Absorption __Lum'inesc ence
Com-
pound ;rax
a ' nrl3 ~ . 1,)-' ;ma~, nm n >max ~ e 9 I0 ~ ?-max ' n r r l rl

[a 335 4,75 400 0,58 IIe 338 2,85 400 0,54

lb 341 2,27 405 0,52 llf 347 3,27 410 (~,47
Ic 347 420 0,52 lIg 339 1.90 425 0143
ld 355 1.78 465 0,26 " I l i a 354 2,25 430 0,54
le 338 2,60 400 0,48 IVa 327 3,33 395 0,55
If 348 _. 415 0,45 IVb 334 2,25 400 0,46
Ig 340 t .90 425 0,40 IVc 345 2,24 415 0,50
Ila 335 3,15 395 0,56 IVe 333 2,85 395 0,51
II,b 340 2,59 405 0,52 IVf 344 410 0,43
IIc 347 2,30 415 0,47 336 2,04 415 0,40
Ild 353 1,29 460 0,23 346 2,50 405
Weak
lighting
*Poorly soluble.

Contrary to the formyl-substituted 2,5-diary!oxazoles, compounds I-IV manifest in toluene

quite intensive luminescence. They emit light in the region of 400-460 nm with the quantum
yield (n) varying in the range of 0.2-0.6 (Table 2). Such an effect is attributed to the
mesomeric effect of substituents having lone electron pairs on the distribution of the elec-
tron density in the CO group, due to which the energy of the n ~ ~* transition increases to
a greater degree than that of the ~ z* transition, and the probability of the radiationless
losses of electron density decreases.
Replacement of the hydrogen atom in the aldehyde group by the hydroxyl (compound Ia),
methoxyl (IIa), or amino group (IVa) results in the hypsochromic shift (11-19 nm) of the
long-wave band in the absorption spectra. This effect is the most significant in the case
of the amino group which decreases the electron-withdrawing properties of the carbonyl group
in these compounds to a greater extent than in the case of the corresponding aldehyde V.
A more complicated relationship was observed in the absorption and luminescence spectra
of the acid chlorides, due to the dual character of the halogen inducing both the mesomeric
and inductive effects. The absorption and luminescence maxima of IIIa are shifted in the
bathochromic and bathofluoric fashion with respect to the spectrum of the analogous compound
with the aldehyde group (V). In spite of a strong inductive effect of the halogen, the in-
tensity of luminescence in toluene is not weaker than that of the acid, ester, and amide.

1023
This indicates the importance of the inductive and mesomeric effects of the substituent
linked to the carbonyl group in the formation of the spectral and luminescent properties of
2,5-diaryloxazoles.
Introduction of electron-releasing suhstituents, interacting with the CO group through
the system of conjugated bonds, into the 5-phenyl radical of compounds I, II, and IV, leads,
similarly as in the case of aldehydes, to long-wave shifts of absorption and luminescence
bands. The methyl group (Ib, lib, IVb) causes small bathochromic and bathofluoric effects,
considerably increasing under the influence of stronger electron-releasing substituents, the
methoxy and dimethylamino groups (Ic, llc, IVc, Id, lld). The increase of the Stockes shift
in the compounds having the dimethylamino group (Id, lid) up to 6700 cm-I is, presumably,
due to the flattening of their molecules during the transition to the excited state.
The chlorosubstituted compounds (le, lie, IVe) are not different from the unsubstituted
compounds with respect to the position of the absorption and luminescence maxima; however,
their absorption spectra have the structured character. An analogous phenomenon has also
been observed in the case of the corresponding formyl-substituted 2,5-diaryloxazoles [3].
The complication of the structure of the 5-aryl fragment of compounds I, II, and IV dur-
ing replacement of the phenyl radical by the 4-biphenyl (If, llf, IVf) or by the l-naphthyl
radical is accompanied by a shift of the absorption and luminescence spectra toward longer
wave lengths. It is interesting to note that the absorption maxima of compounds with the
l-naphthyl radical are shifted hypsochromically as compared with the compounds containing
the 4-biphenylyl moiety, while in the luminescence spectra the opposite relationship takes
place. We have observed analogous effects during investigation of other substituted 2,5-
diaryloxazoles with the l-naphthyl radical, and these effects have been explained by the
nonplanar structure of molecules of these compounds in the ground state and their planariza-
tion during the transition to the excited state.
Taking into consideration the photostabilizing influence of electron-withdrawing substit-
uents in the series of 2,5-diaryloxazoles, we investigated the stability of solutions of
compounds la (J* 66%), lla (J* 52%), IVa (J* 28%), and for comparison of 2,5-diphenyioxazole
(J* 25%), in dioxane toward the unfiltrated UV irradiation. The photostabi!ity was charac-
terized by the change in the luminescence intensity of the samples at the maximum of radia-
tion (J*) with respect to the luminescence intensity of unradiated samples at the maximum of
radiation, which was assumed to be 100%.
The effect of the carboxyl, carbomethoxy, and carbamide groups on the stability of 2,5-
diaryloxazoles toward UV irradiation is the more pronounced, the stronger electron-withdraw-
ing properties of the introduced substituent.

EXPERIMENTAL
The absorption spectra of the toluene solutions were measured on aHitachi-330 spectrom-
eter (c 1.10 -4 M); the luminescence spectra were taken on a system consisting of a ZMR-3
monochromator, F~U-18, and an M-95 microammeter. The photoluminescence was induced by a
SVDSh-500 lamp, from the spectrum of which light with the wavelength of 365 nm was isolated
using a DMR-4 monochromator. The absolute luminescence quantum yields were determined by
the equal absorption method [5]. The photostabillty was characterized by the change in the
fluorescence intensity of dioxane solutions of luminophores (c 1"10-3 M, layer thickness
2 cm) at the radiation maximum with respect to the fluorescence intensity of unradiated sam-
ples during radiating them with unfiltered light of mercury-quartz PRK-2 lamp. The power of
the lamp was 375 watt, the distance between the lamp and the sample was equal to 12 cm, the
temperature of the radiated field was 26~ the radiation time -- 6h, and the illumination of
the field was 25,000 ix.
2-(4-Carbomethoxyphenyl)-5-aryloxazoles (lla-g). To a mixture of solutions of equimolar
quantities of i mmole of acid chloride of monomethyl terephthalate [4] in 150 ml of benzene
and m-aminomethylarylketone hydrochloride in 400 ml of water was added with intensive stir-
ring at 25~ a 10% solution of sodium carbonate until litmus paper showed the basic reaction,
The mixture was stirred for i h, the precipitated amide was filtered off, washed with water,
and dried. The cyclization of the amide during preparation of compounds lla, b, e was car-
ried out in a 10-fold (by weight) amount of concentrated H2SO~. A dark-brown solution was
kept at 25~ for 2 h and poured on i kg of ice. The precipitate was filtered off, washed
with 500 ml of water, and dried. During synthesis of compounds llc, d, f, g the amide was
boiled for 2 h in a four-fold (by weight) amount of POCI3. The obtained solution was poured

1024
in small portions on 1 kg of ice. The precipitate was filtered, washed with 500 ml of water,
and dried. The purification was carried out by chromatography of their heptane solution on
Silochrome S-120 in a continuous action column.
2-(4-Carboxyphenyl)-5-aryloxazoles (Ia-g). To a refluxed suspension of a 1 mmole of 2-
(4-carbomethoxyphenyl)-5-aryloxazole in a 15-fo!d (by weight) amount of ethanol (during pre-
paration of Ia, c, d) or acetone (during synthesis of Ib, e-g) was added in 15 min 2 mmole
of sodium hydroxide in 50 ml of water. The mixture was refluxed for additional 3 h and poured
in 2 liters of water (for compound If -- in 4 liters), then it was heated to boiling and fil-
tered when still hot. After cooling to 20~ the solution was acidified with hydrochloric
acid (for compound Id -- with acetic acid) to pH 6. The precipitate was filtered off, washed
with 500 ml of water and dried. Purification of compounds was carried out by chromatography
of their benzene solutions on Silochrome S-120 in a continuous action column.
Acid Chloride of 2-(4-Carboxyphenyl)-5-phenyloxazole (IIIa). A sample of 1 mmole of 2-
(4-carboxyphenyl)-5-phenyloxazole in l O 0 m l o f thionyl chloride was boiled for 2 h. Excess of the
thionyl chloride was evaporated under vacuum of a water aspirator. The compound was purified by re-
crystallization from benzene with addition of charcoal. Acid chlorides IIb, c, e-gwere obtainec
analogously.
2-(4-Carbamidophenyl)-5-aryioxazoles (IVa-c, e-g). To a solution of 1 mmole of acid
chloride of 2-(4-carboxyphenyl)-5-aryloxazole in 200 ml of benzene was added at 20~ 150 ml
of 10% aqueous solution of ammonia with vigorous stirring. The precipitate was filtered
off, washed with water, and dried. The compounds were purified by chromatography of their
benzene solutions on Silochrome S-120 in a continuous action column.

LITERATURE CITED
I. B. M. Krasovitskii and V. M. Shershukov, Khim. Geterotsik!. Soedin., No. I, 35 (1979).
2. B. M. Krasovitskii, V. M. Shershukov, and L. M. Yagupol'skii, Khim. Geterotsikl. Soedin.,
No. 8, 1042 (1982).
. V. L. Volkov, B. M. Krasovitskii, and V. M. Shershukov, Physics and Chemistry of Opti-
cal and Scintillation Materials [in Russian], Vol. 14, Scientific-Research Institute
of Mort,crystals, Kharkov (1985), p. 131.
. B. M. Krasovitskii, V. L. Volkov, V. M. Shershukov, and S. A. Berezubova, Physics and
Chemistry of Monocrystals and Scintillators [in Russian], Vol. 7, Scientific-Research
Institute of Monocrystals, Kharkov (1981), p. 184.
. A. S. Cherkasov, Zh. Fiz. Khim., 29, 2209 (1955).

1025
 2-(4-CYANOPHENYL)-5-ARYLOXAZOLES

B. M. Krasovitskii, V. M. Shershukov, and V. L. Volkov UDC 547.787.2:535.37

2-(4-Cyanophenyl)-5-aryloxazoles have been obtained by dyhydration of 4-(5-

aryloxazolyl-2)benzamides with thionyl chloride in DMF$, then the spectral and
luminescent properties of the former have been investigated. Introduction of
the cyano group into the 2-phenyl radical of 2,5-diphenyloxazole leads to
significant bathochromic and bathofluoric effects.

The bathochromic and bathofluoric effects, in several cases an enhancement of the quan-
tum yield of luminescence, and the resistance of 2,5-diaryloxazoles toward UV irradiation
during introduction of electron-withdrawing substituents in their aromatic rings [i, 2] are
the factors which set the basis for synthesis of 2-(4-cyanophenyl)-5-aryloxazoles (I) (Table
I) and studies on application thereof as organic luminophores.
The previously synthesized amides of the corresponding 4-(5-aryloxazolyl-2)benzoic
acids [3] served as the intermediates in preparation of I by reaction with thionyl chloride
in DMFA.
Introduction of the cyano group in the para-position of the 2-phenyl radical in 2,5-
diphenyloxazole (lla) leads to significant bathochromic and bathofluoric effects. All the
synthesized compounds intensively radiate light in toluene solutions in the blue-green re-
gion of the spectrum with the quantum yield (n) of 0.45-0,60 (Table 2).

Li /' ,

I1 a= g I,a- f

I a Ar=C6H~, b Ar=4-CH3--C6H,, c Ar=4-C1--C6H4, d Ar=4-CH30--C6H4, e

Ar=4-C6Hs--C6H4, f Ar=l-CloHT; tI a R=C6Hs, b R=4-HOOC--CsH~, c R=4-H3COOC -
--C6H4, d R=4-CIOC--C.~H~, e R=4-H=NOC--C6H4, f R=4-F2HCOIS--CsH4, g
R=C~H~-- (CO)~O

Compounds Ib, c, containing a methyl group or chlorine in the 5-phenyl radical, practi-
cally do not differ in their spectral and luminescent properties from the unsubstituted 2-(4-
cyanophenyl)-5-phenyloxazole (Ia). On introduction into the 5-phenyl radical of an electron-
releasing substituent, the methoxy group (Id), interacting with the cyano group along the
conjugated chain, we observed a significant long-wave shift of the absorption and luminescence
maxima. The same effect takes place when the structure of the 5-aryl fragment becomes more
complex; the phenyl radical is replaced by the 4-biphenylyl (Ie). The absorption maximum
of the compound with a l-naphthyl radical (If), having in the ground state less planar struc-
ture than in the excited state, is, as a rule, shifted toward shorter wavelengths, as com-
pared with the compound containing a 4-biphenylyl radical. According to the location of
their luminescence maxima, these compounds are similar.
Comparison of the spectral and luminescent properties of compound la with those of the
previously studied 2,5-diaryloxazoles, containing other electron-withdrawing substituents
(llb-f) in the para-position of the 2-phenyl ring, shows that the cyano group, according
to the induced by itself bathochromic and bathofluoric effects, is close to the carboxyl,

Scientific-Industrial Association "Monokristallreaktiv" ("Single Crystal Reagent"),

Khar'kov 310141. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1265-
1266, September, 1986. Original article submitted June 5, 1985.

1026 0009-3122/86/2209-1026512.50 ~ 1987 Plenum Publishing Corporation

 TABLE i. 2- (4-Cyanophenyl) -5-aryloxazoles
ia-f
C'om- MP Found Emp~ical for- Calc. N, Yield, ~o
pou~ ' ~ N,% mula ~o

la 179--180 11,2 CIsH,0N~O 11,4 88

Ib 185--186i 10,6 C~THI2N:O 10,8 96
Ic 249--2501 10,1 CI6HgC1N20 t0,0 91
Id 164--165! I0,0 CIvHI:N:O2 10,1 90
9I? 229--230; 8,9 C22Hj,N~O 8,7 88
145--146j 9,4 C2oHI~N~O 9,5 83

TABLE 2. Spectral and Luminescent Properties of Compounds I

and I! in Toluene
Corn_ I, Absorption Luminescence Corn- Absorption Luminescence
po~rnd [ pound
Zm.x n m e . 10-4 ~-m~x
,nm ~1 ?'max' n r f l ~" 10"4 },max, n m
1 ~]

Ia 337 3,50 395 0,62 lla 307 2,58 365 0,51

Ib 339 2,17 405 0,51 lib 335 4175 400 0,58
Ic 337 2,49 395 0,51 llc 335 3115 395 0,56
Id 350 2,43 425 {},48 lid 354 2,25 430 0,54
Ie 346 2,71 420 0,42 lie 327 3.33 395 0,55
If 340 1,90 425 0,43 llf 340 2174 405 0,78
llg 364 1,87 455 0,6[

carbomethoxy, and difluoromethylsulfonyl groups. Taking into consideration the effect of

electron-withdrawing substituents on the spectral and luminescent properties of 2,5-diaryl-
oxazoles they can be arranged in the following order:

c~O ~O c~O C~ O (' 5 0

< C~ < < C~N ~ SOzCHF. < < "" O
NH 2 \OCH 3 \OH z ~C| C~O

EXPERIMENTAL
The absorption spectra of the toluene solutions were measured on a Hitachi-330 spectro-
photometer (c i.i0-~); the luminescence spectra were taken on a system consisting on a ZMR-3
monochromator, an FEU-18 receiver of optical radiation, and an M-95 microammeter. The photo-
luminescence was induced by an SVDSh-500 lamp, from the spectrum of which light with the
wavelength of 365 nm was isolated using a DMR-4 monochromator. The absolute quantum yields
of luminescence were determined by the equal absorption method [4].
2-(4-Cyanophenyl)-5-aryloxazoles (Ia-f). To a solution of 0.I mmole of 2-(4-carbamido-
pheny!)-5-aryloxazoie [3] in i00 ml of DMFA at 0~ was added dropwise, with vigorous stirring,
5 ml of thionyl chloride, maintaining temperature below 3~ The reaction mixture was
stirred at this temperature for 1 h and then for 3 h at 60~ The obtained solution was
poured on ice and the Precipitate was filtered, washed with water, and dried (Table 2).
The compounds were purified by chromatography of their hexane (for Ia, b, f) or heptane
(Ic-e) solutions on Silochrom S-120 in a continuous action column.

LITERATURE CITED
i, B. M. Krasovitskii and V. M. Shershukov, Khim. Geterotsikl. Soedin., No. I, 35 (1979).
2. B. M. Krasovitskii, V. M. Shershukov, and L. M. Yagupoi'skii, Khim. Geterotsikl. Soed.,
No. 8, 1042 (1982).
. B. M. Krasovitskii, V. M. Shershukov, and V. L. Volkov, Khim. Geterotsikl. Soed., No. 9,
1261 (1986).
. A. S. Cherkasov, Zh. Fiz. Khim., 29, 2209 (1955).

1027
HETARYLETHYLENE DERIVATIVES OF 2,5-DIARYLOXAZOLES
AND 2,5-DIARLOXADIAZOLES AND THEIR LUMINESCENCE
AND SCINTILLATION PROPERTIES

L; Sh. Afanasiadi, L. D. Patsenker, S. A. Verezubova, UDC 547.787.2'732:

A. P. Shkumat, and V. K. Polyakov 543.422:541.651

A number of new organic luminophores were synthesized via the Wittig reaction
from 2-(4-bromomethylphenyl)-5-phenyloxazole or 2-(4-bromomethylphenyl)-5-
phenyl-l,3,4-oxadiazole and various heterocyclic aldehydes containing a thio-
phene ring.

The synthesis of organic luminophores in series of aryl- and hetarylethylene derivatives

of 2,5-diphenyioxazole and 2,5-diphenyl-l,3,4-oxadiazole (I, II) demonstrated the possibility
of obtaining intensely luminescing substances [1-3].
The subjects of the present communication are the synthesis and investigation of the
fluorescence and scintillation properties of hetarylethylene derivatives (III, IV) of 2,5-
diphenyloxazole and 2,5-diphenyl-l,3,4-oxadiazole that have more complex structures and con-
tain a thiophene ring.

tit+ r v

Itl X=CH, tV X=N: [[1.[V a Arc pheny~; b Ar = +-chloro~henyl;c Arc +-bro~ophenyl

]Ild Ar= 4-1olyh llle,IVd Ar +=4-rnethoxyphenyl;lllf.IVy.A~ ~=4-nitropnenylilllg
Ar= 8-phenyt-2-oxazotyl~

The synthesis of III and IV was accomplished via the Wittig reaction. 2-(4-Bromomethyl-
phenyl)-5-phenyloxazole or 2-(4-bromomethylphenyl)-5-phenyl-l,3,4-oxadiazole and 5-aryl-2-
formy!thiophenes served as the starting compounds.

. . . . . . . . . . . . % [ [ Z FV

In conformity with the well-known concepts regarding the mechanism of the Wittig reac-
tion and kinetic studies, electron-donor substituents in aromatic aldehydes decrease the
rate of this reaction [4, 5]. Under the most widely used conditions for this synthesis
(methanol as the solvent, alkali metal methoxides as the basic agents for conversion of the
phosphonium salt to the corresponding phosphorane, and a reaction temperature of 20~ 2-
formyl-5-(4-methoxyphenyl)thiophene does not react with the phosphonium salt, since the
thiophene radical evidently displays an electron-donor effect in this reaction. This made
it necessary to search for more severe conditions for the synthesis, which we subsequently
carried out by heating to 50~ in isopropyl alcohol using sodium isopropoxide as the basic
agent for conversion of the phosphonium salt to the corresponding phosphorane.
The Wittig reaction is nonstereospecific and leads to the formation of mixtures of
trans and cis isomers [4, 6]. Only the trans isomers have practical value, since they

All-Union Scientific-Research Institute of Single Crystals, Monokristallreaktiv, Khar-

kov 310141. A. M~ Gor'kii Kharkov State University, Kharkov 310077. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 9, pp. 1267-1270, September, 1986. Original article
submitted June ii, 1985.
1028 0009-3122/86/2209-1028512.50 ~ 1987 Plenum Publishing Corporation
 TABLE I. Characteristics of the Smthesized Compounds
Absorption "luorescence S S
found, Empirical calc., Yield,
Corn-Imp, ~ % formula % %
pound ~-rlqax~s . i0-~ kl'P* aX' rj
nm | lm

Ilia 214--215 C27HIgNOS 45

IIIb 217--218 C2rHI~C1NOS 73

IIIc 213--214 C2rHIsBrNOS 37,5

IIId [98--199 C~H21NOS 52
Ille 211--212 C2~.H21NOaS 55

IIIf 234--235 C~THIsNiOaS 62

Illg 202--203 CaoH2oN20~S 46
IVa 233--234 C.o6HIsN~OS 51

FCo 229--230 i[C26HI,CIN~OS-

: 62
1
IVc 250--251 C2~HtTBrN2OS 64

IVd 199--201 C~vH~oN~02S 48

]Ve 266--267 C~eH,rNaOaS 58

luminesce more intensely. For conversion of the cis isomer to the trans form the reaction
product was therefore heated in xylene with crystalline iodine for 4 h.
The structures of III and IV were confirmed by IR spectral data. Out-of-plane deforma-
tion vibrations of the hydrogen atoms of the trans-vinylene group at 945-960 cm -i and char-
acteristic frequencies of thiophene (710-730, 1410-1420, 1510-1550 cm-:), oxazole and oxadia-
zole (1560-1590 cm-l), phenyl (620-740, i000, 1445, 1500 cm-:), and 1,4-phenylene (485, 640,
iii0, 1250 cm-~) rings appear in the spectra. It should be noted that the stretching vibra-
tions of the C---Cbond are masked to a significant extent by the absorption of the aryl frag-
ments.
As a rule, two bands are observed in the absorption spectra (Table i). The interpreta-
tion of the short-wave band with a maximum at 315-320 nm (g = 22,000-29,000 liter.mole-:.cm -l)
for III and at 297-301 ran (s = 23,000-30,000 liter.mole-~.om -:) for IV is difficult because
of the possibility of superimposition of several electron transitions localized in the aryla-
zole and thienylethylene fragments. In the case of III and IV this band is only slightly sen-
sitive to the introduction of CHa and OCH3 groups and halogen atoms into the phenyl ring but
changes substantially when a nitro group is present (IIIf and IVe).
The long-wave band that is responsible for fluorescence and is more sensitive to the
effect of substituents in the arylthiophene fragment is of considerably greater interest
for consideration.
A comparison of the spectral characteristics of IIIa and its aromatic analog I (Ar =
C6H5 C6H~) shows that replacement of the benzene ring by a thiophene ring changes the
--
character of the absorption spectra significantly and is accompanied by a bathochromir shift
of the long-wave band. This effect is evidently a consequence of not only an increase in
the extent of the ~ system but is also associated with the electron-donor character of the
thiophene ring.
The absorption intensity of IIIa is substantially lower than that of its aromatic ana-
log. From the point of view of their electronic structures these two systems are formally
similar. However, if one ascribes the decrease in the extinction coefficient only to the
presence of the heteroatom, the same regularity should also have occurred in series of, for
example, furylethylene derivatives of 2,5-diphenyloxazole, but, in fact, this was not ob-
served [2, 7]. The explanation of this fact requires further theoretical examination.
When substituents with a relatively weakly expressed electronic effect (CI, CH3, OCH3)
are introduced into the phenyl ring bonded to the thiophene ring, the position of the absorp-
tion maximum of the long-wave band remains virtually unchanged.

1029
 TABLE 2. Scintillation Character-
istics of III
Scientillation efficiency, %
Com-
-a -methvlnaDh- J ditolvtmeth a - ~ l n a p h -
pound th.alene ('c 5 - anr ('c 5 thalene (c 0.1
g/liter) I g/liter g_/titer) - -

Ilia 48 52 60
Iilb 50 54 62
Ilic 50 54 66
llld 56
llie 42 50 48
llIf 46 56

The long-wave absorption band in the spectrum of the simplest I (Ar = C~Hb) corresponds
to primary localization of the electronic excitation in the So + S: transition in the aryla-
zolylethylene fragment and is the result of the superimposition of electron shifts that take
place in two directions: from the phenylazole grouping and from the phenyl ring containing
the substituent to the ethylene bridge [8]. As in the I series, the introduction of a nitro
group into the phenylthienyl fragment leads to a significant change in the nature of the
long-wave absorption band, which becomes a band of charge transfer from the phenyl grouping
to the nitrophenylthienyl grouping.
One's attention is directed to the large extinction coefficient of l!!g. This increase
in the probability of an electron transition is evidently not only a consequence of an in-
crease in the overall extent of the ~-electron system of the molecule, owing to which the
probability of its interaction with the field of the light wave increases, but is also the
result of the perturbing effect of the phenyloxazole residue introduced into the 5 position
of the thiophene ring.
Upon irradiation with UV light all of the III and IV obtained fluoresce in the crystal-
line state and in toluene solutions at 20~ Their quantum yields range from 0.01 to 0.41
and are substantially lower than in the case of the similarly constructed fury!ethylene de-
rivatives of 2,5-diphenyloxazole and 2,5-diphenyl-l,3,4-oxadiazole [2], The decrease in the
photoluminescence quantum yield may be due to intercombination conversion reinforced by the
presence of a heavy sulfur atom.
The fluorescence spectra of the investigated compounds are characterized by a weakly
expressed vibrational structure. There is almost no difference in their spectra. However,
the oxadiazole analogs have considerably lower fluorescence quantum yields than their oxazole
derivatives. It should be noted that the nitro group does not exert its characteristic quench-
ing effect [9], and lllf and IVe fluoresce just like the unsubstituted compound.
Substituents in the phenyl ring bonded to the thiophene ring have a relatively small
effect on the positions of the fluorescence bands, although one can note a tendency for an
increasing bathochromic shift of these band when substituents with a weakly expressed elec-
tronic effect are introduced: CI < CH3 < OCH~. As in the absorption spectra, a substantial
shift of the fluorescence hands to the longer-wave region is observed for the nitro deriva-
tives (lllf, IVe).
We investigated III as spectral activators (concentration 5 g/liter) and shifters (con-
centration 0.I g/liter) in liquid scintillators (LS). The efficiencies of the LS were mea-
sured from the change in the photocurrent of an FEU-13 photomultiplier; ~37Cs served as the
source of y excitation. A solution of a mixture of p-terphenyl (4 g/liter) with 1,4-bis(5-
phenyl-2-oxazolyl)benzene (0.i g/liter) in toluene, which is usually utilized for this pur-
pose, was used as the standard scintillator. In the investigation of III as spectral shift-
ers in ~-methylnaphthalene, 2-(l-naphthyl)-5-phenyloxazole (a-NPO) was used as the activator.
It is apparent from the data in Table 2 that III cannot be used as spectral activators and
shifters in LS. The effect of the heavy sulfur atom evidently has a negative influence on
the efficiency of the LS.

EXPERIMENTAL
The absorption spectra of toluene solutions of the compounds (c 5.10 -s M) were measured
with a Specord spectrophotometer. The luminescence spectra were recorded with an apparatus
consisting of a ZMR-3 mirror monochromator, an FEU-18 optical emission detector, and an M-95

1030
microammeter; photoluminescence was excited with an SVDSh-500 lamp, from the spectrum of
which light with a wavelength of 365 nm was isolated by means of a DMI~-4 quartz monochromator.
The IR spectra were obtained with a UR-20 spectrometer.
The hetarylethylene derivatives of 2,5-diphenyloxazole and 2,5-diphenyl-l,3,4-oxadiazole
were obtained by the method in [7] and were purified by chromatography on aluminum oxide in
benzene with subsequent recrystallization from a suitable solvent.

LITERATURE CITED
i. L . M . Podgornaya, V. P. Leonov, V. I. Grigor'eva, L. P. Snagoshchenko, and R. N. Nur-
mukhametov, Zh. Prikl. Spektrosk., 26, 285 (1977).
2. B . M . Krasovitskii, N. P. Egorova, L. Sh. Afanasiadi, I. V. Lysova, V. K. Polyakov,
and S. V. Tsukerman, Khim. Geterotsikl. Soedin., No. 5, 617 (1982).
3. V . I . Grigor'eva, B. M. Krasovitskii, Yu. V. Naboikin, L. A. Ogurtsova, A. P. Podgornyi,
F. S. Pokrovskii, and V. G. Tishchenko, in: Scintillators and Organic Luminophores [in
Russian], No. i, All-Union Scientific-Research Institute of Single Crystals, Kharkov
(1972), p. 169.
4. G. Wittig and U. SchBllkopf, Chem. Ber., 87, 1318 (1954).
5. A . J . Spezial and D. E. Bissing, J. Am. Chem. Soc., 85, 1888 (1963).
6. B . M . Krasovitskii and V. I. Grigor'eva, Khim. Geterotsikl. Soedin., No. 6, 1127 (1968).
7. B . M . Krasovitskii, S. V. Tsukerman, L. Sh. Afanasiadi, V. K. Polyakov, N. P. Egorova,
and E. M. Shaulova, Khim. Geterotsikl. Soedin., No. 12, 1616 (1977).
8. V . I . Grigor'eva, Master's Dissertation Abstract, Moscow (1969).
9. E. Lippert, Z. Phys. Chem., ~, 328 (1954).

POLYNUCLEAR HETEROCYCLIC C O ~ O U N D S BASED ON THE ADDUCT

OF o-CINNAMOYLBENZOIC ACID AND CYCLOHEXANONE

L. N. Donchak, V. A. Kaminskii, and M. N. Tilichenko UDC 547.759.4'751'781:

542.953:543.422

The product of addition of cyciohexanone to o-cinnamoylbenzoic acid, which has

the 4-phenyl-8a-hydroxyperhydrochroman-2-spiro-3'-phthalide structure, reacts
with nitrogen-containing nucleophiles to give hydrogenated derivatives of oxa-
(aza, thia)indolizinespiroPhthalide and pyrido[l',2':l,2]imidazo[2,3-a]-isoin-
dole, as well as 4-R-l-phthalazones. An isoindolo[!,2-a]quinoline derivative
and a compound with a 7,8-diaza-D-homosteroid skeleton were obtained from the
latter.

Semicyclic 1,5-diketones that contain reactive substituents in the ortho position rela-
tive to the aroyl carbonyl group are convenient starting compounds for the synthesis of poiy-
nuclear (including new) heterocyclic systems; in particular, the synthesis of compounds with
a heterosteroid skeleton is possible. We have previously described the synthesis and proper-
ties of o-hydroxy- and o-amino-substituted semicyclic 1,5-diketones [I, 2]. In order to
synthesize an o-carboxy-substituted diketone we realized the addition of cycl~hexanone to o-
cinnamoyibenzoic acid; we have previously briefly reported the synthesis and some properties
of adduct I [3] (see scheme on following page).
The addition proceeds readily in the presence of KOH; adduct I has the 4-phenyl-8a-hy-
droxyperhydrochroman-2-spiro-3'-phthalide (IA) structure [3]. In the reaction of I with
nitrogen nucleophiles we isolated products, the formation of which can be explained by prior
opening of the hydropyran and phthalide fragments and conversion of I to the o-carboxy-sub-

Far-Eastern State University, Vladivostok 690600. Translated from Khimiya Geterotsik-

licheskikh Soedinenii, No. 9, pp. 1271-1275, September, 1986. Original article submitted
April 18, 1985.

0009-3122/86/2209-1031512.50 9 1987 Plenum Publishing Corporation 1031

 r/"~.h
i t

i " Of{
... O I i
/"
"~--- ! ! O O
L<-.L." 9 "~ , "-_'b-. .'i-
iio 0
IA I,,B II.m

~ i NBzNHz
r I~ C6H ~ C6~

0 0 0 0
V ~ W-_ILK
I !n~-C!

C~_~ ~ C~

0 0
X ~
IIX = O; I I I X = S; V I I R = H ; V I I I R = C t - I O ; I X R = COCHa

stituted semicyclic 1,5-diketone form (IB); however, one cannot exclude the possibility that
the reactions proceed without opening of the phthalide ring, for example, through interme-
diate cation C:

CI6H

o C

Whereas the reaction of I with nucleophiles that contain an aromatic amino group [3]
requries heating and acidic catalysis, the reaction with nucleophiles that contain an ali-
phatic amino group, as well as with hydrazine, proceeds at room temperature in the absence
of acidic agents. The products of the reaction of I with ethanolamine and with B-mercapto-
ethylamine (which has not been previously subjected to reaction with 1,5-diketones) are to
a certain extent similar to the products of the reaction of the previously investigated 1,5-
diketones with bifunctional nucleophiles [4]; the difference is the presence of the phthalide
structure. However, in the case of the reaction with ethylenediamine the reaction proceeds
via a different scheme: in addition to the formation of a hydropyridine ring, the second
amino group of the nucleophile reacts with the phthalide fragment to give a phthalimidine
structure (IV).
The IR spectra of II and III (Table l) do not contain absorption bands of ~ bonds or
OH (II) and SH (III) groups; the carbonyl group of the phthalide fragment gives an intense
band at 1745 cm -I. On the other hand, absorption of a ~ bond at 1655 cm -~ appears in the
spectrum of IV, and, instead of absorption of a phthalide carbonyl group, an intense band
at 1700 cm-: (phthalimidine C=O) is observed; absorption of N--H bonds is absent.
In the PMR spectrum of II the protons of the oxazolidine fragment give two multiplets
(each 2H) at 4.0 ppm (CH2--O) and 2.8 ppm (CH=--N); in the spectrum of III the protons of the
thiazolidine fragment give an overall multiplet (4H) centered at 2.9 ppm. Signals of aromat-
ic protons of the phthalide fragment are observed in the spectra at 7.5-7.9 ppm, The signal
of a benzyl proton in the 4 position of the piperidine ring shows up in the form of a triplet
of doublets with a width of -30 Hz; this indicates an axial orientation of the 3-H, 4-H, and

1032
 TABLE i. Data from the IR, PMI{, and Mass Spectra of II-XI
Com- IR specruIn, PMR spectrum, ppm Mass spectrum,* m / z (rela-
pound cm-1 (SSCC, Hz) tive intensity, %)

1495, 1600, 1612 2,32 t (12), IH; 2,76 m, 2H; 375 (28), 333 (26), 332 (lO0),
t744 2,90 q (12; 4), 1H;3,58 td. 318 (20), 298 (lO), t86 (25),
(12; 4,5), 1H; 4,00 m, 2H; 172 (19), 130 ( l l ) , ll5 (13)
7,55 t (7), 2H; 7,69 t (7),
IH; 7,89d (7), 1H
III 1500, 1603, 1614 2,08 q (12; 4), 1H; 2,35 t 391 (92), 348 (100), 314 (15)
1746 (12), I.H; 2,80--3,05 m, 4H; 235 (30), 202 ( l l ) , 130 (13),
3,57 t0. (12; 4,5); 1H; 129 (10), 104 (20)
7,55 t (7), 2H; 7,70 t (7),
1H; 7,88 d (7), 1H
IV 1494, 1600, 1614, 356 (100), 355 (I0), 328 (10),
1654, 1700 269 (10), 256 (13), 255 (62),
243 (23), 200 (13), 188 (16),
174 (13), 163 (10)
V I500, 1600, 1670, 360 (8), 344 (24), 248 (34),
3200, 3320, 3400 160 (100)
VI !1505, 1600. 1665. 346 (3), 249 (21), 248 (100),
1706, 3195T, 3405 247 (28), 160 (53), 149 (14),
91 (39)
VII 1500, 1605, 1660, 348 (7), 330 (25), 248 (100),
3410, 3620 160 (741
VIII 1500, 1600, 1660, 376 (15), 348 (II). 330 (19),
1720, 3400 248 (80), 160 (I00)
IX 1500, 1600, 1660, 390 (20). 346 (13), 3gO (18),
I710, 3400 248 (I00), 160 (68)
X 1490, 1602, 1685 3.50 d (5):I: , 1H: 4.55 q 3t5 (loo), 300 (i0), 287 (15~,
(12; 3,5), 1H: 7,80d (6), IH 286 (25), 238 (20), 211 (30),
141 (9). 114 (8)
XI 1500, 1580, 1602, 4-,82 br..~ ill; 8,14 d (7), 1H; 332 (45), 289 .(12), 246 (20),
1655, 3190, "3400 8,54 s, 1H 201 (12), 160 (IO), 149 (30),
148 (36), I47 (45),:146 (36),
132 (42), 120 (100)

*The M + peaks and ion peaks with intensities g5% are present-
ed.
*Broad band.
~The lines of the doublet are broadened.

5-H protons. The PMR spectral data do not make it possible to draw a conclusion regarding
the way in which the rings are fused in the perhydroquinoline fragment of II and III; how-
ever, an examination of the PMR spectra of previously obtained [3] products (XII, XIII) of
the reaction of I with o-aminophenol and o-phenylenediamine makes it possible to assume
cis fusion of the perhydroquinoline fragment. It has been previously noted that a signifi-
cant shift of the signal of one aromatic proton to strong field - to 5.3 ppm [2, 4] - as a
consequence of its shielding by the other aromatic ring is observed in the PMR spectra of
the products of the reaction of semicyclic 1,5-diketones with o-aminophenol and o-phenylene-
diamine. This effect is manifested to an even greater degree in the spectra of XII and XIII:
their spectra contain doublets (IH, J = 7 Hz) at 4.75 ppm, whereas signals of aromatic pro-
tons below 7.0 ppm are absent in the spectra of II and III. An examination of models of XII
and XIII shows that such a significant strong-field shift of the signal of an aromatic proton
should be observed in the case of an axial orientation of the aromatic substitutent attached
to the nitrogen atom of the perhydroquinoline system (and, consequently, in the case of cis
fusion of the system); in this case aromatic proton HA is shielded markedly by the "phthalide"
benzene ring. The presence of an acceptor group in the shielding ring intensifies this ef-
fect [2].

~> c%--~
i I

O
5,~! X-Q~ .vJII X x r i H

1033
 TABLE 2. Characteristics of the Synthesized Compounds

mp, ~ Found, % I Empirical Calc,, %

;om- (frometh- Yield, ~c
~ound anol) formula
c IN C H N

II 148--149 76,3 6,5 3,7 C=~H=sNOa 76,8 6,7 3,7 64

Ill 169--170 73,6 6,4 3,3 C24H2sNO= 73,7 6,4 3,6 59
IV 153--155 80,6 7,0 7,8 C24H24N20 80,9 6,7 7,9 45
V 193--194 73,2 6,7 15.5 CuuH24N40 73.3 6.7 15,6 89
VI 172--173 76,7 6,3 810 CmHmNaO= 76:3 6,4 8,1 98
VII 207--208 75,4 7,1 7.9 C22H=4N202 75,8 7,0 8,0 93
VIII 203--204 73,7 .6,5 711 CmH24N2Oa 73.4 6,4 7,4 71
IX 208--209 74,0 6,9 7,1 C24Ha6N2Oa 7319 6,7 7,2 75
X 177--178 83,3 7,1 4,1 CmHmNO 83,8 6.7 4,1 35
XI 265--267 79,5 7,5 8,3 Ci2H24N20 79,5 7'2 8,4 20

According to the mass-spectral data, the measured molecular masses of II-IV correspond
to the calculated values. The mass spectrum of IV contains an [M-- 28] + ion peak; this prob-
ably corresponds to detachment of ethylene from the molecular ion as a result of retrodiene
decomposition of the cyclohexene fragment. Peaks of [M -- 28] + ions are absent in the spectra
of II and IiI, as well as in the spectra of XII and XIII, but peaks of rearranged [M-- C3H7] +
ions, which are characteristic for decomposition of the perhydroquinoline structure [5~, are
observed; this peak is absent in the spectrum of IV. High intensity of the [M-- C3H7] ~ ion
peaks is characteristic for cis-decahydroquinoline structures [5]; this also confirms the
assumption of cis fusion in XII and XIII and to a certain extent serves as an indication of
the same fusion in II and III.
Regardless of the reagent ratio and the reaction conditions, the reaction of I with hy-
drazine leads to the formation of hydrazonophthalazone V. Absorption bands at 1670 cm -t
(phthalazone ~ ) and at 3200-3400 cm -t (NH, NH=) are observed in its IR spectrum; the absorp-
tion of the phtha!azone C ~ bond is overlapped by vibrations of the benzene ring [6], and the
band of the hydrazone C-~ bond is evidently overlapped by the band of the ~ bond. Compound
V is readily converted by acidic hydrolysis to ketophthalazone VI, in the IR spectrum of
which an intense band at 1706 cm-t (ketone C-~) additionally appears.
We studied the reduction of ketophthalazone VI to obtain, in particular, a compound with
a 7,8-diaza-D-homosteroid skeleton. Reduction with potassium borohydride leads to hydroxy-
phthalazone VII (the band at 1706 cm-t in the IR spectrum vanishes, and an absorption band
of an OH group appears at 3620 cm-:); we also obtained its O-formyl and O-acetyl derivatives
(VIII, IX). The presence of intense ion peaks with m/z 248 and 160, which correspond to re-
arranged ions with 4-styryl- and 4-methyl-l-phthalazone structures, respectively, is charac-
teristic for the mass spectra of V-IX.
We were able to obtain XI, which has a 7,8-diaza-D-homosteroid skeleton, by reduction
of ketophthalazone VI with zinc dust and HCI at room temperature. The reaction proceeds very
slowly, and XI is formed in low yield. When the reaction temperature is raised, the yield
of XI does not increase, and hydrogenated isoindoloquinoline derivative X is formed along
with it; this is the result of ring contraction, which occurs rather frequently when phthala-
zones are heated [7].
Absorption bands at 1685 cm -~ (phthalimidine C ~ ) and at 1656 cm -I (C=C) are observed
in the IR spectrum of X; absorption of N-H bonds is absent. The spectrum of XI contains
bands at 1665 (phthalazone C-~) and 3200-3400 cm-: (N--H); a band of a C-~ bond is not observed
According to the mass-spectral data, the measured molecular masses of X and XI correspond to
the calculated values. The spectrum of X contains a peak of an [M-- C2H~] + fragment ion,
which confirms the presence of a cyclohexene fragment, whereas this peak is absent in the
spectrum of XI. A weak-field signal (IH) of a proton adjacent to a nitrogen atom and a ben-
zene ring appears in the PMR spectra of X and XI. In the spectrum of X it is observed in
the form of a quartet at 4.55 ppm, whereas it is observed in the form of a broad singlet at
4.82 ppm in the spec=rum of XI. The singlet form of the signal may serve as an indication
of cis-B/C fusion in the heterosteroid system of XI.

EXPERIMENTAL
The IR spectra of the synthesized compounds in mineral oil and chloroform were recorded
with a Specord IR-75 spectrometer. The PMR spectra of solutions in deuterochloroform were

1034
obtained with a Bruker HX-90E spectrometer with tetramethylsilane (TMS) as the internal stan-
dard. The mass spectra were obtained with an LKB-9000 spectrometer at an ionizing voltage of
70 V. The course of the reactions and the purity of the compounds obtained were monitored by
thin-layer chromatography (TLC) on Silufol plates in hexane-ether systems (2:1 and 3:1). The
characteristics of the synthesized compounds are presented in Table 2.
Reaction of 4-Phenyl-8a-hydroxyperhydrochroman-2-spiro-3'-phthalide with Aliphatic Am-
ines. A solution of 3.5 g (0.01 mole) of I and 0.012 moles of the amine (ethanoiamine, 8-
mercaptoethylamine, ethylenediamine) in 30 ml of ethanol was maintained at room temperature
for 18-30. h, after which it was diluted with water, and the aqueous mixture was extracted
with ether. After removal of the ether from the extract, the residue crystallized (II-IV).
!--(2'-Oxocyclohexyl)-l-phenyl-2-(4"-phthalazony!)ethane Hydrazone (V). A solution of
17.5 g (0.05 mole) of I and i0 g (0.2 mole) of hydrazine hydrate in 150 ml of ethanol was
maintained at room temperature for 18 h, after which it was worked up as in the preceding
case.
l_-(2'-Oxocyclohexyl)-l-phenyl-2-(4"-phthalazonyl)ethane (VI). A mixture of 4 g of V
and 40 ml of concentrated HCI was heated on a water bath for 4 h, after which the product
was removed by filtration and washed successively with water, sodium carbonate solution,
and water.
l-(2'-Hydroxycyclohexyl)-l-phenyl-2-(4"-phthalazonyl)ethane (VII)._ A 3.5-g (0.01 mole)
sample of ketophthalazone VI was added to a solution of 3 g (0.055 mole) of KBH~ in a mix-
ture of 50 ml of dimethylformamide (DMFA) and i0 ml of water, and the mixture was refluxed
for 5 h. It was then cooled and diluted with water, and VII was removed by filtration and
washed with water. Compounds VIII and IX, respectively, were obtained by refluxing VII with
85% HCOOH or glacial CHsCOOH for 6 h with subsequent dilution with water.
Reduction of Ketophthalazone VI with Zinc and HCI. A mixture of 3.5 g of VI, 1 g of
ainc dust, and 5 mi of concentrated HCI in 30 ml of tetrahydrofuran (THF) was stirred at room
temperature for 50 h or refluxed for 5 h; more zinc dust and HCI were added as they were con-
sumed. The mixture was then filtered and diluted with water, and the aqueous mixture was
made alkaline with 25% ammonium hydroxide and extracted with ether. After removal of the
ether by distillation, the crystalline residue was chromatographed with a column packed with
silica gel; products X and XI, as well as the unchanged ketophthalazone VI, were e!uted with
petroleum ether-diethyl ether.

LITERATURE CITED
i. L. N. Donchak, V. A. Kaminskii, and M. N. Tilichenko, Khim. Geterotsikl. Soedin., No. 2,
239 (1975).
2. L. N. Donchak, A. N~ Saverchenko, V. A. Kaminskii, and M. N. Tilichenko, Khim. Geterot-
sikl. Soedin., No. 7, 956 (1984).
3. L. N. Donchak, V. A. Kaminskii, and M. N. Tilichenko, Zh. Org. Khim., 15, 1558 (1978).
4. L. M. Eremeeva, T. V. Moskovkina, Yu. V. Vasilenko, A. N. Saverchenko, V. A. Kaminskii,
and M. N. Tiiichenko, Khim. Geterotsikl. Soedin., No. 2, 240 (1979).
5. V. G. Zaikin and N. S. Vul'fson, Khim. Geterotsikl. Soedin., No. ii, 1443 (1978).
6. B. I. Buzykin, N. N. Bystrykh, A. P. Stolyarov, S. A. Flegontov, B. Vo Zverev, and Yu.
P. Kitaev, Khim. Geterotsikl. Soedin., No. 3, 405 (1976).
7. R. Elderfield, Heterocyclic Compounds, Vol. 6, Wiley (1957).

1035
OPTICAL AND ELECTROPHYSICAL PROPERTIES OF METAL COMPLEXES
OF TETRA(I,4-DITHIACYCLOHEXENO)PORPHYRAZINE

G. P. Shaposhnikov, V. P. Kulinich, Yu. M, Oslpov, UDC 547.979.733:621,315.592:

a~d R. P. Smirnov 543.422.6

The optical and electrophysical characteristics of metal complexes of tetra-

(l,4-dithiacyclohexeno)porphyrazine were measured. The presence of 1,4-dithi-
acyclohexene rings in the molecules of the investigated compounds leads to the
appearance of bands corresponding to an n ~ ~* transition in the absorption
spectra. The positions of the long-wave bands corresponding to a ~ + ~* tran-
sition are determined by the nature of the metal. All of the complexes have
semiconductor properties; the specific electrical conductivities range from
i0 - ~ to i0 -~ ~-~,cm -~.

A study of complexes of porphyrazine derivatives with metals is extremely urgent, since

it makes it possible to establish the effect and role of various structural elements of mole-
cules with respect to their physicochemical properties.
We have previously synthesized complexes of tetra(l,4-dithiacyclohexeno)porphyrazine
(HaTDTP) (I) with di-, tri-, and tetravalent metals (CIo-=MTDTP) (II-XVII):

~.~x H N --~ --_~N' N---

!

I II ""N'vlI

lI ~.=Cu2~-; IIl M=Zn2~; IV ,~I=~2-; V N~=Cd2+; VI ,~=Fe=~; VII ~Ii=Co~-;

VIII ,\1=Ni-~ IX :'~.=pb2"-; X ,\i~Sn2-; XI 5~=A13~-: XII ,'q=Cr ~', XIII ,~4.=Ga3-~;
XIV 5i=Ina XV .'~l=Ge~+; XVI 7~i=Sn4~-; XVII 51=Zr 4~

In the present communication we present the results of an investigation of their optical

properties and electrical conductivities as compared with an extensively studied class of com-
pounds, viz., phthalocyanines [3], which have a similar porphyrazine macroring.
Data from the electronic absorption spectra of the investigated I-XVII, which are pre-
sented in Table i and Fig. i, show that replacement of the benzene rings in the phthalocyanine
molecule by 1,4-dithiacyclohexene rings leads to a substantial change in the electronic-optica
properties and, above all, to the appearance of a new band at 525-595 nm.
The electronic spectrum of free HaTDTP in ~-chloronaphthalene (Fig. la) contains three
absorption bands at 500-700 nm and a Soret band at 360 nm. As in the case of metal phthalo-
cyanines [3], the formation of metal complexes II-XVII is accompanied by merging of two long-
wave absorption bands to form one band; this is explained by an increase in the degree of
molecular symmetry. The position of this band depends on the nature of the central metal
atom. In contrast to the spectra of phthalocyanine and its metal complexes, the spectra of
I-XVII are characterized by the presence in the visible region of an additional band at 525-
595 nm, which does not show up sufficiently distinctly in the spectra of the complexes with
divalent metals (II-X).
The appearance of this band in the spectra of HaTDTP and its metal complexes makes it
possible to assume that an n ~ ~* transition is permitted due to excitation of the n e~ectrons
Ivanovo Chemical-Engineering Institute, Ivanovo 153460. Translated from Khimiya Geterot-
siklicheskikh Soedinenii, No. 9, pp. 1276-1279, September, 1986. Original article submitted
April 23, 1985.

1036 0009-3122/86/2209-1036512.50 9 1987 Plenum Publishing Corporation

 iiil
~- iIII

~v~! ~ ~ a F ~ '

',, \ " ",,. _ ..-- I \ i/., !It

, -" - -- -7. . . . . . . . "> i' % \.-

ii!'I <'I .... C. . . . 't ::" n m

F i g . 1. E l e c t r o n i c a b s o r p t i o n s p e c t r a in
~ - c h l o r o n a p h t h a l e n e : a) I i b) XVITI c)
p h t h a l o c y a n i n e ; d) d i c h l o r o z i r c o n i u m p h t h a l -
ocyanine.

