α,α-Difluoro-β-iminophosphonates, an alternative strategy towards the synthesis of α,α-difluoro-β-aminophosphonate derivatives

alpha,alpha-Difluoromethylenephosphonates are generally known as stable natural phosphate mimics with significantly improved biological activities. A number of alpha,alpha-difluoroalkylphosphonates have already been found to be important enzyme inhibitors. Herein, we report an alternative strategy towards the synthesis of alpha,alpha-difluoromethylene-beta-aminophosphonate derivatives. A small library of N-substituted alpha,alpha-difluoro-beta-aminophosphonates was designed and described via NMR study. The protocol began with the condensation of beta-ketophosphonates with a series of primary amines. The key step of the synthesis is an electrophilic fluorination, mediated by Selectfluor (R), of the mixture of beta-enamino/beta-iminophosphonates leading to alpha,alpha-difluoro-beta-iminophosphonates followed by reduction. The title compounds may behave as convenient building blocks for further more advanced modification.