Chemistry

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Open Access
Application of the cross-metathesis reaction as alternative methodology for the synthesis of paramethoxycinnamate analogues as sunscreen components
(University of the Free State, 2016-01) Swart, Marthinus Rudi; Marais, C.; Bezuidenhoudt, B. C. B.
2-Ethylhexyl p-methoxycinnamate [Octyl methoxycinnamate (OMC)] is an organic compound that is commercially used in the cosmetic industry as a UV blocker in sunscreen creams and lotions. Commercial production of this compound, however, is hampered by multiple synthetic steps, high temperatures, tedious work-up procedures, halogenated by-products, and low atom economy. Due to the abundance of naturally occurring essential-oil phenylpropenoids like estragole, eugenol, and safrole, which can easily be transformed into anethole, isoeugenol, and isosafrole by catalytic double bond isomerisation, the possibility of utilizing one of these b-methylstyrenes, i.e. anethole, together with 2-ethylhexyl acrylate in metathesis based methodology for the preparation of OMC looked promising and was investigated. Model metathesis reactions between trans-b-methylstyrene and methyl acrylate over Grubbs 2nd generation catalyst, however, produced only the homometathesis product, trans-stilbene, in very high yields (>99%). Solvent, temperature and reactant ratio studies failed to change the course of the reaction towards the desired cross-metathesis product. Since Forman et al. reported the addition of phenol to the reaction mixture to enhance crossmetathesis over self-metathesis, the reaction was repeated with p-cresol (2 eq.) as additive. In order to prevent secondary metathesis reactions from occurring, the propene side-product was also stripped away by entrainment with argon, which led to the successful formation of methyl cinnamate in 38% yield. In order to determine the general applicability of the new process, the electronic effect, if any, of substituents in the para-position of the b-methylstyrene and the steric/electronic influence of the alkyl group attached to the α,b-unsaturated carbonyl compound on the outcome of the reaction were investigated. Trans-pmethoxy- b-methylstyrene (trans-anethole) (1 eq.) and trans-4- trifluoromethylsulfonyloxy-b-methylstyrene (1 eq.) were therefore reacted with methyl acrylate (2 eq.) under the optimized reaction conditions [Grubbs 2nd generation catalyst (0.5 mol%), p-cresol (0.25 eq.), refluxing DCM (10 mL), 2 hours] and it was found that an electron-donating group in the para-position caused a slight decrease in cross-metathesis product formation (36% vs 38% for unsubstituted trans-b-methylstyrene) whereas an electron-withdrawing group (triflate) in the same position enhanced cinnamate formation (43% vs 38%). The concomitant homo-metathesis reaction followed the opposite trend with the p-triflate suppressing stilbene formation (4% vs 18% for unsubstituted trans-b- methylstyrene) and a p-methoxy group enhancing the formation of the stilbene (50% vs 18%). When the influence of the O-alkyl group attached to the α,b-unsaturated carbonyl moiety was investigated, it was found that the yield of the cinnamate product increased with increasing steric bulk of the alkyl group. For the reaction of unsubstituted trans-b-methylstyrene with methyl acrylate and n-butyl acrylate, respectively, the yield increased from 38 to 55%, while for reaction between trans-anethole and these acrylates it went from 36 to 41%. Substituting the ester O-alkyl moiety in the α,b-unsaturated system with an alkyl group (3-buten- 2-one) and a hydrogen (acrolein), resulted in moderate yields of 34 and 32% for the reactions between the ketone and unsubstituted trans-b-methylstyrene and trans-anethole, respectively, while with acrolein only trace amounts (< 5%) of the cross–metathesis products were obtained. In all these reactions, the respective stilbenes were formed in 18 (for the reaction between methyl or nbutyl acrylate and trans-b-methylstyrene) to 58% (for the reaction of acrolein with trans-b-methylstyrene) yield. Finally, trans-β-methylstyrene and transanethole were reacted with 2-ethylhexyl acrylate to form 2-ethylhexyl cinnamate and the desired 2-ethylhexyl p-methoxycinnamate (OMC), which could be isolated as major products from the reaction in 64 and 47% yields, respectively. Due to the higher reactivity of trans-anethole, the cross-metathesis product (OMC) in this instance was accompanied by 32% of 4,4’-dimethoxystilbene. In an effort to determine how p-cresol addition affects the catalytic cycle of Grubbs 2nd generation catalyst and thus how it influences product formation, a full NMR study of the addition of cresol to the catalyst, the catalyst and trans-b-methylstyrene, the catalyst and methyl acrylate, as well as all the reactants together, was embarked upon. Despite severely restricted rotation, which necessitated the spectra to be recorded at 60 oC, room temp., and -40 oC, all the 1H and 13C NMR resonances in the spectra of the Grubbs II catalyst could be allocated unambiguously to the appropriate protons and carbon atoms. 31P NMR studies allowed for the confirmation of a hydrogen bonding complex between cresol and the catalyst, while it also indicated some dissociation of the tricyclohexylphosphine from the catalyst to occur. The liberated tricyclohexylphosphine, however, prefers to react with the acrylate in a 1,4- addition process rather than forming a complex with the cresol as was postulated by Forman et al. This was confirmed by the preparation of the zwitterionic phosphonium salt through reaction of tricyclohexylphosphine with methyl acrylate in the presence of LiCl. Addition of cresol to the reaction mixture enhances the formation of the salt in its protonated form, while it also induces accelerated formation of oligomeric forms of the initially formed monomeric zwitterionic phosphonium salt. Although Forman et al. proposed the addition of phenols to stabilize the Grubbs catalyst by slowing down the dissociation of the tricyclohexylphosphine from the metal and once dissociated, prevents the phosphine from binding to the metal again, this explanation does not allow for the fact that the more reactive styrene analogue becomes less reactive than the acrylate moiety when cresol is added to the reaction mixture, as is evident from the fact that cresol addition enhances cross-metathesis. It was determined during the current study that the crossmetathesis products (cinnamates) are indeed the result of the primary metathesis process and are not formed through secondary metathesis of the stilbene products. In order to explain the formation of the cross-metathesis over homo-metathesis products in the presence of cresol, it is proposed that an associative mechanism rather than a dissociative process is prevailing when cresol is added to the reaction mixture. In this instance the co-ordination number of the ruthenium temporarily increases from 5 to 6 to allow for the additional ligand to be attached to the metal centre. The catalyst complex therefore becomes sterically more crowded and the steric size of the incoming ligand (reactant) would play a decisive role in its ability to react with the metal centre in the first step of the reaction. Since acrylate represents a mono substituted alkene and the alkyl group resides in a remote location with regard to the reaction centre, it would be sterically less demanding when compared to trans-b-methylstyrene and lead to enhanced formation of the cross-metathesis product. This assumption was proven by substituting methyl acrylate with methyl crotonate during the reaction and the resulting drop in cross-metathesis product from 38 to 31% yield observed. Support for this proposal comes from results by Fogg and co-workers, who reported cross-metathesis to be the dominant reaction when b-methylstyrenes were reacted with acrylates over the Hoveyda-Grubbs catalyst. Finally, with a number of cinnamates (OMC, methyl p-methoxycinnamate, methyl cinnamate, n-butyl cinnamate, n-butyl p-methoxycinnamate, and 2- ethylhexyl cinnamate) and 3-buten-2-ones [4-phenyl-3-buten-2-one and 4-(4- methoxyphenyl)-3-buten-2-one] available, it was decided to evaluate the UV-B blocking properties of these compounds through utilization of UV spectroscopy in an effort to determine if OMC would, in principle, be the best sunscreen component of the series. By comparing the UV spectra of OMC to that of the other compounds, it was determined that methyl cinnamate, n-butyl cinnamate, methyl p-methoxycinnamate and n-butyl p-methoxycinnamate could be promising candidates in the development of new and maybe better sunscreen lotions and should be subjected to biological evaluation processes.
Open Access
Chemical profile of walnuts (Juglans regia L.) and synthesis of stilbenes from Arformosia elata
(University of the Free State, 2007-01) Sonopo, Molahlehi Samuel; Kamara, B. I.; Bezuidenhoudt, B. C. B.
