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

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.

Fig. 1

Strategies in activation of ClCF₂H. a Previous work, activation of ClCF₂H via a difluorocarbene pathway. b This work, a new activation of ClCF₂H through a difluoromethyl radical pathway

Fig. 2

Ten-gram scale reaction of aryl chlorides with ClCF₂H. a Reaction of ClCF₂H with 2c. b Reaction of ClCF₂H with 2l. c Reaction of ClCF₂H with 2v. d Reaction of ClCF₂H with 6k

Fig. 3

Reaction of ClCF₂H with zinc. a Reaction of ClCF₂H with zinc in DMA. b Reaction of ClCF₂H with zinc under standard reaction conditions. c Reaction of arylchloride 2c with difluoromethyl zinc species

Fig. 4

Mechanistic studies. a Reaction of nickel complex B1 with ClCF₂H. b B1 or NiCl₂/ditBuBpy catalyzed reaction of 2a with ClCF₂H. c Reaction of C1 with 2a. d X-ray crystal structure of C1. e Experiments to trap the difluoromethyl radical by reaction of 2c and 8 with ClCF₂H. f Reaction of B1 and 8 with ClCF₂H. g Reaction of 2a and 8 with C1

Fig. 5

The role of DMAP. a [NiCl₂(ditBuBpy)] (D1) catalyzed reaction between 2a and 1 with or without DMAP. b [NiCl₂(DMAP)₄] (D2) catalyzed reaction between 2a and 1 with or without ditBuBpy. c Reaction of B1 with ClCF₂H in the presence of DMAP. d Reaction of B1 with ClCF₂H without DMAP

Fig. 6

Proposed reaction mechanism. a Proposed mechanism via a radical-cage-rebound process. b Proposed mechanism via a radical chain process