InCl3 mediated one-pot synthesis of indol-3-yl pyridine and 2,2′-bipyridine derivatives through multi-component reaction

Article abstract of DOI:10.1016/j.tet.2009.06.097

A simple protocol for the efficient preparation of 2-(1H-Indol-3-yl)-6-methoxy-4-aryl pyridine-3,5-dicarbonitrile and 6-methoxy-4-aryl-2,2′-bipyridine-5-carbonitrile derivatives has been achieved through one-pot multi-component reaction under reflux condi

Full text of DOI:10.1016/j.tet.2009.06.097

Tetrahedron 65 (2009) 7620–7629
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
InCl3 mediated one-pot synthesis of indol-3-yl pyridine and 2,20-bipyridine
derivatives through multi-component reaction
*
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:
Received 4 May 2009
Received in revised form 24 June 2009
Accepted 25 June 2009
Available online 1 July 2009
A simple protocol for the efficient preparation of 2-(1H-Indol-3-yl)-6-methoxy-4-aryl pyridine-3,5-di-
carbonitrile and 6-methoxy-4-aryl-2,20-bipyridine-5-carbonitrile derivatives has been achieved through
one-pot multi-component reaction under reflux condition. Particularly valuable features of this method
include high yields of products in short reaction time and broad substrate scope. It is an efficient and
promising synthetic strategy to build indol-3-yl pyridine and 2,20-bipyridine skeletons.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
synthetic routes, longer reaction time, drastic reaction conditions,
as well as narrow application scope of substrates. In addition, to the
Multi-component reactions (MCRs) are powerful tools in modern
medicinal chemistry, enabling straightforward access to large
number of structurally related, drug-like compounds1–3 and thereby
facilitating lead generation of ‘privileged medicinal scaffolds.’4–6
Hence, combined with the use of combinatorial chemistry and high
throughput parallel synthesis, such reactions have constituted an
increasingly valuable approach to drug discovery efforts in recent
years.7
best of our knowledge, there have been very few reports about the
synthesis of indol-3-yl derivatives including pyridine moie-
ties.10,16,18–21 As part of our ongoing research on the development of
novel synthetic routes for biologically active heterocyclic com-
pounds and use of green chemistry techniques in organic synthe-
sis,22–25 herein, we report a simple, facile and one-pot procedure
for the synthesis of indol-3-yl pyridine derivatives.
The 3-substituted indole nucleus is prevalent in numerous nat-
ural products and is extremely important in medicinal chemistry.8,9
It scaffolds are found in a number of biologically active compounds
especially with anticancer, anti-tumour,10 anti-inflammatory, hy-
poglycemic, analgesic and anti-pyretic activities.11 Many indole al-
kaloids are recognized as one of the rapidly growing groups of
marine invertebrate metabolites for their broad spectrum of bi-
ological properties.12,13
The pyridine substructure is one of the most important hetero-
cycle found in natural products, pharmaceuticals, and functional
materials.14 Pyridine derivatives containing multi-functional groups
such as streptonigrin, streptonigrone and lavendamycin are repor-
ted as anticancer drugs, and cerivastatin is reported as the HMG-
CoA enzyme inhibitors.15 Moreover, substituted pyridines are
reported as leukotriene B-4 antagonists.16,17
2. Results and discussion
In an initial endeavor, we carried out the reaction of p-tol-
ualdehyde (1b), malononitrile (3) and 3-cyanoacetyl indole (2)26
with various types of Lewis acids and bases in methanol (Table 1).
Excellent results were obtained with InCl3 as the catalyst at reflux
temperature (65 ꢀC). Having established that InCl3 was catalyst of
choice, we investigated the efficacy of different solvents for the
synthesis of indol-3-yl pyridine derivatives (Table 2). After sys-
tematic screening we have found that InCl3/Methanol under reflux
to give good yield of the product in the shorter reaction time
(Scheme 1).
Table 1
Screening of various Lewis acids and bases in methanol
Due to the vast medicinal utility of pyridine and 3-substituted
indole derivatives various methods to prepare these compounds
have been reported. Literature review reveals that all published
approaches involve multi-step sequences, and their usefulness is
limited by the lack of generality. However, methods for the syn-
thesis of these important compounds often suffer from tedious
Entry
Base
Yield (%)a,b
1
2
3
4
5
6
AlCl3
NaOH
Piperidine
Triethylamine
KOH
0
79
0
0
70
88
InCl3
a
* Corresponding author. Tel.: þ91 44 24913289; fax: þ91 44 24911589.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Isolated yield.
All reactions carried out for 1.5 h at 65ꢀC
b
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.097

P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
7621
absorptions at 3313 and 2232 cmꢁ1 supported the presence of –NH
Table 2
and –C^N functional groups. The 1H NMR spectrum exhibited
Screening of various solvents on formation substituted pyridines using InCl3
Entry
Co-Solvent
Reflux temp
(ꢀC)a
Yield (%)b,c
a broad distinguishable singlet at
–NH protons and a sharp distinguishable singlet appeared at
for methoxy protons. Aromatic protons were seen in the range of
7.25–8.58. A distinctive peak at
55.9 in the 13C NMR spectrum
confirmed the presence of methoxy group. The two cyano group
attached carbon characteristic peaks were appeared at 91.8 and
d
12.22 (D2O exchangeable) for
d
4.25
1
2
3
4
5
6
DMF
153
83
82
100
79
65
64
48
71
74
78
88
Dichloroethane
Acetonitrile
Water
Ethanol
Methanol
d
d
d
96.7. The mass spectrum displayed the molecular ion [MþH]þ peak
at m/z 418.13. The structure of the compound 4g was further
established by single crystal X-ray diffraction analysis (Fig. 1).27
On the basis of the above results, we extended our protocol for
the synthesis of 2,20-bipyridine derivatives. Many bipyridine de-
rivatives are capable of forming multinuclear complexes. Fused
2,20-pyridines are useful substructures in the design of supramo-
lecular compounds. These are chelating ligands which show par-
ticularly high affinities for transition metal ions which frequently
a
Reflux tempature of the solvent.
Isolated yield.
All reactions carried out with 20 mol % InCl3 for 1.5 h in methanol and co-solvent
b
c
as 1:1 ratio.
CN
O
CHO
+
stabilize unusual low oxidation state species because of both d
p–
NC
CN
O
CN
CN
InCl3
pp
*
back-bonding by the cations and their capacity to form ligated
+
anion radicals.28 A mixture of 2-acetylpyridine (5) (1.0 mmol), al-
dehyde (1) (1.0 mmol) and indium(III)chloride (20 mol %) in 30 mL
methanol was refluxed. After 30–45 min (monitored by TLC)
malononitrile (3) (1.0 mmol) was added and the reflux was con-
tinued for 2–3 h which resulted in the formation of highly
substituted 2,20-bipyridine derivative (6). The substrate scope of
the reaction under the optimized conditions was investigated, and
the reaction was modifiable to a wide variety of substituted alde-
hydes (Scheme 4 and Table 4).
Methanol, Reflux.
N
H
N
N
3
1b
2
H
4b
Scheme 1.
A mixture of 3-cyanoacetyl indole (2) (1.0 mmol), aldehyde (1)
(1.0 mmol) and indium trichloride (20 mol %) in methanol (30 mL)
was refluxed. After complete disappearance of the both starting
materials (monitored by TLC) malononitrile (3) (1.0 mmol) was
added and the reflux was continued for 1–2 h which resulted in the
formation of highly substituted pyridine derivative (Scheme 2). The
feasibility of the reaction was further studied with various
substituted aldehydes. On sequential addition of the substrates
under optimized conditions, the reaction proceeded smoothly with
a wide range of functionalized aldehydes, including those con-
taining ether, nitro, halogens phenyl group and heterocyclic ring.
However the same reaction proceeded with aliphatic aldehydes
under optimized condition, we unable to get desired product and
the results are summarized (Table 3).
The structures of the compounds 6a–h were investigated with
spectral studies and elemental analysis as demonstrated for com-
pound 6d as follows: In the IR spectrum, the C^N stretching fre-
quency was appeared at 2215 cmꢁ1. In the 1H NMR spectrum of
aromatic protons were resonated in the range of
sharp singlet in the region : 4.19 signals confirmed the presence of
methoxy proton. A sharp peak at : 94.5 corresponding to cyano
group attached carbon in 13C NMR spectrum and the aromatic
carbons were appeared in the region : 114.1–161.1. And also
methoxy carbon characteristic peak was appeared at : 54.8. A
d: 7.35–8.67. A
d
d
d
d
distinguishing peak was observed at m/z: 322.27 in the mass
spectrum for [MþH]þion. Finally structure of compound 6d was
confirmed by single crystal X-ray diffraction analysis (Fig. 2).29
On the other hand, terephthaldialdehyde (7) (0.5 mmol), 3-
cyanoacetyl indole (2) (1 mmol) and malononitrile (3) (1.0 mmol)
in methanol under optimized condition gave 61% of product 8. The
reaction took longer time for complete formation of the product.
The crude product was precipitated in ice cold water and extracted
with ethyl acetate. The product was purified by column chromato-
graphy (Scheme 5).
R3
R2
CN
CHO
R1
CN
R1
R2
O
NC
CN
CN
InCl3
+
+
Methanol, Reflux.
N
H
N
O
R3
1a-k
N
3
2
H
4a-k
Scheme 2. Synthesis of indol-3-yl pyridine derivatives derivatives.
The structure of compound (8) was established on the basis of
elemental analysis and spectral data. In IR spectrum, stretching
frequencies at 2269 and 3298 cmꢁ1 confirmed the presence of C^N
and NH functional groups respectively. The 1H NMR spectrum
Based on the above results, a plausible mechanism is propo-
sed,7(Scheme 3) 3-cyanoacetyl indole 2 reacts with corresponding
showed a sharp singlet at
distinct singlet in the region of
(D2O exchangeable). The aromatic proton resonated in the region of
7.25–8.58. In 13C NMR spectrum, the apparent signal at
56.7
corresponds to methoxy carbon and cyano group attached carbons
appeared at 91.9 and 97.8 respectively. The aromatic carbons were
demonstrated in region of
d
4.24 for methoxy protons and broad
aldehyde 1 to give a
a,
b
unsaturated ketone 2a and it further reacts
d
12.17 corresponds to NH proton
with malononitrile 3 to yield 2b. Michael addition product 2b
combines with methanol and InCl3 to form a intermediate 2c and
its upon protonation to give on intermediate (2d & 2e). Protonation
of 2e affords to yield Hantzsch dihydropyridine derivative (2f) with
an elimination of water, finally deprotonation of 2f leads to for-
mation of highly substituted pyridine derivative (4). However in the
reverse reaction, malononitrile is first allowed to react with the
corresponding aldehyde followed by 3-cyanoacetyl indole attack do
not lead to the formation of corresponding pyridine derivatives.
The structures of the compounds 4a–k were confirmed through
spectral analysis and elemental analysis as exemplified for com-
pound 4g as follows: In the IR spectrum of compound 4g,
d
d
d
d
112.9–164.3. In mass spectrum shows,
a sharp distinguishable peak at m/z 625.40 corresponds to [MþH]þ
peak.
Due to the unique pharmacological properties of indeno pyri-
dines, our protocol was extended to the synthesis of indenopyr-
idine derivatives, Indenopyridines are attractive synthetic targets,
because they exhibit broad range of important biological proper-
ties, such as insecticidal, phosphodiesterase inhibiting, antifungal,

7622
P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
Table 3
Table 3 (continued)
Synthesis of indol-3-yl pyridine derivatives
Entry Aldehyde (1)
Product (4)a
Time (h) Yield (%)a,b
Entry Aldehyde (1)
Product (4)a
Time (h) Yield (%)a,b
NO2
CHO
CHO
NC
CN
O
11
3.5
3.0
3.5
70
61
72
NC
CN
O
1
2.0
85
N
NO2
1k
N
4k
4a
1a
N
H
N
H
S
CHO
NC
CN
O
12
13
S
CHO
NC
CN
2
1.5
2.0
88
84
N
1l
4l
1b
N
O
N
4b
H
N
H
O
CHO
NC
CN
O
NC
CN
O
O
CHO
3
N
N
1m
N
4c
4m
1c
N
N
H
H
OMe
CHO
N
NC
CN
O
NC
CN
O
4
1.5
90
14
3.5
63
CHO
1n
1d
N
N
4n
4d
OMe
N
H
N
H
Cl
NC
CHO
CN
Cl
N
5
3.0
2.5
74
79
NC
CN
O
N
O
4e
1e
15
4.5
69
N
N
CHO
1o
N
H
4o
N
H
Cl
CHO
NC
CN
O
6
H
1f
N
N
Cl
4f
CHO
N
H
CN
O
NC
16
4.5
69
Cl
N
H
1p
N
4p
CHO
N
H
Cl
Cl
CN
NC
7
3.0
76
a
All the products characterized by NMR, IR and mass spectroscopy.
Isolated yield.
1g
b
N
O
Cl
4g
N
H
Br
antispermatogenic, antifertility, antagonistic and antiarrhythmic
activities.30 A mixture of aldehyde (1.0 mmol), 3-cyanoacetyl indole
(1.0 mmol) and indium trichloride (20 mol %) in 30 mL methanol
was refluxed. After 30–45 min (monitored by TLC) 2-indanone
(1.0 mmol) and ammonium acetate in excess was added, finally
reflux was continued for 5–6 h. On sequential addition of the
substrates under optimized conditions, the reaction proceeds
smoothly to form of highly substituted indenopyridines (Scheme
6). The generality of the reaction was further extended to the
synthesis of various substituted indenopyridine derivatives under
optimized condition (Table 5).
CHO
NC
CN
O
8
2.5
3.0
77
74
1h
N
F
Br
4h
N
H
CHO
9
NC
CN
O
1i
N
4i
F
N
H
The structures of compounds 10a–f were identified by spectral
studies and elemental analysis. In the IR spectrum of 10g, absorp-
tion peaks at 3316 and 2229 cmꢁ1 showed the presence of –NH and
–C^N functional groups. The 1H NMR spectrum exhibited a broad
CHO
NC
CN
O
singlet at
distinct singlet showed at
protons were seen in the range
d
8.61 (D2O exchangeable) for –NH protons and a sharp
4.20 for methylene protons. Aromatic
6.78–8.54. A distinguishing peak
N
10
4j
1.5
89
N
H
d
1j
d

P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
7623
R3
R2
CN
CHO
R1
O
N
R1
R2
NC
O
InCl3
-H2O
CN
CN
+InCl3
-
+
+
CN
O
R3
R1
N
H
N
H
-
N
InCl3
CH3O
R3
InCl3H+
R2
N
H
2a
1
2
2b
R3
R3
R3
R3
R2
R2
R2
R1
R2
R1
R1
R1
N
N
N
H
N
NC
NC
H+
NC
H+
-InCl3
NC
-H2O
O
OMe
O
OMe
O
OMe
N
H
OMe
N
NH
NH
..
2
N
H
N
H
InCl3
N
H
N
H
2c
2d
2e
2f
R3
R3
R2
R2
R1
R1
H
N
N
NC
NC
-2H
N
H
N
OMe
OMe
N
H
N
H
2f
Scheme 3. Plausible mechanism for formation of indol-3-yl pyridine derivatives.
4
at
d
29.7 in the 13C NMR spectrum confirmed the presence of
R3
N
methylene carbon. The cyano group attached carbon showed
a distinguishing peak at
397.47 in the mass spectrum.
R2
d
104.5. The [MþH]þ peak appeared at m/z
CHO
R1
CN
R1
+
CN
CN
InCl3
Methanol, Reflux.
+
N
R2
O
O
R3
N
1a-h
6a-h
5
3
Scheme 4. Synthesis of 2,20-bipyridine derivatives.
3. Conclusions
We have developed simple one-pot synthesis for the formation
of substituted pyridines, a privileged medicinal scaffold through
three-component reactions of structurally diverse aldehydes with
3-cyanoacetyl indole and malononitrile. By incorporating two bi-
ologically potential moieties in a single molecule will enhance the
biological activity of these compounds. Further studies to delineate
the scope and limitations of the present methodology are
underway.
4. Experimental section
4.1. General
All the substituted aldehydes, malononitrile, 2-indanone, in-
dole, CDCl3 and DMSO-d6 were purchased from Aldrich Chem-
icals. Acetic anhydride and all other reagents were purchased
from S. D. Fine Chem. Limited and were used as received. Meth-
anol was distilled from Mg/I2 under nitrogen and stored over 3Å
Figure 1. Ortep diagram of compound 4g.

7624
P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
Table 4
and DMSO-d6 using TMS as internal standard with JEOL 500 MHz
Synthesis of 2,20-bipyridine derivatives
and Bruker 500 MHz high resolution NMR spectrometer. Multi-
plicities were abbreviated as follows: singlet (s), doublet (d),
triplet (t), multiplet (m), and broad (br). The mass spectra were
recorded using a Electrospray Ionisation Method with Thermo
Finnigan mass spectrometer. Melting points were determined in
capillary tubes and are uncorrected. Analytical TLC was performed
on pre-coated plastic sheets of silica gel G/UV-254 of 0.2 mm
thickness (Macherey-Nagel, Germany). Elemental analysis data
were recorded using Thermo Finnigan FLASH EA 1112 CHN
instrument.
Entry
Aldehyde (1)
Product (6)a
Time (h)
3.0
Yield (%)a,b
CHO
CN
1
78
1a
N
O
6a
N
CHO
4.2. General procedure for the synthesis of indol-3-yl
pyridine and 2,20-bipyridine derivatives (4a–k and 6a–h)
2
2.5
80
CN
O
1b
N
6b
6c
6d
N
A mixture of 3-cyanoacetyl indole (or) 2-acetylpyridine
(1.0 mmol), aldehyde (1.0 mmol) and indium trichloride (20 mol %)
in 30 mL of methanol was refluxed. After 15–30 min malononitrile
(1.0 mmol) was added and the reflux was continued for appro-
priate time mentioned in Tables 3 and 4. After the completion of
the reaction (as monitored by TLC), it was poured into water and
extracted with ethyl acetate. The organic layer was dried over
sodium sulfate and concentrated under vacuum. The crude prod-
uct was chromatographed in silica gel (90:10 petroleum ether/
ethyl acetate) and appropriate isolated yield is shown in Tables 3
and 4.
