One-pot multicomponent synthesis and anti-microbial evaluation of 2′-(indol-3-yl)-2-oxospiro(indoline-3,4′-pyran) derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.05.025

A simple and efficient method for the one-pot three-component synthesis of new spirooxindoles in room temperature is described. The newly synthesized spirooxindoles were screened for anti-microbial activity and the results are good on comparison with of standard antibacterial compounds.

Full text of DOI:10.1016/j.bmcl.2010.05.025

Bioorganic & Medicinal Chemistry Letters 20 (2010) 4252–4258
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
One-pot multicomponent synthesis and anti-microbial evaluation
of 20-(indol-3-yl)-2-oxospiro(indoline-3,40-pyran) derivatives
a
b
A. Nandakumar a, Prakasam Thirumurugan a, Paramasivan T. Perumal a, , P. Vembu , M. N. Ponnuswamy ,
*
P. Ramesh b
a Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, Tamil Nadu, India
b Centre of Advanced Study in Crystallography and Biophysics, University of Madras, Guindy Campus, Chennai 600 025, Tamil Nadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient method for the one-pot three-component synthesis of new spirooxindoles in room
temperature is described. The newly synthesized spirooxindoles were screened for anti-microbial activity
and the results are good on comparison with of standard antibacterial compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 3 January 2010
Revised 21 April 2010
Accepted 11 May 2010
Available online 19 May 2010
Keywords:
Spiroxindoles
3-Cyanoacetyl indole
Anti-microbial activity
Pyran ring
Isatin
Functionalized nitrogen and oxygen containing heterocycles
play a predominant role in medicinal chemistry and they have
been intensively used as scaffolds for drug development. Multi-
component reactions (MCR’s) have emerged as a powerful tool
for delivering the molecular diversity needed in the combinatorial
approaches for the preparation of bioactive compounds.1 Multi-
component reactions, such as the Biginelli,2 Passerini,3 Ugi4 and
Hantzsch, provide a wide variety of important heterocycles.5 For
example, the Hantzsch reaction provides dihydropyridines with
activity against calcium channels, multidrug resistance (MDR) pro-
teins, 5-hydroxytryptamine(5-HT) receptors and anti-inflamma-
tory targets.1b,6,7
with anticancer, anti-tumour,13 anti-inflammatory, hypoglycemic,
analgesic and anti-pyretic activities.14 Many indole alkaloids are
recognized as one of the rapidly growing groups of marine inverte-
brate metabolites for their broad spectrum of biological
properties.15,16
The wide-ranging biological activity associated with many spir-
oxindole and 3-substituted indole derivatives, both naturally
occurring and synthetic, ensures that the synthesis of this
important ring system remains a topic of current interest. Various
Me
Me
N
NH
N
The spirooxindole framework8 represents important structural
organization present in a number of bioactive natural products
such as coerulescine, horsfiline, welwitindolinone A, spirotryprost-
atin A, elacomine and alstonisine. Spirotryprostatin A,9 a natural
alkaloid isolated from the fermentation broth of Aspergillus fumig-
atus, has been identified as a novel inhibitor of microtubule assem-
bly, and pteropodine and isopteropodine have been shown to
modulate the function of muscarinic serotonin receptors10 (Fig. 1).
The 3-substituted indole nucleus substructure is one of the
most important heterocycles found in natural products, pharma-
ceuticals and important medicinal chemistry.11,12 It is found as a
scaffold in a number of biologically active compounds especially
MeO
O
O
O
N
N
N
HO
H
H
H
coerulescine
elacomine
O
horsfiline
Cl
N
H
O
H
CO2Me
H
H
H
NH
O
H
N
CN
H
O
O
N
O
N
N
H
MeO
Me
alstonisine
H
spirotryprostatin A
welwitindolinone A
* Corresponding author. Tel.: +91 44 24913289; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Figure 1. Representative structure of spiroxindole derivatives.
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.05.025

A. Nandakumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4252–4258
4253
Table 1
Table 2
Screening of various bases in methanol
Screening of various solvents for the formation substituted spiroxindole using Et3N
b
Entry
Bases
Yielda,d (%)
Entry
Solvent
Yielda, (%)
1
2
3
4
5
K2CO3
NaOH
Piperidine
Triethylamine
Diethylamine
21b
10b
69c
89c
74c
1
2
3
4
5
6
DMF
69
48
71
54
83
89
Dichloroethane
Acetonitrile
Water
Ethanol
Methanol
a
b
c
Isolated yield.
a
The reactions were carried out with 1.5 equivalents of bases.
