Condensed isoquinolines. 36*. Cyclization of N-alkyl-3-(2- benzoylbenzyl)azolium salts. A novel method of preparing azolo[b]isoquinolines

Article abstract of DOI:10.1007/s10593-010-0632-9

A novel method is proposed for the preparation of azolo[b]isoquinolines based on the alkylation of N-alkyl-1,3-diazoles or 1,3-thiazole derivatives using [2-(bromomethyl)phenyl](phenyl)methanone with subsequent cyclization of the quaternary azolium salts

Full text of DOI:10.1007/s10593-010-0632-9

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
CONDENSED ISOQUINOLINES. 36*. CYCLIZATION OF
N-ALKYL-3-(2-BENZOYLBENZYL)AZOLIUM SALTS. A NOVEL
METHOD OF PREPARING AZOLO[b]ISOQUINOLINES
L. M. Potikha1**, V. V. Sypchenko1, and V. A. Kovtunenko1
A novel method is proposed for the preparation of azolo[b]isoquinolines based on the alkylation of
N-alkyl-1,3-diazoles or 1,3-thiazole derivatives using [2-(bromomethyl)phenyl](phenyl)methanone with
subsequent cyclization of the quaternary azolium salts in the presence of base. The 10(11)-hydroxy
derivatives of the 5,10-dihydro-1H-imidazo[1,2-b]isoquinolinium, 6,11-dihydro-5H-benzimidazo-
[1,2-b]isoquinolinium, 5,10-dihydro-1H-[1,2,4]triazolo[4,3-b]isoquinolinium, or 5,10-dihydro[1,3]-
thiazolo[3,2-b]isoquinolinium bromides obtained in this way readily lose a molecule of water upon
heating with HBr or Ac2O to give the corresponding quasi-aromatic azolo[b]isoquinolinium salts.
Keywords: benzimidazo[1,2-b]isoquinoline, benzophenone, imidazo[1,2-b]isoquinoline, [1,3]thiazolo-
[3,2-b]isoquinoline, [1,2,4]triazolo[4,3-b]isoquinoline.
Treatment of amines with 1,5-dielectrophile synthon equivalents is one of the routes in the design of
isoquinoline type structures. This kind of heterocyclization has been demonstrated by us before for o-bromo-
methylphenylacetonitrile [2] and o-cyanomethylbenzoic acid [3].
In this work we propose the use of [2-(bromomethyl)phenyl](phenyl)methanone (o-bromomethyl-
benzophenone) derivatives 1a,b as novel equivalents of 1,4-dielectrophile synthons in the preparation of the
condensed isoquinolines. Their structure as vinylogs [4] of -bromoacetophenone [5] allows one to proporse
possibility to combine the carbonyl and bromomethyl functions in cyclizations. Their counterparts have been
known for a long time but, in view of their inaccessibility, have had limited use.
We have found that the reaction of the o-bromomethylbenzophenones 1a,b with 1-alkyl-1H-imidazoles
2a,e, 1-methyl-1H-benzomidazole (2b), 1-methyl-1H-1,2,4-triazole (2c), and 4-methyl-1,3-thiazole (2d) in
benzene at room temperature gives high yields (61-89%) of the N-(2-benzoylbenzyl)azolium bromides 3a-d, 4a-e.
The rate of the formation of the quaternary salts 3, 4 and their yield are principally determined by the
basicity of the azole. With its decrease the reaction time increases (from 1-2 days for the imidazoles to 30 days
for thiazole) and the yield is decreased (from 85-89% for the imidazoles to 61% for the thiazole).
_______
* For Communication 35, see [1].
** To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Taras Shevchenko Kiev National University, Kiev 01033, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp.1360-1371, 2010. Original article
submitted October 15, 2009.
1096
0009-3122/10/4609-1096©2010 Springer Science+Business Media, Inc.

