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Cobalt-catalysed alkene hydronitration enabled by anomeric nitroamide

Nature Catalysis volume 8, pages 457–464 (2025)Cite this article

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Abstract

Tertiary nitroalkanes, as well as their reduced products, α-tertiary amines, play an essential role in drug discovery as either key synthetic precursors or final motifs in targeted molecules. Existing methods to prepare tertiary nitro compounds generally rely on polar-bond disconnections, in which strong bases or highly active electrophiles are needed. Here we report the development of an anomeric nitroamide-based reagent that enables selective metal-hydride hydrogen atom transfer-based Co-catalysed alkene hydronitration for the preparation of valuable tertiary nitro compounds. This mild, scalable reaction shows broad functional group tolerance. Its synthetic application is demonstrated via late-stage nitration of complex alkenes derived from drugs and natural products, and simplifying the synthesis of a rare naturally occurring nitro sugar. Simple access to isotopically labelled 15N-containing nitro compounds is also disclosed. The anomeric nitroamide reagent was deemed safe by energetic measurements and its reactivity rationalized based on X-ray crystallographic analysis.

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Fig. 1: Strategies to access tertiary nitroalkanes.
Fig. 2: Reaction optimization and comparison of 16 with precedented nitrating agents.
Fig. 3: Substrate scope of alkene hydronitration.
Fig. 4: Synthetic applications.
Fig. 5: Mechanistic discussion.

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Data availability

The data supporting the findings of this study are available within the Article and its Supplementary Information. Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under the deposition numbers CCDC 2385494 (16), 2329539 (27), 2329540 (35A), 2383725 (35B), 2380454 (36), 2373356 (39), 2376555 (40), 2376557 (41), 2377801 (42), 2377800 (43), 2375144 (48), 2376556 (50), 2373359 (51), 2383726 (56), 2377632 (58), 2375142 (60), 2382868 (62), 2380180 (63) and 2382867 (67). 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 for this work was provided by the National Institutes of Health (grant no. GM-118176, to P.S.B.). We thank L. Pasternack and G. J. Kroon (Scripps Research) for assistance with NMR spectroscopy; J. Lee, B. Sanchez and Q. N. Wong (Scripps Research ASF) for HRMS; and A. Pollatos for proofreading.

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Authors and Affiliations

  1. Department of Chemistry, Scripps Research, La Jolla, CA, USA

    Yu Wang, Marcell M. Bogner & Phil S. Baran

  2. Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA

    Jake B. Bailey & Milan Gembicky

  3. Chemical Process Development, Bristol Myers Squibb, New Brunswick, NJ, USA

    Lauren N. Grant

  4. Oncology Medicinal Chemistry Department, Pfizer Medicine Design, La Jolla, CA, USA

    Paul F. Richardson

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  1. Yu Wang
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Contributions

Y.W. and P.S.B. conceptualized the study and developed the reagents. Y.W. conducted reaction optimization. Y.W. and M.M.B. contributed to the substrate scope and analysed the data. L.N.G. performed computational experiments. P.F.R. performed the safety experiments. J.B.B. and M.G. performed the X-ray crystallographic analysis. Y.W., M.M.B. and P.S.B. wrote the paper. P.S.B. supervised this work. All authors contributed to discussions.

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Correspondence to Phil S. Baran.

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Nature Catalysis thanks Qian Zhang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Tables 1–34, Figs. 1–14, experimental procedures, product characterization and NMR spectra.

Supplementary Data 1

Crystallographic data.

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Wang, Y., Bogner, M.M., Bailey, J.B. et al. Cobalt-catalysed alkene hydronitration enabled by anomeric nitroamide. Nat Catal 8, 457–464 (2025). https://doi.org/10.1038/s41929-025-01336-3

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