Gold-multifaceted catalysis approach to pyrrole synthesis

• Main Author: Ngwerume, Simbarashe
• Published: University of Nottingham 2013
• Subjects: 616.894
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604293

The work presented in this thesis is concerned with the development of novel approaches to the regioselective synthesis of highly substituted pyrroles from simple starting materials. The work detailed herein covers three main research areas: i) A nucleophilic catalysis method for the concise synthesis of substituted NH- or N-Boc-pyrroles, directly from oximes and alkynes; ii) The development of a novel gold-multifaceted catalysis (gold-MFC) method for the regioselective synthesis NH-pyrroles directly from oximes and alkynes, together with a detailed mechanistic investigation which provides an insight into the mechanistic pathway; iii) studies towards an intramolecular macrocyclisation approach towards the synthesis of substituted pyrroles from oximes and alkynes. i) A novel nucleophilic catalysis / microwave irradiation protocol that provides a succinct synthesis of di-, tri, and tetrasubstituted pyrroles in a single operation will be discussed. This one-pot method relies on the use of a nucleophilic catalyst to regioselectively promote the in situ formation of O-vinyloximes from the reaction of oximes and electron deficient alkynes, which after subjection to microwave irradiation afforded the desired pyrroles as single regioisomers. ii) The main body of work in this thesis concerns the development of a novel gold(I)-catalysed method for the regioselective synthesis of highly substituted pyrroles directly from oximes and electron deficient alkynes. This one-pot method was developed via optimisation of two key gold(I)catalysed steps: the formation of O-vinyloximes and rearrangement of preformed O-vinyloximes into the corresponding pyrrole. The cationic gold species was shown to activate multiple mechanistically distinct steps along the reaction pathway and therefore act as a multifaceted catalyst. Notably, this method provides a concise synthesis of di-, tri- and tetrasubstituted pyrroles which contain a functional group handle in the form of an ester at the 3/4-position for further exploitation. The proposed mechanistic pathway is supported by a novel application of the Huisgen cycloaddition click reaction, which was used to probe the relative stability of substituted O-vinyloximes. Further support for the proposed mechanism was provided by high-temperature lH, 2H{lH}, and 13C{lH} NMR experiments. X-ray crystallographic evidence was used to further support the mechanistic hypothesis by confirming the absolute configuration of the oximes, 0- vinyloximes and pyrroles. iii) Preliminary studies into an unprecedented intramolecular pyrrole formation via the direct addition of an oxime to an alkyne are described. ii