A comparative study of the catalytic activity of nanosized oxides in the one-pot synthesis of highly substituted dihydropyridines

Article abstract of DOI:10.1039/c4ra14557g

A four-component reaction of aromatic aldehydes, ethyl cyanoacetate, arylamines, and dimethyl acetylenedicarboxylate has been achieved in the presence of nanosized oxides (ZnO NPs, CuO NPs, CeO₂ NPs, SnO NPs, MgO NPs and CaO NPs) as highly effe

Full text of DOI:10.1039/c4ra14557g

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ARTICLE TYPE
A comparative study of the catalytic activity of nanosized oxides in the
one-pot synthesis of highly substituted dihydropyridines
Javad Safaei-Ghomi*, Elham Heidari-Baghbahadorani, Hossein Shahbazi-Alavi, Mehrnoosh
Asgari‑Kheirabadi
5
Department of Organic Chemistry, Faculty of Chemistry, University of Kashan, Kashan, P.O. Box 87317ꢀ51167, I. R.Iran
Corresponding author. Eꢀmail addresses: safaei@kashanu.ac.ir, Fax: +98ꢀ31ꢀ55912397; Tel.: +98ꢀ31ꢀ55912385
Received (in XXX, XXX) XthXXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
10
A fourꢀcomponent reaction of aromatic aldehydes, ethyl cyanoacetate, arylamines, and
dimethyl acetylenedicarboxylate has been achieved in the presence of nanosized oxides (ZnO
NPs, CuO NPs, CeO2 NPs, SnO NPs MgO NPs and CaO NPs) as highly effective
heterogeneous catalysts to produce of polysubstituted dihydropyridines. Extraordinarily, the
best results obtained in using CeO2 nanoparticles as an efficient catalyst. This method
provides several advantages including mild reaction condition, applicability to wide range of
substrates, reusability of the catalyst and little catalyst loading.
15
systems. Nanoparticles exhibit good catalytic activity due to their
large surface area and active sites which are mainly responsible
for their catalytic activity. Ideally, introducing neat processes and
utilizing ecoꢀfriendly and green catalysts which can be simply
50 recycled at the end of reactions has received significant attention
in recent years .11ꢀ14
1. Introduction
Dihydropyridines represent a common scaffold in numerous
bioactive compounds and have a number of pharmacological
20 properties. These compounds are used as calciumꢀchannelꢀ
modulating agents, treatment of cardiovascular disease,1 the high
MDRꢀmodulating activity,2 HIVꢀ1 protease inhibitors,3 and DNA
cutting activity.4 Compounds with this ring system like tacrineꢀ
dihydropyridines have been designed for the treatment of
25 Alzheimer’s disease.5 Some other examples of dihydropyridines
such prominent drug molecules as nimodipine, nisoldipine,
nitrendipine, amlodipine, nicardipine and nilvadipine utilize with
superior bioavailability and a slower onset and prolonged effect.
Dihydropyridines have been regarded as significant targets of
30 organic synthesis. Therefore, looking for efficient and simple
methods for the synthesis of dihydropyridines is an attractive
challenge. Synthesis of bioactive compounds should be facile,
flexible, rapid and useful in organic synthesis. Multiꢀcomponent
reactions (MCRs) are very flexible, atom economic in nature,
35 convergent, simple and are usually considered for the
development of environmentally benign synthetic methods. Thus,
the synthesis polysubstituted dihydropyridines by the
multicomponent reactions could enhance their efficiency from
economic and ecological points of view. MCRs enhance the
40 efficiency by combining several operational steps without
isolation of intermediates or changing the reaction conditions. 6ꢀ10
Similarly, nanoparticles have received considerable attraction
with the aim of finding significantly applications in organic
reactions. In heterogeneous catalysis, the surface and structural
45 understanding is important for the mechanism of the catalyst
Metal oxides represent a broad class of materials that have been
researched extensively because of their unique properties and
potential applications in diverse fields.15 During the last decade,
55 nanoparticle metal oxides have received significant attention
as efficient catalysts in many organic reactions due to their
high surfaceꢀtoꢀvolume ratio and coordination parts which
provide a larger number of active sites per unit area in
comparison with their heterogeneous counter sites.
