Molecular iodine-catalyzed one-pot synthesis of 4-substituted-1,4- dihydropyridine derivatives via Hantzsch reaction

Article abstract of DOI:10.1016/j.tetlet.2005.05.148

A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine derivatives at room temperature using catalytic amount of iodine were reported with excellent product yields. An easy access to various substituted 1,4-dihydropyridine derivative

Full text of DOI:10.1016/j.tetlet.2005.05.148

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 5771–5774
Molecular iodine-catalyzed one-pot synthesis of
-substituted-1,4-dihydropyridine derivatives via Hantzsch reaction
4
Shengkai Ko, M. N. V. Sastry, Chunchi Lin and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Tingchow Road, Taipei, Taiwan 116, ROC
Received 24March 2005; revised 26 May 2005; accepted 30 May 2005
Available online 7 July 2005
Abstract—A simple, inexpensive and efficient one-pot synthesis of 1,4-dihydropyridine derivatives at room temperature using cat-
alytic amount of iodine were reported with excellent product yields. An easy access to various substituted 1,4-dihydropyridine deriv-
atives quantitatively using commercially available iodine as a catalyst.
ꢀ
2005 Published by Elsevier Ltd.
In recent years, an increasing interest has been focused
on the synthesis of 1,4-dihydropyridyl compounds ow-
ing to their significant biological activity. In particular,
there are several efficient methods developed for the syn-
thesis of 1,4-dihydropyridines, which comprise the use
1
7
8
of microwave, ionic liquid, at high temperature in
9
10
11
dihydropyridine drugs such as nifedipine, nicardipine,
amlodipine and others are effective cardiovascular
refluxing solvent, TMSCl–NaI and metal triflates.
However, the use of high temperatures, expensive metal
precursors and spending longer reaction times limiting
these methods. Thus, the development of a simple, effi-
cient and versatile method for the preparation of 1,4-
dihydropyridine derivatives is an active area of research
and there is a scope for further improvement towards
milder reaction conditions and higher product yields.
2
agents for the treatment of hypertension. 4-Aryl-1,4-
dihydropyridines have been explored for their calcium
channel activity and the heterocyclic rings are found in
a variety of bioactive compounds such as vasodilator,
bronchodilator, antiatherosclerotic, antitumour, antidi-
3
abetic, geroprotective and heptaprotective agents.
Moreover studies have discovered that these compounds
exhibit diverse medical functions such as neuroprotec-
In recent times, the use of molecular iodine12 has re-
ceived considerable attention as an inexpensive, non-
toxic, readily available catalyst for various organic
transformations to afford the corresponding products
in excellent yields with high selectivity. The mild Lewis
acidity associated with iodine enhanced its usage in or-
ganic synthesis to realize several organic transforma-
tions using stoichiometric levels to catalytic amounts.
Owing to numerous advantages associated with this
eco-friendly element, iodine has been explored as a pow-
erful catalyst for various organic transformations. As
the 1,4-dihydropyridines are important biologically ac-
tive compounds, which have profound medical applica-
tions, development of a reaction that uses catalytic
amounts of mild toxic and readily available iodine
should greatly contribute to the creation of environmen-
tally benign processes.
tants, compounds with platelet antiaggregators, cerebral
4
antiischaemic agents and chemosensitizers.
The
remarkable drug activity of these compounds not only
attracted many chemists to synthesize this heterocyclic
nucleus but also became an active research area of
continuing interest. It has been mostly reported that
there are many methods to synthesize 1,4-dihydropyri-
dine derivatives, in view of the biological importance
associated with these compounds. The classical method
involves the mixing of aldehyde with ethyl acetoacetate,
1
3
5
and ammonia in acetic acid or in refluxing alcohol.
However, this method suffers from several disadvan-
tages such as longer reaction times, excess of organic
solvent, lower product yields and harsh refluxing condi-
6
tions. Starting from Hantzsch more than a century ago,
As part of our ongoing interest in the iodine catalyzed
reactions for various organic transformations,
Keywords: Hantzsch reaction; Synthesis of 1,4-dihydropyridine; Simple
and efficient; Molecular iodine; Catalytic amounts.
1
4
*
Corresponding author. Tel.: +886 2 2930 9092; fax: +886 2 2932
249; e-mail: cheyaocf@scc.ntnu.edu.tw
we had the opportunity to further explore its catalytic
activity towards the synthesis of 1,4-dihydropyridines.
4
0040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.05.148

5772
S. Ko et al. / Tetrahedron Letters 46(2005) 5771–5774
a
Table 1. Optimizing the reaction conditions
CHO
O
O
O
O
I2
O
NH4OAc
r.t.
O
(1)
O
O
N
H
1a
2
3
4
5a
b
Entry
Iodine (mol %)
Time (h)
Yield (%)
56
99
1
2
3
0
15
30
1.5
4
4
2.5
70
99
450
a
Benzaldehyde:1,3-cyclohexanedione:ethyl acetoacetate:ammonium acetate = 1:1:1:1.
Crude isolated yields.
b
Herein, we wish to report a novel synthesis of 1,4-DHPs
promoted by the catalytic amount of iodine under ambi-
ent conditions with excellent yields. In an initial endeav-
our, benzaldehyde 1a, 1,3-cyclohexanedione 2, ethyl
acetoacetate 3 and ammonium acetate 4 were stirred at
room temperature in a few drops of ethanol. After 4
hours, only 56% of product 5a was realized after recrys-
tallization of the crude product from ethanol (entry 1 of
Table 1). To improve the product yields and to optimize
the reaction condition, iodine was used in catalytic
amount (15 mol %) and a reaction was carried out under
similar conditions. To our surprise, a significant
improvement in the yield of the product 5a (99% Y)
was observed (entry 2). With this optimistic result in
hand, we further investigated for the best reaction con-
ditions. In this connection, we investigated the reaction
outcome using different amounts of iodine. The increase
in the quantity of iodine from 15 to 30 mol % not only
lessens the reaction time from 4to 2.5 h, but also en-
hanced the product yield from 56% to 99% (entry 3).
Similarly, using 50 mol % of iodine as catalyst the reac-
tion time further reduced to 1.5 h along with a decrease
in the yield of the product 5a (70% Y). At little elevated
temperature (40 ꢁC) using 15 mol % of iodine also gave
better results in terms of both yield and reaction time
(Table 1).
Table 2. Iodine catalyzed the synthesis of 1,4-dihydroquinoline derivatives through Hantzsch reaction
O
O
O
Ar
O
I2
ArCHO
O
NH OAc
O
(
2)
4
O
O
N
H
1
2
3
4
5
a
b
Entry
1
Ar
I
2
(mol %)
Temperature (ꢁC)
Time
Product
Yield (%)
Mp (ꢁC)
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
C
6
H
5
30
15
30
15
30
15
30
15
30
15
30
15
30
15
30
15
30
15
30
15
25
40
25
40
25
40
25
40
25
40
25
40
25
40
25
40
25
40
25
40
2.5 h
30 min
1.5 h
35 min
4h
40 min
3.25 h
35 min
6 h
40 min
2.5 h
45 min
1.5 h
25 min
1.5 h
25 min
3 h
5a
5a
5b
5b
5c
5c
5d
5d
5e
5e
5f
99
93
90
99
97
87
91
87
99
90
99
92
240–241
p-MeC
P-OMeC
p-FC
p-ClC
p-HOC
o-NO
m-NO
p-NO
Isopropyl
6
H
4
241–242
193–195
243–244
234–235
220–222
6
H
4
6
H
4
6
H
4
10
11
12
13
14
15
16
17
18
19
20
6
H
4
1f
5f
1g
1g
1h
1h
1i
2
C
6
H
4
5g
5g
5h
5h
5i
94190–191
91
99
92
99
85
99
99
2
C
6
H
4
198–200
204–205
180–182
2 6 4
C H
1i
25 min
5 h
40 min
5i
1j
5j
1j
5j
a
Crude isolated yields.
After recrystallization.
b

