Copper-mediated C-N cross-coupling reactions and their application in the synthesis of organic compounds are now well-known in the chemical literature. Specifically, the involvement of ancillary ligands has been reported to improve the reaction performance significantly. This improved reaction is often referred to as the ‘modified’ Ullmann reaction. Understanding the reaction mechanism and the role of the ancillary ligands is crucial for further improving the reaction performance. Toward this goal, this project seeks to develop a better catalytic system for Ullmann cross-coupling with a focus upon a better understanding of the reaction mechanism.
Chapter 1 introduces the background of copper-catalysed cross coupling reactions. In Chapter 2, a series of ancillary ligands, with structures similar to amino acids (one of the most widely used 1st generation ligands) were investigated. The relationship between the ligand structure (number of chelating sites, electronics, sterics, the role of NH and COOH motif) and reaction outcome is discussed. Reaction optimisation and substrate scope has been carried out, with iminodiacetic acid (IDA) identified as a new effective ligand for the modified Ullmann reaction. Kinetic and NMR studies reveal further details on the role of copper precursor and the copper oxidation state.
In Chapter 3, a series of novel ligands with modified backbones, compared to current oxalic diamide second-generation ligands, have been synthesised and screened for use in modified Ullmann reactions. The tartramide ligand class showed superior reactivity, especially at room temperature. Detailed mechanistic studies using reaction progress kinetic analysis (RPKA) are reported, thus providing a better understanding of the role played by different substrates, bases and catalysts. Using fine-tuned reaction conditions guided from RPKA analysis, the reaction system was extended to 22 different substrates.
Chapter 4 discusses attempts to develop a novel ortho-NHCOR directed tandem Finkelstein-Ullmann reaction. Initially the ortho-NHCOR directed Ullmann reaction were carried out with organic base, tertbutyl-phosphonium malonate (TBPM). The factors influencing reaction performance are reported, such as reaction temperature, the catalyst systems, the presence of ortho-NHCOR directing groups and the choice of base. Then, with hope to better improve the reaction, tandem Finkelstein-Ullmann reactions were attempted. However, it was not possible to find optimised conditions which were applicable to both steps. Hence, although the one pot Finkelstein-Ullmann reaction was attempted, it proved less efficient than standard Ullmann cross-coupling protocols. Nevertheless, it is found that rapid intramolecular O-arylation cyclisation from ortho-NHCOR substituted aryl halides can be achieved when using tetrabutyl phosphonium malonate as organic base. Mechanistic and optimisation studies were undertaken and it is shown how sequential addition of organic base and CuI can further improve the reaction performance by inhibiting the side reactions.