Nitropyrazoles. 11. Isomeric 1-methyl-3(5)-nitropyrazole-4-carbonitriles in nucleophilic substitution reactions. Comparative reactivity of the nitro group in positions 3 and 5 of the pyrazole ring

Article abstract of DOI:10.1023/B:RUCB.0000035641.63102.14

With reactions of isomeric 1-methyl-3-nitro- and 1-methyl-5-nitropyrazole- 4-carbonitriles with anionic S-, O-, and N-nucleophiles (RSH, PhOH, and 3,5-dimethyl-4-nitropyrazole in the presence of K₂CO₃ or MeONa), it was shown that for

Full text of DOI:10.1023/B:RUCB.0000035641.63102.14

580
Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 580—583, March, 2004
Nitropyrazoles
11.* Isomeric 1ꢀmethylꢀ3(5)ꢀnitropyrazoleꢀ4ꢀcarbonitriles
in nucleophilic substitution reactions. Comparative reactivity of the nitro group
in positions 3 and 5 of the pyrazole ring
I. L. Dalinger, A. A. Zaitsev, T. K. Shkineva, and S. A. Shevelevꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: shevelev@mail.ioc.ac.ru
With reactions of isomeric 1ꢀmethylꢀ3ꢀnitroꢀ and 1ꢀmethylꢀ5ꢀnitropyrazoleꢀ4ꢀcarbonitriles
with anionic Sꢀ, Oꢀ, and Nꢀnucleophiles (RSH, PhOH, and 3,5ꢀdimethylꢀ4ꢀnitropyrazole in
the presence of K2CO3 or MeONa), it was shown that for Nꢀsubstituted 3(5)ꢀnitropyrazoles,
the nitro group in position 5 is much more reactive than in position 3.
Key words: nitropyrazoles, nucleophilic substitution, anionic nucleophiles.
Earlier,2 we demonstrated that the introduction of a
acetic acid (Scheme 1). The starting amine was syntheꢀ
sized according to a known procedure.6
nitro group into a pyrazole ring enables one to develop
efficient synthetic techniques for the pyrazole series and
estimate the electronic effects of some fragments in
pyrazoleꢀcontaining systems.
Scheme 1
An important line in improving the methodology of
synthesis from nitropyrazoles is to investigate nucleophilic
substitution for the nitro groups in positions 3(5) and
develop selective introduction of substituents into either
position.
In a pyrazole ring, positions 3 and 5 are most liable to
a nucleophilic attack;3 these positions are not equivalent
in Nꢀsubstituted pyrazoles. A halogen (chlorine or broꢀ
mine) atom in position 5 is much more reactive than in
position 3 (e.g., see lit.4), despite more considerable steric
hindrances to nucleophilic substitution for the Hal(5)
atom, especially in 4ꢀsubstituted pyrazoles.
Nucleophilic substitution for the nitro group in posiꢀ
tion 5 of Nꢀsubstituted pyrazoles was illustrated with a
number of examples (see lit.5). However, relevant data for
3ꢀnitropyrazoles are lacking. Because the steric effects of
halogen atoms and a nitro group differ, the relative reacꢀ
tivity of the NO2 group in positions 3 and 5 is a priori not
obvious. In the present work, the nitro groups in posiꢀ
tions 3 and 5 were compared in reactivity by using isoꢀ
meric 1ꢀmethylꢀ5ꢀnitropyrazoleꢀ4ꢀcarbonitrile (1) and
1ꢀmethylꢀ3ꢀnitropyrazoleꢀ4ꢀcarbonitrile (2); the presence
of the electronꢀwithdrawing CN group in position 4 faꢀ
cilitates nucleophilic substitution.
Isomeric nitrile 2 was prepared through the methylaꢀ
tion of 3(5)ꢀnitropyrazoleꢀ4ꢀcarbonitrile with dimethyl
sulfate in aqueous alkali followed by separation of isomers
1 and 2 by column chromatography (Scheme 2). The
starting 3(5)ꢀnitropyrazoleꢀ4ꢀcarbonitrile was synthesized
according to a known procedure.7
Scheme 2
1 : 2 = 1 : 4.5
Nitrile 1 was prepared by the oxidation of 5ꢀaminoꢀ1ꢀ
methylpyrazoleꢀ4ꢀcarbonitrile with 85% H2O2 in trifluoroꢀ
SꢀNucleophiles (PhS–, PhCH2S–, PhNHCOCH2S–,
CH3COS–, EtOCSS–), Oꢀnucleophiles (PhO–, MeO–),
and an Nꢀnucleophile (3,5ꢀdimethylꢀ4ꢀnitropyrazole anꢀ
* For Part 10, see Ref. 1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 553—556, March, 2004.
