Gassman indole synthesis
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.
File:Gassman Indole Synthesis Summary.png
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
File:Gassman Mechanism Scheme.png
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
- {{cite journal|author1=Gassman, P. G. |author2=Gruetzmacher, G. |author3=van Bergen, T. J. |journal=J. Am. Chem. Soc.|year=1973|volume=95|pages= 6508|doi= 10.1021/ja00800a088|title= Use of halogen-sulfide complexes in the synthesis of indoles, oxindoles, and alkylated aromatic amines|issue= 19}}
- {{cite journal|author1=Gassman, P. G. |author2=van Bergen, T. J. |author3=Gilbert, D. P. |author4=Cue, B. W. Jr. |journal=J. Am. Chem. Soc.|year=1974|volume=96|pages= 5495|doi= 10.1021/ja00824a028|title= General method for the synthesis of indoles|issue= 17}}
- {{cite journal|author1=Gassman, P. G. |author2=van Bergen, T. J. |journal=J. Am. Chem. Soc.|year=1974|volume=96|pages= 5508|doi= 10.1021/ja00824a029|title= Oxindoles. New, general method of synthesis|issue= 17}}
- {{cite journal|author1=Gassman, P. G. |author2=Gruetzmacher, G. |author3=van Bergen, T. J. |journal=J. Am. Chem. Soc.|year=1974|volume=96|pages= 5512|doi= 10.1021/ja00824a030|title= Generation of azasulfonium salts from halogen-sulfide complexes and anilines. Synthesis of indoles, oxindoles, and alkylated aromatic amines bearing cation stabilizing substituents|issue= 17}}
- Organic Syntheses, Coll. Vol. 6, p. 601; Vol. 56, p. 72 ([http://www.orgsyn.org/orgsyn/prep.asp?prep=cv6p0601 Article])
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