A novel organocatalytic multi-component reaction: An efficient synthesis of polysubstituted pyrano-fused spirooxindoles

Article abstract of DOI:10.1016/j.tetlet.2012.05.019

A practical, simple, and efficient method for the synthesis of pyrano-fused spirooxindoles via an organocatalytic three-component reaction of isatins, malononitrile, and dialkyl acetylenedicarboxylate in the presence of 3,4-dimethylaniline as an organocat

Full text of DOI:10.1016/j.tetlet.2012.05.019

Tetrahedron Letters 53 (2012) 3603–3606
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel organocatalytic multi-component reaction: an efficient synthesis
of polysubstituted pyrano-fused spirooxindoles
⇑
⇑
Zeinab Noroozi Tisseh, Fereshteh Ahmadi, Minoo Dabiri , Hamid Reza Khavasi, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, General Campus, Tehran 1983963113, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical, simple, and efficient method for the synthesis of pyrano-fused spirooxindoles via an organ-
ocatalytic three-component reaction of isatins, malononitrile, and dialkyl acetylenedicarboxylate in the
presence of 3,4-dimethylaniline as an organocatalyst in ethanol is reported. The structures of these prod-
ucts are confirmed by IR, 1H NMR and 13C NMR spectroscopy, mass spectrometry, and single-crystal X-ray
diffraction studies.
Received 4 February 2012
Revised 11 March 2012
Accepted 3 May 2012
Available online 11 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spirooxindole
Isatin
Acetylenic ester
Organocatalytic reaction
The synthesis of novel heterocyclic compounds with potential
biological activity is one of the main challenges in chemical biology
and medicinal chemistry. The search for new and efficient synthetic
methodologies to access small molecules of privileged structures is
of significant interest.1 Multicomponent reactions (MCRs) have
proved to be very influential and efficient bond-forming tools in or-
ganic, combinatorial, and medicinal chemistry.2 In addition to the
fundamental atom economy and selectivity underlying such reac-
tions, the simpler procedures, shorter reaction times, energy sav-
ings, and environmental friendliness have all led to numerous
efforts to design and execute MCRs in both academia and industry.3
The spirooxindole moiety is an important heterocycle found in
many pharmacological agents and natural products such as
coerulescine, horsfiline, welwitindolinone A, spirotryprostatin A,
elacomine, and alstonisine.4 Spirotryprostatin A, a natural alkaloid
isolated from the fermentation broth of Aspergillus fumigatus, has
been identified as a novel inhibitor of microtubule assembly, and
pteropodine and isopteropodine have been shown to modulate
the function of muscarinic serotonin receptors.5,6
Compoundshavingthepyranstructuralmotifexhibitawiderange
of biological activities, such as diuretic, analgesic, myorelaxant,7 anti-
coagulant,8 anticancer,9 anti-tumor,10 and anti-HIV.11 In addition,
they are also useful for the treatment of neurodegenerative disorders
including Alzheimer’s disease, amyotrophic lateral sclerosis, Hun-
tington’s disease, and Parkinson’s disease.12 Pyran-annulated oxin-
doles are widely distributed in Nature and exhibit diverse
physiological activities.13 Several synthetic spiroheterocyclic com-
R''
O
R'O2C
R'O2C
CO2R'
CO2R'
N
CN
CN
Et3N
NH2
CN
+ R''NH2
O
N
R
O
N
R
Scheme 1. Synthesis of spirooxindole-fused dihydropyridines by Perumal et al.
R1O2C
O
NH2
R2O2C
X
CN
O
N
R
CO2R1
CO2R2
O
4
NH2
X
NC
CN
+
O +
EtOH, r.t.
8 h
N
R
R1O2C
1
2
3
N
NH2
CN
R2O2C
X
O
N
R
5
Scheme 2. Synthesis of polyfunctionalized pyrano-fused spirooxindoles 4.
pounds, containing both indole and pyran moieties possess anticon-
vulsant, analgesic,14 herbicidal,15 and antimicrobial activities.16
⇑
Corresponding authors. Fax: +98 21 22431661 (A.B.).
