Catalytic, Stereoselective Fluorination Reactions

Abstract

In Chapter 1, we describe a general strategy for 1,3-oxidation of cyclopropanes using aryl iodine(I–III) catalysis, with emphasis on 1,3-difluorination reactions. These reactions make use of practical, commercially available reagents and can engage a variety of substituted cyclopropane substrates. Analysis of crystal and solution structures of several of the products reveals the consistent effect of 1,3-difluorides in dictating molecular conformation through dipole minimization effects. Stereochemical analysis of the 1,3-difluorination reaction suggests a mechanism of cyclopropane activation by iodine(III) analogous to that of alkene activation by iodine(III). The generality of this catalytic, cyclopropane C–C bond activation strategy for 1,3-difunctionalization is demonstrated in the synthesis of 1,3-fluoroacetoxy, 1,3-diol, 1,3-amino alcohol and 1,3-diamine products. In Chapter 2, we report the stereoselective synthesis of syn-β-fluoroaziridine building blocks via chiral aryl iodide-catalyzed fluorination of allylic amines. This method employs HF–pyridine as a nucleophilic fluoride source together with mCPBA as a stoichiometric oxidant and affords access to arylethylamine derivatives featuring fluorine-containing stereocenters with high diastereo- and enantioselectivity. Catalyst-controlled diastereoselectivity in the fluorination of chiral allylic amines enables the preparation of highly enantioenriched 1,3-difluoro-2-amines bearing three contiguous stereocenters. This enantioselective, catalytic method is applied successfully to other classes of multifunctional alkene substrates to afford anti-β-fluoropyrrolidines as well as a variety of 1,2-oxyfluorinated products. Finally, in Chapter 3, we discuss a strategy for asymmetric catalysis of carbocationic rearrangements using alkyl iodanes as stereodefined carbocation surrogates. This approach is demonstrated within the context of Wagner-Meerwein rearrangements of β-cumyl-, β-t-butyl- and β-i-propyl-substituted styrenes. Using a nucleophilic fluoride source, this method affords access to highly enantioenriched 1,3-difluorinated products. Hammett, kinetic isotope effect and computational studies reveal that the enantiodetermining step can vary between intermolecular fluoride attack and intramolecular 1,2-migration depending on the nature of the migrating group. As a competition between external and internal nucleophilic attack is prevalent in iodine(III)-mediated difunctionalization reactions of alkenes, these studies also potentially provide general insight into the mechanisms involved in iodine(III) chemistry.