Catalytic Enantioselective Aza-Friedel-Crafts Reaction of Ketimines and Indoles for Constructing Tetrasubstituted Carbon Centers Adjacent to Two Heteroatoms.

A highly enantioselective aza-Friedel-Crafts reaction of benzothiophene-2,3-dione-derived ketimines and indoles catalyzed by BINOL-derived chiral phosphoric acid was developed for the first time. This protocol enabled the synthesis of structurally diverse enantiopure hybrid 3-indolylmethanamine-benzothiophenes featuring a chiral quaternary carbon center adjacent to both N and S atoms, achieving high yields and high to excellent enantioselectivities (up to 99% yield and 99% ee). The reaction exhibits broad substrate scope, high reactivity, simple operation, and mild conditions. Its synthetic utility was demonstrated by scale-up experiments, diverse transformations, and efficient late-stage functionalization of complex bioactive molecules. This work demonstrates an enantioselective aza-Friedel-Crafts alkylation of indoles and ketimines to construct a tetrasubstituted carbon center adjacent to two heteroatoms.