NaI readily mediated oxidative aromatization of hantzsch 1,4-dihydropyridines with hydrogen peroxide at room temperature: A green procedure

Article abstract of DOI:10.1007/BF03246562

The oxidative conversion of 1,4-dihydropyridines to give the corresponding pyridine derivatives in excellent yields was easily effected using the catalytic amount of NaI in combination with H₂O₂ (30%) as a green external oxidant. The

Full text of DOI:10.1007/BF03246562

J. Iran. Chem. Soc., Vol. 8, No. 4, December 2011, pp. 1052-1057.
JOURIrNaAnLiaOnF THE
Chemical Society
NaI Readily Mediated Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines with
Hydrogen Peroxide at Room Temperature: A Green Procedure
D. Shahabi, M.A. Amrollahi* and A.A. Jafari
Department of Chemistry, Faculty of Science, Yazd University, Yazd 89195-741, Iran
(Received 6 February 2011, Accepted 23 May 2011)
The oxidative conversion of 1,4-dihydropyridines to give the corresponding pyridine derivatives in excellent yields was easily
effected using the catalytic amount of NaI in combination with H2O2 (30%) as a green external oxidant. The process is highly
green wherein the solid products are easily filtered out after the addition of ice-water to the reaction mixture. This non-transition
metal catalyst is cost-effective, affords simple work-up and easy separation of the product.
Keywords: 1,4-Dihydropyridines, Aromatization, H2O2, NaI, Oxidation
INTRODUCTION
and the reaction conditions. Most of the reported reagents
produce by-products which are difficult to separate from the
products. Therefore, the development of an efficient, cost-
effective and green method for the aromatization of 1,4-DHPs
under milder conditions is still desirable. The hydrogen
peroxide was selected as the oxidant over other available
oxidizing agents and sodium iodide was chosen as the catalyst
since they were cheap, operationally safe, environmentally
friendly, and easy to handle and work-up.
1,4-Dihydropyridin (1,4-DHPs) derivatives containing the
1,4-dihydropyridine structure include calcium antagonists [1],
antitubercular agents [2], antitumours [3], bronchodilatings
[4], antidiabetics [5], antivirals [6], antianginals [7] and
neuropeptide Y Y1 receptor antagonists [8]. The oxidative
aromatization of 1,4-DHPs to the corresponding pyridine
derivatives entails the principal metabolic route in particular in
biologically significant NADH redox processes [9], as well as
a facile access to the corresponding pyridine derivatives which
show anti-hypoxic and anti-ischemic activities [10] from the
easily available 1,4-DHPs [11].
Consequently, this aromatization reaction continues to
attract the attention of many organic and medicinal chemists
for the discovery of a plethora of protocols applicable to a
wide range of 1,4-DHPs [12]. Although a variety of reagents
are capable of effecting these oxidations, the transformation is
not always easy to effectand may even be problematic if the
substrate has functional groups sensitive to the oxidizing agent
EXPERIMENTAL
All the chemicals were purchased from Merck Company.
4-Substituted Hantzsch 1,4-dihydropyridines were prepared
using the appropriate aldehyde, ammonium carbonate and
ethyl acetoacetate as reported earlier [19]. All products were
known compounds and their physical and spectroscopic data
were compared with those of authentic samples. Melting
points were measured in capillary tubes using Buchi 545
instrument and are uncorrected. IR spectra were recorded as
KBr pellets on Brucker Spectrum FT-IR. NMR spectra were
obtained using an 11.7 T vertical bore spectrometer (1H 500
*Corresponding author. E-mail: mamrollahi@yazduni.ac.ir

Shahabi et al.
MHz; 13C 125 MHz; 19F 470 MHz). 1H and 13C chemical shifts
(470 MHz, CDCl3) δ -113.1 ppm.
are referenced to TMS as an internal standard, 19F to a dilute
solution of trifluoroacetic acid (TFA) in capillary column as
an external reference.
Diethyl-2,6-dimethyl-4-(4-fluorophenyl)-pyridine-3,5-
dicarboxylate (Table 2, entry 4). Oxidative aromatization of
diethyl-2,6-dimethyl-4-(4-fluorophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (1 mmol, 0.35 g) with H2O2 30% (2.2 mmol,
025 ml), acetic acid (3 ml) and NaI (0.05 mmol, 0.008 g), then
work up as described above gave diethyl 2,6-dimethyl-4-(4-
fluorophenyl)-pyridine-3,5-dicarboxylate as a white solid.
Yield 85%, m.p.: 88-89 °C; FT-IR: υmax (KBr): 2988, 1714,
The procedure for the oxidative aromatization of Hantzsch
1,4-dihydropyridines, and physical and spectral data for some
selected synthesized pyridine derivatives are given below. The
1
identities of the products were confirmed by mp, IR, H, 13C
and 19F NMR spectral data.
1
Diethyl-2,6-dimethyl-4-(2-fluorophenyl)-pyridine-3,5-
dicarboxylate (Table 2, entry 2). To a mixture of Hantzsch
1,4-dihydropyridine (1 mmol), H2O2 30% (2.2 mmol, 0.25 ml)
and acetic acid (3 ml), NaI (0.05 mmol, 0.008 g) was added
and stirred at room temperature for the appropriate reaction
time indicated in Table 2. After ascertaining the completion of
the reaction by TLC, the product was precipitated by addition
of ice-water to reaction mixture. The pure corresponding
1558 cm-1; H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.1 Hz,
6H), 2.62 (s, 6H), 4.06 (q, J = 7.1 Hz, 4H), 7.09 (t, J = 8.6 Hz,
2Harom), 7.26-7.28 (m, 2Harom) ppm; 13C NMR (125 MHz,
CDCl3) δ 14.1, 23.3, 61.8, 115.6 (2JC-F = 21.1 Hz), 127.4,
130.5 (3JC-F = 8.1 Hz), 132.8 (4JC-F = 3.4 Hz), 145.3, 155.9,
163.2 (1JC-F = 247 Hz), 168.1 ppm; 19F NMR (470 MHz,
CDCl3) δ -113.3 ppm.
Diethyl-2,6-dimethyl-4-(3-pyridyl)-pyridine-3,5-di-
carboxylate (Table 2, entry 7). Oxidative aromatization of
diethyl-2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine-3,5-di-
carboxylate (1 mmol, 0.33 g) with H2O2 30% (2.2 mmol, 025
ml), acetic acid (3 ml) and NaI (0.05 mmol, 0.008 g), then
work up as described above gave diethyl 2,6-dimethyl-4-(3-
pyridyl)-pyridine-3,5-dicarboxylate as pale yellow solid. Yield
95%, m.p.: 78-81 °C; FT-IR: υmax (KBr): 2985, 1717, 1558
pyridines were collected with
a simple filtration and
consequently washing with cold water. The crud product was
recrystallized in ethanol to give the pure product as a pale
yellow solid. Yield 85%; m.p.: 45-47 °C; FT-IR: υmax (KBr):
2982, 1722, 1557 cm-1; 1H NMR (500 MHz, CDCl3) δ 1.00 (t,
J = 7.1 Hz, 6H), 2.65 (s, 6H), 4.04 (q, J = 7.1 Hz, 4H), 7.11 (t,
J = 8.6 Hz, 1Harom), 7.14-7.21 (m, 2Harom), 7.36-7.40 (m,
1Harom) ppm; 13C NMR (125 MHz, CDCl3) δ 14.0, 23.6, 61.7,
1
cm-1; H NMR (500 MHz, CDCl3) δ 1.00 (t, J = 7.1 Hz, 6H),
115.6 (2JC-F = 21.2 Hz), 124.1 (3JC-F = 3.6 Hz), 124.8 (2JC-F
=
2.65 (s, 6H), 4.07 (q, J = 7.1 Hz, 4H), 7.34-7.37 (m, 1Harom),
7.63-7.65 (m, 1Harom), 8.54 (d, J = 1.8 Hz, 1Harom), 8.66 (dd,
J1 = 4.9 Hz, J2 = 1.6 Hz, 1Harom) ppm; 13C NMR (125 MHz,
CDCl3) δ 14.1, 23.5, 62.0, 123.2, 127.3, 133.0, 136.3, 143.0,
149.0, 150.0,156.4, 167.7 ppm.
16.7 Hz), 127.5, 130.8 (3JC-F = 7.9 Hz), 131.0 (4JC-F = 2.6 Hz),
141.4, 156.6, 159.7 (1JC-F = 246.4 Hz), 167.6 ppm; 19F NMR
(470 MHz, CDCl3) δ -114.2 ppm.
Diethyl-2,6-dimethyl-4-(3-fluorophenyl)-pyridine-3,5-
dicarboxylate (Table 2, entry 3). Oxidative aromatization of
diethyl-2,6-dimethyl-4-(3-fluorophenyl)-1,4-dihydropyridine-
3,5-dicarboxylate (1 mmol, 0.35 g) with H2O2 30% (2.2 mmol,
025 ml), acetic acid (3 ml) and NaI (0.05 mmol, 0.008 g), then
work up as described above gave diethyl 2,6-dimethyl-4-(3-
fluorophenyl)-pyridine-3,5-dicarboxylate as a pale yellow
solid. Yield 80%, m.p.: 58-60 °C; FT-IR: υmax (KBr): 2995,
RESULTS AND DISCUSSION
Hydrogen peroxide has been used for the oxidation of a
variety of substrates [13] and is generally considered to be a
green oxidant because it is relatively non-toxic and breaks
down in the environment to non-toxic by-products. Literature
survey shows that only a limited number of catalytic methods
employing H2O2 and its supports for the oxidation of 1,4-
DHPs have been developed such as Co(OAc)2/H2O2 [14a],
maleic anhydride/urea-H2O2 [14b] and I2/urea-H2O2 [14c].
As part of our recent studies directed towards the
development of a practical, safe and environmentally friendly
1
1719, 1560 cm-1; H NMR (500 MHz, CDCl3) δ 1.00 (t, J =
7.2 Hz, 6H), 2.62 (s, 6H), 4.06 (q, J = 7.2 Hz, 4H), 7.00-7.10
(m, 3Harom), 7.35-7.36 (m, 1Harom) ppm; 13C NMR (125 MHz,
CDCl3) δ 14.2, 23.8, 62.0, 115.8 (2JC-F = 18.4 Hz), 124.4,
125.1, 127.9, 130.1 (3JC-F = 7.5 Hz), 131.2 (4JC-F = 3.2 Hz),
141.5, 156.7, 159.9 (1JC-F = 247 Hz), 168.3 ppm; 19F NMR
1053

NaI Readily Mediated Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines
procedure for some important transformations [15,16], we
product after a prolonged reaction time (Table 1, entry 1). In
order to show the merit of the presented protocol in
comparison with the other catalysts used for similar reactions,
we have presented the results in Table 1 (entries 11-13). As
can be seen, our method is simpler, more efficient, and uses no
toxic solvents in the reaction media and/or work-up.
According to the obtained results, the catalytic role of NaI in
the oxidation of DHPs can be explained as follows (Fig. 1).
I-, as a soft nucleophile, attacked soft oxy-electrophile
group in HO-OH to in-situ production of I-OH. A softer N-
group in DHPs molecule attacked I-OH that was
thermodynamically an unstable and reactive molecule. HI was
eliminated from N-iodo intermediate to produce pyridine
derivatives. The pure solid product was simply filtered out
after addition of ice-water to the reaction mixture.
wish to report an efficient, convenient and green procedure for
the oxidative aromatization of 1,4-DHPs by H2O2 30% in the
presence of catalytic amount of sodium iodide (NaI).
Based on our initial optimization studies and adopting a
more efficient way to minimize the time, the amount of the
catalyst and oxidant, diethyl 2,6-dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate was chosen as the model
substrate. A mixture of diethyl 2,6-dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate (1 mmol) and aqueous
hydrogen peroxide (30%) in acetic acid was stirred in the
presence of some catalysts at room temperature (Table 1). We
observed a drastic rate enhancement when we used NaI as the
co-oxidant catalyst (Table 1, entry 6) to produce the desired
pyridine in 98% isolated yield after a short reaction time (~5
min). Then, the amount of NaI and hydrogen peroxide was
optimized and 2.2 mmol of H2O2 (0.25 ml) and 5 mol% of NaI
were chosen as the optimized reaction conditions (Table 1,
entries 6-10).
The general applicability of this method was further
evaluated for structurally diverse DHPs under optimized
reaction conditions (Table 2). The results presented in Table 2
indicate the generality of the method and the high efficacy of
this new oxidation system. The reaction was completed
The reactions in the absence of catalysts did not yield any
Table 1. Optimization of Reaction Conditionsa
Ph
Ph
H
EtO2C
CO2Et
EtO2C
CO2Et
Oxidant, Cat. r.t.
CH3CO2H
N
H
N
Entry
Oxidant
Cat (Mol-%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (4 ml, 35 mmol)
H2O2 30% (0.5 ml, 4.4 mmol)
H2O2 30% (0.25 ml, 2.2 mmol)
H2O2 30% (0.25 ml, 2 mmol)
Urea-H2O2
-
CeCl3.7H2O (5)
I2 (5)
24
24
10
24
10
0.08
0.5
1
0.25
0.5
0.5
-
0
60
98
0
75
98
95
96
95
KBr (5)
NBS (5)
NaI (5)
NaI (2.5)
NaI (1)
9
NaI (5)
NaI (5)
Co(OAc)2 (100)
Maleic anhydride
I2 (20)
10
11
12
13
98
97 [14a]
84 [14b]
89 [14c]
Urea-H2O2
12
aReaction conditions: 1,4-DHPs (1 mmol), acetic acid (3 ml), room temperature.
1054

Shahabi et al.
Fig. 1. Catalytic cycle of 1,4-DHPs oxidation mediated by I-OH.
Table 2. Oxidation of 1,4-DHPs with H2O2 in the Presence of Catalytic Amount of NaI at Room Temperaturea
Entry
R
Time (min)
Yield (%)b
m.p. (°C) (Found)Lit.
1
2
3
4
5
6
7
8
C6H5
30
25
25
25
20
30
30
20
30
15
3 h
20
30
30
25
30
98
85
80
85
88
94
95
97
96
96
87
95
90
92
90
98
63-65 (62-64)11m
2-F-C6H4
3-F-C6H4
4-F-C6H4
4-CF3-C6H4
2-Pyridyl
3-Pyridyl
4-Pyridyl
3-O2N-C6H4
4-O2N-C6H4
3-HO-C6H4
4-MeO-C6H4
2-Cl-C6H4
4-Cl-C6H4
2-Furyl
45-47
58-60
88-89 (88-90)11r
56-57
90-92
78-81
100-102
9
60-62 (61-62)11m
112-114 (115)11m
151-153
10
11
12
13
14
15
16
56-58 (57-59)11m
61-63 (61-62)11s
66-68 (65-67)11s
37-39 (38-41)11r
71-73 (72-73)11m
4-CH3-C6H4
aReaction conditions: 1,4-DHPs (1 mmol), acetic acid (3 ml), H2O2 (2.2 mmol), Na I (0.05 mmol), room
temperature. bYields refer to isolated pure products which are characterized by comparison of their mp, IR,
1H, 13C and 19F NMR spectra with those of authentic samples.
1055

NaI Readily Mediated Oxidative Aromatization of Hantzsch 1,4-Dihydropyridines
between 20-30 min in excellent yields, except for the
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compound containing a hydroxyl group in substituent on the
aromatic ring, which was oxidized within 3 h in good yields
(Table 2, entry 11).
CONCLUSIONS
Sodium iodide acted as an efficient catalyst for the
aromatization of 1,4-DHPs employing the hydrogen peroxide
adduct as an environmentally benign oxidant. The reaction
proceeded smoothly at room temperature in acetic acid. The
products of high purity were isolated after a simple work-up
procedure in good to high yields.
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ACKNOWLEDGMENTS
The partial support of this work by the Research Council
of Yazd University is gratefully acknowledged.
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