Application of heteropoly acids as heterogeneous and recyclable catalysts for friedlaender synthesis of quinolines

Article abstract of DOI:10.1155/2010/743123

New convenient conditions for the Friedlaender synthesis of quinolines are described. Quinolines were readily prepared in the presence of heteropolyacids as heterogeneous and recyclable catalysts in good yields.

Full text of DOI:10.1155/2010/743123

ISSN: 0973-4945; CODEN ECJHAO
E-Journal of Chemistry
2010, 7(3), 875-881
http://www.e-journals.net
Application of Heteropoly Acids as
Heterogeneous and Recyclable Catalysts for
Friedländer Synthesis of Quinolines
MAJID M. HERAVI*, NEGAR MOKHTARI HAJ, BITA BAGHERNEJAD,
Y. SH. BEHESHTIA and FATEMEH F. BAMOHARRAM§
Department of Chemistry, School of Science,
Azzahra University, Vanak, Tehran, Iran.
§Department of Chemistry, School of Sciences,
Azad University Khorasan Branch, Mashhad, Iran.
mmh1331@yahoo.com
Received 18 October 2009; Accepted 15 December 2009
Abstract: New convenient conditions for the Friedländer synthesis of
quinolines are described. Quinolines were readily prepared in the presence
of heteropolyacids as heterogeneous and recyclable catalysts in good
yields.
Keywords: Quinolines, Friedlander annulation, α-Methylene group, o-Amino acetophenone,
Heteropoly acids.
Introduction
Quinoline is a well-known structural unit in alkaloids, therapeutics and synthetic analogues
with interesting biological activities such as antimalarial, antibacterial, antiasthmatic,
antihypertensive, anti-inflammatory and tyrokinase PDGF-RTK inhibiting agents1,2. They
are also applied for the preparation of nano- and mesostructures having enhanced electronic
and photonic properties3. Thus, the synthesis of quinolines is an important and useful task in
organic chemistry. Various methods such as Skraup, Doebner von Miller, Friedländer and
Combes methods have been developed for the preparation of quinoline derivatives4,5.
Among them, Friedländer annulation is one of the most simple and straightforward
approaches for the synthesis of polysubstituted quinolines5. Friedländer reactions are generally
carried out either by refluxing an aqueous or alcoholic solution of reactants in the presence of
base or by heating a mixture of the reactants at high temperatures ranging from 150-220 °C in
the absence of catalyst6. Under thermal or base catalysis conditions, o- aminobenzophenone

876
MAJID M. HERAVI et al.
fails to react with simple ketones such as cyclohexanone, deoxybenzoin and β-keto esters7.
Subsequent work showed that acid catalysts are more effective than base catalysts for the
Friedländer annulation8. Acid catalysts such as hydrochloric acid, sulfuric acid, p-toluenesulfonic
acid and phosphoric acids are widely used for this conversion7a,9. However, many of these
classical methods require high temperatures, prolonged reaction times and drastic conditions
and the yields reported are far from satisfactory due to the occurrence of several side
reactions. Therefore, new catalytic systems are being continuously explored in search of
improved efficiencies and cost effectiveness10. In recent times, iodine11, Lewis acids such as
ZnCl2 and AuCl3·3H2O,12 a combination of acidic catalysts [e.g., NaAuCl4, Bi(OTf)3,
Nd(NO3)3·6H2O]13 and microwave irradiation14 and ionic liquids15 have all been found to be
effective for this conversion.
Even some of these methods also suffer form harsh reaction conditions, low yields,
high temperature, tedious work-up and the use of stoichiometric and relatively
expensive reagents. Since quinoline derivatives are increasingly useful and important in
drugs and pharmaceuticals, the development of simple, convenient and high yielding
protocols is desirable. As a part of our continuing effort towards the development of
useful synthetic methodologies16-19, here we report our work on the application of
heteropolyacids as heterogeneous and recyclable catalysts for Friedländer synthesis of
quinolines (Scheme 1).
CH3
COCH3
NH2
O
R2
R1
heteropoly acid
Solvent-free
R2
+
R1
N
1
2
3
Scheme 1
Experimental
All the chemicals were obtained from Merck Company and used as received.
H6[PMo9V3O40], H5[PMo10V2O40] and H6[P2W18O62] were prepared according to the
literatures25. The integrity of the synthesized heteropolyacids has been proven by
comparing of spectral data with those reported in literatur.26–29.All products are known
1
compounds and were characterized by mp, IR, H NMR and GC/MS. Melting points
were measured by using the capillary tube method with an electrothermal 9200
apparatus. 1HNMR spectra were recorded on a Bruker AQS AVANCE-500 MHz
spectrometer using TMS as an internal standard (CDCl3 solution). IR spectra were
recorded from KBr disk on the FT-IR Bruker Tensor 27. GC/MS spectra were recorded
on an Agilent Technologies 6890 network GC system and an Agilent 5973 network
Mass selective detector. Thin layer chromatography (TLC) on commercial aluminum-
backed plates of silica gel, 60 F254 was used to monitor the progress of reactions. All
products were characterized by spectra and physical data.
Typical procedure for preparation of 2,4-dimetyl quinoline-3- carboxylate (3a)
A mixture of 2-amino acetophenone (1 mmol), ethyl acetoacetate (1.2 mmol) and
H6[P2W18O62] (9 x 10-3 mmol) was stirred at 70 ºC under solvent-free conditions for the
appropriate time (Table 1). After completion of the reaction, as indicated by TLC, the
reaction mixture was extracted with diethyl ether (3 × 10 mL). The combined organic layers
were dried over anhydrous MgSO4 and the solvent was evaporated to afford pure quinolines.

