Metal-Free oxidation of urazole and 1,4-dihydropyridine derivatives under mild and heterogeneous conditions by nitro urea, derived from urea nitrate, and silica sulfuric acid

Article abstract of DOI:10.2174/157017810791112450

Mild combination of nitro urea, derived from urea nitrate, and silica sulfuric acid (SiO₂OSO₃H) might act as an efficient oxidizing media, which could be able to oxidize different types of heterocyclic compounds including urazoles and 1,4-dihydropyridines. The process presented here is operationally simple, environmentally benign, and reactions have been mildly carried out in dichloromethane at room temperature.

Full text of DOI:10.2174/157017810791112450

Letters in Organic Chemistry, 2010, 7, 249-254
249
Metal-Free Oxidation of Urazole and 1,4-Dihydropyridine Derivatives
Under Mild and Heterogeneous Conditions by Nitro Urea, Derived from
Urea Nitrate, and Silica Sulfuric Acid
Arash Ghorbani-Choghamarani*,a Mohammad A. Zolfigolb, Maryam Hajjamib, Shahrbanoo
Rastgooa and Shadpour Mallakpourc
aDepartment of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
bFaculty of Chemistry, Bu-Ali Sina University, P.O. Box 6517838683, Hamadan, Iran
cOrganic Polymer Chemistry Research Laboratory, Department of Chemistry, Isfahan University of Technology,
Isfahan, Iran
Received November 24, 2009: Revised January 14, 2010: Accepted January 15, 2010
Abstract: Mild combination of nitro urea, derived from urea nitrate, and silica sulfuric acid (SiO2OSO3H) might act as an
efficient oxidizing media, which could be able to oxidize different types of heterocyclic compounds including urazoles
and 1,4-dihydropyridines. The process presented here is operationally simple, environmentally benign, and reactions have
been mildly carried out in dichloromethane at room temperature.
Keywords: Urazole, 1,4-dihydropyridine, urea nitrate, nitro urea, silica sulfuric acid.
INTRODUCTION
products, laborious work-up, and poor yields of the target
products.
Five- and six-membered heterocyclic compounds often
play important roles in biologically active natural products
and synthetic compounds of medicines [1]. Among them,
RESULTS AND DISCUSSION
urazoles
and
1,4-dihydropyridines
have
attracted
Recently, we have reported various procedures for the
considerable attention. The oxidation of Hantzsch 1,4-
dihydropyridines (DHPs), a class of model compounds of
NADH coenzyme [2], has attracted continuing interest of
organic chemists over the years [3]. The oxidation of these
compounds to corresponding pyridines has been extensively
studied in view of the pertinence of the reaction to the
metabolism of Hantzsch esters and the calcium channel
blocking drugs used in the treatment of various
cardiovascular disorders [4]. In recent years, it was found
that drugs such as nifedipine and niguldipine undergo redox
processes due to the catalysis of cytochrome P-450 in the
liver during their metabolism [5]. Also 1,2,4-Triazole-3,5-
diones are important class of five-membered heterocyclic
compounds, which can be prepared from the oxidation of
urazole derivatives. They have been used as substrate and
reagent both in various organic transformations [6-10].
Oxidation of urazoles by different oxidants is a common way
for the preparation of triazolinediones. However, in some of
these procedures by-products are produced or the products
decompose under the reaction conditions, and/or the workup
is difficult [11]. In recent years, several reports on the
oxidation of urazoles and 1,4-dihydropyridines have been
reported [12-18]. Most of these reported procedures require
use of strong and toxic oxidants, harsh conditions, long
reaction times, necessity of excess reagent, formation of by-
+
generation of nitronium ion (NO2 ), which were applied in
different organic transformations [19-25]. In continuation of
our investigations, we decided to explore an efficient, mild,
heterogeneous and metal-free oxidizing system for the
oxidation of urazoles and dihydropyridines. In this light, we
interested to synthesize nitro urea via reaction of urea with
nitric acid to produce urea nitrate, which immediate
dehydrated to nitro urea (Scheme 1) [26,27].
-
O
OH+NO3
Neat
rt
H2N
NH2
H2N
NH2
+ HNO3 (65%)
-H2O
H2NCONHNO2.XH2O
X=1-2.5
Scheme 1.
Fig. (1) shows the mass spectrum of nitro urea, which
molecular ion peak appears at m/e= 105. Also two major
+
peaks appears at m/e= 46 (NO2 ) and m/e= 60 (urea cation).
After considering on the properties of nitro urea
(NH2CONHNO2.xH2O), we found that this reagent has
oxidizing property in the presence of an acid. Nitro urea
+
(NH2CONHNO2.xH2O) can realize nitronium ion (NO2 ) in
*Address correspondence to this author at the Department of Chemistry,
Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran;
Tel/Fax: +98 841 2227022; E-mail: arashghch58@yahoo.com
the presence of silica sulfuric acid (SiO2-OSO3H), which is
able to oxidize different types of organic compounds.
1570-1786/10 $55.00+.00
© 2010 Bentham Science Publishers Ltd.

