An expedient approach for the synthesis of dispiropyrrolidine bisoxindoles, spiropyrrolidine oxindoles and spiroindane-1,3-diones through 1,3-dipolar cycloaddition reactions

Article abstract of DOI:10.1016/j.tetlet.2009.12.079

A series of dispiropyrrolidine bisoxindoles were synthesized via a multicomponent 1,3-dipolar cycloaddition reaction of isatin, sarcosine and isatylidene malononitrile in refluxing methanol. Also a series of spiropyrrolidine oxindoles and spiroindane-1,3-diones were synthesized using 2-(1H-Indole-3-carbonyl)-3-phenyl-acrylonitrile and 2-(1,3-dioxo-indan-2-ylidene)-malononitrile as dipolarophiles, respectively.

Full text of DOI:10.1016/j.tetlet.2009.12.079

Tetrahedron Letters 51 (2010) 1064–1068
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expedient approach for the synthesis of dispiropyrrolidine bisoxindoles,
spiropyrrolidine oxindoles and spiroindane-1,3-diones through 1,3-dipolar
cycloaddition reactions
*
Neelakandan Vidhya Lakshmi, Prakasam Thirumurugan, Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, 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 series of dispiropyrrolidine bisoxindoles were synthesized via a multicomponent 1,3-dipolar cyclo-
addition reaction of isatin, sarcosine and isatylidene malononitrile in refluxing methanol. Also a series
of spiropyrrolidine oxindoles and spiroindane-1,3-diones were synthesized using 2-(1H-Indole-3-car-
bonyl)-3-phenyl-acrylonitrile and 2-(1,3-dioxo-indan-2-ylidene)-malononitrile as dipolarophiles,
respectively.
Received 20 November 2009
Revised 11 December 2009
Accepted 15 December 2009
Available online 21 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Spiropyrrolidine oxindoles
Spiroindane-1
3-Diones
Multi-component reaction
Isatylidene malononitrile
Dipolarophile
Multicomponent 1,3-dipolar cycloaddition reactions play a key
role in the synthesis of five-membered heterocycles.1 1,3-Dipolar
cycloaddition of ylidic species, such as azomethine ylides with
dipolarophiles, is a powerful method for the construction of biolog-
ically active five-membered heterocycles2 especially substituted
pyrrolidine rings.3 Pyrrolidines are important heterocycles which
have glucosidase inhibitory activity, potent antiviral, antibacterial,
antidiabetic and anticancer activities.4
The heterocyclic spiro-oxindole framework is an important
structural motif in relevant compounds as natural products and
also act as potent nonpeptide inhibitor of the p53-MDM2 inter-
action.5 Spiropyrrolidine oxindole ring systems are found in a
we report a 1,3-dipolar cycloaddition reaction involving the ole-
fin segment of isatylidene malononitrile to synthesize dispiropyr-
rolidine bisoxindoles via generation of azomethine ylides from
isatin and sarcosine. The generated azomethine ylides ap-
proached the dipolarophile isatylidene malononitrile regio-
selectively.
In our initial endeavour, we have investigated a three-compo-
nent reaction of isatin 1a, sarcosine 2 and isatylidene malononitrile
3 in various solvents like methanol, toluene and acetonitrile under
reflux condition to afford functionalized dispiropyrrolidine bisox-
indole 4a with two spiro centres. The best results were obtained
by refluxing the reaction mixture in methanol with high yield of
the product (Scheme 1).
A mixture of isatin 1a (1.0 mmol), sarcosine 2 (1.2 mmol) and
isatylidene malononitrile 3 (1.1 mmol) in methanol was refluxed
for 100 min. The reaction mixture was cooled to room tempera-
ture. The solid precipitated from the reaction was filtered and
recrystallized from ethanol to furnish dispiropyrrolidine bisoxin-
dole 4a as a single regioisomer.
