Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than a century of research, Ciamician-D...

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Bibliographic Details
Published in:Nature communications 2024-11, Vol.15 (1), p.9998-12, Article 9998
Main Authors: Liu, Shaopeng, Yang, Yong, Song, Qingmin, Liu, Zhaohong, Sivaguru, Paramasivam, Zhang, Yifan, de Ruiter, Graham, Anderson, Edward A., Bi, Xihe
Format: Article
Language:English
Subjects:
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Carbenes
Carbon
Chemistry
Drug development
Editing
Humanities and Social Sciences
Indoles
Insertion
multidisciplinary
Organic compounds
Precursors
Pyridines
Pyrroles
Quinolines
R&D
Research & development
Scaffolds
Science
Science (multidisciplinary)
Citations: Items that this one cites
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Summary:Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a functionalized carbon atom into heteroarenes remains rare, especially when performed in complex chemical settings. Despite more than a century of research, Ciamician-Dennstedt (C-D) rearrangement remains limited to halocarbene precursors. Herein, we report a general methodology for the Ciamician-Dennstedt reaction using α-halogen-free carbenes generated in situ from N -triftosylhydrazones. This one-pot, two-step protocol enables the insertion of various carbenes, including those previously unexplored in C-D skeletal editing chemistry, into indoles/pyrroles scaffolds to access 3-functionalized quinolines/pyridines. Mechanistic studies reveal a pathway involving the intermediacy of a 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative aromatization to form different carbon-atom insertion products. Ciamician–Dennstedt rearrangement remains limited to halocarbene precursors. Herein, the authors report a general methodology for the Ciamician-Dennstedt reaction using α-halogen-free carbenes generated in situ from N -triftosylhydrazones.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-024-54379-8