Synthesis of 2-(1H-indol-3-yl)pyridine derivatives through multi-component reaction

Article abstract of DOI:10.3184/030823410X12863016030919

A straightforward and practical approach is established for the synthesis of 2-(1H-indol-3-yl)pyridine derivatives achieved through the one-pot three-component reaction of chalcone, 3-(2-cyanoacetyl)-1H-indole and ammonium acetate. This method offers seve

Full text of DOI:10.3184/030823410X12863016030919

JOURNAL OF CHEMICAL RESEARCH 2010
RESEARCH PAPER 565
OCTOBER, 565–567
Synthesis of 2-(1H-indol-3-yl)pyridine derivatives through
multi-component reaction
Li-Jun Genga,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 East Road, Shijiazhuang 050018, P. R. China
A straightforward and practical approach is established for the synthesis of 2-(1H-indol-3-yl)pyridine derivatives
achieved through the one-pot three-component reaction of chalcone, 3-(2-cyanoacetyl)-1H-indole and ammonium
acetate. This method offers several advantages such as short reaction time, high yields, and simple procedure.
Keywords: 2-(1H-indol-3-yl)pyridine derivatives, 3-(2-cyanoacetyl)-1H-indole, chalcone, multi-component reaction, microwave
irradiation
The publication of the Strecker reaction in 1850 is considered
as the beginning of the multicomponent reaction (MCR) story.1
MCR is important in organic and medicinal chemistry2–4 due to
its diversity, efficiency and rapid access to complex and highly
functionalised organic molecules.5 Hence, combined with the
use of combinatorial chemistry and high throughput parallel
synthesis, such reactions have constituted an increasingly valu-
able approach to drug research.6 In the past decade, there have
been tremendous developments in three- and four-component
reactions and great efforts are being made to find and develop
new MCRs.7,8
A large number of substituted pyridines have attracted atten-
tion from organic and medicinal chemists due to their useful
biological and pharmacological activities,9 such as antifungal,
antimalarial, antiviral and antiproliferative properties.10–12 On
the other hand, 3-substituted indole nucleus is prevalent in
many natural products and is extremely important in medicinal
chemistry.13,14 Due to the medicinal potential of pyridine and
3-substituted indole derivatives, various methods have been
reported for the synthesis of these compounds through the
reaction of aromatic aldehydes and 3-(2-cyanoacetyl)-
1H-indole.15–18 These reactions are based on unsubstituted 3-
(2-cyanoacetyl)-1H-indole as a reactant. Here we report a
facile method for the synthesis of a series of 2-(1H-indol-3-
yl)pyridine derivatives in the presence of 3-(2-cyanoacetyl)-
1H-indole, chalcone and ammonium acetate.
method of preparation as 2a. However, when 2-nitroindole or
5-nitroindole was used, we failed to get the expected product
owing to the lower reactivity of the nitroindoles.
After some preliminary experimentation, it was found that
a mixture of chalcone, 3-(2-cyanoacetyl)-1H-indole, and
ammonium acetate 3 afforded 3-cyano-2-(1H-indol-3-yl)-
4-(2-naphthyl)-6-(4-ethylphenyl)pyridine 4a under microwave
irradiation. In order to improve the isolated yield of 4a, various
reaction conditions including solvents and reaction time were
tested in the one-pot three-component synthesis of target
compound under MW irradiation. Founding HOAc/glycol(1/2)
and 120°C was the optimal experimental conditions.
To extend the scope of this procedure for the synthesis of
2-(1H-indol-3-yl)pyridine derivatives, a series of reactions
were carried out under the optimal conditions. We were pleased
to find that the reaction proceeded smoothly and desired
products were afforded in excellent yields (Table 1).
As shown in Table 1, the reaction proceeded smoothly with
a wide range of functionalised 3-(2-cyanoacetyl)-1H-indole,
including those containing methyl, bromo, methoxyl and
phenyl. The electronic effects of the substitution on the 3-(2-
cyanoacetyl)-1H-indole have no significant influence on the
reaction yield.
In addition, we extended our investigation to the synthesis
of 4b in HOAc/glycol under classical heating conditions.
After refluxing for 8 h, the desired product 4b was obtained in
62% yield, however, the yield of 4b was up to 82% (Table 1,
entry 2) under microwave irradiation condition. Therefore,
microwave irradiation had several advantages over the conven-
tional heating by significantly reducing the reaction times and
improving the reaction yield, owing to a specific non-thermal
microwave effect.
