Cerous methanesulfonate catalyzed facile synthesis of 2-substituted-2,3- dihydro-4(1h)-quinazolinones by grinding technique

Article abstract of DOI:10.1002/jhet.963

2-Substituted-2,3-dihydro-4(1H)-quinazolinones were synthesized in high to excellent yields through direct cyclocondensation of 2-anthranilamide with aldehydes or ketones in the presence of a recyclable cerous methanesulfonate by grinding technique under aqueous conditions.

Full text of DOI:10.1002/jhet.963

1250
Cerous Methanesulfonate Catalyzed Facile Synthesis of
2-Substituted-2,3-dihydro-4(1h)-quinazolinones by
Grinding Technique
Vol 49
a
a
b
a
*
Min Wang, Jingjing Gao, Zhiguo Song, and Lei Wang
aCollege of Chemistry and Chemical Engineering, Bohai University, Jinzhou 121000, China
bCenter for Science and Technology Experiment, Bohai University, Jinzhou 121000, China
*
E-mail: minwangszg@yahoo.com.cn
Received January 27, 2011
DOI 10.1002/jhet.963
Published online 26 October 2012 in Wiley Online Library (wileyonlinelibrary.com).
2-Substituted-2,3-dihydro-4(1H)-quinazolinones were synthesized in high to excellent yields through
direct cyclocondensation of 2-anthranilamide with aldehydes or ketones in the presence of a recyclable
cerous methanesulfonate by grinding technique under aqueous conditions.
J. Heterocyclic Chem., 49, 1250 (2012)
INTRODUCTION
Today much emphasis is laid on the development of clean
synthetic procedures which avoids toxic and hazardous
chemicals and solvents. In our continuous work to explore
simple and eco-friendly procedures for the synthesis of
organic compounds, grinding technique has drawn our
attention because it provides simple manipulation, greater
selectivity, shorter reaction periods, and higher product
yields. Here, we report first a simple and efficient
method for the synthesis of 2-substituted-2,3-dihydro-4
(1H)-quinazolinones via direct cyclocondensation of
2-anthranilamide with aromatic aldehydes or ketones in the
presence of 1 mol % (based on 2-anthranilamide) cerous
methanesulfonate (Ce(MS)3) by grinding technique under
aqueous conditions. (Scheme 1).
2,3-Dihydro-4(1H)-quinazolinones are a class of fused
heterocycles that have drawn much attention due to their
potential biological and pharmaceutical activities such as
antibacterial [1], diuretic [2], and anticancer [3]. Some
2,3-dihydro-4(1H)-quinazolinones are herbicides and plant-
growth regulators [4, 5]. Furthermore, they could be easily
oxidized to 2-substituted-4(3H)-quinazolinones [6], which
are useful as growth inhibitor against leukemia cells [7] and
potent poly(ADP-ribose)polymerase-1 inhibitors [8]. Because
of the importance of 2,3-dihydro-4(1H)-quinazolinones
derivatives, the development of environmentally benign,
high-yielding, and clean synthesis of them is in demand.
In recent years, a number of methods for preparing
2-substituted-2,3-dihydro-4(1H)-quinazolinones have been
reported in the literature [9, 10]. The most common approach
involves condensation of 2-anthranilamide with structurally
diverse aldehydes or ketones in the presence of various
catalysts such as p-TSA [3], HCl [11], SmI2 [12], TiCl4-Zn
[13], Sc(OTf)3 [14], and NH4Cl [15]. In addition, some
modified procedures were also described. For example,
2-substituted-2,3-dihydro-4(1H)-quinazolinones could be
synthesized in ionic liquid without additional catalyst [16].
Xu et al. carried out these reactions in refluxing 2,2,2-
trifluoroethanol [17]. Wang et al. also reported that 2,3-
dihydro-4(1H)-quinazolinones could be obtained with
satisfied yields using heteropoly acid as a catalyst at room tem-
perature [18]. Though all of these reactions can obtain the
object, some of them associated with certain drawbacks such
as costly reagent, harmful solvent, large excess of raw material
and catalyst, and low yields. Moreover, all the reported
reactions were proceeded under uniform stirring conditions.
RESULTS AND DISCUSSION
At the onset of our research, we investigated the model
reaction between 2-anthranilamide and benzaldehyde at
room temperature under different reaction conditions
(Table 1). After screening four metal methanesulfonates,
Ce(MS)3 was determined to be the most effective catalyst,
because it provided the highest yield of the desired product
(entries 1–4). Compared with the reactions carried out with-
out solvent, the condensation in 1 mL of water provided a
higher yield (entry 5). In addition, the amount of catalyst
affected the reaction significantly. We observed that 1 mol
% Ce(MS)3 could catalyze the reaction efficiently and
diminishing the amount of catalyst decreased the yields
(entries 5 and 7). Further, the reusability of Ce(MS)3 was
investigated. When the reaction was completed, the reaction
mixture was washed with water. The catalyst remaining in
© 2012 HeteroCorporation

September 2012
Cerous Methanesulfonate Catalyzed Facile Synthesis of 2-Substituted-
1251
2,3-dihydro-4(1h)-quinazolinones by Grinding Technique
Scheme 1
aqueous phase could be recovered by evaporating the filtrate.
Then Ce(MS)3 was recovered and reused for four consecu-
tive reactions (entry 5). It demonstrated that Ce(MS)3 was
water-tolerant and recyclable for this condensation.
condensation of 2-anthranilamide 1 with aldehyde/ketone 2
promoted by Ce(MS)3 to produce intermediate 4. The
parts of carbonyl and imine in intermediate 4 could be
activated by Ce3+. Thus, intermediate 4 could be converted
to intermediate 5 by intramolecular nucleophile attack of
the nitrogen on imine carbon. Subsequently, 2-substituted-
2,3-dihydro-4(1H)-quinazolinones 3 could formed by a
1,5-proton transfer of 5.
In order to examine the scope and limitation of this
approach, we applied these optimal reaction conditions to a
variety of aldehydes and ketones. The results were illustrated
in Table 2. Generally, the cyclocondensation reaction
proceeded well and afforded the desired products 3a–3n in
good to excellent yields. The reaction was compatible with
a variety of electron-donating and electron-withdrawing
substituents in the aromatic aldehydes. Steric hindrance
seems to have no effects on the efficiency of this transforma-
tion. Besides aromatic aldehydes, cyclohexanone (3n) also
yielded the desired product. However, heteroaryl aldehyde
(3o) and aliphatic aldehyde (3p) could not afford the
corresponding products even if prolonged the reaction time
or elevated the reaction temperature.
In order to investigate the effect of grinding step on the
yield, we also carried out a reaction of 2-anthranilamide
with 2-nitrobenzaldehyde without grinding, that is to say
we heated the ungrounded reaction mixture at 60ꢀC in
the presence of catalyst and water directly after weighting.
After 0.5 h, only 23% yield was produced. The result
demonstrated that the grinding technique is very efficient
for synthesizing the title compounds.
CONCLUSIONS
In conclusion, a novel and environmentally benign
method for synthesizing 2-substituted-2,3-dihydro-4(1H)-
quinazolinones was achieved by using aqueous grinding
technique in the presence of Ce(MS)3. It features simple
operation, short reaction time, stoichiometric raw materials,
easy recyclable catalyst, mild reaction conditions, and good
yields. It makes a valuable contribution to the synthesis of
2-substituted-2,3-dihydro-4(1H)-quinazolinones.
EXPERIMENTAL
Melting points were determined using RY-1 micromelting
point apparatus. Infrared spectra were recorded on Scimitar 2000
series Fourier Transform instrument of VARIAN. 1H NMR spec-
tra were recorded on Bruker AV-500 spectrometer in DMSO-d6
using TMS as an internal standard. Mass spectra were obtained
with an Agilent 1100 series LC/MSD VL ESI instrument. Elemen-
tal analyses were carried out on EA 2400II elemental analyzer
(PerkinElmer) and agreed favorably with the calculated values.
Methanesulfonates were synthesized according to ref. 22.
A possible mechanism for this transformation is proposed
in Scheme 2 [21]. The first step may be involves the
Table 1
General procedure for the synthesis of 2-substituted-2,3-
dihydro-4(1H)-quinazolinones (3). To a equivalent mixture of a
2-anthranilamide 1 (5 mmol) and an aldehyde or ketone 2 (5 mmol)
was added Ce(MS)3 (0.05 mmol) and H2O (1 mL) in a mortar and
ground well with a pestle at room temperature. Then the mixture
(except 3a) was heated at 60ꢀC for appropriate time under
atmosphere. After completion of the reaction, as indicated by TLC
(ethyl acetate/n-hexane, 1/1), the reaction mixture was cooled to
room temperature. Water (15 mL) was added to the reaction
mixture, and the crystalline products were collected by filtration to
give the crude product. The crude products thus obtained were
crystallized from EtOH to give pure products. The catalyst
remaining in the aqueous phase could be recovered by evaporating
the filtrate. The pure products were identified by mp, IR, 1H NMR,
Screening of different reaction conditions for the condensation of
2‐anthranilamide with benzaldehyde.a
Entries
Catalyst (mol %)
Solvent (mL)
Yield (%)
1
2
3
4
5
6
7
Cu(MS)2·4H2O (1)
Al(MS)3·4H2O (1)
La(MS)3·2H2O (1)
Ce(MS)3·2H2O (1)
Ce(MS)3·2H2O (1)
Ce(MS)3·2H2O (1)
Ce(MS)3·2H2O
(0.5)
None
None
None
52
70
78
87
None
H2O (1)
H2O (2)
H2O (1)
91, 89, 88, 85
86
46
8
None
H2O (1)
11
aGrinding for 0.3 h at room temperature.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1252
M. Wang, J. Gao, Z. Song, and L. Wang
Vol 49
Table 2
Reactions of 2‐anthranilamide with diverse aldehydes or ketones in the presence of Ce(MS)3.
Mp (°C)
Entries
R1
R2
Time (h)a+b
Yield (%)
Found
Reported
224–226 19]
3a
3b
3c
3d
3e
3f
3g
3h
3i
C6H5‐
2‐NO2‐C6H4‐
3‐NO2‐C6H4‐
4‐NO2‐C6H4‐
2‐Cl‐C6H4‐
H
H
H
H
H
H
H
H
H
H
H
H
H
–
0.3 + 0
91
93
85
92
94
93
90
85
92
91
84
93
93
86
0
225–227
190–192
200–202
197–200
203–205
206–207
174–176
223–225
183–185
221–223
217–219
226–227
206–208
221–223
–
0.2 + 0.5
0.2 + 1.5
0.2 + 0.5
0.2 + 0.5
0.2 + 0.5
0.2 + 0.5
0.2 + 0.5
0.2 + 0.5
0.2 + 0.5
0.2 + 1.0
0.2 + 0.5
0.2 + 4.0
0.2 + 3.0
0.2 + 20
0.2 + 20
191–194 [19]
‐
‐
‐
4‐Cl‐C6H4‐
205–206 [17]
181–185 [20]
225–227 [12]
180–182 [12]
2,4‐Cl2‐C6H3‐
4‐CH3‐C6H4‐
4‐OCH3‐C6H4‐
2‐OH‐C6H4‐
3j
3k
3l
–
–
–
–
4‐OH‐C6H4‐
4‐OH‐3‐OCH3‐C6H3‐
4‐(CH3)2N‐C6H4‐
‐(CH2)5‐(spirocyclohexanyl)
2‐Furyl‐
3mc
3nc
3o
3p
225–226 [17]
H
H
–
–
CH3CH2‐
0
–
aGrinding time at room temperature.
bTime for reaction mixture kept at 60°C.
cThe molar ratio of 2‐anthranilamide to aldehyde/ketone is 1:1.3.
Scheme 2
MS, and elemental analysis. The characteristic data of some new 2-
substituted-2,3-dihydro-4(1H)-quinazolinones are given below:
2-(3-Nitrophenyl)-2,3-dihydro-4(1H)-quinazolinone (3c). Yellow
solid. IR (KBr): 3337, 3147, 1673, 1635, 1589, 1526, 1447, 1386,
NH), 7.57 (t, 1H, J = 6.2 Hz, ArH), 7.38 (t, 1H, J = 7.5 Hz, ArH),
7.26 (s, 1H, CH). MS (ESI): m/z (%) 270 (M++H, 100). Anal. Calcd.
for C14H11N3O3: C, 62.45; H, 4.12; N, 15.61. Found: C, 62.31; H,
4.09; N, 15.68.
1187, 971, 772 cmÀ1
.
1H NMR (500 MHz, DMSO-d6): d 8.76
2-(4-Nitrophenyl)-2,3-dihydro-4(1H)-quinazolinone (3d). Yellow
solid. IR (KBr): 3363, 3291, 1661, 1613, 1520, 1485, 1348, 1162,
(d, 2H, J = 7.4 Hz, ArH), 8.42 (t, 2H, J = 7.5 Hz, ArH), 7.97 (brs,
1H, NH─CO), 7.87 (dt, 2H, J = 6, 7.5 Hz, ArH), 7.62 (brs, 1H,
1
1012, 859, 753 cmÀ1. H NMR (500 MHz, DMSO-d6): d 8.53 (s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

September 2012
Cerous Methanesulfonate Catalyzed Facile Synthesis of 2-Substituted-
1253
2,3-dihydro-4(1h)-quinazolinones by Grinding Technique
1H, NH─CO), 8.27 (d, 2H, J = 8.6 Hz, ArH), 7.76 (d, 2H, J = 8.6
Hz, ArH), 7.64 (d, 1H, J = 7.6 Hz, ArH), 7.33 (s, 1H, NH), 7.29 (t,
1H, J = 7.4 Hz, ArH), 6.79 (d, 1H, J = 8.1 Hz, ArH), 6.71 (t, 1H, J =
7.4 Hz, ArH), 5.93 (s, 1H, CH). MS (ESI): m/z (%) 270 (M++H,
100). Anal. Calcd. for C14H11N3O3: C, 62.45; H, 4.12; N, 15.61.
Hz, ArH), 6.92 (s, 1H, NH), 6.75À6.65 (m, 4H, ArH), 5.64 (s,
1H, CH), 2.87 (s, 6H, N(CH3)2). MS (ESI): m/z (%) 268 (M++H,
100). Anal. Calcd. for C16H17N3O: C, 71.89; H, 6.41; N, 15.72.
Found: C, 72.07; H, 6.34; N, 15.80.
Found: C, 62.63; H, 4.15; N, 15.52.
2-(2-Chlorophenyl)-2,3-dihydro-4(1H)-quinazolinone (3e).
Acknowledgments. The authors grateful acknowledge the finan-
cial support of the Committee of Science and Technology of
Liaoning Province of China (No. 20091001) and the Education
Committee of Liaoning Province of China (No. 2009A033).
White solid. IR (KBr): 3362, 3196, 1647, 1614, 1503, 1330, 1188,
1
1054, 853, 745 cmÀ1. H NMR (500 MHz, DMSO-d6): d 8.21 (s,
1H, NH─CO), 7.67 (d, 2H, J = 7.8 Hz, ArH), 7.50À7.47 (m, 1H,
ArH), 7.41À7.38 (m, 2H, ArH), 7.27 (t, 1H, J = 6.8 Hz, ArH), 7.01
(s, 1H, NH), 6.77 (d, 1H, J = 7.8 Hz, ArH), 6.73 (dd, 1H, J = 6.8,
7.9 Hz, ArH), 6.14 (s, 1H, CH). MS (ESI): m/z (%) 259 (M++H,
100). Anal. Calcd. for C14H11N2OCl: C, 65.00; H, 4.29; N, 10.83.
Found: C, 65.17; H, 4.24; N, 10.78.
2-(2-Hydroxylphenyl)-2,3-dihydro-4(1H)-quinazolinone (3j).
White solid. IR (KBr): 3410, 3157, 1647, 1616, 1507, 1464, 1332,
1161, 843, 744 cmÀ1. 1H NMR (500 MHz, DMSO-d6): d 9.85 (s,
1H, NH─CO), 7.93 (s, 1H, NH), 7.64 (d, 1H, J = 7.0 Hz, ArH),
7.36 (d, 1H, J = 7.5 Hz, ArH), 7.24 (t, 1H, J = 7.1 Hz, ArH),
7.16 (t, 1H, J = 7.5 Hz, ArH), 6.88 (d, 1H, J = 8.0 Hz, OH),
6.81À6.74 (m, 3H, ArH), 6.68 (t, 1H, J = 7.5 Hz, ArH), 6.02 (s,
1H, CH). MS (ESI): m/z (%) 241 (M++H, 100). Anal. Calcd. for
C14H12N2O2: C, 69.99; H, 5.04; N, 11.66. Found: C, 70.14; H,
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5.01; N, 11.72.
2-(4-Hydroxylphenyl)-2,3-dihydro-4(1H)-quinazolinone (3k).
White solid. IR (KBr): 3338, 3184, 1670, 1605, 1523, 1490, 1288,
1237, 1185, 848, 766 cmÀ1. H NMR (500 MHz, DMSO-d6): d
1
9.52 (s, 1H, NH─CO), 8.14 (s, 1H, NH), 7.64 (d, 1H, J = 7.5
Hz, ArH), 7.33 (d, 2H, J = 8.5 Hz, ArH), 7.26 (t, 1H, J = 7.5 Hz,
ArH), 6.94 (t, 1H, J = 8.5 Hz, OH), 6.79À6.67 (m, 4H, ArH),
5.67 (s, 1H, CH). MS (ESI): m/z (%) 241 (M++H, 100). Anal.
Calcd. for C14H12N2O2: C, 69.99; H, 5.04; N, 11.66. Found: C,
69.83; H, 5.09; N, 11.73.
2-(4-Hydroxyl-3-methoxylphenyl)-2,3-dihydro-4(1H)-
quinazolinone (3l). White solid. IR (KBr): 3389, 3354, 1650,
1610, 1499, 1428, 1157, 1021, 860, 766 cmÀ1 1H NMR (500
.
MHz, DMSO-d6): d 9.06 (s, 1H, NH─CO), 8.09 (s, 1H, NH),
7.62 (d, 1H, J = 6.5 Hz, ArH), 7.25 (dd, 1H, J = 7.2, 8.0 Hz,
ArH), 7.09 (s, 1H, ArH), 6.94 (s, 1H, OH), 6.89 (d, 1H, J = 6.5
Hz, ArH), 6.77 (t, 2H, J = 8.1 Hz, ArH), 6.69 (t, 1H, J = 7.4 Hz,
ArH), 5.65 (s, 1H, CH), 3.76 (s, 3H, OCH3). MS (ESI): m/z (%)
271 (M++H, 100). Anal. Calcd. for C15H14N2O3: C, 66.66; H,
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5.22; N, 10.36. Found: C, 66.48; H, 5.25; N, 10.43.
2-(4-Dimethylaminophenyl)-2,3-dihydro-4(1H)-quinazolinone
(3m). Pale yellow solid. IR (KBr): 3295, 3192, 1655, 1615, 1509,
1487, 1355, 1189, 1065, 819, 754 cmÀ1 1H NMR (500 MHz,
.
DMSO-d6): d 8.07 (s, 1H, NH─CO), 7.63 (d, 1H, J = 7.5 Hz,
ArH), 7.31 (d, 2H, J = 8.6 Hz, ArH), 7.24 (dd, 1H, J = 7.2, 8.0
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet