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Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(ii) carboxylates

Nature Chemistry volume 14, pages 94–99 (2022)Cite this article

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Abstract

Reactions that enable carbon–nitrogen, carbon–oxygen and carbon–carbon bond formation lie at the heart of synthetic chemistry. However, substrate prefunctionalization is often needed to effect such transformations without forcing reaction conditions. The development of direct coupling methods for abundant feedstock chemicals is therefore highly desirable for the rapid construction of complex molecular scaffolds. Here we report a copper-mediated, net-oxidative decarboxylative coupling of carboxylic acids with diverse nucleophiles under visible-light irradiation. Preliminary mechanistic studies suggest that the relevant chromophore in this reaction is a Cu(ii) carboxylate species assembled in situ. We propose that visible-light excitation to a ligand-to-metal charge transfer (LMCT) state results in a radical decarboxylation process that initiates the oxidative cross-coupling. The reaction is applicable to a wide variety of coupling partners, including complex drug molecules, suggesting that this strategy for cross-nucleophile coupling would facilitate rapid compound library synthesis for the discovery of new pharmaceutical agents.

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Fig. 1: Common strategies for decarboxylative coupling usually involve prefunctionalizations of either or both reacting partners, whereas the current strategy enables direct decarboxylative coupling.
Fig. 2: Mechanistic studies.

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All data supporting the findings of this study are available within the paper and its Supplementary Information.

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Acknowledgements

We thank W. B. Swords for helpful discussions. Funding for this work was provided by the NIH (R01GM095666, T.P.Y.), an ACS GCI Pharmaceutical Roundtable Research Grant (T.P.Y.) and Pfizer (T.P.Y.). S.N.G. thanks the NIH for a fellowship grant (F32GM139373) and G.A.L. is the recipient of a 3M Science & Technology Fellowship. Analytical facilities at UW–Madison are funded by the NIH (S10OD012245), NSF (CHE-9304546) and a generous gift from the Paul J. and Margaret M. Bender Fund.

Author information

Author notes

  1. These authors contributed equally: Qi Yukki Li, Samuel N. Gockel.

Authors and Affiliations

  1. Department of Chemistry, University of Wisconsin–Madison, Madison, WI, USA

    Qi Yukki Li, Samuel N. Gockel, Grace A. Lutovsky, Kimberly S. DeGlopper & Tehshik P. Yoon

  2. Medicine Design, Pfizer Inc, Groton, CT, USA

    Neil J. Baldwin, Mark W. Bundesmann, Joseph W. Tucker & Scott W. Bagley

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Contributions

Q.Y.L., S.N.G., G.A.L., K.S.D. and T.P.Y. conceived the project. Experimental work was conducted by Q.Y.L., S.N.G., N.J.B., M.W.B. and J.W.T. S.W.B. and T.P.Y. supervised the research. All authors contributed to the writing and editing of the manuscript.

Corresponding author

Correspondence to Tehshik P. Yoon.

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Competing interests

N.J.B., M.W.B., J.W.T. and S.W.B. are employees and shareholders of Pfizer, Inc. The remaining authors declare no competing interests.

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Peer review information Nature Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

General information, select optimization results, substrate preparation, isolation and characterization, additional mechanistic studies, references, spectral data, Tables 1–25 and Figs. 1–10.

Supplementary Data 1

An excel spreadsheet containing the raw data obtained from the UV–vis spectrometer for the carboxylate titration study. A brief walkthrough of the data processing to obtain the final, published plot is included.

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Li, Q.Y., Gockel, S.N., Lutovsky, G.A. et al. Decarboxylative cross-nucleophile coupling via ligand-to-metal charge transfer photoexcitation of Cu(ii) carboxylates. Nat. Chem. 14, 94–99 (2022). https://doi.org/10.1038/s41557-021-00834-8

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