催化学报  2016, Vol. 37 Issue (4): 517-525   PDF (904 KB)    
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Mehdi Rimaz
Farkhondeh Aali
An environmentally-friendly base organocatalyzed one-pot strategy for the regioselective synthesis of novel 3,6-diaryl-4-methylpyridazines
Mehdi Rimaz , Farkhondeh Aali    
Department of Chemistry, Payame Noor University, PO Box 19395-3697, Tehran, Iran
Received 7 January 2016. Accepted 29 January 2016. Published 5 April 2016.
* Corresponding author. Mehdi Rimaz, Tel:+98-443-5625711;Fax:+98-443-5666999;E-mail:rimaz.mehdi@gmail.com
Abstract: This report describes a new three-component strategy for the regioselective synthesis of a series of tri-substituted pyridazines via a 1,4-diazabicyclo[2.2.2]octane (DABCO)-catalyzed condensation of propiophenones, arylglyoxalmonohydrates and hydrazine hydrate in water. This method provides a green and convenient one-pot route toward a diverse set of 3,6-diaryl-4-methylpyridazines bearing various aryl substituents. This procedure is highly regioselective, operationally simple, uses water as a safe, environmentally friendly solvent, and DABCO as a green base-organocatalyst, and affords good to excellent yields of products.
© 2016, Dalian Institute of Chemical Physics, Chinese Academy of Sciences.
Published by Elsevier B.V. All rights reserved.
Key words: 1,4-Diazabicyclo[2.2.2]octane (DABCO)     Propiophenone     Arylglyoxalmonohydrate     Pyridazine    
环境友好碱有机催化一锅法区域选择性合成新型3,6-二芳基-4-甲基哒嗪
Mehdi Rimaz , Farkhondeh Aali    
帕亚莫·努尔大学化学系, 德黑兰19395-3697, 伊朗
收稿日期: 2016-01-07. 接受日期: 2016-01-29. 出版日期: 2016-04-05.
*通讯联系人. Mehdi Rimaz, 电话: +98-443-5625711; 传真: +98-443-5666999; 电子信箱: rimaz.mehdi@gmail.com
摘要: 报道了一种新型三组分反应策略用于区域选择性合成一系列三取代的哒嗪, 即于水中进行DABCO催化的苯丙酮、芳香乙二醛一水合物和水合肼三组分缩合反应. 该法提供了一种绿色便利的一锅法制备各种芳基取代的3,6-二芳基-4-甲基哒嗪, 它以水为溶剂, DABCO为绿色碱有机催化剂, 具有高区域选择性、操作简便、产物收率高和后处理简单等优点.
关键词: 1,4-二氮杂二环[2.2.2]辛烷     苯丙酮     芳香乙二醛一水合物     哒嗪    

1. Introduction

Nitrogen-containing heterocycle pyridazine is a key intermediate in the synthesis of several fused heterocycles used in drug discovery [1]. Recently, pyridazines have been considered by GlaxoSmithKline to be one of the “most developable” heteroaromatic rings for drug design [2]. Pyridazine analogues have proven to be useful ligands for different targets, and have been proposed as “privileged structures” for drug discovery [3]. Several compounds with pyridazine rings demonstrate biological activity (Fig. 1, 1-4), and there are many examples of naturally occurring pyridazines [4, 5, 6, 7]. Pyridazines have also been recognized as selective GABA-A receptor antagonists, such as minaprine 1 [8]. Volonterio et al. [9] developed a synthesis of pyridazine-based scaffolds such as 2 to target protein/protein interaction as α-helix mimetics, and 3-amino-6-aryl- pyridazines are also considered to be an interesting pharmacophore in drug discovery. Some pyridazines show biological activity in a range of disease areas including obesity [10], neurodegenerative diseases [11], and inflammatory pain, e.g. the selective CB2 agonist 3 [12]. Several pyridazine-containing compounds have also been identified as kinase inhibitors, and compound 4 has been identified as a potent p38 MAPK inhibitor [13].

Multicomponent reactions (MCRs) are capable of achieving high levels of diversity in a concise transformation, as they involve more than two building blocks to be combined in practical, time-saving, one-pot operations. These reactions are perfectly suited to automated synthesis, and have attracted considerable interest owing to their exceptional synthetic efficiency, inherent simple experimental procedures, and their one-pot nature [14, 15, 16, 17]. Typically, the purification of products resulting from MCRs is also facile, as all the organic reagents involved are consumed and incorporated into the target compound [18, 19]. MCRs leading to interesting heterocyclic scaffolds are particularly useful for the construction of diverse chemical libraries of drug-like molecules.

The Paal-Knorr synthesis is one of the most common approaches for the construction various five- or six-membered heterocycles. In the Paal-Knorr synthesis of pyridazines, 1,4-dicarbonyl compounds are converted to pyridazines via a dehydrative cyclization in the presence of hydrazine, and subsequent oxidation [20, 21, 22, 23, 24, 25].

