Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in the presence of Fe3O4@nano-cellulose–OPO3H as a bio-based magnetic nanocatalyst

Article abstract of DOI:10.1002/jccs.201900264

In this research, we have used Fe₃O₄@nano-cellulose–OPO₃H as magnetic bio-based nanocatalyst for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones via condensation of 2-aminobenzamide and different aldehydes. The major advantages of the present methodology are good yields, ecofriendly catalyst, and easy workup.

Full text of DOI:10.1002/jccs.201900264

Received: 1 July 2019
Revised: 19 September 2019
Accepted: 15 October 2019
DOI: 10.1002/jccs.201900264
C O M M U N I C A T I O N
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in the
presence of Fe3O4@nano-cellulose–OPO3H as a bio-based
magnetic nanocatalyst
Bi Bi Fatemeh Mirjalili1
| Zahra Zaghaghi2 | Aazam Monfared2
1Department of Organic Chemistry,
College of Chemistry, Yazd University,
Yazd, Iran
2Department of Chemistry, Payame Noor
University, Tehran, Iran
Abstract
In this research, we have used Fe3O4@nano-cellulose–OPO3H as magnetic
bio-based nanocatalyst for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones
via condensation of 2-aminobenzamide and different aldehydes. The major
advantages of the present methodology are good yields, ecofriendly catalyst,
and easy workup.
Correspondence
Bi Bi Fatemeh Mirjalili, Department of
Organic Chemistry, College of Chemistry,
Yazd University, P. O. Box: 89195-741,
Yazd, Iran.
K E Y W O R D S
2,3-Dihydroquinazolin-4(1H)-ones, 2-Aminobenzamide, bio-based catalyst, Fe3O4@nano-
cellulose–OPO3H, heterogeneous catalyst, magnetic nanocatalyst
Email: fmirjalili@yazd.ac.ir
1 | INTRODUCTION
2 | RESULTS AND DISCUSSION
Quinazolinones and their derivatives are used to synthe-
size similar drugs such as hypnotic/sedatives[1] and anti-
malarial,[2] antibacterial and antioxidant,[3] antitumor,[4]
antifungal and cytotoxic,[5] antiproliferative,[6] and inhibi-
tory activities on α-glucosidase.[7] In Figure 1, the structure
of metolazon (hypertensive),[8] febrifugine (antimalaria),
and methaqualone (sedative) were shown. Quinazolinones
are synthesized via condensation of 2-aminobenzamide
with aldehydes in the presence of an acidic catalyst. Previ-
ously, this reaction has been catalyzed by I2,[9] ZnFe2O4,[10]
silver triflate,[11] Sc(OTf)3,[12] lactic acid,[13] CeCl3,[14]
FeCl3/egg shell,[15] bismuth (III) bromide,[16] Zn-2-amino-
3-hydroxy-pyridine-MCM-41,[17] silica sulfuric acid,[18]
succinimide-N-sulfonic acid,[19] ammonium chloride,[20]
and nano-Fe3O4/TiCl2/cellulose.[21] Fe3O4@nano-cellulose–
OPO3H (Fe3O4@NCs-PA) was previously synthesized in
our laboratory for the first time and used for the synthesis
of dihydro-2-oxopyrroles.[22] In this work, we decided to
investigate the efficiency of Fe3O4@NCs-PA for the synthe-
sis of 2,3-dihydroquinazolin-4(1H)-ones.
The catalytic activity of Fe3O4@NCs-PA was investi-
gated for the synthesis of quinazolinone via a reaction
of 2-aminobenzamide and aldehydes. For optimization
of the reaction conditions, the reaction of 2-aminoben-
zamide and 4-chlorobenzaldehyde was investigated as
a model reaction under various conditions (Table 1).
As shown in Table 1, entry 10, it was found that using
Fe3O4@NCs-PA on 1 mmol of any substance under
reflux condition in water and ethanol (1:1) is the best
reaction condition. The reusability of the Fe3O4@NCs-
PA was investigated using the model reaction
(Table 1, entries 12–15). After the completion of the
reaction, the Fe3O4@NCs-PA was washed with etha-
nol, dried, and reused for another run. No any signifi-
cant reduction in yield was observed.
Finally, the above optimized reaction conditions were
applied for the synthesis of quinazolinone derivatives
(Scheme 1, Table 2). The aromatic aldehydes containing
electron-withdrawing groups were reacted in this proto-
col with high yields.
© 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J Chin Chem Soc. 2019;1–5.
http://www.jccs.wiley-vch.de
1

