Copper(I)-catalyzed synthesis of 5-arylindazolo[3,2- b ]quinazolin-7(5 H)-one via ullmann-type reaction

Article abstract of DOI:10.1021/jo400420b

The treatment of 2-amino-N′-arylbenzohydrazide and o-halogenated benzaldehyde in the presence of CuBr and Cs₂CO₃ gave 5-arylindazolo[3,2-b]quinazolin-7(5H)-one in high yields. This procedure contains an Ullmann-type reaction and prov

Full text of DOI:10.1021/jo400420b

Note
pubs.acs.org/joc
Copper(I)-Catalyzed Synthesis of 5‑Arylindazolo[3,2‑b]quinazolin-
7(5H)‑one via Ullmann-Type Reaction
Dong-Sheng Chen,† Guo-Lan Dou,‡ Yu-Ling Li,† Yun Liu,† and Xiang-Shan Wang*,†
†School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Jiangsu Normal University, Xuzhou Jiangsu 221116, PR China
‡School of Safety Engineering, China University of Mining & Technology, Xuzhou 221116, PR China
S
* Supporting Information
ABSTRACT: The treatment of 2-amino-N′-arylbenzohydra-
zide and o-halogenated benzaldehyde in the presence of CuBr
and Cs2CO3 gave 5-arylindazolo[3,2-b]quinazolin-7(5H)-one
in high yields. This procedure contains an Ullmann-type
reaction and provides an efficient method to construct fused
tetracyclic heterocycles.
Scheme 1. Model Reaction
uinazolinones are important molecules with physio-
Q logical significance and pharmaceutical utility for their
antitumor activity.1 They are also well-known as the “privileged
structures”2 for drug design, which are defined as a class of
molecules that are capable of binding to multiple receptors with
high affinity.3 In addition, indazoles are also good candidates
for biological and medicinal purposes, because it is reported
that their derivatives are used as glucokinase activators for the
treatment of Type 2 diabetes mellitus.4 They are also used as
mineralocorticoid receptor antagonists,5 inhibitors of the PDK1
kinase for treating proliferative disorders6 and anticancer
agents.7 Indazoloquinazoline contains both indazole ring and
quinazoline analogue, which may possess novel bioactivity for
screening. However, only a few synthetic methods have been
reported to synthesize these potentially active fused tetracyclic
heterocycles.8 Of which, the Pd(PPh3)4 mediated reaction of
isatoic anhydride, hydrazine, and o-iodobenzaldehyde was an
efficient procedure to build the indazoloquinazolines.8a In this
reported reaction, the scope of the substrate was limited to o-
iodobenzaldehyde, and expensive metal of Pd was used as
catalyst.
It was well-known that Cu(I) was an efficient and
inexpensive catalyst for this Ullmann-type reaction.9 With this
assumption in mind, we tested the two-component reaction of
2-amino-N′-arylbenzohydrazide and o-halogenated benzalde-
hyde. It was found that the designed reaction was easy to carry
out in the presence of CuBr and Cs2CO3 to give 5-
arylindazolo[3,2-b]quinazolin-7(5H)-one derivatives in high
yields. Furthermore, the scope of the substrate could be
extended from 2-iodobenzaldehyde to various kinds of o-
bromobenzaldehydes, even to substituted o-chlorobenzalde-
hyde and o-fluorobenzaldehyde. Herein, we would like to
report the synthesis of 5-arylindazolo[3,2-b]quinazolin-7(5H)-
one via Ullmann-type reaction catalyzed by CuBr.
and solvent were explored as shown in Table 1. No desired
product of 3a was obtained when the reaction was carried out
Table 1. Synthesis of 3a under Different Reaction
a
Conditions
b
entry
cat (mol %)
solvent
base
yields (%)
1
−
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
Cs2CO3
−
0
2
CuBr (5)
CuBr (1)
CuBr (5)
CuBr (10)
CuI (5)
0
3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
NaHCO3
Et3N
75
91
91
86
84
87
91
85
78
65
78
72
68
65
86
4
5
6
7
CuCl (5)
PdCl2 (5)
Pd(PPh3)4 (5)
Pd(OAc)2 (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
CuBr (5)
8
9
10
11
12
13
14
15
16
17
c
d
toluene
CH3CN
THF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
d
DMF
a
Reagents and conditions: 1a (0.227 g, 1.0 mmol), 2a (0.185 g, 1.0
b
mmol), solvent (10 mL), base (2.0 mmol), reflux. Isolated yields.
c
d
NaHCO3: 4 mmol. 100 °C.
In our initial study, using the reaction of 2-amino-N′-
phenylbenzohydrazide 1a and 2-bromobenzaldehyde 2a as a
model (Scheme 1), several parameters including catalyst, base
Received: February 27, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400420b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
in the absence of CuBr or base (Table 1, entries 1 and 2), and
in the presence of various quantities of CuBr, the yield of
product 3a reached a maximum of 91% with 5 mol % CuBr
(Table 1, entries 3−5). Other metal Lewis acids, such as CuI,
CuCl, PdCl2, Pd(PPh3)4 and Pd(OAc)2, were also tested in this
reaction (Table 1, entries 6−10); CuBr and Pd(PPh3)4 almost
gave the same results. Obviously, the catalytic effect of CuBr
was better than the rest. Various solvents, such as toluene,
CH3CN, DMF and benzene, and different bases were also
tested. Dioxane and Cs2CO3 appeared to be the best medium
for this transformation (entries 4, 11−17).
86% yields selectively (Table 2, entry 11) with halogen fluorine
as a leaving group unexpectedly, which was the same to that of
2,6-dichlorobenzaldehyde. In order to prove this was not a
special example, the different 1 were tested to react with 2-
chloro-6-fulorobenzaldehyde, and they all gave the same results
(Table 2, entries 12 and 19).
To our surprise, the reaction stayed in the stage of 2-(2-
bromo-5-chlorophenyl)-1-methyl-3-(phenylamino)-2,3-dihy-
droquinazolin-4(1H)-one 4 in 95% yield, when 2-(methyl-
amino)-N′-phenylbenzohydrazide was used as a reactant to
react with 2-bromo-5-chlorobenzaldehyde (Scheme 3) at the
Similarly, various kinds of 1 and 2 were tested for this CuBr-
catalyzed reaction; they all reacted smoothly to give 5-
arylindazolo[3,2-b]quinazolin-7(5H)-one derivatives in high
yields (Scheme 2, Table 2). The results are summarized in
Scheme 3. Reaction Including 2-(Methylamino)-N′-
phenylbenzohydrazide
Scheme 2. Reaction of 1 and 2
same reaction conditions. The subsequent C−N coupling
reaction did not occur for the unaromatized 2,3-dihydroquina-
zolin-4(1H)-one. Perhaps, this CuBr/Cs2CO3-catalyzed Ull-
mann-type reaction first occurs by aromatization and then
coupling reaction.
a
Table 2. Synthetic Results for the Products 3
b
time
(h)
yields
(%)
entry
Ar
R
R′
X
products
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
Br
I
3a
12
11
10
10
15
15
16
91
92
86
89
92
92
84
According to the structures 3, 4 and the references,9 we think
that three major events may be involved, which are the
formation of dihydroquinazolinone, oxidation of dihydroquina-
zolinone to quinazolinone by air, and C−N coupling reaction.
The key step is the C−N coupling of hydrazine and halide,
which has been well reported by Ullmann,9n Buchwald9k and
Ma’s groups.9c The possible reaction mechanism is outlined in
Scheme 4.
H
H
H
H
H
H
H
5-F
4-F
Br
Br
Br
Br
Br
3b
3c
3d
3e
3f
5-OMe
5-Cl
4,5-
(OMe)2
8
Ph
H
H
4,5-
OCH2O
Br
3g
16
90
In conclusion, we report a novel and efficient method for the
synthesis of 5-arylindazolo[3,2-b]quinazolin-7(5H)-one deriva-
tives using 5 mol % CuBr as catalyst. The procedure includes
the advantages of available reactant, inexpensive catalyst and
high yields.
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-
5-NO2
Cl
Cl
F
3h
3i
8
84
90
85
87
93
89
87
85
86
88
10
11
12
13
14
15
16
17
18
5-Me 6-Cl
5-Me 2-Cl
15
15
10
10
12
9
H
2-Cl
H
F
3j
5-Me
Br
Br
Br
Br
Br
Br
3k
3l
EXPERIMENTAL SECTION
The 2-amino-N′-arylbenzohydrazides were prepared according to ref
■
10.
5-Me 4-F
5-Br
4-Cl
5-Cl
H
H
3m
3n
3o
3p
H
10
8
General Procedure for the Syntheses of 5-Arylindazolo[3,2-
b]quinazolin-7(5H)-one Derivatives 3. o-Halogenated benzalde-
hyde (1.0 mmol), 2-amino-N′-phenylbenzohydrazide (1.0 mmol),
CuBr (7 mg, 0.05 mmol), Cs2CO3 (652 mg), and dioxane (10 mL)
were added into a dry 25 mL flask. The reaction mixture was stirred at
reflux for 7−16 h before reaching completion, which was monitored by
TLC. The product 3 was purified by column chromatography using
ethyl acetate and petroleum ether (1:5) as eluent.
H
4-F
12
MeC6H4
19
20
4-
H
H
2-Cl
H
F
3q
3r
10
7
91
90
MeC6H4
4-ClC6H4
Br
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.
5-Phenylindazolo[3,2-b]quinazolin-7(5H)-one (3a). Yield 91%
b
1
Isolated yields.
(284 mg). Pale yellow solid, mp 238−239 °C. H NMR (400 MHz,
CDCl3): δH 8.33 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 7.6 Hz, 1H), 7.91 (d,
J = 8.0 Hz, 1H), 7.84−7.80 (m, 1H), 7.64−7.60 (m, 1H), 7.50−7.40
(m, 5H), 7.36 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δC 156.4, 149.1, 148.6, 148.2, 141.8, 134.0, 133.4,
129.5, 128.6, 127.0, 126.7, 125.4, 124.5, 124.3, 123.2, 119.8, 118.8,
112.4. IR (KBr): ν 3050, 1673, 1626, 1602, 1555, 1486, 1472, 1340,
1302, 1281, 1273, 1242, 1212, 1155, 1111, 1076, 1018, 997, 945, 852,
797, 762, 754, 707, 685 cm−1. HRMS (TOF, ESI, m/z): Calcd for
C20H14N3O [M + H]+ 312.1137, found 312.1141.
