Gallium(III) triflate-catalyzed one-pot selective synthesis of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones

Article abstract of DOI:10.1016/j.tetlet.2008.03.127

A series of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones have been synthesized in good to excellent yields and high selectivity by one-pot reaction using isatoic anhydride, ammonium acetate (or amines), and aldehydes in ethanol or in DMSO under mild conditions, respectively. The reaction was efficiently promoted by 1 mol % Ga(OTf)₃ and the catalyst could be recovered easily after the reactions and reused without evident loss of reactivity.

Full text of DOI:10.1016/j.tetlet.2008.03.127

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3814–3818
Gallium(III) triflate-catalyzed one-pot selective synthesis of
2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones
a
a
a
a
a,
*
Jiuxi Chen , Dengze Wu , Fei He , Miaochang Liu , Huayue Wu ,
Jinchang Ding a, Weike Su a,b,
*
a College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, PR China
b College of Pharmaceutical Sciences, Zhejiang University of Technology, Zhejiang Key Laboratory of Pharmaceutical Engineering,
Hangzhou 310014, PR China
Received 16 January 2008; revised 25 March 2008; accepted 26 March 2008
Available online 29 March 2008
Abstract
A series of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones have been synthesized in good to excellent yields and high
selectivity by one-pot reaction using isatoic anhydride, ammonium acetate (or amines), and aldehydes in ethanol or in DMSO under mild
conditions, respectively. The reaction was efficiently promoted by 1 mol % Ga(OTf)3 and the catalyst could be recovered easily after the
reactions and reused without evident loss of reactivity.
Ó 2008 Published by Elsevier Ltd.
Keywords: Gallium(III) triflate; 2,3-Dihydroquinazolin-4(1H)-ones; Quinazolin-4(3H)-ones; One-pot; Selective synthesis
2,3-Dihydroquinazolin-4(1H)-ones are an important
class of heterocycles with a wide range of pharmacological
and biological activities.1 A number of synthetic methods
to prepare these compounds have been described in the
past few years. The typical procedure for the synthesis of
2,3-dihydroquinazolin-4(1H)-ones involves the condensa-
tion reaction of anthranilamide with aldehyde or ketone
using p-toluenesulfonic acids as a catalyst under vigorous
conditions.2 In 2002, our group reported a method to pre-
pare 2,3-dihydroquinazolin-4(1H)-ones by reductive cycli-
zation of o-nitrobenzamide or o-azido-benzamide with
aldehydes and ketones using metallic samarium in the pre-
sence of iodine or SmI2.3 A recent report described the
preparation of 2,3-dihydroquinazolin-4(1H)-ones by the
reductive desulfurization of 2-thioxo-3H-quinazolin-4-ones
with nickel boride in dry methanol.4 Shi reported the syn-
thesis of 2,3-dihydroquinazolin-4(1H)-ones by the novel
reductive cyclization of o-nitrobenzamides and orthofor-
mate, aldehydes, or ketones with the aid of a low-valent
titanium reagent.5 Recently, Kurth reported a one-pot con-
version of 2-nitro-N-arylbenzamides to 2,3-dihydroquin-
azolin-4(1H)-ones using SnCl2.6 Salehi and co-workers
reported a new one-pot synthesis of these compounds using
p-toluenesulfonic acids,7a silica sulfuric acid,7b alum,7c and
Montmorillonite K-10.7d Very recently, we reported a
method for the preparation of 2,3-dihydroquinazolin-
4(1H)-ones in ionic liquids without additional catalyst.7e
Quinazolin-4(3H)-ones are also important building
blocks in the synthesis of natural and pharmacological
compounds.8 Various approaches toward the synthesis of
quinazolin-4(3H)-ones derivatives have been explored dur-
ing the past years. One of the most common approaches is
the cyclization of anthranilamides with aldehyde in the
presence of various promoting agents, such as NaHSO3,9
p-toluenesulfonic acids/DDQ,10 I2,11 CuCl2 (3.0 equiv),12
and FeCl3 (2.0 equiv).13 Some other methods include
cyclization reaction of 2-amino benzamides with substi-
tuted benzoyl chlorides in ionic liquid,14 and cyclization
*
Corresponding authors. Tel./fax: +86 577 88368280 (H.W.); tel./fax:
+86 571 88320752 (W.S.).
E-mail addresses: huayuewu@wzu.edu.cn (H. Wu), suweike@zjut.
edu.cn (W. Su).
of
o-acylaminobenzamides,15
2-amino-benzonitrile,16
0040-4039/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2008.03.127

J. Chen et al. / Tetrahedron Letters 49 (2008) 3814–3818
3815
N-arylorthanilamides,17 nitroenes,18 and aza-Wittig reac-
tions of a-azido-substituted aromatic imides.19 Recently,
Rao reported a one-pot three-component coupling of isa-
toic anhydride/anthranilic acid, orthoesters, and amines
using Nafion-H as a heterogeneous catalyst under micro-
wave irradiation conditions.20
However, methods for the selective synthesis of 2,3-
dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones
have not been explored before. Thus, developing versatile
approaches to synthesize 2,3-dihydroquinazolin-4(1H)-
ones and quinazolin-4(3H)-ones selectively still remains a
highly desired goal in organic synthesis.
Recently, we have successfully applied metal triflates
into several reactions.21 As a result of our great interest
in Lewis acid-catalyzed organic reactions, we herein report
a practical method for the selective synthesis of 2,3-dihy-
droquinazolin-4(1H)-ones and quinazolin-4(3H)-ones by
employing isatoic anhydride, ammonium acetate (amines),
and aldehydes in one-pot.
dichloromethane, acetonitrile, water, THF, ethanol, and
nitromethane, ethanol is the best. Without any catalyst,
the yield was poor even for longer time. Ga(OTf)3 proved
to be a superior catalyst among all the catalysts screened
in this transformation. It should be noted that 1 mol %
of Ga(OTf)3 was efficient enough to catalyze the reaction,
and increasing the amount of catalyst did not improve
the yield significantly (Table 1, entries 13–15). Finally, we
achieved an optimized condition using 1 mol % of
Ga(OTf)3 as the catalyst in ethanol.
Next, we studied the scope of this reaction (Table 2). As
expected, this reaction proceeded smoothly and the desired
products were obtained in good to excellent yields. A series
of aldehydes with either electron-donating or electron-
withdrawing groups attaching to aromatic ring were inves-
tigated. The substitution groups on the aromatic ring had
no obvious effect on the yield. We also examined reaction
of aromatic heterocyclic aldehydes with anthranilamide,
and the desired products of 3m,n were obtained in high
yields (Table 2, entries 13 and 14). Similarly, 3o–s in good
yields were obtained from 5-chloro isatoic anhydride, alde-
hydes, and ammonium acetate (Table 2, entries 15–19).
On the other hand, we investigated the synthesis of 2,3-
disubstituted 2,3-dihydroquinazolin-4(1H)-ones from isa-
toic anhydride, amines, and aldehydes under the optimized
reaction condition (Table 2, entries 20–25 ). The disubsti-
tuted products of 3t–y were obtained in high yields. Mean-
while, we confirmed the structure of 3v by X-ray single
crystal diffraction analysis (Fig. 1).22
Initially, we investigated various conditions in the model
reaction (Table 1). Among all the solvents screened, such as
Table 1
Condensation of isatoic anhydride, p-methylbenzaldehyde, and ammo-
nium acetate under various different reaction conditionsa
O
CHO
O
NH
Catalyst
O
NH4OAc
+
+
N
H
O
N
H
Interestingly, a trace of 3a could be transformed to 2-p-
tolylquinazolin-4(3H)-one 4a when 3a was dissolved in
DMSO for about 12 h. According to the literature,23
DMSO could act as a mild oxidant that oxidize 3a into
4a. The unexpected results prompted us to focus on the
synthesis of quinazolin-4(3H)-ones 4 using isatoic anhy-
dride, aldehyde, and ammonium acetate in the presence
of Ga(OTf)3.
CH3
CH3
3a
Entry
Solvent
Catalyst (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
CH2Cl2
CH3CN
H2O
Cu(OTf)2 (10)
Zn(OTf)2 (10)
Mg(OTf)2 (10)
Sr(OTf)2 (10)
Sc(OTf)3 (10)
Y(OTf)3 (10)
Bi(OTf)3 (10)
La(OTf)3 (10)
Sm(OTf)3 (10)
Eu(OTf)3 (10)
Er(OTf)3 (10)
Yb(OTf)3 (10)
Ga(OTf)3 (10)
Ga(OTf)3 (5)
Ga(OTf)3 (1)
Ga(OTf)3 (0.5)
Ga(OTf)3 (1)
Ga(OTf)3 (1)
Ga(OTf)3 (1)
Ga(OTf)3 (1)
Ga(OTf)3 (1)
None
68
74
43
73
86
80
78
79
80
81
77
78
88
88
Initially, we investigated the reaction of isatoic anhy-
dride, p-methylbenzaldehyde, and ammonium acetate in
DMSO in the presence of Ga(OTf)3. As expected, 4a was
obtained in good yield. The structure of 4a was confirmed
10
11
12
13
14
15c
16
17
18
19
20
21
22d
a
1
by IR, H, 13C NMR, and EI-MS spectral analysis as 2-p-
tolylquinazolin-4(3H)-one. The structure of 3a was deter-
mined by EI-MS analysis (m/z 238, M+) as C15H14N2O,
which matches the expected 2-p-tolyl-2,3-dihydroquinazo-
lin-4(1H)-one. Compared with 3a, the 1H NMR of 4a
showed two additional proton signals disappearing and
another proton signal shifting from 8.26 ppm to
12.44 ppm (N3–H), which was similar to the previously
reported value.1b,12 In the 13C NMR spectrum of com-
pound 4a, the peak of carbon signal also shifted from
66.5 ppm to 152.2 ppm (C-2). All spectral data confirmed
our assignment of 4a as 2-p-tolylquinazolin-4(1H)-one.
Then, various aldehydes with either electron-donating
or electron-withdrawing groups on aromatic ring were
investigated in DMSO in the presence of a catalytic
amount of Ga(OTf)3, and the results are listed in Table
87, 85, 84
81
33
50
42
48
61
15
THF
CH3NO2
EtOH
Reaction conditions: isatoic anhydride (5.5 mmol), ammonium acetate
(6.0 mmol), p-methylbenzaldehyde (5 mmol), catalyst (0.5–10 mol %),
70 °C, 45 min.
b
Isolated total yield.
Catalyst was reused three times.
70 °C for 4 h.
c
d

3816
J. Chen et al. / Tetrahedron Letters 49 (2008) 3814–3818
Table 2
a
One-pot synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by Ga(OTf)3
O
O
R1
R3
R2
R1
NH4OAc
1 mol % Ga(OTf)3
EtOH
N
O
R2CHO
or
+
+
R3NH2
N
H
N
H
O
3
1
Entry
R1
R2
NH4OAc or R3NH2
Time (min)
Product
Yieldb (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
p-(CH3)C6H4
C6H5
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
sBuNH2
50
55
35
45
35
50
50
35
50
70
60
60
40
50
55
50
40
55
50
55
50
50
50
60
60
3a
3b
3c
3d
3e
3f
86
87
86
90
88
86
85
89
83
71
78
73
91
88
80
86
83
83
80
83
87
89
87
79
82
233–2345a
218–2195a
192–1931b
186–1877e
228–2297e
278–280
p-(OCH3)C6H4
2,4-(OCH3)2C6H3
p-(N(CH3)2)C6H4
p-(OH)C6H4
m-(F)C6H4
p-(Cl)C6H4
p-(F)C6H4
o-(NO2)C6H4
m-(NO2)C6H4
p-(NO2)C6H4
2-Furyl
3g
3h
3i
266–267
205–2065a
199–2007e
193–1947e
216–2177e
213–2147e
167–168
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3t
2- Pyridyl
C6H5
187–188
249–2503a
250–251
p-(CH3)C6H4
p-(OCH3)C6H4
p-(F)C6H4
p-(NO2)C6H4
C6H5
p-(OH)C6H4
p-(Cl)C6H4
p-(NO2)C6H4
C6H5
220–221
248–249
220–221
175–176
EtNH2
3u
3v
3w
3x
3y
183–1847c
150–151
nBuNH2
nPr NH2
C6H5NH2
C6H5NH2
125–1267c
214–2157b
219–2207b
p-(Cl)C6H4
For general experimental procedure, see Ref. 25.
Isolated total yield.
b
Fig. 1. X-ray molecular structure and intermolecular hydrogen bond of 3v.
3, which exhibited a Ga(OTf)3-catalyzed cyclization and a
subsequent oxidation.
A tentative mechanism for the formation of 2,3-dihy-
droquinazolin-4(1H)-ones and quinazolin-4(3H)-ones was
proposed (Scheme 1). The first step may involve the con-
densation of isatoic anhydride 1 with ammonia, and then
anthranilamide 5 could be produced with the liberation
of carbon dioxide. Next step, intermediate 6 could be
obtained by addition of 5 with aldehydes promoted by
Ga(OTf)3. The part of amide in intermediate 6 could be
converted into tautomer in the presence of Ga(OTf)3.
Meanwhile, the part of imine in intermediate 6 could be

J. Chen et al. / Tetrahedron Letters 49 (2008) 3814–3818
3817
Table 3
a
One-pot synthesis of quinazolin-4(3H)-ones catalyzed by Ga(OTf)3
O
O
R1
R1
O
1 mol % Ga(OTf)3
DMSO
NH
R2
R2CHO
NH4OAc
+
+
N
H
O
N
1
4
Entry
R1
R2
Product
Time (min)
Yieldb (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
a
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
p-(CH3)C6H4
C6H5
4a
4b
4c
4d
4e
4f
50
55
55
50
55
55
50
55
55
55
60
70
65
55
60
60
84
83
82
89
84
87
92
84
86
89
86
82
81
80
80
79
240–24114
237–23813
245–24611
206–207
278–27913
239–24013
>30013
p-(OCH3)C6H4
2,4-(OCH3)2C6H3
3,4-(CH2O2)C6H3
p-(N(CH3)2)C6H4
p-(OH)C6H4
m-(F)C6H4
m-(Cl)C6H4
p-(Cl)C6H4
p-(Br)C6H4
m-(NO2)C6H4
p-(NO2)C6H4
2-Furyl
C6H5
p-(Cl)C6H4
4g
4h
4i
267
297–298
>30013
4j
4k
4l
296–29713
>30013
4m
4n
4o
4p
>30013
221–22213
212–21314
>30014
For general experimental procedure, see Ref. 26.
Isolated total yield.
b
(OTf)3Ga
OH
O
O
O
NH
NH4OAc
O
O
RCHO
NH2
Ga(OTf)3
NH2
R
Ga(OTf)3
N
N
H
1
NH2
N
CO2
(OTf)3Ga
R
Ga(OTf)3
OH
NH
7
6
5
O
O
1,5-H+ transfer
DMSO
NH
NH
N
H
3
R
N
R
N
R
4
8
Scheme 1. A tentative mechanism for the formation of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones.
activated by Ga(OTf)3. Thus, intermediate 7 could be con-
verted to intermediate 8 by intramolecule nucleophile
attack of the nitrogen on imine carbon. Subsequently,
2,3-dihydroquinazolin-4(1H)-ones 3 could be formed by a
1,5- proton transfer. Finally, we obtained product 4 using
DMSO as a solvent. Furthermore, when anthranilamide
was replaced with 2-(methylamino)-benzamide, no desired
product was obtained under the same conditions. We also
investigated the condensation of anthranilamide 5 with
aldehydes using Ga(OTf)3. The corresponding products
were obtained in good to excellent yields.24 Moreover, 3a
was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
none (DDQ) and 4a was produced in good yield
accordingly.
derivatives has been developed. The present protocol
enjoys simple work-up, short reaction time, easy recovery
and reuse of metal triflates as well as mild reaction
conditions.
Acknowledgment
We are grateful to the National Natural Science Foun-
dation of China (No. 20676123) for financial support.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.127.
In summary, a new catalytic protocol to synthesize 2,3-
dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones

3818
J. Chen et al. / Tetrahedron Letters 49 (2008) 3814–3818
19. (a) Takeuchi, H.; Haguvara, S.; Eguchi, S. Tetrahedron 1989, 45,
References and notes
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4524; (b) Chen, J. X.; Wu, H. Y.; Zheng, Z. G.; Jin, C.; Zhang, X. X.;
Su, W. K. Tetrahedron Lett. 2006, 47, 5383; (c) Su, W. K.; Hong, Z.;
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22. CCDC 634119 contains the supplementary crystallographic data for
3v, which is available free of charge via www.ccdc.cam.ac.uk.
