Palladium-Catalyzed Ligand-Directed C-H and C=C Bond Functionalization.

Abstract

Because of their abundance, C-H bonds are highly attractive starting materials for the elaboration of complex molecules. Transition metal catalysis can enable these typically inert bonds to undergo functionalization via a metal-catalyzed C-H activation step. In particular, ligand-directed PdII/PdIV-catalyzed C-H functionalization reactions have emerged as powerful techniques for diverse bond constructions. Nevertheless, these methodologies face a number of challenges that limit their applicability. These challenges include the common requirement for harsh reaction conditions, the shortage of examples of asymmetric functionalization reactions, and the poor transformability of most directing groups. This thesis describes the development of new methodologies that aim to address these challenges. Chapter 2 describes a new photoredox Pd/Ir-catalyzed C-H arylation reaction that reroutes the mechanism of Pd-catalyzed C-H arylation with diaryliodonium salts from an ionic pathway through a radical-mediated pathway. This radical-mediated transformation proceeds at room temperature in a non-acidic solvent, conditions that are considerably milder than those required for C-H arylation with diaryliodonium salts via a traditional PdII/PdIV mechanism (100 ºC in acetic acid). Chapter 3 details the development of a Pd-catalyzed C-H alkylation reaction that utilizes convenient potassium alkyltrifluoroborate salts in combination with a 1 e- oxidant (MnIII). Several pieces of evidence support an alkyl radical-mediated mechanism for this transformation. The alkylation reaction requires only mild temperatures (25-40 ºC), in contrast to the significantly higher temperatures (70-110 ºC) needed for previous examples of analogous transformations. Chapter 4 describes efforts toward understanding the interplay of chiral directing groups with Pd in the context of high oxidation state Pd catalysis. In this work, we developed a chiral ligand-directed Pd-catalyzed asymmetric alkene dioxygenation reaction. Chapter 5 describes the identification of a transformable directing ligand for Pd-catalyzed C-H functionalization reactions. In situ generated O-acetyl oxime ethers were shown to be effective directing groups that are stable under the reaction conditions required for Pd-catalyzed C-H oxygenation, but can then be readily manipulated to afford ketones, alcohols, amines, and heterocycles.