Highly efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones catalyzed by heteropoly acids in water

Article abstract of DOI:10.1016/j.cclet.2010.03.022

Heteropoly acids efficiently catalyzed the cyclocondensation reaction of anthranilamide with aldehydes in water at ambient temperature and afforded the corresponding 2,3-dihydro-4(1H)-quinazolinones compounds in good to excellent yields. This method provides mild reaction conditions and clean reaction profiles, using a small quantity of catalyst and a simple workup procedure.

Full text of DOI:10.1016/j.cclet.2010.03.022

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 778–781
www.elsevier.com/locate/cclet
Highly efficient synthesis of 2,3-dihydroquinazolin-4(1H)-ones
catalyzed by heteropoly acids in water
b
YingXiao Zong a, Yan Zhao a, WenCai Luo a, Xing Hai Yu a, Jun Ke Wang a,b, , Yi Pan
*
a Key Laboratory of Resources and Environment, Chemistry of West China, Hexi University, Zhangye 734000, China
b School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China
Received 20 October 2009
Abstract
Heteropoly acids efficiently catalyzed the cyclocondensation reaction of anthranilamide with aldehydes in water at ambient
temperature and afforded the corresponding 2,3-dihydro-4(1H)-quinazolinones compounds in good to excellent yields. This
method provides mild reaction conditions and clean reaction profiles, using a small quantity of catalyst and a simple workup
procedure.
# 2010 Jun Ke Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Heteropoly acid; 2,3-Dihydroquinazolin-4(1H)-ones; Water
Recently, the organic reactions in water have attracted much attention [1–5] in synthetic organic chemistry because
water is one of the most abundant, cheapest, and environmentally friendly solvents, and exhibits unique reactivity and
selectivity, which is different from those in conventional organic solvents. Hence, much attention has been
concentrated on Lewis acid catalyzed organic reactions in water.
Heteropoly acids (HPAS) have attracted much attention in the catalytic area due to their unique properties such as
high thermal stability, low cost, ease of preparation and ease of recyclability [6–11], HPAs are promising solid acids to
replace environmentally harmful liquid acid catalysts such as H2SO4. Therefore, developing organic reactions in water
in the presence of heteropoly acid catalysts for industry is desirable.
2,3-Dihydro-4(1H)-quinazolinone is a class of heterocycles that attracted much attention because they possess their
potential pharmaceutical activities [12–15]. Furthermore, 2,3-dihydro-4(1H)-quinazolinones could be easily oxidized
to 4-(3H)-quinazolinones, which are important privileged structures in medicinal chemistry, by NaHSO3 or DDQ (2,3-
dichloro-5,6-dicyano-1,4-benzoquinone) [16,17]. Many classical methods for the synthesis of 2, 3-dihydro-4(1H)-
quinazolinone have been reported [18–27]. For example, they were obtained by reductive cyclization of o-
nitrobenzamide or o-azidobenzamide with aldehydes and ketones promoted by metallic samarium and a catalytic
amount of iodine or SmI2 [23]. The synthesis of 2,3-dihydroquinazolinones was also achieved with the aid of a low-
valent titanium reagent [24–27]. There was also a recent report of carrying out these reactions in ionic liquids [28].
These ionic liquids have been shown to have serious drawbacks, especially imidazoliums with PF6 and BF4 anions that
* Corresponding author at: Key Laboratory of Resources and Environment, Chemistry of West China, Hexi University, Zhangye 734000, China.
E-mail addresses: wangjk@hxu.edu.cn, wjkzyx@yahoo.com.cn (J.K. Wang).
1001-8417/$ – see front matter # 2010 Jun Ke Wang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2010.03.022

