A Simple and Efficient One-pot Synthesis of 1,4-dihydropyridines Using Nano-WO3-supported Sulfonic Acid as an Heterogeneous Catalyst under Solvent-free Conditions

Article abstract of DOI:10.1002/jccs.201500453

Nano-tungsten trioxide-supported sulfonic acid (n-WSA) was found to be an effective heterogeneous catalyst for the one-pot reaction of aromatic aldehydes, β-dicarbonyl compounds and ammonium acetate to afford 1,4-dihydropyridine derivatives in good to excellent yields. The other main advantages of the present method are short reaction times, simple workup, ease in purification and environmentally benign methodology. The reaction conditions were optimized employing Response Surface Method technique (Central Composite Design (CCD)) which is economically considerable because of the minimum number of experiments required to evaluate the effects of multiple parameters on the response.

Full text of DOI:10.1002/jccs.201500453

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
A Simple and Efficient One-pot Synthesis of 1,4-dihydropyridines Using Nano-WO3-
supported Sulfonic Acid as an Heterogeneous Catalyst under Solvent-free Conditions
Mehrnoosh Bitaraf, Ali Amoozadeh* and Somayeh Otokesh
Faculty of Chemistry, Semnan University, Semnan 35131-19111, Iran
(Received: Nov. 9, 2015; Accepted: Jan. 28, 2016; Published Online: Apr. 5, 2016; DOI: 10.1002/jccs.201500453)
Nano-tungsten trioxide-supported sulfonic acid (n-WSA) was found to be an effective heterogeneous cat-
alyst for the one-pot reaction of aromatic aldehydes, b-dicarbonyl compounds and ammonium acetate to
afford 1,4-dihydropyridine derivatives in good to excellent yields. The other main advantages of the pres-
ent method are short reaction times, simple workup, ease in purification and environmentally benign
methodology. The reaction conditions were optimized employing Response Surface Method technique
(Central Composite Design (CCD)) which is economically considerable because of the minimum number
of experiments required to evaluate the effects of multiple parameters on the response.
Keywords: 1,4-dihydropyridines; Nano-WO3-supported sulfonic acid; Heterogeneous catalysis;
Solvent-free; Hantzsch reaction; Response surface method.
INTRODUCTION
Nitrogen containing six-membered heterocycles are
ease of separation and recyclability.22-26
Nano particles have higher numbers of active sites,
due to their high surface/volume ratio.27 Therefore, study-
ing heterogeneous nano-catalysts is considered to be an on-
going research resulted in introduction of many modified
catalysts.28-37 Recently, our research group has introduced
nano-WO3-supported sulfonic acid (n-WSA) as a solid
acidic heterogeneous catalyst and proved its catalytic activ-
ity.38 It has been confirmed that n-WSA is a benign, advan-
tageous heterogeneous catalyst, which is easily separable
and reusable for five consecutive times without significant
loss of activity.
valuable subunits exist in biological and pharmaceutical
compounds. Among them, 1,4-dihydropyridines (1,4-DHPs)
are important pharmacophores widely used in therapeutic
compounds. Their pharmaceutical activities can be men-
tioned as calcium channel blockers,1-3 cardiovascular and
anti-hypertensive,4,5 anti-cancer,6 anti-convulsant,7 anti-
HIV8 and anti-bacterial.9 Also, they can be used syntheti-
cally as reducing agents.10,11 Heretofore, several approa-
ches for the synthesis of 1,4-DHPs have been reported in-
cluding the conventional Hantzsch condensation. The
Hantzsch synthesis of 1,4-dihydropyridines is one-pot con-
densation of aldehydes with ethyl acetoacetate and ammo-
nia in the presence of different catalysts and solvents.12-21
In many of these methods some limitation still exist such as
drastic reaction conditions, long reaction times, low yields,
tedious work-up procedures, difficulties in purification or
use of volatile organic solvents. Also, in many cases, no re-
cycling of the catalyst makes these methods environmen-
tally deficient. So, there has been considerable importance
to carry out solvent-free Hantzsch reaction with a reusable
catalyst which can be specifically interesting from the eco-
nomical and environmental standpoint.
Here, we wish to report an efficient approach for the
synthesis of 1,4-DHP derivatives from different aromatic
aldehydes, b-dicarbonyl compounds and ammonium ace-
tate catalyzed by nano-WO3-supported sulfonic acid under
solvent-free conditions. The aim of our study is to develop
a practically simple methodology for the synthesis and pu-
rification of a wide range of 1,4-DHPs.
RESULTS AND DISCUSSION
Characterization of the nano-catalyst by FE-SEM
From FE-SEM images of n-WSA, it was found that
the average particle size of spherical n-WSA powder is
about 60-75 nm (Figure 1) which reveals that the catalyst is
in nano size.
In the last decades, the green chemistry matter, favors
the performance of reactions under solvent free condition
and in the presence of a recyclable catalyst. To this reason
heterogeneous catalysts have drawn attention due to their
Optimization of the reaction conditions
In order to optimize the reaction condition, at first,
* Corresponding author. Email: aamozadeh@semnan.ac.ir
Supporting information for this article is available on the www under http://dx.doi.org/10.1002/jccs.201500453
336
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Nano-WO3-supported Sulfonic Acid: A Reusable Catalyst
given f-value and shows insignificant lack of fit for this
model. R2 value of 0.9918 shows the good fitness of the
model. The pred-R2 of 0.9488 exhibits good prediction fit-
ness in reasonable agreement with the Adj-R2 of 0.9845.
This means, there is a considerable agreement between ex-
perimental and the predicted responses confirming the suit-
ability of the fitted model.
Also, Polynomial response surface models for yield
are obtained from the experimental design:
Y = -709.05316 + 27.84320X1 + 6.71408X2 +
20.79251X3 + 0.023813X1X2 -0.16987X1X3 -
2
0.033075X2X3 - 0.66570X12 - 0.033571X2
-
2
0.35555X3
Fig. 1. The FE-SEM image of n-WSA.
Table 2. Conditions of predicted experiments in CCD for three
effective factors in the synthesis of 2,6-Dimethyl-4-
phenyl-1,4-dihydropyridine-3,5-diethylcarboxylate
accompanied to the observed responses
the reaction of ethyl acetoacetate (2 mmol), benzaldehyde
(1 mmol) and ammonium acetate (1.5 mmol) was em-
ployed as a representative model reaction in the presence of
n-WSA, which gave rise to 2,6-Dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-diethylcarboxylate. Then, to under-
stand the effect of different variables, several experiments
were studied by central composite design (CCD). In the
present case, the effects of catalyst amonut (X1), tempera-
ture (X2), and reaction time (X3) were performed on reac-
tion yield as response function. A five-level CCD of three
independent variables is shown in Table 1.
Run
X1
X2
X3
Yield (%)
1
2
3
4
5
6
7
8
20.00
20.00
24.00
24.00
20.00
16.00
26.73
16.00
20.00
13.27
20.00
20.00
20.00
24.00
20.00
16.00
16.00
24.00
20.00
20.00
100.00
100.00
120.00
120.00
100.00
120.00
100.00
80.00
100.00
100.00
66.36
100.00
133.64
80.00
100.00
120.00
80.00
80.00
100.00
100.00
23.41
15.00
10.00
20.00
15.00
20.00
15.00
20.00
15.00
15.00
15.00
15.00
15.00
10.00
15.00
10.00
10.00
20.00
15.00
6.59
98.83
95.09
58.94
80.65
96.87
76.34
74.51
85.98
93.27
55.74
60.86
97.23
53.68
47.73
96.45
42.78
37.45
80.93
98.42
41.39
9
10
11
12
13
14
15
16
17
18
19
20
CCD provided 20 runs to derive objective function
for yield, all are collected and shown in Table 2.
The analysis of variance (ANOVA) gives precise in-
formation about the significance level of each term. From
the ANOVA as shown in Table 3, f-value of 134.82 implies
that the model is convincing. Values of prob > F less than
0.0500 indicate the model terms are significant. P-value of
greater than 0.05 measures the significance probability of a
Table 3. The results of ANOVA in CCD for the synthesis of 2,6-
Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
diethylcarboxylate
Table 1. The experimental levels of variables in CCD for the
synthesis of 2,6-Dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-diethylcarboxylate
Sum of
squares
Mean
F
p-value
Source
df
Levels
square value Prob > F
Independent
Lowest Low Central High Highest
variables
Model
8970.78
73.93
57.62
16.31
9044.72
Adj-R2
9
10
5
5
996.75 134.82 < 0.0001
7.39
11.52
3.26
(-1.68)
(-1)
(0)
(+1)
(+1.68)
Residual
Lack of fit
Pure error
Cor total
R2 = 0.9918
X1: Catalyst
amount (g)
X2: Temperature
(°C)
0.012
0.016
0.020
0.024
0.28
3.53
0.0962
80
5
90
10
100
15
110
20
120
25
19
Pred-R2
X3: Time (min)
= 0.9845 = 0.9488
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According to the equation, the coefficients of X1, X2
tended to the condensation of b-dicarbonyl compounds (2)
and ammonium acetate (3) with different aromatic alde-
hydes (1) to obtain other 4-phenyl-1,4-dihydropyridine de-
rivatives (4) (Scheme 1).
and X3 shows positive influence on the yield. Not only the
main factors (X1, X2 and X3) are important, but also the in-
teraction effects of catalyst amount-time, temperature-time
and the square of factors are significant. In order to investi-
gate the interaction effects of parameters on the yield,
three-dimensional profiles, were generated by the model as
indicated in Figure 2. These graphs indicate the interaction
of each two parameters which is an inversely proportional
catalyst amount-time and temperature-time relationship.
The results showed that 0.021 g (7 mol%) of the cata-
lyst, 100 °C reaction temperatures, and 16 minutes reaction
time were the optimum parameters for the synthesis of
2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diethylca
rboxylate (Figure 3).
n-WSA-catalyzed synthesis of 4-phenyl-
1,4-dihydropyridine derivatives derivatives.
Scheme 1
Table 5 indicates the obtained 1,4-dihydropyridine
derivatives using the mentioned procedure and condition.
As it is presented in Table 5, this method is applicable
for a vast variety of aromatic aldehydes carrying both elec-
tron withdrawing and electron releasing groups. According
to the table, the aldehydes with electron withdrawing
groups (Table 5, entries 2-8, 16-22, 31-32) reacted faster
compared to electron releasing substituents (Table 5, en-
tries 9-14, 23-27, 29-30), most probably because of the rate
of enole attack on the carbonyl center of aldehyde. Reac-
tions with aldehydes having a-hydrogens are also possible.
According to the literature,39 the reaction proceeds well ir-
respective of the nature of the aldehyde (aliphatic, aro-
matic, heteroaromatic). But the reactions with aldehydes
having a-hydrogens are not common. The first step of
mechanism is an aldol condensation leads to an a,b-unsat-
urated compound. Aldehydes lacking a-hydrogens can
only function as acceptor reactants and this reduces the
number of undesirable products. All products were isolated
in good to excellent yields and purified using simple
recrystallisation from ethanol. The structures of the pro-
The efficiency of solvent was also examined. The re-
sults are summarized in Table 4. As indicated there, the sol-
vent free condition was found to be the best (Table 4, entry
1), while other selected solvents did not provide a signifi-
cant improvement in the yield (Table 4, Entries 2-6).
Promoted by these results, to explore the generality of
our new conditions, the same reaction procedure was ex-
1
ducts were determined by IR, H NMR and 13C NMR
spectroscopy.
Table 4. Optimization of solvent for the synthesis of 2,6-
Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
diethylcarboxylatea
Fig. 2. Three dimensional response surfaces for the ef-
fect of factors on the reaction yield.
Entry
Solvent
Yieldb (%)
1
2
3
4
5
6
-
98
60
45
33
20
Ethanol (Reflux)
Methanol (Reflux)
Acetonitrile (Reflux)
H2O (Reflux)
CHCl3
Trace
a Reaction condition: ethyl acetoacetate (2 mmol), benzaldehyde
(1 mmol) and ammonium acetate (1.5 mmol), 0.021 g n-WSA,
reaction time: 16 min, 100 °C. b Isolated yield.
Fig. 3. Optimized parameters resulted from the model.
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Nano-WO3-supported Sulfonic Acid: A Reusable Catalyst
Table 5. Synthesis of Hantzsch products by the condensation of aldehydes, b-dicarbonyl compounds
and ammonium acetate
M.p. (°C)
Found Reported
Time
(min)
Yield
(%)
Entry
R1
R2
Product
1
C6H5
OEt
16
20
98
89
154-155
126-128
156-15840
120-12541
2
3
2-Cl- C6H4
4-Cl- C6H4
OEt
OEt
20
25
25
93
92
90
144-145
156-157
158-160
150-15242
155-15742
162-16413
4
5
4-F- C6H4
OEt
OEt
4-Br- C6H4
6
7
8
2-NO2- C6H4 OEt
3-NO2- C6H4 OEt
4-NO2- C6H4 OEt
20
20
10
91
96
95
166-168
162-164
129-130
169-17043
160-16242
133-13542
9
4-OH- C6H4 OEt
15
15
20
91
88
87
226-228
138-141
148-151
229-23143
136-13813
15744
10
4-Me- C6H4
OEt
11
2-OMe- C6H4 OEt
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12
4-Ome-C6H4 OEt
25
90
144-145
140-14242
13
14
15
16
2-furyl
2-Thienyl
C6H5
OEt
OEt
10
10
15
15
89
86
92
87
158-159
173-176
196-199
198-201
160-16245
171-17240
196-19846
194-19646
OMe
OMe
2-Cl-C6H4
17
18
19
4-Cl-C6H4
4-F-C6H4
4-Br-C6H4
OMe
OMe
OMe
15
25
20
90
90
92
196-198
171-172
192-194
197-19840
17047
201-20240
20
21
22
2-NO2-C6H4 OMe
3-NO2-C6H4 OMe
4-NO2-C6H4 OMe
15
20
20
86
89
94
151-153
212-215
174-177
157-16148
211-21240
167-16940
23
24
4-OH-C6H4 OMe
4-Me-C6H4 OMe
15
15
85
88
239-240
177-180
230-23246
173-17440
340
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Nano-WO3-supported Sulfonic Acid: A Reusable Catalyst
25
4-OMe- C6H4 OMe
20
86
185-188
186-18840
26
27
2-furyl
OMe
OMe
20
15
87
90
188-191
170-172
190-19240
171-17240
2-Thienyl
28
29
C6H5
Me
15
10
93
93
178-180
177-178
183-18449
175-17650
4-OMe- C6H4 Me
2-OMe- C6H4 Me
30
10
95
170-172
172-17350
31
32
4-NO2- C6H4 Me
20
15
88
92
134-136
205-206
130-13239
210-21150
3-NO2- C6H4 Me
In order to appraise the efficiency of our methodol-
ogy, the achieved results from the reaction of ethyl ace-
toacetate, benzaldehyde and ammonium acetate have been
compared with those of the formerly reported approaches
on the literature (Table 6). It was found that the present
method is convincingly better than the previous ones with
respect to the reaction time, obtained yields and catalyst
amount (Table 6, entry 6).
Table 6. Comparison of the efficiency of n-WSA with other
reported catalysts in the synthesis of 2,6-Dimethyl-4-
phenyl-1,4-dihydropyridine-3,5-diethylcarboxylate
Entry
Catalyst Mol% Condition Time (h) Yield (%)
1
2
3
4
5
6
MTSA
CuFe2O4
Fe(CF3CO2)3
PPh3
CeCl3-7H2O 10
n-WSA
5
10
5
60 °C, S.F.
r.t., EtOH
70 °C, S.F.
4
4
0.5
5
8651
9819
9052
20 EtOH (reflux)
r.t., CH3CN
7
7213
3
8053
100 °C, S.F. 16 min
98
The reusability of the catalyst is very important eco-
nomically and environmentaly. For this purpose, recycl-
ability and reusability of n-WSA was investigated and de-
picted in Figure 4. Reloading the same catalyst amount for
a new run showed that it can be reused at least five times
without remarkable loss of activity.
(this work)
The first step is the enolization of the b-dicarbonyl in
the presence of n-WSA, followed by its attack on the car-
bonyl center of aldehyde, leads to an unsaturated carbonyl
compound (I) formation. Next step is the formation of an
enamine (II), by condensation of the second equivalent of
the b-dicarbonyl with ammonia. A Michael addition be-
The plausible mechanism for nano-WO3-SO3H cata-
lyzed synthesis of 4-phenyl-1,4-dihydropyridines is shown
in Scheme 2.
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action times, good to excellent yields, simple workup and
green aspects. Also the main predominance of our method
is the ease of purification by just a simple recrystallization
instead of column chromatography most probably due to
the purity of obtained products. Furthermore, the ease of
recovery and reusability of catalyst is another benefit of
this method. Also, using the response surface method for
optimization is economically considerable because of re-
duced number of design point.