2
MIRJALILI ET AL.
FIGURE 1 Some quinazolinones
with pharmaceutical activity
TABLE 1 Synthesis of 2-(4-chlorophenyl)-2,3-dihydroquinazolin-4(1H) one under various conditionsa
Entry
1
Solvent
—
Catalyst (g)
Condition
Grinding
100ꢀC
R.T.
Time (hr)
Yieldb
—
71
—
43
—
74
82
60
95
95
81
87
85
82
75
88
88
91
92
90
99
98
Ref.
Catalystc (0.04)
Catalystc (0.04)
Catalystc (0.04)
Catalystc (0.04)
Catalystc (0.04)
Catalystc (0.04)
Catalystc (0.04)
0.25
1.5
2
2
—
3
—
4
n-hexane
H2O
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
O2/hv
60ꢀC
3.5
3
5
6
EtOH
1
7
MeOH
1
8
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
H2O, EtOH
EtOAc
Nano-Fe3O4 (0.04)
Catalystc (0.05)
Catalystc (0.04)
4
9
1.25
1.25
1.75
1.25
2.30
4
10
11
12
13
14
15
16
17
18
19
20
21
22
Catalystc (0.03)
Catalystc (0.04) second
Catalystc (0.04)third
Catalystc (0.04)fourth
Catalystc (0.04)fifth
I2 (0.05 equiv)
5
15
[9]
H2O
Lactic acid (20 mol%)
Sc (OTf)3(5 mol%)
ZnFe2O4 (30 mol%)
CeCl3(5 mol%)
0.33
0.41
0.17
8
[13]
[12]
[10]
[14]
[15]
[17]
Ethanol
H2O
70ꢀC
M.W
Dimethylcarbonate
Ethanol
H2O
100ꢀC
FeCl3/egg shell
r.t
0.17
2
Zn-2-amino-3-hydroxy-pyridine-MCM-41
90ꢀC
a4-Chlorobenzaldehyde (1 mmol), 2-aminobenzamide (1 mmol).
bIsolated yield.
cFe3O4@NCs-PA.
In addition to aldehydes, we also applied ketones for
the production of 2, 3-dihydroquinazolin-4(1H)-ones. If
we had applied cyclic ketones such as cyclohexanone or
cyclopentanone, the product 2, 3-dihydroquinazolin-4
(1H)-ones with spiro skeleton might have been formed
(Scheme 2).

MIRJALILI ET AL.
3
2.1 | Spectroscopic data for selected
compounds
d6, 400 MHz): δ 8.46 (brs, 1 H), 8.24 (brs, 1 H), 8.06 (brs,
1 H), 7.77 (brs, 1 H), 7.72 (brs, 1 H), 7.60 (brs, 1 H), 7.31
(brs, 1 H), 6.86 (brs, 1 H), 6.79 (brs, 1 H), 6.53 (brs, 1 H),
6.14 (s, 1 H). FT-IR (cm−1): 3281, 3186, 3074, 1649, 1605,
1520, 1483, 1349, 862, 747, 680.
2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (Table 2,
1
entry 1): White solid, H NMR (DMSO-d6, 400 MHz): δ
8.45 (brs, 1 H), 8.16 (m, 1 H), 8.02 (m, 2 H), 7.83 (m, 3 H),
7.69 (brs, 1 H), 7.37 (brs, 1 H), 7.26 (m, 1 H), 7.15 (brs,
1 H), 6.27 (s, 1 H). Fourier Transform Infrared (FT-IR)
(cm−1): 3301, 3176, 3062, 1653, 1610, 1509, 1482.
2-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one
(Table 2, entry 2): yellow solid, 1H NMR (acetone-d6,
400 MHz): δ 8.26 (d, J = 8 Hz, 2 H), 7.87 (d, J = 8 Hz,
2 H), 7.78 (m, 1 H), 7.52 (brs, 1 H), 7.30 (m, 1 H),
6.84–6.79 (m, 2 H), 6.51 (brs, 1 H), 6.11 (s, 1 H). FT-IR
(cm−1): 3352, 3291, 1658, 1609, 1513, 1484, 1346.
2-(2-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one
(Table 2, entry 4): Yellow solid. H NMR (acetone-d6,
1
400 MHz): δ 8.06 (d, J = 7.6 Hz, 1 H), 7.99 (d, J = 7.2 Hz,
1 H), 7.78–7.80 (m, 2 H), 7.62–7.66 (m, 1 H), 7.27–7.32
(m, 2 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.76–6.80 (m, 1 H),
6.50 (s, 1 H), 6.32 (brs, 1 H) FT-IR (cm−1): 3419, 3182,
3005, 1661, 1608, 1531, 1463, 1349, 738.
2-(4-Isopropylphenyl)-2,3-dihydroquinazolin-4(1H)-one
1
(Table 2, entry 6) Pale yellow solid, H NMR (Acetone-d6,
400 MHz): δ 7.78 (brs, 1 H), 7.49 (brs, 2 H), 7.29 (brs, 3H),
7.11 (brs, 1H), 6.84 (m, 1H), 6.77 (m, 1H), 6.16 (brs, 1H),
5.86 (s, 1H), 2.50 (m, 1 H), 1.23 (d, J = 6.4 Hz, 6 H). FT-IR
(Cm−1): 3291, 2952, 1653, 1608, 1433, 751.
2-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one
1
(Table 2, entry 3): Light yellow solid, H NMR (acetone-
2-(2-Chlorophenyl)-2,3-dihydroquinazolin-4(1H) one
(Table 2, entry 7): White solid, 1H NMR (Acetone-d6,
400 MHz): δ 7.78 (m, 2 H), 7.39–7.45 (m, 3 H), 7.25–7.29
(m, 2 H), 6.86 (brs, 1 H), 6.79 (brs, 1 H), 6.33 (brs, 1 H),
6.24 (brs, 1 H). FT-IR (cm−1): 3358, 3183, 3065, 1643,
1608, 1500, 1431, 1122, 1032, 742.
2-(4-Chlorophenyl)-2,3-dihydroquinazolin-4(1H) one
(Table 2, entry 8). White solid, 1H NMR (Acetone-d6,
SCHEME 1 Synthesis of quinazolinones in the presence of
Fe3O4@NCs-PA
TABLE 2 Synthesis of 2,
3-dihydroquinazolin-4(1H)-ones in the
presence of Fe3O4@NCs-PAa
M.P.c
Entry
1
R (Ar)
Time (h)
1.5
Yield (%)b
observed
208–210
307–309
190–193
191–192
199–200
157–161
206–208
193–194
165–169
184–186
190–195
213–216
200–202
160–162
175–176
147–149
>160c
Reported[Ref]
221–222[12]
>300[14]
Ph-H
83
92
89
73
75
78
79
95
82
71
70
88
85
89
90
80
82
80
2
4-NO2-Ph
1
3
3-NO2-Ph
0.5
194–196[14]
191–193[17]
209–211[16]
158–161[11]
210–212 [15]
203–205[15]
166–169[21]
185–189[21]
206–208[15]
218–219[15]
204[23]
4
2-NO2-Ph
1.75
1.5
5
4-OH-Ph
6
4-(CH3)2CH-Ph
2-Cl-Ph
2
7
1
8
4-Cl-Ph
1
9
2,4-(Cl)2-Ph
2,4-(OMe)2-Ph
4-(Me)2N-Ph
4-OH, 3-OMe-Ph
Ph-CH2CH2-
Ph-CH=CH-
Cyclohexyl
n-Pentyl
0.85
1.17
075
075
1.15
1.50
3
10
11
12
13
13
14
16
17
18
155–157[24]
174–175[23]
154[23]
1.20
1.50
3
[25]
H
—
4-HCO-Ph
243–245
245–246[26]
aAldehyde (1 mmol), 2-aminobenzamide (1 mmol), and Fe3O4@NCs-PA (0.04 g) were used.
bIsolated yield.
cDecomposed.

4
MIRJALILI ET AL.
O
N
O
SCHEME 2 Synthesis of quinazolinones
via condensation of 2-aminobenzamide and
ketones
O
N
n
Time Yield
+
NH2
NH2
( )
1
45
50
96
95
n
Fe3O4@NCs/PA
Water/Ethanol
)
(
2
O
N
O
n
+
Reflux
N
(CH3)2CH
CH3
CH3
CH(CH3)2
Time Yield
94
50
400 MHz): δ7.78 (brs, 1 H), 7.62 (brs, 2 H), 7.44 (brs,
2 H), 7.29 (brs, 2 H), 6.82 (m, 2 H), 6.28 (brs, 1 H), 5.94 (s,
1 H). FT-IR (cm−1): 3305, 3180, 3059, 1652, 1604, 1507,
1433, 1089, 749.
2-(2,4-Dichlorophenyl)-2,3-dihydroquinazolin-4 (1H)
one (Table 2, entry 9): White solid, 1H NMR (Acetone-d6,
400 MHz): δ 7.79 (brs, 2 H), 7.53 (brs, 1 H), 7.46 (brs,
1 H), 7.33 (m, 2 H), 6.80–6.85 (m, 2 H), 6.29–6.32 (m,
2 H). FT-IR (cm−1): 3431, 3182, 1646, 1610, 1513, 1435,
1150, 1127, 795, 741.
3.2 | General procedure for synthesis of
2,3-dihydroquinazolin-4(1H)-ones
In a 25 ml round-bottom flask, a mixture of Fe3O4@NCs-
PA(0.04 g), 2-aminobenzamide (1 mmol), aldehyde
(1 mmol), and water: EtOH (1;1, 3 ml) were mixed under
reflux condition. After completion of the reactions that
were monitored by thin layer chromatography (TLC)
(EtOAc: n-Hexane, 1:4).), the catalyst was removed from
the hot reaction mixture using an external magnet. By
adding water to the residue, solid products were obtained
and were filtered, dried, and finally recrystallized from
ethanol and water.
2-(2,4-Dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H)-
one (Table 2, entry 10): off white solid, 1H NMR (Acetone-
d6, 400 MHz): δ 11.10 (brs, 1 H), 8.36 (brs, 1 H), 8.17 (brs,
1 H), 7.78 (brs, 1 H), 7.70 (brs, 1 H), 7.46 (brs, 1 H), 6.77
(brs, 3H), 6.50 (m, 1 H), 3.91 (s, 3 H), 3.85 (s, 3 H). FT-IR
(cm−1): 3316, 1676, 1589, 1481, 1264, 1017, 822, 752.
2-(4-Dimethylaminophenyl)-2,3-dihydroquinazolin-4
4 | CONCLUSIONS
1
1
(1H) one (Table 2, entry 11). White solid, H NMR H
NMR (CDCl3, 500 MHz): δ 7.73 (m, 1 H), 7.29–7.15 (m,
3 H), 6.68–6.59 (m, 4 H), 6.00 (s, 1 H), 5.64 (s, 1 H), 5.09
(s, 1 H), 2.14(s, 3H). FT-IR (cm−1): 3283, 1650, 1610,
1508, 1163, 815, 750.
In summary, we have applied Fe3O4@NCs-PA as a bio-
based, ecofriendly, and efficient catalyst for the synthesis
of 2,3-dihydroquinazolin-4(1H)-ones. Easy workup, excel-
lent yields, and reusability of the catalyst are some of the
advantages of this novel protocol.
2-(3-Methoxy,4-hydroxy-phenyl)-
2,3-dihydroquinazolin-4(1H)-one (Table 2, entry 12) off
white solid, H NMR (CDCl3, 500 MHz): δ 8.22 (s, 1 H,
OH), 7.17 (d, J = 7.8 Hz, 1 H), 6.90 (s, 1 H), 6.67 (t,
J = 7.8 Hz, 1 H), 6.57 (s, 1 H), 6.30 (d, J = 7.7 Hz, 1H),
6.26 (d, J = 7.8 Hz, 1 H), 6.19 (d, J = 7.9 Hz, 1 H), 6.13 (t,
J = 7.8 Hz, 1 H), 5.87 (s, 1 H), 5.11 (s, 1 H), 3.35 (s, 3 H).
FT-IR (cm−1): 3385, 3343, 1641, 1607, 1158, 761.
ORCID
1
Bi Bi Fatemeh Mirjalili https://orcid.org/0000-0002-
6588-4041
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Additional supporting information may be found online
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How to cite this article: Mirjalili BBF,
Zaghaghi Z, Monfared A. Synthesis of 2,3-
dihydroquinazolin-4(1H)-ones in the presence of
Fe3O4@nano-cellulose–OPO3H as a bio-based
magnetic nanocatalyst. J Chin Chem Soc. 2019;1–5.
https://doi.org/10.1002/jccs.201900264