Dealkylation of quaternary 1-alkylazolo[a]pyridinium salts

Article abstract of DOI:10.1007/s10593-012-0995-1

A convenient method is proposed for the preparation of new derivatives of free heterocyclic bases of imidazo[1,2-a]pyridine, pyrido[1,2-a]benzimidazole, and [1,2,4]triazolo[4,3-a]pyridine series. This method entails the dealkylation of N-(2-cyanoethyl)- or N-benzylazolopyridinium quaternary salts in the presence of bases and reaction with ammonium formate in the presence of Pd/C, respectively.

Full text of DOI:10.1007/s10593-012-0995-1

Chemistry of Heterocyclic Compounds, Vol. 48, No. 2, May, 2012 (Russian Original Vol. 48, No. 2, February, 2012)
DEALKYLATION OF QUATERNARY
1-ALKYLAZOLO[a]PYRIDINIUM SALTS
L. M. Potikha1*, A. R. Turelik1, A. V. Shelepyuk1, and V. A. Kovtunenko1
A convenient method is proposed for the preparation of new derivatives of free heterocyclic bases of
imidazo[1,2-a]pyridine, pyrido[1,2-a]benzimidazole, and [1,2,4]triazolo[4,3-a]pyridine series. This
method entails the dealkylation of N-(2-cyanoethyl)- or N-benzylazolopyridinium quaternary salts in the
presence of bases and reaction with ammonium formate in the presence of Pd/C, respectively.
Keywords: imidazo[1,2-a]pyridine, pyrido[1,2-a]benzimidazole, [1,2,4]triazolo[4,3-a]pyridine, alkylation,
cyclization, dealkylation.
Azolo[a]pyridine series heterocyclic system derivatives hold undiminished interest in the search for new
drugs. For example, the imidazo[1,2-a]pyridine heterocyclic system is the basis for many compounds with high
antiviral [1, 2], antibacterial [3, 4], and antifungal activity [5]. Recently there have been found efficient
-amyloid inhibitors [6, 7] and B2 bradykinin receptor antagonists [8]. Pyrido[1,2-a]benzimidazole derivatives
exhibit anticancer activity [9, 10]. Azolopyridines are used as effective psychotropic drugs, including
derivatives of imidazo[1,2-a]pyridines (hypnotics) [11, 12], and [1,2,4]triazolo[3,4-a]pyridine (antidepressants)
[13]. Quite a few of these compounds have been obtained by chemical modification of their simplest
representatives.
We have previously developed a convenient method for the synthesis of azolo[a]pyridinium quaternary
salts 1, permitting the preparation of derivatives with alkyl, aryl, and hetaryl substituents in the pyridine
fragment of the molecule [14-17]. Taking account of the accumulated experience and the synthetic and
biological significance of free heterocyclic bases 2, we have set as an objective and a final goal of synthesizing
a series of these compounds.
R
R
+
N
N
–
N
R1
N
Br
R
R
1
2
The scheme for the preparation of bromide salts 1 entails two steps: 1) alkylation of 1-R-1,3-diazoles 3
with unsaturated -bromo ketone derivatives 4 and 2) subsequent cyclization of quaternary azolium salts 5-7 by
the action of base. A high yield of the cyclization products of azolium salts 5-7 depends primarily on the nature
_______
*To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Taras Shevchenko Kyiv National University, 64 Volodymyrska St., Kyiv 01033, Ukraine.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 364-376, February, 2012. Original
article submitted June 29, 2010. Revision submitted January 31, 2011.
0009-3122/12/4802-0343©2012 Springer Science+Business Media, Inc.
343

