Tandem synthesis of 2,3-dihydroquinazolin-4(1H)-ones on grinding under solvent-free conditions

Article abstract of DOI:10.1002/jhet.759

Citric acid promoted synthesis of a mini-library 2,3-dihydroquinazolin- 4(1H)-ones with good to excellent yields is achieved by tandem reaction of anthranilamides (or anthranilhydrazides) with aldehydes on grinding at room temperature under solvent-free conditions. This method has notable advantages in terms of simple workup, short reaction time, cost-effective, and environmentally benign. Copyright

Full text of DOI:10.1002/jhet.759

March 2012
Tandem Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones on
Grinding under Solvent-Free Conditions
375
Quan-Sheng Ding,a Ji-Lei Zhang,a Jiu-Xi Chen,a* Miao-Chang Liu,a
Jin-Chang Ding,a,b and Hua-Yue Wua*
aCollege of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035,
People’s Republic of China
bDepartment of Light Industry, Wenzhou Vocational and Technical College, Wenzhou, 325035,
People’s Republic of China
*E-mail: jiuxichen@wzu.edu.cn or huayuewu@wzu.edu.cn
Received September 12, 2010
DOI 10.1002/jhet.759
Published online 31 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
Citric acid promoted synthesis of a mini-library 2,3-dihydroquinazolin-4(1H)-ones with good to excel-
lent yields is achieved by tandem reaction of anthranilamides (or anthranilhydrazides) with aldehydes
on grinding at room temperature under solvent-free conditions. This method has notable advantages in
terms of simple workup, short reaction time, cost-effective, and environmentally benign.
J. Heterocyclic Chem., 49, 375 (2012).
INTRODUCTION
benzamide and aldehyde or ketone as reactants with the
aid of a low-valent titanium reagent was also reported
as a facile process to synthesize 2,3-dihydroquinazolin-
4(1H)-ones in the literature [7]. Later, some improved
methods have been reported for the synthesis of these
compounds by one-pot condensation of isatoic anhy-
dride, amine with aldehyde [8]. Recently, List and co-
workers [9] and Rueping et al. [10] independently
reported enantioselective synthesis of these compounds
using chiral phosphoric acid as catalyst. In our previous
work, we reported improved procedures for the prepara-
tion of 2,3-dihydroquinazolin-4(1H)-ones in ionic liquids
without additional catalyst [11] and gallium triflate-cata-
lyzed one-pot selective synthesis of 2,3-dihydroquinazo-
lin-4(1H)-ones and quinazolin-4(3H)-ones [12].
To the best of our knowledge, most of aforemen-
tioned studies on the synthesis of 2,3-dihydroquinazolin-
4(1H)-ones are focused on 2-monosubstituted ones using
anthranilamide as reactant in organic solvent or metal-
catalyzed [4–12]. Few examples has been given to
obtain 2,3-disubstituted substituents 2,3-dihydroquinazo-
lin-4(1H)-ones from N-substituted o-aminobenzamide.
2,3-Dihydroquinazolin-4(1H)-ones are an important
class of fused heterocyclic compounds that have drawn
much attention because of their potential biological and
pharmaceutical activities [1]. On the other hand, 2,3-
dihydroquinazolin-4(1H)-ones could be easily oxidized
to quinazolin-4(3H)-ones, which are important building
blocks in the synthesis of natural and pharmacological
compounds, by NaHSO3 [2] or 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone [3]. The typical procedure for
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
involves the condensation reaction of anthranilamide
with aldehyde using p-TSA as catalyst under vigorous
conditions [4]. However, it is worth pointing out that
the intermediate 1,2-dihydro derivatives could not be
isolated because of a spontaneous oxidation to quinazo-
lin-4(3H)-ones [4(b)]. In 2002, Su et al. [5] and Lu and
coworkers [6] independently reported the preparation of
2,3-dihydroquinazolin-4(1H)-ones by reductive cycliza-
tion of o-nitrobenzamide or o-azido-benzamide with
aldehyde and ketone using metallic samarium in the
presence of iodine or SmI2. In addition, using 2-nitro-
C
V
2011 HeteroCorporation

376
Q.-S. Ding, J.-L. Zhang, J.-X. Chen, M.-C. Liu, J.-C. Ding, and H.-Y. Wu
Vol 49
Scheme 1
citric acid was found to be the couple of choice, which
afforded the desired product of 2-(4-nitrophenyl)-2,3-
dihydroquinazolin-4(1H)-one (3a) with excellent yield
(Table 1, entry 10). Furthermore, the present route to 3a
was successfully applied to a large-scale reaction (Table
1, entry 11).
With the optimized conditions in hand, the reactions
of different anthranilamides with various aldehydes were
examined to explore the scope and generality of this
present protocol for the synthesis of various 2,3-dihydro-
quinazolin-4(1H)-ones and the results were listed in Ta-
ble 2. First, we examined the steric effect in our system.
