Scholarly article on topic 'Bismuth nitrate as an efficient recyclable catalyst for the one-pot multi component synthesis of 1,4-dihydropyridine derivatives through unsymmetrical Hantzsch reaction'

Bismuth nitrate as an efficient recyclable catalyst for the one-pot multi component synthesis of 1,4-dihydropyridine derivatives through unsymmetrical Hantzsch reaction Academic research paper on "Chemical sciences"

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{"Bismuth nitrate" / "1 / 4-Dihydropyridine" / "Hantzsch reaction" / "One-pot synthesis" / "Multi component reaction"}

Abstract of research paper on Chemical sciences, author of scientific article — S. Sheik Mansoor, K. Aswin, K. Logaiya, S.P.N. Sudhan

Abstract Bismuth nitrate catalyzed efficient Hantzsch reaction via four-component coupling reactions of aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexanedione (dimedone), ethyl acetoacetate and ammonium acetate at 80°C temperature was described as the preparation of 1,4-dihydropyridine derivatives. 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives are also prepared under the same experimental conditions using aldehydes, dimedone, malononitrile and ammonium acetate in good yield. The higher catalytic activity of Bi(NO3)·5H2O is ascribed to its high acidity, thermal stability and water tolerance. The process presented here is operationally simple, environmentally benign and has excellent yield. Furthermore, the catalyst can be recovered conveniently and reused efficiently.

Academic research paper on topic "Bismuth nitrate as an efficient recyclable catalyst for the one-pot multi component synthesis of 1,4-dihydropyridine derivatives through unsymmetrical Hantzsch reaction"

Journal of Saudi Chemical Society (2012) xxx, xxx-xxx

King Saud University Journal of Saudi Chemical Society

www.ksu.edu.sa www.sciencedirect.com

ORIGINAL ARTICLE

Bismuth nitrate as an efficient recyclable catalyst for the one-pot multi component synthesis of 1,4-dihydropyridine derivatives through unsymmetrical Hantzsch reaction

S. Sheik Mansoor *, K. Aswin, K. Logaiya, S.P.N. Sudhan

Research Department of Chemistry, C. Abdul Hakeem College, Melvisharam 632 509, Tamil Nadu, India Received 4 July 2012; accepted 10 September 2012

KEYWORDS

Bismuth nitrate; 1,4-Dihydropyridine; Hantzsch reaction; One-pot synthesis; Multi component reaction

Abstract Bismuth nitrate catalyzed efficient Hantzsch reaction via four-component coupling reactions of aromatic aldehydes, 5,5-dimethyl-1,3-cyclohexanedione (dimedone), ethyl acetoacetate and ammonium acetate at 80 °C temperature was described as the preparation of 1,4-dihydropyridine derivatives. 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives are also prepared under the same experimental conditions using aldehydes, dimedone, malon-onitrile and ammonium acetate in good yield. The higher catalytic activity of Bi(NO3)-5H2O is ascribed to its high acidity, thermal stability and water tolerance. The process presented here is operationally simple, environmentally benign and has excellent yield. Furthermore, the catalyst can be recovered conveniently and reused efficiently.

© 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction

Multicomponent reactions (MCRs) in which multiple reactions are combined into one synthetic operation, have been used extensively to form carbon-carbon bonds in the synthetic chemistry (Zhu and Bienayme, 2005; Domling and Ugi, 2000). Such reactions offer a wide range of possibilities for the efficient construction of highly complex molecules in a single pro-

cedural step, thus avoiding the complicated purification operations and allowing savings of both solvents and reagents. In the past decade, there have been tremendous developments in three- and four-component reactions and grand efforts are continue to be made to develop new MCRs (Bertozzi et al., 2002; Bagley et al., 2002). One-pot, four-component synthesis of symmetrically substituted 1,4-dihydropyridines was first reported by Hantzsch (1882). Hantzsch 1,4-dihydropyridines (1,4-DHPs) and their derivatives are an important class of bio-active molecules in the pharmaceutical field (Stout and Meyers, 1982). They possess anti-inflammatory, anti-microbial (Kumar et al., 2011), anti-oxidant, anti-ulcer activities (Swarnalatha et al., 2011). DHPs are commercially used as calcium channel blockers for the treatment of cardiovascular diseases, including hypertension (Gaudio et al., 1994). Recently, the synthesis of DHPs with respect to Multidrug Resistance

* Corresponding author. Tel.: +91 9944093020. E-mail address: smansoors2000@yahoo.co.in (S. Sheik Mansoor). Peer review under responsibility of King Saud University.

1319-6103 © 2012 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.Org/10.1016/j.jscs.2012.09.010

(MDR) reversal in tumor cell gave a new dimension to their applications (Tanabe et al., 1998; Tasaka et al., 2001). In addition, 1,4-DHP class of compounds are excellent starting syn-thons for development of anti-tubercular agents (Eharkar et al., 2002; Desai et al., 2001). Oxidative aromatization reactions of DHPs are taking place in biological systems in the presence of certain enzymes. The nitrogen heterocycles thus prepared by Hantzsch method are of great importance because of their role in biological systems. They have served as model compounds for the NAD-NADPH biological redox systems (Schellenberg and Weheimer, 1965; Kirschbaum, 1968; Norcross et al., 1962).

Realizing the importance of 1,4-dihydropyridine derivatives, several synthesis methods have been reported, like conventional heating (Margarita et al., 1999), refluxing in acetic acid (Ahluwalia et al., 1997) and microwave irradiation (Sapkal et al., 2009) and ultrasound (Ohberg and Westman, 2001). Different other approaches for the syntheses of 1,4-dihydropyridine derivatives using various catalysts, such as TMSCl (sabitha et al., 2003), ionic liquids (sridhar and Perumal, 2005; Ji et al., 2004), L-proline (Karade et al.,

2007), FeF3 (Surasani et al., 2012), Yb(OTf)3 (Wang et al.,

2005), Sc(OTf)3 (Donelson et al., 2006), HClO4-SiO2 (Maheswara et al., 2006), cerric ammonium nitrate (Heravi et al., 2007), heteropoly acid (Cherkupally and Mekalan,

2008), p-TSA (Ko and Yao, 2006), HY-zeolite (Das et al.,

2006), grinding (Kumar et al., 2008), MCM-41-SO3H (Rostamizadeh et al., 2012), aluminum phosphate (Purandhar et al., 2012), and Mont. K-10 (Song et al., 2005) have also been reported and some of the methods are associated with several shortcomings such as long reaction times, expensive reagents, harsh reaction conditions, low-product yields and the use of large quantity of volatile organic solvents. Moreover, the main disadvantage of almost all existing methods is that the catalysts are destroyed in the work-up procedure and cannot be recovered or reused. Therefore, the search continues for a better catalyst for the synthesis of 1,4-DHPs in terms of operational simplicity, reusability, economic viability, and greater selectivity.

Bismuth compounds have recently attracted much attention due to low toxicity, low cost, and good stability. Bismuth has an electron configuration of [Xe]4/145d106s26p3, and due to weak shielding of the 4/ electrons, bismuth compounds exhibit Lewis acidity. Among all, bismuth (III) salts have been widely used and were reported as effective catalysts. Recently, bismuth nitrate is widely used as an effective catalyst for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones (Mohammadpoor-Baltork

et al., 2011), N-substituted pyrroles (Rivera et al., 2009), nitro pyrazoles (Ravi and Tewari, 2012), functionalized piperidine (Brahmachari and Das, 2012), novel pyrrole derivatives (Bandyopadhyay et al., 2012) and amidoalkyl naphthols (Wang et al., 2012). During the course of our studies toward the development of green catalytic processes to synthesize 1,4-dihydropyridine derivatives, we found bismuth nitrate, Bi(NO3)3 as an inexpensive and commercially available catalyst (Mansoor et al., 2012a). It can efficiently catalyze through one-pot condensation of aldehydes, dimedone, ethyl acetoacetate and ammonium acetate (Scheme 1). After the reaction, bismuth nitrate could be easily recovered by a simple phase separation and could be reused many times without loss of its catalytic activity. Application of such catalyst will lead to minimal pollution and waste material.

In addition the growing concern for the influence of the chemical reagents on the environment as well as on human body, recovery and reusability of the chemical reagents has attracted the attention of synthetic organic chemists. More importantly pharmaceutical industry has given more importance toward recovery and reuse of chemical reagents to reduce the cost of a product as well as the environmental burden.

In continuation of our work on the development of simple and environmentally friendly experimental procedures using readily available reagents and catalysts for the synthesis of biologically active molecules, such as 3,4-dihydropyrimidin-2(1H)-ones/-thiones/imines (Mansoor et al., 2011), b-amino ketone compounds (Mansoor et al., 2012a), and amidoalkyl naphthols (Mansoor et al., 2012b), we became interested in the possibility of developing a one-pot synthesis of 1,4-dihydropyridine derivatives catalyzed by Bi(NO3)3. We present our results about a Bi(NO3)3 catalyzed four-component Hantzsch reaction in ethanol. To the best of our knowledge, 1,4-dihydropyridine derivatives catalyzed by Bi(NO3)3 in ethanol under heating have not been reported.

2. Experimental

2.1. Apparatus and analysis

Chemicals were purchased from Merck, Fluka and Aldrich Chemical Companies. All yields refer to isolated products unless otherwise stated. Analytical thin-layer chromatography was performed with E. Merck silica gel 60F glass plates. Visualization of the developed chromatogram was performed by UV light (254 nm). Column chromatography was performed on silica gel 90, 200-300 mesh. Melting points were determined

Ri "" \ " 'EtOH, 80oC

1 2 3 4a - 4p

Scheme 1 The reaction of arylaldehyde, ethyl acetoacetate, dimedone and ammonium acetate.

with a Shimadzu DS-50 thermal analyser. The products were characterized by comparison of their physical data with those of known samples or by their spectral data. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were obtained using Bruker DRX- 500 Avance at ambient temperature, using TMS as internal standard. FT-IR spectra were obtained as KBr discs on a Shimadzu spectrometer. Mass spectra were determined on a Varion - Saturn 2000 GC/MS instrument. Elemental analysis was measured by means of a Perkin Elmer 2400 CHN elemental analyzer flowchart.

2.2. General experimental procedure for the synthesis of ethyl-4-phenyl-2 ,7 ,7-trimethyl-5-oxo-1 ,4,5 ,6 ,7 ,8-hexahydroquinoline-3-carboxylate (4a-4p)

To a stirred mixture of dimedone (2 mmol), ethyl acetoacetate (2 mmol) and Bi(NO3)35H2O (5mol%) in ethanol (5 mL), aldehyde (2 mmol) and ammonium acetate (2 mmol) were added. The reaction mixture was heated at 80 °C and stirred for appropriate time as monitored by TLC. The resulting yellow solid was filtered and recrystallized to give the pure product (Scheme 1). The filtrate was concentrated diluted with ethyl acetate, washed with water and the aqueous layer containing the catalyst could be evaporated under reduced pressure to give a white solid, which could be reused without losing catalytic activity. The catalyst filtered was washed with methanol (3 x 10 ml). All the products obtained were fully characterized by spectroscopic methods such as IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis and have been identified by comparison of the spectral data with those reported.

2.3. Spectral data for the synthesized compounds

2.3.1. Ethyl-4-phenyl-2,7 ,7-trimethyl-5-oxo-1 ,4,5,6,7,8-

hexahydroquinoline-3-carboxylate (4a)

IR (KBr, cm-1): 3295, 2959, 1699, 1605, 1517, 1482, 1345,

1218, 1073, 836, 694. NMR (500 MHz, DMSO-d6) d: 0.82 (s, 3H,CH3), 1.00 (s, 3H, CH3), 1.12 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.27-2.31 (m, 4H, 2xCH2), 2.40 (s, 3H, CH3), 3.98 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.96 (s, 1H, CH), 7.427.65 (m, 5H, ArH), 8.22 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) 8: 14.0, 18.3, 26.4, 29.0, 32.1, 36.6, 50.0, 59.2, 102.3, 109.0, 123.0, 128.7, 145.6, 146.0, 150.0, 154.9, 166.3,

194.1. MS (ESI): m/z 340 (M + H) + . Anal. Calcd for C21H25NO3: C, 74.33; H, 7.37; N, 4.12. Found: C, 74.38; H, 7.42; N, 4.07%.

2.3.2. Ethyl-4-(4-cyanophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4b)

IR (KBr, cm-1): 3296, 2959, 2226, 1697, 1606, 1488, 1379,

1219, 1074, 845, 555. NMR (500 MHz, DMSO-d6) d: 0.81 (s, 3H,CH3), 1.06 (s, 3H, CH3), 1.22 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.26-2.32 (m, 4H, 2xCH2), 2.46 (s, 3H, CH3), 3.91 (q, J = 7.4 Hz, 2H, OCH2CH3), 4.90 (s, 1H, CH), 7.34 (d, J = 8.8 Hz, 2H, ArH), 7.66 (d, J = 8.8 Hz, 2H, ArH), 8.19 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.1, 18.3, 26.4, 29.0, 32.1, 36.7, 50.1, 59.1, 102.4, 108.5, 109.1, 119.0, 128.5, 131.8, 146.0, 149.9, 152.8, 166.3, 194.1. MS (ESI): m/z 365 (M + H) + . Anal. Calcd for C22H24N2O3: C, 72.53; H, 6.59; N, 7.69. Found: C, 72.48; H, 6.63; N, 7.66%.

2.3.3. Ethyl-4-(3-nitrophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4c) IR (KBr, cm-1): 3289, 2959, 1702, 1607, 1528, 1487, 1349, 1217, 1073, 683. 1H NMR (500 MHz, DMSO-d6) d: 0.84 (s, 3H, CH3), 1.03 (s, 3H, CH3), 1.14 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.38 (m, 4H, 2xCH2), 2.32 (s, 3H, CH3), 4.02 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.06 (s, 1H, CH), 7.42 (d, J = 8.4 Hz, 2H, ArH), 7.78 (d, J = 8.4 Hz, 2H, ArH), 8.28 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.0, 18.3, 26.3, 29.0, 32.2, 36.4, 50.0, 59.2, 102.6, 109.2, 120.8, 121.9,

129.3, 134.2, 146.0, 147.3, 149.6, 150.3, 166.3, 194.2. MS (ESI): m/z 385 (M + H) + . Anal. Calcd for C21H24N2O5: C, 65.62; H, 6.25; N, 7.29. Found: C, 65.60; H, 6.22; N, 7.32%.

2.3.4. Ethyl-4-(4-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4d)

IR (KBr, cm-1): 3290, 2962, 1700, 1606, 1522, 1488, 1340, 1216, 1078, 838, 700. 17H NMR (500 MHz, DMSO-d6) d: 0.84 (s, 3H,CH3), 1.06 (s, 3H, CH3), 1.12 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.20-2.38 (m, 4H, 2xCH2), 2.55 (s, 3H, CH3), 3.92 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.12 (s, 1H, CH), 7.42 (d, J = 8.6 Hz, 2H, ArH), 7.76 (d, J = 8.8 Hz, 2H, ArH), 8.23 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.2, 18.0, 26.6, 29.3, 32.0, 36.4, 50.2, 59.5, 102.6, 108.9, 122.9,

128.4. 145.3, 146.3, 150.5, 154.7, 165.9, 193.9. MS (ESI): m/z 418 (M + H) + . Anal. Calcd for C21H24BrNO3: C, 60.30; H, 5.74; N, 3.35. Found: C, 60.35; H, 5.78; N, 3.33%.

2.3.5. Ethyl-4-(4-fluorophenyl)-2,7,7-trimethyl-5-oxo-1 ,4,5 ,6 ,7 ,8-hexahydroquinoline-3-carboxylate (4e)

IR (KBr, cm-1): 3292, 2962, 1695, 1600, 1522, 1486, 1349, 1210, 1070, 822, 700. 1H NMR (500 MHz, DMSO-d6) d: 0.86 (s, 3H,CH3), 0.99 (s, 3H, CH3), 1.10 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.20-2.36 (m, 4H, 2xCH2), 2.48 (s, 3H, CH3), 4.08 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.90 (s, 1H, CH), 7.38 (d, J = 8.4 Hz, 2H, ArH), 7.71 (d, J = 8.2 Hz, 2H, ArH), 8.12 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.4, 18.0, 26.2, 28.9, 32.0, 36.2, 50.2, 59.0, 102.8, 108.9, 122.8, 128.4, 145.8, 146.4, 150.5, 155.1, 166.2, 194.6. MS (ESI): m/z 358 (M + H) + . Anal. Calcd for C21H24FNO3: C, 70.59; H, 6.72; N, 3.92. Found: C, 70.64; H, 6.70; N, 3.88%.

2.3.6. Ethyl-4-(4-(trifluoromethyl)phenyl)-2,7,7-trimethyl-5-oxo-1 ,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4f)

IR (KBr, cm-1): 3281, 2938, 1710, 1603, 1496, 1382, 1324, 1216, 1136, 1065, 862, 598, 531. 1H NMR (500 MHz, DMSO-d6) d: 0.90 (s, 3H,CH3), 1.09 (s, 3H, CH3), 1.15 (t, J = 7.4 Hz, 3H, OCH2CH3), 2.32 (m, 4H, 2xCH2), 2.55 (s, 3H, CH3), 3.90 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.12 (s, 1H, CH), 7.37 (d, J = 8.6 Hz, 2H, ArH), 7.60 (d, J = 8.8 Hz, 2H, ArH), 8.33 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.1, 18.3, 26.5, 29.0, 32.1, 36.3, 50.1, 59.1, 102.8, 109.3, 124.6, 124.7, 128.2, 145.7, 149.8, 151.8, 166.6, 194.1. MS (ESI): m/z 408 (M + H) + . Anal. Calcd for C22H24F3NO3: C, 64.86; H, 5.90; N, 3.44. Found: C, 64.90; H, 5.85; N, 3.50%.

2.3.7. Ethyl-4-(3,4-dimethoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4g)

IR (KBr, cm-1): 3279, 2957, 1695, 1604, 1491, 1379, 1216, 1139, 1031, 788, 730. 1H NMR (500 MHz, DMSO-d6) d:

0.88 (s, 3H,CH3), 1.01 (s, 3H, CH3), 1.16 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.28 (m, 4H, 2xCH2), 2.44 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 3.60 (s, 3H, OCH3), 4.00 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.88 (s, 1H, CH), 7.44 (d, J = 8.6 Hz, 2H, ArH), 7.10 (d, J = 8.8 Hz, 2H, ArH), 8.22 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.2, 18.2, 26.4, 29.2, 32.1, 35.1, 50.3, 55.3, 55.4, 59.0, 103.8, 110.0, 111.4, 111.7, 119.2,

140.4, 144.5, 146.9, 147.9, 149.3, 166.8, 194.2. MS (ESI): m/z 400 (M + H) + . Anal. Calcd for C23H29NO5: C, 69.17; H, 7.27; N, 3.51. Found: C, 69.15; H, 7.24; N, 3.55%.

2.3.8. Ethyl-4-(4-methoxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4h) IR (KBr, cm-1): 3284, 2962, 1692, 1608, 1496, 1382, 1212, 1142, 1036, 792, 734. NMR (500 MHz, DMSO-d6) d: 0.94 (s, 3H,CH3), 1.09 (s, 3H, CH3), 1.20 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.32 (m, 4H, 2xCH2), 2.34 (s, 3H, CH3), 3.62 (s, 3H, OCH3), 3.94 (q, J = 7.4 Hz, 2H, OCH2CH3), 4.84 (s, 1H, CH), 7.24 (d, J = 8.6 Hz, 2H, ArH), 7.14 (d, J = 8.4 Hz, 2H, ArH), 8.26 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.0, 18.4, 26.0, 29.4, 32.0, 35.4, 50.6, 55.0, 55.4, 59.4, 104.0, 110.2, 111.5, 111.9, 119.0, 140.2,

144.8. 146.8, 147.4, 149.8, 166.5, 193.8. MS (ESI): m/z 370 (M + H) + . Anal. Calcd for C22H27NO4: C, 71.54; H, 7.32; N, 3.79. Found: C, 71.50; H, 7.28; N, 3.83%.

2.3.9. Ethyl-4-(4-methylphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4i)

IR (KBr, cm-1): 3274, 2950, 1690, 1600, 1497, 1377, 1214, 1144, 1033, 782, 722. NMR (500 MHz, DMSO-d6) d: 0.96 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.15 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.32 (m, 4H, 2xCH2), 2.40 (s, 3H, CH3), 2.12 (s, 3H, CH3), 4.04 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.98 (s, 1H, CH), 7.04 (d, J = 8.6 Hz, 2H, ArH), 7.10 (d, J = 8.8 Hz, 2H, ArH), 8.38 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 13.9, 17.9, 26.3, 29.0, 32.0, 35.4, 50.4, 55.6, 55.7, 59.2, 103.5, 110.5, 111.3, 111.9, 119.0, 140.4, 144.6, 146.5, 147.7, 149.6, 166.0, 193.9. MS (ESI): m/z 354 (M + H) + . Anal. Calcd for C22H27NO3: C, 74.79; H, 7.65; N, 3.97. Found: C, 74.84; H, 7.69; N, 3.95%.

2.3.10. Ethyl-4-(4-hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4j)

IR (KBr, cm-1): 3486, 3310, 2956, 1698, 1607, 1494, 1280, 1218, 1066, 856, 613. 1H NMR (500 MHz, DMSO-d6) d: 0.82 (s, 3H,CH3), 0.93 (s, 3H, CH3), 1.10 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.36 (m, 4H, 2xCH2), 2.34 (s, 3H, CH3), 3.92 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.14 (s, 1H, CH), 6.94 (d, J = 8.6 Hz, 2H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH), 8.31 (s, 1H, NH), 10.37 (s, 1H, OH). 13C NMR (125 MHz, DMSO-d6) d: 13.8, 18.2, 26.3, 28.8, 31.7, 32.0, 50.1, 59.0,

103.5, 100.3, 113.3, 166.5, 126.3, 140.1, 145.4, 145.8, 149.4, 161.5, 166.7, 193.9. MS (ESI): m/z 356 (M + H) + . Anal. Calcd for C21H25NO4: C, 70.99; H, 7.04; N, 3.94. Found: C, 70.96;

H, 7.00; N, 3.90%.

2.3.11. Ethyl-4-(4-nitrophenyl)-2,7,7-trimethyl-5-oxo-

I,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4k)

IR (KBr, cm-1): 3290, 2960, 1701, 1600, 1521, 1485, 1340, 1214, 1070, 834, 690. 1H NMR (500 MHz, DMSO-d6) d:

0.88 (s, 3H,CH3), 0.97 (s, 3H, CH3), 1.09 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.32 (m, 4H, 2xCH2), 2.40 (s, 3H, CH3), 4.04 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.04 (s, 1H, CH), 7.40 (d, J = 8.6 Hz, 2H, ArH), 7.94 (d, J = 8.8 Hz, 2H, ArH), 8.16 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.3, 18.5, 26.5, 29.1, 32.3, 36.8, 50.2, 59.6, 102.6, 108.9, 122.8, 128.5, 145.3, 146.2, 149.9, 154.5, 168.9, 193.8. MS (ESI): m/z 385 (M + H) + . Anal. Calcd for C21H24N2O5: C, 65.62; H, 6.25; N, 7.29. Found: C, 65.60; H, 6.22; N, 7.32%.

2.3.12. Ethyl-4-(2,4-dichlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4l)

IR (KBr, cm-1): 3295, 2959, 1699, 1605, 1517, 1482, 1345, 1218, 1073, 836, 694. 1H NMR (500 MHz, DMSO-d6) d: 0.83 (s, 3H,CH3), 1.02 (s, 3H, CH3), 1.13 (t, J = 7.2 Hz, 3H, OCH2CH3), 2.30 (m, 4H, 2xCH2), 2.28 (s, 3H, CH3), 3.90 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.10 (s, 1H, CH), 7.64 (m, 3H, ArH), 8.30 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 14.0, 18.3, 26.4, 29.0, 32.1, 36.6, 50.0, 59.2, 102.3, 109.0,

123.0, 128.7, 145.6, 146.0, 150.0, 154.9, 166.3, 194.1. MS (ESI): m/z 408.9 (M + H) + . Anal. Calcd for C21H23Cl2NO3: C, 61.77; H, 5.63; N, 3.43. Found: C, 61.71; H, 5.68; N, 3.45%.

2.3.13. Methyl-4-(4-chlorophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4m)

IR (KBr, cm-1): 3288, 2959, 1682, 1606, 1489, 1381, 1226, 1074, 1013, 840, 776, 538. 1H NMR (500 MHz, DMSO-d6) d: 0.82 (s, 3H, CH3), 1.00 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.29 (m, 4H, 2xCH2), 3.52 (s, 3H, OCH3), 4.85 (s, 1H, Ch), 7.15 (d, J = 8.2 Hz, 2H, ArH), 7.25 (d, J = 8.4 Hz, 2H, ArH), 8.24 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d:

18.3, 26.4, 29.0, 32.0, 35.4, 50.1, 50.6, 102.7, 109.6, 127.7,

129.1, 130.1, 145.6, 146.3, 149.5, 167.0, 194.1. MS (ESI): m/z 360.50 (M + H) + . Anal. Calcd for C20H22ClNO3: C, 66.77;

H, 6.12; N, 3.89. Found: C, 66.72; H, 6.08; N, 3.92%.

2.3.14. Methyl-4-(4-methylphenyl)-2,7,7-trimethyl-5-oxo-

I,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4n)

IR (KBr, cm-1): 3284, 2962, 1678, 1600, 1490, 1386, 1230, 1076, 1010, 836, 780, 542. 1H NMR (500 MHz, DMSO-d6) d: 0.89 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.29 (m, 4H, 2xCH2), 3.48 (s, 3H, OCH3), 4.98 (s, 1H, CH), 7.19 (d, J = 8.6 Hz, 2H, ArH), 7.28 (d, J = 8.4 Hz, 2H, ArH), 8.44 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 17.9, 26.0, 29.3, 31.8, 35.2, 50.0, 50.8, 102.9, 109.9, 127.9, 128.9, 130.3, 145.4, 146.5, 149.3, 166.8, 193.9. MS (ESI): m/z 340 (M + H) + . Anal. Calcd for C21H25NO3: C, 74.34; H, 7.37; N, 4.13. Found: C, 74.30; H, 7.42; N, 4.18%.

2.3.15. Methyl-4-(4-cyanophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4o)

IR (KBr, cm-1): 3276, 2960, 2226, 1708, 1607, 1493, 1379, 1217, 1074, 858, 553. 1H NMR (500 MHz, DMSO-d6) d: 0.80 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.40 (s, 3H, CH3), 2.32 (m, 4H,2xCH2), 3.50 (s, 3H, OCH3), 4.94 (s, 1H, Ch), 7.34 (d, J = 8.2 Hz, 2H, ArH), 7.68 (d, J = 8.4 Hz, 2H, ArH), 8.26 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 18.3,

26.4, 29.0, 32.1, 36.4, 50.0, 50.7, 102.1, 108.5, 109.1, 118.9, 128.3, 131.8, 146.2, 149.9, 152.6, 166.8, 194.1. MS (ESI): m/z

351 (M + H) + . Anal. Calcd for C21H22N2O3: C, 72.00; H, 6.28; N, 8.0. Found: C, 72.06; H, 6.24; N, 8.05%.

2.3.16. Methyl-4-(4-nitrophenyl)-2 ,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (4p) IR (KBr, cm-1): 3277, 2959, 1709, 1605, 1491, 1345, 1217, 1075, 866, 833, 533. 1H NMR (500 MHz, DMSO-d6) d: 0.81 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.49 (s, 3H, CH3), 2.35 (m, 4H, 2xCH2), 3.53 (s, 3H, OCH3), 4.97 (s, 1H, CH), 7.43 (d, J = 8.4 Hz, 2H, ArH), 7.85 (d, J = 8.4 Hz, 2H, ArH), 8.19 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 18.4, 26.4, 29.0, 32.1, 36.4, 50.0, 50.6, 102.0, 109.0, 123.2, 128.5, 145.6, 146.3, 150.0, 154.7, 166.8, 194.1. MS (ESI): m/z 371 (M + H) + . Anal. Calcd for C20H22N2O5: C, 64.86; H, 5.95; N, 7.57. Found: C, 64.82; H, 5.90; N, 7.60%.

2.4. General experimental procedure for the synthesis of 2-amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1 , 4 , 5,6,7,8-hexahydroquinoline (6a-6f)

To a stirred mixture of dimedone (2 mmol), malononitrile (2 mmol) and Bi(NO3)3.5H2O (5mol%) in ethanol (5mL), aldehyde (2 mmol) and ammonium acetate (3 mmol) were added. The reaction mixture was heated at 80 0C and stirred for appropriate time as monitored by TLC. The resulting yellow solid was filtered and recrystallized to give the pure product (Scheme 2). The filtrate was concentrated diluted with ethyl acetate, washed with water and the aqueous layer containing the catalyst could be evaporated under reduced pressure to give a white solid, which could be reused without losing catalytic activity. The catalyst filtered was washed with methanol (3 x 10 ml). All the products obtained were fully characterized by spectroscopic methods such as IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis and have been identified by comparison of the spectral data with those reported.

2.5. The spectroscopic and analytical data for the synthesized compounds are presented below

C18H19N3O: C, 73.72; H, 6.48; N, 14.33. Found: C, 73.73;

H, 6.59; N, 14.35.

2.5.2. 2-Amino-4-(4-chlorophenyl)-3-cyano-7,7-dimethyl-5-oxo-

I,4,5,6,7,8-hexahydroquinoline (6b)

IR (KBr, cm-1): 3444, 3325, 3208, 2171, 1676, 1609, 1507. 1H NMR (500 MHz, DMSO-d6): d: 0.91 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.04-2.48 (m, 4H, 2xCH2), 4.22 (s, 1H, CH), 5.66 (s, 2H, NH2), 7.08-7.20 (m, 4H, ArH), 8.80 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 27.1, 29.5, 32.8, 36.5, 39.5, 50.8, 59.8, 113.4, 121.2, 125.9, 127.0, 128.0, 143.8, 155.6, 167.0, 196.0. MS (ESI): m/z 328.5 (M + H) + . Anal. Calcd for C18H18ClN3O: C, 65.96; H, 5.50; N, 12.83. Found: C, 65.92; H, 5.55; N, 12.89.

2.5.3. 2-Amino-4-(4-methylphenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (6c)

IR (KBr, cm-1): 3432, 3308, 3212, 2188, 1678, 1598, 1500. 1H NMR (500 MHz, DMSO-d6): d: 0.93 (s, 3H, CH3), 1.08 (s, 3H, CH3), 2.06 (s, 3H, CH3), 1.95-2.38 (m, 4H, 2xCH2), 4.38 (s, 1H, CH), 5.80 (s, 2H, NH2), 7.12-7.22 (m, 4H, ArH), 8.76 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 26.8, 29.7, 32.5, 36.4, 39.7, 50.7, 59.4, 112.9, 121.0, 126.4, 127.1, 128.2, 144.2, 155.9, 167.5, 196.9. MS (ESI): m/z 308 (M + H) + . Anal. Calcd for C19H21N3O: C, 74.27; H, 6.84; N, 13.68. Found: C, 74.22; H, 6.80; N, 13.70.

2.5.4. 2-Amino-4-(4-methoxylphenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (6d)

IR (KBr, cm-1): 3420, 3312, 3209, 2166, 1650, 1600, 1499. 1H NMR (500 MHz, DMSO-d6): d 0.99 (s, 3H, CH3), 1.04 (s, 3H, CH3), 3.66 (s, 3H, OCH3)1.90-2.34 (m, 4H, 2xCH2), 4.28 (s, 1H, CH), 5.76 (s, 2H, NH2), 7.22-7.33 (m, 4H, ArH), 8.86 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 26.8, 29.9, 32.7, 36.9, 39.6, 50.6, 59.5, 113.9, 120.8, 126.5, 127.2, 128.4, 143.9, 155.3, 166.9, 196.2. MS (ESI): m/z 324 (M + H) + . Anal. Calcd for C19H21N3O2: C, 70.58; H, 6.50; N, 13.00. Found: C, 70.55; H, 6.54; N, 13.04.

2.5.1. 2-Amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (6a)

IR (KBr, cm-1): 3426, 3315, 3203, 2177, 1657, 1603, 1495. 1H NMR (500 MHz, DMSO-d6): d: 0.98 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.98-2.42 (m, 4H, 2xCH2), 4.31 (s, 1H, CH), 5.73 (s, 2H, NH2), 7.15-7.24 (m, 5H, ArH), 8.86 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 26.9, 29.8, 32.6, 36.7, 39.8, 50.4, 59.6, 113.5, 120.4, 126.1, 127.2, 128.5, 144.0, 155.9, 166.3, 196.6. MS (ESI): m/z 294 (M + H) + . Anal. Calcd for

2.5.5. 2-Amino-4-(3-bromophenyl)-3-cyano-7,7-dimethyl-5-oxo-1 ,4, 5, 6,7,8-hexahydroquinoline (6e)

IR (KBr, cm-1): 3422, 3322, 3202, 2172, 1664, 1608, 1490. 1H NMR (500 MHz, DMSO-d6) d: 0.90 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.04-2.38 (m, 4H, 2xCH2), 4.31 (s, 1H, CH), 5.77 (s, 2H, NH2), 7.06-7.18 (m, 4H, ArH), 8.86 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 27.0, 29.8, 32.9, 36.6, 39.4, 50.5, 59.7, 113.0, 119.9, 126.0, 127.0, 128.3, 144.3, 154.9,

166.6, 195.9. MS (ESI): mjz 372.9 (M + H) + . Anal. Calcd

NH4OAc

CN Bi(NO3)3.5H2 EtOH, 80oC

1 2 5 6a - 6f

Scheme 2 The reaction of arylaldehyde, dimedone, malono nitrile and ammonium acetate.

for C18H18BrN3O: C, 58.08; H, 4.84; N, 11.29. Found: C, 58.12; H, 4.87; N, 11.33.

