Zeng Xin, Li Yao, Min Qiao-Qiao, Xue Xiao-Song, Zhang Xingang
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Nat Chem. 2023 Aug;15(8):1064-1073. doi: 10.1038/s41557-023-01236-8. Epub 2023 Jun 12.
The use of metal catalysts to produce and control the reactivity of carbenes has long offered a powerful approach to organic synthesis; however, difluorocarbene transfer catalysed by metal is an outlier and remains a substantial challenge. In that context, copper difluorocarbene chemistry has been elusive so far. Here we report the design, synthesis, characterization and reactivity of isolable copper(I) difluorocarbene complexes, which enable the development of a copper-catalysed difluorocarbene transfer reaction. The method offers a strategy for the modular synthesis of organofluorine compounds from simple and readily available components. This strategy facilitates a modular difluoroalkylation by coupling difluorocarbene with two inexpensive feedstocks, silyl enol ethers and allyl/propargyl bromides, in a one-pot reaction via copper catalysis, providing a diversity of difluoromethylene-containing products without laborious multistep synthesis. The approach enables access to various fluorinated skeletons of medicinal interest. Mechanistic and computational studies consistently reveal a mechanism involving nucleophilic addition to an electrophilic copper(I) difluorocarbene.
长期以来，使用金属催化剂来产生和控制卡宾的反应活性为有机合成提供了一种强大的方法；然而，金属催化的二氟卡宾转移是一个例外，仍然是一项重大挑战。在这种情况下，二氟卡宾铜化学迄今为止一直难以捉摸。在此，我们报告了可分离的二氟卡宾铜（I）配合物的设计、合成、表征及反应活性，这使得铜催化的二氟卡宾转移反应得以发展。该方法为从简单易得的组分模块化合成有机氟化合物提供了一种策略。通过铜催化在一锅反应中将二氟卡宾与两种廉价原料——硅基烯醇醚和烯丙基/炔丙基溴——偶联，这种策略促进了模块化二氟烷基化反应，无需繁琐的多步合成即可提供多种含二氟亚甲基的产物。该方法能够合成各种具有药用价值的氟化骨架。机理和计算研究一致揭示了一种涉及亲核加成到亲电二氟卡宾铜（I）上的机理。
