Synthesis of 1-aryl indoles via coupling reaction of indoles and aryl halides catalyzed by CuI/metformin

Article abstract of DOI:10.1016/j.tet.2014.06.080

Ullmann-type C-N coupling reaction has been developed for the synthesis of 1-aryl indole derivatives by indoles and aryl halides in the presence of CuI/metformin (CuI/Met) in DMF. This method is very easy, rapid, and high yielding reaction for the synthesis of 1-aryl indoles. In particular, the metformin, which is used as ligand, is inexpensive and nontoxic that is considered to be relatively environmentally benign.

Full text of DOI:10.1016/j.tet.2014.06.080

Tetrahedron 70 (2014) 5626e5631
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of 1-aryl indoles via coupling reaction of indoles and aryl
halides catalyzed by CuI/metformin
Hu Chen , Min Lei ,*, Lihong Hu a
a
b
,b,
*
a
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai, 200237, PR China
Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Shanghai, 201203, PR China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 April 2014
Received in revised form 8 June 2014
Accepted 19 June 2014
Available online 24 June 2014
Ullmann-type CeN coupling reaction has been developed for the synthesis of 1-aryl indole derivatives by
indoles and aryl halides in the presence of CuI/metformin (CuI/Met) in DMF. This method is very easy,
rapid, and high yielding reaction for the synthesis of 1-aryl indoles. In particular, the metformin, which is
used as ligand, is inexpensive and nontoxic that is considered to be relatively environmentally benign.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Aryl halide
CeN coupling reaction
Metformin
Ullmann-type reaction
1. Introduction
and the use of relatively expensive reagents. In particular, many
ligands used in reported methods, which are not yet commercially
The amination of aryl halides have found important applications
available, are difficult to synthesize in lab. Hence, the development
of an efficient and versatile method for the CeN coupling reaction
of indoles and aryl halides for the synthesis of 1-aryl indoles is an
active ongoing research area and there is scope for further im-
provement toward milder reaction conditions and inexpensive
ligands.
1
for the preparation of compounds in biological and material sci-
2
ences. Indoles are one of the most prevalent heterocyclic com-
pounds, which are present as the basic cores in many natural
3
products and potent pharmaceutical compounds. Therefore, syn-
thesis of 1-aryl indole derivatives by Ullmann-type CeN coupling
reaction of indoles and aryl halides in recent years has gained
considerable attention.
Metformin (Met), as shown in Fig. 1, is an oral antidiabetic drug
in the biguanide class, and it is the first-line drug of choice for the
treatment of type 2 diabetes, in particular, in overweight and obese
people and those with normal kidney function. Recently, Met is
In most of the existing methods, the 1-aryl indole derivatives
were synthesized by indoles and aryl halides in the presence of Cu-
4
5
6
23
catalysts, which including CuI, CuI/pipecolinic acid, Cu
2
O,
reported that it can be used as the ligand for coupling reaction.
7
8
9
10
Cu(OAc)
IL,
CuSO
2
$H
Cu(OAc)
/pyridine N-oxide, CuO, CuI/hydrazone,17 Cu(II)TMHD,
2
O, CuI/PPAPM, CuI/diamine, CuBr/DPPhen, CuI/
For example, A. Alizadeh and his co-workers reported that Suzu-
1
1
12
13
14
2
/MW,
CuI/amino acid,
CuI/N-hydroxyimide,
kieMiyaura reactions could proceed smoothly catalyzed by
15
16
18
23a
4
2
Pd(OAc) /Met complex in 2013.
19
and other catalysts. In recent years, several other transition
metals as the catalysts for the this CeN coupling reaction have also
2
0
21
been reported, such as [Fe]/[Cu], Cd(OAc)
da) (ReO ) .
3 4 2
2
$2H
2 2
O, and Cu (p-
22
Although, a number of modified methods under
improved conditions have been reported, many of them suffer from
drawbacks, such as unsatisfactory yields, and long reaction times,
Fig. 1. The structure of metformin (Met).
In connection with our ongoing research for the development of
simple and efficient methods for synthesis of 1-aryl indole de-
rivatives using simple and inexpensive ligands, we now report an
efficient and practical method for the CeN coupling reaction of
*
Corresponding authors. Tel.: þ86 21 2023 1000; fax: þ86 21 2023 1965 (M.L.);
tel./fax: þ86 21 2023 1965 (L.H.); e-mail addresses: mlei@simm.ac.cn (M. Lei),
lhhu@simm.ac.cn (L. Hu).
http://dx.doi.org/10.1016/j.tet.2014.06.080
0
040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

H. Chen et al. / Tetrahedron 70 (2014) 5626e5631
5627
indoles and aryl halides in the presence of CuI/Met as a catalyst
Scheme 1).
absence of CuI/Met (Table 2, entry 1). On the contrary, 45% yield of
3a was obtained when 5 mol % of CuI was added to the mixture
(
(Table 2, entry 2). To our delight, the yields could further increase
significantly if the Met was added as the ligand (Table 2). From the
yield and reaction time of view, the results of Table 3 revealed that
10 mol % of CuI and 20 mol % Met was optimal for this Ullmann-
type CeN coupling reaction (Table 2, entry 7).
Table 2
a
Scheme 1. Synthesis of 1-aryl indoles catalyzed by CuI/Met.
Optimization of the amount of CuI/Met
2
. Results and discussion
Initially, the reaction of 1H-indole 1a (1 mmol), iodobezene
1.5 mmol), CuI (0.1 mmol), Met (0.2 mmol), and Cs CO (2 mmol)
(
2
3
was performed in toluene at reflux temperature for 24 h, affording
the product 1-phenyl-1H-indole 3a in 41% yield (Table 1, entry 1).
To further improve the efficiency of this synthetic approach, various
Entry
CuI (mol %)
Met (mol %)
Time (h)
Yield of 3a (%)b
1
2
3
4
5
6
7
8
0
5
5
0
0
10
20
0
10
20
40
24
24
6
6
24
6
0
45
72
86
55
82
93
93
solvents, such as DMF, DMSO, MeCN, toluene, EtOH, and H
2
O-PEG
4
00, have been applied to promote this Ullmann-type CeN cou-
pling reaction (Table 1). As shown in Table 1, the reaction proceeded
5
ꢀ
smoothly in DMF or DMSO at 130 C for 6 h to obtain the product 3a
10
10
10
20
in 91 and 93% yields, respectively. Conversely, low yields of 3a were
afforded when the mixture was stirred in MeCN, toluene, and EtOH
as solvents under reflux temperature for 24 h (36e41%) (Table 1,
6
6
a
Reaction conditions: 1H-indole 1a (1 mmol), iodobenzene 2a (1.5 mmol),
entries 3e5). Moreover, the reaction also carried out in H
00, unfortunately, only trace amount of 3a was detected by LCeMS
Table 1, entry 6). These results clearly indicated that DMF and
2
O-PEG
ꢀ
Cs
2
CO
3
(2 mmol), DMF (2 mL), 130 C, under nitrogen atmosphere.
4
(
b
Isolated yields.
DMSO were suitable solvents for this Ullmann-type CeN coupling
reaction, and we chose DMF as the reaction medium for all further
reactions.
Table 3
Reaction of indole 1a and substituted benzene 2 catalyzed by CuI/Meta
Table 1
a
Optimization of the reaction solvents and temperature
Entry
PheX 2
Time (h)
Yield of 3a (%)b
1
2
3
4
5
PheI 2a
6
24
48
48
48
93
92
Trace
Trace
Trace
PheBr 2b
PheCl 2c
PheOTs 2d
PheOTf 2e
ꢀ
Yield of 3a (%)b
Entry
Solvent
Temp ( C)
Time (h)
1
2
3
4
5
6
7
8
Toluene
DMF
Reflux
130
130
Reflux
Reflux
Reflux
110
24
6
6
24
24
24
6
41
93
91
39
36
Trace
77
a
Reaction conditions: 1H-indole 1a (1 mmol), substituted benzene 2 (1.5 mmol),
CO (2 mmol), DMF (2 mL),
DMSO
MeCN
EtOH
CuI (0.1 mmol), metformin hydrochloride (0.2 mmol), Cs
2
3
ꢀ
1
30 C, under nitrogen atmosphere.
b
O-PEG 400c
Isolated yields.
H
2
DMF
DMF
110
24
81
After the optimization, we then carried out the reaction of 1H-
a
Reaction conditions: 1H-indole 1a (1 mmol), iodobenzene 2a (1.5 mmol), CuI
0.1 mmol), metformin hydrochloride (0.2 mmol), Cs
indole 1a with aromatic compounds 2 that containing different
leaving groups, such as Ie, Bre, Cle, TsOe, and TfOe. As shown in
Table 3, the reaction of 1a and 2a was proceeded rapidly and effi-
ciently to obtain the product 3a in 93% yield for 6 h (Table 3, entry
(
2
CO
3
(2 mmol), solvent (2 mL),
under nitrogen atmosphere.
b
Isolated yields.
H O (2 mL), PEG 400 (0.5 g).
2
c
1
). Prolonged the reaction time to 24 h, a satisfied yield (92%) could
be obtained when 2a was replaced by 2b as substrate (Table 3, entry
). On the contrary, only trace amount of 3a were observed as in-
ꢀ
Furthermore, the reaction also carried out in DMF at 110 C for
6
h, and the product 3a was obtained in 77% yield (Table 1, entry 7).
Even though prolonged the reaction time to 24 h, the yield of 3a did
not increased significantly (81%). In view of yields and reaction
time, we proceeded all the further reaction at 130 C. Furthermore,
2 3 3 4 3
we also chose K CO , K PO and Et N as the bases for this reaction,
and only 65, 52, 37% yields of 3a were obtained, respectively.
Next, we optimized the amount of CuI/Met in the reaction be-
tween 1H-indole 1a, iodobezene 2a in DMF at 130 C (Table 2). No
2
dicated by LCeMS when using 2c, 2d and 2e as starting materials
even the mixture was stirred at 130 C for 48 h (Table 3, entries
ꢀ
ꢀ
3e5). These results revealed that iodo or bromo aromatic com-
pounds were suitable for this Ullmann-type CeN coupling reaction.
In order to gauge the scope of these conditions, several 1H-in-
doles 1 and aryl halides 2 were examined under the optimized
conditions using CuI/Met as the catalyst. As shown in Table 4,
among the MeO-substituted iodobenzene, 3- or 4-substituted
ꢀ
product 3a was observed when the mixture was stirred for 24 h in

5628
H. Chen et al. / Tetrahedron 70 (2014) 5626e5631
Table 4
a
Synthesis of 1-aryl-1H-indoles catalyzed by CuI/Met
Entry
Indole 1
Aryl halide 2
Time
Product 3
Yield
(h)
of 3 (%)b
1
2
3
4
5
6
7
8
9
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Indole 1a
C
C
6
H
H
5
eI 2a
6
3a
3a
3b
3b
3c
3d
3e
3f
93
92
94
77
89
68
58
94
97
71
6
5
eBr 2b
24
12
24
24
24
24
6
4-MeOeC
4-MeOeC
3-MeOeC
2-MeOeC
2-MeeC
4-CleC
4-NO eC
6
6
6
6
H
H
H
H
4
4
4
4
eI 2f
eBr 2g
eI 2h
eI 2i
6
H
4
eI 2j
H eI 2k
6 4
2
6
H
4
eI 2l
3
24
3g
3h
10
3,4-(OCH
2
O)eC
6
H
3
e
Br 2m
11
12
13
14
Indole 1a
Indole 1a
Indole 1a
Indole 1a
Pyridyl-3-Br 2n
Quinolyl-4-Br 2o
Pyrimidinyl-5-Br 2p
1-Me-1H-imidazolyl-
24
3
24
24
3i
3j
3k
3l
69
91
88
68
5
-Br 2q
Thiazolyl-2-Br 2r
eI 2a
4-CleC
4-NO eC
eI 2a
4-CleC
4-NO eC
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Indole 1a
24
18
18
3
6
6
3m
3n
3o
3p
3q
3r
78
88
91
96
94
92
95
69
91
92
63
93
77
95
62
5-MeOeIndole 1b
5-MeOeIndole 1b
5-MeOeIndole 1b
6 5
C H
6
H
4
eI 2k
2
6
H
4
eI 2l
5-NO
5-NO
5-NO
2
eIndole 1c
2
eIndole 1c
2
eIndole 1c
C
6
H
5
6
H
4
eI 2k
2
6
H
4
eI 2l
3
3s
3t
2-MeeIndole 1d
3-MeeIndole 1e
3-PheIndole 1f
3-CHOeIndole 1g
4-MeOeIndole 1h
5-MeeIndole 1i
C
6
C
6
C
6
C
6
C
6
C
6
C
6
C
6
5
H eI 2a
5
H eI 2a
5
H eI 2a
5
H eI 2a
5
H eI 2a
5
H eI 2a
5
H eI 2a
5
H eI 2a
24
18
18
24
24
24
6
3u
3v
3w
3x
3y
3z
2
6-NO eIndole 1j
7-MeeIndole 1k
24
3aa
a
ꢀ
Reaction conditions: 1H-indole 1 (1 mmol), aryl halide 2 (1.5 mmol), CuI (0.1 mmol), metformin hydrochloride (0.2 mmol), Cs
2
CO
3
(2 mmol), DMF (2 mL), 130 C, under
nitrogen atmosphere.
b
Isolated yields.
substrates showed no significant impact on the yields of the desired
products (Table 4, entries 3, 5). However, the yield was decreased
slightly when using 2-MeO-iodobenzene 2i and 2-Me-iodobenzene
2
j under similar conditions (Table 4, entries 6, 7). This phenomenon
could be explained by the steric effects of the aryl iodides. Aryl
halides with electron withdrawing or donating substituent pro-
duced 1-aryl-1H-indoles 3 in good to excellent yields at reflux. In
view of yields and reaction time, aryl halides containing electron
withdrawing group were better than that containing donating
group. Besides, a similar reaction using hetero-aryl bromides were
also investigated, and the corresponding product 3iem were ob-
tained in moderate yields (58e91%) (Table 4, entries 11e15).
Subsequent reactions of variously substituted 1H-indoles 1 with
iodobezene 2a were attempted under similar conditions. As shown
in Table 4, only moderate yields of products 3t and 3aa were ob-
tained when using 2-Me-1H-indole 1d and 7-Me-1H-indole 1h as
the substrates (58e69%). The reactions proceeded smoothly and
equally well for electron-withdrawing as well as electron-donating
substituents on indoles to afford the corresponding 1-aryl-1H-in-
doles 3 in good to excellent yields (Table 4, entries 16e21, 23e28).
We propose a mechanism of the CuI/Met-catalyzed Ullmann-
type CeN coupling reaction as shown in Scheme 2.2
3,24
Initially,
complex A is formed by CuI and Met in the presence of base and
heat. Then, complex A may react with aryl halide 2 to give
Scheme 2. The probable mechanism of CuI/Met-catalyzed Ullmann-type CeN cou-
pling reaction.

H. Chen et al. / Tetrahedron 70 (2014) 5626e5631
5629
intermediate B, followed by reductive elimination to afford the 1-
aryl-1H-indoles product 3, and complex A is released to complete
the catalytic cycle.
7.21e7.15 (m, 2H), 7.13e7.07 (m, 2H), 6.68 (d, J¼3.2 Hz, 1H), 3.79 (s,
þ
3H); MS (ESI): m/z 224 [MþH] .
1
4
.2.5. 1-(o-Tolyl)-1H-indole (3e). Colorless oil; H NMR (400 MHz,
CDCl
3
):
d
7.70 (dd, J¼6.1, 2.6 Hz, 1H), 7.41e7.36 (m, 2H), 7.34e7.30
3
. Conclusion
(m, 2H), 7.19e7.14 (m, 3H), 7.07e7.03 (m, 1H), 6.68 (d, J¼3.1 Hz, 1H),
þ
2.07 (s, 3H); MS (ESI): m/z 208 [MþH] .
In conclusion, we have demonstrated a simple and efficient
procedure for the synthesis of 1-aryl-1H-indoles by Ullmann-
type CeN coupling reaction in the presence of CuI/Met as the
catalyst. This newly developed procedure offers several advan-
tages, such as broad application scope, excellent yields, mild
reaction conditions, and simple operation. It is noteworthy that
Met as the ligand is inexpensive and eco-friendly, which make
4
6
.2.6. 1-(4-Chlorophenyl)-1H-indole (3f). White
solid;
mp
ꢀ
1
9e69 C; H NMR (400 MHz, CDCl
3
): d 7.69 (d, J¼7.7 Hz, 1H),
7
.54e7.42 (m, 5H), 7.30 (d, J¼3.3 Hz, 1H), 7.24 (t, J¼7.3 Hz, 1H), 7.18
(
[
t, J¼7.3 Hz, 1H), 6.72e6.68 (d, J¼3.3 Hz, 1H); MS (ESI): m/z 228
þ
MþH] .
this method attractive to synthesize
derivatives.
a variety of these
4
.2.7. 1-(4-Nitrophenyl)-1H-indole
(3g). Yellow
solid;
mp
ꢀ
1
131e132 C; H NMR (400 MHz, CDCl ):
3
d
8.41 (d, J¼8.9 Hz, 2H),
7
.74e7.68 (m, 3H), 7.66 (d, J¼8.3 Hz, 1H), 7.39 (d, J¼3.3 Hz, 1H), 7.30
(
(
t, J¼7.6 Hz, 1H), 7.25 (t, J¼7.6 Hz, 1H), 6.78 (d, J¼3.4 Hz, 1H); MS
4
4
. Experimental section
.1. General information
þ
ESI): m/z 239 [MþH] .
1
4.2.8. 1-(Benzo[d][1,3]dioxol-5-yl)-1H-indole (3h). Colorless oil; H
NMR (400 MHz, CDCl
3
):
d
7.68 (d, J¼8.0 Hz, 1H), 7.49 (d, J¼8.0 Hz,
Melting points were measured by a WRS-1B micromelting point
apparatus and are uncorrected. NMR spectra were recorded on
a Bruker AMX 400 instruments using solvent peaks as CDCl so-
lutions. HRESIMS were determined on a Micromass Q-Tof Global
mass spectrometer and ESIMS were run on a Bruker Esquire 3000
Plus Spectrometer. TLC was performed on GF254 silica gel plates
1
1
H), 7.27 (d, J¼3.1 Hz, 1H), 7.22 (t, J¼7.5 Hz, 1H), 7.16 (t, J¼7.5 Hz,
H), 7.00e6.90 (m, 3H), 6.65 (d, J¼3.1 Hz,1H), 6.06 (s, 2H); MS (ESI):
3
þ
m/z 238 [MþH] .
4
(
7
.2.9. 1-(Pyridin-3-yl)-1H-indole (3i). Brown oil; 1H NMR
400 MHz, CDCl ):
8.84 (d, J¼2.4 Hz, 1H), 8.62 (d, J¼4.7 Hz, 1H),
.86 (d, J¼8.0 Hz, 1H), 7.71 (d, J¼7.9 Hz, 1H), 7.53 (d, J¼8.2 Hz, 1H),
3
d
(
Yantai Huiyou Inc., China). The chemicals used in this work were
obtained from commercial channels and were used without
purification.
7
1
.48 (dd, J¼8.0, 4.9 Hz, 1H), 7.33 (d, J¼3.3 Hz, 1H), 7.26 (t, J¼7.4 Hz,
H), 7.21 (t, J¼7.4 Hz, 1H), 6.75 (d, J¼3.4 Hz, 1H); MS (ESI): m/z 195
þ
[MþH] .
4
.2. Experimental procedure for the synthesis of 3
4
.2.10. 4-(1H-Indol-1-yl)quinoline (3j). Brown oil; 1H NMR
(400 MHz, CDCl ):
A solution of the indole 1 (1 mmol), aryl halide 2 (1.5 mmol), CuI
3
d
9.05 (d, J¼4.6 Hz, 1H), 8.25 (d, J¼8.3 Hz,
(
0.1 mmol, 10 mol %), metformin hydrochloride (0.2 mmol,
1H), 7.82e7.74 (m, 3H), 7.53 (t, J¼7.2 Hz, 1H), 7.49 (d, J¼4.6 Hz,
2
0 mol %), Cs
2
CO
3
(2 mmol, 2 equiv), and DMF (2 mL) was heated to
. The reaction mixture was stirred for the appro-
1H), 7.41 (d, J¼3.3 Hz, 1H), 7.25e7.22 (m, 1H), 7.22e7.20 (m,
ꢀ
13
130 C under N
2
2H), 6.84 (d, J¼3.3 Hz, 1H); C NMR (100 MHz, CDCl
3
): d 104.9,
priate time (Table 4), and the progress of the reaction was followed
by TLC. After completion of the reaction, the mixture was cooled to
room temperature, and diluted with EtOAc (10 mL). The solid was
removed by filter, and the filtrate was washed with water and brine.
111.0, 118.4, 121.1, 121.4, 123.0, 123.8, 124.9, 127.4, 129.1, 129.3,
130.2, 130.4, 137.2, 144.4, 150.2, 150.8; MS (ESI): m/z 245
þ
[MþH]þ 245.1073,
[MþH] ; HRMS (ESI): calcd for C17
13 2
H N
found 245.1078.
2 4
The organic layer was dried over Na SO , filtered, and concentrated
under reduced pressure. The residue was purified by column
chromatography to afford the product 3.
4.2.11. 1-(Pyrimidin-5-yl)-1H-indole
97e98 C; H NMR (400 MHz, CDCl
(3k). White
): d 9.21 (s, 1H), 8.98 (s, 2H),
solid;
mp
ꢀ
1
3
7
.72 (d, J¼7.8 Hz, 1H), 7.53 (d, J¼8.3 Hz, 1H), 7.32 (d, J¼3.3 Hz, 1H),
4
.2.1. 1-Phenyl-1H-indole (3a). Colorless oil; 1H NMR (400 MHz,
CDCl ):
7.70 (d, J¼7.9 Hz, 1H), 7.58 (d, J¼7.9 Hz, 1H), 7.54e7.50 (m,
H), 7.40e7.33 (m,1H), 7.36 (d, J¼3.2 Hz,1H), 7.23 (t, J¼7.5Hz,1H), 7.18
7.30 (dd, J¼8.2, 1.1 Hz, 1H), 7.24 (t, J¼7.0 Hz, 1H), 6.81 (d, J¼3.3 Hz,
þ
3
d
1H); MS (ESI): m/z 196 [MþH] .
4
þ
(
t, J¼7.5 Hz, 1H), 6.70 (d, J¼3.2 Hz, 1H); MS (ESI): m/z 194 [MþH] .
4.2.12. 1-(1-Methyl-1H-imidazol-5-yl)-1H-indole (3l). Colorless oil;
1
H NMR (400 MHz, CDCl
3
):
d
7.68 (dd, J¼6.8, 1.4 Hz, 1H), 7.57 (s, 1H),
4.2.2. 1-(4-Methoxyphenyl)-1H-indole (3b). White solid; mp
7.25e7.18 (m, 2H), 7.17 (s, 1H), 7.12e7.09 (m, 2H), 6.70 (dd, J¼3.3,
ꢀ
1
13
71e72 C; H NMR (400 MHz, CDCl
3
):
d
7.69 (d, J¼7.9 Hz, 1H), 7.46
3
0.7 Hz, 1H), 3.34 (s, 3H); C NMR (100 MHz, CDCl ): d 30.7, 104.6,
(
d, J¼7.9 Hz,1H), 7.41 (d, J¼8.7 Hz, 2H), 7.28 (d, J¼3.2 Hz,1H), 7.21 (t,
110.3, 121.1, 121.3, 123.2, 125.6, 128.7, 129.3, 137.0, 137.1, 138.4; MS
þ
[MþH]þ
J¼7.6 Hz, 1H), 7.15 (t, J¼7.4 Hz, 1H), 7.04 (d, J¼8.7 Hz, 2H), 6.66 (d,
(ESI): m/z 198 [MþH] ; HRMS (ESI): calcd for C17
13 2
H N
þ
J¼3.2 Hz, 1H), 3.88 (s, 3H); MS (ESI): m/z 224 [MþH] .
198.1026, found 198.1031.
4
.2.3. 1-(3-Methoxyphenyl)-1H-indole (3c). Colorless oil; 1H NMR
400 MHz, CDCl ):
7.69 (d, J¼7.9 Hz,1H), 7.46 (d, J¼7.9 Hz,1H), 7.41
4.2.13. 1-(2-Thiazolyl)-1H-indole (3m). Colorless oil; 1H NMR
(400 MHz, CDCl ):
(
(
3
d
3
d
8.33 (d, J¼5.4, 0.7 Hz,1H), 7.70 (d, J¼3.5 Hz,1H),
d, J¼8.7 Hz, 2H), 7.28 (d, J¼3.2 Hz, 1H), 7.21 (t, J¼7.6 Hz, 1H), 7.15 (t,
7.67 (d, J¼7.8 Hz, 1H), 7.62 (d, J¼3.6 Hz, 1H), 7.39 (td, J¼7.6, 0.9 Hz,
J¼7.4 Hz, 1H), 7.04 (d, J¼8.7 Hz, 2H), 6.66 (d, J¼3.2 Hz, 1H), 3.88 (s,
1H), 7.27 (td, J¼7.6, 0.9 Hz, 1H), 7.06 (d, J¼3.6 Hz, 1H), 6.73 (dd,
þ
þ
3
H); MS (ESI): m/z 224 [MþH] .
J¼3.1, 0.6 Hz, 1H); MS (ESI): m/z 201 [MþH] .
1
4
6
.2.4. 1-(2-Methoxyphenyl)-1H-indole (3d). White solid; mp
4.2.14. 5-Methoxy-1-phenyl-1H-indole (3n). Colorless oil; H NMR
ꢀ
1
9e71 C; H NMR (400 MHz, CDCl
3
):
d
7.69 (dd, J¼6.7, 1.7 Hz, 1H),
(400 MHz, CDCl
3
):
d
7.54e7.49 (m, 4H), 7.47 (d, J¼8.9 Hz, 1H),
7.44e7.37 (m, 2H), 7.30 (d, J¼3.2 Hz, 1H), 7.24 (d, J¼7.5 Hz, 1H),
7.37e7.33 (m, 1H), 7.32 (d, J¼3.0 Hz, 1H), 7.14 (d, J¼2.3 Hz, 1H), 6.88

5630
H. Chen et al. / Tetrahedron 70 (2014) 5626e5631
(
dd, J¼8.9, 2.2 Hz, 1H), 6.60 (d, J¼3.2 Hz, 1H), 3.88 (s, 3H); MS (ESI):
J¼3.2 Hz, 1H), 7.05 (d, J¼8.7 Hz, 1H), 6.60 (d, J¼3.2 Hz, 1H), 2.47 (s,
þ
þ
m/z 224 [MþH] .
3H); MS (ESI): m/z 208 [MþH] .
4
.2.15. 1-(4-Chlorophenyl)-5-methoxy-1H-indole (3o). White solid;
4.2.26. 6-Nitro-1-phenyl-1H-indole
134e135 C; H NMR (400 MHz, CDCl ):
(3z). Yellow
solid;
mp
ꢀ
1
ꢀ
1
mp 81e82 C; H NMR (400 MHz, CDCl
3
):
d
7.50e7.39 (m, 5H),
3
d
8.45 (d, J¼2.0 Hz, 1H),
7
2
.27 (d, J¼4.4 Hz, 1H), 7.13 (d, J¼2.4 Hz, 1H), 6.89 (dd, J¼8.8,
8.07 (dd, J¼8.8, 2.1 Hz,1H), 7.73 (d, J¼8.8 Hz,1H), 7.63e7.56 (m, 3H),
7.52e7.44 (m, 3H), 6.79 (dd, J¼3.2, 0.9 Hz, 1H); MS (ESI): m/z 239
.4 Hz, 1H), 6.61 (d, J¼3.2 Hz, 1H), 3.87 (s, 3H); MS (ESI): m/z 257
þ
þ
[
MþH] .
[MþH] .
1
4
.2.16. 5-Methoxy-1-(4-nitrophenyl)-1H-indole (3p). Yellow solid;
4.2.27. 7-Methyl-1-phenyl-1H-indole (3aa). Colorless oil; H NMR
ꢀ
1
mp 181e182 C; H NMR (400 MHz, CDCl
2
3
):
d
8.39 (d, J¼9.1 Hz,
(400 MHz, CDCl
3
):
d
7.55 (d, J¼7.8 Hz,1H), 7.47e7.37 (m, 5H), 7.13 (d,
H), 7.66 (d, J¼9.0 Hz, 2H), 7.55 (d, J¼9.0 Hz, 1H), 7.36 (d,
J¼3.2 Hz, 1H), 7.06 (t, J¼7.5 Hz, 1H), 6.94 (d, J¼7.1 Hz, 1H), 6.63 (d,
þ
J¼3.3 Hz, 1H), 7.15 (d, J¼2.4 Hz, 1H), 6.94 (dd, J¼9.0, 2.5 Hz,
J¼3.2 Hz, 1H), 2.02 (s, 3H); MS (ESI): m/z 208 [MþH] .
1
H), 6.70 (d, J¼3.3 Hz, 1H), 3.88 (s, 3H); MS (ESI): m/z 269
þ
[
MþH] .
Acknowledgements
4
8
.2.17. 5-Nitro-1-phenyl-1H-indole
3e84 C; H NMR (400 MHz, CDCl
(3q). Yellow
):
solid;
mp
This work was supported by the National Natural Science
Foundation of China (grants 30925040, 81102329, 81273397), the
Chinese National Science & Technology Major Project ‘Key New
ꢀ
1
3
d
8.65 (d, J¼2.2 Hz, 1H), 8.12
(
(
dd, J¼9.1, 2.2 Hz, 1H), 7.60e7.43 (m, 7H), 6.86 (d, J¼3.3 Hz, 1H); MS
þ
ESI): m/z 239 [MþH] .
Drug
Creation
and
Manufacturing
Program’
(grants
2013ZX09508104, 2012ZX09301001-001, 2011ZX09307-002-03),
4.2.18. 1-(4-Chlorophenyl)-5-nitro-1H-indole (3r). Yellow solid; mp
and the Science Foundation of Shanghai (grant 12XD1405700).
ꢀ
1
184e186 C; H NMR (400 MHz, CDCl
3
):
d
8.64 (d, J¼2.2 Hz, 1H),
8
6
.12 (dd, J¼9.1, 2.2 Hz, 1H), 7.57e7.52 (m, 2H), 7.50e7.42 (m, 4H),
References and notes
þ
.87 (d, J¼3.3 Hz, 1H); MS (ESI): m/z 273 [MþH] .
1. (a) Lober, S.; Hubner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett. 2006, 16, 2955; (b)
4
2
8
2
1
.2.19. 5-Nitro-1-(4-nitrophenyl)-1H-indole (3s). Yellow solid; mp
McGee, M. M.; Gemma, S.; Butini, S.; Ramunno, A.; Zisterer, D. M.; Fattorusso,
C.; Catalanotti, B.; Kukreja, G.; Fiorini, I.; Pisano, C.; Cucco, C.; Novellino, E.;
Nacci, V.; Williams, D. C.; Campiani, G. J. Med. Chem. 2005, 48, 4367; (c) Balle, T.;
Perregaard, J.; Ramirez, M. T.; Larsen, A. K.; Soby, K. K.; Liljefors, T.; Andersen, K.
J. Med. Chem. 2003, 46, 265; (d) Olgen, S.; Akaho, E.; Nebioglu, D. Eur. J. Med.
Chem. 2001, 36, 747; (e) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Saka-
moto, S. J. Med. Chem. 1996, 39, 3971.
ꢀ
1
33e234 C; H NMR (400 MHz, CDCl
3
):
d
8.66 (d, J¼1.9 Hz, 1H),
.47 (d, J¼8.7 Hz, 2H), 8.19 (dd, J¼9.2, 2.1 Hz, 1H), 7.71 (d, J¼8.7 Hz,
H), 7.63 (d, J¼9.1 Hz, 1H), 7.53 (d, J¼3.5 Hz, 1H), 6.96 (d, J¼3.4 Hz,
þ
H); MS (ESI): m/z 284 [MþH] .
2
3
. (a) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron 2007, 63, 1031;
(b) Liu, Y.; Nishiura, M.; Wang, Y.; Hou, Z. J. Am. Chem. Soc. 2006, 128, 5592; (c)
Wu, Y.; Li, Y.; Gardner, S.; Ong, B. S. J. Am. Chem. Soc. 2005, 127, 614; (d) Mar-
tineau, D.; Gros, P.; Fort, Y. J. Org. Chem. 2004, 69, 7914; (e) Jia, W.; Bai, D.;
McCormick, T.; Liu, Q.; Motala, M.; Wang, W.; Seward, C.; Tao, Y.; Wang, S.
Chem.dEur. J. 2004, 10, 994.
. (a) Sumpter, W. G.; Miller, F. M. Natural Products Containing the Indole Nucleus
In. Chemistry of Heterocyclic Compounds: Heterocyclic Compounds with Indole
and Carbazole Systems; John Wiley & Sons: Hoboken, NJ, USA, 2008; Vol. 8; (b)
Vikas, S.; Pradeep, K.; Devender, P. J. Heterocycl. Chem. 2010, 47, 491; (c) Morin,
D.; Zini, R.; Urien, S.; Tillement, J. P. J. Pharmacol. Exp. Ther. 1989, 249, 288; (d)
M_esangeau, C.; Amata, E.; Alsharif, W.; Seminerio, M. J.; Robson, M. J.; Mat-
sumoto, R. R.; Poupaert, J. H.; McCurdy, C. R. Eur. J. Med. Chem. 2011, 46, 5154.
. (a) Zhu, R.; Xing, L.; Wang, X.; Cheng, C. J.; Su, D.; Hu, Y. Adv. Synth. Catal. 2008,
4
.2.20. 2-Methyl-1-phenyl-1H-indole (3t). Colorless oil; 1H NMR
(
3
400 MHz, CDCl ): d 7.59e7.51 (m, 3H), 7.48e7.42 (m, 1H),
7
3
.38e7.33 (m, 2H), 7.12e7.07 (m, 3H), 6.41 (s, 1H), 2.31 (d, J¼0.9 Hz,
þ
H); MS (ESI): m/z 208 [MþH] .
.2.21. 3-Methyl-1-phenyl-1H-indole (3u). Colorless oil; 1H NMR
4
(
400 MHz, CDCl
3
):
d
7.64 (d, J¼7.5 Hz, 1H), 7.57 (d, J¼7.7 Hz, 1H),
7.52e7.48 (m, 4H), 7.35e7.30 (m, 1H), 7.25e7.21 (m, 1H), 7.21e7.16
(
2
m, 1H), 7.15 (d, J¼1.0 Hz, 1H), 2.40 (d, J¼0.9 Hz, 3H); MS (ESI): m/z
þ
08 [MþH] .
4
3
50, 1253; (b) Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You, J. J. Org. Chem. 2005, 70,
8535; (c) Yadav, D. K. T.; Rajak, S. S.; Bhanage, B. M. Tetrahedron Lett. 2014, 55,
31.
. Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2006, 348, 2197.
ꢀ
.2.22. 1,3-Diphenyl-1H-indole (3v). White solid; mp 108e109 C;
4
9
1
H NMR (400 MHz, CDCl
3
): d 8.03e7.99 (m, 1H), 7.76e7.71 (m, 2H),
5
7
.65e7.61 (m, 1H), 7.60e7.54 (m, 4H), 7.54e7.46 (m, 4H), 7.40 (ddt,
6. (a) Correa, A.; Carsten Bolm, C. Adv. Synth. Catal. 2007, 349, 2673; (b) Tang, B.-X.;
Guo, S.-M.; Zhang, M.-B.; Li, J.-H. Synthesis 2008, 1707; (c) Colacino, E.; Ville-
brun, L.; Martinez, J.; Lamaty, F. Tetrahedron 2010, 66, 3730; (d) Huang, Y.-Z.;
Gao, J.; Ma, H.; Miao, H.; Xu, J. Tetrahedron Lett. 2008, 49, 948.
J¼6.7, 6.0, 2.2 Hz, 1H), 7.36e7.31 (m, 1H), 7.31e7.24 (m, 2H); MS
þ
(
ESI): m/z 270 [MþH] .
7. (a) Mao, J.; Hua, Q.; Guo, J.; Shi, D. Catal. Commun. 2008, 10, 341; (b) Xu, Z.-L.; Li,
H.-X.; Ren, Z.-G.; Du, W.-Y.; Xu, W.-C.; Lang, J.-P. Tetrahedron 2011, 67, 5282.
8. Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.dEur. J. 2006, 12, 3636.
. (a) Swapna, K.; Murthy, S. N.; Nageswar, Y. V. D. Eur. J. Org. Chem. 2010, 6678; (b)
Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
4
7
.2.23. 1-Phenyl-1H-indole-3-carbaldehyde (3w). Yellow solid; mp
ꢀ
1
9e80 C; H NMR (400 MHz, CDCl ): d 10.12 (s, 1H), 8.39 (d,
3
9
J¼7.0 Hz, 1H), 7.93 (s, 1H), 7.62e7.47 (m, 6H), 7.41e7.31 (m, 2H); MS
þ
(
ESI): m/z 222 [MþH] .
10. Engel-Andreasen, J.; Shimpukade, B.; Ulven, T. Green Chem. 2013, 15, 336.
1. Chen, W.; Zhang, Y.; Zhu, L.; Lan, J.; Xie, R.; You, J. J. Am. Chem. Soc. 2007, 129,
3879.
2. Huang, H.; Yan, X.; Zhu, W.; Liu, H.; Jiang, H.; Chen, K. J. Comb. Chem. 2008, 10,
617.
3. Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164.
4. Ma, H.-C.; Jiang, X.-Z. J. Org. Chem. 2007, 72, 8943.
1
1
1
4.2.24. 4-Methoxy-1-phenyl-1H-indole (3x). Colorless oil; H NMR
1
(
400 MHz, CDCl ): 7.54e7.49 (m, 4H), 7.39e7.33 (m, 1H),
3
d
1
1
1
7
1
.27e7.25 (m, 1H), 7.21e7.13 (m, 2H), 6.80 (dd, J¼3.3, 0.8 Hz,
1
3
H), 6.60 (dd, J¼7.3, 1.0 Hz, 1H), 4.00 (s, 3H);
C NMR
5. Liang, L.; Li, Z.; Zhou, X. Org. Lett. 2009, 11, 3294.
16. Rout, L.; Jammi, S.; Punniyamurthy, T. Org. Lett. 2007, 9, 3397.
(
100 MHz, CDCl
3
): 55.5, 100.3, 100.9, 104.1, 120.0, 123.3, 124.5,
d
1
1
7. Mino, T.; Harada, Y.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2008, 614.
8. Nandurkar, N. S.; Bhanushali, M. ,J.; Bhor, M. D.; Bhanage, B. M. Tetrahedron Lett.
007, 48, 6573.
126.6, 126.6, 129.7, 137.4, 140.1, 153.6; MS (ESI): m/z 224
þ
14NO [MþH]þ 224.1070,
[
MþH] ; HRMS (ESI): calcd for C15
H
2
found 224.7066.
19. (a) Ziegler, D. T.; Choi, J.; Munoz-Molina, J. M.; Bissember, A. C.; Peters, J. C.; Fu,
G. C. J. Am. Chem. Soc. 2013, 135, 13107; (b) Suramwara, N. V.; Thakareb, S. R.;
Karadec, N. N.; Khaty, N. T. J. Mol. Catal. A Chem. 2012, 359, 28; (c) Cano, R.;
Ramon, D. J.; Yus, M. J. Org. Chem. 2011, 76, 654; (d) Zhu, L.; Cheng, L.; Zhang, Y.;
Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737; (e) Liu, S.; Zhou, J. New J. Chem. 2013,
.2.25. 5-Methyl-1-phenyl-1H-indole (3y). Colorless oil; 1H NMR
400 MHz, CDCl ): 7.52e7.45 (m, 6H), 7.37e7.32 (m, 1H), 7.31 (d,
4
(
3
d

H. Chen et al. / Tetrahedron 70 (2014) 5626e5631
5631
37, 2537; (f) Singh, R.; Allam, B. K.; Raghuvanshi, D. S.; Singh, K. N. Tetrahedron
22. Zou, Y.; Lin, H.; Maggard, P. A.; Deiters, A. Eur. J. Org. Chem. 2011, 4154.
2
013, 69, 1038.
23. (a) Alizadeh, A.; Khodaei, M. M.; Kordestani, D.; Beygzadeh, M. Tetrahedron Lett.
2013, 54, 291; (b) Ghorbani-Vaghei, R.; Hemmati, S.; Veisi, H. Tetrahedron Lett.
2013, 54, 7095.
2
0. (a) Taillefer, M.; Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007, 46, 934; (b) Wang,
Z.; Fu, H.; Jiang, Y.; Zhao, Y. Synlett 2008, 2540.
21. Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy, T. Adv. Synth. Catal. 2008, 350, 395.
24. Tang, B.-X.; Guo, S.-M.; Zhang, M.-B.; Li, J.-H. Synthesis 2007, 1707.