Pd-catalyzed C–H bond activation of Indoles for Suzuki reaction

Article abstract of DOI:10.1007/s12039-019-1649-y

Abstract: We present a practical method for Suzuki coupling by which unprotected or N-protected indoles may be selectively arylated in the C2-position through direct C–H bond activation by electrophilic Pd(TFA) ₂ catalyst. The protocol is operationally simple as it is carried out in dioxane/water mixture, and air as the sole oxidant at room temperature. Various 2-arylated indoles were obtained in good yields. The protocol works for benzofuran, pyrrole and thiophene also. Graphic abstract: Selective C-2 arylation of heterocycles using Pd(II) catalyst via C–H activation was performed under ambient condition. C3–C2 migration of organopalladium intermediate controls the reaction pathway.[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-019-1649-y

J. Chem. Sci.
(2019) 131:71
© Indian Academy of Sciences
https://doi.org/10.1007/s12039-019-1649-y
REGULAR ARTICLE
Pd-catalyzed C–H bond activation of Indoles for Suzuki reaction
∗
ISITA BANERJEE, KESHAB CH GHOSH and SURAJIT SINHA
School of Applied and Interdisciplinary Sciences, Indian Association for the Cultivation of Science, 2A & 2B
Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, West Bengal, India
E-mail: ocss5@iacs.res.in
MS received 14 February 2019; revised 10 May 2019; accepted 24 May 2019
Abstract. We present a practical method for Suzuki coupling by which unprotected or N-protected indoles
may be selectively arylated in the C2-position through direct C–H bond activation by electrophilic Pd(TFA)2
catalyst. The protocol is operationally simple as it is carried out in dioxane/water mixture, and air as the sole
oxidant at room temperature. Various 2-arylated indoles were obtained in good yields. The protocol works for
benzofuran, pyrrole and thiophene also.
Keywords. C–H arylation of indole; boronic acid; Pd catalysis; air.
1
. Introduction
generation of highly active electrophilic Pd-catalyst in
7
e
the presence of Silver(I) carboxylates. Bellina and
co-workers also developed an excellent method for
selective palladium- and copper-mediated C-2 aryla-
tions of indoles with aryl iodides in absence of base
Pd-catalyzed C–C bond formation has become a pow-
erful tool for the construction of complex molecules.
In such reactions, aryl iodides, bromides and triflates
are commonly used as one of the reaction components.
As aryl halides or triflates are not either easily available
or need to be made from corresponding hydrocarbon
1
8
a,b
and ligands.
All these arylation reactions have been
reported using aryl iodide as a coupling partner. Aryl
boronic acids have several advantages over aryl halides
including easy availability, non-toxicity, high stability
and environmental tolerance. Shi and co-workers made
2
or phenol, direct C–H bond activation has become an
alternative method of choice.
3
4
5
6
In this direction, Ru-, Rh-, Ir- and Pd- catalyzed
cross-coupling reactions have been reported through the
activation of C–H bond. Among these metals, Pd is com-
paratively cheap, easily available and its reactivity can
particularly be tuned using a suitable ligand and condi-
tions, andthischemistryhasbeenstudiedwell. Recently,
a few reports have been published to increase the elec-
trophilicity of Pd-catalyst for the activation of C–H bond
of indoles and heteroarenes. A pioneering work on
direct arylation of 1-tosylindole with chloropyrazines
has been reported by Ohta et al.2 Broad applications
and detailed mechanistic study on C-2 and C-3 aryla-
a significant contribution by Pd(OAc) catalyzed direct
2
C-2 arylation with aryl boronic acids as an arylating
7
f
agent. Zhang et al., has reported the C-arylation of
7
g
indoles using aryltrifluoroborate salts. Pd-catalyzed
indole-aryl bond formation was reported by Fagnou
7
h
et al., where unfunctionalized arene was involved in
direct cross-coupling reaction in the presence of an oxi-
dant. In all these cases Pd(II) salts have been used as
catalyst and arylation at the C-2 position of indole was
the major product.
7
8
e
7
i
Gaunt and co-workers have explored the use of
Cu(II) catalyst in selectively C-2 or C-3 arylation of
indoles. In the reaction, medium Cu-catalyst is oxidized
in the presence of diaryl-iodine(III) reagents to form a
highly electrophilic aryl-Cu(III) intermediate that is par-
ticipated in the arylation process. Pd-catalyzed C-3 ary-
lation of indoles was achieved by He and co-workers.7
tion of indoles with aryl halides have been reported by
Sames and co-workers.7
a,b,c
Shortly after, Sanford et al.,
reported arylation with [Ar–I–Ar]BF on indole using
4
electrophilic Pd(II) catalyst.7d Larrosa et al., reported
the arylation of indoles from aryl iodide by in situ
j
*
For correspondence
Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-019-1649-y) contains
supplementary material, which is available to authorized users.
0123456789().: V,-vol

71
Page 2 of 9
J. Chem. Sci.
(2019) 131:71
chromatography (TLC) on silica gel 60 F254 (Merck; layer
thickness 0.25 mm) and visualization was accomplished by
irradiation with UV light at 254 nm or vanillin stain. Col-
umn chromatography was performed on Merck silica gel
(100–200 mesh) with eluent as mentioned, unless otherwise
reported. Proton and carbon NMR spectra were recorded on
BRUKER AVANCE III 500 MHz, BRUKER AVANCE III
HD 400 MHz and BRUKER AVANCE III HD 300 MHz
spectrometers in deuterated solvents at ambient probe tem-
perature (300 K). Proton chemical shifts are reported in ppm
(
δ) relative to tetramethylsilane (TMS) with the solvent reso-
nance employed as the internal standard (CDCl3 δ 7.26 ppm).
Data are reported as follows: chemical shift, multiplicity
Scheme 1. Pd catalyzed direct C–H arylation of indoles.
(
s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet, br = broad, dd = double doublet), coupling con-
stants (Hz) and integration. 13C chemical shifts are reported
in ppm (δ) from tetramethylsilane (TMS) with the solvent
resonance as the internal standard (CDCl3 δ 77.0 ppm). High-
resolution mass spectra were taken using micromass Q-Tof
microsystem by electron spray ionization (ESI) technique. IR
spectra were taken using a Perkin-Elmer FT Infrared Spec-
Successful coupling was observed in the case of
9
a
9b
aromatic sodium sulfonates, arylsulfinic acids, aryl-
9
c
sulfonyl hydrazides and (hetero)arenesulfonyl chlo-
rides also. Recently, heterogeneousPd-catalyzeddirect
C-2 arylation of indoles using diaryliodonium salts
9
d
1
0
under mild conditions was reported by Olofsson
trometer Model Spectrochem Two, the wavenumbers (n) of
11
−1
and Wan’s group. Very recently, Markandeya’s group recorded IR-signals are reported in cm
.
reported the same transformation using phosphine free
1
2
tetradentate Pd catalyst.
2.2 General procedure for the C–H arylation reaction
13
Since indoles are present in many biologically
and pharmacologically active compounds and our lab
is involved in the synthesis of indole-based natural
products and various indole derivatives for biological
screening, we are looking for a suitable methodology
for the derivatization of indole moiety.
During the course of our work, we wanted to synthe-
sis 2-arylated indole using Shi’s protocal (Scheme 1).
Though we obtained the clean product with clean con-
To an oven-dried 25 mL RB containing a magnetic stir bar,
heterocycle (0.6 mmol, 1.0 equiv), Pd(TFA)2 (0.06 mmol,
5 mol%), arylboronic acid (1.2 mmol, 2.0 equiv), TFA (1.2
mmol, 2.0 equiv) and 1,4-Dioxane:H2O (1.0 M, 3:1 ratio) was
added and allowed to stir in the presence of air (open atmo-
1
4
◦
sphere) at 25 C for 4–12 h. After completion of the reaction,
the mixture was filtered through celite and concentrated. The
resulting mixture was diluted with EtOAc (25 mL), washed
with aqueous NaHCO3(2 × 15 mL). The organic layers were
7
f
version, the reaction had to be set up in Schlenk combined, dried over anhydrous Na SO , and concentrated
2
4
line without which the reaction went incomplete and under reduced pressure. The crude material was purified by
poor yield was obtained. Moreover, it requires acetic column chromatography (SiO2, n-Hexane/EtOAc) to give the
desired arylated product.
acid as a solvent and Cu(OAc) as co-oxidant in
2
case of electron-withdrawing heterocycles. Herein, we
explored Pd(II) catalyzed selective C-2 arylation of 2.3 Synthesis and characterization of the arylindole
indoles with aryl boronic acids under mild reaction derivatives
conditionsandextendedtobenzofuran, pyrroleandthio-
phene also.
2
-Phenyl-1H-indole (3a)9a: White solid; yield: 58 mg, 47%;
◦
1
M.p.: 186–188 C; Rf = 0.5 (12% EtOAc/n-hexane). H
NMR (300 MHz, CDCl3): δ 8.25 (s, 1H), 7.66–7.57 (m, 3H),
7
.46–7.26 (m, 4H), 7.22–7.08 (m, 2H), 6.81 (d, J = 2.1
2
. Experimental
13
Hz, 1H) ppm. C NMR (75 MHz, CDCl3): δ 137.8, 136.8,
1
9
1
32.3, 129.2, 128.9, 127.7, 125.1, 122.3, 120.6, 120.2, 110.9,
9.9 ppm. HRMS (ESI): m/z [M+H] calcd for C14H12N:
94.0964; found 194.0966.
2
.1 Materials and physical measurements
+
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification. 2-(o-Tolyl)-1H-indole (3b)9a: White solid; yield: 58 mg,
◦
All reagent-grade solvents were purchased from commer- 47%; M.p.: 92–94 C; Rf = 0.5 (12% EtOAc/n-hexane).
1
cial sources and used after distillation for reaction, work-up
and purification. Reactions monitoring and determination of
H NMR (500 MHz, CDCl3): δ 8.03 (s, 1H), 7.63 (dd,
J = 7.8, 0.4 Hz, 1H), 7.46–7.40 (m, 1H), 7.35 (dd, J =
Rf values for all compounds were performed by thin-layer 8.0, 0.7 Hz, 1H), 7.31–7.22 (m, 3H), 7.21–7.16 (m, 1H),

J. Chem. Sci.
(2019) 131:71
Page 3 of 9
71
+
7
(
.14–7.10 (m, 1H), 6.59 (dd, J = 2.1, 0.8 Hz, 1H), 2.47 HRMS (ESI): m/z [M+H] calcd for C14H11ClN: 228.0575;
s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ = 137.4, found 228.0576.
136.1, 136.0, 132.6, 131.0, 128.9,
128.8, 127.9, 126.0,
2
-(2-Bromophenyl)-1H-indole(3h)17,18:Whiteplates;yield:
122.0, 120.5, 120.0, 110.7, 102.9, 21.0 ppm. HRMS (ESI):
◦
6
5 mg, 40%; M.p.: 75–77 C; Rf = 0.5 (10% EtOAc/n-
+
m/z [M+H] calcd for C H14N: 208.1121; found 208.1123.
1
5
1
hexane). H NMR (300 MHz, CDCl3): δ 8.64 (s, 1H), 7.69 (t,
J = 7.5 Hz, 2H), 7.62 (dd, J = 7.7, 1.7 Hz, 1H), 7.47–7.34
2
-(4-(tert-Butyl)phenyl)-1H-indole (3c)9a: White solid;
◦
yield: 64 mg, 43%; M.p.: 186–188 C; Rf = 0.5 (15% (m, 2H), 7.27–7.20 (m, 2H), 7.20–7.11 (m, 1H), 6.83 (dd,
1
13
EtOAc/n-hexane). H NMR (400 MHz, CDCl3): δ 8.32 (s,
1
J = 2.18, 0.91 Hz, 1H) ppm. C NMR (75 MHz, CDCl3) δ
H), 7.69–7.57 (m, 3H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, 136.2, 133.9, 133.5, 131.4, 129.2, 128.2, 127.7, 122.6, 121.3,
+
J = 8.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 120.8, 120.2, 111.0, 103.6 ppm. HRMS (ESI): m/z [M+H]
1
3
Hz, 1H), 6.81 (d, J = 1.2 Hz, 1H), 1.38 (s, 9H) ppm.
C
calcd for C14H11NBr: 272.0069; found 272.0068.
NMR (75 MHz, CDCl3): δ 150.9, 137.9, 136.7, 129.5, 129.3,
a 18
2
-(4-Bromophenyl)-1H-indole (3i)9
,
: White solid; yield:
125.9, 124.9, 122.1, 120.5, 120.1, 110.8, 99.5, 34.6, 31.2 ppm.
◦
+
101 mg, 62%; M.p.: 210–212 C; Rf = 0.5 (10% EtOAc/n-
HRMS (ESI): m/z [M+H] calcd for C18H20N: 250.1590;
found 250.1592.
hexane). 1H NMR (400 MHz, CDCl3): δ 8.28 (s, 1H),
7
.64 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.5 Hz, 2H),
8.5 Hz, 2H), 7.40 (d, J 8.0 Hz,
yield: 106 mg, 73%; M.p.: 200–202 C; Rf = 0.5 (10% 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.14 (t, J = 7.4 Hz,
2
-(Naphthalen-2-yl)-1H-indole (3d)9a: White solid; 7.51 (d, J
=
=
◦
1
13
EtOAc/n-hexane). H NMR (300 MHz, CDCl ) δ 8.47 (br. 1H), 6.82 (s, 1H) ppm. C NMR (75 MHz, DMSO-d ):
3
6
s, 1H), 8.05 (s, 1H), 7.94–7.79 (m, 4H), 7.68 (d, J = 7.7 δ = 137.1, 136.2, 131.7, 131.4, 128.4, 128.3, 126.8, 121.8,
+
Hz, 1H), 7.57–7.41 (m, 3H), 7.26–7.11 (m, 2H), 6.97 (dd, 120.2, 120.1, 119.5, 111.3 ppm. HRMS (ESI): m/z [M+H]
1
3
J = 2.1, 0.7 Hz, 1H) ppm. C NMR (75 MHz, CDCl3) δ = calcd for C H NBr: 272.0069; found 272.0066.
