Application of Photoredox Catalysis to the Direct alpha-Functionalization of Amines

Abstract

Photoredox catalysis has recently emerged as a powerful means of activating organic molecules for a wide range of valuable synthetic transformations. This field of research employs a number of visible light-absorbing species as catalysts, among which polypyridyl complexes of ruthenium or iridium are the most common. The photoexcited states of these complexes may engage in single-electron transfer with organic molecules, generating diverse useful open-shell (radical) intermediates. These reactions employ readily available light sources and catalysts and typically proceed under mild conditions. Photoredox catalysis is most notable, however, for its ability to promote unique and unusual bond constructions not accessible using existing synthetic methods.

This dissertation describes the application of photoredox catalysis to the development of several amine alpha-functionalization reactions, specifically via the generation of alpha-amino radical intermediates. These unique open-shell intermediates allow for the direct functionalization of a C-H bond adjacent to nitrogen, a transformation for which few general strategies exist.

Employing photoredox catalysis, two distinct mechanisms have been exploited for the alpha-arylation of amines, a transformation that delivers benzylic amine pharmacophores valuable in medicinal chemistry. First, Chapter 2 describes the alpha-arylation of tertiary amines with cyanoarenes, a reaction proposed to proceed via radical-radical coupling of an alpha-amino radical with an arene radical anion. Chapter 3 then describes amine alpha-heteroarylation reactions proceeding via a homolytic aromatic substitution pathway, in which nucleophilic alpha-amino radicals are proposed to directly engage electrophilic chloroheteroarenes. Finally, the reversibility of alpha-amino radical formation allows for the incorporation of deuterium at amine alpha-positions. Chapter 4 describes efforts to harness this pathway for the development of a synthetically useful protocol for the isotopic labeling of amines.