An efficient strategy for functionalized spirolactones and dispirodihydrofuranyl oxindoles using amines and activated alkynes

Article abstract of DOI:10.1016/j.tetlet.2012.04.047

A facile strategy for the synthesis of functionalized spirolactones from isatin, primary amines, and activated alkynes through Huisgen dipolar additions are discussed. A novel route for the formation of dispirodihydrofuranyl oxindoles from activated cyclic electrophiles, amines, and DMAD has also been developed. This method offers several advantages like high yield, readily available starting materials, and involves less hazardous chemical techniques.

Full text of DOI:10.1016/j.tetlet.2012.04.047

Tetrahedron Letters 53 (2012) 3268–3273
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Tetrahedron Letters
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An efficient strategy for functionalized spirolactones and dispirodihydrofuranyl
oxindoles using amines and activated alkynes
⇑
Selvarangam E. Kiruthika, Rangarajan Amritha, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai-600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile strategy for the synthesis of functionalized spirolactones from isatin, primary amines, and acti-
vated alkynes through Huisgen dipolar additions are discussed. A novel route for the formation of dispi-
rodihydrofuranyl oxindoles from activated cyclic electrophiles, amines, and DMAD has also been
developed. This method offers several advantages like high yield, readily available starting materials,
and involves less hazardous chemical techniques.
Received 14 March 2012
Revised 9 April 2012
Accepted 12 April 2012
Available online 20 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Huisgen dipolar additions
Spirolactones
Bisoxindoles
Dihydrofurans
Primary amines
Activated alkynes
Carbonꢀcarbon and carbonꢀheteroatom bond-forming reac-
tions play a vital role in organic synthesis. Polar reactions utilizing
a variety of reactive intermediates in such bond-forming reactions
are well known. Several methods are available for heterocyclic
constructions of which trapping of zwitterionic species by suitable
The development of efficient methods to construct spiro com-
pounds has been a topic of great relevance in organic synthesis
due to their pronounced biological activities. Spirooxindole cores
form an important constituent in many natural and synthetic
biologically active compounds, as well as in many drug mole-
cules.1c,4–6 Such diverse spirocyclic oxindoles are characterized
by a spiro ring fusion at the C3 position of the oxindole core with
varied heterocyclic motifs (Fig. 1).7 Thus fusion of oxindole motifs
with different heterocycles seeks the attention of many organic
chemists in virtue of its biological response as they incorporate
both oxindole and other heterocyclic moieties within a single
framework.8 Spiro compounds, especially spirolactone derivatives
have been reported as anti-convulsants and antitumorals.9 Dispiro
oxindole compounds may provide promising candidates for
p
-systems leading to five membered heterocycles occupies a prime
position, chiefly attributable to the contributions of Huisgen.1
A
number of multi-component reactions involving nitrogen hetero-
cycles, acetylenic esters, and electrophiles for the synthesis of spiro
compounds have been reported.2 In such multi-component reac-
tions replacing nucleophiles derived from nitrogen heterocycles
by several other nucleophiles like isocyanides, primary amines
provide clean procedures for the synthesis of polysubstituted
spirocycles.3
O
O
O
heterocycle motif
spiro centre
O
O
oxindole core
furan-2(5
H
)-one
2,3-dihydro furan
N
H
spirocyclic oxindole
Figure 1. Illustrative representation of spiro oxindole incorporated with a heterocyclic motif at C3.
⇑
Corresponding author. Tel.: +91 44 24911386; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.047

S. E. Kiruthika et al. / Tetrahedron Letters 53 (2012) 3268–3273
3269
Table 1
Screening of solvents and base catalysts for the synthesis of 4a
CH3
O
O
CO2Me
NH2
NH
O
O
NEt3, MeOH
O
+
+
CO2Me
r.t, 4 hrs
85% yield
N
N
CO2Me
H3C
H
H
1
2a
3
4a
Entry
Solvent
Base catalysta
Time (hrs)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
MeOH
MeOH
EtOH
MeOH
DMF
DCM
THF
MeOH
DMF
MeOH
-
24
7
24
10
2.5
4
8
4
10
3
35
50
58
50
50
60
66
85c
20
60
DBU
DBU
NaHCO3
K2CO3
NEt3
NEt3
NEt3
DBU
K2CO3
a
b
c
All the reactions were performed using 20 mol% of base catalyst.
Isolated yield after column chromatography
Isolated yield after recrystallization.
chemical biology and drug discovery, due to the fact that some spi-
rocyclic bisindoles have recently been reported as potent scaffolds
possessing anticancer activity.10
till the completion of the reaction as evidenced by TLC to afford the
product 4a. The reaction was screened under the presence of var-
ious catalysts and solvent systems (Table 1). The study revealed
that the reaction proceeded to completion and also provided the
highest yield (85%) in the presence of 20 mol% of NEt3 in methanol
(Table 1, entry 8).
A plausible mechanism that could be accounted for the three-
component reaction is given in Scheme 1. Initially m-toluidine 2a
adds on to DMAD 3 to provide the zwitterionic intermediate 3a
which adds on to isatin 1 to form 3b and the latter undergoes intra-
molecular addition with concomitant MeOH elimination to give
the spiro lactone 4a (Scheme 1).
We recently reported the synthesis of spirooxindoles by Huis-
gen dipolar addition of zwitterions generated from primary amines
and DMAD to isatylidene malononitrile adducts.11 As a view to
probe the generality of the course of the reaction, we were inter-
ested in the synthesis of spirooxindoles from such zwitterionic
intermediates and isatin. Hence, our present investigation deals
with the reactions of isatin, primary amines, and DMAD to synthe-
size functionalized spirolactones and dispirodihydrofuranyl oxin-
doles. It is also noteworthy to mention that this is the first report
on the synthesis of dispirodihydrofuranyl oxindoles from cyclic
electrophiles, primary amines, and DMAD.
To expand the scope of our process, we examined the use of var-
ious other derivatives of amines to synthesize a series of spiro lac-
tones 4a–h under optimized conditions (Scheme 2).
In an exploratory experiment isatin 1 (1 mmol), m-toluidine 2a
(1 mmol) and DMAD 3 (1 mmol) were stirred at room temperature
H3C
H
H3C
O
O
NH
+
O
O
CH3
NH
CO2Me
NEt3, MeOH
NH
:
OMe
-
2
O
MeO2C
MeO2C
MeO2C
O
N
-MeOH
CO2Me
H
+
N
r.t
O
1
N
H
O
CO2Me
H2
N
H
H3C
2a
3
3a
3b
4a
Scheme 1. Plausible mechanism for the formation of 4a.
O
R
NH
CO2Me
O
O
NEt3, MeOH
O
+
+
NH2
R
CO2Me
r.t
N
N
H
O
CO2Me
H
1
2a-h
3
4a-h
Scheme 2. Synthesis of spirolactone derivatives 4a–h.

3270
S. E. Kiruthika et al. / Tetrahedron Letters 53 (2012) 3268–3273
Table 2
Synthesis of spirolactone derivatives 4a–h
Entry
R
Product
Timea
Yieldb (%)
1
2
3
4
5
6
7
8
3-CH3C6H4
C6H5
4a
4b
4c
4d
4e
4f
4
4.5
4
5
10
5
85
83
82
80
76
78
79
70
4-OCH3C6H4
2,5-(C(CH3)3)2C6H3
4-NO2-C6H4
2,4-(CH3)2C6H3
4-BrC6H4
4g
4h
5
9
4-ClC6H4
a
Completion of the reaction in hrs.
Isolated yield after recrystallization.
b
The reaction proceeded smoothly with aromatic primary
amines possessing both electron withdrawing as well as
electron releasing groups (Table 2) to produce spirolactone deriva-
tives 4a–h in good yields (70–85%). The results are summarized in
Table 2.
Figure 2. ORTEP diagram of dispirodihydrofuranyl bisoxindole 5a.
The structures of compounds 4a–h were consistent with IR, 1H,
13C NMR, mass spectroscopy, and elemental analysis data.12,13 The
IR spectrum of 4a exhibited peaks at 1787, 1712, and 1631 cmꢀ1
for the lactone ester, CO2Me, and amide groups respectively. The
1H NMR spectrum of 4a showed two sharp singlets at d 9.23 and
10.95 ppm for the –NH protons (D2O exchangeable) of the amine
and the oxindole rings respectively, clearly indicating the incorpo-
ration of both the moieties in the product. In 13C NMR spectros-
copy, the spiro carbon atom displayed a signal at d 83.5 ppm and
the lactone carbonyl carbon and ester carbonyl carbon atoms res-
onated at d 162.1 and 167.7 ppm respectively.
To explore the synthetic utility of the spirolactones the latter
was allowed to react with several other activated electrophiles like
isatin. Spirolactone 4a (1 mmol), and isatin 1 (1 mmol) were re-
fluxed in methanol in the presence of NEt3 as a base catalyst to
the completion of the reaction. The reaction mixture was purified
by column chromatography to afford the product as two distinct
diastereomers (5a and 50a) in moderate yield14 (Scheme 3).
The 1H NMR spectrum of 5a exhibited three singlets at d 9.30,
10.23, and 10.39 ppm indicating the presence of three –NH protons
(D2O exchangeable) for the amine and the two oxindole rings,
respectively. In 13C NMR spectroscopy, signal for only one ester
Figure 3. ORTEP diagram of dispirodihydrofuranyl bisoxindole 50g.
Table 3
Studies on spirolactone 4a under various conditions
Entry
Substrates
Conditionsa
Product
carbonyl carbon atom was observed which resonated at
d
1
2
3
4
5
6
7
1 + 2a + 3 (1:1:1)
4a
1 + 2a + 3 (1:1:1)
4a + 1
rt
4a
165.3 ppm. The amide carbonyl carbon atoms resonated at d
173.7 and 174.6 ppm. The absence of the lactone ring carbonyl car-
bon atom marked the cleavage of the lactone ring and the presence
of two amide carbonyl carbon atoms suggested the formation of a
bisoxindole product. The mass spectrum also exhibited a distin-
guishing peak at m/z 468.00. A similar spectrum was exhibited
by 50a.15,16 The structure and relative stereochemistry of the two
diastereomers were further firmly established by single crystal
Reflux
Reflux
rt
Untractable mixture
Untractable mixture
No reaction
4a + 1
1 + 2a + 3 (2:1:1)
1 + 2a + 3 (2:1:1)
Reflux
rt
Reflux
5a (major) + 50a (minor)
4a + unreacted 1
5a (major) + 50a (minor)
a
All the reactions were carried out using NEt3 (20 mol%) as base catalyst and
methanol as solvent
H3C
CO2Me
H3C
H3C
CO2Me
H
N
H
N
O
NH
O
O
O
O
NH
O
NH
O
+
NEt3, MeOH
+
O
CO2Me
reflux
8 hrs
O
N
H
O
N
N
H
N
H
4a
O
H
74% yield
5Ia(minor)
1
5a(major)
dr: 76:24
Scheme 3. Synthesis of dispirodihydrofuranyl bisoxindole 5a and 50a.

S. E. Kiruthika et al. / Tetrahedron Letters 53 (2012) 3268–3273
3271
MeO2C
H
N
H3C
NH
O
H3C
O
H3C
O
O
O
NH
O
5a(major)
..
O
NH
+
N
HN
1
NEt3, MeOH
H
MeO2C
reflux
-CO2
H
H3C
N
CO2Me
N
H
O
NH
CO2Me
O
4a
O
N
H
3c
O
O
NH
5Ia(minor)
Scheme 4. Tentative mechanistic approach for the formation of dispirodihydrofurans 5a and 50a.
CO2Me
CO2Me
H
N
H
N
R
R
CO2Me
O
O
O
NH
O
NEt3, MeOH
reflux
(2:1:1)
NH
O
+
R
NH2
+
O
+
N
O
N
H
O
N
H
CO2Me
H
1
2a -h
3
5Ia-h (minor)
5a-h (major)
Scheme 5. Synthesis of dispirodihydrofuranyl bisoxindole derivatives 5a–h and 50a–h.
X-ray analysis performed for representative compounds 5a and 50g
(Figs. 2 and 3).17,18
In order to propose a suitable mechanism for the formation of
diastereomeric dispirodihydrofuranyl bisoxindoles (5a and 50a)
the reaction parameters such as temperature and stoichiometric
quantities of the starting materials were varied. The observations
are tabulated in Table 3.
Hence with the preceding results in hand a tentative mecha-
nism could be proposed (Scheme 4). At reflux condition, the reac-
tion proceeds further in the presence of isatin 1 (1 mmol) to
provide a mixture of diastereomers. The lone pair of nitrogen
may assist cleavage of the lactone 4a followed by decarboxylation
to give 3c, and the latter undergoes addition to isatin 1 to give a
mixture of two diastereomers 5a and 50a.
Moreover the one pot reaction of isatin 1 (2 mmol), m-toluidine
2a (1 mmol), and DMAD 3 (1 mmol) under reflux also afforded 5a
and 50a (Table 3, entry 7)19 and this path was found to be more
efficient in terms of yield, time, and diastereoselectivity compared
to the reaction of spirolactone 4a and isatin 1 (Table 3, entry 5).
The reaction was extended to synthesize other derivatives of dispi-
rodihydrofuranyl bisoxindoles (Scheme 5).
Interestingly, the reaction proceeds smoothly with other aro-
matic amines to provide dispirodihydrofuranyl bisoxindoles in
good yields (75–85%). The results for the synthesis of dispirodihy-
drofuranyl bisoxindoles 5a–h and 50a–h are summarized in Table
4.
With the optimized conditions in hand, the process was ex-
tended to other electrophiles like acenaphthenequinone 6. The
reaction proceeded in a similar manner and was purified by col-
umn chromatography to provide dispirodihydrofuranyl acenaph-
tho oxindoles (7a–h and 70a–h) as two distinct isomers (Scheme
6).20,21 The results are elaborated in Table 5.
In summary, a promising Huisgen dipolar addition involving
isatin, amines, and DMAD to afford spirolactones was discussed.
This letter also brings forth a novel strategy for the synthesis
of dispirodihydrofuranyl bisoxindoles and dispirodihydrofuranyl
Table 4
Synthesis of dispirodihydrofuranyl bisoxindole derivatives
Entry
R
5
50
Timea
Yieldb,c
drd
Table 5
50a
50b
50c
50d
50e
50f
10
11
11
12
24
15
13
13
85
84
80
77
75
79
80
81
90:10
89:11
85:15
87:13
81:19
92:8
Synthesis of dispirodihydrofuranyl acenaphtho oxindole derivatives
1
2
3
4
5
6
7
8
3-CH3C6H4
C6H5
5a
5b
5c
5d
5e
5f
Entry
4
7
70
Timea
Yieldb
drc
4-OCH3C6H4
2,5-(C(CH3)3)2C6H3
4-NO2-C6H4
2,4-(CH3)2C6H3
4-BrC6H4
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
7a
7b
7c
7d
7e
7f
70a
70b
70c
70d
70e
70f
12
13
12.5
14
24
12
20
17
82
84
75
77
75
79
80
78
80:20
81:19
85:15
87:13
79:21
84:16
83:17
82:18
5g
5h
50g
50h
86:14
82:18
4-ClC6H4
a
Completion of the reaction in hrs.
Reaction carried out with isatin 1 (2 mmol), amines (2a–h) (1 mmol) and DMAD
3 (1 mmol) using 20 mol% of NEt3 as base catalyst and methanol as solvent under
reflux conditions.
4g
4h
7g
7h
70g
70h
b
a
b
c
Completion of the reaction in hrs.
Isolated yield after column chromatography in %.
Based on isolated yield.
c
Isolated yield after column chromatography in %.
Based on isolated yield.
d

3272
S. E. Kiruthika et al. / Tetrahedron Letters 53 (2012) 3268–3273
CO2Me
R
NH
O
O
R
NH
O
O
O
O
NH
O
NEt3, MeOH
reflux
+
CO2Me
N
4a-h
O
H
6
7a-h (major) and 7Ia-h(minor)
Scheme 6. Synthesis of dispiro dihydrofuranyl acenaphthyl oxindole derivatives 7a–h and 70a–h.
8. (a) Zhu, S.-L.; Ji, S.-J.; Yong, Z. Tetrahedron 2007, 63, 9365; (b) Abdel-Rahman, A.
H.; Keshk, E. M.; Hanna, M. A.; El-Bady, S. M. Bioorg. Med. Chem. 2004, 12, 2483;
(c) Da-Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc 2001, 12, 273; (d)
Joshi, K. C.; Chand, P. Pharmazie 1982, 37, 1; (e) Cao, Y.; Jiang, X.; Liu, L.; Shen,
F.; Zhang, F.; Wang, R. Angew. Chem., Int. Ed. 2011, 50, 9124.
9. (a) Peterson, E. M.; Xu, K.; Holland, K. D.; McKeon, A. C.; Rothman, S. M.;
Ferrendelli, J. A.; Covey, D. F. J. Med. Chem. 1994, 37, 275; (b) Kupchan, S. M.;
Dessertine, A. L.; Blaylock, B. T.; Bryan, R. F. J. Org. Chem. 1974, 39, 2477; (c)
Trost, B. M.; Balkovec, J. M.; Mao, M. K.-T. J. Am. Chem. Soc. 1983, 105, 6755.
10. (a) Ji, X.; Liu, X.; Li, K.; Chen, R.; Wang, L. Biomed. Environ. Sci. 1991, 4, 332; (b)
Liu, X. M.; Wang, L. G.; Li, H. Y.; Ji, X. J. Biochem. Pharmacol. 1996, 51, 545; (c)
Wee, X. K.; Yeo, W. K.; Zhang, B.; Tan, V. B. C.; Lim, K. M.; Tay, T. E.; Go, M.-L.
Bioorg. Med. Chem. 2009, 17, 7562.
acenaphtho oxindoles. The diastereomers could be separated easily
by simple column chromatographic purification. The procedure
features readily available starting materials and good yields. It is
a very valuable new addition to the existing methods for the syn-
thesis of functionalized spiro lactones and dispirodihydrofuranyl
oxindoles.
Acknowledgment
One of the authors, S.E.K thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research fel-
lowship. The authors also thank SAIF and Department of Chemis-
try, Indian Institute of Technology, Madras for their technical
support.
11. Kiruthika, S. E.; Lakshmi, N. V.; Banu, B. R.; Perumal, P. T. Tetrahedron Lett. 2011,
52, 6508.
12. Experimental procedure for the synthesis of spirolactone 4a (Table 2, entry
1): Isatin 1 (1 mmol), m-toluidine 2a (1 mmol), and DMAD 3 (1 mmol) were
stirred at room temperature in MeOH in the presence of NEt3 (20 mol%) for 4 h
to give the spirolactones which was filtered and recrystallized from methanol
to afford the pure product 4a as yellow solid. (85% yield).
13. Spectral data for spirolactone 4a (Table 2, entry 1): yellow solid. mp: 132–
134 °C. tmax (KBr): 3284, 3148, 3076, 3040, 2952, 2895, 2846, 2277, 1787,
Supplementary data
1712, 1631, 1463, 1222, 1172, 1011, 955, 867, 759, 626, 496, 450 cmꢀ1 1H
.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
04.047.
NMR (DMSO-d6, 500 MHz): 2.25(s, 3H, -CH3), 3.29(s, 3H, -CH3), 6.91(m, 4H, -
ArH), 6.98(t, 1H, J = 7.7 Hz, -ArH), 7.16(t, 1H, J = 7.7 Hz, -ArH), 7.34(m, 2H, -
ArH), 9.23(s, 1H, -NH, D2O exchangeable), 10.95(s, 1H, -NH, D2O exchangeable).
13C NMR (DMSO-d6, 125 MHz): d 21.5, 51.9, 83.6, 111.0, 111.1, 120.1, 123.0,
123.5, 125.6, 125.6, 128.6, 131.2, 136.8, 138.1, 139.4, 143.4, 162.1, 167.7, 172.7.
MS (ESI): m/z 364.80 [M+H]+; Anal. Calcd For C20H16N2O5: C 65.93; H 4.43; N
7.69%. Found: C 65.90; H 4.46; N 7.70%.
References and notes
14. Experimental procedure for the synthesis of Dispirodihydrofuranyl
oxindole 5a and 50a (Scheme 3): Spirolactone 4a (1 mmol) and Isatin
1
1. (a) Huisgen, R. Proc. Chem. Soc. 1961, 357–369; (b) Huisgen, R. In 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley- Interscience: New York, 1984;
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Novel Reactions; American Chemical Society: Washington, DC, 1994; p 91; (d)
Tzitzikas, T. Z.; Terzidis, M. A.; Stephanatou, J. S.; Tsoleridis, C. A.; Kostakis, G. E.
J. Org. Chem. 2011, 76, 9008–9014.
(1 mmol) were stirred in MeOH in the presence of NEt3 (20 mol%) at reflux for
8 h. The reaction mixture was distilled under reduced pressure and purified by
column chromatography (35% EtOAc/Hexanes) and (50% EtOAc/Hexanes) to
afford the dispirodihydrofuranyl bisoxindoles 50a and 5a respectively as pure
white solids (74% yield)..
2. (a) Nair, V.; Devipriya, S.; Suresh, E. Tetrahedron 2008, 64, 3567; (b) Nair, V.;
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5. (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. In
Spirocyclic Systems in the Total Synthesis of Natural Products; Simon, J., Ed.; John
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15. Spectral data for Dispirodihydrofuranyl oxindole 5a (Table 4, entry 1): white
solid. mp: 238–240 °C. tmax (KBr): 3265, 3028, 2950, 1755, 1715, 1658, 1616,
1575, 1464, 1389, 762 cmꢀ1 1H NMR (DMSO-d6, 500 MHz): d 2.21(s, 3H, -CH3),
.
3.38(s, 3H, -CH3), 6.54(t, 1H, J = 8.4 Hz, -ArH), 6.59(d, 1H, J = 8.4 Hz, -ArH),
6.70(t, 2H, J = 7.7 Hz, -ArH), 6.87(d, 1H, J = 7.7 Hz, -ArH), 6.94(t, 1H, J = 8.4 Hz, -
ArH), 7.12(m, 5H, -ArH), 7.20(d, 1H, J = 8.4 Hz, -ArH), 9.30(s, 1H, -NH, D2O
exchangeable), 10.23(s, 1H, -NH, D2O exchangeable), 10.39(s, 1H, -NH, D2O
exchangeable). 13C NMR (DMSO-d6, 125 MHz): d 21.5, 50.9, 60.2, 62.6, 81.2,
90.5, 109.9, 110.5, 119.3, 121.3, 121.6, 121.7, 122.7, 125.5, 125.7, 127.2, 129.4,
129.6, 129.7, 132.0, 137.7, 138.9, 141.7, 143.6, 165.3, 173.7, 174.6. MS (ESI): m/
z 468.00 [M+H]+; Anal. Calcd For C27H21N3O5: C 69.37; H 4.53; N 8.99%. Found:
C 69.10; H 4.20; N 8.45%..
16. Spectral data for Dispirodihydrofuranyl oxindole 50a (Table 4, entry 1):
white solid. mp: 218–220 °C. tmax (KBr): 3195, 1730, 1659, 1609, 1463, 1397,
1337, 1204, 1087, 1015, 941, 750, 691, 496 cmꢀ1 1H NMR (DMSO-d6,
.
500 MHz): d 2.27(s, 3H, -CH3), 3.37(s, 3H, -CH3), 6.63(d, 1H, J = 7.5 Hz, -ArH),
6.67(d, 1H, J = 7.5 Hz, -ArH), 6.89–6.93(m, 2H, -Ar-H), 6.98(t, 1H, J = 7.5 Hz, -
ArH), 7.11–7.14 (m, 3H, -Ar-H), 7.20(t, 1H, J = 7.5 Hz, -ArH), 7.26–7.28(m, 2H, -
ArH), 7.51(d, 1H, J = 8.0 Hz, -ArH), 9.37(s, 1H, -NH, D2O exchangeable), 10.29(s,
1H, -NH, D2O exchangeable), 10.49(s, 1H, -NH, D2O exchangeable). MS (ESI): m/
z 468.30 [M+H]+.
17. Crystallographic data for compound 5a in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC- 837673. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).
6. (a) Pandey, R. C.; Toussaint, M. W.; Stroshane, R. M.; Kalita, C. C.; Aszalos, A. A.;
Garretson, A. L.; Wei, T. T.; Byrne, K. M.; Geoghegan, R. F.; White, R. J. J. Antibiot.
1981, 34, 1389–1401; (b) Goto, K.; Sudzuki, H. Bull. Chem. Soc. Jpn. 1929, 4, 220–
224; (c) Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya,
K.; Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 8, 2421–2424; (d)
Tomita, M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya, K.;
Sasaki, Y.; Matoba, K.; Goto, K. Tetrahedron Lett. 1967, 8, 2425–2430; (e) Tomita,
M.; Okamoto, Y.; Kikuchi, T.; Osaki, K.; Nishikawa, M.; Kamiya, K.; Sasaki, Y.;
Matoba, K.; Goto, K. Chem. Pharm. Bull. 1971, 19, 770–791.
18. Crystallographic data for compound 50g in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC- 870395. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).
19. Experimental procedure for the synthesis of Dispirodihydrofuranyl
oxindole 5a and 50a (Table 4, entry 1): Isatin 1 (2 mmol), m-toluidine 2a
(1 mmol) and DMAD 3 (1 mmol) were stirred in MeOH in the presence of NEt3
7. Han, Y. Y.; Chen, W. B.; Han, W. Y.; Wu, Z. J.; Zhang, X. M.; Yuan, W. C. Org. Lett.
2012, 14, 490.

S. E. Kiruthika et al. / Tetrahedron Letters 53 (2012) 3268–3273
3273
(20 mol%) at reflux for 10 h. The reaction mixture was distilled under reduced
pressure and purified by column chromatography (35% EtOAc/Hexanes) and
(50% EtOAc/Hexanes) to afford the dispirodihydrofuranyl oxindoles 50a and 5a
respectively as pure white solids (85% yield).
1739, 1671, 1460, 1336, 1269, 1197, 1092, 1006, 939, 831, 775, 686, 625,
540 cmꢀ1 1H NMR (DMSO-d6, 500 MHz): d 2.24(s, 3H, -CH3), 3.46(s, 3H, -CH3),
.
6.50(d, 1H, J = 7.5 Hz, -ArH), 6.90(d, 1H, J = 7.5 Hz, -ArH), 7.06(t, 1H, J = 7.5 Hz, -
ArH), 7.12–7.23(m, 5H, -ArH), 7.39(t, 1H, J = 7.8 Hz, -ArH), 7.45(d, 1H, J = 7.5 Hz,
-ArH), 7.82(t, 1H, J = 7.5 Hz, -ArH), 7.95-7.98 (m, 2H, -ArH), 8.21(d, 1H,
J = 8.0 Hz, -ArH), 9.43(s, 1H, -NH, D2O exchangeable), 10.08(s, 1H, -NH, D2O
exchangeable). 13C NMR (DMSO-d6, 125 MHz): d 21.5, 50.6, 63.4, 93.8, 109.7,
118.0, 121.3, 121.6, 122.0, 123.8, 125.0, 125.3, 126.7, 127.8, 128.6, 129.1, 129.2,
129.9, 130.0, 130.1, 130.5, 131.3, 137.3, 138.9, 141.1, 141.2, 165.6, 174.7, 196.4.
MS (ESI): m/z 503.07 [M+H]+; Anal. Calcd For C31H22N2O5: C 74.09; H 4.41; N
5.57%. Found: C 74.13; H 4.43; N 5.50%.
20. Experimental procedure for the synthesis of dispirodihydrofuranyl
acenaphtho oxindole 7a and 70a (Table 5, entry 1): Spirolactone 4a
(1 mmol) and acenaphthenequinone 6 (1 mmol) were stirred in MeOH in the
presence of NEt3 (20 mol%) at reflux for 12 h. The reaction mixture was
distilled under reduced pressure and purified by column chromatography (30%
EtOAc/Hexanes) and (40% EtOAc/Hexanes) to afford the dispirodihydrofuranyl
acenaphtho oxindoles 70a and 7a as pure yellow solids (82% yield).
21. Spectral data for dispirodihydrofuranyl acenaphtho oxindole 7a (.Table 5,
entry 1): white solid. mp: 242–244 °C. tmax (KBr): 3355, 3058, 2949, 2372,