untitled ISSN 215 Reaction pyrazol Husien Ha Chemistry Depa * Corresponding Tel.: +20.11.208 ARTICLE IN DOI: 10.5155/e Received: 18 No Received in rev Accepted: 01 Ja Published onlin Printed: 31 Mar KEYWORDS Amidines Heterocycles Electrophiles Aminopyrazole Pyrazolotriazin Pyrazolopyrimi 1. Introduct Aminopy synthesis o Various type pyrazolopyri pyrimidines perties as pu Compounds interest beca somal activit antagonist [ selective inh [14] and as K N‐Bis(me extremely i duction of n active methy synthesis of study was t reagents on ethyl ester ( and pyrazolo 53‐2249 (Print) ns with h o[1,5‐a]p asan Abbas‐ artment, Faculty of g author at: Chemis 887165. Fax: +20.96 FORMATION eurjchem.7.1.107‐1 ovember 2015 vised form: 27 Dece anuary 2016 ne: 31 March 2016 rch 2016 S es nes idines tion yrazoles are f biologically es of biological imidines and [1,2] are purin urine antimetab of this class ha ause of their a ty [6], antibacte [11], HMG‐COA hibitors [13], A KDR kinase inhi ethylthio)methy nteresting ele ot only an ami ylene compoun heterocyclic co to investigate t 5‐amino‐3‐ure (4a) in the syn otriazine deriva E / ISSN 2153‐225 htt Europ eterocycl pyrimidine Temirek an Science, South Vall stry Department, Fa 6.5211279. E‐mail a 114.1369 ember 2015 versatile inte interesting p activity have pyrazolotriazin ne analogues a bolites [3] in bi ave attracted a w antitrypanosom erial [7,8], anti‐ A reductase inh AMP phosphor‐d ibitors [15]. ylenecyanamid ctrophilic reag inomethylene g nds but also a C ompounds [18, the action of eido‐1H‐pyrazo nthesis of new atives. uropean Journal Europ 57 (Online)  20 tp://dx.doi.org/ pean Jo Journal web lic amidin es and py d Ahmed M ley University, Qena Faculty of Science, S address: ahmadbak ABSTRACT N‐Bis(methylt malononitrile derivatives (3 aminopyrazol carboxylic aci pyrazolopyrim synthesized c 1H 13C NMR an Cite this: Eur. ermediates for yrazole deriva been establishe nes. Pyrazolo[ and have usefu iochemical reac wide pharmace mal [4,5], antisc ‐viral [9,10], as hibitors [12], C diesterase inhi de (1), [16,17] gent for the group of amine C=N‐C=N unit ,19]. The aim o several electro ole‐4‐carboxylic pyrazolopyrim l of Chemistry 7 pean Journal of C 016 Atlanta Pub 10.5155/eurjche ournal bpage: www. nes: Synth yrazolo[1, ohammed A a, 83523 Egypt South Valley Univer kr672@gmail.com thio)methylenec e in the presence 3a,b), which on le derivatives id ethyl ester (4 midine and pyra compounds (3a,b nd mass spectra . J. Chem. 2016, r the atives. ed for [1,5‐a] ul pro‐ ctions. eutical chisto‐ CRF1 COX‐2 bitors is an intro‐ es and in the of this ophilic c acid midine 2. E 2.1. Elec reco wer cali pea 2.52 rela a s ana Uni 2.2. 2.2. thio and (1.4 (0.0 (1) (2016) 107‐ Chemistry lishing House LL em.7.1.107‐114. of Che .eurjchem.co hesis of se 5‐a][1,3,5 Abo‐Bakr * rsity, Qena, 83523 E (A.M. Abo‐Bakr). cyanamide (1) w e of potassium treatment with (4a,b). The cy 4a) is found to azolotriazine der b‐22a,b) were c . 7(1), 107‐114 Experimental . Instrumentat Melting point ctrothermal me orded on a Be re recorded ibration of spec aks (CDCl3: δ 1H 2 ppm, 13C 40. ative to TMS (1H spectrometer ( alysis was car iversity. . Synthesis .1. General pro o)methylenecy d malononitrile A mixture of N 46 g, 0.01 mol 015 mole) in (2 ‐114 LC ‐ All rights re .1369 emistry m everal new 5]triazine Egypt. was allowed to carbonate in dim hydrazine hydr yclic amidine 5 be useful interm rivatives (5‐22a,b characterized by tion ts (uncorrecte elting apparatu ckman Acculab with Bruker ctra were carri H 7.25 ppm, δ 1 45 ppm). Chem H, 0.00 ppm). M (electron impa rried out at M ocedure for the yananamide (1) e N‐bis(methylthi e) and ethyl cy 0 mL) of dimeth served ‐ Printed y w es react with ethy methylsulfoxide rater resulted th 5‐amino‐3‐ureid mediate for the b). The chemica y their elementa ed) were rec us. The IR spect b 1. 1H and 13C AC‐250 spec ied out by mea 3C 77.00 ppm; mical shifts are Mass spectra we act) Varian CH Microanalysis e reaction of N‐ ) with ethyl cy o)methylenecy yanoacetate or hylsulfoxide in d in the USA ylcyanoacetate o to yield the ure he correspondin do‐1H‐pyrazole‐ synthesis of ne l structures of th al analyses, FT‐I corded on an tra (KBr) were C NMR spectra ctrometer, the ans of solvents (CD3)2SO: δ 1H e given in ppm ere recorded on H‐5. Elemental Unit at Cairo ‐bis (methyl yanoacetate yananamide (1) r malononitrile presence of or ea ng 4‐ ew he R, n e a e s H m n l o ) e 108 Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 Scheme 1 potassium carbonate (2.7 g, 0.02 mole) was stirred at room temperature for 4 h. The reaction mixture was poured portion wise into 50 mL of 10% hydrochloric acid containing crushed ice. The obtained precipitate was collected by filtration and crystallized from appropriate solvent to yield compound 3a and 3b, respectively (Scheme 1). 2‐Cyano‐3‐methylsulfanyl‐3‐ureido‐acrylic acid ethyl ester (3a): Color: Colourless needles. Yield: 85%. M.p.: 225‐227 °C. FT‐IR (KBr, , cm‐1): 3414 (NH2), 3283 (NH), 2214 (CN), 1700, 1689 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.23‐1.37 (t, 3H, CH3), 2.54 (s, 3H, S‐Me), 4.10‐4.18 (q, 2H, ‐CH2), 7.07 (br.s, 2H, NH2), 10.21 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.27 (1C, SCH3), 16.26 (1C, CH3), 60.98 (1C, CH2), 67.21 (1C, =C‐CN), 116.76 (1C, CN), 152.20 (1C, CONH2), 163.68 (1C, COOET), 169.35 (1C, =C‐SMe). MS (EI, m/z (%)): 229 (M+, 31). Anal. calcd. for C8H11N3O3S: C, 41.91; H, 4.84; N, 18.33; S, 13.99. Found: C, 42.45; H, 4.88; N, 17.98; S, 13.75%. (2,2‐Dicyano‐1‐methylsulfanyl‐vinyl)‐urea (3b): Color: Buff crystals. Yield: 83%. M.p.: 295‐297 °C. FT‐IR (KBr, , cm‐1): 3341‐3446 (NH2), 3223 (NH ), 2203‐2214 (2CN), 1673 (C=O)(amide). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 2.5 (s, 3H, SMe), 7.6‐7.93 (br.s, 2H, NH2), 10.95 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 12.61 (1C, SCH3), 115.12 (1C, =C‐ CN), 143.42 (1C, CN), 153.07 (1C, CN), 158.55 (1C, CONH2), 176.49 (1C, =C‐SMe). MS (EI, m/z (%)): 182 (M+, 43). Anal. calcd. for C6H6N4OS: C, 39.55; H, 3.32; N, 30.75; S, 17.60. Found: C, 39.73; H, 3.61; N, 30.43; S, 17.34%. 2.2.2. General procedure for the reaction of 3a and 3b with hydrazine hydrate A mixture of compound 3a or 3b (0.01 mole), hydrazine hydrate (1 mL) in 20 mL ethanol was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the solid formed was crystallized from appropriate solvent to yield compound 4a and 4b, respect‐ tively (Scheme 1). 5‐Amino‐3‐ureido‐1H‐pyrazole‐4‐carboxylic acid ethyl ester (4a): Color: Colourless needles. Yield: 61%. M.p.: 246‐248 °C. FT‐IR (KBr, , cm‐1): 3358‐3491 (2NH2), 3212 (NH), 1691‐ 1647 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.21‐1.27 (t, 3H, CH3), 4.15‐4.23 (q, 2H, ‐CH2), 6.12 (br.s, 2H, ‐NH2), 7.1 (br.s, 2H, NH2), 7.67 (s, 1H, NH), 11.34 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.29 (1C, CH3), 14.60 (1C, =C‐NH2), 38.69 (1C, N=C‐NH), 59.25 (1C, CH2), 60.95 (1C, =C‐COOEt, 154.59 (1C, CONH2), 163.98 (1C, COOEt). MS (EI, m/z (%)): 213 (M+, 66). Anal. calcd. for C7H11N5O3: C, 39.44; H, 5.20; N, 32.85. Found; C, 39.41; H, 4.95; N, 32.78%. (5‐Amino‐4‐cyano‐1H‐pyrazol‐3‐yl)‐urea (4b): Color: Buff crystals. Yield: 48%. M.p.: 262‐264 °C. FT‐IR (KBr, , cm‐1): 3357‐3479 (2NH2), 3280 (NH), 2185 (CN), 1693 (C=O) (amide). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 6.18 (br.s, 2H, NH2), 6.4 (br.s, 2H, NH2), 11.5 (s, 1H, NH), 12.15 (s, 1H, NH). MS (EI, m/z (%)): 166 (M+, 33). Anal. calcd. for C5H6N6O: C, 36.15; H, 3.64; N, 50.58. Found: C, 36.41; H, 3.47; N, 50.43%. 2.2.3. General procedure for the synthesis of pyrazolo[1,5‐a] pyrimidines 5 and 6a,b To a solution of compound 4a (2.13 g, 0.01 mole) in (10 mL) acetic acid, (0.01 mole) of acetylacetone, ethylaceto acetate or diethyl‐3‐oxo‐gluturate) was added. The reaction mixture was refluxed for the appropriate time (7‐14 h). After cooling the reaction mixture was poured into water. The solid product formed crystallized from appropriate solvent to yield compound 5, 6a and 6b, respectively (Scheme 2). 5,7‐Dimethyl‐2‐ureido‐pyrazolo[1, 5‐a]pyrimidine‐3‐carboxy lic acid ethyl ester (5): Color: Buff crystals. Yield: 56%. M.p.: 289‐270 °C. FT‐IR (KBr, , cm‐1): 3369‐3478 (NH2), 3229 (NH), 1693, 1660 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.3 (t, 3H, CH3), 2.13 (s, 3H, CH3), 2.27 (s, 3H, CH3), 4.18 (q, 2H, CH2), 6.0‐6.2 (s, 3H, NH2 + Ar‐H), 6.2 (8.72 (s, 1H, NH). MS (EI, m/z (%)): 277 (M+, 35). Anal. calcd. for C12H15N5O3: C, 51.98; H, 5.45; N, 25.26. Found: C, 51.92; H, 5.46; N, 25.46%. 5‐Methyl‐7‐oxo‐2‐ureido‐6, 7‐dihydro‐pyrazolo[1,5‐a]pyrimi dine‐3‐carboxylic acid ethyl ester (6a): Color: Buff crystals. Yield: 65%. M.p.: 267‐269 °C. FT‐IR (KBr, , cm‐1): 3304‐3477 (NH2), 3294 (NH), 1693, 1640 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.28‐1.32 (t, 3H, CH3), 2.32 (s, 3H, CH3), 4.24‐4.33 (q, 2H, CH2), 5.88 (s, 2H, CH2), 5.95 (s, 2H, NH2), 11.23 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.70 (1C, CH3), 19.06 (1C, CH3), 59.65 (1C, CH2), 83.56 (1C, CH2CO), 99.65 (1C, =C‐CH3), 143 (1C, =C‐N), 144 (1C, N=C‐N), 149 (1C, =C‐COOEt), 154 (1C, CONH2), 157 (1C, COOEt), 162.89 (1C, C=O). MS (EI, m/z (%)): 279 (M+, 27). Anal. calcd. for C11H13N5O4: C, 47.31; H, 4.69; N, 25.08. Found; C, 46.98; H, 4.35; N, 24.78%. 