60 Nanocrystalline zinc oxide is one of the broadly used surface
materials for many chemical transformations, such as
photoactivity and
flameꢀretardancy,16 semiconductor17 and
antibacterial materials.18 Tin and tin oxides are usually
considered as promising potential anode materials for
65 lithiumꢀion batteries due to their high theoretical reversible
capacities, natural abundance and low cost.19 Among the
heterogeneous basic catalysts, magnesium oxide is a versatile
material used as catalyst for several baseꢀcatalyzed organic
transformations. Magnesium oxide (MgO) as a highly effective
70 heterogeneous base catalyst used as an active catalyst in many
reactions including the synthesis of tetrahydrobenzopyran and
3,4ꢀdihydropyrano[c]chromenes20 and 2ꢀaminoꢀ4Hꢀpyrans and 2ꢀ
aminoꢀ5–oxoꢀ5,6,7,8–tetrahydroꢀ4Hꢀchromenes.21
Nanocrystalline copper (II) oxides have been used as an efficient
75 heterogeneous catalyst in various organic transformations such
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as: Cꢀarylation reactions,22 crossꢀcoupling reactions,23 and 55 CeO2 nanoparticles have been found to be 35 nm, 24 nm, 40 nm,
polyhydroquinoline.24 Recently, calcium oxide nanoparticles
were used as an active catalyst in many chemical transformations
including adsorption of Cr (VI) from aqueous solutions,25
transesterification of sunflower oil,26 and catalyzed synthesis of
18 nm, 28 nm, 11nm respectively.
Initially, we carried out the MCR between 4ꢀbromobenzaldehyde
ethyl cyanoacetateat, dimethyl acetylenedicarboxylate and aniline
highly substituted pyridines.27 CeO2 has received much attention 60 at room temperature as a model reaction in the presence of
5
because of its many attractive characteristics, such as unique UV
different catalyst. Meanwhile, we observed the effect of different
solvents on the progress of reaction. Ethanol was found to be
the best solvent, in which the product was obtained in 90%
yield. Unfortunately, when the model reaction was carried out
absorption ability,28 ferromagnetism properties
component of catalyst formulation for the dehydrogenation of
10 ethylbenzene to styrene.30 Recently, cerium nanoparticles were
used as
synthesis of cyclic ureas,31 polyhydroquinolines,
and key
29
a
suitable catalyst in many reactions including 65 in water, the desired product was only obtained in 33% yield.
32
and 1,4ꢀ
The model reaction was carried out in the presence of various
nanocatalysts such CaO, ZnO, CuO, MgO, SnO and CeO2
nanoparticles. When the reaction was carried out using CaO,
MgO and CeO2 nanoparticles as the catalyst, the product could be
disubstitutedꢀ1,2,3ꢀtriazoles.33 In the present research, CeO2
nanoparticles were fabricated by a simple coꢀprecipitation
15 method. Compared with other techniques, the coꢀprecipitation
method is a simple and attractive procedure for preparation of the 70 obtained in moderate to good yield of 65, 72 and 90%,
CeO2 nanoparticles. Herein, we report the use of CeO2
nanoparticles as an efficient catalyst for the preparation of 5ꢀ
respectively. Therefore, metal oxides show different yields due to
kind of metal oxides. The chemical nature and the existing form
of the catalyst play a vital importance for the reaction. From the
results, it is obvious that CeO2 nanoparticles is the best catalyst
ethyl
2,3ꢀdimethyl
6ꢀaminoꢀ1ꢀphenylꢀ1,4ꢀdihydroꢀ4ꢀphenyl
fourꢀcomponent
20 pyridineꢀ2,3,5ꢀtricarboxylate derivatives by
reaction of aromatic aldehydes, ethyl cyanoacetate, arylamines, 75 among those examined which were reported in Table 1. When 2,
and dimethyl acetylenedicarboxylate in ethanol at room
temperature (Scheme 1). Meanwhile, we compare the catalytic
activity of nanosized oxides (ZnO NPs, CuO NPs, SnO NPs MgO
25 NPs and CaO NPs) in the oneꢀpot synthesis of highly substituted
4 and 6 mol% of CeO2 nanoparticles were used; the yields were
85%, 90 % and 90 % respectively. Consequently, 4 mol% of
CeO2 NPs were expedient and excessive amount of CeO2
nanoparticles did not change the yields, significantly. Size of
dihydropyridines. The synthesis of 5ꢀethyl 2,3ꢀdimethyl 6ꢀ 80 prepared CeO2 nanoparticles has been found to be 11nm.
aminoꢀ1ꢀphenylꢀ1,4ꢀdihydroꢀ4ꢀphenylpyridineꢀ2,3,5ꢀ tricarboxyꢀ
late derivatives has been reported using MCRs in the presence
of catalysts including NaOH34, Et3N35 and KF/Al2O3.36
Perhaps, the increased surface area due to small particle size
increased reactivity. The active sites of CeO2 nanoparticles are
responsible for the accessibility of the substrate molecules on
the catalyst surface. Nanoparticle catalysts are highly active
85 since most of the particle surfaces can be available to catalysis
because chemical reactions take place mainly on the surface of
the particles. The chemistry of rare earth differs from main group
elements and transition metals due to the nature of the 4f orbitals,
which are ‘buried’ inside the atom and are shielded from the
90 atom’s environment by the 4d and 5p electrons. Thus, the CeO2
NPs may coordinate with the active groups further than other
catalysts in the present reaction. These orbitals give rare earth
inimitable catalytic, magnetic and electronic property.
