Halogencarbene-free Ciamician-Dennstedt single-atom skeletal editing

Journal article

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.

Authors: Liu, S; Yang, Y; Song, Q; Liu, Z; Sivaguru, P

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 15
• Issue: 1
• Article number: 9998
• Publication date: 2024-11-19
• Acceptance date: 2024-11-10
• DOI: 10.1038/s41467-024-54379-8
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English