New method for the annelation of a pyridine ring on derivatives of imidazole and benzimidazole

Article abstract of DOI:10.1007/s10593-010-0474-5

The interaction of (Z)-1,3-diaryl-4-bromo-2-buten-1-ones with 1-substituted (benz)imidazoles in benzene gave (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H- imidazolium bromides and (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H- benzimidazolium bromides which readily cyclize in the presence of base to form derivatives of 7,9-diarylpyrido[1,2-a]benzimidazole and 6,8-diarylpyrimidazo[1, 2-a]pyridine. The effects of the nature of substituents in the benzene ring of the diarylbutenones and the substituent at N(1) in the (benz)imidazoles on the alkylation and cyclization reactions has been studied. The optimum conditions for the synthesis of the 5-R-4-hydroxy-2,4-diphenyl-4,5-dihydro-1H-pyrido[1,2-a] benz-imidazol-10-ium, 5-R-2,4-diaryl-4-hydroxy-4,5-dihydro-3H-pyrido[1,2-a] benzimidazol-10-ium, and 5-R-2,4-diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium have been found.

Full text of DOI:10.1007/s10593-010-0474-5

Chemistry of Heterocyclic Compounds, Vol. 46, No. 1, 2010
NEW METHOD FOR THE ANNELATION
OF A PYRIDINE RING ON DERIVATIVES
OF IMIDAZOLE AND BENZIMIDAZOLE
L. M. Potikha1*, A. R. Turelyk1, V. A. Kovtunenko1, and A. V. Turov1
The interaction of (Z)-1,3-diaryl-4-bromo-2-buten-1-ones with 1-substituted (benz)imidazoles in
benzene gave (Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-imidazolium bromides and (Z)-1-R-3-(2,4-
diaryl-4-oxo-2-butenyl)-1H-benzimidazolium bromides which readily cyclize in the presence of base to
form derivatives of 7,9-diarylpyrido[1,2-a]benzimidazole and 6,8-diarylpyrimidazo[1,2-a]pyridine. The
effects of the nature of substituents in the benzene ring of the diarylbutenones and the substituent at
N(1) in the (benz)imidazoles on the alkylation and cyclization reactions has been studied. The optimum
conditions for the synthesis of the 5-R-4-hydroxy-2,4-diphenyl-4,5-dihydro-1H-pyrido[1,2-a]benz-
imidazol-10-ium, 5-R-2,4-diaryl-4-hydroxy-4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium, and
5-R-2,4-diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium have been found.
Keywords: γ-bromodypnone, imidazo[1,2-a]pyridine, pyrido[1,2-a]benzimidazole, cyclization of
azolium ylides.
The imidazo[1,2-a]pyridine system has been studied very actively recently, in connection with the
introduction into the practice of medicine of preparations of the type of zolpidem [3], fazadinium [4], and others.
The basic method for the construction of imidazo[1,2-a]pyridine system consists of the construction of the
imidazole part of the bicycle. An alternative possibility is annelation, when the final closing of the
imidazo[1,2-a]pyridine or pyrido[1,2-a]imidazole system is carried out during the construction of the pyridine
ring, has been insufficiently studied [5-7].
In the present work a simple variant of the construction of the pyridine ring on the imidazole or
benzimidazole structure is proposed, based on the "inversion" of the A. E. Chichibabin reaction [8]. The
formation of imidazo[1,2-a]pyridines according to Chichibabin consists of the interaction of α-halo ketones with
2-aminopyridine, which proceeds via the initial formation of a quaternary salt, its deprotonation, and
intramolecular attack on the carbonyl group by a nucleophile. The intermediate carbinolamine is readily
converted into an imidazo[1,2-a]pyridine by dehydration, but it may be isolated in pure form [9]. Our proposed
inverted variant consists, in the first place, in replacing the α-halo ketones by their vinylogs (in this work we
refer to γ-bromodypnone) and secondly, in using imidazole or benzimidazole without substitutions in position 2.
The sequence of conversions in these reactions is identical to the stages of the Chichibabin reaction.
_______
* To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Taras Shevchenko Kiev National University, Kiev01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.1, 95-112, January, 2009. Original article
submitted June 6, 2009.
82
0009-3122/10/4601-0082©2010 Springer Science+Business Media, Inc.

