Nanosized MgO as a Heterogeneous Base Catalysts, Catalyses Multicomponent Reaction of Cyclic Enaminoketones, Malononitrile, and Aromatic Aldehydes

Article abstract of DOI:10.1080/15533174.2014.988812

Nanosized MgO is an efficient catalyst for the synthesis of 1,4-dihydropyridine and imidazo[1,2-a]quinoline derivatives from multicomponent reaction of cyclic enaminoketones, malononitrile and aromatic aldehydes in EtOH at reflux condition. This method pr

Full text of DOI:10.1080/15533174.2014.988812

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Nanosized MgO as a Heterogeneous Base Catalysts,
Catalyses Multicomponent Reaction of Cyclic
Enaminoketones, Malononitrile and Aromatic
Aldehydes
Mehdi Abaszadeha, Mohammad Seifib & Ali Asadipourc
a Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of
Medical Sciences, Kerman 76175493, Iran
b Department of Chemistry, Faculty of Sciences, Najafabad Branch, Islamic Azad University,
Najafabad, Esfahan, Iran
c Department of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical
Sciences, Kerman, Iran
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Accepted author version posted online: 03 Aug 2015.
To cite this article: Mehdi Abaszadeh, Mohammad Seifi & Ali Asadipour (2015): Nanosized MgO as a Heterogeneous Base
Catalysts, Catalyses Multicomponent Reaction of Cyclic Enaminoketones, Malononitrile and Aromatic Aldehydes, Synthesis and
Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry, DOI: 10.1080/15533174.2014.988812
To link to this article: http://dx.doi.org/10.1080/15533174.2014.988812
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Nanosized MgO as a Heterogeneous Base Catalysts, Catalyses Multicomponent Reaction of
Cyclic Enaminoketones, Malononitrile and Aromatic Aldehydes
Mehdi Abaszadeha*, Mohammad Seifib and Ali Asadipourc
a*Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of
Medical Sciences, Kerman 76175493, Iran. E-mail: abaszadeh@kmu.ac.ir.
bDepartment of Chemistry, Faculty of Sciences, Najafabad Branch, Islamic Azad University,
Najafabad, Esfahan, Iran.
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Kerman University of Medical
Sciences, Kerman, Iran.
*Corresponding author
Abstract
Nanosized MgO is an efficient catalyst for the synthesis of 1,4-dihydropyridine and imidazo[1,2-
a]quinoline derivatives from multicomponent reaction of cyclic enaminoketones, malononitrile
and aromatic aldehydes in EtOH at reflux condition. This method provides several advantages
such as mild reaction and high yield with short reaction time.
Keywords: Nanosized MgO; multicomponent reaction; cyclic enaminoketones; malononitrile;
aromatic aldehydes;
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1. Introduction
In recent decades, multicomponent reactions (MCRs) have remarkably developed as a prevailing
method in preparation of many diverse natural and pharmaceutical products and organic
molecules. They are of stupendous attention to chemists due to their high yield, short reaction
[1]
time, being easily handled and their competency in synthesis of miscellaneous structures.
Nowadays, MCRs are being used in order to produce heterocyclic compounds with various
scaffolds and in combinatorial libraries for the synthesis of compounds owning biological
[2]
activities.
As previously documented, among these biologically active compounds 1,4-
dihydropyridines and imidazo[1,2-a]quinolines are particularly well known for their therapeutic
[3]
[4]
applications. Dihydropyridines were reported for their antitumor, calcium channel blokers,
[5]
[6]
[7]
[8]
[9]
[10]
antitubercular, analgesic, antithrombotic, anti-inflammatory, anticonvulsant
and
other pharmacological activities. Some of the marketed drug preparation containing 1,4-
dihydropyridine moieties are Nifedipine, Amlodipine, Oxodipine, etc. Moreover, some of
imidazo[1,2-a]quinoline derivatives have pharmacological properties such as antiallergic [11] and
anxiolytic [12] activity (Scheme 1).
