Synthesis of 2,3-dihydroquinazoline-4(1H)-ones

Article abstract of DOI:10.1080/00397910903064831

An efficient, inexpensive, and heterogeneous catalyst, [Al(H ₂PO₄)₃], was applied in a three-component, one-pot cyclocondensation reaction of isatoic anhydride with primary amines (or ammonium salts) and aldehydes to afford the corresponding quinazolinone derivatives in excellent yields. Reactions occurred under thermal solvent-free conditions. It was found that this solid acidic catalyst could be easily recovered and reused for at least three cycles without any loss of activity.

Full text of DOI:10.1080/00397910903064831

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Synthesis of 2,3-
Dihydroquinazoline-4(1H)-ones
Hamid Reza Shaterian a , Ali Reza Oveisi a & Moones Honarmand a
a Department of Chemistry, Faculty of Sciences, University of Sistan
and Baluchestan, Zahedan, Iran
Version of record first published: 12 Mar 2010.
To cite this article: Hamid Reza Shaterian , Ali Reza Oveisi & Moones Honarmand (2010): Synthesis
of 2,3-Dihydroquinazoline-4(1H)-ones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:8, 1231-1242
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Synthetic Communications1, 40: 1231–1242, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903064831
SYNTHESIS OF
2,3-DIHYDROQUINAZOLINE-4(1H)-ONES
Hamid Reza Shaterian, Ali Reza Oveisi, and
Moones Honarmand
Department of Chemistry, Faculty of Sciences, University of Sistan and
Baluchestan, Zahedan, Iran
An efficient, inexpensive, and heterogeneous catalyst, [Al(H2PO4)3], was applied in a
three-component, one-pot cyclocondensation reaction of isatoic anhydride with primary
amines (or ammonium salts) and aldehydes to afford the corresponding quinazolinone
derivatives in excellent yields. Reactions occurred under thermal solvent-free conditions.
It was found that this solid acidic catalyst could be easily recovered and reused for at least
three cycles without any loss of activity.
Keywords: [Al(H2PO4)3]; 3-(20benzothiazolo)-2,3-dihydroqunazoline-4(1H)-ones; isatoic anhydride;
solvent-free
INTRODUCTION
Quinazolin-4(1H)-ones constitute an important class of heterocycles with a
wide range of pharmacological, physiological, and biological activities, such as
anticancer, antidituric, anticonvulsant, antifertility, antibacterial, antifungal, and
mono-amine oxidase inhibition and are also used as 5-hydroxytryptamine (5-HT)
receptor ligands.[1] Recently, Lindsley and coworkers observed the metabotropic
glutamate receptor (mGluR) properties of this class of compounds (Fig. 1).[2]
A literature survey showed that several methods for synthesis of quinazolinone
compounds were reported such as cyclization of o-acylaminobenzamides,[3]
amidation of 2-aminobenzonitrile followed by oxidative ring closure,[4] solid-phase
synthesis of 2-arylamino-substituted quinazolinones,[5] reduction of the azide
functionality,[6] preparation from isatoic anhydrides and Schiff bases,[7] conversion
of 2-nitro-N-arylbenzamides to 2,3-dihydroquinazolin-4(1H)-ones using SnCl2,
and Pd-catalyzed heterocyclization of nitroenes.[8] All these procedures have certain
limitations such as tedious process, long reaction times, harsh reaction conditions,
and poor yields. It was reported that the synthesis of quinazolinones can be
Received April 21, 2009.
This article is dedicated to Professor Ahmad Akbari, Chancellor of Sistan and Baluchestan
University, who dedicates himself to the progress of science.
Address correspondence to Hamid Reza Shaterian, Department of Chemistry, Faculty of Sciences,
University of Sistan and Baluchestan, P.O. Box 98135-674, Zahedan, Iran. E-mail: hrshaterian@
hamoon.usb.ac.ir
1231