Fig. 4. Reusability of n-WSA for the synthesis of 2,6-
EXPERIMENTAL
Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
diethylcarboxylate, Reaction condition: ben-
zaldehyde (1 mmol), ethyl acetoacetate (2
mmol), ammonium acetate (1.5 mmol), n-WSA
(0.21 g), reaction time: 16 min, under solvent
free condition at 100 °C.
All chemicals were purchased from Merck. Progress of re-
actions was monitored by Thin-Layer Chromatography technique
(TLC) on commercial plates of silica gel 60 F254. The products
were characterized by FT-IR spectra, 1H NMR, 13C NMR. 1H and
13C NMR spectra were run on Bruker Advance Spectrometer 300
and 75 MHz using CDCl3-d and DMSO-d6 as solvents. All chemi-
cal shifts were reported in parts per million (ppm) and tetra-
methylsilane (TMS) was used as an internal reference. Melting
points were measured on a THERMO SCIENTIFIC 9100 appara-
tus.
The plausible mechanism for the synthesis
of 4-phenyl-1,4-dihydropyridines.
Scheme 2
Field emission scanning electron microscopy: particle
size study of n-WSA powder was performed using Philips XL30
field emission scanning electron microscope instrument operat-
ing at 10 kV. The sample was mounted on a double side carbon
disk and sputter-coated with a thin layer of gold to prevent sample
charging problems.
General procedure for the synthesis of catalyst: Accord-
ing to the previous published work,38 the preparation procedure is
described as: Asuction flask was charged with nano-WO3 powder
(4 g, 17 mmol) in dry CH2Cl2 (20 mL), connected to a constant-
pressure dropping funnel and a gas inlet tube to conduct HCl gas
over an adsorbent (i.e., water). Then, chlorosulfonic acid (1 mL,
15 mmol) was added drop-wisely over a period of 30 minutes at
ambient temperature. HCl gas was instantly evolved from the re-
action equipment. When the addition was completed, the ob-
tained mixture was kept stirring for 30 minutes. Then, CH2Cl2
was removed under reduced pressure. The dark green powder of
nano-tungsten trioxide-supported sulfonic acid was obtained,
washed with ethanol (10 mL) and dried at 120 °C for 6 h.
Also, the mmol of H+ per gram of catalyst (3.7 mmol/g of
n-WSA) was measured by the titration of 0.1 g of catalyst with a
standard solution of NaOH (0.1 N). At the outset, the acidic pro-
tons of nano-WO3-SO3H (100 mg) were ion-exchanged with 10
mL of NaCl saturated solution. The process was repeated twice
more, to yield 30 mL of proton-exchanged brine solution. After-
ward, to determine the loading of acidic sites on the prepared cat-
tween unsaturated carbonyl compound (I) and enamine
(II), followed by proton transfers and finally cyclization
gave the corresponding 1,4-dihydropyridine.
In conclusion, an efficient, easy and rapid method for
the synthesis of a variety of 1,4-dihydropyridines, using
n-WSA under solvent free condition is reported. Our
method can make a worthwhile contribution to the current
procedures in the field of 1,4-dihydropyridine synthesis.
The advantages of our method can be mentioned as em-
ploying a reusable and less noxious nano catalyst, short re-
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1
alyst, the obtained solution was titrated by standard solution of
0.1 N NaOH in the presence of a pH meter.
1304, 1121, 1096, 850, 800; H NMR (CDCl3, 300 MHz): d
(ppm): 2.20 (s, 6 H), 3.56 (s, 6 H), 4.91 (s, 1 H), 6.39 (s, 1 H),
7.16-6.76 (m, 4 H); 13C NMR (CDCl3, 75 MHz): d (ppm): 19.28,
38.71, 51.03, 103.49, 114.83, 129.01, 129.12, 143.49, 144.78,
168.21.
General procedure for the synthesis of 2,6-Dimethyl-
4-phenyl-1,4-dihydropyridine-3,5-diethylcarboxylate: A mix-
ture of ethyl acetoacetate (2 mmol, 0.26 g), benzaldehyde (1
mmol, 0.106 g), ammonium acetate (1.5 mmol, 0.115 g) and
n-WSA (0.021 g) was stirred at 100 °C under solvent-free condi-
tion for an appropriate time. Completion of the reaction was mon-
itored by TLC (n-hexane: ethyl acetate, 7:3). Then, the reaction
mixture was cooled, diluted with hot ethanol and stirred for few
minutes. The catalyst was removed by centrifugation and the re-
sultant alcoholic solution was poured into the ice water. The solid
product was filtered and then recrystallized from ethanol to give
pure yellow crystalline 2,6-Dimethyl-4-phenyl-1,4-dihydropyri-
dine-3,5-diethylcarboxylate in 98%. The catalyst can be reused
directly for the next run.