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.019

3604
Z. N. Tisseh et al. / Tetrahedron Letters 53 (2012) 3603–3606
Table 1
The multi-component reactions of amines, acetylenic esters,
Effect of catalyst on the reaction
active carbonyl compounds, and malononitrile based on a Huisgen
1,4-dipole intermediate have been reported for the synthesis of
new heterocyclic compounds.17–19 Perumal and co-workers
described the synthesis of spirooxindole-fused dihydropyridines
via the reaction of isatins, malononitrile, primary amines, and
acetylenic esters in the presence of Et3N (Scheme 1).20
MeO2C
MeO2C
O
NH2
CN
CO2Me
CO2Me
O
EtOH, r.t.
catalyst
CN
O
O
CN
N
N
H
H
Due to the important biological activities of spirooxindoles and
pyrans, we hypothesize that the synthesis of new heterocycles con-
taining both spirooxindole and pyran moieties may result in the
discovery of new drug candidates. Therefore, in continuation of
our efforts on the design and efficient synthesis of new spirooxin-
doles,21–24 herein, we report a novel and efficient method for the
synthesis of polyfunctionalized pyrano-fused spirooxindoles 4 via
the three-component condensation of isatins 1, malononitrile (2),
and dialkyl acetylenedicarboxylates 3 in the presence of 3,4-
dimethylaniline (DMA) as an organocatalyst (Scheme 2). It was
interesting that spirooxindole-fused dihydropyridines 5 were not
detected at all, while pyrano-fused spirooxindoles 4 were obtained
in good yields.
1a
2
3a
4a
Entry
Catalysta
Aniline
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
15
15
10
9
10
8
8
8
15
15
15
15
43
51
75
85
83
90
p-Toluidine
4-Aminophenol
N,N-Dimethylbenzene-1,4-diamine
4,5-Dimethylbenzene-1,2-diamine
3,4-Dimethylaniline
3,4-Dimethylaniline
3,4-Dimethylaniline
4-Nitroaniline
75b
55c
Traced
Traced
Traced
0
10
11
12
Triethylamine
Diethylamine
None
Our initial experiments focused on the three-component reac-
tion of isatin (1a) (1 mmol), malononitrile (2) (1 mmol), and di-
a
b
c
Catalyst = 1 mmol.
Catalyst = 0.7 mmol.
Catalyst = 0.5 mmol.
The Perumal product was obtained in <20% yield.
methyl acetylenedicarboxylate (3a) (1 mmol) as
a
model
d
reaction, in the presence of various aliphatic and aromatic amines
as organocatalysts in EtOH at room temperature (Table 1). It was
found that the reaction using an equimolar amount of DMA re-
sulted in a higher yield and short reaction time (Table 1, entry
6). When this reaction was carried out without a catalyst product
4a was not detected (Table 1, entry 12).
To find the optimal reaction solvent, various examples were
investigated on the DMA-catalyzed model reaction at room tem-
perature (Table 2). The results showed that the solvent affected
Table 2
Effect of solvent on the reaction
Entry
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
CH3CN
1,4-Dioxane
THF
MeOH
EtOH
12
12
12
8
8
12
48
35
43
68
90
55
H2O
R1O2C
O
NH2
CO2R1
R2O2C
O
EtOH, r.t.
X
CN
CN
X
CN
O
O
DMA, 8 h
N
N
CO2R2
R
R
1a-f
4a-l
2
3a-d
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
MeO2C
O
O
O
O
NH2
NH2
NH2
NH2
CN
NH2
NH2
MeO2C
MeO2C
Br
O2N
CN
CN
CN
O
O
O
O
N
H
N
N
N
H
Me
CH2Ph
4a (90%)
4b
(84%)
O
4c (78%)
4d (85%)
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
O
O
O
NH2
NH2
NH2
EtO2C
Br
Br
O2N
CN
CN
CN
CN
O
O
O
O
N
H
N
N
H
N
H
Me
4e (89%)
4f
(90%)
O
4g (93%)
4h (76%)
tBuO2C
H
tBuO2C
H
O
O
O
NH2
CN
NH2
CN
NH2
CN
tBuO2C
tBuO2C
MeO2C
MeO2C
CN
O
O
O
O
N
N
N
H
N
H
CH2Ph
(81%)
CH2Ph
(82%)
4i
4j
4k
4l
(92%)
(89%)
Figure 1. Synthesis of pyranospirooxindoles 4.

Z. N. Tisseh et al. / Tetrahedron Letters 53 (2012) 3603–3606
3605
venagel condensation of
1
and 2. Subsequent Michael-type
addition of the b-enamino ester 7 (formed in situ by reaction of
3 and DMA) to 6 yields intermediate 8. Finally, intermolecular
nucleophilic substitution of H2O on 8, followed by cyclization
and tautomerization affords the corresponding product 4. To help
clarify the proposed mechanism, first, the isatylidene malononitri-
le 6a was synthesized via condensation of isatin 1a and malononit-
rile, and then reaction of 6a with DMAD in the presence of DMA
afforded the corresponding product 4a in 83% yield.
In conclusion, an efficient, atom-economic, and environmen-
tally friendly method for the preparation of polysubstituted pyr-
ano-fused spirooxindoles using readily available starting
materials in EtOH is reported. Prominent among the advantages
of this method are operational simplicity, good yields, and the easy
work-up procedure employed.
Acknowledgement
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
References and notes
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893.
2. (a) Lu, P.; Wang, Y. G. Synlett 2010, 165; (b) Ganem, B. Acc. Chem. Res. 2009, 42,
463; (c) Dömling, A. Chem. Rev. 2006, 106, 17.
3. (a) Gerencser, J.; Dorman, G.; Darva, F. QSAR Comb. Sci. 2006, 439; (b) Ramon, D.
J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1634.
4. (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 63, 2209; (b) Dounay, A. B.;
Hatanaka, K.; Kodanko, J. J.; Oestreich, M.; Overman, L. E.; Pfeifer, L. A.; Weiss,
M. M. J. Am. Chem. Soc. 2003, 125, 6261.
Figure 2. X-ray crystal structure (ORTEP) of compound 4a.
5. For selected reviews, see: (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007; (b)
Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. Spirocyclic
Systems In The Total Synthesis of Natural Products; ApSimon, J., Ed.; John Wiley
and Sons: New York, 1983; Vol. 5, p 264.
6. (a) Chang, M. Y.; Pai, C. L.; Kung, Y. H. Tetrahedron Lett. 2005, 46, 8463; (b)
Baran, S. P.; Richter, R. M. J. Am. Chem. Soc. 2005, 127, 15394; (c) Hilton, S. T.;
Ho, T. C. T.; Pljevaljcic, G.; Jones, K. Org. Lett. 2000, 2, 2639; (d) Cui, C. B.;
Kakeya, H.; Kada, G.; Onose, R.; Osada, H. J. Antibiot. 1996, 49, 527.
7. Bonsignore, L.; Loy, G.; Secci, D.; Calignano, A. Eur. J. Med. Chem. 1993, 28, 517.
8. Cingolani, G. M.; Gualtteri, F.; Pigin, M. J. Med. Chem. 1961, 12, 531.
9. Wu, J. Y. C.; Fong, W. F.; Zhang, J. X.; Leung, C. H.; Kwong, H. L.; Yang, M. S.; Li,
D.; Cheung, H. Y. Eur. J. Pharmacol. 2003, 473, 9.
10. (a) Baraldi, P. G.; Manfredini, S.; Simoni, D.; Tabrizi, M. A.; Balzarini, J.; De
Clercq, E. J. Med. Chem. 1992, 35, 1877; (b) Perrella, F. W.; Chen, S. F.; Behrens,
D. L.; Kaltenbach, R. F.; Seitz, S. P. J. Med. Chem. 1994, 37, 2232.
11. (a) Kashman, Y.; Gustafson, K. R.; Fuller, R. W.; Cardellina, J. H.; McMahon, J. B.;
Currens, M. J.; Buckheit, R. W.; Hughes, S. H.; Gragg, G. M.; Boyd, M. R. J. Med.
Chem. 1992, 35, 2735; (b) Patil, A. D.; Freyer, A. J.; Eggleston, D. S.;
Waltiwanger, R. C.; Bean, M. F.; Taylor, P. B.; Caranfa, M. J.; Breen, A. L.;
Bartus, H. R.; Johnson, R. K.; Hertzberg, R. P.; Westley, J. W. J. Med. Chem. 1993,
36, 4131.
12. (a) Foye, W. O. Principi di Chemico Farmaceutica; Piccin: Padora, Italy, 1991,
416; (b) Andreani, L. L.; Lapi, E. Bull. Chim. Farm. 1960, 99, 583.
13. Sakhuja, R.; Panda, S.; Khanna, L.; Khurana, S.; Jain, S. Bioorg. Med. Chem. Lett.
2011, 21, 5465.
3
+ DMA
CO2R2
CO2R1
R1O2C
NC
N
H
CN
O
NH
CN
H2O
R2O2C
7
1
2
+
CN
O
N
R
N
R
H2O
6
8
R1O2C
R1O2C
OH
O
NH
CN
R2O2C
R2O2C
tautomerization
4
CN
CN
O
O
N
R
N
R
Scheme 3. Possible mechanism for the formation of product 4.
14. Joshi, K. C.; Jain, R.; Sharma, K.; Bhattacharya, S. K.; Goel, R. K. J. Indian Chem.
Soc. 1988, 65, 202.