Table 2. Of course, 2-iodobenzaldehyde also gave a satisfying
result (Table 2, entry 2). Halogen chloride could also act as a
leaving group, when 2,6-dichlorobenzaldehyde or 2-chloro- 5-
nitrobenzaldehyde was used as a reactant (Table 2, entries 9
and 10). Using 2-chloro-6-fulorobenzaldehyde as a starting
material, according to our initial assumptions, 4-fluoro-9-
methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one was the
product. However, it was found that 4-chloro-9-methyl-5-
phenylindazolo[3,2-b]quinazolin-7(5H)-one was obtained in
2-Fluoro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3b).
1
Yield 86% (283 mg). Pale yellow solid, mp 267−268 °C. H NMR
(400 MHz, CDCl3): δH 8.33 (d, J = 8.0 Hz, 1H), 7.94 (dd, J = 7.6 Hz,
B
dx.doi.org/10.1021/jo400420b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 4. Possible Reaction Mechanism
J′ = 2.4 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.85−7.81 (m, 1H), 7.50−
7.46 (m, 3H), 7.44−7.40 (m, 1H), 7.38−7.34 (m, 3H), 7.17 (dd, J =
8.8 Hz, J′ = 4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δC 159.7 (d,
JF−C = 242.8 Hz), 156.3, 148.4, 147.6 (d, JF−C = 4.4 Hz), 145.6, 141.8,
134.1, 129.6, 128.8, 127.1, 126.7, 125.7, 124.4, 121.7 (d, JF−C = 25.5
Hz), 119.9 (d, JF−C = 10.1 Hz), 119.8, 114.0 (d, JF−C = 8.5 Hz), 108.8
(d, JF−C = 25.1 Hz). 19F NMR (400 MHz, CDCl3): δF −117.7. IR
(KBr): ν 3055, 2920, 1678, 1634, 1603, 1556, 1487, 1474, 1344, 1286,
1262, 1245, 1226, 1150, 1131, 1101, 1073, 1008, 962, 890, 862, 818,
807, 768, 754, 704, 688 cm−1. HRMS (TOF, ESI, m/z): Calcd for
C20H13N3OF [M + H]+ 330.1043, found 330.1047.
7.40 (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 6.57 (s, 1H), 4.03 (s, 3H,
CH3O), 3.89 (s, 3H, CH3O). 13C NMR (100 MHz, CDCl3): δC 156.4,
155.1, 148.9, 148.6, 147.9, 145.1, 142.1, 133.9, 129.6, 128.6, 126.7,
126.5, 124.8, 124.6, 119.1, 110.1, 102.7, 94.6, 56.6, 56.4. IR (KBr): ν
3008, 2986, 1674, 1633, 1602, 1592, 1555, 1506, 1493, 1464, 1386,
1331, 1272, 1246, 1218, 1191, 1157, 1123, 1105, 1039, 1016, 980, 894,
860, 815, 771, 738, 706 cm−1. HRMS (TOF, ESI, m/z): Calcd for
C22H18N3O3 [M + H]+ 372.1348, found 372.1345.
5-Phenyl-[1,3]dioxolo[4′,5′:5,6]indazolo[3,2-b]quinazolin-7(5H)-
1
one (3g). Yield 90% (319 mg). Pale yellow solid, mp >300 °C. H
NMR (400 MHz, CDCl3): δH 8.29 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4
Hz, 1H), 7.80−7.63 (m, 1H), 7.56 (s, 1H), 7.49−7.45 (m, 2H), 7.43−
7.39 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 6.60 (s, 1H), 6.09 (s, 2H,
CH2). 13C NMR (100 MHz, CDCl3): δC 156.4, 153.5, 148.9, 148.3,
146.5, 146.2, 141.9, 134.0, 129.6, 128.7, 126.7, 126.6, 124.8, 124.5,
119.0, 116.0, 102.5, 100.7, 93.4. IR (KBr): ν 3101, 3053, 2920, 2866,
1674, 1615, 1598, 1556, 1490, 1472, 1413, 1392, 1348, 1325, 1260,
1215, 1151, 1113, 1032, 1005, 979, 924, 889, 837, 784, 768, 704 cm−1.
HRMS (TOF, ESI, m/z): Calcd for C21H14N3O3 [M + H]+ 356.1035,
found 356.1040.
3-Fluoro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3c).
