Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes

Abstract

Difluorocarbene has important applications in pharmaceuticals, agrochemicals and materials, but all these applications proceed using just a few types of reaction by taking advantage of its intrinsic electrophilicity. Here, we report a palladium-catalysed strategy that confers the formed palladium difluorocarbene (Pd=CF2) species with both nucleophilicity and electrophilicity by switching the valence state of the palladium centre (Pd(0) and Pd(ii), respectively). Controllable catalytic difluorocarbene transfer occurs between readily available arylboronic acids and the difluorocarbene precursor diethyl bromodifluoromethylphosphonate (BrCF2PO(OEt)2). From just this simple fluorine source, difluorocarbene transfer enables access to four types of product: difluoromethylated and tetrafluoroethylated arenes and their corresponding fluoroalkylated ketones. The transfer can also be applied to the modification of pharmaceuticals and agrochemicals as well as the one-pot diversified synthesis of fluorinated compounds. Mechanistic and computational studies consistently reveal that competition between nucleophilic and electrophilic palladium difluorocarbene ([Pd]=CF2) is the key factor controlling the catalytic difluorocarbene transfer.

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Fig. 1: Previous and present approaches to difluorocarbene transfer.
Fig. 2: Diversified synthesis of fluoroalkylated arenes.
Fig. 3: Mechanistic studies.
Fig. 4: Calculated energy profile of the palladium-catalysed difluorocarbene transfer reactions.
Fig. 5: Outline of a possible pathway for controllable palladium-catalysed difluorocarbene transfer.

Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Center under deposition numbers CCDC 1902891 (B1-1), 1916606 (B1-2), 1916607 (A1-2), 1902894 (C1-1a), 1902898 (C2), 1902901 (E1) and 1902900 (cis-G1). Copies of the data can be obtained free of charge from https://www.ccdc.cam.ac.uk/strucutres/. All other data supporting the findings of this study are available within the Article and its Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China (21425208, 21672238, 21790362 and 21421002), the National Basic Research Program of China (973 Program) (No. 2015CB931900), the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB20000000). We thank H.-L. Qin for MS analysis of 18O-labelled compound 7 and G.-Y. Li for 13C NMR analysis of the palladium complexes. K.N.H. acknowledges the National Science Foundation (NSF) for support (CHE-1764320). Computations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575).

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Authors

Contributions

X.Z. and X.-P.F. conceived and designed the experiments. X.Z. directed the project. X.-P.F. performed the experiments and mechanism studies. X.-S.X. conducted the DFT calculations and contributed parts of the mechanism analysis. K.N.H. directed the DFT calculations. X.-Y.Z. conducted parts of the mechanistic studies. Y.-L.G. conducted MS analysis of the palladium complexes. X.L. analysed the X-ray crystal structure of the palladium difluorocarbene complex. X.-P.F., Y.-L.X. and X.Z. analysed the data. X.Z., X.-S.X., S.Z. and K.N.H. co-wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Kendall N. Houk or Xingang Zhang.

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Supplementary information

Supplementary Information

Supplementary experimental procedures, experimental data, optimization data, compound characterization data and computational methods.

A1-2.cif

Crystallographic information file for compound A1-2, CCDC 1916607.

B1-1.cif

Crystallographic information file for compound B1-1, CCDC 1902891.

B1-2.cif

Crystallographic information file for compound B1-2, CCDC 1916606.

C1-1a.cif

Crystallographic information file for compound C1-1a, CCDC 1902894.

C2.cif

Crystallographic information file for compound C2, CCDC 1902898.

cis-G1.cif

Crystallographic information file for compound cis-G1, CCDC 1902900.

E1.cif

Crystallographic information file for compound E1, CCDC 1902901.

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Fu, X., Xue, X., Zhang, X. et al. Controllable catalytic difluorocarbene transfer enables access to diversified fluoroalkylated arenes. Nat. Chem. 11, 948–956 (2019). https://doi.org/10.1038/s41557-019-0331-9

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