One-pot synthesis of arylated 1-methyl-1H-indoles by Suzuki-Miyaura cross-coupling reactions of 2,3-dibromo-1-methyl-1H-indole and 2,3,6-tribromo-1-methyl-1H-indole

Article abstract of DOI:10.1016/j.tet.2013.05.100

Arylated 1-methyl-1H-indoles were prepared by Suzuki-Miyaura cross-coupling reactions of 2,3-dibromo-1-methyl-1H-indole and 2,3,6-tribromo-1-methyl-1H- indole. The reactions proceed with very good regioselectivity in favour of position 2.

Full text of DOI:10.1016/j.tet.2013.05.100

Tetrahedron 69 (2013) 7492e7504
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of arylated 1-methyl-1H-indoles by
SuzukieMiyaura cross-coupling reactions of 2,3-dibromo-1-methyl-
1H-indole and 2,3,6-tribromo-1-methyl-1H-indole
,
,
b
,
,c
Muhammad Farooq Ibad a y, Dhafer Saber Zinad a y, Munawar Hussain a, Asad Ali a
,
Alexander Villinger a, Peter Langer a
,d,
*
a
€
€
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
b Department of Chemistry, College of Science, University of Mosul, Mosul, Iraq
c Department of Chemistry, Abdul Wali Khan University, Mardan, KPK, Pakistan
d
€
€
Leibniz Institut fur Katalyse an der Universitat Rostock e. V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Arylated 1-methyl-1H-indoles were prepared by SuzukieMiyaura cross-coupling reactions of 2,3-
dibromo-1-methyl-1H-indole and 2,3,6-tribromo-1-methyl-1H-indole. The reactions proceed with very
good regioselectivity in favour of position 2.
Received 18 March 2013
Received in revised form 15 May 2013
Accepted 21 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Available online 18 June 2013
Keywords:
Catalysis
Cross-coupling
SuzukieMiyaura reaction
Palladium
N-Heterocycles
1. Introduction
Traditional methods of their synthesis mostly involve multistep
syntheses.7,8 Gribble and Liu reported the synthesis of N-phenyl-
The substituted indole core is a structural component of agro-
chemicals, functional materials, of a broad number of biologically
active compounds, and especially of many pharmaceutical agents.1
Due to its capability of binding with many receptors with excellent
affinity, indole is referred to as a so-called privileged structure.2
They are structural motifs of a variety of biologically active com-
pounds, such as novel COX-2 inhibitors for the treatment of ar-
thritic pain.3 For example, 2,3-bis(4-methoxyphenyl)indole
(‘indoxole’) represents a potent anti-inflammatory agent.4 The
chemistry and biology of indoles have been reviewed several
times.5 Various well-established classical methods have been ap-
plied for the synthesis and functionalization of indoles for more
than 100 years. A great deal of recent work has been focused on the
development of transition metal-catalysed reactions for the direct
arylation of indoles.6 In this context, impressive strategies have
been developed to synthesize C2- and C3-functionalized indoles.7
sulfonyl-2,3-diarylindoles by twofold SuzukieMiyaura reactions of
2,3-dihalo-N-(phenylsulfonyl)indoles.9 However, all attempts to
develop a site-selective reaction failed, because of a similar re-
activity of positions 2 and 3 and formation of diarylated products.
Recently, we developed the first site-selective SuzukieMiyaura
cross-coupling reactions of 2,3-dibromoindoles.10 The success of
these reactions, which provide a convenient one-pot synthesis of
various 2,3-diarylindoles, relies on the use of N-methyl-2,3-
dibromoindole as the starting material and on a proper optimiza-
tion. Herein, we report full details of this work. In addition, we
report what are, to the best of our knowledge, the first Suzu-
kieMiyaura of 2,3,6-tribromoindole.
2. Results and discussion
The SuzukieMiyaura reaction of 2,3-dibromo-N-methylindole11
(1) with arylboronic acids 2aee (2.3 equiv) afforded 2,3-
diarylindoles 3aee (Scheme 1, Table 1). It was found that the re-
action is sensitive to the presence of water. The use of tetrahydro-
furan in combination with an aqueous solution of K2CO3 resulted in
the formation of a mixture containing products in which the loss of
* Corresponding author. Fax: þ49 381 498 6412; e-mail address: peter.langer@
uni-rostock.de (P. Langer).
y
Equal contribution of these coauthors.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.05.100

M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
7493
Table 3
Ar
ArB(OH)2
2a-e
Br
Optimization of the synthesis of 4e
Entry
Solvent
Base
4ea (%)
Ar
Br
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
THF
Et3N
Mixture
41
33
59
53
79
52
53
N
N
i
K3PO4
K2CO3
K3PO4
K2CO3
K3PO4
K3PO4
K3PO4
Me
Me
1
3a-e
Scheme 1. Synthesis of 3aee. Conditions: (i) 1 (1.0 equiv), Ar1eB(OH)2 (2.3 equiv),
THF
K3PO4 (3.0 equiv), Pd(PPh3)4 (3 mol %), 1,4-dioxane, 110 ꢀC, 6 h.
Dioxane
Acetone
THF/dioxane (1:1)
Table 1
Synthesis of 3aee
a
Yields of isolated products.
2,3
Ar
3a (%)
a
b
c
d
e
4-MeC6H4
4-EtC6H4
90
86
90
83
79
3,5-Me2C6H3
4-ClC6H4
4-tBuC6H4
a
Yields of isolated products.
bromine from C3 was accompanied with the formation of mono-
arylated and diarylated indoles. The best yields were obtained
when 1,4-dioxane was used as the solvent. However, the use of dry
tetrahydrofuran resulted in low yields. The employment of DMF
and toluene as solvents required high reaction times and gave
relatively low yields. Finally, K3PO4 was found to be the best base,
followed by K2CO3, while organic bases such as triethylamine or
hydroxylamine resulted in low yields. The reaction was also opti-
mized with regard to the catalyst. It was found that Pd(PPh3)4
(3 mol %) resulted in good yields, while S-Phos and X-Phos also gave
satisfactory results. Good yields were obtained for both electron-
rich and electron-poor arylboronic acids.
