Merck Center for Catalysis at Princeton University, Princeton, NJ, USA.
Process Research and Development, Merck & Co., Inc., Rahway, NJ, USA.
Nat Chem. 2020 May;12(5):459-467. doi: 10.1038/s41557-020-0436-1. Epub 2020 Mar 16.
The introduction of a trifluoromethyl (CF) group can dramatically improve a compound's biological properties. Despite the well-established importance of trifluoromethylated compounds, general methods for the trifluoromethylation of alkyl C-H bonds remain elusive. Here we report the development of a dual-catalytic C(sp)-H trifluoromethylation through the merger of light-driven, decatungstate-catalysed hydrogen atom transfer and copper catalysis. This metallaphotoredox methodology enables the direct conversion of both strong aliphatic and benzylic C-H bonds into the corresponding C(sp)-CF products in a single step using a bench-stable, commercially available trifluoromethylation reagent. The reaction requires only a single equivalent of substrate and proceeds with excellent selectivity for positions distal to unprotected amines. To demonstrate the utility of this new methodology for late-stage functionalization, we have directly derivatized a broad range of approved drugs and natural products to generate valuable trifluoromethylated analogues. Preliminary mechanistic experiments reveal that a 'Cu-CF' species is formed during this process and the critical C(sp)-CF bond-forming step involves the copper catalyst.
引入三氟甲基（CF）基团可以显著改善化合物的生物特性。尽管三氟甲基化化合物具有重要的地位，但烷基 C-H 键的三氟甲基化的通用方法仍然难以捉摸。在这里，我们报告了通过合并光驱动的、十钨酸盐催化的氢原子转移和铜催化作用，开发了一种双催化 C(sp)-H 三氟甲基化反应。这种金属光还原方法能够使用稳定的、商业上可用的三氟甲基化试剂，在一步中将强脂肪族和苄基 C-H 键直接转化为相应的 C(sp)-CF 产物。该反应仅需一个当量的底物，并具有极好的选择性，可用于远离未保护的胺的位置。为了证明这种新方法在后期功能化中的实用性，我们已经直接衍生了广泛的批准药物和天然产物，以生成有价值的三氟甲基化类似物。初步的机理实验表明，在这个过程中形成了“Cu-CF”物种，并且关键的 C(sp)-CF 键形成步骤涉及铜催化剂。
