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A brief introduction to imidazole is given, outlining its physical and chemical properties since its discovery in 1858. The role of imidazole in the natural amino acid (S)-histidine is discussed with reference to its use in catalytic triads and histidine proton shuttles. The decarboxylation of (S)-histidine to give histamine and its importance in biological functions is also discussed with reference to the development of the histamine H2- receptor antagonist Cimetidine and other imidazole containing drugs. In Chapter 1 the chemistry of 5-diazoimidazoles and the resulting imidazolylidene carbene is discussed. Carbenes derived from 5-diazoimidazoles under photolytic conditions were found to undergo O-H and N-H insertion reactions in good yield. Aromatic hydrocarbons were excellent traps for imidazolylidene carbenes and gave a variety of arylimidazoles under thermal and photolytic conditions. Reaction with pyridine led to the first example of a pyridinium ylide formed from an imidazolylidene carbene, while reaction with hexaflurobenzene gave an unusual 8,5-bicylic product. In Chapter 2 attempts to control the tautomeric equilibrium of l-aryl-3-alkyl triazenes and recreate the mode of action for the cytotoxic imidazoletetrazine, Temozolomide, are discussed. Several triazenes that are capable of fixing the tautomeric equilibrium by hydrogen bonding were designed, synthesised and their degradation studied. X-ray crystal structure and IH NMR spectroscopic analysis showed that hydrogen bonding was, In part, responsible for influencing the tautomerisation of the triazenes studied. The outcome of the degradation studies was severely dependent on the nature of the aryl substituents, although it is thought the alkyl substituent also plays a significant role. In Chapter 3 efforts directed towards the total synthesis of the imidazole alkaloids known as the isonaamines are discussed. A synthetic route utilising a cyclisation approach to construct the imidazole core is presented. Several approaches to effect cyclisation of a urea onto an activated alkene are investigated and discussed. The most recent approach focuses on the formation of the 5-membered cyclic product over the 6-membered cyclic product. |
