Copper(I)-catalyzed synthesis of 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one via intramolecular alkyne hydroamination

Article abstract of DOI:10.1016/j.tet.2014.03.048

The 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one derivatives were obtained via intramolecular alkyne hydroamination reaction of 2-amino-N-arylbenzohydrazide and alkynal diethyl acetal in the presence of CuBr and Cs₂CO ₃. This new proced

Full text of DOI:10.1016/j.tet.2014.03.048

Tetrahedron 70 (2014) 2889e2893
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Tetrahedron
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Copper(I)-catalyzed synthesis of 1-arylpyrazolo[5,1-b]quinazolin-
9(1H)-one via intramolecular alkyne hydroamination
*
Dong-Sheng Chen, Mei-Mei Zhang, Yu-Ling Li, Yun Liu, Xiang-Shan Wang
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for Functional Materials, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one derivatives were obtained via intramolecular alkyne
hydroamination reaction of 2-amino-N0-arylbenzohydrazide and alkynal diethyl acetal in the presence of
CuBr and Cs2CO3. This new procedure provides an efficient method to construct fused tricyclic hetero-
cycle containing both pyrazole and quinazoline analogues.
Received 14 November 2013
Received in revised form 9 March 2014
Accepted 13 March 2014
Available online 19 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Pyrazoloquinazoline
CuBr-Catalyzed
Alkyne hydroamination
Synthesis
1. Introduction
report the synthesis of 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-ones
via CuBr/Cs2CO3 catalyzed intramolecular alkyne hydroamination
Pyrazoloquinazolines are important tricyclic heterocycles con-
taining both pyrazole and quinazoline moieties and widely occurred
in biologically active molecules. They are well known structures to
be used to inhibit nerve growth factors1 or serve as kinase inhibitors,
such as selective MPS1 kinase inhibitors,2 phosphodiesterase 10A
inhibitors,3 selective polo-like kinase 1 inhibitors,4 and multi-cyclin-
dependent kinase inhibitors.5 In addition, they are also used as novel
excitatory amino acid antagonists6 and adenosine receptor antago-
nists recently.7 As a consequence, great effort has been devoted to
access pyrazoloquinazoline and its derivatives.8 However, simple,
mild, versatile one-pot preparation of this class compounds is still
highly desirable.
Cu(I) was an efficient and inexpensive catalyst for the coupling
reactions of CeN bond.9 We previously reported that CuBr could
catalyze Ullmann-type reaction of 2-amino-N0-arylbenzohydrazide
and o-halogenated benzaldehyde to construct 5-arylindazolo[3,2-
b]quinazolin-7(5H)-ones in high yields.10 In addition, Cu(I) could
also promote the alkyne hydroamination reaction between amine
and alkyne to form Csp2 eN bond under mild conditions.11 There-
fore, we tested the reaction of 2-amino-N0-arylbenzohydrazide and
alkynal diethyl acetal and found that the designed reaction pro-
ceeded in the presence of CuBr and Cs2CO3 to give 1-arylpyrazolo
[5,1-b]quinazolin-9(1H)-one derivatives in high yields. Herein, we
reaction.
2. Results and discussion
The reaction of 2-amino-N0-phenylbenzohydrazide 1a with 3-
phenylpropynal diethyl acetal 2a was used as a model reaction to
optimize reaction conditions (Scheme 1), and the results are sum-
marized in Table 1. Initially, the reaction in toluene in the presence
of CuCl (5 mol %), K2CO3 (2 equiv) could afford the desired product
3a in 72% yield. Further investigation of various catalysts, CuBr was
found to be more effective than other Cu(I) species, and the reaction
yield increased to 82% when CuBr was employed (entries 1e3).
Several bases such as Na2CO3, NaHCO3, Et3N, and Cs2CO3 were ex-
amined, and Cs2CO3 was found to give the best result (entries 4e7).
Subsequently, different solvents including THF, CH3CN, DMF, ben-
zene, and dioxane were also evaluated and an 89% yield was ob-
tained when dioxane was used as solvent (entry 11). In addition,
lower yields were observed if the loading of catalyst reduced to
1 mol % (entries 13 and 14).
