Chemistry of Hetero Aromatics

Section 1-Chemistry of Heteroaromatics
R2 O SPh R2 O
R2 O
2,3-shift C SPh
CH2 SPh
NHAc NHAc N
R1 R1 R1 Ac
O O
BF3.OEt2
NEt3 HO
O H
OCH2Ph PhCH2O
CN
Ph N
N X
∆ Ph N
X
Ph N Ph N
Section one - Chemistry of Heteroaromatics
Literature of Heterocyclic Chemistry
1. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1984, Pergamon, Vol. 1-8
2. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1996, Pergamon, Vol. 1-11
3. "The Chemistry of Heterocyclic Compounds," Weissberger/Taylor, >50 volumes.
4. "Advances in Heterocyclic Chemistry," Katritzky/Boulton, (Vol. 40, p. 1 has review

by Katritzky which lists heterocyclic reviews).
_____________________________________________________________
Nomenclature of Heterocycles
1. "Nomenclature of Heterocycles" by McNaught/Smith in "Comprehensive Heterocyclic Chem."

1984, Vol. 1, Chap. 2.
2. "Revision of the Extended Hantzsch-Widman System of Nomenclature for Heteromonocycles,"

Pure Appl. Chem. 1983, 55, 409 [IUPAC].
3. McNaught, in Adv. Heterocycl. Chem. 1976, 20, 175.
4. "Nomenclature of Organic Chemistry" (IUPAC) (The "Blue Book") Pergamon, 1979. Has
heterocyclic section.
5. Chemical Abstract Service, "Index Guide" 1982-1986; Appendix IV

"Chemical Substance Index Names"
•includes heterocycles
• generally same as IUPAC, but many exceptions
6. Chemical Abstract service, "Ring Index"
1
Accepted Trivial Names (partial list)

1 1 1 1 9 10 1
7 8 8 9 1
S O O 2 1 O S
2 2 2
2
O
O O
Thiophene Furan Pyran Isobenzofuran Chromene Xanthene Phenoxathiin
(2H-shown) (2H-shown)
1 1 1
H H H N N N
N1 N1 N1 N1 2 2 2
2 2 2 N2
N3
N N
2H-Pyrrole Pyrrole Imidazole Pyrazole Pyridine Pyrazine Pyrimidine
7
1 7 H 6 H
8 1 7 H 1 5
N 1 N1 N
N2 2 N1 N1 N
2 N2 8
NH 2 2
N N 4 N
4 3 3 3 3 3 9
4
Pyridazine Indolizine Isoindole 3H-Indole Indole 1H-Indazole Purine
9 8 1 8 1 8 8 1 1
1 8
1 2 N N N N
N 2 N2
N 3 N3 4
5
4 N
4H-Quinolizine Isoquinoline Quinoline Phthalazine Naphthyridine Quinoxaline
(1,8-shown)
8 1 8 1 8 1 9
N 8 1 H
N 2 N N N 8 1
N 9 N
N3 5 N
3
N 4a
Quinazoline Cinnoline Pteridine 4aH-carbazole Carbazole
1
1 8 9 1 N
H
1 N N3 10
8 1 10
9 N 4 4
N 10 9 4
6 N 7 5
5 4 7
N 5 N
4 6
6
β-Carboline Phenanthridine Acridine Perimidine Phenanthroline
9 10 1 H 1 (1,7-shown)
1 N
N 10
S O1 O1
2
6 5 4
N 5 4
N2 5 N N 2
N S
Phenazine Isothiazole Phenothiazine Isoxazole Furazan
2
Dictionary of Drugs
OMe
N H
C N NCH2CH=CHPh CONHCH2CH(OH)CH2NEt2
N N
H H Ph
Cinprazole--Antiulcerogenic agent Eproxindine--Antiarrhythmic agent
Cl MeNHCH2
N
CO2Me
N
Me
S
Clopidogrel--Antithrombotic agent Manazodil--Vasodilator
Me
NHNH2 N
N H 2C
N N
NHNH2
S
Dihydralazine--Antihypertensive agent Methdilazine--Antihistamine
Me N
N Me N
N N OH
N CH2 C CH2 O Cl
MeO OMe tBu
Epirizole--Antiflammatory agent Vibunazole--Antiviral agent
Elks, J.; Ganellin, C. R. Dictionary of Drugs, Chapman and Hall, 1990, N.Y.
3
Nizatidine--antagonist of histamine at H-2 receptors

S CO2Et
Me2NCH2CNH2 + BrCH2COCO2Et N
Me2NCH2 S
CH2S(CH2)2NH2 CH2S(CH2)2 HN H
N N
MeHN NO2
Me2NCH2 S Me2NCH2 S
Lednicer, D.; Mitscher, L. A.; The Organic Chemistry of Drug
Synthesis Wiley-Interscience: New York; Vols 1-4, 1990
Pefloxacin--antimicrobial agent with oral activity

OH
EtO2C CO2Et
F F F CO2Et
Cl NH2 Cl N Cl N
O O
F CO2Et F CO2H
Cl N N N
Et Et
N
Me
Acrivastine--a nonsedating H-1 antihistamine Me
Me
Br N
Br N Br Br N
O N
Me Me
CHO N N
HO2C
N N
4
1. Trivial Names
No structural information, often based on origin.
CH3
3-Picoline (from coal tar)
N Latin picatas = tarry
(systematic name = 3-methylpyridine)
Currently over 60 trivial names accepted by IUPAC for use as

"parents" in systematic nomenclature. (See McNaught/Smith for full list.)
Examples: Pyrrole Furan Thiophene

N O S
H
2. Extended Hantzsch-Widman Nomenclature
use for less than10-membered rings
stem and prefix

indicates which heteroatoms are present
indicates ring O = oxa-

size and degree
of unsaturation. S = thia- drop "a" ending when
followed by a vowel.
N = aza-
P = phospha-
Priority of heteroatoms
for numbering purposes:
highest
B C N O F
P S Cl
(i.e., O > S > N > P)
Se Br
lowest
5
These compounds remain as trivial names but are not recommended for use in fusion.
8 1 8 1
O H H
O2 N1 N1
5 2 2
4 3
4
Isochroman Chroman Pyrrolidine Pyrroline
H H H H1
N1 N1 N1 N 2
2 2 H
NH NH
2
N3 N 3 3
H 3
Imidazolidine Imidazoline Pyrazolidine Pyrazoline

(∆2 shown) (∆3 shown)
H H 7 H1 7 1
N1 N N
2 1 2
NH
4
3
N 3
H
Piperidine Piperazine Indoline Isoindoline
8
O
7 1
4
5 3 4
N N
6 1 2 H
Quinuclidine Morpholine
6
Stems: (see McNaught/Smith for full discussion)

Ring Size Maximum (e.g.) Fully (e.g.)
Unsaturation Saturated
H
N N
3 -irine -iridine
(N only) (N only)
Azirine Aziridine
O -irane O
-irene
(O,S,...) (O,S,...)
Oxirene Oxirane
N HN
4 -ete -etidine
(N only)
*Exception Azete Azetidine
-etane O
Does not
override (O,S,...)
accepted
trivial Oxetane
names O
5 -ole* -olidine*
(N only) HN S
N
N Oxazole Thiazolidine
H
Pyrrole, O O
-olane*
not "azole"
(O,S,...)
1,3-dioxolane
H
N N
6 -ine* -ane HN NH
N (N only)
N
1,2,3-Triazine 1,2,3-Triazane
-inane
(O,S,...)
7 -epine -epane O
HN
Azepine Oxepane
8 -ocine -ocane
9 -onine -onane
10 -ecine -ecane
7
Indicated Hydrogen -- To locate hydrogen (or a substituent) when fully

unsaturated but a "saturated" atom present
•Use H prefix (pronounce the letter "H")

italicized
•The saturated position takes priority in numbering

1 H
N N
e.g. 2H-azirine 1H-azirine
(not 3H )
3 2
4 1
3 5 N
2H-pyrrole
4H-pyran 2
(not 5H )
2 4
O 3
1
HN 1H-pyrrole
(often leave out the 1H-)
Partial Unsaturation
•Use fully unsaturated name with dihydro, tetrahydro, etc.
3
4 2 2,3-dihydro-1,2,5-thiadiazole
NH
N S (Note numbering toward saturated atom)
5
1
•Alternative: Trivial names are sometimes still used.
"1-pyrroline", "∆1-pyrroline"
N (Better: 3,4-dihydro-2H-pyrrole)
8
Fused Rings ("Fusion names")

•CAS Ring Index useful
•If there is an accepted trivial name for a fused compound, you should use it.
Otherwise, use fusion name. N
e.g.
Quinoline
•Regard common atoms as belonging to both systems:
N N
regard
N and N
N as N HN
Pyrimidine Imidazole
Step 1. Choose one component as "base component."
see "Heterocyclic a. N-rings have priority

Chemistry" 2nd ed. b. If no N, choose ring with highest priority atom
by T. L. Gilchrist for c. Choose system with greatest # of rings
good flowchart -
pp 376-377 d. Start with larger ring size
e. Choose ring with most heteroatoms
In our example, pyrimidine is base component.
Step 2. Other component named as prefix by changing ending:

pyrrole pyrrolo-
imidazole imidazo - (not imidazolo-)

c
N b
Step 3. Label "faces" of base component d
e Na
f
4
Step 4. Number second component 5
N3
HN
1 2
N
Step 5. Combine: N imidazo[1,5-a]pyrimidine
N
italics
Step 6. Number the new ring system (not easy)

9
Replacement Nomenclature
•Use carbocyclic nomenclature with hetero prefixes.
•Most systematic, but not widely used except for
(a) heterocycles containing unusual atoms
(b) >10-membered rings, and
(c) bridged- and spirocyclic systems.
arsabenzene
As
7
O
4
5
3
7-oxabicyclo[2.2.1]hepta-2,5-diene
6 1 2
4 3
7 6 5 2
O 1,6-dioxaspiro[4.5]decane
O
9 10 1
8
(von Baeyer names used for bridged-bicyclics)
AROMATIC HETEROCYCLES
General Aspects
"π-Excessive" "π-Deficient"
X X
X=NH, PH, AsH, SbH, O, S, etc; X=N, P, As, Sb, O , S
10
π-Deficient Heteroaromatics
Basic lone pair in plane of ring Basic compounds
..
Perpendicular to
N H π-system, not involved
in aromaticity
H+
N N H pKa = 5.2
still aromatic (about like an imine)
R H
N
R _C ≡ N _H
_
c.f. Me3N H
R R
9.8 ~5 ~0
( sp3) (sp2) (sp)
>1 heteroatom: Greatly decreased basicity due to electronegativity
N N H pKa = 0.4
π-Nucleophilicity decreased vs
El El
slower than
N
π-Electrophilicity increased vs
Nuc much faster than Nuc

N
11
NaBH4
No reaction
N
CH3I NaBH4
H
H2O, 15oC N
N H
pH >7
CH3 CH3
1-methylpyridinium
NaBH4
pH 2-5 N
CH3
H
H+ H
H
N N
H
CH3 CH3
OCH3 Ph O OCH3
i
Si( Pr)3
O Si(iPr)3
Cl
Cl OEE
N N
1.
O OR* MgBr
Comins
JACS, 1991, 113, 6672 2. H3O
O
O OH Si(iPr)3
H HO
N
N
O OR*
(-)-elaeokanine C
12
Deprotonation at ring C-H generally requires activating group
N O N O
nBuLi
Li
N N
Electrophilic attack at N much faster than attack at carbon
Electrophiles:
El H , Lewis acids (e.g., BF3),
N N alkyl halides (primary iodides
and triflates), and acylating agents
El
π-Excessive Heteroaromatics
1 heteroatom: Poor base - no basic lone pair

Basicity
> 1 heteroatom: May be basic - has basic lone pair
H H
.. lone pair used in
aromaticity, not available for
:
H N H
N protonation
H H
C-3 N-protonation
H Pyrrole is a very
H C-2 poor base. When
protonation is
forced, C-2 is
N N
H preferred.
H H H
Nonaromatic N H Nonaromatic
pka ~ -5.9 H pka ~ -10
Nonaromatic
pka ~ -3.8
13
Calculated π-electron densities:

1.090 1.067 1.000
- 1.2
1.087 1.078
N O
H 1.647 1.710
Regioselectivity
H H El
El +
El El -H
C-3 minor
X
X X X
El
C-2
El El
El
X H X H X H
major
X El
Preferred for X=NH, NR, S
X Preferred for X=O
El
H El
vs.
X X H
Still aromatic Aromaticity disrupted
14
Synthesis of Heteroaromatics
General
•Many methods rely on carbonyl chemistry

N N O
•Analogies: We know how to make:
Look for these fragments in target heterocycle
H
enamine enamine H H 1,4-dicarbonyl
N NH O O O compound
R R RNH2
imine H enamine 1,5-dicarbonyl

H H compound
N NH2 O O O
NH3
•Typically, condense bis-nucleophile with bis-electrophile
bis-electrophiles bis-nucleophiles
O O O O
1,1: ; ; ; 1,1: H2O, NH3, H2S
X X MeO OMe Cl N N
Cl N N
1,2: RNH-NH2, RNH-OH
O O O
1,2:
; ;
R X R X X
X X R 1,3: ; ;
Cl O O RHN NHR R NHR
1,3: O O O O O RNH E E
; ; X
; ;
R R R R R
R
15
Cyclization Reactions for Heterocyclic Synthesis

Electrophile-Nucleophile Interactions
A Classical Method to Prepare Heteroaromatic Ring Systems1
X A X A X X
A A
Y B Y B Y Y
Types of nucleophile-electrophile cyclizations

Y Y Y
X X X X Y X Y
Z Z
Z Z Z
sp3 X: exo-tet sp2 X: exo-trig sp X: exo-dig sp2 Y: endo-trig sp Y: endo-dig
Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734
Synthesis of Five Ring Heteroaromatics Using General Routes
Aldol-Type Condensations
H H H H H H
H O HO
O
O or B XO X O
H2 H
XH2
H H H H
HO OH HO O
- 2 H2O
X H X H X
H
16
Ten Top Methods to Synthesize Furans
1. Cyclization of 1,4-Diketones and Related Compounds (Paal Knorr Reaction)
R2 R3 R1 O
+ R4
H
R1 R4
R2 R3
O O
Obrecht, D. Helvetica Chimica Acta 1989, 72, 447.
To a stirred solution of 10.0 mmol of the acetylenic acetal in toluene (30 mL) was added a 2 N aqueous HCl
solution (10 mL) at room temperature. The mixture was stirred at room temperature, diluted with Et2O (100 mL)
and poured onto ice (50 g). The aqueous phase was extracted with Et2O (100 mL), the combined organic fractions
were washed with brine (50 mL) and the solvent was removed. The residue was chromatographed on SiO2 (80g)
and distilled under reduced pressure.
2. Base Catalyzed Reaction of β-Ketoesters with α-Haloketones

(Feist Benary Reaction)
R1 O R2
R1 R2 CH2COOR3
Cl +
Base
O O COOR3
Feist, F. Ber. 1902, 35, 1545. Benary, E. ibid. 1911, 44, 493.
R1 O CH2COOEt
Br COOEt R1
+ R2
CH2Br O Base R2
Moubarak, I.; Vessiere, R. Synthesis 1980, 52-53.
To a stirred solution of sodium ethoxide, prepared from sodium (2.1 g, 0.092 mol) metal in ethanol (150 mL) is
added the methylene compound (1.0 mol) at –5 °C. The solution turns yellow and, after several min, a solution of
the chloroketone (10 g, 0.037 mol) in ethanol (15 mL) is added. Stirring is continued for 24 h at 25 °C. The mixture
is neutralized by addition of 10% aqueous HCl, the solvent is removed under reduced pressure, water (50 mL) is
added to the residue, the mixture is extracted with ether, and the product is purified by column chromatography
on silica gel.
3. Ring Transformation of Oxazoles

O R3 O
R1 R3
+ ∆ R1
R4 R5
N
R2 R5 R4
Hutton, J.; Potts, B. and Southern, P.F. Synth. Commun. 1979, 9, 789-797.
A mixture of oxazole (14.5 g, 10 mmol) and bis-trimethylsilylbuta-1,3-diyne (19.4 g, 10 mmol) was heated in a
sealed tube at 210°C for 16 h. The crude reaction mixture was distilled and then chromatographed on silica gel
using hexane as the eluent to give 22.6 g of the product in 95% yield.
17
4. Reaction of Allenic Sulfonium Salts and Enolate Anions of 1,3-Dicarbonyl Compounds
H R2 R1 O
C + R4CH2COR1
R3 SMe2 NaOEt
EtOH R5 R4
O O CH2 O CH3
R1 H R1
H2C C R1
+
R2 SMe2 R2
NaOEt O p-TsOH R2
O EtOH R3 O
R3 R3
Batty, J.W.; Howes, P.D. and Stirling, C.J.M. J.Chem.Soc. Perkin1 1973, 65-68.
Aso, M.; Ojida, A.; Yang, G.; Cha, O.J.; Osawa, E. and Kanematsu, K. J.Org.Chem. 1993, 58, 3960-3968.
A solution of the allene (10 mmol) in ethanol (110 mL) was treated with the ketone (10 mmol) and sodium ethoxide
(10 mmol) in ethanol (100 mL). The mixture was heated at reflux for 4 h and the ethanol was distilled and ether
was added to the residue. Filtration and distillation of the filtrate gave the desired product.
5. Direct and Indirect Alkylation of Furan
O 1/ 1 eq base O (1) base O E2

E1 E1
2/ E1+ (2) E2+
E1+, E2+ = Aryl, Alkyl, Acyl
Wong, M., K.; Leung, C., Y. and Wong, H., N., C. Tetrahedron Lett. 1997, 53, 3497.
Song, Z., Z.; Ho, M., S. and Wong, H., N., C. J.Org.Chem. 1994, 59, 3917.
Wong, H.,N.,C. Pure and Appl. Chem. 1996, 68, 2, 335.
To a stirred solution of the silyl furan (1.3 g, 6 mmol) in anhydrous THF (24 mL) was added 6.5 ml of n-BuLi (1
M solution in hexane) through a syringe under nitrogen. The mixture was stirred for 30 min and then benzyl
bromide (1.1 g, 6 mmol) in THF (10 mL) was added dropwise to the mixture. The resulting solution was
stirred for another 30 min and was poured into Et2O (40 mL) and washed with water. The crude product
obtained after evaporation of the solvent was purified by chromatography on a silica gel column (50 g, hexane)
to give the desired product as a colorless oil (1.5 g, 82%).
18
6. Diazo-Promoted Furan Cyclization
COOEt
O O
Ph H
Me OEt Ph Me
Rh(II) O
N2
Davies, H.M.L., Cantrell, W.R., Romines, K.R., Baum, J.S. Org. Synth. CV 9, 422.
A 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, an addition funnel, and a reflux
condenser is flushed with argon. The reaction vessel is charged with 44 g of phenylacetylene (0.44 mol), 0.38 g of
rhodium(II) acetate dimer, and 100 mL of dichloromethane and the mixture is heated at reflux under an argon
atmosphere. The addition funnel is charged with 13.5 g of ethyl diazoacetoacetate (0.087 mol) and 200 mL of
dichloromethane, and this solution is added dropwise over 1.5 h to the reaction mixture. After the reaction mixture is
heated under reflux for an additional 12 h, it is cooled and the solvent is removed under reduced pressure. The
crude product is purified by chromatography on silica gel, followed by vacuum distillation to yield 10 g (50%) of the
furan as a pale yellow liquid.
7. Pd(0) Catalyzed Formation of Polysubstituted Furans
R4 R2 R3
R2
R 3X + C Pd(PPh3)4
R1 Ag2CO3, Et3N R1 R4
O O
Ma, S., Zhang, J. Chem. Commun. 2000, 117.
The reaction was carried out using 1.5 equiv of the 1,2-allenyl ketone, 1.0 equiv of R3X, 5 mol % of Pd(PPh3)4, 2.0 equiv of NEt3,
and 10 mol % of Ag2CO3. The reaction was heated at reflux in toluene for 13 h.
8. Furans from Acetylenes and Allyl Alcohols

O O
OH OsO4
H R2 R2 R2
R1 CpRu(Ph3P)2Cl R1
R1
Trost, B.M. and Flygare, J.A. J. Org. Chem. 1994 59 1078.
NMO (1.00 mmol) followed by osmium tetraoxide (0.008 mmol) were added to a solution of 0.84 mmol of the ketone
in 4 mL of THF, 1 mL of tBuOH, and 1 mL of water at rt. After stirring for 12 h, 2.5 mmol of p-toluenesulfonyl hydrate
was added and stirring was continued for 10 additional h. The reaction was quenched with 100 mg of sodium sulfite
and ether. The ether layer was washed with saturated sodium carbonate, 10% sodium bisulfate, and brine. After
drying (Na2SO4) and evacuation in vacuo, the compound was chromatographed on silica gel (hexane) to give the
desired product in 88% yield.
19
Section One- Chemistry of Heteroaromatics
9. Organoselenium as a Route to Furans via Butenolide Formation
O O R2
R3 R3
R3 DIBAL
O SePh O
H O R1
R1 R1 R2
R2
Greico, P.A., Pogonowski, C.S., Burke, S., J. Org. Chem. 1975, 40, 543.
A solution of DIBAL (0.5 M in THF) was added to 1.5 equiv of butenolide (0.3 M in THF). After 3 h of stirring at -20 oC, the
reaction was quenched by addition of 10 % sulfuric acid and the reaction mixture was warmed to rt. Water and brine
workup followed by drying with MgSO4 yielded the desired furan in 99% yield.
10. New Advances in Oxo- and Thio-substituted Furans

X O
5% AgBF4 R1 R3
R3 R2
O R1 R2 X
X = OAc, OTs, OPO(OEt)2, SAr, SR, RCOO, RO, ArO

Rubin, M., Sromek, A.W., Gevorgyan, V. Synlett 2003, 15, 2265
Copper chloride (0.05 mmol, 5 mg) was loaded into an oven-dried 3 mL microreactor in a glovebox. Anhydrous DMA
(1 mL), triethylamine (0.2 mmol, 28 mL), and acyloxy alkynyl ketone (1 mmol) were successively added. The reactor
was capped with a Mininert valve and then placed in a preheated aluminum block (130oC), shielded from light, and
stirred from 2 to 24 h. After the reaction was complete, the microreactor was allowed to cool and the mixture was
poured into 10 mL of water and thoroughly extracted with hexane. The organic layer was dried over anhydrous
Na2CO3, concentrated, and chromatographed over silica gel using hexane-ethyl acetate as the eluent.
Synthesis of 2-Amido Substituted Furans
O TfO TfO
R Tf2O + R R
N N N
OH O Me NHR
OH O
Me Me Me
Padwa, A., Crawford, K.R., Rashatasakhon, P., Rose, M. J. Org. Chem. 2003, 68, 2609.
Rashatasakhon, P. Padwa, A. Org. Lett. 2003, 5 189.
To a solution of the lactam (0.5 mmol) in 5 mL of DCM at -78 oC, was added pyridine, (2.7 mmol) and then triflic
anhydride. The crude reaction mixture was allowed to warm to rt over 30 min and was stirred at 25oC for an additional 10
min. Water was added and the organic layer was separated. The aqueous layer was extracted with chloroform and the
organic phase was washed with water, brine and then dried over MgSO4. The crude mixture was purified by flash
chromatography on silica gel using 20% Et2O in hexane to give the desired furan in 90% yield.
20
Radical cyclization for furan synthesis
CH2 Me
Br nBu3SnH
NBS PTSA
OR O AIBN O 45 % O
OH OR OR
Srikrishna, A.; Pullaiah, K. C. Tetrahedron Lett. 1987, 5203
Isomerization of alkynyl oxiranes
H R2 R2
O tBuOK H
C C C
R 1 R1 R3
R3
-O
R2 R2 R2
- H
H H - R1
O R3 O R 3 70-86 % O R3
R1 R1
Marshall, J. A.; Dubay, W. J. J. Org. Chem. 1991, 56, 1685
Buxton, S. R.; Holm, K. H.; Skattebol, L. Tetrahedron Lett. 1987, 2167
O C
tBuOK
OMe N2 OMe O H+ O
OMe H PO(OEt)2 OMe OMe 67 %
-40 °C
21
New Syntheses of Substituted Furans

Regiocontroled [3+2] annulation reactions of allenylsilanes with acylium ions
O O O
TBDMS Cl AlCl3 TBDMS + TBDMS
.C C
-20 °C +
+
O
+ O O
TBDMS 76 % TBDMS
TBDMS
H
Danheiser, R. L.; Stoner, E.; Koyama, H.; Yamashita, D;. Klade, C. A. J. Am. Chem. Soc. 1989,111, 4407
Palladium-catalyzed coupling of aryl iodides Larock, R. C.; Stinn, D. E.

Tetrahedron Lett. 1988, 4687
O O O
Pd (0)
I PdI PdI
O O O
HPdI -HPdI
Et PdI 83 % Et
General method for the synthesis of 2 and 3 substituted furans

Padwa, A.; Murphree, S. S. Org. Prep. and Procedures, 1991, 23, 545. Padwa, A.; Murphree, S. S.; Yeske P. E. J. Org. Chem.
1990, 55, 4241. Padwa, A.; Austin, D. J.; Ishida, M.; Muller, C. L.; Murphree, S. S.; Yeske, P. E. J. Org. Chem. 1992, 57, 1161.
Padwa, A.; Ishida, M.; Muller, C.L.; Murphree, S. S. J. Org. Chem. 1992,57, 1170
Br O ONa
Br 1) addition/elimination MeONa
+ H O
2) deformylation H Br
SO2Ph
available from propargyl alcohol SO2Ph
PhSO2 PhSO2 Na-Hg
85 %
O O O
22
Ten Top Methods to Synthesize Pyrroles
I. Paal-Knorr Method
R1 R2 acid 2H2O
+ R3NH2 R1 R2 +
O O N
R3
Grayson, Martin; Eckroth, David Kirk-Othmer Encycl. Chem. Technol., 3rd Ed. 1982, 19, 499-520
Bean, Gerritt P. Chem. Heterocycl. Compd. 1990, 48 (Pyrroles, Pt.(1), 105-294
Patterson, J. M.; Soedigdo, S. J. Org. Chem. 1968, 33, 2057
A mixture consisting of a 40% solution of methylamine in 100 mL of water, 2,5-hexanedione (114 g), and
benzene (150 ml) was slowly heated to reflux in a flask fitted with a Dean-Stark trap. After the water was
collected, the reaction mixture became clear and homogeneous. On distillation, the fraction boiling at 60oC
(11 mm) was collected to give 82 g (75%) of the product.
• Reaction of α-Haloketones with the Anion of β–Dicarbonyl Compounds
O O O
O O O R3
R3 R4 R1NH2
+
R2 CH2X R3 - R4 R2 R4 R2
N
O R1
Lyer, R. N.; Gopalachari, R. Ind. J. Chem. 1973, 11, 1260
• Cyanide or Thiazolium-ion-Catalyzed Michael Addition of a Vinyl Ketone
1. NaCN
R3
O 2. n-BuLi O 1
R NH2
R2 R4
R2 H R2
N R4
O R3 O
3. R3 R1
R4
Stetter, H.; Krasselt, J. J. Heterocycl. Chem. 1977, 14, 573
Jones, R. A. Tetrahedron. 1986, 42, 3753
• Michael Addition of Ethyl Nitroacetate to a Vinyl Ketone

O
NO2
EtO NO2 + R2 R3
R3
EtOOC
O
R2 O
O R2
O3
R3 R1NH2
EtOOC
EtOOC
R2 O N R3
R1
Thompson, W. J.; Buhr, C. A. J. Org. Chem. 1983, 48, 2769
23
2. Knorr Pyrrole Synthesis

Condensation of an α-Aminoketone with a Carbonyl Compound.
R1 O R1 Z HO Z R1 Z
Z O
R1
+
NH2 O R2 N R2 R2 R2
H N N
H H
Rezzano, I.; Buldain, G.; Fryman, B. J. Org. Chem. 1982, 47, 3059
A solution of 7.2 g of sodium nitrite in 25 mL of water was slowly added to a stirred mixture of 19.2 g of benzyl
acetoacetate in 30 mL of acetic acid at 5 °C. The mixture was kept at 5 °C for 15 h and was then slowly
added to a mixture of 13 g of ethyl acetoacetate in 70 mL of glacial acetic acid. Simultaneously, a mixture of
18.5 g of Zn and 18.5 g of anhydrous sodium acetate was added in small portions. When the addition was
completed, the mixture was heated for a further 1.5 h at 75 °C. The mixture was poured over ice-water,
filtered, and the residue was crystallized from methanol to give the product (21 g, 70%).
3. Condensation of α-Aminoketone with 1,3-Dicarbonyl Compounds
R
O O
EWG-CH2NHR1 + R R EWG R
N
R1
EWG=electron-withdrawing group
Mataka, S.; Takahashi, K.; Tsuda, Y.; Tashiro, M. Synthesis, 1982, 157
A mixture of dibenzoylmethane (500 mg) and ethyl glycinate hydrochloride (3.3 g) in dimethylformamide (50
mL) was heated at reflux for 24 h. The solution was poured into water (200 mL) and the resultant mixture was
allowed to stand overnight. The precipitated product was isolated by filtration and recrystallized from hexane to
give colorless prisms (yield, 74%).
R3 R3
R3 H
EtO
+ R1NHCH2CO2R2
CHO O COOEt
N N
R1 COOR2 R1
Walizei, G. H.; Breitmaier, E. Synthesis, 1989, 337
O
O R2
2 R1
R1 + H2NCH2COR
X
N
H
Cohnen, E.; Dewald, R. Synthesis, 1987, 566
24
4. Formation of Pyrroles via 1,3-Dipolar Cycloaddition Reaction
TMS N CN F-
- +
H2C N CH2 HC CCOOMe COOMe
N
Ph
Ph
Ph
COOMe
DDQ N
Ph
A. Padwa, Y. Y. Chen, W. Dent, and H. Nimmessgern, J. Org. Chem., 1985, 50, 4006
To a solution of the nitroolefin (200 mg) and isocyanide (169 mg) in a 1:1 mixture of THF and isopropanol
(5 mL) was added the guanidine base (180 mg). The resulting solution was heated to 50 °C for 3 h,
poured into water, and extracted with CH2Cl2. The organic layer was dried over sodium sulphate and
filtered through a short column of silica gel. Evaporation of the solvent gave the desired pyrrole as a
pale crystalline solid (272 mg, 90%).
5. α-Haloketone-β
β-Ketoester-Amines Synthesis of Pyrroles
R1 COOR3
O O O
R2 RNH2
R1 + R
4 OR3 R1 R4
N
X
R
X=halo
Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474

Roomi, M.W.; MacDonald, S. F. Can. J. Chem. 1970, 48, 1689
Aqueous ammonia was added to the acyl acetate and the halo-compound (0.1 mole) and the mixture
was stirred for 2 h while the temperature rose to 60 °C. After stirring for 24 h, the product was extracted
into ether and the extracts were washed with 10% NaOH, water, 5% HCl, and again with water. The
ether was removed under reduced pressure and the product crystallized from the residue.
N3
heat
CO2Me
N CO2Me 62 % N N
H H H
25
6. Rhodium Mediated Masked 1,4-Dicarbonyl Compounds

O
O O
R1 R1
Rh2(OAc)4 R1 R2NH2
N2 +
Me OBu Me
Me N
O BuO O
R2
Cunha, A. C.; Pereira, L. O. R.; de Souza, R. O. P.; Ferreira, V. F. Synthetic Commun. 2000, 30, 3215.
Deng, G.; Jiang, N.; Ma, Z.; Wang, J. Synlett 2002, 11, 1913.
7. Formation of Pyrroles via the Hantzch Reaction
Condensation of an α-haloketones or aldehydes with β-ketoesters in the presence of an amine.
CO2Et Br CO2Et Me CO2Et

Br
DMF, rt Pd(OAc)2, PPh3,
+ Ph
N Ph N
NH2
Ph H H
Grigg, R.; Savic, V. J. Chem. Soc., Chem. Commun. 2000, 873.

A solution of starting materials was stirred in DMF at rt until TLC showed complettion of the reaction. The
product obtained was subjected to 10 mol % Pd(OAc)2, 20 mol % PPH3, and 2 equiv K2CO3 in DMF at
85oC. The product was poured into a saturated NaHCO3 solution, extracted with EtOAc, washed with
brine, dried, filtered and concentrated. The crude product was chromatographed over silica gel using
EtOAc/petroleum ether as the eluent.
8. Barton-Zard Synthesis of Pyrroles

Condensation of electron-deficient alkenes with isocyanomethylide anions.
R2 R1
SO2R3 CNCH2CO2Et
R2 R1 Base, THF EtO2C
N
H
Uno, G.; Tanaka, M.; Inoue, T.; Ono, N. Synthesis 1999, 3, 471.
Abel, Y.; Haake, E.; Schmidt, W.; Struve, D.; Walter, A., Montforts, F. Helv. Chim. Acta. 1998, 81, 1978.
To a solution of sulfone and ethyl isocyano acetate (2 equiv) in anhydrous THF was added DBU at rt.
After the mixture was stirred for 3 h, aqueous 1 M HCl was added and the mixture was extracted with
EtOAc. The organic phase was washed with H2O, brine, dried, filtered, and concentrated. The residue
was chromatographed on silica gel with EtOAc and hexane as the eluent.
26
9. Synthesis of Pyrroles from Alkenyl β-Dicarbonyl Compounds
NHBn CO2Et CO2Et

CO2Et NaHCO3, I2, DBU, toluene
Al2O3, CH2Cl2, rt ICH2 reflux
N N
Bn Bn
Ferraz, H. M. C.; Pereira, F. L. C.; Leite, F. S.; Nunes, M.; Payret, M. E. Tetrahedron 1999, 55, 10915.
To a solution of the appropriate acyclic β-enamino ester (1 mmol) in anhydrous CH2Cl2 (15 mL) were added solid
NaHCO3 (1.1 mmol), Al2O3 (1 g), and I2 (1.1 mmol). After stirring at rt for 24 h, the reaction mixture was extracted
with ethyl acetate, washed with NaHSO3, NaHCO3, brine, dried, filtered, and concentrated. The crude product
was either recystallized from cold ethanol (solid) or chromatographed over silica gel utilizing hexane:ethyl acetate
as the eluent.
10. Route to Pyrroles via an Intramolecular Wittig Reaction
Me
SPh Me SO2Ph Me
O NaH KOt-Bu
+
Me m-CPBA
PPh3 t-BuOH
NHCOPh Me N Me N
COPh COPh
Burley, I.; Bilic, B.; Hewson, A. T.; Newton, J. R. A. Tetrahedron Lett. 2000, 41, 8969.
The sulfone (1.5 mmol) was dissolved in dry THF (20 mL) and 1 M potassium t-butoxide in t-butanol (1.5 mmol)
was added. The solution was heated at reflux for 2 h. The THF was removed under reduced pressure and the
residue was partitioned between water and ethyl acetate. Flash chromatography with ethyl acetate/hexane as
the eluent gave the pyrrole (93%).
Pyrrole Formation via the Trofimov Reaction

Condensation of ketones and acetylenes (or synthetic equivalents) with oximes
+ KOH/DMSO
H H
100-110oC
NOH
N
H
Mikhaleva, A. I.; Sigalov, M. V.; Kalabin, G. A. Tetrahedron Lett. 1982, 23, 5063.
A mixture of the oxime (88 mmol), KOH (53 mmol), water (10 mmol), and DMSO (100 mL) was autoclaved with
acetylene at 100oC for 1 h (initial pressure 50 psig). Aqueous workup followed by extraction and vacuum
distillation afforded the product.
H H
NH
NOH KOH, DMSO
Trofimov, B. A.; Mikhaleva, A. I. Heterocycles 1994, 37, 1193.
Brandsma, L.; Nedolya, N. A.; Trofimov, B. A. Eur. J. Org. Chem. 1999, 2663.
27
Top Ten Methods to Synthesize Thiophenes
1. Gewald Synthesis
R2 X R2 X
S/Morpholino
CN EtOH/60 oC
1
R1 S NH2
R
NC CN CN NH2
R1 DMSO
+ X
O
MeS SK O 60 oC MeS S
Gewald, K. Angew. Chem., 1961, 73, 114. R1
Rehwald, M.; Gewald, K.; Battcher, G. Heterocycles 1997, 45, 493.
To a mixture of phenacyl bromide (2.0 g, 10 mmol) and acetic acid (4 mL), a solution of the sulfur salt (1.9 g, 10 mmol)
in dimethyl sulfoxide (20 ml) was added dropwise at 60 oC. After complete addition, the mixture was stirred for
30 min and then poured into water (200 mL). After stirring for 2 h the crude product was collected by filtration and
recrystallized from ethanol (66 %).
2. Gomper Synthesis
1) ClCH2CONHR
Y S- 2) NaOH
NH2 Y
Y = -CO2Et, -CN,
3) MeI -CONHMe, -CONH2
CN S-
RNHCO S SMe
Henriksen, L.; Autrup, H. Acta Chem. Scand., 1972, 26, 3342.
Chloracetamide (5 mmol) followed by methyl iodide (5 mmol) were added to the sulfur salt (5 mmol) in dimethyl
formamide (5 mmL). The mixture was stirred for 5 min, diluted with water (100 mL) and heated 70 oC. Potassium
carbonate (5 mmol) was added to induce the cyclization and the solution was left to cool. The product was filtered from
the cold solution and recrystallized from 1-propanol.
3. Fiesselman Synthesis
OH
R1 R2 + HSCH2CO2R3
R1 S CO2R3
O O R2 OH
+ 4
3 1) H , R OH
R + 2 HSCH2CO2H
R1 O 2) NaOR5
2 S CO2R4
R1
R
Note: Acetylenes, β-ketoesters, α,β-dihalocarboxylates, α-haloarylates,
α,β-dihalonitriles, β-chloro acrylonitriles, 1,3-dicarbonyl have been used
Woodward, R. B.; Eastman, R. H. J. Am. Chem. Soc., 1946, 68, 2229.
Fiesselman, H. Schippark, P. Chem. Ber. 1954, 87, 835.
Saito, K.; Kambe, S.; Sakurai, A.; Midorikawa, H. Synthesis, 1982, 12, 1056.
A mixture of the 3-alkyl-alkoxyacrylonitrile (10 mmol) and the mercaptoacetic ester (10 mmol) in a suitable alcohol
(10 mL) containing potassium acetate (15 mmol) is heated at reflux for 0.5-2 h. The crystals which precipitate during
the reaction are collected by filtration.
28
4. Nakayama Synthesis
1 1 2O R3
R O R O O R 3 R
NaSH Base 1
+ R
2 2
S R4
R X R SH X R 4
O
TiCl4/Zn TiCl4/Zn
rt 0oC
R1 R3 OH OH
R1 R3
R2 S R4 R2 R4
S
DDQ H+
R1 R3
Nakayama, J.; Kurado, K. J. Am. Chem. Soc., 1993, 115, 4612. R2 S R4

To a stirred solution of t-BuOK ( 310 mg, 2.7 mmol) in THF (5 mL) was added a solution of the diol (300 mg, 0.9 mmol)
in THF (2 mL) over a period of 30 min at -18 oC under argon. After 1 h the reaction was quenched by adding ice-water
(30 mL) and then pentane (50 mL). The organic layer was washed with water, dried over MgSO4, concentrated, and
chromatographed on a column of silica. The column was eluted with pentane, and the pentane was evaporated slowly
under reduced pressure (86 %).
5. Hinsberg Synthesis and Modifications
R1
O R2 R2 R3
NaOEt, EtOH R1 = ester, cyano, ketone
S +
O R3 R1 S R1
1
R
Hinsberg, O. Ber., 1910, 43, 901.

Miyahara, Y.; Inazu, T.; Yoshiro, T. Bull. Chem. Soc. Jpn., 1980, 53, 1187.
To a stirred solution of the diketone (2.7 g, 10 mmol) and biacetyl (1.0 g, 11.6 mmol) in 40 mL of methanol was added
0.5 mL of a solution of sodium methoxide (0.5 g of sodium dissolved in 100 mL of methanol) at 40 oC. The
precipitation of crystals occurred immediately with the evolution of heat. After stirring for 1 h, the product was collected
by filtration and washed with methanol. To the filtrate, biacetyl (0.5 g) and the base solution (0.5 mL) were added to
give an additional amount of product. The overall yield was 92 %.
29
6. Paal-Knorr Reaction
R2 R3 R2 R3
P4S10
R1 R4
∆ R1 R4
O O S
Volz,W.; Vob, J. Synthesis, 1990, 25, 670.
Moriarty, R.; Prakash, O.; Duncan, M. Syn. Commun. 1985, 15, 789.
To a solution of the diketone (0.5 g, 0.002 mol) in CH2Cl2 (10-15 mL), was added phosphorous pentasulfide (2.2 g, 0.05
mol) with stirring. Solid sodium bicarbonate (0.84 g, 0.01 mol) was added in 5-6 portions during 5 min. After stirring the
reaction mixture overnight at rt, water (50 mL) was added and the mixture was transferred to a separatory funnel and the
aqueous layer was extracted with CH2Cl2 and the combined organic extracts were washed with water. Concentration of
the dried CH2Cl2 extracts gave a crystalline product (75%).
7. Thorpe-Ziegler Cyclization
H2NOC CN H2NOC NH2
H2NOC CN HS CO2Et
EtONa Me S CO2Et Me CO2Et
Me NMe2 S
Ryndina, S. A.; Kadushkin, A. V.; Solov'eva, N. P.; Granik, V. G. Russ. Chem. Bull. 2002, 51, 854.
The ester (120 mmol) and K2CO3 (1 g, 7 mmol) were added to a suspension of the enamine (100 mmol) in 100 mL
of anyhydrous EtOH. The reaction mixture was refluxed for 16 h, diluted with water, and cooled. The precipitate that
formed was filtered off and washed with water to give the aminothiophene.
8. Simmons-Smith Conditions
R1 R2 R1 R2
R1 R2 IZnO
CH2I2/Zn-Cu
O SMe H
O SMe Et2O/THF +
S SMe
MeS Zn S H
I CH2 Me Me
R1= aryl, hetaryl, alkyl I
R2= H, alkyl, allyl, Ph, Bn I-
Ar
Ar
CH2I2/Zn-Cu R1 R2
O OR
MeS Et2O/THF S OR
S SMe
Thomas, A.; Singh, G.; Ila, H. Tet. Lett., 1989, 30, 3093.
To a well stirred suspension of zinc-copper couple (4.0 g) in dry ether (25 mL) under nitrogen atmosphere, was added
a small crystal of iodine and CH2I2 (6.7 g, 25 mmol). The reaction mixture is heated at reflux for 45 min. A solution of
the enone (2.4 g, 10 mmol) in dry THF (15 mL) is added and the reaction mixture was heated at reflux with stirring for
8 h. The solvent is removed under reduced pressure and the residue is diluted in water (200 mL) followed by the
addition of CHCl3 (150 mL). The reaction mixture is filtered, the residue washed with CHCl3 and the combined oragnic
layer is washed with NHCl4 solution and water, dried (Na2SO4) and evaporated to give the crude product.
30
9. From β,γγ-Epoxy Carbonyl Compounds
O O R3 R1
Lawesson's Reagent
3 3
R R p-TsOH (cat.)
S R3
R 1 Benzene/∆
Kang, K.; J. S. Syn. Commun. 1995, 25, 2647.
Benzene (10 mL) and Lawesson's reagent (6 mmol) was added to the epoxide (5 mmol) and the mixture heated to
reflux. After 5 min., p-toluenesulfonic acid (10 mg) was added, and the mixture was further heated for 1 h. The
reaction was partitioned between sat. NaHCO3 and ether. The aqueous layer was extracted with ether. The
combined organic layers were washed with water and dried over Na2SO4. Purification by chromatography on
silica gel gave the thiophene derivative.
10. Thermally From Alkanes and Alkenes
R2 R2 R3
1 Al-Cr catalyst
R + H 2S
R4
∆ R4
R3 R1 S
For a review: Gronowitz, S. Thiophenes and Its Derivatives; Interscience Publisher: New York, vol. 44, pt. 1, pp. 4-11.
Commonly used industrial procedure. However, the yields of the reaction are poor and it is difficult to perform
experimentally. In general, alkenes give better yields than alkanes.
Hinsberg α-Diketone-thiodiacetate Thiophene Synthesis
CO2Et
O O CHO
CHOCHO -EtO S
EtO2CCHSCH2CO2Et H CO2Et
S O
EtO2C
Wynberg, H.; Kooreman, H. J. O
J. Amer. Chem. Soc. 1965, 87, 1739
H
-H+ -H2O
EtO2C O
H+ EtO2C S CO2H
SCH2CO2
31
Ten Top Methods to Synthesize Oxazoles
1. Cyclizations of β-Hydroxy Amides
NH CO2CH3 N
1. DAST CO2CH3
2. DBU, O
O OH NH
NH BrCCl3
68%
Phillips, A.J.; Uto, Y.; Wipf, P.; Reno, M.J.; Williams, D.R., Org. Lett. 2000, 2, 1165.
A sample of DAST (0.24 mmol) is added dropwise at -78°C to a solution of the hydroxy amide in CH2Cl2 (2 mL). After 30
min, the reaction mixture is warmed to -40°C and bromotrichloromethane (0.8 mmol) is added dropwise, followed by
warming to 0°C and addition of DBU (0.8 mmol). The reaction mixture is stirred for 8 h while warming to 20 °C, then
quenched with a saturated NaHCO3 solution. The solution is extracted with EtOAc and the organic layer was dried over
MgSO4, filtered, and concentrated.
2. 2-Substituted 5-Amino-4-cyano-1,3-oxazoles
CN
O N
CN DCC
H NH3•OTs + NH2
OH pyridine O
CN 76%
Freeman, F.; Chen, T.; van der Linden, J.B., Synthesis 1997, 861.
The carboxylic acid (10 mmol) and DCC (10.5 mmol) is added to a stirred solution of the aminomalononitrile
p-toluenesulfonate (10.5 mmol) in pyridine (50 mL) and the mixture is stirred overnight. After removal of the white
precipitate by filtration, the filtrate is concentrated to give the oxazole, which is purified by flash chromatography.
3. 2,5-Disubstituted Oxazoles from N-Propargyl Amides
I Pd2(dba)3, N O
O P(2-furyl)3
NH +
NaOtBu
75%
Arcadi, A.; Cacchi, S.; Cascia, L.; Fabrizi, G.; Marinelli, F., Org. Lett. 2001, 3 , 2501.
A sample of P(2-furyl)3 (0.06 mmol) is added to a solution of Pd2(dba)3 (0.016 mmol) in anhydrous MeCN (3.5 mL)
under argon and the solution is stirred at rt for 15 min. The N-propargylamide (0.63 mmol), iodobenzene (0.75 mmol),
and NaOtBu (1.2 mmol) is added and the mixture stirred at 40°C for 4 h. The reaction mixture is diluted with EtOAc,
washed with 0.1 N HCl and saturated NaHCO3, dried with Na2SO4, filtered, and concentrated under reduced pressure.
The residue is purified with an axially compressed silica gel column using hexane/EtOAc as the eluent.
32
4. Substituted Oxazoles from Ketoximes

pyridine
N OH O O N O
+
Ph Acetyl chloride
O
80% Ph
Bhatt, M.V.; Reddy, G.S., Tet. Lett. 1980, 21, 2359.
Benzylmethylketoxime (20 mmol) is dissolved in dry pyridine (20 mmol) and acetic anhydride (20 mmol). The
mixture is cooled to 0°C and acetyl chloride (26 mmol) is added, then heated over a boiling water bath for 4 h.
Dry HCl gas is passed for 3 h (at 100°C). The reaction mixture is cooled, poured into crushed ice, extracted with
CH2Cl2, then dried, filtered, and concentrated. The residue is purified by column chromatography to afford the
oxazole.
5. 2,5-Disubstituted Oxazoles from Iodobenzene Diacetate
O H
CF3SO3H N
OAc
Ph I +
OAc MeCN Ph O
94%
Varma, R.S.; Kumar, D., J. Heterocyclic Chem. 1998, 35, 1533.
Trifluoromethanesulfonic acid (4.5 mmol) is added to a solution of acetonitrile (10 mL) and iodobenzene diacetate (1.2
mmol) and the reaction mixture is stirred at rt for 20 min. Acetophenone (1.0 mmol) is added and the mixture is heated
at reflux for 2 h, then concentrated to remove excess acetonitrile. The residue is extracted into CH2Cl2 and the organic
layer washed with saturated NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
product is purified by elution through a short pad of silica gel.
6. Ethyl 5-Oxazole Acetate
O O OEt
OEt POCl3 N
O O
NH
Ph 88%
O Ph
Dow, R.L., J. Org. Chem., 1990, 55 (1), 386.

Phosphorus oxychloride (18 mmol) is added to a stirred solution of the keto ester (6 mmol) in DMF (10 mL) and
the reaction mixture is heated at 90°C for 20 min. The mixture is cooled, poured onto ice, and the resulting slurry
was stirred for 30 min. The solution is added to a saturated NaHCO3 solution and extracted with EtOAc. The
organic layer is washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The resulting residue is purified by flash chromatography (silica, EtOAc/hexane).
33
7. Synthesis of Oxazoles from Sulfones
SO2Ph LiN(TMS)2 N
OHC
N O SO2Ph
95%
H I
Short, K.M.; Ziegler, Jr., C.B., Tetrahedron Lett. 1993, 34, 71.
To a solution of the sulfone (0.6 mmol) in dry THF (4 mL) and DMSO (0.5 mL) at 0°C is added lithium
bis(trimethylsilyl)amide (0.7 mmol) under argon. After 40 min, the mixture is diluted with ether and quenched with
1 N HCl. The organic layer is washed with saturated NaHCO3 and brine, then dried with MgSO4, filtered, and
concentrated to a residue which is purified by chromatography to afford the oxazole.
8. Vilsmeier Cyclizations for the Synthesis of Oxazoles
O O
1. NaN3
N
2. POCl3
Br CHO
Br 56% Br
Majo, V.J.; Paramasivan, T.P., Tetrahedron Lett. 1997, 38, 6889.
To an ice-cooled solution of the substituted 2-bromoacetophenone (5 mmol) in DMF (10 mL) was added NaN3
(5.5 mmol) in one portion. After approximately 20 min, POCl3 (30 mmol) was added dropwise. The mixture
is warmed to rt and heated at 90°C for 4.5 h to provide the oxazole in good yield.
9. Synthesis of Oxazoles from Ketones
O EtO2C N
1. PhI(OH)ODNs
EtO2C Ph
2. PhCONH2 O
NO2
71% O
-ODNs = O S NO2
Lee, J.C.; Kim, S.; Lee, Y.C., Syn. Commun. 2003, 33 , 1611.
O
To a solution of ethyl pyruvate (1.0 mmol) in acetonitrile (40 mL) is added [hydroxy(2,4-dinitrobenzenesulfonyloxy)iodo]-
benzene (HDNIB) (1.2 mmol) and the mixture is refluxed for 2 h. After cooling to rt, benzamide (3.0 mmol) is added and
the mixture is refluxed for an additional 10 h. The solvent is removed and the residue extracted with CH2Cl2, followed by
washing with saturated NaHCO3 and H2O. The organic layer is dried with MgSO4 and the solvent was evaporated under
reduced pressure. The resulting product is purified by flash chromatography.
34
Ten Top Methods to Synthesize Isoxazoles

1. Oximation of 1,3-Dicarbonyl Compounds
O O NaOH O
N
Me + NH2OH
O H2O/MeOH
HO Me
Me
Brehm, L.; Johansen, J.S.; Krogsgaard-Larsen, P.; J.
Chem. Soc., Perkin Trans I, 1992, 16, 2059-2063.
To a solution of sodium hydroxide (5.2 g, 130 mmol) in a mixture of water (5 cm) and methanol (100 cm) was added,
the oxoester (23 g, 125 mmol). To this solution at -70 °C was added a filtered solution of sodium hydroxide (10.3 g,
260 mmol) and hydroxylamine hydrochloride (17 g, 240 mmol) in a mixture of water (10 cm) and MeOH (100 cm).
The reaction mixture was stirred for 2 h, and during this period the temperature was raised to 10 °C. Upon addition of
acetone (9 cm, 125 mmol), the reaction mixture was poured into hydrochloric acid at 80 °C, and this mixture was
stirred for 30 min. The volume was reduced to 100 mL by evaporation and left at 5 °C overnight. The product (16.9 g)
was filtered, and the mother liquor was extracted with dichloromethane. The filtrate was dried (magnesium sulfate),
the organic phases were evaporated and the residue was subjected to column chromatography to give 17.4 g of
5-tert-butyl-4-methylisoxazol-3-ol (91%).
2. Cycloaddition of Nitrile Oxides to Unsaturated Compounds
+ - OCH3 benzene O
O N
R N O +
CH3 R CH3
O
Chimichi, S.; Cosimelli, B.; Synth. Commun., 1992, 22, 2909-2920.
A solution of nitroethane (2.5 g, 33 mmol) and triethylamine (15 drops) in dry benzene (15 mL) was added dropwise
to a solution of 4-chlorophenyl isocyanate (8.6 g, 56 mmol) and trans-4-methoxy-3-buten-2-one (3.0 g, 30 mmol) in
dry benzene (25 mL). The reaction mixture was stirred for 1 h, then refluxed for an additional hour. 4-Chlorophenyl
isocyanate (6.2 g, 41 mmol), nitroethane (1 mL, 9.8 mmol), and 5 drops of triethylamine were added to the reaction
mixture. The solid was filtered and the filtrate was concentrated to give a yellow oil, which was distilled to give the
isoxazole (3.3 g, 88% yield).
3. Gold(III) Catalyzed One Pot Synthesis of Isooxazoles from Terminal Alkyne

and Nitric Acid
TBA+AuCl4- O + H2 O
RC CH + HNO3
R N
O
Gasparrini, F.; Giovannoli, M.; Misiti, D.; Natile, G.; Palmieri, G.; Maresca, L. J.Am.Chem.Soc, 1993, 115,
4401-4402.
In a typical experiment, the alkyne (5.0 mmol) was dissolved in nitromethane (8 mL) and treated with aqueous
HNO3, (16 mL, 25.0 mmol,1.5 M) in the presence of tetrabutylammonium tetrachloroaurate (0.25 mmol) and sodium
nitrite (1.0 mmol). The mixture was stirred at 50 oC until complete disappearance of the alkyne and then was
extracted with dichloromethane. The extracts were washed with a saturated aqueous solution of Na2S2O3 which
removed the catalyst and was dried over Na2SO4. The solvent was removed under reduced pressure. The residue
was chromatographed on silica gel to give the isoxazole in 35-50% yield.
35
4. Synthesis of Isoxazoles from α-Halo Ketone and Isocyanide
R1 base O NHR2
X N
R2NC
NOH
R1 Ar
Buron, C.; Kaim, L. El.; Uslu, A. Tetrahedron Lett. 1997, 38, 8027-8030
To a solution of the α-halo ketone oxime (2 mmol) in dry dichloromethane (10 mL) is added the isocyanide (8 mmol)
and sodium carbonate (850 mg, 8 mmol).
5. Condensation of Aromatic Aldehyde and Nitroethane or Nitropropane
Ar EtNO2 / NaOH O Me
O N
H Ar
Me
Best, W.M.; Ghisalberti, E. L. ; Powell, M. J. Chem. Res. (S)., 1998, 7, 388-389
A mixture of nitroethane or nitropropane (9.3 mmol), the aldehyde (4.41 mmol) and ethanol (7 mL) was stirred
rapidly at rt. A solution of NaOH (6.4 M, 2 mL) was added dropwise and the mixture was heated at reflux for 5 to
18 h. The cooled reaction mixture was extracted with ether and the organic layer was washed with brine and
dried over MgSO4. The residue remaining after evaporation of the ether was purifed either by column
chromatography (silica) or by distillation.
6. Condensation of Carboxylic Acid Derivatives with 1,4-Dilithium Oxime Salts
n-BuLi O
N N
OMe +
N OH THF
Me Me
Nitz, T.J.; Volkots, D.L.; Aldous, D.J.; Oglesby, R.C. J. Org. Chem., 1994, 59, 5828-5832
To a chilled (0 °C) solution of acetone oxime (1.1 g, 15 mmol) in THF (30 mL) was added dropwise 2.5 M n-BuLi in
hexane (12 mL, 30 mmol). The initially formed white suspension gave a colorless solution after all of the n-BuLi
had been added. After an additional 30 min, N-methoxy-N-methylisobutylamide (2.6 g, 18 mmol) in THF (120 mL)
was added dropwise over 20 min. After 30 min, the pale yellow solution was poured into a solution of concentrated
H2SO4 (2.5 mL) in THF/water and refluxed for 1 h. The chilled reaction mixture was neutralized with NaHCO3.
Sufficient water was added to dissolve the salts, and the mixture was extracted with ether. The combined ethereal
extracts were washed with brine, dried, and concentrated in vacuo to give a yellow oil which was purified by silica
gel chromatography to give 1.5 g (72%) of a colorless oil.
36
7. Synthesis of Isoxazoles from β,γ-Acetylenic Oximes
OH R2
N R 2 K2CO3 O
N
MeOH
R1
Short, K. M.; Ziegler, C. B.Jr. Tetrahedron Lett., 1993, 34, 75-78.
The alkyne(0.6g) was reacted with potassium carbonate (1.5 g) in methanol (15 mL) for 12 h, then the
solution was concentrated in vacuo. The residue was treated with water and ethyl acetate. The organic phase
was washed with 5% HCl, brine, filtered and the residue was chromatographed on silica gel to give the
isoxazole.
8. Synthesis from Benzyl Propargyl Ether and Methyl Nitroacetate
OBn
O2NCH2CO2Me O
OBn N
OCNC6H4NCO , Et3N
R
Alkyne 1 (3.3 g, 22.7 mmol) and methyl nitroacetate (2.7 g, 22.7 mmol) were combined in THF (100 mL), and
1,4-phenylene diisocyanate (9.1 g, 56 mmol) was added in one portion. Thereaction was initiated by the
addition of a catalytic amount of triethylamine. When the reaction had gone to completion, 2-3 drops of water
were added to quench any excess isocyanate. The polymerized urea by-product was removed by filtration
through a plug of Celite, and the filtrate was concentrated to give the isoxazole (4.2 g, 76%) as a light yellow
solid.
Sammelson, R. E.;Miller, R.; Kurth, M. J. J. Org. Chem., 2000, 65, 2225-2228
9. Cyclization of N,O-Boc α-Keto Hydroxamic Acids Synthesized via Acyl

