Mechanochemical Deoxyfluorination of Carboxylic Acids to Acyl Fluorides and Successive Mechanochemical Amide Bond Formation

Abstract

Diverse methods have been reported for the synthesis of acyl fluorides; however, an environmentally benign synthesis method for acyl fluorides remains underdeveloped. In this study, we developed solvent-free mechanochemical deoxyfluorination of carboxylic acids to acyl fluorides mediated by 1,1,2,2-tetrafluoroethyl-N,N-dimethylamine (TFEDMA) using a ball mill. This method facilitated high product yields in short reaction times even for sterically challenged carboxylic acids. We also realized the mechanochemical coupling of acyl fluorides and amines as well as the TFEDMA-mediated direct mechanochemical coupling reaction of carboxylic acids with amines via a sequential one-pot deoxyfluorination/coupling pathway. Furthermore, this protocol was expanded to include peptide synthesis. The efficiency of the protocol, in terms of speed, solvent-free characteristics, and favorable E-factor, aligns well with the requirements of current environmental policies.