Advances in Chemistry

Advances in Chemistry / 2014 / Article

Research Article | Open Access

Volume 2014 |Article ID 619749 | 10 pages | https://doi.org/10.1155/2014/619749

Synthesis and Antimicrobial Activity of Some Novel Heterocyclic Candidates via Michael Addition Involving 4-(4-Acetamidophenyl)-4-oxobut-2-enoic Acid

Academic Editor: Constantinos Pistos
Received28 May 2014
Revised12 Aug 2014
Accepted20 Aug 2014
Published10 Sep 2014

Abstract

This paper discusses the utility of 4-(4-acetamidophenyl)-4-oxobut-2-enoic acid as a key starting material for the preparation of a novel series of pyridazinones, thiazoles derivatives, and other heterocycles via interaction with nitrogen, sulfur, and carbon nucleophiles under Michael addition conditions and studies the antimicrobial activities of some of these compounds.

1. Introduction

β-Aroylacrylic acid derivatives showed high biological activity and exhibited a broad spectrum of physiological activities [1] (fungicidal, antitumor, hypotensive, hypolipidemic, and antibacterial). Also, β-aroylacrylic acids were considered as inhibitors for phospholipase [2, 3] and they have antiproliferative activity against human cervix carcinoma (Hela cells) [4, 5]. Besides that, β-aroylacrylic esters are important intermediates in field of medical science and agrochemicals [1]. Chemically, β-aroylacrylic acids are convenient polyelectrophilic reagents in the synthesis of heterocyclic compounds, for which the addition of nitrogen, sulfur, phosphorus, or carbon nucleophiles occurs exclusively at the α-carbon of the electrophilic center of the molecule [613]. On the other hand, aryl and heteroaryl substituted (E)-4-oxobut-2-enoic acids and their derivatives represent an important class of compounds with interesting pharmacological indications including antiulcer and cytoprotective properties [14] and kynurenine-3-hydroxylase [15] and human cytomegalovirus protease inhibiting activity [16]. Also several naturally occurring acylacrylic acids show notable antibiotic activity [17] and they are used as starting materials for the preparation of a novel series of pyridazinones and thiazoles, where many studies have been focused on pyridazinones which are characterized to possess good analgesic and anti-inflammatory activities; besides that, these studies have indicated that the heterocyclic ring substitutions at position six and the presence of acetamide side chain that is linked to the lactam nitrogen of pyridazinone ring at position two of the pyridazinone ring improve the analgesic and anti-inflammatory activities along with nil or very low ulcerogenicity [18].

The aim of this work is to study the behaviour of aza- and carba-Michael addition reactions involving 4-(4-acetamidophenyl)-4-oxobut-2-enoic acid and nitrogen and/or carbon nucleophiles which is considered as a first step to prepare pyridazinones, thiazoles, and other heterocyclic compounds.

2. Experimental

Melting points were determined on electrothermal apparatus using open capillary method and are uncorrected. Elemental analyses were carried out by the Micro Analytical Center at Cairo University. The IR spectra were recorded on FT/IR-300E Jasco spectrophotometer as potassium bromide discs. The mass spectra were run by a Shimadzu-GC-MS-QP 1000 EX apparatus at 70 eV. (1H &13C) NMR spectra were recorded on Varian Mercury 300 MHz spectrometer using TMS as internal standard.

2.1. 4-(4-Acetamidophenyl)-4-oxobut-2-enoic Acid (1)

4-(4-Acetamidophenyl)-4-oxobut-2-enoic acid was prepared according to a published procedure [19].

2.2. General Procedure for the Synthesis of Aza-Michael Adduct (2)

A mixture of β-aroylacrylic acid 1 (4 mmol) and nitrogen nucleophile (4 mmol) in dry benzene (20 mL) was left for 2 days. The resulting solid formed after concentration was filtered off, dried, and crystallized from ethanol and afforded the desired products.

2.2.1. 4-(4-Acetamidophenyl)-2-(benzylamino)-4-oxobutanoic Acid (2a)

Yield 72%; m.p. 236°C; IR (KBr): 1610, 1685, 1710, 3246, 3361 and 3532 cm−1; 1H NMR (DMSO): δ ppm 2.08 (s, 3H, CH3CO), 3.35 (s, 2H, methylene of benzyl moiety), 3.38 (m, 2H, diastereotopic methylene protons), 3.39, 3.59, 3.60, 3.95 (q, 1H stereogenic methine proton), 7.24, 7.26 (s, 2H, NH of amino and amide), 7.29 – 7.40 (m, 5H, ArH of benzyl amine moiety), 7.68, 7.72 (d, 4H, ArH), and 10.34 (s, 1H, COOH); 13C NMR (DMSO): δ = 194.11, 179.7, 168.3, 139.95, 131.97, 128.91, 127.61, 126.89, 121.21, 64.13, 51.15, 45.42 and 23.91; MS m/z: 340 [M+]; Anal. Calcd. for C19H20N2O4: C, 67.05; H, 5.92; N, 8.23%. Found: C, 66.92; H, 5.81; N, 8.32%.

