Copper-Catalyzed Decarboxylative N -Arylation of Indole-2-carboxylic Acids

Article abstract of DOI:10.1055/s-0037-1611946

A novel decarboxylative N -arylation of indole-2-carboxylic acids with aryl halides is developed. The reaction proceeds efficiently in the presence of Cu ₂ O as the catalyst to give the corresponding N -aryl indoles in high yields. This synthet

Full text of DOI:10.1055/s-0037-1611946

SYNTHESIS
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©
Georg Thieme Verlag Stuttgart · New York
2019, 51, A–F
paper
A
de
Synthesis
Y. Zhang et al.
Paper
Copper-Catalyzed Decarboxylative N-Arylation of Indole-2-
carboxylic Acids
Yan Zhanga
Zhe-Yao Hua
Xin-Chang Lia
Cu O (10 mol%)
2
R1
R2
R1
2
CO H
+
N
K3PO4 (2 equiv)
N
X
H
Xun-Xiang Guo*a,b
X = I, Br
R2
a
Key Laboratory of Systems Biomedicine (Ministry of Education),
30 examples
up to 99% yield
Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong
University, Shanghai 200240, P. R. of China
xunxiang_guo@sjtu.edu.cn
b
Key Laboratory of Organosilicon Chemistry and Material Technology
of Ministry of Education, Hangzhou Normal University, Hangzhou
311121, P. R. of China
Received: 05.09.2018
Accepted after revision: 17.11.2018
Published online: 10.01.2019
tion between indoles and aryl iodides to give N-aryl indoles
in good yields at room temperature. Owing to their im-
7b
DOI: 10.1055/s-0037-1611946; Art ID: ss-2018-h0593-op
portant biological and pharmacological properties, the de-
velopment of novel synthetic protocols to access N-aryl in-
doles is still highly desirable.
Abstract A novel decarboxylative N-arylation of indole-2-carboxylic
acids with aryl halides is developed. The reaction proceeds efficiently in
the presence of Cu O as the catalyst to give the corresponding N-aryl
2
a) Previous work: Formation of N-aryl indoles from indoles and aryl halides
indoles in high yields. This synthetic method shows good functional
group tolerance and offers an alternative route to construct N-aryl in-
doles.
TM: [Pd],6 [Cu],7 [Fe],8
[Fe/Cu],9 and others10
or TM-free11
R
Ar
X
R
Key words indole-2-carboxylic acids, N-arylation, copper, decarboxyl-
ation, synthetic methods
+
N
N
H
X = I, Br, Cl, OTf, etc.
Ar
b) This work: Cu-catalyzed decarboxylative N-arylation of indole-2-carboxylic acids
N-Aryl indoles are important heterocyclic compounds
that show a wide range of biological and pharmacological
properties. For example, N-aryl indoles exhibit anticancer
Cu2O (10 mol%)
R
CO2H
+
Ar
X
R
N
N
1
H
X = I, Br
potential towards human melanomas, and are selective in-
Ar
2
hibitors of neuronal 5-hydroxytryptamine uptake, ATP-site
Scheme 1 Synthetic strategies towards N-aryl indoles from indoles and
aryl halides; TM = transition metal
3
inhibitors of the platelet-derived growth factor receptor,
and inhibitors of protein kinase C-α.4
For the synthesis of N-aryl indoles, some elegant exam-
ples have been developed for the formation of C–N bonds
between nucleophilic indoles and aryl electrophiles in the
Recently, as part of our interest in developing Cu-cata-
12
lyzed methods to construct heterocycles, we became in-
5–11
13
presence of a catalyst (Scheme 1a).
For example,
terested in indole-2-carboxylic acids, which have been
Hartwig developed an efficient method for the Pd-catalyzed
used widely as intermediates in organic synthesis because
of their good availability. Herein, we report an efficient
method to form N-aryl indoles via copper-catalyzed decar-
boxylative coupling of indole-2-carboxylic acids with aryl
halides.14 In this reaction, decarboxylation and C–N bond
formation occur to afford N-aryl indoles in high yields
(Scheme 1b).