23. DMSO was supposed to act as a mild oxidant, see: (a) Schipper, E.;
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25. General procedure for the one-pot synthesis of 2,3-dihydroquinazolin-
4(1H)-ones: Ga(OTf)3 (0.05 mmol, 1 mol %) was added to a solution
of isatoic anhydrides 1 (5.5 mmol), ammonium acetate or amines
(6.0 mmol), and aldehydes 2 (5 mmol) in ethanol (5 mL). The mixture
was stirred at 70 °C for the specified period of time as indicated in
Table 2. The progress of the reaction was monitored by TLC. After
completion, the reaction mixture was then allowed to cool to room
temperature and water (10 mL) was added. The corresponding solid
product 3 was obtained through simple filtering, and recrystallized
from ethanol. Selected characterization data for the products:
Compound 3a: White solid; IR (KBr): 3440 (NH), 1670 (C@O)
7. (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.;
Otokesh, S.; Baghbanzadeh, M.; Kozehgarya, G.; Mohammadi, A. A.
Tetrahedron Lett. 2005, 46, 6123; (d) Salehi, P.; Dabiri, M.;
Baghbanzadeh, M.; Bahramnejad, M. Synth. Commun. 2006, 36,
2287; (e) Chen, J. X.; Su, W. K.; Wu, H. Y.; Liu, M. C.; Jin, C. Green
Chem. 2007, 9, 972.
8. (a) Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang, G.
J.; Hamel, E. J. Med. Chem. 1990, 33, 1721; (b) Padia, J. K.; Field,
M.; Hinton, J.; Meecham, K.; Pablo, J.; Pinnock, R.; Roth, B. D.;
Singh, L.; Suman-Chauhan, N.; Trivedi, B. K.; Webdale, L. J. Med.
Chem. 1998, 41, 1042.
cmÀ1 1H NMR (400 MHz, DMSO-d6): d 8.26 (s, 1H), 7.62 (d,
.
J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.17–7.25 (m, 3H), 7.07 (s,
1H), 6.75 (d, J = 8.0 Hz, 1H), 6.66 (t, J= 7.6 Hz, 1H), 5.72 (s, 1H), 2.28
(s, 3H). 13C NMR (100 MHz, DMSO-d6): d 163.7, 148.0, 138.7, 137.8,
133.3, 128.9, 127.4, 126.9, 117.1, 115.0, 114.5, 66.5, 20.8. MS (EI,
70 eV): m/z (%) 238 (M+, 47), 237 ([MÀ1]+, 92), 147 (100), 120 (48).
26. General procedure for the one-pot synthesis of quina-zolin-4(3H)-
ones: To a solution of isatoic anhydrides 1 (5.5 mmol), ammonium
acetate (6.0 mmol), and aldehydes 2 (5 mmol) in DMSO (5 mL),
Ga(OTf)3 (0.05 mmol, 1 mol %) were added. The mixture solution
was stirred at 85 °C for an appropriate time as indicated in Table 3.
The progress of the reaction was monitored by TLC. After comple-
tion, the system was cooled to room temperature and water (10 mL)
was added. The solid product 4 was obtained through simple filtering,
and recrystallized from ethanol. Selected characterization data for the
products: Compound 4a: White solid; IR (KBr): 3309 (NH), 1662
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(C@O) cmÀ1 1H NMR (400 MHz, DMSO-d6): d 12.44 (s, 1H), 8.15
.
(d, J = 7.6 Hz, 1H), 8.11 (d, J = 8.0 Hz, 2H), 7.83 (t, J= 7.6 Hz, 1H),
7.73 (d, J = 8.4 Hz, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz,
2H), 2.40 (s, 3H). 13C NMR (100 MHz, DMSO-d6): d 162.2, 152.2,
148.8, 141.4, 134.5, 129.9, 129.1, 127.6, 127.3, 126.3, 125.8, 120.8,
20.9. MS (EI, 70 eV): m/z (%) 236 (M+, 80), 147 (22), 119 (100).
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met. Chem. 1995, 494, 229.