2.2.2. 2-[3-(Imidazole-1-yl)propylamine]-4-(4-acetamido-phenyl)-4-oxobutanoic Acid (2b)

Yield 58%; m.p. 215°C; IR (KBr): 1604, 1680, 2600, 3409 and 3255 cm−1; 1H NMR (DMSO): δ ppm 2.13 (s, 3H, CH3CO), 1.75, 2.43, 4.15 (m, 6H, CH2 of propyl group), 6.67, 7.35, 7.82 (m, 3H, CH of imidazole moiety), 7.12 (s, 1H, NH of amide), 7.97, 8.12 (m, 4H, ArH); 13C NMR (DMSO): δ = 197.5, 180.9, 168.8, 147.8, 137.7, 132.4, 128.9, 128.2, 121.6, 120.5, 64.6, 47.4, 45.8, 44.2, 32.2, 23.9; MS m/z: 358 [M+]; Anal. Calcd. for C18H22N4O4: C, 60.32; H, 6.19; N, 15.63%. Found: C, 60.15; H, 5.95; N, 15.73%.

2.2.3. 4-(4-Acetamidophenyl)-4-oxo-2-(pyridin-2-ylmethylamino)butanoic Acid (2c)

Yield 62%; m.p. 216°C; IR (KBr): 1615, 1675, 1700, 3255, and 3412 cm−1; 1H NMR (DMSO): δ ppm 2.10 (s, 3H, CH3CO), 3.31 (m, 2H, diastereotopic protons CH2), 3.82 (s, 2H, CH2 of picolyl moiety), 7.15, 7.57, 8.22 (m, 4H, CH of pyridine), 7.62, 7.83 (m, 4H, ArH); 13C NMR (DMSO): δ = 197.3, 180.7, 168.8, 161.2, 148.5, 142.8, 139.7, 132.4, 129.1, 124.2, 121.4, 120.8, 64.2, 49.5, 45.6, 24.1; MS m/z: 341 [M+]; Anal. Calcd. for C18H19N3O4: C, 63.33; H, 5.61; N, 12.31%. Found: C, 63.12; H, 5.49; N, 12.52%.

2.2.4. 4-(4-Acetamidophenyl)-4-oxo-2-(3-(trimethoxysilyl)propylamino)butanoic Acid (2d)

Yield 71%; m.p. > 360°C; IR (KBr): 1250, 1265, 1447, 1466, 1625, 1630, 1675, 1680, 3125 and 3300 cm−1; 1H NMR (DMSO): δ ppm 2.07 (s, 3H, CH3CO), 3.45 (s, 9H, CH3 of methoxy), 4.12 (t, 1H, methine), 7.15 (s, 1H, NH of amide), 7.79, 7.85 (m, 4H, ArH); MS m/z: 312 [M+]; Anal. Calcd. for C18H28N2O7Si: C, 52.41; H, 6.84; N, 6.79%. Found: C, 52.14; H, 6.76; N, 6.92%.

2.2.5. 4-(4-Acetamidophenyl)-2-(4-methoxyphenylamino)-4-oxobutanoic Acid (2e)

Yield 79%; m.p. 197°C; IR (KBr): 1633, 1655, 3101, 3250 cm−1; 1H NMR (DMSO): δ ppm 1.97 (s, 3H, CH3CO), 2.75 (m, 2H, methylene), 3.59 (s, 3H, methoxy), 4.12 (m, 1H, methine), 6.51 (s, 4H, ArH), 7.43, 7.87 (d, 4H, ArH); 13C NMR (DMSO): δ = 197.3, 174.8, 168.8, 151.6, 142.8, 139.8, 132.4, 129.1, 121.4, 115.7, 115.2, 63.7, 55.9, 45.4, 24.1; MS m/z: 356 [M+]; Anal. Calcd. for C19H20N2O5: C, 64.04; H, 5.66; N, 7.86%. Found: C, 63.92; H, 5.45; N, 7.91%.

2.2.6. 4-(4-Acetamidophenyl)-2-(3-(dimethylamino)propylamino)-4-oxobutanoic Acid (2f)

Yield 75%; m.p. 134°C; IR (KBr): 1655, 1685, 3177, 3250, 3300 cm−1; 1H NMR (DMSO): δ ppm 1.35, 2.31, 2.47 (m, 6H, propyl group), 2.21 (s, 3H, CH3CO), 2.75 (s, 6H, N-methyl groups), 2.95 (m, 2H, methylene), 4.18 (m, 1H, methine), 6.93 (s, 1H, NH of amide), 7.62, 7.85 (m, 4H, ArH); MS m/z: 335 [M+]; Anal. Calcd. for C17H25N3O4: C, 60.88; H, 7.51; N, 12.53%. Found: C, 60.75; H, 7.33; N, 12.64%.

2.2.7. 4-(4-Acetamidophenyl)-4-oxo-2-(3-(triethoxysilyl)propylamino)butanoic Acid (2g)

Yield 59%; m.p. > 360°C; IR (KBr): 1250, 1265, 1447, 1466, 1625, 1630, 1675, 1680, 2500, 3300 cm−1; MS m/z: 454 [M+]; Anal. Calcd. for C21H34N2O7Si: C, 55.48; H, 7.54; N, 6.16%. Found: C, 55.32; H, 7.29; N, 6.27%.

