Microwave-promoted oxidation of 1,3,5-trisubstituted 4,5-dihydro-1H- pyrazoles by in-situ generation of NO+ and NO2+ respectively from sodium nitrite and sodium nitrate in acetic acid

Article abstract of DOI:10.1002/jhet.5570450241

(Chemical Equation Presented) Microwave-assisted aromatization of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles by in-situ generation of NO ⁺ and NO₂⁺ respectively from sodium nitrite and sodium nitrate in acetic acid has

Full text of DOI:10.1002/jhet.5570450241

Mar-Apr 2008
Microwave-Promoted Oxidation of 1,3,5-Trisubstituted 4,5-
563
+
+
Dihydro-1H-pyrazoles by In-Situ generation of NO and NO
2
respectively from Sodium Nitrite and Sodium Nitrate in Acetic Acid
*
Davood Azarifar, Behrooz Maleki, and Mahta Sahraei
Faculty of Chemistry, Bu-Ali Sina University, Postal Code 65178, Hamadan, Iran. *Corresponding Author;
E-mail: azarifar@basu.ac.ir
Received September 7, 2007
R1
R2
R1
R2
AcOH/ NaNO or NaNO / rt
2 3
or
AcOH/ NaNO2 or NaNO / MW
N
N
N
N
3
Ph
Ph
1a-j
2a-j
Microwave-assisted aromatization of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles by in-situ generation
+
+
of NO and NO2 respectively from sodium nitrite and sodium nitrate in acetic acid has been carried out
efficiently under mild reaction conditions in good to excellent yields.
J. Heterocyclic Chem., 45, 563 (2008).
INTRODUCTION
accessible reagents for the oxidative aromatization of 2-
pyrazolines to 2-pyrazoles including 1,3-dibromo-5,5-
dimethylhydantoin (DBH) [19], N-bromosulphonamides
Application of microwave irradiation as a non-
conventional energy source has found considerable
interest in organic reactions including heterocyclic
chemistry [1]. This has been substantiated by the
appearance of many research publications and reviews in
the literature during the last few decades [2]. The
advantages of microwave irradiation over the classical
thermal conditions probably stems from its simplicity in
handling, increased reaction rates, and improved yields
that render it a versatile technique in organic synthesis
[
20], silica-supported N-bromosuccinimide [21], tri-
chloroisocyanuric acid [22], calcium hypochlorite [23],
bismuth nitrate pentahydrate [24], and 4-(p-chloro-
phenyl)-1,3,4-triazole-3,5-dione [25].
In continuation of our studies in this regard, and also in
light of our knowledge about sodium nitrite and
successfully utilized in various organic reactions [26], we
decided to examine a simple, cheap and efficient method
for the conversion of a number of 1,3,5-trisubstituted 4,5-
dihydro-1H-pyrazoles into the corresponding pyrazoles by
[
3]. Oxidative aromatization of 1,3,5-trisubstituted 4,5-di-
hydro-1H-pyrazoles, conveniently prepared from the
reaction of appropriate chalcones with arylhydrazines [4],
is of considerable synthetic and biological value [5]. The
pyrazoles among other five-membered heterocycles often
possess important biological and medicinal activities as
analgesic, anti-inflammatory, antipyretic, anti-arrhythmic,
psycho analeptic, antidiabetic and antibacterial agents [6].
A variety of oxidants such as zirconium nitrate [7],
carbon-activated oxygen [8], Pd/C/acetic acid [9], cobalt
soap of fatty acids [10], iodobenzene diacetate [11], lead
tetraacetate [12], manganese dioxide [13], potassium
permanganate [14], silver nitrate [15], mercury oxide [16],
molecular oxygen in catalytic amount of N-hydroxy-
phthalimide (NHPI) and cobalt acetate [17], and iodine
pentoxide or iodic acid/sodium bromide [18], have
been previously reported; most suffer from the use of
excess reagent, longer reaction times, higher
temperatures, acidic media, side product formation and
residual toxicity in the products due to the presence of
toxic metal cations like Co(II), Pd(IV), Hg(II), Mn(IV and
VII), Ag(I) and Zr(IV) added as catalysts. In the last few
years, we have been interested to tackle the limitations
and drawbacks allocated to above-mentioned previously
reported protocols, by reporting more robust and readily
+
+
NO and NO generated in-situ respectively from sodium
2
nitrate as versatile and highly useful reagents sodium
nitrite and sodium nitrate in acetic acid under microwave
acceleration condition (Scheme 1).
Scheme 1
R1
R
2
R1
R
2
AcOH/ NaNO
or
AcOH/ NaNO or NaNO / MW
or NaNO / rt
2
3
N
N
N
N
Ph
2
3
Ph
1a-j
2a-j
RESULTS AND DISCUSSION
According to the experimental results collected in
Tables 1 and 2, more efficient conversion of 2-pyrazolines
occurred under microwave irradiation in acetic acid to
yield the corresponding pyrazoles 2a-j in shorter reaction
times and higher yields (54-90%) when compared with
conventional thermal condition. It is important to note
that, when these reactions were conducted in other
solvents such as methanol, acetonitrile or methylene
chloride, no significant conversion was observed and