1066ꢀ5285/04/5303ꢀ0580 © 2004 Plenum Publishing Corporation

Reactivity of nitro groups in a pyrazole ring
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
581
Scheme 4
ion) were used. Except for potassium ethylxanthate and
sodium methoxide, all nucleophiles were generated in situ
by treating a conjugated acid (corresponding to the nuꢀ
cleophilic species) with K2CO3. For the reactivity estiꢀ
mates to be compared, equal concentrations of nitrile 1 in
different solvents were employed. The molar ratio of 1 to
Nu–(NuH) was always 1 : 1.
In the presence of potassium carbonate, nitrile 1
actively reacts with thiophenol and benzylmercaptan
(Scheme 3). In DMF, the reaction is completed over
several minutes at room temperature; in acetonitrile, heatꢀ
ing is required. For instance, the reactions of nitrile 1
with PhSH and PhCH2SH in the presence of K2CO3 in
boiling CH3CN were completed over ~40 min.
Nu = EtOCSS, MeCOS
reaction conditions and the yields and characteristics of
compounds 3a—g are given in Tables 1 and 2.
When heated in ethanol with an additional mole of
K2CO3, compound 3c containing an Nꢀphenylthioꢀ
glycolamide residue undergoes cyclization into the correꢀ
sponding thieno[2,3ꢀc]pyrazole (4) (Scheme 5); the data
for this compound are presented in Tables 3 and 4.
Scheme 3
Scheme 5
Nu = PhS (a), PhCH2S (b), PhNHCOCH2S (c), PhO (d),
MeO (e),
(f)
Under analogous conditions (boiling CH3CN,
K2CO3), an Nꢀphenylthioglycolamide anion is substituted
for the nitro group much more slowly than thiophenol
and benzylmercaptan. The complete conversion (TLC
monitoring) is reached in 8 h. However, the reaction
duration in boiling ethanol is only 2 h.
The other Sꢀnucleophiles are even less reactive in the
substitution reaction than an Nꢀphenylthioglycolamide
anion. For instance, nitrile 1 completely reacts with
thioacetic acid in the presence of K2CO3 in boiling ethanol
over 4 h, while its reaction with potassium ethylxanthate
requires six hours.
It should be noted that the last two nucleophiles yield
sulfide 3g instead of the expected substitution product
(Scheme 4). Analogous substitution reactions for haloꢀ
gens were reported earlier.8
Nitrile 1 completely reacts with sodium methoxide in
DMF over ~30 min. The reaction of nitrile 1 with phenol
in boiling CH3CN in the presence of K2CO3 is completed
over 8 h; i.e., the reactivity of phenol is nearly the same as
that of Nꢀphenylthioglycolamide (see Scheme 3).
3,5ꢀDimethylꢀ4ꢀnitropyrazole is also capable of reꢀ
placing, in the presence of K2CO3, the nitro group in
nitrile 1, although the reaction proceeds comparatively
slowly (boiling acetonitrile, 12 h; see Scheme 3). The
The same Sꢀ, Oꢀ, and Nꢀnucleophiles were used in
reactions with nitrile 2 under the reaction conditions of
Table 1. Conditions for the replacement of the nitro group in
nitrile 1
Comꢀ
pound
Solvent Conversion T/°C Yield
M.p.
/°C
time of
(%)
nitrile 1
3a
3b
3c
DMF
∼3 min
25
80
25
80
80
78
80
25
80
78
78
45
57
42
58
18—20a
Oila
CH3CN ∼40 min
DMF ∼3 min
CH3CN ∼40 min
CH3CN
C2H5OH
CH3CN
DMF
∼8 h
∼2 h
∼8 h
∼30 min
∼12 h
∼4 h
72 155 (from EtOH)
75
3d
3e
3f
72 125 (from EtOH)
37 103 (from EtOH)
71 114 (from EtOH)
48b 191 (from EtOH)
39c
CH3CN
C2H5OH
3g
∼6 h
a Purified by column chromatography.
b The reaction with CH3COSH + K2CO3.
c The reaction with EtOCSSK.

