A new InCl3-catalyzed, facile and efficient method for the synthesis of spirooxindoles under conventional and solvent-free microwave conditions

Article abstract of DOI:10.1016/j.tet.2006.12.042

A simple and efficient method for the one-pot three-component synthesis of new spirooxindoles under conventional and solvent-free microwave irradiation is described.

Full text of DOI:10.1016/j.tet.2006.12.042

Tetrahedron 63 (2007) 2057–2063
A new InCl3-catalyzed, facile and efficient method for the
synthesis of spirooxindoles under conventional and solvent-free
microwave conditions
*
Gnanamani Shanthi, Ganesan Subbulakshmi and Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamilnadu, India
Received 19 September 2006; revised 28 November 2006; accepted 14 December 2006
Available online 17 December 2006
Abstract—A simple and efficient method for the one-pot three-component synthesis of new spirooxindoles under conventional and solvent-
free microwave irradiation is described.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
As part of our endeavor to discover new spirooxindoles of
biocidal interest, and guided by the observation that the pres-
ence of two or more different heterocyclic moieties in a sin-
gle molecule often enhances the biocidal profile remarkably,
we investigated a three-component reaction involving isatin
with malononitrile and a-naphthol, in order to synthesize
a new class of spirooxindoles with fused chromenes. Fused
chromenes have been found to have a wide spectrum of
activities such as antimicrobial,6 antiviral,7 mutagenicity,8
antiproliferative,9 sex pheromone,10 antitumor,11 and central
nervous system activities.12
The indole moiety is probably the most well-known hetero-
cycle, a common and important feature of a variety of natural
products and medicinal agents.1 Spiro compounds represent
an important class of naturally occurring substances charac-
terized by highly pronounced biological properties. The
spirooxindole system is the core structure of many pharma-
cological agents and natural alkaloids.2–5 For example,
spirotryprostatin A, a natural alkaloid isolated from the
fermentation broth of Aspergillus fumigatus, has been iden-
tified as a novel inhibitor of microtubule assembly,5 and pter-
opodine and isopteropodine have been shown to modulate
the function of muscarinic serotonin receptors (Fig. 1).2
2. Results and discussion
In recent years, indium(III) chloride has received consider-
able attention as an inexpensive, nontoxic, readily available
catalyst for various transformations under mild and conve-
nient conditions, affording the corresponding products in ex-
cellent yields with high selectivity. However, there has been
no example of spirooxindoles with fused chromenes, so as
part of our ongoing interest in indium(III) chloride-catalyzed
reactions13 and surface solid state reactions coupled with
microwave irradiation,14 we herein report for the first time
a simple, new, and efficient method for the synthesis of spi-
rooxindoles with fused chromenes, through the three-compo-
nent condensation of isatin, malononitrile, and a-naphthol/
b-naphthol using indium trichloride impregnated silica gel
as a catalyst, under solvent-free conditions (Scheme 1).
Me
N
O
O
O
H
O
N
N
H
O
H
OMe
O
N
N
H
MeO
H
Spirotryprostatin A
Pteropodine
Me
O
H
O
N
H
H
OMe
O
N
H
Isopteropodine
Initially, evaluation of various catalysts and solvent systems
was carried out for the synthesis of spirooxindole with fused
chromenes. After systematic screening, indium(III) chloride
and acetonitrile were found to be the best. The microwave
assisted InCl3/SiO2-catalyzed method was superior to the
Figure 1. Representatives of spirooxindole-containing compounds.
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589;
e-mail: ptperumal@gmail.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.042

2058
G. Shanthi et al. / Tetrahedron 63 (2007) 2057–2063
Table 2. Synthesis of spirooxindoles from 1-naphthol/2-naphthol
O
O
OH
H2N
NC
Entry
Product
MW
(min) (%)
Yielda D (h) Yielda
(%)
InCl3/ SiO2/ MW
(or)
InCl3/ CH3CN
O
+
+
NC
CN
N
O
H
N
H
Reflux
H2N
NC
O
1
3
88
86
1.5
70
6a
Scheme 1. Synthesis of spirooxindoles.
O
N
H
conventional one, as the reaction was high yielding, fast, and
clean without any side products. We also evaluated the
amount of indium trichloride required for this transforma-
tion. As little as 10 mol % of InCl3 catalyzed the reaction
but needs a longer reaction time (8–10 min). With silica
gel alone, the reaction was extremely slow with very poor
yield (10%) (Table 1).
H2N
O
EtO2C
2
3.5
2
68
6b
O
N
H
Table 1. The effect of catalysts and a comparison between conventional and
microwave assisted methods
O
H2N
NC
Entry Catalyst
Acetonitrile/refluxa
MW (solvent-free)a
3
6c
3
90
1.5
75
Time (h) Yieldb (%) Time (min) Yieldb (%)
O
N
CH3
1
2
3
4
5
ZnCl2
FeCl3$6H2O
BiCl3
SnCl2$2H2O
InCl3
3
6
5
4
1.5
45
20
42
45
70
4.5
5
3.5
3.5
3
55
25
48
50
88
H2N
NC
O
4
5
6d
3
87
84
89
2
73
65
71
a
Reactions carried out on a 1 mmol scale.
Isolated yield.
b
O
N
H
We then explored the scope and limitations of the one-pot
reactions involving isatin, malononitrile/ethyl cyanoacetate
with 1-naphthol/2-naphthol (Scheme 2). Results of the inves-
tigation involving thermal heating (method A) as well as
microwave (method B) irradiation are presented in Table 2.
H2N
NC
O
6e
3
1.5
1.5
O
N
CH3
H2N
O
Y
O
H2N
X
O
EtO2C
z
InCl3/ SiO2/ MW
(or)
InCl3/ CH3CN
Reflux
O
+
6f
+
6
3.5
X
NC
N
R
O
O
N
CH3
N
R
1
3
2
a
(or)
O
X = CN
Y = H, Z = OH
Y = OH, Z = H
R = H
Isolated yield.
X = CO2Et
R = CH3
H2N
X
Z
R
X
Y
Encouraged by these results, we were delighted to observe
that this protocol could be extended to a three-component
coupling reaction involving an equimolar quantity of isatin,
malononitrile, and cyclohexanone/dimedone (Scheme 4).
This gave spirooxindoles 9a,b in excellent yields without
the formation of any side products.
O
6a
6b
6c
6d
CN
OH
H
H
H
H
N
R
CO2Et OH
6
CH3 CN
H
OH
H
H
H
CN
OH
6e
6f
CO2Et
H
OH
OH
CH3 CN
H
To further explore the potential of this protocol for heterocy-
clic synthesis, we investigated one-pot reactions involving 1-
phenyl-3-methyl pyrazolon-5-one and 4-hydroxy coumarin
and obtained spirooxindoles in excellent yields (Scheme 5
and Table 3). The X-ray crystal structure of compound 9e
(Fig. 2)18 adds a sharp evidence for the regioselective forma-
tion of spirooxindoles (6 and 9).
Scheme 2. Preparation of spirooxindoles from 1-naphthol/2-naphthol.
We propose the following possible mechanism to account
for the formation of 6. The process represents a typical cas-
cade reaction15 in which the isatin 1 first condenses with ma-
lononitrile 2 to afford isatylidene malononitrile derivative 4.
This step can be regarded as a fast Knoevenagel addition.
The second step involves the ortho C-alkylation of 1-naph-
thol by reaction with the electrophilic C]C double
bond,16 and the nucleophilic addition of the phenolic OH
group on the cyano moiety (Scheme 3).17
The feasibility of employing anilines instead of naphthols
and enones in the reaction was also investigated. Unfortu-
nately, when aniline was used, the reactions were usually
very slow and resulted in a complicated mixture of products.

G. Shanthi et al. / Tetrahedron 63 (2007) 2057–2063
2059
X
O
CN
O
O
(or)
O
O
NC
X
+
O
+
N
+
X
CN
O
O
N
N
R
NR
NR
R = H
R = CH3
1
Ph
OH
X = CN
X = CO2Et
1
2
8
4
R = H
R = CH3
X = CN
X = CO2Et
2
InCl3/SiO2
MW
InCl3/CH3CN
Reflux
InCl3
X
N
..
OH
Ph
O
H2N
X
O
N
H2N
X
O
NR
N
+
O
(or)
4
3
O
O
O
9g-i
N
N
R
InCl3-SiO2
R
9c-f
InCl3
+
Scheme 5. Preparation of spirooxindoles using 1-phenyl-3-methyl pyrazo-
lon-5-one and 4-hydroxy coumarin.
InCl3
N
-
..
HO
N
HO
X
Substituted quinoxaline derivatives are pharmacologically
important compounds. Although rarely described in nature,
both leromycin and actinomycin possessing a quinoxaline
X
O
NR
O
NR
5
Table 3. Synthesis of spirooxindoles from enones
Entry
Reactant
Product
MW Yielda
(min) (%)
D
(h) (%)
Yielda
H2N
NC
O
InCl3
InCl3
O
H
O+
O
HN
X
1
3.5
88
93
1.5 70
N-
X
O
N
H
9a
O
O
NR
H2N
O
NR
O
NC
2
3
3
1.5 75
O
O
O
9b
N
H
Ph
N
O
H2N
H2N
NC
O
Ph
N
N
X
O
O
O
3
90
90
92
1.5 73
N
N
N
O
O
NR
9c
N
H
6
Ph
N
Scheme 3. Plausible mechanism for the reaction of isatin and malononitrile
with a-naphthol.
H2N
EtO2C
O
Ph
N
N
4
5
3
1.5 70
O
O
O
O
N
H
9d
NC
X
+
O
(or)
+
N
R
O
Ph
N
7
1
2
O
H2N
NC
Ph
N
N
R = H
R = CH3
X = CN
X = CO2Et
3.5
1.5 71
O
InCl3/SiO2
MW
InCl3/CH3CN
Reflux
9e
N
CH3
Ph
N
H2N
X
O
H2N
X
O
N
O
H2N
EtO2C
Ph
N
N
O
(or)
6
3
90
2
75
N
O
O
O
9b
O
N
R
9f
N
CH3
9a
R
Scheme 4.
(continued)

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G. Shanthi et al. / Tetrahedron 63 (2007) 2057–2063
Recently, Azizian et al.20 have utilized the carbonyl group of
Table 3. (continued)
MW Yielda
(min) (%)
D
(h) (%)
Yielda
the indenoquinoxaline 10 in a reaction with 4-hydroxy
proline for the synthesis of pyrrolyl indenoquinoxaline de-
rivatives. Taking this into consideration, we replaced isatin
with indenoquinoxaline as the carbonyl component. The
product spiroindenoquinoxaline 11 was confirmed by mass,
IR, 1H NMR, 13C NMR, and elemental analyses (Scheme 6).
Entry
Reactant
Product
H2N
NC
O
O
O
O
7
3.5
3.5
3.5
92
91
95
1.5 72
O
O
O
O
O
N
H
9g
Ph
N
O
O
N
N
CN
CN
NH2
N
InCl3/SiO2
H2N
O
O
O
+
+
O
CN
N
N
MW
(or)
InCl3/CH3CN
Reflux
N
EtO2C
O
8
1.5 68
Ph
O
O
N
9h
N
H
10
2
8
11
Scheme 6. Synthesis of spiroindenoquinoxaline by the three-component
condensation of indenoquinoxaline, malononitrile, and 1-phenyl-3-methyl
pyrazolon-5-one.
H2N
NC
O
O
O
O
9
1.5 74
O
O
N
9i
3. Conclusion
CH3
a
Isolated yield.
In conclusion, we have developed a quick, clean, and simple
method for the synthesis of new spirooxindoles and spiro-
indenoquinoxaline derivatives catalyzed by indium(III)
chloride under solvent-free conditions and also by thermal
heating. Further merits of this method are its generality,
shorter reaction times, and easy work-up. The biological
evaluations of these derivatives are underway.
ring are known to inhibit the growth of Gram-positive bac-
teria and are also active against various transplantable
tumors.19
4. Experimental
4.1. General
Zinc(II) chloride, bismuth(III) chloride, ferric chloride hexa-
hydrate, stannous chloride, isatin, a-naphthol, b-naphthol,
and malononitrile were obtained from S.D. Fine Chemicals.
Indium(III) chloride was purchased from Aldrich. Reagent
grade acetonitrile was used. THF was distilled over sodium-
benzophenone before use. All melting points are uncorrected.
IR spectra were recorded on a Perkin Elmer FT-IR spectro-
photometer. 1H and 13C NMR spectra were recorded in
DMSO-d6 using TMS as an internal standard on a JEOL
spectrometer at 500 MHz and 125 MHz, respectively. Mass
spectra were recorded on a JEOL DX 303 HF spectrometer.
Elemental analyses were recorded using a Thermo Finnigan
FLASH EA 1112 CHN analyzer. Column chromatography
was performed on silica gel (100–200 mesh, SRL, India).
Analytical TLC was performed on precoated plastic sheets
of silica gel G/UV-254 of 0.2 mm thickness (Macherey-
Nagel, Germany).
4.2. General procedure for the synthesis of spiroox-
indoles (6a–f, 9a–i) and spiroindenoquinoxalines (11)
Method A (conventional method). To the reaction mixture
containing isatin (0.147 g, 1 mmol), malononitrile (0.066 g,
1 mmol), and a-naphthol (0.144 g, 1 mmol) in acetonitrile
(10 mL), indium(III) chloride (20 mol %) was added and
stirred at reflux for about 1.5 h. On completion, the reaction
mixture was diluted with water and the precipitate formed
Figure 2. ORTEP diagram of compound 9e.

G. Shanthi et al. / Tetrahedron 63 (2007) 2057–2063
2061
was filtered, dried, and purified by column chromatography
to afford the pure product in 70% yield. This procedure
was followed for the synthesis of all the spirooxindoles
(6a–f and 9a–i) and spiroindenoquinoxaline (11).
7.97 (d, 1H, J¼9.2 Hz). 13C NMR (DMSO-d6, 125 MHz):
d 27.0, 50.4, 57.5, 109.9, 111.4, 117.7, 118.2, 122.9, 124.5,
125.5, 128.2, 129.3, 129.8, 130.5, 131.8, 135.1, 142.8,
148.5, 159.9, 177.5. MS (m/z): 353 (M+). Anal. Calcd for
C22H15N3O2: C, 74.78; H, 4.28; N, 11.89. Found: C, 74.74;
H, 4.22; N, 11.83.
Method B (microwave method). Isatin (0.147 g, 1 mmol),
malononitrile (0.066 g, 1 mmol), and a-naphthol (0.144 g,
1 mmol) were added to silica gel impregnated with in-
dium(III) chloride (44 mg, 20 mol %), prepared by adding a
solution of InCl3 in a minimum amount of THF to silica gel
(2 g, 100–200 mesh activated by heating for 4 h at 150 ꢀC
before use), followed by complete evaporation of solvent
under vacuum. The whole mixture was stirred for 5 min
for uniform mixing and then irradiated in a microwave
oven (BPL SANYO) at 300 W for 3 min. On completion,
the reaction mixture was directly charged on a small silica
gel column and eluted with a mixture of ethyl acetate–hex-
ane (4:6) to afford the pure product in 88% yield as a white
solid. This procedure was followed for the synthesis of all
the spirooxindoles (6a–f and 9a–i) and spiroindenoquinoxa-
lines (11).
4.2.4. 2-Amino spiro[(4H)-benzo(f)chromen-4,30-(30H)-
indol]-(10H)-20-one-3-carbonitrile 6d (Table 2, entry 4).
