Green and one-pot three-component synthesis of 2,3-dihydroquinazolin- 4(1H)-ones promoted by citric acid as recoverable catalyst in water

Article abstract of DOI:10.2174/157017811796505025

Citric acid was used as green, non-toxic and reusable catalyst for the preparation of substituted 2, 3- dihydroquinazolin-4(1H)ones in high purity and good yields via one-pot three-component reaction of isatoic anhydride with a variety of aldehydes and primary amines or ammonium acetate in water at 80 °C.

Full text of DOI:10.2174/157017811796505025

470
Letters in Organic Chemistry, 2011, 8, 470-476
Green and One-Pot Three-Component Synthesis of 2,3-Dihydroquinazolin-
4(1H)-Ones Promoted by Citric Acid as Recoverable Catalyst in Water
Arash Ghorbani-Choghamarani*,a and Tahereh Taghipourb
aDepartment of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
b
Department of Chemistry, Saveh Branch, Islamic Azad University, Saveh, Iran
Received January 26, 2011: Revised March 22, 2011: Accepted April 18, 2011
Abstract: Citric acid was used as green, non-toxic and reusable catalyst for the preparation of substituted 2,3-
dihydroquinazolin-4(1H)ones in high purity and good yields via one-pot three-component reaction of isatoic anhydride
with a variety of aldehydes and primary amines or ammonium acetate in water at 80 ºC.
Keywords: 2,3-Dihydroquinazolin-4(1H)-one, catalysis, citric acid, isatoic anhydride, multicomponent reaction.
INTRODUCTION
All of the 2,3-dihydroquinazolin-4(1H)-ones were easily
obtained by mixing an aldehyde, isatoic anhydride and a
primary amine or ammonium acetate with citric acid (10 mol
Within the repertoire of synthetic strategies available to
organic chemists multi-component reactions (MCRs) are
mostly advantageous because they allow the creation of sev-
eral bonds in a single operation [1-3]. Also, reactions in wa-
ter have attracted special attention in the recent years [4, 6]
because water is the most abundant, cheapest and eco-
friendly solvent.
o
%) in water, then stirring this suspension at 80 C for the
appropriate time. After completion of the reaction, the solid
precipitate, which was formed, was filtrated and washed with
water. Recrystallization of the crude product from wa-
ter/ethanol gave highly pure compound.
In order to investigate the catalytic role of citric acid in
the described system, isatoic anhydride was reacted with 4-
chlorobenzaldehyde and aniline in the absence of the cata-
lyst. Surprisingly, we observed that the corresponding 2,3-
dihydroquinazolin-4(1H)-one was formed in only 50% yield
after 7 h (Table 1, entry 15), which means that citric acid has
a relevant role in the process.
Compounds with biological activity are often derived
from heterocyclic structures [7]. Among them, quinazolinone
derivatives have been found to possess a wide spectrum of
pharmacological activities, e.g. as antibacterial [8], antifun-
gal [9], and antitumor [10, 11] agents. Also, 2,3-
dihydroquinazolin-4(1H)-ones are an important class of het-
erocycles with a wide range of pharmacological and biologi-
cal activities. In view of their useful properties, a number of
elegant studies have been directed toward the synthesis of
2,3-dihydroquinazolin-4(1H)-one derivatives. There are two
main methods: the one-pot multicomponent condensation of
isatoic anhydride, amines and aldehydes [12-14] and the
cyclocondensation of anthranilide with aldehydes [15-17].
Both of them are associated with several shortcomings such
as toxic or expensive catalyst, harsh reaction conditions,
non-recoverability of the catalyst, tedious work-up proce-
dure, and low yields of products.
An important advantage of this catalytic system is the
facile recovery of citric acid from the reaction mixture. At
the end of the reaction, citric acid could be easily recovered
by washing the reaction mixture by water, followed by
evaporation of the water extracts, and used in a next run
avoiding purification. The reaction described in Scheme 2
was repeated in other four runs, each time using recovered
citric acid, whose activity did not show significant decrease.
In conclusion, we have developed a green, versatile and
facile approach to the synthesis of 2,3-dihydroquinazolin-
4(1H)-one derivatives via one-pot multicomponent conden-
sation of isatoic anhydride, aldehydes and primary amines or
ammonium acetate in water at 80 °C. The success of the
method relies on the use of citric acid as an effective, non-
toxic, cheap and recoverable catalyst. This protocol has the
prominent advantages of environmental friendliness, rela-
tively mild reaction conditions, low cost, simple operation,
and reusability of the catalyst.
RESULTS AND DISCUSSION
In light of our recent success in the application of new cata-
lytic systems for organic transformations [18-24] and aiming
to overcome the above-mentioned limitations, we became
interested to promote citric acid as non-toxic, very cheap,
green and efficient catalyst for the synthesis of substituted
2,3-dihydroquinazolin-4(1H)-ones by the one-pot multicom-
ponent condensation of isatoic anhydride, alde- hydes and
primary amines or ammonium acetate in water at 80 ºC
(Scheme 1 and Table 1).
EXPERIMENTAL
General Methods
*Address correspondence to this author at the Department of Chemistry,
Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran;
Tel/Fax: +98 841 2227022; E-mail: a.ghorbani@mail.ilam.ac.ir
Chemicals were purchased from Fluka, Merck and Ald-
rich chemical companies. The known products were charac-
1570-1786/11 $58.00+.00
© 2011 Bentham Science Publishers

Green and One-Pot Three-Component Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
471
COOH
H
H
HOOC
H
O
OH
O
R1
N
H
O
(Cat.)
COOH
R1NH2
+
+ R2CHO
H2O, 80 °C
N
H
O
N
R2
H
1
2
3
4
R1= H, C6H5, p-CH3C6H4, p-(CH3)2CHC6H4
R2= Aryl
Scheme 1.
Table 1. Synthesis of 2,3-dihydroquinazolin-4(1H)-one Derivatives Via Condensation of Isatoic Anhydride, Aldehydes and Primary
Amines or Ammonium Acetate in the Presence of a Catalytic Amount of Citric Acid at 80 °C in Watera
Yield (%)b
Time (Min)
Mp (°C) Found
Mp (°C) Reported
Ref.
Product
Entry
O
H
N
1
73
90
229-230
225-226
13
N
H
4a
O
H
N
2
3
4
5
74
77
78
86
90
230-232
198-200
205-208
202-205
233-234
199-200
207-208
197-199
7
N
H
Me
4b
O
H
N
60
7
N
H
F
4c
O
H
N
120
13
N
H
Cl
4d
O
H
N
180
17
N
H
Br
4e

472 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Ghorbani-Choghamarani and Taghipour
(Table 1). Contd…..
Yield (%)b
Time (Min)
Mp (°C) Found
Mp (°C) Reported
Ref.
Product
Entry
O
H
N
NO2
6
83
180
216-217
216-217
7
N
H
4f
O
H
N
7
85
240
189-190
192-193
7
N
H
OMe
4g
O
N
8
77
90
209-211
214-215
7
N
H
4h
O
N
9
83
90
217-219
219-220
7
N
H
Cl
4i
O
N
10
11
12
79
91
72
90
213-215
186-188
218-220
215-216
186-188
---
12
25
---
N
H
Me
4j
O
N
NO2
60
N
H
4k
O
N
120
N
H
OMe
4l

Green and One-Pot Three-Component Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
473
(Table 1). Contd…..
Yield (%)b
Time (Min)
Mp (°C) Found
Mp (°C) Reported
Ref.
Product
Entry
O
N
N
13
91
90
243-246
---
---
H
4m
Me
O
N
14
15
16
80
50
85
60
7hc
90
208-210
---
---
---
---
---
---
N
H
4n
Me
O
N
---
N
H
4n
Me
O
N
250-252
N
H
Cl
4o
Me
O
N
17
84
60
235-237
241-243
12
N
H
F
4p
Me
O
N
18
84
60
243-246
---
---
N
H
Me
4q

474 Letters in Organic Chemistry, 2011, Vol. 8, No. 7
Ghorbani-Choghamarani and Taghipour
(Table 1). Contd…..
Yield (%)b
Time (Min)
Mp (°C) Found
Mp (°C) Reported
Ref.
Product
Entry
CH(CH3)2
O
N
19
81
60
207-209
---
---
N
H
4r
CH(CH3)2
O
N
20
80
94
88
90
180
90
195-197
206-208
208-209
---
---
---
---
---
---
N
H
Cl
4s
CH(CH3)2
O
N
21
N
H
Br
4t
CH(CH3)2
O
N
22
N
H
Me
4u
aIsatoic anhydride: aldehyde : amine : citric acid = 1 : 1 : 1.1 : 0.1 (mmol). bCrude isolated yield. cReaction performed in the absence of catalyst.
CH3
O
NH2
CH3
CHO
O
O
N
Recovered citric acid
H2O, 80 °C, 90 min
+
+
N
H
O
N
H
Cl
Cl
Run No.
Yield
1
2
3
4
5
85
85
88
87
73
Scheme 2.
terized by comparison of their spectral (1H NMR, and 13C
NMR) and physical data with those of authentic samples.
General Procedure for the Synthesis of 2,3-
dihydroquinazolin-4(1H)-ones
1
Unknown compounds (4l-o,q-u) were identified by their H
Citric acid (0.1 mmol) was added to the mixture of isa-
toic anhydride (1 mmol), primary amine or ammonium ace-
and 13C NMR spectra.

Green and One-Pot Three-Component Synthesis
Letters in Organic Chemistry, 2011, Vol. 8, No. 7
475
1
tate (1.1 mmol) and aldehyde (1 mmol) in water (5 mL). The
mixture was heated at 80 ºC for the appropriate time (reac-
tion progress was monitored by TLC). After completion of
the reaction, the white solid product was filtered off and
washed with water. To obtain high pure 2,3-
dihydroquinazolin-4(1H)-one the crude product was crystal-
lized from water/ethanol mixture (1:1).
4u: H NMR (400 MHz, DMSO-D6): ꢀ = 7.72-7.60 (m,
2H), 7.26-7.09 (m, 9H), 6.72-6.66 (m, 2H), 6.17 (s, 1H),
2.86 (sep, 1H, J= 6), 2.21 (s, 3H), 1.17 (d, 6H, J= 6) ppm;
13C NMR (100 MHz, DMSO-D6): ꢀ = 162.7, 146.8, 146.5,
139.2, 138.5, 138.0, 134.1, 129.4, 128.4, 126.9, 126.7, 126.3,
117.9, 116.0, 115.3, 72.8, 33.4, 24.3, 21.1 ppm.
Selected 1HNMR and 13CNMR Data
ACKNOWLEDGEMENT
1
4l: H NMR (400 MHz, DMSO-D6): ꢀ = 7.71 (d, 1H, J=
Financial support to this work by the Ilam University,
Ilam, Iran is gratefully acknowledged.
7.6 Hz), 7.56 (s, 1H), 7.33-7.17 (m, 8H), 6.84 (d, 2H, J=8.4
Hz), 6.75-6.68 (m, 2H), 6.21 (s, 1H), 3.67 (s, 3H) ppm; 13C
NMR (100 MHz, DMSO-D6): ꢀ = 162.8, 159.6, 147.1,
141.3, 134.2, 133.1, 129.1, 128.4, 128.3, 126.8, 126.4, 117.9,
115.8, 115.3, 114.1, 72.8, 55.5 ppm.
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