Palladium catalyzed direct C-2 arylation of indoles

Article abstract of DOI:10.1016/j.jorganchem.2014.02.017

The synthesis and catalytic evaluation of palladium complexes containing NCN Pincer ligand is reported. The pincer palladium complexes as (pre)catalyst showed efficient catalytic activity for the C-H arylation of N-substituted indoles, allowing the synthesis of 2-arylindoles with moderate to good yields and excellent regioselectivities.

Full text of DOI:10.1016/j.jorganchem.2014.02.017

Journal of Organometallic Chemistry 761 (2014) 28e31
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Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Note
Palladium catalyzed direct C-2 arylation of indoles
*
Jie Feng, Guoping Lu, Meifang Lv, Chun Cai
Chemical Engineering College, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing 210094, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and catalytic evaluation of palladium complexes containing NCN Pincer ligand is reported.
The pincer palladium complexes as (pre)catalyst showed efficient catalytic activity for the CeH arylation
of N-substituted indoles, allowing the synthesis of 2-arylindoles with moderate to good yields and
excellent regioselectivities.
Received 2 January 2014
Received in revised form
19 February 2014
Accepted 24 February 2014
Ó 2014 Elsevier B.V. All rights reserved.
Keywords:
Pincer palladium
N-Methyl indole
C-2 arylation
1. Introduction
ligand (leaching) and giving a high degree of thermal stability. And
due to their unique tridentate coordination architecture, the pincer
2-Arylindoles are a class of important synthetic intermediates of
various biologically and medicinally active molecules [1e7]. Many
traditional approaches to these compounds often require pre-
functionalization of indoles including multistep synthesis pro-
cesses [8e10]. Direct arylations of indoles have been accomplished
in the absence of transition metals using diaryliodonium salts [11].
Recently, great efforts have been devoted to palladium-catalyzed
chemical modifications of indoles via particular direct C(2)eH or
C(3)eH arylations [12e28]. Although the direct CeH arylation of
indoles by employing different transition-metal complexes have
been documented, a large amount, low selectivity and limited
substrates scope, are still the main issues to be addressed [29e33].
PincerePd catalysts are one of the most versatile and useful
tools in an organic chemist’s armory for the formation of carbone
carbon bonds [34e37]. The palladiumepincer complex catalyst was
firstly published by Shaw [38] and van Koten [39] and since then a
large number of publications has appeared on cross-coupling re-
actions. The largest areas are the Heck-coupling/Heck-type re-
actions, Suzuki couplings and related processes. In addition, there
are several recent publications on Sonogashira, Stille, Negishi, and
Hiyama couplings as well [37,40]. All the applications may own to
the unique properties of pincer complexes over conventional
palladium catalysts, because the firm tridentate coordination mode
is responsible for the high stability of the pincer complex pre-
venting, at least to a large extent, the metal dissociating from the
complex is highly selective, highly active to ensure high turnover
numbers, and it permits low catalyst loadings and gives the pos-
sibility for fine-tuning the catalytic properties of the metal center.
As a part of our program devoted to developing metal catalysts,
we focused our attention on the synthesis of new palladium com-
plexes and their application in new reactions. To our knowledge,
there is no report describing the direct CeH arylation of indoles
using NCN PincerePd complexes. Herein, we reported the synthesis
of a schiff-based NCN PincerePd complex and demonstrate that it is
a very active (pre)catalyst for promoting the direct C-2 arylation of
N-methyl indoles.
2. Results and discussion
Although similar NCN structure complex (Pd, Pt, Ni, Au) was
reported [41e44], the palladium catalyst 1e was firstly illustrated in
this paper. The procedures for the synthesis of the catalyst were
shown in Scheme 1 with commercial available raw materials and
simplified steps compared to the literature [41]. 2-Bromo-1,3-
bis(dibromomethyl)benzene 1b was initially synthesized accord-
ing to the literature [45] using 2-bromo-1,3-dimethylbenzene 1a as
raw materials. 1b was then treated with silvernitrate to obtain 2-
bromoisophthalaldehyde 1c [46]. The pincer ligand was prepared
with 1c and aniline under reflux in ethanol [47]. Finally, the catalyst
was synthesized by oxidative addition of Pd(0) species (Pd2(dba)3)
to the carbon-bromide bond of the pincer proligand, which was
isolated as yellow solid (Fig. 1).
With catalyst 1e in hand, the study was initiated with N-methyl-
1H-indole and iodobenzene as model substrates for the reaction
* Corresponding author. Tel.: þ86 25 84315514; fax: þ86 25 84315030.
E-mail address: c.cai@mail.njust.edu.cn (C. Cai).
http://dx.doi.org/10.1016/j.jorganchem.2014.02.017
0022-328X/Ó 2014 Elsevier B.V. All rights reserved.

J. Feng et al. / Journal of Organometallic Chemistry 761 (2014) 28e31
29
Table 1
NBS
AgNO3
Optimal conditions of the CeC coupling between N-methyl-indoles and iodo-
Br
Br
benzene.a
(PhCOO)2
OHC
CHO
Br
Br
Br
Br
Br
1c
1a
1b
NH2
Pd2(dba) 3
toluene
N
Pd
Br
N
N
Br
N
Entry
Solvent
Base
Temperature (ꢀC)
Yield (%)b
Selectivity (%)c
1d
Scheme 1. Preparation of the NCN PincerePd catalyst.
1e
1d
2e
3f
4
5
6
7
8
9
10
11
12
13
14
15
16
DMAc
DMAc
DMAc
DMAc
NMP
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
CsOAc
NaOH
K3PO4
Et3N
80
80
80
80
80
80
80
80
80
80
80
80
80
rt
46
22
77
98
70
74
43
20
0
89
84
20
15
13
68
77
99
89
99
99
90
74
33
87
e
(Table 1). As shown in Table 1, we initially performed a test of the
catalyst loading. Good yields could be obtained in presence of 1 mol
% of catalyst 1e. Same equivalent of Pd(OAc)2 and Pd2(dba)3 were
also tested which show less reactivity(Table 1, entries 1, 2). Slight
decrease of the yield was observed when the catalyst loading of 1e
decreased to 0.5 mol% (Table 1, entry 3). We then examined the
influence of the solvents. The best yields and selectivity were ob-
tained with DMAc (Table 1, entry 4). DMF and NMP were less
effective than DMAc (Table 1, entries 5, 6); whereas HOAc, CH3CN
and water were considered to be ineffective to promote this reac-
tion (Table 1, entries 7e9).
Additionally, a series of bases were selected to improve the ac-
tivity of the couplings. Remarkably, the reaction yields could be
increased by introducing carboxylate salts as base (Table 1, entries
4, 10). It is possible that carboxylate salts could increase the rate of
the palladation step and enhance the electrophilicity of a cationic
palladium species [48]. Other bases such as NaOH, K3PO4 and Et3N
could accelerate the self-couplings of aryl halides which inhibits
the C-2 arylation between N-methyl-indoles and aryl halides in
return (Table 1, entries 11e13). Finally, temperature of the system
was checked with 80 ꢀC as the optimal temperature, moderate yield
could be obtained even decrease the temperature to 80 ꢀC.
With the optimized conditions in hand, a series of N-methyl
indoles and aryl halides were chosen to establish the scope and
generality of the method (Table 2). It is noteworthy that aryl iodides
with both electron-withdrawing and electron-donating substituent
survived the reaction conditions. Comparatively, the aryl iodides
bearing electron-withdrawing groups show higher reactivity than
electron-donating groups except for 1-iodo-4-nitro-benzene which
produce more dehalogened product.
DMF
HOAc
CH3CN
H2O
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
DMAc
93
80
e
e
KOAc
KOAc
KOAc
e
60
110
99
90
a
Reaction conditions: N-methyl-indole (1 mmol), iodobenzene (1.5 mmol), KOAc
(2 mmol), PincerePd (0.01 mmol), DMAc (3 mL), 24 h.
b
Determined by GC; the yield of 3a and 3b.
The selectivity of 3a.
PincerePd was replaced by Pd(OAc)2 (0.05 mmol).
PincerePd was replaced by Pd2(dba)3 (0.05 mmol), PPh3(0.05 mmol).
c
d
e
f
Catalyst loading of PincerePd (0.005 mmol).
substitution in the indole moiety. N-methyl-indole bearing
methoxy group had negative effect on the reactivity, whereas
moderate yield was obtained with indole which afforded 1-phenyl-
1H-indole. Benzothiazole was also tried to replace N-methyl-indole
with lesser reactivity than indoles.
We also attempted to extend our catalytic system to the aryl
bromides and aryl chlorides. Moderate to good yields were ob-
tained using aryl bromides with electron-withdrawing groups. But
the regioselectivity was not as good as aryl iodides with some C-3
arylation product afforded. Aryl chlorides were also tested. The aryl
chloride with even strong electron-withdrawing group, however,
was inactive and only trace amount of conversion was observed.
Finally, a proposed mechanism for the protocol was also illus-
trated in Scheme 2. The Pincer Palladium may work as the direct
catalyst or the catalyst precursor which release Palladium (0) spe-
cies under heated conditions. Observing black particles in the re-
action process, it is possible that the present complexes are not true
catalysts but dispensers of real catalysts. We then tried“mercury
drop” test [49]. Adding an excess of mercury (with respect to the
metal complex) to the reaction mixture will lead to the amalgam-
ation of the surface of a heterogeneous metal particle, thus
poisoning it, but will not affect a homogeneous catalyst. And in this
reaction, the product yield decreases sharply with addition of
100 equiv of Hg(0) per palladium to the reaction mixture. This in-
dicates that Pd(0) species (colloidal palladium or nanoparticles) may
be the direct catalyst in the reaction. Regardless of its function,
however, the NCN Pincer palladium complex is an easy-to-handle,
air stable complex that promotes the C-2 arylation of indoles. Thus
in the first step, the Palladium (0) proceeds to an aryl-palladium
halide intermediate via oxidative addition (Scheme 2). Then, the
carboxylates and the corresponding carboxylic acid could increase
the rate of the palladation step and enhance the electrophilicity of a
cationic palladium species. Finally, the palladium species could
transfer to C-2 product immediately by direct metalation and
Compared to 3c, there is a slightly decrease of the yield of 3d
which may due to the steric effect. We next examined the
Fig. 1. Molecular structure of 1e, hydrogen atoms are omitted for clarity.

30
J. Feng et al. / Journal of Organometallic Chemistry 761 (2014) 28e31
Table 2
use. GC analyses were performed on an Agilent 7890A instru-
m,
Direct arylation of indoles with aryl iodides with pincer palladium complex.a,b
ment (Column: Agilent 19091J-413: 30 m ꢁ 320
m
m ꢁ 0.25
m
carrier gas: N2, Injector: 300 ꢀC, FID detection detector: initial
temperature 80 ꢀC, temperature program: 15 ꢀC/min, final tem-
perature 325 ꢀC. H2 30 mL/min, air 400 mL/min, N2 25 mL/min).
Melting points were determined uncorrected. 1H NMR was
recorded on Bruker DRX 500 and tetramethylsilane (TMS) was
used as a reference.
3.2. The preparation of catalyst 1e
To a solution of 2-bromoisophthalaldehyde (2.13 g, 10 mmol) in
ethanol (25 mL) were added aniline (1.66 g, 20 mmol). The mixture
was heated under reflux. And the reaction was monitored by TLC.
After 24 h, the reaction was almost complete. The reaction mixture
was dried with Na2SO4. Solvent removal and column chromatog-
raphy gave 1d in 95% yield (3.45 g, 9.5 mmol). Under N2 atmo-
sphere, a 25 mL Schlenk tube was charged with 1d (345 mg,
0.95 mmol), Pd2(dba)3 (112.3 mg, 0.5 mmol), and toluene (5 mL).
The mixture was stirred and heated at 60 ꢀC for 12 h. After the
reaction, the solvent was removed, the residue was dissolved in
30 mL of CHCl3, which was washed with water (25 mL ꢁ 2) and
brine (25 mL), and dried over Na2SO4. The solvent was removed in
vacuo and the resulting solid was purified by passing through a
short column (CH2Cl2 as eluent). Catalyst 1e was obtained as a
yellow solid. Yield: 60% (268 mg, 0.57 mmol). 1H NMR (500 MHz,
DMSO)
d
8.59 (s, 2H), 7.65 (d, J ¼ 7.6 Hz, 2H), 7.53 (d, J ¼ 7.5 Hz, 4H),
7.42 (m, 4H), 7.34 (td, J ¼ 7.4, 5.0 Hz, 3H). 13C NMR (126 MHz, CDCl3)
d
183.78, 173.00, 148.06, 142.77, 127.53, 127.43, 127.27, 123.62,
122.86. Anal. Calcd for C20H15BrN2Pd: C, 51.15; H, 3.22; N, 5.96.
Found: C, 51.35; H, 3.13; N, 5.78.
a
Reaction conditions: indoles (1 mmol), aryl halides, (1.5 mmol), KOAc (2 mmol),
catalyst 1e (1 mmol%), DMAc (3 mL), 80ꢀC, 24h.
b
Isolated yield.
c
Reaction conditions: indole (1 mmol), aryl bromides, (1.5 mmolKOAc (2 mmol),
cat 1e (2 mmol%), DMAc (3 mL), 110ꢀC, 24h.
3.3. Single-crystal X-ray analysis of product 1e
d
35 indolewas replaced by benzothiophene.
Crystallographic data (excluding structure factors) for com-
pound 1e (CCDC 948333) have been deposited with the Cam-
bridge Crystallographic Data Centre. Crystallographic data of
complexes was collected at 296 K on a Bruker SMART CCD
reductive elimination. Among the reaction, the Pincer proligand
detached from the catalyst 1e may participate in this catalytic cycle
though it is unclear about the coordinate method. It could help to
improve the yield and selectivity and inhibit the side reaction with
less self-coupling of aryl iodides obtained.
system equipped with graphite-monochromated Mo-K
a radia-
tion ( -4 scan technique. Diffraction
l
¼ 0.071073 nm) using
u
data were integrated by the SAINT program, which was also
used for intensity corrections for Lorentz and polarization ef-
fects. Semi-empirical absorption correction was applied using
SADABS. The structures were solved by direct methods and all
non-hydrogen atoms were refined anisotropically on F2 by full-
matrix least-squares using the SHELXL-97 crystallographic soft-
ware package.
3. Experimental
3.1. General remarks
All the reagents were commercially available and used
without any further purification. The solvents were dried before
Scheme 2. Working hypothesis of the coupling between N-methyl-indole and aryl halides.

J. Feng et al. / Journal of Organometallic Chemistry 761 (2014) 28e31
31
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A mixture of N-methyl-indole (0.013 g, 0.1 mmol), iodobenzene
(0.03 g, 0.15 mmol), KOAc (0.02 g, 0.2 mmol), catalyst (0.1 mg,
0.1 mol%) and DMAc (3 mL) were stirred in a sealed tube at 110 ꢀ
C
for 10 min. Mercury (2 g, 10 mmol) was then added and the mixture
were stirred for another 24 h. After cooling to room temperature,
sulfur (20 mmol, 0.64 g) was added and the mixture was diluted
with ethyl acetate (5 mL) and filtered. The liquid phase was washed
with deionized water and dried over Na2SO4. The resulting liquid
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4. Conclusions
In summary, an efficient Palladium catalyzed method has been
developed for the selective C-2 arylation of N-methyl indoles. This
is the first try applying the Pincer complex to the arylation of N-
methyl indoles and the system works well with the NCN Pincer
Palladium complex as (pre)catalyst. The reaction could be con-
ducted in relatively mild conditions obtaining good yields and
excellent selectivity with aryl iodides and shows moderate activity
with aryl bromides bearing electron-withdrawing groups. The
excellent catalytic performance and easy preparation of the catalyst
make it a useful alternative to other catalysts.
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