Guo Huaixuan, Lai Wenting, Ni Jie, Xu Peng
Department of Chemistry, College of Sciences, Shanghai University, 99 Shangda Road, Shanghai 200444, P. R. China.
Org Lett. 2024 Nov 8;26(44):9568-9573. doi: 10.1021/acs.orglett.4c03609. Epub 2024 Oct 30.
Bis(trifluoromethyl)carbinols are valuable pharmacophores, yet their synthesis is challenging, largely due to a scarcity of safe and effective bis(trifluoromethyl)carbinolation reagents. Here, we realized the hydrobis(trifluoromethyl)carbinolation of alkenes, utilizing stable and readily accessible 2,2-bis(trifluoromethyl)glycolic acid as a source of both the bis(trifluoromethyl)carbinol unit and a hydrogen atom. This process leverages a photoinduced Fe-LMCT-enabled radical decarboxylation process that generates a key bis(trifluoromethyl)carbinol radical intermediate. Our mild protocol facilitates the synthesis of a diverse range of alkyl bis(trifluoromethyl)carbinols, including structurally complex molecules with pharmaceutical relevance.
双(三氟甲基)甲醇是有价值的药效基团,但其合成具有挑战性,主要原因是缺乏安全有效的双(三氟甲基)羟甲基化试剂。在此,我们利用稳定且易于获得的2,2-双(三氟甲基)乙醇酸作为双(三氟甲基)甲醇单元和氢原子的来源,实现了烯烃的氢双(三氟甲基)羟甲基化反应。该过程利用了光诱导的铁-配体中心电荷转移引发的自由基脱羧过程,生成关键的双(三氟甲基)甲醇自由基中间体。我们的温和方案有助于合成多种烷基双(三氟甲基)甲醇,包括具有药物相关性的结构复杂分子。