An eficient one-pot synthesis of 1,4-dihydropyridines catalyzed by magnetic nanocrystalline Fe3O4

Article abstract of DOI:10.1002/jhet.953

An efficient approach for one-pot three-component reaction of aromatic amines, α,β-unsaturated aldehydes and β-keto esters using magnetic nanocrystalline Fe₃O₄ as a catalyst has been described. The corresponding 1,4-dihydropyridines

Full text of DOI:10.1002/jhet.953

1126
An Eficient One‐Pot Synthesis of 1,4‐Dihydropyridines Catalyzed
Vol 49
by Magnetic Nanocrystalline Fe3O4
Shu‐Hong Yang, Fei‐Yang Zhao, Hong‐Yan Lü, Jia Deng,
*
and Zhan‐Hui Zhang
Key Laboratory of Inorganic Nanomaterial of Hebei Province, The College of Chemistry and Material
Science, Hebei Normal University, Shijiazhuang 050016, China
*
E-mail: Zhanhui@126.com
Received January 25, 2011
DOI 10.1002/jhet.953
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
An efficient approach for one‐pot three‐component reaction of aromatic amines, α,β‐unsaturated alde-
hydes and β‐keto esters using magnetic nanocrystalline Fe3O4 as a catalyst has been described. The
corresponding 1,4‐dihydropyridines are obtained in good yields under mild conditions. In addition, the cat-
alyst can be recovered with a magnet and reused at least five consecutive cycles without appreciable loss of
its catalytic activity.
J. Heterocyclic Chem., 49, 1126 (2012).
INTRODUCTION
In recent years, nanocrystalline metal oxides have
been increasing in importance because of their easy
preparation and widespread applications as thermal
insulators, humidity sensors, absorbents for gases, and
destruction of hazardous chemical [23]. As their surface
display both Lewis acid and Lewis base character [24],
possess high surface area and more coordination sites,
they are also considered as heterogenous catalysts
in various organic transformations [25,26]. In particu-
lar, the magnetic nanoparticles iron oxides have
attracted growing interest because of unusual properties
and potential applications in diverse fields such as mag-
netically assisted drug delivery, magnetic resonance
imaging contrast agents, hyperthermia, and magnetic
separation of biomolecules [27,28]. Additionally, the
magnetic property of such particles provides a conve-
nient method for quantitative recovery of the catalyst
by applying an external magnetic field [29–31].
Multicomponent, one‐pot reactions represent a highly
valuable synthetic tool for the construction of novel and
complex molecular structures with a minimum number
of synthetic steps [1–5]. 1,4‐Dihydropyridines (1,4‐DHPs)
and their derivatives are important compounds not only in
organic synthesis but also in medicinal chemistry. They
were found to exhibit a variety of pharmacological and
biological properties such as antitrypanosomal, anticancer,
antibacterial, antitubercular, antitubercular, antileishmanial
and antitrypanosomal, antihyperglycemic, antidyslipi-
demic, antiatherosclerotic, antioxidant, hepatoprotective,
antimutagenic, antidiabetic, geroprotective, and photosen-
sitizing activities [6–11] and HIV protease inhibition
[12]. They are well known as the most important calcium
channel modulators [13] and have emerged as one of the
most important classes of drug for the treatment of
hypertension [14]. Therefore, significant efforts to
prepare 1,4‐DHPs have been made in the past few years.
The classical method for the preparation of these
compounds is the Hantzsch reaction involving the con-
densation of β‐ketoester, aldehyde, and ammonia [15],
but some important type of derivatives, including N‐ary‐1,
4‐DHPs and 5‐ or 6‐unsubstitued 1,4‐DHPs cannot be
synthesized with this method. Until now, there have been
few reports on the synthesis of these unsymmetrical 1,
4‐DHPs [16–22]. Due to the importance of unsymmetrical
1,4‐DHPs from pharmaceutical, industrial, and synthetic
points of view, there still remains a high demand for the
development of an efficient, low‐cost, and eco‐friendly proto-
col to assemble these compounds.
As an extension to our previous work on the develop-
ment of new synthetic methods for important heterocyclic
compounds [32–38], herein, we report the use of Fe3O4
nanoparticles as a magnetically separable catalyst for the
synthesis of 1,4‐dihydropyridines by a one‐pot three‐
component coupling of aromatic amines, α,β‐unsaturated
aldehydes and β‐keto esters (Scheme 1).
RESULTS AND DISCUSSION
In the initial experiment, the condensation of cinnamal-
dehyde, aniline, and acetoacetate was chosen as the model
to examine the efficiency of different catalysts, reaction
© 2012 HeteroCorporation

September 2012
An Eficient One-Pot Synthesis of 1,4-Dihydropyridines Catalyzed by
1127
Magnetic Nanocrystalline Fe3O4
Scheme 1. Synthesis of 1,4‐dihydropyridines catalyzed by magnetic
nano‐Fe3O4.
Using these newly developed conditions, we explored
the scope and limitations of this method, and the results
are summarized in Table 2. Aromatic anilines with both
electron‐donating and electron‐withdrawing groups were
underwent condensation reaction with cinnamaldehyde
and β‐keto esters to give the corresponding 1,4‐dihydro-
pyridines in moderate to good yields. It is noteworthy to
mention that the nature of the substituents on the benzene
ring has shown a delicate effect on this conversion. The
presence of an electron‐withdrawing group on the benzene
ring decreased the reactivity and gave the products in lower
yields. However, aliphatic amines such as benzylamine
formed the mixtures of products containing the desired
compounds in low concentrations. 5,6‐Unsubstituted dihy-
dropyridines can be readily transformed into various com-
plex heterocyclic frameworks, because the presence of
C5 C6‐unsubstituted bond enables the use of these com-
pounds as enamine‐like reagents [20]. Therefore, the pres-
ent method provides a novel strategy for the preparation of
a diverse array of 5,6‐unsubstituted dihydropyridines.
The recyclability of the catalyst was also investigated
with a model reaction of cinnamaldehyde, aniline, and
acetoacetate. After each run, the catalyst was recovered
from reaction mixture using an external permanent magnet,
washed with ethyl acetate, dried under an infrared lamp,
and then used directly in the next run without further puri-
fication. It was shown that the catalyst could be recovered
and reused at least five times without significant loss of cat-
alytic activity.
media, and the amounts of catalyst. It was showed that
nearly no product could be detected, when the reaction
was carried out at room temperature in ethanol for 24 h
in the absence of catalysts (Table 1, entry 1), which indi-
cated that the catalysts should be absolutely necessary for
this transformation. As shown in Table 1, 11 nanocrystal-
line metal oxides such as MgO, CuO, In2O3, Al2O3,
Y2O3, α‐Fe2O3, γ‐Fe2O3, ZnO, ZrO2, TiO2, and Fe3O4
were test for this reaction. Nano‐Fe3O4 was found to
be the most effective catalyst for this transformation,
because it gave the highest yield of product (Table 1,
entry 12). The effect of solvent was also investigated,
and ethanol was found to be the best choice. Only trace
amounts of product were observed when the reaction was
run in water or in tetrahydrofuran. It was also found that
the use of 10 mmol % catalyst is sufficient to promote
the reaction.
Table 1
Optimization of the reaction conditions for the reaction of
cinnamaldehyde, aniline, and acetoacetate.a
Table 2
One‐pot three‐component synthesis of 1,4‐dihydropyridines.
Catalyst
amount
(mol %)
Time
(h)
Yield
(%)b
Time Yield
Entry Catalyst
Solvent
Entry R1 R2 R3
R4
Product (h) (%)a Ref.
1
2
3
4
5
6
7
8
No
CuO
MgO
In2O3
Al2O3
Y2O3
α‐Fe2O3
γ‐Fe2O3
ZnO
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
24
6
6
6
6
6
6
6
6
6
6
6
10
8
8
8
8
6
0
60
63
58
60
59
65
50
62
65
66
70
Trace
Trace
48
52
55
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
Me
H
H
H
H
H
OMe
H
Me
H
H
H
Me
H
CMe3
F
Br
H
Me
H
OMe
H
CMe3
H
Me
F
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
6
6
6
6
6
7
7
6
6
6
6
6
6
6
6
6
7
7
7
6
6
71 [22]
72 [17]
71 [17]
75 [17]
72
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
2
63 [17]
65
70 [20]
73 [20]
75 [17]
80 [20]
73 [17]
80
83 [17]
65 [16]
66 [20]
63 [20]
62 [20]
65 [20]
72 [20]
73 [20]
9
9
10
11
12
13
14
15
16
17
18
19
20
ZrO2
TiO2
10
11
12
13
14
15
16
17
18
19
20
21
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
Fe3O4
THF
Me Me
Me
H
H
H
H
H
H
CH3CN
CH2Cl2
AcOEt
EtOH
EtOH
EtOH
H
H
H
Cl
H
H
H
Cl
H
Br
H
H
48
51
68
5
20
6
6
CH(CH3)2
CH2CH═CH2 4u
4t
aConditions: cinnamaldehyde (1 mmol), aniline (1 mmol), acetoacetate
(1 mmol), solvent (5 mL), and room temperature.
bIsolated yields.
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1128
S.-H. Yang, F.-Y. Zhao, H.-Y. Lü, J. Deng, and Z.-H. Zhang
Vol 49
1‐(4‐tert‐Buty‐phenyl)‐2‐methyl‐4‐phenyl‐1,4‐dihydropyridine‐
3‐carboxylic acid ethyl ester (4m). This compound was obtained
as brownish semisolid; IR: 2996, 1683, 1635, 1616, 1560, 1425,
1120, 1068, 999 cm−1; 1H NMR (400 MHz, CDCl3): δ 1.14
(t, J = 7.2 Hz, 3H), 1.34 (s, 9H), 2.16 (s, 3H), 4.02 (q, J = 7.2
Hz, 2H), 4.68 (d, J = 5.6 Hz, 1H), 5.00 (dd, J = 7.6, 5.6 Hz, 1H),
6.16 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 7.16–7.20
(m, 1H), 7.28–7.36 (m, 4H), 7.41 (d, J = 8.4 Hz, 2H); Anal.
Calcd. for C25H29NO2: C, 79.96; H, 7.78; N, 3.73. Found: C,
80.08; H, 7.92; N, 3.57.
CONCLUSIONS
We have developed a simple, efficient, and general pro-
tocol for the straightforward synthesis of N‐aryl substituted
1,4‐dihydropyridines through three‐component coupling
reaction of aromatic amines, α,β‐unsaturated aldehyde,
and β‐keto esters. Furthermore, the catalyst can be readily
recovered with a permanent magnet and reused without
significant loss of catalytic activity. We expect that this
magnetic catalyst can be found application in many other
industrially important catalytic processes.
Isobutyl 2‐methyl‐1,4‐diphenyl‐1,4‐dihydropyridine‐3‐
carboxylate (4t). This compound was obtained as brownish
liquid; IR: 1960, 2871, 1693, 1595, 1568, 1382, 1353, 1338,
1
1276, 1218, 1110, 1072, 1029, 839 cm−1; H NMR (500 MHz,
CDCl3): δ 0.78 (d, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H),
1.77–1.85 (m,1H), 2.18 (s, 3H), 3.76 (d, J = 7.0 Hz, 2H), 4.69
(d, J = 5.5 Hz, 1H), 5.03 (dd, J = 7.5, 5.5 Hz, 1H), 6.13 (d,
J = 7.5 Hz, 1H), 7.16–7.21 (m, 3H), 7.29–7.36 (m, 5H), 7.42
(t, J = 7.5 Hz, 2H); Anal. Calcd. for C23H25NO2: C, 79.51; H,
7.25; N, 4.03. Found: C, 79.68; H, 7.03; N, 3.90.
Allyl 2‐methyl‐1,4‐diphenyl‐1,4‐dihydropyridine‐3‐carboxylate
(4u). This compound was obtained as yellow liquid; IR: 2931,
1693, 1595, 1566, 1452, 1382, 1355, 1315, 1276, 1218, 1110,
995, 700 cm−1; 1H NMR (500 MHz, CDCl3): δ 2.16 (s, 3H),
4.49–4.51 (m, 2H), 4.72 (d, J = 5.5 Hz, 1H), 4.50 (dd, J = 7.5,
5.5 Hz, 1H), 5.09–5.15 (m, 2H), 5.77–5.85 (m, 1H), 6.17 (d,
J = 7.5 Hz, 1H), 7.17–7.21 (m, 3H), 7.29–7.32 (m, 3H), 7.34–7.37
(m, 2H), 7.40–7.44 (m, 2H); Anal. Calcd. for C22H21NO2: C,
79.73; H, 6.39; N, 4.23. Found: C, 79.88; H, 6.55; N, 4.08.
EXPERIMENTAL
IR spectra were recorded with a Shimadzu FTIR‐8900 spec-
1
trometer using KBr plates. H NMR spectra were measured on
a Varian 400 or a Bruker DRX‐500 spectrometer using CDCl3
as solvent and tetramethylsilane (TMS) as the internal standard.
Elemental analyses were carried out on a Vario EL III CHNOS el-
emental analyzer. Commercially available reagents were used
without further purification. Magnetic Fe3O4 nanoparticles were
prepared and characterized according to the literature [39,40].
General Procedure for Synthesis of 1,4‐dihydropyridines
(4). A mixture of cinnamaldehyde (1 mmol), aniline (1 mmol),
acetoacetate (1 mmol), and nano‐Fe3O4 (0.023 g, 0.1 mmol) in
ethanol (5 mL) was stirred at room temperature for an appropriate
time (monitored by thin-layer chromatography (TLC)). After
completion of the reaction, the catalyst was removed with a permanent
magnet. The solvent was evaporated under reduced pressure, and the
resulting residue was purified by chromatography on silica gel
(hexane/ethyl acetate) to afford the corresponding pure product.
2‐Methyl‐1,4‐diphenyl‐1,4‐dihydropyridine‐3‐carboxylic
acid methyl ester (4a). This compound was obtained as brownish
semisolid; IR: 2947, 1636, 1616, 1436, 1272, 1224, 1120, 1068,
Acknowledgments. We are grateful to the National Natural
Science Foundation of China (20872025 and 21072042), Nature
Science Foundation of Hebei Province (B2011205031), and the
Undergraduate Scientific and Technological Innovation Project
of Hebei Normal University for support of this research.
1001, 952 cm−1; H NMR (400 MHz, CDCl3): δ 2.15 (s, 3H),
1
3.57 (s, 3H), 4.68 (d, J = 5.6 Hz, 1H), 5.02 (dd, J = 7.6, 5.6 Hz,
1H), 6.13 (d, J = 7.6 Hz, 1H), 7.16–7.20 (m, 3H), 7.30–7.36 (m,
5H), 7.39–7.43 (m, 2H); Anal. Calcd. for C20H19NO2: C, 78.66;
H, 6.27; N, 4.59. Found: C, 78.87; H, 6.42; N, 4.43.
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An Eficient One-Pot Synthesis of 1,4-Dihydropyridines Catalyzed by
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet