Tetrahedron 71 (2015) 2616e2621

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Tetrahedron
journal homepage: www.elsevier.com/locate/tet

Efficient and C2-selective arylation of indoles, benzofurans, and

benzothiophenes with iodobenzenes in water at room temperature
Zhongmiao Xu a, Yulong Xu b, Hongfu Lu a, Ting Yang a, Xichen Lin a, Liming Shao b,
Feng Ren a, *
a
Research and Development, GlaxoSmithKline, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China
b
School of Pharmacy, Fudan University, 826 Zhangheng Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, China

a r t i c l e i n f o a b s t r a c t

Article history: A mild, efficient, and C2-selective palladium-catalyzed arylation reaction of indoles, benzofurans, and
Received 5 January 2015 benzothiophenes with iodobenzenes at room temperature has been developed. The methodology allows
Received in revised form 8 March 2015 the use of water, the most environmentally friendly solvent, as the reaction solvent with the addition of
Accepted 13 March 2015
Tween 80 (2% w/w) to increase the solubility of starting materials. The protocol demonstrated wide
Available online 19 March 2015
substrate scope and good yields were obtained for all the 32 examples evaluated (52e93%).
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
CeH Arylation
Indole
Benzofuran
Benzothiophene
Aqueous micelles

1. Introduction compared with indoles, and elevated reaction temperatures

Functionalized indoles, benzofurans, and benzothiophenes
serve as important building blocks of natural products and bi-
ologically active unnatural molecules.1 Among the known methods
in the functionalization of indoles, benzofurans, and benzothio-
phenes, CeH activation/arylation reactions have attracted tre-
mendous interests due to their high atom efficiency.2 However, the
reported methods always suffered from low regio-selectivities (C-2
over C-3) when no directing groups were pre-installed and/or high
reaction temperatures (100e150
C), which significantly limited
the substrate scope and functional group tolerance. Several C2-
selective arylation reactions of indoles using boronic acids or tri-
fluoroborate salts as arylation agents at room temperature were
developed, whereas in these conditions acetic acid had to be used
as the solvent/co-solvent and oftentimes the trifluoroborates were
not commercially available.3 Recently Larrosa has reported the C2-
arylation of N-alkylated indoles at room temperature using more
readily available iodobenzenes as arylation agents.4 However, when
free indoles were used as the substrates, the arylation reactions
required higher temperature (50
C).4 C2-selective arylations of
benzofurans and benzothiophenes were less extensively reported
* Corresponding author. Tel.: þ86 186 1674 3377; fax: þ86 021 6159 0730; e-mail
address: feng.q.ren@gsk.com (F. Ren).
http://dx.doi.org/10.1016/j.tet.2015.03.051
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
(>100
C) were always required for the limited cases in literatur-
e.2a,e,h Herein, we report a mild, efficient, and C2-selective arylation
reaction of indoles, benzofurans, and benzothiophenes at room
temperature with a wide scope of substrates. To the best of our
knowledge, this is the first time the C2-selective arylation of ben-
zofurans and benzothiophenes with iodobenzenes could be ach-
ieved at room temperature. In addition, our methodology allows
the use of water as the reaction solvent, which makes it even more
attractive in the aspect of reducing the hazardous organic waste.5
To develop organic reactions in aqueous solution has been one of
the research focuses in our group.6 A challenge for aqueous re-
actions is the poor solubility of starting materials, and adding sur-
factants to water has been a widely used strategy to improve
solubility.7 Among the surfactants used, polysorbates (also called
Tweens) offer cheap and environmentally friendly choices8 and we
focused our solvents on the Tweens/water micelle system.
2. Result and discussion
We started our exploration of the CeH arylation using 1-methyl-
1H-indole (1a) and iodobenzene (2a) as starting materials and
Tween 80/water (2% w/w) micelle as the solvent (Table 1). To our
delight, our initial attempt using Pd(OAc)2 as the catalyst and
AgOAc as the additive at room temperature led to the formation of
C2-arylation product (3a) in 39% conversion (Table 1, entry 1).
 Z. Xu et al. / Tetrahedron 71 (2015) 2616e2621 2617

Table 1 Table 2
Optimization of the Pd-catalyzed direct arylation conditions of N-methylindole (1a) Substrate scope of Pd-catalyzed direct CeH arylation of indolesa
with iodobenzene (2a)a

Entry Pd(OAc)2 (mol %) Surfactant Additive Conv (%)c

1 2.5 Tween 80 AgOAc 39
2 2.5 Tween 80 K2CO3 4
3 2.5 Tween 80 CF3COOAg 85
4b 2.5 Tween 80 Ag2OþTFA 24
5 2.5 Tween 20 CF3COOAg 81
6 2.5 Tween 40 CF3COOAg 83
7 2.5 Tween 60 CF3COOAg 73
8 2.5 Tween 85 CF3COOAg 68
9 5 Tween 80 CF3COOAg 97
10 5 none CF3COOAg 38
a
Conditions: N-methylindole 1a (1 mmol), iodobenzene 2a (2 mmol), additive
(1.5 mmol), 2% of surfactant/H2O (w/w, 2 ml).
b
0.75 equiv of Ag2O followed by 1.5 equiv of trifluoroacetic acid.
c
Conversions measured by HPLC.

Encouraged by the result, we started to evaluate the effects of dif-

ferent additives to the reaction including K2CO3, CF3COOAg, and
Ag2O plus TFA (Table 1, entries 2e4). Among them, CF3COOAg
provided the best conversion (85%) to the desired product 3a (Table
1, entry 3). Tweens of different sizes were also explored (Table 1,
entries 5e8) and they all resulted in similar or lower conversions
than Tween 80. Increasing the catalyst loading from 2.5 mol % to
5 mol % accelerated the reaction to provide 97% conversion within
1 h (Table 1, entry 9). In comparison, removal of Tween 80 from the
reaction mixture gave a much decreased conversion (38%, Table 1,
entry 10) at otherwise the same reaction condition, and this was
believed to due to the insolubility of starting materials without the
micelle formation of the surfactant in water.
With the optimized reaction condition of C2-selective arylation
of indoles developed, the substrate scope was examined. As shown
in Table 2, iodobenzenes with a variety of different substitutions
were well tolerated for the reaction. Both electron-withdrawing
and electron-donating substitutions were tolerated at the para-
position of the iodobenzene, providing C2-arylation products in
good isolated yields (67e90%, 3beg). Substitution at the meta-po-
sition also demonstrated high reactivity to afford the desired
product (3h) in high yield (93%). Increasing the steric hindrance of
the iodobenzene by introducing ortho-substitutions resulted in
lower yields (52% and 65% for 3i and 3j, respectively). These results
suggested the reactivities of iodobenzenes for the C2-arylation re-
action were sensitive to steric rather than electronic effects. The
scope of indole substrates was also evaluated, and the reaction
showed good tolerability for different substitutions including both
electron-withdrawing and electron-donating groups (3jen). The
electron-withdrawing substituent at the 4-position of the indole
(3n) resulted in a much slower arylation reaction compared with
the electron-donating substituent (3l) and a much longer reaction
time was required (3 days for 3n and 3 h for 3l). It was noteworthy
that for the free indole substrate (3o) high yield (62%) was also
obtained at room temperature whereas elevated temperature was
required in the reported procedure.4 In addition, the high C2-
selectivity of our arylation reactions was striking and there was
no C3-arylation product observed in all the tested substrates, even
for the steric hindered ones (3i and 3j). The mechanistic studies of
palladium-catalyzed arylation of indoles had been reported and the
palladium migration from the 3-position to the 2-position of the
indoleepalladium(II) intermediate was the key to give C2-
selectivity.9 Our aqueous condition must have strongly favored
a
Unless otherwise stated, the reaction was conducted with 1 (1 mmol), 2 (2
equiv.), CF3COOAg (1.5 equiv.) and Pd(OAc)2 (0.05 equiv.) in Tween
80/H2O (2 mL, 2% w/w) at room temperature for 1 hour. Isolated yields.
b
Reaction runs for 3 hours. c Reaction runs for 3 days.
the C3/C2 migration of palladium to provide the high C2-
selectivity of the arylation products.
We then expanded the substrate scope to benzofurans, which
are less electron-rich than indoles. As expected, the CeH arylation
reactions of benzofurans were much slower (Table 3) compared
with indoles, and extended reaction time (overnight) was required
for the reaction to be completed. In addition, TFA had to be used to
accelerate the arylation reactions.10 The substituted iodobenzenes
were well tolerated and generally good isolated yields of C2-
arylation products were obtained at room temperature (5aee), al-
though para-CF3 iodobenzene was less effective and a prolonged
reaction time was required for high yield (5e). On the other hand,
both electron-withdrawing and electron-donating substitutions on
benzofurans were tolerated. Prolonged reaction times were re-
quired for the full conversions to 5f and 5g, due to poor solubility of
starting materials in the reaction mixtures. Again, our arylation
condition for benzofurans was highly C2-selective, and there was
no C3-arylation product observed for all cases.
