Condensed isoquinolines 29. Oxidation reactions of 5-aryl-7,12- dihydroisoquino[2,3-a]quinazolinium salts

Article abstract of DOI:10.1007/s10593-008-0049-x

5-Aryl-7,12-dihydroisoquino[2,3-a]quinazolinium perchlorates are readily oxidized by atmospheric oxygen to form the products of oxidative coupling 5,5′-bis(aryl)-3,3′-dihalo[7,7′]bi[isoquino-[2,3-a] quinazoline-13,13′-diylium perchlorates. Heating 3-chlor

Full text of DOI:10.1007/s10593-008-0049-x

Chemistry of Heterocyclic Compounds, Vol. 44, No. 3, 2008
CONDENSED ISOQUINOLINES
29*. OXIDATION REACTIONS OF 5-ARYL-
7,12-DIHYDROISOQUINO[2,3-a]QUINAZOL-
INIUM SALTS
L. M. Potikha, V. M. Kisil, A. V. Turov, and V. A. Kovtunenko
5-Aryl-7,12-dihydroisoquino[2,3-a]quinazolinium perchlorates are readily oxidized by atmospheric
oxygen to form the products of oxidative coupling 5,5'-bis(aryl)-3,3’-dihalo[7,7']bi[isoquino-
[2,3-a]quinazoline-13,13'-diylium perchlorates. Heating 3-chloro-5-phenyl-7,12-dihydroisoquino-
[2,3-a]quinazolinium perchlorate in nitrobenzene gives the 3-chloro-5-phenylisoquino[2,3-a]quin-
azolin-13-ium perchlorate. The aromatic 5-arylisoquino[2,3-a]quinazoline derivatives obtained react
with nucleophilic reagents to form addition products at the C-12 atom.
Keywords: 5-arylisoquino[2,3-a]quinazoline, isoquinolines, condensed quinazolines, borohydride
reduction, oxidation, oxidative coupling.
The first representatives of the isoquino[2,3-a]quinazoline system were obtained quite recently [2, 3] and
they included 5-aryl-substituted derivatives [2, 4]. However, by contrast to 5-oxoisoquino[2,3-a]quinazolines,
the properties of the latter were not studied. The already existing data for the biological activity of
isoquinoquinazolines [5, 6] and 4-arylquinazolines condensed along the a edge [7-9] points to the potential of
such an investigation.
We have previously proposed [4] a method for the synthesis of the 5-aryl-7,12-dihydroisoquino-
[2,3-a]quinazolinium salts 1a-c consisting of reaction of o-(bromomethyl)phenylacetonitrile with o-amino-
benzophenones 2a-c and subsequent cyclization of the initially formed 2-aryl-3-imino-1,4-dihydroisoquinoline
hydrobromides 3a-c in the presence of perchloric acid. In this work the reaction was subjected to closer study
with the aim of optimizing the method of synthesizing the isoquinoquinazolinium salts 1 and to study the
spectroscopic and chemical properties of the products.
We have found that the outcome of the reaction of o-(bromomethyl)phenylacetonitrile with
benzophenones 2 depends markedly on both the reaction conditions and on the nature of the substituent in
reagent 2. Hence heating in acetonitrile, in some examples (2b,c) gave a mixture of the isoquinolineimine
bromides 3 together with an unknown product. Addition of catalytic amounts of acetic acid to the reaction
mixture virtually suppresses the formation of the side product. When the reaction is carried out in 2-propanol the
unknown material is the sole product. And in the case of the benzophenone 2d gives the unknown material
_______
* For Communication 28 see [1].
__________________________________________________________________________________________
Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: potikha_1@mail.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 428-439, March, 2008. Original article submitted
April 9, 2007.
330
0009-3122/08/4403-0330©2008 Springer Science+Business Media, Inc.

