Multicomponent reaction for synthesis of 2-(indol-3-yl)pyridine derivatives under microwave irradiation

Article abstract of DOI:10.1080/00397911.2010.517375

A short, practical, and efficient preparation of 2-(indol-3-yl)pyridine derivatives via a one-pot procedure of 3-cyanoacetylindole, chalcones, and ammonium acetate under microwave irradiation was described. All these compounds were obtained in good yield,

Full text of DOI:10.1080/00397911.2010.517375

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Multicomponent Reaction for Synthesis
of 2-(Indol-3-yl)pyridine Derivatives
Under Microwave Irradiation
Li-Jun Geng a b , Guo-Liang Feng b , Jiu-Gao Yu a , Hong-Li Zhang b &
Yu-Mei Zhang b
a Department of Chemistry, School of Science, Tianjin University,
Tianjin, China
b School of Science, Hebei University of Science and Technology,
Shijiazhuang, China
Version of record first published: 04 Aug 2011
To cite this article: Li-Jun Geng, Guo-Liang Feng, Jiu-Gao Yu, Hong-Li Zhang & Yu-Mei Zhang
(2011): Multicomponent Reaction for Synthesis of 2-(Indol-3-yl)pyridine Derivatives Under Microwave
Irradiation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 41:23, 3448-3454
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Synthetic Communications1, 41: 3448–3454, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.517375
MULTICOMPONENT REACTION FOR SYNTHESIS OF
2-(INDOL-3-YL)PYRIDINE DERIVATIVES UNDER
MICROWAVE IRRADIATION
Li-Jun Geng,1,2 Guo-Liang Feng,2 Jiu-Gao Yu,1
Hong-Li Zhang,2 and Yu-Mei Zhang2
1Department of Chemistry, School of Science, Tianjin University,
Tianjin, China
2School of Science, Hebei University of Science and Technology,
Shijiazhuang, China
GRAPHICAL ABSTRACT
Abstract A short, practical, and efficient preparation of 2-(indol-3-yl)pyridine derivatives
via a one-pot procedure of 3-cyanoacetylindole, chalcones, and ammonium acetate under
microwave irradiation was described. All these compounds were obtained in good yield,
and their structures were confirmed by 1H NMR, infrared, and elementary analysis.
Keywords Chalcones; 3-cyanoacetylindole; 2-(indol-3-yl)pyridine derivatives; microwave
irradiation; multicomponent reaction
INTRODUCTION
Multicomponent reactions (MCRs), which combine three or more reactants in a
one-pot procedure to give a single product, provide powerful tools in modern med-
icinal chemistry, enabling straightforward access to large number of structurally
related, drug-like compounds[1–3] and thereby facilitating lead generation of privileged
medicinal scaffolds.[4] Hence, such reactions receive paramount importance in organic
and medicinal chemistry. Polyfunctionalized heterocyclic compounds play important
roles in the drug discovery process and analysis of drugs in late development.
The pyridine substructure is one of the most important heterocycles found in
natural products, pharmaceuticals, and functional materials. During the past two
decades, a large number of substituted pyridines have been claimed as having several
Received February 7, 2010.
Address correspondence to Jiu-Gao Yu, Department of Chemistry, School of Science, Tianjin
University, Weijin Road, Tianjin 300072, China. E-mail: gaojuy@tju.edu.cn
3448

