Silica (NPs) supported Fe (III) as a reusable heterogeneous catalyst for the one-pot synthesis of 1, 4-dihydropyridines under mild conditions

Article abstract of DOI:10.1007/s12039-012-0280-y

A cheap and recyclable silica (NPs) supported Fe (III) was prepared as heterogeneous catalyst for the synthesis of various substituted 1,4-dihydropyridines via condensation of aldehydes with ethyl acetoacetate and ammonium acetate in ethanol. The products

Full text of DOI:10.1007/s12039-012-0280-y

c
J. Chem. Sci. Vol. 124, No. 4, July 2012, pp. 933–939. ꢀ Indian Academy of Sciences.
Silica (NPs) supported Fe (III) as a reusable heterogeneous catalyst
for the one-pot synthesis of 1, 4-dihydropyridines under mild conditions
JAVAD SAFAEI-GHOMI∗, ABOLFAZL ZIARATI and SAFURA ZAHEDI
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, 51167, I R Iran
e-mail: safaei@kashanu.ac.ir
MS received 26 December 2011; revised 4 March 2012; accepted 10 April 2012
Abstract. A cheap and recyclable silica (NPs) supported Fe (III) was prepared as heterogeneous catalyst for
the synthesis of various substituted 1,4-dihydropyridines via condensation of aldehydes with ethyl acetoacetate
and ammonium acetate in ethanol. The products were separated from the catalyst simply by filtration and the
catalyst could be recycled and reused for several times without noticeable decrease in the catalytic activity.
Keywords. Heterogeneous catalyst; 1,4-dihydropyridine; multi-component; nano silica; Hantzsch reaction.
1. Introduction
times, low yields, toxicity and recovery and reusabil-
ity of the catalyst. Therefore, introducing clean pro-
cesses and utilizing eco-friendly and green catalysts
which can be simply recycled at the end of reactions
have been under permanent attention. The best known
procedure for the preparation of symmetrical 1,4-DHPs
is the classical Hantzch synthesis: a multicomponent
condensation involving two molecules of β-ketoesters,
one molecule of aldehyde and one molecule of
ammonia.27 The demand for environmentally benign
procedure with heterogeneous and reusable catalyst
promoted us to develop a safe alternate method for
the synthesis of 1,4-dihydropyridines in the presence of
silica (NPs) supported Fe (III) (scheme 1).
Current literature reveals that 1,4-dihydropyridines
exhibit interesting pharmacological and biological
properties. Thus, they have been used as calcium
channel modulators for the treatment of cardiovas-
cular disorders.1 The 1,4-DHPs may lead to other
beneficial effects such as regression of left ventric-
ular pressure and vascular hypertrophy, renal protec-
tion and antiatherogenic activity.2–4 Furthermore, the
DHP skeleton is common in many bronchodilator,
antiatherosclerotic, antitumour, antidiabetic, geropro-
tective and hepatoprotective agents.5,6 They also func-
tion as neuroprotectants, as antiplatelet treatment of
aggregators and are important in Alzheimer’s disease as
antiischaemic agents.7 Among 1,4-DHPs, there are also
examples of drug-resistance modifiers,8 antioxidants9
and a drug for the treatment of urinary urge inconti-
nence. In order to model and understand these biologi-
cal properties and to develop new chemotherapeutic
agents based upon the 1,4-DHP motif, considerable
effort has been devoted to establish efficient and rapid
methods for their synthesis (figure 1).10
Recently, a number of modified methods have been
developed.11,12 Some procedures comprise the use of
microwaves,13 ionic liquids,14 high temperatures at
reflux,15 TMSCl–NaI,16 InCl3,17 I2,18 NaHSO4/SiO2,19
HClO4/SiO2,20 CAN,21 Na- and Cs-Norit carbons,22
tetrabutylammonium hydrogen sulfate,23 fermenting
Baker’s yeast,24 organocatalysts25 and metal triflates.26
However, some of these methods suffer from the draw-
back of green chemistry such as prolonged reaction
2. Experimental
The products were isolated and characterized by phys-
1
ical and spectral data. H NMR and 13C NMR spectra
were recorded on Bruker Avance-400 MHz spectrome-
ters in the presence of tetramethylsilane as internal stan-
dard. The IR spectra were recorded on FT-IR Magna
550 apparatus using with KBr plates. Melting points
were determined on Electro thermal 9200, and are not
corrected. Silica (NPs) supported Fe (III) was obtained
according to the method reported in the literature.
Microscopic morphology of products was visualized by
SEM (LEO 1455VP).
2.1 Preparation of silica (NPs) supported Fe (III)
In a 100 ml flask, nano silica gel (25 g) and FeCl3.6H2O
(2 g) (8% of the weight of SiO2 NPs) were vigorously
∗For correspondence
933

