Sulfone Electrophiles in Cross-Electrophile Coupling: Nickel-Catalyzed Difluoromethylation of Aryl Bromides.

Fluoroalkyl fragments have played a critical role in the design of pharmaceutical and agrochemical molecules in recent years due to the enhanced biological properties of fluorinated molecules compared to their non-fluorinated analogues. Despite the potential advantages conferred by incorporating a difluoromethyl group in organic compounds, industrial adoption of difluoromethylation methods lags behind fluorination and trifluoromethylation. This is due in part to challenges in applying common difluoromethyl sources towards industrial applications. We report here the nickel-catalyzed cross-electrophile coupling of (hetero)aryl bromides with difluoromethyl 2-pyridyl sulfone, a sustainably sourced, crystalline 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 can be applied to small-scale parallel synthesis and benchtop scale-up under mild conditions. As sulfone reagents are uncommon electrophiles in cross-electrophile coupling, the mechanism of this process was investigated. Studies confirmed the formation of •CFH instead of difluorocarbene. A series of modified difluoromethyl sulfones revealed that sulfone reactivity does not correlate exclusively with reduction potential and that coordination of cations or nickel to the pyridyl group is essential to reactivity, setting out parameters for matching the reactivity of sulfones in cross-electrophile coupling.