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    Development of new "green" methodology for the synthesis of substituted phenylacetic acid derivatives as precursors to isoflavonoids and related compounds
    (University of the Free State, 2013-01) Pieterse, Tanya; Bezuidenhout, B. C. B.; Marais, C.
    English: 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 0-200 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 (6-8 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 (6-8 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.