untitled European Journal of Chemistry 4 (2) (2013) 102‐109 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.2.102‐109.723 European Journal of Chemistry Journal homepage: www.eurjchem.com Regioselective synthesis of some functionalized 3,4’‐bis‐(pyrazolyl)ketones and chemoselectivity in their reaction with hydrazine hydrate Hamdi Mahmoud Hassaneen * and Ahmad Sami Shawali Department of Chemistry, Faculty of Science, University of Cairo, Giza, 12613, Egypt *Corresponding author at: Department of Chemistry, Faculty of Science, University of Cairo, Giza, 12613, Egypt. Tel.: +202.35676571; fax: +202.35676571. E‐mail address: hamdi_251@yahoo.com (H. M. Hassaneen). ARTICLE INFORMATION ABSTRACT Received: 16 January 2013 Received in revised form: 02 February 2013 Accepted: 03 February 2013 Online: 30 June 2013 KEYWORDS A new enamino ester, (E)‐ethyl 3‐(dipropylamino)acrylate, was prepared and used for synthesis of various pyrazole derivatives, 4a‐k and 5a‐d. Other new enaminone, (E)‐ethyl 3‐(3‐ (dimethylamino)acryloyl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (8), was also prepared from compound 4a and utilized as precursor for synthesis of different functionalized 3,4'‐bis‐pyrazolyl ketones 9a‐c, 10a‐c. The site selectivity in hydrazinolysis of the latter was studied. The structures of the products namely pyrazolo[3,4‐d]pyridazine derivatives 11(13) were confirmed by spectral and elemental analyses and by alternate unambiguous synthesis. Enaminones Enamino esters Regioselectivity Chemoselectivity Hydrazonoyl halides Pyrazolo[3,4‐d]pyridazines 1. Introduction A literature survey reveals that hydrazonoyl halides are useful versatile precursors for synthesis of numerous heterocyclic compounds. Their chemistry has attracted the interest of many research groups all over the world. At present, there are several review articles by Shawali et al. covering their reactions and applications [1‐9]. Also, literature reports indicate that many pyrazole derivatives found use in various pharmaceutical, agrochemical and many other applications [10‐17]. In the light of these facts and in conjunction with our ongoing studies of the chemistry of hydrazonoyl halides, it was thought interesting to study the 1,3‐dipolar cycloaddition of the nitrilimines derived from hydrazonoyl halides to the enamino ester, namely (E)‐ethyl 3‐(dipropylamino)‐acrylate 1, which has not been reported hitherto. Our objectives after such a study are on one hand to explore the utility of the resulting pyrazole cycloadducts (4a‐k, 5a‐d), expected from the target reaction (Scheme 1) in synthesis of new functionalized 3,4’‐ bis(pyrazolyl)ketones 9 and 10 (Scheme 2 and 3) and on the other hand to explore the site selectivity in hydrazinolysis of the latter heterocyclic compounds 9. 2. Experimental 2.1. Instrumentation All melting points were determined on an electrothermal Gallenkamp apparatus and are uncorrected. Solvents were generally distilled and dried prior their use. The IR spectra were measured on a Pye‐Unicam SP300 instrument in potassium bromide discs. The 1H and 13C NMR spectra were recorded on a Varian Mercury VXR‐300 spectrometer (300 MHz for 1H NMR and 75 MHz for 13C NMR) and the chemical shifts were related to that of the solvent DMSO‐d6. The mass spectra were recorded on a GCMS‐Q1000‐EX Shimadzu and GCMS 5988‐A HP spectrometers, the ionizing voltage was 70 eV. Elemental analyses of the products were carried out at the Microanalytical Center of Cairo University, Giza, Egypt. Hydrazonoyl halides were prepared following literature procedures [18‐24]. DMF‐DMA, dipropylamine and ethyl propiolate were purchased from Merck Company. 2.2. Synthesis 2.2.1. Preparation of (E)‐ethyl 3‐(dipropylamino)acrylate (1) To a solution of ethyl propiolate (9.8 g, 0.1 mol) in methanol (50 mL) was added a solution of dipropylamine (10.1 g, 0.1 mol) in methanol (50 mL) dropwise over a period of 30 min while being stirred. The reaction mixture was stirred for further 1 h and then the solvent was distilled under reduced pressure. The enamino ester, 1, was obtained as oil (Scheme 1). Color: Pale yellow. Yield: 90%. FT‐IR (KBr, cm‐1): 1686 ν(C=O), 1608 ν(C=C). 1H NMR (300 MHz, CDCl3, δ, ppm): 0.79 (t, J = 7 Hz, 6H, (CH3CH2CH2)2N), 1.15 (t, J = 8 Hz, 3H, CH3CH2O), 1.47 (m, 4H, (CH3CH2CH2)2N), 2.97 (t, J = 8 Hz, 4H, (CH3CH2CH2)2N), 4.02 (q, J = 7 Hz, 2H, CH3CH2O), 4.42 (d, J = 13.2 Hz, 1H, =CH‐ CO), 7.36 (d, J = 13.2 Hz, 1H, =CH‐N(CH2CH2CH3)2). 13C NMR (75 MHz, CDCl3, δ, ppm): 11.1, 14.6, 50.3, 58.6, 63.3, 126.1, 151.7, 169.8. Anal. calcd. for C11H21NO2: C, 66.29; H, 10.62; N, 7.03. Found: C, 66.10; H, 10.42; N, 6.82%. 