Efficient procedure for high-yield synthesis of 4-substituted 3,5-dinitropyrazoles using 4-chloro-3,5-dinitropyrazole

Article abstract of DOI:10.1055/s-0031-1291134

The transformations of readily available 4-chloro-3,5-dinitropyrazole and its N-methylated derivative under the action of anionic S-/O-nucleophiles and neutral N-nucleophiles were studied. Independent of the substrate's charge (anionic, R=H, or neutral, R

Full text of DOI:10.1055/s-0031-1291134

2058▌
PAPER
paper
Efficient Procedure for High-Yield Synthesis of 4-Substituted 3,5-Dinitropyra-
zoles Using 4-Chloro-3,5-dinitropyrazole
Synthesis of 4-Substituted 3,5-Dinitropyrazoles
Igor L. Dalinger,* Irina A. Vatsadze, Tatyana K. Shkineva, Galina P. Popova, Svyatoslav A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation
Fax +7(499)1355328; E-mail: dalinger@ioc.ac.ru
Received: 26.11.2011; Accepted after revision: 17.04.2012
For example, it was found that in 3,4-dinitropyrazoles
Abstract: The transformations of readily available 4-chloro-3,5-di-
(pKa <6.57) under the action of heteroatom nucleophiles
nitropyrazole and its N-methylated derivative under the action of
substitution proceeds selectively at position 3 (Scheme 1,
route A). It should be stressed that such a process does not
anionic S-/O-nucleophiles and neutral N-nucleophiles were studied.
Independent of the substrate’s charge (anionic, R = H, or neutral,
R = Me), the nucleophilic substitution proceeds exclusively at posi- depend on the presence of the substituent at N-1. Even in
tion 4 replacing the chlorine nucleofuge. As a result of this study,
the effective synthetic method for the preparation of 4-substituted
3,5-dinitropyrazoles via the nucleophilic substitution in 4-chloro-
azoles (pKa <4.07) enter the substitution reaction with the
3,5-dinitropyrazole was elaborated.
the case of R = H, when the substrate reacts in its anionic
form, only position 3 is functionalized.5 3,5-Dinitropyr-
same set of nucleophiles only in the case when a substitu-
ent R is present at N-1 (Scheme 1, route B). Otherwise, as
a result of an acid-base reaction between NH acid and ba-
Key words: pyrazoles, nitropyrazoles, 3,5-dinitropyrazoles, nu-
cleophiles, nucleophilic substitution, selective substitution
sic nucleophile, the reaction furnishes the respective salt
(Scheme 1, route C).6,8
The current interest in the chemistry of pyrazoles is due to
All known methods of C-4 functionalization, particularly,
their wide practical applications. During last five years the
in the case of N-unsubstituted pyrazoles, are based on the
number of publications on pyrazoles has doubled and is
reactions with the electrophilic reagents.4
still continuing to grow.1 Among pyrazoles, the polynitro-
Quite recently as a result of our work,9,10 as well as of
pyrazoles attract special attention because they belong to
Herve et al.,3 the first examples of fully carbon atom-
high-energy compounds and show some specific proper-
ties.2,3
nitrated pyrazoles – 3,4,5-trinitropyrazole (TNP) and its
N-derivatives, 1-methyl-3,4,5-trinitro-1H-pyrazole10a and
1-methoxymethyl-3,4,5-trinitro-1H-pyrazole11 – became
available for synthetic chemists.
The effective synthetic approaches to 3,4- and 3,5-dinitro-
pyrazoles through direct acid and nonacid nitration, as
well as via C → N isomerization of N-nitropyrazoles, are
well known.4 In a series of papers,5,6 we reported the nu-
cleophilic substitution of NO2 group in 3,4- and 3,5-dini-
tropyrazoles to be a quite powerful method for
functionalization of C-3 and C-5 atoms of a pyrazole ring
with formation of C(3/5)–X bonds (X = O, S, N).
On the basis of systematic investigations, we found that
the rules of nucleophilic substitution in these novel poly-
nitropyrazoles are different compared to previously
known ones. For instance, when TNP12 in the form of its
N-anion reacts with S-, O-, N-nucleophiles, the selective
substitution of 4-NO2 group occurs (Scheme 1, route
NO2
NO2
A
Nu
O2N
O2N
Nu
–
– NO2
N
N
N
N
N
R
R
O2N
Nu
O2N
NO2
NO2
B
Nu
C
Nu
–
–
N
N
N
N
N
N
– NO2
(R = H)
– HNu
R
R
(R = H)
Nu
NO2
NO2
O2N
NO2
O2N
NO2
E
Nu
O2N
Nu
D
Nu
–
–
–
N
N
N
– NO2
– NO2
N
N
R
R
(R = H)
(R = H)
Scheme 1 Nucleophilic substitution in the polynitropyrazoles
SYNTHESIS 2012, 44, 2058–2064
Advanced online publication: 04.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291134; Art ID: SS-2011-N1109-OP
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 4-Substituted 3,5-Dinitropyrazoles
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D).10a,b The results demonstrated the inversion of reactiv-
ity of position 4 in TNP: the ‘nucleophilic’ site becomes
‘electrophilic’. As a result of reactivity study of the wide
range of compounds, the possibility of N-unsubstituted
pyrazoles functionalization via nucleophlic substitution at
C-4 has been established for the first time.
