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

Chang Xu,Xingang Zhang,Xu He,Xue-Ying Zhang,Wen-Hao Guo,Yin-Long Guo

doi:10.1038/s41467-018-03532-1

Chang Xu, Xingang Zhang + Show 4 more

Open Access

https://doi.org/10.1038/s41467-018-03532-1

Copy DOI

Abstract

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.

Highlights

Low reactivity hinders using chlorodifluoromethane (ClCF2H) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical
This study has demonstrated that the activation of ClCF2H by transition metal can be conducted under mild reaction conditions and has wide application potential
The reaction proceeds under mild reaction conditions with high efficiency and enables difluoromethylation of a variety of inexpensive and readily accessible aryl chlorides, including heteroaromatics and commercially available pharmaceuticals

Summary

Introduction

Low reactivity hinders using chlorodifluoromethane (ClCF2H) for general difluoromethylation with organic molecules, despite its availability as an inexpensive industrial chemical. We began our studies on nickel-catalyzed reductive cross-coupling between ClCF2H and aryl chlorides (Fig. 1b).

Results

Conclusion