Enantioselective Friedel–Crafts Reaction for the Synthesis of 4,7-Difunctionalized Indoles Featuring a Chiral Heteroatom-Substituted Quaternary Carbon at the C7 Position

Abstract

Enantioselective functionalization of 4-aminoindoles at the site-specific C7 position via a chiral phosphoric acid-catalyzed Friedel–Crafts reaction with cyclic thioimidates was developed. This approach enables the formation of 4,7-difunctionalized indoles incorporating the chiral N,S-acetal motif with excellent yield and enantioselectivity (up to 99% yield and >99% ee). The protocol is also compatible with isatin-derived ketoimines for the highly enantioselective synthesis of 4,7-difunctionalized indole derivatives bearing aza-quaternary carbon at the C7 position. The synthetic potential was demonstrated by gram-scale experiments and versatile transformations of the products, with the method characterized by low catalyst loading, site specificity, excellent enantioselectivity, and a broad substrate scope.