Rapid and cleaner synthesis of 1,4-dihydropyridines in aqueous medium

Article abstract of DOI:10.1002/hc.20197

The present investigation deals with a novel water soluble Lewis acid complex, Zn[(L)proline]₂ catalyzed Hantzsch 1,4-dihydropyridine derivatives syntheses in aqueous medium assisted by microwave irradiation. The microwave promoted syntheses in aqueous medium afforded moderate to excellent yield (up to 98%) within short reaction time and allowed the reaction to take place with low microwave power (200 W). This synthetic methodology provides easier separation of products and the catalyst exhibits recycling ability without loss of its catalytic activity up to five reaction cycles.

Full text of DOI:10.1002/hc.20197

Heteroatom Chemistry
Volume 17, Number 4, 2006
Rapid and Cleaner Synthesis of
1,4-Dihydropyridines in Aqueous Medium
V. Sivamurugan,1 A. Vinu,2 M. Palanichamy,1 and V. Murugesan1
1Department of Chemistry, Anna University, Chennai 600 025, India
2ICYS fellow, National Institute of Materials Science, 1-2-1, Tsukuba, Ibaraki 305 0047, Japan
Received 1 July 2005; revised 24 September 2005
of organic transformations including stereo selective
ABSTRACT: The present investigation deals
Diels–Alder reactions [2], Claisen rearrangements
with
a novel water soluble Lewis acid com-
[3], aldol reactions [4], allylation reactions [5], ox-
idations including asymmetric epoxidation [6], and
hydrogenation of alkenes [7].
plex, Zn[(L)proline]2 catalyzed Hantzsch 1,4-
dihydropyridine derivatives syntheses in aqueous
medium assisted by microwave irradiation. The
microwave promoted syntheses in aqueous medium
afforded moderate to excellent yield (up to 98%)
within short reaction time and allowed the reaction to
take place with low microwave power (200 W). This
synthetic methodology provides easier separation of
products and the catalyst exhibits recycling ability
without loss of its catalytic activity up to five reaction
Dihydropyridine (DHP) derivatives are impor-
tant class of organic compounds in view of its
vast application in pharmaceuticals. These deriva-
tives are widely known as calcium channel block-
ers and emerge as one of the most substantial
classes of drugs for treatment of cardiovascular
diseases including hypertension [8]. 1,4-DHP het-
erocyclic ring is an essential nucleus in various
bioactive compounds such as vasodilator, bron-
chodilator, geroprotective, and hepatoprotective [9].
Conventionally, 1,4-DHPs were prepared by one pot
three-component condensation of an aryl or alkyl
aldehyde, a ꢀ-dicarbonyl compound and ammonia
in the presence of a mineral acid catalyst under re-
flux condition. Although numerous methods with
improved conditions have been reported, many of
them are suffering from serious drawbacks such as
low catalyst life cycle, occurrence of side reactions,
unsatisfactory yield, high temperatures, and longer
reaction times [10–29]. Hence, the development of an
efficient and versatile method for the preparation of
Hantzsch 1,4-DHPs is an important approach, and
essential to pharmaceutical industries for scale-up
process [30,31]. Microwave-assisted organic synthe-
sis in aqueous medium enhances reaction rate and
yield due to high absorbance of microwave power
by polar medium and also provides easier separa-
tion of products from water-soluble catalysts in low
microwave power compared to solid phase reactions
ꢀ
C
cycles. 2006 Wiley Periodicals, Inc. Heteroatom Chem
17:267–271, 2006; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20197
INTRODUCTION
The development of benign synthetic methodology
for fine and specialty chemicals is of great interest be-
cause of growing environmental awareness. The ba-
sic principles of green chemistry have recognized or-
ganic synthesis in aqueous medium through replac-
ing utilization of toxic organic solvents [1]. The use of
water as a solvent has been accepted for a wide range
Correspondence to: V. Murugesan; e-mail: sivamuruganv@
rediffmail.com.
Contract grant sponsor: University Grants Commission (UGC),
New Delhi, India.
Contract grant sponsor: Council of Scientific and Industrial
Research, New Delhi, India.
c
ꢀ
2006 Wiley Periodicals, Inc.
267