5‐Ethoxycarbonylmethyl‐7‐oxo‐2‐ureido‐6, 7‐dihydro‐pyra zolo[1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (6b): Color: Buff crystals. Yield: 46%. M.p.: 255‐257 °C. FT‐IR (KBr, , cm‐1): 3319‐3447 (NH2), 3274 (NH), 1715, 1701, 1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15 (t, 3H, CH3), 1.22 (t, 3H, CH3), 3.90 (s, 2H, CH2), 4.14‐4.23 (q, 2H, ‐CH2), 4.25‐4.33 (q, 2H, CH2), 5.95 (s, 2H, CH2), 7.45 (br.s, 2H, NH2), 11.85 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.24 (1C, CH3), 14.59 (1C, CH3), 60.77 (1C, CH2), 61.26 (1C, CH2), 84.76 (1C, N=C‐), 103 (1C, CH2 CO), 104 (1C, CH2CO), 143.44 (1C, =C‐N), 147.25 (1C, N‐C=N), 150.66 (1C, =C‐COOEt), 153.74 (1C, CONH2), Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 109 Scheme 2 154.42 (1C, COOEt), 162.19 (1C, COOEt), 168.79 (1C, C=O). MS (EI, m/z (%)): 351 (M+, 24). Anal. calcd. for C14H17N5O6: C, 47.86; H, 4.88; N, 19.93. Found: C, 47.87; H, 4.96; N, 19.50%. 2.2.4. Synthesis of 5‐amino‐7‐(3‐benzyloxy‐phenyl)‐6‐cyano‐ 2‐ureido‐pyrazolo[1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (7) A solution of compound 4a (2.13 g, 0.01 mole) and 2‐(3‐ benzyloxybenzyliden)malononitrile (2.6 g, 0.01 mole) in pyridine (20 mL) was heated under reflux for 2 h. The solvent was then evaporated in vacuum, and the remaining solid product was crystallized from methanol (Scheme 2). Color: Yellow crystals. Yield: 56%. M.p.: 222‐224 °C. FT‐IR (KBr, , cm‐1): 3357‐3479 (2NH2), 3280 (NH), 2195 (CN), 1693 (C=O). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.25‐1.33 (t, 3H, CH3), 4.14‐4.23 (q, 2H, ‐CH2), 5.20 (s, 2H, CH2), 6.18 (br.s, 2H, NH2), 6.4 (br.s, 2H, NH2), 6.95‐7.33 (m, 9H, Ar‐H), 7.15 (s, 1H, NH). MS (EI, m/z (%)): 471 (M+, 0.93). Anal. calcd. for C24H21N7O4: C, 61.14; H, 4.49; N, 20.80. Found: C, 61.34; H, 4.86; N, 20.55%. 2.2.5. General procedure for the synthesis of pyrazolo[1,5‐ a]pyrimidines 9, 10a‐c and 11 To a solution of compound 4a (2.13 g, 0.01 mole) in (10 mL) dimethylformamide and 0.5 g potassium carbonate, an electrophilic reagent namely, 2‐cyano‐3,3‐bis(methylthio) acrylonitrile, 3,3‐bis‐benzyl‐sulfanyl‐2‐cyano‐acrylic acid ethyl ester, 2‐cyano‐3‐ethoxy‐carbonylmethylsulfanyl‐3‐phenyl‐amino acrylic acid ethyl ester, 2‐cyano‐3‐methylsulfanyl‐3‐ureido‐ acrylic acid ethyl ester and ethyl‐2‐cyano‐3,3‐bis‐(methylthio) acrylate and 2‐cyano‐3,3‐bis‐methylsulfanyl‐acryl amide (0.01 mole) was added. The reaction mixture was stirred at room temperature for the appropriate time (6‐14 h). After this time the reaction mixture was acidified with 10% hydrochloric acid. The precipitate that appeared was collected by filtration and crystallized from appropriate solvent to yield compound 9, 10a‐c and 11, respectively (Scheme 3). 7‐Amino‐6‐cyano‐5‐methylsulfanyl‐2‐ureido‐pyrazolo[1, 5‐ a]pyrimidine‐3‐carboxylic acid ethyl ester (9): Color: Yellow crystals. Yield: 62%. M.p.: > 360 °C. FT‐IR (KBr, , cm‐1): 3291‐ 3412 (2NH2), 3180 (NH), 2215 (CN), 1719‐1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.23‐1.37 (t, 3H, CH3), 2.71 (s, 3H, SCH3), 4.20‐4.27 (q, 2H, ‐CH2), 7.43 (br.s, 2H, NH2), 8.74 (br.s, 2H, NH2), 8.62 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.39 (1C, CH3), 16.32 (1C, SCH3), 59.74 (1C, CH2), 84.23 (1C, =C‐N), 84.5 (1C, N=C‐N), 114.12 (1C, =C‐NH2), 142.94 (1C, =C‐S), 153.15 (1C, =C‐COOEt), 153.99 (1C, =C‐CN), 154.46 (1C, CN), 157.40 (1C, CONH2), 163.62 (1C, COOEt). MS (EI, m/z (%)): 335 (M+, 9.6). Anal. calcd. for C12H13N7O3S: C, 42.98; H, 3.91; N, 29.24. Found; C, 42.84; H, 3.92; N, 29.57%. 5‐Benzylsulfanyl‐6‐cyano‐7‐oxo‐2‐ureido‐4, 7‐dihydro‐pyra zolo[1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (10a): Color: Buff crystals. Yield: 62%. M.p.: 322‐324 °C. FT‐IR (KBr, , cm‐1): 3438‐3349 (NH2), 3214 (NH), 2235 (CN), 1686, 1652, 1633 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15‐1.23 (t, 3H, CH3), 3.77 (s, 1H, pyrimidine‐NH), 4.25 (s, 2H, CH2), 4.45‐4.38 (q, 2H, CH2), 6.65 (s, 2H, NH2) 7.35‐7.75 (m, 5H, Ar‐H), 8.78 (s, 1H, NH). MS (EI, m/z (%)): 412 (M+, 26). Anal. calcd. for C18H16N6O4S: C, 52.42; H, 3.91; N, 20.38. Found: C, 52.45; H, 4.10; N, 20.46%. 6‐Cyano‐7‐oxo‐5‐phenylamino‐2‐ureido‐4, 7‐dihydro‐pyra zolo[1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (10b): Color: Yellow crystals. Yield: 51%. M.p.: 343‐345 °C. FT‐IR (KBr, , cm‐1): 3465‐3340 (NH2), 3114‐3285 (NH), 2205 (CN), 1725, 1655 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.32‐1.22 (t, 3H, CH3), 3.8 (s, 1H, pyrimidine‐NH), 4.66 (s, 1H, NH‐Ph), 4.42‐4.15 (q, 2H, CH2), 5.63 (s, 2H, NH2), 8.53 (s, 1H, NH), 7.05‐ 110 Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 Scheme 3 7.45 (m, 5H, Ar‐H). MS (EI, m/z (%)): 381 (M+, 11). Anal. calcd. for C17H15N7O4: C, 53.54; H, 3.96; N, 25.71. Found: C, 53.65; H, 4.15; N, 25.55%. 6‐Cyano‐7‐oxo‐2,5‐diureido‐4,7‐dihydro‐pyrazolo[1,5‐a]pyri midine‐3‐carboxylic acid ethyl ester (10c): Color: Colourless crystals. Yield: 60%. M.p.: 341‐343 °C. FT‐IR (KBr, , cm‐1): 3413‐3211 (NH2 and NH), 2221 (CN), 1684, 1652 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.25‐1.15 (t, 3H, CH3), 3.90 (s, 1H, pyrimidine‐NH), 4.35‐4.18 (q, 2H, CH2), 5.8 (s, 2H, NH2), 6.55‐6.65 (br.s, 2H, NH2), 8.49 (s, 1H, NH), 8.85 (s, 1H, NH). MS (EI, m/z (%)): 348 (M+, 10). Anal. calcd. for C12H12N8O5: C, 41.38; H, 3.47; N, 32.17. Found: C, 41.65; H, 3.78; N, 32.45%. 6‐Cyano‐5‐methylsulfanyl‐7‐oxo‐2‐ureido‐4, 7‐dihydro‐pyra zolo[1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (11): Color: Colourless crystals. Yield: 69%. M.p.: 358‐360 °C. FT‐IR (KBr, , cm‐1): 3374‐3495 (2NH2), 3158 (NH), 2230 (CN), 1705, 1662 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 2.50‐2.47 (t, 3H, CH3), 2.45 (s, 3H, SMe), 3.88 (s, 1H, pyrimidine‐NH), 4.26‐4.35 (q, 2H, ‐CH2), 7.17 (br.s, 2H, NH2), 8.32 (s, 1H, NH). MS (EI, m/z (%)): 336 (M+, 13). Anal. calcd. for C12H12N6O4S: C, 42.85; H, 3.60; N, 24.99. Found: C, 42.56; H, 3.66; N, 25.28%. 2.2.6. General procedure for the reactions of compound 4a with ethoxymethylenemalononitrile and ethoxymethylene cyanoacetate To a solution of compound 4a (2.13 g, 0.01 mole) in (10 mL) acetic acid, ethoxymethylene malononitrile or ethoxy methylene cyanoacetate (0.01 mole) was added. The reaction mixture was refluxed for the appropriate time (4‐6 h). After this time the reaction mixture was poured into water. The solid product formed crystallized from appropriate solvent to yield compound 13a and 13b, respectively (Scheme 4). 5‐Amino‐6‐cyano‐2‐ureido‐pyrazolo[1, 5‐a]pyrimidine‐3‐ carboxylic acid ethyl ester (13a): Color: Yellow crystals. Yield: 47%. M.p.: 357‐359 °C. FT‐IR (KBr, , cm‐1): 3413‐3213 (NH2 and NH), 2213 (CN), 1700, 1689 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15‐1.32 (t, 3H, CH3), 4.2‐4.35 (q, 2H, ‐CH2), 7.10 (br.s, 2H, NH2), 7.88 (br.s, 2H, NH2), 8.50 (s, 1H, Ar‐H), 9.15 (br.s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 19.7 (1C, CH3), 65.7 (1C, CH2), 83.00 (1C, =C‐N), 93.36 (1C, N=C‐N), 120.9 (1C, N=C‐NH2), 153.4 (1C, C=C‐N) , 154.3 (1C, =C‐ COOEt), 158.7 (1C, =C‐CN), 159.5 (1C, CN), 161.5 (1C, CONH2), 169.5 (1C, COOEt). MS (EI, m/z (%)): 289 (M+, 5). Anal. calcd. for C11H11N7O3: C, 45.68; H, 3.83; N, 33.90. Found: C, 45.96; H, 3.63; N, 33.91%. 5‐Amino‐2‐ureido‐pyrazolo[1, 5‐a]pyrimidine‐3,6‐dicarbo‐ xylic acid diethyl ester (13b): Color: Yellow crystals. Yield: 51%. M.p.: 337‐339 °C. FT‐IR (KBr, , cm‐1): 3345‐3456 (NH2), 3165 (NH), 1722, 1680 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.21‐1.34 (m, 6H, 2CH3), 4.20‐4.35 (m, 4H, 2CH2), 6.65 (br.s, 2H, NH2), 8.15 (br.s, 2H, NH2), 8.40 (s, 1H, Ar'H), 9.10 (br.s, 1H, NH). MS (EI, m/z (%)): 336 (M+, 22). Anal. calcd. for C13H16N6O5: C, 46.43; H, 4.80; N, 24.99. Found: C, 46.66; H, 4.65; N, 24.80%. 2.2.7. Synthesis of 4‐amino‐2‐methylsulfanyl‐7‐ureido‐pyra zolo[1,5‐a][1,3,5]triazine‐8‐carboxylic acid ethyl ester (14) To a solution of compound 4a (2.13 g, 0.01 mole) in (10 mL) dimethylformamide and 0.5 g potassium carbonate, N‐ bis(methylthio)methylenecyanamide (1) (1.46 g, 0.01 mole) was added. The reaction mixture was stirred at room temperature for 6bh. After this time the reaction mixture was acidified with 10% hydrochloric acid. The precipitate that appeared was collected by filtration and crystallized from dimethylformamide (Scheme 4). Color: Yellow crystals. Yield: 66%. M.p.: 357‐358 °C. FT‐IR (KBr, , cm‐1): 3325‐3436 (NH2), 3277 (NH), 1722, 1684 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15‐1.32 (t, 3H, CH3), 2.40 (s, 2H, NH2), 2.46 (s, 3H, SMe), 4.20‐4.30 (q, 2H, ‐CH2), 7.25 (s, 2H, NH2), 8.7 (s, 1H, NH). MS (EI, m/z (%)): 311 (M+, 32). Anal. calcd. for C10H13N7O3S: C, 38.58; H, 4.21; N, 31.49. Found: C, 38.86; H, 4.53; N, 31.61%. 2.2.8. Synthesis of 5‐[(2‐Hydroxy‐benzylidene)amino]‐3‐ ureido‐1H‐pyrazolo‐4‐carboxylic acid ethyl ester (15) To a solution of compound 4a (2.13 g, 0.01 mole) in (10 mL) ethanol and (0.1 mL) piperidine, 2‐hydroxybenzaldehyde (1.2 g, 0.01 mole) was added. The reaction mixture was refluxed for 2 h, and the obtained product was crystallized from chloroform (Scheme 4). Color: Yellow crystals. Yield: 78%. M.p.: 279‐380 °C. FT‐IR (KBr, , cm‐1): 3345‐3456 (NH2 and OH), 3165 (NH), 1722, 1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15‐1.35 (t, 3H, CH3), 3.67 (s, 1H, pyrazole‐ NH), 4.20‐4.30 (q, 2H, ‐CH2), 6.65 (s, 2H, NH2), 7.35‐8.25 (m, 4H, Ar‐H), 8.2 (s, 1H, CH‐benzylideneimin), 10.65 (s, 1H, NH), 12.7 (br.s, 1H, OH). MS (EI, m/z (%)): 317 (M+, 100). Anal. calcd. for C14H15N5O4: C, 52.99; H, 4.76; N, 22.07. Found: C, 52.85; H, 4.65; N, 22.32%. 