The field of nanocatalysis is a rapidly growing field which involves the use of nanoparticles as
catalysts for a variety of homogeneous and heterogeneous catalysis applications since
nanoparticles have a large surface to volume ratio compared to bulk materials. Nanocatalysts are
esteemed as materials of enormous surface areas and with new investigation, developments may
offer expanding catalytic abilities. Heterogeneous catalysis characterizes one of the oldest
commercial practices of nanoscience, nanoparticles of metals and other compounds have been
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[13]
extensively used for important chemical reactions.
Nanosized magnesium oxide (MgO) is
known as heterogeneous catalysts and requires no special handling. Nanosized magnesium oxide
(MgO), obtained using a novel but simple procedure, was methodically investigated as a
heterogeneous base catalyst for reactions taking place in the liquid phase, specifically the
Michael addition and the Knoevenagel condensation. [14]
Considering the fact that nanosized magnesium oxide (MgO), has been hugely used in many
chemical reactions, we investigated its use in multicomponent reactions as catalyst and then
scrutinized the three-component reaction of cyclic enaminoketones, malononitrile and aromatic
aldehydes in the presence of nanosized magnesium oxide (MgO), as the catalyst for the synthesis
of both 1,4-dihydropyridine and imidazo[1,2-a]quinoline derivatives.
2. Experimental
Melting points were measured on a Electrothermal-9100 apparatus and are uncorrected. IR
1
spectra were recorded on a Brucker FT-IR Tensor 27 infrared spectrophotometer. H NMR and
13C NMR spectra were recorded on a Avance III 400 Bruker spectrometer at 400 and 100 MHz,
respectively. Elemental analyses were performed using a Heracus CHN-O-Rapid analyzer. The
[15]
[16]
cyclic enaminoketones 1a-d
and 1e-f
were prepared from the according to procedures
described in the literature.
2.1. Preparation of nanosized MgO
The MgO nanoparticles were synthesized by precipitation of the magnesium hydroxide gels in
aqueous solution using Mg(NO3)2 as salt and liquid ammonia as the precipitating agent. Initially,
the pH of 200 mL of distilled water was adjusted to 10.5 by addition of liquid ammonia. To this
solution, 0.1 M magnesium nitrate solution (0.0148 g/mL) was added drop wise with continuous
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stirring. The rate of addition of the salt solution was kept at 20 mL/h. During the addition, the pH
of the mixture decreased due to hydrolysis of the salt. The pH was maintained at 10.5 by
controlled addition of liquid ammonia solution. After completion of the precipitation procedure,
the mixture was stirred at room temperature for 12 h, filtered, repeatedly washed with distilled
water, dried at 120 °C, and calcined at 500 °C for 2 h. [17]
2.2. General procedure for the preparation of 1,4-dihydropyridine (4a-l) and imidazo[1,2-
a]quinoline (4m-r) derivatives:
A mixture of cyclic enaminoketones 1a-f (2 mmol), malononitrile 2 (2 mmol), aromatic
aldehydes 3a-e (2 mmol), and nanosized MgO (55 mol%) in ethanol (10 mL) at reflux for the
time reported in Table 3 (the progress of the reaction being monitored by TLC and was used
hexane/ethyl acetate as an eluent). After completion of the reaction the catalyst was separated
from the reaction mixture by centrifugation. The reaction mixture was poured into ice-cold
water; the crude product was filtered, dried, and recrystallized from ethanol.
2-amino-7,7-dimethyl-5-oxo-1-phenyl-4-(p-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(4b): Yellow crystals; IR (KBr, νmax, cm-1): 3472, 3344 (NH2), 2176 (CN), 1651 (C=O), 1590
1
(C=C). H NMR (400 MHz, DMSO-d6) δH: 7.63-7.12 (m, 9H, CH-Ar), 5.31 (s, 2H, NH2), 4.42
2
2
2
(s, 1H, CH), 2.21 (d, JHH=4 Hz, CH), 2.17 (d, JHH=4 Hz, CH), 2.00 (d, JHH=8 Hz, CH), 1.69
2
(d, JHH=8 Hz, CH), 1.03 (s, 3H, CH3), 0.88 (s, 3H, CH3), 0.73 (s, 3H, CH3). 13C NMR (100
MHz, DMSO-d6) δC: 193.76 (C=O), 156.23, 153.14, 135.02, 134.31, 132.25, 131.66, 130.79,
130.18, 127.77, 126.26, 120.94, 114.82 (CN), 62.70 (C3), 49.80 (CH2), 42.10 (CH2), 38.42 (CH),
34.51 (CMe2), 32.02 (CH3), 29.63 (CH3), 21.11 (CH3). Anal. calcd. for C25H25N3O: C, 78.30; H,
6.57; N, 10.96 %. Found: C, 78.08; H, 6.45; N, 10.83 %.
