Sulfamic acid as a reusable and green catalyst for efficient and simple synthesis of 2-substituted-2,3-dihydroquinazolin-4(1H)-ones in water or methanol

Article abstract of DOI:10.1016/j.cclet.2011.06.008

A series of 2,3-dihydroquinazolin-4(1H)-ones have been synthesized in good to excellent yields through direct cyclocondensation of anthranilamide and aryl aldehydes or ketones in water or methanol under mild conditions. The reaction was efficiently promoted by 10 mol% sulfamic acid (SA, H₂NSO ₃H) and the catalyst could be recovered easily after the reactions and reused without evident loss of reactivity.

Full text of DOI:10.1016/j.cclet.2011.06.008

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1317–1320
www.elsevier.com/locate/cclet
Sulfamic acid as a reusable and green catalyst for efficient and
simple synthesis of 2-substituted-2,3-dihydroquinazolin-4(1H)-ones
in water or methanol
*
Amin Rostami , Ashkan Tavakoli
Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj 6617715143, Iran
Received 19 April 2011
Available online 29 July 2011
Abstract
A series of 2,3-dihydroquinazolin-4(1H)-ones have been synthesized in good to excellent yields through direct cyclocondensa-
tion of anthranilamide and aryl aldehydes or ketones in water or methanol under mild conditions. The reaction was efficiently
promoted by 10 mol% sulfamic acid (SA, H2NSO3H) and the catalyst could be recovered easily after the reactions and reused
without evident loss of reactivity.
# 2011 Amin Rostami. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Sulfamic acid; Catalyst; Anthranilamide; Aldehyde; Ketone; 2,3-Dihydroquinazolin-4(1H)-ones
2,3-Dihydroquinazolinones are a class of heterocycles that attracted much attention because they have been
reported to possess a wide range of pharmaceutical activities including antifertility, antibacterial, antitumor,
antifungal, and mono amine oxidase inhibition [1]. In addition, 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 [4–20]. The typical procedure for the
synthesis of 2,3-dihydroquinazolin-4(1H)-ones involves the condensation reaction of anthranilamide with aldehyde or
ketone using acids as a catalyst under various conditions [4,8,10,14–20]. However, some of these methodologies have
limitations such as harsh reaction conditions, use of expensive acid catalysts in organic solvents, long reaction time
and tedious work-up. Hence, the development of simple, efficient, clean, high-yielding, and environmentally benign
protocols using green catalysts for the synthesis of these important compounds is still desirable and is in demand.
The use of water as a solvent has many advantages in organic synthesis from both economic and environmental
points of view [21]. Also, water has become an attractive medium for many organic reactions, not only as one can
avoid using drying reactants and expensive catalysts and solvents, but also rendering unique reactivity and selectivity
[22]. In recent years, the use of solid acidic catalysts has offered important advantages in organic synthesis, some of
these advantages are: operational simplicity, environmental compatibility, non-toxicity, reusability, low cost, and ease
of isolation [23]. Sulfamic acid (SA, H2NSO3H) is a common inorganic acid with a mild acidity that is nonvolatile,
* Corresponding author.
E-mail address: a_rostami372@yahoo.com (A. Rostami).
1001-8417/$ – see front matter # 2011 Amin Rostami. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.06.008

1318
A. Rostami, A. Tavakoli / Chinese Chemical Letters 22 (2011) 1317–1320
O
O
O
C
NH2SO3H (Cat.)
H2O, 70 oC
or MeOH, rt
NH
R2
NH2
NH2
+
R1 R2
N
H
3a-q
R1
1
2a-q
R1, R2= Aryl, Alkyl, H
Scheme 1.
noncorrosive, stable, low-cost, and commercially available reagent. More important, its water resistance makes it an
outstanding alternative to metal catalysts, in different areas of organic synthesis, as an efficient and green
heterogeneous catalyst [24–26].
In continuation of our efforts to develop more versatile methodologies in organic synthesis [27,28], herein, we
report a simple and straightforward method for the preparation of 2-substituted-2,3-dihydroquinazolin-4(1H)-ones
from direct cyclocondensation of anthranilamide with aldehydes and ketones in the presence of catalytic amounts of
SA as a green catalyst in water at 70 8C or in methanol at room temperature (Scheme 1).
At the onset of the research, in order to optimize the reaction conditions, we investigated the model
cyclocondensation reaction between anthranilamide (1 mmol) and benzaldehyde (1 mmol) in the presence of SA
(10 mol%) under various reaction conditions. The results are illustrated in Table 1. The reaction in methanol is the best
(entry 1). However, the reaction time in water proceeded similar to that in methanol (entry 6). We have improved our
reaction to an environmentally friendly one. We then examined the generality of the reaction in methanol and water.
The results from the reactions of anthranilamide and various aldehydes and ketones in both MeOH and H2O are
shown in Table 2. As shown in entries 1–14, various aromatic aldehydes bearing either electron-donating or electron-
withdrawing groups on aromatic ring and terephthaldehyde aldehyde were investigated. The substitution groups on the
aromatic ring have no obvious effect on the yields and reaction time under the above optimal conditions. However,
aldehydes with strongly electron-withdrawing groups on aromatic ring gave the products with good yield in a long
reaction time (Table 2, entries 10 and 11). It is noteworthy that this synthetic method is efficient for the preparation of
bis-2-substituted-2,3-dihydroquinazolin-4(1H)-ones (Table 2, entry 14).
Most of the aldehydes gave almost the same results in MeOH and H2O, whereas in some cases, the yields of the
products in water tend to be decreased probably due to the lower solubility of starting material or intermediate in the
solvent. To expand the scope further investigations were carried out for condensation of ketones with anthranilamide
and the results were summarized in Table 2 (entries 15–17). In all cases, it was found that ketones can react well with
anthranilamide in good yields.
In order to shown activity of sulfamic acid in this transformation, we subject the condensation of 2-
nitrobenzaldehyde with anthranilamide in the absence of catalyst, the reaction did not occur even after prolonged
reaction time. Interestingly, the catalyst is recycled at least three times (in the case of benzaldehyde) without
considerable loss in its activity (Table 2, entry 1).
Finally, to investigation the feasibility of applying this method on a preparative scale, we performed the synthesis of
2-phenyl-2,3-dihydroquinazolin-4(1H)-one on a 50 mmol scale. As expected, the reaction proceeded, similar to the
case in a smaller scale (Table 2, entry 1).
Table 1
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones under different reaction conditions.
Entry
Reaction conditions
Time (min)
Conversion (%)
1
2
3
4
5
6
MeOH, rt
20
100
130
120
150
30
100
100
100
100
100
100
EtOH, reflux
CH3CN, reflux
CH2Cl2, reflux
n-Hexane, reflux
H2O, 70 8C

A. Rostami, A. Tavakoli / Chinese Chemical Letters 22 (2011) 1317–1320
1319
Table 2
Synthesis of 2,3-dihydroquinazolin-4(1H)-ones in the presence catalytic amount of SA under aqueousa or methanol.b
Entry
Aldehyde or Ketone
Product
Time (min)
Water
Yieldc (%)
Water
Mp (8C) (Ref.)
Methanol
Methanol
1
2
C6H5CHO
3a
3b
3c
3d
3e
3f
30
30
40
30
30
35
70
35
35
90
60
40
80
40
180
50
90
20
15
15
45
25
40
35
15
30
80
70
30
45
30
120
80
70
92, 86, 80d
89, 83, 78d
218–219 [15]
233–234 [15]
192–193 [15]
186–187 [15]
212–214 [12]
228–229 [15]
197–199 [19]
199–200 [15]
205–206 [20]
193–194 [15]
216–217 [15]
278–280 [15]
225–227
4-CH3 C6H4CHO
4-CH3OC6H4CHO
2,4-(CH3O)2C6H4 CHO
3,4-(CH3O)2C6H4CHO
4-(CH3)2 N C6H4CHO
4-Br C6H4 CHO
4-FC6H4 CHO
86
93
95
95
94
89
93
89
76
84
89
86
75e
57
85
78
84
85
80
92
89
89
89
95
84
78
91
93
77e
65f
81
80
3
4
5
6
7
3g
3h
3i
8
9
4-Cl C6H4 CHO
2-NO2 C6H4 CHO
3-NO2 C6H4 CHO
4-OH–C6H4 CHO
2-Naphthaldehyde
Terephthaldehyde
Acetophenone
10
11
12
13
14
15
16
17
3j
3k
3l
3m
3n
3o
3p
3q
243–245 [10]
227–228 [20]
224–226 [8]
183–184 [20]
Cyclohexanone
Acetone
a
Reaction conditions: anthranilamide (1 mmol), aldehyde or ketone (1 mmol), and SA (10 mol%, 10 mg), 70 8C.
Reaction conditions: anthranilamide (1 mmol), aldehyde or ketone (1 mmol), and SA (10 mol%, 10 mg), rt.
b
c
d
e
Isolated yield.
Catalyst was reused for 3 times.
Reaction conditions: in order to preparation of bis-2,3-dihydroquinazolin-4(1H)-one, anthranilamide (2 mmol), terephthaldehyde (1 mmol), and
SA (20 mol%, 20 mg).
f
Reaction in methanol were run under reflux condition.
To show merit of the present work in comparison with reported results in the literature, we compared our results on
the reaction of anthranilamide and benzaldehyde with data from the literature (Table 3). As shown in Table 3, the
previously reported procedures suffer from one or more disadvantages such as elevated reaction temperatures
[8,15,16,19], longer reaction times [19], using transition metal and expensive catalyst [14–16], special efforts for the
preparation of catalyst [8,14], and the need of organic solvents [15,16,18]. Therefore, we believe the present method to
be an improvement with respect to other procedures.
In summary, a very simple, efficient, cost-effective, and eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-
ones through direct cyclocondensation of anthranilamide and aryl aldehydes or ketones in the presence catalytic
amount of sulfamic acid with good to high yields in water or methanol has been devised. In addition, this method are
used for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones in both small and large scale.
General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones under aqueous conditions. In a round
bottomed flask, sulfamic acid (0.1 mmol, 0.010 g) was added to a mixture of anthranilamide (1 mmol, 0.136 g) and
aldehyde or ketone (1 mmol) in water (2 mL), and then themixturewas stirred at 70 8C fortheappropriate time (Table 2).
Table 3
Comparison of the activity of various catalysts in the reaction of anthranilamide and benzaldehyde.
Entry
Catalyst
Condition
Time (min)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
Ga(OTf)3 (1 mol%)
Sc(OTf)3 (5 mol%)
NH4Cl (5 mol%)
EtOH, 70 8C
EtOH, 70 8C
EtOH, rt
40
25
15
90
1.5
8
91
92
92
82
91
94
92
89
[15]
[16]
[18]
Bu4NBr (40 mol%)
PPA–SiO2 (1.25 mol%)
H3PW12O40 (0.1 mol%)
SA (10 mol%)
Solvent-free, 100 8C
Solvent-free, 70 8C
H2O, rt
[19]
[8]
[14]
H2O, 70 8C
MeOH, rt
30
20
This work
This work
SA (10 mol%)

1320
A. Rostami, A. Tavakoli / Chinese Chemical Letters 22 (2011) 1317–1320
After completion of the reaction which confirmed by TLC (eluent: n-hexane/ethyl acetate: 2/1), the crude product was
filtered off and recrystallized from ethanol to give pure product in good to high yields.
General procedure for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones in methanol. In a round bottomed flask,
sulfamic acid (0.1 mmol, 0.010 g) was added to a mixture of anthranilamide (1 mmol, 0.136 g) and aldehyde or ketone
(1 mmol) in methanol (2 mL), and then the mixture was stirred at room temperature for the appropriate time (Table 2).
After completion of the reaction which confirmed by TLC (eluent: n-hexane/ethyl acetate: 2/1), the crude product was
filtered off and recrystallized from ethanol to give products in good to high yields.
All of the obtained 2,3-dihydroquinazolin-4(1H)-ones are known compounds (expect product 3l) and their physical
data, IR and 1H NMR spectra were essentially identical with those of authentic samples. Compound 3l, which is new,
1
was characterized by IR, H NMR, 13C NMR, and MS spectroscopy and elemental analysis.
2-(2-Naphtyl)-2,3-dihydroquinazolin-4(1H)-one (Table 2, entry 13): white solid; mp: 225–227 8C; IR (film) nmax
(cmÀ1): 3282m, 3188w, 3065w, 2926w, 1649vs, 1611m, 1512m, 1486w, 1441w, 1390m, 1315m, 1158w, 825m, 747m.
1H NMR (DMSO-d6, 250 MHz): d 5.90 (s, 1H, CH), 6.6–8.2 (m, 12H, NH + Ar–H), 8.4 (s, 1H, NH). 13C NMR
(DMSO-d6, 62.9 MHz): d 67.41, 114.85, 115.38, 117.58, 125.28, 126.35, 126.70, 126.78, 127.82, 127.97, 128.37,
128.51, 132.91, 133.45, 133.70, 139.22, 148.33, 164.16; MS (EI, 70 eV, m/z): 275.1(M+H)+, 274.1(M+), 273.1
(MÀ1)+, 147, 120, 92; Anal. Calcd. for C18H14N2O: C 78.81, H 5.14, N 10.21; found, C 78.82, H 5.12, N 10. 25.
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