Defining Protocols for the Synthesis of 3-Substituted-5-benzylideneimidazolidine-2,4-diones

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Copyright: Hidayat, Ika-Wiani
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Abstract
This thesis describes a detailed examination of parameters that control formation of substituted benzalhydantoins in a multistep process from aldehydes and 3-un/substituted hydantoins following modifications of the Wheeler and Hoffman process. The purpose of the study was to develop optimal reaction conditions for a planned, automated parallel synthesis of indoles, with the benzalhydantoins as intermediates. An initial comparative study, based on preparative yields, of the synthesis of benzalhydantoins from the condensation of substituted aldehydes and unsubstituted and 3-substituted hydantoins under the established Wheeler and Hoffman procedure was found imprecise. Consequently, an LC-MS analytical method was developed for reaction monitoring. Investigation of the roles of temperature, reaction time, and aldehyde and hydantoin substituents showed dependence on the latter two features and revealed formation of benzylhydantoin alcohols. The process of 3-allylation of benzalhydantoins was investigated as a model for the final step in an alternative preparation of 3-alkylbenzalhydantoins. Overall, an excess of reagent allyl chloride played an important role in optimizing yields, however yields were limited. A microwave-irradiation method gave more rapid conversions and allowed better comparison of reaction rates. A parallel investigation of the scope of tandem allylation-condensation reactions, which indicated that the alkylation of hydantoin and the condensation of aldehydes with hydantoin occurred simultaneously, was described. 3-Unsubstituted benzalhydantoins were obtained as major products, even after prolonged reaction times, suggesting that condensation of aldehydes with 3-substituted hydantoins was slower than with hydantoin itself. A systematic study of the effect of microwave acceleration on the initial condensation was described, and the revealed benzylhydantoin alcohols were found as major products, rather than benzalhydantoins. The alcohols were studied in one example in the solid state by single crystal x-ray crystallographic analysis and found to form as two racemic diastereoisomers that crystallized together in racemic pairs. Twenty-three synthetic (thio)hydantoins and benzalhydantoins were evaluated for antimicrobial activity against Candida albicans, Malassezia furfur, Escherichia coli and Staphylococcus aureus, by the paper disc diffusion method. 3-Allyl-4'-nitro- and 3-n-butyl-2'-bromo-4',5'-dimethoxybenzalhydantoin showed the most promise as drug leads. Five representative benzalhydantoins examined by x-ray crystallography showed disparate behaviour that could not be related to molecular structure nor physicochemical or biological properties.
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Author(s)
Hidayat, Ika-Wiani
Supervisor(s)
Read, Roger W
Black, David St.C
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Publication Year
2015
Resource Type
Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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