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2-amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-1-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-
carbonitrile (4c): White crystals; IR (KBr, νmax, cm-1): 3456, 3328 (NH2), 2160 (CN), 1648
(C=O), 1587 (C=C). 1H NMR (400 MHz, DMSO-d6) δH: 7.63-7.23 (m, 9H, CH-Ar), 5.71 (s, 2H,
2
2
2
NH2), 4.46 (s, 1H, CH), 2.21 (d, JHH=4 Hz, CH), 2.17 (d, JHH=4 Hz, CH), 2.01 (d, JHH=8 Hz,
2
CH), 1.70 (d, JHH=8 Hz, CH), 0.88 (s, 3H, CH3), 0.73 (s, 3H, CH3). 13C NMR (100 MHz,
DMSO-d6) δC: 192.25 (C=O), 157.14, 154.66, 135.29, 133.27, 132.92, 131.62, 131.43, 128.36,
126.03, 122.88, 120.95, 114.95 (CN), 61.69 (C3), 49.75 (CH2), 43.22 (CH2), 38.58 (CH), 35.90
(CMe2), 31.69 (CH3), 29.50 (CH3). Anal. calcd. for C24H22BrN3O: C, 64.29; H, 4.95; N, 9.37 %.
Found: C, 64.07; H, 4.78; N, 9.19 %.
2-amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(4e): Yellow crystals; IR (KBr, νmax, cm-1): 3392, 3328, 3232 (NH2, NH), 2192 (CN), 1654
1
3
(C=O), 1596 (C=C). H NMR (400 MHz, DMSO-d6) δH: 8.82 (s, 1H, NH), 6.94 (d, 2H, JHH=4
3
Hz, CH-Ar), 6.71 (d, 2H, JHH=4 Hz, CH-Ar), 5.65 (s, 2H, NH2), 4.16 (s, 1H, CH), 3.61 (s, 3H,
2
2
2
OCH3), 2.32 (d, JHH=8 Hz, CH), 2.20 (d, JHH=8 Hz, CH), 2.08 (d, JHH=8 Hz, CH), 1.89 (d,
2JHH=8 Hz, CH), 0.92 (s, 3H, CH3), 0.81 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δC:
192.71 (C=O), 156.08, 153.27, 152.59, 137.96, 136.48, 132.71, 131.48, 113.35 (CN), 61.68 (C3),
55.63 (OCH3), 48.25 (CH2), 37.36 (CH2), 36.58 (CH), 32.69 (CMe2), 29.34 (CH3), 27.24 (CH3).
Anal. calcd. for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99 %. Found: C, 70.43; H, 6.48; N, 12.82
%.
2-amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile
(4f): Yellow crystals; IR (KBr, νmax, cm-1): 3392, 3328, 3232 (NH2, NH), 2192 (CN), 1654
1
3
(C=O), 1596 (C=C). H NMR (400 MHz, DMSO-d6) δH: 8.93 (s, 1H, NH), 7.45 (d, 2H, JHH=4
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Hz, CH-Ar), 7.08 (d, 2H, JHH=4 Hz, CH-Ar), 5.82 (s, 2H, NH2), 4.30 (s, 1H, CH), 2.42 (d,
2
2
2
2JHH=8 Hz, CH), 2.31 (d, JHH=8 Hz, CH), 2.18 (d, JHH=8 Hz, CH), 1.98 (d, JHH=8 Hz, CH),
1.02 (s, 3H, CH3), 0.90 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6) δC: 191.89 (C=O), 155.88,
154.12, 136.70, 134.34, 132.19, 131.79, 128.86, 113.41 (CN), 60.61 (C3), 49.59 (CH2), 40.89
(CH2), 39.91 (CH), 33.53 (CMe2), 30.22 (CH3), 28.82 (CH3). Anal. calcd. for C18H18BrN3O: C,
58.08; H, 4.87; N, 11.29 %. Found: C, 57.91; H, 4.75; N, 11.05 %.
