[5418-86-10]  · C4H10S3  · Tris(methylthio)methane  · (MW 154.35)

(precursor to tris(methylthio)methyllithium,2 useful for the preparation of carboxylic acids,2 esters,3 ketene thioacetals,4 a-hydroxy esters,5 b-alkoxy carbonyl lactones6 and for ring expansion of cyclic ketones to cyclic 1,2-keto thioacetals7)

Physical Data: mp 17-18 °C;8 bp 102 °C/15 mm;8 d 1.16 g cm-3; 1H NMR (CCl4) d 4.63 (s, 1H), 2.16 (s, 9H).2b

Form Supplied in: liquid; widely available.

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


Tris(methylthio)methane undergoes rapid deprotonation with n-Butyllithium in THF at -78 °C (eq 1) to provide tris(methylthio)methyllithium (1),2 a useful carboxylate anion equivalent. However, subsequent reactions of (1) with electrophiles must proceed at temperatures well below -20 °C since the anion decomposes at this temperature via a carbenoid pathway to provide tetrakis(methylthio)ethylene (eq 1).2

Alkylation Reactions.2-4

Only primary halides are suitable substrates for alkylation reactions with carbanion (1). Thus reaction with ethyl bromide takes place at -78 °C to afford 1,1,1-tris(methylthio)propane in 70% yield,4a whereas the analogous alkylation reaction using isopropyl iodide is unsatisfactory (22% yield).2a An alkylation reaction of carbanion (1) with a 1,4-cyclic sulfate has been recently examined for the purpose of preparing shikimate substrate analogs (eq 2). The alkyl sulfate and orthothioester functionalities of the resulting alkylation product were hydrolyzed to afford a deoxycarbohydrate upon concomitant lactonization (eq 2).

1,2-Addition Reactions with Carbonyl Compounds.

Tris(methylthio)methyllithium participates in 1,2-addition reactions with a variety of carbonyl compounds including aldehydes,2a,5a,i ketones,2a,5b,c lactones,5d,e,f chloroformates,2a and carbon disulfide.5g A particularly illustrative example was reported in the preparation of a BCE ring model system directed toward the total synthesis of bruceantin (eq 3).5b Thus stereoselective addition of (1) proceeded smoothly provided the reaction mixture was quenched with saturated ammonium chloride at -60 °C. The resulting alcohol tosylate (eq 3) was efficiently converted to the tetrahydrofuran ring and the orthothioester was transformed to the methyl ester functionality to afford the bruceantin BCE ring system (eq 3).

1,4-Addition Reactions to a,b-Unsaturated Carbonyl Compounds.

Conjugate addition reactions of (1) to butenolides,6a,b cyclopentenone,6c and nitroalkenes6d have been reported which are in contrast to the 1,2-addition observed for the reaction of the enone in eq 3, 2-(trimethylsilylmethyl)propenal,5i and cyclohexenone5h (which gives an equal mixture of 1,2- and 1,4-addition products).5h,9 As expected, the enolates that result from the conjugate addition can be trapped.6a,c For example, conjugate addition of (1) to the butenolide shown in eq 4 followed by addition of gaseous formaldehyde gave a product which was easily converted to the antibiotic protolichesterinic acid.6a

The product of a formal conjugate addition reaction to an aryl methyl ketone was obtained when the arenetricarbonylchromium complex shown in eq 5 was treated with (1). This gave an anionic benzocyclohexadienyl intermediate which upon methylation at the metal center underwent CO insertion and acyl transfer to afford a mixture of regioisomers, after decomplexation using triphenylphosphine.6f

Ring Expansion of Strained Ketones.

