A novel method for the synthesis of functionalized spirocyclic oxindoles by one-pot tandem reaction of vinyl malononitriles with isatylidene malononitriles

Article abstract of DOI:10.1016/j.tetlet.2009.12.082

One-pot synthesis of novel spirocyclic oxindoles was achieved via vinylogous Michael addition of vinyl malononitriles on isatin-malononitrile adducts as the key step followed by a sequential tandem reaction.

Full text of DOI:10.1016/j.tetlet.2009.12.082

Tetrahedron Letters 51 (2010) 994–996
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Tetrahedron Letters
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A novel method for the synthesis of functionalized spirocyclic oxindoles
by one-pot tandem reaction of vinyl malononitriles with isatylidene
malononitriles
*
Thelagathoti Hari Babu, A. Abragam Joseph, D. Muralidharan, 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:
One-pot synthesis of novel spirocyclic oxindoles was achieved via vinylogous Michael addition of vinyl
malononitriles on isatin–malononitrile adducts as the key step followed by a sequential tandem reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 22 October 2009
Revised 10 December 2009
Accepted 15 December 2009
Available online 21 December 2009
Keywords:
Vinylogous Michael addition
One-pot tandem reaction
Spirocyclic oxindoles
Spirocyclic systems containing one sp3 carbon atom common to
two rings are structurally interesting.1 The asymmetric structure
of the molecule due to the chiral spiro carbon atom is one of the
important criteria of the biological activities.2,3 Among the spirocy-
clic compounds, the heterocyclic spiro-oxindole framework is an
important structural motif in biologically relevant compounds such
as natural products and pharmaceuticals.4 In addition, the oxindole
moiety constitutes a key structural element in several natural prod-
ucts,5 including the antibioticsperadine6 and the cytostatic welwist-
atin.7 Consequently, the development of novel synthetic strategies
leading to 3,3-disubstituted oxindole derivatives is of paramount
importance. Many synthetic methodologies developed for con-
structing spirocycles containing 2-oxindole were based on cycload-
dition or condensation reactions.8–15 In continuation of our interest
on the synthesis of spirocyclic oxindoles,16, we herein report a novel
method for the synthesis of highly functionalized spirocyclic oxin-
doles bearing hexahydro naphthalene and tetrahydro indene frame-
and yet a simple tertiary amine can smoothly catalyze the Michael
addition of an -dicyanoolefin substrate to nitrostyrene by
deprotonating the acidic -allylic C–H to generate the nucleophilic
a,a
c
carbanion.18a,c Vinylogous Michael addition was involved as a key
step in the synthesis of polysubstituted benzene derivatives from
vinyl malononitriles and nitrostyrenes in one-pot tandem reac-
tion.20 Recently, we reported the Hantzsch ester-promoted reduc-
tive cyclization of isatylidene malononitriles to dispiro[cyclopent-
30-ene]bisoxindoles in one-pot method.21
From the synthetic point of view, one-pot methods are attrac-
tive since they generate less waste, minimize isolation of interme-
diates in multi-step syntheses of complex molecular targets and
save time and cost.22 With this idea in hand and to contribute in
the area of vinylogous Michael addition followed by intramolecular
nucleophilic addition, we investigated a series of reactions of vinyl
malononitriles with isatylidene malononitriles to obtain spirocy-
clic oxindoles in a one-pot tandem procedure. Michael-type reac-
tions are reversible and the products formed can often be
decomposed to the reactants by heating, and hence we conducted
the experiments initially at room temperature.
Our detailed study commenced with the addition of isatylidene
malononitrile (1a) to the stirred solution of cyclohexanone malono-
nitrile (2a) adduct and triethyl amine in ethanol. After 5 min of addi-
tion, there is a complete colour change of maroon isatylidene
malononitrile forming a clear solution. Monitoring by TLC revealed
that the reactants were consumed completely to yield a single prod-
uct spot. On further stirring for five more minutes, a colourless pre-
cipitate was formed which was filtered, washed with 20% EA/PE to
afford a pure product (3a) in 90% yield (Scheme 1).
works by
a
one-pot, multi-step transformation of vinyl
malononitriles with isatylidene malononitriles via vinylogous Mi-
chael addition followed by an intramolecular nucleophilic addition
and isomerization under mild reaction conditions for the first time.
