A facile synthesis of some spirooxoindole derivatives via one-pot three-component reactions

Article abstract of DOI:10.14233/ajchem.2013.14270

Tetrahydrospiro[chromene-4,3'-indole]-2-ones (5a-c) and spiro[indole-3,4'-pyrano(3',2'-d)pyrazole]-2-ones (6a-b) have been synthesized based on the one-pot three-component cyclocondensation reaction of 5-(un)substituted isatins (1a-c) with ethyl cyanoacet

Full text of DOI:10.14233/ajchem.2013.14270

Asian Journal of Chemistry; Vol. 25, No. 9 (2013), 5006-5012
http://dx.doi.org/10.14233/ajchem.2013.14270
A Facile Synthesis of Some Spirooxoindole Derivatives via One-Pot Three-Component Reactions
1,*
1
2
GHADA E. BADRI , FATMA E.M. EL-BAIH and HASSAN M. AL-HAZIMI
1Women Students-Medical Studies and Sciences Sections, Department of Chemistry, College of Science, King Saud University, P.O. Box
22452, Riyadh 11495, Saudi Arabia
2Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia
*Corresponding author: Fax: +966 1 4561735; Tel: +966 552106025; E-mail: gh.articles@hotmail.com
(Received: 6 July 2012;
Accepted: 15 March 2013)
AJC-13124
Tetrahydrospiro[chromene-4,3'-indole]-2-ones (5a-c) and spiro[indole-3,4'-pyrano(3',2'-d)pyrazole]-2-ones (6a-b) have been synthesized
based on the one-pot three-component cyclocondensation reaction of 5-(un)substituted isatins (1a-c) with ethyl cyanoacetate (2) and 5,5-
dimethylcyclohexane-1,3-dione (3) or 5-methyl-2-phenyl-2,4-dihydro-pyrazol-3-one (4) in absolute ethanol containing a catalytic amount
of Et3N carried out under both conventional heating and environmentally benign procedures. The structures of the resulting compounds
were confirmed by spectral {IR, 1H NMR, 13C NMR, 2D NMR [1H-1H COSY, 1H-13C COSY (HETCOR)] and electrospray ionization
tandem mass [( ) ESI-MS/MS]} analysis.
Key Words: Isatin, Spirooxoindole, Ultrasound irradiation, Microwave irradiation, Retro diels-alder fragmentation.
constants are given in Hertz. Results of DEPT-135 experiment
is shown in parentheses where relative to DMSO-d6, (+)
denotes CH3 or CH and (-) denotes CH2. Follow up of the
reactions and checking the purity of the compounds were made
by TLC on silica gel-protected glass sheets (Type Si250F,
'BAKER' of 0.2 mm thickness) using ethanol-chloroform (1:9)
as eluant. The spots were detected by exposure to UV-lamp at
λ 254 nm for few seconds. Mass spectra were obtained using
a quattro premier triple quadrupole mass spectrometer (UPLC-
MS/MS) equipped with electrospray ion source using both
positive and negative ion mode. Ultrasonication was performed
in a J.P. Selecta ultrasound cleaner with a frequency of 60 Hz
and an output power of, 770 W. The reaction flask was located
in the maximum energy area in the cleaner, were the surface
of reaction (reaction vessel) is slightly lower than the level of
the water. The temperature of the water bath was controlled
by the addition or removal of circulated water. Microwave
irradiated reactions were carried out on a Galanz microwave
oven, operating at 1000 W, generating 60 Hz frequency.
Synthesis of spirooxoindoles (5a-c and 6a-b): They were
synthesized by following different methods.
INTRODUCTION
Five-membered nitrogen heterocycles, especially highly
substituted pyrrolidines feature widely in pharmaceuticals,
natural alkaloids, organocatalysts and are also useful building
blocks in organic synthesis1. The indole moiety is probably
the most well-known heterocyclic compound, a common and
important feature of a variety of natural products and medicinal
agents2. Compounds carrying the indole residue, such as isatin
(1H-indole-2,3-dione) and its derivatives exhibiting antimi-
crobial,3-18, antiviral19-23 antiplasmodial24 antitubercular25-27
anticancer28-35 anticonvulsant36-41 antioxidant42,43 activities. Due
to the above mentioned diverse properties of isatins, we
report herein the synthesis of some spirooxoindole compounds
using simple, convenient and an efficient one-pot three-
component reactions.