The alcohols derived from 1,2-addition of (1) to cyclopentanones,7a,b cyclobutanones,7a,b,d or cyclopropyl ketones7c undergo CuI- or acid-promoted regioselective rearrangement to afford ring-expanded 1,2-keto thioacetal products resulting from migration of the more substituted carbon. For example, the alcohol shown in eq 6 rearranged to afford a single 1,2-keto thioacetal, which was subjected to a four-step reaction sequence in order to prepare the sesquiterpene clovene.7d

1. (a) Gröbel, B-T.; Seebach, D. S 1977, 357. (b) Lever, O. W., Jr. T 1976, 32, 1943.
2. (a) Seebach, D. AG(E) 1967, 6, 442. (b) Seebach, D.; Geiss, K-H.; Beck, A. K.; Graf, B.; Daum, H. CB 1972, 105, 3280.
3. (a) Van der Klein, P. A. M.; de Nooy, A. E. J.; Van der Marel, G. A.; Van Boom, J. H. S 1991, 347. (b) Klein, L. L.; Yeung, C. M.; Kurath, P.; Mao, J. C.; Fernandes, P. B.; Lartey, P. A.; Pernet, A. G. JMC 1989, 32, 151.
4. (a) Krief, A.; Denis, J. N. TL 1982, 23, 3407. (b) Hevesi, L.; Nsunda, K. M.; Renard, M. BSB 1985, 94, 1039. (c) Gamage, S. A.; Smith, R. A. J. AJC 1990, 43, 815.
5. (a) Orito, K.; Seki, Y.; Suginome, H.; Iwadare, T. BCJ 1989, 62, 2013. (b) Dailey, O. D., Jr.; Fuchs, P. L. JOC 1980, 45, 216. (c) Holt, D. A.; Levy, M. A.; Oh, H.-J.; Erb, J. M.; Heaslip, J. I.; Brandt, M.; Lan-Hargest, H.-Y.; Metcalf, B. W. JMC 1990, 33, 943. (d) Lartey, P. A.; Riley, D.; Lee, C.-M.; Tadanier, J.; Grief, V.; Hengeveld, J. E. TL 1984, 25, 4075. (e) Yates, P.; Krepinsky, J. J.; Seif-El-Nasr, A. CC 1989, 177. (f) Yates, P.; Seif-El-Nasr, A.; Stanton, J. CJC 1991, 69, 415. (g) Herczegh, P.; Zsély, M.; Szilágyi, L. T 1988, 44, 2063. (h) Seebach, D.; Bürstinghaus, R. CB 1977, 110, 841. (i) Trost, B. M.; Grese, T. A. JACS 1991, 113, 7363.
6. (a) Schlessinger, R. H.; Damon, R. E. TL 1976, 7, 1561. (b) Hanessian, S.; Sahoo, S. P.; Botta, M. TL 1987, 28, 1147. (c) Mikolajczyk, M.; Kielbasinski, P.; Wieczorek, M. W.; Blaszczyk, J. JOC 1990, 55, 1198. (d) Seebach, D.; Bürstinghaus, R. AG(E) 1975, 14, 57. (e) Seebach, D.; Leitz, H. F.; Ehrig, V. CB 1975, 108, 1924. (f) Kündig, E. P.; Inage, M.; Bernardinelli, G. OM 1991, 10, 2921.
7. (a) Knapp, S.; Trope, A. F.; Ornaf, R. M. TL 1980, 21, 4301. (b) Knapp, S.; Trope, A. F.; Theodore, M. S.; Hirata, N.; Barchi, J. J. JOC 1984, 49, 608. (c) Murray, R. K., Jr.; Israel, R. J. JOC 1985, 50, 1573. (d) Funk, R. L.; Novak, P. M.; Abelman, M. M. TL 1988, 29, 1493.
8. Eliel, E. L.; Hartmann, A. A.; Abatjoglou, A. G. JACS 1974, 96, 1807.
9. Tris(phenylthio)methyllithium gives exclusively the 1,4-addition product with cyclohexenone; see: Smith, R. A. J.; Manas, A.-R. B. CC 1975, 216.

Raymond L. Funk

Pennsylvania State University, University Park, PA, USA

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