Magnesium oxide nanotubes: Synthesis, characterization and application as efficient recyclable catalyst for pyrazolyl 1,4-dihydropyridine derivatives

Article abstract of DOI:10.1016/j.tet.2012.06.017

Magnesium oxide nanotubes were prepared by electrospinning technique. The nanocatalysts have been characterized by various sophisticated techniques, including XRD, SEM, and TEM. The activities of these NT catalysts are promoting pyrazolyl 1,4-dihydropyrid

Full text of DOI:10.1016/j.tet.2012.06.017

Tetrahedron 68 (2012) 7196e7201
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Magnesium oxide nanotubes: synthesis, characterization and application
as efficient recyclable catalyst for pyrazolyl 1,4-dihydropyridine derivatives
,
a
a
a,b,c
R. Murugan a , K. Ramamoorthy , S. Sundarrajan , S. Ramakrishna
*
a HEM Laboratory, NUSNNI, National University of Singapore, 2 Engineering Drive 3, 117576 Singapore, Singapore
b Institute of Material Research and Engineering, Singapore 117602, Singapore
c King Saud University, Riyadh 11451, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Magnesium oxide nanotubes were prepared by electrospinning technique. The nanocatalysts have been
characterized by various sophisticated techniques, including XRD, SEM, and TEM. The activities of these
NT catalysts are promoting pyrazolyl 1,4-dihydropyridine syntheses have been extensively investigated.
Various advantages associated with these protocols simple workup procedure, short reaction times, high
yields and reusability of the catalyst.
Received 6 January 2012
Received in revised form 17 May 2012
Accepted 6 June 2012
Available online 20 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Electrospinning
Heterogeneous catalyst
Magnesium oxide nanotubes(NT)
Nanocatalyst
1. Introduction
amounts of the catalyst have been investigated. Herein, we report
the successful preparation of mesopourous magnesium oxide
Metal oxide based nanocatalyst have attracted much attention
in the fields of catalysis, separation, optoelectronics, active adsor-
bents for gases, magnetism, and microelectronics owing to their
unique physical and chemical properties.1e5 The overall perfor-
mances of these nanocatalysts are dependent on the size, shape,
crystal structure, and the textural parameters.6 Development of
efficient and practical catalysts for the organic transformation is
a considerable interest to both academic and industry.7,8 Nano-
catalysis is interesting area in organic synthesis as it provides not
only an alternative to homogeneous catalysis but also has the ad-
vantage of highly porous, large surface area, minimum quantity
requirement, recycling and mild reaction conditions.
nanotubes through a simple and effective electrospinning method
(Fig. 1). The activity and stability of these catalysts in relation to the
aforementioned organic transformations have been extensively
Magnesium oxide is an efficient catalyst and has been the focus
of considerable attention because it catalyses a variety of organic
reactions, such as aldol reaction,9,10 synthesis of chiral epoxy ke-
tones and chiral nitro alcohols,11 CO oxidation,12 asymmetric Mi-
chael addition of malonates to enones,13 asymmetric Henry
reaction,14 benzylic CeH oxidation,15 synthesis of flavanones,16 and
ClaiseneSchmidt.11,17 Here, MgO based nanotubes are introduced as
mild and highly efficient catalysts for the preparation of pyrazolyl
1,4-dihydropyridine derivatives under mild conditions. The method
reported is gave good yields 88e94%. In order to improve the yield
and reaction time, the effect of various solvents, and different
* Corresponding author. Tel.: þ65 6516 6593; fax: þ65 6773 0339; e-mail
Fig. 1. (A) SEM of nanofibers, (B) after calcinations, (C) TEM images of MgO nanotubes,
and (D) XRD pattern of MgO nanotubes.
addresses: mperajen@nus.edu.sg, muruganchem@gmail.com (R. Murugan).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.017

R. Murugan et al. / Tetrahedron 68 (2012) 7196e7201
7197
Cl
investigated. The effects of various reaction parameters on con-
version and product selectivity have been studied.
O
O
N
N
Substituted 1,4-dihydropyridine derivatives are important class of
bioactive compounds in the field of pharmaceutical.18 1,4-DHPs pos-
sess a variety of biological activities like anti-microbial,19,20 bron-
chodilator, antitumour, anti-inflammatory, antiulcer activities,21
antidiabetic agents, antioxidabts,22,23 antitubercular agents,24,25
neuroprotectants,26 and are important in Alzheimer disease as anti-
ischaemic agents.1,4-DHPsare commercially usedascalcium channel
blockers for the treatment of cardiovascular diseases, including hy-
pertension.27 Pyrazolyl 1,4-DHP derivatives have showed potential
biological activities including anti-inflammatory, calcium channel
activity, including control of arthropod pests, and also pyrazolylpyr-
idine ligands exhibit efficient lanthanide sensors.28e31 Therefore, the
synthesis of pyrazolyl 1,4-DHPs has become of interest to synthetic
chemists and biologists. Severalgroups have reported thesynthesis of
1,4-DHPs with I2,32 TMSCl/NaI,33 InCl3,34 Yb(OTf)3,35 FeCl3,36 SiO2/
NaHSO4,37 CAN,38 Al2O3,39 Mg(ClO4)2,40 TCT,41 PTSA,42 and
SiO2esulfonic acid43 promote these type of reactions. Although some
of these reactions are performed under mild conditions, most of them
require a long period for completion, expensive materials, tedious
work-up, the formation of side products, and give only modest yields
of the products. Therefore, development and introduction of a con-
venient, cost effective, milder and efficient method for the pyrazolyl
1,4-DHPs is of practical importance and is still in demand. Recently,
the nanocatalyst has received considerable attention as efficient cat-
alyst for various reactions. Herein, we report that MgO NT is an effi-
cient, cost effective and recyclable catalyst for the synthesis of
biological important pyrazolyl 1,4-DHP derivatives.
Me
OMe
CHO
Cl
MgO nanotube
2a
+
N
MeO2C
Me
CO2Me
Me
N
Acetonitrile, reflux
N
H
AcONH4
3
1d
4g
100
80
60
40
20
0
94
93
93
92
60
13
0
5
10
15
20
25
MgO nanotubes mol %
Fig. 2. Effect of catalyst loading on the synthesis of pyrazolyl 1,4-dihydropyridine 4g;
reaction conditions: 3-(4-chlorophenyl)-1-phenyl-1H-pyrazole-4-carbaldehyde
(1 equiv), methyl 3-oxobutanoate (2 equiv), ammonium acetate (1.2 equiv), acetoni-
trile (10 mL), reflux. aIsolated yields.
same level of selectivity. From the results outlined in Fig. 2 and
15 mol % of MgO NT was chosen for further experiments. Simple
pyrazole and N-phenyl substituted pyrazoles also worked well
without formation of any side products and the results were
summarized in Table 1.
The increase of catalyst loading resulted in the increase of pyr-
azolyl 1,4-dihydropyridine conversion, but further increase led to
the decrease of pyrazolyl 1,4-DHP conversion. The optimal loading of
NT was 15 mol %, in which case conversion attained maxima 94%. It
was found that 15 mol % of NT is sufficient for increasing the con-
version rate and yield. The results indicate that the significant role of
NT as a catalyst for the reactions. It is observed that NT has high
activity level for the transformation under mild reaction conditions.
The yields of products were in the range of 88e94% and the reaction
time varies depending upon the nature of the substrate.
2. Results and discussion
Synthesis of pyrazolyl 1,4-dihydropyridines using NT was first
carried out as a model reaction (Scheme 1), using various amount of
NT as catalyst under proposed operating conditions. The catalyst
precipitated as solid at the bottom layer while centrifuge and could
be easily separated by nanofiber filtration. Various parameters in-
cluding the effect of reaction temperature, catalyst dosage and re-
action time, and the recycling performance of the nanocatalysts
were studied. The results showed that these catalysts exhibited
high activity and good reusability in DHP synthesis. In case of
pyrazolylpyridine synthesis is noteworthy that there was no re-
action without NT catalyst, which indicated that the catalyst is es-
sential for the reaction.
R1
O
O
R3
R2
R4
R3
2.2. Recylability
OR5
N
N
Me
R4
R2
CHO
MgO nanotube
2a-b
+
To investigate the reusability of NT as a recyclable catalyst for
the synthesis of pyrazolyl 1,4-dihydropyridines, a series of recycling
experiments were performed. The solid catalyst has been recovered
by nanofiltration after each reaction and has been washed thor-
oughly first with acetonitrile and then with dichloromethane. The
recovered catalyst is found to exhibit almost the same catalytic
activity (conversion of 4g): first run, 93%, second run, 90% and third
run, 82%. This indicates the still very slow deactivation for the
catalyst, mostly happening during the first three runs, even when
taking into account the weight loss in the operation for recovering
the catalyst. In light of this, the NT still showed excellent reusability
during the three cycles. An interesting phenomenon observed was
that the catalyst appeared at the bottom of the flask as a solid after
centrifuge, there for all of reactions, the solid catalyst could be
conveniently recovered simply by nanofiltration, washed and easily
recycled into the next run. The catalyst has several advantages over
the traditional catalysts, such as high catalytic activity, easy sepa-
ration and giving high yield of desired product, which may meet the
R5O2C
CO2R5
Acetonitrile, reflux
N
N
Me
N
H
Me
R1
1a-h
AcONH4
4a-n
3
Scheme 1. The synthetic scheme of pyrazolyl 1,4-dihydropyridines 4aen.
