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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


(>100  C) were always required for the limited cases in literatur-
Functionalized indoles, benzofurans, and benzothiophenes e.2a,e,h Herein, we report a mild, efficient, and C2-selective arylation
serve as important building blocks of natural products and bi- reaction of indoles, benzofurans, and benzothiophenes at room
ologically active unnatural molecules.1 Among the known methods temperature with a wide scope of substrates. To the best of our
in the functionalization of indoles, benzofurans, and benzothio- knowledge, this is the first time the C2-selective arylation of ben-
phenes, CeH activation/arylation reactions have attracted tre- zofurans and benzothiophenes with iodobenzenes could be ach-
mendous interests due to their high atom efficiency.2 However, the ieved at room temperature. In addition, our methodology allows
reported methods always suffered from low regio-selectivities (C-2 the use of water as the reaction solvent, which makes it even more
over C-3) when no directing groups were pre-installed and/or high attractive in the aspect of reducing the hazardous organic waste.5
reaction temperatures (100e150  C), which significantly limited To develop organic reactions in aqueous solution has been one of
the substrate scope and functional group tolerance. Several C2- the research focuses in our group.6 A challenge for aqueous re-
selective arylation reactions of indoles using boronic acids or tri- actions is the poor solubility of starting materials, and adding sur-
fluoroborate salts as arylation agents at room temperature were factants to water has been a widely used strategy to improve
developed, whereas in these conditions acetic acid had to be used solubility.7 Among the surfactants used, polysorbates (also called
as the solvent/co-solvent and oftentimes the trifluoroborates were Tweens) offer cheap and environmentally friendly choices8 and we
not commercially available.3 Recently Larrosa has reported the C2- focused our solvents on the Tweens/water micelle system.
arylation of N-alkylated indoles at room temperature using more
readily available iodobenzenes as arylation agents.4 However, when 2. Result and discussion
free indoles were used as the substrates, the arylation reactions
required higher temperature (50  C).4 C2-selective arylations of We started our exploration of the CeH arylation using 1-methyl-
benzofurans and benzothiophenes were less extensively reported 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
* Corresponding author. Tel.: þ86 186 1674 3377; fax: þ86 021 6159 0730; e-mail AgOAc as the additive at room temperature led to the formation of
address: feng.q.ren@gsk.com (F. Ren). C2-arylation product (3a) in 39% conversion (Table 1, entry 1).
http://dx.doi.org/10.1016/j.tet.2015.03.051
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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 a
Unless otherwise stated, the reaction was conducted with 1 (1 mmol), 2 (2
5 mol % accelerated the reaction to provide 97% conversion within equiv.), CF3COOAg (1.5 equiv.) and Pd(OAc)2 (0.05 equiv.) in Tween
1 h (Table 1, entry 9). In comparison, removal of Tween 80 from the 80/H2O (2 mL, 2% w/w) at room temperature for 1 hour. Isolated yields.
b
reaction mixture gave a much decreased conversion (38%, Table 1, Reaction runs for 3 hours. c Reaction runs for 3 days.
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. the C3/C2 migration of palladium to provide the high C2-
With the optimized reaction condition of C2-selective arylation selectivity of the arylation products.
of indoles developed, the substrate scope was examined. As shown We then expanded the substrate scope to benzofurans, which
in Table 2, iodobenzenes with a variety of different substitutions are less electron-rich than indoles. As expected, the CeH arylation
were well tolerated for the reaction. Both electron-withdrawing reactions of benzofurans were much slower (Table 3) compared
and electron-donating substitutions were tolerated at the para- with indoles, and extended reaction time (overnight) was required
position of the iodobenzene, providing C2-arylation products in for the reaction to be completed. In addition, TFA had to be used to
good isolated yields (67e90%, 3beg). Substitution at the meta-po- accelerate the arylation reactions.10 The substituted iodobenzenes
sition also demonstrated high reactivity to afford the desired were well tolerated and generally good isolated yields of C2-
product (3h) in high yield (93%). Increasing the steric hindrance of arylation products were obtained at room temperature (5aee), al-
the iodobenzene by introducing ortho-substitutions resulted in though para-CF3 iodobenzene was less effective and a prolonged
lower yields (52% and 65% for 3i and 3j, respectively). These results reaction time was required for high yield (5e). On the other hand,
suggested the reactivities of iodobenzenes for the C2-arylation re- both electron-withdrawing and electron-donating substitutions on
action were sensitive to steric rather than electronic effects. The benzofurans were tolerated. Prolonged reaction times were re-
scope of indole substrates was also evaluated, and the reaction quired for the full conversions to 5f and 5g, due to poor solubility of
showed good tolerability for different substitutions including both starting materials in the reaction mixtures. Again, our arylation
electron-withdrawing and electron-donating groups (3jen). The condition for benzofurans was highly C2-selective, and there was
electron-withdrawing substituent at the 4-position of the indole no C3-arylation product observed for all cases.
(3n) resulted in a much slower arylation reaction compared with We further expanded the substrate scope to benzothiophenes,
the electron-donating substituent (3l) and a much longer reaction which are even less electron-rich. To our delight, both substituted
time was required (3 days for 3n and 3 h for 3l). It was noteworthy iodobenzenes and substituted benzothiophenes were well-
that for the free indole substrate (3o) high yield (62%) was also tolerated and high yields of desired C2-arylation products were
obtained at room temperature whereas elevated temperature was obtained at room temperature, albeit more prolonged reaction time
required in the reported procedure.4 In addition, the high C2- was required (Table 4). Electron-withdrawing substitutions on the
selectivity of our arylation reactions was striking and there was iodobenzene made the reactions less efficient and extremely slow,
no C3-arylation product observed in all the tested substrates, even but good yields could still be obtained (7b and 7e).
for the steric hindered ones (3i and 3j). The mechanistic studies of
palladium-catalyzed arylation of indoles had been reported and the 3. Conclusion
palladium migration from the 3-position to the 2-position of the
indoleepalladium(II) intermediate was the key to give C2- In summary, we have developed a mild, efficient, and highly C2-
selectivity.9 Our aqueous condition must have strongly favored selective palladium-catalyzed arylation reaction of indoles,
2618 Z. Xu et al. / Tetrahedron 71 (2015) 2616e2621

Table 3 as the internal standard. DMSO-d6 is hexadeuteriodimethylsulf-


Substrate scope of Pd-catalyzed direct CeH arylation of benzofuransa 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.
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.) 4.2. General procedure for the CeH arylation of indoles with
in Tween 80/H2O (2 mL, 2% w/w) at room temperature overnight. Isolated iodobenzenes
yields. bReaction runs for 5 days. c Reactions run for 2 days.
To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg
Table 4 (1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol),
Substrate scope of Pd-catalyzed direct CeH arylation of benzothiophenesa 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,
Unless otherwise stated, the reaction was conducted with 6 (100 mg), 2 (2 109.6, 101.3, 31.1, 21.3; HRMS (ESI): calculated for C16H16N [MþH]þ,
a

equiv.), silver(I) trifluoroacetate (1.5 equiv.), trifluoroacetic acid (2 equiv.) 222.1283. Found [MþH]þ, 222.1285.
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.
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,
benzofurans, and benzothiophenes with iodobenzenes at room 2H), 7.38 (d, J¼8.0 Hz,1H), 7.30 (t, J¼8.0 Hz,1H), 7.20 (t, J¼8.0 Hz,1H),
temperature. To the best of our knowledge, this is the first time C2- 7.04 (d, J¼8.0 Hz, 2H), 6.54 (s, 1H), 3.91 (s, 3H), 3.78 (s, 3H); 13C NMR
selective arylation of benzofurans and benzothiophenes with (100 MHz, CDCl3) d 159.4, 141.4, 138.1, 130.6 (2C), 128.0, 125.3, 121.4,
iodobenzenes could be achieved at room temperature. Our meth- 120.2, 119.7, 114.0 (2C), 109.5, 101.0, 55.4, 31.0; HRMS (ESI): calcu-
odology allows the use of water, the most environmentally friendly lated for C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1229.
