ZnO-nanoparticle-promoted synthesis of polyhydroquinoline derivatives via multicomponent Hantzsch reaction

Article abstract of DOI:10.1007/s00706-010-0252-1

Zinc oxide nanoparticles are used as an effective and reusable catalyst for one-pot, four-component couplings of aldehydes, dimedone, active methylene compounds, and ammonium acetate to produce polyhydroquinoline derivatives under solvent-free conditions at room temperature. Compared with other methods, satisfactory results are obtained with high yields, short reaction times, and simplicity in the experimental procedure. The catalyst could easily be recycled and reused four times without noticeable decrease in catalytic activity.

Full text of DOI:10.1007/s00706-010-0252-1

Monatsh Chem (2010) 141:317–322
DOI 10.1007/s00706-010-0252-1
ORIGINAL PAPER
ZnO-nanoparticle-promoted synthesis of polyhydroquinoline
derivatives via multicomponent Hantzsch reaction
•
M. Z. Kassaee Hassan Masrouri Farnaz Movahedi
•
Received: 9 July 2009 / Accepted: 7 January 2010 / Published online: 17 March 2010
Ó Springer-Verlag 2010
Abstract Zinc oxide nanoparticles are used as an effec-
tive and reusable catalyst for one-pot, four-component
couplings of aldehydes, dimedone, active methylene
compounds, and ammonium acetate to produce polyhy-
droquinoline derivatives under solvent-free conditions at
room temperature. Compared with other methods, satis-
factory results are obtained with high yields, short reaction
times, and simplicity in the experimental procedure. The
catalyst could easily be recycled and reused four times
without noticeable decrease in catalytic activity.
surface-to-volume ratio [5]. Also, since ZnO NPs are often
recovered easily by simple workups, which prevents con-
tamination of products, they may be considered as a
promising safe and reusable catalyst. Hence, the inexpen-
sive and highly efficient ZnO NPs are used in the synthesis
of b-phosphono malonates [6], Knoevenagel condensation
[7], Dakin–West reaction [8], degradation of acid red B
and rhodamine B [9], etc.
On the other hand, 1,4-dihydropyridines (1,4-DHPs), as
important ‘‘privileged scaffolds,’’ are very attractive tar-
gets for medicinal synthesis. A recent literature survey
revealed that 1,4-DHPs have several biological applica-
tions, including vasodilator, bronchodilator, geroprotective,
hepatoprotective, neuroprotective [10], chemosensitizer
behavior in tumor therapy [11], as well as cerebral anti-
ischemic activity in the treatment of Alzheimer’s disease.
They can cure the disordered heart rate as a chain-cutting
agent of factor IV channel and also possess calcium
channel agonist–antagonist modulation activities [12–16].
Cardiovascular agents such as nifedipine, nicardipine,
amlodipine, and other related derivatives are dihydropyr-
idyl compounds, which are effective for the treatment of
hypertension [17–19]. As valuable drug candidates, poly-
hydroquinolines not only have attracted the attention of
chemists for synthesis but also represent an interesting
research challenge. Experimentally, the preparation of the
1,4-DHPs was first reported by Hantzsch through a multi-
component, one-step cyclocondensation reaction. Due to
the modest yield of this method, numerous improvements
have since been developed, including the use of micro-
waves [20–22], ionic liquids [23, 24], grinding [25],
refluxing at high temperature [26–29], Bu4NHSO4 [30], L-
proline [31], HY-zeolite [32], silica-supported acids
[33, 34], boronic acids [35, 36], TMSCl–NaI [37], ceric
ammonium nitrate (CAN) [38, 39], metal triflates [40, 41],
Keywords ZnO nanoparticles ꢀ
Polyhydroquinoline derivatives ꢀ Heterogeneous catalyst ꢀ
Hantzsch reaction ꢀ Solvent-free
Introduction
Nanotechnology is of growing importance in many bran-
ches of research because of the opportunity for
miniaturization and the interesting properties associated
with small particle size [1]. In recent decades, nanostruc-
tured materials have attracted much attention for their
novel electronic, magnetic, optical, chemical, and
mechanical properties due to their unique characteristics
which are different from bulk materials [2–4]. One of the
interesting studies in this area is that of transition-metal
oxide nanoparticles. Specifically, zinc oxide nanoparticles
(ZnO NPs) have great potential for use as a catalyst for a
variety of organic and inorganic reactions due to their high
M. Z. Kassaee (&) ꢀ H. Masrouri ꢀ F. Movahedi
Department of Chemistry, Tarbiat Modares University,
P.O. Box 14155-4838, Tehran, Iran
e-mail: kassaeem@modares.ac.ir
123

318
M. Z. Kassaee et al.
O
O
O
R
O
O
R
R'
O
O
R'
R'
R'
CN
5
2
+
3
ZnO NPs (10 mol%)
Solvent free, rt
ZnO NPs (10 mol%)
Solvent free, rt
NH4OAc
R
CHO
N
H
N
H
NH2
1
4
6
Scheme 1
Fig. 1 X-ray diffraction pattern of the synthesized ZnO NPs
Fig. 3 Selected-area electron diffraction (SAED) pattern of ZnO NPs
ammonium acetate under solvent-free conditions at room
temperature (Scheme 1).
Results and discussion
We first prepared ZnO NPs through a solid-state reaction
method reported by Zhu and co-workers [45]. The X-ray
diffraction (XRD) patterns of the ZnO NPs (Fig. 1) could
be indexed to the hexagonal wurtzite structure (space
˚
˚
group: P63mc; a = 3.249 A, c = 5.206 A, JCPDS card no.
36-1451). No impurities were involved in the synthesized
ZnO NPs sample, for which an average size of 21 nm was
estimated by Scherrer’s equation, Dh,k,l = kk/b cosh, where
k is a constant (generally considered as 0.89 for ZnO), k is
the wavelength of Cu Ka (1.54 A), b is the corrected dif-
fraction line full-width at half-maximum (FWHM), and h is
Bragg’s angle [46] .
Fig. 2 TEM image of the synthesized ZnO NPs
baker’s yeast [42, 43], and p-TSA [44]. Nevertheless, many
of these methods still suffer from several drawbacks, such
as unsatisfactory yield, use of ecologically suspected
organic solvents, high temperature, long reaction time, as
well as the use of expensive and nonreusable catalysts.
Therefore, investigation for improved reaction conditions
for synthesis of polyhydroquinoline derivatives using effi-
cient and reusable catalysts under solvent-free conditions is
of prime importance.
˚
The morphology and grain size of the ZnO NPs were
investigated by Transmission electron microscopy (TEM)
(Fig. 2). They had spherical and hexagonal morphology
with a narrow size distribution from 18 to 36 nm and a
mean grain size of 21 nm, confirming the results calculated
from Scherrer’s equation. The presence of some larger
particles should be attributed to aggregating or overlapping
of smaller particles. The selected-area electron diffraction
In this report we employ ZnO NPs as an efficient and
heterogeneous catalyst for synthesis of polyhydroquinoline
derivatives through one-pot, four-component reactions of
aldehydes, dimedone, active methylene compounds, and
123

ZnO-nanoparticle-promoted synthesis
319
Table 1 Zinc oxide nanoparticles (ZnO NPs)-catalyzed four-component synthesis of polyhydroquinoline derivatives
Entry
R
R0
Product
Time (min)
Yield (%)a
M.p. (°C)
M.p. (°C) [Ref.]
1
Ph
OEt
OMe
OEt
OMe
OEt
OMe
OEt
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
CN
4a
4b
4c
4d
4e
4f
20
20
15
15
25
25
20
20
30
30
25
20
20
30
15
20
20
20
15
25
30
20
20
25
40
40
20
30
15
25
15
25
20
30
98
96
96
92
95
95
98
96
92
91
93
92
97
91
89
90
89
86
89
91
85
87
91
91
84
87
91
88
93
85
95
91
89
83
202–203
212–214
254–256
251–252
261–263
270–274
245–246
220–223
231–233
208–210
240–242
214–215
252–253
184–185
241–242
177–178
210–212
232–234
206–208
204–206
230–232
240–242
246–247
66–67
202–204 [40]
213–215 [25]
257–259 [40]
248–250 [25]
260–261 [40]
283–285 [25]
244–246 [39]
221–222 [25]
234–235 [38]
209–211 [25]
241–244 [40]
214–216 [39]
253–255 [40]
184–186 [40]
245–246 [25]
176–179 [31]
208–211 [31]
232–234 [40]
211–212 [39]
204–206 [39]
229–231 [40]
241–244 [25]
246–248 [40]
66–67 [40]
2
Ph
3
4-MeO–C6H4
4-MeO–C6H4
4-Me–C6H4
4-Me–C6H4
4-Cl–C6H4
4-Cl–C6H4
3-Cl–C6H4
2-Cl–C6H4
2,4-Cl2–C6H3
3,4-Cl2–C6H3
4-Br–C6H4
4-F–C6H4
4-NO2–C6H4
3-NO2–C6H4
2-NO2–C6H4
4-OH–C6H4
4-OH, 3-OMe–C6H3
C6H5–CH=CH
4-Me2N–C6H4
2-Thienyl
4
5
6
7
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4v
4w
4x
4y
4z
4aa
6a
6b
6c
6d
6e
6f
2-Furyl
3-Pyridyl
C2H5
145–146
145–147
272–273
148–151
287–289
125–127
285–286
173–175
286–288
133–134
145–146 [40]
144–146 [25]
275–277 [25]
150–155 [25]
289–293 [25]
122–125 [25]
287–288 [25]
174–176 [25]
294–295 [25]
135–137 [25]
n-C3H7
Ph
Ph
CO2Et
CN
4-MeO–C6H4
4-MeO–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-Me–C6H4
4-Me–C6H4
CO2Et
CN
CO2Et
CN
6g
6h
CO2Et
Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate (2 mmol), dimedone (2 mmol), ammonium acetate (2 mmol), and catalyst
(10 mol%) at room temperature under solvent-free conditions
a
Isolated yields
(SAED) pattern of ZnO NPs clearly shows the crystalline
nature of the product, indexed to (100) (002), (101), (102),
(110), and (103), respectively, for the diffraction rings, in
accordance with similar peaks in the XRD pattern (Fig. 3).
The prepared ZnO NPs were investigated as a catalyst in
the synthesis of polyhydroquinoline derivatives. For this
purpose, cyclocondensation of benzaldehyde, dimedone,
ethyl acetoacetate, and ammonium acetate was examined
in the presence of a catalytic amount of ZnO NPs
(10 mol%) under solvent-free conditions at room temper-
ature, which afforded ethyl 1,4,5,6,7,8-hexahydro-2,7,7-
trimethyl-5-oxo-4-phenylquinoline-3-carboxylate in 98%
yield. In order to observe the versatility of the procedure,
active methylene compounds including methyl acetoace-
tate and ethyl acetoacetate (b-ketoesters), malononitrile, as
well as ethyl cyanoacetate were taken in the same experi-
ment. Also, it was found that the reaction can tolerate a
wide range of aliphatic, heterocyclic, and aromatic alde-
hydes carrying either electron-donating or electron-
withdrawing substituents in the ortho, meta, and para
positions (Table 1). All products were characterized on the
basis of their spectroscopic data such as infrared (IR) and
123

320
M. Z. Kassaee et al.
1H and 13C nuclear magnetic resonance (NMR), as well as
physical data.
Table 2 Optimization of the ZnO-NPs-catalyzed model reaction for
synthesis of polyhydroquinoline derivatives
In comparison with the same reaction catalyzed by
commercially available bulk ZnO [47], use of ZnO NPs
reduced the reaction time by a factor of six, with higher
yields (Table 2, entries 11 and 14). To investigate the
effects of media, we carried out the condensation of
benzaldehyde, dimedone, ethyl acetoacetate, and ammo-
nium acetate in various organic solvents at room
temperature using 10 mol% ZnO NPs as the catalyst.
Obviously, the polar solvents such as ethanol and aceto-
nitrile (Table 2, entries 1 and 2) were much better than
nonpolar solvents (Table 2, entries 6 and 7). This could be
attributed to different solubility of ammonium acetate in
the solvents. Ultimately, solvent-free conditions were pre-
ferred due to high yields and short reaction times.
In evaluating the effects of catalyst concentration, the
best yields were found in the presence of just 10 mol%
ZnO NPs. A higher amount of catalyst (20 mol%) did not
improve the results to an appreciable extent (Table 2,
entry 15). We also carried out the model reaction without
any catalyst, but the product was isolated in poor yield
(21%), while the major product obtained was a dimedone
aldehyde adduct. Therefore, the catalyst plays a crucial role
in the success of the reaction in terms of rate and yields of
polyhydroquinoline derivatives.
Entry
Solvent
Catalyst
Time (min)
Yield (%)a
1
MeCN
EtOH
THF
ZnO NPs (10%)
ZnO NPs (10%)
ZnO NPs (10%)
ZnO NPs (10%)
ZnO NPs (10%)
ZnO NPs (10%)
ZnO NPs (10%)
No catalyst
180
60
73
84
62
71
60
37
46
21
53b
55
71
72
83
98
98
2
3
120
90
4
H2O
5
Acetone
Toluene
CH2Cl2
Neat
240
720
720
180
120
120
120
120
90
6
7
8
9
Neat
No catalyst
10
11
12
13
14
15
Neat
Bulk ZnO (5%)
Bulk ZnO (10%)
Bulk ZnO (20%)
ZnO NPs (5%)
ZnO NPs (10%)
ZnO NPs (20%)
Neat
Neat
Neat
Neat
20
Neat
20
Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate
(2 mmol), dimedone (2 mmol), ammonium acetate (2 mmol), and
catalyst
a
Isolated yields
b
Reaction carried out at 60 °C
The catalytic activity and the ability to recycle and reuse
ZnO NPs were studied in this system (Table 3). The cat-
alyst was separated by centrifuging the aqueous layer at
3,000 rpm at 20 °C for 3 min, and was reused as such for
subsequent experiments under similar reaction conditions.
The yields of 4a decreased only slightly with reuse of ZnO
NPs four times.
Table 3 Reusability of the ZnO NPs catalyst
Run
Yield (%)
Recovery of ZnO NPs (%)
1
2
3
4
98
97
97
95
99
99
98
96
A conceivable mechanism for the formation of the
product would be as follows. The ZnO NPs facilitate the
Knoevenagel-type coupling as well as enaminone forma-
tion through Lewis acid sites (Zn2?) coordinated to the
oxygen of carbonyl groups. On the other hand, ZnO NPs
can activate methylene compounds so that deprotonation of
the C–H bond occurs in the presence of Lewis basic sites
(O2-). As a result the formation of polyhydroquinoline
derivatives proceeds by activation of reactants through
both Lewis acid and basic sites of ZnO NPs.
Reaction conditions: benzaldehyde (2 mmol), ethyl acetoacetate
(2 mmol), dimedone (2 mmol), ammonium acetate (2 mmol), and
catalyst at room temperature under solvent-free conditions
Table 4 Comparison of catalytic activity of ZnO NPs with several
known catalysts
Entry Conditions
Yields (%) Ref.
1
2
3
4
5
6
7
8
CAN, EtOH, rt, 1 h
92
95
90
93
93
79
93
[38]
A comparison of the efficiency of catalytic activity of the
ZnO NPs with several previous methods is presented in
Table 4. The results show that this method is superior to some
of the earlier methods in terms of yield and reaction time.
L-Proline, solvent free, rt, 0.5 h
Yb(OTf)3, EtOH, rt, 5 h
Sc(OTf)3, EtOH, rt, 4 h
HY-Zeolite, CH3CN, rt, 2 h
Baker’s yeast, rt, 24 h
[31]
[40]
[41]
[32]
[43]
p-TSA, EtOH, rt, 2 h
[44]
Conclusion
ZnO NPs, Solvent free, rt, 20 min 98
This work
The present four-component, one-pot condensation for
synthesis of polyhydroquinolines by ZnO nanoparticles
Reaction conditions: benzaldehyde, ethyl acetoacetate, dimedone,
ammonium acetate, and catalyst
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ZnO-nanoparticle-promoted synthesis
321
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To a stirred mixture of an aldehyde (2 mmol), dimedone
(2 mmol), an active methylene compound (2 mmol), and
ammonium acetate (2 mmol) was added a catalytic amount
of ZnO NPs (10 mol%) under solvent-free conditions at
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