Aromatization of Hantzsch ester 1,4-dihydropyridines with iodine under normal conditions and ultrasound irradiation

Article abstract of DOI:10.1002/jccs.200500139

A variety of Hantzschester 1,4-dihydropyridines are efficiently oxidized to their corresponding pyridine compounds with iodine under normal conditions and ultra sound irradiation. There actions were carried out in refluxing CH ₃CN.

Full text of DOI:10.1002/jccs.200500139

Journal of the Chinese Chemical Society, 2005, 52, 1001-1004
1001
Aromatization of Hantzsch Ester 1,4-Dihydropyridines with Iodine under
Normal Conditions and Ultrasound Irradiation
Behzad Zeynizadeh,* Karim Akbari Dilmaghani and Asli Roozijoy
Department of Chemistry, Faculty of Sciences, Urmia University, Urmia 57159-165, Iran
A variety of Hantzsch ester 1,4-dihydropyridines are efficiently oxidized to their corresponding pyridine
compounds with iodine under normal conditions and ultrasound irradiation. The reactions were carried out in
refluxing CH3CN.
Keywords: Aromatization; Hantzsch 1,4-dihydropyridines; Iodine; Ultrasound.
INTRODUCTION
Hantzsch ester 1,4-dihydropyridines (1,4-DHPs) as im-
ence of oxalic acid, sodium hydrogen sulfate, magnesium hy-
drogen sulfate or wet SiO2.25
Some of reported methods suffer from limitations in-
cluding low yield of products, the use of excess or strong oxi-
dants, long reaction times, and the requirement for severe
conditions. Therefore, the aromatization of Hantzsch ester
1,4-dihydropyridines still requires a need to develop a mild
and high yielding protocol.
portant calcium channel blockers have been widely utilized
for the treatment of hypertension and angina pectoris.1 These
compounds are oxidatively aromatized to their correspond-
ing pyridine derivatives initially during the metabolism by
the action of cytochrome P-450 in the liver.2 Due to the rele-
vance of this oxidative conversion to the biological NADH
redox process, and that metabolic studies require reference
standards, this transformation has attracted a great deal of at-
tention.1a,3 Furthermore, the aromatization of 1,4-DHPs pro-
vides an easy access to their pyridine compounds. Therefore,
a wide variety of reagents have been developed for this oxida-
tive conversion, e.g., KMnO4,4 CrO3,5 HNO3, HNO3/benton-
ite/microwave,1b,6 MnO2, MnO2/bentonite,7 DDQ,7a PCC,8
CAN,9 Bi(NO3)3.5H2O,10 BaMnO4,11 K2S2O8,12 RuCl3,13
clayfen,14 diphenylpicrylhydrazyl and benzoylperoxide,15
PhI(O2CCF3)2 or sulfur,16 microwave under solid phase con-
dition,17 silica supported Cu(NO3)2 orFe(NO3)3,14,18 nitric ox-
ide,19 tert-butylhydroperoxide,20 Mn(OAc)3,21 tetra-kispyr-
idine cobalt(II) dichromate,22 3-carboxypyridinium chloro-
chromate,23 nicotinium dichromate,24 and NaNO2 in the pres-
On the other hand, the acceleration of reactions with ul-
trasound as an interesting and modern synthetic strategy has
been widely used in organic chemistry and numerous papers
have demonstrated its importance.26 Sonic conditions not
only accelerate the chemical reactions but also reduces the
number of steps which are required by using conventional re-
agents under normal conditions; in addition, the reactions can
be initiated without any additives. In this context, ultra-
sound-assisted aromatization of 1,4-dihydropyridines by us-
ing clay supported cupric nitrate has also been reported.27
Herein, we report an efficient and improved method for
the aromatization of 1,4-dihydropyridines to the correspond-
ing pyridine compounds by using readily available and inex-
pensive iodine in the presence (a) and absence (b) of ultra-
sound irradiation in refluxing CH3CN (Scheme I).
Scheme I
* Corresponding author. E-mail: b.zeynizadeh@mail.urmia.ac.ir

