Part I. Development of a Modular, Air-Stable Nickel Precatalyst; Part II. Nucleophilic (Radio)Fluorination of α-Diazocarbonyl Compounds Enabled by Copper-Catalyzed H–F Insertion

Abstract

Transition-metal catalysis is an enabling strategy for selective bond formation and activation that has become pervasive in modern synthetic organic chemistry. This dissertation outlines two distinct areas in which we contributed to this field:

In Part I, the formulation and implementation of (TMEDA)Ni(o-tolyl)Cl as a new air-stable nickel(II) precatalyst is described. This complex is compatible with a range of reaction conditions and promotes many useful nickel-catalyzed transformations, including various cross-coupling and cyclization reactions. Importantly, the use of TMEDA as a labile supporting ligand enables the exchange with diverse ligand classes, establishing (TMEDA)Ni(o-tolyl)Cl as a modular precatalyst. Investigations into the precatalyst’s activation reveal the mechanism of reduction varies based on the reaction conditions. Evidence supports boron–nickel transmetalation-reductive elimination and nickel–nickel transmetalation-reductive elimination as two possible pathways for activation.

Part II of this dissertation focuses on the development of a copper-catalyzed H–F insertion into α-diazocarbonyl compounds. This strategy takes advantage of the rapid reaction of copper with α-diazocarbonyl substrates to generate a copper carbenoid in situ under mild conditions. Nucleophilic fluorination of this intermediate is then achieved using the combination of potassium fluoride and hexafluoroisopropanol as a reactive equivalent of HF. Details of the initial reaction discovery and optimization of the asymmetric transformation are presented, and further studies examining the scope of the racemic counterpart demonstrate the exceptional functional group tolerance of the method. This approach provides access to valuable α-fluorocarbonyl derivatives, which have broad utility as pharmaceuticals and radiotracers. Furthermore, translation of the method to a radiofluorination protocol was accomplished by using [18F]KF, affording an attractive route to 18F-labeled biomolecules for positron emission tomography.