Ar
N
N
N
_
_
Ar
Br
Br
N
+
+
N
N
N
Ar
R
R
COAr
Br
COAr
COAr
N
1a–d
R
3a–l
2a–l
R
B:
B:
Ar
6
5
3
+
N
Ar
4
+
N
_
Br
N
1
Ar
_
Br
N
R
Ar
1
R
5a–l
4a–l
1 a Ar = Ph, b Ar = 4-MeOC6H4, c Ar = 4-ClC6H4, d Ar = BrC6H4; 2, 4 a–e Ar = Ph, a R = Me,
b R = Et, c R = (CH2)2CN, d R = Bn, e R = Ph; f, g Ar = 4-MeOC6H4, f R = Me, g R = Bn;
h–j Ar = 4-ClC6H4, h R = Me, i R = Bn, j R = Ph; k, l Ar = 4-BrC6H4, k R = Me, l R = Bn;
3, 5 a–e Ar = Ph, a R = Me, b R = Et, c R = CH2Vin, d R = Bn, e R = Vin;
f, g Ar = 4-MeOC6H4, f R = Me, g R = Bn; h, i Ar = 4-ClC6H4, h R = Me,
i R = Bn; j–l Ar = 4-BrC6H4, j R = Et, k R = Me, l R = Bn
Recently [10] we found that 1-alkyl-1H-benzimidazoles and imidazoles interact with (Z)-4-bromo-
1,3-diphenyl-2-buten-1-one (γ-bromodypnone, 1a) to form quaternary (Z)-1-alkyl-3-(2,4-diaryl-4-oxo-2-buten-
yl)-1H-benzimidazol-3-ium 2a,b and (Z)-1-alkyl-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-imidazol-3-ium 3a,b salts.
Subsequent heating them in the presence of base cyclized them into derivatives of the 2,4-diphenylpyrido-
[1,2-a]benzimidazole (4) and 6,8-diphenylimidazo[1,2-a]pyridine (5) systems respectively (Table 1). It was
shown that the structures of the reaction products were determined by the nature of the substituent at N(1) atom
of azole and the conditions of the reaction. These results encouraged us to study in more detail the process of
cyclization of salts of types 2 and 3. For this we chose to use 1-substituted diazoles and derivatives of γ-bromo-
dypnone.
The γ-bromodypnones 1b-d with N-substituents in the benzene ring, like unsubstituted 1a, form
quaternary salts with structures 2 and 3 with 1-alkyl-1H-imidazoles and -benzimidazoles on maintaining of
benzene solutions of the starting materials at room temperature. The influence of the nature of the substituents in
γ-bromodypnone 1 on the reaction time for conversion to the products of alkylation and their yields was
negligible. There was a more notable change in the rate of formation of the quaternary salts in changing from
1-alkyl-1H-benzimidazoles to 1-alkyl-1H-imidazoles. For example, the time for the formation of products of
type 2 was 6-12 h, but for products of type 3 was 1-4 h.
The nature of the substituent at atom N(1) showed a considerable influence on the rate of reaction only
in the case of 1-phenyl-1H-benzimidazole: to obtain the salts 2e and 2j required respectively 8 days (48% yield)
and 10 days (43% yield). Also a quaternary salt of type 2 was not obtained with compound 1d. The structures of
1
compounds 2c-l and 3c-l were determined from their H NMR and IR spectra (Table 2), which corresponded
with data for compounds 2a,b and 3a,b [10]
Intramolecular cyclization into the 5R-2,4-diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium bromides 4a-l
and 1-R-6,8-diaryl-1H-imidazo[1,2-a]pyridin-4-ium bromides 5a-l occurred when salts 2 and 3 were heated in
the presence of a base. We found that products 4 and 5 were formed in high yield and high purity on heating
salts 2 and 3 in ethanol in the presence of morpholine, independent of the structure of the initial quaternary salt
83