With these optimized conditions in hand, we surveyed the
substrate scope of 2-amino-N0-phenylbenzohydrazides and alkynal
diethyl acetals (Table 2, Scheme 2). Initially, 3-phenylpropynal
diethyl
acetal
2a
and
different
2-amino-N0-phenyl-
benzohydrazides were investigated under standard conditions, and
both electron-rich and electron-poor 2-amino-N0-phenyl-
benzohydrazides could afford the corresponding products in high
* Corresponding author. Fax: þ86 516 83500065; e-mail address: xswang1974@
yahoo.com (X.-S. Wang).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.03.048

2890
D.-S. Chen et al. / Tetrahedron 70 (2014) 2889e2893
O
EtO
EtO
CuBr
O
N
NHPh
N
H
+
Ph
N
N
Cs2CO3
NH2
2a
3a
1a
Scheme 1. The model reaction.
Table 1
yields (Table 2, entries 1e13). Subsequently, 2-butynal diethyl ac-
etal and propargylaldehyde diethyl acetal were tested and were
able to give pyrazolo[5,1-b]quinazolin-9(1H)-one under the stan-
dard conditions. All the products of 3 were characterized by 1H
NMR, 13C NMR, IR, and HRMS, and the data were in good agreement
with the preconceived structures. Among these structures, the
structure of 3d was confirmed by X-ray diffraction analysis as
shown in Fig. 1.
Synthesis of 3a under different reaction conditionsa
Entry
Cat. (mol %)
Solvent
Base
Yieldsb/%
1
2
3
4
5
6
7
8
CuCl (5)
CuBr (5)
CuI (5)
Toluenec
Toluenec
Toluenec
Toluenec
Toluenec
Toluenec
Toluenec
CH3CN
K2CO3
K2CO3
K2CO3
Na2CO3
NaHCO3
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
72
82
78
75
68
70
84
58
68
85
89
62
75
89
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (1)
CuBr (10)
d
9
THF
10
11
12
13
14
DMFc
Dioxane
Benzene
Dioxane
Dioxane
a
Reagents and conditions: 1a (0.227 g, 1.0 mmol), 2a (0.205 g, 1.0 mmol), solvent
(10 mL), base (2.0 mmol), reflux.
b
Isolated yields.
c
100 ꢀC.
d
NaHCO3: 4 mmol.
Table 2
The synthetic results for the products 3a
Fig. 1. The crystal structure of 3d.
Entry
Ar
R
R0
Products
Time/h
Yieldsb/%
We propose that three subsequent steps are involved in the
formation of 3, namely cyclization to dihydroquinazolinone 4 cat-
alyzed CuBr, aromatization to quinazolinone by air, and alkyne
hydroamination reaction in the presence of CuBr and Cs2CO3. The
key step is the alkyne hydroamination, which has been reported in
several references.11 The plausible reaction mechanism is outlined
in Scheme 3.
In order to get more insight to the mechanism, the model re-
action of 1a and 2a was treated with CuBr in the absence of Cs2CO3
and the reaction was end up to form the compound of 4 in 90% at
room temperature, which also supported the proposed three step
mechanism (Scheme 4).
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH3
CH3
CH3
CH3
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
6
6
8
5
6
8
6
6
8
6
6
5
8
10
8
8
8
6
89
92
86
90
85
86
90
89
84
90
91
88
85
86
89
84
90
82
4-ClC6H4
4-CH3C6H4
Ph
4-CH3C6H4
Ph
4-ClC6H4
4-CH3C6H4
Ph
7-CH3
7-CH3
7-Br
7-Br
7-Br
7-Cl
6-Cl
6-Cl
6-Cl
5,6-(CH3)2
7-Cl
7-Br
6-Cl
6-Cl
7-Br
9
10
11
12
13
14
15
16
17
18
Ph
4-CH3C6H4
4-ClC6H4
Ph
Ph
4-ClC6H4
Ph
3. Conclusion
4-ClC6H4
4-ClC6H4
In conclusion, we report a novel and efficient method for the
synthesis of 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-one derivatives
using 5 mol % CuBr as catalyst. The method employs readily avail-
able reactant, inexpensive catalyst and affords the tricyclic het-
erocycles in high yields.
a
Reagents and conditions: 1 (1.0 mmol), 2 (1.0 mmol), CuBr (7 mg, 0.05 mmol),
Cs2CO3 (652 mg, 2 mmol), dioxane (10 mL), reflux.
b
Isolated yields.
O
Ar
N
O
EtO
NHAr
CuBr
N
N
H
+
R
R'
R
R'
Cs2CO3
EtO
N
NH2
2
3
1
Scheme 2. The reaction of 1 and 2.

D.-S. Chen et al. / Tetrahedron 70 (2014) 2889e2893
2891
O
Ar
O
EtO
NH
NHAr
N
N
H
NH2
CuBr
R
+
-2EtOH
EtO
O
N
H
R
Cyclization
2
4
1
Ar
O
Ar
NH
N
N
N
Cs2CO3
Alkyne Hydroamination
Air CuBr
Cs2CO3
Aromatization
R
N
N
R
3
Cu
Br
Scheme 3. The plausible reaction mechanism.
HRMS (TOF, ESI, m/z): calcd for C22H15N3OCl [MþH]þ 372.0904,
O
O
found 372.0905.
EtO
EtO
NHPh
+
NHPh
N
H
N
CuBr
Ph
4.2.3. 2-Phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-9(1H)-one
(3c). Yield 86% (302 mg). Pale yellow solid, mp: 273e274 ꢀC; 1H
NMR (CDCl3, 400 MHz): dH 8.24 (d, J¼8.0 Hz,1H), 7.76e7.72 (m, 2H),
7.58e7.56 (m, 2H), 7.37e7.31 (m, 4H), 7.27 (d, J¼8.4 Hz, 2H), 7.10 (d,
J¼8.0 Hz, 2H), 6.63 (s, 1H), 2.28 (s, 3H). 13C NMR (CDCl3, 100 MHz):
dC 158.7, 156.6, 152.0, 149.6, 139.7, 137.4, 133.9, 130.6, 129.5, 129.0,
NH2
N
H
4
Ph
1a
2a
Scheme 4. The model reaction in the absence of Cs2CO3.
128.8, 128.1, 127.8, 126.5, 126.3, 124.0, 118.0, 101.7, 21.3. IR (KBr):
n
3030, 1681, 1616, 1588, 1548, 1505, 1466, 1363, 1326, 1258, 1229,
4. Experimental section
4.1. General
1201, 1180, 1063, 1021, 966, 923, 879, 804, 778, 757, 690 cmꢁ1
.
HRMS (TOF, ESI, m/z): calcd for C23H18N3O [MþH]þ 352.1450, found
352.1450.
The 2-amino-N0-arylbenzohydrazides were prepared according
to Ref. 12.
4.2.4. 7-Methyl-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one
(3d). Yield 90% (316 mg). Pale yellow solid, mp: 238e239 ꢀC; 1H
NMR (CDCl3, 400 MHz): dH 7.94 (s, 1H), 7.59 (d, J¼8.4 Hz, 1H),
7.50e7.48 (m, 3H), 7.33e7.27 (m, 4H), 7.25e7.22 (m, 3H), 7.19 (s,
1H), 6.56 (s, 1H), 2.37 (s, 3H). 13C NMR (CDCl3, 100 MHz): dC 157.5,
155.4, 150.5, 146.6, 139.3, 134.6, 133.1, 129.6, 128.4, 127.9, 127.8,
4.2. General procedure for the syntheses of 1-aryl pyrazolo
[5,1-b]quinazolin-9(1H)-one derivatives 3
127.7, 127.1, 126.9, 125.1, 124.6, 116.8, 101.1, 20.2. IR (KBr):
n 3057,
2-Amino-N0-arylbenzohydrazide (1.0 mmol), alkynal diethyl
acetal (1.0 mmol), CuBr (7 mg, 0.05 mmol), Cs2CO3 (652 mg), and
dioxane (10 mL) were added into a dry flask (25 mL). The reaction
mixture was stirred under reflux for 5e10 h before completion,
which was monitored by TLC. The solid was removed by a hot and
immediate filtration. The filtrate was allowed to cool down to room
temperature, and the product 3 was precipitated as solid and ob-
tained by filtration.
1683, 1584, 1542, 1483, 1445, 1342, 1318, 1260, 1212, 1116, 1077,
1026, 830, 807, 776, 760, 689 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for
C
23H18N3O [MþH]þ 352.1450, found 352.1452.
4.2.5. 7-Methyl-2-Phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-
9(1H)-one (3e). Yield 85% (310 mg). Pale yellow solid, mp:
272e273 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.02 (s, 1H), 7.63 (d,
J¼8.4 Hz, 1H), 7.58e7.54 (m, 3H), 7.37e7.33 (m, 3H), 7.26 (d,
J¼8.0 Hz, 2H), 7.08 (d, J¼8.0 Hz, 2H), 6.62 (s, 1H), 2.44 (s, 3H), 2.28
(s, 3H). 13C NMR (CDCl3, 100 MHz): dC 158.5, 156.5, 151.5, 147.7,
139.5, 137.6, 135.6, 134.0, 130.5, 129.5, 129.0, 128.8, 128.2, 127.7,
4.2.1. 1,2-Diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3a). Yield
89% (300 mg). Pale yellow solid, mp: 257e258 ꢀC; 1H NMR (CDCl3,
400 MHz): dH 8.23 (d, J¼8.0 Hz, 1H), 7.76e7.73 (m, 2H), 7.57e7.55
(m, 2H), 7.41e7.35 (m, 5H), 7.34e7.30 (m, 4H), 6.65 (s, 1H). 13C NMR
(CDCl3, 100 MHz): dC 158.8, 156.5, 152.1, 149.7, 140.1, 133.9, 130.7,
129.6, 129.0, 128.9, 128.8, 128.0, 126.5, 126.3, 124.1, 118.0, 102.0. IR
126.1, 125.7, 117.8, 101.8, 21.244, 21.236. IR (KBr): n 3012, 1678, 1624,
1595, 1506, 1484, 1448, 1358, 1308, 1258, 1209, 1121, 1109, 1061,
1020, 837, 801, 758, 719, 692 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for
C
24H20N3O [MþH]þ 366.1606, found 366.1607.
(KBr):
n 3065, 1679, 1614, 1589, 1548, 1489, 1463, 1360, 1321, 1255,
1228, 1201, 1179, 1100, 1064, 1025, 964, 914, 809, 773, 760,
690 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for C22H16N3O [MþH]þ
338.1293, found 338.1291.
4.2.6. 7-Bromo-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one
(3f). Yield 86% (358 mg). Pale yellow solid, mp: 259e260 ꢀC; 1H
NMR (CDCl3, 400 MHz): dH 8.26 (d, J¼1.6 Hz, 1H), 7.72e7.69 (m, 1H),
7.52 (d, J¼8.8 Hz, 1H), 7.48 (d, J¼8.0 Hz, 2H), 7.32e7.27 (m, 5H),
7.25e7.19 (m, 3H), 6.57 (s, 1H). 13C NMR (CDCl3, 100 MHz): dC 157.9,
154.3, 151.2, 147.4, 138.7, 136.0, 129.8, 128.7, 128.0, 127.91, 127.86,
4.2.2. 1-(4-Chlorophenyl)-2-phenylpyrazolo[5,1-b]quinazolin-9(1H)-
one (3b). Yield 92% (342 mg). Pale yellow solid, mp: 220e221 ꢀC;
1H NMR (CDCl3, 400 MHz): dH 8.23 (d, J¼8.0 Hz, 1H), 7.78e7.72 (m,
2H), 7.56e7.54 (m, 2H), 7.43e7.38 (m, 3H), 7.37e7.33 (m, 3H), 7.27
(d, J¼8.0 Hz, 2H), 6.66 (s, 1H). 13C NMR (CDCl3, 100 MHz): dC 158.7,
156.5, 151.9, 149.6, 138.7, 135.4, 134.1, 130.9, 129.3, 129.2, 129.0,
127.8, 127.1, 127.0, 126.8, 118.2, 115.9, 100.7. IR (KBr):
n 3051, 1674,
1606,1585,1537,1489,1461,1367,1334,1309,1246,1211,1120,1068,
1027, 981, 819, 802, 763, 694 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for
C
22H15N3OBr [MþH]þ 416.0398, found 416.0373.
128.9, 127.7, 126.44, 126.42, 124.4, 118.0, 102.4. IR (KBr):
1681, 1616, 1589, 1550, 1485, 1467, 1362, 1325, 1257, 1229, 1202,
1180, 1097, 1063, 1017, 967, 922, 838, 803, 774, 760, 690 cmꢁ1
n 3031,
4.2.7. 7-Bromo-1-(4-chlorophenyl)-2-phenylpyrazolo[5,1-b]quinazo-
lin-9(1H)-one (3g). Yield 90% (405 mg). Pale yellow solid, mp:
.