15. Joshi, K. C.; Jain, R.; Arora, S. J. Indian Chem. Soc. 1988, 65, 277.
16. Nandakumar, A.; Thirumurugan, P.; Perumal, P. T.; Vembu, P.; Ponnuswamy, M.
N.; Ramesh, P. Bioorg. Med. Chem. Lett. 2010, 20, 4252.
17. Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. Org. Lett. 2010, 12, 3678.
18. Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. ACS Comb. Sci. 2011, 13, 421.
19. Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. ACS Comb. Sci. 2011, 13, 436.
20. Kiruthika, S. E.; Lakshmi, N. V.; Banu, B. R.; Perumal, P. T. Tetrahedron Lett. 2011,
52, 6508.
21. Bazgir, A.; Tisseh, Z. N.; Mirzaei, P. Terahedron Lett. 2008, 49, 5165.
22. Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. Tetrahedron 2009, 65, 2005.
23. Dabiri, M.; Tisseh, Z. N.; Nobahar, M.; Bazgir, A. Helv. Chim. Acta 2011, 94, 824.
24. Ghahremanzadeh, R.; Sayyafi, M.; Ahadi, S.; Bazgir, A. J. Comb. Chem. 2009, 11,
393.
the efficiency of the reaction and EtOH proved to be the best choice
(Table 2, entry 5).
Using the optimized conditions, a variety of isatins 1a–f and
dialkylacetylenedicarboxylates 3a–d were employed to evaluate
the substrate scope of the reaction. Pyranospirooxindoles 4a–l
were obtained in good yields (Fig. 1).25 As anticipated, these reac-
tions proceeded very cleanly at room temperature and no side
reactions were observed. All the compounds described in this Let-
ter have been synthesized for the first time.
The products 4 were stable solids, the structures of which were
fully characterized by IR, 1H NMR and 13C NMR spectroscopy, mass
spectrometry, and elemental analysis. The structure of 4a was con-
firmed by single-crystal X-ray analysis26 (Fig. 2).
25. General procedure for preparation of pyran-annulated spirooxindoles (4).
mixture of isatin 1 (1 mmol) and malononitrile (2) (1 mmol) in EtOH (3 mL)
was stirred for 15 min then treated with solution of dialkyl
acetylenedicarboxylate (1 mmol) and 3,4-dimethylaniline (1 mmol) in
A
a
We have not established an exact mechanism for the formation
of 4, however, a reasonable possibility is shown in Scheme 3. It is
reasonable to assume that product 4 results from the initial forma-
tion of intermediate isatylidene malononitrile 6 by standard Knoe-
3
EtOH (1 mL). The mixture was stirred at room temperature for 8 h. After
completion of the reaction (TLC, eluent: EtOAc/hexane, 1:2), the mixture was
filtered and the precipitate washed with H2O (5 mL) and EtOH (5 mL) to afford
the pure product 4. Dimethyl 20-amino-30-cyano-2-oxospiro[indoline-3,40-pyran]-

3606
Z. N. Tisseh et al. / Tetrahedron Letters 53 (2012) 3603–3606
50,60-dicarboxylate (4a). White powder (90%); mp 216–218 °C. IR (KBr) (mmax
/
pyran]-50,60-dicarboxylate (4i). White powder (yield 92%); mp 178–180 °C. IR
(KBr) (
max/cmꢀ1): 3415, 3310, 3155, 2208, 1745, 1610. 1H NMR (300 MHz,
cmꢀ1): 3391, 3301, 3167, 2200, 1751, 1725, 1706. 1H NMR (300 MHz, DMSO-
d6): dH (ppm) 3.39 (3H, s, OMe), 3.83 (3H, s, OMe), 6.82 (1H, d, 3JHH = 7.4 Hz, H–
Ar), 6.98 (1H, t, 3JHH = 7.2 Hz, H–Ar), 7.15 (1H, d, 3JHH = 7.2 Hz, H–Ar), 7.23 (1H,
t, 3JHH = 7.4 Hz, H–Ar), 7.52, (2H, s, NH2), 10.56, (1H, s, NH). 13C NMR (75 MHz,
DMSO-d6): dC (ppm) 49.5, 52.9, 53.9, 55.7, 110.2, 111.9, 117.3, 122.7, 124.9,
130.0, 132.0, 142.3, 145.7, 159.7, 161.0, 163.6, 177.2. MS, m/z: 355 (M+). Anal.