TABLE 1. Physicochemical Properties of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%*2
mp, °C*
C
3
H
4
Br
5
Cl
6
N
7
1
2c
2d
2e
2f
2
8
9
C26H22BrN3O
C30H25BrN2O
C29H23BrN2O
C26H25BrN2O3
C32H29BrN2O3
C24H19BrCl2N2O
C30H23BrCl2N2O
C29H21BrCl2N2O
C24H19Br3N2O
C30H23Br3N2O
C22H21BrN2O
C26H23BrN2O
C21H19BrN2O
C22H23BrN2O3
C28H27BrN2O3
C20H17BrCl2N2O
66.08
66.11
70.65
70.73
70.25
70.31
63.23
63.29
67.45
67.49
57.34
57.40
62.31
62.30
61.66
61.72
48.70
48.76
53.97
54.00
64.49
64.55
67.91
67.98
63.77
63.81
59.56
59.60
64.70
64.74
53.06
53.12
4.60
4.69
4.91
4.95
4.61
4.68
5.10
5.11
5.07
5.13
3.75
3.81
3.92
4.01
3.70
3.75
3.19
3.24
3.40
3.47
5.11
5.17
5.00
5.05
4.79
4.84
5.18
5.23
5.25
5.24
3.74
3.79
16.91
16.92
15.70
15.68
16.16
16.13
16.22
16.19
14.09
14.03
15.89
15.91
13.85
13.82
14.17
14.16
40.53
40.55
35.97
35.93
19.56
19.52
17.42
17.39
20.24
20.21
18.07
18.02
15.41
15.38
17.68
17.67
8.92
8.90
5.51
5.50
5.69
5.65
5.67
5.68
4.96
4.92
5.60
5.58
4.83
4.84
4.99
4.96
4.77
4.74
4.23
4.20
6.84
6.84
6.15
6.10
7.11
7.09
6.33
6.32
5.41
5.39
6.23
6.20
186-187 a
117-118 a
145-148 b
200-203 a
170-172 a
173-175 a
191-193 a
172-173 b
173-175 a
209-211 a
186-188 a
167-169 a
210-212 a
124-126 a
159-161 a
186-188 a
56
76
48
88
74
87
72
43
86
73
91
87
89
93
82
90
2g
2h
2i
14.16
14.12
12.21
12.26
12.57
12.57
2j
2k
2l
3c
3d
3e
3f
3g
3h
15.67
15.68
3i
C26H21BrCl2N2O
C21H19Br3N2O
C20H17Br3N2O
C26H21Br3N2O
C26H20BrN3
59.05
59.11
45.40
45.44
44.37
44.40
50.58
50.60
68.70
68.73
73.25
73.32
72.91
72.96
65.60
65.69
69.64
69.69
59.47
59.53
64.27
64.31
63.70
63.76
50.28
50.30
55.45
55.50
67.49
67.53
3.98
4.01
3.41
3.45
3.12
3.17
3.45
3.43
4.38
4.44
4.66
4.72
4.46
4.43
4.82
4.88
4.87
4.93
3.50
3.54
3.70
3.78
3.46
3.51
2.90
2.99
3.22
3.26
4.85
4.89
15.11
15.13
43.21
43.18
44.34
44.30
38.85
38.84
17.60
17.59
16.25
16.26
16.75
16.74
16.83
16.81
14.50
14.49
16.51
16.50
14.28
14.26
14.61
14.63
41.85
41.83
36.91
36.92
20.44
20.42
13.45
13.42
5.31
5.30
5.09
5.05
5.19
5.18
4.51
4.54
9.25
9.25
5.73
5.70
5.89
5.87
5.92
5.89
5.10
5.08
5.82
5.79
5.01
5.00
5.15
5.13
4.90
4.89
4.35
4.31
7.20
7.16
142-145 a
202-204 a
199-201 a
157-159 a
274-276 a
235-237 c
361-362 c
268-271 a
251-253 a
305-307 a
264-266 c
352-354 c
289-291 a
74
76
88
72
84
89
83
91
82
88
87
79
91
3j
3k
3l
4c
4d
4e
4f
C30H23BrN2
C29H21BrN2
C26H23BrN2O2
C32H27BrN2O2
C24H17BrCl2N2
C30H21BrCl2N2
C29H19BrCl2N2
C24H17Br3N2
4g
4h
4i
14.64
14.64
12.66
12.65
13.00
12.98
4j
4k
4l
C30H21Br3N2
C22H19BrN2
252-254 c
232-234 a
86
84
5c
84