ArCO
N
Hal
Hal
CH2Br
CH2CN
H2N
_
+
NH2 Br
Ar
2a–g
O
3a–c
Hal
2g
+
N
Hal
–
HClO4
+
N
N
Ar
1a–c
1c
N
Ar
2 ClO4
_
Ar
N
Cl
_
ClO4
N
+
+
N
_
ClO4
Hal
5a–g
N
Ph
+
N
4
N
O
Me
6
1a–c – 5a–g Ar, Hal; a 4-O2NC6H4, Br; b 4-BrC6H4, Br;
c Ph, Cl; d 4-MeC6H4, Br
as the sole product independently of the conditions. the benzophenone 2d the unknown material is the sole
product independently of the conditions. A similar result was obtained upon prolonged heating (6-30 h) the
iminoisoquinoline hydrobromides 3a-c with the 5-arylisoquinoquinazolium 1a-c in acetonitrile and in other
solvents (benzonitrile, DMSO). On the basis of this data and also the tendency of condensed 1,4-dihydro-
isoquinolines towards oxidation discovered by us earlier [10-12] we propose that the products are due to
oxidation by atmospheric oxygen in this case. It would be logical to suggest that such a reaction can also occur
in the presence of other oxidants, e.g. in nitrobenzene since the aromatic derivatives isoquino[2,3-a]quinazolin-
5(6H)-one [10] and 13-oxo-5H,13H-isoquino[3,2-b]quinazolin-13(5H)-one [12] were previously obtained under
these conditions. Heating the 5-aryl-7,12-dihydroisoquino[2,3-a]quinazolinium perchlorates 1a-c in
nitrobenzene also readily formed the oxidation products, the result of this reaction depending on the nature of the
substituent in the 5-aryl group. Hence the 5-(4-nitro-phenyl)- and 5-(4-bromophenyl) derivatives 1a,b gave
products identical to those obtained before by heating the starting salts in benzonitrile or acetonitrile and the
5-(4-tolyl) derivative 1c gave a compound close in spectroscopic parameters to the products of oxidation of salts
1a,b but differing in the presence of an additional proton signal in the aromatic region.
The IR spectra of all of the oxidation products show the absence of carbonyl and hydroxyl stretching
bands in the characteristic regions and the 1H NMR spectra show only signals in the aromatic proton region. On
the basis of the IR and NMR spectroscopic data and elemental analysis the synthesized compound can be
assigned the structure of the aromatic salt 3-chloro-5-phenylisoquino[2,3-a]quinazolin-13-ium perchlorate (4)
for the product of oxidation of salt 1c in nitrobenzene and the products of oxidative coupling as the
5,5'-bis(aryl)-3,3'-dihalo[7,7']bi[isoquino[2,3-a][quinazoline]-13,13'-diylium perchlorates 5a-d in the remaining
331

TABLE 1. Spectroscopic Characteristics of the 5-Arylisoquino-
[2,3-a]quinazoline derivatives 4, 5a-d, 7a,b
1Н NMR spectrum, δ, ppm (J, Hz)
IR spectrum,
Com-
pound
ν, cm-1
1H, s, 1H, s,
Н-12 Н-7
ArH
4
1615 (C=N),
1555, 1500,
1440, 1420,
1355, 1090,
760, 625
9.36 (1Н, d, 3J = 9.0, Н-1); 8.75 (1Н, d, 3J = 8.4, Н-11); 11.41 9.28
8.69 (1Н, dd, 3J = 9.0, 4J = 1.2, Н-2);
8.54 (1Н, d, 3J = 8.0, Н-8); 8.33 (1Н, t, 3J = 8.0, Н-9);
8.19 (1Н, d, 4J = 1.2, Н-4); 8.17 (1Н, t, 3J = 8.0, Н-10);
7.93 (2Н, m, H-2',6'); 7.75 (3Н, m, H-4',3',5')
5a
5b
1615 (C=N),
1595, 1550,
1400, 1350
(NO2), 1100,
660
9.45 (1Н, d, 3J = 9.0, Н-1); 8.99 (1Н, d, 3J = 8.4, Н-11); 11.80
—
—
8.70 (1Н, dd, 3J = 9.0, 4J = 2.0, Н-2);
8.24 (2Н, m, Н-4,10); 8.16 (3Н, m, Н-9,3',5');
8.00 (1Н, d, 3J = 8.0, Н-8); 7.56 (2Н, d, 3J = 8.8, H-2',6')
1600 (C=N),
1585, 1540,
1500, 1420,
1395, 1350,
1090, 620
9.37 (1Н, d, 3J = 9.0, Н-1); 8.96 (1Н, d, 3J = 8.4, Н-11); 11.73