2.1. Effect of solvents and catalyst loading
The influence of various solvents on the conversion of 4g was
studied at reflux conditions over NT catalyst. Compared to aceto-
nitrile, other solvents, such as methanol, ethanol, THF, DCM, CHCl3,
1-butyl-3-methylimidazolium chloride and toluene made the NT
catalyst perform far more poorly. We found the optimal amount of
nanocatalyst (MgO NT) to get complete conversion at reflux con-
dition and the results are presented in Fig. 2. The incremental
amount of nanocatalyst drastically effects the reaction with the

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R. Murugan et al. / Tetrahedron 68 (2012) 7196e7201
Table 1 (continued)
Table 1
Synthesis of pyrazolyl 1,4-dihydropyridines 4aeg
Entry
Reactant
Product
Time (min) Yielda (%)
Entry
Reactant
Product
Time (min) Yielda (%)
Cl
H
N
N
O2N
Cl
O2N
CHO
N
N
CHO
MeO2C
Me
CO2Me
Me
a
45
92
N
N
i
45
30
45
89
92
90
N
H
N
CO2Me
Me
MeO2C
N
H
1a
Me
N
H
4a
1e
4i
H
N
N
Cl
CHO
O2N
Cl
EtO2C
Me
CO2Et
Me
O2N
b
60
89
N
N
N
CHO
N
H
N
H
N
j
1a
N
CO2Et
Me
EtO2C
Me
4b
N
H
MeO
MeO
1e
CHO
4j
N
N
MeS
N
N
c
30
45
45
30
45
91
90
90
88
93
MeO2C
Me
CO2Me
N
N
CHO
N
H
Me
MeS
1b
N
k
MeO2C
Me
CO2Me
Me
4c
N
N
H
MeO
MeO
CHO
4k
N
N
1f
N
N
d
e
f
MeS
EtO2C
Me
CO2Et
Me
N
H
N
N
CHO
1b
MeS
4d
N
l
30
60
60
94
92
89
EtO2C
Me
CO2Et
Me
N
MeO2S
N
H
CHO
4l
1f
N
N
NO2
N
CHO
N
O2N
1c
N
N
m
MeO2S
MeO2C
Me
CO2Me
Me
N
H
N
N
CHO
MeO2S
1g
N
4m
EtO2C
Me
CO2Et
N
N
H
Me
N
N
CHO
4f
N
N
N
1c
N
Cl
N
N
n
MeO2
C
CO2Me
Me
N
N
CHO
Me
N
H
Cl
N
g
1h
N
CO2Me
Me
MeO2C
4n
a
Isolated yield.
Me
N
H
1d
4g
greener aspects in catalysis. The prepared catalyst retains its mes-
oporosity and also exhibits an excellent catalytic activity. Further-
more, catalyst is stable under reaction conditions and catalytic
activity retain after recycling the catalysts.
Cl
N
N
CHO
Cl
N
h
30
91
3. Conclusion
N
EtO2C
Me
CO2Et
Me
N
H
In summary, we have found NT to be valuable additions to the
existing methods available for the various organic transformations
with added advantage of mild reaction conditions, operational
1d
4h

R. Murugan et al. / Tetrahedron 68 (2012) 7196e7201
7199
simplicity, fast and cleaner reaction profiles, and high yields. Vari-
ous reaction parameters, such as reaction time, temperature and
catalyst concentration were studied using NT as an optimized cat-
alyst. Furthermore, the range of usefulness of nanocatalyst in or-
ganic synthetic application has also been extended. This simple
experimental procedure, offers an alternative route to synthesis of
biologically active pyrazole derivatives. The catalyst can be re-
covered and reused up to four cycles for the synthesis of pyridine
derivatives. These catalytic systems may provide ‘greener’ routes to
a large scale production of industrially and pharmaceutically im-
portant products with less byproduct in the chemical industry of
the next millennium.
FRC 1200 fine coater (Jeol Ltd., Singapore) before taking SEM. The
powder X-ray patterns were obtained on a Lab-X 600 X-ray dif-
fractometer using Cu Ka (l51.541 Aꢀ) radiation and XRD pattern of
NTcatalyst are presented in Fig.1D. A JEOL 200 HR-TEM was used to
characterize the NT was operated at 200 kV. The nanocatalysts
were dispersed in ethanol and then a drop of the above dispersion
was taken on a carbon coated copper grid (300 meshes).
4.4. General procedure for the synthesis of pyrazolyl 1,4-
dihydropyridines 4aen
To a solution of pyrazolyl-4-carbaldehye (1a, 172 mg, 1 mmol,
1 equiv) in acetonitrile (10 mL), acetoacetic ester (2a, 232 mg,
2 mmol, 2 equiv), ammonium acetate (92 mg, 1.2 mmol, 1.2 equiv)
and MgO nanotubes (15 mol %) were added at room temperature.
