New 3-amino-5-arylpyridazine-4-carbonitriles have been synthesized by a one-pot three-component reaction of malononitrile with arylglyoxals in the presence of hydrazine hydrate at room temperature in water and ethanol.KEYWORDS Arylglyoxals, arylpyridazines, hydrazine hydrate, one-pot, malononitrile

Ezzati, M

Farajzadeh, S

Khalafy, J

Rimaz, M

English

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A Simple Three-component Synthesis of3-Amino-5-arylpyridazine-4-carbonitrilesJ. Khalafya,*, M. Rimazb, S. Farajzadeha and M. EzzatiaaDepartment of Chemistry, Urmia University, Urmia 57154, Iran.bDepartment of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran.Received 26 December 2012, revised 1 May 2013, accepted 9 June 2013.ABSTRACTNew 3-amino-5-arylpyridazine-4-carbonitriles have been synthesized by a one-pot three-component reaction of malononitrilewith arylglyoxals in the presence of hydrazine hydrate at room temperature in water and ethanol.KEYWORDSArylglyoxals, arylpyridazines, hydrazine hydrate, one-pot, malononitrile.1. IntroductionIn recent years, nitrogen-containing heterocyclic compoundshave been indispensable structural units for both chemists andbiochemists due to their biological and pharmaceutical properties.Among various heterocycles, pyridazines and their annulatedderivatives continue to attract attention due to their wide rangeof interesting biological activities.1The synthesis of pyridazine derivatives2–5 and their pharmaco-logical properties as analgesics,6 insecticidals,7 fungicidals,8–9cardiotonics,10 and bacteriocides11 have been reported, as well asthe synthesis of pyridazine derivatives by reaction of hydrazinewith 1,4-dicarbonyl compounds,12 reaction of arylglyoxals13 withÄ-ketoesters14–15 and alkyl 2-cyanoacetates in presence hydrazinehydrate.16Therefore, continuing our interest in the synthesis of pyri-dazine derivatives, we decided to investigate the synthesis of3-amino-5-arylpyridazine-4-carbonitriles as a new series oftri-substituted pyridazines by reaction of arylglyoxals, malono-nitrile and hydrazine hydrate.2. Results and DiscussionFirstly, the arylglyoxals 2a–j were prepared from the corre-sponding acetophenones 1a–j via oxidation with SeO2 in dioxaneunder reflux conditions (Scheme 1).13The desired pyridazines were prepared by adding arylglyoxals2a–g to hydrazine hydrate 80 % in water and ethanol (1:1) andstirred for 30 min at room temperature to form correspondinghydrazones. The malononitrile 3 was then added to the reactionmixture and stirred at room temperature (Scheme 2). All of theproducts obtained are listed at Table 1.RESEARCH ARTICLE J. Khalafy, M. Rimaz, S. Farajzadeh and M. Ezzati, 179S. Afr. J. Chem., 2013, 66, 179–182,<http://journals.sabinet.co.za/sajchem/>.