The Michael addition reaction is widely recognized as one of the
most versatile carbon–carbon bond-forming reactions in organic
synthesis. Recently, Chen et al. reported that
a,a-dicyanoolefin
compounds can selectively behave as acceptors17 or vinylogous do-
nors18,19 in Michael reactions under easily controllable conditions
* 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.2009.12.082

T. Hari Babu et al. / Tetrahedron Letters 51 (2010) 994–996
995
CN
CN
NC
NC
NC CN
CN
O
NC CN
n= (
1,2
R1
CN
O
)
NH2
NH2
CN
CN
R1
NEt3, EtOH, rt
10-20 mins
NEt3, EtOH, rt
10 mins
CN
CN
+
+
(
)
n=1,2
N
R2
O
O
N
N
R2
N
H
2a-b
2a (n=2)
2b (n=1)
H
3a-l
1a-g
3a
1a
2a
Scheme 2.
Scheme 1.
spirofused cyclohexadienes were purified by column chromatogra-
phy and were characterized by spectral data.25 The reaction of acy-
clic vinyl malononitrile 2d with 1a, followed by chromatographic
purification resulted in an inseparable mixture of two products
3o, as major, and 3p, as minor, in 80:20 ratio as evidenced by 1H
NMR (Scheme 4). Based on the 1H NMR spectrum with two diaste-
reotopic protons resonating at d 2.65 and 2.83 ppm as two doublets
with geminal coupling constant 16.8 Hz, the olefinic proton reso-
nating at d 5.68 ppm as quartet and the methyl protons resonating
at d 1.57 ppm as doublet with coupling constant 6.9 Hz, the major
product was assigned the structure with exocyclic double bond to
the newly formed six-membered ring.
The reactions involving 5-substituted isatylidene malononitr-
iles (1f and 1g) were quite slow compared to the unsubstituted
and N-substituted derivatives with cyclic vinyl malononitriles.
We also attempted the reaction of vinyl malononitrile with isatin
and ethyl cyano acetate adducts. But a mixture of inseparable
products was obtained.
A plausible mechanism for the formation of these novel spirocy-
clic oxindoles is presented in Scheme 5. The first step involves a
facile deprotonation of vinyl malononitrile (2a) under mild basic
conditions to furnish vinylogous carbanion which attacks isatylid-
ene malononitrile (1a) followed by an intramolecular nucleophilic
addition on CN group resulting in an imine (5). The imine on isom-
Figure 1. Ortep diagram of 3b.
The structure of the obtained product (3a) was assigned on the
basis of spectroscopic data.23 The peak at 3339 and 3200 cmꢀ1 is
diagnostic of the primary NH2 group. In the 1H NMR, the NH2 pro-
tons resonated at d 7.51 ppm (exchangeable with D2O). The struc-
ture of the molecule 3b was further confirmed by single-crystal X-
ray data (Fig. 1).24 To understand the generality of this reaction, we
have subjected various isatylidene malononitriles to the reaction of
vinyl malononitriles under mild reaction conditions to provide
highly functionalized spirocyclic oxindoles in excellent yields
(Scheme 2). The results are summarized in Table 1.
CN
NC
Ph
CN
O
NC
CN
Ph
NH2
CN
R1
NEt3, EtOH, rt
18-20 mins
+
R1
CN
O
H3C
N
N
R2
R2
2c
3m-n
1a-b
Some interesting spirofused cyclohexadienes were achieved
with acyclic vinyl malononitriles (2c, 2d) (Scheme 3 and 4). The
Scheme 3.
Table 1
Synthesis of spirocyclic oxindoles
Entry
Isatylidene malononitrile
Vinyl malononitrile
Product
Time (min)
Yielda (%)
R1
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1a
1b
1c
1d
1e
1f
1g
1a
1b
1c
1d
1f
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2d
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
10
12
15
13
12
20
22
15
13
15
13
19
20
18
17
90
92
90
92
90
85
83
90
90
88
91
84
78
81
75b
Methyl
Allyl
Propargyl
Benzyl
H
H
Br
NO2
H
H
H
H
Br
H
H
H
H
H
Methyl
Allyl
Propargyl
H
1a
1b
1a
H
3m
3n
3o, 3p
Methyl
H
a
Isolated yield.
Isolated as a mixture of 3o and 3p.
b

996
T. Hari Babu et al. / Tetrahedron Letters 51 (2010) 994–996
4. For reviews, see: (a) Williams, R. M.; Cox, R. J. Acc. Chem. Res. 2003, 36, 127; (b)
CN
CN
H3C
H3C
NC
Da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem. Soc. 2001, 273.
