Domino synthesis of fused pyrazolo[5,1-b]quinazolin-9(1H)-ones catalyzed by CuI via subsequent Michael addition and elimination

Article abstract of DOI:10.1016/j.tet.2015.09.055

A Domino reaction of 2-aminobenzohydrazides and 2-bromocinnamaldehydes is treated in the presence of CuI and Cs₂CO₃, and gives unexpected pyrazolo[5,1-b]quinazolin-9(1H)-one derivatives in good yields. A possible mechanism containing

Full text of DOI:10.1016/j.tet.2015.09.055

Accepted Manuscript
Domino Synthesis of Fused Pyrazolo[5,1-b]quinazolin-9(1H)-ones Catalyzed by CuI
via Subsequent Michael Addition and Elimination
Yan Zhang, Jing Xu, Chao Li, Xiang-Shan Wang
PII:
S0040-4020(15)30083-1
10.1016/j.tet.2015.09.055
TET 27152
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 July 2015
Revised Date: 15 September 2015
Accepted Date: 22 September 2015
Please cite this article as: Zhang Y, Xu J, Li C, Wang X-S, Domino Synthesis of Fused
Pyrazolo[5,1-b]quinazolin-9(1H)-ones Catalyzed by CuI via Subsequent Michael Addition and
Elimination, Tetrahedron (2015), doi: 10.1016/j.tet.2015.09.055.
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ACCEPTED MANUSCRIPT
Domino Synthesis of Fused Pyrazolo[5,1-b]quinazolin-9(1H)-ones
Catalyzed by CuI via Subsequent Michael Addition and Elimination
Yan Zhang, Jing Xu, Chao Li, Xiang-Shan Wang*
O
R
N
N
R
R1
O
R2
H
N
N
Br
N
R
CuI
Cs2CO3
R1
R2
H
O
+
CHO
NH2
N
N
R1
R2
N

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Domino Synthesis of Fused Pyrazolo[5,1-b]quinazolin-9(1H)-ones
Catalyzed by CuI via Subsequent Michael Addition and Elimination
Yan Zhang, Jing Xu, Chao Li, Xiang-Shan Wang*
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthesis for
Functional Materials, Jiangsu Normal University, Xuzhou Jiangsu 221116, P. R. China
E-mail: xswang1974@yahoo.com
Abstract—A Domino reaction of 2-aminobenzohydrazides and 2-bromocinnamaldehydes is
treated in the presence of CuI and Cs2CO3, and gives unexpected pyrazolo[5,1-b]quinazolin-
9(1H)-one derivatives in good yields. A possible mechanism containing subsequent Michael
addition and elimination is proposed to explain the formation of the pyrazole ring. This new
procedure has the advantages of one-pot, available reactant, and milder conditions.
Keywords: pyrazoloquinazolinone, CuI, 2-aminobenzohydrazide, 2-bromocinnamaldehyde,
Domino reaction
Introduction
Quinazoline is a very useful and active analog for its anti-tumor1 activities in its
derivatives. A well-known clinical medicine is Lapatinib,2 which is an orally active
drug for the treatment of female breast cancer and other solid tumors. In addition, its
derivatives show some other remarkable anti-tumor activities, and are used as various
kinds of inhibitor for human cancers, for example, human gastric cancer BGC823
cells,3 irreversible EGFR tyrosine kinase,4 a panel of three human cancer cell lines
(MGC-803, Bcap-37, and PC3 cells),5 human lung carcinoma cell line A549,6 the

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renal cancer7 and colorectal cancer.8
Figure 1. The structure of Lapatinib
Some quinazoline derivatives also possess various kinds of other pharmacological
and biological activities, such as anti-microbial,9 anti-TMV,10 anti-inflammatory,11
anti-proliferative,12 and antiviral activities.13 Therefore, more and more novel
procedures have been reported in the literature to synthesize these fused bicyclic
heterocycles.14
Pyrazoloquinazoline is a tricyclic heterocycle containing both pyrazole and
quinazoline moieties. It is reported that its derivatives are also well-known
compounds with significant pharmacological activities. They usually serve as nerve
growth factors,15 or various kinds of inhibitors including MAPK inhibitors,16 PDE10A
inhibitors,17 and Chk1 kinase inhibitors.18 Therefore, great effort has been devoted to
the synthesis of pyrazoloquinazoline derivatives in recent years.19 However, an
efficient, mild and one-pot procedure for the synthesis of these potentially active
fused heterocycles is still desirable.
In our previous paper, 1-arylpyrazolo[5,1-b]quinazolin-9(1H)-ones were obtained
via intra-molecular alkyne hydroamination reaction of 2-amino-N'-arylbenzo
hydrazide and alkynal diethyl acetal in the presence of CuBr and Cs2CO3.20 However,

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the reaction was restricted with the reactant of alkynal because it was not available,
and it was not easy to keep as well. In our recent study, alkynal diethyl acetal was
changed to 2-bromocinnamaldehyde to get desired 2-benzylidene-1-phenyl-1H-[1,2]
diazeto[4,1-b]quinazolin-8(2H)-one. However, the designed reaction gave 1,2-di-
phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3a) unexpectedly in 82 % yield
catalyzed by CuI and K2CO3 in reflux dioxane (Scheme 1).
O
Ph
N
N
O
Ph
H
N
N
Br
N
Ph
CuI
K2CO3
H
Ph
O
Ph
+
CHO
NH2
N
N
Ph
1a
2a
N
3a
Scheme 1. The model reaction
Results and discussion
In our initial study, we thought this may be an exception or something wrong with
starting material of 2a, so we repeated this reaction twice, with the same products
being obtained. Subsequently, taking the reaction of 2-amino-N'-phenylbenzo
hydrazide (1a) and 2a as a model, several parameters including catalysts, ligands,
bases and solvents, were optimized first in our lab. According to the structure of 3a, it
was not an Ullmann-type N-Csp2 bond coupling reaction. Perhaps the reaction could
be carried out in the absence of CuI, in fact, no desired product of 3a was obtained
only in the presence of K2CO3 (Table 1, entry 1). On the contrary, it could be carried
out in the absence of base, but the simple condensation product was obtained in 90 %

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(Table 1, entry 2). As our original idea, appropriate ligands might increase the
conversation to a great extent, so selected ligands, such as Ph3P, CH3NHCH2CO2H
and L-proline were applied to the reaction. However, almost equivalent yields of 3a
were found to be abtained. Under ligands-free condition, it still counld be carried out
to give 3a in 82 % yield. Increasing the dosage of the catalyst to 10 or 20 mol%, there
was no influence on the reaction yields. Furthermore, changing catalyst from CuI to
other Cu(I) sources, such as CuBr or CuCl, the yield was almost unchanged either.
And then, various kinds of bases, including inorganic bases, such as Cs2CO3, Na2CO3
and NaHCO3, organic bases, for example, DBU and Et3N, were used to promote the
model reaction, it was found Cs2CO3 gave 3a in a slightly better result (84 % yield).
Finally, common solvents in our lab were screened for this transformation, such as
CH3CN, DMSO, THF and Toluene, and DMSO gave the best yield in 90 % for 3a.
Table 1. Synthetic results of 3a under different reaction conditionsa
Entry
Catalysts (mol%) Ligands (mol%)
Bases
K2CO3
-
Solvents
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Yields (%)b
1
-
-
0
2
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(1)
CuI(10)
CuI(20)
CuBr(5)
CuCl(5)
-
0c
3
-
K2CO3
K2CO3
82
80
81
82
62
82
82
81
80
4
PPh3(10)
5
CH3NHCH2CO2H(10) K2CO3
6
L-proline(10)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
7
-
-
-
-
-
8
9
10
11

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12
13
14
15
16
17
18
19
20
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(5)
CuI(5)
-
-
-
-
-
-
-
-
-
Cs2CO3
Dioxane
Dioxane
84
72
68
74
78
74
90
76
78
Na2CO3
d
NaHCO3 Dioxane
DBU
Dioxane
Dioxane
CH3CN
DMSOe
THF
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Toluene
a
Reagents and conditions: 1a (227 mg, 1.0 mmol), 2a (221 mg, 1.0 mmol), solvent (10 mL), 2
b
c
mmol base, refluxing. Isolated yields. The simple condensation product was obtained in 90 %
yield. d 4 mmol. e 120°C.
With the optimized reaction conditions in hand, subsequently, various kinds of 2-
amino-N'-arylbenzohydrazides were used to react with 2a first. It was found that the
reactions also tolerated significant functionalization in 1; both electron-donating (such
as alkyl) and electron-withdrawing (such as halide) groups on benzene ring could be
accommodated. They all carried out smoothly to give pyrazolo[5,1-b]quinazolin-
9(1H)-one derivatives in good to high yields (Table 2, entries 1~6 and 9~16). In
addition, other 2-bromocinnamaldehydes, such as (Z)-2-bromo-3-(2-fluorophenyl)
acrylaldehyde (2b) and (Z)-2-bromo-3-(4-methoxy phenyl)acrylaldehyde (2c), were
also chosen to react with 2-amino-N'-arylbenzohydrazides, and gave 3g, 3h and 3q in
86%, 87% and 86% yields, respectively (Table 2, entries 7~8 and 17). All the
structures of the products were characterized by NMR, IR and HRMS; their data were
in good agreement to the preconceived structures. The structure of 3o was confirmed
by X-ray diffraction analysis, and its crystal structure was shown in Figure 2.