A monosubstitution group such as nitro on the ortho-,
meta- or para-position for the aromatic aldehydes had
little effect on the yields in the reaction (Table 2, entries
1–3). Next, a series of aromatic aldehydes with either
electron-donating or electron-withdrawing groups attach-
ing to aromatic ring were investigated. In our system,
the substitution groups on the phenyl ring make a bit of
difference on the yields. For instance, anthranilamide
reacted with aromatic aldehydes 2a, 2d, and 2f–2j effi-
ciently and afforded the corresponding products in 95%,
85%, 86%, 85%, 88%, 87%, and 86% yields, respec-
tively (Table 2, entries 1, 4, 6–10). Moreover, we also
examined reaction of aromatic heterocyclic aldehydes
such as thiophene-2-carbaldehyde (2l) and picolinalde-
hyde (2m) with anthranilamide, and the desired products
of 3l and 3m were obtained in high yields (Table 2,
entries 12–13). When aliphatic aldehyde, such as butanal
(2n) was used as substrate, the desired product of 3n
was obtained with excellent yield (Table 2, entry 14).
However, attempt to the reaction of a long chain ali-
phatic aldehyde such as decanal (2o) with anthranila-
mide, the corresponding product of 3o was obtained
with moderate yield (Table 2, entry 15; Scheme 2).
Although an alternative new methodology has also been
employed in ionic liquid, for example, a recent report
about synthesis of 2,2-disubstituted quinazolin-4(1H)-
ones catalyzed by iodine in ionic liquids [13]. However,
ionic liquids, especially imidazolium-based systems con-
taining BF4 or PF6 anions, are toxic in nature because
they liberate hazardous HF, and their high cost and dis-
posability make their utility limited [14]. Therefore, de-
velopment of a facile and green method to synthesize
2,3-dihydroquinazolin-4(1H)-ones appeared to be of
great importance.
In the past few years, significant articles have
appeared reporting solid-state reactions by grinding [15].
Most of these reactions are carried out at room tempera-
ture in absolutely solvent-free environment using only a
mortar and pestle, and therefore the common merit of
these processes is that they are efficient, economical,
and environmentally friendly.
Citric acid, as a very inexpensive, commercially
available and the relatively nontoxic, water-solubility
organoacid has been widely used in organic reactions
[16], but it has been unexplored as a catalyst in the syn-
thesis of 2,3-dihydroquinazolin-4(1H)-ones until now.
As a continuing interest in developing novel synthetic
routes for the formations of quinazolin-4(1H)-one deriva-
tives [11], we herein reported a metal-free, cost-effective,
and environmentally benign approach for the synthesis of
2,3-dihydroquinazolin-4(1H)-one derivatives on grinding
at room temperature under solvent-free conditions.
Table 1
Effect of reaction conditions.a
RESULTS AND DISCUSSION
Entry
Media
Organoacid
Yield (%)b
A model condensation reaction between anthranila-
mide (1a) and p-nitrobenzaldehyde (2a) was initially
conducted to screen the optimal reaction conditions
(Scheme 1).
1
2
silica gel
celatom
none
none
trace
trace
trace
trace
trace
86
3
4
neutral Al2O3
basic Al2O3
acidic Al2O3
silica gel
none
none
5
6
none
As shown in Table 1, entries 1–5 show blank reac-
tions without addition of any catalyst, only trace product
was reached for even longer time. However, we were
delighted to find that the yield could be improved to
86%, when citric acid was employed with silica gel as
grinding medium at room temperature (Table 1, entry
6). Encouraged by these promising results, different
reaction media (neutral Al2O3, basic Al2O3, acidic
Al2O3, silica gel, and celatom) were tested to find more
optimal reaction conditions (Table 1, entries 7–10). The
results showed that the combination of acidic Al2O3 and
citric acid
citric acid
citric acid
citric acid
citric acid
citric acid
7
8
celatom
90
45
neutral Al2O3
basic Al2O3
acidic Al2O3
acidic Al2O3
9
trace
95
94c
10
11
a Reaction conditions: anthranilamide 1a (0.4 mmol), p-nitrobenzalde-
hyde 2a (0.48 mmol), organoacid (0.4 mmol), and media (500 mg),
room temperature, 10 min.
b Isolated yields.
c 1a (0.68 g, 5 mmol), 2a (0.83 g, 5.5 mmol), citric acid (5 mmol),
and acidic Al2O3 (5 g).
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March 2012
Tandem Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones on Grinding under
Solvent-Free Conditions
377
Table 2
Tandem synthesis of 2,3-dihydroquinazolin-4(1H)-ones on grinding under solvent-free conditions.a
1
Entry
R1
R2
R3 (2)
Time (min)
Product
Yield (%)b
Mp (ꢀC)
Mp (ꢀC) [Lit.]
