Sulfonic acid-functionalized silica: A remarkably efficient heterogeneous reusable catalyst for the one-pot synthesis of 1, 4-dihydropyridines

Article abstract of DOI:10.3906/kim-0906-28

An efficient one-pot method for the synthesis of 1, 4-dihydropyridines from β-dicarbonyl compounds, aldehyde, and ammonium acetate is reported using sulfonic acid-functionalized silica at 90 ° C under solvent-free conditions with good to excellent yields. The catalyst is easily prepared, stable (up to 300 ° C), reusable, and efficiently used under reaction conditions. tuebitak.

Full text of DOI:10.3906/kim-0906-28

Turk J Chem
34 (2010) , 613 – 619.
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˙
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ꢀ TUBITAK
doi:10.3906/kim-0906-28
Sulfonic acid-functionalized silica: a remarkably efficient
heterogeneous reusable catalyst for the one-pot
synthesis of 1,4-dihydropyridines
Behzad MOHAMMADI1, Sayyed Mohammad HOSSEINI JAMKARANI1, Taghi A. KAMALI2,
Mahmoud NASROLLAHZADEH3,∗, Ali MOHAJERI2
1Department of Chemistry, Islamic Azad University, Karaj Branch, Karaj-IRAN
2Gas Division, Research Institute of Petroleum Industrial, Tehran-IRAN
3Laboratory of Organic Chemistry, Moshashimi Company, Kardikola Industrial Region,
P.O. Box 47571-54879, Babol-IRAN
e-mail: mahmoudnasr81@gmail.com
Received 09.06.2009
An efficient one-pot method for the synthesis of 1,4-dihydropyridines from β -dicarbonyl compounds,
aldehyde, and ammonium acetate is reported using sulfonic acid-functionalized silica at 90 ◦ C under solvent-
free conditions with good to excellent yields. The catalyst is easily prepared, stable (up to 300 ◦ C), reusable,
and efficiently used under reaction conditions.
Key Words: 1,4-Dihydropyridine, β -dicarbonyl compounds, solid acid, SiO2 -R-SO3 H, heterogeneous
catalyst.
Introduction
Hantzsch 1,4-dihydropyridines (1,4-DHPs) are well known as Ca2+ channel blockers and have emerged as one
of the most important classes of drugs for the treatment of cardiovascular diseases, including hypertension.1,2
1,4-Dihydropyridines possess a wide range of biological activities, being vasodilators, bronchodilators, geropro-
tectives, hepatoprotectives, and antitumor, antiatherosclerotic, and antidiabetic agents.3a−e
Recent studies have revealed that 1,4-DHPs exhibit several other medicinal applications, including
neuroprotectant4a and platelet antiaggregator activity,4b in addition to acting as cerebral antiischemic agents
∗Corresponding author
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Sulfonic acid-functionalized silica: a remarkably efficient..., B. MOHAMMADI, et al.,
in the treatment of Alzheimer’s disease4c and as a chemosensitizer in tumor therapy.4d A recent computational
analysis of the comprehensive medicinal chemistry database showed the DHP framework to be among the
most prolific chemo types found. Development of drug resistance, both intrinsic drug resistance and acquired
drug resistance, remains a clinical obstacle in the chemotherapy of many cancers.5,6 Among the possible
resistance modifiers, the dihydropyridines, calcium antagonists, have been studied extensively as the analogue
of verapamil.7 Furthermore, the photocatalytic oxidation of these compounds to pyridines has been intensively
investigated.8
More than 100 years ago, the first 1,4-DHPs were synthesized by Hantzsch.9 The classical method involves
a one-pot condensation of an aldehyde with 1,3-dicarbonyl compounds and ammonia, either in acetic acid or in
a refluxing alcohol for a longer period.
An important objective of chemistry is to adapt classical processes so that pollution effects are kept
to a minimum, with both reductions in energy usage and consumption of raw materials. Solid acid catalysts
play a prominent role in organic synthesis under heterogeneous conditions. In general, solid acid catalysts are
mainly based on clay10 or silica.11,12 In terms of convenience, silica-based catalysts are inexpensive, easy to
prepare, and insoluble in all organic solvents. Hence, they can be recovered and recycled from reactions. Among
various silica-based heterogeneous catalysts, sulfonic acid-functionalized silica has the advantages of being low
cost, easy to prepare, and able to be recycled.13 Sulfonic acid-functionalized silica behaves as an organic-
inorganic hybrid (interphase) catalyst, wherein a Brønsted acid site has been selectively created. Recently,
silica-functionalized sulfonic acid has been used to catalyze a variety of reactions.14 The catalyst (1) was
prepared14d by the immobilization of propyl thiol on silica using 3-mercaptopropyltrimethoxysilane, followed
by the selective oxidation of the thiol groups by aqueous H2 O2 to the sulfonic acid groups (Scheme 1). The
catalyst shows high thermal stability (up to 300 ˚C).14d
Scheme 1.
In continuation of our recent work on the synthesis of heterocycles15 and application of heterogeneous
reagents for the development of synthetic methodologies,12 we report a new protocol for the preparation of
1,4-dihydropyridines from a wide variety of aromatic aldehydes using sulfonic acid-functionalized silica (1)14d
under thermal and solvent-free conditions (Scheme 2 and Table).
614

