Journal Article

Copper-catalyzed carbo-difluoromethylation of alkenes via radical relay

Zeng, Xiaojun, Yan, Wenhao, Chao, Tzu-Hsuan, Krause, Jeanette A., Liu, Wei, Cheng, Mu-Jeng, Zacate, Samson B., Cai, Aijie

2021

Overview

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 CF 2 H groups along with complex alkyl or aryl groups into alkenes with regioselectivity opposite to traditional CF 2 H 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 CF 2 H analogues of bioactive molecules. Mechanistic studies and density functional theory calculations suggest a unique ligand effect on the reactivity of the Cu-CF 2 H species. Compounds that contain alkyl-difluoromethyl moieties are of interest for medicinal chemistry, but their synthesis is challenging. Here, the authors report a copper-catalyzed radical relay approach for the carbodifluoromethylation of alkenes that simultaneously introduces CF 2 H groups and complex alkyl or aryl groups into alkenes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 140/131 / 140/58 / 639/638/403/933 / 639/638/77/888 / Alkenes / Aromatic compounds / Biocompatibility / Chemical synthesis / Copper / Density functional theory / Functional groups / Humanities and Social Sciences / multidisciplinary / Organic chemistry / Pharmaceutical sciences / Radicals / Regioselectivity / Relay / Science / Science (multidisciplinary) / Substrates