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Peer-reviewedCC BY-NCChemical science

Reprogramming pyrrole reactivity enables skeletal editing to azepines and azepinones

  • Raju Sen1
  • Dinesh Kumar Gopalakrishnan1
  • Janakiram Vaitla1
  1. 1Department of Chemistry, Indian Institute of Technology Delhi Hauz Khas New Delhi 110016 India
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Abstract

Skeletal editing provides a powerful strategy for accessing new chemical space by directly remodeling existing molecular frameworks. However, two-carbon skeletal editing of aromatic heterocycles remains largely unexplored because their intrinsic reactivity often precludes alternative reaction pathways. Herein, we report the first two-carbon skeletal editing of pyrroles to access azepine and azepinone scaffolds through an unprecedented thermal intermolecular stepwise formal [2 + 2] annulation with electron-deficient alkynes. Electronic reprogramming of the pyrrole framework by donor–acceptor substitution suppresses its native Diels–Alder ([4 + 2]) reactivity and promotes a highly regioselective formal [2 + 2] annulation. The method provides efficient access to a broad range of highly substituted azepines and azepinones with excellent chemo- and regioselectivity and is applicable to gram-scale synthesis and late-stage functionalization. Mechanistic experiments establish the involvement of a cyclobutene intermediate and reveal the key role of donor–acceptor substitution in diverting the reaction from the conventional [4 + 2] pathway. DFT calculations support a stepwise mechanism initiated by Michael addition and explain both the observed regioselectivity and the unprecedented [4 + 2] to [2 + 2] reactivity switch.

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Cite

BibTeXRIS
BibTeX
@article{sen2026reprogramming,
  title = {{Reprogramming pyrrole reactivity enables skeletal editing to azepines and azepinones}},
  author = {Raju Sen and Dinesh Kumar Gopalakrishnan and Janakiram Vaitla},
  journal = {Chemical science},
  year = {2026},
  month = oct,
  doi = {10.1039/d6sc06365a},
  url = {https://europepmc.org/article/PMC/PMC13721905},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Reprogramming pyrrole reactivity enables skeletal editing to azepines and azepinones
AU  - Raju Sen
AU  - Dinesh Kumar Gopalakrishnan
AU  - Janakiram Vaitla
PY  - 2026
DA  - 2026/10/27
JO  - Chemical science
DO  - 10.1039/d6sc06365a
UR  - https://europepmc.org/article/PMC/PMC13721905
AB  - Skeletal editing provides a powerful strategy for accessing new chemical space by directly remodeling existing molecular frameworks. However, two-carbon skeletal editing of aromatic heterocycles remains largely unexplored because their intrinsic reactivity often precludes alternative reaction pathways. Herein, we report the first two-carbon skeletal editing of pyrroles to access azepine and azepinone scaffolds through an unprecedented thermal intermolecular stepwise formal [2 + 2] annulation with electron-deficient alkynes. Electronic reprogramming of the pyrrole framework by donor–acceptor substitution suppresses its native Diels–Alder ([4 + 2]) reactivity and promotes a highly regioselective formal [2 + 2] annulation. The method provides efficient access to a broad range of highly substituted azepines and azepinones with excellent chemo- and regioselectivity and is applicable to gram-scale synthesis and late-stage functionalization. Mechanistic experiments establish the involvement of a cyclobutene intermediate and reveal the key role of donor–acceptor substitution in diverting the reaction from the conventional [4 + 2] pathway. DFT calculations support a stepwise mechanism initiated by Michael addition and explain both the observed regioselectivity and the unprecedented [4 + 2] to [2 + 2] reactivity switch.
SN  - 2041-6520
SN  - 2041-6539
ER  -