Meldrum’s Acids
O O
Conc. HCl O
Boc N Me
N
Boc HO
Sorensen, U. S.;Falch, E.; Krogsgaard-Larsen, P. J. Org. Chem., 65, 2000, 1003-1007
The starting ketoamide (450 mg, 1.4 mmol) was dissolved in MeOH (3 mL) and this solution was added to
concentrated HCl (10 mL) at 50 °C. The mixture was stirred for 1 h, cooled to rt, and concentrated in vacuo. The
residue was dissolved in water (10 mL) and the pH adjusted to 3-4 with 2 M aqueous NaOH followed by
extraction with EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the
final product in high yield.
37
Ten Top Methods to Synthesize Pyrazoles
1. Reaction of β-Bifunctional Compounds with Hydrazines
CO2H
O O
MeOH N
+ Ar2NHNH2 •HCl Ar1 N
Ar1 CO2H Et3N
Ar2 94%
Murray, W.; Wachter, M; Barton, D.; Forero-Kelly, Y. Synthesis 1991, 18.
A mixture of the 6-aryl-4,6-dioxohexanoic acid (20 mmol), the aryl hydrazine hydrochloride (20 mmol) and
triethylamine (20 mmol) in methanol (150 mL) was stirred at rt for 6 h. The mixture is concentrated in vacuo
and the residue is taken up in ether, washed with 5% HCl, and brine (40 mL), dried (Na2SO4), filtered, and
concentrated to an oil. The residue is crystallized from ether/ acetone to afford the product in 94% yield.
An Interesting Variation
H K2CO3
+ RNHNH2 N
Br DMF N
R
69%
Neidlein, R.; Schroeder, G. Helv. Chim Acta 1992, 75, 825.
H
N
o o
+ NH2NH2 . H2SO4 N
o o
90%
Otting, C.; Messerle, B. A.; Soler, P. L. J. Am. Chem. Soc. 1996, 118, 5096
Ethanol (35 mL ) and water (55 mL) were added to hydrazine sulfate (2.1 g, 16 mmol) and the solution was stirred
and heated at 75oC for 1.5 h until the hydrazine fully dissolved. Malonaldehyde bis(dimethylacetal) (2.7 g, 16
mmol) was added dropwise and the solution was stirred and heated at 75 oC for 2 h. The mixture was then stirred
for 24 h at room temperature. The ethanol was removed under reduced pressure and the solution was neutralized
with CaCO3. After addition of water the solution was filtered through celite. The eluent was extracted with ether
the ether solution was dried over K2CO3 and filtered again through celite. The volume of ether was reduced by
distillation to give the product.
38
2. β-Substituted Enones and Alkyl Hydrazines
CH3 R
O NH2
HOAc + N
NH2 NH2 R1 + N CH3
R N N
R
R1 R1
80-95%
Alberola, A.; Bleye, L. C.; Gonzalez-Ortega, A.; Sadaba, M. L.; Sanudo, M. C. Heterocycles, 2001, 55, 331.
A mixture of the β-amino enone (2.8 mmol) and the hydrazine derivative (3.4 mmol) in 5 mL of ethanol were stirred at
20oC-80oC with 1 mL AcOH as the catalyst. The solution was poured into water (20 mL) and extracted with methylene
chloride. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo. The
residue was purified by recrystallization or chromatography on silica gel.
3. One-pot Synthesis of 3-Amino Pyrazoles
N2H4.H2O C6H5CHO HN
HN N CN
CN NH2 CN Ph
NaOH
N 85% total yield
NH2
heat N
Bn
Holschbach, M.H.; Wutz, W.; Olsson, R. A. Tetrahedron Lett. 2003, 44, 41.
4. Synthesis of 3-Amino Pyrazoles
O
Me
Me
+ RNHNH2 conc. HCl N
EtOH N
N H2N
R
95%
Butler, D.; Alexander, S.M. J. Hetereocyclic Chem. 1982, 19, 1173.
39
5. Synthesis of 3-Acylaminopyrazoles Starting from Acylated β -Keto Imino Ethers
1. Pyridine, CH2Cl2 H
OEt + N
Cl
NO2 2. NH2NH2 HN N NO2
O NH O
O
93%
Robert, F.; Susan M.
U.S., 6593477, 15 Jul 2003.
A 5.0 g (0.024 mol) sample ofthe imino ether was added to 4.2 mL (0.05 mol) of pyridine in 25 mL of methylene
chloride and cooled in an ice bath. The suspension was stirred for 5 min and 2.9 mL (0.025 mol) of benzoyl chloride
was added dropwise over 3 min. The reaction was stirred 5 min at ice bath temperatures and the bath removed and
the reaction stirred at ambient temperatures for 1 h. The reaction was poured into 100 mL of water and 100 mL of
ethyl acetate added. After shaking, the aqueous layer was removed, the organic layer washed with water, dried
over magnesium sulfate and concentrated to yield 7.0 g (100%) of acylated β-ketone imino ether as a clear oil.
Without purification, 5.0 g (0.018 mol) of this compound was dissolved in 50 mL ethanol at room temperature and
0.64 mL (0.02 mol) hydrazine added dropwise over 1 min. After 30 min the reaction was poured into water, ethyl
acetate added and after shaking, the organic layer was washed once with dilute hydrochloric acid and then with
water. The organic layer was dried over magnesium sulfate and concentrated to give 4.1 g (93%) of a white solid.
6. Synthesis of Fluoro-pyrazoles from Organofluorosilicon Building Blocks

OH
SiR1R2
R
CF2-CF2-RF F - HF, F R
Me-NH-NH2 O
- H2 O
Me-NH-NH2 R RF N
RF N
Et2O, rt F
OSiR1R2 RF=C4F9 Me
R=alkyl, aryl
CF2-RF
R 95%
F
Bouillon, J.- P.; Didier, B.; Dondy, B.; Doussot, P.; Plantier-Royon, R.; Portella, C. Eur. J. Org.
Chem. 2001, 187-192.
To a solution of the starting material (0.6 mmol) in ether (5 mL) was added methylhydrazine (2 equiv., 1.2
mmol). The mixture was stirred at room temperature for 5 h and filtered. After solvent removal, the pyrazole
was purified by silica gel chromatography.
An interesting Variation
(CF2)n-1CF3
Ar 1. (Bu3Sn)2, hv, O2, benzene
CF3(CF2)nI + CH2 Ar N
Cl 2. NH2NH2.AcOH, EtOH N
H 69%
Ohkoshi, M.; Yoshida, M.; Matsuyama, H.; Iyoda., M. Tetrahedron Lett. 2001, 42, 33-36.
40
7. Nitrile Imines as Precursors for Pyrazoles
Ph Ph
Cl Cl NEt3
PhNHN + (Ph)3P N
EtO N
Ph Ph
Ph
90%
Padwa, A.; MacDonald, J. G. J. Heterocyclic Chem. 1987, 24 (4) 1225-1227
To a stirred solution containing 1.5 mmol of diphenyl hydrazonyl chloride and 1.5 mmole of carboxymethylene
triphenyl phosphorane in 30 mL benzene at 250 oC was added 1mL of triethylamine. The solution was allowed
to stir for 6 h and was filtered. The residue obtained upon removal of the solvent was subjected to silica gel
chromatograhy.
8. Hydrazonyl Bromides and β-Dicarbonyl Anions

O
2
R1 Br R
O O R3
NaOEt
N Ar + N
N R2 R3 R1 N
H
Ar
Shawali, A.S.; Abdelhamid, A.O. J. Hetereocyclic Chem. 1976, 13, 989. 78-84%
The appropriate 1,3-dicarbonyl compound (0.01 mol) was added to an ethanolic sodium ethoxide solution.
After stirring for 10 min, the hydrazonyl bromide (0.01 mol) was added and stirring was continued overnight.
The product was collected by filtration or by dilution with water and filtration. Purification by recrystallization
from ethanol gave the product in 78-84% yield.
O OEt
ArHN Br
O N
N O
O N + Et3N
O N
OMe Ar
EtO OMe
72%
Shawali, A.S.; Parkanyi, C. J. Hetereocyclic Chem. 1980, 17, 833.
41
9. Sulfur Monoxide Extrusion from 1,2,6-Thiadiazine S-Oxides
Ar Ar
R 2
1 2 1 R2 R3
NHR R R
Pyridine N
+ SOCl2 toluene
S N
R 3 NH R 3
N O 90°C Ar N
R1
Barluenga, J.; Lopez-Ortiz, J.F.; Gotor, V. J. Chem. Soc., Chem. Commun. 1979, 891.
Barluenga, J.; Lopez-Ortiz, J.F.; Tomas, M.; Gotor, V. J. Chem. Soc., Perkin. Trans. 1 1981, 1891.
Thionyl chloride (0.012 mol) was added to the starting diimine (0.01 mol) in pyridine (50 mL) at 0 °C. The stirred
mixture was warmed to rt and after 2 h, 4N H2SO4 was added. The intermediate thiadiazine S-oxide was extracted
into ether and purified by recrystallization from hexane. Heating this intermediate in toluene at 90 °C for 8 h, followed
by concentration in vacuo and recrystallization from hexane gave the desired pyrazole in 80% yield.
10. Alkyl Diazo Compounds and Multiple Bonds
Et2O CO2Et
CF3 Br 0°C to reflux
+ EtO2CCHN2 2 hr N
CH2 CF3 N
H
86%
Plancquaert, M.; Redon, M; Janousek, Z.; Viehe, H. Tetrahedron 1996, 52, 4383.
Ethyl diazoacetate (11 mmol) in ether (3 mL) was added dropwise to a solution of bromopropene (7.6 mmol) in ether
(2 mL) at 0°C. The temperature was allowed to rise to 20°C, and was then heated at reflux for 2 h . The product
was distilled using a Kugelrohr apparatus and recrystallized from hexane to give 86% of the desired pyrazole.
O O
Et2O
+ CH2N2
H N
N
H
85%
Bowden, K.; Jones, E.R.H. J. Chem. Soc. 1946, 953.
42
Ten Top Methods to Synthesize Imidazoles

1. Synthesis of 1,2,5-Trisubstituted Imidazoles
Oi-Pr R2
N H K2CO3 N X
1
R
1 2 CHCl3/H2O
R NHR Br X N
1
R = n-C4H9, C6H5
2
R = C6H5, CH2Ph-4-CO2H, CH2-1-naphthyl
X = CHO, CN
Shilcrat, S. C.; Mokhallalati, M. K.; Fortunak, J. M. D.; Prigden, L. N. J. Org Chem. 1997, 62, 8449.
A solution of amidine (30 mmol) and 2-bromo-3-(1-methylethoxy)-2-propenal (45 mmol) in chloroform (60 mL) and
water (7.5 mL) was treated with solid potassium carbonate (45 mmol) and stirred at ambient temperature for 18 h.
After cooling, the reaction mixture was partitioned between methylene chloride and water. The organic phase was
washed with water and brine and dried (MgSO4). The product was isolated by flash chromatography on silica with
5% (v/v) acetonitrile/methylene chloride as eluent in 83% yield.
2. TOSMIC Reagent for Synthesis of 4,5-Disubstituted Imidazoles

4 OCHN(SiMe3)2
R-Li
-78 ˚C, 0.5 h
5
R R4
(Method A)
4 TosCR5LiNC
R NSiMe3
HN N
4
Li-N(SiMe3)2
R-CHO 4
-60 ˚C, 0.5 h R = CH3, n-C4H9, C6H5
5
(Method B) R = H, CH3, C6H5CH2
Shih, N. Y. Tetrahedron Letters 1993, 34, 595.
Method A (Preparation of 5-benzyl-4-butylimidazole). To a cold (-78 ˚C) solution of

N,N-bis(trimethylsilyl)formamide (1.6 mL, 7.5 mmol) in anhydrous THF (10 mL) was added slowly a solution of
n-butyl lithium in hexane (4.7 mL, 1.6 N, 7.5 mmol). After the mixture was stirred at -78 ˚C for 30 min, a solution of
the anion of tosylbenzylmethyl isocyanate [prepared by addition of a solution of lithium bis(trimethylsilyl)amide
(7.15 mL, 1 N, 7.16 mmol) to a cold (-55 ˚C) solution of tosylbenzylmethyl isocyanate (2.0 g, 7.16 mmol) in
anhydrous THF (5 mL) followed by stirring for 30 min at -50 to -60˚C] was added by cannula. The resultant
solution was stirred for 30 min at -78 ˚C, allowed to warm to 0 ˚C (2 h) and was then stirred at room temperature for
16 h. The reaction mixture was concentrated, the residue was diluted with 30 mL distilled water, and the solution
was adjusted to pH = 10 by the addition of 1 N HCl. Sodium chloride was added to saturate the aqueous solution
and this solution was extracted with ethyl acetate/ methylene chloride (4 : 1). The combined organic extracts were
dried over anhydrous sodium sulfate and potassium carbonate, concentrated, and purified by flash chromatography
on silica gel to give 5-benzyl-4-butylimidazole (1.0 g, 66%).
Method B. (General procedure). To a solution of an aldehyde (1.5 mmol) in anhydrous THF (2 mL) at -60 ˚C was
added dropwise a solution of lithium bis(trimethylsilyl)amide (1.5 mmol). The resulting solution was warmed to -30
˚C (20 min), and then a solution of the anion of tosylmethylisocyanate (1.4 mmol) was added (prepared as
described in Method A). The resultant solution was stirred for 30 min at -78 ˚C, allowed to warm to 0 ˚C (2 h), and
then stirred at room temperature for 16 h. The reaction mixture was worked up as described in Method A.
43
3. Acid Induced Synthesis of 1,2,5-Trisubstituted-4-Imidazoyl Glycinates
1
R
N CH2CO2R2 H
EtO 1
R H
AcOH N R1 N CO2R2
1 EtO CO2R2
R H 70 ˚C N 1
- 2EtOH N -1RCO2Et
2 R
RO2CCH2 OEt R2O2CCH2 R1 - 2ROH
EtO N CO2R2
H
R1 N CONHCH2CO2R2
1
R = CH3, (CH3)2CH, C6H5CH2, C6H5
N 2
2
RO2CCH2 R1 R = CH3, (CH3CH2)2, CH2CCH
Morel, F.; Lerestif, J. M.; Bazureau, J. P.; Hamelin, J.; Tonnard, F. Heteroatom Chemistry 1996, 7, 187.
A freshly distilled imidate (40 mmol) and glacial acetic acid (13.2 mmol, 0.79 g) were heated to 70 ˚C under dry
nitrogen with vigorous stirring for an appropriate reaction time as monitored by tlc. After elimination of the
corresponding alcohols and ester under reduced pressure, the crude reaction mixture was titurated with dry ethyl
ether. After standing 24 hours at 4 ˚C, the precipitated product was filtered, washed with ether, dried in a desicator
over CaCl2, and recrystallized from a mixture of Et2O/CH2Cl2 to yield the purified product in 96 % yield.
4. Historic Method Improved by Acidic Conditions To Furnish 1-Alkylimidazoles
R
O O O +
+ - H N
[RNH3]X
H H H H
N
1
R = CH3, C4H9, (CH3)2CHCH2, (CH3)3C, C6H11
Gridnev, A. A.; Mihaltseva, I. M. Synthetic Communications 1994, 24, 1547.
A 100 mL flask equipped with a mechanical stirrer dropping funnel and reflux condenser was loaded with glyoxal (0.1
mol, 11.5 mL of 40% aqueous solution), formaldehyde (0.1 mol, 15 mL of 20% aqueous solution) and the
alkylammonium salt (0.1 mol), which had been obtained by acidification of the appropriate alkylamine solution in 8-15
mL of water with phosphoric acid until the pH = 2. The reaction mixture was warmed to 90-95 ˚C and a saturated
aqueous solution of 0.1 mol ammonium chloride was added to the stirred reaction mixture over a period of 60-75
min. After an additional 10 min of stirring at 95 oC, the crimson reaction mixture was chilled, solid KOH was added
and the mixture was extracted with ethyl acetate. The combined extract was evaporated and distilled under vacuum
to provide the product in 50% yield.
44
5. Simmons Smith Reagent for Imidazole Synthesis
R R R
CH2I2,Zn(Cu)
I
Ph N Et2O/THF Ph N CH2 Ph N H
Zn CH2I
N X(CH3)n N
N X(CH3)n 1 X(CH3)n
1 R
R R 1
R
R = H, CH3
1
R = N(CH3)2, N(CH2)5, N(CH2)4O
Ph N H X = S, n = 1
X = N, n = 2
N
R1
Jayakumar, S.; Ishar, M. P. S.; Mahajan, P. Tetrahedron Letters 1998, 39, 6557.
To a well stirred solution of zinc-copper couple (0.1 mmol) in dry ether (20 mL), under a nitrogen atmosphere, a
small crystal of iodine and diiodomethane (0.25 mmol) are added, and the reaction mixture is heated to reflux with
stirring for 10 min. A solution of 1,3-diazabuta-1,3-diene (0.1 mmol) in dry THF (25 mL) is added slowly and the
reaction mixture is again heated to reflux for 3-4 h and monitored by tlc. The solvent is removed under reduced
pressure and the residue is treated with water (100 mL) and CHCl3 (75 mL). The reaction mixture is filtered, the
residue is washed with CHCl3 (30 mL) and the combined organic extract is washed with water, dried over Na2SO4
and evaporated to give the crude product which is purified by column chromatography on silica gel using hexane
-ethyl acetate mixture (10:1) as eluent.
6. Aza-Annulation Provides Imidazole-4-Carboxylates
1
R N CO2CH3 (CH3)2N CO2CH3
(CH3)2N OEt Acetonitrile RNH2
R1
2
RX H OEt N -(CH3)2NH
2
XR
H
CO2CH3 1 N
R 1
R1 CO2CH3 R = CH3 , CH3S
2
RNH N - 2RXH N RX = OEt, SCH3
2 R = N(CH3)2, NH(CO2CH3), PhCH2NH2
XR R
Jouneau, S.; Bazureau, J. P. Tetrahedron Letters 1999, 40, 8097.

A solution of imidate (1.0 mmol) and N,N-dimethylformamide diethylacetal (1.1 mmol) in acetonitrile was heated to
reflux for 72 h. Removal of solvent under reduced pressure was followed by addition of amine (1.1 mmol) and
heating to 70 ˚C for 3 days. The crude product was purified by column chromatography to provide the imidazole
carboxylate in 70 % yield.
45
7. Synthesis of 2-Vinylimidazole Derivatives
R
O O O
Acetonitrile N
R CH3 H2N
reflux
N N
OH H
R = CH3, C6H5, C6H5CH2NH, C2H5O
Veronese, A. C; Vecchiati, G.; Sferra, S.; Orlandini, P. Synthesis 1984, 300.
Allylamine (5.05 mmol) is added to a solution of 3-hydroximino-2,4-pentadione (5 mmol) in anhydrous acetonitrile

(5 mL). The violet solution is stirred at room temperature for 12 h and then heated at reflux for 2 h. The mixture is
concentrated and purified by column chromatography on silica gel using ethyl acetate as eluent. Recrystallization
from ethyl ether-hexane provided the pure product in 65 % yield.
8. Imidazoles via Hetero-Cope Rearrangement

3
3
R
NR 1 1
1 R N Ph R
R
CH2 Cl Ph p-TsOH R3
2 O 2 N
R N R
2
R NEt3
N OH N Ph
Ph NHR3
1
R = 2R = (CH2)4
3
R = CH3
Lantos, I.; Zhang, W.; Shui, X.; Eggleston, D.S. J. Org. Chem. 1993, 58, 7092.
To a cooled solution of N-methylbenzenecarboximidoyl chloride (R3 = Me) (3.1 g, 20 mmol) in dry THF (50 mL) at
-78°C was added a 3.5 molar excess of triethylamine. The mixture was stirred for 0.5 h, and a solution of cyclo-
hexanone oxime (1.1 g, 10 mmol) was added. The solution was heated at reflux for 12 h. Water was added and
the mixture was extracted with CH2Cl2. The combined organic layer was washed with saturated NaCl and dried.
The solvent was removed under reduced pressure and the crude product was purified by column chromatography.
N-Methyl-N-[2-[[(methylamino)phenylmethylene]amino]-1-cyclohexen-1-yl]benzamide was obtained as an oil in
52% yield. The amidine (1 g, 2.8 mmol) was heated with p-toluenesulfonic acid (2.5 molar equiv) in toluene at
reflux in a Dean-Stark apparatus for 12 h. The solution was cooled to ambient temperature and was washed with 1
N NaOH solution. The mixture was concentrated under reduced pressure and purified by chromatography. The
product was obtained as white crystals in 97% yield.
46
9. 1,4-Disubstituted Imidazoles
4
O R
O 1
N
RNH2 1 HCONH2
Br 4 NHR
4
R R
∆ N
ether, -78°
1 R1
R = t-Bu 82% yield
4
Sorrel, T.N.; Allen, W.E. J. Org. Chem. 1994, 59, 1589 R = benzyl
Under an argon atmosphere, a pressure-equalizing dropping funnel charged with the α-bromo ketone (10.0 g) in
diethyl ether (20 mL) was attached to a 300-ml round-bottomed flask, containing a magnetic stir bar and a
solution of the primary amine (3 equiv) in diethyl ether (70 mL). The solution was stirred while cooling in a dry
ice-acetone bath to -78°C. The solution of the bromide was added dropwise over 15 min, and the mixture was
stirred for an additional 1 h at -78°C . The cooling bath was removed and the mixture allowed to warm to room
temperature and to stir for several hours, until precipitation of the HBr salts appeared complete. The contents of
the flask were poured into a separatory funnel and shaken with a small amount of 15% aqueous NaOH until the
white solids dissolved. The ether layer was washed with water and brine and dried over MgSO4. Filtration and
concentration of the solution afforded the crude amino ketone as a light yellow oil. This material could be isolated
by vacuum distillation or flash chromatography, but typically was used immediately in its crude form.
A 300-mL two necked flask with an attached air-cooled condenser was charged with formamide (35 mL), which
was heated to 180°C under argon with stirring. A pressure-equalizing dropping funnel containing the amino ketone
was fitted to the reaction vessel, and the amino ketone was added dropwise over 1 h. The mixture was allowed to
react for an additional 2-3 h at 180°C. After cooling, the dark reaction mixture was treated with an equal volume of
water and 20 mL of 15% aqueous NaOH. The mixture was extracted twice with 200-mL portions of toluene, which
were combined, washed with water and brine, and dried over Na2SO4. The drying agent was removed by filtration,
and the toluene was evaporated at reduced pressure to yield a yellow-brown oil which was purified by flash
chromatography with ethyl acetate as the eluent. Short-path distillation under reduced pressure with use of a
Kugelrohr apparatus afforded the colorless, hygroscopic 1,4-disubstituted imidazole.
10. Imidazoles From 4-Aminoisoxazoles

R1 R1 O R1 O
4 4
4
R NH Acylating R N R N
Reagent 2 H2, Pd/C
R R2
N N H2N R5
O R 5 O R5 EtOH, RT
O
2
R 2
R
O R1 = CH3, Ph, PhCH2
NaOH - R1
HN N R1 -H2O N N R2 = H, CH3, CH2CH3, Ph, CF3, C(CH3)3
EtOH 4 4
R R5 R R5 R4 = H, CH3
O O R5 = H, CH3
Reiter, L. J. Org. Chem. 1987, 52, 2714.

After acylation by standard procedures, 4-(acylamino)isoxazole was hydrogenated at 40 psi over 10 % palladium on
carbon in ethanol (ca. 10 mL/mmol of reactant). After 1 h, the reaction was usually complete by tlc. The catalyst is
removed by filtration and washed with ethanol. The filtrate containing the intermediate β-amino-α,β-unsaturated
ketone was treated with NaOH (pellets, 1.1 equiv) at reflux for 1 h. Solid NH4Cl (1.2 equiv) was then added, the
reaction allowed to cool to r t, and the ethanol removed in vacuo . The residue was slurried in acetone and the
mixture filtered. Concentration of the filtrate gave the crude product which is purified by column chromatography or
recrystallization to give pure imidazole in 80 % yield.
47
Use of Tosmic Reagent for Heterocyclic Synthesis van Leusen, A. M. Lect. Heterocycl.
Chem. 1980, 5, S111. Zwanenburg,
+ - Ts B.; Klunder, A. J. H. in Perspectives in
SO2CH2 N C n-BuLi (2 eq.) the Organic Chemistry of Sulfur.;
N Elsevier Science Publishers:
Amsterdam, 1987, pp 119-144
PhCOOEt Ph
Me O
70 % van Leusen, A. M.; Schut, H.
Tetrahedron Lett. 1976, 285
van Nispen, S. P.J. M.; Mensink, C.; van Leusen, A. M. Tetrahedron Lett. 1980, 3723
van Leusen, A. M.; Siderius, H.; Hoogendoom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337
+ - Ts
SO2CH2 N C n-BuLi (2 eq.) N
PhCN Ph N
Me
60 % H
van Leusen, A. M.; Siderius, H.; Hoogendoom, B. E.; van Leusen, D. Tetrahedron Lett. 1972, 5337
Me CO2Me
+ - NaH
SO2CH2 N C
MeCH=CHCO2Me
N
Me 64 % H
Oldenziel, O. H.; van Leusen, A. M. Tetrahedron Lett. 1972, 5777
+ - Ts
SO2CH2 N C S
KOH N
+ PhCSCH2CO2H
Me 53 % Ph S
Ph NO2
van Leusen, D.; Flentge, E.; van Leusen, A. M. MeNO2
Tetrahedron 1991, 47, 4639
tBuOK N
van Leusen, D.; van Echten E.; van Leusen, A. M. 94 % H
J. Org. Chem. 1992, 57, 2245
+ - Ph CN
+ - 1) PhCHO/nBuOK Ph N C Et2OCCH2CN
Ts C H2 N C
2) POCl3/Et3N tBuOK
H Ts N
99 % H
Ts = Me SO2 Ph CO2Et
Et2OCCH2COMe
tBuOK N
92 % H
48
Applications of Tosmic for Complex Molecule Synthesis
van Leusen, D.; van Leusen, A. M. In Organic Reactions; Overman, L. E., Eds.; Wiley & Sons: New York, 2001, 57,
417; Tandon, V. K.; Rai, S. Sulfur Reports 2003, 24, 307.
1. Reductive Cyanation
O CN
TsCH2N C t-BuOK
+ 69%
t-BuOK MeO MeO
Oldenziel, O. H.; van Leusen, D.; van Leusen, A. M. J. Org. Chem. 1977, 42, 3114.
2. Use as a Connective Reagent
OTHP
OTHP OTHP H Br
NaOH
TsCH2N C + Br Ts
NC NaOH
82%
OTHP Ts NC OTHP O
(NH4)2SO4
C
75% O
Yadav, J. S.; Gadgil, V. R. Tetrahedron Lett. 1990, 31, 6217.
3. Knoevenagel-type Condensation
MeO MeO
1) t-BuOK NC
MeO MeO
TsCH2N C +
CHO 2) POCl3, i-Pr2NH Ts
64%
MeO
NH
MeO
OMe
papaverine
OMe
Barrett, A. G.; Barton, D. H.; Falk, J. R.; Papaioannou, D.; Widdowson, D. A. J. Chem. Soc., Perkin Trans. 1979, 652.
49
4. Synthesis of Oxazoles N C
O Ts
t-BuOK
TsCH2N C + + CH2O
MeO MeO
Na2CO3
O
N 96%
MeO
Van Leusen, D.; Batist, J. N.; Lei, J.; Van Echten, E.; Brouwer, A. C.; Van Leusen, A. M. J. Org. Chem. 1994, 59, 5650.
5. Synthesis of Oxazoles
N NaOMe
TsCH2N C + N
O 35%
N O
N
H N
Dopamine D4 Receptor Ligands

Haubmann, C.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 1999, 9, 3143.
6. Synthesis of Thiazoles
H Tos
H
S
n-BuLi
TsCH2N C + N
O S
79%
OH
Jacobi, P. A.; Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327.
50
7. Synthesis of Pyrroles
OMe Ph OMe Ph
NaH
TsCH2N C + MeO N MeO N
H H
55%
O O
HN
Ph Ph
Black, D. S.; Bowyer, M. C.; Kumar, N. Tetrahedron 1997, 53, 8565.
8. Synthesis of Imidazoles
O N N H
NH2 SO2NH2
N
N CO2Me
1) MeO CHO N
O
2) TOSMIC, K2CO3
CN
CN NH2
NH
Benzamidine Factor Xa Inhibitors
Fevig, J. M.; Pinto, D. L.; Han, Q.; Quan, M. L.; Pruitt, I. C.; Jacobson, I. C.; Galemmo, R. A.; Wang, S.; Orwat, M. J.;
Bostrom, L. L.; Knabb, R. M.; Wong, P. C.; Lam, P. Y.; Wexler, R. R. Bioorg. Med. Chem. Lett. 2001, 11, 641.
9. Synthesis of Pyrimidines
N N
N
N N
N Na/Hg
DBU
TsCH2N C +
80% N Na2HPO4 N
N
H CHO 55%
N N
Ts
Minguez, J. M.; Vaquero, J. J.; Alvarez-Builla, J.; Castano, O.; Andres, J. L. J. Org. Chem. 1999, 64, 7788.
51
Tosmic Reagent and Its Use in Heterocyclic Synthesis

Reaction with Aldehydes to Form Oxazoles
N
K2CO3
TsCH2N C + O
N CHO 82% N
TOSMIC
Saikachi, H.; Kitagawa, T.; Sasaki, H.; van Leusen, A.M. Chem. Pharm. Bull. 1979, 27, 793.
To a mixture of 2-pyridinecarboxaldehyde (0.01 mol) and tosylmethyl isocyanide (1.9 g, 0.01 mol) in 30 mL of
MeOH was added K2CO3 (1.4 g, 0.01 mol). The solution was refluxed for 2 h and the solvent was removed
under reduced pressure. The residue was poured into ice water and extracted with ether. The organic layer was
washed with 2% HCl and water and dried over Na2SO4. After filtration and evaporation of the solvent, the crude
residue was distilled (95-98°C/0.15 torr) to give an 82% yield of the desired oxazole.
Reaction with Carbon Disulfide to Form Thiazoles
Ts Ts
+ -
BuN Br , 10% NaOH N MeI N
TsCH2N C + CS2
S 90% MeS
S S
Bu4N
van Leusen, A.M.; Wildeman, J. Synthesis 1979, 501.
To a solution of tosylmethyl isocyanide (1.9 g, 10 mmol), carbon disulfide (5 mL) and chloroform (10 mL) was
added tetrabutylammonium bromide (3.5 g, 11 mmol) and 10% NaOH (10 mL). The mixture was stirred for 1.5 h
at rt and the layers were separated. The aqueous layer was extracted with chloroform and the combined organic
layers were washed with water and dried over MgSO4. After filtration and removal of the solvent, the crude
residue was taken up in chloroform (20 mL), methyl iodide (2.8 g, 20 mmol) was added, and the mixture was
stirred for 3 h at rt. The solvent was removed and the crude solid was washed with methanol, ether, and dried.
Recrystallization from chloroform/methanol gave 2.6 g (90%) of the desired thiazole.
Formation of Pyrrolo[1,2-c]pyrimidines
H R1
N CHO
R1 DBU, THF N N
TsCH2N C + R2
61-82% Ts
R2 R3
R3
Minguez, J.M.; Vaquero, J.J.; Garcia-Navio, J.L.; Alvarez-Builla, J. Tetrahedron Lett. 1996, 37, 4263.
To a mixture of 214 mg (1.1 mmol) of tosylmethyl isocyanide and 167 mg (1.1 mmol) of DBU in 2 mL of THF was
added 95 mg (1 mmol) of pyrrole-2-carboxaldehyde in 2 mL of THF. The mixture was stirred at rt for 2 h and
then neutralized with acetic acid. The solvent was removed under reduced pressure and the residue was
chromatographed on silica gel and recrystallized from CH3CN to give the desired product in 82% yield.
52
Reaction with Imidoyl Chlorides to Form Imidazoles
Ts
Ph H Ts
NaH N H+ N
TsCH2N C + N
Ph C
Cl Ph 60% N Ph
:
N
Ph Ph
van Leusen, A.M.; Wildeman, J.; Oldenziel, O.H. J. Org. Chem. 1977, 42, 1153.
A solution of tosylmethyl isocyanide (390 mg, 2.0 mmol) and N-phenylbenzimidoyl chloride (430 mg, 2.0 mmol) in 5
mL of DME was added over 15 min to a suspension of NaH (50 mg, 2.0 mmol) in 5 mL of DME at rt. The mixture
was stirred for 45 min and then slowly poured into water. The precipitate was collected and recrystallized from
benzene/hexane to give 450 mg (60%) of the desired imidazole.
Reaction with Olefins to Form 3,4-Disubstituted Pyrroles

H
N
Ph tBuOK (2 eq.)
TsCH2N C +
CN 88% Ph CN
van Leusen, D.; van Echten, E.; van Leusen, A.M. J. Org. Chem. 1992, 57, 2245.
To a stirred solution of t-BuOK (1.0 g, 13 mmol) in THF (30 mL) at -30 °C was added a solution of tosylmethyl
isocyanide (1.2 g, 6.0 mmol) in THF (10 mL). The mixture was stirred for 4 min and a solution of cinnamonitrile (0.77
g, 6.0 mmol) in THF (10 mL) was added over 4 min. After stirring for 15 min at -10 °C, the mixture was poured onto
50 g of ice. The THF was removed under reduced pressure and the precipitate was filtered, washed with water,
and dried under vacuum to give 0.89 g (88%) of the desired pyrrole.
Sequential Tosmic Reactions in the Synthesis of PDE II CO2tBu
CH3
1) NaH, HMDS
N C + CO2tBu
Ts 2) PhSO2Cl, NaH CH3 N
HMDS, Imidazole
SO2Ph
TosMIC
NaH, HMDS
tBuO2C
N Ac
N SO2Ph
HO2C
N OH
H OMe CH3 N
SO2Ph
PDE II
53
Top Ten Methods to Synthesize Thiazoles

1. Modified Hantzsch Type Synthesis
Synthesis of 2,4-Disubstituted Thiazoles from (Z)-(2-Acetoxyvinyl) phenyl-iodanes
R S R
Ph R1CNH2 , Et3N N
AcO I
BF4 MeOH S R1
S n-C8H17
n-C8H17 N
Ph H2N CNH2 , Et3N
AcO I NH2
BF4 MeOH S
Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen, D.-W.;
J. Org. Chem., 2003; 68(20); 7887-7888.
To a stirred solution of (Z)-(2-acetoxy-1-decenyl)-iodane (25 mg, 0.05 mmol) and thiourea (5 mg, 0.06 mmol)
in dry methanol (1.5 mL) was added triethylamine (6 mg, 0.06 mmol) under nitrogen at room temperature and
the mixture was stirred for 5 h. After removal of the solvent under reduced pressure, the residue was dissolved
in a mixture of ether (30 mL) and water (10 mL). The organic layer was washed with water and brine, dried
over Na2SO4, and concentrated. Purification by preparative TLC (hexane-ethyl acetate) gave the thiazole
(91%) as colorless plates.
2. The Charette Synthesis

Synthesis of Thiazole from Thiazoline
O O S O S
1. Tf2O, pyr, CH2Cl2 BrCCl3, DBU
MeHN 2. L-Cysteine . HCl, pyr N N
EtO 99% EtO
90%
DeRoy, P. L.; Charette, A. B.; Org. Lett. 2003; 5, 4163-4165.
To a solution of diispropylamine (5 mL, 51 mmol) in anhydrous THF (80 mL) at -20 oC was added a solution of
butyllithium (1.6 M in THF), stirred for 15 min, and cooled to -78 oC. A solution of the thioester (6 g, 51 mmol)
in THF (20 mL) was cannulated slowly into the yellow solution and stirred for an additional 15 min.
Chlorotrimethylsilane (6.4 mL, 51 mmol) was added, and the solution was stirred for an additional 1 h at
-78oC. The solution was warmed to rt over a 1 h period before being diluted with pentane (150 mL) and
washed with phosphate buffer pH 7 (100 mL). The organic layer was dried over Na2SO4, concentrated, and
distilled under vacuum to furnish the (Z) silylketene thioacetal. To a solution of thiazoline (4.8 g, 24 mmol) in
CH2Cl2 (90 mL) at 0 oC was added DBU (7.2 mL, 48 mmol) and the resulting mixture was stirred for 10 min.
Bromotrichloromethane (2.4 mL, 24.1 mmol) was added dropwise and the reaction was then warm up to rt.
After 1 h, the reaction was quenched with a saturated aqueous solution of NaHCO3 and transferred in a
separatory funnel and the aqueous phase was discarded. The organic phase was dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The crude mixture was purified by column
chromatography on silica gel (20% EtOAc/hexane) to afford the thiazole (4.8 g, 99%) as a colorless oil.
54
3. Cook-Heilbron Type Synthesis
Reaction of α-Aminonitriles with Dithioacids and their Derivatives
R2 NH2 R2 R2
SH NH N
C +
S R1 R1 H2N S R1
S
N N
Et2O
NH2 + CS2
N
C
H2N S SH
N
Cook, A. H.; Heilbron, I.; Levy, A. L.; J. Chem. Soc. 1947, 1598.
α-Aminobenzyl cyanide (13.5 g) was refluxed in ether (250 mL) with carbon disulphide (10 g) for 8 h. Upon
cooling, large yellow crystals were deposited. The yield of yellow crystals (12.8 g) was augmented by
allowing the filtrate to stand in carbon disulphide overnight. The total yield of
5-amino-2-mercapto-4-phenylthiazole was 19.6 g (93%).
4. Isocyanide Synthesis
Reaction of α-Metallated Isocyanides with Thiono Esters
-
C
S +N
EWG
+
base - N
EWGCH2N C- + S
R OEt EWG R
R OEt S
S EtO2C
+ NaCN N
EWGCH2N C- + H OEt
EtOH S
Hartman, G. D.; Weinstock, L. M. Synthesis, 1976, 6, 681.

A solution of ethyl isocyanoacetate (4.5 g, 40 mmol) and O-ethyl thioformate (3.6 g, 40 mmol) in dry ethanol
(15 mL) was added dropwise with vigorous stirring to a suspension of sodium cyanide (0.25 g) in ethanol (10
mL). An exotherm developed during the addition and the reaction mixture was heated at 50 oC for 0.5 h.
The solvent was removed under reduced pressure and the resulting dark oil was extracted several times with
hot hexane to give 5.8 g (92%) of the product.
55
5. One-pot Synthesis of 2-Aminothiazoles using Supported Reagents
Reaction of α-bromo ketone with KSCN/SiO2 and NH4OAc/Al2O3
O O R1
KSCN/SiO2 NH4OAc/Al2O3 N
R2 R2 NHR
R1 R1
R2 S
Br SCN
O Ph N H
Br KSCN/SiO2- NH3OAc/Al2O3
Ph N
97% Ph S
Ph
Kodomari, M.; Aoyama, T.; Suzuki, Y.Tetrahedron Letters 2002, 43, 1717-1720.
A mixture of α-bromo ketone (1 mmol), KSCN/SiO2 (5 mmol) and NH4OAc/Al2O3 (6 mmol) was stirred in
benzene at 80oC for 6 h, and then the used solid reagents were removed by filtration. The filtrate was
evaporated to leave a crude product, which was purified by column chromatography over silica gel.
6. Synthesis of 2-Acylaminomethylthiazoles
Multicomponent solid-phase synthesis
O
NH2 CHO
R1 R2 SH 16h, 20oC
MeOOC
S
R1 O
MeOOC R1
N S
o
N R2 31~96%
N R2 16h, 20 C H
N
O MeOOC
Henkel, B.; Sax, M.; Domling, A. Tetrahedron Letters 2003, 44, 3679-3682.
Deprotected Rink resin (purchased from Pepchem, Tubingen) (200 mg, 0.21 mmol) was washed with 3 mL of
trimethylorthoformate. Isobutyraldehyde (0.19 mL, 2.1 mmol) was dissolved in 3 mL of trimethylorthoformate
and added to the resin which was agitated for 16 h. The resin was filtered and washed with
trimethylorthoformate, a 1:1 mixture of dichloromethane and methanol and finally with methanol. Subsequently,
0.19 g of 3-(N,N-dimethylamino)-2-isocyanoacrylate (1.3 mmol) and 0.15 ml of thiobenzoic acid (1.3 mmol)
dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1) was added to the resin and the mixture
was allowed to react for 16 h. The resin was filtered and washed twice with dichloromethane and methanol and
again three times with dichloromethane. The resin was treated with 3 mL of 50% trifluoroacetic acid in
dichloromethane for 2 h. The cleavage mixture was filtered and the resin washed twice with dichloromethane.
The combined solution was evaporated to dryness. The crude product was obtained in 71% yield and was
purified via preparative HPLC using a methanol/water gradient.
56
7. Synthesis of 4-Substituted 2-Phenylaminothiazoles from Amidines
Reaction of amidine salt with phenyl isothiocyanate
NH NaOH/H2O NH2 S C6H5COCH2Br

HX + Et N C S
THF / 0oC C Et
Ph NH2 Ph N N Et3N
85% H
Ph O Ph OH Ph
-NH3 N
NH2 S NH2 S
68%
Ph
S N Et
C Et C Et H
Ph N N O
Ph N N
Romero-Ortega, M.; Aviles, A.; Cruz, R.; Fuentes, A.; Gomez, R. M.; Plata, A.; J. Org. Chem. 2000, 65, 7244.
A suspension of amidine salt (1 equiv) in THF (2-5 mL/mmol amidine) was added at 0 oC to aqueous sodium
hydroxide (1equiv) and phenyl isothiocyanate (1 equiv), and the reaction mixture was stirred for 1-2 h at this
temperature. The mixture was then diluted with ethyl acetate (20 mL), and the organic phase was washed with
saturated sodium chloride solution and dried (Na2SO4 ). Evaporation of the solvent in vacuo gave the crude
products as a solid. The pure material was obtained after crystallization from hexane-dichloromethane.
The R-bromo carbonyl compound (1 equiv) was added slowly at room temperature to a stirred solution of
the N-phenylthiocarbamoylamidine (1 equiv) in anhydrous THF (2 mL) containing anhydrous triethylamine (1 equiv)
maintained under a nitrogen atmosphere. The reaction mixture was stirred for an additional 2-3 h, diluted with ethyl
acetate (20 mL), the mixture was washed with saturated NH4Cl solution (30 mL). The organic phase was
separated, dried (Na2SO4),and evaporated in vacuo.
8. Hantzsch Type Synthesis

Condensation of α-Halocarbonyl Compounds with Thioamides
R1 O X- R1
NH2 R1 O
+ NH2+ N
R2 X S R3 R2 R3
R2 S R3 S
EtO2C O NH2 MeO2C

H MeOH N H Ph
+ N Ph N
CH2Br S
S
O O
Li, G.; Warner, P. M.; Jebaratnam, D. J. J. Org. Chem., 1996, 61, 778.
Ethyl bromopyruvate (11.6 g, 60 mmol) was added dropwise, over a 0.5 h period, to a 50 oC solution of the
thioamide (11.5 g, 59 mmol) in methanol (100 mL) after which time the reaction was refluxed for an additional 2
h. Most of the product crystallized when the solution was set aside at room temperature overnight. The filtrate
was evaporated, redissolved in benzene, washed successively with a saturated aqueous sodium bicarbonate
and water, dried over anhydrous sodium sulfate, and evaporated. Recystallization of this residue from
methanol provided 12 g (74%) of the product.
57
9. Gabriel Type Synthesis

Reaction of α-Acylaminoketones with Phosphorous Pentachloride
R2 R1
P2S5 N
NH
R3 R1
heat R2 OH
O O S
H
N CO2Me
P2Cl5 N
O CO2Me
O pyridine S
N N
H H
Uchikawa, O.; Fukatsu, K.; Aono, T. J. Heterocyclic Chem. 1994, 31, 877.
To a solution of the diamide (5.2 g) in pyridine (50 mL) was added phosphorous pentasulfide (5.4 g) and the
mixture was heated at 100 oC for 5 h. After being cooled to room temperature, a saturated aqueous sodium
hydrogen carbonate solution was added to the reaction mixture, and the product was extracted with chloroform.
The organic layer was washed with water and dried over magnesium sulfate. The filtrate was concentrated and
the residue was purified by column chromatography. The residue was recrystallized from ethyl acetate to yield 2.8
g (54%) of the product.
10. Dubs Type Synthesis

Condensation of α-Acylthioketones with Ammonia
R2 O O R2 O R2
Et3N O NH4OAc N
+
HS CH3 CH3 HOAc R1 CH3
R1 Br R1 S S
O NH4OAc R2
R2 O
N
+
R1 HS R3 HOAc
Br R1 S R3
Dubs, P.; Stuessi, R. Synthesis, 1976, 6, 696.

2-Bromo-butanone (15 g, 0.1 mol) was added to a solution of thioacetic acid (7.6 g, 0.1 mol) in glacial acetic
acid (84 mL), combined with ammonium acetate (27 g, 0.35 mol), and kept at reflux for 4 h. After
neutralization with a saturated sodium hydroxide solution and extraction with pentane, the combined extracts
were dried and concentrated. The residue was distilled through a Vigreux column to afford 9.1 g (72%) of the
product .
58
Top Ten Methods to Synthesize Isothiazoles

1. From α-Oxo Ketene Dithioacetals
HO R R1
N SCH3
SOCl2, Pyridine
R SCH3 N
S SCH3
R1
R. Karl Dieter and Hsiu Ju Chang; J. Org. Chem. 1989, 54, 1088-1092
Dry methylene chloride (25 mL) was cooled to 0-5oC with an ice/water bath under nitrogen. Thionyl
chloride (5 mmol) was added dropwise and the solution was stirred for 10 min. Pyridine (5 mmol)
was added and the mixture was allowed to stir for another 15 min at 0oC. The oxime in dry
methylene chloride was added dropwise to the solution over a period of 15 min. The solution was
stirred for 1 h at 0oC, warmed to room temp, and was then stirred for another 8-10 h. The reaction
mixture was diluted with 60 mL diethyl ether, washed with 10% HCl, saturated sodium bicarbonate,
distilled water, and brine. The organic phase was dried over MgSO4. Filtration, followed by removal
of the solvent and silica gel column chromatography gave the isothiazole in 75-90% yield.
2. Conversion of 2,5-Disubstituted Furans into Isothiazoles

R1
ethyl carbamate, SOCl2,
pyridine in refluxing benzene R S
N
R O R1
O
Laaman, S.M.; Meth-Cohn, O.; Rees, C.W.; Synthesis 1999, 5, 757-759
A solution of ethyl carbamate (4.3 mmol), SOCl2 (4.3 mmol), and pyridine (2.0 mL) in benzene (20 mL)
was stirred under nitrogen at ambient temperature for 30 min. The appropriate furan (1 mmol) was
added and the mixture was heated at reflux until the starting material was consumed. The solvent
was removed under reduced pressure and the the resulting residue was dissolved in CH2Cl2 (15 mL),
washed with HCl, H2O and dried over MgSO4. The solvent was evaporated and the residue was
purified by flash chromatography giving the isothiazole in 56-100% yield.
3. Oxidative Cyclization of Imino Thioamides

R1 R2
NH S
oxidation
R1 NH2 N
S NH2
R2
Goerdeler, J.; Pohland, H.; Angew. Chem. , Int. Ed. Engl. 1961, 2950
A 1.9 g sample of the β-iminothioamide was taken up in 80 mL of CHCl3 in an ice bath. A mixture of 1.6 g of
bromine in a small amount of CHCl3 was added dropwise. After a short period, the hydrobromide salt
precipitated out of solution. The mixture was stirred for 5 min and the salt was filtered. Recrystallization from
ethanol/ether gave the isothiazole in 85% yield.
59
4. Cyclization of β-Thioacrolein with Liquid Ammonia
O
liq. NH3
H SR N
S
Wille, F.; Capeller, L.; Steiner, A. Angew. Chem. , Int. Ed. Engl. 1962, 335
Wille, F.; Schwab, W.; Schmitzer, J.; Jochum, C. Chem. Ber. 1997, 110, 264
A 67 g sample of the acrolein derivative was taken up in 70 mL of liquid ammonia at -78 oC. The mixture was
stirred until a bright yellow solution had formed. The ammonia solution was left to evaporate at room
temperature and the residue was steam distilled and this was followed by extraction of the distillate with ether
and drying over KOH to give 17.7g of the isothiazole (60% yield).
5. Use of Diene Derivatives for Isothiazole Formation
Cl Cl CCl3
Cl Cl S8
heat N
Cl Cl S
Cl NO2
Kaberdin, R.V.; Potkin, V. I.; Oldekop, Yu. A.; Zh. Org. Khim. 1990, 26(7), 1560-166
The polychloro nitrodiene was heated with neat sulfur to give the isothiazole in 52% yield.
6. Use of Primary Enamines for Isothiazole Formation
X Cl Cl X R
R
+ +S N N
S NC S
NH2 Cl -
Clarke, D,; Emayan K.; Rees C.W.; J. Chem. Soc., Perkins Trans. 1, 1998, 77
A mixture of the enamine (3 mmol) and 4,5-dichloro-1,2,3-dithiazolium chloride (3 mmol) in

dichloromethane (25 mL) was stirred at room temperature for 1 h. Pyridine was added to the mixture
which was allowed to stir for an additional 30 min. The product was separated by flash chromatography
on silica gel eluting with 1:3 dichloromethane/pentane to give the isothiazole in 40-78% yield.
60
7. From Nitrile Sulfide Cycloaddition Chemistry

R R1
R1 N
C R2
C S
O SOCl2 N S heat R2
+ -
-CO2 R C N S
R NH2 R O O R1 oxid
CH
CH
Crosby, J.; McKie, M. C.; Paton, M. R2 R R1
R.;Ross, J. F. ARKIVOC 2000, 1(5),
720-734
N R2
S
Oxathiazolone in xylene was heated (5 h) under reflux with 10 equiv of diethyl furmarate until the
starting material was consumed. After the evaporation of solvent and dipolarophile, by-products were
removed by distillation and/or recrystallization (40-80% yield). The resulting isothiazolone (1.4 mmol)
in dichloromethane (20 mL) was stirred vigorously with 8% aqueous NaOCl (40 mL) and
benzyltriethylammonium chloride (0.2 mmol) until no starting material remained (5 h). The organic
layer was separated, washed with water, dried over MgSO4, and concentrated under vaccum. The
crude isothiazole was purified by recrystallization and/or distillation in 86-92% yield.
8. From Allylic Derivatives using Trithiazyl Trichloride

R3 R4
R2
(NSCl)3
R4 R1 R2 N
S
R3
Duan, X-G.; Duan, X-L.; Rees, C.W.; J. Chem. Soc., Perkins Trans. 1, 1997, 127
Either procedure A or B was used depending on the isothiazole. In procedure A, a mixture of the allylic
derivative (1 mmol) and the trithiazyl trichloride (1 mmol) in 20 mL tetrachloromethane was heated at
reflux overnight. The solvent was evaporated and the residue was purified by flash chromatograhy on
silica using dicloromethane and light petroleum. Procedure B differs only in the use of 4 Ao molecular
sieves (2 g) and 25 mL tetrachloromethane. The sieves were filtered and washed with dichloromethane
to give the isothiazole in good yield.
9. From 1,2,4-Dithiazane Derivatives
CH3 R
CH3 S R heat
N N
CH3 S
CH3 S
Bryce, M. R. et. al., J. Chem. Soc., Chem. Comm., 1992, 478
Bryce, M. R. et. al, J. Chem. Soc., Perkin Trans. 1, 1992, 2295
Bryce, M. R.; Davison, G. R.; Gough, S.; J. Chem. Soc., Perkin Trans. 1, 1994, 2571
A solution of the 1,2,4-dithiazane (1 mmol) in dry toluene ( 5 mL) was heated at reflux for 18 h. The solvent
was removed under reduced pressure and the mixture was chromatographed on silica gel to give the
isothiazole in 55-100% yield.
61
Top Methods to Synthesize Indoles
1. The Leimgruber-Batcho Indole Synthesis
CH3 Me2NCH(OMe)2 NMe2 H2

DMF, 130o Pd-C N
NO2 NO2
97% 80% H
R.D. Clark, D. Repke, Heterocycles, 1984, 22, 195
A solution of methyl 2-methyl-3-nitrobenzoate (9.8 g, 0.05 mol) and DMFDMA (17.8 g, 0.15 mol) in 50 ml of
DMF was heated at 130 oC for 6 h. The DMF was removed under reduced pressure, and the residue was
distilled at 120 oC (0.2 mm) to give 10.7 g (86%) of 6-carbomethoxy-β-dimethylamino-2-nitrostyrene. A mixture
of 7.0 g (28 mmol) of 6-carbomethoxy-β-dimethylamino-2-nitrostyrene in 140 ml of dry benzene containing 1.4
g of 10% Pd/C was shaken in a Parr apparatus under a hydrogen atmosphere of 50 psi for 1.5 h. The catalyst
was removed by filtration and the benzene solution was washed with 5% HCl and brine, dried (MgSO4) and
concentrated. Chromatography of the residue on silica gel afforded 6.9 g (82%) of methyl
indole-4-carboxylate.
2. Fischer Indole Synthesis

H
N
COOC2H5 PPA (4 eq)
O2N NH N COOC2H5
CH3 110 oC, 90 min O2N
83%
Hughes, D. Organic Preparations and Procedures, 1993, 609
Guy, A.; Guette, J-P. Synthesis, 1980, 222
Ethyl 2-(4-nitrophenylhydrozono)-propanoate (3,4-nitophenylhydrazone of ethyl pyruvate (1.5 g, 7 mmol) was
added to a stirred suspension of PPA (6 g) in xylene (15 ml) at 80 oC. The mixture is heated at 110 oC for 1
h, then washed with water, dried over magnesium sulfate and evaporated to dryness. The product is
recrystallized from diisopropyl ether to give the product in 83% yield.
3. The Gassman 2,3-Sigmatropic Shift Protocol
CH3S R1
CH3SCHCOR R1
LiAlH4
R1
R R
NHCl NEt3 N N
H
Gassman, P.G.; Cue, B.W. J. Am. Chem. Soc. 1974, 20, 5495
Gassman, P.G.;Gilbert, D. P. J. Chem. Soc. Chem. Commun. 1974, 201
Hamel, P.; Girard, Y. J. Org. Chem. 1994, 59, 6372
Ishikawa, H.; Uno, T. Chem. Pharm. Bull. 1990, 38, 2459
Gassman, P.G.; Gruetzmacher, G. J. Am. Chem. Soc. 1974, 96, 5512
To a vigorously stirred solution of 0.044 mol of aniline in 150 mL of CH2Cl2 at -65 oC was added dropwise a
solution of 0.044 mol of t-butyl hypochlorite in 20 mL of CH2Cl2. After 5-10 min, 0.044 mol of the sulfide
dissolved in 20 mL of CH2Cl2 was added causing an isotherm. Stirring was continued at -65 oC for 1 h. To this
mixture was added 0.044 mol of triethylamine in 20 mL of CH2Cl2. After the addition was complete, the cooling
bath was removed and the solution was allowed to warm to 25 oC. A 50 mL portion of water was added and the
organic layer was separated, dried, filtered and evaporated. The residue was purified by column
chromatography over silica gel using CH2Cl2 as the eluent. Recrystallization gave the pure indole. A solution of
0.022 mol of the thioindole in absolute ethanol was stirred with an excess of Ra/Ni for 30 min. The organic layer
was decanted from the catalyst and the catalyst was washed thoroughly with ethanol, and the solvent was
removed under reduced pressure to give the indole.
62
4. Preparation of Indoles by Annelation of Pyrroles
O O
H H2SO4
RCO N N
Ts N
R R Ts
OH Ts
Muratake, H.; Natsume, M. Heterocycles, 1989, 29, 783

Muratake, H.; Natsume, M. Heterocycles, 1990, 31, 683
To a solution of 3-cyclohexanoyl-1-(4-methylphenylsulfonyl)pyrrole (85 mg) in THF (3 mL) at -20 oC under

Ar was added the Grignard reagent prepared from 2-(1,3-dioxan-2-yl) ethyl bromide (0.6 mL) and Mg (90
mg) in THF (3.4 mL). After 15 min, the reaction was quenched with aqueous NH4Cl and extracted with
CH2Cl2. After washing, the intermediate carbinol was obtained in 97 % yield. A portion of this product
was dissolved in 6% H2SO4 in isopropanol (4.5 mL). The solution was heated at reflux for 30 min. After
cooling and dilution with water, the solution was extracted with CH2Cl2 and chromatographed to give the
indole in 82% yield.
5. Tin-Mediated Indole Synthesis
n-Bu3SnH (1.1 equiv) R

R AlBN (5%), CH3CN, 100 °C
R1
NC R1X, Pd(PPh3)4 (5%), NEt3 (1 equiv), 100 °C N
H
Fukuyama, T.; Chen, X; J. Am. Chem. Soc, 1994, 116, 3127
A solution of 0.85 mmol ofthe isonitrile, 0.93 mmol of n-Bu3SnH, and 0.04 mol of AIBN in 5 mL of dry
acetonitrile was heated to 100 oC for 1 h in a tightly capped culture under an Ar atmosphere. The reaction
was cooled to room temperature and 1.02 mol of triethylamine, 0.04 mmol of Pd(PPh3)4, and 1.02 mmol of
bromobenzene was added. The mixture was heated for additional 5 h under Ar. The reaction mixture was
partioned between hexane and CH3CN. Ether was added to the combined hexane layer and the organic
layer was washed with a 1:1 mixture of 3N HCl and brine. The extracts were washed with brine, dried
over sodium sulfate and evaporated to dryness in vacuo. The crude product was purified by flash silica
gel chromatography to give desired indole.
63
Synthesis of 3-Substituted Indoles via a Tin Mediated Cyclization

Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127
1) n-Bu3SnH (1.1 equiv)

R
AIBN (5%), CH3CN, 100oC R
NC 2) H3O+ N
H
CO2Me
CO2Me
NC N
H
OTHP
OTHP
NC N
H
R1 R1
R1
NC N C N SnBu3
SnBu3
Bu3SnH R1 H+ R1
N SnBu3 N
2
H R X, Pd(0) H
R1
N R2
H
64
Synthesis of (+) Vinblastine via Radical Indole Cyclizations

Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.; Tokuyama,
H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137
OH (+) Vinblastine
N
N
N
H OH
MeO2C
MeO N OAc
H
Me CO2Me
Ns
N
N
OTFA
Et OH
N +
H MeO N OAc
MeO2C H
OTs Me CO2Me
RO
OR
OH
OR
Et
N
R
MeO2C MeO N
OR H
CO2Me
RO OR
OR
H OR S
N
Et CO2Bn
S MeO N
H
MeO2C CO2Me
OR
RO OR
Plausible Mechanism
R N R
R N R H
-HSSnBu3
RO RO
H OR
SnBu3
SSnBu3
R NH R R R N
N H R
S R H SSnBu3
65
Additional Methods to Synthesize Indoles

Titanium Catalyzed Indole Synthesis
Cl Ph
O TiCl3, Zn, DME Cl OEt
OEt
N >85%
H N O
O H
Fürstner, A.; Hupperts, A.; Seidel, G. Org. Synth. 1999, 76, 142
Fürstner, A.; Ernst, A.; Krause, H.; Ptock, A. Tetrahedron, 1996, 52, 7329
A flask charged with N-(2-benzoyl-4-chlorophenyl)oxanilic acid ethyl ester (13 g, 40 mmol), titanium(III)
chloride (TiCl3) (12.3 g, 80 mmol), zinc dust (10.4 g, 160 mmol) and DME (250 mL) was heated at reflux for 2
hrs with stirring. The mixture was allowed to cool to ambient temperature and then slowly filtered through a
short pad of silica washed with ethyl acetate (5 x 50 ml). The product was recrystallized from ethyl acetate /
hexane to afford ethyl 5-chloro-3-phenylindole-2 carboxylate in 85% yield.
Reductive Coupling of Oxo Amides to Indole Derivatives
O
R1 [Ti] R1
O
N R2 N R2
R3 R3
Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215
CH2R
I Et3Si CH2R
SiEt3
1% Pd(OAc)2, Na2CO3, LiCl
MeO NH2 DMF, 100˚C, 77% MeO N
H
Ma, C.; Cook, J.M.; et. al. J. Org. Chem. 2001, 66, 4525
Wu, T.H.Y.; Ding, S.; Gray, N.S.; Schultz, P.S. Org. Lett. 2001, 3, 3827
Roesch, K.R.; Larock, R.C. J. Org. Chem. 2001, 66, 412
Larock, R.C.; Yum, E.K.; Refvik, M.D. J. Org. Chem. 1998, 63, 7652
Larock, R.C.; Yum, E.K. J. Am. Chem. Soc. 1991, 113, 6689
To a three-neck flask (3 L) equipped with an overhead stir were charged 2-iodo-5-methoxyaniline (150 g, 0.6
mol) and the Schöllkopf derivative (265 g, 0.7 mol), as well as lithium chloride (2.5 g, 0.06 mol), sodium
carbonate (160 g, 1.5 mol), palladium(II) acetate (1.7 g, 1 mol%), and dry DMF (2 L). The mixture was
degassed with a vacuum pump at room temperature. The suspension that resulted was heated for 36 h at
100˚C under an atmosphere of Ar. The reaction mixture was cooled to room temperature and the DMF was
removed under vacuum. Methylene chloride (2L) was added to the residue, and the suspension that resulted
was filtered to remove unwanted salts. After removal of the CH2Cl2, the crude product was purified by flash
chromatography to give 77% (223 g, 0.46 mol) of the desired 6-methoxy substituted indole.
66
Palladium Based Strategy for Indole Synthesis
Witulski, B.; Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem. Int. Ed. 2003, 42, 4257 (& refs. therein)
Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002, 2671 (refs. 2-8)
Takeda, A.; Kamijo, S.; Yamamoto, Y. J. Am. Chem. Soc . 2000, 122, 5662 (refs. 2 & 3)
X R1
R1
R2
Y N Y
3 N
R X R3
a,d f
b
a R1
R c X R1
c a,e
R2 +
N d NH
e Y
Y N R2 Y f R3 R2
R3
b,e a
R2 R
X
X
+
R1
Y NH Y N
R3 R3
Synthesis of Carbazole Intermediate by Domino Palladium Reaction

Saulnier, M.G.; Frennesson, M.S.; Deshpande, M.S.; Vyas, D.M. Tetrahedron Lett. 1995, 36, 7841
Bn Bn
O N O N
O O
NH HN Br Br
COCF3 COCF3 Pd(PPh3)4,K2CO3
N N
MeCN, 50oC, 19h, 52% H H
67
Regiospecific Synthesis of Polysubstituted Indoles by Means of Zirconocene

Stabilized Benzyne Complexes
Cp2Zr CP2Zr El El
+
2 El
N N N
R R R
Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116, 11797
CP2Zr I I
Br Cp2Zr(CH3)Cl
I2, CH2Cl2
2 t-BuLi, THF
N
-78oC to RT N OoC N
R
R R
65-70%
R=Bn; allyl
Alkaloid Synthesis using the Buchwald Zirconium Benzyne Complex

Peat , A. J.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 1028
NH2 NH2 HN
Br Br
Bu4NBr3 Br
MeCH K2CO3
MeO MeO NaI MeO
CH2Cl2
OMe OMe OMe
65% 74%
Me 1. Cp2Zr(Me)Cl Me
N N
Br t-BuLi
Mol I BnNH2
THF
o THF
K2CO3 -78 C - RT
MeO MeO I
96% 2. I2 78%
OMe OMe
CH2Cl2
Me Me
N 2.5 mol% N Me
10 mol% Pd/C N
Pd2(dba)3
P(o-tolyl)3 HCO2NH4
NBn NaO tBu, tol N MeOH, reflux
MeO I MeO MeO N
H 80oC Bn 80%
OMe OMe H
72% OMe
68
Palladium Catalyzed Reductive N-Heterocyclization of Nitroarenes
R1
R2 PdCl2(PPh3)2 R1
SnCl2
+ 2CO + 2CO2 (1)
NO2 N R2
H
PdCl2(PPh3)2
NO2 SnCl2 N
+ 2CO N R + 2CO2 (2)
CH NR
Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59, 3375
R
X [Pd], 2CO
NO2 -2CO2
X = CH
R N R
X -[Pd]
[Pd] H
N -[Pd]
X=N
N R
N
R R
R [1,5] shift
N N R
H
R R
R
N N R
H
69
Synthesis of Carbazole Alkaloids using the Diels-Alder Reaction of
Pyranoindolones with Alkynes Moody, C. J. Synlett 1994, 681
O Me O
Me Me N Me
MeO
N N N N
O OMe Me O
H H H H
murrayaquinone B murrayafoline A ellipticine murrayaquinone A
CO2Et
toluene O
N3 OEt
O reflux
87% N
H O
PhBr
reflux
PhBr 71%
reflux
78% HO
OEt
N
H O
Me Me
N O
N
O +
N N
Me Me
H ellipticine H
ellipticine
H H H
O N O N O N
D
O
A C
B Ar
E O
N F N N
N N
H H H
H
from N3 or NO2 H
staurosporinine O N
O
Ar
N
CO2R
H
70
Use Of Pyridynes for Heterocyclic Synthesis
CH3 CH3
COOH O N
+
N N O heat
N
N NMe2 N
H CH3 H CH3
May, C.; Moody, C. J. I. Chem. Soc. Perkin Trans. 1 1988, 247.
A solution of pyranoindolone (76 mg, 0.36 mmol) and the triazene (180 mg, 0.93 mmol) in dry acetonitrile (15
mL) was heated under reflux for 36 h. The solvent was evaporated and the residue chromatographed on
silica gel eluting with chloroform, slowly increasing to 5 % methanol in chloroform to give ellipticine (18 mg, 20
%), mp 312 - 314 °C and isoellipticine (18 mg, 20 %), mp 244 - 247 °C.
CH3 Cl
N
O
TMS CH3
N
OTf O
PhO2S CH3
+
O and CH3
N Cl N
TBAF
PhO2S CH3
O
N
N
PhO2S CH3 Cl
DÍaz, M. T.; Cobas, A.; Cuitián, E.; Castedo, L. Synlett 1998, 157.
2-Chloro-3-trifluoromethanesulfonyloxy-4-trimethylsilylpyridine (2.07 g, 6.2 mmol) was added portionwise

to a suspension of 1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole (200 mg, 0.62 mmol) and CsF (1 g,
6.2 mmol) in acetonitrile (8 mL). The mixture was stirred at rt until the mesylate was consumed, and then
the solvent was removed and the residue was dissolved in CH2Cl2. The solution was washed with water,
dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed to afford
the major isomer (170 mg, 63 %) (mp 81 °C) in addition to the minor isomer (70 mg, 26 %), mp 185 °C.
I n-BuLi Li OCH3
-78 °C, 2 h O
Cl Cl
O
N
N N
Gribble, G. W.; Saulnier, M. G. Heterocycles 1993, 35, 151.
To a magnetically stirred solution of 3-chloro-4-iodopyridine (1.3 g, 5.4 mmol) in dry THF (25 mL) under N2
at -95 °C was added tert-BuLi (2.0 M in pentane, 5.5 mL, 11.0 mmol). There immediately resulted a
bright red color and after 20 min at -95 °C, furan (4.0 mL, 55 mmol) was added via syringe. The reaction
mixture was allowed to warm to -25 °C over 2 h, maintaining at this temperature for 1 h, and then allowed
to warm to rt overnight. The dark polymeric material was filtered and washed well with Et2O. The organic
portions (300 mL) were washed with saturated aqueous NaHCO3 and the aqueous phase was extracted
further with CH2Cl2. The combined organic portions were washed with brine, dried (K2CO3), and
concentrated in vacuo to afford 0.58 g of a dark oil. Distillation gave 0.26 g (33%) of the cycloadduct as a
light amber liquid: bp 92 - 100 °C / 0.25 mm.
71
Chemical Behavior of Five-Membered π-Excessive Heterocycles
Electrophilic substitution
+
H H H
+
..
X E ..
X E X
+
E
H H
E E
+
..
X X
+
Order of Reactivity
> > > > >

N O Te Se S
H
Intermediates formed by electrophilic attack at C-2 and at C-3

Reaction of indoles with electrophile-preferred site is C-3
H H E
+ E
H + +
E E +
N E N N N+
H H H H
Ring-opening reactions of furans - electrophilic substitution reactions
H
H
H H +
H + H 2O H H+, H2O
H H
O
+ H
..
O O
+ .. O OH O O
72
Furan cationic cyclization reactions

O O
O O
BF3.OEt2
NEt3 HO O
O H
72% H
OCH2Ph PhCH2O O
Tanis, S. P.; Chuang, Y. H.; Head, D. B. J. Org. Chem., 1988, 53, 4929.
Tanis, S. P.; Dixon, L. Tetrahedron Lett., 1987, 2495
Tanis, S. P.; Johnson, G. M.; McMills, M. C. Tetrahedron Lett., 1988, 4521
(CH2)3Me
OH O HCO2H
NH 72% NH O NH O
O O O
O O H
H
BF3.OEt2
(10 equiv) O
S S H
S 64% S O
O O
O
Examples of ring-opening reactions
CN MeO CN
hν MeOH
O CN
CHO CHO
Hiraoka, H. Tetrahedron 1973, 29, 2955
Hoffman, R. V.; Shechter, H. J. Am. Chem. Soc. 1978, 100, 7934
∆
R N2 R R
O -N2 O 100% O
CO2Et CO2Et R=H CO2Et
73
Heteroaromatic lithiates - An alternative route for electrophilic substitution
E RLi E
X E Li E
X X X
Indole lithiation at C-2 position

Katritzky, A. R.; Akutagawa, K. Tetrahedron Lett. 1985, 5935
nBuLi EI
Li EI
N CO2 N H N
nBuLi
H O H
Li
O
El = D, Me, COPh, CO2H 59-86 %
Indole lithiates for alkaloid synthesis
O
K2CO3
N
O N MeOH-H2O
LDA
THF - 100 oC N ∆
N N Li
83 % 100 %
SO2Ph SO2Ph PhO2S O CO2H
Me
1) 2 eq MeLi
O
N Ac2O N - 100 oC to rt
N 90 oC O N 2) NaBH4 N N
H 84 % 96 % H
O CO2H Me
Gribble, G. W. In Adv. in Heterocyclic Natural Product Synthesis; Pearson, W. H., Ed.; JAI Press: Greenwich: 1990
Gribble, G. W.; Saulnier, M. G. J. Org. Chem. 1983, 48, 607
Gribble, G. W., Fletcher, G. L.; Ketcha, D. M.; Rajopadhye, M. J. Org. Chem. 1989, 54, 3264
74
New tactics for effecting Diels-Alder reactions
Cycloadditions at high pressure
1) liq HCN O
CO2Me 2) H3PO4 7 kbar, rt, 24 h
S S O + O
3) HCl, AcOH-H2O (10 g scale)
O
4) SOCl2, ∆
O
50 %
Dauben, W. G.; Kessel, C. R.; Takemura,
K. H. J. Am. Chem. Soc. 1980, 102, 7126
O O O Dauben, W. G.; Gerdes, J. M.; Smith, D.

Ra-Ni, EtOAc O
B. J. Org. Chem. 1985, 50, 2576
O ∆, 3 h O
O 51 % overall O
S (+8 % epimer)
Cantharidin
Smith and Uchida
OMe
H
OMe H
5 kbar, 72 h O
+
H 80%
O O
O H
OH
H
6 steps Smith, A. B.; Liverton, N. J.; Hrib, H.; Sivaramakrishnan, H.;
Winzenberg, K. J. Am. Chem. Soc. 1986, 108, 3040
O
CH2 H Matsumoto, K.; Sera, A.; Uchida, T. Synthesis 1985, 999
Jatropholone A
75
High pressure furan cycloaddition
CH2 CO2Me
CO2Me
H+
+ HC CCH2SMe2 Br
OBn CH2OBn
O O
CN
Me CO2Me LiOH Me O
MeOH OAc
AcO Me
CH2OBn CH2OBn 175,000 psi
O O
CH2Cl2 CN CH2OBn
98 %
O
KOH oxygenated targets
Me
H 2O Furanoheliangolides
91 % O CH2OBn
Paquette, L. A.; Brown, D. S. J. Org. Chem. 1992, 57, 4512
Vinyl furan Diels-Alder reactions
MeO2C MeO2C
290 oC
100 %
O O
MeO2C MeO2C
290 oC
O O
97 %
Cooper, J. A.; Cornwall, P.; Dell C. P.; Knight, D. W. Tetrahedron Lett. 1988, 29, 2107
76
[4+2]-Cycloaddition of Five-Ring Heterocycles with Benzyne
Double cycloaddition of benzyne with furan
CO2Me
NH2
O
N N CO2Me Pb(OAc)4 O
N N + O O
rt 47 %
N N
2 equiv. CO2Me
NH2 CO2Me
Hart, H.; Ok, D. J. Org. Chem. 1986, 51, 979
Cycloaddition with oxazole
NH2 Pb(OAc)4 benzene

Ph Ph
N 0 oC, 0.5 h 80 oC, 3 h
O + N O
N ~ 100 % N -PhCN
N
O Witney, S. E.; Rickson, B.

J. Org. Chem. 1988, 53, 5595
NMe
O
O
O O N Me
rt
78 %
O
Cycloaddition with pyrrole
1) n-BuLi
F Br F
2) H2O
N SiMe3 + HN
49 %
Cl
Anderson, P. S.; Christy, M. E.; Engelhardt, E. L.; Lundell, G. F.; Ponticello, G. S. J. Hetereocyclic Chem. 1977, 14, 213
77
High pressure intramolecular Diels-Alder reaction of furan as a diene
O
R1
12 kbar O
25 oC R
R O R 2 R1
R2 O
Keay, B. A.; Dibble, P. W.
Tetrahedron Lett. 1989, 30, 1045 R, R1, R2 = H, Me 43-65 %
Bansal, R. C.; McCulloch, A. W.; McInnes, A. G.

Diels-Alder reactions of pyrroles Can. J. Chem. 1970, 48, 1472
CO2Me R1
CO2Me N
CO2Me
C AlCl3 R1 AlCl3
+ CO2Me
R2 N R1 C CH2Cl2 85 %
R2 R2 CO2Me
CO2Me CO2Me 75 % CO2Me N
H CO2Me
R1 = H; R2 = Me
Diels-Alder reaction of pyrrole with allene

O O
O CO2Et
N N
KH
N + C
70 % CO2Et 75 % CO2Et
CO2Et
CO2Et CO2Et
CO2Et CO2Et CO2Et

CO2Et
O O
N N Kozikowski, A. P.;
N Kuniak, M. P.
H J. Org. Chem.
O O 1978, 43, 2083
[4+3]-Cycloadditons of furans Noyori, R.; Makino, S.; Okita, T.; Hayakawa, Y.

J. Org. Chem. 1975, 40, 806
Br H2, Pd (C) NH2NH2 OH

Fe2(CO)9
Br BF3-OEt2 H 2O
Zn-Cu
O + O O O O O
Br NBS 2 M KOH
LiCl, DMF
Br
78
CH2TMS
OH
SPh H SPh
Tf2O, CH2Cl2
O
O o
2, 6-lutidine, -78 C
50%
Harmata, M. Acc. Cham. Res. 2001, 34, 595
Halogen-substituted oxyallyl cations

CO2Me
CO2Me
O
Cl Cl 1. Et3N, CF3CH2OH O
+ O
O
2. Zn, MeOH
Cl
OTBS
OTBS
Lee, K.; Cha, J. K. Org. Lett. 1999, 1, 523
Synthesis of (-) -colchicine
MeO MeO
H OMe H
N + TMSOTf N
OAc OAc
MeO OMe MeO
OMe O OMe
OTMS O
O
OMe
MeO
MeO OMe H
H TMSOTf N
N + Boc
Boc MeO OMe
MeO OMe
O OTMS OMe O
OMe
O
Lee, J. C.; Jin, S.-J.; Cha, J. k. J. Org Chem. 1998, 63, 2804
Lee, J. C.; Cha, J. k. Tetrahedron 2000, 56, 10175
79
Pyrrole [4+3 ]-cycloaddition
O Me
Me Me N NaI, Cu MeN Me MeN Me
LAH
+
MeCN O OH
Br Br Me Me
89 %
Fierz, G.; Chidgey, R.; Hoffmann, H. M. R. Angew. Chem. Int. Ed. Engl. 1974, 13, 410 1:1
Vinyl pyrroles as dienes for Diels-Alder reactions
SCH2Ph
S SCH2Ph
1) O O
Me CH2 O
NaH N
N BnCl N 2) DDQ Me
THF 21% overall O
Me Me
Murase, M.; Yoshida, S.; Hosaka, T.; Tobinaga, S. Chem. Pharm. Bull. 1991, 39, 489
Intramolecular [4+2]-cycloaddition of imidazoles
O Me O Me Me O
Me
Me N N N N
N ∆
N Me
o
N 220 C - HCN
N 70 %
Wuonala, M. A.; Smallheer, J. M. Tetrahedron Lett. 1992, 34, 5697
Tandem Diels-Alder/Retro Diels-Alder reaction of oxazoles
N 180 oC N OAc OAc

O + O PhC N + O
OAc 16 h
Ph Ph
90 %
Liotta, D.; Saindane, M.; Ott, W. Tetrahedron Lett. 1983, 24, 2473
80
Oxazole cycloadditions - Synthetic equivalent of 2-aza-1,3-dienes

OH
SO2Me
Me MeSO2 Me Me
130 oC
O + O O O O
N 75 % N - MeSO2H N
Böll, W.; König, H. Ann. 1979, 1657. Firestone, R. A.; Harris, E. E.; Reuter, W. Tetrahedron 1967, 23, 943
Intramolecular Cycloadditions Jacobi, P. A. In Advances in Heterocyclic Natural Product Synthesis,

Pearson, W. H., Ed.; JAI Press: Greenwich, 1992.
with Oxazoles Jacobi, P. A.; Walker, D. G.; Odeh, I. M. A. J. Org. Chem. 1981, 46,
2065.
Jacobi, P. A.; Craig, T. J. Am. Chem. Soc. 1978, 100, 7748.
Jacobi, P. A.; Selnick, H. G. J. Org. Chem. 1990, 55, 202
Me Me
Me O
O
O
∆ H+
O O O O
Me 60 % O 98 %
O
N Me
O O
Gnididione
Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 4859
O O OH
∆
O 94 %
OMe OMe O
O O
N H
Paniculide-A
Jacobi, P. A.; Kaczmarek, C. S. R.; Udodong, U. E. Tetrahedron Lett. 1984, 4859
OMe O
N OMe
O O
O TMS
TMS
N ∆
O
> 50 % N N
O
OTBDMS
OTBDMS (-) Norsecurinine
81
Retro Diels-Alder of Oxazoles

Synthesis of furans or functionality derived from a substituted furan
O O
OMe
PhEt
OMe O
O reflux
N
N
O OH
1) NaBH4
- MeCN OMe 2) pH5 O
94 % O O
H
OH
Jacobi, P. A.; Kaczmarek, C. S. R.;

O O Udodong, U. E. Tetrahedron 1987,
43, 5475
O
H
Paniculide A
Diels-Alder of Thiazole Derivatives

Formation of fused ring thiophenes
Me OEt OEt
R
N S S
R
- MeCN O
R = CH2OMe
O 57 %
H N
H H
∆ S Ra-Ni
S H
Me 85 % Me
74 %
Me Me Me Me Me
Me O Me O Me O
1:1
Jacobi, P. A.; Weiss, K.; Egbertson, M. Heterocycles 1984, 22, 281.
Jacobi, P. A.; Egbertson, M.; Frechette, R. F.; Miao, C. K.; Weiss, K. T. Tetrahedron 1988, 44, 3327.
Jacobi, P. A.; Frechette, R. F. Tetrahedron Lett. 1987, 2937
82
R2
4+2 Cycloaddition of oxazole derivatives
R3 R4
Turchi, I. J.; Dewar, M. J. S. Chem. Rev. 1975, 75, 38 -H2O
N
R4
R1
OH
3
R R4
-R2H
R2
R3 N
R4
O
N R1
O R 2
OH
1 R2 3
R R 3
R 4 R R4
+
N R4 N
H R 4 R 1
R4
R1
H R4 OH
3
R
-R4H
R2 = H N
R4
R1
OH
3
[O], -H2 R R4
R2 = H N
R4
R1
Intramolecular Kondrat'eva Pyridine Synthesis Kondrat'eva, G. Y. Khim. Prom. (Moscow) 1957, 2, 666
Kondrat'eva, G. Y. Izv. Akad. Nauk. SSSR, Ser. Khim.
Addition of DBN is helpful to intramolecular 1959, 484
cycloadditions.
Ac ∆ Ac
N N ∆ NAc
o-DCB -H2O
O
DBN O
N N N
OTBS OTBS OTBS
Bubramanyam, C.; Noguchi, M.; Weinreb, S. M. J. Org. Chem. 1989, 54, 5580
83
Analysis of Two Methods of Constructing Pyridines
Route A Hantzch Synthesis
N N O
H NH2
+ NH3 +
O O O O
Route B Guareschi-Thorpe Synthesis
N N O
H
O + O
+ NH3
NH2 O O
Monocyclic 6-membered heteroaromatics
H H H
O
O .. O HO .. OH
.. HO X X
..
X
XH2 H
84
Top Ten Methods to Synthesize Pyridines
1. Hantzsch Pyridine Synthesis
O O R O O R O
O
NH3 oxid
2 + OR3 R 3O OR3 R 3O OR3
R H
O R2 R2 N R2 R2 N R2
H
Watanabe, Y.; Shiota, K.; Hoshiko, T.; Ozaki, S. Synthesis 1983 761; Pfister, J. R.Synthesis 1990, 689;
Singer, A; McElvain, S.M. Org. Synth., Coll. Vol. II 1943, 214-216.
A mixture of aldehyde, β-ketoester, 60 mL of ethanol, and 10 mL of concentrated aqueous ammonia was heated
for 3 h on a steam bath. To a solution of the above compound in 15 mL of acetone is added a solution of ceric
ammonium nitrate in 3.5 mL water. The orange color of the reagent disappears immediately on addition of each
drop. After stirring for 10 min, the resulting solution is concentrated to a small volume under reduced pressure.
To this mixture is added 20 mL of water and the mixture is extracted with methylene chloride. The organic phase
is washed with brine, dried over MgSO4, and evaporated under reduced pressure.
2. Guareschi-Thorpe Condensation
OR
N N
R NH3 R
O +
or NH4OAc,
RO O RO O AcOH HO N OH
Holder, R.W.; Daub, J.P.; Baker, W.E.; Gilbert, R.H.; Graf, N.A. J. Org. Chem. 1982, 47, 1445-1450.
I. Guareschi, Mem. Reale Accad. Sci. Torino II 1898, 46, 7, 11, 25.
In a round-bottom flask were combined the diester (0.4 mol), the cyanoester ((0.6 mol), ammonium acetate (0.1 mol),
glacial acetic acid (0.5 mol), and benzene (100 mL). The flask was equipped with a Dean-Stark tube fitted to a
condenser attached to a CaCl2 drying tube. The solution was heated at reflux for 45 h. The cooled benzene solution
was washed with with 75 mL portions of water, dried over CaCl2, and concentrated. Distillation through a
10 cm Vigreaux column afforded the product.
85
3. Krohnke Pyridine Synthesis
R3
O
O N O R3 R2
Br N R1
R1 R1 + NH4OAc, AcOH N R2
-
Br
40-97%
R1, R2, R3 many functional groups
Krohnke, F. Synthesis 1976, 1-24.
The pyridinium bromide 2 (6 mmol) and the α,β−unsaturated ketone 3 (6 mmol) are heated with ammonium
acetate (4g) in glacial acetic acid (6 mL) at 80oC for 2 h. The mixture is treated with water (40 mL), the
precipitate is filtered off, dissolved in boiling pyridine (20 mL), and reprecipitated with water.
4. Modified Bohlmann-Ratz Reaction
OH
O R 4
R4
R6 R3
R3
R2 MnO2, NH4OAc
PhMe-AcOH R2 N R6
R2 = Me, Ph reflux
R3 = CO2-alkyl (60-96%)
R4 = H, Et
R5 = alkyl, Ar
Bagley, M.C; Hughes, D.D.; Sabo, H.M.;Taylor, P.H.; Xong, X. Synlett 2003,10, 1443-1446.
Bagley, M.C.; Lunn, R.; Xiong, X. Tetrahedron Lett. 2001, 43, 8331-8334.
A solution of ester (0.3 mmol), propargylic alcohol (0.6 mmol), ammonium acetate (6 mmol), and activated
MnO2 (6.0 mmol) in toluene-glacial acetic acid was heated at reflux overnight. The mixture was allowed to
cool, filtered through Celite, partitioned between a sat. aq. NaHCO3 solution (30 mL) and EtOAc (30 mL) and
the aqueous layer was further extracted with EtOAc (20 mL). The combined organic layers were sequentially
washed with aq. NaHCO3 solution (20 mL) and brine (20 mL), dried (Na2SO4) and evaporated in vacuo.
Further purification was accomplished by flash chromatography on silica gel.
86
5. Inverse Electron Demand Diels-Alder with 1,2,4-Triazine
R1 N N 45 oC R1
+ N N CHCl3 N
R 2 R2
Boger, D. L.; Panek, J. S. J. Org. Chem. 1981, 46, 2179-2182
A solution of enamine (0.8 mmol) in 0.5 mL CHCl3 was added to a stirred solution of 1,2,4-triazene (1.2
mmol) in 0.5 mL CHCl3 under nitrogen at 25oC. The resulting dark orange solution was warmed to 45 oC for
20 h. Chromatography afforded the pure product.
6. Reaction with Vinylogous Iminium Salts
H2N
CN
CN
N N+
NaH, DMF Ar N Me
Ar 15 hr rt, 4 hr 100oC
Petrich, S.A.; Hicks, F.A.; Wilkinson, D.R.; Tarrant, J.G.; Bruno, S.M.; Vargas, M.; Hosein,
K.N.; Gupton, J.T.;Sikorski, J.A. Tetrahedron 1995, 51(6), 1575-1584
A 100 mL three-neck round-bottom flask was equipped with a stir bar, condenser and placed under a nitrogen
atmosphere. Into the flask was placed 0.3g (7.5 mmoles) of a 60% mineral oil dispersion of sodium hydride.
The sodium hydride dispersion was washed twice with dry hexane, and the hexane was removed via cannula.
Part of a 40 mL portion of dry DMF was added to the sodium hydride, and 0.79 g (9.6 mmol) of
3-aminocrotonitrile were subsequently added. The solution was allowed to stir for 15 min. Finally, 1.0 g (2.8
mmol) of vinamidinium salt and the remaining DMF was added, and the reaction was allowed to proceed at
room temperature overnight followed by heating at 100oC for 4 h. The mixture was cooled to room temperature
and the solvent was removed in vacuo. The residue was partitioned several times between water and
chloroform. The combined chloroform extracts were dried and concentrated. The crude product was passed
through a short pack of silica gel and purified by radial chromatography using a gradient solution of hexane:
ethyl acetate.
87
7. Sequential Solventless Aldol Condensation and Michael Addition

