Reaction of 2-aminobenzamides with indoline-2,3-dione in an ionic liquid in the presence and absence of iodine

Article abstract of DOI:10.3184/174751912X13303708813998

The reaction of 2-aminobenzamides with indoline-2,3-dione in ionic liquids, selectively gives 1',3'-dihydrospiro[indolin-2-one-3,2'-quinazolin]-4'-ones in the presence of 5 mol% iodine, while giving 2-(1-acetyl-3-hydroxy-2-oxoindolin- 3-ylamino) benzamide

Full text of DOI:10.3184/174751912X13303708813998

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 157
MARCH, 157–161
Reaction of 2-aminobenzamides with indoline-2,3-dione in an ionic liquid
in the presence and absence of iodine
Jie Shenga, Ke Yanga, Mei-Mei Zhangb and Xiang-Shan Wanga*
aSchool of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials,
Xuzhou Normal University, Xuzhou Jiangsu 221116, P. R. China
bThe Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Xuzhou Normal University, Xuzhou Jiangsu 221116, P. R. China
Thereactionof2-aminobenzamideswithindoline-2,3-dioneinionicliquids,selectivelygives1’,3’-dihydrospiro[indolin-
2-one-3,2’-quinazolin]-4’-ones in the presence of 5 mol% iodine, while giving 2-(1-acetyl-3-hydroxy-2-oxoindolin-
3-ylamino) benzamide derivatives in the absence of iodine. Quinazolinones have great physiological significance and
pharmaceutical uses.
Keywords: quinazolinone, 2-aminobenzamide, indoline-2,3-dione, ionic liquids
Quinazolinones are an important class of molecules with
physiological significance and pharmaceutical utility.1–3 In
particular, the 4(3H)-quinazolinone core, is well-known as a
“privileged structure”4,5 for drug design, which is defined as
being present in a class of molecules that are capable of bind-
ing to multiple receptors with high affinity.6,7 The potential
therapeutic applications of 4(3H)-quinazolinones include anti-
inflammatory,8 antihypertensive,9 anticancer,10 antitumour11
and antibacterial activities.12
Although a number of useful synthetic procedures to
prepare these compounds have been developed,13–24 there are
still several limitations. For example, most of the procedures
involve several steps, give low yields or take place in organic
solvents. Thus, a simple, efficient, and green method to
synthesise quinazoline would be attractive.
catalyst, reaching a maximum of 87% yield with 5 mol%
iodine (Table 1, entries 3, 5, and 6). The yield of 3a was also
dependent on temperature (entries 1–4), proceeding smoothly
at 80 °C. Different imidazolium ionic liquid were also tested,
and [bmim]Br appeared to be the best medium for this
transformation (entry 3 versus 7–11).
After completion of the reaction as monitored by TLC,
products were isolated by simple filtration after the addition of
a small amount of water to the cooled reaction mixture. Water
in the filtrate was removed by distillation under reduced
pressure and the [bmim]Br in the residue could be reused after
being heated at 80 °C for 4 h under reduced pressure. Succes-
sive reuse of the recycled ionic liquid of [bmim]Br in the model
reaction gave high yields of 3a (85%) even after the fourth
cycle.
First of all, these optimised conditions were applied to vari-
ous kinds of 2-aminobenzamides. They all reacted well to give
corresponding spiro[indolin-2-one-3,2′-quinazolin]-4′-one
derivatives 3a–j in good yields (Table 2).
Room temperature ionic liquids (RTILs), especially those
based on the 1-N-alkyl-3-methyl imidazolium cation, have
shown great promise as attractive alternatives to conventional
solvents.25,26
As a continuation of our research devoted to the develop-
ment of new methods for the preparation of heterocycles in
environmentally benign media,27,28 we now report the synthesis
of 1′,3′-dihydrospiro[indolin-2-one-3,2′-quinazolin]-4′-one
derivatives in ionic liquids by a one-pot procedure, involving
the reaction of 2-aminobenzamides with indoline-2,3-dione
catalysed by iodine.
Table 1 Synthetic results of 3a under different reaction
conditions a
Entry
Temp./°C
Ionic liquidb
I2 /mol%
Yield/%c
1
2
r.t.
50
80
100
80
80
80
80
80
80
80
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
[bmim]Br
[emim]Br
[pmim]Br
[emim][BF4]
[pmim][BF4]
[bmim][BF4]
5
5
Trace
73
3
5
87
4
5
87
5
10
20
5
86
Results and discussion
6
86
7
82
Treatment of 2-aminobenzamides 1 with indoline-2,3-dione 2
in the ionic liquid [bmim]Br in the presence of 5 mol% iodine
at 80 °C resulted in the corresponding 1′,3′-dihydrospiro
[indolin-2-one-3,2′-quinazolin]-4′-one derivatives 3a–j in high
yields (Scheme 1).
Using the conversion of 2-aminobenzamide 1a (R = H) and
indoline-2,3-dione 2 into 3a as a model, several parameters
were explored as shown in Table 1. Compound 3a was obtained
successfully in the presence of various quantities of the
8
5
81
9
5
82
10
11
5
80
5
84
a Reaction condition: 2.0 mL solvent, 2-aminobenzamide (0.136 g,
1.0 mmol), and indoline-2,3-dione (0.189 g, 1.0 mmol).
b bmim, 1-butyl-3-methylimidazolium; emim, 1-ethyl-3-methyl-
imidazolium; pmim, 1-propyl-3-methylimidazolium.
c Isolated yields.