1232
H. R. SHATERIAN, A. R. OVEISI, AND M. HONARMAND
Figure 1. Chemical structure of a mGluRs of quinazolin-4(1H)-ones.
catalyzed by p-toluenesulfonic acids,[9] silica sulfuric acid,[10] KAl(SO4)2 ꢀ 12H2O
(alum),[11] montmorillonite K-10,[12] zinc(II) perfluorooctanoate,[13] gallium(III)
triflate,[14] Amberlyst-15,[15] and 1-butyl-3-methylimidazolium bromide [bmim]Br
or [bmim]PF6 as ionic liquids.[16] In addition, quinazolin-4(1H)-ones can easily be
oxidized to their quinazolin-4(3H)-one analogs, which also show important pharma-
cologically active compounds.[1c] Thus, developing versatile approaches to synthesis
of 2,3-dihydroquinazolin-4(1H)-ones still remains a highly desired goal in organic
synthesis. The development of efficient and environmentally benign chemical
processes or methodologies for widely used heterogeneous recyclable catalysts under
solvent-free conditions is one of the major challenges for chemists in organic
synthesis. Meanwhile, the use of solvent-free methods gains importance from the
viewpoint of green chemistry. In continuation of our research on the solid hetero-
geneous acidic catalysts,[17] we herein report a practical method for the synthesis
of 2,3-dihydroquinazolin-4(1H)-ones employing three-component reactions of
isatoic anhydride with a primary amines (or ammonium salts) and aldehydes under
thermal solvent-free conditions in the presence of aluminium tris(dihydrogen
phosphate) as a low-cost, nontoxic, environmentally compatible, reusable, more
economical, and easy-to-handle catalyst (Scheme 1).
Scheme 1. Preparation of disubstituted-2,3-dihydroquinazolin-4(1H)-ones.
Figure 2. Molecular structure of Al(H2PO4)3.

SYNTHESIS OF 2,3-DIHYDROQUINAZOLINE-4(1H)-ONES
1233
Aluminium tris(dihydrogen phosphate) (Fig. 2) is prepared by taking alumina
(neutral) and concentrated phosphoric acid in the molar ratio of Al:H3PO4 as 1:3
under thermal conditions.[18]
RESULTS AND DISCUSSION
At the outset, to optimize the reaction conditions, we carried out the reaction
of isatoic anhydride (1 mmol) with aniline (1.1 mmol) and benzaldehyde (1 mmol) as
a model reaction in the presence of different amounts of the catalyst at different
temperature under thermal solvent-free conditions. The results of this study are
summarized in Table 1. As shown from Table 1, the best results used 0.05 g
(16 mol%) of the catalyst at 100 ꢁC.
Next, we applied the optimal protocol to a diverse range of primary amines
and aldehydes with isatoic anhydride and studied the scope of this reaction for
preparation of varieties of 2,3-dihydroquinazolin-4(1H)-one derivatives (Scheme 1,
Table 2). As shown in Table 2, the direct three-component reactions worked well
with a variety of aryl aldehydes including those bearing electron-withdrawing and
electron-donating groups such as OMe, Cl, Br, and NO2, and the desired compounds
were obtained in good to excellent yields (Table 2, entries 1–8).
Under the same conditions, this reaction did not proceed when aliphatic
aldehydes were used as the starting material.
We also have introduced an efficient and environmental friendly approach for
the synthesis of heterocyclic 3-(20-benzothiazolo)-2,3-dihydroquinazolin-4(1H)-ones
via the three-component condensation reaction of 2-aminobenzothiazole, isatoic
anhydride, and aryl aldehydes under thermal solvent-free conditions in good yields
(Table 2, entries 9–14).
The suggested mechanism of the Al(H2PO4)3-catalyzed preparation of
quinazolinone is shown in Scheme 2. Al(H2PO4)3 can act as Brønsted acid and also
Lewis acid, using the empty aluminium p-orbital (Fig. 2). According to observation
of evolution in the reaction conditions and other reported mechanisms in the
literature,[13,14] we have suggested that an acid–base interaction in Al(H2PO4)3 as
Table 1. Effects of different amounts of catalyst on the reaction rates at different temperatures in the
reaction of isatoic anhydride (1 mmol) with aniline (1.1 mmol) and benzaldehyde (1 mmol) under
solvent-free conditions
Entry
Amount of the catalyst (g)
Temperature (ꢁC)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
0.05
100
100
35
41
80
75
74
45
40
76
74
50
—
0.025
0.0125
0.006
0.003
0.05
100
100
46
3h
100
120
3.5h
17
0.05
0.05
80
50
3h
7h
0.05
Room temperature
24h
aYield refer to the isolated pure product.

1234
H. R. SHATERIAN, A. R. OVEISI, AND M. HONARMAND
Table 2. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones derivatives via Scheme 1
Melting points (ꢁC)
Found
Lit.[Ref]
Time
(min)
Yield
(%)a
Entry
1
R
R0
Product
4a
35
80
75
213–214 214–215[14]
193–196 194–196[13]
2
10 h
4b
3
4
5
6
7
8.5 h
25
70
80
76
70
85
4c
4d
4e
4f
212–215 214–217[11]
213–214 204–205[13]
218–220 222–225[13]
219–220 216–217[10b]
215–216 209–211[13]
10 h
9 h
32
4g
8
9
55
20
20
18
80
85
80
79
4h
4i
209–212 196–199[13]
231–234 233–236[16b]
198–200 190–193[16b]
228–230 231–234[16b]
10
11
4j
4k
12
20
86
4l
179–183 184–186[16b]
(Continued )