2.2.9. Synthesis of 2‐ureido‐pyrazolo[1,5‐a]quinazoline‐3‐ carboxylic acid ethyl ester (16) To a solution of compound 15 (3.17 g, 0.01 mole) in acetic acid (20 mL) was heated under reflux for 4 h. Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 111 N N EtOOC NH N NH2 CH2N O N N COOEt NH N C NH2 O N N EtOOC NH N N NH2 CH2N O RN NH COOEt NH N C NH2 O OH 4a (1) R CN EtO AcOH 13a, b 14 16 15 OHC OH a; R = CN, b; R = CO2Et K2CO3 / DMF EtOH AcOH N NH EtOOC NH NH2 C NH2O SCH3 Scheme 4 The solvent was then evaporated under vacuo, and the remaining solid product was crystallized from dimethyl formamide (Scheme 4). Color: Red crystals. Yield: 82%. M.p.: 312‐314 °C. FT‐IR (KBr, , cm‐1): 3355‐3656 (NH2), 3165 (NH), 1725, 1695 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.18‐1.32 (t, 3H, CH3), 4.15‐4.37 (q, 2H, CH2), 6.95 (br.s, 2H, NH2), 7.45‐8.15 (m, 4H, Ar'H), 8.30 (s, 1H, NH), 9.20 (s, 1H, CH‐ quinazoline). MS (EI, m/z (%)): 299 (M+, 18). Anal. calcd. for C14H13N5O3: C, 56.18; H, 4.38; N, 23.40. Found: C, 56.45; H, 4.24; N, 23.72%. 2.2.10. Synthesis of diazotization of 5‐amino‐3‐ureido‐1H‐ pyrazole‐4‐carboxylic acid ethyl ester (4a) A cold solution of sodium nitrite 1.5 g in (10 mL) of water was added dropwisely to a stirred mixture of compound 4a (2.13 g, 0.01 mole), HCl (10 mL, 5%) and glacial acetic acid (10 mL). The mixture was stirred at 0‐5 °C for 1/2 h and the resulting diazotized solution 17 was used directly in the next reactions (Scheme 5). 2.2.11. General procedure for coupling of diazotized 17 with 2‐naphthol, resorcinol, malononitrile and ethylcyanoacetate A solution of diazonium salt 17 (0.01 mole) was added to a solution of the appropriate coupling reagent namely, 2‐ napthol, resorcinol, ethylcyanoacetate or malononitrile (0.01 mole) in ethanol (50 mL) in the presence of sodium acetate (5g). The solid product formed on standing was collected by filtration and crystallized from the appropriate solvent to give compound 18, 20, 22a and 22b, respectively (Scheme 5). 5‐(2‐Hydroxy‐naphthalen‐1‐ylazo)‐3‐ureido‐1H‐pyrazole‐4‐ carboxylic acid ethyl ester (18): Color: Red crystals. Yield: 65%. M.p.: 312‐314 °C. FT‐IR (KBr, , cm‐1): 3445‐3326 (NH2 and OH), 3165 (NH), 1720, 1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.22‐1.32 (t, 3H, CH3), 3.62 (s, 1H, pyrazole‐ H), 4.15‐4.27 (q, 2H, CH2), 6.60 (s, 2H, NH2), 7.25‐8.90 (m, 6H, Ar'H), 10.80 (br.s, 1H, OH), 12.15 (s, 1H, NH). MS (EI, m/z (%)): 368 (M+, 26). Anal. calcd. for C17H16N6O4: C, 55.43; H, 4.38; N, 22.82. Found: C, 55.66; H, 4.63; N, 22.71%. 5‐(2,4‐Dihydroxy‐phenylazo)‐3‐ureido‐1H‐pyrazole‐4‐carbo‐ xylic acid ethyl ester (20): Color: Orange crystals. Yield: 83%. M.p.: 337‐339 °C. FT‐IR (KBr, , cm‐1): 3445‐3315 (NH2 and OH), 3165 (NH), 1720, 1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.18‐1.37 (t, 3H, CH3), 3.69 (s, 1H, pyrazole‐ H), 4.16‐4.28 (q, 2H, CH2), 6.62 (br.s, 2H, NH2), 7.26‐8.12 (m, 3H, Ar‐H), 11.2 (s, 1H, NH), 12.15 (br.s, 2H, 2OH). MS (EI, m/z (%)): 334 (M+, 34). Anal. calcd. for C13H14N6O5: C, 46.71; H, 4.22; N, 25.14. Found: C, 46.53; H, 4.33; N, 25.43%. 4‐Amino‐7‐ureido‐pyrazolo[5,1‐c][1,2,4]triazine‐3,8‐di carbo‐ xylic acid diethyl ester (22a): Color: Yellow crystals. Yield: 74%. M.p.: 341‐343 °C. FT‐IR (KBr, , cm‐1): 3345‐3326 (NH2), 3165 (NH), 1720, 1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15‐1.38 (m, 6H, 2CH3), 4.33‐4.35 (m, 4H, 2CH2), 6.67 (s, 2H, NH2), 7.2 (br.s, 2H, NH2), 8.4 (s, 1H, NH). MS (EI, m/z (%)): 337 (M+, 17). Anal. calcd. for C12H15N7O5: C, 42.73; H, 4.48; N, 29.07. Found: C, 42.55; H, 4.65; N, 29.25%. 4‐Amino‐3‐cyano‐7‐ureido‐pyrazolo[5, 1‐c][1,2,4]triazine‐8‐ carboxylic acid ethyl ester (22b): Color: Yellow crystals. Yield: 72%. M.p.: 310‐312 °C. FT‐IR (KBr, , cm‐1): 3385‐3326 (NH2), 3277 (NH), 2215 (CN), 1704, 1682 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.15‐1.32 (t, 3H, CH3), 4.20‐4.35 (q, 2H, ‐CH2), 6.58 (s, 2H, NH2), 7.37 (s, 2H, NH2), 8.38 (s, 1H, NH). MS (EI, m/z (%)): 290 (M+, 8). Anal. calcd. for C10H10N8O3: C, 41.38; H, 3.47; N, 38.61. Found: C, 41.66; H, 3.54; N, 38.72%. 2.2.12. 