8.76 (1Н, dd, 3J = 9.0, 4J = 2.0, Н-2);
8.30 (1Н, d, 4J = 2.0, Н-4); 8.26 (1Н, t, 3J = 8.0, Н-10);
8.18 (1Н, t, 3J = 8.0, Н-9); 8.00 (1Н, d, 3J = 8.0, Н-8);
7.56 (2Н, t, 3J = 8.8, H-3',5');
7.18 (2Н, d, 3J = 8.8, H-2',6')
5c
1615 (C=N),
1595, 1550,
9.49 (1Н, d, 3J = 9.0, Н-1); 8.98 (1Н, d, 3J = 8.4, Н-11); 11.73
—
—
8.56 (1Н, dd, 3J = 9.0, 4J = 2.0, Н-2);
8.26 (1Н, t, 3J = 8.0, Н-10); 8.17 (1Н, t, 3J = 8.0, Н-9);
8.14 (1Н, d, 4J = 2.0, Н-4); 8.06 (1Н, d, 3J = 8.0, Н-8);
7.48 (1Н, t, 3J = 7.6, H-4'); 7.35 (2Н, t, 3J = 7.6, H-3',5');
7.22 (2Н, d, 3J = 7.6, H-2',6')
1500, 1395,
1350, 1090,
620
5d*
1610 (C=N),
1595, 1545,
1500, 1425,
1390, 1345,
1090, 620
9.44 (1Н, d, 3J = 9.0, Н-1); 8.99 (1Н, d, 3J = 8.4, Н-11); 11.73
8.78 (1Н, dd, 3J = 9.0, 4J = 2.0, Н-2);
8.31 (1Н, d, 4J = 2.0, Н-4); 8.25 (1Н, t, 3J = 8.0, Н-10);
8.16 (1Н, t, 3J = 8.0, Н-9); 8.04 (1Н, d, 3J = 8.0, Н-8);
7.14 (2Н, t, 3J = 8.8, H-2',6');
7.12 (2Н, d, 3J = 8.8, H-3',5')
7a
7b
1665 (С=N),
1595, 1540,
1485, 770
7.69 (1Н, d, 3J = 7.8, Н-2);
5.08,
2H
5.5
5.5
7.66 (2Н, d, 3J = 9.0, H-2',6');
7.50 (4Н, m, H-1, H-1,3'–5');
7.04-6.96 (4Н, m, Н-1,8,10,11); 6.89 (1Н, t, 3J = Н-9)
1660 (С=N),
1590, 1535,
1485, 770
7.71 (1Н, d, 3J = 7.8, Н-2);
5.02,
2H
7.64 (2Н, d, 3J = 9.0, H-2',6'); 7.48 (3Н, m, H-1,3',5');
7.14 (1Н, s, Н-4); 7.09-6.96 (3Н, m, Н-8,10,11);
6.90 (1Н, t, 3J = Н-9)
_______
* A signal is observed at 2.28 ppm (3H, s, CH3) in the 1H NMR spectrum.
cases. We have carried out a detailed comparative analysis of the spectroscopic characteristics of these
compounds and the model compound 6-methyl-5-oxo-5,6-dihydroisoquino[2,3-a]quinazolin-13-ium perchlorate
(6) (the structure of which has been established before [13]) in order to confirm the structures of the oxidation
products.
1
With this in mind we measured their H and 13C NMR spectra (Table 1) and also used homonuclear
(COSY) and heteronuclear (HMBC and HMQC) 2D correlation spectroscopy. In addition, we have recorded
their NOESY 1D and NOESY spectra to measure the steric proximity of individual protons. The data for the
heteronuclear correlation for the aryl derivatives 4, 5c,d and the simpler compound 6 are given in Table 2. The
available data allows us to perform a full assignment of signals in the proton and carbon spectra and to draw
conclusions regarding the structure of the compound studied. Figure 1 shows the assignments of signals and the
arrows depict the structurally significant HMBC correlations. Hence for compound 6 the proton with a chemical
332

shift of 8.63 ppm has a correlation with two quaternary carbon atoms absorbing at 140.6 and 141.4 ppm which
correspond to the nodal C(7a) and C(6a) atoms. The latter atoms also correlates with the signals for the protons
of the 6-methyl group and H-12 which are 3 chemical bonds distant. Assignment of the carbonyl carbon atom
signal was made on the basis of its correlation on the one hand with the methyl group signal at N-6 and on the
other hand with the H-4 proton signal. It was interesting that the carbonyl atom C-5 has a strong correlation with
the signal for atom H-1 which is 4 chemical bonds distant from it. We consider this correlation as due to a W
type interaction. There is also a 4 bond correlation between the signals for the methyl group protons and the C-7
atom signal.
136.5
136.5-139.2
Hal
8.92
9.3-9.4
11.4-11.7
141.5-
142.4
11.98
8.50
132.1
129.5
125.2-136.3
8.7-8.9
141.1
132.4
136
+
137
8.47
8.2-8.3
N
130.3
N
+
123.8
140.6
111.2
120.9
157.3
121.
126
A
B
139.7-
140.2
141.4
162.7-163.8
139.5
N
O
N
127
8.27
126.5-
128.8
2
32.1
CH3
3.85
8.0-8.5
8.63
R
1
R
7.1-7.9
Figure 1. Structurally significant HMBC correlations for compound 6 (A) and 4, 5b,d (B).
A similar study was made for compounds 4 and 5a-d. For the various spectra we have found a whole
series of analogies with the corresponding spectra of compound 6. Hence a singlet is found to lowest field with a
chemical shift of 11.4-11.8 ppm. In addition there are found several aromatic proton signals to unusually low
1
field. The single marked difference in the H NMR spectra of compound 4 and the salts 5a-d is the presence of
the H-7 one-proton singlet at 9.28 ppm with a small shift of the signals of the 5-phenyl protons to low field.
Assignment of the protons signals was made using 2D COSY spectroscopy. The spin multiplets agree with the
proposed structure and the positions of the cross peaks permit a full assignment of the proton spectra. The low
field shift of a series of signals in the spectrum points to the presence of a delocalized positive charge in the
heterocyclic fragment. Nonbonded interactions also make a contribution to the deshielding of protons located
closely in space due to the angular structure of the molecule. The presence of such an interaction is proved by a
study of NOE correlations. Using the NOESY-1D method with saturation of the H-12 proton signal at 11.7 ppm
for both compounds 5c,d a change in intensity of the H-1 signal of about 30% was found. The H-11 proton
signal changes in intensity by 10-11%. A close value of the NOE was also found for the H-12 proton upon
saturation of the H-1 proton. An interesting feature of the NOE experiments for these compounds is that the
observed effects are negative rather than positive as is usually the case. Stationary NOE experiments also give
very similar results. The only possible explanation for this effect is that the correlation time for the molecule is
too small. This is a feature of molecules with a high molecular weight. Hence this experiment is an indirect
confirmation of the dimer structure of the salt 5a-d molecules. In this case the molecular weight is close to 1000
and negative NOE values are possible. The structure of the carbon skeleton of the molecules of compounds 4
and 5c,d were proved using 13C NMR measurements. The number of signals in the carbon spectra agreed with
the number of non-equivalent carbon atoms present in the molecule. Editing of the spectra according to spin
multiplicities was carried out using the DEPT method. Here, as expected (Table 2), there were located the signal
for the methyl group (for 5d) and 10 CH signals (for 5c,d two were of double intensity) or 11 CH signals in the
case of compound 4. Assignment of the carbon signals of the methine groups were made using the heteronuclear
HMQC spectra. The carbon-proton correlations found are given in Table 2 and the most structurally significant
333

values displayed in Figure 1. The most interesting result is the correlation of the carbon atom signal with a
chemical shift of 141.5-142.4 with the proton signal at 11.4-11.8 ppm. In addition to a secure assignment of the
1
corresponding carbon signal it confirmed that the signal at 11.4-11.8 ppm in the H NMR spectrum is, in fact,
the deshielded H-12 proton. The correlation of the low field signal for H-1 at 9.33-9.37 ppm with the high field
carbon signal at 122 ppm was slightly unexpected. This suggests that a non-bonded interaction rather than
electronic factors made a basic contribution to the deshielding of the H-1 signal.