EXPERIMENTAL
All commercially available chemicals and reagents were
used without further purification. Melting points were acquired
in open capillary tubes and were measured on an electro
thermal digital melting point apparatus. Infrared data were
obtained using Perkin-Elmer, FT-IR spectrometer, as KBr
pellets. 1H, 13C and the 2D NMR spectra were recorded using
a JEOL-NMR spectrometer at 300 MHz and 75 MHz, on
solutions in DMSO-d6 using TMS as an internal standard.
Chemical shifts are given in ppm (δ-scale) and the coupling
Method A (conventional method): To a solution of
5-(un) substituted isatins (1a-c) (1 mmol), ethyl cyanoacetate
(2) (0.13 g, 1 mmol) and triethylamine (3-4 drops) in absolute
ethanol (25 mL), 5,5-dimethyl-cyclohexane-1,3-dione (3)
(0.14 g, 1 mmol) or 5-methyl-2-phenyl-2,4-dihydro-pyrazole
-3-one (4) (0.17 g, 1 mmol) was added and heated under

Vol. 25, No. 9 (2013)
A Facile Synthesis of Some Spirooxoindole Derivatives via One-Pot Three-Component Reactions 5007
refluxed for about 2 h. The progress of the reaction was
followed by TLC.After complication, the solvent was removed
under reduced pressure and the residue was then washed well
with ethanol, dried and recrystallized from methanol to afford
pure products in cases (5a-c), while in cases (6a,b) the solid
was treated with ether or petroleum ether (60-80 ºC) and
recrystallized from water/methanol.
d6): δH (ppm) 0.82 (3H, t, J = 5.5, OCH2CH3), 0.96 (3H, s,
2
7-CH3), 1.01 (3H, s, 7-CH3), 2.07 (1H, d, J = 15.9, Hax-8),
2.14 (1H, d, 2J = 15.9, Heq-8), 2.53 (2H, s, 6-CH2), 3.73 (2H,
q, J = 5.5, OCH2CH3), 6.65 (1H, d, 3J = 8.5, H-7'), 7.01 (1H,
d, 4J = 1.8, H-4'), 7.22 (1H, dd, 3J = 8.5, 4J = 1.8, H-6'), 7.93
(2H, br. s, NH2, D2O exchangeable), 10.32 (1H, br. s, NH,
D2O exchangeable); 13C NMR (75 MHz, DMSO-d6) and DEPT-
135: δC (ppm) 12.9 (OCH2CH3), 26.9, 27.2 [7-(CH3)2], 30.8
(C-7), 39.9 (C-6, overlapped with solvent signals) 46.1, 50.3
(C-8), 58.7 (OCH2CH3), 74.9 (spiro C), 109.3 (C-7'), 111.3,
111.7, 124.3 (C-4'), 129.1 (C-6'), 137.8, 142.8, 158.4, 162.2
(sp2 carbons), 166.7 (CO ester)44, 178.7 (CO 2'-oxoindole)44,
194.2 (CO chromene)44; MS (+) ESI, m/z (%): 461 (50) [M+H]+
(C21H2179BrN2O5+H)+, 463 (54) [461+2]+ (C21H2181BrN2O5+H)+,
443 (6) [461-H2O]+, 433 (12) [461-CO]+, 416 (6) [461-
OC2H5]+•, 389 (96) [461-CO2C2H5+H]+, 371 (4) [461-NH2-
CO2C2H5-H]+•, 347 (4) [461-C5H7NO2-H, RDA fragmentation]+•,
311 (5) [389-Br+H]+, 295 (28) [416-C8H10O+H, RDA fragmen-
tation]+, 279 (54) [295-NH2]+•, 259 (11) [461-C8H10O-HBr,
RDA fragmentation]+, 229 (24) [259-NH-NH2+H]+, 217 (100)
[295-Br+H]+, 213 (74) [259-OC2H5-H]+, 201 (26) [229-CO]+,
199 (31) [259-NH2-OC2H5+H]+•, 169 (18) [C6H5BrN-H]+•, 157
(21) [229-CO2C2H5+H]+.
