Condensed isoquinolines. 17. Enamine properties of benzimidazo[1,2-b] isoquinolin-11(5H)-one in alkylation reactions

Article abstract of DOI:10.1023/B:COHC.0000046697.89737.65

The alkylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one has been studied. This occurs at N₍₅₎ or C₍₆₎ depending on the type of alkylating agent and the reaction conditions. It was shown that C ₍₆₎ alkylation is effected

Full text of DOI:10.1023/B:COHC.0000046697.89737.65

Chemistry of Heterocyclic Compounds, Vol. 40, No. 8, 2004
CONDENSED ISOQUINOLINES.
17*. ENAMINE PROPERTIES OF BENZ-
IMIDAZO[1,2-b]ISOQUINOLIN-11(5H)-ONE
IN ALKYLATION REACTIONS
L. M. Potikha, N. V. Shkilna, V. M. Kisil, and V. A. Kovtunenko
The alkylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one has been studied. This occurs at N(5) or C(6)
depending on the type of alkylating agent and the reaction conditions. It was shown that C(6) alkylation
is effected in reactions with reactive alkyl halides. A repeat alkylation occurs preferentially at the same
position. Interaction with o-xylylidene dibromide leads to spiro[benzimidazo[1,2-b]-isoquinolin-6,2'-
indan]-11-one and 1,6-dihydro-11H-6a,11b-diazobenzo[b]benzo[5,6]cyclohepta-[1,2,3-l,m]fluoren-11-
one, which are derivatives of new heterocyclic systems.
Keywords: heterocyclic enamines, derivatives of 1,6-dihydro-11H-6a,11b-diazabenzo[b]benzo[5,6]-
cyclohepta[1,2,3-l,m]fluoren-11-one
and
spiro[benzimidazo[1,2-b]isoquinolin-6,2'-indan]-11-one,
alkylation.
Depending on the nature of the reagent the acylation of benzimidazo[1,2-b]isoquinolin-11(5H)-one (1)
leads to the formation of two types of benzimidazoisoquinolines substituted at positions 5 or 6 [1]. These results
are in complete agreement with the behavior of secondary enamines [2,3], the structural element of which is
present in the compound 1 molecule. However the most characteristic reaction of enamines, alkylation, has not
yet been studied among derivatives of 1. Only two examples of this reaction are known, the N(5)-methylation
[4,5] and C(6)-diallylation of compound 1 [5]. While continuing the investigations of alkylation in the condensed
isoquinoline series [6,7] in the present work, we have studied the alkylation of benzimidazoisoquinoline 1 by
various alkylating agents under various conditions.
The direction of alkylation in enamines is determined by the nature of the alkylation agent, although on
alkylation with phenacyl or benzyl halides attack at the β-carbon is more preferred [2]. In reality, interaction of
compound 1 with substituted α-bromoacetophenones takes place extremely vigorously with the formation of a
complex mixture of products. Only in the case of reaction with p-bromophenacyl bromide was the C(6)-alkylation
product successfully isolated and characterized, viz. 6-[2-(4-bromophenyl)-2-oxoethyl]benzimidazo[1,2-
b]isoquinolin-11(5H)-one (2). In the cases of phenacyl and p-methoxyphenacyl bromides only compound 3, the
product of oxidative dimerization of compound 1, was successfully identified in the mixture of products. The
ease of formation of compound 3 was noted by us previously [1].
_______
* For Part 16 see [1].
__________________________________________________________________________________________
T. Shevchenko National University, Kiev 01033, Ukraine; e-mail: vkovtunenko@hotmail.com.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1214-1225, August, 2004. Original article
submitted July 12, 2002.
1052
0009-3122/04/4008-1052©2004 Springer Science+Business Media, Inc.

O
N
N
Me
7
O
O
O
N
N
N
N
N
H
H
N
H
N
H
O
N
1
O
3
2
Br
O
O
N
N
N
N
H
+
+
R1
R2
R1
R3
R3
R1
R2
R2
R3
4a–c
5a–c
O
N
N
+
R3
R1
R3
R1
6a–d
R2
R2
4a, 6b R1 = R3 = Me, R2 = H; 4b, 5b, 6c R1 = R3 = H, R2 = NO2;
4c, 5c, 6d R1 = CN, R2 = R3 = H, 5a, 6a R1 = R2 = R3 = H
The main criterion for establishing the direction of alkylation of compound 1 was in all cases the
retention or nonappearance of the signals of the N(5)H or C(6)H protons in the 1H NMR spectra. For example, the
structure of compound 2 as the product of C(6)-alkylation is confirmed by the presence of the signal of the N(5)H
1
group in the IR and H NMR spectra (Table 1), and also by the absence of resonance at 6.3 ppm for the C(6)H
observed in the initial compound 1.
Three types of alkylation product are formed on carrying out the reaction of heterocycle 1 with benzyl
halides in 2-propanol in the presence of i-PrONa, viz. 6-benzylbenzimidoazo[1,2-b]isoquinolin-11(5H)-ones
(4a,b), 6,6-dibenzylbenzimidazo[1,2-b]isoquinolin-11(5H)-ones (5a-c), and 5,6-dibenzylbenzimidazo[1,2-b]-
isoquinolin-11(5H)-ones (6a-d). The amount of alkyl derivatives 4-6 in the mixture formed depends on the
1053

TABLE 1. Spectral Characteristics of 6-R-benzimidazo[1,2-b]isoquinolin-11(5H)-ones
IR spectrum,
ν, cm-1
1Н NMR spectrum, δ, ppm (J, Hz)
Signals of benzimidazo[1,2-b]isoquinoline nucleus
Com-
pound
Signals of substituent
6-CH2,
Other
signals
H-1, d, H-10, d, H-8, t,
H-7, d,
J = 8.0
H-3, t,
J = 8.0
H-4, d, H-9, t,
J = 8.0 J = 8.0 J = 8.0
H-2, t,
Other
signals
C=O
2
N–H
H-5, s
5
Ar–H
J = 8.0
J = 8.0
J = 8.0
2Н, s
1
3
4
6
7
8
9
10
11
12
13
14
15
16
2
1660,
1620
3280
11.72
8.65
8.67
8.37
8.39
7.60
7.56
7.50
7.41
7.31
7.28
7.22
8.12 (2H, d,
J = 8.0, H-2', H-6'),
7.84 (2H, d,
4.76
4.14
J = 8.0, H-3', H-5')
4a
4b
1650
1650
3300
3200
11.74
7.33
7.40
7.42
7.30
7.35
7.27
7.27
7.22
7.23
7.06 (1H, s, H-3'),
6.70 (1H, d,
J = 8.0, H-5'),
6.48 (1H, d,
2.48 (3H, s,
2'-CH3),
2.19 (3H, s,
4'-CH3)
J = 8.0, H-6')
1560,
1340
11.97
8.65
8.37
7.63-7.57
(2H, m)
8.16 (1H, s, H-2'),
8.03 (1H, d,
J = 8.0, H-4'),
7.67 (1H, d,
4.46
(
s,asNO2)
J = 8.0, H-6'),
7.52 (1H, t,
J = 8.0, H-5')

TABLE 1 (continued)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4с
1655
3180
2200
(CN)
11.92
8.67
8.40
7.59
—*
—*
7.34
7.28
7.24
7.89 (1H, d,
J = 8.0, H-3',
7.47-7.37
4.52
(4H, m, H-3, H-7,
H-4', H-5'),
7.03 (1H, d,
J = 8.0, H-6')
8
1650
1655
3200
3180
11.69
(2H)
8.71
(2H)
8.45
(2H)
7.63
(2H)
7.59
(2H)
7.37
(2H)
7.34
(2H)
7.29
(2H)
7.19
(2H)
6.88 (2H, m,
H-3', H-4'),
6.75 (2H, m,
H-2', H-6')
7.71 (1H, d,
J = 7.2, H-3'),
H-4', H-5'*2,
6.98 (1H, d,
J = 7.2, H-6')
4.54
(4H)
11
3280,
3410
12.29
11.84
8.63
8.64
8.37
8.37
7.58
—*
7.47
—*2
7.32
7.33
7.25-7.12
4.41
8.13 (1H, s,
NHAHB),
7.74 (1H, s,
NHAHB)
(5H, m, H-2, H-4,
H-9, H-4', H-5')
(
s,asNH2)
13a
1655
3200
3050
3300,
3410
7.27-7.13
7.58-7.54 (2H, m,
H-8, H-5'),
7.67 (1H, d,
J = 8.0, H-3'),
H-4'*2,
4.41
10.12 (1H, s,
–N'HN''H–
CONH2),
8.11 (1H, s,
–N'HN''H–
CONH2),
(5H, m, H-2, H-4,
H-7, H-9, H-4')
(
s,asNH2)
6.95 (1H, d,
J = 7.2, H-6')
5.99 (2H, s,
NH2)
13b
1640,
1710
1230
(C–O)
11.63
8.66
8.39
8.49
—*
7.27-7.21
7.15
7.94 (1H, m, H-3'),
7.37-7.30
4.62
3.97 (3H, s,
OCH3)
(4H, m, H-3, H-4,
H-9, H-4')
(2H, m, H-7, H-5'),
H-4'*2,
6.90 (1H, m, H-6')
_______
* Overlap of signals of benzimidazo[1,2-b]isoquinoline nucleus and signals of substituent, see column 14.