We further expanded the substrate scope to benzothiophenes,
which are even less electron-rich. To our delight, both substituted
iodobenzenes and substituted benzothiophenes were well-
tolerated and high yields of desired C2-arylation products were
obtained at room temperature, albeit more prolonged reaction time
was required (Table 4). Electron-withdrawing substitutions on the
iodobenzene made the reactions less efficient and extremely slow,
but good yields could still be obtained (7b and 7e).
3. Conclusion
In summary, we have developed a mild, efficient, and highly C2-
selective palladium-catalyzed arylation reaction of indoles,
2618 Z. Xu et al. / Tetrahedron 71 (2015) 2616e2621
Table 3
Substrate scope of Pd-catalyzed direct CeH arylation of benzofuransa
a
Unless otherwise stated, the reaction was conducted with 4 (1 mmol), 2 (2
equiv.), CF3COOAg (1.5 equiv.), TFA (2 equiv.) and Pd(OAc)2 (0.05 equiv.)
in Tween 80/H2O (2 mL, 2% w/w) at room temperature overnight. Isolated
yields. bReaction runs for 5 days. c Reactions run for 2 days.
Table 4
Substrate scope of Pd-catalyzed direct CeH arylation of benzothiophenesa
Unless otherwise stated, the reaction was conducted with 6 (100 mg), 2 (2
a
equiv.), silver(I) trifluoroacetate (1.5 equiv.), trifluoroacetic acid (2 equiv.)
and diacetoxypalladium (0.05 equiv.) in Tween 80/H2O (2 mL, 2% w/w) at
room temperature for 2 days. Isolated yields. bReactions run for 7 days.
benzofurans, and benzothiophenes with iodobenzenes at room
temperature. To the best of our knowledge, this is the first time C2-
selective arylation of benzofurans and benzothiophenes with
iodobenzenes could be achieved at room temperature. Our meth-
odology allows the use of water, the most environmentally friendly
solvent, as the reaction solvent with the addition of Tween 80 (2%
w/w) to increase the solubility of starting materials. In addition, our
protocol demonstrated wide substrate scope, and good yields were
obtained for all the 32 examples evaluated (52e93%).
4. Experimental section
4.1. General
1
H NMR and 13C NMR spectra were recorded on a Bruker 400/600
NMR spectrometer with CDCl3 or DMSO-d6 as the solvent and TMS
as the internal standard. DMSO-d6 is hexadeuteriodimethylsulf-
oxide, CDCl3 is deuteriochloroform. Chemical shifts are given in
parts per million (d) downfield from the NMR solvent. Abbreviations
for NMR data are as follows: s¼singlet, d¼doublet, t¼triplet,
q¼quartet, m¼multiplet, dd¼doublet of doublets, dt¼doublet of
triplets, app¼apparent, br¼broad. J indicates the NMR coupling
constant measured in Hertz. High resolution mass (HRMS) was
operated in positive mode of electrospray ionization (ESI) at an or-
thogonal acceleration time-of-flight (oa-TOF), SYNAPT G2 HDMSTM
(Waters, Manchester, UK). LCMS (Agilent 1200SL-6110) analysis was
conducted for all compound on acidic condition: acidic condition
refers to water containing 0.05% TFA/acetonitrile as mobile phase on
Agilent SB-C18 column (1.8 mm, 4.630 mm), with MS and photo-
diode array detector (PDA). The following conditions were used:
a gradient from 5 to 95% in 5 min (or 6 min) and held at 95% for
1 min; UV detection at 214 and 254 nm; a flow rate of 1.5 ml/min; full
scan; mass range from 100 to 1000 amu. All the compounds possess
95% purity determined using LC/MS analysis. Column chroma-
tography was performed on Isco or Biotage using a pre-packed silica
gel column, a detector with UV wavelength at 254 nm and 280 nm.
4.2. General procedure for the CeH arylation of indoles with
iodobenzenes
To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg
(1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol),
and Tween-80/H2O (2 ml, 2 wt %) were added. The reaction mixture
was allowed to react at room temperature. After 1 h (or otherwise
stated), the mixture was concentrated under reduced pressure, and
the residue was purified on a silica gel chromatography to afford
the desired product.
