de Freitas Perdigão Dias, Tatiana Alexandra
(2019)
Advances in the synthesis and application of quinones.
PhD thesis, University of Nottingham.
Abstract
Chapter 1 presents a brief overview of sustainable methodologies in chemical synthesis, together with the role of quinones.
In Chapter 2 the biological activity of twelve 5-aminoindolequinones against NQO2, an underexplored enzyme, was assessed and three new 5-amino indolequinone derivatives displayed good inhibitory profile against this enzyme. Besides, the UV-visible absorbance curves and the nucleophilic trapping of the activated electrophilic iminium intermediate following reductive activation of the indolequinone scaffold were effectively carried out for two substrates. These experiments were used in order to gather evidence that elimination of the leaving group, required for the activity of these compounds, would happen. The interaction of 5-aminoindolequinone 37 with NQO2 was analysed by mass spectrometry and the formation of the adduct 37/FAD suggests a mechanism-based inhibition of the enzyme.
In Chapter 3 the experiments were performed to advance towards a more sustainable synthesis of 5-aminoindolequinones. A range of reaction conditions, such as time, metal loading, solvent, and concentration of the solution were adjusted throughout the synthetic sequence but the main focus was on the optimisation of the conditions for the reaction between 2-bromo-5-methoxy-1,4-benzoquinone 156 and enamine 158 through a copper(II)-mediated process in the presence of a more environmentally benign solvent system in which water was used as the main solvent. There are no precedents in the literature for the synthesis of these derivatives in water. At the end of the synthetic sequence, sixteen 5-amino substituted indolequinones were prepared.
In Chapter 4 the experiments were designed to develop a more sustainable synthesis of halogenated phenols. A range of reaction conditions were optimised in the reactivity of quinone diazides towards nucleophilic substitution. The concentration of the solution was increased from 0.5 to 1 M, the catalyst loading was reduced from 10 to 0.5 mol% and the reaction time decreased from 1 h to approximately 10 min. Thirteen halogenated phenols were successfully prepared, typically in low to moderate yields.
Finally, Chapter 5 contains details of all experimental procedures, and describes the chemical elimination reductive studies, examined in Chapter 2, the synthesis of 5-aminoindolequinones and their precursors, discussed in Chapter 3, and the synthesis of halogenated phenols and corresponding precursors, quinone diazides, analysed in Chapter 4.
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