(R)-(+)-Methyl p-Tolyl Sulfoxide

[1519-39-7]  · C8H10OS  · (R)-(+)-Methyl p-Tolyl Sulfoxide  · (MW 154.25)

(agent used in the synthesis of chiral b-keto sulfoxides1b,10)

Physical Data: [a]D +146° (acetone, c = 2), +192° (CHCl3, c = 1.2).

Preparative Methods: the most popular means of preparing this reagent is the nucleophilic displacement of (-)-(1R,2S,5R)-Menthyl (S)-p-Toluenesulfinate with methyl Grignard with complete inversion of configuration at sulfur (eq 1).1

This reagent is also prepared by the reaction of Methylmagnesium Bromide with optically active (S)-N-sulfinyloxazolidinone, which is obtained by asymmetric synthesis2 from the oxazolidinone derived from (4R,5S)-norephedrine with a low diastereoselectivity (70:30) (eq 2).

Both enantiomers of methyl p-tolyl sulfoxide are also prepared from diacetyl D-glucose giving, with mesyl chloride, and according to the base used, the (S)-methyl sulfinate with diisopropylethylamine or the (R)-methyl sulfinate with pyridine, which are then transformed with p-tolylmagnesium bromide into the corresponding (S)- or (R)-methyl p-tolyl sulfoxide (eq 3).3

(R)-(+)-methyl p-tolyl sulfoxide is obtained by asymmetric oxidation of the corresponding sulfide with t-Butyl Hydroperoxide in the presence of a stoichiometric amount of a modified Sharpless reagent (Titanium Tetraisopropoxide)-(+)-(R,R)-diethyl tartrate-H2O in a ratio of 1:2:1) in 96% ee.4

(-)-a,a-Dichlorocamphorsulfonyloxaziridine (1) was shown to be a highly efficient reagent for the asymmetric oxidation of methyl p-tolyl sulfide, giving the corresponding (+)-(R)-sulfoxide in 95% ee.5

It was shown recently that chloroperoxidase-catalyzed oxidation of methyl p-tolyl sulfide, using Hydrogen Peroxide or t-BuOOH as the stoichiometric oxidant, afforded the corresponding (+)-(R)-sulfoxide in 99% ee.6

Synthesis of b-Keto Sulfoxides.

Optically active b-keto sulfoxides are very useful building blocks (eq 4) because they can be stereoselectively reduced to afford either diastereomer of the corresponding b-hydroxy sulfoxide under appropriate conditions (Diisobutylaluminum Hydride or Zinc Chloride/DIBAL)8 and thus give access to a wide variety of compounds: chiral carbinols7 by desulfurization with Raney Nickel or Lithium/ethylamine in the case of allylic alcohols;8b epoxides8a via cyclization of the derived sulfonium salt; butenolides7b by alkylation of the hydroxy sulfoxide; 1,2-diols via a Pummerer rearrangement followed by reduction of the intermediate.9

Numerous applications to total synthesis of natural products have been reported. In the case of the macrolide (R)-lasiodiplodin, the achiral ester (eq 5) was reacted with the (+)-(R)-methyl p-tolyl sulfoxide derived anion to give the corresponding b-keto sulfoxide, which was then reduced with DIBAL to give, after desulfurization, the seco-ester of (R)-lasiodiplodin (eq 5).10 This is an example showing that the chirality can be introduced at the end of the synthesis in the desired configuration.

In the synthesis of (S)-zearalenone11 and of a chiral spiroacetal, (2S,6R)-2-methyl-1,7-dioxaspiro[5.6]dodecane,12 the starting product was a functionalized b-keto sulfoxide resulting from the reaction of glutaric anhydride with lithiated (+)-(R)-methyl p-tolyl sulfoxide (eq 6).

It was also shown in the enantioselective synthesis of the macrolide patulolide A13 that the anion of methyl p-tolyl sulfoxide was more reactive towards the imidazolide, prepared from the hemi ethyl sebacate, than the ester group (eq 7).

In a similar way,9 lithiated (+)-(R)-methyl p-tolyl sulfoxide was able to react only with the methyl ester group in presence of a t-butyl ester, as shown in the case of t-butyl methyl octadioate (eq 8).

The enantioselective syntheses of yashabushiketol14 and gingerols15 showed the synthetic utility of chiral epoxides obtained from (R)-methyl p-tolyl sulfoxide (eq 9).

Methyl chloroacetate reacts with the anion of (R)-methyl p-tolyl sulfoxide to give the corresponding d-chloro-b-keto sulfoxide (eq 10), which can be easily transformed into the corresponding b-hydroxy sulfoxide which gives, in presence of a base, the optically active a-sulfinyl epoxides.16 As illustrated here, a-sulfinyl epoxides can be opened by cuprates, leading to chiral homoallylic alcohols.17

(R)-Methyl p-tolyl sulfoxide anion also reacts with b-keto esters to give the corresponding b,d-diketo sulfoxides,18 which are useful in the preparation of optically active 1,3-diols (eq 11).19

Difluoroalkyl sulfinylmethyl ketones have been prepared in enantiomerically pure form from (+)-(R)-methyl p-tolyl sulfoxide in high yield (eq 12).20 The ketone function was then reduced with complete diastereoselectivity.

The absolute configuration at C-32 in recently isolated triterpenoids was assigned by reduction of a b-keto sulfoxide (eq 13).21


A vinylic sulfoxide was prepared from (R)-methyl p-tolyl sulfoxide and benzophenone. Cyclopropanation of the double bond with Dimethylsulfoxonium Methylide gave a good diastereoselectivity (eq 14).22

3-Sulfinylpropionic acid was made from lithium 2-bromoacetate and (R)-methyl p-tolyl sulfoxide (eq 15).23

Sulfinyl dienes were made from a,b-unsaturated esters and methyl p-tolyl sulfoxide followed by enolization of the ketone group (eq 16).24

Although the carbanion of (R)-methyl p-tolyl sulfoxide reacted with aldehydes and ketones with a poor diastereoselectivity,25 it reacts with imines with a much higher stereoselectivity25 as long as the imine substituent is an aromatic ring.26 (R)-(+)-Tetrahydropalmatine was synthesized by addition of (R)-methyl p-tolyl sulfoxide carbanion to 3,4-dihydro-6,7-dimethoxyisoquinoline (eq 17).27

1. (a) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J. W.; Perkins, R. I. JACS 1964, 86, 5637. (b) Solladié, G.; Hutt, J.; Girardin, A. S 1987, 173.
2. Evans, D. A.; Faul, M. M.; Colombo, L.; Bisaha, J. J.; Clardy, J.; Cherry, D. JACS 1992, 114, 5977.
3. (a) Llera, J. M.; Fernández, I.; Alcudia, F. TL 1991, 32, 7299. (b) Fernández, I.; Khiar, N.; Llera, J. M.; Alcudia, F. JOC 1992, 57, 6789.
4. Zhao, S. H.; Samuel, O. K.; Kagan, H. B. T 1987, 43, 5135.
5. Davis, F. A.; Reddy, R. T.; Han, W.; Carroll, P. J. JACS 1992, 114, 1428.
6. (a) Fu, H.; Kondo, H.; Ichikawa, Y.; Look, G. C.; Wong, C. H. JOC 1992, 57, 7265. (b) Colonna, S.; Gaggero, N.; Casella, L.; Carrea, G.; Pasta, P. TA 1992, 3, 95.
7. (a) Solladié, G.; Greck, C.; Demailly, G.; Solladié-Cavallo, A. TL 1982, 23, 5047. (b) Solladié, G.; Fréchou, C.; Demailly, G.; Greck, C. JOC 1986, 51, 1912, 1914.
8. (a) Solladié, G.; Demailly, G.; Greck, C. TL 1985, 26, 435. (b) Solladié, G.; Demailly, G.; Greck, C. JOC 1985, 50, 1552. (c) Kosugi, H.; Konta, H.; Uda, H. CC 1985, 211. (d) Solladié-Cavallo, A.; Suffert, J.; Adib, A.; Solladié, G. TL 1990, 31, 6649.
9. Solladié, G.; Fernandez, I.; Maestro, C. TA 1991, 2, 801.
10. Solladié, G.; Rubio, A.; Carreño, M. C.; García Ruano, J. L. TA 1990, 1, 187.
11. Solladié, G.; Maestro, M. C.; Rubio, A.; Pedregal, C.; Carreño, M. C.; García Ruano, J. L. JOC 1991, 56, 2317.
12. Solladié, G.; Almario, A.; Colobert F. SL 1992, 167.
13. Solladié, G.; Gerber, C. SL 1992, 449.
14. Solladié, G.; Ziani-Chérif, C.; Jesser, F. TL 1992, 33, 931.
15. Solladié, G.; Ziani-Chérif, C. JOC 1993, 58, 2181.
16. Solladié, G.; Hamdouchi C.; Vicente, M. TL 1988, 29, 5929.
17. Solladié, G.; Hamdouchi, C.; Ziani-Chérif, C. TA 1991, 2, 457.
18. Solladié, G.; Ghiatou, N. TA 1992, 3, 33.
19. Solladié, G.; Ghiatou, N. TL 1992, 33, 1605.
20. (a) Bravo, P.; Pregnolato, M.; Resnati, G. JOC 1992, 57, 2726. (b) Bravo, P.; Pregnolato, M.; Resnati, G. TA 1991, 2, 1105.
21. Peiseler, B.; Rohmer, M. JCS(P1) 1991, 2449.
22. Hamdouchi, C. TL 1992, 33, 1701.
23. Albinati, A.; Bravo, P.; Ganazzoli, F.; Resnati, G.; Viani, F. JCS(P1) 1986, 1405.
24. Solladié, G.; Maugein, N.; Morreno, I.; Almario, A.; Carreño, C.; García Ruano, J. L. TL 1992, 33, 4561.
25. Solladié, G. S 1981, 185.
26. Ronan, B.; Marchalin, S.; Samuel, O.; Kagan, H. B. TL 1988, 29, 6101.
27. Pyne, S. G.; Dikic, B. JOC 1990, 55, 1932.

Guy Solladié & Françoise Colobert

University Louis Pasteur, Strasbourg, France

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