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Novel synthesis of N-heterocycles

Dunford, Damian Gordon 2010. Novel synthesis of N-heterocycles. PhD Thesis, Cardiff University.

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In a continuation of studies into metal-catalysed 5-endo-dig cyclisations, we investigated their application to the synthesis of a range of N-heterocycles: indoles, pyrazoles and pyrroles. The second chapter describes an investigation of the application of silver(I) cyclisation methodology to the synthesis of 1,2-disubstituted indoles. Our methodology was applicable to a range of functional groups in both positions, allowing for terpenes, alkenes, aromatic, alkyl and alcohol substituents in position two. Additionally, a range of nitrogen protecting groups were tolerated, including sulfonamides, carbamates, amides and even methyl groups. A few substrates would not cyclise; we propose that the current hypothesis that this is due to pKa differences is insufficient to explain the differing reactivities. This is supported by computational work carried out by a collaborator. Also reported is a successful synthesis of an indole in a flow system; this was achieved using silver nitrate on silica as the stationary phase. Chapter three focuses on the synthesis of pyrazoles from hydrazines prepared using the Mitsunobu alkylation. A regioselective Mitsunobu alkylation has been defined using non-symmetrical disubstituted hydrazines to give a single regioisomer. Exposure of these hydrazines to silver(I) met with limited success with steric hindrance believed to be the explanation as to why some for the hydrazines would not cyclise. Chapter four reports the synthesis of pyrroles using silver(I) and copper(II). The first part focuses on the improvement of Sharland's copper(I)-catalysed pyrrole synthesis which, upon improvement, gave pyrroles cleanly in high yields. Also reported are the successful silver(I)-catalysed synthesis of fused pyrroles such as annulated pyrroles and N-fused pyrrolizines and indolizines by use of silver(I). Finally the silver(I) cyclisation methodology was applied to the successful synthesis of a natural product, pyrrolostatin.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Funders: EPSRC, GlaxoSmithKline
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Jan 2018 01:07

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