Method B (ultrasound irradiation method):A mixture
of 5-(un)substituted isatins (1a-c) (1 mmol), ethyl cyanoacetate
(2) (0.13 g, 1 mmol), 3 or 4 (1 mmol) and triethylamine (3-4
drops) in absolute ethanol (25 mL) was irradiated in an ultra-
sonic bath for 1 h.After completion of the reaction (as indicated
by TLC), the solvent was removed under reduced pressure
and the resulting solid was then washed well with ethanol,
dried and recrystallized from methanol or water/methanol to
afford pure products in most cases (5a-c, 6a), while in case
(6b) the solid was treated with petroleum ether (60-80 ºC)
and recrystallized from water/methanol.
Method C (microwave irradiation method):An equimolar
mixture of 5-(un)substituted isatins (1a-c) (1 mmol), ethyl
cyanoacetate (0.13 g, 1 mmol), 3 or 4 (1 mmol) and triethyl-
amine (3-4 drops) in the minimum quantity of ethanol 96 %
required to form a slurry was irradiated inside a microwave
oven at 300 W for 5 min. After completion, the excess solvent
was removed under reduced pressure and the activated solid
was then recrystallized from methanol to afford pure products
in cases (5a-c), while in cases (6a,b) the solid was treated
with petroleum ether (60-80 ºC) and recrystallized from water/
methanol.
Ethyl 2-amino-5'-chloro-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydrospiro[chromene-4,3'-indole]-2'-one-3-carboxy-
late (5c) (Table-1, entry 3): White powder, m.p. 278 ºC (from
methanol); yield 70 %A, 70 %B, 62 %C; IR (KBr, νmax, cm-1):
3384, 3276, 3215 (NH2, NH), 1725 (C=O ester), 1688 (C=O
ketone), 1650 (C=O γ-lactam); 1H NMR (300 MHz, DMSO-
d6): δH (ppm) 0.82 (3H, t, J = 5.5, OCH2CH3), 0.96 (3H, s,
Ethyl 2-amino-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-
spiro[chromene-4,3'-indole]-2'-one-3-carboxylate (5a)
(Table-1, entry 1): Pale orange fine cubes, m.p. 264 ºC (from
methanol); yield 59 %A, 70 %B, 95 %C; IR (KBr, νmax, cm-1) :
3369, 3235, 3179 (NH2, NH), 1714 (C=O ester), 1687 (C=O
ketone), 1671 (C=O γ-lactam); 1H NMR (300 MHz, DMSO-
d6): δH (ppm) 0.79 (3H, t, J = 5.7, OCH2CH3), 0.94 (3H, s,
2
7-CH3), 1.01 (3H, s, 7-CH3), 2.07 (1H, d, J = 15.7, Hax-8),
2.14 (1H, d, 2J = 15.7, Heq-8), 2.53 (2H, s, 6-CH2), 3.73 (2H,
q, J = 5.5, OCH2CH3), 6.68 (1H, d, 3J = 8.3, H-7'), 6.90 (1H,
d, 4J = 1.9, H-4'), 7.09 (1H, dd, 3J = 8.3, 4J = 1.9, H-6'), 7.93
(2H, br. s, NH2, D2O exchangable), 10.31 (1H, br. s, NH, D2O
exchangable); 13C NMR (75 MHz, DMSO-d6) and DEPT-135:
δC (ppm) 12.4 (OCH2CH3), 26.3, 26.7[(7-(CH3)2], 30.9 (C-7),
39.3 (C-6, overlapped with solvent signals), 43.1, 49.8 (C-8),
58.2 (OCH2CH3), 75.1 (spiro C), 108.7 (C-7'), 111.8, 121.7
(C-4'), 123.7, 126.3 (C-6'), 137.5, 142.5, 158.5, 162.2 (sp2
carbons), 166.8 (CO ester)44, 178.9 (CO 2'-oxoindole)44, 194.2
(CO chromene)44; MS (-) ESI, m/z (%): 415 (36) [M-H]–
(C21H2135ClN2O5-H)–, 417 (14) [415+2]– (C21H2137ClN2O5-H)–,
401 (4) [415-CH3+H]–, 387 (8) [415-CO]–, 370 (6) [415-
OC2H5]−•, 369 (28) [387-H2O]–, 362 (100) [415-H2O-Cl]−•, 360
(10) [415-C2H2-C2H5]−•, 343 (32) [415-CO2C2H5+H]–, 325 (12)
[415-NH2-CO2C2H5-H]−•, 309 (52) [343-Cl+H]–, 302 (3) [415-
C5H7NO2, RDA fragmentation]–, 293 (22) [415-C8H10O, RDA
fragmentation]–.
2
7-CH3), 1.01 (3H, s, 7-CH3), 2.01 (1H, d, J = 15.8, Hax-8),
2.15 (1H, d, 2J = 15.8, Heq-8), 2.55 (2H, s, 6-CH2), 3.70 (2H,
q, J = 5.7, OCH2CH3), 6.67 (1H, d, 3J = 7.1, H-7'), 6.74 (1H,
td, 3J = 7.1, 4J = 1.1, H-5'), 6.83 (1H, d, 3J = 7.1, H-4'), 7.01
3
4
(1H, td, J = 7.1, J = 1.1, H-6'), 7.86 (2H, br. s, NH2, D2O
exchangeable), 10.14 (1H, br. s, NH, D2O exchangeable); 13C
NMR, (75 MHz, DMSO-d6) and DEPT-135: δC (ppm) 12.5
(OCH2CH3), 26.1, 27.2 [7-(CH3)2], 30.9 (C-7), 39.5 (C-6, over-
lapped with solvent signals), 46.1, 50.1 (C-8), 58.2
(OCH2CH3), 75.7 (spiro C), 107.5 (C-7'), 112.5, 119.9 (C-5'),
121.6 (C-4'), 126.6 (C-6'), 135.4, 143.4, 158.5, 161.8 (sp2 car-
bons), 167.1 (CO ester)44, 179.2 (CO 2'-oxoindole)44, 194.1
(CO chromene)44; MS (+) ESI, m/z (%): 383 (2) [M+H]+
(C21H22N2O5+H)+, 367 (2) [383-NH2]+•, 338 (7) [383-OC2H5]+•,
328 (67) [383-C2H2-C2H5]+•, 309 (29) [383-CO2C2H5-H]+, 293
(100) [383-NH2-CO2C2H5-H]+•, 139 (22) [C8H11O2]+, 115 (98)
[C5H9NO2]+•.
Ethyl 6'-amino-3'-methyl-1'-phenylspiro[indole-3,4'-
pyrano(3',2'-d)pyrazole]-2-one-5'-carboxylate (6a) (Table-
1, entry 4): Pale brown powder, m.p. 190 ºC (from water/
methanol); yield 50 %A, 95 %B, 95 %C; IR (KBr, λmax, cm-1):
3352, 3254, 3211 (NH2, NH), 1697 (C=O ester), 1640 (C=O
γ-lactam); 1H NMR (300 MHz, DMSO-d6): δH (ppm) 0.75 (3H,
t, J = 6.9, OCH2CH3), 1.57 (3H, s, 3'-CH3), 3.75 (2H, q, J =
6.9, OCH2CH3), 6.85-6.91 (2H, m, H-5,7), 6.97 (1H, d, 3J =
7.3, H-4), 7.17 (1H, t, 3J = 7.3, H-6), 7.34 (1H, t, 3J = 7.3, H-4''),
7.51 (2H, t, 3J = 8.1, H-3'',5''),7.81 (2H, d, 3J = 8.1, H-2'',6''),
Ethyl 2-amino-5'-bromo-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydrospiro[chromene-4,3'-indole]-2'-one-3-carboxy-
late (5b) (Table-1, entry 2): White powder, m.p. 288 ºC (from
methanol); yield 62 %A, 87 %B, 95 %C; IR (KBr, νmax, cm-1):
3387, 3276, 3213 (NH2, NH), 1726 (C=O ester), 1687 (C=O
ketone), 1653 (C=O γ-lactam); 1H NMR (300 MHz, DMSO-

5008 Badri et al.
Asian J. Chem.
TABLE-1
SYNTHESIS OF 5a-c AND 6a,b via CLASSICAL HEATING, ULTRASOUND AND MICROWAVE IRRADIATION CONDITIONS
Method Aa
Method Bb
Method CC
Entry
Products
R
Time (min)
Yield (%)
Time (min)
Yield (%)
Time (min)
Yield (%)
1
2
3
4
5
5a
5b
5c
6a
6b
H
Br
Cl
H
120
120
120
120
120
59
62
70
50
73
60
60
60
60
60
70
87
70
95
95
5
5
5
5
5
95
95
70
95
95
Cl
aMethod A: Refluxing in abs. ethanol; bMethod B: Ultrasound irradiation at 25-30 ºC in abs. ethanol; cMethod C: Microwave irradiation at 300 W
(in the minimum quantity of ethanol 96 %)
8.21 (2H, br. s, NH2, D2O exchangeable), 10.51 (1H, br. s,
NH, D2O exchangeable); 13C NMR (75 MHz, DMSO-d6) and
DEPT-135: δC (ppm) 10.9 (3'-CH3), 12.3 (OCH2CH3), 46.7,
58.2 (OCH2CH3), 73.8 (spiro C), 97.4, 108.1 (C-7), 119.2 (C-
2'',6''), 120.9 (C-5), 122.4 (C-4), 125.6 (C-6), 126.9 (C-4''),
128.6 (C-3'',5''), 135.1, 136.6, 141.4, 143.2 (C-1''), 143.5, 160.6
(sp2 carbons), 167.1 (CO ester), 178.5 (CO 2-oxoindole); MS
(-) ESI, m/z (%): 415 (54) [M-H]– (C23H20N4O4-H)–, 400 (2)
[415-CH3]−•, 395 (100) [415-NH2-4H]−•, 384 (43) [415-C2H5-
2H]−•, 369 (28) [415-OC2H5-H]–, 348 (400-2x C2H2]−•, 302
(39) [415-C5H7NO2, RDA fragmentation]–, 259 (23) [415-
C10H8N2, RDA fragmentation]–.
functionalized spirooxoindole derivatives (5a-c) (Scheme-I,
Table-1). In comparison, the reaction realized under ultrasound
and microwave irradiation had higher yields than those
performed under classical conditions for less time and tempe-
rature. However, each of them gave the desired 5 and 6 as the
single products. Proposed mechanism for the synthesis of 5 was
described in (Scheme-II)45. The process represent a typical
cascade reaction in which the isatin 1 first condenses with ethyl
cyanoacetate (2) to produce non-isolated isatylidene derivative
7 in absolute ethanol in the presence of Et3N. This step was
regarded as a fast knoevenagel condensation. Then, 7 is attacked
via Michael addition of 3 to give the intermediate 8 followed by
the cycloaddition of hydroxyl group to the cyano moiety to form
the desired product 5. Structural elucidation of spiro[chromene-
4,3'-indole]-2-ones (5a-c) was accomplished using 1D and 2D
NMR spectrometric studies as described for 5b (Fig. 1).
Ethyl 6'-amino-5-chloro-3'-methyl-1'-phenylspiro[indole-
3,4'-pyrano(3',2'-d)pyrazole]-2-one-5'-carboxylate (6b)
(Table-1, entry 5): Dark brown powder, m.p. 200 ºC (from
water/methanol); yield 73 %A, 95 %B, 95 %C; IR (KBr, λmax
,
cm-1): 3355, 3254, 3194 (NH2, NH), 1701 (C=O ester), 1640
1
(C=O γ-lactam); H NMR (300 MHz, DMSO-d6): δH (ppm)
0.82 (3H, t, J = 5.5)
12.9 (+)
7.93 (2H, br. s)
0.79 (3H, t, J = 7.3, OCH2CH3), 1.63 (3H, s, 3'-CH3), 3.78
(2H, q, J = 7.3, OCH2CH3), 6.87 (1H, d, 3J = 8.1, H-7), 7.12
3.73 (2H, q, J = 5.5)
58.7 (-)
H2N
O
4
(1H, br. s, H-4, there is J coupling but not resolved), 7.22
2.07 (1H, d, 2
2.14 (1H, d, 2
J
= 15.9, Hax-8),
= 15.9, Heq-8)
O
O
J
3
4
Br
(1H, d, J = 8.1, H-6, there is J coupling but not resolved),
7.35 (1H, t, 3J = 8.1, H-4''), 7.52 (2H, t, 3J = 8.1, H-3'',5''), 7.81
(2H, d, 3J = 8.1, H-2'',6''), 8.27 (2H, br. s, NH2, D2O exchange-
able), 10.66 (1H, br. s, NH, D2O exchangeable); 13C NMR (75
MHz, DMSO-d6) and DEPT-135: δC (ppm) 11.5 (3'-CH3), 12.9
(OCH2CH3), 47.5, 58.8 (OCH2CH3), 73.7 (spiro C), 97.2, 109.9
(C-7), 119.7 (C-2'',6''), 123.2 (C-4), 125.5, 126.1 (C-4''), 127.4
(C-6), 129.1 (C-3'',5''), 137.1, 137.6, 140.8, 143.7 (C-1''),
143.8, 161.1 (sp2 carbons) 167.4 (CO ester), 178.8 (CO 2-
oxoindole); MS (-) ESI, m/z (%): 449 (76) [M-H]–
(C23H1935ClN4O4-H)–, 451 (16) [449+2]– (C23H1937ClN4O4-H)–,
435 (2) [449-CH3+H]–, 421 (4) [449-CO]–, 403 (6) [449-
OC2H5-H]–, 395 (9) [421-C2H2]–, 382 (42) [435-2x C2H2-H]−•,
336 (100) [449-C5H7NO2, RDA fragmentation]–, 293 (9) [449-
C10H8N2, RDA fragmentation]–, 245 (8) [293-CH3-Cl+2H]–,
219 (6) [245-C2H2]–, 205 (8) [293-CONH-OC2H5]−•, 191 (16)
[219-CO]–, 159 (12) [205-CONH2-2H]–, 117 (65) [205-C2H2-
CO-Cl+H]−•, 76 (14) [C6H4]−•.
4
50.3 (-)
74.9
7
7'
0.96 (3H, s), 1.01 (3H, s)
26.9, 27.2 (+)
O
O
N
H
6.65 (1H, d, 3
oxoindole 7.01 (1H, d, 4
J
J
= 8.5) 109.3 (+)
= 1.8) 124.3 (+)
2.53 (2H, s)
39.9 (-)
7.22 (1H, dd, 3 = 8.5,4
J J = 1.8) 129.1 (+)
Fig. 1. Selected 1H and 13C NMR/DEPT-135 chemical shifts of 5b
The IR spectra of 5 showed absorption bands at 3387-
3179 cm-1 corresponding to the NH2 and N-H stretching, in
addition to bands in the range 1726-1650 cm-1, which are
characteristic to C=O groups. In the 1H NMR spectrum of 5b
demonstrated a triplet at 0.82 ppm (J = 5.5 Hz) duo to 3-CH3
protons of ester group. These protons showed H-1H COSY
1
correlations with 3-CH2 and 1H-13C COSY correlations with
carbon signal at 12.9 (+) ppm. The two singlet at 0.96 and
1.01 ppm were assigned to 7-(CH3)2 chromene protons from
their 1H-13C COSY correlations with C-7 at 26.9 (+) and 27.2
(+) ppm. The 8-CH2 protons appeared as doublets at 2.07 and
2.14 ppm (2J = 15.9 Hz) and showed 1H-13C COSY correlations
with carbon signal at 50.3 (-) ppm. While, 6-CH2 protons
RESULTS AND DISCUSSION
appeared as singlet at 2.53 ppm and showed H-13C COSY
1
In our initial endeavor, we have investigated a three-
component reaction of 5-(un)substituted isatins (1a-c) with ethyl
cyanoacetate (2), 5,5-dimethylcyclohexane-1,3-dione (3) and
Et3N in absolute ethanol by using several methods such as
thermal heating (MethodA), ultrasound irradiation (method B)
and microwave irradiation (method C) conditions to afford
correlations with C-6 at 39.9 (-) ppm. The quartet at 3.73 ppm
(J = 5.5 Hz), related by 1H-1H COSY correlations with 3-CH3
protons of ester group, duo to 3-CH2 showed H-13C COSY
1
correlations with carbon signal at 58.7 (-) ppm. The H-7', 4'
and 6' of the oxoindole ring occurred as two doublets at 6.65

Vol. 25, No. 9 (2013)
A Facile Synthesis of Some Spirooxoindole Derivatives via One-Pot Three-Component Reactions 5009
H2N
H2N
O
O
O
O
O
O
O
Ph
Method A-C
R
R
N
Method A-C
CO2Et
NC
+
N
O
O
O
N
H
O
N
H
O
N
H
N
O
N
Ph
4
6a,b
5a-c
1
2
O
a: R = H
b: R = Cl
a: R = H
b: R = Br
c: R = Cl
3
A: Et3N, Abs. EtOH, reflux, 2 h; B: Et3N, Abs. EtOH, US, 1 h; C: Et3N, Abs. EtOH, MW, 300 W, 5 min
Scheme-I: Synthesis of spirooxoindole derivatives 5 and 6
OH
X
O
O
CN
Abs. EtoH
Et3N
3
X
+
NC
N
H
O
N
H
O
7
2
1
N
N
HO
O
C
C
X
X
O
O
O
O
N
H
N
H
8
H2N
N
HN
H
H
O
X
O
O
X
X
O
O
O
O
N
H
O
O
N
H
N
H
5
X = CO2Et
Scheme-II: Proposed mechanism for the formation of spiro[chromene-4,3'-indol]-2-ones 5
(3J = 8.5 Hz) and 7.01 (4J = 1.8 Hz) and doublet of doublets at
7.22 ppm (3J = 8.5, 4J = 1.8 Hz), respectively, which showed
1H-13C COSY correlations with C-7' at 109.3 (-), C-4' at 124.3
