Skeletal editing by iron-catalyzed carbene insertion of trichloromethanes.
Abstract
Direct interchange between five- and six-membered nitrogen heterocycles by skeletal editing is valuable in drug discovery. Specifically, inserting a carbon atom into oxidatively prone indole affords metabolically stable quinoline. However, tailored reagents for this transformation are limited by safety, availability, and generality. Here, we introduce a C-insertion method that employs stable, commercially abundant trichloromethanes (as chlorocarbene precursors) and simple iron catalysts (FeCl<sub>2</sub>) to directly transform indoles to diverse quinolines. This highly practical method allows rare access to direct C-H and C-D insertion (essential analogs in medicinal chemistry) and many other pharmacophores. Mechanistic studies show key differences in rate, reactivity, and selectivity of this iron carbene versus metal-free carbenes. In addition, the skeletal editing of several drug-like molecules is presented, including a one-step synthesis of a quinoline analog of the psychedelic indole lysergic acid diethylamide (LSD). This analog exhibits lower potency and efficacy for activating 5-HT2A receptors, suggesting therapeutic potential with reduced hallucinogenic properties.
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