4.2.1. 1-Methyl-2-phenyl-1H-indole (3a).4b Yield: 85%; 1H NMR
(400 MHz, CDCl3) d 7.69 (td, J¼1.2, 7.8 Hz, 1H), 7.58e7.54 (m, 2H),
7.54e7.49 (m, 2H), 7.47e7.39 (m, 2H), 7.34e7.27 (m, 1H), 7.23e7.15
(m, 1H), 6.62 (d, J¼0.8 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 141.9, 138.7, 133.2, 129.7, 128.8, 128.3, 128.2, 122.0, 120.8,
120.2, 109.9, 102.0, 31.4; HRMS (ESI): calculated for C15H14N
[MþH]þ, 208.1126. Found [MþH]þ, 208.1127.
4.2.2. 1-Methyl-2-(p-tolyl)-1H-indole (3b).11 Yield: 90%; 1H NMR
(400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.0 Hz, 2H), 7.35
(d, J¼8.0 Hz, 1H), 7.26e7.30 (m, 3H), 7.18 (t, J¼7.6 Hz, 1H), 6.53 (br s,
1H), 3.78 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3) d 141.7,
138.2, 137.8, 129.9, 129.3 (2C), 129.2 (2C), 128.0, 121.5, 120.4, 119.8,
109.6, 101.3, 31.1, 21.3; HRMS (ESI): calculated for C16H16N [MþH]þ,
222.1283. Found [MþH]þ, 222.1285.
4.2.3. 2-(4-Methoxyphenyl)-1-methyl-1H-indole (3c).4b Yield: 85%;
1
H NMR (400 MHz, CDCl3) d 7.65 (d, J¼8.0 Hz, 1H), 7.47 (d, J¼8.0 Hz,
2H), 7.38 (d, J¼8.0 Hz,1H), 7.30 (t, J¼8.0 Hz,1H), 7.20 (t, J¼8.0 Hz,1H),
7.04 (d, J¼8.0 Hz, 2H), 6.54 (s, 1H), 3.91 (s, 3H), 3.78 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 159.4, 141.4, 138.1, 130.6 (2C), 128.0, 125.3, 121.4,
120.2, 119.7, 114.0 (2C), 109.5, 101.0, 55.4, 31.0; HRMS (ESI): calcu-
lated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1229.
4.2.4. 2-(4-Chlorophenyl)-1-methyl-1H-indole (3d).11 Yield: 87%;
1
H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.48 (m, 4H), 7.39
(d, J¼8.0 Hz, 1H), 7.24e7.27 (m, 1H), 7.15 (t, J¼8.0 Hz, 1H), 6.59 (s,
1H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) d 140.2, 138.4, 134.0,
131.3 (2C), 130.5 (2C), 128.8, 127.8, 122.0, 120.6, 120.0, 109.6, 102.0,
31.2; HRMS (ESI): calculated for C15H13ClN [MþH]þ, 242.0737.
Found [MþH]þ, 242.0737.
4.2.5. 2-(4-Fluorophenyl)-1-methyl-1H-indole (3e).11 Yield: 89%; 1H
NMR (400 MHz, CDCl3) d 7.63 (d, J¼7.6 Hz, 1H), 7.45e7.48 (m, 2H),
 Z. Xu et al. / Tetrahedron 71 (2015) 2616e2621
7.36 (d, J¼8.4 Hz, 1H), 7.24e7.27 (m, 1H), 7.13e7.18 (m, 3H), 6.53 (s,
1H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) d 162.6 (d, J¼246 Hz),
140.5, 138.3, 131.1 (d, J¼8.0 Hz), 128.9, 127.9, 121.8, 120.5, 120.0,
115.6 (d, J¼21.5 Hz), 109.7, 101.7, 31.1; 19F NMR: (376 MHz, CDCl3)
d 113.8; HRMS (ESI): calculated for C15H13FN [MþH]þ, 226.1032.
Found [MþH]þ, 225.1030.
4 . 2 . 6 . 1 - M e t hyl - 2 - ( 4 - ( t r i fl u o ro m e t hyl ) p h e nyl ) - 1 H - i n d o l e
(3f).11 Yield: 83%; 1H NMR (400 MHz, CDCl3) d 7.76 (d, J¼8.0 Hz,
2H), 7.66e7.71 (m, 3H), 7.42 (d, J¼8.4 Hz, 1H), 7.31 (t, J¼7.4 Hz, 1H),
7.20 (t, J¼8.0 Hz, 1H), 6.68 (s, 1H), 3.81 (s, 3H); 13C NMR (150 MHz,
CDCl3) d 139.9, 138.8, 136.7, 130.0 (q, J¼21.0 Hz), 129.7 (2C), 128.0,
125.7 (d, J¼4.5 Hz), 125.0 (q, J¼270.0 Hz), 122.4 (2C), 121.0, 120.5,
110.0, 103.0, 31.5; 19F NMR: (376 MHz, CDCl3) 62.5; HRMS (ESI):
calculated for C16H13F3N [MþH]þ, 276.1000. Found [MþH]þ,
276.0995.
4.2.7. 1-Methyl-2-(4-nitrophenyl)-1H-indole (3g).13 Yield: 67%; 1H
NMR (400 MHz, CDCl3) d 8.34 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz,
2H), 7.67 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.3 Hz, 1H), 7.32 (t, J¼8.0 Hz,
1H), 7.19 (t, J¼8.0 Hz, 1H), 6.72 (s, 1H), 3.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 147.0, 139.2, 139.2, 138.9, 129.5, 127.7, 123.9,
123.0, 121.0, 120.5, 109.9, 104.1, 31.5; HRMS (ESI): calculated for
C15H13N2O2 [MþH]þ, 253.0977. Found [MþH]þ, 253.0967.
4.2.8. 1-Methyl-2-(3-nitrophenyl)-1H-indole (3h).12 Yield: 93%; 1H
NMR (400 MHz, CDCl3) d 8.42 (t, J¼1.8 Hz, 1H), 8.31e8.25 (m, 1H),
7.89e7.87 (m, 1H), 7.73e7.65 (m, 2H), 7.46e7.20 (m, 3H), 6.72 (s,
1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.3, 138.7, 138.6,
134.9, 134.5, 129.5, 127.6, 123.7, 122.6, 122.4, 120.9, 120.3, 109.8,
103.2, 31.3; HRMS (ESI): calculated for C15H13N2O2 [MþH]þ,
253.0977. Found [MþH]þ, 253.0974.
4.2.9. 2-(1-Methyl-1H-indol-2-yl)benzonitrile (3i).4b Yield: 52%;
LCeMS: tR¼3.738 min, m/z¼233 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.83 (dd, J¼1.2, 7.8 Hz, 1H), 7.70e7.74 (m, 2H), 7.55 (dd,
J¼1.2, 7.8 Hz, 1H), 7.52 (dd, J¼1.2, 7.8 Hz, 1H), 7.41 (d, J¼8.0 Hz, 1H),
7.32 (dt, J¼1.2, 7.8 Hz, 1H), 7.23e7.15 (m, 1H), 6.76 (s, 1H), 3.72 (s,
3H); 13C NMR (100 MHz, CDCl3) d 138.5, 136.6, 136.3, 133.6, 132.4,
131.4, 128.4, 127.6, 122.6, 121.1, 120.2, 118.0, 113.3, 109.8, 104.4, 31.2.
4.2.10. 1-Methyl-2-(o-tolyl)-1H-indole (3j).4b Yield: 65%; 1H NMR
(400 MHz, CDCl3) d 7.73 (d, J¼8.0 Hz, 1H), 7.34e7.45 (m, 6H),
7.23e7.28 (m, 1H), 6.49 (s, 1H), 3.59 (s, 3H), 2.23 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 140.5, 138.1, 137.3, 132.6, 131.1, 130.0, 128.6,
128.0, 125.5, 121.3, 120.4, 119.6, 109.4, 101.5, 30.3, 20.0; HRMS (ESI):
calculated for C16H16N [MþH]þ, 222.1283. Found [MþH]þ,
222.1289.
4.2.11. 5-Methoxy-1-methyl-2-phenyl-1H-indole (3k). Yield: 70%;
1
H NMR (400 MHz, CDCl3) d 7.44e7.51 (m, 4H), 7.37e7.40 (m, 1H),
7.24 (d, J¼3.6 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 6.91 (dd, J¼8.8, 2.0 Hz,
1H), 6.48 (s, 1H), 3.87 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 154.4, 142.1, 133.8, 132.9, 129.3, 128.5, 128.3, 127.8, 111.9,
110.3, 102.2, 101.3, 55.9, 31.3; HRMS (ESI): calculated for C16H16NO
[MþH]þ, 238.1232. Found [MþH]þ, 238.1231.
4.2.12. 4-Methoxy-1-methyl-2-phenyl-1H-indole (3l).9a Yield: 79%;
1
H NMR (400 MHz, CDCl3) d 7.36e7.53 (m, 5H), 7.18 (t, J¼8.0 Hz, 1H),
7.00 (d, J¼8.2 Hz, 1H), 6.58 (s, 1H), 3.98 (s, 3H), 3.74 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 153.9, 140.9, 140.2, 133.4, 129.8, 128.9, 128.1,
122.9, 119.2, 103.6, 100.3, 99.3, 55.8, 31.2; HRMS (ESI): calculated for
C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1225.
4.2.13. 5-Fluoro-1-methyl-2-phenyl-1H-indole (3m). Yield: 78%; 1H
NMR (400 MHz, CDCl3) d 7.62 (d, J¼8.0 Hz, 1H), 7.45e7.49 (m, 2H),
2619
7.35 (d, J¼8.0 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H), 7.13e7.17 (m, 3H), 6.53
(s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.9 (d,
J¼233 Hz), 143.1, 134.9, 132.5, 129.3, 128.5, 128.1, 128.0 (d, J¼11 Hz),
110.1 (d, J¼10 Hz), 109.7 (d, J¼26 Hz), 105.0 (d, J¼24 Hz), 101.5 (d,
J¼5 Hz), 31.3; 19F NMR: (376 MHz, CDCl3) d 124.8; HRMS (ESI):
calculated for C15H13FN [MþH]þ, 226.1032. Found [MþH]þ,
226.1032.
4.2.14. 2-(4-Chlorophenyl)-1-methyl-1H-indole-4-carbonitrile
(3n). Yield: 72%; 1H NMR (400 MHz, CDCl3) d 7.59 (d, J¼8.0 Hz, 1H),
7.47e7.54 (m, 5H), 7.31 (d, J¼8.0 Hz, 1H), 6.80 (s, 1H), 3.80 (s, 3H);
13
C NMR (100 MHz, CDCl3) d 142.9, 138.0, 135.0, 130.6, 130.0, 129.3,
129.0, 125.3, 121.4, 118.7, 114.3, 102.8, 100.9, 31.5; HRMS (ESI): cal-
culated for C16H12ClN2 [MþH]þ, 267.0689. Found [MþH]þ,
267.0685.
4.2.15. 2-Phenyl-1H-indole (3o).3b Yield: 62%; 1H NMR (400 MHz,
CDCl3) d 8.32 (br s, 1H), 7.62e7.66 (m, 3H), 7.38e7.45 (m, 3H), 7.32
(t, J¼7.2 Hz, 1H), 7.19 (t, J¼7.2 Hz, 1H), 7.12 (t, J¼7.2 Hz, 1H), 6.82 (s,
1H); 13C NMR (150 MHz, CDCl3) 137.9, 136.3, 132.3, 129.2, 129.0,
127.7, 125.2, 122.4, 120.7, 120.3, 110.9, 100.0; HRMS (ESI): calculated
for C14H12N [MþH]þ, 194.0970. Found [MþH]þ, 194.0964.
4.3. General procedure for the CeH arylation of benzofurans
and benzothiophenes with iodobenzenes
To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg
(1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol),
trifluoroacetic acid (2 mmol), and Tween-80/H2O (2 ml, 2 wt %)
were added. The reaction mixture was allowed to react at room
temperature. After the completion of the reaction, the mixture was
concentrated under reduced pressure, and the residue was purified
on silica gel chromatography to afford the desired product.
4.3.1. 2-Phenylbenzofuran (5a).14 Yield: 88%; LCeMS: tR¼4.169
min, m/z¼195 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.92 (d,
J¼8.0 Hz, 2H), 7.66 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.50 (t,
J¼8.0 Hz, 2H), 7.46 (s, 1H), 7.40 (t, J¼8.0 Hz, 1H), 7.31 (t, J¼8.0 Hz,
1H), 7.25 (t, J¼8.0 Hz, 1H).
4.3.2. 2-(4-Chlorophenyl)benzofuran (5b).15 Yield: 87%; LCeMS:
tR¼4.508 min, m/z¼229 [MþH]þ; 1H NMR (600 MHz, CDCl3) d 7.78
(d, J¼8.6 Hz, 2H), 7.57 (d, J¼7.6 Hz, 1H), 7.51 (d, J¼8.2 Hz, 1H), 7.40
(d, J¼8.6 Hz, 2H), 7.25e7.27 (m, 2H), 6.99 (s, 1H); 13C NMR
(150 MHz, CDCl3) d 155.0, 154.8, 134.4, 129.1, 129.1, 129.0, 126.2,
124.6, 123.1, 121.0, 111.2, 101.8.
4.3.3. 2-(p-Tolyl)benzofuran (5c).14 Yield: 88%; LCeMS: tR¼
14
4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.75 (d,
J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.50 (d, J¼8.0 Hz, 1H), 7.29e7.18
(m, 4H), 6.94 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.2,
154.8, 138.6, 129.5 (2C), 129.3, 127.7, 124.9 (2C), 124.0, 122.8, 120.7,
111.1, 100.5, 21.4.
4.3.4. 2-(4-Methoxyphenyl)benzofuran (5d).15 Yield: 78%; LCeMS:
tR¼4.133 min, m/z¼225 [MþH]þ; 1H NMR (CDCl3, 400 MHz) d 7.79
(d, J¼8.0 Hz, 2H), 7.54 (d, J¼7.8 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H),
7.26e7.19 (m, 2H), 6.96 (d, J¼8.0 Hz, 2H), 6.87 (s, 1H) 3.85 (s, 3H).
4.3.5. 2-(4-(Trifluoromethyl)phenyl)benzofuran (5e).16 Yield: 83%;
LCeMS: tR¼4.524 min, m/z¼263 [MþH]þ; 1H NMR: (400 MHz,
CDCl3) d 7.96 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, 2H), 7.62 (d,
J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.34 (dd, J¼8.0, 7.8 Hz, 1H), 7.27
(dd, J¼8.0, 7.8 Hz, 1H), 7.14 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 155.1, 154.2, 133.7, 130.1 (q, J¼33 Hz), 128.8, 125.8 (q, J¼5 Hz),
2620 Z. Xu et al. / Tetrahedron 71 (2015) 2616e2621
19
125.1, 124.9, 124.0 (q, J¼271 Hz), 123.3, 121.3, 111.3, 103.2; F NMR
(376 MHz, CDCl3) d 62.6.
4.3.6. Methyl 2-phenylbenzofuran-5-carboxylate (5f).17 Yield: 84%;
LCeMS: tR¼4.181 min, m/z¼253 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 8.32 (d, J¼1.6 Hz, 1H), 8.02 (dd, J¼1.6, 8.4 Hz, 1H), 7.88e7.86
(m, 2H), 7.54 (d, J¼8.8 Hz, 1H), 7.49e7.45 (m, 2H), 7.41e7.37 (m, 1H),
7.06 (d, J¼0.8 Hz, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 167.2, 157.3, 157.3, 129.8, 129.2, 128.9, 128.2, 126.0, 125.3, 125.0,
123.2, 110.9, 101.5, 52.0.
4.3.7. 5-Methoxy-2-phenylbenzofuran (5g).17 Yield: 87%; LCeMS:
tR¼4.138 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 8.88
(d, J¼7.8 Hz, 2H), 7.49e7.44 (m, 3H), 7.39e7.37 (m, 1H), 7.06 (d,
J¼2.0 Hz, 1H), 6.98 (s, 1H), 6.93 (dd, J¼2.0, 7.8 Hz, 1H), 3.88 (s, 3H);
13
C NMR (100 MHz, CDCl3) d 156.6, 156.0, 149.8, 130.5, 129.7, 128.7,
128.4, 124.8, 112.9, 111.6, 103.2, 101.4, 55.8.
4.3.8. 5-Methyl-2-phenylbenzofuran (5h).15 Yield: 85%; LCeMS:
tR¼4.416 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, DMSO-d6)
d 7.85 (d, J¼7.8 Hz, 2H), 7.43 (t, J¼7.8 Hz, 2H), 7.39 (d, J¼8.0 Hz, 1H),
7.35e7.31 (m, 2H), 7.08 (d, J¼8.0 Hz, 1H), 6.94 (s, 1H), 2.44 (s, 3H).
4.3.9. 7-Methoxy-2-phenylbenzofuran (5i).15 Yield: 80%; LCeMS:
tR¼4.022 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, DMSO-d6)
d 7.89 (d, J¼8.0 Hz, 2H), 7.43 (t, J¼8.0 Hz, 2H), 7.34 (t, J¼8.0 Hz, 1H),
7.19e7.13 (m, 3H), 7.01 (s, 1H), 6.80 (d, J¼8.0 Hz, 1H), 4.04 (s, 3H);
13
C NMR (150 MHz, CDCl3) d 156.1, 145.4, 144.2, 131.0, 130.3, 128.6,
125.1, 123.6, 113.4, 106.7, 101.7, 56.2.
4.3.10. 2-Phenylbenzo[b]thiophene (7a).18 Yield: 76%; LCeMS:
tR¼4.299 min, m/z¼211 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.82
(d, J¼8.0 Hz, 1H), 7.76 (d, J¼8.0 Hz, 1H), 7.71 (d, J¼8.0 Hz, 2H), 7.54
(s, 1H), 7.43e7.40 (m, 2H), 7.36e7.27 (m, 3H); 13C NMR (150 MHz,
CDCl3) d 140.8, 138.2, 138.0, 136.1, 128.8, 127.6, 124.5, 124.4, 123.5,
123.4, 123.0, 129.9.
4.3.11. 2-(4-Chlorophenyl)benzo[b]thiophene (7b).18 Yield: 70%;
LCeMS: tR¼4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.80 (d, J¼8.0 Hz, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.61 (d,
J¼8.0 Hz, 2H), 7.49 (s, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.33e7.30 (m, 2H);
13
C NMR (150 MHz, CDCl3) d 140.8, 137.7, 136.6, 134.5, 133.5, 129.9,
128.9, 124.6, 124.5, 123.8, 123.0, 122.7.
4.3.12. 2-(p-Tolyl)benzo[b]thiophene (7c).18 Yield: 70%; LCeMS:
tR¼4.531 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3):
d 7.94e7.96 (m, 2H), 7.52 (d, J¼8.0 Hz, 2H), 7.40e7.44 (m, 3H), 7.33
(d, J¼8.0 Hz, 2H), 2.47 (s, 3H), 13C NMR (150 MHz, CDCl3): d 140.7,
138.1, 138.0, 137.4, 133.2, 129.5, 129.4, 128.6, 124.4, 124.3, 122.9, 21.3.
4.3.13. 2-(4-Methoxyphenyl)benzo[b]thiophene (7d).18 Yield: 72%;
LCeMS: tR¼4.244 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.91 (s, 1H), 7.54 (d, J¼8.0 Hz, 2H), 7.40 (m, 2H), 7.36 (s, 1H),
7.04e7.07 (m, 2H), 3.91 (s, 3H); 13C NMR (150 MHz, CDCl3) d 159.2,
140.6, 138.2, 137.7, 129.8, 128.6, 124.3, 123.0, 122.9, 122.6, 114.2, 55.4.
4.3.14. 4-(Benzo[b]thiophen-2-yl)benzonitrile (7e).18 Yield: 74%;
LCeMS: tR¼3.964 min, m/z¼236 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.35e7.44 (m, 2H), 7.63 (s, 1H), 7.66 (d, J¼8.0 Hz, 2H), 7.75
(d, J¼8.0 Hz, 2H), 7.79e7.86 (m, 2H); 13C NMR (150 MHz, CDCl3)
d 141.6, 140.3, 139.9, 138.5, 132.7, 126.7, 125.4, 125.0, 124.2, 122.4,
121.8, 118.7, 111.3.
4.3.15. 5-Methyl-2-phenylbenzo[b]thiophene (7f). Yield: 75%;
LCeMS: tR¼4.513 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.82 (d, J¼8.0 Hz, 1H), 7.73 (s, 1H), 7.60 (d, J¼8.0 Hz, 2H),
7.50 (t, J¼8.0 Hz, 1H), 7.44 (d, J¼8.0 Hz, 1H), 7.40 (s, 1H), 7.24 (d,
J¼8.0 Hz, 1H), 2.49 (s, 3H); 13C NMR (150 MHz, CDCl3) d 141.7, 138.2,
137.8, 129.9, 129.3, 129.2, 128.0, 121.5, 120.4, 119.8, 109.6, 101.3, 31.1,
21.3.
4.3.16. 5-Chloro-2-phenylbenzo[b]thiophene (7g).19 Yield: 60%;
LCeMS: tR¼4.590 min, m/z¼245 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.90 (d, J¼2.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 1H), 7.57 (d,
J¼8.0 Hz, 2H), 7.51 (t, J¼8.0 Hz, 2H), 7.45e7.48 (m, 2H), 7.37 (dd,
J¼8.0, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) d 139.2, 138.8, 137.7,
135.4, 130.9, 128.9, 128.7, 127.9, 125.2, 125.0, 123.9, 122.6.
4.3.17. 5-Methoxy-2-phenylbenzo[b]thiophene (7h).20 Yield: 84%;
LCeMS: tR¼4.187 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz,
CDCl3) d 7.81 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼6.0 Hz, 2H),7.53 (t,
J¼6.0 Hz, 2H), 7.44e7.47 (m, 3H), 7.41 (d, J¼2.4 Hz, 1H), 6.99 (dd,
J¼8.0, 2.4 Hz, 1H), 3.88 (s, 3H); 13C NMR (150 MHz, CDCl3) d 157.6,
139.0, 137.8, 136.2, 133.1, 128.8 (2C), 128.6 (2C), 127.5, 124.8, 114.7,
105.7, 55.6.
Acknowledgements
We thank Dr. Ruina Gao for HRMS analysis and Mr. Morris Sui for
NMR analysis.
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.03.051.
References and notes
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