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

作者：Lu, Changhui; Li, Xiaohong; Chang, Shunqin; Zhang, Yuqi; Xing, Donghui; Wang, Shuo; Lin, Yueping; Jiang, Huanfeng; Huang, Liangbin^*

来源：Organic Chemistry Frontiers, 2022, 9(9): 2382-2389.

DOI：10.1039/d2qo00152g

• MICHAEL REACTION
• CHEMISTRY
• KETENES
• COMPLEXES
• AMINES
• CYCLOHEXADIENONES
• DESYMMETRIZATION
• 1ST-CENTURY
• ALKYLATION
• P,N-LIGAND

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.