1
Yield 89% (293 mg). Pale yellow solid, mp 211−212 °C. H NMR
(400 MHz, CDCl3): δH 8.32 (d, J = 8.0 Hz, 1H), 8.26 (dd, J = 8.4 Hz,
J′ = 5.2 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.84−7.80 (m, 1H), 7.52−
7.42 (m, 4H), 7.36 (d, J = 7.6 Hz, 2H), 7.16−7.12 (m, 1H), 6.87 (d, J
= 8.8 Hz, 1H). 13C NMR (100 MHz, CDCl3): δC 166.2 (d, JF−C
=
251.9 Hz), 156.2, 150.2 (d, JF−C = 12.8 Hz), 148.6, 147.3, 141.2, 134.1,
129.7, 128.9, 126.9, 126.7, 125.5, 125.2 (d, JF−C = 10.9 Hz), 124.5,
119.5, 114.9 (d, JF−C = 1.6 Hz), 113.1 (d, JF−C = 24.6 Hz), 99.5 (d,
JF−C = 27.6 Hz). 19F NMR (400 MHz, CDCl3): δF −103.2. IR (KBr):
ν 3066, 3012, 1681, 1633, 1604, 1493, 1467, 1442, 1343, 1284, 1265,
1242, 1218, 1180, 1162, 1140, 1096, 1032, 1005, 976, 833, 782, 771,
744, 703, 688 cm−1. HRMS (TOF, ESI, m/z): Calcd for C20H13N3OF
[M + H]+ 330.1043, found 330.1044.
2-Nitro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3h). Yield
1
84% (299 mg). Pale yellow solid, mp 295−296 °C. H NMR (400
MHz, CDCl3): δH 9.21 (d, J = 1.6 Hz, 1H), 8.48 (dd, J = 8.8 Hz, J′ =
2.0 Hz, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.89−
7.85 (m, 1H), 7.57−7.51 (m, 4H), 7.42 (d, J = 8.4 Hz, 2H), 7.25 (d, J
= 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δC 156.0, 155.6, 148.2,
146.2, 144.3, 139.7, 134.5, 129.9, 129.6, 128.5, 127.4, 126.7, 126.3,
125.2, 120.1, 120.0, 118.8, 112.0. IR (KBr): ν 3064, 1686, 1631, 1600,
1524, 1489, 1471, 1461, 1341, 1294, 1255, 1232, 1128, 1070, 1008,
959, 797, 767, 738 cm−1. HRMS (TOF, ESI, m/z): Calcd for
C20H13N4O3 [M + H]+ 357.0988, found 357.0969.
2-Methoxy-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3d).
1
Yield 92% (314 mg). Pale yellow solid, mp 235−236 °C. H NMR
(400 MHz, CDCl3): δH 8.33 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.4 Hz,
1H), 7.82 (t, J = 7.6 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.48−7.44 (m,
3H), 7.41−7.37 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 7.25−7.22 (m,
1H), 7.13 (d, J = 9.2 Hz, 1H), 3.94 (s, 3H, CH3O). 13C NMR (100
MHz, CDCl3): δC 152.0, 151.2, 143.3, 143.2, 138.9, 137.0, 128.8,
124.3, 123.2, 121.6, 121.5, 120.1, 118.9, 118.7, 114.4, 114.1, 108.6,
98.1, 50.8. IR (KBr): ν 3022, 2959, 2935, 1686, 1633, 1602, 1556,
1495, 1417, 1357, 1291, 1275, 1248, 1198, 1189, 1172, 1154, 1101,
1031, 1009, 956, 888, 847, 833, 805, 767, 748, 712, 688 cm−1. HRMS
(TOF, ESI, m/z): Calcd for C21H16N3O [M + H]+ 342.1243, found
342.1246.
1-Chloro-9-methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one
1
(3i). Yield 90% (324 mg). Pale yellow solid, mp 232−233 °C. H
NMR (400 MHz, CDCl3): δH 8.09 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H),
7.65 (d, J = 8.4 Hz, 1H), 7.50−7.46 (m, 3H), 7.44−7.40 (m, 1H),
7.36−7.34 (m, 3H), 7.08 (d, J = 8.4 Hz, 1H), 2.50 (s, 3H, CH3). 13C
NMR (100 MHz, CDCl3): δC 156.1, 150.3, 146.6, 146.0, 141.7, 136.1,
135.6, 133.2, 130.8, 129.6, 128.7, 127.7, 125.7, 125.3, 124.6, 119.4,
116.2, 110.6, 21.4. IR (KBr): ν 3481, 3415, 3014, 2914, 1681, 1626,
1602, 1486, 1427, 1332, 1297, 1235, 1152, 1136, 1123, 1063, 1028,
965, 825, 794, 779, 747, 726, 696 cm−1. HRMS (TOF, ESI, m/z):
Calcd for C21H15N3OCl [M + H]+ 360.0904, found 360.0904.
1-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3j). Yield
2-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3e).
