南昌大学曾小军ACIE:NMP稳定的ICF2H试剂助力镍/硼协同催化体系实现模块化烷基二氟甲基化反应

图1. TOC (图片来源于ACIE)

摘要：

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.

研究背景：

图2. 研究背景及本策略 (图片来源于ACIE)

研究内容：

图3. 新CF₂H试剂设计 (图片来源于ACIE)

图4. 条件优化 (图片来源于ACIE)

图5. 镍催化二氟甲基化反应烷基溴代物和烷基碘代物底物拓展 (图片来源于ACIE)

图6. 镍催化氢二氟甲基化反应非活化烯烃底物拓展 (图片来源于ACIE)

图7. 芳基碘代物底物范围及合成转化反应 (图片来源于ACIE)

图8. 机理研究及可能的催化循环 (图片来源于ACIE)

总结：

In summary, we have developed a mild and general nickel–boron cooperative catalytic platform that enables the difluoromethylation of alkyl halides, aryl and alkenyl halides, as well as unactivated olefins. This strategy employs difluoroiodomethane (ICF₂H) stabilized by N-methylpyrrolidone (NMP), which functions as a hydrogen bond accepting medium, thereby overcoming longstanding challenges associated with reagent handling and solubility and allowing ICF₂H to be applied at high effective concentrations. The catalytic system displays broad substrate tolerance across diverse functional groups, heterocycles, and complex molecular architectures, and is readily applicable to the late-stage difluoromethylation of bioactive compounds. Mechanistic studies support a radical pathway involving Ni(I/II/III) intermediates, consistent with a Ni–B-mediated activation manifold. Overall, this work establishes a unified and practical approach for the installation of difluoromethyl groups across multiple classes of electrophiles and unsaturated motifs, providing a versatile platform for the synthesis of pharmaceutically relevant scaffolds.

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