*2 Overlap of signals of benzimidazo[1,2-b]isoquinoline.

nature of the substituent in the benzyl radical and on the ratio of the reactants used in the reaction. At an
equivalent ratio of reactants (method A) only in the case of 2,4-dimethylbenzyl chloride was a single reaction
product, the monobenzyl derivative 4a, obtained. In the remaining experiments mixtures were formed either of
the initial 1 with dibenzyl derivatives (5a, 6a, and 5c, 6d), or, as in the case of 3-nitrobenzyl chloride, a mixture
of mono- and dibenzyl derivatives (4b, 5b). The use of a twofold excess af alkylating agent (method B) leads to
an increase in the overall alkylation yield and a growth in the proportion of dibenzylation products. However in
this case also the predominant product with 2,4-dimethylbenzyl chloride (mixture of 4a, 6b) remains the
6-benzyl derivative 4a, probably caused by the reduced reactivity of the reactant itself, and also by steric
hindrance from the side of the ortho substituent towards a second attack at position 6. The 5,6-dialkyl derivatives
6a-d are formed in low yield (10-25%). Only the 5,6-dibenzyl derivative 6a was isolated and characterized, and
in the remaining cases the presence of compounds of the type of 6 were recorded in the mixture with the aid of
1H NMR spectra of the unpurified reaction products.
The benzylation of compound 1 by fusion is complicated in many cases by significant resinification. On
fusing 1 with benzyl chloride (180°C) the 6,6-dibenzyl derivative 5a is obtained in low yield (20%), but on
using o-bromomethylbenzonitrile the monobenzylation product 4c was isolated successfully. Attempts at a
repeat alkylation (without base and on fusing) of the mono-6-benzyl derivatives 4a-c to the dibenzyl derivatives
led to the formation of mixtures of unidentified products. On carrying out the benzylation of heterocycle 1
without base by heating a mixture of the reactants in DMF or MeCN, the formation of dimer 3, already
mentioned above, was observed.
The obtained data indicate the participation of nitrogen analogs of enolate ions in the benzylation in the
presence of i-PrONa, generated both from the initial benzimidazoisoquinoline 1, and from compounds 4. The
impossibility of forming such an anion for 5-methylbenzimidazo[1,2-b]isoquinolin-11(5H)-one (7), obtained
previously [4,5], explains the inertness of the latter in this reaction. It may therefore be stated that the main
direction of alkylation of compound 1 is at position C(6). The repeat alkylation also takes place predominantly at
the same position.
The structure of the benzylation products 4-6 was established by spectral methods (Tables 1, 2). For all
three types of benzyl derivatives the signal of the C(6)H methine proton observed at 6.3 ppm in the initial
1
compound 1 was absent from the H NMR spectra. In the spectra of the monobenzyl derivatives 4a,b there are
1
signals for the N(5)H group (at 11.7-11.9 ppm in the H NMR spectrum and at 3100 cm-1 in the IR spectrum),
which are absent from the spectra of the dibenzyl derivatives 5a-c, 6a. The observed differences in signal form
and the chemical shifts of the methylene protons of the benzyl substituents of dibenzyl derivatives 5 and 6 also
enable their structures to be determined unequivocally. The methylene protons of 5,6-dibenzyl derivatives 6a-d
are observed as two singlets at 3.8-4.4 (C(6)–CH2) and 5.0-5.6 ppm (N(5)–CH2), and the signal of the methylene
groups in 6,6-dibenzyl derivatives 5a-c at 3.9-4.2 ppm is observed as an AB spin system with geminal coupling
constant 13.2 Hz. The nonequivalence of the methylene group protons at C(6) in compounds 5a-c is evidently
caused by steric hindrance to rotation about the C(6)–CH2–Ar single bonds.
