A general and facile synthesis of novel polysubstituted quinazolin-4(3H)-ones

Article abstract of DOI:10.1002/jhet.1001

A simple and efficient approach to synthesize novel polysubstituted quinazolin-4(3H)-ones has been developed, and the key step is a sequential procedure involved iron-mediated reduction and acid-catalytic cyclization. The present method provides a conveni

Full text of DOI:10.1002/jhet.1001

January 2013
A General and Facile Synthesis of Novel Polysubstituted Quinazolin-4
169
(3H)-ones
a
a
a
a
a
a,b
*
*
Minhang Xin, Ying Gao, Hua Xiang, Dong Chen, Yi He, and Qidong You
aDepartment of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University,
24 Tongjiaxiang, Nanjing 210009, People’s Republic of China
bJiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University,
Nanjing 210009, People’s Republic of China
*
E-mail: cpuxianghua@sina.com; youqidong@gmail.com
Received January 30, 2011
DOI 10.1002/jhet.1001
View this article online at wileyonlinelibrary.com.
A simple and efficient approach to synthesize novel polysubstituted quinazolin-4
(3H)-ones has been developed, and the key step is a sequential procedure involved
iron-mediated reduction and acid-catalytic cyclization. The present method provides
a convenient and practical strategy for the synthesis of quinazolin-4(3H)-one
derivatives.
J. Heterocyclic Chem., 50, 169 (2013).
INTRODUCTION
using copper-catalystic N-arylation of quinazolin-4(3H)-
ones with arylboronic acids [5]. Although these protocols
for the synthesis of quinazolin-4(3H)-ones are useful, the
development of flexible, efficient, economically competitive,
and simple methodology is still needed for quinazolin-4
(3H)-ones, especially for the complex polysubstituted
quinazolin-4(3H)-one derivatives [1–7].
Quinazolin-4(3H)-ones have attracted much attention for
their various biological activities and medicinal properties.
For example, they act as the potent phosphoinositide 3-
kinase inhibitors, N-methyl-D-aspartate receptor antago-
nists, histamine receptor agonists, 5-hydroxytryptamine
receptor antagonists, and chemokine receptor antagonists
[1]. Some of them show remarkable activities as antitumor,
anti-neurodegenerative, anti-allergic, and anti-inflammatory
agents. Moreover, therapeutic agents containing the quinazo-
lin-4(3H)-one moiety have been on the market or are in
clinical trials. For example, methaqualone is used as a seda-
tive–hypnotic drug and piriqualone as an anticonvulsant.
Ispinesib (SB-715992), a kinesin spindle protein targeting
inhibitor, has recently warranted in phase II trial and is of po-
tential therapeutic value in malignant melanoma. IC-87114
as a phosphoinositide 3-kinase inhibitor is now on phase I
trial for relapsed or refractory chronic lymphocytic leukemia,
acute myeloid leukemia, and selected B-cell non-Hodgkin’s
lymphoma (Figure 1) [2]. Because of their various applica-
tions, some synthetic strategies for quinazolin-4(3H)-ones
have been reported in the literature. The most common
method employed anthranilic acid as starting material, which
condensed with aromatic amines and orthoesters under
acidic conditions, such as perfluorinated resin-supported
sulfonic acid (Nafion-H), La(NO3)3, Bi(TFA)3–[nbp]FeCl4,
silica gel/FeCl3, ZrOCl2, Yb(OTf)3, and SnCl2Á2H2O [3].
Other method mainly focused on cyclization of 2-aminoben-
zamide or its derivatives or 2-aminobenzonitrile with some
substrates such as arylamines, imidates, iminohalides, and
isocyanides [4]. Moreover, a recent report revealed that qui-
nazolin-4(3H)-one derivatives have also been synthesized
Recently, Shi et al. described a one-pot synthesis of
quinazolin-4(3H)-ones by using TiCl4/Zn-catalyzed cycli-
zation of triethyl orthoformate with o-nitrobenzamides
[6]. However, the procedure suffered from some difficul-
ties such as inconvenient preparation of catalytic system,
poor achievement of catalytic activity, harsh reaction
condition, and disgusting smoking of Lewis acid TiCl4.
Considering the reaction mechanism and the reactive
characteristics of Zn and TiCl4, we elicited that we can
employ a sequential procedure of iron-mediated reduction
and acid-catalytic cyclization instead. In continuation of
our studies on the diversity-oriented synthesis of novel
quinazolin-4(3H)-one unit-containing compounds for a
drug discovery program, herein we report a simple,
efficient, and practical method for the synthesis of novel
polysubstituted quinazolin-4(3H)-ones that involved
acylation and a sequential reaction of iron-mediated reduc-
tion and acid-catalytic cyclization, and the acid-catalytic
condition was also fully discussed (Scheme 1).
RESULTS AND DISCUSSION
In the synthesis of target substituted quinazolin-4(3H)-
ones, 2-nitro-4-benzyloxy-5-methoxy benzoic acid (1)
was used as starting material, which was prepared accord-
ing to the literature method in good yield [7]. Treatment of
© 2013 HeteroCorporation

170
M. Xin, Y. Gao, H. Xiang, and D. Chen
Vol 50
Figure 1. Some drugs and drug candidates containing the quinazolin-4(3H)-one unit.
Scheme 1. Synthetic route of polysubstituted quinazolin-4(3H)-one derivatives.
compound 1 with SOCl2 to offer an acyl chloride, then
with aromatic amines or alkyl amines at room temperature
gave the precursors 2 in excellent yield, as illustrated in
Scheme 1. Our investigation focused on the preparation
of target quinazolin-4(3H)-ones. The iron-mediated reduc-
tion was easily carried out almost quantitatively. Then, we
initially carried out a set of experiments using N-phenyl-2-
amino-4-benzyloxy-5-methoxy benzamide (2aa) as model
substrate for optimizing the acid-catalytic cyclization con-
ditions, and the results are summarized in Table 1. The
reagents formic acid and triethyl orthoformate and the acid
catalysts including concentrated sulfuric acid, zinc chlo-
ride, and p-toluene sulfuric acid (PTSA) were investigated.
To our delight, when acid catalysts were employed, the
yield increased notably, and when PTSA was used, the
excellent yield (98%) of the expected product 3a was
provided (Table 1, entries 1–6). Accordingly, acid catalyst
facilitated the reaction. Next, the catalyst loading was
optimized, and thus, several amounts of PTSA catalyst
were investigated in a range of 100, 50, 20 and 10 mol%
(Table 1, entries 6–9), and it was found that 20 mol%
of PTSA loading is appropriate (Table 1, entry 8). No
decline in the yield was observed on decreasing the cata-
lyst loading from 100 to 20 mol% (Table 1, entries 6–8).
Other different reaction parameters including solvent,
temperature, time, and triethyl orthoformate amount were
also performed. Finally, the optimum conditions for the
ring closure of 3 were to conduct the reaction using tri-
ethyl orthoformate (10 equiv) and PTSA (20 mol%) in
refluxing THF for 3 h.
Thus, on the basis of optimized reaction conditions, we
carried out the synthesis of a number of polysubstituted
quinazolin-4(3H)-ones in good or excellent yields. The
results are summarized in Table 2. In general, anilines
carrying either electron-donating (Table 2, entries 2–5,
12) or electron-withdrawing groups (Table 2, entries 6–
10, 13–15) all afford excellent yields (72–92%). Steric
hindrance is appearing to have little effects on the
efficiency of this one-pot continuous reaction. However,
hydroxyl-substituted aniline gives the lowest yield (39%,
Table 2, entry 11). Other different substituted functional
groups are seemed to be tolerated, such as alkyl, halogen,
ketone, methoxy, and ester in the anilines (Table 2, entries
2–15). Furthermore, this approach was extended to alkyl
amines for preparation of their corresponding quinazolin-
4(3H)-ones (Table 2, entries 16–17). Also, they were found
to be also effective in the reaction system, and the yield is
satisfactory (86% and 86%). In addition, 2-positon methyl
substituted quinazolin-4(3H)-ones were synthesized via us-
ing triethyl orthoacetate instead of triethyl orthoformate
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A General and Facile Synthesis of Novel Polysubstituted Quinazolin-4(3H)-ones
171
Table 1
Optimization of the cyclization conditions.
O
N
O
O
O
catalyst
reagent
O
O
N
N
H
THF, reflux,3h
NH2
3a
2aa
Entry
Reagent
Catalyst
Amount (mol%)a
Yield (%)b
1
2
3
4
5
6
7
8
9
HCOOH
HCOOH
HC(OEt)3
HC(OEt)3
HC(OEt)3
HC(OEt)3
HC(OEt)3
HC(OEt)3
HC(OEt)3
—
H2SO4
—
H2SO4
ZnCl2
PTSA
PTSA
PTSA
PTSA
—
1 drop
—
1 drop
100
100
50
19
39
68
94
96
98
97
98
92
20
10
aReaction conditions of cyclization in the optimized experiments: compound 2aa (100 mg, 0.29 mmol), catalyst (amount), reagent (2.9 mmol, 10 equiv) in
refluxing THF (5 mL).
bYield of isolated and purified product.
Table 2
Synthesis of this polysubstituted quinazolin-4(3H)-ones 3.
O
O
(1)Fe/HCl
THF/H2O
O
O
COOH
NO2
O
O
R1
O
O
R1
R2
SOCl2
N
H
N
(2)R2C(OEt)3
PTSA
R1NH2, Py
r.t.8h
NO2
N
3
1
2
Entry
R1
R2
Product
Yield (%)a
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
98
90
86
72
79
89
90
85
80
89
39
80
80
84
92
86
86
84
87
4-MePh
3-MePh
2-MePh
2,4-Me2Ph
4-ClPh
3-ClPh
2-ClPh
4-FPh
4-(MeCO)Ph
4-HOPh
4-MeOPh
2,4-F2Ph
2,4-Cl2Ph
2-Me-4-(MeOCO)Ph
Cyclohexyl
Benzyl
9
10
11
12
13
14
15
16
17
18
19
4-FPh
4-MeOPh
Me
Me
aYield of isolated and purified product.
Journal of Heterocyclic Chemistry
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M. Xin, Y. Gao, H. Xiang, and D. Chen
Vol 50
Substituted quinazolin-4(3H)-ones 3: general procedure
using one-pot continuous reaction. In a 50-mL reaction vial, the
water (10 mL), iron powder (20 mmol) and concentrated HCl (three
drops) were added to a solution of 2-nitro-4-benzyloxy-5-methoxy
benzamide compound (2, 2 mmol) in THF (30 mL), and then the
mixture was heated at reflux for 3 h. After allowed to cool to room
temperature, the reaction mixture was diluted with saturated brine
(50 mL) and filtrated. The filtrate was extracted with THF and dried
over sodium sulfate, and then the p-toluene sulfuric acid and
orthoesters (20 mmol) were added. The mixture was heated at
reflux for 3 h, allowed to cool to room temperature, and
concentrated. The residue was purified by column chromatography,
eluting with (petroleum ether/EtOAc) to give pure product.
(Table 2, entries 18 and 19). It was found that the reaction
system was also efficient, and the products were afforded
in excellent yields (84% and 87%).
In summary, we have developed a general facile,
practical, and economically competitive method for the
synthesis of this type of polysubstituted quinazolin-4
(3H)-ones. This approach might provide a new access
to the synthesis of novel quinazolinone derivatives as
potential pharmaceutical interest.
EXPERIMENTAL
3-Phenyl-6-methoxy-7-benzyloxyquinazolin-4(3H)-one (3a).
Yield: 98%; yellow solid; mp 178–181ꢀC. IR (KBr): 3428, 2359,
Melting points of compounds were measured on an RY-1
melting point apparatus (Tianjin, China) and were uncorrected.
IR spectra were recorded on a Nicolet Impact-410 instrument
(Thermo Nicolet, USA); samples were prepared as KBr (Beijing,
1677 (C═O), 1608 (C═N), 1498, 1301, 1250, 869, 756 cmÀ1
.
1H-NMR (300 MHz, CDCl3): d = 8.02 (s, 1H, quinazolinone-2-H),
7.70 (s, 1H, quinazolinone-5-H), 7.57–7.48 (m, 5H, ArH),
7.42–7.31 (m, 5H, ArH), 7.20 (s, 1H, quinazolinone-8-H),
5.31 (s, 2H, PhCH2O), 3.95 (s, 3H, OCH3) ppm. MS (EI, m/z):
358 [M]+. Anal. Calcd for C22H18N2O3: C, 73.73; H, 5.06; N,
7.82. Found: C, 73.46; H, 5.29; N, 7.54.
1
China) plates. H-NMR spectra were recorded on a Bruker AV-
300 (300 MHz) spectrometer (Bruker, Germany). Samples were
prepared in CDCl3 or DMSO-d6 with TMS (d = 0) (Beijing,
China) as an internal standard unless noted otherwise. EIMS data
were obtained on SHIMADZU GCMS-QP2010 system (Shimadzu,
Japan). All chemicals were purchased from commercial sources and
were used without further purification unless otherwise noted. The
solvents (such as THF, EtOAc, CH2Cl2, and others) were CP grade
purchased from Nanjing Chemical Co., Ltd. and used without
further purification. Column chromatography was carried out on
silica gel (200–300 mesh, Qindao Ocean Chemical Company,
China). TLC analyses were carried out on silica gel GF254 (Qindao
Ocean Chemical Company, China) glass plates (2.5 cm 10 cm
with 250-mm layer). Concentration and evaporation of the solvent
after reaction or extraction were carried out on rotary evaporator op-
erated at reduced pressure. The 2-nitro-4-benzoxyl-5-methoxy ben-
zoic acid (compound 1) was synthesized according to the literature
procedures in good yield [7].
3-(4-Methylphenyl)-6-methoxy-7-benzyloxyquinazolin-4(3H)-
one (3b). Yield: 90%; yellow solid; mp 194–196ꢀC. IR (KBr): 3477,
2955, 2359, 1674 (C═O), 1606 (C═N), 1501, 1245, 1144, 1057,
1
863, 746 cmÀ1. H-NMR (300 MHz, DMSO-d6): d = 8.19 (s, 1H,
quinazolinone-2-H), 7.52 (s, 1H, quinazolinone-5-H), 7.49 (d,
J= 6.9 Hz, 2H, ArH), 7.43 (d, J= 7.0 Hz, 2H, ArH), 7.40–7.33 (m,
5H, ArH), 7.30 (s, 1H, quinazolinone-8-H), 5.30 (s, 2H, PhCH2O),
3.90 (s, 3H, OCH3), 2.39 (s, 3H, CH3) ppm. MS (EI, m/z): 372
[M]+. Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52.
