A TFPN-mediated acyl fluoride platform: efficient synthesis of esters, thioesters, and macrolactones from carboxylic acids with diverse nucleophiles

Abstract

A TFPN (3,4,5,6-tetrafluorophthalonitrile)-mediated esterification strategy has been developed for the efficient synthesis of esters, thioesters, and macrolactones within remarkably short reaction times. Key to this approach is the utilization of in situ-generated acyl fluorides as transient intermediates, which circumvent stability limitations associated with conventional activated species. This method demonstrates exceptional functional group tolerance across structurally diverse substrates, including chiral molecules with complete stereochemical preservation. Notably, medium-sized macrolactones are efficiently constructed using this protocol. Being operationally simple and scalable, this platform exhibits practical versatility in late-stage functionalization of bioactive molecules, bioconjugation, and polymer chemistry, underscoring its broad synthetic utility.