Barium nitrate catalyzed one pot synthesis of 1,4-dihydropyridines under solvent free conditions at room temperature

Article abstract of DOI:10.1002/jhet.5570450316

(Chemical Equation Presented) Barium nitrate acts as an efficient catalyst for the three-component one pot synthesis of 1,4-dihydropyridines. Barium nitrate is a safe chemical, and reaction without the use of organic solvents makes the process eco-friendly.

Full text of DOI:10.1002/jhet.5570450316

May-Jun 2008
737
Barium Nitrate Catalyzed One Pot Synthesis of 1,4-Dihydro-
pyridines Under Solvent Free Conditions at Room Temperature+
Mukul Sharma, Nisha Agarwal and Diwan S. Rawat*
Department of Chemistry
University of Delhi, Delhi-110007, India
*Corresponding author: dsrawat@chemistry.du.ac.in
Phone: 91-11-27667465, Fax: 91-11-27667501
Received July 9, 2007
+Dedicated to Prof. Richard A. Gibbs on the occasion of his birthday.
O
R
O
O
O
O
Ba(NO3)2, RT
R1
Me
R1
+
+
NH4OAc
R
H
Me
R1
5-45 min, 88-98%
N
H
Me
Barium nitrate acts as an efficient catalyst for the three-component one pot synthesis of 1,4-
dihydropyridines. Barium nitrate is a safe chemical, and reaction without the use of organic solvents makes
the process eco-friendly.
J. Heterocyclic Chem., 45, 737 (2008).
INTRODUCTION
simple filtration and can be reused after activation or
without activation. In searching new catalyst for Hantzsch
products, barium nitrate caught our attention, as it is a
nonvolatile, nonhygroscopic, odorless, crystalline solid
with outstanding physical stability and is a commercially
available, cheap material. The use of barium nitrate as a
catalyst makes the process convenient, economical and
environmentally benign. In continuation of our studies on
the synthesis of biologically active compounds [18,19], we
report herein the barium nitrate catalyzed three-component
one pot synthesis of 1,4-DHPs.
4-Substituted-1,4-dihydropyridines (1,4-DHPs) exhibit
wide variety of biological activities such as
cardiovascular, vasodilator, bronchodilator, antiathero-
sclerotic, antitumour, antidiabetic, hepatoprotective, gero-
protective, antituberculosis, calcium channel blocker
activity, and NO releasing activity [1-5]. DHP based drugs
such as nifedipine, nicardipine, amlodipine and many
others are used for the treatment of hypertension and
cerebrocrast; a DHP derivative has been used as
neuroprotective agent [6,7]. Due to the wide range of
pharmacological and biological activities and the
importance of these heterocycles in organic synthesis,
medicinal chemistry, biochemistry, synthetic efforts in
this field continues [8-11]. Although many methods for
the synthesis of 1,4-DHP have been reported, which
generated many DHP derivatives [12-15], the reported
methods suffer from drawbacks such as longe reaction
times, harsh reaction conditions, costly catalyst and low
yield. Hence, there is still scope to explore milder, safer,
economical and more efficient protocols for the synthesis
of 1,4-DHPs. Very recently, Fan et al [16] and Yadav et al
[17] reported the synthesis of 1,4-DHP in an ionic liquid
[Bmim][BF4], but use of ionic liquid is limited due to high
cost and toxic nature of the BF4 counter ion containing
ionic liquids.
RESULTS AND DISCUSSION
Our synthetic efforts started with the three-component
reaction of pyridin-3-carboxaldehyde, β-keto ester and
ammonium acetate as a model reaction in ethanol at 80
°C. Reaction progress was monitored by TLC and the
desired product was isolated in 90% yield after the usual
work up. It is important to mention here that the same
product has been prepared under solvent free conditions at
80 °C and the reaction is complete after 5 hr [20]. As the
rate of reaction remains same, we decided to see if any
added catalyst increases the rate of reaction, and barium
nitrate caught our attention. Keeping the advantages of
barium nitrate in mind, we envisioned barium nitrate
would perform well in this reaction. When 5 mole % of
barium nitrate was added to the above reaction, the same
reaction was completed within 15 minutes (Scheme 1).
The development of mild, low cost, high performance
acid catalyst and replacement of homogenous catalyst with
heterogeneous catalyst and toxic volatile organic solvents
as reaction media with non toxic solvents or reaction under
solvent free conditions have been areas of active research in
recent years. Heterogeneous solid acids have some
advantageous over conventional homogeneous acid catalyst
as they can be easily removed from the reaction mixture by
Scheme 1
O
R
O
O
O
O
Ba(NO3)2, RT
R1
Me
R1
Me
+
+
NH4OAc
R
H
Me
R1
5-45 min, 88-98%
N
H
1
2
3
4-23

738
M. Sharma, N. Agarwal and D. S. Rawat
Vol 45
Table 1
Synthesis of 1,4-dihydropyridines in presence of 5 mole% barium nitrate.
Isolated
Time
MP (°C)
Reported
Entry
R
R1
Yield (%)
(Min.)
Found
4
5
3-Pyridyl
4-Cl-C6H4
4-Pyridyl
OEt
OMe
OEt
93
91
90
89
93
91
93
95
92
92
95
98
88
89
93
94
86
89
90
90
95
25a
20
10b
10
25
15
20c
5
188-190
196-197
185-186
194-195
191-193
200-202
193-194
159-163
211-213
158-161
164-167
194-195
198-200
188-191
115-116
125-126
177-178
230
189-191[21,22]
198 [21,22]
183-186[21,22]
193-194[21,22]
190-192[21,22]
202-203[21,22]
192-194[21,22]
160-162[21,22]
210-212[21,22]
156-160[23]
166-168[23]
192-194[23]
199-201[23]
188-190[24]
-
5
6
p-Br-C6H4
Me2NC6H4
Me2NC6H4
2-Pyridyl
OMe
OMe
OEt
7
8
9
OEt
OEt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3-NO2-C6H4
3-NO2-C6H4
2-NO2-C6H4
2-Furyl
OMe
OEt
20
25
10
15
22
25
15
15
20
25
45
45
30
OEt
2-Furyl
OMe
OEt
β-Naphthyl
β-Naphthyl
CH3CH=CH
CH3CH=CH
C6H4CH=CH
2,3-(OH)2-C6H3
C6F5
OMe
OMe
OEt
-
OMe
OMe
OEt
176-178[23]
-
129-131
194-195
122-123
-
C6F5
OMe
OEt
193-194[24]
121-123[24]
4-CF3-C6H4
a,b,cReaction time 5, 6, 3, and 3 hrs respectively at 80 °C without any catalyst [20].
Systematic studies revealed that the same reaction can be
performed at room temperature without using any solvent
and the reaction is complete within 20 minutes. This
remarkable activation in the rate of reaction under
environmentally friendly reaction conditions prompted us
to explore the potential of these reaction conditions for the
synthesis of wide range of 1,4-dihydropyridines. A range of
aldehyde (electron rich, electron deficient, aliphatic, as well
as acid sensitive aldehydes) was subjected to reactions with
β-keto esters, and NH4OAc under similar reaction
conditions. The isolated yield of the products was 88-98%
(Table 1). In order to see the recyclability of the catalyst,
after completion of the reaction, reaction mixture was
dissolved in chloroform and catalyst was recovered after
filtration. The catalyst was reused as such for subsequent
experiments for three runs without the load of added
catalyst under these reaction conditions. The reaction was
found to proceed smoothly, afforded comparable yields of
the product (entry 4) as 92, 92, and 90% respectively
confirming the recyclability and reusability of the catalyst
in this reaction. To access the feasibility of the
methodology on higher scales, we carried out the three-
component reaction on a 50 g scale (entry 4, 5, 9) and it
was observed that reaction proceeded smoothly, and the
desired products were isolated in excellent yield. It is worth
mentioning here that some of the reactions (entry 4, 5, 6)
were also carried out in the presence of a catalytic amount
of boric acid, however the yield of the product was poor
and the reaction times are longer.
CONCLUSIONS
In conclusion, we have successfully demonstrated that
barium nitrate can be used as a recyclable mild acid
catalyst in the synthesis of 4-substituted-1,4-dihydro-
pyridines. The advantages such as shorter reaction times
at room temperature, green reaction, milder conditions,
simplicity of the reaction, excellent product yields, simple
procedures and the use of inexpensive commercially
available barium nitrate as a powerful catalyst, makes this
methodology superior to the other known methods.
EXPERIMENTAL
General procedure for the synthesis of 4-substituted-1,4-
dihydropyridines. A mixture of aldehyde (10 mmol), β-keto
ester (20 mmol), and ammonium acetate (15 mmol) in presence
of 5 mole% barium nitrate was stirred at room temperature for 5-
45 minutes. Progress of reaction was monitored by TLC, and
after completion, the reaction mixture was poured into ice
cooled water. In most of the cases, pale yellow solid precipitates
out, but in some cases compounds were isolated after extraction
with ethyl acetate. The combined organic layer was concentrated
under vacuum and purified by silica gel (60-120 mesh)
chromatography using ethyl acetate/hexane as eluent. The
isolated yields of 4-substituted-1,4-dihydropyridines (4-23) were
88-98%. H NMR, 13C NMR and IR are consistent with the
assigned structures and were compared with those reported in
the literature [21-24]. All of the compounds were characterized
by their IR, 1H NMR, 13C NMR and mass spectral data.
1

May-Jun 2008
Barium Nitrate Catalyzed One Pot Synthesis of 1,4-Dihydropyridines
739
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1
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OCH2CH3), 5.05 (s, 1H, CH), 5.79 (s, 1H, NH), 7.40 (d, J = 8Hz,
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Acknowledgements. DSR thanks University Grants
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CSIR for the award of junior research fellowship.
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