Cerium(IV) ammonium nitrate catalyzed green synthesis of 2-substituted 2,3-dihydro-quinazolin-4(1H)-ones using a grinding technique

Article abstract of DOI:10.1007/s10593-011-0846-5

An efficient and facile method for the synthesis of 2-substituted 2,3-dihydro-quinazolin-4(1H)-ones from anthranilamide with aldehydes or ketones in the presence of cerium(IV) ammonium nitrate in water by a grinding technique has been developed. The structures of the new products were proved by IR, ¹H NMR, MS, and elemental analysis. A plausible mechanism for the formation of these products is proposed.

Full text of DOI:10.1007/s10593-011-0846-5

Chemistry of Heterocyclic Compounds, Vol. 47, No. 7, October 2011 (Russian original Vol. 47, No. 7, July, 2011)
CERIUM(IV) AMMONIUM NITRATE
CATALYZED GREEN SYNTHESIS
OF 2-SUBSTITUTED 2,3-DIHYDRO-
QUINAZOLIN-4(1H)-ONES
USING A GRINDING TECHNIQUE
1
1
2
1
M. Wang *, J. J. Gao , Z. G. Song , and L. Wang
An efficient and facile method for the synthesis of 2-substituted 2,3-dihydro-quinazolin-4(1H)-ones from
anthranilamide with aldehydes or ketones in the presence of cerium(IV) ammonium nitrate in water by a
1
grinding technique has been developed. The structures of the new products were proved by IR, H NMR,
MS, and elemental analysis. A plausible mechanism for the formation of these products is proposed.
Keywords: anthranilamide, cerium(IV) ammonium nitrate, 2,3-dihydroquinazolin-4(1H)-one, grinding
technique.
2
,3-Dihydroquinazolin-4(1H)-ones are a class of heterocycles that has attracted much attention because
they possess potential pharmaceutical activities [1–3]. They can be easily oxidized, using KMnO , to quinazolin-
(3H)-ones that are useful as growth inhibitor against leukemia cells [4] and potent poly(ADP-
ribose)polymerase-1 inhibitors [5].
4
4
A number of classical methods for the synthesis of 2,3-dihydroquinazolin-4(1H)-ones have been re-
ported in literature [3, 6–11]. For example, they were obtained by reductive cyclization of o-nitrobenzamide or
o-anthranilamide with aldehydes and ketones using p-TSA [3], HCl [6], SmI [7], TiCl –Zn [8], Sc(OTf) [9],
2
4
3
4 3
NH Cl [10], and H PW12O40 [11] as catalysts. There were also reports carrying out these reactions in ionic
liquids or 2,2,2-trifluoroethanol without catalyst [12, 13]. Despite the diverse routes developed so far, some of
them had to be performed in harmful organic solvent. All of the reported reactions were carried out under
uniform stirring conditions. Therefore, the development of an environmentally benign, high yielding, and novel
protocol for synthesizing 2,3-dihydroquinazolin-4(1H)-ones is significant.
Cerium(IV) ammonium nitrate (CAN), a versatile single-electron oxidant, has been widely used in or-
ganic transformations due to its many advantages such as high reactivity, commercial availability, ease of
_
*
______
To whom correspondence should be addressed, e-mail: minwangszg@yahoo.com.cn.
1
College of Chemistry, Chemical Engineering and Food Safety, Bohai University, Jinzhou 121000, P. R. China.
Center for Science & Technology Experiment, Bohai University, Jinzhou 121000, P. R. China.
2
_
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1039–1044, July, 2011. Original
article submitted March 18, 2011.
009-3122/11/4707-0851©2011 Springer Science+Business Media, Inc.
0
851

handling, and stability in different solvents. The use of this reagent for numerous transformations involving C–C,
C–O, C–N, and C–S bond formation has been described [14–20]. However, application of CAN is limited due to
its poor solubility in common organic solvents. Therefore, adopting water as the solvent is a good alternative.
Organic reactions in water have attracted much attention because water is cheap, abundant, and environmentally
benign. During the course of our studies on green chemistry, we discovered a new technique for the synthesis of
2
-substituted 2,3-dihydroquinazolin-4(1H)-ones, which involved the grinding of anthranilamide 1 with
aldehydes or ketones 2a–n in a mortar at room temperature in the presence of CAN and water (Scheme 1). Then,
the reaction mixture was kept at 60°C until completion of the reaction.
Scheme 1
O
O
O
NH2
CAN
NH
R
+
1
Grinding at rt,
then heat at 60°C
1
R
R
R
NH2
N
H
1
2a–n
3a–n
1
1
1
1
1
1
1
2
, 3 a–l,n R = H; m R + R = (CH
2
)
5
; a R = Ph, b R = 2-NO
2
C
6
H
4
, c R = 3-NO
2
C
6
H
4
, d R = 4-NO
2
C
6
H
4
, e R = 2-ClC
6
H
4
, f R = 4-ClC
6
H
4
,
1
1
1
1
1
1
1
g R = 2,4-Cl C H , h R = 4-MeC H , i R = 4-MeOC H , j R = 2-HOC H , k R = 4-HO-3-MeOC H , l R = 4-Me NC H , n R = Et
2
6
3
6
4
6
4
6
4
6
3
2
6
4
In our study, we first carried out a model reaction between anthranilamide 1 (5 mmol) and 4-nitro-
benzaldehyde 2d (5 mmol) in the presence of CAN to investigate the optimal reaction conditions. Initially, the
reaction mixture was ground well with a pestle at room temperature for 0.2 h. The grinding step is crucial for
this conversion because the likely formation of the melt phase on the solid particles facilitates chemical
reactions [21]. A much lower yield (27%) would be produced without the grinding step. After several trials, we
determined that the appropriate time for grinding is 0.2 h.
Different reaction temperatures, catalyst amounts, and water amounts were tried; the results are shown
in Table 1. It can be seen that the reaction temperature had obvious effect on the yields. The rate of substrate
conversion could be improved by increasing the reaction temperature (entries 1–4). However, when the reaction
temperature reached 80°C the reaction mixture solidified too fast to complete the reaction (entry 4). Therefore,
the suitable reaction temperature is 60°C. In addition, almost no product was produced in the absence of catalyst
(
entry 7). After these trials, the best result was obtained when the reaction was carried out at 60°C in the
presence of 0.5 mol% CAN and 2 ml water (entry 3).
TABLE 1. Condensation of Anthranilamide (1) and 4-Nitrobenzaldehyde
2d) under Various Conditions
(
o
Entry
T, C
Cat., mol%
Water, ml
Heating time, h*
Yield, %
1
2
3
4
5
6
7
8
9
20
40
60
80
60
60
60
60
60
60
0.5
0.5
0.5
0.5
1.0
0.2
0
2
2
2
2
2
2
2
0
1
3
1.5
1.5
1.5
1.0
1.5
1.5
1.5
1.5
1.5
1.5
13
67
94
88
96
62
Trace
75
0.5
0.5
0.5
87
1
0
83
_
________________
*
The reaction mixtures were ground at room temperature for 0.2 h first.
8
52

TABLE 2. Reactions of Anthranilamide 1 with Aldehydes or Ketones
a-n in the Presence of CAN
2
Grinding
time, h
Heating
time, h
Yield,
%
mp, °C
Compound
Found
Reported
3
3
a
0.3
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
–
93
90
97
94
93
92
93
92
94
90
95
81
62
—
225–227
190–192
200–202
198–200
202–204
204–206
174–176
224–225
183–185
222–224
219–221
203–205
225–226
—
224–226 [22]
b
1.5
1.0
1.5
1.0
1.0
1.0
2.0
1.5
2.0
1.0
2.0
2.5
8.0
191–194 [22]
3
c
—
3
d
—
—
3
e
3
f
205–206 [13]
181–185 [23]
225–227 [7]
180–182 [7]
—
3
3
g
h
3
i
3
j
3
k
—
3
l
—
3
m
225–226 [13]
—
3
n
To explore the scope and limitations of this reaction, we extended the cyclocondensation of anthranil-
amide 1 with various aromatic aldehydes, aliphatic aldehydes, and ketones. The results are summarized in Table
2
. Aromatic aldehydes carrying both electron-donating groups and electron-withdrawing groups were all
suitable for use, and steric effects did not influence the yield of products 3a–l. The condensation yield with
ketone 2m was lower than that with aromatic aldehydes (compound 3m). Furthermore, aliphatic aldehyde 2n
failed to give the desired product 3n.
Scheme 2
+
OH
O
O
Ce(IV)
R2
O
– H O
NH
2
NH2
NH2
R2
3
+
R2
1
1
H
N
R
N
H
NH2
1
R
Ce(IV)
R
5
1
2
4
The postulated mechanism for this reaction is shown in Scheme 2 [24]. The first step involves the con-
densation of anthranilamide 1 with aldehyde/ketone 2 promoted by catalyst to produce intermediate 4. The
4
+
amide part of the intermediate 4 could be activated by Ce . Thus, intermediate 4 could be converted to
intermediate 5 by intramolecular nucleophilic attack of the nitrogen on the imine carbon. Subsequently,
quinazolinones 3 could be formed by a 1,5-proton transfer of intermediate 5.
In conclusion, we have demonstrated that 2-substituted 2,3-dihydroquinazolin-4(1H)-ones can be syn-
thesized efficiently from 2-anthranilamide with aromatic aldehydes or ketones in the presence of CAN and water
by the grinding technique. The method is simple, novel, and environmentally benign. It may be an alternative to
the known literature methods.
8
53

EXPERIMENTAL
The IR spectra were recorded on a Varian Scimitar 2000 series Fourier Transform instrument in KBr.
1
13
H and C NMR spectra were recorded on a Bruker AV-500 spectrometer (500 and 125 MHz, respectively) in
DMSO-d using TMS as an internal standard. ESI mass spectra were obtained with an Agilent 1100 series
6
LC/MSD VL ESI instrument. Elemental analyses were carried out on a Perkin-Elmer EA 2400II elemental
analyzer. Melting points were determined using an RY-1 micromelting point apparatus (Tianjin Tianguang
Optical Instrument Limited Company, China).
Synthesis of 2-Substituted 2,3-Dihydroquinazolin-4(1H)-ones 3a–n (General method). To a mixture
of anthranilamide 1 (5 mmol) and the corresponding aldehyde or ketone 2a–n (5 mmol) in a mortar, CAN
(
0.025 mmol, 0.5 mol%) and water (2 ml) were added. The mixture was ground well with a pestle at room
temperature for an indicated time and then kept at 60°C in an oven under atmosphere for the appropriate time
Table 2) until the completion of reaction, as indicated by TLC (ethyl acetate–n-hexane, 1:1). The reaction
(
mixture was cooled to room temperature and was washed thoroughly with water during vacuum filtration. The
products were purified further by crystallization from ethanol.

1
2
-(3-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3c). Yellow solid. IR spectrum, , cm : 3337,
1
3
147, 1674, 1636, 1589, 1526, 1447, 1386, 1187, 971, 772. H NMR spectrum, , ppm (J, Hz): 8.76 (2H, d,
J = 7.4, H Ar); 8.42 (2H, t, J = 7.5, H Ar); 7.97 (1H, br. s, CONH); 7.87 (2H, dt, J = 6.0, J = 1.5, H Ar); 7.62
1
3
(
1H, br. s, NH); 7.57 (1H, dt, J = 6.2, J = 1.4, H Ar); 7.38 (1H, t, J = 7.5, H Ar); 7.26 (1H, s, CH). C NMR
spectrum, , ppm: 163.3; 147.7; 147.2; 144.2; 133.5; 133.3; 129.9; 127.4; 123.2; 121.5; 117.5; 114.9; 114.5;
+
6
5.2. Mass spectrum, m/z (I , %): 270 [M+H] (100). Found, %: C 62.56; H 4.17; N 15.49. C H N O .
rel 14 11 3 3
Calculated, %: C 62.45; H 4.12; N 15.61.
-(4-Nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (3d). Yellow solid. IR spectrum, , cm : 3363,

