Phosphine-Based Redox Catalysis in the Direct Traceless Staudinger Ligation of Carboxylic Acids and Azides

摘要

The synthesis of amide C-N bonds through nucleophilic acyl substitutions constitutes one of the most fundamental transformations in chemical synthesis. Recently, the Staudinger-type ligation of carboxylic acid derivatives (e.g., acid chlorides, anhydrides, acyl selenides, and thioesters) and azides has become a preeminent strategy for amide C—N bond construction (Scheme 1a). However, the generation of stoichiometric by-products (e.g., R3P=O) often complicates efforts to isolate products, leads to waste disposal issues, and limits the overall synthetic efficiency of this method. Thus, a phosphine-catalyzed Staudinger ligation involving the direct coupling of carboxylic acids and azides would concomitantly minimize the formation of undesired by-products while avoiding the need for an additional acid derivatization (Scheme 1b). We envisioned a P~(III)/P~V-redox-driven cycle wherein an acid/base reaction of the carboxylic acid and intermediate aza-ylide would form an activated phosphonium carboxylate in situ and thus enable catalytic C-N bond formation. Herein, we report a conceptually new approach toward the phosphine-catalyzed Staudinger ligation for the chemoselective, direct conversion of carboxylic acids to amides.