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
86
5d
C26H21BrN2
70.70
70.75
4.76
4.80
18.13
18.10
6.37
6.35
273-275 c
269-271 a
227-229 a
242-245 a
299-301 a
239-241 a
268-270 a
317-319 a
257-258 c
228-231 a
292-294 a
288-289 c
282-283 c
5e
5f
C21H17BrN2
66.80
66.85
62.08
62.13
67.00
67.07
55.26
55.33
61.17
61.20
46.91
46.96
45.87
45.92
52.09
52.12
66.15
66.11
61.68
61.72
48.70
48.76
53.24
53.32
4.48
4.54
4.91
4.98
4.98
5.03
3.40
3.48
3.70
3.75
3.15
3.19
2.81
2.89
3.15
3.20
4.92
4.69
3.73
3.75
3.18
3.24
3.17
3.24
21.20
21.18
18.80
18.79
15.95
15.94
18.02
18.04
15.66
15.66
44.73
44.69
45.81
45.83
40.05
40.01
16.95
16.92
14.17
14.16
40.56
40.55
36.71
36.70
7.41
7.43
6.61
6.59
5.59
5.59
6.49
6.45
5.51
5.49
5.23
5.22
5.39
5.36
4.71
4.68
8.90
8.90
4.98
4.96
4.76
4.74
4.30
4.29
81
89
80
86
77
78
85
82
73
81
92
83
C22H21BrN2O2
C28H25BrN2O2
C20H15BrCl2N2
C26H19BrCl2N2
C21H17Br3N2
C20H15Br3N2
C26H19Br3N2
C26H22BrN3O
C29H21BrCl2N2O
C24H19Br3N2O
C29H21Br3N2O
5g
5h
5i
16.30
16.33
13.93
13.90
5j
5k
5l
6b
7j
12.56
12.57
7k
7m
_______
* Solvents for recrystallization: 2-PrOH (a), MeNO2 (b), and AcOH (c).
*2 The yields of compounds 4, 5 made by method A.
Ph
_
Ar
Br
+
N
_
2a,c, Et3N
Br
+
N
Ph
Me2CO
N
COAr
OH
R
N
6a,b
R
2
Ar
Ar
_
_
Br
Ar
Br
2d,
f–i,
k, l
+
+
N
N
Et3N
Me2CO
4d,f–i,k,l
+
+
Ar
N
R
N
OH
OH
R
6d,f–i,k,l
7d,f–i,k,l
Ar
N
N
O
_
Br
+
N
H
N
Ph
2k
1c,d
Ar
N
C6H6, ∆
Me2CO
OH
R
7j,k,m
7 j Ar = 4-ClC6H4, R = Ph; k, m Ar = 4-BrC6H4,
k R = Me, m R = Ph
6 a R = Me, b R = (CH2)2CN;
85