Y.X. Zong et al. / Chinese Chemical Letters 21 (2010) 778–781
779
are as toxic as benzene on certain aquatic ecosystems and also liberate hazardous HF during recycling [29]. However,
despite the diverse routes so far developed for the synthesis of 2,3-dihydro-4(1H)-quinazolinone, only a few
procedures in water have been reported in the literature [30]. Furthermore, the reported reactions in water have been
carried out in the presence of surfactants such as SDS (sodium dodecyl sulfate). Unfortunately, normal-phase
separation is difficult during workup due to the formation of emulsions because of the SDS [31]. Moreover, this
method needed the multifarious procedures.
There is increasing interest in developing environmentally benign catalytic reactions that employ anthranilamide
and aldehydes for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones. Herein we describe a mild, convenient and
simple procedure by condensation of anthranilamide with aldehydes for the preparation of 2,3-dihydroquinazolin-
4(1H)-ones in water using a heteropoly acid catalyst.
At the onset of the research, we chose anthranilamide and benzaldehyde as model reaction to investigate several
Lewis acids and solvents. The results of extensive Lewis acid and solvent screening and optimization are shown in
Table 1. Among four heteropoly acids (HPAs), H3PW12O40 is the best catalyst for the reaction in water. H3PW12O40
catalyze the cyclocondensation reactions in organic solvents such as acetonitrile, toluene, methanol and ethanol gave
desired products in low yield. After some solvents were screened, it was found that water was the solvent of choice,
since the cyclocondensation reactions proceeded smoothly in this solvent and afforded the desired compound in high
yields at room temperature. Hence, in this reaction, H3PW12O40 is much more reactive in water than in other organic
solvents. At room temperature, the cyclocondensation reaction proceeded to completion affording the corresponding
compound in good to excellent yield without the side product. We attempted to add SDS as surfactant to further
improve yield, but no effect has been observed. The reaction in pure water without using any catalyst was tested to
obtain the product in very low yield (entry 5). Furthermore, it is shown that only 0.10 mol% of the catalyst was
sufficient for the completion of the reaction in high yields at room temperature.
Encouraged by this result, in order to build the generality of the reaction, our attention moved to the reactions of
other aldehydes [32], and the results are summarized in 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 investigated. The substitution groups on the aromatic
ring had no obvious effect on the yield. When aromatic aldehydes were replaced by aromatic heterocyclic aldehydes,
the corresponding products were obtained with high yields as well (Table 2, entries 10 and 11). However, the steric
Table 1
Direct condensation of anthranilamide with benzaldehyde catalyzed by heteropoly acid in diffrent solvents.a
Entry
Solvent
Catalyst
Yieldb (%)
1
2
Water
H4SiMo12O40
H3PW12O40
H4SiMo12O40
H3PW12O40
No catalyst
H3PW12O40
H3PW12O40
H3PW12O40
H3PW12O40
H4SiMo12O40
H3PW12O40
H3PW12O40
88
94
92
90
6
Water
3
Water
4
Water
5
Water
6
Diethyl ether
Toluene
EtOH
30
47
78
85
84
72
92
7
8
9
MeOH
MeOH
CH3CN
Water
10
11
12c
a
Reaction conditions: o-aminobenzamide (1 mmol), aldehyde (1 mmol) successively added to a solution of catalyst (0.1 mol%) placed in a test
tube, and the reaction mixture was vigorously stirred at room temperature for 10 min.
b
Yield of isolated product.
c
0.03 g SDS was used.

