Res Chem Intermed (2015) 41:5931–5940

DOI 10.1007/s11164-014-1712-8

Cu-doped ZnO nanocrystalline powder as a catalyst

for green and convenient multi-component synthesis
of 1,4-dihydropyridine

Heshmatollah Alinezhad • Sahar Mohseni Tavakkoli

Received: 15 April 2014 / Accepted: 8 May 2014 / Published online: 9 July 2014
Ó Springer Science+Business Media Dordrecht 2014

Abstract A simple, efficient, and convenient one-step method for synthesis of

Hantzsch 1,4-dihydropyridine, using Cu-doped ZnO nanocrystalline powder as a
catalyst is reported. The method offers several advantages including excellent
yields, green solvent, easy work-up, simplicity in operation and catalyst reusability.

Keywords Cu-doped ZnO nanocrystalline powder
Multi-component

1,4-Dihydropyridines
Hantzsch

Introduction

Multicomponent reactions (MCRs) are those reactions in which three or more

reactants come together in a single reaction vessel to form a new product that
contains portions of all the components [1]. The use of water as a solvent for organic
transformations offers several ‘‘green chemistry’’ benefits because of its low cost
and lack of inflammability, explosive, and carcinogenic properties [2].
In recent years, gigantesque attention has been paid to the synthesis of 1,4-
dihydropyridine (1,4-DHPs) owing to their important biological activity [3]. 1,4-
DHPs-containing drugs, such as nifedipine, nicardipine, amlodipine, felodipine, and
others have been found to be useful as calcium channel blockers [4–6], and are used
as cardiovascular agents for the treatment of hypertension [7].
A variety of methods have emerged to achieve the synthesis of this dihydro-
pyridine nucleus. Therefore, several alternate and more efficient methods have been
developed for the synthesis of 1,4-DHP derivatives by using microwaves, ionic
liquids, reflux at high temperature, TMSI, I2, Yb(OTf)3, CAN [8], silica gel/
NaHSO4 [9] and Sc(OTf)3 [10].

H. Alinezhad (&)
S. Mohseni Tavakkoli

Faculty of Chemistry, University of Mazandaran, PO Box 47415, Babolsar, Iran
e-mail: alinezhad_n@yahoo.com; heshmat@umz.ac.ir

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5932 H. Alinezhad, S. Mohseni Tavakkoli

Nanocrystalline materials have attracted immense attention due to their unique

properties and large potential application in nano-device manufacturing [11–14].
ZnO is thought to be one of the most important oxide materials owing to its unique
features and wide range of technologically significant applications. Furthermore,
ZnO is inexpensive and environmentally friendly as compared to other metal oxides
[15].
Properties of ZnO can be keyed according to the research advertency, by doping
with various metals to plea specific needs and applications. There are a large
number of reports on transition metal-doped ZnO systems, but very less work is
done on Cu-doped ZnO. Cu is an important metallic doping element because (1) it is
a noticeable luminescence activator that can modify the luminescence of ZnO
crystals by creating localized impurity levels [16], (2) it has many physical and
chemical properties similar to Zn, and (3) it can alter the microstructure and optical
properties of ZnO [17].
Now, we wish to report an efficient and simple synthesis of the 1,4-DHPs
derivatives in the presence of a catalytic amount of Cu-doped ZnO nanocrystalline
powder that catalyze the reaction using benzaldehydes, ethyl acetoacetate, or acetyl
acetone and ammonium acetate (Scheme 1).

Experimental

Materials and methods

All materials were purchased from Merck. The reactions were monitored by TLC
using silica gel plates and the products were purified by flash column chromatog-
raphy on silica gel (Merck, 230–400 mesh) and were identified by comparison of
their spectra (1HNMR and 13CNMR) and physical data with those of the authentic
samples. 1H NMR and 13C NMR spectra were recorded with Bruker DRX500
AVANCE (400-MHz) spectrometers using CDCl3 as a solvent. The morphology
and elemental composition were characterized by a digital microscopy imaging
scanning equipment VEGA 3 SB (TESCAN Co., s.r.o., Brno, Czech Republic) and

CHO R1

O O Cu doped ZnO nanocrystalline

powder R2OC COR2
NH4OAc
R2 H2O , reflux
R1 N
H
1
R = H, Cl, CH3, ...
R2 = OEt, CH3

Scheme 1 Synthesis of the 1,4-dihydropyridines derivatives in the presence of a catalytic amount of Cu-
doped ZnO nanocrystalline powder

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Cu-doped ZnO nanocrystalline powder 5933

an energy-dispersive X-ray spectrometer (EDS) attached to the SEM instrument

with the operating voltage of 15 kV.