1
2
H
H
H
H
H
p-(NO2)C6H4 2a
o-(NO2)C6H4 2b
m-(NO2)C6H4 2c
p-(Br)C6H4 2d
o-(Br)C6H4 2e
p-(F)C6H4 2f
p-(Cl)C6H4 2g
p-(CH3)C6H4 2h
p-(CH3CH2)C6H4 2i
p-(OCH3)C6H4 2j
C6H5 2k
10
10
10
10
10
10
15
10
15
10
10
10
10
10
20
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
10
10
10
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
95
98
94
85
87
86
85
88
87
86
83
83
86
88
65
83
80
86
83
82
95
94
94
96
96
99
92
99
86
95
91
98
96
85
204–206
191–192
210–212
200–202
173–175
203–204
205–206
230–232
191–193
191–192
220–222
211–213
184–185
160–162
145–147
200–202
204–206
187–189
203–205
248–250
141–143
127–129
148–149
131–132
212–214
182–184
198–201
203–205
203–205
209–211
195–197
209–211
192–194
223–225
213–214 [12]
193–194 [12]
3
4
H
H
216–217 [12]
205–206 [11]
H
5
6
H
H
H
H
–
199–200 [12]
7
H
H
205–206 [12]
233–234 [12]
–
192–193 [12]
218–219 [12]
213–215 [17a]
187–188 [12]
162–164 [17(b)]
8
9
H
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
H
H
H
H
H
H
H
H
2-thienyl 2l
2-pyridyl 2m
n-Bu 2n
H
H
H
H
H
n-C9H19 2o
–
–
5-Cl
5-Cl
5-Cl
5-Cl
5-Cl
H
o-(NO2)C6H4 2b
p-(Br)C6H4 2d
o-(Br)C6H4 2e
p-(Cl)C6H4 2g
p-(CH3)C6H4 2h
p-(NO2)C6H4 2a
p-(Cl)C6H4 2g
p-(CH3)C6H4 2h
C6H5 2k
p-(NO2)C6H4 2a
o-(Br)C6H4 2e
p-(CH3)C6H4 2h
C6H5 2k
H
H
–
–
H
H
–
3t
250–251 [12]
–
Not reported [17c]
–
120–122 [17d]
n-Bu
n-Bu
n-Bu
n-Bu
3u
3v
3w
3x
4a
4b
4c
4d
4e
4f
H
H
H
–
–
–
–
–
–
–
–
–
–
2,6-(Cl)2C6H3 2p
p-(NO2)C6H4 2a
o-(Br)C6H4 2e
p-(CH3)C6H4 2h
C6H5 2k
4g
4h
4i
2,6-(Cl)2C6H3 2p
4j
a All reactions were run with anthranilamides or anthranilhydrazides 1 (0.4 mmol), aldehydes 2 (0.48 mmol), citric acid (0.4 mmol), and acidic
Al2O3 (500 mg) on grinding at room temperature under solvent-free conditions.
b Isolated yields.
On the other hand, we investigated the influence of
electronic factors of anthranilamides on the results. The
desired product of 3p–3t in good yields were obtained
from the reaction of 5-chloroanthranilamide (1b) with
aldehydes bearing either electron-donating or electron-
withdrawing groups on the benzene ring (Table 2,
entries 16–20). As expected, N-alkyl substitution anthra-
nilamide such as 2-amino-N-butylbenzamide (1c) was
still good partner for the condensation reaction, and the
corresponding products of 3u–3x were isolated in excel-
lent yields (Table 2, entries 21–24).
phenylbenzohydrazide (1d) and 2-amino-N’-(2-ethoxyben-
zoyl)benzohydrazide (1e) with aldehydes. In all cases, cit-
ric acid-promoted tandem reactions proceeded smoothly
and gave the corresponding products in good to excellent
yield (Table 2, entries 25–34). Using the present protocol,
the sterically hindered amines such as 2,6-dichlorobenzal-
dehyde (2p), smoothly reacted with 1d and 1e, the desired
Scheme 2
Next, we investigated synthesis of several new
2,3-dihydroquinazolin-4(1H)-one derivatives from tandem
reaction of anthranilhydrazides such as 2-amino-N’-
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Vol 49
1H), 7.41–7.21 (m, 5H), 7.06 (s, 1H), 6.74–6.64 (m, 2H), 5.71 (s,
1H), 2.59 (q, J ¼ 7.6, 2H), 1.16 (t, J ¼ 7.6, 3H). 13C NMR (125
MHz, DMSO-d6): d ¼ 163.6, 147.9, 144.1, 138.8, 133.2, 127.7,
127.3, 126.9, 117.0, 114.9, 114.3, 66.4, 27.9, 15.7. IR (KBr): 3299
(NH), 1652 (C¼¼O) cm–1. MS (EI, 70 eV): m/z (%) ¼ 252 (Mþ,
11), 207 (23), 147 (70), 119 (100). Anal. Calcd for C16H11N2O:
C, 76.16; H, 6.39; Found: C 76.23; H 6.33 (Table 2, entry 9).
products of 4e and 4j were afforded in 86% and 85%,
respectively (Table 2, entries 29 and 34).
In summary, we have demonstrated a mild and efficient
eco-friendly tandem synthesis of 2,3-dihydroquinazolin-
4(1H)-ones under solvent-free conditions, using citric acid
as a novel organoacid green promoter, which uses neither
harsh conditions nor the use of hazardous or toxicant cata-
lysts and reagents. When compared with previous reported
methodologies, notable advantages of our protocol include
simple operations, short reaction time, metal-free, the rela-
tively nontoxic, inexpensive, water-solubility organoacid,
broad substrates scope, and high yields.
1
2-Nonyl-2,3-dihydroquinazolin-4(1H)-one (3o). H NMR
(300 MHz, DMSO-d6): d ¼ 7.89 (s, 1H), 7.58–7.55 (m, 1H),
7.24–7.19 (m, 1H), 6.73–6.62 (m, 2H), 6.56 (s, 1H), 4.67 (s,
1H), 1.62–1.60 (m, 2H), 1.25–1.19 (m, 14H), 0.85–0.83 (m,
3H). 13C NMR (125 MHz, DMSO-d6): d ¼ 163.9, 148.5,
133.0, 127.3, 116.8, 115.0, 114.3, 64.4, 34.9, 31.3, 29.0, 28.9,
28.7, 23.2, 22.1, 14.0. IR (KBr): 3324 (NH), 1640 (C¼¼O) cm–
1. MS (EI, 70 eV): m/z (%) ¼ 272 (Mþ, 5), 160 (100), 173
(32), 120 (10). Anal. Calcd for C17H26N2O: C, 74.41; H, 9.55;
Found: C 74.34; H 9.73 (Table 2, entry 15).
EXPERIMENTAL
6-Chloro-2-(2-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one
1
Chemicals and solvents were either purchased or purified by
standard techniques. The melting points were uncorrected and
were recorded on Digital Melting Point Apparatus WRS-1B.
IR spectra were recorded on an AVATAR 370 FI-Infrared
Spectrophotometer. NMR spectroscopy was performed on a
Bruker-300 spectrometer or Bruker-500 spectrometer using
DMSO-d6 or CDCl3 as the solvent with tetramethylsilane as
an internal standard at room temperature. The mass spectro-
metric identification of the products was performed on Thermo
Finnigan LCQ-Advantage or SHIMADZU GCMS-QP2010 sys-
tem. Elemental analysis was determined on a Carlo-Erba 1108
instrument.
(3p). H NMR (300 MHz, DMSO-d6): d ¼ 8.41 (s, 1H), 8.09–
8.06 (m, 1H), 7.82–7.62 (m, 3H), 7.58 (s, 1H), 7.31–7.29 (m,
1H), 7.24 (m, 1H), 6.82–6.79 (m, 1H), 6.36 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d ¼ 162.1, 147.5, 145.8, 135.5, 134.0,
133.3, 130.0, 138.9 126.3, 124.8, 121.2, 116.9, 115.5, 62.1. IR
(KBr): 3406 (NH), 1677 (C¼¼O) cm–1. MS (EI, 70 eV): m/z
(%) ¼ 305 ([Mþ2]þ, 5), 303 (Mþ, 16), 268 (67), 181 (99),
153 (100). Anal. Calcd for C14H10ClN3O3: C, 55.37; H, 3.32;
Found: C 55.43; H 3.39 (Table 2, entry 16).
2-(4-Bromophenyl)-6-choloro-2,3-dihydroquinazolin-4(1H)-
1
one (3q). H NMR (300 MHz, DMSO-d6): d ¼ 8.53 (s, 1H),
7.62–7.53 (m, 3H), 7.44–7.41 (m, 2H), 7.38 (s, 1H), 7.31–7.27
(m, 2H), 6.79–6.76 (m, 1H), 5.79 (s, 1H). 13C NMR (125
MHz, DMSO-d6): d ¼ 162.3, 146.3, 140.7, 133.2, 131.3,
129.0, 126.4, 121.7, 120.9, 116.5, 116.0, 65.6. IR (KBr):
3325(NH), 1655 (C¼¼O) cm–1. MS (EI, 70 eV): m/z (%) ¼
338 ([Mþ2]þ, 4), 336 (Mþ, 15), 207 (100), 153 (59). Anal.
Calcd for C14H10BrClN2O: C, 49.81; H, 2.99; Found: C 49.88;
H 3.04 (Table 2, entry 17).
General procedure for the synthesis of 2,3-dihydroquina-
zolin-4(1H)-one derivatives (3). An anthranilamide or anthra-
nilhydrazide 1 (0.4 mmol), aldehyde 2 (0.48 mmol), and citric
acid (0.4 mmol) were dissolved in 5 mL of ethanol in a round-
bottomed flask, then acidic Al2O3 (200–300 mesh, 500 mg)
was added. After 5 min stirring, the solvent was removed to
obtain the mixture of reactants adsorbed on the acidic Al2O3
surface (note: the recovered solvent could be reused in the
next batch). The dry mixture was transferred into a glass mor-
tar. Then the mixture was ground at room temperature with a
glass pestle for the appropriate time in the glass mortar. A
mixture example was taken out and dissolved in ethyl acetate
to monitor the progress of the reaction using TLC. After com-
pletion of the reaction, the mixture was washed with ethyl ace-
tate. The Al2O3 was collected by filtration, which precipitated
from the organic phase and the product was left in the organic
phase. The recovered Al2O3 could be reused in the next batch
after it was dried in oven. The pure products of 3 and 4 were
obtained by silica gel column chromatography. Here, the full
spectral characterization is given for only the previously
unknown products.
2-(2-Bromophenyl)-6-choloro-2,3-dihydroquinazolin-4(1H)-
1
one (3r). H NMR (300 MHz, DMSO-d6): d ¼ 8.40 (s, 1H),
7.68–7.65 (m, 2H), 7.59 (s, 1H), 7.49–7.29 (m, 3H), 7.24 (s,
1H), 6.81–6.78 (m, 1H), 6.12 (s, 1H). 13C NMR (125 MHz,
DMSO-d6): d ¼ 162.4, 146.4, 138.8, 133.2, 132.8, 130.8,
129.1, 128. 1, 126.4, 122.1, 121.1, 116. 6, 115.7, 66.3. IR
(KBr): 3328 (NH), 1643 (C¼¼O) cm–1. MS (EI, 70 eV): m/z
(%) ¼ 340 ([Mþ4]þ, 3), 338 ([Mþ2]þ, 10), 336 (Mþ, 9), 181
(100), 183 (30), 154 (28). Anal. Calcd for C14H10BrClN2O: C,
49.81; H, 2.99; Found: C 49.89; H 3.04 (Table 2, entry 18).
6-Choloro-2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H)-
1
one (3s). H NMR (300 MHz, DMSO-d6): d ¼ 8.53 (s, 1H),
7.53–7.45 (m, 5H), 7.37 (s, 1H), 7.30–7.27 (m, 1H), 6.79–6.76
(m, 1H), 5.81 (s, 1H). 13C NMR (125 MHz, DMSO-d6): d ¼
162.3, 146.4, 140.2, 133.1, 133.1, 128.7, 128.4, 126.4, 120.9,
116.5, 116.0, 65.6. IR (KBr): 3311 (NH), 1655 (C¼¼O) cm–1.
MS (EI, 70 eV): m/z (%) ¼ 296 ([Mþ4]þ, 2), 294 ([Mþ2]þ,
17), 292 (Mþ, 30), 181 (100), 154 (62), 126 (33). Anal. Calcd
for C14H10Cl2N2O: C, 57.36; H, 3.44; Found: C 57.44; H 3.51
(Table 2, entry 19).
1
2-(2-Bromophenyl)-2,3-dihydroquinazolin-4(1H)-one (3e). H
NMR (300 MHz, DMSO-d6): d ¼ 8.24 (s, 1H), 7.69–7.65 (m,
3H), 7.47–7.24 (m, 3H), 7.01 (s, 1H), 6.79–6.70 (m, 2H), 6.10
(s, 1H). 13C NMR (125 MHz, DMSO-d6): d ¼ 163.6, 147.7,
139.1, 133.4, 132.8, 130.7, 129.1, 128.0, 127.4, 122.2, 117.5,
114.7, 114.6, 66.4. IR (KBr): 3361 (NH), 1645 (C¼¼O) cm–1.
MS (EI, 70 eV): m/z (%) ¼ 304 ([Mþ2]þ, 5), 302 (Mþ, 6),
147 (100), 120 (30), 92 (21). Anal. Calcd for C14H11BrN2O:
C, 55.47; H, 3.66; Found: C 55.64; H 3.72 (Table 2, entry 5).
3-Butyl-2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one
1
(3u). H NMR (500 MHz, DMSO-d6): d ¼ 8.21–8.19 (m, 2H),
1
7.67–7.52 (m, 4H), 7.21–7.18 (m, 1H), 6.68–6.64 (m, 2H),
6.02 (s, 1H), 4.00–3.94 (m, 1H), 2.81–2.77 (m, 1H), 1.58–1.46
2-(4-Ethylphenyl)-2,3-dihydroquinazolin-4(1H)-one (3i). H
NMR (300 MHz, DMSO-d6): d ¼ 8.24 (s, 1H), 7.62–7.60 (m,
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Tandem Synthesis of 2,3-Dihydroquinazolin-4(1H)-ones on Grinding under
Solvent-Free Conditions
379
(m, 2H), 1.30–1.26 (m, 2H), 0.85 (t, J ¼ 7.0 Hz, 3H). 13C
NMR (125 MHz, DMSO-d6): d ¼ 162.0, 148.6, 147.4, 145.6,
133.3, 127.5, 127.3, 123.7, 117.5, 115.1, 114.4, 69.0, 44.4,
29.6, 19.5, 13.6. IR (KBr): 3286 (NH), 1628 (C¼¼O) cm–1. MS
(EI, 70 eV): m/z (%) ¼ 325 (Mþ, 11), 203 (100), 147 (72),
119 (20). Anal. Calcd for C18H19N3O3: C, 66.45; H, 5.89;
Found: C 66.50; H 5.83 (Table 2, entry 21).
