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Palladium-catalysed electrophilic aromatic C–H fluorination

Nature volume 554, pages 511–514 (2018)Cite this article

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Abstract

Aryl fluorides are widely used in the pharmaceutical and agrochemical industries1,2, and recent advances have enabled their synthesis through the conversion of various functional groups. However, there is a lack of general methods for direct aromatic carbon–hydrogen (C–H) fluorination3. Conventional methods require the use of either strong fluorinating reagents, which are often unselective and difficult to handle, such as elemental fluorine, or less reactive reagents that attack only the most activated arenes, which reduces the substrate scope. A method for the direct fluorination of aromatic C–H bonds could facilitate access to fluorinated derivatives of functional molecules that would otherwise be difficult to produce. For example, drug candidates with improved properties, such as increased metabolic stability or better blood–brain-barrier penetration, may become available. Here we describe an approach to catalysis and the resulting development of an undirected, palladium-catalysed method for aromatic C–H fluorination using mild electrophilic fluorinating reagents. The reaction involves a mode of catalysis that is unusual in aromatic C–H functionalization because no organometallic intermediate is formed; instead, a reactive transition-metal-fluoride electrophile is generated catalytically for the fluorination of arenes that do not otherwise react with mild fluorinating reagents. The scope and functional-group tolerance of this reaction could provide access to functional fluorinated molecules in pharmaceutical and agrochemical development that would otherwise not be readily accessible.

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Figure 1: Aromatic fluorination catalysed by 1.
Figure 2: Substrate scope of the Pd-catalysed fluorination of arenes.
Figure 3: Mechanism of fluorination catalysed by 1.
Figure 4: Comparison of the positional selectivity of stoichiometric and catalytic fluorinations using 2′.

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Acknowledgements

We thank L. Gitlin for HPLC purification, R. Goddard, S. Palm and J. Rust for X-ray crystallographic analysis, C. Farès for NMR spectroscopy, and M. Blumenthal, D. Kampen and S. Marcus for mass spectrometry. We thank UCB Biopharma for funding and compound separation, the Japan Society for the Promotion of Science and L’Oréal-UNESCO Japan for graduate fellowships to K.Y., the Fonds der Chemischen Industrie for a graduate fellowship for J.D.R., and the German Academic Exchange Service, DAAD for an Otto-Bayer fellowship to J.C.B.

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Author notes

  1. Kumiko Yamamoto and Jiakun Li: These authors contributed equally to this work.

Authors and Affiliations

  1. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, Mülheim an der Ruhr, D-45470, Germany

    Kumiko Yamamoto, Jiakun Li, Jeffrey A. O. Garber, Julian D. Rolfes, Gregory B. Boursalian, Maurice van Gastel, Frank Neese & Tobias Ritter

  2. Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, 02138, Massachusetts, USA

    Kumiko Yamamoto, Jeffrey A. O. Garber, Julian D. Rolfes, Gregory B. Boursalian, Jannik C. Borghs & Tobias Ritter

  3. Global Chemistry, UCB NewMedicines, UCB Biopharma, Braine-L’Alleud, 1420, Belgium

    Christophe Genicot & Jérôme Jacq

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Contributions

K.Y. designed catalyst 1 and optimized the fluorination reaction. K.Y. and J.D.R. conducted mechanistic studies. K.Y. and G.B.B. developed the conceptual approach to the project. J.L., J.A.O.G., J.C.B., K.Y. and J.D.R. explored the substrate scope. J.D.R. performed DFT calculations with input from M.v.G. and F.N. G.B.B. wrote the manuscript with input from all other authors. C.G. and J.J. supported development towards useful examples. K.Y., J.L., J.A.O.G., G.B.B., J.D.R. and T.R. analysed the data. T.R. directed the project.

Corresponding author

Correspondence to Tobias Ritter.

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The authors declare no competing financial interests.

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Reviewer Information Nature thanks J. Groves and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

This file contains procedures and characterization as well as spectra. (PDF 10929 kb)

Supplementary Data

This file contains checkcif 4na containing proof of appropriate x-ray data. (PDF 98 kb)

Supplementary Data

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Yamamoto, K., Li, J., Garber, J. et al. Palladium-catalysed electrophilic aromatic C–H fluorination. Nature 554, 511–514 (2018). https://doi.org/10.1038/nature25749

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