Halogen-Free Ciamician-Dennstedt Single-Atom Skeletal Editing

Author:

Bi Xihe1ORCID,Liu Shaopeng1,Yang Yong1,Song Qingmin1,Liu Zhaohong1ORCID,Sivaguru Paramasivam1ORCID,Zhang Yifan1,Ruiter Graham2,Anderson Edward3ORCID

Affiliation:

1. Northeast Normal University

2. Schulich Faculty of Chemistry, Technion - Israel Institute of Technology

3. University of Oxford

Abstract

Abstract

Single-atom skeletal editing is an increasingly powerful tool for scaffold hopping-based drug discovery. However, the insertion of a single functionalized carbon atom into heteroarenes remains exceedingly rare, especially when performed in complex chemical settings, due to the challenge of overcoming aromaticity without uncontrolled degradation. For example, the Ciamician–Dennstedt rearrangement, in which a carbene is inserted into an indole or pyrrole ring, remains limited to halocarbene precursors despite more than a century of research. Herein, we report a general methodology for the halogen-free Ciamician-Dennstedt reaction, which enables the direct conversion of indoles/pyrroles into structurally diverse quinoline/pyridine scaffolds. The generality and applicability of this methodology were demonstrated by extensive scope investigation and product derivatizations, as well as by concise syntheses and late-stage skeletal editing of complex bioactive compounds. Mechanistic studies reveal a pathway that involves the intermediacy of a 1,4-dihydroquinoline intermediate, which could undergo oxidative aromatization or defluorinative aromatization to form different carbon-atom insertion products.

Publisher

Research Square Platform LLC

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