Alkyl 4-Hydroxybenzoates

A variety of novel procedures has been developed for the synthesis of phenolic esters in the last decade. 

Intermolecular reactions involving non-aromatic precursors have been used to furnish salicylate esters., p-Unsaturated aldehydes have been reacted with the dianion (DA) of ethyl acetoacetate to afford 4-substituted salicylates in good yield (ref. 36). 6-Methylsalicylates result from the addition of the monoanion (MA) at C2 (ref.37). 

Methyl 5-methylsalicylate has been obtained in 71% yield by intramolecular cyclisation of the open-chain ketoester, methyl 6-methylene-3-oxoheptanoate in acetic acid containing 4 equivs. manganese(lli) acetate dihydrate and 4 equivs. iithium chloride at ambient temperature during 24 hours followed by heating of the crude product with lithium chloride at 100°C for 24 hours (ref.38). 

A mixture of phenol and dichloro bis(benzonitrile)palladium ll) in dichloro-methane under carbon monoxide treated and stirred with diisopropylamine during 3 hours furnished phenyl salicylate in 53% yield (ref. 39). 

The intermolecular Michael addition of ethyl 2-cyano-3-phenyl-2-butenoate and ethyl cinnamate in benzene containing sodium hydride and a little dry ethanol followed by aromatisation of the intermediate by refluxing for 1 hour gave after acidification ethyl 3-cyano-4,6-diphenyl-2-hydroxybenzoate in 52% yield (ref.40). 

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Table 11. Physical Properties of Alkyl />Hydroxybenzoates (Parabens)...

Perfumes, Flavors, Cosmetics, and Soap. Many naturally occurring esters in essential oils and some synthetic esters are important fragrance and flavor compounds (61,62). They are used in perfumes, flavors, cosmetics, soaps, detergents, and air fresheners. Benzyl, butyl, ethyl, methyl, and phenyl esters of benzoic acid are used as flavors, perfumes, and food preservatives. Glyceryl 4-aminobenzoate [136-44-7] and 2-ethyUiexyl 4-dimethylaminobenzoate [21245-02-3] are used in cosmetic sunscreen preparations. Alkyl esters of 4-hydroxybenzoic acid, called parabens, have been used under various names for fungus infections of the skin, and as preservatives in lotions and creams (101). Soap and cosmetic fragrances use large amounts of amyl and benzyl saHcylate. Benzyl saHcylate [118-58-1] is also used in deodorant sprays. 2-Ethylhexyl saHcylate [118-60-5] and 2-ethylhexyl 4-methoxycinnamate [5466-77-3] are used in sunscreen formulations (102). 

In addition, Pfister and coworkers investigated 3-hydroxyflavone-6-carboxylic acids as histamine induced gastric secretion inhibitors. After condensing 3-acetyl-4-hydroxybenzoic acid (45) with a variety of aldehydes 46 to deliver the chalcones 47, these purified chalcones were then subjected to the standard AFO conditions to afford flavonols 48 in 51-80% yield. Subsequent alkylation of 48 with methyl iodide or isopropyl iodide followed by saponification of the corresponding esters gave the target compounds. 

A series of alkyl esters (Fig. 10.1) of/ (4)-hydroxybenzoic acid was originally prepared to overcome the marked pH-dependence on activity of the acids. 

The use of preservative eombinations may be used to extend the range and speetrum of preservation. Thus, in the series of alkyl esters of 4-hydroxybenzoic (/ -hydroxybenzoic) acid (parabens), water solubility deereases in the order methyl, ethyl, propyl and butyl ester. By eombining these produets it is possible to aehieve a situation where both the aqueous and oil phase of an emulsion are proteeted. 

The selective alkylation of a chemically distinct phenohc site on a perfluorinated aromatic has been achieved following a polymer assisted solution phase protection of an alternative o-hydroxybenzoic acid unit as the dioxin-4-one (19) (Scheme 2.45) [66]. A diverse set of 22 different alkyl and benzyl bromides were then attached to the free phenol using cesium fluoride as the base, followed by treatment with Amberlyst 15 and Amberlyst A-21 as the work-up. Subsequent hydrolysis of the dioxin-4-one group with NaOH proceeded smoothly and was quenched... 