The result of the reaction depends on the structure of the starting benzophenone 1. In the case of compound 1a it
was not possible to prepare the corresponding bromides 3c and 3d in the pure state and a mixture of quaternary
salts and the starting azole hydrobromide was obtained. Attempts to increase the yield of the quaternary salts 3
and
4
by heating or increasing the time of holding the mixture of reagents at room
temperature gave a reaction mixture of cyclization products, initiated by the starting azole base. A similar result
X
X
_
_
+
Br
+
N
Br
PhCO
N
Br
O
4-ClC6H4CO
N
C6H6
C6H6
Ar
X
+
~ 20°C
~ 20°C
3a–d
2a–e
NO2
4a–e
R
1a,b
1 a R = H, Ar = 4-ClC6H4; b R = NO2, Ar = Ph;
Me
N
N
N
N
N
N
N
(d); 2e, 4e
2–4:
(c),
=
(b),
(a),
N
N
Et
X
N
Me
S
N
Me
Me
_
_
Br
R2
Br
R1
R1
Ar
Ar
OH
R2
N
N
HBr
2
N
+
N
+
5
9a,b
5a–c
a R1 = Me, R2 = H, Ar = 4-ClC6H4; b R1 = Me, R2 = NO2, Ar = Ph;
c R1 = Et, R2 = NO2, Ar = Ph
_
Ar
_
OH
Ar
Me
Br
R
Me
Br
R
N
N
HBr
N
+
N
+
11
1
10a,b
6a,b
B:
a R = H, Ar = 4-ClC6H4; b R = NO2, Ar = Ph
3a–c,
4a–e

_
_
Br
Br
O2N
Ph
Ar
OH
Me
Me
R
N
N
Ac2O
N
N
N
+
N
+
11
7a,b
a R = H, Ar = 4-ClC6H4; b R = NO2, Ar = Ph
_
_
Ph
Ph
Br
O2N
OH
Br
O2N
S
S
HBr
N
+
N
+
8
Me
Me
12
1097

1098

(mixture of quaternary salt 4a and the product of subsequent cyclization) was also obtained in the reaction of the
benzophenone 1b with 2-ethyl-1H-imidazole 2e. The structure of salts 3, 4 was determined by IR and 1H NMR
spectroscopic methods (Table 1).
When heated in the presence of morpholine or triethylamine bases, the quaternary azolium salts cyclized in
high yield (62-93%) to the 1-alkyl-10-aryl-10-hydroxy-5,10-dihydro-1H-imidazo[1,2-b]isoquinolin-4-ium 5a-c,
6-aryl-6-hydroxy-5-methyl-6,11-dihydro-5H-benzimidazo[1,2-b]isoquinolin-12-ium 6a,b, 10-aryl-10-hydroxy-
1-methyl-5,10-dihydro-1H-[1,2,4]triazolo[4,3-b]isoquinolin-4-ium 7a,b, or 10-hydroxy-3-methyl-8-nitro-10-phenyl-
5,10-dihydro[1,3]thiazolo[3,2-b]isoquinolin-4-ium (8) bromides. Carrying out the reaction in acetone in the
presence of morpholine leads to reaction products 5-8 in high purity and virtually without the need for further
purification. With the use of triethylamine as base (in acetone) or ethanol as solvent (morpholine or
triethylamine as base) up to 30% of dehydration products are formed (according to their 1H NMR spectra).
The structure of the hydroxy derivatives of the 1,4-dihydroisoquinoline was suggested by the presence
of signals for OH groups in the IR spectra of compounds 5-8 (Table 2) which showed a broad band for OH at
3171-3064 cm-1 and a medium intensity C–O at 1043-1049 cm-1 in a region characteristic of the C–O stretching
1
vibrations of tertiary alcohols. The H NMR spectra showed a singlet for the OH group (which exchanged with
D2O) in the region 7.9-8.3 ppm and a signal for a methylene group at 5.6-6.4 ppm as two doublets of an AB spin
system with 2J = 16.5-19.0 Hz.
In order to prove the structure of salts 5-8 and to make a full assignment of signals in the NMR spectra
there were measured the 13C NMR, COSY, and NOESY spectra of 5b together with the use of HMBC and
HMQC 2D heteronuclear correlation spectroscopic methods. The results for the 2D NOESY spectra are given in
Figure, 1a and led to a secure assignment of signals in the proton spectrum of compound 5b. The position of the
hydroxyl group proton signal at 8.11 ppm follows from the presence of its negative correlation with the water
signal present in the solvent. This correlation points to the presence of proton exchange. The structure of the
carbon skeleton was confirmed from the basic heteronuclear correlations (Figure, 1b).
It is known [6] that 1(4)-hydroxy 1,4-dihydroisoquinolines readily aromatize in the presence of strong
acids. In our case, heating the hydroxy derivatives of the azolo[b]isoquinolinium bromides 5a,b, 6a,b, 8 in the
presence of hydrobromic acid led to dehydration and gave the 10-aryl-1-methyl-1H-imidazo[1,2-b]isoquinolin-
4-ium 9a,b, 6-aryl-5-methyl-5H-benzimidazo[1,2-b]isoquinolin-12-ium 10a,b, or 3-methyl-8-nitro-10-phenyl-
[1,3]thiazolo[3,2-b]isoquinolin-4-ium (12) bromides. In the case of the [1,2,4]triazolo[4,3-b]isoquinolinium
bromide 7b an efficient conversion to the 1-methyl-8-nitro-10-phenyl-1H-[1,2,4]triazolo[4,3-b]isoquinolin-
4-ium bromide (11) could only be achieved by heating salt 7b in acetic anhydride. Heating it in the presence of
HBr led to only slow dehydration and was accompanied by the formation of side products.
1
A feature of the H NMR spectra (Table 2) of the aromatic azolo[b]isoquinolinium salts 9-12 is the
presence of a signal for the aromatic H-5 proton (H-11 for compounds 10a,b) with a chemical shift greater than
10.0 ppm. By contrast with the IR spectra of the dihydro derivatives 5-8 their IR spectra show a medium
intensity absorption band at 1603-1609 cm-1 which is assigned to C=N stretching bands. All of the salts 9-12 are
colored and their UV spectra show the presence of strong absorption maxima in the range  350-482 nm, which
is a characteristic of azolo[b]isoquinolinium cations [7-9].
With the aim of evaluating the biological potential of the compounds reported here a spectrum of
biological activity was calculated. The PASS (Prediction of Activity Spectra for Substances) [10-12] was used
in the calculations. The selection of active compounds is made by a multilevel assessment of the closest
environment of the atoms and a comparison of the calculated 3D descriptors with a set of those corresponding to
the likely appearance of either high activity or its absence. The final result of the program is the potential
appearance of compound activity (pa) or inactivity (pi) in fractional units. A spectrum of more than 3000 types
of activity was calculated for each compound with activity threshold selected as pa > 0.75 and pi < 0.2. Amongst
the activities characterizing compounds 3 and 4 should be noted the prediction of properties as CC subfamily
1099

1100

1101

TABLE 3. Physicochemical Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C* Yield, %
C
H
Br
Cl
N
S
3a
3b
4a
4b
4c
C18H16BrClN2O 55.22
55.19
C22H18BrClN2O 59.78
59.82
C18H16BrN3O3 53.71
53.75
C22H18BrN3O3 58.40
58.42
C17H15BrN4O3 50.61
50.64
C18H15BrN2O3S 51.50
51.56
C18H16BrClN2O 55.21
55.19
C18H16BrN3O3 53.71
53.75
C19H18BrN3O3 54.78
54.82
C22H18BrClN2O 59.80
59.82
C22H18BrN3O3 58.38
58.42
C17H15BrClN3O 51.98
52.00
C17H15BrN4O3 50.62
50.64
C18H15BrN2O2S 51.57
51.56
C18H14BrClN2 57.83
57.86
C18H14BrN3O2 56.25
56.27
4.09
4.12
4.13
4.11
4.06
4.01
3.98
4.01 17.67
3.77
3.75
3.62
3.61
4.15
4.12
3.99
4.01
4.31
4.36
4.15
4.11
4.02
4.01
3.80
3.85
3.78
3.75
3.58
3.61
3.80
3.78
20.42
20.40
18.10
18.09
19.88
19.86
17.65
9.04
9.05
8.05
8.03
7.18
7.15
6.30
6.34
10.44
10.45
9.30
9.29
13.86
13.89
6.67
6.68
7.18
7.15
10.40
10.45
10.12
10.09
6.35
6.34
9.31
9.29
10.73
10.70
13.91
13.89
6.67
6.68
7.52
7.50
10.97
10.94
135-136
220-221
160-162
171-172
184-186
187-188
85
77
89
63
67
61
89
87
80
92
93
87
88
62
82
90
90
93
63
84
19.80
19.82
19.07
19.06
20.41
20.40
19.87
19.86
19.18
19.20
18.11
18.09
4d
5a
5b
5c
7.60
7.65
9.02
9.05
> 300
(dec.)
280-282
(dec.)
229-230
(dec.)
> 300
(dec.)
290-291
(dec.)
> 300
(dec.)
241-243
(dec.)
264-265
(dec.)
6a
6b
7a
7b
8
8.05
8.03
17.65
17.67
9.05
9.03
20.36
20.35
19.80
19.82
19.09
19.06
21.40
21.38
20.78
20.80
18.87
18.86
18.42
18.40
20.77
20.74
7.62
7.65
9a
9b
10a
10b
11
12
9.50
9.49
> 300
3.68
3.67
3.78
3.81
3.67
3.71
3.43
3.40
298-300
(dec.)
> 300
C22H16BrClN2 62.33
62.36
C22H16BrN3O2 60.83
60.84
C17H13BrN4O2 53.02
53.00
C18H13BrN2O2S 53.85
53.88
8.35
8.37
6.60
6.61
9.70
9.68
14.51
14.54
7.00
6.98
> 300
> 275
(dec.)
> 290
(dec.)
3.28
3.27
19.93
19.91
8.10
7.99
_______
* Compound 11 was recrystallized from 2-propanol, the remainder from
MeOH–hexane (1:1).
6.02 5.92
7.83
128.9
8.09
6.02 5.92
7.83
8.09
48.5
121.6
143.4
8.27
123.7
+
N
8.27
+
N
134.4
7.94
7.94
126.0
148.3
139.9
N
NO2
70.1
N
123.0
8.16
NO2
3.61
H3C
36.3
7.47
OH
141.9
8.16
3.61
H3C
OH
8.11
7.47
8.11
7.47
a
7.45
b
Fig. 1. Structurally significant NOESY (a) and HMBC (b) correlations for compound 5b.
1102