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Y.X. Zong et al. / Chinese Chemical Letters 21 (2010) 778–781
Table 2
Condensation of anthranilamide with aromatic aldehydes in water.a
Entry
R1
R2
Time (min)
Yieldb (%)
1
2
H
H
H
H
H
H
H
H
H
H
H
Cl
Cl
C6H5
8
9
94
97
96
81
90
89
93
90
79
88
90
96
94
p-(CH3O)C6H4
p-(CH3)C6H4
2,3,4,-(CH3O)3C6H2
p-(Cl)C6H4
3
8
4
10
10
9
5
6
2,4-(CH3O)2C6H3
p-(F)C6H4
7
10
10
8
8
p-(NO2)C6H4
o-(NO2)C6H4
2-furyl
9
10
11
12
13
9
2-thiazolyl
9
p-(CH3O)C6H4
p-(CH3)C6H4
6
8
a
Reaction conditions: o-aminobenzamide (1 mmol), aldehyde (1 mmol) successively added to a solution of catalyst (0.1 mol%) in water (2 mL)
placed in a test tube, and the reaction mixture was vigorously stirred at room temperature for 6–10 min.
b
Isolated yield.
effects exhibited by the aldehydes may play an important role and resulted in moderate yield of the product (Table 2,
entry 9). Despite of the low solubility of aldehydes and amines in water, the H3PW12O40-catalyzed cyclocondensation
reactions still proceed efficiently at ambient temperature. The reaction might take place at the interface of organic
materials with water in the heterogeneous system. It was found that vigorous stirring was required for the success of
these reactions.
Finally, the recyclability of the catalyst was investigated. The reaction of anthranilamide and 4-
methylbenzaldehyde in water at room temperature in the presence of H3PW12O40 was investigated. After the
reaction was complete (monitored by TLC), followed by the filtration, the filtrate was saved for the next reaction.
When the same reaction was performed in this filtrate containing the used catalyst, lower yields (84%) of the product
were obtained. According to same procedure, the recyclability of the second run was examined under the same
condition. It was found that the yield of the product was lower (77%). It maybe results from the loss of the catalyst
while the filtration was conducted.
In conclusion, a very simple, highly efficient and eco-friendly synthetic method of 2,3-dihydroquinazolin-4(1H)-
ones has been found. This procedure was accompanied with several advantages, such as low loading of catalyst,
improved yields and clean reaction, which make it an attractive strategy for the synthesis of the solid products.
Moreover, a very easy workup has been realized that does not require organic solvents. When the products are solid
and insoluble in water, the pure products can be obtained directly by filtration and washing the filtrate with water and
by crystallization from ethanol or by column chromatography. No extraction is necessary in some cases. Our ongoing
efforts for the synthesis of other reactions catalyzed by heteropoly acids in water will be reported elsewhere.
Acknowledgment
We gratefully acknowledge the financial support of Key Laboratory of Resources and Environment Chemistry of
West China (No. XZ0704).
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[32] General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones under aqueous conditions: anthranilamide (2 mmol) and aldehydes
(2.1 mmol) was successively added to a solution of catalyst (7 mg) in water (4 mL) placed in a test tube and the reaction mixture was vigorous
stirred at room temperature for 5–10 min. The progress of the reaction is monitored by TLC (thin layer chromatography). After completion of
the reaction, the reaction mixture was filtered to afford the crude product, and the crude product was purified by recrystallized from ethanol. All
of the obtained 2,3-dihydroquinazolin-4(1H)-ones are known compounds in which the spectroscopic data were compared. However, spectral
data for the following product has not been found. 2-(2,3,4-Trimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (entry 4): mp: 173–174 8C.
IR (KBr): 3439, 1672 cmÀ1, 1H NMR (300 MHz, DMSO-d6): d 7.98 (s, 1H), 7.68 (d, 1H, J = 7.8 Hz), 7.34 (d, 1H, J = 8.0 Hz), 7.21–7.24 (m,
1H), 7.08 (s, 1H), 6.74–6.65 (m, 3H), 5.88 (s, 1H), 3.95–3.85 (m, 9H). 13C NMR (75 MHz, DMSO-d6): d 163.2, 161.3, 158.2, 148.3, 132.1,
127.6, 127.8, 122.4, 117.3, 114.9, 114.4, 104.6, 98.6, 56.5, 55.5. MS (ESMS) (M+) Calcd. for C17H18N2O4: 314 (M+, 91), 313 ([MÀ1], 76),
found: 257.06. Elemental analysis Calcd. for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91; found: C, 65.03; H, 5.87; N, 8.82.