Condensed isoquinolines. 38*.. Azolo[b]isoquinolines from 2-(halomethyl)benzoic acid derivatives

Article abstract of DOI:10.1007/s10593-011-0866-1

On interacting 2-(chloromethyl)-, 2-(bromomethyl)benzonitrile or methyl 2-(bromomethyl)benzoate with 1-R-1H-imidazoles and 1-R-1H-benzimidazoles quaternary diazolium salts are formed, the heating of which with bases (K ₂CO₃, Et₃

Full text of DOI:10.1007/s10593-011-0866-1

Chemistry of Heterocyclic Compounds, Vol. 47, No. 8, November, 2011 (Russian Original Vol. 47, No. 8, August, 2011)
CONDENSED ISOQUINOLINES. 38*. AZOLO[b]ISOQUINOLINES
FROM 2-(HALOMETHYL)BENZOIC ACID DERIVATIVES
V. A. Kovtunenko1, L. M. Potikha1**, V. V. Sypchenko1,
A. I. Dmukhovsky1, and A. V. Shelepyuk1
On interacting 2-(chloromethyl)-, 2-(bromomethyl)benzonitrile or methyl 2-(bromomethyl)benzoate with
1-R-1H-imidazoles and 1-R-1H-benzimidazoles quaternary diazolium salts are formed, the heating of
which with bases (K2CO3, Et3N) led to the intramolecular acylation products, 1-alkyl-10-amino-
1H-imidazo[1,2-b]isoquinolin-4-ium halides, 5-alkyl-6-amino-5H-benzimidazo[1,2-b]isoquinolin-12-ium
halides, or 1-alkyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate halides.
Keywords: benzimidazo[1,2-b]isoquinoline, 2-(bromomethyl)benzoate, 2-(bromomethyl)benzonitrile,
imidazo[1,2-b]isoquinoline, cyclization.
Construction of an isoquinoline fragment for the synthesis of condensed derivatives of 3-amino-
isoquinoline as a method of forming the tricyclic azolo[b]isoquinoline system is rarely used [2, 3]. Among the
known methods of constructing these heterosystems in only two variants the key stage of cyclization is the
formation of the C(3)–C(4) bond of the isoquinoline ring. One of them consists of the condensation of phthaloyl
dichloride with benzimidazole in the presence of base [4], and the second, a more general method developed by
us, is based on the cyclization of quaternary azolium salts formed on interacting o-bromomethyl-benzophenones
with 1,3-diazoles [5]. The present work, in the indicated scheme of synthesis of azolo-[b]isoquinolines, uses
derivatives of o-toluic acid, viz. 2-(chloromethyl)benzonitrile (1b), 2-(bromomethyl)-benzonitrile (1a), and
methyl 2-(bromomethyl)benzoate (8). The latter is frequently used in various hetero-cyclizations, including
those for obtaining isoquinoline derivatives [6-9], while nitriles 1a,b are rarely used for this purpose and the
schemes for converting them are more complex [10-13]. The relatively simple method of synthesis of
azolo[b]isoquinolines proposed by us enables the preparation of their previously unavailable amino and hydroxy
derivatives.
On interacting halo nitriles 1a,b with 1-alkyl-1H-imidazoles, 1-alkyl-1H-benzimidazoles, or 1-methyl-
1H-1,2,4-triazole, quaternary azolium salts 2a-e, 3a,b, and 4 were formed respectively. Salts 2a-c were obtained
in high yield (Table 1) on moderate heating (to 50oC) of the reactants in acetonitrile.
_______
*For Communication 37, see [1].
**To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
Taras Shevchenko Kyiv National University, 64 Volodymyrska St., Kyiv 01601, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1212-1222, August, 2011.
Original article submitted February 19, 2011.
996
0009-3122/11/4708-0996©2011 Springer Science+Business Media, Inc.

