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Regiodivergent Nucleophilic Fluorination under Hydrogen Bonding Catalysis: A Computational and Experimental Study.

Matthew A HorwitzAlexander B DürrKonstantinos AfratisZijun ChenJulia SoikaKirsten E ChristensenMakoto FushimiRobert S PatonVéronique Gouverneur
Published in: Journal of the American Chemical Society (2023)
The controlled programming of regiochemical outcomes in nucleophilic fluorination reactions with alkali metal fluoride is a problem yet to be solved. Herein, two synergistic approaches exploiting hydrogen bonding catalysis are presented. First, we demonstrate that modulating the charge density of fluoride with a hydrogen-bond donor urea catalyst directly influences the kinetic regioselectivity in the fluorination of dissymmetric aziridinium salts with aryl and ester substituents. Moreover, we report a urea-catalyzed formal dyotropic rearrangement, a thermodynamically controlled regiochemical editing process consisting of C-F bond scission followed by fluoride rebound. These findings offer a route to access enantioenriched fluoroamine regioisomers from a single chloroamine precursor, and more generally, new opportunities in regiodivergent asymmetric ( bis )urea-based organocatalysis.
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