chemokin antagonists which induce the migration of monocytes from blood to tissue and their differentiation in
the macrophage. The highest indicators for compounds 4a,b are, respectively, 0.854 (pi = 0.009) and 0.862
(pi = 0.008). Also worthy of attention is the prediction of activity for the aromatic salts 9-12 as inhibitors of
prolylamino peptidase occurring in the process of enzymatic decomposition of proteins and responsible for
involved in the metabolism of regulatory peptides for different cell types: 9a pa = 0.821, pi = 0.063; 10a
pa = 0.796, pi = 0.073.
EXPERIMENTAL
IR spectra (KBr tablets) were taken on Perkin-Elmer spectrum BX instrument. UV spectra were
1
recorded in methanol on a Lambda 20 UV-vis spectrometer. H NMR spectra were taken on a Bruker Avance
DRX-500 (500 MHz) instrument. 2D correlation spectroscopic experiments were taken on a Varian Mercury
1
13
400 instrument (400 and 100 MHz for H and C respectively) with TMS used as internal standard. Melting
points were recorded on a Thiele heating apparatus. Monitoring of the compound purities was carried out using
HPLC–mass spectrometry on an Agilent 1100 series instrument with a selective Agilent LC/MSD SL detector
(the sample was introduced in a CF3COOH matrix, EI ionization).
The physicochemical characteristics and elemental analytical data for the synthesized compounds 3-12
are presented in Table 3.
[2-(Bromomethyl)phenyl](4-chlorophenyl)methanone (1a) was prepared by method [13] and [2-(bromo-
methyl)-5-nitrophenyl](phenyl)methanone (1b) as a mixture with a 1b content of 70% using method [14].
3-(2-Benzoylbenzyl)-1-methyl-1H-imidazol-3-ium (3a, 4a), 1-(2-Benzoylbenzyl)-3-methyl-3H-benz-
imidazol-1-ium (3b, 4b), 4-(2-Benzoyl-4-nitrobenzyl)-1-methyl-1H-1,2,4-triazol-4-ium (4c), and 3-(2-
Benzoyl-4-nitrobenzyl)-4-methyl-1,3-thiazol-3-ium (4d) Bromides (General Method). The corresponding
azole 2a-d (1.7 mmol) was added to a solution of [2-(bromomethyl)phenyl](4-chlorophenyl)methanone 1a
(0.5 g, 1.6 mmol) (or 0.73 g of a mixture containing 70% (1.6 mmol) of [2-(bromomethyl)-5-nitrophenyl]-
(phenyl)methanone 1b) in anhydrous benzene (10 ml) and held at room temperature for 1-2 days for compound
2a, 4 days for 2b, 10 days for 2c, or 30 days for 2d. The colorless precipitate was filtered off and washed with
acetone.
10-Aryl-10-hydroxy-1-methyl-5,10-dihydro-1H-imidazo[1,2-b]isoquinolin-4-ium 5a,b, 6-Aryl-
6-hydroxy-5-methyl-6,11-dihydro-5H-benzimidazo[1,2-b]isoquinolin-12-ium 6a,b, 10-Hydroxy-1-methyl-
8-nitro-10-phenyl-5,10-dihydro-1H-[1,2,4]triazolo[4,3-b]isoquinolin-4-ium (7b), and 10-Hydroxy-3-methyl-
8-nitro-10-phenyl-5,10-dihydro[1,3]thiazolo[3,2-b]isoquinolin-4-ium (8) Bromides (General Method). A
mixture of the azolium bromide 3a-b, 4a-d (1.02 mmol) and morpholine (0.5 ml) in acetone (10 ml) was
refluxed for 1.5 h (in the case of thiazolium bromide 4d for 0.5 h). The product was cooled and the precipitate
was filtered off and washed with acetone.
Compound 5b. 13C NMR spectrum (DMSO-d6), , ppm: 148.3 (C-8); 143.4 (C-10a); 141.9 (C-1');
139.9 (C-9a); 134.4 (C-5a); 130.0 (C-2',6'); 129.5 (C-4'); 128.9 (C-6); 126.0 (C-2); 125.8 (C-3',5'); 123.7 (C-7);
123.0 (C-9); 121.6 (C-3); 70.1 (C-10); 48.5 (C-5); 36.3 (CH3).
1-Ethyl-10-hydroxy-8-nitro-10-phenyl-imidazo[1,2-b]isoquinolin-4-ium Bromide (5c) was prepared
by the method reported above for the synthesis of the azolium bromides 3, 4 (solution holding time 1 day) as a
mixture containing the 3-(2-benzoyl-4-nitrobenzyl)-1-ethyl-1H-imidazol-3-ium bromide (4a, 82%) and the
cyclization product 5c. The mixture was treated with morpholine (0.6 ml) and benzene (10 ml) and refluxed for
1 h. The product was cooled and the precipitate was filtered off and washed with acetone.
10-(4-Chlorophenyl)-10-hydroxy-1-methyl[1,2,4]triazolo[4,3-b]isoquinolin-4-ium Bromide (7a)
was prepared by the above method for the azolium bromides 3, 4 (solution holding time 15 days) as a mixture
containing the 4-[2-(4-chlorobenzoyl)benzyl]-1-methyl-1H-1,2,4-triazol-4-ium bromide (3c, 65%) and the
1103

