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Photocatalytic α-arylation of cyclic ketones

Nature Synthesis volume 1, pages 147–157 (2022)Cite this article

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Abstract

The direct α-arylation of carbonyl compounds using aryl halides represents a powerful method to synthesize critical building blocks for diverse useful compounds. Numerous synthetic methods exist to forge C(sp2)–C(sp3) bonds although mild and metal-free direct α-arylation of ketones remains a challenging transformation. Here we report a green-light-mediated α-arylation of ketones from readily available aryl halides via activation of a C(sp2)–X bond (X = I, Br, Cl) and an α-carbonyl C(sp3)–H bond in a single photocatalytic cycle. This approach is characterized by its mild reaction conditions, operational simplicity and wide functional group tolerance. Importantly, the impressive outcome of the multigram photocatalytic reaction underpins the strength of this method as a potentially practical and attractive approach for scale-up industrial purposes. The utility and scope of this reaction were further demonstrated by formal syntheses of several feedstock chemicals that are commercially expensive but critical for synthesizing numerous pharmaceutical agents.

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Fig. 1: Photoredox activation for the α-arylation of cyclic ketones.
Fig. 2: Development of the photoreducing acridiniums.
Fig. 3: Realization of a photocatalytic α-arylation of ketones.
Fig. 4: Synthetic applications.
Fig. 5: Mechanistic insight into the photoredox α-arylation of ketones.
Fig. 6: Proposed mechanistic pathways of photoredox α-arylation of ketones.

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Data and materials availability

All data are available in the manuscript or the supplementary materials. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2085196, 2085197, 2085198 and 2085199. Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

This work is supported by The University of Arizona, the ACS Petroleum Research Fund under grant number 59631, and the National Science Foundation under CAREER award grant number 2144018. The purchase of the Bruker NEO 500 MHz spectrometer was supported by the National Science Foundation under grant number 1920234, and the University of Arizona. We are grateful to V. Huxter and A. Kumar for helping us with the transient absorption spectroscopy. We thank E. Tomat and C. Curtis for the spectroelectrochemical experiments. We thank A. Silswal for helping with the lifetime measurement. We also thank J. Njardarson at The University of Arizona and R.G. Bergman at the University of California, Berkeley for valuable discussions. All NMR data were collected in the NMR facility of the Department of Chemistry and Biochemistry at the University of Arizona, and we thank J. Dai and V. Kumirov for their help. We are also thankful to W. Wang and Y. Dong at The University of Arizona.

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Author notes

  1. These authors contributed equally: Md Mubarak Hossain, Aslam C. Shaikh.

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ, USA

    Md Mubarak Hossain, Aslam C. Shaikh, Jules Moutet & Thomas L. Gianetti

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Contributions

T.L.G. conceived the idea and supervised the work. M.M.H. performed the synthesis of Acr 6–8, their characterization and the catalytic reaction condition optimizations. M.M.H. and A.C.S. synthesized the starting materials, performed the catalytic transformations and characterized the products formed. A.C.S. performed the lifetime measurements, and M.M.H. performed the absorption and emission measurements. J.M. conducted the cyclic voltammetry and X-ray diffraction measurements. M.M.H. and T.L.G. prepared the manuscript for publication.

Corresponding author

Correspondence to Thomas L. Gianetti.

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Competing interests

T.L.G. and M.M.H. (The University of Arizona) are pursuing a provisional patent on this work. A.C.S. and J.M. declare no competing interests.

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Nature Synthesis thanks the anonymous reviewers for their contribution to the peer review of this work. Thomas West was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Supplementary information

Supplementary materials and methods, text, Figs. 1–16 and Tables 1–14.

Supplementary Data 1

Crystallographic data of acridinium 7 (CCDC 2085196).

Supplementary Data 2

Crystallographic data of acridinium 8 (CCDC 2085197).

Supplementary Data 3

Crystallographic data of compound 11 (CCDC 2085198).

Supplementary Data 4

Crystallographic data of compound 46 (CCDC 2085199).

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Hossain, M.M., Shaikh, A.C., Moutet, J. et al. Photocatalytic α-arylation of cyclic ketones. Nat Synth 1, 147–157 (2022). https://doi.org/10.1038/s44160-021-00021-0

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