Reaction of 4,5-dinitroimidazole with ethylenediamine and some transformations of the obtained 5-(2-aminoethylamino)-4-nitro-1H-imidazole

Article abstract of DOI:10.1023/A:1022122208213

The nitro group at position 5 in 4,5-dinitroimidazole was substituted by reaction with ethylenediamine with the formation of 5-(2-aminoethylamino)-4-nitro-1H-imidazole. The acylation of the compound was studied; a new bicyclic derivative of imidazole containing a benzothiazole fragment was obtained.

Full text of DOI:10.1023/A:1022122208213

Chemistry of Heterocyclic Compounds, Vol. 38, No. 11, 2002
REACTION OF 4,5-DINITROIMIDAZOLE
WITH ETHYLENEDIAMINE AND SOME
TRANSFORMATIONS OF THE OBTAINED
5-(2-AMINOETHYLAMINO)-4-NITRO-1H-IMIDAZOLE
O. S. El'tsov and V. S. Mokrushin
The nitro group at position 5 in 4,5-dinitroimidazole was substituted by reaction with ethylenediamine
with the formation of 5-(2-aminoethylamino)-4-nitro-1H-imidazole. The acylation of the compound was
studied; a new bicyclic derivative of imidazole containing a benzothiazole fragment was obtained.
Keywords: benzothiazole, bifunctional amines, dinitroimidazole, imidazolylthioureides, nitro group,
ethylenediamine, acylation.
It is well known that the nitro group at position 5 of 4,5-dinitroimidazole (1) has high mobility and is
easily substituted during the action of nucleophiles such as halide ions, aliphatic amines, CH-active compounds,
and sodium sulfide and sulfite with the formation of the respective 5-substituted 4-nitroimidazoles [1].
The aim of the present work was to study the reaction of the imidazole 1 with ethylenediamine and also
the reactions of the obtained amino derivative with acylating agents and aldehydes, which could be expected to
result in the formation of five-, six-, or seven-membered heterocycles or products with linear structures.
During the reaction of the imidazole 1 with ethylenediamine under conditions similar to those described
earlier [1] it was possible to isolate compound 2a – a salt of the dinitroimidazole 1 and the amine. Its structure
was confirmed by the data from 1H NMR spectroscopy (Table 1) and by the presence of a molecular ion peak at
158 in its mass spectrum. The nitro group in the imidazole 1 was substituted under harsher conditions, i.e., as a
result of reaction with the ethylenediamine, which was used as solvent, at 60°C. The structure of the obtained
5-(2-aminoethylamino)-4-nitro-1H-imidazole (3) was confirmed by 1H NMR spectroscopy (Table 1) and by the
presence of a molecular ion peak 171 in its mass spectrum.
To obtain evidence for the presence of a free β-amino group in compound 3 it was brought into reaction
with aromatic aldehydes in acetic acid. As a result the Schiff bases 4a,b were isolated. Their structures were
proved by 1H NMR spectroscopy, and their individuality was established by elemental analysis (Tables 1 and 2).
During the reaction of the imidazolylethylenediamine 3 with ethyl chlorocarbonate and with acetic
anhydride it could be expected that derivatives of imidazolyltriazepine, imidazolyl-5-imidazoline, or the
products from acylation of the amino group of the ethylenediamine fragment of the molecule would be obtained.
As a result of the reaction only the N-acyl derivatives 5a,b were isolated, and their structures were proved by
1H NMR spectroscopy. Thus, in the 1H NMR spectrum of compound 5a there are two broad one-proton singlets
for the NH groups and signals for the ethyl group in the form of a quartet and a triplet at 3.96 and 1.14 ppm
(Table 1). Correspondingly, in the 1H NMR spectrum of compound 5b there is a broad singlet for the NH protons
__________________________________________________________________________________________
Ural State Technical University, Ekaterinburg 620002, Russia; e-mail: eltsov@htf.ustu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1513-1517, November, 2002. Original article
submitted February 3, 2000.
