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Difluoromethylation of (hetero)aryl chlorides with chlorodifluoromethane catalyzed by nickel.
Nature Communications ( IF 14.7 ) Pub Date : 2018-03-21 , DOI: 10.1038/s41467-018-03532-1
Chang Xu , Wen-Hao Guo , Xu He , Yin-Long Guo , Xue-Ying Zhang , Xingang Zhang

Relatively low reactivity hinders using chlorodifluoromethane (ClCF2H) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical. To date, transformations of ClCF2H 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 ClCF2H 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 ClCF2H in organic synthesis and related chemistry.

中文翻译:

镍催化的(杂)芳基氯与氯二氟甲烷的二氟甲基化。

相对较低的反应性阻碍了使用氯二氟甲烷(ClCF 2 H)与有机分子进行一般的二氟甲基化,尽管它可以作为廉价的工业化学品获得。迄今为止,ClCF 2 H的转化非常有限,并且大多数涉及二氟卡宾中间体。在这里,我们描述了一种通过镍催化的ClCF 2交叉偶联来实现芳族化合物二氟甲基化的策略。H与容易获得的(杂)芳基氯化物。该反应在温和的反应条件下高效进行,并且具有合成简便性,无需形成芳基金属和宽范围的底物范围,包括各种杂芳族化合物和可商购的药物。当前的镍催化工艺的可靠实用性和可扩展性也已经通过数个10克规模的反应证明,而不会损失反应效率。初步的机理研究表明,该反应从芳基氯化物的氧化加成到Ni(0)开始,并且该反应涉及二氟甲基,从而为ClCF 2 H在有机合成和相关化学中的应用提供了途径。
更新日期:2018-03-21
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