268 Sivamurugan et al.
analyzer. The mass spectra were recorded on a
Finnigan Mat 8230 MS spectrometer.
Synthesis and Characterization of
Zn[(L)proline]2 Complex
Zn[(L)proline]2 complex has been successfully syn-
1
thesized and characterized by FTIR, H NMR, MS,
and elemental analysis. The results are in accordance
with our earlier report [33].
Catalytic Studies [34]
The effect of substituents on the reactivity of
Zn[(L)proline]2 catalyst is presented in Table 1. The
results reveal that electronic effect of substituents
has no significant effect on the catalytic activity.
The microwave-irradiated reactions rendered excel-
lent yield in aqueous medium. The presence of polar
medium such as water is capable of absorbing more
microwave energy within less energy input (<200 W)
than solid-phase solvent-free condition. All the reac-
tions were carried out in 200 W microwave power
range with a pulse of 10 s. The progress of reaction
was monitored by TLC analysis. After completion of
the reaction, the reaction mixture was allowed to
stand overnight at 10–15◦C and the product sepa-
rated as fine crystals. The product was filtered and
dried in vacuum for 6 h at 75◦C. This methodol-
ogy provides easier separation of products from the
SCHEME 1 Synthesis of 1,4-dihydropyridine.
[32]. We report herein the synthesis of Hantzsch 1,4-
DHP derivatives catalyzed by Zn[(L)proline]2 com-
plex in aqueous medium assisted with microwave
irradiation (Scheme 1).
RESULTS AND DISCUSSION
All the materials used in this study were extrapure
quality and purchased from E-Merck (Germany).
The melting point of products was determined using
Raga Hot stage apparatus and are uncorrected. The
FTIR spectra of products were recorded on a Nicolet
360 FTIR using KBr pellet technique. The elemental
analyses were carried out in a Heraeus CHNO-rapid
TABLE 1 Synthesis of Hantzsch 1,4-Dihydropyridine Derivatives
Entry
R1
R2
Timea (min)
Yieldb,c (%)
Reference
1
2
3
4
5
6
7
8
4-NO2 C6H4
3-NO2 C6H4
4-CH3O C6H4
4-HO 3-CH3O C6H3
3,4-(CH3O)2 C6H3
2-Furyl
OC H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
CH32
CH3
CH3
CH3
CH3
2
3
2
3
2
3
4
2.5
3
2
2.5
4
3.5
5
3
2
2
2.5
3
4
93
95
98
95
98
92
90
90
95
98
90
95
94
92
95
98
93
95
96
93
90
25
20
20
20
18
19
25
25
20
20
20
18
19
25
20
20
25
20
18
19
25
3-Indolyl
4-NO2 C6H4
3-NO2 C6H4
4-CH3O C6H4
4-HO 3-CH3O C6H3
3,4-(CH3O)2 C6H3
2-Furyl
9
10
11
12
13
14
15
16
17
18
19
20
21
CH3
CH3
3-Indolyl
3-NO2 C6H4
4-CH3O C6H4
4-NO2 C6H4
4-HO 3-CH3O C6H3
3,4-(CH3O)2 C6H3
2-Furyl
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
3-Indolyl
5
aReaction time monitored by TLC analysis.
bIsolated yield after column chromatography.
cThe products were confirmed by FTIR, MS, and elemental analysis.
Heteroatom Chemistry DOI 10.1002/hc

Rapid and Cleaner Synthesis of 1,4-Dihydropyridines in Aqueous Medium 269
TABLE 4 Effect of Water and Ethanol Ratio
TABLE 2 Catalyst Recycling Studiesa
Microwave Irradiation
S. No.
Ratioa
Timeb (min) Yieldc (%)
Catalyst Recycle
Timeb (min)
Yieldc (%)
1
2
3
4
5
6
20 (ethanol):80 (water)
35:65
50:50
65:35
80:20
Ethanol (100%)
5
4
4
4
3.5
3
85
95
96
96
95
93
I
II
III
IV
V
VI
3
3
3
3
3
3
90
85
80
80
80
68
aReactions carried out with 200 W MW power.
bReaction time monitored by TLC analysis.
cIsolated yield.
aModel reaction: 5 mmol of 2-furfuraldehyde, 11 mmol of acetylace-
tone and 10 mmol of ammonium acetate in presence of 0.2 mmol of
catalyst.
bReaction progress monitored by TLC analysis.
cIsolated yield.
with various organic solvents on reaction time and
yield. The results reveal that water with ethanol and
methanol show higher efficiency than other solvents
such as tetrahydrofuran, 1,4-dioxan, and acetoni-
trile. The results confirm enhancement of absorption
of MW power even in low input by polar medium.
The present methodology afforded 1,4-DHPs in ex-
cellent yield in comparison to solid-phase microwave
irradiated reactions, and also increases the solubility
of organic components in aqueous medium. Table 4
shows the effect of water to ethanol ratio. Low water–
ethanol ratio like 80:20 causes insoluble nature of or-
ganic components, whereas high ethanol–water ratio
and in pure ethanol takes longer time for precipita-
tion of products and also utilize more amount of or-
ganic solvents. Water to ethanol ratio of 65:35 is the
optimized solvent medium to obtain maximum yield
of the expected product within a short reaction time
and also utilizes low amount of organic solvents.
water-soluble catalyst with acceptable purity. Mix-
ture of water and ethanol (65:35) has been used in
all the reactions in order to achieve homogeneity of
water and insoluble organic compounds [1].
Catalyst Recycling Studies
The results of catalyst recycling studies under the
same reaction conditions are given in Table 2. The
reaction of 2-furfuraldehyde and acetylacetone in
presence of 0.2 mmol of catalyst in water–ethanol
mixture (65:35) was taken as model reaction for re-
cycling studies. The reaction mixture was irradiated
in a microwave oven with 200 W input power [35].
The results reveal that the catalyst exhibits good cat-
alytic activity up to five cycles. The reduction of yield
in the sixth cycle is due to decomposition of metal
complex upon microwave irradiation. The decom-
position of catalyst was confirmed by atomic adsorp-
tion spectroscopy.
Effect of Microwave Power
Figure 1 illustrates the effect of microwave power
on reaction time and yield. The results reveal that
even with low microwave power (200 and 350 W),
Effect of Water–Organic Solvents
The reaction of aromatic aldehyde and ethyl ace-
toacetate in presence of 0.2 mmol of catalyst was
taken as a model reaction for all catalytic studies.
The values in Table 3 show the influence of water
TABLE 3 Effect of Water and Organic Solvent
S. No.
Solventsa
Timeb (min)
Yieldc (%)
1
2
3
4
5
Methanol
Ethanol
Acetonitrile
Tetrahydrofuran
1,4-Dioxan
4
3
5
5
92
98
90
85
85
4.5
a50:50 Water–organic solvent ratio. Reactions carried out with 200 W
MW power.
bReaction time monitored by TLC analysis.
cIsolated yield.
FIGURE 1 Effect of microwave power.
Heteroatom Chemistry DOI 10.1002/hc

270 Sivamurugan et al.
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obtained within short reaction time. Medium and
high microwave power gave low yield, which may be
due to rapid heating of reaction medium that cause
evaporation of solvent medium and lead to precip-
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CONCLUSIONS
Zn[(L)proline]2 complex is proved to be an effi-
cient catalyst for the preparation of 1,4-DHP deriva-
tives using Hantzsch synthetic route in aqueous
medium. This catalyst can be used for the synthe-
sis of 1,4-DHPs using a wide range of aldehydes
and ꢀ-dicarbonyl compounds. The microwave irra-
diated reactions in aqueous medium in the pres-
ence of catalyst afforded moderate to excellent yield
(98%) within short reaction periods (<5 min). The
Zn[(L)proline]2 exhibits greater catalytic activity
even with low MW power (≈200 W) and it can be
reusable up to five cycles without appreciable loss
of its catalytic activity. The present investigation
provides 1,4-DHPs in high yield within shorter re-
action time and easier separation of products with
acceptable purity. Hence this methodology is a
green protocol with respect to reduce the use of
organic solvents and consuming less microwave
power.
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[34] Microwave Promoted Synthesis of 1,4-Dihydrop-
yridines in Aqueous Medium. A mixture of 5 mmol
of veratraldehyde, 11 mmol of ethyl acetoacetate,
and 10 mmol of ammonium acetate was thoroughly
mixed with 0.2 mmol of Zn[(L)proline]2 complex in
20 mL of double distilled water and 5 mL of abso-
lute ethanol (Scheme 1). The reaction mixture was
taken in an open Erlenmeyer flask and irradiated us-
ing a household microwave oven (model: IFB 17PM
1S) with a power range of 200 W (≈75◦C) and a pulse
of 10 s. The progress of the reaction was monitored
by TLC (silica gel precoated plate, eluent:n-hexane
to ethyl acetate ratio = 80:20) up to disappearance
of reactants. After completion of the reaction, the
mixture was kept at 10–15◦C for 24 h. The prod-
uct slowly crystallized from aqueous phase and
it was separated by simple filtration. The pu-
rification step was not required as the product
was in pure form. The above-mentioned procedure
was followed for all other reactions. The reaction
time and yield for all the reactions are given in
Table 1.
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[35] Catalyst
Recycling
Studies.
2-Furfuraldehyde
(5 mmol), acetylacetone (11 mmol), and ammo-
nium acetate (10 mmol) were thoroughly mixed
Heteroatom Chemistry DOI 10.1002/hc

Rapid and Cleaner Synthesis of 1,4-Dihydropyridines in Aqueous Medium 271
with catalyst (0.2 mmol). The progress of reaction
phase. The catalyst present in aqueous medium was
used for the subsequent cycle. The same procedure
was adopted for all recycling studies. The reaction
time and yield for different cycles are presented in
Table 2.
was monitored by TLC analysis. After completion
of reaction, the reaction mixture was diluted with
dichloromethane and recovered the catalyst by
simple separation from aqueous phase and organic
Heteroatom Chemistry DOI 10.1002/hc