Amino acid catalyzed synthesis of 2,3-dihydroquinazolin-4(1H)-one derivatives

Article abstract of DOI:10.2174/1570178614666171130154814

A simple, convenient and facile approach for the synthesis of a series of 2,3-dihydroquinazolin-4(1H)-ones in an environmentally benign method has been developed. This method involves a direct cyclocondensation of 2-aminobenzamide with aromatic aldehydes and ketones using aspartic acid as a catalyst in water.

Full text of DOI:10.2174/1570178614666171130154814

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Letters in Organic Chemistry, 2018, 15, 246-250
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Amino Acid Catalyzed Synthesis of 2,3-Dihydroquinazolin-4(1H)-one
Derivatives
BENTHAM
S
CIENCE
K. Mohammed Mustaque, A. Subramani, T.K. Shabeer, H. Thajudeen and V.S. Jamal Ahamed*
PG and Research Dept. of Chemistry, The New College, Chennai-600014, Tamilnadu, India
Abstract: A simple, convenient and facile approach for the synthesis of a series of 2,3-
A R T I C L E H I S T O R Y
dihydroquinazolin-4(1H)-ones in an environmentally benign method has been developed. This method
involves a direct cyclocondensation of 2-aminobenzamide with aromatic aldehydes and ketones using
aspartic acid as a catalyst in water.
Received: February 20, 2017
Revised: September 08, 2017
Accepted: October 02, 2017
DOI:
10.2174/1570178614666171130154814
Keywords: Amino acid, catalyst, 2,3-Dihydroquinazolin-4(1H)-ones, 2-aminobenzamide, ketones, water.
1. INTRODUCTION
proline is widely used as an organocatalyst in aldol conden-
sation [29, 30] and Ulmann reaction while tryptophan and
alanine are employed in asymmetric mannich reactions [31,
32]. This prompted us to use amino acid as a catalyst in the
synthesis of DHQs in water. This synthesis involves water as
a solvent, which is environmental-friendly, non-volatile,
nontoxic, perfectly safe and inexpensive when compared
with other organic solvents.
The compound 2,3-dihydroquinazolin-4-(1H)-one (DHQs)
and its derivatives containing nitrogen heterocycles [1] as
core units have pharmacological activities that attract much
attention towards this. As an essential pharmacophore,
quinazolinone derivatives have a variety of biological activi-
ties. Many DHQs are reported to have anticancer [2], analge-
sic, anticonvulsant [3], antiparkinsonian [4], antibacterial [5],
diuretic [6], monoamine oxidase inhibition [7], plant growth
regulation [8] and antihypertensive [9] properties. Due to
their versatile biological applications, DHQ derivatives have
stimulated a great interest in chemists. A variety of ap-
proaches have been developed for the synthesis of DHQs.
The significant methods are (i) cyclocondensation of alde-
hyde or ketone with 2-amino-benzamide and (ii) reaction of
isatoic-anhydride with ammonium acetate or amines, and
aldehyde or ketone [10]. Several catalysts have been em-
ployed for these reactions which include heterogeneous solid
catalysts Amberlyst-15, silica-HClO4 [11], propyl-
phosphonic anhydride (T3P®) [12], CuCl2 [13], ZrCl4 [14],
TiCl4/Zn [15], NH4Cl [16], trichloroacetic acid [17], suc-
cinimide-N-sulfonic acid [18], 2-morpholinoethanesulfonic
acid [19] etc. Recently, recyclable catalysts such as ionic
liquids [20-23], metal-CNTs [24, 25], Fe3O4/chitosan com-
posite nanocatalyst [26], nanocrystalline sulfated zirconia
[27] and PEG-400 [28] were used.
Herein, we report our preliminary finding that aspartic
acid is an efficient catalyst for the cyclocondensation reac-
tion of DHQ synthesis in water. This is the first example for
the synthesis of 2,3-dihydroquinazolin-4(1H)-ones with
amino-acid as catalyst in water (Scheme 1).
O
O
O
Amino acid
H2O, rt, 10-60 min
NH
R`
R
NH2
NH2
R
R'
N
H
R=R`=H, Alkyl, Aryl
Scheme (1). The synthesis of 2,3-dihydroquinazolin-4(1H)-one
derivatives in water.
2. RESULTS AND DISCUSSION
At the commencement of our research, we investigated
the model reaction between 2-aminobenzamide and benzal-
dehyde at room temperature with different amino acids (30
mol%) as catalysts as shown in Table 1.
The exploitation of amino acids as organocatalysts in
asymmetric synthesis became acquainted due to their harm-
less, bio-renewable and low-cost nature. For instance,
After screening nine amino acids, aspartic acid was found
to be the most effective catalyst, since it resulted in the high-
est yield of the desired product (Table 1, entry 7). Compared
with the model reactions carried out without catalyst, the yield
was very low. In addition, the amount of catalyst affected the
*Address correspondence to this author at the PG and Research Dept. of
Chemistry, The New College, Chennai-600014, Tamilnadu, India; Tel: +91-
44-2835 1269; +91-44-2835 0386; Fax: +91-44-2835 2883;
E-mail: vsjamal@gmail.com
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Amino Acid Catalyzed Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives
Letters in Organic Chemistry, 2018, Vol. 15, No. 4 247
3. EXPERIMENTAL SECTION
reaction significantly. We noticed that 30 mol% of aspartic
acid is optimum to catalyze the reaction efficiently and fur-
ther increasing the amount of catalyst decreased the yield
(Table 2, entry 7).
All reagents were obtained from commercial suppliers
and used without further purification unless otherwise noted.
The NMR spectra were recorded on a Bruker 400 MHz in-
strument using DMSO-d6 as the solvent. Chemical shifts (δ)
are expressed in ppm with tetramethylsilane (TMS) as the
internal standard and coupling constants (J) are reported in
Hz.
Table 1. The synthesis of 2,3-dihydroquinazolin-4(1H)-ones
using different amino acids as catalysts.
O
O
H
O
3.1. Synthesis of 2,3-Dihyroquinazolin-4(1H)-one Deriva-
tives
NH
NH2
Amino acid
H2O, rt, 10-60 min
N
H
NH2
In a vial, 2-aminobenzamide (1 mmol), 4 mL of water,
30 mol% of amino acid (aspartic acid) were taken and stirred
for 5 minutes. Then 1 mmol of aldehyde or ketone was
added to the mixture and stirring was continued for 60 min-
utes. The progress of the reaction was monitored by TLC.
After completion of the reaction, water-insoluble product
was obtained. The crude products were obtained directly by
filtration and washed with 20% cold ethanol. Finally, the
solid product was recrystallized from ethanol-water mixture
(80:20).
Entry
Amino Acids
Yield (%)
1
2
3
4
5
6
7
8
9
Phenylalanine
Tryptophan
Arginine
Cystine
20
40
42
87
88
71
95
71
91
Glycine
Proline
3.2. Spectral Characterization of Selected Compounds
Aspartic acid
Histidine
Valine
3.2.1. 2-Phenyl-2,3-dihydroquinazolin-4-(1H)-one, (Entry
1, Table 3)
Yield: 95%. mp 221ºC. FT-IR (ν, cm-1): 3303 (NH),
1652(C=O), 1612 (C=C), 1484 (CHAro).
1H NMR (DMSO-d6, 400 MHz) δ 8.29 (br.s, 1H), 7.63
(d, 1H,), 7.51 (d, 2H), 7.41-7.35 (m, 3H), 7.26 (t, 1H),
7.11(br.s, 1H), 6.76 (d, 1H), 6.69 (t, 1H), 5.76 (s, 1H); 13C
NMR (DMSO-d6, 100 MHz) δ 164.0, 148.3, 142.1, 133.7,
128.9, 128.7, 127.8, 127.3, 117.5, 115.4, 114.8, 67.0.
Table 2. The effect of mol% of aspartic acid on the model
reaction.
Entry
mol% of Aspartic Acid
Yield (%)
3.2.2. 2-(2-Nitrophenyl)-2,3-dihydroquinazolin-4-(1H)-one,
(Entry 6, Table 3)
Yield: 90%. mp 153ºC. FT-IR (ν, cm-1): 3387 (NH
amine), 1669 (C=O), 1592 (C=C), 1342 (NO2), 1486
(CHAro).
1H NMR (DMSO- d6, 400 MHz) δ 8.85 (s, 3H), 8.17 (m,
9H), 8.07 (dd, 1H), 7.92 (m, 11H,), 7.83 (m, 9H), 7.74 (d,
1H), 7.59 (m, 11H), 7.38 (m, 4H), 7.19 (m, 6H), 7.04 (d,
1H), 6.72 (m, 3H), 6.58 (d, 2H), 6.34 (t, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 190.39, 171.73, 168.03, 158072,
149.66, 149.20, 134.71, 134.64, 134.41, 134.38, 134.01,
132.78, 132.32, 132.20, 130.35, 130.28, 130.22, 119.67,
118.13, 116.83, 115.36, 114.79, 62.61.
1
2
3
4
5
6
7
5
30
33
39
47
89
95
81
10
15
20
25
30
35
In order to examine the scope and limitation of this ap-
proach, we applied these optimal reaction conditions to a
variety of aldehydes and ketones. The results are illustrated
in Table 3.
3.2.3. 2-(p-Tolyl)-2,3-dihydroquinazolin-4-(1H)-one, (Entry
9, Table 3)
Generally, the cyclocondensation reaction proceeded well
and afforded the desired products in good to excellent yields.
The reaction was compatible with a variety of electron-
donating and electron-withdrawing substituents in the aro-
matic aldehydes. Steric hindrance seems to have no effect on
the efficiency of this transformation. Besides aromatic alde-
hydes, cyclohexanone (entry 3), aliphatic aldehyde (entry 5)
and heteroaryl aldehydes (entries 4 & 10) also afforded the
desired product.
Yield: 77%. mp 225ºC. FT-IR (ν, cm-1): 3311 (NH
amine), 1655 (C=O), 1606 (C=C), 1482 (CHAro).
1H NMR (DMSO- d6, 400 MHz) δ 8.28 (s, 1H), 7.64 (m,
1H), 7.40 (d, 2H), 7.22 (dd, 3H), 7.09 (s, 1H), 6.77 (d, 1H),
6.69 (t, 1H), 5.74 (s, 1H), 2.30 (s, 3H); 13C NMR (DMSO-
d6, 100 MHz) δ 164.15, 148.40, 139.10, 138.20, 133.74,
129.28, 127.82, 127.28, 117.54, 115.88, 66.87.

248 Letters in Organic Chemistry, 2018, Vol. 15, No. 4
Mustaque et al.
Table 3. The synthesis of 2,3-dihydroquinazolin-4(1H)-ones using aspartic acid as catalyst.
O
O
O
Aspartic acid
NH2
NH
R`
R
R
R'
H2O, rt, 10-60 min
N
H
NH2
Entry
R
R’
Product
Yield (%)
Refs.
O
NH
1
-H
95
[33]
N
H
O
NH
2
3
4
-H
93
60
78
[34]
[35 a-d]
[36]
OCH3
OH
N
H
OCH3
OH
O
O
O
NH
=
=
R'
R'
R
N
H
O
O
O
NH
O
R
N
H
N
H
NH
O
O
NH
5
6
7
-H
-H
-H
-H
94
90
71
[37]
[38]
[39]
N
H
O
NH NO2
NO2
N
H
O
NH
C6H5
N
H
C6H5
O
NH
8
-H
73
[40]
OH
OH
N
H
OH
OH
O
NH
O
9
-H
-H
77
75
[41]
[42]
N
H
CH3
CH3
N
NH
10
N
H
N
O
NH
11
12
-H
-H
91
78
[43]
[44]
N
H
CH3
N
CH3
N
H3C CH3
O
NH
N
H

Amino Acid Catalyzed Synthesis of 2,3-Dihydroquinazolin-4(1H)-One Derivatives
Letters in Organic Chemistry, 2018, Vol. 15, No. 4 249
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In conclusion, a simple, green and effective catalytic syn-
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CONSENT FOR PUBLICATION
Parthasaradhi, Y.; Rakhi, C.; Suresh, S.; Tangenda, S.J. Eur. J.
Med. Chem., 2013, 4, 462-466.
Not applicable.
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CONFLICT OF INTEREST
Ibrahem, I.; Zou, W.; Engqvist, M.; Xu, Y.; Córdova, A. Chem.
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The authors declare no conflict of interest, financial or
otherwise.
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ACKNOWLEDGEMENTS
Financial support from UGC (MRP-5996/15, Comcode:
TNMD043) is gratefully acknowledged.
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