Copper‐Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

• Published in: Angewandte Chemie International Edition 2021-12, Vol.60 (52), p.27070-27077
• Main Authors: Cai, Aijie, Yan, Wenhao, Wang, Chao, Liu, Wei
• Format: Article
• Language: English
• Subjects: Aromatic compounds; Carbon; Catalysis; Catalysts; Chemical reactions; Copper; Cross coupling; difluoromethylation; Halides; Iodides; Iodine; Natural products; Radicals; reaction mechanisms; Reagents; Room temperature
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202111993

The engagement of unactivated alkyl halides in copper‐catalyzed cross‐coupling reactions has been historically challenging, due to their low reduction potential and the slow oxidative addition of copper(I) catalysts. In this work, we report a novel strategy that leverages the halogen ion ability of aryl radicals, thereby engaging a diverse range of alkyl iodides in copper‐catalyzed Negishi‐type cross‐coupling reactions at room temperature. Specifically, aryl radicals generated via copper catalysis efficiently initiate the cleavage of the carbon–iodide bonds of alkyl iodides. The alkyl radicals thus generated enter the copper catalytic cycles to couple with a difluoromethyl zinc reagent, thus furnishing the alkyl difluoromethane products. This unprecedented Negishi‐type difluoromethylation approach has been applied to the late‐stage modification of densely functionalized pharmaceutical agents and natural products. An aryl radical activation strategy has been developed that can engage unactivated alkyl iodides in copper‐catalyzed Negishi‐type cross‐coupling reactions. The strategy is based on the largely overlooked yet highly efficient reactivity of aryl radicals to iodine atoms from alkyl iodides.