Cobalt nanoparticles promoted highly efficient one pot four-component synthesis of 1,4-dihydropyridines under solvent-free conditions

Article abstract of DOI:10.1016/S1872-2067(10)60295-1

A straightforward and general method has been developed for the synthesis of C5-unsubstitiuted 1,4-dihydropyridines by a reaction using dimedone, acetophenone, aromatic aldehydes, and ammonium acetate in the presence of a catalytic amount of Co nanopartic

Full text of DOI:10.1016/S1872-2067(10)60295-1

CHINESE JOURNAL OF CATALYSIS
Volume 32, Issue 12, 2011
Online English edition of the Chinese language journal
Cite this article as: Chin. J. Catal., 2011, 32: 1850–1855.
RESEARCH PAPER
Cobalt Nanoparticles Promoted Highly Efficient One Pot
Four-Component Synthesis of 1,4-Dihydropyridines under
Solvent-Free Conditions
Javad SAFARI1,*, Sayed Hossein BANITABA1, Shiva DEHGHAN KHALILI1,2
1Laboratory of Organic Chemistry Research, Department of Organic Chemistry, College of Chemistry, University of Kashan, Kashan,
87317-51167, Iran
2Islamic Azad University Najafabad Branch, Najafabad, 85141-43131, Iran
Abstract: A straightforward and general method has been developed for the synthesis of C5-unsubstitiuted 1,4-dihydropyridines by a re-
action using dimedone, acetophenone, aromatic aldehydes, and ammonium acetate in the presence of a catalytic amount of Co nanoparticles
as a heterogeneous and eco-friendly catalyst with high catalytic activity at room temperature under solvent-free conditions. This catalyst is
easily separated by magnetic devices and can be reused without any apparent loss of activity for the reaction. In addition, it is very inter-
esting that when using Co nanoparticles as a catalyst, spatially-hindered aldehydes such as 2-methoxy-, 2-fluoro-, and 2-chloro-aldehydes
are suitable for this reaction.
Key words: cobalt nanoparticle; 1,4-dihydropyridine; four-component condensation; heterogeneous catalyst; magnetically separable
catalyst
The efficiency of heterogeneous catalysis in organic syn-
thesis can be improved by nanosized catalysts because of their
extremely small size and their large surface to volume ratios
[1]. Homogeneous systems have the advantage of high cata-
lytic activity and selectivity, but the catalysts are difficult to
separate from the products. To improve catalyst separation
much effort has been devoted to organic reactions in hetero-
geneous mode [2,3]. Recently, it has been shown that Co
nanoparticles (Co NPs), as catalysts, offer great opportunities
for a wide range of applications in organic synthesis and in
chemical manufacturing processes [4–9]. Green chemistry
emphasizes the development of environmentally benign
chemical processes and technologies [10]. Besides typical
multi-step syntheses, an increasing number of organic chemi-
cal compounds are being produced by multicomponent reac-
tions (MCRs). MCRs often comply with the principles of green
chemistry in terms of the economy of steps as well as the many
stringent criteria of ideal organic synthesis. MCRs offer great
possibilities for molecular diversity per step with a minimum
synthesis time, labor, cost, and waste production. As a one-pot
reaction, MCRs generally afford good yields and are funda-
mentally different from two-component and stepwise reactions
in several ways [11] and they permit rapid access to combina-
torial libraries of complex organic molecules for an efficient
lead structure identification and for optimization in drug dis-
covery. 1,4-Dihydropyridines (1,4-DHPs) are an important
class of compounds in the field of drugs and pharmaceuticals
[12–16]. The DHP moiety is common to numerous bioactive
compounds and these include various antihypertensives such
as nifedipine, nicardipine and amlodipine, vasodilator, an-
timutagenic, antitumor, and antidiabetic agents [17–20]. These
examples clearly demonstrate the remarkable potential of
1,4-DHPs derivatives as a source of valuable drugs. Despite the
many methods available for the synthesis of dihydropyridine
derivatives [21–35], their widespread use has accentuated the
need to develop new synthetic routes for N-heterocycles con-
taining the dihydropyridine moiety. Recent protocols have
employed three-component condensations of dimedone, chal-
Received 14 June 2011. Accepted 12 October 2011
*Corresponding author. Tel: +98-361-591-2320; Fax: +98-361-591-2397; E-mail: Safari_jav@yahoo.com, Safari@kashanu.ac.ir
This work was supported by the University Grants Commission, University of Kashan.
Copyright © 2011, Dalian Institute of Chemical Physics, Chinese Academy of Sciences. Published by Elsevier BV. All rights reserved.
DOI: 10.1016/S1872-2067(10)60295-1

Javad SAFARI et al. / Chinese Journal of Catalysis, 2011, 32: 1850–1855
O
O
O
Ar
NH OAc/Cobalt nanoparticles
4
Ar CHO
+
+
solvent-free, r.t., 1ꢀ3 h
O
N
H
1
2(a-m)
3
4(a-m)
Scheme 1. Co NPs efficiently catalyzed synthesis of 1,4-DHPs.
cone derivatives, and ammonium acetate [36,37]. Synthetic
methods should be designed to use substances that have little or
no toxicity to human health and the environment. Therefore,
the possibility of performing multicomponent reactions under
solvent-free conditions with heterogeneous catalysts like Co
NPs as a magnetically separable catalyst can enhance their
efficiency from an economic as well as a green point of view.
Thus, the remarkable catalytic activity and easy synthesis,
operational simplicity, eco-friendliness, and recoverability of
Co NPs encouraged us to use it as a catalyst for the synthesis of
1,4-DHPs [38]. To the best of our knowledge there are no
examples of the use of Co NPs as catalysts for the
four-component synthesis of C5-unsubstitiuted 1,4-DHPs. In a
continuation of our effort to develop new and green chemistry
methods as well as our interest in applications of heterogene-
ous-catalyzed organic reactions [39] we explored the possibil-
ity of synthesizing pure metallic Co NPs and C5-unsubstitiuted
1,4-DHPs by a one-pot and four-component reaction under
solvent-free conditions using Co NPs as a recyclable and
magnetically separable catalyst at room temperature, as shown
in Scheme 1.
analytical X-ray spectroscope (EDS).
1.2 Catalyst preparation
A dark blue solution was formed after dissolving the cobalt
salt (CoCl2·6H2O or CoSO4·7H2O) in ethanol and then a mix-
ture of hydrazine hydrate (N2H4·H2O) and sodium hydroxide
(NaOH) was added to the dark blue solution at 200 °C. After
about 30 min, gray solid particles appeared and reacted quickly.
The suspended gray particles can be precipitated by placing a
magnet under the container. After reaction completion the gray
particles were washed with distilled water, ethanol, and abso-
lute ethanol to remove hydrazine, sodium, and chlorine ions.
The sample was then kept in absolute ethanol [40].
1.3 Synthesis of C5-unsubstitiuted 1,4-DHPs
Dimedone (1 mmol) and an aromatic aldehyde (1 mmol)
were added to a mixture of acetophenone (1 mmol), ammo-
nium acetate (1 mmol), and Co NPs (10 mol%). The mixture
was then stirred at room temperature. The reaction was com-
pleted within 1–2 h, as confirmed by TLC. The mixture was
then extracted with ethyl acetate and the organic layer was
dried over sodium sulphate and concentrated in a vacuum to
afford the crude products. The Co NPs were recovered using a
magnet and reused four times in the same reaction (Table 5).
4-(3,4-dimethoxyphenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-
tetrahydro-5(1H)-quinolinone (4g): mp 201–203 ºC; IR (KBr,
1 Experimental
1.1 General
All reagents were purchased from Merck and Aldrich and
used without further purification. Melting points were deter-
mined in open capillaries using an Electrothermal Mk3 appa-
ratus and are uncorrected. Infrared (IR) spectra were recorded
1
cm–1) 3341, 1674, 1729; H NMR (400 MHz, CDCl3): į 1.15
(s, 3H), 1.16 (s, 3H), 2.22–2.50 (m, 4H), 3.72 (s, 3H), 3.75 (s,
3H), 4.66 (d, J = 5.1 Hz, 1H), 5.22 (d, J = 5.1 Hz, 1H), 5.81 (s,
1H, NH), 6.82 (s, 1H), 7.0–7.30 (m, 5H), 7.34 (d, J = 8.1 Hz,
1H), 7.52 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): į
26.9, 29.3, 32.5, 36.5, 42.5, 50.3, 57.5, 57,8, 107.4, 107.9,
111.5, 121.2, 125.8, 126.7, 128.4, 128.9, 129.1, 129.8, 135.1,
135.7, 148.4, 151.4, 196.8; Anal. Calcd. for C25H27NO3: C,
77.09; H, 6.99; N, 3.60. Found: C, 76.98; H, 6.95; N, 3.58.
4-(3-Bromoyphenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-tetra-
hydro-5(1H)-quinolinone (4h): mp 224–227 ºC; IR (KBr, cm–1)
3340, 1668, 1733; 1H NMR (400 MHz, CDCl3): į 1.14 (s, 3H),
1.15 (s, 3H), 2.20–2.40 (m, 4H), 4.64 (d, J = 4.9 Hz, 1H), 5.27
(d, J = 4.9 Hz, 1H), 5.75 (s, 1H, NH), 7.0–7.30 (m, 5H), 7.32 (s,
1H), 7.38 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.69
(dd, J = 7.5 Hz, J = 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3):
1
using a Perkin-Elmer FT-IR 550 spectrometer. H NMR and
13C NMR spectra were recorded with a Bruker DRX-400
spectrometer at 400 and 100 MHz, respectively. NMR spectra
were obtained in CDCl3 solutions. Elemental analyses (C, H,
and N) were obtained using a Carlo ERBA Model EA 1108
analyzer and carried out on a Perkin-Elmer 240c analyzer.
X-ray diffraction (XRD) patterns were recorded on an X-ray
diffractometer (PAN analytical X'pert-pro) using a Cu KĮ
monochromatized radiation source and a Ni filter in a 2ș range
of 30°–90°. BET surface area analyses were performed at –196
°C using an automated gas adsorption analyzer (Tristar 3000,
Micromeritics). The composition and microstructure of the
specimens were analyzed using a scanning electron microscope
(SEM, JSM-5600LV) equipped with an energy-dispersion

Javad SAFARI et al. / Chinese Journal of Catalysis, 2011, 32: 1850–1855
į 26.8, 29.8, 33.1, 36.1, 41.2, 51.8, 106.9, 108.5, 110.4, 112.8,
1H), 5.62 (d, J = 4.4 Hz, 1H), 5.58 (s, 1H, NH), 7.06 (d, J = 8.1
Hz, 1H), 7.11 (dd, J = 7.9 Hz, J = 7.3 Hz, 1H), 7.14 (d, J = 7.3
Hz, 1H), 7.27 (dd, J = 8.1 Hz, J = 7.9 Hz, 1H), 7.36–7.50 (m,
5H); 13C NMR (100 MHz, CDCl3): į 27.4, 29.4, 32.7, 37.9,
41.9, 50.7, 57.4, 108.3, 110.6, 122.7, 125.3, 125.9, 126.4,
126.8, 127.3, 128.2, 131.6, 132.7, 138.3, 140.2, 197.9; Anal.
Calcd. for C24H25NO2: C, 80.19; H, 7.01, N, 3.90. Found: C,
80.07; H, 6.98; N, 3.86.
125.1, 127.3, 128.4, 129.4, 129.5, 130.4, 135.7, 136.4, 149.1,
156.2, 196.3; Anal. Calcd. for C23H22BrNO: C, 67.65; H, 5.43;
N, 3.43. Found: C, 67.49; H, 5.40; N, 3.39.
4-(3-chloroyphenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-tetra-
hydro-5(1H)-quinolinone (4i): mp 214–217 ºC; IR (KBr, cm–1)
3341, 1664, 1732; 1H NMR (400 MHz, CDCl3): į 1.16 (s, 3H),
1.17 (s, 3H), 2.22–2.45 (m, 4H), 4.55 (d, J = 4.8 Hz, 1H), 5.23
(d, J = 4.8 Hz, 1H), 5.72 (s, 1H, NH), 7.0–7.40 (m, 5H), 7.42 (s,
1H), 7.47 (d, J = 7.2 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.74 (dd,
J = 7.8 Hz, J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): į
26.1, 29.4, 33.7, 35.4, 42.5, 52.1, 107.5, 108.7, 111.1, 112.2,
125.5, 126.7, 128.8, 129.1, 130.5, 131.1, 134.1, 136.8, 150.8,
157.1, 197.4; Anal. Calcd. for C23H22ClNO: C, 75.92; H, 6.09;
N, 3.85. Found: C, 75.90; H, 5.35; N, 3.35.
2
Results and discussion
We had the opportunity to further explore the catalytic ac-
tivity of Co NPs for the synthesis of 1,4-DHPs. The crystallite
size of the Co NPs was determined by XRD and the results are
presented in Fig. 1(a). The XRD peaks were FCC (111), (200),
and (220) for the sample synthesized at 200 °C in an ethanol
hydrazine alkaline system and were assigned using JCPDS
15-806 for the cubic lattice. An examination of the sample by
SEM (Fig. 1(b)) reveals that the diameters of the nanoparticles
are less than 90 nm, which agrees with the size calculated from
the XRD pattern using the Scherrer equation.
4-(4-bromophenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-tetra-
hydro-5(1H)-quinolinone (4j): mp 217–220 ºC; IR (KBr, cm–1)
3344, 1679, 1731; 1H NMR (400 MHz, CDCl3): į 1.11 (s, 3H),
1.13 (s, 3H), 2.20–2.50 (m, 4H), 4.74 (d, J = 4.7 Hz, 1H), 5.34
(d, J = 4.7 Hz, 1H), 5.79 (s, 1H, NH), 7.0–7.25 (m, 5H), 7.36
(d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H); 13C NMR (100
MHz, CDCl3): į 27.4, 29.4, 32.7, 37.9, 41.9, 50.7, 107.1, 108.3,
125.2, 126.1, 127.9, 128.3, 128.7, 128.8, 134.2, 135.8, 147.7,
151.0, 195.5; Anal. Calcd. for C23H22BrNO: C, 67.65; H, 5.43;
N, 3.43. Found: C, 67.49; H, 5.40; N, 3.39.
The lattice parameter of the prepared Co NPs was 0.204 nm,
which is in good agreement with JCPDS 15-806. The crystal-
lite sizes were 83.2, 78.8, and 77.4 nm, respectively, calculated
on the (111), (200), and (220) diffraction maxima from the
half-width of the diffraction peak using Scherrer formula.
In addition the surface area was found to be approximately
4-(2-fluorophenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-tetra-
hydro-5(1H)-quinolinone (4k): mp 198–200 ºC; IR (KBr, cm–1)
3337, 1672, 1750; 1H NMR (400 MHz, CDCl3): į 1.08 (s, 3H),
1.12 (s, 3H), 2.25–2.57 (m, 4H), 4.68 (d, J = 4.8 Hz, 1H), 5.29
(d, J = 4.8 Hz, 1H), 5.67 (s, 1H, NH), 6.95 (dd, J = 9.2 Hz, J =
8.4 Hz, 1H), 7.21 (dd, J = 7.6 Hz, J = 7.2 Hz, 1H), 7.32 (d, J =
7.6 Hz, 1H), 7.42 (dd, J = 8.4 Hz, J = 7.2 Hz, 1H), 7.6–7.90 (m,
5H); 13C NMR (100 MHz, CDCl3): į 27.4, 29.4, 32.7, 37.9,
41.9, 50.7 (d, J = 9.2 Hz), 107.1, 108.3, 116.7 (d, J = 21.4 Hz),
125.2, 126.1, 127.9, 127.9 (d, J = 21.7 Hz), 128.3, 129.7 (d, J =
7.9 Hz), 128.8, 134.2, 135.8, 147.7, 161.0 (d, J = 249 Hz),
195.5; Anal. Calcd. for C23H22FNO: C, 69.51; H, 6.38; N, 4.03.
Found: C, 69.46; H, 5.38; N, 3.35.
(a)
(111)
(220)
(200)
30
40
50
60
70
80
4-(4-fluorophenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-tetra-
hydro-5(1H)-quinolinone (4l): mp 210–213 ºC; IR (KBr, cm–1)
3339, 1676, 1735; 1H NMR (400 MHz, CDCl3): į 1.15 (s, 3H),
1.17 (s, 3H), 2.29–2.40 (m, 4H), 4.56 (d, J = 5.1 Hz, 1H), 5.02
(d, J = 5.1 Hz, 1H), 6.13 (s, 1H, NH), 6.80 (dd, J = 8.9 Hz, J =
7.4 Hz, 2H), 7.31 (dd, J = 8.9 Hz, J = 4.2 Hz, 2H), 7.6–8.55 (m,
5H); 13C NMR (100 MHz, CDCl3): į 26.8, 29.9, 32.2, 36.2,
42.4, 49.9, 107.4, 108.8, 123.2 (d, J = 22 Hz), 126.1, 127.9,
128.3 (d, J = 8 Hz), 129.7, 138.8, 139.2, 140.8, 150.6, 163.5 (d,
J = 244 Hz), 194.5; Anal. Calcd. for C23H22FNO: C, 69.51; H,
6.38; N, 4.03. Found: C, 69.46; H, 5.38; N, 3.35.
2T/(o )
(b)
4-(2-methoxyphenyl)-7,7-dimethyl-2-phenyl-4,6,7,8-tetra-
hydro-5(1H)-quinolinone (4m): mp 196–199 ºC; IR (KBr,
1
cm–1) 3343, 1666, 1745; H NMR (400 MHz, CDCl3): į 1.13
Fig. 1. XRD pattern (a) and SEM image (b) of the prepared Co NPs in
an ethanol hydrazine alkaline system.
(s, 3H), 1.19 (s, 3H), 2.21–2.40 (m, 4H), 4.67 (d, J = 4.4 Hz,

Javad SAFARI et al. / Chinese Journal of Catalysis, 2011, 32: 1850–1855
Table 1 Optimizing the reaction conditions
Table 2 Solvent screening for the reaction between dimedone, benzal-
dehyde, acetophenone, and ammonium acetate
Entry
Co NPs (mol%)
Time (h)
6.0
Isolated yield (%)
1
2
3
4
5
6
7
8
0
2
30
35
45
60
75
98
50
90
Entry
Solvent
EtOH
Time (h)
6.0
Isolated yield (%)
3.0
1
2
3
4
5
6
60
50
4
3.0
MeOH
6.0
6
3.0
acetonitrile
dichloromethane
water
6.0
30
8
3.0
24.0
6.0
trace
80
10
10a
12
1.0
6.0
none
1.0
98
3.0
Reaction conditions: Co NPs (10% mol), dimedone:benzaldehyde:ac-
etophenone:ammonium acetate = 1:1:1:1.
Reaction conditions: dimedone:benzaldehyde:acetophenone: ammonium
acetate = 1:1:1:1. aUsing commercial cobalt powder.
We then continued to optimize the model process mentioned
above by determining the efficiency of several classic solvents
that were chosen as a medium for comparison. In each case, the
substrates were mixed with 10 mol% Co NPs and agitated with
3–5 ml of solvent. Among the tested solvents such as methanol,
ethanol, acetonitrile, dichloromethane, water, and a sol-
vent-free system, the formation of product 4a was found to be
more facile and proceeded to give the highest yield only under
solvent-free reaction conditions (Table 2).
95 cm3/g. The pore volume and pore size were also calculated
from the N2 adsorption result. The pore size was found to be
approximately 46.17 nm and the pore volume approximately
1.55 cm3/g. The theoretical particle size was also calculated
from the surface area, assuming spherical particles, from the
equation DBET = 6000/(ȡ × S), where DBET is the equivalent
particle diameter in nm, ȡ is the density of the material in g/cm,
and S is the specific surface area in m2/g. The particle size
calculated from the equation was 87.93 nm, which confirmed
the nanostructure of the Co NPs sample. The difference be-
tween the particle morphology and the size distribution that
was obtained at different temperatures and at different Co2+
concentrations can be explained by the reaction rate of nu-
cleation [40].
A possible explanation for the higher yield under sol-
vent-free conditions is that the eutectic mixture has a uniform
distribution of reactants and the reacting species are in closer
proximity for the reaction compared with that in a solvent. The
environment of the reaction system in the absence of a solvent
is different from that in solution resulting in a higher concen-
tration of local reaction sites and an improved global effi-
ciency. To further expand the scope of this method the re-
placement of Co NPs by commercial cobalt powder was ex-
amined. We carried out a reaction between dimedone (1),
benzaldehyde (2a), acetophenone (3), and ammonium acetate
using the commercial cobalt powder (10 mol%) under sol-
vent-free conditions at room temperature. When the reaction
was carried out using the commercial cobalt powder, 50% of
product 4a was obtained in 6 h. The catalytic activity of the Co
Subsequent efforts focused on optimizing the concentration
of the catalyst Co NPs and we investigated the model reaction
between dimedone, benzaldehyde, acetophenone, and ammo-
nium acetate at different concentrations of Co NPs such as 2
mol%, 4 mol%, 6 mol%, 8 mol%, 10 mol%, and 12 mol%.
Products were obtained in 35%, 45%, 60%, 75%, 98%, and
90% yields, respectively. This indicates that 10 mol% of Co
NPs produced the best results with respect to the product yield
(Table 1).
Table 3 Co NPs catalyzed unsymmetrical one-pot four-component synthesis of 1,4-DHPs
Melting point (oC)
Product
Ar
Time (h)
Isolated yield (%)
Found
Reported
4a
4b
4c
4d
4e
4f
C6H5
1.0
1.5
2.5, 6.0a
98
90
80, 45a
203–205
222–224
206–208
211–213
184–186
190–192
201–203
224–227
214–216
217–220
198–201
210–213
196–199
206–208 [36]
4-ClC6H4
224–226 [36]
2,4-Cl2C6H3
4-NO2C6H4
4-CH3C6H4
4-MeOC6H4
3,4-MeOC6H3
3-BrC6H4
204–206 [36]
1.5
90
212–214 [37]
1.0
95
186–188 [37]
1.0
92
192–194 [37]
4g
4h
4i
1.5
88
—
—
—
—
—
—
—
1.5
94
3-ClC6H4
1.5
92
4j
4-BrC6H4
1.5
2.0, 6.0a
92
75, 40a
4k
4l
2-FC6H4
4-FC6H4
1.0
3.0, 6.0a
95
65, 30a
4m
2-MeOC6H4
Reaction conditions: Co NPs (10% mol), dimedone:benzaldehyde:acetophenone:ammonium acetate = 1:1:1:1.
aUsing commercial cobalt powder.

Javad SAFARI et al. / Chinese Journal of Catalysis, 2011, 32: 1850–1855
Table 4 Co NPs catalyzed unsymmetrical one-pot four-component synthesis of 1,4-DHPs with different ȕ-keto compounds
O
O
Ar
O
O
O
R
NH4OAc/Cobalt nanoparticles
solvent-free, r.t. 1-2 h
O
+
Ar-CHO +
R
O
O
N
H
1
3 R = Me, Et
2
5(a-f)
Melting point (ÛC)
Product
R
Ar
C6H5
Time (h)
1.0
Isolated yield (%)
95
Found
Reported
5a
5b
5c
5d
5e
5f
Et
Et
203–204
207–210
259–261
237–239
258–260
234–237
216–218
221–222
283–285
258–260
285–287
202–203 [28]
208–210 [28]
260–261 [28]
238–240 [28]
257–259 [28]
235–236 [28]
216–217 [29]
222–223 [29]
>280 [31]
2-ClC6H4
4-MeC6H4
2-thienyl
2.0
1.5
1.0
1.5
1.0
1.5
1.0
1.2
1.0
2.0
85
90
92
93
90
90
95
88
90
85
Et
Et
Et
4-OMeC6H4
3-BrC6H4
2-thienyl
Et
5g
5h
5i
Me
Me
Me
Me
Me
4-ClC6H4
4-MeC6H4
C6H5
5j
260–261 [35]
>270 [30]
5k
3,4,5-OMeC6H2
Reaction conditions: Co NPs (10% mol), dimedone:benzaldehyde:ȕ-ketoesters:ammonium acetate = 1:1:1:1.
NPs was evident when only 30% and 50% product was ob-
tained in the absence of the catalyst and when using the com-
mercial cobalt powder, respectively (Table 1, entries 1 and 7).
The high efficiency of the metal nanoparticles is caused by
their high surface area and also by the high concentration of
low-coordinated sites and structural defects on their surface. As
the particle size is scaled down to a few nanometers, the con-
stituent atoms have highly defective coordination environ-
ments. These properties of the Co NPs gave spatially-hindered
aldehydes such as 2-methoxy-, 2-fluoro-, and 2-chloro-alde-
hydes, which function well in this reaction (Table 3). The Co
NPs also act as a mild Lewis acid and catalyze the
four-component, one-pot synthesis of C5-unsubstitiuted
1,4-DHPs.
lines in excellent yields, we used ȕ-ketoesters to show the
validity of this methodology. We thus carried out
a
four-component coupling reaction among dimedone, some
aromatic aldehydes, alkyl acetoacetate, and ammonium acetate
under the same reaction conditions.
The structural variation of the ȕ-ketoesters did not obviously
affect this conversion because the desired products were ob-
tained in high yields and in relatively short reaction time (Table
4).
We examined the recovery and reuse of the catalyst. The
catalyst was recovered using magnetic decantation and reused
in four consecutive runs without any apparent loss of activity
for the same reaction. The yield of the product in the second,
third, and fourth runs was almost the same as that in the first
run, as shown in Table 5.
An investigation into the reaction scope revealed that vari-
ous aromatic aldehydes (bearing electron-withdrawing and
electron-donating groups) can be used in this protocol (Table
3). The nature of the substituent on the aromatic ring had no
obvious effect on this conversion because high yields were
obtained over relatively short reaction times. The structures of
the isolated products 4a–4m were determined by IR, 1H NMR
and 13C NMR spectroscopy, and elemental analysis.
Figure 2 shows EDAX patterns of the fresh and the 2nd re-
cycle nanoparticles. Interestingly, the total composition of
cobalt was found in the resultant sample. However, EDAX
results show that the catalyst consists mainly of cobalt (98%),
Co
After successfully synthesizing a series of polyhydroquino-
Co
Co
O
Table 5 Reuse of Co NPs in the synthesis of 1,4-DHPs
(2)
(1)
Run
Isolated yield (%)
Fresh
98
97
97
95
94
1
2
3
4
0
2
4
6
8
Energy (keV)
Reaction conditions: Co NPs (10% mol), dimedone:benzaldehyde:aceto-
phenone:ammonium acetate = 1:1:1:1.
Fig. 2. EDAX patterns of fresh (1) and 2nd recycle (2) Co NPs.

Javad SAFARI et al. / Chinese Journal of Catalysis, 2011, 32: 1850–1855
11 Kalinski C, Lemoine H, Schmidt J, Burdack C, Kolb J, Um-
and a small amount of oxygen is also present while no other
elements were found using EDAX. The oxygen detected by
EDAX might come from oxides such as CoO or Co3O4, as a
result of the oxidation of cobalt during the reaction and after
treatment.
kehrer M, Ross G. Synlett, 2008: 4007
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3 Conclusions
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A four-component reaction between dimedone, aromatic
aldehydes, acetophenone, and ammonium acetate is shown to
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a simple synthetic route to C5-unsubstitiuted
1,4-dihydropyridines using Co nanoparticles. We demonstrate
for the first time that Co, in the form of nanoparticles, is a
potential alternative to noble-metal-based catalysts for the
unsymmetrical Hantzsch condensation. The mildness of the
conversion, experimental simplicity, compatibility with vari-
ous functional groups, excellent yields, shorter reaction time,
and easy work-up make this procedure attractive for the syn-
thesis of a variety of these derivatives. Because this heteroge-
neous catalyst can be simply removed using an external mag-
netic device, it also enhances product purity and is economic.
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Acknowledgments
We gratefully acknowledge financial assistance from the
University Grants Commission, University of Kashan.
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