250 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
Ghorbani-Choghamarani et al.
Fig. (1). Mass spectrum of nitro urea (NH2CONHNO2.xH2O).
O
R
O
O
O
H
R
X
X
X
X
NH2CONHNO2.xH2O
SiO2-OSO3H
H3C
N
CH3
H3C
N
H
1
CH3
CH2Cl2, rt
2
X= -OCH3 or -OCH2CH3
Br
F
Cl
O
O
O
O
O
O
O
O
H
H
H
H
MeO
H3C
OMe
CH3
MeO
OMe
CH3
MeO
H3C
OMe
CH3
MeO
H3C
OMe
CH3
N
H
H3C
N
H
N
H
N
H
a
b
c
d
CH3
CF3
OMe
NO2
MeO
O
O
O
O
O
O
O
O
H
H
H
H
MeO
H3C
OMe
CH3
MeO
H3C
OMe
CH3
MeO
H3C
OMe
CH3
MeO
OMe
CH3
N
N
H
N
H
H3C
N
H
H
e
f
g
h

Metal-Free Oxidation of Urazole
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
251
(Scheme 2). Contd…..
OMe
Cl
(CH2)5CH3
CH3
O
O
O
O
H
O
O
O
O
H
H
H
MeO
H3C
OMe
CH3
MeO
H3C
OMe
CH3
MeO
OMe
MeO
H3C
OMe
CH3
N
H
H3C
N
H
CH3
N
H
N
H
i
j
k
l
F
Br
Cl
O
O
O
O
O
O
O
O
H
H
H
H
EtO
H3C
OEt
CH3
EtO
OEt
CH3
EtO
H3C
OEt
CH3
EtO
H3C
OEt
CH3
N
H
H3C
N
H
N
H
N
H
m
n
o
p
OMe
OMe
MeO
O
CH3
O
O
O
O
O
H
H
H
EtO
H3C
OEt
CH3
EtO
OEt
CH3
EtO
H3C
OEt
CH3
N
H
H3C
N
H
N
H
q
r
s
Scheme 2.
Table 1. Oxidation of 1,4-Dihydropyridines 1 to the Corresponding Pyridines 2 Using Nitro Urea I and Silica Sulfuric Acid II in
Dichloromethane at Room Temperature
Substrate/Reagentsa
Entry
Substrate
Product
Time (Min)
Yield (%)b
I
II
1
2
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
0.56
0.56
0.64
0.56
0.56
0.56
1.46
0.56
0.56
0.56
0.56
0.56
0.56
0.7
0.7
0.8
0.7
0.7
0.7
1.82
0.7
0.7
0.7
0.7
0.7
0.7
45
35
96
91
98
99
95
92
94
98
97
90
99
84
99
3
20
4
55
5
30
6
30
7
1g
1h
1i
2g
2h
2i
10
8
180
6 h
130
200
130
240
9
10
11
12
13
1j
2j
1k
1l
2k
2l
1m
2m

252 Letters in Organic Chemistry, 2010, Vol. 7, No. 3
Ghorbani-Choghamarani et al.
(Table 1). Contd…..
Substrate/Reagentsa
Entry
Substrate
Product
Time (Min)
Yield (%)b
I
II
14
15
16
17
18
19
1n
1o
1p
1q
1r
1s
2n
2o
2p
2q
2r
2s
0.96
0.96
0.96
0.56
0.56
0.56
1.2
1.2
1.2
0.7
0.7
0.7
15
94
99
99
99
99
93
180
240
120
180
220
aI and II refer to grams of nitro urea and silica sulfuric acid, respectively. bIsolated yield.
Consequently herein we disclosed a new oxidative
protocol for the conversion of Hantzsch 1,4-
dihydropyridines 1 to the corresponding pyridines 2 using
nitro urea (NH2CONHNO2.xH2O) I, and silica sulfuric acid
(SiO2-OSO3H) II in dichloromethane, as solvents, at room
temperature (Scheme 2 and Table 1).
Oxidation of urazoles has been heterogeneously
performed under mild conditions. All reaction components
except pink-to-red color triazolinedione are insoluble in the
reaction solvent. Therefore, 4-substituted-1,2,4-triazole-3,5-
diones were obtained easily by mixing of urazole, nitro urea
and a catalytic amount of silica sulfuric acid; then stirring of
this mixture at room temperature. Pure products can be
easily isolated from the reaction media by washing the
reaction mixture with dichloromethane, simple filtration and
evaporation of the solvent. The results of Table 2 show that
the oxidation of urazoles by nitro urea needs only a catalytic
amount of acid. Also reasonable turn over frequency (TOF)
of catalyst was observed.
Oxidation of 1,4-dihydropyridines was carried out
heterogeneously under mild conditions. Oxidation reaction
was easily performed by mixing 1 mmol of dihydropyridine,
and appropriate amounts of nitro urea and silica sulfuric
acid, then stirr the resulting mixture at room temperature.
After reaction completion, pure product can easily be
obtained by simple filtration and evaporation of the solvent.
In conclusion, in this research project, an effective and
new oxidizing media has been introduced for the oxidation
of urazoles and Hantzsch 1,4-dihydropyridines under
heterogeneous conditions. Furthermore, this method exhibits
Also different types of 4-substituted urazoles 3 were
converted to the 4-substituted-1,2,4-triazole-3,5-diones 4 by
the same reagents and conditions (Scheme 3 and Table 2).
R1
H
N
N
NH2CONHNO2.xH2O
SiO2-OSO3H
N
N
O
O
O
O
N
N
CH2Cl2, rt
R2
R2
4
3
H
H
H
H
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
N
N
N
N
N
Cl
OMe
Cl
Cl
a
b
c
d
e
H
H
H
H
H
H
H
H
N
N
N
N
N
N
N
N
N
O
O
O
O
O
O
O
O
N
N
N
C(CH3)3
CH2CH2CH2CH3
CH2CH3
f
g
h
i
NO2
Scheme 3.

Metal-Free Oxidation of Urazole
Letters in Organic Chemistry, 2010, Vol. 7, No. 3
253
Table 2. Oxidation of Urazoles to the Corresponding Triazolinediones Using Nitro Urea I and Catalytic Amounts of Silica Sulfuric
Acid II in Dichloromethane at Room Temperaturea
Entry
Substrate
Product
Time (Min)
Yield (%)b
TOF (min-1)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
60
105
105
150
180
90
95
99
97
91
95
98
99
99
90
12.0
7.1
7.0
4.6
4.0
8.2
7.1
5.0
1.1
3g
3h
3i
4g
4h
4i
105
150
10.5 h
aMolar ratio of reaction components: urazole/nitro urea/silica sulfuric acid for entries 1-8: (1 mmol/0.32 g /0.05 g); for entry 9: (1 mmol/0.48 g /0.05 g). bIsolated yields.
substrate versatility, non-toxic conditions and mild reaction
conditions, and easy and clean work-up of products.
Oxidation of 4-phenylurazole 3a to 4-phenyl-1,2,4-
triazoline-3,5-dione 4a with Nitro Urea and Catalytic
Amounts of Silica Sulfuric Acid
A suspension of 4-phenylurazole 3a (0.177 g, 1 mmol),
NH2CONHNO2.xH2O (0.32 g) and SiO2-OSO3H (0.05 g) in
dichloromethane (10 mL) was stirred at room temperature
for 60 min and then filtered. Anhydrous Na2SO4 (3 g) was
added to the filtrate and filtered off after 20 min. The residue
was washed with CH2Cl2 (20 mL). Finally CH2Cl2 was
removed and 4-phenyl-1,2,4-triazoline-3,5-dione 4a was
obtained in 95% yield (0.166 g) as red crystalline solid. Mp
EXPERIMENTAL
Chemicals were purchased from Fluka, Merck and
Aldrich chemical companies. The oxidation products were
1
characterized by comparison of their spectral (IR, H NMR,
and 13C NMR) and physical data with authentic samples.
Preparation of Nitro Urea (NH2CONHNO2.xH2O)
1
172-174 ºC (Lit. [28] mp 168-175 ºC); H NMR (90 MHz,
CDCl3): ꢀ = 7.49 (s) ppm; 13C NMR (22.5 MHz, CDCl3): ꢀ =
In a 50-mL round-bottomed flask, 4 mL of HNO3 (65%)
and 3.46 g of urea was stirred for 2 hours, and a white
crystalline solid (NH2CONHNO2.xH2O) was obtained
quantitatively. M.p. 156-158.4 °C (Ref. [27] 157-159°C);
MS (70 eV): m/z = 105 (M+), 91, 69, 63, 60, 46 (base peak,
158.0 (C=O), 129.9, 129.8, 129.0, 124.3 ppm.
Caution
Urea nitrate and nitro urea are both potential explosives
and must be handled with care, similarly to ammonium
nitrate (The Health and Safety at Work Act 1974, Chapter
37, HMSO ISBN 0 10 543774 3).
+
NO2 ), 44.
Aromatization of Dimethyl 4-(4-trifluoromethylphenyl)-
2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate with
Nitro Urea and Silica Sulfuric Acid
ACKNOWLEDGEMENT
To a solution of compound 1g (0.369 g, 1.0 mmol) in
CH2Cl2 (10 mL), NH2CONHNO2.xH2O (1.46 g) and SiO2-
OSO3H (1.82 g) were added. Reaction mixture was stirred at
room temperature for 10 min (the reaction progress was
monitored by TLC) and then filtered. Anhydrous Na2SO4 (3
g) was added to the filtrate and filtered off after 20 min. The
residue was washed with CH2Cl2 (4ꢀ5 mL). Finally solvent
was removed and product 2g was obtained in 94 % yield
(0.345 g). Pale yellow solid; mp 75-76 ºC; 1H NMR (400
MHz, CDCl3): ꢀ = 7.67-7.65 (d, 2H, J= 8 Hz), 7.39-7.37 (d,
2H, J= 8 Hz), 3.55 (s, 6H), 2.62 (s, 6H) ppm; 13C NMR (100
MHz, CDCl3): ꢀ = 167.9, 156.0, 144.8, 140.2, 131.2-130.2
(q, 1JC-F, 128 Hz), 128.4, 126.4, 125.2-125.0 (q, 1JC-F, 12 Hz),
122.5, 25.3, 23.03 ppm; MS (70 eV): m/z = 369 (M+), 354,
338, 310, 294, 278, 264, 250, 224 (base peak), 209, 192,
164,149, 132,106, 91, 77, 59, 42.
The authors acknowledge Ilam University, Ilam, Iran,
Bu-Ali Sina University Research Council (Grant Number
32-1716), Center of Excellence in Development of Chemical
Methods (CEDCM), and National Foundation of Elites
(BMN), for financial support of this work.
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