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Accessing sulfonamides via formal SO2 insertion into C–N bonds

Nature Chemistry volume 17, pages 1247–1255 (2025)Cite this article

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Abstract

Functional group interconversions are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here we report SO2 insertion into the C–N bond of primary amines, enabling the direct synthesis of primary sulfonamides without preactivation and effectively inverting the nitrogen’s properties (acidity, hydrogen bonding and so on). The key to this transformation is the implementation of an anomeric amide as a dual-function reagent that both serves to cleave the initial C–N bond and delivers a nitrogen atom to the product after SO2 incorporation. The process tolerates a wide array of functionalities and can be run in an automated fashion, thus allowing libraries of amines to be viable progenitors to highly desirable sulfonamides. Mechanistic studies support an isodiazene radical chain mechanism that generates an intermediate sulfinate that reacts with the anomeric amide to forge the S–N bond. Our protocol was used to conduct a high-throughput library diversification campaign, was applied to the synthesis and modification of approved active pharmaceutical ingredients and was used to enable a net CO-to-SO2 isosteric replacement approach.

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Fig. 1: Overview.
Fig. 2: Automating SO2 insertion for rapid library conversion.
Fig. 3: Synthetic utility.
Fig. 4: Mechanistic investigations.
Fig. 5: Mechanism and DFT calculations.

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Data availability

All data are available in the Supplementary Information.

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Acknowledgements

M.K. thanks the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (grant number RS-2023-00237898) for a postdoctoral fellowship. The research reported in this work was supported by a National Science Foundation CAREER Award (2235826) and by Johnson and Johnson Innovative Medicine. M.K. thanks the Korea Advanced Institute of Science and Technology (KAIST) and the Institute for Basic Science (IBS) for providing computational resources. We also thank S. Wolkenberg (Johnson & Johnson) for useful discussions and feedback.

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Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Myojeong Kim, Carys E. Obertone & Mark D. Levin

  2. Discovery Process Research, Johnson & Johnson Innovative Medicine, Spring House, PA, USA

    Christopher B. Kelly

  3. Parallel Medicinal Chemistry, Johnson & Johnson Innovative Medicine, Spring House, PA, USA

    Christopher A. Reiher

  4. High-Throughput Purification, Johnson & Johnson Innovative Medicine, Spring House, PA, USA

    Cristina Grosanu

  5. In Silico Discovery, Johnson & Johnson Innovative Medicine, Spring House, PA, USA

    James C. Robertson

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Contributions

M.K., C.E.O. and C.B.K. designed and conducted experiments and collected and analysed the data. M.K. conducted the computational mechanistic evaluation. C.A.R. and C.G. conducted the high-throughput parallel synthesis experiments. J.C.R. conducted the docking study. M.D.L. and M.K. conceived of the project and wrote the manuscript with input from all authors. M.D.L. and C.B.K. supervised the research.

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Correspondence to Christopher B. Kelly, Christopher A. Reiher or Mark D. Levin.

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Kim, M., Obertone, C.E., Kelly, C.B. et al. Accessing sulfonamides via formal SO2 insertion into C–N bonds. Nat. Chem. 17, 1247–1255 (2025). https://doi.org/10.1038/s41557-025-01848-2

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