A simple and efficient one-pot synthesis of Hantzsch 1,4-dihydropyridines using silica sulphuric acid as a heterogeneous and reusable catalyst under solvent-free conditions

Article abstract of DOI:10.2478/s11696-011-0087-1

A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine derivatives under solvent-free conditions using silica sulphuric acid (SSA) as a heterogeneous and recyclable catalyst is reported.

Full text of DOI:10.2478/s11696-011-0087-1

Chemical Papers 65 (6) 898–902 (2011)
DOI: 10.2478/s11696-011-0087-1
ORIGINAL PAPER
A simple and efficient one-pot synthesis of Hantzsch
,4-dihydropyridines using silica sulphuric acid as a heterogeneous
and reusable catalyst under solvent-free conditions
1
a
b
b
Eskandar Kolvari*, Mohammad Ali Zolfigol*, Nadiya Koukabi,
c
Behzad Shirmardi-Shaghasemi
aDepartment of Chemistry, Faculty of Sciences, Semnan University, P.O. Box 35195-363 Semnan, Iran
bFaculty of Chemistry, Bu-Ali Sina University, Hamedan P.O. Box 6517838683, Iran
cDepartment of Sciences, Payam e Noor University, Hamedan P.O. Box 6517858772, Iran
Received 2 March 2011; Revised 9 July 2011; Accepted 17 July 2011
A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine derivatives under
solvent-free conditions using silica sulphuric acid (SSA) as a heterogeneous and recyclable catalyst
is reported.
ꢀ
c 2011 Institute of Chemistry, Slovak Academy of Sciences
Keywords: 1,4-dihydropyridines, Hantzsch 1,4-dihydropyridine synthesis, heterogeneous catalyst,
silica sulphuric acid, multi-component organic reaction
Introduction
2003), ionic liquid (Ji et al., 2004), HY zeolite (Das et
al., 2006), montmorillonite K-10 (Song et al., 2005),
Fe(III) trifluoroacetate (Adibi et al., 2007), hetero-
polyacid (Heravi et al., 2007), Sc(OTf)3 (Donelson
et al., 2006), PhB(OH)2 (Debache et al., 2008), sil-
ica gel–NaHSO4 (Adharvana Chari & Syamasundar,
2005), Ph3P (Debache et al., 2009), and sulphonic acid
on silica gel (Gupta et al., 2007).
1
,4-Dihydropyridines, among the drugs most wide-
ly used in the treatment of cardiovascular disease (Bei-
gly et al., 2004; Faizi et al., 2003), have a broad range
of pharmacological properties such as antitumour, an-
timutagenic, geroprotective, and antidiabetic effects
(
Stout & Meyers, 1982).
1
,4-Dihydropyridines have also proved to be very
Even though this important C—C bond-forming
reaction has recently undergone much progress, de-
mand remains for the development of efficient proce-
dures involving inexpensive, recyclable catalytic sys-
tems under solvent-free conditions.
important synthetic intermediates, finding applica-
tions in the preparation of a large number of nitrogen
alkaloids (Comins & O’Connor, 1988). The remark-
able drug activity of these compounds has not only at-
tracted many chemists to synthesise this heterocyclic
nucleus but has also become an active research area of
continuing interest (Kumar & Chandra, 2001; Lavilla,
Experimental
2
002).
Since Hantzsch (Hantzsch, 1881) started his work
1,3-Dicarbonyl compounds, aldehydes, urea, and
ammonium acetate were obtained from Merck (Darm-
stadt, Germany), and used as received. Silica sulphuric
acid (SSA) was prepared following the procedure pre-
viously reported (Zolfigol, 2001). Progress of reactions
was monitored by TLC (Silica gel 60 F254). The prod-
more than a century ago, a number of new and more
efficient methods have been developed, including the
use of microwave (Li et al., 2008), ultrasound (Ku-
mar & Maurya, 2008), TMS iodide (Sabitha et al.,
*Corresponding author, e-mail: kolvari@semnan.ac.ir, zolfi@basu.ac.ir

