Microwave-assisted synthesis of 3-cyano-2-(1Hindol-3-yl)pyridine derivatives by a multicomponent reaction

Article abstract of DOI:10.3184/030823410X12756714644327

Preparation of a series of 3-cyano-2-(1H -indol-3-yl)pyridine derivatives through the one-pot multicomponent coupling of aromatic aldehydes, aromatic ketones, 3-(cyanoacetyl)indole and ammonium acetate is studied in the present article. All these compounds were obtained in good yield and their structures were confirmed by 1H NMR, IR and elementary analysis.

Full text of DOI:10.3184/030823410X12756714644327

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 333
JUNE, 333–335
Microwave-assisted synthesis of 3-cyano-2-(1H-indol-3-yl)pyridine
derivatives by a multicomponent reaction
Li-Jun Geng,a,b Guo-Liang Fengb and Jiu-Gao Yua*
aDepartment of Chemistry, School of Science, Tianjin University, Weijin Road, Tianjin 300072, P. R. China
bSchool of Science, Hebei University of Science andTechnology, Yuhua Road, Shijiazhuang 050018, P. R. China
Preparation of a series of 3-cyano-2-(1H -indol-3-yl)pyridine derivatives through the one-pot multicomponent
coupling of aromatic aldehydes, aromatic ketones, 3-(cyanoacetyl)indole and ammonium acetate is studied in the
present article. All these compounds were obtained in good yield and their structures were confirmed by 1H NMR,
IR and elementary analysis.
Keywords: aromatic aldehydes, aromatic ketones, 3-(cyanoacetyl)indole, 3-cyano-2-(1H-indol-3-yl)pyridine derivatives, multi-
component reactions
The pyridine substructure is one of the most important hetero-
cycles found in natural products, pharmaceuticals, and func-
tional materials.1,2 During the last two decades, a large number
of substituted pyridines have been shown to have biological
activity.3−5 Pyridine derivatives containing multi-functional
groups such as streptonigrin, streptonigrone and lavendamycin
are reported as anticancer drugs, and cerivastatin as the enzyme
inhibitors.6 Therefore, it is not surprising that research on
the synthesis of polyfunctionalized heterocyclic compounds
containing pyridine ring fragments has received significant
attention.7,8
Multi-component reactions (MCRs), with three or more
reactants that combine in a one-pot procedure to give a single
product, provide a powerful tool, enabling straightforward
access to a large number of structurally related, drug-like
compounds.9−15 Hence, the recent interest in these reactions in
organic and medicinal chemistry.16−19
Table 1 Synthesis of compounds 5a–k under microwave
irradiation
Entry R1
R2
Product Time Yielda
/min
/%
1
2
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
8
8
85
84
89
88
72
82
81
85
86
83
82
2-OCH3
4-CH3
3-CH3
2,4-Cl2
3
8
4
8
5
12
8
6
3,4-(CH=CH-CH=CH) H
7
H
H
H
4-Br
8
8
4-CH3CH2
8
9
4-(4-PrC6H10)
8
10
11
3,4-(CH=CH-CH=CH) 4-CH3CH2
3,4-(CH=CH-CH=CH) 4-(4-PrC6H10)
5j
5k
8
8
a Isolated yield.
As can be seen from Table 1, the results indicated that this
method works with a wide variety of substrates. A series of
different position substituted aromatic aldehydes including
either electron-withdrawing or electron-donating groups and
different substituted acetophenones proceeded smoothly.
The structures of the compounds 5a–k were fully supported
by IR, 1H NMR spectroscopy and elemental analysis.
Based on the above results, a plausible mechanism was pro-
posed (Scheme 2). Aldehyde 1 reacted with aromatic ketones
2 to give chalcone 6 and 3-(cyanoacetyl)indole 3 with ammo-
nium acetate 4 to afford intermediate 7, chalcone 6 and inter-
mediate 7 further reacted to yield 8. Michael addition product
8 was then cyclised to afford the Hantzsch dihydropyridine
derivative 9 with an elimination of water, finally deprotonation
of 9 leaded to formation of highly substituted pyridine
derivative 5.
