Green synthesis of quinazolinone derivatives catalyzed by iodine in ionic liquid

Article abstract of DOI:10.1080/00397911.2010.524340

A series of quinazolinone derivatives were synthesized by the reaction of 2-aminobenzamides and triethyl orthoformate or triphosgene in ionic liquid of [BMIm]BF4 at 80 °C catalyzed by iodine in good yields. Compared to other methods, this new procedure has the advantages of mild reaction conditions, good yields, operational simplicity, and environmentally friendly procedure. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.524340

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Green Synthesis of Quinazolinone
Derivatives Catalyzed by Iodine in Ionic
Liquid
Shu-Liang Wang a , Ke Yang a , Chang-Sheng Yao a & Xiang-Shan Wang
a
a School of Chemistry and Chemical Engineering , Xuzhou Normal
University, Key Laboratory of Biotechnology on Medical Plant ,
Xuzhou Jiangsu , China
Accepted author version posted online: 20 Jul 2011.Published
online: 06 Oct 2011.
To cite this article: Shu-Liang Wang , Ke Yang , Chang-Sheng Yao & Xiang-Shan Wang (2012) Green
Synthesis of Quinazolinone Derivatives Catalyzed by Iodine in Ionic Liquid, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 42:3, 341-349, DOI:
10.1080/00397911.2010.524340
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Synthetic Communications1, 42: 341–349, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.524340
GREEN SYNTHESIS OF QUINAZOLINONE
DERIVATIVES CATALYZED BY IODINE IN IONIC LIQUID
Shu-Liang Wang, Ke Yang, Chang-Sheng Yao, and
Xiang-Shan Wang
School of Chemistry and Chemical Engineering, Xuzhou Normal University,
Key Laboratory of Biotechnology on Medical Plant, Xuzhou Jiangsu, China
GRAPHICAL ABSTRACT
Abstract A series of quinazolinone derivatives were synthesized by the reaction of
2-aminobenzamides and triethyl orthoformate or triphosgene in ionic liquid of [BMIm]BF4
at 80 ꢀC catalyzed by iodine in good yields. Compared to other methods, this new procedure
has the advantages of mild reaction conditions, good yields, operational simplicity, and
environmentally friendly procedure.
Keywords 2-Aminobenzamides; ionic liquid; quinazolinone; synthesis
INTRODUCTION
Quinazolinone and its derivatives are important compounds for their wide range
of biological activities.[1] These include anti-inflammatory,[2] antihypertensive,[3]
anticancer,[4] antitumor,[5] and antibacterial activity.[6] Therefore, the synthesis of
quinazolinone derivatives is currently of great interest. Although many methods[7]
have been reported for the synthesis of quinazolinones in the literature, the known
methods are not straightforward and involve various disadvantages, such as poor
yields, prolonged reaction times, and the use of toxic organic reagents.
Room-temperature ionic liquids,[8] especially those based on the 1-N-alkyl-3-
methyl imidazolium cation, have attracted much attention in recent years as alterna-
tive green reaction media because of their unique chemical and physical properties
of nonvolatility, nonflammability, thermal stability, and controlled miscibility.
Therefore, room-temperature ionic liquids have found growing applications in
organic reactions. Several examples of these reactions include hydrogenations,[9]
Received March 9, 2010.
Address correspondence to Xiang-Shan Wang, School of Chemistry and Chemical Engineering,
Xuzhou Normal University, Key Laboratory of Biotechnology on Medical Plant, Xuzhou Jiangsu
221116, China. E-mail: xswang1974@yahoo.com
341

342
S.-L. WANG ET AL.
Friedel–Crafts reactions,[10] Heck reactions,[11] Bishler–Napieralski reactions,[12]
olefin hydrodimerizations,[13] and olefin dimerizations.[14]
As a part of a program toward the synthesis of suitably functionalized hetero-
cyclic compounds of potential biological activity in green media,[15] herein we report
a green synthesis of quinazolinone derivatives by the reaction of 2-aminobenzamides
and triethyl orthoformate or triphosgene in ionic liquid of [BMIm]BF4 catalyzed by
iodine at 80 ꢀC.
RESULTS AND DISCUSSION
When the reaction of 2-aminobenzamides 1 and triethyl orthoformate 2 was
performed in ionic liquid of [BMIm]BF4 at 80 ꢀC in the presence of 5 mol% iodine,
good yields of quinazolin-4(3H)-one derivatives 3 were obtained (Scheme 1).
At completion as monitored by thin-layer chromatography (TLC), the reaction
mixture was allowed to cool to room temperature. A little amount of water was
added to the mixture, and the crude product was isolated by filtration. The water
in the filtrate was removed by distillation under reduced pressure, and the ionic
liquid in the residue was then recovered for reuse by evaporation at 80 ꢀC for several
hours in vacuum. Investigations using triethyl orthoformate and 2-aminobenzamide
as model substrates showed the successive reuse of the recycled ionic liquid. Even in
the fourth round, the yield of the product 3a is fairly high (89%).
Scheme 1. Iodine-catalyzed reactions of 1 and 2 in ionic liquid.
Table 1. Synthetic results of 3 in ionic liquid at 80 ꢀC catalyzed by iodinea
Entry
R
Products Time (min) Isolated yields (%)
1
2
H
4-MeC6H4
3a
3b
3c
3d
3e
3f
40
35
30
50
45
30
45
45
30
30
30
30
90
93
98
95
95
98
99
87
90
92
98
90
3
4-MeOC6H4
4-FC6H4
C6H5
4
5
6
C6H5CH2
4-CH3OC6H4CH2
4-i-PrC6H4
7
3g
3h
3i
8
9
4-MeC6H4CH2
3,4-OCH2OC6H3CH2CH2
3-n-Bu
10
11
12
3j
3k
3l
2-FurylCH2
aReaction condition: [BMIm]BF4 (2 mL), 1 (2 mmol), 2 (0.311 g, 2.1 mmol),
iodine (0.026 g, 0.1 mmol), 80 ꢀC.

GREEN SYNTHESIS OF QUINAZOLINONE DERIVATIVES
343
Table 2. Synthetic results of 5 catalyzed by iodine in ionic liquida
Entry
R
Products
Time (min)
Isolated yields (%)
1
2
3
4
5
6
7
8
H
C6H5
5a
5b
5c
5d
5e
5f
45
45
30
45
30
45
60
60
92
98
98
93
95
90
92
93
Cyclohexyl
4-FC6H4
4-CH3OC6H4
C6H5CH2
4-CH3OC6H4CH2
4-MeC6H4
5g
5h
aReaction condition: [BMIm]BF4 (2 mL), 1 (2 mmol), 4 (0.296 g, 1 mmol),
iodine (0.026 g, 0.1 mmol), 80 ꢀC.
Scheme 2. Iodine-catalyzed reactions of 1 and 4 in ionic liquid.
To demonstrate the efficiency and the applicability of the present method, we
performed the reactions of a variety of 2-aminobenzamides 1 with 2 at 80 ꢀC in the
presence of iodine in [BMIm]BF4. As shown in Table 1, a series of 2-aminobenzamides
1 reacted well with 2 to give the corresponding products 3 in good yields under the same
reaction conditions. For aldehyde 1, the yields of 3 were not sensitive to the electronic
properties of the aromatic ring in the presence of electron-withdrawing groups (such as
halide) or electron-donating groups (such as alkyl and alkoxyl group) (Table 1).
To obtain quinazoline-2,4(1H,3H)-dione derivatives, triphosgene 4 was selec-
ted to react with 2-aminobenzamides instead of triethyl orthoformate. As expected,
3-substited quinazoline-2,4(1H,3H)-diones 5 were isolated in good yields (Table 2) in
the same reaction conditions (Scheme 2).
CONCLUSION
In conclusion, we found a green method for the syntheses of quinazolinone
derivatives by the reactions of 2-aminobenzamides and triethyl orthoformate or tri-
phosgene at 80 ꢀC in ionic liquid catalyzed by iodine. The features of this procedure
are mild reaction conditions, good yields, operational simplicity, and environmen-
tally friendly procedure. Meanwhile, [BMIm]BF4 could be reused for several rounds
without significant loss of activity.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
1
Infrared (IR) spectra were recorded on a Tensor 27 spectrometer in KBr. H NMR

344
S.-L. WANG ET AL.
spectra were obtained from solution in dimethylsulfoxide (DMSO-d6) with Me4Si
as internal standard using a Bruker-400 spectrometer. High-resolution mass
spectrographic (HRMS) analyses were carried out using a Bruker-micro-TOF-
Q-MS analyzer.
General Procedure for the Syntheses of Quinazolin-4(3H)-one
Derivatives
A dry 50-mL flask was charged with triethyl orthoformate (0.311 g, 2.1 mmol),
2-aminobenzamides (2.0 mmol), and ionic liquid of [BMIm]BF4 (2 mL). The reaction
mixture was stirred at 80 ꢀC for 30–50 min and then cooled to room temperature. A
little amount of water (5 mL) was added to the mixture, and the generated solid was
filtered off. The water in the filtrate was removed by distillation under reduced press-
ure, and the ionic liquid in the residue was then recovered for reuse by evaporating at
80 ꢀC for 4 h in a vacuum. The crude yellow products were washed with water and
purified by recrystallization from 95% EtOH to give 3.
Selected Data
Quinazolin-4(3H)-one 3a. Mp 212–214 ꢀC. 1H NMR (DMSO-d6, 400 MHz):
d
H 7.51–7.55 (m, 1H, ArH), 7.67 (d, J ¼ 8.4 Hz, 1H, ArH), 7.80–7.84 (m, 1H, ArH),
8.11–8.14 (m, 2H, ArH þ CH), 12.25 (s, 1H, NH); IR (KBr): 3134, 3043, 1704, 1666,
1611, 1468, 1388, 1326, 1255, 1234, 1170, 921, 826, 807, 764, 684 cmꢁ1. HRMS (ESI,
m=z): calcd. for C8H6N2ONa (M þ Naþ) 169.0378; found 169.0382.
3-p-Tolylquinazolin-4(3H)-one 3b. Mp 144–145 ꢀC (lit.[7k] 146–147 ꢀC).
1H NMR (DMSO-d6, 400 MHz): dH 2.39 (s, 3H, CH3), 7.36 (d, J ¼ 8.0 Hz, 1H,
ArH), 7.42 (d, J ¼ 8.0 Hz, 2H, ArH), 7.57–7.61 (m, 1H, ArH), 7.74 (d, J ¼ 8.0 Hz,
1H, ArH), 7.86–7.90 (m, 1H, ArH), 8.20 (dd, J ¼ 8.0 Hz, J ¼ 0.8 Hz, 1H, ArH),
8.32 (s, 1H, CH); IR (KBr): 3032, 2915, 1691, 1642, 1599, 1564, 1513, 1471, 1407,
1324, 1293, 1259, 1190, 1112, 917, 816, 771, 749, 694 cmꢁ1. HRMS (ESI, m=z):
Calcd. for C15H12N2ONa (M þ Naþ) 259.0847; found 259.0852.
3-(4-Methoxyphenyl)quinazolin-4(3H)-one 3c. Mp 193–194 ꢀC (lit.[7k]
189–191 ꢀC). 1H NMR (DMSO-d6, 400 MHz): dH 3.84 (s, 3H, OCH3), 7.10 (d,
J ¼ 8.8 Hz, 2H, ArH), 7.47 (d, J ¼ 8.8 Hz, 2H, ArH), 7.58–7.62 (m, 1H, ArH), 7.74
(d, J ¼ 8.0 Hz, 1H, ArH), 7.86–7.90 (m, 1H, ArH), 8.20 (d, J ¼ 7.6 Hz, 1H, ArH),
8.31 (s, 1H, CH); IR (KBr): 3044, 2955, 1682, 1613, 1565, 1516, 1470, 1442, 1414,
1324, 1288, 1264, 1214, 1181, 1113, 1036, 917, 831, 769,750, 694 cmꢁ1. HRMS
(ESI, m=z): calcd. for C15H12N2O2Na (M þ Naþ) 275.0796; found 275.0788.
3-(4-Fluorophenyl)quinazolin-4(3H)-one 3d. Mp 204–206 ꢀC. 1H NMR
(DMSO-d6, 400 MHz): dH 7.12 (d, J ¼ 8.8 Hz, 2H, ArH), 7.45 (d, J ¼ 8.8 Hz, 2H,
ArH), 7.60 (t, J ¼ 7.6 Hz, 1H, ArH), 7.74 (d, J ¼ 8.8 Hz, 1H, ArH), 7.88 (t,
J ¼ 7.6 Hz, 1H, ArH), 8.20 (d, J ¼ 7.6 Hz, 1H, ArH), 8.31 (s, 1H, CH); IR (KBr):
3067, 1665, 1611, 1564, 1511, 1469, 1419, 1405, 1327, 1293, 1261, 1225, 1185,
1161, 1143, 1113, 1019, 927, 914, 774, 751, 696 cmꢁ1. HRMS (ESI, m=z): calcd.
for C14H9FN2ONa (M þ Naþ) 263.0597; found 263.0594.

GREEN SYNTHESIS OF QUINAZOLINONE DERIVATIVES
345
3-Phenylquinazolin-4(3H)-one 3e. Mp 141–142 ꢀC (lit.[7k] 139–140 ꢀC).
1H NMR (DMSO-d6, 400 MHz): dH 7.52–7.63 (m, 6H, ArH), 7.76 (d, J ¼ 8.0 Hz,
1H, ArH), 7.88–7.92 (m, 1H, ArH), 8.22 (dd, J ¼ 8.0 Hz, J0 ¼ 0.8 Hz, 1H, ArH),
8.36 (s, 1H, CH); IR (KBr): 3050, 2938, 1728, 1666, 1608, 1589, 1478, 1443, 1393,
1328, 1297, 1265, 1238, 1158, 1070, 1024, 918, 772, 748, 700 cmꢁ1. HRMS (ESI,
m=z): calcd. for C14H10N2ONa (M þ Naþ) 245.0691; found 245.0683.
3-Benzylquinazolin-4(3H)-one 3f. Mp 119–120 ꢀC (lit.[7k] 117–118 ꢀC).
1H NMR (DMSO-d6, 400 MHz): dH 5.21 (s, 2H, CH2), 7.26–7.39 (m, 5H, ArH),
7.52–7.56 (m, 1H, ArH), 7.70 (d, J ¼ 8.0 Hz, 1H, ArH), 7.80–7.84 (m, 1H, ArH),
8.16 (dd, J ¼ 8.0 Hz, J0 ¼ 0.8 Hz, 1H, ArH), 8.60 (s, 1H, CH); IR (KBr): 3065,
3036, 2988, 2945, 1678, 1606, 1561, 1474, 1441, 1412, 1366, 1319, 1257, 1226,
1209, 1149, 1102, 1076, 1025, 938, 915, 869, 776, 747, 701, 691 cmꢁ1. HRMS (ESI,
m=z): calcd. for C15H12N2ONa (M þ Naþ) 259.0847, found 259.0856.
1
3-(4-Methoxybenzyl)quinazolin-4(3H)-one 3g. Mp 134–135 ꢀC. H NMR
(DMSO-d6, 400 MHz): dH 3.72 (s, 3H, OCH3), 5.13 (s, 2H, CH2), 6.90 (d, J ¼ 8.8 Hz,
2H, ArH), 7.36 (d, J ¼ 8.8 Hz, 2H, ArH), 7.55 (t, J ¼ 7.6 Hz, 1H, ArH), 7.68 (d,
J ¼ 8.0 Hz, 1H, ArH), 7.80–7.84 (m, 1H, ArH), 8.16 (dd, J ¼ 8.0 Hz, J0 ¼ 0.8 Hz, 1H,
ArH), 8.58 (s, 1H, CH); IR (KBr): 3058, 3001, 2956, 2913, 2837, 1665, 1610, 1563,
1513, 1471, 1368, 1323, 1293, 1245, 1184, 1165, 1103, 1026, 959, 817, 769, 694 cmꢁ1
.
HRMS (ESI, m=z): calcd. for C16H14N2O2Na (M þ Naþ) 289.0953; found 289.0964.
1
3-(4-i-Propylphenyl)quinazolin-4(3H)-one 3h. Mp 126–127 ꢀC. H NMR
(DMSO-d6, 400 MHz): dH 1.27 (d, J ¼ 2.8 Hz, 6H, 2CH3), 2.97–3.04 (m, 1H, CH),
7.43–7.47 (m, 4H, ArH), 7.61 (t, J ¼ 7.6 Hz, 1H, ArH), 7.74–7.60 (m, 1H, ArH),
7.87–7.91 (m, 1H, ArH), 8.21 (d, J ¼ 7.6 Hz, 1H, ArH), 8.35 (s, 1H, CH); IR
(KBr): 3051, 2960, 2925, 2870, 1680, 1614, 1598, 1562, 1509, 1473, 1423, 1324,
1294, 1257, 1185, 1112, 1022, 913, 845, 816, 771, 696 cmꢁ1. HRMS (ESI, m=z): calcd.
for C17H16N2NaO (M þ Naþ) 287.1160; found 287.1167.
3-(4-Methylbenzyl)quinazolin-4(3H)-one 3i. Mp 133–135 ꢀC. 1H NMR
(DMSO-d6, 400 MHz): dH 2.26 (s, 3H, CH3), 5.16 (s, 2H, CH2), 7.15 (d, J ¼ 8.0 Hz,
2H, ArH), 7.27 (d, J ¼ 8.0 Hz, 2H, ArH), 7.56 (t, J ¼ 7.6 Hz, 1H, ArH), 7.67 (d,
J ¼ 8.0 Hz, 1H, ArH), 7.84 (t, J ¼ 7.2 Hz, 1H, ArH), 8.16 (d, J ¼ 8.0 Hz, 1H, ArH),
8.56 (s, 1H, CH); IR (KBr): 3030, 2985, 2942, 2922, 2861, 1672, 1607, 1563, 1517,
1471, 1360, 1321, 1291, 1254, 1173, 1154, 1101, 942, 782, 699, 573 cmꢁ1. HRMS
(ESI, m=z): calcd. for C16H14N2NaO (M þ Naþ) 273.1004; found 273.1015.
3-(2-(3,4-Methylenedioxyphenyl)ethyl)quinazolin-4(3H)-one 3j. Mp 129–
1
130 ꢀC. H NMR (DMSO-d6, 400 MHz): dH 2.94 (t, J ¼ 7.2 Hz, 2H, CH2), 4.18
(t, J ¼ 7.2 Hz, 2H, CH2), 5.98 (s, 2H, CH2), 6.22 (d, J ¼ 8.0 Hz, 1H, ArH), 6.80
(d, J ¼ 8.0 Hz, 1H, ArH), 6.87 (s, 1H, ArH), 7.56 (t, J ¼ 7.6 Hz, 1H, ArH), 7.65 (d,
J ¼ 8.0 Hz, 1H, ArH), 7.80–7.84 (m, 1H, ArH), 8.15 (s, 1H, CH), 8.18 (d, J ¼ 8.0 Hz,
1H, ArH); IR (KBr): 3056, 2977, 2947, 2898, 2777, 1665, 1612, 1561, 1504, 1488,
1443, 1366, 1326, 1270, 1245, 1202, 1156, 1041, 926, 879, 856, 774, 701, 606 cmꢁ1
.
HRMS (ESI, m=z): calcd. for C17H14N2NaO3 (M þ Naþ) 317.0902; found 317.0921.
1
3-(n-Butyl)quinazolin-4(3H)-one 3k. Mp 70–72 ꢀC. H NMR (DMSO-d6,
400 MHz): dH 0.92 (t, J ¼ 7.6 Hz, 3H, CH3), 1.29–1.35 (m, 2H, CH2), 1.64–1.72

346
S.-L. WANG ET AL.
(m, 2H, CH2), 3.98 (t, J ¼ 7.6 Hz, 2H, CH2), 7.53–7.57 (m, 1H, ArH), 7.68
(d, J ¼ 8.0 Hz, 1H, ArH), 7.81–7.85 (m, 1H, ArH), 8.16 (d, J ¼ 8.0 Hz, 1H, ArH),
8.40 (s, 1H, CH); IR (KBr): 3061, 2955, 2930, 2869, 1670, 1612, 1561, 1472, 1372,
1326, 1289, 1256, 1175, 1143, 1107, 937, 876, 768, 696 cmꢁ1. HRMS (ESI, m=z):
calcd. for C12H14N2NaO (M þ Naþ) 225.1004; found 225.1010.
1
3-((Furan-2-yl)methyl)quinazolin-4(3H)-one 3l. Mp 128–129 ꢀC. H NMR
(DMSO-d6, 400 MHz): dH 5.24 (s, 2H, CH2), 6.43–6.48 (m, 2H, ArH), 7.55–7.58
(m, 1H, ArH), 7.62 (s, 1H, ArH), 7.68–7.71 (m, 1H, ArH), 7.82–7.86 (m, 1H,
ArH), 8.16 (d, J ¼ 8.0 Hz, 1H, ArH), 8.49 (s, 1H, CH); IR (KBr): 3105, 3069,
3053, 2938, 1671, 1612, 1561, 1499, 1474, 1355, 1318, 1261, 1178, 1157, 951, 775,
759, 689, 601 cmꢁ1. HRMS (ESI, m=z): calcd. for C13H10N2NaO2 (M þ Naþ)
249.0640; found 249.0655.
General Procedure for the Syntheses of 3-Substituted
Quinazoline-2,4(1H,3H)-diones
A dry 50-mL flask was charged with triphosgene (1.0 mmol), 2-aminobenza-
mides (2.0 mmol), and ionic liquid of [BMIm]BF4 (2 mL). The reaction mixture
was stirred at 80 ꢀC for 30–60 min and then cooled to room temperature. A little
amount of water (5 mL) was added to the mixture, and the generated solid was
filtered off. The water in the filtrate was removed by distillation under reduced
pressure, and the ionic liquid in the residue was then recovered by evaporating at
80 ꢀC for 4 h in a vacuum. The crude yellow products were washed with water and
purified by recrystallization from 95% EtOH to give 5.
Selected Data
1
Quinazoline-2,4(1H,3H)-dione 5a. Mp >300 ꢀC (lit.[71] >300 ꢀC). H NMR
(DMSO-d6, 400 MHz): dH 7.16–7.20 (m, 2H, ArH), 7.62–7.66 (m, 1H, ArH), 7.89
(d, J ¼ 7.6 Hz, 1H, ArH), 11.16 (s, 1H, NH), 11.30 (s, 1H, NH); IR (KBr): 3210,
3165, 3056, 1704, 1662, 1618, 1506, 1484, 1444, 1405, 1300, 1141, 1039, 859, 779,
757, 684 cmꢁ1
.
3-Phenylquinazoline-2,4(1H,3H)-dione 5b. Mp 280–282 ꢀC (lit.[7m] 280–
282 ꢀC). 1H NMR (DMSO-d6, 400 MHz): (dH 7.22–7.25 (m, 2H, ArH), 7.33
(d, J ¼ 6.8 Hz, 2H, ArH), 7.41–7.45 (m, 1H, ArH), 7.47–7.51 (m, 2H, ArH),
7.69–7.73 (m, 1H, ArH), 7.95 (d, J ¼ 7.6 Hz, 1H, ArH), 11.57 (s, 1H, NH); IR
(KBr): 3198, 3072, 3008, 1728, 1659, 1611, 1492, 1448, 1402, 1341, 1289, 1242,
1151, 868, 821, 782, 755, 707, 685 cmꢁ1
.
3-Cyclohexylquinazoline-2,4(1H,3H)-dione 5c. Mp 272–273 ꢀC (lit.[7m]
270–271 ꢀC). 1H NMR (DMSO-d6, 400 MHz): dH 1.13–1.19 (m, 1H,), 1.25–1.35
(m, 2H, CH2), 1.57–1.64 (m, 3H, CH2þCH), 1.80 (d, 2H, J ¼ 12.8 Hz, 2H, CH2),
2.34–2.43 (m, 2H, CH2), 4.70–4.76 (m, 1H, CH), 7.12–7.19 (m, 2H, ArH),
7.60–7.64 (m, 1H, ArH), 7.90 (d, J ¼ 8.0 Hz, 1H, ArH), 11.32(s, 1H, NH); IR
(KBr): 3228, 2930, 2860, 1716, 1640, 1505, 1448, 1400, 1378, 1348, 1279, 1262,
1182, 1157, 1113, 1004, 895, 746, 689 cmꢁ1
.

GREEN SYNTHESIS OF QUINAZOLINONE DERIVATIVES
347
1
3-(4-Fluorophenyl)quinazoline-2,4(1H,3H)-dione 5d. Mp 270–272 ꢀC. H
NMR (DMSO-d6, 400 MHz): dH 7.22–7.25 (m, 2H, ArH), 7.32 (t, J ¼ 8.8 Hz, 2H,
ArH), 7.39 (t, J ¼ 8.8 Hz, 2H, ArH), 7.69–7.73 (m, 1H, ArH), 7.94 (d, J ¼ 7.6 Hz,
1H, ArH), 11.59 (s, 1H, NH); IR (KBr): 3205, 1730, 1651, 1602, 1508, 1440, 1402,
13442, 1275, 1243, 1213, 1169, 840, 811, 761, 718, 690 cmꢁ1. HRMS (ESI, m=z):
calcd. for C14H9FN2O2Na (M þ Naþ) 279.0546; found 279.0536.
3-(4-Methoxyphenyl)quinazoline-2,4(1H,3H)-dione
5e. Mp > 300 ꢀC.
1H NMR (DMSO-d6, 400 MHz): dH 3.81 (s, 3H, CH3O), 7.02 (d, J ¼ 8.8 Hz,
2H, ArH), 7.20–7.24 (m, 4H, ArH), 7.68–7.71 (m, 1H, ArH), 7.94 (d, J ¼ 7.6 Hz,
1H, ArH), 11.52 (s, 1H, NH); IR (KBr): 3196, 3068, 3002, 2933, 2896, 1722,
1662, 1606, 1513, 1489, 1448, 1405, 1284, 1247, 1175, 1156, 1029, 826, 791, 760,
670 cmꢁ1. HRMS (ESI, m=z): calcd. for C15H12N2O3Na (M þ Naþ) 291.0746; found
291.0771.
3-Benzylquinazoline-2,4(1H,3H)-dione 5f. Mp 233–234 ꢀC. 1H NMR
(DMSO-d6, 400 MHz): dH 5.10 (s, 2H, CH2), 7.20–7.26 (m, 3H, ArH), 7.29–7.32
(m, 4H, ArH), 7.66–7.70 (m, 1H, ArH), 7.95 (d, J ¼ 8.0 Hz, 1H, ArH), 11.55
(s, 1H, NH); IR (KBr): 3191, 3054, 3003, 2905, 1712, 1654, 1491, 1453, 1427,
1410, 1353, 1301, 1072, 956, 815, 755, 714 cmꢁ1. HRMS (ESI, m=z): calcd. for
C15H12N2O2Na (M þ Naþ) 275.0796; found 275.0782.
3-(4-Methoxybenzyl)quinazoline-2,4(1H,3H)-dione 5g. Mp 219–220 ꢀC.
1H NMR (DMSO-d6, 400 MHz): dH 3.70 (s, 3H, OCH3), 5.02 (s, 2H, CH2), 6.86
(d, J ¼ 8.4 Hz, 2H, ArH), 7.18–7.21 (m, 2H, ArH), 7.29 (d, J ¼ 8.4 Hz, 2H, ArH),
7.62–7.66 (m, 1H, ArH), 7.93 (d, J ¼ 8.0 Hz, 1H, ArH), 11.51 (s, 1H, NH); IR
(KBr): 3057, 3004, 2905, 1716, 1663, 1609, 1511, 1454, 1429, 1413, 1352, 1306,
1247, 1174, 1098, 1031, 958, 822, 754 cmꢁ1. HRMS (ESI, m=z): calcd. for
C16H14N2O3Na (M þ Naþ) 305.0902; found 305.0908.
3-p-Tolylquinazoline-2,4(1H,3H)-dione 5h. Mp 269–270 ꢀC. (lit.[7m] 265–
1
266 ꢀC). H NMR (DMSO-d6, 400 MHz): dH 2.38 (s, 3H, CH3), 7.19 (d, J ¼ 8.0 Hz,
2H, ArH), 7.23 (d, J ¼ 7.6 Hz, 2H, ArH), 7.28 (d, J ¼ 8.0 Hz, 2H, ArH), 7.68–7.72
(m, 1H, ArH), 7.94 (d, J ¼ 8.0 Hz, 1H, ArH), 11.54 (s, 1H, NH); IR (KBr): 3197,
3069, 3006, 2937, 1722, 1665, 1621, 1607, 1512, 1489, 1447, 1404, 1287, 1243,
1154, 872, 817, 754, 715, 671 cmꢁ1
.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China
(20802061), the Natural Science Foundation (08KJD150019) of Jiangsu Education
Committee, and the Qing Lan Project (08QLT001) for financial support.
REFERENCES
1. Mhaske, S. B.; Argade, N. P. The chemistry of recently isolated naturally occurring
quinazolinone alkaloids. Tetrahedron 2006, 62, 9787–9826.

348
S.-L. WANG ET AL.
2. Alagarsamy, V.; Raja, S. V.; Dhanabal, K. Synthesis and pharmacological evaluation of
some 3-Phenyl-2-substituted-3H-quinazolin-4-one as analgesic, Anti-inflammatory agents.
Bioorg. Med. Chem. 2007, 15, 235–241.
3. Alagarsamy, V.; Pathak, Urvishbhai S. Synthesis and antihypertensive activity of novel
3-Benzyl-2-substituted-3H-[1,2,4]triazolo[5,1-b]quinazolin-9-ones. Bioorg. Med. Chem.
2007, 15, 3457–3462.
4. Murugan, V.; Kulkarni, M.; Anand, R. M.; Kumar, E. P.; Suresh, B.; Reddy, V. M.
Synthesis of 2-[fbis-(2-chloroethyl)aminogmethyl]-6,8-dinitro-1-(4-substitutedphenyl)-1-
H-quinazolin-4-one derivatives as possible antineoplastic agents. Asian J. Chem. 2006,
18, 900–906.
5. Godfrey, A. A. A preparation of quinazolin-4-ones via cyclization of N-(cyanophenyl)
acetamide derivatives. PCT Int. Appl. WO Patent 2005012260 A2, Feb. 10, 2005, Chem.
Abstr. 2005, 142, 198095.
6. Selvam, P.; Girija, K.; Nagarajan, G.; De Clerco, E. Synthesis, antibacterial, and
anti-HIV activities of 3-[5-amino-6-(2,3-dichloro-phenyl)-[1,2,4]triazin-3-yl]-6,8-dibromo-
2-substituted-3H-quinazolin-4-one. Indian J. Pharm. Sci. 2005, 67, 484–487.
7. (a) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Wang, X. S.; Tu, S. J.; Hu, H. W. Synthesis of
1,2-Dihydroquinazolin-4(3H)-ones promoted by low-valent titanium. Chem. J. Chin.
Univ. 2004, 25, 2051–2054; (b) Shi, D. Q.; Rong, L. C.; Wang, J. X.; Zhuang, Q. Y.;
Wang, X. S.; Hu, H. W. Synthesis of quinazolin-4(3H)-ones and 1,2-dihydroquinazolin-4
(3H)-ones with the aid of a low-valent titanium reagent. Tetrahedron Lett. 2003, 44,
3199–3201; (c) Shi, D. Q.; Shi, C. L.; Wang, J. X.; Rong, L. C.; Zhuang, Q. Y.; Wang,
X. S. An efficient synthesis of quinazoline derivatives with the aid of low-valent titanium
reagent. J. Heterocycl. Chem. 2005, 40, 173–183; (d) Yoo, C. L.; Fettinger, J. C.; Kurth,
M. J. Stannous chloride in alcohol: A one-pot conversion of 2-Nitro-N-arylbenzamides
to 2,3-Dihydro-1H-quinazoline-4-ones. J. Org. Chem. 2005, 70, 6941–6943; (e)
Baghbanzadeh, M.; Salehi, P.; Dabiri, M.; Kozehgarya, G. Water-accelerated synthesis
of novel bis-2,3-dihydroquinazolin-4(1H)-one derivatives. Synthesis 2006, 344–348; (f)
Salehi, P.; Dabiri, M.; Zolfigol, M. A.; Baghbanzadeh, M. A Novel method for the
one-pot three-component synthesis of 2,3-dihydroquinazolin-4(1H)-ones. Synlett 2005,
1155–1157; (g) Dabiri, M.; Salehi, P.; Otokesh, S.; Baghbanzadeh, M.; Kozehgarya,
G.; Mohammadi, A. A. Efficient synthesis of mono- and disubstituted 2,3-Dihydro-
quinazolin-4(1H)-ones using KAl(SO4)2 ꢂ 12H2O as a reusable catalyst in water and
ethanol. Tetrahedron Lett. 2005, 46, 6123–6126; (h) Salehi, P.; Dabiri, M.; Baghbanzadeh,
M.; Bahramnejad, M. One-pot, three-component synthesis of 2,3-dihydro-4(1H)-
quinazolinones by Montmorillonite K-10 as an efficient and reusable catalyst. Synth.
Commun. 2006, 36, 2287; (i) Chen, J. X.; Su, W. K.; Wu, H. Y.; Liu, M. C.; Jin, C.
Eco-friendly synthesis of 2,3-dihydroquinazolin-4(1H)-ones in ionic liquids or ionic
liquid–water without additional catalyst. Green Chem. 2007, 9, 972; (j) Chen, J.; Wu,
D.; He, F.; Liu, M.; Wu, H.; Ding, J.; Su, W. Gallium(III) triflate–catalyzed one-pot selec-
tive synthesis of 2,3-dihydroquinazolin-4(1H)-ones and quinazolin-4(3H)-ones. Tetra-
hedron Lett. 2008, 49, 3814–3818; (k) Radmoghadam, K. S.; Mamghani, M. H.;
Samavi, L. H. Convergent one-pot synthesis of 3-Substituted quinazolin-4(3H)-ones
under solvent-free conditions. Synth. Commun. 2006, 36, 2245–2252; (l) Takumi, M.;
Yoshio, I. Highly efficient synthesis of 2,4-dihydroxyquinazolines using carbon dioxide
in the presence of catalytic amount DBU. Tetrahedron Lett. 2002, 58, 3155–3158; (m)
Taub, B.; Hino, J. B. 3-Substituted 2,4-quinazolinediones. J. Org. Chem. 1961, 26,
5238–5239.
8. (a) Wasserscheid, P.; Keim, W. Ionic liquids—new solutions for transition metal catalysis.
Angew. Chem. Int. Ed. 2000, 39, 3772–3789; (b) Welton, T. Room-temperature ionic
liquids: Solvents for synthesis and catalysis. Chem. Rev. 1999, 99, 2071–2083.

GREEN SYNTHESIS OF QUINAZOLINONE DERIVATIVES
349
9. Dyson, P. J.; Ellis, D. J.; Parker, D. G.; Welton, T. Arene hydrogenation in a room-
temperature ionic liquid using a ruthenium cluster catalyst. Chem. Commun. 1999, 25–26.
10. Stark, A.; MacLean, B. L.; Singer, R. D. 1-Ethyl-3-methylimidazolium halogenoalumi-
nate ionic liquids as solvents for friedel–crafts acylation reactions of ferrocene. J. Chem.
Soc., Dalton Trans. 1999, 63–66.
11. (a) Bo¨hm, V. P. W.; Herrmann, W. A. Coordination chemistry and mechanisms of
metal-catalyzed C-C coupling reactions, part 12: nonaqueous ionic liquids: Superior
reaction media for the catalytic heck vinylation of chloroarenes. Chem. Eur. J. 2000, 6,
1017–1025; (b) Carmichael, A. J.; Earle, M. J.; Holbrey, J. D.; McCormac, P. B.; Seddon,
K. R. The heck reaction in ionic liquids: A multiphasic catalyst system. Org. Lett. 1999, 1,
997–1000.
12. Judeh, Z. M. A.; Chi, B. C.; Jie, B.; McCluskey, A. The first bischler–napieralski cycliza-
tion in a room-temperature ionic liquid. Tetrahedron Lett. 2002, 43, 5089–5091.
13. Dullius, J. E. L.; Suarez, P. A. Z.; Einloft, S.; De Souza, R. F.; Dupont, J.; Ischer, J.; Cian,
A. D. Selective catalytic hydrodimerization of 1,3-butadiene by palladium compounds
dissolved in ionic liquids. Organometallics 1998, 17, 815–819.
14. Ellis, B.; Keim, W.; Wasserscheid, P. Linear dimerisation of but-1-ene in biphasic mode
using buffered chloroaluminate ionic liquid solvents. Chem. Commun. 1999, 337–338.
15. (a) Wang, X. S.; Wu, J. R.; Li, Q.; Yao, C. S.; Tu, S. J. A novel and green method for the
synthesis of indeno[2,1-c]pyridine derivatives in ionic liquid catalyzed by malononitrile.
Synlett. 2008, 1185–1188; (b) Wang, X. S.; Zhang, M. M.; Li, Q.; Yao, C. S.; Tu, S. J.
An unexpected ring opening of 2-pyrone ring in the synthesis of 1-arylbenzo[f]
quinoline-2-carboxmide derivatives in Aqueous media catalyzed by TEBAC. Synlett.
2007, 3141–3144; (c) Wang, X. S.; Zhang, M. M.; Jiang, H.; Shi, D. Q.; Tu, S. J.; Wei,
X. Y.; Zong, Z. M. An improved and benign synthesis of 9,10-diarylacridin-1,8-dione
and indenoquinoline derivatives from 3-arylamino-5,5-dimethylcyclohex-2-enone, arylal-
dehyde and 1,3-dicarbonyl compound in ionic liquid medium. Synthesis 2006, 4187–4199.