الفهرس 
The four versions of Gewald reactionOnly 14 pages are availabe for public view
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Abstract
The starting compound 5-amino-3-phenyl-1-(2,4,6-trichlorophenyl)- 1H-thieno[3,2-c]pyrazole-6-carbonitrile (2) was synthesized by the reaction of 3-phenyl-1-(2,4,6-trichlorophenyl)-1H-pyrazol-5(4H)-one (1) with malononitrile, elemental sulfur and N-methylimidazole as a catalyst in dimethylformamide. N N O CN CN S8 N-Methylimidazole N N S NH2 CN 1 2 Scheme 1 Cl DMF Cl Cl Cl Cl Cl 1 2 3 4 5 6 The reaction of compound 2 with malononitrile and/or ethyl cyanoacetate in pyridine gave 8-amino-6-hydroxy-3-phenyl-1-(2,4,6- trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-b]pyridine-7-carbonitrile (3a) and 6,8-diamino-3-phenyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3’,4’:4,5]thieno[2,3-b]pyridine-7-carbonitrile (3b) respectively. Scheme 2 N N S Ar N H2N R CN 3a,b N N S Ar NH2 CN 2 CN X Pyridine 1 2 3 4 5 6 7 8 a R=OH b R=NH2 The reaction of compound 2 with trichloacetonitrile and catalytic amount of triethylamine in boiling dioxane gave 3-phenyl-6- (trichloromethyl)-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3- d]pyrimidin-8-amine (4). 2 N N S Ar N N H2N CCl3 4 CCl3CN Scheme 3 Dioxane / Et3N N N S Ar NH2 CN 1 2 3 4 5 6 8 7 The fusion of compound 2 with triethyl orthoformate gave compound 5 which cyclized by hydrazine hydrate in ethanol to give 8-imino-3-phenyl-1- (2,4,6-trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin-7(8H)- amine (6). 2 N N S Ar N N HN NH2 6 N N S Ar N CN CHOEt 5 N N S Ar NH2 CN Fusion CH(OEt)3 NH2NH2.H2O EtOH / R.T 1 2 3 4 5 6 7 8 Scheme 4 The reaction of compound 2 with phenyl isothiocyanate in pyridine gave 8-imino-3,7-diphenyl-1-(2,4,6-trichlorophenyl)-7,8- dihydro-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidine-6(5H)-thione (7). Scheme 5 N N S Ar N HN S HN Ph 7 N N S Ar NH2 CN 2 PhNCS Pyridine 1 2 3 4 5 6 7 8 The reaction of compound 2 with sodium nitrite in presence of acetic acid and hydrochloric acid gave 4-chloro-7-phenyl-5-(2,4,6-trichlorophenyl)- 5H-pyrazolo[3’,4’:4,5]thieno[2,3-d][1,2,3]triazine (8). N N S Ar N N N Cl 8 NaNO2 / HCl AcOH / 0-5oC Scheme 6 N N S Ar NH2 CN 2 1 2 3 5 4 6 7 8 The fusion of compound 2 with formic acid gave 3-phenyl-1-(2,4,6- trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin-8(7H)-one (9). N N S Ar NH2 CN 2 N N S Ar NH N O 9 Scheme 7 HCOOH Fusion 1 2 3 4 5 6 7 8 150-160oC Summary - iv - The fusion of compound 2 with formamide gave 3-phenyl-1-(2,4,6- trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin-8-amine (10). Fusion 150-160oC N N S Ar NH2 CN 2 N N S Ar N N H2N 10 Scheme 8 HCONH2 1 2 3 4 5 6 7 8 The reaction of compound 2 with carbon disulfide in 10% alcoholic potassium hydroxide gave 3-phenyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo [3’,4’:4,5]thieno[2,3-d]pyrimidine-6,8(5H,7H)-dithione (11). N N S Ar NH2 CN 2 11 Scheme 9 N N S Ar NH HN S S 10% alc.KOH CS2 1 2 3 4 5 6 7 8 The reaction of compound 2 with benzonitrile and/or 4-pyridine carbonitrile in alcoholic sodium ethoxide gave 3,6-diphenyl-1-(2,4,6- trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin-8-amine (12a) and 3-phenyl-6-(pyridin-4-yl)-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3’,4’:4,5] thieno[2,3-d]pyrimidin-8-amine (12b) respectively. N N S Ar NH2 CN 2 12a,b N N S Ar N N H2N X NC X Scheme 10 EtONa / EtOH 1 2 3 4 5 6 7 8 a X= CH b X= N The reaction of compound 2 with some aromatic ketones in acetic acid and few drops of sulphuric acid gave 6-aryl-6-methyl-3-phenyl-1-(2,4,6- trichlorophenyl)-6,7-dihydro-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin- 8(5H)-one derivatives (13a-d). N N S Ar NH2 CN 2 N N S Ar NH HN O CH3 R 13a-d R COCH3 Scheme 11 AcOH / Conc. H2SO4 1 2 3 4 5 6 7 8 a R= H b R= F c R= CH3 d R=NH2 The reaction of compound 2 with some β-ketonitriles and piperidine as catalyst in dimethylformamide gave 2-(8-amino-3-phenyl-1-(2,4,6- trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin-6-yl)-1- substituted ethanone (14a-c). N N S Ar NH2 CN 2 N N S Ar N N H2N X R O 14a-c X CN O R Scheme 12 DMF/ Pipridine/ 1 2 3 4 5 6 8 7 a X=CH, R=Cl b X=CH, R=H c X=N, R=H The reaction of compound 2 with urea, thiourea and/or guanidine nitrate in alcoholic sodium ethoxide gave 8-amino-3-phenyl-1-(2,4,6- trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno[2,3-d]pyrimidin-6-ol (15a), 8-amino-3-phenyl-1-(2,4,6-trichlorophenyl)-1H-pyrazolo[3’,4’:4,5]thieno [2,3-d]pyrimidine-6-thiol (15b) and 3-phenyl-1-(2,4,6-trichlorophenyl)-1Hpyrazolo[ 3’,4’:4,5]thieno[2,3-d]pyrimidine-6,8-diamine (15c) respectively. N N S Ar NH2 CN 2 H2N NH2 X N N S Ar N N XH H2N 15a-c Scheme 13 EtONa / EtOH / 1 2 3 4 5 6 7 8 a X= O b X= S c X=NH All the mentioned reactions were carried out by traditional conventional heating and eco-friendly methods as microwave irradiation, domestic microwave, ultrasonic irradiation and ball-milling as modern techniques in clean organic synthesis, the results of these methods were compared according to time and yield. The structure of all the synthesized compounds was determined by elemental analysis and spectroscopic data including IR, 1H NMR 13C NMR and mass spectral analysis. 1. Antihemolytic activity of some synthesized compounds was measured. 2. Antioxidant activity of the synthesized compounds was studied using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. 3. The cytotoxic activity of some synthesized compounds was evaluated in vitro against normal human lung fibroblast cell line (WI-38) and a panel of four human cancer cell lines, Human prostate cancer (PC-3), Hepatocellular carcinoma (HEPG-2), Colorectal carcinoma (HCT- 116) and Epitheliod carcinoma (Hela). 4. In addition, antimicrobial activity of the synthesized compounds was tested against different types of bacteria two Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli, Pseudomonas aeuroginosa) and two fungi (Candida albicans, Aspergillus flavus).