582
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Dalinger et al.
Table 2. Characteristics of the products obtained by replacement of the nitro group in nitrile 1
Comꢀ
pound
Found
Calculated
Molecular
formula
1H NMR
((CD3)2SO),
δ
IR,
ν/cm–1
MS,
m/z,
[M]+
(%)
C
H
N
S
3a
3b
61.37
61.37
62.93
62.86
4.37
4.21
5.06
4.84
19.63
19.52
19.24
18.33
14.73
14.90
13.81
13.98
C11H9N3S
C12H11N3S
8.21 (s, CH); 7.37, 7.25
(both m, Ph);3.87 (s, Me)
8.04 (s, CH); 7.24, 7.10
(both m, Ph); 4.12 (s, CH2);
3.58 (s, Me)
2232 (CN)
2232 (CN)
215
229
3c
3d
57.49
57.34
4.57
4.44
19.58
20.57
11.05
11.77
C13H12N4OS
C11H9N3O
10.16 (s, NH); 8.11
2244 (CN);
1688 (CO)
272
199
(s, CH); 7.48 (d, Ph);
7.29, 7.05 (both t, Ph);
3.92 (s, Me); 3.76 (s, CH2)
7.96 (s, CH); 7.46, 7.29
(both t, Ph); 7.23 (d, Ph);
3.72 (s, Me)
7.76 (s, CH); 4.20, 3.56
(both s, Me)
8.33 (s, CH); 3.75 (s, NMe) 2240 (CN)
2.54, 2.51 (both s, Me)
65.60
66.32
4.47
4.55
20.81
21.09
—
2228 (CN)
2228 (CN)
3e
3f
52.57
52.55
48.50
48.78
48.82
49.17
5.21
5.14
4.07
4.09
3.09
3.30
30.41
30.64
33.72
34.13
34.01
34.40
—
—
C6H7N3O
C10H10N6O2
C10H8N6S
137
246
244
3g
13.05
13.13
8.18 (s, CH);
3.99 (s, Me)
2228 (CN)
Table 3. Reaction conditions for the synthesis of compounds 4,
5a, and 5e
Scheme 6
Comꢀ
pound
Solvent
τ/h
T/°C Yield
M.p./°C
(%)
4
5a
5e
EtOH
DMF
DMF
12
170
48
80
25
25
86 140 (from MeOH)
17 Oil*
23 111 (from MeOH)
Nu = PhS (a), MeO (e)
* Purified by column chromatography.
thiophenol at 25 °C, the conversion of compound 2 was
not completed even in a week (vs. ∼3 min for nitrile 1
under analogous conditions); yet the substitution product
was isolated. The data for products 5a and 5e are given in
Tables 3 and 4.
nitrile 1. However, substitution in 4ꢀcyanoꢀ1ꢀmethylꢀ3ꢀ
nitropyrazole (2) was successful only with thiophenolate
and methylate anions in DMF (Scheme 6). In the reacꢀ
tion with sodium methoxide, its complete conversion reꢀ
quires approximately two days, whereas nitrile 1 is fully
consumed over 30 min under analogous conditions. With
No reaction of nitrile 2 with benzylmercaptan and
Nꢀphenylthioglycolamide in DMF or CH3CN in the presꢀ
Table 4. Characteristics of compounds 4, 5a, and 5e
Comꢀ
pound
Found
Calculated
Molecular
formula
1H NMR
((CD3)2SO),
δ
IR,
ν/cm–1
MS,
m/z,
[M]+
(%)
C
H
N
S
4
56.96
57.34
4.42
4.44
19.94
20.57
11.56
11.77
C13H12N4OS
9.03 (s, NH); 7.88 (s, CH)
2244 (CN);
229
7.75 (m, Ph); 7.37 (s, NH2); 1612 (CO)
7.30, 7.05 (both m, Ph);
3.90 (s, Me)
5a
5e
61.20
61.37
53.03
52.55
4.01
4.21
5.15
5.14
19.12
19.52
29.37
30.64
14.65
14.90
—
C11H9N3S
C6H7N3O
8.62 (s, CH); 7.46, 7.28
(both m, Ph); 3.92 (s, Me)
8.26 (s, CH); 3.89, 3.74
(both s, Me)
2238 (CN)
215
137
2236 (CN)

Reactivity of nitro groups in a pyrazole ring
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
583
(general procedure). A. Nitrile 1 or 2 (0.38 g, 2.5 mmol) was
dissolved in 10 mL of DMF. A corresponding conjugated acid
(or its salt for sodium methoxide) (2.5 mmol) and potassium
carbonate (0.38 g, 2.75 mmol) were successively added (the
latter was not used in the reactions with sodium methoxide).
The reaction mixture was stirred under the conditions specified
in Tables 1 and 3. After the reaction was completed, the mixture
was poured into water and acidified to pH 4. The product was
extracted with ether (3 to 4 × 10—15 mL, TLC). The extracts
were combined, washed with dilute HCl and water, and dried
over MgSO4. The ether was removed and the residue was either
recrystallized from ethanol or purified by column chromatoꢀ
graphy on silica gel in ethyl acetate—hexane (1 : 4).
B. Nitrile 1 (0.38 g, 2.5 mmol) was dissolved in 10 mL of
acetonitrile (ethanol). A corresponding conjugated acid (or its
salt for potassium Oꢀethylxanthate) (2.5 mmol) and potassium
carbonate (0.38 g, 2.75 mmol) were successively added (the latter
was not used in the reactions with potassium ethylxanthate).
The reaction mixture was stirred under the conditions specified
in Table 1. After the reaction was completed, the solvent was
removed and the residue was dissolved in water. The undissolved
part was filtered off and recrystallized from ethanol.
ence of potassium carbonate occurs at room temperature;
on heating (e.g., at 60 °C), the resulting mixture is diffiꢀ
cult to separate (TLC) and contains no product of nitro
group substitution. Nitrile 2 does not react with 3,5ꢀdiꢀ
methylꢀ4ꢀnitropyrazole or phenoxide anions under the
reaction conditions of nitrile 1 (boiling acetonitrile,
K2CO3). Nor does nitrile 2 react with these nucleophiles
in DMF at 100 °C.
Thus, with isomeric nitriles 1 and 2 as examples, we
showed that in 3(5)ꢀnitropyrazoles, the nitro group in
position 5 is much more reactive than in position 3 as
regards nucleophilic substitution reactions. Apparently,
this difference is due to the significantly higher positive
πꢀcharge in the pyrazoles in position 5,9 though a more
precise answer calls for further investigations into both
the electron density distribution in nitriles 1 and 2 and
the energies of formation of the corresponding 3ꢀ and
5ꢀipsoꢀσꢀcomplexes.
Experimental
1
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 04ꢀ03ꢀ
33097).
H NMR spectra were recorded on Bruker ACꢀ200, Bruker
WMꢀ250, and Bruker ACꢀ300 instruments. Chemical shifts are
referenced to Me4Si. IR spectra were recorded on a Specord
Mꢀ80 instrument (KBr pellets). Mass spectra were recorded on
a Varian MAT CHꢀ6 instrument. The course of the reactions
was monitored and the purity of the compounds was checked by
TLC on Silufol UVꢀ254 plates.
References
1. I. L. Dalinger, V. A. Litosh, and S. A. Shevelev, Izv. Akad.
Nauk, Ser. Khim., 1997, 1198 [Russ. Chem. Bull., 1997, 46,
1149 (Engl. Transl.)].
2. S. A. Shevelev and I. L. Dalinger, Zh. Org. Khim., 1998, 34,
1127 [Russ. J. Org. Chem., 1998 (Engl. Transl.)].
1ꢀMethylꢀ5ꢀnitropyrazoleꢀ4ꢀcarbonitrile (1). Dropwise adꢀ
dition of 85% H2O2 (50 mL) to CF3COOH (75 mL) was folꢀ
lowed by addition of 5ꢀaminoꢀ1ꢀmethylpyrazoleꢀ4ꢀcarbonitrile
(15 g, 0.123 mol) in portions at no higher than 30 °C. The
reaction mixture was kept at 45—50 °C for 3 h, cooled, and
poured into ice water (300 mL). The precipitate that formed
slowly was filtered off, washed with cold water to a neutral
reaction, and dried to give a dark yellow product (8 g, 42%),
m.p. 127 °C (from ethanol). Found (%): C, 39.08; H, 2.53;
N, 36.38. C5H4N4O2. Calculated (%): C, 39.48; H, 2.65;
N, 36.83. 1H NMR ((CD3)2SO), δ: 8.35 (s, CH); 4.20 (s, CH3).