_
Hal
_
NC
Hal
+
N
K2CO3
+
N
N
R
N
NH2
5a,b,e
R
2a–e
_
NC
_
Hal
CN
Br
Br
+
+
Et3N
N
N
N
N
R
NH2
1a,b
R
3a,b
6a,b
NC
_
_
Br
Br
+
N
+
N
Et3N
N
N
N
N
Me
NH2
4
Me
7
1 a Hal = Br, b Hal = Cl; 2a–c, 5a,b Hal = Br, 2d,e, 5e Hal = Cl;
2, 5 a,d R = Me, b,e R = Et, c = Bn; 3,6 a R = Me, b R = Et
With benzimidazole derivatives and 1,2,4-triazole under these conditions, the reaction proceeded more
slowly and led to products 3a,b and 4 in lower yield, increasing which may be achieved by fusing the reactants
(110oC, 5-10 min). The nature of the halogen in the starting halo nitrile did not prove to have a significant effect
on the rate and yield of alkylation product, but in difference to bromides 2a-c, chlorides 2d,e proved to be
hygroscopic compounds, which complicated both the preparation of analytical samples of them and further
conversion into cyclic products. The nature of the anion affected the spectral properties of imidazolium salts
2a,d and 2b,e insignificantly. The greatest marked changes in the spectral picture of chlorides 2d,e, in
comparison with bromides 2a,b were the shift of 0.25-0.27 ppm of the H-2 proton signal in the 1H NMR spectra
towards low field (Table 2), and the high-frequency shift of the band of the stretching vibrations CN by 5 cm-1
in the IR spectra (Table 3). This is caused by the changes in the spatial localization of the anion and the degree
of bonding of it with the cation.
Examples are known of intramolecular cyclization of quaternary salts of 1,3-diazoles at position 2 with
the participation of nitrile [14, 15] or ester [16] groups, such as the intramolecular acylation of derivatives of
α-methylsulfonylacetonitrile or malononitrile on heating in DMF in the absence of a basic catalyst. Conversion
of diazolium salts 2-4 under such conditions does not occur, although cyclization does take place, but only on
heating in the presence of base (K2CO3 or Et3N). We note that a significant role is played by the quality of the
solvent, cyclization products are formed in good yield and with a high degree of purity only on using anhydrous
DMF. 1-Alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium bromides 5a,b are obtained on using potassium
carbonate. On heating 1-benzylimidazolium bromide 2c with base a complex mixture of reaction products is
formed which we link with the effect of the substituent at the N(1) atom. The cyclization product of chlorides
2d,e was isolated under the same conditions in only one case. 1-Ethyl-1H-imidazo[1,2-b]isoquinolinium
chloride (5e) was obtained on using salt 2e, which is less hygroscopic than 2d. The use of Et3N on cyclizing
imidazolium salts 2 leads to a significant increase in reaction time, a reduction in the yield of the desired
997

TABLE 1. Physicochemical Characteristics of Compounds 2-6, 9, and 10
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C*
Yield, %
C
H
Hal
N
2а
С12H12BrN3
51.78
51.82
4.30
4.35
28.76
28.73
15.14
15.11
183-185
89
2b
С13H14BrN3
С18H16BrN3
С16H14BrN3
С17H16BrN3
С11H11BrN4
С12H12BrN3
С13H14BrN3
С13H14ClN3
С16H14BrN3
С17H16BrN3
С13H15BrN2O2
С12H10N2O
С18H14N2O
53.37
53.44
4.86
4.83
27.38
27.35
14.35
14.38
78-80
82
78
80
76
70
51
49
25*2
53
50
92
32
35
2c
61.09
61.03
4.50
4.55
22.53
22.56
11.87
11.86
186-187
251-252
223-224
129-130
3a
58.60
58.55
4.32
4.30
24.31
24.35
12.78
12.80
3b
59.70
59.66
4.69
4.71
23.37
23.35
12.30
12.28
4
47.38
47.33
4.00
3.97
28.62
28.63
20.06
20.07
5a
51.80
51.82
4.37
4.35
28.75
28.73
15.09
15.11
270-273
(decomp.)
5b
53.49
53.44
4.86
4.83
27.31
27.35
14.39
14.38
145-148
(decomp.)
5е
62.99
63.03
5.72
5.70
14.30
14.31
16.98
16.96
251-254
(decomp.)