'&y

0 ~ \\

.. ' ~ - ~ b\ t I/ I', 7, t
os~-.... , ~c_-" S-.. / /'J ti 1\1
- \ i\ \

r-

Fig. 2. Electronic absorption spectra of

XVil (a, b) and d i c h l o r o z i r c o n i u m p h t h a l o -
c y a n i n e (c, d): a, c) in DMFA; b, d) in
H2SO~ 9

of the sulfur atoms of the peripheral 1,4-dithiacyclohexene rings. The basis for this assump-
tion is a comparison of the absorption spectra of metal complexes II-XVII in organic solvents
and in concentrated sulfuric acid (Table 1 and Fig. 2).
It is known [3] that the character of the spectra of phthalocyanine and its metal com-
plexes does not change on passing from organic solvents to sulfuric acid; however, one ob-
serves a strong bathochromic shift (80-120 nm) of almost all of the absorption bands, which
is associated with protonation of the porphyrazine ring at the exocyclic nitrogen atoms.
According to our data (Fig. 2 and Table i), the less intense band vanishes in the spectra of
H2TDTP and CIo-2MTDTP in solution in concentrated sulfuric acid, whereas, as compared with
the corresponding metal phthalocyanines [2], the first long-wave band does not experience
such a significant bathochromic shift, and one even observes a hypsochromic shift in the case
of complexes IX-XI and XV-XVI. It is apparent that in the case of H2TDTP and its metal com-
plexes, in addition to protonation in the principal macroring, protons add to the peripheral
1,4-dithiacyclohexene rings through the n electrons of the sulfur atoms; this leads to dis-
appearance in the electronic spectra of the additional band, which we ascribe to an n ~*
transition. The hypsochromic or bathochromic shift of the first long-wave band, which cor-
responds to a ~ ~ ~* transition, is probably the result of the combined manifestation of
protonation in the macroring and in the 1,4-dithiacyclohexene rings; these processes, taken
separately, should lead to opposite shifts.
As in the case of phthalocyanines [4], the coordination of metal ions with H2TDTP leads
to a hypsochromic shift of the long-wave absorption band, as evidenced by the results of
measurements of the spectra of II-XVII in ~-ch!oronaphthalene (Table i). Unfortunately, the
insolubility of H2 TDTP in other organic solvents did not allow us to trace this tendency in
DMFA and DMSO.

1037
 TABLE I. Positions of the Absorption Bands in the Electron-
ic Spectra and Conductivities of H2TDTP and Its Metal Com-
plexes

COITI- ~., rh'!q (~#

pound a-chloronaph- ~-I. cm-t
DMFA DMSO thalene H2so,

I 709; 625; 523; 360 698; 465 1,O. lO-11

II 668; 525; 415 715; 435
III 365; 602; 525; 368 667; 546; 372 735; 437 2,4. lO-11
IV 660; 602; 527; 385 667; 540; 371 670; 606; 535; 374 4,5. 10-11
V 666; 602; 535; 385 671; 540; 385 668; 600; 525; 408 1,9 10-l~
VI 637; 357 667; 465 5,5 10-1~
VII 640; 345 645; 528; 352 705; 463 3,0.10 -~~
VIII 667; 589 676 6,0 10-~~
IX 684; 570; 424 692; 570; 427 707; 637; 535; 422 705; 455 3,4. 10-H
X 697; 557; 368 674; 460 7,0 10-9
XI 667; 547; 380 671; 550; 380 690; 544; 405 688; 450 5,0.10 -I1
XII 669; 578; 383 i673; 581; 379 690; 667; 595; 385 7O5 6,0 10-I1
XIII 662; 505; 357 666; 5]0; 375 700
XIV 678; 535; 382 680; 541; 383 690; 560; 370 705; 445 1,6 lO-19
XV 675; 555; 377 670; 555; 380 655; 445
XVI 680; 553; 367 685; 550; 368 700; 575; 360 678; 450 1,9 lO-9
XVII 680; 530; 360 672; 534; 366 687; 538 6~2:435

The reason for the hypsochromic shift is probably the absence of degeneracy of the elec-
tronic transitions in the first absorption band of free HaTDTP [4].
It should be noted that in the case of concentrated sulfuric acid both a bathochromic
shift and a hypsochromic shift of the long-wave absorption band are observed on passing from
HaTDTP to its metal complexes (Table i). This peculiarity should be explained by a differ-
ence in the manifestation of the electronic effects of coordination as a function of the
nature of the ion-complexing agent [5].
The positions of the absorption bands in the spectra of metal complexes CIo-2MTDTP in
the same organic solvent are determined by the nature of the metal, viz., by the size of the
atom and its electronic structure. Thus, as compared with the complexes of other metals, an
appreciable bathochromic shift of the first long-wave absorption band (to 50 nm) is observed
in the spectra of the complexes with lead, tin, indium, and zirconium. This should be ex-
plained by the special geometry of their m~lecules. It is known that the atomic radii of
lead, tin, indium, and zirconium (185-1.6 A) exceed the radius of the coordination "window"
of the tetrapyrrole ligands (1.35 A). In contrast to metal complexes, the radii of the
metal atoms in which are commensurable with the coordination "window" of the macrocyclic
ligand, the metal atoms in complexes IX, X, XVI, and XVII therefore deviate from the plane
of the molecule. The special position of the metal, as well as the presence of extra ligands,
promotes polarization of the ~-electron cloud of the macroring and, consequently, draws to-
gether the energy levels of the ~ electrons in the ground and excited states.
One's attention isdirected to the decrease in the degree of resolution of the spectra
of H2TDTP and its metal complexes as compared with phthalocyanine and metal phthalocyanines
(Fig. I); this is a sign of the presence of associated molecules in solution. This fact, as
well as the slight solubility and the inability of the complexes to melt and sublime, is a
consequence of intensification of intermolecular interaction due to the presence of sulfur
atoms along the periphery of the molecules.
Tetra(l,4-dithiacyclohexeno)porphyrazine and its metal complexes have semiconductor
properties. As in the phthalocyanine series, the specific electrical conductivities of
pellets of the compounds increase on passing from the free ligand H2TDTP to its metal com-
plexes from i0 -I~ to i0-" ~-~.cm -I (Table i). The substantial increase in the electrical
conductivity that is characteristic for metal phthalocyanines [6, 7] is not observed on
passing to complexes of H2TDTP with tri- and tetravalent metals. This may he associated
with a decrease in the degree of coplanarity of the molecules, as evidenced by the construc-
tion and analysis of Stuart--Brieg!eb models, and with the formation of looser packing as a
consequence of this.
EXPERIMENTAL
The electronic absorption spectra of the investigated compounds in a-chloronaphthalene,
dimethylformamide (DMFA), dimethyl sulfoxide (DMSO), and sulfuric acid were recorded with a

1038
Specord UV-vis spectrophotometer at 20~ over the range 330-760 nm. The concentration of
the solutions was ~10 -5 M. The specific electrical conductivities were determined from data
obtained from measurements made with direct current. The measurements were made with pellets
pressed under a pressure of 108 Pa, to which silver electrodes were applied by vacuum deposi-
tion. The configuration of the electrodes and the methods used for the measurements provided
for the elimination of surface currents [6]. Prior to the measurements, the samples were
heat treated at 420~ in vacuo (i0-~ Pa) for 4 h.
Compounds I-XVII were obtained by the methods in [I]. Dichlorozirconium phthalocyanine
was synthesized by a k n o ~ method [8].

LITERATURE CITED
i. G . P . Shaposhnikova, V. P. Kulinich, Yu. M. Osipov, and R. P. Smirnov, Summaries of
Papers Presented at the 4th All-Union Conference on the Chemistry and Application of
Porphyrins [in Russian], Erevan (1984), p. 80.
2. B . P . Lever, Inorg. Chem. Radiochem., ~, 68 (1965).
3. B . D . Berezin, Coordination Compounds of Porphyrins and Phthalocyanines [in Russian],
Nauka, Moscow (1978), p. 68.
4. G . P . Gurinovich, A. N. Sevchenko, and K. N. Solov'ev, Spectroscopy of Chlorophyll and
Related Compounds [in Russian], Nauka i Tekhnika, Minsk (1968), p. 189.
5. B . D . Berezin, V. N. Klyuev, and A. B. Korzhenevskii, Izv. Vuzov. Khim. Khim. Tekhnol.,
20, 357 (1977).
6. F. Gutmann and L. E. Lyons, Organic Semiconductors Wiley Interscience, New York
(1967).
7. G . P . Shaposhnikov, V. F. Borodkin, M. !. Al'yanov, M. I. Fedorov, V. A. Shorin, and
F. P. Snegireva, in: Organic Semiconductors [in Russian], M. V. Kurik (ed.), Kiev
(1976), p. 44.
8. V . E . Plyushchev, L. P. Shk!over, and I. A. Rozdin, Zh. Neorg. Khim., ~, 125 (1964).

SYNTHESIS, STRUCTURE, AhD TRANSFORMATIONS

OF I-AZA-3-OXA-7-THIABICYCLO[3.4.0]NONAN-2-ONE

A. V. Eremeev, R. Nurdinov, F. D. Poiyak, UDC 547.869.2:548.312.5:

R. M. Zolotoyabko, A. F. Mishnev, S. V. Belyakov, 542.942
and Ya. Ya. Bleidelis

l-Aza-3-oxa-7-thiabicyclo[3.4.0]nonan-2-one was obtained by reduction of 3,4-

dimethoxycarbonyltetrahydro-l,4-thiazine. The reduction of this product with
lithium aluminum hydride led to 3-hydroxymethyl-4-methyitetrahydro-l,4-thiazine.
The molecular and crystal structures of l-aza-3-oxa-7-thiabicyclo[3.4.0]nonan-
2-one were investigated by x-ray diffraction analysis.

It has been previously shown that the reduction with sodium borohydride of diesters I
and II, obtained by alkylation of methyl tetrahydro-l,4-thiazine-3-carboxylate with methyl
chloroacetate and methyl acrylate, leads to the formation of the corresponding diols III and
IV [i] (see scheme on following page).
However, the reduction of diester V, obtained from methyl tetrahydro-l,4-thiazine-3-
carboxylate and methyl chlorocarbonate, with sodium borohydride under similar conditions did
not lead to the formation of the corresponding diol. The PMR spectrum of the only product
(VIII) did not contain the broad singlets that are characteristic for the protons of hydroxy
groups. In addition, the IR spectrum of VIII does not contain bands of stretching vibrations

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1280-1285, September,
1986. Original article submitted July 3, 1985.

0009-3122/86/2209-1039512.50 9 1987 Plenum Publishing Corporation 1039

 TABLE I. PMR Spectra of the Synthesized Compounds
CON- I Chemical shifts, 6, ppm
pound Remaining singnals
2-H (a)12-H (e) 3-H D-H (a) 5-H (e) 13-H (a} 6-H (e)
I
VI 2,92 2,64 4,19 (e) 3,20 (br) 4,51 (br) 2,72 2,44 2,20 (OH); 3,72 (OCHs);
3,98 (CH=OH)
VIII 2,65 2,56 3,89 (a) 3,13 4,15 2,73 2,48 3,94 (H:--CH~O)
4,45 (H~--CH20)
XI 2,69 2,54 2,75 (aj 2,73 3,16 2,72 2,51 2,30 (OH) ;
2,38 (N--CHJ ;
3,55 (H~--CH20)
3,85 (H~--CH:O)

TABLE 2. Spin-Spin Coupling Constants (J, Hz) of the Syn-

thesized Com ~ounds
Com-
pound 2a2e 3a2a 3e2a 5a5e 6a6e 6aSa 8a5e I
I 6eSa 6e5e ] 7aTe
t

VI
VIII
14,0
13,0
4,0
lO,l
10,3
3,0
3,7
4,2
I3,3
12,7
13,3
13,5
13,8
12,5
12,1
l 1,2
3,1
2,6
I 3,0
3,5
3,2
2,3 I 10,2
2,4 --
XI 12,5 3,0 --

TABLE 3. Z'C NMR Spectra of the Synthesized Com-

pounds
Com- Chemical shifts, 6, ppm
pound ci2~ c~3, c~5, ci6! i c-o i remaining signals

VI
VIII
26,8
25,9
40,5
54,2
51,6
42,3
I
I
27,I 156,4 52,5(OCH3i;59.5(OCHJ
30,5 I 155,9 67,2 (OCHJ '
XI 25,9 63,6 55,7 28,2 -- 42,4 (N--CH3);
62,5 (OCHJ

i \N ~ i...CO'~Mi ,_..o./..o. =
NI "CHzOH.
[ ]
(cHj cO ~, (CH2)~.-OH
i, il Ill, I'V
I, III n = l ; IL IV n = E

of hydroxy groups (3200-3300 cm-Z). The mass spectrum of VIII is characterized by the pres-
ence of a most intense molecular ion with mass 159; this indicates that the reaction product
has a cyclic structure.
The presence of a band at 1735 cm -: in the IR spectrum and a signal of protons of a CH2
group, which resonates in the form of a doublet of doublets with a constant of spin-spin
coupling with the proton of the tetrahydrothiazine ring of 10.7 Hz, made it possible to
choose in favor of bicyclic urethane VIII rather than the isomeric lactone VII.

k"ii ""C0 Mi HzOH

V~ VC62M~ VI VIII

The different pathways in the reduction of I and II as compared with V can evidently
be explained as follows: the ester group attached to the nitrogen atom has reduced reacti-
vity as compared with the ester group attached to the carbon atom. One may therefore assume
the formation of intermediate VI, which, under the reduction conditions, tends to undergo
intramolec~lar cyclization to give bicyclic VIII. Since we were unable to detect the forma-
tion of intermediate VI in the reaction, this compound was synthesized from 3-hydroxyme'thyl-
tetrahydro-l,4-thiazine (IX) [2] and methyl chlorocarbonate.
The experiment showed that VI readily undergoes cyclization to bicyclic urethane VIII
under the conditions of reduction with sodium borohydride.

1040
 Q~j S(7}
""-" '.5~2~ $; ~ ~ I 8/~ ~.: --

0{31 ,r ~ , ~ :

Fig. I. Designations of the atoms and geometry of the VIII

molecule.

TABLE 4. Equations of the Root-Mean-Square (rms) Planes of

the Planar Fragments of the VIII Molecule and Deviations of
the Atoms from Them
Normal Eq. of the plane
Atoms of Deviation of the AX +By + C z - D - 0
Plane atoms from the
the plane
plane,

S~7} -0,1322 0,6854 - 0,7160 t,6245

C(8)
C(6}
C~s} --0,014(4) 0,5516 0.2031 - 0,7875 0,0368
C(6} 0,013(4)
C{sj --0,013(5)
C(9~ 0,014(5)
S {7)* -0,926(1)
-~ti;* 0,574 (3)
C C{5) -0,1556 0,7031 - 0,6938 2,8034
N(I}

D N,ii - o,oo t (3) --0,1447 0,7014 --0,6979 2,7576

C,2> o,oto(4)
O!8} --0,015(3)
C{4} 0,012(5)
--0,007(4)
0 {Io)* 0,010(3)

*These atoms were not taken into account in the calculation

of the rms planes.

i -~[ CIC02Me sS
~N / ~CH OH ~t~N.~TP~ N/&~CH20H - t-BuOll/MeO~- VIII
~20~Me

As we assumed, bicyclic VIII does not undergo further reduction by sodium borohydride.
An investigation of its chemical properties showed that it is stable in both acidic and alka-
line media, as well as under the influence of amines. Prolonged refiuxing of VIII with l,l-
dimethylhydrazine does not give rise to any changes in the starting bicyclic compound. Fur-
ther investigation of its reactivity showed that under the influence of lithium aluminum
hydride the urethane ring opens to give 3-hydroxymethyl-4-methyltetrahydro-l,4-thiazine (XI).
A compound, which was isolated from the reaction mixture by preparative gas chromatography
and was identified as l-aza-3-oxa-7-thiabicyclo[3.3.0]nonane (X), is formed along with ring-
opening product XI when a twofold excess of lithium aluminum hydride is used in the reduc-
tion. It was demonstrated that the physicochemical characteristics of X coincide completely
with the constants presented in [2].

1041
 TABLE 5. Coordinates of the Atoms [.i0 ~ (.i03 for the H
Atoms)] in the VII Structure

A tom x y z A torn x y z

N(1; 8320(4) 123713) 3962(3) H 1~C~4; 1074 (5) 377(4) 471(4)

C~2) 9771(5j 940(4) 341 ! (4) H,2,C,41 1124(7) 255(5) 596 (5)
el31 11104(3J i755(31 4~)31 ~3) H,5~ 852 (5) 189(4) 609 (4)
C!4} [0532(5) 2691(5) 5010(6) m,t,C,o~ 767(51 407 (4) 365(4)
Ci5i 8573(5) ~ 2322(4) 5000 (4) H e,C,6, 759(5) 429 (4) 539(4)
C{6} 7340(5) l 3558(4) 4609~5) 14 , .C..~, 537(6} 223(4) 218(4)
Sc7) 5063(1) / 2965{i) 4390 ( 1) H:2,C~8) 413(5) 121(4) 28914)
C!81 5194(6) I 1635(6) 3124(5) 66316) -18(5) 288(4)
C/g) 6617(5) j 548(51 3581 (5) H,~,C 9, 617(6) -3(5) 440(4)
O(1o) 9932(4) / 98(3) 2553(3)

S~

vm TFH -- \ ~N T----~--~" <'N/<~CH2

X X]

The only reaction product is XI when a fourfold or greater excess of LiAIH~ is used.
Compound X is evidently an intermediate in the reduction of bicyc!ic urethane VIII. This is
confirmed by the fact that the reduction of X led to XI in quantitative yield.
The structures of VI, VIII, and XI were proved by IaC and :H h~VFR spectroscopy. The
spectral parameters are presented in Tables 1-3. The chemical shifts (CS) of the :3C atoms
can be assigned unambiguously on the basis of a study of the t~C NMR spectra under conditions
of complete spin decoupling and without suppression of spin-spin coupling with the protons,
as well as by comparison of the experimental data with the values calculated via an additive
scheme. Thus, the appearance of a signal corresponding to the C(~) atom in the form of a
doublet due to coupling with the 3-H proton and NCHa and OCH3 signals in the form of quartets
is characteristic.
The structures and conformations of the compounds obtained can also be established on
the basis of a study of the chemical shifts and spin-spin coupling constants (SSCC) in the
PMR spectra (Tables 1 and 2). In the case of VIII we were able to perform a complete analy-
sis of the spectrum and measure all of the SSCC. The SSCC of the ring protons [J2,~ =
i0.i Hz (aa)] in VIII corresponds to a ring conformation in which the 3-H proton is axially
oriented, whereas in the PMR spectrum of VI the 3-H proton appears in the form of a broad
multiplet with characteristic SSCC J2,3 = 4.0 Hz (ae), which corresponds to an equatorial
orientation of the 3-H proton and an axial orientation of the CHaOH substituent. Broadening
of the signals in the PMR spectrum corresponding to the protons in the 3 and 5 positions is
characteristic for VI; this is probably due to retarded rotation of the COOCHa group about
the N-C bond. Broadening of the signals hindered an accurate analysis of all of the SSCC
for this compound.
To establish the molecular-crystal structure of VIII we subjected it to an x-ray dif-
fraction study. The geometry of the molecule with designation of the atoms and planes is
presented in Fig. i.
The molecule is a condensed bicyclic system consisting of a six-membered tetrahydro~
thiazine ring with a chair form (see planes A, B, and C in Fig. i) and a planar ( A)
oxazole ring D. The coefficients of the equations of the root-mean-square (rms) planes of
the planar fragments of the molecule and the deviations of the atoms from them are presented
in Table 4.
The N(1) and S(7) atoms deviate 0.574(3) A and 0.925(1) ~, respectively, to opposite
sides from plane B. The dihedral angles between plane A and plane B and between plane C
and plane B are 51.2 ~ and 53.2 ~ respectively. Within the limits of the experimental error,
plane C is r with plane D.
The average lengthsoof the C--S bonds in the tetrahydrothiazine ring [1.809(5) A] and
the C--C bonds [1.523(6) A~ are close to their standard values [3]. Due to conjugation, the
C(a)--N(:) bond [1.351(5) A] is shortened as compared with a single bond; the other two C--N
bonds have the standard values. There are three types of C--O bonds in the molecule: the

1042
C(~)--0(3) bond [1.442(6) A] is a single ~ond, the C(=)--0(3) bond [1.349(5) A] is a sesqui-
bond, and the C(2)--0(:0) bond [1.193(5) A] is a double bond.
The molecules are packed in the crystal at distances no less than the sums of the van
der Waals radii of the corresponding atoms [4].

EXPERIMENTAL
The :H and :3C NMR spectra were obtained with Bruker WH-90 (90 MHz) and Bruker WM-360
(360 Mllz). spectrometers with tetramethylsilane (:H NrMR) and cyclohexane (:3C NMR) as the
internal standards. The mass spectra were recorded with an MS-50 AEI spectrometer (at an
ionizing voltage of 70 eV). The IR spectra of the pure compounds or suspensions in mineral
oil were obtained with UR-20 spectrometer. The x-ray diffraction analysis was performed with
a Syntex diffractometer. Preparative gas chromatography was carried out with a Pye-Unicam
105 chromatograph with columns packed with an SE-30 stationary phase. The course of the
reactions was monitored by means of gas-liquid chromatography (GLC); with a CHROM-5 chromat-
ograph with 2.5-m and 1.5-m columns packed with an SE-30 stationary phase (10%) applied to
Chromaton AW; and thin-layer chromatography (TLC) (with Silufol UV-254 plates, hexane--ethyl
acetate (2:1) as the eluent, and detection in UV light or by development in iodine vapors).
X-Ray Diffraction Analysis of l-Aza-3-oxa-7-thiabicycloI3.4.0]nonan-2-one (VIII). Sin-
gle crystals of VIII were grown from ethyl acetate, had the composition C6H~NO=S, were mono-
clinic, and had the following parameters: a = 7.682(4) A, b = 9.423(5) A, c = 10.054(3) A,
~ = 99.24(3) ~ V = 718.3 ~3, M = 159.2, d c a l c = 1.47 g-cm -3, ~(CuKa) = 33.9 cm -I, Z = 4,
space group P2:/c, and Fooo = 336. The intensities of 1203 independent reflections were
measured with a Syntex P2~ four-circle diffractometer (CuK~ emission, graphite monochromator)
by the 8/2@ scanning method up to 20ma x = 150 ~ In the calculation we used 957 reflections
with J > 2oj. The structure was decoded by the direct method by means of the MULTAN program
of the XTL system and was refined by the method of least squares within a total-matrix aniso-
tropic approximation. Absorption was disregarded, The hydrogen atoms, the coordinates of
which were calculated geometrically, were refined isotropically. The maximum standard devia-
tions of the angular and linear characteristics were, respectively, 0.4 ~ and 0.007 A (disre-
garding the hydrogen atoms). The final value of the divergence factor was 0.041. The coor-
dinates of the anoms are presented in Table 5.*
3-Hydroxymethyl-4-methoxycarbonyltetrahydro-l,4-thiazine (VI). A 1.2-g (12 mmole) sam-
ple of methyl chlorocarbonate was added with stirring at 20~ to a solution of 1.33 g (i0
mmole) of IX and 2.1 ml (15 mmole) of triethylamine in 40 ml of dry tetrahydrofuran (THF),
after which the mixture was stirred for 1 h, the resulting precipitate was removed by filtra-
tion, and the filtrate was evaporated at reduced pressure. The residue was distilled under
a high vacuum [120~ (i0-~ mmHg)] to give 1.6 g (84% of the theoretical yield) of a viscous
oil. Found, %: C 43.9, H 6.9, N 7.4. C:TH:~N03S. Calculated, %: C 44.0, H 6.8, N 7.3.
IR spectrum: vC= 0 1750, vOH 3220-3300 cm-:. Mass spectrum, m/z (relative intensity), %:
174 (M -- OH) (3.3), 160 (M--OMe) (20), (M--MeOH) (53.3), 144 (15.2), 130 (9.5), 128 (7.6),
126 (12.4), 118 (5.7), 117 (9.5), 116 (i00), 115 (5.7), 114 (7.6), 113 (26.6), 112 (13.3),
103 (5.7), 102 (13.6), i01 (16.7), i00 (16.7).
l-Aza-3-oxa-7-thiabicyclo[3.4.0]nonan-2-one (VIII). A 20-ml sample of methanol was
added With stirring in the course of 30 min to a solution of 5.47 g (25 mmole) of 3,4-di-
methoxycarbonyltetrahydro-l,4-thiazine and 3.8 g (i00 mmole) of sodium borohydride in i00 ml
of tert-butyl alcohol, after which the mixture was refluxed for 3 h and then cooled to 20~
The excess sodium borohydride was decomposed with 5 ml of water, the solvent was removed in
vacuo, and the residue was treated with chloroform. The chloroform solution was dried over
anhydrous sodium sulfate, after which the chloroform was evaporated. The residue was re-
crystallized from ethyl acetate to give 2.8 g (70%) of colorless crystals with mp 96-97~
(from ethyl acetate).
An identical compound was obtained in 97% yield by reduction of 1.91 g (i0 m_mole) of
VI with 0.95 g (25 mmole) of sodium borohydride under the conditions presented above. IR
spectrum (Nujol): ~C=O 1735, ~OH 3200-3300 cm-: Mass spectrum, m/z (relative intensity),
%: 159 (M, i00), 144 (20), 126 (23.1), 113 (46.2), i01 (23.1), i00 (15.4). Found, % :
C 45.2, H 5.6, N 9.0. C~H~NO2S. Calculated, %: C 45.3, H 5.7, N 8.8.

*The anisotropic temperature factors can be obtained from the authors.

1043
 3-Hydroxymethyl-4-methyltetrahydro-l,4-thiazine (XI). A solution of 1.59 g (i0 mmole)
of VIII in i0 mi of dry tetrahydrofuran (THF) was added dropwise with stirring in a nitrogen
atomosphere to a suspension of 0.57 g (15 mmole) of lithium aluminum hydride in 25 ml of
dry THF, after which the temperature of the reaction mixture was raised to 40-45~ and stir-
ring was continued at this temperature for 2 h. After the starting VIII had vanished (deter-
mined by monitoring by TLC with ethyl acetate as the eluent), the mixture was cooled, and i
ml of water was added slowly with stirring to the mixture. The resulting mixture was poured
into a chromatographic column and leached out with i00 ml of THF, after which the solvent was
removed i~ va~uo. According to analytical GLC, the mixture consisted of two components,
which were isolated by preparative GLC.
The first substance was identical to X [2] with respect to its physicochemical charac-
teristics, and the second was identified as XI.
Only thiazine XI in the form of a viscous oil was formed in 94% yield when a threefold
excess of LiAIH~ was used in this reaction. IR spectrum: 90H 3200-3324 cm -I. Mass spec-
trum, m/z (relative intensity), %: 147 (M) (8.3), 130 (M-- OH) (18.6), 129 (M -- H20) (12.1),
115 (M-- CH3OH) (20.7), 103 (5.8), 102 (i00), i01 (16.8), i00 (4.0). Found, %: C 48.9,
H 8.9, N 9.7. C~H~3NOS. Calculated, %: C 49.0, H 8.8, N 9.5.

LITERATURE CITED
i, R. Nurdinov, in: Youth Conference on the Search for Physiologically Active Compounds
[in Russian], Erevan (1984), p. Iii.
2. T. A. Crabb and M. J. Hall, J. Chem. Soc., Perkin 2, No. 2, 203 (1976).
3. Tables of Interatomic Distances and Configurations in Molecules and Ions. Chemical
Society Special Publication No. 18, London (1965), p. 228.
4. Yu. V. Zefirov and P. M. Zorkii, Zh. Strukt. Khim., 17, 994 (1976).

1044
LETTERS TO T H E E D I T O R

EFFICIENT METHOD FOR THE HYDROLYSIS

OF 4-CHLOROTETRAHYDROPYRANS

A. S. Arakelyan, A. I. Dvoryanchikov, and A. A. Gevorkyan D~C 547.811:542.938

It is known that 4-chlorotetrahydropyrans I and a number of other compounds that contain

a chlorine atom attached to a tertiary carbon atom undergo primarily dehydrochlorination (no
less than 60-70%) when attempts are made to hydrolyze them under the influence of dilute
aqueous solutions of bases or acids [I].
We have shown that when hydrolysis is realized by means of hydrogen peroxide, the dehy-
drochlorination of 4-chlorotetrahydropyrans I can be suppressed, and tetrahydropyranols II
can be obtained in high yields (63-85%).
F,' R'
C1 H n~
~J /
J
o
! I!
I, II a N=N'=H bN=CH2OCH3. RI=H: c R=H, NI=CH2OCH3

As expected [2], tertiary alkyl chlorides under these conditions form hydroperoxides
that do not undergo further changes under the reaction conditions.
The structures of the compounds obtained were proved by the PMR spectra, as well as by
identification with known samples [by gas-liquid chromatography (GLC)].
A mixture of 0.I mole of chloride I and 0.2 mole of 30% of hydrogen peroxide was stirred
at 50-60 ~ for 16-24 h to give pyranols IIa-c.
Compound IIa. This compound was obtained in 63% yield and had bp 81-83~ (12 mm) and
nD 2~ 1.4420.
Compound IIb. This compound was obtained in 69% yield and had bp 121-122~ (12 mm),
nD ~~ 1.4710, and d~ 2~ 1.0732. P ~ spectrum (CCI~): 1.12 and 1.26 (3H, s, CH3), 1.43-2.05
(3H, m, CH2 and CH), 3.31 (3H, s, OCH3), 3.4-3.8 (6H, m, OCH2), and 4.02 ppm (IH, s, OH).
Compound IIc. This compound was obtained in 85% yield and had bp 128-129~ (12 mm),
nD ~~ 1.4695, and d~ 26 1.0643. PMR spectrum (CCI~): 1.35-1.75 (6H, m, CH2), 3.29 (3H, s,
OCH3), 3.46-3.84 (6H, m, OCH2), and 4.14 ppm (IH, s, OH).

LITERATURE CITED
i. A . A . Gevorkyan, A. S. Arakelyan, A. I. Dvoryanchikov, and A. A. Akhnazaryan, in: New
Methodical Principles in Organic Synthesis. Summaries of Papers [in Russian], Nauka,
Moscow (1984), p. 135.
2. A . I . Rakhimov, The Chemistry and Technology of Organic Peroxide Compounds [in Russian],
Khimiya, Moscow (1979), p. 23.

Institute of Organic Chemistry, Academy of Sciences of the Armenian SSR, Erevan 375094.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, p. 1286, September, 1986.
Original article submitted April 20, 1985; revision submitted April 2, 1986.

0009-3122/86/2209-1045512.50 9 1987 Plenum Publishing Corporation 1045

NEW REACTION OF MALONONITRILE AND ARYLIDENE- AND
I-AKYLETHYLIDENEMALONONITRILES

Yu. T. Abramenko, A. V. Ivashchenko, K. A. Nogaeva, UDC 547.339.2.04'822.7.07

G. V. Gridunova, N. D. Sergeeva, Yu. T. Struchkov,
V. E. Shklover, and P. A. Sharbatyan

The dimerization of l-arylethylidenemalononitriles I [i] and their cross-dimerization

with arylidenemalononitriles II [2], as well as an example of the dimerization of isopropyli-
denemalononitrile in the presence of malononitrile (III) with the formation of l-amino-3-di-
cyanomethyl-3,5,5-trimethyl-l-cyclohexene-2,6,6-tricarbonitrile [3 ], have been previously
described. However, as a result of the cross-dimerization of nitriles la-c and lla, b in the
presence of malononitrile (III), instead of the expected l-amino-3-dicyanomethyl-3,5-diaryl-
l-cyclohexene-2,6,6-tricarbonitriles, we obtained the previously unknown 2,4-diamino-3,5-di-
cyano-6- (2,4-diaryl-l-cyano-i, 3-butadienyl) pyr idine s IVa-e.
Ar z

CH~ CN H (TN CN H

NC mn 2

rva-e

la ArI=C6H~ b ArI=4(C6Hb]C6H4,e AtI:=4CH~C~H, II .~Ar2=C6H~ bAr2=4FC6H~;

IV a % Ar~=C6H~,b,d Ar'=4-CH~CsH~,C ArL=4.(CGH~)CGH4: a c , o Ar~
b.e Ar'~= 4-FC6H4

Mixtures of I-III (0.01 mole each) and several drops of 2 N KOH in ethanol were main-
tained at 30-40~ for 10-15 min, after which they were heated to the boiling point. The 2,4-
diamino-3,5-dicyano-6-(2,4-diaryl-l-cyano-l,3-butadienyl)pyridines IVa-e that crystallized
out from the stirred reaction mixtures were removed by filtration after cooling of the reac-
tion mixtures.
Pyridine IVa. This compound was obtained in 50% yield and had mp 261-263~ (from ace-
tonitrile). PMR spectrum (D3-acetonitrile): 6.17 (4H, broad s, 2 NH2), 6.57 (IH, d, J =
15.8 Hz, I-H), 7.17 (IH, d, J = 15.8 Hz, 2-H), and 7.2-7.7 ppm (10H, m, aromatic protons),
pyridine IVb. This compound was obtained in 46% yield and had mp 284'286~ (sublimed).
PFLR spectrum (d6-acetone): 2.35 (3H, s, CH3), 6.63 (IH, d, J = 15.8 Hz, l-H), 6.90 and 6.97
(2H each, broad s, NH2), 7.27 (IH, d, J = 15.8 Hz, 2-H), and 7.10-7.55 ppm (SH, m, aromatic
protons).
Pyridine IVc. This compound was obtained in 43% yield and had mp 278-280~ (from dioxane
hexane). PMR spectrum (D6-acetone): 6.75 (IH, d, J = 15.8 Hz, l-H), 6.92 and 7.00 (2H each,
broad s, NH2), 7.35 (IH, d, J = 15.8 Hz, 2-H), and 7.30-8.0 ppm (14H, m, aromatic protons).
Pyridine IVd. This compound was obtained in 50% yield and had mp 271-273~ (from dioxane
hexane). PMR spectrum (De-acetone): 2.47 (3H, s, CH3), 6.63 (IH, d, J = 15.8 Hz, l-H), 6.90
and 6.98 (2H each, broad s, NH2), 7.30 (IH, d, J = 15.8 Hz, 2-H), and 7.30-7.45 ppm (9H, m,
aromatic protons).
Pyridine IVe. This compound was obtained in 62% yield and had mp 266-267~ (from aceton-
itrile). PMR spectrum (D6-acetone): 6.63 (IH, d, J = 15.8 Hz, I-H), 6.90 and 6.97 (2H each,
broad s, NH~), 7.33 (IH, d, J = 15.8 Hz, 2-H), and 7.10-7.63 ppm (9H, m, aromatic protons).
The results of elementary analysis of pyridines IVa-e were close to the calculated val-
ues. Intense peaks of the corresponding molecular ions were observed in the mass spectra of
Scientific-Research Institute of Organic Intermediates and Dyes, Moscow 103787. Trans-
lated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1286-1287, September, 1986.
Original article submitted March 26, 1986.

1046 0009-3122/86/2209-1046512.50 0 1987 Plenum Publishing Corporation

these compounds. The structure of pyridine IVa was proved unambiguously by x-ray diffraction
analysis. The mechanism of this reaction and the spectral properties of the synthesized com-
pounds IV will be described in special communications.

LITERATURE CITED
i. Yu. T. Abramenko, A. V. Ivashchenko, K. A. Nogaeva, N. A. Andronova, and E. B. Putsykina,
Zh. Org. Khim., 22, 264 (1986).
2. Yu. A. Sharanin, Yu~ A. Baskakov, Yu. T. Abramenko, Yu. G. Putsykin, A. F. Vasil'eva,
and E. B. Nazarova, Zh. Org. Khim., 16, 2192 (1980).
3. J . K . Williams, J. Org. Chem., 28, 1054 (1963).

1047
iH-ISOBENZOFURYLIUM (PHTHALYLIUM) SALTS (A REVIEW)

D. A. Oparin, T. G. Melent'eva, and L. A. Pavlova LDC 547.728.2.04.(047)

Data on the synthesis, reactions, structure, and stability of phthalylium salts

are correlated.

One of the most important problems in the chemistry of carbenium ions is the dependence
of their relative stability and reactivity on structure. In this respect, the five-membered
cyclic heterocarbenium ions with heteroatom, viz., the iH-isobenzofurylium (phthalylium) ions
are extremely convenient materials for study; they can be synthesized with quite a large var-
iety of substituents, the_r stability is susceptible to quantitative estimation, and their
quantitative properties are extremely sensitive to structural change. Aside from the value
of phthalylium ions in the development of theoretical organic chemistry, work in this direc-
tion is stimulated by the need to solve practical problems. Many phthalylium salts and co-
valently structured compounds based on phthalylium ions are used as dyes [i], medicinals
[2-4], and phototropic compounds [5], and further research in this area could be extremely
fruitful.

i. METHODS OF SYNTHESIS
The most important method of synthesizing phthalylium ions (R ~ = Alk, Ar, ArCH----CH--) is
the ionization of l-hydroxyphthalanes II (R 2 = H) in acid medium. Thus, by the action of
HCIO~, picric acid, or Lewis acids stable crystalline salts containing phthalylium ions were
separated: perchlorates [6-13], picrates [7], tetrachloroferrates (III) [6-9, 14], hexa-
chloroantimonates (V) [9, 14], hexachlorostannates (IV) [6-8], and tetrafluoroborates [15].
It should be noted that in the case of the hydroxyphthalanes (II) that contain an acetylene
group (R ~ = R3CEC -, R 2 = H) at position 2 of the heterocycle, reaction with HFeCI~, HCI0~,
or HSbCI~ causes an acetylene--allene rearrangement, and the resulting salts have the struc-
ture of phthalylidene ketone salts [16-20].
In the synthesis of phthalylium salts ethers of the hydroxyphthalanes II (R 2 = Alk) can
also be used [9, 21-23].
The action of acids causes heterolytic cleavage not only of the C--OR2 bond in hydroxy-
phthalanes and their ethers (II), but also the C--NR~R s bond in amino derivatives of phthal-
anes (III) that contain aromatic (R ~ = H, R 5 = Ar) [24], aliphatic (R ~, R 5 = Alk), or hetero-
cyclic (NR~R 5 = pyrrolidino, piperidino, morpholino) [25] radicals.
In the 1-substituted phthalanes the C(,)--C bond does not as a rule undergo heterolysis.
But in some derivatives, e.g., l-phthalylphenylnitromethanes IV (R 6 = C6H5) and l-phthalyl-
ni~roacetonitriles IV (R e = CN), that contain electron acceptor groups, acidic reagents cause
the cleavage of the strongly polarized carborr-carbon bond to form ph~halylium ions (I) [26].
The action of perchloric acid on l-alkylidene phthalanes (V) gives l-alkylphthalylium per-
chlorates I (R I = CH2R 7) [I] (see scheme on following page).
Phthalylium salts form from hydrobases, viz., the iH-phthalanes VI by oxidation with
Lewis acids [27], and by exchange reactions with active hydride ion acceptors, e.g., trity-
lium hexachloroantimonate [14, 27]. As shown in [27], ortho substituents in the l-At group
do not sterically hinder the oxidation-reduction conversions that involve iH-phthalanes.
Phthalylium salts of I containing an alkoxy group (R ~ = C2H50) at position i can be
synthesized by alkylation of phthalanes Vll with triethyloxonium tetrafluoroborate [21, 28,
29]. The l o w basicity of phthalides prevents alkylating agents such as dimethyl sulfate and
methyl iodide from being used for this purpose [28].

Section of Metabolic Regulation, Academy of Sciences of the Belorussian SSR, Grodno

230009; Lensovet Leningrad Technological Institute, Leningrad 198013. Translated from Khim-
iya Geterotsiklicheskikh soedinenii, No. i0, pp. 1299-1309, October, 1986. Original article
submitted June 12, 1985.

0009-3122/86/2210-1049512.50 O 1987 Plenum Publishing Corporation 1049

 i :' I
6 , t%y~.~./o
R~ / --.OR2 R 1 -"-,,.NR4Rs

, o. ,.". " "

tlX "~'--- ~-- -.B HX ~"r- - -

[~ ! [ -Y ~ -H;o
~ i. I' oi _
% ~. .... = = .....
.~(:tq~o. . . . . . I ~.. .oI
I'

R) R: CItR s
I
VIII I iV NO 2

/ l l F e C l 4 O r ~ l Li;dH N~ff~O~
'/
'/ (CeH~.)3C+'Sr'CI~ III~ o r liCt)Oll
~ " ' -~'r~"'\'.~. ' ~' ~, "~

k.y.
, R ~ "" " I I O;
v Vl ~ll

P h t h a l y l i u m s a l t s a l s o f o r m by t h e a c t i o n o f H F e C I . , HfibC.16, o r HCIO. on o - [ d i a l k T l -
(aryl)hydroxymethyl]phenyl aryl ketones Vlll (Y -- O, R: = At) [30, 31] and their oximes Vlll
(Y = NOH) [32].
l-Styryl substituted phthalylium ions (I, R ~ = ArCH----CH--)were synthesized by condensa-
tion of l-methyi-l-hydroxyphthalane (II, R ~ = CH~, R 2 = H) with aromatic aldehydes in acid
=edium [9, 33]. When o-acetylbenzoic acid was condensed with substituted salicylaldehydes
in the presence of HCIO~, hydroxystyryl derivatives of 3-oxophthalylium (VX) were synthesized
[33]:

~/COCB~

~:~COOH +

IX

2. STRUCTURE OF PHTHALYLIUM IONS

The formation of phthalylium ions by the action of acids on pseudobases was demonstrated
by analysis of the electron spectra of l-hydroxyphthalanes in neutral and acidic solvents
[I0, 34, 35], and by the synthesis of salts [6-15]. Elemental analysis of the latter estab-
lished unequivocally that the reaction of hydroxyphthalanes and acids proceeds with hetero-
!ytic cleavage of the C-OH bond by the equation: ROH + HX + RX + H20; consequently, the
resulting cations are carbenium ions.
In contrast to the covalently structure hydroxyphthalanes, the phthalylium ions absorb
in a longer wave region of the spectrum and are characterized by two absorption maxima of
different intensities. The location of the less intense maximum around -290 nm is practi-
cally independent of the nature of the substituents at C(~) and C(a) [36-38]. Analysis of
the electron spectra of phthalylium ions and their sulfur analogs (thiophthalylium ions) or
nitrogen analogs (isoindolinium ions) showed that this maximum is related to the presence of
the heteronium grouping [37]. The location of the second absorption band is determined by
the nature of the substituent at the positively charged carbon [11-13, 22, 35-43]. It was
shown [13, 36-38] that the long wave absorption band undergoes a bathochromic shift with in-
crease in the electron donor capability of the substituent at the para position of the l-aryl
group. Here a satisfactory correlation has been found of the wave numbers corresponding to
this band with the Braun-Okamoto o+ constants of the substituents [13, 37, 38]. It should

1050
be noted that the sensitivity of reaction series* to the effect of C( ~ substituents on the long-
wave band is independent of the nature of the C(3) substituents (p ~ 4.9.10 ). Lengthening
of the conjugation chain at position 1 (replacement in I of R: = C6H5 by R: = C~H~CH----CH--)
causes a 78 nm bathochromic shift of the long-wave band [I, 9]. Any structural changes in
the conjugated system are distinctly reflected in the location of this band, e.g., replace-
ment of R = H by R = CH3 in the X salts causes a i0 nm hypsochromic shift [!].

CI[~ " / "CH 3 C|[3 CI] 3 "CIO-

X

This set of data convincingly confirms the presence in phthalylium ions of a conjugated
carbenium-oxonium grouping. The substituents at C(3), which are isolated from this grouping
by the sp 3 hybridized carbon, do not significantly affect the location of the long-wave band
[i2, i3, 22, 36, 38].
The IR spectra of the phthalylium salts were compared with those of the respective pseu-
dobases, the l-hydroxyphthalanes [i0, 44]. In going from the covalently structured compounds
to the salts the band intensity decreases in the 920, 1020-1050, and 1150 cm -~ regions (C--O-
C) and the intensity significantly increases in the 1400-1600 cm -: region; this indicates an
increase in the carbon--oxygen bond frequency and the appearance of a strong polar substituent.
The PMR spectra also confirm the conjugated carbenium-oxonium structure of the phthalyl-
ium ions. As has been shown [37], the spectrum of 3,3-dimethyl-l-para-tolylphthalylium per-
chlorate shows a weak-field shift of the proton signals of all alkyl groups as compared to
the spectrum of the oxo compound. The shift of the signal of the methyl of the para-tolyl
substituent is due to its conjugation with the cationic reaction center, while the shift of
the gem-C(CH3)= protons is due to the presence in the phthalylium ion of the electron accep-
tot grouping--O+=which decreases the electron density at C(3).
The molecular structure of l-[2-(2-hydroxyphenyl)]vinyl-3,3-dimethylphthalylium per-
chlorate was studied by x-ray diffraction analysis [33]. The geometric parameters thus ob-
tained and the calculations by the SSP MO method in the ~-electron modification are evidence
for strong delocalization of the positive charge on the cation.

3. CHEMICAL REACTIONS
The reactions of phthalylium salts with various nucleophi!ic reagents are the most typi-
cal and have been studied the most. Here, as a rule, the products of nucleophile addition
to C(:) of the conjugated phthalylium ions are formed. Depending on the structure of the
starting reagents and the reaction conditions, these reaction products can in a number of
cases undergo further conversions to form acyclic compounds or to enlarge the ring; this is
important in the synthesis of new heterocyclic systems.

3.1. Reactions with O-Nucleophiles

l-Aryi(styryl)phthalylium salts are easily hydrolyzed by aqueous salt solutions to form
l-hydroxy-l-aryl(styryl)phthalanes II (R 2 = H) [9, 12, 22, 36, 45, 46]. In the case of I
salts with bulky substituents at position 1 (R ~ = mesityl, 9-anthryl) the final products are
hydroxyphthaianes, the ketoalcohols VIII (Y = O) [30, 31].
Hydrolysis of l-alkoxyphthalylium salts does not stop at the hydroxyphthalane stage,
but gives the respective phthalides VII [47]. The labile l-hydroxy-l-alkoxyphthalanes can
be stabilized not only via cleavage of an alcohol molecule, but also by scission of the het-
erocycle. Thus, when an alcoholic solution of I salts (R * = CH~O, C2H50) is treated with
5% NaHC03 solution, along with phthalide VII the respective o-hydroxymethylbenzoate esters
are also separated [23].
The reaction of phthalylium salts with alkali alcoholate forms ethers II (R ~ = CH3,
C2H5) [9, 21, 23, 29, 46-48]. It has been shown [23] that the reactions of l-eChoxyphthalyl-
ium tetrafluoroborate with sodium methylate (in CHsOH) and of l-methoxyphthalylium tetra-

*For phthalylium ions, the concept "reaction series" here and subsequently means a series
of compounds having a variable substituent at C(~) and constant substituents (within the
limits of each series) at C(3).

1051
fluoroborate with sodium ethylate (in C2HsOH) give (beside the expected addition product,
l-methoxy-l-ethoxyphthalane), l,l-dimethoxy- and l,l-diethoxyphthalanes, respectively, in 80
and 70% yields. It should be noted that ethers II (R = = Alk) with R ~ = Ar are stable when
stored, whereas ethers with R ~ = C=HsO are converted in time to phthalides VII.

3.2. Reactions with Nucleophiles

The reaction of methylmagnesium halide with l-arylphthalylium perchlorate forms l-
methyl-l-arylphthalanes XII [i, 8, 15, 39-43, 45, 49, 50]. But in the case of salt XI (Ar =
9-anthryl), besides l-methylphthalane XII (Ar = 9-anthryl) compounds XIII and XIV were also
separated [31]. The yields of XII-XIV were 15, 53, and 15%, respectively. The similar
course of the reactions was attributed to the low accessibility of position i of the hetero-
cycle due to shielding by the bulky substituent, and the ready accessibility of the meso-
position of the l-anthryl group (resonance structure XV). These authors also conclude that
phthaiylium salts can react with a Grignard reagent both by ionic and free radical mechan-
isms, as indicated by the formation of compound XIV.

