Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
Nat Commun. 2017 Nov 13;8(1):1460. doi: 10.1038/s41467-017-01540-1.
In spite of the important applications of difluoroalkylated molecules in medicinal chemistry, to date, the reaction of difluoroalkylating reagents with unactivated, aliphatic substrates through a controllable manner remains challenging and has not been reported. Here we describe an efficient nickel-catalyzed cross-coupling of unactivated alkylzinc reagen\ts with gem-difluoropropargyl bromides. The reaction proceeds under mild reaction conditions with high efficiency and excellent regiochemical selectivity. Transformations of the resulting difluoroalkylated alkanes lead to a variety of biologically active molecules, providing a facile route for applications in drug discovery and development. Preliminary mechanistic studies reveal that an alkyl nickel intermediate [Ni(tpy)alkyl] (tpy, terpyridine) is involved in the catalytic cycle.
尽管二氟烷基化分子在药物化学中有重要的应用，但迄今为止，通过可控的方式使二氟烷基化试剂与非活化的脂肪族底物反应仍然具有挑战性，并且尚未有报道。在这里，我们描述了一种有效的镍催化的未活化的烷基锌试剂与偕二氟丙基溴的交叉偶联反应。该反应在温和的反应条件下以高效率和优异的区域化学选择性进行。所得的二氟烷基化烷烃的转化可以得到多种具有生物活性的分子，为在药物发现和开发中的应用提供了一种简便的途径。初步的机理研究表明，一个烷基镍中间体[Ni(tpy)alkyl]（tpy，三吡啶）参与了催化循环。
