Journal of Chemistry

Volume 2013 (2013), Article ID 490972, 5 pages

http://dx.doi.org/10.1155/2013/490972

Research Article

Cellulose-Sulfuric Acid as an Efficient Biosupported Catalyst in One-Pot Synthesis of Novel Heteroaryl Substituted 1,4-Dihydropyridines

Manouchehr Mamaghani, Khalil Tabatabaeian, Mohaddesseh Mohammadi, and Alireza Khorshidi

Department of Chemistry, Faculty of Sciences, University of Guilan, P.O. Box 41335-1914, Rasht, Iran

Received 23 May 2013; Accepted 3 September 2013

Academic Editor: Mohamed Afzal Pasha

Copyright © 2013 Manouchehr Mamaghani et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

An efficient method for the synthesis of new heteroaryl substituted dihydropyridine derivatives via a one-pot four-component coupling reaction of heteroaldehyde, 1,3-diketone, ethylacetoacetate, and amonium acetate in the presence of cellulose-sulfuric acid as a biosupported solid acid catalyst was developed. The reaction gave the new derivatives of fused 1,4-dihydropyridines in lower reaction times and excellent yields (85–95%).

1. Introduction

1,4-Dihydropyridines exhibit interesting pharmacological and biological properties. For example, they have been used as calcium channel modulators for the treatment of cardiovascular disorders [1, 2]. They also present vasodilating [3], antifilarial [4], and antitubercular activities [5] and may serve as NADH mimics [6, 7]. Many methods have been reported for the synthesis of 1,4-dihydropyridine derivatives in view of the biological importance associated with these compounds. The best known procedure for preparation of symmetrical 1,4-dihydropyridines is the classical Hantzch synthesis: a multicomponent condensation involving two molecules of β-ketoester, one molecule of aldehyde, and one molecule of ammonia [8, 9]. Other reported methods comprise the use of microwave [10–12], ionic liquids [13, 14], high temperature in refluxing solvent [15–24], TMSCl-NaI [25], and metal triflates [26, 27], which have their own drawbacks such as high temperature, expensive metal precursors, and prolonged reaction times. Thus, development of a simple, efficient, and versatile method for preparation of new derivatives of 1,4-dihydropyridine is a great challenge.

2. Experimental

2.1. General

Melting points were measured on an electrothermal 9100 apparatus and are uncorrected. ¹H NMR spectra were obtained on a Bruker DRX-500 Avance spectrometer, and ¹³C NMR spectra were obtained on a Bruker DRX-125 Avance spectrometer. Chemical shifts of ¹H and ¹³C NMR spectra were expressed in ppm downfield from tetramethylsilane. FT-IR spectra were recorded on a Shimadzu FT-IR-8400S spectrometer. Chemicals were purchased from Merck and Fluka and used without further purification.

2.2. Typical Procedure: Preparation of 3-Aryl-4-fromyl-1-phenylpyrazole

In a round bottomed flask, cyanuric chloride (1.83 g, 10 mmol) was added to dimethyl formamide (2 mL) which resulted in a white solid. To this product a solution of phenylhydrazone acetophenone (1 g, 5 mmol) in dimethyl formamide (15 mL) was added and stirred for 16 h at room temperature. To the resulted mixture, 15% Na₂CO₃ (20 mL) was added and the organic layer was extracted by diethylether ( mL). The ethereal solution was dried by MgSO₄ and filtered, and the filtrate evaporated under vacuum to produce 1,3-diphenyl-4-formylpyrazole (1.12 g) in 90% yield. The product was identified by spectroscopic analysis and comparison of its melting point (mp = 146–148°C) with the reported one (mp = 145–147°C) [28].

Light yellow solid, IR (KBr) (/cm⁻¹): 2850, 2750 (H–C=O), 1670 (C=O), 1590, 1520, 750, 690. ¹H NMR (500 MHz, CDCl₃): δ 10.11 (1H, s), 8.59 (1H, s), 7.89–7.84 (4H, m), 7.58–7.52 (5H, m), 7.44 (1H, t, = 7.44 Hz) ppm; ¹³C NMR (125 MHz, CDCl₃) δ 185.6, 155.2, 139.5, 131.8, 131.4, 130.1, 129.7, 129.4, 129.2, 128.4, 123.0, 120.2 ppm.

2.2.1. 3-(4-Nitrophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde

Yellow solid; FT-IR (neat) (/cm⁻¹): 1680 (HC=O), 1520, 1340 (NO₂). ¹H NMR (500 MHz, CDCl₃) δ 7.49 (1H, t, = 7.40 Hz), 7.59 (2H, t, = 7.90 Hz), 7.85 (2H, d, = 7.74 Hz), 8.21 (2H, d, = 8.70 Hz), 8.38 (2H, d, = 8.70 Hz), 8.62 (1H, s), 10.13 (1H, s); ¹³C NMR (125 MHz, CDCl₃) δ 184.0 (HC=O), 151.7, 148.6, 139.1, 138.1, 134.0, 130.3, 130.1, 128.9, 124.2, 123.4, 120.2.

2.3. General Procedure for the Synthesis of 1,4-Dihydropyridines (5a–i)

A mixture of 3-aryl-4-formylpyrazole (1) (1.0 mmol), 1,3-diketone (2) (1.0 mmol, dimedone or 1,3-cyclohexanedione or indanedione), ethylacetoacetate (3) (1.0 mmol), ammonium acetate (1.0 mmol), and cellulose-sulfuric acid (0.05 g) in ethanol (10 mL) was refluxed in an oil bath for the appropriate time (Table 1). The progress of the reaction was controlled by TLC, and after completion of the reaction the solvent was evaporated under reduced pressure to provide a residue which was purified by recrystallization from ethanol to furnish the desired 1,4-dihydropyridines (5a–i).

Table 1: Synthesis of heteroaryl substituted 1,4-dihydropyridines in the presence of cellulose-sulfuric acid catalyst.

Entrya
Ar
2
Time (min)
Product
Yield (%)b

a
Ph
Dimedone
42 (120)c
5a
90 (75)c

b
-NO₂C₆H₄
Dimedone
45
5b
95

c
-ClC₆H₄
Dimedone
40
5c
94

d
Ph
1,3-Cyclohexanedione
43 (125)c
5d
88 (72)c

e
-NO₂C₆H₄
1,3-Cyclohexanedione
45
5e
87

f
-ClC₆H₄
1,3-Cyclohexanedione
42
5f
86

g
Ph
1,3-Indanedione
39 (120)c
5g
90 (75)c

h
-NO₂C₆H₄
1,3-Indanedione
41
5h
86

i
-ClC₆H₄
1,3-Indanedione
37
5i
85

All products were characterized by ¹H NMR, ¹³C NMR, and IR data.

bIsolated yields.

cMeasured in the absence of the catalyst.

2.3.1. Ethyl 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydro quinoline-3-carboxylate (5a)

Yellow powder, mp = 106–108°C; FT-IR (neat) (/cm⁻¹) 3300, 3200 (NH), 1695 (C=O), 1635 (C=C, olefinic); ¹H NMR (500 MHz, CDCl₃) δ 7.95 (2H, d, = 7.32 Hz), 7.81 (1H, s) 7.69 (2H, d, = 7.90 Hz), 7.41–7.47 (4H, m), 7.37 (1H, t, = 7.38 Hz), 7.26 (1H, t, = 7.38 Hz), 6.03 (1H, s), 5.32 (1H, s), 3.64, 3.97 (2H, m), 2.21, 2.25 (2H, d, = 16.36 Hz), 2.19 (3H, s), 2.13, 2.23 (2H, d, = 16.50 Hz), 1.08 (3H, s), 1.04 (3H, s), 0.92 (3H, t, = 7.09 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 196.0 (C=O, ketone), 167.8 (C=O, ester), 152.2, 148.5, 142.8, 140.5, 135.2, 129.7, 129.6, 128.6, 128.3, 127.9, 127.5, 126.4, 119.3, 112.3, 107.1, 60.0, 51.1, 41.5, 33.1, 30.1, 28.3, 27.4, 19.6, 14.4. Anal. Calcd for C₃₀H₃₁N₃O₃: C, 74.82; H, 6.49; N, 8.73. Found: C, 74.73; H, 6.26; N, 8.56.

2.3.2. Ethyl 2,7,7-Trimethyl-4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5b)

Yellow solid mp = 256–258°C; FT-IR (neat) (/cm⁻¹) 3250, 3200 (NH), 1695 (C=O), 1650 (C=C, olefinic), 1510, 1330 (NO₂); ¹H NMR (500 MHz, CDCl₃) δ 8.44 (2H, d, = 8.88 Hz), 8.38 (2H, d, = 8.88 Hz), 7.80 (1H, s), 7.70 (2H, d, = 7.62 Hz), 7.47 (2H, t, = 7.95 Hz), 7.32 (1H, t, = 7.40 Hz), 5.86 (1H, s), 5.33 (1H, s), 3.95, 3.63 (2H, m), 2.41, 2.25 (2H, d, = 16.46 Hz), 2.33 (3H, s), 2.25, 2.32 (2H, d, = 16.30 Hz), 1.15 (3H, s), 1.07 (3H, s), 0.86 (3H, t, = 7.12 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 196.1 (C=O), 167.4 (C=O, ester), 149.2, 148.0, 147.5, 142.7, 142.0, 140.3, 130.0, 129.8, 128.2, 127.0, 123.8, 119.5, 112.9, 107.7, 60.2, 51.0, 41.8, 33.3, 29.5, 28.0, 27.4, 20.0, 14.4. Anal. Calcd for C₃₀H₃₀N₄O₅: C, 68.42; H, 5.74; N, 10.64. Found: C, 68.25; H, 5.64; N, 10.75.

2.3.3. Ethyl 4-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5c)

White solid, mp = 253–255°C; FT-IR (neat) (/cm⁻¹): 3300, 3200 (NH), 1690 (C=O), 1640 (C=C, olefinic), 1080 (C–Cl); ¹H NMR (500 MHz, CDCl₃) δ 7.98 (2H, d, = 8.20 Hz), 7.97 (1H, s), 7.66 (1H, s), 7.54 (2H, d, = 7.55 Hz), 7.32 (2H, d, = 8.20 Hz), 7.30 (2H, m 2H), 7.14 (1H, t, = 7.34 Hz), 5.13 (1H, s), 3.82, 3.44 (2H, m), 2.25, 2.22 (2H, d, = 16.78 Hz), 2.16 (3H, s), 2.11, 2.07 (2H, d, = 16.16 Hz), 0.95 (3H, s), 1.00 (3H, s), 0.75 (3H, t, = 7.08 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 196.0 (C=O, ketone), 167.8 (C=O, ester), 150.3, 149.8, 143.9, 140.3, 133.8, 133.4, 130.8, 129.7, 129.6, 128.4, 127.7, 126.4, 119.1, 111.8, 106.6, 59.7, 51.1, 40.9, 33.0, 29.5, 27.9, 27.2, 19.1, 14.2. Anal. Calcd for C₃₀H₃₀ClN₃O₃: C, 69.82; H, 5.86; N, 8.14. Found: C, 69.67; H, 5.75; N, 8.05.

2.3.4. Ethyl 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (5d)

Yellow powder, mp = 101–103°C; FT-IR (neat) (/cm⁻¹) 3300, 3200 (NH), 1690 (C=O); ¹H NMR (500 MHz, CDCl₃) δ 7.84 (1H, s), 7.82 (2H, d, = 7.66 Hz), 7.69 (2H, d, = 8.33 Hz), 7.42 (1H, t, = 7.47 Hz), 7.35 (1H, t, = 7.32 Hz), 7.25 (1H, t, = 7.38 Hz), 6.32 (1H, s), 5.30 (1H, s), 3.74, 4.00 (2H, m), 2.30–2.35 (2H, m), 2.16 (3H, s), 1.93, 1.84 (2H, m), 1.84, 1.92 (2H, m), 1.01 (3H, t, = 7.09 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 196.3 (C=O, ketone), 167.7 (C=O, ester), 152.5, 150.6, 143.0, 140.4, 135.3, 129.8, 129.6, 128.4, 128.2, 127.9, 127.5, 126.4, 119.3, 112.9, 106.6, 60.1, 37.4, 27.6, 27.5, 21.4, 19.4, 14.5. Anal. Calcd for C₂₈H₂₇N₃O₃: C, 74.15; H, 6.00; N, 9.27. Found: C, 74.10; H, 6.26; N, 8.10.

2.3.5. Ethyl 2-Methyl-4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-1,4,5,6,7,8-hexa-hydroquinoline-3-carboxylate (5e)

Yellow solid, mp = 202-203°C; FT-IR (neat) (/cm⁻¹) 3300, 3200 (NH), 1690 (C=O), 1640 (C=C, olefinic), 1510, 1330 (NO₂); ¹H NMR (500 MHz, CDCl₃) δ 8.31 (2H, d, = 8.74 Hz), 8.25 (2H, d, = 8.74 Hz), 8.04 (1H, s), 7.73 (1H, s), 7.62 (2H, d, = 7.82 Hz), 7.37 (2H, t, = 7.82 Hz), 7.20 (1H, t, = 7.34 Hz), 5.22 (1H, s), 3.58, 3.86 (2H, m), 2.37 (2H, m), 2.28 (2H, m), 2.22 (3H, s), 1.84, 1.19 (2H, m), 0.80 (3H, t, = 7.08 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 196.5 (C=O, ketone), 167.7 (C=O, ester), 151.3, 149.1, 147.3, 144.1, 142.2, 140.2, 130.7, 130.0, 129.7, 128.3, 126.8, 123.6, 119.3, 113.2, 106.4, 59.9, 37.4, 27.4, 27.3, 21.5, 19.2, 14.4. Anal. Calcd for C₂₈H₂₆N₄O₅: C, 67.46; H, 5.26; N, 11.24. Found: C, 67.30; H, 5.16; N, 11.13.

2.3.6. Ethyl 4-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexa-hydroquinoline-3-carboxylate (5f)

White solid, mp = 257-258°C; FT-IR (neat) (/cm⁻¹) 3300, 3200 (NH), 1690 (C=O), 1645 (C=C, olefinic), 1070 (C–Cl); ¹H NMR (500 MHz, CDCl₃) δ 7.92 (2H, d, = 8.41 Hz), 7.79 (1H, s), 7.72 (1H, s), 7.61 (2H, d, = 7.79 Hz), 7.35 (2H, d, = 8.41 Hz), 7.34 (2H, t, = 7.53 Hz), 7.18 (1H, t, = 7.38 Hz), 5.20 (1H, s), 3.91, 3.59 (2H, m), 2.34–2.31 (2H, m), 2.29–2.24 (2H, m), 2.17 (3H, s), 1.91, 1.89 (2H, m), 0.87 (3H, t, = 7.10 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 196.4 (C=O, ketone), 167.9 (C=O, ester), 151.3, 150.6, 143.7, 140.4, 142.0, 133.9, 133.6, 130.9, 129.6, 129.5, 128.4, 127.8, 126.4, 119.1, 113.0, 106.5, 59.8, 37.5, 27.4, 21.5, 19.1, 14.5. Anal. Calcd for C₂₈H₂₆ClN₃O₃: C, 68.92; H, 5.37; N, 8.61. Found: C, 68.74; H, 5.18; N, 8.52.

2.3.7. Ethyl 4-(1,3-Diphenyl-1H-pyrazol-4-yl)-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]-pyridine-3-carboxylate (5g)

Red solid, mp = 160–162°C; FT-IR (neat) (/cm⁻¹) 3280, 3180 (NH), 1680, 1670 (C=O), 1635 (C=C, olefinic); ¹H NMR (500 MHz, CDCl₃) δ 9.04 (1H, s), 7.90 (2H, d, = 7.21 Hz), 7.76 (1H, s), 7.62 (2H, d, = 7.92 Hz), 7.38–7.27 (m, 7H), 7.22–7.14 (3H, m), 5.12 (1H, s), 3.90, 3.67 (2H, m), 2.30 (3H, s), 0.79 (3H, t, = 7.10 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 192.8 (C=O, ketone), 167.8 (C=O, ester), 154.2, 152.1, 143.8, 140.4, 137.1, 134.6, 134.5, 131.5, 130.2, 129.6, 129.5, 128.5, 128.4, 128.0, 127.9, 126.3, 121.1, 119.1, 118.9, 110.1, 108.7, 60.0, 27.6, 19.3, 14.1. Anal. Calcd for C₃₁H₂₅N₃O₃: C, 76.37; H, 5.17; N, 8.62. Found: C, 76.43; H, 5.10; N, 8.46.

2.3.8. Ethyl 2-Methyl-4-(3-(4-nitrophenyl)-1-phenyl-1H-pyrazol-4-yl)-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carboxylate (5h)

Red solid, mp = 167-168°C; FT-IR (neat) (/cm⁻¹) 3300, 3180 (NH), 1690, 1680 (C=O), 1640 (C=C, olefinic), 1510, 1330 (NO₂); ¹H NMR (500 MHz, CDCl₃) δ 9.31 (1H, s), 8.21 (2H, d, = 8.84 Hz), 8.15 (2H, d, = 8.84 Hz), 7.77 (1H, s), 7.60 (2H, d, = 8.58), 7.30–7.37 (3H, m), 7.24–7.15 (4H, m), 5.08 (1H, s), 3.86, 3.75 (2H, m), 2.33 (3H, s), 0.80 (3H, t, = 7.10 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 192.7 (C=O, ketone), 167.6 (C=O, ester), 154.2, 149.5, 147.3, 144.4, 141.5, 140.1, 136.9, 134.4, 131.6, 130.3, 130.1, 129.7, 129.4, 128.5, 126.9, 123.6, 121.2, 119.2, 119.1, 109.7, 108.2, 60.1, 27.8, 19.4, 14.2. Anal. Calcd for C₃₁H₂₄N₄O₅: C, 69.91; H, 4.54; N, 10.52. Found: C, 69.70; H, 4.38; N, 10.34.

2.3.9. Ethyl 4-(3-(4-Chlorophenyl)-1-phenyl-1H-pyrazol-4-yl)-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carboxylate (5i)

Red solid, mp = 189–191°C; FT-IR (neat) (/cm⁻¹) 3300, 3190 (NH), 1680 (C=O), 1640 (C=C), 1090 (C–Cl); ¹H NMR (500 MHz, CDCl₃) δ 9.16 (1H, s), 7.86 (2H, d, = 8.86 Hz), 7.74 (1H, s), 7.59 (2H, d, = 7.68 Hz), 7.32 (2H, d, = 8.42 Hz), 7.30–7.35 (3H, m), 7.13–7.26 (4H, m), 5.06 (1H, s), 3.89, 3.73 (2H, m), 2.30 (3H, s), 0.83 (3H, t, = 7.11 Hz); ¹³C NMR (125 MHz, CDCl₃/DMSO-d₆) δ 192.8 (C=O, ketone), 167.7 (C=O, ester), 154.2, 150.8, 144.0, 140.2, 137.0, 134.5, 133.7, 133.2, 131.6, 130.8, 130.2, 129.6, 128.6, 128.5, 128.1, 126.5, 121.1, 119.1, 119.0, 109.9, 108.5, 60.1, 27.7, 19.3, 14.2. Anal. Calcd for C₃₁H₂₄ClN₃O₃: C, 71.33; H, 4.63; N, 8.05. Found: C, 71.17; H, 4.45; N, 8.16.

3. Results and Discussion

In continuation of our ongoing interests on the synthesis of 1,4-dihydropyridine derivatives [29, 30], we have developed an efficient method for the synthesis of the target products via a one-pot four-component coupling reaction of heteroarylaldehyde (1) (prepared by the reaction of related arylhydrazone and DMF in the presence of 2,4,6-trichloro-1,3,5-triazine (TCT)) [28], 1,3-diketone (2), ethylacetoacetate (3), and ammonium acetate in the presence of cellulose-sulfuric acid as a biosupported solid acid catalyst (Scheme 1). The reaction gave new derivatives of 1,4-dihydropyridines in lower reaction times (38–45 min) and excellent yields (85–95%) (Table 1).

Scheme 1: Efficient synthesis of fused 1,4-dihydropyridines.

The reactions (entries a, d and g) were also carried out in the absence of cellulose-sulfuric acid in the same conditions which furnished the desired products in much longer reaction times (120–125 min) and lower yields (Table 1).

In order to optimize the effect of the amount of catalyst on the efficiency of the reaction, the preparation of 5a was selected as model reaction under reflux condition. This study gave the optimized amount of the catalyst as 0.05 g/mmol of substrate. The effect of different solvents (EtOH, MeOH, CH₃CN, 1,4-dioxane, and DMF) on the preparation of 5a showed that EtOH was the solvent of choice. Therefore, all the reactions described in this report were carried out under optimized conditions (Table 1). The catalyst which was prepared according to the literature reports [31–33] is recoverable and was run for three consecutive cycles, furnishing the product (5a) without loss of catalytic activity. The structures of all products were deduced from ¹H NMR, ¹³C NMR and IR spectral analyses. ¹H NMR showed H-4 proton at 5.06–5.33 ppm as singlet which clearly confirmed the formation of 1,4-dihydropyridine moiety.

4. Conclusions

In summary, we have developed a convenient and facile protocol for the synthesis of new heteroaryl substituted 1,4-dihydropyridines in the presence of cellulose-sulfuric acid as an efficient biosupported solid acid catalyst in lower reaction times (37–45 min) and excellent yields (85–95%). The simple procedures combined with easy recovery and reuse of the catalyst make this method economic, environmentally benign, and user-friendly process for the synthesis of these biolabile fused 1,4-dihydropyridine derivatives. The method is amenable for iterative combinatorial library generation.

Conflict of Interests

The authors declare no conflict of interests.

Acknowledgment

The authors are thankful to the Research Council of University of Guilan for the partial support of this work.

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