2892
D.-S. Chen et al. / Tetrahedron 70 (2014) 2889e2893
217e218 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.33 (d, J¼1.2 Hz, 1H),
7.79 (dd, J¼8.8 Hz, J0¼1.2 Hz, 1H), 7.60 (d, J¼8.8 Hz, 1H), 7.54 (d,
HRMS (TOF, ESI, m/z): calcd for C22H14N3OCl2 [MþH]þ 406.0514,
found 406.0506.
J¼8.0 Hz, 2H), 7.44e7.37 (m, 3H), 7.34e7.29 (m, 4H), 6.65 (s, 1H). 13
C
NMR (CDCl3, 100 MHz): dC 158.9, 155.3, 152.0, 148.4, 138.3, 137.2,
135.6, 131.0, 129.4, 129.2, 129.0, 128.9, 128.8, 128.2, 127.5, 119.2,
4.2.13. 5,6-Dimethyl-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-
one (3m). Yield 85% (310 mg). Pale yellow solid, mp: 152e153 ꢀC; 1H
NMR (CDCl3, 400 MHz): dH 8.01 (d, J¼8.4 Hz, 1H), 7.57e7.54 (m, 2H),
7.39e7.33 (m, 5H), 7.30e7.25 (m, 3H), 7.16 (d, J¼8.4 Hz, 1H), 6.70 (s,
1H), 2.64 (s, 3H), 2.45 (s, 3H). 13C NMR (CDCl3, 100 MHz): dC 158.4,
156.9, 151.1, 148.3, 142.3, 140.5, 132.2, 130.5, 129.4, 128.9, 128.8, 128.7,
117.2, 102.2. IR (KBr):
n 3055, 1683, 1609, 1588, 1541, 1487, 1461,
1402, 1355, 1261, 1226, 1088, 1015, 821, 807, 767, 692 cmꢁ1. HRMS
(TOF, ESI, m/z): calcd for C22H14N3OBrCl [MþH]þ 450.0009, found
449.9995.
128.3, 128.0, 126.6, 123.3, 116.1, 102.6, 21.0, 13.5. IR (KBr):
n 3107,
4.2.8. 7-Bromo-2-phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-
9(1H)-one (3h). Yield 89% (383 mg). Pale yellow solid, mp:
240e241 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.34 (s, 1H), 7.77 (d,
J¼8.0 Hz,1H), 7.58 (d, J¼8.8 Hz,1H), 7.55 (d, J¼7.6 Hz, 2H), 7.41e7.35
(m, 3H), 7.25 (d, J¼7.2 Hz, 2H), 7.10 (d, J¼8.0 Hz, 2H), 6.62 (s, 1H),
2.29 (s, 3H). 13C NMR (CDCl3, 100 MHz): dC 158.9, 155.3, 152.2, 148.5,
139.9, 137.00, 136.96, 130.7, 129.6, 129.0, 128.9, 128.8, 128.1, 127.9,
3056, 2913, 1672, 1591, 1556, 1487, 1448, 1412, 1361, 1291, 1217, 1135,
1071, 1027, 980, 948, 814, 775, 761, 689 cmꢁ1. HRMS (TOF, ESI, m/z):
calcd for C24H20N3O [MþH]þ 366.1606, found 366.1605.
4.2.14. 7-Chloro-2-Methyl-1-phenylpyrazolo[5,1-b]quinazolin-
9(1H)-one (3n). Yield 86% (266 mg). Pale yellow solid, mp:
188e189 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.14 (s, 1H), 7.63e7.62
(m, 2H), 7.52e7.47 (m, 3H), 7.30e7.25 (m, 2H), 6.24 (s, 1H), 2.21 (s,
3H). 13C NMR (CDCl3, 100 MHz): dC 155.0, 154.2, 151.8, 148.2, 138.0,
134.3, 129.5, 129.3, 128.8, 127.9, 125.9, 125.5, 117.9, 99.9, 13.1. IR
127.8, 119.2, 116.8, 101.5, 21.3. IR (KBr):
n 3060, 3033, 1686, 1610,
1584,1539,1506,1461,1447,1360,1322,1306,1243,1208,1132,1117,
1060, 1020, 976, 900, 835, 758, 691 cmꢁ1. HRMS (TOF, ESI, m/z):
calcd for C23H17N3OBr [MþH]þ 430.0550, found 430.0538.
