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Chemistry of Substituted Quinolinones I. Synthesis of Novel Triazinylmethylquinolinone Derivatives

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Chemistry of Substituted Quinolinones I. Synthesis of Novel Triazinylmethylquinolinone Derivatives Chemistry of Substituted Quinolinones I. Synthesis of Novel Triazinylmethylquinolinone Derivatives M. ABASS* and M. M. ISMAIL Department of Chemistry, Faculty of Education, Ain Shams University, Roxy 117711, Cairo, Egypt e-mail: [email protected] Received 9 April 1999 Functionalization of l#-quinolin-2-one moiety, at the position 3, with pyruvic or 2-thiopyruvic acid substrates, in order to develop novel synthons of heterocyclic derivatives of quinolinone, was achieved through ring-closure and ring-opening routes. The syntheses of some new 3-([l,2,4]triazin- 6-ylmethyl)quinolines have been described. Three multiaza-polynuclear heterocycles, viz. triazino- phthalazine. triazinoindole, and bistriazinoquinoxaline, were also synthesized and are expected to have biological importance. The structures of all new products were verified on the basis of their elemental and spectral analyses. Within the framework of research related to methyl-2-oxoquinolin-3-yl)acrylic acid (IV), which in synthesis and reactions of 4-hydroxy-l#-quinolin-2- its 1H NMR spectrum revealed two additional sig­ ones [1—4], we herein report the synthesis of novel nals at S = 11.61 and 13.74 due to two protons functionally substituted quinolinones. 4-Hydroxy-l#- (phenolic and carboxylic) exchangeable with deu­ quinolin-2-ones represent one of the most important terium on treating with deuterium oxide. More­ classes of heterocycles, possessing a wide spectrum over, acid hydrolysis of the acrylic acid deriva­ of biological activities [5—10]. Also, [l,2,4]triazin-5- tive IV furnished 3-(l,2-dihydro-4-hydroxy-8-methyl- ones are well known to exhibit diverse pharmacologi­ 2-oxoquinolin-3-yl)pyruvic acid (V), which was uti­ cal actions [11—14]. So that it is thought that if both lized, hereafter, as a synthon for some new triazinyl- quinolinone and triazinone moieties are combined in methylquinolines. The mass spectrum of compound V one molecular frame, the possible products might have showed a molecular ion peak at m/z (IT/%): 261 (20), considerable biological potencies. accompanied by an (M + 1) ion peak at m/z (IT/%): 4-Hydroxy-8-methyl-l#-quinolin-2-one (/) was 262 (3), confirming the proposed structural formula of prepared following a method similar to that described this compound (Scheme 1). in Ref. [15], and formylated by the Reimer—Tiemann In order to obtain 2-thiopyruvic acid derivative reaction, giving 3-formyl-4-hydroxy-8-methyl-l#-qui- VIII, as the thio-isomer of compound V, condensa­ nolin-2-one (II). The reaction of the aldehyde II with tion of the aldehyde II with 2-phenyliminothiazolidin- hippuric acid in the presence of sodium acetate did not 4-one (VI) was carried out, in the presence of fused lead to the expected oxazolin-5-one derivative, instead sodium acetate. 5-(l,2-Dihydro-4-hydroxy-8-methyl- 3-benzoylamino-7-methyl-5,6-dihydro-2#-pyrano[3,2- 2-oxoquinolin-3-yl)methylene-2-phenyliminothiazoli- c]quinoline-2,5-dione (III) was produced. The struc­ din-4-one (VII), product of the latter reaction, was ture of compound III was elucidated by its ele­ subjected to an exhaustive alkaline hydrolysis to af­ mental analysis, IR and lH NMR spectral data, ford 3-(l,2-dihydro-4-hydroxy-8-methyl-2-oxoquino- which revealed the involvement of the О—H group lin-3-yl)-2-thiopyruvic acid (VIII). The structure of in an intramolecular cyclization. This cyclization compound VIII was verified from its mass spectrum, may take place as a consequent step after conden­ which revealed a molecular ion peak at m/z (Jr/%): sation of the CHO group with the active methy­ 277 (9) along with an (M + 1) ion peak at m/z (IT/%): lene of hippuric acid. We have obtained similar re­ 278 (1). Beside the analytical and spectral evidences sults in an earlier work [1]. It was found that for the structure VIII, it found a good chemical proof pyranoquinoline III underwent ring-opening, when by its independent synthesis through the condensation treated with aqueous sodium hydroxide solution, of aldehyde II with 2-sulfanylacetic acid (Scheme 2). to give 2-benzoylamino-3-(l,2-dihydro-4-hydroxy-8- Reaction of the pyranoquinoline III with hydrazine *The author to whom the correspondence should be addressed. Chem. Papers 54 (3) 187—195 (2000) 187 M. ABASS, M. M. ISMAIL NHCOC6H5 CHO CHCl3/NaOH Hippuric acid AcONa / AcOH CH3 H / 2.0 M-NaOH OH 6.5 M-HC1 CH3 H CH3 H Scheme 1 .CHO ^_NH AcONa /AcOH 4'0 s \ T с6н5 CH3 H // VI HSCH2C02H TEA 0 2.0 M-NaOH ii) 6.0 M-HC1 OH CH3 H CH3 H VIII Scheme 2 hydrate in DMF caused successive ring-opening and Condensation of