The data on the benzylation of compound 1 and also the possibility of intramolecular alkylation
discovered by us previously [1] using 6-(α-halo)acetyl derivatives of 1 as examples enabled us to hope for
successful heterocyclization using a reactant with two alkylating functions, o-xylylidene dibromide. On carrying
out the reaction in the presence of an equivalent quantity of i-PrONa we obtained the unusual monoalkylation
product 6-{2-[11-oxo-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinolin-6-yl)methyl]benzyl}benzo[4,5]imidazo-
[1,2-b]isoquinolin-11(5H)-one (8). The use of a twofold excess of base leads to a mixture of derivatives of two
new heterocyclic systems, spiro(benzimidazo[1,2-b]isoquinolin-6,2'-indan)-11-one (9) and 1,6-dihydro-11H-
6a,11b-diazabenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one (10) in a 1:5 ratio.
1056

TABLE 2. Spectral Characteristics of 6,6-Dibenzyl Derivatives 5a-c and Spiro-substituted Compounds 9, 12
1Н NMR spectrum (DMSO-d6), δ, ppm (J, Hz)
IR spectrum,
ν, cm-1
Com-
pound
Signals of the benzimidazo[1,2-b]isoquinoline nucleus
H-1, d, H-10, d, H-4, d, H-2, t, H-7, d, H-3, t, H-8, t,
J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0 J = 8.0
Signals of substituents
6-CHАНВ,
Other
H-9, t,
6-CHАНВ,
2Н, d
14
C=O
2
Ar–H
12
signals
2Н, d
1
3
4
5
6
7
8
9
10
11
13
5a
1700
1700
1700
8.31
8.09
7.92
7.90-7.88
(2H, m)
7.48
7.46
7.35
6.86 (2H, t, J = 8.0, H-4'),
6.75 (4H, t, J = 8.0,
H-3', H-5'),
6.39 (4H, d, J = 8.0, H-2', H-6')
4.02
(J = 13.2)
3.79
(J = 13.2)
5b
5c
1510,
1340
8.53
8.22
8.07-8.00
(3H, m)
7.95
7.59
7.56
7.53
7.42
7.80 (2H, d, J = 8.0, H-4'),
7.29 (2H, s, H-2'),
7.15 (2H, t, J = 8.0, H-5'),
6.86 (2H, d, J = 8.0, H-6')
4.14
(J = 13.2)
4.06
(J = 13.2)
(
s,asNO2)
2210
(CN)
8.11
8.31
8.07
7.84-7.80
(2H, m)
7.50-7.42
(4H, m, H-8,
H-9, H-3')
H-3'*,
4.26
(J = 13.2)
4.15
(J = 13.2)
7.18 (2H, t, J = 8.0, H-5'),
7.08 (2H, t, J = 8.0, H-4'),
6.31 (2H, d, J = 8.0, H-6')
9
1695
8.38
(m)
7.64
(2H, m)
7.89
(2H, m,
H-4, H-7')
7.34
7.74-7.61
(4H, m, H-2, H-3,
H-7, H-5')
7.55
7.41-7.38
(2H, m)
7.30 (4H, m, H-4' – H-7')
4.11
(J= 16.5)
3.58
(J = 16.5)
12
1710
(br.)
8.43-8.40
(2H, m)
7.44
7.39
H-5', H-7'*2,
7.58 (1H, t, J = 8.0, H-6'),
7.23 (1H, d, J = 8.0, H-4')
4.57
(1Н,
J = 18.0)
4.04
(1Н,
J = 18.0)
_______
* Overlap of signals of benzimidazo[1,2-b]isoquinoline nucleus and signals of a substituent, see columns 10, 11.
*2 Overlap of signals of benzimidazo[1,2-b]isoquinoline nucleus and signals of a substituent, see columns 6-9.

O
N
O
N
N
N
H
9
O
10
H
N
N
N
N
6
1
O
8
10
The structures of products 8-10 were confirmed by their spectral data (Tables 1, 2) which were
extremely similar to the spectra of benzyl and dibenzyl derivatives 4-6. Among their special features may be
noted the position of the C(7)H proton signal in the 1H NMR spectrum of spiro product 9 observed at higher field
(7.34 ppm) compared with the corresponding signal of 6,6-dibenzyl derivatives 5a-c due to shielding of the
spiroindane fragment by the benzene ring.
In connection with the ease of acylation of compound 1 it seemed of interest to investigate the problem
of the acylation of alkyl-substituted benzimidazoisoquinolines. Experiments on the acylation of compound 7
showed its inertness. The 6-benzyl derivatives 4a,b in dioxane in the absence of base did not interact with
acylating agents, and in pyridine gave a mixture of unidentified products. The conversion of
6-(2-cyanobenzyl)benzimidazoisoquinoline 4c described above proved to be extremely interesting. On boiling in
acetic acid in the presence of HBr this compound is hydrolyzed to amide 11, but on more extended heating in
acetic acid it is possible to obtain the product of intramolecular acylation, spiro(benzimidazo[1,2-b]isoquinolin-
6(11H),2'-indan)-1',11-dione (12).
O
O
O
N
N
N
HOAc,
HBr
HOAc
RH
N
N
N
4c
H
H
HOAc
O
COR
13a,b
CONH2
11
12
13 a R = NHNHCONH2, b R = OMe
1
We drew a conclusion on the spiro structure of compound 12 on the basis of data of its H NMR
spectrum. Apart from the absence from the low field region of signals of exchanging protons of the NH type,
which corresponds both to the C(6) acylation product and to the N(5) acylation product, attention is attracted
primarily by the position and form of the methylene group proton signal. Two one-proton doublets with
J = 18.0 Hz were recorded in the region of 4.0 and 4.5 ppm which correspond in position and form to the
1058

TABLE 3. Physicochemical Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °С*
C
H
N
2*2
C23H15BrN2O2
C24H20N2O
63.96
64.05
3.45
3.51
6.58
6.50
248
(dec.)
65
4a
81.69
81.79
5.65
5.72
8.01
7.95
211
57 (A),
45 (B)
4b
4c
5a
C22H15N3O3
C23H15N3O
C29H22N2O
71.50
71.54
78.98
79.07
83.92
84.03
4.00
4.09
4.30
4.33
5.48
5.35
11.45
11.38
12.10
12.03
6.86
6.76
270
201
159
31 (A)
75
40 (A),
55 (B)
5b
5c
C29H20N4O5
C31H20N4O
68.94
69.04
3.95
4.00
11.19
11.11
195
134
34 (A),
55 (B)
80.07
80.15
4.26
4.34
12.10
12.06
47 (A),
63 (B)
8
C38H26N4O2
C23H16N2O
C23H17N3O2
C23H14N2O2
C24H19N5O3
C24H18N2O3
79.88
79.98
82.10
82.12
75.09
75.19
78.74
78.84
67.74
67.76
75.30
75.38
4.50
4.59
4.72
4.79
4.61
4.66
3.95
4.03
5.54
5.50
4.68
4.74
9.85
9.82
8.35
8.33
11.47
11.44
8.05
8.00
16.43
16.46
7.37
7.33
204
240
294
282
295
215
60
18
76
63
57
75
9
11
12
13a
13b
_______
* Compound 4a was recrystallized from MeCN, 5a from EtOH, and the
remainder from DMF.
*2 Analytical data for Br: 18.56% (found), 18.53% (calculated).
protons of the methylene groups of spiro compound 9, also observed as an AB spin system with J = 16.5 Hz
13
(Table 2). In the C NMR spectrum two signals were observed in the region of absorption of aliphatic carbon
atoms assigned by us to the resonance of C(spiro) (56.68 ppm) and C(3')H2 (42.55 ppm) and there was a signal for
C(1') (199.94 ppm) characteristic of the absorption of carbonyl carbon atoms [8]. In the IR spectrum a broad band
was observed at 1710 cm-1 corresponding to the vibrations of two carbonyl groups. The formation of the
intramolecular acylation product was also confirmed by mass spectral data (350 [M]+, 39%).
Spiroindanone 12, being fairly stable in acid media, proved to be extremely sensitive to the action of
bases. The spiroindanone ring was easily broken with the formation of derivatives of
6-(2-carboxybenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one. On attempting to obtain the semicarbazone we
isolated the acylated semicarbazide 13a, and on boiling in methanol in the presence of Et3N the methyl ester 13b
was obtained.
EXPERIMENTAL
The melting points of the synthesized compounds were determined on Boetius type heating equipment
and are not corrected. The IR spectra (KBr disks) were recorded on a Pye-Unicam SP 3-300 instrument. The
1H and 13C NMR spectra were obtained on a Varian Mercury 400 instrument (400 MHz for 1H and 100 MHz for
1059

13C) in DMSO-d6, internal standard was TMS. The assignment of signals of the aromatic protons was confirmed
by data of COSY HH spectra for compounds 2, 5a, 6a, 10, and 12. The mass spectra were obtained on a Waters
Integrity System instrument, with a Thermabeam detector (mobile phase CH3CN). A check on the progress of
reactions and the purity of the compounds obtained was effected by TLC on Silufol UV-254 plates. The
characteristics of the compounds obtained are given in Tables 1-3.
