Aniline carboxylic acids

Hofmann s amine synthesis can be applied to both aliphatic and aromatic carboxylic acid amides, benzamide, C HsCONH, thus giving aniline, C4H5NH,. 

Various basic substances, such as aromatic amines (naphthyl-amines dissolve with difficulty in dil. HCl, diphenylamine only in cone. HCl, triphenylamine insoluble) nitro-anilines some amino-carboxylic acids. 

Practically all pyridazine-carboxylic and -polycarboxylic acids undergo decarboxylation when heated above 200 °C. As the corresponding products are usually isolated in high yields, decarboxylation is frequently used as the best synthetic route for many pyridazine and pyridazinone derivatives. For example, pyridazine-3-carboxylic acid eliminates carbon dioxide when heated at reduced pressure to give pyridazine in almost quantitative yield, but pyridazine is obtained in poor yield from pyridazine-4-carboxylic acid. Decarboxylation is usually carried out in acid solution, or by heating dry silver salts, while organic bases such as aniline, dimethylaniline and quinoline are used as catalysts for monodecarboxylation of pyridazine-4,5-dicarboxylic acids. 

Benzanthrone has been prepared by three general methods, the first of which is generally regarded as the best (i) by heating a reduction product of anthraquinone with sulfuric acid and glycerol,1 or with a derivative of glycerol, or with acrolein. The anthraquinone is usually reduced in sulfuric acid solution, just prior to the reaction, by means of aniline sulfate, iron, , or copper. It has also been prepared (2) by the action of aluminum or ferric chloride on phenyl-a-naphthyl ketone, and (3) from i-phenylnaphthalene-2-carboxylic acid. ... 

In 1883, Bottinger described the reaction of aniline and pyruvic acid to yield a methylquinolinecarboxylic acid. He found that the compound decarboxylated and resulted in a methylquinoline, but made no effort to determine the position of either the carboxylic acid or methyl group. Four years later, Doebner established the first product as 2-methylquinoline-4-carboxylic acid (8) and the second product as 2- methylquinoline (9). Under the reaction conditions (refluxing ethanol), pyruvic acid partially decarboxylates to provide the required acetaldehyde in situ. By adding other aldehydes at the beginning of the reaction, Doebner found he was able to synthesize a variety of 2-substituted quinolines. While the Doebner reaction is most commonly associated with the preparation of 2-aryl quinolines, in this primary communication Doebner reported the successful use of several alkyl aldehydes in the quinoline synthesis. 

The extent of coupling is also influenced by the solvent. In the hydrogenation of aniline over ruthenium oxide, coupling decreased with solvent in the order methanol > ethanol > isopropanol > t-butanol. The rate was also lower in the lower alcohols, probably owing to the inhibiting effect of greater concentrations of ammonia (44). Carboxylic acid solvents increase the amount of coupling (42). 

Bifunctional catalysis in nucleophilic aromatic substitution was first observed by Bitter and Zollinger34, who studied the reaction of cyanuric chloride with aniline in benzene. This reaction was not accelerated by phenols or y-pyridone but was catalyzed by triethylamine and pyridine and by bifunctional catalysts such as a-pyridone and carboxylic acids. The carboxylic acids did not function as purely electrophilic reagents, since there was no relationship between catalytic efficiency and acid strength, acetic acid being more effective than chloracetic acid, which in turn was a more efficient catalyst than trichloroacetic acid. For catalysis by the carboxylic acids Bitter and Zollinger proposed the transition state depicted by H. 

It is worth mentioning that both the carboxylation of epoxides and anilines are acid-base reactions, which do not entail redox processes. Therefore a catalyst active in these reactions must provide acid-base functionality. In this perspective, positively charged gold could be the real player, although a co-catalytic or promotion effect of ze-rovalent gold could also be important. Therefore the catalysts for the oxidative carbonylation of aniline, supported on Merck Ion-exchanger IV, could be actually bifunctional. On one side, Au could catalyze the oxidation of CO with O2 to CO2, a reaction for which it is... 

It is worth noting that the Ullmann-Goldberg condensation of aryl halides with phenols and anilines worked efficiently in the presence of copper in water.50 For example, the coupling of 2-chlorobenzoic acid with 4-chlorophenol (K2C03/pyridine/copper powder) gave 2-(4-chlorophenoxy)carboxylic acid (Eq. 6.23).51 The Cu(I)-catalyzed transformation of 2-bromobenzoic acid into salicylic acid has also been studied in aqueous media (Eq. 6.24).52... 

With carboxylic acids there was no activation to carboxylic acid imidazolides observed. Reaction with p-toluenesulfonic acid in boiling tetrahydrofuran did not yield the />-toluenesulfonic acid imidazolide, but rather the double p-toluene sulfonate, from which A -sulfonyldiimidazole can be released again quantitatively with imidazole or aniline. Only from the melt of water-free p-toluenesulfonic acid and AyV -sulfonyldiimidazole at 90 °C p-toluenesulfonic imidazolide (m.p. 75.5-77 °C 87% yield) could be obtained1201 (see also Section 10.1.1). 

The commercial extractants currently used fall into the following categories 297 a-hydroxy-ketox-imes, phenolic-oximes,298 dialkylsulfides, esters of pyridine mono and di-carboxylic acids,299- 1 alkyl derivatives of 8-hydroxyquinoline,79,302,303 trialkylamines,304,305 alkyl derivatives of aniline,306 aliphatic ethers, and ketones.307-309... 

To get a complex set of substituents by direct derivatization of benzotriazole is not feasible. In such situations, it is better to have all the substituents in place first and later construct the heterocyclic ring. High reactivity of anilines and their well-developed chemistry makes them good stating materials. In an example shown in Scheme 215, acetanilide 1288 is nitrated to afford nitro derivative 1289 in 73% yield. Catalytic reduction of the nitro group provides methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate 1290 in 96% yield. Nitrosation of compound 1290 in diluted sulfuric acid leads to intermediate 1291, which without separation is heated to be converted to 7-chloro-4-methoxy-l//-benzotriazole-5-carboxylic acid 1292, isolated in 64% yield <2002CPB941>. 

Although there is versatility in the synthetic methodologies of each individual quinolone antibacterial, two different methods are utilized to synthesize the basic skeleton of l,4-dihydro-4-oxoquinoline-3-carboxylic acid. The first method is based on the Gould-Jacobs reaction [9] using appropriately substituted aniline derivatives and diethyl ethoxymalonate, which results in the formation of the intermediate anilinomethylenemalonate. Further thermal cyclization of this intermediate followed by hydrolysis gives rise to the targeted l,4-dihydro-4-oxoquinoline-3-carboxylic acid, according to Scheme 1. 

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