5. Thiericke, R.; Tang, Y. Q.; Sattler, I.; Grabley, S.; Feng, X. Z. Eur. J. Org. Chem.
2001, 261.
6. Tsuda, M.; Mugishima, T.; Komatzu, K.; Sone, T.; Tanaka, M.; Mikami, Y.; Shiro,
M.; Hirai, M.; Ohizumii, Y.; Kobayashi, J. Tetrahedron 2003, 59, 3227.
7. Zhang, X.; Smith, C. D. Mol. Pharmacol. 1996, 49, 288.
NH2
CN
CN
CN
O
NH2
CN
CN
NC
CN
H3C
NEt3, EtOH, rt
17 min
+
+
H3C
O
O
N
N
N
H
H
CH3
H
8. Yong, S. R.; Ung, A. T.; Pyne, S. G.; Skelton, B. W.; White, A. H. Tetrahedron 2007,
63, 1191.
3p
3o
1a
2d
9. Marti, C.; Carreira, E. M. J. Am. Chem. Soc. 2005, 127, 11505.
10. Robertson, D. W.; Krushinski, J. H.; Pollock, G. D.; Wilson, H.; Kauffman, R. F.;
Hayes, J. S. J. Med. Chem. 1987, 30, 824.
Scheme 4.
11. Yong, S. R.; Williams, M. C.; Pyne, S. G.; Ung, A. T.; Skelton, B. W.; White, A. H.;
Turner, P. Tetrahedron 2005, 61, 8120.
12. Feldman, K. S.; Vidulova, D. B.; Karatjas, A. G. J. Org. Chem. 2005, 70, 6429.
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NC
NC CN
NC CN
NC
CN
CN
14. Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137.
base
O
+
15. England, D. B.; Merey, G.; Padwa, A. Org. Lett. 2007, 9, 3805.
16. (a) Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron 2007, 63, 2057; (b)
Savitha, G.; Niveditha, S. K.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett.
2007, 48, 2943.
N
H
1a
2a
17. (a) Chen, Y.-C.; Xue, D.; Deng, J.-G.; Cui, X.; Zhu, J.; Jiang, Y.-Z. Tetrahedron Lett.
2004, 45, 1555; (b) Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G.
J. Org. Chem. 2005, 70, 3584.
18. (a) Xue, D.; Chen, Y.-C.; Cun, L.-F.; Wang, Q.-W.; Zhu, J.; Deng, J.-G. Org. Lett.
2005, 7, 5293; For similar work by Jørgensen, see: (b) Poulsen, T. B.; Alemparte,
C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614; (c) Poulsen, T. B.; Bell,
M.; Jørgensen, K. A. Org. Biomol. Chem. 2006, 4, 63.
H
CN
CN
O
CN
NH2
N
NH
CN
CN
CN
CN
CN
CN
O
O
N
N
H
N
H
19. For a recent review on vinylogous reactions, see: Denmark, S. E., Jr.; Heemstra,
J. R.; Beutner, G. L. Angew. Chem., Int. Ed. 2005, 44, 4682.
H
5
4
3a
20. Xue, D.; Li, J.; Zhang, Z.-T.; Deng, J.-G. J. Org. Chem. 2007, 72, 5443.
21. Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2008, 49, 7139.
22. (a) Lebel, H.; Ladjel, C.; Brethous, L. J. Am. Chem. Soc. 2007, 129, 13321–13326;
(b) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1–21; (c) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186; (d)
Pelissier, H. Tetrahedron 2006, 62, 2143–2173; (e) Pellissier, H. Tetrahedron
2006, 62, 1619–1665.
Scheme 5. Plausible mechanism.
erization yielded the corresponding spirocyclic oxindole (3a) in
one-pot, sequential transformation.
23. General procedure for the synthesis of spirocyclic oxindole (3a): To a stirred
solution of 1 mmol of cyclohexanone malononitrile adduct (2a) and NEt3
(20 mmol %) in ethanol at room temperature, 1 mmol of isatylidene
malononitrile (1a) was added and continued stirring for about 10 min to
form a colourless precipitate. After the reaction was complete as indicated by
TLC, the precipitate was filtered and washed with 20% ethyl acetate/pet ether
to afford pure product (3a) as off-white solid in 90% yield.