OMe
CHO
CN
O
3
3.0
81
N
OMe
1c
N
Cl
CHO
CN
O
4
2.5
74
4.2.1. 4a. 2-(1H-Indol-3-yl)-6-methoxy-4-phenylpyridine-3,5-
dicarbonitrile (Table 3, entry 1)
N
1d
Cl
Light yellow solid; mp 244–246 ꢀC; Rf 0.23 (20% EtOAc/Petro-
leum ether); IR (KBr): 1153,1229, 1427, 1516, 1629, 2230,
N
Cl
3287 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
; d 4.21 (s, 3H, –OCH3),
7.22–7.24 (m, 2H, –Ar–H), 7.52–7.60 (m, 6H, –Ar–H), 8.43–8.45 (m,
CHO
Cl
1H, –Ar–H), 8.57 (s, 1H, –Ar–H), 12.17 (br s, 1H, –NH); 13C NMR
Cl
CN
O
5
3.0
72
(125 MHz, DMSO-d6):
d 56.2, 91.7, 97.0, 112.7, 113.0, 114.6, 118.3,
122.2, 122.6, 123.5, 126.4, 128.8, 129.1, 129.2, 130.9, 132.1, 134.5,
137.2, 159.3, 161.0, 164.8; MS (ESI LCQ-MS): m/z 351.20 [MþH]þ.
Anal. Calcd for C22H14N4O: C, 75.42; H, 4.03; N, 15.99. Found: C,
75.31; H, 4.02; N, 16.04.
N
1e
Cl
CHO
Br
6e
N
Br
4.2.2. 4b. 2-(1H-Indol-3-yl)-6-methoxy-4-(4-tolyl phenyl)pyridine-
3,5-dicarbonitrile (Table 3, entry 2)
6
2.0
78
CN
O
Light yellow solid; mp 228–230 ꢀC; Rf 0.30 (20% EtOAc/Petro-
leum ether); IR (KBr): 1145, 1224, 1306, 1422, 1516, 1620, 2221,
1f
N
F
6f
N
3325 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d 2.41 (s, 3H, –Ar– CH3),
4.21 (s, 3H, –OCH3), 7.19–7.24 (m, 2H, –Ar–H), 7.36–7.52 (m, 5H,
–Ar–H), 8.42 (d, 1H, J¼8.4 Hz, –Ar–H), 8.55 (s, 1H, –Ar–H), 12.19 (br
s, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 21.0, 55.5, 91.3, 96.7,
CHO
F
112.2,112.3,114.0,117.7,121.6,122.0,122.9,125.9,128.2,128.5, 129.2,
131.0, 131.1, 136.4, 140.2, 159.0, 160.5, 164.3; MS (ESI LCQ-MS): m/z
365.20 [MþH]þ. Anal. Calcd for C23H16N4O: C, 75.81; H, 4.43; N,
15.38. Found: C, 75.90; H, 4.42; N, 15.33.
CN
O
7
2.5
77
N
1g
6g
N
4.2.3. 4c. 2-(1H-Indol-3-yl)-6-methoxy-4-(3-methylphenyl)
pyridine-3,5-dicarbonitrile (Table 3, entry 3)
NO2
CHO
Pale yellow solid; mp 286–288 ꢀC; Rf 0.23 (20% EtOAc/Petroleum
ether); IR (KBr): 1163, 1237, 1358, 1434, 1553, 1617, 2366,
CN
O
8
3.0
70
NO2
1h
3262 cmꢁ1; 1H NMR (500 MHz, DMSO-d6):
d 2.37 (s, 3H, –Ar–CH3),
N
N
4.18 (s, 3H, –OCH3), 7.20–7.26 (m, 2H, –Ar–H), 7.34–7.36 (m, 3H,
–Ar–H), 7.43 (t, 1H, J¼7.6 Hz, –Ar–H), 7.52 (d, 1H, J¼7.6 Hz, –Ar–H),
8.42 (d, 1H, J¼8.4 Hz, –Ar–H), 8.55 (s, 1H, –Ar–H), 12.14 (br s, 1H,
6h
All the products characterized by IR, 1H NMR, 13C NMR and mass spectroscopy.
Isolated yield.
a
b
–NH); 13C NMR (125 MHz, DMSO-d6):
d 20.9, 55.7, 91.3, 96.6, 112.2,
112.4, 114.1, 117.7, 121.7, 122.1, 123.0, 125.7, 125.8, 128.6, 128.9, 131.0,
131.3, 133.9, 136.5, 138.0, 158.9, 160.7, 164.3; MS (ESI LCQ-MS): m/z
365.20 [MþH]þ. Anal. Calcd for C23H16N4O: C, 75.81; H, 4.43; N,
15.38. Found: C, 75.72; H, 4.44; N, 15.43.
molecular sieves was purchased from Aldrich. IR measurements
were done as KBr pellets for solids using Perkin–Elmer Spectrum
RXI FT-IR. The 1H and 13C NMR spectra were recorded in CDCl3

P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
7625
Figure 2. Ortep diagram of compound 6d.
4.2.4. 4d. 2-(1H-Indol-3-yl)-6-methoxy-4(4methoxyphenyl)
pyridine-3,5-dicarbonitrile (Table 3, entry 4)
–Ar–H), 7.56 (d, 1H, J¼8.4 Hz, –Ar–H), 8.41–8.43 (m, 1H, –Ar–H),
8.58 (s, 1H, –Ar–H), 12.31 (br s, 1H, –NH); 13C NMR (125 MHz,
DMSO-d6): d 55.2, 55.7, 91.1, 96.4, 112.2, 112.7, 114.1, 117.7, 121.7,
122.0, 122.9, 126.0, 128.9, 130.7, 131.9, 132.8, 135.4, 137.0, 158.8,
159.4, 164.2; MS (ESI LCQ-MS): m/z 381.27 [MþH]þ. Anal. Calcd for
C23H16N4O2: C, 72.62; H, 4.24; N, 14.73. Found: C, 72.72; H, 4.22; N,
14.69.
Yellow solid; mp 268–270 ꢀC; Rf 0.23 (20% EtOAc/Petroleum
ether); IR (KBr): 1163, 1237, 1358, 1434, 1553, 1617, 2366,
3262 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
; d 3.80 (s, 3H, –OCH3),
4.20 (s, 3H, –OCH3), 7.06 (d, 2H, J¼8.4 Hz, –Ar–H), 7.12 (d, 1H,
J¼8.2 Hz, –Ar–H), 7.19–7.22 (m, 1H, –Ar–H), 7.43 (d, 2H, J¼8.4 Hz,
H
N
4.2.5. 4e. 4-(2-Chlorophenyl)-2-(1H-indol-3-yl)-6-methoxy
pyridine-3,5-dicarbonitrile (Table 3, entry 5)
O
N
Pale yellow solid; mp 214–216 ꢀC; Rf 0.31 (20% EtOAc/Petroleum
ether); IR (KBr): 1090, 1145, 1221, 1420, 1519, 2219, 3325 cmꢁ1 1H
;
CN
CN
CN
NC
CHO
CHO
NMR (500 MHz, DMSO-d6): d 4.25 (s, 3H, –OCH3), 7.23–7.26 (m, 2H,
CN
CN
1. InCl3
O
–Ar–H), 7.53–7.63 (m, 4H, –Ar–H), 7.71 (d, 1H, J¼8.4 Hz, –Ar–H),
+
+
8.47–8.49 (m, 1H, –Ar–H), 8.58 (s, 1H, –Ar–H), 12.41 (br s, 1H, –NH);
Methanol
reflux
N
H
13C NMR (125 MHz, DMSO-d6):
d 55.9, 91.9, 97.0, 112.1, 112.6, 113.4,
NC
O
116.8, 121.9, 122.1, 123.2, 125.7, 127.9, 129.9, 130.4, 131.0, 131.5, 132.1,
133.0, 136.6, 158.3, 158.8, 164.2; MS (ESI LCQ-MS): m/z 385.17
[MþH]þ. Anal. Calcd for C22H13ClN4O: C, 68.67; H, 3.41; N, 9.21.
Found: C, 68.75; H, 3.40; N, 9.17.
N
N
H
7
2
3
8
4.2.6. 4f. 4-(4-Chlorophenyl)-2-(1H-indol-3-yl)-6-methoxy
pyridine-3,5-dicarbonitrile (Table 3, entry 6)
Scheme 5. Synthesis of bis(indol-3-yl pyridine) derivatives.
