Difluoromethylated aromatic compounds are of increasing importance in pharmaceuticals, agrochemicals and materials. Chlorodifluoromethane (ClCF2H), an inexpensive, abundant and widely used industrial raw material, represents the ideal and most straightforward difluoromethylating reagent, but introduction of the difluoromethyl group (CF2H) from ClCF2H into aromatics has not been reported. Here, researchers at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, describe a direct palladium-catalyzed difluoromethylation method for coupling ClCF2H with arylboronic acids and esters to generate difluoromethylated arenes with high efficiency. The reaction exhibits a remarkably broad substrate scope, including heteroarylboronic acids, and was used for difluoromethylation of a range of pharmaceuticals and biologically active compounds. Preliminary mechanistic studies revealed that a palladium difluorocarbene intermediate is involved in the reaction. Although numerous metal–difluorocarbene complexes have been prepared, the catalytic synthesis of difluoromethylated or difluoromethylenated compounds involving metal–difluorocarbene complexes has not received much attention. This new reaction therefore also opens the door to understanding metal–difluorocarbene complex catalyzed reactions.

Due to the unique properties of fluorine atom(s), fluorinated compounds play important roles in agrochemicals, pharmaceuticals, and materials science. Over the past decade, impressive achievements have been made in efficient introduction of fluorinated groups into organic molecules. However, most of these approaches used well-known and expensive fluorinating reagents; the use of inexpensive, abundant and widely available industrial raw material fluoroalkanes has received less attention because of their relatively inert reactivities. Most recently, Zhang Xingang's group from Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, CAS, reported the first example of direct formation of difluoromethylated arenes from inexpensive and widely available industrial raw material ClCF2H (Nature Chemistry, 2017, DOI: 10.1038/NCHEM.2746). Dr. Feng Zhang, Min Qiaoqiao and Fu Xiaping are the co-authors of this paper.

CF2H is not only considered as a bioisostere of a hydroxy and thiol group, but also functions as a lipophilic hydrogen bond donor. The selective introduction of CF2H onto aromatic rings can significantly improve their bioactivities compared with their non-fluorinated counterparts. Thus, difluoromethylation is a useful strategy for the modification of biologically active compounds. However, the difluoromethylating reagents used in previous work are expensive and require multistep synthesis. ClCF2H (R22) is the most inexpensive and abundant industrial raw material used for the production of various fluorinated polymers (i.e. polytetrafluoroethylene, PTFE) (Figure 1a). From the point view of cost-efficiency and step-economy, ClCF2H would be an ideal and straightforward difluoromethylating reagent; however, the use of ClCF2H for difluoromethylation of aromatics remains a challenge and has not been reported.

    Zhang’s group, at the Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, discovered the first example of Pd-catalyzed difluoromethylation ofarylboronic acids with bromodifluoroacetate via a difluorocarbene intermediate (Org. Lett. 2016, 18, 44) on the basis of their previous work (J. Am. Chem. Soc. 2010, 132, 4506; Angew. Chem. Int. Ed. 2014, 53, 1669). Although several difluorocarbene metal complexes have been isolated, the use of metal difluorocarbene to catalyze the reaction remains a great challenge. Inspired by their previous work, they have developed the first example of palladium-catalyzed difluoromethylation of (hetero)arylborons with ClCF2H through a transition-metal difluorocarbene pathway, which provides a new mode for activation of ClCF2H. The reaction features several advantages: 1) high efficiency with broad substrate scope; 2) low-cost difluoromethylating reagent; 3) excellent functional group tolerance, even towards heteroaromatics and biologically active molecular complexes. Thus, this convenient approach provides a useful tool for the modulation of drugs and biologically active molecules. Current efforts are devoted to elucidating the detailed mechanism and to lowering the loading amount of catalyst and ClCF2H.

Late-stage difluoromethylation of biologically active molecules. (Image by Zhang Xingang)

For more information, please contact:

Zhang Xingang

Shanghai Institute of Organic Chemistry, CAS

E-mail: xgzhang@sioc.ac.cn