Mesostructured SBA-15-Pr-SO3H: An efficient solid acid catalyst for one-pot and solvent-free synthesis of 3,4-dihydro-2-pyridone derivatives

Article abstract of DOI:10.1007/s12039-013-0511-x

3,4-Dihydro-2-pyridone derivatives have been prepared efficiently via a one-pot four-component reaction of benzaldehyde derivatives, Meldrum's acid, methyl acetoacetate and ammonium acetate in the presence of sulphonic acid-functionalized ordered nanoporo

Full text of DOI:10.1007/s12039-013-0511-x

c
J. Chem. Sci. Vol. 125, No. 6, November 2013, pp. 1359–1364. ꢀ Indian Academy of Sciences.
Mesostructured SBA-15-Pr-SO3H: An efficient solid acid
catalyst for one-pot and solvent-free synthesis
of 3,4-dihydro-2-pyridone derivatives
GHODSI MOHAMMADI ZIARANIa,∗, SOMAYEH MOUSAVIa, NEGAR LASHGARIb
and ALIREZA BADIEIb
aDepartment of Chemistry, Alzahra University, Vanak Square, Tehran, 1993893973, Iran
bSchool of Chemistry, College of Science, University of Tehran, Tehran, Iran
e-mail: gmziarani@hotmail.com; gmohammadi@alzahra.ac.ir
MS received 10 January 2013; revised 22 July 2013; accepted 12 August 2013
Abstract. 3,4-Dihydro-2-pyridone derivatives have been prepared efficiently via a one-pot four-component
reaction of benzaldehyde derivatives, Meldrum’s acid, methyl acetoacetate and ammonium acetate in the pres-
ence of sulphonic acid-functionalized ordered nanoporous SBA-15 as a nano heterogeneous catalyst under
solvent-free conditions. This process is a simple, environmentally friendly, rapid and high yielding reaction.
Keywords. Functionalized SBA-15; pyridone; Meldrum’s acid; multicomponent reaction; solvent-free.
1. Introduction
Therefore, the growth of combinatorial chemistry in
the drug discovery process is considerably dependent
on further advances in heterocyclic MCR methodology
and according to the current synthetic requirements,
environmentally benign multi-component procedures
are particularly welcome.
Propylsulphonic-modified SBA-15 has been proved
to be an efficient heterogeneous nanoporous solid acid
catalyst in the green one-pot synthesis of a variety of
heterocyclic compounds.16–19 As part of our continu-
ing interest in the synthesis of heterocyclic compounds
of biological importance,20–23 we decided to utilize this
catalyst in the synthesis of 2(1H)-pyridone derivatives.
Development of new methods for the synthesis of he-
terocyclic compounds will always be important, not
just because of their remarkable structural diversity, but
also their importance in a broad range of therapeu-
tic areas.1,2 1,4-Dihydropyridine (1,4-DHP) derivatives
are a class of heterocyclic compounds well-known as
Ca+2 channel blockers.3,4 These heterocyclic rings are
also a common feature found in a variety of bioactive
compounds such as vasodilator,5 anti-atherosclerotic,6
anti-diabetic,7 and bioprotector agents.8 Generally, the
basic skeleton of DHP was first discovered by Hantzsch
in 1882.9 In a typical Hantzsch procedure, an alde-
hyde, ammonia, and a β-keto ester are enclosed to give
a dihydropyridine, which is subsequently oxidized to
pyridine.
2. Experimental
2-Pyridones are structurally very similar to 1,4-
dihydropyridines. Many naturally occurring and syn-
thetic compounds containing the 2(1H)-pyridone ring,
possess important pharmacological activities and useful
biological properties.10–12
Multicomponent reactions (MCRs) have been
emerged as rapid and selective synthetic routes towards
molecular complexity and diversity.13 Such proto-
cols have proved to be a valuable asset in medicinal
chemistry, drug design and drug discovery because
of their simplicity, efficiency and high selectivity.14,15
2.1 General remarks
All commercially available chemicals were purchased
from Merck Company and used without further purifi-
cation. IR spectra were recorded from KBr disk using
a Fourier Transform InfraRed (FT-IR) Bruker Ten-
sor 27 instrument. Melting points were measured by
using the capillary tube method with an electro ther-
1
mal 9200 apparatus. The H NMR (250 MHz) was
run on a Bruker DPX at 250 MHz in CDCl3 using
tetramethylsilane (TMS) as internal standard. GC-Mass
analysis was performed on a GC-Mass model: 5973
network mass selective detector, GC 6890 Agilent.
∗For correspondence
1359

1360
Ghodsi Mohammadi Ziarani et al.
Surface areas were calculated by the Brunauer– 8.0 Hz), 3.66 (3H, s, OCH3), 4.34 (1H, dd, J = 8.0 Hz,
Emmett–Teller (BET) method, and pore sizes were J = 1.5 Hz), 7.24–7.73 (2H, m, ArH), 8.03–8.35 (3H,
calculated by the Barrett–Joyner–Halenda (BJH) m, ArH, NH) ppm; MS (EI, m/z): 290 (M+), 273
method. Scanning Electron Microscopy (SEM) analy- (100), 257, 245, 231.
sis was performed on a Philips XL-30 field-emission
scanning electron microscope operated at 16 kV while
Transmission Electron Microscopy (TEM) was carried
out on a Tecnai G2 F30 at 300 kV.
2.4b 4-(2,4-Dichlorophenyl)-5-methoxycarbonyl-6-
methyl-3,4-dihydropyridone (5d): Mp 204–206◦C; IR
1
(KBr): 3229, 1705, 1642, 1591, 800 cm−1; H NMR
2.2 Synthesis and functionalization of SBA-15
(250 MHz, CDCl3): δ 2.45 (3H, s, CH3), 2.78 (1H, dd,
J = 16.5 Hz, J = 1.9 Hz), 2.94 (1H, dd, J = 16.5 Hz,
J = 8.3 Hz), 3.60 (3H, s, OCH3), 4.64 (1H, dd, J =
8.3 Hz, J = 1.9 Hz), 6.96 (1H, d, J = 8.25 Hz, ArH),
7.14 (1H, d, J = 7.5 Hz, ArH), 7.40 (1H, s, ArH), 8.79
(1H, br s, NH) ppm; MS (EI, m/z): 313 (M+, 100),
281, 246, 226, 199.
Nanoporous compound SBA-15 was synthesized and
functionalized according to our previous report20 and
the modified SBA-15-Pr-SO3H was used as nanoporous
solid acid catalyst in the following reactions.
2.3 Typical procedure for the preparation of pyridone
derivatives (5a–h)
2.4c 4-(2,4-Dimethoxyphenyl)-5-methoxycarbonyl-6-
methyl-3,4-dihydropyridone (5f): Mp 136–139◦C; IR
The SBA-Pr-SO3H (0.02 g) was activated in vacuum
at 100◦C and then after cooling to room temperature,
Meldrum’s acid 1 (0.43 g, 3 mmol), methyl acetoacetate
2 (0.32 mL, 3 mmol), aromatic aldehyde 3 (3 mmol),
and ammonium acetate 4 (0.38 g, 5 mmol) were
added to it. The mixture was heated at 140◦C under
solvent-free condition for an appropriate time and the
completion of reaction was indicated by Thin layer
chromatography (TLC). The resulting solid product
was dissolved in hot ethanol, filtered for removing the
unsolvable catalyst and then the filtrate was cooled to
afford the pure product. The catalyst was washed sub-
sequently with diluted acid solution, distilled water and
then acetone, dried under vacuum and re-used several
times without loss of significant activity.
1
(KBr): 3225, 1694, 1611, 1260, 1036 cm−1; H NMR
(250 MHz, CDCl3): δ 1.50 (3H, s, CH3), 2.42 (1H, dd,
J = 16.5 Hz, J = 1.9 Hz), 2.80 (1H, dd, J = 16.5 Hz,
J = 8.3 Hz), 3.46 (3H, s, OCH3), 3.70 (3H, s, OCH3),
3.75 (3H, s, OCH3), 4.63 (1H, dd, J = 8.3 Hz, J =
1.9 Hz), 6.86 (1H, d, J = 5.25 Hz, ArH), 7.04 (1H, d,
J = 9.25 Hz, ArH), 7.26 (1H, s, ArH), 8.20 (1H, br s,
NH) ppm; MS (EI, m/z): 305 (M+), 273, 246 (100),
230.
2.4d 4-(2-Methoxyphenyl)-5-methoxycarbonyl-6-methyl-
3,4-dihydropyridone (5h): Mp 206–208◦C; IR (KBr):
1
3240, 1699, 1634, 1245, 1051 cm−1; H NMR (250
MHz, CDCl3): δ 2.42 (3H, s, CH3), 2.77 (1H, dd,
J = 16.5 Hz, J = 1.9 Hz), 2.87 (1H, dd, J = 16.5 Hz,
J = 8.3 Hz), 3.60 (3H, s, OCH3), 3.83 (3H, s, OCH3),
4.57 (1H, dd, J = 8.3 Hz, J = 1.9 Hz), 6.79–6.96 (2H,
m, ArH), 7.19 (1H, d, J = 7.75 Hz, ArH), 7.26 (1H, d,
J = 10 Hz, ArH), 8.15 (1H, br s, NH) ppm; MS (EI,
m/z): 275 (M+), 260, 243, 216 (100).
2.4 Selected spectral data
2.4a 4-(3-Nitrophenyl)-5-methoxycarbonyl-6-methyl-
3,4-dihydropyridone (5c): Mp 194–196◦C; IR (KBr):
3351, 1704, 1648, 1528, 1348 cm−1; H NMR (250
1
MHz, CDCl3): δ 2.45 (3H, s, CH3), 2.66 (1H, dd, J =
16.4 Hz, J = 1.5 Hz), 3.01 (1H, dd, J = 16.4 Hz, J =
Scheme 1. Synthesis of 5-acetyl-4-aryl-3,4-dihydro-6-methyl-2(1H)
pyridone derivatives in the presence of SBA-Pr-SO3H.

Synthesis of 3,4-dihydro-2-pyridone derivatives
1361
Table 1. Optimization of reaction conditions for the syn- Table 3. Reuse of SBA-Pr-SO3H for synthesis of 5a.
thesis of compound 5d.
Entry
Time (min)
Yield (%)
Entry
Solvent
Time (h)
Yielda (%)
1
2
3
4
40
40
40
40
90
84
80
72
1
2
3
4
5
H2O
EtOH
5
5
5
3
80
81
64
80
95
EtOH/H2O (1:1)
CH3CN
Neat (140◦C)
30 min
aIsolated yields
catalyst from the reaction medium was easily carried
out by simple filtration. The acid catalyst can be reac-
tivated by simple washing subsequently with diluted
3. Results and discussion
Although several approaches for the synthesis of these acid solution, water and acetone, and then reused with-
skeletons have been reported,24–28 development of sim- out noticeable loss of reactivity. Reusability of the cat-
ple and convenient synthetic procedures for the synthe- alyst was investigated under optimized conditions for
sis of such nitrogen-containing heterocycles represents the synthesis of the model compound 5a. As shown
an attractive area of research in synthetic organic chem- in table 3, the process of recycling was completed
istry. In this article, we wish to report our results on four times and no significant decrease in activity was
the synthesis of pyridone derivatives by the reaction of observed. The yields for the four runs were found to be
Meldrum’s acid 1, methyl acetoacetate 2, benzaldehyde 90 %, 84 %, 80 % and 72 %, respectively.
derivatives 3, and ammonium acetate 4 using SBA-Pr-
Due to the greater acidity of Meldrum’s acid (pKa =
SO3H as the nano catalyst (scheme 1). To study the 9.97) in comparison with methyl acetoacetate (pKa =
effect of solvent on this four-component reaction, the 11.0), we do not obtain 1,4-dihydropyridines.32 This
reaction of 2,4-dichlorobenzaldehyde, Meldrum’s acid, reaction may occur via a condensation, addition,
methyl acetoacetate, and ammonium acetate was cho- cyclization and elimination mechanism (scheme 2). The
sen as a model reaction (table 1). The results clearly acid catalyst (SBA-Pr-SO3H) acts as a source of H+,
show that among the different tested solvents such as which can protonate carbonyl group to create a more
H2O, EtOH, MeCN, and solvent-free system, the best reactive species. The reaction occurs via a Knoevenagel
result was obtained after 30 min in solvent-free medium condensation reaction between Meldrum’s acid and
in excellent yield. Then, different substituted aldehy- aldehyde to provide intermediate 6 which undergoes
des were used to undergo the Hantzsch reaction in the a Michael-type addition with enamino compound 7
presence of catalytic amount of SBA-Pr-SO3H under (resulting from the reaction between ammonium acetate
solvent-free condition at 140◦C and all pyridines were and methyl acetoacetate). Intramolecular cyclodehydra-
obtained in high to excellent yields (table 2). After com- tion in intermediate 8 results in the formation of desired
pletion of the reaction (monitored by Thin layer chro- product 5.
matography (TLC)), the crude product was dissolved in
Literature survey reveals that SBA-Pr-SO3H is the
hot ethanol and separation of the heterogeneous solid only catalyst that has been used for the synthesis of
Table 2. SBA-Pr-SO3H catalysed the synthesis of 3,4-dihydro-2-pyridones 5a–h under
solvent-free condition.
Entry
Aldehyde
Product Time (min) Yielda (%) M.p. (◦C)
M.p. (Lit)
1
2
3
4
5
6
7
8
Ph
4-ClC6H4
5a
5b
5c
5d
5e
5f
40
35
30
30
30
30
40
35
90
89
92
95
87
89
88
92
190–193
189–191
194–196
204–206
210–213
136–139
177–179
206–208
197–19829
198–20030
205–20631
–
3-NO2C6H4
2,4-Cl2C6H3
4-NO2C6H4
2,4-(OCH3)2C6H3
4-OCH3C6H4
2-OCH3C6H4
210–21130
–
5g
5h
187–18829
–
aIsolated yields

1362
Ghodsi Mohammadi Ziarani et al.
CO2CH3
CH3
H2C
O
H
O
2
O
SBA-Pr-SO3H
NH3
Ar
H
Ar
O
H
O
O
Ar
O
3
H
CO2CH3
CH3
-H2O
O
H
O
O
O
H2N
SBA-Pr-SO3H
O
6
7
O
O
O
1
Ar
Ar
O
C
O
CO2CH3
CH3
H
CH
CO2CH3
CH3
H3C
CH3
O
O
N
H
CO2
O
O
HN
8
5
Scheme 2. Proposed mechanism.
Table 4. Comparison of different conditions in the synthesis of compound 5a.
Entry
Catalyst
Solvent
Condition
Time (min) Yield (%)
Year
1
2
3
4
-
-
-
AcOH
Reflux
Microwave
10 h
15
12
65
86
85
90
199633
200331
-
-
-
Ultrasound
201130
SBA-Pr-SO3H
Heating (140◦C)
40
This study
pyridone derivatives though the four-component reac- them thermally and hydrothermally stable materials.34
tion and in other reported methods, microwave irradi- Organic functionalities such as R-SO3H can be incorpo-
ation and ultrasound conditions were used to result in rated into mesoporous materials, either by post-grafting
lower yields (table 4).
or direct synthesis methods.35,36 Integration of acidic
Stucky and coworkers introduced hexagonal SBA- functional groups (e.g., −SO3H) into SBA-15 has been
15 having high surface area, long range order and explored to produce promising solid acids.
thick walls (typically between 3 and 9 nm), which make
A schematic illustration for the preparation of SBA-
Pr-SO3H is shown in figure 1. First, the calcined SBA-
15 silica was functionalized with (3-mercaptopropyl)
trimethoxysilane (MPTS) and then, the thiol groups
could be completely oxidized into sulphonic acid
groups by hydrogen peroxide.
The texture properties of SBA-15 and SBA-Pr-SO3H
are given in table 5. The surface area, average pore
diameter calculated by BET method and pore volume
Table 5. Porosimetery values for SBA-15 and functional-
ized SBA-15.
Surface area, Pore volume, Pore diameter,
cm2g−1
cm3g−1
nm
SBA-15
SBA-Pr-SO3H
649
440
0.806
0.660
6.2
6.0
Figure 1. Schematic representation of SBA-Pr-SO3H.

Synthesis of 3,4-dihydro-2-pyridone derivatives
1363
Acc V Spot Magn Dot WD
16.0 kV 2.0 16000x SE 10.2 S3
1µm
Figure 2. SEM and TEM image of SBA-Pr-SO3H.
Figure 3. SBA-Pr-SO3H acts as nano-reactor.
of SBA-Pr-SO3H are 440 m2g−1, 6.0 nm and 0.660 cm3 Supplementary information
g−1, respectively, which are smaller than those of
SBA-15 due to immobilization of sulphonosilane
groups into the pores.
The electronic supporting information can be seen in
www.ias.ac.in/chemsci.
Figure 2 illustrates the Scanning Electron Micro-
scopy (SEM) and Transmission Electron Microscopy
(TEM) images of SBA-Pr-SO3H. Scanning Electron
Microscopy (SEM) image (figure 2, left) shows uni-
form particles of about 1 μm. The same morphology
was observed for SBA-15. It can be concluded that mor-
phology of solid was saved without change during sur-
face modifications. On the other hand, the Transmis-
sion Electron Microscopy (TEM) image (figure 2, right)
reveals parallel channels, which resemble the pores
configuration of SBA-15. This indicates that the pore
of SBA-Pr-SO3H did not collapse during two-step reac-
tions. This catalyst acts as a nano-reactor in this reaction
(figure 3).
Acknowledgement
We thank the Research Council of Alzahra University
and the University of Tehran for financial support.
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