SYNTHESIS OF 2,3-DIHYDROQUINAZOLINE-4(1H)-ONES
Table 2. Continued
1235
Melting points (ꢁC)
Found
Lit.[Ref]
Time
(min)
Yield
(%)a
Entry
13
R
R0
Product
4m
13
15
80
85
229–233 225–230[16b]
14
4n
198–201 198–200[16b]
aThe reaction was conducted in an oil bath at 100 ꢁC; the molar ratio of isatoic anhydride, primary
amines, benzaldehydes, and Al(H2PO4)3 as catalyst was chosen 1:1.1:1:0.16.
the catalyst and isatoic anhydride produces a reactive intermediate (I). The
N-nucleophilic primary amine attack on the carbonyl unite of (I) produces a
reactive intermediate (II), which in turn affords (III) through decarboxylation reac-
tion. The proton transfer of (III) affords 2-amino-N-substituted-amide (IV).
Scheme 2. Suggested mechanism for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones.

1236
H. R. SHATERIAN, A. R. OVEISI, AND M. HONARMAND
Scheme 3. The condensation of anthranilamide and aldehydes in the presence of Al(H2PO4)3 as catalyst.
Subsequently, the reaction of activated aldehyde with (IV) proceeds to prepare the
imine intermediate (V). The part of amide functional group in intermediate (IV)
could be formed using tautomerism in the presence of the catalyst. Thus, intermedi-
ate (VI) could be prepared by intermolecular nucleophilic attack of the amide nitro-
gen on activated imine carbon, followed by a 1,5-proton transfer to yield the final
2,3-dihydroquinazoline-4-(1H)-ones as products.
Clarification of the reaction mechanism in detail is the next subject of investi-
gation, in which the condensation of anthranilamide (IV) with aldehydes using
Al(H2PO4)3 as a catalyst is reported (Scheme 3).
To confirm this suggested mechanism, 2-amino-N-phenylbenzamide (IV) was
prepared from the reaction of isatoic anhydride (1) with aniline (2a) in the presence
of Al(H2PO4)3 (16 mol%) under solvent-free conditions. Next, this product (similar
to intermediate IV in Scheme 2) reacted with benzaldehyde (3a) to give the corre-
sponding product 2,3-dihydroquinazoline-4(1H)-one (Scheme 4).
Encouraged by the success of these results, the ammonium salts such as
ammonium chloride and ammonium acetate were employed as the source of
ammonia instead of primary amines in the reaction (Scheme 1). They were mixed
with isatoic anhydride and benzaldehydes in the presence of Al(H2PO4)3 under
thermal solvent-free conditions (Scheme 5). The desired 2-aryl-2,3-dihydroquinazoline-
4(1H)-one derivatives were obtained in good yields using ammonium acetate and
ammonium chloride in the reaction conditions (Table 3).
We also investigated the recycling of the catalyst under solvent-free con-
a model reaction of isatoic anhydride, benzaldehyde, and
ditions using
ammonium acetate. After completion of the reaction, the reaction was cooled
to room temperature, and the crude solid product was dissolved in hot ethanol.
The hot ethanolic solution was filtered for separation of the catalyst. The catalyst
was washed twice (2 ꢂ 10 mL) using hot ethanol. Then it was dried at 100 ꢁC for
Scheme 4. Confirmation mechanism using 2-amino-N-phenylbenzamide.

SYNTHESIS OF 2,3-DIHYDROQUINAZOLINE-4(1H)-ONES
1237
Scheme 5. Synthesis of 2-aryl-2,3-dihydroquinazoline-4(1H)-ones.
1 h. The recovered catalyst was reused three times without any loss of its activities
(Table 4).
To show the merit of the present work in comparison with reported results in
the literature, we compared results of Al(H2PO4)3 with montmorillonite K-10,[12]
Table 3. Synthesis of 2-aryl substituted 2,3-dihydroquinazoline-4(1H)-one derivatives
Melting points (ꢁC)
NH4X
(X ¼ OAc, Cl) Time (min) Yield (%)a Product Found
Entry
R
Lit.[Ref]
1
2
NH4OAc
NH4OAc
42
4
85
90
5a
5b
202–203 192–193[10a]
187–188 186–187[14]
3
4
5
6
NH4OAc
NH4OAc
NH4OAc
NH4OAc
2 h
10
13
18
70
82
85
81
5c
5d
5e
5f
217–219 213–214[14]
239–241 233–234[10b]
200–202 205–206[16]
205–206 199–200[14]
7
8
NH4OAc
NH4OAc
NH4OAc
NH4Cl
12
8
80
90
90
90
5g
5h
5i
222–225 210–213[12]
227–230 221–223[13]
205–206 205–206[14]
227–230 221–223[13]
9
14
3 h
10
5j
aThe reaction was conducted in an oil bath at 100 ꢁC; the molar ratio of isatoic anhydride, ammonium
salts, benzaldehydes, and Al(H2PO4)3 as catalyst was 1:1.2:1:0.16.