The reaction mixture was stirred at reflux conditions for the time
indicated in Table 1. After complete conversion, as indicated by TLC,
the reaction mixture cooled to room temperature. Reaction mixture
was centrifuged, filtered through nanofilter and washed with eth-
ylacetate. The combined organic layer was concentrated at vacuo.
Purification of the crude product by flash chromatography (30%
EtOAc/hexane) gave the title compound 2a. All the products were
characterized by spectroscopic techniques.
4. Experimental section
4.1. General
All the chemicals were purchased from Aldrich or Merck. Poly-
vinylpyrrolidone (PVP Mn¼1,300,000) were obtained from Sigma-
eAldrich. Magenesium acetate tetra-hydrate purchased from Fluka.
Ethanol was supplied by Labscan Asia Co. Ltd. Pyrazolyl-4-
carbaldehydes needed for the 1,4-dihydropyridine synthesis were
synthesized by VilsmeiereHaack reaction using the literature pro-
cedure.44 Analytical TLC was performed on precoated sheets of silica
gel G of 0.25 mm thickness containing PF254 indicator (Merck).
Known 1,4-DHP derivatives were analyzed by spectroscopic tech-
niques and compared with reported methods. Column chromatog-
raphy was performed with silica gel (100e200 mesh, Merck).
Elemental analyses were done in VarioMicro analyzer. NMR spectra
were obtained on a JEOL 300, 400 and 500 MHz spectrometer. NMR
4.4.1. Dimethyl 2,6-dimethyl-4-[3-phenyl-1H-pyrazol-4-yl]-1,4-
dihydropyridine-3,5-dicarboxylate (4a). Yield (337 mg, 92%) as
a yellow solid, mp 196e198 ꢀC; [Found: C, 65.31; H, 5.74; N, 11.49.
C20H21N3O4 requires C, 65.38; H, 5.76; N, 11.44%]; m/z 367 (Mþ);
nmax (KBr) 3323, 3264, 3083, 2930, 1685, 1625, 1495, 1311,
1021 cmꢁ1
; dH (500 MHz, DMSO-d6) 2.18 (s, 6H, Me), 3.14 (s, 6H,
CO2Me), 5.02 (s, 1H, pyridine CH), 7.21 (s, 1H, pyrazole CH), 7.33 (t, J
7.6 Hz, 2H, Ph), 7.44 (t, J 7.6 Hz,1H, Ph), 7.68 (d, J 7.6 Hz, 2H, Ph), 8.83
(s, 1H, pyridine NH), 12.59 (brs, 1H, pyrazole NH); dC (125 MHz,
DMSO-d6) 18.5, 28.7, 31.2, 99.8, 102.8, 127.6, 128.3, 128.7, 132.1,
138.5, 140.3, 145.6, 167.9.
was recorded in DMSO-d6 and the chemical shifts are given in d.
4.2. Catalyst preparation
Fabrication of magnesium oxide nanofibers polyvinylpyrrolidone
solution was prepared by dissolving 1.5 g of polyvinylpyrrolidone in
8.5 mL of absolute ethanol and stirring for a period of 3 h. To this so-
lution,1.5 g of magnesium acetate tetra hydrate was added and stirred
for overnight. The obtained white colour polyvinylpyrrolidone/mag-
nesium acetate composite sol was taken in a 5 mL plastic syringe at-
tached with a 25 G needle. An electric field of 17 kV (Gamma high-
voltage, FL) was applied between the needle and the ground (alu-
minium foil) at a distance of 13 cm. All the experiments were con-
ducted at room temperature with a relatively low humidity (30%e
40%) conditionwith a flow rate of 1 mL/h. After electrospinning, the as
spunpolyvinylpyrrolidone/magnesium acetate composite fibres were
calcined for 3 h inairat700 ꢀC ata heating rate of10 ꢀC/minin order to
obtain pure magnesium oxide nanotubes (Scheme 2).
4.4.2. Diethyl 2,6-dimethyl-4-[3-phenyl-1H-pyrazol-4-yl]-1,4-
dihydropyridine-3,5-dicarboxylate (4b). Yield (352 mg, 89%) as
a pale yellow solid, mp 216e218 ꢀC; [Found: C, 66.78; H, 6.39; N,
10.59. C22H25N3O4 requires C, 66.82, H, 6.37, N 10.63%]; m/z 395
(Mþ); nmax (KBr) 3325, 3261, 3081, 2950, 1672, 1300, 1145,
1022 cmꢁ1
; dH (500 MHz, DMSO-d6) 0.85 (t, J 7.7 Hz, 6H,
CO2CH2Me), 2.19 (s, 6H, Me), 3.40e3.53 (m, 2H, CO2CH2Me),
3.78e3.84 (m, 2H, CO2CH2Me), 5.10 (s, 1H, pyridine CH), 7.24 (s, 1H,
pyrazole H), 7.32 (t, J 7.7 Hz, 2H, Ph), 7.41 (t, J 7.6 Hz, 1H, Ph), 7.77 (d,
J 7.7 Hz, 2H, Ph), 8.80 (s, 1H, pyridine NH), 12.59 (brs, 1H, pyrazole
NH); dC (125 MHz, DMSO-d6) 14.5, 18.7, 28.7, 59.3, 103.2, 125.9,
127.9, 128.3, 128.6, 132.0, 138.1, 141.2, 145.4, 167.6.
4.4.3. Dimethyl 2,6-dimethyl-4-[3-(3-methoxyphenyl)-1-phenyl-1H-
pyrazol-4-yl]-1,4-dihydro pyridine-3,5-dicarboxylate (4c). Yield
(430 mg, 91%) as a pale yellow solid, mp 140e142 ꢀC; [Found C, 68.39;
H, 5.81; N, 8.89. C27H27N3O5: requires C, 68.48; H, 5.75; N, 8.87%]; m/z
473 (Mþ);nmax (KBr)3327, 3061, 2975,1678,1490,1306,1024 cmꢁ1
; dH
(300 MHz, DMSO-d6) 2.28 (s, 6H, Me), 3.20 (s, 6H, CO2Me), 3.82 (s, 3H,
PhOMe), 5.12 (s, 1H, pyridine CH), 6.92e6.98 (m, 1H, Ph), 7.25 (t, J
7.4 Hz,1H, Ph), 7.37e7.45 (m, 5H, Ph), 7.80 (d, J 7.4 Hz, 2H, Ph), 8.00 (s,
1H, pyrazole CH), 8.84 (s, 1H, pyridine NH); dC (75 MHz, DMSO-d6)
18.6, 29.3, 50.6, 55.6,102.4,113.3,114.3,118.6,121.1,126.4,127.9,129.5,
129.9, 130.4, 136.4, 139.9, 145.8, 150.1, 159.6, 167.8.
Scheme 2. The schematic diagram of MgO nanocatalyst preparation.
4.3. Catalyst characterization
4.4.4. Diethyl 2,6-dimethyl-4-[3-(3-methoxyphenyl)-1-phenyl-1H-
pyrazol-4-yl]-1,4-dihydropyridine-3,5-dicarboxylate
(4d). Yield
(451 mg, 90%) as a pale yellow solid, mp 121e123 ꢀC; [Found C,
69.50; H, 6.27; N, 8.27. C29H31N3O5 requires C, 69.44; H, 6.23; N,
8.38%]; m/z 501 (Mþ); nmax (KBr) 3320, 3062, 2947, 1669, 1300,1149,
Surface morphology of nanocatalysts was characterized by using
a Quanta SEM instrument operating at 10 kV. In order to increase
the conductivity of the samples, they were gold coated using a JEOL

7200
R. Murugan et al. / Tetrahedron 68 (2012) 7196e7201
1032 cmꢁ1
;
dH (300 MHz, DMSO-d6) 0.92 (t, J 7.0 Hz, 6H,
C, 59.79; H, 4.48; N, 10.67. C26H23ClN4O6 requires C, 59.72; H, 4.43;
CO2CH2Me), 2.21 (s, 6H, Me), 3.61 (q, J 7.0 Hz, 2H, CO2CH2Me), 3.81
(s, 3H, PhOMe), 3.67 (q, J 7.6 Hz, 2H, CO2CH2Me), 5.15 (s, 1H, pyri-
dine CH), 6.95 (d, J 7.4 Hz, 1H, Ph), 7.27 (t, J 7.4 Hz, 1H, Ph), 7.36 (t, J
7.4 Hz,1H, Ph), 7.44 (d, J 7.4 Hz, 2H, Ph), 7.49 (d, J 7.4 Hz, 2H, Ph), 7.79
(d, J 7.4 Hz, 2H, Ph), 7.99 (s, 1H, pyrazole CH), 8.78 (s, 1H, pyridine
NH); dC (75 MHz, DMSO-d6) 14.5, 18.8, 29.3, 55.6, 59.3, 102.8, 113.3,
114.5, 118.6, 121.2, 126.4, 127.9, 129.4, 129.9, 130.4, 136.2, 139.8,
145.5, 149.9, 159.6, 167.5.
N, 10.71%]; m/z 522 (Mþ); nmax (KBr) 3325, 3064, 2982, 1692, 1597,
1306, 1034 cmꢁ1
; dH (400 MHz, DMSO-d6) 2.26 (s, 6H, Me), 3.27 (s,
6H, CO2Me), 5.07 (s, 1H, pyridine CH), 7.31 (t, J 7.36 Hz, 1H, Ph), 7.48
(t, J 8.12 Hz, 2H, Ph), 7.86 (d, J 7.88 Hz, 2H, Ph), 7.95 (d, J 8.40 Hz, 1H,
Ph), 8.15 (s, 1H, pyrazole CH), 8.19e8.21 (m, 1H, Ph), 8.52 (d, J
1.92 Hz, 1H, Ph), 8.94 (s, 1H, pyridine NH); dC (100 MHz, DMSO-d6)
18.2, 28.9, 50.2, 101.5, 118.4, 123.7, 124.4, 126.4, 128.3, 129.4, 130.3,
131.6, 132.9, 135.0, 139.1, 145.7, 146.3, 147.5, 167.1.
4.4.5. Dimethyl 2,6-dimethyl-4-{3-[4-(methylsulfonyl)phenyl]-1-
phenyl-1H-pyrazol-4-yl}-1,4-dihydropyridine-3,5-dicarboxylate
(4e). Yield (469 mg, 90%) as a pale yellow solid, mp 147e149 ꢀC;
[Found C, 62.19; H, 5.17; N, 8.12; S, 6.18. C27H27N3O6S requires C,
62.17; H, 5.22; N, 8.06; S, 6.15%]; m/z 521 (Mþ); nmax (KBr) 3325,
4.4.10. Diethyl 2,6-dimethyl-4-(3-[4-chloro-3-nitrophenyl]-1-
phenyl-1H-pyrazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(4j). Yield (506 mg, 92%) as a yellow solid, mp 163e165 ꢀC; [Found
C, 61.08; H, 4.83; N, 10.25. C28H27ClN4O6 requires C, 61.04; H, 4.94;
N, 10.17%]; m/z 550 (Mþ); nmax (KBr) 3322, 3014, 2989, 1676, 1595,
3062, 2971, 1669, 1306, 1035 cmꢁ1
;
dH (300 MHz, DMSO-d6) 2.24 (s,
1369, 1032 cmꢁ1
; dH (400 MHz, DMSO-d6) 0.92 (t, J 7.0 Hz, 6H,
6H, Me), 3.19 (s, 6H, CO2Me), 3.26 (s, 3H, SO2Me), 5.13 (s, 1H, pyri-
dine CH), 7.29 (t, J 7.7 Hz, 1H, Ph), 7.45 (t, J 7.7 Hz, 2H, Ph), 7.84 (d, J
7.8 Hz, 2H, Ph), 8.00 (s, 1H, pyrazole CH), 8.13e8.21 (m, 4H, Ph), 8.91
(s, 1H, pyridine NH); dC (75 MHz, DMSO-d6) 18.7, 29.3, 44.1, 50.7,
102.1,118.8,126.8,127.4,128.6,129.1,129.9,130.9,139.7,139.9,140.2,
146.2, 148.5, 167.7.
CO2CH2Me), 2.26 (s, 6H, Me), 3.72 (q, J 7.0 Hz, 2H, CO2CH2Me),
3.85e3.93 (m, 2H, CO2CH2Me), 5.09 (s, 1H, pyridine CH), 7.32 (t, J
7.0 Hz, 1H, Ph), 7.48 (t, J 7.1 Hz, 2H, Ph), 7.86 (d, J 7.0 Hz, 2H, Ph), 7.93
(d, J 7.1 Hz, 1H, Ph), 8.14 (s, 1H, pyrazole CH), 8.28 (d, J 7.1 Hz, 1H),
8.59 (d, J 7.1 Hz, 1H), 8.89 (s, 1H, pyridine NH); dC (100 MHz, DMSO-
d6) 14.0, 18.4, 28.9, 58.9, 101.9, 118.4, 123.7, 124.3, 126.5, 128.5, 129.4,
130.4, 131.5, 133.0, 134.9, 139.1, 145.5, 146.1, 147.6, 166.9.
4.4.6. Diethyl 2,6-dimethyl-4-{3-[4-(methylsulfonyl)phenyl]-1-
phenyl-1H-pyrazol-4-yl}-1,4-dihydropyridine-3,5-dicarboxylate
(4f). Yield (483 mg, 88%) as a yellow solid, mp 153e156 ꢀC; [Found
C, 63.30; H, 5.69; N, 7.72; S, 5.90. C29H31N3O6S requires C, 63.37; H,
5.68; N, 7.65; S, 5.83%]; m/z 549 (Mþ); nmax (KBr) 3320, 3061, 2947,
4.4.11. Dimethyl 2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-1-
phenyl-1H-pyrazol-4-yl}-1,4-dihydropyridine-3,5-dicarboxylate
(4k). Yield (440 mg, 90%) as a yellow solid, mp 127e129 ꢀC; [Found
C, 66.29; H, 5.47; N, 8.58; S, 6.48. C27H27N3O4S requires C, 66.24; H,
5.56; N, 8.58; S, 6.55%]; m/z 489 (Mþ); nmax (KBr) 3329, 3018, 2932,
1670, 1300, 1035 cmꢁ1
; dH (300 MHz, DMSO-d6) 0.92 (t, J 7.1 Hz, 6H,
CO2CH2Me), 2.23 (s, 6H, Me), 3.24 (s, 3H, SO2Me), 3.61 (q, J 7.1 Hz,
2H, CO2CH2Me), 3.89 (q, J 7.1 Hz, 2H, CO2CH2Me), 5.15 (s, 1H, pyri-
dine CH), 7.29 (t, J 7.1 Hz, 1H, Ph), 7.47 (t, J 7.3 Hz, 2H, Ph), 7.83 (d, J
8.1 Hz, 2H, Ph), 8.02 (d, J 8.1 Hz, 2H, Ph), 8.10 (s, 1H, pyrazole CH),
8.20 (d, J 8.2 Hz, 2H, Ph), 8.90 (s, 1H, pyridine NH); dC (75 MHz,
DMSO-d6) 14.6, 18.9, 29.4, 44.1, 59.4, 60.2, 102.5, 118.8, 126.3, 128.7,
129.9, 130.9, 139.7, 140.0, 140.1, 145.9, 148.3, 157.4.
1597,1372,1034 cmꢁ1
; dH (400 MHz, DMSO-d6) 2.25 (s, 6H, Me), 2.54
(s, 3H, SMe), 3.22 (s, 6H, CO2Me), 5.12 (s, 1H, pyridine CH), 7.27 (t, J
8.3 Hz,1H, Ph), 7.40 (d, J 8.4 Hz, 2H, Ph), 7.46 (t, J 8.4 Hz, 2H, Ph), 7.80
(t, J 8.4 Hz, 4H, Ph), 8.01 (s,1H, pyrazole CH), 8.88 (s,1H, pyridine NH);
dC (100 MHz, DMSO-d6) 14.9,18.1, 28.8, 50.1,101.9,118.0,125.7,125.9,
127.5, 128.5, 129.3, 129.9, 131.2, 137.1, 139.3, 145.3, 149.2, 167.3.
4.4.12. Diethyl 2,6-dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-1-
phenyl-1H-pyrazol-4-yl}-1,4-dihydropyridine-3,5-dicarboxylate
(4l). Yield (486 mg, 94%) as a pale yellow solid, mp 125e127 ꢀC;
[Found C, 67.25; H, 6.12; N, 8.15; S, 6.13. C29H31N3O4S requires C,
67.29; H, 6.04; N, 8.12; S, 6.19%]; m/z 517 (Mþ); nmax (KBr) 3327, 3017,
4.4.7. Dimethyl
pyrazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate
2,6-dimethyl-4-(3-[4-chlorophenyl]-1-phenyl-1H-
(4g). Yield
(443 mg, 93%) as a pale yellow solid, mp 149e150 ꢀC (lit. Mp
151e153 ꢀC24); [Found C, 65.12; H, 5.09; N, 8.84. C26H24ClN3O4 re-
quires C, 65.34; H, 5.06; N, 8.79%]; m/z 477 (Mþ); nmax (KBr) 3320,
2982,1669,1595,1302,1035 cmꢁ1
; dH (400 MHz, DMSO-d6) 0.93 (t, J
3013, 2972, 1693, 1596, 1305, 1032 cmꢁ1
;
dH (300 MHz, DMSO-d6)
8.4 Hz, 6H, CO2CH2Me), 2.23 (s, 6H, Me), 2.54 (s, 3H, SMe), 3.61e3.67
(m, 2H, CO2CH2Me), 3.86e3.87 (m, 2H, CO2CH2Me), 5.14 (s, 1H,
pyridine CH), 7.27 (t, J 8.4 Hz,1H, Ph), 7.37 (d, J 8.3 Hz, 2H, Ph), 7.46 (t, J
8.3 Hz, 2H, Ph), 7.80 (d, J 8.3 Hz,1H, Ph), 7.86 (d, J 8.3 Hz,1H, Ph), 8.00
(s, 1H, pyrazole CH), 8.81 (s, 1H, pyridine NH); dC (100 MHz, DMSO-
d6) 13.9, 15.0, 18.2, 28.9, 58.7, 102.3, 117.9, 125.8, 125.8, 127.4, 128.5,
129.3, 129.8, 131.2, 137.1, 139.3, 144.9, 149.0, 166.9.
2.24 (s, 6H, Me), 3.22 (s, 6H, CO2Me), 5.08 (s,1H, pyridine CH), 7.27 (t, J
8.0 Hz,1H, Ph), 7.45 (t, J 8.0 Hz, 2H, Ph), 7.56 (d, J 8.1 Hz, 2H, Ph), 7.83
(q, J 8.1 Hz, 4H, Ph), 8.04 (s, 1H, pyrazole CH), 8.88 (s, 1H, pyridine
NH); dC (75 MHz, DMSO-d6) 18.7, 29.3, 50.7,102.3,118.6,126.6,128.3,
128.6, 129.9, 130.2, 130.5, 132.6, 133.9, 139.8, 145.9, 148.9, 167.7.