1
4
11
1
1
1
2
37.8, 137.0, 133.6, 132.8, 129.7, 129.3, 128.7, 127.9,
2
-(4-Methoxyphenyl)-1H-indole (3j)9a: White solid;
27.8, 126.7, 126.1, 123.8, 123.0, 122.5, 120.7, 120.3, 110.9,
◦
+
Yield: 104 mg, 78%; M.p.: 228–230 C; Rf = 0.5 (20%
00.7 ppm. HRMS (ESI): m/z [M+H] calcd for C18H14N:
1
EtOAc/n-hexane). H NMR (300 MHz, DMSO-d6): δ 11.40
44.1121; found 244.1127.
(
br. s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 7.7 Hz,
2
-(3-(Trifluoromethyl)phenyl)-1H-indole (3e)16: White
1
1
1
1
H), 7.37 (d, J = 7.9 Hz, 1H), 7.11–6.92 (m, 4H), 6.75 (s,
H), 3.80 (s, 3H) ppm. 13C NMR (75 MHz, DMSO-d6): δ
58.7, 137.7, 136.8, 128.7, 126.3, 124.8, 120.9, 119.6, 119.1,
◦
solid; yield: 80 mg, 51%; M.p.: 145–147 C; Rf = 0.5 (13%
1
EtOAc/n-hexane). H NMR (300 MHz, CDCl3): δ 8.30 (br. s,
+
1
H), 7.86 (s, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.64 (d, J = 7.8
Hz, 1H), 7.58–7.47 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.23
t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 6.87 (d,
14.2, 110.9, 97.2, 55.1 ppm. HRMS (ESI): m/z [M+H]
calcd for C H14NO: 224.1070; found 224.1071.
1
5
(
4
-(1H-Indol-2-yl)benzonitrile (3k)18
:
Yellow solid;
J = 1.5 Hz, 1H) ppm. (75 MHz, CDCl3): δ 137.0, 136.2,
◦
yield: 38 mg, 29%; M.p.: 190–192 C; Rf = 0.5 (20%
1
1
1
33.1, 131.6, 131.2, 129.5, 129.0, 128.2 (d, J =0.9 Hz, 1C),
EtOAc/n-hexane). IR (Neat)
=
3350, 2224, 1605, 1446,
24.10 (q, J = 3.8 Hz, 1C), 123.0, 121.8-121.6 (m, 1C),
−1 1
+
1429, 1301, 1177 cm . H NMR (300 MHz, CDCl ): δ 8.49
20.9, 120.6, 111.1, 101.2 ppm. HRMS (ESI): m/z [M+H]
3
(
s, 1H), 7.82–7.60 (m, 5H), 7.43 (d, J = 8.1 Hz, 1H), 7.30–
calcd for C H11F3N: 262.0838; found 262.0846.
1
5
7
1
1
1
2
.22 (m, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 1.2Hz,
2
-(3-Fluorophenyl)-1H-indole (3f)8g: White solid; yield:
13
H) ppm. C NMR (75 MHz, CDCl3): δ 137.4, 136.5, 135.5,
◦
7
0 mg, 55%; M.p.: 128–130 C; Rf = 0.5 (15% EtOAc/n-
32.8, 128.9, 127.9, 125.2, 123.6, 121.2, 120.8, 118.8, 111.2,
02.6 ppm. HRMS (ESI): m/z [M+H] calcd for C H11N2:
1
hexane). H NMR (300 MHz, CD3OD): δ 7.58 (d, J = 8.2
+
1
5
Hz, 1H), 7.55–7.47 (m, 2H), 7.43–7.34 (m, 2H), 7.11 (m, 1H),
19.0917; found 219.0918.
1
3
7
.04–6.93 (m, 2H), 6.83 (s, 1H) ppm. C NMR (75 MHz,
CD3OD): δ 164.8 (d, J = 243.5 Hz, 1C), 139.0, 137.9, 136.6
d, J = 8.3 Hz, 1C), 131.6 (d, J = 8.5 Hz, 1C), 130.4, 123.2,
4
-(1H-Indol-3-yl)benzonitrile (4k)19
:
Yellow solid;
◦
yield: 30 mg, 23%; M.p.: 165–167 C; Rf = 0.5 (5%
(
EtOAc/n-hexane). IR (Neat): 3339, 2226, 1602, 1537, 1458,
1
21.9 (d, J = 2.8 Hz, 1C), 121.4, 120.7, 114.7 (d, J = 21.6
−
1 1
1
(
2
(
431, 1334, 1178 cm . H NMR (500 MHz, CDCl3): δ 8.47
s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 8.3 Hz,
H), 7.71 (d, J = 8.3 Hz, 2H), 7.51–7.45 (m, 2H), 7.30
Hz, 1C), 112.6 (d, J = 23.1 Hz, 1C), 112.2, 100.8 ppm.
+
HRMS (ESI): m/z [M+H] calcd for C14H11FN: 212.0870;
found 212.0872.
1
3
t, J = 7.2 Hz, 1H), 7.27–7.23 (m, 1H) ppm. C NMR
2
-(2-Chlorophenyl)-1H-indole (3g)9a
:
White solid;
(
75 MHz, CDCl3): δ 140.6, 136.8, 132.6, 127.4, 125.1, 123.1,
◦
yield: 61 mg, 45%; M.p.: 85–87 C; Rf = 0.5 (15% EtOAc/n-
1
(
23.0, 121.1, 119.5, 119.4, 116.7, 111.7, 108.9 ppm. HRMS
ESI): m/z [M+H] calcd for C H11N2: 219.0917; found
1
hexane). H NMR (300 MHz, CDCl3): δ 8.73 (br. s, 1H), 7.65
+
1
5
(
7
7
(
dd, J = 7.6, 1.8 Hz, 2H), 7.47 (dd, J = 7.9, 1.4 Hz, 1H),
219.0916.
.41 (dd, J = 8.1, 0.9 Hz, 1H), 7.36–7.18 (m, 3H), 7.17–
13
3
-(1H-Indol-2-yl)benzonitrile (3l): Yellow solid; yield: 82
.09 (m, 1H), 6.86 (dd, J = 2.1, 0.8 Hz, 1H) ppm. C NMR
◦
mg, 63%; M.p.: 165–167 C; Rf = 0.5 (15% EtOAc/n-
75 MHz, CDCl3): δ 136.4, 135.1, 131.3, 131.2, 130.8, 130.7,
28.8, 128.1, 127.2, 122.6, 120.8, 120.2, 111.0, 103.5 ppm.
hexane). IR (Neat): 3347, 3055, 2236, 1603, 1485, 1431,
1

71
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J. Chem. Sci.