Cl
SR
NO2
NO2
O2N
O2N
i
NH
ClDNP
N
N
NH
3a R = Et 66% (70%)
3b R = Ph 94% (98%)
3c R = 4-BrC6H4 97% (91%)
3d R = 4-ClC6H4 95% (85%)
3e R = 4-ClC6H4CH2 87% (95%)
3f R = CH2CO2H 71% (78%)
At the same time, the N-1 substituted 3,4,5-trinitropyr-
azoles, which cannot form the respective anionic form un-
der the reaction conditions, obey the established rule for
the 3,4- and 3,5-dinitropyrazoles of the terminal nitro
group substitution (Scheme 1, route E).10c,11,13 Thus, the
possibilities of C-4 nucleophilic functionalization in pyr-
azoles are narrowed to the N-unsubstituted TNP. More-
over, the practical applications of TNP derivatives are
restricted by applying the proper safety protocols, espe-
cially when handling multigram quantities.3
Scheme 3 Reactions of ClDNP with S-nucleophiles. Reagents and
conditions: (i) 1. RSH (1.2 equiv), NaOH (2 equiv), H2O, r.t., 8 h; 2.
aq 20% H2SO4 [1. RSH (1.2 equiv), NaOH (2 equiv), H2O, r.t., 3 h; 2.
aq 20% H2SO4]. The reaction conditions used for TNP are given in
square brackets.
Sodium hydroxide, phenols, and 2,2,2-trifluoroethanol
were used as O-nucleophiles. The reaction in water at 70–
80 °C using of two equivalents of NaOH led to formation
of products 4b–g (Scheme 4). Under these conditions the
full conversion was achieved after 12 hours, and yields af-
ter acidification with aqueous 20% H2SO4 are 43–91%.
Four equivalents of NaOH were used for the synthesis of
4-hydroxy-3,5-dinitropyrazole (4a).
In our opinion, the N-unsubstituted 4-chloro-3,5-dinitro-
pyrazole (ClDNP, 1) could be regarded as the alternative
to TNP. Such opinion is based on the fact that compound
1 contains highly activated leaving group at C-4, the chlo-
rine atom, and the NH acidity of ClDNP is comparable to
that of TNP.14,15
4-Chloro-3,5-dinitropyrazole was synthesized by direct
acid nitration of the available 4-chloropyrazole using a
mixture of sulfuric and nitric acids (Scheme 2). It should
be mentioned that, unlike TNP, the ClDNP is much easier
and safer to handle.
Cl
OH
NO2
NO2
O2N
O2N
i
NH
N
N
NH
ClDNP
4a
93% (74%*)
ii
Cl
Cl
Cl
OR
4b R = CH2CF3 43% (49%)
4c R = Ph 90% (50%)
4d R = 2-MeOC6H4 91% (88%)
4e R = 3-F3CC6H4 62% (50%)
4f R = 4-ClC6H4 68% (75%)
4g R = 3,4-Me2C6H3 69% (67%)
NO2
ii
i
O2N
NO2
O2N
NO2
O2N
N
N
N
NH
N
NH
Me
2
N
NH
ClDNP (1)
Scheme 2 Synthesis of 4-chloro-3,5-dinitropyrazole (1) and its N-
methyl derivative 2. Reagents and conditions: (i) H2SO4–HNO3,
100 °C, 5 h, 70%; (ii) Me2SO4 (1.2 equiv), NaHCO3 (2 equiv), H2O,
25 °C, 4 h, 87%.
Scheme 4 Reactions of ClDNP with O-nucleophiles. Reagents and
conditions: (i) 1. NaOH (4 equiv), H2O, 80–90 °C, 12 h; 2. aq 20%
H2SO4 [*1. NaOH (10 equiv), H2O, r.t., 8 h; 2. aq 20% H2SO4 ]; (ii) 1.
3
ROH (1 equiv), NaOH (2 equiv), H2O, 70–80 °C, 12 h; 2. aq 20%
H2SO4 [1. ROH (1 equiv), NaOH (2 equiv), H2O, r.t., 10 h; 2. aq 20%
H2SO4]. The reaction conditions used for TNP are given in square
brackets.
The nucleophilic substitution in ClDNP under the action
of S-, O-, and N-nucleophiles was studied. As in the case
of TNP, the reactions were carried out in water in the pres-
ence of excess of neutral N-nucleophiles (amines) or with
one equivalent of additional base in the case of anionic S-
and O-nucleophiles. Thus ClDNP formed the N-anion pri-
or to the substitution stage. It should be mentioned that
use of only one equivalent of neutral N-nucleophile or
only one equivalent of anionic S/O-nucleophile without
additional base led to formation of ClDNP salt.
Next, ammonia and aliphatic amines were used as N-nu-
cleophiles. In the case of secondary amines, the reactions
in water at 70–80 °C proceed with three equivalents of the
amine (Scheme 5). Under these conditions, the full con-
version is achieved after 18 hours, and yields after acidi-
fication by aqueous 20% H2SO4 are 79–95%.
At the same time, in the cases of reactions with ammonia
and methylamine carried out in commercial water solu-
tions, more drastic conditions like heating in a sealed ves-
sel at an elevated temperature were applied. The full
conversion of ClDNP (1) into 5a in the reaction with the
least reactive ammonia required 10 hours and 170 °C, and
the yield of product monohydrate is 85%7a,10a,16–19
(Scheme 5).
The aliphatic and aromatic thiols were studied as the S-
nucleophiles. The reactions in water at room temperature
with two equivalents of NaOH led to formation of prod-
ucts 3a–f (Scheme 3). Under these conditions, the full
conversion was achieved after eight hours, and yields af-
ter acidification by aqueous 20% H2SO4 were 66–97%.
For comparison reasons, hereafter the yields of the respec-
tive TNP products are shown in parentheses.10a
Methylamine is more reactive than ammonia. For the full
conversion, four hours at 120 °C was required; under
© Georg Thieme Verlag Stuttgart · New York
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I. L. Dalinger et al.
