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
(AMPx) reagents capable of
promoting amidation
processes in 100% water is reported. The process mass intensity of
the AMPx-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 AMPim1 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 AMPim1 were achieved
with up to moderate efficiency. It is proposed that the azaarene in AMPx plays multiple roles in the
amide bond forming process, including as a leaving group, activator,
and base.