Ethyl (Methylthio)acetate

[4455-13-4]  · C5H10O2S  · Ethyl (Methylthio)acetate  · (MW 134.22)

(addition to anilines; the chloride salt adds to anilines to give indolin-2-ones)

Physical Data: bp 70-72 °C/25 mmHg; d 0.905 g cm-3.

Form Supplied in: oil; widely available.

Handling, Storage, and Precautions: water sensitive; protect from atmospheric moisture; stench.

Ethyl (methylthio)acetate can be treated with t-Butyl Hypochlorite in dichloromethane to give the methylsulfonium chloride1 salt which reacts with anilines, via a Sommelet-Hauser type rearrangement of the intermediate azasulfonium salt, to afford ortho addition of ethyl (methylthio)acetate after treatment with Triethylamine and workup. This reaction is very mild and can be done in the presence of ketones, esters, and N-protected nitrogen groups. Treatment of the addition product with HCl gives 3-methylthioindolin-2-ones (eq 1).2

Oxidative removal of the methylthio group with N-Chlorosuccinimide in dichloromethane can be achieved to convert the methylthio group to a carbonyl group.2 The reductive removal of the methylthio group is simply effected by the addition of commercially available Raney Nickel until the starting material has been consumed according to TLC analysis,3 or by the use of Tin metal in ethanolic HCl.4 Since alkylation of indolin-2-ones gives complex mixtures, ethyl (methylthio)acetate is also very useful for the preparation of 3-alkylindolin-2-ones. The methylthio group enables selective deprotonation with Sodium Hydride and quenching with reactive electrophiles,3 such as Iodomethane and Benzyl Bromide. Treatment with Raney nickel affords the alkylated indolin-2-ones (eq 2).

1. Gassman, P. G.; Greutzmacher, G.; van Bergen, T. J. JACS 1974, 96, 5512.
2. Delimoge, I.; Morvan, M.; Nadler, G.; Zimmermann, R. G. JHC 1991, 28, 1525.
3. Karp, G. M. JOC 1992, 57, 4765.
4. Walsh, D. A.; Moran, H. W.; Shamblee, D. A.; Welstead, W. J., Jr.; Nolan, J. C.; Sancilio, L. F.; Graff, G. JMC 1990, 33, 2296.

Dinos Santafianos

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

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