Green synthesis of 2-benzoyl-4-quinazolinones

Article abstract of DOI:10.14233/ajchem.2015.18677

A catalyst-free synthesis of 2-benzoyl-4-quinazolinones is described here. Anthranilamides and á-haloacetophenones were used as the starting reagents. The effects of molar ratio of reactants, catalyst, solvent, base, temperature and time on the reaction were investigated and then the optimal reaction conditions were achieved. All of the substrates examined under the optimized conditions gave high yields. Compared to traditional synthesis method of 2-benzoyl-4-quinazolinones, this method has several advantages, such as no catalyst, cost saving and environmentally benign process.

Full text of DOI:10.14233/ajchem.2015.18677

Asian Journal of Chemistry; Vol. 27, No. 3 (2015), 1157-1159
A
SIAN
J
OURNAL OF HEMISTRY
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http://dx.doi.org/10.14233/ajchem.2015.18677
Green Synthesis of 2-Benzoyl-4-quinazolinones
*
ZHIJIE LI, YAMEI PU, DEZHI QIU, XIAOPING ZHANG and QINGLE ZENG
Institute of Green Catalysis and Synthesis, College of Materials and Chemistry and Chemical Engineering, Chengdu University of Technology,
Chengdu 610059, P.R. China
*Corresponding author: Fax: +86 28 84079074; Tel: +86 13568999842; E-mail: qinglezeng@hotmail.com
Received: 2 September 2014;
Accepted: 21 October 2014;
Published online: 19 January 2015;
AJC-16746
A catalyst-free synthesis of 2-benzoyl-4-quinazolinones is described here. Anthranilamides and α-haloacetophenones were used as the
starting reagents. The effects of molar ratio of reactants, catalyst, solvent, base, temperature and time on the reaction were investigated and
then the optimal reaction conditions were achieved. All of the substrates examined under the optimized conditions gave high yields.
Compared to traditional synthesis method of 2-benzoyl-4-quinazolinones, this method has several advantages, such as no catalyst, cost
saving and environmentally benign process.
Keywords: Catalyst-free, 2-Benzoyl-4-quinazolinones, Anthranilamides, α-Haloacetophenones.
INTRODUCTION
EXPERIMENTAL
Quinazolinones is a kind of important nitrogen-containing
heterocycle. They exist as alkaloids extensively in natural
products1. It is known that the folium isatidis or the saxifrage
plants also have similar core structure. Natural quinazolinone
alkaloids have about 150 species, such as chrysogine2, luotonin
A3 and tryptanthrin4.
The chemicals and reagents were purchased fromAldrich,
Acros, Alfa Aesar, Aladdin, or Kelong Chemicals Company
and used without further purification.
General procedure: An oven-dried test tube with a stir
bar was charged with anthranil amides (1 mmol), α-halo-
acetophenones (1 mmol) and NaHCO3 (1 mmol). And then
DMSO (5 mL) was added by a syringe. The tube was put into
an oil bath preheated at 120 °C and the mixture was kept stirring
at that temperature for 24 h. The reaction mixture was then
cooled to room temperature, quenched with water and extracted
with ethyl acetate (20 mL) for three times. The combined
organic-layer was dried over anhydrous magnesium sulfate
and filtered. The filtrate was condensed under reduced pressure.
The residue was purified by silica gel column chromatography
with a solution of petroleum ether and ethyl acetate (volume
ratio from 1/5 to 2/1) to afford 2-benzoyl-4-quinazolinones.
Detection method: The purities of all the synthesized
compounds were checked by thin-layer chromatography
(TLC) using suitable organic solvents. The IR spectra were
recorded on a Bruker Tensor-27 FT-IR spectrophotometer in
KBr discs. 1H NMR spectra were recorded on a Bruker advance
300 MHz NMR or 400 MHz spectrometer in CDCl3 or DMSO-
d6 containing tetramethylsilane (TMS) as an internal standard.
Melting points were determined on an X-4 melting-point
apparatus with microscope and are uncorrected.
In addition, quinazolinones compounds have shown good
activity in antibacterial5, anti-inflammatory6, anti-
hypertensive7, anti-cancer8 and other aspects. They can reduce
the peripheral vascular resistance. They can also decrease
systolic and diastolic blood pressure. Recently, they have been
rated as antagonist of many biological receptor. Such as the
receptor of 5-HT5A9 which associated with diseases and the
receptor of antidiuretic hormone V310. Besides the biological
activities and the pharmacological activities, quinazolinones
have also shown the good activities in pesticides11,12
.
Because of its important bioactivity and medicinal value,
study of quinazolinones become a hot research field in recent
years. According to the reported synthetic routes, quinazo-
linones are typically synthesized from four substrates, that is,
o-nitrophenyl carboxamides13-15, o-amino-benzamides16-18
,
isatoic anhydrides19-21 and o-halobenzoic acid22-24
As our on-going research on synthesis of heterocycles25-28
.
,
we use anthranil amides and α-haloacetophenones as raw
material to synthesize 2-benzoyl-4-quinazolinones.

1158 Li et al.
Asian J. Chem.
With the optimized conditions at hand, the reaction of
various α-haloacetophenones and anthranilamides were
investigated (Table-1 entry 1-6). The experimental results show
that the reaction has a wide scope of the substrates. Most of
the reactants afforded the corresponding desired products with
high yields. The yield of other α-haloacetophenones have
slightly lower than that of α-bromoacetophenones (entry 1-
6). The α-haloacetophenones containing of electron-donating
groups have higher yields than electron-withdrawing groups
(entries 2,5,6).
RESULTS AND DISCUSSION
Firstly, we took anthranilamide and α-bromoacetophenone
as the model substrates of synthesis of 2-benzoyl-4-quinazo-
linones to optimize the reaction conditions.After examining a
series of molar ratio of reactants, catalyst, solvent, base, tempe-
rature and time. Finally, we achieved the optimized reaction
conditions: catalyst-free, NaHCO3 (1 equivalent), anthranil-
amide (1 mmol), α-bromoacetophenone (1 mmol) in DMSO
(5 mL) at 120 °C for 24 h.
TABLE-1
CATALYST-FREEREACTION OF ANTHRANILAMIDE AND α-HALOACETOPHENONES[a]
O
O
HN
X
R
NaHCO3, DMSO
120 oC, 24 h
NH2
NH2
R
R
+
R
N
O
O
1
3
2
Entry
1
Anthranilamide
2-Benzoyl-4-quinazolinones
Yield (%)
85.0
α-Haloacetophenone
O
O
O
HN
N
Br
NH2
NH2
O
O
O
Br
O
HN
NH2
2
3
4
5
6
7
8
76.8
79.3
79.7
61.8
80.5
75.6
78.1
O
N
NH2
O
O
O
O
Cl
Cl
Cl
Cl
HN
NH2
O
N
O
NH2
O
Cl
Cl
O
Cl
HN
NH2
O
N
NH2
O
Cl
O
O
Br
O2N
HN
NH2
O
N
NH2
O
O2N
O
O
N
Br
O
O
HN
NH2
NH2
O
O
O
O
O
O
O
HN
NH2
Br
NH2
N
O
O
O
O
HN
Br
NH2
NH2
N
O
aReaction conditions:anthranilamide (1 mmol), α-Haloacetophenone (1 mmol), NaHCO3 (1 mmol), DMSO (5 mL), 120 °C, 24 h, air

Vol. 27, No. 3 (2015)
Green Synthesis of 2-Benzoyl-4-quinazolinones 1159
In addition, under the optimized conditions, we also took
α-bromoacetophenone to react with several anthranilamides
to examine the scope of the reaction (Table-1, entries 1,7,8).
The experimental results demonstrate substituted anthranil-
amides also achieved fairly good yields (entries 7,8).
A proposed mechanism is shown in Fig. 1. As a start, a
nucleophilic substitution happens between anthranilamide
and α-bromoacetophenone. Weak alkaline condition is good
to promote this nucleophilic substitution. Then it is oxidized
to generate an α-benzoylimine. The electronegativity of carbon
is smaller than that of nitrogen of α-benzoylimine, it will be
susceptible to be attacked by nitrogen of amide. And thus an
intramolecular nucleophilic addition happens, which generates
an intermediate of six-membered ring. This intermediate is
oxidized by air to give the final product 2-benzoyl-4-quina-
zolinone.
excellent innovation team of Chengdu University of Tech-
nology (No. HY0084) for financial support.
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ACKNOWLEDGEMENTS
The authors thank the National Natural Science Founda-
tion of China (No. 21372034) and the cultivating program for