Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by manganese (III) Schiff base complexes

Article abstract of DOI:10.1016/j.bmc.2005.11.051

Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridine with sodium periodate is reported. The Mn(III)-salophen/NaIO₄ catalytic system converts 1,4-dihydropyridines to their corresponding pyridine derivatives at room temperature in a 1:1,

Full text of DOI:10.1016/j.bmc.2005.11.051

Bioorganic & Medicinal Chemistry 14 (2006) 2720–2724
Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridines
with sodium periodate catalyzed by manganese (III)
Schiff base complexes
a,
b
Masoud Nasr-Esfahani,a,* Majid Moghadam, Shahram Tangestaninejad,
*
Valiollah Mirkhanib and Ahmad Reza Momenic
aDepartment of Chemistry, Yasouj University, Yasouj 75914-353, Iran
bDepartment of Chemistry, Isfahan University, Isfahan 81746-73441, Iran
cDepartment of Chemistry, Islamic Azad University, Shahreza branch, 86145-311 Shahreza, Iran
Received 2 November 2005; revised 27 November 2005; accepted 28 November 2005
Available online 11 January 2006
Abstract—Rapid and efficient oxidation of Hantzsch 1,4-dihydropyridine with sodium periodate is reported. The Mn(III)-salophen/
NaIO4 catalytic system converts 1,4-dihydropyridines to their corresponding pyridine derivatives at room temperature in a 1:1,
CH3CN/H2O mixture. The ability of various Schiff base complexes in the oxidation of 1,4-dihydropyridine was also investigated.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Hantzsch 1,4-dihydropyridines are widely used as calci-
um channel blockers for the treatment of cardiovascular
disorder including angina, hypertension, and cardiac
arrhythmias.24 These compounds are oxidized to pyri-
dine derivatives by the action of cytochrome P-450 in
the liver.25
The heme-containing monooxygenases cytochrome
P-450 is known to play a key role in the oxidative
metabolism of drugs and other environmental products,
allowing their elimination from living organisms.1
Therefore, numerous studies have been performed on
the mimic of this enzyme.2,3 Iron and manganese por-
phyrins proved to be able to catalyze oxidation reactions
In this paper, we report the rapid and efficient oxidation
of 1,4-dihydropyridines with sodium periodate to their
corresponding pyridine derivatives at room temperature
in a 1:1, CH3CN/H2O mixture (Scheme 1).
using various single oxygen Àatom donors such as PhIO,
ClOÀ, H2O2, ROOH or IO4
.
The high efficiency of
4–13
some of these systems makes them potentially useful for
preparative oxidations in organic synthesis. Recently,
mono- and binuclear transition metal complexes derived
from ligands other than porphyrins have also been em-
ployed as catalysts. The use of metal Schiff base com-
plexes, that is, metal salen and metal salophen to
catalyze the oxidation of organic compounds by single
oxygen atom donors has received much attention. Man-
ganese, chromium, nickel, and cobalt Schiff base com-
plexes have been used for these transformations.14–23
We have chosen the salophen ligand because it is similar
to porphyrin, and the electronic and steric nature of the
metal complex can be tuned by introducing electron-
withdrawing and electron-releasing substituents and
bulky groups in the ligand.
2. Results and discussion
2.1. Oxidation of 1,4-dihydropyridine derivatives with
different metal–Schiff base complexes
Initially, in order to show the periodate anion activation
by metal Schiff base complexes, we decided to investi-
gate the activity of various Schiff base complexes of
Fe, Mn, Co, and Ni as metal ions. The obtained results
Keywords: Biomimetic; Schiff base; Periodate; 1,4-Dihydropyridine.
*
Corresponding authors. Tel.: +98 913 3413602; fax: +98 741 2223048
(M.N.-E.); tel.: +98 913 3108960; fax: +98 741 2223048 (M.M.);
e-mail addresses: manas@mail.yu.ac.ir; moghadamm@mail.yu.ac.ir
0968-0896/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.11.051

