Mesoporous alumina sulphuric acid: A novel and efficient catalyst for on-water synthesis of functionalized 1,4-dihydropyridine derivatives via β-enaminones

Article abstract of DOI:10.1016/j.molcata.2014.07.015

A simple, efficient and environmentally benign on-water protocol for the synthesis of novel 1,4-dihydropyridine derivatives via pseudo four component addition and cyclization sequence using mesoporous alumina sulphuric acid as a recyclable and heterogeneous catalyst, has been described. The catalyst showed excellent catalytic activity giving products in high yields and could be reused for seven successive catalytic cycles. The catalyst was characterized by FT-IR, XRD, FE-SEM, EDX and TG analyses. The mesoporosity of alumina was determined by BET and TEM analyses.

Full text of DOI:10.1016/j.molcata.2014.07.015

Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
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Journal of Molecular Catalysis A: Chemical
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Mesoporous alumina sulphuric acid: A novel and efficient catalyst for
on-water synthesis of functionalized 1,4-dihydropyridine derivatives
via ␤-enaminones
Nayeem Ahmed, Zeba N. Siddiqui∗
Department of Chemistry, Aligarh Muslim University, Aligarh 202 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2014
Received in revised form 9 July 2014
Accepted 10 July 2014
Available online 19 July 2014
A simple, efficient and environmentally benign on-water protocol for the synthesis of novel 1,4-
dihydropyridine derivatives via pseudo four component addition and cyclization sequence using
mesoporous alumina sulphuric acid as a recyclable and heterogeneous catalyst, has been described. The
catalyst showed excellent catalytic activity giving products in high yields and could be reused for seven
successive catalytic cycles. The catalyst was characterized by FT-IR, XRD, FE-SEM, EDX and TG analyses.
The mesoporosity of alumina was determined by BET and TEM analyses.
Keywords:
On-water
© 2014 Elsevier B.V. All rights reserved.
Dihydropyridines
Mesoporous alumina sulphuric acid
Heterogeneous catalyst
1. Introduction
straightforward access to large libraries of structurally related,
drug-like compounds and thereby facilitating lead generation and
In the light of green chemistry water is uniquely advanta-
geous as a solvent. It is environmentally benign, non-flammable,
possesses a high heat capacity, and tolerates a wide range of tem-
perature, making it inherently safe. It also possesses the remarkable
ability to catalyze chemical transformations between some insolu-
ble organic reactants and this phenomenon, termed as “on-water”
catalysis by Sharpless and co-workers, was first observed in the
late 1930s but is only now being widely adopted [1–8]. Subsequent
mechanistic studies have established that this behaviour results
from enforced hydrophobic interactions [9] and stabilization of the
activated complex by hydrogen-bond formation [10]. Sharpless’s
group has shown that several uni- and bimolecular reactions are
greatly accelerated when carried out in vigorously stirred aqueous
suspensions. These reactions include the important classes such as
cycloadditions, ene reactions, Claisen rearrangements and nucleo-
philic substitutions [1].
lead optimization in drug discovery [12]. In a true sense, these rep-
resent environmentally friendly processes by reducing the number
of steps, energy consumption and waste production [13].
Nitrogen containing heterocycles are subunits found in numer-
ous natural products and many biologically active pharmaceuticals.
Among these 1,4-dihydropyridine substructures are among the
most prevalent, the most famous ones certainly being the cal-
cium agonists Felodipine, Nicardipine, Nimodipine, Nifedipine
(Fig. 1) and NADPH. In addition, these compounds show other
versatile biological profiles such as anticonvulsant activity, selec-
tive adenosine-A3 receptor antagonism, radioprotective activity,
sirtuin activation and inhibition, antitumor, antidiabetic, or pho-
tosensitizing activities [14–16]. Conventionally, 1,4-DHPs can be
synthesized via the Hantzsch reaction, reduction of pyridines, addi-
tion to pyridines or cycloadditions, etc. but the Hantzsch reaction
still remains a frequently employed tactic for the synthesis of
these compounds [17]. New efforts to develop structurally diverse
1,4-DHPs led to the utilization of enaminones as substrates and
few reports available in literature employing l-proline/MeOH,
TMSCl, TsOH/DCE, NaAuCl4 and AcOH [17,18] as catalytic systems.
However, these methods exhibit limited substrate tolerance and
reactivity, suffer from low yields, and use of toxic solvents. Hence
it is highly desirable to develop a new protocol for the synthesis
of 1,4-DHPs using enaminones, which is highly efficient, environ-
mentally benign and tolerates wide range of substrates.
Multicomponent reactions (MCRs) have become powerful
tools of synthetic organic chemistry in recent years owing to
exceptional synthetic efficiency, intrinsic atom economy, high
selectivity, and procedural simplicity [11]. These reactions enable
∗
Corresponding author. Tel.: +91 9412653054.
E-mail addresses: siddiqui zeba@yahoo.co.in, zns.siddiqui@gmail.com
(Z.N. Siddiqui).
http://dx.doi.org/10.1016/j.molcata.2014.07.015
1381-1169/© 2014 Elsevier B.V. All rights reserved.

N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
233
Fig. 1. Most representative biologically active 1,4-dihydropyridines.
Many industrial processes are catalyzed by strong Brønsted acid
catalysts including sulfuric acid, p-toluenesulfonic acid, etc. How-
ever, such homogeneous acids are costly, require special processing
in the form of neutralization, cannot be separated from homo-
geneous reaction mixtures and are not environmentally benign,
resulting in substantial energy wastage and the production of
large amounts of chemical waste. Replacing such conventional
“homogeneous Brønsted acids” with recyclable solid acids is a very
promising solution to this problem, and the potential of these solid
acids has been extensively studied [19,20].
Keeping in view the importance of enaminones in synthe-
sis of various heterocycles [21] herein, we report the synthesis
of substituted novel 1,4-dihydropyridine derivatives via pseudo
four component addition and cyclization involving ␤-enaminone,
different aldehydes and ammonium acetate catalyzed by meso-
porous alumina sulphuric acid in aqueous media. It is pertinent
to mention that enaminones and related compounds possessing
a nitrogen functionality and an electron-withdrawing group on
adjacent alkene carbons display both the nucleophilic and the elec-
trophilic character. This complementary electronic nature of the
enaminones has led to their utilization as building blocks for the
synthesis of many therapeutic agents such as antitumor, antibacte-
rial, antimalarial, and anti-inflammatory as well as anticonvulsant
agents [22–24].
gel G254 (E. Merck) using chloroform–methanol (3:1) mixture as
mobile phase and visualized by iodine vapours and alcoholic fer-
ric chloride. Enaminones were synthesized by reported procedure
[26].
2.2. Preparation of mesoporous alumina
In a typical synthesis, N-cetyl-N,N,N-trimethylammonium bro-
mide (CTAB) (0.2 mmol), Al2(SO4)3·18H2O (1 mmol), CO(NH2)2
(4 mmol), and sodium tartrate (0.7 mmol) were dissolved in dis-
tilled water to form a clear solution (36 mL) under vigorous stirring
for 0.5 h. The solution was placed in an autoclave with a Teflon
liner and was maintained at 165 ◦C for 8 h. The autoclave was then
allowed to cool and the white precipitate obtained was collected,
washed thoroughly with distilled water and then dried at 80 ◦C for
12 h. The sample was then calcined at 550 ◦C for 3 h to remove the
template [27].
2.3. Preparation of mesoporous alumina supported sulphuric acid
A 0.5 L suction flask was equipped with a constant pressure
dropping funnel. The gas outlet was connected to a vacuum system
through an adsorbing solution of alkali trap. Mesoporous alumina
(1 g) was added into the flask and stirred for 10 min in dry CH2Cl2
(20 mL). Chlorosulfonic acid (1 mL) was added drop wise over a
period of 30 min at room temperature. After complete addition of
chlorosulfonic acid, the reaction mixture was stirred for 90 min,
while the residual HCl was eliminated by suction. The mesoporous
alumina sulphuric acid obtained as solid, was separated from the
reaction mixture by filtration and washed several times with dried
CH2Cl2, ethanol. Finally the catalyst was dried at 120 ◦C for three
hours.
2. Experimental
2.1. General
Melting points of all the synthesized compounds were taken
in a Riechert Thermover instrument and are uncorrected. The IR
spectra were recorded on Perkin Elmer RXI spectrometer using
KBr pellets. 1H NMR and 13C NMR spectra were recorded on a
Bruker DRX-400 spectrometer using tetramethylsilane (TMS) as
an internal standard and DMSO-d6/CDCl3 as solvent. Mass spectra
were recorded on Micromass Quattro II (ESI) spectrometer. Ele-
mental analyses (C, H and N) were conducted using the Elemental
vario EL III elemental analyser and their results were found to be
in agreement with the calculated values. TGA data was obtained
with DSC-60 Shimadzu instrument and the analysis was performed
in the temperature range of 0–600 ◦C at a constant heating rate
of 20 ◦C/min in the nitrogen atmosphere. X-ray diffractograms
(XRD) of the catalyst were recorded in the 2Â range of 20–80◦
with scan rate of 4◦/min on a Rigaku Minifax X-ray diffractome-
2.4. Determination of H+ ion concentration of mesoporous
alumina sulphuric acid
H+ ion concentration of the catalyst was determined by neutral-
ization titration analysis. 100 mg of catalyst was stirred in 20 mL of
0.1 N NaOH solution for 30 min in an Erlenmeyer flask. The excess
amount of base was then neutralized by the addition of 0.1 N HCl
solution to the equivalence point of titration.
2.5. General procedure for “On water” synthesis of
dihydropyridines
˚
ter with Ni-filtered Cu K␣ radiation at a wavelength of 1.54060 A.
The FE-SEM and EDX characterization of the catalyst was per-
formed on QUANTA 200 FEG from FEI Netherlands. TEM analysis
was performed on JEM-2100 F Model (ACC. Voltage: 200 kV) elec-
tron microscope. BET surface area of the sample was measured from
the nitrogen adsorption/desorption isotherms obtained by using a
Quantachrome Autosorb 1C BET analyzer at 77 K temperature [25].
Prior to gas adsorption, the sample was degassed for 3 h at 423 K. All
reagents were purchased from Merck, Aldrich and were used with-
out further purification. The purity of compounds was checked by
thin layer chromatography (TLC) on glass plates coated with silica
A mixture of ␤-enaminone (10 mmol), aldehyde (5 mmol),
ammonium acetate (7 mmol) and catalyst (250 mg) in 10 mL water
was refluxed in an oil bath for appropriate period of time (Table 4).
After completion of reaction (monitored by TLC), the reaction mix-
ture was allowed to cool and added ethyl acetate to extract the
product. The catalyst as insoluble solid was separated by filtration,
washed with ethyl acetate (3× 10 mL) and reused for further cat-
alytic cycles. The filtrate was washed with water (3× 10 mL), dried
over anhydrous Na2SO4 and evaporated under reduced pressure.

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N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
Fig. 2. FT-IR spectra of (a) mesoporous alumina sulphuric acid and (b) mesoporous
alumina.
The crude product was recrystallized from suitable solvent (ethanol
or DMSO) to afford pure product.
3. Results and discussion
␥-Al2O3 nanoparticles owing to an inherently porous morphol-
ogy with an ultrafine crystallite size and a consistently large surface
area, combined with high thermal and chemical stabilities, are
among the most important catalytic nanomaterials used as a sup-
port in heterogeneous catalysis. Its large surface area and open
porosity enable a high dispersion of catalyst which guarantees
efficient contact of the catalyst with the reactant molecules. Meso-
porous ␥-Al2O3 nanoparticles were prepared by hydrothermal
method using aluminium sulphate as precursor. The sulfonic acid
functionalized alumina catalyst was prepared by reaction of meso-
porous alumina with chlorosulfonic acid (Scheme 1). The amount of
acid groups due to functionalization of the surface hydroxyl groups
of alumina was calculated by using neutralization titration method
and found to be 3.6 mequiv./g.
Fig. 3. (a) Powder XRD pattern of mesoporous alumina, (b) XRD pattern of fresh
mesoporous alumina sulphuric acid and (c) XRD pattern of the catalyst after seven
catalytic cycles.
to asymmetric and symmetric stretching modes of O
S O group
whereas the S O stretching band obtained at 600–700 cm−1 has
been merged with the bending and stretching bands of Al O group
[29]. The functionalization of sulfonic groups on the surface of alu-
mina also lead to decrease in the intensity of bands centred around
500–1000 cm−1. The IR spectra thus confirm that the sulfonic
groups functionalized the surface of the alumina nanoparticles.
3.1. FT-IR analysis
3.2. XRD analysis
The FT-IR spectra of the synthesized nanoparticles with and
without SO3H loading are shown in Fig. 2. In the spectra of alumina,
transmission band obtained around 3400 cm−1 is characteristic of
stretching vibrations of OH groups present on the surface of alu-
mina. The band at 500–1000 cm−1 can be attributed to the bending
and stretching vibrations of Al O group [28]. In the spectra of
functionalized alumina, the broad band at 1120 cm−1 is attributed
The formation of alumina and meso-Al-OSO3H was observed by
XRD analysis (Fig. 3). The XRD pattern of alumina shows diffraction
peaks corresponding to ␥-Al2O3 (broad peaks around 30◦, 45◦, 60◦
and 65◦) and ␣-Al2O3 (sharp peaks around 25◦, 35◦, 40◦, 50◦ and
55◦) phases [30]. The XRD spectrum of meso-Al-OSO3H, however
showed some extra peaks and some slight changes in the nature of
Scheme 1. Schematic representation of the synthesis of the catalyst.

N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
235
Fig. 4. FE-SEM images (a and b) of freshly synthesized mesoporous alumina at different magnifications (c) of mesoporous alumina sulphuric acid and (d) EDX analysis of
mesoporous alumina sulphuric acid showing the presence of S in addition to Al and O.
peaks which may be due to the presence of sulfonic acid groups on
the surface of alumina.
molecules with uniform pore size distribution. All these analyses
proved the mesoporous nature of synthesized alumina nanoparti-
cles.
3.3. FE-SEM and EDX analysis
3.5. TG analysis
FE-SEM images (Fig. 4a and b) showed the spherical shape of the
synthesized mesoporous alumina nanoparticles and the size of the
particles was found to be in the range of 400 nm. Fig. 4c showed the
surface of alumina after functionalization with sulfonic acid groups.
It can be observed that there is no change in the shape of alumina
particles after being functionalized with sulfonic acid and the sur-
face morphology is also retained. The successful functionalization
was further confirmed by EDX analysis (Fig. 4d) which showed the
presence of S in addition to Al and O.
The thermal stability of the catalyst and successful incorpora-
tion of sulphuric acid groups on mesoporous alumina surface was
observed by TG analysis (Fig. 7a and b). Fig. 7b shows the TGA curve
of mesoporous alumina. The curve shows a weight loss of 8.97% up
to 180 ◦C which is due to evaporation of moisture trapped in alu-
mina framework. The TG curve then does not show any further
weight loss up to 600 ◦C. In the TG curve of mesoporous alumina
sulphuric acid (Fig. 7a), the first weight loss below 100 ◦C (13.7%
up to 200 ◦C) is due to the removal of solvent and water molecules
trapped in alumina matrix. Another weight loss of 8.9% beginning
from 300 ◦C up to 600 ◦C can be attributed to the decomposition of
sulfonic acid groups from the mesoporous alumina surface. The TG
curve, thus, shows successful incorporation of sulfonic acid groups
on the alumina surface.
3.4. BET and TEM analyses
The mesoporous structure of ␥-alumina was confirmed by N2
adsorption/desorption isotherms (Fig. 5a). The sample showed the
presence of type IV isotherm (definition by IUPAC) [31] which is
a characteristic of mesoporous material. The surface area of the
sample was calculated by Brunauer–Emmett–Teller (BET) method
which employed nitrogen adsorption at different pressures at
the liquid nitrogen temperature (77 K) and was found to be
529.54 m2/g. The pore size distributions were also obtained from
these adsorption isotherms by employing Barrett–Joyner–Halenda
(BJH) method and the pore volume and average pore size obtained
were 0.5 cm3/g and 5.5 nm respectively (Fig. 5b). The less broaden-
ing in the pore width peak denotes the presence of uniform size
pores. TEM images (Fig. 6) of the synthesized alumina particles
were obtained in order to further confirm their mesoporous struc-
ture. The images showed wormhole-like porous structure of the
3.6. Optimization of reaction conditions
3.6.1. Optimization of catalysts
Keeping in view the environmental concerns as well as the vast
utility and scope of reactions carried out in water, we chose water
as the preferred solvent for our reaction. In order to find right cat-
alyst for our reaction we first tried the reaction in the absence of
any catalyst. The reaction failed to produce any yield demonstrat-
ing the need of a catalyst. AcOH and H2SO4 catalyzed reactions gave
unsatisfactory yields (Table 1, entries 1 and 2). We then used hete-
rogenized sulphuric acid catalysts and the yields of the product

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N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
Fig. 5. (a) Nitrogen adsorption isotherm and (b) pore size distribution of mesoporous alumina.
Fig. 6. TEM images of mesoporous alumina showing uniform pore distribution.
started to improve. Among silica, zirconia and alumina supported
sulphuric acid, alumina sulphuric acid catalyzed reaction showed
better results (Table 1, entries 3–5). Organic polymers supported
sulphuric acid catalysts also showed inferior results in comparison
to alumina sulphuric acid (Table 1, entries 8 and 9). We then tried
the reaction using sulphuric acid supported on silica and alumina
nanoparticles (Table 1, entries 10 and 11). With the introduction
of nanoparticles as supports, the yields of the product increased
substantially with decrease in time taken for completion of the
reaction. In order to further optimize the catalyst, the reaction was
performed in presence of Lewis acid catalysts like ZnO, MgO and
meso-Al2O3 (Table 1, entries 14–16) also. The results obtained were
unsatisfactory as low yield of product was obtained after prolonged
reaction times. The results obtained showed that the nano-alumina
sulphuric acid was the most efficient catalyst for this reaction. The
higher activity shown by alumina supported acid may be due to
fine dispersion of sulfonic acid groups on the surface of alumina
as compared to other supports. As a simplistic manner to further
improve this catalytic system, we used mesoporous alumina as
a support for functionalizing sulphuric acid, the results obtained
were highly encouraging and also, as can be seen, lesser amount
of the catalyst was needed to catalyze this reaction efficiently
(Table 1, entry 13). This higher activity shown by mesoporous
alumina sulphuric acid is due to the porous structure generating
a very high surface area which in turn leads to higher number
of sites being available for functionalization with sulfonic acid
group.
Fig. 7. TG analysis (a) of mesoporous alumina sulphuric acid [MAS] and (b) of meso-
porous alumina [MA].

N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
237
Table 1
Effect of various reaction media for the model reaction.a
H
O
O
N
O
O
O
N
O
O
O
O
O
N
(1mole)
NH4OAc
N
N
N
N
+
Water
O
O
N
H
O
1mole
2mole
Entry
Catalyst
Condition
Timeb
Yieldc (%)
1
2
AcOH (10 mol%)
H2SO4 (10 mol%)
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
Water/reflux
7.0 h
6.2 h
3.5 h
4.2 h
3.0 h
3.4 h
4.1 h
5.8 h
5.2 h
2.2 h
1.8 h
45 min
45 min
8.4 h
9.5 h
12.5 h
61
58
72
62
75
66
64
59
61
78
81
90
90
54
48
29
3d
4d
5d
6d
7d
8d
9d
10d
11
12
13
14
15
16
H2SO4–SiO2 (200 mg)
H2SO4–ZrO2 (200 mg)
H2SO4–Al2O3 (200 mg)
NH2SO3H–SiO2 (200 mg)
TsOH–SiO2 (200 mg)
H2SO4–cellulose (200 mg)
H2SO4–xanthan (200 mg)
H2SO4–nanoSiO2 (100 mg)
H2SO4-nanoAl2O3 (100 mg)
H2SO4–meso-Al2O3 (100 mg)
H2SO4–meso-Al2O3 (50 mg)
ZnO (10 mol%)
MgO (10 mol%)
Meso-Al2O3 (10 mol%)
a
Reaction of enaminone (1b) (2 mmol), benzaldehyde (2a) (1 mmol) and ammonium acetate (1 mmol) in the presence of different catalysts in water (10 mL) at reflux
temperature.
b
Reaction progress monitored by TLC.
Isolated yield.
The catalysts prepared by reported procedures [20].
c
d
3.6.2. Effect of solvents/hydrophobic effect
the model reaction was studied. It was found that when the catalyst
amount was increased from 0.03 g to 0.05 g the yield of the prod-
uct increased significantly from 76% to 90%. With further increase
to 0.1 g the time taken and yield obtained did not change. Further
increase in the catalyst concentration decreased the yields mainly
due to the formation of some side products (Table 3).
In order to establish water as a preferred solvent, the model
reaction was studied using different solvents (Table 2). Using AcOH
as a solvent the reaction gave only moderate yield of the product
(Table 2, entry 2). Using ethanol and methanol as solvents, again
unsatisfactory yield of product was obtained (Table 2, entries 3
and 4). In chloroform the reaction did not reach to completion
(Table 2, entry 5). DMF as a solvent again showed unsatisfactory
results (Table 2, entry 6). Using water as a solvent the reaction
showed excellent results in short span of time (Table 2, entry 7).
This enhanced reactivity can be attributed to the strong hydrogen
bond interaction at the organic/water interface, which stabilizes
the reaction intermediates and enhances the rate of reaction [10].
To further understand this impressive rate enhancement for on-
water reactions, firstly, we performed the reaction under neat
conditions (Table 2, entry 1), the reaction completed in 1.5 h with
77% product yield. We then performed experiments for the reaction
by using different concentrations of various solvents with water.
Mixing of 0.5 mL of ethanol to the water containing the reaction
mixture showed no effect. Addition of further 1–2 mL of ethanol
again did not showed any remarkable effect (Table 2, entries 8
and 9). Addition of 3–4 mL of ethanol turned the reaction mixture
homogeneous, and then the rate of reaction decreased considerably
(Table 2, entry 10). We then tried this experiment with addition
of MeOH to the reaction mixture and found similar results. Upon
examining the results we found that the large rate enhancements
occurredif thereactionwasconductedin heterogeneousconditions
than in homogeneous aqueous solution and hydrophobic effects
acted prominently as neat reaction was not as faster as reaction
using water. These studies established the supremacy of water as
a solvent for this reaction.
3.6.4. Catalytic reaction
With these encouraging results in hand, we turned to explore
the scope of the reaction using different aromatic aldehydes (2a–g),
enaminones (1a, 1b) and ammonium acetate as substrates under
the optimized reaction conditions (Table 4). It was observed that
the aromatic aldehydes with electron donating as well as elec-
tron withdrawing groups reacted successfully to furnish the final
products (3a–n) in good yields (Scheme 2). However, the electron
donating groups in aldehydes caused low reactivity and increased
time period for completion of the reaction due to deactivating
effects. In order to further prove the generality of our procedure, we
also used alicyclic and aliphatic aldehydes (Table 4, entries 6, 7, 13
and 14) in the reaction and it was found that the reaction occurred
with high efficiency and good yield of products was obtained. The
structures of the final products were well characterized by using
spectral (IR, 1H, 13C NMR and ESI-MS) and elemental analysis data.
The I.R. Spectrum of 3h showed broad peak at 3431 cm−1 which
was due to stretching frequency of NH group. Two C O groups
connected to dihydropyridine ring showed absorption band at
1731 cm−1 and six C O groups of two pyrimidinetrione moieties
showed sharp absorption band at 1672 cm−1. The absorption band
at 1604 cm−1 was assigned to C C stretching. The 1H NMR Spec-
trum showed a broad singlet at ␦10.28 ppm which was assigned
to the NH proton of dihydropyridine ring. The five protons of aro-
matic region showed a multiplet in the range of ␦ 7.4–7.8 and the
two hydrogen atoms present in dihydropyridine ring gave a singlet
at ␦ 7.25 ppm. Another singlet at ␦ 5.29 confirmed the formation of
dihydropyridine ring. 13C NMR showed signals at ␦ 184.63, 172.11
3.6.3. Catalyst loading
In order to optimize the amount of catalyst for obtaining maxi-
mum yield in lesser amount of time, effect of the catalyst loading on

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N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
Table 2
Effect of different solvents on the model reaction.a
H
O
O
N
O
O
O
N
O
O
O
O
O
N
(1mole)
-SO3H
NH4OAc
N
N
N
N
+
Al2O3
Meso-
O
O
N
H
O
1mole
2mole
Entry
Solvent
Timeb
Yieldc (%)
1
2
3
4
5
Neat
1.5 h
4 h
5 h
5 h
5 h
77
56
53
61
Acetic acid (5 mL)
Methanol (5 mL)
Ethanol (5 mL)
Chloroform
Incomplete reaction
6
7
8
9
DMF
Water (5 mL)
Water (5 mL)/ethanol (1 mL)
Water (5 mL)/ethanol (2 mL)
Water (5 mL)/ethanol (3 mL)
3 h
48
90
88
86
73
45 min
45 min
50 min
3.5 h
10
a
Reaction of enaminone (1b) (2 mmol), benzaldehyde (2a) (1 mmol) and ammonium acetate (1 mmol) in presence of mesoporous alumina sulphuric acid (0.05 g) in
different solvents.
b
Reaction progress was monitored by TLC.
Isolated yield.
c
Table 3
Effect of catalyst loading on the model reaction.a
H
O
O
N
O
O
O
N
O
O
O
O
O
N
(1mole)
-SO3H
NH4OAc
N
N
N
N
+
Al2O3
Meso-
O
O
N
H
O
1mole
2mole
Entry
Catalyst loading (g)
Time (min)b
Yieldc (%)
1
0.03
0.05
0.10
0.15
0.20
63
45
45
45
45
76
90
90
88
86
2
3
4
5
a
Reaction of enaminone (1b) (2 mmol), benzaldehyde (2a) (1 mmol) and ammonium acetate (1 mmol) in presence of different loadings of mesoporous alumina sulphuric
acid in 10 mL water at reflux temperature.
b
Reaction progress was monitored by TLC.
Isolated yield.
c
and 165.21 ppm for C-1ꢀꢀ, C-4ꢀ, 6ꢀ and C-2ꢀ carbons respectively.
Other peaks were present at their normal values and are provided in
(supplementary information) Further structural confirmation was
provided by ESI-mass spectrum which showed the molecular ion
peak as the base peak at m/z 522.1 (M++1).
3.6.5. Reaction mechanism
The plausible mechanism is proposed in Scheme 3. First the
aldehyde group of 2a is activated by the catalyst after which
it undergoes nucleophilic addition of double bond of enam-
inone 1b to form 4. Intermediate 6 then undergoes benzylic
Scheme 2. General scheme for the synthesis of dihydropyridines.

N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
239
Table 4
Synthesis of dihydropyridinesa.
Entry
Enaminone
Aldehyde
Product
Time (min)b
Yield (%)c
H
H
H
O
OH
O
O
O
O
OH
O
OH
O
O
N
N
N
O
N
H
O
1a
2a
3a
1
53
89
Cl
O
OH
O
O
O
O
O
OH
O
OH
O
N
H
Cl
O1a O
2b
3b
2
51
86
OMe
O
OH
O
O
O
O
O
OH
O
OH
O
N
H
3c
OMe
O 1aO
2c
3
57
85
OH
H
O
OH
O
O
O
O
O
OH
O
OH
O
N
N
N
H
OH
2d
O1a O
3d
4
51
87
NO2
O
H
O
OH
O
O
O
OH
O
OH
O
N
H
3e
O
NO2
O 1aO
2e
5
50
83
OH
O
O
O
O
O
OH
O
OH
O
N
N
CHO
N
H
O 1aO
2f
3f
6
7
65
68
84
81
OH
O
O
O
O
O
OH
O
OH
O
N
H
CHO
O 1aO
2g
3g
O
O
O
O
H
O
O
N
O
5
3
4
5'
5'
N
N 3'
4'
N6'
1''
1''
4'
6'
N
3'
N
N
2
O
O
6
N
O
O
2'
2'
1'
H
1
1'
O
O
1b
3h
2a
8
45
90

240
N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
Table 4 (Continued)
Entry
Enaminone
Aldehyde
Product
Time (min)b
Yield (%)c
Cl
H
O
O
N
O
O
O
O
O
N
O
N
O
N
N
O
N
N
H
O
O
N
O
Cl
1b
3i
2b
9
43
89
OMe
H
O
O
N
O
O
O
O
O
N
O
N
O
N
N
N
N
O
N
H
O
OMe
O
O
1b
2c
3j
10
48
87
OH
H
O
O
N
O
O
O
O
O
N
O
N
O
N
N
N
N
N
N
H
O
O
O
O
OH
1b
3k
2d
11
12
13
41
90
NO2
O
N
O
O
O
O
O
N
H
O
O
N
O
N
N
N
O
N
H
O
O
O
NO2
1b
3l
2e
40
86
O
N
O
O
O
O
O
N
O
N
O
N
N
N
N
N
N
N
N
CHO
O
O
N
H
O
O
O
O
O
1b
3m
2f
45
52
85
82
O
N
O
O
O
O
O
N
O
N
O
CHO
N
H
O
1b
2g
3n
14
a
Reaction of enaminones (1a–b) (2 mmol), different aldehydes (2a–g) (1 mmol) and ammonium acetate (1 mmol) in presence of mesoporous alumina sulphuric acid
(0.05 g) in 10 mL water at reflux temperature.
b
Reaction progress was monitored by TLC.
Isolated yield.
c
substitution by another molecule of enaminone 1b followed by
loss of water molecule to generate divinylic compound 7. This
divinylic compound then undergoes Michael addition of ammonia
followed by elimination of dimethyl amine to give 9. The com-
pound 9 then undergoes cyclization by intramolecular Michael
addition of amine followed by elimination of another molecule
of dimethyl amine to give the product 3h. The catalyst could
be regenerated in the last step and reused for further catalytic
cycles [17].
3.7. Hot filtration test
In order to check any leaching of catalyst into the solution during
the reaction, a hot-filtration test was performed using mesoporous

N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
241
H
O
O
O
O3SO
O
HO
N
N
HO
N
H
O
O
O
N
O
O
O
N
H
N
N
2a
N
O
O
O
N
4
1b
5
O
O
O
O
N
N
OH2
OSO3
O
O
N
O
N
N
O
O
O
N
O
O
-H2O
N
N
O
O
N
N
N
O
O
6
N
7
NH3
O
H
O
O
O
O
O
O
N
NHMe2
O
O
N
-
H+ Shift
N
N
O
O
O
N
N
N
O
N
O
O
O
N
H2N
NH2 N
N
9
8
O
H
O
O
O
O
O
NHMe2
-
N
O
O
N
N
N
O
N
O
O
O
N
O
O
N
N
N
H2
O
O
N
N
H2
OSO3
11
OSO3
10
O
O
O
O
N
N
N
O
N
O
N
H
O
O
OSO3H
3h
Scheme 3. Plausible reaction mechanism for the formation of 3 h.
alumina sulphuric acid as a catalyst. A mixture of ␤-enaminone 1b
(1 mmol), aldehyde 2a (0.5 mmol), ammonium acetate (0.7 mmol)
and catalyst (50 mg) in 5 mL ethanol was refluxed for 30 min and
immediately filtered under hot reaction conditions. The reaction
mixture without catalyst was then further refluxed for 6 h under the
same reaction conditions. It was observed that after 6 h there was
no further product formation and the reaction could not proceed to
completion. This result clearly confirms the heterogeneous nature
of the mesoporous catalyst and no leaching of SO3H groups occurs
during the course of reaction.
4. Catalyst recyclability
In order to explore the extent of recyclability of our catalytic
system, the catalyst was recovered by filtration from the reaction
mixture of enaminone 1b, benzaldehyde and ammonium acetate in
water, washed with ethanol (3× 15 mL), ethyl acetate (2× 10 mL),
dried at 100 ◦C for 1.5 h, and reused in subsequent runs. The catalyst
was found to retain its activity for a minimum of seven reaction
cycles and displayed almost high catalytic performance with over
85% product yield (Fig. 8). The XRD (Fig. 3c) of the catalyst after

242
N. Ahmed, Z.N. Siddiqui / Journal of Molecular Catalysis A: Chemical 394 (2014) 232–243
Fig. 8. Recycling data of mesoporous alumina sulphuric acid for the model reaction.
seven runs showed that the catalyst structure is preserved during
its reuse.
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5. Conclusion
In conclusion, an efficient, green and convenient method for
the preparation of new 1,4-dihydropyridines via ␤-enaminones in
water is reported. This new process provides an opportunity to
use water and avoid environmentally harmful conventional organic
solvents. In addition to aromatic aldehydes the reaction was found
to be effective for both alicyclic and aliphatic aldehydes. The simple
procedure for catalyst preparation, easy recovery and reusability
of the catalyst are expected to contribute to its utilization for the
development of benign chemical processes.
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Acknowledgments
The authors are thankful to the Centre of nanotechnology,
Department of Applied Physics and University Sophisticated Instru-
ment Facility (USIF), AMU, Aligarh for providing powder XRD
and TEM facilities. The authors would also like to thank SAIF
Punjab University, Chandigarh for providing NMR and Mass
spectra.
(c) A. Praminik, S. Bhar, Catal. Commun. 20 (2012) 17;
(d) Z.N. Siddiqui, N. Ahmed, Appl. Organomet. Chem. 27 (2013) 553;
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Chem. 370 (2013) 111;
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2014.07.015.
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