4-Hydroxyquinol-2-ones. 86. Synthesis of Methyl (Ethyl) Esters of 1-Substituted 4-Amino-2-oxoquinoline-3-carboxylic Acids

Abstract

Esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids 1 are of interest as potentially biologically active substances and also as a basis for further chemical conversions with an adequately broad synthetic potential.The usual method of obtaining compounds of this family comprises acylation of anthranilonitrile 2 with the acid chloride of an appropriate acid, containing a fairly reactive methylene group, with subsequent closure of the 4-aminoquinoline ring under the action of basic catalysts [2,3]. This method gives good results in the synthesis of 3-alkoxycarbonyl-1H-4-amino-2-oxoquinolines 3 [4] and, in principle, may be used for obtaining 1-N-alkyl derivatives 1 (Scheme 1, method A). Regretably alkylation of anthranilonitrile 2 does not occur quantitatively and the N-alkyl derivatives obtained always contain contamination by the starting material, effective elimination of which is only possible by chromatography (especially in the case of the lower N-alkyl substituents). Using the available N-alkylanthranilic acids in the synthesis of anthranilonitriles 4 [5] may exclude chromatographic purification, but such a modification introduces several additional stages, esterification, amidation in an autoclave, dehydration of the amide, and removal of the N-protecting group [2,3], which is not always justified by far.A second possible variant for obtaining esters of 1-substituted 4-amino-2-oxoquinoline-3-carboxylic acids 1 is the alkylation of the previously isolated 1H-derivatives 3 (method B). As a result of lactam-lactim, enamine-imine, and keto-enol tautomerism for esters 3 it is possible that five tautomeric forms exist (Scheme 2), in which both nitrogen atoms, the oxygen of the 2-C=O group, or the carbon atom at position 3 of the quinoline ring may potentially be nucleophilic centers.We noted previously [4] that the properties of the 4-amino group in esters 3, judging by the chemical shift of its protons in the 1 H NMR spectrum (8.3 ppm), are far closer to an amide than to a normal amine (for example, for anilines the mean value is ~4 ppm [6]). It is also known that in 1H-4-amino-2-oxo-3-phenylquinolines alkylation of the 4-amino group (chemical shift 5.9 ppm) is successfully effected only in the _______ * For Part 85 see [1].

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

“…And although only two examples of one type are considered, it is clear that it is possible to subject not only N-alkyl derivatives to an analogous conversion, but also other available 4-chloro-3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolines, such as N-aryl, tricyclic C (8) /N (1) annelated, and others substituted in the benzene portion of the quinolone nucleus, etc. [4,7].…”

“…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]. Nonetheless, transformation of dicarboxylic acids 4 into the desired 4-methyl derivatives 1 was effected successfully.…”

4-hydroxy-2-quinolones. 109. Alkylation of 4-substituted ethyl 2-oxo-1,2-dihydro-quinoline-3-carboxylates

“…However its reaction with octyl bromide in the system DMF/K 2 CO 3 gives a mixture of N-and O-alkylation products moreover with a predominance of the aromatic 2-alkoxy derivative [3]. One of the reasons for this result would be a consequence of the rather large size of the alkyl group in the octyl bromide.…”

“…Interatomic distances and valence angles are given in Tables 1 and 2. Ethyl 4-Amino-1-ethyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (3c) was prepared by a known method [3]. …”

“…As a rule the result of such reactions are a mixture of the corresponding N-and O-alkyl substituted derivatives, frequently containing some of the starting material [2][3][4][5]. The predominant formation of one of the isomers is determined by many factors including the substituents in the alkylating substance, the structure and size of the introduced alkyl group (in the case of alkyl halides the halogen has an important effect), the base used for generating the anion, the solvent, and other experimental reaction conditions.…”