M. Nasr-Esfahani et al. / Bioorg. Med. Chem. 14 (2006) 2720–2724
2721
R
H
N
R
H
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
Mn(III)-Salophen/NaIO4
CH3CN/H2O, RT
or
N
H
N
if R= H, i-Propyl
Scheme 1.
on catalytic oxidation of 4-phenyl derivative of 1,4-dihy-
dropyridine with sodium periodate in the presence of
different Schiff base complexes (Fig. 1) are shown in Ta-
ble 1. These results indicated that the nature of the metal
ion has an important role on the catalytic activity of
Schiff base complexes. The iron, cobalt, and nickel com-
plexes give a small amount of the corresponding pyri-
dine derivative in the oxidation of 4-phenyl derivative
of 1,4-dihydropyridine. In the case of nickel and cobalt,
these metal ions are not capable of forming the high oxi-
dation state oxo species, and in the case of iron it is not
clear why Fe Schiff bases show lower activity than man-
ganese complexes in the oxidation reactions. However,
the use of manganese (III) complexes give a higher oxi-
dation product in the oxidation of 4-phenyl derivative of
1,4-dihydropyridine.
Table 1. Oxidation of 4-phenyl derivative of 1,4-dihydropyridines by
various metal Schiff base complexes with sodium periodate
Schiff base
Yielda (%) after 5 min
1
2
97
35
6
3
4
7
5
6
6
15
10
30
5
7
8
9
10
11
20
10
a Isolated yields.
2.2. Effect of solvent on the oxidation of 4-phenyl
derivative of 1,4-dihydropyridine
In comparing the influence of Schiff base ligands on cat-
alytic activity, the hindered Schiff base ligand, salophen,
exhibits a significant greater catalytic power than that of
the unhindered Schiff base ligand, salen. On the other
hand, the presence of electron-withdrawing substituents
on the Schiff base complexes decreases the catalytic
activity.
Among the 1:1 mixture of methanol, ethanol, acetone,
acetonitrile (single-phase systems), chloroform, and
carbon tetrachloride (two-phase systems with Bu4NBr
as the phase transfer catalyst) with water, the 1:1 aceto-
nitrile/water mixture was chosen as the reaction
Y
X
O
N
O
N
X
N
N
Y
N
N
M
M
z
z
M
z
X
Y
1
2
Mn
Mn
Fe
C6H4
C6H4
C6H4
C6H4
C6H4
H
NO2
H
Cl
Cl
Cl
-
3
4
Co
Ni
H
5
H
-
6
Mn
Fe
(CH2)2
(CH2)2
C6H4
H
Cl
Cl
Cl
Cl
Cl
Cl
7
H
8
Mn
Fe
H
9
C6H4
H
10
11
Mn
Fe
(CH2)2
(CH2)2
H
H
Figure 1. Transition metal Schiff base complexes used in this study.

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M. Nasr-Esfahani et al. / Bioorg. Med. Chem. 14 (2006) 2720–2724
Table 2. Oxidation of Hantzsch 1,4-dihydropyridines with NaIO4 catalyzed by Mn(III)-salophen
R
H
R
N
H
N
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
or
N
H
Row
R
Time (min)
Yielda (%)
1
2
H
CH3
5
5
97
97
3
4
5
98
96
15
Cl
Cl
5
6
5
97
96
NO2
15
7
8
15
15
95
96
NO2
NO2
9
20
15
94
95
Br
10
OH
11
12
15
15
97
OMe
H3C
CH3
97b
a Isolated yields; All products were identified by comparison with authentic samples (IR, 1H NMR, mp).
b This product is a dealkylated pyridine derivative.

