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19F- and 18F-arene deoxyfluorination via organic photoredox-catalysed polarity-reversed nucleophilic aromatic substitution

Nature Catalysis volume 3, pages 734–742 (2020)Cite this article

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Abstract

Nucleophilic aromatic substitution (SNAr) is routinely used to install 19F– and 18F– in aromatic molecules, but is typically limited to electron-deficient arenes due to kinetic barriers associated with C–F bond formation. Here we demonstrate that a polarity-reversed photoredox-catalysed arene deoxyfluorination that operates via cation-radical-accelerated SNAr enables the fluorination of electron-rich arenes with 19F– and 18F– under mild conditions, and thus complements the traditional arene polarity requirements necessary for SNAr-based fluorination. The utility of our radiofluorination strategy is highlighted by short reaction times, compatibility with multiple nucleofuges and high radiofluorination yields, especially that of an important cancer positron emission tomography agent [18F]5-fluorouracil. Taken together, our fluorination approach enables the development of fluorinated and radiofluorinated compounds that can be difficult to access by classical SNAr strategies, with the potential for use in the synthesis and discovery of positron emission tomography radiopharmaceuticals.

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Fig. 1: Strategies for arene fluorination.
Fig. 2: Nucleofuge scope and a rationale for nucleofuge site selectivity.
Fig. 3: 19F fluorination of electron-rich aromatics.
Fig. 4: Rationale for arene selectivity.
Fig. 5: Nucleofuge scope for the synthesis of [18F]4-fluorobiphenyl ([18F]2).
Fig. 6: Reaction scope of 18F fluorination of aromatics.

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The authors declare that the data supporting the findings of this study are available within the paper and its Supplementary Information or from the authors upon reasonable request.

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Acknowledgements

Financial support was provided in part by the National Institutes of Health (NIBIB) 5R01EB014354 (Z.L.), R01EB029451 (Z.L. and D.A.N.), by the UNC Department of Radiology, Biomedical Research Imaging Center and by the UNC Lineberger Comprehensive Cancer Center UNC LCCC pilot grant (start-up fund to Z.L.). N.E.S.T. and V.A.P are grateful for NSF Graduate Research Fellowships. A.L. thanks the American Australian Association for a Chevron Fellowship. W.C. thanks G. Bida for assistance with cyclotron operation.

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Author notes

  1. These authors contributed equally: Nicholas E. S. Tay, Wei Chen, Alison Levens.

Authors and Affiliations

  1. Department of Chemistry, University of North Carolina at Chapel Hill, Venable Laboratories, Chapel Hill, NC, USA

    Nicholas E. S. Tay, Alison Levens, Vincent A. Pistritto & David A. Nicewicz

  2. Department of Chemistry, Columbia University, New York, NY, USA

    Nicholas E. S. Tay

  3. Biomedical Research Imaging Center, Department of Radiology, and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Wei Chen, Zeng Huang, Zhanhong Wu & Zibo Li

  4. FMC Stine Research Center, Newark, DE, USA

    Alison Levens

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Contributions

N.E.S.T. and A.L. contributed equally to the conception and discovery of the project, designed and performed experiments and performed data interpretation for 19F-deoxyfluorination. W.C. established the labelling conditions and conducted the aromatic labelling experiments. V.A.P. assisted in the synthesis and analysis of substrates, products and standards for 19F-deoxyfluorination. Z.W. and Z.H. contributed to the initial labelling design and discussion. D.A.N. and Z.L. conceived and supervised the project and experiments. N.E.S.T., D.A.N. and Z.L. wrote the manuscript with contributions from all the authors.

Corresponding authors

Correspondence to Zibo Li or David A. Nicewicz.

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Competing interests

Z.L. and D.A.N. have filed US Provisional Patent Application no. 62/812,179 on the technology communicated herein.

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Extended data

Extended Data Fig. 1. Time dependence studies for deoxyradiofluorination with arene S2.

All radiochemical yields (RCYs) are calculated by HPLC isolation starting from azeotropically dried [18F]TBAF, decay corrected and represent one experiment unless otherwise noted. See Supplementary Table 5 for more details.

Supplementary information

Supplementary Information

Supplemental Methods, Figs. 1–133, Tables 1–63, spectra and references.

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Tay, N.E.S., Chen, W., Levens, A. et al. 19F- and 18F-arene deoxyfluorination via organic photoredox-catalysed polarity-reversed nucleophilic aromatic substitution. Nat Catal 3, 734–742 (2020). https://doi.org/10.1038/s41929-020-0495-0

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