1238
H. R. SHATERIAN, A. R. OVEISI, AND M. HONARMAND
Table 4. Reusability of Al(H2PO4)3 in the reaction of isatoic anhydride, ammonium
acetate, and benzaldehyde
Run
Yield (%)a
Time (min)
1
2
3
90
90
89
8
8
8
aThe molar ratio of isatoic anhydride, benzaldehyde, ammonium acetate, and
Al(H2PO4)3 was 1:1:1.2:0.16.
Table 5. Comparison of results of Al(H2PO4)3 with montmorillonite K-10,[12] silica sulfuric acid,[10]
KAl(SO4)2 ꢀ 12H2O(alum),[11] [Zn(PFO)2],[13] Ga(OTf)3,[14] Amberlyst-15,[15] and p-TSA[9] as catalysts in
the reaction of isatoic anhydride, aniline, and benzaldehyde
Entry
Catalyst
Conditions
Time (h)
Yield (%)
1
2
Montmorillonite K-10 (0.3 g)
EtOH, reflux
6.5
4.5
80
85
Silica sulfuric acid, 15 mol% (0.06 g H2O, 80 ꢁC
equal to 0.15 mmol of Hþ)
3
Silica sulfuric acid, 20 mol% (0.06 g Solvent-free,80 ꢁC
equal to 0.15 mmol of Hþ)
5
80
4
5
KAl(SO4)2 ꢀ 12.H2O (alum), (0.2 g)
[Zn(PFO)2] (0.027 g, 0.03 mmol)
Ga(OTf)3 (1 mol%)
EtOH, reflux
H2O=EtOH (1=3), reflux
EtOH, reflux
Solvent-free, 100 ꢁC
Microwave
4
6
78
82
6
60 min
35 min
3 min
1
79
80 (present work)
7
Al(H2PO4)3 (0.05 g, 16 mol%)
Amberlyst-15 (80 mg)
8
81
65
80
9
10
KAl(SO4)2-12H2O(alum) (0.2 g)
Silica sulfuric acid (0.3 mmol,
0.11 g)
H2O, reflux
EtOH, reflux
6.5
11
p-TSA (0.5 mmol)
H2O
2.5
79
silica sulfuric acid,[10] KAl(SO4)2 ꢀ 12H2O(alum),[11] [Zn(PFO)2],[13] Ga(OTf)3,[14]
Amberlyst-15,[15] and p-TSA[9] as catalysts in the reaction of isatoic anhydride,
aniline, and benzaldehyde in the synthesis of 2,3-dihydro-2-phenylquinazolin-
4(1H)-one. As shown in Table 5, Al(H2PO4)3 can act as an effective catalyst with
respect to reaction times and yields of the obtained products. Thus, the present pro-
tocol with Al(H2PO4)3 as a catalyst is convincingly superior to the recently reported
catalytic methods.
In conclusion, a three-component reaction of isatoic anhydride with primary
amines (or ammonium salts) and aldehydes in the presence of an efficient, inexpen-
sive, and heterogeneous catalyst, [Al(H2PO4)3], was applied to afford the corre-
sponding quinazolinone derivatives in excellent yields under thermal solvent-free
conditions. This catalyst could be easily recovered and reused for at least three cycles
without any loss of activity.
EXPERIMENTAL
All reagents were purchased from Merck and Sigma-Aldrich and used without
further purification. Al(H2PO4)3 was prepared according to the reported procedure.[18]

SYNTHESIS OF 2,3-DIHYDROQUINAZOLINE-4(1H)-ONES
1239
All yields refer to isolated products after purification. Products were characterized by
comparison of physical data with authentic samples and spectroscopic data (infra-
red, IR, and NMR). The NMR spectra were recorded on a Bruker Avance DPX
500-MHz instrument. The spectra were measured in dimethylsulfoxide (DMSO)
relative to tetramethylsilane (TMS) (0.00 ppm). IR spectra were recorded on a Jasco
Fourier transform (FT)–IR 460 plus spectrophotometer. Mass spectra were recorded
on an Agilent Technologies 5973 network mass selective detector (MSD) operating
at an ionization potential of 70 eV. Melting points were determined in open capil-
laries with a Buchi 510 melting point apparatus. Thin-layer chromatography
(TLC) was performed on silica-gel polygram SIL G=UV 254 plates.
General Procedure for the Synthesis of
2,3-Dihydroquinazolin-4(1H)-one Derivatives
A stirred mixture of isatoic anhydride (1 mmol), primary amine (1.1 mmol) or
ammonium salts (1.2 mmol), aldehydes (1 mmol), and Al(H2PO4)3 (0.05 g, 16 mol%)
was reacted in an oil bath at 100 ꢁC for the appropriate times. Completion of the
reaction was indicated by TLC. After completion of the reaction, it was cooled to
room temperature, and the crude solid product was dissolved in hot ethanol and fil-
tered for separation of the catalyst. The filtrate, ethanol solution, was concentrated.
The solid product was purified by recrystallization procedure in aqueous EtOH
(70%).
All the products were characterized by comparison of their spectroscopic and
physical data with those of authentic samples.[10–16] The spectral data of some
products are given next.
3-(20-Benzothiazolyl)-2,3-dihydro-2-(2-methoxyphenyl)-quinazolin-
4(1H)-one (Product 4m, Table 2, Entry 13)
Colorless crystals; mp 229–233 ꢁC; IR (KBr): t ¼ 3346, 1647, 1614, 1511, 1460,
1440 cmꢃ1
;
1H NMR (500 MHz, DMSO-d6): dH 8.01 (d, 1H, J ¼ 7.77 Hz), 7.87
(d,1H, J ¼ 7.77 Hz), 7.77 (d, 1H, J ¼ 3.48 Hz), 7.73 (d,1H, J ¼ 7.86 Hz), 7.67 (d,
1H, J ¼ 3.45 Hz), 7.19–7.43 (m, 4H), 7.07 (d, 1H, J ¼ 8.13 Hz), 6.71–6.89 (m, 4H),
3.94 (s, 3H) ppm; 13C NMR (125 MHz, DMSO-d6): dC 162.65, 157.56, 157.08,
148.01, 147.15, 135.85, 133.04, 130.29, 128.68, 127.15, 126.68, 125.50, 124.54,
122.11, 121.46, 120.35, 118.49, 116.01, 113.05, 112.14, 65.71, 56.25 ppm; MS (EI,
70 eV), m=z (%): 388 (60), 253 (100), 238 (50), 167 (20), 132 (25), 77 (20).
2-Amino-N-phenylbenzamide (IV)
White solid; mp 130–132 ꢁC; IR (KBr): t ¼ 3418, 3330, 3290, 1643, 1511, 1438,
1260,747 cmꢃ1 1H NMR (500 MHz, CDCl3): dH 7.75 (s, 1H), 7.57 (d, 2H,
;
J ¼ 7.6 Hz), 7.47 (d, 1H, J ¼ 6.9 Hz), 7.34–7.41 (m, 2H), 7.23–7.28 (m, 1H),
7.12–7.18 (m, 1H), 6.69–6.74 (m, 2H), 5.5 (s, 2H) ppm; 13C NMR (125 MHz,
CDCl3): dC 118.1, 118.8, 119.2, 122.5, 126.7, 129.3, 131.8, 134.8, 139.5, 151.8,
169.2 ppm; MS (EI, 70 eV), m=z (%): 212 (Mþ, 100), 213 (13.35).

1240
H. R. SHATERIAN, A. R. OVEISI, AND M. HONARMAND
2,3-Dihydro-2-(4-methylphenyl)-quinazolin-4(1H)-one (Product 5d,
Table 3, Entry 4)
White solid; mp 239–241 ꢁC; IR (KBr): t ¼ 3313, 3196, 1657, 1610, 1509,
1485 cmꢃ1; 1H NMR (500 MHz, DMSO-d6): dH 8.26 (s, 1H), 7.62 (d, 1H, J ¼ 7.6 Hz),
7.38 (d, 2H, J ¼ 8.0 Hz), 7.17–7.25 (m, 3H), 7.07 (s, 1H), 6.75 (d, 1H, J ¼ 8.0 Hz),
6.66 (t, 1H, J ¼ 7.6 Hz), 5.72 (s, 1H), 2.28 (s, 3H) ppm; 13C NMR (125 MHz,
DMSO-d6): dC 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 ppm; MS (EI, 70 eV) m=z (%): 238 (47), 237 (92), 147 (100), 120 (48).
ACKNOWLEDGMENT
We are thankful to the Sistan and Baluchestan University Research Council
for the partial support of this research.
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