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Divergent synthesis of N heterocycles from carbocycles enabled by electrochemical nitrogen atom insertion

Nature Synthesis (2025)Cite this article

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Abstract

Skeletal editing via nitrogen atom insertion into cyclic frameworks is a non-conventional and powerful strategy for constructing functionalized N heterocycles—privileged scaffolds in both synthetic chemistry and pharmaceutical science. Despite their importance, general methods for the direct insertion of nitrogen into carbocycles, particularly saturated ones, remain limited due to the challenge of selectively activating of inert C–C bonds. Here we report an electrochemical platform that enables efficient nitrogen atom insertion into saturated carbocycles under mild conditions. Two distinct protocols have been developed, allowing access to either functionalized quinolines or N-alkylated saturated N heterocycles, both with excellent selectivity and broad functional group tolerance. Mechanistic studies reveal the involvement of benzylic carbocation and cyclic imine intermediates, which undergo divergent pathways to furnish structurally diverse products. This methodology for N heterocycle synthesis provides a robust route to bioactive scaffolds. The synthetic utility of the approach is highlighted by the synthesis of two ion-channel antagonists.

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Fig. 1: The importance of nitrogen atom insertion into carbocycles and related approaches.
Fig. 2: Reaction design and optimization for divergent electrochemical nitrogen atom insertion into saturated carbocycles.
Fig. 3: Electrochemical nitrogen atom insertion into indanes towards quinolines.
Fig. 4: Electrochemical nitrogen atom insertion into carbocycles towards alkylated N heterocycles.
Fig. 5: Synthetic applications of this divergent electrochemical nitrogen atom insertion method to provide two potential bioactive molecules.
Fig. 6: Mechanistic studies for divergent electrochemical nitrogen atom insertion of carbocycles.

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Data availability

All other experimental and characterization data are available in Supplementary Information. Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under reference numbers CCDC 2405528 (35) and CCDC 2406850 (54). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures. Source data are provided with this paper.

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Acknowledgements

This research was supported by the Ministry of Education of Singapore Academic Research Fund (tier 1: A-8001693-00-00 (M.J.K.) and A-8001040-00-00 (Y.Z.); tier 2: A-8001893-00-00 (Y.Z.)) and by National University of Singapore Foresight Grant: A-8002845-00-00, A-8002845-01-00 and A-8002845-02-00 (M.J.K.). I. I. Roslan assisted with X-ray crystallographic measurements.

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Author notes

  1. These authors contributed equally: Guo-Quan Sun, Xiyan Wang.

Authors and Affiliations

  1. Department of Chemistry, National University of Singapore, Singapore, Republic of Singapore

    Guo-Quan Sun, Xiyan Wang, Rui Hu, Yu Zhao & Ming Joo Koh

  2. Jiangsu Co-Innovation Center for Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing, China

    Rui Hu & Weidong Rao

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Contributions

G.-Q.S., M.J.K. and Y.Z. conceived of the work. G.-Q.S., X.W., R.H. and W.R. conducted the optimization, reaction scope and mechanistic studies. M.J.K. and Y.Z. directed the research. All authors contributed to the writing of the paper.

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Correspondence to Yu Zhao or Ming Joo Koh.

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Nature Synthesis thanks Xu Cheng and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Stephanie Greed, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information

Experimental details, Supplementary sections 1–13, Figs. 1–15, Tables 1–4 and Scheme 1.

Supplementary Data 1

Raw NMR data for verifying the charge-transfer complex.

Supplementary Data 2

Original data for Supplementary Figs. 4–7.

Supplementary Data 3

Single-crystal X-ray diffraction data for compound 35 (CCDC 2405528).

Supplementary Data 4

Single-crystal X-ray diffraction data for compound 54 (CCDC 2406850).

Source data

Source Data Fig. 6

The raw data for cyclic voltammograms in Fig. 6a,b.

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Sun, GQ., Wang, X., Hu, R. et al. Divergent synthesis of N heterocycles from carbocycles enabled by electrochemical nitrogen atom insertion. Nat. Synth (2025). https://doi.org/10.1038/s44160-025-00945-x

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