The regioselective SuzukieMiyaura reaction of 1 with arylbor-
onic acids 2fek (1.0 equiv) afforded the 2-aryl-3-bromo-1-methyl-
1H-indoles 4aef in good yields (Scheme 2, Table 2). The reaction
was optimized in case of product 4e (Table 3). The use of wet sol-
vents resulted in replacement of the bromine by a hydrogen atom
at carbon 3 (vide infra). Thus, solvents had to be thoroughly dried. It
was found that dioxane and the base K3PO4 gave excellent yields of
mono-coupling products and no formation of other products was
observed. While in case of other solvents, such as dichloromethane,
mixtures of products were observed. In case of THF and acetone, the
other isomers were also observed by TLC. The use of Pd(OAc)2 in the
presence of X-Phos or S-Phos gave similar yield as compared to the
use of Pd(PPh3)4 (3e4 mol %). Pd(PPh3)4 was used as the catalyst in
all reactions because of its relatively low price. The structure of 4e
was independently confirmed by X-ray crystal structure analysis
(Fig. 1).12
Fig. 1. ORTEP drawing of the molecular structure of 4e in the crystal. Thermal ellip-
soids with 50% probability at 173 K. Hydrogen atoms are omitted for clarity.
Our next goal was to develop a regioselective synthesis of dia-
rylated indoles 5aee by application of a one-pot double Suzu-
kieMiyaura reaction. This reaction was successfully realized when
1 was reacted with arylboronic acid (1.0 equiv) in the presence of
catalyst and base at 70 ꢀC for 6 h and, subsequently, the next bo-
ronic acid (1.3 equiv) was added and stirring was continued at
110 ꢀC for 8 h (Scheme 3, Table 4). Good yields were obtained for
both electron-rich and electron-deficient arylboronic acids.
Scheme 3. Synthesis of 5aee. Conditions: (i) (1) 1 (1.0 equiv), 2b,k (1.1 equiv), K3PO4
(1.5 equiv), Pd(PPh3)4 (4 mol %), 1,4-dioxane, 70 ꢀC, 6 h; (2) 2d,f,g,l,m (1.3 equiv), K3PO4
(1.5 equiv), 110 ꢀC, 8 h.
Table 4
Synthesis of 5aee
5
2
Ar1
Ar2
5a (%)
a
b
c
d
e
b g
k,d
k,f
k,l
k,m
4-EtC6H4
3-PhC6H4
Ph
4-ClC6H4
4-FC6H4
4-(F3C)C6H4
71
69
59
71
63
2,5-(MeO)2C6H3
2,5-(MeO)2C6H3
2,5-(MeO)2C6H3
2,5-(MeO)2C6H3
Scheme 2. Synthesis of 4aef. Conditions: (i) 1 (1.0 equiv), ArB(OH)2 (1.1 equiv), K3PO4
(1.5 equiv), Pd(PPh3)4 (3 mol %), 1,4-dioxane, 70 ꢀC, 6 h.
Table 2
Synthesis of 4aef
a
Yields of isolated products.
4
2
Ar
4a (%)
a
b
c
d
e
f
b
f
g
h
i
2-EtC6H4
C6H5
3-(C6H5)C6H4
3-(CF3)C6H4
3,4-(MeO)2C6H3
2-(MeO)C6H4
73
84
77
81
79
71
We have mentioned above that the use of wet solvents resulted
in the formation of mixtures including products derived from loss
of the bromine atom from position 3 of the indole. We tried to use
this observation with the goal to develop conditions for the selec-
tive synthesis of these products. The reaction of 1 with arylboronic
acids, carried out in a 1:1 mixture of dioxane and water, allowed for
j
a
Yields of isolated products.

7494
M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
Table 6
Synthesis of 8aek
the synthesis of products 6aee in good yields (Scheme 4, Table 5).
The employment of pure water as the solvent resulted in a decrease
of the yield. The structure of 6a was independently confirmed by X-
ray crystal structure analysis (Fig. 2).12
8
2
Ar
8a (%)
a
b
c
d
e
f
g
h
i
a
b
d
e
h
i
4-MeC6H4
4-EtC6H4
4-ClC6H4
87
94
91
85
78
82
84
82
87
80
85
Br
4-tBuC6H4
3-(CF3)C6H4
3,4-(MeO)2C6H3
4-FC6H4
ArB(OH)2
2a-c,e-f
Ar
Br
N
N
l
i
Me
Me
m
n
o
p
4-(CF3)C6H4
4-(MeO)C6H4
3-ClC6H4
6a-e
1
j
k
Scheme 4. Synthesis of 6aee. Conditions: (1) 2 (1.0 equiv), 2aec,eef (1.1 equiv), K3PO4
(1.5 equiv), Pd(PPh3)4 (3 mol %), 1,4-dioxane/water¼1:1, 90 ꢀC, 6 h.
2-(EtO)C6H4
a
Yields of isolated products.
Table 5
Synthesis of 6aee
for 8 h. The use of 1,4-dioxane as solvent gave the best results. In
contrast to the synthesis of products 3, the employment of an
aqueous solution of potassium carbonate gave better yields than
the use of potassium phosphate. The use of Pd(PPh3)4 (4 mol %)
gave higher yields than Pd(PPh3)2Cl2 or Pd(OAc)2 (3 mol %), with X-
Phos or S-Phos (6 mol %) as a catalyst. Good yields were obtained
for both electron-rich and electron-poor arylboronic acids. The
structures of 8b and 8k were independently confirmed by X-ray
crystallography (Figs. 3 and 4) . The crystal structures were found to
show monoclinic P21/n symmetry. The asymmetric unit contains
single molecule.
6
2
Ar
6a (%)
a
b
c
d
e
a
b
c
e
f
4-MeC6H4
4-EtC6H4
3,5-Me2C6H3
4-(tBu)C6H4
C6H5
92
95
83
81
97
a
Yields of isolated products.
2,6-Diaryl-3-bromo-1-methyl-1H-indoles 9aee were prepared
by reaction of 7 with arylboronic acids 2a,b,d,l,n (2.1 equiv). The
reaction proceeded in good yields (73e83%) and with excellent
site-selectivity (Scheme 6, Table 7). The first attack occurred at
carbon atom C-2 and C-6, while position 3 remained unattacked.
The reactions were best carried out at 90 ꢀC using exactly 2.1 equiv
of the arylboronic acid and 5 mol % of Pd(PPh3)4 as the catalyst. Both
electron-donating and withdrawing groups were examined in this
reaction. K3PO4 (3.0 equiv) gave better yields than K2CO3. The
structure of 9b (Fig. 5) was independently confirmed by X-ray
crystal structure analysis . Both aryl groups and the indole moiety
are twisted out of plane.
The SuzukieMiyaura cross-coupling reaction of 7 with aryl-
boronic acids 2c,b,e,f (1.1 equiv) afforded the 2-aryl-3,6-dibromo-
1-methyl-1H-indoles 10aed in 77e84% yields and with very good
site-selectivity (Scheme 7, Table 8). A solvent mixture of toluene/
1,4-dioxane (4:1), K3PO4 (1.5 equiv) as base and Pd(PPh3)4 (3 mol %)
as a catalyst were used. Compounds 10a and 10d were selected for
optimization studies (Table 9). Compound 10a is derived from an
electron-rich arylboronic acid, while 10d is derived from an
electron-poor arylboronic acid. During the optimization, we have
found that the best yields were obtained when the reactions were
carried out at 65 ꢀC. Significant amounts of side-products, derived
from multi-fold coupling, were formed when the temperature was
higher than 65 ꢀC. A solvent mixture of toluene/1,4-dioxane (4:1),
K3PO4 (1.5 equiv) as base and Pd(PPh3)4 (3 mol %) as a catalyst were
used. The structures of all products were confirmed by spectro-
scopic methods.
The structure of 10b was independently confirmed by 2D-NMR
experiments. In the NOESY spectrum, an interaction was observed
between the aromatic proton attached to carbon atom (C-60) to the
N-methyl group (Fig. 6). In addition, a strong correlation was ob-
served between the aromatic proton of C-7 to the N-methyl group.
In the HMBC spectrum, the aromatic proton of C-2 showed a strong
coupling with carbon C-3 of ring A.
Fig. 2. ORTEP drawing of the molecular structure of 6a in the crystal. Thermal ellip-
soids with 50% probability at 173 K. Hydrogen atoms are omitted for clarity.
2,3,6-Tribromo-1-methyl-1H-indole (7) was prepared as re-
ported10 and was further used in the following reactions as starting
material. 2,3,6-Triaryl-1-methyl-1H-indoles 8aek were prepared in
good yields (78e94%) by SuzukieMiyaura cross-coupling reactions
of 7 with 3.4 equiv of arylboronic acids 2a,b,d,e,h,i,lep (Scheme 5,
Table 6). Products 8b and 8g were selected for optimization studies.
Compound 8b is derived from an electron-rich arylboronic acid,
while 8g is derived from an electron-poor arylboronic acid. The best
yields were obtained when the reactions were carried out at 110 ꢀC
2,3,6-Triaryl-1-methyl-1H-indoles 11aed were prepared by
site-selective Suzuki cross-coupling reactions. A one-pot synthesis
was carried out for product 11a. The first cross-coupling reaction
proceeded by reaction of 7 with 1.1 equiv of 2l at 65 ꢀC for 8 h.
Subsequently, 2e was added (2.1 equiv) to give product 11a in good
Scheme 5. Synthesis of 8. Conditions: (1) 7 (1.0 equiv), 2aeb,d,e,hej,lep (3.3 equiv),
K2CO3 (4 equiv), Pd(PPh3)4 (4 mol %), 1,4-dioxane, 2 mL H2O, 110 ꢀC, 8 h.

M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
7495
Fig. 3. ORTEP drawing of the molecular structure of 8b in the crystal. Thermal ellipsoids with 50% probability at 173 K. Hydrogen atoms are omitted for clarity.
number of side-products were formed and not clean products could
be isolated.
3. Conclusions
The order of reactivity of the three different positions of 2,3,6-
tribromo-1-methyl-1H-indole is C-2>C-6>C3 (Scheme 9). The
first attack occurred at carbon atom C-2. The site-selectivity can be
explained by the fact that carbon atom C-2 is considerable more
electron-deficient than positions 3 and 6. The second attack oc-
curred at position 6, which is electronically less deficient than po-
sition 2. Carbon atom C-3 is less electron-deficient than C-6
because of the electron-donating effect of the nitrogen atom.
In conclusion, a variety of arylated indoles were synthesized
with excellent site-selectivity by SuzukieMiyaura reactions of 2,3-
dibromo-1-methyl-1H-indole and 2,3,6-tribromo-1-methyl-1H-
indole. The site-selectivity can be explained by electronic reasons.
In several cases, monoarylated bromoindoles were found to be very
sensitive to moisture and decompose rapidly with loss of bromine.
In contrast, 2,3-diarylindoles proved to be stable for several days
even at the air. Likewise, the triarylated indoles are highly stable
and can be stored for months.
Fig. 4. ORTEP drawing of the molecular structure of 8k in the crystal. Thermal ellip-
soids with 50% probability at 173 K. Hydrogen atoms are omitted for clarity.
4. Experimental section
Scheme 6. Synthesis of 9aee. Reagents and conditions: (i) 7 (1.0 equiv), 2a,b,d,l,n
4.1. General procedure for the synthesis of 3aee, 4aef and
6aee
(2.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (3.0 equiv), 1,4-dioxane, 90 ꢀC, 8 h.
Table 7
Synthesis of 9aee
The reaction was carried out in a pressure tube. A 1,4-dioxane
(for compounds 3 and 4) or 1:1 dioxane/water (for compounds 6)
solution (4 mL) of 1, K3PO4, Pd(PPh3)4 and arylboronic acid 2 was
stirred at 110 ꢀC (for compounds 3), 70 ꢀC (for compounds 4) or
90 ꢀC (for compounds 6) for 6 h (for compounds 3, 4 and 6). After
cooling to 20 ꢀC, a saturated aqueous solution of NH4Cl was added.
The organic and the aqueous layer were separated and the latter
was extracted with CH2Cl2 (3ꢁ30 mL). The combined organic layers
were dried (Na2SO4), filtered and the filtrate was concentrated in
vacuo. The residue was purified by flash chromatography (silica gel,
heptanes).
9
2
Ar
9a (%)
a
b
c
d
e
a
b
d
l
4-MeC6H4
4-EtC6H4
4-ClC6H4
4-FC6H4
4-(MeO)C6H4
73
79
80
83
83
n
a
Yields of isolated products.
yield (74%). A mixture of the solvents toluene and 1,4-dioxane (4:1),
K3PO4 (1.5 equiv) and Pd(PPh3)4 (5 mol %) were used. Derivatives
11bed were synthesized in two steps via products 10, which were
isolated. Products 11aed were isolated in good yields (72e82%)
(Scheme 8, Table 10). To achieve a good site-selectivity in favour of
position 2 of the substrate, it is important that the first step is
carried out at 65 ꢀC to avoid double coupling and the second step at
90 ꢀC. Both electron-donating and withdrawing groups were ex-
amined for the synthesis of compounds 11aed.
4.1.1. 1-Methyl-2,3-di-p-tolyl-1H-indole (3a). Starting with
1
(289 mg, 1.0 mmol), 2a (313 mg, 2.3 mmol), K3PO4 (636 mg,
3.0 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 3a was
isolated as a colourless oil (280 mg, 90%). 1H NMR (250.13 MHz,
CDCl3):
d
¼3.28 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.63 (s, 3H, NCH3),
7.05e7.27 (m, 10H, ArH), 7.45 (dt, J¼8.0, 0.9 Hz, 1H, ArH), 7.67 (dt,
J¼8.0, 0.9 Hz, 1H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
¼21.2,
d
Unfortunately, the stepwise or one-pot synthesis of indoles
containing three different aryl groups proved to be unsuccessful. A
21.3 (CH3), 31.1 (NCH3), 110.7 (CH), 115.3 (C), 119.9, 120.7, 122.7 (CH),
128.1 (C), 129.7 (2CH), 129.9 (2CH), 130.1 (C), 130.5, 131.9 (2CH),

7496
M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
Fig. 5. Molecular structure of compound 9b.
Br
Ar
Br
ArB(OH)2
2a,b,d,e
Br
N
Br
N
Br
Me
10a-d
i
Me
7
Scheme 7. Synthesis of 10aed. Reagents and conditions: (i) 7 (1.0 equiv), 2a,b,d,e
(1.1 equiv), Pd(PPh3)4 (3 mol %), K3PO4 (1.5 equiv), toluene/1,4-dioxane (4:1), 65 ꢀC, 8 h.
Fig. 6. 2D-NMR correlations of compound 10b.
Table 8
Synthesis of 10aed
Ar2
Br
1) Ar1B(OH)2
10
2
Ar
10a (%)
Ar1
Br
2) Ar2B(OH)2
a
b
c
a
b
d
e
4-MeC6H4
4-EtC6H4
4-ClC6H4
4-tBuC6H4
77
83
79
84
Ar2
N
N
Br
Me
11a-d
i
Me
7
d
Scheme 8. Synthesis of 25aed. Reagents and conditions: (i) 1) Ar1B(OH)2 2d,e,l
(1.1 equiv), Pd(PPh3)4 (5 mol %), K3PO4 (1.5 equiv), toluene/1,4-dioxane (4:1), 65 ꢀC, 8 h,
(2) Ar2B(OH)2 2d,e,k,m,o (2.1 equiv), K2CO3 (aq) (2 M, 1 mL), 1,4-dioxane, 90 ꢀC, 8 h.
a
Yields of isolated products.
133.4, 135.6, 138.3, 138.4, 138.7 (C). IR (ATR, cmꢂ1):
~
n
¼3044 (w),
Table 10
Synthesis of 11aed
3015 (m), 2942 (m), 2914 (m), 2860 (w), 1904 (w), 1613 (w), 1564
(w), 1553 (m), 1519 (m), 1494 (w), 1480 (m), 1464 (m), 1446 (m),
1428 (m), 1414 (w), 1366 (m), 1326 (m), 1258 (m), 1232 (m), 1182
(m), 1150 (m), 1089 (m), 1018 (m), 940 (m), 858 (m), 825 (s), 816 (s),
802 (s), 773 (m), 747 (s), 738 (s), 719 (s), 694 (m), 652 (m), 627 (s),
561 (m), 540 (m). GCeMS (EI, 70 eV): m/z (%)¼312 ([Mþ1]þ, 26),
311 ([M]þ, 100), 295 (8), 281 (8), 140 (8), 139 (6). HRMS (EI) calcd for
11
2
Ar1
Ar2
11a (%)
a
b
c
l,e
4-FC6H4
4-tBuC6H4
4-(MeO)C6H4
4-(MeO)C6H4
2-(MeO)C6H4
74c
81b
82d
72b
e,n
d,n
e,j
4-tBuC6H4
4-ClC6H4
4-tBuC6H4
d
a
C
23H21N [M]þ is 311.16685, found 311.166454.
Yields of isolated products.
b
c
Yield based on 11c (stepwise synthesis).
Yield based on 7 (one-pot synthesis).
Yield based on 11d (stepwise synthesis).
