A new approach to the facile synthesis of mono- and disubstituted quinazolin-4(3H)-ones under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2005.08.043

Quinazolin-4(3H)-one derivatives were synthesized successfully via a one-pot, three component reaction of isatoic anhydride and an orthoester with ammonium acetate or a primary amine catalyzed by silica sulfuric acid under solvent-free conditions. This is the first report on the synthesis of 2-substituted quinazolin-4(3H)-ones by this procedure.

Full text of DOI:10.1016/j.tetlet.2005.08.043

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7051–7053
A new approach to the facile synthesis of mono- and disubstituted
quinazolin-4(3H)-ones under solvent-free conditions
Peyman Salehi,a,* Minoo Dabiri,b Mohammad Ali Zolfigolc and Mostafa Baghbanzadehb
aDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University,
PO Box 19835-389, Evin, Tehran, Iran
bDepartment of Chemistry, Faculty of Sciences, Shahid Beheshti University, Evin, Tehran, Iran
cDepartment of Chemistry, Faculty of Sciences, Bu-Ali Sina University, Hamadan, Iran
Received 31May 2005; revised 30 July 2005; accepted 10 August 2005
Abstract—Quinazolin-4(3H)-one derivatives were synthesized successfully via a one-pot, three component reaction of isatoic anhy-
dride and an orthoester with ammonium acetate or a primary amine catalyzed by silica sulfuric acid under solvent-free conditions.
This is the first report on the synthesis of 2-substituted quinazolin-4(3H)-ones by this procedure.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
R
R’
R
N
Quinazolin-4(3H)-one derivatives 1 possess a broad
spectrum of biological and pharmaceutical activities,1
such as antidiabetic,2 anticonvulsant,3 analgesic,4 anti-
bacterial,5 phosphorylation inhibition,6 EGFR inhibi-
tion,7 PDGFR phosphorylation inhibition,8 CNS
depressant,9 antitumor,10 and diuretic activity.11 Also
quinazolinones are present in a wide variety of natural
products12 (Fig. 1). The most common approach toward
quinazolinones involves the amidation of 2-amino-
benzonitrile, 2-aminobenzoic acid, or its derivatives
followed by oxidative ring closure under basic condi-
tions.13,14 This approach, however, is limited by low
chemical yields. Recently, a synthesis of 2-substituted
quinazolin-4(3H)-ones based on the oxidative cycliza-
tion of anthranilamide with aldehydes was reported.15
However, the method suffers from the use of a toxic cat-
alyst. Reports on solid phase synthesis of related quinaz-
olinones are an additional impetus to explore their
multifaceted importance.16 As mentioned above, several
methods have been reported for the construction of the
quinazolin-4(3H)-one skeleton and new efforts have im-
proved the yields and reaction time.17
N
N
CH3
N
2
1
H3C
O
O
R
N
N
N
Het-aryl
N
CH3
4
3
Figure 1.
In continuation of our efforts to develop more versatile
methodologies for the synthesis of quinazolinone
compounds,18 herein, we report a simple and straight-
forward method for the one-pot preparation of mono-
and disubstituted quinazolin-4(3H)-ones. Toward this
goal, the solvent-free, three component reactions of isa-
toic anhydride, ammonium acetate, and different ortho-
esters, in the presence of catalytic amounts of silica
sulfuric acid as a solid acidic catalyst,19,20 were investi-
gated (Scheme 1).
Keywords: Quinazolin-4(3H)-ones; Silica sulfuric acid; Catalysis;
Solvent free.
*
To the best of our knowledge, there is no report on the
Corresponding author. Tel.: +98 2122481679; fax: +98 21
synthesis of mono-2-substituted quinazolin-4(3H)-ones
22418679; e-mail: p-salehi@cc.sbu.ac.ir
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.043

7052
P. Salehi et al. / Tetrahedron Letters 46 (2005) 7051–7053
O
N
O
NH
Silica sulfuric acid
O
+
NH4OAc +
R
C(OEt)3
Solvent-free, 80oC
R
N
H
O
Scheme 1.
Table 1. Synthesis of 2-substituted quinazolin-4(3H)-ones by the
reaction of isatoic anhydride, ammonium acetate and different
orthoesters under solvent-free conditions
Table 2. Synthesis of 2,3-disubstituted quinazolin-4(3H)-ones by the
reaction of isatoic anhydride, primary amines, and different orthoesters
under solvent free conditions
Entry
R
Yielda (%)
Mpb (°C)
Entry
R
R0
Yielda Mpb
(%)
(°C)
18b
1Me
82
Et
n-Pr
n-Bu
Ph
238–239
81235–236
86
80
78
18b
2
3
4
5
1CH
2
3
4
5
6
7
8
9
1
11
1
1
1
1
1
1
1
4-ClC6H4
4-CH3C6H4
C6H5
78
80
81
156–15818d
148–14918d
145–14618d
151–15218a
230–23118a
100–10118a
64–6618d
3
206–20718b
157–15918b
236–23718b
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
4-CH3CH2C6H4 80
C6H5CH2
C6H5CH2CH2
CH3CH2
2-CH3C6H4
CH3CH2
4-CH3C6H4
4-BrC6H4
4-CH3C6H4
C6H5CH2CH2
4-BrC6H4
C6H5
85
83
87
81
86
81
78
84
81
77
80
79
79
79
78
75
80
a Isolated yield.
b The products were characterized by comparison of their spectro-
scopic and physical data with authentic samples synthesized by the
reported procedures.
113–11518a
96–9718b
0
3CCHH
162–16318d
170–17218d
145–14718d
105–10618a
138–14018a
120–12118d
145–14618d
109–11018a
157–15918d
179–18018d
190–19218d
175–17618a
2
CH3CH2
via a one-pot procedure. As shown in Table 1, the target
compounds were successfully synthesized in high yields.
In this method, ammonium acetate was used as a cheap
and safe source of ammonia for manipulation of N-3 in
the quinazolin-4(3H)-one ring (1) (Fig. 1). Orthoesters,
which install C-2 in the product, were chosen with ali-
phatic and aromatic substituents in order to show the
versatility of the method. In each case, the product
was obtained in good yield.
2
3
4
5
6
7
8
9
3CCHHCH2
3CCHHCH2
3CCHHCH2
3CCHHCH2
2
2
2
2
3CCHHCH2
4-CH3C6H4
2
3CCHHCH2CH2 C6H5CH2CH2
2
6H5 C
6H5 C
C6H5
6H5
C6H5
1
20
21C
4-CH3C6H4
4-ClC6H4
C6H5CH2CH2
a Isolated yield.
The synthesis of 2,3-disubstituted quinazolin-4(3H)-
ones was another goal of this study. When isatoic anhy-
dride, a primary amine, and an orthoester, were mixed
in the presence of catalytic amounts of silica sulfuric
acid under solvent-free conditions, the expected prod-
ucts were obtained satisfactorily (Scheme 2). The results
are summarized in Table 2.
b The products were characterized by comparison of their spectro-
scopic and physical data with authentic samples synthesized by the
reported procedures.
ethyl orthoacetate in the presence of 30 mol % of the
catalyst. After completion of the reaction, ethanol was
added and the mixture was filtered to separate the cata-
lyst. The separated catalyst was used for further runs.
The activity of the catalyst did not show any significant
decrease even after five runs (Table 3).
Several aliphatic and aromatic amines with different
substituents gave the corresponding products in high
yields in all cases. 2-Methyl quinazolinone derivatives
2 (Table 2, entries 1–8) (valuable intermediates for the
synthesis of 2-heteroaryl quinazolinone compounds 4
with special importance in drug discovery)21 were syn-
thesized successfully (Fig. 1). Methaqualone (3), which
has been known as a sedative-hypnotic1a compound
for a long time, was synthesized by the present method
in 81% yield after 4 h (Table 2, entry 8).
In summary, we have developed an efficient and versatile
method for the preparation of a series of 2-mono- and
2,3-disubstituted quinazolin-4(3H)-ones via a one-pot
three component reaction of commercially available
starting materials. The reusability of the catalyst to-
gether with elimination of toxic organic solvents make
the procedure green and environmentally friendly. We
hope that because of the diversity of this method, it
The recyclability of the catalyst was investigated using a
model reaction of isatoic anhydride, ethylamine, and tri-
O
O
R’
N
Silica sulfuric acid
Solvent-free, 80oC
O
R’NH2
+
C(OEt)3
+
R
N
R
N
O
H
Scheme 2.

P. Salehi et al. / Tetrahedron Letters 46 (2005) 7051–7053
7053
Table 3. Recycling of silica sulfuric acid for the reaction of isatoic
anhydride, triethyl orthoacetate, and ethylamine under solvent-free
conditions
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Time (h)
187
2
3
4
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4
85
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4.5
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6.5
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a Isolated yield.
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2. General procedure for the synthesis of mono-substituted
quinazolin-4(3H)-ones
Isatoic anhydride (1mmol), ammonium acetate
(1.2 mmol), and the orthoester (1 mmol) were mixed
thoroughly with silica sulfuric acid and heated at
80 °C for 4 h. After completion of the reaction, hot eth-
anol was added to the mixture, which was then filtered.
The solvent was evaporated and the crude product was
recrystallized from ethanol.
3. General procedure for the synthesis of disubstituted
quinazolin-4(3H)-ones
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A mixture of silica sulfuric acid (0.3 mmol, 0.11 g), isa-
toic anhydride (1mmol), the primary amine (1.2 mmol),
and the orthoester (1mmol) were heated for 4 h at
80 °C. Work-up as above, afforded the disubstituted
product.
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