of the heterocycle; the yield is 60-80% for the 1-methyl, 1-ethyl, and 1-benzyl salts [14, 15]. Earlier bromides
8d [16] and 9a [14] were separated in pure state. In contrast to the 1-alkyl derivatives, the 1-(2-cyano-
ethyl)azolo[a]pyridine quaternary salts are unstable upon heating in the presence of base and, under these
conditions, readily lose the cyanoethyl group. Thus, heating salts 8d and 9a in methanol in the presence of
MeONa leads to 6,8-di(2-thienyl)imidazo[1,2-a]pyridine (10d) and 2,4-diphenylpyrido[1,2-a]benzimidazole
1
(11a), as indicated by the lack of cyanoethyl group signals in both the IR and H NMR spectra of the reaction
products (Table 1).
R
R
_
+
N
Br
COR
N
Br
4a–e
COR
N
N
3a–c
CN
CN
5a–d, 6a–e, 7a,b
morpholine
(6e – Et3N)
Ac2O
(5d – morpholine)
morpholine
R
R
+
+
_
_
_
N
+
R
N
N
N
Br
Br
Br
R
N
NC
N
N
NC
R
R
NC
9a–d
12a,b
8a–d
MeONa

R
N
+
N
_
R
NC
H
A
R
R
R
N
N
N
N
N
N
R
N
R
13a,b
R
10a–d
11a–d
N
N
N
N
=
N
N
N
N
N
3a, 5a–d
; 3b, 6a–e
=
; 3c, 7a,b
=
N
N
N
N
4–13 a R = C6H5, b R = 4-ClC6H4, c R = 4-MeOC6H4, d R = 2-thienyl;
6e R = t-Bu
The dealkylation mechanism likely comprises a step of formation the N-ylide structure A by the action
of base, similar to previously described dealkylation reactions of N-ethynylpyridazino[1,6-a]benzimidazolium
salts under similar conditions [18]. Obviously other 1-(2-cyanoethyl)azolium salts of type 5 in the presence of
344