Firstly, this study presents an in-depth investigation on Walnuts (the nuts of Juglans regia L.). Walnuts (Juglans regia L.) are members of the relatively small Juglandaceae family, which have shown positive results in humans, in the treatment of metabolic syndrome. Besides the very high content of unsaturated fatty acids (60-70%) in Walnuts (Juglans regia L.), previous investigations have revealed tannins as the only phenolics present. Generally, plants have had their biological activities attributed to the presence phenolics, specifically the flavonoids, which are the most abundant polyphenols in nature. Since Walnuts leave behind an astringent taste in the mouth after ingestion, a characteristic associated with presence of phenolics, especially tannins, it was reasonable to assume that Walnuts may also contain flavonoids. Besides having well-established biological activities such as, antioxidant, anticancer, and anti-inflammatory properties, flavonoids are believed to augment the ability of Walnuts to act as a possible candidate for treatment of metabolic syndrome. In the previous studies, isolation of flavonoids has not been reported. Therefore, in this study we carried out an in-depth investigation to establish the presence of flavonoids in the Walnuts Juglans regia L. Pure compounds were obtained after repeated column and preparative thin layer chromatography and characterized by extensive NMR spectroscopic methods. The phenolics isolated in this study as peracetate and permethyl derivatives from the Walnuts Juglans regia L. are: catechin, gallocatechin, penta-O-acetyl-O-β-D-xylopyranosylellagic acid, gallic acid, methyl gallate, pedunculagin, casuarinin, hexaacetoxy-4-O-β-D-glucopyranosylnapthalene and 2,3-O-(S)-heptamethoxy-β-D-glucopyranosyldiphenoyl. Tetra-O-acetyl-9-β-D-glucopyranosylmegastigmen-3-one, tetraacetoxy-3-O-β-D- glucopyranosylsitosterol, glucose and sucrose were isolated as non-phenolics. Secondly, the study exploits methods to synthesize stilbene monomers and dimers isolated from Afrormosia elata. Afrormosia elata (Pericopsis elata) Harms, Fabaceae, is a tree native to the Guinean equatorial forests of West and Central Africa. The bark of this tree is used as a treatment for cancer by the local population. Stilbenes are a class of polyphenols with very 26 limited taxonomic distribution and varied biological activities which include, blood sugar reduction, antibacterial, antifungal, antioxidant, anti-HIV and anti-inflammatory. They posses COX-1 and COX-2 inhibitory effects, affect lipid peroxidation, LDL oxidation, function as phytoalexins, and have chemopreventative effects on cancer. The reported biological activities of stilbenes highlight the importance of stilbenoids as a resource for development of new drugs and pesticides. Since the occurrence of these stilbenoids in plants is in extremely low concentrations, we attempted synthesis of dimeric stilbenes with the aim of developing methods which may yield qualitative amounts. Syntheses of the monomeric stilbenes preceded that of the dimers. The classic Wittig reaction and the most recently developed metathesis reactions were the routes used to synthesize the monomers,while the route via the Heck coupling was considered for synthesis of the dimeric stilbenes.
Open Access
Development of alternative technology for the production of meta-substituted phenolic compounds
(University of the Free State, 2009-11) Sunil, Abraham C.; Bezuidenhoudt, B. C. B.
English: Both m-cresol and resorcinol are important industrial starting materials in the production of many phenolic products. In a process similar to the one for the production of phenol, cresols are produced by reaction of toluene with propylene to give mixtures of o-, m- and p-isopropyltoluene. The corresponding cresols are subsequently obtained together with acetone via the hydroperoxides by air oxidation. Due to their close boiling points, m- and p-cresol are not separable by distillation and has to be obtained from these mixtures by elaborate adduct crystallisation, derivatization or chromatographic procedures, which results in pure synthetic m-cresol to be a very expensive commodity. Since it is known that mcresol can be produced selectively from o- or p-toluic acid, which is readily available from the corresponding xylene, by application of Keading’s Dow Phenol process, it was decided to investigate this methodology as an alternative for the synthesis of pure mcresol. In order to be in a position to optimise this process, it was decided to investigate the mechanism of the reaction through the use of X-ray diffractometry, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), infrared spectrometry (IR) and MALDI-TOF mass spectrometry. The starting point in the copper catalysed process for transforming o-toluic acid into mcresol, has been established by X-ray diffractometry to be the formation of tetrakis(μ2-2-methylbenzoato)bis(2-methylbenzoic acid)copper(II), with the typical paddlewheel structure of Cu(II) carboxylates, when o-toluic acid was reacted with basic copper(II)carbonate and magnesium oxide in refluxing toluene. Apart from the expected four o-toluic acid entities forming the paddlewheel structure, the crystal structure also indicated another toluic acid molecule to be attached to each copper atom through the carbonyl of the carboxylic acid moiety. Extension of the X-ray crystallographic investigation to the copper salts of p-toluic acid, m-toluic acid, p-ethylbenzoic acid, and 2,6-dimethylbenzoic acid indicted all of these compounds, except the copper (II) salt of p-toluic acid, to have structures similar to that of tetrakis(μ2-2-methylbenzoato)bis(2- methylbenzoic acid)copper(II). While the structure of tetrakis(μ2-4-methylbenzoato) bis(4-methylbenzoic acid)copper(II) basically also showed the paddlewheel configuration, the extra two toluic acid molecules attached to the copper atoms in the all of the other cases were absent in the structure of this compound. In this instance, interactions between an oxygen atom of one molecule and the copper of an adjacent molecule leading to an infinite “polymer” type chain along the a-axis of the crystal, was observed. Evidence gathered from DSC, TGA, and MALDI-TOF MS investigations of the transformation of tetrakis(μ2-2-methylbenzoato)bis(2-methylbenzoic acid)copper(II) into the product, suggested that this copper benzoate rearranges and cleaves into o-toluic acid and copper(I) 2-methyl-6-{[(2-methylphenyl)-carbonyl]oxy}benzoate at 164 °C. Decarboxylation of the latter at 249.5 °C gave o-toluic acid and 3-methylphenyl 2- methylbenzoate, which is hydrolysed into o-toluic acid and the desired product, m-cresol. In contrast to the copper salt of o-toluic acid, which showed clear temperature differences for the different steps in the reaction process, the salt of p-toluic acid displayed one continuous decomposition between 160 and 260 oC, thus rendering the identification of reaction intermediates at specific temperatures more or less impossible. In a process similar to that of cresols, resorcinol is commercially produced by selective formation of m-diisopropylbenzene followed by oxidative cleavage of the dihydroperoxide which is obtained through aerial oxidation of the diisopropylbenzene. While this process is used globally, it is hampered by large recycle streams arising from poor o/p selectivity during the alkylation of benzene as well as the limitation of low conversion (20%) in the oxidation step due to the explosivity of the hydroperoxide intermediate. Since it has been demonstrated that the Diels-Alder reaction could be applied to the synthesis of p-cresol from isoprene and vinyl acetate, application of this methodology to the synthesis of resorcinol, was subsequently investigated. Danishefsky’s diene (trans-1-methoxy-3-trimethylsilyloxy-1,3-butadiene), with the appropriate functional groups already trapped in the required enolic form, was selected as model substrate for the preliminary experiments with model dienophiles, methyl vinyl ketone and butyl acrylate and the novel cis- and trans-products, 4-acetyl-3- methoxycyclohexanone and butyl 2-methoxy-4-oxocyclo-hexanecarboxylate, obtained, albeit in low yields (7.49 and 6.59 % and 7.53 and 9.66 % respectively). When the reaction was extended to the more relevant methyl propiolate as dienophile, no direct Diels-Alder products could, however, be isolated and only methyl 4-hydroxybenzoate and methyl 4-{[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]oxy}benzoate were isolated from the reaction mixture in 5.51 and 5.74 % yields respectively. The formation of the phydroxybenzoate is explicable in terms of methanol elimination from the primary Diels- Alder product, while it is clear that the second product originates from conjugate addition of the formed hydroxybenzoate to methyl propiolate. While seemingly negative, the last Diels-Alder reaction, however, showed that the envisaged methodology could in principle be used for the preparation of resorcinol, but that care would have to be taken in order to avoid unwanted methanol release. If Chan’s diene [1,3-bis-(trimethylsilyloxy)-1- methoxy-1,3-butadiene] or an equivalent to it, could be used in a Diels-Alder reaction with an acrylate, the tendency towards methanol elimination might, however, be advantageous as it might lead to the mono-silylated resorcinol derivative in a single step. The viability of this Diels-Alder strategy towards the synthesis of resorcinol will form part of a future investigation. While negative from the point view of methodology for the synthesis of resorcinol, the Diels-Alder reaction between methyl propiolate and Danishefsky’s diene represents a new catalytic process for the preparation of methyl 4-hydroxybenzoate. This compound is widely used as a preservative in food, cosmetics and pharmaceuticals, while its free acid form (p-hydroxybenzoic acid), which is produced by Kolbe-Schmidt carboxylation of potassium phenolate with carbon dioxide, finds application in the liquid crystal industry.
Open Access
Development of methodology for the synthesis of 4-arylflavan-3-ol lactones
(University of the Free State, 2008-05) Van Tonder, Bernadette; Bezuidenhoudt, B. C. B.; Steenkamp, J. A.; Kamara, B. I.
English: The phenolic content of the heartwood of Peltophorum africanum (African wattle) and Burkea africanum (Red syringa) proved to contain a variety of compounds including the novel 4-arylflavan-3-ol lactones, 6-(3,4-dihydroxyphenyl)-6,6a,8,12b-tetrahydroisochromeno[ 3,4-c]chromene-3,8,10,11,12-pentaol and 6-(3,4,5-tri-hydroxylphenyl)- 6,6a,8,12b-tetrahydroisochromeno[3,4-c]chromene-3,8,10,11,12-pentaol respectively. Several attempts at the synthesis of these compounds to give final proof of the structure including the stereochemistry at the three chiral centres, failed due to the fact that the nucleophilicity of the pyrogallol ring of the gallic acid analogue (both protected and fee phenolic) is reduced to such an extent by the presence of the carbonyl group that it cannot effectively react with a C-4 electrophile generated on the flavan-3-ol starting material. In addition it became evident that the starting materials and products are sensitive to more drastic acid and basic reaction conditions to the extent that no desired products could be isolated from the attempted coupling of gallic acid analogues to C-4 functionalised flavan-3-ols. In order to alleviate these problems, it was envisaged to utilize a nucleophile without the carbonyl attached to it, thus changing the substrate to a pyrogallol entity containing a 1- hydroxypropyl - or allyl substituent. After coupling at C-4 of the flavan-3-ol the required carbonyl could then be introduced by consecutive water elimination and isomerization (1-hydroxylpropyl substituent) or isomerization (allyl substituent) followed by ozonolysis (with non-reductive work-up) and subsequent esterification. Since the starting materials for the synthetic strategy were not available commercially, both the flavan-3,4-diol and 1-(3’,4’,5’-trimethoxyphenyl)propan-1-ol had to be synthesized. While the phenylpropan-1-ol analogue was obtained in 64 % yield through utilisation of a Grignard reaction between 3,4,5-trimethoxybenzaldehyde and ethylmagnesium bromide, the required 3’,4’,7-trimethoxyflavan-3,4-diol became available through synthesis and subsequent manipulation of the appropriate chalcone. Thus trans-2’- ethoxymethoxy-3,4,4’-trimethoxychalcone, obtained by standard Claisen-Schmidt condensation of 2-ethoxymethoxy-4-methoxyacetophenone and 3,4- dimethoxybenzaldehyde, was epoxidized with dimethyldioxirane to give the chalcone epoxide in 98 % yield. Deprotection and cyclization to the dihydroflavonol were accomplished in 67.5 % overall yield via treatment of the chalcone epoxide with benzylmercaptan and tin(iv)chloride, followed by reaction of the subsequent -hydroxy- -benzylmercaptodihydrochalcone with silver tetrafluoroborate. Altough the syn- and anti-isomers of the mercaptodihydrochalcone were observed, both of these isomers led to only the 2,3-trans-dihydroflavonol. Finally, NaBH4 reduction of the dihydroflavonol gave the flavan-3,4-diol 70 % yield. Since the starting materials for - and products from the coupling reaction are known to be acid/base sensitive, it was decided to functionalise the flavan-3,4-diol through a mercaptan leaving unit that could be activated by thiophilic Lewis acid in order to induce coupling with the pyrogallol moiety. Silver tetrafluoroborate catalysed model reactions between 4-benzylmercaptochroman and the aromatic nucleophiles, resorcinol and methylated pyrogallol, gave the 4-arylchromans in 62 and 72% yield respectively. When the nucleophile was changed to 1-(3’,4’,5’-trimethoxyphenyl)propan-1-ol or the dehydrated version, 1-(3’,4’,5’-trimethoxy-phenyl)-1-propene, however, no couple could be detected. Since no apparent change in nucleophilicity could be identified as the cause of the reaction not giving any product, the failure can probably be ascribed to steric congestion brought about by the methoxy- and allyl - or propyl groups adjacent to the required point of reaction. As it is known from literature that radicals play an important role in the in vivo synthesis of many natural products, a biomimetic approach towards the synthesis of the 4- arylflavan-3-ol lactones was considered as next alternative. It was therefore envisaged that generation of a phenolic radical at C-2 of the pyrogallol ring of a flav-3-ene 3-gallate ester moiety could result in the formation of the desired lactone. Thus tetra-O-methyl catechin was converted into the 3-keto compound by mild IBX (2-iodoxybenzoic acid) oxidation in 61 % yield. Treatment of the catechin derivative with LDA followed by quenching of the enolate with t-butyldiphenylchlorosilane led to 3-tertbutyldiphneylsilyloxy- 3’,4’,5,7-tetramethoxyflav-3-ene in 84 % yield; thus proving that the double bond was indeed in the right position (between C-3 and C-4 and not C-2 and C-3) for the lactone to be formed. With the position of the double bond established, the enolization reaction was repeated with 2-bromobenzoyl chloride as model electrophile and the enol ester obtained in 22 % yield. In this instance, however, the desired enol ester was accompanied by the 2,3-unsaturated isomer (43 %). With all the uncertainties round the oxidation and enol formation sorted out, the final step in this strategy for the synthesis of the target lactones can now attempted with confidence. AIBN initiated radical cyclization of 3-O-(3”,4”,5”-trimethoxybenzoyl)-3’,4’,7-trimethoxyflav-3-ene and 3-O-(3”,4”,5”-trimethoxybenzoyl)-3’,4’,5’,7-tetramethoxyflav-3-ene will, however, receive attention in a subsequent PhD study.
Open Access
Die eerste oligomeriese neoflavonoiede: struktuur en sintese van modelverbindings
(University of the Free State, 1993-05) Nel, Janetta Wilhelmina; Bezuidenhoudt, B. C. B.; Brandt, E. V.; Ferreira, D.
Afrikaans: Hoewel oligomeriese flavonoïede reeds etlike dekades bekend is, is die eerste bi-isoflavonoïede eers onlangs uit Dalbergia spesies geïsoleer en is oligomere saamgestel uit neoflavonoïede nog onbekend. Ten einde die poel van oligomeriese isoflavonoïede uit te brei is die fitochemiese ondersoek na die fenoliese komponente in die kernhout van Dalbergia nitidula Welw. ex Bak, bekend vir die voorkoms van talle monomeriese iso- en neoflavonoïede, onderneem. Drie nuwe unieke iso-neoflavonoïed dimeriese verbindings bestaande uit 'n seldsame 3-fenielbenso[b]furaan- en vir die eerste keer 'n pterokarpaaneenheid, nl. (6aS,11aS)-2-, (6aS,11aS)-4- en (6aS,11aS)-8-[3-feniel-5-hidroksi-6-metoksibenso-[b]furan-2-ielmetiel]medikarpin, is inderdaad tydens die ondersoek gevind. Hierdie verbindings word in die eterekstrak vergesel deur 'n verdere dimeer waarin dieselfde neoflavonoïedeenheid aan (+ )-vestitol gebind is, nl. (3S)-8-[3-feniel-5-hidroksi-6-metoksi benso[b]furan-2-ielmetiel] vestitol. Benewens die dimere is 2', 7-dihidroksi-4'-metoksi-isoflav-3-een, die vyfde natuurlike isoflaveen, en (6aS,11aS)-2-hidroksi-3,9-dimetoksipterokarpaan as nuwe mono-mere verkry, terwyl 3,8-dihidroksi-9-metoksipterokarpaan vir die eerste keer as die 6aS,11aS isomeer geïsoleer is. Die bekende benso[b]furaan, centrolobofuraan, is ook saam met bekende verbindings soos (±)-ferreirien, di-O-metieldaidzein, (+ )-claussekinoon, 3-hidroksi-9-metoksikumestaan en (+ )-vestikarpin vir die eerste keer in hierdie spesie gevind, terwyl (+ )-medikarpin, (+ )-homopterokarpin, (+ )-vestitol, 3,9-dimetoksikumestaan asook (±)-liquiritigenien en isoliquiritigenien weereens verkry is. Aangesien onsekerheid omtrent die heterosikliese sisteem van die neoflavonoïedeenheid in die dimere bestaan het, is die sintese van 'n neoflavonoieddimeer met 'n seslid heterosikliese ring, (6 aS,11as)-4-[6-hidroksi-7 -metoksineoflav-3-een-3-iel] medikarpin d.m.v. 'n aldol-tipe kondensasie tussen 'n gesubstitueerde bensofenoon en pterokarpanielasetaldehied gevolg deur 'n sikliseringstap, aanvanklik aangepak (Skema). Weens die seldsame substitusiepatroon van die bensofenoon, is 2-hidroksi--4-metoksibensofenoon, as model, d.m.v. 'n Grignardreaksie tussen 4-metoksi-2-O-metoksimetielbensaldehied en fenielmagnesiumbromied daargestel en die pterokarpanielasetaldehied vanaf (+ )-medikarpin deur O-allilering (K2C03/ asetoon/ allielbromied) gevolg deur Claisenherrangskikking (N,N-dimetielanilien) en oksidatiewe splyting (OsO4/N-metielmorfolien-N-oksied gevolg deur NaIO4/MeOH) van die allielgroep, in 14% opbrengs verkry. Intermolekulêre aldolkondensasie (LDA/THF of asynsuur /H2S04) tussen die ptero-karpanielasetaldehied en die bensofenoon kon egter nie bewerkstellig word nie. Ten einde 'n Von Pechman-tipe kondensasie vir die sintese te kan benut moes die pterokarpanielasetaldehied na die ooreenstemmende suur geoksideer word, maar ten spyte van die aanwending van 'n verskeidenheid reagense (piridiniumdichromaat; RuCl3; Tollensreagens; KMn04; Ag20) kon 2-O-etoksimetiel-4,6-dimetoksifenielasetaldehied, as model, nie in noemenswaardige opbrengs na die ooreenstemmende suur geoksideer word nie. A.g.v. die onvermoë om die verlangde pterokarpanielasynsuur daar te stel, is die sintese van 'n model van die neoflavonoïedeenheid, 3-feniel-7-metoksineoflav-3-een, aangepak en is verestering van 2-hidroksi-4-metoksibensofenoon met fenielasetielchloried (K2C03/ asetoon) gevolg deur intramolekulêre siklisering (K2C03/ asetoon) en reduksie van die laktoonfunksionaliteit (B2H6THF) uitgevoer (10% opbrengs). Vergelyking van die chemiese verskuiwing van die CH2Sein in die 1H-KMR-(8 5.09) sowel as 13C-KMR-spektra (8 69.8) met dié van die natuurprodukte (8 4.13 - 4.24 en 8 21.0 onderskeidelik) het egter ondubbelsinnig getoon dat die natuurlike verbindings nie 'n seslid-heterosikliese ring in die neoflavonoïedeenheid bevat nie. Ten einde soortgelyke KMR-vergelyking vir die struktuur met die benso[b]furanielneoflavonoïed te doen, is voortgegaan met 'n modelsintese vir hierdie sisteem en is die verlangde 2-bensiel-3-fenielbenso[b]furaan d.m.v. Friedel-Grafts asilering van resorsinol met chloroasetielchloried, gevolg deur bensilering (bensielbromied, K2C03/asetoon) en Grignardreaksie van die gevormde bensofuranoon met fenielmagnesiumbromied daargestel. Hoewel presiese ooreenstemming in chemiese verskuiwing (8 4.17 en 8 32.8 onderskeidelik in die 1H- en 13C-KMR-spektra) van die metileengroep tussen die gesintetiseerde model en die natuurproduk nie verkry is nie, is dit aan verskille in struktuur en substitusiepatroon toegeskryf en kan 'n benso[b]furaanstruktuur aan die neoflavonoïedeenheid toegeken word.
Open Access
Direkte sintese van isoflavane en 2-bensieldihidrobensofurane via α-alkilering van fenielasynsuuresters
(University of the Free State, 1991-05) Versteeg, Marietjie; Bezuidenhoudt, B. C. B.; Ferreira, D.
Afrikaans: Hoewel verskeie isoflavonoïede wat fisiologiese aktiwiteit vertoon opties aktief geïsoleer is, bestaan daar tans geen metode vir die stereoselektiewe sintese van hierdie groep natuurprodukte nie. Aangesien geen direkte sintese vir isoflavane eweneens bekend is nie en hierdie groep die eenvoudigste chirale isoflavonoïede verteenwoordig, is die ontwikkeling van metodologie vir die enantioselektiewe sintese van isoflavane d.m.v. elektrofiele α-alkllering van fenielasetate uitgevoer. Ten einde die propanoïedskelet van isoflavane te lewer, word bensielelektrofiele met substitusiepatrone tiperend van isoflavonoïede tydens die alkileringsreaksie benodig en is 4-metoksibensielbromied (76%) m.b.v. reduktiewe halogenering (trimetielchlorosilaan) LiBr/tetrametieldisiloksaan direk van anysaldehied berei. Hierdie roete was egter onsuksesvol t.o. v. die sintese van 2-O-metoksimetiel- en 4-metoksi-2-O-metoksimetielbensielbromied, sodat lg. twee bensielbromiede na beskerming van die 2-hidroksigroep d.m.v. reduksie (NaBH4) en reaksie met metaansulfonielanhidried, LiBr en 2,6-lutidien vanaf salisiel- en 2-hidroksi-anysaldehied gesintetiseer moes word (75 en 70% opbrengs). AIkilering (litiumdiïsopropielamied/tetrahidrofuraan/ -78 - -15°C) van mentielasetaat,-propanoaat en -fenielasetaat, verkry deur reaksie van die ooreenstemmende suurchloried met (-)-mentol (60, 24 en 70%), met bensielbromied het mentiel-3-fenielpropanoaat, mentiel-3-feniel-2-metielpropanoaat en mentiel-2,3-difenielpropanoaat in 10, 16 en 50% opbrengs gelewer. Hoewel die opbrengs uit bg. reaksie onbevredigend laag was, is aangetoon dat stereoselektiwiteit m.b.v. 'n chirale alkohol wel verkry kan word en is die diastereomeriese propanoate in 'n verhouding 1.4 - 1.2 : 1 geïsoleer. Ten einde kondisies vir die alkileringsreaksies te optimiseer en dus die opbrengs te verhoog, is m.b.v. D20-blussing bepaal dat die esterenolaat na 15 min by -78°C reeds volledig gevorm is (m.b.v. litiumdiïsopropielamied of litiumisopropielsikloheksielamied) en dat die effektiwiteit van die proses deur die byvoeging van heksametielfosfortriamied verhoog kan word. Ten spyte van hierdie verbeterings was die opbrengs van die alkile-ring, waarskynlik weens basisgekataliseerde eliminasie van die suur, steeds laag en is alkilering met 'n reeks metielfenielasetate voortgesit. Reaksie van metielfenielasetaat, metiel-4-metoksifenielasetaat, metiel-2-metoksifenielasetaat, metiel-3,4-dimetoksifenielasetaat en metiel-2,4-dimetoksifenielasetaat met bensielbromied, 4-metoksibensielbromied, 2-O-metoksimetielbensielbromied en 4-metoksi-2-O-metoksimetielbensielbromied het die ooreenstemmende 2,3-diarielpropanoate in 20 - 86% opbrengste gelewer (Skema I). M.b.v. LiA1H4-reduksie (50 - 98%), gevolg deur verwydering van die metoksimetiel groep (3N HCI, MeOH) en suurgekataliseerde ringsluiting (p-tolueensulfoonsuur/benseen), is isoflavane vanaf die 2"- metoksimetielpropanoate berei (22 - 65% opbrengs). Weens die verhoogde migrasievermoe" het propanole met 'n 4'-metoksi of 3',4'- of 2',4'-dimetoksi B-ring egter tot 2-bensieldihidrobenso[b]furane (18 - 70%) aanleiding gegee en is die eerste direkte sintese ook vir hierdie seldsame groep verbindings daargestel.
Open Access
Enantioselektiewe sintese van trans- en cis-dihidroflavonole via chalkoonepoksiede
(University of the Free State, 1994-12) Van Rensburg, Hendrik; Bezuidenhoudt, B. C. B.; Ferreira, D.