86

87

88

89

(method A). The spectral data (1H NMR and infrared spectra, Table 3) of the products of cyclization agreed with
those of compounds 4a,b and 5a,b [10], on the basis of which we assumed the structures of compounds 4c-l and
5c-l.
Cyclization of salts 2 in acetone gave nondehydrated products and their mixtures with salts of type 4.
Heating of bromide 2a in acetone with Et3N (method B) gave 4-hydroxy-5-methyl-2,4-diphenyl-4,5-dihydro-
1H-pyrido[1,2-a]benzimidazol-10-ium bromide (6a) [10]. The structure of compound 6a was reliably found by
two-dimensional NMR spectroscopy (Fig. 1, A). The reaction of benzimidazolium bromide 2c led to a
compound with a similar structure (6b). 1-Ethyl- (2b) and 1-phenylbenzimidazolium bromides (2e,j) formed the
aromatic salts 4b [10] and 4e,j under similar conditions. From the remaining benzimidazolium salts a mixture of
1
cyclization products was obtained (according to H NMR data), the composition of which depended on the
nature of the substituents in the benzene ring of the dypnone and the substituent at atom N(1) in the
benzimidazole. For example, 1-methylbenzimidazolium bromides 2f,h,k gave mixtures (Table 4) containing
~50% of products of type 6, while in the products of cyclization of 1-benzylimidazolium bromide 2d (Ar = Ph)
the amount of the product of type 6 was 70%.
The second component of the mixture – compound of previously unknown structure – is also present in
the mixture of products from the cyclization of 1-benzylbenzimidazolium bromides 2i and 2l (Ar = 4-ClC6H4,
4-BrC6H4). The basic component of the mixtures in these cases are pyrido[1,2-a]benzimidazolium salt of type 4,
but compounds of type 6 and the unknown (in a ratio of ~1:1) did not exceed 30%. The presence of the
unknown compound and its content in the product mixture was determined from the characteristic signals in the
1
3.50-3.54 ppm region of the H NMR spectrum of the methylene group as a broadened two-proton multiplet or
2
doublet of doublets of the AB-system with J = 17.0 Hz. The presence of such a signal at higher field than for
compounds of type 6 (C(6)H2 5.67-5.83 ppm), and the signal of a methyne proton in the 8.32-8.54 ppm region –
at weaker field in comparison with compounds of type 6, provides a basis for suggesting that the structure of the
unknown compound corresponds to that of the 5-R-2,4-diaryl-4-hydroxy-4,5-dihydro-3H-pyrido[1,2-a]benz-
imidazol-10-ium cation (7).
When morpholine was used in boiling acetone (method C) the 1-methylbenzimidazolium salts 2a and 2f
(Ar = Ph, 4-MeOC6H4) and 1-benzylimidazolium salts 2d,g,i, and l were converted into aromatic salts of type 4.
1-Methylbenzimidazolium bromide 2h (Ar = 4-ClC6H4) gave a mixture consisting of 30% bromide 4h and a
compound of type 7, which, in the case of 1-methylbenzimidazolium bromide 2k (Ar = 4-BrC6H4), was the basic
reaction product (Table 4).
1
To confirm the structure of compounds 7 we studied the IR, H and 13C NMR spectra of pyrido-
[2,1-a]benzimidazolium bromide 7k, and also its 2D HMQC, HMBC, and NOESY spectra. A correlation was
found in the HMBC and NOESY spectra (Fig 1, B) which indicates the connectivity of the methylene group at
3.54 and the methyne proton at 8.53 ppm to the pyridine unit of the 2,4-diaryl-4,5-dihydro-3H-pyrido-
[1,2-a]benz-imidazol-10-ium condensed system. The presence of the OH group in 7k is shown by the presence
of a signal at 7.73 ppm which exchanges with D2O, and by the presence of the signal in the 3166 cm-1 in the IR
spectrum. The presence of the OH group in the molecule is confirmed from its 2D NOESY spectrum: a negative
NOE value is observed for the water signals and the proton at 7.73 ppm (as in the case of compound 6a [10])
which showed the exchange process. The basic difference in the correlation diagrams for the isomers 6 and 7
consists in the observed correlations of the protons of the methylene group. In the case of the 6H isomer
_
Ar
Br
+
Ar
Br
Et3N or morpholine
Me2CO
+
N
N
_
5h,i,k,l
+
N
COAr
3h,i,k,l
OH
N
R
R
Ar
8h,i,k,l
90

(compound 6a, Fig 1., A) there is a cross-peak in the HMBC spectrum at 130.7 ppm which corresponds to the
quaternary atom C(4a) of the benzimidazolium unit. Whereas in the spectrum of the 8H isomer (compound 7k),
the cross-peak is at 71.8 ppm for the quaternary atom C(9) of the pyridine unit bonded to the OH group.
On alkylation of the γ-bromodypnones 1c and 1d with an excess of 1-phenylbenzimidazole in benzene
heated to 50-60°C, cyclic products are obtained: 2,4-diaryl-4-hydroxy-5-phenyl-4,5-dihydro-3H-pyrido-
[1,2-a]benzimidazol-10-ium bromides 7j,m. It should be noted that formation of the cyclic product 7j was
observed even during the isolation of the quaternary salt 2j (~8-10% in the crude product according to 1H NMR
data). This shows that the nature of the substituents in the benzene rings and at atom N(1) in benzimidazolium
salts 2 affect the rate of cyclization – the increased electronegativity of the substituents facilitates the reaction.
128.7
140.9
7.74
1'
NOE
5.81
134.8
140.8
7.80
8.53
129.3
8.32
117.3
8.57
46.1
NOE
+
N
6.45
3.54
5
+
N
125.8
5
42.4
71.8
69.5
130.73
9
128.2
149.28
147.6
132.53
135.56
9
1''
128.3
126.9
N
OH
N
132.9
OH
1
1
7.73
34.4
3.77
7.54
7.69
CH3
8.03
8.10
CH3
3.76
33.1
A
B
Fig. 1 Structure significant HMBC and NOESY Correlations for Compounds 6a (A) and 7k (B)
TABLE 4. Results of the Cyclization Reactions of Salts 2
Com-
pound
Reaction conditions
(method)
Base
Et3N
Result of reaction
B
6
2a
2f
Morpholine
Et3N
В
4
B
6f + 7f (1.5 : 1)
Morpholine
Et3N
В
4f
2h
2k
2d
B
6h +7h (1 : 1.3)
Morpholine
Morpholine
Et3N
В
7h + 4h (2 : 1)
A
4h
B
6k + 7k (1 : 1)
Morpholine
Morpholine
Et3N
В
7k
A
4k
B
6d + 7d (2 : 1)
Et3N
Acetone, ∆, 3.5 h
6d + 4d (1 : 1.4)
Morpholine
Et3N
В
B
В
B
В
B
В
B
B
4d
2g
2i
2l
6g + 7g + 4g (1:1:1)
Morpholine
Et3N
4g
6i + 7i + 4i (1.3:1:4)
Morpholine
Et3N
4i
6l + 7l + 4l (1.8:1: 6)
Morpholine
Et3N
4l
4e
4j
2e
2j
Et3N
91

The dependence of the results of the cyclization imidazolium salts 3 on the nature of substituents in varying
conditions is not as well expressed. The formation of 1-R-6,8-diaryl-8-hydroxy-7,8-dihydro-1H-imidazo[1,2-
1
a]pyridin-4-ium bromides (8) in mixtures with aromatic products 5 (method C) was recorded by H NMR
spectroscopy only in the case of the imidazolium bromides 3h,i, k, l (Ar = 4-ClC6H4, BrC6H4): the signals of the
protons of the C(7)H2 were observed at 3.44 ppm as a multiplet or as a doublet of doublets with 2J = 17.0 Hz. The
formation of 5H-derivatives of type 6 was not observed. The content of products 8 in the mixtures decreased
with increasing electronegativity of the substituents in the initial salts 3 (from 60% for R = Me to 30% for R
=Bn). When using Et3N (method B) the amount of hydroxy derivatives 8 did not exceed 10-15%.
The observed regularities of the cyclization reaction may be explained as follows. The quaternary
azolium salts are capable of forming ylide structures in the presence of bases [6, 11, 12) with participation of
cyclic (structure 9) or acyclic (structure 10) anionic molecular fragments. The latter mechanism (with
participation of intermediate structures of type 11) are realized, for example in reactions with the formation of
indolizines by the reaction of 1-(4-oxo-2,4-diphenyl-2-butenyl)pyridinium salts with bases [13, 14], and also in
the synthesis of some derivatives of pyrrolo[1,2-a]benzimidazole and pyrrole[1,2-a]imidazole [15,16].
In our case, it is evident that conversion of salts 2 into 4-hydroxy-4,5-dihydro-1H-pyrido[1,2-a]benz-
imidazol-10-ium bromides 6 includes a stage of formation of structure 9 (route A). Compounds 6 may be converted
into isomers 7 as a result of tautomeric transfer of a hydrogen atom. However we consider this route to be less
likely since heating compound 6 in acetone with morpholine (in conditions in which formation of isomers of type 7
are observed) led to aromatic products 4. Moreover 4-hydroxy-4,5-dihydro-3H-pyrido[1,2-a]benz- imidazol-
10-ium bromides 7 are less stable to heat than salts of type 6: prolonged heating (2-2.5 h) of a mixture of
compounds 6d + 7d (2:1, obtained from salt 2d by method B) in acetone with Et3N led to the formation of a
mixture of compounds 6d + 4d (1:1.4). Evidently the mechanism for the conversion of salt 2 into 7 includes a
stage for the intermediate formation of structure 11 (route B). When a stronger base is used (morpholine),
2
B:
Ar
Ar
Ar
_
H
+
_
+
+
N
H
N
N
COAr
_
COAr
COAr
H
H
N
N
N
R
R
R
11
10
9
∆
B
A
Ar
Ar
_
Ar
Br
Ar
_
+
Br
+
N
N
+
N
_
COAr
N
Ar
OH
O
N
N
OH
R
6
R
12
R
7
∆
N
H
4
92

the proportion of structures of type 10 and 11 among the products of the reaction of 2 with bases increases.
Further attack of the anionic center C(3')- at the methyne group C(2)H ensures the elimination of the proton on
heating to give product 12.
The observed dependence of the content of compound 7 in the reaction products on the nature of the
substituents in the quaternary azolium salts confirms the correctness of the proposed scheme for the formation of
compounds of types 6 and 7. Increasing electronegativity of the substituents in the benzene rings of the dypnone
units facilitates the formation of structures of type 10 and realization of route B, for both benzimidazolium salts
2 and imidazolium salts 3. The possibility of reaction via route A is determined in large degree by the properties
of azole unit: with increased electronegativity of the substituent at atom N(1), the acidity of proton H-2 increases
and consequently the probability of formation of structure 9 increases. Consequently the fraction of compounds
of type 7 (and type 8 for imidazoles) in the mixture of products from the conversion of benzimidazolium
bromides 2 (and imidazolium bromides 3) is decreased.
The general tendency for hydroxy derivatives of imidazo[1,2-a]pyridinium and pyrido[1,2-a]benz-
imidazolium, expressed as a decrease in their stability with increased acceptor properties of their substituents, does
not depend on their position. For example, the greater stability of derivatives of 4-hydroxypyrido[1,2-a]benz-
imidazolium 7 in comparison with derivatives of imidazo[1,2-a]pyridine 8 is evidently explained by the known
effect [17] of the decreased difference in the energy of formation of dihydro derivatives on going from bicyclic
to tricyclic aromatic systems. In the case of 9-hydroxy derivatives of imidazo[1,2-a]pyridine, the relative
stability of compounds of type 7 is increased by the effect of the increased chain of conjugation in the molecule,
which allows for their formation and their isolation in pure form.
EXPERIMENTAL
1
IR spectra of KBr tablets were recorded with a Perkin-Elmer "Spectrum BX". H NMR spectra were
recorded with a Bruker AVANCE DRX 500 (500 MHz) instrument. Two dimension correlation spectroscopy
1
was carried out with a Varian Mercury 400 instrument (400 and 100 MHz respectively for H and 13C), in
DMSO-d6 with TMS as internal standard. Melting points were measured on a Boetius block. Purity of the
products was monitored by TLC on Silufol UV-254 plates and mass-spectrometric HPLC on an Agilent 1100
series with an Agilent LC/MSD SL selective detector ( samples were introduced in a CF3CO2H matrix, with EI
ionization).
(Z)-4-Bromo-1,3-diphenyl-2-buten-1-one (1a) was prepared by method [18], (Z)-1,3-diaryl-4-bromo-
2-buten-1-ones 1b-d by method [19]. 1-R-1H-Benzimidazoles and 1-R-1H-imidazoles were products of the
company "Enamine".
(Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-benzimidazol-3-ium Bromides 2c-l were prepared by the
synthetic method used for 2a,b, described in paper [10].
(Z)-1-R-3-(2,4-diaryl-4-oxo-2-butenyl)-1H-imidazol-3-ium Bromides 3c-l were prepared by the
method for the synthesis of products 3a,b described in paper [10].
5-R-2,4-diaryl-5H-pyrido[1,2-a]benzimidazol-10-ium Bromides 4c-l. A. A mixture of salt 2
(1.15 mmol) and morpholine (2 ml) in ethanol (10 ml) was heated for 2 h. After cooling, the precipitate formed
was filtered off and washed with acetone to give the pyridobenzimidazolium bromides 4c-l.
B. An analogous method to A, using acetone as solvent and Et3N as base, gave pyridobenzimidazolium
bromides 4c-j (yields 74-88%).
C. An analogous method to B, using morpholine as base, gave pyridobenzimidazolium bromides 4c,f,g,i
and l (yields 78-94%).
1-R-6,8-diaryl-1H-imidazo[1,2-a]pyridin-4-ium Bromides 5c-l. A. Imidazopyridinium bromides 5c-l
were obtained.
B. Imidazopyridinium bromides 5c-g, j were obtained (yields 81-93%).
93

5-(2-Cyanoethyl)-4-hydroxy-2,4-diphenyl-4,5-dihydro-1H-pyrido[1,2-a]benzimidazol-10-ium bromide
(6b) was obtained from salt 2c by method C for the synthesis of products 4. IR spectrum, ν, cm-1: 3100 (OH),
1
3031, 2252 (CN), 1485, 1449, 1136, 1063 (C–O), 750, 702. H NMR spectrum, δ, ppm (J, Hz): 8.32 (1H, d,
3J = 8.0, H-4); 8.22 (1H, d, 3J = 8.0, H-1); 7.94 (1H, s, OH); 7.81 (2H, m, H-2,3); 7.74 (2H, d, 3J = 8.0, H-2',6');
7.57 (2H, d, 3J = 8.0, H-2",6"); 7.47 (6H, m, H-3'-5', H-3"-5"); 6.47 (1H, s, H-8); 5.84 (2H, s, C(6)H2); 4.85 (1H,
m, –CHAHBCN); 4.51 (1H, m, –CHACHBCN); 2.62 (1H, m, NCHAHB–); 2.56 (1H, m, NCHACHB–).
2,4-Bis(4-chlorophenyl)-4-hydroxy-5-phenyl-4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium
Bromide (7j). 1-Phenyl-1H-benzimidazole (0.97 g, 5 mmol) was added to a solution of γ-bromodypnone 1c
(1.31 g, 3.55 mmol) in benzene (50 ml). The mixture was kept at room temperature for a week. The solution was
then heated at 50-60°C for 10 min. The precipitate was filtered off and washed with acetone. IR spectrum,
1
ν, cm-1: 3166 (OH), 3019, 1511, 1474, 1091 (C–O), 747, 661. H NMR spectrum, δ, ppm (J, Hz): 8.70 (1H, d,
4
3J = 8.0, H-4); 8.53 (1H, d, J = 1.5, H-6); 7.88 (3H, m, H-2,2',6'); 7.73 (2H, m, H-3, 9-OH); 7.57 (2H, d,
3J = 8.0, H-3',5'); 7.49-4.41 (5H, m, H-2",6",2"',6"',4"'); 7.33 (2H, m, H-3"',5"'); 7.12 (3H, m, H-1,3",5"); 3.61
(1H, dd, 4J = 1.5, 2J = 18.0, HA-8); 3.37 (1H, d, 2J =18.0, HB-8).
2,4-Bis(4-bromophenyl)-4-hydroxy-5-methyl-4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium
Bromide (7k) was obtained from salt 2 by method C for the synthesis of products 4. IR spectrum, ν, cm-1: 3100
(OH), 3025, 1547, 1482, 1074 (C–O), 1007, 825, 749. 1H NMR spectrum, δ, ppm (J, Hz): 8.57 (1H, d, 3J = 8.0,
H-4), 8.53 (1H, s, H-6), 8.10 (1H, d, 3J = 8.0, H-1), 7.84 (1H, m, H-2), 7.81 (1H, m, H-3), 7.74 (3H, m, H-2',6',
3
9-OH), 7.69 (4H, m, H-3',5',2",6"), 7.62 (2H, d, J = 8.0, H-3",5"), 3.76 (3H, s, CH3), 3.54 (2H, s, CH2).
13C NMR spectrum, δ, ppm: 147.6 (C-9a), 140.8 (C-7), 134.8 (C-1'), 132.9 (C-10a), 132.7 (C-3',5'), 132.4
(C-3",5"), 129.0 (C-3), 128.7 (C-2',6'), 128.3 (C-2",6"), 128.2 (C-4a), 128.1 (C-2), 126.9 (C-1"), 123.1 (C-4'),
123.0 (C-4"), 117.3 (C-6), 114.5 (C-1), 114.3 (C-4), 71.8 (C-9), 42.4 (C-8), 34.4 (CH3).
2,4-Bis(4-bromophenyl)-4-hydroxy-5-phenyl-4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium
Bromide (7m) was made by the method for the synthesis of product 7j, using γ-bromodypnone 1d (1.63 g,
1
3.55 mmol). IR spectrum, ν, cm-1: 3154 (OH), 3025, 1516, 1477, 1077 (C–O), 1007, 816, 750, 694. H NMR
3
3
spectrum, δ, ppm (J, Hz): 8.65 (2H, m, H-4,6), 7.88 (1H, t, J = 8.0, H-2), 7.78 (2H, d, J = 8.0, H-2',6'), 7.72
3
(4H, m, H-3,3',5', 9-OH), 7.48-4.40 (5H, m, H-2",6",2"',6"',4"'), 7.33 (2H, m, H-3"',5"'), 7.28 (2H, d, J = 8.0,
H-3",5"), 7.10 (1H, d, 3J = 8.0, H-1), 3.61 (1H, dd, 4J = 1.5, 2J = 18.0, HA -8), 3.37 (1H, d, 2J = 18.0, HB -8).
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