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Unlocking carbene reactivity by metallaphotoredox α-elimination

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Abstract

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon–metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis3,4,5,6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon–metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N–H, S–H and P–H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

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Fig. 1: Enabling carbene reactivity by radical intermediates.
Fig. 2: Scope of photoredox-enabled iron carbene cyclopropanation using carboxylic acids as precursors.
Fig. 3: Scope of tri- and difluoromethyl cyclopropanation through carbene metallaphotoredox.
Fig. 4: Insertions of σ-bond through metallaphotoredox carbene formation.

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Data availability

All data supporting the findings of this study are available in the main text or in the Supplementary Information.

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Acknowledgements

We acknowledge A. Y. Chan, C. P. Seath, J. A. Rossi-Ashton, R. T. Smith, C. A. Gould and A. Long for their discussions. We also thank R. M. Lambert for assisting with the preparation of this paper. Research reported in this work was supported by the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (R35GM134897), the Princeton Catalysis Initiative, Janssen R&D, and gifts from Merck, Pfizer, Bristol-Myers Squibb, Genentech and Genmab. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS.

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Author notes

  1. These authors contributed equally: Benjamin T. Boyle, Nathan W. Dow

Authors and Affiliations

  1. Merck Center for Catalysis, Princeton University, Princeton, NJ, USA

    Benjamin T. Boyle, Nathan W. Dow & David W. C. MacMillan

  2. Discovery Process Research, Janssen Research & Development, Spring House, PA, USA

    Christopher B. Kelly

  3. Therapeutics Discovery, Janssen Research & Development, Spring House, PA, USA

    Marian C. Bryan

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Contributions

D.W.C.M., N.W.D. and B.T.B. conceptualized the radical approach to carbenes. B.T.B., N.W.D., C.B.K. and M.C.B. designed the experiments. B.T.B. and N.W.D. performed and analysed the experiments. B.T.B., C.B.K., M.C.B., N.W.D. and D.W.C.M. prepared the Article. D.W.C.M. directed the project.

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Correspondence to David W. C. MacMillan.

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D.W.C.M. declares an ownership interest in Penn PhD photoreactor, which is used to irradiate reactions in this work. The other authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Proposed mechanism for iron porphyrin carbene formation through metallaphotoredox catalysis.

Metallaphotoredox-mediated formation of iron porphyrin carbene intermediates exploiting a single-electron reduction mediated α-elimination. Me, methyl; Et, ethyl, Ac, acetyl; Phth, phthalimide; HEH•+, oxidized Hantzsch ester; Ir, Ir(dFCF3ppy)2dttbpy; Fe, iron porphyrin. For further commentary and discussion see Supplementary Fig. 1.

Supplementary information

Supplementary Information

This file contains the following sections: General Information, Optimization Studies, Control Experiments, Mechanistic Studies, General Procedures, Characterization Data, References and Spectra.

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Boyle, B.T., Dow, N.W., Kelly, C.B. et al. Unlocking carbene reactivity by metallaphotoredox α-elimination. Nature (2024). https://doi.org/10.1038/s41586-024-07628-1

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