(-) and C-6' at 129.1 (-) ppm. The D2O exchangeable protons
at 7.93 and 10.32 ppm assigned to NH2 and NH groups,
respectively. Moreover, the 13C NMR exhibited signal at 74.9
for the spiro carbon atom beside three signals in the range of
166.7-194.2 for the carbonyl groups. All other carbons in this
spectrum appeared at their expected chemical shift. The mass
spectrum of 5b further confirmed its structure, which gave
protonated (quasi-molecular) ion [M+H]+ peak at m/z 461 as
well as at m/z 463 for bromine isotope. The plausible mass
fragmentation pattern of 5b was described in Scheme-III.
Furthermore, we have applied this reaction on 5-methyl-
2-phenyl-2,4-dihydropyrazole-3-one (4) instead of 3 under
similar conditions to furnish the respective spiro[indole-

5010 Badri et al.
Asian J. Chem.
+H
+H
H
H
O
O
NH2
+H
Br
H
O
O
O
NH2
Br
O
N
H
O
N
H
-NH2
-Br
+H
O
m/z = 279 (54%)
(C11H679BrNO3)
m/z = 217 (100%)
O
N
H
(C11H9N2O3)
m/z = 295 (28%)
(C11H879BrN2O3)
+H
b-cleavage
(RDA)
+H
H2N
-OC2H5+H
H2N
O
H
O
O
O
Br
Br
+H
NH
H2N
O
a
O
N
H
O
b
O
-CO2C2H5
+H
O
-CO
O
m/z = 389 (96%)
(C18H1879BrN2O3)
m/z = 433 (12%)
(C20H2279BrN2O4)
Br
O
O
N
H
+H
(RDA)
+H
-H2O
a-cleavage
H2N
O
[M+H]+ m/z = 461 (50%)
(C21H2179BrN2O5+H)+
-H
O
O
O
[M+H+2]+ m/z = 463 (54%)
Br
Br
(C21H2181BrN2O5+H)+
O
O
N
H
O
N
H
(RDA)
m/z = 347 (4%)
(C16H1479BrNO3)
b-cleavage
m/z = 443 (6%)
(C21H2079BrN2O4)
-HBr
+H
+H
+H
O
O
O
H
O
NH
NH2
-OC2H5
-H
O
-NH2
O
O
-OC2H5
+H
O
O
O
N
H
N
H
N
H
m/z = 213 (74%)
m/z = 259 (24%)
m/z = 199 (31%)
(C11H5N2O3)
(C13H11N2O4)
(C11H5NO3)
-NH-NH2
+H
+H
O
O
H
O
-CO2C2H5
+H
-CO
O
+H
+H
H
H
O
m/z = 229 (24%)
O
H
(C13H9O4)
O
O
O
m/z = 157 (21%)
m/z = 201 (26%)
(C10H5O2)
(C12H9O3)
Scheme-III: Proposed fragmentation pathways of protonated 5b

Vol. 25, No. 9 (2013)
A Facile Synthesis of Some Spirooxoindole Derivatives via One-Pot Three-Component Reactions 5011
-H
-H
-H
H
N
H2N
H2N
O
O
O
O
O
O
O
O
Cl
Cl
Cl
-C2H2
N
N
N
N
NH
N
N
NH
N
H
O
-CO
-OC2H5
-H
m/z = 403 (6%)
(C21H1235ClN4O3)
m/z = 421 (4%)
(C22H1835ClN4O3)
m/z = 395 (9%)
(C20H1635ClN4O3)
-H
-H
-H
H2N
H2N
a
H2N
O
O
O
b
O
O
O
O
O
O
Cl
Cl
N
N
N
-CH3
N
-2x (C2H2)
-H
Cl
N
N
+H
N
H
O
N
H
O
N
H
O
m/z = 76 (14%)
[M-H]- m/z = 449 (76%)
(C23H1935ClN4O4-H)-
(C6H4)
m/z = 382 (42%)
(C18H1135ClN4O4)
m/z = 435 (2%)
(C22H1635ClN4O4)
[M-H+2]- m/z = 451 (16%)
(C23H1937ClN4O4-H)-
-H
-H
(RDA)
a-cleavage
(RDA)
b-cleavage
O
O
O
N
-H
N
O
O
NH2
-CONH
Cl
Cl
Cl
m/z = 117 (65%)
-C2H2-CO
-Cl+H
O
(C7H3NO)
-OC2H5
NH2
N
H
O
N
H
O
m/z = 336 (100%)
(C18H1135ClN3O2)
m/z = 293 (9%)
(C13H1035ClN2O4)
m/z =205 (8%)
(C10H435ClNO2)
-CONH2
-2H
-CH3-Cl
+2H
-H
Cl
-H
-H
C
C O
O
O
O
O
NH2
NH2
m/z =159 (12%)
(C935ClO)
-C2H2
O
O
m/z = 219 (6%)
O
N
H
O
N
H
(C10H7N2O4)
m/z =245 (8%)
