Copper(I) iodide catalyzed domino process to quinazolin-4(3H)-ones

Article abstract of DOI:10.1055/s-0028-1083245

An efficient synthesis of substituted quinazolin-4(3H)-ones by a one-pot ligand-free CuI-catalyzed coupling/condensative cyclization under mild conditions is described. Our study provides an alternative strategy for the preparation of biologically active quinazolin-4(3H)-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083245

3974
PAPER
Copper(I) Iodide Catalyzed Domino Process to Quinazolin-4(3H)-ones
S
ynthesis
i
of
Q
uin
n
azolin-4(3
H
g
)-ones Zhou,a,b Liangbing Fu,a,b,c Man Lv,a,b Jinsong Liu,b Duanqing Pei,a,b Ke Ding*a,b
a
Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences
International Business Incubator A-3, Guangzhou Science Park, Guangzhou 510663, P. R. of China
State Key Laboratory of Respiratory Diseases, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences
International Business Incubator A-3, Guangzhou Science Park, Guangzhou 510663, P. R. of China
Fax +86(20)32290485; E-mail: ding_ke@gibh.ac.cn
b
c
Graduate School of Chinese Academy of Sciences, 19 Yuquan Road, Beijing 100049, P. R. of China
Received 22 August 2008; revised 12 September 2008
OEt
O
N
Abstract: An efficient synthesis of substituted quinazolin-4(3H)-
ones by a one-pot ligand-free CuI-catalyzed coupling/condensative
cyclization under mild conditions is described. Our study provides
an alternative strategy for the preparation of biologically active
quinazolin-4(3H)-ones.
N
O
O
N
N
N
N
N
Key words: quinazolin-4(3H)-ones, one-pot, ligand-free, copper(I)
iodide, coupling/condensative cyclization
F3CO
O
NPS 53574 (1)
AMG 487 (2)
O
The quinazolin-4(3H)-one moiety represents an important
class of core structures, which exist in many pharmaceu-
tical molecules and natural products possessing a variety
of biological activities. Examples include calcium recep-
tor (CaR) antagonist NPS 53574 (1),1 CXCR3 antagonist
AMG 487 (2),2 cytotoxic agent CB30865 (3),3 ghrelin re-
ceptor antagonist 4,4 and natural alkaloids chaetominine
(5),5 and rutaecarpine (6).6 They are also valuable inter-
mediates for the preparation of quinazolinic kinase inhib-
itors. For example, 6,7-disubstituted quinazolin-4(3H)-
ones 7 are key intermediates for the manufacture of clini-
cally used Gefitnib and Erlotinib7 (Figure 1).
O
HN
N
N
H
N
N
Br
CB30865 (3)
O
N
Ni-Pr
O
F
H
N
O
O
N
N
OH
N
As a part of our chemical biology program, we aimed to
construct a quinazolin-4(3H)-one focused chemical li-
brary for the identification of small molecules modulating
the fates (differentiation, pluripotency, etc.) of embryonic
stem cells. Two typical procedures have generally been
applied for the preparation of quinazolin-4(3H)-ones: 1)
reaction of benzoxazin-4-one with amines;1,4,8 and 2)
cyclodehydration of 2-acylaminobenzoic amides.2a,3b,9
However, both procedures require substituted anthranilic
acids as the same key material, and harsh conditions such
as high temperature, strong bases or strong acids are need-
ed, which makes them incompatible with sensitive sub-
strates. Copper-catalyzed cross-coupling reactions have
been employed for the assembling of different heterocy-
cles.10 We were interested in investigating the potential to
use copper-catalyzed domino coupling/condensative cy-
clization of o-haloarylcarboxamides with imidamides for
the synthesis of substituted quinazolin-4(3H)-ones under
mild conditions. Herein, we would like to report the re-
sults of studies undertaken.
N
chaetominine (5)
4
O
N
O
N
R1O
N
NH
HN
R2O
rutaecarpine (6)
7
Figure 1 Representative structures of biologically important and
natural quinazolin-4(3H)-ones
Our approach is outlined in Scheme 1. o-Haloarylcarbox-
amides 8 may be aminated with imidamides 9 under catal-
ysis with copper(I) iodide to form intermediate A.11 The
in situ condensative cyclization of A would be able to
yield the desired quinazolin-4(3H)-one 10 or 13.
