Flavonoids and isoflavonoids are known to exhibit many important physiological properties
and are especially promising candidates for cancer chemoprevention. Similar to most natural
products, studies directed at the synthesis of flavonoids have, therefore, emerged from the
search for new compounds with beneficial biological properties. Metabolic studies related to
flavonoids are, however, frequently hampered by the inaccessibility of a variety of optically
active compounds. While a single method for the synthesis of enantiomerically enriched
isoflavonoids has been published, this process utilizes phenylacetic acid derivatives which are
not always readily available in all naturally occurring substitution patterns. Even though the
synthesis of phenylacetic acids are possible via a number of routes, these are based on ancient
low yielding chemical processes utilizing harsh reaction conditions, stoichiometric quantities
of reagents and in many cases, poisonous heavy metals like lead and thallium.
In order to address the availability of phenylacetic acid derivatives of variable substitution
patterns, the current study was aimed at the development of methodology for the synthesis of
phenylacetic acid derivatives that would be high yielding, environmentally benign, have a
limited number of process steps, and are applicable to all naturally occurring flavonoid
substitution patterns. In this regard it was envisaged that ozonolysis of substituted
allylbenzenes would comply with all of the stated criteria and was therefore investigated as
methodology for the synthesis of phenylacetic acid derivatives that could serve as building
blocks during isoflavonoid preparations.
Since substituted allylbenzenes of all oxygenation patterns are not available commercially,
the allylic moiety was introduced into the required phenols by means of a allyl phenyl ether
intermediate, through utilization of Williamson ether synthesis (allyl bromide; K2CO3,
refluxing CH3CN) followed by Claisen rearrangement of the neat allyl phenyl ethers, allyl 3-
methoxyphenyl ether and allyl 3,5-dimethoxyphenyl ether, under microwave irradiation (at
200 ºC in 15 min. intervals and 0ô¯200 W variable power) to obtain the desired allylphenols,
1-allyl-2-hydroxy-4-methoxybenzene and 1-allyl-2-hydroxy-4,6-dimethoxy-benzene, in 44
and 88 % yield, respectively. Apart from the desired allylphenol, Claisen rearrangement of
allyl 3-methoxyphenyl ether, however, also led to the formation of 1-allyl-2-hydroxy-6-
methoxybenzene in 45% yield, indicating a lack of selectivity towards the formation of the
sterically less hindered product under the prevailing reaction conditions. Since free phenolic
substituents on the aromatic rings of the envisaged substrates might have a negative effect during ozonolysis reactions, the commercially available allylphenols as well as the two
substrates prepared by allylation and Claisen rearrangement (vide supra) were subjected to
methylation (MeI; K2CO3; refluxing acetone or acetonitrile) and the respective fully
methylated analogues, 1-allyl-3,4-dimethoxybenzene, 1-allyl-2,4-dimethoxybenzene, 1-allyl-
2,4,6-trimethoxy-benzene, and 1-allyl-3,4,5-trimethoxybenzene, obtained in 79, 96, 80, and
77% yield, respectively.
Ozonolysis [O3 (6ô¯8 min.), DCM, 0 °C] with reductive work-up [N-methylmorpholine-Noxide
(NMMO)] of 1-allyl-2-methoxybenzene, 1-allyl-4-methoxybenzene, and 1-allyl-3,4-
dimethoxybenzene afforded the corresponding phenylacetaldehydes in 58, 88 and 15% yield,
respectively. Ozonolysis of the highly oxygenated substrates, 1-allyl-2-hydroxy-4-
methoxybenzene, 1-allyl-2,4,6-trimethoxybenzene, and 1-allyl-3,4,5-trimethoxybenzene,
however, only led to cleavage of the aromatic ring and formation of unidentifiable product
mixtures. Cleavage of the aromatic rings of these substrates was confirmed by 1H NMR
analysis of the reaction mixture [O3 (6ô¯8 min.), CDCl3, -78 °C] where the formation of the
1,2,4-trioxolane intermediate could be detected for the substrates that gave the desired
phenylacetaldehydes but not for the highly oxygenated analogues.
In order to reduce electron density on the aromatic ring of the highly oxygenated substrates
and prevent ring ozonolysis in this way, the free hydroxy function on each substrate was
changed into a trifluoromethanesulfonyl ester and the subtrates, 1-allyl-2-
trifluoromethanesulfonyloxy-4-methoxybenzene, 1-allyl-4-trifluoromethanesulfonyloxy-3-
methoxybenzene, 1-allyl-4-trifluoromethanesulfonyloxy-3,5-dimethoxybenzene, and 1-allyl-
2-trifluoromethanesulfonyloxy-4,6-dimethoxybenzene submitted to ozonation with NMMO
work-up again. While the phloroglucinol based sulfonyl ester gave the desired
phenylacetaldehyde in 71% yield, the other three substrates furnished NMMO induced
double bond migration with the subsequent formation of the benzaldehyde equivalent
products. When the ozonation reaction was repeated on the resorcinol, catechol and
pyrogallol trifluoromethanesulphonyl esters, with replacement of the NMMO with dimethyl
sulphide (DMS) as reductant, the desired phenylacetaldehydes or trioxolanes were, however,
obtained in 63, 32 and 31% yield, respectively.
Ozonolysis with oxidative work-up [(i) O3/MeOH; (ii) Ac2O-Et3N] applied to the
monomethoxy substrates, 1-allyl-2-methoxybenzene and 1-allyl-4-methoxybenzene, afforded
the desired methyl phenylacetates in 91 and 32% yield, respectively. Similar to what was found for the reductive work-up procedure, the higher oxygenated substrates had to be
converted to their respective triflates before ozonolysis of the allylic double bond could be
effected successfully and the phenylacetic acid esters, methyl 4-trifluoromethanesulfonyloxy-
3-methoxyphenyl acetate, methyl 4-trifluoromethanesulfonyloxy-3,5-
dimethoxyphenyl acetate, and methyl 2-trifluoromethanesulfonyloxy-4,6-dimethoxyphenyl
acetate obtained in 9, 17 and 65% yield, respectively.
Since the published process for the stereoselective synthesis of isoflavonoids would require
the phenyl acetates prepared through ozonolysis to be transformed into the corresponding
amides, the possibility of direct formation of the nitrogen derivatives, like anilides, during the
ozonolysis reaction was subsequently investigated. While first attempts at having the aniline
present during the ozonolysis reaction only led to nitrogen oxidation, the process was
amended to addition of the nitrogen nucleophile after formation of the 1,2,4-trioxolane,
which resulted in the desired 2-methoxyphenylacetanilide being formed in 37% yield. The
scope of this novel reaction was subsequently extended to the reaction of 1-allyl-4-
methoxybenzene with acetamide leading to the product being obtained in 39% yield. While
this reaction gave indications that deactivated nitrogen nucleophiles could also be used in this
process, the reaction with 2-imidazolidinone, a secondary amide, did not succeed indicating
that the new reaction still needs to be optimized to be useful in the enantioselective synthesis
of isoflavonoids.
Finally, it was shown during the current study that the phenylacetic acid derivatives prepared
via ozonolysis could be transformed into deoxybenzoins, another isoflavonoid precursor,
through formation of the acid chloride followed by reaction with a phenyl Grignard reagent.
Thus phenylacetyl chloride could be reacted successfully with phenylmagnesiumbromide at -
78 oC in diethyl ether to give the deoxybenzoin in almost 60% yield.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:ufs/oai:etd.uovs.ac.za:etd-07232013-105609 |
| Date | 23 July 2013 |
| Creators | Pieterse, Tanya |
| 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-07232013-105609/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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