The feasibility of the reaction was further studied with various
substituted isatin derivatives. Under optimized conditions, the
reaction proceeded smoothly with various isatin derivatives,
including those containing halogens and N-substituted isatin
derivatives to provide dispiropyrrolidine bisoxindoles 4b–f in good
yields (82–85%). The results are given in Table 1.
number of alkaloids such as horsifiline, spirotryprostatine
A
and B and elacomine.6 Isatin derivatives are useful precursors
in the synthesis of wide number of naturally occurring oxindole
alkaloids.7
The synthesis of spiro-oxindoles via 1,3-dipolar cycloaddition
reaction of piperidone derivatives,5b Baylis–Hillman and Morita–
Baylis–Hillman adducts of isatin has been reported.8,9 Recently,
Murugan et al. have synthesized dispiropyrrolidine oxindoles by
[3+2] cycloaddition reaction of azomethine ylides.10 To the best
of our knowledge, there are only a few methods to synthesize
dispiro-oxindoles using isatin derivatives as both dipoles and
dipolarophiles in 1,3-dipolar cycloaddition reaction.9,11 Herein,
Initially, the reaction proceeds through the generation of azo-
methine ylide (dipole 2a) via the decarboxylative condensation
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.079

N. V. Lakshmi et al. / Tetrahedron Letters 51 (2010) 1064–1068
1065
O
R1
CN
NC
O
HO C
N
H
+
N
2
O
N
R
N
N
H
R
O
1a-f
2
NC
CN
O
R1
_
4a-f
+
N
R1
N
H
3
O
NH
O
methanol, reflux
N
R
N
O
CN
dipole, 2a-f
R
N
CN
R1
5a-f
Scheme 1. Synthesis of dispiropyrrolidine oxindoles 4a–f.
Table 1 (continued)
Table 1
Synthesis of dispiropyrrolidine bisoxindoles 4a–f
Entry Isatin 1
R
R1 Producta
Time Yieldb
(min) (%)
Entry Isatin 1
R
R1 Producta
Time Yieldb
(min) (%)
(4)
(4)
CN
O
NC
CN
NC
N
O
N
O
N
N
H
6
1f
Propargyl
H
120
85
HN
N
H
1
1a
H
H
100
85
O
4f
4a
NC
a
The products were characterized by NMR, IR, mass and elemental analysis.
Isolated yield.
CN
b
N
O
HN
N
H
2
1b
H
Cl
80
83
O
of isatin 1a with sarcosine 2. The possible mode of approach of azo-
methine ylide (dipole 2a) is shown in Figure 1. The regioselectivity
in the product formation can be explained by considering second-
ary interaction of the orbitals of carbonyl group of dipolarophile
312 with those of the ylide 2a as shown in Figure 1. Accordingly,
the observed regioisomer 4a via path A is more favourable due
to the secondary orbital interaction (SOI) which is not possible in
path B. Hence, only one regioisomer 4a was formed as evidenced
by single crystal analysis.13
Cl
4b
NC
CN
N
O
HN
N
H
3
1c
H
Br
80
82
O
The structures of cycloadducts 4a–f were confirmed by spectro-
scopic studies and elemental analysis. The 1H NMR spectrum of
compound 4a exhibited characteristic singlets at d 2.03 for –
NCH3 protons and d 10.75, 11.08 for –NH protons of two oxindole
rings which proved the incorporation of two oxindole rings in the
structure. The amide carbonyl carbon atoms of two oxindole rings
show peaks at d 172.9 and 175.9 ppm in 13C NMR spectrum. These
observed chemical shift values are in accordance with the structure
of the compound 4a. Moreover, the presence of a molecular ion
peak at m/z 370 (M++H+) in the mass spectrum of 4a confirmed
the structure of the cycloadduct 4a. The relative stereochemistry
of the product 4a was established through single-crystal X-ray
analysis13–15 (Fig. 2).
