Nickel-Boryl-Catalyzed Modular Alkyl Difluoromethylation Enabled by an NMP-Stabilized ICF2H Reagent
LiLi Zhao1, Jinghong Zhang1, Yijie Wei2
1School of Chemistry and Chemical Engineering, Nanchang University, Nanchang, Jiangxi, China.
None:
The difluoromethyl (CF2H) 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(sp3)─CF2H 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 (CF2HI) 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 CF2H-containing scaffolds for medicinal chemistry applications.
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