2.5.6. 2-Amino-4-(2-chlorophenyl)-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline (6f)

IR (KBr, cm-1): 3418, 3323, 3205, 2175, 1668, 1600, 1500. 1H NMR (500 MHz, DMSO-d6): d: 1.00 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.90-2.40 (m, 4H, 2xCH2), 4.22 (s, 1H, CH), 5.84 (s, 2H, NH2), 7.18-7.26 (m, 4H, ArH), 8.86 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) d: 26.9, 29.9, 32.5, 36.6, 39.4, 50.8, 59.6, 113.1, 120.9, 126.6, 127.2, 128.0, 144.1, 154.9, 166.8, 194.8. MS (ESI): m/z 328.5 (M + H) + . Anal. Calcd for C18H18ClN3O: C, 65.96; H, 5.50; N, 12.83. Found: C, 65.98; H, 5.45; N, 12.80.

3. Results and discussion

Table 2 The reaction of benzaldehyde, ethyl acetate, dime-done and ammonium acetate: effect of solvent.a

Entry Solvent Amount of Time (h) Yield (%)b

catalyst (mol%)

1 Ethanol 5 4 92

2 Dichloroethane 5 16 46

3 Cyclohexane 5 16 55

4 Acetonitrile 5 4 76

5 Toluene 5 16 40

6 Methanol 5 6 78

7 1,4-Dioxane 5 12 63

a Reaction conditions: benzaldehyde (2 mmol), dimedone (2 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate (2 mmol) heating in the presence of Bi(NO3)3-5H2O (5 mol%) in ethanol (5 mL). b Isolated yields.

We describe herein a versatile, environmentally benign, one-pot multi-component synthesis of 1,4-dihdropyridine derivatives by the reaction of aromatic aldehyde, b-keto esters and ammonium acetate in the presence of Bi(NO3)35H2O (5 mol%) in ethanol. To optimize the reaction conditions, we undertook a model reaction of benzaldehyde 1, dimedone 2, ethyl aceto acetate 3 and ammonium acetate.

3.1. Effect of catalyst and solvent

Our initial work started with screening of catalyst loading and solvent so as to identify optimal reaction conditions for the synthesis of 1,4-dihydropyridine derivatives. First of all, a number of Lewis acid catalysts such as ZnCl2, AlCl3, FeCl3, NbCl3, BiCl3, BiBr3, BiI3, Bi(OTf)3 and Bi(NO3)3.5H2O have been screened using the model reaction in ethanol (Table 1). Bi(NO3)35H2O was found to be the best catalyst under these conditions. The results show that Bi(NO3)35H2O (5 mol%) is effective for good yield (Table 1, entry 12).

The solvents played an important role in the synthesis of 1,4-dihydropyridine derivatives. Various reaction media were screened (ethanol, dichloroethane, cyclohexane, acetonitrile,

Table 3 Optimization of temperature and recyclability of the

catalyst using Bi(NO3)3-5H2O (5 mol%) as catalyst.a

Entry Temperature (°C) Time (h) Yield (%)b

1 50 6 72

2 60 6.5 80

3 70 5 85

4 80 4 92

5 90 4.5 88

6 100 4.5 84

7 80 4 92, 90, 87, 89c

a Reaction conditions: benzaldehyde (2 mmol), dimedone

(2 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate

(2 mmol) in the presence of Bi(NO3)3-5H2O (5 mol%) in ethanol

(5 mL).

b Isolated yields.

c Catalyst was reused four times.

Table 1 The reaction of benzaldehyde, dimedone, ethyl

acetoacetate, and ammonium acetate: effect of catalysis.a

Entry Catalyst Amount of Time (h) Yield (%)b

catalyst (mol%)

1 None - 24 32

2 ZnCl2 100 24 42

3 AlCl3 100 24 48

4 FeCl3 100 24 40

5 NdCl3 20 12 70

6 BiCl3 10 6 81

7 BiI3 10 6 76

8 BiBr3 10 5 79

9 Bi(OTf)3 10 4 70

10 Bi(NO3)3 20 4 84

11 Bi(NO3)3 10 4 89

12 Bi(NO3)3 5 4 92

13 Bi(NO3)3 3 4 82

14 Bi(NO3)3 2 4 80

a Reaction conditions: benzaldehyde (2 mmol), dimedone

(2 mmol), ethyl acetoacetate (2 mmol) and ammonium acetate

(2 mmol) heating in ethanol (5 mL).

b Isolated yields.

94 939291 -908988878685

Number of Runs

Figure 1 Recyclability of the catalyst: The Bi(NO3)3-5H2O catalyst could be reused four times without any loss of its activity towards the synthesis of 1,4-dihydropyridine derivatives.

Table 4 The reaction of arylaldehyde, ethyl acetoacetate, dimedone and ammonium acetate.

Entry R1 R2 Product Time (h) Yield (%)b Mp (°C)

Found Reported

1 4-H C2H5 4a 4.0 92 142-144 140-142 (Ref)c

2 4-CN C2H5 4b 5.0 92 142-144 140-142 (Ref)d

3 3-NO2 C2H5 4c 4.5 88 176-178 176-177 (Ref)d

4 4-Br C2H5 4d 4.5 92 254-256 253-255 (Ref)c

5 4-F C2H5 4e 4.0 90 186-188 184-186 (Ref)c

6 4-CF3 C2H5 4f 5.0 90 187-189 188-190 (Ref)d

7 3, 4-OCH3 C2H5 4g 3.5 94 202-204 204-206 (Ref)d

8 4-OCH3 C2H5 4h 3.5 93 258-260 257-259 (Ref)c

9 4-CH3 C2H5 4i 4.0 92 260-262 260-261 (Ref)c

10 4-OH C2H5 4j 6.5 82 233-235 232-234 (Ref)c

11 4-NO2 C2H5 4k 5.0 86 242-244 242-244 (Ref)d

12 2,4-Cl C2H5 41 5.5 92 142-144 140-142 (Ref)d

13 4-Cl CH3 4m 5.0 95 220-222 221-222 (Ref)e

14 4-CH3 CH3 4n 4.0 87 284-286 283-285 (Ref)e

15 4-CN CH3 4o 6.0 94 220-222 220-222 (Ref)d

16 4-NO2 CH3 4p 5.0 85 252-254 250-252(Ref)d

aReaction conditions: arylaldehyde (2 mmol), dimedone (2 mmol), ethyl acetoacetate of Bi(NO3)3-5H2O (5 mol%) in ethanol (5 mL); all reactions were carried out at 80 b Isolated yield. c Wang et al. (2005). d Surasani et al. (2012). e Kumar et al. (2008).

(2 mmol) and ammonium acetate (2 mmol) in the presence DC.

toluene, methanol and 1,4-dioxane) using the model reaction (Table 2, entries 1-7). It was found that the best results were obtained with 5 mol% Bi(NO3)35H2O in ethanol (Table 1, entry 1). The reaction was completed within 4 h and the expected product was obtained in a 92% yield.

3.2. Optimization of temperature

We have also examined the effect of temperature. The reaction has been studied at various temperatures from 50 to 110 0C. The yield of the product increased up to 80 0C. After 80 0C, increasing temperature leads to decrease in yields. For example the reaction of benzaldehyde, dimedone, ethyl acetoacetate and ammonium acetate at 100 0C in ethanol gave the corresponding product (Table 3, entry 6) in 84% yield, while decreasing the temperature to 80-85 0C

leads to the product in 92% yield. Therefore, our optimized condition is 5 mol% of Bi(NO3)35H2O and 80-85 0C in ethanol.

3.3. Reusability of the catalyst

The reusability of the catalyst is one of the most important benefits and makes it useful for commercial applications. Thus the recovery and reusability of Bi(NO3)35H2O were investigated. In these experiments, the reaction mixture was isolated with ethanol. The catalyst filtered was washed with methanol (3 x 10 ml). The catalyst was easily reused by filtration after washing and drying at 60 0C. The recycled catalyst has been examined in the next run. The Bi(NO3)35H2O catalyst could be reused four times without any loss of its activity (Table 3, entry 6). (Fig. 1)

Table 5 The reaction of arylaldehyde, dimedone, malono nitrile and ammonium acetate.

Entry R1 Product Time (h) Yield (%)b Mp (°C)

Found Reported

1 4-H 6a 4.0 88 278-280 275-277 (Ref)c

2 4-Cl 6b 4.5 87 286-288 287-288 (Ref)c

3 4- CH3 6c 3.5 82 294-296 294-295 (Ref)c

4 4- OCH3 6d 3.5 88 290-292 289-295 (Ref)c

5 3-Br 6e 4.5 89 292-294 293-294 (Ref)c

6 2-Cl 6f 5.0 78 274-276 273-276 (Ref)c

aReaction conditions: arylaldehyde (2 mmol), dimedone (2 mmol), malononitrile (2 mmol) and ammonium acetate (3 mmol) in the presence of

Bi(NO3)3-5H2O (5 mol%) in ethanol (5 mL); all reactions were carried out at 80 oC.

b Isolated yield.

c Kumar et al. (2008).

3.4. Synthesis of ethyl-4-phenyl-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

Under the optimized set of reaction conditions a number of aromatic aldehydes 1 were allowed to undergo MCR with dimedone 2, ethyl acetoacetate 3 and ammonium acetate in the presence of Bi(NO3)35H2O (5mol%) in ethanol (Scheme 1). The results were given in Table 4. All the electron - rich and electron - deficient aldehydes worked well leading to excellent yields of the products. The progress of the reaction was monitored by TLC.

3.5. Synthesis of 2-amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline

In order to check the versatility of the procedure, b-keto esters were replaced with other active methylene compounds such as malononitrile and the reactions were observed to follow the expected results to yield 2-amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline in good to excellent yield (Scheme 2). The results with different aldehydes are given in Table 5.

4. Conclusion

In conclusion, we have developed an easy and efficient method to prepare a variety of 1,4-dihydropyridine derivatives from the reaction of different aryl aldehydes, b-keto compound like 5,5-dimethyl-1,3-cyclohexanedione (dime-done), alkyl acetoacetate and ammonium acetate in the presence of a catalytic amount of Bi(NO3)35H2O at 7580 0C. Under the same experimental conditions, we have also prepared 2-amino-4-phenyl-3-cyano-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinolines in good yield. The higher catalytic activity of Bi(NO3)3 is ascribed to its high acidity, thermal stability and water tolerance. Also the superiority of use of Bi(NO3)3 toward the synthesis of 1,4-dihydropyridine is compared with other Lewis acids, the mildness of the conversion, experimental simplicity, compatibility with various functional groups, high yields of the reaction product, shorter reaction times and the easy workup procedure, makes this procedure attractive to synthesize a variety of these derivatives. Moreover, Bi(NO3)3 can be recovered and reused several times, which makes it useful and attractive for synthesis of these class of compounds for economic viability and greater selectivity. Based on all the results obtained it may be stated that Bi(NO3)3 is an important addition to the realm of Lewis acid to prepare varieties of 1,4-dihydropyridine derivatives.

Acknowledgments

The authors gratefully acknowledge University Grants Commission, Government of India, New Delhi for financial support (Major Research Project: F. No. 40-44/2011(SR)). The authors also acknowledge C. Abdul Hakeem College Management, Dr. W. Abdul Hameed, Principal and Dr. M. S. Dastageer, Head of the Research Department of Chemistry for the facilities and support.

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