During the course of our investigations, we have observed that
the reaction of isatylidene malononitrile with cyclic vinyl malono-
nitriles (2a, 2b) furnishes exocyclic double bond in the newly
formed six-membered ring, whereas the double bond is endocyclic
when acylic vinyl malononitrile (2c) is used.
Several advantages of this method like milder reaction condi-
tion, shorter reaction time, high yield, simple experimental and
isolation procedures make it an efficient route for the synthesis
of novel spirocyclic oxindoles.
In summary, we have demonstrated a novel method for the syn-
thesis of functionalized spirocyclic oxindoles via vinylogous Mi-
chael addition followed by a sequential intramolecular addition
and isomerization reaction in one-pot, tandem procedure.
Spectral data of spiro oxindole 3a (Table 1): Off-white solid. Yield: 90%, mp 238–
240 °C. 1H NMR (500 MHz, DMSO-d6) d: 0.42 (q, 1H, J = 12.2 Hz), 1.41 (m, 1H),
1.52 (m, 1H), 1.59 (m, 1H), 1.86 (m, 1H), 2.05 (m, 1H,), 2.86 (d, 1H, J = 10.7 Hz),
5.88 (m, 1H,), 6.83 (d, 1H, J = 7.65 Hz), 6.97 (d, 1H, J = 7.65 Hz), 7.02 (t, 1H,
J = 7.65 Hz), 7.34 (t, 1H, J = 7.65), 7.51 (s, 2H, D2O exchangeable), 11.35 (s, 1H,
D2O exchangeable). 13C NMR (500 MHz, DMSO-d6) d: 20.7, 23.9, 25.0, 37.4,
42.6, 55.0, 82.0, 111.1(2C), 111.2, 116.0, 122.9, 123.4, 124.2, 125.4, 125.9,
131.4, 142.8, 143.3, 173.7. IR mmax (KBr) : 3339, 3200, 2934, 2216, 1733, 1614,
619 cmꢀ1. Mass (ESI): 342 (M+1). Anal. Calcd for C20H15N5O : C, 70.37; H, 4.43;
N, 20.52. Found: C, 70.31; H, 4.36; N, 20.47.
24. Crystallographic data for compound 3b in this Letter have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication no.
CCDC 749095. 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).
25. General procedure for the synthesis of spirocyclic oxindole (3m): To a stirred
solution of 1 mmol of acetophenone malononitrile adduct (2c) and NEt3
(20 mmol %) in ethanol at room temperature, 1 mmol of isatylidene
malononitrile (1a) was added and continued stirring for the time mentioned
in Table 1. After the reaction was complete as indicated by TLC, the solvent was
evaporated and the crude product was purified by column chromatography
(30% ethyl acetate/pet ether) to afford product (3m). The same procedure was
followed for 3o and 3p also.
Acknowledgement
One of the authors, T.H. thanks the Council of Scientific and
Industrial Research, New Delhi, India for the research fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.082.
Spectral data of spiro oxindole 3m (Table 1):
Brown solid. Yield: 78%, mp 230–232 °C. 1H NMR (500 MHz, DMSO-d6) d: 5.52
(s, 1H,), 6.98 (d, 1H, J = 7.6 Hz), 7.08 (t, 1H, J = 7.65 Hz), 7.35 (m, 7H), 8.22 (s, 2H,
D2O exchangeable) 11.25 (s, 1H, D2O exchangeable). 13C NMR (500 MHz,
DMSO-d6) d: 43.9, 54.7, 77.1, 111.1, 111.3, 112.2, 123.7, 124.6, 131.7, 137.1,
139.3, 148.5, 173.4. IR mmax (KBr) : 3410, 3301, 3196, 2213, 1725, 1643, 799.
Mass (ESI): 364 (M+1). Anal. Calcd for C22H13N5O: C, 72.72; H, 3.61; N, 19.27.
Found: C, 72.67; H, 3.55; N, 19.21.
References and notes
1. Sannigrahi, M. Tetrahedron 1999, 55, 9007.
2. James, D. M.; Kunze, H. B.; Faulkner, D. J. J. Nat. Prod. 1991, 54, 1137.
3. Kobayashi, J.; Tsuda, M.; Agemi, K.; Shigemiri, H.; Ishibashi, M.; Sasaki, T.;
Mikami, Y. Tetrahedron 1991, 47, 6617.