Found: C, 73.87; H, 5.74; N, 7.22.
3-(3-Methylphenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3c). Yield: 86%; pale yellow solid; mp 156–159ꢀC. IR
(KBr): 3422, 2918, 1677 (C═O), 1608 (C═N), 1507, 1303, 1139,
1
1065, 869, 741, 699 cmÀ1. H-NMR (300 MHz, CDCl3): d =8.01
Intermediate substituted nitrobenzamides 2: general
procedure. In a 50-mL reaction vial, a solution of 2-nitro-4-
benzyloxy-5-methoxy benzoic acid (2 mmol) in thionyl chloride
(15 mL) was heated at reflux for 1.5 h, allowed to cool to room
temperature, and concentrated. The residue was diluted with
toluene (20mL), chilled in an ice bath, and then pyridine
(4mmol), and the appropriate amine (1.5mmol) were added. The
reaction mixture was removed from the bath and stirred at room
temperature for 8 h. The separated solid was collected by filtration.
N-Phenyl-2-amino-4-benzyloxy-5-methoxy benzamide (2aa);
compound 2aa provided for optimizing cyclization
conditions. In a 50-mL reaction vial, the water (10 mL), iron
powder (20 mmol), and concentrated HCl (three drops) were
(s, 1H, quinazolinone-2-H), 7.70 (s, 1H, quinazolinone-5-H), 7.50–
7.30 (m, 7H, ArH), 7.20 (s, 1H, quinazolinone-8-H), 7.18 (m, 2H,
ArH), 5.30 (s, 2H, PhCH2O), 4.01 (s, 3H, OCH3), 2.43 (s, 3H,
CH3) ppm. MS (EI, m/z): 372 [M]+. Anal. Calcd for C23H20N2O3:
C, 74.18; H, 5.41; N, 7.52. Found: C, 73.98; H, 5.55; N, 7.52.
3-(2-Methylphenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3d). Yield: 72%; pale yellow solid; mp 198–199ꢀC. IR
(KBr): 3457, 2910, 1673 (C═O), 1609 (C═N), 1499, 1303, 1145,
868, 748 cmÀ1 1H-NMR (300 MHz, CDCl3): d = 7.91 (s, 1H,
.
quinazolinone-2-H), 7.70 (s, 1H, quinazolinone-5-H), 7.51–7.48
(m, 2H, ArH), 7.42–7.34 (m, 5H, ArH), 7.24 (s, 1H,
quinazolinone-8-H), 7.23–7.21 (m, 2H, ArH), 5.32 (s, 2H,
PhCH2O), 4.02 (s, 3H, OCH3), 2.19 (s, 3H, CH3) ppm. MS (EI,
m/z): 372 [M]+. Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41;
N, 7.52. Found: C, 73.81; H, 5.47; N, 7.39.
3-(2,4-Dimethylphenyl)-6-methoxy-7-benzyloxyquinazolin-
4(3H)-one (3e). Yield: 79%; pale yellow solid; mp 99–102ꢀC. IR (KBr):
3442, 2918, 2351, 1683 (C═O), 1608 (C═N), 1499, 1305, 1147, 1058,
876, 846, 757, 696 cmÀ1. 1H-NMR (300 MHz, DMSO-d6): d = 8.12 (s,
1H, quinazolinone-2-H), 7.53 (s, 1H, quinazolinone-5-H), 7.52–7.23
(m, 8H, ArH), 7.19 (s, 1H, quinazolinone-8-H), 5.31 (s, 2H, PhCH2O),
3.90 (s, 3H, OCH3), 2.33 (s, 3H, CH3), 2.03 (s, 3H, CH3) ppm. MS
(EI, m/z): 386 [M]+. Anal. Calcd for C24H22N2O3: C, 74.59; H, 5.74;
N, 7.25. Found: C, 74.21; H, 5.84; N, 7.06.
added to
a solution of N-phenyl-2-nitro-4-benzyloxy-5-
methoxy benzamide (2 mmol) in THF (30 mL), and then the
mixture was heated at reflux for 3 h. After allowed to cool to
room temperature, the reaction mixture was diluted with
saturated brine (50 mL) and filtrated. The filtrate was extracted
with THF, and the organic layer was dried over sodium
sulfate. The solvent was removed in vacuo, and the residue
was triturated to provide a solid. Yield: 99%; yellow solid; mp
1
176–179ꢀC. H-NMR (300 MHz, DMSO-d6): d = 9.72 (s, 1H,
CONH), 7.66–7.64 (m, 2H, ArH), 7.47–7.29 (m, 7H, ArH),
7.26 (s, 1H, ArH), 7.08–7.04 (m, 1H, ArH), 6.48 (s, 1H,
ArH), 5.07 (s, 2H, PhCH2O), 3.75 (s, 3H, OCH3) ppm. MS
(EI, m/z): 348 [M]+.
