Gassman oxindole synthesis

What is Gassman oxindole synthesis?

The Gassman oxindole synthesis, first reported by Gassman et al. in 1973, is a multi-step process for synthesizing oxindoles containing an electron-withdrawing group. Despite being a one-pot reaction, the procedure involves sequential treatment of aniline with tert-butyl hypochlorite, ethyl (methylthio)acetate, triethylamine, and hydrochloric acid, followed by desulfurization using zinc or Raney nickel.

Gassman oxindole synthesis - general reaction scheme
Gassman oxindole synthesis
Gassman oxindole synthesis - general reaction scheme
Gassman oxindole synthesis

However, for anilines with an electron-donating group, the reaction is less favorable due to the disfavored nucleophilic attack of a sulfur atom on the nitrogen atom. As an alternative, these oxindoles can be prepared by treating the anilines with chlorosulfonium salt. The resulting oxindole can then be further oxidized using N-chlorosuccinamide/HgO or direct air oxidation to obtain relevant isatin. Notably, the reaction can accommodate a wide range of functional groups with differing electron characteristics, including N-alkylanilines. It is important to note that when a sulfide with a substituent at the active methylene moiety is used, a 3-substituted oxindole will be produced.

References

General method for the synthesis of oxindoles
Paul G. Gassman and T. J. Van Bergen
Journal of the American Chemical Society 1973 95 (8), 2718-2719
DOI: 10.1021/ja00789a070

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