Benzoic acid, derivatives

Chart 32. Benzoic acid derivatives found in the Hepaticae 

Four new prenyl benzoates, trichocolein (577), tomentellin (581), isotomentellin (582) and demethoxytomentellin (584) have been isolated from Japanese Trichocolea tomentella as the major components (57). The presence of an allyl ester group in (577) was confirmed by hydrogenation 

The IR (1690 cm ) and UV (257 nm) spectra, and the formation of a 2,4-dinitrophenylhydrazone supported the presence of an a,p-unsaturated carbonyl group in tomentellin (581). Hydrogenation of (581) which gave methyl 3-methoxy-4-hydroxybenzoate and tetrahydroderivative, and analysis of the H-NMR and mass spectra [m/z 181 +H (65%) and 151 (100%)] led to the conclusion that tomentellin was 3,7-dimethyl-5-keto-2,6-octadienyl 3,4-dimethoxybenzoate (581). The position of the carbonyl group was further confirmed by the bathochromic shift of the UV absorption band to 257 nm after addition of aq. NaOH. The geometry of the enone system was presumed to be s-cis from the observation that the IR absorption band of the double bond was more intense than that of a carbonyl group. 

The structure assigned to isotomentellin (582) was based on spectral and chemical correlation with (581). Hydrogenation of (582) gave tetrahydro-tomentellin. Failure to observe a bathochromic shift in the UV band at 262 nm after addition of aq. NaOH led to the conclusion that isotomentellin was the C-3/C-4 double bond isomer of (581). 

Hydrolysis of the fourth isoprenyl benzoate (584) gave vanillic acid. Methylation of (584) afforded tomentellin (581). Thus, the structure of demethoxytomentellin was established to be 3,7-dimethyl-5-keto-2,6-octa-dienyl 3-methoxy-4-hydroxybenzoate (584). 

Several hydroxylated and methoxylated derivatives of benzoic acid (phenyl carboxylic acid) occur in nature (Table 52). They are the mother substances of reduced compounds (derivatives of benzaldehyde and benzylalcohol), of de-carboxylated products (hydroquinone-derived compounds), but also of more complex substances, e.g., the gallotannins and ellagitannins. 

OCHg OH OCHg H Sinapic acid Syringic acid 

Benzoic acid and its derivatives are formed in microorganisms, plants and animals. 

In plants and animals dihydrocinnamic acids (D 22.2.1) are the most important precursors of benzoic acids (for the formation of benzoic acid derivatives from shikimic acid cf. D 8 and D 8.2). The dihydrocinnamic acids are cleaved with the formation of a two carbon fragment and an aromatic aldehyde, which may be 

Gentisic acid glycosides act as leaf movement factors in Mimosa species (E 2.2). Gallic acid is an inhibitor of flowering in Kalanchoe blossfeldiana (E 2.2). Benzoic acid, p-hydroxybenzoic acid as well as protocatechuic acid methyl and ethyl esters are secreted from the pygidial glands of water beetles as antiseptics and feeding deterrents (E 5.1). 

Yet another nontricyclic antidepressant consists of a relatively simple morpholine derivative. Acylation of aziridine with p-chlorobenzoyl chloride gives the amide 130. This intermediate is. sufficiently reactive to undergo ring opening on treatment with morpholine. The product is the antidepressant agent moclobemide (131) 33J. 

Esters of tropine have a venerable place in medicinal chemistry. One such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of today s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another ]ii ominent natural product, atropine (133). The product, tropanaerin (134), is described as an iinti.serotonergic agent intended for antimigraine use [34]. 

It has by now been reasonably well established that an ethanolamine function appropriately linked to an aromatic ring is a prerequisite for beta adrenergic activity and/or antagonism. Examples have been met above where those two moieties are attached directly as well as examples where the funetions are separated by an oxymethylene fragment. It has reeently been found that beta blocking activity is retained even when a earbonyl is inserted between the extra oxymethylene 

The benzoic acid moiety common to many of the benzamides is prepared in straightforward manner from the methyl ether of p-aminosalicylic acid 141. Acylation on nitrogen (142) followed by chlorination gives intermediate 143 benzoic acid 144 is then obtained by removal of the acetyl group. Condensation of this acid with an aminopiperidine could be achieved by means of the mixed anhydride (prepared by reaction with ethyl chlonoformate), which affords clebopride (145). Reaction with 3-aminoquinuclidine (146) of the intermediate prepared from acid 144 with carbonyldiimidazole affords zacopride (147) [36]. 

Activity is apparently retained when the aromatic amino group is deleted. Brominadon of acid 148 followed by reaction of the product (149), as its acid chloride, with the (S)-(-)-amino-methylpyrrolidine 150, gives the dopamine antagonist, remoxipride (151) [37] with (S)-configu-ration. 