Dymicky, M. and Huhtanen, C.N. Inhibition of Clostridium botulinumhy p-hydroxybenzoic acid n-alkyl esters, Antimicrob. Agents Chemother, 15 (6) 798-801, 1979. 

Hydroxybenzo[6]thiophenes exist as oxo tautomers and are referred to as thiooxindoles. O- Alkylation of thiooxindole is favoured in polar aprotic solvents thus NaH/HMPT/Me2S04 gives a 90% yield of 2-methoxybenzo[6]thiophene. Treatment of thiooxindole with two equivalents of NaOH and dimethyl sulfate, or... 

All of the above described hydroxythiophenes and hydroxybenzo[6Jthiophenes can of course be alkylated with conventional phenolic alkylating agents to yield the corresponding alkoxy derivatives. However, many of the alkoxy derivatives can be obtained directly by ring closure reactions, and can indeed serve as sources of the hydroxy derivatives by dealkylation (Section 3.14.3.6). 

Both 2- and 3-alkoxybenzo[6 Jthiophenes may be obtained by alkylation of the appropriate hydroxy derivative, but there are competing side reactions (70AHC(11)177). 2-Methoxy-benzo[6 Jthiophene can be prepared by heating 2-bromobenzo[6 Jthiophene with sodium methoxide, and 3-methoxybenzo[7> Jthiophene is obtained by similar treatment of 3-bromobenzo[6 Jthiophene. Alkylation of 3-hydroxybenzo[6 Jthiophene-2-carboxylic ester is more efficient, giving the 3-alkoxy derivative in good yield, and this in turn can be hydrolyzed and decarboxylated in adequate yields (equation 81). 

Enantioselective Birch reduction-alkylation The chiral benzoic acid derivative 1, prepared by condensation of o-hydroxybenzoic acid with L-prolinol followed by cyclization (Mitsunobu reaction), undergoes Birch reduction (K, NH3, THF, t-butyl alcohol) followed by alkylation with C2H5I to give essentially only 2. Acid hydrolysis returns the chiral auxiliary and provides the 2-alkylated cyclo-hexenone 3. 

Hydroxy-6-y-cyclohexylpropylbenzo[6]thiophene-4,7-quinone is obtained by radical alkylation of 5-hydroxybenzo[6]thiophene-4,7-quinone.636... 

This new approach involved alkylation of methyl 4-hydroxybenzoate with (354) using caesium bicarbonate as the acid scavenger [174]. The resulting amide ester (356) was sequentially deprotected and saponified to produce (357). Incorporation of the glutamic acid moiety was best accomplished using solid-phase peptide synthesis techniques and gave consistently better overall yields of (358) [102, 177]. 

Commonly used preservative agents include organic acids such as benzoic acid and salts, the parabens, (alkyl esters ofp-hydroxybenzoic acid), sorbic acid and salts, phenolic compounds, quaternary ammonium compounds, alcohols, and mercurials such as thimerosal in 0.001-0.004% concentration. 

Interestingly, it is possible to etherify hydroxybenzoic acids without the need to protect the carboxyl group (Scheme 6.19). The high charge delocalization of the car-boxylate obviously leads to a sufficient decrease of nucleophilicity to enable clean ether formation under certain conditions. During the planning of such reactions it should, however, be kept in mind that carboxylates can be O-alkylated under conditions similar to those required for the O-alkylation of phenols (see Section 6.9). 

A series of 4-alkylamido-2-hydroxybenzoic acids containing a different number of carbon atoms in the alkyl-amido group has been studied as model ligands for metal ion extraction in aqueous micellar solutions of nonionic surfactants. Their acid-base properties and reactivity towards metal ions in the presence of micelles were investigated. By operating at a proper temperature, the separation of the iron (III) chelate complexes into a micellar rich phase was achieved and the extraction efficiency was correlated with the ligand hydrophobicity. 

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