6a
6b
58.60
58.55
4.31
4.30
24.38
24.35
12.79
12.80
312-315
(decomp.)
59.70
59.66
4.74
4.71
23.32
23.35
12.30
12.28
309-311
(decomp.)
9a
50.21
50.18
4.85
4.86
25.69
25.68
9.01
9.00
150-152
> 300
(decomp.)
10a
72.66
72.71
5.10
5.08
—
14.17
14.13
10b
79.00
78.81
5.12
5.14
—
10.27
10.21
> 250
(decomp.)
_______
*Solvents: MeCN (compounds 2a-c, 3a,b, 4, 9a) and DMF (compounds
5a,b,e, 6a,b, and 10b).
*2Yield is given from calculation on the starting chloro nitrile 1b.
products, and accumulation of side products in the reaction mixture. At the same time in the case of
benzimidazolium salts 3a,b the use of the indicated base was preferred, the yields of 5-alkyl-6-amino-5H-benz-
imidazo[1,2-b]isoquinolin-12-ium bromides 6a,b were greater when using Et3N than with potassium carbonate.
Cyclization of 1,2,4-triazolium salt 4 was accompanied by the formation of a large quantity of side products.
The presence of 10-amino-1-methyl-1H-[1,2,4]triazolo[4,3-b]isoquinolin-4-ium bromide (7) in the reaction
mixture was successfully recorded by 1H NMR on brief heating of salt 4 in the presence of Et3N. The structures
of the amino derivatives of azolo[b]isoquinolines 5-7 were established on the basis of their spectral data. The
1
signal of the primary amino group in the H NMR spectra of salts 5-7 was observed at 6.7-7.3 ppm as a two-
proton singlet exchanging with D2O, and in the IR spectra two stretching vibrational absorption bands at
3354-3307 (as) and 3307-3209 (s) cm-1 correspond to this group. The formation of the aromatic system of
azolo[b]isoquinoline is shown by the presence in their 1H NMR spectra of a one-proton singlet at 10.5-9.1 ppm
at low field, assigned to the H-5 proton signal (for salts 5 and 7) or H-11 (for salts 6) on the basis of the data of
the NOESY experiment carried out for compound 5a (Fig. 1).
998

The structure of the azolo[b]isoquinolinium salts 5b and 6a,b was confirmed by data of UV spectra. The
shape of the absorption curve in the long-wave region corresponded to their 10-aryl- and 6-aryl-substituted
analogs obtained previously [5] (Fig. 2), and the observed bathochromic shift of the absorption maxima (by
~10-20 nm) into the long-wave region agreed with the presence of a more donating NH2 group in the
chromophor.
9.08
8.42
H
H
H 8.38
+
N
H
7.51
H
8.23
7.51
H
N
H3C
NH2
H
7.90
6.78
4.45
Fig. 1. Structurally important NOESY correlations for compound 5a cation.
Fig. 2. Absorption spectra (in MeOH) of 10-(4-chlorophenyl)-1-methyl-1H-imidazo[1,2-b]isoquinolin-4-ium
bromide [5] (1), 6-(4-chlorophenyl)-5-methyl-5H-[3,1]benzimidazo[1,2-b]isoquinolin-12-ium bromide [5] (2),
10-amino-1-ethyl-1H-imidazo[1,2-b]isoquinolin-4-ium bromide (5b) (3), and 6-amino-5-methyl-5H-[3,1]benz-
imidazo[1,2-b]isoquinolin-12-ium bromide (6a) (4).
The sequence of conversions which leads to azolo[b]isoquinoline derivatives may also be carried out
using o-bromomethylbenzoic acid ester 8. On interacting ester 8 with 1-alkylimidazoles in MeCN at room
temperature the corresponding 1-alkyl-3-[2-(methoxycarbonyl)benzyl]-1H-imidazol-3-ium bromides 9a,b were
formed. Compound 9 was isolated in a pure state but salt 9b contained a mixture of products of further
conversions.
999

MeO2C
Br
_
Br
+
N
K2CO3
+
N
N
_
O
R
CO2Me
N
8
9a,b
10a,b
R
a R = Me, b R = Bn
On heating imidazolium bromides 9a,b with bases an intramolecular cyclization occurred with the
formation of derivatives of imidazo[1,2-b]isoquinoline, the structure of which depended on the reaction
conditions. Boiling the reaction mixture for 3 h in ethanol in the presence of potassium carbonate led to 1-alkyl-
1H-imidazo[1,2-b]isoquinolin-4-ium-10-olates 10a,b, difficultly soluble compounds having a deeper color
(orange) than the corresponding amino derivatives 5-7 (yellow). The betaine structure of the cyclization
products 10a,b was established on the basis of data of elemental analysis and spectral characteristics. In
1
particular, in the H NMR spectra all the signals of the aromatic protons of the imidazo[1,2-b]isoquinoline
tricycle were shifted towards high field, and in the IR spectra there were no bands at  > 3100 cm-1. However a
strong band was observed at 1477 cm-1, characteristic of the vibrations of a carboxyl group anion (Table 3). The
structure of compound 10b was also confirmed by UV spectral data, taken in methanol in the presence of NaOH
and HCl. An increase of base did not affect the position of maxima and the shape of the absorption curve, while
in the presence of acid (HCl) a hypsochromic shift of 35 nm was observed for the long-wave maximum
(λ = 445 nm), which is the result of forming a protonated form of type 11. It is known that isoquinolinium salts
readily add nucleophiles at position 1 [17]. Since in the case of azolo[b]isoquinolinium salts the C(5) atom is in
such a position [18], the formation of a protonated form of type 11 assists the progress of such a reaction.
+H
N
N
+
H
N
_
+H
Bn
X
O
N
H
H+
10b
N
N
N
[O]
_
_
Bn
Bn
2X
O
N
OH
11
X
+
H
N
Bn
OH
H+
12 (I = 10%)
10b
N
H+
Bn
OH
+H
N
+H
N
10b
[O]
N
N
14 (I = 40%)
_
Bn
Bn
X
O
O
O
H
H+
N
N
N
N
X = CF3CO2
_
_
Bn
Bn
O
15 (I = 100%)
13
This was confirmed by the mass spectral data of compound 10b, recorded by the GLC method (the low
solubility of methyl derivative 10a did not enable its qualitative mass spectrum to be obtained) on introducing
the sample in CF3CO2H solution. In its spectrum signals were observed for cations with an m/z value
1000

TABLE 2. Data of 1H NMR Spectra of Compounds 2-7, 9, 10
Chemical shifts (DMСО-d6), , ppm (J, Hz)
Protons at С-sp2 Protons at С-sp3
Com-
pound
