Difluoromethylation of (hetero)aryl chlorides with chlorodifluoromethane catalyzed by nickel

• Published in: Nature communications Vol. 9; no. 1; pp. 1170 - 10
• Main Authors: Xu, Chang, Guo, Wen-Hao, He, Xu, Guo, Yin-Long, Zhang, Xue-Ying, Zhang, Xingang
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.03.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 639/638/549/933; 639/638/77/885; 639/638/77/888; Aromatic compounds; Chemical reactions; Chemical synthesis; Chemistry; Chlorides; Chlorodifluoromethane; Coupling (molecular); Cross coupling; Efficiency; Humanities and Social Sciences; Ligands; multidisciplinary; Nickel; Organic chemistry; Pharmaceutical sciences; Science; Science (multidisciplinary); Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03532-1

Relatively low reactivity hinders using chlorodifluoromethane (ClCF 2 H) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical. To date, transformations of ClCF 2 H 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 ClCF 2 H 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 ClCF 2 H in organic synthesis and related chemistry. Transformations with ClCF 2 H are very limited and normally involve a difluorocarbene intermediate. Here, the authors report a nickel-catalyzed difluoromethylation of aryl chlorides with chlorodifluoromethane via a difluoromethyl radical intermediate and apply the method to the synthesis of marketed pharmaceuticals.