N-arylation of indoles with aryl halides under mild reaction
6
conditions. Buchwald reported an Ullmann-type method
for the N-arylation of indoles leading to the formation of N-
aryl indoles in good to high yields by using the combination
of CuI and a racemic trans-N,N′-dimethyl-1,2-cyclohexane-
7a
diamine ligand as a catalyst. Bolm described a novel Fe-
catalyzed N-arylation of an indole with phenyl iodide,8a
whilst Taillefer presented cooperative bimetallic catalysis
with Fe and Cu for the N-arylation of indoles with aryl io-
In an initial study, we chose indole-2-carboxylic acid
(1a) and iodobenzene (2a) as model starting materials to
examine the reaction. As shown in Table 1, the reaction of
compound 1a and 2a in the presence of 10 mol% of CuI in
dimethylacetamide (DMAc) with 2 equivalents of K CO as
9
dides. Fu and Peters developed a very mild reaction meth-
od involving photoinduced Cu-catalyzed C–N bond forma-
2
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

B
Synthesis
Y. Zhang et al.
Paper
the base at 150 °C for 12 hours afforded the desired product
aa in 42% yield (Table 1, entry 1). Although the catalyst
CuOAc provided the product 3aa in 26% yield (Table 1, entry
), the yield increased to 52% when Cu O was used in the
Cu O (10 mol%)
2
R1
CO2H
R1
+
Ph
I
3
N
H
K3PO4 (2 equiv)
NMP, 160 °C, 12 h
N
Ph
1
2a
3
2
2
reaction (Table 1, entry 3). Under the same reaction condi-
Me
OMe
tions, the catalyst Cu(OAc) gave the product 3aa in 38%
2
Me
yield (Table 1, entry 4).
N
N
N
Ph
N
Ph
Ph
aa, 99%
Ph
Table 1 Copper-Catalyzed Decarboxylative N-Arylation of Indole-2-
carboxylic Acids: Optimization of the Reaction Conditions
3
3ba, 93%
3ca, 93%
3da, 70%
a
MeO
F
Cl
catalyst
CO2H
+
Ph
I
N
N
N
N
Me
base, solvent
N
N
Ph
Ph
Ph
Ph
H
Ph
1a
2a
3aa
3ea, 95%
3fa, 90%
3ga, 87%
3ha, 94%
Entry
Catalyst
Base
Solvent
Yield (%)b
N
N
MeO
1
2
3
4
5
6
7
8
9
CuI
K
K
K
K
2
2
2
2
CO
CO
CO
CO
3
3
3
3
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMF
42
26
52
38
28
43
10
7
Ph
Ph
Cl
CuOAc
3ia, 92%
3ja, 52%
Cu
2
O
Scheme 2 Scope of indole-2-carboxylic acids 1
Cu(OAc)
2
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
–
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
Li
Na
Cs
KOAc
2
CO
3
2
CO
3
formed at 160 °C for 12 hours (Table 1, entry 15). In addi-
tion, we observed that the reaction did not give any of the
desired product 3aa in the absence of a copper catalyst (Ta-
ble 1, entry 16).
2
CO
3
K
3
PO
4
69
56
14
trace
75
89
99
0
With optimized conditions in hand, we explored the
substrate scope of indole-2-carboxylic acids. The results are
summarized in Scheme 2. When indole-2-carboxylic acid
(1a) and its derivatives were applied to the reaction under
the optimized conditions, compounds with electron-donat-
ing or electron-withdrawing groups gave the corresponding
products in high yields. For example, compound 1e with a
methoxy group on the 5-position of the indole ring was
treated with 2a, affording the product 3ea in 95% yield. Un-
der the same reaction conditions, fluoro-substituted com-
pound 1f reacted with 2a to give the product 3fa in 90%
yield. We found that a methyl substituent on the 4-, 5-, or
t
1
1
1
1
1
1
0
KO Bu
1
K
K
K
K
K
K
3
3
3
3
3
3
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
2
DMSO
NMP
3
4c
5d
6d
NMP
NMP
1
NMP
a
The reactions were performed in a sealed tube with 1a (0.2 mmol), 2a
0.4 mmol), catalyst (0.02 mmol), and base (0.4 mmol) in solvent (2.0 mL)
at 150 °C for 12 h under N
Yield of isolated product.
Iodobenzene (2a) (0.2 mmol) was used at 150 °C for 24 h.
Iodobenzene (2a) (0.2 mmol) was used at 160 °C for 12 h.
