Preparative synthesis of 4,6-dinitroanthranil

Article abstract of DOI:10.1007/s11172-010-0036-0

A preparative method for the synthesis of 4,6-dinitroanthranil by intramolecular cyclization of 2-azido-4,6-dinitrobenzaldehyde was developed.

Full text of DOI:10.1007/s11172-010-0036-0

Russian Chemical Bulletin, International Edition, Vol. 58, No. 2, pp. 476—478, February, 2009
476
Preparative synthesis of 4,6ꢀdinitroanthranil*
V. V. Mezhnev, M. D. Dutov, and S. A. Shevelev
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: shevelev@ioc.ac.ru
A preparative method for the synthesis of 4,6ꢀdinitroanthranil by intramolecular cyclizaꢀ
tion of 2ꢀazidoꢀ4,6ꢀdinitrobenzaldehyde was developed.
Key words: 2,4,6ꢀtrinitrotoluene, 2,4,6ꢀtrinitrobenzaldehyde, 4,6ꢀdinitroanthranil.
Benzo[c]isoxazoles (also known as 2,1ꢀbenzoisoxaꢀ
Scheme 1
zoles or anthranils) are widely used in organic synthesis,
including the synthesis of valuable biologically active comꢀ
pounds.1 Among nitroꢀcontaining anthranils, 4,6ꢀdinitroꢀ
anthranils are of particular interest because the benzene
fragment can be functionalized not only via modification
of the nitro groups or their ipsoꢀsubstitution but also via
nucleophilic substitution of hydrogen (SNH) that is ortho
to the nitro group, which is facilitated by the formation of
stable anionic σHꢀadducts of nucleophiles with the benꢀ
zene ring.2—6 Some 3ꢀsubstituted 4,6ꢀdinitroanthranils
have been described.7,8 However, the first member of the
series (3ꢀunsubstituted 4,6ꢀdinitroanthranil) remains
virtually inaccessible. In some cases, 4,6ꢀdinitroanthranil
has been detected among other reaction products, though
in very low yields.9—11 It has been reported12 that 4,6ꢀdiꢀ
nitroanthranil can be obtained in 60% yield from picryl
chloride like 6ꢀnitroanthranil from 1ꢀchloroꢀ2,4ꢀdinitroꢀ
benzene. Unfortunately, the experimental procedure has
been omitted.
Scheme 2
We assumed that thermolysis of 2ꢀazidoꢀ4,6ꢀdinitroꢀ
benzaldehyde 1 would be a convenient preparative route
to 4,6ꢀdinitroanthranil 2 (Scheme 1).
In an attempted selective synthesis of azide 1, we studied
the regioselectivity of a reaction of 2,4,6ꢀtrinitrobenzalꢀ
dehyde 3 (see Ref. 13) with NaN3 (Scheme 2).
According to the data obtained (Table 1), the disꢀ
placement of the nitro group by NaN3 from aldehyde 3
is not selective: the reaction always gives a mixture of
2ꢀazidoꢀ4,6ꢀdinitrobenzaldehyde 1 and its paraꢀisomer
4ꢀazidoꢀ2,6ꢀdinitrobenzaldehyde 1´. Their ratio depends
on the solvent and the catalyst.
In less polar solvents, the yield of the orthoꢀproduct
increases. The maximum ratio ortho : para = 4 : 1 was
achieved in THF at room temperature (entry 2) and
in boiling benzene in the presence of 5% Et3N•HCl
(entry 4).
The reaction in diethyl ether in the presence of 5%
18ꢀcrownꢀ6 predominantly gives the paraꢀproduct. This
unexpected outcome can be attributed to the formation of
a too bulky solvate pair strongly shielding the orthoꢀnitro
group and preventing its displacement.
* On the occasion of the 75th anniversary of the foundation
of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 466—468, February, 2009.
1066ꢀ5285/09/5802ꢀ0476 © 2009 Springer Science+Business Media, Inc.

Preparative synthesis of 4,6ꢀdinitroanthranil
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 2, February, 2009
477
Table 1. Displacement of the nitro group from 2,4,6ꢀtrinitroꢀ
benzaldehyde 3 under the action of NaN3
Scheme 3
Entry Solvent
Catalyst
T/ t/h
°C
Ratio of
isomers
ortho : para
1
2
3
4
5
6
DMF
THF
THF
PhH
Et2O+EtOH
Et2O
—
—
20
20 50
1
2 : 1
4 : 1
1 : 1
4 : 1
2.5 : 1
1 : 4
Et3N•HCl 20 20
Et3N•HCl 80 15
—
20 25
18ꢀcrownꢀ6 20 10
Reflux of a mixture of orthoꢀ/paraꢀazidodinitrobenꢀ
zaldehydes in toluene gives 4,6ꢀdinitroanthranil 2, which
can be isolated by column chromatography. Thus, this
synthesis of 4,6ꢀdinitroanthranil 2 cannot be regarded as
a preparative one because of the insufficiently selective
azidation of 2,4,6ꢀtrinitrobenzaldehyde 3.
At the same time, it has been demonstrated14,15 that
the precursor of trinitrobenzaldehyde 3, viz., 4ꢀ(N´,N´ꢀ
dimethylamino)ꢀNꢀ(2,4,6ꢀtrinitrobenzylidene)aniline
Nꢀoxide (4) prepared by condensation of 2,4,6ꢀtrinitroꢀ
toluene with N,Nꢀdimethylꢀ4ꢀnitrosoaniline, regiospeciꢀ
fically reacts with NaN3 in DMF at ~20 °C: only the
2ꢀNO2 group is displaced to give Nꢀ(2ꢀazidoꢀ4,6ꢀdinitroꢀ
benzylidene)ꢀ4ꢀ(N´,N´ꢀdimethylamino)aniline Nꢀoxide
(5) in 85% yield (Scheme 3)*.
We found that acid hydrolysis of azide 5 in toluene
with conc. HCl at ~20 °C followed by in situ reflux of
intermediate 2ꢀazidoꢀ4,6ꢀdinitrobenzaldehyde 1 affords
4,6ꢀdinitroanthranil 2 in 76% yield (with respect to azide
5) (Scheme 4). After the reaction is completed, anthranil
2 is in the organic layer (toluene), while a second hyꢀ
drolysis product, viz., substituted phenylhydroxylamine
(6), is mostly in the acid layer.
Thus, we developed a preparative method for the synꢀ
thesis of 4,6ꢀdinitroanthranil 2.
Experimental
1H and 13C NMR spectra were recorded on Bruker AC 200
and Bruker WM 250 instruments, respectively. Chemical shifts δ
are referenced to SiMe4. Mass spectra were recorded on a Kratos
MSꢀ30 instrument (70 eV). Melting points were measured on a
Boetius hot stage (Kofler technique, heating rate 4 deg min–1).
4,6ꢀDinitroanthranil (2). Concentrated HCl (5 mL) was
added to a solution of Nꢀ(2ꢀazidoꢀ4,6ꢀdinitrobenzylidene)ꢀ
4ꢀ(N´,N´ꢀdimethylamino)aniline Nꢀoxide 5 (0.5 g) (see Refs 14, 15)
in toluene (5 mL). The solution was stirred for 5—6 h, kept for
Scheme 4
* According to a previous concept,16 a reaction of trinitrotoluene with N,Nꢀdimethylꢀ4ꢀnitrosoaniline gives an anil.
Recently,14 it has been demonstrated that the condensation product is the corresponding anil Nꢀoxide (4).

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Mezhnev et al.
16 h, refluxed with stirring for 2 h, and cooled. Another portion
of toluene (5 mL) was added and the organic phase was sepaꢀ
rated and washed with water (5×10 mL) in a separatory funnel.
The organic layer was dried with Na2SO4 and concentrated
in vacuo. The yield of compound 2 was 76%, m.p. 124—125 °C.
1H NMR (DMSOꢀd6), δ: 10.61 (s, 1 H); 9.37 (s, 1 H); 8.62 (s,
1 H). 13C NMR (DMSOꢀd6), δ: 160.68, 154.97, 148.75, 140.91,
120.61, 117.36, 111.48. MS, m/z: [M]+ = 209, [M+1]+ = 210.
Found (%): C, 41.05; H, 1.75; N, 19.51. C7H3N3O5. Calcuꢀ
lated (%): C, 40.20; H, 1.45; N, 20.09.
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This work was financially supported by the Internaꢀ
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Received September 30, 2008;
in revised form December 18, 2008