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O
O
N
R
N
H
CuI
Br
N
N
R
+
R2
N
R1
R2
R1
H
CHO
Cs2CO3
NH2
1
2
3
Scheme 2. Reaction of 1 and 2
Table 2. The reaction time and yields of the products 3a~qa
Entry
1
R
R1 (in 1)
R2
Ph
Ph
Ph
Ph
Ph
Products
3a
Time /h
Yields b /%
Ph
H
9
88
89
90
89
91
91
86
87
90
90
87
88
88
92
93
95
86
2
Ph
5-CH3
5-Br
5-Cl
8
3b
3c
3
Ph
10
8
4
Ph
3d
3e
5
Ph
4-Cl
8
6
Ph
3,4-(CH3)2 Ph
10
7
3f
7
Ph
H
2-FC6H4
3g
8
Ph
5-CH3
H
2-FC6H4
9
3h
3i
9
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-CH3C6H4
Ph
10
7
10
11
12
13
14
15
16
17
4-F
5-F
5-Cl
H
Ph
3j
Ph
7
3k
3l
Ph
5
Ph
10
6
3m
3n
3o
4-CH3C6H4 3-CH3
4-CH3C6H4 4-Cl
4-CH3C6H4 5-Cl
Ph
Ph
8
Ph
7
3p
3q
Ph
H
4-MeOC6H4
8
a
Reaction condition: DMSO (10 mL), 1 (1.0 mmol), 2 (1.0 mmol), CuI (10 mg, 0.05 mmol),
Cs2CO3 (650 mg, 2 mmol), 120 °C. b Isolated yields.

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Figure 2. The crystal structure of 3o
In the crystal structure of 3o, all the rings are the plane structures including the
pyrazole and quinazoline moieties. The pyrazole ring is almost parallel to the
quinazoline ring forming a dihedral angel of 7.0 (1)°. It is nearly perpendicular to the
benzene ring (C11~C16) forming a dihedral angel of 88.8 (1)°, and it makes a
dihedral angel of 39.8 (1)° to another benzene ring (C17~C22).
In Table 1, it was found that 3a was not detected in the absence of CuI. To our
delight, the model reaction could proceed smoothly without base. However, it gave
(Z)-2-(1-bromo-2-phenylvinyl)-3-(phenylamino)-2,3-dihydroquinazolin-4(1H)-one
(4) in 90% yield, and the pyrazole ring was not formed as expected. As a tentative
experimental, the intermediate product 4 was treated with Cs2CO3 in the absence of
CuI. It was found in surprise that 3a could be isolated in 81% yield in DMSO at 120
°C (Scheme 3). Therefore, the separated reactions indicated that CuI is a Lewis
catalyst to form quinazoline, while Cs2CO3 is a base to promote the formation of
pyrazole ring.

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Scheme 3. The separated reaction
According the above separated reaction, subsequent cyclization, aromatization,
Michael addition and elimination may take place in the formation of 3. The plausible
reaction mechanism is outlined in Scheme 4.
Scheme 4. The possible reaction mechanism
Conclusion
In summary, the pyrazolo[5,1-b]quinazolin-9(1H)-one derivatives were obtained
by a Domino reaction of 2-aminobenzohydrazides and 2-bromocinnamaldehydes
catalyzed by CuI and Cs2CO3. This new procedure has the advantages of one-pot,
available reactant, good yields, and milder conditions.
Experimental
Melting points were determined in open capillaries and are uncorrected. IR