(C12H9N2O4)
-CO
-H
O
O
NH2
O
NH
m/z = 191 (16%)
(C9H7N2O3)
Scheme-IV: Proposed fragmentation pathways of deprotonated 6b
3,4'-pyrano(3',2'-d)pyrazole]-2-ones derivatives (6a-b)
(Scheme-II, Table-1). The structure of cycloadducts 6a-b
was confirmed through 1D and 2D NMR spectroscopic data
(Fig. 2).
lations with carbon signal at 11.5 (+) ppm. This spectrum also
appeared signals in the range 7.35-7.81 for the phenyl
protons. The chemical shifts of other proton absorptions in
the latter spectrum of 6b as well as the whole carbon signals
in the 13C NMR spectrum were in complete consistent with its
structure (cf. Experimental). Finally, the mass spectrum
displayed distinguishing peaks at m/z = 449 and 451, which
further supported the formation of 6b (Scheme-IV).
The IR spectra of 6 showed absorption bands in the 3355-
3194 and 1701-1640 cm-1 regions resulting from the NH2, NH
1
and C=O functions, respectively. H NMR spectrum of 6b
exhibited a singlet at 1.63 ppm due to the 3'-CH3 protons of
1
pyrazole ring. Further, 3'-CH3 showed H-13C COSY corre-

5012 Badri et al.
Asian J. Chem.
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0.79 (3H, t,
J
12.9 (+)
= 7.3)
8.27 (2H, br. s)
3.78 (2H, q, J
58.8 (-)
= 7.3)
H N
2
O
7.35 (1H, t, 3
126.1 (+)
J = 8.1)
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O
4''
2''
O
Cl
73.7
O
N
3
7.81 (2H, d, 3
119.7 (+)
J
= 8.1)
2'
7
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N
N
H
6.87 (1H, d, 3
7.12 (1H, br. s) 123.2 (+)
7.22 (1H, d, 3
= 8.1) 129.1 (+)
J
= 8.1) 109.9 (+)
1.63 (3H, s)
11.5 (+)
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J
Fig. 2. Selected 1H and 13C NMR/DEPT-135 chemical shifts of 6b
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Conclusion
Herein we described an effective approach for constructing
a class of spirooxoindole derivatives with high selectivity under
conventional heating, ultrasound and also by microwave
irradiation methods. In general, improvement in rates and
yields of the reactions were observed by carrying out them
under environmentally benign procedures. The biological
evaluations of these derivatives are ongoing in our laboratory
and will be reported in due course.
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ACKNOWLEDGEMENTS
28. P. Kutschy,A. Saloyova, Z. Curillova, T. Kozar, R. Mezencev, J. Mojzis,
M. Pilatova, E. Balentova, P. Pazdera, M. Sabol and M. Zburova, Bioorg.
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This research project was supported by grant from the
Research Center of the Center for Female Scientific and Medical
Colleges in King Saud University.
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