Chemoselective oxidation of 1,4-dihydropyridines with [NO+.Crown.H(NO3)2-]

Article abstract of DOI:10.1081/SCC-100103329

An ionic complex has been obtained from N₂O₄ in the presence of the macrocyclic ether 18-crown-6. This crystalline compound was used as an effective oxidizing agent for the oxidation of dihydropyridines to their corresponding pyridin

Full text of DOI:10.1081/SCC-100103329

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CHEMOSELECTIVE OXIDATION
OF 1,4-DIHYDROPYRIDINES
+
-
WITH [NO .CROWN.H(NO ) ]
3
2
a
Mohammad Ali Zolfigol , Mohammad Hassan
a
b
Zebarjadian , Majid M. Sadegh , Iraj
b
Mohammadpoor-Baltork , Hamid Reza Memarian
b
c
&
Mojtaba Shamsipur
a
Chemistry Department , College of Science, Bu-
Ali Sina University , Hamadan, 65174, I.R. Iran
b
Chemistry Department , College of Science,
Isfahan University , Isfahan, Iran
c
Chemistry Department , College of Science, Razi
University , Kermanshah, Iran
Published online: 09 Nov 2006.
To cite this article: Mohammad Ali Zolfigol , Mohammad Hassan Zebarjadian ,
Majid M. Sadegh , Iraj Mohammadpoor-Baltork , Hamid Reza Memarian & Mojtaba
Shamsipur (2001) CHEMOSELECTIVE OXIDATION OF 1,4-DIHYDROPYRIDINES WITH
+
-
[
NO .CROWN.H(NO ) ], Synthetic Communications: An International Journal for
3 2
Rapid Communication of Synthetic Organic Chemistry, 31:6, 929-934, DOI: 10.1081/
SCC-100103329
To link to this article: http://dx.doi.org/10.1081/SCC-100103329
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SYNTHETIC COMMUNICATIONS, 31(6), 929–934 (2001)
CHEMOSELECTIVE OXIDATION OF
1
,4-DIHYDROPYRIDINES WITH
[
þ
À
NO .CROWN.HðNO Þ ]
3
2
1
,
Mohammad Ali Zolfigol, * Mohammad Hassan
1
Zebarjadian, Majid M. Sadegh, Iraj Mohammadpoor-
2
2
Baltork, Hamid Reza Memarian, and
2
3
Mojtaba Shamsipur
1
Chemistry Department, College of Science, Bu-Ali Sina
University, Hamadan, 65174, I.R. Iran
2
Chemistry Department, College of Science, Isfahan
University, Isfahan, Iran
3
Chemistry Department, College of Science,
Razi University, Kermanshah, Iran
ABSTRACT
An ionic complex has been obtained from N O in the
4
2
presence of the macrocyclic ether 18-crown-6. This crystalline
compound was used as an effective oxidizing agent for the
oxidation of dihydropyridines to their corresponding pyridine
derivatives at room temperature with excellent yields.
Amlodepine besylate, Nifedepine, and related dihydropyridines are
2
þ
Ca channel blockers, and are rapidly emerging as one of the most import-
ant classes of drugs for the treatment of cardiovascular diseases, including
hypertension. In the human body, it has been observed that these
*
Corresponding author. E-mail: Zolfi@basu.ac.ir
29
9
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

9
30
ZOLFIGOL ET AL.
compounds undergo oxidation to form pyridine derivatives. These
oxidized compounds are largely devoid of the pharmacological activity
of the parent compounds. Additionally, dihydropyridines are often pro-
1
,2
duced in a synthetic sequence, which have to be oxidized to pyridines.
The oxidation of dihydropyridines (1) is an old reaction in general
organic chemistry. Even in recent years, several groups have reported new
methods for aromatization, including oxidation with ferric or cupric nitrates
3
,4
5
on a solid support,
nitrate accompanied by ultrasound-promotion, pyridinium chlorochro-
ceric ammonium nitrate, clay-supported cupric
6
7
mate, tert-butylhydroperoxide,
has also been reported a general method using nitric acid. Very recently,
Ohsawa et al. reported an excellent procedure for this transformation. They
have demonstrated the remarkably practical use of NO gas as a clean and
1,2
8
and photochemical oxidation. There
9
1
0
efficient oxidant for this purpose.
We decided to seek a completely homogeneous system for dihydropyr-
idine oxidation, and we have investigated a number of different reaction
þ
conditions based upon the in situ generation of NO . In continuing of
1
1–23
24–28
our study about the applications of NOX,
N O ,
metal nitrate
and complexation of transition metals
with microcyclic ethers, we have found that 18-crown-6 gives an ionic
2
4
2
9–35
dinitrogen tetroxide complexes
3
6
þ
À
complex of N O gas [NO .crown.HðNO Þ ] in quantitative yields.
2
4
3 2
However, in this article we report a simple and convenient method for the
effective conversion of 1,4-dihydropyridines (1) to their corresponding pyr-
idine derivatives (2 or 3) under mild and homogeneous conditions.
Different types of dihydropyridines (1) were subjected to oxidation
þ
À
reaction in the presence of [NO .crown.HðNO Þ ] in dichloromethane
3
2
(
Scheme 1). The oxidation reactions were performed under mild and com-
pletely homogeneous conditions at room temperature with quantitative
yields.
It was also observed that the oxidation of 1,4-dihydropyridines (1i)
bearing alkyl substituents (alkyl moieties may be responsible for generating

DIHYDROPYRIDINE OXIDATION
931
1
, 2
R
1, 2
R
1, 2
R
a
b
c
H
Me
Ph
d
e
f
2-Thienyl-
g
h
i
2-CH O-C H -
6
3
4
2-NO
3-NO
2
-C
-C
6
H
H
4
-
-
2,5-(CH
3
O)
2 6 4
-C H -
2
6
4
3 6 5
CH -CH-C H
Scheme 1.
stable carbocations) at the 4-position gives only dealkylated pyridine deriva-
tive (3). This is in agreement with the observation made by others employing
1
,2
different oxidative conditions. However, aryl-substituted 1,4-dihydropyr-
idines (1c–h) furnished the corresponding pyridine derivatives.
The present oxidation reaction can be readily carried out only by
þ
À
placing [NO .crown.HðNO Þ ], 1 and dichloromethane as the solvent in a
3
2
reaction vessel and efficiently stirring the resulting homogeneous mixture at
room temperature. The reactions were completed immediately. The solvent
was evaporated and the extra pure pyridine derivatives (2 or 3) can be
obtained by passing the residue through a pad of silica gel.
In conclusion, practical, chemoselective, and efficient oxidation
of 1,4-dihydropyridines was achieved by the present methodology.
þ
À
[
a relatively stable and efficient reagent as a source for the delivery of nitro-
NO .crown.HðNO Þ ], with its easy preparation and handling, can act as
3
2
þ
sonium ion (NO ) under mild and homogeneous conditions. Meanwhile,
18-crown-6 can be recycled and reused. The 18-crown-6 is completely
soluble in dichloromethane and also more reactive than those reagents
that were reported previously.
would be an important addition to existing ones.
1
–14
We believe that the present methodology
EXPERIMENTAL
General
Chemicals were purchased from Fluka, Merck, Riedel-dehaen AG,
and Aldrich. The oxidation products were characterized by comparison of
1
13
their spectral (IR, H NMR, C NMR, and TLC) and physical data with
the authentic samples. All Hantzsch 1,4-dihydropyridines were synthesized

9
32
ZOLFIGOL ET AL.
6
,37
þ
À
3
2
by the reported procedures.
[NO .crown.HðNO Þ ] was synthesized
3
8
according to the reported procedure, but a partial difference exists between
our applying method and those reported by others because we used N O4
2
gas instead of liquid N O . Dinitrogen tetroxide (N O ) gas was generated
2
4
2
4
2
4–34
in situ according to our previously reported procedure
as follows.
Generation of NO -N O Gas
2
2
4
Lead(II) nitrate (50 g) was crashed into powder and dried in an oven
ꢀ
at 120 C for three days. The resulting powder was transferred into a
one-necked round-bottomed flask (250 mL) equipped with an air condenser
and a gas trap containing P O . The flask was heated by a Bunsen burner to
generate brownish-red NO -N O gas, which was used immediately for the
2
5
2
2
4
þ
À
subsequent preparation of the [NO .crown.HðNO Þ ].
3
2
þ
ꢀ
2
Preparation of [NO .Crown.HðNO Þ ]
3
A solution of 18-crown-6 (5.286 g, 0.02 mol) in CH Cl (10 mL) was
2
2
prepared in a three-necked round-bottomed flask (50 mL), which was
equipped with a magnetic stirrer, gas inlet tube, thermometer, and a
ꢀ
drying tube, and was cooled to À10 C with an ice-salt bath, while being
stirred. Generation NO -N O gas was bubbled through this solution for
2
2
4
ꢀ
3
[
0 min. The solvent was evaporated under vacuum at 20 C to give
þ
À
2
NO .crown.HðNO Þ ] as a pale yellow deliquescent solid compound,
3
ꢀ
ꢀ
38
ꢀ
ꢀ
1
8
MHz, CDCl /TMS): 3.536 (s, 24H), 11.464 (s, 1H).
.380 g, (ꢁ100%), m.p. 50 –55 C [lit. m.p. 53 –55 C]. H NMR (FT-90
3
Oxidation of Dihydropiridine (1a) to Substituted Pyridine (2a):
A Typical Procedure
þ
A solution of compound 1a (0.253 g, 1 mmol) and I [NO .crown.
À
HðNO Þ , 0.419 g, 1 mmol] in dichloromethane (2 mL) was stirred at room
3
2
temperature [the progress of the reaction was monitored by TLC and
1
1
H NMR, the progress of the reaction by H NMR based upon the
disappearance of the singlet at ꢀ ¼ 5.00–5.35 (CH-4 in dihydropiridine struc-
ture 1)]. The reaction was completed immediately. Dichloromethane was
removed by water bath (40 –50 C) and simple distillation.
ꢀ
ꢀ
The residue was passed through a pad of silica gel [eluent: petroleum
ether]. The yield was 0.248 g, (98%) of a crystalline pale yellow solid (2a),

DIHYDROPYRIDINE OXIDATION
933
ꢀ
ꢀ
3
ꢀ
ꢀ
1
m.p. 69 –72 C [lit. m.p. 72 –73 C]. H NMR (FT-90 MHz, CDCl /TMS): ꢀ
1
3
7
.42 (t, 6H), 2.86 (s, 6H), 4.36 (q, 4H), 8.69 (s, 1H) [lit. ].
ACKNOWLEDGMENTS
Financial support for this work by the research office, Bu-Ali Sina
University, Hamadan, Iran, is gratefully acknowledged.
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Received in the U.K. March 1, 2000