Conboy, Darren (2020) New oxidative transformations towards the synthesis of potential anti-cancer heterocyclic quinone and bis-quinone scaffolds. (PhD thesis), Kingston University, .
Abstract
This thesis describes new oxidative transformations towards the synthesis of nitrogen-containing heterocyclic quinones. Chapter 1 provides a review of literature published over the past decade related to heterocyclic systems possessing a central carbocyclic ring fused onto two five-membered nitrogen-containing heterocycles, including imidazobenzimidazoles. The naming of some synthesized fused heterocyclic systems according to IUPAC rules is derived. Chapter 2 describes the fusion of morpholine and oxetane onto benzimidazole by oxidative cyclization of 3,6-dimethoxy-2-(cycloamino)anilines using hydrogen peroxide with hydroiodic acid. The cyclization serendipitously yielded 1,4,6,9-tetramethoxyphenazine as a by-product, and reaction conditions were optimized to favour phenazine formation. Mechanisms for the HI catalysed reactions via a detected nitroso-intermediate are proposed for the oxidative cyclization and the unexpected intermolecular displacement of the oxazine. An aqueous solution of molecular iodine is capable of the same transformations. Oxidative demethylation gave targeted benzimidazolequinones, including without cleavage of the incorporated oxetane. Chapter 3 reports the synthesis of spirocyclic oxetane-fused imidazobenzimidazoles. Oxone-mediated ring-closures to give imidazobenzimidazoles require acid and the functionalization of 4,6-di(cycloamino)-1,3-phenylenediamines to the anilides. This is in contrast to benzimidazole-forming oxidative cyclizations, which use 2-(cycloamino)anilines and require no acid. New evidence for N-oxide and nitroso-intermediates in respective imidazobenzimidazole and benzimidazole forming reactions is provided. Chapter 4 details the synthesis of the first imidazo[4,5-f]benzimidazole iminoquinone, which was found to be inactive against tumour cells, in contrast to the related imidazo[5,4- f]benzimidazole isomer. Chapter 5 discloses an optimized route to alicyclic ring-fused p-dimethoxybenzimidazole-p-benzimidazolequinone dimers. The dimers possess ambiphilicity, and a selective electrophilic chlorination and bromination at the electron-rich p-dimethoxybenzimidazole-CH using respectively NaCl and NaBr with Oxone in HFIP(aq), is described. The benign halide salt-oxone mix can provide tunable conditions that favour molecular halogen formation allowing one-pot halogenation and quinone formation. In contrast, nucleophilic radical trifluoromethylation occurs selectively at the p-benzimidazolequinone-CH with the product subjected to one-pot chlorination and quinone formation.
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