Scheme 1 Reaction of 1 and 2 at 80 °C catalysed by iodine
* Correspondent. E-mail: xswang1974@yahoo.com

158 JOURNAL OF CHEMICAL RESEARCH 2012
Table 2 Synthetic results of 3 catalysed by iodinea
Experimental
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were recorded on a Tensor 27 spectrometer in KBr
pellets. 1H NMR spectra were obtained from a solution in DMSO-d6
with Me4Si as internal standard using a Bruker-400 spectrometer.
HRMS analyses were carried out using a Bruker-micro-TOF-Q-MS
analyser.
Entry
R
Time/h Product
Yield/%b
1
2
H
8
10
8
12
8
9
3a
3b
3c
3d
3e
3f
87
82
90
84
86
76
72
80
90
84
C6H5CH2
3
C6H5CH2CH2
4-MeOC6H4CH2
4-MeOC6H4(CH2)2
Cyclopropyl
Naphthalen-2-yl
Cyclopentyl
4-MeC6H4CH2
(Furan-2-yl)methyl
4
5
6
Synthesis of spiro[indolin-2-one-3,2′-quinazolin]-4′-one derivatives
3; general procedure
7
14
9
10
10
3g
3h
3i
8
A dry flask (50 mL) was charged with the 2-aminobenzamide 1
(1.0 mmol), indoline-2,3-dione 2 (0.189 g, 1.0 mmol), iodine (0.013 g,
0.05 mmol), and the ionic liquid [bmim]Br (2.0 mL). The reaction
mixture was stirred at 80 °C for 8–14 h, a small amount of water
(5 mL) was then added to the mixture, and the resulting yellow solid
was filtered off. The water in the filtrate was removed by distillation
under reduced pressure, and the ionic liquid in the residue could be
reused by being heated at 80 °C for 4 hours under reduced pressure.
The crude yellow products were washed with water and purified by
recrystallisation from 95% EtOH, the resulting solid was dried at
80 °C for 2 hours under reduced pressure to give 3.
9
10
3j
a Reaction conditions: 2.0 mL [bmim]Br, 1 (1.0 mmol), 2 (0.189 g,
1.0 mmol) and iodine (0.013 g, 0.05 mmol), 80 °C.
b Isolated yields.
In order to get more insight into the reaction, we also
performed the same reaction in the absence of iodine.Although
these reactions proceeded smoothly at 80 °C, they unexpect-
edly gave 2-(1-acetyl-3-hydroxy-2-oxoindolin-3-ylamino)
benzamide derivatives 4a–n (Scheme 2, Table 3). All the
1-Acetyl-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-dione
1
(3a): M.p. 281–283 °C; H NMR (DMSO-d6, 400 MHz): δH 2.55
(s, 3H, CH3), 6.36 (d, J = 8.0 Hz, 1H, ArH), 6.77 (t, J = 7.6 Hz, 1H,
ArH), 7.29 (t, J = 7.6 Hz, 1H, ArH), 7.37 (d, J = 7.6 Hz, 1H, ArH),
7.43 (s, 1H, NH), 7.54 (t, J = 8.0 Hz, 1H, ArH), 7.68 (dd, J = 8.0 Hz,
J′ = 7.6 Hz, 2H, ArH), 8.16 (d, J = 8.0 Hz, 1H, ArH), 8.38 (s, 1H, NH).
IR (KBr): ν 3296, 3122, 3034, 2922, 1776, 1697, 1654, 1608, 1518,
1485, 1412, 1373, 1338, 1305, 1280, 1195, 1166, 1144, 1037, 1017,
797, 786, 763, 754, 710 cm−1. HRMS (ESI, m/z): Calcd for C17H13N3O3
[M + Na]+ 330.0855; found 330.0869.
1
products were characterised by IR, H and 13C NMR and
HRMS, and the analytical data were in good agreement with
the proposed structures. The structure of 3h was additionally
confirmed by X-ray diffraction analysis, and its crystal
structure is shown in Fig. 1.
Although the detailed mechanism of above reactions is
not known, a possible mechanism is shown in Scheme 3. The
reaction of 1 and 2 gives 4 in the absence of iodine firstly,
and then the iodine works as a milder Lewis acid to help
the dehydration reaction to form the Schiff base. Finally, an
intra-molecular cyclisation reaction takes place to give 3.
1-Acetyl-3′-benzyl-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-
1
dione (3b): M.p. 245–247 °C; H NMR (DMSO-d6, 400 MHz): δH
2.13 (s, 3H, CH3), 3.85 (d, J = 15.2 Hz, 1H, CH), 5.13 (d, J = 15.2 Hz,
1H, CH), 6.65 (d, J = 8.0 Hz, 1H, ArH), 6.72 (d, J = 6.8 Hz, 2H, ArH),
6.82–6.86 (m, 1H, ArH), 7.10–7.19 (m, 3H, ArH), 7.30–7.34 (m, 1H,
ArH), 7.35–7.39 (m, 1H, ArH), 7.56 (s, 1H, NH), 7.57–7.61 (m, 1H,
Table 3 Synthetic results of 4 without iodinea
Entry
R
Time/h
Product Yield/%b
1
2
(R)-1-Phenylethyl
(S)-1-Phenylethyl
C6H5
6
6
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
83
78
72
86
90
76
78
89
86
78
90
85
92
85
3
8
4
Cyclohexyl
C6H5CH2CH2
4-FC6H4
4-MeC6H4
H
8
6
5
6
10
10
8
7
8
9
Piperonylethyl
i-Pr
6
10
11
12
13
14
8
n-Bu
6
Et
6
n-Pr
6
(Furan-2-yl)methyl
8
a Reaction condition: 2.0 mL [bmim]Br, 1 (1.0 mmol), 2 (0.189 g,
1.0 mmol), 80 °C.
b Isolated yields.