M. Nasr-Esfahani et al. / Bioorg. Med. Chem. 14 (2006) 2720–2724
2723
medium, because the metal Schiff base complexes are
highly soluble in this solvent and higher pyridine deriv-
ative yields were observed.
Mn(salophen) shows poor ability in the oxidation of
1,4-dihydropyridines and in comparison with NaIO4,
H2O2 showed lower activity. When sodium periodate
is used as the oxygen source, a higher yield is observed.
2.3. Effect of axial ligand on the oxidation of 4-phenyl
derivative of 1,4-dihydropyridine
3. Conclusions
In biomimetic systems using metalloporphyrins and
Schiff base complexes as catalyst, addition of an axial
base is necessary to obtain high catalytic activity. One
comment is that, this catalytic system shows a higher
catalytic activity in the absence of imidazole. When
imidazole is added as axial ligand to this catalytic sys-
tem, the reaction times become higher in the oxidation
of 1,4-dihydropyridines. For instance, the oxidation of
4-phenyl and 4-nitrophenyl derivatives was completed
in 5 and 15 min, respectively. Addition of imidazole as
co-catalyst led to longer reaction times which are 15
and 20 min for 4-phenyl and 4-nitrophenyl derivatives.
These observations show that the 1,4-dihydropyridines
can play the axial ligand role.
Mn(III)salophen/NaIO4 catalytic system have the
following advantages in the oxidation of Hantzsch
1,4-dihydropyridines to their corresponding pyridine
derivatives: (i) understanding the action of cyto-
chrome P-450 in the oxidation of Hantzsch 1,4-dihy-
dropyridines
to
their
corresponding
pyridine
derivatives, (ii) short reaction time, (iii) high efficiency
for oxidation of Hantzsch 1,4-dihydropyridines to
their corresponding pyridine derivatives, (iv) mild
reaction conditions, and (v) ease of preparation of
the catalyst.
Therefore, the present method could be a useful addition
to the available methods in organic synthesis.
2.4. Oxidation of 1,4-dihydropyridine derivatives with
sodium periodate catalyzed by Mn(III)-salophen
4. Experimental
The Mn(III)-salophen/NaIO4 catalytic system can be
used for oxidizing a wide variety of 1,4-dihydropyridine
derivatives to their corresponding pyridine derivatives in
excellent yields at room temperature. All reactions were
completed during the appropriate time and gave only
the corresponding pyridine derivative. The results are
summarized in Table 2. As shown in Table 2, oxidation
of 4-isopropyl derivative was accompanied by expulsion
of this substituent and gave a dealkylated pyridine deriv-
ative (entry 12), which was previously reported by Ortiz
de Montellano in the oxidation of 1,4-dihydropyrines by
cytochrome P-450.26 This approach shows that this syn-
thetic model behaves as cytochrome P-450.
Schiff base complexes 1–11 (Fig. 1) were prepared as de-
scribed by Boucher27 or by the more recently modified
methods.14,28,29 All Hantzsch 1,4-dihydropyridines were
synthesized by the reported procedures.30 1H NMR
spectra were obtained with a Brucker AW80 (80 MHz)
spectrometer.
4.1. General procedure for oxidation of Hantzsch 1,4-
dihydropyridines to their corresponding pyridine
derivatives
All reactions were carried out at room temperature in a
25 mL flask equipped with a magnetic stirring bar. A
solution of sodium periodate (2 mmol in 5 mL H2O)
was added to a mixture of Hantzsch 1,4-dihydropyridine
(1 mmol), Mn-salophen (0.067 mmol) in CH3CN
(5 mL). Progress of the reaction was monitored by
TLC. After the reaction was completed, the reaction
products were extracted with CH2Cl2 (20 mL) and puri-
fied by a silica gel plate or a silica gel column (eluent:
CCl4–Et2O). The identities of products were confirmed
In the absence of manganese (III)-salophen catalyst,
NaIO4 has poor ability to oxidize 1,4-dihydropyridines
to their corresponding pyridine derivatives at room tem-
perature (6–10% yields).
In the catalytic oxidation of 1,4-dihydropyridines, we
examined different oxidants such as NaOCl, NaIO4,
H2O2, tert-butylhydroperoxide, and urea–H2O2 (UHP)
in the oxidation of 1,4-dihydropyridines. The results
are summarized in Table 3. When NaOCl, tert-buty-
lhydroperoxide, and urea–H2O2 (UHP) are used as oxy-
gen sources in acetonitrile or dicholoromethane,
1
by mp, IR, and H NMR spectral data.
Acknowledgment
The partial support of this work by Yasouj University
Council of Research is acknowledged.
Table 3. Effect of various oxidants on the oxidation of 4-phenyl
derivative of 1,4-dihydropyridines
Oxidant
Solvent
Yield (%)a after 5 min
NaIO4
H2O2
CH3CN/H2O
CH3CN
CH3CN
97
87
44
31
23
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H2O2/urea
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CH3CN
a Isolated yields.

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