Pale yellow solid; mp 260–262 ꢀC; Rf 0.31 (20% EtOAc/Petroleum
ether); IR (KBr): 1093, 1222, 1366, 1423, 1490, 1517, 1573, 2222,
R3
3329 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
; d 4.21 (s, 3H, –OCH3),
R2
CN
7.23–7.25 (m, 2H, –Ar–H), 7.53 (d, 1H, J¼8.4 Hz, –Ar–H), 7.62 (q, 4H,
CHO
R1
NC
J¼8.4 Hz, –Ar–H), 8.43 (d, 1H, J¼8.4 Hz, –Ar–H), 8.56 (s, 1H, –Ar–H),
O
R1
R2
1. InCl3
2. NH4OAc
Reflux
12.15 (br s, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 55.7, 91.3,
O
+
+
N
H
N
96.6, 112.1, 112.4, 114.0, 117.6, 121.8, 122.0, 123.0, 125.6, 128.8, 130.2,
130.6, 131.3, 132.7, 135.4, 136.5, 158.8, 159.3, 164.2; MS (ESI LCQ-
MS): m/z 385.20 [MþH]þ. Anal. Calcd for C22H13ClN4O: C, 68.67; H,
3.41; N, 9.21. Found: C, 68.59; H, 3.42; N, 9.25.
R3
N
H
1a-f
2
9
10a-f
Scheme 6. Synthesis of indenopyridine derivatives.

7626
P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
LCQ-MS): m/z 419.13 [MþH]þ. Anal. Calcd for C22H12Cl2N4O: C,
Table 5
Synthesis of indenopyridine derivatives
63.02; H, 2.88; N, 16.91. Found: C, 62.91; H, 2.88; N, 16.9.
Entry Aldehyde (1)
Product (10)a
Time (h) Yield (%)b
4.2.8. 4h. 4-Bromophenyl-2-(1H-indol-3-yl)-6-methoxypyridine-
3,5-dicarbonitrile (Table 3, entry 8)
Pale yellow solid; mp 238–240 ꢀC; Rf 0.31 (20% EtOAc/Petroleum
ether); IR (KBr): 1145, 1235, 1288, 1435, 1522, 1636, 2253,
CHO
NC
3222 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
; d 4.22 (s, 3H, –OCH3),
1
6.0
79
N
10a
7.22–7.27 (m, 2H, –Ar–H), 7.53–7.58 (m, 3H, –Ar–H), 7.80 (d, 2H,
J¼8.4 Hz, –Ar–H), 8.43 (d, 1H, J¼8.4 Hz, –Ar–H), 8.56 (s, 1H, –Ar–H),
1a
N
H
12.14 (brs, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 55.7, 91.3,
96.6, 112.2, 112.7, 114.2, 115.8, 117.8, 121.7, 122.0, 123.0, 126.0, 130.4,
131.3, 131.4, 132.0, 137.0, 158.8, 159.6, 162.2, 164.2, 164.3; MS (ESI
LCQ-MS): m/z 431.13 [MþH]þ. Anal. Calcd for C22H13BrN4O: C,
61.55; H, 3.05; N, 13.05. Found: C, 61.44; H, 3.06; N, 13.09.
CHO
NC
2
6.0
80
N
4.2.9. 4i. 4-(4-Fluorophenyl)-2-(1H-indol-3-yl)-6-methoxy
pyridine-3,5-dicarbonitrile (Table 3, entry 9)
10b
1b
N
H
Pale yellow solid; mp 256–258 ꢀC; Rf 0.30 (20% EtOAc/Petroleum
ether); IR (KBr): 1152, 1227, 1370, 1421, 1511, 1603, 2224, 3317 cmꢁ1
;
OMe
1H NMR (500 MHz, DMSO-d6):
d 4.21 (s, 3H, –OCH3), 7.21–7.26 (m,
2H, –Ar–H), 7.42 (t, 2H, J¼9.15 Hz, –Ar–H), 7.52 (d, 1H, J¼6.8 Hz,
–Ar–H), 7.67–7.69 (m, 2H, –Ar–H), 8.43 (d, 1H, J¼8.4 Hz, –Ar–H),
8.56 (s, 1H, –Ar–H), 12.08 (br s, 1H, –NH); 13C NMR (125 MHz,
CHO
NC
3
5.5
81
N
1c
10c
DMSO-d6):
d 55.7, 91.5, 96.8, 112.1, 114.1, 115.7, 116.0, 117.7, 121.8,
OMe
122.1, 123.1, 125.8, 130.3, 131.3, 131.4, 136.5, 158.8, 159.6, 161.6,
164.9; MS (ESI LCQ-MS): m/z 369.27 [MþH]þ. Anal. Calcd for
C22H13FN4O7: C, 71.73; H, 3.56; N, 15.21. Found: C, 71.62; H, 3.57; N,
15.26.
N
H
4.2.10. 4j. 2-(1H-Indol-3-yl)-6-methoxy-4-(1-naphthyl)pyridine-
3,5-dicarbonitrile (Table 3, entry 10)
CHO
NC
4
5
6
6.5
5.5
6.0
78
75
74
Yellow solid; mp 240.242 ꢀC; Rf 0.21 (20% EtOAc/Petroleum
N
10d
ether); IR (KBr): 1148, 1228, 1422, 1514, 1633, 2235, 3244 cmꢁ1; 1H
NMR (500 MHz, DMSO-d6): d 4.27 (s, 3H, –OCH3), 7.20–7.28 (m, 2H,
1d
N
H
–Ar–H), 7.47–7.70 (m, 6H, –Ar–H), 8.06–8.15 (m, 2H, –Ar–H), 8.53–
Cl
8.56 (m, 2H, –Ar–H), 12.15 (br s, 1H, –NH); 13C NMR (125 MHz,
DMSO-d6):
d 55.8, 92.9, 97.9, 112.2, 112.5, 117.4, 121.0, 121.85, 122.2,
CHO
123.2, 124.5, 125.4, 126.7, 127.0, 127.5, 128.6, 129.8, 130.4, 131.4,
131.7, 133.0, 136.6, 158.9, 159.9, 164.4; MS (ESI LCQ-MS): m/z 351.20
[MþH]þ. Anal. Calcd for C26H16N4O: C, 75.42; H, 4.03; N, 15.99.
Found: C, 75.31; H, 4.02; N, 16.04.
NC
N
1e
10e
Cl
N
H
4.2.11. 4k. 2-(1H-Indol-3-yl)-6-methoxy-4-(3-nitrophenyl)
pyridine-3,5-dicarbonitrile (Table 3, entry 11)
Cl
Yellow solid; mp 242–244 ꢀC; Rf 0.08 (20% EtOAc/Petroleum
ether); IR (KBr): 1098, 1236, 1349, 1433, 1531, 1620, 2216,
CHO
Cl
3386 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
; d 4.28 (s, 3H, –OCH3),
Cl
Cl
NC
7.28–7.31 (m, 2H, –Ar–H), 7.57–7.59 (m, 1H, –Ar–H), 7.94 (t, 1H,
J¼7.6 Hz, –Ar–H), 8.14 (d, 1H, J¼7.6 Hz, –Ar–H), 8.48–8.50 (m, 2H,
–Ar–H), 8.62 (s, 2H, –Ar–H), 12.21 (br s, 1H, –NH); 13C NMR
1f
N
10f
N
(125 MHz, DMSO-d6):
d 55.9, 91.5, 96.6, 112.1, 112.6, 114.0, 117.6,
H
121.9, 122.1, 123.2, 123.9, 125.3, 125.8, 130.7, 131.6, 135.4, 135.5,
136.6, 147.7, 158.1, 158.9, 164.2; MS (ESI LCQ-MS): m/z 395.13
[MþH]þ. Anal. Calcd for C22H13N5O3: C, 66.83; H, 3.31; N, 17.71.
Found: C, 66.74; H, 3.32; N, 17.75.
a
All the products characterized by IR, NMR and Mass spectroscopy.
Isolated yield.
b
4.2.7. 4g. 4-(2,4-Chlorophenyl)-2-(1H-indol-3-yl)-6-methoxy
pyridine-3,5-dicarbonitrile (Table 3, entry 7)
4.2.12. 4l. 2-(1H-indol-3-yl)-6-methoxy-4-(2-thienyl)pyridine-3,5-
dicarbonitrile (Table 3, entry 12)
Pale yellow solid; mp 272–274 ꢀC; Rf 0.31 (20% EtOAc/Petroleum
ether); IR (KBr): 1145, 1225, 1310, 1422, 1522, 2232, 3313 cmꢁ1; 1H
NMR (500 MHz, DMSO-d6): d 4.25 (s, 3H, –OCH3), 7.25–7.26 (m, 2H,
Yellow solid; mp 226–228 ꢀC; Rf 0.76 (40% AcOEt/Petroleum
ether); IR (KBr): 1134, 1226, 1475, 1514, 2222, 3268 cmꢁ1; 1H NMR
–Ar–H), 7.54–7.56 (m, 1H, –Ar–H), 7.66–7.71 (m, 2H, –Ar–H), 7.96 (d,
1H, J¼1.55 Hz, –Ar–H), 8.46–8.48 (m, 1H, –Ar–H), 8.58 (s, 1H, –Ar–
(500 MHz, DMSO-d6): d 4.17 (s, 3H, –OCH3), 7.19–7.24 (m, 1H, –Ar–
H), 7.28 (t, 1H, J¼4.6 Hz, –Ar–H), 7.50 (d, 1H, J¼7.6 Hz, –Ar–H), 7.58
(d, 1H, J¼3.1 Hz, –Ar–H), 7.95 (d, 1H, J¼4.6 Hz, –Ar–H), 8.38 (d, 1H,
J¼6.9 Hz, –Ar–H), 8.56 (s, 1H, –Ar–H), 11.67 (br s, 1H, –NH); 13C NMR
H),12.22 (br s,1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 55.9, 91.8,
96.7, 112.0, 112.5, 113.3, 116.8, 121.9, 122.1, 123.2, 125.7, 128.2, 129.5,
131.5, 131.8, 131.9, 132.3, 136.1, 136.5, 157.2, 158.8, 164.1; MS (ESI
(125 MHz, DMSO-d6):
d 56.3, 91.7, 97.1, 112.6, 113.2, 114.8, 118.5,

P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
7627
122.6, 123.6, 126.5, 128.5, 131.6, 132.2, 132.6, 133.2, 137.4, 153.6,
159.7, 165.1; MS (EI): m/z 357.20 [MþþHþ]. Anal. Calcd for
C20H12N4OS: C, 67.40; H, 3.39; N, 15.72. Found: C, 67.31; H, 3.38; N,
15.74.
(m, 1H, –Ar–H), 8.24 (s, 1H, –Ar–H), 8.45 (d, 1H, J¼7.6 Hz, Ar–H),
8.68 (d, 1H, J¼3.8 Hz, Ar–H); 13C NMR (125 MHz, CDCl3):
d 54.7,
94.7, 114.5, 115.7, 122.1, 124.9, 128.6, 129.0, 130.1, 136.2, 137.2, 149.5,
154.3, 156.5, 157.1, 165.1; MS (ESI LCQ-MS): m/z 288.20 [MþH]þ.
Anal. Calcd for C18H13N3O: C, 75.25; H, 4.56; N, 14.63. Found: C,
75.08; H, 4.57; N, 14.59.
4.2.13. 4m. 4-(2-Furyl)-2-(1H-indol-3-yl)-6-methoxypyridine-3,5-
dicarbonitrile (Table 3, entry 13)
Yellow solid; mp 234–236 ꢀC; Rf 0.72 (40% AcOEt/Petroleum
4.2.18. 6b. 6-Methoxy-4-(4-methylphenyl)-2,20-bipyridine-5-
carbonitrile (Table 4, entry 2)
ether); IR (KBr): 1150, 1229, 1424, 2221, 3301 cmꢁ1 1H NMR
;
(500 MHz, DMSO-d6):
d
4.15 (s, 3H, –OCH3), 6.84–6.86 (m, 1H, –Ar–
White solid; mp 174–176 ꢀC; Rf 0.82 (40% AcOEt/Petroleum
H), 7.17–7.22 (m, 2H, –Ar–H), 7.42 (d, 1H, J¼3.1 Hz, –Ar–H), 7.49 (d,
1H, J¼7.6 Hz, –Ar–H), 8.11 (s, 1H, –Ar–H), 8.11 (d, 1H, J¼7.6 Hz, –Ar–
H), 8.55 (s, 1H, –Ar–H), 12.39 (br s, 1H, –NH); 13C NMR (125 MHz,
ether); IR (KBr): 1141, 1265, 1359, 1441, 1548, 2219, 2945 cmꢁ1 1H
;
NMR (500 MHz, CDCl3):
d 2.41 (s, 3H, –Ar–CH3), 4.18 (s, 3H, Ar–
OCH3), 7.30 (d, 2H, J¼8.4 Hz, –Ar–H), 7.33–7.36 (m, 1H, –Ar–H), 7.60
(d, 2H, J¼7.6 Hz, –Ar–H), 7.82–7.85 (m, 1H, –Ar–H), 8.21 (s, 1H, –Ar–
H), 8.43 (d, 1H, J¼8.4 Hz, Ar–H), 8.67 (d, 1H, J¼3.8 Hz, Ar–H); 13C
DMSO-d6):
d 56.3, 87.8, 93.4, 112.6, 113.1, 113.4, 115.0, 117.4, 118.9,
122.2, 122.6, 123.5, 126.5, 132.7, 137.3, 145.6, 146.7, 160.3, 162.8,
165.6; MS (EI): m/z 341.33 [MþþHþ]. Anal. Calcd for C20H12N4O2: C,
67.40; H, 3.39; N, 15.72. Found: C, 67.31; H, 3.38; N, 15.74.
NMR (125 MHz, CDCl3):
d 21.6, 54.7, 94.5, 114.3, 115.9, 122.1, 124.9,
128.5, 129.7, 133.4, 137.1, 140.4, 149.5, 154.4, 156.4, 157.0, 165.1; MS
(ESI LCQ-MS): m/z 302.20 [MþH]þ. Anal. Calcd for C19H15N3O: C,
75.73; H, 5.02; N, 13.94. Found: C, 75.90; H, 5.00; N, 13.89.
4.2.14. 4n. 2-(1H-indol-3-yl)-6-methoxy-4,40-bipyridine-3,5-
dicarbonitrile (Table 3, entry 14)
Yellow solid; mp 172–175 ꢀC; Rf 0.62 (40% AcOEt/Petroleum
4.2.19. 6c. 6-Methoxy-4-(4-methoxyphenyl)-2,20-bipyridine-5-
carbonitrile (Table 4, entry 3)
ether); IR (KBr): 1233, 1461, 1552, 1617, 2198, 3132 cmꢁ1 1H NMR
;
(500 MHz, DMSO-d6):
d
4.23 (s, 3H, –OCH3), 7.24–7.26 (m, 2H, –Ar–
White solid; mp 210–212 ꢀC; Rf 0.75 (40% AcOEt/Petroleum
H), 7.53–7.55 (m, 1H, –Ar–H), 7.63–7.64 (m, 2H, –Ar–H), 8.44–8.46
(m, 1H, –Ar–H), 8.57 (s, 1H, –Ar–H), 8.81–8.83 (m, 2H, –Ar–H), 12.18
ether); IR (KBr): 1138, 1266, 1445, 1583, 2216, 2945 cmꢁ1; 1H NMR
(500 MHz, CDCl3):
d 3.87 (s, 3H, –Ar–OCH3), 4.19 (s, 3H, Ar–OCH3),
(br s, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d
56.4, 91.5, 96.5,
7.02 (d, 2H, J¼9.1 Hz, –Ar–H), 7.34–7.37 (m, 1H, –Ar–H), 7.68–7.70
(m, 2H, –Ar–H), 7.83–7.86 (m, 1H, –Ar–H), 8.21 (s, 1H, –Ar–H), 8.44
(d, 1H, J¼7.6 Hz, Ar–H), 8.68 (d, 1H, J¼4.6 Hz, Ar–H); 13C NMR
112.6, 113.1, 114.3, 117.9, 122.5, 122.6, 123.8, 123.7, 126.3, 132.2, 137.1,
142.3, 150.7, 158.7, 159.5, 164.7; MS (EI): m/z 352.20 [MþþHþ]. Anal.
Calcd for C21H13N5O: C, 71.79; H, 3.73; N, 19.93. Found: C, 71.70; H,
3.74; N, 19.96.
(125 MHz, CDCl3):
d 54.7, 55.5, 94.2, 114.1, 114.4, 116.0, 122.1, 124.8,
128.5, 130.2, 137.1, 149.5, 154.5, 156.3, 156.6, 161.2, 165.2; MS (ESI
LCQ-MS): m/z 318.27 [MþH]þ. Anal. Calcd for C19H15N3O2: C, 71.91;
H, 4.76; N, 13.24. Found: C, 71.75; H, 4.77; N, 13.28.
4.2.15. 4o. 2-(1H-indol-3-yl)-6-methoxy-4-(1-methyl-1H-indol-2-
yl)pyridine-3,5-dicarbonitrile (Table 3, entry 15)
Yellow solid; mp 242–245 ꢀC; Rf 0.75 (40% AcOEt/Petroleum
ether); IR (KBr): 1155, 1227, 1373, 1437, 1523, 1566, 2227,
4.2.20. 6d. 4-(4-Chlorophenyl)-6-methoxy-2,20-bipyridine-5-
carbonitrile (Table 4, entry 4)
3285 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6):
d
3.74 (s, 3H, –NCH3),
White solid; mp 216–218 ꢀC; Rf 0.81 (40% AcOEt/Petroleum
4.25 (s, 3H, –OCH3), 6.77 (s, 1H, –Ar–H), 6.91 (s, 1H, –Ar–H), 7.11–
7.15 (m, 2H, –Ar–H), 7.26–7.28 (m, 2H, –Ar–H), 7.53–7.57 (m, 2H,
–Ar–H), 8.48–8.49 (m, 1H, –Ar–H), 8.63 (s, 1H, –Ar–H), 12.20 (br s,
ether); IR (KBr): 1141, 1195, 1267, 1361, 1573, 2215, 2939 cmꢁ1 1H
;
NMR (500 MHz, CDCl3):
d 4.19 (s, 3H, Ar–OCH3), 7.35–7.37 (m, 1H,
–Ar–H), 7.47 (d, 2H, J¼8.4 Hz, –Ar–H), 7.62 (d, 2H, J¼8.4 Hz, –Ar–H),
7.83–7.87 (m, 1H, –Ar–H), 8.19 (s, 1H, –Ar–H), 8.43 (d, 1H, J¼7.6 Hz,
Ar–H), 8.67 (d, 1H, J¼3.9 Hz, Ar–H); 13C NMR (125 MHz, CDCl3):
1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 31.6, 56.4, 93.2, 98.2,
111.1, 111.2, 113.1, 114.6, 118.1, 120.8, 121.6, 122.4, 123.6, 123.7, 127.3,
132.3, 132.7, 137.1, 138.7, 152.0, 161.6, 164.9, 166.2; MS (EI): m/z
404.33 [MþþHþ]. Anal. Calcd for C25H17N5O: C, 74.43; H, 4.25; N,
17.36. Found: C, 74.34; H, 4.26; N, 17.39.
d
54.8, 94.5, 114.1, 115.5, 122.2, 125.1, 129.3, 130.0, 134.6, 136.4, 137.2,
149.6, 154.1, 155.6, 156.8, 161.1; MS (ESI LCQ-MS): m/z 322.20
[MþH]þ. Anal. Calcd for C18H12ClN3O: C, 67.19; H, 3.76; N, 13.06.
