Regiospecificity of nucleophilic substitution in 4,6-dinitro-1-phenyl-1H- indazole

Article abstract of DOI:10.1023/B:RUCB.0000035642.41056.81

The reactions of 4,6-dinitro-1-phenyl-1H-indazole with anionic nucleophiles RS^- and N₃^- lead to the regiospecific replacement of the nitro group at position 4. The reaction with N ₂H₄·H₂O + FeCl₃ also results in reduction of only the 4-NO₂ group. Based on this fact, a procedure was developed for the preparation of previously unknown 3-unsubstituted 4-X-6-nitro-1-phenyl-1H-indazoles (X is a residue of a nucleophile or NH ₂). Comparison of the data on the selective nucleophilic substitution (4-NO₂ group) in 3-Z-1-aryl-4,6-dinitro-1H-indazoles shows that in the case of Z = H, the regiospecificity of substitution is determined by the electronic effect of the annelated pyrazole ring.

Full text of DOI:10.1023/B:RUCB.0000035642.41056.81

584
Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 584—587, March, 2004
Regiospecificity of nucleophilic substitution
in 4,6ꢀdinitroꢀ1ꢀphenylꢀ1Hꢀindazole
A. M. Starosotnikov, A. V. Lobach, V. V. Kachala, 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
The reactions of 4,6ꢀdinitroꢀ1ꢀphenylꢀ1Hꢀindazole with anionic nucleophiles RS– and
–
N3 lead to the regiospecific replacement of the nitro group at position 4. The reaction with
N2H4•H2O + FeCl3 also results in reduction of only the 4ꢀNO2 group. Based on this fact, a
procedure was developed for the preparation of previously unknown 3ꢀunsubstituted
4ꢀXꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazoles (X is a residue of a nucleophile or NH2). Comparison of
the data on the selective nucleophilic substitution (4ꢀNO2 group) in 3ꢀZꢀ1ꢀarylꢀ4,6ꢀdinitroꢀ
1Hꢀindazoles shows that in the case of Z = H, the regiospecificity of substitution is determined
by the electronic effect of the annelated pyrazole ring.
Key words: 4,6ꢀdinitroꢀ1Hꢀindazoles, nitro group, nucleophilic substitution.
Systematic studies on the nucleophilic substitution in
rotation of the aromatic nitro group relative to the ring
the benzene fragment of 1Hꢀindazoles, including the reꢀ
placement of the nitro groups, are lacking in the literaꢀ
ture. As part of continuing studies on the synthesis of
benzoannelated heterocycles starting from 1ꢀXꢀ2,4,6ꢀtriꢀ
nitrobenzenes, we have developed1,2 a procedure for
the preparation of 3ꢀZꢀ1ꢀarylꢀ4,6ꢀdinitroꢀ1Hꢀindazoles
(Z = CHO (1), CN (2), or 1,3ꢀdioxolanꢀ2ꢀyl (3)) based
on 2,4,6ꢀtrinitrotoluene (TNT). Under mild conditions,
the reactions of 4,6ꢀdinitroindazoles 1—3 with anionic
Nꢀ, Oꢀ, and Sꢀnucleophiles were found1,2 to result in the
regiospecific replacement of the nitro group at position 4,
i.e., at the position nearest to the heterocyclic moiety.
High mobility of the 4ꢀNO2 group in 4,6ꢀdinitroindazoles
1—3 may be associated with both the influence of the
heterocyclic fragment (electronic effect) and rotation of
the 4ꢀNO2 group out of the plane of the benzene ring under
the influence of the 3ꢀZ substituent in the peri position
with respect to this group (steric effect).
Actually, the rotation of the nitro group can have a
determining effect on the regiospecifity of the replaceꢀ
ment of the nitro group with a nucleophile, as exemplified
by the reactions of TNT.3 The pꢀNO2 group in the TNT
molecule lies in the plane of the benzene ring, whereas
both nitro groups in the ortho positions are substantially
twisted out of the plane of the aromatic system due to the
steric effect of the methyl group, and it is the oꢀNO2
groups in TNT that are replaced in the reactions with the
RS– anions in spite of the fact that the steric and elecꢀ
tronic (+I) effects of the Me group are unfavorable for the
classical nucleophilic substitution. This phenomenon
(steric complementarity) is attributable3 to the fact that
facilitates the formation of the ipsoꢀσꢀcomplex. Quanꢀ
tumꢀchemical calculations (by different methods) of the
structures of indazoles 1—3 demonstrated that the 6ꢀNO2
group in all compounds lies in the plane of the benzene
fragment, whereas the 4ꢀNO2 group is rotated under the
influence of the 3ꢀZ substituent. The angle of rotation
with respect to the plane of the aromatic ring depends on
the character of the Z substituent. For example, the angles
of rotation calculated by the AM1 method are 21.4°
(Z = CHO), 42.5° (Z = 1,3ꢀdioxolanꢀ2ꢀylꢀ), and
10.4° (Z = CN).
