Four-component synthesis of star-shaped 2-(indol-3-yl)pyridine derivatives in one pot

Article abstract of DOI:10.1080/00397911.2011.607933

A protocol for the synthesis of star-shaped 2-(indol-3-yl)pyridine derivatives 4, neat, in the presence of iodine as a catalyst was developed (method A). Based on this strategy, compounds 4-aryl-2-(1H-indol-3-yl)-6- arylnicotinonitriles 6 were synthesized from 3-(cynonoacetyl)indole 1, aromatic aldehyde 2, aromatic ketone 5, and AcONH4 under the conditions of both methods A (solvent free) and B (using AcOH as solvent). The compounds 4-aryl-2-(1H-indol-3-yl)-6-(thiophen-2-yl)nicotinonitriles 8 were also prepared under the conditions of method B.

Full text of DOI:10.1080/00397911.2011.607933

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Four-Component Synthesis of Star-
Shaped 2-(Indol-3-yl)pyridine Derivatives
in One Pot
Li-Yan Zeng a & Chun Cai a
a Chemical Engineering College, Nanjing University of Science and
Technology, Nanjing, China
Accepted author version posted online: 21 Feb 2012.Version of
record first published: 13 Nov 2012.
To cite this article: Li-Yan Zeng & Chun Cai (2013): Four-Component Synthesis of Star-Shaped 2-
(Indol-3-yl)pyridine Derivatives in One Pot, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 43:5, 705-718
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Synthetic Communications1, 43: 705–718, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.607933
FOUR-COMPONENT SYNTHESIS OF STAR-SHAPED
2-(INDOL-3-YL)PYRIDINE DERIVATIVES IN ONE POT
Li-Yan Zeng and Chun Cai
Chemical Engineering College, Nanjing University of Science and
Technology, Nanjing, China
GRAPHICAL ABSTRACT
Abstract A protocol for the synthesis of star-shaped 2-(indol-3-yl)pyridine derivatives 4,
neat, in the presence of iodine as a catalyst was developed (method A). Based on this strat-
egy, compounds 4-aryl-2-(1H-indol-3-yl)-6-arylnicotinonitriles 6 were synthesized from
3-(cynonoacetyl)indole 1, aromatic aldehyde 2, aromatic ketone 5, and AcONH4 under
the conditions of both methods A (solvent free) and B (using AcOH as solvent). The com-
pounds 4-aryl-2-(1H-indol-3-yl)-6-(thiophen-2-yl)nicotinonitriles 8 were also prepared
under the conditions of method B.
Keywords 3-(Cynonoacetyl)indole; 2-(indol-3-yl)pyridine; molecular iodine; multicom-
ponent reactions
INTRODUCTION
According to the statistics of drugs in late development or on the market, 68%
of the medicinal scaffolds are heterocycles,[1] among which pyridine and indole deri-
vatives occupy central positions and have been invoked as venerable pharmaco-
phores.[2,3] Therefore, research on the synthesis of polyfunctionalized heterocyclic
compounds bearing pyridine and indole structures has received significant attention.
Multicomponent reactions (MCRs) also have received significant research interest
from chemical and medicinal communities because of emphasis on green chemistry
and atom economy. The MCR strategy provides efficient access to structurally
diverse chemical libraries, and the utility of MCRs is well presented in the syntheses
of privileged medicinal scaffolds.[4] Because enhanced biological activities could be
achieved when a single molecule bears two or more heterocyclic moieties, we wanted
Received August 26, 2010.
Address correspondence to Chun Cai, Chemical Engineering College, Nanjing University of
Science and Technology, Nanjing 210094, China. E-mail: c.cai@mail.njust.edu.cn
705

706
L.-Y. ZENG AND C. CAI
Figure 1. Natural products containing 3-substituted indole.
to develop a MCR protocol to construct a structure containing fragments of both
indole and pyridine.
As a fragment, 3-substituted indole is widely distributed in natural products.
Illustrative examples are shown in Fig. 1 topsentins I and dragmacidin II,[5,6]
extracted from deep-water sponges and described as potent inhibitors of serine=
threonine protein phosphatases, conjugated indole-imidazole derivatives III,[7] and
meridianins A–E IV,[8–10] which isolated from the tunicate Splidium meridiaum and
showed cytotoxicity in vitro against a range of cancer cell lines. The indole
fragment also formed the cornerstone of a range of biologically and medicinally
important compounds; for example, V-shaped pyridinyl derivatives (Fig. 2) substi-
tuted with one or two indole rings were reported as potential anti-angiogenic
Figure 2. V-shaped pyridinyl derivatives with indole ring.

SYNTHESIS OF 2-(INDOL-3-YL)PYRIDINES
707
inhibitors of the KDR and CDK kinase.[11,12] These structures provide an interesting
framework for the design of novel targeted pharmaceutical agents.
Pyridine is one of the nature’s most versatile building blocks with an estab-
lished medicinal pedigree[13,14] and is featured in a range of structures for drug can-
didates such as streptonigrin, streptonigrone, lavendamycin, and cerivastatin, which
have been reported as anticancer drugs and HMG-CoA enzyme inhibitors in the
literature.[5,15–17] Pyridine nucleus could be virtually constructed by reactions such
as Bohlmann–Rahtz reactions[18] and Kro¨hnke pyridine synthesis.[19] However, lim-
ited publications were devoted to the synthesis of star-shaped pyridines possessing
indole rings.[20–22] More recently, 3-(cyanoacetyl)indole 1 has mushroomed gradually
as a convenient precursor to construct 3-indolyl substituted heterocycles,[20–23]
because the functional group transformations occur at the nitrile and=or ketone moi-
eties to afford further useful indole derivatives. Herein, we explored the synthetic
application of 3-(cyanoacetyl)indole in assembly of new molecules based on the
structure of star-shaped pyridines, with the hope of providing available precursors
for lead discovery.
RESULTS AND DISCUSSION
Following our continuous investigation in the iodine-catalyzed MCR,[24–26] we
initially tested the reported reaction of 3-(cyanoacetyl)indole 1, 4-chlorobenzalde-
hyde 2a, 3-acetylpyridine 3, and AcONH4, using 20 mol% of iodine as catalyst
instead of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).[22] After refluxing the
starting materials in ethanol for 2 h, we smoothly obtained the expected product
4-(4-chlorophenyl)-6-(1H-indol-3-yl)-2,30-bipyridine-5-carbonitrile 4a with a yield
of 32%. The optimization of the reaction conditions was subsequently undertaken,
and the results are collected in Table 1. All of the organic solvents delivered poor
yields except BuOH (Table 1, entry 18), and no product was detected in the case
of H2O (Table 1, Entry 14). We guess that certain side reactions in H2O suppressed
the generation of the target product because an unknown white powder was isolated
quantitatively. Though the BuOH and solvent-free system (Table 1, entry 6)
performed equally well to give the expected product in 53% and 54% yields, respect-
ively, the solvent-free system is favored because of environmental concern. Obvi-
ously, the catalyst loading and the amount of AcONH4, highlighted in entry 11,
wherein the product yielded 76% with 10 mol% of iodine and 1.5 g of AcONH4, were
added into the neat reaction (method A). The pure product could be
collected conveniently from the reaction mixture after being dissolved in ethanol.
We failed to isolate the expected product (Table 1, entry 22) when 50 mol% of
DDQ was added to the reaction with the aim of improving the yield, similar to
the literature report.[22]
With the optimized conditions in hand, representative aromatic aldehydes were
examined, and the results collected in Table 2 implied that this iodine=solvent-free
system was applicable for the synthesis of 4-aryl-6-(1H-indol-3-yl)-2,30-bipyridine-
5-carbonitriles 4; both of the aromatic aldehydes bearing electron-withdrawing
and electron-donating groups were smoothly transformed into the anticipated
products in moderate to good yields. Preliminary experiments unambiguously estab-
lished the feasibility of the strategy involving iodine-catalyzed one-pot synthesis

708
L.-Y. ZENG AND C. CAI
Table 1. Reaction condition screening for the condensation of 3-(cyanoacetyl)indole 1, 4-chlorobenzalde-
hyde 2a, and 3-acetylpyridine 3
Entry
Solvent
Iodine (mol%)
AcONH4 (g)
T (ꢀC)
t (h)
Yield (%)a
1
3
EtOH
EtOH
EtOH
EtOH
—
20
20
20
20
20
25
20
20
15
10
5
1
80
80
2
6
10
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
32
47
1
4
1
80
35
39
13
5
1
6
1
120
120
120
120
120
120
120
120
120
120
120
120
110
120
120
120
120
54
54
7
—
—
1
8
1.5
2
67
54
9
—
—
10
11
12
13
14
15
16
17
18
19
20
21
22b
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
73
76
—
—
71
37
—
0
H2O þKI
AcOEt
i-PrOH
MeOH
n-BuOH
DCE
THF
Dioxane
—
10
10
10
10
10
10
10
10
10
—
31
27
34
53
Trace
15
Trace
—
aIsolated yield.
bDDQ (50 mol%) was added.
of 6-(1H-indol-3-yl)-4-aryl-2,30-bipyridine-5-carbonitriles 4. Based on these
observations, we turned our attention to prepare structurally similar molecules from
3-(cynonoacetyl)indole 1 with the aim of completing the libraries of star-shaped
(indol-3-yl)pyridines. Therefore, the substituted acetophenones were considered to
display the role of 3.
The study commenced with the four-component condensation of 3-(cyanoace-
tyl)indole 1, 4-chlorobenzaldehyde 2a, acetophenone 5a, and AcONH4 under the
condition of method A, depicted in Scheme 1. Fortunately, the target product
4-(4-chlorophenyl)-2-(1H-indol-3-yl)-6-phenylnicotinonitrile 6aa was generated in
2 h (monitored by liquid chromatography–mass spectrometry LC-MS) and yielded
1
61% after 6 h. The structure was confirmed by the analysis of H and 13C NMR.
We noticed that after the reaction was completed, the excess AcONH4, which
should be separated out in ethanol along with the product at room temperature,

SYNTHESIS OF 2-(INDOL-3-YL)PYRIDINES
709
Table 2. Synthesis of 4-aryl-6-(1H-indol-3-yl)-2,30-bipyridine-5-carbonitriles in the presence of iodine
without solvent.a
Entry
R
t (h)
Product
Yield (%)b
1
2
3
4
5
4-Cl (2a)
4-Br (2b)
6
6
4a
4b
4c
4d
4f
76
78
69
51
50
4-MeO (2c)
4-N(Me)2 (2d)
H (2f)
10
12
8
aReaction conditions: 3-(cyanoacetyl)indole 1 (1 mmol), aromatic aldehyde 2 (1 mmol), 3-acetylpyridine
3 (1 mmol), AcONH4 (1.5 g), iodine (0.1 mmol), 120 ꢀC, neat.
bIsolated yield.
cDetected by LC-MS.
disappeared. Instead, AcOH appeared in the reaction mixture. We surmised that
AcOH, decomposed from AcONH4, pushed the reactions forward. Thereafter, a
similar reaction, wherein 1.5 equiv of AcONH4 was added while AcOH (1 ml) was
used as solvent, was carried out in the absence of iodine under refluxing condition;
the transformation was completed in 10 h with several unknown products detected
by LC-MS, and product 6aa was yielded in 55%. Adding 10 mol% of iodine to this
reaction resulted in greater yield of 6aa (73%) in slightly shorter reaction time (5 h),
which was even more efficient than method A (Table 3, entry 1). Unequivocally, the
reaction was efficiently catalyzed by iodine with enhanced selectivity and speed.
Therefore, the combination of 3-(cynonoacetyl)indole 1, aromatic aldehydes 2, aro-
matic ketones 5, and AcONH4 (1.5 equiv) could be conducted in refluxing AcOH
presence of 10 mol% of iodine (method B).
The scope and limitation of the newly explored protocol was probed with
respect to the variation in the aldehyde and acetophenone. As illustrated in
Table 3, all of the selected aldehydes and acetophenones were smoothly transformed
into the corresponding products in moderate to good yields, while the sterically
Scheme 1. Acetophenone participated four-component condensation under condition of Method A.

710
L.-Y. ZENG AND C. CAI
Table 3. Synthesis of 4-aryl-2-(1H-indol-3-yl)-6-arylnicotinonitriles in the presence of iodine under the
conditions of both method A and method B
t (h)
B (A)
Yield (%)a
B (A)b
Entry
R1
R2
Product
1
2
3
4
4-Cl (2a)
4-Br (2b)
H (5a)
5 (6)
4 (4.5)
6aa
6ba
6ca
6da
73 (61)
84 (78)
74
H
H
H
4-MeO (2c)
4-N(Me)2 (2d)
6
6
9 (10)
11
39
51 (53)
43
71
5
6
2-Cl (2g)
H (2f)
H (2f)
H
6ga
6fa
6fb
6ab
6cb
6fc
H
6
3 (5)
7
4-Cl (5b)
4-Cl
4-Cl
79 (70)
87 (85)
81
8
4-Cl (2a)
4-MeO (2c)
H (2f)
1 (1.5)
9
6
6
6
6
10
11
12
4-MeO (5c)
4-MeO
4-MeO
65
77
4-Cl (2a)
4-MeO (2c)
6ac
6cc
45
aIsolated yield.
bReaction conditions: Method A: 3-(cyanoacetyl)indole 1 (1 mmol), aromatic aldehyde 2 (1 mmol), aro-
matic ketone 5 (1 mmol), AcONH4 (1.5 g), iodine (0.1 mmol), 120 ꢀC, neat; Method B: 3-(cyanoacetyl)in-
dole 1 (1 mmol), aromatic aldehyde 2 (1 mmol), aromatic ketone 5 (1 mmol), AcONH4 (1.5 mmol), iodine
(0.1 mmol), AcOH (1.5 ml), refluxing temperature.
hindering 2-chlorobenzaldhyde delivered a slightly lower yield of 43%. Although a
complicated electronic effect was observed, mostly the electron-deficient aromatic
aldehydes or acetophenones were transformed into the corresponding products with
greater yield in a shorter time. Especially in the case of 4-chlorobenzaldehyde and
4-chloroacetophenone (entry 8, Table 3), yellow floccule was formed quickly after
refluxing the starting materials in AcOH for 30 min, and the reaction mixture was
solidified in 1 h with 87% yield of the corresponding product. Comparably, the
electron-rich ones such as 4-(dimethylamino)benzaldehyde (entry 4, Table 3),
4-methoxybenzaldehyde, and 1-(4-methoxyphenyl)ethanone (entry 9, Table 3) led
to somewhat lower yields. Besides, method B apparently behaved better than method
A in terms of the yields and the reaction time, which revealed that the pre-addition of
AcOH is favored.
To further test the effectiveness of this catalytic system under the conditions of
method B, 2-acetylthiophene 7 was reacted with other components; the results are
outlined in Table 4, wherein the selected aromatic aldehydes have been successfully
transformed to the corresponding products in moderate to good yields.

SYNTHESIS OF 2-(INDOL-3-YL)PYRIDINES
711
Table 4. Synthesis of 4-aryl-2-(1H-indol-3-yl)-6-(thiophen-2-yl)nicotinonitriles in the presence of iodine
under the conditions of method Ba
Entry
R
t (h)
Product
Yield (%)b
1
2
3
4
4-Cl (2a)
4-Br (2b)
4-N(Me)2 (2d)
H (2f)
8
6
8a
8b
8d
8f
73
77
59
73
8
10
aReaction conditions: 3-(cyanoacetyl)indole 1 (1 mmol), aromatic aldehyde 2 (1 mmol), 1-(thiophen-2-
yl)ethanonene 7 (1 mmol), AcONH4 (1.5 mmol), iodine (0.1 mmol), AcOH (1.5 ml), refluxing temperature.
bIsolated yield.
In summary, we have successfully designed a versatile strategy for the prep-
aration of star-shaped 2-(indol-3-yl)pyridines via four-component combination of
3-(cynonoacetyl)indole 1, aromatic aldehyde 2, aromatic ketone, and AcONH4 in
a one-pot fashion. Iodine, as an inexpensive, nontoxic, and easily available catalyst,
has effectively promoted the formation of 4-aryl-6-(1H-indol-3-yl)-2,30-bipyridine-
5-carbonitriles 4 under the conditions of method A. With the help of AcOH, method
B was also developed to construct a new series of 4-aryl-2-(1H-indol-3-yl)-6-arylni-
cotinonitriles 6, and 4-aryl-2-(1H-indol-3-yl)-6-(thiophen-2-yl)nicotinonitriles 8 were
obtained in the same way. The present methodology has addressed the current trend
toward green chemistry because of its atom economy and fewer reagents. The series
of these star-shaped pyridines has potential for biological screening.
EXPERIMENTAL
The starting material 3-(cynonoacetyl)indole was prepared according to the
literature;[23] other commercially available compounds were used without further
purification. All melting points are uncorrected. Mass spectra were taken on an Agi-
lent LC-MS 1100 series instrument in the electrospray ionization (positive ESI)
1
mode. H and 13C NMR spectra were recorded at 300 or 500 MHz and 75 MHz,
respectively, in dimethyl sulfoxide (DMSO-d6) or CDCl3, and chemical shifts were
reported in parts per million (ppm) from internal tetramethylsilane (TMS) (d). Infra-
red (IR) spectra were recorded on a Shimadzu spectrophotometer using KBr optics.
Elemental analyses were performed on a Yanagimoto MT3CHN recorder. The
1
structures of all the products were confirmed by H NMR and mass spectroscopy.
1
New compounds 4b, 4d, 6aa–6cc, and 8d were characterized by H and 13C NMR
spectra, mass spectroscopy, and elemental analysis.

712
L.-Y. ZENG AND C. CAI
Typical Procedure for the Synthesis of 4-Aryl-6-(1H-indol-
3-yl)-2,3’-bipyridine-5-carbonitriles 4 (Method A)
The mixture of 3-(cyanoacetyl)indole 1 (1 mmol, 0.185 g), aromatic aldehyde 2
(1 mmol), 3-acetylpyridine 3 (1 mmol, 0.120 g), AcONH4 (1.5 g), and iodine
(0.1 mmol, 0.026 g) were stirred after the temperature was increased to 120 ꢀC. Sev-
eral hours later (Table 2), the mixture was poured into hot ethanol directly, from
which the yellow floccule was precipitated out gradually at room temperature. The
solid (yellow floccule) was filtered off and dried in a vacuum to give the pure
product 4.
Typical Procedure for the Synthesis of 4-Aryl-2-(1H-indol-3-yl)-6-
arylnicotinonitriles 6 (Method B)
AcOH (1.5 ml) was added to the mixture containing 3-(cyanoacetyl)indole 1
(1 mmol, 0.185 g), aromatic aldehyde 2 (1 mmol), aromatic ketone 5 (1 mmol),
AcONH4 (1.5 mmol), and iodine (0.1 mmol, 0.026 g). The starting materials were
heated to refluxing temperature and stirred until a massive insoluble substance
appeared. After the transformation was completed according to the analysis of
LC-MS (every 1 h), the mixture was poured into the sodium thiosulfate solution
(30 ml), and the solid precipitated was filtered and collected for further recrystalliza-
tion in ethanol to afford the pure product 6.
Typical Procedure for the Synthesis of 4-Aryl-2-(1H-indol-3-yl)-6-
(thiophen-2-yl)nicotinonitriles 8 (Method B)
AcOH (1.5 ml) was added to the mixture containing 3-(cyanoacetyl)indole 1
(1 mmol, 0.185 g), aromatic aldehyde 2 (1 mmol), 1-(thiophen-2-yl)ethanonene 7
(1 mmol, 0.126 g), AcONH4 (1.5 mmol), and iodine (0.1 mmol, 0.026 g). The starting
materials were heated to refluxing temperature and stirred. After several hours
(Table 4), the mixture was treated in the same way as compounds 6, and the pure
products were obtained after recrystallization from ethanol.
Spectra Data for 4a–c, 8a, and 8f and New Compounds 4b, 4d, 6aa–
6cc, and 8d
Compound 4a. Yellow floc., mp: 277–280 ꢀC, ESI-MS (m=z) ¼ 407 [M þ 1].
IR (KBr): 3359, 2366, 2347, 2215, 1595, 1570, 1528, 1491, 1437, 1359, 1089, 1014,
1
815, 799, 699 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.89 (s, NH, 1 H), 9.50
(s, J ¼ 4.8 Hz, ArH, 1 H), 8.76 (d, J ¼ 8.2 Hz, ArH, 1 H), 8.68 (d, ArH, 1 H),
8.43–8.49 (m, ArH, 2 H), 8.06 (s, ArH, 1 H), 7.91 (d, J ¼ 8.4 Hz, ArH, 2 H), 7.65
(d, J ¼ 8.4 Hz, ArH, 2 H), 7.59–7.63 (m, ArH, 1 H), 7.52 (d, J ¼ 8.2 Hz, ArH, 1
H), 7.23–7.31 (m, ArH, 2 H).
Compound 4b. Yellow floc., mp: 256–258 ꢀC, ESI-MS (m=z) ¼ 426 [M þ 1].
IR (KBr): 3393, 3174, 2362, 2346, 2214, 1591, 1570, 1529, 1490, 1457, 1433, 1363,
1
1217, 1071, 1011, 813, 795, 702 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.91
(s, NH, 1 H), 9.52 (s, ArH, 1 H), 8.75 (d, J ¼ 4.8 Hz, ArH, 1 H), 8.69 (d, J ¼ 8.1 Hz,

SYNTHESIS OF 2-(INDOL-3-YL)PYRIDINES
713
Hz, ArH, 1 H), 8.37–8.41 (m, ArH, 2 H), 8.11 (s, ArH, 1 H), 7.80–7.87 (m, ArH, 4
H), 7.64 (d, J ¼ 4.7 Hz, ArH, 1 H), 7.56 (d, J ¼ 6.6 Hz, ArH, 1 H), 7.24–7.27 (m,
ArH, 2 H). 13C NMR (75 MHz, CDCl3): d ¼ 157.42, 156.33, 154.04, 151.51,
147.98, 136.22, 135.78, 134.34, 133.66, 130.88, 128.78, 128.21, 125.91, 124.24,
122.63, 121.31, 120.97, 118.56, 116.77, 112.56, 111.96, 104.33, 101.78. Anal. calcd.
for C25H15BrN4: C, 66.53; H, 3.35; N, 12.41. Found: C, 66.59; H, 3.41; N, 12.33.
Compound 4c. Yellow floc., mp: 234–235 ꢀC, ESI-MS (m=z) ¼ 402 [M þ 1].
IR (KBr): 3350, 3162, 2980, 2904, 2832, 2213, 1608, 1582, 1540, 1513, 1249, 1180,
1
1026, 812, 738, 670 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.86 (s, NH, 1 H),
9.49 (s, ArH, 1 H), 8.68–8.73 (m, ArH, 2 H), 8.36–8.39 (m, ArH, 2 H), 8.03 (d,
J ¼ 4.6 Hz, ArH, 1 H), 7.79–7.82 (m, ArH, 2 H), 7.53–7.61 (m, ArH, 2 H),
7.15–7.24 (m, ArH, 4 H).
Compound 4d. Brown floc., mp: 218–220 ꢀC, ESI-MS (m=z) ¼ 416 [M þ 1].
IR (KBr): 3345, 3179, 3163, 2921, 2674, 2209, 1611, 1587, 1560, 1527, 1506, 1431,
1387, 1375, 1324, 1236, 1175, 1140, 1063, 1010, 883, 868, 817, 783, 747, 722,
1
651 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.86 (s, NH, 1 H), 9.50 (s, ArH,
1 H), 8.65–8.74 (m, ArH, 2 H), 8.34–8.40 (m, ArH, 2 H), 7.99 (s, ArH, 1 H), 7.75
(d, J ¼ 8.7 Hz, ArH, 2 H), 7.54–7.64 (m, ArH, 2 H), 7.23–7.25 (m, ArH, 2 H),
6.89 (d, J ¼ 8.7 Hz, ArH, 2 H), 3.03 (s, NMe2, 6H). 13C NMR (75 MHz, CDCl3):
d ¼ 159.38, 153.68, 153.27, 137.10, 136.86, 134.57, 133.81, 131.02, 126.90, 126.06,
123.69, 122.63, 122.47, 121.98, 120.51, 119.66, 114.53, 112.80, 112.13, 102.58,
40.01. Anal. calcd. for C27H21N5: C, 78.05; H, 5.09; N, 16.86. Found: C, 78.01; H,
5.13; N, 16.78.
Compound 6aa. Yellow floc., mp: 242–244 ꢀC, ESI-MS (m=z) ¼ 406 [M þ 1].
IR (KBr): 3319, 3056, 2360, 2342, 2220, 1596, 1580, 1569, 1534, 1490, 1367, 1215,
1144, 1097, 1089, 1014, 876, 831, 796, 773, 749, 693, 668 cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6): d ¼ 11.90 (s, NH, 1 H), 8.36–8.44 (m, ArH, 4 H), 8.00 (s,
ArH, 1 H), 7.88 (d, J ¼ 8.4 Hz, ArH, 2 H), 7.71 (d, J ¼ 8.4 Hz, ArH, 2 H),
7.57–7.65 (m, ArH, 4 H), 7.23–7.31 (m, ArH, 2 H). 13C NMR (75 MHz, CDCl3):
d ¼ 158.38, 157.38, 153.78, 137.58, 136.42, 135.67, 134.71, 130.73, 130.49, 130.33,
128.91, 128.67, 128.61, 127.43, 126.09, 122.31, 121.38, 120.71, 118.59, 116.36,
116.24, 113.06, 112.02, 101.29. Anal. calcd. for C26H16N3Cl: C, 76.94; H, 3.97; N,
10.35. Found: C, 76.90; H, 3.89; N, 10.41.
Compound 6ba. Yellow floc., mp: 222–226 ꢀC, ESI-MS (m=z) ¼ 450 [M þ 1].
IR (KBr): 3323, 3054, 2360, 2331, 2220, 1590, 1578, 1565, 1534, 1488, 1457, 1437,
1
1368, 1214, 1144, 1071, 1011, 875, 829, 793, 773, 747, 692, 668 cmꢁ1. H NMR
(300 MHz, DMSO-d6): d ¼ 11.87 (s, NH, 1 H), 8.35–8.41 (m, ArH, 4 H), 7.99 (s,
ArH, 1 H), 7.77–7.85 (m, ArH, 4 H), 7.56–7.62 (m, ArH, 4 H), 7.22–7.28 (m,
ArH, 2 H). 13C NMR (75 MHz, DMSO-d6): d ¼ 158.40, 157.38, 153.83, 137.56,
136.41, 131.61, 131.11, 130.96, 130.33, 129.36, 128.91, 128.60, 127.43, 126.08,
123.35, 122.30, 122.14, 121.37, 120.70, 118.57, 116.17, 113.05, 112.01, 101.21. Anal.
calcd. for C26H16N3Br: C, 69.34; H, 3.58; N, 9.33. Found: C, 69.28; H, 3.51; N, 9.46.
Compound 6ca. Yellow floc., mp: 236–238 ꢀC, ESI-MS (m=z) ¼ 402 [M þ 1].
IR (KBr): 3302, 3054, 2360, 2331, 2219, 1608, 1583, 1568, 1540, 1528, 1512, 1491,

714
L.-Y. ZENG AND C. CAI
1458, 1437, 1369, 1259, 1216, 1176, 1138, 1030, 837, 776, 769, 749, 695, 668 cmꢁ1. 1H
NMR (300 MHz, DMSO-d6): d ¼ 11.84 (s, NH, 1 H), 8.40 (d, J ¼ 4.5 Hz, ArH, 2 H),
8.34 (d, J ¼ 4.2 Hz, ArH, 2 H), 7.93 (s, ArH, 1 H), 7.81 (d, J ¼ 5.1 Hz, ArH, 2 H),
7.55–7.62 (m, ArH, 4 H), 7.22–7.30 (m, ArH, 3H), 7.12–7.18 (dd, J ¼ 5.1 Hz,
5.1 Hz, ArH, 2H), 3.87 (s, NMe2, 3 H). 13C NMR (75 MHz, DMSO-d6): 160.51,
158.07, 157.44, 154.62, 137.66, 136.33, 130.43, 130.24, 128.91, 128.60, 127.38,
126.09, 122.27, 121.36, 120.68, 119.14, 116.13, 114.12, 113.05, 112.02, 101.18,
55.32. Anal. calcd. for C27H19N3O: C, 80.78; H, 4.77; N, 10.47. Found: C, 80.62;
H, 4.71; N, 10.56.
Compound 6da. Yellow floc., mp: 200–204 ꢀC, ESI-MS (m=z) ¼ 415 [M þ 1].
IR (KBr): 3311, 3061, 2809, 2220, 1610, 1570, 1558, 1520, 1490, 1434, 1370, 1364,
1
1215, 1203, 1169, 1140, 1118, 1010, 988, 822, 773, 768, 746, 693, 670 cmꢁ1. H
NMR (300 MHz, DMSO-d6): d ¼ 11.82 (s, NH, 1 H), 8.38 (d, J ¼ 4.8 Hz, ArH, 2
H), 8.33 (d, J ¼ 4.5 Hz, ArH, 2 H), 7.88 (s, ArH, 1 H), 7.73 (d, J ¼ 5.1 Hz, ArH, 2
H), 7.53–7.61 (m, ArH, 4 H), 7.21–7.27 (m, ArH, 2H), 6.89 (d, J ¼ 5.1 Hz, ArH,
2H), 3.02 (s, NMe2, 6H). 13C NMR (75 MHz, DMSO-d6): d ¼ 157.80, 157.61,
155.00, 151.22, 137.85, 136.29, 130.10, 129.90, 128.88, 128.50, 127.31, 126.13,
123.38, 122.19, 121.34, 120.58, 119.60, 115.61, 113.15, 111.97, 111.71, 100.57,
40.33, 40.05. Anal. calcd. for C28H22N4: C, 81.13; H, 5.35; N, 13.52. Found: C,
81.19; H, 5.49; N, 13.61.
Compound 6fa. Yellow floc., mp: 230–232 ꢀC, ESI-MS (m=z) ¼ 372 [M þ 1].
IR (KBr): 3310, 3062, 2220, 1582, 1572, 1536, 1517, 1491, 1437, 1368, 1233, 1213,
1
1138, 1119, 874, 790, 773, 757, 691, 675 cmꢁ1. H NMR (300 MHz, DMSO-d6):
d ¼ 11.86 (s, NH, 1 H), 8.47–8.53 (m, ArH, 2 H), 8.35–8.40 (m, ArH, 2 H), 7.97
(s, ArH, 1 H), 7.83 (d, J ¼ 4.2 Hz, ArH, 2 H), 7.56–7.63 (m, ArH, 6 H), 7.22–7.28
(m, ArH, 2H). 13C NMR (75 MHz, DMSO-d6): d ¼ 158.21, 157.35, 155.03, 137.55,
136.84, 136.33, 130.36, 129.64, 128.96, 128.87, 127.42, 126.05, 122.32, 121.33,
120.73, 118.83, 116.35, 112.97, 112.05, 101.39. Anal. calcd. for C26H17N3: C,
84.07; H, 4.61; N, 11.31. Found: C, 84.12; H, 4.58; N, 11.39.
Compound 6ga. Yellow floc., mp: 240–242 ꢀC, ESI-MS (m=z) ¼ 406 [M þ 1].
IR (KBr): 3397, 3325, 3129, 3056, 2371, 2347, 2215, 1608, 1570, 1560, 1534, 1474,
1457, 1434, 1363, 1319, 1239, 1214, 1138, 1118, 1053, 878, 801, 769, 758, 746, 701,
668 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6): d ¼ 11.86 (s, NH, 1 H), 8.45–8.48
(m, ArH, 1 H), 8.33–8.38 (m, ArH, 3 H), 7.66–7.74 (m, ArH, 2 H), 7.56–7.64 (m,
ArH, 6 H), 7.22–7.30 (m, ArH, 2 H). 13C NMR (75 MHz, DMSO-d6): d ¼ 158.32,
156.65, 153.06, 137.31, 136.38, 135.88, 131.45, 131.13, 131.01, 130.54, 129.65,
129.04, 128.50, 127.55, 127.40, 125.88, 122.43, 121.35, 120.86, 117.85, 116.78,
112.75, 112.13, 102.59. Anal. calcd. for C26H16ClN3: C, 76.94; H, 3.97; N, 10.35.
Found: C, 76.91; H, 3.86; N, 10.33.
Compound 6fb. Yellow floc., mp: 221–222 ꢀC, ESI-MS (m=z) ¼ 406 [M þ 1].
IR (KBr): 3346, 3057, 2217, 1654, 1595, 1569, 1530, 1490, 1457, 1446, 1428, 1364,
1233, 1214, 1135, 1107, 1093, 1014, 837, 785, 765, 746, 699 cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6): d ¼ 11.91 (s, NH, 1 H), 8.36–8.40 (m, ArH, 4 H), 7.99 (s,
ArH, 1 H), 7.81, 7.83 (d, J ¼ 4.5 Hz, ArH, 2 H), 7.56–7.68 (m, ArH, 6 H),
7.21–7.30 (m, ArH, 2 H). 13C NMR (75 MHz, DMSO-d6): d ¼ 157.37, 156.94,

SYNTHESIS OF 2-(INDOL-3-YL)PYRIDINES
715
155.16, 136.71, 136.34, 135.31, 129.68, 129.18, 128.98, 128.89, 128.74, 128.64, 125.99,
122.31, 121.23, 120.76, 118.74, 116.37, 112.84, 112.10, 101.64. Anal. calcd. for
C26H16N3Cl: C, 76.94; H, 3.97; N, 10.35. Found: C, 76.89; H, 3.90; N, 10.41.
Compound 6ab. Yellow floc., mp: 237–240 ꢀC, ESI-MS (m=z) ¼ 440 [M þ 1].
IR (KBr): 3450, 3390, 3062, 2216, 1595, 1577, 1540, 1527, 1489, 1457, 1437, 1363,
1
1233, 1214, 1136, 1109, 1094, 1012, 829, 799, 799, 613 cmꢁ1. H NMR (300 MHz,
DMSO-d6): d ¼ 11.89 (s, NH, 1 H), 8.37–8.39 (m, ArH, 4 H), 8.02 (d, J ¼ 4.2 Hz,
ArH, 1 H), 7.85–7.88 (m, ArH, 2 H), 7.66–7.71 (m, ArH, 4 H), 7.57 (d, J ¼ 7.4 Hz,
Hz, ArH, 1 H), 7.21–7.27 (m, ArH, 2 H). 13C NMR (75 MHz, CDCl3): d ¼ 157.96,
157.88, 155.86, 137.30, 136.73, 136.65, 136.40, 129.77, 129.53, 129.24, 128.92,
128.87, 128.63, 127.65, 126.62, 123.34, 122.39, 121.65, 118.86, 116.38, 114.77,
111.45, 102.31. Anal. calcd. for C26H15N3Cl2: C, 70.92; H, 3.43; N, 9.54. Found:
C, 70.89; H, 3.59; N, 9.51.
Compound 6cb. Yellow floc., mp: 216–218 ꢀC, ESI-MS (m=z) ¼ 436 [M þ 1].
IR (KBr): 3329, 3062, 2838, 2218, 1609, 1577, 1570, 1537, 1509, 1491, 1458, 1437,
1369, 1298, 1252, 1215, 1134, 1111, 1091, 1031, 1012, 838, 825, 771, 740, 680 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6): d ¼ 11.87 (s, NH, 1 H), 8.34–8.39 (m, ArH, 4 H),
7.96 (d, J ¼ 1.9 Hz, ArH, 1 H), 7.80–7.82 (m, ArH, 2 H), 7.65–7.68 (m, ArH, 2 H),
7.56 (d, J ¼ 7.1 Hz, ArH, 1 H), 7.19–7.26 (m, ArH, 2 H), 7.16–7.19 (m, ArH, 2 H),
3.88 (s, Me, 3 H). 13C NMR (75 MHz, DMSO-d6): d ¼ 160.98, 157.89, 157.21,
155.18, 136.85, 136.69, 135.64, 130.91, 129.57, 129.38, 129.20, 126.42, 122.70,
121.65, 121.16, 119.49, 116.59, 114.53, 113.30, 112.49, 101.86, 55.76. Anal. calcd.
for C27H18ON3Cl: C, 74.39; H, 4.16; N, 9.64. Found: C, 74.45; H, 4.21; N, 9.63.
Compound 6fc. Yellow floc., mp: 238–244 ꢀC, ESI-MS (m=z) ¼ 402 [M þ 1].
IR (KBr): 3385, 3053, 2997, 2834, 2213, 1610, 1581, 1571, 1529, 1516, 1491, 1458,
1435, 1373, 1239, 1217, 1169, 1137, 1119, 1031, 1007, 873, 832, 767, 744, 700,
1
613 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.84 (s, NH, 1 H), 8.33–8.49 (m,
ArH, 4 H), 7.94 (s, ArH, 1 H), 7.81 (d, J ¼ 4.2 Hz, ArH, 2 H), 7.61 (d, J ¼ 4.2 Hz,
ArH, 2 H), 7.56 (d, J ¼ 4.5 Hz, ArH, 1 H), 7.23–7.28 (m, ArH, 2 H), 7.11–7.16
(m, ArH, 2 H), 3.93 (s, Me, 3 H). 13C NMR (75 MHz, DMSO-d6): d ¼ 161.66,
158.31, 157.68, 155.24, 137.38, 136.72, 130.30, 130.00, 129.46, 129.27, 129.08,
126.46, 122.72, 121.68, 121.12, 119.43, 115.87, 114.81, 113.45, 112.46, 100.90,
55.76. Anal. calcd. for C27H19ON3: C, 80.78; H, 4.77; N, 10.47. Found: C, 80.76;
H, 4.83; N, 10.43.
Compound 6ac. Yellow floc., mp: 191–194 ꢀC, ESI-MS (m=z) ¼ 436 [M þ 1].
IR (KBr): 3489, 3356, 3310, 2968, 2219, 1606, 1595, 1575, 1536, 1525, 1514, 1490,
1456, 1438, 1369, 1261, 1242, 1214, 1170, 1142, 1089, 1028, 1014, 835, 798, 782,
1
743 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.96 (s, NH, 1 H), 8.32–8.40 (m,
ArH, 4 H), 7.91 (s, ArH, 1 H), 7.85 (d, J ¼ 8.4 Hz, ArH, 2 H), 7.69 (d, J ¼ 8.3 Hz,
ArH, 2 H), 7.56 (d, J ¼ 7.1 Hz, ArH, 1 H), 7.21–7.25 (m, ArH, 2 H), 7.15 (d,
J ¼ 8.6 Hz, ArH, 2 H), 3.87 (s, Me, 3 H). 13C NMR (75 MHz, DMSO-d6):
d ¼ 161.28, 157.96, 157.25, 153.50, 136.35, 135.74, 134.59, 130.74, 129.82, 129.03,
128.88, 128.64, 128.59, 128.23, 126.05, 122.28, 121.30, 120.69, 118.87, 115.28,
114.35, 113.99, 113.02, 112.08, 100.27, 55.30. Anal. calcd. for C27H18ON3Cl: C,
74.39; H, 4.16; N, 9.64. Found: C, 74.41; H, 4.19; N, 9.66.

716
L.-Y. ZENG AND C. CAI
Compound 6cc. Yellow floc., mp: 168–170 ꢀC, ESI-MS (m=z) ¼ 432 [M þ 1].
IR (KBr): 3255, 3118, 3056, 2836, 2197, 1624, 1607, 1581, 1510, 1457, 1420, 1296,
1251, 1236, 1216, 1179, 1150, 1111, 1031, 917, 833, 744, 642 cmꢁ1 1H NMR
.
(300 MHz, DMSO-d6): d ¼ 11.92 (s, NH, 1 H), 8.31–8.39 (m, ArH, 4 H), 7.87 (s,
ArH, 1 H), 7.79 (d, J ¼ 8.5 Hz, ArH, 2 H), 7.56 (d, J ¼ 7.0 Hz, ArH, 1 H),
7.18–7.26 (m, ArH, 2 H), 7.13–7.18 (m, ArH, 4 H), 3.87 (d, J ¼ 2.1 Hz, Me, 5 H).
13C NMR (75 MHz, DMSO-d6): d ¼ 161.60, 160.87, 158.17, 157.77, 154.85, 136.66,
130.84, 130.41, 129.42, 128.88, 126.47, 122.66, 121.67, 121.05, 119.71, 115.66,
114.78, 114.52, 113.48, 112.44, 100.74, 56.39, 55.76. Anal. calcd. for C28H21O2N3:
C, 77.94; H, 4.91; N, 9.74. Found: C, 77.91; H, 4.83; N, 9.79.
Compound 8a. Yellow floc., mp:> 260 ꢀC, ESI-MS (m=z) ¼ 412 [M þ 1]. IR
(KBr): 3320, 3051, 2364, 2213, 1595, 1578, 1570, 1541, 1490, 1433, 1400, 1369,
1
1236, 1219, 1143, 1013, 829, 744 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.90
(s, NH, 1 H), 8.57 (s, ArH, 1 H), 8.44 (s, ArH, 1 H), 8.16 (d, J ¼ 3.2 Hz, ArH,
1H), 7.97 (s, ArH, 1 H), 7.89 (d, J ¼ 4.1 Hz, ArH, 1 H), 7.81–7.84 (m, ArH, 2 H),
7.69–7.72 (m, ArH, 2 H), 7.56 (s, ArH, 1 H), 7.26–7.31 (m, ArH, 3 H).
Compound 8d. Yellow floc., mp: 219–220 ꢀC, ESI-MS (m=z) ¼ 421 [M þ 1].
IR (KBr): 3430, 3053, 2906, 2361, 2203, 1610, 1576, 1514, 1490, 1437, 1420, 1373,
1
1234, 1199, 1140, 1119, 974, 812, 744, 708 cmꢁ1. H NMR (300 MHz, DMSO-d6):
d ¼ 11.84 (s, NH, 1 H), 8.51 (d, J ¼ 8.8 Hz, ArH, 1 H), 8.41 (s, ArH, 1 H), 8.14 (s,
ArH, 1H), 7.93 (s, ArH, 1 H), 7.84 (d, J ¼ 5.1 Hz, ArH, 1 H), 7.69 (d, J ¼ 4.7 Hz,
ArH, 2 H), 7.55 (d, J ¼ 8.4 Hz, ArH, 1 H), 7.23–7.28 (m, ArH, 3 H), 6.90 (d,
J ¼ 7.6 Hz, ArH, 2 H), 3.03 (s, NMe2, 6 H). 13C NMR (75 MHz, DMSO-d6):
d ¼ 157.66, 155.08, 153.45, 151.43, 144.08, 136.46, 130.80, 130.03, 128.99, 128.54,
128.42, 126.32, 123.42, 122.48, 121.98, 120.81, 119.87, 113.82, 112.79, 112.12,
111.88, 99.68, 40.53, 40.26. Anal. calcd. for C26H20SN4: C, 74.26; H, 4.79; N,
13.32. Found: C, 74.25; H, 4.83; N, 13.41.
Compound 8f. Yellow floc., mp:> 260 ꢀC, ESI-MS (m=z) ¼ 378 [M þ 1]. IR
(KBr): 3306, 3062, 2360, 2219, 1572, 1539, 1525, 1495, 1430, 1369, 1237, 1140,
1
1119, 870, 827, 759, 694 cmꢁ1. H NMR (300 MHz, DMSO-d6): d ¼ 11.87 (s, NH,
1 H), 8.55 (d, J ¼ 4.8 Hz, ArH, 1 H), 8.43 (s, ArH, 1 H), 8.17 (d, J ¼ 2.1 Hz, ArH,
1H), 7.97 (s, ArH, 1 H), 7.88 (d, J ¼ 2.7 Hz, ArH, 1 H), 7.79 (d, J ¼ 3.9 Hz, ArH, 2
H), 7.60–7.64 (m, AH, 3 H), 7.55 (d, J ¼ 4.2 Hz, ArH, 1 H), 7.21–7.29 (m, ArH, 3 H).
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