Methyl Methanethiosulfonate1

[2949-92-0]  · C2H6O2S2  · Methyl Methanethiosulfonate  · (MW 126.22)

(methylsulfenylating agent with many applications;2 reagent for the rapid and selective modification of the essential SH groups of enzymes. The MeS-protecting group is easily removed under mild conditions3)

Alternate Name: S-methyl thiomethanesulfonate.

Physical Data: bp 69-71 °C/0.4 mmHg; d 1.227 g cm-3; n 1.5130.

Form Supplied in: colorless oil; widely available.

Handling, Storage, and Precautions: stench; irritant. Use in a fume hood.

Introduction.

Methyl methanethiosulfonate is a versatile reagent mainly used to form sulfenylated intermediates used en route to the synthesis of various interesting compounds. It is a much more reactive and effective sulfenylating agent than Dimethyl Disulfide or MeSCl.4 MeSSO2Me (and its reaction products) has little odor, which makes it considerably more agreeable to work with than MeSSMe. The MeS group transferred via deprotonation of the substrate's acidic proton with a base, followed by electrophilic substitution, can serve as a protecting group,5 an activating group for carbanion formation, or as a masked ketone or aldehyde. It can serve as a handle for subsequent transformation to various functionalities (e.g. alkene, ketone, and alkyl group) via oxidation or reduction.

Preparation of 2-(Methylthio)alkanoic Acids and Esters and 3-Methylthio-2-alkanones.

2-(Methylthio)alkanoic acids and esters are synthesized by successive treatment of substituted malonic esters with Sodium Ethoxide and MeSSO2Me, followed by alkaline hydrolysis which causes concurrent decarboxylation (eq 1).6

More conveniently, 2-(methylthio)alkanoic esters are prepared from 2-acetylalkanoates (eq 2).7 MeSSMe cannot replace MeSSO2Me as the sulfenylating agent in this transformation. Advantages of these methods over others such as sulfenylation of an alkanoic acid and its ester or alkylation of (methylthio)acetic acid are (1) simplicity of the procedure; (2) efficiency and convenience of using inexpensive base (EtONa) and EtOH as solvent with high product yields; and (3) no bissulfenylation. Moreover, the latter method allows direct a-sulfenylation of 2-acetylalkanoates which also contain an additional keto group, without its protection (eq 2).

This contrasts to thiomethylation of methyl 9-oxodecanoate with MeSSMe and lithium cyclohexyl(isopropyl)amide, as reported by Trost.8 In spite of various reaction conditions employed, Trost's procedure gives less than 30% yield of 2-methylthio-9-oxodecanoate, accompanied by bissulfenylation when the 9-oxo group is not protected. Moreover, toxic HMPA is required to obtain 86% of the sulfenylated ester even when the 9-oxo group is protected. The transformation described in eqs 1 and 2 works with PhSSO2Ph as well.

Similarly, 3-methylthio-2-alkanones are prepared by the reaction of a 3-alkyl-2,4-pentanedione with 1 mol equiv (important) of MeSSO2Me in the presence of EtONa in EtOH at rt or Potassium Carbonate in acetone at reflux followed by addition of MeOH and reflux. An advantage of using weaker base K2CO3 in this reaction is that no bissulfenylation takes place even when excess sulfenylating agent is used. The method was applied to an efficient synthesis of pseudoionone (eq 3).9

Diethyl 1-Methylthio-1(Z),3-butadienephosphonate.

An efficient synthesis of diethyl 1-methylthio-1(Z),3-butadienephosphonate from Diethyl Methylthiomethylphosphonate is carried out in four steps without contamination with the (E) geometric isomer (eq 4).10 The methylthiobutadienephosphonate reacts smoothly with enamines. It also undergoes 1,4-addition with dialkylcuprates to yield exclusively (E)-alkenes. The resultant allylic phosphonates from these additions can be employed for the synthesis of 2-methylthio-substituted butadienes.

One-Pot Procedure for a-Methylthio b-Keto and Enamine Phosphonates.

a-Methylthio b-keto and enamine phosphonates are prepared from diethyl methylphosphonate by a one-pot procedure using a nitrile as an acyl cation equivalent, followed by treatment with MeSSO2Me as an electrophile (eq 5).11

MeSSMe does not undergo this transformation due to the low reactivity of the anion toward the electrophilic sulfur moiety; however, the reaction proceeds smoothly with PhSSPh, PhSCl, and PhSeBr. Interestingly, PhSO2Cl affords a-chloro substituted phosphonates but no a-sulfonylated products.

g-Oxocrotonate Derivatives through Bis(methylsulfenylation).

