Efficient synthesis of mono- and disubstituted 2,3-dihydroquinazolin-4(1H)- ones using KAl(SO4)2·12H2O as a reusable catalyst in water and ethanol

Article abstract of DOI:10.1016/j.tetlet.2005.06.157

KAl(SO₄)₂·12H₂O was found to catalyze efficiently a one-pot three-component cyclocondensation of isatoic anhydride and primary amines or ammonia sources such as (NH₄) ₂CO₃, NH₄OAc and NH₄Cl with aromatic aldehydes under mild conditions to afford the corresponding mono- and disubstituted 2,3-dihydroquinazolin-4(1H)-ones in good yields.

Full text of DOI:10.1016/j.tetlet.2005.06.157

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6123–6126
Efficient synthesis of mono- and disubstituted
2,3-dihydroquinazolin-4(1H)-ones using KAl(SO4)2Æ12H2O as
a reusable catalyst in water and ethanol
Minoo Dabiri,a,* Peyman Salehi,b Somayeh Otokesh,a Mostafa Baghbanzadeh,a
Gholamreza Kozehgarya and Ali A. Mohammadia
aDepartment of Chemistry, Faculty of Sciences, Shahid Beheshti University, Tehran 1983963113, Iran
bDepartment of Phytochemistry, Medicinal Plants and Drugs Research Institute, Shahid Beheshti University, Tehran 19835-389, Iran
Received 12 April 2005; revised 20 June 2005; accepted 29 June 2005
Available online 15 July 2005
Abstract—KAl(SO4)2Æ12H2O was found to catalyze efficiently a one-pot three-component cyclocondensation of isatoic anhydride
and primary amines or ammonia sources such as (NH4)2CO3, NH4OAcand NH 4Cl with aromaticaldehydes under mild conditions
to afford the corresponding mono- and disubstituted 2,3-dihydroquinazolin-4(1H)-ones in good yields.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
larly useful for the creation of diverse chemical libraries
of drug-like molecules for biological screening.10 Very
recently, we reported the preparation of 2,3-disubsti-
tuted quinazolin-4(3H)-ones via multi-component reac-
tions.11 Now, we have designed a three-component
one-step synthesis of 2,3-dihydroquinazolin-4(1H)-ones.
For this, the use of KAl(SO4)2Æ12H2O (alum), which is
relatively non-toxicand inexpensive, was at the centre
of our study. In the course of our work on applications
of KAl(SO4)2Æ12H2O in organicreatcions, we have
found that it is an effective promoter for the preparation
A literature survey of important and valuable physiolog-
ical properties for mono- and disubstituted 2,3-dihydro-
quinazoline-4(1H)-ones includes analgesic, antitumour,
anticancer, diuretic and herbicide activities.1 In addi-
tion, these compounds can easily be oxidized to their
quinazolin-4(3H)-one analogues,2 which also include
important pharmacologically active compounds.3
Several methods have been reported for the synthesis of
2,3-dihydroquinazolinones.3–7 However, these methods
suffer from lengthy procedures and/or low yields and
vigorous conditions.3–7
Table 1. Screening of Lewis acidsa
One-pot transformations, particularly multi-component
reactions (MCRs) are of current interest to organic
chemists.8 Since the first MCR reported in 1850 by
Strecker,9 this methodology has emerged as an espe-
cially attractive synthetic strategy for rapid and efficient
library generation due to the fact that the products are
formed in a single step and diversity can be achieved
simply by varying the reaction components.8,9 MCRs
leading to interesting heterocyclic scaffolds are particu-
LAb
Time (h)
Yieldc (%)
H2O
EtOH
KBr
KCl
LiCl
LiBr
30
30
30
30
30
7
0
0
0
0
0
25
21
79
0
0
0
0
0
40
35
88
I2
AlCl3
NH4Al(SO4)2Æ12H2O
KAl(SO4)2Æ12H2O
30
4
a Yields of 4a using different LAs in the reaction of isatoic anhydride,
ethylamine and benzaldehyde.
b For all reactions 0.5 mmol Lewis acid was used.
c Isolated yields based on isatoicanhydride.
Keywords: KAl(SO4)2Æ12H2O; Multi-component reaction; Cyclocon-
densation; 2,3-Dihydroquinazolin-4(1H)-ones; Reusable catalyst.
*
Corresponding author. Tel./fax: +98 21 2401765; e-mail: m-dabiri@
cc.sbu.ac.ir
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.06.157

6124
M. Dabiri et al. / Tetrahedron Letters 46 (2005) 6123–6126
O
O
R1
R2
alum
N
O
R1NH2
R2CHO
+
+
H2O or EtOH
N
H
4a-o
N
H
1
O
3
2
Scheme 1.
of mono- and disubstituted 2,3-dihydroquinazolin-
O
O
4(1H)-ones.
O
alum
EtOH
NH
+
-
R3CHO
(NH )
+
X
+
O
4
When a mixture of isatoicanhydride 1, ethylamine 2 and
benzaldehyde 3 in H2O or EtOH was stirred under
reflux in the presence of a catalytic amount of alum,
the reaction was completed within 1 h and 4 h, respec-
tively. Work-up gave 4a in 79% and 88% yields, respec-
tively (Table 1 and Scheme 1).
N
H
1
R3
N
H
6a-g
5
-
-
X=CO32-, AcO, Cl
Scheme 2.
After screening several Lewis acids (LAs), we found that
alum was the best promoter for the reaction of isatoic
anhydride 1, ethylamine 2 and benzaldehyde 3 (Table 1).
When isatoicanhydride 1, aromaticaldehydes 5 and
ammonium salts such as ammonium carbonate, ammo-
nium chloride and ammonium acetate were used as the
source of ammonia,12 in the presence of alum with stir-
ring for 4–5 h in EtOH under reflux, 2-aryl substituted
2,3-dihydroquinazoline-4(1H)-ones 6a–g were prepared
in good yields (Scheme 2). The optimized results are
summarized in Table 3.
Encouraged by this success, we examined the reaction of
isatoicanhydride with a range of other aromaticalde-
hydes carrying either electron-releasing or electron-with-
drawing substitutes, affording high yields of products.
Aliphaticamines gave the products in shorter periods
compared to aromatic analogues. The optimized results
are summarized in Table 2.
Presumably, the reaction proceeds through condensa-
tion of isatoicanhydride 1 with primary amine 2 fol-
lowed by decarboxylation to yield the corresponding
2-aminobenzamide 7.13 Condensation of the aromatic
aldehyde with the amino group of 7 then gives imine 8
which undergoes cyclization to afford the dihydroqui-
nazoline product 4 (Scheme 3). Support for this mecha-
nism was obtained when N-methyl isatoicanhydride 9
was reacted with ethylamine and benzaldehyde under
the same conditions; only 2-N-methylamino ethylbenz-
amide15 (7a) was obtained (Scheme 4).
We also checked the reusability of the catalyst by recov-
ering the alum and using it for new runs and found that
the catalyst could be reused several times without any
decrease in the product yield. An example is shown for
the reaction of ethylamine with isatoic anhydride and
benzaldehyde (Table 2, 4a). The catalyst can be removed
from the aqueous phase by removing the water under
vacuum then washing with EtOH and drying at rt.
Table 2. Alum-catalyzed synthesis of 2,3-disubstituted 2,3-dihydroquinazolin-4(1H)-ones by the reaction of isatoic anhydride with primary amines
and aromaticaldehydes
4
R1
R2
Time (h)
Yielda (%)
Mp (°C)
H2O
EtOH
H2O
EtOH
a
b
c
d
e
f
Et
Et
Et
Et
Et
Ph
Ph
Ph
Ph
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
4
4
3
4
5
4
5
4.5
5
4
4.5
5
4
4
79, 75, 76b
88, 85, 87b
134–1372a
132–1352a
160–1612a
176–1782a
124–1262a
205–2067b
186–1887b
195–1977b
214–2177b
164–1652a
145–1462a
188–1902a
214–2167b
120–12115
180–18215
p-ClC6H4
p-O2NC6H4
m-O2NC6H4
p-CH3OC6H4
Ph
m-O2NC6H4
p-O2NC6H4
p-ClC6H4
Ph
p-CH3OC6H4
p-ClC6H4
Ph
p-O2NC6H4
p-HOC6H4
81
79
80
70
65
79
67
73
69
64
65
73
65
70
87
91
92
80
78
85
76
81
78
76
78
80
76
83
g
h
i
Ph
j
Me
Me
Me
p-ClC6H4
n-Pr
Et
k
l
m
n
o
4
a Isolated yield based on isatoicanhydride.
b The catalyst was reused for three runs.

M. Dabiri et al. / Tetrahedron Letters 46 (2005) 6123–6126
6125
Table 3. Alum-catalyzed synthesis of 2-aryl-2,3-dihydroquinazolin-4(1H)-ones by the reaction of isatoic anhydride with ammonium salts and
aromaticaldehydes in EtOH
a
6
R3
X
Time (h)
Yield (%)
Mp (°C)
a
b
c
d
e
f
Ph
p-ClC6H4
CO23À
CO23À
CO23À
CO23À
CO23À
CO23À
CO23À
AcOÀ
AcOÀ
AcOÀ
AcOÀ
AcOÀ
AcOÀ
AcOÀ
ClÀ
4
4
6
4
4
4
4
4
5
6
4
5
5
4
4
5
6
4
5
5
4
83
79
81
75
76
72
78
71
80
71
72
69
72
75
70
77
71
70
72
74
73
218–2205
198–2005
178–1805
165–1671e
233–23414
210–2131e
165–16714
218–2205
198–2005
178–1805
165–1671e
233–23414
210–2131e
165–16714
218–2205
198–2005
178–1805
165–1671e
233–23414
210–2131e
165–16714
p-CH3OC6H4
o-CH3OC6H4
p-CH3C6H4
m,p-(CH3O)2C6H3
2-Furyl
g
a
b
c
d
e
f
Ph
p-ClC6H4
p-CH3OC6H4
o-CH3OC6H4
p-CH3C6H4
m,p-(CH3O)2C6H3
2-Furyl
g
a
b
c
d
e
f
Ph
p-ClC6H4
ClÀ
p-CH3OC6H4
o-CH3OC6H4
p-CH3C6H4
m,p-(CH3O)2C6H3
2-Furyl
ClÀ
ClÀ
ClÀ
ClÀ
g
ClÀ
a Isolated yield based on isatoicanhydride.
O
O
O
R1
N
R1
N
R2CHO
alum
alum
O
R1NH2
H
+
H
R2
NH2
N
H
1
O
N
H
8
2
7
O
R1
R2
N
N
H
4
Scheme 3.
O
O
alum
EtOH, reflux
O
NHEt
EtNH2 + PhCHO
+
N
O
NH
CH3
9
CH3
7a
Scheme 4.
In conclusion, we have described a successful strategy
for the efficient and convenient synthesis of mono- and
disubstituted 2,3-dihydroquinazolinones in a one-pot,
three-component cyclocondensation reaction of isatoic
anhydride, aromaticaldehydes and primary amines or
ammonium salts using the inexpensive, non-toxicand
easily available KAl(SO4)2Æ12H2O as catalyst in H2O
or EtOH. The method offers several advantages includ-
ing high yields of products, a recyclable catalyst and an
easy experimental work-up procedure.
2. General procedure
Preparation of mono- and disubstituted 2,3-dihydroqui-
nazoline-4(1H)-ones in EtOH. To a solution of isatoic
anhydride (1 mmol), primary amine (1.1 mmol) or an
ammonium salt (ammonium carbonate 0.6 mmol,
ammonium acetate 1.2 mmol or ammonium chloride
1.2 mmol) and aldehyde (1 mmol) in ethanol (5 mL)
was added alum (0.15 g, 0.4 mmol). The mixture was
heated at reflux for the specified period of time (see

6126
M. Dabiri et al. / Tetrahedron Letters 46 (2005) 6123–6126
4. Moore, J. A.; Sutherland, G. J.; Sowerby, R.; Kelly, E. G.;
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Tables 2 and 3). After completion of the reaction as indi-
cated by TLC (eluent: 1/3 ethyl acetate–n-hexane), the
solid catalyst was separated by filtration. Water
(10 mL) was added and the precipitated product was
filtered and recrystallized from EtOH.15
Preparation of 2,3-disubstituted 2,3-dihydroquinazoline-
4(1H)-ones in H2O. Alum (0.2 g) was added to a mixture
of isatoicanhydride (1 mmol), primary amine (1.1 mmol)
and aldehyde (1 mmol) in water. The mixture was heated
at reflux for 1 h (see Table 2). After completion of the
reaction, the solid residue was separated, washed with
water (10 mL) and recrystallized from ethanol.
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Lett. 2004, 45, 9011–9014; (b) Zolfigol, M. A.; Safaiee, M.
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Acknowledgement
Financial support from the Research Council of Shahid
Beheshti University is gratefully acknowledged.
References and notes
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À1
15. C17H17N3O3 4n: IR (KBr) (mmax, c m ): 3420, 1680 (C@O);
1H NMR (CDCl3, 500 MHz) dH: 0.94 (3H, t, J = 7.3 Hz),
1.64 (2H, m), 2.77 (1H, ddd, J = 14.1, 8.59, 5.8 Hz), 4.05
(1H, ddd, J = 13.9, 8.7, 6.6 Hz), 5.82 (1H, s, CH), 6.5–8.2
(8H, m, arom); 13C NMR (CDCl3) dC: 12.5, 22.3, 48.1,
71.9, 116.0, 117.4, 120.9, 125.3 (2C), 128.3 (2C), 129.5,
134.9, 145.4, 148.3, 149.2, 164.1 (C@O); MS (m/z, %): 311
(M+, 64), 174 (47.6), 119 (45.2), 105 (44.3), 77 (51.6).
À1
C16H16O2N2 4o: IR (KBr) (mmax, c m ): 3440, 1680 (C@O);
1H NMR (DMSO-d6 500 MHz) dH: 1.0 (3H, t, CH3,
J = 7.08 Hz), 2.83 (1H, dq, J = 13.6, 7.02 Hz), 3.71 (dq,
1H, J = 13.6, 7.16 Hz), 5.73 (1H, d, J = 1.9 Hz), 6.6–6.7
(4H, m), 7.11–7.18 (3H, m), 7.20 (1H, d, J = 1.9, NH), 7.62
(1H, dd, J = 7.6, 1.4 Hz), 9.48 (1H, s, OH); 13C NMR
(DMSO-d6) dC: 14.6, 71.6, 115.6, 116.3, 116.7 (2C), 118.5,
128.9, 129.3 (2C), 133.0, 134.4, 148.1, 159.2, 163.3 (C@O);
MS (m/z, %): 268 (M+, 60), 174 (67.1), 105 (53.5),À717 (40.5).
C10H14N2O 7a: mp 88–90 °C; IR (KBr) (mmax, c m ): 3440,
1
3290, 1620 (C@O); H NMR (CDCl3, 500 MHz) dH: 1.24
(3H, t, J = 1.25 Hz), 2.98 (3H, s), 3.45 (2H, q,
J = 7.25 Hz), 6.03 (1H, br d, NH), 6.5–7.3 (4H, m), 7.49
(1H, br d, NH); 13C NMR (CDCl3) dC: 14.9, 29.7, 34.5,
111.1, 114.5, 115.4, 127.0, 132.6, 150.3, 169.8; MS (m/z, %):
178 (M+, 70), 119 (60.4), 104 (69.5), 77 (52.2).