A Nonclassical N-Methyl Amidation Using N,N-Disubstituted Aminophosphonium Salts

Nonclassical N-methyl amidation reactions represent a valuable alternative to conventional coupling methods and expand access to drug-like molecules. Herein, we report a direct N-methyl amidation using N,N-disubstituted aminophosphonium salts. Treatment of a bench-stable trimethylaminophosphonium salt with silver acetate or quaternary ammonium carboxylates efficiently affords tertiary N-methyl amides at ambient temperature without the use of external coupling reagents. The aminophosphonium salts act as bench-stable and readily accessible N-methylamine equivalents, enabling the simultaneous activation of carboxylic acids and delivery of N-methylamine without overalkylation. Notably, the reaction proceeds via a mechanistically distinct pathway that does not involve iminophosphorane intermediates. This method provides a practical and mild approach to the synthesis of tertiary N-methyl amides.