Br
4c
CN
O
NC
N
O
N
N
H
4
1d
Allyl
H
80
84
4d
NC
CN
N
O
On the basis of the above-mentioned results, we have extended
our protocol to other two dipolarophiles such as 2-(1,3-dioxo-in-
N
N
H
5
1e
Benzyl
H
100
83
O
Ph
dan-2-ylidene)-malononitrile
6 and 2-(1H-Indole-3-carbonyl)-
3-phenyl-acrylonitrile 8 under optimized conditions. The dipolaro-
philes 6 and 8 react with azomethine ylides (dipole 2a–f) generated
4e

1066
N. V. Lakshmi et al. / Tetrahedron Letters 51 (2010) 1064–1068
N
+
_
CN
NC
2a
H
N
N
O
O
Path A
HN
O
N
H
H
SOI
N
O
CN
4a
3
CN
O
(observed)
H
N
+
NH
O
N
_
N
O
CN
CN
O
Path B
HN
H
2a
N
CN
3
5a
(not observed)
CN
SOI- Secondary orbital interaction
Figure 1. Mode of approach of azomethine ylide 2a.
in situ from isatin 1a–f and sarcosine 2 in methanol to yield spiroin-
dane-1,3-diones 7a–f and spiropyrrolidine oxindoles 9a–f, respec-
tively, as single products with good yields (75–87%) as evidenced
by TLC and spectral analysis (Scheme 2). The results are summarized
in Tables 2 and 3.
The products 7a–f and 9a–f were characterized on the basis of
their elemental analysis as well as IR, 1H NMR, 13C NMR and mass
spectral analysis.
carbonyl groups of indandione, respectively. The mass spectrum
displayed the (M++H+) peak at m/z 423.0.16,17
The IR spectrum of 9a showed peak at 1704 cmÀ1 due to the
oxindole ring carbonyl group. In the 1H NMR spectrum of 9a, the
benzylic proton showed a triplet at d 5.40, which clearly proved
the regiochemistry of the cycloaddition reaction. The doublet at d
3.65 (–NCH2 protons) in 1H NMR spectrum of 9a further confirmed
the structure of the product 9a. The signals at d 10.40 and 11.86 in
1H NMR spectrum correspond to –NH protons. The signals at d
174.9 and 180.6 ppm in the 13C NMR spectrum confirm the pres-
ence of amide carbonyl group of oxindole ring and keto carbonyl
group, respectively. The mass spectrum displayed the (M++H+)
peak at m/z 447.2. The stereochemistry of cycloadducts 7a–f and
9a–f was assigned by analogy of compound 4a.18,19
The IR spectrum of 7d showed peak at 1722 cmÀ1 due to the
oxindole ring carbonyl group. The 1H NMR spectrum of compound
7d exhibited a characteristic singlet at d 1.86 (–NCH3 protons) and
two doublets at d 3.55 and 3.95 (–NCH2 protons). The peaks at d
173.3, 196.7 and 197.6 ppm in 13C NMR spectrum indicated the
presence of amide carbonyl group of oxindole ring and two keto
O
R1
R
O
O
HO2C
N
H
N
O
O
+
N
N
CN
CN
R
1a-f
CN
CN
2
O
R1
6
O
methanol, reflux
_
7a-f
+
N
Ph
R1
O
Ph
O
CN
O
N
R
N
R1
CN
O
N
H
3-indolyl
8
dipole, 2a-f
N
R
methanol, reflux
9a-f
Scheme 2. Synthesis of spiroindane-1,3-diones 7a–f and spiropyrrolidine oxindoles 9a–f.

N. V. Lakshmi et al. / Tetrahedron Letters 51 (2010) 1064–1068
1067
Table 2 (continued)
Entry Isatin
R
R1 Producta (7)
Time
(min) (%)
Yieldb
1
Ph
O
N
N
5
1e
Benzyl
H
120
78
CN
CN
O
O
7e
O
N
N
6
1f
Propargyl
H
130
75
CN
CN
O
Figure 2. ORTEP diagram of compound 4a.
O
7f
a
The products were characterized by NMR, IR, mass and elemental analysis.
