Tan Qiujian, Lyu Xiang, Zhao Yu, Fang Huaquan, Xu Xianxiu, Hu Zhongyan
College of Chemistry, Chemical Engineering and Materials Science, Shandong Normal University Jinan 250014 China
School of Pharmaceutical Sciences, Chongqing University Chongqing 401331 China
Chem Sci. 2025 Aug 26. doi: 10.1039/d5sc03774c.
Herein, we present a mechanistically distinct approach to the multicomponent difunctionalisation of styrenes with alkyl halides and oxygen by integrating α-aminoalkyl radical-mediated halogen-atom transfer (XAT) with copper catalysis under air-equilibrated conditions. This strategy eliminates the need for external peroxides or photoredox conditions, offering a streamlined and efficient alternative. Mechanism studies uncover a unique role for the copper catalyst: instead of directly activating alkyl halides, inexpensive CuCl oxidizes a tertiary amine to generate an α-aminoalkyl radical, which then drives XAT to release alkyl radicals. These radicals subsequently add to alkenes, facilitating efficient difunctionalisation. This method accommodates a broad range of alkyl radical precursors, including fluoroalkyl- and alkyl halides, and demonstrates compatibility with diverse styrenes, enabling the modular synthesis of β-(fluoro)alkylated ketones with excellent functional group tolerance under mild conditions. Notably, the strategy's practical utility is exemplified through the late-stage functionalisation of biologically active molecules and pharmaceuticals, showcasing its potential for rapid, efficient access to structurally complex molecules.
在此，我们展示了一种在空气平衡条件下，通过将α-氨基烷基自由基介导的卤原子转移（XAT）与铜催化相结合，实现苯乙烯与卤代烃和氧气进行多组分双官能化的独特机制方法。该策略无需外部过氧化物或光氧化还原条件，提供了一种简化且高效的替代方案。机理研究揭示了铜催化剂的独特作用：廉价的CuCl不是直接活化卤代烃，而是氧化叔胺生成α-氨基烷基自由基，然后该自由基驱动XAT释放烷基自由基。这些自由基随后加成到烯烃上，促进高效双官能化。该方法适用于多种烷基自由基前体，包括氟烷基卤代烃和卤代烃，并证明与多种苯乙烯兼容，能够在温和条件下以优异的官能团耐受性模块化合成β-（氟）烷基化酮。值得注意的是，该策略的实际效用通过生物活性分子和药物的后期官能化得以体现，展示了其快速、高效获得结构复杂分子的潜力。
