Synthesis and Cyclization of 2-Amino- and 2-Methyl-Substituted 1,3-Diaminobenzimidazolium Salts

Article abstract of DOI:10.1007/s10593-014-1627-8

N-Amination of 1-amino(alkylamino, benzylidenamino)-substituted 2-amino- and 2-methylbenzimid-azoles with O-picrylhydroxylamine gave the respective 1,2,3-triamino- and 1,3-diamino-2-methylbenz-imidazolium salts, which cyclized upon treatment with acetic anhydride/K₂CO₃ into previously unreported derivatives of N-amino[1,2,4]triazolo[1,5-a]benzimidazoles and N-aminopyrazolo-[1,5-a]benzimidazoles. The presence of C-acetyl substituent in the formed pyrazolo[1,5-a]benz-imidazoles was interpreted by quantum-chemical calculations as resulting from acylation of the intermediate methylene base, not tricyclic system.

Full text of DOI:10.1007/s10593-014-1627-8

DOI 10.1007/s10593-014-1627-8
Chemistry of Heterocyclic Compounds, Vol. 50, No. 11, February, 2015 (Russian Original Vol. 50, No. 11, November, 2014)
SYNTHESIS AND CYCLIZATION OF 2-AMINO- AND 2-METHYL-
SUBSTITUTED 1,3-DIAMINOBENZIMIDAZOLIUM SALTS
1
1
1**
T. A. Kuz'menko , A. S. Morkovnik , L. N. Divaeva ,
G. S. Borodkin1, and V. V. Kuz'menko*
N-Amination of 1-amino(alkylamino, benzylidenamino)-substituted 2-amino- and 2-methylbenzimid-
azoles with O-picrylhydroxylamine gave the respective 1,2,3-triamino- and 1,3-diamino-2-methylbenz-
imidazolium salts, which cyclized upon treatment with acetic anhydride/K2CO3 into previously
unreported derivatives of N-amino[1,2,4]triazolo[1,5-а]benzimidazoles and N-aminopyrazolo-
[1,5-а]benzimidazoles. The presence of С-acetyl substituent in the formed pyrazolo[1,5-а]benz-
imidazoles was interpreted by quantum-chemical calculations as resulting from acylation of the
intermediate methylene base, not tricyclic system.
Keywords: 1-amino-2-methylbenzimidazole, 1,2-diaminobenzimidazole, О-picrylhydroxylamine, pyr-
azolo[1,5-а]benzimidazole, 1,2,4-triazolo[1,5-а]benzimidazole, N-amination, cyclization.
The molecular and crystal structure of a 1,3-diaminobenzimidazolium salt obtained by direct N-amina-
tion of 1-aminobenzimidazole has been reported [1]. The condensation reaction between 1,3-diamino-2-methyl-
benzimidazolium mesitylenesulfonate and 1,2-diketones has been studied [2]. 3-Amino-1-(arylmethylidene-
amino)benzimidazolium salts have been described recently [3].
In the current work, N-amination method was used for the synthesis of 2-amino- and 2-methyl-
substituted 1,3-diaminobenzimidazolium salts with the purpose of their cyclization into derivatives of
previously unknown 1,2,4-triazolo[1,5-а]- and pyrazolo[1,5-а]benzimidazole N-amines. These tricyclic systems
[4-9] and the structurally related imidazo[1,2-а]benzimidazoles [10, 11] attract interest due to various
pharmacological activity.
The starting 1,2-diamino- (1а), 2-amino-1-benzylamino(benzylidenamino)benzimidazoles 1b,d [12] and
1-amino-2-methylbenzimidazoles 2a,b,d [13, 14] were already known. We prepared 2-amino-1-isopropyl-
aminobenzimidazole (1c) by condensation of 1,2-diaminobenzimidazole with acetone at 100°С in the presence
of HClO4 followed by reduction of the formed azomethine with NaBH4.
Other authors [15] obtained 1,3-diaminoimidazolium salts by amination of imidazoles in aqueous
solution with one of the readily available N-amination reagents, hydroxylamine-О-sulfonic acid [15] and
noted that 2-methylbenzimidazole under such conditions was not aminated due to limited solubility. The
_______
*Deceased.
**To whom correspondence should be addressed, e-mail: asmork2@ipoc.rsu.ru.
1Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 Stachki Ave., Rostov-on-Don
344090, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1714-1724, November, 2014.
