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The Use of Α-Enone Derivative in the Preparation of Some New Heterocyclic Compounds with Expected Biological and Antitumor Activities

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The Use of Α-Enone Derivative in the Preparation of Some New Heterocyclic Compounds with Expected Biological and Antitumor Activities 1049 Advances in Environmental Biology, 7(6): 1049-1057, 2013 ISSN 1995-0756 This is a refereed journal and all articles are professionally screened and reviewed ORIGINAL ARTICLE The use of α-enone derivative in the preparation of some new heterocyclic compounds with expected biological and antitumor activities Zeinab H. Ismail Department of Chemistry, Faculty of Science, Al-Azhar University (Girls), Nasr City, Cairo, Egypt Zeinab H. Ismail: The use of α-enone derivative in the preparation of some new heterocyclic compounds with expected biological and antitumor activities ABSTRACT α-Enone 1, reacts with hydrazines, hydroxylamine hydrochloride, thiourea, diethylmalonate, malononitrile ethyl cyanoacetate to give the corresponding indazole, oxime, isoxazole, quinazoline, chromene and quinoline derivatives. The structures of all the synthesized compounds were confirmed by micro analytical and spectral data. The antimicrobial and the antitumor activities of some of the synthesized compounds were tested. Key words: α-enone, indazole, isoxazole, quinazoline, chromene and quinoline derivatives. Introduction hydrate in DMF to obtain the formohydrazide 4 has failed instead the parent indazole 2a was obtained. Indazole derivatives are reported to exhibit However reaction of 1 with hydroxylamine antibacterial [1,2], antifungal[1.2], antiproliferative hydrochloride in ethanol or pyridine gave the [3], antigiogenic [3], antiarrhythmic and analgesic corresponding oxime and isoxazole 5 and 6, [4] activities and antihypertensive properties [5], respectively. while quinazolines exhibit antitumor [6], Compound 1, was reduced and acetylated by antimicrobial [7] antitubercular [8], antiagonists [9], zinc dust in boiling acetic anhydride solution to give anticonvulsant [10] and analgesic[11] activities. compound (7). On the other hand quinolines exhibit antimalarial Reaction of 1 with indole gave compound 8, [12], antiplasmodial [13], antiproliferative [14], through condensation of 2 moles of indole with the antibacterial [15], antifungal [15]. ketonic group in compound 1. The absence of γC=O Chromene derivatives exhibiting antimicrobial in the infrared spectrum of compound 8, support the [16], antihypertensive and antioxidant [17] activities proposed structure. have also been reported.…. Refluxing of compound 1 and thiourea in The prompted the author to use 2,6-bis(3,4- absolute ethanol with a catalytic amount of dimethoxybenzylidene) cyclohexanone (1) as key potassium hydroxide furnished quinazoline thione intermediate in the synthesis of series of heterocyclic derivative 9 in a good yield. compounds. The new derivatives were prepared The condensation of 1 with diethylmalonate in following the reaction sequences depicted in boiling benzene in the presence of diethyl sodio- Schemes (1-2). malonate as basic