Application of MCM-41-SO3H as an advanced nanocatalyst for the solvent free synthesis of pyrano[3,2-c]pyridine derivatives

Article abstract of DOI:10.1002/jccs.201100667

MCM-41-SO₃H, an ordered mesoporous silica material in which MCM-41 with covalently anchored sulfonic acid groups was used as an acidic catalyst for the rapid and 'green' synthesis of pyrano[3,2-c]pyridine derivatives under solvent-free conditions. Reusability of the catalyst, high yields, short reaction times, simplicity and easy workup are advantages of this novel synthetic procedure compared to the conventional methods reported in the literature.

Full text of DOI:10.1002/jccs.201100667

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Application of MCM-41-SO3H as an Advanced Nanocatalyst for the Solvent Free
Synthesis of Pyrano[3,2-c]pyridine Derivatives
Shahnaz Rostamizadeh,a* Nasrin Shadjoua and Mohammad Hasanzadehb
aDepartment of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
bDrug Applied Research Center, Tabriz University of Medical Science, Tabriz, Iran
(Received: Nov. 15, 2011; Accepted: Feb. 6, 2012; Published Online: ??; DOI: 10.1002/jccs.201100667)
MCM-41-SO3H, an ordered mesoporous silica material in which MCM-41 with covalently anchored
sulfonic acid groups was used as an acidic catalyst for the rapid and ‘green’ synthesis of pyrano[3,2-
c]pyridine derivatives under solvent-free conditions. Reusability of the catalyst, high yields, short reac-
tion times, simplicity and easy workup are advantages of this novel synthetic procedure compared to the
conventional methods reported in the literature.
Keywords: Nanocatalyst; MCM-41-SO3H; Pyrano[3,2-c]pyridine; Solvent free conditions.
INTRODUCTION
Various pyrano[3,2-c]pyridine and their derivatives
by the development of various new silica materials with or-
dered structure.11,12 One of the best-known examples is Si-
MCM-41, which is a structurally well-ordered mesoporous
material with a narrow pore size distribution between 1.5
and 10 nm, depending on the surfactant cation, and a very
high surface area up to 1500 m2g-1.13 It has been proven that
Si-MCM-41 lacks Brönsted acid sites and exhibits only
weak hydrogen-bonding type sites.14,15 An additional pos-
sibility to develop acidic solids is the modification of the
surface of suitable support materials, as the chemical func-
tionalities of these materials can be uniformly modified by
covalent anchoring of different organic moieties.16 While
several types of solid sulfonic acids have been created in
recent years, there have been only a few reports about their
applications as catalyst in chemical transformations.
are important heterocyclic compounds with a broad range
of biological, medicinal, and pharmacological properties.
They are constituents of antitumor, anti-inflammatory and
antifungal drugs.1-3 In view of these useful properties of
pyrano[3,2-c]pyridine, a number of reports for the synthe-
sis of these molecules have been published. El-Subbagh et
al. have reported the synthesis of pyrano[3,2-c]pyridine de-
rivatives through two component reactions between a,b-
unsaturated ketones and malononitrile in BuOH.1 Recently
new method have also been reported in the literature for the
synthesis of these useful heterocycles using microwave ir-
radiation in the presence of DMF as a solvent.4,5 Also these
compounds have been synthesized in the presence of solid
sodium ethoxide as catalyst under solvent-free condition,6
in methanol containing sodium,7 hexadecyltrimethyl am-
monium bromide in aqueous media and 110 °C,8 KF-
Al2O3,9 and sodium hydroxide or piperidine under micro-
wave irradiation.10
Herein, we report, for the first time, the preparation of
pyrano[3,2-c]pyridine derivatives via the novel recently re-
ported MCM-41-SO3H as a nanocatalyst from the reaction
of (E)-3,5-bis(benzylidene)-4-piperidones and malono-
nitrile under solvent-free conditions (Scheme I).
However, these methods are time-consuming and use
a lot of toxic solvents and reagents through classical condi-
tions with microwave irradiation. Most importantly, the
catalysts that have been used for the synthesis of these com-
pounds are not reusable. Thus, the development of a green,
simple, efficient, and general method for the synthesis of
these widely used organic compounds, from readily avail-
able reagents, remains one of the major challenges in or-
ganic synthesis.
Synthesis of pyrano[3,2-c]pyridine deriva-
tives via MCM-41-SO3H
Scheme I
Recently, more attractive possibilities have been arisen
* Corresponding author. Fax: +98(21)22853650; E-mail: rostamizadeh@kntu.ac.ir, shrostamizadeh@yahoo.com
J. Chin. Chem. Soc. 2012, 59, 000-000
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Rostamizadeh et al.
RESULTS AND DISCUSSION
therms after grafting of SO3H group were recorded and
shown in Figure 2. The specific surface area and pore vol-
ume obtained by the N2 adsorption isotherms and calcu-
lated by the Brunauer-Emmett-Teller (BET) method18 were
704 m2g-1 and 0.69 cm3g-1, respectively. The pore diameter
of the MCM-41-SO3H was 3.48 nm derived from the ad-
sorption and desorption branches by the Broekhoff and de
Boer model.19
At first, MCM-41 was synthesized according to the
previously described method using cetyltrimethylammo-
nium bromide (CTMABr), as the templating agent.17 Then
MCM-41 was modified using a 100-mL suction flask
equipped with a constant pressure dropping funnel contain-
ing ClSO3H (81.13 g, 0.70 mol) and a gas inlet tube for con-
ducting HCl gas over an adsorbing solution. Into it was
charged MCM-41 (60.0 g) and ClSO3H was then added
drop wise over a period of 30 min at room temperature. HCl
gas was released from the reaction vessel immediately. Af-
ter completion of the addition, the mixture was shaken for
30 min and a white solid (MCM-41-SO3H) was obtained
(115.9 g) (Scheme II).
To obtain the optimum amount of the catalyst, at first,
we chose 3,5-bis(4-chlorobenzylidene)-1-methylpiperi-
din-4-one (0.33 mmol) and malononitrile (0.33 mmol) un-
der solvent-free conditions as model reactants and exam-
ined the effect of the amount of MCM-41-SO3H. Accord-
ing to these data, the optimum amount of catalyst was 0.015
g. Increasing the amount of catalyst did not improve the
yield and the reaction time, while by decreasing it, the reac-
tion time increased and the yield was lower. Also in the
present of bare MCM-41 the yield and the time of the reac-
tion was not pleasing (Figure 3).
Functionalization of MCM-41with SO3H
groups
Scheme II
In continuation of our work, in order to evaluate the
effect of solvent, we examined different solvents for the
synthesis of 5e in the presence of MCM-41-SO3H as a cata-
lyst. According to our findings, solvent-free conditions
gave the best result for this transformation (Table 1).
MCM-41-SO3H was characterized by scanning elec-
tron microscopy (SEM), Xray diffraction (XRD), and acid-
base titration. The SEM image of mesoporous MCM-41-
SO3H that had been coated with gold for two minutes was
taken to show the surface at high magnification (Figure 1a).
The SEM image display regular chemically clean uniform
porous structure. It is evident from the micrograph that the
calcined and functionalized MCM-41 powder has a uni-
form size and shows little tendency to agglomerate. XRD
analysis was performed from 1.5° (2q) to 10.0° (2q) at a
scan rate of 0.02° (2q)/sec. The XRD patterns of the syn-
thesized MCM-41-SO3H sample are presented in Figure
1b. The sample of MCM-41-SO3H showed relatively well-
defined XRD patterns, with one major peak along with
three small peaks identical to those of MCM-41 materials.
To verify this appearance, the N2 adsorption iso-
Fig. 1. (a) The SEM image of MCM-41-SO3H (b) The
XRD pattern.
2
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Solvent Free Synthesis of Pyrano[3,2-c]pyridine
Table 1. The effect of the solvents for the synthesis of 5e in the
With these results in hand, a variety of aromatic alde-
hydes, possessing both electron-donating and electron-
withdrawing groups were employed for pyrano[3,2-c]pyri-
dine formation and the results indicated that for 3,5-di-
presence of 0.015 g catalyst
Solvent
Reaction conditions
Time (min) Yield (%)
EtOH
Reflux
Reflux
Reflux
Reflux
240
30
75
80
H2O/DMF
H2O
240
300
No reaction
65-97 [1]
BuOH
benzylidenepiperidin-4-one bearing different functional
groups, the reaction proceeded smoothly in all cases. The
products were obtained in relatively short reaction time,
and no impurities were observed by TLC. We have also ob-
served that 3,5-dibenzylidenepiperidin-4-one with elec-
tron-withdrawing groups such as 2,3-dichloro, 2-chloro,
4-fluoro, 4-nitro, 3-nitro, 4-bromo, and 2,4-dichloro re-
acted rapidly whereas with electron-rich groups such as
4-benzyloxy, 4-methoxy, and 4-methyl the reactivity de-
creased and longer reaction time has been required and the
yield of the product decreased (Table 2).
MCM-41 has two-dimensional pore structures, thus,
it is easy for the reactant and product molecules to transfer
into it. It seems that at first the insertion of reactants toward
nanocatalyst channels occurs, and they are accompanied by
the inherent Brönsted acidity of -SO3H groups, which are
capable of bonding with the carbonyl of the 3,5-dibenzyl-
idenepiperidin-4-one moiety. In other words, ionic inter-
mediates (3, 4) are generated inside the nanoreactor by suf-
ficient energy released during the collapse and strong po-
larity of the -SO3H groups. Finally, by using this nanocata-
lyst, the reaction rates and yields under the reaction condi-
tion are enhanced (Scheme III).
Fig. 2. (a) Nitrogen adsorption/desorption isotherm,
(b) Pore size distribution and, (c) BJH of MCM-
41-SO3H.
Proposed mechanism in the presence of
MCM-41-SO3H
Scheme III
Fig. 3. Comparison of the amount of the catalyst and
yields for the synthesis of 5e.
J. Chin. Chem. Soc. 2012, 59, 000-000
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Rostamizadeh et al.
Table 2. The reaction time (min) and the yield (%) of pyrano[3,2-c]pyridine product
Entry
Product
Time (min) Yield (%)
M.P (°C)
Ref
5a
98
95
213-215
-
10
40
5b
193-195
-
5c
5d
5e
5f
10
96
98
93
70
80
78
80
91
213-216
204-205
238-239
203-204
226-228
211-212
238-240
225-226
208-210 [20]
197-198 [20]
238-240 [5]
203-204 [1]
215-217 [5]
200-202 [5]
238-240 [5]
225-227 [5]
5
10
45
5g
5h
5i
25
5
8
5j
15
10
8
5k
5l
95
93
245-246
198-200
245–246 [5]
199-200 [6]
Finally, in order to check the reusability of our cata-
dried and reused for at least four cycles. It is very efficient
with reusability for a four times with consistent activity
lyst, after completion of the reaction, the solid catalyst was
4
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Solvent Free Synthesis of Pyrano[3,2-c]pyridine
2.09 (3H, s, N-CH3), 2.51 (1H, d, J = 14.0 Hz), 3.02 (1H, d,
J = 16.2 Hz), 3.15 (1H, d, J = 14.0 Hz), 3.31 (1H, d, J = 14.8
Hz), 4.7 (1H, s, CH), 6.94 (1H, s, C=CH), 7.05 (2H, s,
NH2), 7.24-7.44 (4H, m), 7.58 (2H, d, J = 8.0 Hz); 13CNMR
(75 MHz, DMSO-d6): 44.2, 53.7, 54.2, 118.8, 119.9, 128.0,
128.9, 129.2, 129.4, 129.6, 130.3, 130.6, 132.0, 136.3,
139.5, 142.7, 160.1; MS (EI): m/e = 42 (100), 81 (46), 113
(30), 149 (70), 181 (60), 216 (53), 250 (91), 293 (12), 346
(11), 390 (14), 449 (19), 492 (22).
(8E)-8-(4-(benzyloxy)benzylidene)-2-amino-4-(4-(ben-
zyloxy)phenyl)-5,6,7,8-tetrahydro-6-methyl-4H-pyrano
[3,2-c]pyridine-3-carbonitrile (5b, C37H33N3O3)
Fig. 4. Catalytic recyclability of MCM-41-SO3H.
M.p = 193-195 ºC; 1HNMR (300 MHz; DMSO-d6):
2.13 (3H, s, N-CH3), 2.54 (1H, d, J = 14.4 Hz), 2.94 (1H, d,
J = 14.0 Hz), 3.25 (1H, d, J = 14.4 Hz), 3.45 (1H, d, J = 14.0
Hz), 3.97 (1H, s, CH), 5.06 (2H, s, OCH2), 5.10 (2H, s,
OCH2), 6.75 (2H, s, NH2), 6.83 (1H, s, C=CH), 7.00 (2H, d,
J = 8.7 Hz), 7.03 (2H, d, J = 8.7 Hz), 7.12 (2H, d, J = 8.7
Hz), 7.18 (2H, d, J = 8.7 Hz), 7.29-7.46 (10H, m): 13CNMR
(75 MHz, DMSO-d6): 44.4, 53.9, 54.4, 55.7, 113.0, 115.3,
115.5, 120.3, 120.4, 127.4, 129.4, 129.5, 130.9, 131.0,
132.3, 132.4, 139.1, 139.6, 139.7, 159.5, 159.6, 159.7,
162.8: MS (EI): m/e = 42 (16), 65 (63), 91 (100), 131 (40),
174 (44), 198 (19), 222 (23), 250 (63), 382 (86), 410 (54),
473 (30), 501 (75), 567 (16).
(Figure 4).
In conclusion, this novel synthetic method is espe-
cially favoured because it provides a synergy of the nano-
sized MCM-41-SO3H and solvent-free condition which of-
fers the advantages of high yields, short reaction times,
simplicity and easy workup compared to the conventional
methods reported in the literature. Most significantly, this
solid acidic catalyst is found to be very efficient with reus-
ability for a number of times with consistent activity.
EXPERIMENTAL
General procedure for the synthesis of 3,5-dibenzyli-
denepiperidin-4-one
In a 50-mL reaction vial, a mixture of the 4-piperi-
done (10 mmol), the appropriate aldehyde (20 mmol), 10%
NaOH (1 mL) and 95% EtOH (30 mL) was stirred at room
temperature for 0.5-2 h. The separated solid was collected
by filtration and for further purification was recrystallized
from ethanol.1
(8E)-8-(2-chlorobenzylidene)-2-amino-4-(2-chlorophen-
yl)-5,6,7,8-tetrahydro-6-methyl-4H-pyrano[3,2-c]pyri-
dine-3-carbonitrile (5c, C23H19Cl2N3O)
M.p = 213-216 ºC; 1HNMR (300 MHz; DMSO-d6): d
2.09 (3H, s, N-CH3), 2.48-2.53 (1H, d, J=14.6 Hz), 2.96-
3.02 (1H, d, J = 16.1 Hz), 3.15-3.20 (1H, d, J = 14.0 Hz),
3.28-3.34 (1H, d, J = 17.0 Hz), 4.6 (1H, s, CH), 6.95 (1H, s,
C=CH), 6.98 (2H, s, NH2), 7.25-7.52 (8H, m); 13CNMR (75
MHz, DMSO-d6): 44.3, 53.9, 54.3, 54.5, 56.0, 127.1,
128.1, 128.9, 129.0, 129.2, 129.4, 129.6, 130.5, 130.8,
131.0, 132.3, 132.8, 133.3, 133.9, 134.0, 139.4, 140.1,
159.5: MS (EI): m/e = 51 (36), 81 (62), 115 (66), 182 (100),
216 (89), 379 (53), 422 (74), 423 (45).
General procedure for the synthesis of pyrano[3,2-
c]pyridine derivatives
A mixture of 3,5-dibenzylidenepiperidin-4-one (0.33
mmol), malononitrile (0.33 mmol), was added to MCM-
41-SO3H (15 mg, 0.09 mmol H+); it was then stirred at 115
°C for an appropriate period of time. After completion of
the reaction (monitored by thin-layer chromatography,
TLC; petroleum ether and EtOAc, 2:1), the reaction mix-
ture was cooled to room temperature and poured into water
(50 mL), filtered to give the crude product, which was fur-
ther purified by recrystallization from 95% EtOH to give
pure product.
(8E)-8-(4-chlorobenzylidene)-2-amino-4-(4-chlorophen-
yl)-5,6,7,8-tetrahydro-6-methyl-4H-pyrano[3,2-c]pyri-
dine-3-carbonitrile (5e, C23H17Cl4N3O)
M.p = 238-239 ºC; 1HNMR (300 MHz; DMSO-d6): d
2.16 (3H, s, N-CH3), 2.98 (1H, d, J = 16.0 Hz), 3.2 (1H, d, J
= 14.3 Hz), 3.28 (1H, d, J = 14.0 Hz), 3.46 (1H, d, J = 14.0
Hz), 4.16 (1H, s, CH), 6.87 (1H, s, C=CH), 6.88 (2H, s,
NH2), 7.25 (4H, d, J = 8.0 Hz), 7.43 (4H, d, J = 8.0 Hz).
(8E)-8-(2,3-dichlorobenzylidene)-2-amino-4-(2,3-dichlo-
rophenyl-5,6,7,8-tetrahydro-6-methyl-4H-pyrano[3,2-c]
pyridine-3-carbonitrile (5a, C23H17Cl4N3O)
M.p = 213-215 ºC; 1HNMR (300 MHz; DMSO-d6): d
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Article
Rostamizadeh et al.
9. Wang, X.-Sh.; Shi, D.-Q.; Du, Y.; Zhou, Y.; Tu, Sh.-J. Synth.
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ACKNOWLEDGEMENTS
We gratefully acknowledge the support of this work
by K. N. Toosi University of Technology.
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