Reaction of 4,6-dichloro-5-nitrobenzofuroxan with aromatic amines and nitrogen-containing heterocycles

Article abstract of DOI:10.1007/s10593-012-1126-8

4,6-Dichloro-5-nitrobenzofuroxan reacts with aromatic and heterocyclic amines via the chlorine atom at the position 4 of the aromatic ring to give monosubstitution products. In a similar reaction with piperazine, both amino groups undergo arylation to giv

Full text of DOI:10.1007/s10593-012-1126-8

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
REACTION OF 4,6-DICHLORO-5-NITROBENZOFUROXAN
WITH AROMATIC AMINES AND NITROGEN-CONTAINING
HETEROCYCLES
E. M. Gibadullina1*, E. A. Chugunova1, E. V. Mironova1, D. B. Krivolapov1,
A. R. Burilov1, L. M. Yusupova2, and M. A. Pudovik1
4,6-Dichloro-5-nitrobenzofuroxan reacts with aromatic and heterocyclic amines via the chlorine atom
at the position 4 of the aromatic ring to give monоsubstitution products. In a similar reaction with
piperazine, both amino groups undergo arylation to give a compound containing two benzofuroxan
fragments.
Keywords: benzofuroxan, amination, aromatic ring, arylation, monosubstitution.
In recent decades the biological activity of benzofuroxans has been actively studied. Compounds having
antibacterial, antifungal, antiparasitic, cytotoxic, and herbicidal activity have been found [1, 2]. It should be
noted that if unsubstituted benzofuroxan shows modest biological activity, then the presence of functional
groups (nitro, methoxy etc.) in its molecule leads to a sharply increased efficacy of the derivatives obtained [3].
We have previously examined the reaction of 4,6-dichloro-5,7-dinitrobenzofuroxan with aromatic amines,
where both chlorine atoms react to give double substitution products [4, 5]. A study of the acaricidal and
bactericidal properties of the compounds obtained has revealed the dependence of their activity on the structure
of the substituting aromatic amine [6].
4,6-Dichloro-5-nitrobenzofuroxan derivatives (1), including compounds with fungicidal properties [3], are
undoubtedly of interest in terms of biological activity. We have previously shown that the reaction of 4,6-dichloro-
5-nitrobenzofuroxan (1) with aliphatic amines (methylamine, dimethylamine, and 2,2-dimethoxyethylmethyl-
amine) is accompanied by the substitution of the chlorine atom at the position 4 of the aromatic ring [7].
In this study, we report the reaction of furoxan 1 with aromatic and heterocyclic amines with the aim of
preparing novel types of aminated benzofuroxans and studying their properties. The amines selected were
o-aminophenol, o-phenylenediamine, o-toluidine, m-nitroaniline, and benzylamine. The ratio of starting
reagents and the nature of the solvent were varied. In spite of using an excess of the amine, only the chlo-
rine atom at the position 4 of the benzene ring reacted, and the monosubstituted products 2-5 were obtained.
_______
*To whom correspondence should be addressed, e-mail: elmirak@iopc.ru.
1A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Center, Russian Academy of
Sciences, 8 Academician Arbuzov St., Kazan' 420088, Russia.
2Kazan National Research Technological University, 68 Karl Marx St., Kazan' 420015, Russia; e-mail:
luizamagdanurovna@yandex.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1318-1325, August, 2012.
Original article submitted April 5, 2011.
1228
0009-3122/12/4808-1228©2012 Springer Science+Business Media New York