Isolated yield.
b
Table 2
Synthesis of spiroindane-1,3-diones 7a–f
Entry Isatin
R
R1 Producta (7)
Time
(min) (%)
Yieldb
1
This method offers several advantages such as high yield,
simple experimental and isolation procedures making it an
H
N
O
N
Table 3
Synthesis of spiropyrrolidine oxindoles 9a–f
CN
CN
O
1
2
3
1a
1b
1c
H
H
120
120
130
82
78
83
Entry Isatin R
R1 Producta
Time Yieldb
(min) (%)
1
(9)
O
Ph
O
7a
N
H
O
N
1
2
3
1a
1b
1c
H
H
H
H
60 87
60 85
60 82
CN
O
N
N
H
N
H
CN
CN
9a
O
H
Cl Cl
Ph
O
O
N
Cl
Br
Cl
CN
O
7b
H
N
H
O
N
N
H
N
9b
Ph
CN
CN
O
O
H
Br
Br
N
O
Br
CN
O
N
H
N
H
7c
9c
Ph
O
O
N
N
N
CN
O
4
1d
Allyl
H
120
76
4
1d
Allyl
H
60 80
N
CN
CN
N
O
H
O
9d
7d
(continued on next page)

1068
N. V. Lakshmi et al. / Tetrahedron Letters 51 (2010) 1064–1068
N. P.; Bakulev, V. A.; Deryabina, T. G.; Subbotina, J. O.; Kodess, M. I.; Dehaen, W.;
Table 3 (continued)
Toppet, S.; Robeyns, K.; Meervelt, L. V. Tetrahedron 2009, 65, 7662.
3. Ahrendt, K. A.; Williams, R. M. Org. Lett. 2004, 6, 4539.
Entry Isatin R
R1 Producta
(9)
Time Yieldb
(min) (%)
4. (a) Augustine, T.; Kanakam, C. C.; Vithiya, S. M.; Ramkumar, V. Tetrahedron Lett.
2009, 50, 5906; (b) Karthikeyan, K.; Kumar, R. S.; Muralidharan, D.; Perumal, P.
T. Tetrahedron Lett. 2009, 50, 7175.
1
Ph
5. (a) Basavaiah, D.; Reddy, R. K. Org. Lett. 2007, 9, 57; (b) Kumar, R. R.; Perumal,
S.; Senthilkumar, P.; Yogeeswari, P.; Sriram, D. Eur. J. Med. Chem. 2009, 44, 3821.
6. Hilton, S. T.; Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639.
7. Wang, L.; Zhang, Y.; Hu, H. -Y.; Fun, H. K.; Xu, J.-H. J. Org. Chem. 2005, 70, 3850.
8. Shanmugam, P.; Viswambharan, B.; Madhavan, S. Org. Lett. 2007, 9, 4095.
9. Shanmugam, P.; Viswambharan, B.; Selvakumar, K.; Madhavan, S. Tetrahedron
Lett. 2008, 49, 2611.
10. Murugan, R.; Anbazhagan, S.; Narayanan, S. S. Eur. J. Med. Chem. 2009, 44, 3272.
11. (a) Babu, A. R. S.; Raghunathan, R. Tetrahedron Lett. 2007, 48, 6809; (b) Casaschi,
A.; Dedimoni, G.; Faita, G.; Invernizzi, A. G.; Grünanger, P. Heterocycles 1994,
37, 1673; (c) Bovio, B.; Locchi, S. J. Chem. Crystallogr. 2002, 32, 69; (d) Rehn, S.;
Bergman, J.; Stensland, B. Eur. J. Org. Chem. 2004, 413; (e) Babu, A. R. S.;
Raghunathan, R. Tetrahedron 2007, 63, 8010.
O
N
CN
O
5
1e
Benzyl
H
80 80
N
N
H
Ph
9e
Ph
O
N
CN
O
12. Pardasani, R. T.; Pardasani, P.; Chaturvedi, V.; Yadav, S. K.; Saxena, A.; Sharma, I.
Heteroat. Chem. 2003, 14, 36.
13. Ramesh, P.; Sundaresan, S. S.; Lakshmi, N. V.; Perumal, P. T.; Ponnuswamy, M.
N. Acta Crystallogr., Sect. E 2009, 65, o1945.
6
1f
Propargyl H
100 78
N
N
H
14. Typical experimental procedure for 4a:
A mixture of isatin 1a (1.0 mmol),
sarcosine 2 (1.2 mmol) and isatylidene malononitrile 3 (1.1 mmol) in methanol
was refluxed for 100 min and cooled to room temperature. The solid formed in
the reaction mixture was filtered, dried and recrystallized from ethanol to
obtain the pure product in good yield (85%).
9f
a
The products were characterized by NMR, IR, mass and elemental analysis.
Isolated yield.
b
15. Spectral data of compound 4a (Table 1, entry 1): White solid; mp 236–238 °C; Rf
0.25 (50% EtOAc/petroleum ether); IR (KBr): 3422, 1724, 1625, 1469, 757,
652 cmÀ1 1H NMR (500 MHz, DMSO-d6):
; d 2.03 (s, 3H), 4.15 (ABq, 2H,
J = 8.7 Hz), 6.59 (d, 1H, J = 7.6 Hz, -Ar-H), 6.72 (d, 1H, J = 7.65 Hz, -Ar-H), 6.93 (t,
1H, J = 7.65, -Ar-H), 7.02 (t, 1H, J = 7.65 Hz, -Ar-H), 7.14 (t, 1H, J = 7.65 Hz, -Ar-
H), 7.23–7.25 (m, 2H, -Ar-H), 7.56 (d, 1H, J = 7.65 Hz, -Ar-H), 10.75 (br s, 1H, –
NH, D2O exchangeable), 11.08 (br s, 1H, -NH, D2O exchangeable); 13C NMR
(125 MHz, DMSO-d6): 34.4, 61.1, 62.9, 76.9, 110.6, 110.7, 115.3, 116.1, 120.1,
122.1, 122.6, 123.0, 126.6, 127.5, 131.4, 131.7, 143.5, 143.8, 172.9, 175.9; MS
(ESI LCQ-MS): m/z 370 [M++H+]. Anal. Calcd for C21H15N5O2: C, 68.28; H, 4.09;
N, 18.96. Found: C, 68.32; H, 4.02; N, 18.90.
efficient route to the synthesis of dispiropyrrolidine bisoxin-
doles, spiropyrrolidine oxindoles and spiroindane-1,3-diones
that are important compounds in organic and medicinal
chemistry.
In summary, we have demonstrated multicomponent 1,3-dipolar
cycloaddition reactions which give an array of dispiropyrrolidine
bisoxindoles and spiropyrrolidine oxindoles using isatylidene mal-
ononitrile and 2-(1H-Indole-3-carbonyl)-3-phenyl-acrylonitrile,
respectively, and spiroindane-1,3-diones using 2-(1,3-dioxo-in-
dan-2-ylidene)-malononitrile. The products were isolated by
recrystallization without involving further purification process like
column chromatography.
16. Typical experimental procedure for 7d:
A mixture of isatin 1a (1.0 mmol),
sarcosine (1.2 mmol) and 2-(1,3-dioxo-indan-2-ylidene)-malononitrile
2
6
(1.1 mmol) in methanol was stirred for 120 min. The solid formed in the
reaction mixture was filtered, dried and recrystallized from ethanol to obtain
the pure product in good yield (76%).
17. Spectral data of compound 7d (Table 1, entry 1): Yellow solid; mp 238–240 °C;
Rf 0.25 (50% EtOAc/petroleum ether); IR (KBr): 3366, 1722, 1618, 1469, 1327,
1262, 761 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 1.86 (s, 3H), 3.55 (d, 1H,
;
J = 9.9 Hz), 3.95 (d, 1H, J = 9.2 Hz), 4.13–4.26 (m, 2H), 5.10 (d, 1H, J = 11.45 Hz),
5.20 (d, 1H, J = 16.1 Hz), 5.70–5.75 (m, 1H), 6.81 (d, 1H, J = 8.4 Hz, -Ar-H), 6.94
(t, 1H, J = 7.65 Hz, -Ar-H), 7.23 (t, 1H, J = 7.65, -Ar-H), 7.33–7.36 (m, 1H, -Ar-H),
7.46 (d, 1H, J = 7.6 Hz, -Ar-H), 7.60 (t, 1H, J = 7.65 Hz, -Ar-H), 7.65 (d, 1H,
J = 7.65 Hz, -Ar-H), 7.78–7.83 (m, 1H, -Ar-H); 13C NMR (125 MHz, DMSO-d6):
33.6, 41.8, 53.4, 57.5, 74.0, 74.2, 89.3, 109.7, 117.8, 122.5, 123.4, 124.1, 125.1,
128.4, 130.5, 131.6, 132.5, 133.5, 137.7, 145.5, 152.5, 166.4, 173.3, 196.7,
197.6; MS (ESI LCQ-MS): m/z 423.0 [M++H+]. Anal. Calcd for C25H18N4O3: C,
71.08; H, 4.29; N, 13.26. Found: C, 71.02; H, 4.22; N, 13.28.
Acknowledgement
One of the authors, N.V., thanks the Council of Scientific and
Industrial Research, New Delhi, India, for the research fellowship.
Supplementary data
18. Typical experimental procedure for 9a:
A mixture of isatin 1 (1.0 mmol),
sarcosine 2 (1.2 mmol) and 2-(1H-Indole-3-carbonyl)-3-phenyl-acrylonitrile
8 (1.1 mmol) in methanol was refluxed. The reaction mixture was allowed to
reflux for 60 min and was cooled to room temperature. The solid formed in the
reaction mixture was filtered, dried and recrystallized from ethanol to obtain
the pure product in good yield (87%).
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.079.
References and notes
19. Spectral data of compound 9a (Table 3, entry 1): White solid; mp 234–236 oC; Rf
0.25 (50% EtOAc/petroleum ether); IR (KBr): 3397, 3278, 1704, 1620, 1442,
747 cmÀ1 1H NMR (500 MHz, DMSO-d6): d 2.12 (s, 3H), 3.65 (d, 2H, J = 8.4 Hz),
;
1. (a) Tsuge, O.; Kanemasa, S.. In Advances in Heterocyclic Chemistry; Katritzky, A.
5.40 (t, 1H, J = 8.4 Hz), 6.58 (d, 1H, J = 7.65 Hz, -Ar-H), 6.76 (s, 1H, -Ar-H), 7.16–
7.22 (m, 3H, -Ar-H), 7.26 (t, 1H, J = 6.9 Hz, -Ar-H), 7.31–7.34 (m, 4H, -Ar-H),
7.49 (d, 2H, J = 6.9 Hz, -Ar-H), 7.81 (d, 1H, J = 7.65 Hz, -Ar-H), 8.11–8.14 (m, 1H,
-Ar-H), 10.40 (br s, 1H, –NH, D2O exchangeable), 11.86 (br s, 1H, –NH, D2O
exchangeable); 13C NMR (125 MHz, DMSO-d6): 35.6, 45.18, 56.6, 66.5, 77.1,
110.6, 112.8, 112.9, 119.8, 122.2, 122.5, 123.2, 124.1, 125, 125.9, 126.7, 128.2,
128.8, 130.0, 131.4, 134.6, 135.9, 138.0, 144.2, 162.7, 174.9, 180.6; MS (ESI
LCQ-MS): m/z 447.2 [M++H+]. Anal. Calcd for C28H22N4O2: C, 75.32; H, 4.97; N,
12.55. Found: C, 75.41; H, 4.92; N, 12.48.
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