One-pot synthesis of mono- and disubstituted (3H)-quinazolin-4-ones in dry media under microwave irradiation

Article abstract of DOI:10.1081/SCC-200048462

AlCl₃/ZnCl₂ mixture supported on silica gel is an efficient medium for one-pot synthesis of (3H)-quinazolin-4-ones in the absence of solvent under microwave irradiation or classical heating. The reaction of orthoesters with 2-aminobenzamides ends up with the formation of monosubstituted (3H)-quinazolin-4-ones. One-pot synthesis of disubstituted (3H)-quinazolin-4- ones is also achieved by the reaction of isatoic anhydride with primary amines and orthoesters.

Full text of DOI:10.1081/SCC-200048462

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One‐Pot Synthesis of
Mono‐ and Disubstituted
(3H)‐Quinazolin‐4‐ones in
Dry Media Under Microwave
Irradiation
Minoo Dabiri a , Peyman Salehi b , Ali A. Mohammadi
a & Mostafa Baghbanzadeh a
a Department of Chemistry, Faculty of Science,
Shahid Beheshti University, Tehran, 1983963113, Iran
b Department of Phytochemistry, Medicinal Plants
Research Institute, Shahid Beheshti University,
Tehran, Iran
Version of record first published: 28 Jul 2007.
To cite this article: Minoo Dabiri , Peyman Salehi , Ali A. Mohammadi &
Mostafa Baghbanzadeh (2005): One‐Pot Synthesis of Mono‐ and Disubstituted
(3H)‐Quinazolin‐4‐ones in Dry Media Under Microwave Irradiation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:2, 279-287
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Synthetic Communicationsw, 35: 279–287, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200048462
One-Pot Synthesis of Mono- and
Disubstituted (3H)-Quinazolin-4-ones in
Dry Media Under Microwave Irradiation
Minoo Dabiri
Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Tehran, Iran
Peyman Salehi
Department of Phytochemistry, Medicinal Plants Research Institute,
Shahid Beheshti University, Tehran, Iran
Ali A. Mohammadi and Mostafa Baghbanzadeh
Department of Chemistry, Faculty of Science, Shahid Beheshti
University, Tehran, Iran
Abstract: AlCl3/ZnCl2 mixture supported on silica gel is an efficient medium for one-
pot synthesis of (3H)-quinazolin-4-ones in the absence of solvent under microwave
irradiation or classical heating. The reaction of orthoesters with 2-aminobenzamides
ends up with the formation of monosubstituted (3H)-quinazolin-4-ones. One-pot
synthesis of disubstituted (3H)-quinazolin-4-ones is also achieved by the reaction of
isatoic anhydride with primary amines and orthoesters.
Keywords: AlCl3/ZnCl2-SiO2, (3H)-quinazolin-4-ones, solvent-free, microwave
irradiation
Received in the UK November 5, 2004
Address correspondence to Minoo Dabiri, Department of Chemistry, Faculty of
Science, Shahid Beheshti University, Tehran 1983963113, Iran. E-mail: m-dabiri@
sbu.ac.ir

280
M. Dabiri et al.
INTRODUCTION
It appeared that Lewis acids supported on a solid phase might be a good
alternative condition for synthesis of organic compounds in dry media.[1]
The coupling of microwave irradiation with the use of catalysts of mineral
supported reagents, under solvent-free conditions, provides chemical
processes with special attributes such as enhanced reaction rates, higher
yields, and improved ease of manipulation.[2] The application of AlCl3/
ZnCl2 on silica gel as an efficient Lewis acid system for Fries rearrangement,
in the absence of solvent under microwave irradiation has already been
reported.[3,4]
Interest in the synthesis of many substituted quinazolinones has been
renewed because of the potential use of the products as physiologically
active compounds[5–9,44] showing important biological activities such as
antibacterial[10–12] and as potent non-nucleoside reverse transcriptase inhibi-
tors of human immunodeficiency virus (HIV-1).[13] A number of synthetic
methods for the preparation of substituted (3H)-quinazolin-4-ones have
been described via alternate pathways: (1) reaction of thioureas with isatoic
anhydride;[14] (2) from N–(2-nitrobenzoyl)amides in the presence of
Ru3(CO)12 catalyst;[15] (3) reaction of N-arylnitrillium salts with isocyanates,
which referred to as Meerwein’s quinazolin synthesis;[16] (4) treatment of
anthranilic acid with amino acids and aldehydes;[17] (5) through azo-Wittig
reaction;[18] (6) starting from 4H-3,1-benzoxazin-4-ones.[19] Recently, the
synthesis of the mono substituted quinazolinones in solution and also dry
media has been reported.[17,20] Disubstituted 4-(3H)-quinazolinones are
also synthesized through a multistep reaction in solution under microwave
irradiation.[21–25] Here we report a rapid, efficient, and one-pot procedure for
the synthesis of mono-and disubstituted (3H)-quinazolin-4-ones in the
presence of an AlCl3/ZnCl2 mixture supported on silica gel, under solvent-
free conditions by using microwave irradiation or classical heating.
RESULTS AND DISCUSSION
When 2-aminobenzamides (1) and orthoesters (2) were mixed with AlCl3/
ZnCl2 mixture supported on silica gel and subjected to microwave irradiation
Scheme 1.

One-Pot Synthesis of Mono- and Disubstituted (3H)-Quinazolin-4-ones
281

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M. Dabiri et al.
the corresponding mono-substituted (3H)-quinazolin-4-ones (3) were
obtained in good yields (Scheme 1).
The reactions were conducted with similar success by classical heating
within 2–3.5 hr (Table 1, entries 1–10). After conventional workup, the
products (3) were purified by recrystallization from EtOH.
To improve the method of synthesis of 2,3-disubstituted quinazolin-4-
ones in one step, we also investigated the reaction of isatoic anhydride (4),
primary amines (5), and orthoesters (6) in the presence of AlCl3/ZnCl2-
SiO2 under microwave irradiation or conventional heating (Scheme 2).
As shown in Table 2, in both conditions the corresponding 2,3-
disubstituted (3H)-quinazolin-4-ones were obtained in good yields, although
slightly higher yields were achieved under microwave irradiation. Aromatic
primary amines were used with similar success to aliphatic amines.
In conclusion, mono- and disubstituted (3H)-quinazolin-4-ones could be
prepared in one step by the use of AlCl3/ZnCl2-SiO2 system under both
microwave irradiation and conventional heating in good to excellent yields.
The workup procedure is very easy, including washing the reaction mixture
with hot ethanol followed by filtration and recrystallization of the products.
The method also enjoys the chemical and environmental advantages of
solvent-free reactions.[42]
EXPERIMENTAL
All of the products are known compounds and were identified by comparison
1
of their physical and spectral data (IR, HNMR) with those of authentic
samples. Yields refer to isolated products. Melting points were obtained in
open capillaries on an Electrothermal 9200 melting point apparatus and are
not corrected. AlCl3/ZnCl2-SiO2 was prepared according to the reported
procedure.[3,4] Progresses of the reactions were followed by dissolving a
sample in ethanol and monitoring on precoated TLC aluminum sheets.
Preparation of the Solid Support
.
A mixture of silica gel (50 g, Merck, 70–230 mesh), AlCl3 6H2O (40 g), and
ZnCl2 (10 g) was added to 150 mL of water, and the mixture was stirred
Scheme 2.

One-Pot Synthesis of Mono- and Disubstituted (3H)-Quinazolin-4-ones
283

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M. Dabiri et al.
thoroughly to give a gel-like material. Then water was evaporated in vacuo,
and the gel was left to stand at 1208C overnight. The resulting solid
granules were ground and further activated by heating to 2308C in vacuo.
The catalyst was stored under dry condition.
General Procedure for the Formation of Mono-Substituted
(3H)-quinazolin-4-ones Under Classical Heating
A stirred mixture of 2-aminobenzamide (1) (1.2 mmol),[43] orthoester (2)
(1 mL) and catalytic amounts of AlCl3/ZnCl2-SiO2 (0.04 g) was heated
at 808C for 2–3.5 hr under solvent-free conditions. After cooling to room
temperature, the solid product was washed with hot ethanol. Then
solvent was evaporated, and the crude product was recrystallized from
ethanol. In all cases, the reaction periods were optimized by interrupting
the reactions in each 30 min and monitoring the progress of the reaction
by TLC.
General Procedure for the Synthesis of Disubstituted
(3H)-quinazolin-4-ones by Classical Heating
A stirred mixture of isatoic anhydride (4) (1 mmol), primary amines (5)
(1.2 mmol), orthoesters (2) (1–1.5 mL) and catalytic amounts of AlCl3/
ZnCl2-SiO2 (0.04 g) was heated at 808C for 3–3.5 hr in the absence of
solvent. After cooling to room temperature, the solid product was washed
with hot ethanol. The solvent was evaporated, and the crude product was
recrystallized from ethanol.
General Procedure for the Preparation of Mono-substituted
(3H)-quinazolin-4-ones Under Microwave Irradiation
2-Aminobenzamide (1) (1.2 mmol), orthoester (2) (1 mL) and catalytic
amounts of AlCl3/ZnCl2-SiO2 (0.04 g) were mixed thoroughly in a tall
beaker, covered with a stemless funnel, which then was placed in the
microwave oven. The mixture was irradiated for two subsequent 3 min
periods (irradiation conditions were (1) 210 W, 3 min and (2) 385 W,
3 min). The precipitates were filtered, washed with hot ethanol, and was
cooled to room temperature. The crude product was recrystallized from
96% ethanol to give the products. In all cases, the reaction periods were
followed by interrupting the reactions in every 1 min and monitoring the
progress of the reaction by TLC.

One-Pot Synthesis of Mono- and Disubstituted (3H)-Quinazolin-4-ones
285
General Procedure for the Formation of Disubstituted
(3H)-quinazolin-4-ones Under Microwave Irradiation
Isatoic anhydride (4) (1 mmol), primary amines (5) (1.2 mmol), orthoesters (2)
(1–1.5 mL) and catalytic amounts of AlCl3/ZnCl2-SiO2 (0.04 g) were mixed
thoroughly in a tall beaker and covered with a stemless funnel, which then was
placed in the microwave oven. The mixture was irradiated for two subsequent
3 min periods (irradiation conditions were (1) 210 W, 3 min and (2) 385 W,
3 min). The precipitates were filtered, washed with hot ethanol, and
cooled to room temperature. The crude product was recrystallized from
96% ethanol.
ACKNOWLEDGMENT
Financial support by Research Council of Shahid Beheshti University is
gratefully acknowledged.
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