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Title: Development of aza-Heck cyclisations for the synthesis of chiral nitrogen heterocycles
Author: Race, Nicholas J.
ISNI:       0000 0004 5921 2868
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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The synthesis of chiral N-heterocycles through palladium- and copper-catalysed aza-Heck cyclisations of oxime esters has been developed. Initial studies focussed on the development of a palladium-catalysed aza-Heck-π-allyl cascade with carbon, nitrogen and hydride nucleophiles. These reactions were limited to oxime esters bearing gem-α-disubstitution. Investigation into aza-Heck cyclisations involving 1,2-disubstituted alkenes was subsequently undertaken. Here, control of β-hydride elimination regioselectivity was crucial to obtaining chiral products. A series of oxygen-based, sulfur-based and aryl substituents were evaluated for their ability to promote regioselective β-hydride elimination. Both oxygen and sulfur substituents gave low selectivity, whereas aryl groups promoted β-hydride elimination in the direction of chiral products. Catalyst-controlled cyc1isation of alkyl-substituted alkenes provided chiral products and a selectivity model for this process was proposed. Highly diastereoselective manipulations of the dihydropyrrole products obtained from this chemistry allowed access to more complex N-heterocycles. A complementary copper-catalysed aza-Heck cyclisation was next developed. Mechanistic studies of both palladium- and copper-catalysed reactions revealed a mechanistic dichotomy. Reactions involving electron-deficient palladium catalysts proceed through the formation of imino-Pd(II) intermediates, whereas copper catalysts form an iminyl radical, or radical-like species. Reactions involving electron-rich palladium catalysts also resulted in the formation of an iminyl radical, and in the presence of a hydrogen-atom donor formed the product of a 'reductive' aza-Heck reaction. Finally, an enantioselective palladium-catalysed aza-Heck reaction has also been developed. Spirocyclic P,N-based SIPHOX ligands were privileged for this transformation and the synthesis of a series of SIPHOX derivatives allowed the aza-Heck reaction to proceed in high yield and enantioselectivity. A selectivity model was proposed for these reactions
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available