Methanethiol

MeSH

[74-93-1]  · CH4S  · Methanethiol  · (MW 48.12)

(conjugate base is utilized in nucleophilic aliphatic1 and aromatic substitution;2 addition to alkenes,3 alkynes,3 and as a Michael donor;3c formation of S,S-acetals for carbonyl protection,4 umpolung reagent formation,5 and thionium ion generation;6 formation of O,S-acetals by protecting group interconversion;7 formation of glycosylation substrates,8 thioesters,9 and thiocarbamates10)

Physical Data: mp -123 °C; bp 6 °C; d 0.8665 g cm-3 (4 °C).

Solubility: sol water at 20 °C (23.30 g L-1); very sol ethyl alcohol, ether.

Form Supplied in: gas; lecture bottle; widely available.

Handling, Storage, and Precautions: flammable, corrosive gas with a pungent odor. It is imperative that methanethiol be used in a well-ventilated hood. Exposure can be minimized by slow distillation from the storage container into the reaction vessel11 and/or trapping the boil-off in a solution containing a strong oxidizing agent (e.g. KMnO412).

Nucleophilic Substitutions.

Reaction of methanethiolate (MeS-), prepared from the reaction of MeSH with base, with primary and secondary alkyl halides or sulfonates provides methyl alkyl sulfides in good to excellent yields. As with alkoxide nucleophiles, primary substrates are most useful, secondary substrates provide lower yield, and elimination predominates with tertiary substrates. Displacement of appropriate primary chlorides provides sulfinyl sulfides (eq 1),13 secondary tosylates can afford methylthio derivatives of proline (eq 2),14 and SN2 addition to substituted cyclopentenes results in stereospecific anti addition (eq 3).15

Epoxides undergo nucleophilic cleavage to provide b-hydroxy sulfides. Epichlorohydrin reacts with methanethiolate to provide an important intermediate for the generation of 1,3-bis(methylthio)allyllithium (eq 4),11 a,b-epoxy ketones yield a-thiomethyl enones,16 and 4-methyloxetanone provides b-(methylthio)butyric acid (eq 5).17 Nucleophilic aromatic substitution of activated aryl halides is well documented2 and even unactivated aryl halides react with methanethiolate in HMPA to give substituted arenes (eq 6),18 with other alkanethiolates demonstrating this reactivity in various aprotic solvents (DMA,19 DMF,20 and polyglymes21).

Additions to Carbon-Carbon Multiple Bonds.

Electrophilic and radical addition of methanethiol and nucleophilic addition of methanethiolate to carbon-carbon multiple bonds is well documented.3 Recent examples include the radical addition to a-allylglycine derivatives to provide trifunctional amino acids,22 the stereospecific nucleophilic addition of potassium methanethiolate to alkyl alkynyl sulfides (eq 7),23 under phase-transfer catalysis, and addition to propargyl sulfone.24 Methanethiolate undergoes Michael addition to alkenes conjugated to electron-withdrawing substituents.3c When Michael addition is followed by protonation at low temperatures, high diastereoselectivity is obtained with nitro alkenes (eq 8).25

Formation of S,S- and O,S-Acetals.

Thioacetals are generally regarded as robust protecting groups for carbonyl compounds. Reactions of aldehydes, ketones, or acetals with MeSH and catalytic Brønsted or Lewis acid provides dimethyl dithioacetals, generally in good to excellent yield.4 For labile substrates, Titanium(IV) Chloride at low temperature has proven successful (eq 9).12a Acetal exchange occurs readily with MeSH in the presence of Bromodimethylborane to give O,S-acetals, allowing conversion of MEM and MOM ethers into (methylthio)methyl (MTM) ethers (eq 10).7 Formation of methyl thioglycosides (eq 11)8 with the methanethiol analog methyl trimethylsilyl sulfide (MeSSiMe3) provides the 1,2-trans-thioglycoside stereospecifically.

The utility of these thioacetals includes desulfurization with Raney Nickel to give methylene or methyl compounds26 and the well documented5 use as acyl anion equivalents or umpolung reagents upon deprotonation. Dimethyl dithioacetals provide intermediate thionium ions upon treatment with Dimethyl(methylthio)sulfonium Tetrafluoroborate (DMTSF); these undergo inter- and intramolecular additions with allylstannanes,27 silyl enol ethers,6,28 vinylsilanes,6 and indoles (eq 12).29 Methyl S-glycosides undergo stereospecific glycosylation under the influence of nitrosyl tetrafluoroborate.8

Other Applications.

Methanethiol reacts with derivatized carboxylic acids and isocyanates to provide thioesters9 and thiocarbamates,10 respectively. Lithium methanethiolate cleaves hindered methyl esters to the corresponding acids30 and, under forcing conditions, methyl phenyl ethers to phenols. Pyrrolizidinediones have been reduced with Sodium Borohydride in EtOH to give the corresponding ethoxy lactams. Exchange with MeSH under acidic conditions then provides the lactam thioether (eq 13).31 Reduction of analogous pyrrolizidinediones in the presence of MeSH provides the corresponding lactam thioethers directly (eq 14).32


1. (a) Reid, E. E. Organic Chemistry of Bivalent Sulfur; Chemical Publishing: New York, 1960; Vols. 2 and 3. (b) Peach, M. E. In The Chemistry of the Thiol Group; Patai, S., Ed.; Wiley: New York, 1984; Vol. 2, p 721.
2. Peach, M. E. In The Chemistry of the Thiol Group; Patai, S., Ed.; Wiley: New York, 1984; Vol. 2, p 735.
3. (a) Stacey, F. W.; Harris, J. F., Jr. OR 1963, 13, 150. (b) Tagaki, W. In Organic Chemistry of Sulfur; Oae, S., Ed.; Plenum: New York, 1977; Chapter 6. (c) Ohno, A.; Oae, S. In Organic Chemistry of Sulfur; Oae, S., Ed.; Plenum: New York, 1977; Chapter 4.
4. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991.
5. (a) Lever, O. W., Jr. T 1976, 32, 1943. (b) Gröbel, B.-T.; Seebach, D. S 1977, 357. (c) Seebach, D. AG(E) 1979, 18, 239.
6. Trost, B. M.; Murayama, E. JACS 1981, 103, 6529.
7. Morton, H. E.; Guindon, Y. JOC 1985, 50, 5379.
8. Pozsgay, V.; Jennings, H. J. JOC 1988, 53, 4042.
9. Haslam, E. T 1980, 36, 2409.
10. South, M. S. JHC 1991, 28, 1003.
11. Erickson, B. W. OS 1974, 54, 19.
12. (a) Braish, T. F.; Saddler, J. C.; Fuchs, P. L. JOC 1988, 53, 3647. (b) Ager, I. R.; Barnes, A. C.; Danswan, G. W.; Hairsine, P. W.; Kay, D. P.; Kennewell, P. D.; Matharu, S. S.; Miller, P.; Robson, P.; Rowlands, D. A.; Tulley, W. R.; Westwood, R. JMC 1988, 31, 1098.
13. Anklam, E. SC 1989, 19, 1583.
14. Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; Gold, E. H.; Sommer, J. A.; Brown, A. D.; Chiu, P. J. S.; Moran, R.; Sybertz, E. J.; Baum, T. JMC 1988, 31, 875.
15. Pan, Y.; Hutchinson, D. K.; Nantz, M. H.; Fuchs, P. L. T 1989, 45, 467.
16. Abul-Hajj, Y. J. JMC 1986, 29, 582.
17. Breitschuh, R.; Seebach, D. S 1992, 83.
18. Chianelli, D.; Testaferri, L.; Tiecco, M.; Tingoli, M. S 1982, 475.
19. Odorisio, P. A.; Pastor, S. D.; Spivack, J. D.; Rodebaugh, R. K. PS 1982, 13, 309.
20. Testaferri, L.; Teicco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M. S 1983, 751.
21. Pastor, S. D.; Hessell, E. T. JOC 1985, 50, 4812.
22. Broxterman, Q. B.; Kaptein, B.; Kamphuis, J.; Schoemaker, H. E. JOC 1992, 57, 6286.
23. Bjørlo, O.; Verkruijsse, H. D.; Brandsma, L. SC 1992, 22, 1563.
24. Barre, V.; Uguen, D. TL 1987, 28, 6045.
25. Kamimura, A.; Sasatani, H.; Hashimoto, T.; Kawai, T.; Hori, K.; Ono, N.; JOC 1990, 55, 2437.
26. Pettit, G. R.; van Tamelen, E. E. OR 1962, 12, 356.
27. Trost, B. M.; Sato, T. JACS 1985, 107, 719.
28. Trost, B. M.; Murayama, E. TL 1982, 23, 1047.
29. Amat, M.; Linares, A.; Bosch, J. JOC 1990, 55, 6299.
30. Kelly, T. R.; Dali, H. M.; Tsang, W.-G. TL 1977, 3859.
31. Beckwith, A. L. J.; Boate, D. R. JOC 1988, 53, 4339.
32. Thomas, E. W.; Rynbrandt, R. H.; Zimmermann, D. C.; Bell, L. T.; Muchmore, C. R.; Yankee, E. W. JOC 1989, 54, 4535.

Wayne E. Zeller

Illinois State University, Normal, IL, USA



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