Copper-catalyzed N-arylation of 2-arylindoles with aryl halides

Article abstract of DOI:10.1016/j.cclet.2014.04.021

10 mol% CuI combined with the DMEDA ligand can efficiently catalyze the N-arylation of 2-arylindoles with aryl iodides and aryl bromides in good to excellent yields. The aryl halides bearing electron-rich or electron-deficient functional groups can be wel

Full text of DOI:10.1016/j.cclet.2014.04.021

Accepted Manuscript
Title: Copper-catalyzed N-arylation of 2-arylindoles with aryl
halides
Author: Wei Liu Li-Ya Han Rui-Li Liu Li-Ge Xu Yan-Lan Bi
PII:
S1001-8417(14)00191-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2014.04.021
CCLET 2965
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
28-3-2014
12-4-2014
14-4-2014
Please cite this article as: W. Liu, L.-Y. Han, R.-L. Liu, L.-G. Xu, Y.-L. Bi, Copper-
catalyzed N-arylation of 2-arylindoles with aryl halides, Chinese Chemical Letters
(2014), http://dx.doi.org/10.1016/j.cclet.2014.04.021
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Graphical Abstract
Copper-catalyzed N-arylation of 2-arylindoles with aryl halides
∗
Wei Liu , Li-Ya Han, Rui-Li Liu, Li-Ge Xu, Yan-Lan Bi
College of Food Science and Technology, Henan University of Technology, Zhengzhou 450001, China
CuI/DMEDA
R
+
X
Ar
R
K PO , 110 oC
N
H
3
4
N
Ar
R = Ph, Me, etc.
X = I, Br
20 examples
up to 98% yield
Air-stable CuI combined with the DMEDA ligand can efficiently catalyze the N-arylation of 2-arylindoles with aryl iodides and aryl bromides in
good to excellent yields (up to 98%). The aryl halides bearing electron-rich or electron-deficient functional groups can be well tolerated under this
mild reaction conditions.
—
——
∗
Corresponding author.
E-mail address: liuwei307@hotmail.com
Page 1 of 6

Original article
Copper-catalyzed N-arylation of 2-arylindoles with aryl halides
∗
Wei Liu , Li-Ya Han, Rui-Li Liu, Li-Ge Xu, Yan-Lan Bi
College of Food Science and Technology, Henan University of Technology, Zhengzhou 450001, China
ARTICLE INFO
ABSTRACT
Article history:
10 mol% CuI combined with the DMEDA ligand can efficiently catalyze the N-arylation of
2-arylindoles with aryl iodides and aryl bromides in good to excellent yields. The aryl halides
bearing electron-rich or electron-deficient functional groups can be well tolerated under this
mild reaction conditions.
Received 28 January 2014
Received in revised form 12 April 2014
Accepted 14 April 2014
Available online
Keywords:
2
-Arylindoles
Aryl halides
N-Arylation
Copper
1
. Introduction
During the past ten years significant advances have been achieved in the development of C-N cross-coupling reactions [1-4]. In the
presence of several transition metal catalysts (Cu, Pd, Ni, etc.), various nitrogen-containing compounds, such as pharmaceuticals,
agrochemicals and other functional molecules, could be efficiently prepared. In terms of the cost and toxicity, the copper-catalyzed
Ullmann-type C-N coupling reaction represents one of the most desirable methods to prepare the numerous N-containing molecules in
chemical industry [2]. The pioneering work has established the fact that ligands are crucial in the copper-catalyzed C-N coupling
reactions [1].
The indole-containing compounds are among the most important and ubiquitous heterocyclic frameworks in nature. Copper-
catalyzed N-arylation of nitrogen heterocycles with aryl halides have been developed with various ligands. In 2002, Buchwald first
found that the diamine ligands were efficient for copper catalyzed N-arylation of simple indoles [5-7]. In 2004, Taillefer developed
Chxn-Py-Al-copper complex for the C-N coupling reactions [8]. Subsequently, many useful ligands, such as L-proline [9], 1,1'-
binaphthyl-2,2'-diamine [10], benzotriazole [11], 2-(2'-pyridyl)benzimidazole [12], 8-hydroxyquinalidine [13], tetrazole-1-acetic acid
[
14] and 4,7-dipyrrolidinyl-1,10-phenanthroline [15], were developed for promoting the copper-catalyzed N-arylation of indoles and
other nitrogen heterocycles with aryl halides. Recently, we have been focusing on the preparation of N-containing heterocycles based
on cheap and green catalyst systems (Cu-based catalysts) via C-N cross-coupling reactions (Scheme 1, c). Other elegant catalytic [16-
2
1] or non-catalytic [22-25] methods were developed for the facile synthesis of substituted indoles. Recently, Lutz Ackermann and
coworkers [26-27] developed a one-pot substituted indole synthesis base on Pd/Cu catalysis (Scheme 1, a). Katz and coworkers [28]
reported an interesting strong base mediated benzodipyrrole syntheses from diethynyldifluorobenzenes (Scheme 1, b). To the best of
our knowledge, there are limited examples for the N-arylation of 2-arylindoles and its derivatives via Cu-catalysis. Herein, we reported
our results on the copper-catalyzed N-arylation of arylindoles with aryl halides in the presence of the DMEDA ligand with excellent
yields under mild conditions.
2
. Experimental
Reagents were obtained commercially and used as received. Solvents were purified and dried by standard methods. Toluene was
dried and distilled from sodium/benzophenone immediately prior to use under a nitrogen atmosphere. Unless noted otherwise, all other
compounds have been reported in the literatures or are commercially available. All reactions were performed in oven-dried glassware.
Thin layer chromatography (TLC) employed glass 0.25 mm silica gel plates. Flash chromatography columns were packed with 200-
1
13
3
00 mesh silica gel. H NMR and C NMR data were recorded in CDCl solutions with Varian Mercury (300 MHz) spectrometers
3
—
——
∗
Corresponding author.
E-mail address: liuwei307@hotmail.com
Page 2 of 6

using tetramethylsilane (TMS) as an internal standard. Analytical gas chromatography (GC) was performed using an Aglient 6890 Gas
Chromatography fitted with a flame ionization detector.
Representative procedure for the synthesis of 1,2-diphenylindole (3a): A 10 mL Schlenk tube was charged with 2-phenylindole 1a
(
193.2 mg, 1.0 mmol), CuI (10 mol%, 19.0 mg, 0.1 mmol) and K PO (424 mg, 2.0 mmol). The Schlenk tube was evacuated and filled
3 4
with N (this procedure was repeated three times), and then toluene (2.0 mL), DMEDA (20 mol%, 17.6 mg, 0.2 mmol) and
2
o
iodobenzene 2a (244.8 mg, 1.2 mmol) were added. The resulting mixture was stirred at 110 C for 24 h. After cooling to room
temperature, the reaction mixture was quenched and extracted with ethyl acetate (10 mL × 3). The organic extracts were combined,
dried over Na SO and concentrated under reduced pressure, and then purified by silica gel chromatograph (petroleum ether) to yield
2
4
the desired product as a white solid ( 245.1mg, 91% yield). The data of compounds 3a-q can be found in Supporting information.
3. Results and discussion
The C-N coupling reaction between 2-phenylindole (1a) and iodobenzene (2a) was selected as the model reaction to explore the
suitable reaction conditions (Table 1). Commonly used and air-stable copper salt CuI was chosen as the catalyst and several other
reaction parameters, such as ligand, base and solvent were carefully optimized. Using anhydrous K PO (2 equiv.) as the base and
3
4
toluene as the solvent, a series of bidentate N-containing ligands were tested. In the absence of any ligands, CuI (10 mol%) could not
o
independently promote the conversion of 2-phenylindole (1a) after 24 h at 110 C (Table 1, entry 1). The use of ethylenediamine (EDA)
led to a 55% yield of the desired N-arylation product (3a) (Table 1, entry 2). When N,N'-dimethylethylenediamine (DMEDA) was used,
a 100% conversion of 1a was observed and a 96% yield of the desired N-arylation product (3a) was obtained (Table 1, entry 3).
However, the use of tetramethyl substituted ethylenediamine (TMEDA) resulted in no consumption of 1a (Table 1, entry 4).
Presumably, the increased level of substitution at nitrogen leads to reduced binding capacity. Other commonly used ligands, such as
cyclohexane-1,2-diamine (CHDA), 2,2'-bipyridine (bipy), 1,10-phenanthroline (phen) and L-proline were also examined but all offered
poor to moderate yields of 3a (Table 1, entries 5-8). 8-Hydroxyquinoline (quinolin-8-ol) showed inferior efficiency as well (Table 1,
entry 9). The preliminary results showed that the combination of air stable CuI (10 mol%) and DMEDA (20 mol%) appeared to be an
efficient catalyst system for the N-arylation of 2-phenylindole (1a) with aryl iodides (2). Base is also crucial for this transformation.
K PO was the most efficient among the tested bases (Table 1, entries 11-14), and other tested strong bases (t-BuOK, t-BuONa and t-
3
4
BuOLi) produced no or lower conversion (Table 1, entries 12-14). Amongst all tested solvents, toluene is a superior solvent to others
dioxane and DMF) (Table 1, entries 15 and 16). It required 24 h to complete conversion of 1a, while a shorter reaction time (12 h) led
to a 66% yield of 3a (Table 1, entry 10). Moreover, ligandless reaction conditions [16-17] were also examined for this reaction (Table
, entries 17 and 18), the results showed that using 20 mol% CuI as catalyst and DMF as solvent, no reaction was observed in the
presence of K PO or Cs CO .
(
1
3
4
2
3
With the optimized reaction conditions in hand, the substrate scope of the N-arylation of 2-arylindole (1) with aryl halides (2) was
studied and the results were shown in Table 2. Electron-rich and electron-deficient aryl iodides reacted smoothly with 2-phenylindole
(
1a) and offered good to excellent yields in most cases. 1-Iodo-4-methylbenzene (2b) and 1-iodo-4-methylbenzene (2c) reacted with 2-
phenylindole (1a) to generate the corresponding N-arylation products (3b and 3c) in 90% and 87% yield, respectively. 1-Iodo-4-
methoxybenzene (2e) and 1-iodo-3-methoxybenzene (2f) reacted well with 2-phenylindole (1a) and produced the corresponding N-
arylation products (3e and 3f) in 84% and 87% yield, respectively. Notably, aryl iodides bearing ortho-substituents (Me, OMe and Cl)
reacted sluggishly and no or lower conversions were observed (3d, 3g and 3j), which might be attributable to the influence of steric
hindrance. The reactions of 1-fluoro-4-iodobenzene and 1-chloro-4-iodobenzene gave 75% and 74% yield (3h and 3i), respectively.
Electron-deficient aryl iodide bearing ester group was also favored in this system and produced the corresponding N-arylation product
(
2
3m) in 80% yield. Other aryl iodides, such as 1-butyl-4-iodobenzene and 4-iodo-1,2-dimethylbenzene can be efficiently coupled with
-phenylindole (1a) and gave the coupling products in 94% and 86% yield (3k and 3l), respectively. Under the standard reaction
conditions, the Cu-catalyzed N-arylation of other substituted indoles were examined as well. Carbazole and 2-methylindole can
undergo the C-N coupling smoothly and afforded the corresponding N-arylation products (3n and 3o) in 98% and 94% yield,
respectively. Moreover, 2-(4-fluorophenyl)-indole and 2-(4-chlorophenyl)-indole were also suitable under the same reaction conditions
and afforded the N-arylation products (3p and 3q) in 81% and 86% yield, respectively.
Aryl bromides were tested under the standard reaction conditions (10 mol% CuI/20 mol% DMEDA) and a 62% yield of the coupled
product was obtained after 24 h. When the less reactive Ph-Cl was tested, lower conversion was observed with 20 mol% CuI catalyst at
o
elevated temperature (120 C) after 36 h (Table 2, 3a). Considering the modest outcome of the less reactive aryl bromides, 20 mol%
CuI and 40 mol% DMEDA was employed to promote the reactions and good yields (80%-84%) of the corresponding N-arylation
products (3a, 3b and 3e) were achieved (Scheme 2).
4
. Conclusion
In conclusion, we have developed a simple and efficient method for the synthesis of substituted indoles using cheap CuI as the
catalyst and DMEDA as the ligand. Electron-rich and electron-deficient aryl iodides and aryl bromides all can afford the corresponding
N-arylation products with 2-arylindole in good to excellent yields under mild reaction conditions. Further investigation on promoting
the conversion of aryl halides bearing ortho-substituents will be reported in due course.
Page 3 of 6

Acknowledgments
This work was supported by the National Natural Science Foundation of China (No. 21102036) and Plan for Scientific Innovation
Talent of Henan University of Technology (No. 11CXRC02) and startup fund from HAUT (No. 2010BS042).
References
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Page 4 of 6

Ph
Ph
Pd/Cu cat.
+
H2N Ar
H2N Ar
Ph (a)
Ph (b)
N
Lutz Ackermann's work
X
F
Ar
KOt-Bu, DMSO
+
+
Jeffrey L. Katz's work
N
Ar
Cu cat.
R
X
Ar
R
(c)
N
H
N
This work
Ar
Scheme 1. Methods for the preparation of 1,2-arylindoles.
Ph
Ph
R
2
4
0 mol% CuI
0 mol% DMEDA
K3PO4, toluene
10 oC, 24 h
NH
N
+
Br
R
R = OMe, 3e 80%
CH , 3b 84%
3
1
H, 3a 81%
Scheme 2. N-Arylation of 2-phenylindole with aryl bromides.
Table 1
a
Reaction conditions for C-N coupling.
Cu Cat.
+
I
110 o
C
N
N
H
1a
2a
3a
b
Entry
[Cat.] (mol%)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (20)
CuI (20)
Ligand
none
EDA
DMEDA
TMEDA
CHDA
Bipy
Phen
L-proline
Quinolin-8-ol
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
none
Base
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
DMF
Time (h)
24
24
24
24
24
24
24
24
24
12
24
24
24
24
24
24
Yield (%)
1
2
3
4
5
6
7
8
9
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
3
K
2
PO
PO
PO
PO
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
4
4
4
4
<5
55
c
96 (91 )
<5
42
60
65
27
20
66
68
<5
8
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
CO
3
t-BuOK
t-BuONa
t-BuOLi
33
84
0
0
<5
K
3
K
3
K
3
PO
PO
PO
4
4
4
d
d
DMF
DMF
24
24
none
Cs
2
CO
3
a
Unless otherwise noted, the reaction was carried out with 1a (1.0 mmol), 2a (1.2 mmol), CuI (0.10 mmol), ligand (0.20 mmol), base (2.0 mmol), solvent (2.0
o
mL), 110 C, under nitrogen atmosphere.
b
Yield was determined by GC analysis.
Isolated yield.
The reaction was carried out with 1a (1.4 mmol) and 2a (1.0 mmol).
c
d
Page 5 of 6

Table 2
a
Substrates scope for N-arylation of 2-arylindole.
10 mol% CuI
2
0 mol% DMEDA
R
X
Ar
R
+
K3PO4, toluene
110 oC, 24 h
N
H
N
Ar
1
2
3
N
N
N
N
N
N
N
H3C
H3C
3c, 87%
3
a, 91% (X=I); 62% (X=Br);
1% (X=Cl)b
3b, 90%
CH3
OMe
3
d, 0%
3e, 84%
1
N
N
N
N
MeO
Cl
MeO
f, 87%
F
Cl
3
3g, <5%
3h, 75%
3
i, 74%
3j, 0%
CH3
R'
N
N
N
N
N
CH3
nBu
CH3
CO Et
OMe
OMe
p, 81% (R' = F);
3q, 86% (R' = Cl)
2
OMe
3
3k, 94%
3l, 86%
3m, 80%
3n, 98%
3o, 94%
a
o
The reaction was carried out with 1 (1.0 mmol), 2 (1.2 mmol), CuI (0.10 mmol), DMEDA (0.20 mmol), K
3
PO
4
(2.0 mmol), toluene (2.0 mL), 110 C, under
nitrogen atmosphere.
b
o
3 4
CuI (0.20 mmol), DMEDA (0.40 mmol), K PO (2.0 mmol), toluene (2.0 mL), 120 C, 36 h.
Page 6 of 6