Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)₂Zn(CF₂H)₂] and Improved Synthesis of the ICHF₂ Precursor

Abstract

Complex [(DMPU)2Zn(CF2H)2] 1 is a crystalline organometallic reagent with utility in various catalytic difluoromethylation reactions under mild conditions. Unfortunately, this reagent is not commercially available and the procedure for the preparation of this air- and moisture-sensitive zinc complex has only been reported on a small scale. Herein, we report the development of a continuous process for the preparation of reagent 1 on >100 g scale by using a continuous stirred-tank reactor. The key to success is the design of a continuous reactive crystallization process in which the precipitation of the zinc complex 1 is driven by its low solubility in the reaction solvent. The improved synthesis of the iododifluoromethane precursor 2 from readily available bromodifluoroacetic acid further enables the synthesis of complex 1 on a larger scale.