As part of our ongoing program to develop efficient and robust MC methods for the preparation of heterocyclic compounds [25, 26, 27, 28, 29, 30], we sought to develop a convenient preparation of 3,6-diaryl substituted 4-methylpyridazines 5-38 via a regioselective one-pot condensation reaction of substituted propiophenones 39a-d with arylglyoxalmonohydrates 40a-j and hydrazine in the presence of catalytic amounts of 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-7-ene (DBN) as shown in Scheme 1. To the best of our knowledge, there are no reports in the literature for the formation of pyridazine derivatives via base-organocatalyzed condensation of propiophenones with arylglyoxalmonohydrates in the presence of hydrazine hydrate.

Fig. 1. Selected biologically active substituted pyridazines.
2. Experimental
2.1. General procedures for the regioselective DABCO-catalyzed one-pot synthesis of 3,6-diaryl-4-methylpyridazine derivatives

To a mixture of arylglyoxalmonohydrate (1 mmol), propiophenone (1 mmol) and DABCO (50 mol%) in water (10 mL) were added hydrazine hydrate (4 mmol). The suspension was stirred at 25 °C until precipitation ceased (2-4 h). After completion of the reaction, the mixture was filtered and purified by recrystallization from ethanol.

Scheme 1. Regioselective base-organocatalyzed one-pot synthesis of 3,6-diaryl-4-methylpyridazines.
2.2. Analytical data for the products

3-(3-Bromophenyl)-6-phenyl-4-methylpyridazine (5): white crystals; 86%; mp 115 °C. IR (KBr): νmax=3063, 2971, 2929, 1577, 1392, 1261, 1042, 886 cm−1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 7.39 (t, 1H, J=7.8), 7.47-7.67 (m, 5H), 7.74 (s, 1H), 7.84 (s, 1H), 8.14 (d, 2H, J=6.3).13C NMR (75 MHz, CDCl3) δ 19.9, 122.5, 124.4, 124.7, 126.4, 127.8, 128.8, 129.8, 131.0, 132.8, 133.3, 136.1, 139.0, 157.8, 159.1. Anal. found, C, 62.83; H, 4.06; N, 8.68. C17H13BrN2 requires C, 62.79; H, 4.03; N, 8.61.

3-(3-Bromophenyl)-6-(4-bromophenyl)-4-methylpyridazine (6): yellow crystals; 72%; mp 157 °C. IR (KBr): νmax=3083, 3053, 2969, 1589, 1421, 1074, 1004, 850 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 7.39 (t, 1H, J=8.1), 7.53-7.7 (m, 4H), 7.72 (s, 1H), 7.82 (s, 1H), 8.02 (d, 2H, J=8.1). 13C NMR (75 MHz, CDCl3) δ 19.8, 122.5, 124.3, 124.7, 126.1, 127.5, 128.8, 129.5, 131.3, 133.1, 134.9, 136.3, 138.8, 157.7, 159.4. Anal. found, C, 50.57; H, 2.97; N, 7.00. C17H12Br2N2 requires C, 50.53; H, 2.99; N, 6.93.

3-(3-Bromophenyl)-6-(4-chlorophenyl)-4-methylpyridazine (7): yellow crystals; 88%; mp 176 °C. IR (KBr): νmax=3091, 3057, 3032, 1586, 1414, 1386, 1089, 893 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 7.39 (t, 1H, J=7.8), 7.47-7.67 (m, 4H), 7.72 (s, 1H), 7.82 (s, 1H), 8.08 (d, 2H, J=7.8).13C NMR (75 MHz, CDCl3) δ 19.8, 122.6, 124.4, 126.1, 127.3, 128.4, 128.8, 129.2, 130.0, 131.1, 133.3, 136.2, 138.9, 156.7, 159.4. Anal. found, C, 56.79; H, 3.32; N, 7.85. C17H12BrClN2 requires C, 56.77; H, 3.36; N, 7.79.

3-(3-Bromophenyl)-6-(4-fluorophenyl)-4-methylpyridazine (8): white crystals; 82%; mp 141 °C. IR (KBr): νmax=3122, 3080, 3042, 2925, 1590, 1416, 1223, 1099, 843 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 7.17-7.3 (m, 2H), 7.40 (t, 1H, J=7.8), 7.53-7.67 (m, 2H), 7.72 (s, 1H), 7.83 (s, 1H), 8.08-8.19 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 19.9, 114.9, 115.2, 116.9, 117.2, 124.3, 126.1, 128.1, 128.8, 129.9, 131.2, 132.9, 136.2, 138.9, 156.8, 162.5. Anal. found, C, 54.54; H, 3.55; N, 8.20. C17H12BrFN2 requires C, 59.49; H, 3.52; N, 8.16.

3-(3-Bromophenyl)-6-(4-methoxyphenyl)-4-methylpyridazine (9): white crystals; 78%; mp 119 °C. IR (KBr): νmax=3057, 3015, 2960, 2939, 2842, 1589, 1428, 1249, 1034, 842 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.47 (s, 3H), 3.93 (s, 3H), 7.06 (d, 1H, J=8.1), 7.34-7.5 (m, 2H), 7.53-7.69 (m, 3H), 7.54 (s, 1H), 7.79-7.89 (m, 2H).13C NMR (75 MHz, CDCl3) δ 19.9, 56.2, 110.9, 113.0, 115.3, 118.4, 120.2, 124.8, 128.8, 131.0, 132.9, 136.1, 137.4, 139.0, 159.3. Anal. found, C, 60.87; H, 4.23; N, 7.99. C18H15BrN2O requires C, 60.86; H, 4.26; N, 7.89.

3,6-Bis(3-bromophenyl)-4-methylpyridazine (10): yellow crystals; 71%; mp 109 °C. IR (KBr): νmax=2960, 2931, 2859, 1584, 1566, 1379, 1426, 1065, 883 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.48 (s, 3H), 7.36-7.48 (m, 2H), 7.53-7.7 (m, 3H), 7.74 (s, 1H), 7.84 (s, 1H), 8.09 (d, 1H, J=7.8), 8.30 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 20.0, 123.7, 126.5, 129.4, 129.7, 130.2, 130.9, 131.4, 132.0, 133.0, 133.7, 136.5, 137.9, 156.2, 159.9. Anal. found, C, 50.54; H, 2.31; N, 7.06. C17H12Br2N2 requires C, 50.53; H, 2.99; N, 6.93.

3-(3-Bromophenyl)-6-(3-methoxyphenyl)-4-methylpyridazine (11): white crystals; 70%; mp 104 °C. IR (KBr): νmax=3067, 3008, 2971, 2920, 2849, 1589, 1467, 1377, 1038, 855, 773 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 3.89 (s, 3H), 7.06 (d, 2H, J=8.7), 7.38 (t, 1H, J=8.1), 7.54-7.65 (m, 2H), 7.69 (s, 1H), 7.83 (s, 1H), 8.11 (d, 2H, J=8.7). 13C NMR (75 MHz, CDCl3) δ 20.9, 56.1, 113.3, 113.3, 115.4, 115.5, 123.8, 125.6, 127.5, 128.8, 130.8, 135.9, 139.2, 157.3, 158.6, 161.3. Anal. found, C, 60.83; H, 4.25; Br, N, 7.99. C18H15BrN2O requires C, 60.86; H, 4.26; N, 7.89.

3-(3-Bromophenyl)-6-(3,4-dimethoxyphenyl)-4-methylpyri-dazine (12): yellow crystals; 84%; mp 174 °C. IR (KBr): νmax=3066, 2998, 2939, 2842, 1587, 1422, 1021, 873, 768 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 3.96 (s, 3H), 4.01 (s, 3H), 6.98 (d, 1H, J=7.5), 7.38 (t, 1H, J=7.8), 7.70 (s, 1H), 7.83 (s, 1H), 7.94 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.9, 55.1, 56.8, 109.0, 110.0, 110.3, 110.9, 111.9, 112.2, 120.4, 123.9, 128.8, 135.9, 139.1, 149.6, 150.8, 157.1, 158.7. Anal. found, C, 59.23; H, 4.45; N, 7.27. C19H17BrN2O2 requires C, 59.27; H, 4.46; N, 7.39.

3-(3-Bromophenyl)-6-(3,4-methylenedioxyphenyl)-4-methyl-pyridazine (13): yellow crystals, 80%; mp 153 °C. IR (KBr): νmax=3071, 2996, 2912, 2786, 1586, 1491, 1256, 1038, 874 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.43 (s, 3H), 6.06 (s, 2H), 6.96 (d, J=8.1, 1H), 7.38 (t, J=8.1, 1H), 7.68-7.53 (m, 4H), 7.72 (s, 1H), 7.82 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.8, 101.5, 102.9, 106.4, 107.5, 107.8, 108.2, 109.5, 122.2, 124.1, 125.9, 128.8, 136.0, 139.1, 148.6, 149.3, 157.2, 158.8. Anal. found, C, 58.59; H, 3.49; N, 7.77. C18H13BrN2O2 requires C, 58.56; H, 3.55; N, 7.59.

3-(3-Bromophenyl)-6-(4-hydroxy-3-methoxyphenyl)-4-methylpyridazine (14): white crystals; 74%; mp 179 °C. IR (KBr): νmax=3328, 3083, 3057, 2969, 1589, 1421, 1398, 1389, 1074, 1005, 829, 697 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 4.03 (s, 3H), 5.93 (s, 1H), 7.39 (d, J=8.4, 1H), 7.49 (t, J=8.4, 1H), 7.63-7.58 (m, 2H), 7.71 (s, 1H), 7.85 (s, 1H), 8.00 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.9, 57.0, 108.5, 110.5, 113.5, 119.0, 121.2, 123.8, 128.2, 130.9, 132.8, 135.8, 139.1, 146.3, 147.8, 158.9, 159.3. Anal. found, C, 58.23; H, 4.05; N, 7.76. C18H15BrN2O2 requires C, 58.24; H, 4.07; Br, N, 7.55.

3-(4-Bromophenyl)-6-phenyl-4-methylpyridazine (15): white crystals; 78%; mp 163 °C. IR (KBr): νmax=3055, 2930, 1587, 1445, 1389, 1075, 1004, 830 cm-1. 1H NMR (300 MHz, CDCl3): δ 2.44 (s, 3H), 7.46-7.58 (m, 5H), 7.65 (d, 2H, J = 8.1), 7.74 (s, 1H), 8.13 (d, 2H, J=6.3). 13C NMR (75 MHz, CDCl3) δ 19.9, 126.2, 126.5, 127.4, 127.9, 129.6, 130.8, 131.6, 132.3, 135.7, 136.2, 157.6, 159.5. Anal. found, C, 62.81; H, 4.05; N, 8.72. C17H13BrN2 requires C, 62.79; H, 4.03; N, 8.61.

3,6-Bis(4-bromophenyl)-4-methylpyridazine (16): yellow crystals; 72%; mp 174 °C. IR (KBr): νmax=3085, 1590, 1483, 1401, 1072, 1002, 822 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.47 (s, 3H), 7.55 (d, J=8.4, 2H), 7.61-7.73 (m, 4H), 7.74 (s, 1H), 8.02 (d, 2H, J=8.4). 13C NMR (75 MHz, CDCl3) δ 20.0, 124.9, 127.7, 129.5, 129.7, 130.2, 130.9, 131.6, 132.0, 132.4, 133.0, 156.6, 159.6. Anal. found, C, 50.55; H, 2.96; N, 7.04. C17H12Br2N2 requires C, 50.53; H, 2.99; N, 6.93.

3-(4-Bromophenyl)-6-(4-chlorophenyl)-4-methylpyridazine (17): white crystals; 88%; mp 176 °C. IR (KBr): νmax=3095, 3030, 1593, 1483, 1400, 1073, 1006, 824 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 7.46-7.58 (m, 4H), 7.66 (d, 2H, J=8.4), 7.71 (s, 1H), 8.08 (d, 2H, J=8.4). 13C NMR (75 MHz, CDCl3) δ 19.9, 124.6, 126.1, 128.1, 129.1, 129.8, 130.8, 131.6, 132.4, 135.6, 136.2, 156.5, 159.6. Anal. found, C, 56.80; H, 3.38; N, 7.89. C17H12BrClN2 requires C, 56.77; H, 3.36; N, 7.79.

3-(4-Bromophenyl)-6-(4-fluorophenyl)-4-methylpyridazine (18): white crystals; 92%; mp 188 °C. IR (KBr): νmax=3080, 2975, 1593, 1505, 1379, 1228, 1071, 1001, 831 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 7.16-7.27 (m, 2H), 7.53 (d, 2H, J=8.4), 7.64 (d, 2H, J=8.1), 7.71 (s, 1H), 8.08-8.18 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 19.9, 114.9, 115.2, 116.8, 117.1, 128.2, 129.9, 130.8, 132.4, 156.6, 159.4, 162.4, 165.7. Anal. found, C, 54.51; H, 3.53; N, 8.28. C17H12BrFN2 requires C, 59.49; H, 3.52; N, 8.16.

3-(4-Bromophenyl)-6-(4-methoxyphenyl)-4-methylpyridazine (19): white crystals; 90%; mp 133 °C. IR (KBr): νmax=3000, 2970, 2930, 2835, 1589, 1492, 1399, 1256, 1034, 1000, 835 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 3.88 (s, 3H), 7.04 (d, 2H, J=8.1), 7.53 (d, 2H, J=7.8), 7.62 (d, 2H, J=7.8), 7.67 (s, 1H), 8.09 (d, 2H, J=8.1). 13C NMR (75 MHz, CDCl3) δ 19.9, 56.0, 113.3, 113.8, 114.7, 115.5, 127.6, 129.3, 130.7, 132.0, 132.3, 157.0, 158.9, 161.3. Anal. found, C, 60.89; H, 4.22; N, 8.03. C18H15BrN2O requires C, 60.86; H, 4.26; N, 7.89.

3-(4-Bromophenyl)-6-(3-bromophenyl)-4-methylpyridazine (20): white crystals; 71%; mp 132 °C. IR (KBr): νmax=3055, 3010, 1590, 1566, 1375, 1047, 1000, 886 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 7.40 (t, 1H, J=8.1), 7.54 (d, 2H, J=8.4), 7.59-7.71 (m, 3H), 7.72 (s, 1H), 8.07 (d, 1H, J=7.8), 8.29 (s, 1H).13C NMR (75 MHz, CDCl3) δ 19.9, 123.7, 126.5, 129.4, 129.7, 130.2, 130.9, 131.4, 132.0, 133.0, 133.7, 136.5, 137.9, 156.2, 159.9. Anal. found, C, 50.57; H, 2.30; N, 7.10. C17H12Br2N2 requires C, 50.53; H, 2.99; N, 6.93.

3-(4-Bromophenyl)-6-(3,4-dimethoxyphenyl)-4-methylpyri-dazine (21): yellow crystals; 91%; mp 174 °C. IR (KBr): νmax=2935, 2830, 1604, 1587, 1401, 1091, 1023, 838 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 3.95 (s, 3H), 4.01 (s, 3H), 7.99 (d, 1H, J=8.4), 7.45-7.6 (m, 3H), 7.64 (d, 2H, J=8.4), 7.71 (s, 1H), 7.94 (s, 1H).13C NMR (75 MHz, CDCl3) δ 20.0, 56.7, 57.3, 109.0, 109.9, 110.4, 110.8, 111.8, 112.2, 130.1, 131.6, 132.0, 136.3, 149.5, 150.9, 156.9, 159.0. Anal. found, C, 59.30; H, 4.48; N, 7.42. C19H17BrN2O2 requires C, 59.27; H, 4.46; N, 7.39.

3-(4-Bromophenyl)-6-(3,4-methylenedioxyphenyl)-4-methyl-pyridazine (22): yellow crystals; 79%; mp 166 °C. IR (KBr): νmax=3075, 2900, 1592, 1504, 1451, 1250, 1107, 1001, 818 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 6.05 (s, 2H), 6.94 (d, 1H, J=8.1), 7.52 (d, 2H, J=8.1), 7.56-7.69 (m, 4H), 7.70 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.9, 101.5, 106.5, 107.9, 108.1, 109.4, 122.1, 126.0, 129.7, 130.8, 131.6, 132.3, 136.2, 148.5, 157.0, 159.1. Anal. found, C, 58.56; H, 3.53; N, 7.69. C18H13BrN2O2 requires C, 58.56; H, 3.55; N, 7.59.

3-(4-Chlorophenyl)-6-phenyl-4-methylpyridazine (23): white crystals; 28%; mp 163 °C. IR (KBr): νmax=3087, 3070, 3041, 2927, 1597, 1587, 1490, 1451, 1092, 1006, 789 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 7.53-7.47 (m, 5H), 7.62 (d, 2H, J=8.4), 7.73 (s, 1H), 8.13 (d, 2H, J=6.3). 13C NMR (75 MHz, CDCl3) δ 19.9, 124.6, 126.0, 127.5, 128.8, 129.7, 129.8, 130.1, 131.6, 135.0, 136.0, 157.6, 159.4. Anal. found, C, 72.77; H, 4.69; N, 10.17. C17H13ClN2 requires C, 72.73; H, 4.67; N, 9.98.

3-(4-Chlorophenyl)-6-(4-bromophenyl)-4-methylpyridazine (24): white crystals; 67%; mp 174 °C. IR (KBr): νmax=3090, 3055, 3035, 2960, 2925, 1592, 1486, 1404, 1091, 1004, 824 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 7.50 (d, 2H, J=8.4), 7.57-7.69 (m, 4H), 7.72 (s, 1H), 8.02 (d, 2H, J=8.4). 13C NMR (75 MHz, CDCl3) δ 20.0, 124.6, 126.0, 127.6, 128.1, 129.8, 129.3, 131.5, 132.9, 135.2, 136.2, 156.5, 159.7. Anal. found, C, 56.81; H, 3.35; N, 7.95. C17H12BrClN2 requires C, 56.77; H, 3.36; N, 7.79.

3,6-Bis(4-chlorophenyl)-4-methylpyridazine (25): white crystals; 66%; mp 181 °C. IR (KBr): νmax=3090, 3060, 3030, 1587, 1487, 1376, 1090, 1008, 827 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.46 (s, 3H), 7.47-7.56 (m, 4H), 7.62 (d, 2H, J=8.1), 7.72 (s, 1H), 8.09 (d, 2H, J=8.4). 13C NMR (75 MHz, CDCl3) δ 20.0, 124.6, 126.0, 127.4, 127.5, 128.1, 129.1, 129.8, 130.4, 131.3, 136.2, 156.5, 159.6. Anal. found, C, 64.80; H, 3.81; N, 9.03. C17H12Cl2N2 requires C, 64.78; H, 3.84; N, 8.89.

3-(4-Chlorophenyl)-6-(4-fluorophenyl)-4-methylpyridazine (26): white crystals; 81%; mp 182 °C. IR (KBr): νmax=3090, 3080, 2970, 2925, 2855, 1596, 1487, 1389, 1089, 1003, 842 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 7.16-7.29 (m, 2H), 7.50 (d, 2H, J=8.4), 7.62 (d, 2H, J=8.4), 7.70 (s, 1H), 8.08-8.18 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 19.9, 115.2, 115.8, 116.8, 117.1, 124.5, 129.7, 131.3, 136.1, 156.6, 159.4, 162.4, 165.7. Anal. found, C, 68.39; H, 4.07; N, 9.40. C17H12ClFN2 requires C, 68.35; H, 4.05; N, 9.38.

3-(4-Chlorophenyl)-6-(4-methoxyphenyl)-4-methylpyridazine (27): white crystals; 78%; mp 150 °C. IR (KBr): νmax=3070, 3050, 3000, 2970, 2840, 1608, 1585, 1487, 1392, 1091, 1017, 824 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 3.92 (s, 3H), 7.05 (d, 2H, J=8.4), 7.49 (d, 2H, J=8.4), 7.62 (d, 2H, J=8.4), 7.68 (s, 1H), 8.11 (d, 2H, J=8.1). 13C NMR (75 MHz, CDCl3) δ 20.0, 56.0, 113.2, 113.8, 114.1, 115.5, 127.5, 129.2, 129.9, 131.3, 135.5, 135.9, 157.1, 158.9. Anal. found, C, 69.59; H, 4.88; N, 9.13. C18H15ClN2O requires C, 69.57; H, 4.86; N, 9.01.

3-(4-Chlorophenyl)-6-(3-bromophenyl)-4-methylpyridazine (28): yellow crystals; 71%; mp 132 °C. IR (KBr): νmax=3091, 3056, 3011, 2971, 2932, 1567, 1487, 1376, 1091, 1001, 843 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 7.40 (t, 1H, J=7.8), 7.50 (d, 2H, J=8.4), 7.57-7.67 (m, 3H), 7.72 (s, 1H), 8.07 (d, 1H, J=7.8), 8.29 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 20.0, 124.9, 126.3, 127.6, 129.2, 129.5, 130.8, 131.3, 131.8, 133.6, 135.2, 136.3, 138.1, 156.2, 159.8. Anal. found, C, 56.80; H, 3.38; N, 7.90. C17H12BrClN2 requires C, 56.77; H, 3.36; N, 7.79.

3-(4-Chlorophenyl)-6-(3-methoxyphenyl)-4-methylpyridazine (29): white crystals, 77%, mp 150 °C. IR (KBr): νmax=3007, 2936, 2835, 1595, 1581, 1493, 1390, 1255, 1174, 1035, 843, 795 cm-1. 1H-NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 3.92 (s, 3H), 7.06 (d, J=8.4 Hz, 1H), 7.44 (t, J=8.4 Hz, 1H), 7.51 (d, J=8.7 Hz, 2H), 7.64-7.61 (m, 3H), 7.74 (s, 1H), 7.81 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 19.8, 54.6, 110.9, 120.2, 124.7, 127.5, 128.9, 129.5, 129.8, 131.0, 131.6, 135.4, 136.0, 137.5, 157.3, 159.5. Anal. found, C, 69.60; H, 4.84; N, 9.21. C18H15ClN2O requires C, 69.57; H, 4.86; N, 9.01.

3-(4-Chlorophenyl)-6-(3,4-dimethoxyphenyl)-4-methylpyri-dazine (30): white crystals; 78%; mp 182 °C. IR (KBr): νmax=3086, 3061, 3001, 2966, 2942, 2902, 2842, 2882, 1587, 1464, 1240, 1091, 1023, 838 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 3.95 (s, 3H), 4.00 (s, 3H), 6.98 (d, 1H, J=8.4), 7.47 (d, 2H, J=7.8), 7.51-7.64 (m, 3H), 7.69 (s, 1H), 7.93 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 20.0, 55.3, 56.6, 108.8, 109.1, 109.8, 110.7, 111.3, 111.7, 125.6, 127.7, 128.6, 131.3, 135.5, 135.9, 156.9, 158.9. Anal. found, C, 66.99; H, 5.04; N, 8.31. C17H17ClN2O2 requires C, 66.96; H, 5.03; N, 8.22.

3-(4-Chlorophenyl)-6-(3,4-methylenedioxyphenyl)-4-methyl-pyridazine (31): yellow crystals, 80%, mp 166 °C. IR (KBr): νmax=3081, 3046, 3006, 2966, 2897, 2787, 1592, 1505, 1452, 1108, 1001, 819 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.42 (s, 3H), 6.05 (s, 2H), 6.94 (d, J=8.1, 1H), 7.48 (d, J=8.1, 2H), 7.66-7.54 (m, 4H), 7.71 (s, 1H).13C NMR (75 MHz, CDCl3) δ 19.9, 101.5, 106.6, 107.4, 108.8, 109.3, 125.7, 127.5, 129.7, 130.3, 131.3, 135.5, 135.9, 148.5, 157.0, 159.0. Anal. found, C, 66.59; H, 4.04; N, 8.81. C18H13ClN2O2 requires C, 66.57; H, 4.03; N, 8.63.

3-(4-Chlorophenyl)-6-(4-hydroxy-3-methoxyphenyl)-4-methylpyridazine (32): white crystals; 78%; mp 150 °C. IR (KBr): νmax=3529, 3078, 3049, 2939, 1596, 1510, 1489, 1270, 1029, 824, 789 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 4.01 (s, 3H), 6.01 (s, 1H), 7.05 (d, 1H, J=8.1), 7.51-7.47 (m, 3H), 7.62 (d, 2H, J=8.1), 7.70 (s, 1H), 7.99 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 55.2, 56.9, 108.5, 110.4, 113.5, 115.6, 118.9, 120.8, 121.1, 123.9, 125.7, 127.4, 129.4, 129.7, 131.5, 135.9. Anal. found, C, 66.17; H, 4.61; N, 8.76. C18H15ClN2O2 requires C, 66.16; H, 4.63; N, 8.57.

3-(4-Methylphenyl)-6-phenyl-4-methylpyridazine (33): whitecrystals; 70%; mp 133 °C. IR (KBr): νmax=3055, 2930, 1586, 1490, 1392, 1092, 10018, 839 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 2.46 (s, 3H), 7.33 (d, 2H, J=7.8), 7.45-7.60 (m, 5H), 7.74 (s, 1H), 8.13 (d, 2H, J=6.3). 13C NMR (75 MHz, CDCl3) δ 20.0, 20.1, 125.0, 126.2, 126.6, 127.9, 128.1, 129.6, 130.0, 130.5, 136.5, 138.9, 157.2, 160.4. Anal. found, C, 83.07; H, 6.20; N, 10.91. C18H16N2 requires C, 83.04; H, 6.19; N, 10.76.

3-(4-Methylphenyl)-6-(4-bromophenyl)-4-methylpyridazine (34): white crystals; 94%; mp 166 °C. IR (KBr): νmax=3090, 2922, 2850, 1588, 1486, 1407, 1073, 1003, 821 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 2.48 (s, 3H), 7.33 (d, 2H, J=7.5), 7.57 (d, 2H, J=7.5), 7.66 (d, 2H, J=8.1), 7.75 (s, 1H), 8.03 (d, 2H, J=8.1).13C NMR (75 MHz, CDCl3) δ 20.1, 21.3, 124.8, 127.7, 128.2, 128.5, 129.5, 129.9, 130.1, 130.4, 131.4, 133.0, 156.2, 160.5. Anal. found, C, 63.78; H, 4.45; N, 8.30. C18H15BrN2 requires C, 63.73; H, 4.46; N, 8.26.

3-(4-Methylphenyl)-6-(4-chlorophenyl)-4-methylpyridazine (35): yellow crystals; 68%; mp 184 °C. IR (KBr): νmax=3090, 3035, 1918, 1586, 1438, 1406, 1090, 1008, 824 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 2.47 (s, 3H), 7.33 (d, 2H, J=7.8), 7.45-7.6 (m, 4H), 7.73 (s, 1H), 8.08 (d, 2H, J=8.7). 13C NMR (75 MHz, CDCl3) δ 20.1, 21.3, 125.0, 126.6, 127.4, 128.2, 129.2, 129.8, 130.0, 130.3, 136.9, 139.2, 156.1, 160.5. Anal. found, C, 73.39; H, 5.18; N, 9.66. C18H15ClN2 requires C, 73.34; H, 5.13; N, 9.50.

3-(4-Methylphenyl)-6-(4-fluorophenyl)-4-methylpyridazine (36): white crystals; 69%; mp 175 °C. IR (KBr): νmax=3075, 2920, 1590, 1506, 1378, 1222, 1099, 818 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.45 (s, 3H), 2.47 (s, 3H), 7.17-7.29 (m, 2H), 7.33 (d, 2H, J=7.8), 7.56 (d, 2H, J=7.8), 7.70 (s, 1H), 8.09-8.18 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 20.1, 21.3, 115.2, 116.1, 116.7, 117.0, 126.1, 128.1, 128.3, 129.9, 156.3, 160.4, 162.4, 165.7. Anal. found, C, 77.70; H, 5.46; N, 10.20. C18H15FN2 requires C, 77.68; H, 5.43; N, 10.07.

3-(4-Methylphenyl)-6-(4-methoxyphenyl)-4-methylpyridazine (37): yellow crystals; 75%; mp 134 °C. IR (KBr): νmax=3005, 2925, 2835, 1609, 1583, 1395, 1256, 1023, 845 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.40 (s, 3H), 2.44 (s, 3H), 3.88 (s, 3H), 7.04 (d, 2H, J=8.1), 7.31 (d, 2H, J=7.8), 7.56 (d, 2H, J=7.8), 7.69 (s, 1H), 8.11 (d, 2H, J=8.7). 13C NMR (7.5 MHz, CDCl3) δ 20.1, 21.3, 56.0, 113.3, 113.7, 115.0, 115.5, 126.0, 127.6, 128.1, 130.0, 138.9, 156.7, 159.8, 161.2. Anal. found, C, 78.57; H, 6.24; N, 9.77. C19H18N2O requires C, 78.59; H, 6.25; N, 9.65.