7.11–7.09 (m, 2H), 6.75–6.68 (m, 3H), 6.64–6.60 (m, 2H). 13C
NMR (125 MHz, DMSO-d6): d ¼ 161.8, 147.6, 146.7, 135.4,
134.0, 133.8, 130.6, 129.7, 128.7, 127.2, 119.0, 116.1, 113.0,
112.3, 111.6, 71.2. IR (KBr): 3247 (NH), 1652 (C¼¼O) cm–1.
MS (EI, 70 eV): m/z (%) ¼ 387 ([Mþ4]þ, 6), 385 ([Mþ2]þ,
33), 383 (Mþ, 51), 276 (100), 278 (72). Anal. Calcd for
C20H15Cl2N3O: C, 76.17; H, 5.43; Found: C 76.24; H 5.51
(Table 2, entry 29).
1
3-Butyl-2-p-tolyl-2,3-dihydroquinazolin-4(1H)-one (3w). H
NMR (500 MHz, DMSO-d6): d ¼ 7.65–7.63 (m, 1H), 7.26–
7.13 (m, 6H), 6.65–6.61 (m, 2H), 5.78 (s, 1H), 3.89–3.86 (m,
1H), 2.73–2.71 (m, 1H), 2.25 (s, 3H), 1.53–1.43 (m, 2H),
1.28–1.24 (m, 2H), 0.85 (t, J ¼ 7.0 Hz, 3H). 13C NMR (125
MHz, DMSO-d6): d ¼ 162.2, 146.2, 138.2, 137.6, 133.0,
129.0, 127.3, 126.1, 117.0, 115.1, 114.2, 69.9, 44.0, 29.5, 20.6,
19.5, 13.6. IR (KBr): 3299 (NH), 1625 (C¼¼O) cm–1. MS (EI,
70 eV): m/z (%) ¼ 294 (Mþ, 13), 203 (100), 147 (60), 119
(12). Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; Found: C
77.59; H 7.60 (Table 2, entry 23).
2-Ethoxy-N-(2-(nitrophenyl)-4-oxo-1,2-dihydroquinazolin-
1
3(4H)-yl)benzamide (4f). H NMR (300 MHz, DMSO-d6): d
¼ 9.91 (s, 1H), 8.29–8.26 (m, 2H), 7.83–7.72 (m, 3H), 7.58–
7.34 (m, 4H), 7.06–6.97 (m, 2H), 6.83–6.78 (m, 2H), 6.33 (s,
1H), 3.99 (q, J ¼ 7.0 Hz, 2H), 1.10 (t, J ¼ 7.0 Hz, 3H). 13C
NMR (125 MHz, DMSO-d6): d ¼ 164.8, 162.4, 156.2, 148.0,
147.1, 145.8, 134.3, 132.9, 130.4, 129.3, 128.1, 123.5, 121.5,
120.5, 118.2, 114.6, 113.4, 113.1, 73.5, 64.2, 14.1. IR (KBr):
3274 (NH), 1677, 1651 (C¼¼O) cmꢁ1. MS (ESI): m/z (%) ¼
432 (Mþ, 100). Anal. Calcd for C23H20N4O5: C, 63.88; H,
4.66; Found: C 63.95; H 4.60 (Table 2, entry 30).
2-(4-Nitrophenyl)-3-(phenylamino)-2,3-dihydroquinazolin-
1
4(1H)-one (4a). H NMR (300 MHz, DMSO-d6): d ¼ 8.52 (s,
N-(2-(2-bromophenyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-
1
2-ethoxybenzamide (4g). H NMR (300 MHz, DMSO-d6): d ¼
1H), 8.24–8.21 (m, 2H), 7.78 (s, 1H), 7.72–7.63 (m, 3H),
7.33–7.16 (m, 3H), 6.86–6.71 (m, 5H), 6.10 (s, 1H). 13C NMR
(125 MHz, DMSO-d6): d ¼ 162.3, 148.0, 147.6, 147.4, 146.4,
134.0, 128.9, 127.8, 127.6, 123.5, 119.4, 117.8, 114.7, 114.1,
112.4, 72.7. IR (KBr): 3266 (NH), 1612 (C¼¼O) cm–1. MS (EI,
70 eV): m/z (%) ¼ 360 (Mþ, 51), 253 (100), 207 (37), 120
(17). Anal. Calcd for C20H16N4O3: C, 66.66; H, 4.48; Found:
C 66.71; H 4.55 (Table 2, entry 25).