Fig. 1 The crystal structure of the 3h.
Scheme 2 Reaction of 1 and 2 in the absence of iodine.

JOURNAL OF CHEMICAL RESEARCH 2012 159
Scheme 3 A possible reaction mechanism.
ArH), 7.69 (d, J = 7.6 Hz, 1H, ArH), 7.81 (d, J = 7.6 Hz, 1H, ArH) ,
8.09 (d, J = 8.4 Hz, 1H, ArH). IR (KBr): ν 3213, 3124, 3029, 2954,
1765, 1720, 1622, 1586, 1522, 1491, 1466, 1432, 1384, 1369, 1353,
1331, 1302, 1264, 1239, 1198, 1169, 1157, 1125, 1016, 978, 758, 748,
702 cm−1. HRMS (ESI, m/z): Calcd for C24H19N3O3 [M + Na]+
420.1324; found 420.1345.
1-Acetyl-3′-phenethyl-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-
dione (3c): M.p. 175–176 °C; 1H NMR (DMSO-d6, 400 MHz): δH 2.57
(s, 3H, CH3), 2.72–2.84 (m, 2H, CH2), 3.40–3.49 (m, 2H, CH2), 6.66
(d, J = 8.0 Hz, 1H, ArH), 6.78–6.84 (m, 3H, ArH), 7.12–7.19 (m, 3H,
ArH), 7.29–7.34 (m, 1H, ArH), 7.43–7.47 (m, 1H, ArH), 7.59 (s, 1H,
NH), 7.63–7.67 (m, 1H, ArH), 7.74 (dd, J = 7.6 Hz, J′ = 1.2 Hz, 1H,
ArH), 7.79 (d, J = 7.2 Hz, 1H, ArH), 8.24 (d, J = 8.0 Hz, 1H, ArH).
IR (KBr): ν 3220, 3125, 3069, 3026, 2959, 2940, 1764, 1716, 1623,
1589, 1521, 1490, 1466, 1455, 1434, 1390, 1368, 1351, 1332, 1303,
1266, 1241, 1198, 1168, 1119, 1033, 1015, 761, 744, 697 cm−1. HRMS
(ESI, m/z): Calcd for C25H21N3O3 [M + Na]+ 434.1481; found
434.1484.
1-Acetyl-3′-(4-methoxybenzyl)-1′H-spiro[indoline-3,2′-quinazoline]-
2,4′(3′H)-dione (3d): M.p. 227–229 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 2.12 (s, 3H, CH3), 3.65–3.69 (m, 4H, OCH3+CH), 5.24 (d, J =
14.8 Hz, 1H, CH), 6.57–6.59 (m, 2H, ArH), 6.63–6.68 (m, 3H, ArH),
6.83 (t, J = 7.6 Hz, 1H, ArH), 7.29–7.33 (m, 1H, ArH), 7.40–7.44
(m, 1H, ArH), 7.53 (s, 1H, NH), 7.59–7.63 (m, 1H, ArH), 7.73 (d, J =
7.6 Hz, 1H, ArH), 7.80 (d, J = 7.6 Hz, 1H, ArH), 8.11 (d, J = 8.0 Hz,
1H, ArH). IR (KBr): ν 3302, 3011, 2959, 2934, 1763, 1722, 1628,
1612, 1588, 1512, 1485, 1468, 1432, 1377, 1367, 1353, 1334, 1320,
1302, 1290, 1268, 1250, 1199, 1177, 1167, 1111, 1032, 1017, 977,
962, 789, 779, 759, 695 cm−1. HRMS (ESI, m/z): Calcd for C25H21N3O4
[M + Na]+ 450.1430; found 450.1439.
1-Acetyl-3′-(4-methoxyphenethyl)-1′H-spiro[indoline-3,2′-quina-
zoline]-2,4′(3′H)-dione (3e): M.p. 185–187 °C; 1H NMR (DMSO-d6,
400 MHz): δH 2.55 (s, 3H, CH3), 2.64–2.71 (m, 1H, CH), 2.75–2.82
(m, 1H, CH), 3.41–3.69 (m, 5H, OCH3+CH2), 6.64–6.70 (m, 3H,
ArH), 6.73–6.75 (m, 2H, ArH), 6.80–6.83 (m, 1H, ArH), 7.29–7.33
(m, 1H, ArH), 7.43–7.47 (m, 1H, ArH), 7.58 (s, 1H, NH), 7.62–7.66
(m, 1H, ArH), 7.72–7.74 (m, 1H, ArH), 7.78 (d, J = 7.6 Hz, 1H, ArH),
8.25 (d, J = 8.4 Hz, 1H, ArH). IR (KBr): ν 3311, 3066, 3015, 2951,
2933, 2911, 2835, 1769, 1717, 1633, 1514, 1489, 1466, 1400, 1375,
1335, 1300, 1267, 1242, 1199, 1181, 1158, 1124, 1106, 1034, 1016,
968, 827, 779, 758 cm−1. HRMS (ESI, m/z): Calcd for C26H23N3O4
[M + H]+ 442.1767; found 442.1768.