2.3. 4-Benzylamino-6(4-acetamidophenyl)-2,3,4,5-tetrahydro-3(2H) Pyridazinone (3)

A mixture of aza-Michael adduct 2a (1.3 g, 0.003 mol) and hydrazine hydrate 80% (0.5 mL) in ethanol (20 mL) was refluxed for 2 hours. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from ethanol and afforded compound 3. Yield 56% m.p. 160°C; IR (KBr): 1663, 3213 and 3357 cm−1; 1H NMR (DMSO): δ ppm 1.75 (m, 2H, methylene) 2.11 (s, 3H, CH3CO), 3.49 (S, 2H, PhCH2), 7.35 (m, 5H, ArH of benzyl moiety), 7.85, 7.93 (m, 4H, ArH); 13C NMR (DMSO): δ = 168.8, 163, 146.4, 140.9, 140.3, 132.1, 129.3, 128.5, 127.9, 127.1, 121.6, 67.1, 52.2, 33.8, 23.9; MS m/z: 336 [M+]; Anal. Calcd. for C19H20N4O2: C, 67.84; H, 5.99; N, 16.66%. Found: C, 67.72; H, 5.86; N, 16.75%.

2.4. (E)-3-(4-Acetamidobenzoyl)-2-(benzylamino)-4-phenylbut-3-enoic Acid (4a)

A mixture of aza-Michael adduct 2a (1.3 g, 0.003 mol) and benzaldehyde (0.32 g, 0.003 mol) in ethanol (20 mL) was treated with few drops of triethylamine and refluxed for 2 hours. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from toluene and afforded compound 4a. Yield 74%; m.p. 183°C; IR (KBr): 1604, 1651, 1686, 3176, 3252 and 3302 cm−1; 1H NMR (DMSO): δ ppm 2.09 (s, 3H, CH3CO), 3.59 (s, 2H, methylene of benzyl moiety), 4.21 (s, 1H, methine), 7.25 (s, 1H, NH of amide), 7.21, 7.45 (m, 5H, ArH of benzylamine moiety), 7.49, 7.91 (m, 9H, phenyl protons), 7.74 (s, 1H, CH of methine), 10.93 (s, 1H, COOH); 13C NMR (DMSO): δ = 190.32, 173.91, 168.73, 144.12, 139.92, 138.19, 134.95, 134.13, 131.18, 128.23, 126.93, 121.89, 60.17, 51.52 and 24.12; MS m/z: 428 [M+]; Anal. Calcd. for C26H24N2O4: C, 72.88; H, 5.65; N, 6.54%. Found: C, 72.76; H, 5.43; N, 6.62%.

2.5. (E)-3-(4-Acetamidobenzoyl)-2-(benzylamino)-4-(pyridin-2-yl)but-3-enoic Acid (4b)

A mixture of aza-Michael adduct 2a (1.3 g, 0.003 mol) and 2-pyridinecarboxaldehyde (0.32 g, 0.003 mol) in ethanol (20 mL) was treated with few drops of triethylamine and refluxed for 2 hours. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from toluene and afforded compound 4b. Yield 69%; m.p. 182°C; IR (KBr): 1608, 1655, 1685, 3175 and 3251 cm−1; 1H NMR (DMSO): δ ppm 2.13 (s, 3H, CH3CO), 3.61 (s, 2H, methylene of benzyl moiety), 7.28 (s, 1H, NH of amide), 7.22, 7.48 (m, 5H, ArH of benzylamine moiety), 7.93 (m, 9H, phenyl protons), 8.12 (s, 1H, of ethylene), 10.95 (s, 1H, COOH); 13C NMR (DMSO): δ = 190.4, 174.2, 168.8, 154.6, 148.7, 144.2, 140.3, 139.9, 137.1, 135.2, 131.3, 128.4, 127.8, 124.2, 122.6, 122, 60.4, 51.6, 24.1; MS m/z: 429 [M+]; Anal. Calcd. for C25H23N3O4: C, 69.92; H, 5.40; N, 9.78%. Found: C, 69.58; H, 5.32; N, 9.91%.

2.6. General Procedure for the Synthesis of Pyridazinone Derivatives 5(b, c, e, f)

A mixture of aza-Michael adducts 2(b, c, e, f) (0.003 mol) and hydrazine hydrate 80% (0.5 mL) in ethanol (20 mL) was refluxed for 2 hours. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from ethanol and afforded compound 5(b, c, e, f).

2.6.1. N-(4-(5-(3-(1H-Imidazole-1-yl)propylamino)-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) Acetamide (5b)

Yield 71%; m.p. 275°C; IR (KBr): 1621, 1650, 1666, 2962, 3286 and 3400 cm−1; 1H NMR (DMSO): δ ppm 2.18 (s, 3H, CH3CO), 3.55 (m, 1H, methine), 1.65, 2.76, 4.27 (m, 6H, CH2 of propyl group) 6.83, 7.18, 7.72 (m, 3H, CH of imidazole moiety), 7.15 (s, 1H, NH of amide), 7.51, 8.11 (m, 4H, ArH), 10.95 (s, 1H, COOH); MS m/z: 354 [M+]; Anal. Calcd. for C18H22N6O2: C, 61.00; H, 6.26; N, 23.71%. Found: C, 60.91; H, 6.15; N, 23.85%.

2.6.2. N-(4-(6-Oxo-5-(pyridin-2-ylmethylamino)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) Acetamide (5c)

Yield 73%; m.p. over 360°C; IR (KBr): 1616, 1670 and 3200 cm−1; 1H NMR (DMSO): δ ppm 2.19 (s, 3H, CH3CO), 4.45 (d, 2H, methylene), 3.75 (m, 1H, methine), 7.34 (s, 1H, NH of acetamide), 7.52, 7.75 (m, 4H, ArH), 7.43, 7.89 and 8.57 (m, 4H, pyridine ring); 13C NMR (DMSO): δ = 168.8, 163, 161.4, 148.5, 146.4, 140.9, 139.7, 132.1, 129.5, 124.2, 121.8, 120.8, 66.9, 50.3, 33.6, 23.9; MS m/z: 337 [M+]; Anal. Calcd. for C18H19N5O2: C, 64.08; H, 5.68; N, 20.76%. Found: C, 63.92; H, 5.49; N, 20.89%.

2.6.3. N-(4-(5-(4-Methoxyphenylamino)-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) Acetamide (5e)

Yield 70%; m.p. 194°C; IR (KBr): 1600, 1668, 3189 and 3331 cm−1; 1H NMR (DMSO): δ ppm 1.79 (m, 2H, methylene of pyridazinone), 1.89 (s, 3H, CH3CO), 3.95 (s, 3H, of methoxy), 6.85 (m, 4H, ArH), 7.41 (s, 1H, NH of acetamide), 7.65, 7.96 (m, 4H, ArH); 13C NMR (DMSO): δ = 168.71, 162.82, 151.57, 146.32, 140.7, 139.7, 132.13, 127.7, 121.54, 115.61, 115.25, 69.34, 55.69, 33.17 and 23.95; MS m/z: 352 [M+]; Anal. Calcd. for C19H20N4O3: C, 64.76; H, 5.72; N, 15.90%. Found: C, 64.53; H, 5.58; N, 16.14%.

2.6.4. N-(4-(5-(3-(Dimethylamino)propylamino)-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) Acetamide (5f)

Yield 57%; m.p. 286°C; IR (KBr): 1600, 1649, 3108, 3187, 3262 and 3304 cm−1; 1H NMR (DMSO): δ ppm 1.67 (m, 2H, methylene of pyridazinone), 2.17 (s, 3H, CH3CO), 2.33 (s, 6H, N-methyl), 1.46, 2.38, and 2.69 (m, 6H, propyl group), 7.39 (s, 1H, NH of acetamide), 7.52, 7.76 (m, 4H, ArH); 13C NMR (DMSO): δ = 169, 146.6, 140.8, 132.1, 129.3, 121.6, 67.4, 58.9, 47.1, 45.2, 26.8, 23.9; MS m/z: 331 [M+]; Anal. Calcd. for C17H25N5O2: C, 61.61; H, 7.60; N, 21.13%. Found: C, 61.43; H, 7.39; N, 21.32%.

2.6.5. N-(4-(6-Oxo-5-(3-(trimethoxysilyl)propylamino)-1,4,5,6-tetrahydropyridazin-3-yl)phenyl) Acetamide (5d)

A mixture of keto acid 2d (1.2 g, 0.003 mol) and hydrazine hydrate 80% (0.5 mL) in dry benzene (20 mL) was heated gently for 30 minutes. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from ethanol and afforded compound 5d. Yield 58%; m.p. over 360°C; IR (KBr): 1596, 1630, 1675, and 3180 cm−1; 1H NMR (DMSO): δ ppm 1.92 (m, 2H, methylene of pyridazinone), 2.33 (s, 3H, CH3CO), 3.68 (s, 9H, of methoxy), 7.49 (s, 1H, NH of acetamide), 7.73, 7.91 (m, 4H, ArH); MS m/z: 408 [M+]; Anal. Calcd. for C18H28N4O5Si: C, 52.92; H, 6.91; N, 13.71%. Found: C, 62.74; H, 6.82; N, 13.95%.

2.7. N-(4-(2-(3-Oxo-1,2,3,4-tetrahydroquinoxalin-2-yl)acetyl) phenyl) Acetamide (6)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and o-phenylenediamine (0.43 g, 0.004 mol) in isopropyl alcohol (20 mL) was refluxed for 2 hours. The resulting solid formed after concentration was filtered off, dried, and crystallized from isopropyl alcohol and afforded compound 6. Yield 74%; m.p. 220°C; IR (KBr): 1673, 3186 and 3373 cm−1; 1H NMR (DMSO): δ ppm 2.33 (s, 3H, CH3CO), 3.45 (m, 2H, methylene), 4.22 (t, 1H methine), 5.47, 7.95 (s, 2H, NH of quinoxaline ring), 7.63, 7.84 (m, 4H, ArH), 6.83: 8.14 (m, 4H, ArH of quinoxaline); 13C NMR (DMSO): δ = 197.5, 172.6, 168.8, 143, 139.9, 132.3, 129.1, 127.1, 125.2, 121.8, 121.4, 117.2, 114.7, 64.5, 45.8, 24.1; MS m/z: 323 [M+]; Anal. Calcd. for C18H17N3O3: C, 66.86; H, 5.30; N, 13.00%. Found: C, 66.73; H, 5.45; N, 13.19%.

2.8. 4-(4-Acetamidophenyl)-2-(2-hydroxyphenylamino)-4-oxobutanoic Acid (7)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and o-aminophenol (0.44 g, 0.004 mol) in isopropyl alcohol (20 mL) was refluxed for 2 hours. The resulting solid formed after concentration was filtered off, dried, and crystallized from isopropyl alcohol and afforded compound 7. Yield 62%; m.p. 247°C; IR (KBr): 1616, 1675, 3255 and 3394 cm−1; 1H NMR (DMSO): δ ppm 2.18 (s, 3H, CH3CO), 3.25 (m, 2H, methylene), 5.43 (s, 1H, ArOH), 4.15 (m, 2H, methine), 6.82, 6.91 (m, 4H, ArH), 7.18 (s, 1H, NH of acetamide), 7.84, 7.89 (m, 4H, ArH); MS m/z: 342 [M+]; Anal. Calcd. for C18H18N2O5: C, 63.15; H, 5.30; N, 8.18%. Found: C, 62.95; H, 5.19; N, 8.29%.

2.9. N-(4-(2-(3-Oxopiperazin-2-yl)acetyl)phenyl) Acetamide (8)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and ethylenediamine (0.26 g, 0.004 mol) in dry benzene (20 mL) was refluxed for 1 hour. The resulting solid formed after concentration was filtered off, dried, and crystallized from ethanol and afforded compound 8. Yield 69%; m.p. 204°C; IR (KBr): 1663, 3136, 3149 and 3294 cm−1; 1H NMR (DMSO): δ ppm 2.37 (s, 3H, CH3CO), 2.93, 3.46 (m, 4H, methylene of piperazine moiety), 4.27 (t, 1H, methine), 7.14 (s, 1H, NH of acetamide), 7.83, 8.11 (m, 4H, ArH); 13C NMR (DMSO): δ = 169.92, 168.89, 142.79, 132.19, 129.12, 121.45, 61.96, 46.22, 45.62, 36.43 and 24.17; MS m/z: 275 [M+]; Anal. Calcd. for C14H17N3O3: C, 61.08; H, 6.22; N, 15.26%. Found: C, 61.92; H, 6.13; N, 15.35%.

2.10. N-(4-(2-(2-Amino-5-oxo-4,5-dihydrothiazol-4-yl)acetyl)phenyl) Acetamide (9)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and thiourea (0.3 g, 0.004 mol) in ethanol (20 mL) and few drops of glacial acetic acid were refluxed for 2 hours. The resulting solid formed after concentration was filtered off, dried, and crystallized from ethanol and afforded compound 9. Yield 77%; m.p. 238°C; IR (KBr): 1602, 1650, 1681, 3300 and 3347 cm−1; 1H NMR (DMSO): δ ppm 2.23 (s, 3H, CH3CO), 2.91 (m, 2H, methylene), 7.18 (s, 1H, NH of acetamide), 7.79, 7.88 (m, 4H, ArH), 8.62 (s, 2H, amino); MS m/z: 291 [M+]; Anal. Calcd. for C13H13N3O3S: C, 53.60; H, 4.50; N, 14.42%. Found: C, 53.43; H, 4.39; N, 14.64%.

2.11. N-(4-(6-Aminothiazolo[5,4-c]pyridazin-3-yl)phenyl) Acetamide (10)

A mixture of compound 9 (0.87 g, 0.003 mol) and hydrazine hydrate 80% (0.5 mL) in ethanol (20 mL) was refluxed for 2 hours. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from ethanol and afforded compound 10. Yield 55%; m.p. 244°C; IR (KBr): 1604, 1650, 3308 and 3417 cm−1; 1H NMR (DMSO): δ ppm 2.13 (s, 3H, CH3CO), 6.78 (s, 2H, amino), 7.18 (s, 1H, NH of acetamide), 7.64 (s, 1H, of pyridazinone), 7.82, 7.93 (m, 4H, ArH); 13C NMR (DMSO): δ = 168.67, 161.25, 142.38, 138.41, 128.57, 127.59, 125.18, 119.59, 108.14 and 24.18; MS m/z: 285 [M+]; Anal. Calcd. for C13H11N5S: C, 54.72; H, 3.89; N, 24.55%. Found: C, 54.63; H, 3.75; N, 24.81%.

2.12. N-(4-(6-Amino-4H-thiazolo[4,5-e][]oxazin-3-yl)phenyl) Acetamide (11)

A mixture of compound 9 (0.87 g, 0.003 mol) and hydroxylamine hydrochloride (0.2 g, 0.003 mol) and few drops of sodium hydroxide 30% in ethanol (20 mL) was refluxed for 1 hour. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from ethanol and afforded compound 11. Yield 53%; m.p. 223°C; IR (KBr): 1620, 1660, 3200 and 3350 cm−1; 1H NMR (DMSO): δ ppm 2.24 (s, 3H, CH3CO), 4.15 (s, 2H, oxazine ring), 6.85 (s, 2H, amino), 7.21 (s, 1H, NH of acetamide), 7.55 : 8.22 (m, 4H, ArH); MS m/z: 288 [M+]; Anal. Calcd. for C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43%. Found: C, 53.96; H, 4.11; N, 19.62%.

2.13. 2-(2-(4-Acetamidophenyl)-2-oxoethyl)-3-(ethoxycarbonyl)-4-oxopentanoic Acid (12)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and ethyl acetoacetate (0.52 g, 0.004 mol) and few drops of sodium hydroxide 30% in ethanol (20 mL) was left for 3 days and then acidified by HCl and the resulting solid formed after concentration was filtered off, dried, and crystallized from toluene and afforded compound 12. Yield 73%; m.p. over 360°C; IR (KBr): 1666, 1700, 3200 and 3332 cm−1; 1H NMR (DMSO): δ ppm 1.43 (t, 3H, CH3 of ester) 2.26 (s, 3H, CH3CO of acetamide), 2.45 (s, 3H, CH3CO), 3.11 (d, 2H, methylene), 3.45, 3.84 (m, 2H, of 2 methine groups), 4.35 (q, 2H, methylene of ester), 7.17 (s, 1H, NH of acetamide), 7.63, 7.82 (m, 4H, ArH); MS m/z: 363 [M+]; Anal. Calcd. for C18H21NO7: C, 59.50; H, 5.83; N, 3.85%. Found: C, 59.34; H, 5.72; N, 3.94%.

2.14. 2-(2-(4-Acetamidophenyl)-2-oxoethyl)-3-benzoyl-4-ethoxy-4-oxobutanoic Acid (13)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and ethyl benzoyl acetate (0.77 g, 0.004 mol) and few drops of sodium hydroxide 30% in ethanol (20 mL) was left for 2 days and then acidified by HCl and the resulting solid formed after concentration was filtered off, dried, and crystallized from toluene and afforded compound 13. Yield 72%; m.p. over 360°C; IR (KBr): 1640, 1676, 1700, 1740, 3200 and 3415 cm−1; 1H NMR (DMSO): δ ppm 1.39 (t, 3H, CH3 of ester) 2.17 (s, 3H, CH3CO), 3.33 (d, 2H, methylene), 3.95, 4.23 (m, 2H, of 2 methine groups), 4.42 (q, 2H, methylene of ester), 7.19 (s, 1H, NH of acetamide), 7.68, 7.89 (m, 4H, ArH), 7.58, 766, 7.99 (m, 5H, ArH); 13C NMR (DMSO): δ = 197.68, 195.32, 178.42, 169.82, 168.78, 142.71, 135.35, 132.87, 132.11, 128.46, 121.29, 61.16, 51.58, 36.13, 30.27, 23.94 and 14.25; MS m/z: 425 [M+]; Anal. Calcd. for C23H23NO7: C, 64.93; H, 5.45; N, 3.29%. Found: C, 64.81; H, 5.39; N, 3.34%.

2.15. 2-(2-(4-Acetamidophenyl)-2-oxoethyl)-3-acetyl-4-oxopentanoic Acid (14)

A mixture of β-aroylacrylic acid 1 (1 g, 0.004 mol) and acetylacetone (0.4 g, 0.004 mol) and few drops of sodium hydroxide 30% in ethanol (20 mL) was left for 2 days and then acidified by HCl and the resulting solid formed after concentration was filtered off, dried, and crystallized from toluene and afforded compound 14. Yield 74%; m.p. over 360°C; IR (KBr): 1630, 1661, 1690, 1710, 3200 and 3428 cm−1; 1H NMR (DMSO): δ ppm 2.27 (s, 3H, CH3CO of acetamide), 2.45 (s, 6H, CH3CO), 3.23 (m, 2H, methylene), 3.44, 3.63 (m, 2H, of 2 methine groups), 7.31 (s, 1H, NH of acetamide), 7.59, 7.78 (m, 4H, ArH); MS m/z: 333 [M+]; Anal. Calcd. for C17H19NO6: C, 61.25; H, 5.75; N, 4.20%. Found: C, 61.16; H, 5.59; N, 4.32%.

2.16. N-(4-(1,4-Dioxo-5-phenyl-2,3,4,4a,9,9a-hexahydro-1H-pyridazino[4,5-d][]diazepin-8-yl)phenyl) Acetamide (15)

A mixture of compound 13 (1.28 g, 0.003 mol) and hydrazine hydrate (80% 0.5 mL) in ethanol (20 mL) was refluxed for 3 hours. The reaction mixture was allowed to cool and the separated product was filtered off, dried, and crystallized from ethanol and afforded compound 15. Yield 45%; m.p. over 360°C; IR (KBr): 1645, 1673, 3241, 3297 and 3321 cm−1; 1H NMR (DMSO): δ ppm 1.53 (m, 2H, methylene of diazepine), 2.12 (s, 3H, CH3CO), 2.67, 3.24 (m, 2H of 2 methine of diazepine), 7.14 (s, 1H, NH of acetamide), 7.43, 7.85 (m, 5H, ArH), 7.62, 7.74 (m, 4H, ArH), 8.13 (d, 2H, 2 NH of pyridazinone); 13C NMR (DMSO): δ = 177.1, 174.2, 168.9, 157.6, 146.5, 140.7, 134.1, 132.2, 130.9, 129.3, 128.7, 128.3, 121.6, 38.7, 26.6, 26.4, 23.9; MS m/z: 389 [M+]; Anal. Calcd. for C21H19N5O3: C, 64.77; H, 4.92; N, 17.98%. Found: C, 64.61; H, 4.86; N, 18.09%.

3. Results and Discussion

The authors aimed through this research to study the behaviour of 4-(4-acetamidophenyl)-4-oxobut-2-enoic acid 1 towards some nitrogen nucleophiles. Thus the aza-Michael reaction of compound 1 with nitrogen nucleophiles, namely, benzylamine, 3-(1-H-imidazole-1-yl)-propylamine, 2-picolylamine, 3-(trimethoxysilyl)propyl amine, p-anisidine, 3-(N,N-dimethyl)aminopropylamine, and 3-(triethoxysilyl)propylamine, in dry benzene afforded the aza-Michael adducts’ compounds (2a–g), respectively (Scheme 1). The structures of compounds (2a–g) were confirmed by elemental analysis and spectral data; EIMS of compound 2a exhibits m/e 340 (M+̣) and 1H NMR of compound 2a in DMSO shows signals at (δ ppm) 2.08 (s, 3H, CH3CO), 3.35 (s, 2H, methylene of benzyl group), 3.38 (m, 2H, diastereotopic methylene protons), 3.393.95 (q, 1H, stereogenic methine proton), 7.24 and 7.26 (s, 2H, NH of amido group, exchangeable), 7.297.40 (m, 5H, ArH of benzylamine moiety), 7.68 and 7.72 (2d, 4H, phenyl protons), and 10.34 (s, 1H, COOH, exchangeable).

619749.sch.001

Furthermore the structure of compound 2a was established chemically from the reaction with aromatic aldehydes (Scheme 2); when compound 2a was allowed to react with benzaldehyde and/or pyridine-2-carboxyaldehyde in boiling ethanol in the presence of triethylamine (TEA) as a base it afforded the arylidene derivatives’ compounds (4a, b). The structures of compounds (4a, b) were confirmed by elemental analysis and spectral data; EIMS of compound 4a exhibits the molecular ion peak m/e 428 (M+̣) and 1H NMR of 4a reveals signals at (δ ppm) 2.09 (s, 3H, CH3CO), 3.59 (s, 2H, methylene of benzyl moiety), 7.25 (s, 1H, NH of amide), and 10.93 (s, 1H, COOH).

619749.sch.002

In the recent years a substantial number of 3-(2H)-pyridazinones have been reported to possess antimicrobial [20, 21], potent analgesic [22], anti-inflammatory [2226], antifeedant [27], herbicidal [28], antihypertensive [2931] and antiplatelet, [3234], anticancer [35], and other anticipated biological [9] and pharmacological properties [36, 37]. From the previous facts, authors planned to synthesize pyridazinones’ derivatives through reacting acids 2a–f with hydrazine hydrate (Schemes 2 and 3).

619749.sch.003

Thus when acids 2a–f were allowed to react with hydrazine hydrate in boiling ethanol they afforded interesting pyridazinone derivatives 3 (Scheme 2) and (5b–f) (Scheme 3). The structures of compounds (5b–f) were ascertained by elemental analysis and spectral data; EIMS of compound 5b exhibits m/e 354 (M+̣) and 1H NMR of compound 5b in DMSO shows signals at (δ ppm) 2.18 (s, 3H, CH3CO), 3.55 (m, 1H, methine), 1.65, 2.76, and 4.27 (m, 6H, CH2 of propyl group), 6.83, 7.18, and 7.72 (m, 3H, CH of imidazole moiety), 7.15 (s, 1H, NH of amide), 7.51 and 8.11 (m, 4H, ArH), and 10.95 (s, 1H, COOH).

However the reactions of and β unsaturated carbonyl compounds with binucleophiles provide a convenient route to interesting heterocycles (Scheme 4).

619749.sch.004

Recently [38] it was reported that β-aroylacrylic acids react with o-phenylenediamine to give quinoxalin-2-ones. Thus when compound 1 was allowed to react with o-phenylenediamine in isopropyl alcohol it yielded the quinoxaline derivative compound 6; the reaction takes place via aza-Michael addition followed by dehydration leading to the desired product; the structure of compound 6 was confirmed by elemental analysis and spectral data. IR spectrum of compound 6 revealed strong absorption bands at 1673, 3107, 3186, 3260, and 3373 cm−1 attributable to and bonded and nonbonded, respectively.

While the reaction of compound 1 with o-aminophenol in isopropyl alcohol afforded the aza-Michael adduct compound 7, the structure of compound 7 was confirmed by elemental analysis and spectral data. Another binucleophile, namely, ethylenediamine, was reacted with 4-(4-acetamidophenyl)-4-oxobut-2-enoic acid 1 to give the piperazine derivative compound 8 via the addition of amino group to the carbon of the activated double bound followed by ring closure; the structure of N-(4-(2-(3-oxopiperazin-2-yl)acetyl)phenyl)acetamide 8 was confirmed by elemental analysis and spectral data; 1H NMR of compound 8 in DMSO exhibits signals at (δ ppm) 2.37 (s, 3H, CH3CO), 2.93 and 3.46 (m, 4H, methylene of piperazin moiety), 4.27 (t, 1H, methine), 7.14 (s, 1H, NH of acetamide), and 7.83 and 8.11 (m, 4H, ArH).

Previously [39], it has been reported that thiourea reacted with 4-(4-chloro-3-methyl)phenyl-4-oxobut-2-enoic acid and yielded 2-amino-4-hydroxy-5-(4′-chloro-3′-methyl)benzoyl methyl thiazole. This prompted us to extend the study of the behaviour of the activated olefinic double bond in 4-(4-acetamido)phenyl-4-oxobut-2-enoic acid 1 towards the same reagent. Thus when acid 1 was allowed to react with thiourea in boiling ethanol in the presence of few drops of glacial acetic acid, it afforded N-(4-(2-(2-amino-5-hydroxy-thiazol-4-yl)acetyl)phenyl)acetamide 9 (Scheme 5). The structure of compound 9 was confirmed by elemental analysis and spectral data; IR spectrum of 9 shows well-defined absorption bands attributable to and groups at 3347 and 3300 cm−1, carbonyl group bands at 1681 and 1650 cm−1, and of thiazole at 1602 cm−1.

619749.sch.005

Furthermore, the reaction of thiazole derivative 9 with hydrazine hydrate and hydroxyl amine was investigated. In this way polynuclear systems containing a thiazole ring fused with another heterocyclic ring are usually formed (Scheme 6). Condensation of 9 with hydrazine hydrate in boiling ethanol yielded N-(4-(6-aminothiazolo[5,4-c]pyridazin-3-yl)phenyl)acetamide 10 (Scheme 6). The reaction of the thiazole 9 with hydroxylamine hydrochloride in alcoholic sodium hydroxide affected condensation with carbonyl group and subsequent ring closure, yielding oxazine derivative compound 11.

619749.sch.006

The structures of compound 10 and compound 11 were confirmed by elemental analysis and spectral data; EIMS of compound 10 exhibits m/e 285 (M+̣), while 1H NMR of compound 11 in DMSO shows signals at (δ ppm) 2.24 (s, 3H, CH3CO), 4.15 (s, 2H, CH2 of oxazine ring), 6.85 (s, 2H, amino), 7.21 (s, 1H, NH of acetamide), and 7.61–7.85 (m, 4H, phenyl protons).

On the other hand, the authors studied the behavior of 4-(4-acetamidophenyl)-4-oxobut-2-enoic acid 1 towards some carbon nucleophiles under Michael reaction conditions. So when acid 1 was allowed to react with carbon nucleophiles, namely, ethyl acetoacetate, ethyl benzoylacetate, and acetylacetone, it yielded the Michael adducts 12, 13, and 14, respectively (Scheme 7).

619749.sch.007

Furthermore the interaction of Michael adduct compound 13 with hydrazine hydrate gave the diazepine derivative compound 15 (Scheme 8); the structures of compounds 12–15 were confirmed by elemental analysis and spectral data.

619749.sch.008

4. Antimicrobial Activity

β-Aroylacrylic acid and its derivatives represent one of the most active classes of compounds that possess a wide spectrum of biological activity. Many of these compounds have been used for the treatment of various diseases and exhibit antibacterial activity and a broad spectrum of physiological (fungicidal, antitumor, hypotensive, hypolipidemic, etc.) activities [1]. In the present work, synthesis of some β-aroylacrylic acids and their derivatives was reported. Some of the new synthesized compounds have been tested for their antimicrobial activity evaluation. Antimicrobial activity of the tested samples was determined using a modified Kirby-Bauer disc diffusion method [40]. Briefly, 100 µl of the test bacteria was grown in 10 mL of fresh media (Mueller-Hinton agar) until they reached a count of approximately 108 cells/mL for bacteria [41]. 100 µl of microbial suspension was spread onto agar plates corresponding to the broth in which they were maintained. The tested organisms were the gram +ve bacteria (Staphylococcus aureus ATCC 25923 and Bacillus subtilis MTCC 121) and the gram −ve bacteria (Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853), by using sterile Whatman-No1 filter paper disks (8.0 mm diameter). Each compound was dissolved in DMSO. Filter paper disks were loaded with certain amount of the tested material (30 μg/disk) and then left with care under hot air to complete dryness. The disks were deposited on the surface of agar plates and the disks were incubated at 5°C for 1 h, to permit good diffusion. All the plates were then incubated for 24 h at 37°C. The diameter of inhibition zones was measured in mm. Table 1 represents the antibacterial activity of some new synthesized compounds.


SampleInhibition zone diameter (mm/mg sample)
Escherichia coliATCC 25922
(G−)
Pseudomonas aeruginosa ATCC 27853
(G−)
Staphylococcus aureus ATCC 25922
(G+)
Bacillus subtilis MTCC 121
(G+)

2b++++++
2e+++
3+++
6++++++
8+++
10+++++++++
11++++++
15++++++++

−: no activity, +: weak activity (diameter 5 : 10 mm), ++: moderate activity (diameter 10 : 15 mm), and +++: strong activity (diameter > 15 mm).

5. Conclusions

Novel pyridazinone, thiazole, diazepine, and other heterocyclic compounds were successfully synthesized through simple methods. The structures for the new synthesized compounds were confirmed by elemental analysis, FTIR, NMR, and mass spectra. These compounds were evaluated for in vitro antibacterial activities against some strains of bacteria. And some of them showed significant activities for both gram positive and gram negative bacteria, where it was found that compounds 2b, 2e, and 3 showed moderate to weak activity against gram +ve and gram −ve bacteria which may be due to the pyridazinone moiety, while compounds 6 and 8 showed moderate to weak activity against gram +ve and gram −ve bacteria because of quinoxaline and pyrazine moiety, and compounds 10 and 11 showed strong to moderate activity against gram +ve and gram –ve bacteria which may be due to thiazole ring; finally compound 15 showed strong activity against gram +ve and gram −ve bacteria because of diazepine moiety.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

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