Original article submitted August 5, 2014.
0009-3122/15/5011-1575©2015 Springer Science+Business Media New York
1575

TABLE 1. Physicochemical Characteristics of Compounds 3-12
Found, %
Com-
pound
Empirical
formula
Calculated, %
H
Mp*,°С
Yield, %
C
N
C13H12N8O7
39.92
39.80
50.12
49.80
44.24
44.24
49.97
50.00
42.31
42.11
43.15
42.97
52.33
52.39
52.70
52.61
44.47
44.35
57.42
57.63
67.90
67.70
61.89
61.98
57.75
57.74
69.46
69.30
69.75
69.80
62.26
62.21
3.27
3.08
3.67
3.76
3.91
4.18
3.50
3.36
5.14
5.05
3.18
3.35
3.95
3.98
3.72
3.57
6.18
6.05
4.63
4.84
5.52
5.37
6.10
6.32
4.78
4.85
5.27
5.45
4.60
4.76
5.16
5.22
28.74
28.56
23.42
23.23
25.72
25.80
23.53
23.33
35.18
35.08
24.92
25.06
20.15
20.37
20.65
20.45
25.91
25.86
30.43
30.55
22.16
21.93
25.71
25.81
37.38
37.41
25.38
25.25
25.57
25.44
20.88
20.73
218-220
182-184
153-154
174-176
325-326
167-168
162-164
201-203
289-290
190-191
101-102
139-140
214-215
185-186
151-152
221-223
144-146
205-207
138-140
194-195
141-142
87
91
58
84
74
82
83
84
79
3а
3b
3c
C20H18N8O7
C16H18N8O7
C20H16N8O7
C7H10ClN5
C14H13N7O7
C21H19N7O7
C21H17N7O7
3d
3e*2
4a
4b
4d
4e*3
5a
5b
5c
.
C8H11ClN4 H2O
C11H11N5O
C18H17N5O
C14H17N5O
C9H9N5
70 (from 3a)
72 (from 3e)
62
63
75
86
6a
6b
7
C16H15N5
C16H13N5
92 (from 3d)
91 (from 6a)
30 (from 4a),
67 (from 4d)
C14H14N4O2
C21H20N4O2
C16H16N4O3
C10H10N4
8a
8b
9
69.87
69.98
61.42
61.53
64.65
64.50
71.85
71.68
5.70
5.59
5.20
5.16
5.27
5.41
5.48
5.70
15.40
15.54
17.82
17.94
29.95
30.09
17.80
17.60
69
46
87 (from 8a)
84 (from 9)
10
11
12
C19H18N4O
C17H14N4
76
74.30
74.43
5.19
5.14
20.54
20.42
69
_______
*Compounds 5a, 8a were recrystallized from EtOAc, compounds 5b,c, 7, 8b, 10 –
from n-heptane, compounds 6a,b, 11 – from benzene, compounds 9, 12 – from
EtOH.
*2Found, %: Cl 17.63. Calculated, %: Cl 17.76.
*3Found, %: Cl 16.53. Calculated, %: Cl 16.36.
N-amino derivatives 1 and 2 also had low solubility in water. When selecting N-amination reagent suitable for non-
aqueous media, we preferred О-picrylhydroxylamine (PHA) [16]. This reagent was not inferior in its reactivity to
О-mesitylenesulfonylhydroxylamine, widely used for amination of nonionized azoles [2, 17], but was significantly
more stable and easy to purify.
The amination of N-amines 1a-d and 2a,b,d with PHA was achieved by brief heating of reagents in
equimolar amounts in dichloromethane, giving 75-86% yields of the picrates 3a-d and 4a,b,d (Table 1). The
picrates 3a and 4a were readily converted to the corresponding chlorides 3e, 4e by refluxing in hydrochloric
acid (Scheme 1). The salts 3 and 4 were relatively stable and decomposed only at elevated temperatures.
1576

Scheme 1
NH2
X–
R
+
N
N
PHA
N
R
CH2Cl2, EtOH
, 5 min
N
NR1R2
1a–d
2a,b,d
NR1R2
3a–d
(3a, 4a)
HCl, H2O, , 5 min
4a,b,d
3e, 4e
1, 3 R = NH2; 2, 4 R = Me;
a,e R1 = R2 = H; b R1 = H, R2 = Bn; c R1 = H, R2 = CHMe2;
d R1 + R2 = CHPh; a–d X = picryl, X = Cl
The triaminobenzimidazolium cation 3a belongs to a rare type of structures with 1,2,3-pattern of amino
groups. According to performed quantum-chemical study (B3LYP/6-31G**), this system has a planar
framework of non-hydrogen atoms and exists as three conformers A, B, and C of C2v or Сs symmetry (Fig. 1).
The 2-amino group of these compounds has sp2-hybridized nitrogen atom, is located in the benzimidazole ring
plane, and strongly conjugated to the heterocyclic -system, as evidenced also by the calculated С(2)–N bond
length of 1.323 Å, which was substantially shorter than, for example, in aniline. The nitrogen atoms in the N-
amino groups were sp3-hybridized and not conjugated to benzimidazole ring, similarly as in 1,3-diamino-
benzimidazolium cation [1] and in other N-aminoazoles [18, 19], because the axes of lone electron pairs were
Fig. 1. The conformers of 1,2,3-triaminobenzimidazolium cation 3a and their symmetry. The numbers indicate
some bond lengths and internuclear distances in Å.
1577

located in the plane of heterocycle. The lone electron pairs of both N-amino groups in the main conformer A
were oriented towards the С-amino group, while in the minor form B with relative energy 4.9 kcal/mol only one
of the lone electron pairs had such orientation, while the other pointed towards the benzene fragment. The same
orientation was also observed for both lone electron pairs of N-amino groups in the least favored (by
10.5 kcal/mol) form C.
1
The H NMR spectra of salts 3 and 4 contained N-amino group signals in the region of 6.0-6.8 ppm,
while the signals of С-amino group in salts 3 were observed at lower field (8.5-9.3 ppm) due to its strong
conjugation and some deshielding by lone electron pairs of the adjacent nitrogen atoms (Table 2).
The picrates of 1,2,3-triaminobenzimidazolium 3a, 1-alkylamino derivatives 3b,c and the chloride 3e,
similarly to 3-alkyl-1,2-diaminobenzimidazolium salts [12], were cyclized by the action of acetic anhydride in
the presence of potassium carbonate, leading to triazole ring closure and forming 4-acetylamino-substituted
2-methyl-1,2,4-triazolo[1,5-а]benzimidazoles 5a-с (Scheme 2).
Scheme 2
Compounds 5, as shown in the example of amides 5a,b, were easily deacylated in conc. HCl, forming
N-aminotriazolobenzimidazoles 6. The amine 6a gave Schiff base 7 upon heating in acetic acid with
benzaldehyde, but did not condense with benzaldehyde in refluxing ethanol in the presence of piperidine. The
azomethine 7 could also be obtained by cyclization of 1-benzylidenamino-2,3-diaminobenzimidazolium picrate
(3d).
Scheme 3
1,3-Diamino-2-methylbenzimidazolium salts 4, similarly to the corresponding 3-alkyl-substituted
analogs [13], underwent condensation reactions with acetic anhydride in the presence of K2CO3, resulting in
1578

annelation of pyrazole ring. The salt 4a thus gave a chromatographically separable mixture of 4-monoacetyl- 8a
and 4-diacetylamino derivatives of 3-acetyl-2-methylpyrazolo[1,5-а]benzimidazole 9 in 2:3 ratio and good total
yield. The 1-benzylamino-substituted salt 4b was similarly cyclized to the corresponding pyrazolo-
benzimidazole 8b (Scheme 3).
TABLE 2. The 1Н NMR Spectra of Compounds 3-12
Com-
Chemical shifts, δ, ppm (J, Hz)
pound
6.04 (4Н, s, 1,3-NH2); 7.26-7.50 (4Н, m, H Ar); 8.54 (2H, s, 2-NH2); 8.58 (2H, s, Н picryl)
3a
3b
4.19 (2Н, d, J = 4.8, CH2); 5.96 (2H, s, 3-NH2); 7.12-7.44 (10H, m, H Ar, NH);
8.54 (2H, s, 2-NH2); 8.59 (2H, s, H picryl)
1.02 (6Н, d, J = 6.0, СН(СН3)2); 3.69 (1Н, sept, J = 6.9, СН); 6.11 (2Н, s, 3-NH2);
6.90 (1Н, s, NH); 7.31-7.37 (2Н, m, Н-5,6); 7.44-7.52 (2Н, m, Н-4,7);
8.56 (2Н, s, Н picryl); 8.73 (2Н, s, 2-NH2)
3с
6.14 (2Н, s, 3-NH2); 7.29-7.61 (5Н, m, H Ar); 7.95-8.24 (4Н, m, H Ar);
8.57 (2Н, s, Н picryl); 9.06 (2Н, s, 2-NH2); 9.26 (1Н, s, =СН)
3d
6.17 (4Н, s, 1,3-NH2); 7.25-7.51 (4Н, m, Н Ar); 8.67 (2Н, s, 2-NH2)
3e
4а
4b
2.82 (3Н, s, СН3); 6.62 (4Н, s, 1,3-NH2); 7.57-7.91 (4Н, m, H Ar); 8.58 (2Н, s, Н picryl)
2.58 (3H, s, CH3); 4.30 (2H, d, J = 4.5, СН2); 6.59 (2Н, s, 3-NH2);
7.24-7.32 (5H, m, Н-5,6,3',4',5'); 7.56-7.60 (2Н, m, Н-4,7); 7.85-7.93 (3Н, m, Н-2',6', NH);
8.54 (2Н, s, Н picryl)
2.94 (3Н, s, СН3); 6.78 (2Н, s, 3-NH2); 7.56-7.81 (5Н, m, Н Ar); 7.93-8.27 (4Н, m, H Ar);
8.57 (2Н, s, Н picryl); 9.38 (1Н, s, =СН)
4d
2.85 (3Н, s, СН3); 6.78 (4Н, s, 1,3-NH2); 7.56-7.93 (4Н, m, Н Ar)
4e
5a
2.28 (3Н, s, COCH3); 2.48 (3Н, s, СН3); 7.24-7.35 (3Н, m, Н-5,6,7);
7.71 (1Н, d, J = 6.6, Н-8); 11.12 (1Н, s, NH)
1.93 (3Н, s, СОСН3); 2.50 (3Н, s, СН3); 4.67 (1Н, d, J = 14.1) and 5.34 (1Н, d, J = 14.1, СН2);
6.73 (1Н, d, J = 8.1, Н-5); 7.07-7.26 (7Н, m, Н-6,7, H Ph); 7.66 (1Н, d, J = 8.1, Н-8)
5b
1.19 (3Н, d, J = 6.0) and 1.30 (3Н, d, J = 6.6, СН(СН3)2); 1.73 (3Н, s, СОСН3);
2.53 (3Н, s, СН3); 5.07 (1Н, sept, J = 6.8, СН); 7.24-7.37 (3Н, m, Н-5,6,7);
7.75-7.78 (1Н, m, Н-8)
5с
2.50 (3Н, s, СН3); 4.83 (2Н, s, NH2); 7.22-7.36 (2Н, m, Н-6,7); 7.53 (1Н, d, J = 7.8, Н-5);
7.67 (1Н, d, J = 8.1, Н-8)
6a
6b
7
2.56 (3Н, s, СН3); 4.46 (2Н, d, J = 4.8, СН2); 5.07 (1Н, t, J = 4.8, NH);
7.19-7.28 (5Н, m, Н-6,7,3',4',5'); 7.37-7.43 (3Н, m, Н-5,2',6'); 7.63-7.66 (1Н, m, Н-8)
2.61 (3Н, s, СН3); 7.33-7.49 (5Н, m, Н-6,7,3',4',5'); 7.73 (1Н, d, J = 8.1, Н-5);
7.89 (1Н, d, J = 8.1, Н-8); 7.92-7.95 (2Н, m, Н-2',6'); 9.50 (1Н, s, =СН)
2.25 (3Н, s, NCOCH3); 2.42 (3Н, s, СН3); 2.61 (3Н, s, ССОСН3);
7.24-7.33 (3Н, m, Н-5,6,7); 7.75-7.78 (1Н, m, Н-8); 8.83 (1Н, s, NH)
8a
8b
1.94 (3Н, s, NCOCH3); 2.45 (3H, s, CH3); 2.67 (3H, s, COCH3); 4.32 (1H, d, J = 14.1) and
5.50 (1Н, d, J = 14.4, СН2); 6.77 (1Н, d, J = 8.1, Н-5); 6.99-7.24 (7Н, m, Н-6,7, Н Ph);
7.71 (1Н, d, J = 8.1, Н-8)
2.37 (6Н, s, N(COCH3)2); 2.42 (3Н, s, СН3); 2.62 (3Н, s, СОСН3);
9
7.36-7.39 (2Н, m, Н-6,7); 7.66-7.76 (1Н, m, Н-8); 7.82-7.94 (1Н, m, Н-5)
2.43 (3Н, s, СН3); 4.55 (2Н, s, NH2); 5.63 (1Н, s, H-3); 7.17-7.28 (2Н, m, Н-6,7);
7.36 (1Н, d, J = 7.8, Н-5); 7.71 (1Н, d, J = 7.5, Н-8)
10
11
12
2.51 (3Н, s, СН3); 2.66 (3Н, s, СОСН3); 4.08 (2Н, d, J = 6.3, СН2); 6.97 (1Н, t, J = 6.3, NH);
7.24-7.31 (7Н, m, Н-6,7, Н-Ph); 7.45 (1Н, d, J = 8.1, Н-5); 7.73 (1Н, d, J = 9.0, Н-8)
2.51 (3Н, s, СН3); 6.05 (1Н, s, Н-3); 7.24-7.35 (2Н, m, Н-6,7);
7.42-7.46 (3Н, m, Н-3',4',5'); 7.74-7.86 (4Н, m, Н-5,8,2',6'); 8.32 (1Н, s, СН)
Characteristically, the pyrazolo[1,5-a]benzimidazoles thus obtained from quaternary 1-amino-2-methyl-
benzimidazolium salts always contained 3-acyl group [13, 20]. However, it remains unclear if this was linked to
bis-acylation of the intermediate methylene base, or electrophilic substitution in the formed tricyclic systems at
the most electron-rich position 3 [21, 22].
Quantum-chemical study of the model compound 2,4-dimethylpyrazolo[1,5-a]benzimidazole D in an
acetylation reaction with acetic anhydride and the relevant bimolecular transition state TS1 (Scheme 4, Fig. 2) was
performed by DFT with B3LYP/6-31G** functional and showed that this process required very high activation
1579

energy (G≠ 40.1 kcal/mol relative to the pre-reaction complex) and followed an unusual aromatic substitution
mechanism, which will be discussed in a separate publication. On the other hand, monoacetylation of the strong
nucleophilic methylene base E through the transition state TS2, occurring analogously to the classical
electrophilic substitution in arenes, had low energy barrier (G≠ 12.3 kcal/mol relative to the pre-reaction
complex) and was not rate-limiting for the reaction considered. The introduction of second acetyl group (transition
state TS3) was significantly more difficult (G≠ 24.6 kcal/mol), but easier than acetylation of pyrazolobenz-
imidazole ring. Thus, bisacetylation of methylene base was the favored direction of this reaction.
Scheme 4
Amides 8a and 9 were hydrolyzed during prolonged refluxing in conc. HCl, forming 4-aminopyrazolo-
1
benzimidazole 10 (Scheme 3). The H NMR spectrum of the mixture after running the reaction for 30 min
featured a signal due to the H-3 proton (5.79 ppm) that was approximately 20 times larger than the NH2 group
signal (4.54 ppm), indicating unexpectedly more facile cleavage of С-acetyl group compared to the N-acetyl
group. At the same time, the N-acetyl fragment in the molecule of N-benzylacetamide 8b was cleaved faster and
3-acetyl-4-benzylamino derivative 11 was formed after 30 min in 76% yield.
The N-benzylacetamides 5b and 8b were characterized by chemical non-equivalence of the benzylic
methylene protons, which gave two doublets at 4.67 (4.32) and 5.34 (5.50) ppm in the 1Н NMR spectra. The
Fig. 2. The geometry and imaginary frequencies (i) of the transition states TS2 and TS3 in the acetylation
reaction of methylene base Е.
1580

two methyl groups in N-(isopropyl)acetamidotriazolo[1,5-a]benzimidazole 5c were also non-equivalent. This
was apparently linked to the hindered rotation of N-substituent due to steric influence of acetyl group, because
this effect was not observed for the starting salts 3b, 4b,c and the deacylated derivatives 6b and 11.
1
The H-5 and H-8 proton signals in the H NMR spectra of triazolo[1,5-a]- and pyrazolo[1,5-a]benz-
imidazoles usually existed as doublets and were always observed in a lower field region (7.5-7.7 ppm) compared to
the combined multiplet of H-6 and H-7 protons (7.2-7.3 ppm). However, in the spectra of compounds 5b and
8b, the signal of the H-5 proton was at the highest field (6.73 and 6.77 ppm) compared to signals of other
aromatic protons. It would be logical to expect that the Н-5 proton in these cases was affected by ring currents of
the nearby phenyl ring in the benzyl substituent. Quantum-chemical study of compound 8b with the B3LYP/6-
31G** method allowed to identify the conformer with the Н-5 proton at less than 3 Å distance from phenyl
group and forming almost 90° angles with two pairs of its carbon atoms (Fig. 3). The increased shielding of the
Н-5 proton and the specific effect of phenyl group was additionally demonstrated by SOS DFPT calculations
[23] of chemical shifts for this conformer and for two non-optimized model structures obtained from it by
substituting the N-acetyl or benzyl group with hydrogen atom, while restraining the configuration of all other
atoms. The carbonyl group dipole also created certain shielding effect, although the H-5 proton signal in the
spectrum of N-isopropylacetamide 5c was observed in the region typical for such compounds.
Fig. 3. The conformer of compound 8b, causing the additional shielding of the H-5 proton. The numbers
indicate calculated and experimental (in parentheses) chemical shifts of protons as well as some internuclear
distances (Å) and angles (deg).
The N-amine 10 smoothly reacted with benzaldehyde upon heating in ethanol, forming the Schiff base
12, which could not be obtained by cyclization of 3-amino-1-benzylidenamino-2-methylbenzimidazolium
picrate (4d) with acetic anhydride. In this case, the reaction produced 4-acetamidopyrazolobenzimidazole 8a
(Scheme 5).
Scheme 5
Pyrazolo[1,5-а]benzimidazole derivatives also have been synthesized from 1-amino-3-alkylbenz-
imidazoline-2-thiones [24, 25], therefore 4-amino derivatives of this heterocycle could be obtained from
1,3-diamino-1,3-dihydrobenzimidazole-2-thione (13), which we obtained by thiolation of 1,3-diaminobenz-
imidazolium chloride [1] with sulfur in refluxing DMF (Scheme 6).
1581

Scheme 6
NH2
S
NH2
Cl–
+
N
N
S, Et3N
DMF
, 0.5 h
N
N
NH2
NH2
13
Thus, the range of already known N-amino derivatives of imidazo[1,2-a]- [26], pyrrolo[1,2-a]- [14],
pyridazino[1,6-a]- [2], 1,2,4-triazino[2,3-a]-, and 1,2,4-triazino[4,3-a]benzimidazoles [27] was extended by the
synthesis of new examples of little studied N-amino-substituted condensed tricyclic systems based on
benzimidazole.
EXPERIMENTAL
IR spectra were recorded for powdered samples on a Varian Excalibur 3100 FT-IR instrument by
attenuated total internal reflectance technique. The 1H NMR spectra for compounds 1с, 3, 4, 13 were acquired in
DMSO-d6 solution, for compounds 5-12 in CDCl3, using a Varian Unity-300 spectrometer (300 MHz). The
1
chemical shifts of H nuclei are reported relative to the residual protons of deuterated solvents (δ 2.49 ppm for
DMSO-d6 and 7.24 ppm for CDCl3). Melting points were determined on a Fisher-Johns Melting Point
Apparatus. Elemental analysis was performed by classical microanalysis techniques [28]. The reaction progress
and the purity of obtained compounds were controlled by TLC (alumina plates of activity level III, eluent
CHCl3, visualization with iodine vapor in wet chamber). Literature methods were used for the synthesis of
starting materials: 2-aminobenzimidazoles 1a,b,d [12], 2-methylbenzimidazoles 2a [13], 2b,d [14], and
О-picrylhydroxylamine [16].
The SOS DFPT calculations of shielding constants and chemical shifts [21] were performed with the
DeMon software (theory level B3LYP/6-31G**//PW91-PW91/IGLOII) [29]. The structures of the studied
compounds and transition states TS1, TS2 were optimized with the Firefly 8.0 software [30], partially based on
the Gamess code [31]. The energy levels of the identified structures were calculated with correction for the zero-
point vibration energy (scaling factor 0.961 [32]).
2-Amino-1-isopropylaminobenzimidazole (1с). A suspension of 1,2-diaminobenzimidazole (1а)
(2.96 g, 20 mmol) in acetone (20 ml) was treated with 3-5 drops of 70% HClO4 and heated for 5 h at 100°С.
The mixture was evaporated to dryness, the residue was treated with conc. NH4OH (5 ml), extracted with CHCl3
(25-30 ml), and separated by chromatography on alumina column (30×50 mm), eluent EtOAc, Rf 0.5. Yield
3.21 g (85%), mp 104-106°С (isooctane). Sodium borohydride (0.72 g, 20 mmol) was added portionwise to a
solution of the obtained azomethine (1.88 g, 10 mmol) in methanol (20 ml). The mixture was refluxed for 0.5 h,
cooled, and quenched with water (100 ml). The precipitate formed was filtered off. Yield 1.75 g (92%), mp 188-
190°С (benzene). IR spectrum, ν, cm-1: 3413, 3273, 3057, 2859, 1647, 1615. 1H NMR spectrum, δ, ppm (J, Hz):
0.95 (6Н, d, J = 6.3, СН(СН3)2); 3.53 (1Н, sept.d, J = 6.3, J = 1.8, СН); 6.17 (2Н, s, NH2); 6.19 (1Н, d, J = 1.8,
NH); 6.84-6.93 (2Н, m, Н-5,6); 7.08-7.12 (2Н, m, Н-4,7). Found, %: C 63.26; H 7.25; N 29.31. C10H14N4.
Calculated, %: C 63.13; H 7.42; N 29.45.
1,2,3-Triaminobenzimidazolium Picrates 3a-d and 1,3-Diamino-2-methylbenzimidazolium
Picrates 4a,b,d (General Method). A solution of amine 1а-d, 2a,b,d (5 mmol) in dichloromethane (25 ml) and
ethanol (3-5 ml) was treated by portionwise addition of О-picrylhydroxylamine (1.22 g, 5 mmol) over 5-7 min.
The mixture was refluxed for 5 min, the yellow-green precipitate that formed after cooling was filtered off,
washed with CHCl3 (10 ml), and recrystallized from H2O (compounds 3a,c, 4a), MeCOOH (compound 3b),
DMF (compound 3d), or EtOH (compounds 4b,d).
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1,2,3-Triaminobenzimidazolium Chloride (3e). Picrate 3a (0.39 g, 1 mmol) was suspended in 18%
HCl (5 ml) and refluxed for 5 min. The mixture was cooled, the colorless precipitate was filtered off, washed
with EtOH (5 ml), and recrystallized from H2O. Yield 0.15 g.
Chloride 4e was obtained from picrate 4a analogously to compound 3е.
N-(2-Methyl-4H-[1,2,4]triazolo[1,5-а]benzimidazol-4-yl)acetamide (5a). A mixture of picrate 3a
(0.78 g, 2 mmol) and K2CO3 (0.28 g, 2 mmol) in Ac2O (5 ml) was refluxed for 5 h. The mixture was cooled,
quenched with water (20 ml), the precipitate that formed after quenching was filtered off and washed with
water. The product was purified by chromatography on alumina column (20×50 mm), eluent – chloroform,
Rf 0.45. Yield 0.32 g. IR spectrum, ν, cm-1: 3222, 1714, 1596.
Compound 5а from chloride 3е and compounds 5b,c were obtained analogously to the procedure
above.
2-Methyl-4H-[1,2,4]triazolo[1,5-а]benzimidazol-4-amine (6a). A solution of amide 5a (0.46 g,
2 mmol) in conc. HCl (5 ml) was refluxed for 20 min, then cooled. The precipitate formed was filtered off,
treated with 22% solution of NH4OH, washed with water. IR spectrum, ν, cm-1: 3329, 3155, 1619, 1587. Yield
0.28 g.
4-Benzylamino derivative 6b was synthesized analogously.
N-Benzylidene-2-methyl-4H-[1,2,4]triazolo[1,5-а]benzimidazol-4-amine (7). А. The picrate 3d
(0.48 g, 1 mmol) was mixed with K2CO3 (0.14 g, 1 mmol) and Ac2O (5 ml) and refluxed for 4 h. The volatiles
were removed by evaporation, residue was separated by chromatography on alumina column (15×50 mm),
eluent – chloroform, Rf 0.9. Yield 0.25 g. IR spectrum, ν, cm-1: 1574, 1561, 1500.
B. A solution of amine 6a (0.19 g, 1 mmol) and benzaldehyde (0.1 ml, 1 mmol) in acetic acid (3 ml)
was refluxed for 1 h, then cooled, diluted with water to double volume; the precipitate formed was filtered off
and washed with water. Yield 0.24 g. There was no melting point depression observed for a sample mixed with
the product obtained according to method A.
Reaction of Picrate 4a with Acetic Anhydride. A mixture of picrate 4a (0.78 g, 2 mmol) and K2CO3
(0.28 g, 2 mmol) in Ac2O (7 ml) was refluxed for 3 h. The mixture was then cooled, quenched with water
(20 ml); the obtained solution was neutralized with NaHCO3, and extracted with CHCl3 (3×10 ml). The mixture
was separated by chromatography on alumina column (15×100 mm), eluent – CHCl3. The first fraction was
N-acetyl-N-(3-acetyl-2-methyl-4H-pyrazolo[1,5-а]benzimidazol-4-yl)acetamide (9), Rf 0.7. Yield 0.29 g
(46%). IR spectrum, ν, cm-1: 1743, 1724, 1643. The second fraction was N-(3-acetyl-2-methyl-4Н-pyr-
azolo[1,5-а]benzimidazol-4-yl)acetamide (8a), Rf 0.4. Yield 0.16 g (30%). IR spectrum, ν, cm–1: 3193, 1677,
1639, 1605.
Compound 8a was obtained from 4d under the same conditions.
N-(3-Acetyl-2-methyl-4Н-pyrazolo[1,5-а]benzimidazol-4-yl)-N-benzylacetamide (8b) was obtained
analogously to compound 8a. IR spectrum, ν, cm-1: 1698, 1640, 1546.
2-Methyl-4Н-pyrazolo[1,5-а]benzimidazol-4-amine (10). A solution of diacetamide 9 (0.31 g, 1 mmol)
or amide 8a (0.27 g, 1 mmol) in conc. HCl (3 ml) was refluxed for 6 h, then cooled and neutralized with 22%
aqueous ammonia solution. The precipitate formed was filtered off and washed with water. Yield 0.16 g.
1-(4-Benzylamino-2-methyl-4H-pyrazolo[1,5-а]benzimidazol-3-yl)ethanone (11). A solution of
amide 8b (0.36 g, 1 mmol) in conc. HCl (5 ml) was refluxed for 0.5 h, cooled, neutralized with 22% aqueous
ammonia; the precipitate was filtered off. Yield 0.24 g. IR spectrum, ν, cm-1: 3271, 1625, 1549.
N-Benzylidene-2-methyl-4H-pyrazolo[1,5-а]benzimidazol-4-amine (12). A solution of 4-amino
derivative 10 (0.19 g, 1 mmol) and benzaldehyde (0.1 ml, 1 mmol) in ethanol (3 ml) was refluxed for 1.5 h in
the presence of catalytic amount of piperidine. The mixture was cooled, the precipitate formed was filtered off
and washed with ether. Yield 0.19 g.
1,3-Diamino-1,3-dihydro-2Н-benzimidazole-2-thione (13). A mixture of 1,3-diaminobenzimid-
azolium picrate (0.38 g, 1 mmol) [1], elemental sulfur (0.04 g, 1.25 mmol), and triethylamine (0.15 ml, 1 mmol)
in DMF (4 ml) was refluxed for 0.5 h. The mixture was then cooled, quenched with water (10 ml); the
1583

precipitate formed was filtered off and separated by chromatography on alumina column (15×30 mm), eluent –
chloroform, Rf 0.2. Yield 0.15 g (83%). Colorless crystals. Mp 204-206°С (DMF–Н2О, 20:1). IR spectrum, ν,
cm-1: 3325, 3285, 1639, 1610. 1H NMR spectrum (DMSO-d6), δ, ppm: 5.75 (4Н, s, 1,3-NH2); 7.16-7.32 (4Н, m,
Н Ar). Found, %: C 47.00; H 4.56; N 31.02; S 17.62. C7H8N4S. Calculated,%: C 46.66; H 4.44; N 31.11,
S 17.78.
This work was performed within the framework of project part of the State Assignment for scientific
activity (Project No. 4.196.2014/K), with equipment at the Collective Use Center "Molecular Spectroscopy" of
the Southern Federal University.
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