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U. Jansen, J. Runsink, J. Mattay

Notizen/ Notes

283

Diastereomeric 5,6-Dimethyl-4H-l,3-dioxin-4-onesfrom (- )-(1R,4S)-

Menthone: Synthesis and NMR Analysis

Ursula Jansen*)')', Jan Runsink', and Jochen Mattay*

Institut fur Organische Chemie, Technische Hochschule Aachen", Prof.-Pirlet-StraDe 1, D-5100 Aachen

Organisch-Chemisches Institut der Universitit Miinsterb, Orlkansring 23, D-4400 Munster

Received September 14, 1990

Key Words: 4H-1,3-Dioxin-4-ones f Spirocyclic enones

Menthone

The two diastereomers of spirocyclic 5,6-dimethyl-4H-1,3-di- oxin-4-one (5,6)have been synthesized by acetalization of tert-

butyl

Their structures have been determined by NMR analysis.

2-methyl-3-oxobutanoate

(2) with

(- )-menthone (4).

The synthesis of enantiomerically pure compounds via chiral ace- toacetic acid derivatives has become increasingly important in pre- parative organic chemistry for both ground-state'.') as well as ex- cited-state procedure^^-^). In the course of our investigations concerning chiral olefins and dienes we synthesized the two diastereomers of the spirocyclic acetals 5 and 6 by reaction of tert- butyl 2-methyl-3-oxobutanoate (2) with (- Fmenthone (4) accord- ing to a procedure which has been reported earlier by Kato" and Demuth The structures of 5 and 6 have been assigned by means of NMR analysis, i.e. by comparing the data of 5 and 6 with those of 7 and 8') obtained from 'H-NMR multiplet decoupled Hetcor spectra and I3C-NMR spectra. First attempts to synthesize 2 from 1 according to procedures reported by Knunyants9)(20% aq. KOH, Me2S04)or by Scolastico et al.") (NaOEt, Me1 or NaOH, tBu4NHS04,MeI) have yielded insufficient conversions of 1. Methylation of the enamine 3 with dimethyl sulfate according to Mistryukov's method"' (for the syn- thesis of the corresponding ethyl ester) has also failed in our hands, though 3 can be synthesized from 1 and dimethylamine in 77% yield according to Arnold's procedureI2', which has been modified by us. The E configuration of 3 has been confirmed by NOE ex- periments: Irradiation at 6 = 2.90 (NCHJ gives an NOE of 2.6% at 6 = 4.50 (2-H) but no NOE is observed upon irradiation of CH3-

00

1

NaH, Me1

DMF

00

4

I

2

4. Finally, only the application of a method reported by Barrett and Sheth"Ihas furnished 2 in high purity and in high yield. (-)-Menthone (4) (from (-)-menthol by oxidation with chromic acid according to Brown and GargI4), cf. experimental part) and 2 are converted to the acetals 5 and 6 by the application of the Kato/Demuth-procedure4~" to the synthesis of 7 and 8 from 1, however with few modifications. The best results have been ob- tained with equimolar mixtures of 2 and 4. An excess of 2 (up to 300 mol-%) results in a higher conversion, but, the enhanced for- mation of sideproducts dramatically hinders the purification of 5 and 6. For more details see experimental section.

AcZO, HZSO,

2+ -qyo

4

20 OC

*

0

5 (R=CH,)

[7 (R=H)I

rkmth4)

/

I0

+I New address: Institut

fur Anorganische Chemie, Technische

Hochschule Aachen, Prof.-Pirlet-StraBe 1, D-5100 Aachen.

The two diastereomers 5 and 6 are separated by means of HPLC. Since none of them are crystalline we have performed the structural assignment on the basis of NMR spectral data. Accurate 'H-NMR chemical shifts for the acetals 5, 6 and 7,8 were determined from 'H-NMR multiplet decoupled Hetcor spectra. In addition the I3C- NMR chemical shifts have been measured. The complete data are summarized in the experimental part. Here we only focus on the

Liebigs Ann. Chem. 1991, 283-285

OVCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1991

0170-2041/91/0303-0283

$ 3.50+.25/0

284

chemical shifts which are typical for the main products 5 and 7 as well as the minor products 6 and 8 (see Tables 1 and 2).