O R1
R1 R1
R2 O R3 NH4OAc
NaOH(s) grind O AcOH
grind
64-92%
H O R3 R2 N R3
R2 O R2 O
Cave, G.W.V.; Raston, C.L. J. Chem. Soc., Perkin Trans. 1 2001, 24, 3258-3264
Aldehyde (9.7 mmol) ,ketone (9.7 mmol), and NaOH (9.7 mmol) were combined using a mortar and pestle,
and the yellow medium was aggregated until a yellow powder formed (~10 min). The second ketone (9.7
mmol) was added with stirring (~10 min). The powder was tranferred to a suspension of ammonium acetate
(5g, excess) in glacial acetic acid (25 mL) and heated at reflux for 2 h. The crude product was precipitated
out of solution by the addition of water, collected and washed with water and ethanol.
8. Kondrat'eva Pyridine Synthesis
Ac o-DCB, DBN Ac
N N
∆
O
CO2Me N
N
Subramanyam, C.; Noguchi, M.; Weinreb, S.M. J. Org. Chem. 1989, 54, 5580-5585
A solution of oxazole (0.4 mmol) and DBN (0.4 mmol) in anhydrous o-dichlorobenzene (60 mL) was
deoxygenated with argon for 45 min. The mixture was heated at 150o C under argon for 1.5 h and then
cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flash
chromatography.
88
9. Metal-Mediated [2+2+2] Cycloaddition
C(O)NEt2 C(O)NEt2 C(O)NEt2

Ti(O-i-Pr)4/2 i-prMgCl R1 1. Ts C N 1
R
+ 1.25 eq. Ti(O-i-Pr)2 +
N
2. H (or I2)
-50o C
R1 R2 55-70% H
R2 (or
2 I)
R
Suzuki, D.; Tanaka, R.; Urabe, H Sato, F. J. Am. Chem. Soc. 2002, 124, 3518-3519
Varela, J.A.; Saa¢Chem. Rev. 2003, 103, 3787-3801
To a stirred solution of N,N-diethyl-2-nonynamide (25 mg, 1.2 mmol) and Ti(O-i-Pr)4 (0.44 mL, 1.5
mmol) in 10 mL of Et2O was added i-PrMgCl (1.40 M in Et2O, 2.1 mL, 3.0 mmol) at -78 °C under
argon to give a yellow homogeneous solution. The solution was warmed to -50 °C over 30 min,
during which period its color turned red. After stirring at -50 °C for an additional 5 h, 1-octyne (0.14
mL, 0.9 mmol) was introduced to the reaction mixture at -50 °C and the solution was stirred for
another 3 h. Then, pulverized p-toluenesulfonylnitrile (260 mg,1.4 mmol) was added and the reaction
mixture was stirred for 3 h at -50 °C. The reaction wasterminated by the addition of water (0.5 mL)
and quickly warmed to room temperature. The resulting heterogeneous mixture was dried over
anhydrous sodium sulfate and filtered through a short pad of Celite. The filtrate was concentrated in
vacuo to give a crude oil, which was chromatographed on a silica gel column.
10. Tandem Aza-Wittig/Electrocyclization
CO2Et
R1CHO Ph
N
PPh3 or
R2NCO R3 N CO2Et
Ph ∆
R3 = R1 or R2NH-
68-86%
Barluenga, J.; Ferrero, M.; Palacios, F. J. Chem. Soc., Perkin Trans. 1 1990, 2193-2197
Molina, P.; Arques, A.; Fresneda, P.M.; Vinader, M.V.;Foces, M.C.F.; Cano, F.H. Chem. Ber. 1989, 122, 307-313
The aldehyde or isocyanate (5 mmol) was added to a stirred solution of the phosphazene (5 mmol) in
dry acetonitrile (20 mL) or toluene (20 mL) and the mixture was heated at reflux for 12-28 h. The
solvent was evaporated and the residue was purified by column chromatography.
89
Quinoline Synthesis
C Skraup
C Doebner-von Miller
Combes
C Conrad-Limpach
N
Knorr
C
C
Friedlander
C Pfitzinger
N
Arylamine-Glycerol Quinoline Synthesis

Skraup, Z. H. Monatsh. 1880, 1, 316. Skraup, Z. H. Ber. 1880, 13, 2086
Manske, R. H. F.; Kulka, M. Organic Reactions 1953, 7, 59.
Yale, H. A.; Bernstein, J. J. Amer. Chem. Soc. 1
O
HO
H2SO4 C6H5NH2 C
H
HO CH2 CH CHO
H2SO4
N
HO H
HO H
H2SO4 oxidation
- H2 O
N N
H
Can replace glycerol with pre-formed α,β-unsaturated compounds.

However, this increases risk of carbonyl polymerization.
MeO CH2 CHCHO MeO
PPA, arsenic acid

NH2 N
60 %
NO2
Yale, H. A.; Bernstein, J. J. Amer. Chem. Soc. 1948, 70, 254
90
Top Methods to Synthesize Quinolines

1. Vilsmeier Approach to Quinolines
DMF CH3 CH2
NHAc POCl3 N Cl N Cl
H H
NMe2 Me2N NMe2

CHO H2O
Cl
N Cl N Cl N Cl
Meth-Cohn, O.; Narine, B. Tetrahedron Lett., 1978, 19, 2045.
Meth-Cohn, O. Heterocycles, 1993, 35, 539.
To the Vilsmeier complex prepared from DMF (20 mmol) and POCl3 (60 mmol) in 1,2-dichloroethane (150 mL) at
0 °C, was added acylanilide (20 mmol) with stirring. The solution was heated to reflux for 5 h, cooled, poured
into ice water, made alkaline (pH 9) with 40% aqueous NaOH, and stirred for 30 min. The aqueous phase was
extracted with CH2Cl2, the combined organic layer was dried (MgSO4) and evaporated. The residue was
purified by chromatography on alumina to give 2-chloro-quinoline-3-carbaldehyde.
2. Synthesis of Quinolines via Intramolecular Cyclization of Oxime Derivatives
OH
N
Bu4NReO4
R RX
CF3SO3H N
R
RX
X = O, N; R = Me, Et
H
RX RX RX
[oxid]
N R N R N R
Kusama, H.; Yamashita, Y.; Narasaka, K. Chem. Lett., 1995, 5.
To a 1,2-dichloroethane suspension (6 mL) of 4-(3,4-methylenedioxyphenyl)butan-2-one oxime (0.98 mmol),

4-chloranil (0.51 mmol), and Molecular Sieves 5 Å (100 mg), was added a solution of trifluoromethanesulfonic acid
(1.0 mmol) in 1,2-dichloroethane (4 mL) and the mixture was immediately heated at reflux. After 1 h, the
reaction was quenched with a saturated aqueous sodium hydrogen carbonate solution and the resulting
inorganic materials were filtered through Celite. The organic layer was extracted with CH2Cl2. After
evaporation of the solvent, the crude product was purified by chromatography to afford the quinoline.
91
3. Palladium Catalyzed Annulation Approach
I CH(OH)R2 CH(OH)R2
R
R
(Ph3)2PdCl2, NH
NH
Et 3N, DMF, rt COR1
COR1
R1 = CH3,
CF3
NaOEt in EtOH R
N R2
Mahanty, J.; De, M.; Das, P.; Kundu, N. G. Tetrahedron, 1997, 53, 13397.
A mixture of o-iodoaniline (1.0 mmol), (Ph3P)2PdCl2 (0.014 mmol) in Et3N (15 mL) was stirred under N2 at rt for
15 min. Freshly distilled propargyl alcohol (2.5 - 3.0 mmol) was added and the mixture was further stirred at rt
for 24 h. The solvent was removed under reduced pressure and the residue was purified by column
chromatography to give the substituted hydroxyalkynyl anilide. To the freshly prepared sodium ethoxide
(1.3 mmol) in ethanol (3 mL) was added the above hydroxy-alkynyl anilide (0.28 mmol). The reaction mixture
was refluxed under N2 for 5 h. The mixture was cooled, poured into H2O and extracted with CHCl3. The
combined organic layer was washed with saturated brine, H2O and dried (Na2SO4). The solvent was
removed and the resulting residue upon chromatography gave the quinoline as a light yellow solid.
4. Fischer Carbene Benannulation Approach
Me Me
1) s-BuLi,
2) Cr(CO)6,
Cr(CO)5
Me N 3) MeSO3F Me N
Boc Boc OMe
Me OH
R R
Me N
Boc OMe
Peterson, G. A.; Wulff, W. D. Tetrahedron Lett., 1997, 38, 5587.
A THF solution of α-lithio-1,4-dihydropyridine was transferred to a slurry of chromium hexacarbonyl in THF at

-45 °C. The reaction mixture was allowed to warm to rt overnight and then was methylated by the addition of 1
equiv of methyl fluorosulfonate. The reaction was quenched after 30 min with sodium bicarbonate, and
purification by silica gel chromatography gave the carbene complex as a red oil. The benzannulation was
carried out under argon in THF at 0.04 M with the carbene complex together with 1.5 equiv of alkyne at 60 °C
for 42 h. The dihydroquinoline product was isolated as yellow oil.
92
H H
O NAr O NAr
Na2S
O NO2 O NH2
O
p-CH3OC6H4COCH3, HO
O N
Borsche, W.; Sell, F. Chem. Ber. 1950, 83, 78
(164) Borsche, W.; Barthenheier, J. Annalen 1941, 548, 50
OMe
Pfitzinger, W. J. Prakt. Chem. 1886, 33 (2), 100
O CO2 CO2
2
R R2
NaOH O NaOH
O +
N NH2 O R1 N R1
H
R2
H , Cu powder
+ CO2
1
N R
Isoquinoline Synthesis
Bischler - Napieralski
Pictet - Gams
N Pictet - Spengler
Pomeranz - Fritsch
N
Difference in isoquinoline ring structure necessitates different starting materials to those used in quinoline synthesis.
93
Ten Top Methods to Synthesize Isoquinolines
1. The Bischler-Napieralski Method
H OMe
N OMe N
POCl3 MeO Br
O
MeO Br
MeO
OMe
Kametani, T.; Fukumoto, K. Heterocycl. Compd. 1981, 142.
Jones, G. Compr. Heterocycl. Chem. II, 1996, 179, 182.
Zhou, D. -M.; Yue, B. -Z.; Cui, J. -Q.; Cai, M. -S.; Zhang, L. -H. Heterocycles 1997, 45, 439.
Cerri, A.; Mauri, P.; Mauro, M.; Melloni, P. J. Heterocycl. Chem. 1993, 30, 1581.
A solution of the amide (1.2 mmol) and phosphorus oxychloride (1.3 g, 8.5 mmol) in dry acetronitrile (20 mL)
was heated at reflux for 2-5 h. The excess reagent and solvent were removed under vacuum and the
residue was poured into 5% sodium hydroxide and then extracted with CH2Cl2. The extracts were dried over
magnesium sulfate and evaporated to give a white solid in 91% yield. The solution was dissolved in CH2Cl2
and HCl gas was bubbled through to give the hydrochloride salt.
Pictet-Gams Modification of the Bischler-Napieralski Reaction
OH OH
HO2C BnO BnO
+
NH2 NH
O
CO2Me
BnO
N CO2Me
POCl3
MeCN
CO2Me
A solution of 2.2 g (10 mmol) of the acid and 1.5 mL (20 mmol) of thionyl chloride in 20 mL of benzene was
heated at reflux for 1.5 h. After cooling, the solution was evaporated. The residue contained 2.4 g (100%) of the
corresponding acetyl chloride as an orange solid which was used in the next reaction without any further
purification. To a solution of 2.4 g (10 mmol) of the amino alcohol in 11 mL of 1 N (11 mmol) NaOH and 20 mL
of dioxane was added a solution of 2.4 g of the acid chloride in 15 mL of ether and 3 mL of dioxane. After
stirring for 1.5 h, the mixture was filtered, the solid was washed with water and dried to give 3.6 g (80%) of the
amide as a white solid. To a stirred and boiling solution of 2.7g (6 mmol) of the amide in 50 mL of acetonitrile
was added dropwise 5.6 mL (60 mmol) of phosphorus oxychloride. After 1.5 h at reflux, the solution was cooled
and aqueous 5% sodium hydrogen carbonate was added carefully until pH 8.0 was reached. The mixture was
extracted with ethyl acetate. The organic phase was dried and the solvent evaporated. The residue was
purified by silica gel chromatography to give 2.1 g (85%) of the isoquinoline as a white solid.
94
Bischler - Napieralski-Synthesis
- Reagents used for ring-closure include P2O5, PCl5, POCl3, and PPA.
- Electron-donating substituents improve yield and rate of reaction by enhancing the
electrophilic ring-closure step.
- Isoquinolines unsubstituted at 1-position require N-formylamines as precursors. This results in poor
yields unless the benzene ring contains e- releasing groups.
P2O5, POCl3
+
NH xylene NH NH
- H+
Ph Ph
O Ph OPOCl2
OPOCl2
- POCl2(OH) Pd / C 160oC
N N
Ph Ph
2. The Pictet-Spengler Method
O
HO OBn HO
H
NH2.HCl N
MeOH, reflux
BnO

Jones, G. Compr. Heterocycl. Chem. II, 1996, 170.
Hom, R. K.; Katzellenbogen, J. A. J. Org. Chem. 1997, 62, 6290.
The amine salt, which was synthesized from norphenylephrine hydrochloride according to literature
procedures, was dissolved in methanol (30 mL) and to this solution was added the (benzyloxy)- acetaldehyde
(3.5 g , 1.1 equiv.) with stirring at rt. This mixture was heated at reflux for 18 h. Concentration and flash
chromatography of the residue yielded 4.2 g (73%) of the product.
95
Modified Pictet-Spengler Initiated by Pummerer Reaction for Alkaloid Synthesis
MeO
MeO MeO
+ O
N
N O Ac2O N O MeO
MeO MeO
+ + H SMe
SMe SMe
O O
O O O- O O
MeO MeO
O
N N
MeO MeO
H
SMe 72 %
X O
Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 27.
3. Pomeranz-Fritsch Method
OEt
conc. H2SO4
N N
OEt MeOH, 2 h
Me Me

Chelucci, G.; Cabras, M. A.; Saba, A.; Sechi, A. Tetrahedron: Asymmetry 1996, 7, 1027.
Jones, G. Compr. Heterocycl. Chem. II, 1996, 190.
A solution of o-methylbenzylideaminoethanaldiethoxyacetal (2.0 g, 10 mmol) in MeOH (5 mL) under a nitrogen

atmosphere was slowly added to concentrated H2SO4 (50 mL) and heated at 160oC. The mixture was made
basic with 50% NaOH solution and the product was removed from the resulting black solution by steam
distillation. The distillate was extracted with ether, the organic phase separated, dried over anhydrous Na2SO4
and the solvent was evaporated. The residue was purified by Kougelrohr distillation to give 0.36 g (25%) of
8-methylisoquinoline.
96
5. Intramolecular Pummerer Reaction
SOPh SPh
Pummerer R1 R1
R1 reaction
N N
N R1 COR2 R1 COR2
R1 COR2
97%-98%
Suhinohara, T.; Toda, J.; Sano, T. Chem. & Pharm. Bull. 1997, 45(5), 813-819.
Toda, J.; Sakagami, M; Sano, T. Chem & Pharm. Bull. 1999, 47(9). 1269-1275.
Padwa, A; Waterson, A. G. Curr. Org. Chem. 2000, 4, 175-203.
TFAA (5 equiv.) was added to 500 mg of the sulfoxide in 40 mL of the appropriate solvent at room temperature and
the mixture was stirred for several hours. The reaction mixture was concentrated under reduced pressure and the
product was purified by column chromatography. NaBH4 (10 equiv.) was then added in small portions to a stirred
solution of the product with NiCl26H20 in MeOH-THF (3:1)(40 mL) under ice cooling. After the addition, stirring was
continued at room temperature for 30 min. The reaction mixture was filtered and the filtrate was concentrated in
vacuo. The residue was suspended in water, acidified with 5% HCl-H20, and extracted with CHCl3. The product was
isolated by column chromatography and was purified by recrystallization.
......................................................................................................................................
6. One-Pot Synthesis of Ethyl Isoquinoline-3-Carboxylate by Domino Reaction
EtONa, dry EtOH

CO2Et ∆, MgSO4, 4h.
O O
+ H2N
O CO2Et N CO2Et
-H2O
CO2Et
O O OH
CO2Et CO2Et CO2Et
CO2Et
N -CO2 N -EtOH N
80%
Meziane, M.A.; Sylvain, R.; Bazureau, J.P. Tet. Lett. 2001, 42, 1017-1020.
97
7. Tetrahydroisoquinolines from Perhydrobenzoxazines
- Creates stereogenic carbon at C-1 simultaneously with ring closure.

- The perhydrobenzoxazine starting material is obtained in high yield in three
steps.
R
R
1. t-BuLi R
o HO
Br Et2O, -90 C
N
2. Et2AlCl R
o
O -90 C to rt R1
N R1
77-83%
1. PCC, NaOAc
mol. sieves, CH2Cl2
2. KOH, MeOH/THF
HN
R
R1
Pedrosa, R.; Andres, C.; Iglesias, J.M. J. Org. Chem, 2001, 66, 243-250.
A solution of the substrate in dry ether was treated with t-BuLi (2.2 equiv) at -90oC, and after 5 min, 2 equiv
of Et2AlCl was added. The mixture was allowed to reach room temperature and was stirred 16 h. Isolation
and purification by flash chromatography, after hydrolysis afforded the tertrahydroisoquinoline derivative.
8. Benzal Aminoacetal Isoquinoline Synthesis
- Intially for aldimine which is recycled to isoquinoline

- Acetal group prevents amonialdehyde self-condensation.
- 3-Substituted aldehyde give 7-substituted isoquinolines- these are difficult
to prepare by other methods.
EtO OEt
H2NCH2CH(OEt)2
N N
HO
HO CHO
Cl
Cl
Gensler, W. J. Organic Reactions, 1951, 6, 191
98
9. Chiral Vinyl Sulfoxide Cyclization R1

RO N
R1 COCF3
RO N
COCF3 RO
RO CHO .. Tol
S
+ O
O
H : R1
(MeO)2P C S RO N
Ar COCF3
Li
RO
Ar= C6H5, CH3C6H4, 2,4,6-(iC3H7)3C6H2 Tol ..
S
O
PhCH2NEt3OH
RO RO -OH
N + N
R1 R1
RO RO
Tol Tol
S S
O .. O ....
Pyne,S.G., J. Chem. Soc., Chem. Commun., 1986, 1688.
Pyne, S. G., Chapman, S.L., J . Chem. Soc., Chem. Commum., 1986, 1688.
Pyne, S.G., Bloem, P., Chapman, S.L., Dixon, C.E., Griffith, R., J.Org. Chem., 1990, 55, 1086.
Pyne, S.G., Tetrahedron Lett., 1979, 28, 4737.
10. Dieckmann Type Condensation
O O O
OMe CO2Et
NaOEt OH-
N CO2Et N
Me H+ N
Me Me

Grethe, G.; Lee. H. L.’ Uskokovic, M.; Brossi, A. J. Org. Chem. 1968, 33, 494.
Klein, J. T.; Davis, L.; Effland, R. C. J. Heterocycl. Chem. 24, 1987, 725.
A 16.3 g (0.7 mol) portion of sodium metal was added to absolute ethanol (150 mL) and after the reaction was
complete, the excess ethanol was removed by distillation. A solution of N-(2-carboxmethoxybenzyl)-sarcosine
ethyl ester (150 g, 0.57 mol) in benzene (200 mL) was added, and slow azeotropic distillation was carried out.
The solvent was removed, the resultant yellow solid was dissolved in ethanol (200 mL) and 2N sodium
hydroxide (600 mL)was added and the mixture was heated at reflux for 2 h. The mixture was cooled slowly to
room temperature, then acidified with 6N hydrocloric acid, and refluxed for 3 h. The reaction mixture was cooled,
was made basic with 6 N sodium hydroxide, and was extracted with chloroform. The chloroform extracts were
washed with water, brine, dried over MgSO4, and evaporated to give 84 g (92%) of the product.
99
Pictet-Spengler Cyclization in Heterocyclic Synthesis
MeCHO H2SO4
NH2 N 40 % N
H
Me Me
tetrahydroisoquinoline
NH2 N H2SO4 N H
MeCHO
N N Me 86 % N Me
H H H
Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030 tetrahydro-β-carboline
Decker, H.; Becker, P. Liebigs Ann. Chem. 1913, 395, 342
Whaley, W. M.; Govindachari, T. R. Org. React. (N. Y.) 1951, 6, 151
Ungemach, F.; Cook, J. M. Heterocycles, 1978, 9, 1089
Oxidative Pictet Spengler Cyclizations
MeO MeO
TMSCH2I MeO
NHCOR NCOR CAN
MeO MeO NCOR
MeO
R=Ph, OBn TMS
Single Electron Transfer Mechanism:
R +. R -SiR3 R R SET R + R
R R SET N N N
N
CAN . CH CH2
SiR3 SiR3 2
Used for the synthesis of indolopiperidines, pyroglutamic acid derived pyrrolidinones, and
phenanthreneindolizidines
Mariano, P.; Kim, H. J.; Yoon, U. C.; Jung, Y.; Park, N. S.; Cederstrom, E.; J.. Org. Chem.
1998, 63, 860.
100
Regiospecific Silyl Directed Pictet Spengler Cyclization
NH HCHO, pH=6
R N
OMe
OMe
R=SiMe3
98%
Used for the synthesis of tetrahydropalmatine, canadine, sinactine, corypalmine and

isocorypalmine
Miller, R.; Cutter, P.; Schore, N.; Tetrahedron 2002, 58 , 1471.
Miller, R.; Tsang, T.; Tet. Lett. 1988, 51, 6715.
Thio-orthoEsters in Pictet Spengler Cyclizations
(R6S)3CH
HN N
SO2R5 dichloromethane, reflux SO2R5
SR6
R5= Ts, R6= Ph
ZnCl2, dichloromethane
N
N TMS SO2R5
SO2R5
SR6
Silveira, C.; Bernardi, C.; Braga, A.; Kaufman, T.; Tet.. Lett 2003, 44, 6137.
Mercuric Acetate Catalysed Pictet Spengler Reaction
N CO2Me
N CO2Me
N
H N H
H
Hg(OAc)2 / 10% AcOH / 50% EtOH
101
Pictet Spengler Cyclization using Titanium Isopropoxide as an Imination

Reagent
Ti (O-iPr)4 MeO
MeO
NH2 O N
MeO MeO
R1 R2 Me Ph
R1= Me, Ph,

R2= Ph, Me, Et, CH2SPh
MeO MeO
CF3COOH
HCOOH / Ac2O +
N CHO N CHO
MeO MeO
R1 R2
R1 R2
Horiguchi, Y..; Nakamura, M.; Kida, A.; Kodama, H.; Saitoh, T.; Sano, T.: Heterocycles. 2002, 59,
691.
α-Chloro α-Phenylthio Ketones in the Pictet Spengler Reaction
Silveira, C.; Bernardi, C.; Braga, A.; Kaufman, T.; Tet.. Lett. 2001, 42, 8947.
O
SPh
R1 R R1
Cl
HN N
R2 Ts SnCl4 / ZnBr2, R2 Ts
R3 dichloromethane, R3
-78oC O R
R1= H, OMe, R2= OMe, H
R3= OMe, H, R= Ph, tBu O-methyl velucryptine and
other benzoyl isoquinoline
alkaloids
102
Various methods used to generate iminium ion precursors

Grierson, D. S. Org. React. (N. Y.) 1990, 39, 85
Grierson, D. S.; Vuilhorgne, M.; Husson, H. P. J. Org. Chem. 1982, 47, 4439
Kametani, T.; Suzuki, T.; Kamada, S.; Unno, K. Heterocycles 1982, 19, 815
CO2Me CO2Me
PhPOCl2
N CO2H HCl (aq) N
N N Hβ = 80 %
Hα = 20 %
H 83 % H H
N CN N Hβ = 75 %
N 1) AgBF4, THF N Hα = 25 %
H
H H
2) MeOH, HCl
MeO2C CO2Me MeO2C CO2Me
HO2C
N
PhPOCl2
CO2Me HCl (aq) N CO2Me
N N
60 % H Hβ = 75 %
H H
Hα = 25 %
MeOH
N HCl N + N
N N N
70 % H H
H H H
Et Et Et
MeO2C CO2Me MeO2C CO2Me MeO2C CO2Me
69 % 10 %
103
Bimolecular Mannich reaction using pyrroles
EtO2C Me EtO2C Me EtO2C Me

CH2O CH2O
Me N C6H11NH2 Me N Me N
H H N H N
75%
H
OH
EtO2C Me
Me N Burke, W. J.; Hammer, G. N. J.