With this idea in mind, we first chose the coupling reac-
tion of 2-iodo-N-phenylbenzamide (8a) and methanimi-
damide acetate (9a) as the model to screen suitable
reaction conditions. Initially, the reported standard condi-
tions (10% CuI, 20% L-proline, and K2CO3 in DMF at 80
°C)11 for the amination of aryl halide were utilized
SYNTHESIS 2008, No. 24, pp 3974–3980
x
x.
x
x
.
2
0
0
8
Advanced online publication: 01.12.2008
DOI: 10.1055/s-0028-1083245; Art ID: F18308SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Quinazolin-4(3H)-ones
3975
R2
O
3
HN
O
R2
NH
R1
R1
O
X
R1
R2
NH
CuI
N
NH
NH2
2
R3
+
H
N
N
H2N
R3
H
R3
1
B
A
8
9
H
R2
R3
O
O
N
R2
R3
NH
N
R1
R1
N
N
H
NH2
– NH3
– NH2R2
O
O
R2
R3
NH
N
R1
R1
N
R3
N
11
10 or 13
Scheme 1 A copper(I) iodide catalyzed coupling/condensative cyclization strategy for the synthesis quinazolin-4(3H)-ones
(Table 1, entry 1). It was found that most of the 2-iodo-N-
phenylbenzamide (8a) was consumed after six hours. GC-
MS analysis indicated that two cross-coupling products
10a (77.5%) and 11a (2.1%) were formed, which may be
due to the transformation of intermediate A to its thermo-
dynamic favored isomer B (Scheme 1). Compound 10a
was purified by chromatography with an isolated yield of
75%. The structure of 10a was further verified by using
X-ray crystallographic analysis (Figure 2).12
Table 1 Synthesis of 3-Phenylquinazolin-4(3H)-one (10a) via
Coupling/Condensative Cyclization of 2-Iodo-N-phenylbenzamide
(8a) and Methanimidamide Acetate (9a)a
O
I
O
O
Ph
Ph
NH
H2N
N
CuI
N
NH
+
H
AcOH
9a
N
N
8a
10a
11a
Entry
Solvent
Yield (%)b
10a
11ac
1d
2e
3
DMF
75
77
65
75
50
78
16
18
62
5
2.1
DMF
1.2
EtOH
n.d.
n.d.
n.d.
2.3
4
i-PrOH
t-BuOH
Figure 2 X-ray crystal structure of compound 10a
5
In order to investigate the role of L-proline ligand in this
copper-catalyzed coupling/condensative cyclization, L-
proline was removed from the reaction system. Interest-
ingly, the removal of L-proline did not show any influence
on isolated yield of compound 10a, which indicated that
L-proline was unnecessary for this copper-catalyzed dom-
ino coupling reaction (entries 1 and 2). We next examined
this ligand-free copper(I) iodidecatalyzed domino cou-
pling reaction in different solvents and the results are
summarized in Table 1. It was clear that polar organic sol-
vents such as ethanol, isopropyl alcohol, ethylene glycol,
acetonitrile, and DMF were good solvents for this cou-
pling reaction. DMF and ethylene glycol, in particular,
seemed to be the optimal solvent for this reaction (entries
2 and 6), in which the copper-catalyzed coupling reaction
was accomplished in six hours with isolated yields of 77
6e
7
ethylene glycol
toluene
n.d.
n.d.
n.d.
n.d.
8
dioxane
MeCN
9
10
H2O
a Reaction conditions: 8a (1.0 mmol), 9a (2.0 mmol), CuI (0.1 mmol),
K2CO3 (3.0 mmol), solvent (3.0 mL), 80 °C, 16 h, under N2.
b Isolated yield.
c GC-MS yield; n.d. = not determined.
d Conditions: L-proline (20%), 6 h.
e Conditions: 80 °C, 6 h.
Synthesis 2008, No. 24, 3974–3980 © Thieme Stuttgart · New York

3976
J. Zhou et al.
PAPER
and 78%, respectively. Other solvents, such as dioxane, Table 2 Synthesis of 3-Substituted Quinazolin-4(3H)-ones via
Copper(I) Iodide Catalyzed Coupling/Condensative Cyclizationa
toluene, and water, were detrimental to the coupling reac-
tion (entries 7, 8, and 10). Accordingly, DMF was chosen
O
O
O
as the solvent for the following studies.
R
R
NH
CuI
N
N
H2N
NH
+
H
To explore the scope and the limits of our newly devel-
oped domino coupling reaction, we varied the o-haloaryl-
carboxamides and imidamides (Table 2). First, less active
2-bromo-N-methylbenzamide (8b) was treated with meth-
animidamide acetate (9a) under the optimized conditions.
