An efficient protocol for multicomponent synthesis of spirooxindoles employing L-proline as catalyst at room temperature

Article abstract of DOI:10.1002/jhet.451

An efficient three-component one-pot synthesis of medicinally important spirooxindoles is described by the reaction of isatin, malononitrile/ethyl cyanoacetate, and dimedone/barbituric acid using L-proline as catalyst in ethanol at room temperature. This approach is convenient, mild, and affords the products in high yields without the use of chromatography.

Full text of DOI:10.1002/jhet.451

November 2010
An Efficient Protocol for Multicomponent Synthesis of
Spirooxindoles Employing L-Proline as Catalyst
at Room Temperature
1323
Dushyant Singh Raghuvanshi and Krishna Nand Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi,
Uttar Pradesh 221005, India
*
E-mail: knsinghbhu@yahoo.co.in
Received November 14, 2009
DOI 10.1002/jhet.451
Published online 23 August 2010 in Wiley Online Library (wileyonlinelibrary.com).
An efficient three-component one-pot synthesis of medicinally important spirooxindoles is described
by the reaction of isatin, malononitrile/ethyl cyanoacetate, and dimedone/barbituric acid using L-proline
as catalyst in ethanol at room temperature. This approach is convenient, mild, and affords the products
in high yields without the use of chromatography.
J. Heterocyclic Chem., 47, 1323 (2010).
INTRODUCTION
remains enough scope for an efficient, high yielding,
and mild approach to achieve such systems.
Indole nucleus is the most common and important
feature of a variety of natural products and pharmaceuti-
cals [1,2]. Sharing of the indole 3-carbon atom in the
formation of spirooxindole system has stimulated much
interest in medicinal and biological chemistry [3–9].
The unique structural array and the pharmacological ac-
tivity displayed by the class of functionalized spirooxin-
dole compounds have made them attractive synthetic
targets [10]. Azaspiro derivatives are well-known
Multicomponent reactions (MCRs) have recently
emerged as valuable tool in the preparation of structur-
ally diverse drug-like heterocyclic compounds [28,29].
The MCR strategy offers significant advantages over
conventional linear-type synthesis due to its flexible,
convergent, and atom efficient nature [30]. Reactions
using organocatalysts have attracted a great deal of
attention in recent years to avoid the use of expensive
transition metals [31]. Several amino acids have
undoubtedly been the most successful catalysts in enam-
ine- and iminium-type transformations. L-Proline has
been regarded as the simplest ‘enzyme’ and has been
elegantly used as a versatile organocatalyst in various
synthetic routes for carbonAcarbon and carbonAheter-
oatom bonds [32–34]. The rigid ring structure, easy
availability, nontoxic nature, economical viability, and
simple to use make this tiny molecule a remarkable
organocatalyst in synthesizing molecules of biological
interest.
[
10,11], but the preparation of the corresponding oxa
analogues has evolved at a relatively slow pace [12].
Among the oxygen-containing heterocycles fused with
indole ring system, chromene-based structures are found
to manifest diverse activities such as antidepresssant,
antihypertensive, anti-tubulin, antiviral, antioxidative,
etc., [13–23]. The current interest in 5,6,7,8-tetrahydro-
4H-chromene derivatives bearing nitrile functionality,
especially 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chro-
mene-3-carbonitriles, arises from their potential applica-
tion in the treatment of human neurodegenerative disor-
ders [24]. Owing to their medicinal utility, some reports
on the multicomponent entry to chromene based spi-
Considering the biomedical applications of spirooxin-
dole derivatives and in view of the limitations of the
existing methods, we were prompted to exploit the cata-
lytic potential of L-proline (10 mol %) for a facile and
efficient multicomponent synthesis of functionalized spi-
rooxindoles by the reaction of isatins, malononitrile or
rooxindoles have appeared employing TEBA-H O (2–6
2
ꢀ
h, 60 C) [25], electrocatalytic strategy (NaBr/ROH, 32–
6
4 min) [26], and InCl /SiO (1.5 h; MW, 3–3.5 min)
3 2
[27]. Despite the availability of these methods, there
V
C
2010 HeteroCorporation

1
324
D. S. Raghuvanshi and K. N. Singh
Vol 47
Scheme 1
comparable to the yield obtained under L-proline cata-
lyzed conditions in ethanol (entry 9). The other catalysts
viz., ZnCl , K CO , and KF/Al O did not work well
2
2
3
2 3
under the investigated conditions.
