Nitropyrazoles 22. on reactivity of 3,5-dinitro-4-(phenylsulfonyl)pyrazole and its N-methyl derivative

Article abstract of DOI:10.1007/s11172-012-0067-9

3,5-Dinitro-4-(phenylsulfonyl)pyrazole (5) obtained by oxidation of 3,5-dinitro-4-(phenylthio)pyrazole with 30% H₂O₂ in AcOH was involved into nucleophilic substitution reaction with thiophenol, which proceeded with substitution of t

Full text of DOI:10.1007/s11172-012-0067-9

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 469—471, February, 2012
469
Nitropyrazoles
22*. On reactivity of 3,5ꢀdinitroꢀ4ꢀ(phenylsulfonyl)pyrazole and its Nꢀmethyl derivative
I. A. Vatsadze, I. L. Dalinger, T. K. Shkineva, G. P. Popova, and S. A. Shevelev.
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: dalinger@ioc.ac.ru
3,5ꢀDinitroꢀ4ꢀ(phenylsulfonyl)pyrazole (5) obtained by oxidation of 3,5ꢀdinitroꢀ4ꢀ
(phenylthio)pyrazole with 30% H2O2 in AcOH was involved into nucleophilic substitution
reaction with thiophenol, which proceeded with substitution of the phenylsulfonyl group at
position 4. NꢀMethylꢀ3,5ꢀdinitroꢀ4ꢀ(phenylsulfonyl)pyrazole obtained by methylation of 5 with
dimethyl sulfate was involved into nucleophilic substitution reaction with thiophenol, pꢀbromoꢀ
phenol, and morpholine with the regioselective substitution of the nitro group at position 5 to
form 5ꢀRꢀ3ꢀnitroꢀ4ꢀ(phenylsulfonyl)pyrazoles.
Key words: pyrazole, nitro group, nitropyrazoles, 3,5ꢀdinitropyrazoles, (phenylsulfonyl)ꢀ
nitropyrazoles, nucleophilic substitution, nucleophiles, regioselective substitution, methylation.
Earlier, taken nucleophilic substitution in 3,4,5ꢀtriꢀ
nitroꢀ1Hꢀpyrazole 1 and its Nꢀmethyl derivative 2 as an
example, we have found that traditional regioselectivity of
nucleophilic substitution (at position 3 or 5) depends on
the ability of trinitropyrazole derivatives to form an
Nꢀanion under the reaction conditions: for the first time,
a possibility of nucleophilic substitution of the nitro group
at position 4 of the trinitropyrazole Nꢀanion was demonꢀ
strated on a wide body of examples.2
nucleophilic substitution in these compounds did not
change in going from the N anion of NH pyrazole 3 to its
Nꢀmethyl derivative 4. In all the cases occurs the substituꢀ
tion of the Cl atom at position 4 (see Ref. 4).
Thus, the direction of nucleophilic substitution in
4ꢀXꢀ3,5ꢀdinitropyrazoles was found to depend not only
on the ability to form an anion under the reaction conꢀ
ditions, but also on the nature of the leaving group at
position 4.
At the same time, practical application of trinitropyrꢀ
azole derivatives 1 and 2 for the directed functionalization
of the pyrazole ring by nucleophilic substitution of an NO2
group is limited by the necessity of using certain precauꢀ
tions when the starting compounds 1 and 2 are handled on
a multigram scale (see Ref. 3).
Recently, we have found that 4ꢀchloroꢀ3,5ꢀdinitropyrꢀ
azole derivatives 3 and 4 can serve as convenient starting
compounds for the selective functionalization of position
4 in 3,5ꢀdinitropyrazoles. However, regioselectivity of the
In this connection, investigation of regularities of
nucleophilic substitution in dinitropyrazoles containing,
besides NO2 groups, an additional leaving group seems an
actual problem.
In the present work, we studied nucleophilic substituꢀ
tion in 3,5ꢀdinitroꢀ4ꢀ(phenylsulfonyl)ꢀ1Hꢀpyrazole (5)
and its Nꢀmethyl derivative, 1ꢀmethylꢀ3,5ꢀdinitroꢀ4ꢀ
(phenylsulfonyl)ꢀ1Hꢀpyrazole (6).
