Efficient one-pot synthesis of polyhydroquinoline derivatives using silica sulfuric acid as a heterogeneous and reusable catalyst under conventional heating and energy-saving microwave irradiation

Article abstract of DOI:10.1080/00397910802513060

An efficient Hantzsch four-component condensation reaction for the synthesis of polyhydroquinoline derivatives was reported under two conditions: solvent-free conventional heating and energy-saving microwave irradiation. The process is simple and environm

Full text of DOI:10.1080/00397910802513060

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Efficient One-Pot Synthesis of
Polyhydroquinoline Derivatives
Using Silica Sulfuric Acid as a
Heterogeneous and Reusable
Catalyst Under Conventional
Heating and Energy-Saving
Microwave Irradiation
a
a
Akbar Mobinikhaledi , Naser Foroughifar
,
a
a
Mohammad Ali Bodaghi Fard , Hassan Moghanian
,
a
a
Sattar Ebrahimi & Mehdi Kalhor
a
Department of Chemistry, Faculty of Sciences,
Arak University, Arak, Iran
Version of record first published: 04 Mar 2009.
To cite this article: Akbar Mobinikhaledi , Naser Foroughifar , Mohammad Ali
Bodaghi Fard , Hassan Moghanian , Sattar Ebrahimi & Mehdi Kalhor (2009): Efficient
One-Pot Synthesis of Polyhydroquinoline Derivatives Using Silica Sulfuric Acid as a
Heterogeneous and Reusable Catalyst Under Conventional Heating and Energy-Saving
Microwave Irradiation, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 39:7, 1166-1174
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1
Synthetic Communications , 39: 1166–1174, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802513060
Efficient One-Pot Synthesis of Polyhydroquinoline
Derivatives Using Silica Sulfuric Acid as a
Heterogeneous and Reusable Catalyst Under
Conventional Heating and Energy-Saving
Microwave Irradiation
Akbar Mobinikhaledi, Naser Foroughifar, Mohammad Ali Bodaghi
Fard, Hassan Moghanian, Sattar Ebrahimi, and Mehdi Kalhor
Department of Chemistry, Faculty of Sciences, Arak University,
Arak, Iran
Abstract: An efficient Hantzsch four-component condensation reaction for the
synthesis of polyhydroquinoline derivatives was reported under two conditions:
solvent-free conventional heating and energy-saving microwave irradiation. The
process is simple and environmentally benign, and the use of a heterogeneous
and reusable catalyst, high yields, and short reaction times are the key features
of this protocol.
Keywords: Heterogeneous, polyhydroquinoline, silica sulfuric acid
INTRODUCTION
In recent years, much attention has been focused on the synthesis of
1
activities.
,4-dihydropyridyl compounds because of their significant biological
1,2]
[
Cardiovascular agents such as nifedipine, nicardipine, and
other related derivatives are dihydropyridyl compounds, which are
[
effective in the treatment of hypertention. They are also common
3]
Received September 13, 2008.
Address correspondence to Akbar Mobinikhaledi, Department of Chemistry,
Faculty of Sciences, Arak University, Arak 38156-879, Iran. E-mail:
akbar_mobini@yahoo.com
1
166

One-Pot Synthesis of Polyhydroquinoline
1167
features of various bioactive compounds such as vasodilator, bronchodi-
lator, antiatherosclerotic, antitumor, geroprotective, hepatoprotective,
[4–7]
and antidiabetic agents.
Numerous methods have been reported for
the synthesis of polyhydroquinoline (PHQ) derivatives, because of biolo-
gical importance associated with these compounds. The classical method
involves a three-component coupling of an aldehyde, ethylacetoacetate,
[
8,9]
and ammonia in acetic acid or in refluxing ethanol.
However, these
methods suffer from several disadvantages such as long reaction times,
use of volatile and excess organic solvents, low product yields, and harsh
reaction conditions. Thus, chemists have developed several efficient
methods for the synthesis of PHQ derivatives, which includes the use
[
10,11]
[12–14]
[15]
of ionic liquids,
[17]
microwave irradiation,
[18]
TMSCl,
poly-
[
16]
[19]
mers, I , HClO ꢀ SiO , ceric ammonium nitrate (CAN), metal
2
20]
4
2
[
[21]
triflates,
and heteropolyacid.
However, the use of high tempera-
tures, expensive metal precursors, and environmentally harmful catalysts
limit the use of these methods. Thus development of a simple and efficient
method for preparation of PHQ derivatives is an active research area,
and there is a scope for further improvement involving milder and less
hazardous reaction conditions. In recent years, the preparation of silica
[
22]
sulfuric acid (SSA) as a heterogeneous stable acidic reagent
some of its catalytic activities in synthetic methodology have been
and
[
23–29]
reported.
Because of the unique catalyst features of SSA, we investigated the
use of SSA for the synthesis of PHQ derivatives (Fig. 1).
RESULTS AND DISCUSSION
We optimized the conditions by examining the reaction involving
p-chlorobenzaldehyde, ethylacetoacetate, dimedone, and ammonium
acetate to afford the appropriate PHQ (4c). A summary of the obtained
results is provided in Table 1. Entry 5 describes the yields of three con-
secutive condensations leading to PHQ (4c, Table 2) and refers to the
Figure 1. Synthesis of polyhydroquinoline derivatives with the promotion of SSA.

