Department of Chemistry, University of Cincinnati, Cincinnati, OH, 45221, USA.
Angew Chem Int Ed Engl. 2021 Dec 20;60(52):27070-27077. doi: 10.1002/anie.202111993. Epub 2021 Nov 17.
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.
由于未活化的卤代烷烃的还原电位较低，且其与一价铜催化剂的氧化加成反应较为缓慢，因此其在铜催化交叉偶联反应中的应用一直具有挑战性。在这项工作中，我们报告了一种新策略，该策略利用了芳基自由基的卤原子提取能力，从而在室温下使各种碘化烷基能够参与铜催化的 Negishi 型交叉偶联反应。具体而言，通过铜催化生成的芳基自由基能够有效地引发碘化烷基中碳-碘键的断裂。生成的烷基自由基随后进入铜催化循环，与二氟甲基锌试剂偶联，从而得到烷基二氟甲烷产物。这种前所未有的 Negishi 型二氟甲基化方法已被应用于高度官能化的药物和天然产物的后期修饰。
