4-Hydroxy-2-quinolones 130. The reactivity of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates

Abstract

The high reactivity of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates is governed by the simultaneous presence of the 4-OH and 2-C=O groups in the pyridine part of the molecule.Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates are known to be quite powerful acylating agents. They readily react with primary and many secondary aliphatic, aromatic, and heterocyclic amines to form the corresponding amides in high yields [2][3][4][5]. The almost unlimited potential for modification of the quinolone and amide parts of the molecule allows a targeted change to the physicochemical and hence biological properties of the indicated compounds. This has led to increased interest from the viewpoint of chemists and pharmacologists engaged in a search for novel biologically active compounds based on them and which can give rise to medicinal compounds with improved properties There is also interest in the theoretical question regarding the reason for the high reactivity of the ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates which are key in such investigations because the reason remains unclear. Our report attempts to answer the question.The first step in our investigation was a comparative analysis of the steric structural features of the simplest member of the homologous series, i.e. ester 1 and of the isomers 4-ethoxycarbonyl-3-hydroxy-2-oxo-1,2-dihydroquinoline (2) and 3-ethoxycarbonyl-4-hydroxy-1-oxo-1,2-dihydroisoquinoline (3) stable to amidation. With this aim, all three esters were studied by X-ray structural analysis. Hence in the case of the isoquinoline derivative 3 it was found that the heterocyclic fragment is planar to within 0.022 Å (see Fig.

4-Hydroxyquinolin-2-ones and their Close Structural Analogues as a New Source of Highly Effective Pain-Killers

“…Lower esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids have a high reactivity [31][32][33][34]; due to it their transformation into various N-R-amides usually causes no complications. That is why problems arosen in amidation of dimethoxy substituted ester 11 by primary alkylamines appeared to be unexpected to a great extent.…”

4-Hydroxy-2-quinolones 144. Alkyl-, arylalkyl-, and arylamides of 2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and their diuretic properties

“…Hence the course of the reaction of ester 4 with amines is not largely determined by the acidity of the 2-OH group (pK a = 8.91 ± 0.01) but by the structural affinity of the starting components (although a constructive role for the group giving the reacting molecules a suitable orientation in space is not in doubt). For comparison the pK a of the 4-OH group in ethyl 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates is about 8.6 [7] and similar complications did not arise in their amidation with the exception of the case of ammonia reported above. It was interesting that the stable salts formed by the alkylamides 1a-u at the 2-OH group were not observed and their separation would not necessarily demand acidification of the reaction medium.…”

“…1 H NMR spectrum, δ, ppm (J, Hz): 8.57 (1H, d, J = 6.8, H-6); 7.59 (1H, t, J = 7.2, H-8); 6.96 (1H, d, J = 8.8, H-9); 6.79 (1H, t, J = 6.8, H-7); 4.05 (2H, q, J = 7.2, OCH 2 CH 3 ); 3.54 (2H, t, J = 5.2, OCH 2 CH 2 N); 2.82 (2H, t, J = 5.2, OCH 2 CH 2 N); 1.18 (3H, t, J = 7.2, CH 3 ). 13 C NMR spectrum, δ, ppm: 168.3 (CO 2 ), 168.0 (C (2) ), 156.0 (C (4) ), 150.3 (C (9a) ), 138.0 (C (8) ), 128.3 (C (6) ), 122.0 (C (9) ), 111.7 (C (7) ), 93.2 (C (3) ), 59.6 (OCH 2 CH 3 ), 59.2 (OCH 2 CH 2 N), 42.4 (OCH 2 CH 2 N), 15 …”

“…The bicyclic fragment of the molecule of this compound and the O (1) , O (2) , C (9) , O (3) , N (3) , and C (10) electron density in the molecule which is revealed in lengthening of the O (2) -C (6) bonds 1.234 (2) and O (3) -C (9) 1.257(2) Å when compared with their mean value of 1.210 Å [9] and also the N (1) -C (1) 1.330(2) and C (7) -C (8) 1.402(2) Å bonds (mean values 1.313 and 1.331 Å respectively). The O (1) -C (8) 1.323 (2), N (1) -C (8) 1.336 (2), and C (6) -C (7) 1.408(2) Å bonds are shortened when compared with their mean values of 1.333, 1.376, and 1.455 Å.…”

4-Hydroxy-2-quinolones 138. Synthesis and study of structure-biological activity relationships in a series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid anilides

“…Removal of this restriction enables amidation of the previously prepared 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids and their esters. The lowest alkyl esters of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids are highly reactive [9] and efficiently acylate primary and secondary amines in the majority of cases. According to the methods frequently met in the literature amidation is brought about by refluxing the corresponding 3-alkoxycarbonylquinolone and a 40-150% excess of the aniline in a suitable solvent (pyridine, toluene, xylene, bromobenzene) for 3-36 h with simultaneous distillation of the alcohol evolved [3,5,10,11].…”