Continuous Process for Preparing the Difluoromethylating Reagent [(DMPU)<sub>2</sub>Zn(CF<sub>2</sub>H)<sub>2</sub>] and Improved Synthesis of the ICHF<sub>2</sub> Precursor
Sébastien Monfette, Yuan‐Qing Fang, Matthew M. Bio, Adam R. Brown, Ian T. Crouch, Jean‐Nicolas Desrosiers, Shengquan Duan, Joel M. Hawkins, Cheryl M. Hayward, Nikita Peperni, Joseph P. Rainville
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.