Department of Chemistry and Biochemistry , Miami University , Oxford , Ohio 45056 , United States.
State Key Laboratory of Coal Conversion , Institute of Coal Chemistry, Chinese Academy of Sciences , Taiyuan , Shanxi 030001 , P. R. China.
J Am Chem Soc. 2019 Dec 18;141(50):19941-19949. doi: 10.1021/jacs.9b11549. Epub 2019 Dec 6.
We report herein the first catalytic strategy to harness amidyl radicals derived from -chloroamides for C-C bond formation, allowing for the discovery of the first catalytic benzylic C-H difluoromethylation. Under copper-catalyzed conditions, a wide variety of -chlorocarboxamides and -chlorocarbamates direct selective benzylic C-H difluoromethylation with a nucleophilic difluoromethyl source at room temperature. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage difluoromethylation of bioactive molecules. This copper-catalyzed, chloroamide-directed strategy has also been extended to benzylic C-H pentafluoroethylation and trifluoromethylation. Mechanistic studies on the difluoromethylation reactions support that the reactions involve the formation of benzylic radicals via intramolecular C-H activation, followed by the copper-mediated transfer of difluoromethyl groups to the benzylic radicals.
我们在此报告了首例利用 - 氯酰胺衍生的酰胺基自由基进行 C-C 键形成的催化策略，从而发现了首例催化苄基 C-H 二氟甲基化反应。在铜催化条件下，多种 - 氯代羧酰胺和 - 氯代氨基甲酸酯可在室温下与亲核二氟甲基源进行选择性苄基 C-H 二氟甲基化。该可扩展的方案具有广泛的底物范围和官能团耐受性，可实现生物活性分子的后期二氟甲基化。这种铜催化、氯酰胺导向的策略也已扩展到苄基 C-H 五氟乙基化和三氟甲基化反应。对二氟甲基化反应的机理研究表明，反应通过分子内 C-H 活化形成苄基自由基，然后铜介导将二氟甲基基团转移到苄基自由基上。