Dinitropyrazole 5 was obtained by the oxidation of
3,5ꢀdinitroꢀ4ꢀ(phenylthio)pyrazole 7 with 30% H2O2 in
acetic acid (Scheme 1). As typical representatives of Nꢀ,
Oꢀ, and Sꢀnucleophiles we have chosen morpholine,
pꢀbromophenol, and thiophenol. The reaction was carried
out in water in the temperature range 20—90 C. In the
case of morpholine, we used a threeꢀfold excess of the
latter, in the case of phenol and thiophenol, the reaction
was carried out using two equivalents of NaOH as a deproꢀ
tonating agent. Thus, the conditions of the reaction of
dinitropyrazole 5 with nucleophiles were completely the
same as in nucleophilic substitution in pyrazoles 1 and 3
(see Refs 2 and 4).
Comꢀ
pound
1
X
R
Comꢀ
pound
3
X
R
NO2
NO2
H
Me
Cl
Cl
H
Me
2
4
It was found that under indicated conditions, only
thiophenol was involved into the reaction with (phenylꢀ
* For Part 21, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 466—468, February, 2012.
1066ꢀ5285/12/6102ꢀ469 © 2012 Springer Science+Business Media, Inc.

470
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Vatsadze et al.
Scheme 2
sulfonyl)pyrazole 5, which led to the formation of phenyl
substituted derivative 7 in 90% yield (see Scheme 1).
pꢀBromophenol and morpholine did not give the reaction.
Scheme 1
i.
(3 equiv.), MeOH, 25 C, 10 h; ii. nꢀBrC6H4OH
i. 30% H2O2—AcOH, 60 °C, 12 h, 70%; ii. PhSH (1 equiv.)/NaOH
(2 equiv.), H2O, 25 °C, 7 h, 90%; iii. Me2SO4 (1.2 equiv.)/NaHCO3
(2 equiv.), H2O, 25 °C, 7 h, 75%
(1.1 equiv.)/NaOH (1.1 equiv.), MeCN/H2O, 25 C, 10 h;
iii. PhSH (1.1 equiv.)/NaOH (1.1 equiv.), MeCN/H2O, 25 C,
10 h.
Thus, a conclusion can be drawn that the regioselecꢀ
tivity of nucleophilic substitution in 3,5ꢀdinitroꢀ4ꢀ(phenylꢀ
sulfonyl)pyrazole 5 is the same as in 4ꢀXꢀ3,5ꢀdinitropyrꢀ
azoles 1 (X = NO2) and 3 (X = Cl). Namely, the 4ꢀPhSO2
group is the group which undergoes the selective replaceꢀ
ment as a result of formation of an anion under the reacꢀ
tion conditions.* However, the reactivity of pyrazole 5 (to
be exact, of its Nꢀanion) is considerably lower than that of
anions of pyrazoles 1 and 3, which give the nucleophilic
substitution reaction with Oꢀ and Nꢀnucleophiles, as well.
The simplest nonionizable representative of 3,5ꢀdiꢀ
nitroꢀ4ꢀ(phenylsulfonyl)pyrazoles, 1ꢀmethylꢀ3,5ꢀdinitroꢀ
4ꢀ(phenylsulfonyl)pyrazole 6, was obtained upon the acꢀ
tion of dimethyl sulfate on pyrazole 5 in water in the presꢀ
ence of NaHCO3 in 75% yield (see Scheme 1).
corresponding to the PhSO2 group. Moreover, the substiꢀ
tution of the NO2 group rather than the PhSO2 group was
confirmed by mass spectra and elemental analysis. The
choice between substitution of the 3ꢀNO2 or 5ꢀNO2 group
was made in favor of position 5 based on the analysis the
13C NMR spectra of 5ꢀsubstituted 3ꢀnitropyrazoles.6 It is
known7 that in the NMR spectra of nitropyrazoles, the
signals for the carbon atoms are arranged in the following
order C(3)  C(5) > C(4). In the NMR spectra of comꢀ
pounds 8—10, the most downfield signal for the carbon
atom is broadened because of the quadruple relaxation on
the 14N nuclei of the NO2 group and, therefore, is attribꢀ
utable to the fragment C(3)—NO2.
