Nitropyrazoles 21. Selective nucleophilic substitution of the nitro group in 1-amino-3,4-dinitropyrazole

Article abstract of DOI:10.1007/s11172-012-0066-x

Nucleophilic substitution of the nitro group in a model representative of N-aminopyrazoles, 1-amino-3,4-dinitropyrazole, has been studied for the first time. The compound was shown to undergo nucleophilic substitution with S-nucleophiles. The reaction was

Full text of DOI:10.1007/s11172-012-0066-x

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 467—468, February, 2012
467
Nitropyrazoles
21.* Selective nucleophilic substitution of the nitro group in 1ꢀaminoꢀ3,4ꢀdinitropyrazole
T. K. Shkineva, I. L. Dalinger, I. A. Vatsadze, A. V. Kormanov, 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
Nucleophilic substitution of the nitro group in a model representative of Nꢀaminopyrꢀ
azoles, 1ꢀaminoꢀ3,4ꢀdinitropyrazole, has been studied for the first time. The compound was
shown to undergo nucleophilic substitution with Sꢀnucleophiles. The reaction was effected
with regioselective substitution of the nitro group at position 3 and in good yields.
Key words: pyrazole, nitro group, nitropyrazoles, 3,4ꢀdinitropyrazoles, Nꢀaminonitropyrꢀ
azoles, nucleophilic substitution, nucleophiles.
In the last years, pyrazole Nꢀamino derivatives are unꢀ
der active studies due to a wide range of biological activity
found in them.2
captane. The reaction was carried out in acetonitrile
at room temperature in the presence of Et3N as a base.
The substitution products were formed in 63—78% yields,
with the complete conversion being achieved within 4 h
(Scheme 1).
Earlier, we have developed an efficient method of
Nꢀamination of nitropyrazoles in water with hydroxylꢀ
amineꢀOꢀsulfonic acid.3 However, this method in the case
of unsymmetric nitropyrazoles does not possess the reꢀ
quired Nꢀregioselectivity: in a number of cases the reacꢀ
tion gives a mixture of Nꢀamino isomers. At the same
time, in our preceding works we have shown that substiꢀ
tution of the NO2 group in polynitropyrazoles is a versaꢀ
tile method for the synthesis of molecules containing
C(pyrazole)—X(O, S, N) bonds.4,5
Scheme 1
In our opinion, nucleophilic substitution of an NO2
group in Nꢀaminodinitropyrazoles is one of the ways
for the selective synthesis of unsymmetric Nꢀaminonitroꢀ
pyrazoles.
2: R = Ph (a), C6H4Brꢀp (b), C6H4Meꢀp (c), CH2C6H4Clꢀp (d)
i. RSH/Et3N, MeCN, 25 C, 4 h.
Earlier, it has been shown that if no additional groups
prone to nucleophilic substitution were present in the molꢀ
ecules of 3,4ꢀdinitropyrazoles, then, independent on the
ability to ionization under the reaction conditions, i.e.,
the presence or the absence of a substituent at the atom
N(1) of the ring, only the 3ꢀNO2 group is substituted for
selectively upon the action of nucleophiles.5 In the present
work, we report the results on the studies of the reaction of
a model 1ꢀaminoꢀ3,4ꢀdinitropyrazole3 (1) with the most
reactive nucleophiles, i.e. Sꢀnucleophiles, such as thiols in
the presence of bases. It should be noted that nucleophilic
substitution in Nꢀaminonitropyrazoles is the subject of
studies for the first time.
1
The structure of compounds 2 was established by H
and 13C NMR spectroscopy and confirmed by IR and
mass spectra, as well as by elemental analysis.
The direction of nucleophilic substitution was deterꢀ
mined based on the observations in the 1H and 13C NMR
spectra similar to those found in the spectra of 3ꢀsubstiꢀ
tuted 1ꢀmethylꢀ4ꢀnitropyrazoles synthesized by us earliꢀ
er.5 In the 1H NMR spectra of compounds 2a—d, because
of a decrease in the electronꢀwithdrawing power of the
pyrazole ring, an upfield shift of the signal for the NH2
group is observed from  7.24 (1) to  6.83—6.96 (2).
In the 13C NMR spectra of compounds 2a—d, the presꢀ
ence of the upfield broad signal for the C(4)—NO2 at
 128.33—129.18 (cf. with  125.52 for compound (1))
with the absence of a broad signal at  141.6—148.3 attriꢀ
As the Sꢀnucleophiles, we have chosen thiophenol,
pꢀbromoꢀ, pꢀmethylthiophenol, and pꢀchlorobenzylmerꢀ
* For Part 20, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 464—465, February, 2012.
1066ꢀ5285/12/6102ꢀ467 © 2012 Springer Science+Business Media, Inc.