(KBr):
n 3061, 3013, 1693, 1614, 1591, 1542, 1488, 1468, 1422, 1383,
1357, 1330, 1299, 1252, 1215, 1174, 1138, 1113, 1071, 1029, 993, 890,
4.2.9. 7-Chloro-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one
(3i). Yield 84% (312 mg). Pale yellow solid, mp: 237e238 ꢀC; 1H
NMR (CDCl3, 400 MHz): dH 8.17 (s, 1H), 7.68e7.63 (m, 2H), 7.55 (d,
828, 788, 767, 695 cmꢁ1
. HRMS (TOF, ESI, m/z): calcd for
C
17H13N3OCl [MþH]þ 310.0747, found 310.0748.
J¼7.6 Hz, 2H), 7.38e7.35 (m, 5H), 7.32e7.31 (m, 3H), 6.64 (s, 1H). 13
C
4.2.15. 7-Bromo-1-(4-chlorophenyl)-2-methylpyrazolo[5,1-b]quinazo-
lin-9(1H)-one (3o). Yield 89% (345 mg). Pale yellow solid, mp:
215e216 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.30e8.28 (m, 1H),
7.78e7.75 (m, 1H), 7.57e7.54 (m, 1H), 7.45 (dd, J¼8.4 Hz, J0¼1.2 Hz,
2H), 7.23e7.20 (m, 2H), 6.25 (s, 1H), 2.19 (s, 3H). 13C NMR (CDCl3,
100 MHz): dC 154.9, 154.1, 151.7, 148.4, 137.0, 136.5, 135.5, 129.6, 128.7,
NMR (CDCl3, 100 MHz): dC 158.9, 155.4, 152.1, 148.2, 139.8, 134.4,
130.8, 129.7, 129.4, 129.0, 128.9, 128.8, 128.03, 127.98, 127.8, 125.6,
118.8, 101.7. IR (KBr):
n 3060, 1675, 1611, 1583, 1540, 1490, 1465,
1448, 1365, 1337, 1309, 1248, 1211, 1174, 1132, 1065, 1027, 831, 764,
694 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for C22H15N3OCl [MþH]þ
372.0904, found 372.0903.
128.1,127.2,118.3,116.5,100.5,13.0. IR (KBr): n 3060,1672,1608,1591,
1538, 1489, 1463, 1385, 1358, 1335, 1305, 1278, 1218, 1174, 1133, 1089,
1016, 970, 882, 832, 817, 777, 740, 690 cmꢁ1. HRMS (TOF, ESI, m/z):
calcd for C17H12N3OBrCl [MþH]þ 387.9852, found 387.9852.
4.2.10. 6-Chloro-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one
(3j). Yield 90% (334 mg). Pale yellow solid, mp: 246e247 ꢀC; 1H
NMR (CDCl3, 400 MHz): dH 8.13 (d, J¼8.8 Hz, 1H), 7.70 (s, 1H), 7.54
(d, J¼7.6 Hz, 2H), 7.40e7.35 (m, 5H), 7.33e7.31 (m, 3H), 7.26 (d,
J¼7.6 Hz, 1H), 6.64 (s, 1H). 13C NMR (CDCl3, 100 MHz): dC 158.9,
156.0, 152.8, 150.6, 140.1, 139.7, 130.8, 129.7, 129.0, 128.9, 128.8,
4.2.16. 6-Chloro-2-Methyl-1-phenylpyrazolo[5,1-b]quinazolin-
9(1H)-one (3p). Yield 84% (260 mg). Pale yellow solid, mp:
212e213 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.10 (d, J¼8.8 Hz, 1H),
7.67 (d, J¼2.0 Hz, 1H), 7.52e7.46 (m, 3H), 7.29e7.27 (m, 2H), 7.23
(dd, J¼8.8 Hz, J0¼2.0 Hz, 1H), 6.24 (s, 1H), 2.19 (s, 3H). 13C NMR
(CDCl3, 100 MHz): dC 155.5, 154.2, 152.4, 150.6, 139.9, 138.0, 129.5,
128.1, 128.0, 127.8, 125.6, 124.7, 116.3, 101.7. IR (KBr):
n 3074, 1692,
1582, 1539, 1489, 1453, 1432, 1362, 1338, 1282, 1249, 1211, 1158,
1108, 1067, 1025, 969, 920, 876, 812, 760, 691 cmꢁ1. HRMS (TOF,
ESI, m/z): calcd for
372.0892.
C
22H15N3OCl [MþH]þ 372.0904, found
129.3, 127.9, 126.0, 125.4, 124.1, 115.4, 99.8, 13.0. IR (KBr): n 3072,
3033, 1690, 1581, 1537, 1488, 1455, 1433, 1354, 1336, 1275, 1216,
1185, 1099, 1070, 996, 918, 871, 829, 768, 692 cmꢁ1. HRMS (TOF, ESI,
m/z): calcd for C17H13N3OCl [MþH]þ 310.0747, found 310.0748.
4.2.11. 6-Chloro-2-Phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-
9(1H)-one (3k). Yield 91% (351 mg). Pale yellow solid, mp:
253e254 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.14 (d, J¼8.8 Hz, 1H),
7.69 (d, J¼2.0 Hz, 1H), 7.56e7.53 (m, 2H), 7.41e7.34 (m, 3H),
7.27e7.24 (m, 3H), 7.10 (d, J¼8.0 Hz, 2H), 6.62 (s, 1H), 2.29 (s, 3H).
13C NMR (CDCl3, 100 MHz): dC 158.9, 156.0, 152.7, 150.6, 140.0, 139.7,
137.0, 130.7, 129.6, 129.0, 128.8, 128.0, 127.9, 125.5, 124.5, 116.3,
4.2.17. 6-Chloro-1-(4-chlorophenyl)-2-methylpyrazolo[5,1-b]quinazo-
lin-9(1H)-one (3q). Yield 90% (309 mg). Pale yellow solid, mp:
202e203 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.10 (d, J¼8.8 Hz, 1H),
7.67 (d, J¼2.0 Hz, 1H), 7.48e7.46 (m, 1H), 7.45e7.44 (m, 1H),
7.26e7.23 (m, 2H), 7.22e7.21 (m, 1H), 6.25 (s, 1H), 2.19 (s, 3H). 13
C
101.4, 21.6. IR (KBr):
n
3032,1683,1605,1579,1538,1506,1455,1433,
NMR (CDCl3, 100 MHz): dC 155.5, 154.1, 152.3, 150.5, 140.1, 136.5,
135.5, 129.6, 127.8, 127.3, 125.5, 124.4, 115.4, 100.4, 13.0. IR (KBr):
3082,1677,1636,1595,1538,1483,1456,1434,1388,1355,1280,1221,
1087, 1073, 1012, 992, 922, 870, 844, 810, 768, 684 cmꢁ1. HRMS (TOF,
ESI, m/z): calcd for C17H12N3OCl2 [MþH]þ 344.0357, found 344.0356.
1364, 1338, 1283, 1230, 1212, 1108, 1076, 1064, 918, 807, 768, 759,
692 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for C23H17N3OCl [MþH]þ
386.1060, found 386.1060.
n
4.2.12. 6-Chloro-1-(4-chlorophenyl)-2-phenylpyrazolo[5,1-b]quina-
zolin-9(1H)-one (3l). Yield 88% (357 mg). Pale yellow solid, mp:
260e261 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 8.13 (d, J¼8.0 Hz, 1H),
7.71 (s, 1H), 7.53 (d, J¼7.2 Hz, 2H), 7.42e7.37 (m, 3H), 7.33 (d,
J¼8.8 Hz, 2H), 7.29e7.27 (m, 3H), 6.64 (s, 1H). 13C NMR (CDCl3,
100 MHz): dC 158.9, 156.0, 152.6, 150.5, 140.2, 138.3, 135.6, 131.0,
129.4, 129.2, 129.01, 128.95, 127.9, 127.5, 125.7, 124.9, 116.3, 102.2. IR
4.2.18. 7-Bromo-1-(4-chlorophenyl)pyrazolo[5,1-b]quinazolin-
9(1H)-one (3r). Yield 82% (307 mg). Pale yellow solid, mp:
223e224 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 9.55 (s, 1H), 8.54 (s, 1H),
8.29 (d, J¼2.4 Hz, 1H), 8.12e8.09 (m, 1H), 7.79 (d, J¼8.8 Hz, 1H), 7.29
(d, J¼8.8 Hz, 2H), 6.80 (d, J¼8.8 Hz, 2H). 13C NMR (CDCl3, 100 MHz):
dC 159.0, 150.9, 147.1, 146.6, 138.1, 130.5, 129.5, 129.4, 128.8, 124.8,
(KBr):
n
3084, 1682, 1609, 1585, 1540, 1489, 1455, 1433, 1358, 1339,
124.5, 120.4, 115.2, 114.7. IR (KBr):
1541, 1488, 1463, 1300, 1251, 1212, 1176, 1090, 1016, 827, 819, 766,
n 3034, 1698, 1672, 1607, 1578,
1254, 1211, 1088, 1066, 1017, 972, 919, 868, 804, 761, 744, 692 cmꢁ1
.

D.-S. Chen et al. / Tetrahedron 70 (2014) 2889e2893
2893
692 cmꢁ1. HRMS (TOF, ESI, m/z): calcd for C16H8N3OBrCl [MꢁH]ꢁ
Ponti, A. D.; Fachin, G.; Ferguson, R. D.; Lansen, J.; Moll, J. K.; Pesenti, E.; Posteri,
H.; Perego, R.; Rocchetti, M.; Storici, P.; Volpi, D.; Valsasina, B. J. Med. Chem.
2010, 53, 3532e3551.
371.9539, found 371.9538.
5. Traquandi, G.; Ciomei, M.; Ballinari, D.; Casale, E.; Colombo, N.; Croci, V.;
Fiorentini, F.; Isacchi, A.; Longo, A.; Mercurio, C.; Panzeri, A.; Pastori, W.; Pe-
varello, P.; Volpi, D.; Roussel, P.; Vulpetti, A.; Brasca, M. G. J. Med. Chem. 2010,
53, 2171e2187.
4.3. Syntheses of 3-(phenylamino)-2-(phenylethynyl)-2,3-
dihydroquinazolin-4(1H)-one 4
6. Varano, F.; Catarzi, D.; Colotta, V.; Filacchioni, G.; Galli, A.; Costagli, C.; Carla, V.
J. Med. Chem. 2002, 45, 1035e1044.
7. Catarzi, D.; Colotta, V.; Varano, F.; Poli, D.; Squarcialupi, L.; Filacchioni, G.;
Varani, K.; Vincenzi, F.; Borea, P. A.; Dal Ben, D.; Lambertucci, C.; Cristalli, G.
Bioorg. Med. Chem. 2013, 21, 283e294.
2-Amino-N0-phenylbenzohydrazide 1a (227 mg, 1.0 mmol), 3-
phenylpropynal diethyl acetal (204 mg, 1.0 mmol), CuBr (7 mg,
0.05 mmol), and dioxane (10 mL) was added into a dry flask
(25 mL). The reaction mixture was stirred at room temperature for
3 h and the product 4 was obtained by filtration.
8. (a) Yang, X.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. RSC Adv. 2012, 2, 11061e11066; (b) Al-
Etaibi, A.; John, E.; Ibrahim, M. R.; Al-Awadi, N. A.; Ibrahim, Y. A. Tetrahedron
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Schweizer, E. E.; Hayes, J. E. J. Org. Chem. 1988, 53, 5562e5564; (k) Schweizer, E.
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4.3.1. 3-(Phenylamino)-2-(phenylethynyl)-2,3-dihydroquinazolin-
4(1H)-one (4). Yield 90% (305 mg). Pale yellow solid, mp:
154e155 ꢀC; 1H NMR (CDCl3, 400 MHz): dH 7.99 (dd, J¼8.0 Hz,
J0¼1.6 Hz, 1H), 7.43e7.38 (m, 1H), 7.33e7.29 (m, 3H), 7.28e7.23 (m,
4H), 7.03 (d, J¼7.6 Hz, 2H), 6.98e6.92 (m, 2H), 6.81 (d, J¼8.0 Hz,1H),
6.74 (s, 1H), 5.76 (d, J¼2.8 Hz, 1H), 4.81 (d, J¼2.4 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): dC 164.3, 146.6, 145.5, 134.2, 132.0, 129.3, 129.0,
128.9, 128.3, 121.7, 121.3, 120.3, 115.42, 115.39, 113.9, 85.3, 84.1, 64.8.
HRMS (TOF, ESI, m/z): calcd for C22H17N3ONa [MþNa]þ 362.1269,
found 362.1267.
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We are grateful to the National Natural Science Foundation of
China (20802061, 21104064), a Project Funded by the Priority Ac-
ademic Program Development of Jiangsu Higher Education In-
stitutions, Qing Lan Project (10QLD008, GSFM2011003) and College
Industrialization Project (JHB2012-31) of Jiangsu Province for fi-
nancial support.
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