Afrikaans: Die studie van polimeriese flavonoïede en flobatanniene word gekortwiek deur die feit dat opties aktiewe monomere wat vir die sintese hiervan benodig word slegs uit natuurlike bronne beskikbaar is. Indien hierdie verbindings dus gemaklik volgens 'n eenvoudige proses enantiomeries suiwer gesintetiseer kan word, sal dit die bestudering van oligomeriese flavonoïede aansienlik vergemaklik. Die groot vooruitgang op die gebied van stereoselektiewe epoksidasie het die moontlikheid daargestelom opties-aktiewe chalkoonepoksiede as voorlopers te gebruik vir die sintese van dihidroflavonole met stereoselektiwiteit by beide die 2- en 3-posisies wat dan toegang bied tot flavan-3-ole en flavan-3,4-diole, die monomeriese voorlopers van polimeriese flavonoïede. Ten einde hierdie uitdaging aan te spreek, is die asimmetriese sintese van 'n reeks poli-geoksigeneerde chalkoonepoksiede naamlik (-)-(αR,βS)- en (+)-(αS,βR)-4-metoksi-, (-)-(αR,βS)- en (+ )-(αS,βR)-4,41-dimetoksi-, (-)-(αR,βS)- en (+ )-(αS,βR)-3,4,4'-trimetoksi-, (-)-(αR,βS)- en (+ )-(αs,βR)-4,41 ,61-trimetoksi-, (-)-(αR,βS)-3,4,41,61-tetrametoksi- en (-)-(αR,βS)- en (+ )-(αS,βR)-3,4,5,41-tetrametoksi-2'-O-metoksimetielchalkoonepoksied d.m.v. 'n drie-fase epoksidasie sisteem (H202, CCl4, poli-(L)- ofpoli-(D )-alanien) in 79-99% opbrengs en redelike tot goeie ee (49-86%) gesintetiseer. In 'n vorige studie het die omskakeling van (-)-(αR,βS)-4,4'-dimetoksi-2'-O-metoksimetielchalkoonepoksied na die (2R,3R)-trans-4', 7-dimetoksidihidroflavonol veral twee probleme, naamlik 'n aansienlike verlies in optiese suiwerheid en kompeterende isoflavoonvorming opgelewer. Aangesien verdeling van die sikliseringsproses in twee of drie stappe nl. epoksiedopening, ontskerming van die 2'-OH groep gevolg deur vorming van die dihidroflavonol hierdie probleem moontlik sou omseil, is vervanging van die metoksimetiel beskermende groep met trimetielsilieletoksimetiel (SEM) groep, ten einde ontskerming voor epoksiedopening uit te voer, ondersoek. Hoewel beskerming en stereoselektiewe epoksidasie (H202, CCI4, poli-(L)-alanien) met hierdie groep suksesvol uitgevoer kon word, was verwydering van die SEM groep met tris( dimetielamino )swawel(trimetielsiliel)- difluoried en tetrabutielammoniumfluoried sonder reaksie met die epoksied onmoontlik en het die omgekeerde, nl. epoksiedopening voor ontskerming, dus aandag geniet. Nadat verskeie sisteme (BnSH/pTSA, BnSH/MgBr2, BnSH/LiCI04, EtSH/SnCI4, BnSH/-SnCI4) geëvalueer is, is gevind dat bensielmerkaptaan en SnCl4 as Lewissuur nie alleen die oksiraanring van die reeks 2'-O-metoksimetielchalkoonepoksiede open nie, maar ook die 2'-OH ontskerm om in goeie opbrengste (63-90%) die α,21-dihidroksi-β-bensieltiodihidrochalkone te lewer. Siklisering deur benutting van die tiofiliese Lewissuur, silwertetrafluoroboraat, het nie alleen die 2,3-trans-dihidroflavonole [(2R,3R)-, (2S,3S)-4'-metoksi-, (2R,2R)-,(2S,3S)-4' ,7-dimetoksi-, (2R,3R)-, (2S,3S)-3' ,4' ,7-trimetoksi-, (2R,3R)-,(2S,3S)-4' ,5,7-trimetoksi-, (2R,3R)-3' ,4' ,5,7-tetrametoksi- en (2R,3R)-, (2S,3S)-3' ,4',-5',7-tetrametoksidihidroflavonol] in goeie opbrengs (47--80%), maar vir die eerste keer ook die 2,3-cis-dihidroflavonole [(2S,3R)-, (2R,3S)-4'-metoksi-, (2S,2R)-, (2R,3S)-4' ,7-dimetoksi-, (2S,3R)-, (2R,3S)-3' ,4' ,7-trimetoksi-, (2S,3R)-, (2R,3S)-4' ,5,7-trimetoksi-,(2S,3R)-3' ,4',5,7-tetrametoksi- en (2S,3R)-, (2R,3S)-3' ,4' ,5' ,7-tetrametoksidihidroflavonol] in 5-15% opbrengs gelewer. Verder is gevind dat hierdie reaksies sonder enige verlies in optiese suiwerheid uitgevoer kon word sodat die ee van die uitgangschalkoonepoksiede nou 'n bepalende rol in die ee van die dihidroflavonole speel.
Open Access
Evaluation of ligand modified palladium catalysts in the wacker oxidation of alkenes
(University of the Free State, 2012-08) Saku, Duduetsang; Bezuidenhoudt, B. C. B.; Marais, C. M.
The industrial application of Wacker oxidation of terminal olefins in aqueous aerobic mixtures with PdCl2 and CuCl/CuCl2 has largely been limited to shorter chain alkenes, that is, ethylene. As the alkene chain length increases, so do the challenges that render the reaction inapplicable for large scale production. Longer chain alkenes tend to isomerize due to the limited solubility in organic-aqueous mixtures. More so, the use of co-oxidants such as CuCl or CuCl2 in stoichiometric amounts results in the formation of toxic chlorinated by-products which make the system corrosive. Pd0 aggregation from the PdII active state, is also pertinent in these reactions hence the use of large amounts of a co-oxidant. Small TONs and TOFs have subsequently been reported. As one of the approaches to curb these challenges, ligand support and modification has recently been viewed with interest because it promises efficient stabilization of Pd0, wherein the efficiency of O2 to re-oxidize the Pd0 species is relied upon thereby avoiding Pd0 aggregation. Ligand support can also be used to alter the electronic environment of the PdII centre thereby affecting its activity and selectivity. The application of phosphorus-palladium complexes in this study is not only a new approach in Wacker oxidation but the utilization of the π-accepting and or σ-donating abilities of phosphorus compounds was also advantageous in altering the PdII electronic environment. No co-oxidants were used in this study w.r.t. the oxidation of 1-octene and the complexes evaluated were comparable to those reported in literature with PdCl2/DMA systems under similar conditions. Since oxygen is the preferred oxidant in all oxidation reactions because of its natural abundance, its reported enhanced selectivity and ease of separation from products, it was decided to evaluate the utilization of this reagent as first choice in the current investigation of ligand supported palladium catalysts in the Wacker oxidation. Due to the fact that the phosphite based palladium catalyst, PdCl2[P(OPh)3]2, is readily soluble in DMA, it was determined that no pre-stirring as for PdCl2 was required for this catalyst. In order to obtain the optimum reaction conditions for oxygen as oxidant with this catalyst, conditions like solvent, reaction temperature, O2 pressure and water, catalyst, and substrate concentration were varied. The optimized conditions were determined to be 0.5 mol% of catalyst in DMA:H2O (6:1) under 9 atm of O2 at 80°C, while the optimum substrate concentration was found to be 0.2M. PdCl2[P(OPh)3]2 showed the highest activity of the catalysts evaluated and gave a TOF of >1370 (mol/mol/hr), which compared favourably with other known catalysts like PdCl2, PdCl2(CH3CN)2 Pd(OAc)2, and Pd(CF3SO3)2 where TOF’s of 1429, 1420, 817 and 524 respectively, were obtained under the conditions optimized for PdCl2[P(OPh)3]2. While the palladium metallocycle [Pd(u-Cl)(C6H4O)(OC6H6)2]2 gave TOF’s (1380 mol/mol/hr) virtually the same as PdCl2[P(OPh)3]2, total conversion for the latter catalyst was only 93%, so it can be regarded as the second best of all the catalysts evaluated. The monomers thereof, PdCl[(C6H4O)(C6H6O)2P(OPh3)] and PdCl[(C6H4O)(C6H6O)2(PPh3)], revealed the least basic P(OPh3) to be more reactive (TOF >900 mol/mol/hr) than the TPP containing analogue, where the latter showed no activity within the first hour of reaction. While all the active catalysts showed good selectivities of >80%, the metallocycle [Pd(u-Cl)(C6H4O)(OC6H6)2]2 proved to be the best with a selectivity of 89%. Catalyst recyclability was also observed to at least 3 cycles, with selectivities maintained above 80%. No Pd0 ‘fall-out’ or aggregation was observed with any of the catalysts evaluated. For the palladium phosphinite catalysts 1,2-Ph(OPPh2)2PdCl2 and 1,3-Ph(OPPh2)2PdCl it was found that both were active in the Wacker oxidation of 1-octene albeit with very low rates for the latter complex (1,3-Ph(OPPh2)2PdCl). The low reactivity of 1,3-Ph(OPPh2)2PdCl was similar to that of the phosphines (PPh3)2PdCl2 and (3,5-CF3-PPh2Cl)2PdCl2 where (PPh3)2PdCl2 showed some conversion only after 3 hours and (3,5-CF3-PPh2Cl)2PdCl2 gave only 53% conversion after an hour. Through a comparison of the reactivity of 1,2-Ph(OPPh2)2PdCl2 with that of the hydrolyzed equivalent [μ-ClPd(PPh2OH)(PPh2O)]2, it seemed as if the phosphinite catalysts are prone to hydrolysis under the prevailing conditions as the final conversion of both these catalysts were almost the same (85 and 79% respectively). Hydrogen peroxide and tert-butylhydroperoxide (TBHP) were also evaluated as alternative oxidants with PdCl2[P(OPh)3]2 as catalyst and H2O2 was found to be the better of the two oxidants with conversion (99%), selectivity (86%), and TOF (1220) almost as good as those found for oxygen (100, 82% and 1370 respectively). In addition, the catalyst could also be recycled three times although degradation of the H2O2 was observed and additional peroxide (12 eq.) had to be added with each cycle of substrate. TBHP, however, suffered from moderate selectivities of only 60-65%, while the catalysts was deactivated during the first oxidation cycle and could therefore not be recycled at all. Although all phosphite catalysts promoted isomerization to internal 1-octene isomers to some extent, the cyclopalladated [Pd(u-Cl)(C6H4O)(OC6H6)2]2 catalysts proved to be the best in this aspect of the reaction w.r.t. oxygen as oxidant and led to very low quantities of isomerised products being observed (3 - 4%). It was also evident that the type and amount (for H2O2 and TBHP) of oxidant played a crucial role in enhancing or suppressing isomerization and hydrogen peroxide (at only 2% isomerization) was found to be the best oxidant in this regard followed by oxygen (13%).
Open Access
New methodology for the biomimetic synthesis of Flavan-3,4-diols and derivatives
(University of the Free State, 2019-06) Van Jaarsveldt, Jeanette; Bezuidenhoudt, B. C. B.; Van Tonder, J. H.
Abstract not available
Open Access
New ring closing metathesis based methodology for the synthesis of monomeric flavonoids
(University of the Free State, 2017-02) Pieterse, Tanya; Bezuidenhoudt, B. C. B.; Marais, C.
Although the physiological activity of flavonoids stimulated investigations into more efficient synthetic methods for the preparation of these compounds, many of these routes entail multiple steps and require the utilization of stoichiometric and often poisonous reagents. Known methodologies are also hampered by difficulties around the isolation of the desired product and often lead to inseparable mixtures, low yields, and tedious synthetic processes. To circumvent these problems and to bring the synthesis of flavonoids in line with modern synthetic methodologies, it was decided to embark on a process of preparing the different classes of flavonoids through the application of a catalytic process, like ring closing metathesis (RCM), as key step in the methodology. Developing this methodology would have the added advantage that all the different classes of flavonoids would be reachable from readily available starting materials and the application of basically a single catalytic reaction in the final process step. For entry into the first class of flavonoids, i.e. compounds with a 2-phenylchromane skeleton, the preparation of flav-2-enes were investigated as key intermediate. In this regard, allyl phenyl ethers, prepared via Williamson etherification [K2CO3 (2.0 e.q), CH3CN, reflux], were subjected to Claisen rearrangement in a neat microwave assisted process to obtain the substituted allyl benzenes, 1-allyl-2-hydroxy-4-methoxybenzene and 1-allyl-2-hydroxy-4,6- dimethoxybenzene, in 44% and 88% yields, respectively. Subsequent esterification of the allyl phenols with substituted benzoyl chlorides [aq. NaOH (2.0 M, 40.0 mL) or 4- dimethylaminopyridine (0.2 eq.), dry pyridine (1.0 eq.), dichloromethane, reflux] afforded a series of the benzoates, i.e. 2-allylphenyl benzoate, 2-allylphenyl 4-methoxybenzoate, 2- allylphenyl 3,4-dimethoxybenzoate, 2-allylphenyl 3,4,5-trimethoxybenzoate, 2-allyl-5- methoxyphenyl 3,4-dimethoxybenzoate, 2-allyl-5-methoxyphenyl 3,4,5-trimethoxybenzoate, 2-allyl-3,5-dimethoxyphenyl 3,4-dimethoxybenzoate and 2-allyl-3,5-dimethoxyphenyl 3,4,5- trimethoxybenzoate in 68 – 98% yield. During methylenation of these esters through utilisation of the Tebbe reagent, it was found that the reaction is largely dependent on the concentration of the substrate, as well as reaction time and temperature. High yields (71 – 94%) were obtained with an increase in concentration of the ester and a brief period at elevated temperature (80 – 90°C). While a series of substituted diaryl vinyl ethers could be prepared, methylenation of substrates containing a phloroglucinol-type substitution pattern on what was to become the A-ring of the flavonoid failed. Ring closing metathesis of all the vinyl ethers in hand under standard metathesis conditions [Grubbs II, dichloromethane, reflux] led to the formation of flav-2-ene, 4'-methoxyflav-2-ene, 3',4'-dimethoxyflav-2-ene, 3',4',5'-trimethoxyflav-2-ene, 3',4',7-trimethoxyflav-2-ene and 3',4',5',7-tetramethoxyflav-2- ene in 41 – 96% yields. Attempts at the epoxidation of flav-2-ene with m-CPBA with and without a base (NaHCO3), did not yield any of the desired product. Construction of the isoflavonoid nucleus was first attempted through preparation of the isoflav-2-ene analogue via the deoxybenzoin intermediate, which could be prepared by phenylmagnesium bromide addition to the corresponding phenyl acetate. Although the phenyl acetates (methyl 4-methoxyphenyl acetate, methyl 4-trifluoromethylphenyl acetate, methyl 3-methoxy-4-trifluoromethanesulfonyloxyphenyl acetate and methyl 3,5- dimethoxyphenyl-4-trifluoromethanesulfonyloxyacetate) could be prepared in excellent yields (80 – 99%) via ozonolysis of the substituted allyl benzenes, the transformation of these compounds into the required deoxybenzoins was hampered by the inability (even at temperatures as low as -78 °C) to stop the reaction of the Grignard reagent with the substrate at the ketone stage. The methodology for the preparation of isoflavenes was therefore adapted to the synthesis of the isoflav-3-ene analogues, which could be constructed through a one-pot reaction of the substituted benzaldehyde with substituted α-bromoacetophenones followed by Wittig reaction with methyltriphenylphosphonium bromide to afford vinyl benzene intermediates, 4-methoxy-2-[(2-phenylallyl)oxy]-1-vinylbenzene, 1,5-dimethoxy-3-[(2- phenylallyl)oxy]-2-vinylbenzene, 1-{[2-(4-methoxyphenyl)allyl]oxy}-2-vinylbenzene, 4- methoxy-2-{[2-(4-methoxyphenyl)allyl]oxy}-1-vinylbenzene and 1,5-dimethoxy-3-{[2-(4- methoxyphenyl)allyl]oxy}-2-vinylbenzene, in 61 – 89% yield. Subsequent ring closing metathesis of the 7- and/or 4' substituted vinyl benzenes proceeded smoothly over Grubbs II catalyst in refluxing DCM and gave the isoflav-3-enes, (7-methoxyisoflav-3-ene, 4'- methoxyisoflav-3-ene and 4',7-dimethoxyisoflav-3-ene) in 57% to quantitative yields. RCM of the vinyl benzenes with a phloroglucinol-type substitution pattern, however, required elevated temperatures (refluxing toluene) and/or the addition of 1,4-benzoquinone in order to form the isoflav-3-enes, 5,7-dimethoxyisoflav-3-ene and 4',5,7-trimethoxyisoflav-3-ene, in decent yields (67 and 65%, respectively). Subsequent epoxidation of 7-methoxyisoflav-3-ene with m-CPBA and NaHCO3 in dichloromethane again failed to give any of the desired isoflavene epoxide. Although the neoflavonoid nucleus could be reached through Claisen rearrangement of 1- cinnamyloxybenzenes followed by vinylation of the phenolic hydroxy entity or Wittig mediated methylenation of 2-allyloxybenzophenones, followed by ring closing metathesis, this methodology was not viewed as being appropriate for application to oxygenated substrates as a number of process steps would be required to obtain oxygenated starting materials. It was therefore decided to follow a process where the appropriate acetophenones would be converted into the substituted styrenes by a Grignard reaction-dehydration process. Since electron-rich acetophenones are notorious for being lousy substrates in Grignard reactions the addition of aluminium triflate to the reaction mixture to enhance the reactivity of the reactant was investigated and it was found that the addition of Al(OTf)3 to the reaction mixture had a significant effect on the reaction of 4-methoxyphenylmagnesium bromide and 2-allyloxy-4-methoxyacetophenone. Not only did the presence of the Lewis acid increase the reaction rate, but it also led to the direct formation of the substituted styrene in 66% yield. Extending this reaction to the addition of phenylmagnesium bromide to 2-allyloxy-4,6- dimethoxyacetophenone and the addition of 4-methoxyphenylmagnesium bromide to 2- allyloxy-4,6-dimethoxyacetophenone and 2-allyloxy-4,5-dimethoxyacetophenone gave the substituted styrene products in moderate to high yields (52 – 94%). When 3,4- dimethoxyphenylmagnesium bromide was utilised in reactions with 2-allyloxy-4- methoxyacetophenone and 2-allyloxy-4,5-dimethoxyacetophenone, however, the analogous alcohols were obtained in 50% and 4% yields, respectively. When employing standard Grignard conditions (THF, -60 °C) i.e. without Al(OTf)3 activation, the tertiary alcohol products could be obtained 60% and 80% yields, respectively. Subsequent CuSO4-mediated dehydration of the alcohols yielded the desired styrenes (75% and 65%, respectively). Ring closing metathesis of all the styrene intermediates in hand proceeded smoothly and yielded the series of neoflav-3-enes, (4',7-dimethoxyneoflav-3-ene, 5,7-dimethoxyneoflav-3-ene, 4',5,7-trimethoxyneoflav-3-ene, 4',6,7-trimethoxyneoflav-3-ene, 3',4',7-trimethoxyneoflav-3- ene and 3',4',6,7-tetramethoxyneoflav-3-ene) in excellent yields (67% – quant.). Since it was shown that aluminium triflate had an enhancing effect on the addition of Grignard reagents to the acetophenones required for the synthesis of neoflavenes and that the styrenes could be obtained in a one-step process, it was decided to explore the scope of this novel process towards other ketones. During this investigation it was determined that the addition of Grignard reagents like phenylmagnesium bromide, benzylmagnesium bromide and ethylmagnesium bromide, to electron-rich ketones, i.e. 4-methoxyacetophenone, 2,4- dimethoxyacetophenone, 2,4-dimethoxypropiophenone and 4-chromanone, led to the formation of respective alkenes in 46 – 97% yields, while no product formation was observed for the less activated substrates like 4-chloroacetophenone and α-tetralone. It was furthermore observed that for the reaction of 4-methoxyacetophenone with ethyl - and benzylmagnesium bromide only the E-isomers of the product was formed, while only the Z-isomer was obtained during the addition of ethylmagnesium bromide to 2,4-dimethoxyacetophenone. The reaction of 2,4-dimethoxypropiophenone with phenylmagnesium bromide, on the other hand, yielded both geometric isomers in a 1:1 ratio. The stereoselectivity found during the reactions of 4- methoxy- and 2,4-dimethoxyacetophenone with ethyl - and benzylmagnesium bromide is probably explicable in terms of an E2 elimination process involving the preferred sterically less hindered gauche conformation of the transition state. Extending the reaction to the addition of phenylmagnesium bromide to α,β -unsaturated systems, like chalcone, indicated Al(OTf)3 to also have an activating effect in this regard, albeit to a marginal extent, since only an 8% increase in the yield of the 1,4-addition product was observed. Finally, indications were also found that Al(OTf)3 may also be utilized in catalytic quantities for this reaction when p-methoxy-1-phenylstyrene could be prepared in 82% yield by utilising Al(OTf)3 in 10 mol%; thus rendering the new methodology the first Grignard based Lewis acid catalysed process for the direct synthesis of alkenes.
Open Access
Parameters influencing regioselectivity in the palladium catalysed carbonylation of stilbenes and related alkenes
(University of the Free State, 2013-01) Serdyn, Maretha; Bezuidenhoudt, B. C. B.; Marais, C.
English: 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.
Open Access
Structure and synthesis of a novel homoisoflavanone from Scilla natalensis and synthesis of selected procyanidins through the C-4 functionalization of flavan-3-ols
(University of the Free State, 2008-05) Kuo, Chen-Miao; Bezuidenhoudt, B. C. B.; Kamara, B. I.
English: Scilla natalensis planch (Hyacinthaceae), commonly known as Wild squill, Blue squill, Blue hyacinth, Blouberglelie, Blouslangkop, Inguduza, is one of the plants that are widely used in traditional medicines and it grows naturally over large parts of Southern Africa. While the plant is widely used in traditional medicine by indigenous African people, phytochemical investigations have revealed this plant to contain a variety of biologically active compounds that show anti-inflammatory, antibacterial, antischistosomic, anthelmintic and cytotoxicity activity. In order to determine whether its traditional use is supported by actual pharmacological effects, it was decided to re-investigate the chemical composition of Scilla natalensis. Repeatetive column - and preparative thin layer chromatography together with acetylation of the methanol extract of the bulbs of the plant led to the isolation of five known compounds, 3’,4’-Di-O-acetylchavicol, 4’,4’’-Di-O-acetyl-3”-methoxynyasol, 5,7-Diacetoxy-3-(3’-acetoxy-4’-methoxybenzyl)chroman-4- one, 4’-O-acetyl-5,7-di-O-methyl-naringenin, and 2”,3”,4”,5,6”-Penta-O-acetyl-4’-O-methyl- apigenin-7-O-β-D-glucopyranoside as well as the novel homoisoflavanone, 5,6,7-triacetoxy-3- (3’,4’-dimethoxybenzyl)-chroman-4-one. While the isolated metabolites were all identified and characterised by spectroscopic means involving 1- and 2D-NMR experiments, all of the known compounds were isolated from Scilla natalensis for the first time. Since the homoisoflavonoids have been found to possess widespread physiological activity and to give final proof of the structure of the isolated novel homoisoflavanone, in particular the position of the third OH on the A-ring, the synthesis of this compound was attempted. While several synthetic routes towards homoisoflavanones have been reported in literature, it was decided to follow the dihydrochalcone approach for the synthesis of this new homoisoflavanone. In this methodology the dihydrochalcone is subjected to α-alkylation with a C-1 fragment containing another leaving group that can be displaced in the final cyclization process for formation of the heterocyclic C-ring. The desired dihydrochalcone would become available by reduction of the chalcone which can be formed by aldol condensation of the appropriate acetophenone and benzaldehyde. In this instance, however, this synthetic approach was hampered by the unavailability of the required 2,3,4,6-hydroxyacetophenone. It was therefore decided to test the synthesis on a model compound, 2-hydroxyacetophenone, and to investigate the appropriate C-1 fragment to use, before attempting the challenging synthesis of the required acetophenone. Thus standard Claisen-Schmidt aldol condensation between 2-hydroxyacetophenone and 3,4-dimethoxybenzaldehyde afforded the required chalcone (68 % yield), which was subjected to hydrogenation over 5 % Pd/C to give the dihydro equivalent in quantitative yield. To introduce the C-1 fragment it was decided to utilise a modified Baker-Venkataraman rearrangement strategy followed by reduction of the ester functionality and subsequent Mitsunobu cyclization. While ester formation between ethylchloroformate and 2’-hydroxy-3,4-dimethoxydihydrochalcone proceeded well, the rearrangement part of the reaction led to the unexpected formation of 3-(3’,4’-dimethoxybenzyl)-4-hydroxycoumarin. Although this product could be transformed into the desired homoisoflavanone, it would take three more steps and it was therefore decided to evaluate a Vilsmeier- Haack type α-formylation for introducing the additional carbon atom into the dihydrochalcone moiety. While treatment of the 2’-hydroxydihydrochalcone with N,N-dimethylformamide (DMF), PCl5 and BF3etherate afforded only the 3-(3’,4’-dimethoxybenzyl)-isoflavone in 40 % yield, subsequent hydrogenation over 10 % Pd/C led to the isolation of three products, i.e. 3-(3’,4’-dimethoxybenzyl)chromane (43%), 3-(3’,4’-dimethoxybenzyl)chromanone (the desired homoisoflavanone) (3%), and the 3,4-cis- and trans-3-(3’,4’-dimethoxybenzyl)chroman-4ols (3% each). Although the desired product was obtained in only 3% yield due to over-hydrogenation, the reaction was not repeated on larger scale as it was already established that the homoisoflavanone could indeed be formed in this way. In the second part of this dissertation the issue of determining the absolute configuration at the different chiral centres of flavonoids was to be addressed. Although this has up to now been done by circular dichroism (CD) measurement, this method has led to ambiguities and is plagued with a host of empirical rules that has to be applied. It was therefore decided to investigate the application of vibrational circular dichroism (VCD) to the determination of the absolute conformation of flavonoids. In order to generate a data base and eventually apply the technique of VCD to the stereochemistry of proanthocyanidins, it was decided that the investigation should be started form a flavonoid with only one chiral centre and systematically increase the number of stereo centres until the level of oligomeric compounds is reached. Since (+)-catechin [(2R,3S)-(+)-3,3’,4’,5,7-penta-hydroxyflavan, and (-)-epicatechin [(2R,3R)-(-)-3,3’,4’,5,7-pentahydroxy- flavan] are freely available in optical active form and can be transformed into their respective enantiomers, the whole synthetic endeavour was based on these compounds. In this dissertation the aim therefore was to functionalize (+)-catechin and (-)-epicatechin in the 4-position followed by the synthesis of 4-arylflavan-3-ols and ultimately proanthocyanidins B1 to B4. Thus DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) oxidation of tetra-O-methyl-(+)-catechin, tetra-O-benzyl-(+)-catechin, and tetra-O-benzyl-(-)-epicatechin in the presence of ethylene glycol, gave the 4-hydroxyethoxy derivatives in 46, 60, and 50 % yields respectively. Treatment of the latter two compounds with perbenzylated fluoroglucinol under TiCl4 catalysis led to only the corresponding 2,4-cis-4-arylflavan-3-ols in 65 and 55 % yields. The formation of proanthocyanidins B1, B2, B3, and B4 were successfully achieved through similar coupling of perbenzyled catechin and - epicatechin with their respective 4-hydroxyethoxy analogues. It has, however, to be mentioned that the characterization of the perbenzylated B1 to B4 products by NMR were virtually impossible, since the spectra of these compounds were very complicated because of severe duplication of signals due to restricted rotation. In order to have all possible isomers available in free phenolic form for VCD studies, debenzylation of the synthesised 4-arylflavan-3-ols and procyanidins B1 to B4 as well as the synthesis of B5 to B8 will be attended to during the candidate’s PhD studies.
Open Access
Studies directed at the stereoselective synthesis of flavonoids through the hydrogenation of prochiral precursors
(University of the Free State, 2008-11) Van Tonder, Johannes Henning; Bezuidenhoudt, B. C. B.; Steenkamp, J. A.
English: The in vitro studies of biologically active flavonoids are hampered by the inaccessibility of all monomeric units in enantiomerically pure form. Although a number of these scalemic flavonoids can be obtained synthetically, current methodologies are tedious and often result it low yields and e.e.s being obtained. Stereoselective conjugated hydrogenation of the more readily available prochiral a,b-unsaturated carbonyl flavonoid motifs, i.e. flavones, isoflavones and flavonols, provide a plausible solution to this problem and was therefore investigated during the first part of this dissertation. Since the stereoselective 1,4-reduction of an a,b-unsaturated system also contains an element of regioselectivity, a regioselective hydrogenation study was conducted first before the reaction would be extended to include stereoselective aspects. Because Wilkinson’s catalyst is commercially available, has the potential to be modified with chiral ligands and is a well known hydrogenation catalyst, it was chosen as catalyst for the initial evaluation of the idea. While Wilkinson’s catalyst is well known for hydrogenation of ordinary alkenes, no literature on it being used for the reduction of a,b-unsaturated carbonyl compounds could be found, so the effectiveness of this catalyst in the hydrogenation of differently substituted nonflavonoid substrates were first investigated. In this regard a solvent study on chromone, evaluating acetone, tetrahydrofurane and dichloromethane (DCM), showed DCM to be the solvent of choice for this reaction and led to the formation of 4-chromanone in 7.8 %, 14.3 % and 46.2 % respectively. By using 2-cyclohexenone as substrate, optimum hydrogenation conditions were determined to be ca. 30 bar and 100 oC, because reactions at higher temperatures (110 oC) and pressures (40 bar) were inhibited by rhodium fall-out. In order to evaluate the effect of different levels of substitution around the olefinic double bond on the reaction rate for cyclic- as well as acyclic olefins, 2-cyclohexenone, 3-methyl-2- cyclohexenone, 3-buten-2-one, 3-penten-2-one, 4-methyl-3-penten-2-one, 3-methyl-3-penten- 2-one, crotonaldehyde, and chalcone were subjected to the hydrogenation reaction. While no hydrogenation could be achieved for the trisubstituted acyclic ketones, i.e. 4- methyl-3-penten-2-one and 3-methyl-3-penten-2-one, as well as crotonaldehyde, the trisubstituted cyclic equivalent, 3-methyl-2-cyclohexenone, indeed gave the saturated ketone albeit with a very low reaction rate [kobs = 0.000174644 s-1 (80 oC and 20 bar)]. The hydrogenation rates of the remaining acyclic substrates, 3-buten-2-one and 3-penten-2-one (kobs = 0.0245703 and 0.000226852 s-1 respectively at 80 oC and 10 bar), followed the expected order of monosubstituted > disubstituted, while the effect of a cyclic structure proved to be rather insignificant (kobs = 0.000254025 s-1 for 2-cyclohexenone). Aromatic disubstitution, however, reduced the reaction rate by ca. 50 % (kobs = 0.000143572 s-1 for chalcone). While the reaction rate (kobs) for the volatile substrates could easily be determined by GC and GC/MS analysis, the reactor set-up and analytical methodology were changed for the flavonoid like solid substrates. For these solids, reactions were followed by NMR and t½ (time to achieve 50 % conversion) used as indication of the reaction rate. In order to be able to compare t½ with the previously measured reaction rate, the hydrogenation of chalcone was repeated and it was found that the concentration of the reactant has a major influence on the rate of the reaction. In a study where the concentration of chalcone was varied between 0.083 M and 0.50 M the optimum concentration was determined as 0.166 M (t½ = 27 min.) for reactions at 80 oC, 20 bar hydrogen pressure and a catalyst concentration of 0.72 mM. Extension of the reaction to chromone indicated the heterocyclic ring to have a profound influence on the reaction rate (t½ = 72 h vs. 27 min. for chalcone), while the flavonoid substrates, flavone and 4',7-dimethoxyisoflavone, having trisubstituted double bonds could not be hydrogenated at all using Wilkinson’s catalyst. In a completely different approach, the introduction of chirality into a planar flavonoid molecule (flavone or isoflavone type compound) by means of an arene metal complex was investigated. If a bulky tricarbonylmetal centre could be directed to one face of the A-ring of a flavonoid unit, that face of the adjacent unsaturated heterocyclic C-ring would become inaccessible to a hydrogenating reagent. In order to investigate the feasibility of such an approach, the tricarbonylchromium(0) complexes of several mononuclear and flavonoid type substrates were to be synthesised. Compounds like benzene, toluene, anisole, chlorobenzene, acetophenone, and chromanone were therefore subjected to thermolysis (72 h) with hexacarbonylchromium(0) in refluxing dibutyl ether-THF and it was found that while the activated substrates showed excellent reactions (85 - 98 % conversion), conversions for the compounds containing deactivating substituents [acetophenone (40 %) and chromanone (28 %)] were rather low. With the knowledge of the mononuclear substrates in hand, the study was extended to the flavonoids where selectivity between the two aromatic rings would be a major issue in the success of the envisaged methodology. Although successful from a reaction point of view (products obtained in 33 and 43 % yield respectively), reaction of the carbonyl containing substrates 4',7-dimethoxyisoflavone and flavone, with hexacarbonylchromium(0), however, yielded only the ‘unwanted products’, tricarbonyl(B-h6-4',7-dimethoxyisoflavone)- chromium(0) and tricarbonyl(B-h6-flavone)chromium(0). In an effort to move complex formation to the A-ring of the flavonoid moiety, substrates with increasing levels of reduced heterocyclic rings like chroman-4-ol, flavan-4-ol, flavan, and 7-methoxyflavan, were subjected to the reaction with hexacarbonylchromium(0). Although the first two compounds still contained a 4-subsitutent with a negative inductive effect, it is known that a benzylic OH group is capable of directing complexation towards the adjacent aromatic ring and it was hoped that this influence would facilitate reaction onto the A-ring. Formation of cis- and trans-tricarbonyl(h6-chroman-4-ol)chromium(0) in an ca. 3:1 ratio (14 % yield) from the reaction of chroman-4-ol with the chromium reagent, confirmed the benzylic–OH to be capable of directing the attacking chromium moiety to the anticipated face of the adjacent aromatic ring. Reaction of the flavan-4-ol substrate, however, indicated the A-ring still not to be the preferred binding site, since tricarbonyl(B-h6-flavan-4-ol)chromium(0) and tricarbonyl(A-h6-flavan-4-ol)chromium(0) were formed in 2.8 and 1.7 % yields, respectively. Finally, reaction of both flavan and 7-methoxyflavan, the latter with an activated dihydroxylated A-ring, yielded products originating from complexation onto both the A- and B-rings, i.e. tricarbonyl(A-h6-flavan)chromium(0), tricarbonyl(B-h6-flavan)chromium(0), tricarbonyl(A-h6-7-methoxyflavan)chromium(0), and tricarbonyl(B-h6-7-methoxyflavan)- chromium(0) as well as the bimetallic complex from the 7-methoxyflavan.
Open Access
Synthesis of novel polymer-bound morpholine-N-oxides as possible oxidants in alkene oxidation
(University of the Free State, 2008-03) Buitendach, Blenerhassitt Edward; Swarts, J. C.; Bezuidenhoudt, B. C. B.
English: In this dissertation is reported the syntheses and characterisation of polysuccinimide- and polyepichlorohydrin-bound morpholine-N-oxide as possible polymeric oxidants. The use of 1H NMR spectroscopy to determine polymer chain length and degree of fuctionalisation is described in detail. The synthesised polymers were used as potential oxidants in catalytic oxidation of alkenes. However, none of the preliminary trials on the epoxidation and dihydroxylation of trans-stilbene were successful. Two metal-containing phthalocyanines; one coordinated to Mn(III), the other to Zn(II), were synthesized by metal insertion into the metal-free non-peripheral octa substituted phthalocyanine (2HPc-(C13H27)8). The initial complex, 2HPc-(C13H27)8, was synthesized by tetramerization of 3,6-tridecylphthalonitrile, which was prepared by a three-step synthesis from thiophene. Characterization of the phthalocyanines included electrochemical and thermal analysis. The cyclic voltammograms of the 2H and Zn phthalocyanines showed two ringbased oxidations (0.116 V; 0.487 V and 0.044 V; 0.558V respectively) as well as two ringbased reductions (-1.791 V; -1.456 V and -2.054 V; -1.663 V respectively), vs Fc/Fc+ at 100 mV/s. The Mn derivative showed two ring-based oxidations (0.373 V and 0.864 V) while only one ring-based reduction was observed (-1.732 V). The Mn(II) oxidation was observed at 0.641 V while Mn(III) reductions was observed at -0.742 V and -0.660 V (for Cl- and CH3Oaxial ligands) giving large Ep values of 1.566 V and 1.484 V.The newly synthesized tridecyl-substituted metal-free and zinc phthalocyanines exhibited liquid crystalline mesophase behavior when subjected to differential scanning calorimetric studies of between 40 oC – 120 oC and 40 oC – 280 oC respectively, giving mesophase temperature ranges of 12.4 oC and 83.0 oC respectively. The manganese phthalocyanine, xii however, did not show any liquid crystal behavior. The manganese tridecyl-substituted phthalocyanine was used as catalyst in the molecular oxygen based epoxidation of transstilbene and gave low yields of the desired epoxide, trans-stilbene oxide. Epoxidation of trans-stilbene using N-methylmorpholine-N-oxide as oxidant and Mn(III)salen as co-catalyst gave trans-stilbene oxide in moderate yields.

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