Isomerization of 2-phenacyl-1H-benzimidazole arylhydrazones to 1-aryl-5-(o-aminoanilino)-3-phenylpyrazoles by trifluoroacetylation and hydrazinolysis

Article abstract of DOI:10.1007/s10593-005-0236-y

A convenient preparative two-stage method was developed for the isomerization of 2-phenacyl-1H-benzimidazole arylhydrazones to previously unknown 5-(o-aminoanilino)-1-aryl-3-phenylpyrazoles. The transformation scheme includes recyclization during acylation with trifluoroacetic anhydride leading to the formation of 1-aryl-3-phenyl-5-(o-trifluoroacetylaminoanilino)pyrazoles, which then undergo hydrazinolysis. 2005 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-005-0236-y

Chemistry of Heterocyclic Compounds, Vol. 41, No. 7, 2005
ISOMERIZATION OF 2-PHENACYL-
1H-BENZIMIDAZOLE ARYLHYDRAZONES
TO 1-ARYL-5-(o-AMINOANILINO)-3-PHENYLPYRAZOLES
BY TRIFLUOROACETYLATION AND HYDRAZINOLYSIS
I. B. Dzvinchuk and M. O. Lozinskii
A convenient preparative two-stage method was developed for the isomerization of 2-phenacyl-1H-
benzimidazole arylhydrazones to previously unknown 5-(o-aminoanilino)-1-aryl-3-phenylpyrazoles. The
transformation scheme includes recyclization during acylation with trifluoroacetic anhydride leading to
the formation of 1-aryl-3-phenyl-5-(o-trifluoroacetylaminoanilino)pyrazoles, which then undergo
hydrazinolysis.
Keywords: benzimidazoles, hydrazones, pyrazoles, trifluoroacetic anhydride, hydrazinolysis,
recyclization.
Recyclization is particularly attractive on account of the possibility of obtaining functionalized
compounds with a mutual arrangement of structural fragments that is difficult to obtained by other methods of
preparative organic chemistry [1-5]. It was interesting from this standpoint to develop a method for recyclization
of 2-phenacyl-1H-benzimidazole arylhydrazones 1a-e to the isomeric previously unknown 1-aryl-5-phenyl(o-
aminophenyl)-3-phenylpyrazoles 2a-e. Solution of this problem may increase the prospects for the synthesis of
new pyrazole-containing compounds (Scheme 1).
It should be noted that the direct recyclization of compounds 1 to the required products is essentially
intramolecular transamination, which must be subject to substantial steric and energetic hindrances. The process
requires intramolecular nucleophilic attack by the not very reactive arylhydrazone fragment at position 2 of the
extremely reactive benzimidazole system followed by opening of the imidazole ring on account of cleavage of
the nitrogen–carbon bond. We were unable to find conditions for such direct isomerization. On heating and with
acid catalysis phenylhydrazones of type 1 are transformed in a different direction and undergo Fischer
indolization [6]. As we found earlier [7], the recyclization of 2-phenacyl-1H-benzimidazole phenylhydrazone
(1a) can be initiated during acylation with benzoyl chloride, leading to the production of the N-benzoyl-
substituted compound 3, which is not however transformed into the required product when heated with
hydrazine hydrate for 12 h.
We were unable to synthesize compounds 2 by using trifluoroacetic anhydride, which contains an easily
removed acyl group.
The reaction of compounds 1a-e with trifluoroacetic anhydride is accompanied by recyclization with the
formation of 1-aryl-3-phenyl-5-(o-trifluoroacetylaminoanilino)pyrazoles 4a-e, the hydrazinolysis of which leads
to the required anilinopyrazoles 2a-e.
__________________________________________________________________________________________
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Kiev, Ukraine 02094; e-mail:
iochkiev@ukrpack.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1002-1006, July,
2005. Original article submitted September 20, 2003.
0009-3122/05/4107-0845©2005 Springer Science+Business Media, Inc.
845

Scheme 1
(CF3CO)2O
N
N
PhCOCl
Ar=Ph
Ph
NHAr
H
N
NHCOCF3
NHCOPh
1a–e
H
H
N
N
N
N
Ph
Ph
Ar
Ph
N
N
3
4a–e
NH2
H
N2H4
N2H4
N
2a
–CF3CONHNH2
N
Ph
Ar
N
2a–e
1, 2, 4 a Ar = Ph, b Ar = O2NC6H4, c Ar = 3-ClC6H4, d Ar = 4-FC6H4, e Ar = 4-MeC6H4
TABLE 1. The Characteristics of the Synthesized Compounds 1c-e, 2a-e,
and 4a-e
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %
С
Н
N
1c
1d
1e
2a
2b
2c
2d
2e
4a
4b
4c
4d
4e
C21H17ClN4
C21H17FN4
69.78
69.90
73.36
73.24
77.68
77.62
77.16
77.28
67.83
67.91
69.73
69.90
73.13
73.24
77.43
77.62
65.36
65.40
59.02
59.10
60.44
60.47
62.79
62.75
4.63
4.75
5.05
4.98
5.82
5.92
5.67
5.56
4.55
4.61
4.48
4.75
4.77
4.98
5.75
5.92
4.18
4.06
3.49
3.45
3.65
3.53
3.72
3.66
15.47
15.53
16.15
16.27
16.32
16.46
17.08
17.16
18.69
18.86
15.39
15.53
16.14
16.27
16.29
16.46
13.18
13.26
14.89
14.98
12.19
12.26
12.65
12.72
225-226.5
240-242
77
85
75
94
99
98
94
98
81
92
70
80
77
C22H20N4
221-222.5
156-157
C21H18N4
C21H17N5O2
C21H17ClN4
C21H17FN4
170-171.5
109-110.5
173-174.5
173-175
C22H20N4
C23H17F3N4O
C23H16F3N5O3
C23H16ClF3N4O
C23H16F4N4O
C24H19F4N4O
144-145
203.5-205
125-126.5
142-143.5
160-161.5
66.12
66.05
4.16
4.39
12.75
12.84
846

TABLE 2. The IR and 1H NMR Spectra of Compounds 1c-e, 2a-e, and 4a-e
IR
spectrum,
Com-
pound
ν, cm-1,
С=N, С=О
and N–H
1Н NMR spectrum, δ, ppm (J, Hz)
1
2
3
1с
1595,
3365
4.45 (2Н, s, СН2); 6.83 (1Н, d, J = 8.1, 3-ClC6H4: H-4); 7.08-7.17 (2H,
m, H-5,6); 7.20-7.26 (1Н, m, p-protons C6H5); 7.26-7.31 (3H, m, 3-ClC6H4:
H-2,4,5); 7.35-7.40 (2Н, m, m-protons C6H5); 7.45 (1Н, d, J = 6.9, H-7);
7.52 (1Н, d, J = 7.2, H-4); 7.85 (2Н, d, J = 7.5, o-protons C6H5);
10.39 (1H, s, NNH); 12.40 (1H, s, H-1)
1d
1e
1615,
3340
4.43 (2Н, s, СН2); 7.09-7.15 (4H, m, H-5,6 and 4-FC6H4: H-3,5);
7.24-7.30 (3Н, m, p-protons C6H5 and 4-FC6H4: H-2,6); 7.33-7.38 (2Н, m,
m-protons C6H5); 7.46 (1Н, m, H-7); 7.51 (1Н, m, H-4); 7.85 (2Н, d,
J = 7.8, o-protons C6H5); 10.29 (1H, s, NNH); 12.40 (1H, s, H-1)
1610,
3340
2.24 (3Н, s, СН3); 4.41 (2Н, s, СН2); 7.08-7.18 (2 × 2H, 2d, J = 8.4,
4-CH3C6H4); 7.09-7.16 (2H, m, H-5,6); 7.23-7.28 (1Н, m, p-protons C6H5);
7.33-7.38 (2Н, m, m-protons C6H5); 7.44 (1Н, d, J = 6.9, H-7); 7.52 (1Н, d,
J = 7.2, H-4); 7.84 (2Н, d, J = 7.8, o-protons C6H5); 10.20 (1H, s, NNH);
12.40 (1H, s, H-1)
2a
2b
3350,
3380,
3460
4.85 (2H, s, NH2); 6.30 (1H, s, H-4); 6.45-6.51 (1H, m, 2-NH2C6H4: H-4);
6.67-6.71 (2H, m, 2-NH2C6H4: H-3,5); 6.76 (1H, d, J = 8.1, 2-NH2C6H4:
H-6);7.06 (1H, s, NH); 7.29-7.43 (4H, m, p- and m-protons СC6H5 + p-proton
NC6H5); 7.46-7.51 (2H, m, m-protons NC6H5); 7.73 (2H, d, J = 7.8, o-protons
NC6H5); 7.83 (2Н, d, J = 6.9, o-protons СC6H5)
3330,
3390,
3480
4.94 (2H, s, NH2); 6.28 (1H, s, H-4); 6.46-6.51 (1H, m, 2-NH2C6H4: H-4);
6.72-6.78 (3H, m, 2-NH2C6H4: H-3,5,6); 7.32-7.46 (4H, m, NH + p-
and m-protons С6H5); 7.86 (2H, d, J = 7.2, o-protons СC6H5);
8.10 and 8.34 (2 × 2Н, 2d, J = 6.9, p-С6Н4)
2c
3370,
3455
4.86 (2H, s, NH2); 6.23 (1H, s, H-4); 6.45-6.51 (1H, m, 2-NH2C6H4: H-4);
6.70-6.77 (3H, m, 2-NH2C6H4: H-3,5,6); 7.21 (1H, s, NH);
7.30-7.84 (9H, m, C6H5 + 3-ClC6H4)
2d
3350,
3375,
3450
4.83 (2H, s, NH2); 6.26 (1H, s, H-4); 6.45-6.50 (1H, m, 2-NH2C6H4: H-4);
6.67-6.72 (2H, m, 2-NH2C6H4: H-3,5); 6.74 (1H, d, J = 7.8, 2-NH2C6H4: H-6);
7.06 (1H, s, NH); 7.29-7.34 (3H, m, p-protons C6H5 + FC6H4: H-2,6);
7.34-7.42 (2H, m, m-protons C6H5); 7.72-7.77 (2H, m, 4-FC6H4: H-3,5);
7.82 (2H, m, J = 6.9, o-protons C6H5)
2e
4a
3350,
3375,
3460
2.35 (3H, s, CH3); 4.81 (2H, s, NH2); 6.29 (1H, s, H-4); 6.45-6.50 (1H, m,
2-NH2C6H4: H-4); 6.66-6.70 (2H, m, 2-NH2C6H4: H-3,5); 6.75 (1H, d, J = 7.8,
2-NH2C6H4: H-6); 6.95 (1H, s, NH); 7.27-7.33 (3H, m, p-protons
C6H5 + CH3C6H4: H-3,5); 7.37-7.42 (2H, m, m-protons C6H5); 7.60 (2Н, d,
J = 8.1, CH3C6H4: H-2,6); 7.81 (2Н, d, J = 7.2, o-protons C6H5)
6.60 (1Н, s, Н-4); 6.80 (1H, d, J = 7.8, 2-CF3CONHC6H4: H-6); 6.85 (1Н, m,
2-CF3CONHC6H4: H-4); 7.12 (1Н, m, 2-CF3CONHC6H4: H-5); 7.18 (1H, d,
J = 7.8, 2-CF3CONHC6H4: Н-3); 7.29-7.36 (2Н, m, p-protons NC6H5
and CC6H5); 7.41-7.46 (4Н, m, m-protons NC6H5 and CC6H5); 7.75 (2Н, d,
J = 7.5, o-protons NC6H5); 7.77 (1H, s, NH); 7.87 (2Н, d, J = 6.9,
o-protons C6H5); 10.74 (1H, s, NHCO)
1700,
3200,
3280,
3600
4b
4c
1700,
3315
6.72 (1H, s, H-4); 6.78 (1H, d, J = 8.1, 2-CF3CONHC6H4: H-6); 6.89 (1H, m,
2-CF3CONHC6H4: H-4); 7.14 (1H, m, 2-CF3CONHC6H4: H-5); 7.22 (1H, d,
J = 7.8, 2-CF3CONHC6H4: Н-3); 7.36-7.49 (3Н, m, p- and m-protons C6H5);
7.93 (2Н, d, J = 7.2, o-protons C6H5); 8.11 (1Н, s, NHHet);
8.15 and 8.28 (2 × 2Н, 2d, J = 9.3, 4-NO2C6H4); 10.80 (1H, s, NHCO)
1710,
3200,
3300
6.54 (1H, s, H-4); 6.84 (1H, d, J = 8.1, 2-CF3CONHC6H4: H-6); 6.90 (1H, m,
2-CF3CONHC6H4: H-4); 7.15 (1H, m, 2-CF3CONHC6H4: H-5); 7.22 (1H, d,
J = 7.5, 2-CF3CONHC6H4: H-3); 7.33-7.88 (9Н, m, C6H5 + 3-ClC6H4);
7.86 (1Н, s, NHHet); 10.73 (1H, s, NHCO)
847

TABLE 2 (continued)
1
2
3
4d
1700,
3295,
3420
6.59 (1H, s, H-4); 6.79 (1H, d, J = 7.8, 2-CF3CONHC6H4: H-6); 6.86 (1H, m,
2-CF3CONHC6H4: H-4); 7.13 (1H, m, 2-CF3CONHC6H4: H-5); 7.18 (1H, d,
J = 7.8, 2-CF3CONHC6H4: H-3); 7.24-7.30 and 7.76-7.80 (2 × 2Н, 2m,
4-FC6H4); 7.43 and 7.43 (1H and 2H, 2m, p- and m-protons C6H5);
7.76 (1Н, s, NHHet); 7.87 (2Н, d, J = 7.2, o-protons C6H5);
10.73 (1H, s, NHCO)
4e
1700,
3285,
3425
2.32 (3H, s, CH3); 6.58 (1H, s, H-4); 6.79 (1H, d, J = 7.8, 2-CF3CONHC6 H4: H-6);
6.85 (1H, m, 2-CF3CONHC6H4: H-4); 7.13 (1H, m, 2-CF3CONHC6H4: H-5);
7.18 (1H, d, J = 7.8, 2-CF3CONHC6H4: H-3); 7.24-7.63 (2 × 2Н, 2d, J = 8.1,
4-CH3C6H4); 7.33 and 7.42 (1H and 2H, 2m, p- and m-protons C6H5);
7.67 (1Н, s, NHHet); 7.87 (2Н, d, J = 7.2, o-protons C6H5);
10.72 (1H, s, NHCO)
The first stage of the synthesis (recyclization initiated by acylation) takes place in dioxane at 20-25°C
and is complete in 1 h. In order to obtain complete conversion of the trifluoroacetic anhydride a 1.5-fold excess
above the theoretical amount is used. The reaction takes place smoothly, and the yields of compounds 4a-e
amount 70-92%.
The second stage of the synthesis (hydrazinolysis) takes place in boiling methanol and is complete in
30 min. The trifluoroacetylhydrazine formed in the reaction has high solubility and does not interfere with the
isolation of the products 2a-e, the yields of which are close to quantitative.
The synthesized new compounds (Table 1) are perfectly stable crystalline substances, the structure of
which was supported by data from the IR and 1H NMR spectra (Table 2).
Thus, a new convenient method was found for the isomerization of 2-phenacyl-1H-benzimidazole
arylhydrazones to 5-(2-aminoanilino)-1-aryl-3-phenylpyrazoles by the action of trifluoroacetic anhydride
followed by hydrazinolysis of the obtained pyrazolylaminotrifluoroacetanilides.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian VXR-300 spectrometer (300 MHz) in DMSO-d6 with
TMS as internal standard. The IR spectra were recorded on a UR-20 instrument in tablets with potassium
bromide. The reactions and the purity of the products were monitored by TLC on Silufol UV-254 plates in the
9:1 benzene–ethanol solvent system (with development in UV light). Compounds 1a,b and 3 were obtained by
the methods in [7, 8].
2-Phenacyl-1H-benzimidazole 3-Chlorophenylhydrazone (1c). A mixture of 2-phenacyl-1H-
benzimidazole (10 mmol), 3-chlorophenylhydrazine hydrochloride (11 mmol), pyridine (15 mmol), and dioxane
(5 ml) was heated at 95-100°C for 1.5 h. We added water (3 ml) and 2-propanol (3 ml) and stirred the mixture
until crystallization began. After cooling the precipitate was filtered off, washed with 2-propanol, and dried at
115°C for 5 h under the vacuum of a water-jet pump. The product is formed in the analytically pure form.
The arylhydrazone 1d was obtained similarly.
2-Phenacyl-1H-benzimidazole 4-Tolylhydrazone (1e). A mixture of 2-phenacyl-1H-benzimidazole
(5 mmol), 4-tolylhydrazine (7 mmol), and dioxane (5 ml) was heated for 1.5 h in the presence of five drops of
glacial acetic acid at 95-100°C. We added water (2.5 ml) and stirred the mixture until crystallization began. After
cooling the precipitate was filtered off, washed with 2-propanol, and dried at 115°C for 5 h under the vacuum of
a water-jet pump. The product is formed in the analytically pure form.
848

1-Aryl-3-phenyl-5-(2-trifluoroacetylaminoanilino)pyrazoles (4a-e). To a suspension of the respective
compound 1a-e (2 mmol) in anhydrous dioxane (2.0 ml) with cooling on a water bath (20-25°C) and stirring we
added trifluoroacetic anhydride (0.42 g, 3 mmol) over 3-4 min. The solution was kept at 20-25°C for 1 h and was
then diluted with a mixture of 1 ml of an aqueous solution (20%) of ammonia and 3 ml of water. The mixture
was heated with stirring until the oil that separated had completely crystallized. If crystallization did not occur
the reaction mixture was evaporated to half the volume and diluted with 2 ml of 2-propanol. After cooling the
precipitate was filtered off, washed with a cold 1:1 mixture of water and 2-propanol, dried at 90°C, and
recrystallized from toluene.
5-(2-Aminoanilino)-1-aryl-3-phenylpyrazoles 2a-e. To a mixture of the respective compound 4a-e (0.3
g) in methanol (1.5 ml) heated on a bath (95-100°C) we added hydrazine hydrate (80%) (0.3 ml). The mixture
was boiled for 30 min and diluted with water with stirring (1.5 ml). If the product separated as an oil, ether (0.5
ml) was added. After cooling the precipitate was filtered off, washed with a 1:1 mixture of methanol and water,
and dried at 100°C for 5 h. The products were formed in the analytically pure form.
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849