Efficient cleavage of tertiary amide bonds via radical–polar crossover using a copper(ii) bromide/Selectfluor hybrid system

Abstract

A novel approach for the efficient cleavage of the amide bonds in tertiary amides is reported. Based on the selective radical abstraction of a benzylic hydrogen atom by a CuBr₂/Selectfluor hybrid system followed by a selective cleavage of an N–C bond, an acyl fluoride intermediate is formed. This intermediate may then be derivatized in a one-pot fashion. The reaction proceeds under mild conditions and exhibits a broad substrate scope with respect to the tertiary amide moiety as well as to nitrogen, oxygen, and carbon nucleophiles for the subsequent derivatization. Mechanistic studies suggest that the present reaction proceeds via a radical–polar crossover process that involves benzylic carbon radicals generated by the selective radical abstraction of a benzylic hydrogen atom by the CuBr₂/Selectfluor hybrid system. Furthermore, a synthetic application of this method for the selective cleavage of peptides is described.