3019, 2955, 1769, 1717, 1644, 1616, 1522, 1489, 1467, 1372, 1350,
1333, 1302, 1265, 1217, 1196, 1164, 1141, 1099, 1028, 1015, 962,
762, 748 cm−1. HRMS (ESI, m/z): Calcd for C20H17N3O3 [M + Na]+
370.1168; found 370.1174.
SAFETY CAUTION: The preparation of the N-(2-naphthyl)
-2-aminobenzamide starting material involved 2-naphthylamine.
2-Naphthylamine (β-naphthylamine, naphthalene-2-amine) is a
known potent carcinogen. Studies of workers with occupational
exposure to it have shown clear evidence of a link between expo-
sure and bladder cancer. In the UK, it appears in Schedule 2 of the
Control of Substances Hazardous to Health Regulations (COSHH)
1999 which prohibits its ‘manufacture and use for all purposes’.
1-Acetyl-3′-(naphthalen-2-yl)-1′H-spiro[indoline-3,2′-quinazoline]-
2,4′(3′H)-dione (3g): M.p. 204–205 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 2.65 (s, 3H, CH3), 6.78 (d, J = 8.0 Hz, 1H, ArH), 6.85–6.89 (m, 1H,
ArH),7.17 –7.21 (m, 2H, ArH), 7.24–7.28 (m, 1H, ArH), 7.38–7.42
(m, 1H, ArH), 7.44–7.50 (m, 2H, ArH), 7.56 (s, 1H, NH), 7.74–7.77
(m, 2H, ArH), 7.80–7.86 (m, 5H, ArH). IR (KBr): ν 3291, 3057, 3013,
2936, 2869, 1771, 1715, 1641, 1507, 1487, 1370, 1334, 1302, 1265,
1236, 1217, 1199, 1168, 1127, 1101, 1062, 1038, 1016, 974, 909, 801,
752 cm−1. HRMS (ESI, m/z): Calcd for C27H19N3O3 [M + Na]+
456.1324; found 456.1317.
1-Acetyl-3′-cyclopentyl-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-
dione (3h): M.p. 223–225 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 1.18–1.42 (m, 3H, 3CH), 1.50–1.52 (m, 1H, CH), 1.68–1.82 (m,
2H, CH2), 2.04–2.15 (m, 2H, CH2), 2.56 (s, 3H, CH3), 2.92–3.00 (m,
1H, CH), 6.59 (d, J = 8.0 Hz, 1H, ArH), 6.75–6.79 (m, 1H, ArH),
7.25–7.29 (m, 1H, ArH), 7.41 (t, J = 7.6 Hz, 1H, ArH), 7.49 (s, 1H,
NH), 7.56–7.60 (m, 1H, ArH), 7.67 (d, J = 8.0 Hz, 2H, ArH), 8.23 (d,
J = 8.4 Hz, 1H, ArH). IR (KBr): ν 3360, 3283, 2951, 2869, 1771,
1718, 1695, 1654, 1616, 1512, 1489, 1466, 1449, 1429, 1372, 1347,
1302, 1269, 1235, 1200, 1164, 1116, 1037, 1015, 790, 753, 691 cm−1.
HRMS (ESI, m/z): Calcd for C22H21N3O3 [M + Na]+ 376.1661; found
376.1687.
1-Acetyl-3′-(4-methylbenzyl)-1′H-spiro[indoline-3,2′-quinazoline]-
2,4′(3′H)-dione (3i): M.p. 242–244 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 2.10 (s, 3H, CH3), 2.19 (s, 3H, CH3), 3.71 (d, J = 15.2 Hz, 1H, CH),
5.21 (d, J = 15.2 Hz, 1H, CH), 6.57 (d, J = 7.6 Hz, 2H, ArH), 6.64
(d, J = 8.0 Hz, 1H, ArH), 6.83 (t, J = 7.6 Hz, 1H, ArH), 6.92 (d, J =
8.0 Hz, 2H, ArH), 7.29 –7.33 (m, 1H, ArH), 7.38–7.42 (m, 1H, ArH),
7.54 (s, 1H, NH), 7.58–7.62 (m, 1H, ArH), 7.72 (d, J = 7.6 Hz, 1H,
ArH), 7.80 (d, J = 7.6 Hz, 1H, ArH), 8.09 (d, J = 8.4 Hz, 1H, ArH).
IR (KBr): ν 3331, 3044, 2945, 1758, 1722, 1631, 1614, 1591, 1511,
1488, 1468, 1435, 1416, 1372, 1351, 1334, 1310, 1299, 1269, 1236,
1196, 1180, 1168, 1114, 1039, 1016, 970, 960, 950, 767, 754, 692
cm−1. HRMS (ESI, m/z): Calcd for C25H21N3O3 [M + Na]+ 434.1481;
found 434.1512.