* To whom correspondence should be addressed.E-mail: jkhalafi@yahoo.com / j.khalafi@urmia.ac.irScheme 1Synthesis of arylglyoxals 2a–j.Scheme 2Synthesis of 3-amino-5-arylpyridazine-4-carbonitrile.The mechanism of reaction is shown in Scheme 3. The alterna-tive structure for the products described herein, namely the3-amino-6-arylpyridazine-4-carbonitriles (6), was consideredunlikely because this procedure involves adding the hydrazineto the arylglyoxal first, and then the malononitrile after 30 min,assuring the prior formation of the monohydrazone (5). Toconfirm this, the preparation of (4c) was carried out in twostages, with the isolation of the hydrazone (5c), which was thenreacted with malononitrile, leading to the formation of theproduct (4c). The spectral data of 4c prepared by the two-stagemethod was identical with that produced in the one-pot sequence.Further evidence for the proposed mechanism comes from thefact that the reaction of arylglyoxals 2h–j with hydrazine formedmonohydrazone derivatives in 30 min at room temperature, butfailed to cyclize to the corresponding pyridazines even underreflux conditions for 4 h. This may be due to the presence of elec-tron-donating hydroxy and methoxy groups at the p-position ofarylglyoxals 2h–j, which deactivate the keto-carbonyl group ofarylglyoxals by resonance effect.Attempts to synthesize compound 6 by reaction of arylglyoxalswith malononitrile followed by addition of hydrazine hydrateunder different solvent systems and temperatures failed due todecomposition in the first step (Scheme 4).2. ExperimentalGeneral ProceduresMelting points were determined on a Philip Harris apparatus(Model C4954718). Infrared spectra were recorded on aThermonicolet (Nexus 670) Fourier-transform (FT)-infraredspectrometer, using KBr discs. 1H (300 MHz) and 13C (75.5 MHz)NMR measurements were recorded on a Bruker 300 spectrometerin [D6]DMSO using TMS as the internal reference. Micro-analyses were performed on a Leco Analyzer 932.General Procedure for Synthesis of3-Amino-5-arylpyridazine-4-carbonitrilesA mixture of arylglyoxal (1 mmol) and hydrazine hydrate 80 %(4 mmol) in water and ethanol (1:1) (3 mL) was stirred at roomtemperature for 30 min. Then malononitrile (1 mmol) was addedto the reaction mixture and was stirred for a further 30 min atroom temperature. The product was then collected as a whiteprecipitate, washed with hot water (2 × 5 ml) and purified byrecrystallization from ethanol.3-Amino-5-phenylpyridazine-4-carbonitrile (4a)White solid, 78 %, mp 247 °C (dec.). 1H-NMR (300 MHz) Ç(ppm) 8.75 (s, 1H, Ar), 7.65–7.57 (m, 5H, Ar), 7.39 (bs, 2H,exchanged by D2O addition, NH2).13C-NMR Ç (ppm) 159.37,142.17, 141.96, 133.47, 130.98, 129.53, 129.09, 114.96, 93.62. FT-IRåmax 3437, 3300, 3105, 2219, 1641, 1562, 1498, 1474, 1441, 1162,764 cm–1. Mass spectrum m/z (%): 196 ([M+], 70), 168 (24), 140 (68),127 (17), 114 (44), 102 (100), 87 (25), 76 (88), 74 (48), 66 (61), 63 (74),51 (96), 50 (80). Anal. Calc. for C11H8N4: C, 67.34; H, 4.11; N, 28.55.Found: C, 67.45; H, 4.01; N, 28.12.3-Amino-5-(4-bromophenyl)pyridazine-4-carbonitrile (4b)White solid, 86 %, mp 290 °C (dec.). 1H-NMR (300 MHz) Ç(ppm) 8.72 (s, 1H, Ar), 7.77 (d, J 8.4 Hz, 2H, Ar), 7.64 (d, J 8.4 Hz,2H, Ar), 7.37 (bs, 2H, exchanged by D2O addition, NH2).13C-NMRÇ (ppm) 159.29, 141.64, 141.19, 132.65, 132.54, 131.21, 124.80,114.78, 93.64. FT-IR åmax 3442, 3296, 3089, 2214, 1645, 1589, 1559,1494, 1475, 1403, 1389, 1098, 1073, 1008, 925, 818 cm–1. Mass spec-trum m/z (%): 276 ([M++2], 28), 274 ([M+], 29), 196 (35), 180 (28),RESEARCH ARTICLE J. Khalafy, M. Rimaz, S. Farajzadeh and M. Ezzati, 180S. Afr. J. Chem., 2013, 66, 179–182,<http://journals.sabinet.co.za/sajchem/>.Table 1 List of pyridazine products.Entry Arylglyoxal Pyridazine Yield/%140 (100), 113 (37), 102 (88), 87 (27), 75 (95), 66 (57), 50 (80). Anal.Calc. for C11H7BrN4: C, 48.02; H, 2.56; N, 20.37. Found: C, 48.12; H,2.48; N, 20.29.3-Amino-5-(4-chlorophenyl)pyridazine-4-carbonitrile (4c)White solid, 87 %, mp 290 °C (dec.). 1H-NMR (300 MHz) Ç(ppm) 8.75 (s, 1H, Ar), 7.73 (d, J 8.4 Hz, 2H, Ar), 7.66 (d, J 8.4 Hz,2H, Ar), 7.43 (bs, 2H, exchanged by D2O, NH2).13C-NMR Ç (ppm)159.30, 141.71, 141.07, 139.99, 132.33, 131.04, 129.60, 114.80, 96.60.FT-IR åmax 3450, 3300, 3091, 2220, 1646, 1594, 1560, 1496, 1475, 1096,829 cm–1. Mass spectrum m/z (%): 232 ([M++2], 34), 230 ([M+],100), 202 (20), 174 (12), 140 (20), 136 (34), 101 (40), 75 (43), 66 (23),51 (23). Anal. Calc. for C11H7ClN4: C, 57.28; H, 3.06; N, 24.29.Found: C, 57.31; H, 3.01; N, 24.33.3-Amino-5-(4-fluorophenyl)pyridazine-4-carbonitrile (4d)White solid, 83 %, mp 260 °C (dec.). 1H-NMR (300 MHz) Ç(ppm) 8.71 (s, 1H, Ar), 7.78–7.70 (m, 2H, Ar), 7.38 (t, J 8.4 Hz, 2H,Ar), 7.40 (bs, 2H, exchanged by D2O addition, NH2).13C-NMR Ç(ppm) 165.50, 159.31, 141.90, 141.22, 131.74, 131.62, 116.78, 116.48,114.91. FT-IR åmax 3467, 3291, 3091, 2220, 1643, 1604, 1564, 1511,1478, 1235, 1162, 1099, 833 cm–1. Mass spectrum m/z (%): 214([M+], 50), 158 (26), 120 (100), 107 (40), 101 (60), 75 (40), 66 (48), 57(10). Anal. Calc. for C11H7FN4: C, 61.68; H, 3.29; N, 26.16. Found:C, 61.59; H, 3.14; N, 26.02.3-Amino-5-(4-nitrophenyl)pyridazine-4-carbonitrile (4e)Yellow solid, 88 %, mp 279 °C (dec.). 1H-NMR (300 MHz) Ç(ppm) 8.79 (s, 1H, Ar), 8.41 (d, J 8.7 Hz, 2H, Ar), 7.98 (d, J 8.7 Hz,2H, Ar), 7.54 (s, 2H, exchanged by D2O addition, NH2).13C-NMR Ç(ppm) 159.24, 148.99, 141.33, 140.33, 139.88, 130.81, 124.45, 114.52,93.86. FT-IR åmax 3446, 3425, 3311, 3112, 2218, 1656, 1603, 1568,1526, 1501, 1480, 1359, 1320, 1105, 855 cm–1. Mass spectrum m/z(%): 241 ([M+], 4), 140 (17), 115 (15), 104 (15), 99 (24), 89 (80), 83(22), 75 (46), 68 (26), 63 (100), 51 (60). Anal. Calc. for C11H7N5O2: C,54.77; H, 2.93; N, 29.03;. Found: C, 54.69; H, 2.98; N, 29.10.3-Amino-5-(3-bromophenyl)pyridazine-4-carbonitrile (4f)White solid, 76 %, mp 208 °C (dec.). 1H-NMR (300 MHz) Ç(ppm) 8.76 (s 1H, Ar), 7.92 (s, 1H, Ar), 7.78 (d, J 7.8 Hz, 1H, Ar), 7.7(d, J 7.8 Hz, 1H, Ar), 7.53 (t, J 7.8 Hz, 1H, Ar), 7.43 (bs, 2H,exchanged by D2O addition, NH2).13C-NMR Ç (ppm) 159.26,141.68, 140.68, 135.805, 133.65, 131.64, 131.58, 128.31, 122.58,114.71, 93.85. FT-IR åmax 3464, 3309, 3164, 2219, 1637, 1559, 1492,1407, 1321, 1154, 1113, 1093, 939, 881, 774, 709, 693 cm–1. Massspectrum m/z (%): 276 ([M++2], 87), 274 ([M+], 72), 180 (30), 167(22), 140 (100), 113 (24), 101 (54), 75 (35), 66 (21), 55 (18). Anal. Calc.for C11H7BrN4: C, 48.02; H, 2.56; N, 20.37. Found: C, 48.16; H, 2.52;N, 20.21.3-Amino-5-(3-methoxyphenyl)pyridazine-4-carbonitrile (4g)White solid, 72 %, mp 190 °C. 1H-NMR (300 MHz) Ç (ppm) 8.7(s, 1H, Ar), 7.49 (t, J 7.8 Hz, 1H, Ar), 7.37 (bs, 2H, exchanged byD2O addition, NH2), 7.27–7.23 (m, 2H, Ar), 7.14 (bd, J 8.1 Hz, 1H,Ar), 3.82 (s, 3H, OCH3).13C-NMR Ç (ppm) 159.92, 159.35, 149.43,141.96, 134.73, 130.78, 121.22, 116.72, 114.92, 114.42, 93.74, 55.82.FT-IR åmax 3463, 3265, 3109, 2215, 1623, 1558, 1463, 1325, 1249, 1104,1037, 856, 780, 695 cm–1. Mass spectrum m/z (%): 226 ([M+], 100),183 (18), 155 (91), 140 (25), 132 (35), 128 (49), 102 (65), 91 (55), 77(31), 63 (43), 57 (38). Anal. Calc. for C12H10N4O: C, 63.71; H, 4.46; N,24.76. Found: C, 63.67; H, 4.49; N, 24.83.RESEARCH ARTICLE J. Khalafy, M. Rimaz, S. Farajzadeh and M. Ezzati, 181S. Afr. J. Chem., 2013, 66, 179–182,<http://journals.sabinet.co.za/sajchem/>.Scheme 3Mechanism for the synthesis of 3-amino-5-arylpyridazine-4-carbonitriles.Scheme 4Attempted synthesis of 3-amino-6-arylpyridazine-4-carbonitriles.3. ConclusionsThe procedure outlined provides a straightforward route tovarious 3-amino-5-arylpyridazine-4-carbonitriles with possiblepharmaceutical applications.AcknowledgementsWe thank the University of Urmia for the financial support.References1 J.M. Quintela, M.C. Veiga, S. Conde and C. Peinador, Monatsh. Chem.,1996, 127, 739.2 A.M. Amer, M. El-Mobayed, A.M. Ateya and T.S. Muhdi, Monatsh.Chem., 2002, 133, 79.3 M.A.-M. Gomaa, Tetrahedron Lett., 2003, 44, 3493.4 S.M. Al-Mousawi, M.S. Moustafa, H. Meier, H. Kolshorn and M.H.Elnagdi, Molecules, 2009, 14, 798.5 F.M. Abdelrazek, A.A. Fadda and A.N. Elsayed, Synth. Com., 2011, 41,1119.6 F. Rohet, C. Rubat, P. Coudert and J. Couquelet, Bioorg. Med. Chem.,1997, 5, 655.7 T. Numata, T. Obato, K. Hirat and M. Kudo, Jpn. Kokai Tokyo Koho Jp.,1989, 63, 159.8 H. Yoshioka, T. Obato, K. Fujii, Y. Fukud and A. Ooka, Eur. Pat. Appl.Ep., 1989, 283, 271.9 G. Matolesy, World Rev. Pev. Pest Contr., 1971, 10, 50.10 H. Okujima, A. Naeimatsu, M. Kobayashi, R. Funlya and K. Kitada,Jpn. Kokai Tokyo Jp., 1989, 63, 215 .11 G.N. Preshin, L.I. Sherbakova, T.N. Zykova and V.N. Sokolova,Farmakol. Toksikol., 1971, 35, 466.12 T. Eicher and S. Hauptmann, The Chemistry of Heterocycles, 2nd edn.,Wiely-VCH Veriag GmbH, 2003, 392.13 H.A. Riley and A.R. Gray, Organic Syntheses, Collect. Vol. II, 1943, 509.14 G. Fodor and O. Kovacs, J. Am. Chem. Soc., 1949, 71, 1045.15 M. Rimaz and J. Khalafy, Arkivoc., 2010, ii, 110.16 M. Rimaz, J. Khalafy and P. Najafi Moghadam, Aust. J. Chem., 2010, 63,1396.RESEARCH ARTICLE J. Khalafy, M. Rimaz, S. Farajzadeh and M. Ezzati, 182S. Afr. J. Chem., 2013, 66, 179–182,<http://journals.sabinet.co.za/sajchem/>.

A Simple Three-component Synthesis of 3-Amino-5-arylpyridazine-4-carbonitriles

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A Simple Three-component Synthesis of 3-Amino-5-arylpyridazine-4-carbonitriles

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