Silica-sulfuric acid catalyzed nitrodeiodination of iodopyrazoles

Article abstract of DOI:10.1080/00397911.2011.584261

We report here the synthesis of nitropyrazoles in good to excellent yields from iodopyrazoles over silica-sulfuric acid catalyst for the first time. The present procedure require less acid, offers a simplified workup procedure, and may be applied for the

Full text of DOI:10.1080/00397911.2011.584261

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Silica–Sulfuric Acid Catalyzed
Nitrodeiodination of Iodopyrazoles
P. Ravi a , Girish M. Gore b , Arun K. Sikder b & Surya P. Tewari a
a Advanced Centre of Research in High Energy Materials (ACRHEM),
University of Hyderabad, Hyderabad, India
b High Energy Materials Research Laboratory (HEMRL), Pune, India
Accepted author version posted online: 12 Jan 2012.Version of
record first published: 02 Aug 2012.
To cite this article: P. Ravi , Girish M. Gore , Arun K. Sikder & Surya P. Tewari (2012): Silica–Sulfuric
Acid Catalyzed Nitrodeiodination of Iodopyrazoles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 42:23, 3463-3471
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Synthetic Communications1, 42: 3463–3471, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.584261
SILICA–SULFURIC ACID CATALYZED
NITRODEIODINATION OF IODOPYRAZOLES
P. Ravi,1 Girish M. Gore,2 Arun K. Sikder,2 and
Surya P. Tewari1
1Advanced Centre of Research in High Energy Materials (ACRHEM),
University of Hyderabad, Hyderabad, India
2High Energy Materials Research Laboratory (HEMRL), Pune, India
GRAPHICAL ABSTRACT
Abstract We report here the synthesis of nitropyrazoles in good to excellent yields from
iodopyrazoles over silica–sulfuric acid catalyst for the first time. The present procedure
require less acid, offers a simplified workup procedure, and may be applied for the nitration
of a wide variety of iodoazoles in drug and pharmaceutical industries.
Keywords Heterogeneous catalysis; iodopyrazoles; nitrodeiodination; nitropyrazoles;
silica–sulfuric acid
INTRODUCTION
Nitropyrazoles are structural units found in biologically active compounds
(cholesterol lowering, antiinflammatory, anticancer, antidepressant and
antipsychotic agents), dyestuffs, and recently high-energy materials.[1–7] Several di-
and trinitropyrazoles were synthesized using different nitration mixtures.[8–12] The
C-nitropyrazoles are obtained by rearrangement of N-nitropyrazoles in
chlorobenzene, nitrobenzene, anisole, aniline, n-decane, N-methylformamide, propy-
lene glycol, xylene, benzonitrile, or mesitylene at 110 to 200 ꢀC for 3–7 h. Normally,
Received March 12, 2011.
Address correspondence to P. Ravi, Advanced Centre of Research in High Energy Materials
(ACRHEM), University of Hyderabad, Hyderabad 500 046, India. E-mail: rpiitb@hotmail.com
3463

3464
P. RAVI ET AL.
C-nitropyrazoles are formed quantitatively and in some instances side reactions, parti-
cularly denitrations of N-nitropyrazoles, are observed.[7,8] The controlled iodination or
oxidative iodination of pyrazoles prior to nitration has been found to be desirable to
synthesize nitro compounds in greater yields.[7] The problems associated with the con-
ventional nitration mixtures have prompted researchers to search for alternative meth-
odologies. The limitations and drawbacks of the conventional methods such as tedious
workup, strongly acidic media, oxidation ability of reagents, thermal rearrangements,
and safety problems can be avoided by using silica–sulfuric acid.[13–16]
Silica–sulfuric acid is easier to handle because it holds the acidity internally, is
readily separable from the products by simple filtration, is recyclable, and requires
milder reaction conditions. The syntheses of nitropyrazoles using different nitration
mixtures are known, however, to our knowledge, synthesis of these compounds from
iodopyrazoles with nitric acid over silica–sulfuric acid catalyst has not yet been reported.
We report here the nitrodeiodination of different iodopyrazoles over silica–
sulfuric acid catalyst for the first time.
RESULTS AND DISCUSSION
Silica–sulfuric acid was prepared using 98% sulfuric acid as per the literature
method.[13] The catalyst has been reactivated at 120 ꢀC for 6 h prior to use. The starting
materials with nitric acid and the catalyst in tetrahydrofuran (THF) have been stirred
at room temperature, and the evaporation of solvent under vacuum comprises the reac-
tion conditions for successful, regiospecific nitration with a series of iodopyrazoles. To
ascertain the optimum conditions, several reactions were carried out on 4-iodopyrazole
(1a) and 4-iodo-1-methypyrazole (1b) as the model substrates varying the amounts of
catalyst in THF at room temperature (Scheme 1). We found that there was no prom-
ising change in the yields of 2a and 2b when the reactions were prolonged or the catalyst
increased. The substitution of iodine atom (i.e., nitrodeiodination) proceeded smoothly
in fuming nitric acid over silica–sulfuric acid at room temperature. The iodopyrazoles
and their corresponding nitro compounds are summarized in Table 1.
Pyrazoles are usually nitrated at the 4-position, facilitated by electron-donating
groups and retarded by electron-withdrawing groups. The substrates with
Scheme 1. Nitrodeiodination of monoiodopyrazoles.

NITRODEIODINATION OF IODOPYRAZOLES
3465
Table 1. Nitrodeiodination of iodopyrazoles
Mp (ꢀC)
Entry
Substrate
Product
Time (h) Yield (%) Found
Literature
1
2.5
2.5
92
86
164–165
162–164[3]
2
91–92
91–92[12]
3
4
2.0
2.5
92
87
135–136 134–136[8]
187–188 186–187[8]
5
6
7
8
2.0
2.0
2.0
2.5
98
92
87
85
125–126 124–127[17]
159–161 160–162[3]
96–97
87–88
97–98[18,19]
87–89[8]
(Continued )

3466
P. RAVI ET AL.
Table 1. Continued
Mp (ꢀC)
Time (h) Yield (%) Found Literature
Entry
Substrate
Product
9
2.5
3.0
3.0
82
78
75
87–88
20–21
20–21
87–89[8]
21–22[12]
21–22[12]
10
11
12
2.5
88
126–127
125–126[20]
162–163[20]
91–92[21]
13
2.5
81
161–162
14
15
2.5
2.5
85
96
92–93
87–88
87–89[8]
(Continued )

NITRODEIODINATION OF IODOPYRAZOLES
3467
Table 1. Continued
Mp (ꢀC)
Entry
16
Substrate
Product
Time (h) Yield (%) Found
Literature
2.5
86
20–21
21–22[12]
17
18
3.0
3.5
92
86
189–190
188–190[5]
90–91
91–93[5]
electron-donating groups readily underwent nitration in excellent yields (92%), and
the deactivated substrates underwent nitration in good yields (>80%). The free 3-
and 5-positions of pyrazoles are strongly deactivated by the nitro group at the 4-pos-
ition and thus the yields are lower despite harsh conditions and the nature of nitration
mixture. The nitration of mononitro- (2a and 2b) and dinitropyrazoles (4 and 6) have
been observed to be highly resistant irrespective of nitration mixture and the reaction
conditions. However, 1-phenylpyrazole and its analogs underwent substitution at the
4-position of the pyrazole ring.[1] The mononitration of 1-phenyl-4-iodopyrazole (7a),
1-(p-nitrophenyl)-4-iodopyrazole (8a), and 1-benzyl-4-iodopyrazole (9a) gave 1-phenyl-
4-nitropyrazole (7b), 1-(p-nitrophenyl)-4-nitropyrazole (8b), and 1-benzyl-4-nitropyra-
zole (9b) respectively.
Diiodo- (3c and 5c) and triiodopyrazoles (10a and 11a) were also nitrated into
dinitro- (4 and 6) and trinitropyrazoles (10b and 11b) respectively in good yields. The
dinitro compounds (4 and 6) are completely deactivated by vicinal nitro groups, thus
hindering the substitution at the 5-position of the pyrazole ring.[1] The presence of
vicinal nitro groups in 4 and 6 deactivated the 5-position and thus the nitration
has not been observed. Instead, quantitative starting compounds were recovered.
3,4,5-Trinitropyrazole (10b) is known to exhibit remarkable and unprecedented
properties.[5] It is neither hygroscopic nor highly acidic in nature. It displays low
sensitivity to external stimuli and outstanding thermal and chemical stability of any fully
nitrated aromatic compounds. The exceptional stability and low sensitivity of 10b is due
to its low acidity (pKa 2.35). Increasing nitro groups on pyrazole ring increases the acid-
ity. Therefore, if nitration, methylation, or amination is possible at the 1-position of 10b,
it will enhance the chemical stability. 1-Methyl-3,4,5-trinitropyrazole (11b) is under