1168
A. Mobinikhaledi et al.
Table 1. Optimization of reaction conditions
a
Entry
Solvent
Catalyst
Yield (%)
1
2
3
4
5
6
CH Cl
SSA
SSA
SSA
SSA
SSA
None
35
67
73
39
91,93,90
43
2
3
2
CH
CN
2 5
C H OH
Toluene
b
d
None
None
c
a
Refluxed for 6 h.
ꢁ
b
6
0 C for 40 min.
ꢁ
c
1
00 C for 3 h.
d
Isolated yield after three consecutive runs.
reusability of SSA. Entry 6 shows the catalytic effect of SSA in this
ꢁ
reaction. The reactions proceeded efficiently and smoothly at 60 C
(oil bath) and were completed within 30 min–2 h. Table 2 shows the
generality of the present protocol, which is equally effective for aro-
matic, aliphatic, unsaturated, and heterocyclic aldehydes. Moreover,
the experimental procedure is very simple, and there was no undesirable
side product.
Recently Bose and coworkers have developed an energy-efficient
protocol for a solvent-free reaction that is mildly exothermic but not
spontaneous. They found that many of these reactions require a short
burst of energy for the initiation of the reaction. After such initiation,
the exothermic reaction proceeds on its own to completion without addi-
[30]
tional energy input.
We used this protocol for the synthesis of PHQ
derivatives using a domestic oven at medium high power in the presence
of SSA as a catalyst. Interestingly, we found that this method was very
efficient, and the products were prepared in high yields in a short time
with only a short burst of microwave energy needed. A summary of
obtained data is provided in Table 3.
CONCLUSION
In conclusion, we have demonstrated that the four-component Hantzsch
reaction can effectively synthesize PHQ derivatives with the promotion of
SSA, which provides a simple and efficient method in two conditions.
Mild reaction conditions, high yields, generality, and simplicity of the
procedure; stability and reusability of the catalyst, and avoidance of
harmful organic solvents are features of this new protocol.

1
169

1
170

One-Pot Synthesis of Polyhydroquinoline
1171
EXPERIMENTAL
General
All of the products are known compounds and were characterized by
comparison of their physical and spectroscopic data with those
reported in the literature. Melting points were obtained in open capil-
laries on an Electrothermal 5000 digital apparatus and are not cor-
rected. A National microwave oven, model no. NN-K571MF
(
1000 W), was used for microwave-assisted reactions. Infrared (IR)
spectra were recorded on a Galaxy series Fourier transform infrared
FT-IR) 5000 spectrometer. NMR spectra were recorded on a Brucker
00-MHz spectrometer in dimethyl sulfoxide (DMSO-d ) with tetra-
(
3
6
methylsilane (TMS) as an internal standard. Silica sulfuric acid was
[
22]
prepared according to the reported procedure.
Progress of the reac-
tions was followed by dissolving a sample in ethyl acetate and
monitoring by thin-layer chromatography (TLC) using n-hexane=
EtOAc (2:1 v=v) as an eluent.
General Procedure for the Synthesis of 4a–v (Table 2) Under
Solvent-Free Conventional Heating Conditions
A mixture of aldehyde (1.0 mmol), dimedone or 1,3-cyclohexanedione
(
1.0 mmol), ethyl acetoacetate (1.0 mmol), ammonium acetate (2.0 mmol),
ꢀ
and silica sulfuric acid (0.08 g, 0.20 mmol) was heated at 60 C for an
appropriate time (TLC). The resulting solid product was treated
with hot ethanol or acetonitrile and then filtered. The filtrate was
concentrated to afford the crude product. The pure product was obtained
by recrystallization from absolute ethanol.
General Procedure for the Synthesis of 4a–i (Table 3) Under
MW Irradiation
A mixture of aldehyde (1.0 mmol), dimedone or 1,3-cyclohexanedione
(
1.0 mmol), ethyl acetoacetate (1.0 mmol), ammonium acetate (2.0 mmol),
and SSA (0.08 g, 0.20 mmol) was mixed and irradiated by microwaves for
min and then allowed to go to completion. The resulting solid product
1
was treated with hot ethanol or acetonitrile and then filtered. The filtrate
was concentrated to afford the crude product. The pure product was
obtained by recrystallization from absolute ethanol.

1172
A. Mobinikhaledi et al.
Physical and Spectroscopic Data for Selected Compounds
Ethyl-1,4,7,8-tetrahydro-2-methyl-4-(phenyl)-5(6H)-oxoquinoline-3-
carboxylate (Table 2, 4a)
ꢁ
Mp 243–245 C; IR (KBr) (nmax): 3284, 3140, 1691, 1608, 1479, 1379,
ꢂ1 1
1
222, 1180, 1072 cm ; H NMR (DMSO-d ): dH: 1.12 (3H, t, J ¼ 7.0 Hz,
6
CH ), 1.87–2.27 (6H, m, CH ), 2.46 (3H, s, CH ), 3.97 (2H, q, J ¼ 7.0 Hz,
3 2 3
CH ), 4.90 (1H, s, CH), 7.04–7.20 (5H, m, Ar), 9.14 (1H, s, NH) ppm.
2
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(phenyl)-5(6H)-oxoquinoline-
-carboxylate (Table 2, 4g)
3
ꢁ
Mp 203–205 C; IR (KBr) (nmax): 3288, 2962, 1699, 1610, 1485, 1381,
ꢂ1
1
1
211,1072 cm ; H NMR (DMSO-d ): dH: 0.84 (3H, s, CH ), 1.00
6 3
(
3
9
3H, s, CH ), 1.13 (3H, t, J ¼ 7.1 Hz, CH ), 2.14–2.50 (4H, m, CH ),
3
3
2
.97 (2H, q, J ¼ 7.1 Hz, CH ), 4.84 (1H, s, CH), 7.03–7.20 (5H, m, Ar),
2
.07 (1H, s, NH) ppm.
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(4-methylphenyl)-5(6H)-
oxoquinoline-3-carboxylate (Table 2, 4h)
ꢁ
Mp 261–262 C; IR (KBr) (n ): 3277, 3207, 3078, 2962, 1701, 1647, 1604,
max
ꢂ1 1
1
493, 1381, 1280, 1215, 1090cm ; H NMR (DMSO-d ): dH: 0.84 (3H, s,
6
CH ), 1.00 (3H, s, CH ), 1.14 (3H, t, J ¼ 7.1 Hz, CH ), 1.98–2.44 (4H, m,
3
3
3
CH ), 2.24 (3H, s, CH ), 2.29 (3H, s, CH ), 3.96 (2H, q, J ¼ 7.1 Hz,
2
3
3
CH ), 4.79 (1H, s, CH), 6.95–7.03 (4H, m, Ar), 9.03 (1H, s, NH) ppm.
2
Ethyl-1,4,7,8-tetrahydro-2,7,7-trimethyl-4-(4-bromophenyl)-5(6H)-
oxoquinoline-3-carboxylate (Table 2, 4n)
ꢁ
Mp 253–255 C; IR (KBr) (n ): 3280, 3217, 3065, 2951, 1695, 1637,
max
ꢂ1
1
1
0
1
608, 1489, 1381, 1263, 1210, 1092 cm ; H NMR (DMSO-d ): dH:
6
.82 (3H, s, CH ), 1.00 (3H, s, CH ), 1.12 (3H, t, J ¼ 7.0 Hz, CH ),
3
3
3
.94–2.44 (4H, m, CH ), 2.29 (3H, s, CH ), 3.96 (2H, q, J ¼ 7.0 Hz,
2
3
CH ), 4.82 (1H, s, CH), 7.08–7.39 (4H, m, Ar), 9.12 (1H, s, NH) ppm.
2
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the Research
Council of Arak University.

One-Pot Synthesis of Polyhydroquinoline
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