Covalently anchored sulfonic acid on silica gel as an efficient and reusable heterogeneous catalyst for the one-pot synthesis of Hantzsch 1,4-dihydropyridines under solvent-free conditions

Article abstract of DOI:10.1055/s-2007-983839

A highly efficient one-pot synthesis of Hantzsch 1,4-dihydropyridines under solvent-free conditions catalyzed by sulfonic acid covalently anchored onto the surface of silica gel is reported here. All types of aldehydes, including aromatic, unsaturated, and heterocyclic aldehydes, gave excellent yields. The silica gel/sulfonic acid catalyst (SiO₂-SO₃H) is completely heterogeneous and can be recycled for eight consecutive runs without significant loss of activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983839

PAPER
2835
Covalently Anchored Sulfonic Acid on Silica Gel as an Efficient and Reusable
Heterogeneous Catalyst for the One-Pot Synthesis of Hantzsch 1,4-Dihydro-
pyridines under Solvent-Free Conditions
S
ulfonic
Acid on
a
Silica Ge
l
m
as Catalyst for Synt
a
hesis of 1,4
n
-
DihydropyridinesGupta,a Rajive Gupta,a Satya Paul,*a Andre Loupyb
a
Department of Chemistry, University of Jammu, Jammu-180 006, India
Fax +91(191)2505086; E-mail: paul7@rediffmail.com
Laboratoire des Reactions Sélectives sur Supports, Paris-South University, 91405 Orsay cedex, France
E-mail: andre.loupy@cegetel.net
b
Received 18 April 2007; revised 1 June 2007
long time. However, yields of 1,4-DHPs obtained by the
Hantzsch method are generally low, particularly in the
case of aliphatic and unsaturated aldehydes. Although nu-
merous modified methods7 have been reported, many of
Abstract: A highly efficient one-pot synthesis of Hantzsch 1,4-di-
hydropyridines under solvent-free conditions catalyzed by sulfonic
acid covalently anchored onto the surface of silica gel is reported
here. All types of aldehydes, including aromatic, unsaturated, and
heterocyclic aldehydes, gave excellent yields. The silica gel/sulfon- them suffer from drawbacks such as harsh reaction condi-
ic acid catalyst (SiO2–SO3H) is completely heterogeneous and can
tions, low yield of products, cumbersome workup proce-
be recycled for eight consecutive runs without significant loss of ac-
tivity.
dures, and long reaction times. Therefore, there is need to
develop a heterogeneous catalyst for the one-pot synthesis
of 1,4-dihydropyridines that is mild, recyclable, easily
separable, compatible with acid-sensitive functional
Key words: 1,3-dicarbonyl compounds, supported catalysis, 1,4-
dihydropyridines, heterogeneous catalysis, solvent-free conditions
groups, and cost-effective.
In recent years, heterogeneous catalysts8 have gained con-
Since the discovery of 1,4-dihydropyridines (1,4-DHPs)
siderable interest, since these can be recovered after the
by Hantzsch in 1881,1 there has been continued interest in
reaction and reused several times to achieve very high
this heterocyclic nucleus, as these are analogues of
turnover numbers. Reactions with these catalysts are gen-
NADH coenzymes and an important class of drugs.2 The
erally clean and selective and give high yields of products.
1,4-DHP motif is found in a number of chemotherapeutic
Recently, the use of silica-functionalized sulfonic acid has
agents for the treatment of cardiovascular disease such as
been reported in a number of organic transformations.9
hypertension and angina pectoris,3 and in neuro-
protectant4 and platelet anti-aggregatory agents,5 in addi-
tion to acting as a cerebral antischemic agent in the
treatment of Alzheimer’s disease,5 and also as a
chemosensitizer in tumor therapy.6 A recent computation-
al analysis of the comprehensive medicinal chemistry da-
tabase found the DHP framework to be among the most
prolific chemotypes. Thus, there is a continued interest in
the synthesis of 1,4-DHP nucleus.
In this paper, we wish to report a mild, cost-effective, and
solvent-free procedure for the one-pot synthesis of 1,4-di-
hydropyridines by the condensation of aldehydes (aro-
matic, unsaturated, and heterocyclic), b-keto esters, and
ammonium acetate in the presence of a catalytic amount
of sulfonic acid covalently anchored onto the surface of
silica gel (SiO2–SO3H) under stirring at 60 °C in solvent-
free conditions (Scheme 1).
For the preparation of sulfonic acid covalently anchored
onto the surface of silica gel (SiO2–SO3H), activated silica
was refluxed with trimethoxy(3-sulfanylpropyl)silane in
The classical synthesis of 1,4-DHPs involves the one-pot
condensation of an aldehyde with ethyl acetoacetate and
ammonia in either acetic acid or refluxing alcohol for a
2
O
O O
Si
O
R1
O
H
HO3S
R2
R2
O
O
O
O
(SiO2-SO3H)
R2
R1CHO
+ NH4OAc
+
O
solvent-free, 60 °C
N
H
1
2
3
Scheme 1
SYNTHESIS 2007, No. 18, pp 2835–2838
x
x.
x
x
.
2
0
0
7
Advanced online publication: 08.08.2007
DOI: 10.1055/s-2007-983839; Art ID: Z09807SS
© Georg Thieme Verlag Stuttgart · New York

2836
R. Gupta et al.
PAPER
toluene for 24 hours (Scheme 2). This gave 3-sulfanylpro-
pyl-substituted silica, which was then oxidized with 30%
hydrogen peroxide in the presence of concentrated sulfu-
ric acid, to give sulfonic acid covalently anchored onto the
surface of silica gel (Scheme 2). The detailed experimen-
tal procedure for the preparation and characterization of
this silica gel/sulfonic acid catalyst was reported else-
where.9g
Table 1 Solvent-Free One-Pot Synthesis of 1,4-Dihydropyridines
3a–o Catalyzed by Sulfonic Acid on Silica Gela
Compound R1
R2
Et
Time (h) Yieldb (%)
3a
Ph
5.5
5
90
92
86
88
85
83
87
86
89
88
95
89
85
86
89
3b
3cc
3dc
3ec
3fc
3g
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
2-O2NC6H4
3-O2NC6H4
CH=CHPh
2-furyl
Et
Et
6
Et
4.5
5.5
6
O
OH
SH
(MeO)3Si
Et
O
O
Si
SH
OH
OH
toluene, reflux, 24 h
Et
Et
4.5
7
i. 30% H2O2
ii. 0.5 M H2SO4
3h
3i
Et
O
O
O
Si
SO3H
2-thienyl
Ph
Et
7
iii. distilled H2O
3j
Me
Me
Me
Me
Me
Me
5
SiO2-SO3H
3k
3lc
3mc
3nc
3o
4-MeOC6H4
4-ClC6H4
4-O2NC6H4
2-O2NC6H4
CH=CHPh
5
Scheme 2
5.5
5
To optimize the reaction conditions, the reaction of
4-methoxybenzaldehyde, ethyl acetoacetate, and ammo-
nium acetate was selected as the model to examine the ef-
fects of the silica gel/sulfonic acid catalyst (5–20 mol%)
at several temperatures in different solvents (MeCN,
CH2Cl2, H2O). The results were evaluated qualitatively by
thin-layer chromatography. The best conditions employ
the silica gel/sulfonic acid catalyst, 4-methoxybenzalde-
hyde, ethyl acetoacetate, and ammonium acetate in a
0.12:1:2:1.5 mole ratio at 60 °C for five hours under sol-
vent-free conditions.
6
4.5
a Reagents and conditions: 1 (1 mmol), 2 (2 mmol), NH4OAc (1.5
mmol), SiO2–SO3H (0.2 g), 60 °C.
b Isolated yield.
c n-Hexane (1 mL) was added to homogenize the reaction mixture.
amount of sulfonic acid as that applied for the silica gel/
sulfonic acid reaction. It was found that lower yields were
obtained and, moreover, the reaction times were longer
(SiO2–SO3H, 5 h, 92% yield; polystyrene-SO3H, 6.5 h,
82% yield; PEG-SO3H, 6.25 h, 85% yield).
Under these optimized conditions, the reactions between
various aromatic/heterocyclic aldehydes and b-keto esters
(ethyl acetoacetate and methyl acetoacetate) in the pres-
ence of ammonium acetate was investigated (Scheme 1,
Table 1). It was found that all the reactions proceeded
smoothly to give the corresponding 1,4-dihydropyridines
in high yields (Table 1). Both aromatic aldehydes bearing
electron-donating substituents such as 4-methoxybenz-
aldehyde (giving 3b, 92%) and electron-withdrawing
groups such as 4-nitrobenzaldehyde (giving 3d, 88%)
gave excellent yields. The procedure worked well for vi-
nyl (giving 3g, 87%; 3o, 89%) as well as heterocyclic al-
dehydes (giving 3h, 86%; 3i, 89%) in addition to aromatic
aldehydes. The mildness of the procedure makes it very
selective, as it tolerates a variety of functionalities, includ-
ing chloro, methoxy, nitro, and vinyl groups. The results
are summarized in Table 1, which clearly demonstrates
the generality and scope of the reaction with respect to
various aromatic, heterocyclic, and unsaturated alde-
hydes.
When a heterogeneous catalyst is used, an important issue
is the deactivation and recyclability of the catalyst. To test
this, a series of eight consecutive runs of the reaction of
4-methoxybenzaldehyde, ethyl acetoacetate, and ammo-
nium acetate with the silica gel/sulfonic acid catalyst were
carried out. The results are shown in Figure 1. It demon-
strates that there is no significant change in the activity of
the catalyst. Furthermore, there is no change in the ther-
mogravimetric analysis (TGA) of the fresh catalyst and
the catalyst after its eighth use; this indicates that no loss
of any organic functionality has taken place during repeat-
ed chemical reactions. Thus, this makes the process still
more cost-effective.
With the silica gel/sulfonic acid catalyst, the proposed
mechanism for the synthesis of 1,4-dihydropyridines 3 in-
volves acid-catalyzed cyclocondensation of intermediates
A and B, generated respectively by Knoevenagel conden-
sation of one equivalent of ethyl acetoacetate with alde-
hyde and reaction of a second equivalent of ethyl
acetoacetate with ammonia generated from ammonium
acetate (Scheme 3).
To compare the activity of the silica gel/sulfonic acid sys-
tem with other supported sulfonic acids, we carried out the
reaction giving 3b (Table 1) with polystyrene-supported
sulfonic acid10 and polyethylene glycol supported sulfonic
acid11 under similar conditions, with the same mol%
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PAPER
Sulfonic Acid on Silica Gel as Catalyst for Synthesis of 1,4-Dihydropyridines
2837
catalyst under solvent-free conditions. Moreover, the mild
reaction conditions, high yields of products, ease of work-
up, compatibility with various functional groups, and the
ecologically clean procedure will make the present meth-
od a useful and important addition to the present method-
ologies for the synthesis of Hantzsch 1,4-dihydro-
pyridines.
Silica gel (K100, 0.063–0.200 mm) was purchased from Merck
(Germany) and trimethoxy(3-sulfanylpropyl)silane from Aldrich
Chemical Company. All melting points were determined on a Perfit
melting point apparatus and are uncorrected. 1H NMR spectra were
obtained on a Bruker DPX-200 NMR spectrometer (200 MHz) of
samples in CDCl3 or CDCl3–DMSO-d6 with TMS as an internal
standard. The IR spectra of samples prepared as KBr discs were re-
corded on a Perkin-Elmer FTIR spectrophotometer. MS data were
recorded on an Esquire 3000 (ESI) spectrometer. Thermal analysis
was carried out on a DTG-60 Shimadzu thermal analyzer and ele-
mental analysis was carried out on a Leco-CHNS-932 elemental an-
alyzer (Leco Corporation, USA).
Figure 1 Recyclability of the silica gel/sulfonic acid catalyst in the
one-pot synthesis of 3b. Reagents and conditions: 4-MeOC6H4CHO,
AcCH2CO2Et, NH4OAc, SiO2–SO3H, 60 °C.
2
O
O O
Si
1,4-Dihydropyridines 3a–o; General Procedure
To a mixture of aldehyde 1 (1 mmol), b-keto ester 2 (2 mmol), and
NH4OAc (1.5 mmol) in a 25-mL round-bottomed flask, SiO2–SO3H
(0.2 g) was added. The reaction mixture was stirred at 60 °C in an
oil bath for the appropriate time (Table 1). After completion of the
reaction (monitored by TLC), the mixture was triturated with
CH2Cl2 (2 × 5 mL) and the SiO2–SO3H was collected by filtration.
The product was obtained after removal of the solvent under re-
duced pressure and crystallization (EtOAc–PE). The catalyst was
washed with distilled H2O (3 × 50 mL) followed by CH2Cl2 (2 × 25
mL) and dried at 110 °C for 2 h. It could then be reused for further
reactions.
–O3S
H
O
O
O
O
R2
R2
O
O
R1-CHO
– H2O
– H2O
NH3
O
R1
O
R2
R2
The structures of the products were confirmed by IR, 1H NMR, and
MS data and by comparison with authentic samples prepared ac-
cording to literature methods.
O
H
O
2
O
H2N
A
B
O
O O
Si
Diethyl 2,6-Dimethyl-4-[(E)-2-phenylvinyl]-1,4-dihydropyri-
dine-3,5-dicarboxylate (3g); Typical Procedure
To a mixture of cinnamaldehyde (1.32 g, 10 mmol), AcCH2CO2Et
(2.6 g, 20 mmol), and NH4OAc (0.92 g, 12 mmol) in a 50-mL
round-bottomed flask, SiO2–SO3H (0.4 g) was added. The reaction
mixture was then stirred at 60 °C in an oil bath for 5 h. After the re-
action mixture (monitored by TLC) had cooled to r.t., it was tritu-
rated with CH2Cl2 (2 × 15 mL) and the SiO2–SO3H was collected by
filtration. The product was obtained after removal of the solvent un-
der reduced pressure and crystallization (EtOAc–PE).
–O3S
H
R1
O
R1
O
H
O
O
H
H
R2
R2
R2
R2
O
O
O
O
– H2O
N
H
OH
HN
Yield: 2.84 g (82%); cream-colored crystals.
3
Diethyl 2,6-Dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicar-
boxylate (3a)
Scheme 3
IR (KBr): 3344, 2958, 1705, 1652, 1497 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.30 (t, J = 8.4 Hz, 6 H, 2 × CH3),
2.22 (s, 6 H, 2 × CH3), 4.09 (m, J = 8.4 Hz, 4 H, 2 × OCH2), 5.02 (s,
1 H, C-4H), 5.90 (br s, 1 H, NH), 7.26–7.38 (m, 5 H, HAr).
During the last decade, the use of microwaves12 in organic
synthesis has been highly recognized as they speed up the
chemical reactions, and clean products are obtained in
high yields. To reduce the reaction time from hours to
minutes, we have carried out the reaction leading to prod-
uct 3b under similar conditions. Unfortunately, lower
yields were obtained (320-W power, 2 min, 63% yield).
ESI-MS: m/z = 328 [M+ – 1], 352 [M+ + 23].
Diethyl 4-(4-Chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-
3,5-dicarboxylate (3c)
IR (KBr): 3354, 2952, 1701, 1647, 1333 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.15 (t, J = 7.5 Hz, 6 H, 2 × CH3),
2.24 (s, 6 H, 2 × CH3), 4.03 (m, J = 7.6 Hz, 4 H, 2 × OCH2), 4. 80
(s, 1 H, C-4H), 5.76 (br s, 1 H, NH), 7.09 (d, J = 8.2 Hz, 2 H, HAr),
7.17 (d, J = 8.2 Hz, 2 H, HAr).
In conclusion, we have developed a mild, simple, cost-ef-
fective, and green procedure for the synthesis of 1,4-dihy-
dropyridines using a recyclable silica gel/sulfonic acid
Synthesis 2007, No. 18, 2835–2838 © Thieme Stuttgart · New York

2838
R. Gupta et al.
PAPER
ESI-MS: m/z (%) = 363 [M+ – 1], 387 [M+ + 23].
References
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IR (KBr): 3320, 2947, 1702, 1647, 1343 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.18 (t, J = 7.2 Hz, 6 H, 2 × CH3),
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3,5-dicarboxylate (3e)
IR (KBr): 3370, 2942, 1712, 1648, 1435 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.20 (t, J = 7.8 Hz, 6 H, 2 × CH3),
2.32 (s, 6 H, 2 × CH3), 4.10 (m, J = 7.7 Hz, 4 H, 2 × OCH2), 5.08 (s,
1 H, C-4H), 5.69 (br s, 1 H, NH), 7.35–8.16 (m, 4 H, HAr).
ESI-MS: m/z = 372 [M+ – 1], 396 [M+ + 23].
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IR (KBr): 3348, 2992, 1702, 1652, 1497 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.30 (t, J = 8.8 Hz, 6 H, 2 × CH3),
2.21 (s, 6 H, 2 × CH3), 4.16 (m, J = 8.6 Hz, 4 H, 2 × OCH2), 5.22 (s,
1 H, C-4H), 5.94 (br s, 1 H, NH), 6.80–7.07 (m, 3 H, HAr).
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270.
1H NMR (200 MHz, CDCl3): d = 2.32 (s, 6 H, 2 × CH3), 3.76 (s, 6
H, 2 × CH3), 4.76 (d, J = 7.2 Hz, 1 H, C-4H), 5.66 (br s, 1 H, NH),
6.12 (d, J = 6.1 Hz, 1 H, =CH), 6.45 (d, J = 15.8 Hz, 1 H, =CH),
7.13–7.46 (m, 5 H, HAr).
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ESI-MS: m/z = 354 [M+ – 1], 378 [M+ + 23].
Acknowledgment
One of the authors (Raman Gupta) is thankful to the University of
Jammu for the award of a Research Fellowship.
Synthesis 2007, No. 18, 2835–2838 © Thieme Stuttgart · New York