NH2
4
1
2
3
2a
9.51 (1Н, s, Н-2);
5.76 (2Н, s, 3-СН2);
3.97 (3Н, s, 1-СН3)
—
—
—
7.90 (1Н, d, 3J = 7.8, Н-3');
7.87 (1Н, s, Н-4); 7.79 (1Н, s, Н-5);
7.75 (1Н, t, 3J = 8.0, Н-5');
7.65 (1Н, d, 3J = 8.0, Н-6');
7.60 (1Н, t, 3J = 8.0, Н-4')
2b
9.61 (1Н, s, Н-2); 7.96 (1Н, s, Н-4);
7.86 (1Н, d, 3J = 7.8, Н-3');
7.77 (1Н, s, Н-5);
5.75 (2Н, s, 3-СН2) ;
4.31 (2Н, q, 3J = 7.2, 1-CH2);
1.50 (3Н, t, 3J = 7.2, СН3)
7.75 (1Н, t, 3J = 8.0, Н-5');
7. 66 (1Н, d, 3J = 8.0, Н-6');
7.60 (1Н, t, 3J = 8.0, Н-4')
2с
9.75 (1Н, s, Н-2); 7.94 (1Н, s, Н-4);
7.86 (1Н, d, 3J = 8.0, Н-3');
7.81 (1Н, s, Н-5);
5.77 (2Н, s, 3-СН2);
5.55 (2Н, s, 1-СН2)
7.76 (1Н, t, 3J = 8.0, Н-5');
7. 69 (1Н, d, 3J = 8.0, Н-6');
7.61 (1Н, t, 3J = 8.0, Н-4');
7.52 (2Н, d, 3J = 7.0, Н-2'',6'');
7.38 (3Н, m, Н-3''–Н-5'')
2d*
2e*
9.78 (1Н, s, Н-2); 7.87 (1Н, s, Н-4);
7.83 (1Н, d, 3J = 7.8, Н-3');
.76 (3Н, m, Н-5,5',6'); 7.58 (1Н, m, Н-4')
5.80 (2Н, s, 3-СН2);
3.99 (3Н, s, 1-СН3)
—
—
9.86 (1Н, s, Н-2); 7.97 (1Н, s, Н-4);
7.86 (1Н, d, 3J = 7.8, Н-3');
7.78 (1Н, s, Н-5);
5.78 (2Н, s, 3-СН2);
4.32 (2Н, q, 3J = 7.2, 1-CH2);
1.51 (3Н, t, 3J = 7.2, СН3)
7.75 (1Н, t, 3J = 8.0, Н-5');
7. 70 (1Н, d, 3J = 8.0, Н-6');
7.60 (1Н, t, 3J = 8.0, Н-4')
6.07 (2Н, s, 3-СН2); 4.20
(3Н, s, 1-СН3)
3a
10.09 (1Н, s, Н-2);
—
8.08 (1Н, d, 3J = 8.0,
Н-4); 7.89 (1Н, d, 3J = 8.0, Н-7);
7.86 (1Н, d, 3J = 7.8, Н-3');
7.73–7.57 (5Н, m, Н-5,6, Н-4'–Н-6')
3b
4
10.34 (1Н, s, Н-2);
6.10 (2Н, s, 3-СН2);
—
—
8.14 (1Н, d, 3J = 8.0, Н-4);
7.86 (1Н, d, 3J = 7.8, Н-3');
7.82 (1Н, d, 3J = 8.0, Н-7);
7.72–7.57 (5Н, m, Н-5,6, Н-4'–Н-6')
4.66 (2Н, q, 3J = 7.2, 1-CH2);
1.64 (3Н, t, 3J = 7.2, СН3)
10.42 (1Н, s, Н-5); 9.36 (1Н, s, Н-3);
7.88 (1Н, d, 3J = 7.8, Н-3');
7.77 (1Н, t, 3J = 8.0, Н-5');
7.72 (1Н, d, 3J = 8.0, Н-6');
7.62 (1Н, t, 3J = 8.0, Н-4')
5.86 (2Н, s, 4-СН2);
4.13 (3Н, s, 1-СН3)
5a
9.08 (1Н, s, Н-5), 8.42 (1Н, m, Н-6);
8.38 (1Н, d, 3J = 1.6, Н-3);
4.45 (3Н, s, 1-СН3)
6.78
(2Н, s)
8.23 (1Н, d, 3J = 1.6, Н-2);
4.89 (2Н, q, 3J = 7.0, 1-CH2);
1.47 (3Н, t, 3J = 7.0, СН3)
5b
5e
9.20 (1Н, s, Н-5); 8.48 (2Н, m, Н-3,6);
8.36 (1Н, s, Н-2); 7.91 (1Н, m, Н-9);
7.52 (2Н, m, Н-7,8)
6.81
(2Н, s)
9.15 (1Н, s, Н-5); 8.52 (1Н, m, Н-6);
8.45 (1Н, br. s, Н-3); 8.32 (1Н, br. s, Н-2);
7.92 (1Н, m, Н-9); 7.53 (2Н, m, Н-7,8)
4.89 (2Н, q, 3J = 7.0, 1-CH2);
1.47 (3Н, t, 3J = 7.0, СН3)
6.91
(2Н, s)
1001

TABLE 2 (continued)
1
2
3
4
6a
