One-pot synthesis of polyhydropyridine derivatives via hantzsch four component condensation in water medium: Use of a recyclable lewis acid [Ce(SO4)2.4H2O] catalyst

Article abstract of DOI:10.4314/bcse.v26i3.16

An efficient and eco-friendly method for the synthesis of polyhydroquinoline derivatives using Ce(SO₄)₂.4H ₂O as mild and heterogeneous Lewis acid catalyst via the Hantzsch reaction in very short reaction time is reported.

Full text of DOI:10.4314/bcse.v26i3.16

Bull. Chem. Soc. Ethiop. 2012, 26(3), 461-465.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v26i3.16
ISSN 1011-3924
 2012 Chemical Society of Ethiopia
SHORT COMMUNICATION
ONE-POT SYNTHESIS OF POLYHYDROPYRIDINE DERIVATIVES VIA
HANTZSCH FOUR COMPONENT CONDENSATION IN WATER MEDIUM: USE OF
A RECYCLABLE LEWIS ACID [Ce(SO4)2.4H2O] CATALYST
Elaheh Mosaddegh* and Asadollah Hassankhani
Department of Materials Science, International Center for Science, High Technology &
Environmental Sciences, P.O. Box 76315-117, Kerman, Iran
(Received July 4, 2011; revised December 27, 2011)
ABSTRACT. An efficient and eco-friendly method for the synthesis of polyhydroquinoline derivatives using
Ce(SO4)2.4H2O as mild and heterogeneous Lewis acid catalyst via the Hantzsch reaction in very short reaction
time is reported. A mixture of an appropriate aldehyde, dimedone, ethyl acetoacetate and malononitrile in the
presence of the Ce(SO4)2.4H2O at reflux conditions in water based media resulted in good to excellent yields of
the corresponding products. The catalyst can be used as selective for some aromatic aldehydes in the reaction
conditions.
KEY WORDS: Ce(SO4)2.4H2O, Polyhydroquinoline, Hantzsch reaction, Muticomponent reaction,
Dihydropyridine
INTRODUCTION
4-Substituted 1,4-dihydropyridines (1,4-DHPs) are an important class of drugs that exhibit
several medicinal and biological applications, which include neuroprotectant and platelet anti-
aggregatory activity, in addition to cerebral antiischemic activity in the treatment of Alzheimer’s
disease and as chemo sensitizer in tumor therapy [1]. Members of the 1,4-dihydropyridine
family are being used as antimalarial, anti-inflammatory, antiasthamatic, antibacterial, tyrosine
kinase inhibiting agents [2], and drugs for the treatment of congestive heart failure [3] and
cardiovascular [4]. Therefore, their synthesis has been the focus of much interest for organic
and medicinal chemists [5].
Numerous synthetic methods have been reported for the preparation of 1,4-dihydropyridines
under classical or modified conditions [6-20]. However, the low yields, occurrence of several
side products, use of stoichimetric amount of reagents, expensive metal precursors, catalysts
that are harmful to environment, use of expensive and toxic transition metallic reagents,
complicated work-up methods and longer reaction times limit the use of these methods.
Therefore, for the increasing environmental and economical concerns in recent years, it is now
essential for chemists to search environmentally reactions under natural conditions as many as
possible.
Organic reactions under green solvents have attracted much interest from chemists
particularly from the viewpoints of green chemistry. Green chemistry approaches are significant
due to the reduction in by-products and waste produced, and lowering of energy costs. The
possibility of performing multi-component reactions under green solvent conditions with a
heterogeneous catalyst could enhance their efficiency from an economic as well as ecological
point of view [21-24]. In this regard, a new, simple, mild and efficient method for the one-pot
synthesis of 1,4-dihydropyrimidine derivatives is reported herein. As a part of our interest in
heterogeneous catalyzed organic reactions [25-27], in this paper, we wish to report a
__________
*Corresponding author. E-mail: mosaddegh_e@yahoo.com

462
Elaheh Mosaddegh and Asadollah Hassankhani
Ce(SO4)2.4H2O catalyzed four-component Hantzsch reaction using a mixture of water-ethanol
as a green solvent under reflux condition. In this study, Ce(SO4)2.4H2O has been employed as
mild Lewis acid catalyst with high catalytic activity and reusability in H2O-EtOH media for
Hantzsch condensation. Moreover, the catalyst can be easily recovered after reactions and
reused three times without any loss of its activity.
