Enantioselective Difluoromethylation of Unactivated Alkyl Halides via a Formal Nickel(II/IV) Cycle
Xian Zhao1,2, Lingfeng Yin1,2, Chia-Jung Yang3
1Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, United States.
Abstract:
Nickel-catalysed enantioconvergent cross-coupling has emerged as a key strategy for constructing stereochemically defined C(sp3) centres. However, the reliance on nickel(I)/nickel(III) catalytic cycles has limited the range of compatible alkyl electrophiles and nucleophiles. Here, we report an aryl-radical-enabled oxidative addition mechanism that connects NiII and formal NiIV oxidation states, enabling the enantioselective difluoromethylation of unactivated alkyl halides. Mechanistic investigations, including X-ray crystallography, EPR spectroscopy, and DFT calculations, support the involvement of a nickel(II/III/IV) cycle via the stepwise oxidative addition of NiII intermediates. The broad substrate scope and compatibility with pharmaceutically relevant molecules highlight the potential of this catalytic platform in asymmetric catalysis.
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