-H2O Am. Chem. Soc. 1954, 76, 1294
N
68%
Amidoalkylation reaction of furan ring Shono, T.; Matsumura, K.; Tsubata, K.;
Takata, J. Chem. Lett. 1981, 1121
Me
+ HN OMe NHCO2Me
O O
CO2Me
Me
Mannich type cyclization from pyridinium ion precursors
CO2Me CO2Me MeO2C

O O H O
Me Me RSO3H
H2
O O O
N N PhH, 80 oC N
+
70 %
Wenkert, E. Acct. Chem. Res. 1968, 1, 78. Wenkert, E.; Dave, K. G.; Stevens, R. V. J. Am. Chem. Soc. 1968, 90, 6177
Oppolzer, W., Hauth, H., Pfaeffli, P., Wenger, R. Helv. Chim. Acta. 1977, 60, 180
OSiMe3
Br H
N H N
N N
N HO
N DMF, Pri2NEt H
o MeO2C
H 70 C CHO
74 % Vincamine
104
Heteroaromatic azadiene
Diels-Alder reactions
CO2CH3 R1
N R
O N
N NH R
R2
R
CO2CH3
R N R R = CO2CH3
R=H R = H, Cl
N N R = CO2Et R1
R = CO2CH3
R = SCH3 N N
R N R
R O
R = CO2CH3 R = CO2CH3
O EDG R = SCH3 R2
N R = SCH3
R1
N
R
R R N N
N N N R
R
N R=H N N R = CO2CH3 O
N N R = CO2Et R = SCH3 R2
R
R R = SO2CH3
R
R1
R
N
O N
N N
R2
R
Boger, D. L. Chem. Rev. 1986, 86, 781
1,2,4-Triazine - enamine [4 + 2] cycloaddition
N R1 R1
N
N N + N
R2 R2
Catalytic Diels-Alder Reaction

O R1 R1
N N
H
+
N N N
R2 R2
+ pyrrolidine - pyrrolidine
N
N N N
N R1 R1
N -N2
+ N R1
N N N
R2 R2 R2
105
Representative 1,3,5-triazine - amidine Diels-Alder reactions

CO2Et CO2Et
R = H, 90 oC, 24 h, 85 %
NH-HCl R = Me, 100 oC, 72 h, 80 %
N N N N
+ R
NH2 o
R = SMe, 90 C, 48 h, 90 %
EtO2C N CO2Et H 2N CO2Et
R = Ph, 100 oC, 24 h, 82 %
R
CO2Et H
H
N NH N N CO2Et
N N 100 oC, 24 h, 75 %
+
N
EtO2C N CO2Et
CO2Et
CO2Et
H H
NH N N CO2Et
N N N 100 oC, 36 h, 52 %
+
N
EtO2C N CO2Et
CO2Et
Diene and dienophile substituent effects
Diene Reactivity
CO2Et SMe
N N N N N N
EtO2C N CO2Et N MeS N SMe
Dienophile Reactivity
NH-HCl NH-HI NH-HCl

R R R
NH2 SMe OMe
NH2-HCl NH2-HI NH2-HCl

R R R
NH2 SMe OMe
106
[4+2]-Cycloaddition of 1,2,4,5-Tetrazines
SCH3 SCH3 CH H
CH3 3 N
N CH3
N N N
+
N N N
CH3
SCH3 CH3 SCH3 CH3 CH3
cis-Trikentin A
Boger, D. L., Zhang, M. J. Am. Chem. Soc. 1991, 113, 4230
A solution of 3,6-bis(methylthio)-1,2,4,5-tetrazine (5.6 g, 32 mmol) in benzene (25 mL) at 0 °C was treated with
the pyrrolidine enamine of 2,4-dimethylcyclopentanone (11.3 g, 2.1 equiv), and the resulting solution was allowed
to warm to room temperature and stirred for 1 h. Glacial acetic acid (25 mL) was added, and the resulting
reaction mixture was stirred for 10 h at room temperature before the solvent was removed in vacuo.
Chromatography followed by recrystallization afforded 6.6 g (85%) of the product as a white crystalline solid.
CO2CH3
N N
N N CONH2
CO2CH3 N
CO2CH3 COCH3 OH
N
+ N
OCH3 OCH3
CO2CH3 NH
H COCH3
HO
O PDE-I
CH3O OCH3
Boger, D. L., Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717
A mixture of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (14.6 g, 74 mmol) and 4,4-dimethoxybut-3-en-2-one

(14.4 g, 110 mmol) in 250 mL of dry dioxane was warmed with stirring at 60 °C under N2. The solvent was
removed in vacuo, and the residue was dissolved in CH2Cl2 and filtered through a short column of silica gel.
Flash chromatography afforded the product (13.9 g, 70%) as a yellow, crystalline solid.
CO2CH3 CO2CH3
NMe2 NMe2
N N N
+
N N N N N
CO2CH3 CO2CH3
Benson, S. C., Gross, J. L., Snyder, J. K. J. Org. Chem. 1990, 55, 3257
Dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (1.0 g, 5.0 mmol) and dimethylcyanamide (0.4 mL, 0.35 g, 5 mmol)
were dissolved in anhydrous o-xylene (10 mL) under argon and refluxed for 12 h. After cooling to room
temperature, the crude reaction mixture was subjected to flash chromatography on silica gel to give the pure
product (0.71 g, 59% yield).
107
Preparation of OMP
N CO2CH3
N +
Et3SiO
CH3 25 oC
N CH3 87 %
CH3O2C N
N
H
N N H
H N CO2CH3 R N R
N N Zn/HOAc
CH3O2C CH3 25 oC, 63 % CH3 CH3

CH3
OMP
NaOH; R = CO2CH3
-CO2 R=H
Key steps of the prodigiosin total synthesis
C5H11 N CO2CH3 +
CH3O 25 oC
N
N OCH3 93 %
CH3 CH3O2C N
CH3O N
NH
H
N CO2CH3 N
NH N Zn/HOAc CH3O2C R
68 %
CH3O2C
PRODIGIOSIN CH3O
OCH3
R = CO2CH3
77 %
R=H
Intramolecular 1,2-diazine - allene Diels-Alder reaction

NH2 NR NCOCH3
o
N 235 C, 22 h
70 % N 76 %
SCH3 N SO2CH3
i) SO2CH3 SO2CH3
N N N
R = COCH3
N N N
ii) m-CPBA NR NCOCH3
SCH3 97 % x 95 % SO2CH3
68 % N 120-160 oC
N
NH2 27 h, 87 %
SO2CH3
Ac Ac Ac Ac
N N N N
-N2 -CH3SO2H
N
N
SO2CH3 SO2CH3 SO2CH3

108
Key steps of the streptonigrin total synthesis

NO2
CH3O N CO2CH3
N
80 oC
NH N
O N + CH3O2C N
82 %
CH3O SCH3
A B NO2
N COOH N
H 2N N CH3O CH3
C
O OCH2Ph
H 2N CH3 N CO2CH3
N
OH
N OCH3
D CH3O2C N
OCH3
OCH3 NO2
OCH3 CH3O
N CO2CH3
STREPTONIGRIN N
6.2 kbar
CH3O2C CH3
o OCH2Ph
25 C, 50 %
OCH3
OCH3
1,2,4,5-Tetrazine - thioimidate Diels-Alder reaction
N CO2CH3 Ar N CO2CH3
N
N N
CH3O2C N Ar NH CH3O2C N
X
-HX
N
CO2CH3 X H
N Ar N CO2CH3
N NH
N X -N2 N
CH3O2C CH3O2C N
Ar
N CO2CH3
N
+ N CO2CH3
NH N N
N CH3O2C N
N
X CH3O2C N
X = SCH3 80 oC, 4 h, 70 %
Diels-Alder Reactivity: NH2, NR2 > OEt = SCH3
X = OEt 80 oC, 20 h, 33 % Elimination (Aromatization): SCH3 > OEt >> NH2, NR2
X = NH2, NEt2 25 oC, 1 h, 0 %
109
Hetero Diels-Alder Reactions

Cycloadditions involving heteroaromatic azadienes
N
N CO2Me
N rt -N2
+ N N
N N 49 % -pyrrolidine N
CO2Me NR2 CO2Me

Boger, D. L. Chem. Rev. 1986, 86, 781
Dittmar, W.; Sauer, J.; Steigel. A. Tetrahedron Lett. 1969, 5171
Boger, D. L.; Coleman, R. S. J. Am. Chem. Soc. 1987, 109, 2717
NH
CN
SMe CO2Me
1) H2S, Et2NH dioxane
NO2 N dioxane N 80 °C, 22 h
NO2 N N
+
2) MeI, MeCN N N 82 %
MeO 42 % MeO
MeO2C
NO2
MeO R2N
Me
CH2Cl2, 6.2 Kbar
N CO2Me OBn rt, 120 h
N + 4 eq
N 65 %
MeO2C N OMe
(2.8 : 1)
OMe
NO2 O
MeO MeO
N CO2Me N CO2H
N 10 steps
NH2 N
MeO2C Me O
NH2 Me
OBn OH
OMe OMe
OMe OMe
Streptonigrin
110
Indole as a dienophile in inverse electron demand Diels-Alder reaction

CO2Me CO2Me
N N -N2 N
+
N N -H2 N
N N
R
R CO2Me CO2Me
R = Bz Benson, S. C.; Palabrica, C. A.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257
Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990, 55, 3257
Inverse electron demand 4+2 reactions of pyridazines

Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 1955
R1 R1
R2 Me2N OMe R2 X
N
+
N CH2 X = NMe2, OMe
R3 R3
57-93 %
R4 R4
NOTE: Dimethyl aniline derivative formed predominately.
Neunhoeffer, H.; Werner, G. Tetrahedron Lett. 1972, 1517

Neunhoeffer, H.; Werner, G. Liebigs Ann. Chem. 1973, 437
CO2Me
CO2Me MeO2C MeO2C NEt2

N MeC≡CNEt2 NEt2 -N2
N
N N 74 %
CO2Me MeO2C Me
Me
Inverse electron demand 4+2 reactions of 1,2,4,5-tetrazines

Neunhoeffer, H. Comprehensive Heterocyclic Chemistry; Pergamon: London, 1984; Vol. 3, p 550
Neunhoffer, H. Chemistry of Heterocyclic Compounds, Wiley: New York, 1978, Vol. 33, pp. 1095-1097
R N R
R
R1CH=CHR1
N
1 - N2 R1
N N N R N
N N N H - H2 N
R R1 R1
R H R
Sauer, J.; Heinrichs, G. Tetrahedron Lett. 1966, 4979
111
Diels-Alder reactions of electron deficient heteroaromatic dienes

EtO Ph N CO2Me
N CO2Me
NH -N2 N N
N N H
N OEt EtOH N
Ph
MeO2C Ph 27 %
CO2Me CO2Me
N N
N N
CO2Me H R N CO2Me
CO2Me
NNMe2 N NMe2
N N NMe2 -N2 N N
R = alkyl, Ph N R 56-81% N
R
MeO2C H
CO2Me
Roffey, P.; Verge, J. P. J. Heterocycl. Chem. 1969, 6, 497
Seitz, G.; Overheu, W. Arch. Pharm. 1979, 312, 452
Müller, K.; Sauer, J. Tetrahedron Lett. 1984, 2541
Balcar, J.; Chrismam, G.; Huber, F. X.; Sauer, J. Tetrahedron Lett. 1983, 1481
Burg, B.; Dittmar, W.; Reim, H.; Steigel, A.; Sauer, J. Tetrahedron Lett. 1975, 2897
CO2Me N CO2Me
CO2Me
N N
N N PhCl, ∆ N -N2 N N
+ C N
N N N 78 % N
NMe2 NMe2
MeO2C NMe2
CO2Me CO2Me
Seitz, G.; Overheu, W. Chem. Zeit. 1979, 103, 230
Route to condensed pyrazines via internal cycloadditions using nitriles as dienophiles

Taylor, E. C.; French, L. G. J. Org. Chem. 1989, 54, 1245
Taylor, E. C.; French, L. G. J. Org. Chem. 1986, 51, 1967
CN
Ph N Ph N
N X 225-235 oC X
71 %
Ph N Ph N
X = O, NCOCF3
112
Diels-Alder Reaction of 1,2,4,5-tetrazine-3,6-dicarboxylate

Boger, D. L.; Wysocki, R. J. J. Org. Chem. 1989, 54, 714
N N
N CO2Me MeO2C O
MeO2C CO2Me
N N N - N2
dioxane N N
+ O O
reflux N OMe - MeOH N
MeO OMe
MeO2C OMe 70 %
CO2Me
MeO
OR
RO N N MeO2C
several o C
NAc 230 C
steps HN B NAc
87 % N
MeO O MeO
Ac
MeO OH
O
R = t-BuMe2Si
Inverse Electron Demand Diels-Alder Reaction of Triazines with Indole

Fan, W. -H.; Parikh, M.; Snyder, J. K. Tetrahedron Lett. 1995, 36, 6591
Ph Ph
Ph
N Ph N N
(Im)2CO
N N N N N
CH2Cl2 N
K
N
R1HN O (50%)
R1 1
(R = CH3)
Ph Ph
Ph Ph
N
∆
N N N
N N
O N O N
CH3 CH3
113
Intermediates in the Electrophilic Substitution of Pyridine
+ +
H H H
N N N
E E + E
+ H H H
E E E
+ +
N N N
H E H E H E
+ +
N N N
+
- -
Intermediates in the Nucleophilic Displacement of X by Y in X-Substituted
Pyridines
- -
X X X
N N N
Y Y - Y
- X X X
Y Y Y
- -
N N N
X Y X Y X Y
- -
N N N
-
114
Synthesis of Thieno Fused Quinoline Derivatives

H
Br Pd(PPh3)4 H
O B(OH)2
+ O
NO2 NO2
S
S
Gronowitz, S.; Lawitz, K. Chemica Scripta 1983, 22, 265
S Gronowitz, S.; Bobosik, V.; Lawitz, K. Chemica Scripta 1986, 26, 383
Gronowitz, S. Chemica Scripta 1987, 27, 535
FeSO4 Gronowitz, S.; Hornfeldt, A.; Yang, Y. Chemica Scripta 1986, 26, 383
Gronowitz, S.; Hornfeldt, A.; Yang, Y. Chemica Scripta 1986, 26, 311
90 % Gronowitz, S.; Bobosik, V.; Lawitz, K. Chemica Scripta 1984, 23, 120
N Gronowitz, S.; Peters, D. Heterocycles 1990, 30(1), 645
B(OH)2 O2N
Br
Pd(PPh3)4 S
+ FeSO4
H
NO2 S 73 %
H N
O S
O
Proposed Catalytic Cycle for the Suzuki Reaction
R' R'-X
R
Pd (0)
Reductive Elimination Oxidative Addition
R'-Pd
R R'-Pd-X
RO
R"O-Na
B
RO R'-Pd-OR"
R NaX
transmetallation B
OR
Suzuki, A. Acc. Chem. Res. 1982, 15, 178
Suzuki, A.; Yanagai, T.; Miyaura, N. Synth. Commun. 1981, 11, 513
Suzuki, A.; Suginome, H.; Yamada, K.; Miyaura, N. J. Am. Chem. Soc. 1985, 107, 972
Suzuki, A.; Makoto, S.; Norio, M. Tetrahedron Lett. 1986, 27, 3754
Suzuki, A.; Satoh, M.; Miyaura, N. Tetrahedron Lett. 1984, 23, 120
115
Suzuki Coupling of Polycondensed Thiophenes
B(OH)2 S 1. Pd (0) S
Br NaHCO3
CHO +
90 %
2. HCl
NHBoc N
Yang, Y.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1989, 26, 865
S Br N 1. Pd (0) S
CHO
+ NaHCO3
60 %
2. TsONH2 N+
B(OH)2 HClO4
N ClO4-
Gonowitz, S. J. Heterocyclic Chem. 1992, 29, 1049
S S
Br Pd (0)
NaHCO3 S 81 %
S NHBoc N
B(OH)2
+
CHO S 1. Pd (0)
NaHCO3 S
S 67 %
2. HCl
Br NHBoc N
Gonowitz, S. J. Heterocyclic Chem. 1994, 31, 641
S Pd (0) S
CHO N
+ Na2CO3
55 %
H2N N
B(OH)2 N
I
Malm, J.; Rehn, B.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1994, 31, 11
OtBu S
S Br Pd (0) OtBu
(OH)2B NaHCO3
+ N
N 55 %
S t S
N O Bu
N OtBu
Peters, D.; Hornfeldt, A-B.; Gonowitz, S. J. Heterocyclic Chem. 1990, 27, 2165
116
Synthesis of Benzophenanthridines
NHt-BOC O O
N
B(OH)2 H O Pd (0) O
+
Br O 47%
Snieckus, V. Chem. Rev. 1990, 90, 879 Benzo(c)phenanthridine

Snieckus, V. Pure Appl. Chem. 1990, 62, 671
Snieckus, V.; Siddiqui, M. A. Tetrahedron Lett. 1988, 29, 5463
Snieckus, V. Siddiqui, M. A. Tetrahedron Lett. 1990, 31, 1523
Snieckus, V.; Alo, B. I.; Kandil, A.; Patil, A.; Sharp, M.; Siddiqui, M. J. Org. Chem. 1991, 56, 3763
O
NHt-BOC N
H
B(OH)2 Pd (0)
+
Br 18%
Benzo(k)phenanthridine
NHt-BOC O
N
B(OH)2 Pd (0)
H
+
Br 30%
Benzo(j)phenanthridine
Synthesis of 6H-[2]benzopyrano[4,5-c]pyridin-6-one
CON(i-Pr)2
CON(i-Pr)2 Br
N Pd(0)
+ N
B(OH)2 Et2NOCO 80%
Et2NOCO
O
CON(i-Pr)2
O
+
N H 3O
92 %
Et2NOCO N
Sharp, M. J., Snieckus, V. Tetrahedron Lett. 1985, 26, 5997
117
Pd(0) Cross Coupling for Heteroaromatic Synthesis
General Reaction Scheme
Pd(0) Cat.
R-X + R'-M R-R'
R = (het)aryl, alkynyl, vinyl, benzyl R' = (het)aryl, alkynyl, vinyl, alkyl, benzyl
X = I,Br,Cl,OTf, SR" M = B, Sn, Zn, Si, In
General Pd(0) Cross Coupling Catalytic Cycle
Pd (0) R-X
R-R'
Reductive Elimination Oxidative Addition
R-Pd-R' R-Pd-X
R'-Pd-R
M-X R'-M
Transmetallation
Cross Coupling Example

F
Alllyl)2Pd2Cl2
O O O NaOEt, CH3CN
+ 99% yield
OEt F
I
Sia2B O O O
N OEt
HMG-CoA Reductase Inhibitor

NK-104 N
Miyachi, N.; Yanagawa, Y.; Iwasaki, H.; Ohara, Y.; Hiyama, T. Tetrahedron Lett. 1993, 43, 8267-8270
118

The Suzuki-Miyaura Coupling
OAc Pd(PPh3)4
Br O
B(OH)2
N + Br DME
NaHCO3
AcO N
OAc O Br
Br
2.5 M HCl O
N O HN
AcO N 86% O N
H
Wellmar, U.; Hornfeldt, A.; Gronowitz, S. J. Heterocyclic Chem. 1995, 32, 1159
Br N
BEt2
Pd(DIPHOS)2 70%
+
THF, K2CO3
Cl N N
Cl N
De, D.; Krogstad, J. Org. Lett, 2000, 7, 879-882
CON(iPr)2
CON(iPr)2 Br Pd(PPh3)4
+ N 81%
N
Tol / aq.
B(OH)2 Et2NOCO Na2CO3
Et2NOCO
Alo, B.I.; Kandil, A.; Patil, P.A.; Sharp, M.J.; Siddiqui, M.A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.
To a suspension of Pd(PPh3)4 (0.03 equiv) in anhydrous DME was added the aryl bromide and the mixture
was stirred for 10 min at rt. To this solution were added sequentially, the arylboronic acid (1.5 equiv) in a
minimum of EtOH and aqueous Na2CO3 (2M solution, 2.0 equiv). The mixture was refluxed for 18 h, cooled,
and subjected to filtration. The filtrate was evaporated to dryness and the residue was treated with a
saturated NaCl solution. Standard workup followed by column chromatography gave the biaryl product
(81%).
119
The Stille Coupling
O2N
Bu3Sn SnBu3 Bu3Sn COPh COPh
PhCOCl, p-NO2PhBr
PdCl2(PPh3)2 Pd(PPh3)4
O THF O O
HMPA
82% 81%
Yang, Y.; Wong, H. N. C. J. Chem. Soc., Chem. Commun. 1992, 656.
Yang, Y.; Wong, H. N. C. Tetrahedron 1994, 32, 9583.
B
NH2 NH2
CON(i-Pr)2
I CON(i-Pr)2
N OMe
Pd(PPh3)4/NaOH N OMe
THF,61%
N N
Bu3Sn N
Pd(PPh3)4/LiCl O
OTf +
N dioxane NMe
79% N N
N OMe
N OMe O
Amphimedine
Guillier, F.; Nivoliers, F.; Godard, A.; Marsais, F.; Queguiner, G.; Siddiqui, M.A..; Snieckus, V. J. Org. Chem. 1995,60,
292.
Cl
O
N N
+ O Pd[P(2-furyl)3]2
THF N N
N SnBu3 88%
Cl
Cl N
Ph
Ph
Langli, G.; Gundersen, L.; Rise, F. Tetrahedron, 1996, 15, 5625-5638.
A mixture of dichloropurine (126 mg, 0.45 mmol), stannylfuran (0.17 mL, 0.54 mmol), Pd2dba3 (13 mg, 0.013
mmol) and tri(2-furyl)phosphine (23 mg, 0.10 mmol) was added to dry DMF (3 mL) and heated under N2 at
50 oC for 22 h. The reaction mixture was evaporated in vacuo and a saturated solution of KF in methanol
(20 mL) was added. The resulting mixture was stirred at ambient temperature overnight and evaporated in
vacuo. Flash chromatography gave 123 mg of the product (88%yield).
120
The Negishi Coupling
Me Nucleotide
I ClZn N Me N N Analogue
N N + N Pd(PPh3)4
N N
N P(O)(Oi-Pr)2 83%
H2N N O P(O)(Oi-Pr)2
H2N N N
O
Cesnek, M.; Hocek, M.; Holy, A. Coll. Czech. Chem. Commun. 2000, 65, 1357.
O O
O O
(i) tBuLi, THF, -78o C
(ii) ZnCl2, -78o C to rt
N (iii) Pd(OAc)2 N N
82% yield
N N
N Bn
Bn
O I O
p38MAP kinase inhibitor
O O
Dobler, M. R. Tetrahedron Lett. 2003, 44, 7115-7117.
(i) tBuLi, THF, -78o C OMe

(ii) ZnCl2, -78o C to rt N
N Br (iii) Pd(PtBu3)2
N
85%
MeO N Cl
Lutzen, A,; Hapke, M,; Staats, H.; Bunzen, J. Eur. J. Org Chem. 2003, 3948-3957.
tBuLi (1.9 mL, 2.8 mmol) was added to THF (8 mL) at -78o C. A solution of 2-bromo-methylpyridine (500 mg, 2.9
mmol) in THF (2 mL) was added dropwise. After the mixture had been stirred at -78o C for 30-45 min, a solution of
anhydrous ZnCl2 (490 mg, 3.6 mmol) in THF (5 mL) was added slowly and the reaction mixture was stirred for 2-3 h at
room temperature. Next a solution of Pd(PtBu3)2 (19 mg, 0.038 mmol, 3% Pd) and 2-chloro-6-methoxypyridine (380 mg,
2.6 mmol) in THF (5 mL) was added and the reaction heated at reflux until no further consumption was observed by
TLC. After cooling to room temperature, a suspension of EDTA (3 g, 10.3 mmol) in water (60 mL) was added and stirred
for 15 min then brought to pH 8 with saturated Na2CO3. The mixture was extracted several times with CH2Cl2 and the
solvent was removed in vacuo. The pure product (447 mg, 85%) was obtained after column chromatography.
121
The Liebeskind-Srogl Coupling
4% Pd2dba3 82%
O
CO2Me 16% TFP
EtO2C O + 1.3 equiv. CuTC
S (HO)2B CO2Me
SMe EtO2C S
S 5% Pd(PPh3)4 O
Bu3Sn O S
2.2 equiv. CuMeSal 96%
SPh +
N N
TFP = P(2-furyl)3
CuTC = copper (I) thiophene-2-carboxylate Liebeskind, L.S.; Srogl, J. Org. Lett. 2002, 4, 979-981.
CuMeSal = copper (I) 3-methylsalicylate Egi, M.; Liebeskind, L.S. Org. Lett. 2003, 5, 801-802.
The Sonogashira Coupling
NEt2
5% Pd(PPh3)2Cl2 N N
N N 5% CuI
Et2N Bu 65%
N N + H Bu
2 equiv. TEA N N
DMA
Cl
Novak, Z.; Kotschy, A. Org. Lett. 2003, 5, 3495-3497.
5% Pd(PPh3)2Cl2 H
I N
10% CuI 96%
+ H Bu Bu
TBAF,THF
NHCOPh
Suzuki, N.; Yasaki, S.; Yasuhara, A.; Sakamoto, T. Chem. Pharm. Bull. 2003, 51, 1170-1173.
122
The Hiyama Coupling
Me CN
Me o
(i) BuLi, THF, -78 C +
(ii) EtSiCl3 Cl2(Et)Si N Br
Br N
-78o C to rt
5% Pd(PPh3)2Cl2 N
Me CN 92%
KF, DMF
Hiyama, T. J. Organometallic Chem. 2002, 653, 58-61.
10% Pd(OAc)2
S 20% PPh3 S
2 equiv. PhSi(OCH3)3
2 equiv TBAF
Br DMF Ph
Mowery, M.E.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.
Indium Cross Coupling
S O
S 4% Pd(PPh3)4 61%
Br + 1/3InPh3
1 atm CO Ph
THF
Me OHC O 95%
OHC Me 4% Pd(PPh3)2Cl2
O N Me
Br + Benzene
Me In
Me
Lee, P.H.; Lee, S.W.; Lee, K. Org. Lett. 2003, 5, 1103-1106.

Jaber, N.; Schumann, H.; Blum, J. J. Heterocyclic Chem. 2003, 4, 565-567.
123
Metallation/Cross Coupling for Polycondensed Heteroaromatics
Suzuki Coupling
Pd(PPh3)4 CON(iPr)2 O
CON(iPr)2 Tol / aq.
Na2CO3 2N HCl O
N
B(OH)2 Br reflux
N
Et2NOCO
Et2NOCO N
81% 92%
Alo, B.I.; Kandil, A.; Patil, P.A.; Sharp, M.J.; Siddiqui, M.A.; Snieckus, V. J. Org. Chem. 1991, 56, 3763.
To a suspension of Pd(PPh3)4 (0.03 equiv) in anhydrous DME was added the aryl bromide and the mixture
was stirred for 10 min at rt. To this solution were added sequentially, the arylboronic acid (1.5 equiv) in a
minimum of EtOH and aqueous Na2CO3 (2M solution, 2.0 equiv), and the mixture was refluxed for 18 h,
cooled, and subjected to filtration. The filtrate was evaporated to dryness and the residue was treated with
a saturated NaCl solution. Standard workup followed by column chromatography gave the biaryl product
(81%). A solution of the biaryl compound (0.30 g, 0.75 mmol) was refluxed in 2 M HCl (10 mL) for 24 h.
Normal workup followed by chromatography afforded 0.14 g (92%) of the cyclized product.
Aryl Lithiation Followed by Suzuki Coupling
OMe
OMe B(OH)2 MeO CHO
MeO CHO CONiPr2 Pd(PPh3)4/DMF
2M aq Na2CO3 MeO
+
MeO OMe reflux 93% CONiPr2
Br OMe
OMe
OMe OMe
MeO OMe
LDA MeO
NH2 THF
MeO N
CONiPr2 36% MeO
OMe OMe
OMe
OMe
Fu, J.-M.; Zhao, B. -P; Sharp, M.J.; Snieckus, V. Can. J. Chem. 1994, 72, 227.
A mixture of Pd(PPh3)4 (0.44 g, 0.40 mmol) and 5-bromo-2,3,4-trimethoxybenzaldehyde (2.2 g, 8.0 mmol) in
DME was stirred at room temperature for 5 min. To this mixture was added dropwise a solution of
2-N,N-diisopropylcarboxamido-3,4-dimethoxyphenylboronic acid (3.2 g, 10.4 mmol) dissolved in a
minimum amount of EtOH and an aqueous solution of 2 M Na2CO3. The resulting mixture was heated at
reflux for 12 h, cooled, and the solid was removed by filtration. The filtrate was evaporated to dryness
and the residue was washed with ether. Standard workup followed by flash chromatography afforded the
biaryl product (93%). To a solution of LDA (2.2 mmol) in THF (5 mL) was added a solution of amine (0.28
g, 0.6 mmol) in THF (1 mL) at 0 °C. The mixture was stirred for 10 h. Standard workup followed by flash
chromatography afforded 0.076 g (36%) of the cyclized product.
124
Stille Coupling on the Merrifield Resin
O O
Br Pd(0)
O PhSnBu3 O
N N
O
1. LiOH/H2O HO
2. 1M HCl N 96%
Chamoin, S.; Houldsworth, S.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4175.
Commercial Merrifield resin (1% cross linked, 1 mequiv Cl/g, 0.15 g) was swollen in anhydrous DMF (5 mL) and the
system was flushed with argon (30 min). A sample of Pd(PPh3)4 (0.05 equiv) was added and the reaction mixture was
stirred (10 min). The stannane (3 equiv) was added and the mixture was stirred at 60 °C (24 h), cooled to rt, and
treated with NH4Cl solution (5 mL) and stirred (10 min). The resin was removed by filtration (fritted glass funnel) and
the filtrate was washed successively with DMF (5 mL), H2O (15 mL), EtOAc (10 mL), MeOH (15 mL), and dried in
vacuo (12 h). To cleave the product from the solid support, the resin was swollen in THF (2.5 mL) for 30 min.,
LiOH•H2O (5 equiv) dissolved in MeOH:H2O (2:1, 1.5 mL) was added, and the mixture was refluxed for 18-42 h.
After cooling to rt, a solution of 1M HCl (3 mL) was added and the whole was stirred (10 min) and subjected to
filtration (fritted glass funnel). The resin was successively washed with THF (30 mL), and Et2O (30 mL) and the filtrate
was repeatedly extracted with EtOAc. The combined organic extract was washed with brine, dried (Na2SO4) and
evaporated to dryness to give the acid (96%).
Application of the Buchwald-Hartwig Amination Protocol
Aniline
CONEt2 Pd2(dba)3, BINAP CONEt2 1. N-Methylation
NaOtBu 98%
Br 90 - 100 °C N 2. LDA
H
79%
81%
O
N
Me MacNeil, S.L.; Gray, M.; Briggs, L.E.; Li, J.J.; Snieckus, V. Synlett 1998, 419.
A thick-walled screw cap glass tube was charged with a mixture of N,N-diethyl 2-bromobenzamide, aniline (0.2 mL, 2.3
mmol), NaOt-Bu (0.27 g, 2.8 mmol), Pd2(dba)3 (5 mg, 0.006 mmol), BINAP (10 mg, 0.017 mmol) and toluene (5 mL)
under a N2 atmosphere. The tube was sealed and heated (90-100 °C) with stirring for 21 h, and cooled to rt. Addition
of aqueous NH4Cl and standard workup, followed by flash column chromatography afforded N,N-diethyl
N-phenylanthranilamide (430 mg, 81%). A solution of N,N-diethyl N-phenylanthranilamide (0.11 g, 0.40 mmol) in THF (3
mL) was cooled to 0 °C under argon atmosphere and treated with a solution of LDA (1.4 mmol) in THF (2 mL)
precooled to 0 °C for 1.5 h and warmed to rt. Addition of aqueous NH4Cl and standard workup, followed by silica gel
flash column chromatography afforded N-methylacridone (0.07 g, 79%).
125
A Route to Quinazolinones via Intramolecular Aza-Wittig Reaction
O O O
PPh3 Me
N Me N
Me 25 oC, 2 h
N3 N Me
99 %
Takeuchi, H.; Eguchi, S. Tetrahedron Lett. 1989, 30, 3313