30
<Scheme 1>
35 2. Results and discussion
In the beginning, we prepared nanosized oxides by simple
techniques. The particle size diameter (D) of the nanoparticles
has been calculated by the Debye–Scherrer equation (D =Kλ/β
cos θ), where β FWHM (fullꢀwidth at halfꢀmaximum or halfꢀ
40 width) is in radian and θ is the position of the maximum of the
diffraction peak. K is the soꢀcalled shape factor, which usually
takes a value of about 0.9, and λ is the Xꢀray wavelength
(1.5406Å for CuKα). Fig.1 shows the XRD spectra of
nanoparticles (see supplementary information). According to the
45 Debye–Scherrer equation, the average particle sizes of the asꢀ
synthesized nanoparticles were calculatedand the results show
that nanoparticles were obtained with an average diameter of 10ꢀ
50 nm as confirmed by XRD analysis. The pattern agrees well
with the reported pattern for nanosized oxides. In order to
50 investigate the morphology and particle size of nanoparticles,
SEM image of nanoparticles was presented in Fig.2 (see
supplementary information). The SEM image shows particles
with diameters in the range of nanometers. The results shown that
the average particles size of CaO, ZnO, CuO, MgO, SnO and
95 <Table1 >
We also investigated recycling of nanosized oxides as catalyst
under reflux conditions in ethanol. The results showed that CeO2
NPs can be reused several times without noticeable loss of
catalytic activity (Yields 90 to 89%) (Fig. 3). The extreme
100 stability of the CeO2 nanoparticles is mainspring of the
continuous and high catalytic activity. The morphology of CeO2
nanoparticle was
investigated
by
scanning
electron
microscopy (SEM) before use and after reuse of five times
with images shown in Fig. 4 (see supplementary information).
105 Interestingly, the shape and size of the nanoparticles remained
unchanged before and after reaction. We suppose that, this is also
the possible reason for the extreme stability of the CeO2
nanoparticles presented herein.
< Fig 3>
110 < Fig 4>
2
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A series of aromatic aldehydes and amines were investigated
(Table 2). The results were excellent in yields using aromatic
aldehydes, either bearing electronꢀwithdrawing substituents or
electronꢀdonating substituents.
3.3.Preparation of ZnO nanoparticles
1
5
All the products were well characterized by IR, H NMR and 13C
55 Zinc oxide nanoparticles were prepared according to the
38
NMR.
procedure reported by Shen et al. In a typical procedure,
zinc acetate (9.10 g, 0.05 mol) and oxalic acid (5.4 g, 0.06
mol) were combined by grinding in an agate mortar for 1 h
at room temperature. Afterwards, the formed ZnC2O4. 2H2O
60 nanoparticles were calcinated at 450 °C for 30 min to
produce ZnO nanoparticles under thermal decomposition
conditions. Crystallite size of ZnO has been found to be 24
nm.
<Table 2 >
A plausible mechanism for the preparation of highly substituted
10 dihydropyridines using CeO2 NPs is shown in Scheme 2. Firstly,
we assumed that the reaction occurs via a Knoevenagel
condensation between ethyl cyanoacetate and aldehyde, to form
the intermediate I1 on the active sites of CeO2 NPs, and make
aldehydes more electrophilic. Then, arylamine added to
15 acetylenedicarboxylate to give the intermediate I2. Michael
addition of I2 to I1 yielded the adduct I3. The migration of the
hydrogen atom will provide the intermediate I4 and subsequent
intramolecular addition of the amino group to the C≡N gave the
cyclic intermediate I5. In the end, the Nꢀaryl dihydropyridine was
20 formed by the tautomerization of the imino group to the amino
group. The role of CeO2 NPs probably would be activation of the
nitrile to transform into amine.
3.4. Preparation of CuO nanoparticles
65 Copper (II) oxide nanoparticles were prepared according to the
procedure reported by Jang et al.39 A solution of copper acetate
(1.0 g) and acetic acid (1.0 mL) in 250 mL of distilled water was
o
heated at 100 C. Then 0.8 g of NaOH was added quickly under
vigorous stirring. The reaction mixture being cooled to room
70 temperature and the obtained black powders were separated by
centrifugation. The collected precipitate then washed several
times with distilled water, ethanol and dried at 100oC for 10 h.
The results show that spherical CuO nanoparticles were obtained
with an average diameter of 40 nm as confirmed by XRD
75 analysis.
<Scheme 2 >
25
3. Experimental
3.5.Preparation of MgO nanoparticles
3.1. Chemicals and apparatus
We prepared Magnesium oxide nanoparticles (NPs) in this study
using ultrasound technique. A solution of 1 mol/L sodium
hydroxide was added dropꢀwise to a solution prepared from
80 dissolving 2 g of Mg (NO3)2.6H2O and 0.5 g polyvinyl pyrolydon
(PVP) as surfactant. Then the reaction mixture was sonicated for
30 min ultrasonic power 90W. The prepared gel was centrifuged
and washed several times with deionized water and ethanol, and
finally calcined in a furnace at 600 oC for 2 h. The crystallite size
85 diameter (D) of the MgO NPs has been calculated by Debye–
Scherrer equation (D = Kλ/βcosθ). The results show that
hexagonal MgO NPs40 were gained with an average diameter of
18 nm. Nano magnesium oxide has a network crystalline
structure contain of Lewis basic and Lewis acid. All these factors
90 cause that nano magnesium oxide employs as an efficient
catalyst.
The products were isolated and characterized by physical and
1
30 spectral data. H NMR and 13C NMR spectra were recorded on
Bruker Avanceꢀ400 MHz spectrometers in the presence of
tetramethylsilane as internal standard. The IR spectra were
recorded on FTꢀIR Magna 550 apparatus using with KBr plates.
Melting points were determined on Electro thermal 9200, and are
35 not corrected. The elemental analyses (C, H, N) were obtained
from a Carlo ERBA Model EA 1108 analyzer. Powder Xꢀray
diffraction (XRD) was carried out on a Philips diffractometer of
X’pert Company with monochromatized Cu Kα radiation (λ=
1.5406 Å). Microscopic morphology of products was visualized
40 by SEM (LEO 1455VP) and ((MIRA 3 TESCAN).
3.2. Preparation of CaO nanoparticles
3.6. Preparation of SnO nanoparticles
Calcium oxide nanoparticles were prepared in accordance with
the procedure reported by Tang et al.37 NaOH (1 g) was added to
45 a mixture of ethylene glycol (12 ml) and Ca (NO3)2. 4H2O (6 g)
and the solution stirred vigorously at room temperature for 10
min; the gel solution was kept about 5 h at static state.
Afterwards, it was washed using water and dried under vacuum
drying. Finally, the prepared CaO nanoparticles were calcinated
50 at 700 °C for 3 h. The sample is characterised by Xꢀray
diffraction (XRD) and scanning electron microscopy (SEM). The
average crystallite size of CaO has been found to be 35 nm.
Tin oxide nanoparticles were prepared according to the procedure
reported in the literature.41ꢀ42 A 100 ml aqueous solution of 10ꢀ2
95 M is prepared by dissolving 0.225 g of tin (II) chloride
(SnCl2.2H2O) in dilute HCl. The solution was continuously
stirred and diluted NH4OH was added dropꢀwise to obtain a
precipitate. The solution pH increased to 5. The precipitate was
washed several times to remove excess ions. The precipitate
100 dispersed in water kept under irradiation of microwave for 18
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min. The sample is characterised by Xꢀray diffraction (XRD) and
scanning electron microscopy (SEM). Size of prepared SnO 50 1-phenyl pyridine-2,3,5-tricarboxylate (5b)white solid; m.p.
5-ethyl 2,3-dimethyl 6-amino-4-(4-chlorophenyl)-1,4-dihydro-
nanoparticles in the presence of microwave was reduced until 28
nm.
129ꢀ130 oC; IR (KBr): νmax 3426, 3278, 2951, 1749, 1714, 1657,
1597, 1503cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.20 (t, J =
6.8Hz, 3H, CH3), 3.41 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 4.05
(q, J = 6.8Hz, 2H, CH2), 4.98 (s, 1H, CH), 6.24 (brs, 2H, NH2),
55 7.26 (m, 2H, ArH), 7.33ꢀ7.38 (m, 2H, ArH), 7.51 (m, 5H, ArH)
ppm; 13C NMR (100MHz, CDCl3) δ 169.4, 166.0, 163.9, 151.2,
145.6, 141.5, 135.2, 131.8, 130.5, 130.4, 129.9, 129.3, 128.2,
107.2, 79.8, 59.4, 52.4, 51.9, 36.6, 14.5 ppm; Anal.Calcd.For
C24H23ClN2O6: C, 61.21; H, 4.92; N, 5.95.Found C, 61.38; H,
60 4.85; N, 5.87.
5
3.7. Preparation of CeO2 nanoparticles
Nano CeO2was prepared according to the procedure reported
in the literatures with some modification.43 CeO2 nanoparticles
were prepared by a coꢀprecipitation technique with postꢀ
annealing in air. Briefly, 3 g of highly pure Ce(NO3)3.6H2O was
10 dissolved in the mixture of 50 ml deionised water and 20 ml
alcohol. Then, the appropriate amount of aqueous ammonia
solution (28 wt%) was added to the above solution till the pH
value reached 8. Where after, the mixture was stirred for 4 h at
room temperature and then dried at 80°C for 6 h. After, the solid
15 was treated at 700°C for 2 h to obtain the CeO2 nanoparticles. The
pattern agrees well with the reported pattern for CeO2
nanoparticles (JCPDS No. 43ꢀ1002). The crystalline size was
calculated from FWHM using Scherrer’s formula and was
observed to be 11 nm.
5-ethyl 2,3-dimethyl 6-amino-4-(4-chlorophenyl)-1,4-dihydro-
1-m-tolylpyridine-2,3,5-tricarboxylate (5c)white solid; m.p.
o
152ꢀ153 C; IR (KBr): νmax 3453, 3275, 2978, 2947, 1734, 1710,
1664, 1596, 1500cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J =
65 6.6Hz, 3H, CH3), 2.41 (s, 3H, CH3), 3.43 (s, 3H, OCH3), 3.63 (s,
3H, OCH3), 4.06 (q, J = 6.6Hz, 2H, CH2), 4.97 (s, 1H, CH), 6.25
(brs, 2H, NH2), 7.26ꢀ7.33 (m, 8H, ArH)ppm; 13C NMR
(100MHz, CDCl3) δ 169.4, 166.1, 163.8, 151.3, 145.7, 141.6,
140.2, 135.1, 131.8, 131.1, 130.9, 129.6, 129.3, 128.2, 127.3,
70 107.1, 79.2, 59.4, 52.4, 61.8, 36.7, 21.2, 14.4 ppm;
Anal.Calcd.For C25H25ClN2O6: C, 61.92; H, 5.20; N, 5.78.Found
C, 61.88; H, 5.16; N, 5.81.
20 3.8. General procedure for the preparation of 5-ethyl
2,3-dimethyl
6-amino-1-phenyl-1,4-dihydro-4-phenyl
pyridine-2,3,5-tricarboxylate derivatives:
5-ethyl
2,3-dimethyl
6-amino-1,4-dihydro-1,4-diphenyl
A mixture of aldehyde (2 mmol), ethyl cyanoacetate (2 mmol)
and 4 mol% of CeO2 NPs were stirred in 3 mL ethanol at room
25 temperature for 30 minutes. Then, a solution of dimethyl
acetylenedicarboxylate (2 mmol) and aromatic amine (2 mmol) in
2 mL ethanol was added to it. The whole solution was stirred at
room temperature within 140ꢀ160 minutes (Table 2). The reaction
was monitored by TLC. After completion of the reaction, the
30 solvent was concentrated and the reaction mixture was
diluted in CHCl3; the catalyst was isolated by centrifuging
and the heterogeneous catalyst was recovered. The CHCl3 was
evaporated and the solid separated out was filtered and was
washed with ethanol to get pure product. The structures of the
o
pyridine-2,3,5-tricarboxylate (5d)white solid; m.p. 136ꢀ140 C;
75 IR (KBr): νmax3378, 3269, 2955, 1744, 1713, 1656, 1595, 1492
1
cmꢀ1; H NMR (400 MHz, CDCl3) δ 1.21 (t, J= 6Hz, 3H, CH3),
3.43 (s, 3H, OCH3), 3.63 (s, 3H, OCH3), 4.06 (q, J = 6Hz, 2H,
CH2), 5.02 (s, 1H, CH), 6.23 (brs, 2H, NH2), 7.19 (m, 1H, ArH),
7.29(m, 3H, Ar), 7.42(m, 3H, ArH), 7.52(m, 3H, ArH) ppm; 13C
80 NMR (100MHz, CDCl3) δ 169.6, 166.3, 164.1, 151.3, 147.0,
141.4, 135.4, 130.5, 130.3, 129.8, 128.1, 127.8, 126.3, 107.7,
80.3, 59.4, 52.4, 51.8, 37.1, 14.4 ppm; Anal.Calcd.For
C24H24N2O6: C, 66.04; H, 5.54; N, 6.42.Found C, 66.12; H, 5.47;
N, 6.51.
35 products were fully established on the basis of their 1H NMR, 13
NMR and FTꢀIR spectra.
