Abstract
M.Sc. (Chemistry)
Indoles are ubiquitous in nature. A large number of indole alkaloids and related secondary metabolites (more than a thousand have been characterised) are naturally produced in nature, many of which have important pharmacological or medical properties. The development of new synthetic methodologies towards these natural products still remains a very active area of research with the modern approaches based almost exclusively on transition metal catalysts. However, none of these methods can be described as a ring synthetic approach to 3-alkyl substituted indoles. The dissertation described herein explores the possibility of obtaining alkyl substituted indoles via the Rh catalysed hydroformylation of an appropriate arylalkynylaniline.
The development of such a methodology required a highly regioselective hydroformylation of the arylalkynylaniline substrate in favour of the branched adduct. However, literature pertaining to the hydroformylation of alkynes, in particular arylalkynes, is somewhat scant. Therefore, the main objective of this study involved a detailed investigation of which factors affect the outcome of the hydroformylation of phenylacetylene. Variation of ligand concentration, temperature and syngas pressure had little to no effect on the regioselectivity. However, a dramatic change toward the branched isomer was observed when bidentate ligands with medium size bite angles (dppe and the other ligand) were employed. Because of the improved selectivity, dppe was chosen for further investigations in this study. The effects of both steric and electronic substituents on the phenylacetylene structure were also investigated. It was found that the introduction of an electron-withdrawing group in the para-position of the phenylacetylene structure caused a decrease in reaction rate, but had little effect on the regioselectivity. Replacement of the terminal acetylene proton with a bulky substituent led to the exclusive formation of the branched isomer. However, similar replacement of the proton with a methyl substituent resulted in marked decrease in selectivity indicating an electronic effect.
In addition to the right regioselectivity to obtain indoles, an intramolecular condensation was necessary to obtain a five-membered heterocyclic component of the indole. 2-Ethynylaniline was used as the model compound to test the possibility of synthesis of indole through this route...