16‐ureido‐11,12,14,15‐tetraaza‐cyclopenta[a] phenanthrene‐17‐carboxylic acid ethyl ester (19) To a solution of compound 18 (3.68 g, 0.01 mol) in acetic acid (20 mL) was heated under reflux for 3 h. The solvent was then evaporated in vacuo, and the remaining solid product was crystallized from dimethylformamide (Scheme 5). Color: Red crystals. Yield: 77%. M.p.: 330‐332 °C. FT‐IR (KBr, , cm‐1): 3445‐3326 (NH2), 3165 (NH), 1715, 1695 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.24‐1.35 (t, 3H, CH3), 4.15‐4.37 (q, 2H, CH2), 6.95 (s, 2H, NH2), 7.15‐8.25 (m, 6H, Ar‐H), 8.87 (s, 1H, NH). MS (EI, m/z (%)): 350 (M+, 100). Anal. calcd. for C17H14N6O3: C, 58.28; H, 4.03; N, 23.99. Found: C, 58.45; H, 4.24; N, 23.72%. 112 Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 Scheme 5 2.2.13. 8‐Hydroxy‐2‐ureido‐benzo[e]pyrazolo[5,1‐c][1,2,4] triazine‐3‐carboxylic acid ethyl ester (21) To a solution of compound 20 (3.34 g, 0.01 mol) in acetic acid (20 mL) was heated under reflux for 4 hrs. The solvent was then evaporated in vacuo, and the remaining solid product was crystallized from dimethylformamide (Scheme 5). Color: Yellow crystals. Yield: 85%. M.p.: 368‐370 °C. FT‐IR (KBr, , cm‐1): 3445‐3326 (NH2 and OH), 3165 (NH), 1715, 1695 (C=O's). 1H NMR (250 MHz, DMSO‐d6, δ, ppm): 1.17‐1.31 (t, 3H, CH3), 4.14‐4.36 (q, 2H, CH2), 6.65 (s, 2H, NH2), 7.14‐7.88 (m, 3H, Ar‐H), 9.10 (s, 1H, NH), 11.45 (br.s, 1H, OH). MS (EI, m/z (%)): 316 (M+, 19). Anal. calcd. for C13H12N6O4: C, 49.37; H, 3.82; N, 26.57. Found: C, 49.45; H, 3.64; N, 26.75%. 3. Results and discussion 3.1. Chemistry The reaction of N‐bis(methylthio)methylenecyanamide (1) with ethylcyanoacetate or malononitrile was conducted at room temperature in the presence of potassium carbonate in dimethysulfoxide followed by treatment with 10% hydro‐ chloric acid, afforded the urea derivatives 3a,b. This suggests that the isolated derivatives 3a,b were formed through the intermediates 2a,b. The FT‐IR spectrum showed the presence of absorption bands of NH2 and NH groups at 3414 and 3283 cm‐1 for compound 3a, and at 3446 and 3223 cm‐1 for compounds 3b, respectively. Also, the 1H NMR spectrum showed the presence of NH2 and NH groups at δ 7.07 and 10.21 ppm for compound 3a and at δ 7.60 and 10.95 ppm for compound 3b, respectively. The 13C NMR of compounds 3a and 3b showed eight and six different signals for eight and six different carbons, respectively (Scheme 1). The treatment of compound 3a,b with hydrazine hydrate in ethanol afforded the corresponding aminopyrazole derivatives 4a,b [20] (Scheme 1). The chemical structures of compounds 4a and 4b were in agreement with their spectral data and elemental analyses (Experimental part). The 13C NMR spectrum of compound 4a showed the presence of seven different signals corresponding to seven different carbons at δ 14.29 (1C, CH3), 14.60 (=C‐NH2), 38.69 (N=C‐NH), 59.25 (CH2), 60.95 (=C‐COOEt, 154.59 (CONH2) and at δ 163.98 ppm (COOEt), which proved its structure. Condensation of compound 4a with acetylacetone in acetic acid yielded 5,7‐dimethyl‐2‐ureido‐pyrazolo[1,5‐a]pyrimidi‐ ne‐3‐carboxylic acid ethyl ester (5). While the reaction of compound 4a with ethyl acetoacetate or diethyl‐3‐oxoglutu‐ rate produced the corresponding pyrazolopyrimidine derivati‐ ves 6a,b, respectively [21] (Scheme 2). The elemental analyses and spectroscopic data are in consistent with the assigned structures of compounds 5 and 6a,b. The mass spectrum showed molecular ion peak at m/z 277 for compound 5, at m/z 279 for compound 6a and at m/z 351 for compound 6b. 13C NMR of compounds 6a and 6b showed eleven and fourteen different signals for eleven and fourteen different carbons, respectively (Experimental part). Compound 4a was reacted with 2‐(3‐benzyloxy‐benzyl‐ iden)malononitrile in pyridine to give 5‐amino‐7‐(3‐benzyl oxy‐phenyl)‐6‐cyano‐2‐ureido‐4,7‐dihydropyrazolo[1, 5‐a] pyri‐ midine‐3‐carboxylic acid ethyl ester (7), while the other isomer 8 was not traced. The chemical Structure of compound 7 was considered more likely based on the ring nitrogen, which is the most nucleophilic centre in the molecule. Moreover, 1H NMR showed an amino function at δ 6.7 ppm and ‐CH signal of C‐7 at δ 5.6 ppm. The mass spectrum of compound 7 showed molecular ion peak at m/z 471 corresponding to its molecular formula (C24H21N7O4). Some Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 113 analogues related compounds reported in the literature [21‐ 23] (Scheme 2). Stirring an equimolar mixture of compound 4a and 2‐ cyano‐3,3‐bis(methylthio)acrylonitrile [24] in dimethyl form‐ amide containing catalytic amount of potassium carbonate at room temperature resulted in the formation of the corres‐ ponding 7‐amino‐6‐cyano‐5‐methylsulfanyl‐2‐ureido pyrazolo [1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (9) (Scheme 2). The chemical structure of compound 9 was assigned on the bases of its spectral and elemental data. IR spectrum of compound 9 showed absorption bands at 3291‐3412 cm‐1 for 2NH2, 3180 cm‐1 for NH, 2215 cm‐1 for CN and at 1682‐1719 cm‐1 for 2C=O. The 1H NMR spectrum of compound 9 showed signals at δ 1.23 for CH3, δ 2.71 for SCH3, δ 4.2 for CH2, δ 7.43, 8.74 for 2NH2 and at δ 8.62 ppm for NH. Also, the mass spectrum showed molecular ion peak at m/z 335 corres‐ ponding to its formula (C12H13N7O3S). The 13C NMR spectrum of compound 9 showed twelve different signals at δ 14.39, 16.32, 59.74, 84.23, 84.5, 114.12, 142.94, 153.15, 153.99, 154.46, 157.40, 163.62 ppm for twelve different carbon atoms, which adds additional confirmation for the proposed structure. In a similar manner compound 4a was reacted with 3,3‐ bis‐benzyl‐sulfanyl‐2‐cyano‐acrylic acid ethyl ester [24], 2‐ cyano‐3‐ethoxy‐carbonylmethylsulfanyl‐3‐phenyl‐amino acr‐ ylic acid ethyl ester and 2‐cyano‐3‐methylsulfanyl‐3‐ureido‐ acrylic acid ethyl ester [20], to give the corresponding pyrazolo[1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester 10a‐c, respectively (Scheme 3). The mass spectra of compounds 10a‐ c showed molecular ion peaks at m/z 412 for compound 10a, at m/z 381 for compound 10b and at m/z 348 for compound 10c, led to the assignment of their molecular formulae. Analogously, condensation of compound 4a with ethyl‐2‐ cyano‐3,3‐bis(methylthio)acrylate and 2‐cyano‐3,3‐bis‐methyl sulfanyl‐acrylamide [25], afforded the similar product 6‐ cyano‐5‐methyl‐sulfanyl‐7‐oxo‐2‐ureido‐4,7‐dihydropyrazolo [1,5‐a]pyrimidine‐3‐carboxylic acid ethyl ester (11). The spectral and analytical data ruled out the alternative products 12a and 12b (Scheme 3), where the 1H NMR spectrum of compound 11 showed signals at δ 2.50 for CH3, δ 2.45 for SMe, δ 3.88 for pyrimidine‐NH, δ 4.26 for CH2, δ 7.17 for NH2 and at δ 8.32 ppm for NH, and the mass spectrum showed molecular ion peaks at m/z 336. Heating of compound 4a with ethoxymethylene malononitrile [26] or ethoxymethylene cyanoacetate in acetic acid afforded the pyrazolo pyrimidine derivatives 13a,b, respectively (Scheme 4). The chemical structures of com‐ pounds 13a and 13b were proved according their elemental and spectroscopic data, The 13C NMR spectrum of compound 13a showed the presence of eleven different signals corresponding to thier different carbons at δ 19.7 (CH3), 65.7 (CH2), 83.00 (=C‐N), 93.36 (N=C‐N), 120.9 (N=C‐NH2), 153.4 (C=C‐N) , 154.3 (=C‐COOEt), 158.7 (=C‐CN), 159.5 (CN), 161.5 (CONH2) and at δ 169.5 ppm (COOEt), which gives additional confirmation for the proposed structure. When compound 4a was stirred with N‐bis(methylthio) methylenecyanamide (1) in the presence of potassium carbonate in dimethylformamide at room temperature, the corresponding 4‐amino‐2‐methylsulfanyl‐7‐ureido‐pyrazolo [1,5‐a][1,3,5]triazine‐8‐carboxylic acid ethyl ester (14) was obtained. Refluxing of equimolar quantities of compound 4a and salicylaldehyde in ethanol containing catalytic amount of piperidine gave 2‐ureido pyrazolo[1,5‐a]quinazoline‐3‐car‐ boxylic acid ethyl ester (15). Compound 15 was cyclized into the pyrazoloquinazoline 16 by refluxing in acetic acid (Scheme 4). The structures of compounds 14, 15 and 16 were in agreement with their spectral data and elemental analyses. The mass spectrum showed molecular ion peak at m/z 311 for compound 14, at m/z 317 for compound 15 and at m/z 299 for compound 16, which were in consistent with their corres‐ ponding formulae (Experimental part). Treatment of compound 4a with nitrous acid in presence of concentrated hydrochloric acid/acetic acid mixture gave the corresponding diazonium salt 17 [20], which could not be isolated in pure status but its formation was indicated via coupling with some phenols and active methylene reagents. So, coupling of the diazonium salt 17 with 2‐naphthol and resorcinol afforded the corresponding arylazo derivatives 18 and 20, respectively. Cyclic condensation of compound 18 and 20 in refluxing acetic acid gave the corresponding 19 and 21, respectively (Scheme 5). This result is in contrast with the reported direct formation of cyclic pyrazolo[1,5‐c][1,2,4] triazine on coupling diazotized aminopyrazoles with naphthols [27]. The elemental analyses and spectroscopic data are in consistent with the assigned structures of compounds 18, 19, 20 and 21. The 1H NMR of compounds 18 and 20 showed presence of the phenolic (OH) at δ 10.8 ppm and δ 11.2 ppm as broad peaks, respectively, which it disappeared in compound 19. Mass spectra of compounds 18, 19, 20 and 21 showed ion peaks at m/z 368, 350, 334 and at m/z 316, respectively, which were in agreement with assigned structures. In contrast to the previous results, the salt 17 was coupled with ethyl cyanoacetate to yield compound 22a of the molecular formula C10H10N8O3 (m/z 290), which was formulated as the pyrazolo[1,5‐c][1,3,5]triazine based on its spectral data. Thus, the FT‐IR spectrum showed the presence of an amino function at 3320 cm‐1, and an ester carbonyl at 1720 cm‐1. The 1H NMR spectrum showed an absorption band at δ 8.8 ppm that it was integrated for two protons and was assigned for the amino group. The downfield shift of this amino function could be explained by the anisotropic effect of the ring nitrogen. In addition, 1H NMR showed two ethyl ester groups. In the same way, compound 17 was coupled with malononitrile to afford the corresponding pyrazolo[1,5‐c] [1,3,5]triazine, 22b (Scheme 5). The FT‐IR spectrum of compound 22b showed the presence of an amino function at 3385‐3326 cm‐1, and cyno function at 2215 cm‐1 and the 1H NMR spectrum showed absorption bands at δ 8.38 ppm for NH, δ 7.37 and 6.58 for two NH2 and at δ 1.15 and 4.20 ppm corresponding to the ethyl ester group, which were in agreement with its structure. 4. Conclusion In conclusion, a series of new heterocyclic derivatives of condensed pyrazolopyrimidine, pyrazoloquinazoline and pyrazolotriazine derivatives starting with the cyclic amidine 4a were synthesized. The structures of the newly synthesized compounds were established on the basis of their spectral data (IR, 1H NMR, 13C NMR, Mass) and elemental analyses. Acknowledgement The authors are grateful to South Valley University, Qena, Egypt for help and support. References [1]. Marcos, P. M.; Elisandra, S.; Clarissa, P. F.; Fernanda, A. R.; Helio, G. B.; Nilo, Z. J. Braz. Chem. Soc. 2009, 20(2), 205‐213. [2]. Ghozlan, S. A. S.; Abdelrazek, F. M.; Mona, H. M.; Khaled, E. A. J. Heterocyclic. Chem. 2010, 47, 1379‐1385. [3]. Liekens, S.; Bronckaers, A.; Balzarini, J. Lancet Oncol. 2009, 10(6), 628‐635. [4]. Novinson, T.; Bhooshan, B.; Okabe, T.; Revankar, G. R.; Wilson, H. R.; Robins, R. K.; Senga, K. J. Med. Chem. 1976, 19, 512‐516. [5]. Asem, S. D.; Shunan, K.; Jai, N. V. J. Mol. Divers. 2015, 19(4), 759‐771. [6]. Senga, K.; Novinson, T.; Wilson, H. R.; Robins, R. K. J. Med. Chem. 1981, 24, 610‐613. [7]. Wedad, M. A.; Tahir, M. I. M.; Siti‐Noor‐Adnalizawati, A.; Siti‐Farah, H.; Nazlina, I.; Yaacob, W. A. Eur. J. Med. Chem. 2013, 64, 464‐476. [8]. Essam, A.; Said, A. S.; Assy, M. G.; Atef, M. A. Am. J. Org. Chem. 2013, 3(1), 16‐23. 114 Abbas‐Temirek and Abo‐Bakr / European Journal of Chemistry 7 (1) (2016) 107‐114 [9]. Aymn, E. R.; Mohamed, I. H.; Randa, E. A.; Jehan, A. M. Bioorgan. Med. Chem. 2008, 16(15), 7102‐7106. [10]. Refaee, M.; Ahmed, K. E.; Mahmoud, F. I.; Sayed, A. S. Eur. J. Chem. 2011, 2(3), 347‐355. [11]. Charles, Q. H.; Keith, M. W.; Dimitri, E. G.; James, R. M.; Chen, C. Bioorg. Med. Chem. Lett. 2004, 14(15), 3943‐3947. [12]. Suzuki, M.; Iwasaki, H.; Fujikawa, Y.; Sakashita, M.; Kitahara, M.; Sakoda, R. Bioorg. Med. Chem. Lett. 2001, 11, 1285‐1288. [13]. Almansa, C.; Merlos, M.; Rafanell, J. G.; Arriba, A. F.; Cavalcanti, F. I.; Gomez, I. A.; Miralles, A. J. Med. Chem. 2001, 44, 350‐361. [14]. Fraley, M. E.; Hoffman, W. F.; Rubino, R. S.; Hungate, R. W.; Tebben, A. J.; Rutledge, R. Z.; Mcfall, R. C.; Huckle, W. R.; Kendall, R. I.; Coll, K. E.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2002, 12(19), 2767‐2770. [15]. Mark, E. F.; William, F. H.; Robert, S. R.; Randall, W. H.; Andrew, J. T.; Ruth, Z. R.; Rosemary, C. M. ; William, R. H.; Richard, L. K.; Kathleen, E. C.; Kenneth, A. T. Bioorg. Med. Chem. Lett. 2002, 12, 3537‐3541. [16]. Hantzsch, A.; Wolvekamp, M. Justus liebigs Ann. Chem. 1904, 331, 265‐297. [17]. Gompper, R.; Gang, M.; Saygin, F. Tetrahedron Lett. 1966, 7(17), 1885‐1889. [18]. Erra‐Balsells, R.; Frasca, A. R. Austr. J. Chem 1988, 41(1), 103‐110. [19]. Biondic, M. C.; Erra‐Balsells, R. J. Photochem. Photobiol. , Sec. A Chem. 1990, 51, 341‐353. [20]. Tominaga, Y.; Ohno, S.; Fujito, H.; Mazume, H. J. Heterocyclic. Chem. 1991, 28, 1039‐1042. [21]. Sadek, K. U.; Selim, N. A.; Elnagdi, M. H.; Otto, H. H. Bull. Chem. Soc. Jpn. 1993, 66, 2927‐2930. [22]. Ibrahim, N. S.; Sadek, K. U.; Abdel‐Al, F. A. Arch. Pharm. (Weinheim) 1987, 320, 240‐246. [23]. Hassanien, A. A.; Amrb, A. E.; Ghozlan, S. A. S. J. Chin. Chem. Soc. 2000, 47 (6), 1273‐1278. [24]. Dieler, R. K. Tetrahedron 1986, 42(12), 3029‐3096. [25]. Elgemeie, G. H.; Elghandour, A. H.; Elzanate, A. M.; Ahmed, S. A. J. Chem. Soc., Perkin Trans. I 1997, 21, 3285‐3289. [26]. Schmidt, H. W.; Junek, H. Monatsh. Chem. 1977, 108(4), 895‐900. [27]. Reimlinger, H.; VanOverstaeten, A. Chem. Ber. 1961, 94(4), 1036‐ 1041.