In this connection, it was of interest to study the diꢀ
rection and the ease of nucleophilic substitution in 3ꢀunꢀ
substituted 4,6ꢀdinitroꢀ1ꢀphenylꢀ1Hꢀindazole (Z = H),
in which both the 6ꢀNO2 and 4ꢀNO2 groups are in the
plane of the benzene fragment, and to compare these data
with the results obtained for 3ꢀsubstituted analogs, which
could allow one to separate the electronic effect (Z = H)
from the steric one.
4,6ꢀDinitroꢀ1ꢀphenylꢀ1Hꢀindazole (6) was syntheꢀ
sized according to a known procedure4,5 starting from
2,4,6ꢀtrinitrobenzaldehyde6 (4) (Scheme 1).
Only data on the melting points of the target comꢀ
pound 6 and intermediate 2,4,6ꢀtrinitrobenzaldehyde
Nꢀphenylhydrazone (5) are available in the literature.4,5
Earlier, these compounds have been identified only based
on elemental analysis data, whereas their spectroscopic
characteristics are lacking in the literature. We carried out
a detailed study of the structure of dinitroindazole 6 using
different spectroscopic methods and elemental analysis.
In particular, we made the assignment of the signals of the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 557—560, March, 2004.
1066ꢀ5285/04/5303ꢀ0584 © 2004 Plenum Publishing Corporation

Nucleophilic substitution in dinitroindazole
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
585
Scheme 1
The reactions proceeded at 80—90 °C, i.e., under more
drastic conditions than those used in the reactions of
3ꢀsubstituted dinitroindazoles 1 and 2 (20 °C).2 This is,
apparently, associated with their much higher electrophiꢀ
licity compared to indazole 6 due to the presence of strong
electronꢀwithdrawing groups (CHO, CN) in compounds
1 and 2. The nitro group at position 6 remained intact
even in the presence of an excess of the nucleophile.
Under more drastic conditions, the reactions led to deꢀ
struction of the starting dinitroindazole 6.
The fact that the reactions produced only one of two
possible products of the replacement of the nitro group
1
was established by H NMR spectroscopy of the crude
reaction product. The direction of substitution was proved
as follows. We performed the complete assignment of the
signals of the C and H atoms in the H and 13C NMR
1
Reactions and conditions: i. PhNHNH2•HCl, EtOH, 78 °C;
ii. NaOH, H2O/EtOH, 20 °C.
spectra of mononitro derivative 7c based on the results of
2D 1Hꢀ13C NMR spectroscopy (HSQC, HMBC) and deꢀ
termined the chemical shifts of the C(4) (δ 133.5) and
C(6) (δ 147.6) atoms. In the spectrum of the starting
dinitroindazole 6, the signal of the C(4) atom is observed
at lower field (δ 138.7). The 13C NMR spectra of other
products of replacement of the nitro group, viz., monoꢀ
nitroindazoles 7a,b and 8, show signals of the C(4) atom
at higher field (δ 132—135) compared to that in the specꢀ
trum of the starting dinitro derivative 6, whereas the
chemical shifts of the signals of the C(6) atom remain
virtually unchanged (δ 147—148). These data provide unꢀ
ambiguous evidence that only the nitro group at posiꢀ
tion 4 is replaced regardless of the nature of the nucleoꢀ
phile used.
1
H and C atoms in the H and 13C NMR spectra of comꢀ
pound 6 based on the data on the complete assignment of
the signals of the H and C atoms in mononitroindazole 7c
(see below).
We studied the reactions of indazole 6 with thiols as
nucleophiles in the presence of K2CO3 or NaN3 in
Nꢀmethylpyrrolidone (NMP) or DMF. The reactions led
to the replacement of the nitro group only at position 4 to
give previously unknown 4ꢀsubstituted 6ꢀnitroꢀ1ꢀphenylꢀ
1Hꢀindazoles (Scheme 2).
Scheme 2
Judging from the times of conversion of the starting
dinitroindazoles 1—3 and 6 performed under the same
conditions with the use of benzylthiol as a nucleophile
(cf. lit. data1,2), the rate of replacement of the nitro group
in 3ꢀunsubstituted dinitroindazole 6 is much lower than
that in 3ꢀformylꢀ and 3ꢀcyanoindazoles 1 and 2 and is
approximately equal to the rate of replacement of the
4ꢀNO2 group in dinitro derivative 3.
Therefore, the regiospecific replacement of the 4ꢀNO2
group in dinitroindazole 6 is determined only by the elecꢀ
tronic effect of the annelated pyrazole fragment. Apparꢀ
ently, this effect is not associated with the characteristic
features of the electron density distribution in dinitroꢀ
indazole 6. Judging from the 13C NMR spectroscopic
data, the effective positive charge on the C(6) atom is
even higher than that on the C(4) atom, because the
signal of the C(6) atom is observed at much lower field
than the signal of the C(4) atom (δ 145.4 and 138.7,
respectively; the signals of the carbon atoms in the same
aromatic system containing the same substituents are
compared, cf. lit. data7). Apparently, the effect of the
pyrazole ring consists in providing higher stability of the
ipsoꢀσꢀcomplex of the nucleophile with dinitroindazole 6
at the C(4) atom compared to that at the C(6) atom.
Reactions and conditions: i. RSH, K2CO3, NMP, 80—90 °C;
ii. NaN3, DMF, 80 °C.
Compound 7
R
Yield (%)
a
b
c
Ph
4ꢀClꢀC6H4
CH2Ph
57
37
53

586
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Starosotnikov et al.
and N,Nꢀdimethylꢀpꢀnitrosoaniline (7 g, 47 mmol) in pyridine
(15 mL). The reaction mixture was stirred at 20 °C for 24 h. The
precipitate that formed was filtered off, washed with cold acetone
(30 mL), and dried in air to prepare 2,4,6ꢀtrinitrobenzaldehyde
4ꢀ(dimethylamino)phenylimine in a yield of 11.15 g (70%). The
product was used without additional purification. A suspension
of 2,4,6ꢀtrinitrobenzaldehyde 4ꢀ(dimethylamino)phenylimine
(10 g, 27 mmol) in concentrated HCl (80 mL) was stirred at
60 °C for 2 h. The precipitate that formed was filtered off,
washed with water, and dried in air to prepare 2,4,6ꢀtrinitroꢀ
benzaldehyde (4) in a yield of 5.19 g (77%). M.p. 118—120 °C
Reduction of dinitroindazole 6 with hydrazine hydrate
in the presence of iron(III) chloride afforded monoamino
derivative 9 as the only reaction product, i.e., the nitro
group at position 4 was selectively reduced (Scheme 3).
Scheme 3
1
(cf. lit. data6: 119 °C). H NMR, δ: 9.17 (s, 2 H, Pic); 10.57 (s,
1 H, CHO).
2,4,6ꢀTrinitrobenzaldehyde Nꢀphenylhydrazone (5). A susꢀ
pension of 2,4,6ꢀtrinitrobenzaldehyde (4 g, 16.6 mmol) and
PhNHNH2•HCl (2.4 g, 16.6 mmol) in EtOH (50 mL) was
refluxed for 24 h. After cooling, the precipitate that formed was
filtered off, washed with cold EtOH (10 mL), and dried in air to
prepare compound 5 in a yield of 5.19 g (85%). M.p. 213 °C (cf.
lit. data4: 202 °C). 1H NMR, δ: 6.94 (m, 1 H, Ph); 7.03 and 7.28
(both m, 2 H each, Ph); 8.11 (s, 1 H, CH=N); 8.89 (s, 2 H, Pic);
11.63 (s, 1 H, NH).
Reactions and conditions: N2H4•H2O, Cactiv, FeCl3•6H2O,
MeOH, 65 °C.
The fact that the reaction gave rise to the 4ꢀamino
1
derivative was confirmed by H NMR spectroscopy. In
particular, the NOESY experiment revealed the presence
of interaction through space between the orthoꢀprotons of
the Nꢀphenyl substituent and H(7) in compound 9
(δ 7.60). There are also interactions between the protons
of the amino group and two other aromatic protons of the
indazole system (H(5), δ 7.10; H(3), δ 8.65). These facts
unambiguously confirm reduction of the nitro group at
position 4.
Interestingly, the reactions with the use of other reꢀ
ducing systems (Fe/HCl—H2O or Fe/CH3COOH) also
did not produce the isomeric 6ꢀamino derivative. In all
cases, only the 4ꢀNO2 group was reduced.
4,6ꢀDinitroꢀ1ꢀphenylꢀ1Hꢀindazole (6). A solution of NaOH
(0.12 g, 3 mmol) in water (5 mL) was added to a suspension of
hydrazone 5 (1.0 g, 3 mmol) in EtOH (25 mL). The reaction
mixture was stirred at ~20 °C for 1 h. The precipitate that formed
was filtered off and recrystallized from EtOH to prepare
dinitroindazole 6 in a yield of 0.8 g (93%). M.p. 157—159 °C
1
(EtOH) (cf. lit. data5: 148 °C). H NMR, δ: 7.59 (m, 1 H, Ph);
7.71 and 7.86 (both m, 2 H each, Ph); 8.86, 8.93, and 8.96 (all s,
1 H each, Harom). 13C NMR, δ: 113.3 (C(7)); 113.8 (C(5));
119.9 (C(3a)); 123.3 (CPho); 128.5 (CPhp); 129.8 (CPhm); 134.3
(C(3)); 137.7 (CPhipso); 138.7 (C(4)); 139.5 (C(7a)); 145.4
(C(6)). IR, ν/cm–1: 1532, 1344 (NO2). Found (%): C, 54.55;
H, 2.82; N, 19.37. C13H8N4O4. Calculated (%): C, 54.93;
H, 2.84; N, 19.71.
The structures and compositions of the compounds
1
were established by H and 13C NMR and IR spectrosꢀ
Synthesis of mononitroindazoles 7a—c (general procedure).
A mixture of dinitroindazole 6 (0.28 g, 1 mmol), the correꢀ
sponding thiol (1 mmol), and K2CO3 (0.14 g, 1 mmol) in NMP
(5 mL) was stirred at 80—90 °C for 5 h. The reaction mixture
was cooled, poured into water (50 mL), acidified to pH 2, and
extracted with ethyl acetate (3×30 mL). The organic layer was
dried over MgSO4, the solvent was evaporated, and the residue
was chromatographed on a column (SiO2 35ꢀ63/toluene).
6ꢀNitroꢀ1ꢀphenylꢀ4ꢀphenylthioꢀ1Hꢀindazole (7a). The yield
copy and confirmed by elemental analysis.
To summarize, we developed a procedure for the synꢀ
thesis of previously unknown 4ꢀRꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀ
indazoles starting from 4,6ꢀdinitroꢀ1ꢀphenylꢀ1Hꢀindazole
based on high mobility of the 4ꢀNO2 group and the ease
of its reduction.
1
Experimental
was 57%. M.p. 128—130 °C. H NMR, δ: 7.50—7.80 (m, 11 H,
Ph, H(5)); 8.32 (s, 1 H, H(7)); 8.40 (s, 1 H, H(3)). 13C NMR, δ:
The 1H and 13C NMR spectra were recorded on Bruker
ACꢀ200 and Bruker AMꢀ300 instruments, respectively. The
chemical shifts (δ) are given relative to Me4Si. All samples for
NMR spectroscopy were prepared in a 1 : 1 DMSOꢀd6/CCl4
mixture. The IR spectra were measured on a Specord Mꢀ80
instrument in KBr pellets. The course of the reactions and the
purities of the compounds synthesized were monitored by TLC
on Silufol UVꢀ254 plates. The reactions were carried out with
the use of anhydrous DMF. All other solvents were not subꢀ
jected to special dehydration.
105.1, 114.5, 122.8. 123.4, 126.5, 127.8, 129.2, 129.7, 129.9,
130.3, 132.6, 133.1, 134.0, 137.0, 138.4, 146.9. IR, ν/cm–1
:
1524, 1336 (NO2). Found (%): C, 65.55; H, 3.89; S, 9.17.
C19H13N3O2S. Calculated (%): C, 65.69; H, 3.77; S, 9.23.
4ꢀ(4ꢀChlorophenyl)thioꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazole (7b).
1
The yield was 37%. M.p. 144—146 °C. H NMR, δ: 7.28—7.75
(m, 10 H, H(5), Ph, 4ꢀClPh); 8.33 (s, 1 H, H(7)); 8.43 (s, 1 H,
H(3)). 13C NMR, δ: 105.7, 115.8, 122.8, 127.0, 127.8, 129.1,
129.6, 129.8, 130.0, 131.2, 134.0, 137.1, 138.4, 146.9. Found (%):
C, 59.93; H, 3.28; S, 8.17. C19H12ClN3O2S. Calculated (%):
C, 59.76; H, 3.17; S, 8.40.
4ꢀBenzylthioꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazole (7c). The yield
was 53%. M.p. 123—125 °C. 1H NMR, δ: 4.51 (s, 2 H, CH2);
7.26—7.86 (m, 10 H, Ph); 7.92 (s, 1 H, H(5)); 8.32 (s, 1 H,
2,4,6ꢀTrinitrobenzaldehyde6 (4).* Several crystals of I2 were
added to a suspension of 2,4,6ꢀtrinitrotoluene (10 g, 44 mmol)
* Improved procedure.

Nucleophilic substitution in dinitroindazole
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
587
H(7)); 8.42 (s, 1 H, H(3)). 13C NMR, δ: 36.2 (CH2); 104.9
(C(7)); 133.3 (C(5)); 123.5 (CPho); 126.8 (C(3a)); 128.0 (CBnp);
128.5 (CPhp); 129.1 (CBnm); 129.5 (CBno); 130.5 (CPhm); 133.5
(C(4)); 134.8 (C(3)); 136.7 (CBnipso); 137.2 (C(7a)); 139.0
(CPhipso); 147.6 (C(6)). Found (%): C, 66.72; H, 4.03; S, 8.70.
C20H15N3O2S. Calculated (%): C, 66.46; H, 4.18; S, 8.87.
4ꢀAzidoꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazole (8). A suspension of
dinitroindazole 6 (0.28 g, 1 mmol) and NaN3 (0.1 g, 1.3 mmol)
in anhydrous DMF (5 mL) was stirred at 70—80 °C for 6 h. After
cooling, the reaction mixture was poured into water and acidiꢀ
fied to pH 3. The precipitate that formed was filtered off and
recrystallized from EtOH. The yield of compound 8 was
Found (%): C, 61.25; H, 4.09. C13H10N4O2. Calculated (%):
C, 61.41; H, 3.96.
This study was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
32261).
References
1. V. M. Vinogradov, A. M. Starosotnikov and S. A. Shevelev,
Mendeleev Commun., 2002, 198.
1
2. A. M. Starosotnikov, A. V. Lobach, V. V. Kachala, V. M.
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2003, 1690 [Russ. Chem. Bull., Int. Ed., 2003, 52, 1782].
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Shevelev, Izv. Akad. Nauk, Ser. Khim., 2001, 2297 [Russ.
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Khim., 2001, 252 [Russ. Chem. Bull., Int. Ed., 2001, 50, 261];
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Leng, J. Chem. Soc., Chem. Commun., 1982, 918.
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0.23 g (83%). M.p. 127—129 °C (EtOH). H NMR, δ: 7.51 (m,
1 H, Ph); 7.66 (t, 2 H, Ph, 3J = 6.0 Hz); 7.78 (m, 3 H, Ph,
H(5)); 8.33 (s, 1 H, H(7)); 8.46 (s, 1 H, H(3)). 13C NMR, δ:
103.4, 104.7, 120.7, 122.7, 127.8, 129.7, 132.8, 134.5, 137.9,
138.3, 147.2. IR, ν/cm–1: 2128 (N3); 1528, 1344 (NO2).
Found (%): C, 55.85; H, 2.49. C13H8N6O2. Calculated (%):
C, 55.72; H, 2.88.
4ꢀAminoꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazole (9). Ferric chloride
hexahydrate (20 mg) and N2H4•H2O (0.2 mL, 8 mmol) were
added to a suspension of dinitroindazole 6 (0.57 g, 2 mmol) and
activated carbon (0.18 g) in MeOH (40 mL). The reaction mixꢀ
ture was refluxed for 1 h (TLC control). Then the hot mixture
was filtered off from the carbon and the filtrate was cooled. The
precipitate that formed was filtered off, washed with cold
MeOH (10 mL), and dried in air. The yield of compound 9 was
0.35 g (69%). M.p. 142—144 °C. 1H NMR, δ: 6.56 (s, 2 H,
3
NH2); 7.10 (s, 1 H, H(5)); 7.42 (t, 1 H, Ph, J = 6.0 Hz); 7.60
(m, 3 H, H(7), Ph); 7.71 (d, 2 H, Ph, 3J = 6.0 Hz); 8.53 (s, 1 H,
H(3)). 13C NMR, δ: 92.34 (C(7)); 96.5 (C(5)); 117.2 (C(3a));
122.2 (CPho); 126.8 (CPhp); 129.4 (CPhm); 134.3 (C(3));
138.3 (C(4)); 139.2 (CPhipso); 143.5 (C(7a)); 148.7 (C(6)).
Received December 23, 2003