An Lun, Xiao Yu-Lan, Zhang Shu, Zhang Xingang
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai, 200032, China.
School of Materials and Energy, University of Electronic Science and Technology of China, 2006 Xiyuan Avenue, West High-Tech Zone, Chengdu, Sichuan, 611731, China.
Angew Chem Int Ed Engl. 2018 Jun 4;57(23):6921-6925. doi: 10.1002/anie.201802713. Epub 2018 May 2.
Although iron-catalyzed cross-coupling of Grignard reagents with alkyl halides has been well established, the adoption of the reaction for fluoroalkylations has not been reported because traditional catalytic systems often lead to defluorination reactions. Described herein is the investigation of an iron-catalyzed cross-coupling between arylmagnesium bromides and difluoroalkyl bromides with modified N,N,N',N'-tetramethyl-ethane-1,2-diamine (TMEDA) as a ligand. The use of this bulky diamine, in which a butylene is substituted at one carbon atom of the ethylene backbone in TMEDA, enables the iron-catalyzed difluoroalkylation under mild reaction conditions with a wide range of difluoroalkyl bromides, including vulnerable bromodifluoromethane, thus providing a general and cost-efficient route for applications in medicinal chemistry.
尽管格氏试剂与卤代烃的铁催化交叉偶联反应已经得到了充分确立，但该反应在氟烷基化中的应用尚未见报道，因为传统催化体系常常会导致脱氟反应。本文描述了以改性的N,N,N',N'-四甲基乙烷-1,2-二胺（TMEDA）作为配体，对芳基溴化镁与二氟烷基溴之间的铁催化交叉偶联反应的研究。使用这种在TMEDA的乙烯主链的一个碳原子上被丁烯取代的大位阻二胺，能够在温和的反应条件下实现铁催化的二氟烷基化反应，可用于多种二氟烷基溴，包括易反应的溴二氟甲烷，从而为药物化学应用提供了一条通用且经济高效的路线。