Calcd for C17H13N3O6: C, 57.47; H, 3.69; N, 11.83. Found: C, 57.36; H, 3.75; N,
11.73. Dimethyl 20-amino-5-bromo-30-cyano-1-methyl-2-oxospiro[indoline-3,40-
pyran]-50,60-dicarboxylate (4b). White powder (yield 84%); mp 222–224 °C. IR
m
DMSO-d6): dH (ppm) 1.00 (9H, s, 3Me), 1.45 (9H, s, 3Me), 6.84 (1H, d,
3JHH = 7.4 Hz, H–Ar), 6.99 (1H, t, 3JHH = 7.4 Hz, H–Ar), 7.12 (1H, d, 3JHH = 7.2 Hz,
H–Ar), 7.26 (1H, t, 3JHH = 7.2 Hz, H–Ar), 7.44 (2H, s, NH2), 10.61 (1H, s, NH).13
C
NMR (75 MHz, DMSO-d6): dC (ppm) 27.1, 27.6, 49.3, 55.8, 82.8, 84.5, 110.1,
111.6, 114.0, 117.5, 122.6, 124.9, 129.8, 132.5, 133.5, 142.8, 146.8, 159.8, 159.9,
162.3, 177.5. MS, m/z: 439 (M+). Anal. Calcd for C23H25N3O6: C, 62.86; H, 5.73;
N, 9.56. Found: C, 62.93; H, 5.79; N, 9.48.
26. X-ray data for 4a: C17H13N3O6, M = 355.30 g/mol, triclinic system, space group
(KBr) (
m
max/cmꢀ1): 3407, 3310, 2209, 1761, 1649, 1604. 1H NMR (300 MHz,
Pı,
a = 6.8979(5),
b = 84.134(6),
= 79.308(6)°, V = 833.15(11) Å3, Z = 2, Dc = 1.416 g cmꢀ3
(Mo
) = 0.110 mmꢀ1
crystal dimensions: 0.50 ꢁ 0.40 ꢁ 0.35 mm. The
b = 11.0423(9),
c = 12.3365(10) Å,
a = 64.503(6),
¯
DMSO-d6): dH (ppm) 3.14 (3H, s, NMe), 3.41 (3H, s, OMe), 3.82 (3H, s, OMe),
7.04 (1H, s, H–Ar), 7.53 (2H, s, H–Ar), 7.64 (2H, s, NH2). 13C NMR (75 MHz,
DMSO-d6): dC (ppm) 27.1, 49.0, 53.1, 54.0, 54.9, 109.6, 111.3, 115.2, 117.1,
127.5, 132.8, 134.0, 143.1, 147.4, 159.6, 161.0, 163.4, 175.4. MS, m/z: 449 (M+,
81Br), 447 (M+, 79Br). Anal. Calcd for C18H14BrN3O6: C, 48.23; H, 3.15; N, 9.37.
Found: C, 48.07; H, 3.08; N, 9.24. Diethyl 20-amino-5-bromo-30-cyano-1-methyl-
2-oxospiro[indoline-3,40-pyran]-50,60-dicarboxylate (4f). Cream powder (yield
c
,
l
Ka
,
structure was solved using SHELXS. The structure refinement and data
reduction were carried out with SHELXL from the X-Step32 suite of
programs.27 The non-hydrogen atoms were refined anisotropically by full
matrix least-squares on F2 values to final R1 = 0.0434, wR2 = 0.1337 and
S = 1.065 with 243 parameters using 4453 independent reflections (h
range = 1.83–29.25°). Crystallographic data for 4a have been deposited with
the Cambridge Crystallographic Data Centre, CCDC 859396. Copies of the data
can be obtained, free of charge, on application to The Director, Union Road,
Cambridge CB2 1EZ, UK. Fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk.
90%); mp 190–192 °C. IR (KBr) (m
max/cmꢀ1): 3455, 3280, 2191, 1719, 1634,
1604. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 0.81 (3H, s, Me), 1.25 (3H, s, Me),
3.14 (3H, s, NMe), 3.83 (2H, s, OCH2), 4.27 (2H, s, OCH2), 7.03–7.06 (1H, m, H–
Ar), 7.50–7.58 (4H, m, H–Ar and NH2).13C NMR (75 MHz, DMSO-d6): dC (ppm)
13.6, 14.0, 49.0, 55.0, 61.8, 63.2, 63.3, 109.4, 111.2, 115.1, 117.1, 127.5, 132.8,
134.0, 143.2, 147.5, 159.7, 160.5, 162.8, 175.5. MS, m/z: 477 (M+, 81Br), 475 (M+,
79Br). Anal. Calcd for C20H18BrN3O6: C, 50.44; H, 3.81; N, 8.82. Found: C, 50.32;
H, 3.73; N, 8.89. Di-tert-butyl 20-amino-30-cyano-2-oxospiro[indoline-3,40-
27. X-STEP32 Version 1.07b, X-ray structure evaluation package, 2000, Stoe & Cie,
Darmstadt, Germany.