The starting compound chalcone 1 was prepared according
to the procedure described by Mauricio et al.19 The synthesis
of 3-(2-cyanoacetyl)-1H-indole (2a–c, 2e, 2f) have been
carried out using a similar method to the literature,20 the
preparation of 7-methyl-3-(2-cyanoacetyl)-1H-indole (2d) and
5-bromo-3-(2-cyanoacetyl)-1H-indole (2f) used the same
Scheme 1
* Correspondent. E-mail: jgyu2010@126.com

566 JOURNAL OF CHEMICAL RESEARCH 2010
Table 1 Synthesis of compounds 4a–i under microwave irradiation at 120°C
Entry
R1
R2
Product
Time/min
Yielda/%
M.p. /°C
1
2
3
4
5
6
7
8
9
4- CH2CH3
4- CH2CH3
4- CH2CH3
4- CH2CH3
4- CH2CH3
4- CH2CH3
4- CH2CH3
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
8
8
12
8
12
8
8
86
82
79
85
74
80
83
82
84
239
1-CH3
2-CH3
7-CH3
2-C6H5
5-Br
5-OCH3
H
190–191
201–202
273–274
228–229
263
218–219
264–265
237–238
8
8
4-(4-PrC6H10)
H
a Isolated yield.
analyses were performed by a Heraeus CHN-O-RAPID analyser.
Microwave reactions were carried out in a Xianghu XH-100B micro-
wave oven (450W). TLC analysis was performed on 0.25mm silica
gel GF254 plates. All chemicals were purchased and used without
further purification.
A mixture of chalcone 1 (2 mmol), 3-(2-cyanoacetyl)-1H-indole 2
(2 mmol) and ammonium acetate 3 (0.62 g, 8 mmol) in HOAc 2 mL
and glycol 4 mL were irradiated for the given time at 120 °C. After
the completion of the reaction (the reaction was followed by TLC), the
mixture was allowed to cool to room temperature and extracted with
dichloromethane, washed with H2O (3×10 mL) and the organic layer
dried over MgSO4 and concentrated under vacuum. The crude product
was chromatographed on silica gel (200–300 mesh) using a mixture
of petroleum ether and dichloromethane as eluent to afford the pure
product 4.
3-Cyano-2-(1H-indol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)pyridine
(4a): Pale yellow powder. IR (KBr) ν 3440, 3049, 2961, 2930, 2216,
1599, 1536, 1457, 1437, 1422 cm−1. 1H NMR (500 MHz, DMSO-d6):
δ 11.85 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.39
(d, J = 1.0 Hz, 1H), 8.30 (d, J = 8.0 Hz, 2H), 8.16 (d, J = 8.5 Hz, 1H),
8.09−8.04 (m, 3H), 7.93 (d, J = 8.5 Hz, 1H), 7.67−7.64 (m, 2H), 7.57
(d, J = 7.0 Hz, 1H), 7.45 (d, J = 8.5 Hz, 2H), 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, 85.60; H, 5.25; N, 9.23%.
3-Cyano-2-(N-methylindol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)
pyridine (4b): Pale yellow powder. IR (KBr) ν 3054, 2961, 2360,
2213, 1566, 1520, 1460, 1359 cm−1. 1H NMR (500 MHz, DMSO-d6):
δ 8.44 (d, J = 7.5 Hz, 1H), 8.39 (d, J = 4.5 Hz, 2H), 8.29 (d, J = 8.0
Hz, 2H), 8.15(d, J = 8.5 Hz, 1H), 8.09−8.05 (m, 3H), 7.92 (d, J = 8.5
Hz, 1H ), 7.67−7.65 (m, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.45 (d, J =
8.0 Hz, 2H), 7.35−7.28 (m, 2H), 4.00 (s, 3H), 2.74−2.69 (m, 2H), 1.25
The structures of compounds 4a–i were elucidated by IR,
1H NMR and elementary analysis. The IR spectrum of 4d, for
instance, exhibited the absorption band at 3303 cm−1 due to the
presence of NH functional and the band at 2215 cm−1 showed
the presence of C≡N. In the 1H NMR spectrum (DMSO) of 4d,
a sharp singlet at δ 11.83 corresponds to NH proton, methyl
protons (N–CH3) were resonated in the range of δ 2.56.
Based on the above results, a plausible mechanism was
proposed (Scheme 2). 3-(2-cyanoacetyl)-1H-indole reacted
with ammonia from ammonium acetate to give intermediate 5,
which further reacted with chalcone to yield 6. Michael addi-
tion product 6 was then cyclised to afford the Hantzsch dihy-
dropyridine derivative 7 with elimination of water, finally
deprotonation of 7 led to formation of highly substituted
pyridine derivative 4.
In summary, we have demonstrated an efficient synthesis of
3-cyano-2-(1H-indol-3-yl)-4-(2-naphthyl)pyridine derivatives
involving three-component condensation of chalcone, 3-(2-
cyanoacetyl)-1H-indole and ammonium acetate under micro-
wave irradiation in a simple one-pot procedure. High efficiency
and short reaction time were the advantages of this protocol.
Experimental
Melting points were determined on an electrothermal digital melting
point apparatus and uncorrected. 1H NMR spectra were obtained on a
Varian VXP-500s spectrometer using DMSO-d6 as solvent and tetra-
methylsilane (TMS) as internal reference. IR Spectra was determined
on a Nicolet 6700 spectrophotometer using KBr pellets. Elementary
Scheme 2

JOURNAL OF CHEMICAL RESEARCH 2010 567
(t, J = 7.5 Hz, 3H). Anal. Calcd for C33H25N3: C, 85.50; H, 5.44; N,
9.06. Found: C, 85.40; H, 5.52; N, 9.12%.
3-Cyano-2-(1H-indol-3-yl)-4-(2-naphthyl)-6-phenylpyridine (4h):
Pale yellow powder. IR (KBr) ν 3438, 3058, 2920, 2217, 1599, 1534,
1
1456, 1436, 1425 cm−1. H NMR (500 MHz, DMSO-d6): δ 11.86 (s,
3-Cyano-2-(2-methyl-1H-indol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)
pyridine (4c): Pale yellow powder. IR (KBr) ν 3393, 3054, 2963,
2361, 2217, 1568, 1522, 1459 cm−1. 1H NMR (500 MHz, DMSO-d6):
δ 11.63 (s, 1H), 8.43 (s, 1H), 8.26 (d, J = 8.0 Hz, 2H), 8.18 (s, 1H),
8.16 (d, J = 8.5 Hz, 1H), 8.12−8.06 (m, 2H), 7.98−7.96 (m, 1H), 7.72
(d, J = 8.0 Hz, 1H ), 7.66−7.65 (m, 2H), 7.42 (t, J = 8.0 Hz, 3H),
7.17−7.10 (m, 2H), 2.71−2.69 (m, 2H), 2.64 (s, 3H), 1.24 (t, J = 7.5
Hz, 3H). Anal. Calcd for C33H25N3: C, 85.50; H, 5.44; N, 9.06. Found:
C, 85.59; H, 5.38; N, 9.10%.
3-Cyano-2-(2-methyl-1H-indol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)
pyridine (4d): Pale yellow powder. IR (KBr) ν 3303, 3056, 2965,
2362, 2215, 1565, 1548, 1503, 1440 cm−1. 1H NMR (500 MHz,
DMSO-d6): δ 11.83 (s, 1H), 8.39 (d, J = 3.0 Hz, 2H), 8.30 (d, J = 8.5
Hz, 2H), 8.26 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.10−8.06
(m, 2H), 8.05 (s, 1H), 7.94 (dd, J = 8.5 Hz and J = 1.5 Hz, 1H ),
7.68−7.64 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.15 (t, J = 7.5 Hz, 1H),
7.06 (d, J = 7.0 Hz, 1H), 2.72−2.71 (m, 2H), 2.56 (m, 3H), 1.25 (t,
J = 7.5 Hz, 3H). Anal. Calcd for C33H25N3: C, 85.50; H, 5.44; N, 9.06.
Found: C, 85.38; H, 5.46; N, 9.15%.
3-Cyano-2-(2-phenyl-1H-indol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)
pyridine (4e): Pale yellow powder. IR (KBr) ν 3348, 3057, 2964,
2362, 2336, 2214, 1562, 1535, 1501, 1455 cm−1. 1H NMR (500 MHz,
DMSO-d6): δ 12.01 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 8.14 (d, J = 8.5
Hz, 2H), 8.09 (d, J = 8.0 Hz, 1H), 8.02 (t, J = 7.5 Hz, 2H), 7.74 (d,
J = 8.5 Hz, 2H), 7.65−7.62 (m, 2H), 7.55−7.42 (m, 6H), 7.36 (d,
J = 8.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.0 Hz, 1H),
2.71−2.68 (m, 2H), 1.22 (t, J = 7.5 Hz, 3H). Anal. Calcd for C38H27N3:
C, 86.83; H, 5.18; N, 7.99. Found: C, 86.91; H, 5.12; N, 7.92%.
3-Cyano-2-(5-bromo-1H-indol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)
pyridine (4f): Pale yellow powder. IR (KBr) ν 3335, 2970, 2919,
2360, 2215, 1576, 1566, 1532, 1508, 1441 cm−1. 1H NMR (500 MHz,
DMSO-d6): δ 12.04 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.50 (d, J = 3.0
Hz, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.29 (d, J = 8.0 Hz, 2H), 8.15 (d,
J = 9.0 Hz, 1H), 8.10−8.06 (m, 3H), 7.93 (dd, J = 8.5 Hz and J = 2.0
Hz, 1H), 7.67−7.65 (m, 2H), 7.55 (d, J = 9.0 Hz, 1H), 7.45 (d, J = 8.5
Hz, 2H), 7.40 (dd, J = 8.5 Hz and J = 2.0 Hz, 1H), 2.74−2.71 (m, 2H),
1.25 (t, J = 7.5 Hz, 3H). Anal. Calcd for C32H22N3Br: C, 72.73;
H, 4.20; N, 7.95. Found: C, 72.80; H, 4.18; N, 7.83%.
3-Cyano-2-(5-methoxyl-1H-indol-3-yl)-4-(2-naphthyl)-6-(4-ethylphenyl)
pyridine (4g): Pale yellow powder. IR (KBr) ν 3295, 2964, 2361,
2216, 1565, 1506, 1535, 1437 cm−1. 1H NMR (500 MHz, DMSO-d6):
δ 11.74 (s, 1H), 8.43 (d, J = 3.0 Hz, 1H), 8.37 (s, 1H), 8.36 (s, 1H),
8.35 (s, 1H), 8.16 (s, 1H), 8.14−8.13 (t, J = 2.5 Hz, 1H), 8.10−8.06 (m,
2H), 8.03 (s, 1H), 7.92 (dd, J = 6.5 Hz and J = 2.0 Hz, 1H ), 7.67−7.65
(m, 2H), 7.47−7.43 (m, 3H), 6.91 (dd, J = 8.5 Hz and J = 2.5 Hz, 1H
), 3.85 (s, 3H), 2.72−2.71 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H). Anal.
Calcd for C33H25N3O: C, 82.65; H, 5.25; N, 8.76. Found: C, 82.55;
H, 5.28; N, 8.82%.
1H), 8.47−8.43 (m, 2H), 8.41−8.38 (m, 3H), 8.16 (d, J = 8.5 Hz, 1H),
8.10−8.05 (m, 3H), 7.95 (dd, J = 8.5 Hz and J = 1.5 Hz, 1H), 7.67−7.56
(m, 6H), 7.30−7.24 (m, 2H). Anal. Calcd for C30H19N3: C, 85.49; H,
4.54; N, 9.97. Found: C, 85.58; H, 4.60; N, 10.09%.
3-Cyano-2-(1H-indol-3-yl)-4-(2-naphthyl)-6-[4-(4-propylcyclohexanyl)
phenyl]pyridine (4i): Pale yellow powder. IR (KBr) ν 3329, 3057,
2948, 2917, 2215, 1560, 1532, 1457, 1439 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), 7.67−7.63 (m, 2H), 7.56 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 8.5
Hz, 2H), 7.27−7.22 (m, 2H), 2.60−2.53 (m, 1H), 1.85 (t, J = 10.0 Hz,
4H), 1.51−1.49 (m, 2H), 1.34−1.30 (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, 85.76; H, 6.37; N, 7.82%
Received 16 June 2010; accepted 24 August 2010.
Paper 1000205 doi: 10.3184/030823410X12863016030919
Published online: 22 October 2010
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