Catalytic aromatization of hantzsch 1, 4-dihydropyridines by bis (salicylaldehyde-1, 2-phenylenediimine) Mn (III) chloride using urea hydrogen peroxide as mild and efficient oxidant

Article abstract of DOI:10.3987/COM-05-10446

A variety of Hantzsch 1,4-dihyropyridines were oxidized efficiently by a catalytic amount of bis(salicylaldehyde-1,2-phenylenediimine)Mn(III) chloride (Mn(III)-salophen I) in the presence of urea hydrogen peroxide adduct (UHP II) as convenient and mild ox

Full text of DOI:10.3987/COM-05-10446

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HETEROCYCLES, Vol. 65, No. 9, 2005, pp. 2181 - 2188
Received, 16th May, 2005, Accepted, 4th August, 2005, Published online, 5th August, 2005
CATALYTIC AROMATIZATION OF HANTZSCH 1, 4-
DIHYDROPYRIDINES BY BIS (SALICYLALDEHYDE-1, 2-
PHENYLENEDIIMINE) Mn (III) CHLORIDE USING UREA HYDROGEN
PEROXIDE AS MILD AND EFFICIENT OXIDANT
Bahador Karami*, Morteza Montazerozohori, and Masoud Nasr- Esfahani
Department of Chemistry, Yasouj University, Yasouj 75914-353, Iran;
E-mail:karami@mail.yu.ac.ir
Abstract – A variety of Hantzsch 1,4-dihyropyridines were oxidized efficiently by a
catalytic amount of bis(salicylaldehyde-1,2-phenylenediimine)Mn(III) chloride
(Mn(III)-salophen I) in the presence of urea hydrogen peroxide adduct (UHP II) as
convenient and mild oxidant to afford the related pyridine derivatives in high yields
at room temperature.
INTRODUCTION
It has been recognized Hantzsch 1,4-dihydropyridines act as vital drugs in the treatment of
angina and hypertension. Some of these compounds such as Amlodipine, Felodipine,
Isradipine, Lacidipine, Nicardipine and Nimodipine are commercially available.
Therapeutic success of these compounds is related to their efficiency to bind to calcium
channels and consequently to decrease the passage of the transmembrance calcium current
for the treatment of cardiovascular diseases.1-4 In addition to biological application of 1,4-
dihydropyridines, these compounds are used for preparation of pyridine derivatives in
organic synthesis. Various reagents and methods have been introduced for this purpose,
such as ferric or cupric nitrates on a solid support (clayfen or claycop),5 ceric ammonium
nitrate,6 clay-supported cupric nitrate accompanied by ultrasound-promotion,7 manganese
dioxide or DDQ,8 nitric oxide,9 bismuth nitrate pentahydrate,10 PCC, 11 tetrakis-pyridine
cobalt(II) dichromate (TPCD),12 nicotinium dichromate,13 S-nitrosoglutathione,14 N2O4
complex of 18-crown-6,15 diphenylpicrylhydrazyl and benzoyl peroxide as free radical
oxidizing agents,16 KMnO4,17 CrO3,18 HNO3,19 HNO2,20 tert-butyl hydroperoxide,21 silica gel
supported ferric nitrate (silfen),22 N2O3,23 photochemical oxidation, 24 inorganic acidic salts
and sodium nitrite or nitrate and catalytic oxidation.25-27
Amongst above methods, chemists today have been interested to resemble biotic systems

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because of their high efficiency and mild conditions. In this direction, many efficient
enzymatic model systems such as metal porphyrins28-31 and metal-tetra dentate Schiff base
complexes have been used for the oxidation of organic compounds32-37 in the presence of
PhIO, OCl-, persulfates and periodate38-42 as oxygen donating compounds. Although
manganese Schiff base complexes have been used as biomimetic catalyst in several
oxidation methods, development of their application in this category of reaction is
important for chemists yet.
In the present paper, we report a new role of Mn (III) - salophen (I) as biomimetic catalyst
for the oxidation of 1,4-dihyropyridines to the corresponding pyridine derivatives using
urea hydrogen peroxide(II) as single oxygen donating compound. We have chosen urea
hydrogen peroxide adduct(II) because it has been used as an odorless, safe, non-toxic and
easy to use white crystalline powder which releases hydrogen peroxide locally on
application in many reports. Over the past few years, several papers have been published
on the use of urea hydrogen peroxide adduct(II) in the oxidation reactions such as Baeyer-
Villiger oxidation of ketones,43 oxidation of sulfides to sulfones,44 oxidation of aromatic
aldehyde,45 epoxidation of alkenes.46 Recently we reported oxidation of imines to
oxaziridines and nitrones using UHP(II) / maleic anhydride system.47 In these application,
urea-hydrogen peroxide(II) alone or in combination with carboxylic acid or anhydride as
catalyst (rarely inorganic complex as co-catalyst) has acted as mild and efficient oxidant.48
RESULTS AND DISCUSSION
Metal Schiff base complexes have been used widely as efficient catalysts for oxidation of various substrates
with hydrogen peroxide. During the search for a good mediator or catalyst that can transfer active oxygen of
UHP(II) to 1,4-dihydropyridines oxidation systems, we found Mn(III)- salophen(I) suitably catalyses
oxidative aromatization of 1, 4-dihydropyridines in the presence of UHP(II) as oxidant (Scheme 1).
Therefore, general factors in the catalytic system such as solvent, exigency of an axial ligand, amount of the
catalyst, oxidant and temperature were investigated by a typical reaction on 1c Among the methanol,
acetonitrile, chloroform, dichloromethane and carbon tetrachloride, we found methanol as the best solvent.
Very low aromatization in the absence of imidazole as axial ligand revealed necessity of it for the efficient
catalytic conversion. Various molar ratios of the catalyst to the substrate, 1/50, 1/25, 1/15 and 1/10 were
used and based on the completion time of the reaction, 300 min, 180 min, 90 min and 50 min , we
recognized 1/10 molar ratio as optimum. With this optimum amount of the catalyst to the substrate,

HETEROCYCLES, Vol. 65, No. 9, 2005
2183
different molar ratio of the oxidant, UHP(II) to the substrate 2/1, 4/1 and 6/1 were used. With 2/1 molar
ratio, the reaction was not completed even with prolonged time. The 4/1 molar ratio completed the
conversion in 180 min but the 6/1 molar ratio resulted maximum conversion in minimum reaction time. In
0
some reactions containing UHP(II), 0 C has reported the proper temperature but we did not observe
considerable change between 0 0C and room temperature in the progress of reaction. After optimization of
these factors, a variety of 1, 4-dihydropyridines were subjected to the catalytic oxidative aromatization
(Scheme1, Table 1).
H
R2
H
R2
R1
R1
R1
R1
R1
R1
Mn(III)-salophen, UHP
Methanol, rt
+
Me
Me
N
H
Me
N
N
Me
Me
Me
3
2
1
C=N
O
N=C
Mn
H2NCONH2......H2O2
O
Cl
II
I
Scheme 1
The aromatization reactions were carried out under the optimized conditions at room temperature with good
to excellent yields. The results were summarized in Table 2. As shown in Table 2 the oxidation of
1,4-dihydropyridines(1) (Entries 5, 6) bearing secondary or tertiary alkyl substituent (alkyl moieties may be
responsible for generating stable carbocations) at the 4-position gives only dealkylated pyridine
derivative(3). This is in agreement with the observation made by other employing different oxidative
conditions.49 However, aryl- substituted 1, 4-dihydropyridines(1) (Entries 4, 7-12 and 15) furnished the
corresponding pyridine derivatives (2) (Table 2).
Based on these evidences and other reported mechanism, 48 the shown mechanism in Scheme 2 is proposed
for the oxidation of 1,4- dihydropyridines in our reaction conditions.
In Scheme 2 Mn (III)-salophen(I) is converted to [MnV (O)-salophen](4) by released H2O2 from UHP(II),
which is the oxidant that affords a hydroperoxy manganese species(3). Also hydroperoxy manganese can
be assumed as the active species without the presence of oxo-compound(4), 48 but necessity of axial ligand

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HETEROCYCLES, Vol. 65, No. 9, 2005
for convenient progress of the reaction support(4) as an important oxidant in our reactions. In the next stage,
1, 4- dihydropyridines(1) approaches to oxidant species(4) and 1, 4- dihydropyridine- MnIII- salophen
Table 1. 1, 4-Dihydropyridines (1) and their corresponding pyridine derivatives (2 or 3).
1,2,3 R1
R2
1,2,3
R1
R2
COOEt
H
COOEt
4-MeO-C6H4-
a
i
COOEt
COOEt
Me
Et
COOEt
COOEt
4-Cl-C6H4-
b
c
j
k
O
COOEt
COOEt
COOEt
COOEt
COOEt
Ph
COOEt
COMe
COMe
COMe
4-Br-C6H4-
d
e
f
l
i-Pr
H
m
n
o
t-Bu
Me
Ph
3-NO2-C6H4-
2-MeO-C6H4-
g
h
Table 2. Oxidation of 1,4-dihydropyridines (1) to their corresponding pyridine derivatives (2 or 3) by Mn
(III)-salophen (I) using UHP (II) in methanol at room temperature.
Entry Substrate
Product
Time (min) Yield a,b (%) Ref.
1
1a
1b
1c
1d
1e
1f
3a
2b
2c
2d
3e
3f
10
40
50
15
60
40
90
20
45
60
20
60
40
40
30
93
92
91
90
94
94
90
88
89
92
92
91
87
90
91
25-26
25-26
25-26
25-26
25-26
25-27
25-26
25-26
25-26
25
2
3
4
5
6
7
1g
1h
1i
2g
2h
2i
8
9
10
11
12
13
14
15
1j
2j
1k
1l
2k
2l
25-27
26-27
25-27
25, 27
25, 27
1m
1n
1o
2m
2n
2o
a Isolated yields. b0.1 mmol (I): 0.5 mmol imidazole: 6 mmol (II): 1 mmol substrate

HETEROCYCLES, Vol. 65, No. 9, 2005
2185
complex is formed that releases pyridine derivative (2 or 3), water and regenerated Mn (III)-salophen (I).
In conclusion, we described a facile, mild and biomimetic oxidation of 1, 4- dihydripyridines(1) to relative
H2NCONH2.....H2O2
Mn(III)-Salophen
I
NH2CONH2
II
H O
+
2 or 3
2
Mn(III)-Salophen
3
H
O
R2
R1
R1
O
H
..
N
NH+ Me
O
Me
N
Mn(III)-Salophen
H
O
OH-
Mn(V)-Salophen
4
N
1
N
H
Scheme 2
pyridine derivatives using catalytic amounts of Mn (III) - salophen (I) as biotic model catalyst in the
presence of UHP (II) as stable, safe and non-toxic oxidant. Several advantages of this method including
high yields of products, relatively short reaction times, inexpensive (catalytic amount of Mn (III) - salophen
(I) and ease of preparation of catalyst which make this reaction convenient and efficient in organic
synthesis.
EXPERIMENTAL
Chemicals were purchased from Aldrich, Fluka and Merck. UHP (II) was synthesized according to
previous report. Mn (III)-salophen (I) was prepared as previous described method.50 1,4- Dihydropyridines
(1) were prepared according to literature.20 The reactions were monitored by TLC. The products were
isolated and identified by comparison of their physical and spectral data with those in the literatures.25-27 IR
1
spectra were recorded on FT-IR JASCO-680 and the H-NMR spectra were obtained on a Brucker
instrument 300 MHz model.
General procedure for aromatization of 1,4- dihydropyridines (1)

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To a solution of 1 mmol of 1,4- dihydropyridine (1) in 15 mL of methanol, 6 mmol of UHP(II), 0.1 mmol
of Mn(III)-salophen (I) and 0.5 mmol of imidazole were added at rt. Completion of aromatization reaction
was followed by TLC (n-hexane: ethyl acetate, 8:2). After completion of the reaction, the solvent was
evaporated under vacuum at rt and then 10 mL of CH2Cl2 was added and filtered on silica gel.
Dichloromethane was removed by water bath to afford corresponding pyridine derivative.
ACKNOWLEDGEMENTS
Financial support for this work by Yasouj University is acknowledged.
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