9.76 (s, 1H), 7.75–7.63 (m, 4H), 7.48–7.31 (m, 5H), 7.08–6.99
(m, 2H), 6.80–6.77 (m, 2H), 6.62 (s, 1H), 4.00 (q, J ¼ 6.9 Hz,
2H), 1.10 (t, J ¼ 6.9 Hz, 3H). 13C NMR (125 MHz, DMSO-
d6): d ¼ 164.3, 162.6, 156.4, 147.0, 137.4, 134.2, 133.1,
132.9, 131.0, 130.7, 129.7, 128.2, 128.0, 123.0, 120.9, 120.6,
117.8, 114.5, 113.2, 113.0, 73.5, 64.4, 14.2. IR (KBr): 3290
(NH), 1675, 1651 (C¼¼O) cm–1. MS (ESI): m/z (%) ¼ 467
(Mþ, 100), 385 ([Mþ2]þ, 94). Anal. Calcd for C23H20BrN3O3:
C, 59.24; H, 4.32; Found: C 59.29; H 4.40 (Table 2, entry 31).
2-Ethoxy-N-(4-oxo-2-p-tolyl-1,2-dihydroquinazolin-3(4H)-
2-(2-Bromophenyl)-3-(phenylamino)-2,3-dihydroquinazol-in-
1
4(1H)-one (4b). H NMR (300 MHz, DMSO-d6): d ¼ 8.27 (s,
1H), 7.70–7.64 (m, 2H), 7.48–7.29 (m, 5H), 7.19–7.14 (m,
2H), 6.82–6.72 (m, 5H), 6.22 (s, 1H). 13C NMR (125 MHz,
DMSO-d6): d ¼ 162.7, 147.5, 146.0, 138.7, 134.0, 133.1,
130.6, 128.9, 128.1, 127.5, 127.4, 122.2, 119.3, 117.7, 114.9,
113.7, 112.2, 73.3. IR (KBr): 3236 (NH), 1651 (C¼¼O) cm–1.
MS (EI, 70 eV): m/z (%) ¼ 393 (Mþ, 53), 395 ([Mþ2]þ, 51),
286 (100), 288 (99). Anal. Calcd for C20H16BrN3O: C, 60.93;
H, 4.09; Found: C 60.89; H 4.16 (Table 2, entry 26).
1
yl)benzamide (4h). H NMR (500 MHz, DMSO-d6): d ¼ 9.73
(s, 1H), 7.72–7.60 (m, 2H), 7.46–7.31 (m, 5H), 7.21–7.19 (m,
2H), 7.08–6.99 (m, 2H), 6.80–6.75 (m, 2H), 6.14 (s, 1H), 4.01
(q, J ¼ 7.0 Hz, 2H), 2.29 (s, 3H), 1.14 (t, J ¼ 7.0 Hz, 3H).
13C NMR (125 MHz, DMSO-d6): d ¼ 164.2, 162.7, 156.3,
147.6, 138.5, 135.7, 134.0, 132.9, 130.5, 128.9, 127.9, 127.5,
121.2, 120.5, 117.6, 114.5, 113.4, 113.2, 74.1, 64.4, 20.7, 14.1.
IR (KBr): 3290 (NH), 1682, 1645 (C¼¼O) cm–1. MS (ESI,): m/
z (%) ¼ 401 (Mþ, 100). Anal. Calcd for C24H23N3O3: C,
71.80; H, 5.77; Found: C 71.73; H 5.83 (Table 2, entry 32).
2-Ethoxy-N-(4-oxo-2-phenyl-1,2-dihydroquinazolin-3(4H)-
3-(Phenylamino)-2-p-tolyl-2,3-dihydroquinazolin-4(1H)-one
1
(4c). H NMR (300 MHz, DMSO-d6): d ¼ 8.36 (s, 1H), 7.64–
7.58 (m, 2H), 7.32–7.13 (m, 7H), 6.86–6.69 (m, 5H), 5.85 (s,
1H), 2.26 (s, 3H). 13C NMR (125 MHz, DMSO-d6): d ¼
162.6, 147.9, 146.9, 137.8, 137.6, 133.7, 128.9, 128.8, 127.5,
126.3, 119.1, 117.3, 114.6, 114.3, 112.3, 73.4, 20.6. IR (KBr):
3266 (NH), 1609 (C¼¼O) cm–1. MS (EI, 70 eV): m/z (%) ¼
329 (Mþ, 54), 330 (Mþ1, 13), 222 (100), 130 (15). Anal.
Calcd for C21H19N3O: C, 76.57; H, 5.81; Found: C 76.62; H
5.89 (Table 2, entry 27).
1
yl)benzamide (4i). H NMR (500 MHz, DMSO-d6): d ¼ 9.77
(s, 1H), 7.74–7.73 (m, 1H), 7.60–7.33 (m, 9H), 7.08–6.99 (m,
2H), 6.82–6.77 (m, 2H), 6.19 (s, 1H), 4.01 (q, J ¼ 7.0 Hz,
2H), 1.15 (t, J ¼ 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-
d6): d ¼ 164.2, 162.7, 156.3, 147.5, 138.6, 134.0, 132.9,
130.5, 129.1, 128.4, 128.0, 127.6, 121.2, 120.5, 117.6, 114.5,
113.4, 113.2, 74.3, 64.3, 14.2. IR (KBr): 3307 (NH), 1709,
1680 (C¼¼O) cm–1. MS (ESI): m/z (%) ¼ 387 (Mþ, 100).
