Thioamide synthesis via copper-catalyzed C–H activation of 1,2,3-thiadiazoles enabled by slow release and capture of thioketenes?

Organic Chemistry Frontiers Pub Date: 2022-03-16 DOI: 10.1039/D2QO00152G

Abstract

Thioketenes, as highly reactive intermediates, are extremely prone to dimerization, which severely limits their further synthetic applications. Herein we developed a Cu-catalyzed thioacylation of amines via a C–H activation/coordinated stabilization protocol to ensure the slow-release of thioketenes, which are captured by various amines to afford thioamides. This method is characterized by its simplicity, efficiency and broad substrate scope in both 1,2,3-thiadiazoles and amines. Its versatility is further illustrated by the late-stage thioamidation of N-containing drugs, peptides, catalysts, and ligands. Mechanism studies demonstrate that the active Cu(I) species is formed via the reduction of Cu(II) during the induction period, and the rate-determining step is the C–H activation of 1,2,3-thiadiazole.

Graphical abstract: Thioamide synthesis via copper-catalyzed C–H activation of 1,2,3-thiadiazoles enabled by slow release and capture of thioketenes
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