(2019) 131:71
364, 1306, 1233 cm 1. 1H NMR (300 MHz, CDCl3): δ 8.49 3H) ppm. 13C NMR (75 MHz, DMSO-d6): δ 159.4, 140.5,
−
1
(
br. s, 1H), 7.94 (s, 1H), 7.89 (td, J = 7.3, 1.7 Hz, 1H), 7.66 138.8, 128.7, 126.9, 125.0, 123.9, 120.9, 115.7, 114.5, 112.3,
+
(
1
d, J = 7.8 Hz, 1H), 7.62–7.51 (m, 2H), 7.44 (d, J = 8.1 Hz, 101.3, 97.9, 55.3 ppm. HRMS (ESI): m/z [M+H] calcd for
H), 7.30–7.21 (m, 1H), 7.19–7.12 (m, 1H), 6.89 (d, J = 1.3 C16H13N2O: 249.1028; found 249.1027.
13
Hz, 1H) ppm. C NMR (75 MHz, CDCl3): δ 137.2, 135.2,
1
1
3
-(4-Methoxyphenyl)-1H-indole-5-carbonitrile
(4q):
33.7, 130.7, 129.8, 129.2, 128.9, 128.4, 123.3, 121.0, 120.7,
18.6, 113.2, 111.2, 101.6 ppm. HRMS (ESI): m/z [M+H]
◦
+
Yellow solid; yield: 43 mg, 29%; M.p.: 165–167 C; Rf =
0
2
.5 (32% EtOAc/n-hexane). IR (Neat): 3337, 2961, 2841,
calcd for C H11N2: 219.0917; found 219.0924.
1
5
−1
1
221, 1608, 1503, 1276, 1250, 1181 cm
.
H NMR
2
-(4-Methoxyphenyl)-1-methyl-1H-indole
(3m)20
:
(500 MHz, CDCl ): δ 8.74 (s, 1H), 8.22 (s, 1H), 7.52 (d,
J = 8.7 Hz, 2H), 7.50–7.43 (m, 2H), 7.40 (d, J = 2.4 Hz,
3
◦
White solid; yield: 107 mg, 75%; M.p.: 118–120 C; Rf = 0.5
1
13
(
10% EtOAc/n-hexane). H NMR (400 MHz, CDCl3): δ 7.63 1H), 7.03 (d, J = 8.7 Hz, 2H), 3.88 (s, 3H) ppm. C NMR
(
d, J = 7.8 Hz, 1H), 7.44 (d, J = 8.6 Hz, 2H), 7.36 (d, (75 MHz, CDCl ): δ 158.6, 138.1, 128.7, 126.4, 125.8, 125.6,
3
J = 8.2 Hz, 1H), 7.27–7.20 (m, 1H), 7.14 (t, J = 7.4 Hz, 125.0, 123.1, 120.8, 118.8, 114.5, 112.3, 102.9, 55.3 ppm.
+
1
H), 7.01 (d, J = 8.6 Hz, 2H), 6.51 (s, 1H), 3.88 (s, 3H), 3.73 HRMS (ESI): m/z [M+H] calcd for C H N O: 249.1022;
1
6
13
2
(
s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ 159.4, 141.4, found 249.1026.
1
38.1, 130.6, 127.9, 125.2, 121.4, 120.2, 119.7, 113.9, 109.5,
3-(4-Methoxyphenyl)-2-methyl-1H-indole (3r)21: Yellow
+
100.9, 55.3, 31.0 ppm. HRMS (ESI): m/z [M+H] calcd for
◦
solid; yield: 44 mg, 31%; M.p.: 127–129 C; Rf = 0.5 (5%
C16H16NO: 238.1226; found 238.1228.
1
EtOAc/n-hexane). H NMR (300 MHz, CDCl3): δ 7.92 (br.
1-Butyl-2-(4-methoxyphenyl)-1H-indole (3n): Colourless
s, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 8.7 Hz,
1
oil: yield: 117 mg, 70%; Rf = 0.5 (12% EtOAc/n-hexane). H
2
6
H), 7.33 (d, J = 8.2 Hz, 1H), 7.21–7.06 (m, 2H), 7.05–
.99 (m, 2H), 3.88 (s, 3H), 2.49 (s, 3H) ppm. 13C NMR
NMR (400 MHz, CDCl3): δ 7.71 (d, J = 7.8 Hz, 1H), 7.53–
7
1
.41 (m, 3H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz,
H), 7.06 (d, J = 8.7 Hz, 2H), 6.55 (s, 1H), 4.20 (t, J = 7.5
(
75 MHz, CDCl3): δ 157.8, 135.1, 130.9, 130.4, 128.0, 127.7,
1
21.4, 119.8, 118.7, 114.1, 113.9, 110.2, 55.3, 12.4 ppm.
+
Hz, 2H), 3.93 (s, 3H), 1.81–1.69 (m, 2H), 1.35–1.20 (m, 2H),
HRMS (ESI): m/z [M+H] calcd for C16H16NO: 238.1226;
1
3
0
1
1
.89 (t, J = 7.3 Hz, 3H) ppm. C NMR (75 MHz, CDCl3): δ
found 238.1230.
59.3, 141.1, 137.1, 130.6, 128.2, 125.6, 121.1, 120.3, 119.6,
13.8, 109.9, 101.4, 55.2, 43.6, 32.0, 19.9, 13.6 ppm. HRMS
2
-(4-Methoxyphenyl)benzofuran
(3s)22:
Colourless
◦
+
flakes; yield: 51 mg, 38%; M.p.: 149–151 C; R = 0.5 (5%
(
ESI): m/z [M+H] calcd for C19H22NO: 280.1696; found
f
1
EtOAc/n-hexane). H NMR (300 MHz, DMSO-d6): δ 11.40
280.1698.
(
br. s, 1H), 7.79 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 7.7 Hz,
5-Bromo-2-(4-methoxyphenyl)-1H-indole(3o):Whitesolid;
1
1
1
1
H), 7.37 (d, J = 7.9 Hz, 1H), 7.11–6.92 (m, 4H), 6.75 (s,
◦
Yield: 67 mg, 37%; M.p.: 178–180 C; Rf = 0.5 (22%
13
H), 3.80 (s, 3H) ppm. C NMR (75 MHz, DMSO-d6): δ
1
EtOAc/n-hexane). H NMR (300 MHz, DMSO-d6): δ 11.64
57.9, 149.9, 149.6, 146.5, 130.9, 129.9, 127.7, 116.6, 116.1,
(
s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 1.7 Hz,
+
15.6, 114.3, 113.3, 54.9 ppm. HRMS (ESI): m/z [M+H]
1
1
3
1
1
H), 7.33 (d, J = 8.5 Hz, 1H), 7.16 (dd, J = 8.5, 1.8 Hz,
H), 7.04 (d, J = 8.7 Hz, 2H), 6.75 (d, J = 1.5 Hz, 1H),
.80 (s, 3H) ppm. 13C NMR (75 MHz, DMSO-d6): δ 159.0,
39.3, 135.5, 130.7, 126.5, 124.2, 123.3, 121.6, 114.3, 112.9,
calcd for C H13O2: 225.0916; found 225.0918.
1
5
2
-(4-Methoxyphenyl)-1H-pyrrole (3t): White solid;
◦
yield: 46 mg, 44%; M.p.: 143–145 C; Rf = 0.5 (15%
1
+
EtOAc/n-hexane). H NMR (300 MHz, CDCl3): δ 8.35 (s,
11.6, 96.8, 55.1 ppm. HRMS (ESI): m/z [M+H] calcd for
1
H), 7.41 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H),
C H13BrNO: 302.0175; found 302.0174.
1
5
6.82 (d, J = 1.3 Hz, 1H), 6.50–6.24 (m, 2H), 3.84 (s, 3H)
2-(4-Methoxyphenyl)-1H-indol-5-ol(3p):Whitesolid;yield:
13
ppm. C NMR (75 MHz, CDCl3): δ 158.2, 132.1, 125.8,
◦
1
03 mg, 72%; M.p.: 237–239 C; Rf = 0.5 (25% EtOAc/n-
1
25.2, 118.1, 114.3, 109.8, 104.8, 55.3 ppm. HRMS (ESI):
1
hexane). H NMR (400 MHz, CD3OD): δ 7.67 (d, J = 8.8
+
m/z [M+H] calcd for C11H11NO: 174.0913; found 174.09.
Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H),
.88 (d, J = 2.1 Hz, 1H), 6.63 (dd, J = 8.6, 2.3 Hz, 1H), 6.52 2-(4-Methoxyphenyl)thiophene (3u)23
:
White solid;
6
(
s, 1H), 3.83 (s, 3H) ppm. 13C NMR (100 MHz, CD3OD): δ yield: 26 mg, 38%; M.p.: 107–109 C; Rf = 0.5 (5%
◦
1
1
60.6, 151.7, 140.2, 133.8, 131.6, 127.4, 127.2, 115.3, 112.3, EtOAc/n-hexane). H NMR (300 MHz, CDCl3): δ 7.53 (d,
1
+
12.2, 105.1, 98.0, 55.8 ppm. HRMS (ESI): m/z [M+H]
J = 8.8 Hz, 2H), 7.39–7.32 (m, 3H), 6.94 (d, J = 8.8 Hz,
2H), 3.84 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3): δ =
calcd for C H14NO2: 240.1019; found 240.1026.
1
5
1
58.9, 142.0, 128.7, 127.5, 126.2, 126.0, 118.9, 114.2, 55.3
2
-(4-Methoxyphenyl)-1H-indole-5-carbonitrile
(3q):
ppm.
◦
Yellow solid; yield: 37 mg, 25%; M.p.: 122–124 C; Rf =
0
1
.5 (32% EtOAc/n-hexane). IR (Neat): 3338, 2219, 1614, Mechanistic Investigation:
−1 1
470, 1421, 1347, 1323, 1221 cm . H NMR (300 MHz,
Catalyst Poisoning Test24: To investigate the reaction mech-
anism, Hg(0) poisoning test was performed using Hg(0)
DMSO-d6): δ 12.04 (s, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.8
Hz, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4, 1.5
Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 3.80 (s,
(1.0 mmol, 1 equiv) with indole (0.6 mmol, 1.0 equiv)

J. Chem. Sci.
(2019) 131:71
Page 5 of 9
71
Table 1. Optimization of reaction conditions.a
Entry
Catalyst
Oxidant Additive (Equiv)
Solvent
Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
Pd(MeCN) Cl2
BQ
BQ
BQ
BQ
BQ
H2SO4 (2)
H2SO4 (2)
H3PO4 (2)
AcOH (2)
AcOH (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (2)
TFA (3)
TFA (1)
TFA (2)
TFA (2)
Toluene
MeCN
MeCN
MeCN
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
12
12
12
12
12
12
12
12
12
12
4
N.R.
Trace
Trace
11
17
18
32
N.R.
5
38
78
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
BQ
Cu(OAc)2
K2S2O8
Ag O
2
10
11
12
13
14
15
Air
Air
Air
Air
Air
Air
EtOAc
Dioxane : H2O(3 : 1)
Dioxane:H2O (3:1)
Dioxane:H2O (3:1)
Dioxane:H2O (3:1)
Dioxane:H2O (3:1)
4
4
4
4
76
54
46
74
b
c
aUnless otherwise stated, all the reactions were carried out using 1a (0.2 mmol, 1.0 equiv), 2a (0.4
mmol, 2.0 equiv), catalyst (5 mol%), oxidant (0.34 mmol, 1.7 equiv), additive (0.4 mmol, 2.0 equiv)
◦
b
c
for 4–12 h at 25 C in open atmosphere. With 2 mol% Pd(TFA) . With 10 mol% Pd(TFA) .
2
2
N.R. = no reaction.
and 4-methoxyphenylboronic acid (1.2 mmol, 2.0 equiv) as that air was the most effective for the promotion of
coupling partners, Pd(TFA) (0.06 mmol, 5 mol%), TFA (1.2 reaction (Table 1, entries 10, 11). Other organic and inor-
2
mmol, 2.0 equiv) following general procedure. The reaction
afforded the desired product (3j) in comparable yield (76%)
suggesting that the reaction goes through homogeneous catal-
ysis.
ganic oxidants gave inferior results under these reaction
conditions. In order to drive the reaction to completion,
◦
the reaction mixture was allowed to heat at 70 C for a
long time but no improvement was observed. The homo-
coupling product from boronic acid was obtained as
a minor product which could be separated by column
chromatography. Reducing the amount of catalyst from
3
. Results and Discussion
5
to 2 mol% affected the yield significantly (Table 1,
Initially, the reaction was studied using indole as a sub- entry 14). However, increasing the catalyst loading did
strate and 4-methoxyphenylboronic acid as an arylating not affect the yield to a great extent (Table 1, entry 15).
agenttoscreentheoptimalconditions, andtheresultsare
summarized in Table 1. Pd(OAc) and Pd(MeCN) Cl
With the optimized reaction conditions in hand
Pd(TFA) (5 mol%), air, TFA (2 equiv), 1,4-dioxane/
2
2
2
2
turned out to be less efficient catalysts for this coupling water (3:1) at RT, direct C-2 arylation of indoles
reaction (Table 1, entries 1 to 5) whereas the use of was extended to various boronic acids as summarized
Pd(TFA) gave better yields (entries 6 to 10). When in Table 2. Both electron-donating and electron-with-
2
the reaction was carried out in Toluene, MeCN, 1a drawing substituents on the phenyl ring of the boronic
was almost completely recovered (Table 1, entries 1– acids underwent the transformation in moderate to good
4
). Pleasingly, when EtOAc was used as a solvent with yields. However, phenylboronic acids bearing electron-
TFA as an additive under an aerobic condition, the 2- withdrawing groups were shown to be less compatible
arylindole was obtained in 38% yield (Table 1, entry under these reaction conditions. In addition, boronic
1
0). More surprisingly, 78% yield was obtained when acids with an ortho substituent delivered the desired
a mixture of 1,4-dioxane and water (3:1) was used as a products in lower yields indicating that steric hin-
solvent (Table 1, entry 11).
drance could play a role in this reaction (Table 2,
Subsequently, different acids such as H SO , H PO , compound 3b, 3g). 2-Napthylboronic acid also under-
2
4
3
4
AcOH were tested, but none of them could give compa- went coupling and provided the desired product 3d
rable results as with TFA. Screening of oxidant revealed in 73% yield within 4 h. Moreover, halogen atom (F,

71
Page 6 of 9
J. Chem. Sci.
(2019) 131:71
Table 2. Direct Arylation of Indoles, Benzofuran, Pyrrole and Thiophene with various Arylboronic
acids.a
aReaction conditions;, all the reactions were carried out with heterocycle (0.6 mmol, 1.0 equiv),
boronic acid (2.0 equiv), Pd(TFA) (5 mol%), 1,4-dioxane/H2O (3:1 2.0 mL), 0.5 M) in presence
2
b
of air (open atmosphere) for 4–12 h; yield refers to isolated materials. Both the products were
isolated.
Cl, Br) substituted aryl rings in indole derivatives can acid C-3 arylated products 4k, 4q were obtained along
be used as a precursor for elaboration by transition with C-2 arylated indole derivatives. 2-Methyl indole
metal-catalyzed coupling reactions. Unfortunately, no exhibited lower yield to arylation affording the corre-
product was obtained when cyclohexylboronic acid was sponding 3-arylindole derivative (Table 2, compound
used in the current reaction system, and the starting 3r). We were pleased that benzofuran, pyrrole and thio-
material was completely recovered. With the positive phene were also compatible with the current protocol
results above, various structurally diverse indole deriva- (Table 2, compounds 3s, 3t, 3u). However, when imida-
tives were explored to further expand their substrate zole and 7-azaindole were subjected to these conditions,
scope. N-alkyl indoles were well-tolerated under this no desired products were obtained.
protocol (Table 2, compound 3m, 3n). Irrespective of
On the basis of the above experimental results,
the electronic nature of substituents on the 5- posi- a plausible mechanism for this reaction is proposed
tion of the indole ring, the coupling reaction could be in Scheme 2. Initially, the reaction of Pd(II) with
performed affording the desired products in moderate arylboronic acid afforded the palladium intermediate.
yields (Table 2, compound 3o, 3p, 3q, 4q). Surprisingly, Following this step, indole coordination occurs at the
in case of 5-cyano indole and 4-cyanophenylboronic metallic centre through C-3 position and then C3–C2

J. Chem. Sci.
(2019) 131:71
Page 7 of 9
71
Acknowledgements
Financial support from the Science and Engineering Research
Board, Department of Science and Technology, Govern-
ment of India (Grant No. (SR/S1/OC/0087/2012) is gratefully
acknowledged. I. B. and K.C.G are thankful to Council for
Scientific and Industrial Research (CSIR) New Delhi for the
fellowship.
References
1
. (a) Corbet J-P and Mignani G 2006 Selected Patented
Cross-Coupling Reaction Technologies Chem. Rev. 106
Scheme 2. Proposed mechanism for direct C-H arylation of
indole with boronic acid.
2651; (b) Hassan J, Sevignon M, Gozzi C and Shulz
M 2002 Aryl-Aryl Bond Formation One Century after
the Discovery of the Ullmann Reaction Chem. Rev. 102
migration of the Pd centre afforded the complex lead-
ing to the C-2 regioisomer. Furthermore, blocking the
C2–H position by a –Me group showed low conversion
towards the C-3 regioisomer supporting the fact that
the presence of –Me group at C-2 position inhibits the
C3–C2 migration. Additionally, in substrates containing
electron-withdrawing group (e.g.- cyano) the migra-
tion from C3–C2 becomes slow as expected (which
provides extra stability to the palladium intermediate
leading to the formation of a mixture of C-3 and C-
1
359; (c) Anastasia L and Negishi E 2002 In Handbook
of Organopalladium Chemistry for Organic Synthesis E
Negishi (Ed.) (New York: J. Wiley & Sons) p. 311;
(
d) Roy D and Uozumi Y 2018 Recent Advances in
Palladium-Catalyzed Cross-Coupling Reactions at ppm
to ppb Molar Catalyst Loadings Adv. Synth. Catal. 360
6
02; (e) Nicolaou K C, Bulger P G and Sarlah D 2005
Palladium-Catalyzed Cross-Coupling Reactions in Total
Synthesis Angew. Chem. Int. Ed. 44 4442
2. (a) Yu J-Q and Shi Z (Eds.) 2010 C–H Activation. Top-
ics in Current Chemistry (Berlin: Springer) p. 380; (b)
Bheeter C B, Chen L, Soulé J-F and Doucet H 2016
Regioselectivity in palladium-catalysed direct arylation
of 5-membered ring heteroaromatics Catal. Sci. Tech-
nol. 6 2005; (c) Joucla L, Batail N and Djakovitch L 2010
“On Water” Direct and Site- Selective Pd-Catalysed C-H
Arylation of (NH)-Indoles Adv. Synth. Catal. 352 2929;
2
aryl indole derivatives). Though the exact role of
TFA is not known, it might be said that deprotona-
tion of Pd intermediate formed through electrophilic
substitution is favoured in acidic conditions allowing
C3–C2 migration.15 In order to know the homogeneity
of the catalyst, we performed the reaction in the pres-
(d) Lebrasseur N and Larrosa I 2012 Recent Advances
in the C2 and C3 Regioselective Direct Arylation of
Indoles Adv. Heterocycl. Chem. 105 309; (e) Akita Y,
Itagaki Y, Takizawa S and Ohta A 1989 Cross-coupling
reactions of chloropyrazines with 1-substituted indoles
Chem. Pharm. Bull. 37 1477; (f) Basu D, Kumar S,
Sudhir V S and Bandichhor R 2018 Transition metal
catalyzed C-H activation for the synthesis of medicinally
relevant molecules: A Review J. Chem. Sci. 130 1
. (a) Kakiuchi F and Murai S 2002 Catalytic C-H/Olefin
Coupling Acc. Chem. Res. 35 826; (b) Ackermann
L 2014 Carboxylate-Assisted Ruthenium-Catalyzed
Alkyne Annulations by C-H/Het-H Bond Functionaliza-
tions Acc. Chem. Res. 47 281
. (a) Manan R S and Zhao P 2016 Merging rhodium-
catalysed C–H activation and hydroamination in a highly
selective [4 + 2] imine/alkyne annulation Nat. Com-
mun. 7 1; (b) Colby D A, Bergman R G and Ellman
J A 2010 Rhodium-Catalyzed C-C Bond Formation via
Heteroatom-Directed C-H Bond Activation Chem. Rev.
ence of an excess of Hg(0) w.r.t Pd(TFA) in catalyst
2
poisoning experiment,24 where no inhibitory activity
of the catalyst was noticed (see the Experimental Sec-
tion).
3
4
4
. Conclusions
In summary, we have standardized the Suzuki reac-
tion for the conversion of indole to C-2 arylated indole
derivatives using air as the sole oxidant and Pd(II)
as a catalyst. Particularly, free –NH indoles are well-
tolerated for this transformation, thus expected to show
great potentiality in the formation of complex molecules
used in many pharmaceutical chemistries.
110 624; (c) Song G, Wang F and Li X 2012 C–C, C–
O and C–N bond formation via rhodium(III)-catalyzed
oxidative C–H activation Chem. Soc. Rev. 41 3651
Supplementary Information (SI)
5. (a) Mkhalid I A I, Barnard J H, Marder T B, Mur-
phy J M and Hartwig J F 2010 C-H Activation for
the Construction of C-B Bonds Chem. Rev. 110 890;
(b) Li L, Brennessel W W and Jones W D 2008
Rhodium(III) Catalyzed Arylation of Boc-Imines via
1H, 13C NMR spectra for the characterization of compounds
are given in the supporting information. Supplementary Infor-
mation is available at www.ias.ac.in/chemsci.

71
Page 8 of 9
J. Chem. Sci.
(2019) 131:71
C–H Bond Functionalization J. Am. Chem. Soc. 130
Direct Arylation of (Hetero) Arenes with Aryl Boronic
Acids Angew. Chem. Int. Ed. 47 1473; (g) Zhao J, Zhang
Y and Cheng K 2008 Palladium-Catalyzed Direct C-2
Arylation of Indoles with Potassium Aryltrifluoroborate
Salts J. Org. Chem. 73 7428; (h) Stuart D R, Ville-
mure E and Fagnou K 2007 Elements of Regiocontrol in
Palladium-Catalyzed Oxidative Arene Cross-Coupling
J. Am. Chem. Soc. 129 12072; (i) Phipps R J, Grimster N
P and Gaunt M J 2008 Cu(II)-Catalyzed Direct and Site-
Selective Arylation of Indoles Under Mild Conditions
J. Am. Chem. Soc. 130 8172; (j) Zhang Z, Hu Z, Yu Z,
Lei P, Chi H, Wang Y and He R 2007 Direct palladium-
catalyzed C-3 arylation of indoles Tetrahedron Lett. 48
2415
1
2414; (c) Schultz D M and Wolfe J P 2012 Disguise
gets a reaction Nature 483 42; (d) Larsen M A and
Hartwig J F 2014 Iridium-Catalyzed C-H Borylation
of Heteroarenes: Scope, Regioselectivity, Application
to Late-Stage Functionalization, and Mechanism J. Am.
Chem. Soc. 136 4287
6
. (a) Alberico D, Scott M E and Lautens M 2007 Aryl-Aryl
Bond Formation by Transition-Metal-Catalyzed Direct
Arylation Chem. Rev. 107 174; (b) Campeau L-C, Stuart
D R and Fagnou K 2007 Palladium-Catalyzed Domino
Heck/C-H Activation/Intermolecular Direct Arylation
Reactions Aldrichim. Acta 20 35; (c) Satoh T and Miura
M 2007 Catalytic Direct Arylation of Heteroaromatic
Compounds Chem. Lett. 36 200; (d) Seregin I V and
Gevorgyan V 2007 Direct transition metal-catalyzed
functionalization of heteroaromatic compounds Chem.
Soc. Rev. 36 1173; (e) Godula K and Sames D 2006
C–H Bond Functionalization in Complex Organic Syn-
thesis Science 312 67; (f) Kakiuchi F and Chatani N
8. (a)BellinaF, CalandriC, CauteruccioSandRossiR2007
Efficient and highly regioselective direct C-2 arylation of
azoles, including free (NH)-imidazole, -benzimidazole
and -indole, with aryl halides Tetrahedron 63 1970; (b)
Bellina F, Cauteruccio S and Rossi R 2006 Palladium-
and Copper-Mediated Direct C-2 Arylation of Azoles -
Including Free (NH)-Imidazole, -Benzimidazole and -
Indole - Under Base-Free and Ligand-less Conditions
Eur. J. Org. Chem. 1379; (c) Toure’ B B, Lane B S
and Sames D 2006 Catalytic C-H Arylation of SEM-
Protected Azoles with Palladium Complexes of NHCs
and Phosphines Org. Lett. 8 1979; (d) Beck E M,
Grimster N P, Hatley R and Gaunt M J 2006 Mild
Aerobic Oxidative Palladium (II) Catalyzed C-H Bond
Functionalization: Regioselective and Switchable C-H
Alkenylation and Annulation of Pyrroles J. Am. Chem.
Soc. 128 2528; (e) Dwight T A, Rue N R, Charyk D,
Josselyn R and DeBoef B 2007 C-C Bond Formation
via Double C-H Functionalization: Aerobic Oxidative
Coupling as a Method for Synthesizing Heterocoupled
Biaryls Org. Lett. 9 3137
9. (a) Wu M, Luo J, Xiao F, Zhang S, Deng G-J and Luo H-
A 2012 Palladium-Catalyzed Direct and Site-Selective
Desulfitative Arylation of Indoles with Sodium Sulfi-
nates Adv. Synth. Catal. 354 335; (b) Miao T, Li P,
Wang G-W and Wang L 2013 Microwave-Accelerated
Pd-Catalyzed Desulfitative Direct C-2 Arylation of Free
(NH)-Indoles with Arylsulfinic Acids Chem. Asian J. 8
3185; (c) Liu C, Ding L, Guo G, Liu W and Yang F-
L 2016 Palladium-catalyzed direct arylation of indoles
with arylsulfonyl hydrazides Org. Biomol. Chem. 14
2824; (d) Hfaiedh A, Ammar H B, Soulé J-F and
Doucet H 2016 Palladium-catalyzed direct desulfitative
C-2 arylations of 3-halo-N-protected indoles using (het-
ero)arenesulfonylchloridesOrg. Biomol. Chem. 144947
2
003 Catalytic Methods for C-H Bond Functionaliza-
tion: Application in Organic Synthesis Adv. Synth. Catal.
45 1077; (g) Lyons T W and Sanford M S 2010
3
Palladium-Catalyzed Ligand-Directed C-H Functional-
ization Reactions Chem. Rev. 110 1147; (h) Wencel-
Delord J, Dröge T, Liu F and Glorius F 2011 Towards
mild metal-catalyzed C–H bond activation Chem. Soc.
Rev. 40 4740; (i) Jia C, Kitamura T and Fujiwara Y
2
001 Catalytic Functionalization of Arenes and Alka-
nes via C-H Bond Activation Acc. Chem. Res. 34 633;
j) Motoyama T, Shimazaki Y, Yajima T, Nakabayashi
(
Y, Naruta Y and Yamauchi O 2004 Reactivity of the
Indole Ring in Palladium(II) Complexes of 2N1O-Donor
Ligands: Cyclopalladation and π-Cation Radical For-
mation J. Am. Chem. Soc. 126 7378; (k) Tollari S,
Demartin F, Cenini S, Palmisano G and Raimondi P 1997
Cyclometallation of indole derivatives: cyclopaUadation
of gramine and 1-methyl gramine and CO insertion J.
Organomet. Chem. 527 93; (l) Sehnal P, Taylor R J K
and Fairlamb I J S 2010 Emergence of Palladium (IV)
Chemistry in Synthesis and Catalysis Chem. Rev. 110
8
24; (m) Jiao L, Herdtweck E and Bach T 2012 Pd (II) -
Catalyzed Regioselective 2–Alkylation of Indoles via a
Norbornene-Mediated C-H Activation: Mechanism and
Applications J. Am. Chem. Soc. 134 14563
7
. C-H activation of indoles: (a) Lane B S, Brown M
A and Sames D 2005 Direct Palladium-Catalyzed C-2
and C-3 Arylation of Indoles: A Mechanistic Rationale
for Regioselectivity J. Am. Chem. Soc. 127 8050; (b)
Lane B S and Sames D 2004 Direct C-H Bond Ary- 10. Malmgren J, Nagendiran A, Tai C-W, Bäckvall J-E and
lation: Selective Palladium-Catalyzed C-2 Arylation of
N-Substituted Indoles Org. Lett. 6 2897; (c) Sezen B
and Sames D 2003 Selective C-Arylation of Free (NH)-
Olofsson B 2014 C-2 Selective Arylation of Indoles
with Heterogeneous Nanopalladium and Diaryliodo-
nium Salts Chem. Eur. J. 20 13531
Heteroarenes via Catalytic C-H Bond Functionalization 11. Duan L, Fu R, Zhang B, Shi W, Chen S and Wan Y
J. Am. Chem. Soc. 125 5274; (d) Deprez N R, Kalyani
D, Krause A and Sanford M S 2006 Room Tempera-
ture Palladium-Catalyzed 2-Arylation of Indoles J. Am.
2016 An Efficient Reusable Mesoporous Solid-Based Pd
Catalyst for Selective C2 Arylation of Indoles in Water
ACS Catal. 6 1062
Chem. Soc. 128 4972; (e) Lebrasseur N and Larrosa 12. Markandeya S V, Renuka C, Lakshmi P K, Rajesh A,
I 2008 Room Temperature and Phosphine Free Palla-
dium Catalyzed Direct C-2 Arylation of Indoles J. Am.
Chem. Soc. 130 2926; (f) Yang S-D, Sun C-L, Fang Z,
Li B-J, Li Y-Z and Shi Z-J 2008 Palladium-Catalyzed
Sridhar C and Babu K R 2018 Design and applications
of new phosphine-free tetradentate Pd-catalyst: Regios-
elective C-H activation on 1-substituted 1,2,3-triazoles
and indoles(NH-Free) Synth. Commun. 48 135

J. Chem. Sci.
(2019) 131:71
Page 9 of 9
71
1
3. (a) Sundberg R J The Chemistry of Indoles 1970 (Lon-
lective CH Functionalization Angew. Chem. Int. Ed. 44
3125
don: Academic Press); (b) Sundberg R J 1996 Indoles
(
London: Academic Press); (c) Humphrey G R and 16. Chan Sik C, Jun Ho K, Kim T-J and Sang Chul S 2004
Kuethe J T 2006 Practical Methodologies for the Syn-
thesis of Indoles Chem. Rev. 106 2875; (d) Brancale
Palladium-catalysed synthesis of 2-substituted indole J.
Chem. Res. 630
A and Silvestri R 2007 Indole, a Core Nucleus for 17. Dalton L, Humphrey G L, Cooper M M and Joule
1
Potent Inhibitors of Tubulin Polymerization Med. Res.
Rev. 27 209; (e) Harper S, Avolio S, Pacin B, Di Fil-
ippo M, Altamura S, Tomei L, Paonessa G, Di Marco
S, Carfi A, Giuliano C, Padron J, Bonelli F, Migliaccio
J A 1983 lndole ß-Nucleophilic Substitution. Part 7.
ß-Halogenation of Indoles. Attempted Intramolecular ß-
Nucleophil ic Substitution of α-Aryl indoles J. Chem.
Soc., Perkin Trans. 1 2417
G, De Francesco R, Laufer R, Rowley M and Narjes 18. Moncea O, Poinsot, D, Fokin A A, Schreiner P R and
F 2005 Potent Inhibitors of Subgenomic Hepatitis C
Virus RNA Replication through Optimization of Indole-
N-Acetamide Allosteric Inhibitors of the Viral NS5B
Polymerase J. Med. Chem. 48 4547; (f) Soto S, Vaz E,
Hierso J-C 2018 Palladium-Catalyzed C2-H Arylation
of Unprotected (NH)-Indoles “On Water” Using Primary
Diamantyl Phosphine Oxides as a Class of Primary Phos-
phine Oxide Ligands ChemCatChem 10 2915
Dell’ Aversana C, Alvarez R, Altucci L and de Lera A R 19. Zhang Z, Hu Z, Yu Z, Lei P, Chi H, Wang Y and He R
2
012 New synthetic approach to paullones and charac-
2007Directpalladium-catalyzedC-3arylationofindoles
Tetrahedron Lett. 48 2415
20. Denmark S E and Baird J D 2004 Palladium-Catalyzed
Cross-Coupling Reactions of 2-Indolyldimethylsilanols
with Substituted Aryl Halides Org. Lett. 6 3649
terization of their SIRT1 inhibitory activity Org. Biomol.
Chem. 10 2101
1
4. (a) Jana G K, Paul S and Sinha S 2011 Progress
in the Synthesis of Iboga-alkaloids and their Con-
geners Org. Prep. Proc. Int. 43 541; (b) Jana G K 21. Bellina F, Benelli F and Rossi R 2008 Efficient and Prac-
and Sinha S 2012 Total synthesis of ibogaine, epii-
bogaine and their analogues Tetrahedron 68 7155; (c)
Chakraborty A and Sinha S 2011 Synthesis of 3-[2-
tical Synthesis of 4(5)-Aryl-1H-imidazoles and 2,4(5)-
Diaryl-1H-imidazoles via Highly Selective Palladium-
Catalyzed Arylation Reactions J. Org. Chem. 73
5529
(1,3-butadienyl)]-1H-indoles en route to murrapanine
analogue Tetrahedron Lett. 52 6635; (d) Chakraborty 22. Denmark S E, Smith R C, Chang W-T T and Muhuhi
A, Jyothi K and Sinha S 2014 Palladium-catalyzed
synthesis of 2-allylindole and 2-allylbenzofuran deriva-
tives from 2-((trimethylsilyl)ethynyl)arenes Tetrahe-
J M 2009 Cross-Coupling Reactions of Aromatic and
Heteroaromatic Silanolates with Aromatic and Het-
eroaromatic Halides J. Am. Chem. Soc. 131 3104
dron Lett. 55 6795; (e) Banerjee T S, Paul S, 23. Sudo Y, Yamaguchi E and Itoh A 2017 Photo-
Sinha S and Das S 2014 Synthesis of iboga-like
isoquinuclidines: Dual opioid receptors agonists hav-
ing antinociceptive properties Bioorg. Med. Chem. 22
oxidative Cross-Dehydrogenative Coupling-Type Reac-
tion of Thiophenes with α-Position of Carbonyls Using
a Catalytic Amount of Molecular Iodine Org. Lett. 19
1610
6062
1
5. Grimse N P, Gaunlett C, Godfrey C R A and 24. Chatterjee A and Jensen V R 2017 A Heterogeneous Cat-
Gaunt M J 2005 Palladium-Catalyzed Intermolecular
Alkenylation of Indoles by Solvent-Controlled Regiose-
alyst for the Transformation of Fatty Acids to α-Olefins
ACS Catal. 7 2543