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A hydrogenative oxidation strategy for the single-step synthesis of lactams from N-heteroarenes using water

Nature Catalysis volume 8, pages 98–106 (2025)Cite this article

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Abstract

Using water as a hydrogen or oxygen source in organic synthesis has enabled various reductive and oxidative transformations, but incorporation of both hydrogen and oxygen atoms into the same molecule, representing an atom-economic and environmentally benign process, has scarcely been explored. Here we report a hydrogenative oxidation strategy using water as both a source of H2 and formal oxidant, enabling the direct synthesis of lactams from N-heteroarenes and thereby eliminating the need for additional reductants and oxidants and minimizing waste generation. The reaction can be initiated either under low H2 pressure or with a catalytic amount of H2, leading to the efficient transformation of various N-heteroarenes into lactams in excellent yield thanks to an in situ-generated, piperidine-based, ruthenium pincer complex that balances the hydrogenation and dehydrogenation processes. This study will promote the design of other hydrogenative oxidation reactions using water.

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Fig. 1: Hydrogenative oxidation of N-heteroarenes.
Fig. 2: Condition optimization for catalytic hydrogenative oxidation of quinoline.
Fig. 3: Substrate scope of catalytic hydrogenative oxidation of N-heteroarenes.
Fig. 4: Investigation of the active catalyst.
Fig. 5: Mechanistic study of hydrogenative oxidation of quinoline.

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Data availability

Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2348166 (Ru-9) and CCDC 2348165 (Ru-10). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. Data are available from the corresponding author on request.

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Acknowledgements

We thank I. Efremenko for her valuable assistance with the computational work. C.Y. thanks the Sustainability and Energy Research Initiative-Weizmann Institute of Science for a research fellowship.

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Author notes

  1. These authors contributed equally: Yaoyu Liang, Jie Luo.

Authors and Affiliations

  1. Department of Molecular Chemistry and Materials Science, Weizmann Institute of Science, Rehovot, Israel

    Yaoyu Liang, Jie Luo, Cai You & David Milstein

  2. Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel

    Yael Diskin-Posner

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  1. Yaoyu Liang
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Contributions

D.M., Y.L. and J.L. conceived and directed the project and designed the experiments. Y.L. and J.L. performed and analysed the experiments. C.Y. performed selected experiments and provided insightful discussions. Y.D.-P. analysed crystals. All authors were involved in paper preparation.

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Correspondence to David Milstein.

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Nature Catalysis thanks David Morales-Morales, Jianliang Xiao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Information

Supplementary Notes 1–13, Tables 1–6, Figs. 1–118, methods and references.

Supplementary Data 1

Coordinates for the calculated structures.

Supplementary Data 2

Crystallographic information file for Ru-9.

Supplementary Data 3

Crystallographic information file for Ru-10.

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Liang, Y., Luo, J., You, C. et al. A hydrogenative oxidation strategy for the single-step synthesis of lactams from N-heteroarenes using water. Nat Catal 8, 98–106 (2025). https://doi.org/10.1038/s41929-024-01286-2

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