Synthesis of a new polyheterocyclic system - Pyrazolo[5′,1′:2, 3]pyrimido[1,6-a]benzimidazole

Article abstract of DOI:10.1007/s10593-006-0012-7

Cyanoethylhydrazones of 2-aroylmethyl-1H-benzimidazoles undergo recyclization on reaction with trifluoroacetyl anhydride to give 3-aryl-1-cyanoethyl-5-(2-trfluoroacetaminoanilino)pyrazoles. The recyclization products may be cyclized with closing of the benzimidazole ring in two ways: with formation of 1-(5-pyrazolyl)benzimidazoles or 5,6-dihydroderivatives of a new polyheterocyclic system - pyrazolo[5′,1′:2,3]pyrimido[1,6-a] benzimidazole. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-006-0012-7

Chemistry of Heterocyclic Compounds, Vol. 41, No. 11, 2005
SYNTHESIS OF A NEW POLYHETEROCYCLIC SYSTEM –
PYRAZOLO[5',1':2,3]PYRIMIDO[1,6-a]BENZIMIDAZOLE
I. B. Dzvinchuk and M. O. Lozinskii
Cyanoethylhydrazones of 2-aroylmethyl-1H-benzimidazoles undergo recyclization on reaction with
trifluoroacetyl anhydride to give 3-aryl-1-cyanoethyl-5-(2-trfluoroacetaminoanilino)pyrazoles. The
recyclization products may be cyclized with closing of the benzimidazole ring in two ways: with
formation of 1-(5-pyrazolyl)benzimidazoles or 5,6-dihydroderivatives of a new polyheterocyclic system –
pyrazolo[5',1':2,3]pyrimido[1,6-a]benzimidazole.
Keywords: benzimidazoles, hydrazones, pyrimidines, trifluoroacetyl anhydride, acylation, recyclization,
cyclocondensation.
We have shown previously that the reaction of hydrazones of 2-arylmethyl-1H-benzimidazoles with
acylating agents is accompanied by recyclization with the formation of 5-(o-acylaminoanilino)pyrazoles [1-4],
which on heating can be cyclized to 1-(5-pyrazolyl)-1H-benzimidazoles [1, 4, 5]. In the present work we have
used these examples of molecular design to construct a new polyheterocyclic system starting from the
cyanoethylhydrazones of 2-phenacyl-1H-benzimidazoles 1a-e.
H
CF3
O
NHCH2CH2CN
N
CH2CH2CN
H
N
Ar
(F3CCO)2O
N
N
N
N
N
H
Ar
2a–e
1a–e
dioxane–CF3COOH
100°C, 4 h
AcOH–conc. HCl
100°C, 5 h
N
N
CF3
N
CH2CH2CN
N
N
N
N
N
Ar
4a–e
3a–e
Ar
1-4 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-BrC6H4, d Ar = 4-ClC6H4, e Ar= 4-O2NC6H4
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukraine National Academy of Sciences, Kiev 02094; e-mail:
iockiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, 1685-1690, November,
2005. Original article submitted June 1, 2004.
0009-3122/05/4111-1419©2005 Springer Science+Business Media, Inc.
1419

TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
1a
1b
1c
1d
1e
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
C18H17N5
71.22
71.27
5.37
5.65
22.95
23.09
162-163
122-123
94
83
93
91
37
83
71
81
71
90
87
86
78
78
82
90
90
88
86
95
C19H19N5O
68.33
68.45
56.45
56.56
5.57
5.74
4.14
4.22
20.95
21.01
18.37
18.32
C18H16BrN5
C18H16ClN5
C18H16N6O2
C20H16F3N5O
C21H18F3N5O2
C20H15BrF3N5O
C20H15ClF3N5O
C20H15F3N6O3
C20H14F3N5
183.5-185
171-172
63.88
64.00
4.85
4.77
20.84
20.73
61.97
62.06
60.12
60.15
4.49
4.63
4.18
4.04
24.03
24.12
17.47
17.54
196-198
152-153.5
87-88.5
58.61
58.74
4.17
4.23
16.22
16.31
50.19
50.23
3.07
3.16
14.56
14.64
161-162.5
158-159.5
186-187.5
121-122.5
120-121.5
105-106.5
102-103
55.32
55.37
3.36
3.49
16.09
16.14
54.08
54.06
3.62
3.40
18.79
18.91
62.87
62.99
3.58
3.70
18.29
18.36
C21H16F3N5O
C20H13BrF3N5
C20H13ClF3N5
C20H13F3N6O2
C18H14N4
61.25
61.31
3.79
3.92
16.93
17.02
52.04
52.19
2.66
2.85
15.12
15.22
57.79
57.77
3.01
3.15
16.72
16.84
56.22
56.34
3.18
3.07
19.64
19.71
146.5-148
217-218.5
189-190
75.63
75.51
4.97
4.93
19.49
19.57
C19H16N4O
72.21
72.14
59.23
59.19
5.03
5.10
3.51
3.59
17.63
17.71
15.28
15.34
C18H13BrN4
C18H13ClN4
C18H13N5O2
257.5-259
233-234.5
301-302
67.43
67.40
4.11
4.08
17.43
17.47
65.32
65.25
3.78
3.95
21.03
21.14
It was established that interaction of compounds 1a-e with trifluoroacetic anhydride was accompanied
by recyclization with formation of the expected 3-aryl-1-cyanoethyl-5-(trifluoroacetylaminoanilino)pyrazoles
2a-e. The latter can cyclize with closing of the benzimidazole ring in two ways. On heating with trifluoroacetic
acid in dioxane a reaction proceeds with participation of the trifluoroacetyl group to form the 1-(5-pyrazolyl)-2-
trifluoromethyl-1H-benzimidazoles 3a-e. On heating with a mixture of acetic and hydrochloric acids the
trifluoroacetyl group is removed as a result of hydrolysis and cyclization occurs with participation of the
cyanoethyl group and simultaneous closing of the benzimidazole and pyrimidine rings to give compounds of the
previously unknown pyrazolo[5',1':2,3]pyrimido[1,6-a]benzimidazole system, 4a-e.
1420

TABLE 2. 1H NMR Spectra of Compounds 1a-e – 4a-e
Com-
pound
Chemical shifts, δ, ppm, J (Hz)
1
2
1a
2.80 (2H, t, J = 6.3, CH2CN); 3.51 (2H, dt, J1 = 6.3, J2 = 4.5, CH2N); 4.23 (2H, s, CH2);
7.12-7.15 (2H, m, H-5,6); 7.24-7.29 (1H, m, HAr-4); 7.31-7.36 (2H, m, HAr-3, 5);
7.45 (1H, d, J = 7.2, H-7); 7.53 (1H, d, J = 8.1, H-4); 7.79 (3H, m, HAr-2,6 + NH);
12.38 (1H, s, H-1)
1b
2.78 (2H, t, J = 6.0, CH2CN); 3.48 (2H, dt, J1 = 5.7, J2 = 4.5, CH2N);
3.75 (3H, s, OCH3); 4.20 (2H, s, CH2); 6.89 and 7.73 (2 × 2H, two d, J = 7.8, HAr-2,6
and HAr-3,5); 7.12-7.14 (2H, m, H-5,6); 7.44 (1H, d, J = 5.4, H-7);
7.53 (1H, d, J = 6.0, H-4); 7.59 (1H, t, J = 4.5, NH); 12.32 (1H, s, H-1)
1с
1d
1е
2.80 (2H, t, J = 6.0, CH2CN); 3.51 (2H, dt, J1 = 5.7, J2 = 4.5, CH2N); 4.22 (2H, s, CH2);
7.12-7.14 (2H, m, H-5,6); 7.47 (2H, m, H-4,7); 7.52 and 7.73 (2 × 2H, two d,
J = 8.4, HAr-2,6 and HAr-3,5); 7.82 (1H, t, J = 4.5, NH); 12.35 (1H, s, H-1)
2.79 (2H, t, J = 6.3, CH2CN); 3.51 (2H, dt, J1 = 6.0, J2 = 4.5, CH2N); 4.21 (2H, s, CH2);
7.12-7.14 (2H, m, 5-, H-6 ); 7.38 and 7.79 (2 × 2H, two d, J = 8.7, HAr-2,6 and HAr-3,5);
7.46 (1H, m, H-7); 7.51 (1H, m, H-4); 7.80 (1H, m, NH); 12.33 (1H, s, H-1)
2.82 (2H, t, J = 6.6, CH2CN); 3.51 (2H, dt, J1 = 6.0, J2 = 4.5, CH2N); 4.28 (2H, s, CH2);
7.12-7.14 (2H, m, H-5,6); 7.45 (1H, m, H-7); 7.51 (1H, m, H-4);
7.98 and 8.17 (2 × 2H, two d, J = 9.0, HAr-2,6 and HAr-3,5); 8.15 (1H, m, NH);
12.37 (1H, s, H-1)
2a
2b
2c
2d
2е
3.05 (2H, t, J = 6.9, CH2CN); 4.26 (2H, t, J = 6.6, CH2N); 6.49 (1H, s, H-4);
6.83 (1H, d, J = 7.5, 2-CF3CONHC6H4: H-6); 6.89 (1H, m, 2-CF3CONHC6H4: H-4);
7.17-7.23 (2H, m, 2-CF3CONHC6H4:H-3,5); 7.28-7.33 (1H, m, HAr-4); 7.38-7.43 (2H, m,
HAr-3,5); 7.63 (1H, s, NH); 7.81 (2H, d, J = 7.5, H Ar-2,6); 10.75 (1H, s, NHCO)
3.03 (2H, t, J = 6.6, CH2CN); 3.78 (3H, s, OCH3); 4.23 (2H, t, J = 6.3, CH2N);
6.41 (1H, s, H-4); 6.82 (1H, d, J = 7.5, 2-CF3CONHC6H4: H-6); 6.88 (1H, m,
2-F3CONHC6H4: H-4); 6.96 and 7.73 (2 × 2H, two d, J = 8.7, HAr-3,5 and HAr-2,6);
7.17-7.22 (2H, m, 2-CF3CONHC6H4: H-3,5); 7.61 (1H, s, NH); 10.76 (1H, s, NHCO)
3.05 (2H, t, J = 6.9, CH2CN); 4.26 (2H, t, J = 6.9, CH2N); 6.52 (1H, s, H-4);
6.84 (1H, d, J = 7.5, 2-CF3CONHC6H4: H-6); 6.89 (1H, m, 2-CF3CONHC6H4: H-4);
7.18-7.23 (2H, m, 2-CF3CONHC6H4: H-3,5); 7.60 and 7.76 (2 × 2H, two d, J = 8.7,
HAr-2,6 and HAr-3,5); 7.67 (1H, s, NH); 10.79 (1H, s, NHCO)
3.05 (2H, t, J = 6.6, CH2CN); 4.27 (2H, t, J = 6.6, CH2N); 6.52 (1H, s, H-4);
6.84 (1H, d, J = 7.8, 2-CF3CONHC6H4: H-6); 6.90 (1H, m, 2-CF3CONHC6H4: H-4);
7.18-7.23 (2H, m, 2-CF3CONHC6H4: H-3,5); 7.47 and 7.83 (2 × 2H, two d, J = 8.7,
HAr-2,6 and HAr-3,5); 7.67 (1H, s, NH); 10.80 (1H, s, NHCO)
3.08 (2H, t, J = 6.6, CH2CN); 4.32 (2H, t, J = 6.6, CH2N); 6.69 (1H, s, H-4);
6.87-6.95 (2H, m, 2-CF3CONHC6H4: H-4,6); 7.20-7.25 (2H, m, 2-CF3CONHC6H4: H-3,5);
7.75 (1H, s, NH); 8.09 and 8.28 (2 × 2H, two d, J = 8.7, HAr-2,6 and HAr-3,5);
10.80 (1H, s, NHCO)
3a
3b
3.05 (2Н, m, СН2CN), 4.20 (2Н, m, СН2N), 7.33 (1Н, s, H-4'), 7.38-7.60 (6H, m,
Н-5,6,7 + НAr-3,4,5), 7.93 (2Н, d, J = 6.9, НAr-2,6), 8.01-8.04 (1H, m, Н-4)
3.04 (2Н, m, СН2CN), 3.81 (3H, s, OCH3), 4.15 (2Н, m, СН2N),
7.04 and 7.84 (22Н, two d, J = 8.4, HAr-3,5 and HAr-2,6), 7.22 (1Н, s, H-4'),
7.45 (1H, d, J = 8.1, H-7), 7.55 (2H, m, H-5,6), 8.02 (1H, d, J = 8.1, Н-4)
3c
3d
3е
4a
3.06 (2Н, m, СН2CN), 4.18 (2Н, m, СН2N), 7.36 (1Н, s, H-4'), 7.44-7.47 (1H, m, H-7),
7.54-7.57 (2H, m, H-5,6), 7.69 and 7.87 (2 × 2Н, two d, J = 9.0, HAr-2,6 and HAr-3,5),
8.00-8.03 (1H, m, Н-4)
3.06 (2Н, m, СН2CN), 4.20 (2Н, m, СН2N), 7.37 (1Н, s, H-4'), 7.45-7.48 (1H, m, H-7),
7.52-7.55 (2H, m, H-5,6), 7.57 and 7.94 (2 × 2Н, two d, J = 8.7, HAr-2,6- and HAr-3,5),
8.01-8.04 (1H, m, Н-4)
3.07 (2Н, m, СН2CN), 4.26 (2Н, m, СН2N), 7.47-7.50 (1H, m, H-7), 7.56 (1Н, s, H-4'),
7.56-7.58 (2H, m, H-5,6), 8.02-8.05 (1H, m, Н-4), 8.19 and 8.36 (2 × 2Н, two d, J = 9.0,
HAr-2,6 and HAr-3,5)
3.58 (2H, t, J = 5.1, ССН2), 4.55 (2H, t, J = 5.4, NСН2), 7.33-7.37 (2H, m, H-9,10),
7.40 (1H, s, H-1), 7.42-7.48 (3H, m, HAr-3,4,5), 7.73 (1H, d, J = 6.3, H-11),
7.97 (2H, d, J = 5.4, H-11), 8.07 (1H, d, J = 6.6, H-8)
1421

TABLE 2 (continued)
1
2
4b
4c
4d
4е
3.62 (2H, t, J = 6.9, ССН2), 3.81 (3H, s, OCH3), 4.52 (2H, t, J = 6.9, NСН2),
7.02 and 7.89 (2 × 2Н, two d, J = 8.7, HAr-2,6 and HAr-3,5), 7.29 (1H, s, H-1),
7.32-7.44 (2H, m, H-9,10), 7.73 (1H, d, J = 7.5, H-11), 8.05 (1H, d, J = 7.8, H-8)
3.57 (2H, t, J = 6.9, ССН2), 4.55 (2H, t, J = 6.9, NСН2), 7.32-7.44 (2H, m, H-9,10),
7.43 (1H, s, H-1), 7.66 and 7.91 (2 × 2Н, two d, J = 8.4, HAr-3,5- and HAr-2,6),
7.73 (1H, d, J = 8.1, H-11), 8.05 (1H, d, J = 7.8, H-8)
3.57 (2H, t, J = 6.9, ССН2), 4.55 (2H, t, J = 6.9, NСН2), 7.32-7.44 (2H, m, H-9,10),
7.40 (1H, s, H-1), 7.52 and 7.98 (2 × 2Н, two d, J = 8.7, HAr-3,5 and H Ar-2,6),
7.72 (1H, d, J = 8.1, H-11), 8.04 (1H, d, J = 7.8, H-8)
3.59 (2H, t, J = 6.9, ССН2), 4.60 (2H, t, J = 7.2, NСН2), 7.32-7.445 (2H, m, H-9,10),
7.59 (1H, s, H-1), 7.72 (1H, d, J = 8.1, H-11), 8.05 (1H, d, J = 7.5, H-8),
8.19 and 8.30 (2 × 2Н, two d, J = 9.3, HAr-3,5 and HAr -2,6)
The synthesized compounds are completely stable crystalline substances. The structure and composition
1
of all the compounds have been confirmed elemental analysis (Table 1) and H NMR spectra (Table 2). The
structures of compounds 2a and 3a have also been confirmed by IR spectra and 19F NMR spectra, and compound
4a by mass spectroscopy.
According to the 1H NMR spectra there is restricted rotation about the bond connecting the
benzimidazole and pyrazole rings in compounds 3a-e because of steric hindrance. Each of the protons of the two
linked CH2 groups appears in unexpected chemical surroundings: consequently the signals of these groups have
increased multiplicity. It is known [6] that compounds of this type exist as racemic mixtures. Evidently the
heterocyclic fragments of compounds 3a-e do not lie in the same plane. This is shown clearly by the shift of the
signal of proton H-7 of the benzimidazole unit to strong field (7.44-7.50 ppm) in comparison with the signal of
the proton in the same position in the benzimidazole ring in compounds 4a-e (7.72- 7.73 ppm). In compounds
4a-e the heterocyclic system is close to coplanar and the pyrazole ring shows a maximum deshielding effect on
the closest hydrogen atom of the benzimidazole fragment. In the given cases both protons of each of the
mutually bonded methylene groups are chemically equivalent; and the signals of these groups appear as well
expressed triplets.
Thus the cyclocondensation of 3-aryl-1-cyanoethyl-5-(tifluroacetaminoanilino)pyrazoles on heating with
hydrochloric acid is a preparatively satisfactory and effective method for the synthesis of compounds of the
previously unknown tetracyclic pyrazolo[5',1':2,3]pyrimido[1,6-a]benzimidazole system.
EXPERIMENTAL
1H and 19F NMR spectra of DMSO-d6 solutions with TMS and CFCl3 standards were recorded with a
Varian VXR-300 (300 MHz) spectrometer. IR spectra of KBr disks were recorded with a UR-20 instrument and
mass spectra with a MX-1321 machine (70 eV, 220°C). The course of reactions and the purity of the compounds
synthesized were monitored by TLC on Silufol UV-254 strips with 9:1 benzene–ethanol solvent and detection
with UV light.
Cyanoethylhydrazone of 2-Phenacyl-1H-benzimidazole (1a).
A mixture of 2-phenacyl-1H-
benzimidazole (5 mmol), cyanoethylhydrazine (7.5 mmol), 2-propanol (2.5 ml), and glacial acetic acid (1 drop)
was boiled for 1 h. Water (2.5 ml) was added and the mixture was boiled with stirring until crystallization began.
After cooling the precipitate was filtered off, washed with 2-propanol and water (1:1), and dried for 5 h at 80°C.
The product was obtained in an analytically pure form.
Hydrazones 1b-d were prepared analogously from the corresponding 2-aroylmethylbenzimidazoles [7].
1422

Cyanoethylhydrazone of 2-(4-Nitrophenacyl)-1H-benzimidazole (1e).
A
mixture of
2-(4-nitrophenacyl)-1H-benzimidazole (12 mmol) [7], cyanoethylhydrazine (28 mmol), DMSO (10 ml), and
glacial acetic acid (6 drops) was stirred at 90-95°C for 5 h. The solution was kept at 15-17°C for 20 h. The
precipitate was filtered off and washed with 2-propanol. The product was obtained analytically pure after drying
in water pump vacuum at 115°C for 5 h.
1-Cyanoethyl-3-phenyl-5-(o-trifluoroacetaminoanilino)pyrazole (2a). Trifluoroacetic anhydride
(6 mmol) was added dropwise, while keeping the temperature 17-20°C, to a stirred mixture of compound 1a
(4 mmol) and anhydrous dioxane (2 ml). The reaction mixture was kept at 20°C for 1 h, water (20 ml) and 20%
aqueous ammonia (2 ml) were added, heated to 60°C and stirred until crystallization began. After cooling, the
precipitate was filtered off, washed with water, a 1:1 mixture of water and 2-propanol, dried at 75°C and
crystallized from toluene. IR spectrum, ν, cm-1: 1735 (C=O), 2275 (C≡N), 3270, 3435 (N–H). 19F NMR
spectrum, δ, ppm: -73.32.
Pyrazoles 2b-e were obtained analogously from compounds 1b-e. The amount of anhydrous dioxane
was increased to 4 ml in the preparation of compound 2e.
1-(1-Cyanoethyl-3-phenylpyrazol-5-yl)-2-trifluoromethyl-1H-benzimidazole (3a). A solution of
compound 2a (0.5 g) in a mixture of anhydrous dioxane (5 ml) and trifluoroacetic acid (0.5 ml) was kept at
100°C for 4 h. The solvent was evaporated at a water pump vacuum while heating to 100°C and the residue was
dissolved in a minimum quantity of benzene. The solution was passed through a short column of aluminum
oxide with benzene as eluant. The benzene was evaporated and the residue was crystallized from ethanol. IR
spectrum, ν, cm-1: 2270 (C≡N). 19F NMR spectrum, δ, ppm: -60.81.
Pyrazolylbenzimidazoles 3b-e were prepared analogously from compounds 2b-e.
5,6-Dihydro-2-phenylpyrazolo[5',1':2,3]pyrimido[1,6-a]benzimidazole (4a). A mixture of compound
2a (0.5 g), acetic acid (1 ml) and concentrated hydrochloric acid (1 ml) as maintained at 100°C for 5 h. The
mixture was then evaporated with stirring and heated to 140°C. The solid residue was boiled with pyridine
(5 ml), the mixture was stirred and carefully diluted with 20% aqueous ammonia (2 ml) and water (3 ml). After
cooling the reside was filtered off, washed with water and 2-propanol, and dried at 115°C for 5h with a water
pump vacuum to give an analytically pure product. Mass spectrum, m/z, (Irel, %): 286 M+ (100), 258 (12), 143
(12), 101 (4).
Compounds 4b-e were made analogously from compounds 2b-e.
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1423