Reactions of 4,6-dinitrobenzo[c]isoxazoles with nucleophiles

Article abstract of DOI:10.1007/s11172-010-0128-x

Reactions of nucleophiles with 3-R-4,6-dinitrobenzo[c]isoxazoles (anthranils) were stud- ied. Reactions of 4,6-dinitroanthranil (R = H) with anionic O- and S-nucleophiles (phenols and benzenethiols in the presence of K₂CO₃) do not re

Full text of DOI:10.1007/s11172-010-0128-x

Russian Chemical Bulletin, International Edition, Vol. 59, No. 3, pp. 662—664, March, 2010
662
Reactions of 4,6ꢀdinitrobenzo[c]isoxazoles with nucleophiles
V. V. Mezhnev, M. D. Dutov, V. V. Kachala, 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: Shevelev@ioc.ac.ru
Reactions of nucleophiles with 3ꢀRꢀ4,6ꢀdinitrobenzo[c]isoxazoles (anthranils) were studꢀ
ied. Reactions of 4,6ꢀdinitroanthranil (R = H) with anionic Oꢀ and Sꢀnucleophiles (phenols
and benzenethiols in the presence of K2CO3) do not result in displacement of the nitro groups.
The malonodinitrile anion (Cꢀnucleophile) attacks the C(3) atom with opening of the isoxazole
ring followed by recyclization into 2ꢀaminoꢀ5,7ꢀdinitroquinolineꢀ3ꢀcarbonitrile Nꢀoxide. The
5ꢀNO2 group in the latter is smoothly replaced under the action of benzenethiol and 4ꢀchloꢀ
rophenol in the presence of K2CO3. In the case of 3ꢀsubstituted anthranil (R = COCH3), one
nitro group (4ꢀNO2) is replaced under the action of benzenethiol and NaN3.
Key words: 2,4,6ꢀtrinitrotoluene, 4,6ꢀdinitrobenzo[c]isoxazole, anthranils, nucleophilic subꢀ
stitution, 4,6ꢀdinitroquinoline Nꢀoxide.
Benzo[c]isoxazoles (2,1ꢀbenzoisoxazoles, or anthraꢀ
quinoline Nꢀoxide derivatives. The initial step of the reacꢀ
tion is believed18 to involve addition of the malonodiꢀ
nitrile anion to the C(3) atom of anthranil. We found that
4,6ꢀdinitroanthranil (1) readily reacts with malonodinitrile
in boiling ethanol in the presence of piperidine (Pip), quanꢀ
titatively yielding earlier unknown 2ꢀaminoꢀ5,7ꢀdinitroꢀ
quinolineꢀ3ꢀcarbonitrile Nꢀoxide (2) (Scheme 1).
nils) are widely used for synthetic purposes (including the
preparation of useful biologically active compounds1).
Among nitroanthranils, 4,6ꢀdinitroanthranils are of parꢀ
ticular interest because their benzene fragment can be funcꢀ
tionalized not only by modification of the nitro groups
and their ipsoꢀsubstitution but also by nucleophilic substiꢀ
tution of the hydrogen atom (SNH) that is ortho to the
nitro group. The SNH reaction is favored by the formation
of stable anionic σHꢀadducts of nucleophiles with the benꢀ
zene ring.2—5 Some substituted 3ꢀRꢀ4,6ꢀdinitroanthranils
are known.6—11 Recently, we have developed a preparative
method for the synthesis of the first member of the series
(unsubstituted 4,6ꢀdinitroanthranil) from 2,4,6ꢀtrinitroꢀ
toluene (TNT).12
Scheme 1
It is known that various fiveꢀmembered aromatic
heterocycles annulated with 4,6ꢀdinitrobenzene usually
smoothly react with anionic nucleophiles to give, through
displacement of the 4ꢀNO2 group, the corresponding
ipsoꢀsubstitution products.13—16
In the present work, we studied reactions of 4,6ꢀdinitroꢀ
anthranil (1) with anionic Oꢀ and Sꢀnucleophiles (pheꢀ
nols and benzenethiols in the presence of a base). Howevꢀ
er, the reaction did not occur under conditions accepted
as standard for this type of reactions (K2CO3, Nꢀmethylꢀ
pyrrolidone (NꢀMP), 20—50 °C). An increase in the temꢀ
perature to 90 °C resulted in the decomposition of the
starting compound. Apparently, this is due to the instabilꢀ
ity of 3ꢀunsubstituted anthranils under basic conditions at
elevated temperatures.1
i. Pip/EtOH, reflux.
Roomꢀtemperature reactions of compound 2 with benꢀ
zenethiol and 4ꢀchlorophenol in the presence of K2CO3 in
NꢀMP and with sodium azide in DMF involve displaceꢀ
ment of one nitro group to give the corresponding substiꢀ
tution products in high yields (Scheme 2).
3ꢀUnsubstituted anthranils are known17 to react with
malonodinitrile in the presence of an organic base, giving
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 647—649, March, 2010.
1066ꢀ5285/10/5903ꢀ0662 © 2010 Springer Science+Business Media, Inc.

