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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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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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).
The authors declare no competing interests.
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Supplementary experimental procedures, experimental data, optimization data, compound characterization data and computational methods.
Crystallographic information file for compound A1-2, CCDC 1916607.
Crystallographic information file for compound B1-1, CCDC 1902891.
Crystallographic information file for compound B1-2, CCDC 1916606.
Crystallographic information file for compound C1-1a, CCDC 1902894.
Crystallographic information file for compound C2, CCDC 1902898.
Crystallographic information file for compound cis-G1, CCDC 1902900.
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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