Carboxylic acids reaction with quinolines

Treatment of ethyl l-oxo-l//-pyrimido[l,2-a]quinoline-2-carboxylates with ammonia in methanol and hydrazine hydrate in ethanol at ambient temperature afforded 2-carboxamides and 2-carbohydrazides, respectively (74MIP1 79MIP2). Reaction of l-oxo-l//-pyrimido[l,2,-a]quinoline-2-carboxylic acids (169) with A-. /V-carbonyldiimidazole in dimethyl-formamide, then with 5-aminotetrazole gave 7V-(5-tetrazolyl)-1 -oxo-1H-pyrimido[l,2-a]quinoline-2-carboxamides (170) (77GEP2630469 77USP 4017625). 

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]. 

Cyclization of methyl 4-(c/s-3,5-H-2-oxomorpholin-5-yl)butyrate in boiling toluene provided c/s-4,9a-H-4-phenylperhydropyrido[2,l-c][l,4]ox-azine-3,6-dione [95H(41)1931], Heating l,4-oxazin-2-one 163 afforded [l,4]oxazino[4,3-a]quinoline-4,6-dione 164 (94IZV299, 94JFC119). The reaction of carboxylic acid 165 with l.l -carbonyldiimidazole in the presence of 4-methylmorpholine afforded pyrido[2,l-c][l,4]oxazin-4-one (61)... 

This is an example of the Doebner synthesis of quinoline-4-carboxylic acids (cinchoninic acids) the reaction consists in the condensation of an aromatic amine with pyruvic acid and an aldehj de. The mechanism is probably similar to that given for the Doebner-Miller sj nthesis of quinaldiiie (Section V,2), involving the intermediate formation of a dihydroquinoline derivative, which is subsequently dehydrogenated by the Schiff s base derived from the aromatic amine and aldehyde. 

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 describes the condensation of an o-aminophenylglyoxylic acid 16 (which can be generated in situ from an isatin IS) with 2 results in a quinoline-4-carboxylic acid (17), which is the subject of its own chapter in this book. ... 

Esterification of the corresponding quinoline-4-carboxylic acid gave the ester 511 which upon reaction with pyrrolidine in THE gave the amide 512. Its phosphorylation and reaction with 513 in presence of KOBu afforded 514 which is useful in the treatment of anxiety, sleep disorders, panic states, convulsions, muscle disorders (95WOP9514020) and chronic neurodegen-erative diseases (97WOP9700074) (Scheme 87). 

Thermal cyclization of the arylaminomethylenemalonate afforded quinoline 3-carboxylate 630 whose reaction with 1,1-dibromoethane gave oxazolo[5,4,3-(/]quinoline 631. Acid hydrolysis and reaction with N-methylpiperazine gave 632 whose bactericidal activity is superior to that of pipemidic acid (82JAPK57203085) (Scheme 108). 

The Pfitzinger reaction of isatins with a-methylene carbonyl compounds is widely used for the synthesis of substituted quinoline-4-carboxylic acids. Ivachtchenko and colleagues have recently reported on the Pfitzinger reaction in a series of 5-sulfa-moylisatins (Scheme 6.239) [422]. Treatment of 5-sulfamoylisatins with diethyl mal-... 

Markees and Schwab cyclized A-alkyl-Af-arylaminomethylenemal-onates (106, R3 = H) by treatment with phosphorus pentoxide (72HCA1319). Equal amounts of aminomethylenemalonates (106, R3 = H) and phosphorus pentoxide were warmed to about 130°C, when exothermic reactions occurred. The temperature of the reaction mixtures rose to about 190°C. After the work-up process, quinoline-3-carboxylic acids (696) were obtained in 41-63% yields. Better yields (76-96%) were achieved when the reactions were carried out in nitrobenzene. 

Af-Ethyl-A-(3-halo-2-methylphenyl)aminomethylenemalonates (106, R = Et, R1 = Me, R2 = Hlg, R3 = H) were heated in polyphosphoric acid, prepared from phosphoric acid and phosphorus pentoxide, at 140°C for 40 min. The reaction mixture was then poured into water, and the product was hydrolyzed with 10% aqueous sodium hydroxide to give quinoline-3-carboxylic acids (696, R = Et, R1 = Me,R2 = Hlg) in 68-70% yields (80GEP3007006). 

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