C
85 5-ethyl 2,3-dimethyl 6-amino-4-(4-bromophenyl)-1,4-dihydro-
1-phenylpyridine-2,3,5-tricarboxylate (5e) white solid; m.p.
138ꢀ141oC; IR (KBr): νmax 3490, 3292, 2951, 1739, 1712, 1662,
1602, 1497cmꢀ1; 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J=
6.8Hz, 3H, CH3), 3.41 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 4.08
90 (q, J = 6.8Hz, 2H, CH2), 4.98 (s, 1H, CH), 6.24 (brs, 2H, NH2),
7.29 (m , 2H, ArH), 7.41 (m, 4H, ArH), 7.51 (m, 3H, ArH) ppm;
13C NMR (100MHz, CDCl3) δ 169.4, 165.9, 163.9, 150.9, 145.9,
141.3, 136.7, 133.8, 131.9, 131.2, 130.3, 129.6, 120.2, 107.6,
80.2, 59.6, 52.6, 52.0, 36.7, 14.4 ppm; Anal.Calcd.For
95 C24H23BrN2O6: C, 55.93; H, 4.50; N, 5.44.Found C, 55.82; H,
4.41; N, 5.50.
3.9.Spectral data
5-ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-
4-phenyl pyridine-2,3,5-tricarboxylate (5a) white solid; m.p.
o
40 185ꢀ186 C; IR (KBr): νmax 3380, 3269, 2953, 1745, 1712, 1653,
1
1490 cmꢀ1; H NMR (400 MHz, CDCl3) δ 1.24 (t, J = 6Hz, 3H,
CH3), 3.48 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 4.10 (q, J= 6Hz,
2H, CH2,), 5.01 (s, 1H, CH), 6.17 (brs, 2H, NH2), 7.20 ( 1H,
ArH), 7.27 ( 5H, ArH), 7.47 ( 3H, ArH) ppm; 13C NMR
45 (100MHz, CDCl3) δ 169.5, 166.1, 164.0, 150.9, 146.7, 141.0,
136.4, 134.0, 131.9, 130.1, 128.1, 127.8, 126.4, 108.2, 80.6, 59.5,
52.6, 51.9, 37.0, 14.4 ppm; Anal.Calcd.For C24H23ClN2O6: C,
61.21; H, 4.92; N, 5.95.Found C, 61.39; H, 4.82; N, 5.85.
5-ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-
4-(4-methoxy phenyl)pyridine-2,3,5-tricarboxylate (5f) white
o
solid; m.p. 181ꢀ182 C; IR (KBr): νmax 3390, 3274, 2950, 1742,
100 1712, 1655, 1608, 1500 cmꢀ1; H NMR (400 MHz, CDCl3) δ
1
1.23 (t, J = 6.8Hz, 3H, CH3), 3.46 (s, 3H, OCH3), 3.63 (s, 3H,
4
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OCH3), 3.73 (s, 3H, OCH3), 4.07 (q, J = 6.8Hz, 2H, CH2), 4.94
(s, 1H, CH), 6.14 (brs, 2H, NH2), 6.83 (d, 2H, ArH), 7.25 (m,
polysubstituted dihydropyridines in the presence of CeO2
nanoparticles is reported. The procedure offers several
4H, ArH ), 7.45 (d, J=8 , 2H, ArH) ppm; 13C NMR (100MHz, 55 advantages including cleaner reaction profiles, use of easily
available, cheap, high yields, shorter reaction time and simple
experimental, reusability of the catalyst and little catalyst
loading.This green nanocatalyst could be used for other
significant organic reactions and transformations. Further
60 explorations of similar protocols are underway in our laboratory.
Meanwhile, this recoverable catalyst will provide a regular
platform for heterogeneous catalysis, green chemistry, and
environmentally benign protocols in the near future.
CDCl3) δ ppm; 169.5, 166.2, 164.0, 158.1, 150.8, 140.8, 139.2,
136.4, 134.0, 131.9, 130.1, 128.7, 113.5, 108.4, 80.8, 59.4, 55.2,
52.6, 51.9, 36.1, 14.4; Anal.Calcd.For C25H25ClN2O7: C, 59.94;
H, 5.03; N, 5.59.Found C, 59.83; H, 5.09; N, 5.49.
5
5-ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-
4-(3-nitrophenyl)pyridine-2,3,5-tricarboxylate
(5g)
light
10 yellow solid; m.p. 186ꢀ187 oC; IR (KBr): νmax 3437, 3223, 3108,
2987, 2954, 1751, 1710, 1663, 1603, 1524 cmꢀ1; H NMR (400
1
Acknowledgments
MHz, CDCl3) δ 1.25 (t, 3H, CH3), 3.49 (s, 3H, OCH3), 3.65 (s,
3H, OCH3), 4.09 (m, 2H, CH2), 5.11 (s, 1H, CH), 6.26 (brs, 2H,
NH2), 7.40 (d ,J = 7.5 Hz, 2H, ArH), 7.47 (td, J=8.4Hz, J= 2Hz,
15 1H, ArH), 7.51 (d, J=7.5 Hz, 2H, ArH), 7.72 (d, J=7.2Hz, 1H,
ArH), 8.06(d, J=7.5Hz, 1H, ArH), 8.32(1H, ArH) ppm; 13C NMR
(100MHz, CDCl3) δ 169.0, 165.6, 163.5, 151.2, 149.0, 148.3,
141.8, 136.8, 134.0, 133.4, 131.8, 130.3, 128.9, 122.9, 121.5,
107.0, 79.7, 59.7, 52.7, 52.1, 37.2, 14.4 ppm; Anal.Calcd.For
20 C24H22ClN3O8: C, 55.87; H, 4.30; N, 8.15.Found C, 55.83; H,
4.19; N, 8.26.
65 The authors acknowledge a reviewer who provided helpful
insights. The authors are grateful to University of Kashan for
supporting this work by Grant NO: 159196/XXI.
Electronic Supplementary Information (ESI) available: See
70 DOI: 10.1039/b000000x/
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5-ethyl 2,3-dimethyl 6-amino-1-(4-chlorophenyl)-1,4-dihydro-
4-p-tolylpyridine-2,3,5-tricarboxylate (5h) white solid; m.p.
191ꢀ192oC; IR (KBr): νmax 3389, 3274, 2950, 1742, 1712, 1654,
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25 1607, 1498 cmꢀ1; H NMR (400 MHz, CDCl3) δ 1.25 (t, J =
6.6Hz, 3H, CH3), 2.32 (s, 3H, CH3), 3.47 (s, 3H, OCH3), 3.64 (s,
3H, OCH3), 4.09 (q, J = 6.6Hz, 2H, CH2), 4.97 (s, 1H, CH), 6.16
(brs, 2H, NH2), 7.10 (d, J = 7.2Hz, 2H, ArH),7.28 (d, J = 7.2Hz,
2H, ArH), 7.33 (d, J = 7.8Hz, 2H, ArH), 7.47 (d, J = 7.8Hz, 2H,
30 ArH) ppm; 13C NMR (100MHz, CDCl3) δ 169.5, 166.2, 164.0,
150.9, 143.8, 140.9, 136.4, 135.8, 134.1, 131.9, 130.1, 128.9,
127.6, 108.4, 80.8, 59.5, 52.6, 51.9, 36.5, 21.1, 14.4 ppm;
Anal.Calcd.For C25H25ClN2O6: C, 61.92; H, 5.20; N, 5.78.Found
C, 61.81; H, 5.15; N, 5.82.
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2,3-dimethyl
6-amino-1,4-dihydro-4-(4-isopropyl
85 7. F. Yu, R. Huang, H. Ni, J. Fan, S. Yan, J. Lin,Green
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phenyl)-1-phenylpyridine-2,3,5-tricarboxylate (5i) white solid;
m.p. 142ꢀ144oC; IR (KBr): νmax 3391, 2956, 1747, 1709, 1657,
1597, 1495 cmꢀ1; H NMR (400 MHz, CDCl3) δ 1.26 (m, 3H,
1
8. Z. Xu, F. D. Moliner, A. P. Cappelli andC.
Hulme,Org.Lett., 2013, 15, 2738.
CH3), 1.30ꢀ1.58 (6H, CH3), 2.89 (m,1H, CH), 3.43 (s, 3H,
40 OCH3), 3.66 (s, 3H, OCH3), 4.10 (q, J = 6 Hz, 2H, CH2), 5.00
(s, 1H, CH), 6.25 (brs, 2H, NH2), 7.17(m, 2H,ArH), 7.28 (d, J=
6Hz, 2H, ArH), 7.33 (d, 2H, J=5.9Hz, ArH), 7.42(m, 1H,ArH),
7.51(m, 2H, ArH)ppm; 13C NMR (100MHz, CDCl3) δ 169.6,
166.3, 164.1, 151.3, 147.0, 141.4, 135.4, 130.5, 130.3, 129.8,
45 128.1, 127.8, 126.3, 107.7, 80.3, 59.4, 52.4, 51.8, 37.1, 33.6,
24.3, 14.4 ppm; Anal.Calcd.For C27H30N2O6: C, 67.77; H, 6.32;
N, 5.85.Found C, 67.81; H, 6.15; N, 5.79.
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In conclusion, we compare the catalytic activity of nanosized
50 oxides in the oneꢀpot synthesis of highly substituted
dihydropyridines. An efficient, environmentally benign, atom
economical and simple methodology for the preparation of
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6
|Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C4RA14557G
O
NH2
R'
CO2Me
CO2Me
MeO2C
MeO2C
CO2Et
NH2
CN
CeO2 NPs
+
+
+
R
CO2Et
EtOH, rt
N
1
2
3
4
5 a-i
Scheme 1.Synthesis of highly substituted dihydropyridines
7

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O
CN
CN
+
ArCH=C
CO2Et
Ar H
CO2Et
Ar
I1
EtO2C
CO2Me
CO2Me
CO2Me
C
N
+
Ar'NH2
Ar'H2N CO2Me
Ar'H2N CO2Me
O
OMe
I3
I2
Ar
Ar
EtO2C
H2N
CO2Me
CO2Me
EtO2C
HN
CO2Me
CO2Me
Ar
EtO2C
CO2Me
C
N
N
Ar'
N
Ar'
ArHN CO2Me
I5
I4
= CeO2 NPs
Scheme 2.Proposed Mechanism for the Four-Component Reaction
8
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Table1.Optimization of reaction conditions using different catalysts a
Entry
1
Catalyst (mol%)
none
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH3CN
H2O
Time (min)
24h
Yield % [Ref]
0
NaOH (10)
480
85 (ref. 34)
2
Et3N (30)
600
86 (ref 35)
65
3
CaO NPs (10)
ZnO NPs (10)
CuO NPs (15)
MgO NPs (6)
SnO NPs (8)
MgO NPs (6)
CeO2 NPs (4)
CeO2 NPs (4)
CeO2 NPs (4)
CeO2 NPs (2)
CeO2 NPs (4)
CeO2 NPs (6)
MgO NPs (4)
SnO NPs (4)
CuO NPs (4)
ZnO NPs (4)
CaO NPs (4)
250
4
275
59
5
250
52
6
210
72
7
250
54
8
220
63
9
290
33
10
11
12
13
14
15
16
17
18
19
20
DMF
180
60
CH3CN
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
160
75
160
85
140
90
137
90
140
61
140
38
140
35
140
40
140
47
a 4-bromobenzaldehyde (2 mmol), ethyl cyanoacetate (2 mmol), dimethyl acetylenedicarboxylate (2 mmol) and aniline (2 mmol),
bIsolated yield
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Table 2.Synthesis of 5-ethyl 2,3-dimethyl 6-amino-1-phenyl-1,4-dihydro-4-phenylpyridine-2,3,5-tricarboxylate
derivatives using CeO2NPsa
Entry
R
R´
Product
Time (min)
151
Yield (%)a
M.P ºC,
(ref)
5a-i
O
NH2
MeO2C
MeO2C
CO2Et
NH2
85
185ꢀ186
(ref.35)
N
1
5a
Cl
Cl
Cl
O
NH2
2
142
88
129ꢀ130
(ref. 35)
5b
MeO2C
MeO2C
CO2Et
NH2
N
Cl
Cl
O
NH2
NH2
NH2
3
4
5
146
143
140
84
87
90
152ꢀ153
(ref. 35)
5c
5d
5e
MeO2C
MeO2C
CO2Et
NH2
N
Cl
O
MeO2C
MeO2C
CO2Et
NH2
136ꢀ140
138ꢀ141
N
Br
O
MeO2C
MeO2C
CO2Et
NH2
N
Br
OCH3
NH2
Cl
O
181ꢀ182
(ref. 35)
MeO2C
MeO2C
CO2Et
NH2
6
153
81
5f
N
OCH3
Cl
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NO2
O
NH2
Cl
MeO2C
CO2Et
NH2
148
85
186ꢀ187
(ref. 35)
7
5g
N
MeO2C
NO2
Cl
O
NH2
191ꢀ192
(ref. 35)
MeO2C
MeO2C
CO2Et
NH2
8
150
84
5h
N
Cl
Cl
O
NH2
9
144
85
142ꢀ144
5i
MeO2C
MeO2C
CO2Et
NH2
N
a aromatic aldehydes (2 mmol), ethyl cyanoacetate (2 mmol), dimethyl acetylenedicarboxylate (2 mmol), aromatic amine (2 mmol)
b Isolated yield
11

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90
80
70
60
50
40
30
20
10
0
Run 1
Run 2
Run 3
Run 4
Run 5
Yield %
CaO
ZnO
CuO
MgO
SnO
CeO2
Nanoparticles
Figure 3.Recycling of nanosized oxides as catalyst
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Graphical abstract
A flexible and highly efficient protocol for the synthesis of highly substituted dihydropyridinesusing nano CeO2 has been
developed.
13