2-(INDOL-3-YL)PYRIDINE DERIVATIVES
3449
Table 1. Solvent optimization for the synthesis of 4a under MWa
Entry
Solvent
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
MeOH
EtOH
20
20
10
10
10
10
10
10
40
50
55
60
60
83
74
70
HOAc
Glycol
HOAc=glycol (1:1)
HOAc=glycol (1:2)
HOAc=glycol (1:3)
HOAc=glycol (2:1)
aThe reaction was carried out under MW at 200 W.
bIsolated yields.
biological activities.[5] The antiviral,[6] antimicrobial,[7] and antibacterial[8] properties
of these compounds have opened up the possibility of their potential use as a novel
class of totally synthetic antimicrobial agents active against pathogenic bacteria.
Thus, further exploration of pyridine chemistry appears to be worthwhile.
Because of our interest in multicomponent syntheses and our observation that
the presence of two or more different heterocyclic moieties in a single molecule often
enhances the biocidal profile remarkably, we report a simple, facile, and one-pot
procedure for the synthesis of a series of indol-3-yl pyridine derivatives.
The starting compound, chalcone 1, was prepared according to the procedure
described by Mauricio et al.[9] The compound 3-cyanoacetylindole 2 was prepared
according to the procedure described by Bergman et al.[10]
After some preliminary experimentation, it was found that a mixture of chal-
cone 1a, 3-cyanoacetylindole 2, and ammonium acetate 3 afforded 2-(indol-3-yl)
pyridine derivative under microwave irradiation conditions.
Choosing an appropriate solvent was of crucial importance for the successful
microwave (MW)–assisted synthesis. In our initial endeavor, we investigated the efficacy
of different solvents for the syntheses of indol-3-yl pyridine derivatives. All the reactions
were carried out at a power of 200 W. The results are summarized in Table 1. As shown
in Table 1, excellent results were obtained with HOAc=glycol (1:2) as the solvent.
Encouraged by this success, we have extended this reaction to various chal-
cones 1b–j under similar conditions (HOAc=glycol ¼ 1=2), furnishing the respective
2-(indol-3-yl) pyridine derivatives in good yield (Scheme 1). The results are
summarized in Table 2.
As shown in Table 2, this reaction proceeded smoothly with a wide range
of differently substituted chalcones, including either electron-withdrawing or
Scheme 1.

3450
L.-J. GENG ET AL.
Table 2. Synthesis of compounds 4 under microwave irradiation
Entry
1
Chalcone
Product
Time (min)
Mp (ꢁC)
Yielda (%)
4a
10
247–248
83
2
4b
10
268–269
85
3
4
5
6
4c
4d
4e
4f
10
10
12
10
211
86
85
70
86
213–214
276
224–225
7
8
4g
4h
10
10
239–240
84
87
239
9
4i
4j
10
10
238–239
80
81
10
268
aIsolated yields.
electron-donating groups. We have also observed delicate electronic effects: That is,
chalcones with electron-donating groups on the aromatic aldehydes (Table 2, entries
2 ꢀ 4) displayed high reactivity, reacting rapidly and giving better yields, while the

2-(INDOL-3-YL)PYRIDINE DERIVATIVES
3451
Scheme 2.
substitution of electron-withdrawing groups (Table 2, entry 5) decreased the reac-
tivity, requiring longer reaction times and giving lower isolated yields. Moreover, dif-
ferently substituted acetophenones (Table 2, entries 6–9) displayed the same high
reactivity as acetophenone under this standard condition.
Based on these results, a plausible mechanism was proposed (Scheme 2).
3-Cyanoacetylindole reacted with ammonia from ammonium acetate to give inter-
mediate 5, which further reacted with corresponding chalcones to yield 6. Michael
addition product 6 was then cyclized to afford the Hantzsch dihydropyridine deriva-
tive 7 with elimination of water, and finally deprotonation of 7 led to formation of
highly substituted pyridine derivative 4.
In summary, our results point to a sequential application of multicomponent
reaction of chalcones, 3-cyanoacetylindole, and ammonium acetate for the synthesis
of 2-(indol-3-yl)pyridine derivatives under MW irradiation. The experimental sim-
plicity, compatibility with various functional groups, short reaction times, easy
workup procedure, and efficient yields make this procedure attractive for synthesiz-
ing a variety of these derivatives.
EXPERIMENTAL
Melting points were recorded on an Electrothermal digital melting-point
apparatus and are uncorrected.1H NMR spectra were determined on a Varian
VXP-500s spectrometer using dimethylsulfoxide (DMSO-d6) as solvent and tetra-
methylsilane (TMS) as internal reference. Infrared (IR) spectra were obtained on a
Nicolet 6700 spectrophotometer using KBr pellets. Elementary analyses were per-
formed by a Carlo-Erba EA1110 CNNO-S analyzer. Microwave reactions were
carried out in a Xianghu XH-100B microwave oven.
General Procedure for the Preparation of 2-(Indol-3-
yl)-3-cyanopyridine 4a–4j
Chalcone 1 (2 mmol), 3-cyanoacetylindole 2 (2 mmol), and ammonium acetate
3 (0.62 g, 8 mmol) were added to a mixture of acetic acid (2 mL) and glycol (4 mL).

3452
L.-J. GENG ET AL.
The mixture was irradiated for the given time at a power of 200 W. After the com-
pletion of the reaction (the reaction was followed by thin-layer chromatography,
TLC), the mixture was allowed to cool to room temperature, extracted with dichlor-
omethane, and washed with brine (3 ꢂ 10 mL). The organic layer was dried over
MgSO4 and evaporated in vacuo to give the crude product, which was chromato-
graphed on silica gel (200–300 mesh) using a mixture of petroleum ether and dichlor-
omethane as eluent to afford the pure products 4a–4j.
2-(Indol-3-yl)-3-cyano-4,6-diphenyl Pyridine (4a)
White powder; IR (KBr) n 3313 (NH), 3062, 2219 (CN), 1582, 1571, 1536,
1
1436, 1234, 1139, 772, 758 cmꢀ1. H NMR (500 MHz, DMSO-d6): d 11.83 (s, 1H),
8.40–8.38 (m, 2H), 8.35 (d, J ¼ 8.5 Hz, 2H), 7.96 (s, 1H), 7.83–7.81 (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, 84.12; H, 4.68; N, 11.25.
2-(Indol-3-yl)-3-cyano-4-(4-methylphenyl)-6-phenyl Pyridine (4b)
Pale yellow powder; IR (KBr) n 3314 (NH), 3055, 2927, 2218 (CN), 1581, 1569,
1
1536, 1492, 1438, 1269, 1235, 749, 690 cmꢀ1. H NMR (500 MHz, DMSO-d6): d
11.84 (s, 1H), 8.40–8.34 (m, 4H), 7.93 (s, 1H), 7.73 (d, J ¼ 8.5 Hz, 2H), 7.62–7.55
(m, 4H), 7.43 (d, J ¼ 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, 84.22; H, 4.90; N, 10.98.
2-(Indol-3-yl)-3-cyano-4-(3-methylphenyl)-6-phenyl Pyridine (4c)
Pale yellow powder; IR (KBr) n 3309 (NH), 3060, 2977, 2218 (CN), 1583, 1569,
1
1539, 1485, 1440, 1273, 1254, 745, 688 cmꢀ1. H NMR (500 MHz, DMSO-d6): d
11.85 (s, 1H), 8.41–8.34 (m, 4H), 7.95 (s, 1H), 7.63–7.55 (m, 6H), 7.51 (t, J ¼ 7.5 Hz,
Hz, 1H), 7.41 (d, J ¼ 8.0 Hz, 1H), 7.28–7.21 (m, 2H), 2.45 (s, 3H). Anal. calcd. for
C27H19N3: C, 84.13; H, 4.97; N, 10.90. Found: C, 84.18; H, 4.87; N, 10.97.
2-(Indol-3-yl)-3-cyano-4-(2-methoxyphenyl)-6-phenyl Pyridine (4d)
White powder; IR (KBr) n 3302 (NH), 3056, 2956, 2933, 2211 (CN), 1583,
1
1538, 1456, 1434, 1255, 773, 750 cmꢀ1. H NMR (500 MHz, DMSO-d6): d 11.81
(s, 1H), 8.42 (d, J ¼ 7.0 Hz, 1H), 8.33 (d, J ¼ 2.5 Hz, 1H), 8.31 (d, J ¼ 7.0 Hz, 2H),
7.88 (s, 1H), 7.60–7.53 (m, 5H), 7.50 (dd, J ¼ 7.5 Hz and J ¼ 2.0 Hz, 1H),
7.26–7.23 (m, 3H), 7.16 (t, J ¼ 8.0 Hz, 1H), 3.85 (s, 3H). Anal. calcd. for
C27H19N3O: C, 80.78; H, 4.77; N, 10.47. Found: C, 80.67; H, 4.85; N, 10.55.
2-(Indol-3-yl)-3-cyano-4-(2,4-dichlorophenyl)-6-phenyl Pyridine (4e)
Pale yellow powder; IR (KBr) n 3321 (NH), 3055, 2925, 2843, 2219 (CN), 1570,
1554, 1535, 1494, 1217, 819, 774, 742 cmꢀ1. 1H NMR (500 MHz, DMSO-d6): d 11.88
(s, 1H), 8.45 (d, J ¼ 8.5 Hz, 1H), 8.37 (d, J ¼ 3.0 Hz, 1H), 8.32 (d, J ¼ 8.5 Hz, 2H),
7.98 (s, 1H), 7.93 (d, J ¼ 2.0 Hz, 1H), 7.73–7.67 (m, 2H), 7.61–7.56 (m, 4H),

2-(INDOL-3-YL)PYRIDINE DERIVATIVES
3453
7.28–7.25 (m, 2H). Anal. calcd. for C26H15Cl2N3: C, 70.92; H, 3.43; N, 9.54. Found:
C, 70.85; H, 3.50; N, 9.62.
2-(Indol-3-yl)-3-cyano-4-phenyl-6-(4-ethylphenyl) Pyridine (4f)
White powder; IR (KBr) n 3368 (NH), 3057, 2968, 2932, 2217 (CN), 1568,
1
1531, 1493, 1447, 1366, 1236, 793, 766, 745 cmꢀ1. H NMR (500 MHz, DMSO-
d6): d 11.83 (s, 1H), 8.41 (d, J ¼ 7.5 Hz, 1H), 8.38 (d, J ¼ 2.5 Hz, 1H), 8.27 (d,
J ¼ 8.5 Hz, 2H), 7.91 (s, 1H), 7.82–7.80 (m, 2H), 7.61–7.59 (m, 3H), 7.56 (d,
J ¼ 7.5 Hz, 1H), 7.43 (d, J ¼ 8.5 Hz, 2H), 7.26–7.22 (m, 2H), 2.72–2.70 (m, 2H),
1.25 (t, J ¼ 7.5 Hz, 3H). Anal. calcd. for C28H21N3: C, 84.18; H, 5.30; N, 10.52.
Found: C, 84.25; H, 5.22; N, 10.51.
2-(Indol-3-yl)-3-cyano-4-naphthyl-6-(4-ethylphenyl) Pyridine (4g)
Pale yellow powder; IR (KBr) n 3440 (NH), 3048, 2961, 2929, 2215 (CN), 1566,
1536, 1456, 1437, 1388, 1176, 786, 770, 744 cmꢀ1. 1H NMR (500 MHz, DMSO-d6): d
11.84 (s, 1H), 8.44 (d, J ¼ 8.0 Hz, 1H), 8.42 (d, J ¼ 2.5 Hz, 1H), 8.39 (s, 1H), 8.30 (d,
J ¼ 8.0 Hz, 2H), 8.15 (d, J ¼ 8.5 Hz, 1H), 8.11–8.05 (m, 3H), 7.93 (d, J ¼ 8.5 Hz, 1H),
7.67–7.64 (m, 2H), 7.57 (d, J ¼ 7.0 Hz, 1H), 7.45 (d, J ¼ 8.5 Hz, 2H), 7.26–7.24 (m,
2H), 2.72–2.71 (m, 2H), 1.25 (t, J ¼ 7.5 Hz, 3H). Anal. calcd. for C32H23N3: C,
85.50; H, 5.16; N, 9.35. Found: C, 85.57; H, 5.20; N, 9.26.
2-(Indol-3-yl)-3-cyano-4-phenyl-6-(4-(4-propyl)cyclohexanylphenyl)
Pyridine (4h)
White powder; IR (KBr) n 3428 (NH), 2956, 2919, 2846, 2213 (CN), 1569,
1
1530, 1446, 1428, 1239, 1135, 767, 746, 703 cmꢀ1. H NMR (500 MHz, DMSO-
d6): d 11.82 (s, 1H), 8.41 (d, J ¼ 7.0 Hz, 1H), 8.38 (d, J ¼ 3.0 Hz, 1H), 8.25 (d,
J ¼ 8.5 Hz, 2H), 7.90 (s, 1H), 7.81–7.79 (m, 2H), 7.61–7.59 (m, 3H), 7.55 (d,
J ¼ 7.5 Hz, 1H), 7.43 (d, J ¼ 8.0 Hz, 2H), 7.26–7.22 (m, 2H), 2.50 (t, J ¼ 2.0 Hz,
1H), 1.84 (t, J ¼ 9.0 Hz, 4H), 1.51–1.48 (m, 2H), 1.34–1.30 (m, 3H), 1.22–1.19 (m,
2H), 1.06–1.03 (m, 2H), 0.90 (t, J ¼ 7.0 Hz, 3H). Anal. calcd. for C35H33N3: C,
84.81; H, 6.71; N, 8.48. Found: C, 84.83; H, 6.65; N, 8.55.
2-(Indol-3-yl)-3-cyano-4-naphthyl-6-(4-(4-propyl)cyclohexanylphenyl)
Pyridine (4i)
Pale yellow powder; IR (KBr) n 3329 (NH), 2947, 2917, 2215 (CN), 1570, 1532,
1457, 1144, 770, 745 cmꢀ1. 1H NMR (500 MHz, DMSO-d6): d 11.84 (s, 1H), 8.44 (d,
J ¼ 7.0 Hz, 1H), 8.41 (d, J ¼ 3.0 Hz, 1H), 8.39 (s, 1H), 8.28 (d, J ¼ 8.0 Hz, 2H), 8.15
(d, J ¼ 8.5 Hz, 1H), 8.10–8.05 (m, 2H), 8.03 (s, 1H), 7.93 (dd, J ¼ 8.5 Hz and
J ¼ 2.0 Hz, 1H), 7.67–7.64 (m, 2H), 7.56 (d, J ¼ 7.5 Hz, 1H), 7.45 (d, J ¼ 8.5 Hz,
2H), 7.27–7.23 (m, 2H), 2.60–2.53 (m, 1H), 1.85 (t, J ¼ 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 ¼ 7.0 Hz,
3H). Anal. calcd. for C39H35N3: C, 85.84; H, 6.46; N, 7.70. Found: C, 85.72; H,
6.53; N, 7.81.

3454
L.-J. GENG ET AL.
2-(Indol-3-yl)-3-cyano-4-naphthyl-6-phenyl Pyridine (4j)
Pale yellow powder; IR (KBr) n 3438 (NH), 3058, 2919, 2216 (CN), 1565, 1533,
1
1456, 1436, 1151, 754, 744 cmꢀ1. H NMR (500 MHz, DMSO-d6): d 11.86 (s, 1H),
8.45–8.43 (m, 2H), 8.41–8.38 (m, 3H), 8.16 (d, J ¼ 8.5 Hz, 1H), 8.10–8.06 (m, 3H),
7.95 (d, J ¼ 8.5 Hz, 1H), 7.67–7.56 (m, 6H), 7.28–7.23 (m, 2H). Anal. calcd. for
C30H19N3: C, 85.49; H, 4.54; N, 9.97. Found: C, 85.51; H, 4.48; N, 9.96.
ACKNOWLEDGMENT
This work was financially supported by the Research Foundation of Hebei
University of Science and Technology.
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