0009-3122/02/3811-1331$27.00©2002 Plenum Publishing Corporation
1331

of the imidazole ring at 12.19 ppm, signals for the NH protons of ethylenediamine fragment in the form of two
triplets at 7.99 and 7.72 ppm on account of their splitting at the adjacent protons of the –CH2CH2– groups, and a
three-proton singlet for the acetyl fragment at 1.92 ppm (Table 1). During attempts at the cyclization of
compounds 5a,b in the presence of a 1% alcohol solution of potassium hydroxide, alkali metal alcoholates,
phosphorus oxychloride, and concentrated sulfuric acid resinification of the reaction mixture was observed, and
a multitude of chromatographically inseparable products was formed.
NO2
NO2
NH2–R1
N
N
–
NO2
N
NO2
N
H
+
NH3–R1
NH2(CH2)2NH2
2a–d
1
NO2
NO2
NH(CH2)2NHC
N
NO2
NH(CH2)2NHC
N
X
N
O
NH(CH2)2NH2
N
H
N
H
N
H
R4
N
3
6a–c
R3
5a,b
NO2
N
NO2
NH(CH2)2NH
N
2
NH(CH2)2N=CHR
N
H
S
N
H
4a,b
7
2 a R1 = (CH2)2NH2, b R1 = (CH2)2OH, c R1 = (CH2)3COOH, d R1 = C6H4NH2-o; 4 a R2 = C6H4–Cl-p, b R2 = C6H4–Cl-o;
5 a R3 = OEt, b R3 = Me; 6 a R4 = NH2, X = O, b R4 = NHC6H4–Cl-p, X = O, c R4 = NHPh, X = S
TABLE 1. The 1H NMR Spectra of the Synthesized Compounds
Com-
Chemical shifts, δ, ppm, CCSS, J (Hz)
pound
+
6.93 (1H, s, 2-H); 5.18 (5H, br. s, NH3 , NH2); 2.78 (4H, s, CH2CH2)
2а
7.60 (3H, br. s, NH3+); 6.94 (1H, s, 2-H); 3.52 (2H, t, J = 4.91, CH2 );
2.80 (2H, t, J = 4.91, CH2 )
2b
8.28 (3H, br. s, NH3+); 6.94 (1H, s, 2-H); 2.80 (2H, t, J = 7.00, CH2 );
2.33 (2H, t, J = 7.28, CH2 ); 1.62 (2H, dt, J1 = 7.28, J2 = 7.00, CH2)
2c
9.28 (5H, br. s, NH3+, NH2); 7.80 ( 4H, m, Harom); 7.07 (1H, s, 2-H)
2d
3
12.25 (1H, br. s, NH); 7.31 (1H, br. s, NH); 6.94 (1H, s, 2-H); 5.39 (2H, br. s, NH2);
3.49 (2H, m, CH2); 2.99 (2H, t, J = 5.99, CH2)
12.15 (1H, s, NH); 8.85 (1H, s, CH); 7.93-7.49 (4H, m, Harom); 7.70 (1H, t, J = 5.95, NH);
4а
4b
5а
5b
7.43 (1H, s, 2-Н); 3.92 (2H, t, J = 5.80, CH2); 3.72 (2H, dt, J1 = 5.95, J2 = 5.80, CH2)
12.05 (1H, s, NH); 8.66 (1H, s, CH); 7.88-7.39 (4H, m, Harom); 7.75 (1H, t, J = 5.91, NH);
7.36 (1H, s, 2-Н); 3.89 (2H, t, J = 5.79, CH2); 3.68 (2H, dt, J1 = 5.91, J2 = 5.79, CH2)
12.20 (1H, br. s, NH); 7.72 (1H, s, 2-H); 7.48 (1H, br. s, NH); 7.16 (1H, br. s, NH);
3.96 (2H, q, J = 7.02, CH2); 3.46-3.20 (4H, m, CH2CH2); 1.14 (3H, t, J = 7.02, CH3)
12.19 (1H, s, NH); 7.99 (1H, t, J = 5.17, NH); 7.72 (1H, t, J = 5.82, NH);
7.47 (1H, s, 2-Н); 3.43 (2H, dt, J1 = 5.17, J2 = 7.33, CH2);
3.28 (2H, dt, J1 = 5.82, J2 = 7.33, CH2); 1.92 (3H, s, CH3)
12.21 (1H, br, s, NH); 7.70 (1H, t, J = 6.21, NH); 7.36 (1H, s, 2-H);
6.13 (1H, t, J = 5.30, NH); 5.56 (2H, s, NH2); 3.41 (2H, dt, J1 = 6.21, J2 = 6.04, CH2);
3.21 (2H, dt, J1 = 5.30, J2 = 6.04, CH2)
6а
12.10 (1H, br. s, NH); 8.67 (1H, s, NH); 7.76 (1H, t, J = 5.36, NH); 7.49-7.22 (4H, m,
6b
H
arom); 7.39 (1H, s, 2-Н); 6.30 (1H, t, J = 5.68, NH);
3.45 (2H, dt, J1 = 5.68, J2 = 6.00, CH2); 3.35 (2H, dt, J1 = 5.36, J2 = 5.99, CH2)
12.22 (1H, br. s, NH); 9.56 (1H, s, NH); 7.95 (2H, br. s, 2NH); 7.46 (1H, s, 2-H);
6c
7
7.37-7.08 (5H, m, C6H5); 3.76 (2H, m, CH2); 3.59 (2H, m, CH2)
12.23 (1H, s, NH); 8.83 (1H, br. s, NH); 7.93 (1H, br. s, NH); 7.76-7.09 (4H, m, Harom);
7.53 (1H, s, 2-H); 3.66 (4H, m, CH2CH2)
1332

In the reactions of the imidazole 3 with sodium isocyanate, p-chlorophenyl isocyanate, and phenyl
isothiocyanate only products with linear structures were isolated, i.e., the 4-nitroimidazolyl-5-ureido and
4-nitroimidazolyl-5-thioureido derivatives 6a-c. The 1H NMR spectra of compounds 6b,c contain signals for the
aromatic protons and singlets for the NHAr protons, while the signals for the NH groups of the ethylenediamine
fragment are superimposed on each other, forming a broad two-proton singlet at 7.95 ppm (Table 1).
Examples of the oxidative cyclization of thioamides [2] and imidazolylthioureides [3] are known from
the literature. It could be expected that during treatment of compound 6c with bromine cyclization would take
place with the participation of only one of the nitrogen atoms or of the benzene ring of the substituent (synthesis
of benzothiazoles according to Hugershoff) [4]. When the reaction was conducted in glacial acetic acid the
individual compound was isolated and characterized. The presence of only four aromatic protons in the region
1
of 7.76-7.09 ppm in its H NMR spectrum made it possible to assign the compound the structure of the
benzothiazole 7.
Thus, in the reaction of compound 3 with acylating agents the formation of only linear derivatives was
observed, and it was not possible to detect the products from cyclization involving the nitrogen atoms. In order
to check the discovered features of the behaviour of the imidazole 3 we tried to produce other
nitroaminoimidazoles by substitution of the nitro group in compound 1 by bifunctional amines. For the latter we
chose ethanolamine, γ-aminobutyric acid, and o-phenylenediamine. In the reaction of the dinitroimidazole 1
with these compounds only their salts 2b-d were isolated, as demonstrated by the molecular peaks 158 in the
1
mass spectra of these compounds, corresponding the molecular mass of 4,5-dinitroimidazole. In the H NMR
spectra of the products from the reaction of the dinitroimidazole 1 with bifunctional amines signals are observed
for the protons of the introduced amines, and at the same time there are no signals for the NH protons of the
imidazole ring. In contrast to the reaction with ethylenediamine the reactions of the imidazole 1 with above-
TABLE 2. The Characteristics of the Synthesized Compounds
Found, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
Calculated, %
C
H
N
C3H2N4O4·C2H8N2
C3H2N4O4·C2H7NO
C3H2N4O4·C4H9NO2
C3H2N4O4·C6H8N2
C5H9N5O2
27.78
27.52
4.81
4.59
38.70
38.53
199-201
191-193
162-164
220-222
121-120
160-161
148-150
179-181
190-192
184-186
229-231
210-212
228-229
93
75
80
51
43
65
61
59
82
61
55
75
48
2а
2b
2c
2d
3
27.76
4.38
31.80
27.39
4.11
31.96
32.42
32.18
4.51
4.21
26.59
26.82
40.80
3.52
31.80
40.60
3.76
31.58
35.39
35.08
4.94
5.26
40.62
40.93
C12H12ClN5O2
C12H12ClN5O2
C8H13N5O4
49.31
4.28
23.74
4а
4b
5а
5b
6а
6b
6c
7
49.06
4.09
23.85
48.89
49.06
3.94
4.09
24.25
23.85
39.78
5.66
29.02
39.51
5.35
28.81
C7H11N5O3
39.24
39.44
5.46
5.16
33.08
32.86
C6H10N6O3
33.99
5.00
39.51
33.64
4.67
39.25
C12H13СlN6O3
C12H14N6O2S
44.66
44.37
4.22
4.01
25.73
25.88
47.46
4.34
27.77
47.06
4.58
27.45
C12H12N6O2S
47.21
47.37
4.12
3.95
28.01
27.63
1333

mentioned bifunctional amines, heated in the range of 60-90°C, led to resinification of the reaction mass, which
only contained a mixture of products with close chromatographic mobility, as a result of which it was not
possible to isolate the individual compounds.
EXPERIMENTAL
The 1H NMR spectra were recorded on a Bruker WM-250 instrument at 250 MHz in DMSO-d6 solution
with TMS as internal standard. The reaction and the individuality of the products were monitored by TLC on
Sorbfil UV-254 plates in the 1:2:1 butanol–acetic acid–water system. The mass spectra were recorded on a
Varian MAT-311A instrument (accelerating potential 3 kV, ionization energy 70 eV). The melting points were
not corrected. The characteristics of the synthesized compounds are given in Tables 1 and 2.
2'-Aminoethylammonium Salt of 4,5-Dinitro-1H-imidazole (2a). To
a solution of the
dinitroimidazole 1 (1 g, 6.3 mmol) in ethanol (15 ml) we added ethylenediamine (1.27 ml, 18.99 mmol). The
reaction mixture was kept at room temperature for 15 min. The precipitated dinitroimidazole salt was filtered
off, washed on the filter with ethanol (5 ml), and dried. We obtained 1.28 g of the salt 2a.
2'-Hydroxyethylammonium Salt of 4,5-Dinitro-1H-imidazole (2b). The compound was obtained
similarly to compound 2a.
n
The compound was
3'-Carboxy- -propylammonium Salt of 4,5-Dinitro-1-H-imidazole (2c).
obtained similarly to compound 2a.
2'-Aminophenylammonium Salt of 4,5-Dinitro-1H-imidazole (2d). To a solution of dinitroimidazole
1 (1 g, 6.33 mmol) in butyric acid (7 ml) we added o-phenylenediamine (2.05 g, 18.99 mmol). The mixture was
kept at 100°C for 4 h. The reaction mixture was poured onto ice, and the precipitated salt 2d was filtered off,
crystallized from ethanol, and dried. Yield of the salt 2d 0.86 g.
5-(2-Aminoethylamino)-4-nitro-1H-imidazole (3). To dinitroimidazole 1 (1 g, 6.33 mmol) we added
ethylenediamine (2.53 ml, 37.98 mmol). The reaction mixture was kept at 60°C for 4 h and was then diluted
with ethanol and cooled. The precipitate was filtered off, washed on the filter, and dried. We obtained 0.46 g of
compound 3.
5-[2-(4-Chlorobenzylideneamino)ethylamino]-4-nitro-1H-imidazole (4a). To
a
solution of
compound 3 (0.2 g, 1.17 mmol) in a mixture of ethanol (5 ml) and acetic acid (2 ml) we added
4-chlorobenzaldehyde (0.18 g, 1.28 mmol). The solution was boiled for 3.5 h and cooled. The precipitated
compound 4a was filtered off, crystallized from 70% aqueous ethanol, and dried. Yield 0.22 g.
5-[2-(2-Chlorobenzylideneamino)ethylamino]-4-nitro-1H-imidazole (4b). The compound was
obtained similarly to compound 4a.
5-(2-Ethoxycarbonylaminoethylamino)-4-nitro-1H-imidazole (5a). To a suspension of compound 3
(0.2 g, 1.17 mmol) in DMF (2 ml) at 5°C we added in portions ethyl chlorocarbonate (0.12 ml, 1.28 mmol) and
triethylamine (0.18 ml, 1.28 mmol). The obtained solution was kept for 30 min. The solvent was evaporated to
dryness, and the residue was crystallized from 70% aqueous ethanol and dried. We obtained 0.21 g of
compound 5a.
5-(2-Acetylaminoethylamino)-4-nitro-1H-imidazole (5b). A solution of compound 3 (0.2 g,
1.17 mmol) in acetic anhydride (4 ml) was kept at room temperature for 30 min. The precipitated compound 5b
was filtered off, washed on the filter with ethanol, and dried. Yield 0.20 g.
5-(2-Aminocarbonylaminoethylamino)-4-nitro-1H-imidazole (6a). To a solution of compound 3
(0.2 g, 1.17 mmol) in a mixture of ethanol (5 ml) and acetic acid (2 ml) we added potassium isocyanate (0.1 g,
1.28 mmol). The solution was boiled for 3.5 h and cooled. The precipitated compound 6a was filtered off,
crystallized from 70% aqueous ethanol, and dried. Yield 0.15 g.
1334

5-[2-(4-Chlorophenylaminocarbonylamino)ethylamino]-4-nitro-1H-imidazole (6b). To a solution of
p-chlorophenyl isocyanate (0.19 g, 1.28 mmol) in chloroform (15 ml) we added compound 3 (0.2 g, 1.17 mmol)
and acetic acid (0.1 ml). The obtained suspension was boiled for 2 h and cooled. The precipitated imidazole 6b
was filtered off, crystallized from 70% aqueous ethanol, and dried. Yield 0.21 g.
4-Nitro-5-(2-phenylaminothiocarbonylaminoethylamino)-1H-imidazole (6c). To a solution of
compound 3 (0.2 g, 1.17 mmol) in a mixture of ethanol (5 ml) and acetic acid (2 ml) we added phenyl
isothiocyanate (0.15 ml, 1.28 mmol). The solution was boiled for 4.5 h and cooled. The precipitated imidazole
6c was filtered off, crystallized from 70% aqueous ethanol, and dried. Yield of the imidazole 6c 0.26 g.
5-(2-Benzothiazol-2-ylaminoethylamino)-4-nitro-1H-imidazole (7). To a solution of compound 6c
(0.2 g, 0.65 mmol) in acetic acid (10 ml) at 70°C we added bromine (0.09 ml, 1.96 mmol). The reaction mixture
was kept at this temperature for 30 min. It was then cooled, and the precipitated imidazole 7 was filtered off,
crystallized from ethanol, and dried. Yield 0.09 g.
The authors express their gratitude for financial support from the Russian Fund for Fundamental
Research (grant No. 98-03-33044a).
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1.
V. S. Mokrushin, N. A. Belyaev, M. Yu. Kolobov, and A. N. Fedotov, Khim. Geterotsikl. Soedin., 808
(1983).
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4.
K. Gewald and U. Hain, J. Pr. Chem., 317, 329 (1975).
Y. Wang, P. R. Lowe, W. Thomson, J. Clark, and M. F. G. Stevens, Chem. Commun., 363 (1997).
R. Elderfield (editor), Heterocyclic Compounds [Russian translation], Vol. 5, IL, Moscow (1961).
1335