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dc.contributor.advisorBezuidenhoudt, B. C. B.
dc.contributor.advisorMarais, C.
dc.contributor.authorSerdyn, Maretha
dc.date.accessioned2015-11-12T10:30:22Z
dc.date.available2015-11-12T10:30:22Z
dc.date.issued2013-01
dc.identifier.urihttp://hdl.handle.net/11660/1618
dc.description.abstractEnglish: Flavonoids are polyphenolic naturally occurring compounds with a wide variety of biological and physiological activities, like anti-platelet, anti-inflammatory, antioxidant, antiviral, antiallergenic, and antitumor properties. The potential therapeutic value of these compounds gave impetus to the development of numerous synthetic routes to not only get access to more material than possible through the isolation thereof from natural sources, but also to have access to flavonoids with substitution patterns different to those of naturally occurring analogues. Existing synthetic methodologies, however, involve tedious multistep processes, stoichiometric amounts of sometimes toxic reagents that produce large amounts of waste, harsh reaction conditions and are not always high yielding. With this in mind, it was envisaged that isoflavonoids might be accessible via a catalytic process entailing hydroesterification of 2-hydroxystilbenes. If the desired regio-isomer could be obtained during this reaction, cyclization between the 2-hydroxy group and the introduced ester moiety would give rise to the heterocyclic C-ring of the corresponding isoflavonoid. Although it is known that steric factors play a prominent role in regioselective control during hydroesterification processes, little is known about the role of the electronic environment around the double bond during these reactions. To address this issue and determine the feasibility of hydroesterification methodology for the synthesis of isoflavonoids, various stilbenes with electron-withdrawing and electron-donating groups, respectively on the two aromatic rings were envisaged as substrates to be subjected to palladium catalysed hydroesterification reactions. Since the Wittig reaction is well-known for the formation of alkenes such as the envisaged stilbenes, this approach was followed in order to prepare the required starting materials. Although the phosphonium salts, benzyltriphenylphosphonium bromide and p-methoxybenzyltriphenylphosphonium chloride, required as reactant in the Wittig reaction, could easily be prepared from the benzyl halide and triphenylphosphine (PPh3) in good yields (98 % and 76 %, respectively), preparation of the p-methoxybenzyl bromide/chloride were more challenging and led to an overall yield for the phosphonium salt of only 45 %. Other methodologies towards the synthesis of substituted phosphonium salts, i.e. treatment of p-methoxybenzyl alcohol with PPh3 in trifluoroacetic acid and cleavage of the benzyl methyl ether, p-methoxybenzyl methyl ether, with PPh3 .HBr, were therefore investigated but yields of only 10 and 38 %, respectively, were obtained. With the best methodology for the synthesis of phosphonium salts determined, attention was subsequently turned towards the final step in the preparation of the envisaged starting materials, i.e. synthesis of the oxygenated stilbenes. Methoxystilbene was therefore prepared according to the traditional Wittig reaction between benzyltriphenylphosphonium bromide and p-anisaldehyde, with BuLi as base and the product obtained in only 33 %. In an effort to improve on the yield, the same Wittig reaction was performed utilizing an organic/aqueous (aldehyde and aq. NaOH) biphasic solvent system with NaOH as base, which led to an increase in yield (54 %). Application of the same methodology to the synthesis of 2- methoxystilbene and 4-ethoxymethoxystilbene resulted in the formation of the desired products in 53 and 55 % yields, respectively. The latter compound, 4-ethoxymethoxystilbene, was subsequently subjected to acid catalysed deprotection (quantitative yield) followed by reaction with trifluoromethanesulfonyl chloride and triethylamine to obtain a stilbene, 4-trifluorosulfonyloxystilbene, protected with an electronwithdrawing substituent in 