Biomimetic aromatization of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by a new polystyrene-bound manganese porphyrin

Article abstract of DOI:10.1139/v05-255

Efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by a polystyrene-bound manganese(III) porphyrin is reported. This catalyst shows high activity in the oxidation of various 1,4-dihydropyridines at room temperature. This

Full text of DOI:10.1139/v05-255

1
Biomimetic aromatization of Hantzsch 1,4-
dihydropyridines with sodium periodate catalyzed
by a new polystyrene-bound manganese porphyrin
Majid Moghadam, Masoud Nasr-Esfahani, Shahram Tangestaninejad,
Valiollah Mirkhani, and Mohammad Ali Zolfigol
Abstract: Efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by a polystyrene-bound
manganese(III) porphyrin is reported. This catalyst shows high activity in the oxidation of various 1,4-dihydropyridines
at room temperature. This heterogeneous catalyst can be reused five times without significant loss of its activity.
Key words: biomimetic oxidation, supported metalloporphyrin, periodate, 1,4-dihydropyridine.
Résumé : On a effectué l’oxydation efficace des 1,4-dihydropyridines de Hantzsch par le biais d’une réaction avec du
periodate de potassium catalysée par une porphyrine de manganèse(III) liée à du polystyrène. Ce catalyseur présente
une grande activité pour l’oxydation, à la température ambiante, de diverses 1,4-dihydropyridines. Ce catalyseur hétéro-
gène peut être réutilisé jusqu’à cinq fois dans perte significative de son activité.
Mots clés : oxydation biomimétique, métalloporphyrine déposée sur un support, periodate, 1,4-dihydropyridine.
[Traduit par la Rédaction] Moghadam et al.
4
Introduction
able microenvironment for the “accommodation” of the
porphyrin catalytic center.
In the last two decades, metalloporphyrins have been suc-
cessfully used as models for the cytochrome P-450 enzyme
with respect to the oxidation of organic compounds such as
hydrocarbons (1–3). Development in this area is based on
different strategies with the aim of designing selective,
stable, and high turnover catalytic systems (4). Several sim-
ple oxidants such as iodosylbenzene, hypochlorite, m-
chloroperbenzoic acid, hydrogen peroxide, and periodates
have been extensively studied in oxygenation reactions cata-
lyzed by metal complexes to understand the mechanism of
the cytochrome P-450 monooxygenation enzyme (5–10). Great
efforts have been made toward the chemical modification of
the metalloporphyrin microenvironment in the studies of the
cytochrome P-450 model. One method is to immobilize the
metalloporphyrins onto solid supports. Such immobilization
not only modifies the metalloporphyrin microenvironment,
but also increases the catalytic activity of metalloporphyrins,
so one can prepare the catalysts, which are easier to handle
and easily separate from reaction medium. Among the
metalloporphyrin microenvironment models, polystyrene de-
rivatives are often utilized because they can provide a suit-
Amlodepine besylate, nifedepine, and related dihydropyri-
dines are Ca2+ channel blockers and are rapidly emerging as
one of the most important classes of drugs for the treatment
of cardiovascular diseases, including hypertension cardiac
arrhythmias (11). In the human body, it has been observed
that these compounds undergo oxidation to form pyridine
derivatives by the action of cytochrome P-450 in the liver.
This observation led us to investigate the ability of this bio-
mimetic catalyst to act in the oxidation of 1,4-dihydropy-
ridines. These oxidized compounds are largely devoid of the
pharmacological activity of the parent compounds (12, 13).
Recently, we reported on the oxidation of 1,4-dihydro-
pyridines with tetra-n-butylammonium periodate catalyzed
by homogeneous Mn(TPP)Cl (14). In this paper, we report
on the efficient oxidation of 1,4-dihydropyridines with so-
dium periodate at room temperature catalyzed by a
Mn(TPyP) supported on chloromethylated polystyrene
(CMP) (Scheme 1).
Results and discussion
The manganese(III) tetrapyridylporphyrin supported on
polystyrene (Mn(TPyP)–CMP) is easily prepared from com-
mercially available porphyrin and chloromethylated polysty-
rene (Fig. 1).
The high catalytic activity of this heterogeneous catalyst
in the alkene epoxidation and alkane hydroxylation and oxi-
dation of alcohols (15, 16) prompted us to investigate its
ability in the oxidation of 1,4-dihydropyridines with sodium
periodate at mild reaction conditions. The oxidation of 1,4-
dihydropyridines by Mn(TPyP)–CMP and sodium periodate
yielded the corresponding pyridine derivative in CH3CN–
Received 6 July 2005. Published on the NRC Research Press
Web site at http://canjchem.nrc.ca on 3 February 2006.
M. Moghadam1 and M. Nasr-Esfahani. Department of
Chemistry, Yasouj University, Yasouj 75914-353, Iran.
S. Tangestaninejad and V. Mirkhani. Department of
Chemistry, Isfahan University, Isfahan 81746-73441, Iran.
M.A. Zolfigol. Department of Chemistry, Bu-Ali Sina
University, Hamadan 65173, Iran.
1Corresponding author (e-mail: moghadamm@mail.yu.ac.ir).
Can. J. Chem. 84: 1–4 (2006)
doi:10.1139/V05-255
© 2006 NRC Canada

