Oxidative-aromatization of Hantzsch ester 1,4-dihydropyridines by KBrO 3/SnCl4-5H2O under mild condition

Article abstract of DOI:10.1081/SCC-200049787

Different kinds of Hantzsch ester 1,4-dihydropyridines were oxidatively aromatized to their corresponding pyridine derivatives by KBrO ₃/SnCl₄ · 5H₂O system in refluxing CH₃CN. The products were obtained in high to excellent yields.

Full text of DOI:10.1081/SCC-200049787

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Oxidative‐Aromatization of Hantzsch Ester
1,4‐Dihydropyridines by KBrO3/SnCl4ꢀ·ꢀ5H2O
Under Mild Condition
Behzad Zeynizadeh a , Karim Akbari Dilmaghani a & Asli Roozijoy a
a Department of Chemistry, Faculty of Sciences, Urmia University, Urmia,
Iran
Published online: 12 Apr 2011.
To cite this article: Behzad Zeynizadeh , Karim Akbari Dilmaghani & Asli Roozijoy (2005):
Oxidative‐Aromatization of Hantzsch Ester 1,4‐Dihydropyridines by KBrO3/SnCl4ꢀ·ꢀ5H2O Under Mild Condition,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:4, 557-562
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Synthetic Communicationsw, 35: 557–562, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200049787
Oxidative-Aromatization of Hantzsch Ester
1,4-Dihydropyridines by KBrO3/
.
SnCl4 5H2O Under Mild Condition
Behzad Zeynizadeh, Karim Akbari Dilmaghani, and Asli Roozijoy
Department of Chemistry, Faculty of Sciences, Urmia University,
Urmia, Iran
Abstract: Different kinds of Hantzsch ester 1,4-dihydropyridines were oxidatively
.
aromatized to their corresponding pyridine derivatives by KBrO3/SnCl4 5H2O
system in refluxing CH3CN. The products were obtained in high to excellent yields.
.
Keywords: Aromatization, Hantzsch 1,4-dihydropyridines, KBrO3, SnCl4 5H2O
Aromatization of Hantzsch ester 1,4-dihydropyrines (1,4-DHPs) into the
corresponding pyridine derivatives occurred in the first-pass metabolism by
the action of cytochrome P-450 in the liver.[1] These compounds have been
known as calcium channel blockers for the treatment of cardiovascular
diseases.[2a,2b] So, this transformation in the aspect of gaining reference
standards for the studying in vivo reactions and easy access to pyridine deriva-
tives has attracted a great deal of attentions.
A vast variety of oxidants and reagents were reported for this oxidative
reaction e.g., HNO3,[2b,3] KMnO4,[4] CrO3,[5] MnO2,[6] pyridinium chlorochro-
mate,[7] ceric ammonium nitrate,[8] BaMnO4,[9] K2S2O8,[10] phenyliodine(III)
bis(trifluoroacetate) and elemental sulfur,[11] SiO2/Fe(NO3)3 or Cu(NO3)2,[12]
Received in the UK 19 August 2004
Address correspondence to Behzad Zeynizadeh, Department of Chemistry, Faculty
of Sciences, Urmia University, Urmia 57159-165, Iran. E-mail: b.zeynizadeh@mail.
urmia.ac.ir

558
B. Zeynizadeh, K. A. Dilmaghani, and A. Roozijoy
ter-butylhydroperoxide,[13] Mn(OAc)3,[14] NaNO2 in the presence of oxalic
acid, sodium hydrogen sulfate, magnesium hydrogen sulfate and wet
SiO2,[15] [hydroxyl(tosyloxy)iodo]benzene,[16] H2O2/Co(OAc)2,[17] iodo-
benzene diacetate,[18] FeCl3.6H2O[19] and [NOþ Crown H(NO3)2 ].
2
[20]
.
.
However, some of these methods suffer from disadvantages such as using
strong or excess amounts of oxidants, low yield of products, long reaction
times, and the requirement for severe conditions. The importance of this
synthetic methodology in organic reactions and developing a mild and high
yielding protocol for the transformation of 1,4-dihydropyridines to pyridines
compounds encouraged us to become interest in this subject.
Herein, we report a mild and efficient method for the oxidative-
aromatization of 1,4-dihydropyridines to the corresponding pyridine deriva-
.
tives with KBrO3/SnCl4 5H2O system in refluxing CH3CN (Scheme 1).
Literature review showed that, recently, use of potassium bromate in the
presence of sodium bisulfite has been reported for the aromatization of 1,4-
DHPs.[21] Our experiments led us to the fact that solely KBrO3 in a variety
of solvents could not affect the transformation of 1,4-dihydropyridines to
pyridine compounds. To explore the further utility of this mild oxidizing
agent, we decided to increase the potentiality of KBrO3 toward aromatization
of 1,4-dihydropyridines in the presence of additives such as Sn(II) or Sn(IV)
halides as an activator. For optimization of the reaction conditions, we
accomplished a set of experiments with diethyl 2,6-dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate (4-substituted-1,4-DHP) (1) as a model
compound in aprotic solvents such as CH2Cl2, CH3CN, THF, C6H6, and
.
different amounts of potassium bromate in the presence of SnCl2 H2O or
.
SnCl4 5H2O. The obtained results showed that the molar ratio of substrate/
KBrO3/Sn(II or IV) (1 : 1 : 0.5) in refluxing CH3CN is the best optimal for
.
this achievement. KBrO3/SnCl2 H2O system in refluxing acetonitrile
.
showed a faster reaction rate relative to KBrO3/SnCl4 5H2O but the yield
of aromatized products were low (30–40%).
The usefulness of this procedure was examined by subjecting different
.
kinds of 4-substituted-1,4-dihydropyridines toward KBrO3/SnCl4 5H2O sys-
tem. The results summarized in Table 1 indicate the scope of the reaction
with respect to various 1,4-DHPs (1–13). As shown in Table 1, generally,
the reactions are clean, efficient, and completed within 30–100 min. The
method is mild and tolerates several substituted aryl groups on 4-position.
It was observed that oxidation of 1,4-dihydropyrine with secondary alkyl
group proceeds rapidly and gave dealkylated pyridine compound (14) in 96%
yield. This is in agreement with the observation made by other employed
oxidative conditions. 4-(2-Furyl) substituted 1,4-dihydropyridines (5,6) showed
40% aromatization with tolerance of the heterocyclic group.
In conclusion we have introduced a convenient and efficient procedure for
the transformation of 1,4-dihydropyridines to their corresponding pyridine
derivatives. In addition, availability of the reagents, high-yielding protocol

Oxidative-Aromatization of Hantzsch Ester
559

a
.
Table 1. Aromatization of 1,4-dihydropyridines with KBrO3/SnCl4 5H2O system
Refluxing CH3CN
Time (min)
Lit. Mp.
(8C)
Compound
R
R1
Product
Yield (%)b
Mp. (8C)
1
2
C6H5
C6H5
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
C2H5
CH3
C2H5
CH3
CH3
C2H5
15
16
40
100
80
90
92
63–64
135–136
59–62
103–104
40–42
Oil
62–63[6a]
135–136[23]
61–63[6a]
104–105[23]
Oil[14]
3
3-NO2C6H4
2-NO2C6H4
2-Furyl
17
18
95
92
4
100
35
5
19 1 14
20 1 14
14
40 þ 60
40 þ 60
96
6
2-Furyl
40
30
Oil[14]
7
(CH3)2CH
4-(MeO)C6H4
4-(MeO)C6H4
4-MeC6H4
4-ClC6H4
2-ClC6H4
69–70
49–50
114–115
71–72
137–138
70–71
—
69–70[6a]
50[19]
115[23]
72–73[14]
137–139[23]
69–70[23]
—
8
21
22
60
40
98
97
9
10
11
12
13
23
24
35
42
97
96
25
26
45
45
98
94
4-Hydroxyl-3-methoxyphenyl
aAll reactions have a molar ratio as substrate KBrO3/SnCl4 5H2O (1 : 1 : 0.5).
.
bYields refer to isolated pure products.

Oxidative-Aromatization of Hantzsch Ester
561
and easy work-up procedure make this method an important addition to the
present methodologies.
EXPERIMENTAL
General
All Hantzsch ester 1,4-dihydropyridines were synthesized by the reported
procedures.[22] The products were characterized by a comparison with
authentic samples (melting or boiling points) and their 1H-NMR or IR
spectra. All yields referred to isolated pure products. TLC was used for the
purity determination of substrates, products, and reaction monitoring over
silica gel PolyGram SILG/UV 254 plates. Products were purified by a
column chromatography packed with silica gel.
Aromatization of Diethyl 2,6-Dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate (1) with KBrO3/SnCl4 5H2O
System. A Typical Procedure
.
In a round-bottomed flask (10 mL) equipped with magnetic stirrer and
condenser, to a solution of 1,4-DHP (1) (0.329 g, 1 mmol) in CH3CN
.
(3 mL), KBrO3 (0.167 g, 1 mmol) and SnCl4 5H2O (0.175 g, 0.5 mmol)
were added. The resulting mixture was stirred under reflux condition for
40 min. TLC monitored the progress of reaction (eluent; CCl4/Et2O: 5/3).
At the end of reaction, distilled water (4 mL) was added to the reaction
mixture and stirred for an additional 5 min. The mixture was extracted with
CH2Cl2 (3 ꢀ 8 mL) and dried over anhydrous sodium sulfate. Evaporation
of the solvent and short column chromatography of the resulting crude
material over silica gel by eluent of CCl4/Et2O: 5/3 affords the pure
corresponding pyridine (15) (0.295 g, 90% yield, mp. 63–648C, Lit.[6a]
62–638C) (Table 1).
ACKNOWLEDGMENT
The authors gratefully acknowledge the financial support of this work by the
Research Council of Urmia University.
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