Synthesis and reactions of 1-aryl-3-formyl-4,6-dinitro-1H-indazoles

Article abstract of DOI:10.1070/MC2002v012n05ABEH001641

The title compounds were prepared by the reactions of picrylacetaldehyde with aryldiazonium salts followed by the intramolecular cyclization of the resulting picrylglyoxal monoarylhydrazones, and the regiospecific substitution for the nitro group at the 4-position under the action of anionic N-, O- and S-nucleophiles was found.

Full text of DOI:10.1070/MC2002v012n05ABEH001641

Mendeleev Commun., 2002, 12(5), 198–200
Synthesis and reactions of 1-aryl-3-formyl-4,6-dinitro-1H-indazoles
Vasilii M. Vinogradov, Aleksei M. Starosotnikov and Svyatoslav A. Shevelev*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 5328; e-mail: shevelev@mail.ioc.ac.ru
10.1070/MC2002v012n05ABEH001641
The title compounds were prepared by the reactions of picrylacetaldehyde with aryldiazonium salts followed by the intramolecular
cyclization of the resulting picrylglyoxal monoarylhydrazones, and the regiospecific substitution for the nitro group at the 4-position
under the action of anionic N-, O- and S-nucleophiles was found.
Previously,1 we reported on the synthesis of picrylacetaldehyde
from 2,4,6-trinitrotoluene. In the studies of picrylacetaldehyde as
a multipurpose synthon, we found that it can serve as a pre-
cursor of various heterocyclic compounds with functional substi-
tuents. In particular, we developed a method2 for the synthesis
of 6-nitrobenzo[d]isoxazoles with different substituents at the
3- and 4-positions.
Here we report a convenient procedure for the preparation of
previously unknown 1-aryl-3-formyl-4,6-dinitro-1H-indazoles
from picrylacetaldehyde and the synthesis of 1,3,4-substituted
6-nitroindazoles on this basis.
the course of the synthesis of compounds 2 (Scheme 2). These
latter can be completely converted into hemiacetals 3a,b on
boiling in ethanol for 30 min. Crystalline hemiacetal 3a elimi-
nates an alcohol molecule on heating in air (80 °C, 8 h) to re-
generate formyldinitroindazole 2a.
The reactions of formyldinitroindazoles were studied using
3-formyl-4,6-dinitro-1-phenyl-1H-indazole 2a as an example.
We found that the test compound reacts with N-, O- and S-
nucleophiles (in DMF or N-methylpyrrolidone solutions) so that
substitution for only the nitro group at the 4-position takes place
to give previously unknown 4-substituted 3-formyl-6-nitro-1-
phenyl-1H-indazoles 4–6 as sole products (Scheme 3). Phenol
and thiols were used as nucleophiles in the presence of solid
K2CO3 (in an equimolar amount), as well as NaN3. The reaction
with NaN3 was performed at room temperature, whereas the
reactions with phenol and thiols were performed at 80 and 60 °C,
respectively, to the complete conversion of parent indazole 2a.
Note that the results were identical in the reactions of aldehyde
2a and its hemiacetal 3a.
At the first stage, to obtain dinitroindazoles, picrylacetalde-
hyde reacted with aryldiazonium salts to form picrylglyoxal
monohydrazones 1a–c (Scheme 1).
NH
Ar
N
i
O
Pic
O
Pic
picrylacetaldehyde
1a–c
a Ar = Ph
b Ar = -ClC H
1
In addition to H and 13C NMR data (including NOE), the
Pic = 2,4,6-(NO2)3C6H2
direction of substitution was also supported chemically. Thus,
glycol 7 was isolated after the reaction with thioglycerol; this
glycol afforded intramolecular cyclic acetal under conditions of
catalysis with p-toluenesulfonic acid (Scheme 4). This product
can be formed only by substitution for the nitro group at the
4-position.
p
6
4
c Ar = -MeOC H
p
6
4
Scheme 1 Reagents and conditions: i, ArNH2 (1 equiv.), H2O–HCl, NaNO2
(1 equiv.), EtOH, AcONa, 5–10 °C, 1 h.
