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 Road, 200032, Shanghai, China.
Nat Commun. 2018 Mar 21;9(1):1170. doi: 10.1038/s41467-018-03532-1.
Relatively low reactivity hinders using chlorodifluoromethane (ClCFH) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical. To date, transformations of ClCFH are very limited and most of them involve difluorocarbene intermediate. Here, we describe a strategy for difluoromethylation of aromatics through nickel-catalyzed cross-coupling of ClCFH with readily accessible (hetero)aryl chlorides. The reaction proceeds under mild reaction conditions with high efficiency and features synthetic simplicity without preformation of arylmetals and broad substrate scope, including a variety of heteroaromatics and commercially available pharmaceuticals. The reliable practicability and scalability of the current nickel-catalyzed process has also been demonstrated by several 10-g scale reactions without loss of reaction efficiency. Preliminary mechanistic studies reveal that the reaction starts from the oxidative addition of aryl chlorides to Ni(0) and a difluoromethyl radical is involved in the reaction, providing a route for applications of ClCFH in organic synthesis and related chemistry.
尽管氯二氟甲烷（ClCFH）作为一种廉价的工业化学品易得，但由于其反应活性相对较低，限制了其在有机分子的普遍二氟甲基化反应中的应用。迄今为止，ClCFH 的转化非常有限，大多数转化都涉及二氟卡宾中间体。在这里，我们描述了一种通过镍催化 ClCFH 与易得的（杂）芳基氯化物的交叉偶联反应实现芳烃二氟甲基化的策略。该反应在温和的反应条件下以高效率进行，具有合成简单的特点，无需预先形成芳基金属，且底物范围广泛，包括各种杂芳烃和市售药物。通过几个 10 克规模的反应，证明了当前镍催化过程的可靠实用性和可扩展性，反应效率没有降低。初步的机理研究表明，反应从芳基氯化物对 Ni(0)的氧化加成开始，并且涉及二氟甲基自由基，为 ClCFH 在有机合成和相关化学中的应用提供了途径。
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