Quinoline carboxylic acids decarboxylation

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. 

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 Pfitzinger reaction entails the synthesis of quinoline-4-carboxylic acids 2 via condensation of isatic acids formed from isatins 1 and a-methylene carbonyl compounds in the presence of strong aqueous bases. Subsequent decarboxylation can afford the corresponding quinolines. " ... 

Esters of 9-oxo-6,9-dihydro-triazolo[4,5-/]quinoline-8-carboxylic acids 176 can be hydrolyzed and decarboxylated to afford the 9-oxo-6,9-dihydrotriazolo[4, 5-/]quinolines 177 (Scheme 55) (87CCC2918, 88CCC1068,90JMC2640). These in turn were aromatized with POCI3 to the appropriate 9-chloroderivatives 178,... 

Like other carboxylic acids, 2-nit rodibenz[b,/]oxepin-10-carboxylic acid can be decarboxylated in the presence of copper and quinoline to give 2-nitrodibenz[/ ,/]oxepin (2) in 45% yield.101... 

Elimination of sulfur from methyl dibenzo[/),/]thiepin-10-carboxylatcs 15 (R2 = Me) can be achieved in moderate yields (39-55%) upon refluxing in diethyl phthalate in the presence of copper bronze.60 For the dibenzo[A,/]thiepin-10-carboxylic acids 15 (R2 = H), the loss of sulfur is accompanied by decarboxylation. Thus, treatment of these acids with copper bronze in refluxing quinoline for four hours gives the corresponding phenanthrenes 16 (R3 = H) in moderate yield (50%). However, the exposure time to high temperatures influences the product formation. Thus, the decarboxyiated dibenzothiepins are obtained after refluxing for only five minutes.60... 

The decarboxylation of aromatic acids is most often carried out by heating with copper and quinoline. However, two other methods can be used with certain substrates. In one method, the salt of the acid (ArCOO ) is heated, and in the other the carboxylic acid is heated with a strong acid, often sulfuric. The latter method is accelerated by the presence of electron-donating groups in ortho and para positions and by the steric effect of groups in the ortho positions in benzene systems it is... 

Interestingly, the Fischer indole synthesis does not easily proceed from acetaldehyde to afford indole. Usually, indole-2-carboxylic acid is prepared from phenylhydrazine with a pyruvate ester followed by hydrolysis. Traditional methods for decarboxylation of indole-2-carboxylic acid to form indole are not environmentally benign. They include pyrolysis or heating with copper-bronze powder, copper(I) chloride, copper chromite, copper acetate or copper(II) oxide, in for example, heat-transfer oils, glycerol, quinoline or 2-benzylpyridine. Decomposition of the product during lengthy thermolysis or purification affects the yields. 

Almotriptan has also been synthesized via decarboxylation of the carboxylic acid intermediate 65, but a detailed preparation of 65 was not provided in the patent literature (Scheme 22)." The patent indicates that the carboxy indole 65 was prepared according to the method of Gonzalez.°° Thus, (2-oxo-tetrahydro-3-furanyl)-glyoxylic acid ethyl ester (62) was heated in aqueous H2SO4 to give 2-oxo-5-hydroxypentanoic acid in situ, which was treated with hydrazine 59 to produce hydrazone 63. Fischer cyclization of 63 using HCl gas in DMF gave the lactone 64, which was converted to carboxylic acid 65. Decarboxylation of 65 was catalyzed by cuprous oxide in quinoline at 190 °C to afford almotriptan (5)." ... 

Alkyl radicals for such reactions are available from many sources such as acyl peroxides, alkyl hydroperoxides, particularly by the oxidative decarboxylation of carboxylic acids using peroxy-disulfate catalyzed by silver. Pyridine and various substituted pyridines have been alkylated in the 2-position in high yield by these methods. Quinoline similarly reacts in the 2-, isoquinoline in the 1-, and acridine in the 9-position. Pyrazine and quinoxaline also give high yields of 2-substituted alkyl derivatives <74AHC(16)123). 

Pyrrole-2-carboxylic acid easily loses the carboxylic group thermally. Pyrrole-3-carboxylic acid and furan-2- and -3-carboxylic acids also readily decarboxylate on heating to about 200°C. Thiophene-carboxylic acids require higher temperatures or a copper-quinoline catalyst. In furans, 2-carboxylic acid groups are lost more readily than 3-carboxylic acid groups (Scheme 64). 

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