1-Acetyl-3′-cyclopropyl-1′H-spiro[indoline-3,2′-quinazoline]-2,4′(3′H)-
dione (3f): M.p. 231–232 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 0.30–0.41 (m, 2H, CH2), 0.46–0.59 (m, 2H, CH2), 2.16–2.20
(m, 1H, CH), 2.57 (s, 3H, CH3), 6.33 (d, J = 8.0 Hz, 1H, ArH), 6.79 (t,
J = 7.2 Hz, 1H, ArH), 7.27–7.31 (m, 1H, ArH), 7.38 (t, J = 7.6 Hz, 1H,
ArH), 7.54 (s, 1H, NH), 7.54–7.58 (m, 1H, ArH), 7.66–7.72 (m, 2H,
ArH), 8.22 (d, J = 8.0 Hz, 1H, ArH). IR (KBr): ν 3276, 3124, 3068,

160 JOURNAL OF CHEMICAL RESEARCH 2012
1-Acetyl-3′-(furan-2-ylmethyl)-1′H-spiro[indoline-3,2′-quinazoline]-
2,4′(3′H)-dione (3j): M.p. 204–205 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 2.32 (s, 3H, CH3), 3.81 (d, J = 15.6 Hz, 1H, CH), 5.16 (d, J =
15.6 Hz, 1H, CH), 5.67 (d, J = 2.8 Hz, 1H, ArH), 6.23–6.24 (m, 1H,
ArH), 6.64 (d, J = 8.0 Hz, 1H, ArH), 6.82 (t, J = 7.2 Hz, 1H, ArH),
7.29 –7.33 (m, 1H, ArH), 7.41–7.47 (m, 2H, ArH), 7.58 (s, 1H, NH),
7.59–7.63 (m, 1H, ArH), 7.72 (d, J = 7.6 Hz, 2H, ArH), 8.19 (d,
J = 8.0 Hz, 1H, ArH). IR (KBr): ν 3323, 3131, 3056, 2946, 1766,
1722, 1636, 1613, 1593, 1507, 1487, 1468, 1429, 1387, 1368, 1347,
1332, 1299, 1269, 1237, 1202, 1172, 1121, 1011, 979, 968, 755 cm−1.
HRMS (ESI, m/z): Calcd for C22H17N3O4 [M + Na]+ 410.1117; found
410.1144.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-phenethylben-
zamide (4e): M.p. 192–193 °C; H NMR (DMSO-d6, 400 MHz): δH
1
1.95 (s, 3H, CH3), 2.88–2.92 (m, 2H, CH2), 3.52–3.57 (m, 2H, CH2),
7.20–7.34 (m, 7H, ArH), 7.37–7.40 (m, 1H, ArH), 7.55–7.63 (m, 3H,
ArH), 7.75 (d, J = 8.0 Hz, 1H, ArH), 8.54 (d, J = 8.4 Hz, 1H, ArH),
8.92 (t, J = 6.4 Hz, 1H, NH), 10.43 (s, 1H, NH), 12.40 (s, 1H, OH). 13
C NMR (CDCl3, 100 MHz): δC 25.6, 35.4, 41.1, 118.5, 120.9, 121.0,
121.5, 122.4, 124.1, 126.5, 126.8, 128.78, 128.84, 132.8, 134.4, 136.5,
138.47, 138.51, 142.5, 160.9, 168.5, 169.4, 191.3. IR (KBr): ν 3388,
3281, 3107, 3061, 3030, 2948, 1688, 1637, 1579, 1513, 1447, 1368,
1327, 1295, 1256, 1228, 1195, 1180, 1161, 1124, 1107, 1049, 1004,
983, 886, 860, 754, 699 cm−1. HRMS (ESI, m/z): Calcd for C25H23N3O4
[M + Na]+ 452.1586; found 452.1597.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-(4-fluorophenyl)
benzamide (4f): M.p. 224–225 °C; H NMR (DMSO-d6, 400 MHz):
Synthesis of 2-(1-acetyl-3-hydroxy-2-oxoindolin-3-ylamino)
benzamide derivatives 4; general procedure
1
δH 1.96 (s, 3H, CH3), 7.22–7.27 (m, 3H, ArH), 7.33 (t, J = 7.6 Hz, 1H,
ArH), 7.40–7.43 (m, 1H, ArH), 7.56–7.65 (m, 3H, ArH), 7.77–7.80
(m, 2H, ArH), 7.92 (d, J = 7.6 Hz, 1H, ArH), 8.46 (d, J = 8.0 Hz, 1H,
ArH), 10.46 (s, 1H, NH), 10.64 (s, 1H, NH), 11.77 (s, 1H, OH). IR
(KBr): ν 3308, 3066, 1687, 1644, 1608, 1578, 1521, 1447, 1402,
1371, 1335, 1295, 1261, 1214, 1162, 1125, 1101, 1084, 1058, 1013,
986, 902, 884, 858, 836, 754 cm−1. HRMS (ESI, m/z): Calcd for
C23H18FN3O4 [M + Na]+ 442.1179; found 442.1187.