Sulfonic acid-functionalized silica: a remarkably efficient..., B. MOHAMMADI, et al.,
O
R
O
O
O
R2
R2
SiO2-R-SO3H
R1
R2 NH4OAc
+
RCHO
+
90 0C, Solvent-free
R1
N
H
R1
2
1
4a-o
3
Scheme 2.
Experimental section
General
All reagents were purchased from the Merck and Aldrich chemical companies and used without further purifi-
cation. The NMR spectra were recorded on Bruker Avance DRX 250, 300, and 500 MHz instruments. The
chemical shifts (δ) are reported in ppm relative to the TMS as the internal standard. J values are given in
Hz. The IR spectra were recorded on a Shimadzu 470 spectrophotometer. TLC was performed on silica gel
polygram SIL G/UV 254 plates.
Preparation of 3-mercaptopropylsilica (MPS)14d
˚
Mesoporous amorphous silica gel (average pore diameter: 60 A) was activated by refluxing in concentrated hy-
drochloric acid (6 M) for 24 h and then washed thoroughly with the deionized water and dried before undergoing
chemical surface modification. The activated silica gel (10 g) was refluxed with 3-mercaptopropyltrimethoxysilane
(MPTMS, 5 mmol) in dry toluene for 18 h. The solid materials were filtered off and washed with hot toluene
for 12 h in a continuous extraction apparatus (Soxhlet), and then dried in an oven at 110 ◦ C overnight to give
the surface-bound thiol (MPS) group.
Preparation of solid silica-based sulfonic acid 114d
The thiol groups of the modified silica (MPS, 5 g) were oxidized with a 30% H2 O2 solution (50 mL) and
concentrated H2 SO4 (2 drops) in methanol (15 mL) for 12 h at room temperature. The solid was filtered off
and washed 3 times with deionized water (50 mL). In order to ensure that all of the sulfonic acid groups were
protonated, the solid was suspended in 10 wt% H2 SO4 solution (30 mL) for 4 h. The solid was then filtered
off, washed thoroughly with deionized water, and dried at 120 ◦ C overnight.
The organic composition of the solid sulfonic acid was quantitatively determined by thermogravimetric
analysis (TGA), acid-base titration, and ion exchange pH analysis.14d Typically, a loading of approximately
0.35 mmol/g was obtained. When the washed sulfonated product 1 was placed in an aqueous NaCl solution, the
solution pH dropped virtually instantaneously to approximately pH 2, as ion exchange occurred between protons
and sodium ions (proton exchange capacity: 0.33 mmol/g of sulfonic acid 1, which is in good agreement with
615

Sulfonic acid-functionalized silica: a remarkably efficient..., B. MOHAMMADI, et al.,
the results obtained from TGA and titration). This result also shows that more than 94% of the surface-bound
thiol groups were converted to the corresponding sulfonic acid group.14d
General procedure for the synthesis of 1,4-dihydropyridines
A mixture of aldehyde (1 mmol), β-dicarbonyl compounds (2 mmol), NH4 OAc (1.5 mmol), and SiO2 -R-SO3 H
(0.1 g) was heated at 90 ◦ C with stirring for 60 min. After completion of the reaction (as indicated by TLC),
the reaction mixture was washed with ice-cold water and extracted with EtOAc, followed by a water and brine
solution, and dried with anhydrous Na2 SO4 . The solution was concentrated in a vacuum to afford the crude
product, and then the crude product was purified by using column chromatography. All of the products were
known compounds, and the spectral data and melting points were identical to those reported in the literature.
Catalyst reuse and stability
Sulfonic acid-functionalized silica works under heterogeneous conditions, but its reaction centers are highly
mobile, as in a homogeneous catalyst. It is an inexpensive and nonhazardous solid acid catalyst. It can easily
be handled and removed from the reaction mixture by simple filteration. The recovered catalyst was reused
consecutively 5 times with a minimum of variation of the yields of the products (Table, entry 2). This reusability
demonstrates the high stability and turnover of solid silica-based sulfonic acid under operating conditions. The
simplicity, together with the use of an inexpensive, nontoxic, and environmentally benign catalyst under solvent-
free conditions, is another remarkable feature of the procedure.
Results and discussion
However, the yields of 1,4-DHPs obtained by the Hantzsch method are generally low. Due to some disadvantages
of this method, several efficient methods have been developed for the synthesis of 1,4-DHPs, which comprise
the use of microwaves, ionic liquid, high temperatures in refluxing solvents, TMSCl-NaI, and metal triflates.16
However, the use of large quantities of volatile organic solvents, high temperatures, expensive metal precursors,
longer reaction times, stoichiometric use of reagents and catalysts, and unsatisfactory yields limit these methods.
Additionally, the clean handling of some anhydrous metal halides is not easy enough in the laboratory apart
from their hygroscopic nature, due to the strong tendency for hydrolysis. Therefore, it is desirable to develop
a more efficient and convenient method for the synthesis of 1,4-dihydropyridines.
First, we optimized the amount of SiO2 -R-SO3 H catalyst required in the reaction between aldehyde, 1,3-
dicarbonyl compounds, and ammonium acetate. The optimum amount of SiO2 -R-SO3 H was found to be 0.1 g
in the presence of aldehydes (1 mmol), 1,3-dicarbonyl compound (2 mmol), and ammonium acetate (1.5 mmol).
As shown in the Table, benzaldehyde and other aromatic aldehydes containing electron-withdrawing groups
(such as the nitro or halide groups) or electron-donating groups (such as the alkoxy group) were employed and
gave the corresponding 1,4-dihydropyridine. The nature of the substituent on the benzaldehyde did not affect
the reaction time. This is a new method for the synthesis of these compounds, and in all cases the reaction
gives the products in good yields (86%-93%) and prevents problems that many associate with solvent use, such
as cost, handling, safety, and pollution.
616

Sulfonic acid-functionalized silica: a remarkably efficient..., B. MOHAMMADI, et al.,
Table. One-pot synthesis of 1,4-dihydropyridines under solvent-free conditions using SiO2 -R-SO3 H.
Entry
1
R
R1
R2
Product Yielda % Reference
C6H5
CH3 OMe
CH3 OEt
CH3 OMe
CH3 OMe
CH3 OEt
CH3 OEt
CH3 OEt
CH3 OEt
CH3 OEt
CH3 OMe
CH3 OEt
CH3 OMe
CH3 OEt
4a
4b
4c
4d
4e
4f
93
93,90b
88
17
17, 18
17
2
C6H5
3
2-OMeC6H4
2-NO2C6H4
2-NO2C6H4
2-BrC6H4
4-ClC6H4
4-NO2C6H4
4-BrC6H4
4-MeC6H4
4-MeC6H4
4-OMeC6H4
4-OMeC6H4
4
90
17
5
90
17
6
91
17
7
4g
4h
4i
90
17
8
89
17, 18
17, 18
17
9
90
10
11
12
13
14
15
4j
88
4k
4l
89
17
87
16i
4m
4n
4o
89
17
3,4-(OMe)2C6H3 CH3 OEt
3,4-Cl2C6H3 CH3 OEt
86
16i
87
16i
aYields refer to the pure isolated products.
bYield after the fifth cycle.
Conclusions
We have developed a novel and highly efficient method for the synthesis of 1,4-dihydropyridines by treatment
of aromatic aldehydes with a 1,3-dicarbonyl compound in the presence of silica solid sulfonic acid as a catalyst.
The significant advantages of this methodology are high yields, a simple work-up procedure, cleaner reaction,
and easy preparation and handling of the catalyst. The catalyst can be recovered by filtration and reused.
Acknowledgement
We are grateful to the Gas Division and the Moshashimi Company for the partial support of this research.
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