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A general arene C–H functionalization strategy via electron donor–acceptor complex photoactivation

Nature Chemistry volume 15, pages 43–52 (2023)Cite this article

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Abstract

The photoactivation of electron donor–acceptor complexes has emerged as a sustainable, selective and versatile strategy for the generation of radical species. However, when it comes to aryl radical formation, this strategy remains hamstrung by the electronic properties of the aromatic radical precursors, and electron-deficient aryl halide acceptors are required. This has prevented the implementation of a general synthetic platform for aryl radical formation. Our study introduces triarylsulfonium salts as acceptors in photoactive electron donor–acceptor complexes, used in combination with catalytic amounts of newly designed amine donors. The sulfonium salt label renders inconsequential the electronic features of the aryl radical precursor and, more importantly, it is installed regioselectively in native aromatic compounds by C–H sulfenylation. Using this general, site-selective aromatic C–H functionalization approach, we developed metal-free protocols for the alkylation and cyanation of arenes, and showcased their application in both the synthesis and the late-stage modification of pharmaceuticals and agrochemicals.

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Fig. 1: Photoactivation of EDA complexes drives the metal-free radical C–H functionalization of arenes.
Fig. 2: Development of the photochemical C–H alkylation protocol.
Fig. 3: Synthesis and late-stage functionalization of pharmaceuticals and agrochemicals.
Fig. 4: Mechanistic studies and proposed reaction pathway.

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Data availability

Materials and methods, experimental procedures, useful information, mechanistic studies, 1H NMR spectra, 13C NMR spectra and mass spectrometry data are available in the Supplementary Information. Crystallographic data for compounds 2, 31, 33, 44, 64 and 69 have been deposited with the Cambridge Crystallographic Data Centre, with deposition numbers CCDC 2120242, 2120244, 2120243, 2122516, 2122517 and 2120245, respectively. Correspondence and requests for materials/raw data should be addressed to the corresponding author).

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Acknowledgements

We thank EPSRC (PhD Studentship to L.v.D. and PDRA funding to A.D. (EP/T013419/1)), the Leverhulme Trust (PDRA funding to J.A.R.-A. (RPG-2016-360)) and the University of Manchester (Lectureship to G.E.M.C.) for their generous support. Additionally, we thank the Natrajan group for their assistance with the photophysical studies, and the Leonori group for insightful discussion.

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Author notes

  1. These authors contributed equally: Abhishek Dewanji, Leendert van Dalsen.

Authors and Affiliations

  1. Department of Chemistry, The University of Manchester, Manchester, UK

    Abhishek Dewanji, Leendert van Dalsen, James A. Rossi-Ashton, Eloise Gasson, Giacomo E. M. Crisenza & David J. Procter

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Contributions

J.A.R.-A., G.E.M.C. and D.J.P. conceived the project. L.v.D. and A.D. designed and performed the experimental work, with contributions from J.A.R.-A., E.G. and G.E.M.C. All the authors contributed to the analysis and interpretation of data. G.E.M.C. and D.J.P. wrote the manuscript with input from all the authors.

Corresponding author

Correspondence to David J. Procter.

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Nature Chemistry thanks the anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–5, Schemes 1–3, discussion and Tables 1–17.

Supplementary Data 1

Crystallographic data for compound 2; CCDC reference 2120242.

Supplementary Data 2

Crystallographic data for compound 31; CCDC reference 2120244.

Supplementary Data 3

Crystallographic data for compound 33; CCDC reference 2120243.

Supplementary Data 4

Crystallographic data for compound 44; CCDC reference 2122516.

Supplementary Data 5

Crystallographic data for compound 69; CCDC reference 2120245.

Supplementary Data 6

Crystallographic data for compound 64; CCDC reference 2122517.

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Dewanji, A., van Dalsen, L., Rossi-Ashton, J.A. et al. A general arene C–H functionalization strategy via electron donor–acceptor complex photoactivation. Nat. Chem. 15, 43–52 (2023). https://doi.org/10.1038/s41557-022-01092-y

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