The Gassman indole synthesis is a series of chemical reactions used to synthesize substituted indoles by addition of an aniline and a ketone bearing a thioether substituent.

The Gassman indole synthesis

This is a one-pot chemical reaction, and none of the intermediates are isolated. R₁ can be hydrogen or alkyl, while R₂ works best with aryl, but can also be alkyl. Electron-rich anilines, such as 4-methoxyaniline, tend to fail in this reaction.

The 3-position thiomethyl group is often removed using Raney nickel to give the 3-H-indole.

Reaction mechanism

The reaction mechanism of the Gassman indole synthesis

The reaction mechanism of the Gassman indole synthesis is divided among three steps.

The first step is the oxidation of the aniline 1 using tert-butyl hypochlorite (tBuOCl) to give the chloramine 2.

The second step is the addition of the keto-thioether to give the sulfonium ion 3, and is typically done at low temperatures (−78 °C).

The third and final step is the addition of a base, which in this case is triethylamine. Upon warming to room temperature, the base will deprotonate the sulfonium ion creating the sulfonium ylide 4, which quickly undergoes a [2,3]-sigmatropic rearrangement to give the ketone 5. The ketone 5 will undergo a facile condensation to give the desired 3-thiomethylindole 6.

References

• Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. (1973). "Use of halogen-sulfide complexes in the synthesis of indoles, oxindoles, and alkylated aromatic amines". J. Am. Chem. Soc. 95 (19): 6508. doi:10.1021/ja00800a088.
• Gassman, P. G.; van Bergen, T. J.; Gilbert, D. P.; Cue, Jr., B. W. (1974). "General method for the synthesis of indoles". J. Am. Chem. Soc. 96 (17): 5495. doi:10.1021/ja00824a028.{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Gassman, P. G.; van Bergen, T. J. (1974). "Oxindoles. New, general method of synthesis". J. Am. Chem. Soc. 96 (17): 5508. doi:10.1021/ja00824a029.
• Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. (1974). "Generation of azasulfonium salts from halogen-sulfide complexes and anilines. Synthesis of indoles, oxindoles, and alkylated aromatic amines bearing cation stabilizing substituents". J. Am. Chem. Soc. 96 (17): 5512. doi:10.1021/ja00824a030.
• Organic Syntheses, Coll. Vol. 6, p. 601; Vol. 56, p. 72 (Article)