Bulgarian Chemical Communications, Volume 41, Number 3 (pp. 241-247) 2009
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Bulgarian Chemical Communications, Volume 41, Number 3 (pp. 241–247) 2009 Simple and convenient procedures for the synthesis of novel heterocyclic compounds containing 1-phenyl-3-pyridylpyrazole moiety
2009 Bulgarian Academy of Sciences, Union of Chemists in Bulgaria * To whom all correspondence should be sent: E-mail: dr_hala_fawzy@yahoo.com H. F. Rizk* Chemistry Department, Faculty of Science, Tanta University, Tanta, Egypt Received July 11 2008; Revised November 15, 2008 New 1-phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid ethyl ester has been obtained by the reaction of 5-chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carbaldehyde with ethyl bromoacetate and sodium sulphide. Alkaline hydrolysis of the ester gave the corresponding acid, while reaction of the same ester with hydrazine hydrate gave the corresponding hydrazide. Reactions of the hydrazide with potassium isocyanate and ammonium isothiocyanate gave the corresponding triazole and thiadiazole, respectively. The treatment of 5-chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carbaldehyde with hydroxylamine hydrochloride gave 4-cyanopyrazole-5-one. Reaction of the latter with POCl3 afforded 5-chloro-4-cyanopyrazole, which cyclized by hydrazines to give pyrazolo[3,4-c]pyrazol-3-yl-amine derivatives. The reaction of 4-nitrosopyrazol-3-ol with o-aminophenol and o-phenylenediamine afforded the corresponding dipyrazolyl derivative, benzoxiazine and quinoxaline, respectively. The reduction of 4-nitrosopyrazol-3-ol with Zn/AcOH affored 4-(5-hydroxy-1-phenyl-3-pyridin-3-yl-1H-pyrazol-4-ylimino)2-phenyl-5-pyridin-3-yl-2,4-dihydropyrazol-3-one, which was also obtained from reaction of 2-phenyl-5-pyridine-3-yl-2H-pyrazole-3,4-dione with benzylamine. Finally, the reaction of 4-nitrosopyrazol-3-ol with 5-chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carb-aldehyde gave 3,5-diphenyl-7-pyridin-3-yl-1-pyridin-4-yl-3,5-dihydro-4-oxa-2,3,5,6,8-pentaazocyclopenta [f]azulene.
5-Pyrazolones are very important class of hetero-cyclic compounds due to their biological and phar-macological activities [1, 2] such as anti-inflamma-tory [3], herbicidal [4], fungicidal [5], bactericidal [5], plant growth regulation [4], antipyretic pro-perties [6] and protein kinase inhibiting effect [7]. They are also used as key starting materials for the synthesis of commercial arylazopyrazolone dyes [8, 9]. In conjunction with our interest in preparing pyrazolone derivatives, we tried to prepare sulphur heterocyclic moieties fused to pyrazole ring, which might have some interesting bioactive properties. We report herein the results of the reactions of 5-chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carb-aldehyde and 4-nitroso-2-phenyl-5-pyridin-3-yl-2H-pyrazol-3-ol with different readily available reagents. RESULTS AND DISCUSSION Firstly, the Vilsmeier-Haack reaction of 2-phenyl-5-pyridin-3-yl-2,4-dihydro-pyrazol-3-one (1) gave 5-chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carbaldehyde (2) in 55% yield. Treatment of (2) with ethyl bromoacetate and sodium sulphide in ethanol produced 1-phenyl-3-pyridin-3-yl-1H-thieno [2,3-c]pyrazole-5-carboxylic acid ethyl ester (3) in 70% yield. Alkaline hydrolysis of (3) gave 1-phenyl-3-pyri-dine-3-yl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (4) in 85% yield. The reaction of (3) with hydrazine hydrate afforded 1-phenyl-3-pyridine-3-yl-1H-thi-eno[2,3-c]pyrazole-5-carboxylic acid hydrazide (5) in 65% yield. When compound (5) reacted with potassium cyanate in 50% acetic acid cyclization took place to give 5-(1-phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]pyrazol-5-yl)-4H[1,2,4]-triazol-3-ol (6) in 50% yield. Similarly, treatment of (5) with am-monium thiocyanate in ethanol in presence of con-centrated HCl gave (1-phenyl-3-py-ridin-3-yl-1H-thieno[2,3-c]pyrazol-5-yl)-[1,3,4]thia-diazol-2-yl-amine (7) in 45% yield (Scheme 1). This result is consistent with the one that was reported by Balagh et al. [10]. The reaction of 5-chloropyrazole-4-carbaldehyde (2) with hydroxylamine hydrochloride in ethanol gave directly 5-oxo-1-phenyl-3-pyridin-3-yl-4,5-di-hydro-1H-pyrazole-4-carbonitrile (10) in 85% yield through the removal of HCl from the nonisolable oxime (8). The chlorination of compound (10) with POCl3 gave 5-chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carbonitrile (11) in 90% yield. Conden-sation of compound (11) with hydrazine hydrate and phenyl hydrazine afforded the corresponding 6-phenyl-4-pyridin-3-yl-1,6-dihydro-pyrazolo[3,4-c] pyrazol-3-yl amine (12a) and 1,6-diphenyl-4-pyri-din-3-yl-1,6-dihydro-pyrazolo[3,4-c]pyrazol-3-yl amine (12b). The mechanism supposed by us for the reaction is outlined in Scheme 2. This mechanism is in accordance with that proposed by El-Sayed et al. [11].
