Catalyst-free synthesis of dihydropyridine from barbituric acid in water

Article abstract of DOI:10.1007/s11164-012-0543-8

An operationally simple, atom-economical, and green procedure has been developed for the synthesis of dihydropyridine derivatives by a simple condensation of barbituric acid, aldehyde, and ammonium acetate in water under catalyst-free conditions. Excellen

Full text of DOI:10.1007/s11164-012-0543-8

Res Chem Intermed (2012) 38:2271–2275
DOI 10.1007/s11164-012-0543-8
Catalyst-free synthesis of dihydropyridine
from barbituric acid in water
•
Najmadin Azizi Akbar Mobinikhaledi
•
•
Alireza Khajeh Amiri Hossein Ghafuri
Received: 5 March 2012 / Accepted: 23 March 2012 / Published online: 21 April 2012
Ó Springer Science+Business Media B.V. 2012
Abstract An operationally simple, atom-economical, and green procedure has
been developed for the synthesis of dihydropyridine derivatives by a simple con-
densation of barbituric acid, aldehyde, and ammonium acetate in water under cat-
alyst-free conditions. Excellent yields and purity were obtained with only filtration
and washing with hot water and ethanol.
Keywords Aldehydes Á Barbituric acid Á Dihydropyridine Á
Novel hydrogen bonding Á Water chemistry
Introduction
The development of multipoint hydrogen-bonding motifs that form complexes with
high stability and selectivity is an important subject for the understanding of
conformational analysis [1–3], protein structure [4–6], crystal packing [7], molecular
recognition processes [8, 9], the stabilization of inclusion complexes [10], and the
stability and possibly even in the activity of biological macromolecules [11, 12].
Electronic supplementary material The online version of this article (doi:
10.1007/s11164-012-0543-8) contains supplementary material, which is available to authorized users.
N. Azizi (&)
Chemistry and Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
e-mail: azizi@ccerci.ac.ir
A. Mobinikhaledi Á A. K. Amiri (&)
Department of Chemistry, Faculty of Sciences, Arak University, Arak 38156-879, Iran
e-mail: a_khajehamiri@yahoo.com
H. Ghafuri
Department of Chemistry, Payame Noor University, Damavand Branch, Tehran, Iran
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N. Azizi et al.
With the increasing interest in developing environmentally benign reactions, the
atom-economic processes, or reactions without using any catalyst, and organic
solvent are one of the most exciting challenges in chemistry. The toxicity and
volatile nature of many organic solvents, particularly chlorinated hydrocarbons,
which are widely used in large amounts for organic reactions, have posed a serious
threat to the environment. Thus, the design of a green catalytic reaction under
catalyst-free conditions in water has received tremendous attention in recent times
in the area of green synthesis [13–16].
Experimental
Materials and methods
All chemicals were purchased from commercial sources and were used without
further purification. Water and other solvents were distilled before being used. IR
spectra were prepared on a Galaxy series FT-IR 5000 spectrophotometer using KBr
discs. NMR spectra of DMSO-d6 solutions of samples were recorded on Bruker
spectrophotometer 500 MHz for 1H NMR and 125 MHz for the 13C NMR.
Chemical shifts are reported in ppm units relative to TMS as internal standard.
Most of these compounds have melting point higher than 300 °C.
General procedure
To a well-stirred mixture of an aldehyde (5 mmol), and barbituric acid (10 mmol) in
water/ethanol (10 mL) was added ammonium acetate (8 mmol) and the reaction
mixture was heated under reflux for 12–18 h. The reaction was allowed to cool and
the resulting precipitate was filtered and then washed with hot water and ethanol to
give pure dihydropyridines. All compounds were known and IR and 1H NMR
spectra were found to be identical to the ones described in literature.
Results and discussion
In continuation to our research work devoted to the development of green organic
chemistry in water and deep eutectic solvent [17–22]. Herein, we described an
efficient, novel, and green methodology for the direct synthesis of biologically
active and hydrogen bond-forming dihydropyridine derivatives with a one-pot
reaction of barbituric acid, aldehyde, and ammonium acetate performed at excellent
yields without a catalyst in water (Table 1).
1,4-Dihydropyridines are generally synthesized by the classical Hantzsch
reaction, which involves the condensation of aldehydes b-ketoester and ammonia
or ammonium acetate in acetic acid [23]. However, this method cannot be applied
for the synthesis of different substituted biologically active 1,4-dihydropyridines.