54 % yield. In an effort to improve the yields obtained for the stilbene preparation process to beyond ca. 50 %, a microwave assisted Perkin-type reaction between phydroxybenzaldehyde and phenylacetic acid with a piperidine-imidazole catalyst system and PEG-400 as solvent, was embarked upon and hydroxystilbene obtained in 42 % yield. Although the yield was almost the same as what was found with the Wittig method, this reaction did not require protection of the free phenolic hydroxy group or the time consuming preparation of starting materials and needed reaction times of only 10 minutes, as well as the added advantage of it being an environmentally more favourable procedure compared to the Wittig reaction. Since Pd(OAc)2 together with PPh3 and the Lewis acid activator/co-catalyst Al(OTf)3 have been reported as one of the best catalyst systems for the methoxycarbonylation of many different aliphatic alkenes, this catalyst system was utilized in the methoxycarbonylation (35 bar CO pressure, 95 °C) of model substrates like hex-1-ene, styrene and allylbenzene and obtained conversions to the corresponding methyl ester products of 70, 99 and 57 %, respectively. When trans-stilbene was, however subjected to the same reaction conditions and catalyst system, virtually no product was formed, so it was decided to use the model substrate, trans-β-methylstyrene, for determining the best catalyst system and reaction conditions for the methoxycarbonylation of substrates that has the double bond in conjugation with an aromatic ring. While it was found during this investigation that the reaction conditions of 35 bar and 95 °C was indeed the optimum for trans-β-methylstyrene, PdCl2 proved to be more reactive than Pd(OAc)2 when applied to the methoxycarbonylation of substrates with conjugated double bonds, with a 90 % conversion to the products, methyl 4-phenylbutanoate, methyl 2-methyl-3-phenylpropanoate and methyl 2-phenylbutanoate, in a 6:2:1 ratio. Due to the insolubility of trans-stilbene in pure methanol, a solvent study was embarked upon and MeOH:THF (1:1) was found to be the best alternative to pure methanol (conversion of 61 vs. 90 % in pure MeOH). With the optimum reaction conditions determined, the influence of a higher degree of substitution around the double bond as well as position of substituents attached to the double bond were investigated, it was also decided to evaluate the effect of the electron-donating and electron-withdrawing substituents attached to the aromatic ring, on the outcome of the reaction. Subjecting α-methylstyrene and 2-methyl-1- phenylprop-1-ene to the reaction conditions, led to the conversion (38 and 22 %, respectively) and isolation of the expected products, methyl 3-phenylbutanoate and methyl 3-methyl-4-phenylbutanoate, indicating that the steric environment around the double bond indeed has a significant influence on the reaction. The electronic effects were studied through the methoxycarbonylation of trans-anethole (the p-methoxy equivalent of trans-β-methylstyrene) and 1-(4'-trifluoromethanesulfonyloxyphenyl)prop-1-ene and, while the three expected products were obtained, it was found that an aromatic methoxy substitutent has an inhibiting effect on the reaction (21 % vs. 90 % conversion of trans-β-methylstyrene), while the substrate with the deactivating group showed a much improved conversion (31 %) compared to the p-methoxy analogue. Performing the methoxycarbonylation of trans-β-methylstyrene (in MeOH) in the presence of anisole (1:1) proved that aromatic methyl ethers indeed have a detrimental effect on the reaction, since only trace amounts of the products could be detected in this instance. Since chiral induction during the enantioselective synthesis of isoflavonoids has been achieved through utilization of amide chiral auxiliaries, like 2-imidazolidinones, it was decided to investigate the possibility of transforming an alkene into an amide in a one-step reaction and therefore circumvent the need for a second reaction to obtain the desired amide. Trans-β-methylstyrene was therefore subjected to the methoxycarbonylation conditions developed before [PdCl2/Al(OTf)3/PPh3, 35 bar CO, 95 °C], but in an inert solvent (THF) containing aniline as nucleophile and 53 % conversion to N,2-diphenylbutanamide and 2-methyl-N,3-diphenylpropanamide in a 6:1 ratio was obtained. Encouraged by the success of the first ever palladium catalysed aminocarbonylation reaction, the scope of the reaction was extended to include substrates like benzamide, n-butylamine and piperidine, but these nucleophiles were found to be unreactive, so more work is clearly needed to determine the conditions necessary for the successful utilization of these compounds in aminocarbonylation reactions. Finally, attention was turned to the methoxycarbonylation of the stilbenes, therefore trans- and cis-stilbene as well as trans-2-methoxystilbene were subjected to the palladium catalysed reaction, but only very low conversions (trace amounts up to 4 %) were found. Since everything pointed towards the electronic effect of conjugation, which deactivates the double bond to such an extent that the reaction with the palladium catalyst is supressed, being the cause of the failure of stilbenes to undergo methoxycarbonylation, 1,3- diphenylprop-1-ene, a substrate with the double bond not in conjugation with the two aromatic rings, were therefore subjected to the reaction and a conversion of 27 % to the product, methyl 2,4-diphenylbutanoate, was obtained. This result clearly demonstrates that the failure of stilbenes to undergo hydroesterification reactions originates in the fact that the double bond is in conjugation with two aromatic rings.en_ZA
dc.description.abstractAfrikaans: Flavonoïede verteenwoordig polifenoliese verbindings met ‘n verskeidenheid biologiese en fisiologiese aktiwiteite, onder andere anti-inflammatoriese, antivirale, antiallergeniese en antigewas-vormende eienskappe, wat algemeen in die natuur voorkom. Die potensiële terapeutiese waarde van hierdie verbindings was dan ook die dryfkrag agter die ontwikkeling van metodologie om nie net toegang te verkry tot meer material as wat vanuit die natuur geïsoleer kan word nie, maar ook om flavonoïede te kan sintetiseer met spesifieke, nie beskikbare, substitusie patrone. Bestaande metodes vir die sintese van hierdie groep verbindings maak egter gebruik van tydrowende multistap prosesse, stoichiometriese hoeveelhede soms giftige reagense wat groot hoeveelhede giftige afval genereer en ekstreme reaksie kondisies, terwyl hoë opbrengste nie altyd haalbaar is nie. Ten einde hierdie leemtes aan te spreek, is die moontlikheid geïdentifiseer dat isoflavonoïede berei kan word deur middel van ‘n katalitiese proses gebaseer op die hidro-esterifisering van 2-hidroksistilbene. Die sukses van genoemde benadering is egter daarvan afhanklik dat die verlangde regio-isomeer, wat siklisering tussen die hidroksigroep van die stilbeen en die nuut gevormde ester funksie na ‘n seslid ring moontlik sal maak, tydens die hidro-esterifiseringsreaksie verkry moet word. Alhoewel die invloed van steriese faktore op die regioselektiewe uitkoms van hidro-esterifiseringsreaksies bekend is, is die effek van die elektroniese omgewing rondom die dubbelbinding van die alkeen steeds nie behoorlik ondersoek nie. Een van die doelstellings van hierdie ondersoek was dus die vasstelling van die invloed wat elektron-onttrekkende substituente op een van die aromatiese ringe van die stilbeen en elektron-donerende substituente geheg aan die ander ring, op die palladium gekataliseerde hidro-esterifiseringsreaksie sou hê. Aangesien die Wittig reaksie een van die beste metodes vir die vorming van alkene verteenwoordig, is besluit om hierdie roete vir die sintese van die verlangde stilbene te volg en is die bereiding van die benodigde fosfoniumsoute as eerste stap in die ondersoek aangepak. Hoewel die eenvoudige fosfoniumsoute, bensieltrifenielfosfoniumbromied en p-metoksibensieltrifenielfosfoniumbromied of chloried, wat vir die ondersoek benodig is, maklik deur behandeling van die ooreenstemmende bensielbromied met trifenielfosfien (PPh3) in 98 % en 76 % opbrengste onderskeidelik verkry kon word, was bereiding van die geöksigeneerde bensielhalied nie so eenvoudig nie en het dit die algehele opbrengs oor die twee stappe tot slegs 45 % verlaag. Verskeie ander metodes, soos behandeling van p-metoksibensielalkohol met PPh3 in trifluoroasynsuur en splyting van die bensielmetieleter, p-metoksibensielmetieleter, met PPh3 .HBr, is vir die bereiding van die suurstofdraende fosfoniumsoute ondersoek, maar slegs 10 en 38 % opbrengste kon onderskeidelik vir hierdie twee metodes verkry word. Met die evaluering van metodes vir die bereiding van fosfoniumsoute afgehandel is aandag vervolgens aan die bereiding van die verlangde stilbene geskenk. Metoksistilbeen is gevolglik met behulp van ‘n tradisionele Wittig-reaksie (BuLi) tussen bensieltrifenielfosfoniumbromied en p-anisaldehied berei, en ‘n lae opbrengs van slegs 33 % is verkry. Ten einde die opbrengs uit die reaksie te verbeter, is dieselfde reaksie in ‘n organies-waterige (aldehied en aq. NaOH) bifasiese sisteem met natriumhidroksied as basis herhaal wat daartoe gelei het dat die produk in 54 % opbrengs verkry kon word. Toepassing van dieselfde metode op die bereiding van 2-metoksi- en 4-etoksimetoksistilbeen het daartoe gelei dat die onderskeie produkte in 53 en 55 % opbrengs verkry kon word. Laasgenoemde verbinding (4-etoksimetoksistilbeen) is dan ook in 54 % opbrengs na die ooreenstemmende 4-trifluorometaansulfonieloksistilbeen omgeskakel deur middel van suur gekataliseerde hidroliese (kwantitatiewe opbrengs) gevolg deur reaksie met trifluorometaansulfonielchloried en triëtielamien. Aangesien opbrengste van hoër as ca. 50 % vir die vorming van stilbene nie verkry kon word nie, is die toepassing van ‘n mikrogolf gebaseerde Perkin-tipereaksie vir die bereiding van hidroksistilbene vervolgens ondersoek. ‘n Mengsel van p-hidroksibensaldehied en fenielasynsuur in PEG-400 is dus in die teenwoordigheid van ‘n piperidien-imidasool katalisator vir 10 minute aan mikrogolf bestraling blootgestel wat toe daartoe gelei het dat 4- hidroksistilbeen in 42 % opbrengs verkry kon word. Hoewel die opbrengs nie dramaties beter was as wat met die Wittig-reaksie gevind is nie, moet dit in aanmerking geneem word dat beskerming van hidroksigroepe tydens toepassing van hierdie proses nie nodig is nie, dat die tydrowende bereiding van reagense omseil word en dat die reaksietyd slegs 10 minute beloop sowel as die gebruik van omgewingsvriendeliker reaksie kondisies. Aangesien Pd(OAc)2, tesame met trifenielfosfien (PPh3) en die Lewissuur, Al(OTf)3, aktiveerder/kokatalisator, algemeen in die literatuur vir die metoksikarbonilering van verskillende alifatiese alkene bedryf is, is hierdie sisteem vir die metoksikarbonilering (35 bar CO druk en 95 °C) van ‘n aantal modelsubstrate soos heks-1-een, stireen en allielbenseen benut en omskakelings van 70, 99 en 57 %, na die ooreenstemmende metielester produkte, is verkry. Benutting van hierdie katalisatorsisteem en reaksiekondisies tydens die metoksikarbonilering van trans-stilbeen het egter tot geen noemenswaardige produkvorming gelei nie, daarom is besluit om optimisering van die katalisatorsisteem en reaksiekondisies vir substrate met dubbelbindings in konjugasie met ‘n aromatiese ring met behulp van trans-β-metielstireen, as modelverbinding, uit te voer. Hoewel tydens die ondersoek gevind is dat 95 °C en 35 bar inderdaad die optimale reaksiekondisies vir die metoksikarbonilering van trans-β-metielstireen verteenwoordig, is egter gevind dat PdCl2 ‘n meer reaktiewe katalisatorsisteem as Pd(OAc)2 tot gevolg het en het die toepassing daarvan op trans-β-metielstireen tot ‘n 90 % omskakeling na die produkte, metiel-4-fenielbutanoaat, metiel- 3-feniel-2-metielpropanoaat en metiel-2-fenielbutanoaat, in ‘n 6:2:1 verhouding gelei. Weens die onoplosbaarheid van trans-stilbeen in suiwer metanol, is ‘n ondersoek na die beste oplosmiddelsisteem vir nie-polêre verbindings ook onderneem en is vasgestel dat ‘n MeOH:THF (1:1) mengsel die beste alternatiewe oplosmiddel vir hierdie tipe substraat verteenwoordig (omskakeling 61 vs. 90 % vir suiwer MeOH). Met die beste katalissisteem en reaksiekondisies vir die metoksikarbonilering van gekonjugeerde alkeen substrate bepaal, is aandag vervolgens aan die effek van meer substituente geheg aan die