468
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Shkineva et al.
1ꢀAminoꢀ3ꢀ[(4ꢀchlorobenzyl)thio]ꢀ4ꢀnitropyrazole (2d). The
yield was 73%, m.p.. 142—143 C. Found (%): C, 42.18; H, 3.19;
N, 19.68. C10H9ClN4O2S. Calculated (%): C, 42.48; H, 3.23;
butable to the C(3)—NO2 (see Ref. 6) indicates the forꢀ
mation of 3ꢀsubstituted 1ꢀaminoꢀ4ꢀnitropyrazoles.
1
N, 19.90. H NMR, : 4.31 (s, 2 H, CH2); 6.96 (s, 2 H, NH2);
Experimental
7.39 (d, 2 H, Ph, J = 8.8 Hz); 7.49 (d, 2 H, Ph, J = 8.8 Hz); 8.70
(s, 1 H, H(5)). 13C NMR, : 32.99 (CH2); 128.29 (CH); 129.18
(br.s, C(4)); 130.25 (C(5)); 130.88 (CH); 131.86; 136.30; 141.87.
IR, /cm–1: 3331, 3236 (NH2), 1526, 1500, 1471, 1460, 1402,
1360, 1325 (NO2). MS, m/z: 284, 286 [M]+.
Melting points were measured on a Boetius heating stage
and were not corrected. 1H and 13C NMR spectra were recorded
on Bruker ACꢀ300 and Bruker DRXꢀ500 spectrometers in
[2H6]DMSO at 298 K. 1H and 13C chemical shift are given
relative to SiMe4. IR spectra were recorded on Bruker ALPHA
spectrometer in KBr pellets. Mass spectra were recorded on
a Finnigan MAT INCOS 50 (direct injection, EI, 70 eV) and
Bruker MicroOTOF II instruments. Reaction progress and puriꢀ
ty of compounds were monitored by TLC on Merck Silicagel 60
F254 plates. Elemental analysis was performed on a Perkin Elmer
Series II 2400 instrument.
1ꢀAminoꢀ3,4ꢀdinitropyrazole (1) was obtained according to
the known procedure.3 The yield was 52%, m.p.. 81—83 C.
1H NMR, : 7.24 (s, 2 H, NH2); 8.83 (s, 1 H, H(5)). 13C NMR,
: 125.52 (br.s, C(4)); 132.20 (C(5)); 144.36 (br.s, C(3)). HRMS
ESI(–), m/z: 157.0008 [M – NH2]–, calculated for C3H2N4O4
157.0003.
Reaction of 1ꢀaminoꢀ3,4ꢀdinitropyrazole with Sꢀnucleophiles
(general procedure). Triethylamine (2.3 mmol) was added to
a solution of the corresponding thiol (2.3 mmol) in CH3CN
(5 mL) at room temperature, the mixture was stirred for 10 min,
followed by addition of 1ꢀaminoꢀ3,4ꢀdinitropyrazole (1)
(2.2 mmol) and stirring for 4 h. The solvent was evaporated at
reduced pressure, the residue was washed with hexane and reꢀ
crystallized from CCl4.
1ꢀAminoꢀ4ꢀnitroꢀ3ꢀphenylthiopyrazole (2a). The yield was
78%, m.p.. 126—127 C. Found (%): C, 45.75; H, 3.41; N, 23.71.
C9H8N4O2S. Calculated (%): C, 46.02; H, 3.56; N, 23.83.
1H NMR, : 6.86 (s, 2 H, NH2); 7.43 (m, 3 H, Ph); 7.59 (m, 2 H,
Ph); 8.70 (s, 1 H, H(5)). 13C NMR, : 128.80 (br.s, C(4)); 129.12
(CH); 129.38 (CH); 130.54 (CH); 133.38; 133.98 (CH); 141.16.
IR, /cm–1: 3336, 3228 (NH2), 1592, 1571, 1556, 1364, 1334
(NO2), 808. MS, m/z: 236 [M]+.
References
1. I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, G. P. Popova,
S. A. Shevelev, Izv. Akad. Nauk, Ser. Khim., 2012, 461 [Russ.
Chem. Bull., Int. Ed., 2011, 60, 464].
2. (a) V. V. Kuzmenko, A. F. Pozharskii, Adv. Heterocyclic Chem.,
1993, 53, 85; (b) V. M. Vinogradov, I. L. Dalinger, S. A.
Shevelev, Khim. Farm. Zh., 1994, 37 [Pharm. Chem. J.
(Engl. Transl.), 1994]; (c) M. I. RodriguezꢀFranco, I. Dorꢀ
ronsoro, A. Martinez, C. Perez, A. Badia, Arch. Pharm., 2000,
333, 118; (d) WO 2004069196 A2 20040819, 2004.
3. (a) V. M. Vinogradov, I. L. Dalinger, S. A. Shevelev, Menꢀ
deleev Commun., 1993, 111; (b) V. M. Vinogradov, I. L. Dalinꢀ
ger, V. I. Gulevskaya, S. A. Shevelev, Izv. Akad. Nauk, Ser.
Khim., 1993, 1434 [Russ. Chem. Bull. (Engl. Transl.), 1993,
42, 1369].
4. (a) I. L. Dalinger, T. I. Cherkasova, S. A. Shevelev, Mendeꢀ
leev. Commun., 1997, 58; (b) 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]; (c) 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]; (d) I. L.
Dalinger, T. I. Cherkasova, G. P. Popova, T. K. Shkineva,
I. A. Vatsadze, S. A. Shevelev, M. I. Kanishchev, Izv. Akad.
Nauk, Ser. Khim., 2009, 404 [Russ. Chem. Bull., Int. Ed., 2009,
58, 410]; (e) 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]; (f) 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].
1ꢀAminoꢀ3ꢀ[(4ꢀbromophenyl)thio]ꢀ4ꢀnitropyrazole (2b). The
yield was 63%, m.p.. 206—207 C. Found (%): C, 34.30; H, 2.24;
N, 17.78. C9H7BrN4O2S. Calculated (%): C, 34.50; H, 2.32; N,
17.94. 1H NMR, : 6.88 (s, 2 H, NH2); 7.51 (d, 2 H, Ph, J = 8.7 Hz);
7.62 (d, 2 H, Ph, J = 8.7 Hz); 8.72 (s, 1 H, H(5)). 13C NMR, :
122.74; 128.33 (br.s, C(4)); 129.61; 130.53 (C(5)); 132.33 (CH);
135.86 (CH); 140.48. IR, /cm–1: 3328, 3236 (NH2), 1528, 1496,
1460, 1404, 1364, 1324 (NO2), 1084, 1008, 824, 816. MS, m/z:
314, 316 [M]+.
5. I. L. Dalinger, I. A. Vatsadze, T. K. Shkineva, I. O. Kortusov,
G. P. Popova, V. V. Kachala, S. A. Shevelev, Izv. Akad. Nauk,
Ser. Khim., 2010, 1739 [Russ. Chem. Bull., Int. Ed., 2010,
59, 1786].
6. L. Larina, V. Lopyrev, Nitroazoles. Synthesis, Structure and
Applications, Springer, LLC, 2009, 196.
1ꢀAminoꢀ3ꢀ[(4ꢀmethylphenyl)thio]ꢀ4ꢀnitropyrazole (2c). The
yield was 72%, m.p.. 178—179 C. Found (%): C, 47.99; H, 4.03;
N, 22.39. C10H10N4O2S. Calculated (%): C, 48.21; H, 4.09;
1
N, 22.57. H NMR, : 2.31 (s, 3 H, CH3); 6.83 (s, 2 H, NH2);
7.26 (d, 2 H, Ph, J = 8.1 Hz); 7.49 (d, 2 H, Ph, J = 8.1 Hz); 8.70
(s, 1 H, H(5)). 13C NMR, : 20.73 (CH3); 124.87; 129.35 (br.s,
C(4)); 130.01 (CH); 130.44 (C(5)); 134.37 (CH); 139.11; 141.90.
IR, /cm–1: 3331, 3236 (NH2), 1526, 1500, 1471, 1460, 1402,
1360, 1325 (NO2) 1082, 944, 825, 808. MS, m/z: 250 [M]+.
Received August 2, 2011;
in revised form November 10, 2011