solvent, as the reaction solvent with the addition of Tween 80 (2%
w/w) to increase the solubility of starting materials. In addition, our 4.2.4. 2-(4-Chlorophenyl)-1-methyl-1H-indole (3d).11 Yield: 87%;
protocol demonstrated wide substrate scope, and good yields were 1
H NMR (400 MHz, CDCl3) d 7.66 (d, J¼8.0 Hz, 1H), 7.48 (m, 4H), 7.39
obtained for all the 32 examples evaluated (52e93%). (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,
4. Experimental section 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.
4.1. General Found [MþH]þ, 242.0737.

1
H NMR and 13C NMR spectra were recorded on a Bruker 400/600 4.2.5. 2-(4-Fluorophenyl)-1-methyl-1H-indole (3e).11 Yield: 89%; 1H
NMR spectrometer with CDCl3 or DMSO-d6 as the solvent and TMS 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 2619

7.36 (d, J¼8.4 Hz, 1H), 7.24e7.27 (m, 1H), 7.13e7.18 (m, 3H), 6.53 (s, 7.35 (d, J¼8.0 Hz, 1H), 7.24 (t, J¼8.0 Hz, 1H), 7.13e7.17 (m, 3H), 6.53
1H), 3.71 (s, 3H); 13C NMR (100 MHz, CDCl3) d 162.6 (d, J¼246 Hz), (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.9 (d,
140.5, 138.3, 131.1 (d, J¼8.0 Hz), 128.9, 127.9, 121.8, 120.5, 120.0, J¼233 Hz), 143.1, 134.9, 132.5, 129.3, 128.5, 128.1, 128.0 (d, J¼11 Hz),
115.6 (d, J¼21.5 Hz), 109.7, 101.7, 31.1; 19F NMR: (376 MHz, CDCl3) 110.1 (d, J¼10 Hz), 109.7 (d, J¼26 Hz), 105.0 (d, J¼24 Hz), 101.5 (d,
d 113.8; HRMS (ESI): calculated for C15H13FN [MþH]þ, 226.1032. J¼5 Hz), 31.3; 19F NMR: (376 MHz, CDCl3) d 124.8; HRMS (ESI):
Found [MþH]þ, 225.1030. calculated for C15H13FN [MþH]þ, 226.1032. Found [MþH]þ,
226.1032.
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, 4.2.14. 2-(4-Chlorophenyl)-1-methyl-1H-indole-4-carbonitrile
2H), 7.66e7.71 (m, 3H), 7.42 (d, J¼8.4 Hz, 1H), 7.31 (t, J¼7.4 Hz, 1H), (3n). Yield: 72%; 1H NMR (400 MHz, CDCl3) d 7.59 (d, J¼8.0 Hz, 1H),
7.20 (t, J¼8.0 Hz, 1H), 6.68 (s, 1H), 3.81 (s, 3H); 13C NMR (150 MHz, 7.47e7.54 (m, 5H), 7.31 (d, J¼8.0 Hz, 1H), 6.80 (s, 1H), 3.80 (s, 3H);
13
CDCl3) d 139.9, 138.8, 136.7, 130.0 (q, J¼21.0 Hz), 129.7 (2C), 128.0, C NMR (100 MHz, CDCl3) d 142.9, 138.0, 135.0, 130.6, 130.0, 129.3,
125.7 (d, J¼4.5 Hz), 125.0 (q, J¼270.0 Hz), 122.4 (2C), 121.0, 120.5, 129.0, 125.3, 121.4, 118.7, 114.3, 102.8, 100.9, 31.5; HRMS (ESI): cal-
110.0, 103.0, 31.5; 19F NMR: (376 MHz, CDCl3) 62.5; HRMS (ESI): culated for C16H12ClN2 [MþH]þ, 267.0689. Found [MþH]þ,
calculated for C16H13F3N [MþH]þ, 276.1000. Found [MþH]þ, 267.0685.
276.0995.
4.2.15. 2-Phenyl-1H-indole (3o).3b Yield: 62%; 1H NMR (400 MHz,
4.2.7. 1-Methyl-2-(4-nitrophenyl)-1H-indole (3g).13 Yield: 67%; 1H CDCl3) d 8.32 (br s, 1H), 7.62e7.66 (m, 3H), 7.38e7.45 (m, 3H), 7.32
NMR (400 MHz, CDCl3) d 8.34 (d, J¼8.0 Hz, 2H), 7.70 (d, J¼8.0 Hz, (t, J¼7.2 Hz, 1H), 7.19 (t, J¼7.2 Hz, 1H), 7.12 (t, J¼7.2 Hz, 1H), 6.82 (s,
2H), 7.67 (d, J¼8.0 Hz, 1H), 7.40 (d, J¼8.3 Hz, 1H), 7.32 (t, J¼8.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) 137.9, 136.3, 132.3, 129.2, 129.0,
1H), 7.19 (t, J¼8.0 Hz, 1H), 6.72 (s, 1H), 3.81 (s, 3H); 13C NMR 127.7, 125.2, 122.4, 120.7, 120.3, 110.9, 100.0; HRMS (ESI): calculated
(100 MHz, CDCl3) d 147.0, 139.2, 139.2, 138.9, 129.5, 127.7, 123.9, for C14H12N [MþH]þ, 194.0970. Found [MþH]þ, 194.0964.
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.
4.3. General procedure for the CeH arylation of benzofurans
4.2.8. 1-Methyl-2-(3-nitrophenyl)-1H-indole (3h).12 Yield: 93%; 1H and benzothiophenes with iodobenzenes
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, To a microwave reaction vial, Pd(OAc)2 (5 mol %), CF3COOAg
1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) d 148.3, 138.7, 138.6, (1.5 mmol), iodobenzene (2.0 mmol), N-methylindole (1.0 mmol),
134.9, 134.5, 129.5, 127.6, 123.7, 122.6, 122.4, 120.9, 120.3, 109.8, trifluoroacetic acid (2 mmol), and Tween-80/H2O (2 ml, 2 wt %)
103.2, 31.3; HRMS (ESI): calculated for C15H13N2O2 [MþH]þ, were added. The reaction mixture was allowed to react at room
253.0977. Found [MþH]þ, 253.0974. temperature. After the completion of the reaction, the mixture was
concentrated under reduced pressure, and the residue was purified
4.2.9. 2-(1-Methyl-1H-indol-2-yl)benzonitrile (3i).4b Yield: 52%; on silica gel chromatography to afford the desired product.
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, 4.3.1. 2-Phenylbenzofuran (5a).14 Yield: 88%; LCeMS: tR¼4.169
J¼1.2, 7.8 Hz, 1H), 7.52 (dd, J¼1.2, 7.8 Hz, 1H), 7.41 (d, J¼8.0 Hz, 1H), min, m/z¼195 [MþH]þ; 1H NMR (400 MHz, DMSO-d6) d 7.92 (d,
7.32 (dt, J¼1.2, 7.8 Hz, 1H), 7.23e7.15 (m, 1H), 6.76 (s, 1H), 3.72 (s, J¼8.0 Hz, 2H), 7.66 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼8.0 Hz, 1H), 7.50 (t,
3H); 13C NMR (100 MHz, CDCl3) d 138.5, 136.6, 136.3, 133.6, 132.4, J¼8.0 Hz, 2H), 7.46 (s, 1H), 7.40 (t, J¼8.0 Hz, 1H), 7.31 (t, J¼8.0 Hz,
131.4, 128.4, 127.6, 122.6, 121.1, 120.2, 118.0, 113.3, 109.8, 104.4, 31.2. 1H), 7.25 (t, J¼8.0 Hz, 1H).

4.2.10. 1-Methyl-2-(o-tolyl)-1H-indole (3j).4b Yield: 65%; 1H NMR 4.3.2. 2-(4-Chlorophenyl)benzofuran (5b).15 Yield: 87%; LCeMS:
(400 MHz, CDCl3) d 7.73 (d, J¼8.0 Hz, 1H), 7.34e7.45 (m, 6H), tR¼4.508 min, m/z¼229 [MþH]þ; 1H NMR (600 MHz, CDCl3) d 7.78
7.23e7.28 (m, 1H), 6.49 (s, 1H), 3.59 (s, 3H), 2.23 (s, 3H); 13C NMR (d, J¼8.6 Hz, 2H), 7.57 (d, J¼7.6 Hz, 1H), 7.51 (d, J¼8.2 Hz, 1H), 7.40
(100 MHz, CDCl3) d 140.5, 138.1, 137.3, 132.6, 131.1, 130.0, 128.6, (d, J¼8.6 Hz, 2H), 7.25e7.27 (m, 2H), 6.99 (s, 1H); 13C NMR
128.0, 125.5, 121.3, 120.4, 119.6, 109.4, 101.5, 30.3, 20.0; HRMS (ESI): (150 MHz, CDCl3) d 155.0, 154.8, 134.4, 129.1, 129.1, 129.0, 126.2,
calculated for C16H16N [MþH]þ, 222.1283. Found [MþH]þ, 124.6, 123.1, 121.0, 111.2, 101.8.
222.1289.
4.3.3. 2-(p-Tolyl)benzofuran (5c).14 Yield: 88%; LCeMS: tR¼
4.2.11. 5-Methoxy-1-methyl-2-phenyl-1H-indole (3k). Yield: 70%; 14
4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 7.75 (d,
1
H NMR (400 MHz, CDCl3) d 7.44e7.51 (m, 4H), 7.37e7.40 (m, 1H), J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 7.50 (d, J¼8.0 Hz, 1H), 7.29e7.18
7.24 (d, J¼3.6 Hz, 1H), 7.10 (d, J¼8.0 Hz, 1H), 6.91 (dd, J¼8.8, 2.0 Hz, (m, 4H), 6.94 (s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 156.2,
1H), 6.48 (s, 1H), 3.87 (s, 3H), 3.72 (s, 3H); 13C NMR (100 MHz, 154.8, 138.6, 129.5 (2C), 129.3, 127.7, 124.9 (2C), 124.0, 122.8, 120.7,
CDCl3) d 154.4, 142.1, 133.8, 132.9, 129.3, 128.5, 128.3, 127.8, 111.9, 111.1, 100.5, 21.4.
110.3, 102.2, 101.3, 55.9, 31.3; HRMS (ESI): calculated for C16H16NO
[MþH]þ, 238.1232. Found [MþH]þ, 238.1231. 4.3.4. 2-(4-Methoxyphenyl)benzofuran (5d).15 Yield: 78%; LCeMS:
tR¼4.133 min, m/z¼225 [MþH]þ; 1H NMR (CDCl3, 400 MHz) d 7.79
4.2.12. 4-Methoxy-1-methyl-2-phenyl-1H-indole (3l).9a Yield: 79%; (d, J¼8.0 Hz, 2H), 7.54 (d, J¼7.8 Hz, 1H), 7.49 (d, J¼8.0 Hz, 1H),
1
H NMR (400 MHz, CDCl3) d 7.36e7.53 (m, 5H), 7.18 (t, J¼8.0 Hz, 1H), 7.26e7.19 (m, 2H), 6.96 (d, J¼8.0 Hz, 2H), 6.87 (s, 1H) 3.85 (s, 3H).
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, 4.3.5. 2-(4-(Trifluoromethyl)phenyl)benzofuran (5e).16 Yield: 83%;
122.9, 119.2, 103.6, 100.3, 99.3, 55.8, 31.2; HRMS (ESI): calculated for LCeMS: tR¼4.524 min, m/z¼263 [MþH]þ; 1H NMR: (400 MHz,
C16H16NO [MþH]þ, 238.1232. Found [MþH]þ, 238.1225. 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
4.2.13. 5-Fluoro-1-methyl-2-phenyl-1H-indole (3m). Yield: 78%; 1H (dd, J¼8.0, 7.8 Hz, 1H), 7.14 (s, 1H); 13C NMR (100 MHz, CDCl3)
NMR (400 MHz, CDCl3) d 7.62 (d, J¼8.0 Hz, 1H), 7.45e7.49 (m, 2H), 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 7.50 (t, J¼8.0 Hz, 1H), 7.44 (d, J¼8.0 Hz, 1H), 7.40 (s, 1H), 7.24 (d,
(376 MHz, CDCl3) d 62.6. 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,
4.3.6. Methyl 2-phenylbenzofuran-5-carboxylate (5f).17 Yield: 84%; 21.3.
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 4.3.16. 5-Chloro-2-phenylbenzo[b]thiophene (7g).19 Yield: 60%;
(m, 2H), 7.54 (d, J¼8.8 Hz, 1H), 7.49e7.45 (m, 2H), 7.41e7.37 (m, 1H), LCeMS: tR¼4.590 min, m/z¼245 [MþH]þ; 1H NMR (400 MHz,
7.06 (d, J¼0.8 Hz, 1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) CDCl3) d 7.90 (d, J¼2.0 Hz, 1H), 7.84 (d, J¼8.0 Hz, 1H), 7.57 (d,
d 167.2, 157.3, 157.3, 129.8, 129.2, 128.9, 128.2, 126.0, 125.3, 125.0, J¼8.0 Hz, 2H), 7.51 (t, J¼8.0 Hz, 2H), 7.45e7.48 (m, 2H), 7.37 (dd,
123.2, 110.9, 101.5, 52.0. 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.
4.3.7. 5-Methoxy-2-phenylbenzofuran (5g).17 Yield: 87%; LCeMS:
tR¼4.138 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3) d 8.88 4.3.17. 5-Methoxy-2-phenylbenzo[b]thiophene (7h).20 Yield: 84%;
(d, J¼7.8 Hz, 2H), 7.49e7.44 (m, 3H), 7.39e7.37 (m, 1H), 7.06 (d, LCeMS: tR¼4.187 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz,
J¼2.0 Hz, 1H), 6.98 (s, 1H), 6.93 (dd, J¼2.0, 7.8 Hz, 1H), 3.88 (s, 3H); CDCl3) d 7.81 (d, J¼8.0 Hz, 1H), 7.63 (d, J¼6.0 Hz, 2H),7.53 (t,
13
C NMR (100 MHz, CDCl3) d 156.6, 156.0, 149.8, 130.5, 129.7, 128.7, J¼6.0 Hz, 2H), 7.44e7.47 (m, 3H), 7.41 (d, J¼2.4 Hz, 1H), 6.99 (dd,
128.4, 124.8, 112.9, 111.6, 103.2, 101.4, 55.8. 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,
4.3.8. 5-Methyl-2-phenylbenzofuran (5h).15 Yield: 85%; LCeMS: 105.7, 55.6.
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), Acknowledgements
7.35e7.31 (m, 2H), 7.08 (d, J¼8.0 Hz, 1H), 6.94 (s, 1H), 2.44 (s, 3H).
We thank Dr. Ruina Gao for HRMS analysis and Mr. Morris Sui for
4.3.9. 7-Methoxy-2-phenylbenzofuran (5i).15 Yield: 80%; LCeMS:
NMR analysis.
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); Supplementary data
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. Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2015.03.051.
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 References and notes
(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, 1. (a) Garg, N. K.; Sarpong, R.; Stolz, B. M. J. Am. Chem. Soc. 2002, 124, 13179; (b)
CDCl3) d 140.8, 138.2, 138.0, 136.1, 128.8, 127.6, 124.5, 124.4, 123.5, Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (c) Qin, Z.; Kastrati, I.; Chan-
drasena, R. E. P.; Liu, H.; Yao, P.; Petukhov, P. A.; Bolton, J. L.; Thatcher, G. R. J. J.
123.4, 123.0, 129.9. Med. Chem. 2007, 50, 2682.
2. For selected recent reviews on CeH functionalization, see: (a) Chen, X.; Engle,
4.3.11. 2-(4-Chlorophenyl)benzo[b]thiophene (7b).18 Yield: 70%; K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094; (b) Wencel-
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740; (c) Li, B.-J.;
LCeMS: tR¼4.385 min, m/z¼209 [MþH]þ; 1H NMR (400 MHz, Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588; (d) Arockiam, P. B.; Bruneau, C.; Dixneuf,
CDCl3) d 7.80 (d, J¼8.0 Hz, 1H), 7.75 (d, J¼8.0 Hz, 1H), 7.61 (d, P. H. Chem. Rev. 2012, 112, 5879; (e) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.
