Joseph Ebbin, Smith Ian, Tunge Jon A
Department of Chemistry, The University of Kansas 1567 Irving Rd, Lawrence KS 66045 USA
Chem Sci. 2023 Nov 16;14(47):13902-13907. doi: 10.1039/d3sc05583c. eCollection 2023 Dec 6.
The selective installation of fluorine-containing groups into biologically relevant molecules has been used as a common strategy for the development of pharmaceutically active molecules. However, the selective incorporation of -difluoromethylene groups next to sterically demanding secondary and tertiary alkyl groups remains a challenge. Herein, we report the first cobalt-catalyzed regioselective difluoroalkylation of carboxylic acid salts. The reaction allows for the facile construction of various difluoroalkylated products in good yields tolerating a wide range of functionalities on either reaction partner. The potential of the method is illustrated by the late-stage functionalization of molecules of biological relevance. Mechanistic studies support the formation of a cobalt(i) species and the intermediacy of difluoroalkyl radicals, thus suggesting a Co(i)/Co(ii)/Co(iii) catalytic cycle.
将含氟基团选择性地引入到具有生物学相关性的分子中，已被用作开发具有药物活性分子的常用策略。然而，在空间位阻较大的仲烷基和叔烷基旁边选择性引入二氟亚甲基仍然是一个挑战。在此，我们报道了首例钴催化羧酸盐的区域选择性二氟烷基化反应。该反应能够轻松构建各种二氟烷基化产物，产率良好，且能耐受反应底物上的多种官能团。该方法的潜力通过具有生物学相关性分子的后期官能团化得以体现。机理研究支持了钴（I）物种的形成以及二氟烷基自由基的中间体存在，从而表明存在一个Co（I）/Co（II）/Co（III）催化循环。
