Chemoselective Transamidation of Thioamides by Transition‐Metal‐Free N−C(S) Transacylation
Guangchen Li, Yang‐Yang Xing, Hui Zhao, Jin Zhang, Xin Hong, Michal Szostak
Abstract
Abstract Thioamides represent highly valuable isosteric in the strictest sense “single‐atom substitution” analogues of amides that have found broad applications in chemistry and biology. A long‐standing challenge is the direct transamidation of thioamides, a process which would convert one thioamide bond (R−C(S)−NR 1 R 2 ) into another (R−C(S)−NR 3 N 4 ). Herein, we report the first general method for the direct transamidation of thioamides by highly chemoselective N−C(S) transacylation. The method relies on site‐selective N‐ tert ‐butoxycarbonyl activation of 2° and 1° thioamides, resulting in ground‐state‐destabilization of thioamides, thus enabling to rationally manipulate nucleophilic addition to the thioamide bond. This method showcases a remarkably broad scope including late‐stage functionalization (>100 examples). We further present extensive DFT studies that provide insight into the chemoselectivity and provide guidelines for the development of transamidation methods of the thioamide bond.