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1
spectra were recorded on a Tensor 27 spectrometer in KBr pellet. H NMR spectra
were obtained from a solution in DMSO-d6 with Me4Si as internal standard using a
Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker-micro-
TOF-Q-MS analyzer.
Detailed procedure for XRD analysis of 3o
The data were collected on a Bruker-APEX-II CCD area detector diffractometer with
graphite monochromated MoK
scan technique (2.49 < < 22.93°). 2640 independent reflections were collected, of
which 2089 reflections with I > 2 (I) were considered to be observed. The structure
α (λ = 0.71073 Å) radiation, using the phi and omega
θ
σ
was solved by direct methods using SHELXTL program and expanded using Fourier
technique. The non-hydrogen atoms were refined anisotropically and the hydrogen
atoms were determined with theoretic calculation and refined isotropically. The
crystal belongs to monoclinic, space group C2/c with a = 21.2894(13), b = 9.7191(7),
c = 18.8536(13) Å,
β µ
= 99.671(4) º, Z = 8, V = 3845.6(4) Å3, Dc = 1.333 g.cm-3,
(MoK
α
) = 0.098 mm-1, F(000) = 1600, The final R = 0.0435, wR = 0.1147, w = 1/[σ2
2
2
(Fo ) + (0.0656P) 2 + 3.5026P], P=(Fo +2Fc2)/3. S = 1.023, (
∆/
σ
)
max = 0.001. (∆ρ
)
max
= 0.762 e/Å3 and (∆ρ
)
min = –0.217 e/Å3.
General procedure for the syntheses of 3.
A dry 50 mL flask was charged with 2-aminobenzohydrazide 1 (1.0 mmol), 2-
bromocinnamaldehyde (1.0 mmol), CuI (10 mg), Cs2CO3 (650 mg) and DMSO (10
mL). The reaction mixture was stirred at 120 °C for 5-10 h. After completion of the
reaction, as indicated by TLC, the solid was filtered off by a fast and hot filtration.

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The DMSO was recovered by distillation under reduced pressure, and the residue was
purified by recrystallization from 95% EtOH to give final product 3.
1,2-Diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3a): Yield 88 % (297 mg). Pale
yellow solid, m.p.: 258~260 °C (Lit.20 257~258 °C); 1H NMR (CDCl3, 400 MHz): δH
6.65 (s, 1H, ArH), 7.30~7.41 (m, 9H, ArH), 7.55~7.57 (m, 2H, ArH), 7.73~7.76 (m,
13
2H, ArH), 8.23 (d, J = 8.0 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 102.0,
118.0, 124.1, 126.3, 126.5, 128.0, 128.8, 128.9, 129.0, 129.6, 130.7, 133.9, 140.1,
149.7, 152.1, 156.5, 158.8. HRMS (ESI, m/z): Calcd for C22H16N3O [M+H]+
338.1293, found 338.1289.
7-Methyl-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3b): Yield 89 % (313
mg). Pale yellow solid, m.p.: 236~238 °C (Lit.20 238~239 °C); 1H NMR (CDCl3, 400
MHz): δH 2.37 (s, 3H, CH3), 6.56 (s, 1H, ArH), 7.19~7.33 (m, 8H, ArH), 7.48~7.50
13
(m, 3H, ArH), 7.57 (d, J = 8.4 Hz, 1H, ArH), 7.94 (s, 1H, ArH). C NMR (CDCl3,
100 MHz): δC 20.2, 101.1, 116.8, 124.6, 125.1, 126.9, 127.1, 127.7, 127.8, 127.9,
128.4, 129.6, 133.1, 134.6, 139.3, 146.6, 150.5, 155.4, 157.5. HRMS (ESI, m/z): calcd
for C23H18N3O [M+H]+ 352.1450, found 352.1454.
7-Bromo-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3c): Yield 90 % (375
mg). Pale yellow solid, m.p.: 261~262 °C (Lit.20 259~260 °C); 1H NMR (CDCl3, 400
MHz): δH 6.57 (s, 1H, ArH), 7.19~7.32 (m, 8H, ArH), 7.48 (d, J = 8.0 Hz, 2H, ArH),
7.52 (d, J = 8.8 Hz, 1H, ArH), 7.71 (dd, J = 8.8 Hz, J’ = 1.6 Hz, 1H, ArH), 8.27 (d, J =
1.6 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 100.7, 115.9, 118.2, 126.8, 127.0,
127.1, 127.8, 127.86, 127.9, 128.0, 128.7, 129.8, 136.0, 138.7, 147.4, 151.2, 154.3,

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157.9. HRMS (ESI, m/z): calcd for C22H15N3OBr [M+H]+ 416.0398, found 416.0383.
7-Chloro-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3d): Yield 89 % (331
mg). Pale yellow solid, m.p.: 237~239 °C (Lit.20 237~238 °C); 1H NMR (CDCl3, 400
MHz): δH 6.64 (s, 1H, ArH), 7.31~7.38 (m, 8H, ArH), 7.55 (d, J = 7.6 Hz, 2H, ArH),
13
7.63~7.68 (m, 2H, ArH), 8.17 (s, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 101.7,
118.8, 125.6, 127.8, 127.9, 128.0, 128.8, 128.9, 129.0, 129.4, 129.7, 130.8, 134.4,
139.8, 148.2, 152.1, 155.4, 158.9. HRMS (ESI, m/z): calcd for C22H15N3OCl [M+H]+
372.0904, found 372.0901.
6-Chloro-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3e): Yield 91 % (338
mg). Pale yellow solid, m.p.: 245~246 °C (Lit.20 246~247 °C); 1H NMR (CDCl3, 400
MHz): δH 6.64 (s, 1H, ArH), 7.26 (d, J = 7.6 Hz, 1H, ArH), 7.31~7.40 (m, 8H, ArH),
13
7.54 (d, J = 7.6 Hz, 2H, ArH), 7.70 (s, 1H, ArH), 8.13 (d, J = 8.8 Hz, 1H, ArH). C
NMR (CDCl3, 100 MHz): δC 101.7, 116.3, 124.7, 125.6, 127.8, 128.0, 128.1, 128.8,
128.9, 129.0, 129.7, 130.8, 139.7, 140.1, 150.6, 152.8, 156.0, 158.9. HRMS (ESI,
m/z): Calcd for C22H15N3OCl [M+H]+ 372.0904, found 372.0894.
5,6-Dimethyl-1,2-diphenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3f): Yield 91 %
(332 mg). Pale yellow solid, m.p.: 155~156 °C (Lit.20 152~153 °C); 1H NMR (CDCl3,
400 MHz): δH 2.45 (s, 3H, CH3), 2.64 (s, 3H, CH3), 6.70 (s, 1H, ArH), 7.16 (d, J = 8.4
Hz, 1H, ArH), 7.27~7.39 (m, 8H, ArH), 7.54~7.57 (m, 2H, ArH), 8.01 (d, J = 8.4 Hz,
13
1H, ArH). C NMR (CDCl3, 100 MHz): δC 13.5, 21.0, 102.6, 116.1, 123.3, 126.6,
128.0, 128.3, 128.7, 128.8, 128.9, 129.4, 130.5, 132.2, 140.5, 142.3, 148.3, 151.1,
156.9, 158.4. HRMS (ESI, m/z): calcd for C24H20N3O [M+H]+ 366.1606, found

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366.1603.
2-(2-Fluorophenyl)-1-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3g): Yield
1
86 % (306 mg). Pale yellow solid, M. p. 221~222 °C; H NMR (CDCl3, 400 MHz):
δH 6.77 (d, J = 1.6 Hz, 1H, CH), 7.11~7.17 (m, 2H, ArH), 7.32~7.34 (m, 3H, ArH),
7.36~7.40 (m, 4H, ArH), 7.48~7.52 (m, 1H, ArH), 7.70 (d, J = 3.2 Hz, 2H, ArH), 8.27
(d, J = 8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 104.7 (d, JF-C = 4.7 Hz),
116.37 (d, JF-C = 21.2 Hz), 116.42, 117.9, 124.2, 124.3(d, JF-C = 3.7 Hz), 126.5 (d, JF-C
= 10.3 Hz), 127.4, 128.9, 129.6, 131.3, 132.5 (d, JF-C = 8.5 Hz), 133.9, 139.4, 148.0,
149.6, 151.9, 152.4, 156.4, 160.1 (d, JF-C = 251.9 Hz). IR (KBr):
ν 3065, 1677, 1627,
1591, 1548, 1487, 1464, 1456, 1362, 1322, 1256, 1231, 1201, 1113, 1063, 1028, 970,
806, 772, 767, 732, 706 cm-1. HRMS (ESI, m/z): Calcd for C22H14FN3ONa [M+Na]+
378.1013, found 378.1017.
2-(2-Fluorophenyl)-7-methyl-1-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3h):
1
Yield 87 % (321 mg). Pale yellow solid, m. p.: 186~188 °C; H NMR (CDCl3, 400
MHz): δH 2.47 (s, 3H, CH3), 6.75 (d, J = 1.6 Hz, 1H, CH), 7.10~7.16 (m, 2H, ArH),
7.30~7.33 (m, 3H, ArH), 7.35~7.39 (m, 3H, ArH), 7.48~7.52 (m, 1H, ArH), 7.59
(dd, J = 8.4 Hz, J’ = 2.0 Hz, 1H, ArH), 7.68 (d, J = 8.4 Hz, 1H, ArH), 8.05 (s, 1H,
ArH). 13C NMR (CDCl3, 100 MHz): δC 21.3, 104.9 (d, JF-C = 4.9 Hz), 116.3 (d, JF-C
= 21.3 Hz), 116.5, 117.8, 124.3(d, JF-C = 3.8 Hz), 125.6, 126.2, 127.3, 128.9, 129.4,
131.3(d, JF-C = 1.6 Hz), 132.4 (d, JF-C = 8.5 Hz), 134.5, 135.7, 139.9, 147.6, 151.4,
152.2, 156.3, 160.1 (d, JF-C = 251.9 Hz). IR (KBr):
ν 3055, 3037, 1686, 1586, 1552,
1486, 1444, 1355, 1316, 1258, 1211, 1151, 1129, 1107, 1078, 1063, 1028, 977, 838,

