Abstract
Rapid and facile access to novel chromeno[4,3-b]pyridine-2,5-dione derivatives was achieved by a mild base catalysed reaction of 4-chloro-3-formylcoumarin and acetoacetamides in PEG-300 as recyclable solvent. The compounds were evaluated for their antimicrobial activities against 3 Gram-positive and 3 Gram-negative bacteria (Staphylococcus epidermis, Vibrio parahaemolyticus, Bacillus subtilis, Escherichia coli, Staphylococcus aureus and Klebsiella pneumonia) with Cefotaxime control. They were further subjected to antioxidant studies using DPPH test with ascorbic acid control. While compounds 5d and 5k showed promising broad spectrum antibacterial properties against all the evaluated bacteria, compound 5g exhibited good antioxidant properties.
Tricyclic chromeno[4,3-b]pyridine-2,5-diones are precipitated as pure products from the reaction of 4-chloro-3-formyl-coumarin and acetoacetamides in PEG-300 as recyclable solvent and evaluated for their antimicrobial and antioxidant properties.
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1 Introduction
Coumarins and 2-pyridones are classic heterocyclic scaffolds which constitute vital substructures of several natural products and received enormous admiration for their wide range of applications. Secondary metabolites and synthetic intermediates of 2-pyridone scaffolds demonstrate broad spectrum of synthetic, material and biological applications [1]. Ricinine [2] with its remarkable CNS stimulant activity was the first isolated 2-pyridone natural product followed by the discovery of analogous antibiotic natural products such as elfamycin, [3] ilicolicin [4] and efratomycin [5]. With excellent vasodilating properties, [6] synthetic 2-pyridone analogues milrinone and amrinone are extensively used for the treatment of acute congestive heart failure. Similarly, L-697,661 was identified as a specific non-nucleoside reverse transcriptase inhibitor which demonstrates efficient anti-HIV properties [7]. 2-Pyridone is an integral core of several alkaloids [8] and is a key structural intermediate in the bacterial metabolism [9]. Krawczyk et al. have developed 2-pyridones as novel class of multi-drug resistant modulators [10]. On the other hand, coumarins [11] exhibit excellent antioxidant, [12] antibacterial, [13] antirhinovirus, [14] cytotoxic, [15] anticancer, [16] antimicrobial, [17] and antihypertensive properties [18]. Aminocoumarins such as novobiocin, clorobiocin and coumermycin A1 with nitrogen functional group attached to the coumarin ring are elegant class of antibiotics which inhibit DNA gyrase enzyme involved in cell division of bacteria [19].
Fused heterocyclic scaffolds with nitrogen and oxygen atoms are fundamental to the medicinal chemistry for the development of several new drugs. To date, very few reports are available in the literature regarding the synthesis of fused chromeno[4,3-b]pyridine-2,5-dione scaffolds. One of the earliest documented report by Soliman et al. demonstrates synthesis of these scaffolds by the reaction of 4-hydroxycoumarin and aminocrotonitrile [20]. In a multi-step protocol, Heber et al. reported the reaction of alkylaminocoumarin-3-carbaldehydes with Wittig ylides to achieve the required targets, albeit in poor yields [21]. Ivanov et al. reported Erlenmeyer–Ploechl reaction of alkylaminocoumarin-3-carbaldehydes with N-acetylgylcine derivatives to yield the chromeno[4,3-b]pyridine-2,5-dione derivatives [22]. However, the method suffers from the limitations of harsh reaction conditions of refluxing acetic acid and limited to the synthesis of only N-alkyl derivatives in poor yields. Similarly, alternative synthesis of these fused systems reported by Kafka et al. using camphoranils with excess of dimethylmalonate suffer from poor yields [23]. Owing to the necessity for an improved methodology for the synthesis of these fused scaffolds and prevalence of impressive biological properties of both pyridine-2-ones and coumarins, we were interested in developing a mild synthetic protocol for the synthesis of the fused chromeno[4,3-b]pyridine-2,5-dione scaffolds.
2 Experimental
The solvents, bases and other general reagents were of AR grade and purchased from Otto Chemie. 1H and 13C NMR spectra are recorded on 400 MHz Bruker Biospin FT-NMR spectrometer with CDCl3 as solvent and TMS as internal standard. Melting points were determined using NETZSCH DSC 200 instrument. IR spectra were recorded over Bruker a alpha-T spectrophotometer. Mass spectral analysis was carried out using EIMStechniques. Elemental analysis was performed on Elementar Vario EL III CHNS analyzer. Analytical thin-layer chromatography (TLC) was performed on 0.2 mm precoated plate Kieselgel 60 F254 (Merck).
