الفهرس 
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Abstract
Summary
The current work aims to use the 2-oxoquinolin-3-carboxaldehyde 1 as key starting material for the synthesis of new heterocyclic compounds containing quinoline moiety.
2-oxoquinolin-3-carboxaldehyde 1 was reacted with hippuric acid and acetic anhydride in presence of fused sodium acetate to form the oxazol-5(4H)-one derivative 2 under Perkin conditions, also with 4-acetylbiphenyl in methanol and aqueous potassium hydroxide (50%) to form the chalcone derivative 3. The reaction of 1 with thiocarbohydrazide in ethanol and drops of acetic acid by different molar ratios form thiocarbohydrazone derivative 4 and Tetrazinethione derivative 5 instead of the condensation adduct 5ʹ (Scheme 1)
Scheme 1
The oxazol-5(4H)-one derivative 2 was reacted with some nucleophilic reagents to synthesize new heterocyclic compounds. the imidazolone derivative 6 was obtained via treatment of oxazolone derivative 2 with ammonium acetate in boiling ethanol. Heating of 2 with benzylamine in boiling benzene yielded N-benzylamide derivative 7. (Scheme 2)
Scheme 2
On the other hand, the behavior of oxazolone 2 was studied towards some bidentate nucleophiles such as hydrazine hydrate in ethanol at room temperature, phenyl hydrazine in boiling benzene, 2-aminoethanol and 1,2-diaminoethane in ethanol containing acetic acid to afford hydrazide derivative 8, phenyl hydrazide derivative 9 and amide derivatives 10, 11 respectively (Scheme 3).
Scheme 3
Additionally, reaction oxazolone derivative 2 with 2-aminoaniline was found to be dependent on the reaction conditions. Indeed, carrying out the reaction in boiling ethanol containing drops of glacial acetic acid afforded the amide derivative 12, While undergoing the same reaction in boiling dioxane containing drops of glacial acetic acid gave benzimidazole derivative 13 which was also obtained by refluxing the amide 12 with boiling dioxane and glacial acetic.
In turn Treatment of oxazolone derivative 2 with 4-amino aniline in ethanol and drops of glacial acetic acid gave the amide derivative 14 (Scheme 4).
Scheme 4
Furthermore, the reaction of oxazolone derivative 2 with anthranilic acid was found to depend on the reaction conditions. Initially, refluxing in acetic acid in the presence of anhydrous sodium acetate for 30 min. furnished the amide derivative 15. Meanwhile, heating the reaction mixture in absolute ethanol containing anhydrous sodium acetate led to ring-opening of the lactone followed by decarboxylation to afford the anilide derivative 16 (Scheme 5).
Scheme 5
Formation N-(2-Oxo-2H-pyrano[2,3-b] quinolin-3-yl) benzamide 17 was successfully obtained by different synthetic routes, from the reaction of oxazol-5(4H)-one derivative 2 with thioglycolic acid or anthranilic acid in glacial acetic acid and fused sodium acetate or from the heating of amide derivatives 7&15 with glacial acetic acid or reaction of oxazol-5(4H)-one with benzylamine in the same solvent. (Scheme 6).
Scheme 6
In the same context, acetylation of hydrazide 8 was mainly dependent on the reaction conditions. Thus, stirring the reaction mixture at room temperature afforded the monoacetylated product 18. While under refluxing conditions, the oxazolone derivative 2 was obtained as a non-expected product. The reaction of phenyl isothiocyanate with hydrazide 8 in boiling dioxane furnished thiosemicarbazide derivative 19 which was successfully transformed into thiazolidine derivative 20 via treatment with ethyl chloroacetate in refluxing ethanol and anhydrous sodium acetate. On the other hand, stirring a solution of hydrazide 8 with carbon disulfide in ethanol containing potassium hydroxide produced the potassium salt 21 which was subsequently treated with hydrazine to construct 4-amino-5-mercapto-1,2,4-triazole derivative 22. (Scheme 7).