2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,
5-dimethylcarboxylate (Table 5, entry 19): IR (KBr, cm-1):
1
3349, 3005, 2953, 1704, 1650, 1528; H NMR (CDCl3, 300
MHz): d (ppm): 2.26 (s, 6 H), 3.56 (s, 6 H), 5.02 (s, 1 H), 6.29 (s, 1
H), 8.01-7.26 (m, 4 H); 13C NMR (CDCl3, 75 MHz): d (ppm):
19.44, 39.60, 51.16, 102.88, 121.39, 122.69, 128.76, 134.24,
146.37, 148.31, 149.65, 167.67.
ACKNOWLEDGEMENTS
We thank the Department of Chemistry of Semnan
University for supporting this work.
Spectral data of some compounds
2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-diethyl
carboxylate (Table 5, entry 1): IR (KBr, cm-1): 3342, 1691,
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6.2 (b, 1 H), 7.04-7.22 (m, 5 H); 13C NMR (CDCl3, 75 MHz): d
(ppm): 14.26, 19.40, 39.63, 59.74, 103.93, 126.10, 127.84,
127.98, 144.23, 147.85, 167.81.
2. Yamamoto, T.; Niwa, S.; Ohno, S.; Tokumasu, M.;
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2,6-Dimethyl-4-(4-chlorophenyl)-1,4-dihydropyridine-
3,5-diethylcarboxylate (Table 5, entry 3): IR (KBr, cm-1): 3335,
3. Yamamoto, T.; Ohno, S.; Niwa, S.; Tokumasu, M.; Hagihara,
M.; Koganei, H.; Fujita, S.-I.; Takeda, T.; Saitou, Y.;
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1
1695, 1645, 1499, 1219, 789; H NMR (CDCl3, 300 MHz): d
(ppm): 1.3 (t, 6 H, J = 7.13 Hz), 2.19 (s, 6 H), 4 (b, 4 H), 4.89 (s, 1
H), 6.30 (s, 1 H), 7.15-7.06 (q, 4 H); 13C NMR (CDCl3, 75 MHz):
d (ppm): 14.27, 19.31, 39.24, 59.85, 103.50, 127.92, 129.36,
131.66, 144.56, 146.45, 167.68.
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2,6-Dimethyl-4-(4-hydroxyphenyl)-1,4-dihydropyridine-
3,5-diethylcarboxylate (Table 5, entry 9): IR (KBr, cm-1): 3443,
3341, 1698, 1640, 1493, 1213, 778; 1H NMR (CDCl3, 300 MHz):
d (ppm): 1.11 (t, 6 H, J = 7.11 Hz), 2.23 (s, 6 H), 3.05 (b, 4 H), 4.86
(s, 1 H), 7.04-6.56 (m, 4 H), 7.98 (s, 1H); 13C NMR (Acetone D,
75 MHz): d (ppm): 13.77, 17.87, 38.54, 58.87, 103.39, 114.40,
128.83, 139.76, 144.38, 155.54, 167.23.
6. Abbas, H.-AS.; El Sayed, W. A.; Fathy, N. M. Eur. J. Med.
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2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dimet-
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1648, 1477, 1205, 765; H NMR (CDCl3, 300 MHz): d (ppm):
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Rhouati, S.; Carboni, B. Tetrahedron Lett 2009, 50, 5248.
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2.23 (s, 6 H), 3.75 (s, 6 H), 4.95 (s, 1 H), 6.09 (b, 1 H), 7.14-7.21
(m, 4 H); 13C NMR (CDCl3, 75 MHz): d (ppm): 19.41, 39.28,
51.03, 103.64, 126.23, 127.60, 128.05, 144.61, 147.48, 168.22.
2,6-Dimethyl-4-(4-flourophenyl)-1,4-dihydropyridine-
3,5-dimethylcarboxylate (Table 5, entry 16): IR (KBr, cm-1)
3351, 3248, 3102, 3002, 2950, 2843, 1698, 1654, 1503, 1443,
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