Benzimidazo[1,2-b]isoquinolin-11(5H)-one (1) was obtained by the procedure of [4], and
5-methylbenzimidazo[1,2-b]isoquinolin-11(5H)-one (7) by the procedure of [5].
6-[2-(4-Bromophenyl)-2-oxoethyl]benzimidazo[1,2-b]isoquinolin-11(5H)-one (2). p-Bromophenacyl
bromide (3.61 g, 13 mmol) was added to a solution of benzimidazoisoquinoline 1 (2.34 g, 10 mmol) in DMF
(10 ml) and the mixture boiled for 40 min. After cooling, the precipitated solid was filtered off, and washed with
acetone. Recrystallization was from DMF.
Alkylation of Benzimidazo[1,2-b]isoquinolin-11(5H)-ones with Benzyl Halides in Solution was
carried out using various ratios of reactants calculated on heterocycle 1 (10 mmol). A. Sodium (0.25 g, 11 mmol)
and benzyl halide (11 mmol). B. Sodium (0.5 g, 22 mmol) and benzyl halide (22 mmol).
Compound 1 (2.34 g, 10 mmol) was added to a solution of sodium isopropylate in 2-propanol (10 ml)
and dissolved on heating. The appropriate benzyl halide was added to the solution obtained and the mixture
boiled for 1.5-2 h. After cooling the reaction mixture, the solid formed was filtered off, washed thoroughly with
water, and with alcohol, and recrystallized from DMF. Further isolation of products was carried out separately
from the solid and the filtrate.
When using benzyl chloride (method A) a solid (0.93 g) was obtained consisting, according to data of
the H NMR spectrum*, of compound 6a and initial 1 in a ratio of 1:1. On alkylation by method B the solid
1
(1.03 g) consisted exclusively of 5,6-dibenzylbenzimidazo[1,2-b]isoquinolin-11(5H)-one (6a), the yield of
which was 25%; mp 242-244°C (DMF). IR spectrum, ν, cm-1: 1650 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
8.79 (1H, d, J = 8.0, C(1)H); 8.42 (1H, d, J = 8.0, C(10)H); 7.56 (1H, t, J = 8.0, C(8)H); 7.46 (1H, d, J = 8.0, C(7)H);
7.23-7.37 (8H, m, C(2)H-C(4)H, C(9)H, C(3')H, C(5')H); 7.19 (2H, m, C(4')H); 7.10 (4H, m, C(2')H, C(6')H; 5.26 (2H, s,
5-CH2); 4.18 (2H, s, 6-CH2). Found, %: C 83.96; H 5.30; N 6.79. C29H22N2O. Calculated, %: C 84.03; H 5.35;
N 6.76.
When alkylating with 2,4-dimethylbenzyl chloride by method A the solid consisted exclusively of NaCl.
On alkylating by method B the solid (0.25 g) contained a mixture of 6-(2,4-dimethylbenzyl)benzimidazo-
[1,2-b]isoquinolin-11(5H)-one (4a) and 5,6-di(2,4-dimethylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-
1
one (6b). According to the data of the H NMR spectrum, δ, ppm (J, Hz): 8.81 (m, ArH); 8.45 (m, ArH);
6.30-7.60 (m, ArH); 5.03 (s, 5-CH2, 6b); 4.15 (s, 6-CH2, 4a); 3.83 (s, 6-CH2, 6b); 2.49 (s, 2'-CH3, 4a); 2.23 (s,
5-[2',4'-(CH3)2C6H4CH2], 6b); 2.19 (s, 4'-CH3, 4a); 1.96 (s, 6-(2'-CH3-4'-CH3-C6H4CH2), 6b); 1.85 [s, 6-(2'-CH3-
4'-CH3-C6H4CH2), 6b], ratio 4a:6b, 5:1.
By method A from 3-nitrobenzyl chloride a mixture (0.22 g) was obtained, consisting, according to data
of the 1H NMR spectrum, of 6-(3-nitrobenzyl)-benzimidazo[1,2-b]isoquinolin-11(5H)-one (4b) and initial 1 in
a ratio of 3:2. By method B a mixture (0.3 g) was obtained of the 6-benzyl derivative 4b and 5,6-di(3-
1
nitrobenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (6c). According to data of the H NMR spectrum,
δ, ppm (J, Hz): 11.96 (br. s, NH, 4b); 8.35-8.90 (m, ArH); 7.15-8.19 (m, ArH); 5.65 (s, 5-CH2, 6c); 4.47 (s,
6-CH2, 4b and 6-CH2, 6c), the 4b:6c ratio in the mixture was 5:1.
