Quinoline carboxylic acids => aniline

Besides quinoline, carboxylic acid reactions of anilines with arylidenepyruvic acids can yield other heterocyclic compounds (Scheme 3.78), in particular 5-aryl-3-(2-arylamino)furan-2-ones 280 (by stirring the starting materials in ethanol at room temperature) [214, 215] and l,5-diarylpyrrolidine-2,3-dione 281 (by refluxing in ethanol) [216]. 

The three-component reaction of pyruvic acid, aldehydes and anilines can also yield pyrrolidine-2,3-dione [198], but in most cases the products of such multicomponent condensations are quinoline carboxylic acids identical to compounds obtained via the reaction of arylidenepyruvic acids [217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228]. 

Subsequent investigations have reinforced earlier evidence for the wide occurrence of hydrogen bonding of azines. Bonding of all the monocyclic azines,many substituted azines, and azinones with water, alcohols, and dilute acids has been studied by electronic absorption spectra and the variation of the effect with changes in the position of the substituent noted. Quinolines and acridines with chloroform, alcohols, phenols, carboxylic acids, aniline, and pyrrole show the influence of hydrogen bonding on... 

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. 

Three-component coupling of an aniline, pyruvic acid, and an aldehyde to provide a quinoline-4-carboxylic acid. 

The application of 4-oxo-4-arylbut-2-enonic acids 274 as unsaturated carbonyls in reactions with anilines allows the synthesis of quinoline-2-carboxylic acids 275 [212] (Scheme 3.76). Reactions of anilines with arylidenepyruvic acids can also yield quiniline carboxylic acids (or their decarboxylated analogues)... 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

Aromatic 0-hydroxy carboxylic acids behave very similarly to fi-oxo carboxylic acids they sometimes lose carbon dioxide when merely boiled with water, but this is a general reaction when they are heated with pyridine, quinoline, aniline, or dimethylaniline. This behavior can certainly be ascribed to reaction of aromatic 0-hydroxy acids as the keto tautomer ... 

The Doebner reaction is a three component coupling of an aniline (1), pyruvic acid (2), and an aldehyde (3) to provide a 4-carboxyl quinoline (4). That product can be decarboxylated to furnish quinoline 5. 

The Doebner reaction can provide the 4-carboxyl quinoline when the Pfitzinger reaction does not." Pfiztinger reaction of pinnacolone with isatin did not provide the desired quinoline. Doebner reaction of aniline with acetaldehyde and pyruvic acid did furnish the quinoline, albeit in only 8% yield. 

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