Tungstophosphoric acid supported on titania as an eco-friendly, green and reusable catalyst for the solvent-free hantzsch multi-component condensation

Article abstract of DOI:10.3987/COM-08-11379

Tungstophosphoric acid supported on titania (PW/TiO₂), catalyzed three and four component coupling of various β-dicarbonyl compounds, aldehydes and amines under solvent free conditions. Different 4-aryl, N-hydroxy ethyl and N-aryl substituted 1

Full text of DOI:10.3987/COM-08-11379

HETEROCYCLES, Vol. 75, No. 9, 2008
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HETEROCYCLES, Vol. 75, No. 9, 2008, pp. 2225 - 2233. © The Japan Institute of Heterocyclic Chemistry
Received, 2nd March, 2008, Accepted, 21st April, 2008, Published online, 24th April, 2008. COM-08-11379
TUNGSTOPHOSPHORIC ACID SUPPORTED ON TITANIA AS AN
ECO-FRIENDLY, GREEN AND REUSABLE CATALYST FOR THE
SOLVENT-FREE HANTZSCH MULTI-COMPONENT CONDENSATION
Ezzat Rafiee,* Sara Eavani, Solmaz Rashidzadeh, and
Mohammad Joshaghani
Department of Chemistry, Faculty of Science, Razi University, 67149,
Kermanshah, Iran. Kermanshah Oil Refining Company, Kermanshah, Iran
E-mail: ezzat_rafiee@yahoo.com; e.rafiei@razi.ac.ir
Abstract – Tungstophosphoric acid supported on titania (PW/TiO2), catalyzed
three and four component coupling of various β-dicarbonyl compounds, aldehydes
and amines under solvent free conditions. Different 4-aryl, N-hydroxy ethyl and
N-aryl substituted 1, 4-dihydropyridines and polyhydroquinoline derivatives, have
been synthesized with high to excellent yields. Short reaction times, simple
work-up, and mild reaction conditions are advantages of this procedure. The
catalyst is reusable without loss of activity for five runs.
INTRODUCTION
At the beginning of the new century, a shift in emphasis in chemistry is apparent with the desire to
develop environmentally benign routes to a myriad of materials.1 Green chemistry approach hold out
significant potential not only for reduction of by products, a reduction in the waste produced, and
lowering of energy costs but also in the development of new methodologies toward previously
unobtainable materials, using existing technologies.2 Of all of the existing areas of chemistry, medicinal
and pharmaceutical chemistry, with their traditionally large volume of waste/ product ratio , are perhaps
the most ripe for greening.3
In the main stream of the current interest in one-pot multicomponent reactions4 that permit a rapid access
to combinatorial libraries of organic molecules for efficient lead structure identification and optimization
in drug discovery,5,6 the acid-catalyzed condensation of aldehyde, β-ketoester, and ammonia, known as
the Hantzsch reaction from the name of its inventor,7 is receiving increased attention. This reaction
generated multi functionalized products including 1, 4-dihydropyridines (1, 4-DHP), polyhydroquinolines
derivatives and other related heterocyclic compounds. Five- and six-membered heterocyclic compounds
are important constituents that often exist in biologically active natural products and synthetic compounds

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HETEROCYCLES, Vol. 75, No. 9, 2008
of medicinal interest. 4-Aryl-1, 4-DHPs are analogues of NADH coenzymes which have been explored
for their calcium channel activity.8 Cardiovascular agents such as nifedipine, amlodipine, felodipine,
nimodipine (Figure 1) and other related derivatives are dihydropyridyl compounds which are effective for
the treatment of angina and hypertension.9
Cl
Cl
O2N
Cl
O
NO2
O
O
O
O
O
O
O
OMe
O
MeO
OEt
MeO
OMe
EtO
OMe
O
N
N
N
N
H
OCH2CH2NH2
H
H
H
Nifedipine
Amlodipine
Nimodipine
Felodipine
Figure 1. Typical medicinal 1, 4-DHPs
These compounds exhibit various medicinal functions such as neuroprotectant, platelet anti-aggregatory
activity, chemosensitizer in tumor therapy and cerebral antischemic activity in the treatment of
Alzheimer’s disease.10-13 Moreover, they serve as key intermediates in biogenesis of indol alkaloids14,15
and participate actively in biochemical oxidoreductase and transaminase reactions.16 These examples
clearly indicates the remarkable potential of 1, 4-DHP derivatives as a source of valuable drug units.
The classical method for the synthesis of these compounds, suffer from several disadvantages such as
long reaction times, poor yields, harsh reaction conditions and use of large quantities of volatile organic
solvents. Thus, a number of modified methods under improved conditions have been reported.17-31
However, unsatisfactory yields, high temperatures, expensive metal precursors, use of hazardous solvents
and non recyclable or reused catalysts limit the use of some of these procedures. Additionally, since the
classical approach yielding N-alkyl or N-aryl 1, 4-DHPs derivatives with negative results or very poor
yields, most of these studies have been devoted to Hantzsch synthesis of N-unsubstituted DHPs. Modified
synthetic methodologies for N-substituted 1, 4-DHPs reportly provided improve yields, but used
expensive reagents or high temperatures and required long reaction times.32,33 Hence, the development of
simple procedure by using of reusable catalyst and solvent free condition is of prime importance.
The strong Brönsted acidity34,35 of heteropolyacids (HPAs) and the softness of the heteropoly anions are
responsible for their high catalytic activities in the reactions.36 In comparison with the conventional liquid
acid catalysts, HPAs have advantages of being non-corrosive, environmentally benign, and presenting
fewer disposal problems. Due to the more reactivity of these compounds than conventional inorganic and
organic acids, they have found interesting industrial applications in synthesis of antioxidants, medicinal
preparations, vitamins, and biologically active substance and some are already applied in practice.37-40
Another crucial point is the chemical stability and also, it should be anchored to physically robust
framework in order to secure recovery without detriment of catalytic properties. The main disadvantage

HETEROCYCLES, Vol. 75, No. 9, 2008
2227
of HPAs as catalysts is their very low surface area (< 10 m2g-1) and thus, it becomes necessary to disperse
them on supports that possess large surface area. Several supports such as silica, alumina, clays, carbon
and titania have been used to enhance the dispersion of HPA, thereby increasing the accessibility to their
acidic sites. Among them, titania is known to enhance the activity in many cases due to the strong
interaction between the active phase and the supports.41
In view of the biological importance of 1, 4-DHPs and in continuation of our attempt toward “Green”
synthesis,42-44 this paper describes the improvement of one-pot symmetrical and unsymmetrical Hantzsch
reactions using PW/TiO2 as a reusable and non-toxic catalyst under solventless conditions.
RESULTS AND DISCUSSION
At first the three component condensation reaction of benzaldehyde (1 mmol), ethyl acetoacetate (2
mmol) and ammonium acetate (1 mmol) was performed in the presence of catalytic amount of several
supported HPAs (Table 1). Various supported HPAs accelerated the reaction but PW/TiO2 gave superior
results in term of yield and reaction time (Table 1, entries 1-14). With this optimistic results in hand,
further investigations were done by using various quantities and different weight percent of PW (Table 1,
entries 14-18). Increasing of the quantity of catalyst from 2 mol% to 3 mol%, leads to the formation of
side product. Similar result was obtained when PW loading on support was increased. Thus, 2 mol%
(based on aldehyde) of 40% PW/TiO2 was selected as optimized reaction condition to exam the
universality of catalyst’s application.
Aromatic, heterocyclic and unsaturated aldehydes react with ethyl acetoacetate and ammonium acetate in
the presence of PW/TiO2 and the corresponding products were obtained in excellent yields (Table 2,
entries 1-6). However, acetophenone afforded relevant lower yield (entry 7). Bioactive N-substituted 1,
4-DHPs were prepared with good yields (entries 8-12). These compounds containing reactive
functionalities for further manipulation of 1, 4-DHP moieties, for example, synthesis of N-hydroxyethyl 1,
4-DHPs (1h, 1i) and its bis analogous (1j), let us achieving to the designed new complex molecules with
multi 1, 4-DHP moieties in future.32 N-aryl-5, 6-unsubstituted dihydropyridines (1k, 1l) are also important
from a synthetic point of view, since the presence of a C5-C6-unsubstituted bond enables the use of these
compounds as enamine-like reagents, allowing the preparation of a variety of complex heterocyclic
frame-works.33
Based on these observations, catalytic efficiency of PW/TiO2 in the unsymmetrical Hantzsch reaction has
been studied. The model reaction was carried out by mixing of benzaldehyde, dimedone, ethyl
acetoacetate and ammonium acetate in the presence of PW/TiO2 at rt and corresponding
product was obtained with 24% yield. Whereas by increased the temperature to 80 ºC, a significant
improvement was observed and the yield of the product was increased to 95% after 15 min (Table 3,

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HETEROCYCLES, Vol. 75, No. 9, 2008
entries 1, 2). Encouraged by these results, study was continued by using various aldehydes in the presence
of the catalyst at 80 ºC. Aliphatic, aromatic and heterocyclic aldehydes afforded the polyhydroquinolines
in excellent yields at short reaction times (Table 3, entries 2-8).
To the best of our knowledge, there is no report in the literature to introduce PW/TiO2 as a reusable
catalyst. When the reaction was carried out in acetonitrile as solvent, analysis of the reaction crud
indicates a leaching of 90% of the PW. But in solventless conditions PW/TiO2 could be recovered and
subsequently reused several times. It showed no loss of activity after five successive runs, the yield of the
product for model reaction remained 90% after fifth run.
Table 1. Effect of different catalysts for condensation of benzaldehyde, ethyl acetoacetate and ammonium
acetate
Ph
O
O
EtO2C
CO2Et
CHO
catalyst, no solvent
rt
NH4OAc
+
+
OEt
N
H
Entry
Catalyst
Time (min)
Yield (%)a
79
1
40 wt.%PW/K10 (2mol %)
40 wt.%PMo/K10 (2mol %)
40 wt.%SiW/K10 (2mol %)
40 wt.%PW/KSF (2mol %)
40 wt.%PMo/KSF (2mol %)
40 wt.%SiW/KSF (2mol %)
40 wt.%PW/γ-Al2O3 (2mol %)
40 wt.%PMo/γ-Al2O3 (2mol %)
40 wt.%SiW/γ-Al2O3 (2mol %)
40 wt.%PW/C (2mol %)
11
10
15
16
20
20
20
20
25
20
25
30
7
2
80
3
91
4
95
5
94
6
96
7
92
8
91
9
70
10
11
12
13
14
15
16
17
18
58
40 wt.%PMo/C (2mol %)
40 wt.% SiW/C (2mol %)
40 wt.% PMo/TiO2 (2mol %)
40 wt.% PW/TiO2 (2mol %)
20 wt.%PW/TiO2 (2mol %)
60 wt.%PW/TiO2 (2mol %)
40 wt.%PW/TiO2 (1.4mol %)
40 wt.%PW/TiO2 (3mol %)
59
52
61
5
92
8
63
10
11
10
44
88
91
aIsolated yield.

HETEROCYCLES, Vol. 75, No. 9, 2008
2229
Table 2. TiO2-supported H3PW12O40 catalyzed synthesis of Hantzsch products
O
O
40% PW/TiO2 (2mol%)
no solvent, rt
R1CHO
product
R2
amine
+
+
1a-l
Time (min)
/ Yield (%)
Entry R1
R2
Amine
Product
Ref
28
Ph
EtO2C
CO2Et
Me
1
OEt NH4OAc
OEt NH4OAc
5/92
Me
N
H
1a
EtO2C
Me
2
3
22/96
28
25
28
NH
S
S
EtO2C
EtO2C
Me
Me
1b
1c
1d
OEt NH4OAc
OEt NH4OAc
11/81
28/94
NH
Me
O
O
EtO2C
EtO2C
Me
4
Me
Cl
NH
Me
EtO2C
EtO2C
Me
Me
5
OEt NH4OAc
OMe NH4OAc
15/82
25
NH
Me
Cl
1e
EtO2C
CHPh
H
O
C
O
6
7
12/93
15/63
28
28
MeO
OMe
Me
Me
N
H
PhOC
1f
Me
NH
Me
Ph
NH4OAc
MeO
MeO
PhOC
1g
MeO2C
MeO2C
Me
8
9
OMe HO(CH2)2NH2
OMe HO(CH2)2NH2
27/71
12/98
32
32
O2N
O2N
N CH2CH2OH
Me
1h
1i
MeO2C
Me
N CH2CH2OH
Me
O
MeO2C
O
Me
HO(H2C)2N
Me
CO2Me
MeO2C
Me
N(CH2)2OH
Me
10
OMe HO(CH2)2NH2
28/86
32
OHC
CO2Me MeO2C
1j

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HETEROCYCLES, Vol. 75, No. 9, 2008
N
11
OEt PhNH2
35/63
30/62
33
33
Me
CO2Et
1k
1l
Cl
N
12
OEt 4-Cl-PhNH2
Me
CO2Et
aIsolated yield.
Table 3. TiO2-supported H3PW12O40 catalyzed synthesis of polyhydroquinoline derivatives
O
R1
O
O
O
O
R2
40% PW/TiO2 (2mol%)
R1CHO
R2
NH4OAc
+
+
+
°
no solvent, 80 C
N
H
O
2a-h
Entry R1
1b
R2
Product
Time (min) Yield (%)a
Ref
27
OEt
OEt
OEt
2a
60
15
6
24
95
92
2
3
2b
2c
27
21
O
4
5
OEt
OEt
2d
2e
4
3
98
98
27
27
(Me)2N
6
7
8
OEt
OEt
OMe
2f
5
98
89
91
21
21
27
n-MeCH2CH2
2g
2h
20
12
Me
aIsolated yield. bThis reaction was performed at rt.
In summary, we have described a simple, rapid and versatile catalytic method for the synthesis of various
Hantzsch products in high to excellent yields. In addition, it is possible to apply the tents of “Green
Chemistry” to the generated of biologically interesting Hantzsch products using solvent less medium
approach that are less expensive and non-hazardous than those with organic solvents. Recycability of
supported catalyst is the main feature of this procedure.

HETEROCYCLES, Vol. 75, No. 9, 2008
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EXPERIMENTAL
MATERIALS AND METHODS
H3PW12O40, H4SiW12O40, and H3PMo12O40 hydrate from Aldrich, Merck and. Carbon, KSF and K10
montmorillonite clay were obtained from Fluka. γ-Alumina and titania were obtained from Aldrich and
Degussa respectively. The tungsten or molybdenum content in the catalysts was measured by inductively
1
coupled plasma (ICP) atomic emission spectroscopy on a Spectro Ciros CCd spectrometer. H NMR
spectra were recorded on a Bruker Avance 200 MHz NMR spectrometer with CDCl3 as the solvent and
TMS as the internal standard.
PREPARATION OF THE CATALYSTS
The catalysts were prepared using solutions of tungstophosphoric acid (PW), molybdophosphoric acid
(PMo), or tungstosilicic acid (SiW). The solutions were used to impregnate supports with different
characteristics. The solids employed as supports were activated carbon, γ-Al2O3, TiO2, KSF and K 10
montmorillonites.
Titania-supported PW (PW/TiO2) catalysts were prepared by impregnating titania (5.0 g) with an aqueous
solution of PW (with concentrations depending upon the loadings, 20, 40 and 60 wt% PW on titania).
The mixture was stirred overnight at rt, followed by drying using a rotary evaporator. For
preparation of the PW/K 10, K 10 montmorillonite was dried in an oven at 120 °C for 2 h prior to its use
as support. After drying, 5.0 g of K 10 was taken. To prepare a catalyst with 40% loading of PW, 2.0 g of
PW was dissolved in 4 cm3 of dry MeOH. This solution was added dropwise to predried K 10 with
constant stirring with a glass rod. Initially with addition of PW solution, the clay was in the powdery form,
but on further addition of PW solution, the clay turned to a paste form. The paste on further stirring for 10
min resulted in a free flowing powder. A similar procedure was followed for the synthesis of PW/KSF. A
catalyst based on PW supported on γ-Al2O3 was also prepared. The solution of PW was prepared by
dissolving 2.0 g of PW in 25 cm3 of water and 25 cm3 of MeOH. Then 5.0 g of γ-Al2O3 was dropped into
the above solution under vigorous stirring to be impregnated for 24 h. For preparation of PW/C, carbon
was first subjected to an acid and base treatment to remove impurities. The catalyst was prepared by the
pore filling impregnation technique with a PW solution. After the impregnation, all catalysts were dried at
rt for 24 h, and calcined at 200 °C for 3 h.
TYPICAL PROCEDURE FOR HANTZSCH THREE COMPONENT CONDENSATION
A mixture of aldehyde (1 mmol), β-dicarbonyl compound (2 mmol, and 1 mmol for entries 11, 12, Table
2), amine (1 mmol) and appropriate amount of the catalyst (Table 1), was stirred at ambient temperature.
Progress of the reaction was monitored by TLC. After completion of the reaction, the resulting solid
product was crushed, diluted with acetonitrile (2×5 cm3) and filtered. Filtrate was concentrated in vaccuo
to afford the crude product. A pure product was obtained as a yellow solid by further recrystallation in

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ethanol. At the end of the reaction, the reaction mixture was treated with MeCN and filtered to
recover the catalyst. The wet catalyst was washed with ether and recycled to check the reusability of the
catalyst.
TYPICAL PROCEDURE FOR HANTZSCH FOUR COMPONENT CONDENSATION
A mixture of aldehyde (1 mmol), EtOAc (1 mmol), dimedone (1 mmol) and ammonium
acetate (1 mmol) was stirred at 80 ºC in the presence of appropriate amount of the catalyst (Table 1) until
all reactants were consumed (monitored by TLC). Purification of products and recyclization of the
catalyst are similar to above procedure.
ACKNOWLEDGEMENTS
The authors thank the Razi University Research Council and Kermanshah Refinery Company for support
of this work.
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