Recently, several modifications for this classical method have been reported for the
facile and efficient synthesis of important dihydropyridine derivatives [24–32].
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Catalyst-free synthesis of dihydropyridine from barbituric acid in water
2273
Table 1 Optimization of reaction condition
O
O
Ph
O
CHO
+
NH4OAc
HN
NH
HN
NH
Solvent,
10 h
O
O
O
N
H
N
N
H
O
H 3
Entry
Solvent (10 mL)
Temperature (°C)
Yields (%)
1
2
Toluene
CCl4
110
80
30
20
10
50
30
60
70
80
30
85
3
THF
60
4
CH3CN
CH2Cl2
CH3OH
C2H5OH
Water
80
5
50
6
60
7
80
8
100
100
100
9
SFC
10
Water/ethanol (5:1)
Reaction condition: barbituric acid (10 mmol), benzaldehyde (5 mmol), ammonium acetate (8 mmol),
solvent (10 mL)
In spite of the potential utility of these reagents, most of the existing methods for
the synthesis of 1,4-dihydropyridines suffer from drawbacks such as low yields,
long reaction times, occurrence of several side products, unsatisfactory yields, long
reaction times, and pollution of the environment due to the use of organic solvent
and/or acidic or basic promoters.
While searching for new acidic partners in the Hantzsch reaction, we thought that
the suitable new active methylene compounds with additional acidic groups on the
barbituric acid could trigger both the aldehyde activation and the conjugate addition
in the key step of the reaction. Indeed, we were delighted to find for the first time
that barbituric acid (10 mmol) reacts with benzaldehyde (5 mmol) and ammonium
acetate (8 mmol) by a very efficient three-component reaction under catalyst-free
conditions. This reaction proceeds smoothly at refluxing water within a few hours to
provide the desired new dihydropyridine 3 in 80 % yield (Table 1).
Encouraged by this result, it seemed appropriate to explore the influence of the
other solvents. After substantial solvent screening in the model reaction, it was
found that the use of water/ethanol (5:1) resulted in a slightly improved yields. The
nonpolar solvents, such as toluene, CCl4 did not give desired products under similar
reaction conditions (Table 1, entries 1, 2). The polar aprotic solvents (CH2Cl2, THF,
and CH3CN) also afforded comparatively lower yields (Table 1, entries 3–5).
The polar protic solvents (C2H5OH and CH3OH) still gave comparatively lower
conversions (Table 1, entries 6, 7).
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N. Azizi et al.
F
Cl
Cl
O
O
O
O
O
O
O
O
HN
NH
HN
O
NH
HN
NH
HN
NH
O
N
H
N
N
O
O
N
H
N
H
N
H
O
N
H
N
N
H
O
O
N
H
N
N
H
O
H
H
H
H
3a30 : 85%
3b30: 80%
3c30: 78%
3d29: 82%
Br
NO2
NO2
O
F
O
O
O
O
O
O
O
HN
O
NH
HN
NH
HN
NH
HN
NH
N
H
N
N
H
O
O
N
N
N
O
O
N
N
N
O
O
N
N
N
H
O
H
H
H
H
H
H
H
H
H
3e26: 76%
3f26: 70%
3g26: 72%
3h30: 80%
OMe
CH3
CO2Me
O
Br
O
O
O
O
O
O
O
HN
O
NH
HN
NH
HN
NH
HN
NH
N
N
N
H
O
H
H
O
O
N
N
N
O
O
N
H
N
N
O
O
N
H
N
N
H
H
H
H
H
H
H
3j26: 55%
3k26: 62%
3l30: 80%
3i26: 78%
Cl
OMe
O
X
O
O
Cl
O
O
O
O
O
HN
NH
HN
NH
HN
O
NH
HN
NH
O
N
H
N
N
O
H
H
O
O
N
H
N
H
N
H
O
N
N
N
H
O
N
N
N
H
O
H
H
3p X= O12
3q X= S30
H
H
55%
50%
3m30: 60%
3n12: 72%
3o12: 72%
Fig. 1 Synthesis of dihydropyridines in water
The high-yield, simple reaction protocol, and originality of this green process
prompted us to explore the reaction more widely. The reaction between various
aromatic aldehydes with different substituents, barbituric acid, and ammonium
acetate were carried out under optimum conditions and the selected data are
summarized in Fig. 1. From these results, we could see that all reactions proceeded
smoothly to afford the corresponding products in moderate to good yields. We also
found that all aromatic aldehydes carrying either electron-donating or electron-
withdrawing substituents reacted efficiently to give improved yields compared to
the classical Hantzsch reaction. When aliphatic aldehydes were used in this protocol
under the above-optimized conditions, unfortunately, the expected products could
not be obtained.
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Catalyst-free synthesis of dihydropyridine from barbituric acid in water
2275
Conclusions
In summary, a simple and entirely green protocol has been devised for the first
practical synthesis of novel dihydropyridine via a one-pot three-component reaction
of aromatic aldehydes, barbituric acid, and ammonium acetate in water. The yields
are excellent and the product isolation is very straightforward. Because of the
organic and catalyst-free reaction condition, pure products were obtained with
simple filtration and washing with hot water.
Acknowledgments The financial support of this work provided by Chemistry and Chemical Research
Center of Iran and Iran National Science Foundation (INSF) is gratefully appreciated.
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