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

Abstract

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.

Solvent- and catalyst-dependent palladium-catalyzed switchable chemodivergent cascade cyclizations of trimethylenemethanes with ortho-formyl cinnamates

“…Surprisingly, an array of N -aryl substituted ureas and thioureas gave better results (entries 11–16), in which both the reactivity and yield were enhanced dramatically. Schreiner's urea C6 10 with a bis(3,5-trifluoromethyl)phenyl group proved to be the best HBD catalyst, giving 4a in 92% yield (entry 14). It should be noted that the bifunctional urea C8 was also tested to afford 4a in 91% yield (entry 16).…”