3-(4-Methylphenyl)-6-(3,4-dimethoxyphenyl)-4-methylpyri-dazine (38): white crystals; 61%; mp 170 °C. IR (KBr): νmax=3005, 2940, 2840, 1605, 1588, 1422, 1259, 1025, 821 cm-1. 1H NMR (300 MHz, CDCl3) δ 2.44 (s, 3H), 2.46 (s, 3H), 3.94 (s, 3H), 4.01 (s, 3H), 6.98 (d, 1H, J=8.4), 7.31 (d, 2H, J=7.5), 7.48-7.64 (m, 3H), 7.74 (s, 1H), 7.96 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 20.2, 21.3, 55.2, 56.7, 109.2, 109.9, 110.4, 110.9, 11.8, 112.2, 126.4, 128.5, 129.9, 139.0, 149.5, 151.0, 156.4, 159.9. Anal. found, C, 75.00; H, 6.32; N, 8.84. C20H20N2O2 requires C, 74.98; H, 6.29; N, 8.74.

3. Results and discussion

During our research program on the synthesis of aryl-substituted pyridazine derivatives [25], we used the reaction of 3-bromopropiophenone (39a)with phenylglyoxalmonohydrate (40a) and hydrazine hydrate in water as a model reaction. This one-pot system afforded hydrazone compounds as by-products at room temperature, 50 °C and at reflux (Table 1, entries 1-3). This could be a reflection of the low acidity of the α-hydrogens on propiophenone, and so we investigated the use of organic bases such as DABCO, DBU and DBN to catalyze this reaction. With an initial concentration of 10 mol% of either DABCO, DBU or DBN at 25 °C for 6 h, the desired pyridazine derivative was afforded in 25%, 15% and 10% yield, respectively (Table 1, entries 4-6). The influence of solvent was also investigated, and the results are summarized in Table 1. No product was isolated when the reaction was carried out in pure EtOH (entries 7-9), and a much longer time was needed when the reaction was carried out in a 1:1 ratio of EtOH:H2O (entries 10-12). Attempts to improve the reaction conditions by running the reaction in H2O, EtOH and H2O:EtOH (1:1) in the presence of 10 mol% of the organic bases at 50 °C failed. Monitoring the reaction progress via TLC showed that an increase in the reaction temperature led to an increase in by-product formation, and no pyridazine products were formed. The above results indicated that H2O accelerated the reaction, and it was found to the best solvent for this reaction at room temperature (25 °C). Encouraged by these results, we continued to focus on optimizing the amounts of the basic organocatalysts for the reaction. Tuning the catalyst concentration revealed that increasing the amounts of DBU and DBN from 20 to 40 mol% led to a small increase in the yield (Table 1, entries 13-18). Using 50 mol% of both DBU and DBN caused a decrease in yield (Table 1, entries 19 and 20). Surprisingly, in the case of DABCO, an increase in concentration caused a significant increase in the yield of the pyridazine product (Table 1, entries 21-23), and adding 50 mol% of DABCO to the reaction mixture led to the best result (Table 1, entry 24). Further increases in the molar ratio of DABCO did not improve the reaction yield and, in contrast, it caused a significant decrease in the efficiency of the reaction (Table 1, entry 25).

Table 1
Optimization of the reaction conditions.

With the optimized reaction conditions in hand, we moved on to examine the substrate scope using a wide variety of propiophenones and arylglyoxal monohydrates (Table 2). Arylglyoxalmonohydrates bearing electron-withdrawing groups gave better yields, in shorter reaction times, than the arylglyoxalmonohydrates bearing electron-donating groups. It is worthwhile to note that all of the reactions proceeded selectively to generate the 3,6-diaryl-4-methylpyridazine as a single regioisomer.

Table 2
Substrate scope study using different propiophenones and arylglyoxalmonohydrates.

Full characterization including IR, 1H NMR, 13C NMR and elemental analysis proved the identity of all the pyridazine products 5-38. The diagnostic singlet around δ ≈7.70 in the 1H NMR spectra was ascribed to the C5-H of the pyridazine ring. All of the compounds 5-38 are believed to be the only regioisomers present, and no evidence for the formation of the other isomer was observed for all new pyridazine derivatives. As the formyl group is more electrophilic than the keto group in the arylglyoxal scaffold [25, 26, 27, 28, 29, 30] (Scheme 2), the regioselectivity is due to carbanion 41 attacking the formyl group of arylglyoxal 42, leading to the formation of Knoevenagel adduct 44 through path a. In the IR spectra, the characteristic absorption band at 1580 cm-1 can be assigned to the C=N bonds of the pyridazine ring. In the 13C NMR, two signals located at the lowest fields, between δ ≈ 156-159, were assigned as the carbon atoms of the corresponding C=N groups. Efforts toward preparing a single crystal from these substituted pyridazines is ongoing.

Scheme 2. Proposed mechanism for the regioselective DABCO-catalyzed synthesis of 3,6-diaryl-4-methylpyridazine derivatives.
4. Conclusions

We have developed an eco-friendly, regioselective and highly efficient three component base-organocatalyzed reaction involving various arylglyoxalmonohydrates, substituted propiophenones and hydrazine hydrate, to produce novel 3,6-diaryl-4-methylpyridazines bearing diverse aryl substituents. Mild reaction conditions, operational simplicity and facile workup are the main advantages of this synthetic strategy.

Acknowledgments

This work was partially supported by the Research Council of Payame Noor University.

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