On using 2-cyanobenzyl bromide (method A) a mixture (0.23 g) was obtained consisting, according to
1
data of the H NMR spectrum, of 5,6-di(2-cyanobenzyl)-benzimidazo[1,2-b]isoquinolin-11(5H)-one (6d) and
initial 1 in a ratio of 1:3. By method B a mixture (0.2 g) was obtained of 6,6-di(2-cyanobenzyl)benzimidazo-
1
[1,2-b]isoquinolin-11(5H)-one (5c) and the 5,6-dibenzyl derivative 6d. According to data of the H NMR
spectrum, δ, ppm (J, Hz): 8.05-8.85 (m, ArH); 7.10-7.90 (m, ArH); 6.30 (m, ArH); 5.46 (s, 5-CH2, 6d);
4.05-4.28 (m, 6-CH2, 5c and 6-CH2, 6d), the ratio of 5c:6d in the mixture was 1:6.
_______
*Data of the 1H NMR spectrum of the initial compound 1 are given in [1].
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The filtrate was evaporated in vacuum, water (15 ml) was added to the residual oil, and the mixture left
for 1 day. The solid formed was filtered off, and washed with a small amount of 2-propanol. On using benzyl
chloride by method A 1.65 g (40%) and by method B 2.26 g (55%) of 6,6-dibenzylbenzimidazo[1,2-b]-
isoquinolin-11(6H)-one (5a) was obtained.
When using 2,4-dimethylbenzyl chloride by method A 2.0 g (57%) or method B 1.58 g (45%) of
6-(2,4-dimethylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (4a) was obtained (Tables 1 and 3).
When using 3-nitrobenzyl chloride a mixture was obtained (method A) of 6-(3-nitrobenzyl)-
benzimidazo[1,2-b]isoquinolin-11(5H)-one (4b) and 6,6-di(3-nitrobenzyl)benzimidazo[1,2-b]isoquinolin-
11(5H)-one (5b), which was separated by recrystallization from DMF (Tables 1-3). The solid precipitated on
cooling was filtered off and the monobenzyl derivative 4b (1.14 g, 31%) was obtained. Water was added to the
filtrate and the precipitate of dibenzyl derivative 5b was filtered off. Yield 1 g (34%). The 6,6-dibenzyl
derivative 5b (1.67 g, 55%) was obtained by method B.
Using o-bromomethylbenzonitrile compound 5c (2.18 g by method A or 2.92 g by method B) was
obtained (Tables 2 and 3).
6-(2-Cyanobenzyl)benzo[4,5]imidazo[1,2-b]isoquinolin-11(5H)-one (4c) (Tables 1 and 3). A mixture
of compound 1 (2.34 g, 10 mmol) and o-bromomethylbenzonitrile (2.94 g, 15 mmol) was fused on an oil bath at
135°C for 40 min. The mixture was cooled, and acetone (10 ml) added. The resulting solid was filtered off,
washed with acetone, and dissolved with heating in morpholine (5 ml). After cooling, water (20 ml) was added,
and the solid formed was filtered off.
6-{2-[(11-Oxo-5,11-dihydrobenzo[4,5]imidazo[1,2-b]isoquinol-6-yl)methyl]-benzyl}benzo[4,5]-
imidazo[1,2-b]isoquinolin-11(5H)-one (8) (Tables 1 and 3). Compound 1 (2.34 g, 10 mmol) was added to a
solution of i-PrONa (0.9 g, 11 mmol) in 2-propanol (10 ml), and dissolved on heating. o-Xylylidene dibromide
(3.16 g, 12 mmol) was added and the mixture was boiled for 1.5-2 h. The resulting solid was filtered off, and the
filtrate evaporated in vacuum. Water (15 ml) was added to the residual oil, and the mixture was left for 1 day.
The solid was filtered off, washed thoroughly with water, and with alcohol, and recrystallized from DMF.
1,6-Dihydro-11H-6a,11b-diazabenzo[b]benzo[5,6]cyclohepta[1,2,3-l,m]fluoren-11-one (10). Benz-
imidazoisoquinoline 1 (2.34 g, 10 mmol) was added to a solution of sodium (0.5 g, 22 mmol) in 2-propanol
(10 ml) and dissolved on heating. o-Xylylidene dibromide (3.16 g, 12 mmol) was added to the solution obtained,
and the mixture was boiled for 1.5 h. After cooling the solid formed was filtered off. Further isolation of
alkylated products was carried out separately for the solid and the filtrate (see below). The solid formed was
filtered off, washed thoroughly with water, and recrystallized from DMF. Yield 2.18 g (65%); mp 246-248°C
(DMF). IR spectrum, ν, cm-1: 1645 (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.64 (1H, d, J = 8.0,
C(10)H); 8.36 (1H, d, J = 8.0, C(12)H); 8.04 (1H, d, J = 8.0, C(15)H); 7.70 (2H, m, C(7)H, C(14)H); 7.54 (1H, dd,
Jo = 8.0, Jm = 2.0, C(5)H); 7.43 (2H, m, C(2)H, C(8)H); 7.22-7.30 (3H, m, C(3)H, C(4)H, C(13)H); 7.16 (1H, t, J = 8.0,
C(9)H); 5.58 (2H, s, 6-CH2); 4.50 (2H, s, 1-CH2). Found, %: C 82.09; H 4.70; N 8.32. C23H16N2O. Calculated, %:
C 82.12; H 4.79; N 8.33.
Spiro(benzimidazo[1,2-b]isoquinolin-6,2'-indan)-11-one (9) (Tables 2 and 3) was isolated from the
filtrate remaining after filtering off cycloheptafluorene 10. The solvent was evaporated in vacuum, water (10 ml)
was added to the residual oil, and the mixture left for 1 day. The solid formed was filtered off, washed with
water, and with alcohol, and recrystallized from DMF.
6-(Carbamoylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (11) (Tables 1 and 3). A mixture of
benzimidazoisoquinoline 1 (2.34 g, 10 mmol) and o-bromomethylbenzonitrile (2.94 g, 15 mmol) was melted in
an oil bath at 135°C for 40 min. The mixture was cooled and acetone (10 ml) was added. The resulting solid was
filtered off and washed with acetone. The solid substance obtained was boiled for 3 h in acetic acid (15 ml),
during which time the hydrobromide of the 6-(2-cyanobenzyl)-substituted compound 4c gradually dissolved and
the solid benzamide 11 was precipitated. After cooling, the solid was filtered off, washed with AcOH, and with
alcohol, and recrystallized from AcOH.
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Spiro[benzimidazo[1,2-b]isoquinolin-6(11H),2'-indan]-1',11-dione (12) (Tables 2 and 3). A
suspension of benzamide 11 (3.67 g, 10 mmol) in AcOH (20 ml) was boiled for 4 h. The initial benzamide
gradually dissolved. After cooling, the precipitated solid was filtered off, washed with AcOH, and with alcohol,
and recrystallized from DMF. 13C NMR spectrum, δ, ppm: 199.94 (C-1'); 155.29 (C-3'a); 154.13 (C-5a); 142.73
(C-4a); 139.69 (C-6a); 137.33 (C-5'); 135.70 (C-8); 132.32 (C-7'a); 131.69 (C-11b); 129.41, 129.14, 127.75,
126.36, 126.17, 125.94, 125.85, 125.51 (C-2, C-3, C-7, C-9, C-10, C-10a, C-4', C-6', C-7'); 119.99 (C-4); 115.54
(C-1); 56.68 (C-6); 42.55 (C-3'). Mass spectrum, m/z (I, %): 350 (39) [M]+, 321 (41), 292 (6).
6-(2-Semicarbazidocarbonylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (13a) (Tables 1 and
3). A mixture of semicarbazide hydrochloride (2 g) and anhydrous sodium acetate (2 g) in absolute ethanol
(20 ml) was boiled and filtered hot. Spiroindanone 12 (0.9 g, 2.6 mmol) was added to the filtrate and the mixture
was heated on the water bath for 1.5 h until complete solution of the initial compound. Water (10 ml) was added,
and the mixture cooled. The precipitated solid was filtered off, washed with water, and with alcohol, and
recrystallized from DMF.
6-(2-Methoxycarbonylbenzyl)benzimidazo[1,2-b]isoquinolin-11(5H)-one (13b) (Tables 1 and 3).
Triethylamine (2 ml) was added to a suspension of spiroindanone 12 (1.75 g, 5 mmol) in methanol (20 ml) and
the mixture was boiled for 4 h. The initial compound gradually dissolved and solid methyl benzoate 13b was
precipitated. After cooling, the solid was filtered off, washed with methanol, and recrystallized from DMF.
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