Aluminum phosphate [AlPO4(H)]: A mild and efficient recyclable catalyst for one-pot synthesis of polyhydroquinoline via the hantzsch reaction under solvent-free conditions

Article abstract of DOI:10.1002/jhet.793

Polyhydroquinolines have been synthesized in good to excellent yields (80-90%) and short reaction times (15-30 min) in the presence of aluminum phosphate [AlPO₄] as heterogeneous catalyst at 90°C; the reaction workup is simple and the catalyst

Full text of DOI:10.1002/jhet.793

232
Aluminum Phosphate [AlPO4(H)]: A Mild and Efficient
Recyclable Catalyst for One-Pot Synthesis of Polyhydroquinoline
via the Hantzsch Reaction Under Solvent-Free Conditions
Vol 49
K. Purandhar,a V. Jyothi,a P. Pratap Reddy,b M. Adharvana Chari,c
and K. Mukkantid*
aResearch and Development, Matrix Laboratories Limited, Anrich Industrial Estate, Medak
District-502325, A.P., India
bResearch and Development, Macleods Pharmaceuticals Ltd., Shanthi Nagar, Andheri (E),
Mumbai-400 093, Maharashtra, India
cInternational Center for Materials Nanoarchitectonics (MANA), National Institute of Material
Science, Tsukuba, Japan
dDepartment of Chemistry, JNTUH, Kukatpally, Hyderabad-500072, A.P., India
*E-mail: kmukkanti@gmail.com
Received September 25, 2010
DOI 10.1002/jhet.793
Published online 2 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
Polyhydroquinolines have been synthesized in good to excellent yields (80–90%) and short reaction
times (15–30 min) in the presence of aluminum phosphate [AlPO4] as heterogeneous catalyst at 90ꢀC;
the reaction workup is simple and the catalyst aluminum phosphate [AlPO4] can be easily separated
from the product and reused.
J. Heterocyclic Chem., 49, 232 (2012).
INTRODUCTION
antioxidant [9] (diludine is routinely used [10]), hepato-
protective [11], antimutagenic [12], geroprotective [13],
bronchodilating [14], antidiabetic [15], herbicidal [16],
photosensitizing activities [17] and posses hypotension of
long duration (more than 17 min) when administered
intravenously to the anaesthetized animal [18]. More
extensive studies indicate that these compounds exhibit
different medical functions such as neuroprotectants, pla-
telet antiaggregators, cerebral antiischemic agents, and
chemosensitizers [19].
The polyhydroquinolines are potent active compounds
and these compounds have been receiving a lot of atten-
tion in the recent years owing to their excellent biologi-
cal activities. The chemistry of dihydropyridines (DHPs)
and their cyclic analogs polyhydroquinolines up to the
year 2006 had been reviewed in several surveys of liter-
ature [1,2]. Among the polyhydroquinoline compounds,
1,4-dihydropyridines are more important as its applica-
tion in medicine and industry and investigations along
these lines include the synthesis of model compounds
NAD (P) H-analogs of 1,4-dihydronicotinamide and
their involvement in hydrogen transfer reactions is im-
portant task. Recently, several review papers have
appeared on the subject [3] including the transfer of
hydrogen and other groups by chiral DHP [4]. These
compounds are chiefly obtained by using various modifi-
cations of Hantzsch synthesis. Most extensively studied
are the calcium antagonists, whose synthesis [5] and
properties [6] have been treated in a number of reviews.
Several papers describe investigations of individual drug
[7] such as vasodilators and antihypertensive remedies—
nifedipine, nitrendipine. Calcium transport agonists have
been also found among 1,4-DHP [8]. 1,4-DHP posses
Generally, the basic skeleton of DHP was first discov-
ered [20] by Hantzsch in 1882 and this classical method
involves the three-component coupling of an aldehyde
with ethyl acetoacetate and ammonia in acetic acid or in
refluxing alcohol. Numerous methods have been
reported [21–32] for the synthesis of polyhydroquinoline
derivatives, because of the biological importance associ-
ated with 1,4-DHP ring and polyhydroquinoline deriva-
tives. However, these methods suffer from drawbacks
such as a long reaction time, an excess of organic sol-
vent, lower product yields, and harsh refluxing condi-
tions. Thus, chemists have developed several alternate
and more efficient methods for the synthesis of polyhy-
droquinoline derivatives, which include the use of
microwaves, ionic liquids, refluxing at high temperature,
C
V
2011 HeteroCorporation

January 2012 Aluminum Phosphate [AlPO4(H)]: A Mild and Efficient Recyclable Catalyst for One-Pot
Synthesis of Polyhydroquinoline via the Hantzsch Reaction Under Solvent-Free Conditions
233
Scheme 1. Synthesis of polyhydroquionoline derivatives.
tri methyl silyl chloride (TMSCI)-NaI, metal triflates, I2,
HClO4ꢁSiO2 and very recently ceric ammounium nitrate
(CAN) was reported to be efficient for this transforma-
tion. However, the use of high temperatures, expensive
metal precursors, catalyst that are harmful to the envi-
ronment and long reaction times limits the use of these
methods. Thus the development of a simple and efficient
method for the preparation of plolyhydroquinoline deriv-
atives is an active area of research and there is scope
for further improvement involving milder reaction con-
ditions and higher product yields.
satisfactory yields. It was observed that the yield of the
final product increases with increasing the temperature
and amount of the catalyst in the reaction mixture. The
yield of the final product increases from 25% to 90%
with increasing the temperature from room temperature
to 90ꢀC.
Encouraged by these results, we examined several
aromatic aldehydes under the optimized reaction con-
ditions. Many aromatic aldehydes underwent smooth
reaction with 5,5-dimethyl-1,3-cyclohexanedione, ethyl
acetoacetate, and ammonium acetate to give high yields
of products (Table 2). Aromatic aldehydes containing
both electron-donating and electron-withdrawing groups
worked well in this reaction. Clearly, the effect of the
nature of the substituents on the aromatic ring showed
no obvious effect on this conversion, because they were
obtained in excellent yields. The catalyst also found to
be very active for the preparation of polyhydroquinoline
derivatives and substituted aldehydes have been used
with similar success to provide the corresponding prod-
ucts in high yields, which are also of much interest with
respect to biological activity.
In view of its inherent properties like environmental
compatibility, reusability, greater selectivity, operational
simplicity, noncorrosiveness, low cost and ease of isola-
tion, we wish to describe our results on AlPO4(H) [33–
35] catalyzed four-component reactions of aldehydes,
dimedones, ethyl acetoacetate, and ammonium acetate
(Scheme 1). In addition, to the best of our knowledge,
there are no reports on the use of AlPO4(H) as a hetero-
geneous catalyst in a solvent-free media at 90ꢀC for this
conversion. This fact has prompted us to investigate
AlPO4(H) for the synthesis of polyhydroquinoline deriv-
atives in a facile and practical manner.
We investigated the reusability of the AlPO4 catalyst
in this reaction, and we used p-chlorobenzaldehyde
(10 mmol), 5,5-dimethyl-1,3-cyclohexanedione (10 mmol),
ethyl acetoacetate (10 mmol), ammonium acetate (15 mmol),
and 4.06 mmol of AlPO4(H) together, and then the
Intially, p-chlorobenzaldehyde was selected as a rep-
resentative aldehyde along with 5,5-dimethyl-1,3-cyclo-
hexanedione, ethylacetoacetate, ammonium acetate, and
AlPO4(H) as catalyst to optimize the reaction conditions.
As can be seen from Table 1, it was found that the reac-
tion in the presence of catalytic amount of AlPO4(H)
needs shorter reaction time than that without any cata-
lyst at room temperature (Table 1, entries 1 and 2).
But when the reaction was investigated at 90ꢀC under
solvent-free media, the reaction catalyzed by AlPO4(H)
was completed with higher yield and in shorter reaction
time (Table 1, entries 3 and 4). Obviously, the tempera-
ture and the catalyst have important effect on the reac-
tion. So the best condition was that the reaction was cat-
alyzed by 10 mg, 0.813 mmol of AlPO4(H) at 90ꢀC.
Using the optimized conditions reported in Table 1
(entry 3), we continued to investigate the reaction
at temperature of 90ꢀC under solvent-free media with
10 mg of AlPO4(H); the desired product was obtained in
Table 1
The effect of temperature and weight of the catalyst in the synthesis of
polyhydroquinoline derivatives.
Temperature
(ꢀC)
AlPO4(H)
weight (mg)
Time
(min)
Yield
(%)a
Entry
1
2
3
4
5
RT
RT
90
No catalyst
150
150
15
25
60
90
90
90
10
10
15
20
90
90
15
15
Reaction conditions—substrates: p-chloro benzaldehyde; 5,5-dimethyl-
1,3-cyclohexanedione; ethyl acetoacetate; ammonium acetate.(1:1:1:1.5).
a Isolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Table 2
AlPO4(H) catalyzed synthesis of polyhydroquinoline derivatives with various aldehydes under solvent-free conditions.
Entry
Aldehyde (1)
Product (5)a
Time (min)
15
Yield (%)b
87
a
b
c
d
e
f
15
20
25
15
30
30
20
30
90
89
89
90
85
85
80
82
g
h
i
a All the products were characterized by IR, 1H NMR, and mass spectroscopy.
b Isolated yields.

January 2012 Aluminum Phosphate [AlPO4(H)]: A Mild and Efficient Recyclable Catalyst for One-Pot
Synthesis of Polyhydroquinoline via the Hantzsch Reaction Under Solvent-Free Conditions
235
DMSO-d6): d 0.85 (s, 3H, ACH3), 1.50 (s, 3H, ACH3),
1.20 (t, 3H, J ¼ 7.5 Hz, ACH3), 2.10 (dd, 2H, ACHA),
2.30 (s, 3H, ACH3 and dd merged with singlet, 2H,
ACH2A), 4.00 (q, 2H, J ¼ 7.4 Hz, AOCH2A), 4.88 (s,
1H, ACH2A), 7.00–7.21 (m, 5H, ArH), 8.70 (brs, 1H,
ANHA). electro spray ionisation-mass spectrometry
(ESI-MS): m/z 340 [Mþ].
Table 3
Recyclability of the catalyst for synthesis of 5e (Table 2).
Cycle No.
1
2
3
4
5
6
7
Time (min)
Yield (%)
15
90
15
90
15
87
25
85
30
80
30
75
40
60
Compound (5b). m.p.: 268–270ꢀC. IR (KBr): 3275
(NAH), 1700 (C¼¼O) cmꢂ1
.
1H-NMR (300 MHz,
mixture in round bottomed flask was stirred at 90ꢀC for
15 min without any solvent. When the reaction was com-
pleted, the catalyst was separated by simple filtration by
diluting with methanol and recovered AlPO4(H) was
reused in subsequent reactions, and the results are pre-
sented in Table 3.
CDCl3 þ DMSO-d6): d 0.90 (s, 3H, ACH3), 1.10 (s,
3H, ACH3), 1.20 (t, 3H, J ¼ 7.2 Hz, ACH3), 2.09 (dd,
2H, ACH2A), 2.20 (s, 3H, ACH3), 3.33 (s, 3H, ACH3
and dd merged with singlet, 2H, ACH2A), 4.00 (q, 2H,
J ¼ 6.4 Hz, AOCH2A), 4.80 (s, 1H, ACHA), 6.90 (d,
2H, J ¼ 8.2 Hz, ArH), 7.09 (d, 2H, J ¼ 8.2 Hz, ArH),
8.62 (brs, 1H, ANHA). ESI-MS: m/z 354 [Mþ].
In conclusion, the present study describes a conven-
ient and efficient process for the synthesis of polyhydro-
quinoline derivatives through a four-component coupling
of various aromatic aldehydes, 5,5-dimethyl-1,3-cyclo-
hexanedione, ethyl acetoacetate, and ammonium acetate
in a solvent-free media at 90ꢀC using AlPO4(H) as a
heterogeneous catalyst. The catalyst is highly active,
stable, and could be reused several times without much
loss of its activity. Present methodology offers very
attractive features such as reduced reaction times, higher
yields, and has wide scope in organic synthesis. This
simple procedure with ease of recovery makes this
method economic, benign, and a waste-free chemical
process for the synthesis of polyhydroquinoline deriva-
tives. We believe that this procedure is convenient, eco-
nomic, and a user-friendly process for the synthesis of
polyhydroquinoline derivatives. This catalyst is highly
fascinating; this could also be used for several acid cata-
lyzed organic transformations and could replace the
existing homogenous catalysts which are currently being
used in the industry.
Compound (5c). m.p.: 200–203ꢀC. IR (KBr): 3395
(NAH), 1695 (C¼¼O), cmꢂ1
.
1H-NMR (300 MHz,
CDCl3 þ DMSO-d6): d 0.92 (s, 3H, ACH3), 1.00 (s,
3H, ACH3), 1.20 (t, 3H, J ¼ 7.3 Hz, ACH3), 2.10 (dd,
2H, ACH2A), 2.30 (s, 3H, ACH3 and dd merged with
singlet, 2H, ACH2A), 3.73 (s, 3H, AOCH3), 4.50 (q,
2H, J ¼ 7.4 Hz, AOCH2A ), 4.79 (s, 1H, ACHA), 6.59
(d, 1H, J ¼ 5.2 Hz, ArH), 6.72 (s, 1H, ArH), 6.78 (d,
1H, ArH) 7.05 (t, 1H, J ¼ 7.4 Hz, ArH), 8.60 (brs, 1H,
ANHA). ESI-MS: m/z 370 [Mþ].
Compound (5d). m.p.: 243–245ꢀC. IR (KBr): 3275
(NAH), 1644 (C¼¼O) cmꢂ1
.
1H-NMR (300 MHz,
DMSO-d6): d 0.90 (s, 3H, ACH3), 1.00 (s, 3H, ACH3),
1.15 (t, 3H, J ¼ 7.3 Hz, ACH3), 2.10 (dd, 2H,
ACH2A), 2.35 (s, 3H, ACH3 and dd merged with sin-
glet, 2H, ACH2A), 3.73 (s, 3H, AOCH3), 4.00 (q, 2H,
J ¼ 7.2 Hz, AOCH2A), 4.82 (s, 1H, ACHA), 6.70 (d,
2H, J ¼ 9.0 Hz, ArH), 7.15 (d, 2H, J ¼ 9.0 Hz, ArH),
8.80 (brs, 1H, ANHA).
Compound (5e). m.p: 250–253ꢀC. IR (KBr): 3274
(NAH), 1706 (C¼¼O) cmꢂ1
.
1H-NMR (300 MHz,
DMSO-d6): d 0.89 (s, 3H, ACH3), 1.10 (s, 3H, ACH3),
1.19 (t, 3H, J ¼ 7.2 Hz, ACH3), 2.10 (dd, 2H,
ACH2A), 2.30 (s, 3H, ACH3 and dd merged with sin-
glet, 2H, ACH2A), 4.00 (q, 2H, AOCH2A ), 4.89 (s,
1H, ACH), 7.10 (d, 2H, J ¼ 9.0 Hz, ArH), 8.62 (brs,
1H, ANHA). ESI-MS: m/z 374 [MþþH].
TYPICAL PROCEDURE
Aldehyde (2 mmol), dimedone (2 mmol), ammonium
acetate (3 mmol), ethyl acetoacetate (5 mL), and
AlPO4(H) (10 mg, 0.813 mmol) were successively
charged in to a 50 mL round bottomed flask, equipped
with a magnetic stirrer. Then the reaction mixture pro-
ceeded at 90ꢀC for 15–30 min and a solid product was
gradually formed. After completion of reaction as indi-
cated by thin layer chromatography (TLC), the resulting
solid product was diluted with methanol, filtered and
catalyst was washed with methanol for reuse and filtrate
was concentrated in vaccuo to afford the crude product.
A pure product was obtained as a yellowish solid by
further recrystallization in ethanol.
Compound (5f).
m.p.: 208–210ꢀC. IR (KBr): 3292 (NAH), 1698
1
(C¼¼O) cmꢂ1. H-NMR (300 MHz, CDCl3 þ DMSO-
d6): d 0.85 (s, 3H, ACH3), 1.09 (s, 3H, ACH3 and dd
merged with triplet, 3H, J ¼ 7.2 Hz, ACH3), 2.00 (dd,
2H, ACH2A), 2.25 (dd, 2H, ACH2A), 2.43 (s, 3H,
ACH3), 4.00 (q, 2H, AOCH2A), 5.72 (s, 1H, ACHA),
7.20 (t, 2H, J ¼ 6.4 Hz, ArH), 7.45 (m, 2H, ArH), 7.65
(d, 1H, J ¼ 8.0 Hz, ArH), 8.60 (brs, 1H, ANHA).
Compound (5a). m.p.: 251–253ꢀC. IR (KBr): 3288
Compound (5g). m.p.: 278–280ꢀC. IR (KBr): 3300
(NAH), 1699 (C¼¼O) cmꢂ1
.
1H-NMR (300 MHz,
(NAH), 1695 (C¼¼O) cmꢂ1
.
1H-NMR (200 MHz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

236
K. Purandhar, V. Jyothi, P. P. Reddy, M. A. Chari, and K. Mukkanti
Vol 49
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CDCl3 þ DMSO-d6): d 0.95 (s, 3H, ACH3), 1.09 (s,
3H, ACH3), 1.25 (t, 3H, J ¼ 7.2 Hz, ACH3A), 2.10
(dd, 2H, ACH2A), 2.30 (s, 3H, ACH3 and dd merged
with singlet, 2H, ACH2A), 3.75 (s, 3H, AOCH3), 4.05
(q, 2H, J ¼ 6.4 Hz, AOCH2A), 4.79 (s, 1H, ACHA),
6.25 (s, 1H, ArAH), 6.35 (s, 1H, ArAH), 7.18 (brs, 1H,
AOH), 7.85 (s, 1H, AOH), 8.49 (brs, 1H, ANHA). ESI-
MS: m/z 402 [MþþH].
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Compound (5h). m.p.: 230–233ꢀC. IR (KBr): 3395
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(NAH), 1690 (C¼¼O) cmꢂ1
.
1H-NMR (300 MHz,
CDCl3 þ DMSO-d6): d 0.92 (s, 3H, ACH3), 1.00 (s,
3H, ACH3), 1.25 (t, 3H, J ¼ 15.4 Hz, ACH3), 2.00 (dd,
2H, ACH2A), 2.22 (s, 3H, ACH3 and dd merged with
singlet, 2H, ACH2A), 3.70 (s, 3H, AOCH3), 4.05 (q,
2H, AOCH2), 4.75 (s, 1H, ACHA), 6.50 (s, 2H,
ArAH), 6.70 (s,1H, ArH), 8.02 (s, 1H, AOH), 8.65 (brs,
1H, ANHA). ESI-MS: m/z 386 [MþþH].
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Compound (5i). m.p.: 243–245ꢀC. IR (KBr): 3415
(NAH), 1685 (C¼¼O) cmꢂ1
.
1H-NMR (300 MHz,
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(s, 3H, ACH3), 1.25 (t, 3H, J ¼ 7.0 Hz, ACH3), 2.12
(dd, 2H, ACH2A), 2.30 (s, 3H, ACH3 and dd merged
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