Studies in the synthesis of benzoxazole compounds

Kleinhans, Dewald Johannes (2015-12)

Thesis (PhD)--Stellenbosch University, 2015.

Thesis

ENGLISH ABSTRACT: Benzoxazoles are an important class of π-electron-excessive, benzene-fused heterocyclic compounds found in natural products and display a wide range of pharmacological applications. It is therefore a widely used starting scaffold for drug and agrochemical discovery programs. Other applications include: chiral auxiliaries in asymmetric reactions, chiral receptors for the resolution of racemic mixtures, fluorescent whitening dyes, various photochromic materials and as ligands for a wide range of catalytic reactions. Due to our interests in resorcinarenes, we came across 4-hydroxybenzoxazoles, a structural motif that has not been explored as potential asymmetric ligands. In this thesis it was attempted to investigate the synthesis, functionalisation and coordination chemistry of these compound class and finally look at a method of synthesising chiral 4-hydroxybenzoxazoles from amino acids. A small library of achiral 4-hydroxybenzoxazoles were synthesised in good yields. These compounds were then reacted with various transition metals, of which only the Pd-salts proved to return any usable compounds. The first structural evidence of the bonding of 4- hydroxybenzoxazoles was recorded from single crystal X-ray diffraction analysis of the coordination compounds that formed. Different coordination modes were recorded, depending on the ligand and the Pd-salt used. The PdCl2 compounds were also tested for catalytic activity with a Heck reaction, showing good conversions for the reaction between iodobenzene and styrene to form stilbene. Further examination pointed to the ligands playing an insignificant role in the reaction and the products possibly due to only the PdCl2’s reactivity. During this period it was also attempted to functionalise the phenol group with P(III) groups and repeat the coordination and catalytic studies. Efforts to synthesise these compounds were not successful, with oxidation of the P(III) to P(V) groups or degradation of these compounds. Efforts to synthesise these via phosphorous protection, utilising BH3 or the in situ trapping of the compounds with transition metals, were also not successful. During the trapping experiments the phosphinite and Pd-salt formed a re-arranged product that is a known and useful catalyst on its own. Finally a small library of chiral benzoxazoles and 4-hydroxybenzoxazoles were synthesised, starting from amino acids and utilising a Mitsunobu reaction to perform the ring closing. Antimicrobial tests with these compounds did not return any appreciable results.

AFRIKAANSE OPSOMMING: Bensoksasool is 'n belangrike klas van π-elektron-ryk, benseen-saamgesmelte heterosikliese verbindings wat in natuurlike produkte voorkom en 'n wye verskeidenheid van farmakologiese funksies vertoon. Dit is dus 'n baie algemene basis struktuur vir dwelm- en landbouchemiese ontdekkings programme. Ander gebruike sluit in: chirale ligande in asimmetriese reaksies, chirale reseptore vir die resolusie van rasemiese mengsels, fluoresserende verwittings kleurstowwe, verskeie fotochromiese materiaal en as ligande vir 'n wye verskeidenheid van katalitiese reaksies. As gevolg van ons belangstelling in resorsinarene, het ons op 'n strukturele motief afgekom wat nog nie ondersoek is as potensiële asimmetriese ligande nie, die 4- hidroksiebensoksasole. In hierdie tesis is gepoog om die sintese, funksionalisering en koördinasie chemie van hierdie klas verbindings te ondersoek en uiteindelik 'n metode te ontwikkel om die sintese van chirale 4-hidroksiebensoksasole vanaf aminosure te bewerkstellig. 'n Klein biblioteek van achirale 4-hidroksiebensoksasole was gesintetiseer in goeie opbrengste. Hierdie verbindings was toe behandel met verskeie oorgangsmetale, waarvan slegs die Pdsoute enige bruikbare verbindings gevorm het. Die eerste strukturele bewyse van die binding van die 4-hidroksiebensoksasole is aangeteken met behulp van enkelkristal X-straaldiffraksie ontleding van die koördinasieverbindings wat gevorm is. Verskillende koördinasie mode is aangeteken, afhangende van die ligand en die Pd-sout wat gebruik was. Die PdCl2 verbindings is ook vir katalitiese aktiwiteit met 'n Heck reaksie getoets. Die reaksie het baie goeie omskakeling gewys vir die reaksie tussen iodobenseen en stireen na stilbeen. Verdere ondersoeke het getoon dat die ligande nie ‘n beduidende rol in die reaksie speel nie en die produkte moontlik slegs as gevolg van die PdCl2 se reaktiwiteit is. Gedurende hierdie tydperk was daar ook probeer om die fenol groep met P(III) groepe te funksionaliseer. Met die uitgangstowwe sou die koördinering en katalitiese studies herhaal word. Pogings om hierdie verbindings te sintetiseer was nie suksesvol nie, met oksidasie van die P(III) na P(V) groepe of afbreking van hierdie verbindings. Pogings om dit te sintetiseer via fosfor beskermingstegnieke, deur gebruik te maak van BH3 of die in situ vasvang van die verbindings met oorgangsmetale, was ook nie suksesvol nie. Gedurende die vasvang eksperimente het die fosfien en PdCl2 ‘n herrangskikkings-produk gevorm wat op sy eie ‘n bekende en nuttige katalisator is. Ten slotte was 'n klein biblioteek van chirale bensoksasole en 4-hidroksiebensoksasole gesintetiseer, vanaf aminosure. Om die ringsluiting te bewerkstellig was ‘n Mitsunobu reaksie gebruik. Antimikrobiese toetse met hierdie verbindings het nie enige noemenswaardige resultate opgelewer nie.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/97900
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