Nickel–Boryl‐Catalyzed Modular Alkyl Difluoromethylation Enabled by an NMP‐Stabilized ICF ₂ H Reagent

ABSTRACT The difluoromethyl (CF 2 H) moiety is a privileged pharmacophore that imparts enhanced metabolic stability, lipophilicity, and bioisosteric properties to drug candidates. While aryl difluoromethylation methods are well‐established, catalytic approaches for constructing C( sp 3 )─CF 2 H bonds remain underdeveloped. Herein, we introduce a nickel/boron‐cooperative catalytic system for the cross‐electrophile difluoromethylation of diverse alkyl halides, as well as hydrodifluoromethylation of unactivated alkenes, utilizing difluoroiodomethane (CF 2 HI) stabilized as a liquid reagent through hydrogen‐bonding interaction with N‐methylpyrrolidone (NMP). This stabilization enables high‐concentration handling and overcomes volatility and solubility issues. The mild protocol exhibits excellent functional group tolerance, accommodates complex heterocycles, and facilitates late‐stage modification of bioactive compounds. Mechanistic investigations reveal a radical pathway mediated by Ni(I/II/III) intermediates. This versatile platform expands access to CF 2 H‐containing scaffolds for medicinal chemistry applications.