CH~

-I
CH~
CH3MgHal --- ~ XII

cI%
/'cm2 cIt 3
Ar
XI

I (~= 9-anthryl)

CI%

1 .cm~

XFr

The main course of the reaction of l-styrylphthalylium perchlorates XVI with aminoalkyl-
magnesium halide is nucleophilic addition of aminoalkyl to C(:) to form phthalanes XVII [51,
52]; however, in some cases the Grignard reagent can also add at the double bond. Thus, in
the reaction of perchlorate XVI (R = H, Ar = p-CH3OCsH~) with dimethylaminopropylmagnesium
chloride, along with the main product XVII (R = H, R ~ = CH2, R 2 = R s = CH3, Ar = p-CHsOC6H~)
compound X-VIII was separated in 19% yield [52].
CH~

CH,~
CIMzCH2-R ~- CH~,'R~R ~

~"-~ ~ i XVII

R'TR
A.r
C~i3

X'VI

H cg(cH~) ~N(c~.fl z
I
B, R~, ~-I~. cHz; R' = alkylene CeH,.OCH~ - p
k'VllI

The reaction of l-arylphthalylium perchlorate with phenylnitromethane and nitroacetomi-

trile in the presence of organic bases forms (l-aryl-l-phthalyl)phenylnitromethanes IV (R 6 =
C~H~) and (l-aryl-l-phthalyl)nitroacetonitriles IV (R 6 = CN) [26].
Heating l-arylphthalylium perchlorate XI with excess dimethylaniline gives l-aryl-l-
p-dimethylaminophenylphthalanes XIX [31, 45, 50]:

1052
 ri'~.
CsH.N(CH~)
~ /S"~,-------!--
CH-
Ar/~CoHZ~(CHj)~-p
XEK
3.3. Reactions with N-Nucleophiles
The reaction of perchlorates XI with secondary aliphatic and cyclic amines forms the
respective l-aminophthalanes III [25, 53]. It was shown [25] that in ether-'water medium the
course of the reaction depends on the acidity of the cations and the basicity and steric
structure of the amines. Thus, under these conditions 3,3-dimethyl-l-phenylphthaiylium
perchlorate did not react with most of the amines tested; only the hydrolysis product of the
phthalylium salt, l-hydroxy-3,3-dimethyl-l-phenylphthalane, was isolated. In those cases
where aminophthalanes did form, the yields did not exceed 25%. When Ar = C~Hs was replaced
by Ar = p-CH3OCeH~, l-aminophthalanes III were obtained with most of the amines and their
yield was appreciably increased. But with amines such as dibutylamine, diisopropylamine,
and 2,6-dimethylpiperidine in no case was the respective derivative obtained. The course
of the reaction of phthalylium salts I (R ~ = C~Hs, X = CIO~) with primary aromatic amines
(aniline, o- and p-toluidines) depends on the synthesis conditions. At room temperature in
the presence of pyridine there is nucleophilic addition of amine to the conjugated carbenium-
oxonium ion to form the amine N-derivative, l-arylaminophthalanes III (R: = C6H5, R ~ = H,
R 5 = Ar), whereas with heating the final products are the amine C-derivatives that are iso-
meric with the arylaminophthalanes, viz., l-p-aminoarylphthalanes. With p-toluidine under
these conditions compound III (R I = C6H5, R ~ = H, R 5 = p-CHsC6H~) was obtained [24].
The reaction of phthalylium ions (using either the salts [50] or the hydroxyphthalanes
in the presence of strong mineral acids that cause them to ionize [i, 7, 8, Ii, 12, 31, 36,
39-43, 45, 49]) with 2,4-dinitrophenylhydrazine forms hydrazinophthalanes XX, which in the
case of bulky radicals at C(~) can be converted to the acyclic isomers XXI [41, 45]. Boil-
ing an alcoholic solution of l-hydroxy-l, 3,3-triphenylphthalane and 2,4-dinitrophenylhydra-
zine in the presence of concentrated hydrochloric acid gave phthalazine XXII, the product
of intramolecular dehydration of a hydrazone like XXI [55].
-_ cH~ ~ ~'~-R~
i
i NH2OH.HC C6H5
X~ XXI XAI[

I Arl Arl Arl i Ar~" ArI

~~HO NOH -1t20 N
H

R2=2,4_(NO2)zC~It3 .'0~II

The formation of l,l,4-triaryl-2,3-benzoxazines XXIII by the reaction of 1,3,3-triaryl-

phthalylium ions with hydroxylamine also probably proceeds via the formation of oximinophtha-
lane addition products followed by isomerization to the hydroxyoximes [56, 57].
When gaseous ammonia is passed through a suspension of perchlorate XXIV in benzene,
spiropyranes of the 2-oxaindane series XXV form, that exhibit photochromic properties [5]:
C~ CH~
~/'~ 9 CH3 ~Y'~-- ~ C H ~
9 | .c,o:

R
XX~

1053
 TABLE i. PKR+ Values of Phthalylium Ions

W=R a Rx PKR+ R ~=R: Ra PKR"

CHa CHa -2,46 [34] CHa 2-BrC6H, -2,73 [10]

CHa C~H~ -- 1,71 [39], CHa 3-BrC6H~ -2.98 [431
- 1,77 [341 CHa 4-BrC6H4 -2,37 [431
CHa 2-CHaCsH4 -o,31 IlOl, CHa 3-FCsH4 -2.~6 142~
--0,29 [411 CHa 4-FC~H4 - 1.68 [42]
CHa 3-CHaCeH~ --1,48 [41] CHa 4- (CHs}:NC6H4 +4,94 [37]
CHa 4-CHaC~H, -0.83 [34]. CHa 4- {C~Hs)2NC6H4 +5,14 [37]
-0,76 141] CHa 1-Naphthyl - o,71 [351
CHa 2-CHaOC6H~ -r [1o1, CHa 2- Naph t.h~,1 - - 1 , 4 6 [35]
--0,90 [40], CHa 4-CaIqsC6H4 - - 1,44 [35]
--0,95 [671 CHa Mesityl. + 1,93 [30]
CHa 3-CHaOC~H~ -2,12 [4o] CHa 9- Anthryl + 1,9 I31]
CHa 4-CHaOCsH~ +0,56 [34], CHa C~H~CH= CH~ +1;o8 [9]
+ 0,58 [40] CHa 9 Phenan~hryl - 1.02 I45}
CHa 2-C:H~OC~H4 -1,o4 [Io], CHa* CsHs - 2 , 8 5 Ilal
-- 1 . 0 7 [ 6 7 ! CHa* a.CHaC6H4 -2.58 [131
CHa 4-C.~HsOC~H4 +0,58 [67J CHa* 4-CHaC6H4 - L91 [lal
CHa 2-CIC6H~ -~,9~ [~o1, CHa* 4-CH.~OC6H4 -0,60 [131
-2,78 [391 C'rts 4-CIC6H4 --3,47 I13]
CHa 3-CIC~H4 -2,96 [15, 391 CH~* 4-(CH.~):NC6H4 +3,58 [131
CHa 4,CIC6H~ -2.18 [391 CHa* 4- (C..Ha):NC6H4 +8,99 [13]
C=Hs C~H8 -0,94 itq iso,C~Hv 3-CH~C6H4 +o,96 1121
C=Hs 2-CH~C~I-t~ +o,72 [I 11 /so-CaHv 4-CHaC~H~ + 1,64 [12]
CaHs 3-CHaCsH4 -0,79 [1 l] iso-CsI% l-Naphthyl +0.72 [12]
C=Hs 4-CHaC~H~ +o,o5 Ill1 iso-C,'.H7 2-Naphthyl +0,58 [12]
C:Hs 2-CHaOCuH4 +o,o3 f361 :~so-CJ-Ir 4-C~H~G6H~ +0,84 [12]
C:H8 3-CHaOC~H~ - 1.45 I361 C~Hs C~th -3.74 [68]
C:H~ 4-CI-I~OC~H~ + 1,38 I361 C~lls 2-CH~C~H4 --2,27 [38j
C:Hs 3-CIC~H~ -2,30 [36] Cd-Is 3-CH,~Cgd4 --3,21 [381
C2Hs 4-C1Cg4~ - !,59 [361 CsHa 4-CHaCsH4 -2,74 [38}
CaHs 3-BrC6H4 - -2 , 4 1 {36] CoI-t~ 2-CHaOC6H4 -2,80 {381
C~Hs 4-BrC~H~ -- },76 [36] C~Hs 4-CHaOCsH~ - 1,o6 i38]
C=H~ 3-FC~Ft~ --220 [361 C~Hs 4-C~C~H~ --4.12 i38]
C=Hs 4-FC6H4 --0,91 [36i CsHs 4- (CHahNCsH4 +~ [66]
C=Hs 4- (CltJ :NCsI-t~ +5.66 [66] C~l-ls 4- {C.-H~)=NC~H4 -;-3,33 [66]
C:Hs 4- C.Hs) q'<C61-L +6.14 [66] 4-CHaC~I-t4 CeHs -3,22 [22]
C=Hs 1-Naphthyl -O,Ol [111 4-CHaCsH~ 4-CIhCsH~ -2,49 I221
C2Hs 2~Naphth'yl -0,82 [[ II 4-CF!aCsH~ 4-CiC~H~ -3,83 [22]
C=Hs 4-C~H~C~H~ -1,o7 Iltl 4-CIC6H~ Csl la --4,51 [22]
C~Hs +o.71 [121 4-C1C~H4 4-CH~C~tI~ -3,38 [221
iso-CaH~ 2-CHaC~H4 +2,06 [12] 4-C1C6H4 4-CIC6H~ -5.27 [22]

*R 2 = C6H5.

3.4. Reactions with P-Nucleophiles

The reaction of triphenylphosphine and phthalylium tetrachloroferrates (III) forms sta-
ble phthalylphosphonium salts XXVI [58]:

At'

<4. . I .0 -Fe,rl$
RI--Ar, X=FeCl 6 %. ~ "><'+ 9
'2. " " P ( , % H ~ ~ ,
X~2/I

3.5. Reduction Reactions

When phthalylium salts I (R ~ = Ar, X = FeCI~) are treated with zinc dust in water-ether
medium in the presence of HCI, diphthalides XXVII form by reductige dimerization [14, 59].
In contrast to their nonannelated analogs, the bisdihydrofuryls [60, 61], the latter are
stable and do not tend to dissociate into radicals. The introduction of substituents at the
ortho position of the l-aryl group in order to sterically stabilize the intermediate radicals
was unsuccessful [59].

1054
 l-Arylphthalylium tetrachloroferrates (III) are reduced by lithium aluminum hydride to
IH-phthalanes Vl (R: = At) [27]. The reaction of l-ethoxy-3,3-dimethylphthalylium tetra-
fluoroborate (XXVIII) with LiAIHa does not stop at the ethoxyphthalane stage, but forms 3,3-
dimethylphtha!ane (XXIX) [47]:
CII~ CH~

OC2H 5
XT~WI I I XXLX

Formic acid was also used as reducing agent [6, 8, 14, 27, 39-43, 49]. In that case,
IH-phthalanes VI were formed. It was shown [27] that the oxidizing activity of phthalylium
ions changes in the same direction as their acidity. The action of HCOOH on 1,3,3-trimethyl-
ph~halylium perchlorate gives the salt X (R = H) [i].
Substances such as 1,3-dimethyl-2-phenylbenzimidazoline [14, 27], 1,2,4-triphenyl-l,2-
dihydrophthalazine [62], and 3,3-dimethyl-2-phenyl-l-p-anisylisoindoline [63] that contain
labile hydride hydrogens can also be used to reduce phthalylium salts. The reaction forms
phthalanes VI and the respective benzimidazolium, dihydrophthalazinium, or isoindolinium
salts. Attempts to use 2,3,3-triphenyl-l-arylisoindolines as hydride ion donors were unsuc-
cessful [64].

3.6. Other Reactions

As exemplified by 1,3,3-trimethylphthalylium perchlorate, it was shown that the hydro-
gens of a methyl at position 1 are highly mobile. The perchlorate condenses easily with
aromatic aldehydes to form l-styrylphthalylium perchlorates I (R: --ArCH=CH--) [i, 9, 52, 65],
and with acetic anhydride and ethyl orthoformate to form cyanine dyes X (R = CH3 and R = H,
respectively) [i, 65].
Tetrafluoroborate XXVIII takes part in exchange reactions with l-ethoxy-l-ethylthio-
3,3-dimethyl(phenyl)thiophthalanes to form ether II (R: = C2H50, R 2 -- C2H5) [47].
The action of sodium iodide in acetonitrile on l-ethoxyphthalylium tetrafluoroborate
gives phthalide, and as a byproduct ethyl o-iodomethylbenzoate [21].
When phthalylium tetrachloroferrate I is boiled with 57% HCIO~, the FeCI~ anion (X) is
easily replaced by CIO~ [37].

4. STABILITY OF PHTHALYLIUM IONS

An important feature of phthalylium ions that distinguishes them from many other types
of cyclic cations is the possibility of quantitative study of acid--base conversions in which
they are involved; such reactions are not complicated by side reactions and are reversible
(except for the l-alkoxyphthalylium salts, see p.1051). Over a definite acidity range there
is an equilibrium between the carbocations and the corresponding pseudobases [34, 35]: R+ +
KR+
H~O $ ROH + H +. In the case of phthalylium ions that have a dialkylamino group in the l-aryl
substituent, the solution contains ammonium ions in addition to the carbenium ions and the
KR +
hydroxy compounds [37, 66]: R + + H20 ;t ROH + H +
I~.
HR+OH. A large number of publications
have been devoted to the stability of phthalylium ions (pKR+ values were determined by spec-
trophotometry) and the effect of various structural segments on stability and reactivity
(Table i).
Phthalylium ions are about i/i0 as stable as the analogously structured thiophthalylium
ions [37, 44, 69], and 10 -9 as stable as the isoindolinium ions [37, 70]; this convincingly
demonstrates the participation of the heteroatom in ion stabilization and confirms the pre-
sence of the carbenium heteronium grouping. But the change of pKR+ within the group of
phthalylium ions over quite wide limits indicates that cation stability is not determined
by the heterocyclic grouping only. The substituents in the heterocycle also take part in
positive charge delocalization.
Substituents located alpha to the heteroatom and joined directly to a carbon carrying
a positive charge have a significant effect on phthalylium ion stability: electron donor

1055
substituents stabilize the ions, while electron acceptor substituents promote hydrolysis.
The replacement of aryl by methyl, which shows only an inductive effect, reduces cation re-
sistance in hydrolysis; lengthening the Conjugation chain (replacement of R 3 = CbH5 by R 3 =
C~H~CH==CH--) increases cation stability.
In a quantitative estimate of the effect of substituent in the l-phenyl group on phthal-
ylium ion stability, it was shown [71, 72] that the Hammett o-constants are suitable for de-
scribing the effect of meta substituents as well as p-CH3, p-F, p-Cl, and p~Br which do not
have an appreciable tendency to undergo conjugation~ The pKR+ values of all the ortho and
para substituents with distinct electron donor properties (CH30, C2H50, and especially (CH3)2N
and (C=Hb)2N) deviate from the PKR+-O straight line.
The electrophilir Braun--Okamoto o+ constants reflect quite fully the effect of direct
>olar conjugation of the above-mentioned para substituents with the reaction center [13, 37,
38]. In this case, it has been shown [13, 38] that the sensitivity of the reaction series
no the effects of meta and para substituents in the l-aryl group is practically independent
of the nature of the substituents at position 3 (p ~ 3.7).
The effect of ortho substituents on the pKR+ of phthalylium ions is ambiguous; in all
the reaction series o-CH3 increases cation resistance to hydrolysis as compared with the para
isomer, whereas o-CH30, o-C=Hb0, o-Cl, and o-Br decrease it. The effect of o-tolyl is due
no the +I effect of methyl, which decreases the fractional positive charge on C(:) of the
ca~ion, and increases the hydroxy mobility in the pseudobases that are in equilibrium with
the cations [I0]. The low pKR+ values of phthalylium ions that have CH30, C2HsO, CI, or Br
in the ortho position of the l-aryl substituent are due mainly to two circumstances~ the
-I effect of these groups that destabilizes the cations, and to the strong BMBC intermolecu-
far hydrogen bonds between the hydroxyls in the l-hydroxyphthalanes and the ortho substituents
nhat stabilize the pseudobases [i0, 38].
It was shown [73] that in the phthalylium ions series the "ortho effect" is due not to
steric, but to electronic factors. A satisfactory single correlation was found between pKR+
for ortho, meta, and para substituted compound and the a+d constants [73, 74].
Substituents in position 3 of the heterocycle that are structurally removed from the
reaction center have somewhat less effect on cation stability than substituents at C(~)~
Tnis effect is inductive in nature [12, 22, 36, 38]. As the inductive effect of the substi-
tuent increases, so does cation stability. Exceptions are phthalylium ions with bulky group-
ings, e.g., iso-C3HT, at C(3). The stability of cations with these groups is due, besides
the inductive effect, to an additional steric effect [22]. The effect of substituents at
C(3) on phthalylium ion stability can be described quantitatively in a one-parameter equation
by the Taft inductive o* constants (p ~ i~8) [22].
With increasing temperature, phthalylium ion stability decreases. It was shown [75]
that the entropy factor makes the principal contribution to the change in free energy of car-
bocation hydrolysis.

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I~SS SPECTROMETRIC DECOMPOSITION OF B-PHENYLOXIRANECARBOXYLIC

ESTERS

O. S. Anisimova, V. V. Chistyakov, A. I. Bokanov, UDC 543.51:547.717

V. I. Shvedov, and Yu. N. Sheinker

The electron-impact mass spectra of the E- and Z-isomers of the u,B-methyl

substituted esters of B-phenyloxiranecarboxylic acids have been studied.

Ethylene oxide derivatives, particularly the B-phenyloxiranecarboxylic acids and their

esters, are interesting materials for study in connection with their structural features,
tendency to isomerize, and unequivocal course of their addition reactions; this has been
responsible for the study of this class of compounds by various chemical and spectral methods
[1-4]. However, the oxiranecarboxylic acids have been insufficiently studied by mass spec-
trometry. Hitherto, the electron-impact mass spectra have been considered for a series of
ethyl and tart-butyl esters of B-phenyloxiranecarboxylic acids [5, 6]. The authors of [5]
proposed an interpretation of those spectra on the basis of rearrangements of the molecular
ion (M+) before decomposition, opening of the oxirane ring at the C-C and C--O bonds, and
migration of the substituents located at the a- and B-carbons. However, the methods used in
[5] to establish the decomposition sequence were extremely limited in scope, due to the ab-
sence at that time of the DADI procedure and defocusing in the first field-free space.
The present work presents a chromato-mass spectrometric study of the E-isomer of a-
methyl-B-phenyloxiranecarboxylic acid E-I, and the E- and Z-isomers of the oxiranecarboxylic
esters II-V:
R s ~ = COOR T

0
E-isomers Z-isomem
[-V ll-V

E-I I~x=R~=H, R2=CH3; E-,Z-I[ RI=C2Hs, R2=CH3, R3=H: E-,Z-III RT=R~-=CI't3;

R3=H; E-,Z-IV RI=C2Hs, R2=H, R3=CH3; E-,Z-V RL=C~Hs, R-~=R~=CHs

S. Ordzhonokidze All-Union Scientific Research Institute of Pharmaceutical Chemistry,

~!oscow 119021. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i0, pp. 1310-
13i4, October, 1986. Original article submitted June 17, 1985.

1058 0009_3122/86/2210_1058512.50 9 1987 Plenum Publishing Corporation

 TABLE I. Electron-lmpact Mass Spectra of Compounds I-V at 70
eV*

Corn- m / z (intensity, %)
pound

E-I 134 (4), 133 (3), 132 (5), lOS (8), I07 (100), 105 (12), I04 (3), 103 (3),
91 (24), 90 (54), 89 (42), 80 (3), 79 (40), 78 (3), 7(3 (16), 72 (3), 65 (4),
54 (4), 63 (4)
E-II 136 (10), 135 (lO0), 133 (9), I32 (4), 108 (6), 107 (81), 105 (21), 103
(3,L 91 16), 90 (22!, 89 (17), 79 (33), "77 (10), 43 (87)
Z-II 136 (10), 135 (IO0), 133 (7), 132 (3), 108 (5). 107 (65), 105 (141, 91 (4).
90 (1~), ~9 (141, 79 (21), 77 (8). 43 (86)
E-III 133 (6), 132 (3), 122 (9), 12l (t00). 107 (3), 105 (12). 91 (5), 90 (23),
89 (16), 79 (6), 77 (13), 63 (5), 51 (6), 43 (23)
Z-Ill 133 (4), 122 (9), 12l (100), 107 (3), 1(15 (11), 91 (5), 90 (24), 89 (14),
79 (-t), 77 (t0), 63 (4), 51 (51, 43 (I6)
E-IV 206 (.!), 205 (61, 1~9 (5). 17,M (~,), 161 (5). 160 (i4), 150 (3), 149 (10).
133 (61, 134 (6), 133 (51), 132 (10(!), 121 (14). 119 (3), 105 (72), 104
(62i, 103 (61), 9l (6), 79 (19), 7~ t36), 77 (-16), 51 (12), -13 (54)
Z.-IV 206 t:3). 205 (51, 178 (4), 161 (4), 160 (11), 149 (14), 135 (6), 134 (4),
133 (30), 132 (100). 121 (13), 119 3). 105 (5.t), 104 (63). 103 (5-), 91
((J), 79 (26), 73 (41), 77 (43), 51 (I1), 43 (60)
E-V 219 (3), 174 (6). 149 (55), 147 (31), 146 (72). t32 (5). 131 (6), 121
(52), I19. (13), 105 (21), 104 (IOO). 103 (55). 91 (15), 78 (32), 77 (25),
51 (i~),43 (90)
Z-V 219 (4), 178 (5), 174 (7), ]73 i3), 149 (59), 147 (39), 1,16 (92), 132 (8).
131 (9). 121 (61). I19 (15), 105 (23). 104 (lO0), 103 (66), 9l (20), 78
(,17), 77 (39), 5l (13), 43 (aS).

*lon peaks with intensity Z3% of maximum are shown.

In considering the data (Table i) it must be noted first of all that the mass spectra
of individual E- and Z-isomers show no stereoselectivity in the principal decomposition
routes.

Scheme i~
7+.
+ _C202CH 9 Vh~. /CH 3 _COCII2 _3+.
PhCH=OEt -~- 9 ~ /'~COOEt ~ PhCH2C00Et '
~I' 135 ~ 0 ~0~ ~4' 164

"i-c2 ., .

?hCH=OH PhCH=C/ ~ * -CO

~C00Et
~2' I07 19(] ~5' 160
+ -COCH~" +.
9 i -CO I PhCHCOCH 5 --.-- FhCI!
". -~CO @3, 133 o&)
-,.Coo

13Z "~..~ ~I 105

+
89 COCH~
43

%In all cases in the schemes, the number characterizing the

ion determines the m/z value.

The fragmentation sequence of the compounds was determined from the DADI spectra and by
defocusing in the first field-free space. It was established that the decisive course of
fragmentation of the a-methyl substituted compounds I-III is the formation of ion r and its
decomposition products (Scheme i). P h C R 3 ~ R *, the structure proposed for r in [5], was con-
firmed by the dependence of the change in mass number on substituents R ~ and R 3 (Table 2,
compounds l-V). Study of the mass spectra of esters E-If and Z-II in which the ester oxygen
is replaced by isotope ~80%% showed that ~ contained an appreciable amount of tracer. This
means that r forms by the migration of alkoxy to the B-carbon followed by detachment of

##~lixtures of isomers E-, Z-III were obtained by transesterification with C= H s Isnu

~;, in the pre-
sence of C2HsISONa.

1059
 A o~

1.1
U ~ ~ .

mue---- m j ~

.r..t

=
0

~
~J

I 9~

,m

0 ~ (I

m
!
>

0
+ ~
i0
L~

1060
 TABLE 3. lon Peak Intensity
in Spectra of Isomeric Esters
E-, Z-II at 12 eV
Relative inten-
sity,qo
Ion
E-II Z-If

9
IM-o]~ 40
21 23
100 100

s 2. The other decomposition paths for M + of compounds I-III are related to the stepwise
:ietachment of the ester group (ion ~ ) with elimination of an O atom,* RIOH molecules (r
and COCH2 ( ~ ) , but the intensities of these peaks in the 70 eV spectra do not exceed 1%
~Table 2). Scheme 1 shows as an example the steps in the decomposition of esters E-, Z-II.
It is important to note that according to our data the ion with mass number 105 forms
only by decomposition of [M-- COOEr] + (#3) and apparently has the composition and structure
shown in Scheme i. Direct formation from M + of benzoyl cation with the same mass number was
no~ observed. Analogously in the case of the 8-methyl substituted esters E-, Z-IV, andV the
molecule ion does not decompose to form acetyl cation.% These data indicate the absence of
rearrangements related to the scission cleavage of C--C and C--O bonds or the mirgration of 8-
substituents to the s-carbon as presumed in [5]:

Scheme 2
Ph.~ / N2
R' ~C ~ 2 ~ 2 / ~ " C OOR ' PhCO
\ 0 . Io5

P h x c . . . . C "'Rz
IR5~ ~ / / ~COOR ~ ~ -,'- R'~CO~
0 43

It is evident that the oxirane ring actually opens by electron-impact ionization before
decomposition, but of the two C--O bonds the more polarized bond of oxygen with benzyl carbon
<the 8-carbon) is preferentially cleaved.t% This is indicated by the fact that all the sub-
sequent rearrangements proceed by migration of groups from the s-carbon to the cationic cen-
ter at the 8-carbon (Scheme 3).
It should be noted that the rearrangements involving opening of the oxirane ring are
very favored energetically; the peaks of the respective ions appear in the spectra even when
the energy of the ionizing electrons is reduced, and the #~ peak in the spectra of esters
E- and Z-II at 12 eV remains maximal as before (Table 3). It is clear that the very ease of
heterocycle opening under electron impact conditions causes the spectra of the E- and Z-iso-
mers to coincide. As follows from Table 3, even at 12 eV energy the spectra of the E- and
Z-isomers are practically the same.
It is known that the introduction of alkyl substituent at the 8-carbon in 8-phenyloxi-
ranecarboxylic esters causes a rotation of the plane of the phenyl ring, due to the steric
effect of the 8-substituent [7]; this apparently creates conditions favorable for the elim-
ination of the ortho-hydrogen atom. From the favorability of the subsequent detachment of
a COOC2H5 group it can be presumed that the resulting [M -- HI + ion has a bicyclic structure
as shown in Scheme 4 for the 8-methyl substituted esters E-, Z-IV and -V.

*Since the metastable transition that confirms detachment of oxygen from the molecule ion
by dissociative ionization was not observed, the possible thermal nature of this process
cannot be excluded.
+In the spectra of E-, Z-IV, and -V, acetyl cation forms only by detachment of a benzene mole-
cule from ~= (Scheme 4).
#*Opening of the oxirane ring by cleavage of the C--C is less probable, because in this ring
the C--O bond is more easily cleaved [i, 3].

1061
 Scheme 3

Ph. /P.2 i"

"C ...... C ! [- Ph C "R2 "i 'Ph. ~--'+"
R ~ / \\ // ~COOR 1 ___~,,.
F.~~ OI COOR ~
"0"
-~e.
Ph /R 2 i / i I -COCOOR ~
3~C~C~ I
R. I ~ ~0 !
COOR Ph R 2 ~+"
R --C--C C--~O
i -~c~
0
11@ E, Z - V

A comparison of the mass spectra of esters II-V shows the great effect of substituent
location on the course of decomposition. In the spectra of E- and Z-IV (R2 =H, R s =CHs) the
peak intensity of ~ falls to i0-14%, whereas there is a sharp increase in intensity of the
ions involved in eliminati=n of a hydrogen M + and of those formed by stepwise detachment
of ethoxycarbonyl. This decomposition route is decisive in the spectra of compounds E- and
Z-IV (Table 2).
As shown by the spectra of compounds E- and Z-IV-Db, inwhichall phenyl hydrogens are re-
placed by deuterium,* the [M -- H] + ion forms exclusively by elimination of phenyl hydrogen.
i~ne elimination of an ethyl alcohol molecule that is typical of compounds E- and Z-IV(to form
cs) also goes to an appreciable extent with capture of a phenyl hydrogen. This is indicated
by the 3:1 ratio of the peak intensities of ions, I[M_C2Hb0D]+/I[M_C=HbOH]+o
The most intense peaks in the spectra of compounds E-, Z-IV and-V correspond to ~6 [M --
HC00C=Hb] + and the products of the subsequent elimination therefrom of the species COR2-H
(~7) and C0R 2 (r

Scheme 4
.R ~ .... ~o

~ -C202 R2 9 ~i / "~O/C~- -.COOC2H s -COOC~ll s" ~H~/RZ

, ,~ = C6Hs-C-C~o
@3

\. z 5 ~ 105"

9 \\ . C O O C ~ H s"

43 ~+.

L Lo!~ -

tAccording to the high resolution spectrum of ester E-IV t h e

ion with mass number 105 has 89% of composition CsH9 [5].

As a result of the introduction of methyl groups at either the a- or B-positions of the

oxirane, both decomposition routes in the spectra of ethers E- and Z-V (migration of ethoxyand
elimination of ortho-hydrogen from the benzene ring) are of nearly equal probability (Table
2); ioe., the decomposition of 8-phenyloxiranecarboxylic esters by electron impact depends
to a substantial extent on the nature of the substitution in the oxirane ring.

*E- and Z-isomers of ester IV-Ds were obtained fromDb-aeetophenone under the usual conditions
of the Darzens reaction [4].

1062
 EXPERIMENTAL
Electron impact mass spectra, DADI spectra, and defocusing spectra in the first field-
free space were obtained on a Varian ~ T - I I 2 . Electron ionization energies were 70 and 12
eV. Ionization chamber temperature was 180 ~ . Samples were introduced into the mass spectro-
meter through a Varian Aerograph 1440 chromatograph. Column, 3% SE-30 on Chromosorb W (180
cm x 2 mm), He at 20 ml/min, Tin j = 220 ~ , Tse p = 230*, Tco I = 120-230 ~ (10~
Esters II-V were synthesized by the Darzens method [4], viz., the reaction of benzalde-
hyde or a6etophenone with monochloroacetate or 2-bromopropionate esters. In all cases, es-
ters were obtained as a i:i mixture of E- and Z-isomers. E- and Z-isomers were separated
during mass spectral photography by introduction of the samples into the mass spectrometer
through the chromatograph. Retention times: E-, Z-II 6'30" and 4'50"; E-, Z-Ill 5'20" and
3'50"; E-, Z-IV7'50"and 5'00";E-, Z - V 4 ' 4 0 " a n d 4'00", respectively.
Acid E-I was obtained by hydrolysis of the mixture of E- and Z-II esters [8].

LITERATURE CITED
]. M. S. Malinovskii, Hydroxyolefins and Their Derivatives [in Russian], Goskhimizdat,
Moscow (1961), pp. 130, 398.
2. P. V. Zimakov (ed.), Ethylene Oxide [in Russian], Khimiya, Moscow (1967), p. 57.
3. R. A. Kuroyan, A. I. Markosyan, A. P. Engoyan, and S. A. Vartanyan, Zh. Org. Khim., 19,
1947 (1983).
4. R. Adms (ed.), Organic Reactions [Russian translation], Coll. Vol. 5, Inostr. Lit.,
Moscow (1951), p. 319.
. J. Baldas and Q. N. Porter, Austral. J. Chem., 20, 2655 (1967).
6. R. K. Bansal, K. Sethi, and F. W. Bachelor, Indian J. Chem., .19B, 515 (1980).
7. A. V. Shchelkunov (ed.), Structure of Ethylene Oxide Derivatives [in Russian], Nauka,
Alma Ata (1973), pp. 17, 31.
8. A. I. Bokanov, I. V. Persianova, and V. I. Shvedov, Zh. Org. Khim., 18, 1122 (1982)~

PHOTOCHEMISTRY OF UNSATURATED LACTONESo

2.* PHOTOANNELATION OF 2-ACETYL-3,4,4-TRIMETHYL-2-BUTEN-4-
OLIDE BY TERMINAL ALKYNES

A. A. Avetisyan, A. Kh. Margaryan, G. K. Nalbandyan, UDC 547.314.217.1'728:514.14:

and T. V. Avetisyan 543.422'51

The photochemical cycloaddition of 2-acetyl-3,4,4-trimethyl-2-buten-4-olide to

l-heptyne and l-chloro-2-propyne was carried out. The reaction gives isomeric
cycloadducts of the "head to head" and "head to tail" types. The influence of
solvent on the directivity of the reaction was investigated. The possibility
was shown of using the cycloadducts obtained in the synthesis of difficulty
available polyfunctionally substituted butanolides and heterocyclic compounds
containing a spirocyclobutene fragment.

The use of u,8-unsaturated lactones in their photoannelation reaction by alkynes has

been dealt with in only one paper by Japanese authors [2]. To broaden the field of applica-
tion of this reaction, we studied the photocycloaddition of 2-acetyl-3,3,4-trimethyl-2-buten-
4-olide (I) to l-heptyne (lla) and l-ehloro-2-propyne (lib).

*For Communication I, see [i].

Erevan State University, Erevan 375025. Translated from Khimiya Geterotsiklicheskikh
Soedinenii, No. i0, pp. 1315-1320, October, 1986. Original article submitted January 7,
1985; revision submitted September 19, 1985.

0009-3122/86/2210-1063512.50 ~ 1987 Plenum Publishing Corporation 1063

 Irradiation of a solution of compounds I and lla in benzene in a nitrogen atmosphere
leads to a mixture of three reaction products llla-Va in a yield of 68-70% in a ratio of i0:
12:13, which was determined by GLC at the end of photolysis.

~20~

0 ~ CH~ ~0 -
' ~I _ ~..:::o o.~ ~'" %a.

I IIIa ~a Va

Thus, the structural directivity of the reaction is weakly expressed, and the content
of the type "head to head" (HH, Illa) isomer and the type "head to tail" (HT, IVa) isomer
in the reaction mixture is approximately the same. According to the data of PMR and IR spec-
tra, the predominating isomer Va is not a cycloadduct, but 2-acetyl-2-(2'-heptenyl)-3-methyl-
ene-4,4-dimethy~utan-4-olide. In particular, in the IR spectra of compound Va there are
characteristic absorption bands of the stretching vibrations of the C=Cbondsat 1650 and 1695
c ~ ~, and in the PMR spectrum, the methylene group protons in the heptenyl radical resonate
in the form of multiplets, while the protons of the exocyclic methylene gro w at the 3-posi-
tion of the butanol,de resonate in the form on an AB-spin system.
An indirect proof for the correct assignment of the structure of compound Va is the fact
of its quantitative isomerization into isomer llla, when its chloroform solution is left to
stand over Al20a at 20~ for several days. It could be assumed that compounds Ilia and Va
are formed via a common 1,4-biradical intermediate A.
However, experiments with a variety of solvents in the photocycloaddition reaction of
lactone i to l-heptyne show that a low degrees of conversion, the ratio of the reaction
products Ilia and Va depends on the polarity of the solvent. Isomer Va predominates in weak-
ly polar solvents (hexane, benzene), while isomer Ilia predominates in more polar solvents
(acetone, acetonitrile). These data indicate that different intermediates precede the reac-
tion products llla and Va. The formation of cycloadduct Ilia, possibly proceeds via 1,4-
biradical intermediate of type A~

C}I3~" ~ 9

cu,_ ~o -3 [- c~l .o -~

IlL,

[~-It 3 ' C l t } i ~" Ct{~- . 0

-- 0:. ~/'~"/" . C, C|{~ CH$ CH 3 -.I
B O/~-T--~q "- ~ '" A
I II
~.%. 'V-'~-2%
CH 3

The addition of lactone I to compound lib under standard conditions leads to isomeric
cycloadducts lllb and IVb in a yield of 30-32% in a ratio of 11:2. The yield of cycloadducts
decreases because of the formation of a polymeric film on the walls of the reactor, whCch hin-
ders the UV irradiation.
O O

hu / I :
+ HC~C~CI'I=C~ - - ,,, i }} o\

c,i \ c~z lib .... - 9 c;~zcl

"~ CI{3 ~ C L 3 x~ii: ~ ' 3 I ~ CII~ CTI3 ~ ,

i lllb IVb

The mass spectrometric data were found to be particularly informative in the assignment
of structures of the isomeric cycloadducts of the HH type (Ilia, b) and HT type (IVa, b).
Thus, the M + of the structural isomers llla, b undergo under electron impact a McLafferty

1064
 tg [Iv a]
jill a]

i 3

L r l ' i i I k ~ i
0,1 0,2 013 0,4 0,5 0,6 0,7 0,8 0,9 ~.10 2'
Fig. i. Influence of aprotic solvents on
the ratio of cycloadducts corresponding to
type "head to tail" (IVa) and "head to
head" (Ilia) addition. The concentration
of the starting reagents I and lla is the
same in all solvents and equals to 0.16
and 1.60 M, respectively. Solvents: i)
cyclohexane, 2) benzene, 3) ethyl acetate,
4) acetone, 5) acetonitrile.

type rearrangement with hydrogen transfer from the substituent at the C(7) atom to the lac-
tone ring carbonyi group according to a coordinate six-membered mechanism, followed by split-
ting off of an allenic radical [3]. The peak intensity of the ion formed as a result of this
process (m/z 169) in the mass spectra of isomers Ilia, b is high and equal to i00 and 45%,
respectively, while in the mass spectra of isomers IVa, b this peak is practically absent.
The differences in the IR and PMR spectra of the isomeric cycloadducts lead us to ex-
pect that they could be used in the assignment of structures in the photocycloaddition reac-
tions of acetylenes to a,8-unsaturated lactones. Thus, in the IR spectra of isomers IVa, b,
the frequency of the absorption band of the lactone carbonyl is 8-10 cm-~ higher than in the
spectra of isomers llla, b. In the PMR spectra of isomers IVa, b, the olefinic proton reson-
ates in a weaker field than in isomers lla, b, the difference being up to 0.15 ppm.
During the photocycloaddition of lactone I to monosubstituted acetylenes lla, b, compar-
able amounts of type HH and HT adducts are obtained, which cannot be correctly interpreted
by taking into account the influence of polarization of the z-electronic cloud in the unsaturated
substrate on the structural directivity of the photoannelation (the Corey hypothesis [4])~
If we take as a basis the currently accepted suppositions on the intermediate formation
of 1,4-biradicals in the photoannelation reaction [5, 6], the formation of HH (Ilia, b) and
HT (iVa, b) cycloadducts is possible from the intermediately formed alternative biradical
intermediates A, B (HH) and C, D (HT).

CI{~. 0 CII2 . 0 o CII... ~ 0 CIi_ ~0

0 -"~'~ R ~ " " O~ --.f.~1

\~--_---U H
c ~o. / / CH 3 \~..
~n 3 CH3
\"
CH~ CH~ CH3
/ CtI~ CH~ R CH3 CH~ C H ~ R

A B C D
P'=C5RI I' CH2CI

It was shown that biradical B does not contribute to the formation of type HH cycload-
ducts (see above). The absence of the contribution of an intermediate biradical D to the
formation of the type HT cycloadduct indicates the absence in the reaction mixture of a pos-
sible product with an exocyclic double bond in the 3-position and a l-heptenyl radical in
the 2-position of the butanolide [7].
Thus, during the photoannelation of compound I by alkynes IIa, b, the isomeric cyclo-
adducts are apparently formed via the intermediate biradicals A and C, which are the most
stable of those alternatively possible, and the structure of which is determined by an ini-
tial binding of the unsaturated substrate with the lactone C(8) atom.
In the absence of specific interactions between the reagents and the solvent, and with
an equal mechanism of formation of the isomeric cycloadducts, their ratio is determined by
the Kirkwood--Onsager parameter ~, which is characteristic for reactions with the participa-
tion of electrically neutral, but polar molecules [8-12]
~-1 p

1065
where s is the dielectric constant, p is density and M is molecular weight of the solvent.
For five aprotic solvents, a linear dependence was observed between the logarithm of a
ratio of concentrations of cycloadducts IVa and llla and the Kirkwood--Onsager parameter (Fig.
i): log [IVa]/[llla] = 0.06 + tan @.~.i02, where tan @ = 0.132 (correlation coefficient r =
0.95).
Because of the high preparative yield of the cycloadducts ih the addition reaction of
iactone i to l-heptyne IIa and the ease of isomerization of compound Va into cycloadduct IIIa,
they can be used as the starting compounds in the synthesis of difficultly available polyfunc-
uionally substituted butanolides, as well as heterocyclic compounds containing a spirocyclo-
butene fragment. Thus, the reaction of cyc!oadduct IIIa with OsO~ in 80% aqueous acetone,
followed by the decomposition of the osmatecomplex by NaIO~ leads to 2-acetyl-2-hexanoyl-3-
hydroxymethyl-3,4,4-trimethylbutane-4-olide (VI) in a yield of 64%.

CII .O {;il~x .G r- CH3. /.0 -I

o. -~</ o_ ' Y/ c ~ . , , ( o%~.~.c.,,,
- /~ _ ~]_ 2 i]i % n , o~oJNam4 " ) --(--~-~
I -: 1 /---r---%o~
o ;[~ - o I o I o
CI~,5 1. Ci13 / \ ~CH~ CIIs H
CH 3 CIt~ L CH~ CH 3
JI I a Vl VII

When the reaction is carried out in 99% acetone, according to the PMR spectral data
(9.5 ppm -- the aldehyde proton), not only compound VI is formed, but also a small amount of
4-formyl derivative VII. Judging from the integral curve in the PMR spectrum of the mixture,
the ratio of products VI and VII is approximately 3:1. The reaction of cycloadduct IVa with
guanidine in an alcoholic solution of sodium ethylate leads to spiro[5,3]none-2-amino-4,8-
dimethyl-7-pentyl-8-hydroxyisopropyl-l,3-diaza-l,3,6-triene (VIII) in a 45.5% yield.

c)L. ~ O cil3

* . 2~\ < \./_..

" CH~ ~ CHj--? ~CH 3

IVa VIII OH

The transformation products of the cycloadducts were isolated by preparative TLC on

silica gel, and were characterized by PMR, IR spectra, and elemental analysis. Thus, the
photocycioaddition products of 2-acetyl-3,4,4-trimethyl-2-buten-4-olide to monosubstituted
aikynes, are by themselves of interest as starting materials in the synthesis of difficultly
available organic compounds.

EXPERIMENTAL
The irradiation of the solution of lactone I with monosubstituted alkynes IIa, b in ben-
zene was carried out in a flat-bottomed reactor at 20~ in a nitrogen atmosphere. A PRK-2M
lamp (375 W), mounted horizontally on the bottom of a mirror-like illuminating tray at a dis-
tance of 20 cm from the bottom of the apparatus, served as the UV radiation source. The pur-
ity of the reagents and reaction end products was verified by GLC on a LKhM-8MD apparatus
(catharometer), using a 3 m x 3 mm metallic column with OV-17 (5%) filler, on a Chromaton
N-AW HMDS carrier (0.16-0.20 mm) at a flow rate of helium of 40 ml/min. The overall yield
of the reaction products was determined from peak areas on the chromatograms by the internal
standard method (n-eicosane). The IR spectra were run on UR-20 spectrophotometer (CCi,,
CHCIa) and the PMR spectra on a Perkin-Elmer R-20B spectrometer (60 MHz), at a 10-12% sample
concentration, using TMS as internal standard, while the mass spectra were measured on an
~ - 1 3 0 3 mass spectrometer at a temperature of II0-I15~ and at an ionizing voltage of 50 eV.
Preparative Separation of Adducts Ilia, !Va, and Va. A solution of 2 g (0.01 mole) of
acetos I, 8.4 g (0.15 mole) of l-heptyn e l l a in 9.0 g of benzene were placed in a photo
lysis reactor. After 28 h from the beginning of the irradiation, the volatile products were
distilled on a rotary evaporator at 55~ (33 gPa), and the residue, a yellow oil containing
the reaction products and unreacted starting lactone, was preparatively separated on a glass
column (i m x 25 ram) filled with 120 g of a brand L40/100 silica gel. The reaction products
(given in order of emergence from the column) were isolated by elution with a 20:10:1 hexane--
benzene--ethyl acetate mixture.

1066
 2-Acetyl-2-(2'-heptenyl)-3-methylene-4~4-dimethylbutan-4-olide (Va), yellow oil. GLC:
Tcolumn 225~ fret* 5.5. IR spectrum (CCI~): 3090, 1770, 1720, 1685, 1650, 915 cm-:. PMR
spec=rum (CCI~): 0.66-1.60 (15H, m); 1.80-2.26 (5H, m); 4.85 (HA, d), 5.10 (HB, d, JAB = I
Hz); 5.40-5.60 ppm (2H, m).
l-Acetyl-4,4,5-trimethyl-7-pentyl-3-oxabicyclo[3.2.0]hept-6-en-2-one (IIIa), yellow oil.
GLC: Tcolumn 225 ~ fret 6.0. IR spectrum (CCI~): 3050, 1752, 1708, 1630 cm-I. PMR spec-
trum (CCI~): 0.62-1.62 (18H, m); 1.90-2.37 (SH, m); 5.95 ppm (IH, t, J = 1.5 Hz). Mass
spectrum, m/z, %: M + 264 (17), 205 (44), 178 (75), 177 (46), 169 (i00), 166 (45), 163 (48),
149 (48), 135 (65), 122 (46), 121 (79), 107 (45), 93 (41), 91 (38), 79 (38), 77 (38), 55 (43).
l-Acetyl-4,4,5-trimethy!-6-pentyl-3-oxabicyclo[3.2.0]hept-6-en-2-one (IVa), yellow oil.
GLC: Tcolumn225=C, ire t 8.5. IR spectrum (CCIg): 3055, 1760, 1708, 1630 cm-~. ~ PMR spectrum
(CCI~): 0.62-1.62 (18H, m); 1.77-2.35 (5H, m); 6.10 ppm (IH, t, J = 1.5 Hz). Mass spectrum,
m/z, %: M + 264 (21), 205 (43), 178 (47), 177 (53), 163 (47), 149 (55), 122 (44), 121 (i00),
107 (33), 93 (23), 91 (23), 79 (21), 77 (21), 57 (23), 55 (25).
Preparative Separation of Adducts IIIb and IVb. A solution of 2 g (0.01 mole) of aceto-
lactone I, 11.2 g (0.15 mole) of propargyl chloride IIb in 6.8 g of benzene is placed in a
photolysis reactor. After 22 h from the beginning of irradiation, the volatile products were
distilled on a rotary evaporator at 40-45~ (33 gPa), and the residue, a brown viscous mass
containing the desired end products was clarified by treatment with activated carbon in chlor-
oform. Chloroform was evaporated and the residue was separated by preparative column chroma-
tography on a glass column (3 m x 25 mm), filled with i00 g of brand L40/100 silica gel. The
reaction products were isolated (in the order of emergence from the preparative column) by
elution with a 30:1 benzene-chloroform mixture.
l-Acety!-4,4,5-trimethyl-7-chloromethyl-3-oxabicyclo[3.2.0]hept-6-en-2-one (IIIb), yel-
low oil. GLC: Tcolumn 200~ tret 6.1. IR spectrum (CCI~): 3050, 1758, 1712, 1608 cm -~.
P ~ spectrum (CC14): 1.20 (3H, s); 1.33 (3H, s); 1.14 (3H, s); 2.16 (3H, s); 3.41 and 5.06
(2H, quartet, A- and B-parts of ABX system, JAB = 15 Hz); 6.23 ppm (iH, t, X-parts of ABX
system, JAX = JBX : 2 Hz). Mass spectrum, m/z, %: 242 (15), 207 (19), 185 (18), 184 (29),
183 (30), 169 (45), 163 (16), 158 (16), 156 (43), 149 (34), 147 (32), 121 (41), 120 (i00).
l-Acetyl-4,4,5-trimethyl-6-chloromethy!-3-oxabicyclo[3.2.0]hept-6-en-2-one (IV), yellow
oil. GLC: Tcolum n 200~ Tre t 9.15. IR spectrum (CCIa): 3050, 1770, 1712, 1610 cm -~.
PMR spectrum (CCI~): 1.24 (3H, s); 1.32 (6H, s); 2.27 (3H); 4.00 (2H, d, J : 1.6 Hz); 6.35
ppm (IH, t, J = 1.6 Hz). Mass spectrum, m/z, %: M + 242 (12), 184 (32), 183 (20), 182 (83),
163 (29), 158 (18), 156 (47), 149 (68), 121 (98), 120 (i00), 105 (57).
2-Acetyl-2-hexanoyl-3-hydroxymethyl-3,4,4-trimethylbutan-4-olide (VI). A solution of
0.18 g (0.68 mole) of compound IIIa in 16 ml of acetone is placed in a i00 ml three-necked
flask, and 40 mg of OsO~ are added with stirring. After 1 h, the solution acquired a brown
color (due to the formation of an osmate complex). The reaction mixture was left to stand
overnight. A 4 m! portion of water was added to the dark solution, and then 0.36 g (1.36
m~mole) of NaiO~.3H=O was added, with ice-cooling, in portions, in the course of 8 h. Stir-
ring was continued for 24 h. The reaction mixture was filtered through a column with silica
gel (5 g), the filtrate was evaporated in vacuo, the residue was extracted by ether, and the
extract was dried over MgSO~. Ether was evaporated, and the residue (154 mg) was chromato-
graphed on a plate (20 20 cm) with silica gel L40/100 (layer thickness 1.5 mm) in a 2:2:1
hexane--benzene--acetone system. From the zone with Rf 0.36, 130 mg (64%) of butanolide VI
were isolated. IR spectrum (CHCI~): 3595, 3470, 1770, 1715, 1060 cm -~. PMR spectrum
(CDCI~): 0.62-1.65 (18H, m); 2.0-2.75 (6H, m, CH3C--, --CH2C--, OH); 4.07 ppm (2H, d, J = 3.75
Hz).
Spir~[5,3]n~n-2-amin~-4,8-dimethy~-7-pent~-8-hydr~xyis~pr~py~-~,3-diaza-~,3,6-triene
(VIIi). A 5 ml portion of absolute ethanol and 0.088 g (0.16 mmole) of metallic sodium were
placed in a three-necked flask fitted with a stirrer with a mercury seal and reflux condenser
and 0.086 g (0.9 mmole) guanidine hydrochloride was added with stirring. Stirring was con-
t%nued for another 30 min at 20~ and 0.22 g (0.83 mmole) of compound IVa, dissolved in i ml
of absolute alcohol, was added. The mixture was stirred at the boiling point of the solution
for 14 h. Alcohol was distilled off in a weak vacuum, 5 ml of water were added to the resi-
due, and the mixture was acidified by HCI. The mixture was extracted by ether and ethyl ace-

*tret -- retention time in the GLC column, min.

1067
tare, and the extracts were dried over MgSO~. The solvents were evaporated to yield 0o153
g of a crude product, contaminated by impurities (TLC). The raw mixture was chromatographed
on a plate (20 20 cm) with silica gel L40/100 in a 3:1:1 benzene--hexane--ether system. From
the zone with Rf 0.69, 0.ii g (45%) of compound VIII was isolated. IR spectrum (CHCI3):
3590, 3500, 3420, 3310, 1690, 1645, 1608 cm -~. Found, %: C 66.6; H 8.9; N 13.8. C~TH27N30=.
Calculated, %: C 66.9; H 8.9; N 13.8.
Influence of Solvents. The experiments were carried out in absolute solvents at 26 i
2~ The experimentally found values (mean of 3-4 measurements) are given for the same de-
gree of the occurrence of the reaction (degree of consumption of the lactone 15 3%). The
dependence of log [IVa]/[llla] on g was calculated by the method of least squares.

LITERATURE CITED
i. A. A. Avetisyan, A. Kh. 5~rgaryan, and A. O. Gukasyan, Zh. Org. Khim., 19, 586 (1983).
2. Hiroshi Kosugi, Shizuo Sekiguchi, Ryu-ichi Sekita, and Hisashi Uda, Bull. Chem. Socl
Japan, 49, 520 (1976).
3. E. P. Serebryakov, S. D. Kulomzina, A. Kh. Margaryan, and O. S. Chizhov, Izv. Akad. Nauk
SSSR, Set. Khim., No. 8, 1798 (1977).
4. E. G. Corey, J. D. Bass, R. le Mahieu, and R. B. Mitra, J. Am. Chem. Soc., 86, 5570
(1964).
5. P. G. Bauslaugh, Synthesis, ~, 287 (1970).
6. P. de Mayo, Acc. Chem. Res., ~, 41 (1971).
7. A. Kh. Margaryan, E. P. Serebryakov, and V. F. Kucherov, Izv. Akad. Nauk SSSR, Ser.
Khim., No. 2, 408 (1978) o
, I. M. Hartmann, W. Hartmann, and G. O. Schenk, Chem. Bet., i00, 3146 (1967).
9. B. D. Challand and P. de Mayo, Chem. Comm., 16, 982 (1968).
i0. G. Mark, F. Mark, and O. E. Plansky, Annalen, 719, 151 (1968).
ii. G. Mark, H. Matthaus, F. Mark, J. Leitich, and D. Henneberg, Monatsh. Chem., i02, 37
(197!).
S. D. Kulomzina, E. P. Serebryakov, and V, F. Kucherov, Izv. Akad. Nauk SSSR, Ser. Khim.
No. 12, 2739 (1975).

THE CHEMISTRY OF 1,5-DIKETONE DERIVATIVES.