Synthesis of Cu-doped ZnO nanocrystalline powder

Synthesis of Zn1-x Cux O (1 % Cu-doped) nano powder were carried out using the
same technique followed by Alinezhad et al. [18] with some modifications after
optimization of reaction conditions. The targets in the experiment were specifically
designed using high-purity zinc nitrate hexahydrate (99.99 %) and copper sulfate
pentahydrate (99 %) powders. The copper-doped ZnO catalyst was prepared by a
two-step procedure: (1) preparation of precursor by co precipitation method; (2)
formation of Cu/ZnO nanopowder by thermal decomposition. The method is
considered to be fast, simple, and inexpensive, allowing for the production of fine,
homogeneous crystalline powders without the risk of contamination.
The stoichiometric quantities of zinc and copper salts were dissolved in 100 ml
of deionized double-distilled water (solution A). Separately, a solution was prepared
by dissolving appropriate amounts of sodium hydroxide and sodium carbonate in
deionized double-distilled water (solution B). Solution A was heated to 85 °C and
solution B was mixed drop-wise into this solution with constant stirring. During the
whole process, temperature was maintained at 85 °C. This mixing was done for 1 h
while refluxing through water condenser at 85 °C. The final solution was allowed to
cool at room temperature and the greenish precipitate that formed was washed three
times with 20 ml of de-ionized water in order to remove unnecessary impurities and
then dried overnight at 50 °C under a vacuum. Finally, the precursors were calcined
at a temperature of 450 °C for 90 min in the muffle furnace under air atmosphere to
obtain the nanocrystalline Cu/ZnO powder.
Figure 1 shows a scanning electron micrograph of the nanocrystalline Zn1-x Cux
O sample. In order to confirm the presence of Cu in the synthesized ZnO
nanoparticles, the compositional analysis and purity of the as-synthesized nanocat-
alyst was obtained using EDS. Figure 2 shows the representative EDX spectra of
nanocrystalline sample where the estimated amount of Cu dopant was nearly 1 %.
From the similarity of the Zn and Cu peak intensity line traces, it is clear that after
the synthesis process, zinc and copper were homogenously distributed inside the
nanoparticle.

General experimental procedure for 1,4-DHPs formation catalyzed by Cu-doped

ZnO nanocrystalline powder

A mixture of benzaldehyde (1 mmol), ethyl acetoacetate or acetyl acetone

(2 mmol), ammonium acetate (1 mmol), and 10 mol% of Cu-doped ZnO
nanocrystalline powder was refluxed in water (5 ml). The reaction process was
monitored by TLC (n-Hexane: EtOAc, 1:1). Upon completion of the transformation,
the reaction mixture was cooled to room temperature and extracted with CH2Cl2
(3 9 5 ml). The organic layer was washed with brine and water and dried over
Na2SO4. After evaporation of the solvent, the crude yellow products were purified

123
5934 H. Alinezhad, S. Mohseni Tavakkoli

Fig. 1 SEM photo of 1 % Cu-

doped ZnO nanocrystalline
powder

Fig. 2 Representative EDX spectra of 1 % Cu-doped nanocatalyst sample

by crystallization from ethanol to afford 1,4-DHP derivatives in high to excellent

yields.

Results and discussion

At first, to optimize the reaction condition, we studied the reaction of benzaldehyde

(1 mmol), ethyl acetoacetate or acetyl acetone (2 mmol) and ammonium acetate
(1 mmol) as model compounds in the presence of Cu-doped ZnO nanocrystalline

123
Cu-doped ZnO nanocrystalline powder 5935

Table 1 Optimization of the reaction conditions

Entry Solvent Time (h) Yield (%)a

1 Ethanol 5 90
2 H2 O 1.5 97
3 CH2Cl2 4 5
4 Ethanol/H2O(1:1) 4 85
5 – 2 40

Reactions were carried out with benzaldehyde, ethyl acetoacetate, and ammonium acetate in 1:2:1 molar
ratio in the presence of 10 mol% Cu-doped ZnO nanocrystalline powder under reflux conditions
a
Yields refer to isolated pure products

Table 2 Effect catalyst amount on the synthesis of 1,4-DHPs

Entry Catalyst (mol%) Time (h) Yield (%)a

1 5 1.5 75
2 10 1.5 97
3 15 1.5 97

Reactions were carried out with benzaldehyde, ethyl acetoacetate, and ammonium acetate in 1:2:1 molar
ratio under reflux conditions
a
Yields refer to isolated pure products

