A simple and environmentally benign nitration of pyrazoles by impregnated bismuth nitrate

Article abstract of DOI:10.1002/jhet.1093

We report herein a facile, rapid, and environmentally friendly synthesis of nitropyrazoles in good yields using silica-bismuth nitrate and silica-sulfuric acid-bismuth nitrate at room temperature for the first time. The relatively non-toxic nature, ease o

Full text of DOI:10.1002/jhet.1093

1
322
A Simple and Environmentally Benign Nitration of Pyrazoles by
Impregnated Bismuth Nitrate
Vol 50
a
b
a
b
P. Ravi, * Girish M. Gore, Surya P. Tewari, and Arun K. Sikder
a
Advanced Centre of Research in High Energy Materials,
University of Hyderabad, Hyderabad 500 046, India
High Energy Materials Research Laboratory, Pune 411 021, India
b
*
E-mail: rpiitb@hotmail.com
Received April 18, 2011
DOI 10.1002/jhet.1093
Published online 9 September 2013 in Wiley Online Library (wileyonlinelibrary.com).
We report herein a facile, rapid, and environmentally friendly synthesis of nitropyrazoles in good
yields using silica‐bismuth nitrate and silica‐sulfuric acid‐bismuth nitrate at room temperature for
the first time. The relatively non‐toxic nature, ease of handling, easy availability, and low cost make
the present procedure attractive for the nitration of a wide variety of diazoles in the drug and pharmaceu-
tical industries.
J. Heterocyclic Chem., 50, 1322 (2013).
INTRODUCTION
formed quantitatively and in some instances side reactions
particularly denitrations of N‐nitropyrazoles are observed
[9,11]. The problems associated with the conventional
nitration mixtures have prompted the researchers to search
for the alternative methodologies. The limitations and draw-
backs of the traditional nitration methodologies such as
tedious work‐up, strongly acidic media, oxidation ability of
the reagents, thermal rearrangements, and safety problems
can be avoided using the impregnated metal nitrates.
Nitropyrazoles are structural units found in biologically
active compounds (cholesterol lowering, anti‐inflammatory,
anti‐cancer, anti‐depressant, and anti‐psychotic agents),
dyestuffs, and explosives [1–8]. The presence of nitro group
in the pyrazole ring considerably enlarges the possibility of
functionalization of various types of biologically active com-
pounds. The nitration of pyrazoles has been performed using
nitric acid–sulfuric acid [5–11], nitric acid–acetic anhydride
The supported metal nitrates such as Bi(NO ) /SiO
2
3
3
[5–11], or nitric acid–trifluoroacetic anhydride [12]. The
or clay [13,14], AgNO /BF [15] Cu(NO ) /clay [16], Ce
3 3 3 2
C‐nitropyrazoles have been synthesized by thermal
rearrangement of N‐nitropyrazoles in chlorobenzene, nitro-
benzene, anisole, aniline, N‐methylformamide, propylene
glycol, xylene, benzonitrile, n‐decane, or mesitylene at
(NH ) (NO ) /H SO /SiO [17], Fe(NO ) /clay [18], and
4 2 3 6 2 4 2 3 3
other metal nitrates/clay activated by acetic anhydride
[19] have been used for the nitration of a variety of
aromatic compounds. Bismuth nitrate is an inexpensive,
easy‐to‐handle, and commercially available solid being
1
20–200°C for 3–7 h. Normally, C‐nitropyrazoles are
©
2013 HeteroCorporation

November 2013
A Simple and Environmentally Benign Nitration of Pyrazoles
by Impregnated Bismuth Nitrate
1323
used for the nitration [13,14]. The supported bismuth
nitrate is the most active and long‐lived catalyst for the
nitration of arenes [20–24]. Also, it is easier to handle,
readily separable from the products by simple filtration,
recyclable, and require the milder reaction conditions.
Though the synthesis of nitropyrazoles using different
nitration mixtures are known however, to our knowledge
synthesis of these compounds with silica‐bismuth nitrate
and silica‐sulfuric acid‐bismuth nitrate has not yet been
reported. We report herein the nitration of different
pyrazoles using silica‐bismuth nitrate (method A) and
silica‐sulfuric acid‐bismuth nitrate (method B) at
room temperature.
via the nitration routes I and II. The reaction was very se-
lective and no side‐chain substitution products were
observed. The reaction rates of methylpyrazoles were
increased with increasing number of methyl groups. An
exceptionally higher yield of 3,5‐dimethyl‐4‐nitropyrazole
(2g) was obtained from 3,5‐dimethylpyrazole (1g) in 3 h.
The crude obtained after the nitration of 1a and 1b
irrespective of nitration mixture and reaction conditions
contains 4‐nitropyrazoles (<10%). Thus, 1‐methyl‐4‐
nitropyrazole has been observed to be a major side prod-
uct in the synthesis of 1‐methyl‐3‐nitropyrazole (2b) and
1‐methyl‐3,4‐dinitropyrazole (3b). The prolonged nitra-
tion of 1a, 1b or mononitro compounds (2a, 2b)
gave higher yields of polynitropyrazoles (3a–3c) using
acid‐bismuth nitrate in two or three folds via direct
nitration (III).
RESULTS AND DISCUSSION
Pyrazoles are usually nitrated at position 4, facilitated by
electron‐donating and retarded by electron‐withdrawing
groups [21–27]. Mixing the starting materials with
silica‐bismuth nitrate or silica‐sulfuric acid‐bismuth
nitrate in tetrahydrofuran (THF) and evaporation of the
solvent under vacuum comprise the reaction conditions
for successful, regiospecific nitration with a series of
pyrazoles. To ascertain the optimum conditions, several
reactions were carried out on pyrazole (1a) and
Herve et al. [6] obtained 1‐methyl‐3,4,5‐trinitropyrazole
(3c) by the stepwise nitration followed by the methylation
of alkali salts of 3,4,5‐trinitropyrazole (3d). 1‐Methylpyrazole
(1b) on nitration gave 76% (method A) and 88% (method B)
yields of trinitro compound (3c). However, we have
detected no nitration of 3b even after 48 h rather recovered
the quantitative amount of dinitro compound (3a). The
deactivated substrates (2b, 2l) underwent nitration in good
yields. 3,5‐Dinitropyrazole (2k) and 1‐methyl‐3,5‐
dinitropyrazole (2l) have not been formed as the by‐
products in the synthesis of 3a and 3b. Our attempts to
obtain 1‐methyl‐3,4‐dinitropyrazole (3b) from 1‐methyl‐
4‐nitropyrazole were unsuccessful, even the nitration was
carried out at 120°C for 6 h. The mono‐, (2a, 2b) and
dinitro compounds (3b) are formed presumably by the
nitration of pyrazole (1a, 1b). 3‐Nitropyrazole (2a) and
1‐methyl‐3‐nitropyrazole (2b) have been obtained by
the [1,5]-sigmatropic rearrangement of 3H‐pyrazole and
l‐methyl‐2‐nitropyrazolium species, respectively [9–11].
The synthesis of 1‐methyl‐3,4‐dinitropyrazole (3b)
from 1‐methyl‐3‐nitropyrazole (2b) shows that it cannot
be from 1‐methyl‐4‐nitropyrazole. The nitration of
1
‐methylpyrazole (1b) as the model substrates by varying
the amounts of impregnated bismuth nitrate in THF at
room temperature (Scheme 1).
Pyrazoles with electron‐donating groups readily
underwent nitration in excellent yields (> 92%). The
deactivated substrates underwent nitration in good yields
(
> 80%). The substrates with electron‐donating and
electron‐withdrawing groups and their corresponding nitro
compounds using silica impregnated with bismuth nitrate
(
method A) and silica‐sulfuric acid impregnated with
bismuth nitrate (method B) are summarized in Table 1.
Pyrazole (1a) and methylpyrazoles (1b–g) have been
nitrated in excellent yields with silica‐bismuth nitrate and
silica‐sulfuric acid‐bismuth nitrate. The general scheme
for the nitration of pyrazoles is shown (Scheme 2). 1,3‐
Dimethylpyrazole (1e) and 1,4‐dimethylpyrazole (1f) were
also nitrated to nitropyrazoles (2e and 2f) in higher yields
1
‐methylpyrazole‐2‐oxide (1h) gave 52% (method A)
and 67% (method B) of 1‐methyl‐5‐nitropyrazole‐2‐oxide
(
2h) (Scheme 3).
‐Nitro‐1‐phenylyrazole (1i) and 1‐benzyl‐4‐nitropyrazole
1j) have also been nitrated to examine the position of
4
(
substitution in the substrate. It has been known that the
use of mixed acid leads to nitration of the conjugate acid
of the base, whilst nitric acid–acetic anhydride nitrates
the free base, the change in the reacting form of the sub-
strate leading to the change of orientation. The orientation
of mononitration of 1i depends on the reagent being used:
mixed acid gives 1‐(p‐nitrophenyl)pyrazole, whilst nitric
acid–acetic anhydride gives 4‐nitro‐1‐phenylpyrazole
Scheme 1. Nitration of pyrazoles.
[
23–27]. The para substituted products (2i and 2j) have
been obtained from 1‐(p‐nitrophenyl)‐4‐nitropyrazole
2i) and 1‐(p‐nitrobenzyl)‐4‐nitropyrazole (2j), respectively.
(
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P. Ravi, G. M. Gore, S. P. Tewari, and A. K. Sikder
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Table 1
Nitration of pyrazoles using impregnated bismuth nitrate.
Method A
Time (h)
Method B
m.p. (°C)
Literature
Entry
Substrate
Product
Yield (%)
Time (h)
Yield (%)
Found
1
2
3
6
6
6
78
6
6
6
83
162–163
160–162 [9]
95
91
98
96
80–82
80–83 [9]
155–157
156–157 [9]
4
5
6
7
6
3
3
3
94
86
92
95
6
3
3
3
96
95
97
98
186–187
160–162
96–97
186–187 [9]
162–163 [5]
96–97 [23]
126–128 [5]
126–127
8
6
52
6
67
108–109
109–111 [22]
(Continued)
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A Simple and Environmentally Benign Nitration of Pyrazoles
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Table 1
(
Continued)
Method A
Time (h)
Method B
m.p. (°C)
Literature
Entry
9
Substrate
Product
Yield (%)
Time (h)
Yield (%)
Found
3
88
3
93
162–163
162–163 [24]
10
3
94
3
97
91–92
90–91 [25]
1
1
1
1
2
3
4
6
4
92
88
91
4
6
4
95
92
94
86–88
21–22
21–22
87–89 [9]
20–22 [9,21]
20–22 [9,21]
1
4
5
10
76
93
10
88
98
91–92
91–93 [6]
1
3
3
189–190
188–189 [6]
16
4
91
4
96
90–92
91–92 [6]
Finally, the recycling of impregnated bismuth nitrate
was done by evaporating the solvent after completion
of the reaction and the recovered solid was dried. It
has been found that the impregnated bismuth nitrate
works efficiently up to third cycle thereafter it loses
its activity.
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P. Ravi, G. M. Gore, S. P. Tewari, and A. K. Sikder
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Scheme 2. Nitration of pyrazoles using silica impregnated with bismuth nitrate (method A) and silica‐sulfuric acid impregnated with bismuth nitrate
(method B). The scheme showing the nitration of pyrazoles via 4‐nitropyrazoles (route I), 3‐nitropyrazoles (route II), and the polynitration of pyrazoles
(route III).
purification. Melting points were recorded by a capillary melt-
Scheme 3. Nitration of 1‐methylpyrazole‐2‐oxide.
ing point apparatus and were uncorrected. Analytical thin layer
chromatography silica gel GF‐254 type was routinely used to
monitor the progress of reactions. IR spectra were recorded
on Perkin–Elmer FT‐IR‐1600 spectrophotometer in KBr
matrix. The peak signals are reported in wave numbers
−
1
1
13
(
cm ). H‐NMR and C‐NMR spectra were recorded on 300
MHz Varian instrument with CDCl or DMSO‐d solvent.
3
6
The chemical shift values are reported in δ units (ppm) relative
to TMS as the internal standard. GC‐MS was carried out with
glass columns packed with 3% OV‐17 on Chromosorb W,
100‐120 mesh, treated with DMCS in a Varian 1400 instrument
fitted with flame ionization detector, nitrogen being used as
carrier gas.
Caution: All polynitropyrazoles are considered as danger-
ous and proper precaution should be taken in handling
and storage.
CONCLUSION
In summary, we have shown a simple, rapid, and
environmentally benign nitration of different pyrazoles with
silica‐bismuth nitrate and silica‐sulfuric acid‐bismuth nitrate
avoiding thermal rearrangements of N‐nitropyrazoles.
Exceptionally higher yields of 1‐methyl‐3‐nitro pyrazole
2b), 3‐methyl‐4‐nitropyrazole (2c), 4‐methyl‐3‐nitropyrazole
2d), 1,4‐dimethyl‐3‐nitropyrazole (2f), and 3,5‐dimethyl‐
(
(
4
Silica‐sulfuric acid. Silica‐gel of 100–200 mesh (60.0 g) was
soaked with 98% sulfuric acid (75 mL), repeatedly washed
with water and filtered to get a white solid. Then it was dried at
‐nitropyrazole (2g) have been obtained. Moreover, the
silica‐sulfuric acid‐bismuth nitrate catalyzed reactions
have been found to be superior in terms of yields of the
products and time of the reaction over silica‐bismuth
nitrate. The relatively non‐toxic nature, ease of handling,
easy availability, and low cost make the present procedure
attractive for the nitration of a wide variety of diazoles in
the drug and pharmaceuticals industries.
1
20–130°C for 24 h to give silica‐sulfuric acid (76.0 g). The
catalyst was re‐activated prior to use by heating in the oven at
120°C for 6 h.
Silica‐bismuth nitrate. Bismuth nitrate (10 mmol) was added
to acetone (188 mL) in 500 mL evaporating flask. The mixture
was stirred vigorously for 15 min. Silica‐gel (15 g) was added
in small amounts and stirring was continued for another 15
min. The solvent was removed using rotary evaporator on a
water bath keeping the temperature 30–35°C and the
obtained solid was crushed to get floury powder.
Silica‐sulfuric acid‐bismuth nitrate. Silica‐sulfuric acid
(0.8 g, 0.24 mol) and bismuth nitrate (0.16 g, 0.036 mol) taken in
a mortar was grinded to get homogeneous floury powder.
EXPERIMENTAL
All the reagents and solvents have been obtained from
Merck, Alfa‐Aesar or Aldrich and used without further
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A Simple and Environmentally Benign Nitration of Pyrazoles
by Impregnated Bismuth Nitrate
1327
General procedure for the synthesis of nitropyrazoles.
Method A. The mixture of silica‐bismuth nitrate (1.5 g) and
pyrazole (17 mmol) in THF (20 mL) was stirred for required
time. The reaction was monitored by TLC with ethyl acetate
and hexane (3:2) as solvent. Silica‐sulfuric acid was filtered off
and the solvent was removed to get nitro compounds. The pure
compounds were obtained from column chromatography.
[7] Zhang, Y.; Guo, Y.; Joo, Y. H.; Parrish, D. A.; Shreeve, J. M.
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[
[
Method B..
The mixture of silica‐sulfuric acid‐bismuth
1
nitrate (0.96 mg) and pyrazole (17 mmol) in THF (20 mL) was
stirred for required time. The reaction was monitored by TLC
with ethyl acetate and n‐hexane (3:2) as solvent. Silica‐sulfuric
acid‐bismuth nitrate was filtered off and the solvent was
removed to get nitro compounds. The pure compounds were
obtained from column chromatography.
[
[
[
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[
Acknowledgments. The first author wishes to acknowledge for the
sustaining financial support by Defence Research Development
Organisation, India through Advanced Centre of Research in High
Energy Materials.
[
2
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet