Synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)-one derivatives in ionic liquids catalyzed by iodine

Article abstract of DOI:10.1007/s11164-015-2072-8

The iodine-catalyzed reaction of 2-(2-aminophenyl)quinazolin-4(3H)-ones and benzaldehydes was treated in ionic liquids, giving a series of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)-one derivatives in high yields. This novel procedure has the advantages

Full text of DOI:10.1007/s11164-015-2072-8

Res Chem Intermed
DOI 10.1007/s11164-015-2072-8
Synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-
8(6H)-one derivatives in ionic liquids catalyzed
by iodine
Yong-Gang Ma1 Yan Zhang1 Bin-Bin Feng1
Xiang-Shan Wang1
•
•
•
Received: 17 February 2015 / Accepted: 20 April 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract The iodine-catalyzed reaction of 2-(2-aminophenyl)quinazolin-4(3H)-ones
and benzaldehydes was treated in ionic liquids, giving a series of 6-aryl-5H-quinazoli-
no[4,3-b]quinazolin-8(6H)-one derivatives in high yields. This novel procedure has the
advantages of high yields, being metal-free and having a mild reaction condition.
Graphical Abstract
Keywords Quinazolinoquinazoline Á Ionic liquids Á Iodine Á Synthesis
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2072-8)
contains supplementary material, which is available to authorized users.
&
Xiang-Shan Wang
xswang1974@yahoo.com
1
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis
for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu,
People’s Republic of China
123

Y. Ma et al.
Introduction
It is well known that quinazoline derivatives always indicate good anti-tumor
activities [1–4]. A noteworthy compound is lapatinib (Fig. 1), which is an orally
active drug mainly used for the treatment of breast cancer [5]. In addition, it is
reported that quinazoline derivatives have other remarkable pharmacological and
biological activities, such as anti-inflammatory [6], anti-microbial [7], anti-tobacco
mosaic virus (TMV) [8], and anti-tubercular activities [9]. Quinazolinoquinazoline
is a tetracyclic heterocycle containing two quinazoline analogs, and its derivatives
have significant hypnotic activity [10] and are also used as anti-inflammatory agents
[11]. They are likely to indicate particular bio-activities, especially for anti-tumor
activity for biological activity screening.
Therefore, many procedures involving synthesis of quinazolinoquinazolines have
been reported in recent years [12–18]. In addition, to obtain these potentially bio-
active quinazolino[4,3-b]quinazoline derivatives, 2-(2-aminophenyl)quinazolin-
4(3H)-one is usually used as a catalyst to react with another reagent, such as
Schiff bases [19], ortho esters [20], and anhydrides [21]. Although theses useful
synthetic procedures have been developed, several limitations still remain, for
example, low yields or flammable organic solvents. Thus, a simple, efficient, and
‘‘green’’ method for synthesis of quinazolinoquinazolines is attractive.
In our recent study, it was surprising to find that quinazolino[4,3-b]quinazoline
derivatives were very easy to obtain in high yields via simple condensation of 2-(2-
aminophenyl)quinazolin-4(3H)-ones and aldehydes. As a continuation of synthe-
sising polycyclic heterocycles catalyzed by iodine [22–25], herein, we report on the
synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)-one derivatives in ionic
liquids catalyzed by iodine.
Results and discussion
Treatment of benzaldehyde (1a) and 2-(2-aminophenyl)quinazolin-4(3H)-one (2a)
in an ionic liquid of [BMIm]Br in the presence of 5 mol% iodine at 80 °C resulted
in the corresponding 6-phenyl-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3a) at a
96 % yield (Eq. 1).
Fig. 1 The structure of
lapatinib
N
N
O
l
C
HN
NH
S
O
O
O
F
123

Synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)…
O
N
O
N
CHO
N
NH
NH NH2
I2
IL
+
3a
1a
2a
Equation 1. The model reaction
In our initial study, using the reaction of benzaldehyde (1a) and 2a as a model,
several parameters, including reaction temperature, catalysts and the type of ionic
liquids, were explored, as shown in Table 1. 3a was not detected by thin layer
chromatography (TLC) in the absence of iodine at 80 °C (Table 1, entry 1), and was
successfully obtainable in the presence of various quantities of the catalyst. In the
presence of 5 mol% iodine, only trace amounts of 3a were monitored by TLC at
room temperature (Table 1, entry 2). With increased temperature, it gave a
maximum yield of 96 % at 80 °C (Table 1, entries 3–5). At the same temperature,
increasing the amount of catalyst did not improve the yield of 3a to a great extent
(Table 1, entries 4, 6 and 7). Different imidazolium-based ionic liquids were
also tested, such as [EMIm]Br, [PMIm]Br, [EMIm][BF4], [PMIm][BF4] and
Table 1 Synthetic results of 3a under different reaction conditions
Entry
Temp. (°C)
Ionic liquida
Time (h)
I2 (mol%)
Yields (3a, %)b
1
80
r.t.
50
80
100
80
80
80
80
80
80
80
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[BMIm]Br
[EMIm]Br
[PMIm]Br
[EMIm][BF4]
[PMIm][BF4]
[BMIm][BF4]
24
24
12
8
0
5
0
2
Trace
82
96
96
92
89
89
90
87
85
86
3
5
4
5
5
8
5
6
8
10
20
5
7
8
8
9
9
10
8
5
10
11
12
5
10
10
5
5
Reaction condition: 2 mL solvent, 2a (0.237 g, 1.0 mmol), and benzaldehyde (0.106 g, 1.0 mmol)
a
BMIm 1-butyl-3-methylimidazolium, EMIm 1-ethyl-3-methylimidazolium, PMIm 1-methyl-3-
propylimidazolium
b
Isolated yields
123

Y. Ma et al.
[BMIm][BF4], and [BMIm]Br appeared to be the best medium for this transfor-
mation (entry 4 vs. 8–12).
After the completion of reaction monitored by TLC, products were isolated by
simple filtration after adding a small amount of water to the cooled reaction mixture.
Water in the filtrate was removed by distillation under reduced pressure, and the
[BMIm]Br in the residue was reused after being evaporated at 80 °C for 4 h in a
vacuum. Successive reuse of the recycled ionic liquid of [BMIm]Br in the model
reaction gave high yields of 3a (92 %) even after the fourth cycle (Table 2).
The generality of this transformation was examined under the above optimized
reaction conditions, and the results are summarized in Table 3. A broad range of
benzaldehydes (Eq. 2) reacted with 2-(2-aminophenyl)quinazolin-4(3H)-one (2a)
successfully. Benzaldehydes 1 bearing both electron-donating (such as alkyl and
alkoxy groups) and electron-withdrawing substituents (such as halogens) on the
benzene ring can be used in the direct reaction to synthesize the desired 6-aryl-5H-
quinazolino[4,3-b]quinazolin-8(6H)-one derivatives (Table 3, entries 1–11) in high
yields (86–96 %). In addition, other 2-(2-aminophenyl)quinazolin-4(3H)-ones
(2b–2d) were prepared according to the corresponding nitro compounds via a
reduction reaction by 50 % hydrazine hydrate [26]. And they were then submitted to
react with 1 under the same reaction condition. To our delight, they were all carried
out smoothly to afford 3l–3p in 86–94 % yields (Table 3, entries 12–16).
Equation 2. The reaction of 1 and 2
According to the structure of the 3 products, we suggest that iodine catalyzes the
reaction as a mild Lewis acid. A Schiff base may be formed first in the presence of
iodine, and then intra-molecular cyclization takes place to give the final 3 products.
The possible reaction mechanism is shown as follows (Scheme 1),
Table 2 Yields of 3a in the reuse of recycled ionic liquid
Cycle
1
2
3
4
Yields (3a %)
92
90
90
92
Reaction condition: 2 mL [BMIm]Br, 2a (0.237 g, 1.0 mmol), and 1a (0.106 g, 1.0 mmol), 80 °C
123

Synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)…
Table 3 Synthetic results for
the 3 products
Entry
R
R0
Products Time (h) Yieldsa (%)
1
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
8
8
96
92
90
90
87
94
92
89
92
86
84
94
86
91
90
92
2
4-Br
3
2,4-Cl2
2,3-(MeO)2
4-F
6
4
10
10
10
12
8
5
6
4-Cl
7
3,4-(MeO)2
2-F
3g
3h
3i
8
9
3-OH
3,4-Cl2
4-Me
4-Cl
9
10
11
12
13
14
15
16
3j
10
10
8
3k
2-Cl 3l
2-Cl 3m
2-Cl 3n
3-Cl 3o
2-Br 3p
4-Me
4-Br
10
8
Reagents and conditions: 1
(1.0 mmol), 2 (1.0 mmol),
iodine (0.05 mmol), and
[BMIm]Br (2 mL)
4-Br
8
4-Me
9
a
Isolated yields
r
A
O
N
O
N
I2
NH
NH NH2
I2
N
r
A
H
C O
+
-
H
2O
1
2
r
A
O
-
I2
N
NH
N
3
Scheme 1 The possible reaction mechanism
Conclusion
In conclusion, we have developed a novel procedure leading to 6-aryl-5H-
quinazolino[4,3-b]quinazolin-8(6H)-one derivatives catalyzed by iodine in ionic
liquids. The procedure includes a simple reaction of 2-(2-aminophenyl)quinazolin-
4(3H)-one and benzaldehyde, and has the advantages of high yields (86–96 %),
being metal-free and mild reaction conditions.
123

Y. Ma et al.
Experimental
Melting points were determined in open capillaries and were uncorrected. Infrared
(IR) spectra were recorded on a Tensor 27 spectrometer using a KBr pellet. Proton
nuclear magnetic resonance (1H NMR) spectra were obtained from a solution in
deuterated dimethyl sulfoxide (DMSO-d6) or deuterated chloroform (CDCl3 with
tetramethylsilane (Me4Si) as the internal standard using a Bruker-400 spectrometer.
High-resolution mass spectrometry (HRMS) analyses were carried out using a
Bruker-micro-TOF-Q-MS analyzer.
General procedure for the syntheses of 3
A 25-mL flask was charged with benzaldehyde (1.0 mmol), 2-(2-aminophenyl)quina-
zolin-4(3H)-one (1.0 mmol), I2 (0.05 mmol), and [BMIm]Br (2 mL). The mixture
was stirred at 80 °C before reaching completion, which was monitored by TLC.
When it was cooled down to room temperature, water (5 mL) was added to the
mixture. The solid was filtered off and purified by recrystallization from 95 % EtOH
to give pure 3.
6-Phenyl-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3a) Pale yellow powder,
m.p. 228–229 °C (Lit [19]. 226–227 °C); 1H NMR (DMSO-d6, 400 MHz): dH
6.80–6.85 (m, 1H, ArH), 6.93 (d, J = 8.0 Hz, 1H, ArH), 7.17–7.19 (m, 2H, ArH),
7.23–27 (m, 4H, ArH), 7.32–7.36 (m, 1H, ArH), 7.51–7.54 (m, 1H, ArH), 7.75 (d,
J = 8.4 Hz, 1H, ArH), 7.85–7.90 (m, 1H, ArH), 8.01 (d, J = 3.6 Hz, 1H, NH),
8.11–8.14 (m, 1H, ArH), 8.20 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): dC 63.7, 116.3, 120.7, 126.0, 126.2, 127.1, 127.2, 127.3, 127.5,
127.7, 128.6, 128.7, 133.5, 134.6, 139.2, 143.6, 147.1, 148.2, 160.7. IR (KBr): m
3356, 3062, 3029, 2968, 1665, 1594, 1556, 1498, 1468, 1382, 1317, 1255, 1173,
1076, 768, 750, 700 cm-1. HRMS (ESI, m/z): Calcd. for C21H16N3O [M ? H]?
326.1293, found 326.1275.
6-(4-Bromophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3b) Pale yellow
1
powder, m.p. 267–269 °C; H NMR (DMSO-d6, 400 MHz): dH 6.82–6.86 (m, 1H,
ArH), 6.93 (d, J = 8.0 Hz, 1H, ArH), 7.19 (d, J = 8.4 Hz, 2H, ArH), 7.25 (d,
J = 3.6 Hz, 1H, CH), 7.33–7.37 (m, 3H, ArH), 7.50–7.54 (m, 1H, ArH), 7.75 (d,
J = 8.4 Hz, 1H, ArH), 7.85–7.89 (m, 1H, ArH), 7.99 (d, J = 3.6 Hz, 1H, NH), 8.12
(d, J = 7.2 Hz, 1H, ArH), 8.19 (dd, J = 8.0 Hz, J0 = 0.8 Hz, 1H, ArH). 13C NMR
(DMSO-d6, 100 MHz): dC 62.5, 116.1, 116.5, 119.5, 120.3, 122.0, 126.8, 127.2,
127.4, 127.8, 128.5, 132.0, 134.3, 135.6, 139.4, 145.3, 147.5, 148.2, 160.1. IR
(KBr): m 3340, 3062, 2927, 1682, 1595, 1556, 1485, 1385, 1324, 1274, 1154, 1066,
1006, 895, 822, 766, 700 cm-1. HRMS (ESI, m/z): Calcd. for C21H15BrN3O
[M ? H]? 404.0398, found 404.0392.