1002 J. Chin. Chem. Soc., Vol. 52, No. 5, 2005
Zeynizadeh et al.
RESULTS AND DISCUSSION
efficient, and completed within 1-7 hrs. The method is mild
and tolerates several substituted aryl groups on the 4-position
of 1,4-DHPs. It was observed that oxidation of 1,4-dihydro-
pyridine with a secondary alkyl group proceeded rapidly and
gave dealkylated pyridine compound 14 in excellent yield.
Substituted 2-furyl moiety on the 4-position of 1,4-DHPs (5,
6) showed a complete aromatization; however, the corre-
sponding pyridine compounds including 2-furyl group were
obtained in 60-65% yields.
Literature review shows that the aromatization of
Hantzsch ester 1,4-dihydropyridines by using molecular io-
dine in the presence of an alkali or organic base in methanol
has been reported recently.28 Though the I2-base system in
MeOH is efficient for the aromatization of 1,4-DHPs, this
method suffers from relatively long reaction times and basic
conditions. Therefore, the biological importance of 1,4-dihy-
dropyridines oxidation and our ongoing attention to the devel-
opment of ultrasound-assisted organic reactions,29 prompted
us to reinvestigate the aromatization of 1,4-DHPs by molecu-
lar iodine in the presence and absence of ultrasound irradia-
tion under an aprotic solvent system and neutral conditions.
At first, we investigated the optimum conditions for the
In the next attempt, we decided to investigate the influ-
ence of sonic conditions on the aromatization of 1,4-DHPs.
We saw that the irradiation of compound 1 with ultrasound by
using 2 molar equivalents of iodine in acetonitrile showed a
little influence at room temperature. Whereas, when this re-
action was irradiated with ultrasound in refluxing CH3CN,
the rate of reaction was increased dramatically and it was
completed in 15 minutes. The irradiation was carried out with
30% power amplitude of sonicator (600 W) via a micro-tip
probe.
oxidative-aromatization of diethyl 2,6-dimethyl-4-phenyl-
1,4-dihydropyridine-3,5-dicarboxylate (4-substituted 1,4-
DHP) (1) as a model compound with iodine in aprotic sol-
vents such as CH2Cl2, CH3CN, THF, and C6H6 under normal
conditions. We performed a set of experiments and found that
using 2 molar equivalents of iodine and simply refluxing in
CH3CN are optimal for the complete aromatization of the
1,4-DHP (5 h, 96%). Then we applied these conditions for the
aromatization of different 4-substituted alkyl and aryl 1,4-
dihydropyridines. The reactions were performed with good
to excellent yields of the corresponding pyridine compounds
(60-97%). The results of these transformations are summa-
rized in Table 1, which indicates the scope of our protocol to
various 1,4-DHPs (1-13). Generally, the reactions were clean,
To show the further utility of sonic conditions, we aro-
matized different 4-substituted alkyl, aryl, and heteroaryl
1,4-dihydropyridines with 2 molar equivalents of iodine in
the presence of ultrasound in refluxing CH3CN. The reactions
were carried out in short reaction times, and the correspond-
ing pyridine compounds were obtained in high to excellent
yields (70-98%) (Table 1).
Investigation of the results showed that this system tol-
erated all substituted aryl groups on 1,4-dihydropyridines.
Under sonic conditions, dihydropyridine 7 with isopropyl
Table 1. Oxidative aromatization of 1,4-dihydropyridines with iodine under normal conditions and ultrasound irradiationa
Normal Conditions
Product Time (h) Yield (%)b Product Time (min) Yield (%)b
US Irradiation
Compound
R
R1
Mp. (°C) Lit. Mp. (°C)
1
2
3
4
5
6
7
8
C6H5
C6H5
3-NO2C6H4
2-NO2C6H4
2-Furyl
C2H5
CH3
C2H5
CH3
C2H5
CH3
CH3
C2H5
CH3
C2H5
CH3
CH3
C2H5
15
16
17
5
6
7
4
5
5.5
1
3
4
4
96
94
95
15
16
17
15
20
30
40
10
15
5
40
45
30
35
25
20
98
96
95
63-64
135-136
59-62
103-104
40-42
Oil
69-70
49-50
114-115
71-72
137-138
70-71
-
62-637a
135-13631a
61-637a
104-10531a
Oil21
18
91
18
94
19+14
20+14
14
21
22
23
24
25
26
60+40
65+35
96
93
93
95
95
94
97
19+14
20+14
14
21
22
23
24
25
26
70+30
70+30
98
94
94
97
96
94
98
2-Furyl
(CH3)2CH
Oil21
69-707a
5031b
4-(MeO)C6H4
4-(MeO)C6H4
4-MeC6H4
4-MeC6H4
2-ClC6H4
9
11531a
10
11
12
13
72-7321
137-13931a
69-7031a
-
4
4
1
4-Hydroxy-3-
methoxyphenyl
a All reactions were performed with 2 molar equivalents of iodine in refluxing CH3CN.
b Yields refer to isolated pure products.

Aromatization of 1,4-Dihydropyridines with Iodine
J. Chin. Chem. Soc., Vol. 52, No. 5, 2005 1003
group also showed a complete dealkylation reaction. In addi-
tion, the aromatization of 4-(2-furyl)-1,4-DHPs (5, 6) under
sonic conditions produced the corresponding pyridine com-
pounds in 70% yield including 2-furyl moiety. Comparison
of the results shows that though the behavior of the oxidation
reaction is almost the same in both systems; however, per-
forming the reactions under sonic conditions gives faster re-
action rates and better efficiency than those under conven-
tional conditions.
tored by TLC (eluent; CCl4/Et2O: 5/3). At the end of reaction,
a solution of sodium thiosulfate (2%, 5 mL) was added to the
reaction mixture, and it was stirred for an additional 10 min.
The mixture was extracted with CH2Cl2 (3 ´ 10 mL) and dried
over anhydrous sodium sulfate. Evaporation of the solvent
and short column chromatography of the resulting crude ma-
terial over silica gel (eluent; CCl4/Et2O: 5/3) afforded the
pure pyridine compound (15) (0.321 g, 98% yield, Table 1).
ACKNOWLEDGEMENTS
CONCLUSION
We are thankful to the Research Council of Urmia Uni-
versity for the partial support of this work.
We have shown that iodine as an inexpensive and readily
available reagent can efficiently oxidize varieties of 1,4-di-
hydropyridines to their corresponding pyridine compounds
in the presence or absence of ultrasound irradiation in re-
fluxing acetonitrile under neutral conditions. Sonic condi-
tions not only accelerated dramatically the rate of reactions
but also showed a better efficiency than normal conditions.
The cheapness and availability of the oxidant and shorter re-
action times are the advantages that could make this method
an alternative or useful addition to the present methodolo-
gies.
Received December 20, 2004.
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