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

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.