Chemoselective Transamidation of Thioamides by Transition-Metal-Free N-C(S) Transacylation

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)-NR¹ R² ) into another (R-C(S)-NR³ N⁴ ). 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.