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Regio-orthogonal single N-atom insertion into indoles via NO translocation

Nature Synthesis (2026)Cite this article

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Abstract

The atom-by-atom manipulation of the core molecular framework has come into reality recently. In particular, the late-stage diversification of robust aza-arenes such as indole has been at the centre of research activity because of its importance in biological and pharmaceutical studies. The previous single-atom modifications of indoles were made possible through the insertion of a reactive nitrene species into the enamine-like C2–C3 bond, resulting in the incorporation of a new atom at the 3-position. Here we discovered an alternative reaction mode, in which the N-nitroso group underwent a sequential intramolecular translocation and deoxygenative rearrangement to afford regiochemically orthogonal 1,4-diazines that had been lacking in skeletal editing. This activation of the nearly inert aromatic C3–C9 bond was applicable to various indoles including bio-relevant molecules to furnish quinoxalines, a class of underexplored pharmacophores. The combined experimental and computational studies revealed the reaction mechanism for the unique selectivity pattern.

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Fig. 1: Research outline.
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Fig. 2: Reaction development.
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Fig. 3: Substrate scope.
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Fig. 4: Synthetic applications.
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Fig. 5: Mechanistic investigations.
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Fig. 6: Computational analysis of the reaction mechanism.
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Data availability

The data supporting the findings of this study are available within this article and its Supplementary Information, which includes experimental details, characterization data, copies of NMR spectra for all new compounds and density functional theory calculation details. The computation output files and the variable time normalization analysis kinetic data are provided as source data. Crystallographic data for 3y have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number CCDC 2418467, which can be accessed free of charge via https://www.ccdc.cam.ac.uk/structures/. All data are available from the corresponding author upon reasonable request. Source data are provided with the paper.

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Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (grant nos. RS-2025-00517801, W.J.C. and RS-2024-00409659, W.J.C.). We thank the Surface Physical Property Laboratory at GIST Advanced Institute of Instrumental Analysis (GAIA) for the X-ray crystallographic analysis of 3y.

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  1. These authors contributed equally: Mugeon Song, Ilju Jeong.

Authors and Affiliations

  1. Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea

    Mugeon Song  (송무건), Ilju Jeong  (정일주), Ha Eun Kim  (김하은), Jaeseong Jin  (진재성), Hyeon Moon  (문현), Jeong Kyun Im  (임정균), Jungi Jung  (정준기), Junhyuk Jo  (조준혁) & Won-jin Chung  (정원진)

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Contributions

W.J.C. conceived of the research concept. M.S. discovered the preliminary reactivity. W.J.C., M.S., and I.J. designed the synthetic strategy. M.S. and I.J. performed the leading synthetic work. M.S., I.J. and H.E.K. designed and performed the mechanistic experiments. H.E.K. and I.J. performed the main computational analysis. J. Jin performed the supporting computational analysis. H.M., J.K.I. and J. Jung performed the supporting synthetic work. J. Jo contributed to the initial idea formulation. W.J.C., M.S. and I.J. wrote the paper. All authors discussed the results, and contributed to editing the paper and preparing the Supplementary Information. M.S. and I.J. contributed equally to this work.

Corresponding author

Correspondence to Won-jin Chung  (정원진).

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Nature Synthesis thanks Yifeng Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Joel Cejas-Sánchez, in collaboration with the Nature Synthesis team.

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Supplementary information

Supplementary Information. (download PDF )

Experimental Details including Notes, Methods, Sections 1–4, Tables 1–3, Figs. 1–3 and NMR spectra.

Supplementary Data 1.

Crystallographic data for compound 3y, CCDC 2418467.

Source data

Source Data Fig. 5. (download XLSX )

Statistical source data file for the kinetic data for variable time normalization analysis in Fig. 5c.

Source Data Fig. 6. (download ZIP )

Computational data and Cartesian coordinates for Fig. 6.

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Song, M., Jeong, I., Kim, H.E. et al. Regio-orthogonal single N-atom insertion into indoles via NO translocation. Nat. Synth (2026). https://doi.org/10.1038/s44160-026-01046-z

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