Lambert, P. H.; Vautier, M.; Carrie J. Chem. Soc., Chem. Commun. 1982, 1224
Lambert, P. H.; Carrie, R. J. Org. Chem. 1985, 50, 5352
Molina, P.; Alajarin, M.; Ferao, A. Synthesis 1986, 843
Molina, P.; Alajarin, M.; Vidal, A. Tetrahedron Lett. 1988, 3849
Intramolecular aza-Wittig reaction forisoxazolo[4,3-c]quinoline formation
N O N O N O
R PPh3 R R
COR toluene, 25 oC COR 94 %

N3 N PPh3 N R
R = Me
Purwono, B.; Smalley, R. K.; Porter, T. C. Synlett. 1992, 231.
Efficient route to iminolactam derivatives via intramolecular aza-Wittig reaction
O 1) PPh3, xylene O
rt, 1 h
(CH2)n N (CH2)n N
2) reflux, 2h
O N3 a. n = 1; 92 % N
b. n = 2; 92 %
Eguchi, S.; Takeuchi, H. J. Chem. Soc., Chem. Commun. 1989, 602
126
Conversion of Butenyl Azides into Benz[f]indoles by Aza-Wittig reaction
PPh3 Ph2C C O
Ar N3 Ar N PPh3
toluene, rt
Et2O
Ar Ar
Ar
N
toluene Mn2O2
C
reflux 50 % N
N H
Ph Ph
Ph
Molina, P.; Leonardo, C. L. Tetrahedron Lett. 1993, 34, 2809
Epoxidation - Staudinger Reaction of o-Allylphenyl Azides
R1 R1
R2 PPh3 R2
O O
CHCl3
N3 N PPh3
R1 = OCH2Ph
R2 = OMe
R1 R1 R1
R2 R2 R2
N N 45 %
O OPPh3 N
PPh3
Molina, P.; Alajarin, M.; Lazaro, A. L. Tetrahedron Lett. 1992, 33, 2387
For a review of the Staudinger reaction see: Gololobov, Y. G.; Zhmurova, I. N.; Kasushim, L. F. Tetrahedron 1981, 37, 437
127
Use of the Aza-Wittig Reaction for Heterocyclic Synthesis
1. Oxazoles via an Intramolecular Aza-Wittig Reaction
O
O R2 (EtO)3P, CyH, 90 °C,

sealed tube, 24 h R O
N3 R2
R 93%
1 N
R R1
R = p-MeC6H4
R1 = H
R2 = Me
Takeuchi, H.; Yanagida, S.; Ozaki, T.; Hagiwara, S.; Eguchi, S. J. Org. Chem. 1989, 54, 431
To a stirred solution of the vinyl azide (1 mmol) in dry cyclohexane (5 mL) in a sealed tube was added triethyl
phosphite (10 mmol). Nitrogen gas evolution started immediately and ceased after 1 h. The mixture was
heated at 90 °C for 24 h with continued stirring. The cooled mixture was chromatographed on a short silica gel
column, eluting with ethyl acetate-hexane to give the oxazole.
2. Vinylogous Urethanes via an Intramolecular Aza-Wittig Reaction
R2 R1 R1
Ph3P, Et2O, rt, 24 h
R
N3 n 96% n R
NH
O O R2 O
R = OEt
Lambert, P.H.; Vaultier, M.; Carrie, R. J. Org. Chem. 1985, 50, 5352 R1 = R2 = H
To a solution of 10 mmol of the azide in 20 mL of anhydrous ether was added 2.6 g (10 mmol) of
triphenylphosphine, with stirring, until all the phosphine had dissolved. Nitrogen evolution started after a few
seconds. The reaction mixture was kept at room temperature for 24 h. The solvent was removed in vacuo,
and the residue triturated with 40 mL of a 1:1-mixture of ether and petroleum ether. Triphenylphosphine
oxide was collected by filtration, and the crystals were thoroughly washed with cold ether. After removal of
the solvent, the product was purified by Kugelrohr distillation.
3. Imidazolinones via an Intramolecular Aza-Wittig Reaction

O
O O
Ph3P, PhH, rt, 2 h R1
N3 N R2
R 99%
1 2 N
R R R
R=
O R1 = Me
Takeuchi, T.; Hagiwara, S.; Eguchi, S. Tetrahedron 1989, 45, 6375
R2 = H
To a stirred solution of the imide (1 mmol) in benzene (10 mL) was added triphenylphosphine (1.1 mmol).
The mixture was stirred for 2 h at room temperature and the solvent was removed under reduced pressure.
The residue was chromatographed on a silica gel column to give the imidazolinone.
128
4. 2,3-Dihydro-1H-pyrrolo[1,2-a]benzimidazol-1-one via an
Intramolecular Aza-Wittig Reaction
1. Ph3PBr2
NH2 2. Et3N N
O
60%
N N
O O
Al-Khathlan, H.; Zimmer, H. J. Heterocyclic Chem. 1988, 25, 1047
A solution of dibromotriphenylphosphorane prepared from 1.4 g of triphenylphosphine and 0.84 g of

bromine in CH2Cl2 was added dropwise to a solution of 1 g of the amine in 150 mL of CH2Cl2. To this
mixture was added triethylamine (1.0 g, 10.5 mmol) and the solution was refluxed for 12 h. The resulting
solution was extracted with water, dried over anhydrous magnesium sulfate, the solvent was distilled to
afford the product.
5. Pyrrolo[2,1-b]quinazolines via an Intramolecular Aza-Wittig Reaction
O CO2Me O CO2Me
Ph3P, rt, 4 h,
N then 80 °C, 9 h
N
HCl/THF
N3 N
O
Okawa, T.; Sugimori, T.; Eguchi, S.; Kakehi, A. Heterocycles, 1998, 47, 375.
To a solution of the azide (0.144 g, 0.5 mmol) in dry benzene (25 mL) was added triphenylphosphine
(0.14 g, 0.55 mmol) under a nitrogen atmosphere at rt. The reaction mixture was stirred for 4 h then
heated to 80 °C for 9 h. After the solvent was evaporated, flash chromatography of the residue gave
the quinazolinyl carboxylate.
Tandem aza-Wittig / electrocyclization reaction
OMe OMe CO2Me

CH3COCH=CHCO2Me
CHCl3, 34 h, 45 oC
N PPh3 Me
S N
S
Bonini, C.; Funicello, M.; Scialpi, R. Spagnolo, P. Tetrahedron 2003, 59, 7515.
129
Synthesis of Vasicinone Based on Intramolecular aza-Wittig Reaction with Imide
O (1) PBu3, toluene, rt O

O
1 h, reflux, 2 h, 76%
N N
OTBDMS o
(2) TBAF, THF, 0 C rt
N3 N
15 h, 82%
OH
l-Vasicinone
Eguchi, S.; Suzuki, T.; Okawa, T.; Matsushita, Y. J. Org. Chem. 1996, 61, 7316.
Synthesis of Benzodiazepines and Benzothiadiazepines via aza-Wittig Reaction with Ketone
R1 (1) PhMgBr, THF R1 OH

X -40 oC X
N NH
S (2) P(OMe)3, MeOH
N R1 60 oC N
O R1
PR3 83% 2 steps PR3
X = SO2 or CO
R = n-Bu, Ph or polymer support
R1 = H, Me
R1 O X NH
X R1
Dess-Martin NH Toluene, reflux
N
N
R1 R1
PR3
Anwar, B.; Grimsey, P.; Hemming, K.; Krajniewski, M.; Loukou, C. Tetrahedron Lett. 2000, 41, 10107.
Synthesis of 2, 4-Disubstituted Thiazoline via aza-Wittig Reaction with Thioester
TBS
TESO Me O O PPh3, THF, 50 oC
CO2Me
S 67%
Me N3 Me
TBS Chen, J.; Forsyth, C. J. Org. Lett. 2003, 5, 1281.

TESO Me O S Me Chen, J.; Forsyth, C. J. J. Am. Chem. Soc. 2003, 125, 8734.
N CO2Me
Me
130
Key step in the Synthesis of the Indole Alkaloid Hamacanthin B

via an Aza-Witig Reaction with Ketone
N3 O
NH PBu3, toluene, reflux
Br Br
O 12 h, 82%
NTs NH
NH O
N
Br Br
NR NH
R = Ts
L-Selectride
R = H, (Hamacanthin B)
Jiang, B.; Yang, C.-G.; Wang, J. J. Org. Chem. 2002, 67, 1396.
Synthesis of Phloeodictine A1 via aza-Wittig with an Imide
O O
O N
o
PPh3, toluene, 25 C, 30 min
N N3 N
O O
H2N NH2
N NH
reflux, 4 h 5
N N
retro Diels-Alder
O N
10
OH
Phloeodictine A1
Neubert, B. J.; Snider, B. B. Org. Lett. 2003, 5, 765.
131
Synthesis of the marine alkaloid variolin B via aza-Wittig reaction
OCH3
OCH3
PhCH(CH3)NCO
N CO2Et
N CO2Et N
N THF, rt, 100% H N
H N
C
PPh3
NCH(CH3)Ph
NH2
N
OCH3
N
OH
N N
CO2Et
Ph N N N
N
N
CH3 H NH2
Variolin B
Molina, P.; Fresneda, P. M.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2002, 43, 1005.
Fresneda, P. M.; Molina, P.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2000, 41, 4777.
Preparation of 2-amino-1,4-disubstituted imidazoles via aza-Wittig reaction
CO2Et CO2Et
Ph PPh3 / Et2O, rt Ph Ts-NCO, Et2O, rt
N3 N PPh3
CO2Et
CO2Et Ph
Ph R-NH2, Et2O, 0 oC
N C NH Ts
N C N Ts HN
R
Ph N Ph N
NHTs NH2
O N N
R R
Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem. 1999, 64, 2540.
132
1. Pd Catalyzed Amination of Five-membered Heterocyclic Halides
O Br NMePh 56%
O
Br NMePh 82%
S 2% Pd(dba)2, PtBu3 S Hartwig, J. F.; Utsunomiya, M.;
Hooper, M. W. J. Org. Chem.
Br PhNHMe NMePh 2003, 68, 2861.
85%
1.1 eq. NaOtBu, tol
O O
Br NMePh
93%
S S
In a dry box, aryl bromide (0.5-2.5 mmol), amine (0.5-2.5 mmol), and NaOtBu (0.55 - 2.75 mmol) were weighed directly
into a screw capped vial. A stir bar and 0.5-2.5 mL of toluene were added. Pd(dba)2 (2 mol %, 0.01-0.05 mmol) and
PtBu3 (2 mol %, 0.01-0.05 mmol) were weighed directly into a small vial and suspended in 0.5-2.5 mL of toluene. The
catalyst suspension was then added to the reactants to give a purple mixture. The mixture was allowed to stir for 16 h at
room temperature in the drybox or at 100 °C for 16 h outside the drybox. After this time, the mixture was poured into
pentane (15 mL), filtered, and concentrated in vacuo. The crude product was adsorbed onto neutral alumina and purified
by flash chromatography.
N N
Br NnBu2 71%
S 5% Pd(O2CCF3)2, S
t n
P Bu3, HN Bu2
N N
Cl 1.1 eq. base, tol
NnBu2
S 77%
S
N N
Cl N O
N 74%
5% Pd(O2CCF3)2, PtBu3 N
Me Me
1.1 eq. base, tol,
N HN O N
Cl N O 51%
O O
In a drybox, aryl halide (1.0 mmol), NaOtBu or K3PO4 (1.10 mmol), and amine (1.0-4.0 mmol) were added to a
suspension of Pd(O2CCF3)2 and PtBu3 (0.02-0.05 mmol) in 1.0-2.0 mL of toluene in a screw capped vial. A small stirbar
was added, and the vial was sealed with a cap containing a PTFE septum. The mixture was allowed to stir at room
temperature in the drybox or at elevated temperature outside of the drybox. After the reaction, the mixture was adsorbed
onto neutral alumina and purified by flash chromatography.
133
Pd(0) catalyzed amination of heteroaromatics - Section one - Chemistry of Heteroaromatics
2. Pd Catalyzed Amination of Chloropyridines
N N 95%
H
N Cl N 5 mol % Pd(OAc)2, O
+ t
Cl BuONa, DMF, 80oC O
O N 70%
N cat.
Ph N Bn
Cl P(R)2 N(H)Bn N
+ H NBn t
2 1 - R= Bu + N
N . N N
HCl 2 - R=Cy
70% (27:1)
Buchwald, S. L.; Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J. J. Org. Chem. 2000, 65, 1158.
An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with palladium
acetate (0.5 mol %), 1 (1.0 mol %), and NaOt-Bu (1.4 equiv) and evacuated and backfilled with argon. The flask was
capped with a rubber septum, and toluene (2 mL/mmol halide), the aryl chloride (1.0 equiv), and the amine (1.2 equiv)
were added through the septum (aryl chlorides or amines that were solids at room temperature were added as solids
following the addition of NaOt-Bu). The septum was replaced with a Teflon screwcap, the flask was sealed, and the
mixture was heated to 80 °C with stirring until the starting aryl halide had been completely consumed as judged by GC
analysis. The mixture was cooled to room temperature, diluted with ether (30 mL), filtered through Celite, and concentrated
in vacuo. The crude product was purified by flash chromatography on silica gel. N-(2-Pyridyl)morpholine: conducted on a
2 mmol scale using a reaction temperature of 100 °C and ligand 2. N-(3-Pyridyl)morpholine: 1 mol % Pd(OAc)2 and a
reaction temperature of 110 °C gave. N-Benzyl-4-aminopyridine: 1 mol % Pd(OAc)2, 2 mol % 2, 2.8 equiv of NaOt-Bu,
dioxane solvent, and a reaction temperature of 100 °C, determined to contain 3.6% of bis(4-pyridyl)benzylamine by 1H
NMR analysis.
General Catalytic Cycle for Buchwald-Hartwig Amination

L Pd0 L
L -L Ar-X
Ar-NRR' oxidative addition
L Pd0
reductive elimination
Ar
Ar
L PdII L PdII
NRR' X
NHRR'
NaX + tBuOH
L Ar amine coordination
II
deprotonation Pd
NaOtBu X NHRR'
Verkade, J. G.; Xu, J.; Urgaonkar, S. J. Org. Chem. 2003, 68, 8416.
134
3. Pd Catalyzed Amination of Bromopyridines
H
N N N 93%
cat. Pd(OAc)2,
+ 1.5 eq. NaOtBu, tol, O
N Br O
i-Bu Me
i-Bu P N 84%
Br Ph N N i-Bu N
Ph
+ HN cat.
N Me Me N
Verkade, J. G.; Xu, J.; Urgaonkar, S. J. Org. Chem. 2003, 68, 8416.
An oven dried Schlenk flask equipped with a magnetic stirring bar was charged with Pd(OAc)2 or Pd(dba)2 and CS2CO3
(1.5 mmol). Amine (1.2 mmol) and aryl bromide (1.0 mmol) were also added at this time. The flask was capped with a
rubber septum, evacuated, and then flushed with argon. This cycle was repeated three times. The ligand was then added
via syringe from a stock solution. Aryl bromide (if a liquid, 1.0 mmol), amine (if a liquid, 1.2 mmol), and toluene (3 mL)
were then successively added by syringe. The reaction mixture was heated to 80oC until the starting material had been
completely consumed as judged by TLC (15-20 h). The mixture was cooled to room temperature, adsorbed onto silica
gel, and then purified by column chromatography using a mixture of hexane and ethyl acetate as the eluent.
4. Pd Catalyzed Amination of Pyrazine and Quinoline
N
N 80%
cat. Pd(OAc)2,
N N
1.4 eq. NaOtBu, tol,
N Cl Me
Cy2P 83%
N Cl microwave, 10 min N N
Me
Maes, B. U. W.; Loones, K. T. J.; Lemiere, G. L. F.; Dommisse, R. A. Synlett. 2003, 12, 1822.
A pressure vial of 10 mL was charged with (azahetero)aryl chloride (1 mmol), amine (1.2 mmol or 1.5 mmol) and
t-BuONa (0.13 g, 1.4 mmol) in air. Subsequently the vial as flushed with Ar for 1 min. Then, 1 mL of a stock solution of
precatalyst [Pd/2L: Pd(OAc)2 and DCPB [DCPB = 2-(dicyclohexylphosphanyl)biphenyl] in anhydrous toluene was added
via a syringe and the resulting mixture was flushed with Ar for an additional 2 min under magnetic stirring. Next, the vial
was sealed with an Al crimp top with septum and heated at 150 °C or 200 °C in a CEM Discover microwave apparatus.
The initial power supplied was 300 W. Once the temperature was reached (IR measurement), the power dropped and
fluctuated to maintain the temperature at the desired value. The total heating time of all reactions was 10 min. After the
reaction vials were cooled down to rt. using a propelled air flow, they were opened and filtered over Celite and rinsed
well with 100 mL CH2Cl2 or Et2O. The filtrate was subsequently evaporated under reduced pressure and the residue
purified by flash column chromatography on silica gel.
135
5. β-Carbolinone Synthesis
CO2Me
O O CO2Me
5 mol %Pd(OAc)2
1. , Rh(II) Br
SO2Ph 10% Xantphos
N +
N2 2. Tf2O N
TfO NH2 1.5 eq. Cs2CO3, tol.
O
CO2Me CO2Me
Br 10 mol %
Pd(PPh3)2
N 1.2 eq. Cs2CO3, N
N N
H dioxane, 110oC H
O O
80% 65%
Padwa, A.; Harris, J. M. J. Org. Chem. 2003, 5, 4195.
A flame-dried 10 mL round bottom flask was charged with tris(dibenzylideneacetone), dipalladium(0) (4.0 mg, 0.005
mmol, 2.5 mol %), Xantphos (10 mg, 0.02 mmol, 10 mol %), pyridone (0.05 g, 0.18 mmol), and Cs2CO3 (0.09 g, 0.27
mmol). The solid reactants were dissolved in 5 mL of dioxane and the appropriate aniline derivative (25 uL, 0.27 mmol)
was added to the flask. The flask was capped with a condensor and kept under an atmosphere of argon. The reaction
was heated at 100oC for 1-2 h or until the starting triflate had been completely consumed as judged by TLC. The reaction
mixture was then cooled to room temperature, diluted with ethyl acetate, filtered through a pad of celite and concentrated
under reduced pressure. The crude material was purified by flash column chromatography on silica gel or florisil to give
the 2,3-dihydro-1H-indolizin-5-one.
6. Tetrahydopyrroloquinolines - Dehydrobufotenine
I Me
NHMe N
MeO 10 mol %Pd(PPh3)4
K2CO3, NEt3 MeO
N
N
CO2Et Me
CO2Et
Me N 81%
1. BBr3 HO
2. MeI NH
50% - 6 steps;
17% overall yield
Buchwald, S. L.; Peat, A. J. J. Am. Chem. Soc. 1996, 118, 1028.
Pd(PPh3)4 (92 mg, 0.08 mmol) was added to a mixture of the indole (0.32 g, 0.80 mmol), NEt3 (4 mL), and K2CO3 (0.33
g, 2.4 mmol) in toluene (10 mL). The yellow mixture was heated to 200 °C for 15 h, cooled to rt, and poured into a
separatory funnel containing Et2O (15 mL) and water (15 mL). The organic layer was washed with water (10 mL) and
brine (10 mL), dried over MgSO4, and filtered, and the solvents were removed using a rotary evaporator. The product
was purified by flash chromatography (4:1 hexane/ethyl acetate) to give 0.18 g (82%) of the product as a white powder.
136
7. Functionalized Pyrido[2,3-b]indoles
O
O HO
LiHMDS SnCl4, O
H -78oC TFA, Me2S
N Br BocHN O N Br NHBoc
Me O Me
O 57%
O
O 5 mol % Pd2(dba)3,
10 mol %BINAP O
t o
N Br NH2 BuONa, DMF, 80 C N N
Me Me
51%
90%
Dodd, R. H.; Abouabdellah, A. Tetrahedron Lett. 1998, 39, 2119.
For procedure see: Buchwald, S. L.; Marcoux, J.; Wagaw, S. J. Org. Chem. 1997, 62, 1568.
8. Pd Catalyzed Coupling of Glycosylamines and 6-Chloropurines
OBn OBn
SEM
BnO BnO
O N N cat. Pd2(dba)3 O N N
+
BnO NH2 N N (-) BINAP, NaOtBu, tol. BnO N N MPM
H
OBn OBn N
Cl
74%
SEM= Me3SiCH2CH2OCH2- OH
HO
o O N N
1. BBr3, CH2Cl2, -78 C
2. recrystallization (H2O) HO N NH
H
OH N
81%
Chida, N., Suzuki; T.; Tanaka, S.; Yamada, I. Tetrahedron Lett. 1999, 40, 2573.
To a mixture of mannopyranosylamine (32 mg, 60 umol) and 6-chloropurine (33 mg, 120 umol), in toluene (2.5 ml) was
bubbled a stream of Ar for 15 min. The reaction mixture was then heated at 140oC in a sealed tube for 9 hr. After cooling,
the mixture was diluted with ether and washed with brine, and dried. Removal of the solvent left a syrup, which was
chromatographed on a column of silica gel (4 g), with EtOAc-toluene (1:3) to give the product as an anomeric mixture.
137
9. Multiamino Based Structures
N HN (CH2)CH3
Cl H N
N N 2 mol% Pd2(dba)3, NH
+ H2N (CH2)CH3 N
BINAP, NaOtBu
F
F 77%
Senanayake, C. H.; Hong, Y.; Xiang, T.; Vandenbossche, C.P.; Tanoury, G. J.;
Bakale, R. P.; Wald, S. A. Tetrahedron Lett. 1998, 39, 3121.
Anhydrous toluene was degassed with argon for 20 min. prior to use. A dry 25 mL 2-neck flask was charged with
N-propylethylenediamine (0.43 mL, 3.5 mmol), tris(dibenzylideneacetone)-dipalladium(0) [Pd2(dba)3] (40 mg, 0.044
mmol), 2,2'-Bis(diphenylphosphino)- 1-1 '-binaphthyl (81 mg, 0.13 mmol) [BINAP], sodium tert-butoxide (300 mg, 3.2
mmol), and aryl halide (500 mg, 2.9 mmol). The resulting mixture was evacuated and purged with argon, followed by the
addition of anhydrous toluene (10 mL). The solution was degassed with argon for 5 min, at which time it was heated to
85°C for 2 h. The reaction was cooled to room temperature, quenched with 0.1N NaOH and the aqueous layer extracted
with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. Silica gel
column chromatography was performed using EtOAc:MeOH.
10. Selective Pd Catalyzed Aminations of Dichloropyridines

Cl Cl
2% Pd(OAc)2, 2% BINAP
H2N-Ar, 20 eq. K2CO3 R
N Cl N N
H CH3
R= N
N N CH3
83% 90%
O N
N
N N
60% 91%
Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027.
A round bottom flask was flushed with nitrogen and charged with Pd(OAc)2 (13 mg, 0.06 mmol, 2%), (±)-BINAP (37 mg,
0.06 mmol, 2%) and toluene (10ml). The mixture was stirred under nitrogen for 10 min. In another round bottom flask,
dichloropyridine (0.44 g, 3 mmol), amine (3.6 mmol, 1.2 equiv.) and K2CO3 (8.3 g, 60 mmol) were weighed. Then, the
Pd(OAc)2/BINAP solution was added, and the flask was rinsed with an additional 17 mol toluene. The resulting mixture
was subsequently refluxed in an oil bath under N2 with vigorous stirring until the starting dichloropyridine had
disappeared as judged by TCL and DCI-MS. After cooling down, the solid material was filtered off and washed with 100
ml CH2Cl2. The solvent was evaporated and the resulting crude product was purified by flash column chromatography.
138

Chemistry of Hetero Aromatics

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Section 1-Chemistry of Heteroaromatics

Literature of Heterocyclic Chemistry

1. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1984, Pergamon, Vol. 1-8

2. "Comprehensive Heterocyclic Chemistry," Katritzky/Rees, 1996, Pergamon, Vol. 1-11

3. "The Chemistry of Heterocyclic Compounds," Weissberger/Taylor, >50 volumes.

4. "Advances in Heterocyclic Chemistry," Katritzky/Boulton, (Vol. 40, p. 1 has review

1. "Nomenclature of Heterocycles" by McNaught/Smith in "Comprehensive Heterocyclic Chem."

2. "Revision of the Extended Hantzsch-Widman System of Nomenclature for Heteromonocycles,"

3. McNaught, in Adv. Heterocycl. Chem. 1976, 20, 175.

5. Chemical Abstract Service, "Index Guide" 1982-1986; Appendix IV

6. Chemical Abstract service, "Ring Index"

Accepted Trivial Names (partial list)

Quinazoline Cinnoline Pteridine 4aH-carbazole Carbazole

Cinprazole--Antiulcerogenic agent Eproxindine--Antiarrhythmic agent

Clopidogrel--Antithrombotic agent Manazodil--Vasodilator

Dihydralazine--Antihypertensive agent Methdilazine--Antihistamine

Epirizole--Antiflammatory agent Vibunazole--Antiviral agent

Nizatidine--antagonist of histamine at H-2 receptors

Pefloxacin--antimicrobial agent with oral activity

Acrivastine--a nonsedating H-1 antihistamine Me

No structural information, often based on origin.

(systematic name = 3-methylpyridine)

Currently over 60 trivial names accepted by IUPAC for use as

Examples: Pyrrole Furan Thiophene

2. Extended Hantzsch-Widman Nomenclature

use for less than10-membered rings

stem and prefix

indicates ring O = oxa-

Isochroman Chroman Pyrrolidine Pyrroline

Imidazolidine Imidazoline Pyrazolidine Pyrazoline

Piperidine Piperazine Indoline Isoindoline

Stems: (see McNaught/Smith for full discussion)

Indicated Hydrogen -- To locate hydrogen (or a substituent) when fully

•Use H prefix (pronounce the letter "H")

•The saturated position takes priority in numbering

•Use fully unsaturated name with dihydro, tetrahydro, etc.

•Alternative: Trivial names are sometimes still used.

Fused Rings ("Fusion names")

Step 1. Choose one component as "base component."

see "Heterocyclic a. N-rings have priority

In our example, pyrimidine is base component.

Step 2. Other component named as prefix by changing ending:

imidazole imidazo - (not imidazolo-)

Step 6. Number the new ring system (not easy)

(von Baeyer names used for bridged-bicyclics)

Basic lone pair in plane of ring Basic compounds

still aromatic (about like an imine)

>1 heteroatom: Greatly decreased basicity due to electronegativity

Nuc much faster than Nuc

Deprotonation at ring C-H generally requires activating group

Electrophilic attack at N much faster than attack at carbon

1 heteroatom: Poor base - no basic lone pair

Calculated π-electron densities:

Preferred for X=NH, NR, S

X Preferred for X=O

Still aromatic Aromaticity disrupted

•Many methods rely on carbonyl chemistry

Look for these fragments in target heterocycle

imine H enamine 1,5-dicarbonyl

Cyclization Reactions for Heterocyclic Synthesis

Types of nucleophile-electrophile cyclizations

sp3 X: exo-tet sp2 X: exo-trig sp X: exo-dig sp2 Y: endo-trig sp Y: endo-dig

Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734