1
Yield 92% (318 mg). Pale yellow solid, mp 272−273 °C. H NMR
(400 MHz, CDCl3): δH 8.32 (d, J = 8.0 Hz, 1H), 8.23 (s, 1H), 7.90 (d,
J = 8.4 Hz, 1H), 7.85−7.81 (m, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.50−
7.47 (m, 3H), 7.45−7.41 (m, 1H), 7.35 (d, J = 7.6 Hz, 2H), 7.13 (d, J
= 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δC 156.2, 148.4, 147.4,
147.0, 141.4, 134.2, 133.7, 130.1, 129.7, 128.9, 127.1, 126.7, 125.8,
124.5, 122.8, 120.1, 119.8, 113.6. IR (KBr): ν 3047, 3008, 1680, 1628,
1601, 1556, 1490, 1467, 1338, 1317, 1285, 1254, 1232, 1189, 1154,
1144, 1124, 1064, 1009, 953, 872, 817, 797, 767, 753, 729, 700, 689
cm−1. HRMS (TOF, ESI, m/z): Calcd for C20H13N3OCl [M + H]+
346.0747, found 346.0741.
1
87% (301 mg). Pale yellow solid, mp 263−264 °C. H NMR (400
MHz, CDCl3): δH 8.31 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H),
7.84−7.81 (m, 1H), 7.51−7.47 (m, 4H), 7.44−7.41 (m, 1H), 7.36 (d, J
= 8.0 Hz, 3H), 7.07 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δC 156.2, 150.3, 148.5, 146.6, 141.5, 133.9, 133.4, 131.0,
129.6, 128.9, 127.9, 126.4, 125.9, 125.4, 124.8, 119.6, 116.0, 110.6. IR
(KBr): ν 3046, 1691, 1599, 1554, 1468, 1425, 1335, 1293, 1252, 1236,
1154, 1105, 1002, 964, 789, 763, 723 cm−1. HRMS (TOF, ESI, m/z):
Calcd for C20H13N3OCl [M + H]+ 346.0747, found 346.0727.
9-Methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3k).
2,3-Dimethoxy-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one
1
(3f). Yield 84% (312 mg). Pale yellow solid, mp 234−235 °C. H
NMR (400 MHz, CDCl3): δH 8.30 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.4
Hz, 1H), 7.81−7.77 (m, 1H), 7.61 (s, 1H), 7.51−7.47 (m, 2H), 7.44−
1
Yield 93% (302 mg). Pale yellow solid, mp 235−236 °C. H NMR
C
dx.doi.org/10.1021/jo400420b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(400 MHz, CDCl3): δH 8.27 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.82 (d,
J = 8.4 Hz, 1H), 7.66−7.59 (m, 2H), 7.49−7.46 (m, 2H), 7.43−7.38
(m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 2.50 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3): δC 156.3, 149.0, 147.6,
146.6, 141.9, 135.7, 135.6, 133.2, 129.5, 128.4, 126.8, 126.0, 124.3,
123.1, 119.6, 118.9, 112.4, 21.4. IR (KBr): ν 3050, 3015, 1671, 1630,
1606, 1488, 1465, 1344, 1301, 1273, 1237, 1213, 1152, 1107, 1077,
1036, 1002, 957, 883, 822, 777, 769, 752, 708, 696 cm−1. HRMS
(TOF, ESI, m/z): Calcd for C21H16N3O [M + H]+ 326.1293, found
326.1293.
1141, 1101, 1005, 974, 951, 839, 818, 762, 707, 685 cm−1. HRMS
(TOF, ESI, m/z): Calcd for C21H15N3OF [M + H]+ 344.1199, found
344.1195.
1-Chloro-5-p-tolylindazolo[3,2-b]quinazolin-7(5H)-one (3q).
1
Yield 91% (327 mg). Pale yellow solid, mp 261−262 °C. H NMR
(400 MHz, CDCl3): δH 8.31 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.4 Hz,
1H), 7.84−7.80 (m, 1H), 7.50−7.46 (m, 2H), 7.35 (d, J = 8.0 Hz,
1H), 7.29−7.23 (m, 4H), 7.05 (d, J = 8.4 Hz, 1H), 2.40 (s. 3H). 13C
NMR (100 MHz, CDCl3): δC 156.2, 150.5, 148.5, 146.5, 139.0, 138.9,
133.9, 133.3, 130.9, 130.2, 127.9, 126.4, 125.8, 125.2, 124.8, 119.7,
115.9, 110.6, 21.2. IR (KBr): ν 3051, 2920, 1682, 1618, 1599, 1510,
1484, 1466, 1432, 1334, 1301, 1251, 1158, 1136, 1001, 964, 773, 750
cm−1. HRMS (TOF, ESI, m/z): Calcd for C21H15N3OCl [M + H]+
360.0904, found 360.0896.
3-Fluoro-9-methyl-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one
1
(3l). Yield 89% (306 mg). Pale yellow solid, mp 220−221 °C. H
NMR (400 MHz, CDCl3): δH 8.25−8.22 (m, 1H), 8.10 (s, 1H), 7.79
(d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.51−7.48 (m, 2H),
7.45−7.41 (m, 1H), 7.35 (d, J = 7.6 Hz, 2H), 7.14−7.10 (m, 1H), 6.87
(d, J = 8.8 Hz, 1H), 2.50 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δC 166.1 (d, JF−C = 251.4 Hz), 156.2, 150.2 (d, JF−C = 12.8 Hz), 146.8,
5-(4-Chlorophenyl)indazolo[3,2-b]quinazolin-7(5H)-one (3r).
1
Yield 90% (311 mg). Pale yellow solid, mp 236−237 °C. H NMR
(400 MHz, CDCl3): δH 8.32 (d, J = 8.0 Hz, 1H), 8.29 (d, J = 8.0 Hz,
1H), 7.91 (d, J = 8.4 Hz, 1H), 7.85−7.81 (m, 1H), 7.66−7.62 (m,
1H), 7.50−7.42 (m, 4H), 7.31 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz,
1H). 13C NMR (100 MHz, CDCl3): δC 156.4, 148.8, 148.6, 148.0,
140.4, 134.4, 134.2, 133.5, 129.8, 127.1, 126.6, 126.1, 125.6, 124.6,
123.3, 119.7, 118.9, 112.3. IR (KBr): ν 3055, 1683, 1623, 1602, 1556,
1489, 1483, 1340, 1305, 1273, 1140, 1090, 1016, 946, 933, 835, 765,
751 cm−1. HRMS (TOF, ESI, m/z): Calcd for C20H13N3OCl [M +
H]+ 346.0747, found 346.0741.
146.6, 141.4, 135.8, 135.7, 129.7, 128.8, 126.7, 126.0, 125.1 (d, JF−C
=
10.9 Hz), 124.4, 119.3, 115.1 (d, JF−C = 1.6 Hz), 113.1 (d, JF−C = 24.5
Hz), 99.5 (d, JF−C = 27.7 Hz), 21.4. 19F NMR (400 MHz, CDCl3): δF
−103.6. IR (KBr): ν 3057, 1683, 1632, 1606, 1491, 1458, 1443, 1379,
1336, 1286, 1224, 1153, 1099, 1076, 1037, 1002, 975, 940, 903, 874,
831, 816, 777, 749, 737, 708 cm−1. HRMS (TOF, ESI, m/z): Calcd for
C21H15N3OF [M + H]+ 344.1199, found 344.1197.
9-Bromo-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3m).
1
General Procedure for the Syntheses of the Product 4. 2-
Bromo-5-chlorobenzaldehyde (0.219 g, 1.0 mmol), 2-(methylamino)-
N′-phenyl benzohydrazide (0.241 g, 1.0 mmol), CuBr (7 mg, 0.05
mmol), Cs2CO3 (652 mg), and dioxane (10 mL) were added into a
dry 25 mL flask. The reaction mixture was stirred at reflux for 3 h
before reaching completion, which was monitored by TLC. The hot
mixture was treated by immediate filtration to remove the catalyst and
base. The filtrate was cooled to room temperature, and the product 4
was obtained by filtration without further purification.
Yield 87% (339 mg). Pale yellow solid, mp 273−274 °C. H NMR
(400 MHz, CDCl3): δH 8.44 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 8.0 Hz,
1H), 7.87 (dd, J = 8.8 Hz, J′ = 2.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H),
7.66−7.62 (m, 1H), 7.51−7.47 (m, 2H), 7.44−7.41 (m, 2H), 7.34 (d, J
= 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3): δC 155.1, 149.0, 148.4, 147.4, 141.4, 137.1, 133.7, 129.6,
129.1, 128.8, 128.7, 124.52, 124.49, 123.2, 121.0, 118.6, 118.5, 112.3.
IR (KBr): ν 3054, 1672, 1623, 1593, 1543, 1494, 1469, 1342, 1300,
1263, 1208, 1153, 1126, 1076, 1026, 950, 892, 826, 806, 749 cm−1.
HRMS (TOF, ESI, m/z): Calcd for C20H13N3OBr [M + H]+
390.0242, found 390.0228.
2-(2-Bromo-5-chlorophenyl)-1-methyl-3-(phenylamino)-2,3-dihy-
droquinazolin-4(1H)-one (4). Yield 95% (420 mg). Pale yellow solid,
1
mp 221−222 °C. H NMR (400 MHz, CDCl3): δH 8.01 (d, J = 8.0
10-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3n).
1
Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.36 (s,
1H), 7.29−7.25 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.97−6.90 (m,
4H), 6.64 (d, J = 8.4 Hz, 1H), 6.39 (s, 1H), 6.36 (s, 1H), 2.93 (s, 3H).
13C NMR (100 MHz, CDCl3): δC 162.5, 146.4, 146.2, 138.9, 134.9,
134.4, 134.3, 130.9, 129.3, 129.0, 127.0, 121.9, 121.3, 118.8, 114.2,
114.1, 112.0. 77.6, 35.5. IR (KBr): ν 3277, 3022, 2920, 1649, 1604,
1494, 1457, 1432, 1377, 1319, 1215, 1173, 1162, 1097, 1026, 1012,
Yield 85% (294 mg). Pale yellow solid, mp 208−209 °C. H NMR
(400 MHz, CDCl3): δH 8.27 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.8 Hz,
1H), 7.90 (s, 1H), 7.66−7.63 (m, 1H), 7.51−7.47 (m, 2H), 7.45−7.39
(m, 3H), 7.36 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3): δC 155.8, 149.6, 149.1, 149.0, 141.4, 140.2, 133.8,
129.6, 128.7, 128.1, 126.4, 126.0, 124.6, 124.5, 123.4, 118.4, 118.1,
112.3. IR (KBr): ν 3050, 1675, 1626, 1594, 1543, 1485, 1467, 1456,
1329, 1279, 1265, 1121, 1074, 1024, 946, 874, 762, 753 cm−1. HRMS
(TOF, ESI, m/z): Calcd for C20H13N3OCl [M + H]+ 346.0747, found
346.0736.