In conclusion, we found yet another example in the
series of 4ꢀXꢀ3,5ꢀdinitropyrazoles, regioselectivity of
nucleophilic substitution in which changes depending on
the ability to form an anion under the reaction conditions.
We used morpholine, pꢀbromophenol, and thiophenol
as model Nꢀ, Oꢀ, and Sꢀnucleophiles. The reaction with
morpholine (3 equiv.) was carried out in methanol at room
temperature. The complete conversion was reached withꢀ
in 10 h and the yield of the substitution product 8 was 76%
(Scheme 2). In the case of pꢀbromophenol and thiopheꢀ
nol, which were used in a small excess (1.1 equiv.), the
reaction was performed in a mixture of water—acetonitrile
at room temperature during 10 h, using 1.1 equiv. of NaOH
as a deprotonating agent. The yields of the substitution
products 9 and 10 were 82 and 86%, respectively (see
Scheme 2).
Experimental
Melting points were measured on a Boetius heating stage
and were not corrected. 1H and 13C NMR spectra were recorded
on a Bruker ACꢀ300 spectrometer in [2H6]DMSO at 298 K. 1H
and 13C chemical shift are given relative to SiMe4. Mass spectra
were recorded on a Finnigan MAT INCOS 50 (direct injection,
EI, 70 eV) and Bruker MicroOTOF II instruments. Reaction
progress and purity of compounds were monitored by TLC on
Merck Silicagel 60 F254 plates. Elemental analysis was performed
on a Perkin Elmer Series II 2400 instrument.
Analysis of the 1H and 13C NMR spectra of compounds
8—10 showed that all the spectra still have the signals
* It is obvious that the pKa value for compound 5 is lower than
the pKa value of 3,5ꢀdinitropyrazole (see Ref. 5: pKa = 3.15).
3,5ꢀDinitroꢀ4ꢀ(phenylthio)ꢀ1Hꢀpyrazole (7) was obtained acꢀ
cording to the known procedure.2c

Reactivity of dinitro(phenylsulfonyl)pyrazoles
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
471
3,5ꢀDinitroꢀ4ꢀ(phenylsulfonyl)ꢀ1Hꢀpyrazole (5). Pyrazole 7
(12.5 g, 0.047 mol) was added to a solution of 30% H2O2 (25 mL)
in AcOH (200 mL). The mixture was kept for 12 h at 60 C, the
solvent was evaporated at reduced pressure, the residue was reꢀ
crystallized from EtOH—H2O to obtain the product (9.8 g, 70%)
with m.p. 191—193 C. Found (%): C, 36.42; H, 2.05; N, 19.01.
C9H6N4O6S. Calculated (%): C, 36.25; H, 2.03; N, 18.79.
1H NMR, : 7.65 (m, 3 H, Ph); 8.05 (m, 2 H, Ph). 13C NMR, :
107.15 (C(4)); 127.56 (CH); 129.23 (CH); 133.70 (CH); 141.30;
154.54 (C(3,5)). MS: m/z = 298 [M]+.
Reaction of compounds 5 with Sꢀnucleophiles. Sodium hydrꢀ
oxide (0.12 g, 3 mmol) was added to a solution of pyrazole 5
(0.89 g, 3 mmol) in H2O (10 mL) and the mixture was stirred for
10 min. A solution prepared from NaOH (0.12 g, 3 mmol) and
thiophenol (0.34 mL, 3.3 mmol) in H2O (10 mL) was added to
the solution obtained. The mixture was stirred for 7 h at room
temperature, acidified with 20% H2SO4 to pH 1, a precipitate
formed was filtered off, dried, and recrystallized from a mixture
of MeOH—H2O to obtain compound 7 (0.72 g, 90%) with m.p.
155—156 C (see Ref. 2c).
(m, 2 H, Ph); 7.55 (m, 4 H, Ph); 7.72 (m, 3 H, Ph). 13C NMR, :
36.24 (NMe); 105.13 (C(4)); 116.38 (C(Br)); 118.32 (CHPh);
127.09 (CHPh—SO2)); 129.16 (CHPh—SO2); 132.82 (CHPh); 134.10
(CHPh—SO2); 140.26 (C—SO2); 148.64 (C(5)); 149.18 (C(3));
155.37 (C—O—Ph). MS: m/z = 437, 439 (1 : 1) [M]+.
1ꢀMethylꢀ3ꢀnitroꢀ4ꢀ(phenylsulfonyl)ꢀ5ꢀ(phenylthio)ꢀ1Hꢀpyrꢀ
azole (10). The yield was 86%, m.p. 123—125 C. Found (%):
C, 51.36; H, 3.61; N, 11.33. C16H13N3O4S2. Calculated (%):
1
C, 51.19; H, 3.49; N, 11.19. H NMR, : 3.88 (s, 3 H, NMe);
7.20 (m, 2 H, Ph); 7.34 (m, 3 H, Ph); 7.62 (m, 2 H, Ph); 7.71
(m, 1 H, Ph); 7.89 (m, 2 H, Ph). 13C NMR, : 38.71 (NMe);
118.91 (C(4)); 126.30 (CH); 127.83 (CH); 128.62 (CH); 129.07
(CH); 129.38 (CH); 131.32; 134.28 (CH); 138.28 (C(5)); 140.02;
151.63 (C(3)). MS: m/z = 375 [M]+.
References
1. T. K. Shkineva, I. L. Dalinger, I. A. Vatsadze, A. V. Korꢀ
manov, S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim., 2012,
464 [Russ. Chem. Bull., Int. Ed., 2012, 61, 467].
1ꢀMethylꢀ3,5ꢀdinitroꢀ4ꢀ(phenylsulfonyl)ꢀ1Hꢀpyrazole (6).
The compound 5 (0.89 g, 3 mmol) was added to a solution of
NaHCO3 (0.50 g, 6 mmol) in H2O (10 mL), followed by stirring
during 10 min. After addition of Me2SO4 (0.34 mL, 3.6 mmol),
the mixture was stirred for 7 h at room temperature. A precipiꢀ
tate formed was filtered off, dried in air, and recrystallized from
MeCN to obtain the product (0.70 g, 75%) with m.p. 155—157 C.
Found (%): C, 38.68; H, 2.77; N, 18.13. C10H8N4O6S. Calcuꢀ
lated (%): C, 38.46; H, 2.58; N, 17.94. 1H NMR, : 4.12 (s, 3 H,
NMe); 7.77 (m, 3 H, Ph); 8.15 (m, 2 H, Ph). 13C NMR, : 41.35
(NMe); 112.62 (C(4)); 128.29 (CH); 129.82 (CH); 135.23 (CH);
138.66; 144.52 (C(5)); 150.05 (C(3)). MS: m/z = 312 [M]+.
4ꢀ[1ꢀMethylꢀ3ꢀnitroꢀ4ꢀ(phenylsulfonyl)ꢀ1Hꢀpyrazoleꢀ5ꢀyl]ꢀ
morpholine (8). Morpholine (0.53 mL, 6 mmol) was added to
a solution of pyrazole 6 (0.62 g, 2 mmol) in MeOH (15 mL), the
mixture was kept during 10 h at room temperature. The solvent
was evaporated at reduced pressure, the solid residue was washed
with water on the filter and recrystallized from a mixture
of MeOH—H2O to obtain the product (0.53 g, 76%) with
m.p. 163—165 C. Found (%):C, 48.05; H, 4.64; N, 16.10.
C14H16N4O5S. Calculated (%): C, 47.72; H, 4.58; N, 15.90.
1H NMR, : 3.23 (t, 4 H, J = 4.4 Hz); 3.72 (t, 4 H, J = 4.4 Hz);
3.94 (s, 3 H, NMe); 7.68 (m, 3 H, Ph); 8.05 (m, 2 H, Ph).
13C NMR, : 36.75 (NMe); 49.47; 66.37; 108.13 (C(4)); 126.87
(CH); 129.31 (CH); 133.76 (CH); 141.31; 150.84 (C(3)); 151.04
(C(5)). MS: m/z = 352 [M]+.
2. (a) I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, G. P. Popꢀ
ova, S. A. Shevelev, Mendeleev Commun., 2010, 20, 253;
(b) I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, G. P. Poꢀ
pova, S. A. Shevelev, Mendeleev Commun., 2010, 20, 355;
(c) I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, G. P. Poꢀ
pova, S. A. Shevelev, Mendeleev Commun., 2011, 21, 149.
3. G. Herve, C. Roussel, H. Graindorge, Angewandte Chem.,
Int. Ed., 2010, 49, 3177.
4. I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, G. P. Popova,
S. A. Shevelev, Synthesis, 2012, in press.
5. J. Catalan, J. L. Abband, J. Elguero, Adv. Het. Chem., 1987,
41, 187.
6. (a) A. A. Zaitsev, I. L. Dalinger, A. M. Starosotnikov, V. V.
Kachala, Yu. A. Strelenko, T. K. Shkineva, S. A. Shevelev,
Zh. Org. Khim., 2005, 41, 1538 [Russ. J. Org. Chem.
(Engl. Transl.), 2005, 41, 1507]; (b) A. A. Zaitsev, T. I.
Cherkasova, I. L. Dalinger, V. V. Kachala, Yu. A. Strelenko,
T. K. Shkineva, I. V. Fedyanin, V. N. Solkan, G. P. Popova,
S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim.., 2007, 2004 [Russ.
Chem. Bull., Int. Ed., 2007, 56, 2074]; (c) A. A. Zaitsev, I. A.
Vatsadze, I. L. Dalinger, V. V. Kachala, Yu. V. Nelyubina,
S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim., 2009, 2045 [Russ.
Chem. Bull., Int. Ed., 2009, 58, 2109]; (d) A. A. Zaitsev, I. O.
Kortusov, I. L. Dalinger, V. V. Kachala, G. P. Popova, S. A.
Shevelev, Izv. Akad. Nauk, Ser. Khim., 2009, 2054 [Russ. Chem.
Bull., Int. Ed., 2009, 58, 2118]; (e) A. A. Zaitsev, D. V. Zaiko,
I. L. Dalinger, V. V. Kachala, T. K. Shkineva, S. A. Shevelev,
Izv. Akad. Nauk, Ser. Khim., 2009, 2058 [Russ. Chem. Bull.,
Int. Ed., 2009, 58, 2122].
Reaction of compound 6 with Oꢀ and Sꢀnucleophiles (general
procedure). pꢀBromophenol or thiophenol (1.1 mmol) was addꢀ
ed to a solution of NaOH (1.1 mmol) in H2O (5 mL), the mixꢀ
ture was stirred for 10 min, followed by addition of pyrazole 6
(1 mmol)) in CH3CN (7 mL). After stirring of the reaction mixꢀ
ture for 10 h at room temperature, the solvent was evaporated
in vacuo, the solid residue was washed with water on the filter
and recrystallized from a mixture of MeOH—H2O.
7. (a) L. Larina, V. Lopyrev, Nitroazoles. Synthesis, Structure
and Applications, Springer, LLC, 2009, 196; (b) A. A. Zaitsev,
I. L. Dalinger, S. A. Shevelev, Usp. Khim., 2009, 78, 643
[Russ. Chem. Rev. (Engl. Transl.), 2009, 78, 589].
5ꢀ(4ꢀBromophenoxy)ꢀ1ꢀmethylꢀ3ꢀnitroꢀ4ꢀ(phenylsulfonyl)ꢀ
1Hꢀpyrazole (9). The yield was 82%, m.p. 135—137 C. Found (%):
C, 43.98; H, 2.82; N, 9.70. C16H12BrN3O5S. Calculated (%):
C, 43.85; H, 2.76; N, 9.59. 1H NMR, : 3.75 (s, 3 H, NMe); 7.15
Received August 2, 2011;
in revised form November 10, 2011