Mild and efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by a new polystyrene-bound Mn(TPP)Cl

Article abstract of DOI:10.1016/j.bmcl.2005.12.072

Mild and efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by Mn(TTP)Cl supported on polystyrene-bound imidazole is reported. This heterogeneous catalyst is of great stability and reusability in the oxidation of 1,4-dihy

Full text of DOI:10.1016/j.bmcl.2005.12.072

Bioorganic & Medicinal Chemistry Letters 16 (2006) 2026–2030
Mild and efficient oxidation of Hantzsch 1,4-dihydropyridines
with sodium periodate catalyzed by a new
polystyrene-bound Mn(TPP)Cl
Majid Moghadam,a,* Masoud Nasr-Esfahani,a,*
Shahram Tangestaninejadb and Valiollah Mirkhanib
aDepartment of Chemistry, Yasouj University, Yasouj 75914-353, Iran
bDepartment of Chemistry, Isfahan University, Isfahan 81746-73441, Iran
Received 12 October 2005; revised 6 December 2005; accepted 19 December 2005
Available online 19 January 2006
Abstract—Mild and efficient oxidation of Hantzsch 1,4-dihydropyridines with sodium periodate catalyzed by Mn(TTP)Cl supported
on polystyrene-bound imidazole is reported. This heterogeneous catalyst is of great stability and reusability in the oxidation of
1,4-dihydropyridines with sodium periodate without significant loss of its catalytic activity.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1,4-Dihydropyridines are calcium antagonists,1 antitu-
bercular agents,2 and neuropeptide Y Y1 receptor
antagonists.3 They possess neuroprotective,4 platelet
antiaggregation,5 and antidiabetic6 activities. Aromati-
zation of 1,4-dihydropyridines has received considerable
attention owing to the fact that 1,4-dihydropyridine-
based calcium channel blockers are oxidatively convert-
ed to pyridine derivatives by the action of cytochrome
P-450 in the liver.7 In addition, the corresponding
pyridine derivatives show antihypoxic and antiischemic
activites.8 Additionally, dihydropyridines are often pro-
duced in a synthetic sequence and have to be oxidized to
pyridines.9 Numerous reagents and procedures have
been recommended for this purpose, such as NO,9 ferric
or cupric nitrates on a solid support (clayfen or
claycop),10 ceric ammonium nitrate,11 clay-supported
cupric nitrate accompanied by ultrasound promotion,12
manganese dioxide or 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ),13 nitric oxide,14 bismuth nitrate
pentahydrate,15 pyridinium chlorochromate (PCC),16
tetrakis-(pyridine) cobalt(II) dichromate (TPCD),17
nicotinium dichromate,18 S-nitrosoglutathione,19 N2O4
complex of 18-crown-6,20 diphenylpicrylhydrazyl and
benzoyl peroxide as free radical oxidizing agents,21
KMnO4,22 CrO3,23 HNO3,24 HNO2,25 tert-butylhydrop-
eroxide,26 silica gel supported ferric nitrate (silfen),8
N2O3,27 photochemical oxidation,28 inorganic acidic
salts, sodium nitrite or nitrate,29–32 and Mn(TPP)Cl/(n-
Bu)4NIO4.33
Despite these intensive efforts, most of the reported oxi-
dation procedures require long reaction times, utilize
strong oxidants in large excess, afford products with
only modest yields, and non-reusability of the catalyst.
Therefore, the development of more effective methods
for aromatization of 1,4-dihydropyridines is still
necessary.
Metalloporphyrins have been successfully used as mod-
els for the cytochrome P-450 enzyme with respect to the
oxidation of organic compounds such as hydrocar-
bons.34–36 Development in this area is based on different
strategies with the aim of designing selective, stable, and
high turnover catalytic systems.37 Several simple oxi-
dants such as iodosylbenzene, hypochlorite, m-chloro-
perbenzoic acid, hydrogen peroxide, and periodates
have been extensively studied in oxygenation reactions
catalyzed by metal complexes in order to understand
the mechanism of cytochrome P-450 monooxygenation
enzyme.38–43 Great efforts have been made to the chem-
ical modification of metalloporphyrin microenviron-
Keywords: Dihydropyridines; Metalloporphyrin; Supported catalyst;
Periodate; Oxidation.
*
Corresponding authors. Tel.: +98 913 3108960; fax: +98 741 2223048
(M.M); tel.: +98 913 3413602; fax: +98 741 2223048 (M.N.-E); e-mail
addresses: moghadamm@mail.yu.ac.ir; manas@mail.yu.ac.ir
0960-894X/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.12.072

M. Moghadam et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2026–2030
2027
CH3CN/ Imidazole
NaI/ Reflux
ment in the studies of cytochrome P-450 model. One
way is to immobilize the metalloporphyrins onto solid
supports. Such immobilization not only modifies the
metalloporphyrin microenvironment, but also increases
the catalytic activity of metalloporphyrins, and let to
prepare the catalysts which are easier to handle and eas-
ily separate from reaction medium. Among the models
of metalloporphyrin microenvironment, the polystyrene
derivatives are often utilized, because they can provide
suitable microenvironment for the ‘accommodation’ of
porphyrin catalytic center.
Cl
N
N
Mn(TPP)Cl
N
N
Recently, we have reported the oxidation of 1,4-dihy-
dropyridines with tetra-n-butylammonium periodate
catalyzed by homogeneous Mn(TPP)Cl.33 In this paper,
we report the efficient oxidation of 1,4-dihydropyridines
with sodium periodate at room temperature catalyzed
by a Mn(TPP)Cl supported on polystyrene-bound imid-
azole, Mn(TPP)Cl-PSI (Scheme 1).
N
N
N
Mn
N
Figure 1. The preparation of supported catalyst used in this study.
Table 1. Effect of various oxidants on the oxidation of 4-phenyl
derivative of 1,4-dihydropyridines
Chloromethylated polystyrene surface modification with
imidazole to give the PSI was carried out through the
method described by Alvarez-Builla and co-workers.44
The supported MnP was prepared by stirring a suspen-
sion of the support, (PSI), in a solution of MnP in tolu-
ene as solvent, because of better solvation and swelling
of the polymer in it. The free manganese porphyrin
was removed by subsequent washing of the catalyst with
toluene, dichloromethane, and acetone, respectively
(Fig. 1).
Oxidant
Solvent
Yielda (%)
NaIO4
H2O2
CH3CN/H2O
CH3CN
CH3CN
96
82
47
30
25
22
34
38
H2O2/urea
NaOCl
CH3CN
CH3CN
t-BuOOH
n-Bu4NIO4
t-BuOOH
NaIO4
CH3CN
t-BuOH/H2O
t-BuOH/H2O
a Isolated yields.
The high catalytic activity of this heterogeneous catalyst
in the alkene epoxidation and alkane hydroxylation45
prompted us to investigate its ability in the oxidation
of 1,4-dihydropyridines with sodium periodate under
mild reaction conditions. The oxidation of 1,4-dihydro-
pyridines by Mn(TPP)Cl-PSI and sodium periodate
yielded the corresponding pyridine derivative in 1:1
CH3CN/H2O as solvent, whereas trace amounts of
product were detected when the identical reaction was
carried out in the absence of periodate. The effect of
other oxidants was also studied in the oxidation of 4-
phenyl derivative of 1,4-dihydropyridines. The obtained
results showed that NaIO4 is more effective than H2O2,
NaOCl, t-BuOOH, (n-Bu)4NIO4, and UHP (Table 1).
Also, we investigated the aromatization of 1,4-dihydro-
pyridines as a test case in a mixture of EtOH, MeOH,
CH3COCH3, CH3CN, and t-BuOH (single phase sys-
tems), CH2Cl2, CHCl3, and CCl4 (two phase systems
with n-Bu4Br as phase transfer catalyst) with water as
reaction media at ambient temperature. The results,
which are summarized in Table 2, showed that the oxi-
dation of 1,4-dihydropyridines in the 1:1 mixture of
Table 2. Effect of solvent on the oxidation of 4-phenyl derivative of
1,4-dihydropyridines
Solvent
Yield after 40 mina (%)
CH3CN/H2O
CH3COCH3/H2O
CH3OH/H2O
CH3CH2OH/H2O
t-BuOH/H2O
CHCl3/H2O
96
78
52
47
38
17
30
8
CH2Cl2/H2O
CCl4/H2O
a Isolated yields.
CH3CN/H2O led to a higher corresponding pyridine.
The blank experiment, in the absence of catalyst,
showed that the presence of catalyst is crucial in the oxi-
dation reactions. All reactions proceeded efficiently
within 40–80 min to provide the corresponding pyri-
dines in excellent yields (Table 3). As shown in Table
3, oxidation of 4-isopropyl derivative was accompanied
R
N
H
R
H
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
Mn(TPP)Cl-PSI/NaIO4
CH3CN/H2O, RT
EtOOC
Me
COOEt
Me
or
N
H
N
R= H, i-Propyl
Scheme 1.

2028
M. Moghadam et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2026–2030
Table 3. Oxidation of Hantzsch 1,4-dihydropyridines with NaIO4 catalyzed by Mn(TPP)Cl-PSI
R
H
R
N
H
N
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
EtOOC
Me
COOEt
Me
or
N
H
Row
R
H
Time (min)
Yielda (%)
1
2
40
50
96
95
CH3
3
4
50
80
97
96
Cl
Cl
5
6
55
70
96
93
NO2
7
8
90
92
93
NO2
NO2
100
9
10
11
12
120
80
91
Br
92
OH
80
95
OMe
H3C
CH3
40
96b
13
14
55
70
93
92
O
S
a Isolated yields; All products were identified by comparison with authentic samples (IR, 1H NMR, and mp).
b The product is a dealkylated pyridine derivative.

M. Moghadam et al. / Bioorg. Med. Chem. Lett. 16 (2006) 2026–2030
Table 4. The results of [Mn(TPP)-PSI] catalyst recovery and the
2029
References and notes
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1
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tral data confirmed the identities of the products.

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