Tandem imine generation/N-cyclization/C-alkylation sequence to access N-functionalized indoles featuring an aza-quaternary carbon

Abstract

The elaboration of CN double bonds provides a facile route to structurally diverse amine derivatives that play an important role in drug discovery and development. While tandem synthesis based on the C-attack addition of nucleophiles to CN bonds has been well established, very limited progress has been made in the exploitation of sequential tandem reactions starting from imine N-attack nucleophilic addition reactions. Here, we report the first one-pot tandem sequences based on an intramolecular ketimine N-attack addition reaction. Accordingly, a tandem imine generation/N-cyclization/C-alkylation sequence that allows the facile synthesis of N-functionalized indoles, featuring a nitrogen attached to an aza-quaternary carbon from α-keto-esters or isatins, 2-(2-nitroethyl)anilines, and alkyl bromides or iodides, is described. The obtained N-functionalized indoles, which merge an indole moiety into C^α-tetrasubstituted α-amino acid derivatives, or 3,3-disubstituted oxindoles, are interesting for medical research but difficult to access by other methods. The resulting adducts are of high synthetic value, as evidenced by a variety of diversification reactions for the synthesis of N-functionalized indoles and indole-containing heterocycles.