3468
P. RAVI ET AL.
Table 2. Nitrodeiodination of monoiodopyrazoles over recycled catalyst
Entry
1
Substrate
Product
Time (h)
Yield (%)
1a
2a
2.5
2.5
2.5
6.0
24
92
74
56
32
5
2
1b
2b
2.5
2.5
2.5
6.0
24
86
60
44
35
7
consideration as a next-generation melt-cast explosive.[5] The crude obtained after
nitration of 3,4,5-triiodo-1-methylpyrazole (11a) has been found to contain <12% yields
of 3,5-diiodo-4-nitropyrazole and 5-iodo-3,4-nitropyrazole.[7] The nitration of 11a with
nitric acid for 3.5h gave greater yield (86%) of trinitropyrazole (11b). To establish the
generality of nitrodeiodination and its applicability to the synthesis of polynitro
compounds, we have nitrated 3a–c, 10a, and 11a and found that the vicinal electron
withdrawing groups have not prevented ipso nitration at 4- or 3-positions of pyrazole.
The nitration of iodo compounds for 2 to 3.5 h showed the absence of starting com-
pounds. It has been found that nitration of iodonitropyrazoles (5a and 5b) required
more time, and the yields of 6 were 78% and 75% respectively. The determination of
nitro group position was based on the difference in the reactivity toward electron-
withdrawing groups of the 3- or 4-position of the ring and the comparison of spectral
data of nitro compounds.
Finally, we have tested the catalyst recycling on the nitrolysis of 1a and 1b.
After filtration, washing with methanol, and heating at 120 ꢀC for 12 h, the catalyst
was reused three times and showed good to excellent yields. Table 2 summarizes the
yields of nitropyrazoles (2a and 2b) with the recycled catalyst. The catalyst works
efficiently up to the third cycle and thereafter it loses its activity.
CONCLUSION
In summary, we have shown a facile, rapid, and convenient method for the
nitrodeiodination of iodopyrazoles with silica–sulfuric acid, making the present
procedure attractive for the nitration of a wide variety of iodoazoles in drug and
pharmaceutical industries. Exceptionally higher yields have been obtained; however,
2a, 2b, 4, and 6 were found to be highly resistant to nitration. The nitration of iodo-
pyrazoles takes place only when catalyst is added or the polyiodo compounds are
heated with nitric acid. The failure to synthesize nitro compounds or partially nitro-
deiodinated compounds is due to the use of relatively less concentrated nitric acid.
EXPERIMENTAL
Melting points were recorded by a capillary melting-point apparatus and were
uncorrected. All the reagents and solvents obtained from Merck, Alfa-Aesar, or

