美国辛辛那提大学Wei Liu团队通过碳-碘键芳基活化实现铜催化烷基碘化物二氟甲基化。相关研究成果发表在2021年10月15日出版的《德国应用化学》。

由于原电位较低，并且铜（I）催化剂的氧化加成速度较慢，未活化的卤代烷在铜催化的交叉偶联反应中的参与一直具有挑战性。

该文中，研究人员报告了一种新的策略，该策略利用芳基的卤素提取能力，从而在室温下在铜催化的Negishi型交叉偶联反应中参与多种烷基碘化物。具体而言，通过铜催化生成的芳基有效地引发烷基碘化物的碳-碘键的断裂。由此产生的烷基自由基进入铜催化循环以与二氟甲基锌试剂偶联，从而提供烷基二氟甲烷产物。

该前所未有的Negishi型二氟甲基化方法已应用于密集功能化药物制剂和天然产物的后期改性。

附：英文原文

Title: Copper-Catalyzed Difluoromethylation of Alkyl Iodides Enabled by Aryl Radical Activation of Carbon–Iodine Bonds

Author: Aijie Cai, Wenhao Yan, Chao Wang, Wei Liu

Issue&Volume: 2021-10-15

Abstract: 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 abstraction 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.

DOI: 10.1002/anie.202111993

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202111993