PAPER
NHMe
NH
Cl
NH2
NO2
NO2
NO2
ii
i
O2N
O2N
O2N
NH
N
N
N
NH
ClDNP
5b, 65% (87%)
5a, 85% (80%)
iii
NR1R2
5c R1R2 = -(CH2)4- 80% (80%)
5d R1R2 = -(CH2)2O(CH2)2- 95% (74%)
5e R1R2 = -(CH2)6- 83% (87%)
NO2
O2N
5f R1R2 = -(CH2)5- 79% (89%)
N
NH
5g R1R2 = -(CH2)2CMe(CH2)2- 92% (74%)
5h R1R2 = -(CH2)2NMe(CH2)2- 80% (84%)
Scheme 5 Reactions of ClDNP with N-nucleophiles. Reagents and conditions: (i) 1. aq NH3 (10 equiv), H2O, 170 °C, 10 h; 2. aq 20% H2SO4
[1. aq NH3 (10 equiv), H2O, r.t., 10 h; 2. aq 20% H2SO4]; (ii) 1. aq MeNH2 (10 equiv), H2O, 120 °C, 4 h; 2. aq 20% H2SO4 [1. MeNH2 (10
equiv), H2O, r.t., 10 h; 2. aq 20% H2SO4]; (iii) 1. NR1R2 (3 equiv), H2O, 70–80 °C, 18 h; 2. aq 20% H2SO4 [1. NR1R2 (3.5 equiv), H2O, r.t., 10
h; 2. aq 20% H2SO4]. The reaction conditions used for TNP are given in square brackets.
these conditions the yield of 5b was 65% (Scheme 5).
O
Cl
SPh
Here, the rising of the temperature or increasing the reac-
tion time led to the ClDNP destruction.
NO2
NO2
O2N
O2N
ii
i
N
N
N
N
N
NO2
O2N
The structures of compounds 3–5 were established using
the comparison of their 1H NMR, IR, and mass spectra as
well as their melting points with respective samples ob-
tained from TNP.10a
Me
8, 79%
Me
2
N
N
iii
Me
7, 80%
OR
4-(N-Methylnitramino)-3,5-dinitropyrazole (6) was syn-
thesized via direct nitration of 5b (Scheme 6).
NO2
O2N
9a R = 4-BrC6H4 83%
N
N
9b R = 2-MeOC6H4 85%
Me
Me
NO2
NHMe
N
Scheme 7 Reactions of 4-chloro-1-methyl-3,5-dinitropyrazole (2)
with N-, S-, and O-nucleophiles. Reagents and conditions: (i) mor-
pholine (3 equiv), MeOH, reflux, 7 h; (ii) PhSH (1.1 equiv), NaOH
(1.1 equiv), MeCN–H2O, r.t., 10 h; (iii) ROH (1.1 equiv), NaOH (1.1
equiv), MeCN–H2O, r.t., 10 h.
NO2
NO2
O2N
O2N
i
NH
NH
N
N
5b
6, 60%
Scheme 6 Synthesis of 6. Reagents and conditions: (i) HNO3–Ac2O,
CF3CO2H, 0–5 °C, 2 h.
tions require ten hours at room temperature, and the yields
of 8 and 9a,b are 79% and 83–85%, respectively.
The structures of the products 7–9 were established on the
base of 1H and 13C NMR and mass spectral data. The mass
spectra of these compounds do not contain the isotopic
patterns, which could be assigned to the chlorine-contain-
ing species. In the 13C NMR spectra, the presence of two
broadening low-field signals at δ = 143–151 and 138–146
ppm is characteristic of the C3-NO2 and C5-NO2, respec-
tively. The signals of N-methyl group (1H: δ = 4.19–4.31;
13C: δ = 42.7–43.3) are shifted towards low field com-
pared to the spectra of the isomeric 5-substituted 1-meth-
yl-3,4-dinitropyrazoles (1H: δ = 3.73–3.95; 13C: δ =
36.30–39.19).10c
Thus, we have shown that regiospecificity of the nucleo-
philic substitution in ClDNP (taken in its anionic form) is
similar to that of TNP. Although exploitation of ClDNP
requires more drastic conditions compared to TNP, the
nucleophilic substitution in ClDNP using S-, O-, and N-
nucleophiles was proven to be the effective synthetic
method for preparing 4-X-3,5-dinitropyrazoles (X = O, S,
N), particularly, when multigram quantities are needed.
4-Chloro-1-methyl-3,5-dinitropyrazole (2) was obtained
via methylation of ClDNP with dimethyl sulfate (see
Scheme 2). The investigation of nucleophilic substitution
in 2 has again proved that the nucleophilic attack occurs
at position 4 (Scheme 7).20,21
The structure of 8 was additionally confirmed by its inde-
pendent synthesis via the alkylation of 3,5-dinitro-4-phen-
ylthiopyrazole (Scheme 8). All these data prove that it is
the Cl atom in 1-methyl-3,5-dinitro-4-chloropyrazole that
undergoes substitution under the action of nucleophiles.
For example, the respective products 7–9 are formed as a
result of the reactions of pyrazole 2 with 3 equivalents of
morpholine in methanol, or 1.1 equivalents of thiophenol,
4-bromo- and 2-methoxyphenols in the presence of 1.1
equivalents of NaOH in aqueous acetonitrile (Scheme 7).
In the case of morpholine, the full conversion was
achieved after seven hours of refluxing, and the yield of 7
was 80%. For the anionic S- and O-nucleophiles, the reac-
In conclusion, we have shown that unlike TNP, in ClDNP
the nucleophilic substitution proceeds exclusively with Cl
atom substitution at position 4, and this result does not de-
pend on of the charge of the substrate molecule. Thus, 4-
chloro-3,5-dinitropyrazole is shown to be an unique start-
Synthesis 2012, 44, 2058–2064
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Synthesis of 4-Substituted 3,5-Dinitropyrazoles
2061
4-(Ethylthio)-3,5-dinitro-1H-pyrazole (3a)
SPh
N
SPh
Yield: 0.43 g (66%); canary solid; mp 92–93 °C.
NO2
O2N
NO2
O2N
i
IR (KBr): 3544, 3428 (NH), 1556, 1512, 1480, 1400, 1348, 1320
cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 1.15 (t, J = 7.4 Hz, 3 H, CH3), 2.95
(q, J = 7.4 Hz, 2 H, CH2Me).
N
N
NH
Me
8, 90%
3b
Scheme 8 Independent synthesis of 3,5-dinitro-4-phenylthiopyrazole
(8). Reagents and conditions: (i) Me2SO4 (1.2 equiv), NaHCO3 (2
equiv), H2O, r.t., 4 h.
MS: m/z = 218 [M]+.
3,5-Dinitro-4-(phenylthio)-1H-pyrazole (3b)
Yield: 0.75 g (94%); bright yellow-orange solid; mp 155–156 °C.
IR (KBr): 3540, 3428 (NH), 1556, 1512, 1440, 1376, 1320 cm–1
(NO2).
1H NMR (DMSO-d6/TMS): δ = 7.35 (m, C6H5).
MS: m/z = 266 [M]+.
ing molecule for the preparative synthesis of 4-substituted
3,5-dinitropyrazoles using S-, O-, and N-nucleophiles.
Melting points were determined on Reichert Kofler thermopan ap-
paratus and are uncorrected. NMR spectra were recorded in DMSO-
d6 solutions at 298 K on Bruker AC-300 [operating at 300.13 MHz
(1H), 75.47 (13C)] spectrometer. TMS was used as internal standard
for 1H and 13C NMR spectra. IR spectra were measured on a Bruker
ALPHA spectrometer as KBr pellets. Mass spectra were obtained
on Finnigan MAT INCOS 50 (EI, 70 eV) and Bruker MicrOTOF II
instruments. Elemental analysis was performed with Perkin-Elmer
Series II 2400 analyzer. The course of the reactions was monitored
and the purity of the compounds was checked by TLC using Merck
silica gel 60 F254 plates. Compounds 3–5 obtained from ClDNP
were identified by comparison of their properties with those pub-
lished recently.10a
4-[(4-Bromophenyl)thio]-3,5-dinitro-1H-pyrazole (3c)
Yield: 1.00 g (97%); canary solid; mp 136–137 °C.
IR (KBr): 3588, 3088 (NH), 1552, 1472, 1404, 1388, 1316 cm–1
(NO2).
1H NMR (DMSO-d6/TMS): δ = 7.17 (d, J = 8.4 Hz, 2 H, C6H5),
7.45 (d, J = 8.4 Hz, 2 H, C6H5).
MS: m/z = 344, 346 (1:1, [M]+).
4-[(4-Chlorophenyl)thio]-3,5-dinitro-1H-pyrazole (3d)
Yield: 0.85 (95%); bright yellow-orange solid; mp 138–139 °C.
IR (KBr): 3580, 3088 (NH), 1552, 1480, 1472, 1388, 1316 cm–1
(NO2).
4-Chloro-3,5-dinitro-1H-pyrazole (1)
To a stirred solution 4-chloropyrazole (15.6 g, 0.12 mol) in H2SO4
(d = 1.824 g·cm–3, 190 mL) was added HNO3 (d = 1.51 g·cm–3, 20
mL) dropwise at 15–25 °C and the stirring was continued for 5 h at
100–105 °C. The resulting mixture was poured into ice-water (1 L),
and extracted with EtOAc (2 × 300 mL). The combined organic lay-
ers were washed with H2O (50 mL) and dried (MgSO4). The solvent
was then removed in vacuo and the residue was crystallized from
H2O.; yield: 16.9 g (70%); yellowish solid; mp 157–159 °C.
IR (KBr): 3253 (NH), 1572, 1531, 1421, 1325 cm–1 (NO2).
13C NMR (DMSO-d6/TMS): δ = 148.97 (C-3,5), 103.09 (C-4).
MS: m/z = 192, 194 (4:1, [M]+).
1H NMR (DMSO-d6/TMS): δ = 7.15 (d, J = 8.2 Hz, 2 H, C6H5),
7.45 (d, J = 8.2 Hz, 2 H, C6H5).
4-[(4-Chlorobenzyl)thio]-3,5-dinitro-1H-pyrazole (3e)
Yield: 0.82 g (87%); canary solid; mp 166–167 °C.
IR (KBr): 2968, 2924 (NH), 1560, 1488, 1472, 1396, 1312 cm–1
(NO2).
1H NMR (DMSO-d6/TMS): δ = 4.23 (s, 2 H, CH2), 7.15 (d, J = 8.2
Hz, 2 H, C6H5), 7.39 (d, J = 8.2 Hz, 2 H, C6H5).
MS: m/z = 314, 316 (3:2, [M]+).
S-(3,5-Dinitro-1H-pyrazole-4-yl) Hydrogenthiocarbonate (3f)
Yield: 0.53 g (71%); yellow solid; mp 114–115 °C.
IR (KBr): 1712, 1680 (CO2H), 1560, 1408, 1396, 1324, 1316 cm–1
(NO2).
Anal. Calcd for C3HClN4O4: C, 18.70; H, 0.52; N, 29.10. Found: C,
18.88; H, 0.65; N, 29.22.
4-Chloro-1-methyl-3,5-dinitro-1H-pyrazole (2)
To a stirred solution of NaHCO3 (0.51 g, 6 mmol) in H2O (10 mL)
was added ClDNP (1; 0.58 g, 3 mmol). The mixture was stirred for
10 min, followed by addition of Me2SO4 (0.34 mL, 3.6 mmol). The
stirring was continued for 4 h at r.t. The precipitate formed was col-
lected by filtration and dried over P2O5; yield: 0.54 g (87%); white
solid; mp 101–103 °C (Lit.22 mp 101.5–102.5 °C).
1H NMR (DMSO-d6/TMS): δ = 4.25 (s, CH3).
13C NMR (DMSO-d6/TMS): δ = 148.10 (C-3), 143.15 (C-5),
1H NMR (DMSO-d6/TMS): δ = 3.72 (s, 2 H, CH2).