powder (10 mol%) as a catalyst in H2O (5 ml). We evaluated the effect of different
solvents ethanol/H2O (1:1), ethanol (96 %), H2O, dichloromethane, and solvent-free
conditions, on the reaction rate. Protic solvents like H2O afforded the product in
higher yield and shorter reaction time (Table 1).
We next investigated the other amounts of Cu-doped ZnO nanocrystalline
powder (5 and 15 mol%) for this reaction. The optimum yield of the 1,4-DHPs was
obtained when 10 mol% of Cu-doped ZnO nanocrystalline powder was used
(Table 2).
Therefore, in an optimized reaction condition, benzaldehydes (1 mmol), ethyl
acetoacetate or acetyl acetone (2 mmol), and ammonium acetate (1 mmol) in
aqueous media at reflux condition were mixed with Cu-doped ZnO nanocrystalline
powder (10 mol%). The results are summarized in Table 3.
As shown in Table 3, when the electron-withdrawing substituents are present in
benzaldehyde, the reaction rate increases (2–6, 12, 15), whereas the effect is the
reverse in the case of benzaldehyde with strong electron-donating substituents such
as –OMe and –OH, of course with lower yields (entries 8, 9, 13, and 14).
A tentative mechanism for the synthesis of 1,4-DHPs catalyzed by Cu-doped
ZnO nanocrystalline powder is proposed. From a mechanistic point of view, the first
step of this reaction can be visualized as the nano doped-catalyzed formation of
Knoevenagel product I. A second key intermediate is ester enamine II, produced by

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5936 H. Alinezhad, S. Mohseni Tavakkoli

Table 3 Synthesis of 1,4-DHPs using Cu-doped ZnO nanocrystalline powder (10 mol%) as a catalyst
Entry R1 R2 Producta Time Yields M.p. °C (l) References
(h) (%)b

1 H –OEt 1.5 97 156–158 (158–160) [19]

EtOOC COOEt

N
H

Cl
2 4-Cl –OEt 0.5 98 145–147 (147–148) [19]

EtOOC COOEt

N
H

3 4-Br –OEt Br
0.5 97 146–148 (148–150) [20]

EtOOC COOEt

N
H

4 2-Cl –OEt 0.7 95 216–217 (216–218) [23]

Cl

EtOOC COOEt

N
H

5 3-Cl –OEt Cl
0.5 96 140–142 (141–143) [22]

EtOOC COOEt

N
H

NO2
6 4-NO2 –OEt 0.7 95 129–131 (130–132) [19]

EtOOC COOEt

N
H

7 4-Me –OEt CH3

1.5 93 136–138 (135–137) [21]

EtOOC COOEt

N
H

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Cu-doped ZnO nanocrystalline powder 5937

Table 3 continued
Entry R1 R2 Producta Time Yields M.p. °C (l) References
(h) (%)b

8 4-OMe –OEt OMe

1.75 92 158–160 (161–163) [19]

EtOOC COOEt

N
H

9 4-OH –OEt OH
1.75 95 240–242 (240–242) [23]

EtOOC COOEt

N
H

10 4-N(Me)2 –OEt N(Me)2

1.75 93 202–203 (203) [25]

EtOOC COOEt

N
H

11 H –Me 1.5 95 184–186 (184–186) [24]

MeOC COMe

N
H

NO2
12 4-NO2 –Me 0.7 94 202–205 (202–205) [24]

MeOC COMe

N
H

13 4-OMe –Me OMe

1.75 90 176–179 (176–179) [26]

MeOC COMe

N
H

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5938 H. Alinezhad, S. Mohseni Tavakkoli

Table 3 continued
Entry R1 R2 Producta Time Yields M.p. °C (l) References
(h) (%)b

OH
14 4-OH –Me 1.75 92 215–218 (215–218) [26]

MeOC COMe

N
H

Cl
15 4-Cl –Me 0.5 97 151–154 (151–154) [26]

MeOC COMe

N
H

16 4-Me –Me Me
1.5 93 176–178 (172–173) [27]

MeOC COMe

N
H

Reactions were carried out with benzaldehyde, ethyl acetoacetate, or acetyl acetone and ammonium
acetate in 1:2:1 molar ratio in the presence of 10 mol% Cu-doped ZnO nanocrystalline powder in H2O
under reflux condition
a
Products were characterized with 1H, 13
C-NMR, mp
b
Yields refer to isolated pure products

condensation of the second equivalent of the b-ketoester with ammonia. Conden-

sation of these two fragments gives intermediate III, which subsequently cyclizes to
the 1,4-DHP (Scheme 2).

Conclusions

We have developed a new catalytic method for the synthesis of 1,4-DHPs using Cu-
doped ZnO nanocrystalline powder as a catalyst in water under reflux condition.
The simple experimental work-up procedure and catalyst preparation, excellent
product yields, use of a green solvent, and a catalytic amount of Cu-doped ZnO
nanocrystalline powder are notable advantages of this method.

Acknowledgments Financial support from the Research Council of University of Mazandran is

gratefully acknowledged.

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Cu-doped ZnO nanocrystalline powder 5939

NH4OAc NH3 + AcOH

O
O O O
O OH
H3C
OEt
Ar H Nano doped H3C OEt
Ar H - H 2O
Ar H

I
O
O O
NH3
OEt
H3C OEt - H 2O
H2N CH3
II

O O O O Ar O
O Ar O

H3C OEt OEt R R Cyclisation

R R
Ar H H3C CH3 dehydration
H3N CH3 O HN H3C N CH3
H

I II III

Scheme 2 The proposed mechanism of synthesis of 1,4-DHPs using Cu-doped ZnO nanocrystalline
powder (nano doped)

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