A dry flask (50 mL) was charged with the 2-aminobenzamide 1
(1.0 mmol), indoline-2,3-dione 2 (0.189 g, 1.0 mmol), and the ionic
liquid [bmim]Br (2 mL). The reaction mixture was stirred at 80 °C for
6-10 h, and then a small amount of water (5 mL) was added to the
mixture, and the generated yellow solid was filtered off. The water in
the filtrate was removed by distillation under reduced pressure, and
the ionic liquid in the residue could be reused by being evaporated at
80 °C for 4 h under reduced pressure. The crude solid was washed
with water and purified by recrystallisation from 95% EtOH to
give 4.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-(4-methylphenyl)
1
benzamide (4g): M.p. 248–249 °C; H NMR (DMSO-d6, 400 MHz):
δH 1.96 (s, 3H, CH3), 2.31 (s, 3H, CH3), 7.19–7.26 (m, 3H, ArH), 7.32
(t, J = 7.6 Hz, 1H, ArH), 7.41 (d, J = 8.0 Hz, 1H, ArH), 7.56–7.66 (m,
5H, ArH), 7.92 (d, J = 7.6 Hz, 1H, ArH), 8.47 (d, J = 8.4 Hz, 1H,
ArH), 10.45 (s, 1H, NH), 10.51 (s, 1H, NH), 11.83 (s, 1H, OH). IR
(KBr): ν 3290, 3107, 3033, 2923, 1698, 1638, 1579, 1510, 1447,
1404, 1365, 1325, 1295, 1255, 1161, 1123, 1053, 1003, 984, 908, 886,
815, 759 cm−1. HRMS (ESI, m/z): Calcd for C24H21N3O4 [M + Na]+
438.1430; found 438.1445.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-((R)-1-phenylethyl)
benzamide (4a): M.p. 201–202 °C; H NMR (DMSO-d6, 400 MHz):
1
δH 1.51 (d, J = 6.8 Hz, 3H, CH3), 1.93 (s, 3H, CH3), 5.21–5.28 (m, 1H,
CH), 7.23–7.29 (m, 3H, ArH), 7.34–7.39 (m, 3H, ArH), 7.44–7.46 (m,
2H, ArH), 7.56–7.61 (m, 3H, ArH), 7.94 (d, J = 7.6 Hz, 1H, ArH),
8.53 (d, J = 8.4 Hz, 1H, ArH), 9.17 (d, J = 8.0 Hz, 1H, NH), 10.41
(s, 1H, NH), 12.30 (s, 1H, OH). IR (KBr): ν 3337, 3299, 3275, 3238,
3104, 3065, 3032, 2975, 2934, 1709, 1694, 1625, 1580, 1519, 1449,
1370, 1318, 1297, 1258, 1228, 1182, 1164, 1127, 990, 887, 757, 728,
700 cm−1. HRMS (ESI, m/z): Calcd for C25H23N3O4 [M + Na]+
452.1586; found 452.1599.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-((S)-1-phenylethyl)
benzamide (4b): M.p. 200–201 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 1.51 (d, J = 6.8 Hz, 3H, CH3), 1.93 (s, 3H, CH3), 5.21–5.28 (m, 1H,
CH), 7.22–7.29 (m, 3H, ArH), 7.34–7.37 (m, 3H, ArH), 7.45 (d,
J = 8.0 Hz, 2H, ArH), 7.56–7.60 (m, 3H, ArH), 7.95 (d, J = 8.0 Hz,
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)benzamide (4h):
1
M.p. 217–218 °C; H NMR (DMSO-d6, 400 MHz): δH 1.95 (s, 3H,
CH3), 7.20–7.27 (m, 2H, ArH), 7.35 (d, J = 8.0 Hz, 1H, ArH), 7.55–
7.61 (m, 3H, ArH), 7.80 (s, 1H, NH), 7.86 (d, J = 8.0 Hz, 1H, ArH),
8.34 (s, 1H, NH), 8.57 (d, J = 8.4 Hz, 1H, ArH), 10.42 (s, 1H, NH),
12.69 (s, 1H, OH). 13 C NMR (DMSO-d6, 100 MHz): δC 23.2, 119.8,
120.7, 121.7, 123.3, 123.7, 126.9, 128.8, 130.0, 132.3, 132.4, 136.0,
138.4, 159.6, 168.7, 170.3, 187.4. IR (KBr): ν 3412, 3217, 3116,
1694, 1650, 1610, 1580, 1518, 1449, 1398, 1337, 1297, 1258, 1232,
1160, 1126, 886, 757 cm−1. HRMS (ESI, m/z): Calcd for C17H15N3O4
[M + Na]+ 348.0960; found 348.0992.
1H, ArH), 8.53 (d, J = 8.0 Hz, 1H, ArH), 9.18 (d, J = 8.0 Hz, 1H, NH),
13
10.42 (s, 1H, NH), 12.31 (s, 1H, OH).
C NMR (DMSO-d6,
100 MHz): δC 22.1, 23.3, 48.5, 119.86, 119.88, 121.63, 121.66, 123.4,
123.7, 126.0, 126.7, 128.3, 128.6, 130.0, 132.1, 132.4, 136.0, 137.9,
144.4, 159.6, 167.0, 168.6, 187.3. IR (KBr): ν 3336, 3276, 3238,
3065, 3032, 2975, 2934, 1709, 1694, 1625, 1580, 1519, 1449, 1371,
1319, 1297, 1258, 1228, 1182, 1164, 1127, 990, 887, 757, 700 cm−1.
HRMS (ESI, m/z): Calcd for C25H23N3O4 [M + H]+ 430.1767; found
430.1755.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-piperonyle-
thylbenzamide (4i): M.p. 211–213 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 1.95 (s, 3H, CH3), 2.79–2.83 (m, 2H, CH2), 3.47–3.52 (m, 2H,
CH2), 5.96 (s, 2H, CH2), 6.71–6.73 (m, 1H, ArH), 6.82–6.86 (m, 2H,
ArH), 7.21–7.28 (m, 2H, ArH), 7.36–7.39 (m, 1H, ArH), 7.54–7.62
(m, 3H, ArH), 7.74 (d, J = 7.6 Hz, 1H, ArH), 8.53 (d, J = 8.4 Hz, 1H,
ArH), 8.87 (t, J = 6.4 Hz, 1H, NH), 10.43 (s, 1H, NH), 12.38 (s, 1H,
OH). IR (KBr): ν 3352, 3287, 3184, 3115, 3071, 2932, 2901, 1687,
1642, 1583, 1518, 1448, 1372, 1325, 1298, 1251, 1190, 1165, 1128,
1105, 1037, 992, 936, 924, 888, 872, 806, 755 cm−1. HRMS (ESI,
m/z): Calcd for C26H23N3O6 [M + Na]+ 496.1485; found 496.1516.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-isopropylben-
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-phenylbenza-
mide (4c): M.p. 237–239 °C; 1H NMR (DMSO-d6, 400 MHz): δH 1.96
(s, 3H, CH3), 7.15–7.18 (m, 1H, ArH), 7.24 (t, J = 7.2 Hz, 1H, ArH),
7.31–7.35 (m, 1H, ArH), 7.38–7.43 (m, 3H, ArH), 7.56–7.65 (m, 3H,
ArH), 7.76–7.78 (m, 2H, ArH), 7.93 (d, J = 7.6 Hz, 1H, ArH), 8.46 (d,
J = 8.0 Hz, 1H, ArH), 10.45 (s, 1H, NH), 10.56 (s, 1H, NH), 11.77 (s,
1H, OH). IR (KBr): ν 3323, 3287, 3106, 3063, 1699, 1668, 1660,
1639, 1623, 1599, 1578, 1511, 1447, 1433, 1362, 1326, 1298, 1254,
1223, 1160, 1121, 1002, 984, 890, 754, 713, 694 cm−1. HRMS (ESI,
m/z): Calcd for C23H19N3O4 [M + Na]+ 424.1273; found 424.1275.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-cyclohexyl-
benzamide (4d): M.p. 203–205 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 1.10–1.18 (m, 1H, CH), 1.29–1.40 (m, 4H, 2CH2), 1.63 (d, J = 11.6
Hz, 1H, CH), 1.75–1.76 (m, 2H, CH2), 1.85–1.86 (m, 2H, CH2), 1.95
(s, 3H, CH3), 3.81–3.83 (m, 1H, CH), 7.21–7.28 (m, 2H, ArH), 7.36–
7.39 (m, 1H, ArH), 7.53–7.62 (m, 3H, ArH), 7.80 (d, J = 7.6 Hz, 1H,
ArH), 8.51 (d, J = 8.4 Hz, 1H, ArH), 8.59 (d, J = 7.6 Hz, 1H, NH),
10.42 (s, 1H, NH), 12.32 (s, 1H, OH). 13C NMR (CDCl3, 100 MHz):
δC 24.9, 25.5, 25.6, 33.0, 48.9, 118.4, 120.9, 121.3, 121.5, 122.4,
124.1, 126.6, 132.7, 134.4, 136.5, 138.5, 142.5, 160.9, 167.6, 169.5,
191.4. IR (KBr): ν 3402, 3309, 2932, 2849, 1689, 1634, 1579, 1515,
1448, 1370, 1339, 1297, 1256, 1222, 1162, 1127, 1058, 885, 857, 753,
697 cm−1. HRMS (ESI, m/z): Calcd for C23H25N3O4 [M + Na]+
430.1743; found 430.1755.
1
zamide (4j): M.p. 178–180 °C; H NMR (DMSO-d6, 400 MHz): δH
1.20 (d, J = 6.4 Hz, 6H, 2CH3), 1.94 (s, 3H, CH3), 4.09–4.22 (m, 1H,
CH), 7.21–7.27 (m, 2H, ArH), 7.36 (d, J = 8.0 Hz, 1H, ArH), 7.54–
7.62 (m, 3H, ArH), 7.81 (d, J = 8.0 Hz, 1H, ArH), 8.52 (d, J = 8.4 Hz,
1H, ArH), 8.61 (d, J = 7.6 Hz, 1H, NH), 10.44 (s, 1H, NH), 12.36 (s,
13
1H, OH). C NMR (CDCl3, 100 MHz): δC 22.7, 25.6, 42.2, 113.2,
118.4, 120.9, 121.2, 122.4, 124.1, 126.6, 132.7, 134.4, 136.5, 138.5,
142.5, 161.0, 163.1, 169.4, 191.4. IR (KBr): ν 3298, 3109, 3069,
2979, 2933, 1769, 1713, 1697, 1635, 1606, 1585, 1518, 1449, 1371,
1340, 1300, 1257, 1229, 1204, 1162, 1147, 1131, 888, 781, 756, 692
cm−1. HRMS (ESI, m/z): Calcd for C20H21N3O4 [M + Na]+ 390.1430;
found 390.1447.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-(n-butyl)
benzamide (4k): M.p. 180–181 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 0.92 (t, J = 7.2 Hz, 3H, CH3), 1.34–1.41 (m, 2H, CH2), 1.51–1.59
(m, 2H, CH2), 1.95 (s, 3H, CH3), 3.28–3.33 (m, 2H, CH2), 7.21–7.27
(m, 2H, ArH), 7.36 (d, J = 8.0 Hz, 1H, ArH), 7.54–7.62 (m, 3H, ArH),
7.80 (d, J = 7.6 Hz, 1H, ArH), 8.54 (d, J = 8.0 Hz, 1H, ArH), 8.81 (t,
J = 5.2 Hz, 1H, NH), 10.42 (s, 1H, NH), 12.42 (s, 1H, OH). 13 C NMR

JOURNAL OF CHEMICAL RESEARCH 2012 161
(CDCl3, 100 MHz): δC 13.7, 20.2, 25.6, 31.5, 39.9, 118.5, 120.9,
121.2, 121.5, 122.4, 124.1, 126.6, 132.7, 134.3, 136.5, 138.5, 142.5,
161.0, 168.5, 169.4, 191.3. IR (KBr): ν 3381, 3319, 3083, 3061, 2958,
2934, 2873, 2856, 1686, 1640, 1598, 1580, 1518, 1447, 1371, 1337,
1296, 1261, 1231, 1181, 1162, 1126, 1107, 884, 751 cm−1. HRMS
(ESI, m/z): Calcd for C21H23N3O4 [M + Na]+ 404.1586; found
404.1612.
Data Centre as supplementary publication with No. CCDC-
855710, respectively. Copies of available material can be
obtained, free of charge, on application to the Director, CCDC,
12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44 1223
336033 or E-mail: deposit@ccdc.cam.ac.uk).
Received 6 September 2011; accepted 10 February 2012
Paper 1100878 doi: 10.3184/174751912X13303708813998
Published online: 22 March 2012
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-ethylbenzamide
1
(4l): M.p. 153–154 °C; H NMR (DMSO-d6, 400 MHz): δH 1.17 (t,
J = 7.2 Hz, 3H, CH3), 1.95 (s, 3H, CH3), 3.30–3.33 (m, 2H, CH2), 7.24
(dd, J = J′ = 8.0 Hz, 2H, ArH), 7.36 (d, J = 8.4 Hz, 1H, ArH), 7.56
(t, J = 8.0 Hz, 3H, ArH), 7.81 (d, J = 8.0 Hz, 1H, ArH), 8.54 (d, J =
8.4 Hz, 1H, ArH), 8.83 (t, J = 4.8 Hz, 1H, NH), 10.43 (s, 1H, NH),
12.47 (s, 1H, OH). 13 C NMR (CDCl3, 100 MHz): δC 14.7, 25.6, 35.1,
118.4, 120.9, 121.0, 121.5, 122.4, 124.1, 126.7, 132.8, 134.4, 136.5,
138.5, 142.5, 160.9, 168.4, 169.4, 191.3. IR (KBr): ν 3392, 3319,
3104, 3061, 2975, 2934, 2877, 1688, 1656, 1635, 1605, 1578, 1516,
1445, 1371, 1330, 1297, 1277, 1227, 1179, 1161, 1122, 987, 885, 752,
699 cm−1. HRMS (ESI, m/z): Calcd for C19H19N3O4 [M + Na]+
376.1273; found 376.1295.
2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-(n-propyl)
benzamide (4m): M.p. 160–161 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 0.93 (t, J = 7.6 Hz, 3H, CH3), 1.53–1.62 (m, 2H, CH2), 1.95 (s, 3H,
CH3), 3.26 (dd, J = J′ = 6.4 Hz, 2H, CH2), 7.22–7.27 (m, 2H, ArH),
7.36 (d, J = 8.0 Hz, 1H, ArH), 7.54–7.61 (m, 3H, ArH), 7.81 (d,
J = 8.0 Hz, 1H, ArH), 8.54 (d, J = 8.4 Hz, 1H, ArH), 8.83 (t, J =
5.2 Hz, 1H, NH), 10.43 (s, 1H, NH), 12.43 (s, 1H, OH). IR (KBr):
ν 3388, 3322, 3105, 3056, 2961, 2932, 2867, 1775, 1689, 1657, 1636,
1606, 1580, 1549, 1446, 1371, 1336, 1298, 1283, 1260, 1228, 1162,
1125, 1107, 884, 751 cm−1. HRMS (ESI, m/z): Calcd for C20H21N3O4
[M + Na]+ 390.1430; found 390.1458.
References
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2-((1-Acetyl-3-hydroxy-2-oxoindolin-3-yl)amino)-N-(furan-2-ylmethyl)
benzamide (4n): M.p. 188–189 °C; 1H NMR (DMSO-d6, 400 MHz):
δH 1.95 (s, 3H, CH3), 4.52 (d, J = 5.6 Hz, 2H, CH2), 6.36 (d, J =
3.2 Hz, 1H, ArH), 6.43 (s, 1H, ArH), 7.22–7.27 (m, 2H, ArH), 7.36 (d,
J = 8.0 Hz, 1H, ArH), 7.56–7.62 (m, 4H, ArH), 7.85 (d, J = 7.6 Hz,
1H, ArH), 8.56 (d, J = 8.4 Hz, 1H, ArH), 9.34 (t, J = 5.2 Hz, 1H, NH),
10.43 (s, 1H, NH), 12.43 (s, 1H, OH). IR (KBr): ν 3344, 3277, 3254,
3168, 3123, 3091, 2995, 1687, 1673, 1643, 1582, 1524, 1452, 1366,
1329, 1310, 1296, 1284, 1259, 1232, 1191, 1164, 1146, 1011, 886,
791, 767, 755 cm−1. HRMS (ESI, m/z): Calcd for C22H19N3O5 [M +
Na]+ 428.1222; found 428.1250.
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Conclusion
In summary, a mild, facile and environmentally benign method
has been developed for the synthesis of 1′,3′-dihydrospiro
[indolin-2-one-3,2′-quinazolin]-4′-one and 2-(1-acetyl-3-hydroxy-
2-oxoindolin-3-ylamino)benzamide derivatives in high yields
in ionic liquids. The advantages of this procedure include
mild reaction conditions, high yields, one-pot procedure,
operational simplicity and being environmentally benign.
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We are grateful to the National Natural Science foundation of
China (20802061), the Priority Academic Program Develop-
ment of the Jiangsu Higher Education Institutions and the Qing
Lan Project (08QLT001, 10QLD008) of the Jiangsu Education
Committee for financial support.
Crystallographic data for the structure of 3h reported in this
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