934
Javad Safaei-Ghomi, Abolfazl Ziarati and Safura Zahedi
NO2
O
CH3
N
H3C
O
CH3
H3CO2C
H3C
N
CH3
H
.HCl
Lercanidipine
O2N
O
Cl
N
Cl
O
O
CO2CH3
O
H3C
O
O
CH3
.HCl
H3C
N
CH3
H
H3C
N
CH3
H
Felodipine
Barnidipine Hydrochoride
Figure 1. The pharmaceutical compounds with DHP skeleton.
O
Ar
O
O
O
FeCl3/SiO2 NPs
AcONH4
3
+
CH3
+
ArCHO
2
H3C
O
O
CH3
H3C
O
EtOH, reflux
H3C
N
H
CH3
1
4a-n
Scheme 1. Synthesis of 1,4-dihydropyridines on silica (NPs) supported Fe (III) under reflux conditions.
stirred under solvent-free conditions at room tempera- reflux in ethanol (3 mL). The reaction was monitored
ture for 24 h to achieve a homogeneous adsorption. The by TLC. After cooling to room temperature, the reac-
obtained powder was yellow and heated for 1 h at 100◦C tion mixture was filtered and the heterogeneous catalyst
to activate the catalyst.
was recovered. The filtrate was poured into cold water
and extracted with ethyl acetate. The organic layer was
washed with brine and water and dried over Na2SO4.
After evaporation of the solvent, the crude yellow prod-
ucts were purified by crystallization from ethanol to
afford 1,4-dihydropyridines.
2.2 Preparation of 1,4-dihydropyridine derivatives
A mixture of aldehyde 1 (1 mmol), ethyl acetoacetate
2 (2 mmol), ammonium acetate 3 (2 mmol) and sil-
ica (NPs) supported Fe (III) (0.6 mol%) was heated at
2.3 Reusability of catalyst
Table 1. Reaction of p-nitrobenzaldehyde, ethyl acetoac-
etate and ammonium acetate in diverse catalytic conditions.
The recovered catalyst from the experiment was washed
by acetone (3 × 5 mL). Then, it was dried in an
oven at 100◦C and used in the synthesis of 1,4-
dihydropyridines. Then the catalyst was recycled for
five times.
Entry
Catalyst (mol%)
Time (min)
Yield,a%
1
2
3
4
5
6
8
none
FeCl3 (10)
SiO2 NPs (10)
FeCl3/SiO2 (10)
FeCl3/SiO2 NPs (0.8)
FeCl3/SiO2 NPs (0.6)
FeCl3/SiO2 NPs (0.5)
180
150
130
100
20
20
20
0
41
27
75
93
94
90
2.4 Selected spectral data
2.4a Diethyl 4-(4-bromophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4f): 1H NMR (400 MHz,
CDCl3): δ = 1.23 (t, 6H, 2CH3CH2), 2.31 (s, 6H,
aIsolated yield

Synthesis of 1, 4-dihydropyridines catalysed by reusable Silica (NPs) supported Fe (III)
935
19.4, 39.3, 59.8, 103.4, 119.8, 129.8, 130.8, 144.3,
146.9, 167.5. FT-IR (KBr): 3355, 1696, 1651, 1487,
1213, 1092, 783 cm−1.
2.4b Diethyl 4-(4-Nitrophenyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (4b): 1H NMR (400 MHz,
CDCl3): δ = 1.23 (t, 6H, 2CH3CH2), 2.36 (s, 6H,
2CH3), 4.09 (q, 4H, 2CH3CH2), 5.09 (s, 1H, CH), 5.72
(s, 1H, NH), 7.26 (d, 2H, 2CHarom.), 8.09 (d, 2H,
2CHarom.). 13C NMR (100 MHz, CDCl3): δ = 14.2,
19.4, 39.3, 59.8, 103.4, 119.8, 130.0, 130.8, 144.3,
146.9, 167.5. FT-IR (KBr): 3343, 1706, 1646, 1486,
1212, 1115, 786 cm−1.
Figure 2. SEM image of the FeCl3/SiO2 NPs.
2.4c Diethyl 4-(2-thienyl)-2,6-dimethyl-1,4-dihydro-pyri-
dine-3,5-dicarboxylate (4m): 1H NMR (400 MHz,
CDCl3): δ = 1.24 (t, 6H, 2CH3CH2), 2.31 (s, 6H,
2CH3), 4.09 (q, 4H, 2CH3CH2), 4.99 (s, 1H, CH),
5.88 (s, 1H, NH), 7.12 (d, 1H, 1CHarom.), 7.20 (d,
1H, 1CHarom.), 7.29 (d, 1H, 1CHarom.). 13C NMR
(100 MHz, CDCl3): δ = 14.2, 19.3, 39.6, 59.7, 103.8,
126.1, 127.8, 144.3, 147.8, 167.8. FT-IR (KBr): 3358,
1686, 1641, 1487, 1215, 1082, 773 cm−1.
Cl
Cl
Cl
Bronsted site
Lewis site
Fe
OH
O
O
O
O
O
Si
Si
Si
Si
O
n
Scheme 2. Bronsted acidity arising from inductive effect
of Lewis acid center coordinated to nanosilica support.
3. Results and discussions
We report here a simple and convenient method for
the synthesis of 1,4-dihydropyridines by condensation
of aldehydes with ethyl acetoacetate and ammonium
2CH3), 4.09 (q, 4H, 2CH3CH2), 4.94 (s, 1H, CH), 5.82
(s, 1H, NH), 7.16 (d, 2H, 2CHarom.), 7.33 (d, 2H,
2CHarom.). 13C NMR (100 MHz, CDCl3): δ = 14.2,
O
FeCl3/SiO2 NPs
O
H
O
OH
H3C
O
O
OEt
FeCl3/SiO2 NPs
H3C
OEt
H
Ar
H
Ar
Ar
(I)
FeCl3/SiO2 NPs
O
O
O
NH3
OEt
OEt
H3C
H2N
CH3
(II)
Ar
O
O
O
O
Ar
OEt
EtO
cyclisation
dehydration
I
+
II
EtO
H3C
OEt
CH3
CH3
H3C
N
HN
O
H
(III)
Scheme 3. The proposed mechanism of the synthesis of 1,4-dihydropyridines in the
presence of silica (NPs) supported Fe (III).

936
Javad Safaei-Ghomi, Abolfazl Ziarati and Safura Zahedi
our knowledge there are no reports on the applicability
of silica (NPs) supported Fe (III) for the synthesis of
1,4-dihydropyridines in the literature.
Table 2. Preparation of 1,4-dihydropyridines in the pres-
ence of silica (NPs) supported Fe (III) in different solvents.
Entry
Solvent
Time (min)
Yield,a%
In the preliminary experiments, the catalytic
behaviours of five types of catalyst were compared in
the reaction of p-nitrobenzaldehyde, ethyl acetoacetate
and ammonium acetate at reflux conditions (table 1).
In the absence of catalyst, the reaction did not
progress at all. Notably, silica (NPs) supported Fe (III)
shows an activity higher than those reported in hetero-
geneous, we believe that nano silica surface chemistry
plays an important role in this reaction.
1
2
3
4
5
6
CH3CN
Toluene
H2O
EtOH
EtOH/H2O
Solvent-free
70
90
90
20
60
75
37
31
49
94
73
29
aIsolated yield
To obtain a visual image of the supported catalyst,
scanning electron microscopy (SEM) was carried out.
By SEM image some information about the morphol-
ogy of the catalyst particles was obtained as presented
in figure 2. The SEM image shows particles with diame-
ters in the range of nanometers to micrometers. As indi-
cated in figure 2, the gray particles is nano silica which
are supported by FeCl3 white particles.
Silica (NPs) supported Fe (III) can act as Bronsted
and Lewis acid catalysts,28 as illustrated in scheme 2.
The effect of catalyst and its abilities to act as a
Brønsted or Lewis acid (empty π orbital of Fe in sil-
ica (NPs) supported Fe (III)) is suggested in scheme 3.
In this mechanism, we propose that an acid–base inter-
action between silica (NPs) supported Fe (III) and loan
pair of oxygen polarizes C=O bond of aldehyde. Then
knovenagel product (I) and ester enamine (II) were pre-
pared by this interaction. Condensation of these two
fragments gives intermediate (III) which subsequently
cyclizes to the 1,4-dihydropyridine.29
Table 3. The catalyst reusability for the synthesis of 1,4-
dihydropyridines.
Entry
Cycle
Yield,a%
1
2
3
4
5
6
Fresh
94
94
94
93
93
93
1
2
3
4
5
aIsolated yield
acetate in ethanol at reflux conditions in the presence
of silica (NPs) supported Fe (III). Silica (NPs) sup-
ported Fe (III) is an inexpensive heterogeneous reagent,
which can be prepared easily by treating ferric chloride
with silica nanoparticle. Ease and safety in handling,
rate enhancement, high yields and easy work up pro-
cedures for reuse are the properties which made us to
use this interesting reagent as a catalyst. To the best of
Table 4. Silica (NPs) supported Fe (III) catalysed synthesis of 1,4-dihydropyridines 4a–n.
Mp (◦C)
Measured
Entry
Ar
Time (min)
Product
Yield,a%
Reported
O
C
O
1
30
91
157–159
128–130
158–16030
H3
C
O
O
CH3
H3
N
H
CH3
4a
NO2
NO2
O
O
2
20
94
129–13130
H3C
O
O
CH3
H3
C
N
H
CH3
4b

Synthesis of 1, 4-dihydropyridines catalysed by reusable Silica (NPs) supported Fe (III)
Table 4. (continued)
937
Mp (◦C)
Entry
Ar
Time (min)
Product
Yield,a%
Measured
Reported
NO2
NO2
O
C
O
3
25
89
161–163
162–16430
H3
C
O
O
CH3
H3
N
H
CH3
4c
Cl
Cl
O
O
4
5
6
7
8
20
28
32
40
40
93
93
87
87
85
145–147
153–155
161–162
133–135
160–162
147–14830
H3C
H3C
H3C
H3C
H3C
O
O
CH3
H3
C
N
H
CH3
4d
Cl
Cl
Cl
O
O
C
–
O
O
O
O
O
O
O
O
CH3
CH3
CH3
CH3
Cl
H3
H3
H3
H3
N
H
CH3
4e
Br
Br
O
C
O
162–16429
135–13731
161–16330
N
H
CH3
4f
CH3
CH3
O
C
O
N
H
CH3
4g
OCH3
OCH3
O
C
O
N
H
CH3
4h

938
Javad Safaei-Ghomi, Abolfazl Ziarati and Safura Zahedi
Table 4. (continued)
Mp (◦C)
Measured
Entry
Ar
Time (min)
Product
Yield,a%
Reported
F
F
O
C
O
9
35
89
156–158
147–149
150–15232
H3
C
O
O
CH3
H3
N
H
CH3
4i
F
O
C
O
10
25
86
–
H3
H3
H3
C
C
C
O
O
O
O
O
O
CH3
CH3
CH3
F
H3
H3
H3
N
H
CH3
4k
O
O
C
O
O
11
12
27
33
91
91
160–162
170–172
160–16131
N
H
CH3
4l
S
O
C
O
S
171–17331
N
H
CH3
4m
N
O
C
O
N
13
26
90
166–168
–
H3C
O
O
CH3
H3
N
H
CH3
4n
aIsolated yield
Expectedly, the catalytic system should be influ- toluene. Also, it was observed that the good results were
enced by various reaction parameters, such as amount not obtained in solvent-free conditions. The results are
of the employed catalyst and solvent system. To presented in (table 2).
establish the optimal reaction conditions, a set of
First, we optimized the amount of silica (NPs) sup-
experiments varying the amount of silica (NPs) sup- ported Fe (III) as catalyst in the model reaction. The
ported Fe (III), and effect of solvent were taken into optimum amount of silica (NPs) supported Fe (III) was
account.
chosen to be 0.6 mol%. The same reaction was carried
We have screened effect of different solvents with out five times consequently to check the reusability of
varying polarity and protic nature. It was observed that catalyst and it was found that, all the five times, it gave
ethanol proved to be the best choice for this reac- almost the same yield of product without significant
tion over any organic solvents such as acetonitrile and decrease in activity (table 3).

Synthesis of 1, 4-dihydropyridines catalysed by reusable Silica (NPs) supported Fe (III)
939
The study was then extended to preparation of var-
ious 1,4-dihydropyridines using silica (NPs) supported
Fe (III) in high yields. Reactions were carried out in
ethanol at reflux conditions. The results are listed in
table 4.
8. Sridhar R, and Perumal P T 2005 Tetrahedron 61 2465
9. Heravi M M, Behbahani F K, Oskooie H A, and Shoar
R H 2005 Tetrahedron Lett. 46 2775
10. Buhler F R, and Kiowski W J 1987 Hypertens. 5 S3
11. Alajarin R, Vaquero J J, Garcia Navio J L, and Alvarez-
Builla J 1992 Synlett. 4 297
12. Sausins A, and Duburs G 1988 Heterocycles 27 269
13. Agarwal A, and Chauhan P M S 2005 Tetrahedron Lett.
46 1345
4. Conclusion
14. Ji S J, Jiang Z Q, Lu J, and Loh T P 2004 Synlett. 5 831
15. Dondoni A, Massi A, Minghini E, Bertoasi V 2004
Tetrahedron 60 2311
In conclusion, it was demonstrated that a novel read-
ily available, economic silica (NPs) supported Fe (III)
has been prepared. This catalyst could behave as recy- 16. Sabitha G, Reddy G S K K, Reddy C S, and Yadav J S
2003 Tetrahedron Lett. 44 4129
clable and heterogeneous solid acid for the synthesis of
various substituted 1,4-dihydropyridines. The conden-
sation of aldehydes with ethyl acetoacetate and ammo-
nium acetate in ethanol afforded 1,4-dihydropyridines,
offering the practical convenience in the product sep-
aration from the catalytic system. The merit of this
methodology is that it is simple, fast, mild and efficient.
17. Babu G, and Perumal P T 2000 Aldrichim. Acta 16 33
18. Ko S, Sastry M N V, Lin C, and Yao C F 2005 Tetrahe-
dron Lett. 46 5771
19. Adharvana Chari M, and Syamasundar K 2005 Catal.
Commun. 6 624
20. Maheswara M, Siddaiah V, Rao Y K, Tzeng Y M, and
Sridhar C 2006 J. Mol. Catal. 260 179
21. Ko S, and Yao C F 2006 Tetrahedron 62 7293
22. Perozo-Rondon E, Calvino-Casilda V, Martin-Aranda R
M, Casal B, Duran- Valle C J, and Rojas-Cervantes M L
2006 Appl. Surf. Sci. 252 6080
Acknowledgements
The authors are thankful to University of Kashan for
supporting this work by Grant NO: 65384. Also, au-
thors thank Prof. Stephen G Pyne and Dr Abdolhamid
Bamoniri for their help.
23. Tewari N, Dwivedi N, and Tripathi R P 2004 Tetrahe-
dron Lett. 45 9011
24. Lee J H 2005 Tetrahedron Lett. 46 7329
25. Kumar A, and Maurya R A 2007 Tetrahedron 63 1946
26. Wang L M, Sheng J, Zhang L, Han J W, Fan Z, Tian H,
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27. Hantzsch A 1882 Justus Liebigs Ann. Chem. 1 215
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1313
29. Debache A, Ghalem W, Boulcina R, Belfaitah A,
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