Substituted benzoic acids acylation

The aerobic reduction of aryl and alkyl carboxylates to the corresponding aldehydes. The reaction involves formation of an acyl-AMP intermediate by reaction of the carboxylic acid with ATP NADPH then reduces this to the aldehyde (Li and Rosazza 1998 He et al. 2004). The oxidoreductase from Nocardia sp. is able to accept a range of substituted benzoic acids, naphthoic acids, and a few heterocyclic carboxylic acids (Li and Rosazza 1997). 

Studies on acylation and deacylation of trypsinlike enzymes by nophenyl eaters of substituted benzoic acids have shown (hat the rate of descylstion is influenced by the benzoic acid substituent. There is a linear correlation between the rate of deacylation and the inductive effect of the substituent (Fig. 3). This is also true of all trypsinlike serine proteases tested. However, the... 

Acyl cations are postulated as intermediates of the hydrolysis of some substituted benzoic acid esters (Newman, 1941 Treffers and Hammett, 1937) and j3-lactones (Olson and Hyde, 1941) in strong acid solutions mo the Aac1 mechanism (Ingold, 1953, 1969). 

The reactions are catalyzed by acyl-CoA amino acid A-acyltransferase, of which two distinct A-acyltransferases exist in mammalian mitochondria. The predominant transferase conjugates medium-chained fatty acyl CoA and substituted benzoic acid derivatives with glycine and is termed an aralkyl-CoA glycine A-acyltransferase, while the other enzyme conjugates arylacetic acid derivatives with glycine, glutamine, or arginine and is an arylacetyl-CoA amino acid A-transferase. 

Sulfur tetrafluoride converts carboxylic acids, in the first reaction step, into the acyl fluorides, and in the second step into trifluoromethyl compounds. By selecting suitable reaction conditions, the acyl fluorides can be isolated. " Thus. /> ra-substituted benzoic acids react at 20 C to yield the acyl fluorides almost exclusively." Substitution of the carbonyl oxygen requires higher reaction temperatures. Similar findings have been made with a series of different cyclohcxanedicarboxylic acids. ... 

Although this is the classical method of anhydride formation it has been replaced to a large extent by the acylation of free carboxylic acids (method 341). The conditions employed and the solvents used in this reaction vary widely. Excellent directions are given for the preparations of nicotinic anhydride (89%) and acetic propionic anhydride (60%) from the respective potassium and sodium salts of the carboxylic acids. Silver salts of acids have also been used. The reaction has been extended to the preparation of mixed anhydrides of short- and long-chain fatty acidsbut has failed in the preparation of mixed anhydrides of substituted benzoic acids. ... 

The Hammett p value of 2.23 translates to a Bronsted p of-2.23 because a is essentially a pA a of the substituted benzoic acid. As expected, electron withdrawing substituents in the acyl group of esters increase the rate of alkaline hydrolysis. The results indicate that the... 

Rather interesting conclusions can be drawn from an examination of the serine protease-catalyzed hydrolysis of a series of esters or anilides of basic substituted benzoic acids and amidinophenyl esters of aromatic carboxylic acids [1-10]. They react with the serine proteases like a substrate by acylation of the serine residue of the active center and by simultaneous release of the alcoholic... 

Table 2 Half-Time (min) of Reactivation of Serine Proteinases Acylated with Substituted Benzoic Acids at pH 7.5 and 37°C...

A series of acylated recombinant tPAs (r-tPA) was prepared by reaction of r-tPA with 4-amidinophenyl esters of substituted benzoic acids. The different acyl derivatives contained 5-10% of free enzyme. During deacylation, which is markedly influenced by pH and temperature, 80-100% of the amidolytic activity of the enzyme was recovered in active form. 

Guanidino and amidino phenylesters of substituted benzoic acids act as temporary inhibitors of serine proteases and may serve for the preparation of stable acyl enzymes acting as prodrugs [44]. The enzymes inactivated by active-site acylation regain their activity via deacylation in physiological environment. This opens up new pharmacological aspects to the acylated enzymes trypsin and related serine proteases and their action as proenzymes. 

Some of the latest developments in terms of substrates for the Heck reactions are nitrophenyl benzoates [55], acyl benzoates (mixed anhydrides) [236], and substituted benzoic acids [53]. For the last two, the leaving groups are carbon dioxide and carbon monoxide, respectively. A variety of alkenes have been coupled with these substrates. While esters and anhydrides presumably react in a catalytic cycle like that of the classical Heck reaction [237], arenecarboxylic acids, when treated with an equimolar amount of a silver salt as reoxidant, appear to undergo a nonclassical Heck reaction as demonstrated by the coupling with 2-cyclohexenone to give a 3-arylcyclohexenone. 

The decarboxylative acylation of ortho-substituted benzoic acids involving nucleophilic addition to nitriles occurs under palladium catalysis (Scheme 4.35) [40]. 

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

This does not occur in the case of catalyst and reactants here described. With Bronsted-type catalysis, the reaction between the benzoyl cation, Ph-C" =0, and the hydroxy group in phenol is quicker than the electrophilic substitution in the ring. This hypothesis has been also confirmed by running the reaction between anisole and benzoic acid in this case the prevailing products were (4-methoxy)phenylmethanone (the product of para-C-benzoylation) and methylbenzoate (obtained by esterification between anisole and benzoic acid, with the co-production of phenol), with minor amounts of phenylbenzoate, phenol, 2-methylphenol and 4-methylphenol. Therefore, when the 0 atom is not available for the esterification due to the presence of the substituent, the direct C-acylation becomes the more favored reaction. 

Substituted benzylic alcohols and aromatic aldehydes can be oxidized efficiently to substituted benzaldehydes and benzoic acids, respectively, with F-Teda BF4.101,102 The conversion proceeds via the acid fluoride which enables aldehydes to function as acylating agents in a one-pot procedure. 

The scope of the chemistry outlined in Figure 16.21 can be further expanded by including other acids susceptible to irreversible reaction with a primary amine. These can be other halocarboxylic acids, such as (chloromethyl)benzoic acids, or acrylic acid, which reacts with amines to yield N-substituted (1-alanines. N-Substituted oligo((5-ala-nines) have been successfully prepared by sequentially acylating support-bound amines with acrylic acid and then performing a Michael addition with primary amines [239]. 

Propose a mechanism for the reaction of benzoic acid with oxalyl chloride. This mechanism begins like the thionyl chloride reaction, to give a reactive mixed anhydride. Nucleophilic acyl substitution by chloride ion gives a tetrahedral intermediate that eliminates a leaving group, which then fragments into carbon dioxide, carbon monoxide, and chloride ion. 

Intramolecular if>so-acylationst Grisadienediones such as 2 can be obtained by treatment of a substituted o-phenoxy benzoic acid ester (1) with dry hydrogen chloride and an excess of TiCl4 at 0-25°. The synthesis involves an intramolecular (pro-acylation.1... 

The standard methods for the synthesis of xanthones are via the benzophe-none 17 and diaryl ether intermediates 18 (Fig. 7). The intermediate ben-zophenone derivatives 17 can be obtained by condensation between an ortho-oxygenated benzoic acid and an activated phenol, in the presence of phosphorus oxychloride and zinc chloride (a) [44]. This intermediate is also accessible through condensation by the Friedel-Crafts acylation of appropriately substituted benzoyl chlorides with phenolic derivatives (b) [45]. Then the oxidative or dehydrative processes cause the cyclization of 2,2 -di-oxygenated ben-zophenone to xanthone (c) [46]. 

The acid chloride of tetra-fluoro benzoic acid 203 acylated the magnesium enolate 204 of diethyl malonate to give 205. The chelated magnesium enolate avoids O-acylation. Condensation with ethyl orthoformate puts in the masked aldehyde group and 206 is ready for a succession of aromatic nucleophilic substitutions.39... 

Figure 2 Schematic representation of acylation of serine proteases by amidinophenyl benzoates deacylation rate (ks) depends on benzoic acid substitution (R).

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