Further confirmation of the structure of molecules came from proton-carbon correlation using the
gradient HMBC method and led to a full assignment of the signals in the 13C NMR spectra. The chemical shift of
the C-5 atom proved to be unexpected. As a signal occurs in the spectrum at 162.7-163.8 ppm it would be
TABLE 2. Proton-Carbon Correlations for compounds 4, 5b,d, 6
13С NMR
spectrum, δ, ppm
Chemical shifts of protons for which
HMBC correlations exist, δ, ppm
1H NMR spectrum, δ, ppm;
Atom
number
HMQC correlation
1
2
3
4
Compound 4
9.33
8.69
—
1
122.0
136.5
136.3
132.3
121.6
163.8
140.2
126.5
139.5
128.3
137.6
129.4
130.8
126.2
141.5
135.8
135.6
130.5
129.8
132.1
—
2
8.19, 9.33
3
8.19
4
8.19
—
8.69
4a
5
9.33
—
7.93, 8.19
6a
7
—
11.41
9.28
—
8.55, 8.17
7a
8
11.41, 8.75, 8.56, 8.33
8.56
8.33
8.17
8.75
—
—
8.75
9
10
11
11a
12
13a
1'
—
11.41, 8.33
9.28, 8.17
—
11.41
—
11.41, 8.69, 8.19
7.75
—
2'
7.93
7.75
7.75
Compound 6
8.92
8.26
7.99
8.47
—
7.75
3'
7.93
4'
7.93
1
119.1
136.5
132.1
129.5
120.9
157.3
141.4
111.2
140.6
127.0
138.6
130.3
130.6
123.8
141.1
137.0
32.1
7.99
2
8.47, 7.99
3
8.92
4
8.26, 7.99
4a
5
8.92, 7.99
—
8.92, 8.47, 3.85
10.98, 3.85
10.98, 8.27, 3.85
8.63, 8.50, 8.27
8.63, 7.92
6a
7
—
8.63
—
7a
8
8.27
8.19
7.92
8.50
—
9
8.50, 7.92
10
11
11a
12
13a
CH3
—
10.98, 8.19
10.98, 8.63, 8.50, 8.27, 7.92
—
10.98
—
10.98, 8.92, 8.47, 8.26
—
3.85
334

TABLE 2. (continued)
1
2
3
4
Compound 5b
9.37
8.76
—
1
121.8
139.6
125.5
132.4
121.7
162.7
139.7
128.8
139.6
126.9
138.5
132.5
131.8
126.2
142.2
136.6
134.4
132.3
132.6
126.0
—
2
8.30
3
9.37, 8.76, 8.30
4
8.30
—
8.76
4a
5
9.37
—
9.37, 8.30, 7.18
6a
7
—
11.73
—
8.00
7a
8
—
11.73, 8.96, 8.18
8.00
8.18
8.26
8.96
—
—
9
8.96
10
11
11a
12
13a
1'
8.18, 8.00
11.73
8.26, 8.00
11.73
—
8.96
11.73, 9.37, 8.76, 8.30
—
7.56
2'
7.18
7.56
—
7.56
3'
7.18
4'
7.56, 7.18
Compound 5d
9.44
8.78
—
1
122
139.2
125.2
132.4
121.8
163.4
139.7
128.5
139.6
126.9
138.2
132.1
131.6
126
—
2
8.31
3
9.44, 8.78, 8.31
4
8.31
—
8.78
4a
5
9.44
—
9.44, 8.31, 7.14
6a
7
—
11.74
—
8.04, 11.74
7a
8
—
8.99, 8.16, 8.04
8.04
8.16
8.25
8.99
—
—
9
8.99
10
11
11a
12
13a
1'
—
11.74, 8.16, 8.04
11.74, 8.99, 8.04
8.99
142.4
136.6
132.4
130.2
130
11.73
—
11.74, 9.44, 8.78, 8.31
7.12
—
2'
7.14
7.12
—
7.12, 2.28
—
3'
4'
142.4
21.4
7.14, 2.28
7.14
CH3
2.28
logical to assign it to the C-6a atom since it is located between two heterocyclic nitrogen atoms. However, this
signal has correlations with the H-4 and H-2' protons. Hence the C-5 atom is not more than three chemical bonds
distant from the given protons and this is only possible in the case that the signal at 162.7-163.8 ppm
corresponds to the C-5 atom. This correlation is very strong and occurs in all three compounds studied. It also
occurs when the spectra are measured in trifluoroacetic acid. The signal for the C-7 atom (through which the
dimerization of the molecules 5c,d occurs) is basically identified by its correlation with the H-8 proton. A
similar correlation is also observed in the case of salt 4.
335

An additional confirmation that the compounds 5a-d are the products of oxidative coupling of the
5-arylisoquinazolinium salts 4 is the high similarity of their UV spectra indicating that they are isoelectronic. In
addition the result obtained points to the absence of an interaction between the conjugated systems of the two
fragments of the molecule in the compounds 5 which can be fully understood in view of the steric hindrance to
their coplanarity.
Cl
Cl
–
8'
ClO4
+
N
5'
3
RNH2
N
1b,c
6
N
Ph
Ph
N
4
N
R
PyH
8a,b
NaBH4
Hal
a R = CH2Ph, b R = CHMe2
N
N
Ar
7a,b
a Ar = Ph, Hal = Cl; b Ar = 4-BrC6H4, Hal = Br
We were unable to record the mass spectra of the 5-arylisoquinoquinazolinium salts 4 and 5a-d because,
on the one hand, of the limits of many methods of molecular weight investigation of the studied compounds
(close to 1000 for the dimers 5a-d) and, on the other, to their lability in the presence of nucleophiles including
the traces of water contained in the solvents used. None the less such a result was quite expected. It had been
found previously [10] that the 6-methyl-5-oxo-5,6-dihydroisoquino[2,3-a]quinazolin-13-ium perchlorate 6,
which is closely related structurally to the salts 4 and 5a-d, readily reacts with nucleophilic reagents. The
reaction occurs at position 12 of the heterosystem and gives products of nucleophilic addition with subsequent
fission of the isoquinoline ring at the C(12)–N(13) bond. In the case of compound 4 it was found that the 5-aryl-
isoquino[2,3-a]quinazolinium perchlorates react by the same scheme. Hence reaction of salt 4 with sodium
borohydride in alcohol gives 3-chloro-5-phenyl-12H-isoquino[2,3-a]quinazoline (7a) which was also obtained
by treating the 3-chloro-5-phenyl-7,12-dihydroisoquino[2,3-a]quinazolinium perchlorate 1c with pyridine. It was
found that the yield of compound 7a was not high both in the reduction of salt 4 and in the deprotonation of salt
1c. The 3-bromo-5-(4-bromophenyl)-12H-isoquinoquinazoline 7b was also obtained in low yield from the salt
1b. This is evidently connected with the high susceptibility of compounds 7a,b towards oxidation and this
1
explains the difficulties in isolation and purification. The H NMR spectra of freshly prepared solutions of
compounds 7a,b in DMSO-d6 confirm their structure as products of the deprotonation of the
7,12-dihydroisoquino-[2,3-a]quinazoline system at position 7 or addition of hydride anion to atom C-12 in salt 1c:
the signal for the C(12)H2 methylene group is observed at 5.1 and 5.02 ppm (2H, s) and the C-7 methine proton
signal at 5.5 ppm.
The reaction of 3-chloro-5-phenylisoquino[2,3-a]quinazolin-13-ium perchlorate 4 with amines conforms
to the pattern found for 5-oxoisoquinoquinazolinium salts 6 [10]. Hence treatment with primary amines gives
2-(2-iminomethyl)benzyl-substituted 6-chloro-4-phenylquinazolines 8a,b as shown by the spectroscopic data for
1
the products obtained. Features of their H NMR spectra are the presence of the imino group proton at 9.04 and
8.90 ppm and aromatic protons occurring as nonoverlapping groups of signals with different spin systems
336

allowing their exact assignment. The reaction of the salt 4 with secondary amines also occurs readily. However,
the separation and characterization of the corresponding adducts of structure 7 could not be achieved because of
their high susceptibility to oxidation.
EXPERIMENTAL
The melting points of the synthesized compounds were determined on a Boetius type heating apparatus
and are not corrected. IR spectra for the compounds as KBr tablets were recorded on a Pye-Unicam SP3-300
1
instrument. H and 13C NMR spectra were taken on a Varian Mercury 400 (400 and 100 MHz) spectrometer
using DMSO-d6 and with TMS as internal standard and UV spectra on a Specord M400 spectrophotometer.
Monitoring of the reaction course and purity of the compounds obtained was carried out by TLC on Silufol
UV-254 plates.
3-Chloro-5-phenylisoquino[2,3-a]quinazolin-13-ium Perchlorate (4). A solution of the 3-chloro-
5-phenylisoquinoquinazolinium salt 1c (2.21 g, 5 mmol) in nitrobenzene (10 ml) was refluxed for 30 min. After
cooling, acetone (30 ml) was added. The yellow precipitate formed was filtered off and washed with acetone.
Yield 0.88 g (40%); mp > 300ºC (MeCO2H). UV spectrum (MeOH), λmax, nm (ε×10-3): 209 (22.1), 224 (26.8),
316 (29.4), 358 (11.0), 515 (4.4). Found, %: C 59.82; H 2.99; Cl 16.10; N 6.37. C22H14Cl2N2O4. Calculated, %:
C 59.88; H 3.10; Cl 16.07; N 6.35.
5,5-Bis(aryl)-3,3'-dihalo[7,7']bi[isoquino[2,3-a]quinazoline]-13,13'-diylium perchlorates 5a-c. A
solution of the 5-arylisoquinoquinazolinium salt 1a-c (10 mmol) in benzonitrile (20 ml) was refluxed for 30 min.
Solvent was removed in vacuo and 2-propanol (20 ml) was added to the residual oil. The yellow precipitate
formed was filtered off and washed with 2-propanol. Recrystallization from acetic acid gave the dimer
perchlorates 5a-c as a yellow crystalline material.
Compound 5a. Yield 2.13 g (40%); mp > 300ºC (MeCO2H). Found, %: C 49.75; H 2.13, Br 15.10;
Cl 6.70; N 7.97. C44H24Br2Cl2N6O12. Calculated, %: C 49.88; H 2.28; Br 15.08; Cl 6.69; N 7.93.
Compound 5b. Yield 4.24 g (75%); mp > 300ºC (MeCO2H). Found, %: C 46.71; H 2.01; Br 28.36;
Cl 6.30; N 5.00. C44H24Br4Cl2N4O8. Calculated, %: C 46.88; H 2.15; Br 28.35; Cl 6.29; N 4.97.
Compound 5c. Yield 2.6 g (60%); mp > 300ºC (MeCO2H). Found, %: C 59.92; H 2.75; Cl 16.12;
N 6.40. C44H26Cl4N4O8. Calculated, %: C 60.02; H 2.98; Cl 16.11; N 6.36.
3,3'-Dibromo-5,5'-bis(4-methylphenyl)-[7,7']bi[isoquino[2,3-a]quinazoline]-13,13'-diylium
Perchlorate (5d). o-Bromomethylacetophenone (1.26 g, 6 mmol) was added to a solution of (2-amino-
5-bromophenyl)-(4-methylphenyl)methanone 2d (1.45 g, 5 mmol) in acetonitrile (20 ml). The mixture was
refluxed for 18 h. The precipitate formed on cooling the mixture was filtered off. The solid material was
dissolved in acetic acid and a 70% solution of perchloric acid (3 ml) was added to the warm solution and heated
for 3 min. The precipitate formed on cooling was filtered off and washed with acetic acid and acetone. Yield
3.39 g (68%); mp > 300ºC (MeCO2H). UV spectrum (MeOH), λmax, nm (ε×10-3): 208 (49.9), 232 (62.3), 318
(59.2), 540 (10.9). Found, %: C 55.27; H 2.91; Br 16.05; Cl 7.20; N 5.65. C46H30Br2Cl2N4O8. Calculated, %:
C 55.39; H 3.03; Br 16.02; Cl 7.11; N 5.62.
3-Chloro-5-phenyl-12H-isoquino[2,3-a]quinazoline (7a). A. NaBH4 (10 mmol) was added portionwise
to a suspension of the 3-chloro-5-phenylisoquinoquinazolinium salt 4 (2.2 g, 5 mmol) in methanol (20 ml) and
heated for 1 h. After cooling a dark-blue precipitate of compound 7a was formed. It was filtered off, carefully
washed with sodium carbonate solution (15%) and water, and recrystallized from 2-propanol. Yield 0.43 g
(25%); mp 136-138ºC (2-propanol). Found, %: C 76.88; H 4.35; Cl 10.37; N 8.25. C22H15ClN2. Calculated, %:
C 77.08; H 4.41; Cl 10.34; N 8.17.
B. The 3-chloro-5-phenylisoquinoquinazolinium perchlorate 1c (2.21 g, 5 mmol) was dissolved with
heating in pyridine (10 ml). Water (50 ml) was added to the solution and the precipitate was filtered off and
washed with water and alcohol. Yield 0.34 g (20%).
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3-Bromo-(4-bromophenyl)-12H-isoquino[2,3-a]quinazoline (7b) was prepared by the method B
reported above for compound 7a using 3-bromo-5-(4-bromophenyl)isoquinoquinazolinium perchlorate 1b
(2.83 g, 5 mmol). Yield 0.51 g (22%); mp 168-170ºC (2-propanol). Found, %: C 56.36; H 2.83; Br 34.31;
N 6.15. C22H14Br2N2. Calculated, %: C 56.68; H 3.03; Br 34.28; N 6.01.
N-({2-[(6-Chloro-4-phenyl-2-quinazolinyl)methyl]phenyl}methylidene)(phenyl)methanamine (8a).
The 3-chloro-5-phenylisoquinoquinazolinium perchlorate 4 (0.44 g, 1 mmol) was dissolved with heating in
benzylamine (4 ml), heated for a further 3 min, and left overnight. Water (50 ml) was added to the solution and
the precipitate was filtered off and washed with water and alcohol. Yield 0.28 g (63%); mp 122-124ºC
(2-propanol). IR spectrum, ν, cm-1: 1630 (C=N), 1550, 1490, 1390, 700. UV spectrum (MeOH),
1
λ
max, nm (ε×10-3): 206 (132.3), 232 (133.3), 320 (23.5), 520 (1.6). H NMR spectrum, δ, ppm (J, Hz): 9.04
(1H, s, –N=CH–); 7.96 (1H, d, 4J = 2.4, H-5'); 7.93 (2H, m, H-6,8'); 7.87 (1H, dd, 3J = 8.8, 4J = 2.4, H-7'); 7.65
(2H, m, H-2",6"); 7.55 (3H, m, H-3"-5"); 7.41 (1H, d, J =8.0, H-3); 7.36 (1H, t, J = 8.0, H-4); 7.28 (1H, t,
3J = 8.0, H-5); 7.15 (5H, s, NCH2–C6H5); 4.72 (2H, s, –NCH2–Ph); 4.71 (2H, s, CH2). Found, %: C 77.66;
H 4.83; Cl 7.93; N 9.40. C29H22ClN3. Calculated, %: C 77.76; H 4.95; Cl 7.91; N 9.38.
3
3
N-({2-[(6-Chloro-4-phenyl-2-quinazolinyl)methyl]phenyl}methylidene)-2-propanamine (8b) was
prepared by the method reported for compound 8a using 2-propylamine (4 ml). Yield 0.2 g (51%); mp
130-132ºC (2-propanol). IR spectrum, ν, cm-1: 1625 (C=N), 1550, 1490, 695. 1H NMR spectrum, δ, ppm (J, Hz):
8.89 (1H, s, –N=CH–); 7.98 (1H, d, 4J = 2.4, H-5'); 7.95 (1H, d, 3J = 8.8, H-8'); 7.88 (1H, dd, 3J = 8.8, 4J = 2.4,
H-7'); 7.86 (1H, dd, 3J = 8.0, 4J = 1.6, H-6); 7.68 (2H, m, H-2",6"); 7.59 (3H, m, H-3"-5"); 7.38 (1H, d, 3J = 8.0,
3
4
3
H-3); 7.32 (1H, td, J = 8.0, J = 1.6, H-4); 7.25 (1H, t, J = 8.0, H-5); 4.66 (2H, s, CH2); 3.47 (1H, m,
3
CH(CH3)2); 1.07 (6H, d, J = 6.4, CH(CH3)2). Found, %: C 74.89; H 5.32; Cl 8.88; N 10.59. C25H22ClN3.
Calculated, %: C 75.08; H 5.54; Cl 8.87; N 10.51.
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