Pd-Catalyzed Difluoromethylations of Aryl Boronic Acids, Halides, and Pseudohalides with ICF2H Generated ex Situ

An expedient ex-situ generation of difluoroiodomethane (DFIM) and its immediate use in a Pd-catalyzed difluoromethylation of aryl boronic acids and ester derivatives in a two-chamber reactor is reported. Heating a solution of bromodifluoroacetic acid with sodium iodide in sulfolane proved to be effective for the generation of near stoichiometric amounts of DFIM for the ensuing catalytic coupling step. A two-step difluoromethylation of aryl (pseudo)halides with tetrahydroxydiboron as a low-cost reducing agent, both promoted by Pd catalysis, proved effective to install this fluorine-containing C-1 group onto several pharmaceutically relevant molecules. Finally, the method proved adaptable to deuterium incorporation by simply adding D2O to the DFIM-generating chamber.

Automated summary

An expedient method for the ex-situ generation of difluoroiodomethane (DFIM) and its immediate use in a Pd-catalyzed difluoromethylation reaction is reported. The method involves heating a solution of bromodifluoroacetic acid with sodium iodide in sulfolane to generate near stoichiometric amounts of DFIM, which is then used for the subsequent catalytic coupling step. The method allows for the installation of fluorine-containing C-1 groups onto pharmaceutically relevant molecules and is adaptable for deuterium incorporation by adding D2O to the DFIM-generating chamber.