Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Shaopeng Liu, Yong Yang, Qingmin Song, Zhaohong Liu (), Paramasivam Sivaguru, Yifan Zhang, Graham Ruiter, Edward A. Anderson () and Xihe Bi ()
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Shaopeng Liu: Northeast Normal University
Yong Yang: Northeast Normal University
Qingmin Song: Northeast Normal University
Zhaohong Liu: Northeast Normal University
Paramasivam Sivaguru: Northeast Normal University
Yifan Zhang: Northeast Normal University
Graham Ruiter: Technion—Israel Institute of Technology
Edward A. Anderson: University of Oxford
Xihe Bi: Northeast Normal University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-54379-8

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