4.4.8. Diethyl 2,6-dimethyl-4-(3-[4-chlorophenyl]-1-phenyl-1H-pyr-
azol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(4h). Yield
4.4.13. Dimethyl
2,6-dimethyl-4-{3-[2-nitrophenyl]-1-phenyl-1H-
(460 mg, 91%) as a pale yellow solid; mp 127e129 ꢀC (lit. Mp
128e130 ꢀC24); [Found C, 66.52; H, 5.51; N, 8.25. C28H28ClN3O4
requires C, 66.46; H, 5.58; N, 8.30%]; m/z 505 (Mþ); nmax (KBr) 3325,
pyrazol-4-yl}-1,4-dihydropyridine-3, 5-dicarboxylate (4m). Yield
(449 mg, 92%) as a yellow solid, mp 117e119 ꢀC; [Found C 63.84 H
4.98N11.33.C26H24N4O6 requires C,63.93;H, 4.95;N,11.47%];m/z488
3061, 2967, 1695, 1594, 1302, 1024 cmꢁ1
;
dH (300 MHz, DMSO-d6)
(Mþ); nmax (KBr) 3325, 3017, 1669, 1590, 1529, 1372, 1034 cmꢁ1
; dH
0.92 (t, J 7.0 Hz, 6H, CO2CH2Me), 2.23 (s, 6H, Me), 3.64 (q, J 7.1 Hz, 2H,
CO2CH2Me), 3.87 (q, J 7.0 Hz, 2H, CO2CH2Me), 5.11 (s, 1H, pyridine
CH), 7.28 (t, J 7.1 Hz,1H, Ph), 7.45 (t, J 8.0 Hz, 2H, Ph), 7.52 (d, J 8.0 Hz,
2H, Ph), 7.80 (d, J 8.0 Hz, 2H, Ph), 7.93 (d, J 8.0 Hz, 2H, Ph), 8.03 (s,1H,
pyrazole CH), 8.82 (s, 1H, pyridine NH); dC (75 MHz, DMSO-d6) 14.5,
18.8, 29.3, 59.4, 102.6, 118.6, 126.6, 128.3, 128.5, 129.9, 130.3, 130.5,
132.7, 133.8, 139.7, 145.7, 148.8, 167.4.
(400 MHz, DMSO-d6) 2.15 (s, 6H, Me), 3.52 (s, 6H, CO2Me), 5.16 (s,1H,
pyridine CH), 7.21e7.27 (m, 1H, Ph), 7.37e7.54 (m, 2H, Ph), 7.61 (t, J
7.6Hz,1H, Ph), 7.62e7.68(m, 2H, Ph), 7.68e7.78 (m,1H, Ph), 7.78e7.99
(m, 2H, Ph), 8.01 (s, 1H, pyrazole CH), 8.92 (s, 1H, pyridine NH); dC
(100 MHz, DMSO-d6) 19.4, 29.7, 50.9, 102.7, 118.8, 123.9, 126.2, 126.6,
127.5, 128.5, 129.2, 129.7, 131.8, 132.8, 139.7, 144.1, 147.1, 149.3, 167.6.
4.4.14. Dimethyl 2,6-dimethyl-4-(3-pyrazine-1-phenyl-1H-pyrazol-
4-yl)-1,4-dihydropyridine-3,5-dicarboxylate (4n). Yield (396 mg,
89%) as a pale yellow solid, mp 129e131 ꢀC; [Found C, 64.65; H,
5.26; N,15.76. C24H23N5O4 requires C, 64.71; H, 5.20; N,15.72%]; m/z
4.4.9. Dimethyl 2,6-dimethyl-4-(3-[4-chloro-3-nitrophenyl]-1-
phenyl-1H-pyrazol-4-yl)-1,4-dihydropyridine-3,5-dicarboxylate
(4i). Yield (465 mg, 89%) as a yellow solid, mp 189e191 ꢀC; [Found

R. Murugan et al. / Tetrahedron 68 (2012) 7196e7201
7201
445 (Mþ); nmax (KBr) 3321, 3014, 2945, 1671, 1559, 1311, 1032 cmꢁ1
;
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dH (400 MHz, DMSO-d6) 2.32 (s, 6H, Me), 3.36 (s, 6H, CO2Me), 5.58
(s, 1H, pyridine CH), 7.26e7.27 (m, 1H, Ph), 7.43 (t, J 7.6 Hz, 2H, Ph),
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The authors gratefully acknowledge the funding support of the
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