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Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium

Abstract

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, we describe a direct palladium-catalysed 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 understand metal–difluorocarbene complex catalysed reactions.

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Figure 1: A catalytic approach to difluoromethylated arenes using ClCF2H.
Figure 2: Pd-catalysed difluoromethylation of biologically active molecules.
Figure 3: Mechanistic studies.

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Acknowledgements

Financial support for this work was provided by the National Basic Research Program of China (973 Program) (2012CB821600 and 2015CB931900), the National Natural Science Foundation of China (21425208, 21672238, 21421002 and 21332010), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB20000000), and SIOC. We thank Y. Guo (SIOC) and H.-Y. Wang (SIOC) for assistance with MS analysis of palladium difluorocarbene complexes. We thank W. A. van der Donk and S. Zhang for proof-reading and helpful discussion.

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Z.F., Q.-Q.M. and X.-P.F. contributed equally to this work. X.Z. and Z.F. conceived and designed the experiments. Z.F., Q.-Q.M. and X.-P.F. performed the experiments. X.-P.F. conducted mechanistic studies. A.L. prepared some starting materials. Q.-Q.M. and X.-P.F. analysed the data. X.Z. wrote the paper. All of the authors discussed the results and commented on the manuscript.

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Correspondence to Xingang Zhang.

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Feng, Z., Min, QQ., Fu, XP. et al. Chlorodifluoromethane-triggered formation of difluoromethylated arenes catalysed by palladium. Nature Chem 9, 918–923 (2017). https://doi.org/10.1038/nchem.2746

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