Aromatization of Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines with HIO3 and I2O5 in water

Article abstract of DOI:10.1016/j.tetlet.2006.10.108

Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines were converted to the corresponding pyridines and pyrazoles efficiently by the treatment of a catalytic amount of HIO₃ or I₂O₅ in water.

Full text of DOI:10.1016/j.tetlet.2006.10.108

Tetrahedron Letters 47 (2006) 9283–9285
Aromatization of Hantzsch 1,4-dihydropyridines and
,3,5-trisubstituted pyrazolines with HIO and I O in water
1
3
2 5
Lingzhi Chai, Yankai Zhao, Qiuju Sheng and Zhong-Quan Liu*
Academy of Organic Chemistry, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China
Received 1 October 2006; revised 18 October 2006; accepted 20 October 2006
Available online 13 November 2006
Abstract—Hantzsch 1,4-dihydropyridines and 1,3,5-trisubstituted pyrazolines were converted to the corresponding pyridines and
pyrazoles efficiently by the treatment of a catalytic amount of HIO or I O in water.
3 2 5
Ó 2006 Elsevier Ltd. All rights reserved.
Five- and six-membered heterocyclic compounds often
play important roles in biologically active natural prod-
ucts and synthetic compounds of medicines. Among
suffer from expensive transition metal oxidants, rela-
tively high oxidant loading and use of organic solvents.
1
them, Hantzsch 1,4-dihydropyridines (1,4-DHPs) have
attracted considerable attention as calcium channel
blockers for the treatment of cardiovascular diseases
We wish to report herein an efficient aqueous room tem-
perature aromatization with a number of economic,
environmental benign, and safe iodine(V) agents (Tables
1 and 2). To the best of our knowledge, this is the first
example of HIO (iodic acid, IA) and its anhydride I O
5
(iodine pentoxide, IP)-mediated metal-free aroma-
tization of dihydropyridines and pyrazolines in
water.
2
and are oxidatively transformed into the corresponding
pyridine derivatives by the action of cytochrome p-450
3
2
3
in the liver. Aromatization of 1,4-DHPs has been exten-
4
sively explored by using various oxidants. However,
most of the oxidative processes suffer from the use of
4
b
4c
4d
strong oxidants such as HNO , KMnO4, or CAN
3
4
e
Despite their extensive use in industry,18 IA and IP have
rarely been employed in organic synthesis. It is seen
from Table 1 that a variety of 1,4-DHPs are aromatized
to the corresponding pyridines in excellent isolated
yields by using 20 mol % of IP at room temperature in
water. Among them, the deisopropyl aromatic pyridine
is produced in the case of 4-isopropyl-HEH (1d). It is
seen from Table 2, various 1,3,5-trisubstituted pyrazo-
lines are aromatized to the corresponding pyrazoles in
almost quantitative yields by using 20 mol % of IP cata-
lyzed by 5 mol % of KBr at room temperature in water.
In general, the reactions are very clean, efficient, and are
and I –CH OH. Recently, attention has been paid to
2
3
more efficient and environmentally benign processes,
5
such as electrochemical oxidation and catalytic aerobic
6
7
8
oxidation using Pd/C, RuCl3, activated carbon,
9
10
Fe(ClO4)3 or NHPI as the catalyst.
1
,3,5-Trisubstituted pyrazolines are important five-
membered heterocyclic compounds, which can be easily
prepared from phenylhydrazine and chalcone deriva-
tives. The processes of oxidative aromatization of these
dihydroheteroaromatics provide the corresponding pyr-
azoles, which are known to possess diverse biological
activities, including antiinflammatory, antidiabetic, anti-
1
9
completed within 5 h.
1
1
arrhythmic, and antibacterial activities. For this con-
version of pyrazolines, a number of processes have
been reported, which employed reagents such as
In order to study the possible mechanism of the aroma-
tization, a series of experiments were carried out. We
presume iodine(V) reagents should be the terminal oxi-
1
2
13
14
15
16
AgNO3, KMnO4, HgO, MnO2, Pb(OAc)4, iodo-
1
7
benzene diacetate. However, many of these systems
dants as I observed in the procedure. The quantitative
2
ratio of I O /HEH may be about 1/5 according to the
2
5
stoichoimetric calculation. In fact, it accords commend-
ably with the following experimental results (Table 3).
*
0
Corresponding author. E-mail: liu_z_q@sina.com
However, about 40 mol % of HIO was required in the
3
040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.108

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284
L. Chai et al. / Tetrahedron Letters 47 (2006) 9283–9285
and Table 2. Conversion of 1,3,5-trisubstituted pyrazolines to pyrazoles by
Table 1. Conversion of 1,4-DHPs to pyridines mediated by HIO
3
a
a
I
2
O
5
using HIO
3
2 5
and I O catalyzed by KBr
O
R
O
O
R
O
R1
R2 20 mol% I O / 5 mol% KBr R1
R2
2
0 mol% I O5
2
5
2
EtO
OEt
EtO
OEt
N N
R3
H O, rt
2
N N
H O, rt
2
R3
N
H
1
N
1
'
2
2
'
b
b
Entry
Substrate
T (h)
Yield (%)
Entry
R
H
CH
CH
CH
T (h)
Yield (%)
1
1
1
1
a
b
c
2 (min)
100
95
98
Ph
Ph
N
2
a
3.5
98
3
2
3
4
1.5
24
N N
Ph
CH
2
CH
3
c
d
CHCH
3
94
p-ClC H4
Ph
Ph
6
1
1
e
f
1
96
92
O
2b
3
96
96
N
Ph
3.5
p-BrC H4
6
2
2
c
4.5
N N
1
1
g
h
2
98
96
Ph
p-MeC H4
6
Ph
2.5
d
5
8
4
97
96
96
H CO
3
N
N
Ph
1
1
i
j
1
95
95
p-MeOC H
Ph
6
4
Cl
2e
N
N
Ph
12
Ph
Ph
C H -p-Cl
6
4
O N
2
2
f
a
1
N N
The products were identified by comparing their H NMR and
EI-MS spectral data with those reported in the cited references.
Isolated yield.
b
c
a
1
The products were identified by comparing their H NMR and
EI-MS spectral data with those reported in the cited references.
Isolated yield.
The oxidative product is same to the substrate 1a.
b
oxidation. Therefore, we prefer to I O as the oxidant
2
5
2 5
Table 3. Conversion of 1g to pyridine by using I O
considering the cost. Additionally, the aromatization
reaction can be smoothly carried out without oxygen
by protection of nitrogen (Scheme 1).
O
O
O
O
I O
2
5
EtO
OEt
EtO
OEt
It is believed to be a free radical procedure of the aroma-
tization. Detailed mechanistic studies on the oxidation
are undertaken.
H O, rt
2
N
H
N
Entry
Quantity of
T (h)
Yield (%)
2 5
I O (mol %)
In conclusion, this work demonstrated a novel and mild
method for the aromatization of Hantzsch 1,4-dihydro-
pyridines and 1,3,5-trisubstituted pyrazolines by
using catalytic, low-cost, and environmentally friendly
iodine(V) reagents in water. Extension of this procedure
to other substrates is underway in our laboratory.
1
2a
1
15
4
7
15
2
<5
50
70
75
98
10
10
10
20
2
2
3
b
c
Cl
Cl
O
O
O
O
2
0 mol% I O
2 5
EtO
OEt
EtO
OEt
N , H O, rt
2
2
N
H
N
Scheme 1.

L. Chai et al. / Tetrahedron Letters 47 (2006) 9283–9285
9285
Acknowledgement
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1
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838.
19. Typical procedure: the starting materials were put into
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2
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2
3
anhydrous MgSO , isolated through column chromato-
4
2
000, 11, 1532; (f) Mao, Y.-Z.; Jin, M.-Z.; Liu, Z.-L.; Wu,
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0
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compounds 1 a: diethyl 4-(4-chlorophenyl)-2,6-dimethyl-
4
e
3,5-pyridinedicarboxylate, pale yellow solid; mp 65–
1
66 °C; H NMR (300 MHz, CDCl ): d = 0.95 (t, 6H,
3
5
6
7
8
9
J = 7.2 Hz), 2.59 (s, 6H), 4.02 (q, 4H, J = 7.2 Hz), 7.18 (d,
2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz); C NMR
1
3
. Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett.
(75 MHz, CDCl ): d = 13.5, 22.8, 61.4, 126.7, 128.2, 129.5,
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2
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134.6, 134.9, 144.7, 155.5, 167.5; EI-MS: m/z = 363, 361,
0
316, 288, 270, 139, 43. Compound 2 a: 1,3,5-triphenyl-
1
0 1
3
pyrazole: H NMR (300 MHz, CDCl ): d = 6.83 (s, 1H),
3
13
7.4 (m, 13H), 7.92 (d, 2H, J = 7.6Hz); C NMR (75 MHz,
2
CDCl ): d = 105.2, 125.3, 125.8, 127.4, 128.0, 128.3, 128.4,
3
. Heravi, M. M.; Behbahani, F. K.; Oskooie, H. A.; Shoar,
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MS: m/z = 296, 86, 84, 77.