Iodine(III)-Catalyzed, Enantioselective 1,2-Difluorination of Cinnamamides

Abstract

Iodine(III) catalysis has emerged as an effective strategy for enabling a wide range of alkene difunctionalization reactions. In Chapter 1, we describe the development of an enantioselective 1,2-difluorination of cinnamamides catalyzed by chiral aryl iodides. Using HF-pyridine as a fluoride source and mCPBA as a stoichiometric oxidant, the aryl iodide catalyst can be oxidized in situ to an iodoarene difluoride, which difluorinates cinnamamide substrates. These reactions can afford both 1,2-difluoride and rearranged 1,1-difluoride products arising from competing anchimeric assistance pathways. We identified that selectivity for the 1,2-difluorination pathway can be achieved by incorporation of an N-tert-butyl amide substituent into the substrate and by tuning the HF loading. The products of the reaction and their derivatives contain vicinal, fluoride-bearing stereocenters and may serve as building blocks for the preparation of compounds including this motif. In Chapter 2, we describe the synthesis of chiral iodoarene difluorides via the direct oxidation of iodoarenes with XeF2. When reacted with an alkene in biphasic HF-pyridine/dichloromethane these compounds recapitulate the catalytic reactivity described in Chapter 1, and studies in the isolated phases of the reaction mixture indicate that steps involving substrate fluorination likely take place in the HF-pyridine layer. Studies of the stoichiometric reactivity of chiral iodoarene difluorides have also revealed that HF is not required to activate them toward reaction with alkenes; the homogeneous, stoichiometric reaction between a chiral iodoarene difluoride and a cinnamamide substrate proceeds with high chemoselectivity and enantioselectivity in hexafluoroisopropanol. In Chapter 3, we report progress toward the development of an electrocatalytic 1,2-difluorination of alkenes. We found that p-iodotoluene catalyzes the electrochemical difluorination of a terminal alkene substrate in hexafluoroisopropanol solvent with Et3N-3HF as the fluoride source. We also examined resorcinol-derived catalysts in this transformation and identified catalyst features that impact reactivity, gaining insights that could potentially inform development of chiral catalysts compatible with electrochemical oxidation.