Regiodivergent Nucleophilic Fluorination under Hydrogen Bonding Catalysis: A Computational and Experimental Study.
Horwitz MA., Dürr AB., Afratis K., Chen Z., Soika J., Christensen KE., Fushimi M., Paton RS., Gouverneur V.
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.