Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Chemistry

First Advisor

Patrick J. Walsh

Second Advisor

Marisa C. Kozlowski

Abstract

Metal-catalyzed direct C−H bond activation arylation reactions of non- or weakly acidic C−H bonds have recently received much attention. Compared to traditional catalysts that activate C−H bonds, conventional deprotonative cross-coupling processes (DCCP) undergoes an in-situ C−H deprotonation and metalation of the substrate under catalytic cross-coupling conditions. DCCP reactions are generally directing-group-free methods employing simple starting materials under mild reaction conditions. This thesis describes mechanistic study of DCCP-type triarylation of benzylic methyl groups and introduces two novel methods of deprotonative carbonylation of weakly acidic benzylic C(sp3)−H bonds.

In Chapter 1, a comprehensive mechanistic study of our palladium-catalyzed deprotonative triarylation of heteroarylmethanes at the benzylic C-H bonds is reported. The reaction works with a variety of aryl halides, enabling the rapid synthesis of triaryl(heteroaryl)methanes. Mechanistic studies point to Pd(cataCXium A)2 being the resting state of the catalyst and reductive elimination being the turnover-limiting step in the ultimate catalytic cycle.

In Chapter 2, a novel highly selective palladium-catalyzed deprotonative carbonylation of azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. The methods enable access to key components of numerous biologically active natural products and synthetic compounds. The key to success is the presence of a NIXANTPHOS-based palladium catalyst, which efficiently activates aryl bromides and facilitates the deprotonative cross-coupling process under CO.

Chapter 3 presents a novel, selective and high-yielding palladium-catalyzed carbonylative arylation of a variety of weakly acidic (pKa 25–35 in DMSO) benzylic and heterobenzylic C(sp3)−H bonds with aryl bromides. The Josiphos-based catalytic system, identified by high-throughput experimentation (HTE), solved the selectivity issue in deprotonative carbonylation reactions, providing ketone products without the formation of direct coupling byproducts. Additionally, (Josiphos)Pd(CO)2 was identified as the catalyst resting state. A kinetic study suggests that the oxidative addition of aryl bromides is the turnover-limiting step. Key catalytic intermediates including (Josiphos)Pd(Ar)(Br) and (Josiphos)Pd(COAr)Br were also isolated.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS