Studies in Nickel-Catalyzed Cross Coupling: Mechanistic Investigations of Iminium Oxidative Addition and the Development of a Phosphine Framework for Nickel Catalysis

Abstract

Transition metal-catalyzed cross coupling has developed into one of the most

powerful synthetic strategies in all of chemistry. Crucial to the success of cross coupling

has been its incredible versatility in terms of coupling partner scope and the development

of highly active Pd catalysts which permit coupling under extremely mild conditions.

In this thesis, we describe two projects in the rapidly growing field of Nicatalyzed cross coupling. First, we disclose mechanistic studies on the oxidative addition

of iminium ions to nickel in the context of catalytic reactions. Iminium and oxocarbenium

ions are an underexplored class of electrophiles, and their incorporation into cross

coupling could yield valuable α-substituted amines and ethers. Organometallic and

stereochemical studies in support of the iminium mechanism are reported, as well as

examples of oxidative addition to iminium salts in catalytic contexts.

Second, we detail the development and structural characterization of a modular

and novel class of phosphines for enabling Ni catalysis. Our studies find that existing

ligands, including those designed for Pd, are ineffective in the Ni-catalyzed Suzuki

coupling of acetals, prompting us to investigate new phosphine architectures. The

properties of the phosphine ligands are quantified using molecular parameters.

Regression analysis identifies a correlation between remote steric hindrance and ligand

effectiveness, a concept that could guide future ligand design for nickel. Our study also

uncovers a disparity between cone angle and % buried volume, two steric parameters

previously believed to be equivalent. We expect that research disclosed in this thesis will

benefit the field of Ni-catalyzed cross coupling by both expanding the substrate scope

and enhancing the activity of Ni catalysts.