2-amino-5-oxo-1,4-diphenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (4g): Pink crystals;
1
IR (KBr, νmax, cm-1): 3472, 3296 (NH2), 2176 (CN), 1648 (C=O), 1590 (C=C). H NMR (400
MHz, DMSO-d6) δH: 7.52-7.09 (m, 10H, CH-Ar), 5.26 (s, 2H, NH2), 4.41 (s, 1H, CH), 2.21-1.49
(m, 6H, 3CH2). 13C NMR (100 MHz, DMSO-d6) δC: 192.75 (C=O), 155.18, 153.49, 142.28,
140.33, 135.26, 131.61, 131.23, 131.08, 130.50, 125.88, 124.68, 114.06 (CN), 62.89 (C3), 49.12
(CH2), 41.75 (CH2), 38.34 (CH), 26.60 (CH2). Anal. calcd. for C22H19N3O: C, 77.40; H, 5.61; N,
12.31 %. Found: C, 77.18; H, 5.47; N, 12.13 %.
2-amino-5-oxo-1-phenyl-4-(p-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (4h): Yellow
crystals; IR (KBr, νmax, cm-1): 3472, 3328 (NH2), 2192 (CN), 1638 (C=O), 1590 (C=C). 1H NMR
(400 MHz, DMSO-d6) δH: 7.61-7.11 (m, 9H, CH-Ar), 5.32 (s, 2H, NH2), 4.46 (s, 1H, CH), 2.27
(s, 3H, CH3), 2.22-1.56 (m, 6H, 3CH2). 13C NMR (100 MHz, DMSO-d6) δC: 192.86 (C=O),
156.82, 154.27, 136.07, 135.51, 134.52, 134.14, 133.54, 131.63, 131.32, 128.85, 125.96, 115.44
(CN), 63.23 (C3), 48.69 (CH2), 41.24 (CH2), 37.69 (CH), 25.88 (CH2), 21.46 (CH3). Anal. calcd.
for C23H21N3O: C, 77.22; H, 5.96; N, 11.82 %. Found: C, 77.01; H, 5.78; N, 11.69 %.
2-amino-4-(4-chlorophenyl)-5-oxo-1-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (4i):
Brown crystals; IR (KBr, νmax, cm-1): 3408, 3328 (NH2), 2176 (CN), 1657 (C=O), 1600 (C=C).
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1H NMR (400 MHz, DMSO-d6) δH: 7.61-7.41 (m, 5H, CH-Ar), 7.39 (d, 2H, 3JHH=4 Hz, CH-Ar),
7.30 (d, 2H, 3JHH=4 Hz, CH-Ar), 5.41 (s, 2H, NH2), 4.51 (s, 1H, CH), 2.29-1.56 (m, 6H, 3CH2).
13C NMR (100 MHz, DMSO-d6) δC: 193.11 (C=O), 155.12, 153.68, 140.94, 135.16, 132.03,
130.87, 130.83, 129.94, 128.51, 127.47, 126.97, 115.35 (CN), 63.69 (C3), 49.28 (CH2), 41.52
(CH2), 38.14 (CH), 25.30 (CH2). Anal. calcd. for C22H18ClN3O: C, 70.30; H, 4.83; N, 11.18 %.
Found: C, 70.04; H, 4.68; N, 10.99 %.
2-amino-5-oxo-4-phenyl-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (4j): Yellow crystals; IR
(KBr, νmax, cm-1): 3408, 3328, 3232 (NH2, NH), 2176 (CN), 1638 (C=O), 1596 (C=C). 1H NMR
(400 MHz, DMSO-d6) δH: 8.96 (s, 1H, NH), 7.27-7.12 (m, 5H, CH-Ar), 5.75 (s, 2H, NH2), 4.34
(s, 1H, CH), 2.28-1.76 (m, 6H, 3CH2). 13C NMR (100 MHz, DMSO-d6) δC: 192.94 (C=O),
156.59, 153.98, 137.94, 133.74, 132.82, 131.70, 130.29, 113.40 (CN), 62.12 (C3), 49.10 (CH2),
42.89 (CH2), 38.58 (CH), 25.40 (CH2). Anal. calcd. for C16H15N3O: C, 72.43; H, 5.70; N, 15.84
%. Found: C, 72.29; H, 5.52; N, 15.67 %.
2-amino-5-oxo-4-(p-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (4k): Yellow crystals;
1
IR (KBr, νmax, cm-1): 3424, 3328, 3232 (NH2, NH), 2176 (CN), 1651 (C=O), 1596 (C=C). H
NMR (400 MHz, DMSO-d6) δH: 8.93 (s, 1H, NH), 7.04 (d, 2H, 3JHH=4 Hz, CH-Ar), 7.01 (d, 2H,
3JHH=4 Hz, CH-Ar), 5.73 (s, 2H, NH2), 4.30 (s, 1H, CH), 2.23 (s, 3H, CH3), 2.20-1.72 (m, 6H,
3CH2). 13C NMR (100 MHz, DMSO-d6) δC: 192.58 (C=O), 155.97, 153.22, 138.00, 133.13,
132.73, 131.85, 129.64, 113.43 (CN), 62.29 (C3), 49.28 (CH2), 40.90 (CH2), 38.36 (CH), 26.12
(CH2), 21.57 (CH3). Anal. calcd. for C17H17N3O: C, 73.10; H, 6.13; N, 15.04 %. Found: C, 72.89;
H, 5.98; N, 14.88 %.
2-amino-4-(4-chlorophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitrile (4l): Yellow
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crystals; IR (KBr, νmax, cm-1): 3392, 3328, 3232 (NH2, NH), 2176 (CN), 1657 (C=O), 1600
1
3
(C=C). H NMR (400 MHz, DMSO-d6) δH: 9.00 (s, 1H, NH), 7.31 (d, 2H, JHH=4 Hz, CH-Ar),
7.14 (d, 2H, 3JHH=4 Hz, CH-Ar), 5.81 (s, 2H, NH2), 4.35 (s, 1H, CH), 2.28-1.73 (m, 6H, 3CH2).
13C NMR (100 MHz, DMSO-d6) δC: 193.05 (C=O), 156.11, 154.01, 135.56, 133.77, 132.79,
131.57, 127.61, 114.94 (CN), 63.14 (C3), 48.92 (CH2), 41.40 (CH2), 37.29 (CH), 25.28 (CH2).
Anal. calcd. for C16H14ClN3O: C, 64.11; H, 4.71; N, 11.83 %. Found: C, 63.87; H, 4.59; N, 11.69
%.
3. Results and discussion
There are several methods for the synthesis of 1,4-dihydropyridine and imidazo[1,2-a]quinoline
derivatives; these compounds were conventionally prepared using multicomponent reaction of
[18]
cyclic enaminoketones, malononitrile and aromatic aldehydes.
Although, many reported
methods are effective enough, use of expensive or poisonous catalysts, low yields, tedious work-
up processes, long reaction times and hazardous conditions make it less favorable. Therefore, the
introduction of a mild, easy, efficient and environmentally benign method to synthesize 1,4-
dihydropyridine and imidazo[1,2-a]quinoline derivatives is still needed.
Our contribution is intended to describe the application of a new catalyst in their synthesis of
1,4-dihydropyridine and imidazo[1,2-a]quinoline derivatives. Our investigations show that
multicomponent reaction of cyclic enaminoketones, malononitrile and aromatic aldehydes in the
presence of a catalytic amount of nanosized MgO under reflux in EtOH to afford the
corresponding 1,4-dihydropyridine and imidazo[1,2-a]quinoline derivatives in good to excellent
yields and short reaction time (Scheme 2).
Moreover, in order to optimize the conditions of reactions, several polar and non-polar solvents
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were used in the reaction of 3-anilino-5,5-dimethylcyclohex-2-en-1-one 1a, malononitrile 2 and
benzaldehyde 3a as the model for reactions to study the solvent effects for preparing compound
4a. In each case, the substrates were mixed together with 55 mol% nanosized MgO agitated with
10 mL solvent at reflux. The results are shown in Table 1. It is noteworthy to mention that the
polar solvents such as EtOH afford better yields than non polar solvents. The polar solvent may
stabilize the activated intermediates and this increase reaction rate. In addition homogenization
of the solid mixture through dissolution in the polar solvents improved the yields and decreased
reaction time. In the absence of solvent the target product is afforded with yields <20% at the
same time.
In addition, the amount of used catalyst was optimized. The best results were obtained when the
reactions were carried out in the presence of 55 mol% nanosized MgO. The results are shown in
Table 2.
Finally based on the findings, multicomponent reaction of cyclic enaminoketones, malononitrile
and aromatic aldehydes in the presence of nanosized MgO were examined so as to synthesize
1,4-dihydropyridine and imidazo[1,2-a]quinoline derivatives (Table 3). The reaction of various
aromatic aldehydes containing electron-withdrawing groups (4c, 4f, 4i, 4l, 4o, 4r) and electron-
donating groups (4b, 4e, 4h, 4k, 4n, 4q) were examined. They all gave the products in goods
yields (Table 3). The aldehydes containing electron-withdrawing groups gave the products in
shorter time as compared to the aldehydes containing electron-donating groups. The presence of
electron-withdrawing substituents on aromatic rings markedly increases the electrophilicity of
the corresponding aromatic aldehydes and 2-arylidenemalononitrile derivatives (Ι) in the
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Knoevenagel condensation and Michael addition reaction and this increase the reactivity and
then reaction rate.
In these reactions, in first step Knoevenagel condensation takes place to form the 2-
arylidenemalononitrile derivatives (Ι). The active methine of cyclic enaminoketones reacts with
the electrophilic C=C double bond of 2-arylidenemalononitrile giving the intermediate ΙΙ. The
latter is then cyclized by nucleophilic attack of the NHR' group on the cyano (CN) moiety, giving
intermediate ΙΙΙ. Finally, the expected product 4a-l (1,4-dihydropyridine derivatives) is afforded
by tautomerization. Here, the catalytic activity of MgO was established for Knoevenagel
condensation and Michael addition reactions (Scheme 3).
Wherein R'=CH2COOEt, upon intermolecular cyclization and elimination of EtOH gave rise to
imidazo[1,2-a]quinoline derivatives (4m-r) (Scheme 4).
Conclusion
In summary nanosized MgO could be used as a catalyst for synthesis of 1,4-dihydropyridine and
imidazo[1,2-a]quinoline derivatives which are often encountered in biologically active
compounds. This method was simple and efficient and the reaction products were isolated by
easy work-up procedure and do not need any further purification steps.
Acknowledgement
The authors express their great appreciation to Kerman University of Medical Sciences,
Pharmaceutics Research Center, Institute of Neuropharmacology for support of this
investigation.
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Chem. 1988, 31, 1098-1115.
[12] Clements, S.J.; Danswan, G.; Gardner, C.R.; Matharu, S.S.; Murdoch, R.; Tully, W.R.;
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[13] http://www.nanowerk.com.
[14] Xu, C.; Bartley, J.K.; Enache, D.I.; Knight, D.W.; Hutchings, G.J. Synthesis 2005, 3468-
3476.
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[16] Lichitsky, B.V.; Dudinov, A.A.; Krayushkin, M.M. Arkivoc 2001, ix, 73-79.
[17] Kumar, D.; Reddy, V.B.; Mishra, B.G.; Rana, R.K.; Nadagouda, M.N.; Varma, R.S.
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1951-1954.
