Pd-Catalyzed Coupling of Aryl Chloride, Isocyanides, and Thiocarboxylate To Synthesize Thioamides

Abstract

Although aryl chlorides are among the most abundant and stable aromatic electrophiles, the coupling of aryl chlorides with isocyanides has remained an unsolved challenge. Herein, we report a general transformation of aryl chlorides, isocyanides, and thiocarboxylates to synthesize thioamides. The sterically hindered and electron-rich Josiphos ligand significantly facilitates the rate-determining oxidative addition step and reduces the toxicity of isocyanides toward the metal center. The combination of thiocarboxylate as the nucleophile and Josiphos as the ligands enabled the coupling-tolerated various 1°, 2°, and 3° isocyanides, which provides a rapid, efficient, and versatile method for the synthesis of large quantities of thioamides, including those of pharmaceutical relevance.