Reactions of 4,6ꢀdinitroanthranil with nucleophiles
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 3, March, 2010
663
Scheme 2
Scheme 3
i. K2CO3, NꢀMP, 50 °C; ii. DMF, 50 °C.
XAr = SPh (a), pꢀOC6H4Cl (b)
i. K2CO3, NꢀMP, ~20 °C; ii. DMF, ~20 °C.
1
>320 °C. H NMR (DMSOꢀd6), δ: 9.31, 8.79, 8.70 (all s, 1 H,
H(6), H(7), H(4)); 8.52 (s, 2 H, NH2). MS, m/z: 275 [M+].
Found (%): C, 43.25; H, 1.96; N, 25.21. C10H5N5O5. Calculatꢀ
ed (%): C, 43.56; H, 1.83; N, 25.45.
The displacement of the 5ꢀNO2 group in the reactions
with benzenethiol and 4ꢀchlorophenol was confirmed by
a NOE experiment, which revealed couplings of the H(4)
and H(6) protons of the quinoline system with the H(2)
and H(6) protons, respectively, of benzenethiol and
4ꢀchlorophenol.
3ꢀAcetylꢀ4,6ꢀdinitroanthranil6 possessing a substituꢀ
ent in the position 3 is stable under basic conditions at
elevated temperatures; its reactions with anionic nucleoꢀ
philes proceed with displacement of one nitro group
(Scheme 3).
The displacement of the 4ꢀNO2 group in a reaction
with benzenethiol was confirmed by a NOE experiment,
which revealed couplings of the acetyl protons and the
H(5) proton of the anthranil fragment with the H(2) and
H(6) protons of benzenethiol.
Replacement of the nitro group in 2ꢀaminoꢀ5,7ꢀdinitroquinoꢀ
lineꢀ3ꢀcarbonitrile Nꢀoxide (2) (general procedure). A nucleoꢀ
philic component (2.54 mmol) was added to a solution of
2ꢀaminoꢀ5,7ꢀdinitroquinolineꢀ3ꢀcarbonitrile Nꢀoxide (2) (0.7 g,
2.54 mmol) in NꢀMP (7 mL) (or DMF for NaN3). Phenols
and benzenethiols were added together with K2CO3 (0.39 g,
2.54 mmol). The reaction mixture was stirred at room temperaꢀ
ture for 6 h and poured onto ice. The precipitate that formed was
filtered off and washed with cold acetone.
2ꢀAminoꢀ7ꢀnitroꢀ5ꢀ(phenylthio)quinolineꢀ3ꢀcarbonitrile
Nꢀoxide (3a). Yield 86%, m.p. 252—254 °C. 1H NMR (DMSOꢀd6),
δ: 8.56 (s, 1 H, H(4)); 8.02 (s, 1 H, H(8)); 7.35—7.57 (m, 7 H,
Ar, NH2); 7.12 (s, 1 H, H(6)). Found (%): C, 56.55; H, 3.07;
N, 16.81. C16H10N4O3S. Calculated (%): C, 56.80; H, 2.98;
N, 16.56.
2ꢀAminoꢀ5ꢀ(4ꢀchlorophenoxy)ꢀ7ꢀnitroquinolineꢀ3ꢀcarboꢀ
nitrile Nꢀoxide (3b). Yield 81%, m.p. 305 °C (decomp.). 1H NMR
(DMSOꢀd6), δ: 8.72, 8.68 (both s, 1 H, H(8), H(4)); 8.40 (s, 2 H,
NH2); 7.60, 7.35 (both d, 2 H, AA´BB´, pꢀPhCl, J = 8.5 Hz);
7.25 (s, 1 H, H(6)). Found (%): C, 53.62; H, 2.59; N, 15.47.
C16H10ClN4O4. Calculated (%): C, 53.87; H, 2.54; N, 15.71.
2ꢀAminoꢀ5ꢀazidoꢀ7ꢀnitroquinolineꢀ3ꢀcarbonitrile Nꢀoxide (4).
Yield 85%, m.p. >320 °C. 1H NMR (DMSOꢀd6), δ: 8.68 (s, 1 H,
H(4)); 8.28—8.40 (m, 3 H, H(8), NH2); 7.93 (s, 1 H, H(6)).
Found (%): C, 43.95; H, 2.02; N, 36.37. C10H5N7O3. Calculatꢀ
ed (%): C, 44.29; H, 1.86; N, 36.15.
Replacement of the 4ꢀnitro group in 1ꢀ(4,6ꢀdinitro[c]isoxazolꢀ
3ꢀyl)ethanone (5) (general procedure). A nucleophilic compoꢀ
nent (0.4 mmol) was added to a solution of 1ꢀ(4,6ꢀdinitroꢀ
[c]isoxazolꢀ3ꢀyl)ethanone (5) (0.1 g, 0.4 mmol) in NꢀMP (1 mL)
(or DMF for NaN3). Benzenethiol was added together with
Experimental
1
H NMR spectra were recorded on a Bruker ACꢀ200 instruꢀ
ment in DMSOꢀd6. Chemical shifts δ are referenced to SiMe4.
The mass spectrum was recorded on a Kratos MSꢀ30 instrument
(70 eV). The melting points of the compounds obtained were
measured on a Boetius hotꢀstage microscope according to the
Kofler procedure (heating rate 4 deg min–1).
2ꢀAminoꢀ5,7ꢀdinitroquinolineꢀ3ꢀcarbonitrile Nꢀoxide (2).
Malonodinitrile (0.17 g, 2.4 mmol) and several drops of piperiꢀ
dine were added to a solution of 4,6ꢀdinitroanthranil (2) (0.5 g,
2.4 mmol) in ethanol (5 mL). The reaction mixture was refluxed
for ~20 h and poured into water. The precipitate that formed was
filtered off and dried. The yield of compound 2 was 98%, m.p.

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Mezhnev et al.
K2CO3 (0.054 g, 0.4 mmol). The reaction mixture was stirred
at 50 °C for 2 h and poured onto ice. The precipitate that
formed was filtered off, washed with water, and recrystallized
from EtOH.
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13. O. Yu. Sapozhnikov, V. V. Mezhnev, M. D. Dutov, V. V.
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1ꢀ(6ꢀNitroꢀ4ꢀ(phenylthio)benzo[c]isoxazolꢀ3ꢀyl)ethanone
(6). Yield 76%, m.p. 138—141 °C. 1H NMR (DMSOꢀd6), δ: 8.58
(s, 1 H, H(7)); 7.70—7.55 (m, 5 H, SPh); 7.34 (s, 1 H, H(5));
2.78 (s, 3 H, CH3). Found (%): C, 58.12; H, 3.45; N, 8.72.
C15H10N2O4S. Calculated (%): C, 57.32; H, 3.21; N, 8.91.
1ꢀ(4ꢀAzidoꢀ6ꢀnitrobenzo[c]isoxazolꢀ3ꢀyl)ethanone (7). Yield
70%, m.p. 150 °C (decomp.). 1H NMR (DMSOꢀd6), δ: 8.96
(s, 1 H, H(7)); 7.94 (s, 1 H, H(6)); 2.84 (s, 3 H, CH3). Found (%):
C, 44.13; H, 2.24; N, 27.89. C9H5N5O4. Calculated (%):
C, 43.73; H, 2.04; N, 28.33.
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Received April 2, 2009;
in revised form November 5, 2009