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Table 1: Solvent effects on the multicomponent reaction of 3-anilino-5,5-dimethylcyclohex-2-
en-1-one 1a, malononitrile 2 and benzaldehyde 3a
Time
(min)
Yield
(%)
Entry Solvent
1
2
3
4
Toluene
THF
EtOAc
CH3CN
75
42
40
35
73
82
85
87
5
Ethanol
20
91
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Table 2: Optimized the quantity of catalysts on the multicomponent reaction of 3-anilino-5,5-
dimethylcyclohex-2-en-1-one 1a, malononitrile 2 and benzaldehyde 3a
Mol%
catalyst (min)
Time
Yield
(%)
Entry
1
2
3
4
5
25
35
45
55
65
38
33
27
20
20
80
84
87
91
91
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Table 3: Multicomponent reaction of cyclic enaminoketones 1a-f, malononitrile 2 and aromatic
aldehydes 3a-e
M. P.
M. P.
Compd.
No.
Yield
(%)
Time
(min)
Ar
R'
R
reported
(°C)
observed
(°C)
246-248
[18a]
244-245
91
20
C6H5
C6H5
Me
4a
243-245
269-271
89
92
24
17
4-CH3-C6H4
4-Br-C6H4
C6H5
C6H5
Me
Me
4b
4c
265-267
[18a]
262-264
279-281
90
88
21
27
C6H5
H
H
Me
Me
4d
4e
4-CH3O-
C6H4
210 (dec.)
110 (dec.)
235 (dec.)
91
89
87
18
23
25
4-Br-C6H4
C6H5
H
Me
H
4f
4g
4h
C6H5
C6H5
4-CH3-C6H4
H
228-230
254 (dec.)
269-271
92
88
87
20
24
29
4-Cl-C6H4
C6H5
C6H5
H
H
H
H
4i
4j
4-CH3-C6H4
H
4k
296-298
>300
91
90
22
36
4-Cl-C6H4
C6H5
H
H
4l
CH2-
COOEt
>300 [18b]
Me
4m
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CH2-
COOEt
>300 [18b]
>300 [18b]
>300
>300
89
92
40
33
4-CH3-C6H4
4-Cl-C6H4
Me
Me
4n
4o
CH2-
COOEt
274-275
[18b]
CH2-
COOEt
270-272
283-285
289-290
89
87
90
40
43
35
C6H5
H
H
H
4p
4q
4r
287-289
[18b]
CH2-
COOEt
4-CH3-C6H4
4-Cl-C6H4
290-291
[18b]
CH2-
COOEt
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O
O
Cl
NO2
MeO2C
CO2Et
MeO2C
CO2Me
MeO2C
CO2Me
O
NH2
N
N
N
H
H
H
Nifedipine
Oxodipine
Amlodipine
OCH3
N
N
N
N
CO2Et
Antiallergic activity
CO2Et
Anxiolytic activity
Scheme 1: Some of the marketed drug preparation containing 1,4-dihydropyridine moieties and
some of imidazo[1,2-a]quinoline derivatives with pharmacological properties
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O
Ar
CN
if R'=H, Ph
R
N
NH2
R
O
R'
O
CN
EtOH, MgO
4a-l
R
+
+
Ar
H
reflux
CN
NH
R'
R
O
Ar
CN
1a-f
2
3a-e
if R'=CH2COOEt
R
N
NH
O
R
4m-r
Scheme 2: Synthesis of 1,4-dihydropyridine and imidazo[1,2-a]quinoline derivatives
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Ar
CN
CN
CN
CN
- H2O
Ar
H
HC
H
H
O
I
....Mg2+ ........ O2- ......
O
....Mg2+ ...... O2- ......
O
Ar
H
CN
CN
R
R
R'
C
N
Ar
C
N
N
H
N
R
R
R'
....Mg2+ ...... O2- ......
....Mg2+ ...... O2- ......
...Mg2+ .... O2- ....
II
O
Ar
O
Ar
H
CN
NH
CN
R
R
N
N
NH2
R
R
R'
R'
1,4-Dihydropyridines (4a-l)
III
Scheme 3: The suggested mechanism for the synthesis of 1,4-dihydropyridine derivatives (4a-l)
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O
Ar
O
Ar
N
CN
CN
NH
- EtOH
R
R
N
NH2
..
OEt
R
R
O
O
Imidazo[1,2-a]quinoline (4m-r)
Scheme 4: The suggested mechanism for the synthesis of imidazo[1,2-a]quinoline derivatives
(4m-r)
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