Development and Mechanistic Studies of Palladium-Catalyzed Ligand-Directed C-H Bond Functionalization Reactions.

Abstract

C−H bonds are abundant in organic molecules and have great potential to be utilized as starting materials for the functionalization of many pharmaceuticals and natural products. With the use of Pd-catalysts these typically inert bonds can be activated and transformed into diverse functional groups and more complex products. Substrates with coordinating ligands can direct activation/functionalization to a specific C−H bond and help to overcome issues of site-selectivity. However, many functionalization reactions require high temperatures and forcing reaction conditions. Herein we report Pd-catalyzed C–H functionalization reactions with milder conditions as well as a mechanistic study to improve reaction conditions and increase understanding. Chapter 1 introduces these ideas with subsequent chapters devoted to the study of specific methodologies. Chapter 2 details the palladium-catalyzed C−H fluorination of 8-methylquinoline derivatives with nucleophilic fluoride. This transformation involves the use of AgF as the fluoride source in combination with a hypervalent iodine oxidant. The scope and mechanism of the reaction are discussed. In an effort to explore conditions relevant for PET imaging, short reaction times were investigated for this transformation. Chapter 3 describes the development of a room-temperature ligand-directed C−H arylation reaction using aryldiazonium salts. This was achieved by the successful merger of palladium-catalyzed C−H functionalization and visible-light photoredox catalysis. The unusually mild conditions utilized in this transformation (room temperature, CH3OH solvent) are proposed to be due to the kinetically reactive aryl radical oxidants formed under the reaction conditions. This method is general for a variety of directing groups and tolerates many common functional groups. Chapter 4 explores the mechanism of a room temperature palladium-/iridium-catalyzed C−H arylation reaction using diaryliodonium salts as the aryl source. This use of visible-light photoredox catalysis in combination with palladium catalyzed C−H functionalization is interesting mechanistically, and could potentially lead to other functionalization reactivity through similar methods. Stern-Volmer quenching studies along with kinetic studies are discussed in detail.