Work

Carbon-Atom Scavengers Enable Divergent, Selective Carbon Deletion of Azaarenes

Year: 2025

Type: article

Abstract: Divergent synthesis is a powerful strategy that provides simultaneous access to multiple derivatives of a given substrate. However, the emerging developments in skeletal editing have largely delivered methods that lack this potential for diversification. Herein, we report the serendipitous discovery of reagent-controlled selective deletion of C3 or C2 carbon atoms of quinolines, affording indoles. An initial observation that an impurity in commercial samples of DBU promoted cyclization of a benzoxazepine-derived imidate led to the identification of indoline and aminoethanol as C3- and C2-selective carbon-atom scavengers, respectively. These two methods successfully convert a broad scope of quinolines and related azaarenes to the corresponding indoles and azaindoles, enabling divergent carbon deletion. In-depth mechanistic studies support the HFIP-promoted ring opening of 3,1-benzoxazepines to amidine intermediates as a rate-determining step, while providing insights into the selectivity afforded by indoline. These methods and their associated mechanisms offer a blueprint for the rational design of reagent-controlled, divergent skeletal edits.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.5c06577

Authors: Jisoo Woo, Tergitë Zeqiri, Alec H. Christian, Michael C. Ryan, Mark D. Levin

Institutions: University of Chicago, Merck & Co., Inc., Rahway, NJ, USA (United States)

Language: English

Topic: Synthesis of Indole Derivatives

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: Bristol-Myers Squibb Foundation, National Institute of General Medical Sciences, MSD Sharp and Dohme

Award: Construction of Heteroarenes Through Single Atom Insertion Strategies