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.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-07162013-154217 |
| Date | 16 July 2013 |
| Creators | Serdyn, Maretha |
| Contributors | Dr C Marais, Prof BCB Bezuidenhoudt |
| Publisher | University of the Free State |
| Source Sets | South African National ETD Portal |
| Language | en-uk |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.uovs.ac.za//theses/available/etd-07162013-154217/restricted/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University Free State or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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