Palladium And Nickel Catalyzed Transformations Forming Functionalized Heterocycles PDF Download

"This thesis describes the development of new palladium and nickel catalyzed carbonylation reactions to efficiently and rapidly generate products with minimal waste. These reactions can be carried out using commercially and/or readily available starting materials, including imines, acid chlorides, aryl iodides, alkynes, alkenes and carbon monoxide. In chapter 2, we describe a palladium catalyzed carbonylative synthesis of polysubstituted imidazoles. This transformation involves a tandem catalytic process, where a single palladium catalyst mediates both the carbonylation of aryl halides to form acid chlorides, as well as cyclocarbonylation of a-chloroamides, to generate 1,3-dipoles. Finally, a regioselective 1,3-dipolar cycloaddition with electron poor imines furnishes tetra-substituted imidazoles. Overall this provides a route to prepare imidazoles from five readily available building blocks: two electronically distinct imines, aryl halides and two molecules of CO. In chapter 3, we describe a nickel catalyzed approach to synthesize of isoindolinones via the carbonylation of aryl iodides in the presence of imines. In this, the nickel catalyzed in situ generation of acid chlorides via aryl halide carbonylation allows the formation of a chloroamides, which in turn undergo an intramolecular cyclization to form isoindolinones. This reaction offers an efficient alternative to traditional syntheses of isoindolinones, which often require the initial assembly of the appropriate aryl-tethered precursors for cyclization. In chapter 4, we describe the development of a palladium catalyzed, electrophilic approach to the carbonylative C-H bond functionalization of a range of heterocycles. Mechanistic studies show that the Pd/PtBu3 catalyst can mediate the in situ formation of highly electrophilic aroyl iodide intermediates, which react with heterocycles forming aryl-(hetero)aryl ketones. This provides a general methodology to construct ketones from aryl iodides and electron rich heterocycles without the need to prefunctionalize the heterocycle, install directing groups, or exploit high energy starting materials (e.g. acid chlorides). Chapter 5 describes mechanistic studies on the palladium catalyzed multicomponent synthesis of 1,3-oxazolium-5-olates (Münchnones). Previous work in our laboratory has shown that Münchnones can be generated via the palladium catalyzed multicomponent coupling of acid chlorides, imines and CO. In order to better understand this reaction, we synthesized and characterized key reactive intermediates, studied stoichiometric model reactions, and performed kinetic studies on catalytic reaction. These allowed the elucidation of the role of the catalyst structure, rate determining steps, as well as the importance of off cycle steps in this transformation. In chapter 6, we show how the mechanistic insights laid out in the previous chapter can be applied to create a highly active catalytic system for synthesis of 1,3-oxazolium-5-olates. By employing a sterically encumbered pyrrole-based phosphine ligand, which can be more easily displaced by carbon monoxide for carbonylation, we have created a catalyst that is more than ten times more active that previous systems for this reaction. When coupled with alkyne cycloaddition, this offers a broadly generalizable route to form polysubstituted pyrroles from simple imines, acid chlorides and alkynes. This approach has been applied to the multicomponent synthesis of Atorvastatin (i.e., Lipitor). " --