EXPERIMENTAL
General. Melting points were determined on a Gallenkamp melting point apparatus and are
uncorrected. NMR spectra were recorded at 500 (1H) and 125.77 (13C) MHz on Bruker DRX-
500 Avance spectrometer at 500 and 125.77 MHz, respectively. All compounds were known in
the literature, the NMR and IR spectra of the products were in agreement with earlier data.
Typical procedure for the preparation of 1,4,5,6,7,8-hexahydro-2,7,7-trimethyl-5-oxo-4-(4-
hlorophenyl)-3-quinolinecarboxyl acid ethyl ester (Table 2, entry 2). In a typical general
procedure, a mixture of benzaldehyde (1 mmol), dimedone (1 mmol), ethyl acetoacetate (1
mmol) and ammonium acetate (1.5 mmol) in H2O-EtOH (2:3, 5 mL) was refluxed thoroughly in
the presence of catalytic amount of Ce(SO4)2.4H2O (20 mg, 5 mol%) to afford the 4-substituted-
1,4-dihydropyridines. After completion of the reaction (15 min) confirmed by TLC, the mixture
was filtered to separate from the soluble catalyst. The solid product was washed with H2O and
finally was recrystallised from ethanol and characterized. The structures of the products were
1
confirmed from physical and spectroscopic data (IR and H NMR) in comparison with the
literature data. The selected spectral data of five representative 4-substitited 1,4-dihydropyridine
derivatives are given below.
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-(4-chlorophenyl)-3-quinolinecarboxyl acid ethyl
ester (Table 2, entry 2). IR (KBr): 3391, 2970, 1706, 1636, 1495, 1378, 1238, 1074, 1027, 863
1
cm-1; H NMR (500.13 MHz, CDCl3): δ = 0.92 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.19 (t, J = 7.2
Hz, 3H, CH3), 2.13-2.33 (m, 4H, 2CH2), 2.37 (s, 3H, CH3), 4.06 (q, J = 7.1 Hz, 2H, OCH2), 5.03
(s, 1H, CH), 6.25 (s, 1H, NH), 7.15-7.25 (m, 4H, ArH), 7.21 (d, J = 8.0 Hz, 2H, ArH); 13C NMR
(125.77 MHz, CDCl3): δ = 14.23, 19.22, 27.17, 29.41, 32.47, 36.16, 40.87, 50.76, 59.89,
105.44, 111.52, 122.81, 129.16, 131.74, 140.25, 147.15, 149.28, 167.27, 195.52.
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-(2,4-dichlorophenyl)-3-quinolinecarboxyl acid
ethyl ester (Table 2, entry 3). IR (KBr): 3297, 2970, 1706, 1659, 1612, 1495,1238, 1121, 1074,
1
863, 770 cm-1; H NMR (500.13 MHz, CDCl3): δ = 0.95 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.20
(t, J = 7.1 Hz, 3H, CH3), 2.01-2.27 (m, 4H, 2CH2), 2.29 (s, 3H, CH3), 4.07 (m, 2H, OCH2), 5.36
(s, 1H, CH), 6.93 (s, 1H, NH), 7.11-7.36 (m, 3H, ArH); 13C NMR (125.77 MHz, CDCl3): δ =
14.25, 19.18, 27.19, 29.31, 32.47, 35.87, 40.91, 50.78, 59.88, 104.78, 110.66, 126.59, 129.26,
129.26, 132.11, 132.93, 133.90, 142.90, 144.20, 149.40, 167.28, 195.49.
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-(4-bromophenyl)-3-quinolinecarboxyl acid ethyl
ester (Table 2, entry 4). IR (KBr): 3297, 2970, 1706, 1659, 1612, 1495,1285, 1238, 1074, 1027,
853 cm-1; 1H NMR (500.13 MHz, CDCl3): δ = 0.94 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.21 (t, J =
7.2 Hz, 3H, CH3), 2.14-2.32 (m, 4H, 2CH2), 2.37 (s, 3H, CH3), 4.08 (q, J = 7.1 Hz, 2H, OCH2),
5.03 (s, 1H, CH), 6.52 (s, 1H, NH), 7.01 (d, J = 7.9 Hz, 2H, ArH), 7.21 (d, J = 8.0 Hz, 2H,
ArH); 13C NMR (125.77 MHz, CDCl3): δ = 14.22, 19.32, 27.14, 29.41, 32.68, 36.38, 41.02,
50.76, 59.90, 105.67, 111.70, 119.81, 129.86, 130.95, 143.77, 146.15, 148.53, 167.22, 195.51.
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Short Communication
463
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-(4-methylphenyl)-3-quinolinecarboxyl acid ethyl
ester (Table 2, entry 5). IR (KBr): 3297, 2970, 1706, 1648, 1612, 1495,1378, 1215, 1074, 1051,
863 cm-1; 1H NMR (500.13 MHz, CDCl3): δ = 0.96 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.23 (t, J =
7.2 Hz, 3H, CH3), 2.15-2.32 (m, 4H, 2CH2), 2.27 (s, 3H, CH3), 2.34 (s, 3H, CH3), 4.08 (q, J =
7.1 Hz, 2H, OCH2), 5.04 (s, 1H, CH), 6.73 (s, 1H, NH), 7.01 (d, J = 7.9 Hz, 2H, ArH), 7.21 (d, J
= 8.0 Hz, 2H, ArH); 13C NMR (125.77 MHz, CDCl3): δ = 14.24, 19.24, 21.02, 27.21, 29.43,
32.67, 36.18, 40.98, 50.87, 59.76, 106.19, 112.11, 127.89, 128.61, 135.36, 143.49, 144.28,
148.67, 167.57, 195.64.
1,4,5,6,7,8-Hexahydro-2,7,7-trimethyl-5-oxo-4-(3-bromophenyl)-3-quinolinecarboxyl acid ethyl
ester (Table 2, entry 9). IR (KBr): 3297, 2970, 1706, 1636, 1612, 1495,1402, 1214, 1074, 1074,
1051, 793 cm-1; 1H NMR (500.13 MHz, CDCl3): δ = 0.96 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.23
(t, J = 7.2 Hz, 3H, CH3), 2.15-2.32 (m, 4H, 2CH2), 2.34 (s, 3H, CH3), 4.05-4.13 (m, 2H, OCH2),
5.04 (s, 1H, CH), 7.01 (s, 1H, NH), 7.07-7.43 (m, 4H, ArH), 7.21 (d, J = 8.0 Hz, 2H, ArH); 13
C
NMR (125.77 MHz, CDCl3): δ = 14.23, 19.23, 27.16, 29.41, 32.69, 36.75, 40.85, 50.80, 59.91,
105.44, 111.33, 122.08, 126.89, 129.14, 129.46, 131.12, 144.21, 149.30, 149.48, 167.25,
195.67.
RESULTS AND DISCUSSION
In the efforts to develop an efficient and environmentally benign methodology for the synthesis
of DHPs we initiated our studies by subjecting catalytic amount of Ce(SO4)2.4H2O to the
mixture of benzaldehyde, ethyl acetoacetate and ammonium acetate in H2O as solvent at room
temperature. Unfortunately, the resulted yield was poor (40% after 80 min). To effect the
reaction, various solvent systems were screened at different temperatures. It was interesting to
observe that different products could be obtained in different ratio of H2O/EtOH as solvent. It
was seen that the synthesis of DHP was efficiently catalyzed by Ce(SO4)2.4H2O in aqueous
media at elevated temperature leading to high yield of product (Scheme 1).
X
X
O
X
Ce(SO4)2.4H2O (5 mol%)
NH4OAc
O
O
O
O
O
O
+
+
OEt
EtO
OE
t
Or
OEt
O
H2O/EtOH (2:3)
Reflux
N
H
N
H
CHO
1
2
3
4a
4b
Scheme 1
The reaction condition was then optimized by conducting the reaction in different
temperatures and employing different catalyst loadings. The results are summarized in Table 1.
It is evident that the best result was obtained by the application of 5 mol% of Ce(SO4)2.4H2O in
H2O/EtOH (2:3) as solvent at reflux condition (Table 1, entry 1). All compounds were known
and their physical and spectroscopic data were compared with those of authentic samples and
found to be identical [17-19].
In order to examine the scope and generality of this procedure, the methodology was
extended to different aromatic aldehydes. The results are presented in Table 2. Both electron
rich and electron deficient aromatic aldehydes reacted well to afford 4a in good to high yields. It
is an interesting that para-substituted benzaldehydes (entries 11-13, Table 2), whether the
substituent is EDG or EWG, afforded the unexpected dihydropyrimidinones 4b. It could be
because of the steric effect of 4-aryl ring system. So Ce(SO4)2.4H2O can be acted as selective
Bull. Chem. Soc. Ethiop. 2012, 26(3)

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Elaheh Mosaddegh and Asadollah Hassankhani
catalyst to obtain 4-Substituted dihydropyridines 4a or 4b as products in Hantzsch reaction
conditions.
Table 1. Optimizing the reaction conditions.
Entry
Solvent
Condition
Reflux
Reflux
R.T.
Time (min)
Yield (%)
Products
4a
Catalyst (g)
0.02
1
2
3
4
5
6
7
8
H2O/EtOH (2:3)
H2O/EtOH (1:2)
H2O/EtOH (3:1)
H2O/EtOH (2:1)
H2O/EtOH (1:1)
EtOH
15
25
15
35
30
48
60
80
87
86
60
45
86
94
91
40
4a
4b
4b
4a
4a
4a
4a
0.02
0.04
0.04
0.02
0.02
0.02
0.04
R.T.
Reflux
Reflux
Reflux
R.T.
H2O
H2O
Table 2. Ce(SO4)2.4H2O catalyzed the synthesis of polyhydroquinoline derivatives through Hantzsch
reaction.
Entry
1
2
3
4
6
7
8
9
10
11
12
13
Ar
C6H5
Time (min) Yields (%)a
TONb
18.4
17.4
18
16
16
16.4
16.2
16.4
19.2
19
M.p. (oC)
203-204
243-245
241-243
254-256
258-260
237-238
198-200
234-236
231-233
162-164
130-132
202-204
15
15
15
15
15
20
15
8
92
87
90
80
80
82
81
82
86
95
85
80
4-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
4-CH3OC6H4
4-OHC6H4
1-naphthyl
3-BrC6H5
3-CH3OC6H5
3-NO2C6H4
4-NO2C6H4
4-(CH3)2NC6H4
11
20
20
20
17
16
aYields refer to isolated pure products. b Turn over number (TON) is the ratio of the number of moles of the
product to the number of moles of the catalyst.
The recovery and reusability of Ce(SO4)2.4H2O was investigated due to the most important
benefits for commercial applications. In these experiments, the reaction mixture was filtered and
washed with H2O. The soluble catalyst was easily reused after distillation of solvent, washing
with CHCl3 and drying at 60 oC.
The recycled catalyst was examined in next run in the reaction between 4-
chlorobenzaldehyde, ethyl acetoacetate, dimedone and ammonium acetate. Pleasingly,
Ce(SO4)2.4H2O was successfully recycled three times without any loss of its activity.
CONCLUSIONS
In conclusion, the present method is an operationally simple and environmentally friendly
procedure for the synthesis of compound 4a using catalytic amount of Ce(SO4)2.4H2O. Also,
Ce(SO4)2.4H2O can be used as selective for some aromatic aldehydes in the reaction conditions.
In addition low cost, availability, recyclability, low toxicity, moderate Lewis acidity and
moisture compatibility of the catalyst, good to excellent yields of products and short reaction
time make this methodology a valid contribution to the existing processes in the field of 4-
substituted-1,4-dihydropyridines derivatives synthesis.
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465
ACKNOWLEDGEMENTS
We thank the International Center for Science, High Technology and Environmental Sciences,
for partial financial support of this investigation.
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Bull. Chem. Soc. Ethiop. 2012, 26(3)