1
2
1
3
291, 1661, 1613, 1521, 1486, 1348, 1162, 1012, 859, 753. H NMR spectrum, , ppm (J, Hz): 8.53 (1H, s,
CONH); 8.27 (2H, d, J = 8.6, H Ar); 7.76 (2H, d, J = 8.6, H Ar); 7.64 (1H, d, J = 7.6, H Ar); 7.33 (1H, s, NH);
13
7
.29 (1H, t, J = 7.4, H Ar); 6.79 (1H, d, J = 8.1, H Ar); 6.71 (1H, t, J = 7.4, H Ar); 5.93 (1H, s, CH). C NMR
spectrum, , ppm: 163.2; 149.2; 147.4; 147.2; 133.4; 127.9; 127.3; 123.5; 117.4; 114.8; 114.5; 65.2. Mass
+
spectrum, m/z (I , %): 270 [M+H] (100). Found, %: C 62.57; H 4.05; N 15.53. C H N O . Calculated, %:
rel
14 11
3
3
C 62.45; H 4.12; N 15.61.
1
2
-(2-Chlorophenyl)-2,3-dihydroquinazolin-4(1H)-one (3e). White solid. IR spectrum, , cm : 3362,
1
3
7
197, 1647, 1614, 1504, 1330, 1188, 1054, 853, 745. H NMR spectrum, , ppm (J, Hz): 8.21 (1H, s, CONH);
.67 (2H, d, J = 7.8, H Ar); 7.50−7.47 (1H, m, H Ar); 7.41−7.38 (2H, m, H Ar); 7.27 (1H, t, J = 6.8, H Ar); 7.01
1
3
(
1H, s, NH); 6.78 (1H, d, J = 7.8, H Ar); 6.73–6.99 (1H, m, H Ar); 6.14 (1H, s, CH). C NMR spectrum, ,
ppm: 163.5; 147.6; 137.8; 133.3; 131.8; 130.2; 129.5; 128.6; 127.4; 127.3; 117.4; 114.6; 114.5; 63.6. Mass
+
spectrum, m/z (I , %): 259 [M+H] (100). Found, %: C 65.12; H 4.34; N 10.74. C H ClN O. Calculated, %:
rel
14 11
2
C 65.00; H 4.29; N 10.83.
1
2
-(2-Hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3j). White solid. IR spectrum, , cm : 3410,
1
3
7
157, 1648, 1616, 1508, 1464, 1332, 1161, 843, 744. H NMR spectrum, , ppm (J, Hz): 9.85 (1H, s, CONH);
.93 (1H, s, NH); 7.64 (1H, d, J = 7.0, H Ar); 7.36 (1H, d, J = 7.5, H Ar); 7.24 (1H, t, J = 7.1, H Ar); 7.16 (1H,
t, J = 7.5, H Ar); 6.88–6.86 (1H, m, OH); 6.81−6.74 (3H, m, H Ar); 6.68 (1H, t, J = 7.5, H Ar); 6.01 (1H, s,
1
3
CH). C NMR spectrum, , ppm: 163.9; 148.0; 135.0; 133.1; 129.2; 127.2; 127.1; 127.0; 118.7; 116.9; 115.3;
+
1
14.7; 114.5; 61.2. Mass spectrum, m/z (Irel, %): 241 [M+H] (100). Found, %: C 69.83; H 5.09; N 11.74.
C H N O . Calculated, %: C 69.99; H 5.04; N 11.66.
1
4
12
2
2
2
-(4-Hydroxy-3-methoxyphenyl)-2,3-dihydroquinazolin-4(1H)-one (3k). White solid. IR spectrum,
1
1

, cm : 3389, 3354, 1650, 1610, 1500, 1428, 1157, 1021, 860, 766. H NMR spectrum, , ppm (J, Hz): 9.06
(
1H, s, CONH); 8.09 (1H, s, NH); 7.62 (1H, dd, J = 6.5, J = 1.2, H Ar); 7.25 (1H, m, H Ar); 7.09 (1H, d, J = 1.2,
H Ar); 6.94 (1H, s, OH); 6.89 (1H, dd, J = 6.5, J = 1.5, H Ar); 6.77 (2H, t, J = 8.1, H Ar); 6.69 (1H, t, J = 7.4,
13
H Ar); 5.65 (1H, s, CH); 3.76 (3H, s, OCH ). C NMR spectrum, , ppm: 167.2; 149.3; 147.8; 133.2; 132.1;
3
8
54

+
1
31.9; 129.8; 128.9; 127.9; 127.3; 117.0; 114.9; 114.3; 66.5; 56.0. Mass spectrum, m/z (Irel, %): 271 [M+H]
(
100). Found, %: C 66.75; H 5.14; N 10.27. C H N O . Calculated, %: C 66.66; H 5.22; N 10.36.
15
14
2
3
2
-(4-Dimethylaminophenyl)-2,3-dihydroquinazolin-4(1H)-one (3l). Pale-yellow solid. IR spectrum,
1
1

, cm : 3295, 3192, 1655, 1615, 1509, 1487, 1356, 1189, 1066, 819, 754. H NMR spectrum, , ppm (J, Hz):
8
.07 (1H, s, CONH); 7.63 (1H, d, J = 7.5, H Ar); 7.31 (2H, d, J = 8.6, H Ar); 7.24–7.21 (1H, m, H Ar); 6.91
13
(
1H, s, NH); 6.75−6.65 (4H, m, H Ar); 5.64 (1H, s, CH); 2.86 (6H, s, N(CH ) ). C NMR spectrum, , ppm:
3
2
1
63.7; 150.6; 148.1; 133.0; 128.6; 127.6; 127.2; 116.8; 115.0; 114.3; 111.8; 66.6; 40.1. Mass spectrum, m/z
+
(I , %): 268 [M+H] (100). Found, %: C 72.01; H 6.35; N 15.80. C H N O. Calculated, %: C 71.89; H 6.41;
rel 16 17 3
N 15.72.
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