dubbelbindingkoolstowwe en verskillende posisies vir die substituente gegee, terwyl die invloed van elektron-onttrekkende en elektron-skenkende groepe gebind aan die aromatiese ringe ook bestudeer is. Ten einde die invloed van groepe gebind aan die dubbelbinding te bepaal, is α-metielstireen en 1-feniel-2- metielprop-1-een aan die beste metoksikarbonileringskondisies blootgestel en ‘n omskakeling van 38 en 22% na die verwagte produkte, metiel-3-fenielbutanoaat en metiel-4-feniel-3-metielbutanoaat, verkry. Bogenoemde toon aan dat die steriese omgewing rondom die dubbelbinding inderdaad ‘n groot effek op die reaktiwiteit van die dubbelbinding uitoefen. Die elektroniese effek van groepe gebind aan die aromatiese ringe is met behulp van ‘n vergelyking van die reaktiwiteit van trans-anetool (die 4-metoksi-ekwivalent van β-metielstireen) met die van 1-(4'-trifluorometaansulfonieloksifeniel)prop-1-een, ondersoek en is ‘n omsetting van slegs 21 % na die verwagte produkte uit die anetoolreaksie gevind (vergelyking met 90 % vir trans-β-metielstireen), terwyl die substraat met die elektron-onttrekkende groep ‘n omsetting van 32 % gelewer het. Dit was dus duidelik dat ‘n aromatiese metoksigroep die metoksikarbonileringsreaksie nadelig beïnvloed. Ten einde hierdie waarneming te bevestig, is die metoksikarbonilering van trans-β-metielstireen (in metanol) in die teenwoordigheid van anisool (1:1) herhaal en is slegs spoorhoeveelhede van die produkte gevind. Aangesien chirale induksie tydens die enantioselektiewe sintese van isoflavonoïede deur middel van die benutting van amied chiralehulpmiddels soos 2-imidasolidinone, bereik is, is besluit om die moontlikheid dat alkene deur middel van ‘n hidro-esterifiseringstipe reaksie direk in n amied omgeskep kan word, te ondersoek. Trans-β-metielstireen is gevolglik aan metoksikarbonilering onderwerp [PdCl2/Al(OTf)3/PPh3, 35 bar CO, 95 °C], maar in ‘n inerte oplosmiddel (THF) en die teenwoordigheid van anilien as model nukleofiel (alkeen:anilien, 1:1) en die verwagte produkte, N,2-difenielbutaanamied en N,2-difeniel-2- metielpropaanamied, in 51 % omsetting en ‘n 6:1 verhouding gevind. Uitbreiding van die eerste palladium gekataliseerde aminokarbonilering deur ander nukleofiele soos bensamied, n-butielamien en piperidien in te sluit, was egter onsuksesvol, daardeur blyk dit dat heelwat navorsing nog gedoen moet word ten einde die algemene toepaslikheid van hierdie nuwe reaksie moontlik te maak. Met die bostaande kennis beskikbaar, is aandag weereens na die metoksikarbonilering van stilbene gedraai en is trans- en cis-stilbeen sowel as trans-2-metoksistilbeen aan die palladium gekataliseerde reaksie onderwerp. Aangesien slegs spoorhoeveelhede van die verlangde produkte verkry kon word, het alle data dus daarop gedui dat konjugasie tussen die dubbelbinding en die twee aromatiese ringe die dubbelbinding sodanig deaktiveer dat die reaksie met die palladium katalisator bykans ten volle onderdruk word. Ten einde vas te stel of hierdie toestand wel die oorsaak van die mislukte metoksikarbonilering van stilbene was, is ‘n substraat, 1,3-difenielprop-1-een, waarin ‘n addisionele koolstofatoom tussen een fenielring en die dubbelbinding ingevoeg is, berei en aan metoksikarbonilering onderwerp. Die feit dat die produk, metiel-2,4-difenielbutanoaat, in 27 % omsetting verkry kon word, het dan ook eenduidig bewys dat die oorsaak van die onreaktiwiteit van stilbene in die konjugasie van die dubbelbinding met die twee aromatiese ringe geleë is.af
dc.description.sponsorshipNational Research Foundation (NRF)en_ZA
dc.language.isoenen_ZA
dc.publisherUniversity of the Free Stateen_ZA
dc.subjectFlavonoids -- Synthesisen_ZA
dc.subjectCarbonyl compounds -- Synthesisen_ZA
dc.subjectPalladium catalystsen_ZA
dc.subjectStilbeneen_ZA
dc.subjectChemistry, Organicen_ZA
dc.subjectDissertation (M.Sc. (Chemistry))--University of the Free State, 2013en_ZA
dc.titleParameters influencing regioselectivity in the palladium catalysed carbonylation of stilbenes and related alkenesen_ZA
dc.typeDissertationen_ZA
dc.rights.holderUniversity of the Free Stateen_ZA


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