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South African Journal of Chemistry

On-line version ISSN 1996-840X

S.Afr.j.chem. (Online) vol.66  Durban Aug. 2013

 

RESEARCH ARTICLE

 

A simple three-component synthesis of 3-amino-5-arylpyridazine-4-carbonitriles

 

 

J. KhalafyI, *;  M. RimazII;  S. FarajzadehI;  M. EzzatiI

IDepartment of Chemistry, Urmia University, Urmia 57154, Iran
IIDepartment of Chemistry, Payame Noor University, P.O. Box 19395-3697, Tehran, Iran

 

 


ABSTRACT

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.


 

 

1. Introduction

In recent years, nitrogen-containing heterocyclic compounds have been indispensable structural units for both chemists and biochemists due to their biological and pharmaceutical properties. Among various heterocycles, pyridazines and their annulated derivatives continue to attract attention due to their wide range of interesting biological activities.1

The synthesis of pyridazine derivatives2-5 and their pharmacological properties as analgesics,6 insecticidals,7 fungicidals,8-9 cardiotonics,10 and bacteriocides11 have been reported, as well as the synthesis of pyridazine derivatives by reaction of hydrazine with 1,4-dicarbonyl compounds,12 reaction of arylglyoxals13 with β-ketoesters14-15 and alkyl 2-cyanoacetates in presence hydrazine hydrate.16

Therefore, continuing our interest in the synthesis of pyri-dazine derivatives, we decided to investigate the synthesis of 3-amino-5-arylpyridazine-4-carbonitriles as a new series of tri-substituted pyridazines by reaction of arylglyoxals, malono-nitrile and hydrazine hydrate.

 

2. Results and Discussion

Firstly, the arylglyoxals 2a-j were prepared from the corresponding acetophenones 1a-j via oxidation with SeO2 in dioxane under reflux conditions (Scheme 1).13

 

 

The desired pyridazines were prepared by adding arylglyoxals 2a-g to hydrazine hydrate 80 % in water and ethanol (1:1) and stirred for 30 min at room temperature to form corresponding hydrazones. The malononitrile 3 was then added to the reaction mixture and stirred at room temperature (Scheme 2). All of the products obtained are listed at Table 1.

 

 

 

 

The mechanism of reaction is shown in Scheme 3. The alternative structure for the products described herein, namely the 3-amino-6-arylpyridazine-4-carbonitriles (6), was considered unlikely because this procedure involves adding the hydrazine to the arylglyoxal first, and then the malononitrile after 30 min, assuring the prior formation of the monohydrazone (5). To confirm this, the preparation of (4c) was carried out in two stages, with the isolation of the hydrazone (5c), which was then reacted with malononitrile, leading to the formation of the product (4c). The spectral data of 4c prepared by the two-stage method was identical with that produced in the one-pot sequence.

 

 

Further evidence for the proposed mechanism comes from the fact that the reaction of arylglyoxals 2h-j with hydrazine formed monohydrazone derivatives in 30 min at room temperature, but failed to cyclize to the corresponding pyridazines even under reflux conditions for 4 h. This maybe due to the presence of electron-donating hydroxy and methoxy groups at the p-position of arylglyoxals 2h-j, which deactivate the keto-carbonyl group of arylglyoxals by resonance effect.

Attempts to synthesize compound 6 by reaction of arylglyoxals with malononitrile followed by addition of hydrazine hydrate under different solvent systems and temperatures failed due to decomposition in the first step (Scheme 4).

 

 

2. Experimental

General Procedures

Melting points were determined on a Philip Harris apparatus (Model C4954718). Infrared spectra were recorded on a Thermonicolet (Nexus 670) Fourier-transform (FT)-infrared spectrometer, using KBr discs. 1H (300 MHz) and 13C (75.5 MHz) NMR measurements were recorded on a Bruker 300 spectrometer in [D6]DMSO using TMS as the internal reference. Microanalyses were performed on a Leco Analyzer 932.

General Procedure for Synthesis of 3-Amino-5-arylpyridazine-4-carbonitriles

A mixture of arylglyoxal (1 mmol) and hydrazine hydrate 80 % (4 mmol) in water and ethanol (1:1) (3 mL) was stirred at room temperature for 30 min. Then malononitrile (1 mmol) was added to the reaction mixture and was stirred for a further 30 min at room temperature. The product was then collected as a white precipitate, washed with hot water (2x5 ml) and purified by recrystallization from ethanol.

3-Amino-5-phenylpyridazine-4-carbonitrile (4a)

White solid, 78 %, mp 247 °C (dec.). 1H-NMR (300 MHz) δ (ppm) 8.75 (s, 1H, Ar), 7.65-7.57 (m, 5H, Ar), 7.39 (bs, 2H, exchanged by D2O addition, NH2). 13C-NMR δ (ppm) 159.37, 142.17, 141.96, 133.47, 130.98, 129.53, 129.09, 114.96, 93.62. FT-IR vmax 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) δ (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-NMR δ (ppm) 159.29, 141.64, 141.19, 132.65, 132.54, 131.21, 124.80, 114.78, 93.64. FT-IR vmax 3442, 3296, 3089, 2214, 1645, 1589, 1559, 1494, 1475, 1403, 1389, 1098, 1073, 1008, 925, 818 cm-1. Mass spectrum m/z (%): 276 ([M++2], 28), 274 ([M+], 29), 196 (35), 180 (28), 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) δ (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 δ (ppm) 159.30, 141.71, 141.07, 139.99, 132.33, 131.04, 129.60, 114.80, 96.60. FT-IR vmax 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) δ (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 δ (ppm) 165.50, 159.31, 141.90, 141.22, 131.74, 131.62, 116.78, 116.48, 114.91. FT-IR vmax 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) δ (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 δ (ppm) 159.24, 148.99, 141.33, 140.33, 139.88, 130.81, 124.45, 114.52, 93.86. FT-IR vmax 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) δ (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 δ (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 vmax 3464, 3309, 3164, 2219, 1637, 1559, 1492, 1407, 1321, 1154, 1113, 1093, 939, 881, 774, 709, 693 cm-1. Mass spectrum 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) δ (ppm) 8.7 (s, 1H, Ar), 7.49 (t, J 7.8 Hz, 1H, Ar), 7.37 (bs, 2H, exchanged by D2O 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 δ (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 vmax 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.

 

3. Conclusions

The procedure outlined provides a straightforward route to various 3-amino-5-arylpyridazine-4-carbonitriles with possible pharmaceutical applications.

 

Acknowledgements

We thank the University of Urmia for the financial support.

 

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Received 26 December 2012
Revised 1 May 2013
Accepted 9 June 2013

 

 

* To whom correspondence should be addressed. E-mail: jkhalafi@yahoo.com / j.khalafi@urmia.ac.ir

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