6-(2,4-Dichlorophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3c) Pale yellow
1
powder, m.p. 249–250 °C; H NMR (DMSO-d6, 400 MHz): dH 6.84–6.90 (m, 3H,
ArH), 7.20 (dd, J = 8.4 Hz, J0 = 2.0 Hz, 1H, ArH), 7.30–7.34 (m, 1H, ArH), 7.37
(d, J = 3.6 Hz, 1H, CH), 7.47–7.51 (m, 1H, ArH), 7.70–7.72 (m, 2H, NH ? ArH),
123

Synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)…
7.78 (d, J = 7.6 Hz, 1H, ArH), 7.85–7.89 (m, 1H, ArH), 8.08 (dd, J = 8.0 Hz,
J0 = 1.2 Hz, 1H, ArH), 8.24 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH). 13C NMR
(CDCl3, 100 MHz): dC 61.6, 115.8, 116.8, 120.3, 120.7, 126.6, 127.15, 127.23,
127.4, 127.6, 127.7, 130.3, 132.7, 133.7, 134.4, 134.9, 135.2, 142.8, 147.5, 148.1,
160.0.IR (KBr): m 3421, 3065, 2965, 1626, 1484, 1415, 1346, 1305, 1154, 1045,
864, 749, 700, 666 cm-1. HRMS (ESI, m/z): Calcd. for C21H12Cl2N3O [M–H]-
392.0358, found 392.0353.
6-(2,3-Dimethoxyphenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3d) Pale
yellow powder, m.p. 238–240 °C; 1H NMR (DMSO-d6, 400 MHz): dH 3.78 (s, 3H,
CH3O), 3.93 (s, 3H, CH3O), 6.30 (d, J = 7.6 Hz, 1H, ArH), 6.80–6.83 (m, 3H,
ArH), 6.96 (d, J = 8.4 Hz, 1H, CH), 7.25–7.29 (m, 1H, ArH), 7.36 (s, 1H, ArH),
7.41 (s, 1H, ArH), 7.46–7.49 (m, 1H, ArH), 7.76 (d, J = 8.4 Hz, 1H, NH),
7.83–7.87 (m, 1H, ArH), 8.08 (d, J = 8.0 Hz, 1H, ArH), 8.21 (d, J = 8.0 Hz, 1H,
ArH). 13C NMR (CDCl3, 100 MHz): dC 55.8, 60.8, 61.0, 112.9, 115.6, 116.5, 117.5,
120.0, 120.5, 124.0, 126.2, 127.0, 127.4 127.6, 132.4, 133.4, 134.7, 144.2, 145.9,
148.1, 148.3, 152.7, 160.4. IR (KBr): m 3333, 3006, 2932, 2832, 1667, 1596, 1558,
1482, 1385, 1321, 1271, 1225, 1155, 1067, 1005, 926, 864, 745, 700, 637 cm-1
HRMS (ESI, m/z): Calcd. for C23H20N3O3 [M ? H]? 386.1505, found 386.1512.
.
6-(4-Fluorophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3e) Pale yellow
1
powder, m.p. 234–235 °C; H NMR (CDCl3, 400 MHz): dH 5.00 (d, J = 3.2 Hz,
1H, NH), 6.82 (d, J = 8.0 Hz, 1H, ArH), 6.86–6.91 (m, 2H, ArH), 6.98–7.02 (m,
1H, ArH), 7.28–7.30 (m, 2H, ArH), 7.34–7.39 (m, 2H, ArH), 7.43–7.47 (m, 1H,
ArH), 7.75–7.77 (m, 2H, ArH), 8.31 (d, J = 8.0 Hz, 1H, ArH), 8.34 (d, J = 8.0 Hz,
1H, ArH). 13C NMR (DMSO-d6, 100 MHz): dC 62.5, 115.9 (d, JF–C = 21.5 Hz),
116.0, 116.4, 119.4, 120.4, 126.8, 127.1, 127.4, 127.7, 128.4 (d, JF–C = 8.4 Hz),
134.3, 135.5, 136.2 (d, JF–C = 3.0 Hz), 145.4, 147.6, 148.2, 160.1, 162.2 (d,
JF–C = 243.1 Hz). IR (KBr): m 3357, 3064, 2961, 2871, 1685, 1604, 1555, 1503,
1469, 1386, 1328, 1236, 1154, 1103, 1021, 991, 894, 846, 767, 697, 616 cm-1
HRMS (ESI, m/z): Calcd. for C21H13FN3O [M–H]- 342.1043, found 342.1048.
.
6-(4-Chlorophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3f) Pale yellow
1
powder, m.p. 259–260 °C (Lit [19]. 251 °C); H NMR (DMSO-d6, 400 MHz): dH
6.82–6.86 (m, 1H, ArH), 6.93 (d, J = 8.0 Hz, 1H, ArH), 7.19 (d, J = 8.4 Hz, 2H,
ArH), 7.25 (d, J = 3.6 Hz, 1H, CH), 7.33–7.37 (m, 3H, ArH), 7.50–7.54 (m, 1H,
ArH), 7.75 (d, J = 8.4 Hz, 1H, ArH), 7.85–7.89 (m, 1H, ArH), 7.99 (d, J = 3.6 Hz,
1H, NH), 8.12 (d, J = 7.2 Hz, 1H, ArH), 8.19 (dd, J = 8.0 Hz, J0 = 0.8 Hz, 1H,
ArH). 13C NMR (DMSO-d6, 100 MHz): dC 62.5, 116.1, 116.5, 119.5, 120.3, 126.8,
127.2, 127.4, 127.8, 128.1, 129.1, 133.4, 134.3, 135.6, 138.9, 145.3, 147.5, 148.2,
160.1. IR (KBr): m 3344, 3063, 1682, 1595, 1556, 1487, 1469, 1385, 1325, 1274,
1258, 1154, 1084, 1010, 895, 824, 766, 704, 611 cm-1. HRMS (ESI, m/z): Calcd.
for C21H15ClN3O [M ? H]? 360.0904, found 360.0887.
6-(3,4-Dimethoxyphenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3g) Pale
yellow powder, m.p. 176–177 °C; 1H NMR (DMSO-d6, 400 MHz): dH 3.62 (s, 3H,
123

Y. Ma et al.
CH3O), 3.64 (s, 3H, CH3O), 6.39 (dd, J = 8.4 Hz, J0 = 2.4 Hz, 1H, ArH), 6.74 (d,
J = 8.4 Hz 1H, ArH), 6.81–6.85 (m, 1H, ArH), 6.92 (d, J = 8.0 Hz, 1H, ArH), 7.04
(d, J = 2.0 Hz, 1H, ArH), 7.18 (d, J = 3.6 Hz, 1H, CH), 7.32–7.36 (m, 1H, ArH),
7.50–7.54 (m, 1H, ArH), 7.75 (d, J = 8.0 Hz, 1H, ArH), 7.85–7.89 (m, 1H, ArH),
7.94 (d, J = 3.6 Hz, 1H, NH), 8.13 (d, J = 8.0 Hz, 1H, ArH), 8.20 (dd, J = 8.0 Hz,
J0 = 1.2 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): dC 55.7, 55.8, 63.6, 109.3,
110.9, 116.2, 117.7, 118.6, 120.6, 120.7, 126.2, 127.1, 127.5, 127.7, 132.1, 133.5,
134.6, 143.8, 147.1, 148.1, 148.9, 149.2, 160.7. IR (KBr): m 3390, 3061, 2996, 2936,
2837, 1668, 1596, 1557, 1514, 1467, 1386, 1321, 1258, 1137, 1018, 859, 743, 699,
639 cm-1. HRMS (ESI, m/z): Calcd. for C23H20N3O3 [M ? H]? 386.1505, found
386.1508.
6-(2-Fluorophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3h) Pale yellow
1
powder, m.p. 202–204 °C; H NMR (CDCl3, 400 MHz): dH 5.13 (s, 1H, NH),
6.65–6.72 (m, 2H, ArH), 6.86–6.93 (m, 1H, ArH), 6.92–6.95 (m, 1H, ArH),
7.06–7.11 (m, 1H, ArH), 7.19–7.22 (m, 1H, ArH), 7.25–7.29 (m, 1H, ArH),
7.44–7.47 (m, 1H, ArH), 7.58 (s, 1H, CH), 7.78–7.83 (m, 2H, ArH), 8.28 (d,
J = 8.0 Hz, 1H, ArH), 8.35 (d, J = 8.0 Hz, 1H, ArH). 13C NMR (DMSO-d6,
100 MHz): dC 59.8 (d, JF–C = 3.7 Hz), 115.7, 116.0 (d, JF–C = 21.0 Hz), 116.9,
120.4, 120.5, 124.2 (d, JF–C = 3.5 Hz), 126.0 (d, JF–C = 12.1 Hz), 126.4, 126.7 (d,
JF–C = 3.1 Hz), 127.2, 127.5, 127.6, 130.4 (d, JF–C = 8.3 Hz), 133.5, 134.8, 143.5,
147.6, 148.2, 160.1, 160.3 (d, JF–C = 244.0 Hz). IR (KBr): m 3402, 3067, 3029,
1669, 1555, 1484, 1388, 1321, 1259, 1221, 1160, 1000, 1035, 887, 828, 758, 702,
632 cm-1. HRMS (ESI, m/z): Calcd. for C21H15FN3O [M ? H]? 344.1199, found
344.1204.
6-(3-Hydroxyphenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3i) Pale yellow
1
powder, m.p. 276–278 °C; H NMR (DMSO-d6, 400 MHz): dH 6.52 (s, 1H, ArH),
6.59–6.64 (m, 2H, ArH), 6.80–6.84 (m, 1H, ArH), 6.91 (d, J = 8.0 Hz, 1H, ArH),
7.03–7.07 (m, 1H, ArH), 7.15 (d, J = 3.6 Hz, 1H, CH), 7.31–7.36 (m, 1H, ArH),
7.50–7.54 (m, 1H, ArH), 7.75 (d, J = 8.0 Hz, 1H, ArH), 7.85–7.89 (m, 1H, ArH),
7.94 (d, J = 3.6 Hz, 1H, NH), 8.12 (d, J = 8.0 Hz, 1H, ArH), 8.20 (d, J = 8.0 Hz,
1H, ArH), 9.46 (s, 1H, OH). 13C NMR (DMSO-d6, 100 MHz): dC 62.8, 113.2,
115.5, 116.0, 116.3, 116.9, 119.2, 120.4, 126.7, 127.2, 127.4, 127.7, 130.1, 134.2,
135.5, 141.4, 145.7, 147.8, 148.2, 157.9, 160.1. IR (KBr): m 3461, 3401, 3075, 2991,
1653, 1589, 1556, 1489, 1392, 1318, 1279, 1153, 998, 878, 761, 703, 664 cm-1
HRMS (ESI, m/z): Calcd. for C21H14N3O2 [M–H]- 340.1086, found 340.1085.
.
6-(3,4-Dichlorophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3j) Pale yellow
1
powder, m.p. 218–220 °C; H NMR (DMSO-d6, 400 MHz): dH 6.85–6.89 (m, 1H,
ArH), 6.97 (d, J = 8.0 Hz, 1H, ArH), 7.02 (dd, J = 8.4 Hz, J0 = 1.6 Hz, 1H, ArH),
7.28 (d, J = 3.6 Hz, 1H, CH), 7.35–7.39 (m, 1H, ArH), 7.50–7.55 (m, 3H, ArH),
7.76 (d, J = 8.0 Hz, 1H, ArH), 7.86–7.90 (m, 1H, ArH), 8.01 (d, J = 3.6 Hz, 1H,
NH), 8.12–8.14 (m, 1H, ArH), 8.21 (dd, J = 8.0 Hz, J0 = 0.8 Hz, 1H, ArH). 13C
NMR (DMSO-d6, 100 MHz): dC 62.1, 116.0, 116.5, 119.7, 120.3, 126.4, 126.9,
127.2, 127.4, 127.8, 128.6, 131.2, 131.5, 131.9, 134.4, 135.6, 141.1, 145.1, 147.3,
148.1, 160.1. IR (KBr): m 3309, 3026, 2956, 1682, 1613, 1554, 1469, 1376, 1323,
123

Synthesis of 6-aryl-5H-quinazolino[4,3-b]quinazolin-8(6H)…
1244, 1150, 1027, 905, 763, 744, 709, 621 cm-1. HRMS (ESI, m/z): Calcd. for
C21H12Cl2N3O [M–H]- 392.0358, found 392.0353.
6-(p-Tolyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3k) Pale yellow powder,
m.p. 197–198 °C (Lit [19]. 202–203 °C); 1H NMR (DMSO-d6, 400 MHz): dH 2.17
(s, 3H, CH3), 6.79–6.83 (m, 1H, ArH), 6.91 (d, J = 8.0 Hz, 1H, ArH), 7.05 (s, 4H,
ArH), 7.21 (d, J = 4.0 Hz, 1H, CH), 7.30–7.35 (m, 1H, ArH), 7.49–7.53 (m, 1H,
ArH), 7.74 (d, J = 8.0 Hz, 1H, ArH), 7.84–7.88 (m, 1H, ArH), 7.96 (d, J = 4.0 Hz,
1H, NH), 8.11 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 8.19 (dd, J = 8.0 Hz,
J0 = 1.2 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): dC 21.0, 63.6, 116.3, 117.7,
120.6, 120.7, 125.9, 126.1, 127.1, 127.5, 127.7, 129.4, 133.5, 134.6, 136.4, 138.4,
143.7, 147.2, 148.2, 160.7. IR (KBr): m 3324, 3031, 2954, 1658, 1614, 1555, 1469,
1382, 1329, 1260, 1154, 1113, 1025, 897, 757, 696, 617 cm-1. HRMS (ESI, m/z):
Calcd. for C22H17N3ONa [M ? Na]? 362.1269, found 362.1267.
2-Chloro-6-(4-chlorophenyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3l) Pale
1
yellow powder, m.p. 246–248 °C; H NMR (DMSO-d6, 400 MHz): dH 6.97 (d,
J = 8.8 Hz, 1H, ArH), 7.18 (d, J = 8.4 Hz, 2H, ArH), 7.27 (d, J = 2.8 Hz, 1H,
CH), 7.34–7.39 (m, 3H, ArH), 7.52–7.56 (m, 1H, ArH), 7.78 (d, J = 8.0 Hz, 1H,
ArH), 7.87–7.90 (m, 1H, ArH), 8.05 (d, J = 2.0 Hz, 1H, ArH), 8.19–8.20 (m, 2H,
ArH ? NH). 13C NMR (DMSO-d6, 100 MHz): dC 62.6, 117.1, 118.4, 120.5, 123.1,
126.2, 127.17, 127.19, 127.9, 128.1, 129.2, 133.5, 133.9, 135.7, 138.7, 144.2, 146.3,
147.9, 160.0. IR (KBr): m 3344, 3063, 1682, 1595, 1556, 1487, 1469, 1385, 1325,
1274, 1258, 1154, 1084, 1010, 895, 824, 766, 704, 611 cm-1. HRMS (ESI, m/z):
Calcd. for C21H14Cl2N3O [M ? H]? 394.0514, found 394.0516.
2-Chloro-6-(p-tolyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3m) Pale yellow
1
powder, m.p. 255–256 °C; H NMR (DMSO-d6, 400 MHz): dH 2.17 (s, 3H, CH3),
6.96 (d, J = 8.8 Hz, 1H, ArH), 7.03 (d, J = 8.4 Hz, 2H, ArH), 7.07 (d, J = 8.4 Hz,
2H, ArH), 7.23 (d, J = 3.2 Hz, 1H, CH), 7.35 (d, J = 8.4 Hz, J0 = 2.4 Hz, 1H,
ArH), 7.51–7.55 (m, 1H, ArH), 7.77 (d, J = 8.0 Hz, 1H, ArH), 7.85–7.89 (m, 1H,
ArH), 8.05 (d, J = 2.4 Hz, 1H, ArH), 8.18–8.20 (m, 2H, ArH ? NH). 13C NMR
(DMSO-d6, 100 MHz): dC 21.0, 62.9, 117.2, 118.3, 120.5, 122.8, 126.0, 126.1,
127.1, 127.2, 127.9, 129.6, 133.8, 135.6, 136.7, 138.2, 144.5, 146.6, 147.9, 160.0.
IR (KBr): m 3324, 3080, 3024, 2920, 1655, 1559, 1468, 1424, 1317, 1232, 1171,
1143, 1018, 902, 818, 775, 706, 620 cm-1. HRMS (ESI, m/z): Calcd. for
C22H15ClN3O [M–H]- 372.0904, found 372.0910.
6-(4-Bromophenyl)-2-chloro-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3n) Pale
1
yellow powder, m.p. 262–264 °C; H NMR (DMSO-d6, 400 MHz): dH 6.97 (d,
J = 8.8 Hz, 1H, ArH), 7.12 (d, J = 8.4 Hz, 2H, ArH), 7.25 (d, J = 3.6 Hz, 1H,
CH), 7.38 (d, J = 8.4 Hz, J0 = 2.4 Hz, 1H, ArH), 7.48 (d, J = 8.4 Hz, 2H, ArH),
7.53–7.56 (m, 1H, ArH), 7.78 (d, J = 8.0 Hz, 1H, ArH), 7.87–7.91 (m, 1H, ArH),
8.05 (d, J = 2.4 Hz, 1H, ArH), 8.18–8.20 (m, 2H, ArH ? NH). 13C NMR (DMSO-
d6, 100 MHz): dC 62.6, 117.1, 118.5, 120.5, 122.1, 123.1, 126.2, 127.18, 127.21,
127.9, 128.4, 132.1, 133.9, 135.7, 139.1, 144.2, 146.3, 147.9, 160.0. IR (KBr): m
3314, 3079, 2965, 1657, 1558, 1469, 1424, 1371, 1339, 1311, 1246, 1172, 1143,
123

Y. Ma et al.
1071, 1009, 902, 818, 776, 695 614 cm-1. HRMS (ESI, m/z): Calcd. for
C21H14BrClN3O [M ? H]? 438.0009, found 438.0012.
6-(4-Bromophenyl)-3-chloro-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3o) Pale
1
yellow powder, m.p. 219–220 °C; H NMR (DMSO-d6, 400 MHz): dH 6.86 (dd,
J = 8.4 Hz, J0 = 2.0 Hz, 1H, ArH), 6.99 (d, J = 2.0 Hz, 1H, CH), 7.12 (d,
J = 8.4 Hz, 2H, ArH), 7.26 (d, J = 3.6 Hz, 1H, ArH), 7.48–7.55 (m, 3H, ArH),
7.74 (d, J = 8.0 Hz, 1H, ArH), 7.85–7.89 (m, 1H, ArH), 8.10 (d, J = 8.4 Hz, 1H,
ArH), 8.17–8.24 (m, 2H, ArH ? NH). 13C NMR (DMSO-d6, 100 MHz): dC 62.6,
114.8, 115.5, 119.6, 120.3, 122.2, 127.1, 127.2, 127.8, 128.4, 129.3, 132.1, 135.7,
138.8, 139.1, 146.4, 146.8, 147.9, 160.0. IR (KBr): m 3298, 3060, 1657, 1592, 1559,
1470, 1370, 1346, 1320, 1260, 1159, 1089, 1009, 903, 833, 763, 697 cm-1. HRMS
(ESI, m/z): Calcd. for C21H14BrClN3O [M ? H]? 438.0009, found 438.0005.
2-Bromo-6-(p-tolyl)-5H-quinazolino[4,3-b]quinazolin-8(6H)-one (3p) Pale yel-
1
low powder, m.p. 230–231 °C; H NMR (DMSO-d6, 400 MHz): dH 2.17 (s, 3H,
CH3), 6.89 (d, J = 8.4 Hz, 1H, ArH), 7.01–7.07 (m, 4H, ArH), 7.22 (d, J = 3.6 Hz,
1H, CH), 7.46 (dd, J = 8.8 Hz, J0 = 2.4 Hz, 1H, ArH), 7.51–7.55 (m, 1H, ArH),
7.77 (d, J = 8.0 Hz, 1H, ArH), 7.84–7.89 (m, 1H, ArH), 8.17–8.20 (m, 3H,
ArH ? NH). 13C NMR (DMSO-d6, 100 MHz): dC 21.0, 62.8, 110.2, 117.7, 118.7,
120.5, 126.0, 127.1, 127.9, 129.1, 129.7, 135.6, 136.5, 136.6, 138.2, 144.8, 146.5,
147.9, 160.0. IR (KBr): m 3375, 3062, 2920, 2832, 1672, 1592, 1560, 1495, 1469,
1421, 1370, 1323, 1167, 1143, 1092, 1024, 898, 817, 766, 696 cm-1. HRMS (ESI,
m/z): Calcd. for C22H17BrN3O [M ? H]? 418.0555, found 418.0528.
Acknowledgments We are grateful to the National Natural Science foundation of China (20802061),
the Major Natural Science Foundation of Jiangsu Province (14KJA150004) and a project funded by the
Priority Academic Program Development of Jiangsu Higher Education for financial support.
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