Scheme 1. 
Scheme 2. Table 1. Physical data of compounds 2–25.
The nitrosation of 2-phenyl-5-pyridin-3-yl-2,4-dihydro-pyrazol-3-one (1) gave 4-nitroso-2-phenyl-5-pyridin-3-yl-2H-pyrazol-3-ol (13) in 80% yield (Scheme 3). When compound (13) was heated with 2-aminophenol and 2-phenylenediamine at 140°C with ammonium acetate afforded the dimer (17), pyrazolo[3,4-b]benzoxazine (18a) and pyrazolo [3,4-b]quinoxaline (18b). This result could be explained by the nucleophilic attack of both amino groups of 2-phenylenediamine or hydroxyl and amino groups of o-aminophenol on the C4 and C5 of nitroso compound (13) to give intermediate (15) followed by simultaneous elimination of both water and hydroxylamino molecules yielding the pyra-zolo[3,4-b]benzoxiazine (18a) and pyrazolo[3,4-b] quinoxaline (18b) (Scheme 3). However, dipyra-zolyl compound (17) could be formed from pyra-zole radical (16), which would be obtained from the intermediate (15) via elimination of an amine mole-cule and nitric oxide (Scheme 3). Analogous results were previously reported by El-Rady [12].
The acidic hydrolysis of 4-nitrosopyrazole (13) with concentrated HCl at 0°C gave the expected dione (19) in 60% yield (Scheme 4). Compound (23) could be obtained by two routes: (a) by the reaction of compound (19) with benzylamine in alcoholic medium, which produced the imine intermediates (20) and (21) followed by air oxida-tion of amino compound (22) to afford (23). The route (b) involved the air oxidation of intermediate (24). Finally, compound (25) was obtained in 75% yield by the reaction of (2) with the amino inter-mediate (24), which could be obtained by reduction of nitroso compound (13). EXPERIMENTAL All melting points were measured on a Gallen-Kamp melting point apparatus and are uncorrected. The IR spectra were measured on Perkin-Elmer-1430 spectrophotometer using KBr tablets technique. 1H and 13C NMR spectra were recorded on a Bruker AV400 spectrometer operating at 400 MHz for 1H and 100 MHz for 13C measurements at Chemistry Department, University of Wales Swansea, UK.
Scheme 3. 
Scheme 4. Low-resolution mass spectra were recorded on a VG 12.253 spectrometer, electron impact (EI) at 70 eV. Microanalyses were performed by the Micro-analysis Laboratory at Cairo University. Progress of reaction was monitored by thin-layer chromato-graphy (TLC) using benzene/acetone (3:1) mixture as an eluent.
5-Chloro-1-phenyl-3-pyridin-3-yl-1H-pyrazole-4-carbaldehyde (2). The pyrazolone (1) [13] (1.3 g, 0.0057 mol) was added to a cold Vilsmeier reagent prepared by the addition of POCl3 (2.75 ml, 0.0285 mol) to DMF (5 ml, 0.068 mol) at 0°C, and the reaction mixture was heated for 8 h at 80°C. The reaction mixture was poured onto ice-cold water (10 ml) and basified with K2CO3 solution to reach pH = 9. The pale yellow solid phase thus separated was filtered and recrystallized from benzene. 1-Phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]pyrazo-le-5-carboxylic acid ethyl ester (3). A solution of (2) (22.98 g, 0.081 mol) in ethanol (50 ml) was added to a solution of sodium sulphide nonahydrate (19.41 g 0.081 mol) in ethanol (500 ml) at 40°C. The reaction mixture was refluxed for 2 h, and then ethyl bromoacetate (9.0 ml, 0.0081mol) was added in a dropwise manner. The reaction temperature was kept constant at 50°C and triethylamine (11 ml) was added and the reaction mixture was allowed to stay overnight at room temperature. The precipitate, which was formed, was then filtered and recrystal-lized from ethanol. 1-Phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]pyrazo-le-5-carboxylic acid (4). A solution of (3) (3.5 g, 0.01 mol) in a mixture of ethanol (62.5 ml) and water (15 ml) was treated with aqueous 85% potas-sium hydroxide (0.95 g, 0.017 mol). The reaction mixture was refluxed for 2 h. The reaction mixture was left to cool down and water was added to dis-solve the salt obtained. Concentrated hydrochloride acid was added in a dropwise manner until the solution became acidic. The formed solid phase was filtered, washed with water and recrystallized from water/ethanol solvent. 1-Phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]pyrazo-le-5-carboxylic acid hydrazide (5). A mixture of (3) (3.5 g, 0.01 mol), 98% hydrazine hydrate (7.5 g, 0.15 mol) and ethanol (100 ml) was heated under reflux on a steam bath for 2 h. A colourless solid was formed, filtered and recrystallized from ethanol. 5-(1-Phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]pyra-zol-5-yl)-4H-[1,2,4]-3-ol (6). A solution of potas-sium cyanate (1.7 g, 0.022 mol) in (10 ml) water was added dropwise to a cold (0°C) solution of (5) (6.7 g, 0.02 mol) a mixture of acetic acid (40 ml) and water (40 ml). The reaction mixture was left for one hour at 0°C upon stirring and then heated under reflux for 4 h. A pale yellow solid was formed after 3 h. The formed solid phase was filtered, washed with water, dried and recrystallized from ethanol.
5-(1-Phenyl-3-pyridin-3-yl-1H-thieno[2,3-c]py-razol-5-yl)-4H-[1,3,4]thiodiazol-2-ylamine (7). A mixture of (5) (3.35 g, 0.01 mol), ammonium thio-cyanate (2.3 g, 0.03 mol) and concentrated HCl (9 M, 4 ml) in ethanol (200 ml) was heated under reflux for 15 h. The solvent was removed by distillation and water (500 ml) was added. The formed solid phase was dried and recrystallized from ethanol. 5-Oxo-1-phenyl-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-4-carbonitrile (10). Hydroxylamine hydro-chloride (2.0 g, 0.29 mol) in water (5 ml) was treated with NaOH solution (4 M) to reach pH = 8. A solution of (2) (2.83 g, 0.01 mol) in ethanol (40 ml) was added and the reaction mixture was heated under reflux for 2 h. The mixture was left to cool down, poured into ice-cold water (100 ml) and acidified with 20% aqueous HCl (4 M). The formed solid phase was filtered, washed with water, dried and recrystallized from ethanol. 5-Chloro-1-phenyl-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-4-carbonitrile (11). Compound (10) (2.6 g, 0.01 mol) was heated under reflux with POCl3 (15 ml) for 1 h. The reaction mixture was left to cool down, poured into ice-cold water. The formed solid phase was filtered and recrystallized from ethanol. Table 2. Spectroscopic data of compounds 2–25.
6-Phenyl-4-pyridine-3-yl-1,6-dihydro-pyrazolo [3,4-c]pyrazol-3-ylamine (12a) and 1,6-diphenyl-4-pyridin-3-yl-1,6-dihydro-pyrazolo[3,4-c]pyrazol-3-yl amine (12b). Compound (11) (2.8 g, 0.01 mol) was heated with hydrazine derivatives (0.51 mol) for 6 h in ethanol (30 ml). The reaction mixture was left to cool down and poured into water. The formed solid phase was filtered and recrystallized from ethanol. 4-Nitroso-2-phenyl-5-pyridin-3-yl-2H-pyrazol-3-ol (13). A solution of 2-phenyl-5-pyridin-3-yl-2,4-dihydro-pyrazol-3-one (1) (2.37 m, 0.01 mol) in acetic acid (40 ml) was added in a dropwise manner to a solution of sodium nitrite (0.075 g, 0.01 mol) in water (2 ml). The mixture was left for 15 min upon stirring. An orange solid phase was formed, filtered and washed with petroleum ether. 2,2-Dipenyl-5,5-di-pyridin-3-yl-2,4,2,4-tetra-hydro-[4,4]bipyrazolyl-3,3-dione (17). A mixture of (13) (0.8 g, 0.003 mol), ammonium acetate (1 g, 0.013 mol), o-aminophenol and/or o-phenylene-diamine (0.003 mol) and ammonium acetate (1 g, 0.013 mol) was heated at 140°C for 30 min then diluted with methanol. A buff crystal was precipi-tated, washed with hot methanol and filtered. 1-Phenyl-3-pyridin-4-yl-4-hydro-1H-pyrazolo [3,4-b]benzoxiazine (18a) and 1-phenyl-3-pyridin-4-yl-4,9-dihydro-1H-pyrazolo[3,4-b]quinoxaline (18b). A mixture of (13) (0.8 g, 0.003 mol), ammonium acetate (1 g, 0.013 mol), o-aminophenol and/or o-phenylenediamine (0.003 mol) and ammonium acetate (1 g, 0.013 mol) was heated at 140°C for 30 min, diluted with methanol, the formed precipitate was filtered. The filtrate was concentrated and the coloured precipitate was filtered off and recrystal-lized from ethanol. 2-Phenyl-5-pyridin-3-yl-2H-pyrazole-3,4-dione (19). To a stirred solution of (13) (2.66 g, 0.01 mol) in ether (100 ml), 10% H2SO4 (100 ml) was added dropwise at 0°C. The mixture was stirred for 30 min at room temperature. The organic layer was sepa-rated and ammonium sulphate (5 g) was added, the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were dried over anhydrous MgSO4 and the solvent was removed under reduced pressure. The formed solid phase was collected, washed with cold ethanol and recrystal-lized from ethanol.
REFERENCES
Прости и подходящи процедури за синтезата на нови хетероциклични съединения съдържащи 1-фенил-3-пиридилазолова част Х. Ф. Ризк Химически департамент, Факултет по науки, Университет на Танта, Танта, Египет Постъпила на 11 юли 2008 г.; Преработена на 15 ноември 2008 (Резюме) Получен е нов етилов естер на 1-фенил-3-пиридин-3-ил-1H-тиено[2,3-c]пиразол-5-карбоксилова киселина чрез реакция на 5-хлор-1-фенил-3-пиридин-3-ил-1H-пиразол-4-карбалдехид с етилбромацетат и натриев сулфид. При алкалната хидролиза на естера се получава съответната киселина, докато при реакцията на същия естер с хидразинхидрат се получава съответния хидразид. При реакциите на хидразида с калиев изоцианат и амониев изотиоцианат се получават съответния триазол и тиодиазол. При взаимодействието на 5-хлор-1-фенил-3-пиридин-3-ил-1H-пиразол-4-карбалдехид с хидроксиламин хидрохлорид се получава 4-цианопиразол-5-он. Реацията на последния с POCl3 дава 5-хлор-4-цианопиразол, който циклизира с хидразини до пиразоло[3,4-с]пиразол-3-иламинови производни. Реакцията на 4-нитрозопиразол-3-ол с о-аминофенол и о-фенилендиамин дава съответното дипиразолилово производно, бензоксиазин и хиноксалин. Редукцията на 4-нитрозопиразол-3-ол с Zn/AcOH дава 4-(5-хидрокси-1-фенил-3-пиридин-3-ил-1Н-пиразол-4-илимино)2-фенил-5-пиридин-3-ил-2,4-дихидропиразол-3-он, който бе получен също при реакция на 2-фенил-5-пиридин-3-ил-2Н-пиразол-3,4-дион с бензиламин. Накрая, реакцията на 4-нитрозопиразол-3-ол с 5-хлор-1-фенил-3-пиридин-3-ил-1Н-пиразол-4-карбалдехид дава 3,5-дифенил-7-пиридин-3-ил-1-пиридин-4-ил-3,5-дихидро-4-окса-2,3,5,5,8-пентаазоцикло-пента[f]азулен. Каталог: bcc volumes bcc volumes -> Bulgarian Chemical Communications, Volume 41, Number 2 (pp. 104-109) 2009 bcc volumes -> Bulgarian Chemical Communications, Volume 41, Number 1 (pp. 23-30) 2009 bcc volumes -> Bulgarian Chemical Communications, Volume 41, Number 2 (pp. 127-132) 2009 bcc volumes -> Bulgarian Chemical Communications, Volume 40, Number 4 (pp. 464-468) 2008 bcc volumes -> Bulgarian Chemical Communications, Volume 41, Number 2 (pp. 133-137) 2009 bcc volumes -> Bulgarian Chemical Communications, Volume 40, Number 4 (pp. 397-400) 2008 bcc volumes -> Bulgarian Chemical Communications, Volume 46, Number 2 (pp. 330 333) 2014 bcc volumes -> Bulgarian Chemical Communications, Volume 44, Number 4 (pp. 307 309) 2012 bcc volumes -> Bulgarian Chemical Communications, Volume 47, Number 2, 2015 bcc volumes -> Bulgarian Chemical Communications, Volume 44, Number 4 (pp. 283 288) 2012 Изтегляне 80.79 Kb. Сподели с приятели:
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