J¼8.0 Hz, 2H), 7.49 (s, 1H), 7.37 (d, J¼8.0 Hz, 2H), 7.33e7.30 (m, 2H); Adv. Synth. Catal. 2014, 356, 17; (f) Giri, R.; Thapa, S.; Kafle, A. Adv. Synth. Catal.
13 2014, 356, 1395; (g) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744 For
C NMR (150 MHz, CDCl3) d 140.8, 137.7, 136.6, 134.5, 133.5, 129.9, selected examples of C-2 arylation of benzofurans and benzothiophenes: (h)
128.9, 124.6, 124.5, 123.8, 123.0, 122.7. Tamba, S.; Okubo, Y.; Tanaka, S.; Monguchi, D.; Mori, A. J. Org. Chem. 2010, 75,
6998 For selected examples of C-2 arylation of indoles: (i) Feng, J.; Lu, G.; Lv, M.;
Cai, C. J. Organomet. Chem. 2014, 761, 28; (j) Lu, G.-P.; Cai, C. Synlett 2012, 2992.
4.3.12. 2-(p-Tolyl)benzo[b]thiophene (7c).18 Yield: 70%; LCeMS:
3. (a) Yang, S. D.; Sun, C. L.; Fang, Z.; Li, B. J.; Li, Y. Z.; Shi, Z. J. Angew. Chem., Int. Ed.
tR¼4.531 min, m/z¼225 [MþH]þ; 1H NMR (400 MHz, CDCl3): 2008, 47, 1473; (b) Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 7428; (c)
d 7.94e7.96 (m, 2H), 7.52 (d, J¼8.0 Hz, 2H), 7.40e7.44 (m, 3H), 7.33 Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128,
(d, J¼8.0 Hz, 2H), 2.47 (s, 3H), 13C NMR (150 MHz, CDCl3): d 140.7, 4972; (d) Nimje, R. Y.; Leskinen, M. V.; Pihko, P. M. Angew. Chem., Int. Ed. 2013,
52, 4818.
138.1, 138.0, 137.4, 133.2, 129.5, 129.4, 128.6, 124.4, 124.3, 122.9, 21.3. 4. (a) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008, 130, 2926; (b) Islam, S.;
Larrosa, I. Chem.dEur. J. 2013, 19, 15093.
4.3.13. 2-(4-Methoxyphenyl)benzo[b]thiophene (7d).18 Yield: 72%; 5. Sheldon, R. A.; Arens, I. W. C. E.; Hanefeld, U. Green Chemistry and Catalysis;
Wiley-VCH: Weinheim, Germany, 2007.
LCeMS: tR¼4.244 min, m/z¼241 [MþH]þ; 1H NMR (400 MHz, 6. Xu, Z.; Yang, T.; Lin, X.; Elliott, J.; Ren, F. Tetrahedron Lett. 2015, 56, 475.
CDCl3) d 7.91 (s, 1H), 7.54 (d, J¼8.0 Hz, 2H), 7.40 (m, 2H), 7.36 (s, 1H), 7. (a) Bai, L.; Wang, J.-X.; Zhang, Y. Green Chem. 2003, 5, 615; (b) Li, C.-J. Acc. Chem.
7.04e7.07 (m, 2H), 3.91 (s, 3H); 13C NMR (150 MHz, CDCl3) d 159.2, Res. 2010, 43, 581; (c) Li, C. J. Metal-Mediated CeC Bond Formation in Aqueous
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140.6, 138.2, 137.7, 129.8, 128.6, 124.3, 123.0, 122.9, 122.6, 114.2, 55.4. Lindstro€m, U. M., Ed.; Blackwell: Oxford, UK, 2007; (d) Li, C.-J.; Chen, L. Chem.
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LCeMS: tR¼3.964 min, m/z¼236 [MþH]þ; 1H NMR (400 MHz, G. Angew. Chem., Int. Ed. 2005, 44, 7174.
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(d, J¼8.0 Hz, 2H), 7.79e7.86 (m, 2H); 13C NMR (150 MHz, CDCl3) Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2012.
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