A solvent-free synthesis of polyhydroquinolines via Hantzsch multicomponent condensation catalyzed by nanomagnetic-supported sulfonic acid

Article abstract of DOI:10.17159/0379-4350/2015/v68a3

A simple and efficient procedure for the synthesis of polyhydroquinolines was developed, involving a one-pot four-component Hantzsch condensation of aromatic aldehydes, 1,3-cyclohexanediones, alkyl acetoacetate and ammonium acetate in the presence of a ca

Full text of DOI:10.17159/0379-4350/2015/v68a3

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RTICLE
S. Otokesh, N. Koukabi, E. Kolvari, A. Amoozadeh, M. Malmir and S. Azhari
15
S. Afr. J. Chem., 2015, 68, 15–20,
<
http://journals.sabinet.co.za/sajchem/>.
A Solvent-free Synthesis of Polyhydroquinolines via
Hantzsch Multicomponent Condensation Catalyzed by
Nanomagnetic-supported Sulfonic Acid
Somayeh Otokesh, Nadiya Koukabi*, Eskandar Kolvari, Ali Amoozadeh*,
Masoumeh Malmir and Saeede Azhari
Department of Organic Chemistry, Faculty of Chemistry, Semnan University, Semnan, Iran.
Received 18 September 2014, revised 17 November 2014, accepted 18 November 2014.
ABSTRACT
A simple and efficient procedure for the synthesis of polyhydroquinolines was developed, involving a one-pot four-component
Hantzsch condensation of aromatic aldehydes, 1,3-cyclohexanediones, alkyl acetoacetate and ammonium acetate in the presence
of a catalytic amount of nanomagnetic-supported sulfonic acid under solvent-free conditions. The method offers several advantages
including high yields, short reaction times, a simple work-up procedure and catalyst reusability for several runs. Furthermore,
easy isolation of the catalyst from the reaction mixture was enabled by use of an external magnet.
KEYWORDS
Nanomagnetic-supported sulfonic acid, multicomponent reaction, solvent-free conditions, heterocyclic compound, Hantzsch
reaction.
16,17
1
. Introduction
drugs.
In continuation of our investigation on the use of
Since the beginning of this century, different sciences have nano-g-Fe O -SO H as catalyst for MCRs and our interest in
2
3
3
1
8,19
seen a rapid increase due to interest in materials at the synthesis of heterocycles containing a nitrogen atom,
we
nano-scale. Nanomaterials have attracted attention because of report an efficient and facile synthesis of hexahydroquinolines
physical, electronic and magnetic properties. The field of under solvent-free conditions (Scheme 1).
nanomagnetic particles is a subset of nanomaterials. The
applications for these materials are very diverse such as metal 2. Experimental
1
2
ion separations, enzyme immobilization, magnetic resonance
3
4
2.1. General
imaging (MRI), drug delivery and catalysis. In chemistry,
nanomagnetic catalysts have emerged as one of the most useful
heterogeneous catalysts due to their numerous applications in
All chemicals were purchased from Merck, Fluka or Across
companies and used without any further purification. Nano-g-
2
0
5
Fe O -SO H was prepared with the reported method. Melting
2 3 3
organic synthesis. These catalysts have been studied in various
points were recorded on electro thermal 9100 apparatus and are
uncorrected. NMR spectra were recorded with a Bruker Avance
significant protocols in organic chemistry because they are robust,
inexpensive and readily available. Also, they can be easily prepared
from their available metal salts and most importantly can be
recycled for several runs without any loss of selectivity and
1
13
spectrometer ( H NMR 300, 400 MHz and C NMR 75, 100 MHz)
in pure deuteriated chloroform and DMSO with tetramethylsilane
(TMS) as the internal standard. The IR spectra were recorded on
a Perkin-Elmer model 783 spectrophotometer (Waltham, MA,
6
activity.
In the context of green chemistry, the design and development
of organic synthesis performed through multicomponent reac-
tions (MCRs) have become a significant area of research in
organic chemistry since such processes improve atom economy,
–
5
USA). UV-Vis spectra were obtained as ethanol solutions (10 M)
on a Shimadzu UV-1650PC spectrophotometer.
7
2.2. General Method for the Synthesis of
efficiency and convergence. Therefore, MCRs are often useful
Polyhydroquinolines (
)
alternatives to sequential multistep synthesis. The synergistic
use of nanomagnetic particles and MCRs allows efficient synthesis
of diverse nitrogen-containing heterocycles. One of the most
prominent methods to prepare these compounds is the Hantzsch
condensation reaction providing polyhydroquinolines. The
polyhydroquinoline moiety is a fertile source of biologically and
pharmacologically important molecules such as vasodilator,
bronchodilator, anti-atherosclerotic, hepto-protective, anti-tumor,
anti-mutagenic, geroprotective, anti-diabetic agents, HIV protease
A mixture of aromatic aldehyde (1 mmol), alkyl acetoacetate
1 mmol), 1,3-cyclohexanedione (1 mmol), ammonium acetate
1.1mmol) andnano-g-Fe O -SO H(0.031g)washeatedat60 °C.
(
(
2
3
3
After completion of the reaction (monitored by TLC), the mixture
was cooled to room temperature and triturated with hot ethanol
(
5 mL). In the presence of a magnetic stirrer bar, nano-g-Fe O -
2 3
SO H moved on to the stirrer bar steadily and the reaction mix-
3
ture turned clear within 10 s. The catalyst was isolated by simple
decantation. After evaporation of the solvent, the crude product
8–15
inhibition and most importantly as calcium channel blockers.
was recrystallized from EtOH/H O to give a pure product.
2
All mentioned cases demonstrate clearly the remarkable potential
of the polyhydroquinoline derivatives as a source of valuable
2
.3. Spectral Data of Some Representative Compounds
*
To whom correspondence should be addressed. E-mail: koukabi@gmail.com /
aamozadeh@semnan.ac.ir
Ethyl 2-Methyl-5-oxo-4-phenyl-4,6,7,8-tetrahydro-1H-quino-
ISSN ISSN 0379-4350 Online / ©2015 South African Chemical Institute / http://saci.co.za/journal
DOI: http://dx.doi.org/10.17159 /0379-4350/2015/v68a3

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Scheme 1
–
1
line-3-carboxylate (5j) (90 %) as a light cream solid.; (recrystallized 848 (C-Cl) cm ; d
from EtOH/H
O, TLC– n-hexane:ethyl acetate, 8:2, Rf = 0.14); CH -CH
M.p. 240–242 °C, nmax (KBr) 3296 (NH), 1641 (C=O) (acid), 1608 H), 2.54–2.59 (7, 1H, 8 H), 2.59–2.66 (m, 1H, 6 H), 2.74–2.82 (m, 1H,
H
(400 MHz, DMSO-d
6
) 1.12 (t, 3H,
3
2
3
2
-O-C=O), 2.3 (t, 1H, 8 H), 2.31 (s, 3H, CH ), 2.5 (t, 1H, 8
–
1
(
1
C=O) (ketone), 1488 (OC
.17 (t, 3H, CH -CH -O-C=O), 1.59 (m, 2H, CH
CH ), 2.30–2.46 (m, 4H, 6,8 H), 4.05 (q, 2H, -O-CH
H,4 H), 5.94 (s, 1H, NH), 7.08–7.31 (m, 5H, 2’, 3’, 4’, 5’, 6’ H) ppm. 167.1 (C=OOC
2
H
5
) (ester) cm ; d
H
(300 MHz, CDCl
, 7 H), 1.97 (m, 3H, 7.22–7.28 (m, 5H, 2’,6’, 2”, 4”, 6” H), 7.31–7.33 (m, 4H, 3’, 5’, 3”, 5”
-CH
), 5.01 (s, H), 9.21 (d, 1H, NH)ppm;d (100 MHz, DMSO-d ) 194.2 (C-5),
), 151.3 (C-2), 150.8 (C-1a), 147.1 (C-1”), 145.7
(C-1’), 143.8 (C-4’), 130.7 (C-2’ and C-6’), 129.8 (C-3’ and C-5’),
28.8 (C-3” and C-5”), 128.1 (C-2” and C-6”), 127.1 (C-4”), 111.0
C-5a), 103.6 (C-3), 44.3 (O-CH -CH ), 43.7 (C-6), 38.8 (C-4), 36.0
C-8), 33.7 (C-7), 18.7 (1C, CH ), 14.5 (1C, CH -CH O) ppm. UV
max in EtOH): 363 nm; 421.14 (100.0 %), 422.14 (32.3 %), 423.15
27.2 %) m/z: 421 (100 %), 422 (32.3 %) and 423 (27.2 %), (Found:
3
)
6 H),), 3.17 (t, 1H, NH), 3.98 (q, 2H, -O-CH
2
-CH
3
),4.90 (d, 1H, 4 H),
3
2
2
3
2
3
C
6
1
2
H
5
UV (lmax in EtOH): 378 nm.
1
Ethyl 4-(p-Methoxyphenyl)-2-methyl-5-oxo-7-phenyl-4,6,7,8-tetra-
hydro-1H-quinoline-3-carboxylate (5l) (96 %) as a white solid.;
(
(
(
(
2
3
3
3
2
(
8
(
(
CH
6
(
7
recrystallized from EtOH/H
:2, Rf = 0.12); M.p. 236–238 °C, nmax (KBr) 3280 (NH), 1689 (C=O)
acid), 1606 (C=O) (ketone), 1479 (OC ) (ester), 1222 (OCH
/ ppm (300 MHz, CDCl ) 1.27 (m, 3H,
-O-C=O), 2.23–2.37 (m, 3H, CH ), 2.38–2.52 (m, 5H,
,7,8 H), 3.71 (s, 3H, CH -O-Ph), 4.07 (m, 2H, -O-CH -CH ), 5.05
m, 1H, 4 H), 6.71–7.12 (m, 4H, 2’, 3’, 5’, 6’ H), 6.96 (s, 1H, NH),
.17–7.29 (m, 5H, 2”,3”,4”,5”,6” H); d /ppm (75 MHz, CDCl ) 195.2
C-5), 167.5 (C=OOC ), 157.8 (C-4’), 150 (C-2), 149.5 (C-1a),
43.4 (C-1”), 142.6 (C-1’), 139.7 (C-2’ and C-6’), 139.3 (C-3” and
2
O, TLC– n-hexane:ethyl acetate,
l
2
H
5
3
)
C,71.19; H, 5.71; N, 3.32; Cl, 8.40; O, 11.38 %. Calcd. for
(421.11); C,71.19; H,5.71; N, 3.32; Cl, 8.40; O,
–
1
ether) cm ; d
-CH
H
3
C
1
25
H
24ClNO
3
3
2
3
1.38 %).
3
2
3
3
. Results and Discussion
Hammett acidity function (H ) can be used to effectively
express the ability and acidity strength of an acid in organic
solvents. This method using 4-nitro aniline with Hammett indi-
cators is a simple quantitative method, which can be obtained
from the relative intensities of the absorption band by UV-visible
spectrometer. The acidity of the solution can be calculated by
using the following Hammett equation in the form of H , the
acidity function as given:
C
3
0
(
1
2
H
5
21
C-5”),128.8 (C-2”and C-6”), 127 (C-4”), 126.6 (C-3’ and C-5’), 113.2
(
3
C-5a), 106.2 (C-3), 59.8 (O-CH
8.8 (C-4), 35.8 (C-8), 34.4 (C-7), 19.1 (1C, CH
CH -CH
28.6 %), 419.20 (4.8 %) m/z: 417 (100), 418 (28.6 %) and 419 (4.8 %),
Found: C,74.82; H, 6.83; N, 3.37 %. Calcd. for C26 (417.19);
2
-CH
3
), 55.1 (O-CH
3
), 39.5 (C-6),
), 14.2 (1C,
3
3
2
O). UV (lmax in EtOH): 224 nm; 417.19 (100.0 %), 418.20
0
(
(
H27NO
4
0 s s
H = pK(I)aq + log[I]
/[HI+]
C,74.80; H,6.52; N 3.35 %).
where [I] represents the indicator base, pK(I)aq is the protonation
constant of the dye in aqueous solution (for example the pK(I)aq
Ethyl 2-Methyl-5-oxo-4,7-diphenyl-4,6,7,8-tetrahydro-1H-quino-
line-3-carboxylate (5n) (99 %) as a white solid; (recrystallized from
value of 4-nitroaniline is 0.99), which can be obtained from many
EtOH/H
2
O, TLC– n-hexane:ethyl acetate, 8:2, Rf = 0.13); M.p.
+
references, [I]
s
and [HI ]
s
are respectively the molar concentra-
2
13–215 °C, nmax (KBr) 3276 (NH), 1701 (C=O) (acid), 1606 (C=O)
–
1
tions of solvated non-protonated and protonated forms of the
(
(
(
ketone), 1487 (OC
t, 3H, CH -CH -O-C=O), 2.32 (s, 3H, CH
d, 1H, 8 H), 2.59 (m, 1H, 7 H), 2.68 (dd, 1H, 6 H), 2.79 (dd, 1H, 6
-CH ), 4.98(s, 1H, 4H), 7.11
m, 1H, 4’ H), 7.19–7.24 (q, 5H, 2’, 4’, 6’, 2”, 6” H), 7.3–7.36 (m, 4H,
2
H
5
) (ester), cm ; d
H
(400 MHz, DMSO-d
6
) 1.14
indicator. According to the Beer-Lambert law, the value of
3
2
3
), 2.35 (dd, 1H, 8 H), 2.5
+
[I]
s
/[IH ]
s
can be determined and calculated from UV-visible
spectrum measurements. In the present experiment, 4-nitroaniline
was chosen as the basic indicator and CCl was chosen as the
solvent because of its aprotic nature. A dilute solution (10 M) of
-nitroaniline in CCl was prepared and used as a stock solution
H), 3.17(s, 1H, NH), 4.0(q, 2H, -O-CH
2
3
4
(
–
4
3
’, 5’, 3”, 5” H), 9.21(s, 1H, NH) ppm;d
C
(100 MHz, DMSO-d )
6
4
4
194.4 (C-5), 167.3 (C=OOC ), 151.1 (C-2), 148.1 (C-1a), 145.3
2
H
5
throughout the experiments. The maximal absorbance of the
non-protonated form of 4-nitroaniline was observed at 331 nm
(
1
(
(
CH
3
(
C
C-1”), 143.9 (C-1’), 128.9 (C-2’ and C-6’), 128.3 (C-3’ and C-5’),
27.9 (C-3” and C-5”),127.4 (C-2” and C-6”), 127 (C-4”), 126.2
C-4’), 111.2 (C-5a), 104.2 (C-3), 59.5 (O-CH -CH ), 44.4 (C-6), 38.8
C-4), 36.2 (C-8), 34 (C-7), 18.7 (1C, CH ), 14.6 (1C,
-CH O),ppm.UV (lmax in EtOH): 361 nm; 387.18 (100.0 %),
88.19 (27.2 %), 389.19 (4.6 %) m/z: 417 (100), 418 (27.2 %) and 419
4.6 %), (Found: C,77.47; H, 6.52; N, 3.63; O, 12.37 %. Calcd. for
(387.18); C,77.47; H,6.52; N 3.63; O, 12.37 %).
in CCl
form of the indicator in nano-g-Fe
to the sample of the indicator in CCl
indicator was partially in the form of [IH ]. The results obtained
are listed in Table 1, which shows the acidity strength of
4
. As shown in Fig. 1, the absorbance of the non-protonated
-SO H was weak compared
, which indicated that the
2
3
2
O
3
3
3
4
3
2
+
nano-g-Fe
2
O
3
-SO
3
H.
25
H
25NO
3
First, in order to optimize the conditions, the reaction of
Ethyl 4-(p-chlorophenyl)-2-methyl-5-oxo-7-phenyl-4, 6, 7, benzaldehyde, ethyl acetoacetate, 5,5-dimethyl-1,3-cyclohex-
-tetrahydro-1H-quinoline-3-carboxylate (5o) (98 %) as a white anedione and ammonium acetate was chosen as a model system
solid; (recrystallized from EtOH/H O, TLC– n-hexane:ethyl ace- under thermal conditions. The results listed in Table 2 show that
tate, 8:2, Rf = 0.12); M.p. 190–192 °C, nmax (KBr) 3274 (NH), nanomagnetic-supported sulfonic acid is the best catalyst
701(C=O) (acid), 1606 (C=O) (ketone), 1487 (OC ) (ester), affording the highest yield (Table 2, Entry 10), while both
8
2
1
2
H
5

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carried out with different solvents (Table 4). Fortunately, when
the reaction was carried out in solvent-free condition, good
yields and short reactions times were achieved which was
consistent with context of ‘sustainable chemistry’, concerning
green chemistry aspects; ‘the best solvent is no solvent at all’.
In order to show the merit of method in comparison with
other reported results in the literature for similar reactions, we
compared the results of nano-g-Fe O -SO H with other catalysts
2
3
3
used for the synthesis of polyhydroquinoline derivatives in
Table 5. This method has the following advantages: Magnetic
separation can eliminate expensive centrifugation (compared to
2
2
methods using nano catalysts without magnetic properties ),
nano-sized magnetic particles have large specific surface area so
adsorption capacity is high, for this reason, the reaction rate
increased leading to energy savings. In contrast to other meth-
23–34
ods,
the products are obtained in a shorter time. These results
clearly indicate that nano-g-Fe O -SO H is an efficient, magnetic
2
3
3
and reusable acidic catalyst, and the present method is found to
be very effective for the synthesis of polyhydroquinoline deriva-
tives.
Figure 1 Absorption spectra of (a) 4-nitroaniline (indicator) and (b) nano-
g-Fe O -SO H (catalyst) in CCl .