MS: m/z = 246 (M – 2 H)+.
4-Hydroxy-3,5-dinitro-1H-pyrazole (4a)
To a stirred solution of ClDNP (1; 2 g, 0.01 mol) in H2O (20 mL)
was added NaOH (1.66 g, 0.04 mol) and the stirring was continued
for 12 h at 80–90 °C. After cooling, the mixture was diluted with
EtOH (40 mL), the precipitate formed was collected by filtration,
suspended in H2O (3 mL), and acidified with aq 20% H2SO4 to pH
1. The resulting mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried (MgSO4), the solvent was
removed in vacuo, and the residue was crystallized from toluene;
yield: 1.67 g (93%); cream solid; 198–200 °C (dec.) [Lit.3 DSC
(8 °C/min) 194 °C (dec.)].
105.92 (C-4), 43.83 (NCH3).
MS: m/z = 206, 208 (4:1, [M]+).
4-Alkyl-/arylthio-3,5-dinitro-1H-pyrazoles 3a–f; General Pro-
cedure
To a solution of ClDNP (1; 0.58 g, 3 mmol) in H2O (10 mL) was
added NaOH (0.24 g, 3 mmol), and the mixture was stirred for 10
min. Then, a solution of NaOH (0.24 g, 3 mmol) and the appropriate
thiol (3.6 mmol) in H2O (10 mL) was added slowly. The stirring was
continued for 8 h at r.t. and then the mixture was acidified with aq
20% H2SO4 to pH 1. The precipitate formed was collected by filtra-
tion, dried, and crystallized from MeOH–H2O.
IR (KBr): 3397, 3272 (NH), 1632, 1531, 1496, 1340 (NO2), 1246,
1210, 833, 843 cm–1.
13C NMR (DMSO-d6/TMS): δ = 134.76 (C-4), 139.36 (C-3,5).
4-Alkoxy/aryloxy-3,5-dinitro-1H-pyrazoles 4b–g; General Pro-
cedure
To a solution of ClDNP (1; 0.58 g, 3 mmol) in H2O (10 mL) was
added NaOH (0.24 g, 3 mmol), and the mixture was stirred for 10
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I. L. Dalinger et al.
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min. Then, a solution of NaOH (0.24 g, 3 mmol) and the appropriate
phenol (or 2,2,2-trifluoroethanol) (3 mmol) in H2O (10 mL) was
added slowly. The stirring was continued for 12 h at 70–80 °C, and
then the mixture was acidified with aq 20% H2SO4 to pH 1. The pre-
cipitate formed was collected by filtration, dried, and crystallized
from MeOH–H2O. In the case of 4b, the resulting mixture was ex-
tracted with EtOAc (2 × 10 mL). The combined organic layers were
dried (MgSO4), the solvent was removed in vacuo, and the residue
was triturated with hexane.
For obtaining the nonhydrated compound, 5a monohydrate was
added slowly to boiling toluene (200 mL) and the mixture was kept
under reflux with Dean–Stark trap for 1 h. After cooling, the precip-
itate was collected by filtration and dried on air; yield: 10.1 g (70%);
canary solid; DSC (10 °C/min) endotherm peak 183.5 °C, exotherm
peak 187.3 °C [Lit.17 DSC (10 °C/min) endotherm peak 175.7–
177.0 °C, exotherm peak 183.6 °C].
IR (KBr): 3436, 3324, 3172 (NH), 1650, 1525, 1350 cm–1 (NO2).
13C NMR (DMSO-d6/TMS): δ = 128.96 (C-4), 138.84 (C-3,5).
3,5-Dinitro-4-(2,2,2-trifluoroethoxy)-1H-pyrazole (4b)
–
HRMS-ESI (–): m/z [M – H]– calcd for C3H2N5O4 : 172.0112;
found: 172.0117.
Yield: 0.33 g (43%); pale beige solid; mp 133–135 °C.
IR (KBr): 3674, 3490 (NH), 1596, 1560, 1478, 1334 cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 4.83 (q, J = 8.8 Hz, CH2CF3).
MS: m/z = 256 [M]+.
4-Methylamino-3,5-dinitro-1H-pyrazole (5b)
A solution of ClDNP (1; 16 g, 0.083 mol) in aq 40% MeNH2 (150
mL, 1.74 mol) was kept in a stainless steel bomb at an internal tem-
perature of 120 °C for 4 h. After cooling, the solution was acidified
with aq 20% H2SO4 to pH 1, the precipitate formed was collected
by filtration, dried, and crystallized from EtOH–H2O (1:1); yield:
10.1 g (65%); orange solid; mp 170–171 °C.
3,5-Dinitro-4-phenoxy-1H-pyrazole (4c)
Yield: 0.68 g (90%); beige solid; mp 162–164 °C.
IR (KBr): 3492, 3260 (NH), 1620, 1564, 1436, 1372, 1300 cm–1
(NO2).
1H NMR (DMSO-d6/TMS): δ = 7.07 (m, 3 H, C6H5), 7.32 (m, 2 H,
IR (KBr): 3360, 3144 (NH), 1620, 1488, 1424, 1388, 1352, 1304
cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 3.00 (s, NCH3).
MS: m/z = 187 [M]+.
C6H5).
MS: m/z = 250 [M]+.
4-(2-Methoxyphenoxy)-3,5-dinitro-1H-pyrazole (4d)
4-Amino-Substituted 3,5-Dinitro-1H-pyrazoles 5c–h; General
Procedure
Yield: 0.77 g (91%); pale yellow solid; mp 144–145 °C.
IR (KBr): 3490, 3488 (NH), 1556, 1512, 1372, 1336 cm–1 (NO2).
To a solution of ClDNP (1; 0.38 g, 2 mmol) in H2O (5 mL) was add-
ed the appropriate amine (6 mmol) and the reaction mixture was left
for 18 h at 70–80 °C. After cooling, the precipitate was collected by
filtration, washed with cold MeOH (1 mL), suspended in H2O (3
mL), and acidified with aq 20% H2SO4 to pH 1. The resulting pre-
cipitate was collected by filtration, dried, and crystallized from
EtOH–H2O (1:1).
1H NMR (DMSO-d6/TMS): δ = 3.81 (s, 3 H, CH3), 6.80 (m, 1 H,
C6H5), 6.88 (m, 1 H, C6H5), 7.03 (m, 1 H, C6H5), 7.13 (m, 1 H,
C6H5).
MS: m/z = 280 [M]+.
3,5-Dinitro-4-[3-(trifluoromethyl)phenoxy]-1H-pyrazole (4e)
Yield: 0.59 g (62%); pale yellow solid; mp 136–138 °C.
IR (KBr): 3628, 3490, 2992 (NH), 1596, 1512, 1480, 1316 cm–1
(NO2).
3,5-Dinitro-4-(pyrrolidin-1-yl)-1H-pyrazole (5c)
Yield: 0.36 g (80%); brown solid; mp 170–172 °C.
IR (KBr): 3330, 2944 (NH), 1612, 1420, 1366, 1304 cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 7.38 (m, 1 H, C6H5), 7.45 (m, 2 H,
1H NMR (DMSO-d6/TMS): δ = 1.92 (m, 4 H, CH2), 3.36 (m, 4 H,
C6H5), 7.57 (m, 1 H, C6H5).
CH2).
MS: m/z = 318 [M]+.
MS: m/z = 227 [M]+.
4-(4-Chlorophenoxy)-3,5-dinitro-1H-pyrazole (4f)
Yield: 0.64 g (75%); off-white solid; mp 129–131 °C.
4-(3,5-Dinitro-1H-pyrazol-4-yl)morpholine (5d)
Yield: 0.46 g (95%); orange solid; 238 °C (dec.).
IR (KBr): 3574, 2992 (NH), 1596, 1512, 1402, 1310 cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 7.09 (d, J = 8.7 Hz, 2 H, C6H5),
7.38 (d, J = 8.7 Hz, 2 H, C6H5).
IR (KBr): 3024, 2972 (NH), 1604, 1500, 1456, 1392, 1368 cm–1
(NO2).
1H NMR (DMSO-d6/TMS): δ = 3.22 (m, 4 H, CH2), 3.75 (m, 4 H,
CH2).
MS: m/z = 243 [M]+.
MS: m/z = 284, 286 (2:3, [M]+).
4-(3,4-Dimethylphenoxy)-3,5-dinitro-1H-pyrazole (4g)
Yield: 0.58 g (69%); pale yellow solid; mp 206–208 °C.
IR (KBr): 3580, 2992 (NH), 1560, 1488, 1368, 1336 cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 2.15 (s, 6 H, CH3), 6.76 (m, 1 H,
C6H5), 6.83 (m, 1 H, C6H5), 7.03 (m, 1 H, C6H5)
MS: m/z = 278 [M]+.
1-(3,5-Dinitro-1H-pyrazol-4-yl)azepane (5e)
Yield: 0.42 (83%); orange solid; mp 188–190 °C.
IR (KBr): 3022, 2980 (NH), 1600, 1556, 1480, 1392, 1336 cm–1
(NO2).
1H NMR (DMSO-d6/TMS): δ = 1.65 (m, 8 H, CH2), 3.24 (m, 4 H,
CH2).
MS: m/z = 255 [M]+.
4-Amino-3,5-dinitro-1H-pyrazole (5a)
A solution of ClDNP (1; 16 g, 0.083 mol) in aq 25% NH3 (150 mL,
1.74 mol) was kept in a stainless steel bomb at an external temper-
ature of 170 °C for 10 h. After cooling, the solution was acidified
with aq 20% H2SO4 to pH 1. The resulting mixture was extracted
with EtOAc (3 × 50 mL) and the combined organic layers were
dried (MgSO4). The solvent was removed in vacuo and the residue
was crystallized from H2O; yield: 13.5 g (85%) of monohydrate of
5a as a yellow solid; mp 166–168 °C (Lit.17 mp 169–171 °C).
1-(3,5-Dinitro-1H-pyrazol-4-yl)piperidine (5f)
Yield: 0.38 g (79%); yellow solid; mp 166–168 °C.
IR (KBr): 3232, 2932, 2848 (NH), 1600, 1404, 1304 cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 1.61 (m, 6 H, CH2), 3.12 (m, 4 H,
CH2).
MS: m/z = 241 [M]+.
Synthesis 2012, 44, 2058–2064
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PAPER
Synthesis of 4-Substituted 3,5-Dinitropyrazoles
2063
1-(3,5-Dinitro-1H-pyrazol-4-yl)-4-methylpiperidine (5g)
13C NMR (DMSO-d6/TMS): δ = 42.69 (NCH3), 107.99 (C-4),
127.49 (CH), 128.55 (CH), 129.40 (CH), 132.84, 146.22 (C-5),
151.12 (C-3).
Yield: 0.46 g (92%); yellow-orange solid; mp 138–139 °C.
IR (KBr): 3248, 2960, 2932 (NH), 1528, 1464, 1364, 1300 cm–1
(NO2).
MS: m/z = 280 [M]+.
1H NMR (DMSO-d6/TMS): δ = 0.93 (m, 3 H), 1.30 (m, 2 H), 1.55
(m, 1 H), 1.64 (m, 2 H), 3.08 (m, 2 H), 3.21 (m, 2 H).
Anal. Calcd for C10H8N4O4S: C, 42.86; H, 2.88; N, 19.99. Found:
C, 43.15; H, 3.01; N, 20.37.
MS: m/z = 255 [M]+.
Method B: To a solution of NaHCO3 (0.34 g, 4 mmol) in H2O (10
mL) was added compound 3b (0.53 g, 2 mmol). The mixture was
stirred for 10 min, followed by addition of Me2SO4 (0.23 mL, 2.4
mmol). The stirring was continued for 4 h at r.t. The precipitate
formed was collected by filtration and dried over P2O5; yield: 0.50
g (90%); mp 107–109 °C.
1-(3,5-Dinitro-1H-pyrazol-4-yl)-4-methylpiperazine (5h)
Yield: 0.40 g (80%); yellow solid; 247 °C (dec.).
IR (KBr): 2960, 2692 (NH), 1596, 1412, 1402, 1372, 1304, 1272
cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 2.81 (s, 3 H, NCH3), 3.15 (m, 2 H,
CH2), 3.42 (m, 4 H, CH2), 3.58 (m, 2 H, CH2).
MS: m/z = 256 [M]+.
4-Aryl-1-methyl-3,5-dinitro-1H-pyrazoles 9a,b; General Proce-
dure
To a solution of NaOH (2.2 mmol) in H2O (3 mL) was added the ap-
propriate phenol (2.2 mmol) and the mixture was stirred for 10 min.
Then, a solution of pyrazole 2 (2 mmol) in MeCN (10 mL) was add-
ed and the reaction mixture was left for 10 h at r.t. The solvent was
removed in vacuo, and the residue was collected by filtration,
washed with H2O (3 mL), and crystallized from CCl4.
4-(N-Methylnitramino)-3,5-dinitro-1H-pyrazole (6)
To a suspension of pyrazole 5b (0.47 g, 2.5 mmol) in CF3CO2H (5
mL) was added HNO3 (d = 1.51 g·cm–3, 1.65 mL) dropwise with
stirring at 0 °C, followed by slow addition of Ac2O (0.50 mL). The
stirring was continued for 2 h at 0–2 °C. The resulting mixture was
poured into ice-water (30 mL), and extracted with CH2Cl2 (3 × 7
mL). The combined organic layers were washed with H2O (3 mL)
and dried (MgSO4). The solvent was removed in vacuo and the res-
idue was crystallized from CHCl3; yield: 0.35 g (60%); pale yellow
solid; mp 151–153 °C.
4-(4-Bromophenoxy)-1-methyl-3,5-dinitro-1H-pyrazole (9a)
Yield: 0.63 g (83%); pale brown solid; mp 158–160 °C.
IR (KBr): 1604, 1584, 1484, 1444, 1322, 1312 cm–1 (NO2).
1H NMR (DMSO-d6/TMS): δ = 4.31 (s, 3 H, NCH3), 7.15 (d,
J = 8.7 Hz, 2 Harom), 7.52 (d, J = 8.7 Hz, 2 Harom).
13C NMR (DMSO-d6/TMS): δ = 43.32 (NCH3), 115.42 (CBr),
117.66 (CH), 128.36 (C-4), 132.55 (CH), 138.51 (C-5), 143.13 (C-
3), 155.76 (C–O).
IR (KBr): 3331 (NH), 1616, 1554, 1429, 1360, 1287 (NO2), 842
cm–1.
13C NMR (DMSO-d6/TMS): δ = 147.42 (C-3,5), 111.82 (C-4),
40.75 (CH3).
MS: m/z = 186 [M – NO2]+, 233 [M + H]+.
MS: m/z = 342, 344 (1:1, [M]+).
Anal. Calcd for C10H7BrN4O5: C, 35.01; H, 2.06; N, 16.33. Found:
C, 35.25; H, 2.18; N, 16.52.
Anal. Calcd for C4H4N6O6: C, 20.70; H, 1.74; N, 36.20. Found: C,
21.00; H, 1.80; N, 37.22.
4-(2-Methoxyphenoxy)-1-methyl-3,5-dinitro-1H-pyrazole (9b)
4-(1-Methyl-3,5-dinitro-1H-pyrazol-4-yl)morpholine (7)
To a solution of pyrazole 2 (0.41 g, 2 mmol) in MeOH (10 mL) was
added morpholine (0.53 mL, 6 mmol) and the reaction mixture was
refluxed for 7 h. After cooling to 0–5 °C, the precipitate was collect-
ed by filtration, dried over P2O5, and crystallized from MeOH–H2O;
yield: 0.41 g (80%); orange solid; mp 140–142 °C.
Yield: 0.50 g (85%); beige solid; mp 136–138 °C.
IR (KBr): 1600; 1580, 1504, 1448, 1332, 1316, 1256, 1212 (NO2),
1172, 744 cm–1.
1H NMR (DMSO-d6/TMS): δ = 3.71 (s, 3 H, OCH3), 4.29 (s, 3 H,
NCH3), 6.83 (m, 1 Harom), 6.95 (m, 1 Harom), 7.15 (m, 2 Harom).
IR (KBr): 2960, 2904, 2868, 1596, 1516, 1432, 1424, 1308, 1288,
1264 (NO2), 1104 cm–1.
1H NMR (DMSO-d6/TMS): δ = 3.12 (t, J = 4.6 Hz, 4 H, CH2), 3.71
(t, J = 4.6 Hz, 4 H, CH2), 4.12 (s, 3 H, NCH3).
13C NMR (DMSO-d6/TMS): δ = 43.18 (NCH3), 55.90 (OCH3),
113.29 (CH), 115.08 (CH), 120.45 (CH), 124.35 (CH), 129.67 (C-
4), 138.15 (C-5), 143.10 (C-3), 145.46 (C–O), 148.59 (C–OMe).
MS: m/z = 294 [M]+.
13C NMR (DMSO-d6/TMS): δ = 42.91 (NCH3), 50.47, 66.37,
127.26 (C-4), 139.21 (C-5), 145.60 (C-3).
Anal. Calcd for C11H10N4O6: C, 44.90; H, 3.43; N, 19.04. Found: C,
45.28; H, 3.60; N, 19.18.
MS: m/z = 258 [M + H]+.
Anal. Calcd for C8H11N5O5: C, 37.36; H, 4.31; N, 27.23. Found: C,
37.65; H, 4.46; N, 27.74.
References
(1) (a) Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011, 15,
1423. (b) Schmidt, A.; Dreger, A. Curr. Org. Chem. 2011,
15, 2897. (c) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.;
Simon-Fuentes, A. Chem. Rev. 2011, 111, 6984. (d) Fustero,
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Thermochim. Acta 2002, 384, 187. (b) Agrawal, J. P.;
Hodgson, D. L. Organic Chemistry of Explosives; Wiley:
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1-Methyl-3,5-dinitro-4-phenylthio-1H-pyrazole (8)
Method A: To a solution of NaOH (0.09 g, 2.2 mmol) in H2O (3 mL)
was added thiophenol (0.23 mL, 2.2 mmol), and the mixture was
stirred for 10 min. Then, a solution of pyrazole 2 (0.41 g, 2 mmol)
in MeCN (10 mL) was added. The stirring was continued for 10 h
at r.t. The mixture was diluted with H2O (30 mL), the precipitate
was collected by filtration, and crystallized from MeOH–H2O;
yield: 0.44 g (79%); canary solid; mp 107–109 °C.
IR (KBr): 1540, 1484, 1440, 1412, 1388, 1324, 1296 (NO2), 748
cm–1.
1H NMR (DMSO-d6/TMS): δ = 4.23 (s, 3 H, NCH3), 7.39 (m, 5 H,
C6H5).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2058–2064

2064
I. L. Dalinger et al.
PAPER
D. A.; Shreeve, J. M. Chem.–Eur. J. 2010, 16, 10778.
(g) Zhang, Y.; Huang, Y.; Parrish, D. A.; Shreeve, J. M.
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(b) Dalinger, I. L.; Vatsadze, I. A.; Shkineva, T. K.; Popova,
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(c) Dalinger, I. L.; Vatsadze, I. A.; Shkineva, T. K.; Popova,
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(12) Data for TNP: pKa = 0.05 (ref. 10a); pKa = 2.35 (ref. 3).
(13) Dalinger, I. L.; Vatsadze, I. A.; Shkineva, T. K.; Popova, G.
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(14) For the first time 4-chloro-3,5-dinitropyrazole was used in
our work,15 though no details on synthesis and
characterization were published. Apparently, pKa value for
ClDNP should be less than the pKa for 3,5-dinitropyrazole
(3.15; ref. 7).
(15) Vinogradov, V. M.; Dalinger, I. L.; Shevelev, S. A.
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(16) Lebedev, V. P.; Matyushin, Yu. N.; Inozemtcev, Ya. O.;
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Proceedings of 29th International Annual Conference of
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(17) Schmidt, R. D.; Lee, G. S.; Pagoria, P. F.; Mitchell, A. R.;
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(18) The synthesis of 5a from ClDNP was mentioned in the
conference procedure,19 but no experimental details were
given.
(19) Ek, E.; Latypov, N.; Knutsson, M. Proceedings of 13th
Seminar on New Trends in Research of Energetic Materials;
April 21–23; Pardubice: Czech Republic, 2010, 89.
(20) 4-Bromo-1-methyl-3,5-dinitropyrazole, which is
structurally similar to ClDNP, reacts in the same manner
affording the respective 4-substituted 3,5-dinitropyrazoles
(ref. 21).
(4) (a) Boyer, J. H. Nitroazoles; VCH Publishers: Essen, 1986,
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(5) (a) Dalinger, I. L.; Cherkasova, T. I.; Popova, G. P.;
Shkineva, T. K.; Vatsadze, I. A.; Shevelev, S. A.;
Kanishchev, M. I. Russ. Chem. Bull. 2009, 58, 410.
(b) Dalinger, I. L.; Vatsadze, I. A.; Shkineva, T. K.;
Kortusov, I. O.; Popova, G. P.; Kachala, V. V.; Shevelev, S.
A. Russ. Chem. Bull. 2010, 59, 1786.
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Mendeleev Commun. 1997, 7, 58. (b) Zaitsev, A. A.;
Dalinger, I. L.; Starosotnikov, A. M.; Kachala, V. V.;
Strelenko, Yu. A.; Shkineva, T. K.; Shevelev, S. A. Russ. J.
Org. Chem. 2005, 41, 1507. (c) Zaitsev, A. A.; Cherkasova,
T. I.; Dalinger, I. L.; Kachala, V. V.; Strelenko, Yu. A.;
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P.; Shevelev, S. A. Russ. Chem. Bull. 2007, 56, 2074.
(d) Zaitsev, A. A.; Kortusov, I. O.; Dalinger, I. L.; Kachala,
V. V.; Popova, G. P.; Shevelev, S. A. Russ. Chem. Bull.
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L.; Kachala, V. V.; Shkineva, T. K.; Shevelev, S. A. Russ.
Chem. Bull. 2009, 58, 2122.
(7) Catalan, J.; Abboud, J. L. M.; Elguero, J. Adv. Heterocycl.
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(8) Thompson, A. M.; Blaser, A.; Anderson, R. F.; Shinde, S. S.;
Franzblau, S. G.; Ma, Z.; Denny, W. A.; Palmer, B. D.
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(21) Coburn, M. D. J. Heterocycl. Chem. 1971, 8, 153.
(22) Manaev, V. P.; Andreeva, M. A.; Perevalov, V. P.;
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Chem. USSR 1982, 52, 2291.
(9) Dalinger, I. L.; Popova, G. P.; Vatsadze, I. A.; Shkineva, T.
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Synthesis 2012, 44, 2058–2064
© Georg Thieme Verlag Stuttgart · New York