Application of Heteropoly Acids as Heterogeneous Catalyst
877
Table 1. H6[P2W18O62] catalyzed synthesis of Friedländer Quionlines.
M.P, ˚C
Yield , %a
Quinoline
Observed
Reported
25 ˚C 40 ˚C 70 ˚C
CH3
O
O
COOEt
oil
oil20
OEt
1
2
2
3
55
50
85
75
92
91
N
CH3
2a
3a
CH3
O
O
104
105-10621
O
N
3b
2b
O
CH3
O
65-66
6621
3
4
5
3
45
45
50
70
72
79
91
92
91
O
N
2c
3c
CH3
O
O
COCH3
CH3
2
.
5
oil
oil21
H3C
Ph
CH3
N
2d
2e
3d
CH3
O
O
COOEt
Ph
OEt
oil
oil22
4
5
N
3e
CH3
C O C H 3
127
125-12623
N
6
7
50
43
77
70
91
90
N O 2
2 f
3f
NO2
CH3
O
oil
oil24
5
N
CH3
2g
3g
a Isolated Yields .
1
3a : H NMR (CDCl3, 500 MHz): δ 7.99 (d, J = 7.3 Hz, 1H), 7.97 (d, J = 7.3 Hz, 1H),
7.69 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 2.62
(s, 3H), 1.46 (t, J = 7.1 Hz, 3H); GC/Ms: 230 (M++1).
1
3b: H NMR (CDCl3, 500 MHz): 8.47 (d, J = 8.4 Hz, 1 H), 8.59 (d, J = 8.4 Hz, 1 H),
δ = 8.07 (t, J = 8.4 Hz, 1 H), 8.05 (t, J = 8.4 Hz, 1 H), 3.24 (s, 2H), 3.06 (s, 3H), 2.54
(s, 2H), 1.16 (s, 6H) ; GC/Ms: 239 (M++1).

878
MAJID M. HERAVI et al.
Reusability of the catalyst
We investigated the reusability and recycling of heteropoly acids. At the end of the
reaction, the catalyst could be recovered by a simple filtration. The recycled catalyst
could be washed with methanol and subjected to a second run of the reaction process.
To assure that catalysts were not dissolved in methanol, the catalysts were weighed after
filtration and before using and reusing for the next reaction. The results show that these
catalysts are not soluble in methanol. In Table 4, the comparison of efficiency of
H6[P2W18O62] in synthesis of 3a after five times is reported. As it is shown in Table 4
the first and second reaction using recovered H6[P2W18O62] afforded similar yield to
those obtained in the first run. In the third, fourth and fifth runs, the yields were
gradually decreased.
Results and Discussion
In a typical example we have carried out a reaction of 2-amino acetophenone with ethyl
acetoacetate in the presence of Wells–Dawson type of heteropoly acid H6[P2W18O62] under
solvent-free condition to afford the corresponding ethyl 2,4-dimetyl quinoline-3-carboxylate
(3a) in 92% yield without any side products. These two components coupling reaction
proceeded efficiently under solvent-free condition with high selectivity. Both ketones and β-
keto esters afforded excellent yields of products in a short reaction time. In the absence of
catalyst, the reaction did not yield any product even after long reaction time (8-12 h). This
method not only affords the products in good yields but also avoids the problems associated
with catalyst cost, handling, safety and pollution. These catalysts can act as eco-friendly for
a variety of organic transformations, non-volatile, non-explosive, easy to handle and
thermally robust. This method is equally effective for both cyclic and acyclic ketones. The
scope and generality of this process is illustrated by reacting various ketones and β-keto
esters. The results are presented in Table 1. In all cases, the reactions proceeded rapidly
under solvent-free condition with high efficiency.
Effect of the catalyst type
Initially, we compared the catalytic performance of Keggin, H5[PMo10V2O40],
H6[PMo9V3O40] with Wells–Dawson, H6[P2W18O62] in the synthesis of quinoline
derivatives. The results are shown in Table 2. The yield of product decreases in the
following order:
H6[P2W18O62] > H5[PMo10V2O40] > H6[PMo9V3O40]
As could be seen Wells–Dawson type of heteropoly acid H6[P2W18O62], is more
effective than the other heteropoly anions and in the presence of this catalyst the highest
yields of products are obtained. The interesting feature of this poly anion compared the other
heteropoly acids is its hydrolytic stability (pH 0-12), which is very important in catalytic
processes. In addition this poly anion is more stable than the Keggin catalysts under thermal
conditions, which makes high temperature for the reactions possible.
A significant interpretation for observed different activities of tested heteropoly anions
is very difficult. Their properties can be varied by their constitutive elements as heteroatom,
polyatom, and counter-cation. However, because one of the important factors that affect the
oxidation capacity and activity of poly anions which is the energy gap between the highest
occupied molecular orbital (HOMO) and the lowest unoccupied orbital (LUMO), it is
suggested that the energy and composition of the LUMOs have significant effects on the
redox properties and activity of the studied poly anions as catalyst. The highest activity for

Application of Heteropoly Acids as Heterogeneous Catalyst
879
H6[P2W18O62] is attributed to the energy and composition of the LUMO, strong acidic
property, and higher acidic protons. The larger number of protons may low the activation
barrier and the large anion can provide many sites on the oval-shaped molecule that are
likely to render the catalyst effective.
Table 2. Synthesis of Quionlines using various heteropoly acids under solvent-free condition.
Entry
1
Catalyst
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
Product
3a
3a
3a
3b
3b
3b
3c
Yield, %a
92
88
85
91
85
80
91
86
83
92
85
81
91
83
79
91
85
2
3
4
5
6
7
3c
3c
3d
3d
3d
3e
3e
3e
3f
3f
80
90
84
80
3f
3g
3g
3g
H5[PMo10V2O40]
H6[PMo9V3O40]
a Isolated Yields.
The reaction was studied with various moles of H6[P2W18O62] from 2x10-3 mmol to
9x10-3 mmol. In all cases, with 9x10-3 mmol catalyst, the maximum yields of quinoline
derivatives was obtained within 2-3 h. The progress of the reaction was followed by TLC
and GC and the results indicate that the yields were affected by changing the catalyst moles.
The reactions proceeded well with 9x10-3 mmol catalyst and use of an increased amount of
catalyst does not make much difference.
Effect of temperature
The effect of temperature was studied by carrying out the reactions at different temperatures
[25 ºC, 50 ºC and 70 ºC)]. As it shown in Tables 1 by raising the reaction temperature from
ambient temperature (25 ºC ) to 70 ºC, the yield of reactions increased. From these results, it
was decided that 70 ºC would be the best temperature for all reactions. The reaction
proceeds very cleanly under solvent-free condition and free of side products.
Effect of the solvent
The synthesis of quinoline derivatives at reflux temperature was carried out using
various common solvents such as acetic acid, ethanol, methanol, THF and acetonitrile.
The results are shown in Table 4. With using all of the catalysts the highest yield of
products was obtained under solvent-free condition. In addition, the time required for
completion of the reaction was found to be less under solvent-free condition.

880
MAJID M. HERAVI et al.
Table 3. Synthesis of 3a in the presence of different solvents.
Temperature,
ºC
Entry
1
Solvent
Catalyst
Time, h Yield, %a
-
-
-
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
70 ºC
70 ºC
70 ºC
2
2.5
2.5
3
92
88
85
89
84
80
84
80
80
77
75
70
75
70
70
75
70
70
75
73
70
2
3
4
5
6
7
Acetic acid H6[P2W18O62]
Acetic acid H5[PMo10V2O40]
Acetic acid H6[PMo9V3O40]
acetonitrile H6[P2W18O62]
acetonitrile H5[PMo10V2O40]
acetonitrile H6[PMo9V3O40]
Ethanol
Ethanol
Ethanol
THF
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
3.5
3.5
4
5
5
H6[P2W18O62]
4
5
5
4
5
5
4
5
5
5
6
6
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
H6[P2W18O62]
H5[PMo10V2O40]
H6[PMo9V3O40]
THF
THF
methanol
methanol
methanol
CHCl3
CHCl3
CHCl3
a Isolated Yields .
Table 4. Reuse of the H6[P2W18O62] for synthesis of 3a.
Yield, %a Time, h
Entry
92
90
84
80
75
2
2.5
3
3
3.5
1
2
3
4
5
a Isolated Yields.
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