Found: C, 67.32; H, 3.77; N, 13.11.
4.2.16. 4p. 2,4-di-1H-indol-3-yl-6-methoxypyridine-3,5-
dicarbonitrile (Table 3, entry 16)
4.2.21. 6e. 4-(2,4-Dichlorophenyl)-6-methoxy-2,20-bipyridine-5-
carbonitrile (Table 4, entry 5)
Yellow solid; mp 230–233 ꢀC; Rf 0.41 (40% AcOEt/Petroleum
ether); IR (KBr): 1147, 1227, 1304, 1519, 1555, 1611, 2222, 3263,
White solid; mp 164–166 ꢀC; Rf 0.85 (40% AcOEt/Petroleum
3364 cmꢁ1 1H NMR (500 MHz, DMSO-d6):
; d 4.22 (s, 3H, –OCH3),
ether); IR (KBr): 1142, 1264, 1362, 1559, 2225, 2952 cmꢁ1; 1H NMR
7.13 (t, 1H, J¼6.9 Hz, –Ar–H), 7.21–7.24 (m, 3H, –Ar–H), 7.52–7.54
(m, 2H, –Ar–H), 7.57 (d, 1H, J¼7.6 Hz, –Ar–H), 7.96 (s, 1H, –Ar–H),
8.44–8.46 (m, 1H, –Ar–H), 8.59 (s, 1H, –Ar–H), 10.89 (br s, 1H, –NH),
(500 MHz, CDCl3):
d
4.21 (s, 3H, Ar–OCH3), 7.31 (d, 1H, J¼8.4 Hz,
–Ar–H), 7.36–7.38 (m, 2H, –Ar–H), 7.54 (d, 1H, J¼2.3 Hz, –Ar–H),
7.84–7.87 (m, 1H, –Ar–H), 8.13 (s, 1H, –Ar–H), 8.45 (d, 1H, J¼7.6 Hz,
Ar–H), 8.66 (d, 1H, J¼3.8 Hz, Ar–H); 13C NMR (125 MHz, CDCl3):
11.87 (br s, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 56.1, 91.7,
97.7, 109.0, 112.8, 112.9, 113.0, 115.6, 119.2, 120.5, 120.7, 122.1, 122.6,
122.8, 123.4, 125.3, 126.6, 129.0, 132.0, 136.7, 137.1, 155.3, 159.8,
162.6, 165.5; MS (EI): m/z 390.20 [MþþHþ]. Anal. Calcd for
C24H15N5O: C, 74.02; H, 3.88; N, 17.98. Found: C, 74.11; H, 3.87; N,
17.95.
d 54.8, 96.7, 115.2, 122.2, 125.1, 127.6, 130.2, 131.3, 133.3, 136.4, 137.2,
149.6, 153.9, 154.0, 156.8, 164.4; MS (ESI LCQ-MS): m/z 356.27
[MþH]þ. Anal. Calcd for C18H11Cl2N3O: C, 60.69; H, 3.11; N, 11.80.
Found: C, 60.82; H, 3.10; N, 11.75.
4.2.22. 6f. 4-(4-Bromophenyl)-6-methoxy-2,20-bipyridine-5-
carbonitrile (Table 4, entry 6)
4.2.17. 6a. 6-Methoxy-4-phenyl-2,20-bipyridine-5-carbonitrile
(Table 4, entry 1)
White solid; mp 204–206 ꢀC; Rf 0.83 (20% AcOEt/Petroleum
White solid; mp 168–170 ꢀC; Rf 0.8 (40% AcOEt/Petroleum
ether); IR (KBr): 1245, 1363, 1448, 1546, 2220, 2924 cmꢁ1; 1H NMR
ether); IR (KBr): 1197, 1266, 1463, 1547, 1580, 2221 cmꢁ1
;
1H NMR
(500 MHz, CDCl3): d 4.21 (s, 3H, Ar–OCH3), 7.36–7.39 (m, 1H, –Ar–
(500 MHz, CDCl3):
H), 7.50–7.52 (m, 3H, –Ar–H), 7.69–7.71 (m, 2H, –Ar–H), 7.83–7.85
d
4.20 (s, 3H, Ar–OCH3), 7.35–7.37 (m, 1H, –Ar–
H), 7.56–7.58 (m, 2H, –Ar–H), 7.64–7.66 (m, 2H, –Ar–H), 7.85–7.88
(m, 1H, –Ar–H), 8.21 (s, 1H, –Ar–H), 8.45 (d, 1H, J¼8.4 Hz, Ar–H),

7628
P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
8.68 (d, 1H, J¼4.6 Hz, Ar–H); 13C NMR (125 MHz, CDCl3):
d
54.8,
appropriate time mentioned as in Table 5. After the completion of
the reaction (as monitored by TLC), it was poured into water and
extracted with ethyl acetate. The organic layer was dried over so-
dium sulfate and concentrated under vacuum. The crude product
was chromatographed (90:10, petroleum ether/ethyl acetate) and
appropriate isolated yield was shown in Table 5.
94.5, 114.1, 115.4, 122.2, 124.8, 125.0, 130.2, 132.3, 135.1, 137.2, 149.6,
154.2, 155.7, 156.8, 162.8, 165.1; MS (ESI LCQ-MS): m/z 366.27
[MþH]þ. Anal. Calcd for C18H12 BrN3O: C, 59.03; H, 3.30; N, 11.43.
Found: C, 59.21; H, 3.29; N, 11.43.
4.2.23. 6g. 4-(4-Fluorophenyl)-6-methoxy-2,20-bipyridine-5-
carbonitrile (Table 4, entry 7)
4.4.1. 10a. 2-(1H-Indol-3-yl)-4-phenyl-9H-indeno[2,1-b]pyridine-
3-carbonitrile (Table 4, entry 1)
White solid; mp 198–200 ꢀC; Rf 0.81 (40% AcOEt/Petroleum
ether); IR (KBr): 1146, 1224, 1364, 1437, 15,554, 2218 cmꢁ1; 1H NMR
Light brown solid; mp 298–300 ꢀC; Rf 0.31 (20% EtOAc/Petro-
leum ether); IR (KBr): 1102, 1377, 1467, 1598, 2180, 3344,
(500 MHz, CDCl3): d 4.19 (s, 3H, Ar–OCH3), 7.18–7.21 (m, 2H, –Ar–H),
7.35–7.38 (m, 1H, –Ar–H), 7.67–7.70 (m, 2H, –Ar–H), 7.83–7.87 (m,
1H, –Ar–H), 8.19 (s, 1H, –Ar–H), 8.44 (d, 1H, J¼7.6 Hz, Ar–H), 8.67 (d,
1H, J¼3.8 Hz, Ar–H); 13C NMR (125 MHz, CDCl3): 54.8, 94.5, 114.3,
115.6,116.1, 116.2,122.2, 125.0, 130.6, 130.7,137.2, 149.5,154.2, 155.9,
156.6, 162.9, 164.9, 165.1; MS (ESI LCQ-MS): m/z 306.20 [MþH]þ.
Anal. Calcd for C18H12 FN3O: C, 70.81; H, 3.96; N, 13.76. Found: C,
70.99; H, 3.95; N, 13.71.
3394 cmꢁ1; 1H NMR (500 MHz, CDCl3):
d 4.21 (s, 2H, –Ar–CH2), 6.74
(d, 1H, J¼7.6 Hz, –Ar–H), 7.15 (t, 1H, J¼7.6 Hz, –Ar–H), 7.25 (s, 1H,
–Ar–H), 7.30–7.34 (m, 3H, –Ar–H), 7.45 (d, 3H, J¼7.6 Hz, –Ar–H),
7.58 (t, 3H, J¼7.6 Hz, –Ar–H), 8.29 (d, 1H, J¼3.0 Hz, –Ar–H), 8.52–
8.56 (m, 1H, –Ar–H), 8.61 (br s, 1H, –NH); 13C NMR (125 MHz,
CDCl3):
d 29.7, 104.0, 111.4, 114.3, 118.4, 121.6, 122.3, 123.0, 123.3,
125.2, 126.4, 127.2, 127.3, 128.1, 129.3, 129.7, 130.3, 133.9, 135.8,
136.3, 137.9, 141.4, 147.0, 155.4, 168.4; MS (ESI LCQ-MS): m/z 384.47
[MþH]þ. Anal. Calcd for C27H17N3: C, 84.57; H, 4.47; N,10.96. Found:
C, 87.50; H, 4.48; N, 11.01.
