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C(sp3)–C(sp3) bond formation through nitrogen deletion of secondary amines using O-diphenylphosphinylhydroxylamine

Nature Synthesis volume 3, pages 913–921 (2024)Cite this article

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Abstract

The nitrogen deletion of secondary amines has emerged as an effective strategy for direct molecular skeletal editing and carbon–carbon bond formation. However, current methods are often limited to acyclic bis(α-primary) amines and cyclic amines, which possess two stabilizing elements at the α-position of amine. Here we report the use of O-diphenylphosphinylhydroxylamine as a reagent for nitrogen deletion of secondary amines to form C(sp3)–C(sp3) bonds. This method overcomes substrate requirements of other methods and tolerates a range of secondary amine substrates. The process can be readily applied to multiple nitrogen deletion processes, is tolerant of both air and water, forms water-soluble byproducts and can be readily scaled to a hundred-gram scale. The versatility of the method is further showcased through the direct editing of natural products, pharmaceutical compounds, N-coordinated ligands, a three-dimensional amine cage and the synthesis of several bioactive compounds.

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Fig. 1: N-deletion of secondary amines.
Fig. 2: Optimization of reaction conditions and mechanistic studies.
Fig. 3: Substrate scope of N-deletion.
Fig. 4: Editing and synthesis of bioactive compounds.
Fig. 5: Editing functional N-heterocycles.

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Data availability

The data that support the findings of this study are available within the paper and its supplementary information files.

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Acknowledgements

Financial support for this work was provided by the National Natural Science Foundation of China, 22071100 (H.L.) and 22271148 (H.L.).

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  1. These authors contributed equally: Ting Guo, Jinghao Li.

Authors and Affiliations

  1. School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Ting Guo, Jinghao Li, Zhangkai Cui, Zefan Wang & Hongjian Lu

  2. The Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Normal University, Wuhu, China

    Hongjian Lu

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Contributions

T.G., J.L. and H.L. designed the experiments. T.G., J.L., Z.C. and Z.W. performed the experiments and analysed the data. All authors participated in writing the manuscript. H.L. conceived and supervised the project.

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Correspondence to Hongjian Lu.

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Supplementary Figs. 1–55, characterization data and additional experimental details.

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Guo, T., Li, J., Cui, Z. et al. C(sp3)–C(sp3) bond formation through nitrogen deletion of secondary amines using O-diphenylphosphinylhydroxylamine. Nat. Synth 3, 913–921 (2024). https://doi.org/10.1038/s44160-024-00559-9

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