751, 720 cm−1
. HRMS (TOF, ESI, m/z): Calcd for
C21H17N3OBrClNa [M + Na]+ 464.0141, found 464.0137.
9-Chloro-5-phenylindazolo[3,2-b]quinazolin-7(5H)-one (3o).
Yield 86% (297 mg). Pale yellow solid, mp 266−267 °C. H NMR
ASSOCIATED CONTENT
■
1
S
* Supporting Information
(400 MHz, CDCl3): δH 8.29 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.86 (d,
J = 8.8 Hz, 1H), 7.45 (dd, J = 8.8 Hz, J′ = 2.0 Hz, 1H), 7.68−7.64 (m,
1H), 7.53−7.49 (m, 2H), 7.47−7.43 (m, 2H), 7.37 (d, J = 8.0 Hz,
2H), 7.23 (d, J = 8.4 Hz, 1H). 13C NMR (100 MHz, CDCl3): δC
155.3, 149.0, 148.3, 147.1, 141.4, 134.4, 133.6, 131.0, 129.6, 128.7,
128.6, 125.9, 124.54, 124.46, 123.2, 120.6, 118.5, 112.3. IR (KBr): ν
3058, 1673, 1624, 1597, 1545, 1494, 1483, 1471, 1342, 1299, 1265,
1153, 1127, 1074, 829, 806, 759, 751, 701 cm−1. HRMS (TOF, ESI,
m/z): Calcd for C20H13N3OCl [M + H]+ 346.0747, found 346.0734.
3-Fluoro-5-(p-tolyl)indazolo[3,2-b]quinazolin-7(5H)-one (3p).
1
13
Copies of H NMR and C NMR spectra for compounds
3a−r and 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xswang1974@yahoo.com.
Notes
1
Yield 88% (302 mg). Pale yellow solid, mp 226−227 °C. H NMR
The authors declare no competing financial interest.
(400 MHz, CDCl3): δH 8.31 (d, J = 8.4 Hz, 1H), 8.27−8.23 (m, 1H),
7.88 (d, J = 8.0 Hz, 1H), 7.83−7.79 (m, 1H), 7.47−7.44 (m, 1H), 7.29
(d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.12 (t, J = 8.8 Hz, 1H),
6.84 (d, J = 8.4 Hz, 1H), 2.41 (s, 3H, CH3). 13C NMR (100 MHz,
CDCl3): δC 166.2 (d, JF−C = 251.7 Hz), 156.3, 150.4 (d, JF−C = 12.8
Hz), 146.8, 147.3, 139.1, 138.6, 134.1, 130.3, 126.9, 126.7, 125.4, 125.2
(d, JF−C = 11 Hz), 124.6, 119.5, 114.8 (d, JF−C = 1.6 Hz), 113.0 (d,
JF−C = 24.5 Hz), 99.4 (d, JF−C = 27.5 Hz), 21.3. 19F NMR (400 MHz,
CDCl3): δF −103.4. IR (KBr): ν 3094, 3064, 1678, 1632, 1603, 1557,
1509, 1492, 1467, 1436, 1344, 1317, 1289, 1266, 1241, 1198, 1163,
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science foundation of
China (20802061, 21104064), a project funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions, Qing Lan Project (10QLD008, GSFM2011003)
and College Industrialization Project (JHB2012-31) of Jiangsu
Province for financial support.
D
dx.doi.org/10.1021/jo400420b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Kirihata, M. Org. Biomol. Chem. 2012, 10, 1381−1387. (m) Monnier,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954−6971.
(n) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382−2384.
(10) Shemchuk, L. A.; Chernykh, V. P.; Krys’kiv, O. S. Russ. J. Org.
Chem. 2008, 44, 1006−1008.
REFERENCES
■
(1) (a) Abdel Gawad, N. M.; Georgey, H. H.; Youssef, R. M.; El-
Sayed, N. A. Eur. J. Med. Chem. 2010, 45, 6058−6067. (b) Kamal, A.;
Vijaya Bharathi, E.; Janaki Ramaiah, M.; Dastagiri, D.; Surendranadha
Reddy, J.; Viswanath, A.; Sultana, F.; Pushpavalli, S. N. C. V. L.; Pal-
Bhadra, M.; Srivastava, H. K.; Narahari Sastry, G.; Juvekar, A.; Sen, S.;
Zingde, S. Bioorg. Med. Chem. 2010, 18, 526−542. (c) Evarts, J. B.;
Ulrich, R. G. Preparation of atropisomers of 2-purinyl-3-tolyl-
quinazolinone derivatives as anti-inflammatory and anticancer agents.
PCT Int. Appl. WO 2010111432 A1 30 Sep 2010; Chem. Abstr. 2010,
153, 456375. (d) Wu, H.; Xie, X.; Liu, G. J. Comb. Chem. 2010, 12,
346−355. (e) Giri, R. S.; Thaker, H. M.; Giordano, T.; Williams, J.;
Rogers, D.; Vasu, K. K.; Sudarsanam, V. Bioorg. Med. Chem. 2010, 18,
2796−2808. (f) Giri, R. S.; Thaker, H. M.; Giordano, T.; Chen, B.;
Nuthalapaty, S.; Vasu, K. K.; Sudarsanam, V. Eur. J. Med. Chem. 2010,
45, 3558−3563. (g) Liu, J.; Ali, S. M.; Ashwell, M. A.; Ye, P.; Guan, Y.;
Ng, S.-C.; Palma, R.; Yohannes, D. Preparation of quinazolinone
quinazolinone derivatives useful in treatment of proliferative diseases
and cancer. PCT Int. Appl. WO 2009002808 A2 31 Dec 2008; Chem.
Abstr. 2009, 150, 98369.
(2) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893−930.
(3) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfieldt, J. J. Med. Chem.
1988, 31, 2235−2246. (b) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A.
M. Mini-Rev. Med. Chem. 2007, 7, 1108−1119.
(4) Pfefferkorn, J. A.; Tu, M.; Filipski, K. J.; Guzman-Perez, A.; Bian,
J.; Aspnes, G. E.; Sammons, M. F.; Song, W.; Li, J.-C.; Jones, C. S.
Bioorg. Med. Chem. Lett. 2012, 22, 7100−7105.
(5) Lan, P.; Liu, K.; Ogawa, A.; Shen, H.; Yang, C.; Wang, Y.; Beresis,
R.; Qi, C. Preparation of 1H-indazole derivatives as mineralocorticoid
receptor antagonists. PCT Int. Appl. 2012, WO 2012139495 A1
20121018.
(6) Bearss, D. J.; Vankayalapati, H.; Sorna, V.; Warner, S. L.; Sharma,
S. Preparation of substituted 3-(1H-benzo[d]imidazol-2-yl)-1H-
indazole analogs as inhibitors of the PDK1 kinase for treating
proliferative disorders. PCT Int. Appl. 2012, WO 2012135799 A1
20121004.
(7) Isami, S.; Muramatsu, N.; Tanimura, S. Preparation of salts of
indazole derivatives as anticancer agents. PCT Int. Appl. 2011, WO
2011158931 A1 20111222.
(8) (a) Siva Kumar, K.; Mahesh Kumar, P.; Sreenivasa Rao, V.; Jafar,
A. A.; Meda, C. L. T.; Kapavarapu, R.; Parsa, K. V. L.; Pal, M. Org.
Biomol. Chem. 2012, 10, 3098−3103. (b) Bhavani, A. K. D.; Reddy, P.
S. N. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1992, 31B,
736−739. (c) Reddy, V. R. K.; Reddy, P. S. N.; Ratnam, C. V. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1992, 31B, 499−502.
(d) Reddy, V. R. K.; Reddy, P. S. N.; Ratnam, C. V. Synth. Commun.
1991, 21, 49−61. (e) Reddy, Y. P.; Reddy, G. S.; Reddy, K. K. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1979, 18B, 125−127.
(f) Hill, D. T.; Stanley, K. G.; Libsch, S. S.; Loev, B. J. Heterocycl. Chem.
1976, 13, 1325−1326. (g) Walser, A.; Zally, W. J.; Fryer, R. I. J.
Heterocycl. Chem. 1974, 11, 863−866.
(9) (a) Feng, Z.; Chen, F.; Zhang, X. Org. Lett. 2012, 14, 1938−1941.
(b) Jiang, M.; Li, M.; Wang, F.; Zhao, Y.; Zhao, F.; Dong, X.; Zhao, W.
Org. Lett. 2012, 14, 1420−1423. (c) Xiong, X.; Jiang, Y.; Ma, D. Org.
Lett. 2012, 14, 2552−2555. (d) Sang, P.; Xie, Y.; Zou, J.; Zhang, Y.
Org. Lett. 2012, 14, 3894−3897. (e) Kavala, V.; Wang, C. C.; Barange,
D. K.; Kuo, C. W.; Lei, P. M; Yao, C. F. J. Org. Chem. 2012, 77, 5022−
5029. (f) Xu, W.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13,
1274−1277. (g) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem.
2007, 72, 672−674. (h) Wang, C.; Li, S.; Liu, H.; Jiang, Y.; Fu, H. J.
Org. Chem. 2010, 75, 7936−7938. (i) Zhou, F.; Guo, J.; Liu, J.; Ding,
K.; Yu, S.; Cai, Q. J. Am. Chem. Soc. 2012, 134, 14326−14329.
(j) Chen, Z.; Ye, C.; Gao, L.; Wu, J. Chem. Commun. 2011, 47, 5623−
5625. (k) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3,
3803−3805. (l) Tanimori, S.; Kobayashi, Y.; Iesaki, Y.; Ozaki, Y.;
E
dx.doi.org/10.1021/jo400420b | J. Org. Chem. XXXX, XXX, XXX−XXX