2.* PREPARATION OF 2-HYDROXY-I,3,5-TRIPHENYL-I,5-PENTANEDIONE
.~ND SOME HETEROCYCLE DERIVATIVES

T. V. Moskovkina, V. I. Vysotskii, UDC 547.422.5.04'811'829.07:

and M. N. Tilichenko 543.422

The preparation of 2-hydroxy-l,3,5-triphenyl-l,5-pentanedione by the addition

of ~-hydroxy- or ~-acetoxyacetophenone to chalcone is described. The 2-hydroxy-
1,5-diketone obtained does not show a tendency to form an intramolecular hemi-
acetal; instead, an acetate is formed. Reaction with hydroxylamine hydrochlor-
ide gives 3-aza-2,8-dioxa-l,4,6-triphenylbicyclo[3.2.1]oct-3-ene, and with ammon-
ium acetate 2,4,6-triphenylpyridine and 3-amino-2,4,6-triphenylpyridine are
formed. On reaction with p-toluenesulfonic acid the hydroxydiketone is convert-
ed into 3-oxo-2,4,6-~riphenyl-2,3-dihydro-4H-pyran.

We have previouslydescribed [i] the preparation of 2-hydroxy-l,5-diketones by the oxi-

dation of methoxy derivatives of hexahydrochromene or decahydroxanthene and we found that

*Communication l, see [1].

Far Eastern State University, Vladivostok 690600. Translated from Khimiya Geterotsikli-
cheskikh Soedinenii, No. i0, pp. 1321-1324, October, 1986. Original article submitted May i
1985.

1068 0009-3122/86/2210-1068512.50 ~ 1987 Plenum Publishing Corporation

they can exist in both the open form and in the form of a hemiacetal with a five-membered
ring.
The present communication describes the preparation of the first example of an aliphatic-
aromatic u-hydroxy-l,5-diketone -- 2-hydroxy-l,3,5-triphenyl-l,5-pentanedione (I). This com-
pound is formed in 50% yield by the action of u-hydroxyacetophenone (II) with chalcone (III)
in the presence of a n a l c o h o l i c solution of sodium hydroxide, and in 40% yield by condensa-
tion of chalcone (III) with ~-acetoxyacetophenone in the presence of sodium hydride.

Ph Ph
~/
, /OH /OCOCH~ > "-~/0COCH3

p h / ~ 0 +0~/~p h 0//~,ph +III Ph/~',0 ~ " ' P h

,
O~ Ph ~ Ph

5 7 NH20H, [ICI ~ ,~ Ts0H

Ph
~
_
2
Ph Ph/ Jk~o 0/~ph -H20 Ph Ph
V
Ph \\ CH3COONH4 Ph

p h ....~ - - ~ TM

Fh N Ph Ph "N Ph
13 VI %qI
A

The infrared spectrum of compound (I) shows absorption bands at 3480 (O--H) and 1684 cm -~
(C----O). The molecular ion 344 (8)* decomposes with the loss of a molecule of water 326 (26)
and then of a benzoyl radical 221 (80). The most intense peak is that of the ion 239, the
appearance of which is associated with the loss of a CsHsCO particle by the molecular ion.
In the proton NMR spectrum, the signal of the hydroxyl group at 3'.68 ppm has-the form of a
doublet (J = 7 Hz) on account of spin-spin interaction with the proton at the C(=) carbon.
This signal disappears on the addition of deuteromethanol to the solution. From the form of
this hydroxyl signal, one can exclude from consideration the hemiacetal form (A) where this
signal would appear as a singlet. This splitting as a result of spin-spin interaction with
a-hydrogen atoms is observed in the spectra of acyloins [i, 2]. The signal of the C(=) pro-
ton appears on the NMR spectrum as a doublet of doublets at 5.53 ppm (J = 1.5; 7 Hz), and on
running the spectrum of a solution of the compound to which deuteromethanol has been added,
the signal degenerates to a doublet with J = 1.5 Hz. The methylene group proton signals
form an AB-system in the spectrum, each component of which is split into a doublet on account
of interaction with the protons of the C(3) atom: HA = 3.27 ppm (J = 24.0; 9.1 Hz), HB =
4.15 ppm (J = 24.0; 10.3 Hz). The signal of the benzyl proton at C(3) is overlapped by the
HB proton signal and was not analyzed. The nature of the signals in the proton NMR spectrum
points to a rigid spatial structure for compound (I).
To study the chemical properties of the hydroxydiketone I we carried out a series of
functional reactions. Reaction with acetic anhydride in pyridine results in the formation
of the acetate IV. The absorption band for the hydroxy group is absent from the IR spectrum
of the acetate and there are bands at 1748 (C----Oin an ester), 1690, and 1686 cm-: (ketone
C--O).
In the mass spectrum of compound IV, in the region of the greatest m/z values, a peak
at 344 corresponds to the loss of a CH2=C.---O fragment by the molecular ion. The most intense
peak in the spectrum is that of the ion [ M - CHsCOOH, --COC6H5] + 221 and there are also ion
peaks [M-- CH3COOH] + 326 (65), [M-- C6H5CO] + 281 (50), and [M-- C~Hs] 309 (ii). Thus, com-
pounds I and IV undergo complex fragmentation on electron impact.
The proton NMR spectrum shows a signal for the C(2) proto n in the form of a doublet at
6.40 ppm (J = 4.1 Hz). The signal of the benzyl proton at position 3 gives a multiplet cen-
tered at 4.21 ppm. The protons of the methylene group form an AB system in the spectrum,
each component of which is split into a doublet on account of interaction with the proton of
the C(3) atom: H A = 3.35 ppm (J = 18.0; 5.0 Hz), HB = 3.81 ppm (J = 18.0; 9.0 Hz).
*Notation is: m/z (% of maximum peak).

1069
 TABLE i. 2-Hydroxy-l,3,5-triphenyl-l,5-pentanedione and SOme
Heterocycle Derivatives
Found. % Calculated, % Yield
Corn- rap:~ Empirical formula
ound E C H N C H N

I 132--133 80,52 5,83 -- C~H~oO~ 80,23 5,80 -- 52

IV 103--105 77,90 5,50 C2sH2204 77,72 5,70 98
V 146--147 80,90 5,60 4,25 C~HIgNO~ 80,94 5157 4,15 40
VII 136--t37 85180 5.50 8,~5 C~3H~sN2 85,70 5 , 4 3 8168 31
VIII 126--128 83,00 5,70 C~3H1802 82,82 5,52 37

By reacting compound I with hydroxylamine hydrochloride, we obtained 3-aza-2,8-dioxa-

1,4,6-triphenylbicyclo[3~ (V) in addition to the expected 3-hydroxy-2,4,6-
triphenylpyridine. The structure of compound V was confirmed by the following results: in
its IR sPectrum , functional group bands were absent; there was only a small-intensity band
at 1606 cm-~ due to a C=N group. In the proton spectrum, there were signals at 2.80 (7-H,
J = i0.0; 14.2 Hz), 3.20 (7-H, J = i0.0, 14.2 Hz), 5.30 ppm (5-H, J = I0.0 Hz). A signal
for the benzyl proton in the form of a multiplet was found at 4.1 ppm. In the mass spectrum
of (V), the molecular ion peak at 341 (33) corresponds to the calculated molecular weight,
and its breakdown included loss of a C6HsCNO fragment, peak 222 (66). One possible route
to the formation of compound (V) is through an oxime of a hemiacetal of structure A with
subsequent dehydration.
Ammonium acetate in acetic acid reacted with compound I to form two products: the known
2,4,6-triphenylpyridine (VI) and 3-amino-2,4,6-triphenylpyridine (VII). The latter showed a
band in its IR spectrum due to an amino group in the 3570-3400 cm-: region; in the mass spec-
trum, the molecular ion peak 322 (I00) corresponded to the calculated molecular weight. The
protons of =he amino group were represented in the proton spectrum by a singlet at 4.0 ppm
which disappeared on addition of deuteromethanol to the sample solution; there were also sig-
nals from the aromatic protons.
Dehydration of compound I by p-to!uenesulfonic acid led to the formation of 3-oxo-2,4,6-
triphenyl-2,3-dihydro-4H-pyran (VIII) together with the expected 2-benzoyl-3,5-diphenyl-2,3-
dihydrofuran (the product of the dehydration of structure A). The value of m/z for the molec-
ular ion in the mass spectrum was in a g r e e m e n t w i t h the molecular weight calculated for
VI!I -- 326 (38). In the IR spectrum there were bands at 1706 ( ~ ) , and 1676 cm -: (C.-~).
The proton spectrum showed a signal for a vinyl proton in the form of a doublet at 6.30 ppm
(J = 5.0 Hz), and for a benzyl proton on the C(2) atom, a doublet at 5.55 ppm (J = 1.5 Hz,
long-range interaction with the proton at position 4); there was also a signal from the C(~)
proton at 4.65 ppm (J = 1.5; 5.0 Hz).

EXPERIMENTAL
Infrared spectra were run on a Specord 75-IR instrument, either in chloroform solution
or as nujol mulls. Bruker HX-90E and Bruker WH-250 spectrometers (90 and 250 Ml~z) were used
for the NMR spectra with solutions in CDCIs. Mass spectra were determined on an LKB-9000S
instrument at 70 V. The individual substances were monitored by TLC on Silufol UV-254 plates
using petroleum ether/ethyl acetate (7:3) and petroleum ether/diethyl ether (i:i). Develop-
ment was effected in UV light or by iodine vapor. Identification of substances prepared by
different routes was established by mixed melting points, comparison of the thin-laye r
chromatograms, and by their IR spectra.
2-Hydroxy-l,3,$-triphenyl-l,5-pentanedione (I). ~.* To a solution of 10.4 g (0.05
mole) chalcone and 6.8 g (0.05 mole) hydroxyacetophenone in 80 ml ethanol i0 ml 10% alcoholic
NaOH was added dropwise with stirring at 20~ A precipitate appeared after 2 h. The mix-
ture was kept at 20~ for 24 h and the precipitate then filtered off and washed with EtOH
(2 x 20 ml), water (2 x 20 ml), and again with EtOH (i0 ml) after which it was dried to yield
compound I.
B. Sodium hydride (0.6 g) was suspended in 15 ml dry ether. In one procedure, 1.8 g
(0.01 mole) a-acet0xyacetophenone was added and stirred 3 h and then a solution of 2.1 g

*With the participation of E. S. Karaulov and N. N. Gnitetskaya.

1070
(0.01 mole) chalcone in 20 ml dry ether added. The mixture was stirred I h and then the ab-
sence of starting materials established by TLC. The reaction mixture was washed with water
and the ether layer dried over MgSO~. The ether was evaporated and the residue dissolved in
20 ml of a 10% solution of NaOH in MeOH. After 4 h the precipitated solid was separated,
yielding 1.4 g (40%) compound I.
2-Acetoxy-l,3,5-triphenyl-l,5-pentanedione (IV). To a mixture of 6 ml dry pyridine and
6 ml acetic anhydride was added 2 g compound I and the mixture left to stand for 24 h. It
was diluted with water and left until the oil which deposited solidified and crumbled to a
powder. The reaction product was filtered off, washed with water, and dried. Yield, 2.2 g
compound IV.
3-Aza-2~8-dioxa-!,4,6-triphenylbicyclo[3.2.1]oct-3-ene (V). To a hot solution of 3.44
g (0.01 mole) hydroxydiketone I in 90 ml EtOH a solution of 1.4 g (0.02 mole) hydroxylamine
hydrochloride in 5 ml water was added dropwise over 5 min. The mixture was heated at bp for
4 h, 0.4 g (0.005 mole) hydroxylamine hydrochloride added and again heated at bp for 3 h.
It was cooled to 20~ and the crystals which deposited were filtered off to yield 1.2 g
compound V. The mother liquor was concentrated to half volume and after cooling and filter-
ing a further 0.25 g compound V was obtained.
2,4,6-Triphenylpyridine (Vl) and 3-Amino-2,4,6-triphenylpyridine (VII). To 2.0 g (0.006
mole) compound I was added 3 g ammonium acetate and 15 ml acetic acid. The reaction mixture
was heated for i h on a boiling water bath, cooled, and 2,4,6-triphenylpyridine (VI) filtered
off, yielding 0.2 g, mp 137.5~ [3]. The mother liquor was neutralized with Na2C03 and the
oil which separated extracted with ether. Evaporation of the ether yielded 1.5 g of an oily
product which TLC showed to contain two components. This mixture was divided by preparative
YLC on Grade II alumina in 7:3 petroleum ether/ethyl acetate, the chromatography being carriec
out twice. From the zone with Rf 0.75, 0.4 g 2,4,6-triphenylpyridine VI was eluted with di-
ethyl ether and from the Rf 0.65 zone, i g of the aminopyridine VII which was recrystallized
from ethanol.
3-Oxo-2~4,6-triphenyl-2,3-dihydro-4H-pyran (VIII). Compound I (1.8 g, 0.005 mole) was
dissolved in 50 ml dry benzene and 10-15 g p-toluenesulfonic acid added and the mixture heat-
ed to boiling in the flask of a Dean--Stark apparatus and refluxed for 9 h. After cooling,
the solid which separated was filtered off. Yield, 0.6 g compound VIII.

LITERATURE CITED
i. T . V . Moskovkina, V. I. Vysotskii, and M. N. Tilichenko, Khim. Geterotsikl. Soedin.,
No. 2, 177 (1985).
2. B. Plesnicar, J. Smolikova, A. Jehli6ka, and O. Exner, Collect. Czech. Chem. Commun.,
43, 2754 (1978).
3. K. Dimroth, Newer Methods of Preparative Organic Chemistry, Vol. 3, Academic Press
(1964), p. 413.

1071
2,2-DI>~THYL-5-(5-R-2-FURFURYLIDENE)-I,3-DIOXAN-4,6-DIONES.
i. SYNTHESIS, PROPERTIES, AND STRUCTURE

G. D. Krapivin, V. G. Kul'nevich, and N. I. Val'ter UDC 547.841.5'727.07:

543.422:541.63

5-R-Furanaldehydes react with Meldrum's acidunder Knoevenagel reaction condi-

tions. The reaction products have s-cis conformation. The pF~ values of the
electroneutral Lewis acids synthesized were determined.

2,2-Dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid [i], isopropylidene malonate) is a

virtually nonenolizable CH-acid. Its structure has been studied by a number of workers [2-
5] while the structures of its 5-alkyl and 5,5-diakyl derivatives were studied in other work
[6-8]. However, its arylidene derivatives, which behave as electroneutral Lewis acids cap-
able of the reversible addition of the anions of hard bases, still give rise to confusion
[9-11]. The problem of the conformation of such structures has also not been resolved. Of
the 5-R-furfurylidene derivatives of Meldrum's acid, the simplest representative (R = H, I)
obtained as a result of a laborious synthesis has been described [12].
We have developed simple methods for the synthesis of 5-R-furfurylideneisopropylidene
malonates I-VIII and attempted to clarify the arrangement of the heterocycles in the isomole-
cules. According to Dreiding molecular models (without taking account of distortions in bond
lengths and angles), rotation of the furan ring relative to the exocyclic o-bond
o
leads to ap-
?roximation of Hs and the carbonyl group oxygen in the s-cis rotamer to ~0.9 A. The distance
between the furan ring oxygen and the carbonyl group oxygen in the s-trans form is ~1.3 A,
i.e., these forms are strained and we should expect, a priori, a stable rotamer with mutually
perpendicular arrangement of the ring planes.
We have found that the reaction of furan aldehydes with Meldrum's acid proceed readily
under Knoevenagel reaction conditions to give good product yields. Products 1-VIII are iso-
lated from the reaction mixture upon cooling as brightly colored crystals. These conditions
were used for the synthesis of benzylidene derivatives of Meldrum's acid.
" 0 lI~. ~H 4 0
0 ---~ ~ ..... -- OH- CIT:~. /0--~," ~-----~]

I-%'I
Br

$r Hou t --I
H~ VII VIII HOL

I [~=H: lI R=CH3; III }~=CI; IV t~=Br; V l~=NO2; VI Iq=N(CH3)2

The electronic spectra of 1-VIII (Table i) indicate conjugation between the heterocycles.
The substituent at C(5) of the furan ring has a significant effect on the position of the
long-wavelength absorption maximum (K-band) according to the Fieser-q4oodward rule: A% for
I-IV, VII and VIII are--4, 12, --4, --4, 0 and i0 nm, respectively.
The substituent also affects the position of the IR stretching band of the carbonyl
groups (Table i): electron-withdrawing substituents shift the 9C0 band toward higher fre-
quencies, while electron-donor groups produce a shift toward lower frequencies.
These results are in accord with the data of other workers [9, 12, 13]. Effective con-
jugation is a serious argument against the structure, in which the furan ring plane is per-
pendicular to the plane of the acylal ring.

Krasnodar Polytechnical Institute, Krasnodar 350700. Translated from Khimiya Geterots-

iklicheskikh Soedinenii, No. I0, pp. 1325-1329, October, 1986. Original article submitted
June 28, 1982.

1072 0009-3122/86/2210-1072512.50 O 1987 Plenum Publishing Corporation

 TABLE i. Characteristics of the Compounds Synthesized
Electronic IIR spee- Found, % Calculated, %
i spectrum in I trum, Chemical Yield,
Corn- rap, "C ethanol, luCO, formula
pound ) ' m a x , nm ]em-1 %
c H Her C H Het
(log ~) ]
I 93--9,t 216 (3,78); I740, 59,5 4,6 -- C.H,~O5 59,5 4,5 -- 86
262 (3,04); 1720
364 (4,47,)
II 96--97 219 i3,66); 1730, 61,0 5,2 -- C~91t203 61,0 5,1 -- 68
262 (3,30); i721
396 (4,27)
r"
Ill 108--109 217 (3,90); 1732, 51,5 3,5 13,8 C tI~,O~ 51,5 3.5 3,~ 94
261 (3,8~); 1722
370 (-t,25}
IV 122 215 (3,75); 1736, 44,0 3,0 26,3 Cl~I-t,,BrO5 43,9 3,0 6,3 83
262 (2,95); 1722
379 (4,43)
V 1-t8 2,57 (4,32); 1762. 49,5 I 3,5 5,2 ",...~g-<' NOr
' 49,6 3,4 5,2 75
366 (4,09) 1730 I
VI 176 236 (3.90); 1730, 59,2 4,9 5,2 Cl~Hi~WO~ 59,3 4,9 5,3] 94
271 (4,00); 1675
456 {4.58)
VII 37--138 215 (4,15); I759, 34,9 2.4 41,9 CllHsBr20~ 34,7 2,1 2,1 92
262 (4,42) ; 1719
3~0 (4,33)
VIII 190 258 (4.26); 1711 57,5 4,2 -- CndII~O~ 57,5 4,3 -- 80
404 (4,56)

The PMR spectra of l-Vlll (Table 2) have an upfield signal for the protons of the two
methyl groups (6H), which supports the proposal of Schuster [7] for oscillation of the iso-
propylidene unit relative to the plane of part of the acyla! ring (the oxygen atom and C(,),
C(5) and C(6) are located in one plane [4]).
The arrangement of the furan ring proton signals in the PMR spectrum differs from that
usually observed in the spectra of furan compounds with an electron-withdrawing substituent
at C(2) since the signal for H3 is at a position anomalous for 8-furan protons (8.25-8.87 ppm
Table 2). Quantum chemical calculations for I [14] show the following q-charge on the furan
ring carbon atoms: +0.0697 (C(s)), -0.0943 (C(,)) a n d - 0 . 0 1 5 3 (C(3)), i.e., the PMR spec-
nrum should show the usual arrangement for the proton signals Hs > H3 > H~. Thus, the down-
field shift of the proton for H3 is a consequence exclusively of the anisotropic effect of
the carbonyl function. The carbonyl group has an analogous effect on the shielding of the
3-H proton in the furan ring in the Z-s-cis isomers of a-methyl-B-furylacrylic acids [15, 16]
and H~ in 3-acylindoles [17]. These deshielded protons are in the plane of the carbonyl
group. Thus, we may assume that H3 in I-VIII is also in the same plane as the carbonyl group
and, thus, the furan and acylal rings are coplanar. The strong anisotropic effect of the
carbonyi group on shielding of the 3-H proton is possible in the s-cis form.
Support for this hypothesis is found in the coupling constant between the olefinic pro-
ton Hol and furan protons (Table 2). The high steric specificity of coupling constants 5j
and ~J between the protons of the ring and substituents has been used repeatedly for predict-
ing the conformation of furanaldehydes and 2-vinylfuran derivatives [18-20]. The long-range
proton coupling in 1-VII indicates coplanarity of the bonds between the coupled nuclei, i.e.,
coplanarity of the furan ring and the exocycli c C-~ bond. The value of ~JHolH 4 (Table 2) is
characteristic for the W5 arrangement of the bonds between Hol and 4-H [16, 18] which is rea
lized only in the s-cis rotamer.
We should note special features of the coupling between the furan ring protons in I-
VIII. Thus, the Ha--H~ and H~--Hs coupling in I hardly differs from the usually observed val-
ues, while 4JHaHs (<0.i Hz) is significantly less than the coupling constants characteristic
for other furan compounds [18, 20]. It is striking that aJH3H~ in the spectrum of dimethyl-
amino derivative VI is 5.0 Hz, which may be a consequence of an increase in the fraction of
quinoid structure in the total resonance energy of the molecule.
The PMR spectrum of VIII has two downfield narrow singlets of equal intensity (Table 2).
The position of the signals in this spectrum corresponds to the s-cis,s-cis conformation of
VIII. The absence of coupling between Hol and Ha is a consequence of degeneracy of the AA'BB
spectrum [21] due to the symmetry of the s-cis,s-cis conformation of VIII.

1073
 TABLE 2. PMR Spectra of Compounds Synthesized
6, ppm J, Hz
! ,I, Other signals and
}13 lI~ II M 4/II~:iIl3 :]ItcH 4 coupling constants

[
i8,32 6,80 8,10 i1,70 0,8 0,4 0,4 8,03 (Hs); ~IIL#I =0,6;
i aJ:T4H~ = 1,7; 4Ji_i~H5 =0,1
I
II ! 8,-'8 6,68 8,07 11,68 0,7 0,5 3,9 2,27 (CHa)
III 18,30 6,75 7,98 11,68 0,7 0.5 4.0
IV 8,25 6,68 8,03 1,68 0,8 05 3,9
V 8.27 7,60 8,03 1,72 0,7 0,4 4.1
VI . 8,87 6,07 7,70 i l , 5 5 1,0 0.3 5,0 3,20 lc, 6H, N(CHa)2]
VII 8.27 7,97 1,68 0,4
VIII 8,a8 8,27 1,72

TABLE 3. pKa Values of the Compounds Synthesized

Electronic spectrum,
Com- k m a x . nm (log t) p 90
pH of the buffer solutions
pound
o,I N HC1 0,1 N NaOH

I 364 (4,52) 262 (4,30) 6,56; 6,81; 7,00; 7,24 6,84--+0,05

II 389 (4,38) 262 (4,09) 6,56; 6,81; 7,00; 7,24; 7,42; 7,85 7,60-+ 0,03
Ill 370 (4,54) 261 (4,20) 6,45; 6,78; 7,03; 7,25; 7,51 7,01 -+0,06
IV 380 (4,44) 261 (4,23) 6,45; 6,78; 7,03; 7,25; 7,51; 7,68 7,06-+0,09
V 366 (4,46) 260 (4,33) 5,02; 5,20; 5,42; 5,59 4,63-+ 0,05
VI 458 (4,61) 267 (4,27) 11,04; tl,22; tl,48; 11,78; 11,95 12,07 + 0,04
VII 380 (4,48) 262 (4,66) 6,45; 6,78; 7,03; 7,25; 7,51 7,08~-0,05

It was noted above that arylidene derivatives of Meldrum's acid display properties of
electroneutral Lewis acids. Furfurylidene derivatives I-VIII, which add the anions of strong
bases reversibly with decoloration of the solution, are not an exception. In this case, t h e
long-wavelength band disappears and the intensity of the band at 260-270 nm, which correspond
to conjugation between the two carboxyl groups through the carbanion [8, i0, 12], increases
significantly. The substituent has only a slight effect on the position of the band at 260-
270 nm, indicating the lack of conjugation between the carbanion formed and the furan ring.
The color of the solutions is restored upon acidification of the alkaline solutions of
I-VIII. The intensity of the K-band increases with increasing acidification and reaches
maximum value in acid media, in which there is no absorption at 260-270 nm.
All the compounds obtained are strong Lewis acids. There is a linear correlation be-
tween the pKa values and the polar o+ constants of the substituents [R = H, CH3, NOa,
N(CH3)a] described by the equation

pK.= 6.84(177 + (r=0.996; s=0.091). (1)

Halogen derivatives III and IV display weaker acid properties than would be expected
in light of the ~+ constants of the halogens as substituents.
The high sensitivity of the carbon atom of the exocyclic C=C bond to substitution of
C(=) of the furan ring indicates strong transfer of substituent electronic effects to this
ring, which is possible only in the case of a coplanar or almost coplanar arrangement of the
heterocycleso
The pKa values found (Table 3) also hold interest for quantitative evaluation of the
effect of the furan ring as a specific substltuent in comparison with the benzene ring and
for evaluation of the conductance of substltuent electronic effects through the furan ring
in comparison with the benzene ring. Thus, 2-furancarboxylic acid (pKa 3.16) is stronger
than benzoic acid (pK~ 4~20) [22]. If we take p = 1.00 for this pair, the o-constant of the
furan ring is 1.04, i.e., the furan ring in carboxylic acids is electron-withdrawing rela-
tive to the benzene ring.
Benzylideneisopropylidene malonate (pKa 4.5 [12]) is a stronger acid than corresponding
furan derivative I. If we also take p = 1.00 for this pair, the o-constant of the furan

]074
ring is --2.34 and, thus, the furan ring in Lewis acids is an electron-donor in comparison
with the benzene ring.
According to Schuster et al. [12], the introduction of the nitro group at C(~) of the
benzene ring in benzylideneisopropylidene malonate leads to enhancement of the acid proper-
ties (the pKa value for the nitro derivative is 3.5). The Hammett equation may be used to
calculate the p(o+), which in this case, is 1.28. Comparison of the calculated p(c +) con-
stants of the benzene furan series (Eq. (i)) shows that the furan ring much more effectively
transfers substituent electronic effects to the electron-deficient reaction site.

EXPERIMENTAL
The electronic spectra were recorded and the spectrophotometric titration [23] was car-
ried out at 25 ~ on a Specord UV-VIS spectrometer. The IR spectra were taken on a UR-20 spectrometer
The P ~ spectra were taken on a Tesla BS-467 spectrometer at 60 MHz in deuteroacetone with
~S as the internal standard. The coupling constants were determined using double reson-
ance and INDOR techniques.
2,2-Dimethyl-5-(2-furfurylidene)-l,3-dioxane-4,6-dione (I). A sample of 0.96 g (i0
r~oles) furfural and one or two drops of triethylamine were added to a solution of 1.44 g
(i0 mmoles) Meldrum's acid in 20 ml ethanol. The reaction mixture was left for 20~ for 3
h, cooled, and the yellow crystalline needles precipitated were recrystallized from ethanol.
Products II-VIII were obtained by analogous procedures.

LITERATURE CITED
i, A. Meldrum, J. Chem. Soc., 93, 598 (1908).
2. D. Davidson and S. Bernard, J. Am. Chem. Soc., 70, 3426 (1948).
3. D. K~bel and P. Schuster, Monatsch. Chem., 103, 1483 (1972).
4. E. P. Klimovitskii, L. K. Yuldasheva, and B. A. Arbuzov, Izv. Akad. Nauk SSSR, Ser.
Khim., No. 7, 1577 (1973).
D. K~bel and P. Schuster, Monatsch. Chem., 104, 1421 (1973).
6. M. Eigen, C. Ilgenritz, and W. Kruse, Chem. Ber., 98, 1623 (1965).
7. I. Schuster and P. Schuster, Tetrahedron, 25, 199 (1969).
8. A. N. Kost, I. N. Khaimov, Yu. Dzhurakulov, K. Kh. Khaidarov, L. D. Lebedeva, and A. L~
Kotov, Khim. Geterotsikl. Soedin., No. ii, 1482 (1975).
9 G. Swoboda, J. Swoboda, and F. Wessely, Monatsch. Chem., 95, 1283 (1964).
i0 P. Margaretha, Monatsch. Chem., i01, 811 (1970).
ii C. F. Bernasconi and G. D. Leonarduzzi, J. Am. Chem. Soc., 102, 1361 (1980).
12 P. Schuster, O. E. Plansky, and F. Wessely, Monatsch. Chem., 95, 53 (1964).
13 B. Eistert and F. Geiss, Tetrahedron, ~, 1 (1959).
14 O. E. Plansky and P. Schuster, Monatsch. Chem., 94, 281 (1964).
15 L. M. Jackmann and R. M. Willey, J. Chem. Soc., 2886 (1960).
16 M. Dand~rov~, J. Kov~$, D. V~gh, and V. Zv~k, Coll. Czech. Chem. Commun., 47, 3412
(1982).
17. A. N. Kost, V. I. Minkin, V. A. Bukylin, Yu. V. Kolodyazhnyi, and V. V. Druzhinina,
Khim. Geterotsikl. Soedin., No. 12, 1674 (1982).
18. T. H. Huckerby, Tetrahedron Lett., No. 4, 353 (1981).
19. D. J. Chadwick and I. A. Cliff, Khim. Geterotsikl. Soedin,, No. 5, 576 (1984)~
20. E. Ya. Lukevits (ed.), Advances in Furan Chemistry [in Russian], Izd. Zinatne, Riga
(1978), p. 51.
21. Jo Emsley, J. Finney, and L. Suttclife, High-Resolution NMR Spectroscopy [Russian trans-
lation], Vol. i, Izd. Mir, Moscow (1968), p. 326.
22. A. F. Pozharskii, The Theoretical Basis of Heterocyclic Chemistry [in Russian], Izd~
Khimiya, Moscow (1985), p. 109.
23. I. Ya. Bershtein and Yu. L. Kaminskii, Spectrophotometric Analysis in Organic Chemistry
[in Russian], Izd. Khimiya, Leningrad (1975), p. 141.

1075
ISO~RIZATION OF 5-ACYL-6-HALO-I,6-DIAZABICYCLO[3.1.0]HEXANES,
A CASE OF INVERSION RATHER THAN 1,2-ACYL MIGRATION*

G. V. Shustov, S. N. Denisenko, I. I. Chervin, UDC 547.863:548.737:

A. B. Zolotoi, O. A. D'yachenko, So V. Konovalikhin, 542.422:541=621
G. V. Shilov, L. O. Atovmyan, and R. G. Kostyanovskii

X-ray diffraction structural analysis and ~ C and ~SN NMR spectroscopy were used
to establish that the final product of the halogenation of 5-acyl-l,6-diazabicy-
clo[3.1.0]hexane is the exo-6-halo derivative. Thus, the observed transformation
of the initially formed endo-N-chloro isomer is an inversion and not 1,2-acyl mi-
gration as previously proposed.

In our previous communication [2], we proposed that N-chloro derivatives lla and lib
formed upon the chlorination of 5-acyl-l,6-diazabicyclo[3.1.0]hexanes la and Ib readily iso-
merize with retention of the diazabicyclohexane skeleton. The final reaction products,
chlorides Ilia and lllb, were assigned the structure of 6-acyl-5-chloro-l,6-diazabicyclo-
[3.1.0]hexanes and their formation was postulated to proceed through 1,2-acyl migration.
N-Bromo derivatives lllc and llld were obtained in a further study of the halogenation of
bicyclic diaziridines la and Ib. The structure of bromide llld as the methylamide of exo-6-
bromo-l,6-diazabicyclo[3.1.0]hexane-5-carboxylic acid was established by diffraction struc-
tural analysis (Fig. i). The unit cell of crystals of llld contain two independent
molecules. The bicyclic fragment in both molecules has boat conformation with flexure an-
gles relative to the central C(2)N(~)C(s)C(~) plane about 30 ~ [along the C(=)...C(~) line]
and 80 ~ [along the N(~)...C(5) line].

Cl COR COR CI 9
IIa,b Ilia,b .C.
IIal
"AI 4" N 2 + CH;:-'I'H~ + 01[2~:C~ "COR

i-l D c

COIl ' i i COR "Br

; a,b III cjd
I--IT! a,b R=OMe;c,dR=NIIMe

I - - I l l a,b R=OMe;c,d R=NHMe, Reagents and conditions:

A: ~-BuOCl, CH.~CI.o, -30=; B : CH~CI.~, 20=; C : GDCI3, 60~ ;D: P vH'Br3-, K~CO3, CH.~CI=, H~O, 20~

The final chlorination products, chlorides Ilia and lllb and exo-bromides lllc and llld
are identical in their ~3C NMR spectra (Table i), while esters Ilia and lllc and amide llld
identically undergo smooth decomposition into nitrogen, ethylene, and a-haloacrylate upon
heating in CDCI3 at 60~ for 6 h. This indicates a common structure for Illa, lllh, lllc,
and llld as N-halo derivatives with exo orientation of the halogen atom. Then, the chlorine
atom in the initially formed chlorides lla and lib is in the endo orientation. This assign-
ment is indicated by analysis of the ~*C N-MR spectra (Table i). Previous work [3, 4] has
shown that the chemical shift of C(3) of bicyclo[3.1.0]hexanes is a diagnostic test for the
boat and chair conformation, which is determined by the orientation of the substituent at
C(6). The boat form obtains in the case of exo orientation with characteristic upfield shift

*Communication 52 in the series "Asymmetric Nitrogen;" for Communication 51, see [i].
Branch of the institute of Chemical Physics, Academy of Sciences of the USSR, Chernogo-
lovka 142432. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i0, pp. 1330-
1333, October, 1986. Original article submitted July i, 1985.

1076 0009-3122/86/2210-1076512.50 O 1987 Plenum Publishing Corporation

 J.~Sr
b,2
9 C:, N " 24,<'~\/n~' 7 0 , O F"~
'X ,/~%
O'O/C[ <~,3 5,7 P 0%~/CMe

oo+o
0 "~ Ct5' 0,0 3,7 O0 1,8
- - . . ~ l,a II a III a IV

Fig. 1 Fig. 2
Fig. i. Bromide IIId with 30% thermal oscillation probability
ellipsoids.
Fig. 2. 2J:~c:s N coupling constants (Hz) for caLbon atoms in
Ia-IIIa and IV.

TABLE i. Chemical Shifts (ppm) in the :3C NMR Off

Resonance Spectra for 5-Acyl-6-halo-l,6-diazabicy-
clo[3.1.0]hexanes in CDCI3
Com-
pound c(2)(t) c~)(t) ct 4 > ( t ) cL~)(s) ~le{ q) co IS)

Ila 55.25 28.60 27,60 74,02 53,27 167.40

Ilb 54.65 28.35 26 40 75,01 25,50 166,42
Ilia 55,94 20,87 29128 76,70 53,00 165.18
IIlb 55,56 20.94 28,54 76,73 25,30 164,43
II1r 55.43 20,45 28.59 75,39 52,42 165.16
IIid 55142 20,90 28,20 75,85 25,04 165,34

for C(3) (syn-y-effect), while the chair form with deshielded C13) is thermodynamically fav-
ored in the case of a 6-endo substituent. The similar upfield shifts for C(3) in chlorides
IIIa and IIIb and bromides IIIc and IIId and a significantly deshielded C(3) in IIa and IIb
indicate the identical exo orientation of the 6-halogen for IIIa-d and endo orientation for
IIa and IIb. The same Conclusion may be drawn from the stereospecific 2JI~c:5 N constants,
-which, as shown in the case of aziridine IV and its derivatives [5], are greater for the :3C
nuclei in the cis position to the unshared electron pair of the :SN atom (Fig. 2). Thus,
chlorides IIa and IIb are endo isomers of 5-acyl-6-chloro-l,6-diazabicyclo[3.1.0]hexane and
IIIa and IIIb are the corresponding exo isomers. The transformations IIa + I I I a and IIb
IIIb observed by :3C NMR spectroscopy involve inversion and not 1,2-acyl migration. We shoui
note i) endo stereospecificity for the chlorination of diaziridines Ia and Ib, and 2) that the
configurational stability of N-chlorodiaziridines IIa and IIb is significantly less* than
would be expected on the basis of current concepts concerning the nature of inversion of the
nitrogen atom [6]. The unusually high rate of inversion of N-chiorodiaziridines IIa and
IIb is one of the reasons for the erroneous proposal for the structure of final chlorination
products IIIa and IIIb and the nature of the transformation of IIa and IIb. We may also as-
sume that the bromination of diaziridines Ia and Ib also proceeds stereospecifically through
the formation of the corresponding endo-N-bro~o isomer with subsequent inversion to exo-
bromides IIIc and IIId. However, this isomer could not be detected under the conditions for
observation of endo-chloride IIa, which is apparently a consequence of the still lower con-
figurational stability of these endo-N-bromo derivatives.

EXPERIMENTAL
The PMR spectra were taken on a Jeol ICM-C-60 HL spectrometer at 60 MBz relative to
HMDS. The 13C NMI~ spectra were taken on a Bruker WM-400 spectrometer at 100.62 MHz relative
to ~ . The UV spectra were taken on a Specord UV-VIS spectrometer. The mass spectra were

*N-Chlorodiaziridines IIa and IIb completely isomerize to exo isomers IIIa and IIIb over 1
h at 20~

1077
 TABLE 2. Atomic Coordinates in Molecules A and B ( a)

AtOM x :'~1oM

Br,~ 4466(2) 0789(I) 703~(3) O(10} 3598(13) 15~3(7) 0298(19)

O,~ 3275(9) 1440(5) 5266(15) N~ il) 3557(10) 0752(6) 2876(19)
N,I> 3248(9) 0718(6) 8028(18) "~t!6) 3207(10) 0610(7) 1699(24)
N~) 3630(10) 0568(7) 6783(24) "3466(10) 1579(6) 2504(17)
C,2) 2756(14) 0401(7) 8220(23) C,12) 4036(17) 0431(10) 3173(31)
C,~ 2476{15) 0314(8) 6780(28) C;13) 4399* 0373(9) 1790(28)
Cm 2569(11) 0698(9) 6043(27) C(14) 4319(15) 0760(9} 1035(32)
C~s~ 3160(1) 0884(6} 6609(21) C15) 3703/12) 0944(8) 1640(24)
C, h 3299(111) 1296(7) 6431(22) C()7) 358~(12) 1370(6) 1452(29)
C,~) 3511(11) 1966(6) 7333{23) C~9) 3392(15) 2002(6) 2459(26)
Br(Io) 2356 (2) 0833(1) i787(4) N~8) 3396(10) 1546(5) 7506(17)

*Coordinate fixed.

TABLE 3. Bond Lengths (~) and Bond Angles (deg) in Molecules

A and B

Atom ;Molecule Molecule Molecule Molecule

A B Atom A B

~I'( i ) --,N$~6) 1.94 (2) 1,96(2) ~r/i~N,6jC(5) 112(2) 111(2)

1,26(3) 1,25 (3) 6l(t) 56(1)
1,57 (3) 1.47 (3) CI 7)-~( 8)C, 9) I22(2) 122(2)
1,50(3)- 1,51(4) N())C~2)C~a) t06(2) to4(2)
N, ~,--Ce~ 1,53 (3) 1,42(3) 104(2) lO6(2)
N,s,--C a) 1,46(3) 1,54(3) C~3)CmC~s~ 106(2) lo4(2)
1,37(3) 1,28(3) N~I>C~3NI6) 63(I) 59(2)
.'Nr,8)--C: .% 1,43(3) 1,42(3) 108(2) lto(2)
C,>--C~a)
r., 1,58(4) 1,59(4) N,I)C,5~C,7) 116(2) 121(2)
C(3) --k..i 4) 1,49(4) 1.5o(4) N~6)C~s~C,4) 109(2) 108(2)
C<4)--C~s) ~.5~(3) 1,57(4) N,6,C,s~C,r~ 125(2) 126(2)
C,5,--C<7) 1,41 (3) 1.45(3) 122(2) 1t9(2)
104 (2) 106(2) O,z,C, 7,C,s) 118(2) t19(2)
56(~) 64(2) 120(2) 123(2)
C,~)N,,)C,s~ 107(2) 110(2) N(s)Ctr)C(5) i21(2) 117(2)
io5(i) 108(~)

taken on a Finnigan 4021 spectrometer. 5-Acyl-l,6-diazabicyclo[3.1.0]hexanes la and Ib were

described in our previous work [2, 7] and their N-chloro derivatives lla, llb, llla, and lilb
~ere described in our previous work [2].
Bromination of 5-acyl-l,6-diazabicyclo[3.1.0]hexanes la and Ib (general procedure). A
solution of 5 mmoles diaziridine la or Ib [2, 7] in 5 ml ChaCia was shaken in a separatory
funnel with a solution of 1.62 g (5 mmoles) pyridinium bromide perbromide [8] and 0.67 g (5
mmo!es) KaCOa in 15 ml water. The organic layer was separated and dried over magnesium sul-
fate. The solvent was evaporated in vacuum and the r e s i d u e w a s recrystallized.
exo-6-Bromo-57carbomethoxy-!,6-diazbicyclo[3.1.0]hexane (lllc) was obtained in 88% yield
mp 47.5-48~ (from hexane). UV spectrum in heptane: ~max 244 n m (log ~ 3.58). Found, %:
C 32.9; H 4.0; N 12.7. C6HgBrN2Oa. Calculated, %: C 32.6; H 4.1; N 12.7.
exo-6-Br0mo-brN-methylcarbqm0yl-l,6-diazabicyclo[3.1.0]hexane (llld) was obtained in 83%
yield, mp I02-I03~ (from CC14). Found, %: C 32.6; H 4.7; N 19.0. C6H~oBrNaO. Calculated,
%: C 32.8; H 4.6; N 19.1. T h e transparent white crystals of amide llld turned somewhat yel-
low-red even during the crystallization process. In daylight and, especially, in sunlight,
the crystals become dark red and rapidly decompose with the release of a characteristic bro-
mine odor. Crystals of llld are rectangular parallelepiped platelets extended along the C-
axis and are orthorhombic in symmetry. The major crystallographic parameters are: C~HxoBrNaO
M = 220.106; a = 21.310(4); b = 33.306(12); c = 9.990(6), V = 7090.4 ~3, Z = 32, dealt =
1.528 g/cm 3, space group F2ddo A total of 961 reflections with I ~ 3Ol were measured on a
RED-4 four-circle diffractometer using the 8/2e method, CuK a radiation, 0.056 5 sin e/X
0.540. Absorption was not taken into account (~CuK~ = 66.8 cm-X). The bromine atomic coor-
dinates were found by the direct method. The coordinates of the other nonhydrogen atoms
were found from the Fourier map. The structure was refined in the full-matrix anisocropic
approximation for all atoms to R = 0.i01 using the Roentgen-75 program [9]. The atomic coor-

1078
dinates are given in Table 2. The bond lengths and angles are given in Table 3. The high
R factor and significant scatter in the equivalent and monotypic bond lengths is a consequence
of sample decomposition during the measurement. An illustration of the molecule was obtained
using the ELLIPS program [I0].
Thermolysis of exo-5-Carbomethoxy-6-chloro-l,6-diazabicyc!o[3.1.O]hexane (lila). A
solution of 90 mg (0.5 mmole) chloride llla in 0.5 ml CDCI3 was heated in a sealed ampule at
80~ for 10 h. Removal of the solvent gave 58 mg (95%) methyl a-chloroacrylate, which was
identical in its PMR and mass spectra to an authentic sample. P ~ spectrum in CDCIs: 3.8
(MeO), 6.0, and 6.5 ppm (JAB = 1.5 Hz). Mass spectrum at 20 eV, m/z (relative intensity), %:
~ 122 (25), 120 (74), 119 (7), 104 (7), 102 (17), 91 (32), 89 (i00), 85 (28), 63 (20), 61
(59), 59 (38), 54 (7), 41 (8).
Thermo!ysis of N-halo derivatives lllb-d were carried out by the above procedure and
the corresponding a-haloacrylates were identified by comparison of their PMR spectra with
those of authentic samples.

LITERATURE CITED
i. A. B. Zolotoi, O. A. D'yachenko, L. O. Atovmyan, G. V. Shustov, S. N. Denisenko, and
R. G. Kostyanovskii, Izv. Akad. Nauk SSSR, Ser. Khim., No. ii, 2441 (1986).
2. S. N. Denisenko, G. V. Shustov, R. G. Kostyanovskii (Kostyanovsky), Chem. Commun.,
No. I0, 1275 (1983).
3. M. Christl, H. Leininger, and E. Brunn, J. Org. Chem., 47, 661 (-1982).
4. G. V. Shustov, S. N. Denisenko, I. I. Chervin, and R. G. Kostyanovskii (Kostyanovsky),
Tetrahedron, 41, 5719 (1986).
5. R. G. Kostyanovskii, A. I. Mishchenko, A. V. Prosyanik, and N. L. Zaichenko, Izv. Akad.
Nauk SSSR, Ser. Khim., No. 7, 1572 (1983).
6. J. Lehn, Topics in Current Chemistry, Vol. 15 (1970), p. 313.
7. G. V. Shustov, S. N. Denisenko, and R. G. Kostyanovskii, Izv. Akad. Nauk SSSR, Ser.
Khim., No. 8, 1831 (1985).
8. L. Fieser and M. Fieser, Reagents for Organic Synthesis [Russian translation], Vol. 3,
Izd. Mir, Moscow (1970), p. 119.
9. V. I. Andrianov, Z. Sh. Safina, and B. L. Tarnopol'skii, Roentgen-75. An Automated
Program System for the Interpretation of Crystal Structures [in Russian], Branch of
the Institute of Chemical Physics, Academy of Sciences of the USSR, Chernogolovka
(1975).
!0. A. I. Chekhlov, Kristallografiya, 26, 596 (1981).

1079
>~SS SPECTROMETRIC STUDY OF RING-CHAIN TAUTOMERS
OF 3-A~IINO(HYDROXY)PYRAZOLIDINES

A. G. Kalandarishvili, P. B. Terent'ev, S. V. Afanas'eva, UDC 543.51:547.773:

L. A. Sviridova, R. R. Razakov, Yu. G. Bnndel', 541.623
A. S. Sadykov, and N. S. Kulikov

The mass spectrometric fragmentation of substituted 3-amino-, 3-hydrazino-, and

3-hydroxypyrazolidines has been studied. In the gas phase these compounds exist
partly as the acyclic tautomers.

Ring-chain tautomeric conversions play an important role in organic chemistry [i, 2].
In the study of this kind of conversion it is of considerable interest to investigate the
effect of structural factors and state of aggregation on the ease of formation and relative
stability of the cyclic and linear tautomers.
Lately, mass spectrometry has been used widely; it enables the content of tautomeric
forms to be estimated in the gas phase, where solvation effects and intermolecular interac-
tions are absent, In the presence of individual fragmentation of each possible tautomeric
structure, one can estimate even the quantitative proportions of tautomers of molecular ions
(M+) from the data on mass spectrometric decomposition [3-7]. A relation has been estab-
lished between the proportion of tautomeric forms and the state of aggregation of such com-
pounds as substituted azines [4], alkyl(aryl)benzazolylazoketoximes [5], 2-hydroxymorpholines
that contain nitrogen and oxygen [6], and oxazolidines and B-diketoximes [7].
It has previously been shown [8, 9] that hydroxypyrazolidines in solution exist mainly
in the cyclic form, but their hydrazino derivatives are predominantly linear, and the frac-
tion of the latter form increases with increase of solvent polarity.
It was therefore of interest to study the possible identification of the cyclic and
linear forms of such compounds in the gas phase. For this purpose, we obtained and analyzed
the mass spectra (Table I) of the 3-amino(hydrazino)pyrazolidines I-XIV and the hydroxypyra-
zolidines XV-XVII.

R~ --X ~ R~ ~.X=.CH._CHz

~2oc'~'N~"n4 = SN.--~
~ ~2ocJ ~
A 1-xvn B

It is known that the loss of the radical located in ~-position to nitrogen is typical
for ~ of pyrazolidines [i0] and aminoisoindoles [ii]. 2-Hydroxymorpholines in the gas phase
show two tautomeric forms of M+; the presence of the linear structure N-(8-hydrolxy+ethyl)-N-
(B-oxoethyl)amine is confirmed by the formation of the [M -- CHO] + and [M -- CH2OH] ions [6].
Starting from what has been said above and the general concepts of the mass spectromet-
ric behavior of alicyclic and aliphatic compounds containing nitrogen [12], it might be pre-
sumed that in such compounds the charge would be localized predominantly on nitrogen. For
~ of form A one might expect scission of the C--X bond to form [M-- RtXH]+; and for M + of the
linear structure B, dissociation of the hydrazine bond and the 8-C--C bond to form [M --
HNCOR2] + and [M -- RIX = CHCH2] +, respectively.
The mass spectra of compounds I-XIX (Table i) in all cases contain M + peaks the stabilit~
of which (Table 2) depends only slighly on the electronic properties of the aryl substituent

M. V. Lomonosov Moscow State University, Moscow 117234. Institute of Bioorganic Chem-

istry, Academy of Sciences of the Uzbek SSK, Tashkent. Translated from Khimiya Geterotsik-
licheskikh Soedinenii, No. i0, pp. 1334-1338, 1986. Original article submitted June 24, 198

1080 0009-3122/86/2210-1080512.50 O 1987 Plenum Publishing Corporation

 TABLE i. Mass Spectra of Compounds I-XIX*

Com- m / z ( r e l a t i v e i n t e n s i t y , %)
pound

I 281 (14.0), 238 (7,0), 223 (17,0), 163 (I0,0), 150 (17,0), 146 (71,0), 132
(100,0), 120 (28,0), 119 (17,0), 91 (17,0), 77 (43,0)
II 295 (4,0), 237 (4,0), 163 (4,0), 150 (6,0), 146 (100,0), 132 (6,0), 120 (7,0),
118 (10,0), t04 (9,0), 91 (15,0), 77 (15,0)
IIl 359 (8,0), 301 (9,0), 212 (83,0), 189 (9,0), 163 (22,0), 150 (67,0), 146
(100,0), 130 (67,0), 120 (24,0), 104 (33,0), 77 (58,0)
IV 3tl (20,0), 253 (7,0), t62 (100,0), 150 (18,0), 146 (46,0), 135 (14,0), 112
(10,0), 108 (23,0), 104 (10,0), 91 (8,0), 77 (15,0)
V 326 (25,0), 283 (14.0), 268 (13.0), 177 (64,0), 163 (14,0), 150 (t00,0), 146
(69,0), t30 (22,0), 108 (30,0), 104 (22,0), 77 (36,0)
VI 295 (0,3), 163 (2,0), 150 (10,0), 146 (100,0), 132 (7,0), 120 (7,0), 118
(5,0), 108 (I5,0), 104 (II,0), 91 (15,0), 77 (26,0)
VII 287 (37,0), 243 (17,0), 228 (33,0), 189 (12.0), 163 (33,0), 150 (75,0), 146
(100.0). 139 (100.0), i20 (62,0), 108 (87.0), 104 (33,0)
VIII 292 (9.0), 249 (14.0). 234 (10,0), t77 (60,0), 164 (16,0), t49 (28,0), 129
(8.0), 116 (28,0), 112 (20,0), 92 (23,0), 77 (42,0)
IX 341 (3.0), 191 (17.0), 189 (30,0). 163 (90,0), 150 (28,0), 147 (10,0), 121
(40,0). 119 (12.0). 108 (44,0), 104 (80,0), 77 (60,0)
X 324 (20,0), 266 (10,0), 189 (17,0), 175 (32,0), 163 (60,0), 146 (100,0), 121
(20.0). 108 (t6,0/. 105 (77.0). 9I (7,0), 77 (50,0)
XI 290 (4,07. 231 (8,0). I55 (4,0), 129 (15,0), 121 (20,0), 113 (14,0), 105
(I00,0), 87 (25.0), 77 (50,0), 43 (30,0)
XII 248 (10,0), 189 (17,0), 163 (100,07. 150 (14.0), 146 (22,0), 121 (50,0), 108
(17,0). 104 (67,0). 99 (40.0), 91 (22,0), 77 (39,0)
XIII 214 (3.07, 156 (6,7), 129 (100,0), 105 (17,0), 98 (58,0), 87 (83,0), 85 (21,0),
71 (16,0). 69 (21,0), 59 (29,0), 43 (66,0)
XIV 262 (36,07, 189 .(24,0), 163 (100,0), 150 (32,0), 146 (80,0), 121 (32,0), 113
(32,0), 108 (32,0). 104 (31,0), 91 (28,0), 77 (60,0)
XV 206 (29,0), 189 (7,0), 163 (100,0), 150 (37,0), 146 (37,0), 121 (15,0), 108
(64,0), 104 (37,0), 95 (28.0), 91 (37,0), 77 (71,0)
XVI 296 (7,0), 205 (4,7), 191 (45,0), 175 (I0,1), 173 (6,5), 148 (12,0), 122
(7,0), 105 (45,0), 104 (8,9), 91 (100,0), 77 (21.0)
XVII 220 (34,0), 178 (47,0), 177 (100,0), 163 (19,0), 160 (15,7), 145 (15,7),
135 (37.5), 118 (28,0), I07 (50,0), 91 (14,0), 77 (56,0)
XVIII 220 (26,0), 177 (100,0), 146 (87,0), t21 (4,0), 119 (6,8), 104 (42,0), 91
(15,0), 77 (75,0), 71 (18,7), 65 (7,7), 43 (31.0)
XIX 234 (18,0), 191 (78,0), 162 (4,6), 146 (100,0), 120 (17,0), 118 (19,0), 107
(16,0). 104 (85,0). 91 (27,0), 77 (90,0), 43 (66,0)
ID 282 (17,0). 281 (6,7), 223 (16,0), 162 (31,0), 146 (60,0), 133 (76,0), 132
(81,0), I19 (50,0), 104 (78,0), 91 (50,0), 77 (100,0)
XVD 207 (19,0). 206 (10,0), 163 (60,0), 146 (60,0), 121 (I1,0), 119 (10,0), 108
(15,0), 104 (45,0), 91 (27,0), 77 (100,0), 65 (10,0)

* T h e molecular ion peak and the i0 most intense peaks are

given.

TABLE 2 . Intensity of Characteristic Ion Peaks in Mass Spec-

tra of 3-Aminopyrazolidines I-IX, 3-Hydrazinopyrazolidines,
and 3-Hydroxy(alkoxy)pyrazolidines X-XIX (% ~ 9 )
Com-
RI Ra 9 , 02 Oa
IJ O~ ~s qbc
pound *
I

I Calls CGHs 2,6 0,411.012,6:1,5 0,9 15,5 0,314.8 2.6 9,6 2,6 72,1
II 4-CHsCeH4 C~Hs 1,9 0,215.6J 1,0 1.0 0,2 15,6 0,412,7 1,0 4,7 6,6 85,7
IIl 4-BrC6H4 C~Ha 1.7 0,8 8.51 1,3 1,8 0,2 14,0 0,212,5 0,6 4.8 2.8 73,8
IV 4-CHaOC6HI C6H~ 1,9 0,4 9.61 1,4 3.0 0,2 19,6 19.611,9 0~3 3.0 2.2 69,3
V 4-NO=C6H4 C~H,~ 4.3 0,3 9,41 1,7 2,0 1,9 8.7 0,3]3,0 1,4 5,0 2,4 70,0
VI CH.~--C~Hs C~H5 0,1 0,0; 1 4 , 0 1 0 , 3 0,6 0,1 14.0 0.2 30 0,6 7,0 12,7 92,6
VII C~Hu (cyclo) C~H5 1,7 0,5 3,41 0,9 I,I 0,7 2.0 o.71ml 1,1 1.0 1.4 59.0
VIII 4-NO2C~H~ CH(CHa)2 0,9 0.2 .... 0,6 4,8 0,8 3,4 211 0,9! 1.2 5,8 0,2 14,7
IX HNC6H4NO2 CGH5 0,4 3,3 2,41 - - 9,0 0,I 0.5 0,517,3 I 3,0 5,0 0,6 37,5
X NF[COC6Hs C~Hs 4,7 2,5 14,21 1,4 8,5 0,3 4,5 1,4 2.5 (1,7 7,1 1,5 59,6
XI NHCOC6Hs CH(CH3)= 0,9 0,7 1.61 0,5 2,8 -- 1,1 o,21o,5i 0,5 5,6 0,7 39,6
XII N(CHa)2 CH(CHa)~ 0,5 2,2 - - , 0,8 12,0 -- 2,5 0 '5 2 0' 1 i 2,5 8,0 0,2 14,2
XIII CH(CH3)~ C6Hs 1,5 2,0 2,61 1,6 12.0 -- 4,8 o,818,o~ 0,8 3,0 0,3 23,1
XIV NHCOCHa Coils 3.5 2,0 6.81 1,2 8,5 0,2 2.7 0,712,7 0,7 5,1 0,8 45,8
XV H C~Ha 2,2 "0.5 2.31 0,2 3,2* 3,2 5,3 0,312,3 1.0 4.2 -- 21,0
XVI H CH,--C~H~ 2,8 0,4 1.31 1,3 0,4 11,1 0,7 0,712,2 3,0 25,0 0,7 41,4
XVII H C6H~ 6,5 - - 2.41- 15,5'* 15,5 0,4 -- 8,7 -- 100
XVIII CI-t~ C,;H5 4.9 - - 1 3 , 4 1 - - 0,2 15,0 3.0 0,116,4 1,0 11,6 -- 100
NIX C2H5 C6H~ 2,0 -10.0I--
-

I
0,3 7,8 3,6 0,418,6 0,8 9,3 - - 100

* I--XIV XH=NH, XV--XIX XH=O; I--XV, XVII--XIX R2=CHa, XVI R 2= C6H5;

I-=XV, XVIII, XIX R4=H, X V i XVII R4=Ct-la.
**Ions ~ and ~5 identical in elemental composition.

1081
 m / z I&6F~O

m / Z I~9<C~<)

m / z 223(~ 3)
i m / z 189[~]

Fig. i. DADI spectrum of the mole-

cular ion of compound I.

Scheme
~+"
RI--XH 1 +" R ~ --X :=CII-CH 2
\CIIR ,I
HN N/

A I;
T ' 1 r
i -COR2 "i-R'XS -co,
21v( * )-HNCOX 2
T
,!
i
R ~ --XH
"]....
+ll I R ~X=CH-CH= R'--X~C H
R4 R20C/NxNzP'~-R*
~/CHN R --CH--CI{~

R ~ --XH-~CH R3 ~3
R
, l
--CH~CH
\ ~--~CHR4
HN--N
C~OR~
~4 ~6 R4
04

& .... J\
II20C"N--N'-R3
~g 7 ",
~+.
R3N~CHR41
~a
* Memstable ions

and of R z, and decreases when the aromatic radical at the nitrogen at position 1 is replaced
by an aliphatic substituent (isopropyl, Table 2). In the spectra of these compounds one
might expect to find [M -- HNC(0H)R2] + (the MacLafferty rearrangement), but such fragments
do not appear. Consequently, in M+ conformational rearrangement must be slower than dis-
sociation of the corresponding bonds. The mass spectra of I-XVI contain the fragment ions
~z-~4 and ~6, that are typical f o r M + o f both cyclic and linear tautomers (see diagram). Study
of the mass spectra of the metastable ions by the DADI technique [13, 14] enabled us to es-
tablish that ions ~z-~s and ~, form in one step directly from M+ (Fig. 1).
Analysis of the mass spectra of deutero derivatives I and XV showed that ions #z, ~=,
~a, and ~7 contain no deuterium, and the peaks corresponding to ions #~ and @s are shifted
by one unit toward larger masses. In @6 deuterium is only partially retained; this confirms
that ~ can form from either form A or form B,
To confirm the proposed scheme of ion fragmentation, mass spectra were obtained of known
fixed cyclic forms, viz., the l-phenyl,2-acetyl-3-methoxy(ethoxy)pyrazolidlnes XVIII and XIX
Their mass spectra are characterized by intense peaks of ions @z, r @5, and ~ , but @3 and
~ do not appear; the fragmentation sequence of M + and the fragment ions was established by
a study of the mass spectra of the metastable ions by the DADI method.

1082
 Thus, it can be concluded that M+ of compounds I-XVI in the gas phase exists in two
tautomeric forms, cyclic A and linear B (Scheme).
For a quantitative estimate of the proportions of forms A and B in the gas phase we used
ions ~ a n d ~2 (cyclic form A) and ~s, ~ and ~7 (form B), and the fraction of cyclic A was de-
termined from the ratio: A, % = ( ~ + ~2/~I + ~= + ~3 + ~ + ~7)-i00. In the case of compound
XV, ion r was not included in the quantitative estimate of tautomer ratio because its ele-
mental composition is the same as that of ~5.
From Table 2 it follows that the introduction of either electron donor or electron ac-
ceptor substitutents into the phenyl group (radical R I) does not affect the tautomer ratio
in the gas phase (compounds I-V). Replacement of the aryl residue by benzyl (compound VI)
increases the content of cyclic M +, whereas in the case of alicyclic R ~ there is an appre-
ciable increase in the fraction of linear M+. The quantitative tautomer ratio changes sharp-
ly when the phenyl radical and the nitrogen at position 1 are replaced by isopropyl. This
confirms the assumption given above that the positive charge is localized predominantly on
the pyrazolidine ring nitrogens.
In contrast to aminopyrazolidines, in hydrazinopyrazolidines IX-XIV in the gas phase
the fration of M+ in form B increases, and it becomes preponderant in the spectrum of XII
(Table 2).
According to our data the 3-hydroxypyrazolidines XV and XVI are present in the gas
phase predominantly as noncyclic form B, in contrast to solutions [8].
The appearance of the M+ tautomers in the gas phase may result from the different vol-
atiiities of the forms, which may cause the gas mixture to be enriched in the less polar
form. Furthermore, we should not exclude the possibility of rearrangements taking place in
~ itself; these can also cause the ions that are typical of the second tautomer to appear
in the spectrum. In this connection, we obtained and analyzed the mass spectrum of hydroxy-
pyrazolidine XVII, the crystal structure of which has been established by x-ray diffraction
analysis to be cyclic only. As-follows from the data of Table 3, in the gas phase this com-
pound is exclusively in the cyclic form. Thus, the factors given above, at least for the
compounds that we have studied, do not play a significant role, and the ratio of M + tautomeri
forms observed in the gas phase in all probability quite accurately reflects the true ratio
of tautomers of neutral molecules in the absence of solvating and intermolecular interactions

LITERATURE CITED
i. V. I. Minkin and V. A. Bren', Izv. Vuzov. KhimyaKhim. Tekhnol., 25, No. 6, 663 (1982).
2. R. E. Val'ter, Ring-Chain Isomerism inOrganic Chemistry [in Rus-sian], Zinatne, Riga
(1978).
3. R. A. Khmel'nitskii, N. A. Klyuev, A. F. Dolgikh, and N. P. Bednyagina, Izv. Timiryaz.
Skh. Akad., No. 5, 205 (1975).
4. Yu. N. Sheinker, Izv. Sibir. Otd. Akad. Nauk. SSSR, Ser. Khim. Nauk, No. 2, 37 (1980).
5. N. A. Klyuev, I. S. Shpileva, L. I. Medvedeva, G. I. Lipunova, and N. P. Bednyagina,
Khim. Geterotsikl. Soedin., No. ii, 1506 (1981).
6. L. Simonotti, G. Pasquaucci, and G. Pifferi, J~ Heterocyc. Chem., 21, 595 (1984).
7. M. E. Rennenkamp, I. U. Pauksteli, and R. C. Cooks, Tetrahedron, 27, 4407 (1971).
8. K. N. Zelenin, A. V. Dovgilevich, I. P. Bezhan, G. A. Golubeva, L. A. Sviridova, L. V.
Pastushenkov, E. G. Gromova, T. A. Gatchina, and S. V. Pomogaibo, Khim. Geterotsikl.
Soedin., No. 5, 659 (1984).
9. K. N. Zelenin, G. A. Golubeva, S. V. Afanas'eva, L. A. Sviridova, I. P. Bezhan, M. Yu.
Malov, and Yu. G. Bundel', Khim. Geterotsikl. Soedin., No. 9, 1238 (1985).
i0. B. B. Snider, R. S. E. Conn, and S. Sealfon, J. Org. Chem., 44, 218 (1979).
li. O. S. Anisimova, Yu. N. Sheinker, and R. E. Valter, Khim. Geterotsikl. Soedin., No. 8,
1080 (1984).
12. P. B. Terent'ev, Mass Spectrometry in Organic Chemistry [in Russian], Vysshaya Shkola,
Moscow (1979).
13. D. H. Smith, C. Djerassi, K. H. Maurer, and U. Rapp, J. Am. Chem. Soc., 96, 3482 (1974).
14. R. R. Razakov, A. K. Kasimov, Kh. A. Aslanov, and A. S. Sadykov, Khim. Geterotsikl.
Soedin., No. i, 81 (1981).

1083
NITROSOCHLORINATION REACTION OF SUBSTITUTED IMIDAZOL!N-2-ONES

V. V. Golovko, A. I. Statsenskaya, Yu. A. Baskakov, UDC 547.781.3'785.1.04:

and Yu. G. Putsykin 543.422

Interaction of nitrosyl chloride with l-arylimidazolin-2-ones in methanol leads

to the formation of 4,5-dimethyoxyimidazolidin-2-ones. Under similar conditions
1,5-diarylimidazo!in-2-ones give 1,5-diaryl-4-oximino-5-alkoxyimidazolidin-2-
ones. When the reaction is carried out in an aprotic solvent 1,5-diaryl-4-nitro-
soimidazolin-2-ones are separated, and when treated with alcohol they give the
final reaction products. An increase in temperature and duration of the reac-
tion results in the formation of 1,5-diaryl-5-hydroxyhydantoins.

The familiar electrophilic addition reaction of nitrosyl chloride to the double bond
in a number of functionally unsubstituted olefins [i, 2] has no analogous references in the
literature for a number of unsaturated heterocycles.
We have studied the nitrosochlorination reaction of l-aryl- and 1,5-diarylimidazolin-2-
ones (I, II). It is shown that when compound Ic undergoes nitrosochlorination in methanol
a product is formed, which, according to the data from elemental analysis and IR spectra,
corresponds to the structure of l-(4-chlorophenyl)-4,5-dimethoxyimidazolidin-2-one (III).
In fact, the presence in the PMR spectrum of two singlets at 3.18 and 3.31 ppm from the pro-
tons of the methoxy groups, two singlets at 4.50 and 4.90 ppm from the protons at the 4- and
5-positions of the ring, a multiplet at 7.40 ppm from the aromatic protons, and finally a
broad singlet at 8.40 ppm from the NH group proton supports the proposed structure.

0
J] ,
/~. C6 I~CI"4 IIN/~NI C,I{,CI"' N. ~<N/C~}~,CI-~I HN " ~ N v6H~CI"4
HN "N /
H/~------~C1 -HN0 H./u-----~C! j CH30" -OCH~
IC Iv If!

Evidently, nitrosochlorination of the unsuhstituted double bond of the heterocycle in-

volves the intermediate formation of the A3-imidazolin-2-one (IV), in which successive re-
placement of the chlorine atom by a methoxy group and addition of methanol to the double bond
lead to compound III.
On interaction of nitrosyl chloride with compounds II in alcohol products V are obtainec
which display in their IR spectra intense absorption bands in the region of stretching vibra-
tions of C----Nand C----Ogrou~s and a monovalent C-q3--C bond. In the spectra of these compounds
in CCI~ solution there are intense absorption bands of the free hydroxyl group at 3590-3600
cm-:, which is confirmed also by the data of the PMR spectra (a singlet at 10.20-10.40 ppm
from the proton of the HON group). In the PMR spectra of compounds V signals are also ob-
served from the protons of the methoxy and ethoxy groups at 3.20-3.40 ppm or 1.50-1.80 ppm
(triplet) and 3.60-4.00 ppm (quartet) (J = 6.0 Hz), respectively, as well as multiplets from
the protons of the aromatic rings. This data has made it possible to assign the structure
of 1,5-diaryl-4-oximino-5-alkoxyimidazolidin-2-ones to the compounds V obtained. In this
case, the conversion route of compounds II to compounds V probably includes the intermediate
formation of the nitrosochloride (VI) and nitrosoolefin (VII).
When comparing the results of the reaction of unsaturated heterocycles I and II with
NOCI it should be noted that this reaction evidently conforms to the same mechanism as the
nitrosochlorination of olefins such as styrene [3] and substituted styrenes [4]. The effect

All-Union Scientific Research Institute of Chemical Plant Protection Agents, Moscow

109088. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i0, pp. 1339-1342,
October, 1986. Original article submitted June 19, 1985.

1084 0009-3122/86/2210-I084512.50 ~ 1987 Plenum Publishing Corporation

 TABLE i. Properties of Compounds I, II, and V
o o

R ~ N / L N "'E ~N" N

~i~'~-Rz I_ION"~ "xOR~

I, II %'
IR spectrum (KBr), Found, % Calculated,
mp, cm'l Empirical % .=-
formula
C=C C=O C=N C

Ia CsHs 680 1670 67,4 4,8 t7,8 C.,H~N~O ~q7,5 5,0 17,5 82
Ib 3-CIC,:,H.~ ~,651~s8o I 3,6 [.~ o CgI-{C1NoO
lC
ld
4-CiC~d14
3,4-CIeC,J-Is
670lj690 I
66011e,80I
li:i ,2,61 c H,a#2o
55,5 3,6 14,41 63
-:7,2 2~7 12 2 87
Ila CH~ 6651,6701 16.0 ! C,~H,oN,O 68c! 5,8 1611172
lib CcH~ t 675[1685[ ,514 11,91 C,sl-I~eX]O V6',2 5,1 11,91 85
IIc _9-CIC,;H4 670] 16.~ 10.91 C,sH,ICIN20 10,3 / 88
lid 3-CIC,;H4 :670[ ! 69{3| |67,2 4.3 10.5/ CIsHHCIN~O ~6.5 4,1 10,31 93
IIe 4-CIC.A14 68511c.9 q /56,7 .l.4 10.2 Clst-IIICIN~O t~6,~ 4,1 10,3195
I I f i C,~He, 68c / i 695/ / 77,0 5,8 l l,d I Ci~I-tl4N~O 76,8 5,6 11 2! 94
IIg 4-CC~H; .Gso/~soei /67,3 4,3 9.7 / C~oHI~CIN.~O 67,~, 4,6 9,8185
Va i C4Is / 172e116.9C IOOO ]644} 5,2 13,g C[~HIsNsOs 64'f?]
Vb C:Hs /1740117oc 1o5o ]66 1 5,4 t3,5 / C~rHI:N~.Os {55,64c]5.55'1/14,i
13.5 73
78
Vc 3-CICBIq4 [ 174ql G96 II50 |58,{1 4,5 12.6] Clg-l,4ClN~O~ 57. 3 12,7 85
Vd 4-CIC~H~ tl7aoIIr~c 11oo 1582o 4,6 12,'t / C!,dtM21NsOs 57 ',3!I2,7 ;9
Ve 4-C1C~,H., 1~72o117oo 1{215{3 |59,3 1,312.1 / C,7H,~C NsO3 12,2 83
V 3,4-C!.oC,M~ ] 172[]]1700 1150 | 53,9 3.7 I1,0[ C,;H!sC!eNaO: 53,7 !,0 II,I 85
vg &H~ 117401!690 i05c /65,7 5,8 13.8| C:;H~rNsO~ 85,6 5,5 13,5 77
\h 3-CIC~t-I:, It 7.'-'ClCgu II0C 158,9 4,7 12.5[ Ctr}l~6ClNsOs 59,0 4,7 12,2 81

*la-d, !la-e, V a - f R = H; llf, g, Vg, h R = CH3; I R a = H ;

II R 2 = C , H b ; Va, c, d, g, h R 3 = CH3; Vb, e, f R 3 = C a H b .

of the N-arylurea fragment of rings i and II on the polarization of the double bond corre-
lates with the effect of the substituent on the C(5) carbon atom of compounds II.
An attempt to isolate compound VI or its isomeric a-chloroxime proved unsuccessful.
However, nitrosochlorination of compound lib dissolved in an aprotic solvent -- diethyl ether
leads to the separation of a solid crystalline substance Vlla, which displays in its IR spec-
trum an intense band from vibrations of the C--C and C--O bonds at 1680 cm -~ with a shoulder
at 1715 cm -~, a bending deformation band of the NH group at 1500 cm -~, and an intense broad
band at 1390 cm -~ which can be attributed to the nitroso group conjugated with the aromatic
ring. In this case, the shift of the band to lower frequency may be related to the forma-
tion of hydrogen bonds N--H---O=N -. On the basis of this information and also the data from
elemental analysis compound Vlla was assigned the structure of 1,5-diphenyl-4-nitrosoimidaz-
oiin-2-one.
o o o

,, ~N" ,,, NOCI :" -"'

" R~'OH ~ "/ u. N
, ~ R,
__! -Jz,~."IC'-. I ',.%H 5 = !
a~ ' " C~H.R oI: HO,<2~---~OR~ ON/------~C H

4~OC~ --
IoI ~ . ::,.+" o
' Ii
R Q ~R ~ i R. ~\ R'
~N / N" _ ~ "N I N/
Hq____~c~H, I ! L-c6u~
L ON ~'Cl J 0 / / ' - - ' - - ~ OH
vl VIII

VIIa R=H, R'=C6Hs;b R=H, RI=C6H4--CI-3

Compound Vllb is obtained in a similar manner from compound IId. The monomeric struc-
ture of these products, in contrast to, for example, the dimeric structure of styrene nitro-
soolefins [4], is supported by the data of the mass spectra, in which the peaks of the mole-
cular ion (MT) are recorded at values of m/z 265 and 269/271, respectively. The presence
of an intense peak from a benzoyl cation in the mass spectra of both compounds makes it pos-
sible to propose the following rearrangement of M+:

1085
 O -] ~" O -I +" Oi 1 --I+'

CN ~.
0,~, C~,[~ ii-~-/"

Chemical confirmation of the structure of nitroso product Vlia is provided by the forma-
tion of compound Va from Vlla on boiling in alcohol solution.
An increase in temperature and duration of the reaction of nitrosyl chloride with com-
pound II leads to the separation of 1,5-diaryl-5-hydroxyhydantoins (VIII), which are evident-
ly products of acid hydrolysis of the intermediate ~-chloroxime formed.

EXPERIMENTAL
IR spectra were recorded on a Perkin--Elmer 457 instrument in KBr pellets and in CCI~;
P}~ spectra were recorded on Tesla BS-487c and Bruker HX-90E instruments using solutions in
DMSO-d6 with internal standard HMDS; mass spectra were recorded on a LKB 2091 mass spectrom-
eter. The properties of the compounds obtained are given in Table I.
l-Arylimidazolin-2-ones (i). Ten mmole of N-arylcarbamoylaminoacetaldehyde dimethyl
acetal [5] was dissolved in 30-40 ml of concentration HCI at 20~ The precipitate formed
was filtered off and recrystallized from alcohol.
l-Alkyl(aryl)-5-phenylimidazolin-2-one s (II). Ten mmole of N-alkyl(aryl)carbamoyl-a-
aminoacetophenone [6] was dissolved in 30-40 ml of concentration HCI at 20~ The precipi-
tate formed was filtered off and recrystallized from alcohol.
l-(4-Chlorophenyl)-4,5-dimethoxyimidazolidin-2-one (III). To a solution of 2 mmole of
compound Ic in 50 ml of absolute methanol was added dropwise a solution of 2.5 mmole Of n i t r o
syl chloride in i0 ml of absolute methanol at -i0 to --15~ The solution was kept at this
temperature for 3-4 h, after which the mixture was left to stand at 20~ for 2 days. The
solvent was evaporated under vacuum, and 70-80 ml of water was added to the residual oil.
The aqueous layer was extracted with benzene (3 30 ml). The extract was dried over magne-
sium sulphate, the benzene was evaporated, and the residual oil without further purification
was crystallized out by freezing (--40 to --60~ Yield, 60%; mp, 93-96~ IR spectrum
(KBr): 1090 (C--O-C), 1690 (C--O), 3450 cm -~ (NH). Found, %: C 52.2; H 5.3; N 10.9. Cz~H~3-
CIN=O3. Calculated, %: C 51.5; H 5.1; N 10.9.
l-Alkyl(aryl)-4-oximino-5-alkoxy-5-phenylimidazolidin-2-ones (VP). A. To a solution
of i0 mmole of compound II in 30 ml of methanol (or ethanol) was added dropwise a solution
of 20 mmole of nitrosyl chloride in 15-20 ml of methanol (or ethanol) at a temperature of
--10 to --15~ The reaction mass was maintained for 1-2 h (chromatographic monitoring by
TLC), the solvent was then evaporated under vacuum, and the residue was recrystallized to
give compounds V.
B. A solution of i0 mmole of compound Vlla in methanol was boiled for 30 min, the sol-
vent was evaporated, and the residue was recrystallized from benzene to give compound Va.
l-Aryl-4-nitroso-5-phenylimidazolin-27ones (VII). To a solution of i0 mmo!e of com-
pound llb in 30 ml of diethyl ether was added a solution of 20 mmole of nitrosyl chloride
in 30 ml of ether at --i0 to --15~ The reaction mass was maintained for 30 min, the solvent
was evaporated under vacuum, and the residue was recrystallized from diethyl ether. Yield,
77%; mp, 125-127~ Found, %: C 67.7; H 4.0; N 15.9. C ~ b H ~ N ~ 0 2 . Calculated, %: C 67.9;
H 4.2; N 15.8. Compound VlIb was obtained in a similar manner from compound lid. Yield,
70%; mp, 131=C. Found, %: C 60.8; H 3.2; CI 12.1; N 14.3. C~bH~oCIN30~~ Calculated, %:
C 60.1; H 3.4; C1 11.8; N 14.0.
l-Aryl-5-phenyl-5-hydr0xyhydantoin (VII!), To a suspension of 2 mmole of compound llb
in 30 ml of dry ether was added dropwise a solution of 5 mmole of nitrosyl chloride in I0
ml of dry ether. The mixture was kept at a temperature of --i0 to --15~ for 2 h, and it was
then increased to 20~ and the reaction mass was left overnight. The solvent was evaporated
and the residual reaction product, having first been washed with dry hexane, was recrystal-
lized from benzene. Yield, 60%; mp, 180~ IR spectrum (CCI~): 3590 (OH); (KBr): 1700,
1780 (~---O), 3450 cm -: (NH). Found, %: C 67.2; H 4.6; N i0.0. C~bH:=N=O~. Calculated, %:
C 67.2; H 4.5; N 10.4.

1086
 LITERATURE CITED
Io L. I. Beckham, W. A. Fessler, and M. A. Kise, Chem. Rev., 48, 319 (1951).
2. P. P. Kaudzyauskas and N. S. Zefirov, Usp. Khim., 37, 1243 (1968).
3. Yu. B. Putsykin and L. B. Volodarskii, Izv. SO Akad. Nauk SSSR, Ser. Khim. Nauk, No. 4,
I01 (1968).
4. I. Beger, R. Holm, and W~ Pritzkow, Tetrahedron Left., No. 6, 2617 (1965).
5. I. Krenzer and R. Luchenbaugh, British Patent No. 751557; Chem. Abs., 51, 4441 (1957).
6. Yu. A. Baskakov, L. D. Tomina, M. I. Fadeeva, V. V. Golovko, and N. I. Kiseleva, USSR
Inventor's Certificate No. 420,619; published in Byull. Izobret., No. ii, 86 (1974).

F~SS-SPECTROMETRIC STUDY OF THE CYCLIZATION OF DIAZO COMPOUNDS.

9.* 2-DIAZO-2-CYANOACETAMIDES

A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, UDC 543.51:547.791.4

V. A. Bakulev, Yu. M. Shafran, and V. S. Petrosyan

An analysis of the electron impact mass-spectra of 2-diazo-2-cyanoacetamides and

the 4-cyano-5-hydroxy-l,2,3-triazoles isomeric to them, showed that the molecu-
lar ions of these compounds do not isomerize one into another. The diazo com-
pounds decompose, undergoing aWolff rearrangement. To study the fragmentation
of the diazoamides, one can use the crystalline adducts of these diazo compounds
with triphenylphosphine, and to study the fragmentation of the triazoles, their
salts with aliphatic amines.

I t was shown previously [2] that diazoketones with a heteroatomic grouping in the car-
bon chain eliminate a molecule of nitrogen and cyclize to form heterocyclic compounds. This
takes place in solution by the action of an acid as well as in the gas phase by the action
of electron impact. Such an analogy allowed a prediction to be made on the basis of mass-
spectral data of the direction and approximate yield of the cyclic product when the reaction
was carried out in solution [i, 2].
The question of th linear or cyclic form of diazo compounds containing C-~, C----S,or
C----NH groups in position a to the diazo group has already been investigated in papers by Wolff
[3, 4] and Dimroth [5]. At the present time, it is reliably known that diazoketones and
diazoesters exist exclusively in the linear form [6]: the alternative, 1,2,3-oxadiazole
form is unstable and is easily opened as a result of an electrocyc!ic reaction to the more
stable linear form [7]. Diazothioketones exist exclusively in the form of thiadiazoles and
attempts to obtain these compounds in the linear form have not, so far, led to success [6].
Diazoamides occupy an intermediate position and can exist in the linear form as well as in
the cyclic, triazole form, which can, under certain conditions, change back and forth [6, 8,
9]. These structural features of diazo compounds are determined unambiguously by the in-
crease in the eiectronegativity of the heteroatoms in the order S < N 9 O.
Comparing the stability of the molecular ions (M+) of the linear diazo compounds and
their isomeric heterocyclic systems, one can suppose that M + of the cyclic isomers should be
rather stable (aromatic system) and decompose along a specific path characteristic for such
ring. At the same time, M ~ of the linear, diazo compounds are significantly less stable, as
a rule, and in the spectra of many of them, the M+ pea k is not observed at all [i, 2, 9].

*See [!] for No. 8 in the series.

M. V. Lomonosov Moscow State University, Moscow 117234. The Scientific Research Insti-
tute of Organic Intermediates and Dyes, Moscow 103787. S. M. Kirov Urals Polytechnic Insti-
tute, Sverdlovsk 620002. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. i0,
pp. 1343,1349, October, 1986. Original article submitted March 25, 1985.

0009-3122/86/2210-1087512.50 9 1987 Plenum Publishing Corporation 1087

 T A B L E i. Intensities of the Peaks Characterizing the lonic
Fragments in the Mass-Spectra of Compounds 1-IV

Com- m / z , intensity (in %) of the ionic peaks

pound
II0 82 67 ,56 [ 64 58 54
I
53 52 t 44 39 38

I
I1
10,5
27,3
53,21,1
III [27,5 14,3
1;5
7,7
2,3
5,9
1,9 I<O,l
0,4 [ IA
2,0 <0,1
4~
5,8
0,9
4,1
1,,
2,1
9,110,9
17,8
615 I 0.8
2,1
14,5
1,3
11,4
4.5
115
5,7
8,9
3.2
7,3
IV ] 54,0 0,9 12 2,3 0,3 t 0 5 4"~ 0,8 1,6 19,0 ] 2,2 1,4 1,4 3,2
V J 50,1 0,9 1,5 1,9 0,3 0[5 6,6 0,7 1,7 19,3 I 2,1 1,3 1,4 3,5

TABLE 2. Elemental Composition of Some Ionic

Fragments of Compounds I-V from High-Resolution
Mass-S)ectrometry

Ion Compo- Found (compound) Caleu-

mass sirion la ted

44 CONH~ 44,0143 (I), 44,0145 (IV) 44,0136

54 C2NO 53,9989 (I), 53,9984 (II) 53.9979
C2H2N~ 54,0202 (I), 54,0197 (II) 54.0186
55 C~HNO 55,0042 (1), 55.0051 (II) 55,0057
58 CX2H20 58,0167 (If) 58,0162
64 C3N2 64.0090 (If), 64,0086 (V) 64,0092
67 C:~HNO 67,0069 (1), 67,0059 (II) 67,0057
C2HN~ 67,0181 (I), 67,0169 (II), 67,0171
67,0178 (Ill)

In the case of the diazoamides and their isomeric triazolates, this position has experimen-
tal support [9].
In studying the decomposition of diazoesters, the authors of [I0] came to the conclusion
that the high stability of the M + ions of these compounds, which was noted earlier in [ii],
was apparently to be explained by the isomerization of M + to heterocyclic systems and espec-
ially to oxadiazoles. In their opinion, the excess energy of M + (a range of 0-20 eV [12])
allows the linear form to isomerize to the cyclic, although this does not occur in solution
at the low energies common to thermal excitation [3-7]. Possibly, this process is also ex-
plained by the low electron density on the diazo group in the M +, inasmuch as the charge in
the M + of diazo compounds is localized on the diazo group itself [13]o Thus, the formation
of the cyclic form of diazoesters as a result of electron impact is quite realistic; i.e.,
even so electronegative an element as oxygen can form a bond to a diazo group. Consequently,
it was proper to expect that the cyclization of the M + of diazoamides to triazoles would
take place more readily when the alkoxy group was replaced by an amino group, inasmuch as a
nitrogen atom is less electronegative and bonds to a diazo group more readily than an oxygen
atom, [6].
In studying the possible isomerization of diazoamide M + to triazoles, we analyzed the
mass-spectra of compounds I-X. It must be noted that in solution, diazoamides I and VI are
converted by the action of bases into triazolates IV, V, IX, and X, which, on acidification
of the solution, change into triazoles II and VII [14].
CN .CN
N-~C - C - CON[-IR~ N ----C NC'-" ~--'CONHR 1 N---C/
H ~1 c I + II N~C
N.
I1
N2 N" Oli N=N--PPh~ O...iI,-.NHzR e

I, vI IlL Vlll
II. %II IV. V, IX. X

I--V RI=H; VI--X R~=CH3; IV, IX R~=H; V, X R2=CH~

As can be seen from Table I, the differences in the relative intensities of the peaks
of the ionic fragments in the spectra of diazoamide I and its crystalline adduct with tri-
phenylphosphine, III, are insignificant. This allows one to use adduct III, which is easily
isolated from the reaction medium, to study the behavior of the less readily accessible
diazoamide I under the action of electron impact. There is also almost complete agreement

1088
 TABLE 3. Intensities of the Peaks Characterizing the Ionic
Fragments in the Mass-Spectra of Compounds VI-X

Com[I m / z , intensity (in %) of the ionic ~eaks

p~ 1 ~24 96 95 81 69 68 67 66 58 54 53 39 38

VI 18,5 12,4 4.5 1,7 6,1 1,6 13,1 6,0 9,8 2,9 4,4
VII 25,4 0,9 17 3,2
3,5 019 3,4 15,9 0,7 4,3 3,5 21,2 2,0 3,0
VIII "18.3 I1,1 5.2 5.0 1.5 4,7 2,0 10,0 5,3 8,6 5,4 5,4
IX 2217 0 , 6 Id 3,5 018 3i4 15,8 0,7 4,2 3.7 21,4 2,0 3,1
X 24,8 2,0 1,0 3,6 1,2 31o 15,0 0,7 5,1 4,0 21,0 2,0 3,2

TABLE 4. Elemental Composition of lons of Compounds VI-X

from High-Resolution Mass-Spectrometry

Ion Composition Found (compound) Calculated

mass

53 C2N2H 53,0152 (VI), 53,0146 (IX) 53,0140

67* C3HNO 67,0060 (VI), 67,0054 (IX) 67,0058
C2HN~ 67,0174 (Vl), 67,0182 (IX) 67,0171
C3H3N2 67,0301 (VI), 67,0308 (VII), 67,0302 {IX) 67,0296
68** C~H2NO 68,0124 (VII, 68,013t (IX}, 68,0129 IX) 68,0136
C3H4N2 C8,0365 (VI), 68,0380 (IX), 68,037l (X} 68,0376
69 C3H3NO 69,0204 (Vl), 69,0207 (VII) 68,02t4
81 CsN~HO 81,0085 (VI), 81,0084 (IX) 81,0089

*The ratio of the intensities of the peak of ions C3HNO:C2HN~:

C3H3N= in the spectrum of diazoamide VI is 3:5:2, and 2:5:100
in the spectrum of triazole IX.
**The ratio of the intensities of the peaks of ions C~H2NO:
C~H~Na in the spectrum of diazoamide VI is 1:4, and 1:3 in the
spectra of triazoles IX and X.

between the spectra of triazole II and triazolates IV and V; i.e., M + of the latter lose a
molecule of amine and form a pseudomolecular triazole ion. It must be noted that it is the
triazole ion itself that is formed, not the supercharged triazolate anion, as observed in
[9]. This is explained by the lower acidity of the triazoles studied and the consequent low-
er ionicity of the bond between the heterocycle and the amine. Such a conclusion regarding
the structure of triazolates IV and V is in complete agreement with the data from NMR spectre
scopy [14]. Thus, it is possible to use triazolates IV and V to study the decomposition of
triazoie II.
Along with this, it can be seen from Table i that the mass-spectra of diazoamide I and
its isomeric triazole II differ substantially, supplying grounds for the conclusion that the
5~ of these compounds differ structurally. Analysis of the mass-spectra and of the data in
[15, 16], allowed us to describe the decomposition of cyclic triazoles by the scheme given
below. The fragmentation of the diazoamide M + starts with the elimination of a molecule of
nitrogen accompanied by a Wolff rearrangement [17, 18], although in this case it is an amino
group, not an alkyl radical that migrates. Another characteristic path is the rupture of
the C(N=)--CO bond (see Scheme i) with the formation of ions 44 and 66.
As can be seen from Table i, the maximum ion in the spectra of compounds I-V is M + with
a mass of ii0, while its intensity in the case of the linear diazoamide is about one-half,
which was also to be expected. Moreover, the [M -- N2] + ion (82) is also observed for both
isomers, the intensity being i0 times greater in the case of the linear form, in complete
accord with the data on the decomposition of diazo compounds [i, 2, 17, 18]. The formation
of ion [M -- N2, --HI+ (81) is possible only from the cyclic form, the triazole [15, 16], while
this process is not characteristic of the linear ion (82) forming through the decomposition
of the diazoamide. The total lack of the peak for this ion with compounds I and III is evi-
dence that the isomerization of the linear ii0 ion to a cyclic form does not take place.
This is also shown by the absence of peaks of ions 58 and 64 in the spectra of diazoamides
i and III (see Table I). The first of them is formed by splitting out cyanogen from the B
tautomeri~ form of the triazole [15], and the second, by splitting out a water molecule from

1089
 Scheme i

NC~ C-~COII-~ T ..,~ -co ]!

HN=CH-CN ....... fIN """ E~
67(1%) -H.?0
54(66% I; 50Y~ II) ~
"OH

I -NIl y I
~
~
/
82
,,
,%
HH2 q t
~COt l +
NC-CP-NH ICN i i' NC-C-mCOH"i
NC--C:C=0 / N . r 67(10%)
82

\ Nc--CN " -Ar 81 /" ~.,s/

I~ '~+ 52 NC-C~O ~ ,~'.
/~./
54(50,~ [I; 33% [) //
/ /
/!
I J' /
/
H N = C = C = O ~ -+ /
~+
i CN " N C x c - - c "0H i'"
N c _ C _ C O N H 2 I" i N--C~
->+.-- i H N tl t M
N... N / N I
llI N2 !V,V
1 a . J
M + (l) I 1 0 ~ ~.~ (H) 11o B

/ \-. -. .P
//
,i" / //
/"
1 \
\
~
- ~. NC_CN~
5o
\ %N; /
/;
Ctt NoO-]t
N ~t 58
NCCHN 21 " +
CONH 2 II c.-cH
67 (99~) 44

cyclic ion 82. The existence of part of ~ of triazole II in the form of tautomeric form B
is supported by the formation of ions 52 and 67, besides ion 58. The peaks of the two form-
er are quite intense. Besides the [M -- N=] + ion, the formation of ions with masses 67, 66,
44, and 38 are characteristic of the linear structure (see Scheme i and Table i) o
The elemental composition of several ions was confirmed by means of high-resolution
mass-spectrometry (Table 2).
Ions 54 and 67 are compound. The ratio of intensities of the peaks of ions C=NO/C=H=N=
in the mass spectra of compounds II, IV, and V is i:i, whereas for compounds I and III it is

TABLE 5. Mass-Spectra of Compounds I-XI

Corn- Values of m / z (relative intensities of the peaks of the ions in
pound percent of the maximum)*

I II0 (I00); 82 (38,4); 67 (28,6); 55 (21,9), 54 (I0,7); 53 (34,2); 44 (54,8);

43 (12,8); 39 (17,51; 38 (34,2)
II Ill (5,1); II0 (I00); 67 (3,9); 64 (4,5); 58 (9.0); 54 (3,9); 53 (34,5); 52
(4,2); 39 (4.8); 38 (6,3)
Ill II0 (100); 82 (46,1); 67 (18.5); 55 (15,4); 54 (7,7); 53 (24,6); 44 (,13,0);
43 (13.8); 39 (21,5); 38 (27,7)
IV Ill (5,1); If0 (I00); 81 (3,2); 67 (4,4); 58 (9,2); 54 (3,4); 53 (36,9); 52
(4,3); 43 (4.0); 38 (6,2)
V I l l (53); ll0 (I00); 81 (3.1); 67 (3,8); 58 (14.1); 54 (3,9); 53 (39.9); 52
{4.2); 43 (4,4): 38 (7.3)
VI 124 (I00); 96 (69.2); 81 (17,6); 69 (25,3); 67 (34,4); 58 (72,4); 54 (34,4);
53 (55,2); 39 (16,3); 38 (24,9)
VII 124 ([00); 81 (13,8); 68 {13,4); 67 (62,6); 58 (16,9); 54 (13,8); 53 (83,5);
41 (12.7); 39 (7.9): 38 (11,8)
VIII 124 (I00), 96 (61,6); 81 (28,0); 69 (27,7); 67 (26,1); 58 (55,6); 54 (29,4);
53 (47,8); 39 (30,0); 38 (30,0)
IX 124 (I00); 81 (15,6); 68 {16.0); 67 (70,4); 58 (18,4); 54 (17,4); 53 (97,2);
41 (12.~); 39 (9,2); 38 (14,0)
X 124 (100); 96 (9,6); 81 (14,7); 68 {12,5); 67 (59,7); 58 (20,7); 53 (83,3);
41 (12,7); 39 (8,2); 38 (13,1)
XI 138 (100); 95 {50,0); 81 {41,7); 72 (70,8); 69 (87,5); 67 (79,2); 44 (37,5);
42 (66,7); 39 (16,5): 38 (20,4)

*The ten strongest peaks in the spectrum are given.

1090
 Scheme 2

Nit
.CN
-CO + /~
N C C =_C 0 ~ H ~r 11
NC--C--C------0 + -CO - N+ H ~ _ = C _ C N = N j
0"7(23%) 81 53
OH
81
,. ~ . + " ]7
I " CII 3 CH~N'ZC - CN
I -
"~ \ 9ay.',~U
CH~ ~ CIt3--N

Nc--C----C----0 " -C0

+.
/
./
.," 96

'\,\ -HCN
C ~ N = c.-cN3<

\ 7 0 g VII/ ./
/
..-

/
/" +
CH2---N/~]~.H

NC -- C -- CONHCII 3 C I I 3 N = C = C = g ?T ~" 01t

/ . , //"
~ 95
96 69 /

+
CII2=N=C=C=O /'

\30% VII/
\ CN
9+ N----C "
.u .... ~ N(:--C- CCN'ICH 3 ~ - ~ -- Ii ]I ~ 9 - M+
il N .c
VIII N2 N OH L~, X
I
M ~ (VI) 1 ~ 4 CII 3
\, / _ ~ ( v n ) Iz+
HOC.=_CCN~ ".
,~*i-" '\
\
~" /
/
" "'\-,~ eT(2r.)
/ ,\ CH~NC0-t //
~" N ~'+

67(50~.) C2N3-- T
o6 e7(5~)

1:2. This agrees with the easy decomposition of the ketones forming as a result of the Wolff
rearrangement with the elimination of a molecule of CO [17, 18]. The ratio of the intensities
of the peaks of ions CsHN0/C2HN3 (67) on the decomposition of the cyclic structures is i:i0,
but l:100 for the linear ones. This fact is explained by the impossibility of splitting out
an HN3 molecule in a single step in the case of the diazoamide and the disadvantage in split-
ting out an h~ particle from an [M -- N2] + ion. Both paths are possible for the triazole, al-
though as the low intensities of these fragments show, neither are very effective in this
case as well.
Substitution of a methyl on the nitrogen atom introduces a substantial change in the
mechanism of the decomposition of the compounds being studied that allows one to suggest a
specific scheme for the decomposition of compounds VI-X based on data from the ordinary spec-
tra and high-resolution spectra (Tables 3 and 4).
The spectra of compounds VI and VIII, as of VII, IX, and X, are consistent among them-
selves; i.e., the conclusion drawn from the analysis of the spectra of compounds I-V concern-
ing the possibility of studying the behavior of diazoamides under the action of electron im-
pact from the spectra of their triphenylphosphine adducts and of studying the behavior of
the triazoles from the spectra of the triazolates is completely confirmed. At the same time,
the differences in the relative intensities of the fragment ions formed during the decomposi-
tion of the linear (VI, VIII) and cyclic (VII, IX, X) compounds are sufficiently great so
that one can conclude that in this case the isomerization of M + of diazoamide VI to the M + of
triazole VII does not take place; i.e., the structure of the M + of these compounds is differ-
ent 9
A methyl substituent on the nitrogen atom precludes the tautomeric conversion to the
triazole and leads not only to a decrease in the stability of M + but also the impossibility
of decomposition by elimination of a cyanogen molecule (ion 72, analogous to ion 58 for com-
pounds II, IV, and V, is completely absent for compounds VII, IX, and X). It also decreases
the fraction of [M-- CHsNC0] + ion in the total current of isobaric lone of mass 67 (see Table
4) from 90 to 5%. The [M -- N=, --H]+ ion (95) peak, which is characteristic of the decomposi-

1091
tion of triazoles, is completely absent for diazoamides VI and VIII, showing that these com-
pounds do not isomerize to the M + of the triazoles. The decomposition of the linear diazo
compounds without cyclization is confirmed by the high intensities of the [M -- N2] + ions (96)
and ions 69 and 58. Ions 67 and 53, the peaks of which are very intense (see Table 3), are
most characteristic of the decomposition of the cyclic structure of triazole VII. The con-
clusion drawn concerning the different structures of M+ in the case of triazole VII and diazo-
amide VI is also confirmed by the high-resolution spectra (see Table 4). The increase in
the fraction of the C3H~N2 ion current with respect to that of the isobaric C3H2NO ion in
the decomposition of diazoamide VII is explained by the elimination of CO, which is charac-
teristic of ketones and was noted in the discussion of the decomposition of compounds I-V.
Splitting out a molecule of CH~NCO from the linear ion is considerably more advantageous
than from the cyclic M + w h e r e the tautomeric conversion is impossible. On the other hand,
elimination of an HCO radical from the cyclic [M -- N=] + ion occurs readily. This explains
the differences in the relative intensities of the isobaric ions with mass 67 (see Table 4).
To verify the mechanism of decomposition of diazoamides, we synthesized the dimethyl
substututed compound, which is unable to cyclize in solution.
ICH
Nc--C --CO-N
I ~C~
I +
N=N--PPh~

The adduct of this compound with triphenylphosphine, XI, was studied mass-spectroscopic-
ally. All of the peaks observed in its spectrum (Table 5) are produced by ions forming as
a result of the Wolff rearrangement or of the rupture of single bonds in the linear [M --
PPh3] + ion (138).
Thus, analysis of the mass-spectra of compounds I-XI has shown that the isomerization
of ~ of diazoamides to M+ of triazoles is not observed. Differences in the behavior of the
investigated diazoamides under electron impact and in solution [14] are apparently explained
by the fact that the first step in the isomerization in solution is the splitting out of a
proton to form an anion capable of isomerizing while in the gas phase a cation-radical under-
goes transformation. The possibility of finding an isomerization product in the gas phase
with the help of mass-spectrometry of negative ions is not precluded. The elucidation of
this matter is the goal of future investigations.

EXPERIMENTAL
Compounds I-XI were all obtained by the procedure in [14]. The mass-spectra were taken
on anMAT-311 Ainstrumentwith use of a system for the direct introduction of a sample into
the ion source at a temperature of 20~ It should be noted that when the samples were heat-
ed, the intensity of the M+ peak decreased sharply with a simultaneous increase in the inten-
sities of fragments with masses of 44 and 53 (l-V), 53 and 58 (VI-X), and 68 and 72 (XI).
At temperatures of II0-130~ the mass-spectra of the cyclic and linear compounds become
identical because the same products are formed as a result of thermal decomposition and fur-
ther ionization of these leads to analogous mass-spectra. It is exactly to avoid thermal
decomposition that the spectra of compounds I-XI are obtained without heating the inlet.
Electron energy, 75 eV.

LITERATURE CITED
i. A. T. Lebedev, P. A. Sharbatyan, A. G. Kazaryan, T. P. Pokidova, V. Go Kartsev, and
V. S. Petrosyan, Khim. Geterotsikl. Soedin., No. i, 17 (1986).
2. A. To Lebedev, Dissertation for Kand. Khim. Nauk., Moscow (1982).
3. L. Wolff, Annalen, 333, i (1904).
4. L. Wolff and R. Krucke, Annalen, 364, 48 (1912).
5. O. Dimroth, Annalen, 363, 336 (1910).
6~ R. Kh'yuzgen, Khim. Geterosikl. Soedin. No. 5, 579 (1981).
7. G. D. Buckely and W. S. Levy, J. Chem. Soc., No. ii, 3016 (1951).
8. J. H. Looker and J. N. Carpenter, Can. J. Chem., 45, 1727 (1967).
9. P. Murray-Rust, J. McManus, S. P. Lennon, A. E. A. Porter, and Ya. A. Rechka, J. Chem.
Soc., Perkin i, No. 4, 713 (1984).
i0. D. S. Wulfman, S. Roberts, D. K. Henderson, J. C. Romine, R. McDanie, and D. W. Beistel,
Can. J. Chem., 62, 554 (1984).

1092
ii. K. P. Zeller, H. Meier, and E. Muller, Annalen, 749, 178 (1971).
12. F. W. McLafferty, Interpretation of Mass Spectra, Univ. Sci. Books, Mill Valley, Cali-
fornia, 1980, p. 303.
13. J. Innorta, S. Torroni, A. Foffani, and S. Sorriso, Ann. (Rome), 66, i (1976).
14. M. Yu. Shafran, V. A. Bakulev, V. S. Mokrushin, S. A. Alekseev, A. T. Lebedev, and
P. A. Sharbatyan, Khim. Geterotsikl. Soedin., No. 7, 926 (1986).
15. A. Maquiestiau, J. VanHaverbeke, R. Flammang, and J. Elgiero, Org. Mass Spectrom.,
~, 571 (1973).
16. S. Adamopoulos and N. E. Alexandrou, J. Heterocycl. Chem., 21, 145 (1984).
17. C . W . Thomas and L. L. Leverson, 0rg. Mass Spectrom., 13, 39 (1978).
18. K.-P. Zeller, H~ Meier, and E. ~uller, Tetrahedron, 28, 5831 (1972).

SYNTHESIS AND CONVERSIONS OF 2-ARYL DERIVATIVES

OF s-TRIAZOLO[4,3-a]PYRIMIDINE

I. Krezhel' UDC 547.853'792'556.8.07:

543.422.25

The reaction of arylhydrazines and l-ethoxycarbonyl-2-methylthio-l,4,5,6-tetra-

hydropyrimidines forms 2-ary!-3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyri-
midines. The reaction of 2-phenyl substituted triazolo[4,3-a]pyrimidine with
various acylating agents to give 8-acyl derivatives and the effect thereon of
hydrogen chloride were studied. The amine-imine tautomerism of these compounds
was studied by PMR spectroscopy.

Among guanidine derivatives there are substances that have a wide spectrum of pharmaco-
logical activities [!, 2]. We have previously synthesized derivatives containing guanidine
residues [3] and isothioureide residues bioisosteric with guanidines [4, 5]. In a further
search for new biologically active compounds, the present work undertakes to synthesize com-
pounds containing a guanidine grouping in a cyclic system.
The starting material was l-ethoxycarbonyl-2-methylthio-l,4,5,6-tetrahydropyrimidine (I)
[6]. The reaction of compound I with phenyl- or 4-sulfonamidophenylhydrazines (II, III)
forms materials of cyclic structure; on the basis of elemental analysis and IR and PMR spec-
tra these were assigned the structures of 2-aryl-3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-
a]pyrimidines (IV, V).

SCH. N__N/Ar
' ~ 11 2
-\ CO~C2H 5
+ - --,.,,,-
. . }iN,~ ,7 5'

II. Ill
IV, V

II, IV Ar--C6Hs; III, V Ar=p-C6H4SO2NH2

W~en compared with the spectrum of I, the IR spectra of crystalline IV and V are char-
acterized by the disappearance of the valence vibration band of the ether bond (1730 and I13C
cm-~), and the appearance of valence and deformation vibration bands of the NH group in the
3300-3100, 1510, and 1535 cm-~ regions and of the amide C-~ valence vibration bands in the
1690-1720 cm -~ region. The PMR spectra of IV and V also show the disappearance of the SCHs
and OCH=CHs proton signals and the appearance of aryl proton and NH proton signals. In con-
nection with the presence of the amide group, these compounds can exist in the tautomeric
forms A and B.

Department of Pharmaceutics, Lodz Academy of Medicine, Poland, Lodz 90-145. Translated

from Khimiya Geterotsiklicheskikh Soedinenii, No. i0, pp. 1350-1353, October, 1986. Original
article submitted June 20, 1985; revision submitted November 25, 1985.

0009-3122/86/2210-1093512.50 9 1987 Plenum Publishing Corporation 1093

 liNeN ~Ar N__N/At

N~ ' N / ~ O ~ HN N 0

A B
The conclusion concerning the form in which IV and V exist enables us to analyze the
P~iR spectra obtained in CDCI3 (IV) and DMSO-D6 (V). The high field portion of the spectra
shows two signals: a multiplet in the 3.02"3.40 ppm region, and a triplet in the 3.45-3.80
ppm region. On the basis of binary homonuclear resonance and deuterium exchange these were
assigned to the protons at C(7) and C(s), respectively. Upon suppression of the broadened
signal in the 5.99-6.16 ppm region (in the case of IV) ( N ~ N ) the multiplet signal at 3.02-
3.40 ppm is converted to a triplet; this shows the spin-spin coupling of the C(7)H(2)--N(s)H
protons. When D20 is added to the sample, the NH--O=N proton signal disappears, while the
C(7)H(2) multiplet is also converted to a triplet. From these data, allowing for the inte-
grated signal intensities, it can be presumed that these compounds exist (at least predomin-
antly) as one tautomeric form, viz., form B.
In connection with the presence in compounds IV and V of a tautomeric amidine segment,
two series of isomeric derivatives, C and D, can form in the reaction with acylating reagents
(acid chlorides, acid anhydrides, chlorocarbonic esters). The ability of the synthesized com-
pounds to undergo acylation is exemplified by compound IV. Investigation showed that acyla-
tion yields only the compound with structure C.

R "N--- -N ~ C s H s

It," + R-c"O-X ...... //

~" 'J D + HX

v~a-f ~ N _ _ _ N , . Ce}|5

"~J C
vll a - f
V[, VII a R=C6H~.b R=C6HsCH=CH, c R=4-C1C~H~, d R=g-CHaC6Hs, e R=CH~,
f R=C2Hs, V l a - d X=Cl, e X=CH~COO, f X=OC1

The structures of these compounds were established by IR and PMR spectroscopy. In the
IR spectra of acylation products Vlla-f, as compared with the spectra of starting material I,
the typical bands of N-H-bond valence and deformational vibrations disappear. In the spectra
of Vlla-f a new band appears in the 1660-1690 cm-I region that corresponds to the valence vi-
brations of amide C-~. The PMR spectra of the acyl derivatives lack the NH signals, but con-
tain the proton signals of the aryl and alkyl substituents. The question as to whether acyla
Lion took place at N(~) or N(a) of compound IV was decided by PMR spectroscopy using model
compounds (starting materials I and IV) in the consideration of the chemical shifts of the
protons bonded at C(7) and C(5). In the spectrum of compound I, with a fixed C----Nbond in the
pyrimidine ring the methylene protons at C(~) and C(7) form a single multiplet in the 3.32-
3.80 ppm region. In the spectrum of IV with the deshielded C.=N bond in the triazole ring,
the methylene protons at C(7) and C(5~ form two different multiplets (see above); in this
case the protons at C(7 ) are located in the stronger field in the 3.02-3.40 ppm region. In the
spectra of all the acyl derivatives the methylene protons at C(5) and C(7) form one multi-
plet in the 3.55-4.17 ppm region. Such a shift of methylene proton signals at C(7) in the
acyl compounds toward the weak field as compared with compounds I and IV indicates the de-
shielding effect of the acyl residue, which is located at N(8) and not at N(t).
Compound IV reacts with HCI to form the hydrochloride. In the IR spectrum of the hydro-
chloride (in KBr) the O-0 band of the N--C(>-NPh ureide grouping is shifted toward the high
frequency region up to 1760 cm-~, as compared with the C-~ frequency (1720 cm-~) of unpro-
uonated IV; this is evidence for weakened conjugation in the N-CO--NPh system.
In the PMR spectrum of the hydrochloride the signal of the methylene protons at C(7)
appears as a triplet, and not as a multiplet as in IV; this is evidence for the absence of
a proton at N(8). In the weak field in the 8.45-8.90 ppm region there is a broadened signal
of two protons that disappears when D20 is added to the sample. The equivalence of the h~

1094
protons appears in the P ~ spectrum of the hydrochloride, while the IR spectra are evidence
for the formation of a cationic system that includes all the nitrogen atoms in the molecule.

EXPERIMENTAL
Melting points were determined in a Boetius microblock. PMR spectra were obtained in
Varian EM-360 and Tesla 487 (80 ~ z ) instruments, in CDCI3 with TMS as internal standard.
IR spectra were recorded on a Unicam SP-200G spectrometer in KBr tablets. The course of the
reaction and the individuality of the compounds obtained were monitored by TLC on Silufol UV-
254 plates in 7:3 chloroform-acetone, with development by iodine vapor.
Starting compounds l-ethoxycarbonyl-2-methylthio-l,4,5,6-tetrahydropyrimidine (I) and
4-sulfonamidophenylhydrazine (III) were synthesized according to [6] and [7], respectively.
2-Phenyl-3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyrimidine (IV). A mixture of
1.01 g (5 mmole) of compound I and 0.54 g (5 mmole) of phenylhydrazine in 5 ml of absolute
ethyl alcohol was boiled for 7 h. The reaction mixture was evaporated to dryness in vacuum
and the residue was triturated with ether (i0 ml). The precipitate was filtered off and
crystallized from an ethyl a l c o h o l ~ t h e r mixture. Yield, 0.76 g (70%); mp, 176-178 ~ IR
spectrum: 3300, 3260, 1535 (N-H), 1720 (N-CO--N), 1640 cm-~ (C=N). PMR spectrum: 1.85-2.42
(m, 2H, 6-CH2); 3.02-3.40 (m, 2H, 7-CH2); 3.43-3.8 (t, 2H, 5-CHz); 5.99-6.16 (br. s, IH, N-H);
6.93-8.0 ppm (m, 5H, Ar). Found, %: C 61.0; H 5.5; N 25.8. C~IH:2N~O. Calculated, %:
C 61.1; H 5.6; N 25.9.
2-14-Sulfonamidophenyl)-3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyrimidine (V).
A mixture of 0.5 g (2.5 mmole) of compound I and 0.47 g (2.5 mmole) of compound Ill in IU ml
of dry pyridine was boiled for i h. The pyridine was distilled off in vacuum and the resi-
due was washed with ether (i0 ml) and ethanol (2 I0 ml). After recrystallization from
ethyl alcohol the yield was 0.32 g (74%); mp, 322-324 ~ IR spectrum: 3300, 3200 (NH2, NH),
1690 (N-CO), 1640 (C=N), 1340,i160 cm -~ (SOt). PMR spectrum (DMSO-D6): 1.7-2.2 (m, 2H,
6-CH2); 3.16-3.4 (m, 2H, 7-CH2); 3.42-3.88 (t, 2H, 5-CH2); 6.82-7.1 (br. s, 3H, S02NH2,
C=N); 7.67-8.22 ppm (m, 4H, Ar). Found, %: C 44.6; H 4.3; N 23.6. C::H:3Ns03. Calculated,
%: C 44.7; H 4.4; N 23.7.
2-Pheny!-3-oxo-8-benzoyl-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyrimidine (Vlla). A
mixture of 1.08 g (5 mmole) of IV and 0.7 g (5 mmole) of benzoyl chloride Via was boiled for
1 h in 5 ml of pyridine. After cooling, 20 ml of dry ether was poured into the reaction mix-
ture and the whole was left for 12 h. The precipitate was filtered off, dried, and recrystal
lized from ethyl alcohol. Yield, 1.25 g (78%); mp, 222-224 ~ . IR spectrum: 1715, 1660 (N--
CO-N--Ph, N-CO-C), 1615 cm -: (C--N). PMR spectrum: 1.91,2.38 (m, 2H, 6-CH2); 3.68-4.17 (m,
4H, 5-CH2, 7-CH2); 7.0-7.72 ppm (m, 10H, Ar). Found, %: C 67.3; H 4.9; N 17.3. C18H~N~02.
Calculated, %: C 67.5; H 5.0; N 17.5.
2-Phenyl-3-oxo-8-cinnamoyl-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyrimidine (Vllb) was
synthesized by the procedure described above from IV and cinnamoyl chloride Vlb in 68% yield;
mp, 212-214 ~ . IR spectrum: 1712, 1670 (N-CO-N, N-CO-C), 1625 cm -~ (O N). PMR spectrum:
1.82-2.31 (m, 2H, 6-CH2); 3.6-4.11 (m, 4H, 5-CH2, 7-CH2); 7.01-8.07 ppm (m, 12H, CP~-CH, At).
Found, %: C 69.2; H 5.2; N 16.0. C2oH:sN402. Calculated, %: C 69.3; H 5.2; N 16.2.
2-Phenyl-3-oxo-8-(4-chlorobenzoyl)-2,3,5,6,7,8-hexahydro -s-triazolo[4,3-a]pyrimidine
(Vlic) was synthesized analogously from IV and 4-chlorobenzoyl chloride Vlc in 74% yield;
mp, 171-172 ~ IR spectrum: 1725, 1675 (N-CO--N, N--CO-C), 1615 cm -~ (O=N). PMR spectrum:
1.91-2.41 (m, 2H, 6-CH2); 3.58-4.04 (m, 4H, 5-CH2, 7-CH2); 7.00-7.95 ppm (m, 9H, At). Found,
%: C 60.8; H 4.2, N 15.6. C:sH~sCIN402. Calculated, %: C 60.9; H 4.3; N 15.7.
2-Pheny~-3-~x~-8-(3-methy~benz~y~)-2~3~5~6~7~8-hexahydr~-s-triaz~[4,3-a]pyrimidine
(VIId) was synthesized analogously from IV and 3-methylbenzoyl chloride VId in 82% yield;
mp, 175-176 ~ IR spectrum: 1730, 1675 (N--CO--N, N-CO-C), 1625 cm -* (C--N). PMR spectrum:
1.91-2.40 (m, 5H, 6-CHa); 3.58-4.09 (m, 4H, 5-CH2); 6.98-7.62 ppm (m, 9H, Ar). Found, %:
C 68.4; H 5.3; N 16.9. C~gH~eN~O2. Calculated, %: C 68.2; H 5,4; N 16.7.
.2-Pheny!-3-oxo-8-acetyl-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyrimidine (VIIe). A.
A mixture of 0.54 g (2.5 mmole) of IV and 1 g (i0 mmole) of acetic anhydride in 5 ml of dry
pyridine was boiled for 2 h. The solution was evaporated to dryness in vacuum, and the re-
sidue was triturated with ether. The precipitate was filtered off and crystallized from
ethyl alcohol. Yield, 0.43 g (67%); mp, 175-177 ~ IR spectrum: 1690 (N--CO-N, N-CO-C,

1095
broad band), 1612 cm -: (C=N). PMR spectrum: 1.82-2.32 (m, 2H, 6-CH2); 2.62 (s, 3H, COCH~);
3.62-4.11 (m, 4H, 5-CH2, 7-CH2); 7.00-7.91 ppm (m, 5H, Ar). Found, %: C 60.3; H 5.4; N
21.4%. C:~HI~N~O. Calculated, %: C 60.4: H 5.5: N 21.7%.
B. To a solution of 1.08 g (5 mmole) of IV in 15 ml of dry chloroform containing 3 ml
of pyridine, cooled to 0 =, was added dropwise with stirring 0.39 g (5 mmole) of acetyl chlor-
ide in 5 ml of chloroform. The mixture was stirred at 20 ~ for 2 h, and the solution was
evaporated to dryness in vacuum. The residue was washed with i0 ml of water, dried, and cry-
stallized from ethyl alcohol. Yield, 0.88 g (68%).
2-Pheny!-3-oxo-8-ethoxycarbony!-2,3,5,6,7,8-hexahydrg-s-triazo io [4,3-a ]pyrimidine (Vll f)
was synthesized analogously to Vile by procedure B from IV and C2HsOCOCI (Vlf). Yield, 72%;
mp, 170-172 ~ IR spectrum: 1745 (O=C--O), 1715 (N-CO-N), 1605 cm-~ (C--N). PMR spectrum:
1.21-1.54 (m, 3H, CH3); 1.88-2.35 (m, 2H, 6-CH2); 3.55-4.00 (m, 4H, 5-CH2, 7-CH2); 4.12-
4.58 (q, 2H, --OCH=); 6.95-8.12 ppm (m, 5H, At). Found, %: C 58.1; H 5.5; N 19.3. C:~H:6-
N~03. Calculated, %: C 58.3; H 5.6; N 19.4.
2-Phenyl-3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo [4,3-a ]pyrimidine hydrochloride (VIII).
To a solution of 0.22 g (1.03 mmole) of IV in i0 ml of ethyl alcohol was added 5 ml of ether
saturated with HCI and the mixture was left at 20 = for 18 h. The crystals that separated
were filtered off and washed with ether. Yield, 0.16 g (66%); mp, 190-192 ~ IR spectrum:
1760 (N-CO-N), 1680 (C--N), 3200-3080, 2700-2400 cm -~. PMR spectrum: 1.79-2.20 (m, 5H, 6-
CH=); 3.12-3.41 (m, 2H, 7-CH2); 3.48-3.76 (t, 2H, 5-CH2); 7.00-8.04 (m, 5H, Ar); 8.45-8.9
ppm (hr. s, 2H, NH). Found, %: C 52.1; H 5.1; N 22.0. C:IH:sCIN~O. Calculated, %: C 52.3;
H 5.2; N 22.2.

LITERATL~E CITED
G. J. Durant, A. M. Rose, and A. L. Green, in: Progress in Medicinal Chemistry (G. P.
Ellis and G. B. West, ads.), Butterworth and Co., London (1970), p. 124.
2. W. Kobinger, in: Central Action of Drugs in Blood Pressure Regulation (D. S. Davies
and J. L. Reid, eds.), Pitman Medical, London (1975), p. 162.
3. S. Groszkowski, I~ Bieniarz, and I. Kre~el, Pharmazie, 39, 497 (1984).
4o S. Groshkovski, I. Krezhel', and L, Kozhytska, Khim. Geterotsikl. Soedin., No. 6, 823
(1984).
5o S. Groszkowski, I. Kre~el, and L. Korzycka, Acta Polon. Pharm., 41, 21 (1985).
6. A. K. Bose, J. C. Kapur, and M. S. Manhas, Synthesis, 891 (1974).
7~ Methoden der Organischen Ehemie, Vol. X/2 Georg Thieme Verlag, Stuttgart, p. 169o
p. 169.

1096
SYNTHESIS OF ACID--BASE TRANSFOP~iATIONS OF 3-AROYL-6-METHYL-
2-OXOPYRIDINES

V. A. Lepikhin, V. M. Petrichenko, and M. E. Konshin UDC 547.824.07:542.938:

543.422.6

In hydrolysis of 3-aroyl-6-methyl-2-methoxypyridines, 3-aroyl-6-methyl-2-oxopy-

ridines are formed, which with methyl iodide in an alkaline medium give the cor-
responding 1-methyl derivatives.

Compounds have been found among 3-aroyl-2-oxopyridines with valuable biological proper-
ties [!]. In [2] we have noted the ease of hydrolysis of 3-aroyl-6-methyl-2-methoxypyridi~e
(ia-e) to the corresponding 2-oxo derivative. In the present work, we describe methods of
synthesis of 3-aroyl-6-methyl-2-oxopyridines (lla-e) based on this reaction and their UV
spectra and acid-base transformations are examined.

Ia-e ~ ua-e !~" CH~

~\~ ~/ ma-d

CL~ ~ ~'" " H

vl
iv. v

I--Ill a R=H, b R=p-CH3, e R=p-CI, d R=p-BL e R=p-CH30; IV RI=H; %: RI=CH3

When ketones Ia-e are boiled with 10% hydrochloric acid, 3-aroyl-6-methyl-2-oxopyridines
(IIa-e) are formed in 77-87% yields. Compounds IIa-e are colorless crystalline substances,
in whose IR spectrum absorption bands are present at 3290 (NH) and 1640-1660 cm -~ (CO). In
the PMR spectrum of compound IIa, proton signals are observed at 2.15 (3H of the CH(3) group)
6.08 (H of the pyridine ring at C(s)); 7.32 (H of the pyridine ring at C(,)); a multiplet
with a center at 7.58 (5H of the benzene ring) and 11.88 ppm (NH of pyridone). The PMR spec-
tra of compounds IIb-e also correspond to the structure ascribed to them.
When ketones IIa-d are heated with methyl iodide in an aqueous--alcoholic solution of
potassium hydroxide, 3-aroyl-l,6-dimethyl-2-oxopyridines IIIa-d are formed in good yields.
Their IR spectra contain an absorption band at 1650-1660 cm -I (CO), but in contrast to the
spectra of the initial compounds IIa-d, they do not have an absorption band of the pyrodine
hq~ group at 3290 cm -~.
To clarify the structure of the ketones, we examined their UV spectra and evaluated
them on the example of the spectra of Ia, IIa, and IIIa, In the spectrum of IIa in ethanol,
there are bands with maxima at 254 and 335 nm. An intense absorption is also observed in
the 220 nm region, but the maximum of this band lies beyond the limits of the resolving pow-
er of the apparatus. The UV spectra of compounds IIa and IIIa are similar to one another.
The absorption curve of compound Ia differs substantially from those of IIa and IIIa and has
a maximum at 260 and 292 nm. From the similarity of the spectra of compounds IIa and IIIa,
it can be concluded that compounds IIa-e in alcoholic solution have a pyridone and not a
pyridol structure.
In the spectra of compound IIa at a 0.01 H=SO~ concentration, a 6 nm bathochromic shift
of the maximum at 254 nm is observed, which is probably due to the influence of the medium.

The Perm State Pharmaceutical Institute, Perm 614000. Translated from Khimiya Getero-
tsiklicheskikh Soedinenii, No. i0, pp. 1354-1356, October, 1986. Original article submitted
Harch 26, 1985.

0009-3122/86/2210-I097512.50 9 1987 Plenum Publishing Corporation 1097

 lg~l
!~x % / '\
,,o i- ,.\~ \ -. / ,,.
lr 7

",~ / t \~\ \

I . . . . . I, I L ..... s 1 I
230 260 290 320 350 380 410 k , nm
Fig. i. UV spectra of 2-oxopyridine lla:
i) in ethanol; 2) in 0.01 M HaSO~; 3) in 2
M HaSO~; 4) in 6 M H=SO~; 5) in 0.i N NaOH.

TABLE i. Characteristics of Compounds Synthesized

.~om- ; e.
Found, % I Calculated. % Q

~ound mp, ~ - P K a p . a " z~ ......... Empirical =.

formula
bt Hal I C t-t Hal N

I ]a 228--230 0,78 73,I 5,3

6,6 -- ClaHI,NO= 73,2 5,2 - - 6,6 87
lib 230--232[ 0,83 73,8 6.3 Ci4HtaNO2 73,9 5,8__ I~-,3 6,2 84
IIc 238--239 I 1.27~_0.06 -- 5.6 CI3HzoCINO.~ -- 5,6 82
Ild 242--243 I 1.22 27,4 4,9 C,,,d-l,oBrNO2 5-~ 27,3 4,8 87
lie 233--234 I -- 69,2 5.4 5,7 C~jiiaNOa 677,1 5,7 77
Ilia 110--112 I 1,09 73.8 5.8 6,3 CI4HIaNO.~ 73,9 5,8 6.2 75
IIlb 139--140 / -- 74[5 612 6,0 Cj~HlsNO.. 74,6 5,9 76
IIIc 125--127 / 1.35 13,6 5,3 C.H~.~CINO2 5,3 13-..5 5,4 67
9 llld 123--124 / 26,2 4,4 Ct4HI2BrNO 26,1 4.6 69

When the acidity of the medium is further increased, the intensity of the bands at 260 and
335 nm gradually decreases. Parallel to this, the intensity of the absorption at 306 nm in-
oreases and reaches its highest value at a 6 M concentration of the acid, and a maximum ap-
pears instead of minimum. The spectrum of compound lla is similar to the spectrum of deriva-
tive la [3] in 15% sulfuric acid, where it is present in the form of a singly charged pyri-
dinium ion. This leads us to conclusion that in 6 M sulfuric acid, compound lla exists in
the form of a pyridinium ion of type IV. In the acidity range from 0.i to 6 M, an equili-
brium between forms lla and IV is observed. In this case, the presence of only two ions is
confirmed by an isobestic point at 272 nm. The absorption spectra of compounds Ilia in sul-
furic acid solutions are characterized by a similar pattern, and are only inappreciably
shifted to the long-wave region, and hence under these conditions they exist in the form of
pyridinium ions V.
There is a linear interdependence between the optical densities of the solutions of
compounds lla-d, llla-c, and the acidity of the medium expressed in Ho units, with an angu-
lar coefficient close to unity.
The equilibrium constants of II ~ IV and III ~ V were determined spectrophotometrically.
Since 2-pyridones represent a resonance hybrid of pyridone and zwitterionic structures [4,
5], with a considerable predominance of the latter, the K a values of compounds II and III
should also be considered as ionization constants of the corresponding zwitter ions (K~zw).
The values of pKap.a.ZW* of compounds lla-d vary from-0.78 to --1.27, and for Ilia they are
equal to --1.09 and --1.35 Ho units. They are little dependent on the substituents in the
aryl radical and are one order of magnitude lower than the values of PKap.a. ZW of 2-pyridone
and its N-methyl derivative [4], which is explained by the electron--acceptor influence of
the aroyl group, In the spectrum of compound lla in sodium hydroxide solution (Fig. i), the
maximum of the long-wave band is bathochromically shifted compared with the spectrum of lla
in ethanol. It was thus possible to determine the value of pKap.s. TM, equal to 10.85 0.051
and to find the characteristic lla ~ VI equilibrium.

*The indexes p.a. and p.s. designate the addition and splitting off of a proton.

1098
 EXPERImeNTAL
The IR spectra were recorded on a UR-20 spectrophotometer in chloroform (for compounds
l!a-e) and in carbon tetrachloride (for Ilia-d). The PMR spectra were run on a RYa-2310
spectrometer (60 MHz), using HMDS as internal standard. The UV spectra were recorded on a
SF-16 spectrophotometer for i.i0 -~ mole/liter solutions. The constants of the basic (for
compounds lla-d and Ilia, c) and acidic (for lla) ionization in a sulfuric acid--water or
sodium hydroxide-water system were determined spectrophotometrically on the same apparatus
at 20 I~ The analytical wave-length corresponded to the basic ionization of compounds
(lla-d as 306 nm, compounds llla, c at 315 nm, and for acidic ionization at 365 nm. The
pKap.a. ZW and pKap.s.ZW values were calculated from seven points at a given reliability of
0.98 according to formulas given in [6]. The yields, physical constants, and analytical
data of the compounds obtained are listed in Table i.
3-Aroyl-6-methyl-2-oxopyridines (lla-e). A 0.05 mole portion of 3-aroyl-6-methyl-2-
methoxypyridine (la-e) in 20 ml of 10% hydrochloric acid is boiled for 4 h. The mixture is
cooled, the precipitate is separated and crystallized from ethanol.
3-Aroyl-l,6-dimethyl-2-oxopyridines (Ilia-d). A solution of 0.014 mole of potassium
hydroxide in 8 ml of water and 5 ml of methyl iodide are added to a solution of 0.01 mole
of compound II in 30 ml of ethanol. The mixture is boiled for 2 h, the solvent and excess
of methyl iodide are distilled, and the residue is crystallized from water.

LITERATURE CITED
i. V . A . Lepikhin, A. S. Zaks, M. L. Suslina, and-M. E. Konshin, Manuscript deposited at
V!NITI [All-Union Institute of Scientific and Technical Information], No. 7592 (1984) o
2. V . M . Petrichenko and M. E. Konshin, in: Synthetic Methods Based on Organoelemental
Compounds [in Russian], Perm' (1982), p. 69.
3. V . M . Petrichenko and M. E. Konshin, Zh. Org. Khim., 19, 1332 (1983).
4. A. Albert, Physical Methods in Chemistry of Heterocyclic Compounds [Russian trans!ationZ
Khimiya, Moscow (1966), p. 88.
5. V . I . Zaionts, Zh. Org. Khim., ~, 402 (1978).
6. A. Albert and E. Sergent, Ionization Constants of Acids and Bases [Russian translation],
Khimiya, Moscow (1964), p. 68;

SYNTHESIS AND ACID-BASE TRANSFORMATIONS OF (4-STYRYLPYRIDINIO)-

ALKANESULFONATES

O. S. Eikher-Lorka and G.-K. K. Kupyatis UDC 547.829'822.6:543.422.6

(4-Styrylpyridinio)alkanesulfonates were synthesized by condensation of 2-(4-

methylpyridinio)- and 2-(4-ethylpyridinio)-l-ethanesulfonates with aromatic
aldehydes, and also by quaternization of 4-styrylpyridine by sulfoalkylating
agents. For the p- and o-hydroxystyrylpyridinium compounds in aqueous solutions,
the pKa values were determined spectrophotometrically. It is believed that the
planarity of the o-hydroxypyridinium compounds is disturbed because of the reac-
tion of the hydroxy and the ~-sulfonatomethyl groups.

It is known that pyridylsulfobetaines [i] and also unsaturated quaternary pyridine salts
[2] are used in galvanotechniques. The possibility was examined of using stilbazoles as
antioxidants and antitumorigenic preparations [3], and also as solvent polarity indicators
[4]. We synthesized quaternary pyridiniumsalts containing a sulfo group and a double bond

Insti=ute of Chemistry and Chemical Technology, Academy of Sciences of the Lithuanian

SSR, Vilnyus 232600. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. iO,
pp. 1357-1362, October, 1986. Original article submitted December 26, 1984; revision sub-
mitted January 27, 1986.

0009-3122/86/2210-1099512.50 9 1987 Plenum Publishing Corporation 1099

 TABLE i. Characteristics of Styrylpyridinium Compounds
, ,~

Com- Imp, *C )'max. ] Yield,

nm, Empirical
pound r~, '~ (decomp~ pH-- 6 formula %
:pHall)
II 344--345 346 Ci~HI~NO~S 73 (A)
54 I 5)
III 247--248 346 CI6H~TNO3S 72
X H OH H 310--311 298 Cj4HI3NO4S 5
Xl H OCHa H 316--317 298 CIoHIsNO4S 5
XII C21-ls OHH H 317--318 360 (433) CIoHI;NO4S 42
XIII C~H5 OH 227--228 3413(64833) CI~HI~NO,{S 78
XIV C~t-'Is OH OH 228--229 CI~HI~NOsS o
XV C~Hs N(CIIa)~ H 278--279 428 C,~H.o2N~O3S 34
XVI CH2CH.~OH H 285--287 325 Cj~HIrNO4S 27
xVII CII..CH~OH O~ H 308--309 363 (436) CI6HITNOsS 59
XVIII CH~CI'I~OH OH 265--266 3553(54933) CI6HtrNOsS 82
XIX CIt~CI-I~OFI H~ H 276--277 CITH~gNO~S 58
XX CH~CH2OH CI H 263--264 328 CI~HI~C1NO4S 17
Xyl CH~CH(OH)CH~OH H H 209--210 326 CIrH~..NOsS 28
XXiI C~H~ OH H 246--247 360 (433) CI6HI~NNaO4S 96
XXItI C~H~ t4 OH 203--205 341 (433) CI6HB;NNaO4S 95

aFor compounds XII, XIII, XVII, XVIII, the following pKa values
were found spectrophotometrically: 8.70; 8.60; 8.76; 8.58, re-
spectively.

in side chains. 2-(4-Styrylpyridinio)ethanesulfonate (II) was synthesized by two methods:

condenstation of 2-(4-methylpyridinio)ethanesulfonate (I) with benzaldehyde and quaterniza-
tion of 4-styrylpyridine (IV) by sodium B-bromoethanesulfonate in an ethylene glycol solu-
tion. 3-(4-Styrylpyridinio)propanesulfonate (III) was obtained by quatern!zation of 4-sty-
rylpyridine (IV) with its 1,3-propane sultone in aeetonitrile (Tables i, 2).
Sulfobetaines VII-IX were synthesized by the quaternization of sodium 2-(4-pyridyl)-
ethanesulfonate (V) by ethyl bromide, ethylene chlorohydrin and glycerin a-monochlorohydrin.
They, as well as 2-(4-pyridyl)ethanesulfonic acid (VI), were further condensed with substi-
tuted benzaldehydes.

~ H3 ('H---CHC611 = CHr.CHCeH5

.y "--i C6H5CIt0 (/"'~

I I
cIL,cufio ~ ({:nzhso~
I If, Ht IV
II n=2; I11 n=3

The sodium salt (V) has an absorption band at 1605 cm-x in the IR spectrum, while in the
iR spectrum of acid VI this band is absent and an absorption band appears at 1635 cm-x. Us-
ing the data in [5, 6] as abasis, weassigned the first band to the C=N group vibrations, and
+
the second to C----Nin the pyridine ring. In the PMR spectra (D20), the a-protons of the pyri-
dine ring give signals in the form of doublets for compounds V-VII, respectively, with a
shift at 8.44, 8.69, 8.66 ppm, and the B-protons - at 7.33, 8.00, 7.90 pp, respectively. It
is seen that the signals of the pyridine ring protons of compounds VI and VII almost coin-
cide, and are present in a weaker field than the signals of base V. From these data we con-
cluded that 2-(4-pyridyl)ethanesulfonic acid exists in the form of a sulfobetaine (Vl). De-
spite this, its condensation with 4-hydroxy- and 4-methoxybenzaldehydes was successfully
accompolished only in absolute DMSO at elevated temperature (IIO*C) in the presence of an
equivalent amount of piperidine. The yield of the desired end products Xand XI was only 5%.
The condensation of sulfobetaines VII-IX with substituted benzaldehydes was carried out
in a mixture of absolute ethanol with absolute DMSO (4:1) in the presence of piperidine.
The u s e of absolute ethanol alone as the solvent decreases the yields nearly by half. The
presence and the nature of the substituents in the substituted benzaldehydes also noticeably
influence the course of the reaction. In the presence of electron-donor hydroxy and methoxy
groups, suifobetaines XII, XIII, XVII-XIX were synthesized in a 42-82% yield. An exception

ii00
 TABLE 2 . Chemical Shifts of Styrylpyridinium Protons (6, ppm)
H-Py (d)b -CH-----
Com- CHzSOz-
N--Alk {s) C~H~R~R: C
pound (s)
2-H 3-H

II 4,67 t; 3,06t 8,78 8.02 7,82--7,07

III 4,58t ; 2,38m; 8,84 8,11 8,02--7,24
2,16t
X 3,98 8,61 8,09 7,26 7,64 d; 6,69 d
XI 41ol 8,64 8, I2 7,33 L 7 8 d ; 6,88d; 371 s
XII 4,44q; 1,43t 4,00 8,77 8,18 7,36 17,70d ; 6,71d
XIII 4,46 q; 1,42 t 4,02 8,78 8,12 7,33 t7,22--6,62
XIV 4,48q; 1,44t 4,02 8,80 8,15 7,40 8,13--7,95
16,36--6.13
XV 4,49 q; 1,66 t 4,42 8.64 8,13 7,56 17,79d.; 6,93d; 3.09s
XVI 4,47 t ; 3,72 t 4,02 8,73 8,19 7,84--7,69; 7,44--7,22
XVII 4,44 t ; 3,70 t 4,02 8,67 8,17 7,37 7,69d,; 6,72 d
XVIII 4,44t ; 3,71t 4,01 8167 8,1l 7,33 8,08--7,73; 7,20--6,56
XIX 4,44 t ; 3,72 t 3,99 8,67 8.17 7.38 7.77 d ; 6,86d ; 3,98 s
XX 4,47 t ; 3,71 t 3,98 8,71 8,07 7,33 7,79 d ; 7,33 d
XXI 4,49 d ; 3,87 rn; 4,00 8,65 S, 16 7,96--7,67; 7,44--7,13
3,44 d
XXII 4,52 q; 1,66 t 4,52 8,54 ~,08 7,56 7,67d ; 6,72 d
XXIII 4,5tq; 1,60t 4,51 8,69 8,13 7,56 7,98--7,89; 7,40--7,22;
7,13 --6,89

aCompounds XV, XXII, XXIII were dissolved in a i:i CD3CN--D20

mixture, the remaining compounds were dissolved in (CDs)2SO.
bJ2~ = 6 Hz.
CFor para-substituted compounds J23 = 8 Hz.

was only the reaction with 2,4-dihydroxybenzaldehyde where, because of the resinification of
the reaction mixture and the difficulties which this presents during the purification of
the product, the yield of the sulfobetaine XIV was only 10%. In the presence of an electron
acceptor substituent, or in the absence of substituents, the yields of sulfobetaines XVI, XX,
XXI were lower, being equal to 17-28% (Table I). Despite the fact that the SOa- group is
electron-accepting and should increase the acidity of the CH2 group protons, our reactions
were carried out under more rigid conditions than the condensations of quaternary salts of y-
picoline with the corresponding benzaldehydes [7, 8]. This can be explained by the poor
solubility of sulfobetaines VI-IX in absolute solvents.
CIIzCII.,SO~Na ell !CII:,SO~"
j " I

9 \=/ '~--(/ \'~-I~'

i \=-S
R R 2~
V YI -IX X-~I
O
OH 0- r[

I I ! l
C2H ~ C2H 5 C2H 5 C2H 5

XII, XXII -- ~ s u M ~ m m d XIII, XXIII -- o - s u M f i m t e d VI, X, XI R = H ; VII,

XII--XV R=C:Hs; VIII, XVI--XX R=CH~CH~OH; IX, XXI R=CH2CH(OH)CH2OH;
R ~ a n d R2 s e e T a b l e 1

The hydroxy-substituted sulfobetaines Xll and XlIl were conver~ed by reaction with so-
dium hydroxide into anhydro-bases XXII, XXIII in yields of 95-96%. In the study of electron-
ic absorption spectra of compounds XII, XIII, XVII, XVIII in neutral and alkaline media, it
was found that the transition from para-substituted to ortho-substituted compounds leads to
a hypsochromic shift of the principal band of the z,~*-transitions, which indicates a dis-
turbance of the planarity of the molecules and decrease in the resonance interaction of the
aromatic and heterocyclic rings [7]. This is evident only in the phenol forms, i.e., in a

ii01
 0,5"I
0,%-
0,7
0,6i Fig. i. Absorption spectra of com-
pound Xll at different pH values of
05 the medium, i) 6.5; 2) 7.3; 3) 7.72;
4) 8.50; 5) 8.77; 6) 8.90; 7) 9.03;
8) 10.04.
0,3i
0,4
0,2
0,1
!

350 400
.

,~0 X, nm
neutral medium, and can happen only because of an in6eraction of the ortho-OH group with the
SO~- group (Table i). When the absorption spectra of quaternary salts of styrylpyridines
XII, XIII, XV-XIX were compared with those of analogous compounds, previously synthesized
by other authors, which have a CH3 group [7] or H [7, 8] instead of the CH2SOa- group, it
was found that the bulky CH2SO~- group disturbs the planarity of the molecule and hypsochro-
micaily shifts the absorption band of the n,~*-transitions approximately in the same way the
CH~ group (Table i).
We determined the acidity constants of the phenol groups in compounds XII, XIII, XVII,
XVIII spectrophotometrically. Figure ! shows the absorption spectra of 3-(4-hydroxyphenyl)-
2-(!-ethyl-4-pyridinio)-2-propenesu!fonate (XI!) at different pH. The spectra of monohy-
droxy-substituted sulfobetaines at different pH have a sharply expressed isobestic point,
which indicates the binarityof the system, p,o-Dihydroxystyrylpyridiniosulfobetaine XIV
has no isobestic point, but only intersection points of the curves in pairs, which indicates
a multicomponent character of the system [9]. The numerical values of pKa were determined
according to the formula:
_ . DA--D
pK= = p H + Lg D ~ _ D . , ,

where D A and DHA are optical densities of a solution containing only an A or HA form, D is
the optical density of the solution at an intermediate pH value [9].
The pKa values found are higher than those in compounds without a CH2S03- group [i0,
ii] (Table i). This can be also explained by lower planarity of the molecules of compounds
that we synthesized, which hinders the intramolecular charge transfer from the phenol group
to the pyridinium ring and increases the negative charge on the phenol group oxygen atom.
The structure of the compounds obtained was confirmed by UV, IR, and PMR spectra (Tables
I and 2). In the IR spectra of all the compounds there are absorption bands at 1050-1015
and 1190-1150 cm-~ related to the stretching vibrations of the sulfo group S--~, while for
compounds II, III, X-XXIII there are overlapping bands in the 1645-1600 cm-: region, which
+
can be related to both the ethylene bond ~(C-=O) and the w(O=N) bond in the pyridine ring.
Elemental analysis data agreed with those calculated for compounds II and III only. Mero-
cyanines, whose class also includes the compounds that we synthesized, can also form stable
hydrates with undefined composition [12]. Therefore, for the remaining compounds a too low
carbon content and an increased hydrogen content were obtained, compared with the calculated
data.

EXPERIMENTAL
The iR spectra ware run on a Specord 71-1R spectrophotometer in KBr tablets and the
PMR spectra on a Hitachi R-22 spectrometer (90 MHz), using HMDS as internal standard. The
UV spectra were recorded in water on a Specord UV-vis spectrophotometer. The purity of the
compounds was controlled by TLC on Silufol UV-254 plates in a 2:2:1:1 ethanol--acetonitrile--
chloroform-water system. To determine the pKa, 3.10-~ mole/liter solutions of sulfobetaines
in water were prepared, which directly before measuring the spectra were diluted by a borate
buffer to a working concentration of 6-10-5 mole/liter. For each compound, the pKa were cal-
culated with respect to two series of optical densities, measured at %max of the two conju-
gate forms.

1102
 2-(4-Styrylpyridinio)ethanesulfonate (II), A. A mixture of 4.02 g (20 mmoles) of 2-
(4-methylpyridinio)ethanesulfonate (I) [13], 3.18 g (30 mmoles) of benzaldehyde, i00 ml of
absolute ethanol and 2 m! of piperidine was stirred for 12 h at 80~ It was then cooled
to 20~ the crystals were filtered, dried in a vacuum-desiccator, and recrystallized from
85% aqueous ethanol. Yield, 4.2 g. Found, %: C 62.5; H 5.4; S 10.8. C~bH:bN03S. Calcu-
lated, %: C 62.3; H 5.2; S ii.i.
B. A solution of 6.7 g (37 mmoles) of 4-styrylpyridine and 7.8 g (37 mmoles) of sodium
S-bromoethanesulfonate in 80 ml of ethylene glycol was boiled for i0 h. The mixture was
cooled to 20~ the crystals were filtered, washed with ether, and dried in a vacuum-desic-
cator. Yield, 5.8 g. Samples of sulfobetaine II, synthesized by methods A and B were iden-
tical in their IR spectra.
3-(4-Styrylpyridinio)propanesulfonate (III). A solution of 4.53 g (25 mmoles) of 4-
styrylpyridine and 3.06 g (25 mmoles) of propane sultone in 50 ml of acetonitrile was boiled
with stirring for 8 h. The solution was evaporated, and the residue was recrystallized from
ethanol. Yield, 5.49 g. Found, %: C 63.1; H 5.7; S i0.0. C~6H~TNO3S. Calculated, %:
C 63.3; H 5.6; S 10.6.
2-(l-Ethyl-4-pyridinio)ethanesulfonate (VII). A solution of 8.4 g (40 mmoles) of sodium
2-(4-pyridyl)ethanesulfonate (V) and 6.53 g (60 mmoles) of ethyl bromide in a mixture of !0
ml of acetonitrile and 15 ml of water was stirred for 12 h at 40~ The solution was then
evaporated in vacuo, the residue was dissolved in 20 ml of concentrated HCI, and the undis-
solving sodium bromide was filtered. The filtrate was evaporated in vacuo, and the residue
recrystallized from ethanol. Yield, 6.2 g (72%); 229-230.5~ P ~ spectrum: 8.66 (2H,
d, 2H'Py); 7.90 (2H, d, 3H-Py); 4.53 (2H, q, CH2--N); 3.29 (4H, s, CH2CH2); 1.56 (3H, t, CH3).
Sulfobetaines VIII, IX were synthesized by the method in [14].
3-(4-Hydroxyphenyl)-2-(4-pyridinio)-2-propenesulfonate (X). A mixture of 5.24 g (28
mmoles) of 2-(4-pyridyl)ethanesulfonic acid (VI) [15], 4.9 g (40 mmoles) of 4-hydroxybenzal-
dehyde, 3 ml (30 mmoles) of piperidine, and 30 ml of absolute DMSO was stirred at Ii0 ~ to
complete dissolution of VI (-12 h). Dimethyl sulfoxide was evaporated in vacuo, and the
residue was chromatographed on a column with silica gel (acetonitrile-water, 5:1). Yield,
0.41 g.
Sulfobetaine XI was obtained in a similar way.
3-(4-Hydroxyphenyl)-2-(l-ethyl-4-pyridinio)-2-propenesulfonate (XII). A mixture of
10.8 g (50 mmoles) of sulfobetaine VII, 7.4 g (60 mmoles) of 4-hydroxybenzaldehyde, 3 ml
(30 mmoles) of piperidine, 40 ml of absolute ethanol and i0 ml of absolute DMSO was vigorous-
ly stirred at 80~ to complete dissolution of VII (-5 h). The solution was evaporated to
half of its volume, the crystals that separated were filtered, washed with water, and recrys-
tallized from 85% aqueous ethanol. Yield, 6.7 g.
Styrylpyridiniosulfobetaines XIII-XXI were synthesized in a similar way. Compound XV
was purified by crystallization from a 5:1 acetonitrile-water mixture, sulfobetaine XIV -- by
chromatography on a column, similarly as in the case of X.
Sodium 3-(4-hydroxyphenyl)-2-(l-ethyl-4-pyridinio)-2-propenesulfonate (XXII). Water was
evaporated in vacuo at 50~ from a solution of 4.8 g (15 mmoles) of sulfobetaine XII and
0.64 g (16 mmoles) of sodium hydroxide in 30 ml of water. The residue was recrystallized
from 85% aqueous ethanol. Yield, 4.9 g.
Compound XXII was synthesized in a similar way.
The authors wish to express their gratitude to A. Lazauskene, A. Mazheikene, and So
Plevokas for measuring the spectra.

LITERATURE CITED
I. K. Pl~ss and B. R. D~Martin, U. S. Patent No. 4,148,797; Ref. Zh. Khim., 3L327P (1980).
2. R. F. Nambridge, U. S. Patent No. 3,484,345; Ref. Zh. Khim., 2L262P (1971).
3. G. N. Bogdanov, A. N. Rozenberg, and A. K. Sheinkman, Khim. Geterotsikl. Soedin., No.
12, 1660 (1971).
4. H. W. Gibson and F. C. Bailey, Tetrahadron, 30, 2043 (1974).
5. N. A. Drobinskaya, L. V. Ionova, M. Ya. Karpeiskii, and V. L. Florent'ev, Khim. Getero-
tsikl. Soedin., No. 3, 356 (1971).

1103
 6. M. Katcka and T. Urbanski, Bull. Acad. Sci. Polon. Ser. Sci. Chim., 15, 413 (1967).
7. A. N. Rozenberg, G. N. Bogdanov, and A. K. Sheinkman, Khim. Geterotsikl. Soedin., No. 8,
1087 (1972).
8. A. P. Phillips, J. Org. Chem., 14, 302 (1949).
9. I. Ya. Bershtein and Yu. L. Kaminskii, Spectrophotometric Analysis in Organic Chemistry
[in Russian], Khimiya, Leningrad (1975), pp. 42, 144.
i0. U. Steiner, M. H, Abdel-Kader, P. Fischer, and H. E. Kramer, J. Am. Chem. Soc., i00,
3190 (1978).
ii. H. W. Gibson and F. C. Bailey, J. Chem. Soc., Perkin 2, No, 2, 196 (1978).
12. M. I. Minch and S. Sadiq Shah, J. Org. Chemo, 44, 3252 (1979).
13. G.-K. K. Kypyatis and V. V. Mozolis, Deposted in Lit. NIINTI, No. 956 Li-D82; Ref. Zh.
Khim., 6Zh251 Dep. (1983).
14. G.-K. K. Kupyatis, Deposited in Lit. NINNTI No. 1089 Li-D83; Ref. Zh. Khim., 2Zh227
Dep. (1984).
15. W. E. Doering and R. A. N. Well, J. Am. Chem. Soc., 69, 2461 (1947).

ACID HYDROLYSIS OF N-~THYL DERIVATIVES OF 4-PHENYL-5-OXO-

4,5-DEHYDROINDENO[I,2-b]PYRIDINE

V. K. Lusis, D. Kh. Mutsenietse, and G. Xa. Dubur UDC 547.655'828.07:542.938:

543.422

The splitting of the dihydropyridine ring of N-methyl-substituted 4-phenyl-5-

oxo-4,5-dihydroindeno[l,2-b]pyridine in an acid medium takes place at the C--N
bond. During the splitting of 1,2-dimethyl-4-phenyl-4,5-dihydroindeno[l,2-b]-
pyridine, 4-phenyl-4-(indane-l,3-dion-2-yl)butan-2-one is formed, while in the
case of the 3-ethoxycarbonyl derivative of indenopyridine, together with the
Michael retroreaction leading to 2-benzylideneindane-l,3-dione, a re~yr
of the intermediate product into a derivative of dihydroindeno-2-pyridone
takes place.

It is known [i] that during alkylation, 5-oxo-iH-4,5-dihydroindeno[l,2-b]pyridines form

C- and N-alkylation products, i.e., they exhibit properties characteristic of enamino ketones
In the present work, it was shown that splitting of the dihydropyridine ring of 1,2-dimethyl-
4-phenyl-5-oxo-4,5-dihydroindeno[l,2-b]pyridine (la) and its 3-ethoxycarbonyl derivative (Ib)
in an acid medium proceeds as an acid hydrolysis of enamines.
According to the generally accepted scheme, the hydrolysis of enamines includes the
protonation of the B-carbon atom, followed by the addition of water to the ~-carbon atom and
cleavage of the C--N bond. Since themolecule of dihydroindenopyridine I contains two frag-
ments, which are enamine systems: C(~a)--C(gb)--N and C(3)--C(2)--N, a cleavage of both the N--
C(gb) and N--C(2) bond is possible with the formation of intermediate products A and B. How-
ever, these primary hydrolysis products were not detected in the reaction mixture, but pro-
ducts of their further transformation were isolated. Thus, during the hydrolysis of 1,2-
dimethyl-3-ethoxycarbonyl-4-phenyl-5-oxo-4,5-dihydroindeno[l,2-b]pyridine (Ib), 2-benzyli-
deneindane-l,3-dione (II), 2-Benzylindane-l,3-dione (III), and l-methyl-3-acetyl-4-phenyl-
2,5-dioxo-2,5-dihydroindeno[l,2-b]pyridine (IV) were detected~ Indenopyridone IV is an oxi-
dized form of l-methyl-3-acetyl-4-phenyl-2,5-dioxo-2,3,4,5-tetrahydroindeno[l,2-b]pyridine
(V), formed as the result of an intramolecular interaction of an ester group with the l-
methylamino functional group of the intermediate product B. Structure IV was confirmed by
spectral methods and alternativesynthesis: cyclization of N-monomethyl a-acetyl-8-phenyl-
B-(indane-l,3-dion-2-yl)propionamide (Vl) into 2,5-dioxo-2,3,4,5-tetrahydroindenopyridine

Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, Riga 226006.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1363-1366, October, 1986.
Original article submitted April 30, 1985.

1104 0009-3122/86/2210-1104512.50 9 1987 Plenum Publishing Corporation

(V) and oxidation of the latter. Cyclization of monoamide (Vl) proceeds similarly to the
cyclization of diamides of e-(indane-l,3-dion-2-yl)benzylmalonic acid [2], but at elevated
temperature, instead of cyclization, the Michael retroreaction with the formation of compound
II takes place.
If the formation of indenopyridone IV unequivocally confirms the cleavage of the N--C(2)
bond during the hydrolysis of compound Ib, then compound II can formally be obtained in this
reaction by splitting of both the intermediate compound A (hydrolysis at the N--C(gb) bond)
and B (hydrolysis at the N--C(2) bond), followed by the replacement of the NHCH3 group of the
OH group. However, the formation of 2-benzylideneindane-l,3-dione from the intermediate
product B is excluded, since 4-phenyl-4-(indane-l,3-dion-2-yl)-3-ethoxycarbonylbutan-2-one
(Vllb) does not change under the conditions of the acid hydrolysis of lb. Hence, it can be
concluded that during the hydrolysis of compound Ib, 2-benzylideneindane-l,3-dione (II) is
formed as the result of the Michael retroreaction from the intermediate product A, arising
after the cleavage of the N--C(gb) bond. Compound III should be regarded as a reduction pro-
duct of compound II. Tetrahydro-2-oxopyridine V, a precursor of pyridone IV, isolated from
the reaction mixture, and dihydroindenopyridine Ib can serve as reducing agents, since Loth
the ability of hydrogenated pyridones to reduce benzylideneacetophenone [3], and the ability
of the IH analog of compound Ib to reduce 2-arylideneindane-l,3-diones [4] are known. It is
impossible to unequivocally determine the direction of the process, for example, by the re-
duction of dione II by dihydroindenopyridine Ib in the presence of HCI, because of its acid
hydrolysis. During the reduction of compound II by tetrahydropyridone V in an acidified
alcoholic medium, as well as in its reduction by dihydroindenopyridine Ib in acetic acid,
the presence of 2-benzylindane-l,3-dione (III) in the reaction mixture was confirmed by li-
quid chromatography. A quantitative ratio of the hydrolysis products of Ib (IV:If + III)
indicates a different rate of hydrolysis of the N--C(2) and N--C(gb) bonds and leads to the
conclusion that the cleavage of the N--C(gb) bond proceeds more easily.

o ~ 0 0

N"!~ H~ I ~v7 - - %o N./~"'~"~ ~" "-----~I~ o~'c.~

~
I I i I
Ia,b c}I3 L A cH3 B cI% _
// i \
R=H \ R=COOC2H 5

IV]
r

o 0 0 t'GH5
m u %'1~a,b

CH 5 CH~ CH 3
%q V IV

Ia, %qla R=It; 6 I~COOC2tl 5

The main product of the hydrolysis of compound la is 4-phenyl-4-(indane-l,3-dion-2-yl)-

butan-2-one (VIIa). The absence of compound II from the hydrolysis products of Ia shows that
the Michael retroreaction does not take place. If it is proved that during the hydrolysis
of compound Ib, the splitting of the dihydropyridine ring proceeds with the participation of
the two enamine systems (both at the N--C(,b) and at the N-C(2) bond), then the formation of
compound VIIa as the result of splitting of derivative Ia does not indicate a cleavage of
only one given bond. In the hydrolysis of compound Ia with a cleavage of the N--C(2) bond,
the intermediate product B cannot recyclize, and replacement of the NHCHs group by an OH
group in products A and B leads to the formation of derivative VIIa.
The data obtained confirm the enamine character of 1,4-dihydropyridine system. It is
not excluded that also the previously noted instability of certain N-methyldihydropyridines
in an acid medium [5] can be explained by a similar hydrolysis.

1105
 EXPERIMENTAL
The PMR spectra were run on a Bruker WH-90 spectrometer, using TMS as internal standard,
and the IR spectra on a Perkin-Elmer 580 B spectrophotometer in Nuiol; the mass spectra were
measured on a MS-50 AEI mass spectrometer at an energy of the ionizing electrons at 70 eV.
Compounds la, b were obtained according to [i].
Hydrolysisof 1,2-dimethyl-3-ethoxycarbonyl-4-phenyl-5-oxo-4,5-dihydroindeno[l,2-b]-
pyridine (Ib) o A 3.59 g (i0 mmoles) portion of compound Ib is dissolved in 200 ml of ethan-
ol, 40 ml of water and 8.8 ml (i00 mmoles) Of concentrated HCI are added, and the mixture is
boiled for 2 h. It is then cooled, and 0.93 g of l-benzylideneindane-l,3-dione (II) is fil-
tered. The filtrate (F) is diluted with i liter of water and extracted by ether (4 200
ml). The ether extracts are extracted by a 4% aqueous solution of NaOH (5 200 ml). After
evaporation, another 0.2 g of compound II is obtained from the ether solution, the total
yield of II being 48%. The alkaline aqueous solution is acidified by dilute HCI (i:i) and
extracted by ether (4 200 ml). The ether extract is washed with water, dried and evaporat-
ed. The residue is recrystallized from methanol to yield 0.65 g (27%) of 2-benzylindane-l,3-
dione (III). According to physlcochemical characteristics, compounds II and III are identical
with authentic samples of 2-benzyl- [6] and 2-benzylideneindane-l,3-diones [7]. The acid
aqueous layer (filtrate F) after the extraction of compounds II and III, is made alkaline by
a NaOH solution to pH 9-10 and extracted by ether (3 200 ml). The ether layer is washed
with water, dried, and evaporated. The residue is chromatographed on a column with silica
gel (LIO0/160), eluting first with a 5:1 chloroform--acetone mixture, and then with a 9:7:1
chloroform--hexane-acetone mixture, A yellow-ora~ge fraction is collected. Yield, 0.56 g
(18%) of compound IV, mp, 183~ (from methanol). IR spectrum: 1715, 1710, 1695 (CO),
i642 cm -: (C=C), PMR spectrum (DMSO): 2.18 (s, 3H, COCH3); 3.97 (s, 3H, NCH3); 7,13-7.76
(m, 8H) and 7.96-8.09 ppm (m, IH, aromatic protons). Mass spectrum, m/z, %: 329 (51) [M]+',
328 (33) [M-- HI +, 314 (i00) [M-- CH3] +, 300 (8) [M-- CO -- H] +, 286 (17) [M-- COCH~] +, 258
(i0) [M-- COCH~ -- CO] + , 195 (16). Found, %: C 76.4; H 4.8; N 4.4. C2~H:bNO3. Calculated,
%: C 76.4; H 4.6; N 4.3.
N-Monomethyl ~-acetyl-8-phenyl-8-(indane-l~3-dion-2-yl)propionamide (Vl) is obtained by
condensation of equimolar amounts of benzalindanedione and N-monomethyl acetoacetamide in the
presence of a 3% sodium methylate, in analogy with [8]. Mp, I12-I14~ (from ethanol). PM.R
spectrum (CDCI3): 2.42 (s, 3H, COCH,); 2.52 (d, 3H, NCH , JNH-CH, = 5.0 Hz); 3~ (d, IH,
2-H, J2H-~H = 4.5 Hz); 4.20 (m, IH, 8-H); 4.77 (d, IH, ~-H, JSH-~H = 13.0 Hz); 6.16 (m, IH,
h"H); 7.08 (s, 5H, CeHb); 7.61-7.96 ppm (m, 4H, H of indene ring).
l-Methyl-3-acetyl-4-phenyl-2~5-dioxo-2,3,4,5-tetrahydroindeno[l,2Tb]pyridine (V) is ob-
tained by cyclization of 0.70 g (20 mmoles) of amide Vl in 25 ml of concentrated HCI at 20~
(12 h). Yield, 0.36 g (55%). Red crystals, mp 142-143~ (from methanol). Mass spectrum,
m/z, %: 331 (7) [M] +', 329 (3) [M-- H2] +', 314 (6) [M-- H~--CH,] +, 302 (12) [M-- CO-- HI +,
288 (i00) [M-- COCH,] +, 260 (6) [M-- COCH,--CO] ~, 254 (31) [M-- C6H~] +, 236 (15) [M-- C6H, --
H20] +, 212 (6). Found, %: C 76.0; H 5.5; N 4.3. C2~H~TNO3. Calculated, %: C 76.1; H 5.2;
N 4.2.
l_MethYl-3-acetyl-4-phenyl-2,5-dioxo-dihxdroindeno[l,2-b]pyridine (IV). A 0.4 g of
sodium nitrite is gradually added at 40~ to 0.i g of compound V in 5 ml of glacial acetic
acid. The reaction mixture is diluted with i00 ml of water, and a yellow-orange precipitate
is filtered and recrystallized from methanol. Pyridone IV monohydrate is obtained, which
loses water at II0~ After drying in vacuo, the synthesized product is identical in its
physicochemical characteristics with an authentic sample of pyridone IV, isolated during the
hydrolysis of lb.
Hydrolysis of 1,2-dimethyl-4-phenyl-5-oxo-4,5-dihydroindeno[l,2-b]pyridine (la). A 0.9 g
portion (3 mmoles) of compound la is dissolved in 65 ml of ethanol, 12.5 ml of water and 2~
ml (30 mmoles) of concentrated HCI are added, and the mixture is boiled for 15 min. It is
then cooled, diluted with 300 ml of water, and extracted by ether (4 150 ml). The ether
extracts are extracted by 4% aqueous solution of NaOH (4 x 200 ml). The alkaline aqueous
solution is acidified by hydrochloric acid, and extracted by ether (5 x 150 ml). The ether
extracts obtained are washed with water, dried, and evaporated. The residue is recrystallized
from methanol. Yield, 0.75 g (82%) of pure dione VII. According to the data of IRandPMR
spectra and elemental analysis, the product obtained is identical with an authentic sample
synthesized according to [9].

1106
 Reduction of 2-benzylideneindane-l,3-dione (II) by Tetrahydropyridine (V). A 0.04 ml por-
tion of concentrated HCI is added to a solution of 0.12 g (500 mmoles) of compound II and
0.17 g (500 mmoles) of compound V in i0 ml of 80% ethanol, and the mixture is boiled for 20
h. The reaction mixture is diluted with water and extracted by chloroform (2 x 30 ml). The
chloroform extract is dried and evaporated. According to the data of liquid chromatography
(Zorbah SIL; ethyl acetate--hexane, 35:15), the residue contains 49%-of 2-benzylindane-l,3-
dione III.

LITERATURE CITED
1. V. K. Lusis, D. Kh. Mutsenietse, A. Z. Zandersons, I. B. Mazheika, and G. Ya. Dubur,
Khim. Geterotsikl. Soedin., No. 3, 393 (1984).
2. Yu. E. Pelcher, A. K. Aren, Z. A. Bomika, and G. Ya. Vanag, Khim. Geterotsikl. Soedin.,
No. 2, 305 (1969).
3. J. Kuthan, P. Nesvadba, Z. Donnerova, and P. Trska, Coil. Czech. Chem. Communs., 42,
2152 (1977).
4, G Ya. Dubur and Ya. R. Uldrikis, Khim. Geterotsikl. Soed~n., No. i, 83 (1970).
5. W Traber and P. Karrer, Helv. Chim. Acta, 41, 2066 (1958).
6. G Ya. Vanag and T. T. Dumpis, Dokl. Akad. Nauk SSSR, !25, 549 (1959).
7. A K. Aren, B. E. Aren, and G. Ya. Vanag, Dokl. Akad. Nauk SSSR, 135, 320 (1960).
8. L P. Zalukaev and I. K. Anokhina, Zh. Obshch. Khim., 34, 840 (1964).
9, L P. Zalukaev, Zh. Obshch. Khim., 26, 3125 (1956).

1,2,5-TRI}~THYL-4-(p-HYDROXYARYL)-&3-TETRAHYDROPYRIDINES
AND THEIR SPATIAL STRUCTURE

V. A. Rezakov, S. K. Das, A. Ao Fomichev, UDC 543.422.25:547.823

and N. S. Prostakov

The condensation of 1,2,5-trimethu with phenol and isomeric

cresols yields 1,2,5-trimethyl-4-(p-hydroxyphenyl)- and (p-hydroxytolyl)-A 3-
tetrahydropyridines, the structure and conformation of which have been studied
by proton NMR spectroscopy.

The condensation of y-piperidones with phenol (cresols) is of interest for the prepara-
tion of piperidine derivatives containing hydroxyphenyl groups in the y-position. Compounds
of this type are examined for their physiological activity [i].
We have studied the compounds formed by condensation of 1,2,5-trimethylpiperidine-4-one
(i) with phenol and isomeric cresols in the presence of boron trifluoride etherate. In all
cases, the compounds obtained were dehydration products of 1,2,5-trimethyl-4-(p-hydroxyaryl)-
piperidine-4-ones.
OH
OH ~ RI
0 R~
CH~ R2 CN
CH~ BF'~(C2Hs)20~ ~NACH3
T f
CH 3 CH 3
I llab,lll-rv
I! a~ RI=R2=H; III RI=H, R2=CH~; IV R~=CH~, R2=H

Patrice Lumumba Peoples' Friendship University, Moscow 117923. Translated from Khimiya
Geterotsikiicheskikh Soedinenii, No. I0, pp. 1367-1370, October, 1986. Original article sub-
mitted ~ y 21, 1985; revision submitted January 24, 1986.

0009-3122/86/2210-11075i2.50 9 1987 Plenum Publishing Corp ration 1107

 TABLE i. Chemical Shifts of Protons in Substituted AS-Tetra -
hydropyridines (6, ppm)

COITI" 2-H [ 3-H 5-H 6-H a 6-H e N--CH3' I Protonsof the

pound I 2-CH~ 5-CH~ 4- substiment

Ila 2,88 [ 5,52 3,01 2,19 3,06 2,4211,23 0,83 t System AA'BB':
7,I0 (2H, d);
lib 2,88 5,65 2,78 2,64 2,74 2,41 1,24 1,11 16,81
7,25 i2H,
(2H, d);
6,78 (2H, b)
Ill 2,84 5,49 3,00 2,17 3,04 2,40 ! 1,21 0,84 I 2,23 (CH3);
7,01 (2'-H)
6,70 (5'-H) ;
6,88 {6'-H)
IV 2,88 5,47 3,09 2,16 2,98 2,43 1,19 10,76 I 2,28 (CH3);
' 6,65 (3'-H);
[ 6,64 (5'-H);
i 6,90 (6'-H)

The structure and stereochemistry of the substituted tetrahydropyridines obtained were

established by examination of the proton NMR spectra (Tables i and 2).
It follows from these results that in all cases A3-tetrahydropyridines are formed, not
the A"-isomers as would be expected. This can be unambiguously deduced, for example, from
the fact that the methylene protons at the a-carbon atom of the tetrahydropyridine ring have
as a neighbor the 5-H methylene proton with which vicinal spin-spin coupling is observed
(Table 2)~ Taking into account the fact that the initial piperidone (I) is a mixture of
trans- and cis-isomers, according to the position of the methyl groups, with a considerable
predominance of the first [2], the formation of isomers of the tetrahydropyridines would be
expected. However, only in the case of the condensation of the piperidone (I) with phenol
was the separation accomplished, with the aid of column chromatography, into the individual
isomers, precominantly the trans-2,5-isomer lla with very small amounts of the cis-2,5-isomer
llb. Examination of the spin-spin coupling constants JHH (Table 2) enables one also to de-
termine the preferred conformation of these configurational isomers. In the case of the
trans-isomers of lla, III, and IV this is semi-chair, with equatorial orientation of the 2-
and 5-methyl substituents, and in the case of the cis-isomer of lib, semi-chair with 2e,5a-
orientation of these substituents:

e-- ~ e, e- et

a CH3~f N CI% CH3~.. N

IIa. ~'rr,... IV IIb

Change in the orientation of the 5-methyl substituent on transition from the trans-
isomers lla, III, and IV to the cis-isomer llb can be traced in terms of the values of the
two vicinal spin-spin coupling constants of the protons on C(5) and C(6) (Table 2). Thus,
in the trans-isomers the large value of one of these constants (9-10 Hz) points to trans-
biaxial orientation, and the value of the second constant (5.5 Hz) could be ascribed to gauche
interaction which in the aggregate supports the equatorial orientation of the 5-methyl group.
The small value of one of these constants in the cis-isomer (2.5 Hz) can be explained only by
gauche-biequatorial orientation of the corresponding protons, which have between them a di-
hedral angle close to 90" and this also leads to a minimal value of the vicinal spin-spin
coupling constant according to the Karplus relationship [3]. The value of the second of
these constants in the cis-isomer (4.2 Hz, Table 2) is such that one can assign it to the
gauche-interactlon 3Jae whence the axial orientation of the 5-methyl substituent in the cis-
isomer lib can be unequivocally deduced.
It is interesting to note that change in the orientation of the methyl substituent from
equatorial to axial on transition from isomer lla to lib leads to deshielding of its protons,
in contrast to a saturated six-membered ring, which can be explained by the vicinity of the
--eiectron system of the double bond. The exceptionally large values of the long-range spin-
spin coupling constants -- homoallylic 5J2.5 = 2.5-3, and ~J5,3 = 1.5-1.7 Hz (Table 21 -- are
characteristic for the spatial structure of the trans-isomers and result from the effect of
~-~ overlap [4] with axial orientation of the interacting protons in the vicinity of the

1108
 TABLE 2. Spin-Spin Coupling Constants of
Protons in the Tetrahydropyridine Ring of
Compounds lla, lib, III, and IV (Hz)
Corn- Proton i n n e r a c t i o n s
p o u n d oa,% ti ~.,5 6,,,5 2,3 5,2 5.3 I 2.2-CH~ 5.5-CH:

IIa --II,5 9.0 5,5 2,0 3,0 1.5 7,0 7,0

lib -Ill5 4,2 2.5 2.5 1.8 2.0 6,5 7,0
Ili -1115 9,5 5,5 2,0 2,5 1,5 7.0 7,0
IV -ll,O 10,0 5,5 1,7 3,0 1,7 6,8 7,1

double bond. In contrast, the vicinal spin-spin coupling constant 3J2,3 in both trans- and
cis-isomers has the small value of 1.7-2 Hz (Table 2) on account of the dihedral angle between
protons 2-H and 3-H being close to 90 ~ .
The orientation of the N-methyl group must be considered differently on account of the
low energy barrier for inversion of the nitrogen atom in a six-membered ring [5]. The PMR
results which we obtained give support to its preferentially equatorial position, both in the
trans-isomers lla, III, and IV and in the cis-isomer llb. Evidence of this is the large dif-
ference in the chemical shifts of the methylene protons on C(6) in the trans-isomers (0.8-
0.9 ppm, Table i) because of supplementary deshielding of the 6e proton in the gauche-orien-
tation with respect to the unshared electron pair of nitrogen. Leveling of the chemical
shifts of these protons in the cis-isomer lib (2.64 and 2.75 ppm, Table i) can be explained
by selective shielding of the 6e proton by the 5-methyl group in the cis-ae-orientation with
respect to this proton. Equatorial orientation of the N-methyl group in the trans- and cis-
isomers is also supported by the difference Sn the vicina! 3Jae of the protons at C(5) and
C(6) in these isomers. The substantially greater value of this coupling constant in the
trans-isomers (5.5 Hz, Table 2) in comparison with the cis-isomers (4.2 Hz) is explained by
the positive contribution in the gauche-orientation of one of the interacting protons (6e)
with the unshared electron pair of the heteroatom [6] in the trans-isomer. The reason for
the predominance of the trans-le,2e-configuration of the methyl groups could be steric 1,2-
interaction, making their cis-configuration much more disadvantageous at the strain angles
(smaller than those of saturated six-membered rings) of a semi-chair configuration in cyclic
mono-enes [7] such as A3-tetrahydropyridine.
Thus, it follows from our PMR data that the dehydration products which we have studied
are, in all cases, A3-tetrahydropyridines, the molecules of which have semi-chair configura-
tion, the le,2e,5e-orientation of the methyl substituents predominating in the trans-2,5-
isomers lla, III, and IV, and the le-2e,5a-conformer in the cis-isomer llb.

EXPERIMENTAL
A WH-360 spectrometer (360 Mllz) was used to obtain the proton NNR spectra of 2-5% solu-
tions in CDCI3. First-order analysis of the spectra was performed. The double resonance
method was used for unambiguous assignment of the signals and for determining the spin-spin
coupling constants.
1,2,5-Trimethyl-4-(p-hydroxyphenyl)-A3-tetrahydropyridine (II). To a mixture of 18.8 g
(0.2 mole) phenol and 3.34 g (24 mmoles) borontrifluoride etherate at 0~ was added 5.1 g
(0.03 mole) piperidone (I). The reaction mixture was kept at 20~ for i0 days. Water (500
ml) was added and the solution shaken in a separating funnel with I00 ml ether. The aqueous
solution was saturated with sodium carbonate. The reaction product was extracted with four
50 ml portions of ether and the extract dried over sodium sulfate. The residue after dis-
tilling off the ether was 3.72 g (47%) of a glass-like mass. A portion of the residue (0.56
g) was taken for chromatographic separation, using aluminum oxide of activity II in a column
with h = 60 cm, d = 3.5 cm; the e luent was a mixture of i:i hexane:ethyl acetate. The sepa-
ration yielded 0.06 g (10.7%) compound llb, colorless crystals , mp 136-137~ from heptane,
Rf 0.75. Found, %: N 6.4; M+ 217. C:~H~gNO. Calculated, %: N 6.4; M + 217. Further elu-
tion gave 0.31 g (55.4%) compound lla, colorless crystals, mp 130-1310C from heptane, Rf
0.72. Found, %: N 6.4; M + 217. C14H~gNO. Calculated, %: N 6.4; M + 217. Hydrochioride
of compound lla, mp 189-191~ (from 3:1 acetone:alcohol).
l~2,5-Trimethyl-4-(4-hydroxy-3-methylphenyl)-A~-tetrahydropyridine (II). The reaction
mixture was made up from 12.8 g (0.12 mole) o-cresol, 11.7 g (0.08 mole) BF3 etherate, and

1109
5.85 g (0.042 mole) piperidone (I), and the experiment carried out in a similar.manner to
the preceding. From the ether extract there was obtained 3.5 g residue in which TLC (the
same system) showed two compounds with Rf 0.72 and 0.69. The residue was crystallized from
heptane, yielding 2.98 g (31%) compound III, mp 160-161~ Kf 0.69. Found, %: N 6.0; M +
231. C~bH=,NO. Calculated, %: N 6.1; M + 231.
1,2,5-Trimethyl-4-(4-hydroxy-2-methYlphenyl)-A3-tetrahydropyridine (IV) was prepared
by a similar condensation of piperidone (I) with m-cresol using the same molar proportions
of reactants, the yield beimg 3.05% of (IV),mp 120-121~ from heptane; Rf 0.51. Found, %:
N 6ol; M + 231. C~bH2~NO. Calculated, %: N 6.1; M + 231.

LITERATURE CITED
l, D. M. Zimmerman, R. Nikander, J. S. Horng, and D. T. Wong, Nature, 275, 332 (1978).
2. M. M. A. Hassan and A. F. Casy, Org. Magn. Reson., ~, 197 (1970).
3. M. Karplus, J. Chem. Phys., 30, ll (1959).
4. M. Barfieid and B. Chakralarti, Chem. Rev., 69, 757 (1969).
5. F. A. L. Anet and Io Yavari, J. Am. Chem. Soc., 99, 2794 (1977).
6. M. Anteunis, Bull. Soc. Chim. Belg., 75, 413 (1966).
F. R. Jensen and C. H. Bushweller, Adv. Alicyclic Chem., ~, 139 (1971).

SYNTHESIS OF 1,5-~THANO-2-BENZAZOCiNES FROM 3-HYDROXY-

i,3-DIMETHYL-6-PHENYL-4-PIPERIDONE

G. V. Pshenichnyi, V. A. Mashenkov, and L. S. Stanishevski$ UDC 547.823:543.422

Reaction of 3e-hydroxy-le,3a-dimethyl-6e-phenyl-4-piperidone with cyanoacetic

ester affords 6e,8a-dimethyl-2-oxo-be-phenyl-3-cyanofuro[2,3-c]piperidine, the
epoxide of which undergoes intramolecular cyclization on treatment with 80%
H2SO~ to give 1,2,5,6-tetrahydro-2-endo-4-dimethyl-l,5-methano-6-oxo-2-benza-
zocin-3-ene. It has been found that the latter is formed via the intermediate
3-hydroxy-6e,8a-dimethyl-2-oxo-be-phenylfuro[2,3-c]piperidine.

1,5-Methano-2-benzazocines have so far received little attention as a result of the lack

of satisfactory methods for their preparation. Compounds of this type have been obtained by
adding amidines to di-, tri-, and tetranitronapthalenes [I]. We have developed a new method
for the synthesis of 1,5-methano-2-benzazocines based on the acid-catalyzed reaction of the
epoxy-lactone (II). The latter compound was obtained by condensing the ~-ketol (I) with
ethyl cyanoacetate.
The conversion of the epoxylactone (III) into the ketone (V) evidently involves hydroly-
sis of the cyano-group and the epoxide ring, decarboxylation, and dehydration to give the
intermediate lactone (IV). Subsequent intramolecular reactions of the lactone (IV) involve
opening of the lactone ring, decarbonylation, and dehydration (see scheme on following page).
Reduction of the ketone (V) with complex hydrides of aluminum and boron showed that
attack on the carbonyl group by the hydride ion takes place from the sterically more acces-
sible exo-position, subsequent reduction of the double bond with sodium borohydride in ethan-
ol taking place from the endo-position.
The structures of all the compounds obtained were confirmed by their elemental analyses
and their IR, PMR, and mass spectra. For example, in the PMR spectra of (II-IV), the protons
of the piperidine ring are seen as two spin systems, AMX and AX, examination of which shows

V. I. Lenin Belorussian State University, Minsk 220080. Translated from Khimiya Getero-
tsiklieheskikh Soedinenii, No. i0, pp. 1371-1374, October, 1986. Original article submitted
May 31, 1985; revision submitted December 2, 1985.

iii0 0f09-3122/86/2210-iii0512.50 9 1987 Plenum Publishing Corporation

 O .~ CN O -~ CN /.OH

,o o . , \ / . . o

cH;'L ) --- --- c~ ---- ~,;"

--N--'"Ph ~N/'"Ph "~N'/'"Ph ""Ph
CH 3 CH~ CH~ CH 3
I II III
,
Iv

V
.,,CH 3 . ,,CH~ ,,,CH 3

CH: .. CH CH 3
HO
VII Vl V

that the ring has the chair conformation, the methyl group at nitrogen being equatorially
oriented [2]. The o b s e r v e d m a r k e d n o n e q u i v a l e n c e o f t h e p r o t o n s o f t h e a r o m a t i c n u c l e u s i n
( V - V I I ) i s due to t h e i r p r e s e n c e i n a r i n g w i t h a n e i g h b o r i n g e l e c t r o n a c c e p t o r . A particu-
larly large paramagnetic shift is experienced by the proton in the 7-position. The P ~ and
IR s p e c t r a o f t h e l a c t o n e (IV) snow t h a t t h i s compound e x i s t s s o l e l y i n t h e e n o l f o r m , w h e t h -
e r in solution in CCI~ or CHCIs, or in the solid state, in agreement with data for bicyclic
~-ketolactones [3]. That the hydroxyl group occupies the endo-position in the benzazocines
(VI) and (VII) is confirmed by the weak IHB (A~ = 30 cm-~) in (VI) between the hydroxyl hy-
drogen and the ,~-electrons of the double bond [4], and by the value of the coupling constant
between the 5-H and 6-H [5]. The exo-position of the 4-CHs group in the benzazocine (VII)
is confirmed by the value of the coupling constant between 4-H and the protons at C(s) and
C(5). Experiments utilizing the nuclear Oberhauser effect (NOE) showed clear dipole-dipole
interactions between the 2-CH3 and 10-H protons in benzazocines (V) and (VII), indicating
that the N-methyl group occupies the endo-position in these compounds.
Thus, the method of preparation of 1,5-methano-2-benzazocines which has been developed
is adequately simple in use, and can be employed as a preparative method of synthesis of
these difficultly-accessible compounds.

EXPERIMENTAL
The IR spectra of the compounds in solution in CCI~, CHCIs, and C2CI~, and in KBr disks,
were obtained on Specord-75 IR and UR-20 instruments. The PMR spectra of 5-10% solutions
in CDCI3 were obtained on Tesla BS-567A (i00 MHz) and Bruker WM-360 (360 Fmz) spectrometers,
and the NOE experiments were carried out by differential spectroscopy, internal standard HNDS.
F~ss spectra were obtained on a Varian MAT-311 mass spectrometer at 70 eV. Carbon monoxide
was measured with a CO-0,2 indicator tube. The properties of the compounds obtained are
given in Table i. In the mass spectra of all the compounds, the molecular ion peaks are in
agreement with the calculated molecular masses.
6e,8a-Dimethyl-2-oxo-5e-phenyl-3-cyanofuro[2,3-c]piperdine (II). To a solution of 2.19
g (I0 mmoles) of the piperidone (I) [6] in 5 ml of ethanol was added 1.70 g (15 mmoles) of
ethyl cyanoacetate and 0.34 g (5 mmoles) of sodium ethoxide. The mixture was kept for 30
min at 20~ and the lactone (II) which separated was filtered off and washed with cold ethan-
ol.
6e-Sa-Dimethyl-2-oxo-5e-phenyl-3-cyano-3,9e-epoxyfuro[2,3-c]piperidine (III). To a
solution of 5.36 g (20 mmoles) of the lactone (II) in 200 ml of benzene was added 40 ml of
15% H20~ and 1 g of tetrabutylammonium hydroxide. The mixture was stirred vigorously for 2
h at 20~ the aqueous layer separated, and the benzene layer washed with water, dried over
K2CO3, and passed through a thin layer of silica gel grade L40/I00. After evaporation of
part of the benzene, the residue was crystallized from a i:i mixture of benzene and hexane.
3-Hydroxy-6e,8a-dimethyl-2-oxo-5e-phenylfuro[2,3-c]piperidine (IV). A solution of 1.7
g (6 mmoles) of the lactone (III) in 50 ml of 25% sulfuric acid was boiled for 36 h, and the
mixture cooled, treated with 10% sodium hydroxide to pH 8-9, extracted with benzene, and the
extract dried over Na2SO~. The solvent was then partially evaporated, and the residue crys-
tallized from 2:1 mixture of benzene and hexane.
1,2,5,6-Tetrahydro-2-endo-4-dimethyl-l,5-methano-6-oxo-2-benzazocin-3-ene (V). The
lactone (III) or (IV) (i0 mmoles) was dissolved in i0 ml of 80% sulfuric acid, and the mix-
ture kept for 3.5 h at 140-150~ After cooling, the mixture was poured into i00 ml of 10%

iiii
b~

ro

TABLE i. Properties of Compounds (II-VII)

IR spectrum, Found. % I Calculated. % Yield,

Com- rap, *C PMR spectrum, ppm (L H~.) Empirical
pound I V+cm-1 %
N formula .
c I ,, I N
r:. t
II 152--153 1,79 (s, ~-CIL); 2,06 (,s 6-r 2,24 (d, /irm:ll,0, 7a-H); 1450 (c.::- r 71,5 10,5 [ Cl~lll~N~O2 71,s I 6,0 10,4 93
2.72 ( d.d, ;14~.+,~= 13,5, ,l.,.~. = 10,0, .I,~-111; 3,06" (d.d, J4,,,r,,,~3,(), 17711 {C:+~O),
53-111, 3,1o (d.d,., 4e-ll); 3,37 (d. 7e-H); 7,22--7,41 (5It, m, 2235 (C ~- N)
Haron0
Ill 95--96 1,48 is. 8-Ctls); 1,89 (d.d. J+.,4,,=14. 3, .14,.,s,,~:3,5, 4e-H); 2.04 1800 ( ( : = o ) , .67,2 5,7 9,9 C.~I Ij6N,~Oa 67,11 I 5.7 9.9 73
(s, 4-CHj; 2.25 (d. Jgem=12,0.73-lt);2,48 {d. do J4,,.s,,=ll,5, 2250 ( C ~ N )
4a-It); 3.19 (d.d. 5a-H); 3,24 (d. 7e-H); 7,2t--7r {51t, m
ll~iom)
IV 163--164 l.ti8 (s. ~-Ctl:J; 2,01 (~. 6~CH:0; 2,07 (d~ /l~em=ll,0,7a-lt); 1720 (C~ ~C), 49,5 G,4 5,,1 Cjsl 1~TNOs G9,5 I 6,6 5,4 411
2,31 ( d.d., J4,,,4,,= 14,0, J4,,.s.= 10,5, 43-1t); 2,83~[d~ ]4..s.=3,0, 177(I ((:~ o ) ,
5a-11); '-',99 (d.d, 4e-ll); 3,26 (d~ 7e-tl); 7,24--7,37 15ti, m, 3535 (o1.1)
I1 atom )
103--104 1,64 (s, 4.C11~); 2,013nd2.23 (twod.t., /gem~ 12.6/u,l=/u.s= 1650 It+ C), 78,7 7,1 I1.7 C~.d I.,NO 78,8 I 7,1 G,6 974
=2,4. N-CII2); 2,71 (s, 2-CHa); 2,93 (t,, 5-H); 4,10 (t. 1-111; 11;75 (C .o)
5,59 Is. 3-111; 7,22 (d.d. Jg,~o=7.2. J~j0=0.6, 10-tl); 7.36 (dot~ I
JT,8=t~,, 7,2, 8 H ) ; 7,53 (d.t. Jm.=0,6. 9-11); 8.t6 (d.4 7-1t) I
VI 101--102 1,8.1 (d .l~cih, 3 =1,0, 4-CH:J; 1,85--1,99 (rfl N--CH2); 2,45-- 1640 (c.-:c), 78,4 7,9 78,1 [ 8,0 6,5 1 O0
3590 (oil), I
2,57 (m,o-tl); 2,59 (s, 2-Clta); 3,91 (t. Jt.N CH~=2'6~ 1-11); 3620 tO~l) I
4,9!) ~d 1s,6=5,0, 6-111; 5,43 (q., 3-111; 6,99--7,35and7,61--7.73 !
I
(411+ m, Harom)
VII 158--159 1,27 (d. Ji-cJh, 4 =4,5. 4-Ct1:~);I,51 and2.44 (two d.t, Jgem= 13,0 3420 (Oli) 77,5 8,9 6.3 ~_',411~NO 77,,I I 8,8 4,5 9,t
1.,,: 1H:=2,6, N--CIE); 1,83 (d.d, ./gem~l'2,0. J.1,,,,t,,::'-4,3, I
33-11~: i.96--'2.110 (m 5-111; 2.116 IS, 2-Cll:d; 2.12 (i:l, 3e-II);
2,2g Ira.,le-II); 3,54 (t, I-II): '1,89 (d, 1s.6: 6,3, 4-H); 6.89
(d, d~ -r , ,, :: 7,2, 1~..,.:0.6. 10-111; 7,18 (d~t,./z,,=?~,~- 7,2, 8-tl);
7,29 d t, 17,,=0,6, 9-11); 7,62 (d.~ 7-tt)
sodium hydroxide solution, and extracted with benzene. The extract was dried over Na2SO~
and passed through a thin layer of silica gel grade L40/100. After removal of part of the
benzene, the residue was crystallized from a 2:1 mixture of benzene and hexane, The yield
of (V) from (IV) was 89%, and from (III), 76%.
,2,5,6-etrahydr-6-end-hydrxy-2-end-(4-dimethy-,5-methan-2-benzazcin-3-ene
(VI). A. To a suspension of 0.46 g (12 mmoles) of lithium aluminum hydride in i00 ml of
ether was added dropwise 2,66 g (36 mmoles) of tart-butanol, the mixture kept for 30 min,
2.13 g (~0 mmoles) of the 2-benzazocine (V) added, and the mixture stirred for 1 h 30 min.
The mixture was then treated dropwise with i0 ml of water, and the solid filtered off,
washed with ether, and the combined ether solutions dried over Na2SO~. Evaporation of the
ether gave 1.65 g (77%) of (VI).
B. To a solution of 1.70 g (8 mmoles) of the ketone (V) in 50 ml of ether was added
0.3 g (8 mmoles) of lithium aluminum hydride, followed after 15 min by the dropwise addition
of 5 ml of water. Subsequent workup was as described above. Yield, 100%.
,2,3,4,5,6-Hexahydr-6-end-hydrxy-2-end-4-ex-dimethy-,5-methan-2-benzazcine
(VII). A. To a solution of 1.72 g (8 mmoles) of the enamine (VI) in 50 ml of ethanol was
added 0.47 g (13 mmoles) of sodium borohydride, and the mixture boiled for 15 min. After
cooling, it was acidified with acetic acid, evaporated, i0 ml of water added, basified with
solid sodium carbonate, and extracted with ether. After removal of the ether, the residue
was crystallized from a 3:1 mixture of benzene and hexane.
B. To a solution of 0.49 g (2.3 mmoles) of the ketone (V) in 30 ml of ethanol was added
0.28 g (7.8 mmoles) of sodium borohYdride , and the mixture boiled for 15 min. After cooling,
the mixture was worked up as in the preceding preparation, to give 0.4 g (80%) of (VII).

LITERATURE CITED
i. R . R . Bard and M. J. Strauss, J. Org. Chem., 41, 2421 (1976).
2. V . F . Bystrov, Usp. Khimii, 41, 512 (1972).
3. C.J.W. Brooks, G. Eglinton, and D. S. Magrill, J. Chem. Soc., 308 (1961).
4. M. Tichi, Advances in Organic Chemistry [Russian translation], Vol. 5, Mir, Moscow
(1968), 117.
5. N . S . Zefirov, Usp. Khimii, 44, 413 (1975).
6. L . S . Stanishevskii, I. G. Tishchenko, and A. Ya. Guzikov, Zh. Org. Khim., ~, 2612
(1971).

1113
ALKYLATION OF QUINDOLINE AND QUINDOLINE-II-CARBOXYLIC ACID

Yu. A. Degutis and A. B. Ezyarskaite UDC 547.759'832.04

The reaction between quindoline-ll-carboxylic acid and alcohols in acid media

gives the quindoline-ll-carboxylate esters, but quindoline-ll-carboxylic acid
or its hydrocb_loride react with haloalkanes in the presence of basic catalysts
and water binders to give 10-alkylquindoline-ll-carboxylate esters. 10-Alkyl-
quindolines were obtained similarly. Alkylation of l-alkylquindoline-ll-car-
boxylate esters in neutral media affords the quaternary salts.

The possibility of using derivatives of quindoline-ll-carboxylic acid and quindoline in

5he manufacture of components of electrophotographic layers led us to examine synthetic
routes to these compounds. Quindoline-ll-carboxylic acid (I) is one of the most readily ac-
cessible derivatives of quindoline [1-6]. There have been no reports of its alkylation, only
its reaction with methyl iodide to give the quindol~e quaternary salt having been described.
The acid (I) was obtained by reacting isatin with NO-diacetylindoxyl [6], but it was
isolated from the reaction mixture as its potassium salt, which was then converted into the
acid ( i ) o r its hydrochloride.
In order to obtain hitherto unknown derivatives of indolo[3,2-b]quinoline, we examined
the alkylation of the acid (I) and quindoline (II). Heating the acid (I) with ethanol or
1-butanol in the presence of concentrated sulfuric acid gave the quindoline-l!-carboxylate
esters (lllb, c). The reaction of (I) with 1-butanol was carried out in benzene with azeo-
tropic removal of the water formed.

RO______~H ~ X

COOH CCDR
I III a - C

l l l a R=CH3, b'R=C2Hs, c R=p-C4Hg; X=CI, Br

The methyl and ethyl esters of quindoline-ll-carboxylic acid (llla, b) were also obtained by
reacting the acid (I) with alkyl halides in the presence of potassium hydroxide and calcium oxide
in DMF at 20~ The identity of the esters (lllb) obtained by the two methods was establishe
by TLC and the melting point of a mixed sample.

R COOR
~'a-d
IVa R=p-C~Hg, b R=CH2(CH2)sCH~, c R=CH=C~Hs, d I~=CH2CH=CH2; X=C[, Br

Treatment of the acid (I) with alkylating agents in ethyl methyl ketone in the presence
of potassium hydroxide and calcium oxide at 65~ gave both the ester, and products alkylated
at the nitrogen of the five-membered ring, to give the quindolines (IVa-d).
It was established by TLC that even after 20-30 min from the commencement of the reac-
tion, new compounds were formed, and after 3-5 h the alkylation of the acid (I) under these
conditions had proceeded to completion. This method enables 10-substituted quindolinecar-
boxylic acids to be obtained. The resulting esters (IVa-d) are soluble in benzene, toluene,
acetone, ether, chloroform, methylene chloride, dichloroethane, and alcohols.

A. Snechkus Kaunas Polytechnical Institute, Kaunas 233006. Translated from Khimiya

Geterotsiklicheskikh Soedinenii, No. i0, pp. 1375-1379, October, 1986. Original article
submitted January 25, 1985; revision submitted July 5, 1985.

1114 0009-3122/86/2210-1114512.50 9 1987 Plenum Publishing Corporation

 TABLE 1. 10-Alkylquindoline-ll-carboxylate Es-
ters
Corn- mpo *C" Found,, Empirical Calcu- .
pound N, % forrnula ~ated, N, Yield, %

IVa 7t-v'u ,o" 7,8 7,5 58,8

IVb il-' .5,8 C:olqS'~202 6,1 65,5
IVc 157--158,5 8.0 7,9 78,0
IVd 75--76 8,9 C:.H,~X:O: 8,2 76,0

*(IVa, d) from a mixture of ether and light pe-

troleum, and (IVc) from benzene.
%Purified by chromatography on plates with a thin
layer of alumina, eluent a 4:5 mixture of ethyl
methyl ketone and n-hexane, Rf 0.82.

In order to establish the position of the substituent in the 6-benzocarboline system,

benzyl 10-benzylquindoline-ll-carboxylate (IVc) was alkylated with methyl iodide at 20=C.

r+ I-

- C<ItsCH e COOC~12Cetl 5
V

The resulting salt (V) (yield 50%) was soluble in alcohols, but insoluble in ether.
The structures of these quindoline-ll-carboxylic acid derivatives were confirmed by
their elemental analyses and their IR and PMR spectra. Comparing the PKR spectra of the
methyl and ethyl esters (Ilia, b), identical signals are seen for the aromatic protons and
XH (singlet, 9.57 ppm), whereas in the spectrum of the benzyl ester (IVc) this signal is
absent, although two singlets for the benzyl CH2 groups are seen at 5.11 and 5.52 ppm. This
is confirmation of the fact that under these conditions, alkylation of the NIl group in addi-
tion to the ionized carboxyl group takes place.
According to [6], quindoline (II) is obtained on heating the acid (I) at 300=C in paraf-
fin. We have obtained quindoline by decarboxylating (I) at 270=C in diphenyl ether.
The alkylation of quindoline (II) by alkyl halides in solution in ethyl methyl ketone
in the presence of powdered potassium hydroxide and a water-binding agent such as calcium
oxide has been examined.

li I

%7[ a R=C~Hb, b R=p-QHg. c R=CH={CH2)bCH3. d R=CH2C~Hb, e R=CH,CH=CH:;

X=CL Br, [

Alkylation of (II) takes place readily at 70~ being complete in 3-3.5 h. The 10-
alkylquindolines (Via-e) were obtained in high yields. This method thus enables alkyl sub-
stituents to be successfully introduced into the five-membered ring (in the lO-position)
without affecting the more basic nitrogen in the 5-position of the six-membered ring.
The 10-alkylquindolines (Via-e) are readily soluble in ether, acetone, and chloroform,
but they are insoluble in water. Their hydrochlorides (Vlla-e) were obtained by passing
gaseous hydrogen chloride into ether or benzene solutions of the appropriate 10-alkylquin-
doline (Via-e), and the free bases by treating the hydrochlorides (Vlla-e) with sodium car-
bonate solution.
The PF~ spectra of (Vla-e) and (Vlla-e) are in agreement with the structures of the 10-
alkylquindoiines and their hydrochlorides.

1115
 TABLE 2. Yields and Constants of 10-Alkylquindolines (Vlb-d)
and Their Hydrochlorides (Vlla-e)

~om- Found, N, % Empirical Calculated,N, 070

rap, ~ Yield,
)ound formula ~
CI N ci N

Vlb 92,5--94.5 - - 10,O - - 10 9 68,2

VIc 77,5--78,5 8.4 C:2t-I~}N2 67,0
Vld 147,5--149,5 C2~Ht~N2 9,1 67,4
Vlla 266--268 127,4 8,9 CIrHjaCIN=*' I2.6 84,3
VIlb 226--228 11,6 77 CIgH,~CIN.~ 11;4 70 87,2
Vile 203.5--205,5 t0,1 C2:H~BCIN2 10,1 90.5
Vlld 228.5--230.5 9,8 C~HIrCIN2 10,3 92,6
Vile 249--251 12,3 C~ftj:,C1N2 12,0 91,9

*(Vlb-d) were crystallized from ether--light petroleum, and

(Vlla-e) from ethanol-ether.
**Found, %: C 72.7; H 5.6. Calculated, %: C 72.2; H 5.3.

TABLE 3. PMR Spectral Parameters of 10-Alkylquindolines (Vla-

d) and Their Hydrochlorides (Vllb-d)

Corn- 6, ppm (in CDCI~)

pound
N--CHz R CHarom

Via 4,20 (2H, q) 1,33 (3H,t , CHa) 7,13--8,55 (gH, m)

Vlb 4.04 (2H. t) 0.63--2.00 (7H, m, CH.~CH~CH3) 6,93--8.63 (9H, m)
Vlc 4,55 (2H, t) 0,63--2,03 [13H, m, tCH2)~CHa] 7.18--8.60 (9H. m)
VId 4,04 (2H, s) 6,93--~,63 (14H, m)
Vllb 4,48 (2H, t) 0,70--I.93 {7H, m, CH2CI-I2CH~) 7.00--9.21 (9H, m)
VIIr 4 50 (2H, t) 0,63--1.99 [13H. m, (CI-I..)sCH~] 7.o0--9.15 (9H, m)
Vltd* 5,31 (2H, s5 6,5~;--~5,41 {141{, m)

*In CFaCOOH,

EXPERIMENTAL
P ~ spectra were obtained on a Tesla BS-487C spectrometer (80 MHz), internal standard
H~DS, chemical shifts being given on the 6 scale. The course of the reactions was followed,
and the purity of the products established by TLC on Silufol UV-254 plates (eluent, a 4:5
mixture of ethyl methyl ketone and hexane).
The properties of the compounds obtained are given in Tables i and 2, and their PMR
spectra in Table 3.
Quindoline Hydrochloride. A mixture of 5.25 g (20 mmoles) of the acid (I) and 53.0 g
of diphenyl ether was heated for 6 h at 270~ The mixture was cooled to 15~ and 40 ml of
light petroleum added. The solid was filtered off, washed with light petroleum (3 50 ml),
dried, heated in 150 ml of i N hydrochloric acid, and filtered. The filtrate was cooled to
give 4.0 g (78.4%) of quindoline hydrochloride.
Quindoline (II), The acid solution obtained as above was neutralized with sodium car-
bonate to pH 7.5, and extracted with benzene (3 50 ml). The extract was dried with mag-
nesium sulfate, and the solvent removed. Yield, 2.52 g (57.6%); mp 251-252.5~ (from ethan-
ol). Rf 0.61. According to [6], mp 251-252~
Ethyl Quindoline-ll-carboxylate (lllb). A. A mixture of 2.60 g (8.70 mmoles) of quin-
doline-ll-carboxylic acid hydrochloride (or 2.28 g of (I)), 50 ml of ethanol, and 1.5 m_l
(28 mmoles) of concentrated sulfuric acid was boiled under reflux for i0 h. The mixture was
cooled, 50 ml of water and i00 ml of benzene added, and neutralized with aqueous sodium car-
bonate to pH 7.5. The benzene layer was separated and dried over magnesium sulfate to give
0.80 g (31.6%) of product, mp 137.5-139~ Rf 0.87. PMR spectrum (in CDCIa): 1.45 (3H, t,
CHa), 4.51 (4H, q, CHa), 7.07-9.05 (8H, m, CHarom), 9.57 ppm (IH, s, NH). Found, %: N 9.4.
C~sH:,NaO=. Calculated, %: N 9.6.
B. To a solution of 2.60 g (i0 mmoles) of (I) in 20 ml of DMF was added 2.24 g (40
,v~no!es) of potassium hydroxide, 2.24 g (40 mmoles) of calcium oxide, and 10.5 ml (130 mmoles)

1116
of ethyl iodide, and the mixture kept for 15 h. There were then added 60 m! of benzene and
i00 ml of water. The benzene layer was separated, washed with water (2 60 ml), and dried
over magnesium sulfate. The solvent was removed, and the residue recrystallized from hexane
to give i.i0 g (37.9%) of product, mp 136.5-138~ Rf 0.87.
Butyl Quindoline-l!-carboxylate (lllc). A mixture of 1.5 ml (28 mmoies) of concentrated
sulfuric acid, 2.60 g (I0 mmoles) of (I), and 40 ml of n-butanol was heated for 6 h with azeo-
tropic removal of the water formed. The butanol was distilled off, 40 ml of benzene and 50
ml of water added, and the mixture neutralized with aqueous sodium carbonate to pH 7.5. The
benzene layer was dried over magnesium sulfate, and the solvent removed to give 1.30 g (40.9%)
of product, mp 143-144~ (from hexane), Rf 0.88.
Methyl Quindoline-ll-carboxylate (Ilia). To a solution of 2.60 g (I0 mmoles) of (I) in
20 ml of D ~ was added 2.24 g (40 mmoles) of potassium hydroxide, 2.24 g (40 mmoles) of cal-
cium oxide, and 9.7 ml (130 mmoles) of methyl iodide, and the mixture kept for 48 h. To the
mixture were then added 60 ml of benzene and i00 ml of water, and the benzene layer was sep-
arated, washed with water (2 60 ml), and dried over magnesium sulfate. The solvent was re-
moved, and the residue recrystallized from hexane to give 0.90 g (32.6%) of product, mp 152.5-
154~ Rf 0.87. PMR spectrum (in CDCI3): 4.10 (3H, s, CH3), 7.17-9.07 (8H, m, CHarom), 9.57
ppm (IH, s, NH).
Esters of 10-Alkylquindoline-ll-carboxylic Acids (IVa-d). A mixture Of i0 mmoles of (I),
120 ml of ethyl methyl ketone, 30 mmoles of potassium hydroxide, and 30 mmoles of calcium
oxide was stirred with heating for 30-35 min, then cooled to I0-15~ and 50 mmoles of the
appropriate a!kyl halide added gradually (over 1.5 h) with stirring. The reaction was car-
ried out at 65~ for 3-5 h. The mixture was then cooled and filtered, and the solvent and
excess alkylating agent removed in a rotary evaporator. The residue was extracted with ben-
zene (2 40 ml), and the benzene layer separated, washed with water, and dried over magne-
sium sulfate. The solution was concentrated to half its volume, and 30 ml of light petroleum
or hexane added to the residue. PMR spectrum of (IVc) (in CDCI3): 5.11 (2H, s, CH2N), 5.52
(2H, s, CH=O), 6.97-8.57 ppm (18H, m, CHarom) ; (IVd) 4.77-6.35 (i0 H, m, allyl protons),
7.17-8.55 ppm (SH, m, CHarom).
10-Benzyl-ll-benzyloxycarbonylquindolinium Iodide (V). A mixture of 0.50 g (1.2 mmoles)
of the benzyl ester (IVc) and 5.0 ml (80 mmoles) of methyl iodide was kept at 20~ for 24 h.
Excess methyl iodide was distilled off, and the residual crystalline solid dissolved in ethan-
ol and treated with ether (i0 ml) until the product had been completely precipitated. Yield,
45-50%, orange crystals, mp 177-i79~ Found, %: C 63.4; H 4.6; N 4.8. C3:H251N202. Cal-
culated, %: C 63.7; H 4.3; N 4.8.
10-Alkylquindoline Hydrochlorides (Vlla-e). A mixture of 6.3 mmoles of quindoline
hydrochloride, 25 mmoles of powdered potassium hydroxide, 25 mmoles of calcium oxide, and 50
ml of ethyl methyl ketone was heated for 1.5 h at 65~ The mixture was cooled to 10~ 32
mmoles of the alkyl halide added gradually over i h, and the mixture kept at 65~C for 6-6.5
h. It was then cooled and filtered, and the filtrate evaporated in a rotary evaporator un-
til all the solvent and excess alkyl halide had been removed. The residue was extracted with
ether (2 50 ml), and the ether layer separated, washed with water (2 i00 ml), and dried
over magnesium sulfate. It was then filtered, and a stream of hydrogen chloride passed
through the solution. The yellow, pulverulent hydrochloride which separated was filtered
off and washed thoroughly with ether.
lO-Alkylquindolines (VIb-d). The hydrochloride (Vllb-d) (I0 mmoles) was shaken with 5%
aqueous sodium carbonate, and extracted with ether (2 60 ml). The organic layer was sep-
arated, and dried over magnesium sulfate. The ether was removed, and the residue recrystal-
lized from light petroleum (or a mixture of ether and hexane).