The reactions were carried out in 20 mol% of bases.
Isolated yield.
b
All reactions were carried out with 20 mol% Et3N for 0.5 h in methanol.
d
All the reactions were carried out for 1.5 h at ambient temperature.
R
N
CN
O
O
O
NC
Methanol / Et3N
RT, 0.5 h
CN
CN
+
+
O
CN
N
R
H2N
O
N
H
N
H
1a-e
2
3
4a-e
Scheme 1. Synthesis of spiroxindoles from isatin, malanonitrile and 3-cyanoacetyl indole.
Table 3
Synthesis of spiroxindoles from isatin, malanonitrile and 3-cyanoacetyl indole
Entry
Compound
Producta
Time (min)
Yieldb (%)
H
N
O
O
CN
NC
1
30
88
O
O
4a
N
H
H2N
O
1a
1b
N
H
Me
N
O
N
O
NC
CN
4b
2
3
4
5
30
45
40
60
89
85
83
85
H2N
O
Me
N
H
Benzyl
N
O
O
CN
NC
O
N
4c
1c
1d
H2N
O
Benzyl
N
H
Propragyl
N
O
O
CN
NC
O
4d
N
H2N
O
Propragyl
N
H
EtO2C
N
O
O
CN
NC
O
4e
N
1e
CO2Et
H2N
O
N
H
a
All the products characterized by NMR, IR and mass spectroscopy.
Isolated yield.
b

4254
A. Nandakumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4252–4258
NC
CN
O
Et3N
-H2O
+
NC
CN
O
O
N
H
N
H
2
2a
1
CN
OH
CN
O
N
H
N
H
3a
3
HN
HN
CN
O
NC
O
CN
O
H
CN
OH
+
NC
NC
CN
O
H
O
N
N
N
N
H
N
H
H
N
H
3c
3a
2a
3b
H
N
H
N
O
H
O
NC
CN
NC
CN
O
HN
O
H2N
N
N
H
3d
H
4
Scheme 2. Plausible mechanism for the formation spiroxindole derivatives.
routes, longer reaction time, drastic reaction conditions, as well
as narrow substrate scope.17–20 To the best of our knowledge, there
have been no reports for the synthesis of indol-3-yl derivatives
including spiroxindole moieties. As part of our ongoing research
on the development of novel synthetic routes for the synthesis of
biologically active heterocyclic compounds and use of green chem-
ical techniques in organic synthesis,21–23 herein, we report a simple
and facile one pot procedure for the synthesis of indol-3-yl spiro-
oxindole derivatives in methanol at ambient temperature.
On continuation of earlier work,24 we carried out a reaction of
isatin (1a), malononitrile (2) and 3-cyanoacetyl indole (3) in the
presence of in various bases and solvents at ambient temperature
(Tables 1 and 2). Excellent results were obtained when triethyl
amine was used as a base under ambient temperature condition in
methanol with high yield of the product in a shorter reaction time.
So we followed the reaction by stirring a mixture of isatin (1a), mal-
ononitrile (2), 3-cyanoacetyl indole (3) and triethyl amine (20 mol%)
in methanol under ambient temperature condition (Scheme 1). Un-
der these conditions, the reaction preceded smoothly with a wide
range of functionalized isatins, including those containing benzyl,
propagyl, ester and methyl groups (Table 3).25
Based on the above results, a plausible mechanism is proposed
(Scheme 2). Initially, isatin 1 reacts with malononitrile 2 to give a
corresponding isatin–malononitrile adduct 2a and 3-cyanoacetyl
indole 3 in the presence of base (Et3N) enolise to give 3a. 3a further
reacts with isatin–malononitrile adduct 2a to give intermediates
3b and 3c. The intermediate 3c further rearranges via proton trans-
fer to give 3d. Finally, the intermediate 3d affords to yield spirox-
indole derivative (4) via proton transfer.
Figure 2. ORTEP diagram of compound 4a.
methods for the preparation of these compounds have been re-
ported. However these methods suffer from tedious synthetic

A. Nandakumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4252–4258
4255
R
N
CN
O
O
CN
Methanol / Et3N
RT, 2-6h
EtO2C
CN
O
+
+
O
H2N
O
CO2Et
N
R
N
H
N
H
1a-g
5
3
6a-g
Scheme 3. Synthesis of spiroxindoles from isatin, ethylcyano acetate and 3-cyanoacetyl indole.
Table 4
Synthesis of spiroxindoles from isatin, ethylcyano acetate and 3-cyanoacetyl indole
Entry
Compound
Producta
Time (min)
Yieldb (%)
H
N
O
O
CN
EtO2C
1
4.0
78
O
O
6a
N
H
1a
1b
1c
H2N
O
N
H
Me
N
O
N
O
EtO2C
CN
2
4.5
79
6b
H2N
O
Me
N
H
Benzyl
O
N
O
CN
EtO2C
3
5.0
74
O
6c
N
H2N
O
Benzyl
N
H
Propragyl
N
O
O
CN
EtO2C
4
5
6
7
5.5
5.5
6.0
6.0
73
75
72
74
O
1d
N
6d
6e
6f
H2N
O
Propragyl
N
H
EtO2C
N
O
O
EtO2C
CN
O
1e
N
H2N
Allyl
O
CO2Et
N
H
N
O
O
EtO2C
CN
O
N
1f
H2N
O
Allyl
N
H
Butyl
N
O
O
EtO2C
CN
O
6g
N
1g
H2N
O
Butyl
N
H
a
All the products characterized by NMR, IR and mass spectroscopy.
Isolated yield.
b

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A. Nandakumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4252–4258
CN
O
O
O
R1
CN
CN
R1
O
Methanol / Et3N
RT, 2-6h
+
+
H2N
O
R2
N
N
R2
10a-f
R3
R3
7
8a-b
9a-c
Scheme 4. Synthesis of spiroxindole derivatives from acenapthenequinone precursor.
Table 5
Synthesis of spiroxindole derivatives from acenapthenequinone precursor
Entry
8
9
Producta
Time (h)
Yieldb (%)
CN
O
CN
CN
O
8a
1
CN
1.5
76
NC
9a
10a
N
H
H2N
O
N
H
CN
O
CN
CN
O
NC
2
3
4
5
CN
1.5
1.5
4.5
4.0
75
71
77
78
8a
N
9b
10b
H2N
O
N
CN
O
CN
CN
O
NC
CN
8a
N
H
9c
10c
H2N
O
N
H
CN
O
CN
O
CN
EtO2C
8b
CO2Et
9a
N
H
10d
H2N
O
O
O
N
H
CN
O
CN
O
CN
EtO2C
CO2Et
8b
N
H
9c
10e
H2N
N
H
CN
O
CN
O
CN
6
EtO2C
CO2Et
4.5
76
N
8b
9b
10f
H2N
N
Me
a
All the products characterized by NMR, IR and mass spectroscopy.
Isolated yield.
b

A. Nandakumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4252–4258
4257
The structure of products 4a–e were confirmed by spectral
studies and elemental analysis as exemplified for compound 4a
as follows (Table 3, entry 1): the IR spectrum of 4a showed absorp-
tions at 3343, 2205 and 1707 cmꢀ1 indicating the presence of –
NH2, cyano and carbonyl functionalities, respectively. In the 1H
NMR spectrum, aromatic signals were seen at d 6.91–8.15, a broad
singlet at d 7.60, 10.76 and 12.05 showed the presence of –NH2 and
–NH groups (D2O exchangeable). The carbonyl carbon resonated at
d 177.7 in the 13C NMR spectrum. Mass spectral analysis also sup-
ported the structural assignment (m/z 380.07 [M+H]+). Finally, the
structure of 4a was confirmed unambiguously by single crystal
X-ray analysis28 (Fig. 2).
Based on the above results, we extended our protocol to the
synthesis spiroxindole derivatives using various substituted isatin,
3-cyanoacetyl indole and cyanoethylacetate under optimized con-
ditions (Scheme 3). The reaction proceeded very smoothly and
gave high yield of the product in short reaction times without
the formation of any side products. The substrate scope of the reac-
tion under the optimized conditions was investigated, and the
reaction was found to be amenable to a variety of substituents
on isatin (Table 4).26
thenequinone, 3-cyanoacetyl indole and malononitrile or cyano-
ethyl acetate under optimized condition gave good yield of
spirooxindole derivatives (Scheme 4). The reaction proceeded
smoothly with a wide range of functionalized substituted 3-cyano-
acetyl indoles and malononitrile or cyanoethyl acetate (Table 5).27
The structure of compounds (10a–f) were established based on
detailed spectroscopic studies and elemental analysis as exempli-
fied for compound 10c as follows (Table 5, entry 3): in the IR spec-
trum of compound (10c) stretching frequencies at 3446, 3276 and
2364 cmꢀ1 confirm the presence –NH2, –NH and C„N functional
groups. The 1H NMR spectrum showed chemical shift of d: 12.04
(br s, D2O exchangeable) which corresponds to NH protons. The
aromatic protons resonated the region of d: 7.04–9.13. The sharp
singlet appeared in the region d: 15.5 correspond to CH3 carbon.
The aromatic carbons appeared in the region of d: 101.2–162.8.
The mass spectrum displayed the molecular ion [M+H]+ peak at
m/z 429.00.
All the synthesized compounds were screened for their in vitro
anti-microbial (antibacterial and antifungal) activities against
Staphylococcus epidermidis, Staphylococcus aureus, Bacillus subtilis
and Aspergillus niger by disc diffusion method (CUP Plate Method).
The preliminary studies were carried out for total aerobic
microbial count by using plate count method for four microorgan-
isms. The microorganism’s suspensions at concentration of
10ꢀ4 CFU/ml were incubated to the corresponding plates with
the aerobic microgram 500 counts. The plates were incubated at
36 °C for 24–48 h in the incubation chamber kept sufficiently hu-
mid. At the end of the incubation period the zone of inhibition
was tested. Out of 17 compounds, four compounds were taken
for reference for preliminary screening of microorganisms. The
four compounds namely 4a, 4b, 4d and 4e were screened with
12 microorganisms in various concentrations of the compounds
The structures of the compounds 6a–g were investigated with
spectral studies and elemental analysis as demonstrated for com-
pound 6b as follows (Table 4, entry 2): in the IR spectrum, the
C„N stretching frequency appeared at 2203 and 2369 cmꢀ1
,
respectively, and the stretching frequency at 3251 and 3370 corre-
spond to –NH and –NH2 functional groups, respectively. In the 1H
NMR spectrum of aromatic protons resonated in the range of d:
7.01–8.12. A broad singlet in the region d: 12.00 signal confirmed
the presence of –NH proton. A characteristic peak at d: 94.5 corre-
sponding to cyano group attached carbon in 13C NMR spectrum
and the aromatic carbons appeared in the region d: 114.1–161.1.
A methoxy carbon characteristic peak appeared at d: 54.8. A distin-
guishing peak was observed at m/z: 322.27 in the mass spectrum
for [M+H]+ion.
namely 25, 50, 75, 100 and 150
were prepared in DMSO solution at a concentration of 1000
From the stock solution, various concentration of test solutions
(25, 50, 75, 100 and 150 g/ml) were prepared by serial dilution. It
lg/ml, respectively. The samples
lg/ml.
To further explore the potential of this protocol for heterocyclic
synthesis, we investigated one-pot reactions involving acenap-
l
was found that the four compounds were effective against four
microorganisms namely S. epidermidis, S. aureus, B. subtilis and A.
niger in 100
Hence we screened anti-microbial activity of all 18 compounds
with concentration of 100 g/ml against the four microorganisms
lg/ml concentration.
Table 6
Anti-microbial activity of compounds 4a–10fa
l
S.
Product and
Zone of inhibition in diameter (mm)
and the results are summarized in Table 6. The diameter of zone
of inhibition was measured in millimetre. All the compounds
showed good (4a, 4b, 4c, 4e, 10a and 10b) and moderate inhibition
against S. epidermidis, S. aureus, B. subtilis and A. niger on compari-
son with standards.
In conclusion, we have developed a simple and efficient one-pot
synthesis for the formation of substituted spiroxindole derivatives.
A privileged medicinal scaffold synthesized through three-compo-
nent reactions of structurally diverse isatin with 3-cyanoacetyl in-
dole and malononitrile (or) cyanoethyl acetate. Spiroxindole
derivatives showed a good antifungal and antibacterial activity.
Further studies to delineate the scope and limitations of the pres-
ent methodology are underway.
No reference drug
Staphylococcus Staphylococcus Bacillus Aspergillus
aureus
epidermidis
subtilis niger
1.
2.
3.
4.
5.
6.
7.
8.
9.
4a
4b
4c
4d
4e
6a
6b
6c
6d
29
27
29
18
24
18
18
16
16
14
18
16
38
39
20
20
20
19
26
30
28
31
19
25
18
14
15
16
10
13
14
39
38
16
18
16
18
28
28
26
30
20
26
19
13
14
17
12
14
17
40
36
19
17
18
18
30
28
27
24
25
25
23
23
24
25
21
21
27
29
28
26
27
26
22
28
10. 6e
11. 6f
12. 6g
13. 10a
14. 10b
15. 10c
16. 10d
17. 10e
18. 10f
19. Gentamicin
sulphate
Acknowledgement
The authors, A. Nandakumar and P. Thirumurugan, thank the
Council of Scientific and Industrial Research, New Delhi, India, for
the research fellowship.
20. Chloramphenicol 29
21. Nysatin NA
31
NA
32
NA
25
28
Supplementary data
These bold font shows that these compounds are more active than the standard
drugs. NA, not applicable.
No zone of inhibition was obtained, when blank experiment was performed
with the same concentration of DMSO.
a
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2010.05.025.

4258
A. Nandakumar et al. / Bioorg. Med. Chem. Lett. 20 (2010) 4252–4258
ethanol and the appropriate yield of the product is 89%. 20-Amino-60-(1H-indol-
3-yl)-1-methyl-2-oxospiro[indoline-3,40-pyran]-30,50-dicarbonitrile
(Table 3,
References and notes
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(KBr): 1152, 1250, 1356, 1416, 1471, 1526, 1617, 1666, 2202, 2368, 2929,
3171, 3360 cmꢀ1 1H NMR (500 MHz, DMSO-d6): d 3.19 (s, 3H, N–CH3), 7.12–
;
7.18 (m, 3H, Ar-H), 7.23 (t, J = 6.85 Hz, 1H, Ar-H), 7.38–7.42 (m, 2H, Ar-H), 7.49
(d, J = 8.4 Hz, 1H, Ar-H), 7.65 (s, 2H, –NH2), 7.96 (d, J = 8.45 Hz, 1H, Ar-H), 8.15
(d, J = 3.05 Hz, 1H, Ar-H), 12.06 (br s, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 27.1, 50.1, 54.4, 81.4, 105.5, 109.7, 113.0, 117.5, 117.8, 121.8, 122.1, 123.4,
124.2, 124.9, 125.4, 130.6, 131.5, 136.5, 143.5, 158.5, 160.3, 176.0; MS (EI): m/z
394.00 [M++H+]; Anal. Calcd for C23H15N5O2: C, 70.22; H, 3.84; N, 17.90. Found:
C, 70.31; H, 3.85; N, 17.92.
26. Typical experimental procedure for 6b: A reaction mixture of 1-methyl isatin
(1 mmol), ethylcyano acetate (0.066 g, 1 mmol) and 3-cyanoacetyl indole
(0.184 g, 1 mmol) in methanol (10 ml), triethyl amine (20 mol%) was added
and stirred for 4.5 h. On completion, the reaction mixture was poured into
crushed ice and the precipitate formed was filtered, dried and purified by column
chromatography to afford the pure product. The isolated product was further
purified by recrystallisation in ethanol and the appropriate yield of the product is
79%. Ethyl 20-amino-50-cyano-60-(1H-indol-3-yl)-1-methyl-2-oxospiro[indoline-
3,40-pyran]-30-carboxylate (Table 4, entry 2) white solid; mp 232–235 °C; Rf
0.25 (40% AcOEt/petroleum ether); IR (KBr): 1020, 1153, 1297, 1352, 1439, 1509,
;
1623, 1693, 2203, 2369, 2929, 3251, 3370 cmꢀ1 1H NMR (500 MHz, DMSO-d6): d
0.66 (t, J = 6.9 Hz, 3H, –CH3), 3.14–3.17 (m, 3H, N–CH3), 3.65–3.69 (m, 2H, –CH2
–
), 7.01–7.03 (m, 2H, Ar-H), 7.16–7.31 (m, 4H, Ar-H), 7.49 (d, J = 8.4 Hz, 1H, Ar-H),
7.97–8.12 (m, 4H, –NH2, Ar-H), 12.00 (br s, 1H, –NH); 13C NMR (125 MHz, DMSO-
d6): d 14.0, 26.9, 51.3, 59.5, 73.1, 84.1, 105.5, 108.7, 112.9, 117.6, 121.6, 122.8,
123.3, 123.8, 124.0, 129.3, 130.1, 134.6, 134.9, 136.5, 144.0, 156.7, 160.0,
167.4,177.7; MS (EI): m/z 441.13 [M++H+]; Anal. Calcd for C25H20N4O4: C, 68.17;
H, 4.58; N, 12.72. Found: C, 68.23; H, 4.58; N, 12.74.
27. Typical experimental procedure for 10c:
A
reaction mixture of
acenapthenequinone (1 mmol), ethylcyano acetate (0.066 g, 1 mmol) and 2-
methyl 3-cyanoacetyl indole (0.184 g, 1 mmol) in methanol (10 ml), triethyl
amine (20 mol%) was added and stirred for 4.5 h. On completion, the reaction
mixture was poured into crushed ice and the precipitate formed was filtered,
dried and purified by column chromatography to afford the pure product. The
isolated product was further purified by recrystallisation in ethanol and the
appropriate yield of the product is 71%. 20-Amino-60-(2-methyl-1H-indol-3-yl)-
2-oxo-2H spiro[acenaphthylene-1,40-pyran]-30,50-dicarbonitrile (Table 5, entry 3)
blue solid; mp 165–168 °C; Rf 0.48 (40% AcOEt/petroleum ether); IR (KBr):
1229, 1302, 1457, 1540, 1578, 1621, 1708, 2199, 2364, 3011, 3276, 3446 cmꢀ1
;
19. Abdallah, T. A. J. Heterocycl. Chem. 2007, 44, 961.
20. Zaki, M. E. A.; Proenc, M. F. Tetrahedron 2007, 63, 3745.
1H NMR (500 MHz, DMSO-d6): d 2.64 (s, 3H, –CH3), 4.47 (br s, 2H, NH2), 7.04–
7.13 (m, 3H, Ar-H), 7.34 (s, 1H, Ar-H), 7.51 (s, 1H, Ar-H), 7.68 (s, 1H, Ar-H), 7.91
(s, 1H, Ar-H), 8.43 (s, 1H, Ar-H), 8.84 (s, 1H, Ar-H), 9.13 (s, 1H, Ar-H), 12.04 (br s,
1H, –NH); 13C NMR (125 MHz, DMSO-d6): d 15.5, 57.3, 77.7, 88.5, 101.2, 112.0,
114.6, 116.8, 117.6, 119.4, 120.9, 122.1, 122.4, 122.8, 126.2, 126.9, 128.9, 131.0,
131.8, 132.2, 134.0, 135.2, 146.4, 153.0, 162.8, 176.1, 183.4; MS (EI): m/z
429.00 [M++H+]; Anal. Calcd for C27H16N4O2: C, 75.69; H, 3.76; N 13.08. Found:
C, 75.73; H, 3.75; N, 13.09.
21. Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett. 2009, 50, 4145.
22. (a) Thirumurugan, P.; Muralidharan, D.; Perumal, P. T. Dyes Pigments 2009, 81,
245; (b) Thirumurugan, P.; Perumal, P. T. Tetrahedron 2009, 7620.
23. Damodiran, M.; Perumal, P. T. Bioorg. Med. Chem. Lett. 2009, 19, 3611.
24. Shanthi, G.; Subbulakshmi, G.; Perumal, P. T. Tetrahedron 2007, 63, 2057.
25. Typical experimental procedure for 4b: To a stirred solution of N-methyl isatin
(0.147 g, 1 mmol), malononitrile or ethylcyano acetate (0.066 g, 1 mmol) and
3-cyanoacetyl indole (0.184 g, 1 mmol) in methanol (10 ml), triethyl amine
(20 mol%) was added and stirring was continued for 30 min. On completion,
the reaction mixture was poured into crushed ice and the precipitate formed
was filtered, dried and purified by column chromatography to afford the pure
product. The isolated product was further purified by recrystallisation in
28. Crystallographic data of compound 4a in this paper have been deposited with
the Cambridge Crystallographic Data centre as supplemental Publication No.
CCDC-772945. 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).