condensing agent afforded the Treatment of compound 1 with hydrazine chromene derivative (10). hydrate or phenyl hydrazine in absolute ethanol Enone 1 reacts under Michael conditions with afforded indazole derivatives 2a-b in a one-pot malononitrile to give the quinoline derivative (11). reaction. The olefinic double bond of 1 is activated Reaction of 1 with ethyl cyanoacetate in the by the Ketone group therefore the β-carbon atom will presence of catalytic amount of piperidine furnished accepted nucleophiles. The formation of indazole the chromene derivative (12), while its reaction with derivatives 2a-b can be visualized on the basis of ethyl cyanoacetate in the presence of ammonium cyclocondensation of hydrazines with enone 1. acetate gave the quinoline derivative (13). Treatment of compound 2a with Structure of compound 12, was further benzenesulfonylchloride, phenylisothiocyanate or established by its reaction with o-aminophenol bromine gave derivatives 2c-d and 3, respectively. and/or p-aminopyridine in absolute ethanol to give The formation of compound 3 proceeds through the corresponding amide derivatives 14a-b, however dehydrogenation and addition of bromine to the its reaction with hydrazine hydrate gave the exocyclic double bond. Reaction of 1 with hydrazine corresponding chromeno-pyrazole derivative (15) Corresponding Author Zeinab H. Ismail, Department of Chemistry, Faculty of Science, Al-Azhar University (Girls), Nasr City, Cairo, Egypt 1050 Adv. Environ. Biol., 7(6): 1049-1057, 2013 through elimination of one molecule of ethanol and ammonia. Yield 75%; m.p. 198-200oC; IR (KBr) γ: 1598 -1 1 Compound 13 exists in a lactam-lactim (C=N) cm ; HNMR (DMSO-d6) δ: 1.25-2.26 (m, tautomerism, the existence of the lactim form was 6H, 3xCH2), 2.76 (d, 1H, CH pyrazole), 3.71 (d, 1H, proved by its reaction with POCl3 to give the chloro CH pyrazole), 3.74-3.81 (s, 12H, 4xOCH3), 6.03 (s, derivative (16). The chloro compound (16) has been 1H, CH- olefinic), 6.64-7.77 (m, 11H, Ar-H). MS used as starting material for the preparation of new (70ev) m/z%: 484 (M+) (4.52). Anal. Calcd. for compounds. Thus its reaction with sodium methoxide C30H32N2O4 (484.24); C, 74.36; H, 6.66; N, 5.78 gave the corresponding methoxy derivative (17), Found: C, 74.40; H, 6.61; N, 5.90%. however its reaction with hydrazine hydrate gave the corresponding pyrazoloquinoline derivative (18). 2,6-Bis (3,4-dimethoxybenzylidene) cyclohexanone The structure of compounds 2-19 was apparent oxime (5): from the mass spectra. The 1HNMR spectroscopic data as well as IR spectra, were also in agreement Yield 62% m.p. 160-162oC; IR (KBr) γ: 1596 -1 1 with the proposed structures. (C=N) cm ; HNMR (DMSO-d6) δ: 1.23-2.17 (m, 6H, 3xCH2), 3.76 (s, 12H, 4xOCH3), 6.75-8.03 (m, Experimental: 8H, AR-H and 1H, CH-olefinic) 8.8 (s, 1H, OH). MS + (70ev) m/z%: 409 (M ) (25.88). Anal. Calcd. for Melting points were determined in open C24H27NO5 (409.19); C, 70.40; H, 6.65; N, 3.42 capillary tubes on a Gallen Kamp melting point Found: C, 70.45; H, 6.35; N, 3.45%. apparatus and are uncorrected. The elemental analysis were carried out at the Micro Analytical 8-(3,4-Dimethoxybenzylidene)-4-(3,4- Unit, Faculty of Science, Cairo University by using dimethoxyphenyl)-3a,4,5,6,7,8- Perkin-Elmer 2400 CHN elemental analysis. The IR hexahydrochromeno[2,3-c]pyrazol-3-ol (15): spectra recorded on a Shimadzu-440 IR spectrophotometer using KBr technique. The Yield 63%; m.p. 145-147oC; IR (KBr) γ: 1593 1HNMR spectra were measured on a Bruker Proton (C=N), 3424 (OH, Br), 3299 (NH) cm-1; 1HNMR NMR-Avance 300 (300 MHz, spectrometer) with (DMSO-d6) δ: 1.23-2.39 (m, 6H, 3xCH2), 3.74-3.8 (s, chemical shift (δ) expressed in ppm downfield from 12H, 4xOCH3), 4.00 (s, 1H, CH pyran), 4.32 (s, 1H, TMS as internal standard in DMSO-d6. Mass spectra OH), 6.68-7.5 (m, 6H, AR-H and 1H, CH-olefinic), were recorded on Hewlett Packard model MS-5988 9.84 (s, 1H, NH). MS (70ev) m/z%: 476 (M+) (0.24). spectrometer. Anal. Calcd. for C27H28N2O6 (476.19); C, 68.05; H, 5.92; N, 5.88 Found: C; 68.10; H, 5.95; N, 5.44%. Reaction of 1, 12 and 16 with hydrazines and NH2OH.HCl: 8-(3,4-Dimethoxybenzylidene)-4-(3,4- dimethoxyphenyl)-4,5,6,7,8,9-hexahydro-3aH- To a solution of 1, 12 and/or 16 (0.01 mole) in pyrazolo[3,4-b]quinolin-3-amine(18): ethanol or DMF (20ml) and equimolar amounts of hydrazine hydrate, phenylhydrazine and/or Yield 64%; m.p. 135-137oC; IR (KBr) γ: 3327- -1 1 NH2OH.HCl was added and the reaction mixture was 3183 (NH-NH2), 1604 (C=N) cm ; HNMR refluxed for 2-15 hours (TLC). The crude material (DMSO-d6) δ: 1.09-2.2 (m, 6H, 3xCH2), 2.7 (d, 1H, was filtered off and recrystallized from ethanol to CH pyridine), 3.34 (d, 1H, CH pyridine), 3.73 (s, give compounds 2a,b,5,15 and 18. 12H, 4xOCH3), 4.6-5.1 (s, 3H, NH-NH2), 6.86-8.6 (m, 7H, AR-H and 1H, CH-olefinic). MS (70ev) 7-(3,4-Dimethoxybenzylidene)-3-(3,4- m/z%: 474 (M+) (53.49). Anal. Calcd. for dimethoxyphenyl)-3,3a,4,5,6,7-hexahydro-2H- C27H30N4O4 (474.23); C; 68.34; H, 6.37; N, 11.81 indazole (2a): Found: C, 68.50; H, 6.40; N, 11.90%. Yield 82%; m.p. 172-174oC; IR (KBr) γ: 1593 7-(3,4-Dimethoxybenzylidene)-3-(3,4- -1 1 (C=N), 3298 (NH) cm ; HNMR (DMSO-d6) δ: dimethoxyphenyl)-2-(phenyl-sulfonyl)-3,3a,4,5,6,7- 1.34-2.40 (m, 6H, 3xCH2), 2.8 (d, 1H, CH pyrazole), hexahydro-2H-indazole (2c): 3.7 (s, 12H, 4xOCH3), 4.26 (d, 1H, CH pyrazole), 6.68-7.25 (m, 6H, ArH), 7.4 (s, 1H, CH-olefinic), 9.8 A solution of 2a (0.01 mole) in pyridine (10ml), (s, 1H, NH). MS (70ev) m/z%: 411 (M++3) (0.97). and benzenesulfonyl chloride (0.01 mole) was heated Anal. Calcd. for C24H28N2O4 (408.2); C, 70.57; H, on water bath for 3 hours. Then, the reaction mixture 6.91; N, 6.86 Found: C, 70.64; H, 6.68; N, 6.9%. was poured into ice/HCl mixture. The crude material was filtered off and recrystallized from pet. ether 7-(3,4-Dimethoxybenzylidene)-3-(3,4- (60-80oC): Yield 82%; m.p. 120-122oC; IR (KBr) γ: dimethoxyphenyl)-2-phenyl-3,3a,4,5,6,7-hexahydro- 1597 (C=N), 1264 (O=S=O) cm-1; MS (70ev) m/z%: + 2H-indazole (2b): no parent ion; 141 (C6H5SO2 ) (63.64) Anal. Calcd. 1051 Adv. Environ. Biol., 7(6): 1049-1057, 2013 for C30H32N2O6S (548.20); C; 65.67; H, 5.88; N, (100ml) was refluxed for 1 hour, and treated with 5.11, S, 5.84 Found: C, 65.66; H, 5.78; N, 5.20; S, more zinc dust (5 g) and refluxed for 1 hour, the 5.70%.
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