An efficient sequence of reactions to transform an alkoxycarbonylmethyl group to g-oxocrotonate via bis(methylsulfenylation) is described in a synthesis of brefeldin-A (eq 6).12

It is important that the methoxycarbonylmethyl group is treated twice with 1 equiv of Lithium Diisopropylamide and MeSSO2Me each to effect a one-pot bis(methylsulfenylation). Two equiv of both LDA and MeSSO2Me cannot be present at the outset of the reaction since destruction of the reagent(s) occurs faster than the introduction of the second MeS group.13 It is also noteworthy that a direct, one-step hydrolysis of the thioacetal group in the homologated ester to give ultimately the required g-oxocrotonate is possible only with the dimethyl thioacetal but not with the diphenyl equivalent.8

Dithioacetal Formation.

Dithioacetals are prepared from activated methylene compounds with MeSSO2Me absorbed on Potassium Fluoride-Alumina (eq 7). Microwave irradiation without solvent provides a powerful activation for this preparation. MeSCl gives only poor yields and MeSSMe does not react under these conditions.14

Stereoselective Methylsulfenylation of Enones and Alkenes.

An a-oxoketene dithioacetal containing two different alkylthio substituents was prepared stereoselectively from a b-alkylthio-a,b-enone via treatment with LDA and MeSSO2Me in THF-HMPA (eq 8).15 Use of MeSCl in this reaction yields a 1:1 mixture of the stereoisomers, possibly due to isomerization of the double bond geometry by the chloride ion formed in the reaction (eq 9). The reaction of the a-oxoketene dithioacetal with organocuprate reagents proceeds stereospecifically (eq 10), in that the alkylthio substituent syn to the ketone carbonyl is replaced by the cuprate ligand in all cases studied.

1-(Methylthio)-substituted cyclopropenes are easily prepared by electrophilic substitution of the protected monolithiated 3,3-dimethylcyclopropenes. Upon heating or under photolysis, the substituted cyclopropenes rearrange to allenes via possible mechanisms described in eq 11. Both the substituted cyclopropenes and rearranged products provide an interesting combination of functionalities, which make them potentially useful building blocks in organic synthesis.16

Unsymmetrical Disulfides.

Unsymmetrical aryl and alkyl disulfides are prepared from silyl sulfides and MeSSO2Me in CHCl3 at 60 °C.17 Methyl 2- and 4-pyridyl disulfide are prepared conveniently from 2- and 4-thiopyridone and MeSSO2Me in the presence of NaOH in H2O in excellent yields.18

Related Reagents.

Dimethyl Disulfide; Methylsulfenyl Trifluoromethanesulfonate; Methyl p-Toluenethiosulfonate.


1. Trost, B. M. CRV 1978, 78, 363.
2. Laszlo, P.; Mathy, A. JOC 1984, 49, 2281.
3. (a) Smith, D. J.; Maggio, E. T.; Kenyon, G. L. B 1975, 14, 766. (b) Welches, W. R.; Baldwin, T. O. B 1981, 20, 512.
4. (a) Scholz, D. S 1983, 944 (methylsulfenylation of cyclic ketones). (b) Wladislaw, B.; Marzorati, L.; Ebeling, G. PS 1990, 48, 163 (methylsulfenylation of o-, m-, p-substituted benzylsulfones). See also Ref. 14.
5. Shah, N. V.; Cama, L. D. H 1987, 25, 221 (MeS group is used for protection of the azetidinone NH; the protected N-SMe is acid stable).
6. Ogura, K.; Itoh, H.; Morita, T.; Sanada, K.; Iida, H. BCJ 1982, 55, 1216.
7. Ogura, K.; Sanada, K.; Takahashi, K.; Iida, H. TL 1982, 23, 4035.
8. Trost, B. M.; Salzmann, T. N.; Hiroi, K. JACS 1976, 98, 4887.
9. Ogura, K.; Sanada, K.; Takahashi, K.; Iida, H. PS 1983, 16, 83.
10. Martin, S. F.; Garrison, P. J. S 1982, 394.
11. Lee, K.; Oh, D. Y. SC 1991, 21, 279.
12. (a) Le Drian, C.; Greene, A. E. JACS 1982, 104, 5473. (b) Greene, A. E.; Le Drian, C.; Crabbé, P. JOC 1980, 45, 2713.
13. In contrast to bis(phenylsulfenylation). See (a) Ref. 8; also (b) Trost, B. M.; Massiot, G. S. JACS 1977, 99, 4405; (c) Trost, B. M.; Mao, M. K. T. TL 1980, 21, 3523.
14. Villemin, D.; Ben Alloum, A.; Thibault-Starzyk, F. SC 1992, 22, 1359.
15. Dieter, R. K.; Silks, III, L. A.; Fishpaugh, J. R.; Kastner, M. E. JACS 1985, 107, 4679.
16. Kirms, M. A.; Primke, H.; Stohlmeier, M.; De Meijere, A. RTC 1986, 105, 462.
17. Capozzi, G.; Capperucci, A.; Degl'Innocenti, A.; Del Duce, R.; Menichetti, S. TL 1989, 30, 2995.
18. Kitson, T. M.; Loomes, K. M. Anal. Biochem. 1985, 146, 429.

Kumiko Takeuchi

Eli Lilly and Company, Indianapolis, IN, USA



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