Table 1. Significant NMR data of 5 and 6"'

Nucleus

5

6

AS

 

-~

-

5-H

1.74

1.56

-0.18

8-H

2.24

2.35

+0.11

c-5

28.48

29.73

+1.25

c-8

25.32

25.00

-0.32

'H and I3C NMR. Varian VXR 300 (300 MHz/75 MHz), TMS as internal standard, in CDCI?, 6.

Table 2. Significant NMR data of 7 and Sahsc)

Nucleus

7

8

AS

5-H

1.78

1.57

-0.21

8-H

2.21

2.34

+0.13

c-5

28.65

29.77

+1.12

c-8

25.68

25.14

-0.54

See footnote a) of Table 1. - see also ref. '1.

cf. ref.4aJ.-

For complete data

Both sets of diastereomers 5/7 and 6/8 do correspond to each other indicating the same basic structure. Since the structure of 8 has been confirmed by X-ray analysis4a1we now can assign the (2S,2'S,5R) configuration to 5 and the (2S,2'R,5R) configuration

to 6.

Financial support by the Deutsche Forschungsgemeinschaft, the Minister ,fur Wissenschaft und Forschung des Landes Nordrhein- Westfalen, and the Fonds der Chenzischen Industrie is gratefully ac- knowledged. We also thank the Bayer AG for generous gifts of chemicals. The structural assignment of 5 and 6 on the basis of NMR spectral data was only possible by M. Demuth's help, who provided us with two samples of 7 and 8.

Experimental

All reactions were carried out under nitrogen, and the solvents were dried before use. Commercially available tert-butyl 3-oxobu- tanoate (1) was purified by distillation in a spinning band column (Normag). (-)-Menthol (99%) and iodomethane (990/,) were used without further purfication. - Liquid chromatography: Silica gel 60 (0.063-0.200 pm) from Woelm and Celite 545 from Bayer (for filtration). - HPLC: Kontron 420 chromatograph and chromo- sorb Si 60 columns (250 x 20 mm). - GC: Siemens Sichromat 3 or Sichromat 1-4, 25 m HP Ultra 2. - IR: Perkin Elmer 1700. - 'H and '3C NMR: Varian VXR 300 (300 MHz/75 MHz), TMS as internal standard, Hetcor, multiplet decoupled, 'H resolution 4 Hz. - MS: Varian MAT 212, 70 eV. - Microanalyses: Mikroan- alytisches Laboratorium der Technischen Hochschule Aachen.

tert-Butyl 2-Methyl-3-oxobutanoate (2): 31.6 g (0.20 mol) of tert- butyl 3-oxobutanoate (1) is added dropwise to a mixture of 5.0 g (0.2 mol) of NaH (97% in white oil) in 150 ml of THF at 0°C. Then 28.4 g (0.20 mol) of iodomethane is slowly added, and the mixture is stirred for 12 h. After evaporation of the solvent the residue is dissolved in some water and the solution extracted with three por- tions of ether. The combined ether layers are washed with an aque-

U. Jansen, J. Runsink, J. Mattay

ous solution of sodium sulfite (loo/,) and water. After drying with magnesium sulfate and removal of the solvent the remaining oil is fractionated in a spinning band column (reflux ratio 120:5) to give 2 with 98% purity. Yield 24.1 g (70%), b.p. 106-108"C/48-51 Torr (ref.'31b.p. 66-67"C/6 Torr). - 'H NMR (CDCI,): 6 = 1.28 (d, J = 7.05 Hz, 3H, CHCH,), 1.47 (s, 9H, tBu), 2.23 (s, 3H, CH,CO), 3.42 (q, J = 7.05 Hz, 1H, CHCH,). - l3CNMR (CDC13):

6 = 12.6 (CHCH,), 21.8 (CH,CO), 27.9 [C(CH,),], 54.7 (CHCH3),

81.6 [C(CH,)J,

tert-Butyl (E)-3-(Dimethylamino)-2-butenoate(3): Gaseous di- methylamine is passed through 50 g (0.31 mol) of neat 1 at 40°C within 5 h. After 12 h unreacted amine is evaporated under reduced pressure, and the residue is crystallized from pentane at - 20 "C to yield 45.1 g (77%) of 3, m.p. 43 - 45 "C (ref. ") 43 "C). - IR (CDC13):

P = 3007 cm-' (=CH), 1683 (C=O), 1583 (C=C). - 'H NMR (CDCI,): 6 = 1.46 [s, 9H, C(CH,),], 2.41 (s, 3H, =CCH3) 2.90 [s, 6H, N(CH&], 4.50 (s, lH, =CH). - I3CNMR (CDCI,): 6 = 15.2 (=CCH3), 28.7 [C(CH,),], 39.6 [N(CH,)J, 77.3 [C(CH,),], 86.4 (=CH), 160.8(=C-N), 169.0 (CO). -MS (70 eV): m/z (YO)= 185 (22) [M'], 129 (36), 112 (65), 84 (loo), 44 (34), 42 (24).