(
2
.
b
c
6
-position of the indole ring had little effect on the yield of
d
the reaction (see products 3ba, 3da, and 3ha). However,
product 3ja with a chloro group on the 7-position of the in-
dole ring was obtained in a lower 52% yield.
We used Cu O as the catalyst to optimize the other reac-
2
tion conditions. It was found that bases such as Li CO ,
We next examined the scope of aryl iodides. As shown
in Scheme 3, various aryl iodides could be employed in the
reaction to give the corresponding products in high yields.
Aryl iodides with electron-donating and electron-with-
drawing groups afforded the corresponding products 3ab–
al in high yields under the optimized conditions. For exam-
ple, 3-iodotoluene reacted with 1a to provide the product
3ab in 93% yield. Under the same reaction conditions, the
product 3ae was formed in 95% yield when 3-chloroiodo-
benzene was used in the reaction. It was found that the
presence of substituents on the 3- or 4-position of the aryl
iodides had little effect on the product yields. 3-Fluoroiodo-
2
3
Na CO , Cs CO , and KOAc afforded the product 3aa in poor
2
3
2
3
to low yields (Table 1, entries 5–8). Further optimization re-
vealed K PO as the best base with a 69% yield of product
3
4
3aa being obtained (Table 1, entry 9). The effect of the sol-
vent was investigated, and N-methylpyrrolidone (NMP)
proved to be optimal giving the product 3aa in 75% yield
(Table 1, entries 11–13).
We found that the reaction provided 3aa in 89% yield
when the reaction time was extended to 24 hours with one
equivalent of 2a (Table 1, entry 14). To our delight, the yield
was greatly improved to 99% when the reaction was per-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

C
Synthesis
Y. Zhang et al.
Paper
I
Br
Cu2O (10 mol%)
2
Cu O (10 mol%)
N
N
R2
R2
CO2H
+
CO2H
+
K3PO4 (2 equiv)
NMP, 160 °C, 12 h
3 4
K PO (2 equiv)
NMP, 160 °C, 12 h
N
H
R2
N
R2
H
1a
2
3
1a
4
3
N
N
N
N
N
N
Me
OMe
F
Me
OMe
Ph
3ab, 93%
3ac, 84%
3ad, 91%
3aa, 93%
3ab, 89%
3ac, 95%
N
N
N
N
N
N
Cl
Me
OMe
Me
OMe
Cl
3ae, 95%
3af, 88%
3ag, 92%
3af, 88%
3ag, 93%
3aj, 80%
N
N
N
N
N
N
Me
tBu
Cl
F
CF3
CN
3ah, 93%
3ai, 90%
3aj, 90%
3ak, 88%
3al, 82%
3am, 19%
Scheme 4 Scope of aryl bromides 4
N
N
Based on the above experimental results and related lit-
erature reports, a possible mechanism is given in Scheme 5.
Treatment compound 1a with the copper(I) species forms a
copper carboxylate complex A, which undergoes decarbox-
ylation to produce the arylcopper species B. Next, anion ex-
change occurs to afford species C.15 The copper(III) species
D is generated by the oxidative addition of the aryl halide to
species C.16 Finally, reductive elimination leads to the prod-
uct 3 and reforms the copper(I) species for the next catalyt-
ic cycle.
CF3
CN
3ak, 93%
3al, 79%
Scheme 3 Scope of aryl iodides 2
benzene gave the product 3ad in 91% yield, whilst product
ai was obtained in 90% yield when 4-fluoroiodobenzene
was employed in the reaction with 1a.
3
In order to further extend the substrate scope, we inves-
tigated the use of aryl bromides in this reaction. As shown
in Scheme 4, the reaction of 1a with bromobenzene (4a) in
CuI]
[
CO2H
N
N
the presence of 10 mol% of Cu O with 2 equivalents of
3
Ar
reductive
elimination
H
2
1
a
K PO in NMP at 160 °C for 12 hours proceeded well to af-
3
4
ford the product 3aa in 93% yield. This reaction was not af-
fected by the electronic properties of the substituents on
the aryl bromides. Substrates with electron-donating or
electron-withdrawing groups on the aromatic ring gave the
corresponding products in high yields. However, the reac-
tion showed an obvious steric effect because the meta- and
para-substituted products 3ab and 3af were obtained in ex-
cellent yields, while the ortho-substituted product 3am was
formed in a very low 19% yield.