Only trace amount of coupling product was determined by
GC/MS. Higher temperature or longer reaction time did
not significantly improve the reaction efficiency. We next
studied the potential influence of the N-substituted groups
of 2-iodobenzamides on the efficiency of the coupling re-
action. As shown in Table 2, almost all the N-substituted
2-iodobenzamides tested could react with methanimid-
amide acetate (9a) to yield the corresponding 3-substitut-
ed quinazolin-4(3H)-ones in excellent or moderate yields.
The steric hindrance of N-substituted group had some in-
fluence on the domino coupling reaction. For example, the
coupling of N-methyl-2-iodobenzamide (8c) with meth-
animidamide acetate (9a) gave 3-methylquinazolin-4(3H)-
one (10c) in a yield of 81%, but when N-ethyl-2-iodo-
benzamide (8e) or N-isopropyl 2-iodobenzamide (8f) was
used, the coupling yield was only 63% and 55%, respec-
tively. Most of the N-aryl 2-iodobenzamides 8h–q also
gave the domino coupling products in satisfactory yields,
except that only 20% 3-(4-nitrophenyl)quinazolin-4(3H)-
one (10r) was isolated when N-4-nitrophenyl-2-iodo-
benzamide (8r) was utilized. The major by-product was
quinazolin-4(3H)-one 11a. This might be due to the
strong electron-withdrawing function of nitro group to de-
crease the nucleophilic property of the nitrogen atom in N-
4-nitrophenyl-2-iodobenzamide (8r). Interestingly, al-
though 2-iodo-N-(thiazol-2-yl)benzamide (8s) produced
only quinazolin-4(3H)-one 11a in DMF or ethylene gly-
col, it was converted into 3-(thiazol-2-yl)quinazolin-
4(3H)-one (10s) in a yield of 91% when the reaction was
conducted in isopropyl alcohol for 16 hours.
AcOH
9a
N
X
N
8
10
11a
Compd 8
R
X
I
Yield of 10 (%)b
a
b
c
d
e
f
Ph
Me
Me
H
77
3.3c
81
82
63
55
84
72
73
83
67
62
69
56
71
75
66
20
91d
Br
I
I
Et
I
i-Pr
Bn
I
g
h
i
I
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-ClC6H4
I
I
j
I
k
l
I
I
m
n
o
p
q
r
s
I
I
4-BrC6H4
I
4-AcC6H4
4-CNC6H4
4-NO2C6H4
2-thiazolyl
I
I
I
I
a Reaction conditions: 8 (1.0 mmol), methanimidamide acetate (2.0
mmol), CuI (0.1 mmol), K2CO3 (3.0 mmol) and DMF (3.0 mL),
80 °C, 6 h, under N2.
The coupling reactions of substituted 2-iodobenzamides
with different substituted imidamides were also investi-
gated (Table 3). As shown in Table 3, almost all the sub-
strates tested successfully yielded the coupling products
13a–p in satisfactory yields. Electronic property of substi-
b Isolated yield.
c Yield based on GC/MS.
d In i-PrOH, 16 h.
tuted groups in 2-iodobenzamides 12 had huge influence (11b) in both cases, which might be due to the fact that 2-
on the efficiency of this ligand-free CuI-catalyzed cou- phenyl group favored the formation of thermodynamic
pling/condensative cyclization. For example, the cou- stable intermediate B and increased the nucleophilic prop-
pling/condensative cyclization of 2-iodo-5-methoxy- erty of N-2 atom to induce the condensative cyclization
benzamide (12i) with benzamidine (9c, R2 = Ph) yielded from a different orientation (Scheme 1, intermediate B).
the corresponding 6-methoxy-2-phenylquinazolin-4(3H)-
one (13i) in 76%. When 2-iodo-5-nitrobenzamide (12j)
was used, only 12% of 6-nitro-2-phenylquinazolin-4(3H)-
one (13j) was isolated. Noteworthily, the reaction of 2-
iodo-N-methylbenzamide (8c) or 2-iodo-N-phenylbenz-
amide (8a) with benzamidine 9c only produced trace
amounts of 3-methyl-2-phenylquinazolin-4(3H)-one (13l)
or 2,3-diphenylquinazolin-4(3H)-one (13n) respectively.
