Copper-catalyzed carbo-difluoromethylation of alkenes via radical relay

Aijie Cai, Wenhao Yan, Xiaojun Zeng, Samson B. Zacate, Tzu-Hsuan Chao, Jeanette A. Krause, Mu-Jeng Cheng and Wei Liu ()
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Aijie Cai: University of Cincinnati
Wenhao Yan: University of Cincinnati
Xiaojun Zeng: University of Cincinnati
Samson B. Zacate: Miami University
Tzu-Hsuan Chao: National Cheng Kung University
Jeanette A. Krause: University of Cincinnati
Mu-Jeng Cheng: National Cheng Kung University
Wei Liu: University of Cincinnati

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: Abstract Organic molecules that contain alkyl-difluoromethyl moieties have received increased attention in medicinal chemistry, but their synthesis in a modular and late-stage fashion remains challenging. We report herein an efficient copper-catalyzed radical relay approach for the carbo-difluoromethylation of alkenes. This approach simultaneously introduces CF2H groups along with complex alkyl or aryl groups into alkenes with regioselectivity opposite to traditional CF2H radical addition. We demonstrate a broad substrate scope and a wide functional group compatibility. This scalable protocol is applied to the late-stage functionalization of complex molecules and the synthesis of CF2H analogues of bioactive molecules. Mechanistic studies and density functional theory calculations suggest a unique ligand effect on the reactivity of the Cu-CF2H species.

Date: 2021
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DOI: 10.1038/s41467-021-23590-2

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