10.54 (1Н, s, Н-11); 8.76 (1Н, m, Н-1);
8.58 (1Н, m, Н-10); 8.18 (1Н, m, Н-7);
8.06 (1Н, m, Н-4);
4.54 (3Н, s, СН3)
6.98
(2Н, s)
7.90 (1Н, t, 3J = 8.0, Н-3);
7.73 (1Н, t, 3J = 8.0, Н-2);
7.67 (2Н, m, Н-8,9)
6b
10.12 (1Н, s, Н-11); 8.77 (1Н, m, Н-1);
8.61 (1Н, m, Н-10); 8.18 (1Н, m, Н-7);
8.06 (1Н, m, Н-4); 7.85 (1Н, t, 3J = 8.0,
Н-3); 7.72–7.69 (3Н, m, H-2,8,9)
5.07 (2Н, q, 3J = 7.0, CH2);
1.45 (3Н, t, 3J = 7.0, СН3)
6.86
(2Н, s)
7*2
9a
9.91 (1Н, s, Н-5); 9.21 (1Н, s, Н-3);
8.52 (1Н, d, 3J = 8.0, Н-6);
8.02 (1Н, d, 3J = 8.0, Н-9);
7.57 (2Н, m, Н-7,8)
4.62 (3Н, s, СН3)
7.23
(2Н, s)
9.23 (1Н, s, Н-2);
5.76 (2Н, s, 3-СН2);
3.90 (3Н, s, 1-СН3);
3.88 (3Н, s, ОСН3)
—
—
8.02 (1Н, d, 3J = 8.0, Н-3');
7.80 (1Н, s, Н-4); 7.78 (1Н, s, Н-5);
7.70 (1Н, t, 3J = 8.0, Н-5');
7.58 (1Н, t, 3J = 8.0, Н-4');
7.41 (1Н, d, 3J = 8.0, Н-6')
9b*3
9.54 (1Н, s, Н-2);
5.79 (2Н, s, 3-СН2);
5.55 (2Н, s, 1-СН2);
3.84 (3Н, s, ОСН3)
8.00 (1Н, br. d, 3J = 7.8, Н-3');
7.96 (1Н, s, Н-4); 7.80 (1Н, s, Н-5);
7.70 (1Н, t, 3J = 8.0, Н-5');
7.59 (1Н, t, J = 8.0, Н-4');
7.49-7.36 (6Н, m, Н-6', Н-2''–Н-6'')
10a
10b
8.31 (1Н, d, 3J = 8.0, Н-6);
7.95 (1Н, s, Н-5);
4.45 (3Н, s, СН3)
—
—
7.16-7.03 (4Н, m, Н-2,3,8,7);
6.74 (1Н, d, 3J = 8.0, Н-9)
8.36 (1Н, d, 3J = 8.0, Н-6);
7.93 (1Н, s, Н-5); ');
6.23 (2Н, s, 1-СН2)
7.37 (3Н, m, Н-3,3',5'); 7.30 (1Н, m, Н-4');
7.25 (1Н, s, Н-2);
7.18 (1Н, t, 3J = 8.0, Н-8);
7.09 (1Н, t, 3J = 8.0, Н-7);
6.76 (1Н, d, 3J = 8.0, Н-9)
_______
*Spectra of hydrates of 2d and 2e are given.
*2Mixture of compounds 4 and 7, 18% content of salt 7.
*3Spectrum of a mixture containing 85% salt 9b.
corresponding to the dimerization product, but the signal for the protonated form of the starting compound 11
was absent. Dimerization may be effected in two ways, with the participation of the protonated form of 11 and
the formation of compound 12, to which the low intensity signal (10%) in the spectrum corresponds, or without
its participation with the formation of dimer 13. Oxidation of compound 12 leads to salt 14, to which the signal
with Irel = 40% corresponds, and oxidation of compound 13 leads to salt 15 with a signal of intensity 100%.
Further conversions of salts 12 and 14 may also lead to the most stable product 15. In the spectrum of compound
10b low intensity signals are observed for the products of cleavage of substituents at atoms N(1) and N(1') in a
type 15 dimer.
1002

TABLE 3. Data of IR Spectra of Compounds 2-6, 9, 10
Com-
pound
, cm–1
2a
3087, 2992, 2224 (CN), 1575, 1161, 778, 766, 755, 621
2b
2с
3054, 3013, 2956, 2222 (CN), 1561, 1450, 1163, 765
3075, 2227 (CN), 1566, 1556, 1455, 1359, 1212, 1150, 765, 713
3410 (Н2О), 3137, 3075, 2227 (CN), 1633, 1563, 1450, 1161, 765
3410 (Н2О), 3147, 3090, 2227 (CN), 1633, 1569, 1454, 1161, 765
3008, 2222 (CN), 1571, 1486, 1445, 1367, 1347, 1217, 1130, 776, 758, 747
2d*
2e*
3a
3b
3018, 2977, 2956, 2222 (CN), 1569, 1483, 1444, 1427, 1269, 1210, 778,
765, 755
4
3106, 3023, 2972, 2222 (CN), 1574, 1437, 1163, 985, 768, 626
5a
5b
3322(asNH2), 3221(sNH2), 3081, 1636 (C=N+), 1611, 1497, 1463, 1432, 1337, 797
3307 (NH2), 3209 (NH2), 3054, 1636 (C=N+), 1605, 1421, 1331, 1321, 1243,
820, 737
5e
6a
3312 (NH2), 3209 (NH2), 3065, 1644 (C=N+), 1604, 1494, 1421, 1334, 1323,
1243, 822, 737
3354 (NH2), 3307 (NH2), 3173, 3018, 1638 (C=N+), 1605, 1507, 1481, 1419,
323, 737
6b
3328 (NH2), 3271 (NH2), 3178, 2980, 1638 (C=N+), 1605, 1501, 1481, 1419,
1331, 1241, 758, 747
9a
3090, 3034, 1706 (C=O), 1429, 1269 (asCOC), 1197, 1166, 1080 (sCOC), 745, 625
9b*2
3059, 2951, 1713 (C=O), 1558, 1455, 1437, 1272 (asCOC), 1148,
1083 (sCOC), 729, 716
10a
10b
3086, 1569, 1545, 1504, 1477 (C–O–), 1312, 754
3064, 1566, 1543, 1509, 1477 (C–O–), 1416, 1310, 760, 706
_______
*Spectra of the hydrates of 2d and 2e are given.
*2Spectrum of a mixture containing 85% salt 9b.
EXPERIMENTAL
1
The IR spectra were recorded on a Perkin–Elmer Spectrum BX instrument in KBr disks. The H NMR
spectra were recorded on a Bruker Avance DRX 500 instrument (at 500 MHz) with TMS as internal standard.
The NOESY experiment was carried out on a Varian Mercury 400 instrument (at 400 MHz), internal standard
was TMS. The UV spectra were obtained on a Perkin–Elmer Lambda 20 UV-vis spectrometer in methanol.
Melting points were determined on a Tile heating instrument. A check on the purity of the obtained compounds
was effected by the GLC mass spectrometric method on an Agilent 1100 Series instrument, with an Agilent
LC/MSD SL selective detector (samples were introduced in a matrix of CF3CO2H, ionization by EI).
3-(2-Cyanobenzyl)-1-R-1H-imidazolium Bromides 2a-c (General Method). 1-R-1H-imidazole
(2.55 mmol) was added to a solution of 2-(bromomethyl)benzonitrile (1a) (0.5 g, 2.55 mmol) in MeCN (10 ml).
The mixture was heated on a water bath at 50oC for 10 h. The solvent was evaporated in vacuum, and diethyl
ether (10 ml) was added to the residue. The solid was filtered off and washed with ether.
3-(2-Cyanobenzyl)-1-R-1H-imidazol-3-ium chlorides 2d,e were obtained by the method of synthesis
of products 2a-c using 2-(chloromethyl)benzonitrile 1b. Oily products were obtained (2d,e·nH2O) rapidly
deliquescing in the air, which were dried and stored without access to air.
1003

3-(2-Cyanobenzyl)-1-R-1H-benzimidazol-3-ium Bromides 3a,b and 4-(2-Cyanobenzyl)-1-methyl-
1H-1,2,4-triazol-4-ium Bromide (4) (General Method). A mixture of benzonitrile 1a (0.5 g, 2.55 mmol) and
1-R-1H-benzimidazole or 1-methyl-1H-1,2,4-triazole (2.55 mmol) was heated on an oil bath for 5-10 min at
110oC. Acetone (10 ml) was added to the melt, which was triturated, and the crystalline solid was filtered off
and washed with acetone.
1-Alkyl-10-amino-1H-imidazo[1,2-b]isoquinolin-4-ium Bromides 5a,b (General Method).
Potassium carbonate (0.3 g, 2.17 mmol) was added to a solution of salt 2a,b (2.16 mmol) in anhydrous DMF (10
ml). The mixture was stirred for 1 h at room temperature, then heated for 30 min gradually raising the
temperature to 100oC. After cooling, the solid was filtered off, washed with acetone and with water, and then
recrystallized from DMF.
Compound 5b. UV spectrum, λmax, nm (log ε): 242 (5.02), 270 (5.08), 341* (4.17), 354 (4.39), 378*
(4.41), 396 (4.67), 415 (4.71).
10-Amino-1-ethyl-1H-imidazo[1,2-b]isoquinolin-4-ium chloride (5e) was obtained by the method of
synthesis of products 5a,b, using the hydrate of chloride 2e.
5-Alkyl-6-amino-5H-benzimidazo[1,2-b]isoquinolin-12-ium bromides 6a,b were obtained by the
method of synthesis of products 5a,b, using Et3N (0.5 ml, 3.6 mmol) in place of K2CO3.
Compound 6a. UV spectrum, λmax, nm (log ε): 282 (5.44), 344 (4.55), 361 (4.65), 423* (4.76), 442
(4.99), 467 (4.99).
Compound 6b. UV spectrum, λmax, nm (log ε): 280 (5.46), 342 (4.56), 359 (4.65), 422* (4.80), 440
(5.03), 465 (5.03).
3-[2-(Methoxycarbonyl)benzyl]-1-methyl-1H-imidazol-3-ium Bromide (9a). 1-Methyl-1H-imidazole
(1 ml, 12.2 mmol) was added to a solution of 2-(bromomethyl)benzoic acid ester 8 (2.79 g, 12.2 mmol) in
acetonitrile (25 ml) and the mixture was maintained at room temperature for 2 day. The precipitated solid was
filtered off, washed with a small volume of acetonitrile, and recrystallized from acetonitrile.
1-Methyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate (10a). Salt 9a (3 g, 9.64 mmol) was dissolved
by heating in ethanol (50 ml) and K2CO3 (2.66 g, 19.30 mmol) was added. The mixture was boiled for 3.5 h,
cooled, and the solid filtered off. The filtrate was evaporated, acetonitrile (10 ml) was added to the residue, and
triturated. The solid was filtered off, thoroughly washed with hot water, and with hot DMF.
1-Benzyl-1H-imidazo[1,2-b]isoquinolin-4-ium-10-olate (10b). 1-Benzyl-1H-imidazole (1 g, 6.32 mmol)
was added to a solution of 2-(bromomethyl)benzoic acid ester 8 (1.45 g, 6.32 mmol) in acetonitrile (25 ml). The
solution was maintained at room temperature for 2 day and 50% solvent evaporated. Diethyl ether (20 ml) was
added, the solution was separated from the oily residue containing imidazolium salt 9b (85%). The residue was
dissolved in ethanol (30 ml) and K2CO3 (1.74 g, 12.64 mmol) was added. The mixture was boiled for 3 h, and
after cooling, the solid was filtered off. The filtrate was evaporated, acetonitrile (10 ml) was added to the
residue, and triturated. The solid was filtered off, thoroughly washed with hot water, and crystallized from DMF.
UV spectrum, λmax, nm (log ε): 262 (5.23), 340* (4.82), 353 (5.00), 407* (4.91), 445 (5.06). Mass
spectrum, m/z (Irel, %): 549 (10), 548 (40), 547 [M]+ (100), 456 (10), 365 (15), 199 (11).
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