S. Ko et al. / Tetrahedron Letters 46(2005) 5771–5774
5773
Table 3. Iodine catalyzed the synthesis of 1,4-dihydroquinoline derivatives through Hantzsch reaction
O
O
O
Ar
O
I2
ArCHO
O
NH OAc
O
(3)
4
O
O
N
H
1
6
3
4
7
a
b
Entry
1
Ar
I
2
(mol %)
Temperature (ꢁC)
Time
1.5 h
30 min
2 h
35 min
2.5 h
35 min
2.5 h
Product
Yield (%)
Mp (ꢁC)
1
2
3
4
5
6
7
8
1a
1a
1c
1c
1e
1e
1f
C
6
H
5
30
15
30
15
30
15
30
15
25
40
25
40
25
40
25
40
7a
7a
7c
7c
7e
7e
7f
93
93
93
90
92
99
99
97
209–210
243–245
230–232
237–238
p-OMeC
p-ClC
p-HOC
6
H
4
6
H
4
6
H
4
1f
35 min
7f
a
Crude isolated yields.
After recrystallization.
b
Based on these observations, we have also conducted the
reaction using 15 mol % of iodine at elevated tempera-
ture (40 ꢁC). As expected, the reaction completed within
catalytic activity of iodine is remarkable and the use of
low cost, commercially available iodine as catalyst for
the synthesis of 1,4-DHPs in excellent yields is also sig-
nificant under the aspect of environmentally benign pro-
cesses. The advantages such as shorter reaction times,
milder conditions, simplicity of the reaction, excellent
product yields, the easy procedures to carry out the reac-
tion makes the inexpensive and commercially available
iodine as a powerful catalyst for the synthesis of 1,4-
DHPs.
3
0 min with excellent product yield is another significant
finding regarding these reactions. In order to evaluate
the efficiency of iodine as a catalyst, a range of aryl-
and alkyl aldehydes 1b–j were subjected to react with
2
, 3 and 4 in the presence of either 30 or 15 mol % of
iodine to generate 5 and the results are summarized in
1
5
Table 2. For example, with 30 mol % of iodine as
catalyst p-chlorobenzaldehyde (Table 2, entries 9 and
1
0) takes 6 h to complete, whereas the same reaction
Acknowledgements
takes place within 40 min at 40 ꢁC without significant
loss yields. In general, the yields are little less with
Financial support of this work by the National Science
Council of the Republic of China and National Taiwan
Normal University (ORD93-C) is gratefully acknow-
ledged.
1
5 mol % of catalyst and the reaction times are also
short. Both aliphatic and aromatic aldehydes react
equally good to give the products with excellent yields.
The aryl group substituted with different groups and
same groups located at different positions of the aro-
matic ring has not shown much effect on the formation
of the final product.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
Next, we investigated the effect of substitution in 1,3-
cyclohexanedione system such as 5,5-dimethyl-1,3-
cyclohexanedione. Aromatic aldehydes such as benzal-
dehyde and different substituted benzaldehydes reacts
with dione 6, ethyl acetoacetate and ammonium acetate
in the presence of iodine to afford the products in excel-
lent yields. Interestingly, we have not observed much
difference in the product yields either with 30 mol % at
ambient temperature or with 15 mol % at higher temper-
ature (40 ꢁC). The reduced reaction times with all sub-
strates using 6 may be due to the more reactivity of
2005.05.148.
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2
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drops) of ethanol. The mixture was then stirred at room
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1
IL Farmaco 2002, 57, 123; (h) Dondoni, A.; Massi, A.;
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2
3
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lized from ethanol to give the product 5a as a yellow solid
1
9011; (k) Moseley, J. D. Tetrahedron Lett. 2005, 46, 3179.
(0.304 g, 98% Y) (mp: 240–241 ꢁC. H NMR (CDCl3,
1
1
1
0. Sabitha, G.; Reddy, G. S. K. K.; Reddy, Ch. S.; Yadav, J.
S. Tetrahedron Lett. 2003, 44, 4129.
1. Wang, L.-M.; Sheng, J.; Zhang, L.; Han, J.-W.; Fan, Z.;
Tian, H.; Qian, C.-T. Tetrahedron 2005, 61, 1539.
400 MHz): d 1.18 (t, 3H, J = 6.8 Hz), 1.80–2.10 (m, 2H),
2.30–2.44 (m, 7H), 4.05 (q, 2H, J = 6.8 Hz), 5.09 (s, 1H),
6.07 (s, 1H), 7.10 (t, 1H, J = 7.6 Hz), 7.20 (t, 2H,
1
3
J = 7.6 Hz), 7.30 (d, 2H, J = 7.6 Hz). C NMR (CDCl3,
2. (a) For examples: Kim, K. M.; Ryu, E. K. Tetrahedron
Lett. 1996, 37, 1441; (b) Firouzabadi, H.; Iranpoor, N.;
Hazarkhani, H. J. Org. Chem. 2001, 66, 7527; (c)
Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
100 MHz): d 14.16, 19.34, 21.01, 27.46, 36.38, 37.00, 59.78,
106.06, 113.46, 125.99, 127.90, 127.98, 143.30, 147.12,
+
149.58, 167.41. HRMS calcd for C19
311.1521, found: 311.1526.
H21NO
3
(M )