Due to our interest in the multicomponent syntheses and
in multi-functional pyridine derivatives, we report a simple
and suitable protocol for the preparation of a series of 3-cyano-
2-(1H-indol-3-yl)pyridine derivatives. The target compounds
were synthesised by four-component reaction of aldehydes,
aromatic ketones, 3-(cyanoacetyl) indoles and ammonium
acetate under microwave irradiation condition. The starting
compounds, 3-(cyanoacetyl)indoles was prepared according to
the procedure described by Slatt et al.20
In our initial study, various reaction conditions including
solvents and microwave power were tested in the one-pot four-
component synthesis of target compounds under MW irradia-
tion. We found HOAc/glycol(1/2) and 350W was the optimal
experimental conditions. Under these conditions, a series of
new 3-cyano-2-(1H-indol-3-yl)pyridine derivatives were syn-
thesised in good yields (Scheme 1). The optimised results are
summarised in Table 1.
In summary, our results pointed to a sequential application
of multicomponent reaction of aldehydes 1, aromatic ketones
Scheme 1
* Correspondent. E-mail: jgyu2010@126.com

334 JOURNAL OF CHEMICAL RESEARCH 2010
Scheme 2
1
1572, 1537, 1437 cm−1. H NMR (500 MHz, DMSO-d6): δ 11.84
(s, 1H), 8.40−8.39 (m, 2H), 8.35 (d, J = 8.5 Hz, 2H), 7.97 (s, 1H), 7.82
(m, 2H), 7.62−7.55 (m, 7H), 7.25−7.23 (m, 2H). Anal. Calcd for
C26H17N3: C, 84.07; H, 4.61; N, 11.31. Found: C, 84.14; H, 4.58;
N, 11.45%.
2, 3-(cyanoacetyl)indole 3, and ammonium acetate 4 for
the synthesis of multi-functional 3-cyano-2-(1H-indol-3-yl)
pyridine derivatives under microwave irradiation. The experi-
mental simplicity, compatibility with various functional
groups, short reaction times, the easy workup procedure, and
efficient yields, maked this procedure attractive to synthesise
a variety of these derivatives.
3-Cyano-2-(1H-indol-3-yl)-4-(2-methoxyphenyl)-6-phenylpyridine
(5b): White power; m.p. 213–214 °C. IR (KBr) ν 3302 (NH), 3056,
2957, 2212 (CN), 1603, 1583, 1538, 1456, 1434 cm−1. 1H NMR (500
MHz, DMSO-d6): δ 11.81 (s, 1H), 8.42 (d, J = 7.0 Hz, 1H), 8.33 (d,
J = 2.5 Hz, 1H), 8.31 (d, J = 7.0 Hz, 2H), 7.88 (s, 1H), 7.61−7.53
(m, 5H), 7.50 (dd, J = 7.5 Hz and J = 2.0 Hz, 1H), 7.26−7.23 (m, 3H),
7.16 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H). Anal. Calcd for C27H19N3O:
C, 80.78; H, 4.77; N, 10.47. Found: C, 80.71; H, 4.88; N, 10.45%.
3-Cyano-2-(1H-indol-3-yl)-4-(4-methylphenyl)-6-phenylpyridine
(5c): Pale yellow power; m.p. 268 °C. IR (KBr) ν 3314 (NH), 3055,
Experimental
Melting points were recorded on an electrothermal digital melting
1
point apparatus and uncorrected. H NMR spectra were determined
on a Varian VXP-500s spectrometer using DMSO-d6 as solvent and
tetramethylsilane (TMS) as internal reference. The IR spectra was
obtained on a Nicolet 6700 spectrophotometer using KBr pellets.
Elementary analyses were performed by a Heraeus CHN-O-RAPID
analyzer. Microwave reactions were carried out in a xianghu
XH-100B microwave oven.
2927, 2219 (CN), 1581, 1570, 1536, 1492, 1438 cm−1. H NMR
1
(500 MHz, DMSO-d6): δ 11.84 (s, 1H), 8.40−8.36 (m, 4H), 7.93
(s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.62−7.55 (m, 4H), 7.43 (d, J =
8.0 Hz, 2H), 7.27−7.21 (m, 2H), 2.44 (s, 3H).Anal. Calcd for C27H19N3:
C, 84.13; H, 4.97; N, 10.90. Found: C, 84.25; H, 4.92; N, 10.99%.
3-Cyano-2-(1H-indol-3-yl)-4-(3-methylphenyl)-6-phenylpyridine
(5d): Pale yellow power; m.p. 211–212 °C. IR (KBr) ν 3309 (NH),
3060, 2922, 2219 (CN), 1584, 1570, 1539, 1485, 1441 cm−1. 1H NMR
(500 MHz, DMSO-d6): δ 11.85 (s, 1H), 8.42−8.34 (m, 4H), 7.95 (s,
1H), 7.63−7.55 (m, 6H), 7.50 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 8.0 Hz,
1H), 7.28−7.22 (m, 2H), 2.45 (s, 3H). Anal. Calcd for C27H19N3:
C, 84.13; H, 4.97; N, 10.90. Found: C, 84.22; H, 5.06; N, 10.97%.
3-Cyano-2-(1H-indol-3-yl)-4-(2,4-dichlorophenyl)-6-phenylpyri-
dine (5e): Pale yellow power; m.p. 276 °C. IR (KBr) ν 3321 (NH),
3056, 2220 (CN), 1571, 1554, 1535, 1494 cm−1. 1H NMR (500 MHz,
DMSO-d6): δ 11.89 (s, 1H), 8.45 (d, J = 8.5 Hz, 1H), 8.37 (d,
Experimental procedure
A mixture of aldehyde 1 (2 mmol), aromatic ketone 2 (2 mmol),
3-(cyanoacetyl)indole 3 (2 mmol), and ammonium acetate 4 (8 mmol)
in HOAc 2 mL and glycol 4 mL were irradiated at 350 W and 110–
130 °C. After completion of the reaction (the reaction was followed
by TLC), the mixture was allowed to cool to room temperature
and collected by filtration, washed with cool water (3 × 5 mL). The
crude product was separated by column chromatography on silica
(200–300 mesh), eluted with a mixture of petroleum ether and
dichloromethane to afford the pure product (5a–k):
3-Cyano-2-(1H-indol-3-yl)-4,6-diphenylpyridine (5a): White power;
m.p. 248–249 °C. IR (KBr) ν 3314 (NH), 3062, 2219 (CN), 1583,

JOURNAL OF CHEMICAL RESEARCH 2010 335
J = 3.0 Hz, 1H), 8.33 (d, J = 8.5 Hz, 2H), 7.98 (s, 1H), 7.93 (d, J =
2.0 Hz, 1H), 7.73−7.68 (m, 2H), 7.61−7.56 (m, 4H), 7.28−7.25 (m,
2H). Anal. Calcd for C26H15Cl2N3: C, 70.92; H, 3.43; N, 9.54. Found:
C, 70.83; H, 3.49; N, 9.60%.
3-Cyano-2-(1H-indol-3-yl)-4-naphthyl-6-phenylpyridine (5f): Pale
yellow power; m.p. 264–265 °C. IR (KBr) ν 3438 (NH), 3058, 2919,
2217 (CN), 1599, 1533, 1456, 1436, 1424 cm−1. 1H NMR (500 MHz,
DMSO-d6): δ 11.86 (s, 1H), 8.46−8.43 (m, 2H), 8.41−8.38 (m, 3H),
8.16 (d, J = 8.5 Hz, 1H), 8.10−8.06 (m, 3H), 7.95 (dd, J = 8.5 Hz and
J = 1.5 Hz, 1H), 7.67−7.56 (m, 6H), 7.29−7.24 (m, 2H). Anal. Calcd
for C30H19N3: C, 85.49; H, 4.54; N, 9.97. Found: C, 85.61; H, 4.48;
N, 10.06%.
6-(4-Bromphenyl)3-cyano-2-(1H-indol-3-yl)-4-phenylpyridine
(5g): Yellow power; m.p. 228–229 °C. IR (KBr) ν 3340 (NH), 3057,
2216 (CN), 1589, 1581, 1529, 1457cm−1. 1H NMR (500 MHz, DMSO-
d6): δ 11.84 (s, 1H), 8.39 (d, J = 3.0 Hz, 1H), 8.36 (d, J = 7.5 Hz, 1H),
8.30 (d, J = 8.5 Hz, 2H), 7.98 (s, 1H), 7.82−7.80 (m, 3H), 7.78 (s, 1H),
7.62−7.60 (m, 3H), 7.56 (d, J = 7.5 Hz, 1H), 7.26−7.22 (m, 2H). Anal.
Calcd for C26H16N3Br: C, 69.34; H, 3.58; N, 9.33. Found: C, 69.49;
H, 3.54; N, 9.27%.
7.26−7.24 (m, 2H), 2.72−2.71 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H). Anal.
Calcd for C32H23N3: C, 85.50; H, 5.16; N, 9.35. Found: C, 85.61;
H, 5.20; N, 9.29%.
3-Cyano-2-(1H-indol-3-yl)-4-naphthyl-6-[4-(4-propylcyclohexyl)
phenyl]pyridine (5k): Pale yellow power; m.p. 237–238 °C. IR (KBr)
ν 3329 (NH), 3056, 2948, 2917, 2215 (CN), 1570, 1532, 1457,
1438 cm−1. 1H NMR (500 MHz, DMSO-d6): δ 11.84 (s, 1H), 8.44 (d,
J = 7.0 Hz, 1H), 8.41 (d, J = 3.0 Hz, 1H), 8.39 (s, 1H), 8.28 (d, J =
8.0 Hz, 2H), 8.15 (d, J = 8.5 Hz, 1H), 8.10−8.05 (m, 2H), 8.03 (s, 1H),
7.93 (dd, J = 8.5 Hz and J = 2.0 Hz, 1H), 7.67−7.64 (m, 2H), 7.56
(d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 7.27−7.23 (m, 2H),
2.60−2.53 (m, 1H), 1.85 (t, J = 10.0 Hz, 4H), 1.51−1.49 (m, 2H),
1.34−1.31 (m, 3H), 1.22−1.19 (m, 2H), 1.07−1.05 (m, 2H), 0.88 (t,
J = 7.0 Hz, 3H). Anal. Calcd for C39H35N3: C, 85.84; H, 6.46; N, 7.70.
Found: C, 85.72; H, 6.55; N, 7.78%.
Received 18 March 2010; accepted 12 May 2010
Paper 1000009 doi: 10.3184/030823410X12756714644327
Published online: 2 July 2010
3-Cyano-2-(1H-indol-3-yl)-4-phenyl-6-(4-ethylphenyl)pyridine
(5h): White power; m.p. 225−226 °C. IR (KBr) ν 3369 (NH), 3057,
2968, 2218 (CN), 1568, 1532, 1493, 1447cm−1. 1H NMR (500 MHz,
DMSO-d6): δ 11.83 (s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 8.38 (d, J =
2.5 Hz, 1H), 8.27 (d, J = 8.5 Hz, 2H), 7.92 (s, 1H), 7.82−7.80 (m, 2H),
7.62−7.59 (m, 3H), 7.56 (d, J = 7.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H),
7.26−7.23 (m, 2H), 2.72−2.70 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H). Anal.
Calcd for C28H21N3: C, 84.18; H, 5.30; N, 10.52. Found: C, 84.23;
H, 5.42; N, 10.41%.
3-Cyano-6-[4-(4-propylcyclohexyl)phenyl]2-(1H-indol-3-yl)-4-
phenylpyridine (5i): White power; m.p. 239 °C. IR (KBr) ν 3428
(NH), 2956, 2919, 2846, 2214 (CN), 1569, 1530, 1492, 1446cm−1.
1H NMR (500 MHz, DMSO-d6): δ 11.82 (s, 1H), 8.41 (d, J = 7.0 Hz,
1H), 8.38 (d, J = 3.0 Hz, 1H), 8.25 (d, J = 8.5 Hz, 2H), 7.90 (s, 1H),
7.80 (d, J = 8.0 Hz, 2H), 7.61−7.59 (m, 3H), 7.55 (d, J = 7.5 Hz, 1H),
7.43 (d, J = 8.0 Hz, 2H), 7.26−7.22 (m, 2H), 2.50 (t, J = 2.0 Hz, 1H),
1.84 (t, J = 9.0 Hz, 4H), 1.51−1.48 (m, 2H), 1.35−1.31 (m, 3H),
1.22−1.19 (m, 2H), 1.06−1.03 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H). Calcd
for C35H33N3: C, 84.81; H, 6.71; N, 8.48. Found: C, 84.73; H, 6.65;
N, 8.58%.
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