Studies on copper-catalysed reactions: aromatic halide exchange and intramolecular Ullmann arylation
Creators: name: Jin, Xiaodong
Publisher: name: Imperial College London
Year: 2017

description: The use of ancillary ligands in the copper(I)-catalysed aromatic halide exchange reaction and the intramolecular Ullmann arylation reaction has been shown to significantly improve the reaction rate in these systems. This has allowed the adoption of milder reaction conditions (usually ≤ 110 ºC) and lower catalyst loadings (usually ≤ 10 mol%). Recent advances in the mechanistic understanding and application of these copper-catalysed reactions are fully discussed in Chapter 1. Despite these recent advances in ancillary ligand promoted copper(I) catalysis, there are still many remaining challenges inhibiting the wider adoption of these reactions in industry and academia. To date only a few ligands have been reported to efficiently promote the copper(I)-catalysed aromatic halide exchange reaction (Finkelstein reaction), the most successful being N,N′-dimethylethylenediamine (DMEDA) and trans-N,N’-dimethyl-1,2-cyclohexanediamine (TDCHDA). However both of these ligands require high reaction temperatures and vigorous air-free conditions, show poor or no reactivity with aryl-chlorides, and are relatively expensive. Therefore, a detailed ligand screening program to optimise and improve the copper-catalysed Finkelstein halide exchange reaction has been undertaken and is reported in Chapter 2. A new cheap and effective ligand, diethylenetriamine, has been developed and studied for both copper(I) and copper(II) mediated aromatic Finkelstein reactions. This gave satisfactory yields over a wide range of substrates and, in contrast to existing systems, showed excellent tolerance to air and moisture. Further studies using structural studies and kinetic profiling have also been undertaken in order to better understand the mechanism of the reaction and the potential role played by the ligand. In terms of copper(I)-catalysed intramolecular Ullmann arylation, the possible intermediates on the catalytic pathway and the role of the ligand have been little studied and are currently not fully understood. Therefore, in order to build an improved mechanistic understanding, a series of reactivity and mechanistic studies was carried out. Chapter 3 describes these for the copper(I)-intramolecular N-arylation of 1,2-dimethylbenzimidazole. The solid-state structures of the copper(I) intermediates have been isolated under air-free conditions and characterised by X-ray crystallography to reveal the different complexes that might be present in the reaction mixture. Detailed kinetic profiling of copper(I)-catalysed intramolecular N-arylation using bis(tetra-n-butylphosphonium) malonate as a soluble base is presented revealing negligible catalyst deactivation, but significant catalyst inhibition. The rate dependence study on catalyst concentration reveals a non-integer order in [Cu]total. New catalytic systems using sub-mol% catalyst loadings have been investigated as well as aryl chloride activation at higher temperatures. Chapter 4 presents a series of studies on the identity of possible copper(I) intermediate complexes in the intramolecular Ullmann O- and S-arylation reactions used in the preparation of benzoxazoles and benzothiazoles. Isolated copper(I) complexes have been shown to react on heating to give cyclised products with or without the addition of 1,10 phenanthroline as ligand. The results identify the copper(I) complexes as potential reaction intermediates and show the positive effect of 1,10 phenanthroline on reaction rate. Reaction calorimetry studies show substrate inhibition occurs during the reaction.