2.1 General procedure for synthesis of acetoacetamides derivatives (3a–p)
To a stirred solution of amine (0.01 mol) in 10 ml of PEG-300 was added to ethylacetoacatate (0.03 mol) in 100 ml round bottom flask and refluxed at 120 °C for 1.5–2 h. After completion of the reaction (monitored by TLC) the reaction mixture was cooled and extracted with cold diethyl ether (3 × 10 mL) and purified by column chromatography (10–25% EtOAc in Hexane) gave the pure product 3a–p. Final products were confirmed with the reported literature [24].
2.2 General method for the synthesis of 3-acetyl-1-phenyl-1H-chromeno[4,3-b]pyridine-2,5-dione 5a–p
To a solution of 4-chloro-3-formylcoumarin 1a (0.5 mmol) in PEG-300 (2 mL) was added acetoacetamides 3a (0.5 mmol) and triethylamine (0.5 mmol) then stirred at 25°C for 15 min. The precipitate obtained was filtered by Whatman filter paper, washed with water and dried. Similar procedure was employed in case of substrates 5b–p.
2.2a 3-Acetyl-1-phenyl-1H-chromeno[4,3-b]pyridine-2, 5-dione (5a):
White solid, mp 153–154°C; [Found: C, 72.42; H, 3.92; N, 4.22. C20H13NO4 requires C, 72.50; H 3.95; N, 4.23%]; ν max (KBr) 1719, 1702, 1679, 1618, 1583, 1479, 1418, 1240, 1041 cm−1; δ H (400 MHz CDCl3) 8.73 (1H, s), 7.72 (1H, d, J 6.8 Hz), 7.56–7.50 (4H, m), 7.44–7.43 (2H, m), 7.30 (1H, d, J 6.8 Hz), 7.28–7.25 (1 H, m), 2.71 (3H, s); δ C (100 MHz, CDCl3) δ: 203.42, 159.84, 159.20,, 152.57, 145.68, 138.61, 137.14, 133.53, 129.78, 129.64,127.02, 126.07,125.98, 125.13, 118.77, 114.50, 103.35, 31.41, 8.57.; LCMS: MH+, 332.
2.2b 3-Acetyl-1-(4-fluorophenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5b):
White solid, mp 134–135°C; [Found: C, 68.70; H, 3.43; N, 4.00. C20H12FNO4 requires C, 68.77; H, 3.46; N, 4.01%]; ν max (KBr) 1721, 1705, 1680, 1621, 1579, 1469, 1421, 1245, 1048 cm−1; δ H (400 MHz CDCl3) 8.69 (1H, s), 7.70 (1H, dd, J 7.6 Hz, J 1.2Hz), 7.58 (1H, td, J 7.6 Hz,J 1.2 Hz), 7.49–7.40 (2H, m), 7.32 (1H, dd, J 6.8 Hz, J 0.8 Hz), 7.30–7.20 (3H, m), 2.70 (3 H, s); δ C (100 MHz CDCl3) 203.25, 163.87, 161.87, 159.83, 159.10, 152.54, 145.52, 137.22, 134.49, 133.63, 128.17, 127.01, 125.97, 125.18, 118.80, 116.60, 114.41, 103.51, 31.39; LCMS: MH+, 350.
2.2c 3-Acetyl-1-(3-fluorophenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5c):
White solid, mp 138–139 °C; [Found: C, 68.70; H, 3.43; N, 4.00. C20H12FNO4 requires C, 68.77; H, 3.46; N, 4.01%]; ν max (KBr) 1721, 1705, 1683, 1621, 1587, 1488, 1421, 1243, 1021 cm−1; δ H (400 MHz CDCl3) 8.70 (1H, s), 7.71 (1H, d, J 6.8 Hz), 7.59–7.51 (2H, m), 7.31 (1H, d, J 6.8 Hz), 7.30–7.26 (4H, m), 2.70 (3H, s); δ C (100 MHz CDCl3) 203.18,163.59, 161.60, 159.58, 159.03, 152.54, 145.28, 139.66, 139.58, 137.23, 133.69, 131.05, 130.98, m127.02, 126.07, 125.20, 121.91, 118.80, 117.13, 116.96, 114.35, 114.33, 114.13, 103.65, 31.39; LCMS: MH+, 350.
2.2d 3-Acetyl-1-(4-bromophenyl)-11H-chromeno[4,3-b]pyridine-2,5-dione (5d):
White solid, mp 138–139°C; [Found: C, 55.80; H, 2.88. C18H11BrO5 requires C, 55.84; H, 2.86%]; ν max (KBr) 1721, 1705, 1682, 1621, 1577, 1472, 1410, 1233, 1033 cm−1; δ H (400 MHz CDCl3) 7.83–7.77 (2H, m), 7.59–7.51(2H, m), 7.45 (1H, d, J 8.8 Hz), 7.32 (1H, t, J 7.6 Hz), 7.21 (1H, d, J 8.4 Hz), 6.80 (1H, d, J 8.8 Hz), 2.10 (3H, s); δ C (100 MHz CDCl3)203.14, 159.54, 158.96, 145.18, 137.42, 137.11, 133.60, 132.74, 127.71, 126.91, 125.88, 125.13, 123.83, 118.71, 114.29, 103.55, 45.79, 31.33, 8.56; LCMS: MH+, 411.
2.2e 3-Acetyl-1-(3-bromophenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5e):
White solid, mp 132–133°C; [Found: C, 58.56; H, 2.95, N, 3.41. C20H12BrNO4 requires C, 58.50; H, 2.92, N, 3.41%]; ν max (KBr) 1723, 1705, 1683, 1620, 1533, 1480, 1420, 1245, 1033 cm−1; δ H (400 MHz CDCl3) 8.68 (1H, s), 7.76–7.70 (3H, m), 7.57 (1H, td, J 6.8 Hz, 0.8 Hz), 7.49–7.38 (3H, m), 7.33 (1H, d, J 6.8 Hz), 7.28 (1H, dd, J 6.8 Hz, 0.8 Hz), 2.70 (3H, s); δ C (100 MHz CDCl3) 203.09, 159.55, 158.58, 152.51, 145.20, 139.48, 137.22, 133.67, 132.95, 130.82, 129.37, 127.00, 126.01, 125.18, 124.90, 122.90, 118.77, 114.32, 103.64, 58.30, 31.37, 18.33; LCMS: MH+, 411.
2.2f 3-Acetyl-1-(4-chlorophenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5f):
White solid, mp 130–131°C; [Found: C, 65.61; H, 3.28, N, 3.82. C19H14O5 requires C, 65.67; H, 3.31, N, 3.83%]; ν max (KBr) 1723, 1706, 1683, 1630, 1579, 1481, 1420, 1238, 1033 cm−1; δ H (400 MHz CDCl3) 8.67 (1H, s), 7.68 (1H, d, J 6.8 Hz), 7.61–7.46 (3H, m), 7.40 (1H, d, J 7.2 Hz), 7.30 (1H, d, J 6.4 Hz), 7.25 (1H, t, J 6.0 Hz), 2.68 (3H, s); δ C (100 MHz CDCl3) 203.18, 159.65, 159.02, 152.52, 145.28, 137.17, 136.95, 135.85, 133.65, 129.81, 127.48, 126.98, 125.96, 125.18, 118.77, 114.36, 103.59, 60.32, 31.38, 14.13; LCMS: MH+, 366.
2.2g 3-Acetyl-1-p-tolyl-1H-chromeno[4,3-b]pyridine-2,5-dione (5g):
White solid, mp 132–133°C; [Found: C, 73.03; H, 4.38, N, 4.06 C20H16O6 requires C, 72.96; H, 4.38, N, 4.05%]; ν max (KBr) 1722, 1705, 1683, 1621, 1579, 1480, 1420, 1230, 1039 cm−1; δ H (400 MHz CDCl3) 8.70 (1H, s), 7.70 (1H, d, J 6.4 Hz), 7.55 (1H, t, J 5.6 Hz), 7.33–7.23 (6H, m), 2.69 (3H, s), 2.42 (3H, s); δ C (100 MHz CDCl3) 203.45, 159.86, 159.15, 152.44, 145.75, 139.91, 136.92, 136.02, 133.37, 130.07, 126.90, 125.69, 125.00, 118.64, 114.44, 103.10, 31.33, 21.08, 18.26; LCMS: MH+, 346.
2.2h 3-Acetyl-1-m-tolyl-1H-chromeno[4,3-b]pyridine-2,5-dione (5h):
White solid, mp 138–139°C; [Found: C, 73.03; H, 4.38, N, 4.06 C20H16O6 requires C, 72.96; H, 4.38, N, 4.05%]; ν max (KBr) 1721, 1705, 1682, 1623, 1579, 1482, 1420, 1241, 1039 cm−1; δ H (400 MHz CDCl3) 8.70 (1H, s)), 7.70 (1H, s, J 6.4 Hz), 7.55 (1H, t, J 5.6 Hz), 7.33–7.23 (6H, m), 2.69 (3H, s), 2.42 (3H, s); δ C (100 MHz CDCl3) 203.51, 159.95, 159.30, 152.63, 145.79, 139.99, 138.58, 137.15, 133.53, 130.59, 129.48, 127.07, 126.62, 125.99, 125.16, 123.07, 118.82, 114.58, 103.27, 31.46, 21.30; LCMS: MH+, 346.
2.2i 3-Acetyl-1-(4-methoxyphenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5i):
White solid, mp 230–232°C; [Found: C, 58.22; H, 2.69; N, 3.75. C21H15NO5 requires C, 58.23; H, 2.71, N, 3.77%]; ν max (KBr) 1722, 1708, 1683, 1620, 1579, 1480, 1420, 1239, 1039 cm−1; δ H (400 MHz CDCl3) 8.70 (1H, s), 7.70 (1H, d, J 6.8 Hz), 7.55 (1H, t, J 6.8 Hz), 7.35–7.22 (4H, m), 7.02 (1H, d, J 7.2 Hz), 3.86 (3H, s), 2.70 (3H, s); δ C (100 MHz CDCl3)) 203.50, 160.30, 160.02, 159.22, 152.51, 145.87, 136.97, 133.42, 131.29, 127.20, 125.06, 118.70, 114.70, 103.13, 55,59, 31.38; LCMS: MH+, 362.
2.2j 3-Acetyl-1-(3-methoxyphenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5j):
White solid, mp 133–135°C; [Found: C, 69.73; H, 4.15; N, 3.87. C21H15NO5 requires C, 69.80; H, 4.18, N, 3.88%]; ν max (KBr) 1723, 1707, 1688, 1620, 1579, 1481, 1420, 1240, 1041 cm−1; δ H (400 MHz CDCl3) 8.71 (1H, s), 7.70 (1H, d, J 6.4 Hz), 7.56 (1H, t, J 6.4 Hz), 7.44 (1H, t, J 6.4 Hz), 7.31 (1H, d, J 6.4 Hz), 7.39–7.21 (2H, m), 7.04 (1H, d, J 6.8 Hz), 7.00–6.96 (2H, m), 3.85 (3H, s), 2.71 (3H, s); δ C (100 MHz CDCl3) 203.44, 160.33, 159.15, 152.53, 145.70, 139.57, 137.05, 133.50, 130.40, 126.98, 125.93, 125.10, 118.09, 115.76, 114.47, 111.87, 103.22, 55.58, 31.40; LCMS: MH+, 362.
2.2k 3-Acetyl-1-(3-nitrophenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5k):
White solid, mp 134–136°C; [Found: C, 63.77; H, 3.28; N, 7.44. C20H12N2O6 requires C, 63.83; H, 3.21, N, 7.44%]; ν max (KBr) 1725, 1706, 1681, 1620, 1579, 1477, 1420, 1238, 1038 cm−1; δ H (400 MHz CDCl3) 8.71 (1H, s), 8.42–8.31 (2H, m), 7.83 (1H, d, J 6.4 Hz), 7.77 (1H, t, J 6.4 Hz), 7.70 (1H, d, J 6.4 Hz, ), 7.59 (1H, t, J 6.0 Hz), 7.33 (1H, d, J 6.8 Hz), 7.28 (1H, t, J 6.0 Hz), 2.71 (3H, s); δ C (100 MHz CDCl3) 202.81, 159.50, 158.86, 152.64, 148.75, 144.65, 139.29, 137.65, 134.02, 132.32, 130.69, 127.16, 126.30, 125.39, 124.65, 121.87, 118.96, 114.27, 104.34, 31.44; LCMS: MH+, 377.
2.2l 3-Acetyl-1-(2-nitrophenyl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5l):
White solid, mp 138–140°C; [Found: C, 62.12; H, 3.54; N, 3.81. C19H13NO7 requires C, 62.13; H, 3.57, N, 3.81%]; ν max (KBr) 1723, 1704, 1682, 1620, 1579, 1482, 1420, 1218, 1045 cm−1; δ H (400 MHz CDCl3) 8.69 (1H, s), 8.23 (1H, d, J 6.4 Hz), 8.12 (1H, d, J 6.8 Hz), 7.82–7.71 (2H, m), 7.77 (1H, t, J 6.4 Hz), 7.70 (1H, t, J 6.4 Hz, ), 7.59 (1H, t, J 6.0 Hz), 7.33–722 (2H, m), 2.69 (3H, s); δ C (100 MHz CDCl3) 160.12, 158.50, 152.57, 151.22, 144.21, 137.57, 132.38, 125.30, 125.01, 124.01, 120.32, 119.18, 118.12, 117.57, 103.77, 98.56, 91.40, 23.56, 21.07; LCMS: MH+, 377.
2.2m 3-Acetyl-1-(pyridin-2-yl)-1H-chromeno[4,3-b]pyridine-2,5-dione (5m):
white solid, mp 132–135°C; [Found: C, 68.61; H, 3.61 N, 8.42. C19H12N2O4 requires 68.67; H, 3.64 N, 8.43%]; ν max (KBr) 1724, 1707, 1682, 1621, 1581, 1481, 1421, 1239, 1040 cm−1; δ H (400 MHz CDCl3) δ 9.04 (1H, s), 8.69 (1H, s), 8.08 (1H,t, J 6.0 Hz), 7.93 (1H, d, J 5.4 Hz), 7.69–7.59 (3H, m), 7.41–7.36 (2H, m), 2.64 (3H, s); δ C (100 MHz CDCl3) 188.30, 186.10, 165.55, 161.27, 159.09, 154.79, 135.93, 135.47, 129.64, 125.86, 125.72, 125.45, 124.67, 117.46, 116.49, 114.45, 110.17; LCMS: MH+, 333.
2.2n 3-Acetyl-1-butyl-1H-chromeno[4,3-b]pyridine-2,5-dione (5n):
White solid, mp 138–141°C; [Found: C, 69.37; H, 5.46, N, 4.49. C24H16O5 requires C, 69.44; H, 5.50, N, 4.50%]; ν max (KBr) 1721, 1707, 1681, 1620, 1579, 1460, 1421, 1219, 1039 cm−1; δ H (400 MHz CDCl3) 8.62 (1H, s), 7.66 (1H, d, J 6.0 Hz), 7.52 (1H, t, J 6.8 Hz), 7.29 (1H, d, J 6.4 Hz), 7.26–7.21 (1H, m), 4.08 (1H, t, J 6.0 Hz), 2.67 (3H, s), 1.82 (2H, q,), 1.42 (m, 2H), 0.98 (3H, t); δ C (100 MHz CDCl3) 203.75, 159.98, 159.31, 152.43, 145.34, 136.63, 133.20, 126.81, 125.13, 124.97, 118.64, 114.58, 102.67, 50.73, 31.42, 31.03, 19.76, 13.48; LCMS: MH+, 312.
2.2o 3-Acetyl-1-ethyl-1H-chromeno[4,3-b]pyridine-2,5-dione (5o):
White solid, mp 132–134°C; [Found: C, 67.77; H, 4.58, N, 4.94, C16H13NO4 requires C, 67.84; H, 4.63, 4.94%]; ν max (KBr) 1725, 1708, 1679, 1621, 1592, 1479, 1456, 1246, 1050 cm−1; δ H (400 MHz CDCl3) 8.67 (1H, s), 7.67 (1H, dd, J 6.4 Hz, 0.8 Hz), 7.54 (1H, td, J 6.8, J 1.2 Hz), 7.31 (1H, dd, J 6.8 Hz, J 0.8 Hz), 7.24 (1H, td, J 6.8, J 0.8 Hz), 4.16 (2H, q, J 5.6 Hz), 2.68 (3H, s), 1.47 (3H, t, J 5.6 Hz); δ C (100 MHz CDCl3) 203.77, 159.86, 159.29, 152.42, 144.97, 136.66, 133.21, 126.80, 125.13, 124.98, 118.64, 114.57, 102.85, 46.05, 31.45, 14.39, 8.54; LCMS: MH+, 284.
2.2p 3-Acetyl-1-benzyl-1H-chromeno[4,3-b]pyridine-2,5-dione (5p):
White solid, mp 135–137°C; [Found: C, 72.97; H, 4.34; N, 4.05 C21H15NO4 requires C, 73.03; H, 4.38, N, 4.06%]; ν max (KBr) 1723, 1705, 1681, 1621, 1592, 1489, 1458, 1247, 1053 cm−1; δ H (400 MHz CDCl3) 8.63 (1H, s), 7.66 (1H, d, J 6.0 Hz), 7.52 (1H, t, J 6.0 Hz), 7.44–7.31 (5H, m), 7.30–7.19 (2H, m), 5.24 (2H, s), 2.68 (3H, s); δ C (100 MHz CDCl3) 203.62, 160.09, 159.15, 152.46, 145.08, 136.77, 134.13, 133.34, 129.27, 128.96, 128.73, 126.88, 125.33, 125.04, 118.67, 114.54, 103.13, 53.22, 31.47; LCMS: MH+, 346.
3 Results and discussions
Application of green and sustainable chemistry protocols has seen enormous surge in recent times for the development of novel and eco-friendly methodologies towards the synthesis of valuable synthetic scaffolds and drug intermediates. Polyethylene glycol (PEG) has gained wide popularity as alternative solvent in contributing to such green methodologies by successfully plummeting the generation of industrial waste [25].
We have earlier demonstrated the utility of 4-chloro-3-formylcoumarin as a versatile starting material for the syntheses of various privileged heterocycles such as chromeno-quinolines, [26a] chromeno-benzazepines, [26b] chromeno-pyrimidine-N-oxides [26c] and chromeno-trioxabicylco[3,3,1]nonadienes [26d]. In continuation of our efforts to synthesize novel heterocyclic molecules of biological importance, we envisaged a mild base mediated synthesis of the target molecules from 4-chloro-3-formylcoumarin and acetoacetamides via simultaneous nucleophilic N-alkylation and Knoevenagel reactions using PEG-300 as a recyclable eco-friendly solvent.
The popular methodologies for the synthesis of acetoacetamides in general employ reaction of amines with excess of ethyl acetoacetate in solvents such as benzene, toluene or xylenes at reaction temperatures up to 140°C [24]. As an alternative eco-friendly procedure for the synthesis of starting materials 3a–p, we explored the possibility of PEG-300 as a benign solvent for their reaction. We found that there are no reports utilizing PEG-300 as a solvent for the synthesis of the acetoacetamides to date. When the reaction of aniline 1a was conducted in PEG-300 with 1 equivalent of ethyl acetoacetate, the product 3a was isolated in moderate yields (60%) after 2 h of reaction at 120°C (table 1, entry 1). Increasing the quantity of ethyl acetoacetate to 2 equivalents resulted in good yields (81%) of the required acetoacetamide 3a (table 1, entry 2). The present optimized reaction conditions successfully circumvented the utilization of large excess of ethyl acetoacetate unlike the earlier reported methodologies. As shown in table 1, the reaction conditions were further exploited for the synthesis of acetoacetamides 3b–p (entries 2–16) successfully with a variety of functional groups in good yields (56–81%). The methodology worked satisfactorily for aryl, heteroaryl and aliphatic substrates.
To further optimize the reaction conditions for the synthesis of chromeno[4,3-b]pyridine-2,5-diones 5a–p, 4-choloro-3-formylcoumarin 4 and acetoacetanilide 3a were chosen as model substrates. An initial reaction was attempted where 4 was reacted with acetoacetamide 3a in PEG-300 employing triethylamine base. Completion of the reaction was indicated by the formation of a precipitate which could be easily filtered from the reaction mixture. To our satisfaction, we found that the product obtained was in good yield (83%) and of high purity (table 2, entry 1). To ascertain the efficiency of triethylamine, various bases as shown in table 2 were screened for the reaction. While bases such as K2CO3 and NaHCO3 gave moderate yields (50–60%) of product 5a after 6 h of reaction, surprisingly, sodium acetate and DMAP did not catalyse the reaction (table 2, entries 2–5). Competitive yields of 5a were observed when DMAP (78%) and DBU (70%) were employed as bases (table 2, entries 6 and 7). Triethylamine was considered as the best base from the standardization of reaction conditions. PEG solvent could easily be recycled by washing with small quantities (5 ml) of diethyl ether. Our attempts to synthesize the target chromeno[4,3-b]pyridine-2,5-dione 3a in one-pot procedure starting from aniline 1a unfortunately did not yield satisfactory results.
To validate general feasibility of the methodology, variety of aromatic and aliphatic acetoacetamides 3b–p were utilized in the reaction with 4-chloro-3-formylcoumarin under the optimized reaction conditions. As demonstrated in table 3, halogen substituted acetoacetamides 3b–f possessing p-fluoro, m-flouro, p-bromo, m-bromo and p-chloro substituents reacted smoothly to afford the corresponding benzopyrano-2-pyridoneproducts 5b–f in 78–82% yields. While electron donating substrates 3g–j possessing methyl and methoxy substituents afforded slightly higher yields (84–90%) of the corresponding products 5g–j, the electron withdrawing substrates p-NO2 and m-NO2 groups afforded 72 and 75% yields of products 5k and 5l, respectively. Heteroaromatic and aliphatic substrates 3m–p also furnished good yields (72–84%) of coumarino[4,3-b]pyrid-2-one products 5m–p under the optimized reaction conditions. The present recyclable eco-friendly methodology offers advantages of the obtaining pure precipitates of 5a–p in good to excellent yields without requirement of tedious purification protocols.
For evaluation of antibacterial properties of the synthesized compounds 5a–p (table 4), clinically active Gram-negative Escherichia coli, Vibrio parahaemolyticus, Klebsiella pneumonia and Gram-positive Staphylococcus epidermidis, Bacillus subtilis, and Staphylococcus aureus bacteria were selected. Dimethyl sulfoxide was chosen as negative control while Cefotoxime was chosen as positive control due to its broad spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria. The concentration at which the compounds inhibited the visible growth of the microbial cultures was taken as MIC for that compound by using the standard protocol of NCCLS Broth Microdilution MIC method [27]. The MIC values listed in table 4 suggest that compounds 5d, 5j, 5k, 5n and 5o showed promising broad spectrum antibacterial activities. More specifically, compounds 5d and 5k demonstrated maximum activity, where 5d was more selective in inhibiting Staphylococcus aureus (3.13 μg/mL) and 5k exhibits maximum activity against both Staphylococcus aureus and Staphylococcus epidermidis (3.13 μg/mL).
The evaluation of total antioxidant activities of the compounds 5a–p were evaluated using free radical scavenging activity determined by 1,1-diphenyl picryl hydrzyl (DPPH) procedure [28]. The inhibition percentage equation of the radical scavenging the radical scavenging activity was calculated by using the equation
where A 0 is absorbance of the blank and A S is absorbance of the sample at 515 nm. All assays were conducted in triplicate. Testing was performed with 180 μL of 0.004% methanolic solution of DPPH pipetted into each well of a 96-well plate followed by 20 μL (20 mg/ml) of sample or solvent for the blank. Ascorbic acid was used as the positive control. The mixture was incubated at 30°C for 1 h, and the absorbance at 515 nm was measured with a microplate reader. From the results of the screening studies displayed in table 4, it can be suggested that all the compounds except 5f, 5h, 5l and 5p exhibit moderate to good antioxidant properties. Among the analogs, compound 5g displayed best antioxidant property with 62.13% inhibition followed by 5e, 5k and 5c with 55.48%, 49.34% and 42.41% activities, respectively.
In summary, a series of novel chromeno[4,3]pyridine-2,5-diones 5a–p were synthesized by a mild eco-friendly high yielding methodology using PEG as a recyclable solvent. The compounds were further subjected to antimicrobial and antioxidant screening where 5d and 5k displayed potent antimicrobial activities and compound 5g displayed promising antioxidant properties (table 4).
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We thank the Management of Sankar Foundation for financial support and encouragement. The authors also thank SAIF, Cochin University of Science and Technology for elemental analysis.
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JAGGAVARAPU, S.R., KAMALAKARAN, A.S., JALLI, V.P. et al. Facile eco-friendly synthesis of novel chromeno[4,3-b]pyridine-2,5-diones and evaluation of their antimicrobial and antioxidant properties. J Chem Sci 126, 187–195 (2014). https://doi.org/10.1007/s12039-013-0565-9
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DOI: https://doi.org/10.1007/s12039-013-0565-9