equimolar amounts of either the ring-closure transformations to give 3-(l,6-dihydro-6- pyruvic acid V or 2-thiopyruvic acid VIII with ben­ oxo-3-phenyl[l,2,4]triazin-5-yl)methyl-4-hydroxy-8- zoic hydrazide afforded one and the same prod­ methyl-l#-quinoHn-2-one {IX). The structure of this uct. It was found that condensation reaction took product was supported by the presence of a phe­ place at the a-oxo (or a-thioxo) group of the pyru­ nolic OH group, and also by the absence of both vic acid side chain, giving rise to 3-(l,2-dihydro-4- carboxylic and amino groups, as it is indicated hydroxy-8-methyl-2-oxoquinolin-3-yl)pyruvic acid 2- in its IR and XH NMR spectra. Similarly, heat­ benzoylhydrazone {XI). On stirring the benzoylhy- ing the quinolinylmethylenethiazolidine VII with hy­ drazone derivative with concentrated sulfuric acid, 4- drazine hydrate gave 4-hydroxy-8-methyl-3-(5-oxo-3- hydroxy-8-methyl-3-(6-oxo-2-phenyl[l,3,4]oxadiazin- phenylimino-2,3,4,5-tetrahydro[l,2,4]triazin-6-yl)me- 5-yl)methyl-l#-quinolin-2-one {XII) was obtained. thyl-l#-quinolin-2-one {X). lE NMR spectrum of Treating the oxadiazinylmethylquinoline XII with am­ compound X revealed four different singlet signals cor­ monium acetate in boiling acetic acid furnished 3-(4,5- responding to four deuterium exchangeable protons of dihydro-5-oxo-3-phenyl[l,2,4]triazin-6-yl)methyl-4- three (N—H) groups, and one more downfield shifted hydroxy-8-methyl-l#-quinolin-2-one {XIII), an iso­ (О—H) group (Scheme 3). mer of the compound IX. Also, the compound XIII 188 Chem. Papers 54 (3) 187—195 (2000) SUBSTITUTED QUINOLINONES. I NHCOC6H5 N2H4-H20 DMF N2H4-H20 DMF CH3 H C6H5 Scheme 3 OH •о %Л CH3 H CH H NH 3 XV R = H X « AniHne XVII R = H 'о %^C6H5 XVI R = C6H5 XVIII R = C6H5 CH3 H ш Scheme 4 was directly obtained from reaction of ammonium ac­ ternatively, the resultant XVI was easily prepared etate and the 2-benzoylhydrazone XL from the condensation of 4-phenylthiosemicarbazide Treatment of either V or VIII with hydrazine hy­ with the pyruvic acid derivative V in ethanol. By drate resulted in the same condensation product, 3- the same manner, 3-(l,2-dihydro-4-hydroxy-8-methyl- (l,2-dihydro-4-hydroxy-8-methyl-2-oxoquinolin-3-yl)- 2-oxoquinolin-3-yl)pyruvic acid 2-thiosemicarbazone pyruvic acid 2-hydrazone {XIV). The structure of XIV (XV) was obtained from condensation of V and was emphasized by its elemental and spectral analyses. thiosemicarbazide. Each of compounds XV and XV/ In addition, when compound XIV was reacted with underwent ring-closure reaction when they were cured phenyl isothiocyanate in ethanol, 3-(l,2-dihydro-4- with sodium ethoxide in boiling ethanol, furnishing 4- hydroxy-8-methyl-2-oxoquinolin-3-yl)pyruvic acid 2- hydroxy-8-methyl-3-(5-oxo-3-thioxo-2,3,4,5-tetrahyd- (4-phenylthiosemicarbazone) {XVI} was obtained. Al­ ro[l,2,4]triazin-6-yl)methyl-lЯ-quinolin-2-ones XV// Chem. Papers 54 (3) 187—195 (2000) 189 M. ABASS, M. M.ISMAIL N—NH2 C H CÔ" 6 5 T ш CH H 3 XX N-NH NH Op"„ 2 CH3 H NH V x = o 2 /—N N—4 VIII X = S D I XXIII H N-N N-N >=* NH2 H XXIV Scheme (R = H) and XVIII (R = Ph), respectively. Moreover, (IT/%): 425 (13), accompanied by an (M + 1) ion when the hydrazone XIV was reacted with phenyl peak at m/z (IT/%): 426 (3), and the base peak at isothiocyanate in the presence of sodium ethoxide, m/z 187, corresponding to the 2,4-dioxo-8-methyl-3- compound XVIII was attained. Beside the spectral ev­ methylenequinolinium ion [CnHgNC^]"*"- idences for the structures of the latter two products, Finally, when Vand/or VIII were heated with 2,3- it was found that the reaction of aniline with XVII led bishydrazonoquinoxaline (XXIII) [18] in DMF, 2,7- to the replacement of the thioxo group to give the pre­ bis((l,2-dihydro-4-hydroxy-8-methyl-2-oxoquinolin-3- viously obtained phenyliminotriazinylmethylquinoline y^methy^-l^-dioxo-bisll^^jtriazino^^-a^'^'-c]- X (Scheme 4). quinoxaline (XXIV) was obtained. The elemental and It was intended that the reaction of the pyruvic spectroscopic data are in good agreement with the acid V and/or its thio-isomer VIII with a-hydrazino- proposed structure of compound XXIV. *H NMR JV-heterocycles might result in some new multiaza- spectrum of XXIV showed duplicated integration of polynuclear systems of expected biological impor­ the characteristic 4-hydroxy-8-methyl-l#-quinolin-2- tance. Thus, compounds V and/or VIII were sub­ one moiety protons, along with four methylene pro­ jected to react with l-hydrazono-4-phenylphthalazine tons at S = 3.85, while the integration of the pro­ (XIX) [16] in boiling DMF, affording 3-(l,2-dihydro-4- ton signals corresponding to the aromatic protons re­ hydroxy-8-methyl-2-oxoquinolin-3-yl)methyl-4-oxo-7- gion indicated that ten aromatic protons were present phenyl[l,2,4]triazino[3,4-a]phthalazine (XX).
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