345

346

347

base also may be converted to ylides with localization of the negative charge on carbon atom C-1 of the
cyanoethyl substituent, which may complicate the formation of imidazo[1,2-a]pyridinium bromides 8. Indeed,
heating imidazolium salts 5a-c in the presence of amines such as triethylamine, morpholine, and pyridine leads
to complex mixtures of products, in which the content of 6,8-diaryl-1-(2-cyanoethyl)-1H-imidazo[1,2-a]pyridin-
1
4-ium bromides 8a-c does not exceed 50% as indicated by H NMR spectroscopy. Different conditions
involving heating salts 5a-c in acetic anhydride at reflux were used to obtain bromides 8a-c as pure compounds.
1-(2-Cyanoethyl)benzimidazolium and 1-(2-cyanoethyl)triazolium quaternary salts proved more
resistant to the action of amines. 2,4-Diarylpyrido[1,2-a]benzimidazolium 9a-c and 6,8-diaryl[1,2,4]triazolo-
[4,3-a]pyridinium derivatives 12a,b were obtained in high yields from compounds 6a-c and 7a,b upon heating
in the presence of morpholine (Table 2).
Only two pure azolium quaternary salts were used for carrying out the cyclization, namely, compounds
6a [14] and 7b, while the other salts were used as mixtures. It is interesting to note that cyclization products are
formed upon alkylation of benzimidazole 3b and triazole 3c by bromo ketones 4b,c and 4a, respectively, in
benzene already at room temperature. The amount of these cyclization products only increases upon attempts to
purify salts 6b,c and 7a by recrystallization.
The action of MeONa on 1-(2-cyanoethyl)azolo[a]pyridine bromides 8a-d, 9a-c, 12a,b gave the
corresponding free bases, namely, 6,8-diarylimidazo[1,2-a]pyridines 10a-c, 2,4-diarylpyrido[1,2-a]benzimida-
zoles 11b,c, and 6.8-diaryl[1,2,4]triazolo[4,3-a]pyridines (Table 2).
In previous work [14, 15], we have shown that the conversion of azolium salts 5-7 to azolo[a]pyridines
1 by the action of base proceeds through formation of azolo[a]pyridinium hydroxyl derivatives, whose structure
depends on the structure of the starting compound and the reaction conditions. Dealkylation of these azolium
salts may also occur. Thus, the alkylation of benzimidazole 3b by di(2-thienyl)bromo ketone 4d in benzene at
room temperature gives a 1:1 mixture of salt 6d and 5-(2-cyanoethyl)-4-hydroxy-2,4-di(2-thienyl)-4,5-dihydro-
3H-pyrido[1,2-a]benzimidazol-10-ium bromide (14). Cyclization in this case is initiated by starting
1
benzimidazole 3b. The structure of bromide 14 was established from the H NMR spectrum of the mixture of
compounds 6d and 14 using the pyridine fragment signals characteristic of 3H-4,5-dihydropyrido[1,2-a]benz-
imidazolium derivatives (at positions 1 and 3) [14]. Heating the mixture of compounds 6d and 14 in the
presence of morpholine gave the salt 14 dealkylation product, namely, 2,4-di(2-thienyl)-3,4-dihydropyrido-
[1,2-a]benzimidazol-4-ol (15), instead of the expected 5-(2-cyanoethyl)pyrido[1,2-a]benzimidazolium bromide
9d. The signal for the 3-CH2 group in the 1H NMR spectrum of product 15, as in the case of salt 14, appears as
two doublets, while the signal for H-1 appears as a singlet. The broad singlet at 6.83 ppm, which disappears
upon deuterium exchange following the addition of D2O, was assigned to the OH group, which corresponds to
the broad IR band at 3020 cm-1. It turned out that the dehydration reaction leading to pyridobenzimidazolium
bromide 9b is predominant only in the presence of Et3N: heating a mixture of compounds 6d and 14 in acetone
for 1 h leads to a 9:1 mixture of compounds 9d and 14. Increasing the reaction time in this case leads to the
appearance of dealkylation products in the reaction mixture. Free base 11d was obtained from a mixture of
products 9d and 14 by the same procedure as used for compounds 10a-d and 11a-c by the action of MeONa.
The alkylation of azoles 3a-c using bromo ketone 4e gives the desired product, namely, 3-[(2Z)-2-tert-
butyl-5,5-dimethyl-4-oxohex-2-en-1-yl]-1-(2-cyanoethyl)-1H-benzimidazol-3-ium bromide (6e) in only one
reaction. Upon brief heating with Et3N, bromide 6e is converted into 2,4-di-tert-butyl-5-(2-cyanoethyl)-4-hydroxy-
4,5-dihydro-1H-pyrido[1,2-a]benzimidazol-10-ium bromide (16). Similar to the case of bromide 14, the
predominant direction of the reaction with base is also dealkylation. Bromide 16 was obtained as a pure compound
and its structure was determined from NOE experiments. More prolonged heating of bromide 6e under these
conditions gives a mixture of dealkylation products, namely, a 1:2 mixture of 2,4-di-tert-butyl-3,4-dihydro-
pyrido[1,2-a]benzimidazol-4-ol (17) and 2,4-di-tert-butyl-1,4-dihydropyrido[1,2-a]benzimidazol-4-ol (18). The
use of pyridine, which is a stronger base, leads to a mixture of the same products but with predominant formation
of compound 17 (88%). Obviously, similar to its dithienyl derivative 15, 3,4-dihydro derivative 17 is formed from
3,4-dihydropyridobenzimidazolium quaternary salt 19, which is an analog of bromide 14.
348

TABLE 2. Physicochemical Characteristics and Elemental Analysis Data
Found, %
Calculated, %
Br
——————
Com-
pound
Empirical
formula
Mp, °С
(solvent)
Yield,
%
C
H
Cl
N
5а
С22H20BrN3O
62.50 4.81 18.90
62.57 4.77 18.92
—
9.90
9.95
159-160 (MeNO2)
162-164 (MeNO2)
117-119 (MeNO2)
196-198 (MeNO2)
89
82
87
83
53
81
79
71
83
87
89
92
87
85
5b
5c
С22H18BrCl2N3O 53.69 3.72 16.30 14.41 8.60
53.79 3.69 16.27 14.43 8.55
59.71 5.05 16.57
59.76 5.01 16.56
61.08 7.02 18.51
61.11 6.99 18.48
С24H24BrN3O3
С22H30BrN3O
-
-
8.73
8.71
9.70
9.72
6e
7b
8a
С21H17BrCl2N4O 51.18 3.51 16.25 14.43 11.31 196-197 (MeNO2)
51.24 3.48 16.23 14.41 11.38
65.28 4.50 19.79
65.36 4.49 19.76
55.85 3.39 16.90 14.93 8.83
55.84 3.41 16.89 14.98 8.88
62.02 4.80 17.19
62.08 4.78 17.21
59.60 3.50 15.30 13.51 8.01
59.68 3.47 15.27 13.55 8.03
65.40 4.75 15.50
65.38 4.70 15.53
С22H18BrN3
—
10.33 262-263 (2-PrOH)
10.39
8b
8c
С22H16BrCl2N3
С24H22BrN3O2
С26H18BrCl2N3
С28H24BrN3O2
С19H14N2
303-304 (AcOH)
242-244 (2-PrOH)
360-362 (AcOH)
210-212 (2-PrOH)
—
9.00
9.05
9b
9c
—
8.15
8.17
10a
10b
10c
84.35 4.99
84.42 5.22
67.21 3.60
67.27 3.57
76.29 5.43
76.34 5.49
63.75 3.58
63.80 3.57
—
—
—
—
—
10.40 113-114
10.36 (2-PrOH-H2O, 2:1)
С19H12Cl2N2
С21H18N2O2
20.93 8.24
20.90 8.26
—
166-167 (2-PrOH)
8.47
8.48
9.95
9.92
101-102
(2-PrOH-H2O, 2:1)
120-122
10d* С15H10N2S2
—
(2-PrOH-H2O, 2:1)
172-174 (2-PrOH)
11a
11b
11c
С23H16N2
86.18 5.00
86.22 5.03
70.91 3.60
70.96 3.62
78.87 5.33
78.93 5.30
68.60 3.61
68.64 3.64
—
—
—
—
—
8.76
8.74
93
91
88
83
76
83
92
89
72
78
70
73
58
73
С23H14Cl2N2
С25H20N2O2
18.20 7.25
18.21 7.20
195-196 (2-PrOH)
139-140 (2-PrOH)
138-141 (2-PrOH)
—
—
—
7.33
7.36
8.44
8.43
11d* С19H12N2S2
12a
12b
13a
13b
15*
16
С21H17BrN4
С21H15BrCl2N4
С18H13N3
62.18 4.19 19.75
62.23 4.23 19.72
53.15 3.21 16.80 14.96 11.85 288-289 (2-PrOH)
53.19 3.19 16.85 14.95 11.82
13.80 194-195 (2-PrOH)
13.82
79.62 4.85
79.68 4.83
63.50 3.30
63.55 3.26
65.10 4.05
65.12 4.03
—
—
—
—
15.50 146-147 (2-PrOH)
15.49
С18H11Cl2N3
С19H14N2OS2
С22H30BrN3O
С15H22N2
20.85 12.31 224-225 (2-PrOH)
20.84 12.35
—
—
—
—
8.01
7.99
9.69
9.72
181-191 (2-PrOH)
61.09 7.02 18.50
61.11 6.99 18.48
268-270 (2-PrOH)
22a
23
78.18 9.60
78.21 9.63
81.35 8.60
81.38 8.63
59.15 6.05
59.18 6.07
—
—
—
12.15 114-115
12.16 (2-PrOH-H2O, 2:1)
10.01 121-122
9.99 (2-PrOH-H2O, 2:1)
С19H24N2
24
С9H11ClN2
19.43 15.32 > 190, decomp.
19.41 15.34 (MeNO2)
25
С27H21BrCl2N2O2 58.35 3.60 14.30 12.69 5.05
181-191 (2-PrOH)
58.30 3.81 14.36 12.75 5.04
_______
*Analysis data for sulfur (found/calculated, %): 22.68/22.71 for compound 10d,
19.25/19.29 for compound 11b, and 18.31/18.30 for compound 15.
349

The composition of the mixtures of products 17 and 18 and the structure of the mixture components
were determined using GC/MS (the molecular ion peaks have the same value m/z: 299.2 [M+H]+, but different
1
1
retention times) and H NMR spectroscopy. The position of the H NMR signals for the pyridine ring protons
serves as a criterion for discerning between hydroxy derivatives 17 and 18. In the spectrum of compound 18, as
in the spectrum of salt 16, from which it is formed, the signal for the 1-CH2 group is observed downfield, while
the signal for methine H-3 is observed upfield in comparison with its isomer 17. Products 17 and 18 have
similar chromatographic mobility (Rf = 0.51 for 17 and Rf = 0.45 for 18 using 9:1 benzene–ethanol as the eluent)
and solubility. Thus, we were unable to separate the mixture of these products.
3b + 4d
S
S
S
O
48 h
_
Br
+
N
H
N
N
N
OH
6d
+
N
HO
S
15
NC
14
Bu-t
Bu-t
N
N
N
N
+
Bu-t
Bu-t
HO
HO
18
B:
B:
17
Bu-t
Bu-t
_
_
Br
Br
+
+
Et3N
N
Py
N
6e
Bu-t
Bu-t
N
N
HO
19
HO
16
NC
NC
The observed behavior of pyridobenzimidazolium hydroxy derivatives 14, 16, and 19 in the presence of
bases may arise since deprotonation in the cyanoethyl fragment and, as a consequence, rapid dealkylation
become favored with increasing of electron-donor effect of the substituents at the pyridine cycle.
In a search for alternative methods for the preparation of free azolo[a]pyridine bases from their
quaternary salts, we studied the feasibility of debenzylation of salts of type 1. It was found that upon reaction
with ammonium formate in the presence of Pd/C as a catalyst [19], dialkyl derivatives of 1-benzylimidazo[1,2-a]-
pyridinium bromides 20a,b [17] and the di-tert-butyl derivative of 5-benzylpyrido[1,2-a]benzimidazolium
bromide 21 [17] are converted in good yield to the corresponding free bases 22a,b and 23. Free base 22b could
not be separated from impurities but its salt, namely, 6,8-dimethyl-1H-imidazo[1,2-a]pyridin-4-ium chloride
(24), was obtained as a pure product.
The phenacyl group can also be used as a protective alkyl group in the synthesis of imidazole
derivatives. However, this approach has not proved fully successful. 3-[(2Z)-2,4-Bis(4-chlorophenyl)-4-oxobut-
2-en-1-yl]-1-(2-oxo-2-phenylethyl)-1H-imidazol-3-ium bromide (25), obtained by a general method [14], cyclizes
in the presence of morpholine to give 6,8-bis(4-chlorophenyl-1-(2-oxo-2-phenylethyl)-1H-imidazo[1,2-a]-
pyridin-4-ium bromide (26), which proved unstable upon heating and could not be purified by recrystallization.
Dealkylation of salt 26 using the method of Kim et al. [20] leads to base 10b.
350

+
Me
_
+
R
_
R
HCO2NH4
Pd/C
N
N
N
HCl
Cl
Br
N
N
N
H
Me
R
20a,b
R
22a,b
Ph
24
Bu-t
Bu-t
+
_
N
HCO2NH4
Pd/C
N
Br
Bu-t
N
Bu-t
N
21
23
Ph
R
+
+
N
Morpholine
R
4b
Zn, AcOH
Ultrasound
N
N
10b
N
N
N
COR
_
O
O
_
Br
O
R
Br
Ph
Ph
Ph
25
26
20, 22 a R = t-Bu, b R = Me; 25, 26 R = 4-ClC6H4
Thus, we propose a convenient method for the preparation of new heterocyclic products, namely free
imidazo[1,2-a]pyridine, pyrido[1,2-a]benzimidazole, and [1,2,4]triazolo[4,3-a]pyridine bases by means of the
dealkylation of azolo[a[pyridinium salts. The most efficient method for the preparation of diaryl and di(2-thienyl)
derivatives of azolo[a]pyridines is decyanoethylation of the indicated quaternary salts upon heating with base,
while the most efficient method for the preparation of dialkylazolo[a]pyridines is debenzylation using
ammonium formate in the presence of Pd/C.
EXPERIMENTAL
1
The IR spectra were recorded on a Perkin Elmer BX spectrometer using KBr pellets. The H NMR
spectra were recorded on a Bruker Avance DRX-500 spectrometer at 500 MHz. The NOESY experiments
(mixing time 200 msec) were carried out on a Mercury Varian 400 spectrometer (400 MHz) in DMSO-d6 with
TMS as internal standard. The purity of the products was monitored by LC/MS on an Agilent 1100
chromatograph using an Agilent LC/MSD SL selective detector (the sample was introduced in a CF3CO2H matrix,
electron impact ionization). Ultrasonic irradation was carried out in an Intersonic device (25 kHz  5%). The
elemental analyses were carried out on a universal Vario MICRO Cube CHNS analyzer. The Schoniger method
was used for determination of halogen atoms. Commercial samples of 3-azolylpropanonitriles 3a-c and 2-(1H-imid-
azol-1-yl)-1-phenylethanone obtained from Enamine were used. (Z)-4-Bromo-1,3-diphenyl-2-buten-1-one (4a)
was obtained according to Wasserman [21], while our previous procedures were used to obtain (Z)-4-bromo-
1,3-diaryl-2-buten-1-ones 4b,c [22] and (Z)-4-bromo-1,3-di(2-thienyl)-2-buten-1-one (4d) [16]. (4Z)-5-(Bromo-
methyl)-2,2,6,6-tetramethylhept-4-en-3-one (4e) was obtained according to van Tamelen and Whitesides
[23].
3-(2-Cyanoethyl)-1-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]-1H-imidazol-3-ium Bromides 5a-c, 3-(2-
Cyanoethyl)-1-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]-1H-benzimidazol-3-ium Bromides 6b,c, and 1-(2-Cyano-
ethyl)-4-[(2Z)-2,4-diaryl-4-oxobut-2-en-1-yl]-1H-1,2,4-triazol-4-ium Bromides 7a,b (General Method).
Diazole 3a-c (3.55 mmol) was added to a solution of -bromodipnone 4a-c (3.55 mmol) in benzene (30 ml). The
mixture was maintained for 24-48 h at room temperature. The precipitate formed was filtered off, washed
351

with acetone, and recrystallized from nitromethane. Salts 6b,c and 7a were obtained as mixtures containing the
starting diazole and the cyclization product: 6b + 3b (20%), 6c + 3b (<10%) + 9c (<10%), 7a + 3c (20%) + 12a
(<10%).
3-[(2Z)-2-tert-Butyl-5,5-dimethyl-4-oxohex-2-en-1-yl]-1-(2-cyanoethyl)-1H-benzimidazol-3-ium
bromide (6e) was obtained by the method for the synthesis of products 5a-c using 3-(1H-benzimidazol-1-yl)-
propanonitrile (3b) and (4Z)-5-(bromomethyl)-2,2,6,6-tetramethylhept-4-en-3-one (4e).
6,8-Diaryl-1-(2-cyanoethyl)-1H-imidazo[1,2-a]pyridin-4-ium Bromides 8a-c (General Method).
1-(2-Cyanoethyl)imidazolium salt 5a-c (3.00 mmol) was dissolved in acetic anhydride (40 ml) and heated at
reflux for 1 h. The solvent was evaporated at reduced pressure. The residue was dissolved with heating in
acetone (25 ml) and heated at reflux for 10 min. The solvent was evaporated at reduced pressure to 50-70%
original volume. After cooling, the precipitate formed was filtered off.
2,4-Diaryl-5-(2-cyanoethyl)-5H-pyrido[1,2-a]benzimidazol-10-ium Bromides 9b,c and 6,8-Diaryl-
1-(2-cyanoethyl)-1H-[1,2,4]triazolo[4,3-a]pyridin-4-ium Bromides 12a,b (General Method). A mixture of
benzimidazolium salt 6b,c or triazolium salt 7a,b (2.30 mmol) and morpholine (4 ml) in acetone (25 ml) was
heated for 2 h. After cooling, the precipitate formed was filtered off and washed with acetone.
6,8-Diarylimidazo[1,2-a]pyridines 10a-c (General Method). A. Salt 5a-c (2 mmol) was added to a
solution of MeONa (0.16 g, 3 mmol) in methanol (20 ml) and dissolved without heating. The resultant solution
was maintained at 25C for 30 min and, then, water (40 ml) was added. The precipitate formed was filtered off
and washed with water.
B. Imidazolium bromide 25 (1.11 g, 2 mmol) was dissolved in ethanol (20 ml). Then, morpholine
(3 ml) was added and the solution was heated at reflux for 1 h. The solvent was evaporated and the residue was
washed with acetone to give a mixture containing 80% 6,8-bis(4-chlorophenyl)-1-(2-oxo-2-phenylethyl)-
1H-imidazo[1,2-a]pyridin-4-ium bromide (26), which was dissolved in 1:1 methanol–acetic acid mixture
(15 ml). Then, zinc powder (2.8 g) was added. The mixture obtained was subjected to ultrasonic irradiation for
3 h. The mixture was stirred for an additional 1 h at 25C. Zinc was filtered off and water (20 ml) was added.
Pyridine derivative 10b was extracted from the solution using benzene. The solvent was evaporated and 2-propanol
(20 ml) was added to the residue. The precipitate was filtered off. Yield 0.22 g (32%).
6,8-Di-(2-thienyl)imidazo[1,2-a]pyridine (10d) was obtained according to method A for synthesis of
products 10a-c using salt 5d [16].
2,4-Diarylpyrido[1,2-a]benzimidazoles 11b,c and 6,8-diaryl[1,2,4]triazolo[4,3-a]pyridines 13a,b
were obtained according to method A for the synthesis of products 10a-c using salts 9b,c and 12a,b.
2,4-Di-(2-thienyl)pyrido[1,2-a]benzimidazole (11d). 3-(1H-Benzimidazol-1-yl)propanonitrile (3b)
(0.61 g, 3.55 mmol) was added to a solution of (2Z)-4-bromo-1,3-di(2-thienyl)but-2-en-1-one (4d) (1.11 g, 3.55
mmol) in benzene (30 ml). The mixture was maintained for 48 h at room temperature. The precipitate formed
was filtered off and washed with acetone to give a 1:1 mixture of 3-(2-cyanoethyl)-1-[(2E)-4-oxo-2,4-di(2-
thienyl)but-2-en-1-yl]-1H-benzimidazol-3-ium bromide (6d) and 5-(2-cyanoethyl)-4-hydroxy-2,4-di(2-thienyl)-
4,5-dihydro-3H-pyrido[1,2-a]benzimidazol-10-ium bromide (14). Then, acetone (20 ml) and Et3N (3 ml) were
added and the mixture was heated at reflux for 1 h. The solvent was evaporated. The residue was washed with
acetone to give a 9:1 mixture of 5-(2-cyanoethyl)-2,4-di(2-thienyl)-5H-pyrido[1,2-a]benzimidazol-10-ium
bromide (9d) and salt 14. Then, method A for the synthesis of products 10a-c was used.
2,4-Di-(2-thienyl)-3,4-dihyropyrido[1,2-a]benzimidazol-4-ol (15). Methanol (25 ml) and morpholine
(4 ml) were added to a 1:1 mixture of 6d and 14 (1g) and the resultant solution was heated for 2 h. After
cooling, the precipitate formed was filtered off and washed with acetone.
2,4-Di-tert-butyl-5-(2-cyanoethyl)-4-hydroxy-4,5-dihydro-1H-pyrido[1,2-a]benzimidazol-10-ium
Bromide (16). A mixture of benzimidazolium salt 6e (1 g, 2.31 mmol) and Et3N (4 ml) in acetone (25 ml) was
heated for 45 min. After cooling, the precipitate formed was filtered off and washed with acetone.
352

2,4-Di-tert-butyl-3,4-dihydropyrido[1,2-a]benzimidazol-4-ol (17) and 2,4-Di-tert-butyl-1,4-dihydro-
pyrido[1,2-a]benzimidazol-4-ol (18). A. These products were prepared according to the procedure for the
synthesis of product 16 from salt 6e. The reaction mixture was heated for 2 h to give a 1:2 mixture of products
17 and 18.
B. Benzimidazolium salt 6e (1 g, 2.31 mmol) was dissolved in pyridine (20 ml) and heated at reflux for
1 h. The solvent was evaporated at reduced pressure. Then, water(30 ml) was added to the residue. The
precipitate formed was filtered off and washed with water and 2-propanol to give a mixture of compounds 17
and 18 containing 88% compound 17.
6,8-Di-tert-butylimidazo[1,2-a]pyridine (22a). A suspension of imidazopyridinium bromide 20a [17]
(0.16 g, 0.40 mmol), ammonium formate (15 g, 0.24 mol), and 10% Pd/C (0.12 g) in methanol (40 ml) was
heated for 2 h. After cooling, the precipitate formed was filtered off and the solvent was evaporated. Then,
water (50 ml) was added and the mixture was extracted with chloroform (2×50 ml). The organic phase was
dried over sodium sulfate. The precipitate was filtered off and the solvent was evaporated. The residue was
recrystallized from 2-propanol.
2,4-Di-tert-butylpyrido[1,2-a]benzimidazole (23) was obtained according to the procedure for the
synthesis of product 22a using 5-benzyl-2,4-di-tert-butyl-5H-pyrido[1,2-a]benzimidazol-10-ium bromide 21
[17]. Adding water to the oily residue gave a precipitate, which was filtered off and washed with water and
2-propanol.
6,8-Dimethyl-1H-imidazo[1,2-a]pyridin-4-ium Chloride (24) was obtained according to the
procedure for the synthesis of product 22a using imidazopyridinium bromide 20b [17]. 6,8-Dimethylimidazo-
[1,2-a]pyridine (22b) was isolated as an oil containing 20% impurities. This crude product was dissolved in
2-propanol and concentrated hydrochloric acid (2 ml) was added. The precipitate formed was filtered off and
washed with 2-propanol.
3-[(2Z)-2,4-Bis(4-chlorophenyl)-4-oxobut-2-en-1-yl]-1-(2-oxo-2-phenylethyl)-1H-imidazol-3-ium
Bromide (25). -Bromodipnone 4b (1.31 g, 3.55 mmol) was added to a solution of 2-(1H-imidazol-1-yl)-
1-phenylethanone (0.65 g, 3.50 mmol) in benzene (40 ml). The mixture was maintained for 3 h and the
precipitate formed of salt 25 was filtered off.
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