Scheme 7
Furthermore, Condensation of the hydrazide 8 with 2-oxoquinoline-3-carbaldehyde under reflux in acetic acid for 10 min. acquired the corresponding hydrazone derivative 23a. While refluxing with 2-oxoquinoline-3-carbaldehyde, 1,3-diphenylpyrazole-4-carbaldehyde, 4-methoxy benzaldehyde, and 4-nitrobenzaldehyde in the same solvent for 1 h led to the construction of imidazolone derivatives 24a-d. Cyclization of hydrazide 8 in 4% alcoholic sodium hydroxide resulted in the construction of triazinone derivative 25. Heating the later compound 25 with phosphorus oxychloride afforded the chlorotriazine derivative 26. (Scheme 8)
Scheme 8
The work was extended to study the reactivity of chalcone derivative 3 towards some nucleophilic reagents, the pyrazolines derivatives 27&28 were obtained from the reaction of chalcone derivative 3 with hydrazine and phenyl hydrazine in ethanol and/or dimethyl formamide respectively. In addition, the chalcone derivative 3 was reacted with thiosemicarbazide in ethoxide to afford the thiazepine derivative 29. On the other hand, 2-aminopyridine-3-carbonitrile and 2-aminopyrane-3-carbonitrile derivatives 30&31 were synthesized by reaction of chalcone derivative 3 with malononitrile in ethanol and ammonium acetate and/or ethanol and piperidine respectively. (Scheme 9).
Scheme 9
The thiocarbohydrazone derivative 4 was treated with some carbon electrophiles to prepare new heterocyclic compounds. Triazinone derivative 32 and triazole derivative 33 was formed from the treatment of thiocarbazone derivative 4 with chloroacetyl chloride and/or phenyl isothiocyanate in dioxane. The reaction of thiocarbohydrazone derivative 4 with acetic anhydride depends on reaction conditions, carrying out the reaction at r.t afforded the acetohydrazide derivative 34 while upon heating gave the Tetrazinethione derivative 35. otherwise, boiling of thiocarbohydrazone derivative 4 with isatin in dioxane containing drops acetic acid and with 2-chloro-N-(4-sulphamoylphenyl) acetamide in di methyl formamide containing drops triethyl amine yielded the 2-oxoindolin-3-ylidene and triazinone derivatives 36 and 37 respectively (Scheme 10).
Scheme 10
On the other hand, hydrazone derivative 38 and thiosemicarbazide derivative 39 were obtained from the reaction of thiocarbohydrazone derivative 4 with p-anisaldehyde and/or 2-bromo-1-(3-nitrophenyl) ethan-1-one in AcOH and/or Ethanol/AcONa respectively. In turn, thiocarbohydrazone derivative 4 was reacted with dimethyl acetylene dicarboxylate in methanol and ethyl bromoacetate in Dioxane/AcONa to form (E), (Z) thiadiazinone derivative 40 and ethyl glycinate derivative 41. finally, 2-oxocoumarine-3-yl hydrazone derivative 42 was formed from the treatment of thiocarbohydrazone derivative 4 with 3-acetylcoumarine in Dioxane/AcOH. Scheme 11
Scheme 11
Biological activity
1-Insecticidal activity
The synthesized compounds 2, 6-26 were tested for insecticidal activity. The results showed that most synthesized compounds exhibited a wide range of insecticidal activity. Moreover, compounds 8, 19, and 22 were the most potent against both Mythimna separata and Nilaparvata lugens at 500 µg/mL. While compounds 9, 11, 12, 14, and 15 showed moderate insecticidal activity. The rest compounds provided weak potency.
2-Antioxidant activity
Determination of Total Antioxidant Capacity (TAC)
The synthesized compounds 3, 4, 5, 27-42 were tested for their in vitro antioxidant activity. The results showed that compounds 31, 33, 34 and 42 exhibited high activity, compounds 5, 27, 35, 36 and 37 showed moderate activity and the other compounds showed weak activity.
3- Anticancer activity
The synthesized compounds 3, 4, 5, 27-42 were tested for their in vitro anticancer activity against two cell lines (HCT-116 and MCF-7). The results showed that compounds 32, 33 and 38 exhibited very strong cytotoxic activity. In addition, compounds 4, 40 and 42 were also considered strongly cytotoxic. Finally, compounds 5, 34, 36, 39, 41 were moderate in their cytotoxic activity, and compounds 3, 28 and 35 were weakly cytotoxic.