5
64
D. Azarifar, B. Maleki and M. Sahraei
Vol 45
nearly all the starting pyrazolines remained unreacted.
The unique role of acetic acid in promoting these
conversions could be possibly attributed to: (i) higher
solubility of sodium nitrite and sodium nitrate in acetic
In conclusion, the advantages allocated to this method
include: easy handling, low cost, easy accessibility, high
stability and nontoxicity of the reagents used, mild
reaction conditions and high yields of the products. These
properties render this as efficient and convenient method
to oxidize 2-pyrazolines to the pyrazoles.
+
+
acid; (ii) acetic acid-assisted generation of NO and NO2
and (iii) deprotonation of the reaction intermediate ring
systems by acetate anion produced in the reaction
mixture, as shown in the suggested mechanism (Scheme
Scheme 2
2
). The application of microwave (MW) irradiation
AcOH
+
AcONa
NO (or NO2+) + H2O
NaNO2 (or NaNO3)
-
technique has profound effect for the acceleration of the
reactions with providing short times, high conversions.
The rate-enhancing role of microwave irradiation in
Scheme 2 is now believed to be presumably due to the
selective absorption of MW energy by polar acetic acid
molecules that brings about rapid superheating of these
molecules. Numerous repetitions of the reactions under
different molar conditions indicated that, the most
effective conversions occur when stoichiometric amounts
of the sodium nitrite and sodium are taken in the reaction
mixtures.
H
H
H
H
R1
H
R1
H
R2
AcO
R2 NO (or NO2+)
+
HNO (or HNO2)
N
N
N
N
NO (or NO2 )
Ph
Ph
H
H
H
N
R2
R1
R2
1
R
AcO
AcOH
N
N N
P
h
Ph
Table 1
Oxidative aromatization of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles 1a-j (1 mmol) with sodium nitrite (1 mmol) at room temperature and under
microwave irradiation conditions in acetic acid [a].
Time
(min)
Yield [c]
(%)
Mp (°C)
Reported [d]
1
2
Substrate
Product [b]
R
R
Found
138-140
79-81
140-142
112-114
76-78
130-132
68-70
146-148
128-130
92-94
1
1
1
1
1
a
b
c
d
e
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
OC
5 (0.17)
20 (0.34)
20 (0.5)
15 (0.34)
20 (0.34)
20 (0.34)
20 (0.34)
10 (0.34)
20 (0.5)
82 (90)
74 (80)
56 (74)
56 (84)
68 (80)
80 (80)
56 (78)
78 (80)
72 (80)
68 (78)
139-140
78-80
142-143
114-115
77-79
130-133
67-70
148-150
126-128
93-95
4-CH
3
6
H
4
4-NO
2
C
6
H
4
4-ClC
Ph
4-ClC
2-ClC
6
H
4
3 6 4
4-CH OC H
1
f
2-naphthyl
2-naphthyl
2-naphthyl
Ph
6
H
H
4
4
1
1
g
h
6
2-CH
4-BrC
3-ClC
3
C
6
H
4
1
1
i
j
6 4
H
2j
Ph
6
H
4
20 (0.34)
[
a] The reaction times and yields obtained under microwave irradiation are given in parentheses. [b] All the isolated products were characterized
1 13
on the basis of their physical properties and ir, H nmr and C nmr spectral analysis and by direct comparison with authentic materials. [c] Isolated
yields. [d] Literature data, 2a-c [7], 2d-j [24].
Table 2
Oxidative aromatization of 1,3,5-trisubstituted 4,5-dihydro-1H-pyrazoles 1a-j (1 mmol) with sodium nitrate (1 mmol) at room temperature and
under microwave irradiation conditions in acetic acid [a].
Time
(min)
Yield [c]
(%)
Mp (°C)
Reported [d]
1
R
2
R
Substrate
Product [b]
Found
1
1
1
1
1
a
b
c
d
e
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
120 (0.34)
360 (0.67)
340 (0.67)
385 (0.83)
300 (0.67)
335 (0.67)
345 (0.67)
150 (0.5)
68 (72)
52 (70)
48 (62)
54 (70)
62 (74)
60 (70)
60 (62)
74 (80)
56 (76)
60 (70)
140-142
79-81
139-141
115-116
78-80
132-134
69-71
149-151
126-128
94-96
139-140
78-80
142-143
114-115
77-79
130-133
67-70
148-150
126-128
93-95
4-CH
3
OC
6
H
4
4-NO
2
C
6
H
4
4-ClC
Ph
4-ClC
2-ClC
6
H
4
3 6 4
4-CH OC H
1
f
2-naphthyl
2-naphthyl
2-naphthyl
Ph
6
H
H
4
1
1
g
h
6
4
2-CH
4-BrC
3-ClC
3
C
6
H
4
1
1
i
j
6
H
4
200 (0.67)
200 (0.5)
2j
Ph
6 4
H
[
a] The reaction time and yields obtained under microwave irradiation are given in parentheses. [b] All the isolated products were characterized on
1 13
the basis of their physical properties and ir, H nmr and C nmr spectral analysis and by direct comparison with authentic materials. [c] Isolated
yields. [d] Literature data, 2a-c [7], 2d-j [24].

Mar-Apr 2008
Oxidation of 1,3,5-Trisubstituted 4,5-Dihydro-1H-pyrazoles
565
EXPERIMENTAL
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