E. Kolvari et al./Chemical Papers 65 (6) 898–902 (2011)
899
O
O
O
SSA
CHO
OEt
NH
OAc
EtO
OEt
4
8
0 °C
Solvent-free
O
N
H
I
II
III
Fig. 1. Silica sulphuric acid-catalysed synthesis of the Hantzsch 1,4-dihydropyridines.
ucts were characterised by H and 13C NMR spectra.
SSA (0.005 mmol) was added to a mixture of
aldehyde (1 mmol), β-keto compound (2 mmol), and
NH4OAc (1.5 mmol) in a 25 mL round-bottom flask.
1
Table 1. Influence of the amount of SSA on the Hantzsch syn-
thesis of 1,4-dihydropyridines (benzaldehyde : ethyl
acetoacetate : NH4OAc, νi = 1 : 2 : 1.5, solvent-free,
◦
8
0 C)
◦
The reaction mixture was stirred at 90 C in an oil
SSA
Time
min
Isolated yield
%
bath for an appropriate time. After completion of the
reaction (monitored by TLC), the mixture was trit-
urated with CH2Cl2 (10 mL), and SSA was removed
by filtration. The resulting solution was condensed un-
der reduced pressure. Finally, the raw product was re-
crystallised from EtOH–H2O solution (ϕr = 3 : 1). The
catalyst was washed with H2O (150 mL), followed by
Entry
mmol
1
2
3
4
5
0
90
80
45
25
85
93
95
96
98
98
0.02
0.01
0.005
0.0025
◦
CH2Cl2 (50 mL), and dried at 110 C for 2 h. It was
available for reuse in further reactions.
Results and discussion
conditions. A significant improvement was observed in
the reaction time and product yield (Table 1, entry 2).
Having obtained such a positive result, in our further
investigation we focused on optimisation of the reac-
tion conditions. In connection with this, we investi-
gated the reaction product using differing amounts of
SSA. A decrease in the quantity of SSA from 2 mol %
to 0.5 mol % not only shortens the reaction time from
80 min to 25 min, but also enhances the product yield
from 95 % to 98 % (Table 1). Using 0.25 mol % of
SSA resulted in an increase in reaction yield to 98 %,
but the reaction time increased unexpectedly to 85
min (Table 1, entry 5). Therefore, SSA (0.5 mol %) is
sufficient to catalyse the reaction effectively.
The mechanism of Hantzsch dihydropyridine syn-
thesis has been thoroughly investigated by NMR (Ka-
tritzky et al., 1986). The known mechanism for this
reaction consists of three reaction paths (Fig. 2):
the acid-catalysed Knoevenagel condensation between
aliphatic or aromatic aldehyde (IV ) with a 1,3-
dicarbonyl compound (V ) yields an alkylidene or
arylidene-1,3-dicarbonyl (VI ) compound; the acid-
catalysed condensation between ammonia (VIII ) and
a 1,3-dicarbonyl compound (V ) leads to the α-amino
α,β-unsaturated carbonyl compound (VIII ); the re-
action between both condensation products (VI and
VIII ) leads to the formation of a 1,4-dihydropyridine
(IX). Our results (Table 1) are wholly consistent with
this mechanism; however, it is recognised that it is of-
ten necessary to adjust the reaction medium to achieve
the right acidity when the reaction involves a nucle-
ophilic attack by basic nitrogen compound on car-
bonyl (Fig. 2). The protonation of carbonyl oxygen
In recent years, heterogeneous solid acid catalysts
have gained in importance, for economic and environ-
mental considerations. Reactions with such reagents
and catalysts often have the advantages of ease of
set-up and operation, mild reaction conditions, in-
creased yield, and greater selectivity. In general, het-
erogeneous solid acid catalysts are based on clay (Ba-
dathala, 2004) and silica (Karimi & Khalkhali, 2007;
Niknam et al., 2009; Zolfigol, 2001). In terms of conve-
nience, silica-based catalysts are inexpensive, easy to
prepare, and insoluble in most organic solvents, which
means that they have the advantage of recyclability
from various reactions. Thus, the possibility of per-
forming multi-component reactions under solvent-free
conditions with heterogeneous catalysts such as sil-
ica sulphuric acid could enhance their efficiency from
an economic as well as a “green chemistry” perspec-
tive. Moreover, to date there has been no report us-
ing SSA as a catalyst in the Hantzsch condensation.
This method not only maintains the simplicity and
reduced reaction time, but also consistently provides
good to excellent yields of the respective products.
In an initial endeavour, 1 equivalent of benzaldehyde
(
I ), 2 equivalents of ethyl acetoacetate (II ), and 1.5
◦
equivalents of ammonium acetate were stirred at 80 C
under solvent-free conditions to give the correspond-
ing 1,4-dihydropyridine (III ) (Fig. 1; Table 1, entry 1)
(
Zolfigol & Safaiee, 2004).
To improve product yields and to optimise reac-
tion conditions, SSA was used in a catalytic amount (2
mol %), and the reaction was performed under similar

9
00
E. Kolvari et al./Chemical Papers 65 (6) 898–902 (2011)
O
O
O
O
H+
R2
1
R CHO
R2
IV
V
R1
VI
H+
NH4+
H+
NH3
O
O
NH2
O
NH3
R2
R2
VII
V
VIII
O
R1
O
O
O
NH2
O
R2
R2
R2
H+
R2
R1
N
H
VI
VIII
IX
Fig. 2. Reaction pathway of the Hantzsch 1,4-dihydropyridines synthesis.
99
97
95
93
91
−
H+
N
O
O
H
H
N
H
H+
O
O
Suitable
H
H
H
H+
Unsuitable
0
5
10
Amount of catalyst/ µmol
15
20
N
N
H
Fig. 4. Effect of the amount of SSA on the Hantzsch 1,4-
Fig. 3. Effect of acid on addition of nucleophilic nitrogen to
dihydropyridines synthesis (data from Table 1).
carbonyl compounds.
increases reactivity towards a nucleophilic attack, and
the reaction will be enhanced by high acidity, but
ammonia may also undergo protonation to form am-
monium ion, which lacks unshared electrons and is
no longer nucleophilic. So far as nitrogen compounds
are concerned, addition is favoured by low acidity
Table 2. Effect of temperature on the SSA-catalysed synthe-
sis of 1,4-dihydropyridines (benzaldehyde : ethyl ace-
toacetate : NH4OAc, νi = 1 : 2 : 1.5, solvent-free, 0.5
mol % SSA)
Temp.
Time
min
Isolated yield
%
Entry
◦
(Fig. 3) (Morrison & Boyd, 1992). Therefore, the reac-
C
tion medium must be sufficiently acidic for an appre-
ciable fraction of the carbonyl compound to be proto-
nated, but not so acidic for the concentration of free
nitrogen compound to become too low (Fig. 4).
Using 0.5 mol % of SSA at a slightly elevated tem-
1
2
3
4
70
80
90
85
25
15
15
95
98
98
98
100
◦
perature (90 C) also gave better results in terms of
reaction time (15 min) (Table 2, entry 3). In view of
these results, we selected the optimised reaction con-
ditions to determine the scope of this SSA-catalysed
reaction. A wide range of aromatic, aliphatic and het-
eroaromatic aldehydes (IV ) was subjected to react
with β-keto compounds (V ) in the presence of am-
different substitutions in the aryl group of aldehydes
did not show much effect on the formation of the final
product and the expected product (IX) is achieved in
good to high yields.
When a heterogeneous catalyst is used, the recy-
clability of the catalyst is an important issue. To test
this, a series of three consecutive runs of the reaction
of benzaldehyde, ethyl acetoacetate, and ammonium
acetate with the SSA catalyst were carried out. The
◦
monium acetate and 0.5 mol % of SSA, at 90 C under
solvent-free condition to generate the corresponding
1
,4-dihydropyridines (Fig. 5), the results of which are
summarised in Table 3. As can be seen from this table,

E. Kolvari et al./Chemical Papers 65 (6) 898–902 (2011)
901
Table 3. SSA-catalysed Hantzsch synthesis of 1,4-dihydropyri-
Table 4. Reuse of SSA in the Hantzsch synthesis of 1,4-
1
dines IV (all products are characterised by IR,
H
dihydropyridine (benzaldehyde : ethyl acetoacetate
NMR, 13C NMR spectroscopic data, and melting
points)
: NH4OAc, νi = 1 : 2 : 1.5, solvent-free, 90 C, 0.5
◦
mol % SSA)
Time Isolated yield
Run
1
2
3
Entry
R1
R2
Isolated yield/%
98
97
96
min
%
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
Ph— —OEt
15
50
25
30
50
2
15
15
25
25
10
10
20
10
15
25
15
10
60
98
94
90
87
92
93
89
91
89
93
88
95
92
91
92
95
81
85
80
p-MeC6H4— —OEt
p-ClC6H4— —OEt
p-OH-C6H4— —OEt
p-NO2C6H4— —OEt
p-CNC6H4— —OEt
o-OMeC6H4— —OEt
o-ClC6H4— —OEt
4-OH-3-OMe C6H3— —OEt
n-Pr— —OEt
results shown in Table 4. demonstrate that there is no
significant change in the activity of the catalyst.
Conclusions
1
1
1
1
1
1
1
1
1
1
In conclusion, we successfully developed a sim-
ple and efficient method for preparation of a vari-
ety of 4-substituted-1,4-dihydropyridines by the one-
pot three-component reactions of different aromatic,
aliphatic and heteroaromatic aldehydes, β-keto com-
pounds and ammonium acetate in the presence of a
catalytic amount of silica sulphuric acid under solvent-
free conditions. A better conclusion may be drawn by
comparing the performance of the present work with
some other recent reports available in the literature,
as illustrated in Table 5.
2-Furyl— —OEt
p-FC6H4— —OMe
p-BrC6H4— —OMe
Ph— —OMe
o-OMeC6H4— —OMe
p-NO2C6H4— —OMe
Ph— —CH3
o-OMeC6H4— —CH3
p-NO2C6H4— —CH3
The catalytic activity of SSA is remarkable, and
the use of the environmentally benign, recyclable SSA
Table 5. Hantzsch synthesis of diethyl 4-phenyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate using ammonium acetate as
nitrogen source: SSA compared with other methods
Time
h:min
Yield
Entry
Conditions
%
1
2
3
4
5
6
7
8
SSA
H2SO4
SiO2
0:15
0:35
0:55
4:00
6:00
5:00
5:30
1:30
98a
a
80
75
a
PhB(OH)2 (Debache et al., 2008)
Silica gel/NaHSO4 (Adharvana Chari & Syamasundar, 2005)
Ph3P (Debache et al., 2009)
Sulphonic acid on silica gel (Gupta et al., 2007)
Neat (Zolfigol & Safaiee, 2004)
90
85
72
90
93
◦
a) Benzaldehyde : ethyl acetoacetate : NH4OAc, νi = 1 : 2 : 1.5, solvent-free, catalyst 0.5 mol %, 90 C.
O
O
R1
O
R2
R2
R2
1
SSA
0 °C
R CHO
NH OAc
4
9
O
N
H
IV
V
V
a
a
−
–
c
Vc
IX
1
R : aryl, alkyl
2
R : (a = —OEt; b = —OMe; c = —Me)
Fig. 5. Synthesis of Hantzsch 1,4-dihydropyridines catalysed with SSA.

9
02
E. Kolvari et al./Chemical Papers 65 (6) 898–902 (2011)
as a catalyst in the synthesis of 4-substituted-1,4-
dihydropyridines in good yields is also significant.
Hantzsch, A. (1881). Condensationprodukte aus Aldehydammo-
niak und Ketonartigen Verbindungen. Berichte der Deu-
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Acknowledgements. The authors acknowledge the Semnan
University Research Council, Bu-Ali Sina University Research
Council, (Grant Number 32-1716), and Centre of Excellence
in Development of Chemical Methods (CEDCM). We also
acknowledge the great help received from Mr. Mehdi Damali
Amiri in editing this manuscript.
1
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