Alkyl hydroxy benzoate

Routledge, E.J., Parker, J., Odum, J., Ashby, J., and Sumpter, J.P., Some alkyl hydroxy benzoate preservatives (parabens) are estrogenic, Toxicol. Appl. Pharmacol., 153, 12-19, 1998. 

Figure 5.24 The homologous series of alkyl 2-hydroxy-benzoates...

The highly substituted indole, ecopladib (82), which shares many structural elements with the phospholipase inhibitor varespladib (37), shows similar biological activity. Alkylation of hydroxy benzoate (72) with the dimethyl acetal from bromoacetaldehyde (73) affords the ether (74). Acid-catalyzed reaction of this intermediate with 2-methyl-5-chloroindole (75) in the presence of triethylsilane leads in effect to condensation of the acetal with the activated 3 position on the indole ring to afford 76. The nature of the reduction of the aldehyde carbon is not immediately apparent. Alkylation of the anion on nitrogen from reaction of the indole with sodium hydride and bromodiphenylmethane then adds the third... 

Benzoic acids bearing ortho alkyl, hydroxy, or amino substituents undergo loss of water through a rearrangement reaction similar to that observed for orf/zo-substituted benzoate esters, as illustrated at the end of Section 8.6J. 

Hydroxy-benzoates, preferably /7-hydroxy-benzoic acid alkyl esters, are listed under Acids and not under Esters because of their exceptional acidic character. 

Ethyl 4-hydroxybenzoate is a highly effective preservative with moderately good solubility in water. The spectrum of effectiveness in demonstrated by the MIC in Table 81. As a food preservative ethyl 4-hydroxybenzoate is often used in combination with propyl 4-hydroxybenzoate (8.1.11.3.) thus it is possible in most cases to use smaller overall amounts of alkyl 4-hydroxybenzoate than would otherwise be necessary. The favourable properties of ethyl 4-hydroxy benzoate makes it also highly suitable for preserving cosmetics and pharmaceuticals most frequently mixtures of alkyl 4-hydroxybenzoates are used. 

Aromatic carboxylic acids produce intense molecular ion peaks. The most important fragmentation pathway involves loss of OH to form the CeHsC O" (miz = 105), followed by loss of CO to form the ion (mIz = 77). In the mass spectrum of para-anisic acid (Fig. 8.71), loss of OH gives rise to a peak at miz =135. Further loss of CO from this ion gives rise to a peak at miz =107. Benzoic acids bearing ortho alkyl, hydroxy, or amino substituents undergo loss of water through a rearrangement reaction similar to that observed for orffto-substituted benzoate esters, as illustrated at the end of Section 8.8R. 

Zeolites H-BEA and H-Y were found to be the most active catalysts, however all catalysts readily form the phenyl benzoate (Table 4.1). In the conditions of the reaction, the formation of phenyl benzoate (PB) occurs rapidly via O-acylation of phenol. Direct C-alkylation of phenol with benzoic anhydride (B) and Fries rearrangement of phenyl benzoate results in the formation of 2- and 4-hydroxy-benzophenones (2-HPB and 4-HPB) (Scheme 4.3). 

Preparations of acylpyrazines from methylpyrazines have been described in Sections IV.2A(2) (635) and IV.2A(3) (634, 642, 645-647, 650-651). Recently it has been shown that 2-hydroxy(or mercapto)-3-methylpyrazine with two equivalents of butyllithium in dry tetrahydrofuran gave the colored dilithium salt (71, X = 0 or S), which reacted with alkyl benzoates and gave 2-benzoylmethyl-3-hydroxy(or mercapto)pyrazines (72, X = O or S, Y = 0). Similar reactions occurred with thio esters to give the thiocarbonyl compounds (72, X = O or S, Y = S)(1446). 

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