2‑Azaaryl-1-methylpyridinium Halides: Aqueous-Soluble Activating Reagents for Efficient Amide Coupling in Water

In this work, a class of 2-azaaryl-1-methylpyridinium (AMP x ) reagents capable of promoting amidation processes in 100% water is reported. The process mass intensity of the AMP x -promoted reactions is similar to or lower than that of reactions using conventional coupling reagents, which suggests that the former has potential as a green amide synthesis method. It was found that the N-methylimidazole-based AMP im1 could be used to couple a wide range of carboxylic acids with amines, including natural amino acids to form peptide bonds. Tandem oxidation–amidation and reduction–amidation reactions in the presence of AMP im1 were achieved with up to moderate efficiency. It is proposed that the azaarene in AMP x plays multiple roles in the amide bond forming process, including as a leaving group, activator, and base.