Stuart, David R2013-11-082013-11-0820102010Source: Dissertation Abstracts International, Volume: 71-11, Section: B, page: 6789.http://hdl.handle.net/10393/29976http://dx.doi.org/10.20381/ruor-13232Aromatic heterocycles, particularly those containing nitrogen, have been identified as important motifs in a wide variety of pharmaceuticals, agrochemicals, fine chemicals, and materials of technological interest. Thus, the development of efficient methods for both the functionalization and preparation of these compounds has received much attention from the synthetic community. Traditional transition metal catalysis has featured prominently in both of these veins; however, there has been a recent surge of interest in the development of catalytic methodologies aimed at the conversion of C-H bonds to more highly oxidized functionality. This body of work describes both the functionalization and preparation of aromatic N-heterocycles in this context. Described in this thesis is the development of methods for both the functionalization and preparation of nitrogen containing aromatic heterocycles from readily available precursors devoid of pre-activation. First, the advancement of palladium(0)-catalyzed direct arylation of quinoline and isoquinoline N-oxides with aryl bromides as a viable solution to the "2-azine organometallic problem" is presented (Chapter 2). This project serves in the formation of the pharmaceutically relevant 2-arylquinolines and 1-arylisoquinolines. These studies also assisted in the identification of a catalyst system (Pd(OAc)2 (5 mol%), PMetBu2·HBF4 (10 mol%)) enabling high regioselectivity in the direct arylation of unsymmetrical azine N-oxides, such as isoquinoline N-oxide and 3-substituted pyridine N-oxides. The experimental observations were validated computationally with a concerted metallation deprotonation transition state model. In a subsequent section, the development and mechanistic investigation of the palladium(I1)-catalyzed oxidative cross-coupling of two unactivated arenes is presented (Chapter 3). The physical parameters of this century-old problem are addressed and observations which may provide solutions to both regio- and chemoselectivity are described for the oxidative arylation of indoles. Protocols for the C2- and C3-oxidative arylation of N-pivaloyl and N-acetylindole, respectively, are offered. Additionally, the mechanism is discussed, including the observation that both the oxidant (AgOAc or Cu(OAc)2) and nitrogen protecting group (pivaloyl or acetyl) appear to have a significant effect on regioselectivity. Finally, the rhodium(III)-catalyzed oxidative coupling of acetanilides or enamides with alkynes to form highly decorated indoles or pyrroles, respectively, is described (Chapter 4). This methodology was applied to the synthesis of Paullone, a pharmaceutical agent. An in-depth mechanistic evaluation of this oxidative indole-forming annulation process based on kinetic studies and free energy correlations is also reported.239 p.enChemistry, Organic.Thesis