N
CO2[CuI]
[CuIII]
N
D
H
A
Ar
X
oxidative
addition
decarboxylation
CO2
Ar-X
CuI]
[
anion
exchange
N
H
N
B
[CuI]
C
Scheme 5 The proposed reaction mechanism
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

D
Synthesis
Y. Zhang et al.
Paper
In conclusion, we have demonstrated a novel method for
5-Methyl-1-phenyl-1H-indole (3da)17
the synthesis of N-aryl indoles based on the Cu O-catalyzed
Yield: 29.0 mg (70% yield); colorless oil.
2
decarboxylative coupling of indole-2-carboxylic acids with
substituted aryl iodides and bromides. This method shows
good functional group tolerance and provides the N-aryl in-
doles in high yields.
1
H NMR (600 MHz, CDCl ): δ = 7.56–7.42 (m, 6 H), 7.37–7.25 (m, 2 H),
3
7.04 (d, J = 8.6 Hz, 1 H), 6.58 (d, J = 3.2 Hz, 1 H), 2.46 (s, 3 H).
13
C NMR (151 MHz, CDCl ): δ = 140.1, 134.3, 129.8, 129.7, 128.0,
3
126.3, 124.2, 124.1, 120.9, 110.3, 103.2, 21.5.
5
-Methoxy-1-phenyl-1H-indole (3ea)17
All reacations were carried out with standard Schlenk techniques un-
der predried nitrogen. Preparative thin-layer chromatography was
performed using glass plates precoated with silica gel. Melting points
were obtained using a WRS-3 digital melting point apparatus and are
uncorrected. NMR spectra were recorded at 298 K on a Bruker
Yield: 42.6 mg (95%); colorless oil.
1
H NMR (600 MHz, CDCl ): δ = 7.52–7.44 (m, 5 H), 7.33–7.27 (m, 2 H),
3
7.13 (d, J = 2.4 Hz, 1 H), 6.87 (dd, J = 8.9, 2.4 Hz, 1 H), 6.59 (d, J = 3.0 Hz,
1
H), 3.85 (s, 3 H).
13
C NMR (151 MHz, CDCl ): δ = 154.7, 140.0, 131.1, 130.0, 129.7,
1
13
3
AVANCE III 600 spectrometer (600 MHz for H, 151 MHz for C) with
128.5, 126.3, 124.1, 112.6, 111.5, 103.3, 102.8, 56.0.
deuterated chloroform (CDCl ) as the solvent. Chemical shifts are re-
3
1
ported in δ (ppm) referenced to SiMe as the internal standard for H
4
5-Fluoro-1-phenyl-1H-indole (3fa)18
13
NMR and CDCl (δ 77.16) for C NMR. The following abbreviations are
3
used: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. The
Yield: 38.2 mg (90%); colorless oil.
metal complexes CuI, Cu O, and CuOAc were purchased from Alfa Ae-
1
2
H NMR (600 MHz, CDCl ): δ = 7.54–7.42 (m, 5 H), 7.36–7.32 (m, 2 H),
3
s
a
r
.
C
u
(
O
A
c
)
w
a
s
p
u
r
c
h
a
s
e
d
f
r
o
m
A
l
a
d
d
i
n
C
h
e
m
i
s
t
r
y
C
o
.
L
t
d
.
K
P
O
2
3
4
7.31 (dd, J = 9.2, 2.4 Hz, 1 H), 6.94 (td, J = 9.2, 2.4 Hz, 1 H), 6.61 (d, J =
2.8 Hz, 1 H).
and Cs CO were purchased from Alfa Aesar. K CO3 was purchased
2
3
2
from Sinopharm Chemical Reagent Co. Ltd.
13
C NMR (151 MHz, CDCl ): δ = 158.3 (d, J = 235.6 Hz), 139.7, 132.6,
3
1
1
29.8, 129.7, 129.6, 126.8, 124.4, 111.4 (d, J = 9.2 Hz), 110.9, 110.7,
05.9 (d, J = 22.6 Hz), 103.5 (d, J = 4.4 Hz).
N-Aryl Indoles 3; General Procedure
A mixture of Cu O (0.02 mmol), K PO (0.4 mmol), indole-2-carboxyl-
2
3
4
ic acid (1) (0.2 mmol), and aryl halide (2) (0.2 mmol) in NMP (2.0 mL)
-Chloro-1-phenyl-1H-indole (3ga)19
5
was stirred at room temperature under a N atmosphere. The mixture
2
Yield: 39.4 mg (87%); colorless oil.
1H NMR (600 MHz, CDCl
): δ = 7.63 (d, J = 2.0 Hz, 1 H), 7.49 (t, J = 7.6
was then heated to 160 °C and stirred at this temperature for 12 h.
After completion of the reaction, the mixture was cooled to room
temperature and diluted with EtOAc. The mixture was washed with
H O and aq NaCl, dried over MgSO and filtered. After evaporation of
3
Hz, 2 H), 7.46–7.41 (m, 3 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 3.2 Hz,
1 H), 7.14 (dd, J = 8.8, 2.0 Hz, 1 H), 6.59 (d, J = 3.2 Hz, 1 H).
2
4
the solvent, the residue was purified by preparative thin-layer chro-
matography on silica gel with PE/EtOAc (50:1) as eluent to give the
product 3.
13
C NMR (151 MHz, CDCl ): δ = 139.5, 134.4, 130.4, 129.8, 129.3,
3
126.9, 126.1, 124.4, 122.7, 120.6, 111.7, 103.2.
6
-Methyl-1-phenyl-1H-indole (3ha)20
1
-Phenyl-1H-indole (3aa)17
Yield: 38.8 mg (94%); colorless oil.
Yield: 38.1 mg (99%); colorless oil.
1
H NMR (400 MHz, CDCl ): δ = 7.56 (d, J = 8.0 Hz, 1 H), 7.54–7.46 (m, 4
3
1
H NMR (600 MHz, CDCl ): δ = 7.68 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 8.2
3
H), 7.37–7.30 (m, 2 H), 7.25 (d, J = 3.2 Hz, 1 H), 7.00 (dd, J = 8.0, 1.0 Hz,
1
Hz, 1 H), 7.48 (d, J = 4.2 Hz, 4 H), 7.39–7.28 (m, 2 H), 7.25–7.14 (m, 2
H), 6.67 (d, J = 3.2 Hz, 1 H).
H), 6.62 (dd, J = 3.2, 1.0 Hz, 1 H), 2.45 (s, 3 H).
13
C NMR (101 MHz, CDCl ): δ = 140.1, 136.4, 132.3, 129.7, 127.5,
3
13
C NMR (151 MHz, CDCl ): δ = 139.9, 136.0, 129.7, 129.4, 128.1,
3
127.2, 126.4, 124.6, 122.2, 120.9, 110.5, 103.5, 22.0.
126.5, 124.5, 122.5, 121.2, 120.5, 110.6, 103.7.
6
-Methoxy-1-phenyl-1H-indole (3ia)7b
4
-Methyl-1-phenyl-1H-indole (3ba)17
Yield: 40.9 mg (92%); colorless oil.
Yield: 38.7 mg (93%); colorless oil.
1
H NMR (600 MHz, CDCl ): δ = 7.54 (d, J = 8.6 Hz, 1 H), 7.51–7.44 (m, 4
3
1
H NMR (400 MHz, CDCl ): δ = 7.48 (d, J = 4.4 Hz, 4 H), 7.40 (d, J = 8.2
3
H), 7.36–7.31 (m, 1 H), 7.20 (d, J = 3.2 Hz, 1 H), 7.04 (d, J = 2.0 Hz, 1 H),
Hz, 1 H), 7.35–7.29 (m, 2 H), 7.15–7.09 (m, 1 H), 6.97 (d, J = 7.2 Hz, 1
H), 6.69 (dd, J = 3.2, 0.8 Hz, 1 H), 2.59 (s, 3 H).
6.84 (dd, J = 8.6, 2.0 Hz, 1 H), 6.59 (d, J = 3.2 Hz, 1 H), 3.78 (s, 3 H).
13
C NMR (151 MHz, CDCl ): δ = 156.8, 140.0, 136.7, 129.8, 127.1,
3
13
C NMR (101 MHz, CDCl ): δ = 140.1, 135.7, 130.7, 129.7, 129.3,
3
126.5, 124.4, 123.6, 121.7, 110.3, 103.6, 94.3, 55.8.
127.5, 126.5, 124.5, 122.6, 120.7, 108.3, 102.1, 18.9.
7
-Chloro-1-phenyl-1H-indole (3ja)17
4
-Methoxy-1-phenyl-1H-indole (3ca)17
Yield: 23.6 mg (52%); white solid; mp 54–55 °C (PE).
Yield: 41.7 mg (93%); colorless oil.
1
H NMR (600 MHz, CDCl ): δ = 7.58 (d, J = 7.8 Hz, 1 H), 7.48–7.35 (m, 5
3
1
H NMR (400 MHz, CDCl ): δ = 7.48 (d, J = 4.4 Hz, 4 H), 7.36–7.28 (m, 1
3
H), 7.20–7.14 (m, 2 H), 7.06 (t, J = 7.6 Hz, 1 H), 6.65 (d, J = 3.0 Hz, 1 H).
H), 7.23 (d, J = 3.2 Hz, 1 H), 7.19–7.10 (m, 2 H), 6.79 (dd, J = 3.2, 0.8 Hz,
1
13
C NMR (151 MHz, CDCl ): δ = 140.3, 132.3, 131.9, 131.7, 128.4,
3
H), 6.57 (dd, J = 7.4, 0.8 Hz, 1 H), 3.97 (s, 3 H).
128.2, 128.0, 124.0, 120.9, 119.9, 117.3, 103.3.
13
C NMR (101 MHz, CDCl ): δ = 153.6, 140.1, 137.4, 129.7, 126.6,
3
126.5, 124.5, 123.3, 120.0, 104.1, 100.9, 100.3, 55.5.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

E
Synthesis
Y. Zhang et al.
Paper
-(3-Methylphenyl)-1H-indole (3ab)21
1
H NMR (600 MHz, CDCl ): δ = 7.68 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 8.2
1
3
Hz, 1 H), 7.51 (d, J = 8.4 Hz, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 3.2
Hz, 1 H), 7.29–7.09 (m, 2 H), 6.66 (d, J = 3.2 Hz, 1 H), 1.38 (s, 9 H).
Yield: 38.5 mg (93%); colorless oil.
1
H NMR (400 MHz, CDCl ): δ = 7.67 (d, J = 7.8 Hz, 1 H), 7.55 (d, J = 8.2
3
13
C NMR (151 MHz, CDCl ): δ = 149.6, 137.3, 136.1, 129.3, 128.2,
Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.31–7.26 (m, 3 H), 7.23–7.13 (m, 3
H), 6.65 (d, J = 3.2 Hz, 1 H), 2.42 (s, 3 H).
3
126.6, 124.1, 122.3, 121.2, 120.3, 110.7, 103.3, 34.8, 31.5 (3 C).
13
C NMR (101 MHz, CDCl ): δ = 139.9, 139.8, 136.0, 129.5, 129.4,
3
1
-(4-Fluorophenyl)-1H-indole (3ai)21
128.1, 127.3, 125.1, 122.4, 121.5, 121.2, 120.4, 110.7, 103.5, 21.6.
Yield: 38.0 mg (90%); colorless oil.
-(3-Methoxyphenyl)-1H-indole (3ac)17
1
H NMR (600 MHz, CDCl ): δ = 7.68 (ddd, J = 7.6, 1.4, 0.8 Hz, 1 H),
1
3
7
.49–7.39 (m, 3 H), 7.26 (d, J = 3.2 Hz, 1 H), 7.23–7.11 (m, 4 H), 6.67
Yield: 37.5 mg (84%); colorless oil.
(dd, J = 3.2, 0.8 Hz, 1 H).
1
H NMR (400 MHz, CDCl ): δ = 7.67 (d, J = 7.8 Hz, 1 H), 7.59 (d, J = 8.2
3
13
C NMR (151 MHz, CDCl ): δ = 162.0, 160.4, 136.2, 136.0 (d, J = 3.0
Hz, 1 H), 7.38 (t, J = 8.2 Hz, 1 H), 7.32 (d, J = 3.2 Hz, 1 H), 7.24–7.13 (m,
3
Hz), 129.3, 128.1, 126.3 (d, J = 8.4 Hz), 121.9 (d, J = 194.8 Hz), 120.5,
2
H), 7.10–7.02 (m, 2 H), 6.87 (ddd, J = 8.2, 2.6, 0.8 Hz, 1 H), 6.66 (dd,
116.6 (d, J = 22.7 Hz), 110.3, 103.7.
J = 3.2, 0.8 Hz, 1 H), 3.83 (s, 3 H).
13
C NMR (151 MHz, CDCl ): δ = 160.6, 141.0, 135.9, 130.4, 129.5,
3
1
-(4-Chlorophenyl)-1H-indole (3aj)17
128.0, 122.5, 121.2, 120.5, 116.6, 112.0, 110.7, 110.3, 103.7, 55.5.
Yield: 41.0 mg (90%); colorless oil.
-(3-Fluorophenyl)-1H-indole (3ad)18
1
H NMR (600 MHz, CDCl ): δ = 7.67 (d, J = 8.0 Hz, 1 H), 7.49 (d, J = 8.0
1
3
Hz, 1 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.40 (d, J = 8.6 Hz, 2 H), 7.26 (d, J = 3.2
Hz, 1 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.17 (t, J = 7.6 Hz, 1 H), 6.67 (d, J = 3.2
Hz, 1 H).
Yield: 40.3 mg (91%); colorless oil.
1
H NMR (600 MHz, CDCl ): δ = 7.68 (d, J = 7.8 Hz, 1 H), 7.59 (d, J = 8.4
3
Hz, 1 H), 7.44 (dd, J = 14.6, 7.8 Hz, 1 H), 7.30 (t, J = 6.4 Hz, 2 H), 7.23 (d,
J = 8.8 Hz, 2 H), 7.18 (t, J = 7.4 Hz, 1 H), 7.04 (t, J = 8.4 Hz, 1 H), 6.69 (s,
13
C NMR (151 MHz, CDCl ): δ = 138.5, 135.9, 132.1, 129.9, 129.5,
3
127.8, 125.6, 122.7, 121.4, 120.7, 110.4, 104.2.
1
H).
13
C NMR (151 MHz, CDCl ): δ = 164.2, 162.5, 141.4 (d, J = 9.0 Hz),
3
1
-[4-(Trifluoromethyl)phenyl]-1H-indole (3ak)21
135.7, 131.0 (d, J = 9.2 Hz), 129.6, 127.8, 122.1 (d, J = 214.4 Hz), 120.9,
119.8 (d, J = 3.0 Hz), 113.3 (d, J = 21.1 Hz), 111.6 (d, J = 24.2 Hz), 110.5,
104.4.
Yield: 48.8 mg (93%); white solid; mp 55–56 °C (PE).
1
H NMR (600 MHz, CDCl ): δ = 7.75 (d, J = 8.6 Hz, 2 H), 7.69 (d, J = 7.8
3
Hz, 1 H), 7.60 (d, J = 8.6 Hz, 2 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.32 (d, J = 3.2
Hz, 1 H), 7.25 (td, J = 7.6, 1.0 Hz, 1 H), 7.19 (td, J = 7.6, 1.0 Hz, 1 H), 6.71
1
-(3-Chlorophenyl)-1H-indole (3ae)21
(
1
d, J = 3.2 Hz, 1 H).
Yield: 43.3 mg (95%); colorless oil.
3
1
C NMR (151 MHz, CDCl ): δ = 142.9, 135.6, 129.8, 128.3 (q, J = 33.2
3
H NMR (600 MHz, CDCl ): δ = 7.68 (d, J = 7.8 Hz, 1 H), 7.56 (d, J = 8.2
3
Hz), 127.5, 127.1 (q, J = 3.6 Hz), 124.1 (q, J = 271.8 Hz), 124.0, 123.1,
1
Hz, 1 H), 7.51 (s, 1 H), 7.44–7.36 (m, 2 H), 7.33–7.28 (m, 2 H), 7.23 (d,
J = 8.2, Hz, 1 H), 7.18 (t, J = 7.0 Hz, 1 H), 6.69 (s, 1 H).
21.6, 121.1, 110.5, 105.1.
13
C NMR (151 MHz, CDCl ): δ = 141.1, 135.7, 135.3, 130.7, 129.6,
3
1
-(4-Cyanophenyl)-1H-indole (3al)23
127.7, 126.6, 124.5, 122.8, 122.4, 121.4, 120.9, 110.5, 104.5.
Yield: 34.5 mg (79%); white solid; mp 91–92 °C (PE/EtOAc).
-(4-Methylphenyl)-1H-indole (3af)19
1
H NMR (600 MHz, CDCl ): δ = 7.77 (d, J = 8.6 Hz, 2 H), 7.69 (d, J = 7.8
1
3
Hz, 1 H), 7.59 (d, J = 8.6 Hz, 3 H), 7.32 (d, J = 3.2 Hz, 1 H), 7.27 (t, J = 7.6
Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1 H), 6.74 (d, J = 3.2 Hz, 1 H).
Yield: 36.5 mg (88%); colorless oil.
1
H NMR (600 MHz, CDCl ): δ = 7.67 (d, J = 7.6 Hz, 1 H), 7.52 (d, J = 8.2
3
13
C NMR (151 MHz, CDCl ): δ = 143.6, 135.3, 133.9, 130.0, 127.2,
Hz, 1 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.34–7.26 (m, 3 H), 7.20 (t, J = 7.4 Hz,
3
123.9, 123.3, 121.7, 121.5, 118.6, 110.5, 109.4, 105.8.
1
H), 7.15 (t, J = 7.4 Hz, 1 H), 6.65 (d, J = 3.2 Hz, 1 H), 2.41 (s, 3 H).
13
C NMR (151 MHz, CDCl ): δ = 137.4, 136.4, 136.1, 130.3, 129.3,
3
1
-(2-Methylphenyl)-1H-indole (3am)17
128.2, 124.4, 122.3, 121.2, 120.3, 110.6, 103.3, 21.2.
Yield: 7.8 mg (19%); colorless oil.
-(4-Methoxyphenyl)-1H-indole (3ag)19
1
H NMR (600 MHz, CDCl ): δ = 7.69 (d, J = 7.0 Hz, 1 H), 7.38–7.27 (m, 4
1
3
H), 7.18–7.11 (m, 3 H), 7.03 (d, J = 7.4 Hz, 1 H), 6.66 (s, 1 H), 2.05 (s, 3
H).
Yield: 40.9 mg (92%); white solid; mp 57–59 °C (PE).
1
H NMR (600 MHz, CDCl ): δ = 7.67 (dd, J = 8.0, 1.0 Hz, 1 H), 7.44 (dd,
3
13
C NMR (151 MHz, CDCl ): δ = 138.4, 137.1, 136.0, 131.3, 128.8,
J = 8.0, 1.0 Hz, 1 H), 7.40–7.35 (m, 2 H), 7.25 (d, J = 3.2 Hz, 1 H), 7.22–
3
128.4, 128.3, 128.2, 126.9, 122.1, 121.0, 120.0, 110.7, 102.6, 17.8.
7.11 (m, 2 H), 7.04–6.97 (m, 2 H), 6.64 (dd, J = 3.2, 0.8 Hz, 1 H), 3.84 (s,
3
H).
13
C NMR (101 MHz, CDCl ): δ = 158.3, 136.4, 132.9, 129.1, 128.4,
3
Funding Information
126.1, 122.3, 121.1, 120.2, 114.8, 110.5, 103.0, 55.7.
We are grateful to the National Natural Science Foundation of China
1
-[4-(tert-Butyl)phenyl]-1H-indole (3ah)22
(Grant No. 21172142).
N
ati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
1
7
2
1
4
2)
Yield: 46.6 mg (93%); white solid; mp 115–117 °C (PE).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F

F
Synthesis
Y. Zhang et al.
Paper
Supporting Information
(11) (a) Yuan, Y.; Thomé, I.; Kim, S. H.; Chen, D.; Beyer, A.;
Bonnamour, J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth. Catal.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611946.
2010, 352, 2892. (b) Cano, R.; Ramón, D. J.; Yus, M. J. Org. Chem.
2011, 76, 654. (c) Chen, J.; Wu, J. Angew. Chem. Int. Ed. 2017, 56,
3951.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
(
12) (a) Guo, X.-X. J. Org. Chem. 2013, 78, 1660. (b) Gu, D.-W.; Guo,
X.-X. Org. Biomol. Chem. 2014, 12, 6114. (c) Guo, X.-X.; Gu, D.-
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D.-W.; Zi, J.; Wu, X.-Y.; Guo, X.-X. Org. Lett. 2016, 18, 2439.
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–F