NITRODEIODINATION OF IODOPYRAZOLES
3469
Aldrich and used without further purification. Analytical thin-layer chromatography
(silica gel GF-254 type) was routinely used to monitor the progress of reactions. Four-
ier transform (FT-IR) spectra were recorded on a Perkin Elmer FT-IR-1600 spectro-
photometer in KBr matrix. The peak signals are reported in wave numbers (cmꢁ1). 1H
NMR and 13C NMR spectra were recorded on a 300-MHz Varian instrument with
dimethylsulfoxide (DMSO-d6) and CDCl3 solvents. The chemical shift values are
reported in d units (parts per million) relative to tetramethylsilane (TMS) as an inter-
nal standard. Gas chromatography–mass spectrometry (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, and
nitrogen was used as carrier gas.
Caution: All nitropyrazoles are considered as dangerous and proper precau-
tions should be taken in handling and storage.
Preparation of Silica–Sulfuric Acid
Silica gel (60 g) was soaked with 98% sulfuric acid (75 mL), repeatedly washed
with water, and filtered to get a white solid. Then it was dried in an oven at 120–
130 ꢀC for 24 h to obtain silica–sulfuric acid (76.42 g). The catalyst was reactivated
heating in an oven at 120 ꢀC for 6 h prior to use.
Nitrodeiodination of Monoiodopyrazoles (1a–g, 3a, 3b, 5a, 5b, 7a, 8a,
and 9a)
Iodopyrazole (1 mmol) in THF (10 mL) was added to silica–sulfuric acid (250mg)
in a two-necked, round-bottom flask. Nitric acid (q 1.52g cmꢁ3, 10 mL) was added
dropwise, and the mixture was stirred for the required time at room temperature.
The catalyst was recovered by filtration, and the filtrate was extracted with dichloro-
methane. The solvent was removed under reduced pressure to get nitropyrazole.
Nitrodeiodination of Diiodopyrazoles (3c and 5c)
Iodopyrazole (1 mmol) in THF (10 mL) was added to silica–sulfuric acid
(500 mg) in a two-necked, round-bottom flask. Nitric acid (q 1.52 g cmꢁ3, 20 mL)
was added dropwise, and the mixture was stirred for the required time at room
temperature. The catalyst was recovered by filtration and the filtrate was extracted
with dichloromethane. The solvent was removed under reduced pressure to get
dinitropyrazole.
3,4-Dinitropyrazole (4). IR, t (KBr disc) cmꢁ1: 1545, 1504, 1370 and 1326
(CꢁNO2); 2901 (CꢁH); 3135 (N-H). 1H NMR (300 MHz, CDCl3, 300 K) d (ppm) ¼
10.77 (br s, 1-H), 8.32 (s, 5-H). 13C NMR (300 MHz, CDCl3, 300 K) d (ppm) ¼ 135
(C-3), 133 (C-4), 132 (C-5). EI-MS: m=z 158 (Mþ.). Anal. calcd for C3H2N4O4: C,
22.80; H, 1.26; N, 35.44. Found: C, 22.81; H, 1.24; N, 35.54.
1-Methyl-3,4-dinitropyrazole (6). IR, t (KBr disc) cmꢁ1: 1550, 1534, 1520,
1370 and 1340 (CꢁNO2); 2998 (CꢁH). 1H NMR (300 MHz, CDCl3, 300 K)
d (ppm) ¼ 4.06 (s, 3-H); 8.32 (s, 5-H). 13C NMR (300 MHz, CDCl3, 300 K)

3470
P. RAVI ET AL.
d (ppm) ¼ 38.5 (t, CH3), 147 (C-3), 126 (C-4), 132 (C-5). EI-MS: m=z 172 (Mþ.). Anal.
calcd for C4H4N4O4: C, 27.94; H, 2.32; N, 32.56; O, 37.20. Found: C, 27.90; H, 2.31;
N, 32.52; O, 37.16.
Nitrodeiodination of Triiodopyrazoles (10a and 11a)
Iodopyrazole (1 mmol) in THF (10 mL) was added to silica-sulfuric acid
(500 mg) in a two-necked, round-bottom flask. Nitric acid (q 1.52 g cmꢁ3, 30 mL)
was added dropwise, and the mixture was stirred for the required time at room
temperature. The catalyst was recovered by filtration, and the filtrate was extracted
with dichloromethane. The solvent was removed under reduced pressure to get
trinitropyrazole.
3,4,5-Trinitropyrazole (10b). IR, t (KBr disc) cmꢁ1: 1552, 1522, 1446, 1411,
1
1373, 1348 and 1286 (CꢁNO2), 3147 (N-H). H NMR (300 MHz, CDCl3, 300 K) d
(ppm) ¼ 12.3 (s, 1H, NH). 13C NMR (300 MHz, CDCl3, 300 K) d (ppm) ¼ 122 (C-4),
143 (C-3), 349 (C-5). EI-MS: m=z 203 (Mþ.). Anal. calcd for C3HN5O6: C, 17.74; H,
0.51; N, 34.52; O, 47.41. Found: C, 17.76; H, 0.48; N, 34.48; O, 47.30.
1-Methyl-3,4,5-trinitropyrazole (11b). IR, t (KBr disc) cmꢁ1: 1555, 1529,
1
1452, 1382, 1326 (CꢁNO2), 2998 (CH3). H NMR (300 MHz, CDCl3, 300 K) d
(ppm) ¼ 4.1 (s, 3H). 13C NMR (300 MHz, CDCl3, 300 K) d (ppm) ¼ 43.2 (t, CH3),
123 (t, C4), 137 (t, C3), 149 (t, C5). EI-MS: m=z 217 (Mþ.). Anal. calcd for
C4H3N5O6: C, 22.12; H, 1.38; N, 32.26; O, 44.28. Found: C, 22.0; H, 1.2; O, 44.36.
ACKNOWLEDGMENT
The Defence Research Development Organisation (DRDO), India, is grate-
fully acknowledged for financial support through the Advanced Centre of Research
in High Energy Materials (ACRHEM).
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