2
3
3
4
bulk-Fe O and bulk-Fe O -SO H provide lower yields (Table 2,
To determine the recyclability of the catalyst, the same model
2
3
2
3
3
Entries 4, 6). This is due to its higher surface areas and surface reaction was again studied under optimized conditions. The
vacancies which are responsible for the excellent catalytic activity. results are shown in Table 6. It is important to mention that our
Finally, for comparison, iron chloride salts, FeCl .4H O and new conditions also provide a fast and facile work-up; after
2
2
FeCl .6H O, were also investigated for synthesis of polyhydro- completion of the reaction, the mixture was triturated with hot
3
2
quinoline. The results showed that the conversions were trace ethanol. Within a few seconds, after stirring was stopped, the
amounts (Table 2, Entries 2, 3). By screening different amounts of reaction mixture turned clear and the catalyst was deposited on
nano-g-Fe O -SO H, we found that product 5a was obtained in the magnetic bar, which was easily removed with an external
2
3
3
yields ranging from 40 to 98 (Table 2, Entries 7–11). Thus, the best magnet, after being washed with acetone and dried in air, the
amount of catalyst was 0.031 g (8 mol%) (Table 2, Entry 10). nano-g-Fe O -SO H catalyst could be used at least five times
2
3
3
In the following study of the model reaction, we examined the without significant loss of activity. This efficient recyclability is
influence of various temperatures on the reaction rate as well as most probably due to bound covalently sulfonic groups (-SO H)
3
yields of products. As indicated in Table 3, the best yield was ob- to magnetic nanoparticles. However, the slight reduction of
tained at 60 °C (Table 3 Entry 3), so we considered it as optimum catalytic activity of the catalyst after recycling is probably due to
temperature. Higher temperatures decreased the total yield by the blockage of active sites on the catalyst surface (Fig. 2).
producing byproduct as shown by TLC (Table 3, Entries 4, 5).
In order to evaluate the generality of our new conditions, we
The choice of solvent was crucial. To this end, the reaction was studied the reaction of aromatic aldehydes with electron-
a
Table 1 Calculation of Hammett acidity function (H ) of nano-g-Fe O -SO H .
0
2
3
3
+
Entry
Catalyst
Amax
[I] /%
[IH ] /%
H0
s
s
1
2
–
1.52
1.16
100
78.47
0
–
1.65
Nano-g-Fe O -SO H
21.52
2
3
3
a
Solvent, CCl ; indicator, 4-nitroaniline (pK(I) = 0.99), 1.44*10–4 mol/L; catalyst, nano-g-Fe O -SO H (20 mg), 25 °C.
4
aq
2
3
3
a
Table 2 Iron-based catalyzed Hantzsch four-component condensation of polyhydroquinoline .
b
Entry
Catalyst
Catalyst amount/mol%
Time/min
Yield /%
1
2
3
4
5
6
7
8
9
None
–
15
15
19
19
8
0.5
1
3
300
65
65
65
65
65
65
65
65
65
65
Trace
Trace
Trace
34
50
56
40
50
85
98
FeCl .4H O
2
2
FeCl .6H O
3
2
Bulk-Fe O
nano-g-Fe O
Bulk-Fe O -SO H
Nano-g-Fe O -SO H
Nano-g-Fe O -SO H
Nano-g-Fe O -SO H
Nano-g-Fe O -SO H
Nano-g-Fe O -SO H
2
3
2
3
2
3
3
2
3
3
2
3
3
2
3
3
10
1
8
16
2
3
3
1
90
2
3
3
a
b
Benzaldehyde (1mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), ammonium acetate (1.1 mmol), solvent-free, at 60 °C.
Yields refer to isolated products.

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a
Table 3 Effect of temperature on the reaction rate.
b
Entry
Temperature/°C
Yield/%
1
2
3
4
5
25
50
60
70
80
Trace
70
98
85
83
a
b
Benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), ammo-
nium acetate (1.1 mmol) and 0.031 g nano-g-Fe O -SO H, solvent-free, for 60
2
3
3
minutes.
Yields refer to isolated products.
a
Table 4 Choice of suitable solvent for reaction.
Figure 2 Reusability of nano-g-Fe O -SO H.
2 3 3
b
Entry
Solvent
Time/min
Yield/%
the reactions were clean and rapid. The nature and location of
substituent groups in the aromatic ring has been shown not to
have much effect on the formation of the final product and af-
ford the expected products in high yields.
The methodology was extended for large-scale synthesis of
polyhydroquinolines. First, the reaction was done using
benzaldehyde, ethyl acetoacetate, 5,5-dimethyl-1,3-cyclohex-
anedione on 1 mmol scale (Table 8, Entry 1). Then, the same reac-
tion was expanded with different amounts of benzaldehyde
such as 1 g (9.4 mmol), 5 g (47 mmol), 10 g (94 mmol) and 20 g
1
2
3
4
5
6
7
8
9
H O
EtOH
200
130
105
120
85
120
120
160
180
65
Trace
53
61
57
71
70
57
45
35
2
CH CN
3
DMF
CHCl3
CH Cl
2
2
DMF
DMSO
C H CH
6
5
3
1
0
Free
98
(
188 mmol) without affecting the yield of the product 5a (Table 8,
Entries 2–5). While scaling up the reaction, it was found that
mol% of the catalyst is sufficient to promote the reaction effec-
a
b
Benzaldehyde (1 mmol), ethyl acetoacetate (1 mmol), dimedone (1 mmol), ammo-
nium acetate (1.1 mmol) and 0.031 g nano-g-Fe O -SO H, at 60 °C.
8
2
3
3
Yields refer to isolated products.
tively without significantly affecting the rate of the reaction. This
procedure was also applied to several other substituted benz-
donating and electron-withdrawing groups, ethyl acetoacetate aldehydes and the products 5b, 5d, 5e, 5j, 5l and 5m were also
and different 1,3-cyclohexanediones in the presence of ammo- synthesized (Table 8, Entries 6–23). Finally, the methodology
nium acetate and 0.031 g of nano-g-Fe O -SO H under obtained could successfully be used for the synthesis of polyhydroquino-
2
3
3
conditions. The results are summarized in Table 7. In all cases, lines on a large scale.
Table 5 Comparison of the results obtained for the synthesis of polyhydroquinoline catalyzed by nano-g-Fe O -SO H with those recently reported
2
3
3
catalysts.
c
ref
Entry
Catalyst/mol%
Solvent
Condition
Time/min
Yield /%
2
2
3
4
5
6
7
8
9
0
1
2
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
Nanoparticles-TiO / 10
Co NPs/ 10
p-TSA/ 10
Ethanol
Solvent-free
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
Ethanol
Methanol
Solvent-free
Ethanol
Reflux
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
30
60
92 2
2
95 2
120
120
120
300
240
60
360
90
20
120
180
240
65
93
2
GaCl / 2
92 2
3
ZrCl / 5
94
4
2
Yb(OTf) / 5
90 2
3
Sc(OTf) / 5
93 2
3
CAN/ 10
L-Proline/ 10
CTAB/ 1
(bzacen) MnCl/ 2.5
ASA/ 20
92
3
Reflux
Reflux
Reflux
92 3
0
1
2
3
4
5
80 3
90
o
33
34
35
70 C
92
95
92
o
Hf(NPf ) / 1
60 C
2
4
o
Bi(NO ) .5H O/ 5
80 C
3
3
2
o
Nano-g-Fe O -SO H/ 8
Solvent-free
60 C
This work
2
3
3
Table 6 Reusability of nano-g-Fe O -SO H in the synthesis of polyhydro-
2
3
3
quinoline.
Entry
1
2
3
4
5
a
Yield/%
98
97
97
96
94
a
Isolated yield

R
ESEARCH
A
RTICLE
S. Otokesh, N. Koukabi, E. Kolvari, A. Amoozadeh, M. Malmir and S. Azhari
19
S. Afr. J. Chem., 2015, 68, 15–20,
<
http://journals.sabinet.co.za/sajchem/>.
a
Table 7 Synthesis of polyhydroquinolines under solvent-free conditions at 60 °C by nano-g-Fe O -SO H as a catalyst.
2
3
3
b
Ar
R1
R ,R
Product
Time/ min
Yield /%
M.P./ C
2
3
ref
Found
3
6
Ph
p-MeC H
p-MeOC H
p-HOC H
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H, Ph
Me
H, Ph
H, Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
65
105
90
98
99
93
93
91
89
90
93
95
90
93
96
95
99
98
202–204
2
7
261–263 2
6
4
7
258–259
6
4
2
7
7
7
50
232–234 3
6
4
2
,6-DiClC H
210
240
70
100
110
330
300
90
244–246 2
263–264 3
6
4
p-Me NC H
p-ClC H
o-Cl-C H
2
6
4
8
245–247
208–209
6
4
3
8
6
4
39
2
-HO-5-BrC H
247
6
3
4
0
Ph
p-ClC H
p-MeOC H
p-MeC H
Ph
p-ClC H
240–242 4
0
248–249
6
4
c
236–2384
283–285
213–215
190–192
6
4
1
175
170
130
6
4
c
c
6
4
a
Aromatic aldehyde (1 mmol), alkyl acetoacetate (1 mmol), 1,3-cyclohexanedione (1 mmol), ammonium acetate (1.1 mol) and 0.031 g nano-g-Fe O -SO H, solvent-free,
2
3
3
at 60 °C.
b
c
Yields refer to isolated products.
New compounds.
Table 8 Large-scale synthesis of polyhydroquinolines using nano-g- Acknowledgement
a
Fe O -SO H.
2
3
3
The authors gratefully acknowledge Semnan University
Research Council for financial supporting this work.
b
Product
Amount of
aldehyde/mmol
Time/min
Yield /%
Supplementary material
The IR, MS and NMR spectra for the novel compounds (5l, 5n
and 5o) are presented as supplementary material.
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
a
a
a
a
a
b
b
b
d
d
d
e
e
e
j
1
9.4
47
94
188
1
8.3
166.5
1
8.2
163.8
1
5.7
114.3
1
9.4
188
1
65
65
65
65
65
105
105
105
50
50
50
210
210
210
330
330
330
90
90
90
175
175
175
98
98
96
96
93
99
97
95
93
93
91
91
90
90
90
90
88
96
94
92
95
93
92
References
1
2
3
4
T. Sen, A. Sebastianelli and I.J. Bruce, J. Am. Chem. Soc., 2006, 128,
130–7131.
C. Song, L. Sheng and X. Zhang, Appl. Microbiol. Biotechnol., 2012, 96,
23–132.
R.S. Chaughule, S. Purushotham and R.V. Ramanujan, Proc. Natl.
Acad. Sci., India, Section A: Phys. Sci., 2012, 82, 257–268.
7
1
A. Andrade, R. Ferreira, J. Fabris and R. Domingues, Coating Nano-
magnetic Particles for Biomedical Applications, 2011, Intech, DOI:
1
0.5772/19519.
M. Gawande, A. Rathi, P. Branco and R. Varma, Appl. Sci., 2013, 3,
56–674.
5
6
6
7
8
R.B.N. Baig and R. S. Varma, Chem. Commun., 2013, 49, 752–770.
M. JoseCliment, A. CormaandS. Iborra, RSCAdvances, 2012, 2, 16–58.
j
j
l
l
A. Kumar, S. Sharma, V.D. Tripathi, R.A. Maurya, S.P. Srivastava,
G. Bhatia, A.K. Tamrakar and A.K. Srivastava, Bioorg. Med. Chem.,
7.3
146.9
1
8.3
166.5
2010, 18, 4138–4148.
l
9
K. Turhan, S.A. Ozturkcan, Z. Turgut, M. Karadayi, A. Aslan and
M. Gulluce, Toxicol. Ind. Health, 2012, 28, 605–613.
m
m
m
1
1
0 V. Gupta and U. Misra, Med. Chem. Res., 2008, 17, 437–444.
1 B. Bülbül, G.S. Öztürk, M. Vural, R. ÔimÕek, Y. Sario—lu, A. Linden,
M. Ülgen and C. Ôafak, Eur. J. Med. Chem., 2009, 44, 2052–2058.
a
b
Reaction condition: nano-g-Fe O -SO H (8 mol%), solvent-free, at 60 °C.
Isolated yield.
2
3
3
12 M.S. Al-Said, M.M. Ghorab, M.S. Al-Dosari and M.M. Hamed, Eur. J.
Med. Chem., 2011, 46, 201–207.
1
3 J. Mielcarek, I. Khmelinskii, M. Sikorski, H. Stefaniak, J. Photochem.
4
. Conclusion
Photobiol. A., 2007, 192, 197–203.
In conclusion, we have developed a simple new catalytic 14 H. Abu-Melha, Spectrochim. Acta Part A: Molecular and Biomolecular
method for the synthesis of polyhydroquinoline derivatives via
Spectroscopy., 2013, 113, 115–122.
one-pot, four-component Hantzsch condensation of 1,3-cyclo- 15 C. Safak and R. Simsek, Mini Rev. Med. Chem., 2006. 6, 747–755.
1
1
1
1
6 N.K. Ladani, D.C. Mungra, M.P. Patel and R.G. Patel, Chin. Chem. Lett.,
hexanedione, aryl aldehydes, alkyl acetoacetate and ammonium
acetate in the presence of nanomagnetic-supported sulfonic acid
as an efficient, reusable, and green heterogeneous catalyst under
solvent-free conditions. Our new method offers several advan-
tages including short reaction times, the use of mild reaction
conditions, avoiding the use of harmful acids and involving a
simple work-up procedure.
2011, 22, 1407–1410.
7 N. Edraki, A.R. Mehdipour, M. Khoshneviszadeh and R. Miri, Drug
Discov. Today, 2009, 14, 1058–1066.
8 E. Kolvari, N. Koukabi and O. Armandpour, Tetrahedron, 2014, 70,
1383–1386.
9 N. Koukabi, E. Kolvari, A. Khazaei, M.A. Zolfigol, B. Shirmardi-
ShaghasemiandH. Khavasi, R. Chem.Commun., 2011, 47, 9230–9232.

R
ESEARCH
A
RTICLE
S. Otokesh, N. Koukabi, E. Kolvari, A. Amoozadeh, M. Malmir and S. Azhari
20
S. Afr. J. Chem., 2015, 68, 15–20,
<
http://journals.sabinet.co.za/sajchem/>.
2
2
2
0 N. Koukabi, E. Kolvari, M.A. Zolfigol, A. Khazaei, B. Shirmardi-
30 N.N. Karade, V.H. Budhewara, S.V. Shindeb and W.N. Jadhavb, Lett.
Org. Chem., 2007, 4,16–19.
31 J.-J. Xia and K.-H. Zhang, Molecules, 2012, 17, 5339–5345.
ShaghasemiandB. Fasahati, Adv. Synth. Catal., 2012, 354, 2001–2008.
1 H. Xing, T. Wang, Z. Zhou and Y. Dai, J. Mol. Catal. A: Chem., 2007, 264,
5
3–59.
3
3
2 E. MosaddeghandA. Hassankhani, ArabianJ. Chem., 2012, 5, 315–318.
3 M. Arsalan, C. Faydali, M. Zengin, M. Kucukislamoglu and
H. Demirhan, Turk. J. Chem., 2009, 33, 769–774.
2 M. Tajbakhsh, E. Alaee, H. Alinezhad, M. Khanian, F. Jahani,
S. Khaksar, P. Rezaee and M. Tajbakhsh, Chin. J. Catal., 2012, 33,
1
517–1522.
3
3
4 M. Hong, C. Cai and W.-B. Yi, J. Fluorine Chem., 2010, 131, 111–114.
5 S.S. Mansoor, K. Aswin, K. Logaiya and S.P.N. Sudhan. J. Saudi Chem.
Soc., 2012, in press.
2
2
2
2
2
2
2
3 J. Safari, S.H. Banitaba and S. Dehghankhalili. Chin. J. Catal., 2011, 32,
850–1855.
4 S.R. Cherkupally and R. Mekala, Chem. Pharm. Bull., 2008, 56,
002–1004.
1
3
3
3
6 M.M. Kurbanova, E.Z. Huseynov, A.V. Gurbanov, A.M. Maharramov
1
and S.W. Ng, Acta Crystallogr., Sect. E., 2012, 68, 2233–2233.
5 D.R. Patil, M.B. Deshmukh, S.M. Salunkhe, D.K. Salunkhe, G.B.
Kolekar and P.V. Anbhule. Der. Pharma. Chemica., 2010, 2, 342–348.
7 G.M. Ziaran, A.R. Badiei, Y. Khaniania and M. Haddadpour, Iran. J.
Chem. Chem. Eng., 2010, 29, 1–10.
8 S.B. Sapkal, K.F. Shelke, B.B. Shingate and M.S. Shingare, Tetrahedron
Lett., 2009, 50, 1754–1756.
6 C.S. Reddy and M. Raghu, Indian J. Chem., Sect. B. 2008, 47B,
1
578–1582.
7 L.M. Wang, J. Sheng, L. Zhang, J.W. Han, Z. Fan, H. Tian and
C.T. Qian, Tetrahedron, 2005, 61, 1539–1543.
39 M. M. Kurbanova, E. Z. Huseynov, A. V. Gurbanov, A. M. Mahar-
ramov and R. Kia, Acta Crystallogr., Sect. E., 2013, 69, 541–541.
8 J.L. Donelson, R.A. Gibbs and S.K. De, J. Mol. Catal. A: Chem., 2006,
256, 309–311.
40 P. Rao, R. Kumari and S. Oruganti, Chem. Biol. Interf., 2013, 3, 38–49.
41 A. Kumar and R.A. Maurya, Tetrahedron Lett., 2007, 48, 3887–3890.
9 C.S. Reddy and M. Raghu, Chin. Chem. Lett., 2008, 19, 775–779.

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