Anal. Calcd for C23H21N3O3: C, 71.30; H, 5.46; Found: C
71.24; H 5.54 (Table 2, entry 33).
3-(Phenylamino)-2-phenyl-2,3-dihydroquinazolin-4(1H)-one
1
(4d). H NMR (300 MHz, DMSO-d6): d ¼ 8.35 (s, 1H), 7.66–
7.61 (m, 2H), 7.45–7.15 (m, 8H), 6.87–6.68 (m, 5H), 5.90 (s,
1H). 13C NMR (125 MHz, DMSO-d6): d ¼ 162.6, 147.8,
146.8, 140.7, 133.7, 128.9, 128.3, 127.5, 126.4, 119.2, 117.4,
114.6, 114.3, 112.4, 73.6. IR (KBr): 3311(NH), 1640(C¼¼O)
cm–1. MS (EI, 70 eV): m/z (%) ¼ 315 (Mþ, 56), 208 (100),
152 (20), 77 (25). Anal. Calcd for C20H17N3O: C, 76.17; H,
5.43; Found: C 76.22; H 5.51 (Table 2, entry 28).
N-(2-(2,6-dichlorophenyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-
1
yl)-2-ethoxybenzamide (4j). H NMR (500 MHz, DMSO-d6): d
¼ 9.68 (s, 1H), 7.71–7.68 (m, 2H), 7.52–7.42 (m, 5H), 7.33–
7.30 (m, 1H), 7.22 (s, 1H), 7.08–7.01 (m, 2H), 6.73–6.67 (m,
2H), 4.02 (q, J ¼ 6.5 Hz, 2H), 1.15 (t, J ¼ 6.5 Hz, 3H). 13C
NMR (125 MHz, DMSO-d6): d ¼ 164.9, 161.7, 156.5, 147.3,
135.8, 134.1, 133.3, 132.0, 131.2, 130.8, 127.8, 120.6, 120.4,
116.9, 113.7, 113.2, 111.8, 71.0, 64.4, 14.1. IR (KBr): 3319
(NH), 1645, 1615 (C¼¼O) cm–1. MS (ESI): m/z (%) ¼ 459
2-(2,6-Dichlorophenyl)-3-(phenylamino)-2,3-dihydroquina-
1
zolin-4(1H)-one (4e). H NMR (500 MHz, DMSO-d6): d ¼
7.97 (s, 1H), 7.61–7.59 (m, 1H), 7.48–7.46 (m, 2H), 7.42 (s,
1H), 7.38–7.35 (m, 1H), 7.27–7.24 (m, 1H), 7.16 (s, 1H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

380
Q.-S. Ding, J.-L. Zhang, J.-X. Chen, M.-C. Liu, J.-C. Ding, and H.-Y. Wu
Vol 49
([Mþ4]þ, 11), 457 ([Mþ2]þ, 63), 455 (Mþ, 100). Anal. Calcd
for C23H19Cl2N3O3: C, 60.54; H, 4.20; Found: C 60.59; H
4.27 (Table 2, entry 34).
[8] (a) Baghbanzadeh, M.; Salehi, P.; Dabiri, M.; Kozehgarya,
G.; Synthesis 2006, 344; (b) Salehi, P.; Dabiri, M.; Zolfigol, M. A.;
Baghbanzadeh, M. Synlett 2005, 1155; (c) Dabiri, M.; Salehi, P.; Oto-
kesh, S.; Baghbanzadeh, M.; Kozehgarya, G.; Mohammadi, A. A. Tetra-
hedron Lett 2005, 46, 6123; (d) Salehi, P.; Dabiri, M.; Baghbanzadeh,
M.; Bahramnejad M. Synth Commun 2006, 36, 2287; (e) El-Sabbagh, O.
I.; Ibrahim, S. M.; Baraka, M. M.; Kothayer, H. Arch Pharm 2010, 343,
274; (f) Zhang, Z. H.; Lu, H. Y.; Yang, S. H.; Gao, J. W. J Comb Chem
2010, 12, 643; (g) Rostamizadeh, S.; Amani, A. M.; Mahdavinia, G. H.;
Sepehrian, H.; Ebrahimi, S. Synthesis 2010, 1356; (h) Saffar-Teluri, A.;
Bolouk, S. Monatsh Chem 2010, 141, 1113.
Acknowledgments. The authors are grateful to the National Key
Technology R&D Program (No. 2007BAI34B00), the National
Natural Science Foundation of China (No. 21072153), the Natu-
ral Science Foundation of Zhejiang Province (No. Y4080107),
and the Wenzhou Science and Technology Bureau Program (No.
G20090076) for financial support.
[9] Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J Am Chem
Soc 2008, 130, 15786.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet