Reactivity and Selectivity in Aryl C–H Functionalization by Electrophilic Radicals

Abstract

Two main challenges hinder the development of new, broadly useful C–H functionalization reactions: (1) most C–H bonds constitute part of the relatively inert backbone of an organic molecule, so it is difficult to elicit sufficient reactivity from these bonds, and (2) C–H bonds are ubiquitous in organic molecules, so it is difficult to control the selectivity of which C–H bond is functionalized. The subject of this thesis is the functionalization of C–H bonds in aromatic molecules. In addition to the relevant background, herein are described two new reactions which address the challenges of reactivity and selectivity in C–H functionalization described above.

In Chapter 1 is described a new reaction in which an amine-N-oxide-ligated palladium complex, in conjunction with a silver cocatalyst, catalyzes imidation of arenes by the reagent N-fluorobenzenesulfonimide. The reaction enables imidation of a variety of arenes at or below room temperature, requires no coordinating directing group on the substrate, and gives synthetically useful yields with the arene as the limiting reagent. Mechanistic data is presented which implicates an unusual mechanism devoid of commonly invoked organometallic intermediates: oxidation of the palladium catalyst occurs as the turnover-limiting step, while C–H bond functionalization occurs subsequently at a higher oxidation state of the catalyst. The unusual imidation reactivity is ascribed to unique features of the amine-N-oxide ligand, which are also discussed.

Described in Chapter 2 is a new radical aromatic substitution reaction with nearly complete para selectivity for a variety of monosubstituted arenes. We present a rationale for the unprecedented degree of positional selectivity exhibited by the reaction: we propose that arene-to-radical charge transfer in the transition state of radical addition, elicited by the unusually high electron affinity of the radical, is the factor primarily responsible for the positional selectivity. The utility of the reaction is illustrated by a direct synthesis of aryl piperazines, a common motif in medicinal chemistry.