1-Aryl-3-formyl-4,6-dinitro-1H-indazoles 2a–c (Scheme 2)
are formed on the treatment of hydrazones 1a–c with alkalies
or alkali metal carbonates. The best results were obtained with
K2CO3 in EtOH at room temperature. Hydrazones 1a–c undergo
cyclization due to intramolecular nucleophilic substitution for
the nitro group (Scheme 2). Hydrazones 1a–c were used without
additional purification because compounds 2a–c were formed to
a degree even in the course of their preparation.
Regiospecific substitution for an ortho or para nitro group
was previously observed in substituted di- and polynitroben-
zenes,3,4 as well as (peri nitro group) in 4,6-dinitrobenzo-
N3
O
N
N
O2N
O2N
O2N
A characteristic property of formyldinitroindazoles 2 with no
electron-donor groups at the N-aryl substituent is the formation
of stable hemiacetals 3a,b, which are partially formed even in
Ph
4
i
NO2
OPh
O
O
O
O
NO2
ii
N
N
N
i
N
N
O2N
NH
Ar
O2N
NO2
NO2
Ph
Ph
5
iii
2a
1a–c
SR
HO
NO2
OEt
O
N
N
N
N
N
N
Ph
O2N
O2N
6a c
–
Ar
Ar
a R = Ph
b R = CH2Ph
c R = cyclohexyl
2a–c
3a,b
Ar = Ph
a
b
c
Ar = p-ClC6H4
Ar = p-MeOC6H4
Scheme 3
Reagents and conditions: i, NaN3 (1 equiv.), DMF, 20 °C, 24 h;
ii, PhOH (1 equiv.), K2CO3 (1 equiv.), N-methylpyrrolidone, 80 °C, 24 h;
iii, RSH (1 equiv.), K2CO3 (1 equiv.), N-methylpyrrolidone, 60 °C, 24 h.
Scheme 2 Reagents and conditions: i, K2CO3 (1 equiv.), EtOH, 20 °C, 24 h.
– 198 –

Mendeleev Commun., 2002, 12(5), 198–200
carboxylation to compound 11 and added ammonia and then
HO
underwent decarboxylation to amino acid 12.
OH
The structures of the synthesised compounds were supported
by 1H and 13C NMR spectroscopy, mass spectrometry (molecular
ions were detected in all cases), IR spectroscopy and elemental
analysis.†
Thus, we developed a convenient method for the synthesis
of multifunctional compounds, 1-aryl-3-formyl-4,6-dinitro-1H-
indazoles, and prepared a number of new 1-phenyl-3-R-4-R'-
nitroindazoles on this basis.
O
O
NO2
S
S
O
O
i
ii
N
N
N
N
N
N
O2N
O2N
O2N
Ph
Ph
Ph
2a
7
8
Scheme 4 Reagents and conditions: i, HSCH2CH(OH)CH2OH (1 equiv.),
K2CO3 (1 equiv.), N-methylpyrrolidone, 20 °C, 48 h; ii, TosOH (5 mol%),
benzene, refluxing for 8 h.
This work was supported by the Russian Foundation for Basic
Research (grant no. 01-03-32261).
[b]thiophene5 and 4,6-dinitrobenzo[d]isoxazole2 derivatives.
The formation of stable hemiacetals 3a,b (Scheme 2) from
formyldinitroindazoles 2a,b is indicative of the high electro-
philicity of the formyl group. Indeed, indazole 2a (or its hemi-
acetal) readily reacts with compounds containing active methylene
units. For example, unsaturated compound 9 was formed with
cyanoacetic ester (Scheme 5). The reaction of compound 2a
with malonic acid should be particularly noted. In this case,
various products were formed depending on reaction conditions
(Scheme 5). Methylenemalonic acid derivative 10 was obtained
when the reaction was performed in ethanol in the presence of
NH4OAc, whereas acrylic acid derivative 11 was obtained on
heating in pyridine with the use of piperidine as a catalyst; that
is, dicarboxylic acid 10 underwent decarboxylation under these
conditions. If the reaction was performed in acetic acid in the
presence of an excess of NH4OAc (Rodionov reaction condi-
tions6), acrylic acid derivative 11 (28% yield) and 3-aminopro-
pionic acid derivative 12 (20% yield, Scheme 5) were formed.