Under the optimized set of reaction conditions (entry
), isatin, 5-bromoisatin, N-methylisatin, and N-acetyli-
9
satin 1 were allowed to undergo L-proline (10 mol %)
catalyzed multicomponent reaction with malononitrile or
ethyl cyanoacetate 2 and barbituric acid or dimedone 3
in an equimolar ratio in ethanol at room temperature.
The results are given in Table 2. After the reaction was
over (TLC), the resulting solid was filtered and washed
from ethanol/methanol to yield pure substituted spiroox-
indoles 4a–4p. All the products were crystalline and
fully characterized based on their melting points, ele-
ethyl cyanoacetate, and barbituric acids or dimedone at
room temperature (Scheme 1).
RESULTS AND DISCUSSION
To optimize the reaction conditions, a typical reaction
of isatin 1a, malononitrile 2, and dimedone 3a was car-
ried out in the presence of various catalysts in ethanol
and water at different temperatures. The outcome is
given in Table 1. The optimum concentration of the cat-
alyst L-proline was also determined for the model reac-
tion at 5, 10, and 15 mol % in ethanol at room tempera-
ture, affording the product 4a in 75, 92, and 92% yields
respectively. After systematic screening, the best result
is obtained when the reaction is carried out with 10 mol
1
13
mental analyses, and spectral data (IR, H NMR,
NMR).
C
CONCLUSIONS
The present report describes L-proline catalyzed multi-
component synthesis of spirooxindoles in excellent
yields. This protocol is efficient, simple, mild, eco-
friendly, and also advantageous in terms of short reac-
tion time and easy workup.
%
of L-proline in ethanol at room temperature (cf. entry
). Organocatalytic activity of L-proline is mainly due to
9
its Lewis base character, capability for inducing enam-
ine formation, and hydrogen bonding with electronega-
tive atoms of other functionalized groups. It is worth-
while to mention that the reaction is also catalyzed
EXPERIMENTAL
IR spectra were recorded on a JASCO FT/IR-5300 spectro-
photometer; whereas, NMR was run on a JEOL AL300 FT
NMR spectrometer. The chemical shifts are given in d ppm
with respect to TMS as internal standard. Elemental analysis
(C, H, N) for final compounds were performed on a Model
significantly by an ionic liquid [bmim]BF in water. The
4
use of ionic liquid alone as solvent could improve the
yield of the product further (entries 14 and 15), but not
Table 1
Optimization of reaction conditions for the preparation of 4a.
a
Yield (%)
ꢀ
Entry
Catalyst
Temperature ( C)
Time (min)
EtOH
2
H O
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
Nil
Nil
ZnCl
ZnCl
RT
60
RT
60
RT
60
RT
60
120
120
120
90
120
90
Trace
25
17
34
28
56
35
62
92
90
90
65
68
Nil
10
12
20
25
52
27
65
85
85
84
74
79
2
2
K
K
2
CO
CO
3
2
3
KF-Al
KF-Al
2
O
3
120
90
2
O
3
L-Proline
L-Proline
L-Proline
RT
60
7
15
1
1
1
1
1
1
Reflux
RT
60
RT
60
15
30
[bmim]BF
[bmim]BF
[bmim]BF
[bmim]BF
4
4
4
4
20
120
90
b
(77)
b
(81)
a
Yield based on isatin.
Yield obtained by the use of ionic liquid as solvent without water or ethanol.
