Nickel- and Palladium-Catalyzed Mono-α-Arylation of Carbonyl Compounds and the Synthesis of Heterocycles from Nickel-Enolates

Abstract

The transition metal-catalyzed mono-α-arylation of carbonyl compounds is a powerful class of C(sp2)-C(sp3) bond forming reactions that is broadly useful for the synthesis of biologically active compounds. Through the application of various ancillary ligands which can dramatically influence the steric and electronic properties of the metal, this class of reactions has greatly matured in scope since its discovery over 20 years ago, encompassing a large array of both (hetero)aryl (pseudo)halide and carbonyl substrates. Notwithstanding the advances in the field of metal-catalyzed α-arylation chemistry, reactions employing earth-abundant transition metals (e.g., nickel) remain underexplored in comparison to palladium-catalyzed methodologies. Furthermore, chemoselective examples are limited, despite the potential utility in the synthesis of complex molecules; and mono-α-arylations of the most cheap and abundant esters, amides, and ketones remains a challenge, where substrate/base pairings can result in undesired reactivity. With the intent of addressing these limitations, this dissertation documenting my doctoral research describes the development of a bisphosphine/palladium-catalyzed protocol for the chemoselective synthesis of α-(o-chloro)aryl ketones from (2-chloro)aryl (pseudo)halides, as well as the development of competent catalyst systems for the nickel-catalyzed α-arylation of cheap and abundant carbonyl compounds with aryl chlorides, featuring the use of the “DalPhos” (DALhousie PHOSphine) ligand family – previously employed for C(sp2)-N/O bond forming reactions. Moreover, the complementarity of these Pd- and Ni-catalyzed α arylation systems is highlighted in the development of two useful new nickel-catalyzed heterocycle-forming reactions, starting from easily accessed α-(o-chloro)aryl ketones and taking advantage of a single mechanistic landscape involving intermediates more commonly associated with the metal-catalyzed α-arylation of carbonyl compounds.