2.2.2. Synthesis of ethyl 1‐aryl‐3‐substituted‐1H‐pyrazole‐4‐ carboxylates (4a‐k, 5a‐d) General procedure: To an equimolar mixture (5 mmol each) of the (E)‐ethyl 3‐(dipropylamino)acrylate, 1, and the appropriate hydrazonoyl halide 2(3) in dioxane (50 mL) was Hassaneen and Shawali / European Journal of Chemistry 4 (2) (2013) 102‐109 103 H COOEt H H NR2 COOEt H N N X ArR' N N ArR' N N Ar R' COOEt NR2N N Ar R' COOEt N N Ar R' COOEt R2NH -R2NH TEA 2(3) 1 + - 6 4(5) R= CH3CH2CH2 + 2(4) R’ Ar 3(5) R’ Ar a CH3CO 4-NO2-C6H4 a C6H5CH=CH C6H5 b 2-Thenoyl C6H5 b 2-Furyl 4-NO2-C6H4 c 2-Thenoyl 4-Cl-C6H4 c 2-Thienyl 4-NO2-C6H4 d 2-Thenoyl 4-NO2-C6H4 d C2H5COO 4-NO2-C6H4 e C6H5CO C6H5 f C6H5CO 4-CH3-C6H4 g C6H5CO 4-Cl-C6H4 h 2-Naphthoyl C6H5 i 2-Naphthoyl 4-CH3-C6H4 j 2-Naphthoyl 4-Cl-C6H4 k 2-Naphthoyl 4-NO2-C6H4 Scheme 1 added triethylamine (1.0 g, 10 mmol) and the reaction mixture was refluxed for 4 h, then the solvent was distilled under reduced pressure. To the residue left, ethanol was added and the solid produced was collected and crystallized from the appropriate solvent to give the corresponding pyrazole derivative. The compounds prepared together with their physical constants are given below (Scheme 1). Ethyl 3‐acetyl‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (4a): Color: Golden yellow crystals. Yield: 78% (EtOH). M.p.: 160‐162 °C. FT‐IR (KBr, cm‐1): 3120 ν(CH), 1735, 1697 ν(C=O). 1H NMR (300 MHz, CDCl3, δ, ppm): 1.36 (t, J = 7.2 Hz, 3H, CH3CH2O), 2.69 (s, 3H, CH3CO), 4.33 (q, J = 7.5 Hz, 2H, CH3CH2O), 7.97 (d, J = 9 Hz, 2H, Ar‐H), 8.97 (d, J = 9 Hz, 2H, Ar‐ H), 8.39 (s, 1H, =CH‐N). 13C NMR (75 MHz, CDCl3, δ, ppm): 14.06, 28.67, 61.26, 117.17, 119.68, 125.38, 132.09, 142.92, 146, 67, 151.90, 161.36, 193.04. MS (EI, m/z (%)): 303 (M+, 48), 288 (26), 260 (100). Anal. calcd. for C14H13N3O5: C, 55.45; H, 4.32; N, 13.86. Found: C, 55.21; H, 4.31; N, 13.65%. Ethyl 1‐phenyl‐3‐(thiophene‐2‐carbonyl)‐1H‐pyrazole‐4‐ carboxylate (4b): Color: Yellow crystals. Yield: 70% (MeOH). M.p.: 89‐90 °C. FT‐IR (KBr, cm‐1): 3144 ν(CH), 1697, 1640 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm):1.37 (t, J = 7.5 Hz, 3H, CH3CH2O), 4.14 (q, J = 7.5 Hz, 2H, CH3CH2O), 7.25‐8.19 (m, 8H, Ar‐H), 9.11 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.00, 60.72, 115.97, 119.72, 121.12, 128.22, 129.13, 129.89, 132.50, 136.66, 138.60, 142.87, 150.24, 161.51, 180.44. Anal. calcd. for C17H14N2O3S: C, 62.57; H, 4.32; N, 8.59; S. 9.81. Found: C, 62.65; H, 4.41; N, 8.41; S, 9.70%. Ethyl 1‐(4‐chlorophenyl)‐3‐(thiophene‐2‐carbonyl)‐1H‐ pyrazole‐4‐carboxylate (4c): Color: Colorless crystals. Yield: 75% (EtOH). M.p.: 129‐130 °C. FT‐IR (KBr, cm‐1): 3124 ν(CH), 1705, 1631 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.16 (t, J = 7 Hz, 3H, CH3CH2O), 4.17 (q, J = 7 Hz, 2H, CH3CH2O), 7.27 (m, 1H, Ar‐H), 7.61 (d, J = 9 Hz, 2H, Ar‐H), 7.68 (m, 1H, Ar‐H), 8.01 (d, J = 9 Hz, 2H, Ar‐H), 8.17 (m, 1H, Ar‐H), 9.24 (s, 1H, =CH‐ N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.82, 60.41, 115.80, 120.87, 128.93, 129.57, 132.24, 132.72, 136.58, 136.77, 137.27, 142.58, 150.14, 161.09, 180.04. MS (EI, m/z (%)): 362 (M++2, 4), 360 (M+, 13), 314 (16), 138 (15), 111 (100). Anal. calcd. for C17H13ClN2O3S: C, 56.60; H, 3.63; N, 7.77; S, 8.87. Found: C, 56.51; H, 3.41; N, 7.57; S, 8.62%. Ethyl 1‐(4‐nitrophenyl)‐3‐(thiophene‐2‐carbonyl)‐1H‐ pyrazole‐4‐carboxylate (4d): Color: Yellow crystals. Yield: 80% (MeCN). M.p.: 178‐80 °C. FT‐IR (KBr, cm‐1): 1695, 1654 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.16 (t, J = 7 Hz, 3H, CH3CH2O), 4.18 (q, J = 7 Hz, 2H, CH3CH2O), 7.29 – 8.26 (m, 3H, Ar‐H), 8.29 (d, J = 9 Hz, 2H, Ar‐H), 8.40 (d, J = 9 Hz, 2H, Ar‐H), 9.43 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.76, 60.52, 116.39, 120.06, 120.62, 125.24, 128.96, 133.53, 136.79, 136.99, 142.40, 142.75, 146.07, 150.88, 160.85. MS (EI, m/z (%)): 371 (M+, 11), 327 (25), 326 (19), 111 (100). Anal. calcd. for C17H13N3O5S: C, 54.99; H, 3.53; N, 11.32; S, 8.62. Found: C, 54.81; H, 3.41; N, 11.22, S, 8.41%. Ethyl 3‐benzoyl‐1‐phenyl‐1H‐pyrazole‐4‐carboxylate (4e): Color: Yellow crystals. Yield: 65% (EtOH). M.p.: 102‐103 °C. FT‐ IR (KBr, cm‐1): 3116 ν(CH), 1735, 1690 ν(C=O). 1H NMR (300 MHz, CDCl3, δ, ppm):1.16 (t, J = 7 Hz, 3H, CH3CH2O), 4.21 (q, J = 7 Hz, 2H, CH3CH2O), 7.38‐7.91 (m, 10H, Ar‐H), 9.11 (s, 1H, =CH‐ N). MS (EI, m/z (%)): 320 (M+, 25), 319 (20), 105 (100), 77 (75). Anal. calcd. for C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C, 70.91; H, 4.91; N, 8.42%. Ethyl 3‐benzoyl‐1‐(p‐tolyl)‐1H‐pyrazole‐4‐carboxylate (4f): Color: Colorless crystals. Yield: 75% (EtOH). M.p.: 148‐150 °C. FT‐IR (KBr, cm‐1): 1710, 1669 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.04 (t, J = 7 Hz, 3H, CH3CH2O), 2.35 (s, 3H, Ar‐CH3), 4.10 (q, J = 7 Hz, 2H, CH3CH2O), 7.33‐7.91 (m, 9H, Ar‐ H), 9.17 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.6, 20.4, 60.2, 115.3, 119.3, 128.7, 129.4, 129.9, 131.9, 133.8, 136.2, 136.3, 137.4, 150.5, 161.1, 189.2. MS (EI, m/z (%)): 334 (M+, 28), 289 (17), 105 (100), 91 (15), 77 (71). Anal. calcd. for 104 Hassaneen and Shawali / European Journal of Chemistry 4 (2) (2013) 102‐109 C20H18N2O3 (334.38): C, 71.84; H, 5.43; N, 8.38. Found: C, 71.71; H, 5.31; N, 8.22%. Ethyl 3‐benzoyl‐1‐(4‐chlorophenyl)‐1H‐pyrazole‐4‐ carboxylate (4g): Color: Colorless crystals. Yield: 75% (EtOH). M.p.: 148‐150 °C. FT‐IR (KBr, cm‐1): 3116 ν(CH), 1709, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.09 (t, J = 7 Hz, 3H, CH3CH2O), 4.15 (q, J = 7 Hz, 2H, CH3CH2O), 7.33‐8.01 (m, 9H, Ar‐H), 9.20 (s, 1H, =CH‐N). MS (EI, m/z (%)): 356 (M++2, 10), 354 (M+, 31), 309 (21), 138 (10), 105 (100), 77 (83). Anal. calcd. for C19H15ClN2O3: C, 64.32; H, 4.26; N, 7.90. Found: C, 64.11; H, 4.22; N, 7.82%. Ethyl 3‐(2‐naphthoyl)‐1‐phenyl‐1H‐pyrazole‐4‐carboxylate (4h): Color: Yellow crystals. Yield: 73% (EtOH). M.p.: 122‐124 °C. FT‐IR (KBr, cm‐1): 1716, 1678 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 0.97 (t, J = 7 Hz, 3H, CH3CH2O), 4.05 (q, J = 7 Hz, 2H, CH3CH2O), 7.42‐8.01 (m, 11H, Ar‐H), 8.42 (s, 1H, Ar‐H), 9.20 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.57, 60.28, 115.61, 119.35, 123.88, 126.99, 127.60, 127.80, 128.46, 129.06, 129.56, 131.62, 131.83, 132.04, 132.48, 133.68, 135.28, 138.36, 150.90, 161.23, 189.35. MS (EI, m/z (%)): 370 (M+, 52), 341 (11), 325 (29), 297 (12), 155 (76), 127 (100), 104 (22), 77 (49). Anal. calcd. for C23H18N2O3: C, 74.58; H, 4.90; N, 7.56. Found: C, 74.32; H, 4.71; N, 7.33%. Ethyl 3‐(2‐naphthoyl)‐1‐(p‐tolyl)‐1H‐pyrazole‐4‐carboxylate (4i): Color: Yellow crystals. Yield: 80% (EtOH). M.p.: 115‐116 °C. FT‐IR (KBr, cm‐1): 1718, 1685 ν(C=O).1H NMR (300 MHz, CDCl3, δ, ppm):0.97 (t, J = 7 Hz, 3H, CH3CH2O), 2.41 (s, 3H, Ar‐ CH3), 4.01 (q, J = 7 Hz, 2H, CH3CH2O), 7.42‐8.08 (m, 10H, Ar‐H), 8.42 (s, 1H, Ar‐H), 9.11 (s, 1H, =CH‐N). MS (EI, m/z (%)): 384 (M+, 60), 383 (42), 155 (70), 127 (100), 91 (26). Anal. calcd. for C24H20N2O3: C, 74.98; H, 5.24; N, 7.29. Found: C, 75.02; H, 5.01; N, 7.44%. Ethyl 3‐(2‐naphthoyl)‐1‐(4‐chlorophenyl)‐1H‐pyrazole‐4‐ carboxylate (4j): Color: Colorless crystals. Yield: 75% (MeCN). M.p.: 132‐134 °C. FT‐IR (KBr, cm‐1): 1701, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 0.95 (t, J = 7 Hz, 3H, CH3CH2O), 4.01 (q, J = 7 Hz, 2H, CH3CH2O), 7.52‐8.04 (m, 10H, Ar‐H), 8.41 (s, 1H, Ar‐H), 9.17 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.58, 60.35, 115.80, 120.81, 123.83, 127.06, 127.64, 128.50, 129.14, 129.49, 129.65, 131.85, 132.20, 132.29, 132.45, 133.60, 135.32, 137.20, 151.06, 161.13, 189.23. MS (EI, m/z (%)): 406 (M++2, 17), 404 (M+, 44), 359 (29), 249 (17), 154 (51), 138 (22), 127 (100). Anal. calcd. for C23H17ClN2O3: C, 68.23; H, 4.23; N, 6.92. Found: C, 68.11; H, 4.11; N, 6.72%. Ethyl 3‐(2‐naphthoyl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐ carboxylate (4k): Color: Yellow crystals. Yield: 80% (DMF). M.p.: 200‐202 °C. FT‐IR (KBr, cm‐1): 1701, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 0.98 (t, J = 7 Hz, 3H, CH3CH2O), 4.04 (q, J = 7 Hz, 2H, CH3CH2O), 7.59‐8.40 (m, 10H, Ar‐H), 8.43 (s, 1H, Ar‐H), 9.40 (s, 1H, =CH‐N). MS (EI, m/z (%)): 415 (M+, 47), 370 (18), 260 (14), 155 (82), 127 (100), 77 (18). Anal. calcd. for C23H17N3O5: C, 66.50; H, 4.13; N, 10.12. Found: C, 66.71; H, 4.01; N, 10.21%. (E)‐Ethyl 1‐phenyl‐3‐styryl‐1H‐pyrazole‐4‐carboxylate (5a): Color: Pale yellow crystals. Yield: 73% (EtOH). M.p.: 104‐106 °C. FT‐IR (KBr, cm‐1): 3128 ν(CH), 1705 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.32 (t, J = 7 Hz, 3H, CH3CH2O), 4.28 (q, J = 7 Hz, 2H, CH3CH2O), 7.28‐7.95 (m, 12H, Ar‐H, HC=CH), 8.95 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.40, 60.27, 113.52, 117.86, 119.27, 126.81, 127.58, 128.53, 129.04, 129.73, 132.11, 132.55, 136.49, 138.85, 150.23, 162.73. MS (EI, m/z (%)): 318 (M+, 94), 317 (100), 289 (16), 271 (22), 245 (31), 140 (11), 115 (14), 77 (92). Anal. calcd. for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.61; H, 5.82; N, 8.61%. Ethyl 3‐(furan‐2‐yl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐ carboxylate (5b): Color: Yellow crystals. Yield: 78% (DMF). M.p.: 198‐200 °C. FT‐IR (KBr, cm‐1): 3124 ν(CH), 1686 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.30 (t, J = 7 Hz, 3H, CH3CH2O), 4.3 (q, J = 7 Hz, 2H, CH3CH2O), 6.6 (m, 1H, furan‐H), 7.38 (m, 1H, furan‐H), 7.79 (m, 1H, furan‐H), 8.33 (d, J = 9 Hz, 2H, Ar‐H), 8.36 (d, J = 9 Hz, 2H, Ar‐H), 9.20 (s, 1H, =CH‐N). MS (EI, m/z (%)): 327 (M+, 100), 299 (14), 282 (47), 270 (19), 255 (15), 236 (25), 103 (12). Anal. calcd. for C16H13N3O5: C, 58.72; H, 4.00; N, 12.84. Found: C, 58.91; H, 4.12; N, 12.60%. Ethyl 1‐(4‐nitrophenyl)‐3‐(thiophen‐2‐yl)‐1H‐pyrazole‐4‐ carboxylate (5c): Color: Golden yellow crystals. Yield: 82% (AcOH). M.p.: 178‐180 °C. FT‐IR (KBr, cm‐1): 3120 ν(CH), 1718 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.30 (t, J = 7 Hz, 3H, CH3CH2O), 4.26 (q, J = 7 Hz, 2H, CH3CH2O), 7.14 (m, 1H, thiophene‐H), 7.61 (m, 1H, thiophene‐H), 8.04 (m, 1H, thiophene‐H), 8.29 (d, J = 9 Hz, 2H, Ar‐H), 8.32 (d, J = 9 Hz, 2H, Ar‐H), 9.15 (s, 1H, =CH‐N). MS (EI, m/z (%)): 343 (M+, 100), 315 (21), 298 (54), 252 (33), 120 (13). Anal. calcd. for C16H13N3O4S: C, 55.98; H, 3.82; N, 12.24; S, 9.32. Found: C, 55.71; H, 3.62; N, 12.01; S, 9.41%. Diethyl 1‐(4‐nitrophenyl)‐1H‐pyrazole‐3, 4‐dicarboxylate (5d): Color: Pale yellow crystals. Yield: 82% (EtOH). M.P.: 148‐ 150 °C. FT‐IR (KBr, cm‐1): 3133 ν(CH), 1743, 1702 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.25‐133 (2t, J = 7 Hz, 6H, 2 CH3CH2O), 4.24‐4.35 (2q, J = 7 Hz, 4H, 2 CH3CH2O), 8.14 (d, J = 9 Hz, 2H, Ar‐H), 8.36 (d, J = 9 Hz, 2H, Ar‐H), 9.23 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 14.13, 14.24, 61.15, 62.05, 116.47, 120.23, 125.53, 133.42, 142.80, 145.92, 146.39, 161.10, 161.79. Anal. calcd. for C15H15N3O6 (333.30): C, 54.05; H, 4.54; N, 12.61. Found: C, 54.21; H, 4.33; N, 12.41%. 2.2.3. Synthesis of 2‐aryl‐7‐substituted‐2H‐pyrazolo[3,4‐d] pyridazin‐4(5H)‐ones (7a‐k) A mixture of the appropriate ethyl 1‐aryl‐3‐substituted‐1H‐ pyrazole‐4‐carboxylate 4a‐k (3 mmol) and hydrazine hydrate (13 g, 3 mmol) in ethanol (30 mL) was refluxed 1 h and then cooled. The product that was separated was filtered off and crystallized from the appropriate solvent to give the corresponding product 7. The compounds prepared together with their physical constants are listed below (Scheme 2). 7‐Methyl‐2‐(4‐nitrophenyl)‐2H‐pyrazolo[3,4‐d]pyridazin‐ 4(5H)‐one (7a): Color: Colorless crystals. Yield: 78% (DMF). M.p.: 358‐360 °C. FT‐IR (KBr, cm‐1): 3259 ν(NH), 1666 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.50 (s, 3H, CH3), 8.20 (d, J = 6 Hz, 2H, Ar‐H), 8.42 (d, J = 6 Hz, 2H, Ar‐H), 9.50 (s, 1H, =CH‐ N), 11.95 (s, 1H, NH). MS (EI, m/z (%)): 271 (M+, 100), 213 (21), 149 (14), 127 (20), 103 (16). Anal. calcd. for C12H9N5O3: C, 53.14; H, 3.34; N, 25.82. Found: C, 52.91; H, 3.12; N, 25.51%. 2‐Phenyl‐7‐(thiophen‐2‐yl)‐2H‐pyrazolo[3,4‐d]pyridazin‐ 4(5H)‐one (7b): Color: Colorless crystals. Yield: 81% (DMF). M.p.: 228‐230 °C. FT‐IR (KBr, cm‐1): 3240 ν(NH), 1684 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.21‐8.34 (m, 9H, Ar‐H, NH), 9.43 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 78.91, 116.28, 120.41, 120.91, 127.85, 127.93, 128.11, 129.80, 135.11, 136.98, 138.68, 144.1, 157.90. MS (EI, m/z (%)): 294 (M+, 100), 237 (26), 151 (16), 149 (12), 77 (83). Anal. calcd. for C15H10N4OS: C, 61.22; H, 3.43; N, 19.04; S, 10.87. Found: C, 61.01; H, 3.11; N, 18.73; S, 10.61%. 2‐(4‐Chlorophenyl)‐7‐(thiophen‐2‐yl)‐2H‐pyrazolo[3,4‐d] pyridazin‐4(5H)‐one (7c): Color: Pale yellow crystals. Yield: 83% (DMF). M.p.: 272‐274 °C. FT‐IR (KBr, cm‐1): 3230 ν(NH), 1684 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.2 (m, 1H, Ar‐H), 7.50‐8.10 (m, 6H, Ar‐H, NH), 8.34 (m, 1H, Ar‐H), 9.43 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 78.91, 116.28, 120.41, 120.91, 127.85, 127.93, 128.11, 129.80, 135.11, 136.98, 138.68, 144.1, 157.90. MS (EI, m/z (%)): 330 (M++2, 38), 328 (M+, 100), 271 (19), 138 (12), 111 (61). Anal. calcd. for C15H9ClN4OS: C, 54.81; H, 2.76; N, 17.04; S, 9.73. Found: C, 54.61; H, 2.56; N, 17.34; S, 9.51%. 2‐(4‐Nitrophenyl)‐7‐(thiophen‐2‐yl)‐2H‐pyrazolo[3,4‐d] pyridazin‐4(5H)‐one (7d): Color: Yellow crystals. Yield: 80% (DMF). M.P.: >360 °C. FT‐IR (KBr, cm‐1): 3336 ν(NH), 1682 ν(C=O). MS (EI, m/z (%)): 339 (M+, 100), 338 (37), 132 (16), 111 (21), 103 (12), 83 (14). Anal. calcd. for C15H9N5O3S: C, 53.10; H, 2.67; N, 20.64; S, 9.43. Found: C, 52.81; H, 2.41; N, 20.51; S, 9.61%. Hassaneen and Shawali / European Journal of Chemistry 4 (2) (2013) 102‐109 105 4(7) R Ar a CH3 4-NO2-C6H4 b 2-Thinyl C6H5 c 2-Thinyl 4-Cl-C6H4 d 2-Thinyl 4-NO2-C6H4 e C6H5 C6H5 f C6H5 4-CH3-C6H4 g C6H5 4-Cl-C6H4 h 2-Naphthyl C6H5 i 2-Naphthyl 4-CH3-C6H4 j 2-Naphthyl 4-Cl-C6H4 k 2-Naphthyl 4-NO2-C6H4 Scheme 2 2,7‐Diphenyl‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (7e): Color: Colorless crystals. Yield: 85% (DMF). M.p.: 228‐230 °C. FT‐IR (KBr, cm‐1): 3230 ν(NH), 1671 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.49‐8.34 (m, 10H, Ar‐H), 9.45 (s, 1H, =CH‐ N), 12.54 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 117, 120.8, 127.8, 128.0, 128.7, 129.1, 129.7, 130.1, 135.0, 139.0, 139.01, 145.4, 158.4. MS (EI, m/z (%)): 288 (M+, 100), 211 (28), 155 (12), 128 (12), 77 (96). Anal. calcd. for C17H12N4O: C, 70.82; H, 4.20; N, 19.43. Found: C, 70.55; H, 4.01; N, 19.10%. 7‐Phenyl‐2‐(p‐tolyl)‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (7f): Color: Colorless crystals. Yield: 84% (DMF). M.p.: 262‐264 °C. FT‐IR (KBr, cm‐1): 3199 ν(NH), 1667 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.49 (s, 3H, Ar‐CH3), 7.41‐ 8.32 (m, 9H, Ar‐H), 9.37 (s, 1H, =CH‐N), 12.51 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 20.5, 116.5, 120.2, 120.8, 127.2, 127.5, 128.4, 129.3, 130.0, 133.7, 136.4, 138.4, 144.9, 158.1. MS (EI, m/z (%)): 302 (M+, 100), 301 (64), 245 (16), 210 (17), 185 (12), 129 (13), 91 (77), 77 (33). Anal. calcd. for C18H14N4O: C, 71.51; H, 4.67; N, 18.53. Found: C, 71.41; H, 4.52; N, 18.22%. 2‐(4‐Chlorophenyl)‐7‐phenyl‐2H‐pyrazolo[3,4‐d]pyridazin‐ 4(5H)‐one (7g): Color: Pale yellow crystals. Yield: 85% (DMF). M.p.: 296‐298 °C. FT‐IR (KBr, cm‐1): 3221 ν(NH), 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.3‐8.2 (m, 9H, Ar‐H), 9.41 (s, 1H, =CH‐N), 12.4 (s, 1H, NH). MS (EI, m/z (%)): 324 (M++2, 24), 322 (M+, 100), 321 (27), 211 (29), 185 (13), 127 (14), 111 (36), 77 (23). Anal. calcd. for C17H11ClN4O: C, 63.26; H, 3.44; N, 17.36. Found: C, 63.11; H, 3.22; N, 17.61%. 7‐(Naphthalen‐2‐yl)‐2‐phenyl‐2H‐pyrazolo[3,4‐d]pyridazin‐ 4(5H)‐one (7h): Color: Colorless crystals. Yield: 85% (DMF). M.p.: 259‐261 °C. FT‐IR (KBr, cm‐1): 3210 ν(NH), 1675 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.51‐8.33 (m, 11H, Ar‐H), 9.04 (s, 1H, Ar‐H), 9.46 (s, 1H, =CH‐N), 12.61 (s, 1H, NH). MS (EI, m/z (%)): 338 (M+, 100), 337 (15), 261 (16), 176 (12), 127 (16), 77 (64). Anal. calcd. for C21H14N4O: C, 74.54; H, 4.17; N, 16.56. Found: C, 74.31; H, 3.92; N, 16.62%. 7‐(Naphthalen‐2‐yl)‐2‐(p‐tolyl)‐2H‐pyrazolo[3,4‐d] pyridazin‐4(5H)‐one (7i): Color: Colorless crystals. Yield: 85% (DMF). M.p.: 280‐282 °C. FT‐IR (KBr, cm‐1): 3212 ν(NH), 1677 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.4 (s, 3H, Ar‐ CH3), 7.41‐8.31 (m, 10H, Ar‐H), 9.1 (s, 1H, Ar‐H), 9.33 (s, 1H, =CH‐N), 12.55 (s, 1H, NH). MS (EI, m/z (%)): 352 (M+, 100), 351 (20), 295 (11), 261 (11), 176 (16), 127 (9), 91 (40). Anal. calcd. for C22H16N4O: C, 74.98; H, 4.58; N, 15.90. Found: C, 74.72; H, 4.33; N, 15.70%. 2‐(4‐Chlorophenyl)‐7‐(naphthalen‐2‐yl)‐2H‐pyrazolo[3,4‐d] pyridazin‐4(5H)‐one (7j): Color: Colorless crystals. Yield: 82% (DMF). M.p.: 286‐288 °C. FT‐IR (KBr, cm‐1): 3215 ν(NH), 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.71‐8.31 (m, 10H, Ar‐H), 9.10 (s, 1H, Ar‐H), 9.41 (s, 1H, =CH‐N), 12.59 (s, 1H, NH). MS (EI, m/z (%)): 374 (M++2, 36), 372 (M+, 100), 371 (26), 261 (14), 176 (14), 151 (10), 127 (18), 111 (27). Anal. calcd. for C21H13ClN4O: C, 67.66; H, 3.51; N, 15.03. Found: C, 67.41; H, 3.21; N, 14.88%. 7‐(Naphthalen‐2‐yl)‐2‐(4‐nitrophenyl)‐2H‐pyrazolo[3,4‐d] pyridazin‐4(5H)‐one (7k): Color: Yellow crystals. Yield: 83% (DMF). M.p.: 354‐356 °C. FT‐IR (KBr, cm‐1): 3320 ν(NH), 1680 ν(C=O). MS (EI, m/z (%)): 383 (M+, 100), 382 (35), 279 (9), 261 (15), 168 (12), 127 (17). Anal. calcd. for C21H13N5O3: C, 65.79; H, 3.42; N, 18.27. Found: C, 65.71; H, 3.35; N, 18.04%. 2.2.4. Synthesis of (E)‐ethyl 3‐(3‐(dimethylamino)acryloyl)‐ 1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (8) To a solution of ethyl 3‐acetyl‐1‐(4‐nitrophenyl)‐1H‐ pyrazole‐4‐carboxylate 4a, (6 g, 20 mmol) in dioxane (50 mL), DMF‐DMA (2.36 g, 20 mol) was added. The reaction mixture was refluxed for 6 h and then cooled to room temperature. The solid that precipitated was filtered off and crystallized from acetonitrile to give the enaminone 8 (Scheme 3). Color: Yellow crystals. Yield: 75% (DMF). M.p.: 198‐200 °C. FT‐IR (KBr, cm‐1): 1700 ν(C=O), 1647 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.27 (t, J = 7 Hz, 3H, CH3CH2O), 3.14 (s, 6H, (CH3)2N), 4.22 (q, J = 7 Hz, 2H, CH3CH2O), 6.27 (d, J = 13 Hz, 1H, =CH‐CO), 8.0 (d, J = 7 Hz, 2H, Ar‐H), 8.21 (d, J = 7 Hz, 2H, Ar‐H), 8.76 (d, J = 13 Hz, 1H, =CH‐N(CH3)2), 9.15 (s, 1H, =CH‐N). MS (EI, m/z (%)): 358 (M+, 31), 341 (27), 295 (100), 260 (49), 245 (19), 199 (16), 180 (16), 138 (20). Anal. calcd. for C17H18N4O5 (358.35): C, 56.98; H, 5.06; N, 15.63. Found: C, 56.71; H, 4.92; N, 15.41%. 9 R’ Ar 10 R’ Ar a C6H5CO C6H5 a C6H5CH=CH C6H5 b 2-Naphthoyl C6H5 b 2-Furyl 4-NO2-C6H4 c CH3CO C6H5 c 2-Thienyl 4-NO2-C6H4 Scheme 3 2.2.5. Synthesis of ethyl 3‐(1‐aryl‐3‐substituted‐1H‐pyrazole‐ 4‐carbonyl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylates (9a‐c, 10a‐c) To a mixture of the appropriate hydrazonoyl halide 2e, 2h, 2l and 3a‐c (3 mmol) and (E)‐ethyl 3‐(3‐(dimethylamino) acryloyl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylate 8 (1.07 g, 3 mmol) in dioxane was added triethylamine (0.6 g, 6 mmol) and the mixture was refluxed for 5 h, then cooled. The triethylamine hydrochloride that precipitated was filtered off. The filtrate was distilled under reduced pressure and the 106 Hassaneen and Shawali / European Journal of Chemistry 4 (2) (2013) 102‐109 residue left was triturated with ethanol (15 mL) and the solid that produced was collected and crystallized from the appropriate solvent to give the corresponding bis‐3,4'‐ pyrazolyl derivative. The compounds prepared together with their physical constants are listed below (Scheme 3). Ethyl 3‐(3‐benzoyl‐1‐phenyl‐1H‐pyrazole‐4‐carbonyl)‐1‐(4‐ nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (9a): Color: Golden yellow crystals. Yield: 72% (MeCN). M.p.: 166‐168°C. FT‐IR (KBr, cm‐1): 1715, 1697, 1662 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.21 (t, J = 7 Hz, 3H, CH3CH2O), 4.22 (q, J = 7 Hz, 2H, CH3CH2O), 7.64‐8.30 (m, 14H, Ar‐H), 9.20 (s, 1H, =CH‐ N), 9.37 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.8, 60.5, 112.4, 116.5, 119.4, 119.8, 123.6, 125.1, 128.1, 128.7, 129.4, 129.7, 133.6, 133.7, 136.0, 136.7, 138.4, 142.5, 145.9, 151.3, 180.0, 188.9. MS (EI, m/z (%)): 535 (M+, 18), 489 (9), 385 (8), 275 (13), 105 (82), 77 (100). Anal. calcd. for C29H21N5O6: C, 65.04; H, 3.95; N, 13.08. Found: C, 64.81; H, 3.77; N, 12.79. Ethyl 3‐(3‐(2‐naphthoyl)‐1‐phenyl‐1H‐pyrazole‐4‐carbonyl)‐ 1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (9b): Color: Pale yellow crystals. Yield: 80% (DMF). M.p.: 258‐260 °C. FT‐IR (KBr, cm‐1): 1732, 1690, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.17 (t, J = 7 Hz, 3H, CH3CH2O), 4.14 (q, J = 7 Hz, 2H, CH3CH2O), 7.46‐8.05 (m, 15H, Ar‐H), 8.46 (s, 1H, Ar‐H), 9.23 (s, 1H, =CH‐N), 9.44 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.9, 60.5, 116.4, 119.8, 120.9, 121.0123.7, 123.9, 124.7, 126.9, 127.5, 128.1, 128.4, 129.0, 129.7, 129.8, 131.8, 132.6, 133.4, 133.7, 135.2, 138.4, 142.2, 145.6, 151.4, 151.7, 160.7, 180.1, 180.9. MS (EI, m/z (%)): 585 (M+, 42), 584 (24), 325 (14), 270 (13), 155 (69), 154 (53), 127 (100), 104 (23), 77 (36). Anal. calcd. for C33H23N5O6: C, 67.69; H, 3.96; N, 11.96. Found: C, 67.39; H, 3.71; N, 11.61. Ethyl 3‐(3‐acetyl‐1‐phenyl‐1H‐pyrazole‐4‐carbonyl)‐1‐(4‐ nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (9c): Color: Golden yellow crystals. Yield: 72% (MeCN). M.p.: 208‐210 °C. FT‐IR (KBr, cm‐1): 1714, 1693, 1662 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.22 (t, J = 7 Hz, 3H, CH3CH2O), 2.5 (s, 3H, CH3CO), 4.22 (q, J = 7 Hz, 2H, CH3CH2O), 7.46‐8.40 (m, 9H, Ar‐ H), 9.34 (s, 1H, =CH‐N), 9.39 (s, 1H, =CH‐N). MS (EI, m/z (%)): 473 (M+, 50), 386 (74), 372 (32), 213 (44), 171 (52), 103 (26), 77 (100). Anal. calcd. for C24H19N5O6: C, 60.89; H, 4.05; N, 14.79. Found: C, 60.52; H, 3.81; N, 14.41%. (E)‐Ethyl 1‐(4‐nitrophenyl)‐3‐(1‐phenyl‐3‐styryl‐1H‐ pyrazole‐4‐carbonyl)‐1H‐pyrazole‐4‐carboxylate (10a): Color: Pale yellow crystals. Yield: 75% (MeCN). M.p.: 232‐234 °C. FT‐ IR (KBr, cm‐1): 1710, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.17 (t, J = 7 Hz, 3H, CH3CH2O), 4.30 (q, J = 7 Hz, 2H, CH3CH2O), 7.41‐8.41 (m, 16H, Ar‐H, HC=CH), 9.0 (s, 1H, =CH‐N), 9.6 (s, 1H, =CH‐N). MS (EI, m/z (%)): 533 (M+, 67), 532 (56), 321 (56), 260 (28), 245 (31), 91 (25), 77 (100). Anal. calcd. for C30H23N5O5: C, 67.54; H, 4.35; N, 13.13. Found: C, 67.31; H, 4.21; N, 13.01%. Ethyl 3‐(3‐(furan‐2‐yl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐ carbonyl)‐1‐(4‐nitrophenyl)‐1H‐pyrazole‐4‐carboxylate (10b): Color: Brown crystals. Yield: 70% (EtOH). M.p.: 148‐150 °C. FT‐ IR (KBr, cm‐1): 1715, 1671 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.16 (t, J = 7 Hz, 3H, CH3CH2O), 4.19 (q, J = 7 Hz, 2H, CH3CH2O), 6.68‐8.40 (m, 11H, Ar‐H), 9.34(s, 1H, =CH‐N), 9.48 (s, 1H, =CH‐N). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 13.8, 60.5, 111.7, 113.8, 116.1, 119.5, 119.6, 120.0, 120.9, 121.0, 121.3, 125.3, 133.4, 137.2, 142.7, 144.1, 145.7, 145.9, 152.4, 161.0, 181.2. MS (EI, m/z (%)): 542 (M+, 93), 541 (45), 374 (15), 249 (17), 236 (64), 235 (48), 149 (15), 103 (56), 102 (46), 76 (100). Anal. calcd. for C26H18N6O8: C, 57.57; H, 3.34; N, 15.49. Found: C, 57.61; H, 3.21; N, 15.12%. Ethyl 1‐(4‐nitrophenyl)‐3‐(1‐(4‐nitrophenyl)‐3‐(thiophen‐2‐ yl)‐1H‐pyrazole‐4‐carbonyl)‐1H‐pyrazole‐4‐carboxylate (10c): Color: Brown crystals. Yield: 71% (EtOH). M.p.: 236‐238 °C. FT‐ IR (KBr, cm‐1): 1714, 1666 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.19 (t, J = 7 Hz, 3H, CH3CH2O), 4.22 (q, J = 7 Hz, 2H, CH3CH2O), 6.96‐8.30 (m, 11H, Ar‐H), 9.18 (s, 1H, =CH‐N), 9.61 (s, 1H, =CH‐N). MS (EI, m/z (%)): 558 (M+, 23), 557 (17), 409 (26), 308 (100), 111 (80), 93 (20). Anal. calcd. for C26H18N6O7S: C, 55.92; H, 3.25; N, 15.05;S, 5.73. Found: C, 55.71; H, 3.01; N, 14.79; S, 5.55%. 2.2.6. Synthesis of 2‐(4‐nitrophenyl)‐7‐(1‐phenyl‐3‐ substituted‐1H‐pyrazol‐4‐yl)‐2H‐pyrazolo[3,4‐d]pyridazin‐ 4(5H)‐ones (11a‐c, 13a‐c) General procedure: A mixture of the appropriate ethyl 3‐(1‐ aryl‐3‐substituted‐1H‐pyrazole‐4‐carbonyl)‐1‐(4‐nitrophenyl)‐ 1H‐pyrazole‐4‐carboxylate 9(10) (3 mol) and hydrazine hydrate (5 mL, 99%) was refluxed for 3 h and then cooled. The solid that precipitated was collected, washed with hot ethanol and finally crystallized from the appropriate solvents. The compounds 11a‐c and 13a‐c prepared together with their physical constants are listed below (Scheme 4 and 5). N N O N N R O NO2 COOEt N N NHN N N R O O NO2 N N N N N N R COOEt NO2 H2NNH2.H2O 9 11 12 9(11) R a C6H5 b 2-Naphthyl c CH3 Scheme 4 7‐(3‐Benzoyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐2‐(4‐nitrophenyl)‐ 2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (11a): Color: Yellow crystals. Yield: 82% (DMF). M.p.: 308‐310 °C. FT‐IR (KBr, cm‐1): 3242 ν(NH), 1695, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.51‐8.25 (m, 14H, Ar‐H), 9.22 (s, 1H, =CH‐N), 9. 14 (s, 1H, =CH‐N), 12.41 (s, 1H, NH). MS (EI, m/z (%)): 503 (M+, 18), 502 (36), 367 (54), 311 (55), 252 (54), 154 (64), 153 (73), 105 (27), 104 (82), 103 (100). Anal. calcd. for C27H17N7O4: C, 64.41; H, 3.40; N, 19.47. Found: C, 64.13; H, 3.11; N, 19.11%. 7‐(3‐(2‐Naphthoyl)‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐2‐(4‐nitro phenyl)‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (11b): Color: Yellow crystals. Yield: 85% (DMF). M.p.: 302‐304 °C. FT‐IR (KBr, cm‐1): 3240 ν(NH), 1697, 1665 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.40‐8.24 (m, 15H, Ar‐H), 8.70 (s, 1H, Ar‐H), 9.16 (s, 1H, =CH‐N), 9.55 (s, 1H, =CH‐N), 12.41 (s, 1H, NH). 13C NMR (75 MHz, DMSO‐d6, δ, ppm): 116.4, 117.8, 119.5, 120.4, 120.6, 124.6, 124.7, 127, 127.6, 128.3, 129.0, 129.7, 1219.8, 132.0, 132.6, 133.1, 134.0, 135.2, 138.9, 142.7, 145.5, 146.2, 149.4, 157.5, 180.1. MS (EI, m/z (%)): 553 (M+, 56), 552 (52), 380 (13), 277 (15), 276 (13), 127 (100), 77 (54). Anal. calcd. for C31H19N7O4: C, 67.27; H, 3.46; N, 17.71. Found: C, 67.31; H, 3.11; N, 17.55%. Hassaneen and Shawali / European Journal of Chemistry 4 (2) (2013) 102‐109 107 N N O N N Ar COOEt NO2 R' N N NHN N N Ar O NO2 R' H2NNH2.H2O 10 13 10(13) R’ Ar a C6H5CH=CH C6H5 b 2-Furyl 4-NO2-C6H4 c 2-Thienyl 4-NO2-C6H4 Scheme 5 7‐(3‐Acetyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐2‐(4‐nitrophenyl)‐2H‐ pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (11c): Color: Pale yellow crystals. Yield: 81% (DMF). M.p.: 322‐324 °C. FT‐IR (KBr, cm‐1): 3255 ν(NH), 1700, 1670 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.4 (s, 3H, CH3CO), 7.69‐8.52 (m, 9H, Ar‐H), 9.44 (s, 1H, =CH‐N), 9.64 (s, 1H, =CH‐N), 12.60 (s, 1H, NH). MS (EI, m/z (%)): 441 (M+, 44), 440 (25), 398 (17), 397 (51), 142 (49), 104 (34), 77 (100). Anal. calcd. for C22H15N7O4: C, 59.86; H, 3.43; N, 22.21. Found: C, 59.81; H, 3.22; N, 22.01%. (E)‐2‐(4‐Nitrophenyl)‐7‐(1‐phenyl‐3‐styryl‐1H‐pyrazol‐4‐yl)‐ 2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (13a): Color: Colorless crystals. Yield: 79% (DMF). M.p.: 256‐258 °C. FT‐IR (KBr, cm‐1): 3359 ν(NH), 1688 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 7.41‐8.41 (m, 17H, Ar‐H, HC=CH, NH), 9.21 (s, 1H, =CH‐ N), 9.72 (s, 1H, =CH‐N). MS (EI, m/z (%)): 501 (M+, 72), 500 (37), 424 (100), 378 (42), 250 (19), 77 (100). Anal. calcd. for C28H19N7O3: C, 67.06; H, 3.82; N, 19.55. Found: C, 66.99; H, 3.62; N, 19.77%. 7‐(3‐(Furan‐2‐yl)‐1‐(4‐nitrophenyl)‐1H‐pyrazol‐4‐yl)‐2‐(4‐ nitrophenyl)‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (13b): Color: Yellow crystals. Yield: 77% (DMF). M.p.: > 360 °C. FT‐IR (KBr, cm‐1): 3280 ν(NH), 1692 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 6.6 (m, 1H, Ar‐H), 7.11 (m, 1H, Ar‐H), 8.27‐ 8.46 (m, 10H, Ar‐H, NH), 9.39 (s, 1H, =CH‐N), 9.77 (s, 1H, =CH‐ N). MS (EI, m/z (%)): 510 (M+, 100), 509 (56), 481 (17), 388 (16), 373 (23), 255 (21), 217 (22), 195 (25), 103 (30), 76 (54). Anal. calcd. for C24H14N8O6 (510.43): C, 56.48; H, 2.76; N, 21.95. Found: C, 56.19; H, 2.51; N, 22.10%. 2‐(4‐Nitrophenyl)‐7‐(1‐(4‐nitrophenyl)‐3‐(thiophen‐2‐yl)‐ 1H‐pyrazol‐4‐yl)‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (13c): Color: Pale yellow crystals. Yield: 80% (DMF). M.P.: 258‐260 °C. FT‐IR (KBr, cm‐1): 3348 ν(NH), 1686 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 6.82‐8.23 (m, 12H, Ar‐H, NH), 9.11 (s, 1H, =CH‐N), 9.62 (s, 1H, =CH‐N). MS (EI, m/z (%)): 526 (M+, 100), 481 (76), 322 (38), 122 (38). Anal. calcd. for C24H14N8O5S (526.43): C, 54.76; H, 2.68; N, 21.59; S, 6.08. Found: C, 54.44; H, 2.40; N, 21.81; S, 5.82%. 2.2.7. Synthesis of (E)‐7‐(2‐(dimethylamino)vinyl)‐2‐(4‐nitro phenyl)‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one (14) To a solution of 7‐methyl‐2‐(4‐nitrophenyl)‐2H‐ pyrazolo[3,4‐d]pyridazin‐4(5H)‐one, 7a (2.71 g, 0.01 mol) in dioxane (50 mL), was added dimethylformamide‐ dimethylacetal (1.2 g, 0.01 mol). The reaction mixture was refluxed for 10 h and then cooled to room temperature. The solid that was formed was filtered off and crystallized to give the enamine 14 (Scheme 6). Color: Pale yellow. Yield: 80% (DMF). M.p.: 278‐280 °C. FT‐IR (KBr, cm‐1): 3255 ν(NH), 1660 ν(C=O). 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.86 (s, 6H, (CH3)2N), 7.85‐8.43 (m, 6H, Ar‐H, HC=CH), 9.12 (s, 1H, =CH‐N), 13.12 (s, 1H, NH). MS (EI, m/z (%)): 326 (M+, 35), 326 (31), 271 (97), 270 (100), 240 (45), 214 (52), 114 (45), 172 (31), 121 (21), 110 (24), 89 (34). Anal. calcd. for C15H14N6O3: C, 55.21; H, 4.32; N, 25.75. Found: C, 55.01; H, 4.40; N, 25.55%. 2.2.8. Alternate synthesis of 11a and 13c To an equimolar mixture of the enamine 14 and the hydrazonoyl chloride 2l (5 mmol each) in dioxane (50 mL) was added triethylamine (0.6 g, 5 mmol) and the reaction mixture was refluxed for 8 h, then the solvent was distilled under reduced pressure. To the residue left was triturated with ethanol and the solid formed was collected and crystallized from DMF to give a product that proved identical in all respect (M.p., Mixed m.p., IR, 1H NMR and elemental analysis) with 11c obtained above from 9c and hydrazine hydrate.When the above procedure was repeated using the hydrazonoyl chloride 3a in lieu 2l, the product obtained proved to be 13a identical in all respect with that one obtained from reaction of 10a with hydrazine hydrate. 3. Results and discussion The target new enamino ester 1, which has not been reported hitherto, was prepared in this study by reaction of dipropylamine with ethyl propiolate in methanol at room temperature (Scheme 1). Its structure was verified by elemental analysis and spectroscopic methods (IR and NMR) (see Experimental). For example, its 1H NMR spectrum displayed a quartet and triplet signals at δ 1.15 and 4.02 due to the CH3CH2OCO group, two doublet signals at δ 4.42 and 7.36 with coupling constant J = 13 Hz assignable to the two olefinic protons. The latter coupling constant value indicates that the enamino ester prepared exists predominantly in the E‐ configuration. In addition to such signals, the 1H NMR spectrum reveals three signals at δ 0.79 (6H), 1.47 (4H) and 2.97 (4H) assignable to the resonances of the protons of the (CH3CH2CH2)2N‐ moiety. Next, the reactions of the enamino ester 1, as a dipolarophile, with various nitrilimines, generated in situ by dehydrohalogenation of the respective N‐aryl hydrazonoyl halides were examined. Thus, in our hands, reaction of compound 1 with each of compounds 2a‐k in refluxing dioxane in the presence of triethylamine yielded, in each case, a single product that was identified, on the basis of its elemental analysis and spectral (IR, NMR and MS) data as the corresponding ethyl 1‐aryl‐3‐substituted‐1H‐pyrazole‐4‐ carboxylate 4a‐k (Scheme 1). Similar reactions of compound 1 with the halides 3a‐d under the same conditions afforded regioselectively the pyrazole derivatives 5a‐d (Scheme 1). The other possible regio‐ isomeric structure namely ethyl 1‐aryl‐3‐substituted‐1H‐ pyrazole‐5‐carboxylate 6 was discarded. This is because the 1H NMR spectra of the products 4(5) isolated showed in each case a singlet signal in the region δ 8.60– 9.22, which corresponds to H‐5 of the pyrazole ring residue in the products. This assignment is consistent with literature reports which indicate that in pyrazole derivatives, the signal of H‐5 usually appears at δ 8.66‐8.69 whereas that of H‐4 appears at δ 5.81‐5.89 [25]. The formation of compounds 4(5) rather than compound 6 indicates that the studied reaction of compound 1 with compounds 2(3) is regiospecific. To account for the formation of compounds 4(5), it is suggested, as depicted in Scheme 1 that the reaction of compound 1 with each of compounds 2 and 3 proceeds via 1,3‐dipolar cycloaddition of the nitrilimine, derived from compounds 2(3), to the activated double bond in the enamino ester, 1, to give the respective cycloadducts which in turn undergo in situ elimination of dipropylamine to afford compounds 4(5) as the end products. 108 Hassaneen and Shawali / European Journal of Chemistry 4 (2) (2013) 102‐109 Scheme 6 The assigned structures 4 for the isolated products were further confirmed by their chemical reactions. For example, treatment of compounds 4a‐k each with hydrazine hydrate in refluxing ethanol yielded in each case one product whose spectroscopic (MS, IR, NMR) and elemental analysis data were consistent with the structure of the corresponding 2‐aryl‐7‐ substituted‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5H)‐one, 7a‐k (Scheme 2). Condensation of the pyrazole derivative 4a with DMF‐DMA in refluxing dioxane afforded the corresponding enaminone, 8 (Scheme 3). The structure of the latter enaminone was confirmed by its spectral and elemental analyses. For example, its IR spectrum showed C=O bands at ν 1700 and 1647 cm‐1. Its 1H NMR spectrum revealed a singlet signal at δ 3.14 (6H) for the protons of the (CH3)2N‐ group, two characteristic doublets at δ 6.27 (d, 1H) and 8.76 (d, 1H) with coupling constant J = 13 Hz assignable to the two olefinic protons. This coupling constant value indicates that this enaminone, 8, has the indicated trans‐configuration. Similar to the enamino ester 1, the enaminone, 8, reacted with various hydrazonoyl halides 2e, 2h, 2l and 3a‐c in refluxing dioxane in the presence of triethylamine and yielded the corresponding bis‐3,4’‐pyrazolyl ketones, 9a‐c and 10a‐c (Scheme 3). The structures of the latter products were established by their spectral and elemental analysis data (see Experimental). Next, hydrazinolysis of the products 9 was studied to shed some light on its site selectivity as it can theoretically lead to the formation of the products 11 and/or 12 (Scheme 4). When each of compounds 9 was refluxed with hydrazine hydrate in ethanol, it yielded chemoselectively a single product in each case as evidenced by TLC analysis of the crude product. The isolated products proved to be the corresponding 2‐(4‐ nitrophenyl)‐7‐(3‐aroyl‐1‐phenyl‐1H‐pyrazol‐4‐yl)‐2H‐pyra‐ zolo[3,4‐d]pyridazin‐4(5H)‐one, 11, (Scheme 4). The structures of the latter products 11 were established on the basis of their spectral and elemental analysis data (see Experimental). For example, the IR spectra of products 11 revealed two C=O bands near ν 1697 and 1665 cm‐1 in addition to NH band at ν 3240 cm‐1. Their 1H NMR spectra revealed the absence of the triplet and quartet signals characteristic of the ester group, ‐COOCH2CH3. Similar treatment of compounds 10 with hydrazine hydrate in refluxing ethanol afforded the corresponding 2‐(4‐ nitrophenyl)‐7‐(1‐phenyl‐3‐substituted‐1H‐pyrazol‐4‐yl)‐2H‐ pyrazolo[3,4‐d]pyridazin‐4(5H)‐one, 13 (Scheme 5). The structures of the latter products were established by their spectral and elemental analysis data (see Experimental). To provide further evidence for the assigned structures of the products 11 and 13, they were prepared by an unambiguous alternate synthesis (Scheme 6). Thus, treatment of compound 7a with DMF‐DMA in dioxane yielded the corresponding enamine14. Reaction of the latter with each of the hydrazonoyl chlorides 2l and 3a in dioxane in the presence of triethylamine afforded two products that proved identical in all respects with compounds 11c and 13a, prepared from hydrazinolysis of compounds 9c and 10a, respectively (Scheme 4 and 5). 4. Conclusion In summary, ethyl 3‐(dipropylamino)acrylate and C‐acyl nitrilimines proved useful precursors for synthesis of 3,4‐bis‐ (functionalized carbonyl) derivatives of pyrazole 4 and 3,4'‐bis‐ (pyrazolyl) ketones, 9(10). In addition, reaction of 4 with hydrazine hydrate afforded the corresponding pyrazolo[3,4‐ d]pyridazin‐4(5)‐ones, 7. Similar hydrazinolysis of 9(10) proved to be site selective as it yielded the corresponding 7‐ substituted‐2H‐pyrazolo[3,4‐d]pyridazin‐4(5)‐ones, 11(13). References [1]. Shawali, A. S.; Parkanyi, C. J. Heterocycl. Chem. 1980, 17, 833‐854. [2]. Shawali, A. S. Heterocycles 1983, 20, 2239‐2285. [3]. Shawali, A. S. Chem. Rev. 1993, 93, 2731‐2777. [4]. Shawali, A. 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