Zeng Xin, Yang Jimin, Deng Wei, Feng Xiao-Tian, Zhao Hai-Yang, Wei Lanfeng, Xue Xiao-Song, Zhang Xingang
Key Laboratory of Fluorine and Nitrogen Chemistry and Advanced Materials (Chinese Academy of Sciences), Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
J Am Chem Soc. 2024 Jun 7. doi: 10.1021/jacs.4c04949.
Despite the synthetic versatility of difluorocarbene, its high reactivity severely regulates widespread applications of difluorocarbene in organic synthesis. Here, we report a copper difluorocarbene-involved catalytic coupling, representing a new mode of the difluoromethylation reaction. This method allows difluoromethylation of a wide range of readily available allyl/propargyl electrophiles with NaBHCN and low-cost difluorocarbene precursor BrCFCOK, featuring high cost-efficiency, high stereo- and regioselectivities, and high functional group tolerance, even with complex drug-like molecules. Applying the method led to the efficient synthesis of deuterated difluoromethylated compounds of medicinal interest. The resulting difluoromethylated allyl and allenyl products can serve as versatile synthons for diverse transformations, rendering the approach attractive for synthesizing complex fluorinated structures. Experimental mechanistic studies and computational calculations reveal that the formation of a difluoromethylcopper(I) intermediate through the nucleophilic attack of boron hydride on the copper(I) difluorocarbene is the key step in the reaction.
尽管二氟卡宾具有合成多样性，但其高反应活性严重限制了二氟卡宾在有机合成中的广泛应用。在此，我们报道了一种涉及二氟卡宾铜的催化偶联反应，代表了二氟甲基化反应的一种新模式。该方法能够使多种易得的烯丙基/炔丙基亲电试剂与硼氢化钠和低成本的二氟卡宾前体溴代三氟丙酮钾发生二氟甲基化反应，具有高成本效益、高立体和区域选择性以及高官能团耐受性，甚至对于复杂的类药物分子也是如此。应用该方法能够高效合成具有药用价值的氘代二氟甲基化化合物。所得的二氟甲基化烯丙基和联烯基产物可作为多种转化反应的通用合成子，使得该方法对于合成复杂的氟化结构具有吸引力。实验机理研究和计算计算表明，通过硼氢化物对二氟卡宾铜（I）的亲核进攻形成二氟甲基铜（I）中间体是该反应的关键步骤。