Journal of Heterocyclic Chemistry
b
DOI 10.1002/jhet

November 2010
An Efficient Protocol for Multicomponent Synthesis of Spirooxindoles
Employing L-Proline as Catalyst at Room Temperature
1325
Table 2
L-Proline catalyzed multicomponent synthesis of spirooxiindole derivatives 4.
a
Yield (%)
ꢀ
Product
R
R
1
R
2
X
Y
Time (min)
Mp ( C)
4
a
H
Br
H
H
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CH
CH
CH
CH
CH
CH
CH
CH
NH
NCH
NCH
NCH
2
2
2
2
2
2
2
2
C(CH
C(CH
C(CH
C(CH
3
3
3
3
)
)
)
)
2
2
2
2
7
6
92
87
94
92
90
86
96
93
85
94
90
91
87
85
90
86
305–306
304–305
247–248
232–233
310–311
273–274
245–246
251–252
277–278
228–229
225–226
228–229
228–230
260–262
189–190
264–265
4b
4
c
CH
COCH
3
6
7
4d
H
3
3
3
4
4
e
f
H
H
H
CH
CH
CH
CH
CH
2
6
Br
H
2
6
7
4g
3
2
2
4h
H
H
COCH
H
H
6
7
4
4
i
j
CO
CO
CO
CO
H
H
3
3
3
6
6
4k
CH
3
4
l
H
COCH
7
4m
H
Br
H
H
H
H
H
CO
2
2
2
2
Et
CH
CH
2
C(CH
C(CH
3
3
)
)
2
2
12
12
15
15
4n
CO
CO
CO
Et
Et
Et
2
4o
NH
NH
CO
CO
4p
Br
a
Yields based on isatins.
CE-440 CHN Analyzer. The TLC spots were detected using
iodine chamber. All commercially available chemicals were
purchased from Aldrich (USA) and E. Merck (Germany).
General experimental procedure for the synthesis of spi-
rooxindoles 4. L-Proline (10 mol %) was added to a mixture
of isatin (1, 1 mmol), malononitrile or ethyl cyanoacetate
3370, 3325, 3178, 2960, 2205, 1711, 1672, 1356, 1224, 1053
ꢂ1
1
cm
CH ), 2.11 (s, 2H, CH ), 2.56 (s, 2H, CH ), 3.14 (s, 3H,
;
H NMR (300 MHz, DMSO-d ): d ¼ 1.04 (s, 6H, 2
2 2
6
3
3 2
NCH ), 6.94–7.06 (m, 3H, Ar), 7.14–7.32 (m, 3H, Ar, NH )
1
3
ppm; C NMR (75 MHz, DMSO-d
6
): d ¼ 26.5, 27.3, 27.9,
32.0, 39.9, 46.5, 50.2, 57.1, 108.2, 110.8, 116.8, 122.2, 122.9,
128.5, 134.6, 144.0, 158.9, 164.3, 176.6, 194.7 ppm; Anal.
Calcd. for C H N O : C, 68.75; H, 5.48; N, 12.03. Found:
(
1 mmol), and dimedone or barbituric acid (1 mmol) in etha-
nol (2 mL), and the resulting mixture was stirred at room tem-
perature for 6–15 min. Upon completion of the reaction
20 19 3 3
C, 68.67; H, 5.54; N, 11.95.
0
0
0
0
(
TLC), the mixture was allowed to cool to room temperature.
1 -Acetyl-2-amino-7,7-dimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hex-
0
The resulting solid was filtered and washed successively with
water (2 ꢁ 20 mL) and cold ethanol (2 ꢁ 0.5 mL) to afford
pure product 4 (white shiny powder).
ahydrospiro[chromene-4,3 -indole]-3-carbonitrile (4d). IR
(KBr): 3335, 3194, 2962, 2208, 1754, 1720, 1675, 1350, 1271,
ꢂ1
1
1054 cm ; H NMR (300 MHz, DMSO-d ): d ¼ 1.01 (s, 3H,
6
0
0
0
2
chromene-4,3 -indole]-3-carbonitrile (4a). IR (KBr): 3376,
-Amino-7,7-dimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydrospiro
0
CH
CH
3
2
), 1.06 (s, 3H, CH ), 2.13–2.21 (m, 2H, CH
3
2
), 2.57 (s, 2H,
[
), 2.64 (s, 3H, CH CO), 7.17–7.26 (m, 2H, Ar), 7.29–7.38
3
ꢂ1
3
1
313, 3143, 2961, 2192, 1722, 1655, 1349, 1219, 1054 cm
;
(m, 1H, Ar), 7.55 (s, 2H, NH ), 8.06 (d, J ¼ 7.8 Hz, 1H, Ar)
2
13
ppm; C NMR (75 MHz, DMSO-d ): d ¼ 6.3, 27.1, 27.8,
H NMR (300 MHz, DMSO-d ): d ¼ 1.02 (s, 3H, CH ), 1.05
6
3
6
(
(
s, 3H, CH ), 2.10–2.19 (m, 2H, CH ), 2.58 (s, 2H, CH ), 6.79
d, J ¼ 7.5 Hz, 1H, Ar), 6.89 (t, J ¼ 7.5 Hz, 1H, Ar), 6.97 (d,
3
2
2
32.4, 39.8, 47.6, 49.5, 57.1, 110.8, 115.5, 117.3, 123.4, 126.2,
128.8, 133.0, 139.5, 158.8, 164.9, 171.0, 177.9, 195.4 ppm;
J ¼ 7.5 Hz, 1H, Ar), 7.14 (t, J ¼ 7.5 Hz, 1H, Ar), 7.23 (s,
19 3 4
Anal. Calcd. for C21H N O : C, 66.83; H, 5.07; N, 11.13.
1
3
2
H, NH ), 10.41 (s, 1H, NH) ppm; C NMR (75 MHz,
2
Found: C, 66.78; H, 5.14; N, 11.04.
0
0
0
DMSO-d ): d ¼ 27.1, 27.7, 32.0, 40.0, 46.9, 50.1, 57.5, 109.3,
2-Amino-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydrospiro-[chromene-
0
6
1
1
5
10.9, 117.4, 121.8, 123.1, 128.2, 134.5, 142.1, 158.9, 164.2,
78.1, 194.9 ppm; Anal. Calcd. for C19 : C, 68.05; H,
.11; N, 12.53. Found: C, 67.94; H, 5.17; N, 12.42.
-Amino-5 -bromo-7,7-dimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hex-
0
4,3 -indole]-3-carbonitrile (4e). IR (KBr): 3356, 3295, 3178,
ꢂ1
1
; H NMR
H
17
N
3
O
3
2956, 2214, 1708, 1656, 1353, 1212, 1071 cm
(300 MHz, DMSO-d
2.32 (m, 2H, CH ), 2.65–2.71 (m, 2H, CH
): d ¼ 1.92–2.05 (m, 2H, CH
), 2.13–
6
2
0
0
0
0
2
ahydrospiro[chromene-4,3 -indole]-3-carbonitrile (4b). IR
2
2
), 6.76 (d, J ¼ 7.5
Hz, 1H, Ar), 6.89 (t, J ¼ 7.5 Hz, 1H, Ar), 7.02 (d, J ¼ 7.5
13
(
KBr): 3361, 3287, 3163, 2956, 2200, 1729, 1657, 1352, 1224,
Hz, 1H, Ar), 7.14 (t, J ¼ 7.5 Hz, 1H, Ar), 7.24 (s, 2H, NH
2
),
ꢂ1
1
1
2
¼
056 cm ; H NMR (300 MHz, DMSO-d
6
): d ¼ 1.03 (s, 6H,
10.42 (s, 1H, NH) ppm; C NMR (75 MHz, DMSO-d
6
): d ¼
CH ), 2.15 (s, 2H, CH ), 2.45–2.65 (m, 2H, CH ), 6.78 (d, J
19.10, 26.9, 36.14, 46.5, 57.3, 108.9, 112.2, 117.6, 121.5,
123.8, 128.5, 135.0, 142.3, 158.7, 166.7, 178.4, 195.2 ppm;
3
2
2
8.0 Hz, 1H, Ar), 7.19 (s, 1H, Ar), 7.24–7.36 (m, 3H, Ar,
1
3
NH ), 10.52 (s, 1H, NH) ppm; C NMR (75 MHz, DMSO-
Anal. Calcd. for C17
found: C, 66.29; H, 4.33; N, 13.56.
13 3 3
H N O : C, 66.44; H, 4.26; N, 13.67;
2
d
1
1
3
6
): d ¼ 27.3, 27.8, 32.2, 39.9, 47.1, 50.0, 56.8, 110.3, 111.6,
0
0
0
0
13.4, 117.3, 126.5, 131.0, 136.9, 141.5, 158.9, 165.2, 177.7,
94.9 ppm; Anal. Calcd. for C H BrN O : C, 55.09; H,
.89; N, 10.14. Found: C, 54.90; H, 3.96; N, 10.03.
2-Amino-5 -bromo-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydrospiro
0
[chromene-4,3 -indole]-3-carbonitrile (4f). IR (KBr): 3428,
ꢂ1
1
9
16
3 3
3314, 3185, 2953, 2210, 1702, 1678, 1360, 1180, 1085 cm
1
;
0
0
0
0
2
spiro[chromene-4,3 -indole]-3-carbonitrile (4c). IR (KBr):
-Amino-1 ,7,7-trimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydro-
0
H NMR (300 MHz, DMSO-d
2
2.12–2.37 (m, 2H, CH ), 2.55–2.77 (m, 2H, CH
6
): d ¼ 1.77–2.06 (m, 2H, CH
2
),
2
), 6.77 (d, J
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1
326
D. S. Raghuvanshi and K. N. Singh
Vol 47
¼
7.3 Hz, 1H, Ar), 7.16–7.63 (m, 4H, Ar, NH
2
), 10.56 (s, 1H,
): d ¼ 19.5, 27.0,
6.8, 47.4, 56.5, 111.5, 113.6, 117.0, 125.9, 130.8, 137.3,
41.2, 159.0, 166.9, 177.5, 195.4 ppm; Anal. Calcd. for
59.18; H, 4.14; N, 19.17. Found: C, 58.97; H, 4.36; N,
19.03.
13
NH) ppm; C NMR (75 MHz, DMSO-d
6
0
0
0
0
3
1
1 -Acetyl-7-amino-1,3-dimethyl-2,2 ,4-trioxo-1,1 ,2,2 ,3,4-
0
hexahydrospiro[indole-3 ,5-pyrano[2,3-d]pyrimidine]-6-car-
bonitrile (4l). IR (KBr): 3385, 3310, 3208, 3186, 2218, 1725,
C H BrN O : C, 52.87; H, 3.13; N, 10.88; found: C, 52.78;
1 12
7
3 3
ꢂ1
1
H, 3.05; N, 10.76.
0
1695, 1660, 1500, 1387 cm ; H NMR (300 MHz, DMSO-
): d ¼ 2.61 (s, 3H, CH ), 3.04 (s, 3H, CH ), 3.42 (s, 3H,
CH
), 7.20 (t, J ¼ 7.2 Hz, 1H, Ar), 7.25–7.40 (m, 2H, Ar),
0
0
0
2
chromene-4,3 -indole]-3-carbonitrile (4g). IR (KBr): 3460,
-Amino-1 -methyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydrospiro
0
d
6
3
3
[
3
ꢂ1
1
13
C
3
371, 3142, 2956, 2202, 1709, 1671, 1359, 1221 cm
;
H
7.86 (s, 2H, NH ), 8.10 (d, J ¼ 7.9 Hz, 1H, Ar) ppm;
2
NMR (300 MHz, DMSO-d ): d ¼ 1.77–2.05 (m, 2H, CH ),
NMR (75 MHz, DMSO-d ): d ¼ 26.4, 27.6, 29.7, 48.6, 57.5,
6
2
6
2
.10–2.35 (m, 2H, CH
2
), 2.57–2.90 (m, 2H, CH
2
), 3.15 (s, 3H,
87.2, 115.3, 116.6, 124.0, 126.0, 129.2, 132.4, 139.8, 149.5,
152.6, 158.2, 159.9, 170.8, 177.5 ppm; Anal. Calcd. for
C H N O : C, 58.02; H, 3.84; N, 17.80. Found: C, 57.85; H,
3 2
NCH ), 6.86–7.11 (m, 3H, Ar), 7.18–7.37 (m, 3H, Ar, NH )
13
ppm; C NMR (75 MHz, DMSO-d ): d ¼ 19.6, 26.5, 26.9,
6
19 15 5 5
3
1
6.7, 46.4, 57.5, 108.3, 112.0, 117.6, 122.8, 124.0, 128.7,
33.4, 143.8, 158.6, 166.2, 176.7, 195.2 ppm; Anal. Calcd. for
3.92; N, 17.65.
Ethyl 2-amino-7,7-dimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahy-
0
0
0
0
C
4
18
H
15
N
.82; N, 12.95.
3
O
3
: C, 67.28; H, 4.71; N, 13.08; found: C, 67.13; H,
drospiro[chromene-4,3 -indole]-3-carboxylate (4m). IR (KBr):
ꢂ1
3368, 3237, 3113, 2959, 1684, 1614, 1525, 1474, 1349 cm
1
;
0
0
0
0
1
chromene-4,3 -indole]-3-carbonitrile (4h). IR (KBr): 3441,
-Acetyl-2-amino-2 ,5-dioxo-1 ,2 ,5,6,7,8-hexahydrospiro
0
H NMR (300 MHz, DMSO-d ): d ¼ 0.79 (t, J ¼ 6.9 Hz, 3H,
6
[
CH ), 0.95 (s, 3H, CH ), 1.01 (s, 3H, CH ), 1.98–2.18 (m, 2H,
3
3
3
ꢂ1
3
329, 3187, 2200, 1750, 1712, 1669, 1358, 1275, 1202 cm
;
CH
2
), 2.45–2.61 (m, 2H, CH
2
2
), 3.67–3.71 (m, 2H, CH ), 6.65
1
H NMR (300 MHz, DMSO-d
6
): d ¼ 1.81–2.09 (m, 2H, CH
), 2.56 (s, 3H, CH
H, CH ), 7.13–7.25 (m, 2H, Ar), 7.27–7.43 (m, 1H, Ar), 7.56
2
),
(d, J ¼ 7.2 Hz, 1H, Ar), 6.73 (t, J ¼ 7.2 Hz, 1H, Ar), 6.81 (d,
J ¼ 7.2 Hz, 1H, Ar), 7.01 (t, J ¼ 7.2 Hz, 1H, Ar), 7.85 (s,
2
2
.14–2.42 (m, 2H, CH
2
3
CO), 2.60–2.86 (m,
13
2H, NH ), 10.13 (s, 1H, NH) ppm; C NMR (75 MHz,
2
2
13
(
(
1
1
m, 2H, NH ), 8.06 (d, J ¼ 7.4 Hz, 1H, Ar) ppm; C NMR
DMSO-d ): d ¼ 13.0, 26.6, 27.7, 31.5, 46.6, 50.6, 58.8, 76.3,
2
6
75 MHz, DMSO-d
6
): d ¼ 19.8, 25.8, 26.5, 36.0, 47.9, 57.2,
11.9, 115.5, 117.1, 123.4, 125.6, 128.8, 133.1, 139.0, 158.8,
15 3 4
66.9, 170.6, 178.2, 195.5 ppm; Anal. Calcd. for C19H N O :
108.1, 113.0, 120.5, 122.1, 127.2, 135.9, 144.0, 159.0, 162.3,
22 2 5
167.6, 179.76, 194.5 ppm; Anal. Calcd. for C21H N O : C,
65.96; H, 5.80; N, 7.33. Found: C, 65.81; H, 5.72; N, 7.20.
0
0
0
0
C, 65.32; H, 4.33; N, 12.03; found: C, 65.25; H, 4.43; N,
1.91.
-Amino-2,2 ,4-trioxo-1,1 ,2,2 ,3,4-hexahydrospiro[indole-3 ,5-
pyrano[2,3-d]pyrimidine]-6-carbonitrile (4i). IR (KBr): 3446,
285, 3142, 3035, 2208, 1700, 1645, 1512, 1441, 1398, 1245
Ethyl 2-amino-5 -bromo-7,7-dimethyl-2 ,5-dioxo-1 ,2 ,5,6,7,
0
1
8-hexahydrospiro[chromene-4,3 -indole]-3-carboxylate (4n). IR
(KBr): 3365, 3240, 3187, 2955, 1690, 1612, 1520, 1472, 1345
cm ; H NMR (300 MHz, DMSO-d ): d ¼ 0.82 (t, J ¼ 7.2
Hz, 3H, CH ), 0.96 (s, 3H, CH ), 1.0 (s, 3H, CH
(m, 2H, CH ), 2.53 (s, 2H, CH ), 3.72–3.74 (m, 2H, CH ),
0
0
0
0
7
ꢂ1
1
6
3
3
3
3
), 2.0–2.1
ꢂ1
1
cm ; H NMR (300 MHz, DMSO-d ): d ¼ 6.76 (d, J ¼ 7.9
6
2
2
2
Hz, 1H, Ar), 6.90 (t, J ¼ 7.9 Hz, 1H, Ar), 7.10–7.15 (m, 2H,
6.62 (d, J ¼ 7.8 Hz, 1H, Ar), 6.99 (s, 1H, Ar), 7.20 (d, J ¼
7.8 Hz, 1H, Ar), 7.91 (s, 2H, NH ), 10.29 (s, 1H, NH) ppm;
Ar), 7.34 (s, 2H, NH
1
2
), 10.45 (s, 1H, NH), 11.04 (s, 1H, NH),
): d
46.8, 57.7, 86.9, 109.4, 116.8, 121.6, 124.0, 128.5, 134.1,
2
1
2.29 (br s, 1H, NH) ppm; C NMR (75 MHz, DMSO-d
3
13
6
C NMR (75 MHz, DMSO-d
46.8, 50.5, 58.9, 76.5, 108.3, 113.8, 120.7, 122.1, 127.3, 136.0,
144.3, 159.2, 162.1, 167.7, 179.75, 194.7 ppm; Anal. Calcd.
6
): d ¼ 13.2, 26.5, 27.9, 31.5,
¼
1
42.3, 149.2, 153.3, 158.5, 161.7, 177.8 ppm; Anal. Calcd. for
C
2
15
H
9
N
5
O
4
: C, 55.73; H, 2.81; N, 21.66. Found: C, 55.60; H,
.72; N, 21.49.
-Amino-1,3-dimethyl-2,2 ,4-trioxo-1,1 ,2,2 ,3,4-hexahydrospiro
2 5
for C21H21BrN O : C, 54.68; H, 4.59; N, 6.07. Found: C,
54.55; H, 4.61; N, 5.92.
0
0
0
0
0
0
7
Ethyl 7-amino-2,2 ,4-trioxo-1,1 ,2,2 ,3,4-hexahydrospiro[in-
0
0
[indole-3 ,5-pyrano[2,3-d]pyrimidine]-6-carbonitrile (4j). IR
dole-3 ,5-pyrano[2,3-d]pyrimidine]-6-carboxylate (4o). IR
(KBr): 3425, 3318, 3162, 2201, 1692, 1650, 1578, 1468, 1390,
(
KBr): 3348, 3182, 3015, 2205, 1715, 1668, 1540, 1478, 1385,
ꢂ1
1
225 cm ; H NMR (300 MHz, DMSO-d
ꢂ1
1
1342 cm ; H NMR (300 MHz, DMSO-d
1
CH
6
): d ¼ 3.00 (s, 3H,
6
): d ¼ 0.77 (t, J ¼
3
), 3.35 (s, 3H, CH
3
), 6.79 (d, J ¼ 7.3 Hz, 1H, Ar), 6.87 (t,
7.2 Hz, 3H, CH ), 3.69–3.72 (m, 2H, CH
3
2
), 6.65 (d, J ¼ 7.5
J ¼ 7.3 Hz, 1H, Ar), 7.09–7.16 (m, 2H, Ar), 7.56 (s, 2H,
Hz, 1H, Ar), 6.77 (t, J ¼ 7.5 Hz, 1H, Ar), 6.92–7.08 (m, 2H,
1
3
NH ), 10.42 (s, 1H, NH) ppm; C NMR (75 MHz, DMSO-
Ar), 7.92 (s, 2H, NH ), 10.21 (s, 1H, NH), 10.94 (s, 1H, NH),
2
2
13
d ): d ¼ 27.3, 29.5, 47.8, 57.6, 87.2, 109.5, 116.7, 121.7,
12.14 (br s, 1H, NH) ppm; C NMR (75 MHz, DMSO-d ): d
6
6
123.8, 128.3, 133.4, 142.2, 149.5, 152.0, 158.0, 159.0, 177.4
ppm; Anal. Calcd. for C17
¼ 13.1, 46.2, 59.2, 76.3, 89.2, 108.3, 120.8, 122.7, 127.4,
H
13
N
5
O
9.93. Found: C, 57.95; H, 3.62; N, 19.81.
4
: C, 58.12; H, 3.73; N,
135.3, 144.0, 149.1, 152.2, 158.6, 161.2, 167.4, 179.4 ppm;
1
14 4 6
Anal. Calcd. for C17H N O : C, 55.14; H, 3.81; N, 15.13.
0
0
0
0
7
drospiro[indole-3 ,5-pyrano[2,3-d]pyrimidine]-6-carbonitrile
-Amino-1,1 ,3-trimethyl-2,2 ,4-trioxo-1,1 ,2,2 ,3,4-hexahy-
0
Found: C, 54.95; H, 3.74; N, 15.02.
0
0
0
0
Ethyl 7-amino-5 -bromo-2,2 ,4-trioxo-1,1 ,2,2 ,3,4-hexahy-
0
(
1
4k). IR (KBr): 3354, 3248, 3150, 2212, 1725, 1682, 1493,
ꢂ1
drospiro[indole-3 ,5-pyrano[2,3-d]pyrimidine]-6-carboxylate
(4p). IR (KBr): 3420, 3315, 3160, 2201, 1692, 1655, 1579,
1
376, 1210 cm ; H NMR (300 MHz, DMSO-d
6
): d ¼ 3.02
ꢂ1
1
(
s, 3H, CH ), 3.14 (s, 3H, CH ), 3.38 (s, 3H, CH ), 6.92–
3
1463, 1395, 1348 cm ; H NMR (300 MHz, DMSO-d ): d ¼
3
3
6
7
7
.10 (m, 2H, Ar), 7.20 (d, J ¼ 7.3 Hz, 1H, Ar), 7.27 (t, J ¼
0.79 (t, J ¼ 7.5 Hz, 3H, CH ), 3.70–3.73 (m, 2H, CH ), 6.68
3
2
1
3
.3 Hz, 1H, Ar), 7.64 (s, 2H, NH
): d ¼ 26.7, 27.5, 29.3, 47.4, 57.8, 87.6,
08.5,116.6, 122.5, 123.5, 128.9, 132.9, 143.8, 149.7, 152.2,
58.0, 159.9, 176.4 ppm; Anal. Calcd. for C H N O : C,
2
) ppm; C NMR (75
(d, J ¼ 7.5 Hz, 1H, Ar), 6.94–7.11 (m, 2H, Ar), 7.93 (s, 2H,
2
MHz, DMSO-d
1
1
6
NH
NH) ppm; C NMR (75 MHz, DMSO-d
59.5, 76.4, 89.5, 108.1, 121.0, 122.9, 128.1, 135.5, 144.2,
), 10.22 (s, 1H, NH), 10.94 (s, 1H, NH), 12.16 (br s, 1H,
13
6
): d ¼ 13.3, 46.1,
1
8 15 5 4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2010
An Efficient Protocol for Multicomponent Synthesis of Spirooxindoles
Employing L-Proline as Catalyst at Room Temperature
1327
1
C
49.3, 152.5, 158.4, 161.0, 167.2, 179.5 ppm; Anal. Calcd. for
13BrN : C, 45.45; H, 2.92; N, 12.47. Found: C, 45.29;
H, 2.83; N, 12.35.
[18] Hiramoto, K.; Nasuhara, A.; Michiloshi, K.; Kato, T.; Kiku-
gawa, K. Mutat Res 1997, 395, 47.
17
H
4 6
O
[
19] Tangmouo, J. G.; Meli, A. L.; Komguem, J.; Kuete, V.;
Ngounou, F. N.; Lontsi, D.; Beng, V. P.; Choudhary, M. I.; Sonden-
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Acknowledgment. The authors thank the Department of Bio-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet