Ethoxyvinylarenes as versatile intermediates for heterocycle synthesis

• Main Author: Swindlehurst, Marianne
• Other Authors: Whelligan, Daniel
• Published: University of Surrey 2017
• Subjects: 547
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.720375

In the field of drug discovery, pyrrolopyridine moieties are often incorporated into bioactive molecules. This is due to their ability to form both pi-stacking and hydrogen bonding interactions when binding to target proteins. This project aimed to provide a robust and rapid method of synthesis that will provide access to substituted pyrrolopyridines. The work is based on a previously published method involving the synthesis of ethoxyvinyl(amino)arenes, by Suzuki reaction of halo-aminoarenes, followed by cyclisation. It was hoped this method would be advanced by applying alternative cyclisation reactions to the ethoxyvinyl(amino)arenes to give 3-substituted products in one step. In comparison with previous methods, this route would be inexpensive, robust and applicable to a wide range of substrates. It was also envisaged that alternative starting materials could be used to make it a more generalised method for the synthesis of bicyclic arenes. Work began with testing the reproducibility of the previously published method of synthesising the ethoxyvinyl(amino)arenes. This was done successfully, although a change in ligand (SPhos to RuPhos) proved beneficial, with seven different analogues being synthesised in yields ranging from 36% to 98%. This same reaction was attempted with halo-hydroxypyridines, with a novel route to furopyridines in mind, but with no success. The synthesis of non-commercially available halo-hydroxypyridines themselves also proved to be challenging with no material being isolated. Various methods were tested for the bromo-cyclisation of ethoxyvinyl(amino)arenes to 3-bromopyrrolopyridines. A two-step method using acid cyclisation followed by bromination was entirely successful. Two-step, one-pot and one-step methods both appeared to promote polymerisation/oligermisation. Success was achieved with a one-step method employing an acid additive but only on selected ethoxyvinyl(amino)arene isomers and with varying yields. The work was extended to the attempted synthesis of anti-malarial precursors using the bromo-pyrrolopyridine isomers as building blocks and converting them to alkyl-linked glutarimides. This led to the successful and novel synthesis of the reactants vinyl glutarimide and glutarimylethylborolane. However, successful conditions for their palladium catalysed cross coupling with the bromides were not found.