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Title: C-H activation studies towards the synthesis of highly functionalised quinazolinones
Author: Maiden, Tracy M. M.
ISNI:       0000 0004 5993 3606
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2016
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A new synthetic strategy towards highly functionalised quinazolines and quinazolinones has been developed. The C-H amidation/cyclisation methodology allows for the conversion of simple benzoic acids into synthetically useful heterocyclic scaffolds. Investigations revealed palladium, copper and ruthenium catalysis to be unsuitable for the C-H amidation transformation, whilst rhodium catalysis was found to be optimal in conjunction with sulfonamides and trifluoroacetamide. Additionally, in the case of the trifluoroacetamide, mild temperatures of 25 to 40 °C were sufficient to promote the reaction. Utilisation of these conditions allowed for the synthesis of a range of highly functionalised amino-substituted aromatic oxazolines. Transformation of these valuable motifs into the corresponding quinazolines could be readily achieved following a simple and efficient cyclisation procedure. Additionally, the corresponding quinazolinones could be rapidly afforded via an acid promoted reaction. Furthermore, the utility of the synthetic strategy was shown by the total synthesis of the tyrosine kinase inhibitor, Erlotinib, and the multi-gram scale synthesis of the Halofuginone quinazolinone. Studies were extended towards the synthesis of 2-substituted quinazolinones. The use of methyl benzimidate hydrochloride allowed for the successful introduction of a phenyl substituent, however attempts to incorporate alternative groups were unsuccessful. Additionally, attempts to functionalise the 2-position of the quinazolinone after cyclisation using xanthate radical precursors were also unsuccessful. Application of the C-H amidation/cyclisation strategy was successfully realised upon pyridine scaffolds. The presence of a 2-substituent on the pyridine heterocycle was found to be crucial to allow rhodium-catalysed C-H amidation to occur. Investigations revealed that a range of 2-substituents could be utilised to allow reactivity upon the pyridine motif. Whilst furans were not successfully aminated under the reaction conditions, thiophenes were found to be compatible. Post C-H amidation functionalisation was extensively explored. Transformation into the azaquinazolinone was readily achieved via utilisation of the previously established cyclisation conditions. Additionally, functionalisation of the 2-halo substituent allowed for the incorporation of amino, alcohol, aryl and alkyl functional groups in good yields, affording medicinally relevant pyridines.
Supervisor: Harrity, Joseph P. A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available