The functionalization of the C-3 position of the indole nucleus through Friedel-Crafts alkylation is typically restricted to alkyl halides, which generally involves the application of harsh conditions. As an alternative, an efficient approach to the selective C-3 alkylation using trichloroacetimidates has been developed. Trichloroacetimidates are readily prepared from the corresponding alcohol and are much more reactive than unactivated alcohols. Using these conditions benzylic imidates with electron-withdrawing substituents can be used as reaction partners, which allows for the formation of more complex indole systems. The scope of these alkylation reactions in terms of the trichloroacetimidate alkylating agent, as well as the indole nucleophile, have been investigated. Use of an excess of the trichloroacetimidate electrophile was shown to provide the 3,3’-indolenine product directly. Differentially substituted 3,3’-indolenines could also be accessed via sequential addition of the two different imidates.

Selective Friedel-Crafts alkylation of indoles with trichloroacetimidates

256th National Meeting (2018)

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