LITERATURE CITED
le E. Grandmougin, Rev. chim. ind., 41, 130 (1932).
2. M. E. Giraud, Compt. rend., 89, 104 (1897).
3. E. Nolting and O. R. Steuer, Berichte, 43, 3512 (1910).
4. F. Fichter and S. Rohner, Berichte, 43, 3489 (1910).
5. J. Arm.it and R. Robinson, J. Chem. Soc., 121, 836 (1922).
6. S. J. Holt and V. Petrov, J. Chem. Soc., No. 4, 607 (1947).

1117
REACTION OF AZINIUM CATIONS.
5.* ADDITION OF WATER AND METHANOL TO 1,4-DIAZINIUM CATIONS
IN THE PRESENCE OF BASES. EQUILIBRIUM CONSTANTS AND PMR
SPECTRA OF THE MONO- AND DIADDUCTS

V~ N. Charushs I. V. Kazantseva, M. G. Ponizovskil, UDC 547.86:543.422

L. G. Egorova, E. Oo Sidorov, and O. N. Chupakhin

The PKR+ values and equilibrium constants for the addition of hydroxide ions to
1,4-diazinium ions were determined by spectrophotometry. The ratios i:i and 1:2
of the methoxyl adducts of the 1,4-diazinium ions in the sodium methoxide-meth-
anol-D~ system and the equilibrium constants for the transformations of the mono-
adducts into the diaddition products were determined by PMR spectroscopy,

The progress in the investigation of nucleophilic substitution reactions in the series

of aromatic and azaaromatic compounds is due to the development of theories about the nature,
structure, and characteristics of the products from the addition of nucleophiles to the aro-
matic ring (anionic or neutral o-adducts) and also to the accumulation of quantitative data
on the formation rates of the o-complexes and their stability constants [2]. There are pu b -
lished data [3] on the covalent adducts of some azinium ions with the hydroxide ion, but
the addition of nucleophiles to 1,4-diazinium ions has been studied little. At the same
time, a distinctive feature of heterocycles containing the 1,4-diazine structure and their
protic and quaternary salts is the addition of nucleophilic reagents to the carbon atoms of
both C=N bonds in the pyrazine ring. This effect has been observed in a series of deriva-
tives of pyrazine [4], quinoxaline [5, 6], pyrido[2,3-b]pyrazine [7, 8], pteridine [9, I0],
pyrazino[2,3-e]-l,2,4-triazine [ii], and other heterocycles. Using this property, we used
the addition of 1,3- and 1,4-bifunctional nucleophiles to 1,4-diazinium ions for the annel-
lation of the most varied five- and six-membered carbocycles and heterocycles to the pyra-
zine ring [12, 13]. The general scheme for such cyclizations is largely similar to that for
diaddition reactions; the differences lie in the fact that the second stage is realized by
an intramolecular mechanism and can be regarded as a manifestation of a ring--chain equili-
brium.
H H
N ROH N [ tOE

H H

I X- YH
~.~/ ~\N ~T~X~ ~"N ~,/~Xf~

IV V
X, Y = O~q~, and CH-ac~ve center;R=H, CHs; Ri = alkyl;
R2 = subsfituent, annellated b e n z e n e , or a z a a r o m a t i c ring
In both cases, the first stage is the reversible addition of the nucleophiles at the
a-position of the 1,4-diazinium ions with the formation of adducts (II) and (IV), Reallza-
tion of the second stage, i.e., displacement of the equilibria II ~ III and IV ~ V toward
the diadducts (III) or the cyclic adducts (V), requires the following conditions: a) the
o-adducts (II) and (IV) must be relatively stable and exist at least for the time required
for approach and interaction of the second pair of reaction centers; b) the carbon atom of
the C=N bond must be sufficiently electrophilic to undergo attack by the nucleophile; c)
the process of addition to the C~N bond must be thermodynamically favorable; in particular,

*For Communication 4, see [i].

S. M. Kirov Urals Polytechnical Institute, Sverdlovsk 620002. Translated fromKhimiya Getero~
tsiklicheskikh Soedinenii, No. i0, pp. 1380-1388, October, 1986. Original article submitted
June 17, 1985.
1118 0009-3122/86/2210-ii18512.50 9 1987 Plenum Publishing Corporation
 A
1,0

0,8

0,40'6 I 5-11a 6

0,2
l-la

~L , , , z . A'C._
m-I
50 46 42 38 34 30 26.1000

Fig. 1. The variations in the electronic

spectra of 3-aminocarbonylpyrazinium iodide
(la) in aqueous solutions at 20~ as a func-
tion of the pH: 5.69 [i, 100% cation (la)];
7.49 (2); 7.85 (3); 8.31 (4); 8.86 (5); 9.36
[6, 100% h y d r o x y l complex (IIa)].

cyclizations with dinucleophiles IV ~ V can be realized on the condition of the closure of

unstrained rings. Our previously published papers on the reactions of quaternary 1,4-dia-
zinium salts with nucleophiles and 1,3- and 1,4-dinucleophiles (see [12, 13]) indicate that
substituents in the pyrazine ring, including a condensed benzene or azaaromatic ring, have
a significant effect both on the stability of the a-adducts (II) or (IV) and on the secon-
dary addition of the nucleophiles to the C=N bond and, in particular, on the ring--chain
equilibrium IV $ V.
In order to evaluate the effects of the substitutents on the reactivity of the a and B
position of the pyrazinium salts and also on the stability of their adducts with nucleophiles
quantitatively, in the present work we studied the addition of water and methanol to a series
of 1,4-diazinium quaternary salts (la-l). In the cations (la-l) the structure was varied
by the introduction of substituents into the pyrazine system and by annellation of the ben-
zene ring and also the pyridine and pyrimidine rings. The choice of substituents in the
pyrido[2,3-b]pyrazinium (Ig, h) and pteridinium (li-k) salts was based on their steric and
electronic effects, which direct the quaternization to the pyrazine ring [14]. The choice
of nucleophilic reagents was based on the fact that investigation of the equilibria in an
aqueous medium at various pH values made it possible to characterize the formation of the
pseudobases (II) (R = H) quantitatively, while the use of the sodium methoxide-deuterometh-
anol system is suitable for analysis of the structure of the addition products (II) and (III)
(R = CH3) and determination of their ratios by PMR spectroscopy.
R3

"'V%
x- N-~ . i ~ / - -~.N~
I. X- R~ " I ~ N J % ' N ~! F
R CH~
Ia.b R: ~c,f zg.h

C2H~ CzlI~
xi-k I-/:
a , c - f X=I, b X=BF4;a,c,e,f R'=CH~.b,d R'=C..H~;a,%d,f R2=H, b R2=COOCH3,
e R2=C~H~; a R3=CONH2, b R~=COOCH3, c-e R3=H, t R3=CHs; g RI=N(CH3)=,
h N'= piperidino, i N~=H, j R'=SCH3, k R'= morpholino, i,j R== morpholino,
k R==CH3

The equilibrium between the quaternary azinium salts (I) and the pseudobase (II) (R =
H) is usually described by Eq. (i) and the equilibrium constant K: (2) or by scheme (3) and
the KR+ values (4), which are related to K: by Eq. (5) through the ionic product of water
K~=o [3]:

1119
 TABLE I. Spectral Characteristics of the 1,4zDiazinium Salts
(la-l) in Water at 20~

Cations Hydrated forms

~.max,nm (lg e) pH I Amax,rllll (Ige)

O

la 62 226 (4,10), 280 (3,71) 9,4 229 (4,08), 267 (3,97), 313 (3,66)
Ib 1,5 287 (3 85). 7,0 265 (3,83), 312 (3,85)
Ic 4,0 336 (3,84),. I0,5 301 (3,33), 340 (3,13),a
Id 4,0 338 (3,90) ~ 12,0 309 (3,34), 347 (3,35)D
le 6,0 259 (4,50), 38t (3,99) 10,4 230 (4,48), 372 (3,89)
If 6.3 225 (4,25), 255 (4.52), 347 (3,92) i2,6 229 (4,40), 290 (3,60), 346 (3,51)
227 (4,23), 251 (4.28), 439 (4,20) 13,9 358 (4,26)
6,0 225 (4,42), 446 (4,21) 13,9 358 (4,23)
li 3,0 247 (4,18), 272 (3,85), 445 (3,97)] 9,0 262 (4,35), 311 (3,81)
lj 3,5 242 (4,24), 299 (3,95), 444 (4,04) 9.51227 (4,18), 265 (4.42), 328 (3,98)
Ik 3,5 249 (4.36), 286 (4.03) 9,4 ] 234 (4,30), 323 (4,18)
II 3,4 227, 285, 386, 479 c 9,1 [234, 354c

apublished data [6].

bAnalogous spectra were obtained for N-ethylquinoxolinium
fluoroborate and its hydroxyl complex, which indicates the
absence of an effect from the counter-ion.
CThe e value was not determined on account of the poor stabil-
ity.

i N ~. NH~I.IO R

(i)

la-I ~.~a- Z u~b,c,d,f,k,l

[rl]
K I --
[I][OH-] ' (2)

I+H20:~: II+H+, (3)

[II][H+] (4)
KlV= ' [U '

KR+
KI = - - (5)
KII2O

In order to determine the pKR+ values for the cations (la-Z) we studied the variation
of the electronic absorption spectra for the salts (la-Z) in relation to the pH of their
aqueous solutions and used a method of calculation similar to that in which the ionization
constants of acids pK~ are calculated [15]. As an example, Fig. 1 shows the variation in the
spectra of an equilibrium mixture of 3-aminocarbonylpyrazinium iodide (la) and its covalent
hydration product (lla) (R = H) with variation in the pH of the solution. The spectral char-
acteristics of aqueous solutions of compounds (la-Z) at the same pH values, where only the
cation or only its hydrated forms exist in the solution, are given in Table i. The values
of the constants pKR+exp t calculated from the experimental data are summarized in Table 2.
It should be noted that in a number of cases the diaddition products (III)are formed in
addition to the pseudobases (If) during the hydration of the 1,4-diazinium ions, by virtue
of which the experimental (apparent) values of the constants KR+exp t reflect the overall
contribution from the mono- and diadducts in the addition of water to the cations (1) and,
consequently,

KR+expt= [ H + ] ( [ I I "] + [ I I I ][ ) = K RI, + ( I + ]~ ) (6)

The true PKR+ values will in this case be smaller than pKR+expt by log (i + [III]/[II]),
Since it is difficult to determine the [III]/[II] ratio in the aqueous medium by spectropho-
tometry on account of the overlap of their absorption bands, to calculate the PKR+ values we
measured the ratio of the corresponding methoxyl adducts in CDaOD solution by the PMR method,

1120
 TABLE 2. PKR+ Values and Equilibrium Constants K: for the
Addition of OH- to 1,4-Diazinium Ions (la-Z) in Aqueous Solu-
tions at 20~ and also the Constants K 2 for the Equilibrium
between the Mono- and Diadducts (II) and (III) in Methanol at
20~

Cation ~nmh a l ' Pe x1~+

pt {llI]lllI] PA'R+ Ki, liter/mole K~, l i t e r / m o t e

la 267 8 , 0 4 - 0,06 oil 8,04 1,35 X 106

ib 312 3,22--.0.05 2/5 3,07 1,26X 1011 1,6XlO -2
1c 335 8.62"-0.06 [6] 2/3 8.40
8,67--.0.06 315 8,47 5,01X 105 2,4X 10 -2
;d 338 9.26_+0.05 315 9,06 1,29 X 105 2,4 -2
le 259 8.39--.0,06 o/1 8.39 6,00X t0 ~
If 255 lO,4-O,1 2/5 10,25 8,3X 103 1,6X10 -2
12,5 0/1 12,5 46,8
lI ii 446
445
12,5 0/I 12,5 46,8
1,48 X 109
5.00---0.02 O/l 5,00
Ij 441 7.014- 0,06 0'1 7,01 1,45 10 z
Ik 323 6,74~0,04 1/23 6,72 2,82X 107 1,76 -a
ll 285 6,32 0,03 3,/ 1 5,72 2,82 X 108 1,2 I0 -I

assuming that the transition from water to methanol does not give rise to significant dis-
placements of the equilibrium II ~ III. Such an approach has already been used before to
determine the PKR+ values of the N-methylquinoxalinium ion (Ic) [6].
Our determination of the PKR+ values for a series of quinoxalinium cations (Ic-f) gave
results which agree well with published data. For l-methyl-3-phenylquinoxalinium iodide (ie),
which according to the PMR spectra only forms the monoaddition product, we obtained the val-
ue PKR~ = 8.39, almost coinciding with PKR+ = 8.40 for the cation (Ic) [6] (Table 2).
The variation of the K t values in the series of 1,4-diazinium ions (Table 2) indicates
enhanced stability for the hydroxyl complexes with the introduction of accepting substituents
or with enlargement of the aromatic system. This is consistent with the relationships govern-
ing the formation of anionic G-complexes in the series of polynitro aromatic compounds [2,
16]. Thus, it was not possible to determine the pKR+ value for N-methylpyrazinium iodide
not substituted in the ring on account of the instability of the hydroxyl adduct at 20~ and
the irreversibility of the transformations in the alkaline medium. The introduction of an
accepting amide group at position 3 of the pyrazinium salt (la) confers stability on the
covalent adduct (lla). The effect of the amide group on K: is comparable with the effect of
an anneilated benzene ring (Table 2). Even more stable hydroxyl complexes are formed in the
reactions of cations containing two accepting groups (Ib) or an annellated pyrimidine ring
(li-k) (Table 2). The formation of the adducts (lla-l) is a reversible process; the electron-
ic spectra of the acidified aqueous solutions indicate total regeneration of the cations (la-
;).
The dependence of the electronic spectra of the 1,4-diazinium ions on the pH of the me-
dium makes it possible to control the formation of the hydroxyl complexes, but by this method
it is difficult to determine whether the diaddition products (Iii) are formed in the solution
in addition to the adducts (II) and in what amount. In order to determine the degree to
which the reversible addition of water to the C~N bond of the hydroxyl adducts (II) is rea-
lized and to determine the [III]/[II] ratio we investigated the mono- and diaddition of so-
dium methoxide to 1,4-diazinium ions (la-~) by PM_R spectroscopy. The PMR spectra of the
salts (la-l) are given in Table 3.
The adducts of the 1,4-diazinium ions (la-l) with sodium methoxide are stable at 20~
and are detected in the PMR spectra by the characteristic signals for the protons of the
pyrazine ring in the region of 5.3-5.9 (the absorption of the H a proton at the tetragonal
carbon atom) and 7.0-7.6 ppm (the H 8 proton of the azomethine bond). The adduct of the pter-
idinium salt (lj) with sodium methoxide [compound (IIj)] could not only be recorded in the
P}~ spectra but could also be isolated from the solution in the form of crystals melting at
86-87~ (see the experimental section).
As well as the monoaddition products, the cations (Ib-d, f, k, l) also form the products
from diaddition of methanol (lllb-d, f, k, Z). In the diadducts (III) the H a and H B protons
belong to tetragonal carbon atoms and resonate in the region of 4.4-4.7 ppm (Table 3), free

1121
 TABLE 3. PMR Spectra of the Products from Covalent Addition
of Methanol (lla-j, lllb, c, d, f, k) to Pyrazinium Salts (lla-
k) in a Solution of CDsONa (i M) in CD30D at 20~

Corn- Chemical shifts, 6, ppm (J, Hz)

pound Ha [ H8 7(H __H~/ N--R' otherprotons

IIa 3,25 s 7.53 dd (2-H, 12.5= 1,

12.6= 1,2)
.lib 3.4t q 3.93 s (6H, COOCH3)
(N--CH_o) ;
1,26 t (--CHa)
IIIb 1.10 t (--CHa); 3,78 s (6H, COOCH~)
3,40 q
(N--CH2)
Ilc 3,19 s 6,7--7,5 (4H ofibenzene
rin~)
IIIc 3,14s 6.63s (4H of benzene
ring)
lid 1.27 t (--CHa); 6,7--7,8 (4H of benzene
3.60 q ring)
(N--CH2)
IIId 1.17 t (--CHa): 6.58 s (4H of benzene
3,60 q ring~
(N--CH2)
II e 3,27 s 6,7--7,7 (TH): 7.9--8,3 (2H)
II f 3,18s 6.58 s (2H, 6-H, 8-H); 2,31s
(CH3): 2,43 S tCHz}
IIIf &lSs 6,35 s (2H, 6-H, 8-H); 2,20 s
(CH3); 2,37 s (CHa)
II g 3,22 s 3,08 s [6H, N(CHa)2]; 5,99
(7-H); 7,35 (8-H, 1r,8=8,5)
II h 3,23s 1,3--1,9 m (6H of pipefidine
ring ): 3,2--3,8 m (4H,
N--CH2); 6,15 d (71H); 7,38 d
(8-H, 1r,8=8,5)
lli 1,28 t (--CH;) 3,6--4,1 m (IOH, protons of mor-
pholine ring and N--CH.~);
ko8 s (249
1,22 t (--CH3) 2,41 s (3H, SCHa); 3.2--4,0m
( 10H, protons of morpholine
ring a n d N--CH2)
llk 1,3I t (--CHa) 2.42 s (3H, CHa); 3,4--4,1
( IOH, p.rotom of morpholine
ringand N--CH2)
lllk 1,20t (--CHa) 2,2o s (3H, CHa); 3,4--4,1 m
(t OH, orotom of morpholine
ring an~t N--CH~) r t f
llZ t,33 t (--CH~); 6,8--8,0 m (7H, p o om o ben-
3,75 Cl benzene rings and 3-H)
(N--CH2)

III/ 1,3I t (--CHa); 6,8--7,9 m (6H, protons of

3,65 q benzene nngs
(N--CH2)

aprotons at tetragonal carbon atom.

bThe assignment of the signals may be reversed.

from absorption of the H a protons of the monoadduct. This makes it possible to detect the
formation of the mono- and diadducts clearly. The ratios of the mono- and diadducts [III]/
[II], used for the calculation of Kx and PKR+ , are given in Table 2. The Ka values, which
characterize the equilibrium II ~ III, were also determined (Table 2):

[III]
K== [II] [CH3oH] '
where the concentration of methanol was taken as 0/mole wt. = 2 4 , 7 M.
The obtained values of the K2 constants show that in the series of i,4-diazinium ions
the capacity for diaddition is most characteristic of the pyrazinium salts having an extend-
ed aromatic system on account of the annellation of one or two benzene rings (Ic-f, Z) or
two accepting groups [the cation (Ib)]. It is these salts which enter readily into cycliza-
tion with dinucleophiles [12, 13]. Diaddition appears to a lesser degree in the reaction
of the 2-morpholino-4-methylpteridinium ion (Ik) with methanol at 20=C. The Ka value for the

1122
equilibrium Ilk ~ lllk is an order of magnitude lower than the corresponding constants for
the equilibrium between the mono- and diadducts of quinoxalinium and two orders of magnitude
lower than for the benzoquinoxalinium derivatives (Table 2). In the reactions Of monocyc!ic
and pyrido-annellated pyrazinium salts (la, g, h) with sodium methoxide in methanol the di-
addition products were not detected.
Examination of the characteristics of the pteridinium ions (li-k) in comparison with
the quinoxalinium ions (Ic-f) makes it possible to see that the equilibrium constants K: at
the stage of the formation of the products from the monoaddition of methanol (li-k) are sev-
eral orders of magnitude larger than the corresponding constants K~ for the adducts (llc-f),
whereas the capacity for diaddition in the pteridines (li-k) is appreciably reduced and only
appears in the cation (Ik) with a methyl group at position 4 of the pyrimidine ring. The
morpholine residue at C(~) is conjugated mesomerically in the cations (li, j) with the C(~)
atom and significantly reduces its electrophilicity, thereby exclusing both diaddition and
cyclization with dinucleophiles, whereas the electron-donating effect of the same substituent
at position 2 of the cation (Ik) on the reactivity of the C(6) atom is smaller and allows it
to react with nucleophiles. Thus, the reactions of the cations (li, j) with dinucleophiles
stop at the foruation of the product from addition to C(7) [17], whereas the cations (Ik)
forms cyclic adducts with thioureas and with the anilides of ~-dicarbonyl compounds through
addition at the C(~) and C(7) atoms, i.e., derivatives of 5,Sa,6,7,Sa,9-hexahydro-8H-imidazo-
[4,5-g]- and 5,5a,7,8,8a,9-hexahydro-6H-pyrrolo[2,3-d]pteridine, respectively [18].

CI-I. CH. } r II_

~ N
N "" "'~ :k fIN

""N & ~ N / ' k " N//" NII2 (/w / /- ,

0 "-~/ I CIzH5 BF 4- oO CzH 5

Thus, the quantitative data characterizing the equilibrium processes in the formation
of the mono- and diadducts of 1,4-diazinium ions with methanol make it possible to understand
the differences in their transformations under the influence of bifunctional nucleophiles.
They may prove useful for evaluating the possibility of the participation of pyrazinium salts
in cyclizations with dinucleophiles.

EXPERIMENTAL
The electronic spectra of aqueous solutions of the salts (Ia-~) were investigated on a
Specord UV-vis spectrometer at 20=C by monitoring the pH of the medium with an EV-74 univer-
sal ionometer. The method described in [15] was used to calculate the pKR+expt values. The
P ~ spectra of solutions of the salts (Ia-l) (c = 0.45 M) in a solution of sodium methoxide
(c = 1 M) in methanol-D~ were recorded at 20=C on a Bruker WP-80 spectrometer at 80.13 MHz
with ~iS as internal standard.
The pyrazinium (Ib) [19], quinoxalinium (Ic-f) [20], pyrido[2,3-b]pyrazinium (Ig, h)
[21], and pteridinium (Ii) [14] quaternary salts were obtained by the previously described
methods.
3-Aminocarbonyl-l-methTlpyrazinium Iodide (Ia). To 25 g (0.2 mole) of aminocarbonyl-
pyrazine we added 200 ml of methyl iodide and 70 ml of DMSO. The solution was kept at 50=C
for 24 h. The precipitate was filtered off and washed with ethanol and ether. The yield
was 53 g (98%). The product formed orange plates (from ethanol); mp 194-198=C. PMI~ spec-
trum (DMSO-D6): 4.48 (3H, s, N--CHs); 8.28 and 8.63 (2H, bs, NHa); 9.3-9.7 ppm (3H, protons
of pyrazine ring). Found, %: C 27.0; H 2.9; N. 16.1 C6HeIN~O. Calculated, %: C 27.2;
H 3.0; N 15.9.
2-Methylthio-4-morpholinopteridine was obtained in three stages from 4,5-diamino-2,6-
dimercaptopyrimidine [22].
Stage i. 4,5-Diamino-2,6-dimethylthiopyrimidine. To a solution of 5 g (29 mmoles) of
4,5-diamino-2,6-dimercaptopyrimidine and 2 g (50 mmoles) of sodium hydroxide in 30 ml we
added 6 ml of ethanol. We then added dropwise with stirring 7.2 g (57 mmoles, 5.4 ml) of
dimethyl sulfate. Spontaneous heating of the reaction mass was observed, and a precipitate
was formed. The precipitate was filtered off, washed with ethanol, dried in air, and re-
crystallized from ethanol. The yield was 3.9 g (67%); mp 193-194~ Found, %: C 35.8;
H 5.0; N 27.4; S 31.9. C6H,oN~Sa. Calculated, %: C 35.6; H 5.0 N 27.7; S 31.7.

1123
 Stage 2. 2,4-Dimethylthiopteridine. A 13-g sample (64.3 mmoles) of 4,5-diamino-2,6 ~
thiomethylpyrimidine was suspended in 120 ml of ethanol and heated to 70~ A boiling solu-
tion of i0 ml of 40% aqueous glyoxal in 16 ml of ethanol was added in portions (with froth-
ing). After a few minutes a precipitate began to separate from the solution. The mixture
was heated for a further 30 min and cooled. The precipitate was filtered off and recrystal-
lized from a i:i mixture of ethanol and high-boiling petroleum ether. The yield was i0 g
(69%). P ~ spectrum (deuterochloroform): 2.65 (3H, s, SCH3); 2.69 (3H, s, SCH3); 8.73 (IH,
d, 6-11, 3J6,7=1.9 Hz); 9.06 ppm (iH, d, 7-H). Found %: C 42.7; H 3.8; N 25.0; S 28.7.
CsHaN~S~: Calculated, %: C 42~ H 3.6; N 25.0; S 28.5.
Stase 3. 2-Methylthio-4-morpholinopteridine. A mixture of 2 g (8.9 mmoles) of 2,4-
dimethylthiopteridine and 8 ml of morpholine in 50 ml of ethanol was boiled for 24 h. The
precipitate was then filtered off. The yield was 2 g (85%); mp 185-187~ (from petroleum
ether, bp 80-I000C). PMR spectrum (deuterochloroform): 2.62 (3H, s, SCH~); 3.86 and 4.48
(SH, m, morpholino); 8,49 (IH, d, 6-H, 3J6,7 = 2.0 Hz); 8.83 ppm (IH, d, 7-H). Found, %:
C 50.0; H 4.9; N 26.3; S 12.2. C:IH~3NbOS. Calculated, %: C 50.2; H 5.0; N 26.3; S 12.2.
2-Methylthio-4-morpholino-4-ethylpter%dinium Fluoroborate (lj). To a suspension of
1.5 g (5.7 mmoles) of 2-methylthio-4-morpholinopteridinium [21] in 7 ml of dry chloroform we
added a solution of 2.2 g (11.4 mmoles) of triethyloxonium fluor0borate in 8 ml of dry chloro-
form. The mixture was heated to boiling and kept for i h. The precipitate represented a
mixture of the fluroborates of (lj) and 2-methylthio-4-morpholino-l-ethylpteridinium, as
follows from the P ~ spectra and comparison with the published [14] characteristics of the
isomeric pteridinium salts. The mixture was separated by fractional crystallization from
absolute ethanol, giving i.i g (51%) of the salt (lj); mp 180-183=C. PMR spectrum (deuter-
ochloroform): 1.69 (3H, t, N=CH3); 2.65 (3H, s, SCH3); 3.8-4.7 (8H, m, protons of morpho-
line ring); 4.90 (2H, q, N--CH=); 8.92 (IH, d, 7-H); 9.00 ppm (IH, d, 6-H, ~J~,7 =3.5 Hz).
Found, %: C 41.1; H 4.7; N 18.2. C:~HIsBF4NbOS. Calculated, %: C 41.2; H 4.8; N 18,5.
2-Methylthio-4-morpholino-l-ethylpteridinium fluoroborate was obtained with a yield of 0.6
g (28%); mp 135-139~ PMR spectrum (deuterochloroform): 1.49 (3H, t, CHs); 2.76 (3H, s,
SCH3); 3.98 (4H, m, protons of morpholine ring); 4.37 (2H, m, protons of morpholine ring);
4.66 (2H, q,N--CH2); 5.02 (2H, m, protonsofmorpholinering); 8.82 (IH, d, 7-11, sJ6,7=l.8Hz);
8.90 ppm (IH, d, 6-H). Found, %: C 41.3; H 4.8; N 18.0. C:3HIsBF~NbOS. Calcuiated, %:
C 41.3; H 4.8; N 18.5.
2_Methylthio_4-morpholino-7-methoxy-8-ethyl-7,8-dihydropteridine (IIj). A 0.4-g sample
(i.i mmoles) of (Ij) was suspended in 2.8 ml of a solution of sodium methoxide in methanol
and was stirred until the initial salt had completely dissolved. This took place with the
spontaneous release of heat and was accompanied by the simultaneous formation of a colorless
precipitate of (IIj). The precipitate was filtered off, washed with water and with methan-
ol, and dried in air, The yield was 0.3 g (89%); mp 86-87~ P ~ spectrum (deuterochloro-
form): 1.29 (3H, t, CH3); 2.48 (3H, s, SCH3); 3.25 (3H, s, OCH3); 3.40-4.30 (8H, m, H of
morpho!ine ring); 5.45 (IH, d, 7-H, 3J~,7 = 3.0 Hz); 7.15 ppm (IH, d, 6-H). Found, %: C 51.6;
H 6.6; N 21.8; S i0.0. C:4H2:NbS02. Calculated, %: C 52.0; H 6.6; N 21.7; S 9.9.
4-Methyl-2-morpholinopteridine was obtained in three stages from 4-amino-5-nitro-6-
methyl-2-chloropyrimidine [23].
Stage i. 4-Amino-5-nitro-6-methyl-2-morpholinopyrimidine$ A mixture of 7 g (37 mmoles)
of 4-amino-5-nitro-6-methyl-2-chloropyrimidine and i0 ml of morpholine in 50 ml of ethanol
was boiled for 45 min. The mixture was then Cooled, and the precipitate was filtered off.
The yield was 5.2 g (62%). The product formed yellow needles (from ethanol); mp 179-180~
P ~ spectrum (deuterochloroform): 2.69 (3H, s, CH3); 3.6-4.1 ppm (SH, m, protons of mor-
pholine ring). Found, %: C 45.4; H 5.6. CgH~3NbO3. Calculated, %: C 45.2; H 5.5.
Stage 2. 4,5-Diamino-6-meChyl-2-morpholinopyrimidine. A 5-g sample (21 mmoles) of 4-
amino-5-nitro-6-methyl-2-morpholinopyrimidine was dissolved in 200 ml of acetone, and 25 g
of sodium bicarbonate in 200 ml of water was added to the solution with stirring. Then 25
g of sodium dithionite was added over 15 min. The mixture was stirred for 5 min, and 500
ml of water was added. The solution was concentrated to 300 ml, and the precipitate was
filtered off and recrystallized from ethyl acetate. The yield was 1.3 g (30%); mp 166-167~
P ~ spectrum (DMSO-D~): 2.08 (3H, s, CH3); 3.3-3.9 (SH, m, protons of morpholine ring);
5.97 ppm (2H, bs, NH=). Found, %: C 51.6; H 7.2. CgH:~NbO. Calculated, %: C 51.7; H 7.2.
Stage 3. 4-Methyl-2-morpholinopteridine. A 1.2-g sample (5.7 mmoles) of 4,5-diamino-
6-methyl-2-morpholinopyrimidine was dissolved in 70 ml of ethanol, and i.i g (8.8 mmoles) of

1124
po~yglyoxal added to the solution. The mixture was boiled for 40 min. The ethanol was evap-
orated to dryness, and the solid residue was recrystallized from ethanol. The yield was
0.75 g (60%); bp 125~ PMR spectrum (deuterochloroform): 2.91 (3H, s, CH~); 3.60-4.30 (8H,
m, protons of morpholine ring); 8.53 (IH, d, 6-H, 3J6,7 = 2.0 Hz), 8.86 ppm (IH, d, 7-H).
Found, %: C 57.0; H 5.8, C~H~3NsO. Calculated, %: C 57.1; H 5.7.
4-Methyl-2-morpholino-8-ethylpteridinium Fluoroborate (Ik). To a suspension of 0.5 g
(2.2 mmoies) of 4-methyl-2-morpholinopteridine in 3 ml of methylene chloride we added 0.62 g
(3.3 mmoles) of triethyloxonium fluoroborate in 2 ml of methylene chloride. When the initial
salt had dissolved, the mixture was kept for 30 min and cooled, and the precipitate was fil-
tered off. The yield was 0.5 g (67%); mp 181-184~ (from ethanol). PMR spectrum (DMSO-D6):
1.50 (3H, t, CH3); 2.88 (3H, s, CH3); 3.60-4.30 (8H, m, protons of morpholine ring); 4.73
(2H, q, N-CH2); 8.97 (IH, d, 6-H, 3J~,7 = 3.5 Hz); 9.21 ppm (IH, d, 7-H). Found, %: C 44.8;
H 5.1; N 20.1. C:~HIsBF~NsO. Calculated, %: C 45.0; H 5.2; N 20.2.
!-Ethylbenzoquinoxalinium Fluoroborate (If). To a suspension of 0.8 g (4.4 mmoles) of
benzoquinoxaline in 15 ml of methylene chloride we added a solution of 1.25 g (6.6 mmoles)
of triethyloxonoium fluoroborate. The mixture was stirred for i0 min until the initial sub-
stances had completely dissolved. The solution was kept at 20~ for 1 h, and the precipitatec
salt (If) was filtered off, washed with ethanol and with ether, dried in air, and recrystal-
iized from ethanol. The yield was 1 g (76%); mp 183-186~ Found, %: C 56.5; H 4.4.
C:~H:3BF~N2. Calculated, %: C 56.8; H 4.4.

LITERATURE CITED
I. V. N. Charushin, G. M. Petrova, 0. N. Chupakhin, E. 0. Sidorov, G. G. Aleksandrov, A. I.
Chernyshev, N. A. Klyuev, and N. N. Sorokin, Khim. Geterotsik!. Soedin, No. 3, 389 (1986}
2. F. Terrier, Chem. Rev., 82, 77 (1982).
3. J. W. Bunting, Heterocycles, 14, 2015 (1980).
4. A. K. Sheinkman, Kh. Ya. Lopatinskaya, N. A. Klyuev, and T. K. Torosyan, Khim. Geterot-
sikl. Soedin., No. 2, 234 (1980).
5. J. A. Zoltewicz, T. M. Oestreich, J. K. 0'Halloran, and L. S. Helmick, J. Org. Chem.,
38, 1949 (1973).
6. J. W. Bunting and M. G. Meathrel, Can. J. Chem., 50, 919 (1972).
7. D. Boutte, G. Quequiner, and P. C. Pastour, Compt. Rend., 273, 1529 (1971).
8. 0. N. Chupakhin, V. N. Charushin, I. Ya. Postovskii, N. A. Klyuev, and E. N. Istratov,
Zh. 0bshch. Khim., 14, 431 (1978).
9. A. Albert and J. J. McCormack, J. Chem. Soc., Perkin I, 2630 (1973).
i0. A. Nagel, H. C. van der Plas, and A. vanVeldhuizen, Rec. Tray. Chim., 94, 95 (1975).
ii~ C. C. Tzeng, and P. J. Panzica, J. Heterocycl. Chem., 20, 1123 (1983).
i2. V. N. Charushin and O. N. Chupakhin, Usp. Khim., No. I0, 1648 (1984).
13. V. N. Charushin, M. G. Ponizovskii, and O. N. Chupakhin, Khim. Geterotsikl. Soedin.,
No. 8, I011 (1985).
14. I. V. Kazantseva, V. N. Charushin, 0. N. Chupakhin, A. I. Chernyshev, and S. E. Esipov,
Khim. Geterotsikl. Soedin., No. 9, 1257 (1985).
i5. A. Albert and E. Sergent, lonization Constants of Acids and Bases, Wiley (1962)~
16. G. A. Artamkina, N. P. Egorov, and I. P. Beletskaya, Chem. Rev., 82, 427 (1982).
17. V. N. Charushin, I. V. Kazantseva and L. G. Egorova, in: Advances in the Chemistry of
Azines [in Russian], Sverdlovsk (1985), p. 146.
18. I. V. Kazantseva, V. G. Baklykov, V. N. Charushin, and 0. N. Chupakhin, Khim. Getero-
tsikl. Soedin.,No. 3, 420 (1986).
i9. V. N. Charushin, V. G. Baklykov, O. N. Chupakhin, N. N. Vereshchagina, L. M. Naumova,
and N. N. Sorokin, Khim. Geterotsikl. Soedin., No. 12, 1684 (1983).
20. V. N. Charushin, M. G. Ponizovskii, O. N. Chupakhin, A. I. Rezvukhin, Go M. Petrova,
and Yu. A. Efremov, Khim. Geterotsikl. Soedin., No. ii, 1543 (1981).
21. I. Ya. Postovskii, V. N. Charushin, Go A. Mikrushina, S. K. Kotovskaya, A. S. Barybin,
0. N. Chupakhin, and A. I. Chernyshchev, Khim. Pharm. Zh., No, ii, 49 (1982).
22. A. G. Beaman, J. Am. Chem. Soc., 83, 4038 (1961).
23. S. Gabriel and 7. Colman, Berichte, 34, 1246 (1901).

1125
HETEROCYCLIC ANALOGS OF PLEIADIENE.
59.* REACTION OF I-ACETONYL- AND I-PHENACYLPERIMIDINIUM
SALTS WITH HYDRAZINE AND AMMONIUM ACETATE

V~ V. Dal'nikovskaya, T. A, Kuz'menko, and A. F. Pozharskii UDC 547.856.7'873:

543.422

l-Acetonyl-3-methyl- and l-methyl-3-phenacylperimidinium salts react with hydra-

zine hydrate to give tetrahydro-derivatives of the hitherto unknown heterocy-
clic system 1,2,4-triazino[4,3-a]perimidine. On boiling in acetic acid with
ammonium acetate, 3-phenacyl- and 3-(2',4'-dimethyl)phenacyl-l-methylperidinium
salts are converted into l-methylamino-8-(4-phenylimidazol-l-yl)naphthalenes,
with small amounts of ll-methylimidazo[l,2-a]perimidines also being formed.

The previously-synthesized [2] l-acetonyl- and l-phenacylperimidinium salts (i) contain

a carbonyl group and a highly electron-deficient u-carbon atom in the ring, in a favorable
position for intramolecular cyclizations. To examine the feasibility of such reactions and
the synthesis of condensed hetero-systems derived from perimidine, we have investigated the
reactions of the salts (I) with hydrazine and ammonium acetate.
Salts (la-d) (other salts were not used in the reaction) react with hydrazine hydrate
at room temperature to give even after 30 min 70-96% yields of tetrahydro-derivatives of the
hitherto unknown heterocyclic system 1,2,4-triazino[4,3-a]perimidine (II). A similar reac-
tion has been described for 2-phenylacylquinolinium and l-phenacy!-3-cyanopyridinium salts
[3], but in these instances cyclization takes place with heating. The higher reactivity of
the perimidinium salts may be due to the high positive charge at C(=) in these compounds [4].
0
II If... ~ R

@ -- >=i
(x /~--N H ( '~--N CIO 4-
~_. :7 f "~_._// I
CR~ cH a CH 3

~a-f n.a-d maob

l - - I I I a R=CH~: b R=C6Hb; c R=C~H4NOrp;d R=C6H4Br-p;e R=CGH4CI-p;f R=
=CsH4OCH3-p; g R=2,q-C6Ha(CHa)=

The structures of (lla-d) were proved by their elemental analyses and IR and PM~ spec-
troscopy. A characteristic feature of the PMR spectra is the nonequivalence of the CH= pro-
tons, these being seen as two doublets centered at 3.92 and 4.20 ppm for (lla) and 4.42 and
4.80 ppm for (llb), indicating that the hydrogenated triazine ring is nonplanar. The proton
at the ~-carbon in (lla) appears as a singlet at 5.17 ppm, whereas in (lib) it is weakly spli
into a doublet (5.45 ppm, J = 1.8 Hz), apparently as a result of spin coupling with the
neighboring NH proton [in (lib) the latter is also broadened as compared with the NH proton
in (lla)].
It was of interest to dehydrogenate (II) in order to obtain the heteroaromatic 1,2,4-
triazino[4,3-a]perimidinium cation (III). In the cases of (lla) and (llb), we found that
dehydrogenation proceeds readily on treatment with an excess of trityl perchlorate in methyl-
ene chloride. The products were bright yellow, extremely hygroscopic crystalline solids,
which on the basis of their IR spectra and elemental analyses, were assigned the structures
of cations (Ilia) and (IIIb). Specifically, the IR spectra of these compounds contained no
absorption above 3100 cm-~. It should be emphasized that the color of the salts (IIIa, b)
in itself is an indication of the formation of the perimidinium ring. Perimidines and peri-

*For No. 58, see [i].

M. A. Suslov Rostov State University 344090. Research Institute for Physical and Organ-
ic Chemistry, Rostov-on-Don 344090. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 10, pp. 1389-1395, October, 1986. Original article submitted June 17, 1985.

1126 0009-3122/86/2210-1126512.50 9 1987 Plenum Publishing Corporation

midinium salts are yellow in color, whereas 2,3-dihydroperimidines are colorless. Hence,
the change from the colorless (II) to the yellow salts (I!I) indicates aromatization of the
perimidine ring.
It is reported in the literature [5] that N-phenacyl salts of nitrogen heterocycles
react in two ways with ammonium acetate. One route, typical of quinolines [5] and isoquino-
iines [6], leads to the formation of dihydroimidazo[l,2-a]quinolines and imidazo[l,2-b]iso-
quinolines, such as (V). The other route, characteristic of benzimidazoles [7], gives 1,4-
diarylimidazoles (VIII). Both reactions are readily understood when the possible modes of
stabilization of the key intermediates (IV) and (VII), which contain hydride-mobile hydrogen
atoms, are considered. In the absence of an external oxidant, the only logical mode of stab-
ilization of the intermediate (IV) is by hydride rearrangement to (V), which has aromatized
benzene and imidazole rings. The intermediate (VII) is stabilized by fission of the C--N bond,
but the result is the same, with the imidazole ring being formed in addition to the benzene
ring. It is easy to see that the transfer of a hydride ion in the latter case, for example
to the C=C double bond of the dihydroimidazole ring, would be energetically less favored.
It must be borne in mind that in the presence of an external oxidant, or as a result of hy-
dride disproportionation these reactions could theoretically also lead to the formation of
fully aromatized imidazo[l,2-a]quinolines or imidazo[l,2-a]benzimidazoles, such as (VI).
Compounds of this type have been obtained in small amounts only with quinoline and isoquino-
line [5]. If the reaction is carried out in the presence of an oxidant such as ferric chlor-
ide, however, (VI) becomes the main reaction product [8].
It H

~" ~'~'N"" ~NH N N

'~_.~ E I I I
IV g VI

/At j~r

~(;... N.. N_7-ti ,~.... zN :N

t I
VII CH.,s VIII CH3

Since perimidines and perimidinium salts display features of both azines and azoles in
their reactions with nucleophiles [4], it is difficult to predict their mode of reaction
with ammonium acetate. We have found that the salt (la) fails to react with ammonium acetate
even on prolonged boiling in acetic acid, and the l-methyl-3-phenacylperimidinium salts (Ib-
f) react extremely slowly. For example, after boiling (Ib) for 18 h with ammonium acetate
in acetic acid, 36% of the starting salt was recovered. The reaction products isolated in
this instance were the previously-described [9] ll-methylimidazo[l,2-a] perimidine (XIb) (13%)
and l-methylamino-8-(4-phenylimidazol-l-yl)naphthalene (Xb) (34%). The IR spectrum of (Xb)
showed no absorption for the carbonyl group, but absorption for the free NH group at 3480
cm -I (in chloroform) was present. The PMR and mass spectral data were also in agreement with
the structure (Xb). For example, in the PMR spectrum of (Xb) in deuterochloroform, in the
aromatic proton region, a multiplet at 7.75 ppm and two quartets at 6.57 and 6.35 ppm, char-
acteristic of the 2-H and 7-H protons in 1,8-diaminonaphthalenes [i0], were present. The
signal for the N-methyl group at 2.12 ppm is split to a doublet by spin coupling with the NH
Froton (J = 4 Hz), and the broadened NH signal is seen at 3.60 ppm. Under double resonance
conditions at the absorption frequency of the NH proton, the latter signal disappears, and
the methyl signal becomes a singlet (see scheme on following page).
To contrast to (Ib), the analogous salts (Ic-f) give no naphthalenes (X) on heating
with ammonium acetate, only the imidazo[l,2a]perimidines (Xlc-f) being isolated in yields
of 28-45 %. Attention is drawn to the fact that salts (Ic-f) and the corresponding inter-
mediates (IXc-f) contain electron-acceptor groups in the para-position of the phenacyl sub-
stituent, which facilitate the reduction of the double bonds conjugated therewith (see, for
example, the report on the polarographic reduction of substituted azobenzenes [II]). All
these groups possess positive MacDaniel--Brown On-constants, namely +0.71 (NO=), +0.39 (Br),
+0.37 (CI), and +0.12 (OCH3) [12]. These results show indirectly that the principal mode

1127
 Wo
-II
~H.,~r --R /R

~-'--N
Ac0NH. ---N /~H2 -H 0 ): '\/// NH
I b-g
, --N H
) ! , !
CH 3 CH~

:xb-g

_ . _ ,_ + 5_-_(
CH 3 CH3 CH~
xb.g ~ b-g xl:
of stabilization of the intermediates (IXc-f) is by hydride disproportionation, whereas in
the case of (IXb) stabilization with opening of the 2,3-dihydroperimidine ring predominates.
A second product of hydride disproportionation should evidently be the corresponding imidazo-
iidino[i,2-a]-2,3-dihydroperimidine, but there can be little doubt [4] that such compounds
would be highly susceptible to oxidation, and would be chemically unstable. This probably
also explains the fact that the reactions of salts (Ib-f) with ammonium acetate result in
considerable resinification and the formation of a complex mixture of difficulty-separable
compounds, each of which is presen t in small amounts. It is clear that the intermediate
(IXc), which has a p-nitro-group, should show the greatest tendency to undergo hydride dis-
proportionation. In fact, salt (Ic) gave the highest yields (45%) of the corresponding imi-
dazo[l,2-a]perimidine (Xlc).
When we had established the factors described above, it appeared to us of interest to
use them to predict the course of the reaction of some new perimidinium salt with ammonium
acetate. It was natural to select for this purpose a salt for which the reaction would lead
to the preferential formation of a naphthalene derivative (X). Such a salt should contain
electron-donor substituents in the phenacyl moiety. We decided on the salt (Ig), which con-
tains methyl groups in the 2- and 4-positions of the phenacyl substituent. In accordance
with expectations, the principal product of the reaction of (ig) with ammonium acetate was
the aminonaphthalene (Xg), obtained in 40% yield. The second product (12%) was the imidazo-
[l,2-a]perimidine (Xlg).
We also obtained (Xlc-g) by direct synthesis by the reaction Between 2-amino-l-methyl-
perimidine and the appropriate phenacyl bromides in the presence of sodium carbonate, as
described in [9]. Under these conditions, however, p-nitrophenacyl bromide gave the yield
(XII), which contains two p-nitrophenacyl residues. Compound (Xlc) was obtained by reacting
2-amino-l-methylperimidine with p-nitrophenacyl bromide in a ratio of 2:1, in acetone.
It is rather difficult to understand why the perimidinium salts (I) react with ammonium
acetate with greater difficulty than quinlinium and isoquinolinium salts, although the latter
are more T-deficient. A possible explanation is as follows. The acetic acid--ammonium ace-
tate system contains mainly two nucleophiles, the acetoxy ion and ammonia. The reaction
(!) ~ (X) and (XI) requires ammonia, but its concentration in the mixture is of course much
ies than the concentration of acetoxy ions, the latter being much weaker nualeophiles
than ammonia. In the case of the relatively low-n-deficient quinolinium and isoquinolinium
salts, the acetoxy ions are scarcely bonded to them at all, thus facilitating their reaction
with ammonia. On the other hand, the highly T-deficient perimidinium salts are able to react
with AcO- ions to form covalent adducts (XIII). This results in a considerable shift of the
equilibrium shown below to the right, as a result of which the concentration of free perimi-
dinium cations in the mixture decreases sharply, and their reaction with ammonia is
retarded.

COR COR COR

Cg~ CIt 3 CtI 3