Homogenous transition metal

Abstract

The application of homogenous transition metal catalysis to the arylation of enolates to develop new synthetic procedures which are more environmentally benign, atomefficient and economically viable than current methods was the motivation behind the current work. The specific choice of molecules with an aromatic group in the a- position of a ketone, carboxylic acid, amide or other electron-withdrawing group arose from the fact that many natural products, pharmaceutical actives and synthetic intermediates contain such a substructure while the syntheses of these substructures are often cumbersome. The application of homogenous catalysis to various types of enolates was explored and in the process several developments were achieved and discoveries made. These included the use of inorganic bases under phase transfer conditions for the Heck reaction of acrylic acid as well as the synthesis and application of phosphine and phosphite ligands in the Heck reaction of acrylic acid esters. The successful use of low palladium loadings (as low as 0.01mol%) in the arylation of diethyl malonate using aryl chlorides and the application to the synthesis of ketoprofen and phenobarbital was demonstrated. The novel application of palladium catalysis to the arylation of methanesulfonamides and the first example of a bromoindole derivative as the aryl halide partner in an enolate arylation reaction was demonstrated. Ligand-free palladium catalysed phenylation of pinacolone followed by Baeyer Villiger oxidation led to a proposed novel synthetic route to tert-butyl esters of 2-arylacetic acids. The palladium and copper catalysed arylation of acetoacetate esters, with in situ decarbonylation, provided a different route to 2-arylacetic acid esters which are useful in the preparation of non-steroidal anti-inflammatory compounds.