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Please login to access the full content or check if you have access via Method 4: From Arylamines and Alkylsulfanylmethyl Ketones; Gassman Indole Synthesis

DOI: 10.1055/sos-SD-110-00001

Joule, J. A.Science of Synthesis Knowledge Updates, (2010249.

The Gassman synthesis[‌202‌‌205‌] produces sulfur-substituted indoles, but from these the sulfur can, if required, be easily hydrogenolyzed with Raney nickel[‌202‌] or removed using trifluoroacetic acid/thiosalicylic acid.[‌202‌,‌206‌] The synthesis (Scheme 59) involves N-chlorination of the arylamine 170, and then reaction of the resulting chloroamine with α-alkylsulfanyl ketones 171 whereby a sulfonium salt 172 is produced. An alternative route to these same intermediates is the reaction of an arylamine with a chlorosulfonium salt and this is considered preferable for arylamines with electron-donating substituents. Base-catalyzed Sommelet–Hauser rearrangement generates the 3—3a bond in 173 and, after rearomatization, intramolecular amine-to-carbonyl addition in 174 (to give 175) and loss of water leads to a 3-(methylsulfanyl)-1H-indole 176. When there is also a substituent at the newly formed indole 3-position, that is when the products are 3-substituted 3-(methylsulfanyl)-3H-indoles, reduction of the imine unit then loss of methanethiol provides 2,3-disubstituted indoles.[‌202‌,‌207‌]

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