Nickel-Catalyzed Cross-Electrophile Difluoromethylation of Aryl Bromides with a Non-ODS Derived Sulfone Reagent

Fluorinated molecules are ubiquitous in medicinal and agricultural chemistry. Despite the enhanced biological activity of difluoromethyl-containing compounds, industrial adoption of methods for difluoromethylation lag behind those for trifluoromethylation and fluorination. Many approaches to difluoromethylation rely directly or indirectly on the use of gaseous, ozone-depleting substances (ODS), which pose challenges for industrial application. We report here the nickel-catalyzed cross electrophile coupling of aryl bromides and difluoromethyl 2-pyridyl sulfone, a crystalline, non-ODS derived difluoromethylation reagent. The scope of this reaction is demonstrated with 24 examples (67 ± 16% average yield) including a diverse array of heteroaryl bromides and precursors to difluoromethyl- containing preclinical pharmaceuticals. This reaction demonstrates facile application to small-scale parallel screening and benchtop scale-up.