It has been documented in an earlier volume that appropriately substituted molecules with two strongly electron withdrawing substituents meta to one another in a benzene ring often possess diuretic properties and, even though the prototypes usually have two substituted sulfonamide moieties so disposed, other groups can replace at least one of them. An example of this is piretanide (24), where one such group is a carboxyl 

Reduction to the corresponding ] -substituted pyrrolidine (23) (lakes place with sodium borohydride/boron trifluoride. Saponification completes the synthesis of the diuretic agent piret-.inide (24).  

Because of resonance stabilization of the anion, a tet-nazolyl moiety is often employed successfully as a bioisosteric replacement for a carboxy group. An example in this subclass is provided by azosemide (27). Benzonitrile analogue is prepared by phosphorus oxychloride dehydration of the corresponding benzamide. Next, a nucleophilic aromatic displacement reaction of the fluorine atom leads to The synthesis concludes with the 1,3-dipolar addition of azide to the nitrile liinction to produce the diuretic azosemi de (27).  

A lipid lowering agent of potential value in hypercholesterolemia is cetaben (31). It is synthesized facilely by monoalkylation of ethyl -aminobenzoate with hexadecyl bromide and then saponification.  

Benzamide known as benti romide, is a chymotrypsin substrate of value as a diagnostic acid for assessment of pancreatic function. It is synthesized by amide formation between 

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If the benzoyl derivative is soluble in alkali, precipitate it together with the benzoic acid derived from the reagent by the addition of hydrochloric acid filter and extract the product with cold ether or light petroleum (b.p. 40-60°) to remove the benzoic acid. 

Benzoic acid and naphthoic acid are formed by the oxidative carbonylation by use of Pd(OAc)2 in AcOH. t-Bu02H and allyl chloride are used as reoxidants. Addition of phenanthroline gives a favorable effect[360], Furan and thiophene are also carbonylated selectively at the 2-position[361,362]. fndole-3-carboxylic acid is prepared by the carboxylation of 1-acetylindole using Pd(OAc)2 and peroxodisulfate (Na2S208)[362aj. Benzoic acid derivatives are obtained by the reaction of benzene derivatives with sodium palladium mal-onate in refluxing AcOH[363]. 

The benzoic acid derivative 457 is formed by the carbonylation of iodoben-zene in aqueous DMF (1 1) without using a phosphine ligand at room temperature and 1 atm[311]. As optimum conditions for the technical synthesis of the anthranilic acid derivative 458, it has been found that A-acetyl protection, which has a chelating effect, is important[312]. Phase-transfer catalysis is combined with the Pd-catalyzed carbonylation of halides[3l3]. Carbonylation of 1,1-dibromoalkenes in the presence of a phase-transfer catalyst gives the gem-inal dicarboxylic acid 459. Use of a polar solvent is important[314]. Interestingly, addition of trimethylsilyl chloride (2 equiv.) increased yield of the lactone 460 remarkabiy[3l5]. Formate esters as a CO source and NaOR are used for the carbonylation of aryl iodides under a nitrogen atmosphere without using CO[316]. Chlorobenzene coordinated by Cr(CO)j is carbonylated with ethyl formate[3l7]. 

Oxidation (Section 11 13) Oxidation of alkylben zenes occurs at the benzylic position of the alkyl group and gives a benzoic acid derivative Oxidiz mg agents include sodium or potassium dichro mate in aqueous sulfuric acid Potassium perman ganate (KMn04) is also an effective oxidant... 

Resolution methods using nonopticaHy active agents are also used by taking advantage of the fact that certain benzoic acid derivatives of (A)-menthol can be inoculated with crystals of one enantiomer to induce immediate crystallization of that enantiomer. Although repeated crystallizations and separations must be done, the technique has been successhil for (—)-mentho1 (157). 

The reduction of a benzenoid ring, except in benzoic acid derivatives, occurs only in the presence of a proton donor having a pKa of 19 or less (pKa of ammonia is about 33). With the exception of the vinyl group, the other functional groups listed above do not require a proton donor of this acidity in order to be reduced, although the course of reduction may then be complex, e.g. as with esters. " Consequently, a variety of functional groups should be capable of selective reduction in the presence of a benzenoid ring if the reaction medium does not contain an acid of pKa <19. A few examples of such selective reductions have been reported in the steroid literature. 

In conditions of base catalysis, the acetylenylpyrazolecarboxylic acid hydrazides, as opposed to benzene derivatives, are more difficult to cyclize compared with the benzoic acid derivatives and are isomerized only after heating in alcohol in the presence of KOH, forming not five- but six-membered lactams. The yields of pyri-dopyrazoles were 80-90% (Scheme 133 Table XXVIII) (85IZV1367 85MI2). 

Hydroxyl elimination is necessary for the formation of benzaldehyde and benzoic acid derivatives and, ultimately, benzene and toluene (Fig. 7.46).2 It is proposed that a cleavage between the hydroxyl group and aromatic ring leads to benzenoid species which undergo further cleavage coupled with oxidation to give various decomposition products. 

Astles PC, Brown TJ, Handscombe CM, Harper MF, Harris NV, Lewis RA, Lockey PM, McCarthy C, McLay IM, Porter B, Roach AG, Smith C, Walsh RJA. Selective endothelin A receptor antagonists. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives. Eur J Med Ghent 1997 32 409-23. 

Zellner G, H Kneifel, J Winter (1990) Oxidation of benzaldehydes to benzoic acid derivatives by three Desul-fovibrio strains. Appl Environ Microbiol 56 2228-2233. 

Benzoic acid derivatives also altered the electrical potential across the cell membrane in neurons of the marine mollusk Navanax lnermls (46). Salicylic acid (1-30 mM) caused a depolarization very rapidly (1-2 min) and decreased the ionic resistance across the membrane. As pH was decreased, more salicylic acid was required to reverse the effect of pH on the membrane potential (47). This result is contradictory to the influence of pH on the amount of salicylic acid required to affect mineral absorption in roots (32). The ability of a series of salicylic and benzoic acid derivatives to increase PD correlated with their octanol/water partition coefficients and pKa values (48). The authors proposed that the organic acid anions bound directly to membranes to produce the observed results. 

Figure 5. Relationship of depolarization of membrane electrical potential (E) in excised roots of barley 250 flM benzoic acids against their partition coefficients (log P). The numbers correspond to specific benzoic acid derivatives (1) salicylic, (2) -hydroxybenzoic, (3) protocatechuic, (4) gentisic,...

The coordination modes found in Ni11 complexes with 2-(diphenylphosphino)nicotinic acid and its methyl ester and 2-(diphenylphosphino)benzoic acid and its methyl ester are surprising.696 The complex with the benzoic acid derivative shows the expected P,0 coordination with a six-membered chelate ring (252), while the nicotinic acid analogue forms a four-membered chelate ring with P,N binding (251). 

The Hammett equation is the best-known and most widely studied of the various linear free energy relations for correlating reaction rate and equilibrium constant data. It was first proposed to correlate the rate constants and equilibrium constants for the side chain reactions of para and meta substituted benzene derivatives. Hammett (37-39) noted that for a large number of reactions of these compounds plots of log k (or log K) for one reaction versus log k (or log K) for a second reaction of the corresponding member of a series of such derivatives was reasonably linear. Figure 7.5 is a plot of this type involving the ionization constants for phenylacetic acid derivatives and for benzoic acid derivatives. The point labeled p-Cl has for its ordinate log Ka for p-chlorophenylacetic acid and for its abscissa log Ka for p-chloroben-zoic acid. The points approximate a straight line, which can be expressed as... 

Equations of this type can be written for any pair of the many reactions for which linear log-log plots could be made. Consequently, it is convenient to choose a reference reaction to which others can be compared. The large amount of accurate data on the ionization of benzoic acid derivatives at 25 °C made this reaction an appropriate choice, and a new con-... 

C). The value of a may be determined from its definition in terms of the ionization constant if the appropriate benzoic acid derivative has been measured. Such a values may then be used to determine p values for other reactions, and these p values in turn lead to the possibility of determining new o values. Equation 7.4.24 implies that a plot of log KA or log kA versus oA should be linear for a given series of reactions involving the same reactive groups. Extensive experimental evidence attests to this relation. Table 7.2 contains some values that have been reported in the literature. Extensive tabulations... 

Woodson LC, Ames MM, Selassie CD et al. Thiopurine methyltransferase. Aromatic thiol substrates and inhibition by benzoic acid derivatives. Mol Pharmacol 1983 24 471-478. 

Scheme 6.246 Intramolecular Diels—Alder cyclization of biodihydroxylated benzoic acid derivatives.

In another application, the group of Berteina-Raboin demonstrated the solid-supported synthesis of the indole core of melatonin analogues under microwave irradiation (Scheme 7.6) [26]. A benzoic acid derivative was coupled to Rink amide resin by... 

Simple phenolic compounds include (1) the phenylpropanoids, trans-cinnamic acid, p-coumaric acid and their derivatives (2) the phenylpropanoid lactones called coumarins (Fig. 3.4) and (3) benzoic acid derivatives in which two carbons have been cleaved from the three carbon side chain (Fig. 3.2). More complex molecules are elaborated by additions to these basic carbon skeletons. For example, the addition of quinic acid to caffeic acid produces chlorogenic acid, which accumulates in cut lettuce and contributes to tissue browning (Fig. 3.5). 

Synthetic applications of the asymmetric Birch reduction and reduction-alkylation are reported. Synthetically useful chiral Intermediates have been obtained from chiral 2-alkoxy-, 2-alkyl-, 2-aryl- and 2-trialkylsllyl-benzamides I and the pyrrolobenzodlazeplne-5,ll-diones II. The availability of a wide range of substituents on the precursor benzoic acid derivative, the uniformly high degree of dlastereoselection in the chiral enolate alkylation step, and the opportunity for further development of stereogenic centers by way of olefin addition reactions make this method unusually versatile for the asymmetric synthesis of natural products and related materials. 

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