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829, 818, 778, 757, 708, 695 cm-1. HRMS (ESI, m/z): Calcd for C22H14FN3ONa
[M+Na]+ 392.1170, found 392.1164.
1-(4-Chlorophenyl)-2-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3i): Yield
1
90 % (335 mg). Pale yellow solid, m.p.: 217~218 °C (Lit.20 220~221 °C); H NMR
(CDCl3, 400 MHz): δH 6.66 (s, 1H, ArH), 7.28~7.43 (m, 8H, ArH), 7.54~7.56 (m, 2H,
ArH), 7.72~7.78 (m, 2H, ArH), 8.23 (d, J = 8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100
MHz): δC 102.4, 118.0, 124.4, 126.42, 126.44, 127.7, 128.9, 129.0, 129.2, 129.3,
130.9, 134.1, 135.4, 138.7, 149.6, 151.9, 156.5, 158.7. HRMS (ESI, m/z): calcd for
C22H15N3OCl [M+H]+ 372.0904, found 372.0906.
1-(4-Chlorophenyl)-6-fluoro-2-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3j):
1
Yield 90 % (351 mg). Pale yellow solid, m. p. 267~268 °C; H NMR (CDCl3, 400
MHz): δH 6.63 (s, 1H, CH), 7.05~7.10 (m, 1H, ArH), 7.27~7.30 (m, 2H, ArH),
7.32~7.34 (m, 2H, ArH), 7.34~7.39 (m, 2H, ArH), 7.40~7.44 (m, 2H, ArH), 7.52~7.54
(m, 2H, ArH), 8.22 (dd, J = 8.8 Hz, J’ = 6.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100
MHz): δC 102.1, 111.1 (d, JF-C = 21.7 Hz), 113.5 (d, JF-C = 24.1 Hz), 114.7 (d, JF-C
=
2.1 Hz), 127.5, 128.96, 129.01, 129.1 (d, JF-C = 11.1 Hz), 129.2, 129.4, 131.0, 135.6,
138.4, 151.7 (d, JF-C = 13.5 Hz), 152.7, 155.9, 158.9, 166.5(d, JF-C = 251.8 Hz). IR
(KBr):
ν 3042, 1682, 1587, 1557, 1488, 1475, 1445, 1365, 1346, 1289, 1278, 1250,
1186, 1157, 1120, 1096, 1063, 1017, 977, 966, 921, 892, 809, 773, 760 cm-1. HRMS
(ESI, m/z): Calcd for C22H14ClFN3O [M+H]+ 390.0804, found 390.0809.
1-(4-Chlorophenyl)-7-fluoro-2-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3k):
1
Yield 87 % (339 mg). Pale yellow solid, m. p. 242~244 °C; H NMR (CDCl3, 400

ACCEPTED MANUSCRIPT
MHz): δH 6.65 (s, 1H, CH), 7.27~7.30 (m, 2H, ArH), 7.32~7.35 (m, 2H, ArH),
7.38~7.42 (m, 3H, ArH), 7.46~7.51 (m, 1H, ArH), 7.53~7.55 (m, 2H, ArH), 7.73 (dd,
J = 8.8 Hz, J’ = 4.8 Hz, 1H, ArH), 7.84 (dd, J = 8.4 Hz, J’ = 3.2 Hz, 1H, ArH). 13C
NMR (CDCl3, 100 MHz): δC 102.3, 110.7 (d, JF-C = 23.5 Hz), 118.7 (d, JF-C = 8.3
Hz), 123.1 (d, JF-C = 24.6 Hz), 127.6, 128.7 (d, JF-C = 8.0 Hz), 128.9, 129.0, 129.2,
129.4, 131.0, 135.6, 138.5, 146.3, 151.4, 155.8 (d, JF-C = 3.7 Hz), 158.5, 159.2 (d, JF-C
= 244.3 Hz). IR (KBr):
ν 3099, 3052, 3030, 1682, 1626, 1602, 1592, 1479, 1449,
1402, 1349, 1323, 1280, 1254, 1232, 1203, 1141, 1126, 1101, 1088, 1067, 1032,
1015, 891, 845, 835, 814, 779, 763 cm-1. HRMS (ESI, m/z): Calcd for C22H14ClFN3O
[M+H]+ 390.0804, found 390.0804.
7-Chloro-1-(4-chlorophenyl)-2-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3l):
1
Yield 88 % (357 mg). Pale yellow solid, m. p. 236~238 °C; H NMR (CDCl3, 400
MHz): δH 6.65 (s, 1H, CH), 7.27~7.30 (m, 2H, ArH), 7.31~7.34 (m, 2H, ArH),
7.37~7.42 (m, 3H, ArH), 7.52~7.50 (m, 2H, ArH), 7.66~7.67 (m, 2H, ArH), 8.17 (t, J
13
= 1.6 Hz, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 102.2, 118.8, 125.6, 127.5,
128.1, 128.9, 129.0, 129. 2, 129.4, 129.8, 131.0, 134.5, 134.6, 138.3, 148.1, 152.0,
155.5, 158.8. IR (KBr):
ν 3078, 1687, 1614, 1590, 1543, 1487, 1466, 1448, 1402,
1358, 1340, 1322, 1299, 1244, 1208, 1178, 1132, 1118, 1089, 1068, 1016, 897, 836,
810, 775, 765, 748, 700, 691 cm-1. HRMS (ESI, m/z): Calcd for C22H13Cl2N3ONa
[M+Na]+ 428.0328, found 428.0320.
2-Phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-9(1H)-one (3m): Yield 88 % (309
mg). Pale yellow solid, m.p.: 276~277 °C (Lit.20 273~274 °C); 1H NMR (CDCl3, 400

ACCEPTED MANUSCRIPT
MHz): δH 2.28 (s, 3H, CH3), 6.63 (s, 1H, ArH), 7.10 (d, J = 8.0 Hz, 2H, ArH),
7.28~7.37 (m, 6H, ArH), 7.56~7.58 (m, 2H, ArH), 7.72 (d, J = 8.0 Hz, 2H, ArH), 8.24
(d, J = 8.0 Hz, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 21.3, 101.7, 118.0, 124.0,
126.3, 126.5, 127.8, 128.1, 128.8, 129.0, 129.5, 130.6, 133.9, 137.4, 139.7, 149.6,
152.0, 156.6, 158.7. HRMS (ESI, m/z): calcd for C23H18N3O [M+H]+ 352.1450, found
352.1450.
5-Methyl-2-phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-9(1H)-one (3n): Yield
92 % (336 mg). Pale yellow solid, m. p. 233~235 °C; 1H NMR (CDCl3, 400 MHz): δH
2.30 (s, 3H, CH3), 2.72 (s, 3H, CH3), 6.74 (s, 1H, CH), 7.11 (d, J = 8.0 Hz, 2H, ArH),
7.25 (t, J = 7.6 Hz, 1H, ArH), 7.28~7.30 (m, 2H, ArH), 7.38~7.40 (m, 3H, ArH),
13
7.58~7.62 (m, 3H, ArH), 8.13 (dd, J = 8.0 Hz, J’ = 0.8 Hz, 1H, ArH). C NMR
(CDCl3, 100 MHz): δC 18.2, 21.3, 102.2, 117.9, 123.6, 124.3, 127.8, 128.3, 128.8,
128.9, 129.5, 130.5, 134.1, 134.4, 137.6, 139.6, 148.5, 151.2, 156.8, 158.5. IR (KBr):
ν
3057, 3022, 2968, 2905, 1681, 1610, 1590, 1567, 1504, 1478, 1449, 1421, 1376,
1361, 1335, 1306, 1227, 1214, 1126, 1070, 978, 852, 803, 781, 762, 698 cm-1. HRMS
(ESI, m/z): Calcd for C24H18N3O [M-H]- 364.1444, found 364.1450.
6-Chloro-2-phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-9(1H)-one (3o): Yield
1
93 % (359 mg). Pale yellow solid, m.p.: 250~251 °C (Lit.20 253~254 °C); H NMR
(CDCl3, 400 MHz): δH 8.14 (d, J = 8.8 Hz, 1H, ArH), 7.69 (d, J = 2.0 Hz, 1H, ArH),
7.56~7.53 (m, 2H, ArH), 7.41~7.34 (m, 3H, ArH), 7.27~7.24 (m, 3H, ArH), 7.10 (d, J
13
= 8.0 Hz, 2H, ArH), 6.62 (s, 1H, ArH), 2.29 (s, 3H, CH3). C NMR (CDCl3, 100
MHz): δC 21.6, 101.4, 116.3, 124.5, 125.5, 127.9, 128.0, 128.8, 129.0, 129.6, 130.7,

ACCEPTED MANUSCRIPT
137.0, 139.7, 140.0, 150.6, 152.7, 156.0, 158.9. HRMS (ESI, m/z): calcd for
C23H17N3OCl [M+H]+ 386.1060, found 386.1058.
7-Chloro-2-phenyl-1-(p-tolyl)pyrazolo[5,1-b]quinazolin-9(1H)-one (3p): Yield
95 % (366 mg). Pale yellow solid, m. p. 240~241 °C; 1H NMR (CDCl3, 400 MHz): δH
2.29 (s, 3H, CH3), 6.62 (s, 1H, CH), 7.10 (t, J = 8.0 Hz, 2H, ArH), 7.25~7.27 (m, 2H,
ArH), 7.34~7.39 (m, 3H, ArH), 7.54~7.57 (m, 2H, ArH), 7.64~7.65 (m, 2H, ArH),
8.17~8.18 (m, 1H, ArH). 13C NMR (CDCl3, 100 MHz): δC 21.3, 101.5, 118.7, 125.6,
127.8, 127.91, 127.93, 128.8, 129. 0, 129.3, 129.6, 130.7, 134.3, 137.0, 139.9, 148.2,
152.1, 155.5, 158.8. IR (KBr):
ν 3067, 3034, 1684, 1613, 1583, 1540, 1506, 1448,
1359, 1336, 1322, 1307, 1242, 1229, 1208, 1198, 1179, 1133, 1118, 1060, 1020, 904,
837, 807, 790, 776, 758, 727, 692 cm-1. HRMS (ESI, m/z): Calcd for C23H17ClN3O
[M+H]+ 386.1055, found 386.1056.
2-(4-Methoxyphenyl)-1-phenylpyrazolo[5,1-b]quinazolin-9(1H)-one (3q): Yield
86% (316 mg). Pale yellow solid, m. p. 252~254 °C; 1H NMR (CDCl3, 400 MHz): δH
3.81 (s, 3H, OCH3), 6.60 (s, 1H, CH), 6.88 (d, J = 8.8 Hz, 2H, ArH), 7.32~7.36 (m,
4H, ArH), 7.41~7.43 (m, 2H, ArH), 7.53 (d, J = 8.8 Hz, 2H, ArH), 7.73~7.75 (m, 2H,
13
ArH), 8.23~8.25 (m, 1H, ArH). C NMR (CDCl3, 100 MHz): δC 55.3, 100.8, 114.3,
117.9, 120.3, 123.9, 126.2, 126.5, 128.1, 128.9, 129.5, 130.5, 133.9, 140.6, 149.7,
152.3, 156.5, 158.8, 161.4. IR (KBr):
ν 2927, 2835, 1672, 1586, 1551, 1506, 1486,
1459, 1439, 1423, 1359, 1325, 1313, 1295, 1260, 1229, 1201, 1180, 1025, 834, 791,
768, 687, 665 cm-1. HRMS (ESI, m/z): Calcd for C23H18N3O2 [M+H]+ 368.1399,
found 368.1388.

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Acknowledgement:
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 Institutions for financial support.
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