1
Their structure was demonstrated using IR and H NMR spectroscopy, and also by X-ray structural analysis
(Figs. 1 and 2). Reaction of furoxan 1 with benzylamine gave compound 6. The highest yield of the target
compounds in the reported reactions was achieved with using DMSO as solvent.
R
HN
Cl
NH2
O2N
Cl
O2N
Cl
N
N
N
N
DMSO
O
O
+
2
R
_
·HCl
NH2
2–5
O
O
R
1
2 R = 2-NH2, 3 R = 2-Me, 4 R = 2-OH, 5 R = 3-NO2
HN
Ph
N
DMSO
room temp., 30 min
O2N
Cl
1 + 2PhCH2NH2
O
N
–PhCH2NH2·HCl
6
O
The ease of furoxan 1 interaction with aromatic amines depends on the nature of the substituents in the
aromatic ring. The methyl-, amino-, and hydroxy derivatives readily form the products 2-4 at room temperature,
while interaction of furoxan 1 with m-nitroaniline requires prolonged heating. Ortho- and para-nitroanilines, and
also 2,4-dichloro- and 2,5-dichloroanilines do not react with furoxan 1. In the reaction of furoxan 1 with
o-phenylenediamine only one amino group undergoes arylation, apparently for steric reasons.
Fig. 1. Molecular structure of compound 3 with atoms represented by thermal vibration
ellipsoids of 50% probability.
1229

Fig. 2. Molecular structure of compound 4 with atoms represented by thermal vibration ellipsoids
of 50% probability.
In the same way as with aromatic amines, morpholine reacts with furoxan 1 by substituting one chlorine
atom at the position 4 of the aromatic ring. The structure of compound 7 was established by X-ray structural
analysis (Fig. 3).
O
N
Dioxane
O
O2N
Cl
room temp., 30 min
N
N
1 + 2
O
O
N
H
–
N
·HCl
H
O
7
Unlike with o-phenylenediamine, in the reaction of equimolar amounts of furoxan 1 and piperazine both
amino groups of the latter take part, leading to the compound 8 with structure confirmed by X-ray structural
analysis data (Fig. 4).
O
O
N
N
Cl
NO2
H
N
Dioxane
N
N
1
+
H
N
N
H
Cl
O2N
N
N
–
O
8
O
N
·HCl
H
1230

Fig. 3. Molecular structure of compound 7 with atoms represented by thermal vibration ellipsoids
of 50% probability.
Fig. 4. Molecular structure of the compound 8 with atoms represented by thermal vibration
ellipsoids of 50% probability.
1231

TABLE 1. Crystallographic Parameters and Refinement Details for the
Structures of Compounds 3, 4, 7, and 8
Parameter
Color, habit
3
4
7
8
Red, prismatic
C13H9ClN4O4
320.69
Red, prismatic
C12H7ClN4O5
322.67
Red, prismatic
C10H9ClN4O5
300.66
Red, prismatic
C16H10Сl2N8O8
689.43
Empirical formula
M
Symmetry
Triclinic
Monoclinic
Monoclinic
Triclinic
(partial molecular
position)
Space group
P-1
С2/с
P21/c
P-1
Unit cell parameters
a, Å
b, Å
5.2531(5)
11.374(1)
12.625(1)
113.293(1)
100.156(1)
95.593(1)
670.2(1)
2
29.815(5)
4.578(5)
21.469(5)
—
4.9584(8)
28.360(5)
8.868(2)
—
8.5434(8)
8.6446(8)
11.778(1)
73.417(1)
75.234(1)
64.229(1)
742.08(12)
1
c, Å
, deg.
, deg.
, deg.
V, Å3
112.327(5)
—
103.379(2)
—
2711(3)
8
1213.2(3)
4
Z
dcalc, g/cm3
1.589
1.581
1.646
1.543
Absorption coefficient,
3.11
3.13
3.43
2.96
Mo, cm-1
F(000)
328
1312
616
356
 interval, deg.
R(int)
1.98-26.00
0.0150
2.89-26.00
0.2278
2.47-27.00
0.0198
2.67-26.00
0.0174
Range of index
measurements
–6  h  6,
–14  k  14,
–15  l  15
–36  h  32,
–5  k  5,
–26  l  22
–6  h  6,
–36  k  36,
–11  l  10
–10  h  10,
–10  k  10,
–14  l  14
Total reflections
6771
2605
2116
6162
2553
721
9782
2643
2284
9415
2913
2465
Independent reflections
Reflections with I >2(I)
Final p factor
values
R
0.0337
0.0890
0.0953
0.0953
1.049
235
0.1367
0.2143
0.3405
0.2812
0.986
198
0.0346
0.0874
0.0407
0.0919
1.040
217
0.0332
0.0906
0.0402
0.0962
1.052
208
Rw
Rall
Rw all
Refinement parameter
Number of refinement
parameters
According to X-ray analysis, the asymmetric part of the unit cell in the crystals of compounds 3, 4, and
7 contains one independent molecule of the compound, while the molecule of compound 8 occupies a particular
position, where the center of symmetry of the crystal coincides with the center of piperazine ring. In addition to
a molecule of this compound, the unit cell of crystal 8 contains a solvent molecule of dioxane (Fig. 4). In the
molecules of compounds 8 and 7, the piperazine and morpholine rings assume a "chair" type conformation.
It should be noted that the possibility of a true intermolecular hydrogen bonding is only realized in the
molecule of compound 4, where a classical O–H···O type hydrogen bond leads to the formation of chains along
the 0y axis.
The crystals of compounds 3, 7, 8 show shortened C–H···O type contacts, which means that the
benzofuroxan 3 forms dimers, compound 8 forms associates with two molecules of solvent for each molecule of
the title compound, and compound 7 forms chains along the 0z axis.
1232

EXPERIMENTAL
IR spectra were recorded on a Bruker Vector 22 Fourier spectrometer. Crystalline materials were
1
studied in vaseline oil. H NMR spectra were recorded on a Bruker Avance-600 instrument (600 MHz) using
acetone-d6 (compounds 2, 5) or CDCl3 (compounds 3, 4, 6-8) with the residual solvent signals as internal
standards (7.26 ppm for CDCl3 and 2.05 ppm for acetone-d6). Elemental analysis was carried out on a Carlo-
Erba EA 1108 instrument. Melting points for the compounds prepared were determined using a Boetius hot
stage apparatus. The starting 4,6-dichloro-5-nitrobenzofuroxan (1) was prepared by method [7].
4-(2-Aminophenylamino)-6-chloro-5-nitro-2,1,3-benzoxadiazole 1-Oxide (2). A solution of o-phe-
nylenediamine (0.108 g, 1.0 mmol) in DMSO (5 ml) was added dropwise with stirring at room temperature to a
solution of the 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) in DMSO (5 ml). The reaction mixture
was maintained for 30 min, poured into water, and the precipitate formed was filtered off, washed with water,
and dried in vacuo (40ºC, 0.06 mm Hg) to constant weight. It was recrystallized from hexane. Yield 0.110 g
(70%); mp 195-196ºC. IR spectrum, , cm-1: 1360 (NO2 sym.), 1562 (NO2 asym.), 1625 (furoxan), 3092 (ArH),
1
3224, 3227 (NH2), 3417 (NH). H NMR spectrum, , ppm: 3.57 (2H, br. s, NH2); 6.60-6.63 (2H, m, H Ar);
6.69-6.71 (2H, m, H Ar); 7.38 (1H, s, H-7); 8.21 (1H, s, NH). Found, %: C 44.91; H 2.45; Cl 11.20; N 21.75.
C12H8ClN5O4. Calculated, %: C 44.81; H 2.51; Cl 11.02; N 21.77.
6-Chloro-4-(2-methylphenylamino)-5-nitro-2,1,3-benzoxadiazole 1-oxide (3) was prepared similarly
to compound 2 from 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) and o-methylaniline (0.107 g,
1.0 mmol). Yield 0.110 g (70%); mp 118-119ºC. IR spectrum, , cm-1: 1359 (NO2 sym.), 1561 (NO2 asym.),
1
1612 (furoxan), 3096 (ArH), 3306 (NH). H NMR spectrum, , ppm: 2.10 (3H, s, CH3); 6.71-6.73 (2H, m,
H Ar); 7.05 (1H, s, H-7); 7.21-7.24 (2H, m, H Ar); 8.26 (1H, s, NH). Found, %: C 49.01; H 2.78; Cl 11.19;
N 17.32. C13H9ClN4O4. Calculated, %: C 48.69; H 2.83; Cl 11.06; N 17.47.
6-Chloro-4-(2-hydroxyphenylamino)-5-nitro-2,1,3-benzoxadiazole 1-oxide (4) was prepared
similarly to compound 2 from 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) and o-aminophenol
(0.109 g, 1.0 mmol). Yield 0.130 g (79%); mp 140-141ºC. IR spectrum, , cm-1: 1362 (NO2 sym.), 1563 (NO2
asym.), 1625 (furoxan), 3096 (ArH), 3400 (NH), 3427 (OH). 1H NMR spectrum, , ppm: 5.32 (1Н, s, ОН); 6.89
(1Н, s, Н-7); 6.93 (3Н, m, Н Ar); 7.22-7.23 (1Н, m, Н Ar); 8.43 (1Н, s, NH). Found, %: С 44.69; Н 1.95; Cl
11.03; N 17.18. C12H7ClN4O5. Calculated, %: C 44.67; H 2.19; Cl 10.99; N 17.36.
6-Chloro-5-nitro-4-(3-nitrophenylamino)-2,1,3-benzoxadiazole 1-Oxide (5). A solution of m-nitro-
aniline (0.138 g, 1.0 mmol) in DMSO (5 ml) was added dropwise with stirring at room temperature to a solution
of the 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) in DMSO (5 ml). The reaction mixture was
maintained at 70ºC for 8 h, poured into water, and the precipitate formed was filtered off, washed with water,
and dried in vacuo (40ºC, 0.06 mm Hg) to constant weight. Yield 0.208 g (73%); mp 159-160ºC. IR spectrum,
, cm-1: 1331 (NO2 sym.), 1360 (NO2 sym.), 1536 (NO2 asym.), 1564 (NO2 asym.), 1620 (furoxan), 3087 (ArH),
1
3312 (NH). H NMR spectrum, , ppm (J, Hz): 7.39 (1Н, s, Н-7); 7.66 (1Н, t, J = 8.1, Н Ar); 7.80 (1Н, d, J =
7.7, Н Ar); 8.08 (1Н, d, J = 8.1, Н Ar); 8.22 (1Н, s, Н Ar); 9.26 (1Н, s, NH). Found, %: С 40.88; Н 1.76; Cl
10.13; N 19.87. C12H6ClN5O6. Calculated, %: С 40.99; H 1.72; Cl 10.08, N 19.92.
4-Benzylamino-6-chloro-5-nitro-2,1,3-benzoxadiazole 1-oxide (6) was prepared similarly to
compound 2 from 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) and benzylamine (0.107 g, 1.0
mmol). Yield 0.129 g (82%); mp 149-150°C. IR spectrum, , cm-1: 1362 (NO2 sym.), 1562 (NO2 asym.), 1622
(furoxan), 3090 (ArH), 3310 (NH). 1H NMR spectrum, , ppm (J, Hz): 5.26 (2Н, d, J = 8.8, СН2Ph); 6.71 (1Н,
s, H-7); 7.34-7.36 (5Н, m, H Ph); 8.29 (1Н, s, NH). Found, %: С 49.08; Н 2.99; Cl 11.24; N 17.25.
C13H9ClN4O4. Calculated, %: С 48.69; H 2.83; Cl 11.06; N 17.47.
6-Chloro-4-morpholino-5-nitro-2,1,3-benzoxadiazole 1-oxide (7) was prepared similarly to
compound 2 from 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) and morpholine (0.087 g, 1.0
mmol). Yield 0.140 g (93%); mp 169-170ºC. IR spectrum, , cm-1: 1365 (NO2 sym.), 1565 (NO2 asym.), 1621
1233

1
(furoxan), 3086 (ArH). H NMR spectrum, , ppm: 2.83–2.84 (4Н, m, CH2NCH2); 3.61-3.62 (4Н, m,
CH2OCH2); 7.01 (1Н, s, H-7). Found, %: С 39.69; H 3.22; Сl 11.87; N 18.48. C10H9ClN4O5. Calculated, %:
С 39.95; H 3.02; Сl 11.79; N 18.63.
N,N'-Bis[6-chloro-5-nitro-2,1,3-benzoxadiazol-1-oxide-4-yl]piperazine (8) was prepared similarly to
compound 2 from 4,6-dichloro-5-nitrobenzofuroxan (1) (0.125 g, 0.5 mmol) and piperazine (0.043 g,
0.5 mmol). Yield 0.090 g (70%); mp 164-165ºC. IR spectrum, , cm-1: 1360 (NO2 sym.), 1563 (NO2 asym.),
1
1622 (furoxan), 3099 (ArH). H NMR spectrum, , ppm: 3.12 (8Н, s, 4СH2); 6.89 (2Н, s, H-7,7'). Found, %:
С 37.51; H 2.14; Сl 14.02; N 21.70. C16H10Cl2N8O8. Calculated, %: С 37.45; H 1.96; Сl 13.82; N 21.83.
X-ray structural analysis of compounds 3, 4, 7, and 8 was carried out on a Bruker Smart APEX II
CCD automatic diffractometer (graphite monochromator; MoK = 0.71073 Å, -scanning; temperature 293
K). Semiempirical calculation of the absorption was carried out using the SADABS program [8]. The structures
were solved by the direct method with the SIR program [9] and refined in the isotropic and then in the
anisotropic approximation with the SHELXL97 program [10]. In structures 3 and 7, the coordinates of the
hydrogen atoms were revealed in Fourier difference synthesis and refined isotropically. In structures 4 and 8 the
hydrogen atoms were placed in geometrically calculated positions and included in the refinement using the
"rider" model. All of the calculations were performed using the WinGX and APEX2 programs [11]. All of the
figures and analysis of the intermolecular interactions were carried out with the help of the PLATON program
[12]. The atomic coordinates and geometric parameters for the structure of compounds 3, 4, 7, 8 were placed in
the Cambridge Crystallographic Data Center with the reference numbers CCDC 822929, 822931, 822930, and
822928, respectively. The crystallographic parameters and structure refinement details for compounds 3, 4, 7, 8
are given in Table 1.
REFERENCES
1.
2.
3.
4.
H. Cerecetto, E. Dias, R. Di Maio, M. González, S. Pacce, P. Saenz, G. Seoane, L. Suescun,
A. Mombrú, G. Fernández, M. Lema, and J. Villalba, J. Agric. Food Chem., 48, 2995 (2000).
V. G. Granik, M. E. Kaminka, N. B. Grigor'ev, I. S. Severina, M. A. Kalinkina, V. A. Makarov, and
V. I. Levina, Khim.-Farm. Zh., 36, No. 10, 7 (2002).
L. I. Khmel'nitskii, S. S. Novikov, and T. I. Godovikova, in: Chemistry of Furoxans: Reactions and
Uses [in Russian], Nauka, Moscow (1996), p. 384.
L. V. Spatlova, L. M. Yusupova, and I. F. Falyakhov, in: Organic Synthesis in the New Century.
Proceedings of the All-Russian School Conference in Organic Synthesis [in Russian], St. Petersburg
(2002), p. 94.
5.
6.
L. V. Spatlova, Authors Abstract. Diss. Cand. Chem. Sci., Kazan' (2003).
L. M. Yusupova, I. F. Falyakhov, L. V. Spatlova, T. V. Garipov, T. A. Shindala Mahammad Hamid,
and D. R. Ishkaeva, RF Pat. 2 255 935; Byul. Izobr., No. 19 (2005)
7.
E. A. Chugunova, E. M. Kasymova, A. R. Burilov, D. B. Krivolapov, L. M. Yusupova, and
M. A. Pudovik, Zh. Obshch. Khim., 79, 1713 (2009).
8.
9.
G. M. Sheldrick, SADABS, Bruker AXS Inc., Madison (1997).
A. Altomare, G. Cascarano, C. Giacovazzo, and D. Viterbo, Acta Crystallogr. Sect. A: Found.
Crystallogr., A47, 744 (1991).
10.
G. M. Sheldrick, SHELX-97. Programs for crystal structure analysis (Release 97-2), Vols. 1, 2,
University of Gottingen (1997).
11.
12.
L. J. Farrugia, J. Appl. Crystallogr., 32, 837 (1999).
A. L. Spek, Acta Crystallogr., Sect. A: Found. Crystallogr., A46, C-34 (1990).
1234