(-)-(fR,IS)-Menthone (4): A solution of 10 g (0.04 ml) of so- dium dichromate in 7.5 ml of sulfuric acid (96%) and 42.5 ml of water is added to 15.6 g (0.01 mol) of (-)-menthol in 40 ml of diethyl ether within 30 min. The temperature is kept below 25°C. After stirring for 3.5 h again one tenth of the above mentioned chromic acid solution is added. This is repeated twice. According

to GC analysis the reaction mixture now contains less than 1YOof the starting material. After extraction with diethyl ether (3 x 20 ml), drying with magnesium sulfate, and evaporation of the sol- vent at 10 Torr the remaining oil is fractionated through a 20-cm Vigreux column. Yield of 4 14.2 g (%!YO), b.p. 88-93"C/14 Torr

(ref. 14),

Preparation of the Spiro Compounds 5 and 6: 15.4 g (0.10 mol) of (-)-methone (4), 17.2 g (0.10 mol) of 2, and 100 ml (1 mol) of an- hydrous acetic acid are filled into a 250-ml three-necked flask equipped with gas-inlet tube, thermometer, and dropping funnel. The mixture is cooled with stirring to - 15 "C. Then 7.5 ml of conc. sulfuric acid is added dropwise over 2-2.5 h such that the tem- perature of the mixture does not exceed -1O'C. After the addition has been terminated the temp. of the mixture is allowed to rise to room temperature. The end of the reaction is determined by GC:

analysis. Then 1.4 1 of an aqueous solution of sodium hydrogen- carbonate (10%) is added by cooling with ice (pH 7.0-7.5). The aqueous solution is extracted three times with 400 ml of diethyl ether, and the combined organic layers are washed first with 200 ml of saturated Na2C03solution and then with 200 ml of water. After drying with magnesium sulfate and evaporating the remaining oil (40 g) is worked up as follows:

169.7 (COO), 203.8 (CO).

84%, b.p. 66 - 67 "C/4 Torr).

(i)(R)-3-Menthenyl acetate (fully characterized by NMR and m. p.

155- 156°C) is removed at 0.001 Torr at room temp. to yield 14.3 g

of a viscous oil. (ii) In order to separate the oil from polymeric material it is filtered over a 40-cm column containing silica gel with cyclohexane] ethyl acetate (90: 10) as eluent to give 12.4 g (49%) of a yellow oil. which only contains the two compounds 5and 6 according to NMR analysis (56 = 4.2: 1). (iii) Separation of the two diastereomers is performed by HPLC with cyclohexane/ethyl acetate (90:10) as eluent.

(2S,2'S,SR) -2-Isopropyl-S,5',6'-trirnethylspiro(cyclohexane-I,.?. [4H/(1,3]dioxin]-4'-one (5): IR (CDCI,): P = 1725 cm-' (C =O), 1651(C=C). - 'H NMR (CDCI,): 6 = 0.85 (7-H),0.88 (10-H),0.89 (4-H, ax), 0.93 (9-H), 0.95 (6-H, ax), 1.45 (2-H), 1.56 (3-H, ax), 1.65

Liebigs Ann. Chem. 1991, 283-285

Diastereomeric 5,6-Dimethyl-4H-1,3-dioxin-4-onesfrom (-)-(I R,4S)-Menthone

285

(3-H, eq), 1.74 (5-H, ax), 1.75 (4-H, eq), 1.78 (5’-CH3),1.95 (6’-CH3),

2.24 (8-H), 2.58 (6-H, eq). - I3C NMR (CDCI,): 6 = 10.37 (5’-

CH,), 17.58 (6’-CH3), 18.43(C-lo),21.50 (C-7),22.17 (C-3),23.22 (C- 9), 25.32 (C-8),28.48 (C-5),34.20 (C-4),41.10 (C-6),49.51 (C-2),99.55

(C-53, 107.93 (C-I), 162.40 (C-6’), 162.68 (C-4). - MS (70 eV):

m/z (%) = 252 (17) [M’], 210 (13), 55 (59), 154 (86), 139 (52), 136 (36), 112 (IOO), 111 (15), 99 (25), 98 (12), 70 (16), 69 (19), 55 (26), 43 (31), 41 (42). - [cL]~ = f8.6 (C = 1.019, CH2C1,).

C1SH2403(252.4)

Calcd. C 71.39 H 9.59 Found C 71.22 H 9.38

(2S,2’R,5R)-2-Isopropyl-5,5’,6-trimethylspiro[cyclohexane-1,2’-

[4H](1,3]dioxin]-4’-one (6):IR (CDC13):F = 1710 cm-’ (C=O), 1652 (C=C). - ‘H NMR (CDCI3):6 = 0.88 (9-H),0.89 (7-H),0.95 (10-H),0.97 (4-H, ax), 1.06 (6-H, ax), 1.51 (2-H), 1.53(3-H, ax), 1.56

(5-H, ax), 1.70(3-H, eq). 1.78 (4-H, eq), 1.82 (5’-CH3),2.00 (6’-CH3),

2.35 (8-H), 2.60 (6-H, eq). -I3C NMR (CDCI3):6 = 10.36 (5’-CH3),

17.54

(6’-CH3), 18.15 (C-9), 21.66 (C-7), 21.77 (C-3), 23.16 (C-lo),

25.00

(C-8),29.73 (C-5),34.02 (C-4),40.54 (C-6), 49.33 (C-2), 100.15

(C-5’), 107.82 (C-l), 162.11 (C-4’),

162.93(C-6’).

CAS Registry Numbers

1: 1694-31-1 12: 39149-65-0 / 3: 131635-40-0 / 4: 14073-97-3 ,I5:

131682-97-8 / 6: 131722-65-1

I) Taken in part from the Diplomarbeit, Technische Hochschulc Aachen, 1989. 2, D. Seebach, R. Imwinkelried, T. Weber in Modern Synthetic Methods (R. Scheffold,Ed.), vol. 4, p. 125, Springer Verlag, Berlin

1986.

3, D. Seebach, J. Zimmermann, U. Gysel, R. Ziegler, T.-K. Ha, J.

Am. Chem. Soc. 110 (1988) 4763.

4, 4a) M. Demuth, A. Palomer, H.-D. Sluma, A. K. Dey, C. Kriiger,

Y.-H.

Engl. 25 (1986) 1117. - 4h) M. Demuth, G. Mikhail, Synthesis

Tsay, Angew. Chem. 98 (1986) 1093; Anyew. Chem. Znt. Ed.

5,

1989, 145.

M. Sato, K. Sekiguchi, H. Ogasawara, C. Kaneko, Synthesis

1985, 224. - 5h) M. Sato, K. Takayama, T. Furuya, N. Tnukai,

C. Kaneko, Chem. Pharm. Bull. 35 (1987) 3971.

6, J. D. Winkler, J. P. Hey, F. J. Hannon, Heterocycles 25 (1987)

55.

’) M. Sato, H. Ogasawara, K. Oi, T. Kato, Chem. Pharm. Bull. 31 (1983) 1896. *) We are indebted to M. Demuth for providing us with samples

of the acetals 7 and 8. 9, I. L. Knunyants, J. Gen. Chem. (USSR) 7 (1937) 2852 [Chem. Abstr. 32 (1938) 290S2].

L.

Colombo, C. Gennari, G. Poli, C. Scolastico, F. Aragozzini,

C.

Merendi, J

Chem. Soc., Perkin Trans. 1, 1983, 2745.

‘I) E. A. Mistryukov, Izvest. Akad. Nauk. SSSR Otdel. Khim. Nauk.

1961, 1512 [Chem. Abstr. 56 (1962) 400al.

Z. Arnold, A. Holy, Collect. Czech. Chem. Commun. 30 (1965) 40

[Chem. Abstr. 62 (1965) 11673aI. 13) A. G. M. Barrett, H. G. Sheth, J. Org. Chem. 48 (1983) 5017. 14) H. C. Brown, C. P. Garg, J. Am. Chem. Soc. 83 (1961) 2952.

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