White solid (295 mg, 87%); mp: 236 ꢀC. nmax (KBr): 3446,
1
3321, 2200, 1704, 1653, 1170 cmꢁ1. H NMR (DMSO-d6,
500 MHz): d 6.86 (m, 2H), 7.00 (d, 1H, J¼8.0 Hz), 7.04 (d,
1H, J¼8.6 Hz), 7.16 (br s, 2H, –NH2, D2O exchangeable),
7.23 (t, 2H, J¼7.5 Hz), 7.29 (d, 1H, J¼9.2 Hz), 7.32 (t, 1H,
J¼7.5 Hz), 7.88 (d, 1H, J¼8.0 Hz), 7.96 (d, 1H, J¼8.6 Hz),
10.98 (s, 1H, –NH, D2O exchangeable). 13C NMR (DMSO-
d6, 125 MHz): d 50.8, 57.8, 110.8, 111.7, 117.7, 118.4,
123.2, 123.4, 124.8, 125.4, 127.9, 129.5, 129.7, 130.7,
131.5, 131.6, 135.9, 141.3, 148.5, 159.9, 179.1. MS (m/z):
339 (M+). Anal. Calcd for C21H13N3O2: C, 74.33; H, 3.86;
N, 12.38. Found: C, 74.26; H, 3.80; N, 12.34.
4.2.1. 2-Amino spiro[(4H)-benzo(h)chromen-4,30-(30H)-
indol]-(10H)-20-one-3-carbonitrile 6a (Table 2, entry 1).
White solid (298 mg, 88%); mp: 222 ꢀC. nmax (KBr):
4.2.5. 2-Amino-10-methyl spiro[(4H)-benzo(f)chromen-
4,30-(30H)-indol]-20-one-3-carbonitrile 6e (Table 2, entry
5). White solid (296 mg, 84%); mp: 266 ꢀC. nmax (KBr):
1
3420, 3319, 2196, 1704, 1653, 1170 cmꢁ1
.
1H NMR
3453, 2191, 1686, 1650, 1174 cmꢁ1. H NMR (DMSO-d6,
(DMSO-d6, 500 MHz): d 6.52 (d, 1H, J¼9.2 Hz), 6.96 (m,
2H), 7.05 (d, 1H, J¼7.5 Hz), 7.25 (t, 1H, J¼7.5 Hz), 7.43
(br s, 2H, –NH2, D2O exchangeable), 7.53 (d, 1H,
J¼9.2 Hz), 7.58 (t, 1H, J¼8.0 Hz), 7.63 (t, 1H, J¼8.1 Hz),
7.85 (d, 1H, J¼8.0 Hz), 8.24 (d, 1H, J¼8.1 Hz), 10.67 (s,
1H, –NH, D2O exchangeable). 13C NMR (DMSO-d6,
125 MHz): d 52.42, 54.8, 110.6, 115.3, 119.1, 121.3,
123.2, 123.3, 123.7, 125.1, 125.6, 127.6, 127.9, 128.2,
129.8, 133.6, 135.2, 142.4, 144.1, 161.6, 179.3. MS (m/z):
339 (M+). Anal. Calcd for C21H13N3O2: C, 74.33; H, 3.86;
N, 12.38. Found: C, 74.29; H, 3.81; N, 12.32.
500 MHz): d 3.42 (s, 3H, –NMe), 6.85 (d, 1H, J¼8.6 Hz),
7.38 (br s, 2H, –NH2, D2O exchangeable), 7.22 (m, 5H),
7.48 (d, 2H, 8.0 Hz), 7.88 (d, 1H, J¼8.0 Hz), 7.97 (d, 1H,
J¼9.2 Hz). 13C NMR (DMSO-d6, 125 MHz): d 27.8, 51.4,
56.5, 109.1, 112.4, 117.2, 118.8, 123.4, 124.9, 125.5,
128.7, 129.4, 129.9, 130.7, 132.5, 135.8, 142.8, 149.3,
159.2, 178.5. MS (m/z): 353 (M+). Anal. Calcd for
C22H15N3O2: C, 74.78; H, 4.28; N, 11.89. Found: C,
74.74; H, 4.23; N, 11.84.
4.2.6. Ethyl 2-amino-10-methyl spiro[(4H)-benzo(f)chro-
men-4,30-(30H)-indol]-20-one-3-carboxylate 6f (Table 2,
entry 6). Colorless solid (356 mg, 89%); mp: 260 ꢀC. nmax
4.2.2. Ethyl 2-amino spiro[(4H)-benzo(h)chromen-4,30-
(30H)-indol]-(10H)-20-one-3-carboxylate 6b (Table 2,
entry 2). Colorless solid (332 mg, 86%); mp: 229 ꢀC. nmax
1
(KBr): 3430, 1705, 1662, 1164 cmꢁ1. H NMR (DMSO-
d6, 500 MHz): d 1.71 (t, 3H, J¼6.9 Hz, –CO2CH2CH3),
3.21 (s, 3H, –NMe), 3.55 (m, 2H, –CO2CH2CH3), 6.47 (d,
1H, J¼7.5 Hz), 7.04 (t, 1H, J¼7.5 Hz), 7.10 (d, 1H,
J¼7.5 Hz), 7.15 (d, 1H, J¼7.5 Hz), 7.36 (t, 1H,
J¼8.1 Hz), 7.47 (br s, 2H, –NH2, D2O exchangeable), 7.51
(d, 1H, J¼8.6 Hz), 7.57 (t, 1H, J¼8.1 Hz), 7.64 (t, 1H,
J¼8.1 Hz), 7.86 (d, 1H, J¼8.6 Hz), 8.24 (d, 1H,
J¼8.6 Hz). 13C NMR (DMSO-d6, 125 MHz): d 13.2, 27.1,
51.0, 54.6, 67.6, 109.6, 115.2, 118.9, 121.3, 123.3, 123.8,
125.0, 125.2, 127.6, 128.2, 129.9, 133.6, 134.4, 143.9,
144.2, 161.6, 168.5, 177.6. MS (m/z): 400 (M+). Anal. Calcd
for C24H20N2O4: C, 71.99; H, 5.03; N, 7.00. Found: C,
71.95; H, 5.00; N, 6.95.
