Ruthenium(II)-catalyzed direct addition of indole/pyrrole C2-H bonds to alkynes

Article abstract of DOI:10.1021/jo501460h

A ruthenium-catalyzed C2-hydroindolation of alkynes has been achieved. This protocol provides a rapid and concise access to kinds of 2-alkenyl-substituted N-(2-pyridyl)-indoles in which the pyridyl moiety can be easily removed to afford free (N-H) indoles under mild conditions. Various arenes and alkynes, including electron-deficient and electron-rich internal alkynes and terminal alkynes, allow for this transformation. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501460h

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Article
Ruthenium(II)-Catalyzed Direct Addition
of Indole/Pyrrole C2-H Bonds to Alkynes
Libo Liang, Shaomin Fu, Dongen Lin, Xiao-Qi Zhang, Yuanfu Deng, Huanfeng Jiang, and Wei Zeng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501460h • Publication Date (Web): 24 Sep 2014
Downloaded from http://pubs.acs.org on October 2, 2014
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Ruthenium(II)-Catalyzed Direct Addition of Indole/Pyrrole C2-
H Bonds to Alkynes
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Libo Liang,a,† Shaomin Fu,a,† Dongen Lin, a Xiao-Qi Zhang,b Yuanfu Deng, a Huanfeng Jiang, a
and Wei Zeng*, a
a School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510641, China
b College of Pharmacy, Jinan University, Guangzhou 510632, P. R. China
zengwei@scut.edu.cn (W. Zeng.).
ABSTRACT: A ruthenium-catalyzed C2-hydroindolation of alkynes has been achieved. This protocol provides a rapid and
concise access to kinds of 2-alkenyl substituted N-(2-pyridyl)indoles in which the pyridyl moiety can be easily removed to afford
free (N-H) indoles under mild conditions. Various arenes and alkynes including electron-deficient and electron-rich internal
alkynes and terminal alkynes allow for this transformation.
INTRODUCTION
Transition-metal catalyzed addition of aryl C-H bonds to alkynes belongs to a synthetically important C-C bond forming reac-
tion, 1 as this approach provides an atom- and step -economic strategy for constructing various alkenyl aromatic compounds
directly from inactivated simple arenes instead of the conventional aryl halides or arylmetallic reagents. 2 Of these processes,
hydroarylation of alkynes through chelation assistance has lately attracted increasing interest because it allows site-selectively
installing alkenyl group into aromatic molecules. 3 For example, Ackermann, 4 Chang, 5 Yoshikai 6 and Hiyama/Nakao 7 groups,
etc., have revealed that transition-metal catalysts could effectively enhance addition of phenyl C-H 4-6 or pyridine C-H7 bonds to
alkynes with the aid of heteroatom-containing groups, but there are rare reported cases involved in hydroindolation of alkynes
3a, 3d
via C-H functionalization,
despite alkenyl-substituted indole nucleus can be found in natural products and complex
biologically active molecules. 8
Remarkably, comparison with C2- position of indole, C3-position is an inherently nucleophilic reactive site, therefore Lewis
9
acids could easily realize the additions of indole C3-H bonds to alkynes via Friedel-Craft–type process. Nevertheless,
heteroatom directed ortho-metelation reaction provides concise access to site-selective indole C2-H functionalization, 10 but
there are very rare examples about C2-hydroindolation of alkynes. To date, the pioneering reports by Schipper, Yoshikai and
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Kanai group described that Rh(III) (5 mol %) catalysts, 11 Co(II) (10 mol %)/Grignard reagent (0.60 equiv) catalytical system 12 or
3
4
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Co(III) (5 mol %) catalyst
could enable effective intermolecular C2-hydroindolation of alkynes, in which N, N-
5
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7
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dimethylcarbonyl or pyrimidyl group was employed as a directing group, respectively. Unfortunately, these protocols only allow
the use of electron-rich internal alkynes or aryl substituted terminal alkynes. Herein we demonstrated a valuable complementary
approach to C2-hydroindolation of alkynes using ruthenium salts as catalyst, and the substrate scope could be further extended
to electron-poor internal alkynes and acyl- or alkyl-substituted terminal alkynes.
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RESULTS AND DISCUSSION
Initially, we investigated the effect of various Ru catalyst (5 mol %) on the addition of N-(2-pyridyl)indole (1a) C2-H to
diphenylacetylene (2a) in the presence of AgSbF6 (20 mol %) and PivOH (1.0 equiv) using 1, 4-dioxane as solvent at 110 oC for 24
h (Table 1, entries 1-5), and we soon found the dimeric species [RuCl2(p-cymene)]2 provided 54% yield of the desired alkenylation
product 3a, whose structure was already unambiguously assigned by its single crystal X-ray analysis [see Supporting Information
(SI) for more details] (compare entries 1-4 with 5). Subsequently, further improvement of the reaction (83% yield of 3a) was
achieved when AgBF4 and AcOH was employed as an additive and a proton source, respectively (compare entries 5-9 with 10). It
is worth noting that only trace of 3a could be observed in the absence of AgBF4 (compare entry 10 with 11). 14 To our delight, after
various solvents including toluene, acetonitrile and 1, 2-dichloroethane (DCE) were evaluated for this transformation, the yield
of product 3a was significantly increased to 97% using 7 mol % of [RuCl2(p-cymene)]2 in toluene (compare entries 10, 12 with 13).
Most importantly, the similar yield (98% yield of 3a) could also be obtained in DMF solvent system even no silver salt additives
were employed (compare entry 13 with 14). By the way, when DMF was used as solvent and the spots on the TLC plate of the
reaction mixture looks very clean. On the contrary, alternative solvents afforded poorer results in the absence of silver additives
(entries 15 and 16).
Table 1. Optimization of the Reaction Parameters a
H
Ph
Ru catalyst
Ph
proton source
+
N
Ph
N
solvent, Ar
o
N
110 C, 24 h
N
Ph
2a
1a
3a
Ru salts
(5 mol %)
additive
(20 mol %)
proton
source
yield
(%) b
entry
solvent
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
1
RuCl3
AgSbF6
PivOH
nr c
2
3
4
5
Ru3(CO)12 AgSbF6
PivOH
PivOH
PivOH
PivOH
trace
nr c
A d
B e
C f
AgSbF6
AgSbF6
AgSbF6
c
nr
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1,
dioxane
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
1, 4-
dioxane
4-
C
C
C
C
C
C
6
AgOAc
AgPF6
AgBF4
AgBF4
AgBF4
__
PivOH
PivOH
PivOH
73
40
75
7
8
9
i-PrOH 19
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10
11
AcOH
AcOH
AcOH
83
trace
94 g
C
C
12
AgBF4
13
14
15
AgBF4
__
toluene AcOH
DMF AcOH
CH3CN AcOH
DCE AcOH
97g
98 g
73 g
C
C
__
16
__
62 g, h
C
a Unless otherwise noted, all the reactions were carried out using
N-(2-pyridyl)indole (1a) (0.10 mmol) and alkyne (2a) (0.10 mmol)
with Ru catalyst (5 mol %) in the presence of additive (20 mol %)
and proton source (1.0 equiv) in 1, 4-dioxane (2.0 mL) at 110 ˚C
for 24 h under Ar in a sealed reaction tube, followed by flash
chromatography on SiO2. b Isolated yield. c nr = no reaction. d A =
e
f
RuH2(CO)(PPh3)2;
B = RuHCl(CO)(PPh3)3; C = [RuCl2(p-
cymene)]2; 7 mol % of catalyst C was used; h DCE = 1, 2-
g
dichloroethane.
With an optimized catalytic system in hand, we first investigated the reactivity of various N-(2-pyridyl)indole derivatives. As
shown in Table 2, all of 5- or 6- or 7- substituted indole substrates exhibited excellent reactivity with exclusive E-stereochemistry,
no matter whether electronic-withdrawing (such as 5-CN, 5-NO2, 5-CO2Et, 5- halide, 6-halide, etc) or electron-donating groups
(such as 5-MeO, and 7-Me, etc) are introduced to the benzene ring. For example, the C2-hydroindolation of diphenylacetylene
(2a) with 5-ethoxycarbonyl-N-(2-pyridyl) indole (1h) and 7-methyl-N-(2-pyridyl)indole (1k) could afford the desired alkenylation
product 3f and 3k in 91% and 94% yield, respectively (entries 8 and 11). On the contrary, the substituted group (R2) at C3-
position of indole showed significantly electronic effects, the substrate (1l) with electron-donating group (3-Me) on the indole
ring produced 96% yield of 3l. However, 3-acetyl-N-(2-pyridyl) indole (1m) underwent obviously worse conversion and provided
lower yield of 3m (25%, entries 12 and 13). Moreover, this reaction protocol could also smoothly convert N-(2-pyridyl)pyrrole (1n)
to the corresponding 2, 5-bis-alkenylation pyrrole derivative 3n (40% yield) and 2-alkenylation pyrrole product 3o (52% yield)
possibly due to a double migratory insertion of alkyne 2a into Ru(II) intermediate (entries 14), respectively. For the N-(2-
pyrimidyl)indole (1o), the desired 2-alkenylation derivatives 3p could also be obtained in 83 % yield (entry 15).
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Subsequently, we further investigated the scope of the C2-hydroarylation of N-(2-pyridyl) indole (1a) by employing differently
substituted alkynes. It was found that this transformation tolerated a variety of electron-rich internal alkynes, such as diaryla-
cetylene (2a), aryl alkyl alkyne (2c), aryl hydroxymethyl alkyne (2d), aryl methoxylmethyl internal alkyne (2e), dialkyl alkyne
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(2g), silyl-substituted alkyne (2h), aryl alkenyl alkyne (2j) and aryl alkynyl alkyne (2k), etc., could couple with 1a in good to ex-
cellent yields (entries 17, 18, 19, 21, 22, 24 and 25). It is worth noting that unsymmetric internal alkyne 2c gave two products 3s
and 3t in around 2:1 ratio where the reaction was under steric control (entry 17). In contrast, aryl hydroxymethyl internal
alkyne 2d and aryl methoxylmethyl internal alkyne 2e provided 3u (89% yield) and 3v (83% yield) with high regioselectivity
probably due to the weak coordination between Ru(II) and ether or alcohol oxygen atom (entries 18 and 19). Importantly, this
reaction protocol remarkably tolerated electron-poor internal aryl ethoxycarbonyl alkyne (2f), and gave the desired alkenylation
product 3w in 93% yield (entry 20). Moreover, electron-rich and electron-poor terminal alkynes (2b and 2i) also allowed for this
transformation, and afforded the corresponding 1,1-disubstituted alkene (3q) and 1, 2-disubstituted alkene 3y (54% yield) with
high regioselectivity (entries 16 and 23), which is different from the Ru-catalyzed alkenylation of N, N-dimethylbenzamide with
terminal alkynes. 15 Surprisingly, when hept-1-yne (2l) was applied to this reaction system, the major product was the C2-
alkylation compounds 3zb and 3zc (3zb/3zc = 6.7) which were possibly derived from the C2-alkenylation indole intermediates
via a reduction process, in which DMF act as a reducing agent (entry 26). 16 On the contrary, employing toluene as solvent fur-
nished the desired C2-alkenylation products 3zd and 3ze in the overall yield of 86% (entry 27).
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Table 2. Ru(II)-Catalyzed Addition of Indole C2-H Bonds to Al-
kynes
R2
R2
R3
R3
[RuCl2(p-cymene)]2 (7 mol %)
AcOH (1.0 equiv)
DMF, Ar,110 oC, 24 h
R1
R1
R4
+
N
N
R4
N
N
2
1
3
entry
indole 1
alkyne 2
Ph
3, yield (%) b
3a, 98
1
1a, R1 = R2 = H
Ph
2a
2
3
4
5
1b, R1 = 5-MeO, R2 = H
1c, R1 = 5-F, R2 = H
1d, R1 = 5-Cl, R2 = H
1e, R1 = 5-Br, R2 = H
2a
2a
2a
2a
3b, 97
3c, 80
3d, 94
3e, 95
6
1f, R1 = 5-NO2, R2 = H
2a
3f, 74
7
8
9
10
11
12
13
1g, R1 = 5-CN, R2 = H
1h, R1 = 5-CO2Me, R2 = H
1i, R1 = 6-F, R2 = H
2a
2a
2a
2a
2a
2a
2a
3g, 94
3h, 91
3i, 85
3j, 86
3k, 94
3l, 96
3m, 25
1j, R1 = 6-Cl, R2 = H
1k, R1 = 7-Me, R2 = H
1l, R1 = H, R2 = 3-Me
1m, R1 = H, R2 = 3-Ac
Ph
Ph
N
Ph
Ph
N
N
N
14
2a
3n, 40
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Ph
1n
Ph
3
4
5
Ph
N
N
Ph
6
7
3o, 52
Ph
N
N
Ph
8
9
N
N
N
15
16
N
2a
3p, 83
1o
10
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H
H
N
Ph
N
Ph
3q
Ph
1a, R1 = R2 = H
H
N
N
H
2b
3r
3q + 3r = 81 c
(3q /3r = 1:4) d
Et
N
Ph
N
Ph
3s, 62
1a, R1 = R2 = H
Et
17
18
Ph
2c
N
Et
N
3t, 34
Ph
Ph
N
CH2OH
1a, R1 = R2 = H
CH2OH
N
2d
3u, 89
Ph
Ph
N
OMe
1a, R1 = R2 = H
1a, R1 = R2 = H
N
OMe
19
2e
3v, 83
CO Me
2
Ph
N
Ph
CO2Me
N
20
2f
3w, 93
n-Pr
N
n-Pr
n-Pr
N
1a, R1 = R2 = H
n-Pr
21
2g
3x, 95
(E/Z = 4.2:1) e
H
H
N
Ph
N
Ph
3q
3r
Ph
1a, R1 = R2 = H
SiMe
3
22
N
H
2h
N
3q + 3r = 98 c
3q/3r = 1:19 d
CO2Et
H
N
H
O
OEt
N
23
24
1a, R1 = R2 = H
1a, R1 = R2 = H
2i
3y, 54
H
N
Ph
Ph
N
2j
3z, 81
(E/Z = 6.7:1) e
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Ph
2
3
4
5
6
7
8
9
Ph
N
Ph
25
26
1a, R1 = R2 = H
N
Ph
2k
3za, 88
CH3
6
N
N
3zb f
H
CH3
CH3
1a, R1 = R2 = H
4
N
N
CH3
4
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2l
3zc f
3zb + 3zc = 76
3zb/3zc = 6.7:1
Me
4
N
N
3zd g
H
CH3
27
1a, R1 = R2 = H
4
N
Me
4
2l
N
3ze g
3zd + 3ze = 86
3zd/3ze = 2.3:1
a Unless otherwise noted, all the reactions were carried out using N-substituted in-
dole or pyrrole (1) (0.10 mmol) and alkyne (2) (0.20 mmol) with [RuCl2(p-cymene)]2
catalyst (7 mol %) in the presence of AcOH (1.0 equiv) in DMF (2.0 mL) at 110 ˚C for
24 h under Ar in a sealed reaction tube, followed by flash chromatography on SiO2. b
Isolated yield. c the total isolated yield of mixture 3q and 3r. d The ratio of 3q/3r was
determined by 1H NMR spectroscopy. e The ratio of E/Z was determined by 1H NMR
spectroscopy. f When PivOH was used as the source of H atoms, the overall yield of
3zb and 3zc would decrease to 56%. g The solvent (DMF) was changed to toluene.
Finally, we easily removed the pyridyl group on the alkenylation product 3 under CH3OTf/NaOH conditions to provide the
corresponding free (N-H) indole derivative 4, several examples were shown in Table 3 (see SI for more details), which could be
used for further synthetic transformations. 12
Table 3. Several Examples about the Removal of the Pyridine Di-
recting Groupa
R2
R3
R2
R1
R3
1) MeOTf/CH2Cl2, 0 oC-r.t, 24 h
2) NaOH/MeOH, 60 oC, 12 h
R4
R1
N
R4
N
N
H
4
3
entry
N-(2-pyridyl)indole 3
free (N-H) indole 4
yield (%) b
Ph
N
Ph
Ph
N
1
90
82
N
Ph
H
3a
4a
MeO
Ph
N
Ph
MeO
Ph
N
2
N
H
Ph
3b
4b
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Br
Ph
Ph
N
Br
Ph
N
3
86
86
N
Ph
H
5
6
7
8
3e
4c
Me
Ph
Me
N
Ph
Ph
4
N
N
Ph
9
H
3l
4d
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a The CH2Cl2 (7.5 mL) solution of N-(2-pyridyl)indole 3 (0.3 mmol) with MeOTf (0.36
o
mmol) was stirred from 0 C – r.t. for 24 h. After removal of the solvent, aqueous
NaOH (2.0 M, 1.8 mL) and MeOH (3.6 mL) was added to the corresponding mixture,
respectively, and then stirred at 60 ˚C for 12 h under Ar atmosphere, followed by
flash chromatography on SiO2. b Isolated yield.
To further investigate the mechanism, the H/D exchange of 3-methyl-N-(2-pyridyl)indole 1l was conducted in Ru(II)/CD3OD
system for 96 h in absence of alkyne 2a, 95% deuterium incorporation at C2-position was observed (Scheme 1, Eq. 1). Notably, 82%
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(C7-position of indole) and 95% (C6-position of pyridine) deuterium incorporation was also observed (see SI for more details
1
about its H NMR spectra). 17, 18 On the other hand, the content of C2-deuterium in D-1la under Ru(II)/CH3OH system 19 and
Ru(II)/AcOH system could be decreased from 95% to 5% and 18%, respectively (Eq. 2 and Eq. 3) (See SI for more details about
the corresponding 1H NMR spectrum of D-1la, D-1lb and D-1lc). These results clearly demonstrate that the first step of a reversi-
ble Csp2-H bond cleavage process was involved in the transformation. Subsequently, the intermolecular isotope effect (KH/KD
=
0.99) further indicated that the reversible Csp2-H bond breaking was not the rate-limiting step of the reaction (Eq. 4).
Scheme 1. Preliminary Mechanistic Studies
Me
Me
95% deuterium incorporation
H(D)
95% deuterium incorporation
[RuCl2(p-cymene)]2 (7 mol %)
CD3OD (5.0 equiv)
m-xylene, Ar,110 oC, 96 h
without 2a
N
N
(1)
N
H(D)
N
H(D)
D-1la
1l
82% deuterium incorporation
Me
Me
5% deuterium incorporation
H(D)
H(D)
88% deuterium incorporation
[RuCl2(p-cymene)]2 (7 mol %)
CH3OH(6.0 equiv)
m-xylene, Ar,110 oC, 96 h
N
N
(2)
N
H(D)
D-1la
N
H(D)
H(D)
H(D)
without 2a
D-1lb
54% deuterium incorporation
18% deuterium
incorporation
Me
Me
Me
Ph
Ph
[RuCl2(p-cymene)]2 (7 mol %)
AcOH (1.0 equiv)
DMF, Ar,110 oC, 1.5 h
H(D)
H(D)
N
Ph
N
N
+
93% deuterium
incorporation
+
(3)
N
H(D)
H(D)
D-1la
N
N
H(D)
Ph
H(D)
H(D)
H(D)
D-1lc
2a
D-3l (30% yield)
74% deuterium incorporation
Me
Ph
Me
Ph
[RuCl2(p-cymene)]2 (7 mol %)
AcOH (1.0 equiv)
DMF, Ar,110 oC, 1.5 h
H(D)
N
N
Ph
(4)
+
N
H(D)
H(D)
D-1la
N
Ph
KH/KD=0.99
H(D)
H(D)
2a
D-3l
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On the basis of the above observations, we proposed the possible mechanism as Scheme 2. The transformation is initiated by
the coordination of the nitrogen atom from the pyridine ring to cationic ruthenium center, followed by an electrophilic substitu-
tion to produce the five-membered cycloruthenium complexes B with concomitant loss of a proton. 17b, 20 Of course, the possibil-
ity of OAc-assisted deprotonative cyclometalation pathway could also not be ruled out. 4, 21 Subsequently, alkynes (C) insertion
into ruthenium-C2 (indole) bond would lead to alkenyl Ru intermediates D, which would be further protonated to afford
alkenylation product E and regenerated the ruthenium catalyst.
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Scheme 2. The Proposed Catalytic Cycle
4
R
N
3
N
R
Ru(II)
N
A
E
N
H
+
+
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(II)Ru
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Ru(II)
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N
R
B
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N
D
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R
R
C
In summary, we have developed the first ruthenium-catalyzed C2-hydroindolation of alkynes, which provides efficient access
to various alkenylation indoles. 22 This new approach tolerates variety arenes and alkynes, especially for electron-poor internal
alkynes and acyl- or alkyl-substituted terminal alkynes which have not been easily accessible through existing synthetic methods.
11-13 Moreover, the pyridyl moiety could also be easily removed to produce free (N-H) indoles that can be further broadly used in
organic transformations.
EXPERIMENTAL SECTION
General Information. All reactions were carried out in flame-dried sealed tubes with magnetic stirring. Unless otherwise
noted, all experiments were performed under argon atmosphere. Solvents were treated with 4 Å molecular sieves or sodium and
distilled prior to use. Flash chromatography was performed on silica gel (40~63 mm) by standard technique. H and 13C NMR
1
spectra were recorded on a 400 MHz NMR spectrometer (400 MHz for 1 H and 100 MHz for 13 C). Splitting patterns are designat-
ed as singlet (s), doublet (d), triplet (t), quartet (q). Splitting patterns that could not be interpreted or easily visualized are des-
ignated as multiple (m). Low resolution mass spectra were recorded using HPLC Mass Spectrometer. High resolution exact mass
measurements (HR-MS) were performed on a TOF spectrometer. Infrared spectra (IR) were reported as wavelength numbers
(cm-1). Infrared spectra were recorded by preparing a KBr pellet containing the title compound. Crystal data were obtained by
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employing graphite monochromated Mo - Kα radiation (λ = 0.71073 Å) at 293 (2) K and operating in the φ-ω scan mode. The
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structure was solved by direct methods SHELXS-97. Indole substrates including 1-(pyridin-2-yl)-1H-indole (1a) , 5-methoxy-1-
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(pyridin-2-yl)-1H-indole (1b), 23 5-chloro-1-(pyridin-2-yl)-1H-indole (1d), 24 5-bromo-1-(pyridin-2-yl)-1H-indole (1e), 23 1-(pyridin-2-
7
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yl)-1H-indole-5-carbonitrile (1g),
methyl 1-(pyridin-2-yl)-1H-indole-5-carboxylate (1h), 26 7-methyl-1-(pyridin-2-yl)-1H-indole
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(1k), 3-methyl-1-(pyridin-2-yl)-1H-indole (1l), 1-(1-(pyridin-2-yl)-1H-indol-3-yl)ethanone (1m),
2-(1H-pyrrol-1-yl)pyridine
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(1n), 28 and 1-(pyrimidin-2-yl)-1H-indole (1o) 23 were prepared using the previous reported procedure. All the alkyne substrates
are commercially available.
Procedures for the preparation of indole substrates (1c, 1f, 1i and 1j)
Procedure A 23 (Synthesis of 1c and 1f): A mixture of indole starting material (5.0 mmol), 2-bromopyridine (6.0 mmol), KOH
(0.70 g, 12.5 mmol) in DMSO (6 mL) was vigorously stirred at 120 oC under argon atmosphere for 30 h. After cooling the mixture
to ambient temperature, the reaction mixture was diluted with EtOAc (40 mL) and washed with H2O (2 × 30 mL). The aqueous
phase was extracted with EtOAc (3 × 30 mL), and the combined organic phase was dried over Na2SO4. After filtration and evapo-
ration of the solvents in vacuum, the crude product was purified by column chromatography on silica gel (petroleum
ether/EtOAc = 20/1) to give the desired indole derivatives.
5-Fluoro-1-(pyridin-2-yl)-1H-indole (1c): light yellow solid; M. p. = 62−64 °C; 869 mg, 82% yield; 1 H NMR (400 MHz, CDCl3): δ =
8.56-8.55 (m, 1H), 8.23 (dd, J = 9.1 Hz, 4.6 Hz, 1H), 7.83-7.79 (m, 1H), 7.72 (d, J = 3.5 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.29 (dd, J =
9.2 Hz, 2.6 Hz, 1H), 7.16 (ddd, J = 7.3 Hz, 4.9 Hz, 0.7 Hz, 1H), 7.02 (td, J = 9.1 Hz, 2.6 Hz, 1H), 6.66 (d, J = 3.3 Hz, 1H). 13 C NMR (101
MHz, CDCl3): δ = 158.6 (d, J = 236.7 Hz), 152.4, 148.9, 138.5, 131.8, 131.0 (d, J = 10.1 Hz), 127.3, 120.2, 114.5 (d, J = 9.2 Hz), 114.1, 111.2 (d,
J = 25.4 Hz), 106.0 (d, J = 23.4 Hz), 105.4 (d, J = 4.3 Hz). IR (KBr, cm -1): 3057, 1589, 1474, 1343, 1264, 1208, 1145, 741. HRMS (ESI-TOF)
calcd for [M + H]+ C13H10FN2 213.0823, found 213.0825.
5-Nitro-1-(pyridin-2-yl)-1H-indole (1f): yellow solid; M. p. = 88−90 °C; 789 mg, 66% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.63-
8.61 (m, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 9.2 Hz, 1H), 8.18 (dd, J = 9.2 Hz, 2.3 Hz, 1H), 7.90 (td, J = 8.2 Hz, 1.9 Hz, 1H), 7.82
(d, J = 3.5 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.29 (ddd, J = 7.4 Hz, 4.9 Hz, 0.7 Hz, 1H), 6.88 (d, J = 3.2 Hz, 1H). 13 C NMR (101 MHz,
CDCl3): δ = 151.7, 149.1, 142.6, 138.9, 138.0, 129.7, 129.0, 121.4, 118.4, 117.7, 114.8, 113.5, 107.0. IR (KBr, cm -1): 3052, 1586, 1510, 1465, 1343,
1211, 1140, 967, 743. HRMS (ESI-TOF) calcd for [M + H]+ C13H10N3O2 240.0768, found 240.0766.
Procedure B 22 (Synthesis of 1i and 1j): NaH (60% dispersion in mineral oil, 180 mg, 4.5 mmol) was added in portions at 0 oC
o
to a stirred solution of indole starting material (3.0 mmol) in DMF (10 mL). After stirring for 30 min at 0 C, 2-bromopyridine
o
(0.95 g, 6.0 mmol) was added and the mixture was stirred at 110 C for 18 h. After cooling the mixture to ambient temperature,
the reaction mixture was diluted with EtOAc (40 mL) and washed with H2O (2 × 30 mL). The aqueous phase was extracted with
EtOAc (3 × 30 mL), and the combined organic phase was dried over Na2SO4. After filtration and evaporation of the solvents in
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vacuo, the crude product was purified by column chromatography on silica gel (petroleum ether/EtOAc = 20/1) to give the de-
sired indole derivatives.
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6-Fluoro-1-(pyridin-2-yl)-1H-indole (1i): white solid; M. p. = 86−88 °C; 339 mg, 80% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.57-
8.56 (m, 1H), 8.06 (dd, J = 10.8 Hz, 2.1 Hz, 1H), 7.82 (td, J = 8.2 Hz, 1.8 Hz, 1H), 7.66 (d, J = 3.5 Hz, 1H), 7.55 (dd, J = 8.6 Hz, 5.5 Hz,
1H), 7.43 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 7.2 Hz, 5.0 Hz, 1H), 6.97 (td, J = 9.0 Hz, 2.3 Hz, 1H), 6.68 (d, J = 3.5 Hz, 1H). 13 C NMR (101
MHz, CDCl3): δ = 160.5 (d, J = 237.8 Hz), 152.4, 148.9, 138.5, 135.2 (d, J = 12.8 Hz), 126.7, 126.0 (d, J = 3.8 Hz), 121.5 (d, J = 10.1 Hz),
120.2, 114.0, 109.9 (d, J = 24.5 Hz), 105.6, 100.6 (d, J = 28.2 Hz). IR (KBr, cm -1): 3013, 1699, 1591, 1530, 1462, 1346, 1267, 1206, 930, 756.
HRMS (ESI-TOF) calcd for [M + H]+ C13H10FN2 213.0823, found 213.0822.
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6-Chloro-1-(pyridin-2-yl)-1H-indole (1j): white solid; M. p. = 110−112 °C; 393 mg, 86% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.59-
8.57 (m, 1H), 8.33 (m, 1H), 7.83 (td, J = 8.2 Hz, 1.9 Hz, 1H), 7.67 (d, J = 3.5 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 8.2 Hz, 1H),
7.21-7.16 (m, 2H), 6.68 (d, J = 3.3 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ = 152.2, 148.9, 138.6, 135.5, 129.1, 128.9, 126.4, 121.9, 121.7,
120.4, 114.2, 113.7, 105.6. IR (KBr, cm -1): 3057, 1640, 1520, 1445, 1340, 1266, 1203, 1152, 895, 742. HRMS (ESI-TOF) calcd for [M + H]+
C13H10ClN2 229.0527, found 229.0528.
General procedure for the synthesis of the compound 3a-3z, 3za, 3zb, 3zc, 3zd and 3ze
[RuCl2(p-cymene)]2 (0.007 mmol, 7 mol %), AcOH (0.1 mmol, 1.0 equiv), 1-(Pyridin-2-yl)-1H-indole 1a (0.1 mmol, 1.0 equiv), 1,2-
diphenylethyne 2a (0.2 mmol, 2.0 equiv) were dissolved in 2.0 mL of DMF in a tube, and then the tube was sealed under Ar and
heated at 110 °C in an oil bath for 24 h. The reaction progress was monitored by TLC method, after the starting material disap-
peared; the corresponding reaction mixture was then cooled down and removed the solvent in vacuum. The given residue was
purified by column chromatography to give 3a.
(E)-2-(1,2-Diphenylvinyl)-1-(pyridin-2-yl)-1H-indole (3a): white solid; M. p. = 149−151 °C; 35.0 mg, 98% yield; 1 H NMR (400 MHz,
CDCl3): δ = 8.44-8.43 (m, 1H), 7.64-7.62 (m, 1H), 7.55 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.42-7.40 (m, 1H), 7.19-7.02 (m, 14H), 6.92 (s, 1H),
6.75 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 151.9, 149.1, 142.9, 138.7, 138.6, 137.6, 136.8, 134.2, 130.6, 130.2, 129.5, 128.2, 128.0, 127.9,
127.3, 127.0, 123.1, 121.7, 121.5, 121.1, 120.7, 110.9, 107.4. IR (KBr, cm -1) 3057, 1584, 1454, 1355, 1265, 1208, 1148, 744, 701, 552. HRMS (ESI-
TOF) calcd for [M + H]+ C27H21N2 373.1699, found 373.1703.
(E)-2-(1,2-Diphenylvinyl)-5-methoxy-1-(pyridin-2-yl)-1H-indole (3b): yellow solid; M. p. = 160−162 °C; 39.0 mg, 97% yield; 1 H
NMR (400 MHz, CDCl3): δ = 8.43-8.42 (m, 1H), 7.55 (td, J = 7.9 Hz, 1.9 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.15-7.00 (m, 13H), 6.88 (s,
1H), 6.83 (dd, J = 9.0 Hz, 2.5 Hz, 1H), 6.67 (s, 1H), 3.86 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 155.2, 152.0, 149.0, 143.4, 138.6, 137.7
136.8, 134.3, 134.0, 130.6, 130.3, 129.5, 128.8, 128.0, 128.0, 127.4, 127.1, 121.5, 121.4, 113.2, 111.9, 107.5, 102.4, 55.9. IR (KBr, cm -1) 3059,
2924, 2851, 1586, 1462, 1339, 1268, 1215, 1160, 1032, 748. HRMS (ESI-TOF) calcd for [M + H]+ C28H23N2O 403.1805, found 403.1816.
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(E)-2-(1,2-Diphenylvinyl)-5-fluoro-1-(pyridin-2-yl)-1H-indole (3c): light yellow solid; M. p. = 158−160 °C; 31.2 mg, 80% yield; H
NMR (400 MHz, CDCl3): δ = 8.44-8.42 (m, 1H), 7.56 (td, J = 7.8 Hz, 1.9 Hz, 1H), 7.35 (dd, J = 9.0 Hz, 4.5 Hz, 1H), 7.26 (dd, J = 8.7
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Hz, 2.9 Hz, 1H), 7.15-7.00 (m, 12H), 6.93-6.88 (m, 2H), 6.70 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 158.7 (d, J = 235.9 Hz), 151.8,
149.1, 144.5, 138.4, 137.8, 136.7, 135.3, 134.0, 131.3, 130.2, 129.6, 128.7 (d, J = 9.9 Hz), 128.1, 127.5, 127.3, 121.8, 121.7, 111.9 (d, J = 9.4 Hz),
111.3 (d, J = 26.0 Hz), 107.2 (d, J = 4.4 Hz), 105.5 (d, J = 23.6 Hz). IR (KBr, cm -1) 3058, 1584, 1456, 1266, 1202, 1153, 855, 743. HRMS
(ESI-TOF) calcd for [M + H]+ C27H20FN2 391.1605, found 391.1604.
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(E)-5-Chloro-2-(1,2-diphenylvinyl)-1-(pyridin-2-yl)-1H-indole (3d): light yellow solid; M. p. = 129−131 °C; 38.3 mg, 94% yield; H
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NMR (400 MHz, CDCl3): δ = 8.43-8.42 (m, 1H), 7.59-7.54 (m, 2H), 7.33 (d, J = 8.8 Hz, 1H), 7.13-6.98 (m, 13H), 6.92 (s, 1H), 6.69 (s,
1H). 13C NMR (101 MHz, CDCl3): δ = 151.5, 149.2, 144.2, 138.3, 137.9, 137.1, 136.6, 133.8, 131.4, 130.2, 129.6, 129.3, 128.1, 127.5, 127.3, 126.7,
123.3, 121.9, 121.7, 120.0, 112.2, 106.7. IR (KBr, cm -1) 3056, 1588, 1443, 1370, 1323, 1266, 1207, 1068, 866, 750, 702. HRMS (ESI-TOF)
calcd for [M + H]+ C27H20ClN2 407.1310, found 407.1322.
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(E)-5-Bromo-2-(1,2-diphenylvinyl)-1-(pyridin-2-yl)-1H-indole (3e): light yellow solid; M. p. = 176−178 °C; 42.8 mg, 95% yield; H
NMR (400 MHz, CDCl3): δ = 8.43-8.42 (m, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.56 (td, J = 7.9 Hz, 1.8 Hz, 1H), 7.29-7.23 (m, 2H), 7.13-6.98
(m, 12H), 6.92 (s, 1H), 6.69 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 151.5, 149.2, 144.1, 138.3, 137.9, 137.3, 136.6, 133.8, 131.4, 130.2, 129.9,
129.6, 128.1, 127.5, 127.3, 125.9, 123.1, 121.9, 121.7, 114.3, 112.6, 106.5. IR (KBr, cm -1) 3058, 1586, 1445, 1369, 1323, 1266, 1207, 750, 702.
HRMS (ESI-TOF) calcd for [M + H]+ C27H20BrN2 451.0804, found 451.0791.
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(E)-2-(1,2-Diphenylvinyl)-5-nitro-1-(pyridin-2-yl)-1H-indole (3f): yellow solid; M. p. = 187−189 °C; 30.9 mg, 74% yield; H NMR
(400 MHz, CDCl3): δ = 8.58 (d, J = 2.1 Hz, 1H), 8.46-8.44 (m, 1H), 8.07 (dd, J = 9.1 Hz, 2.2 Hz, 1H), 7.61 (td, J = 7.8 Hz, 1.9 Hz, 1H),
7.38 (d, J = 9.1 Hz, 1H), 7.16-7.02 (m, 10H), 6.99-6.95 (m, 3H), 6.92 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 150.7, 149.4, 146.3, 142.7,
141.2, 138.1, 137.8, 136.1, 133.1, 132.4 130.0, 129.6, 128.2, 128.1, 127.6, 127.6, 127.5, 122.6, 121.8, 118.5, 117.5, 111.0, 107.9. IR (KBr, cm -1) 3058,
1641, 1512, 1464, 1330, 1269, 1071, 743, 700. HRMS (ESI-TOF) calcd for [M + H]+ C27H20N3O2 418.1550, found 418.1556.
(E)-2-(1,2-Diphenylvinyl)-1-(pyridin-2-yl)-1H-indole-5-carbonitrile (3g): light yellow solid; M. p. = 171−173 °C; 37.3 mg, 94% yield; 1
H NMR (400 MHz, CDCl3): δ = 8.45-8.43 (m, 1H), 7.98 (s, 1H), 7.60 (td, J = 7.7 Hz, 1.8 Hz, 1H), 7.43-7.38 (m, 2H), 7.14-7.02 (m,
10H), 6.98-6.95 (m, 3H), 6.82 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 150.8, 149.3, 145.4, 140.0, 138.1, 137.9, 136.2, 133.2, 132.2, 130.0,
129.6, 128.2, 128.1, 128.0, 127.6, 127.5, 125.9, 122.5, 121.8, 120.5, 111.9, 106.8, 104.2. IR (KBr, cm -1) 3060, 2220, 1580, 1462, 1368, 1327, 1267,
885, 751. HRMS (ESI-TOF) calcd for [M + H]+ C28H20N3 398.1652, found 398.1653.
(E)-Methyl 2-(1,2-diphenylvinyl)-1-(pyridin-2-yl)-1H-indole-5-carboxylate (3h): light yellow solid; M. p. = 168−170 °C; 39.1 mg, 91%
1
yield; H NMR (400 MHz, CDCl3): δ = 8.44-8.43 (m, 1H), 8.39 (d, J = 1.1 Hz, 1H), 7.87 (dd, J = 8.7 Hz, 1.5 Hz, 1H), 7.58 (td, J = 7.8
Hz, 1.9 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.14-6.96 (m, 13H), 6.85 (s, 1H), 3.93 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 168.0, 151.3,
149.2, 144.4, 141.0, 138.2, 137.9, 136.5, 133.7, 131.4, 130.1, 129.6, 128.0, 127.8, 127.4, 127.3, 124.4, 123.5, 123.1, 122.1, 121.8, 110.5, 107.8, 51.9.
IR (KBr, cm -1) 3058, 2924, 2851, 1710, 1644, 1438, 1310, 1262, 1182, 1133, 1088, 742. HRMS (ESI-TOF) calcd for [M + H]+ C29H23N2O2
431.1754, found 431.1755.
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(E)-2-(1,2-Diphenylvinyl)-6-fluoro-1-(pyridin-2-yl)-1H-indole (3i): light yellow solid; M. p. = 88−90 °C; 33.2 mg, 85% yield; 1 H
NMR (400 MHz, CDCl3): δ = 8.44-8.43 (m, 1H), 7.59-7.51 (m, 2H), 7.17-7.01 (m, 13H), 6.92 (td, J = 9.2 Hz, 2.2 Hz, 2H), 6.88 (s, 1H),
6.71 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 160.7 (d, J = 239.2 Hz), 151.7, 149.1, 143.4 (d, J = 3.8 Hz), 138.8 (d, J = 12.3 Hz), 138.4, 137.9,
136.7, 134.0, 130.7, 130.2, 129.6, 128.1, 127.5, 127.2, 124.7, 121.8, 121.5, 121.4 (d, J = 10.3 Hz), 109.8 (d, J = 24.5 Hz), 107.4, 97.9 (d, J = 27.0
Hz). IR (KBr, cm -1) 3011, 1703, 1579, 1473, 1351, 1268, 755, 702. HRMS (ESI-TOF) calcd for [M + H]+ C27H20FN2 391.1605, found
391.1605.
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(E)-6-Chloro-2-(1,2-diphenylvinyl)-1-(pyridin-2-yl)-1H-indole (3j): light yellow solid; M. p. = 143−145 °C; 35.0 mg, 86% yield; H
NMR (400 MHz, CDCl3): δ = 8.45-8.43 (m, 1H), 7.57 (td, J = 7.8 Hz, 1.9 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.14-6.98 (m,
13H), 6.91 (s, 1H), 6.72 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 151.4, 149.2, 143.7, 139.0, 138.3, 137.9, 136.6, 133.9, 131.1, 130.2, 129.6,
129.1, 128.1, 127.5, 127.3, 126.8, 121.9, 121.9, 121.6, 121.5, 111.2, 107.2. IR (KBr, cm -1) 3053, 1643, 1451, 1336, 1268, 1206, 818, 754, 699.
HRMS (ESI-TOF) calcd for [M + H]+ C27H20ClN2 407.1310, found 407.1309.
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(E)-2-(1,2-Diphenylvinyl)-7-methyl-1-(pyridin-2-yl)-1H-indole (3k): white solid; M. p. = 124−126 °C; 36.3 mg, 94% yield; H NMR
(400 MHz, CDCl3): δ = 8.35-8.34 (m, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.13-6.86 (m, 15H), 6.74 (s, 1H), 1.79 (s, 3H).
13 C NMR (101 MHz, CDCl3) δ = 153.5, 148.3, 144.4, 139.0, 137.7, 136.9, 136.8, 134.4, 131.5, 129.9, 129.6, 128.7, 128.1, 128.0, 127.2, 127.1,
125.6, 125.1, 122.9, 121.7, 120.7, 118.8, 106.1, 19.6. IR (KBr, cm -1) 3059, 2925, 2850, 1588,1471, 1433, 1347, 1266, 1150, 745. HRMS (ESI-
TOF) calcd for [M + H]+ C28H23N2 387.1856, found 387.1856.
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(E)-2-(1,2-Diphenylvinyl)-3-methyl-1-(pyridin-2-yl)-1H-indole (3l): light yellow solid; M. p. = 136−138 °C; 37.1 mg, 96% yield; H
NMR (400 MHz, CDCl3) δ: = 8.38-8.37 (m, 1H), 7.67-7.62 (m, 1H), 7.51 (td, J = 7.9 Hz, 1.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.22-7.17 (m,
2H), 7.14-7.11 (m, 6H), 7.01-6.93 (m, 4H), 6.88-6.86 (m, 3H), 2.44 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 152.0, 148.9, 138.8, 138.6,
137.5, 137.2, 137.0, 133.5, 132.7, 130.1, 129.5, 129.5, 128.1, 127.8, 127.1, 123.4, 121.2, 121.1, 120.6, 119.2, 114.5, 110.8, 10.0. IR (KBr, cm -1) 3056,
2922, 2856, 1584, 1459, 1358, 1266, 751, 699. HRMS (ESI-TOF) calcd for [M + H]+ C28H23N2 387.1856, found 387.1859.
(E)-1-(2-(1,2-Diphenylvinyl)-1-(pyridin-2-yl)-1H-indol-3-yl)ethanone (3m): light yellow solid; M. p. = 176−178 °C; 10.4 mg, 25%
yield; 1 H NMR (400 MHz, CDCl3): δ = 8.56 (d, J = 8.0 Hz, 1H), 8.36-8.35 (m, 1H), 7.51 (td, J = 7.8 Hz, 1.8 Hz, 1H), 7.39-7.33 (m, 3H),
7.30-7.24 (m, 6H), 7.16-7.12 (m, 5H), 7.00-6.98 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 2.34 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 194.9,
149.9, 149.2, 143.0, 140.5, 137.6, 137.1, 135.9, 134.0, 131.9, 128.8, 128.7, 128.6, 128.4, 128.1, 127.1, 126.7, 124.1, 123.4, 123.1, 122.9, 121.5, 117.7,
111.2, 29.8. IR (KBr, cm -1) 3065, 2923, 2850, 1646, 1574, 1454, 1392, 1179, 757, 689. HRMS (ESI-TOF) calcd for [M + H]+ C29H23N2O
415.1805, found 415.1805.
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2-(2,5-Bis((E)-1,2-diphenylvinyl)-1H-pyrrol-1-yl)pyridine (3n): yellow solid; M. p. = 191−193 °C; 20.0 mg, 40% yield; H NMR (400
MHz, CDCl3): δ = 8.09 (d, J = 4.5 Hz, 1H), 7.09 (t, J = 7.7 Hz, 1H), 7.03-6.96 (m, 12H), 6.91-6.87 (m, 8H), 6.77-6.74 (m, 1H), 6.68 (s,
2H), 6.60 (d, J = 7.9 Hz, 1H), 6.35 (s, 2H). 13 C NMR (101 MHz, CDCl3): δ = 152.3, 148.3, 139.2, 139.0, 137.2, 136.6, 134.5, 130.0, 129.4,
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128.8, 127.8, 127.8, 126.8, 126.5, 123.7, 121.7, 111.8. IR (KBr, cm -1) 3063, 1668, 1534, 1462, 1310, 1277, 1223, 1143, 822, 741. HRMS (ESI-TOF)
calcd for [M + Na]+ C37H28N2Na 523.2145, found 523.2149.
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2-(2-((1Z,3E)-1,2,3,4-Tetraphenylbuta-1,3-dienyl)-1H-pyrrol-1-yl)pyridine (3o): yellow solid; M. p. = 183−185 °C; 26.0 mg, 52% yield;
1 H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 4.6 Hz, 1H), 7.28-7.24 (m, 4H), 7.22-7.14 (m, 4H), 7.11 (d, J = 7.6 Hz, 2H), 7.04 – 6.99
(m, 9H), 6.93 (d, J = 7.5 Hz, 2H), 6.79 (s, 1H), 6.73 – 6.69 (m, 2H), 6.44 (d, J = 3.4 Hz, 1H), 6.33 (d, J = 8.0 Hz, 1H), 6.20 (d, J = 3.4
Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ = 151.6, 148.1, 142.2, 139.7, 138.3, 137.6, 137.4, 136.3, 134.4, 133.9, 133.9, 131.1, 130.1, 129.4, 129.3,
128.2, 128.1, 128.0, 127.8, 127.4, 127.3, 127.2, 127.0, 126.4, 122.2, 121.3, 112.9, 111.1. IR (KBr, cm -1) 3066, 1671, 1533, 1466, 1302, 1263, 1219,
1139, 810, 744. HRMS (ESI-TOF) calcd for [M + Na]+ C37H28N2Na 523.2145, found 523.2147.
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(E)-2-(1,2-Diphenylvinyl)-1-(pyrimidin-2-yl)-1H-indole (3p) 29: white solid; M. p. = 150−152 °C; 31.0 mg, 83% yield; H NMR (400
MHz, CDCl3): δ = 8.53 (d, J = 4.8 Hz, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.28-7.20 (m, 2H), 7.13-7.10 (m, 7H),
7.04-7.00 (m, 4H), 6.89-6.87 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ = 158.0, 157.6, 142.8, 138.6, 137.9, 137.2, 135.5, 130.5, 129.7, 128.9,
128.0, 127.7, 127.2, 127.0, 123.8, 122.1, 120.7, 117.1, 112.9, 110.1. IR (KBr, cm -1) 3055, 1703, 1545, 1430, 1346, 1264, 744. MS (ESI) m/z 374.2
[M + H]+.
2-(1-Phenylvinyl)-1-(pyridin-2-yl)-1H-indole (3q): obtained as a 4:1 mixture with its regioisomer (E)-1-(pyridin-2-yl)-2-styryl-1H-
indole 3r; yellow oil; 24.0 mg, 81% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.73-8.72 (m, 1H, 3q), 8.63-8.62 (m, 1H, 3r), 7.89 (td, J =
7.8 Hz, 1.9 Hz, 1H, 3q), 7.79 (td, J = 7.9 Hz, 1.9 Hz, 1H, 3r), 7.65 – 7.61 (m, 1H, 3q), 7.57 (d, J = 8.3 Hz, 1H, 3r), 7.51–7.49 (m, 1H, 3q
and 3r), 7.42 – 7.39 (m, 3H, 3q and 3r), 7.36 – 7.29 (m, 3H, 3q and 3r), 7.24 – 7.21 (m, 1H, 3q and 3r), 7.19 – 7.14 (m, 2H, 3q and 3r),
7.10 (d, J = 4.4 Hz, 2H, 3q), 6.98 (s, 1H, 3q), 6.62 (s, 1H, 3r), 6.58 (d, J = 12.3 Hz, 1H, 3r), 6.45 (d, J = 12.2 Hz, 1H, 3r). 13 C NMR (101
MHz, CDCl3): δ = 151.4, 151.3, 149.7, 149.3, 138.4, 138.2, 138.0, 137.9, 137.2, 137.2, 137.0, 135.6, 131.8, 130.6, 128.8, 128.7, 128.7, 128.4, 127.8,
127.6, 126.6, 123.0, 123.0, 122.1, 121.6, 121.6, 121.5, 121.2, 121.2, 120.8, 120.6, 120.2, 118.5, 111.3, 111.0, 105.5, 102.4. IR (KBr, cm -1) 3052, 1584,
1463, 1344, 1263, 1213, 1140, 956, 741, 694. HRMS (ESI-TOF) calcd for [M + H]+ C21H17N2 297.1386, found 297.1389.
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(E)-2-(1-Phenylbut-1-enyl)-1-(pyridin-2-yl)-1H-indole (3s): yellow oil; 20.1 mg, 62% yield; H NMR (400 MHz, CDCl3): δ = 8.46-
8.45 (m, 1H), 7.60-7.56 (m, 2H), 7.41-7.40 (m, 1H), 7.15-7.07 (m, 7H), 7.01-6.99 (m, 2H), 6.62 (s, 1H), 5.98 (t, J = 7.4 Hz, 1H), 2.19 (p,
J = 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ = 152.0, 149.0, 142.7, 138.7, 138.2, 137.6, 135.8, 132.9, 129.7, 128.4,
127.6, 126.9, 122.7, 121.8, 121.5, 121.0, 120.5, 110.9, 106.1, 22.8, 14.4. IR (KBr, cm -1) 3059, 2924, 2856, 1644, 1527, 1457, 1345, 1265, 742.
HRMS (ESI-TOF) calcd for [M + H]+ C23H21N2 325.1699, found 325.1699.
(E)-2-(1-Phenylbut-1-en-2-yl)-1-(pyridin-2-yl)-1H-indole (3t): yellow oil; 11.0 mg, 34% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.58-
8.57 (m, 1H), 7.67 (td, J = 7.8 Hz, 1.9 Hz, 1H), 7.57-7.54 (m, 2H), 7.25-7.07 (m, 9H), 6.67 (s, 1H), 6.45 (s, 1H), 2.35 (q, J = 7.5 Hz, 2H),
0.99 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ = 152.7, 149.2, 141.8, 138.5, 138.0, 137.4, 136.0, 131.4, 128.6, 128.5, 128.3, 126.8,
123.0 121.7, 121.3, 121.3, 120.4, 111.4, 105.5, 24.2, 13.5. IR (KBr, cm -1) 3054, 2923, 2852, 1638, 1522, 1460, 1342, 1266, 743. HRMS (ESI-TOF)
calcd for [M + Na]+ C23H20N2Na 347.1519, found 347.1521.
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(Z)-3-Phenyl-2-(1-(pyridin-2-yl)-1H-indol-2-yl)prop-2-en-1-ol (3u): brown solid; M. p. = 78−80 °C; 29.0 mg, 89% yield; H NMR
(400 MHz, CDCl3): δ = 8.57 (d, J = 4.7 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (d, J =
7.6 Hz, 1H), 7.34-7.30 (m, 2H), 7.28-7.19 (m, 6H), 6.77 (s, 1H), 6.43 (s, 1H), 4.58 (s, 2H), 4.47 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ
= 151.3, 148.9, 140.8, 138.7, 137.4, 136.2, 134.4, 133.2, 128.9, 128.7, 128.4, 127.6, 123.0, 121.9, 121.5, 121.2, 120.9, 110.6, 105.0, 62.2. IR (KBr,
cm -1) 3374, 3058, 2925, 2855, 1705, 1537, 1457, 1346, 1264, 1012, 742. HRMS (ESI-TOF) calcd for [M + H]+ C22H19N2O 327.1492, found
327.1492.
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(Z)-2-(3-methoxy-1-phenylprop-1-en-2-yl)-1-(pyridin-2-yl)-1H-indole (3v): light yellow oil; 26.2 mg, 83% yield; 1 H NMR (400 MHz,
CDCl3): δ = 8.66 (d, J = 4.5 Hz, 1H), 7.78 (t, J = 7.7 Hz, 1H), 7.63 (d, J = 7.3 Hz, 2H), 7.33 (dd, J = 13.0 Hz, 7.3 Hz, 3H), 7.29–7.13 (m,
6H), 6.85 (s, 1H), 6.63 (s, 1H), 4.18 (s, 2H), 3.30 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 152.6, 149.1, 140.8, 138.6, 138.0, 136.4, 135.6,
130.0, 128.9, 128.6, 128.3, 127.5, 123.2, 122.0, 121.7, 121.3, 120.7, 111.4, 105.7, 70.7, 58.5. IR (KBr, cm -1) 3053, 2922, 2844, 1569, 1471, 1333,
1260, 1203, 1142, 1014, 741. HRMS (ESI-TOF) calcd for [M + H]+ C23H21N2O 341.1648, found 341.1647.
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(E)-Methyl 3-phenyl-3-(1-(pyridin-2-yl)-1H-indol-2-yl)acrylate (3w): yellow solid; M. p. = 88−90 °C; 32.9 mg, 93% yield; H NMR
(400 MHz, CDCl3): δ = 8.48-8.47 (m, 1H), 7.85 (s, 1H), 7.69-7.66 (m, 2H), 7.62 (d, J = 7.8 Hz, 1H), 7.31-7.12 (m, 9H), 6.61 (s, 1H),
3.59 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ = 167.6, 151.3, 149.1, 143.5, 137.8, 136.7, 134.4, 133.5, 130.3, 129.6, 128.7, 128.4, 124.1, 123.1,
121.2, 121.1, 121.1, 119.2, 111.6, 106.7, 52.3. IR (KBr, cm -1) 3057, 2924, 2851, 1713, 1638, 1457, 1382, 1253, 1201, 745, 688. HRMS (ESI-TOF)
calcd for [M + H]+ C23H19N2O2 355.1441, found 355.1442.
(E)-2-(Oct-4-en-4-yl)-1-(pyridin-2-yl)-1H-indole (3x): obtained as a 4.2:1 mixture with its stereoisomer (Z)-2-(oct-4-en-4-yl)-1-
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(pyridin-2-yl)-1H-indole; yellow oil; 28.9 mg, 95% yield; H NMR (400 MHz, CDCl3): δ = 8.65-8.64 (m, 1H, 3x(E) and 3x(Z)), 7.75
(td, J = 7.8 Hz, 1.4 Hz, 1H, 3x(E) and 3x(Z)), 7.58-7.56 (m, 2H, 3x(E) and 3x(Z)), 7.26 – 7.21 (m, 2H, 3x(E) and 3x(Z)), 7.17-7.11 (m,
2H, 3x(E) and 3x(Z)), 6.55 (s, 1H, 3x(E) and 3x(Z)), 5.56 (t, J = 7.4 Hz, 1H, 3x(E)), 5.51 (t, J = 7.4 Hz, 1H, 3x(Z)), 2.13-2.05 (m, 4H,
3x(E) and 3x(Z)), 1.38-1.26 (m, 4H, 3x(E) and 3x(Z)), 0.91-0.79 (m, 6H, 3x(E) and 3x(Z)). 13 C NMR (101 MHz, CDCl3): δ = 152.8,
149.1, 149.1, 142.7, 142.6, 138.1, 137.8, 137.8, 135.1, 133.7, 132.3, 131.7, 128.6, 122.5, 121.5, 121.5, 121.4, 121.0, 120.2, 111.3, 111.2, 104.4, 32.5, 31.0,
30.4, 30.2, 22.7, 21.9, 21.6, 14.1, 14.0, 13.9, 13.9. IR (KBr, cm -1) 3059, 2954, 2863, 1580, 1459, 1348, 1264, 1210, 784, 740. HRMS (ESI-
TOF) calcd for [M + H]+ C21H25N2 305.2012, found 305.2027.
2-(1-Phenylvinyl)-1-(pyridin-2-yl)-1H-indole (3q): obtained as a 19:1 mixture with its regioisomer (E)-1-(pyridin-2-yl)-2-styryl-1H-
indole 3r; yellow oil; 29.0 mg, 98% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.72 (d, J = 4.6 Hz, 1H), 7.88 (t, J = 7.7 Hz, 1H), 7.64-7.62
(m, 1H), 7.51-7.49 (m, 1H), 7.42-7.39 (m, 3H), 7.36-7.29 (m, 3H), 7.23-7.15 (m, 3H), 7.11 (s, 1H), 7.09 (s, 1H), 6.98 (s, 1H). 13 C NMR
(101 MHz, CDCl3): δ = 151.4, 149.7, 138.4, 138.1, 137.9, 137.2, 130.6, 128.8, 128.7, 127.8, 126.6, 123.0, 122.1, 121.6, 121.4, 120.6, 118.4, 111.0,
102.4. IR (KBr, cm -1) 3054, 1582, 1459, 1345, 1267, 1212, 1150, 956, 744, 695. HRMS (ESI-TOF) calcd for [M + Na]+ C21H16N2Na
319.1206, found 319.1214.
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(E)-Ethyl 3-(1-(pyridin-2-yl)-1H-indol-2-yl)acrylate (3y): yellow oil; 15.8 mg, 54% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.70 (d, J
= 4.4 Hz, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.71-7.65 (m, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.40-7.35 (m, 2H), 7.25-7.16 (m, 2H), 7.12 (s, 1H),
6.35 (d, J = 15.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.2 Hz, 4H). 13 C NMR (101 MHz, CDCl3): δ = 166.9, 150.6, 149.9, 138.7,
138.6, 134.9, 133.9, 128.1, 124.5, 122.5, 121.8, 121.5, 121.5, 118.6, 111.1, 106.6, 60.5, 14.3. IR (KBr, cm -1) 3051, 2923, 2848, 1717, 1628, 1451,
1388, 1257, 1189, 751. HRMS (ESI-TOF) calcd for [M + Na]+ C18H16N2O2Na 315.1104, found 315.1107.
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(E)-2-(1-Phenylbuta-1,3-dienyl)-1-(pyridin-2-yl)-1H-indole (3z): obtained as a 6.7:1 mixture with its stereoisomer (Z)-2-(1-
phenylbuta-1,3-dienyl)-1-(pyridin-2-yl)-1H-indole; yellow oil; 26.1 mg, 81% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 4.7 Hz,
1H), 7.76 (d, J = 8.0 Hz, 1H), 7.70-7.64 (m, 2H), 7.36-7.30 (m, 4H), 7.27-7.14 (m, 5H), 7.07-7.03 (m, 1H), 6.75 (d, J = 8.2 Hz, 3H), 5.27
(d, J = 17.4 Hz, 1H), 5.14 (d, J = 10.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3) δ = 152.3, 149.0, 139.5, 137.8, 137.6, 136.7, 133.6, 133.5, 132.7,
129.5, 128.4, 128.3, 127.5, 123.1, 121.3, 121.3, 120.6, 120.5, 119.8, 111.7, 107.2. IR (KBr, cm -1) 3055, 1592, 1466, 1353, 1255, 1218, 1144, 742.
HRMS (ESI-TOF) calcd for [M + Na]+ C23H18N2Na 345.1362, found 345.1369.
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(E)-2-(1,4-Diphenylbut-1-en-3-ynyl)-1-(pyridin-2-yl)-1H-indole (3za): brown oil; 34.8 mg, 88% yield; H NMR (400 MHz, CDCl3):
δ = 8.68 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 7.7 Hz, 2H), 7.79 (t, J = 7.7 Hz, 1H), 7.68 (t, J = 8.2 Hz, 2H), 7.42 (dd, J = 14.0 Hz, 7.5 Hz, 3H),
7.36-7.22 (m, 9H), 7.13 (s, 1H), 6.96 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 152.2, 149.3, 139.6, 138.5, 138.0, 137.3, 136.3, 131.4, 129.1,
128.7, 128.5, 128.4, 128.3, 128.2, 123.4, 122.9, 121.8, 121.5, 121.4, 120.8, 113.9, 111.3, 106.0, 97.3, 87.7. IR (KBr, cm -1) 3058, 2196, 1641, 1456,
1363, 1264, 1208, 1150, 743, 688. HRMS (ESI-TOF) calcd for [M + H]+ C29H21N2 397.1699, found 397.1697.
2-Heptyl-1-(pyridin-2-yl)-1H-indole (3zb): Obtained as a 6.7:1 mixture with its regioisomer 2-(heptan-2-yl)-1-(pyridin-2-yl)-1H-
indole (3zc); yellow oil; 22.2 mg, 76% yield; 1 H NMR (400 MHz, CDCl3): δ = 8.58 (d, J = 4.7 Hz, 1H, 3zb and 3zc), 7.73 (t, J = 7.7 Hz,
1H, 3zb and 3zc), 7.55-7.53 (m, 1H, 3zb and 3zc), 7.34-7.28 (m, 2H, 3zb and 3zc), 7.20-7.17 (m, 1H, 3zb and 3zc), 7.11-7.08 (m, 2H,
3zb and 3zc), 6.44 (s, 1H, 3zc), 6.42 (s, 1H, 3zb), 3.22-3.13 (m, 1H, 3zc), 2.81 (t, J = 7.7 Hz, 2H, 3zb), 1.57-1.50 (m, 2H, 3zb and 3zc),
1.26-1.20 (m, 8H, 3zb; 6H, 3zc), 0.86-0.77 (m, 3H, 3zb; 6H, 3zc). 13 C NMR (101 MHz, CDCl3) δ = 151.7, 149.7, 141.9, 138.3, 137.4, 128.8,
122.1, 121.6, 121.2, 120.6, 119.9, 110.1, 102.1, 31.8, 29.3, 29.1, 28.7, 27.5, 22.7, 14.2. IR (KBr, cm -1) 3055, 2936, 2845, 1582, 1461, 1345, 1246,
1216, 743. HRMS (ESI-TOF) calcd for [M+H]+ C20H25N2+ 293.2012, found 293.1995.
(E)-2-(hept-1-enyl)-1-(pyridin-2-yl)-1H-indole (3zd): obtained as a 2.3:1 mixture with its regioisomer 2-(hept-1-en-2-yl)-1-(pyridin-
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2-yl)-1H-indole (3ze); yellow oil; 24.9 mg, 86% yield; H NMR (400 MHz, CDCl3): δ = 8.62 (s, 1H, 3zd and 3ze), 7.77-7.71 (m, 1H,
3zd and 3ze), 7.62-7.50 (m, 1H, 3zd; 2H, 3ze), 7.45-7.44 (m, 1H, 3zd), 7.30-7.26 (m, 1H, 3zd and 3ze), 7.23-7.10 (m, 3H, 3zd and
3ze), 6.73 (s, 1H, 3zd), 6.69 (s, 1H, 3ze), 6.32 (d, J = 15.9 Hz, 1H, 3zd), 6.25-6.18 (m, 1H, 3zd and 3ze), 5.76-5.70 (m, 1H, 3ze), 2.47
(dd, J = 14.1 Hz, 7.0 Hz, 2H, 3ze), 2.14 (dd, J = 13.8 Hz, 6.8 Hz, 2H, 3zd), 1.51-1.28 (m, 6H, 3zd and 3ze), 0.91-0.86 (m, 3H, 3zd and
3ze). 13 C NMR (101 MHz, CDCl3): δ = 151.5, 149.5, 149.5, 138.5, 138.1, 138.1, 137.5, 136.9, 136.0, 135.2, 134.2, 128.8, 128.8, 122.8, 122.4,
121.9, 121.9, 121.6, 121.6, 121.2, 121.1, 120.5, 120.2, 120.0, 118.9, 111.2, 110.9, 105.3, 101.3, 33.3, 31.8, 31.5, 29.6, 29.4, 28.9, 22.7, 22.6, 14.2. IR
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(KBr, cm -1) 3066, 2955, 2867, 1592, 1463, 1336, 1258, 1203, 962, 887, 744. HRMS (ESI-TOF) calcd for [M + Na]+ C20H22N2Na 313.1675,
found 313.1678.
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Several examples about removal of the pyridyl group of 3
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Methyl trifluoromethanesulfonate (0.36 mmol, 1.2 eq.) was added dropwise to a solution of 3 (0.30 mmol, 1.0 eq.) in CH2Cl2
(7.5 mL) at 0 oC, and the resulting solution was stirred for 24 h at room temperature. Then the solvent was removed under vacu-
um, and the residue was dissolved in MeOH (3.6 mL). A 2M aq NaOH solution (1.8 mL) was added, and stirring was continued at
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60 C for 12 h. The solvents were removed, and the resulting residue was extracted with EtOAc (3 × 30 mL). The combined or-
ganic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column
chromatography to afford 4.
(E)-2-(1, 2-Diphenylvinyl)-1H-indole (4a) 29, 30: light yellow solid; M. p. = 137−139 °C; 80.0 mg, 90.4% yield; H NMR (400 MHz,
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CDCl3): δ = 8.03 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.41-7.40 (m, 3H), 7.35-7.34 (m, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.17-7.06 (m, 6H),
7.01-6.99 (m, 2H), 6.43 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 140.2, 138.4, 136.7, 136.6, 134.0, 130.2, 129.6, 129.0, 128.9, 128.2, 128.2,
127.1, 125.9, 122.7, 120.7, 120.3, 110.8, 103.1. IR (KBr, cm -1) 3455, 3096, 1622, 1489, 1332, 1251, 1201, 1143, 741. MS (ESI) m/z 296.1 [M +
H]+.
(E)-2-(1,2-diphenylvinyl)-5-methoxy-1H-indole (4b) 31: brown solid; M. p. = 142−145 °C; 80.3 mg, 82.4% yield; 1 H NMR (400 MHz,
CDCl3): δ = 7.93 (s, 1H), 7.39 (m, 3H), 7.33 (m, 2H), 7.16 (d, J = 8.8 Hz, 1H), 7.12-7.07 (m, 3H), 7.04 (s, 1H), 7.00-6.98 (m, 3H), 6.82
(d, J = 8.7 Hz, 1H), 6.37 (s, 1H), 3.82 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ: = 154.4, 140.9, 138.3, 136.6, 134.0, 131.9, 130.2, 129.5, 129.3,
129.0, 128.1, 128.1, 127.0, 125.7, 113.0, 111.5, 102.6, 102.2, 55.8. IR (KBr, cm -1) 3458, 3098, 2934, 2862, 1618, 1493, 1335, 1266, 1210, 1163,
744. MS (ESI) m/z 326.2 [M + H]+.
(E)-5-bromo-2-(1,2-diphenylvinyl)-1H-indole (4c): yellow solid; M. p. = 161−163 °C; 96.8 mg, 86.3% yield; 1 H NMR (400 MHz,
CDCl3): δ = 8.04 (s, 1H), 7.64 (s, 1H), 7.42-7.41 (m, 3H), 7.33 (m, 2H), 7.22 (d, J = 10.0 Hz, 1H), 7.15-7.12 (m, 4H), 7.08 (s, 1H), 7.01-
6.99 (m, 2H), 6.39 (s, 1H). 13 C NMR (101 MHz, CDCl3): δ = 141.4, 138.0, 136.2, 135.2, 133.4, 130.6, 130.1, 129.5, 129.1, 128.3, 128.2, 127.3,
126.8, 125.3, 123.0, 113.3, 112.1, 101.9. IR (KBr, cm -1) 3453, 3091, 1621, 1493, 1340, 1256, 1201, 1138, 742, 698. HRMS (ESI-TOF) calcd for
[M + H]+ C22H17BrN+ 374.0539, found 374.0514.
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(E)-2-(1,2-diphenylvinyl)-3-methyl-1H-indole (4d): light yellow solid; M. p. = 120−122 °C; 79.7 mg, 86.0 % yield; H NMR (400
MHz, CDCl3): δ = 7.61 (s, 1H), 7.56 (d, J = 7.7 Hz, 1H), 7.33 (m, 3H), 7.28 (m, 2H), 7.21-7.05 (m, 8H), 6.91 (s, 1H), 2.26 (s, 3H). 13 C
NMR (101 MHz, CDCl3): δ = 138.9, 136.9, 135.6, 135.4, 134.4, 130.3, 129.9, 129.6, 129.5, 128.9, 128.1, 128.0, 126.9, 122.6, 119.4, 118.9, 110.8,
110.6, 10.2. IR (KBr, cm -1) 3457, 3098, 2925, 2854, 1624, 1493, 1338, 1243, 1155, 746. HRMS (ESI-TOF) calcd for [M + H]+ C23H20N+
310.1590, found 310.1587.
ACKNOWLEDGMENTS
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We thank the NSFC (No. 21372085) and GNSF (No.10351064101000000) for financial support.
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Notes
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† These two authors contributed equally to this work
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Supporting Information
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Details for experiments conditions, copies of H and 13 C NMR spectra for all isolated compounds, and single crystal data of 3a.
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This material is available free of charge via the Internet at http://pubs.acs.org.
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J. B.; Swan, L. M.; Denny, W. A. J. Med. Chem. 2006, 49, 4896.
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Graphic Abstract
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R2
R2
R3
R3
RuCl2(p-cymene)2 (7 mol %)
AcOH (1.0 equiv)
R1
H
R1
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R4
N
N
DMF, Ar,110 oC, 24 h
R3 = R4 = H, aryl, alkyl, acyl, alkenyl,
R4
N
N
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2
alkynyl, hydroxylmethyl, alkylsilyl etc.
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