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Light-activated hypervalent iodine agents enable diverse aliphatic C–H functionalization

Nature Chemistry volume 17, pages 365–372 (2025)Cite this article

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Abstract

The functionalization of aliphatic C–H bonds is a crucial step in the synthesis and transformation of complex molecules relevant to medicinal, agricultural and materials chemistry. As such, there is substantial interest in the development of general synthetic platforms that enable the efficient diversification of aliphatic C–H bonds. Here we report a hypervalent iodine reagent that releases a potent hydrogen atom abstractor for C–H activation under mild photochemical conditions. Using this reagent, we demonstrate selective (N-phenyltetrazole)thiolation of aliphatic C–H bonds for a broad scope of substrates. The synthetic utility of the thiolated products is showcased through various derivatizations. Simply by altering the radical trapping agent, our method can directly transform C–H bonds into diverse functionalities, including C–S, C–Cl, C–Br, C–I, C–O, C–N, C–C and C=C bonds.

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Fig. 1: Diversification of aliphatic C–H bonds via hydrogen atom transfer.
Fig. 2: Derivatizations of (N-phenyltetrazole)thioethers and tetrazolothiones.
Fig. 3: C–H diversification using PIMS.
Fig. 4: Regiodivergent C–H (N-phenyltetrazole)thiolation.

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Data availability

The data that support the findings of this study are available within the main text and the Supplementary Information. Crystallographic data for the structure reported in this Article has been deposited at the Cambridge Crystallographic Data Centre, under deposition number 2353098 (PIMS). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.

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Acknowledgements

Financial support was provided by the National Institute of Health (R01GM134088 to S.L.) and Genentech (to S.L.). We thank E. Villemure and J. A. Terrett for helpful discussions, I. Keresztes for his help in structural elucidation of complex products, S. N. MacMillan for her help with single-crystal X-ray diffraction experiments, Y. Wang for his help with density functional theory calculations, J. Wright for his help with thermogravimetric analysis and differential scanning calorimetry and W.-C. Lee for reproducing experiments.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA

    Zhipeng Lu, John Putziger & Song Lin

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  1. Zhipeng Lu
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  2. John Putziger
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Contributions

S.L. supervised the project. Z.L. and S.L. conceived the work. Z.L. and S.L. designed the experiments. Z.L. and J.P. conducted synthetic experiments. Z.L. and S.L. wrote the manuscript. J.P. assisted in writing and editing the manuscript.

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Correspondence to Song Lin.

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Nature Chemistry thanks Fateh Singh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Figs. 1–19, Tables 1–4, Materials, Methods, Discussion and NMR spectral data.

Supplementary Data 1

Crystallographic data for compound PIMS; CCDC reference 2353098.

Supplementary Data 2

The xyz coordinates of the density functional theory calculation results.

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Lu, Z., Putziger, J. & Lin, S. Light-activated hypervalent iodine agents enable diverse aliphatic C–H functionalization. Nat. Chem. 17, 365–372 (2025). https://doi.org/10.1038/s41557-025-01749-4

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