3-(4-Chlorophenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3f). Yield: 89%; yellow solid; mp 240–241ꢀC. IR (KBr):
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A General and Facile Synthesis of Novel Polysubstituted Quinazolin-4(3H)-ones
173
3436, 2926, 2363, 1666 (C═O), 1607 (C═N), 1502, 1285, 1244,
735 cmÀ1 1H-NMR (300 MHz, CDCl3): d = 8.00 (s, 1H,
IR (KBr): 3436, 3053, 2930, 2840, 1673 (C═O), 1611 (C═N),
.
1497, 1251, 1177, 1023, 864, 843, 749, 699 cmÀ1 1H-NMR
.
quinazolinone-2-H), 7.68 (s, 1H, quinazolinone-5-H), 7.53–7.48 (m,
4H, ArH), 7.42–7.35 (m, 5H, ArH), 7.21 (s, 1H, quinazolinone-8-
H), 5.31 (s, 2H, PhCH2O), 4.01 (s, 3H, OCH3) ppm. MS (EI, m/z):
392/394 [M]+. Anal. Calcd for C22H17ClN2O3Á0.5H2O: C, 65.76;
H, 4.51; N, 6.97. Found: C, 66.04; H, 4.39; N, 6.87.
(300 MHz, DMSO-d6): d = 8.18 (s, 1H, quinazolinone-2-H),
7.53 (s, 1H, quinazolinone-5-H), 7.49 (d, J = 9.0 Hz, 2H, ArH),
7.47–7.36 (m, 5H, ArH), 7.30 (s, 1H, quinazolinone-8-H),
7.10 (d, J = 9.0 Hz, 2H, ArH), 5.30 (s, 2H, PhCH2O), 3.90 (s,
3H, OCH3), 3.83 (s, 3H, OCH3) ppm. MS (EI, m/z): 388 [M]+.
Anal. Calcd for C23H20N2O4: C, 71.12; H, 5.19; N, 7.21.
Found: C, 70.91; H, 5.25; N, 6.83.
3-(3-Chlorophenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3g). Yield: 90%; pale yellow solid; mp 221–223ꢀC.
IR (KBr): 3438, 3065, 1676 (C═O), 1609 (C═N), 1503, 1299,
3-(2,4-Difluorophenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3m). Yield: 80%; pale yellow solid; mp 155–156ꢀC.
IR (KBr): 3447, 3065, 1677 (C═O), 1607 (C═N), 1500, 1297,
1
1143, 867, 783, 735, 688 cmÀ1. H-NMR (300 MHz, DMSO-d6):
d = 8.24 (s, 1H, quinazolinone-2-H), 7.70 (s, 1H, quinazolinone-5-
H), 7.58–7.53 (m, 2H, ArH), 7.51–7.49 (m, 4H, ArH), 7.45–7.38
(m, 3H, ArH), 7.32 (s, 1H, quinazolinone-8-H), 5.31 (s, 2H,
PhCH2O), 3.90 (s, 3H, OCH3) ppm. MS (EI, m/z): 392/394 [M]+.
Anal. Calcd for C22H17ClN2O3: C, 67.26; H, 4.36; N, 7.13. Found:
C, 66.93; H, 4.59; N, 6.92.
1143, 1054, 867, 840, 752, 700 cmÀ1 1H-NMR (300 MHz,
.
CDCl3): d = 7.68 (s, 1H, quinazolinone-2-H), 7.50 (s, 1H,
quinazolinone-5-H), 7.48–7.43 (m, 2H, ArH), 7.41–7.31 (m,
4H, ArH), 7.26 (s, 1H, quinazolinone-8-H), 7.07 (t, 2H, ArH),
5.31 (s, 2H, PhCH2O), 4.01 (s, 3H, OCH3) ppm. MS (EI, m/z):
394 [M]+. Anal. Calcd for C22H16F2N2O3: C, 67.00; H, 4.09; N,
7.10. Found: C, 66.92; H, 4.34; N, 6.99.
3-(2-Chlorophenyl)-6-methoxy-7-benzyloxyquinazolin-4(3H)-
one (3h). Yield: 85%; pale yellow solid; mp 176–179ꢀC. IR (KBr):
3424, 2914, 1681 (C═O), 1608 (C═N), 1501, 1309, 1145, 1047,
3-(2,4-Dichlorophenyl)-6-methoxy-7-benzyloxyquinazolin-
4(3H)-one (3n). Yield: 84%; pale yellow solid; mp 84–87ꢀC. IR
(KBr): 3448, 3085, 2938, 1680 (C═O), 1607 (C═N), 1500, 1289,
1
758, 733 cmÀ1. H-NMR (300 MHz, DMSO-d6): d = 8.17 (s, 1H,
quinazolinone-2-H), 7.75–7.71 (m, 1H, ArH), 7.69–7.66 (m, 1H,
ArH), 7.61–7.52 (m, 4H, ArH), 7.50 (s, 1H, quinazolinone-5-H),
7.45–7.36 (m, 4H, ArH), 7.34 (s, 1H, quinazolinone-8-H), 5.32 (s,
2H, PhCH2O), 3.91 (s, 3H, OCH3) ppm. MS (EI, m/z): 392/394
[M]+. Anal. Calcd for C22H17ClN2O3Á0.5H2O: C, 65.76; H, 4.51;
N, 6.97. Found: C, 65.85; H, 4.21; N, 6.80.
1146, 1045, 867, 747, 698, 597 cmÀ1 1H-NMR (300 MHz,
.
CDCl3): d = 7.82 (s, 1H, quinazolinone-2-H), 7.69 (s, 1H,
quinazolinone-5-H), 7.56–7.31 (m, 8H, ArH), 7.22 (s, 1H,
quinazolinone-8-H), 5.31 (s, 2H, PhCH2O), 4.01 (s, 3H, OCH3)
ppm. MS (EI, m/z): 427/429 [M]+. Anal. Calcd for
C22H16Cl2N2O3: C, 61.84; H, 3.77; N, 6.56. Found: C, 61.42;
H, 4.11; N, 6.18.
3-(4-Fluorophenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3i). Yield: 80%; pale yellow solid; mp 207–209ꢀC.
IR (KBr): 3420, 3066, 1677 (C═O), 1609 (C═N), 1497, 1310,
3-(2-Methyl-4-methoxycarbonylphenyl)-6-methoxy-7-
benzyloxyquinazolin-4(3H)-one (3o). Yield: 92%; pale
yellow solid; mp 209–210ꢀC. IR (KBr): 3434, 2946, 1724 (C═O),
1678 (C═O), 1606 (C═N), 1500, 1297, 1267, 1193, 1150,
1144, 1057, 866, 845, 749, 699 cmÀ1 1H-NMR (300 MHz,
.
DMSO-d6): d = 8.21 (s, 1H, quinazolinone-2-H), 7.60–7.58
(m, 2H, ArH), 7.56 (s, 1H, quinazolinone-5-H), 7.55–7.49
(m, 2H, ArH), 7.45–7.36 (m, 5H, ArH), 7.31 (s, 1H,
quinazolinone-8-H), 5.31 (s, 2H, PhCH2O), 3.90 (s, 3H,
OCH3) ppm. MS (EI, m/z): 376 [M]+. Anal. Calcd for
C22H17FN2O3Á0.2H2O: C, 69.54; H, 4.62; N, 7.37. Found: C,
69.60; H, 4.77; N, 6.99.
750 cmÀ1
.
1H-NMR (300 MHz, CDCl3): d = 8.09 (s, 1H,
quinazolinone-2-H), 8.03 (d, J= 8.2 Hz, 1H, ArH), 7.87 (s, 1H, ArH),
7.69 (s, 1H, quinazolinone-5-H), 7.51–7.48 (m, 2H, ArH), 7.43–7.31
(m, 4H, ArH), 7.23 (s, 1H, quinazolinone-8-H), 5.32 (s, 2H,
PhCH2O), 4.02 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 2.24 (s, 3H,
CH3) ppm. MS (EI, m/z): 430 [M]+. Anal. Calcd for C25H22N2O5: C,
69.76; H, 5.15; N, 6.51. Found: C, 69.36; H, 5.22; N, 6.15.
3-(4-Acetylphenyl)-6-methoxy-7-benzyloxyquinazolin-4(3H)-
one (3j). Yield: 89%; pale yellow solid; mp 236–237ꢀC. IR (KBr):
3439, 1681 (C═O), 1665 (C═O), 1607 (C═N), 1499, 1287, 1249,
3-Cyclohexyl-6-methoxy-7-benzyloxyquinazolin-4(3H)-one
(3p). Yield: 86%; yellow solid; mp 194–196ꢀC. IR (KBr): 3441,
2934, 1655 (C═O), 1607 (C═N), 1505, 1287, 1104, 1001, 866,
1142, 1056, 865, 780, 696 cmÀ1 1H-NMR (300 MHz, CDCl3):
.
d = 8.13 (d, J = 8.1Hz, 2H, ArH), 8.08 (s, 1H, quinazolinone-2-
H), 7.69 (s, 1H, quinazolinone-5-H), 7.55 (d, J = 8.1Hz, 2H,
ArH), 7.51–7.48 (m, 2H, ArH), 7.43–7.35 (m, 3H, ArH), 7.26 (s,
1H, quinazolinone-8-H), 5.32 (s, 2H, PhCH2O), 4.02 (s, 3H,
OCH3), 2.67 (s, 3H, CH3) ppm. MS (EI, m/z): 400 [M]+. Anal.
Calcd for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C,
72.29; H, 5.18; N, 6.86.
1
784, 757, 738, 704 cmÀ1. H-NMR (300 MHz, CDCl3): d = 8.04
(s, 1H, quinazolinone-2-H), 7.64 (s, 1H, quinazolinone-5-H),
7.48–7.46 (m, 2H, ArH), 7.41–7.29 (m, 3H, ArH), 7.15 (s, 1H,
quinazolinone-8-H), 5.28 (s, 2H, PhCH2O), 4.81 (m, 1H,
cyclohexyl), 4.01 (s, 3H, OCH3), 2.02–1.92 (m, 4H,
cyclohexyl), 1.81–1.77 (m, 1H, cyclohexyl), 1.69–1.50 (m, 4H,
cyclohexyl), 1.28–1.24 (m, 1H, cyclohexyl) ppm. MS (EI, m/z):
364 [M]+. Anal. Calcd for C22H24N2O3: C, 72.50; H, 6.64; N,
7.69. Found: C, 72.12; H, 6.92; N, 7.55.
3-(4-Hydroxyphenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3k). Yield: 39%; white solid; mp 243–244ꢀC. IR
(KBr): 3432, 3212, 2930, 1651 (C═O), 1609 (C═N), 1500,
1288, 1145, 1056, 865, 751 cmÀ1
.
1H-NMR (300 MHz,
3-Benzyl-6-methoxy-7-benzyloxyquinazolin-4(3H)-one (3q).
Yield: 86%; pale yellow solid; mp 154–157ꢀC. IR (KBr): 3444,
2930, 1663 (C═O), 1606 (C═N), 1501, 1219, 1193, 1013, 867,
CDCl3): d = 8.02 (s, 1H, quinazolinone-2-H), 7.70 (s, 1H,
quinazolinone-5-H), 7.50–7.48 (m, 2H, ArH), 7.42–7.34 (m,
3H, ArH), 7.20 (d, J = 6.3 Hz, 2H, ArH), 7.16 (s, 1H,
quinazolinone-8-H), 6.85 (d, J = 8.7 Hz, 2H, ArH), 6.42 (brs,
1H, PhOH), 5.31 (s, 2H, PhCH2O), 3.99 (s, 3H, OCH3) ppm.
MS (EI, m/z): 374 [M]+. Anal. Calcd for C22H18N2O4: C,
70.58; H, 4.85; N, 7.48. Found: C, 70.26; H, 4.92; N, 7.36.
3-(4-Methoxyphenyl)-6-methoxy-7-benzyloxyquinazolin-4
(3H)-one (3l). Yield: 80%; pale yellow solid; mp 190–191ꢀC.
745, 699 cmÀ1 1H-NMR (300 MHz, CDCl3): d = 8.04 (s, 1H,
.
quinazolinone-2-H), 7.66 (s, 1H, quinazolinone-5-H), 7.48–7.45
(m, 2H, ArH), 7.40–7.31 (m, 8H, ArH), 7.15 (s, 1H,
quinazolinone-8-H), 5.27 (s, 2H, PhCH2O), 5.19 (s, 2H,
PhCH2N), 3.99 (s, 3H, OCH3) ppm. MS (EI, m/z): 372 [M]+.
Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N, 7.52. Found:
C, 73.91; H, 5.41; N, 7.15.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

174
M. Xin, Y. Gao, H. Xiang, and D. Chen
Vol 50
REFERENCES AND NOTES
2-Methyl-3-(4-fluorophenyl)-6-methoxy-7-benzyloxyquinazolin-
4(3H)-one (3r). Yield: 84%; pale yellow solid; mp 197–
198ꢀC. IR (KBr): 3433, 3077, 1687 (C═O), 1608 (C═N),
[1] (a) Crabbe, T.; Welham, M. J.; Ward, S. G. Trends Biochem Sci
2007, 32, 450; (b) Berndt, A.; Miller, S.; Williams, O.; et al. Nat Chem Biol
2010, 6, 117; (c) Mosley, C. A.; Acker, T. M.; Hansen, K. B.; et al. J Med
Chem 2010, 53, 5476; (d) Chenard, B. L.; Welch, W. M.; Blake, J. F.;
et al. J Med Chem 2001, 44, 1710; (e) Nagase, T.; Mizutani, T.; Ishikawa,
S.; et al. J Med Chem 2008, 51, 4780; (f) Nagase, T.; Mizutani, T.; Sekino,
E.; et al. J Med Chem 2008, 51, 6889; (g) Na, Y. H.; Hong, S. H.; Lee, J. H.;
et al. Bioorg Med Chem 2008, 16, 2570; (h) Converso, A.; Hartingh, T.;
Garbaccio, R. M.; et al. Bioorg Med Chem Lett 2009, 19, 1240.
[2] (a) Maira, S.-M.; Stauffer, F.; Schnell, C.; Garcia-Echeverria, C.
Biochem Soc Trans2009, 37, 265; (b) Lee, C. W.; Belanger, K.; Rao, S.
C.; et al. Invest New Drugs 2008, 26, 249.
1499, 1391, 1282, 1027, 855, 756, 700, 593 cmÀ1
.
1H-NMR (300 MHz, CDCl3): d = 7.58 (s, 1H, quinazolinone-5-H),
7.50–7.42 (m, 2H, ArH), 7.40–7.31 (m, 3H, ArH), 7.24
(s, 1H, quinazolinone-8-H), 7.24–7.00 (m, 4H, ArH),
5.30 (s, 2H, PhCH2O), 4.01 (s, 3H, OCH3), 2.26 (s, 3H,
CH3) ppm. MS (EI, m/z): 390 [M]+. Anal. Calcd for
C23H19FN2O3: C, 70.76; H, 4.91; N, 7.18. Found: C,
70.46; H, 5.08; N, 6.97.
2-Methyl-3-(4-methoxyphenyl)-6-methoxy-7-
benzyloxyquinazolin-4(3H)-one (3s). Yield: 87%; white
solid; mp 162–163ꢀC. IR (KBr): 3432, 3057, 2930, 2828,
1688 (C═O), 1609 (C═N), 1499, 1392, 1247, 1026, 841,
[3] (a) Lingaiah, B. V.; Ezikiel, G.; Yakaiah T.; Reddy, G. V.; Rao, P. S.
Synlett 2006, 2507; (b) Narasimhulu, M.; Mahesh, K. C.; Reddy, T. S.; Rajesh,
K.; Venkateswarlu, Y. Tetrahedron Lett 2006, 47, 4381; (c) Khosropour, A. R.;
Mohammadpoor-Baltork, I.; Ghorbankhani, H. Tetrahedron Lett 2006, 47, 3561;
(d) Chari, M. A.; Shobha, D.; Mukkanti, K. Catal Commun 2006, 7, 787;
(e) Sangshetti, J. N.; Kokare, N. D.; Shinde, D. B. Monatsh Chem 2007, 138,
1289; (f) Wang, L. M.; Xia, J. J.; Qin, F.; Qian, C. T.; Sun, J. Synthesis 2003,
1241; (g) Wang, M.; Song, Z.; Zhang, T. J. Heterocyclic Chem 2010, 47, 468.
[4] (a) Connolly, D. J.; Guiry, P. J. Synlett 2001, 1707; (b) Xue, S.;
McKenna, J.; Shieh, W. C.; Repic, O. J. Org Chem 2004, 69, 6474; (c) Shi,
D.; Rong, L.; Wang, J.; Zhuang, Q.; Wang, X.; Hu, H. Tetrahedron Lett
2003, 44, 3199; (d) Lygin, A. V.; Meijere, A.d. Org Lett 2009, 11, 389.
[5] Sreeramamurthy, K.; Ashok, E.; Mahendar, V.; et al. Synlett 2010, 721.
[6] (a) Shi, D.; Rong, L.; Wang, J.; Zhuang, Q.; Wang, X.; Hu, H.
Tetrahedron Lett 2003, 44, 3199; (b) Dou, G.; Wang, M.; Huang, Z.; Shi,
D.; J Heterocyclic Chem 2009, 46, 645.
752, 740, 567 cmÀ1 1H-NMR (300 MHz, CDCl3): d = 7.60
.
(s, 1H, quinazolinone-5-H), 7.49–7.42 (m, 2H, ArH),
7.40–7.31 (m, 3H, ArH), 7.17 (d, J = 8.8 Hz, 2H, ArH), 7.14
(s, 1H, quinazolinone-8-H), 7.06 (d, J = 8.8 Hz, 2H, ArH),
5.29 (s, 2H, PhCH2O), 3.98 (s, 3H, OCH3), 3.88 (s, 3H,
OCH3), 2.22 (s, 3H, CH3) ppm. MS (EI, m/z): 402 [M]+.
Anal. Calcd for C24H22N2O4: C, 71.63; H, 5.51; N, 6.96.
Found: C, 71.59; H, 5.65; N, 6.91.
Acknowledgments. This work was supported by the International
Science and Technology Cooperation Program of Jiangsu
Province, China (no. BZ2008058).
[7] Li, H.; Huang, H.; Zhang, X.; Liu, H.; et al. Acta Pharmacol Sin
2008, 29, 1529.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet