Characteristic features of nucleophilic substitution in the series of 4-RSO2-6-nitro-1-phenyl-1H-indazoles and benzo[d]isoxazoles

Article abstract of DOI:10.1023/A:1026012922607

Oxidation of 3-substituted 4-R-6-nitro-1-phenyl-1H-indazoles and benzo[d]isoxazoles (R = Ph, CH₂CO₂Me) gave the corresponding sulfones treatment of which with PhSH - K₂CO ₃ in N-methylpyrrolidone results in repl

Full text of DOI:10.1023/A:1026012922607

Russian Chemical Bulletin, International Edition, Vol. 52, No. 8, pp. 1797—1799, August, 2003
1797
Characteristic features of nucleophilic substitution in the series of
4ꢀRSO2ꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazoles and benzo[d]isoxazoles
ꢀ
A. M. Starosotnikov and S. A. Shevelev
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
Oxidation of 3ꢀsubstituted 4ꢀRꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazoles and benzo[d]isoxazoles
(R = Ph, CH2CO2Me) gave the corresponding sulfones treatment of which with PhSH—K2CO3
in Nꢀmethylpyrrolidone results in replacement of only the RSO2 group in position 4 with the
6ꢀNO2 group remaining intact, contrary to the known sequence of nucleophilic substitution for
metaꢀarranged nucleofuges.
Key words: 1Hꢀindazoles, benzo[d]isoxazoles, nitro compounds, sulfones, nucleophilic
substitution.
Previously, we reported the synthesis of 3ꢀsubstituted
4,6ꢀdinitrobenzo[d]isoxazoles1 and 1ꢀarylꢀ4,6ꢀdinitroꢀ
1Hꢀindazoles2,3 on the basis of picrylacetaldehyde. It was
found that the nitro group in position 4 of these comꢀ
pounds is highly active and can be replaced under mild
conditions on treatment with a broad range of anionic
Oꢀ, Nꢀ, and Sꢀnucleophiles (thiols, phenols, or alcohols
in the presence of inorganic bases or NaN3).1—3 The reacꢀ
tions are regiospecific, the nitro group in position 6 reꢀ
mains intact even with a large excess of the nucleophile.
The 6ꢀNO2 group in the products of nucleophilic substiꢀ
tution of the 4ꢀNO2 group is not replaced either; under
more drastic reaction conditions (temperature rise above
100 °C), the starting nitro compounds decompose.
Apparently, for the majority of mononitro benzo[d]isoxꢀ
azole and 1Hꢀindazole derivatives we prepared previously,
the electrophilicity of the heteroaromatic system does not
suffice for the replacement of the 6ꢀNO2 group. We sugꢀ
gested that the introduction of a strong electronꢀwithꢀ
drawing substituent that would still be less efficient than
the leaving NO2 group into position 4 of the benꢀ
zo[d]isoxazole or indazole nucleus would enhance the
mobility of the 6ꢀNO2 group, and it could be possible to
replace this group on treatment with nucleophiles. As
such substituent, we chose the RSO2 group. Indeed, it has
been shown recently4 that in the benzene series with metaꢀ
located PhSO2 and NO2 groups, only the NO2 group is
replaced on treatment with PhSH (in the presence of
K2CO3), while the PhSO2 group activates the metaꢀarꢀ
ranged NO2 group virtually in the same way as the nitro
group, as follows from comparison of the conditions of
NO2 replacement in metaꢀdinitro and metaꢀnitro(pheꢀ
nylsulfonyl) derivatives of benzene.
The only exception is 6ꢀnitrobenzo[d]isoxazole 1a,
which reacts with PhSH in the presence of K2CO3 under
rather drastic conditions (100 °C, in Nꢀmethylpyrroliꢀ
done (NMP)) to give the product of replacement of the
6ꢀnitro group, namely, bisꢀsulfide 2 (Scheme 1).
Starting from the previously synthesized1,3 sulfides
1a—c, we prepared 6ꢀnitroꢀ4ꢀRSO2 derivatives of the
benzo[d]isoxazole and 1Hꢀindazole, in particular, comꢀ
pounds 1a—c were oxidized to the corresponding sulꢀ
fones on treatment with 30% aqueous H2O2 in the
CF3COOH medium (Scheme 2).
Scheme 1
In the resulting sulfones, we studied the direction of
nucleophilic substitution taking the reaction of nitroꢀ
sulfones 3a—c with benzenethiol as an example.
We found that on treatment of sulfonyl derivatives
3a—c with PhSH in the presence of K2CO3 in NMP, only
the 4ꢀRSO2 group is replaced to give previously deꢀ
scribed1,3 sulfides 1a,b (Scheme 3).
The reaction proceeds under mild conditions (20 °C)
and regiospecifically (the nitro group in position 6 reꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1703—1705, August, 2003.
1066ꢀ5285/03/5208ꢀ1797 $25.00 © 2003 Plenum Publishing Corporation

1798
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
Starosotnikov and Shevelev
Scheme 2
is the case for 4,6ꢀdinitrobenzoꢀannelated fiveꢀmembered
aromatic heterocycles.1—3,5 To elucidate specific reasons,
separate structural studies and calculations are required.
Experimental
1
H NMR spectra were recorded on a Bruker ACꢀ200 instruꢀ
ment and 13C NMR spectra were run on a Bruker AMꢀ300
spectrometer. The chemical shifts (δ) are referred to Me4Si. The
spinꢀspin coupling constants are given in Hz. All samples for
NMR spectroscopy were prepared in a 1 : 1 DMSOꢀd6—CCl4
mixture. IR spectra were measured on a Specord Mꢀ80 instruꢀ
ment in KBr pellets. Mass spectra were recorded on a Kratos
MSꢀ30 mass spectrometer (EI, 70 eV, m/z). The course of the
reactions was monitored and the purity of substances was checked
by TLC on Silufol UVꢀ254 plates. The solvents were not speꢀ
cially purified.
Compound
R
Z
X
Yield 3 (%)
a
b
c
Ph
Ph
CH=NOMe
CN
O
NPh
NPh
91
98
92
CH2CO2Me
CN
i. H2O2, CF3COOH, 20 °C, 1 h.
Scheme 3
4,6ꢀBis(phenylthio)benzo[d]isoxazoleꢀ3ꢀcarboxaldehyde
Oꢀmethyloxime (2). A mixture of compound 1a (0.58 g,
1.83 mmol), benzenethiol (0.19 mL, 1.83 mmol), K2CO3 (0.26 g,
1.83 mmol), and 6 mL of NMP were stirred for 10 h at 100 °C.
The reaction mixture was poured in water and acidified to pH 2,
the precipitate was filtered off and recrystallized from EtOH to
give 0.47 g (63%) of compound 2. M.p. 113—114 °C (EtOH).
Found (%): C, 64.11; H, 4.15; S, 16.25. C21H16N2O2S2. Calcuꢀ
lated (%): C, 64.26; H, 4.11; S, 16.34. 1H NMR, δ: 4.05 (s, 3 H,
OCH3); 6.60 (s, 1 H, H(5)); 7.20 (s, 1 H, H(7)); 7.30—7.50 (m,
10 H, Ph); 8.50 (s, 1 H, CH=N). 13C NMR, δ: 62.41, 105.50,
116.25, 123.30, 128.95, 129.24, 132.91, 129.43, 129.90, 130.57,
130.80, 133.77, 134.34, 138.10, 142.95, 151.02, 164.10. MS: 392
[M]+. IR, ν/cm–1: 1040, 1060 (C=C), 1580 (C=N).
Starting
compound
Product
Yield of 1 (%)
3a
3b
3c
1a
1b
1b
64
74
94
i. PhSH, K2CO3, NMP, 20 °C.
Preparation of sulfones 3a—c (general procedure). A 30%
solution of H2O2 (2 mL) was added to a solution of 6 mmol of
the corresponding sulfide in 20 mL of CF3COOH and the mixꢀ
ture was stirred for 1 h at 20 °C. The reaction mixture was
poured in water and the precipitate was filtered off, washed with
water, and dried at 100 °C.
mains intact). The rate of replacement of the sulfonyl
group in compounds 3a,c is comparable with the rate of
replacement of the 4ꢀNO2 group in the dinitro derivatives
of the benzo[d]isoxazole1 and 1Hꢀindazole3 series (the
reactions with PhSH under identical conditions proceed
to completion in 24 h), while in compound 3b, this rate
was somewhat lower (full conversion of the starting sulfoꢀ
nyl derivative required 48 h).
The formation of only one of the two possible substiꢀ
tution products was demonstrated by 1H NMR of the
crude reaction product. The compounds obtained were
identified by a set of physicochemical methods, and prodꢀ
ucts 1a,b were also compared with the specimens syntheꢀ
sized previously. The key characteristics (m.p., NMR
spectra, and so on) of the resulting phenylthio derivatives
coincide with those for the obtained previously speciꢀ
mens.
Thus, we demonstrated that nucleophilic substituꢀ
tion in 3ꢀsubstituted 4ꢀRSO2ꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindꢀ
azoles and 4ꢀRSO2ꢀ6ꢀnitrobenzo[d]isoxazoles proceeds
regiospecifically with replacement of only the 4ꢀRSO2
group.
This reaction pathway unusual for the benzene fragꢀ
ment is, apparently, related to the strong influence of the
annelated heterocycle and its substituent in position 3, as
6ꢀNitroꢀ4ꢀ(phenylsulfonyl)benzo[d]isoxazoleꢀ3ꢀcarboxaldeꢀ
hyde Oꢀmethyloxime (3a). M.p. 132—134 °C. Found (%):
C, 49.98; H, 3.31; S, 8.83. C15H11N3O6S. Calculated (%):
C, 49.86; H, 3.07; S, 8.87. 1H NMR (DMSOꢀd6), δ: 4.03 (s,
3 H, OCH3); 7.60—7.80 (m, 3 H, Ph); 7.90 (d, 2 H, Ph, 3JH,H
=
7.3 Hz); 8.65 (s, 1 H, CH=N); 8.80 (s, 1 H, H(5)); 9.20 (s, 1 H,
H(7)). MS: 330 [M – OCH3]+.
3ꢀCyanoꢀ6ꢀnitroꢀ1ꢀphenylꢀ4ꢀ(phenylsulfonyl)ꢀ1Hꢀindazole
(3b). M.p. 207—209 °C. Found (%): C, 58.99; H, 3.15; S, 8.08.
C20H12N4O4S. Calculated (%): C, 59.40; H, 2.99; S, 7.93.
1H NMR (DMSOꢀd6), δ: 7.60—7.90 (m, 8 H, Ph); 8.20 (m,
2 H, Ph); 8.80 (s, 1 H, H(5)); 8.90 (s, 1 H, H(7)).
Methyl 2ꢀ[(3ꢀcyanoꢀ6ꢀnitroꢀ1ꢀphenyl)ꢀ1Hꢀindazoleꢀ4ꢀyl)sulꢀ
fonyl]acetate (3c). M.p. 185—187 °C. Found (%): C, 51.05;
H, 3.15; S, 7.85. C17H13N4O6S. Calculated (%): C, 51.00;
H, 3.02; S, 8.01. 1H NMR (DMSOꢀd6), δ: 3.67 (s, 3 H, OCH3);
4.98 (s, 2 H, CH2); 7.60—7.90 (m, 5 H, Ph); 8.70 (s, 1 H, H(5));
8.90 (s, 1 H, H(7)). 13C NMR (DMSOꢀd6), δ: 113.1, 115.5,
120.3, 123.0, 125.3, 130.9, 131.0, 132.8, 137.8, 140.1, 146.9,
163.5. IR, ν/cm–1: 1724 (CO2Ме), 1540, 1340 (NO2), 1168
(SO2). MS: 400 [M]+.
Preparation of sulfides 1a,b (general procedure). A mixture
of 1 mmol of particular sulfone 3a—c, PhSH (0.1 mL, 1 mmol),

4ꢀ(RꢀSulfonyl)ꢀ6ꢀnitroꢀ1ꢀphenylꢀ1Hꢀindazoles
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 8, August, 2003
1799
K2CO3 (0.14 g, 1 mmol), and 6 mL of NMP was stirred for
24—48 h at 20 °C (TLC monitoring). The reaction mixture was
poured in water and acidified to pH 2, and the precipitate was
filtered off, recrystallized from EtOH, and dried at 80 °C.
6ꢀNitroꢀ4ꢀ(phenylthio)benzo[d]isoxazoleꢀ3ꢀcarboxaldehyde
Oꢀmethyloxime (1a). M.p. 117—118 °C (EtOH). Found (%):
C, 54.54; H, 3.43; S, 9.62. C15H11N3O4S. Calculated (%):
C, 54.70; H, 3.37; S, 9.74. 1H NMR, δ: 4.05 (s, 3 H, OМе);
7.50—7.60 (s, 6 H, Ph, H(5)); 8.57 (s, 1 H, CH=N); 8.74 (s,
1 H, H(7)). 13C NMR (δ: 62.68, 104.00, 117.89, 121.76, 129.89,
130.45, 133.63, 135.64, 138.21, 149.21, 151.87, 162.81. The
sample was identical to that prepared previously.1
References
1. 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].
2. V. M. Vinogradov, A. M. Starosotnikov, and S. A. Shevelev,
Mendeleev Commun., 2002, 198.
3. A. M. Starosotnikov, V. V. Kachala, A. V. Lobach, V. M.
Vinogradov, and S. A. Shevelev, Izv. Akad. Nauk, Ser.
Khim., 2003, No. 8, 1690 [Russ. Chem. Bull., Int. Ed., 2003,
52, No. 8].
4. O. V. Serushkina, M. D. Dutov, O. Yu. Sapozhnikov, B. I.
Ugrak, and S. A. Shevelev, Zh. Org. Khim., 2002, 38, 1819
[Russ. J. Org. Chem., 2002, 38 (Engl. Transl.)].
5. S. A. Shevelev, I. L. Dalinger, and T. I. Cherkasova, Tetraꢀ
hedron Lett., 2001, 42, 8539.
3ꢀCyanoꢀ6ꢀnitroꢀ1ꢀphenylꢀ4ꢀphenylthioꢀ1Hꢀindazole (1b).
M.p. 196—198 °C (EtOH). 1H NMR, δ: 7.50—7.80 (m, 11 H,
Ph, H(5)); 8.42 (s, 1 H, H(7)). The sample was identical to that
prepared previously.3
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 01ꢀ03ꢀ
32261).
Received April 29, 2003