In summary, we have developed a new protocol for the
elaboration of substituted quinazolin-4(3H)-ones via a
ligand-free copper(I) iodide catalyzed coupling/conden-
sative cyclization strategy under mild conditions. This
method allows the use of various o-haloarylcarboxylic
acid derivatives and imidamides to assemble versatile het-
erocycles in a one-pot manner. Our study provides an al-
terative method for the synthesis of biologically active
The major by-product was 2-phenylquinazolin-4(3H)-one
quinazolin-4(3H)-ones.
Synthesis 2008, No. 24, 3974–3980 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinazolin-4(3H)-ones
3977
Quinazoline-4(3H)-ones; 3-Phenylquinazolin-4(3H)-one (10a);
Typical Procedure
Table 3 Synthesis of 2,3-Disubstituted Quinazolin-4(3H)-ones via
Copper(I) Iodide Catalyzed Coupling/Condensative Cyclizationa
2-Iodo-N-phenylbenzamide (8a; 323 mg, 1.0 mmol) and methanim-
idamide acetate (9a; 150 mg, 2.0 mmol), CuI (19 mg, 0.1 mmol),
and K2CO3 (415 mg, 3.0 mmol) were added to DMF (3 mL). Under
N2, the resulting mixture was stirred at 80 °C for 6 h. After the re-
action was complete, the mixture was extracted with EtOAc (3 × 20
mL) and the combined EtOAc layers were washed with H2O (60
mL) and brine (20 mL), respectively. The organic layer was dried
(Na2SO4), filtered, and the solvent was removed in vacuo. The
crude product was then purified by chromatography to yield 10a as
a white solid; yield: 171 mg (77%).
1H NMR (CDCl3): d = 8.39 (d, J = 8.0 Hz, 1 H), 8.20 (s, 1 H), 7.84
(m, 2 H), 7.58 (m, 4 H), 7.28 (m, 2 H).
13C NMR (CDCl3): d = 160.7, 147.3, 146.5, 137.5, 135.0, 129.9 (2
C), 129.5, 128.1, 127.5, 127.4, 127.2 (2 C), 122.4.
O
O
R2
R3
R2
N
CuI
H2N
NH
N
R1
R1
H
+
R3
N
I
12
9
13
Compound 12 R
R1
R2
Yieldof13
(%)b
a
H
H
H
H
H
H
H
H
H
H
H
H
Me
Ph
H
78
b
81
c
4-Cl
4-Cl
4-Cl
71
EI-MS: m/z = 222 (M+).
d
Me
Ph
H
65
e
86
3-Methylquinazolin-4(3H)-one (10c ≡ 10b)
1H NMR (CDCl3): d = 8.25 (d, J = 8.0 Hz, 1 H), 8.02 (s, 1 H), 7.69
(m, 2 H), 7.44 (t, J = 7.2 Hz, 1 H), 3.55 (s, 3 H).
f
3-Me
3-Me
3-Me
5-MeO
5-NO2
H
69
13C NMR (CDCl3): d = 161.7, 148.2, 147.0, 134.3, 127.5 (2 C),
126.7, 122.1, 34.2.
EI-MS: m/z = 160 (M+).
g
Me
Ph
Ph
Ph
Me
Ph
Me
Ph
Me
Me
60
h
66
i
76
Quinazolin-4-ol (10d)
1H NMR (DMSO-d6): d = 12.3 (br, 1 H), 8.11 (m, 2 H), 7.81 (t,
J = 8.0 Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 8.0 Hz, 1 H).
j
12
k (8c)
l (8c)
m (8a)
n (8a)
o (8j)
p (8g)
Me
Me
Ph
52
EI-MS: m/z = 146 (M+).
H
1.5c,d
69
3-Ethylquinazolin-4(3H)-one (10e)
1H NMR (CDCl3): d = 8.29 (d, J = 8.0 Hz, 1 H), 8.06 (s, 1 H), 7.71
(m, 2 H), 7.48 (t, J = 8.0 Hz, 1 Hz), 4.05 (q, J = 7.2 Hz, 2 H), 1.40
(t, J = 7.2 Hz, 3 H).
H
H
Ph
2.3d,e
79
13C NMR (CDCl3): d = 161.0, 148.2, 146.5, 134.3, 127.5 (2 C),
126.8, 122.4, 42.3, 15.1.
EI-MS: m/z = 174 (M+).
H
4-MeOC6H4
Bn
H
73
a Reaction conditions: substituted 2-iodobenzamide 12 (1.0 mmol),
methanimidamide acetate (2.0 mmol), CuI (0.1 mmol), K2CO3 (3.0
mmol), and DMF (3.0 mL), 80 °C for 6 h, under N2.
b Isolated yield.
3-Isopropylquinazolin-4(3H)-one (10f)
1H NMR (CDCl3): d = 8.28 (d, J = 8.0 Hz, 1 H), 8.11 (s, 1 H), 7.71
(m, 2 H), 7.48 (t, J = 7.2 Hz, 1 H), 5.18 (m, 1 H), 1.47 (d, J = 2.8
Hz, 6 H).
c 2-Phenylquinazolin-4(3H)-one 11b was isolated in 80% yield.
d Yield based on GC/MS.
13C NMR (CDCl3): d = 160.9, 147.7, 143.8, 134.4, 127.5, 127.4,
127.1, 122.2, 46.3, 22.2 (2 C).
e 2-Phenylquinazolin-4(3H)-one 11b was isolated in 78% yield.
EI-MS: m/z = 188 (M+).
EI-HRMS: m/z calcd for C11H12N2O (M+): 188.0944; found:
188.0945.
Unless otherwise noted, all reagents were obtained from commer-
cial suppliers and used without further purification. All solvents
were freshly distilled prior to use. The 2-iodoarylcarboxamides
were prepared using standard procedures. X-ray crystallographic
analyses were recorded on an Oxford Gemini R Ultra Diffraction.
GC-MS analyses were performed in electron ionization (EI) mode
on a SHIMADZU QP2010-plus spectrometer. HRMS was carried
out on a Thermo MAT95XP spectrometer. 1H and 13C NMR spectra
were recorded on a Bruker 400M spectrometer using CDCl3 or
DMSO-d6 as solvents. Chemical shifts are reported in parts per mil-
lion (ppm, d units) with the residual solvent peak used as internal
3-Benzylquinazolin-4(3H)-one (10g)
1H NMR (CDCl3): d = 8.34 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H), 7.75
(m, 2 H), 7.52 (t, J = 8.0 Hz, 1 H), 7.33 (m, 5 H), 5.22 (s, 2 H).
13C NMR (CDCl3): d = 161.1, 147.9, 146.6, 135.8, 134.5, 129.2 (2
C), 128.5, 128.2 (2 C), 127.6, 127.5, 127.1, 122.3, 49.8.
EI-MS: m/z = 236 (M+).
3-(2-Methoxyphenyl)quinazolin-4(3H)-one (10h)
1H NMR (CDCl3): d = 8.36 (d, J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 7.78
(m, 2 H), 7.51 (m, 2 H), 7.34 (d, J = 7.2 Hz, 1 H), 7.11 (t, J = 8.8
Hz, 2 H), 3.81 (s, 3 H).
1
1
standard (CDCl3: H, 7.26 ppm; 13C, 77.23 ppm; DMSO-d6: H,
2.50 ppm; 13C, 39.5 ppm), coupling constants are reported in units
of hertz (Hz).
13C NMR (CDCl3): d = 160.8, 154.9, 148.3, 147.4, 134.5, 131.1,
129.3, 127.7, 127.5, 127.3, 126.2, 122.9, 121.2, 112.5, 56.0.
EI-MS: m/z = 252 (M+).
Synthesis 2008, No. 24, 3974–3980 © Thieme Stuttgart · New York

3978
J. Zhou et al.
PAPER
3-(3-Methoxyphenyl)quinazolin-4(3H)-one (10i)
1H NMR (CDCl3): d = 8.36 (d, J = 8.0 Hz, 1 H), 8.12 (s, 1 H), 7.78
(m, 2 H), 7.55 (t, J = 8.0 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 6.70 (m,
3 H), 3.85 (s, 3 H).
13C NMR (CDCl3): d = 160.9, 160.6, 148.0, 146.2, 138.7, 134.7,
130.6, 127.8, 127.7, 127.3, 122.6, 119.3, 115.2, 113.0, 55.7.
4-[4-Oxoquinazolin-3(4H)-yl]benzonitrile (10q)
1H NMR (CDCl3): d = 8.36 (d, J = 8.0 Hz, 1 H), 8.11 (s, 1 H), 7.84
(m, 4 H), 7.60 (m, 3 H).
13C NMR (CDCl3): d = 160.4, 147.8, 144.9, 141.3, 135.3, 133.7 (2
C), 128.4, 128.1 (2 C), 128.0, 127.5, 117.9, 113.4.
EI-MS: m/z = 247 (M+).
EI-MS: m/z = 252 (M+).
3-(4-Nitrophenyl)quinazolin-4(3H)-one (10r)
1H NMR (CDCl3): d = 8.44 (d, J = 8.4 Hz, 2 H), 8.38 (d, J = 8.0 Hz,
1 H), 8.24 (s, 1 H), 7.86 (m, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.64 (t,
J = 6.8 Hz, 1 H).
13C NMR (CDCl3): d = 160.3, 148.0, 147.2, 144.9, 142.7, 135.5,
128.6, 128.2 (2 C), 127.8, 127.6, 125.2 (2 C), 122.1.
3-(4-Methoxyphenyl)quinazolin-4(3H)-one (10j)
1H NMR (CDCl3): d = 8.36 (d, J = 8.0 Hz, 1 H), 8.16 (s, 1 H), 7.80
(m, 2 H), 7.55 (m, 1 H), 7.33 (d, J = 6.8 Hz, 2 H), 7.04 (d, J = 6.8
Hz, 2 H), 3.87 (s, 3 H).
13C NMR (CDCl3): d = 161.1, 160.1, 147.8, 146.7, 134.7, 130.3,
128.3 (2 C), 127.8, 127.6, 127.3, 122.5, 115.0 (2 C), 55.8.
EI-MS: m/z = 267 (M+).
EI-MS: m/z = 252 (M+).
3-(Thiazol-2-yl)quinazolin-4(3H)-one (10s)
1H NMR (CDCl3): d = 9.53 (s, 1 H), 8.44 (d, J = 7.6 Hz, 1 H), 7.84
(m, 2 H), 7.73 (d, J = 3.6 Hz, 1 H), 7.60 (m, 1 H), 7.34 (d, J = 3.6
Hz, 1 H).
13C NMR (CDCl3): d = 159.2, 155.1, 146.7, 141.3, 138.5, 135.5,
128.5, 128.3, 127.5, 121.1, 118.7.
EI-MS: m/z = 229 (M+).
EI-HRMS: m/z calcd for C11H7N3OS (M+): 229.0304; found:
3-(o-Tolyl)quinazolin-4(3H)-one (10k)
1H NMR (CDCl3): d = 8.37 (d, J = 8.0 Hz, 1 H), 8.00 (s, 1 H), 7.80
(m, 2 H), 7.54 (m, 1 H), 7.38 (m, 3 H), 7.25 (d, J = 7.6 Hz, 1 H),
2.21 (s, 3 H).
13C NMR (CDCl3): d = 160.5, 148.2, 146.4, 136.7, 135.9, 134.6,
131.4, 129.8, 127.9, 127.7, 127.6, 127.4, 127.2, 122.5, 17.8.
EI-MS: m/z = 236 (M+).
229.0305
3-(m-Tolyl)quinazolin-4(3H)-one (10l)
1H NMR (CDCl3): d = 8.39 (d, J = 7.6 Hz, 1 H), 8.14 (s, 1 H), 7.80
(m, 2 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.28 (m,
3 H), 2.46 (s, 3 H).
2-Methylquinazolin-4(3H)-one (13a)
1H NMR (CDCl3): d = 11.79 (br, 1 H), 8.28 (d, J = 8.0 Hz, 1 H),
7.76 (t, J = 7.2 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 1 H), 7.47 (t, J = 7.6
Hz, 1 H), 2.59 (s, 3 H).
13C NMR (CDCl3): d = 161.0, 148.1, 146.4, 140.0, 137.6, 134.7,
130.1, 129.6, 127.9, 127.8, 127.7, 127.4, 124.2, 122.6, 21.5.
EI-MS: m/z = 236 (M+).
13C NMR (CDCl3): d = 164.3, 153.4, 149.6, 135.1, 127.2, 126.7,
126.5, 120.5, 22.3.
EI-MS: m/z = 160 (M+).
3-(p-Tolyl)quinazolin-4(3H)-one (10m)
1H NMR (CDCl3): d = 8.39 (d, J = 8.0 Hz, 1 H), 8.14 (s, 1 H), 7.80
(m, 2 H), 7.56 (t, J = 7.2 Hz, 1 H), 7.33 (m, 4 H), 2.46 (s, 3 H).
2-Phenylquinazolin-4(3H)-one (13b)
1H NMR (DMSO-d6): d = 12.5 (br, 1 H), 8.16 (m, 3 H), 7.83 (m, 1
H), 7.73 (d, J = 8.0 Hz, 1 H), 7.54 (m, 4 H).
13C NMR (CDCl3): d = 161.1, 148.1, 146.5, 139.4, 135.1, 134.7,
130.4 (2 C), 127.8, 127.7, 127.4, 126.9 (2 C), 122.6, 21.4.
EI-MS: m/z = 236 (M+).
13C NMR (DMSO-d6): d = 162.7, 152.8, 149.2 (2 C), 135.1, 133.2,
131.9, 129.1 (2 C), 128.2 (2 C), 127.1, 126.3, 121.4.
EI-MS: m/z = 222 (M+).
3-(4-Chlorophenyl)quinazolin-4(3H)-one (10n)
1H NMR (CDCl3): d = 8.35 (d, J = 8.0 Hz, 1 H), 8.09 (s, 1 H), 7.80
(m, 2 H), 7.56 (m, 3 H), 7.38 (d, J = 8.0 Hz, 2 H).
7-Chloroquinazolin-4(3H)-one (13c)
1H NMR (DMSO-d6): d = 12.38 (br, 1 H), 8.11 (m, 2 H), 7.71 (s, 1
H), 7.54 (d, J = 4.8 Hz, 1 H).
13C NMR (CDCl3): d = 160.8, 147.9, 145.7, 136.0, 135.3, 134.9,
130.0 (2 C), 128.5 (2 C), 128.0, 127.8, 127.3, 122.4.
EI-MS: m/z = 256 (M+), 257, 258.
13C NMR (DMSO-d6): d = 160.2, 149.9, 146.9, 138.9, 128.0, 127.0,
126.4, 121.5.
EI-MS: m/z = 180 (M+), 181, 182.
3-(4-Bromophenyl)quinazolin-4(3H)-one (10o)
1H NMR (CDCl3): d = 8.34 (d, J = 7.6 Hz, 1 H), 8.08 (s, 1 H), 7.80
(m, 2 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.55 (t, J = 7.2 Hz, 1 H), 7.31 (d,
J = 8.4 Hz, 2 H).
13C NMR (CDCl3): d = 160.8, 147.9, 145.8, 136.6, 135.0, 133.1 (2
C), 128.9 (2 C), 128.1, 127.9, 127.4, 123.4, 122.4.
7-Chloro-2-methylquinazolin-4(3H)-one (13d)
1H NMR (DMSO-d6): d = 12.17 (br, 1 H), 8.06 (d, J = 7.6 Hz, 1 H),
7.60 (m, 1 H), 7.46 (m, 1 H), 2.36 (s, 3 H).
13C NMR (DMSO-d6): d = 162.2, 154.7, 149.5, 134.7, 127.1, 126.3,
126.1, 121.1, 21.9.
EI-MS: m/z = 300 (M+), 302.
EI-MS: m/z = 194 (M+), 195, 196.
3-(4-Acetylphenyl)quinazolin-4(3H)-one (10p)
7-Chloro-2-phenylquinazolin-4(3H)-one (13e)
1H NMR (DMSO-d6): d = 12.66 (br, 1 H), 7.16 (m, 3 H), 7.79 (s, 1
H), 7.56 (m, 4 H).
13C NMR (DMSO-d6): d = 161.7, 153.8, 149.9, 139.2, 132.4, 131.7,
128.7 (2 C), 128.0, 127.9 (2 C), 126.8, 126.6, 119.8.
1H NMR (CDCl3): d = 8.39 (d, J = 8.0 Hz, 1 H), 8.22 (s, 1 H), 8.16
(d, J = 7.6 Hz, 2 H), 7.85 (m, 2 H), 7.59 (m, 3 H), 2.69 (s, 3 H).
13C NMR (CDCl3): d = 196.9, 160.4, 147.1, 146.0, 141.2, 137.6,
135.3, 129.9 (2 C), 128.4, 127.6, 127.5 (2 C), 122.3, 27.0.
EI-MS: m/z = 264 (M+).
EI-MS: m/z = 256 (M+), 257, 258.
Synthesis 2008, No. 24, 3974–3980 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinazolin-4(3H)-ones
3979
8-Methylquinazolin-4(3H)-one (13f)
3-Benzyl-2-methylquinazolin-4(3H)-one (13p)
1H NMR (DMSO-d6): d = 8.11 (s, 1 H), 7.96 (d, J = 8.0 Hz, 1 H),
7.67 (d, J = 7.2 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 2.53 (s, 3 H).
1H NMR (CDCl3): d = 8.33 (d, J = 7.2 Hz, 1 H), 7.77 (t, J = 7.2 Hz,
1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.49 (t, J = 7.2 Hz, 1 H), 7.29 (m, 5
H), 5.42 (s, 2 H), 2.57 (s, 3 H).
13C NMR (DMSO-d6): d = 166.2, 152.5, 149.6, 140.6, 139.9, 131.4,
128.7, 127.8, 22.48.
EI-MS: m/z = 160 (M+).
13C NMR (CDCl3): d = 162.5, 154.9, 147.4, 136.0, 134.7, 129.2 (2
C), 127.9, 127.3, 126.9, 126.8, 126.7 (2 C), 120.6, 47.4, 23.6.
EI-MS: m/z = 250 (M+).
2,8-Dimethylquinazolin-4(3H)-one (13g)
1H NMR (DMSO-d6): d = 12.15 (br, s), 7.92 (d, J = 8.0 Hz, 1 H),
7.61 (d, J = 7.2 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 2.50 (s, 3 H), 2.36
(s, 3 H).
13C NMR (DMSO-d6): d = 162.5, 153.6, 147.9, 135.1 (2 C), 125.7,
123.8, 121.0, 22.3, 17.8.
Acknowledgment
We thank the Chinese Academy of Sciences (Grant KSCX2-YW-
R-27), National Natural Science Foundation (Grant #20802077) for
the financial support.
EI-MS: m/z = 174 (M+).
EI-HRMS: m/z calcd for C10H10N2O (M+): 174.0788; found:
174.0789.
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7.99 (d, J = 7.6 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.56 (m, 3 H),
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131.8, 129.1 (2 C), 128.2 (2 C), 126.5, 124.0, 121.4, 17.6.
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6-Methoxy-2-phenylquinazolin-4(3H)-one (13i)
1H NMR (DMSO-d6): d = 12.5 (br, 1 H), 8.16 (d, J = 7.2 Hz, 1 H),
7.77 (m, 1 H), 7.51 (m, 6 H), 3.89 (3 H).
13C NMR (DMSO-d6): d = 162.5, 158.3, 150.6, 143.7, 133.3, 131.5,
130.0, 129.7, 129.0 (2 C), 127.9 (2 C), 124.6, 122.3, 56.1.
EI-MS: m/z = 252 (M+).
2,3-Dimethylquinazolin-4(3H)-one (13k)
1H NMR (CDCl3): d = 8.16 (d, J = 8.0 Hz, 1 H), 7.64 (t, J = 7.6 Hz,
1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 3.54 (s, 3
H), 2.55 (s, 3 H).
13C NMR (CDCl3): d = 162.3, 154.6, 147.2, 134.2, 126.8, 126.6,
126.4, 120.2, 31.1, 23.6.
EI-MS: m/z = 174 (M+).
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2-Methyl-3-phenylquinazolin-4(3H)-one (13m)
1H NMR (DMSO-d6): d = 8.11 (d, J = 8.0 Hz, 1 H), 7.84 (t, J = 7.2
Hz, 1 H), 7.66 (d, J = 8.0 Hz, 1 H), 7.50 (m, 6 H), 2.12 (s, 3 H).
13C NMR (DMSO-d6): d = 161.8, 154.9, 147.8, 138.4, 135.0, 130.1
(2 C), 129.4, 128.9 (2 C), 127.1, 126.9, 126.8, 121.0, 24.5.
EI-MS: m/z = 236 (M+).
3-(4-Methoxyphenyl)-2-methylquinazolin-4(3H)-one (13o)
1H NMR (CDCl3): d = 8.26 (d, J = 7.6 Hz, 1 H), 7.75 (t, J = 7.2 Hz,
1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H), 7.16 (d,
J = 8.4 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 3.87 (s, 3 H), 2.26 (s, 3
H).
13C NMR (CDCl3): d = 162.6, 160.2, 155.0, 147.5, 134.7, 130.4,
129.2 (2 C), 127.3, 126.9, 126.8, 121.0, 115.4 (2 C), 55.7, 24.5.
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266.1048.
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crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK;
fax: +44(1223)336033; E-mail: deposit@ccdc.cam.ac.uk].
Synthesis 2008, No. 24, 3974–3980 © Thieme Stuttgart · New York