4.2.24. 6h. 6-Methoxy-4-(3-nitrophenyl)-2,20-bipyridine-5-
carbonitrile (Table 4, entry 8)
White solid; mp 226–227 ꢀC; Rf 0.67 (40% AcOEt/Petroleum
ether); IR (KBr): 1014, 1278, 1356, 1552, 2219 cmꢁ1
;
1H NMR
4.4.2. 10b. 2-(1H-Indol-3-yl)-4-(4-methylphenyl)-9H-indeno[2,1-
b]pyridine-3-carbonitrile (Table 4, entry 2)
(500 MHz, CDCl3):
d 4.24 (s, 3H, Ar–OCH3), 7.39–7.41 (m, 1H, –Ar–
H), 7.72 (t, 1H, J¼7.2 Hz, Ar–H), 7.87 (t, 1H, J¼7.2 Hz, Ar–H), 8.04 (d,
1H, J¼7.6 Hz, Ar–H), 8.28 (s, 1H, –Ar–H), 8.37 (d, 1H, J¼8.4 Hz, Ar–
H), 8.47 (d, 1H, J¼7.6 Hz, Ar–H), 8.54 (s, 1H, –Ar–H), 8.71 (d, 1H,
Light brown solid; mp 201–203 ꢀC; Rf 0.4 (20% EtOAc/Petroleum
ether); IR (KBr): 1234, 1433, 1532, 2229, 3052, 3316 cmꢁ1; 1H NMR
(500 MHz, CDCl3):
d 2.51 (s, 3H, –Ar–CH3), 4.20 (s, 2H, –Ar–CH2),
J¼2.3 Hz, Ar–H); 13C NMR (125 MHz, CDCl3):
d
55.0, 96.1, 114.2,
6.78 (d, 1H, J¼8.5 Hz), 7.10 (t, 1H, J¼7.6 Hz, –Ar–H), 7.29–7.32 (m,
3H, –Ar–H), 7.38–7.43 (m, 5H, –Ar–H), 7.57 (d, 1H, J¼7.6 Hz), 8.28 (d,
1H, J¼3.0 Hz), 8.52–8.54 (m, 1H, –Ar–H), 8.61 (br s, 1H, –NH); 13C
115.0, 122.3, 123.7, 124.8, 125.3, 130.2, 134.5, 137.3, 137.9, 149.6,
153.8, 154.3, 157.4, 165.1; MS (ESI LCQ-MS): m/z 333.27 [MþH]þ.
Anal. Calcd for C18H12 N4O: C, 65.61; H, 3.64; N, 16.86. Found: C,
65.22; H, 3.63; N, 16.81.
NMR (125 MHz, CDCl3):
d 21.6, 29.7, 104.5, 111.3, 114.4, 118.7, 121.5,
122.3, 123.1,123.2, 125.1,126.5,127.0,127.1,127.8, 128.2, 129.5, 130.0,
132.5, 136.3, 138.3, 139.5, 141.4, 148.7, 155.3, 168.1; MS (ESI LCQ-
MS): m/z 397.47 [MþH]þ. Anal. Calcd for C28H19N3: C, 84.71; H,
4.82; N, 10.57. Found: C, 84.68; H, 4.81; N, 10.52.
4.3. Procedure for synthesis of bis(indol-3-yl pyridine)
derivatives
A
mixture of 3-cyanoacetyl indole (1 mmol), dialdehyde
4.4.3. 10c. 2-(1H-Indol-3-yl)-4-(4-methoxyphenyl)-9H-indeno[2,1-
b]pyridine-3-carbonitrile (Table 4, entry 3)
(0.5 mmol) and indium trichloride (20 mol %) in 30 mL of methanol
was refluxed. After 15 min malononitrile (1 mmol) was added and
the reflux was continued for 5 h. After the completion of the re-
action (as monitored by TLC), it was poured into water and
extracted with ethyl acetate. The organic layer was dried over so-
dium sulfate and concentrated under vacuum. The crude product
was chromatographed (60:40 petroleum ether/ethyl acetate) and
isolated yield was 68%.
Yellow solid; mp 228–230 ꢀC; Rf 0.2 (20% EtOAc/Petroleum
ether); IR (KBr): 1304, 1490, 1600, 1657, 2373, 3362 cmꢁ1; 1H NMR
(500 MHz, DMSO-d6):
d 3.81 (s, 3H, –Ar–OCH3), 4.18 (s, 2H, –Ar–
CH2), 6.62 (d, 1H, J¼7.6 Hz, –Ar–H), 7.10–7.20 (m, 5H, –Ar–H), 7.27–
7.31 (m, 1H, –Ar–H), 7.44–7.49 (m, 3H, –Ar–H), 7.59 (d, 1H, J¼6.9 Hz,
–Ar–H), 8.25 (d, 1H, J¼3.1 Hz, –Ar–H), 8.37 (d, 1H, J¼3.1 Hz, –Ar–H),
11.76 (br s, 1H, –NH); 13C NMR (125 MHz, DMSO-d6):
d 36.0, 55.4,
114.1,114.3,122.5,123.0,123.2,124.8,125.0,125.4,126.8,127.1,127.2,
127.3, 128.9, 130.2, 130.3, 130.4, 133.2, 134.0, 139.6, 139.8, 142.1,
142.6, 145.4, 152.3, 159.6, 161.7; MS (ESI LCQ-MS): m/z 413. 46
[MþH]þ. Anal. Calcd for C28H19N3O: C, 81.34; H, 4.63; N, 10.16.
Found: C, 81.23; H, 4.64; N, 10.20.
4.3.1. Phenyl 1,4-bis(2-(1H-indol-3-yl)-6-methoxypyridine-3,5-
dicarbonitrile)
Yellow solid; mp<350 ꢀC; Rf .38 (60% EtOAc/Petroleum ether);
IR (KBr): 1371, 1465, 1565, 2370, 3234, 3347 cmꢁ1
;
1H NMR
(500 MHz, DMSO-d6):
d 4.24 (s, 6H, Ar–OCH3), 7.25–7.27 (m, 4H,
–Ar–H), 7.53–7.56 (m, 2H, –Ar–H), 7.68 (s, 2H, –Ar–H), 7.74 (d, 2H,
J¼8.4 Hz), 7.82 (d, 2H, J¼8.4 Hz), 8.45 (d, 2H, J¼8.4 Hz, –Ar–H), 8.58
(s, 2H, –Ar–H), 12.17 (br s, 2H, –NH); 13C NMR (125 MHz, DMSO-d6):
4.4.4. 10d. 2-(1H-Indol-3-yl)-4-(1-napthyl)-9H-indeno[2,1-b]
pyridine-3-carbonitrile (Table 4, entry 4)
Yellow solid; mp 208–211; Rf 0.22 (20% EtOAc/Petroleum ether);
d
56.7, 91.9, 97.8, 112.9, 113.8, 118.9, 122.8, 123.9, 126.5, 128.8, 130.9,
IR (KBr): 1122, 1234, 1420, 1532, 2220, 3387 cmꢁ1 1H NMR
;
133.6, 137.4, 157.8, 159.8, 161.8, 164.3; MS (ESI LCQ-MS): m/z 625.40
[MþH]þ. Anal. Calcd for C38H24N8O2: C, 73.07; H, 3.87; N, 17.94.
Found: C, 73.19; H, 3.88; N, 17.89.
(500 MHz, CDCl3):
d
4.27 (ABq, 2H, J¼8.9 Hz, –Ar–CH2), 6.86 (t, 1H,
J¼7.6 Hz, –Ar–H), 7.20 (t, 1H, J¼6.9 Hz, –Ar–H), 7.32–7.39 (m, 4H,
–Ar–H), 7.44–7.47 (m, 2H, –Ar–H), 7.54–7.58 (m, 3H, –Ar–H), 7.68 (t,
1H, J¼8.4 Hz, –Ar–H), 8.00 (d, 1H, J¼8.4 Hz, –Ar–H), 8.09 (d, 1H,
J¼8.4 Hz, –Ar–H), 8.31 (d, 1H, J¼2.9 Hz, –Ar–H), 8.60 (br s, 1H, –NH),
4.4. General procedure for the synthesis of indenopyridine
derivatives
8.62–8.65 (m, 1H, –Ar–H); 13C NMR (125 MHz, CDCl3):
d 29.6, 104.6,
111.7, 113.8, 118.4, 121.2, 122.2, 122.8, 122.9, 124.7, 124.9, 125.7, 126.4,
126.5, 126.6, 127.0, 127.1, 127.6, 127.9, 128.8, 129.8, 130.1, 130.6, 133.1,
133.6, 136.6, 137.9, 141.2, 146.7, 155.8, 168.0; MS (ESI LCQ-MS): m/z
434.40 [MþH]þ. Anal. Calcd for C31H19N3: C, 85.89; H, 4.42; N, 9.69.
Found: C, 85.83; H, 4.43; N, 9.64.
A mixture of 3-cyanoacetyl indole (1 mmol), aldehyde (1 mmol)
and indium trichloride (20 mol %) in 30 mL of methanol was
refluxed. After 15–30 min 2-indanone (1 mmol) and ammonium
acetate in excess was added and then reflux was continued for

P. Thirumurugan, P.T. Perumal / Tetrahedron 65 (2009) 7620–7629
7629
4.4.5. 10e. 2-(1H-Indol-3-yl)-4-(4-chlorophenyl)-9H-indeno[2,1-
References and notes
b]pyridine-3-carbonitrile (Table 4, entry 5)
1. (a) Ramon, D. J.; Miguel, Y. Angew. Chem., Int. Ed. 2005, 44, 1602; (b) Li, G.; Wei,
H.-X.; Kim, S.-H.; Carducci, M. D. Angew. Chem., Int. Ed. 2001, 40, 4277; (c) Tu,
S.; Jiang, B.; Zhang, Y.; Jia, R.; Zhang, J.; Yao, C.; Feng Shi. Org. Biomol. Chem.
2007, 5, 355.
2. Patchett, A. A.; Nargund, R. P. Annu. Rep. Med. Chem. 2000, 35, 289.
3. Do¨mling, A. Chem. Rev. 2006, 106, 17.
4. Cui, S. L.; Lin, X. F.; Wang, Y. G. J. Org. Chem. 2005, 70, 2866.
5. Huang, Y. J.; Yang, F. Y.; Zhu, C. J. J. Am. Chem. Soc. 2005, 127, 16386.
6. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115; (b) Do¨mling, A.; Ugi, I. Angew. Chem., Int.
Ed. 2000, 39, 3169.
7. Evdokimov, N. M.; Magedov, I. V.;Kireev, A. S.; Kornienko, A. Org. Lett. 2006, 8, 899.
8. Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045.
9. Xiong, W. N.; Yang, C. G.; Jiang, B. Bioorg. Med. Chem. 2001, 9, 1773.
10. Zhu, S.; Ji, S.; Su, X.; Sun, C.; Liu, Y. Tetrahedron Lett. 2008, 49, 1777.
11. Farghaly, A. M.; Habib, N. S.; Khalil, M. A.; Sayed, O. A. E.; Alexandria. J. Pharm.
Sci. 1989, 3, 90.
Yellow solid; mp 208–211; Rf 0.37 (20% EtOAc/Petroleum ether);
IR (KBr):1275, 1345, 1521, 1608, 2347, 3312 cmꢁ1
;
1H NMR
(500 MHz, DMSO-d6):
d
4.20 (s, 2H, –Ar–CH2), 6.71 (d, 1H, J¼7.6 Hz,
–Ar–H), 7.12 (t, 1H, J¼7.6 Hz, –Ar–H), 7.25–7.30 (m, 3H, –Ar–H),
7.46–7.51 (m, 3H, –Ar–H), 7.58 (t, 3H, J¼7.6 Hz, –Ar–H), 8.30 (d, 1H,
J¼2.9 Hz, –Ar–H), 8.52–8.55 (m, 1H, –Ar–H), 10.80 (br s, 1H, –NH);
13C NMR (125 MHz, DMSO-d6):
d 26.6,103.1,111.6,113.1,118.3,120.8,
121.7,121.9,122.5,124.9,126.2,127.7,127.8,128.0,128.5,129.3,133.7,
135.3, 136.4, 137.6, 141.0, 146.6, 155.5, 168.0; MS (ESI LCQ-MS): m/z
418.40 [MþH]þ. Anal. Calcd for C27H16ClN3: C, 77.60; H, 3.86; N,
10.06. Found: C, 77.51; H, 3.87; N, 10.11.
12. Franco, L. H.; Joffe, E. B. K.; Puricelly, L.; Tatian, M.; Seldes, A. M.; Palermo, J. A.
J. Nat. Prod. 1998, 61, 1130.
13. Zhu, S.; Ji, S.; Zhao, K.; Liu, Y. Tetrahedron Lett. 2008, 49, 2578.
14. (a) Teague, S. J. J. Org. Chem. 2008, 73, 9765; (b) Movassaghi, M.; Hill, M. D.;
Ahmad, O. K. J. Am. Chem. Soc. 2007, 129, 10096.
15. Bringmann, G.; Reichert, Y.; Kane, V. V. Tetrahedron 2004, 60, 3539.
16. Zhou, Y.; Kijima, T.; Kuwahara, S.; Watanabe, M.; Izumi, T. Tetrahedron Lett.
2008, 49, 3757.
17. (a) Cooke, M. W.; Hanan, G. S. Chem. Soc. Rev. 2007, 36, 1466; (b) Constable, E. C.
Chem. Soc. Rev. 2007, 36, 246; (c) Kurth, D. G.; Higuchi, M. Soft Matter 2006, 2,
915; (d) Medlycott, E. A.; Hanan, G. S. Chem. Soc. Rev. 2005, 34, 133; (e) Andres,
P. R.; Schubert, U. S. Adv. Mater. 2004, 16, 1043.
4.4.6. 10f. 2-(1H-Indol-3-yl)-4-(2, 4-dichlorophenyl)-9H-
indeno[2,1-b]pyridine-3-carbonitrile (Table 3, entry 6)
Yellow solid; mp 272–274 ꢀC; Rf 0.33 (20% EtOAc/Petroleum
ether); IR (KBr): 1080, 1491, 1575, 1649, 2237, 3373, 3420 cmꢁ1; 1H
NMR (500 MHz, CDCl3):
d
4.18 (ABq, 2H, J¼9.0 Hz, –Ar–CH2), 6.61
(d, 1H, J¼8.4 Hz, –Ar–H), 7.18 (t, 1H, J¼7.6 Hz, –Ar–H), 7.31–7.39 (m,
4H, –Ar–H), 7.47–7.52 (m, 2H, –Ar–H), 7.60 (d, 1H, J¼7.6 Hz, –Ar–H),
7.70 (d, 1H, J¼1.6 Hz, –Ar–H), 8.32 (d, 1H, J¼3.1 Hz, –Ar–H), 8.56–
8.58 (m, 1H, –Ar–H), 8.61 (br s, 1H, –NH); 13C NMR (125 MHz,
CDCl3):
d 35.6, 108.8, 112.5, 117.0, 120.3, 120.5, 122.1, 122.5, 123.3,
18. Radwan, M. A. A.; Ragab, E. A.; Sabry, N. M.; Shenawy, S. M. E. Bioorg. Med.
Chem. 2007, 15, 3832.
19. (a) Sun, C.; Jun Ji, S.; Liu, Y. Tetrahedron Lett. 2007, 48, 8987; (b) Radwana, M. A.
A.; Sherbiny, M. E. Bioorg. Med. Chem. 2007, 15, 1206.
124.0, 125.4, 126.9, 127.5, 128.8, 129.2, 132.8, 133.3, 136.4, 138.5,
141.8, 143.3, 145.5, 154.8, 162.5; MS (ESI LCQ-MS): m/z 452.33
[MþH]þ. Anal. Calcd for C27H15Cl2N3: C, 71.69; H, 3.34; N, 9.29.
Found: C, 71.77; H, 3.35; N, 9.23.
20. Abdallah, T. A. J. Heterocycl. Chem. 2007, 44, 961.
21. Zaki, M. E. A.; Proenc, M. F. Tetrahedron 2007, 63, 3745.
22. Babu, G.; Perumal, P. T. Aldrichima Acta 2000, 33, 16.
23. Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2008, 49, 7139.
24. (a) Thirumurugan, P.; Muralidharan, D.; Perumal, P. T. Dyes Pigm. 2009, 81, 245;
(b) Thirumurugan, P.; Perumal, P. T. Tetrahedron Lett. 2009, 50, 4145.
25. Karthikeyan, K.; Perumal, P. T.; Etti, S.; Shanmugam, G. Tetrahedron 2007,
63, 10581.
26. Slatt, J.; Romero, I.; Bergman, J. Synthesis 2004, 16, 2760.
27. Ramesh, P.; Subbiahpandi, A.; Thirumurugan, P.; Perumal, P. T.; Ponnuswamy,
M. N. Acta Crystallogr. 2008, E64, o1892.
Acknowledgements
One of the authors, P.T., thanks the Council of Scientific and
Industrial Research, New Delhi, India, for the research fellowship.
Supplementary data
28. Kelly, T. R.; Lebedev, R. L. J. Org. Chem. 2002, 67, 2197.
29. Ramesh, P.; Subbiahpandi, A.; Thirumurugan, P.; Perumal, P. T.; Ponnuswamy,
M. N. Acta Crystallogr. 2009, E65, o995.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2009.06.097.
30. Wang, X. G. S.; Wu, J. R.; Li, Q.; Yao, C. S.; Tu, S. J. Synlett 2008, 8, 1185.