Reactions of polyphenols with α-keto acids

English: Novel methods of carbon-carbon bond formation are of considerable theoretical and practical interest to synthetic organic chemists. This work investigates the formation and synthetic potential of a methine bond (one carbon link) between two aromatic moieties to form diphenylmethane derivatives. This methine link is of industrial importance when the aromatic moiety is hydroxylated. The colour stability of red wine is attributed to a methine bond that is the result of condensation between glyoxylic or pyruvic acid and an anthocyanidin. This bond may be formed spontaneously during the ageing of wine. Wattle extract based adhesives rely on the reaction between formaldehyde and polyphenols to form methine linked polymers. Patented antioxidants rely on the availability of a benzylic proton on a methine link, ortho to a hydroxy group (Irganox®HP-136). The proximity of the two carbonyl double bonds in α-dicarbonyl compounds enhances the reactivity of each other towards nucleophiles. In the case of α-keto acids the α- keto group is more electrophilic than the carboxylic group and susceptible to attack by nucleophiles. The hydroxy groups of phloroglucinol and other polyhydroxybenzenes donate electrons to the aromatic ring to increase the nucleophilicity of the aromatic carbons. Polyphenols thus become ambident nucleophiles that can react either via oxygen or carbon and have the ability to form new carbon-carbon bonds with suitable electrophiles. As part of our ongoing investigation into the importance of p-quinone methides in flavonoid chemistry the reaction of a variety of polyhydroxyphenols with α-keto acids were investigated. Addition of an aromatic ring to a carbonyl group creates a benzylic hydroxy group. With strongly nucleophilic aromatic rings this benzylic substituent is replaced with a second aromatic ring to yield the anticipated methine linked biaryl compound. Phloroglucinol reacts with pyruvic acid to give 4,6-dihydroxy-3-methyl-3-(2,4,6- trihydroxyphenyl)-1-benzofuran-2(3H)-one and with glyoxylic acid to yield 4,6- dihydroxy-3-(2,4,6-trihydroxyphenyl)-1-benzofuran-2(3H)-one. These products are lactones between the phenolic- and carboxylic acid moiety of an intermediate biaryl organic acid. With oxaloacetic acid a 4,5′,6,7′-tetrahydroxy-2H-spiro[benzofuran-3,4′- chroman]-2,2′-dione is isolated. With unreactive aromatic nucleophiles the benzylic hydroxy group is eliminated before substitution can take place if hydrogen is available in the α-position. Tri-omethylphloroglucinol reacts with pyruvic acid to give methyl-2-(2,4,6- trimethoxyphenyl)-acrylate via the elimination of water. This acrylic acid reacts with ozone to form methyloxo-(2,4,6-trimethoxyphenyl)-acetate and with diazomethane to form 2-methoxy(2,4,6-trimethoxyphenyl)-4,5-dihydrofurane. To demonstrate the potential of this reaction we reacted resorcinol with phydroxyphenylpyruvic acid and obtained both the Z and E isomers of 6-hydroxy-3-(4- hydroxybenzylidene)-3H-benzofuran-2-one. This isoaurone synthesis represents an improvement on the recently published synthesis of this natural product. We have developed a novel reaction to form carbon-carbon bonds and synthesize methine linked diaryl compounds. We have developed this reaction into a new procedure to synthesize free phenolic 3-substituted benzofuran-2-ones. We adapted this reaction to improve a recently published method to synthesize a free phenolic isoaurone. We can use our reaction to synthesize acrylic acids with a phenolic substitutuent in the α-position and have started to explore the potential of this α,β- unsaturated carboxylic acid as intermediates for various synthetic procedures.