1-methyl-1H-1,2,4-triazole hydrobromide 2c·HBr. The mixture was treated with morpholine (0.3 ml) and
acetone (10 ml) and refluxed for 1.5 h. The product was cooled and the precipitate was filtered off and washed
with acetone.
10-Aryl-1-methyl-1H-imidazo[1,2-b]isoquinolin-4-ium 9a,b, 6-Aryl-5-methyl-5H-benzimidazo-
[1,2-b]isoquinolin-12-ium 10a,b, and 3-Methyl-8-nitro-10-phenyl[1,3]thiazolo[3,2-b]isoquinolin-4-ium (12)
Bromides (General Method). A mixture of salts 5a,b, 6a,b, 8 (0.7 mmol) and HBr solution (48%, 5 ml) was
refluxed for 4 h. Solvent was evaporated in vacuo. The residue was treated with water (20 ml) and the solid
product was filtered off and washed with water and 2-propanol.
Compound 9a. UV spectrum, max, nm (log ): 242 (4.55), 380 (4.22), 400 (4.21).
Compound 9b. UV spectrum, max, nm (log ): 262 (4.44), 418 (4.21), 430 (4.22).
Compound 10a. UV spectrum, max, nm (log ): 286 (4.55), 426 (3.88), 450 (3.85).
Compound 10b. UV spectrum, max, nm (log ): 290 (4.65), 458 (3.88), 482 (3.89).
Compound 12. UV spectrum, max, nm (log ): 270 (4.47), 412 (4.00), 428 (4.05).
1-Methyl-8-nitro-10-phenyl-1H-[1,2,4]triazolo[4,3-b]isoquinolin-4-ium Bromide (11). A mixture of
compound 7b (0.3 g, 0.75 mmol) in acetic anhydride (4 ml) was refluxed for 2 h. The product was cooled and
the solid formed was filtered off and washed with 2-propanol. UV spectrum (MeOH), max, nm (log ): 260
(4.69), 350 (4.78), 410 (3.81).
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