(KBr): 3430, 3325, 1707, 1669, 1170 cmꢁ1
.
1H NMR
(DMSO-d6, 500 MHz):
d
1.75 (t, 3H, J¼6.9 Hz,
–CO2CH2CH3), 3.52 (m, 2H, –CO2CH2CH3), 6.42 (d, 1H,
J¼7.4 Hz), 6.86 (d, 1H, J¼7.4 Hz), 7.05 (t, 1H, J¼7.5 Hz),
7.12 (d, 1H, J¼7.5 Hz), 7.20 (d, 1H, J¼7.5 Hz), 7.32 (t,
1H, J¼8.0 Hz), 7.44 (br s, 2H, –NH2, D2O exchangeable),
7.52 (d, 1H, J¼8.6 Hz), 7.59 (t, 1H, J¼8.0 Hz), 7.63 (t, 1H,
J¼8.0 Hz), 8.28 (d, 1H, J¼8.6 Hz), 10.76 (s, 1H, –NH,
D2O exchangeable). 13C NMR (DMSO-d6, 125 MHz):
d 13.8, 51.0, 55.2, 66.7, 109.2, 115.5, 118.4, 121.7, 123.3,
123.5, 123.9, 125.2, 125.4, 127.6, 128.0, 130.2, 133.0,
134.4, 143.7, 144.0, 161.8, 168.9, 177.5. MS (m/z): 386
(M+). Anal. Calcd for C23H18N2O4: C, 71.49; H, 4.70; N,
7.25. Found: C, 71.41; H, 4.65; N, 7.20.
4.2.7. 2-Amino spiro[(4H)-5,6,7,8-tetrahydrochromene-
4,30-(30H)-indol]-(10H)-20-one-3-carbonitrile 9a (Table 3,
entry 1). Brown solid (258 mg, 88%); mp: 238 ꢀC. nmax
(KBr): 3443, 3290, 2194, 1710, 1631, 1470, 1218,
4.2.3. 2-Amino-10-methyl spiro[(4H)-benzo(h)chromen-
4,30-(30H)-indol]-20-one-3-carbonitrile 6c (Table 2, entry
3). Colorless solid (318 mg, 90%); mp: 242 ꢀC. nmax (KBr):
1
1148 cmꢁ1. H NMR (DMSO-d6, 500 MHz): d 1.24 (m,
3442, 2195, 1704, 1661, 1597, 1133 cmꢁ1
.
1H NMR
8H, –(CH2)4), 6.79 (d, 1H, J¼7.6 Hz), 6.82 (br s, 2H,
–NH2, D2O exchangeable), 6.96 (t, 1H, J¼7.7 Hz), 7.05
(d, 1H, J¼7.7 Hz), 7.16 (t, 1H, J¼7.7 Hz), 10.44 (br s,
1H, –NH, D2O exchangeable). 13C NMR (DMSO-d6,
(DMSO-d6, 500 MHz): d 3.33 (s, 3H, –NMe), 6.79 (d, 1H,
J¼8.6 Hz), 6.96 (d, 2H, J¼8.0 Hz), 7.20 (br s, 2H, –NH2,
D2O exchangeable), 7.22 (m, 5H), 7.88 (d, 1H, J¼8.0 Hz),

2062
G. Shanthi et al. / Tetrahedron 63 (2007) 2057–2063
125 MHz): d 22.1, 22.4, 23.0, 26.2, 52.3, 54.8, 106.8, 110.1,
119.4, 122.9, 124.8, 129.2, 133.5, 142.3, 145.0, 161.2, 178.9.
MS (m/z): 293 (M+). Anal. Calcd for C17H15N3O2: C, 69.56;
H, 5.06; N, 14.22. Found: C, 69.61; H, 5.15; N, 14.33.
exchangeable), 7.75 (d, 2H, J¼8.0 Hz). 13C NMR
(DMSO-d6, 125 MHz): d 12.2, 27.0, 47.9, 56.2, 96.7,
109.4, 118.4, 120.7, 123.9, 125.1, 127.1, 129.9, 131.9,
137.7, 143.6, 144.4, 145.5, 161.7, 176.3. MS (m/z): 383
(M+). Anal. Calcd for C22H17N5O2: C, 68.92; H, 5.15; N,
13.02. Found: C, 8.87; H, 5.10; N, 12.97.
4.2.8. 2-Amino-5-oxo-7,7-dimethyl spiro[(4H)-5,6,7,8-
tetrahydrochromene-4,30-(30H)-indol]-(10H)-20-one-car-
bonitrile 9b (Table 3, entry 2). Colorless solid (312 mg,
93%); mp: 268 ꢀC. nmax (KBr): 3410, 3306, 3136, 2959,
4.2.12. Ethyl 6-amino-10,3-dimethyl-1-phenyl spiro-
[(30H)-indol-30,4-4(H)-pyrano(3,2-d)pyrazol]-20-one-5-
carboxylate 9f (Table 3, entry 6). White solid (387 mg,
90%); mp: 256 ꢀC. nmax (KBr): 3416, 1708, 1652, 1579,
1181 cmꢁ1. 1H NMR (DMSO-d6, 500 MHz): d 0.67 (t, 3H,
–CO2CH2CH3), 1.49 (s, 3H, –CH3), 3.23 (s, 3H, –NMe),
3.65 (m, 2H, –CO2CH2CH3), 6.97 (t, 1H, J¼7.5 Hz), 7.03
(t, 2H, J¼7.5 Hz), 7.28 (t, 1H, J¼7.5 Hz), 7.33 (t, 1H,
J¼7.4 Hz), 7.50 (t, 2H, J¼8.1 Hz), 7.81 (d, 2H, J¼7.5 Hz),
8.27 (br s, 2H, –NH2, D2O exchangeable). 13C NMR
(DMSO-d6, 125 MHz): d 12.2, 13.9, 26.7, 47.5, 59.4, 74.8,
98.5, 108.3, 120.5, 123.1, 123.4, 126.9, 128.5, 129.9,
135.5, 137.8, 143.9, 144.5, 144.6, 161.9, 168.3, 178.0. MS
(m/z): 430 (M+). Anal. Calcd for C24H22N4O4: C, 66.97; H,
5.15; N, 13.02. Found: C, 66.92; H, 5.09; N, 12.96.
1
2191, 1719, 1679, 1653, 1601, 1218, 1163 cmꢁ1. H NMR
(DMSO-d6, 500 MHz): d 0.97 (s, 3H, –CH3), 1.00 (s, 3H,
–CH3), 2.05 (d, 1H, J¼16.1 Hz, –CHaHb), 2.12 (d, 1H,
J¼16.1 Hz, –CHaHb), 2.52 (d, 2H, J¼6.1 Hz, –CH2), 6.75
(d, 1H, J¼7.7 Hz), 6.84 (t, 1H, J¼6.9 Hz), 6.94 (d, 1H,
J¼6.9 Hz), 7.09 (t, 1H, J¼7.7 Hz), 7.19 (br s, 2H, –NH2,
D2O exchangeable), 10.36 (s, 1H, –NH, D2O exchangeable).
13C NMR (DMSO-d6, 125 MHz): d 19.1, 27.6, 28.1, 47.3,
50.5, 56.6, 58.0, 109.8, 111.3, 117.9, 122.2, 123.6, 128.7,
134.9, 142.6, 159.3, 164.7, 178.6, 195.4. MS (m/z): 335
(M+). Anal. Calcd for C19H17N3O3: C, 67.98; H, 5.03; N,
12.42. Found: C, 68.05; H, 5.11; N, 12.53.
4.2.9. 6-Amino-3-methyl-1-phenyl spiro[(30H)-indol-30,4-
4(H)-pyrano(3,2-d)pyrazol]-(10H)-20-one-5-carbonitrile
9c (Table 3, entry 3). Colorless solid (332 mg, 90%); mp:
248 ꢀC. nmax (KBr): 3446, 3269, 2192, 1686, 1650, 1576,
1174 cmꢁ1. 1H NMR (DMSO-d6, 500 MHz): d 1.55 (s, 3H,
–CH3), 6.95 (d, 1H, J¼7.4 Hz), 7.02 (t, 1H, J¼7.5 Hz),
7.17 (d, 1H, J¼6.9 Hz), 7.28 (t, 1H, J¼7.5 Hz), 7.35 (t, 1H,
J¼7.5 Hz), 7.51 (t, 2H, J¼7.5 Hz), 7.58 (br s, 2H, –NH2,
D2O exchangeable), 7.79 (d, 2H, J¼7.5 Hz), 10.75 (s, 1H,
–NH, D2O exchangeable). 13C NMR (DMSO-d6,
125 MHz): d 12.2, 48.3, 56.7, 96.9, 110.4, 118.5, 120.7,
123.2, 125.4, 127.1, 129.8, 130.0, 132.6, 137.8, 142.1,
144.5, 145.5, 161.6, 178.0. MS (m/z): 369 (M+). Anal. Calcd
for C21H15N5O2: C, 68.28; H, 4.09; N, 18.96. Found:
C, 68.24; H, 4.02; N, 18.90.
4.2.13. 2-Amino-5-oxaspiro[(30H)-indol-30,4-4(H)-
pyrano(3,2-c)chromen]-(10H)-20-one-3-carbonitrile 9g
(Table 3, entry 7). Off-white solid (328 mg, 92%); mp:
250 ꢀC. nmax (KBr): 3301, 2203, 1714, 1671, 1169 cmꢁ1
.
1H NMR (DMSO-d6, 500 MHz): d 6.82 (d, 1H, J¼7.5 Hz),
6.89 (t, 1H, J¼7.5 Hz), 7.17 (m, 2H), 7.45 (d, 1H,
J¼8.6 Hz), 7.49 (t, 1H, J¼8.1 Hz), 7.66 (br s, 2H, –NH2,
D2O exchangeable), 7.72 (t, 1H, J¼7.5 Hz), 7.91 (d, 1H,
J¼8.0 Hz), 10.67 (s, 1H, –NH, D2O exchangeable). 13C
NMR (DMSO-d6, 125 MHz): d 48.1, 57.5, 101.9, 110.1,
112.9, 117.5, 122.6, 123.2, 124.7, 125.6, 129.5, 133.6,
134.2, 142.7, 152.6, 155.6, 158.8, 158.9, 177.7. MS (m/z):
357 (M+). Anal. Calcd for C20H11N3O4: C, 67.23; H, 3.10;
N, 11.76. Found: C, 67.19; H, 3.04; N, 11.71.
4.2.10. Ethyl 6-amino-3-methyl-1-phenyl spiro[(30H)-in-
dol-30,4-4(H)-pyrano(3,2-d)pyrazol]-(10H)-20-one-5-car-
boxylate 9d (Table 3, entry 4). White solid (374 mg, 90%);
mp: 208 ꢀC. nmax (KBr): 3441, 1710, 1652, 1601, 1574,
1156 cmꢁ1. 1H NMR (DMSO-d6, 500 MHz): d 0.69 (t, 3H,
J¼6.9 Hz, –CO2CH2CH3), 1.56 (s, 3H, –CH3), 3.71 (m,
2H, –CO2CH2CH3), 6.82 (m, 2H), 6.93 (d, 1H, J¼7.5 Hz),
7.12 (t, 1H, J¼7.5 Hz), 7.29 (t, 1H, J¼7.5 Hz), 7.46 (t,
2H, J¼8.0 Hz), 7.77 (d, 2H, J¼8.0 Hz), 8.19 (br s, 2H,
–NH2, D2O exchangeable), 10.49 (s, 1H, –NH, D2O
exchangeable). 13C NMR (DMSO-d6, 125 MHz): d 12.3,
13.6, 48.0, 59.5, 75.1, 98.7, 109.4, 120.5, 122.3, 123.7,
126.9, 128.3, 129.9, 136.3, 137.9, 142.7, 144.5, 144.8,
161.9, 168.4, 179.8. MS (m/z): 416 (M+). Anal. Calcd for
C23H20N4O4: C, 66.34; H, 4.84; N, 13.45. Found: C,
66.28; H, 4.80; N, 13.39.
4.2.14. Ethyl 2-amino-5-oxaspiro[(30H)-indol-30,4-4(H)-
pyrano(3,2-c)chromen]-(10H)-20-one-3-carboxylate 9h
(Table 3, entry 8). Off-white solid (368 mg, 91%); mp:
210 ꢀC. nmax (KBr): 3408, 3302, 1716, 1669, 1607,
1175 cmꢁ1. 1H NMR (DMSO-d6, 500 MHz): d 0.79 (t, 3H,
J¼6.9 Hz, –CO2CH2CH3), 3.73 (m, 2H, –CO2CH2CH3),
6.72 (m, 2H), 6.98 (m, 2H), 7.39 (m, 2H), 7.69 (m, 1H),
7.99 (m, 1H), 8.11 (br s, 2H, –NH2, D2O exchangeable),
10.40 (s, 1H, –NH, D2O exchangeable). 13C NMR
(DMSO-d6, 125 MHz): d 13.7, 47.9, 59.7, 76.1, 104.4,
108.9, 112.9, 116.9, 121.5, 123.4, 123.7, 125.4, 128.4,
133.9, 135.2, 144.6, 152.4, 154.3, 158.3, 159.1, 167.7,
179.4. MS (m/z): 404 (M+). Anal. Calcd for C22H16N2O6:
C, 65.34; H, 3.99; N, 6.93. Found: C, 65.29; H, 3.92; N, 6.88.
4.2.15. 2-Amino-10-methyl-5-oxaspiro[(30H)-indol-30,4-
4(H)-pyrano(3,2-c)chromen]-20-one-3-carbonitrile 9i
(Table 3, entry 9). Off-white solid (352 mg, 95%); mp:
244 ꢀC. nmax (KBr): 3452, 2195, 1712, 1672, 1601,
1168 cmꢁ1. 1H NMR (DMSO-d6, 500 MHz): d 3.17 (s, 3H,
–NMe), 6.98 (t, 1H, J¼7.5 Hz), 7.04 (d, 1H, J¼8.1 Hz),
7.25 (d, 1H, J¼7.4 Hz), 7.28 (t, 1H, J¼7.4 Hz), 7.45 (d, 1H,
J¼8.6 Hz), 7.50 (t, 1H, J¼7.5 Hz), 7.71 (br s, 2H, –NH2,
D2O exchangeable), 7.73 (m, 1H), 7.91 (d, 1H, J¼7.5 Hz).
13C NMR (DMSO-d6, 125 MHz): d 27.1, 47.8, 57.1, 101.8,
4.2.11. 6-Amino-10,3-dimethyl-1-phenyl spiro[(30H)-in-
dol-30,4-4(H)-pyrano(3,2-d)pyrazol]-20-one-5-carbo-
nitrile 9e (Table 3, entry 5). White solid (352 mg, 92%);
mp: 200 ꢀC. nmax (KBr): 3450, 2198, 1686, 1603, 1572,
1179 cmꢁ1 1H NMR (DMSO-d6, 500 MHz): d 1.43 (s,
.
3H, –CH3), 3.22 (s, 3H, –NMe), 7.07 (t, 1H, J¼7.4 Hz),
7.12 (d, 1H, J¼8.0 Hz), 7.21 (d, 1H, J¼6.9 Hz), 7.31 (m,
2H), 7.47 (t, 2H, J¼8.6 Hz), 7.62 (br s, 2H, –NH2, D2O

G. Shanthi et al. / Tetrahedron 63 (2007) 2057–2063
2063
5. Khafagy, M. M.; El-Wahas, A. H. F. A.; Eid, F. A.; El-Agrody,
A. M. Farmaco 2002, 57, 715.
6. Smith, W. P.; Sollis, L. S.; Howes, D. P.; Cherry, C. P.; Starkey,
D. I.; Cobley, N. K. J. Med. Chem. 1998, 41, 787.
7. Hiramoto, K.; Nasuhara, A.; Michiloshi, K.; Kato, T.;
Kikugawa, K. Mutat. Res. 1997, 395, 47.
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Abstr. 1993, 119, 139102d.
9. Bianchi, G.; Tava, A. Agric. Biol. Chem. 1987, 51, 2001.
10. Mohr, S. J.; Chirigos, M. A.; Fuhrman, F. S.; Pryor, J. W.
Cancer Res. 1975, 35, 3750.
11. Elagamay, A. G. A.; El-Taweel, F. M. A. A. Indian J. Chem.,
Sect. B 1990, 29, 885.
12. Ballini, R.; Bosica, G.; Conforti, M. L.; Maggi, R.;
Mazzacanni, A.; Righi, P.; Sartori, G. Tetrahedron 2001, 57,
1395.
13. (a) Babu, G.; Perumal, P. T. Aldrichimica Acta 2000, 33, 16; (b)
Babu, G.; Perumal, P. T. Tetrahedron Lett. 1997, 38, 5025; (c)
Babu, G.; Perumal, P. T. Tetrahedron 1998, 54, 1627; (d) Babu,
G.; Nagarajan, R.; Perumal, P. T. Synthesis 2000, 661.
14. (a) Shanmugam, P.; Annie, G.; Perumal, P. T. J. Heterocycl.
Chem. 2003, 40, 879; (b) Hemanth Kumar, K.; Muralidharan,
D.; Perumal, P. T. Synthesis 2004, 63.
15. Domling, A.; Herdtweck, E.; Ugi, I. Acta Chem. Scand. 1998,
52, 107; (b) Kappe, C. O. Tetrahedron 1993, 49, 6937; (c)
Weber, L.; Illgen, K.; Almstetter, M. Synlett 1999, 366.
16. Abdel-Latif, F. F. Indian J. Chem. 1990, 29B, 664.
17. Martin, N.; Seoane, C.; Soto, J. L. Tetrahedron 1988, 44,
5861.
109.1, 112.9, 117.2, 117.4, 123.3, 123.4, 124.4, 125.6, 129.7,
132.8, 134.3, 144.2, 152.6, 155.7, 158.8, 159.1, 176.2. MS (m/
z): 371 (M+). Anal. Calcd for C21H13N3O4: C, 67.92; H, 3.53;
N, 11.32. Found: C, 67.87; H, 3.47; N, 11.26.
4.2.16. 2-Amino-5-methyl-7-phenyl spiro[(110H)-inde-
no(1,2-b)quinoxalin-110,4-4(H)-pyrano(3,2-d)pyrazol]-3-
carbonitrile (11). Pale yellow solid (363 mg, 80%); mp:
236 ꢀC. nmax (KBr): 3313, 2199, 1653, 1594, 1130 cmꢁ1
.
1H NMR (DMSO-d6, 500 MHz): d 1.07 (s, 3H, –CH3),
7.33 (t, 1H, J¼7.5 Hz), 7.49 (t, 2H, J¼7.5 Hz), 7.62 (m,
3H), 7.65 (br s, 2H, –NH2, D2O exchangeable), 7.78 (m,
4H), 8.09 (d, 1H, J¼8.1 Hz), 8.16 (t, 2H, J¼7.4 Hz). 13C
NMR (DMSO-d6, 125 MHz): d 12.4, 48.4, 58.1, 97.8,
118.6, 120.7, 122.3, 126.7, 127.1, 129.6, 129.7, 130.0,
130.3, 130.5, 131.1, 133.6, 136.3, 137.8, 141.9, 142.7,
144.4, 145.7, 150.8, 153.5, 161.6, 163.5, 164.1. MS (m/z):
454 (M+). Anal. Calcd for C28H18N6O: C, 74.00; H, 3.99;
N, 18.49. Found: C, 73.95; H, 3.96; N, 18.44.
Acknowledgements
One of the authors (G. Shanthi) thanks CSIR, New Delhi for
financial support.
References and notes
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Biochem. J. 1998, 333, 543.
18. The X-ray data have been deposited in CCDC with number
611343.
19. (a) Dell, A.; William, D. H.; Morris, H. R.; Smith, G. A.;
Feeney, J.; Roberts, G. C. K. J. Am. Chem. Soc. 1975, 97,
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