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Can. J. Chem. Vol. 84, 2006
Scheme 1.
R
N
R
H
H
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
Mn(TPyP)-CMP/NaIO4
CH3CN/H2O, RT
EtOOC
COOEt
Me
or
N
H
Me
N
Fig 1. The catalyst used in this study.
N
Table 1. Effect of various oxidants on the oxidation of 4-phenyl
derivatives of 1,4-dihydropyridines.
Oxidant
Solvent
Yield (%)a
NaIO4
CH3CN–H2O
CH3CN
97
40
32
17
10
H2O2
N
MnIII
N
N
Cl-
H2O2–urea
NaOCl
CH3CN
+
N
CH2
N
CH3CN
t-BuOOH
CH3CN
aIsolated yields.
Table 2. Effect of solvent oxidation of 4-phenyl derivatives of
1,4-dihydropyridines.
N
Solvent
Yield (%)a after 60 min
H2O (1:1) as solvent, whereas trace amounts of the product
was detected when the identical reaction was carried out in
the absence of periodate. The effects of other oxidants were
also studied in the oxidation of 4-phenyl derivatives of 1,4-
dihydropyridines. The obtained results showed that NaIO4 is
more effective than H2O2, NaOCl, t-BuOOH, and urea-
hydrogen peroxide adduct (UHP) (Table 1). To choose the
reaction media, different solvents were investigated in the
oxidation of 4-phenyl derivatives of 1,4-dihydropyridines.
As shown in Table 2, among the studied solvents, the 1:1
mixture of CH3CN–H2O was chosen as solvent because a
higher amount of pyridine derivative was observed. The
blank experiment, in the absence of catalyst, showed that the
presence of catalyst is crucial in oxidation reactions. In
biomimetic systems using metalloporphyrins as catalyst, ad-
dition of an axial base is necessary to obtain high catalytic
activity. One observation is that this catalytic system shows
higher catalytic activity in the absence of imidazole. When
imidazole is added as axial ligand to this catalytic system,
the reaction times become longer in the oxidation of 1,4-
dihydropyridines. For instance, the oxidation of 4-phenyl
and 4-nitrophenyl derivatives was completed in 60 and
90 min, respectively; but addition of imidazole as co-catalyst
led to longer reaction times of 90 and 150 min for 4-phenyl
and 4-nitrophenyl derivatives, respectively. These observa-
tions show that the 1,4-dihydropyridines can play the axial
ligand role. The Mn(TPyP)–CMP–NaIO4 catalytic system
CH3CN–H2O
CH3COCH3–H2O
CH3OH–H2O
CH3CH2OH–H2O
CHCl3–H2O
97
75
58
42
15
33
8
CH2Cl2–H2O
CCl4–H2O
aIsolated yields.
ble 3, entry 12), which was previously reported by Ortiz de
Montellano et al. (17) in the oxidation of 1,4-dihydropyrines
by cytochrome P-450. This approach shows that this syn-
thetic model behaves in the same way as cytochrome P-450.
We also studied recycling of the used Mn(TPyP)–CMP in
the repeated oxidation reactions. After the first run, the poly-
mer was recovered by filtration followed by washing with
water and acetonitrile and then reused. The catalyst was re-
used five consecutive times without loss of its activity. No
manganese was detectable in the filtrates by atomic absorp-
tion spectrometry.
From a synthetic point of view, the oxidation of Hantzsch
1,4-dihydropyridines is an old reaction in synthetic organic
chemistry. In recent years, several new methods have been
reported for dehydrogenation of Hantzsch 1,4-dihydropy-
ridines with ferric or cupric nitrates on a solid support: ceric
ammonium nitrate, pyridinium chlorochromate, t-BuOOH,
photochemical oxidation, NO gas, inorganic acidic salts –
NaNO3 – wet SiO2, and NaHSO4–NaNO2 (18). Most of the
reported procedures suffer from disadvantages such as pro-
ducing by-products that are difficult to remove from the de-
sired product, using the reagents that are either highly toxic
or present serious environmental problems (or both such as
NO), and nonreusability of heterogeneous catalysts. The
comparison of our reported system with the previously re-
can be used for oxidizing
a wide variety of 1,4-
dihydropyridine derivatives to their corresponding pyridine
derivatives giving excellent yields at room temperature. All
reactions were completed during the appropriate time (until
no starting material is detected by TLC) and gave only the
corresponding pyridine derivatives. The results are summa-
rized in Table 3. As shown in Table 3, the oxidation of the
4-isopropyl derivative accompanied by expulsion of this
substituent gave the dealkylated pyridine derivative (Ta-
© 2006 NRC Canada

Moghadam et al.
3
Table 3. Oxidation of Hantzsch 1,4-dihydropyridines with NaIO4
catalyzed by Mn(TPyP)–CMP.
ported systems shows that the Mn(TPyP)–CMP–NaIO4 cata-
lytic system has the following advantages: mild reaction
conditions, robustness of the catalyst, nontoxicity of re-
agents, and reusability of the catalyst without loss of its ac-
tivity.
R
R
H
H
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
or
N
H
N
N
Experimental
All materials were commercial reagent grade. The
tetrapyridylporphyrin ligand (TPyP) was purchased from the
Fluka Chemical Company (Dubai, UAE), and metalated and
supported according to literature procedures (19, 14). All
Hantzsch 1,4-dihydropyridines were synthesized by the re-
1
ported procedures (20). H NMR spectra were obtained with
a Bruker AW80 (80 MHz) spectrometer.
General procedure for oxidation of 1,4-
dihydropyridines with NaIO4 catalyzed by Mn(TPyP)–
CMP
All of the reactions were carried out at room temperature
under air in a 25 mL flask equipped with a magnetic stirrer
bar. A solution of NaIO4 (2 mmol) in H2O (10 mL) was
added to a mixture of 1,4-dihydropyridines (1 mmol) and
MnTPyP–CMP (20 µmol) in CH3CN (10 mL). The progress
of the reaction was monitored by TLC. After the reaction
was completed, the reaction mixture was filtered and the
pyridine derivative was extracted with CH2Cl2 (2 × 20 mL).
The pyridine derivatives were obtained after evaporation of
the solvent. Further purification was followed using a silica
1
gel plate. IR and H NMR spectral data confirmed the iden-
tities of the products.
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