We found that under reaction conditions acid 11 did not add
ammonia to form amino acid 12. At the same time, methylene-
malonic acid 10 gave a mixture of acids 11 and 12 in 20 and
32% yields, respectively. Thus, the reaction of compound 2a
with malonic acid in the presence of NH4OAc in acetic acid
initially resulted in dicarboxylic acid 10, which underwent de-
References
1 V. M. Vinogradov, I. L. Dalinger, A. M. Starosotnikov and S. A. Shevelev,
Mendeleev Commun., 2000, 140.
2 V. M. Vinogradov, I. L. Dalinger, A. M. Starosotnikov and S. A. Shevelev,
Izv. Akad. Nauk, Ser. Khim.., 2001, 445 (Russ. Chem. Bull., Int. Ed.,
2001, 50, 464).
3 F. Benedetti, D. Marshall, Ch. Stirling and J. Leng, J. Chem. Soc., Chem.
Commun., 1982, 918.
†
NMR spectra were measured in [2H6]DMSO on a Bruker AM-300
instrument using TMS as an internal standard.
1a: yield 79%. 1H NMR, d: 7.05 (m, 1H, Ph), 7.30 (m, 4H, Ph), 9.21
(s, 2H, Pic), 9.53 (1H, CHO), 11.11 (s, 1H, NH).
1b: yield 66%. 1H NMR, d: 7.32 (m, 4H, p-ClC6H4), 9.21 (s, 2H, Pic),
9.56 (1H, CHO), 11.12 (s, 1H, NH).
1c: yield 71%. 1H NMR, d: 3.79 (s, 3H, Me), 6.90, 7.25 (2d, 4H,
p-MeOC6H4), 9.20 (s, 2H, Pic), 9.47 (s, 1H, CHO), 11.10 (s, 1H, NH).
On heating, the hemiacetals lost an ethanol molecule before melting.
2a: yield 91%, mp 190–191 °C (EtOH). 1H NMR, d: 7.71 (m, 3H, Ph),
7.92 (m, 2H, Ph), 8.79, 8.87 (2d, 1H each, 5-H and 7-H, 4JH–H 1.61 Hz),
10.33 (s, 1H, CHO).
2c: yield 82%, mp 210–212 °C (EtOH). 1H NMR, d: 3.92 (s, 3H, Me),
7.22, 7.75 (d, 2H each, p-MeOC6H4, JH–H 8.85 Hz), 8.76 (s, 2H, 5-H
3
and 7-H), 10.32 (s, 1H, CHO).
3a: yield 96%. 1H NMR, d: 1.14 (t, 3H, Me, 3JH–H 6.96 Hz), 3.54, 3.87
(m, 1H each, CH2), 5.95, 6.69 (d, 1H each, OCH and OH, 3JH–H 9.11 Hz),
7.5–7.9 (m, 5H, Ph), 8.53, 8.77 (d, 1H each, 5-H and 7-H, 4JH–H 1.60 Hz).
CN
CO2H
3b: yield 86%. 1H NMR, d: 1.13 (t, 3H, Me, JH–H 6.99 Hz), 3.50,
3
NO2
NO2
3
3.82 (2m, 1H each, CH2), 5.89, 6.83 (d, 1H each, OCH and OH, JH–H
9.32 Hz), 7.68, 7.89 (d, 2H each, p-ClC6H4, JH–H 8.85 Hz), 8.53, 8.80
3
CO2Et
CO2H
(d, 1H each, 5-H and 7-H).
N
N
4: yield 75%, mp 193–194 °C (decomp.). 1H NMR, d: 7.6–7.9 (m, 5H,
Ph), 8.01, 8.35 (s, 1H each, 5-H and 7-H), 10.53 (s, 1H, CHO).
5: yield 70%, mp 192–194 °C. 1H NMR, d: 7.2–7.4, 7.5–7.8, 7.9 (3m,
11H, OPh, NPh, 5-H), 8.32 (s, 1H, 7-H), 10.53 (s, 1H, CHO).
6a: yield 95%, mp 199–200 °C. 1H NMR, d: 7.45 (s, 1H, 5-H), 7.5–7.9
(m, 10H, SPh, NPh), 8.25 (s, 1H, 7-H), 10.43 (s, 1H, CHO).
6b: yield 90%, mp 152–153 °C. 1H NMR, d: 4.48 (s, 2H, CH2), 7.2–7.9
(m, 10H, NPh, CPh), 8.01, 8.24 (d, 1H each, 5-H and 7-H, 4JH–H 1.61 Hz),
10.38 (s, 1H, CHO).
N
Ph
N
O2N
O2N
Ph
9
10
i
ii
NO2
O
6c: yield 89%, mp 173–175 °C. 1H NMR, d: 1.3–1.9, 2.0–2.2 [m, 10H,
(CH2)5], 3.61 (m, 1H, SCH), 7.5–7.9 (m, 5H, Ph), 8.01, 8.30 (d, 1H each,
5-H and 7-H, 4JH–H 1.40 Hz), 10.58 (s, 1H, CHO).
N
N
O2N
iii
Ph
7: yield 62%, oily product. 1H NMR, d: 2.9–3.2, 3.3–3.6 (2m, 2H each,
SCH2, OCH2), 3.80 (m, 1H, OCH), 4.6, 4.9 (br. s, 1H each, OH), 7.5–7.9
2a
4
iv
(m, 5H, Ph), 8.07, 8.21 (2d, 1H each, 5-H and 7-H, JH–H 1.61 Hz),
10.51 (s, 1H, CHO).
8: yield 53%, mp 157–160 °C (decomp.). H NMR, d: 3.20 (m, 2H,
1
[ 10 ]
[ 10 ]
SCH2), 4.05 (dd), 4.52 (d) (1H each, OCH2), 4.81 (m, 1H, OCH), 6.32
(s, 1H, OCHO), 7.4–7.8 (m, 5H, Ph), 8.13, 8.39 (2d, 1H each, 5-H and
7-H, 4JH–H 1.61 Hz).
CO2H
CO2H
H2N
NO2
1
9: yield 46%, mp > 300 °C (decomp.). H NMR, d: 1.41 (t, 3H, Me,
NO2
3JH–H 6.57 Hz), 4.40 (q, 2H, CH2, 3JH–H 6.57 Hz), 7.6–7.8 (m, 3H, Ph),
7.9–8.1 (m, 2H, Ph), 8.86, 8.92, 8.98 (3s, 1H each, HC=C, 5-H and 7-H).
1
+ 11
N
N
10: yield 84%, mp > 300 °C (decomp.). H NMR, d: 7.5–8.0 (m, 5H,
Ph), 8.10, 8.83, 9.01 (3s, 1H each, HC=C, 5-H and 7-H), 12.9 (br. s,
2H, OH).
N
Ph
N
O2N
O2N
11: yield 44%, mp > 300 °C (decomp.). 1H NMR, d: 6.76 (d, 1H,
Ph
HC=C, 3JH–H 15.26 Hz), 7.5–7.7 (m, 3H, Ph), 7.8–7.9 (m, 2H, Ph), 8.04
11
12
3
(d, 1H, HC=C, JH–H 15.26 Hz), 8.78, 8.84 (s, 1H each, 5-H and 7-H),
Scheme 5 Reagents and conditions: i, CH2(CN)CO2Et (1 equiv.), NH4OAc
(10 mol%), AcOH (10 mol%), benzene, 80 °C, 6 h; ii, CH2(CO2H)2, NH4OAc
(2 equiv.), EtOH, 78 °C, 5 h; iii, CH2(CO2H)2, piperidine (10 mol%), Py,
115 °C, 5 h; iv, NH4OAc (3 equiv.), AcOH, 118 °C, 10 h.
12.43 (br. s, 1H, OH).
12: yield 20%, mp 217–218 °C. H NMR, d: 2.9–3.1 (m, 2H, CH2),
1
5.76 (dd, 1H, HCNH2), 7.5–7.9 (m, 6H, NH2, Ph), 8.30 (d, 1H, NH2),
8.61, 8.79 (d, 1H each, 5-H and 7-H, 4JH–H 1.40 Hz).
– 199 –

Mendeleev Commun., 2002, 12(5), 198–200
4 F. Terrier, Nucleophilic Aromatic Substitution, VCH, New York, 1991,
ch. 3.
5 S. A. Shevelev, I. L. Dalinger and T. I. Cherkasova, Tetrahedron Lett.,
2001, 42, 8539.
6 V. M. Rodionov and B. I. Kurtev, Izv. Akad. Nauk SSSR, Ser. Khim.,
1952, 113 (in Russian).
Received: 15th July 2002; Com. 02/1967
– 200 –