IR, ν/cm–1: 2252 (CN); 1536 (NO2); 1344 (NO2). MS,
m/z: 152 [M]+.
1ꢀMethylꢀ3ꢀnitropyrazoleꢀ4ꢀcarbonitrile (2). Dimethyl sulꢀ
fate (27.5 mL) was added dropwise to a solution of 3ꢀnitroꢀ
pyrazoleꢀ4ꢀcarbonitrile (26.5 g, 0.174 mol) in 3.5% NaOH
(320 mL) at no higher than 30 °C. After the precipitation was
completed, the solution was stirred for an additional 1 h. The
precipitate was filtered off, washed with cold water to a neutral
reaction, and dried to give a mixture of 1ꢀmethylꢀ5ꢀnitroꢀ
pyrazoleꢀ4ꢀcarbonitrile (1) and 1ꢀmethylꢀ3ꢀnitropyrazoleꢀ4ꢀ
carbonitrile (2); the total yield was 26 g (86%), 1 : 2 = 1 : 4.5
(1H NMR data). Column chromatography of the mixture on
silica gel in chloroform gave pure 1ꢀmethylꢀ3ꢀnitropyrazoleꢀ4ꢀ
carbonitrile 2 (20 g) as light yellow crystals, m.p. 92 °C.
Found (%): C, 39.86; H, 2.74; N, 36,03. C5H4N4O2. Calcuꢀ
lated (%): C, 39.48; H, 2.65; N, 36.83. 1H NMR ((CD3)2SO), δ:
8.81 (s, CH); 4.05 (s, CH3). IR, ν/cm–1: 2244 (CN); 1540
(NO2); 1348 (NO2). MS, m/z: 152 [M]+.
3. Comprehensive Heterocyclic Chemistry, Ed. A. R. Katrizky,
Pergamon Press, 1984, 5, p. 266
4. (a) A. Michaelis, Liebigs Ann. Chem., 1905, 338, 183;
(b) US Pat. 4 435 416, Chem. Abstr., 1984, 101, 7151.
5. (a) V. P. Perevalov, L. I. Baryshnenkova, E. A. Denisova,
M. A. Andreeva, and B. I. Stepanov, Khim. Geterotsikl. Soedin.,
1984, 1691 [Chem. Heterocycl. Compd., 1984 (Engl. Transl.)];
(b) N. P. Peet, J. Malecha, M. E. LeTourneau, and S. Sunder,
J. Heterocycl. Chem., 1989, 26, 257; (c) V. P. Perevalov,
L. I. Baryshnenkova, V. V. Koroleva, L. G. Kurkina, S. S.
Kramarenko, and B. I. Stepanov, Khim. Geterotsikl. Soedin.,
1990, 628 [Chem. Heterocycl. Compd., 1990 (Engl. Transl.)];
(d) I. L. Dalinger, T. I. Cherkasova, and S. A. Shevelev,
Mendeleev Commun., 1997, 58.
6. R. K. Robins, J. Am. Chem. Soc., 1956, 78, 784.
7. V. M. Vinogradov, T. I. Cherkasova, I. L. Dalinger, and S. A.
Shevelev, Izv. Akad. Nauk, Ser. Khim., 1993, 1616 [Russ. Chem.
Bull., 1993, 42, 1552 (Engl. Transl.)].
8. I. Degany, R. Fochi, and V. Regondi, Synthesis, 1979, 178.
9. A. F. Pozharskii, Teoreticheskie osnovy khimii geterotsiklov
[Theoretical Fundamentals of Heterocyclic Chemistry], Khimiya,
Moscow, 1985, p. 70 (in Russian).
Substitution for the nitro group in 1ꢀmethylꢀ5ꢀnitropyrazoleꢀ
4ꢀcarbonitrile (1) and 1ꢀmethylꢀ3ꢀnitropyrazoleꢀ4ꢀcarbonitrile (2)
Received December 30, 2003;
in revised form February 11, 2004