4-Hydroxy-2-quinolones. 111. Simple synthesis of 1-substituted 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids

Abstract

A preparative method of obtaining 1-substituted 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids is proposed. Features of their spatial structure have been studied.Keywords: 1-R-4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 4-chloroquinolin-2-one, cyanoacetic ester, amidation, hydrolysis, decarboxylation, X-ray structural analysis.1-Substituted 4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 1 are of interest as the basis for the synthesis of various potentially biologically active substances. The obvious synthetic scheme for assembling such compounds presumes alkylation of the appropriate N-substituted ortho-aminoacetophenones with alkoxymalonyl chloride with subsequent closure of the quinoline ring by the action of basic catalysts. However, the practical execution of such a route is severely limited by the availability of the initial N-substituted ortho-aminoacetophenones.Another possible variant for obtaining acids 1 is the N-alkylation of the previously isolated ethyl ester of 1H-4-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid. Regretably such a reaction does not occur unambiguously. The efficiency is reduced to a significant extent by the formation of byproduct 2-O-alkyl-substituted isomers [2].We have proposed an unusual method of replacing the chlorine atom in the ethyl ester of 4-chloro-1H-2-oxo-1,2-dihydroquinoline-3-carboxylic acid by a methyl group [3]. Its structural analogs, i.e. 1-N-alkylsubstituted esters 2, were also involved in the scope of the investigations. As it turned out these also readily react with cyanoacetic ester, like the 1H-derivative. However subsequently the reactions proceeddifferently and, after alkaline hydrolysis of the 4-(cyanoethoxycarbonylmethyl)-3-ethoxycarbonyl-2-oxo-1,2-dihydro-quinolines 3 synthesized in the first stage, the expected 4-methyl substituted acid 1 was not isolated, but only 1-R-4-carboxymethyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 4. To convert the 4-carboxymethyl group into methyl in the hydrolysis process (as occurs in the case of the 1H derivative) was unsuccessful even after doubling the reaction time. Consequently 3-carboxy-1H-quinolin-2-ones exist in basic medium in the aromatic 2-hydroxy form, which surpasses somewhat the 1,2-dihydro form in electron-withdrawing influence on the substituent at position 4. One more of the few examples permitting graphical recording of the difference in reactivity of 2-hydroxyquinolines and 1,2-dihydroquinolin-2-ones is the reaction of the ethyl esters of 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids with pyridine [4].

4-Hydroxy-2-quinolones 140. Synthesis and diuretic activity of arylalkylamides of 4-methyl-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid

“…Of the special features of the spatial structure of acid 1 it should be noted that its bicyclic fragment and the O (1) atom lie in one plane with a precision of 0.02 Å. The bond lengths in the pyridine ring are close to the bond lengths in 2-oxo-1,2-dihydroquinolines studied previously in [12][13][14], and in 4-methyl-substituted derivatives [15]. The formation of a very strong intramolecular hydrogen bond O (3) -H (30) ···O (1) (H···O 1.63 Å, O-H···O 152°) leads to significant lengthening of the O (1) -C (9) bond to 1.257(5) Å in comparison with its mean value [16] 1.210 Å and stabilizes the practically coplanar bicyclic orientation of the carboxyl group (torsion angle C (9 )-C (8) -C (10) -O (3) 9.8(6)°).…”

4-hydroxy-2-quinolones. 114. Synthesis and structure of 6-R-5-hydroxy-2,4-dioxo-2,3,4,6-tetrahydrobenzo-[c][2,7]naphthyridine-1-carbonitriles

“…In addition each tautomer can be described by three resonance structures. The contribution of resonance structures 6.1c and 7.1c are indicated by the shortening of the bond lengths N (1) -C (12) 1.345 (3) …”

Creation of New Local Anesthetics Based on Quinoline Derivatives and Related Heterocycles

“…In particular, in 1-propylsubstituted 4-hydroxy-quinolones-2 the ethyl fragment is placed perpendicular the plane of the quinolone nucleus, as a result the terminal methyl group is far from the bicycle more thansystem is much compact -in spite of the sofa conformation of the tetrahydropyridine ring, (6) atom deviates from its relative plane only in 0.56 Å (Ukrainets et al, 2008). Unlike 1-N-ethylsubstituted 4-hydroxyquinolones-2, in which the methyl group of ethyl substituent is never located in the quinolone cycle plane (Baumer et al, 2004;Ukrainets et al, 2007), tricyclic pyrrolo[3,2,1-ij]-quinoline system is practically flat (Ukrainets et al, 2006a). It is clear that transfer from 1-N-ethyl-and 1-N-propylsubtituted 3a,b to conformation limited pyrrolo-and pyridoquinolines 12-13 should be obligatory reflected to the biological properties.…”