4.1.2. 2,3-Bis(4-ethylphenyl)-1-methyl-1H-indole
(3b). Starting
d
with 1 (289 mg, 1.0 mmol), 2b (262 mg, 2.3 mmol), K3PO4 (636 mg,
3.0 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 3b was
isolated as a yellowish oil (291 mg, 86%). 1H NMR (300.13 MHz,
(C), 120.0, 121.0, 123.0 (CH), 128.1 (C), 128.5, 128.7 (2CH), 130.3 (C),
130.6, 132.0 (2CH), 133.7, 138.3, 138.4, 142.0, 144.9 (C). IR (ATR,
cmꢂ1): ¼3047 (w), 3022 (w), 2961 (s), 2928 (w), 1797 (w), 1765
(w), 1726 (w), 1519 (m), 1463 (s), 1362 (m), 1325 (m), 1257 (m), 1131
(w), 1115 (w), 1089 (m), 1060 (w), 1017 (m), 967 (w), 923 (w), 869
(m), 836 (s), 801 (w), 740 (s), 652 (w), 629 (m), 545 (m). MS (EI,
70 eV): m/z (%)¼340 ([Mþ1]þ, 28), 339 ([M]þ, 100), 324 (34), 309
~
n
CDCl3):
d
¼1.01 (t, J¼7.5 Hz, 3H, CH3), 1.05 (t, J¼7.5 Hz, 3H, CH3), 2.40
(q, J¼7.5 Hz, 2H, CH2), 2.48 (q, J¼7.5 Hz, 2H, CH2), 3.42 (s, 3H, NCH3),
6.90e6.96 (m, 3H, ArH), 7.02e7.10 (m, 7H, ArH), 7.25 (d, J¼8.2 Hz,
1H, ArH), 7.51 (d, J¼7.8 Hz, 1H, ArH). 13C NMR (75.47 MHz, CDCl3):
d¼15.8, 16.0 (CH3), 29.1, 29.2 (CH2), 31.2 (NCH3), 110.7 (CH), 115.4
Table 9
Optimization of the synthesis of 10a and 10d
Entry
Solvent
Base
Ligand
T (ꢀC)
% (10a)a
% (10d)a
1
2
3
4
5
6
7
8
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
Toluene
2 M K2CO3
2 M K2CO3
2 M K2CO3
2 M K2CO3
1.5 equiv K3PO4
1.5 equiv K3PO4
2 M K2CO3
2 M K2CO3
2 M K2CO3
(PPh3)4Pd
70
70
70
70
65
65
65
70
65
65
65
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
No reaction
No reaction
Mixture
30
Mixture
Mixture
Mixture
Mixture
Mixture
Mixture
No reaction
No reaction
Mixture
25
Cy3P, Pd(OAc)2
S-Phos, Pd(OAc)2
(PPh3)2PdCl2
(PPh3)4Pd
Cy3P, Pd(OAc)2
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
(PPh3)4Pd
9
10
11
Dioxane/toluene (1:1)
Dioxane/toluene (4:1)
Dioxane/toluene (1:4)
1.5 equiv K3PO4
1.5 equiv K3PO4
84
79
a
Yields of isolated products.

M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
7497
(2CH), 126.8, 128.1 (C), 130.2, 131.7 (2CH), 133.9 (C), 138.3 (2C),
3
149.9, 150.8 (C). IR (ATR, cmꢂ1):
n
¼3052 (w), 2954 (m), 2928 (m),
~
Br
2903 (m), 2865 (m), 1716 (m), 1661 (m), 1651 (m), 1606 (m), 1520
(m), 1464 (s), 1392 (m), 1362 (s), 1326 (m), 1266 (m), 1233 (s), 1201
(m), 1150 (m), 1109 (m), 1086 (m), 1016 (m), 941 (m), 932 (m), 880
(w), 861 (m), 838 (m), 823 (m), 795 (w), 763 (w), 737 (s), 711 (m),
699 (m), 651 (m), 633 (m), 619 (m), 601 (m), 552 (m). MS (EI, 70 eV):
m/z (%)¼396 ([Mþ1]þ, 32), 395 ([M]þ, 100), 380 (59), 350 (6), 183
(9), 154 (15). HRMS (EI) calcd for C29H33N [M]þ is 395.26075, found
395.260299.
Br
N
Me
Br
2
1
Scheme 9. Order of reactivity.
(5), 294 (5), 281 (5), 278 (4), 146 (5). HRMS (EI) calcd for C25H25
[M]þ is 339.19815, found 339.197901.
N
4.1.6. 3-Bromo-1-methyl-2-phenyl-1H-indole (4a). Starting with 1
(289 mg, 1.0 mmol), 2f (134 mg, 1.1 mmol), K3PO4 (318 mg,
1.5 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 4a was
isolated as a brownish oil (240 mg, 84%). 1H NMR (300.13 MHz,
4.1.3. 2,3-Bis(3,5-dimethylphenyl)-1-methyl-1H-indole (3c). Starting
with 1 (289 mg, 1.0 mmol), 2c (345 mg, 2.3 mmol), K3PO4 (636 mg,
3.0 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 3c was
isolated as colourless crystals (305 mg, 90%), mp 108e109 ꢀC. 1H
CDCl3):
1H, ArH), 7.48 (dt, J¼8.1, 0.8 Hz, 1H, ArH), 7.48e7.57 (m, 6H, ArH).
13C NMR (62.89 MHz, CDCl3):
d
¼3.68 (s, 3H, NCH3), 7.18e7.23 (m, 1H, ArH), 7.26e7.32 (m,
d
¼32.0 (NCH3), 90.0 (C), 111.2, 119.6,
NMR (300.13 MHz, CDCl3):
d
¼2.22 (s, 6H, 2CH3), 2.30 (s, 6H, 2CH3),
121.4, 123.7 (CH), 128.0 (C), 129.4 (2CH), 129.7 (CH), 131.3 (C), 131.6
(2CH), 137.9, 139.0 (C). IR (ATR, cmꢂ1):
n
¼3055 (m), 3028 (m), 2937
~
3.64 (s, 3H, NCH3), 6.82 (d, J¼0.8 Hz, 1H, ArH), 6.97 (s, 2H, ArH), 7.03
(s, 2H, ArH), 7.06 (s, 1H, ArH), 7.11e7.16 (m, 1H, ArH), 7.25 (ddd,
J¼8.2, 7.0, 1.2 Hz, 1H, ArH), 7.46 (dt, J¼8.3, 0.9 Hz, 1H, ArH), 7.73 (dt,
(m), 2880 (w), 2836 (m), 1887 (w), 1714 (w), 1651 (w), 1604 (m),
1574 (m),1479 (m),1462 (s), 1441 (m),1428 (m),1380 (m),1356 (m),
1339 (m), 1320 (m), 1234 (m), 1214 (m), 1176 (m), 1154 (m), 1127
(m), 1103 (m), 1074 (m), 1022 (m), 1010 (m), 968 (w), 944 (m), 921
(m), 828 (m), 792 (m), 735 (s), 697 (s), 677 (m), 614 (m), 583 (m),
547 (m). MS (EI, 70 eV): m/z (%)¼288 ([Mþ1]þ, 81Br, 18), 287 ([M]þ,
81Br, 100), 286 ([Mþ1]þ, 79Br, 20), 285 ([M]þ, 79Br, 98), 206 (7), 205
(21), 204 (35), 191 (13), 190 (12), 178 (8), 176 (7), 164 (6), 163 (6), 102
(14). HRMS (EI) calcd for C15H12BrN [M]þ is 285.01476, found
285.014285.
J¼7.8, 0.9 Hz, 1H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
¼21.3,
d
21.4 (2ArCH3), 31.1 (NCH3), 110.6 (CH), 115.5 (C), 120.1, 120.7, 122.6,
127.9 (CH), 128.1 (C), 128.4, 129.7 (2CH), 130.4 (CH), 132.9, 136.2 (C),
137.9 (2C), 138.3 (C), 138.5 (2C), 138.7 (C). IR (ATR, cmꢂ1):
~
n
¼3026
(w), 2912 (m), 2857 (m), 2728 (w), 2687 (w), 1783 (m), 1598 (m),
1573 (m), 1549 (m), 1538 (m), 1519 (w), 1480 (m), 1467 (m), 1435
(m), 1392 (m), 1379 (m), 1366 (m), 1323 (m), 1288 (m), 1237 (m),
1196 (m), 1153 (m), 1132 (m), 1101 (m), 1036 (m), 1015 (m), 997 (m),
966 (m), 948 (m), 914 (m), 903 (m), 889 (m), 862 (m), 845 (m), 836
(m), 781 (m), 738 (s), 702 (s), 693 (s), 666 (m), 648 (m), 603 (m), 588
(m), 567 (m), 541 (m). MS (EI, 70 eV): m/z (%)¼340 ([Mþ1]þ, 30),
339 ([M]þ, 100), 308 (5). HRMS (EI) calcd for C25H25N [M]þ is
339.19815, found 339.198033.
4.1.7. 2-(Biphenyl-3-yl)-3-bromo-1-methyl-1H-indole (4b). Starting
with 1 (289 mg, 1.0 mmol), 2g (218 mg, 1.1 mmol), K3PO4 (318 mg,
1.5 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 4b was
isolated as a yellowish oil (279 mg, 77%). 1H NMR (250.13 MHz,
CDCl3):
d
¼3.70 (s, 3H, NCH3), 7.24 (td, J¼6.9, 1.1 Hz, 1H, ArH), 7.32
4.1.4. 2,3-Bis(4-chlorophenyl)-1-methyl-1H-indole
(3d). Starting
(td, J¼6.9,1.1 Hz,1H, ArH) 7.38e7.42 (m, 1H, ArH), 7.46e7.67 (m, 6H,
with 1 (289 mg, 1.0 mmol), 2d (360 mg, 2.3 mmol), K3PO4 (636 mg,
3.0 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 3d was
isolated as a yellowish oil (292 mg, 83%). 1H NMR (300.13 MHz,
ArH), 7.72e7.80 (m, 3H, ArH), 7.87 (t, J¼1.5 Hz, 1H, ArH). 13C NMR
(62.89 MHz, (CD3)2CO):
d
¼32.1 (NCH3), 90.3 (C), 111.2, 119.7, 121.4,
123.8 (CH), 127.9 (2CH), 128.0 (C), 128.1, 128.6 (CH), 129.9 (2CH),
CDCl3):
d
¼3.68 (s, 3H, NCH3), 7.12e7.18 (m, 1H, ArH), 7.23e7.32 (m,
130.0, 130.1, 130.4 (CH), 131.9, 137.9, 138.8, 141.2, 142.1 (C). IR (ATR,
5H, ArH), 7.35e7.40 (m, 2H, ArH), 7.44e7.51 (m, 2H, ArH), 7.51 (d,
J¼8.0 Hz, 1H, ArH), 7.67 (d, J¼7.8 Hz, 1H, ArH). 13C NMR (75.47 MHz,
cmꢂ1):
n
¼3055 (m), 3028 (m), 2922 (m), 2851 (m), 1949 (w), 1884
~
(w), 1712 (w), 1599 (m), 1574 (m), 1537 (m), 1500 (w), 1462 (s), 1450
(m), 1430 (m), 1412 (m), 1355 (m), 1338 (m), 1321 (m), 1234 (m),
1204 (m), 1154 (m), 1103 (m), 1019 (w), 1011 (m), 945 (m), 899 (m),
854 (m), 806 (m), 737 (s), 699 (s), 671 (m), 638 (m), 613 (m), 586
(m), 548 (m). MS (EI, 70 eV): m/z (%)¼364 ([Mþ1]þ, 81Br, 22), 363
([M]þ, 81Br, 100), 362 ([Mþ1]þ, 79Br, 24), 361 ([M]þ, 79Br, 100), 281
(10), 280 (20), 267 (7), 266 (6), 204 (8), 181 (5), 180 (5), 133 (7), 120
(5). HRMS (EI) calcd for C16H14BrNO [M]þ is 361.04606, found
361.045430.
CDCl3):
d
¼31.2 (CH3), 110.9 (CH), 114.7 (C), 119.8, 121.3, 123.3 (CH),
127.5 (C), 129.3, 129.6 (2CH), 131.3, 131.8 (C), 132.1, 133.7 (2CH),
134.8, 134.9, 137.4, 138.5 (C). IR (ATR, cmꢂ1):
n
¼3078 (w), 3051 (w),
~
2919 (m), 2850 (m), 1916 (w), 1894 (w), 1567 (w), 1538 (m), 1496
(m), 1478 (m), 1464 (m), 1456 (m), 1430 (m), 1410 (m), 1389 (m),
1364 (m), 1326 (m), 12 97 (w), 1257 (m), 1233 (m), 1177 (w), 1152
(m), 1135 (w), 1121 (w), 1106 (w), 1088 (s), 1044 (m), 1011 (s), 967
(m), 938 (m), 930 (m), 856 (m), 846 (m), 836 (m), 830 (m), 820 (s),
794 (m), 761 (w), 743 (s), 727 (s), 719 (s), 705 (m), 688 (m), 666 (m),
644 (m), 622 (m), 607 (m), 578 (m), 557 (m), 540 (m). MS (EI,
70 eV): m/z (%)¼354 ([Mþ1]þ, 37Cl, 15), 353 ([M]þ, 37Cl, 67), 352
([Mþ1]þ, 35Cl, 24), 351 ([M]þ, 35Cl,100), 315 (9), 314 (5), 301 (6), 266
(7), 265 (6), 140 (17), 139 (13). HRMS (EI): calcd for C21H15Cl2N [M]þ
is 351.05761, found 351.057126.
4.1.8. 3-Bromo-2-(3-(trifluoromethyl)phenyl)-1-methyl-1H-indole
(4c). Starting with 1 (289 mg, 1.0 mmol), 2h (209 mg, 1.1 mmol),
K3PO4 (318 mg, 1.5 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane
(4 mL), 4c was isolated as a yellowish oil (287 mg, 81%). 1H NMR
(300 MHz, (CD3)2CO):
d
¼3.73 (s, 3H, NCH3), 7.21e7.26 (m, 1H, ArH),
7.30e7.36 (m, 1H, ArH), 7.51 (dt, J¼8.3, 0.8 Hz, 1H, ArH), 7.56 (dq,
4.1.5. 2,3-Bis(4-tert-butylphenyl)-1-methyl-1H-indole (3e). Starting
with 1 (289 mg, 1.0 mmol), 2e (409 mg, 2.3 mmol), K3PO4 (636 mg,
3.0 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 3e was
isolated as a greenish oil (313 mg, 79%). 1H NMR (250.13 MHz,
J¼7.9, 0.6 Hz, 1H, ArH), 7.79e7.89 (m, 3H, ArH), 7.94e7.95 (m, 1H,
ArH). 13C NMR (62.89 MHz, (CD3)2CO):
d¼32.1 (NCH3), 111.3, 119.8,
121.6 (CH), 123.4 (C), 124.2 (CH), 125.2 (q, JF,C¼271 Hz, ArCF3), 126.3
(q, JF,C¼3.9 Hz, CH, ArH), 127.8 (C), 128.2 (q, JF,C¼3.9 Hz, CH, ArCH),
130.5 (CH), 131.2 (q, JF,C¼32 Hz, ArC), 132.4 (C), 135.4 (d, J¼1.1 Hz,
CH, ArH), 137.2, 138.0 (C). 19F NMR (282.40 MHz, (CD3)2CO):
~
CDCl3):
NCH3), 6.39e7.54 (m, 12H, ArH). 13C NMR (62.89 MHz, CDCl3):
¼31.1 (NCH3), 31.6 (s, 3C, C(CH3)3), 31.7 (s, 3C, C(CH3)3), 34.9, 35.2
(C(CH3)3), 110.6 (CH), 116.9 (C), 120.0, 120.7, 122.7 (CH), 125.8, 126.1
d
¼1.18 (s, 9H, [C(CH3)3]), 1.23 (s, 9H, [C(CH3)3]), 3.52 (s, 3H,
d
d
¼ꢂ114.49 (3F, CF3). IR (ATR, cmꢂ1):
¼3056 (m), 2940 (m), 1613
n
(m), 1592 (m), 1574 (m), 1462 (m), 1423 (m), 1380 (m), 1356 (m),

7498
M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
1340 (m), 1321 (s), 1310 (s), 1278 (m), 1235 (m), 1211 (m), 1165 (s),
1120 (s), 1105 (s), 1095 (s), 1073 (s), 1052 (m), 1010 (m), 946 (m), 926
(w), 907 (m), 858 (m), 808 (m), 781 (w), 770 (w), 737 (s), 701 (s),
694 (s), 651 (m), 643 (m), 608 (w), 586 (m), 547 (m). MS (EI, 70 eV):
m/z (%)¼356 ([Mþ1]þ, 81Br, 18), 355 ([M]þ, 81Br, 98), 354 ([Mþ1]þ,
79Br, 20), 353 ([M]þ, 79Br, 100), 274 (6), 273 (14), 272 (15), 205 (10),
204 (23), 190 (5). HRMS (EI) calcd for C16H11BrF3N [M]þ is
353.00215, found 353.001842.
HRMS (EI) calcd for
315.024969.
C
16H14BrNO [M]þ is 315.02533, found
4.2. General procedure for the synthesis of 5aee
The reaction was carried out in pressure tube. To a dioxane
suspension (4 mL) of 1 (215 mg, 0.75 mmol), Pd(PPh3)4 (4 mol %)
and Ar1B(OH)2 (0.82 mmol) was added K3PO4 (234 mg, 1.1 mmol)
and the solution was degassed by bubbling argon through the so-
lution for 10 min. The mixture was heated at 70 ꢀC under argon
atmosphere for 6 h. The mixture was cooled to 20 ꢀC. To the solu-
tion was added Ar2B(OH)2 (0.90 mmol) and K3PO4 (254 mg,
1.2 mmol) and the solution was degassed again. The reaction
mixture was heated under argon atmosphere for 8 h at 110 ꢀC. After
cooling to 20 ꢀC, the solution was diluted with water and extracted
with CH2Cl2 (3ꢁ25 mL). The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (silica gel, heptanes).
4.1.9. 3-Bromo-2-(2-ethylphenyl)-1-methyl-1H-indole (4d). Starting
with 1 (289 mg, 1.0 mmol), 2b (165 mg, 1.1 mmol), K3PO4 (318 mg,
1.5 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane (4 mL), 4d was
isolated as a brownish oil (229 mg, 73%). 1H NMR (300.13 MHz,
CDCl3):
d
¼1.21 (t, J¼7.7 Hz, 3H, CH3), 2.63 (q, J¼7.6 Hz, 2H, OCH2),
3.64 (s, 3H, NCH3), 7.02e7.07 (m, 1H, ArH), 7.12e7.18 (m, 1H, ArH),
7.19e7.28 (m, 3H, ArH), 7.32e7.36 (m, 2H, ArH), 7.54 (dt, J¼7.9,
0.9 Hz, 1H, ArH). 13C NMR (62.89 MHz, CDCl3):
d
¼15.5 (CH3), 28.7
(CH2), 31.1 (NCH3), 101.2 (C), 109.6, 119.8, 120.4, 121.5 (CH), 128.0
(2CH), 128.0 (C), 129.4 (2CH), 130.2, 138.3, 141.7, 144.0 (C). IR (ATR,
cmꢂ1):
n
¼3049 (m), 3023 (m), 2963 (m), 2929 (m), 2873 (m), 1916
4.2.1. 3-(Biphenyl-3-yl)-2-(4-ethylphenyl)-1-methyl-1H-indole
(5a). Starting with 1 (215 mg, 0.75 mmol), 2b (123 mg, 0.82 mmol),
2g (178 mg, 0.9 mmol), K3PO4 (488 mg, 2.3 mmol), Pd(PPh3)4
(4 mol %) and 1,4-dioxane (4 mL), 5a was isolated as a brownish
~
(w), 1609 (m), 1543 (m), 1495 (m), 1462 (s), 1429 (s), 1412 (m), 1374
(m), 1357 (s), 1337 (s), 1313 (s), 1238 (m), 1213 (m), 1163 (m), 1129
(m), 1116 (m), 1099 (m), 1063 (w), 1050 (w), 1004 (m), 966 (w), 945
(w), 924 (w), 895 (w), 837 (s), 792 (s), 783 (s), 749 (s), 733 (s), 700
(m), 666 (m), 623 (w), 586 (m), 568 (m), 546 (m). MS (EI, 70 eV): m/
z (%)¼315 (95), 313 (100), 300 (40), 299 (42), 235 (5), 204 (10).
oil (206 mg, 71%). 1H NMR (300 MHz, (CD3)2CO):
d¼1.29 (t, J¼7.6 Hz,
3H, CH3), 2.73 (q, J¼7.6 Hz, 2H, CH2), 3.70 (s, 3H, NCH3), 7.14e7.20
(m, 1H, ArH), 7.24e7.43 (m, 14H, ArH), 7.51 (dt, J¼8.1, 1 Hz, 1H, ArH),
7.81 (dt, J¼7.9, 0.9 Hz, 1H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
4.1.10. 3-Bromo-2-(3,4-dimethoxyphenyl)-1-methyl-1H-indole
(4e). Starting with 1 (289 mg, 1.0 mmol), 2i (200 mg, 1.1 mmol),
K3PO4 (318 mg, 1.5 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane
(4 mL), 4e was isolated as a yellowish solid (272 mg, 79%), mp
d
¼16.1 (CH3), 29.3 (CH2), 31.1 (NCH3), 110.8 (CH), 115.2 (C), 119.9,
121.0, 122.8, 124.8 (CH), 127.7 (2CH), 127.7 (C), 128.0 (CH), 128.9
(2CH), 129.2, 129.3 (CH), 129.6 (2CH), 129.7 (CH), 130.4 (C), 132.1
(2CH), 136.9, 138.4, 139.0, 141.6, 142.1, 145.4 (C). IR (ATR, cmꢂ1):
~
146e148 ꢀC. 1H NMR (300.13 MHz, CDCl3):
d
¼3.59 (s, 3H, NCH3),
n
¼3400 (br), 3051 (m), 3025 (m), 2962 (m), 2928 (m), 2871 (m),
3.84 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.93e6.95 (m, 2H, ArH),
1710 (m), 1650 (w), 1643 (w), 1609 (m), 1599 (m), 1582 (m), 1518
(w), 1493 (m), 1463 (s), 1428 (m), 1410 (m), 1363 (s), 1325 (m), 1261
(m), 1247 (m), 1218 (m), 1182 (m), 1152 (w), 1131 (m), 1115 (m), 1088
(m),1049 (w),1016 (m), 974 (w), 918 (w), 897 (m), 879 (m), 856 (m),
834 (s), 812 (s), 799 (m), 784 (m), 742 (s), 699 (s), 648 (m), 630 (m),
615 (m), 578 (m), 567 (m), 548 (m). MS (EI, 70 eV): m/z (%)¼388
([Mþ1]þ, 32), 387 ([M]þ, 100), 372 (5), 357 (5), 343 (6). HRMS (EI)
calcd for C29H25N [M]þ is 387.19815, found 387.198028.
7.11e7.27 (m, 4H, ArH), 7.50e7.53 (m, 1H, ArH). 13C NMR
(62.89 MHz, CDCl3):
d
¼30.6 (CH3), 54.9, 55.0 (OCH3), 88.9 (C), 108.6,
109.9, 112.8, 118.2, 119.5, 121.7 (CH), 121.8 (C), 122.4 (CH), 126.1,
135.7, 137.0, 147.8, 148.4 (C). IR (ATR, cmꢂ1):
n
¼3052 (w), 2960 (w),
~
2924 (W), 1607 (w), 1584 (w), 1502 (m), 1462 (m), 1445 (m), 1404
(w), 1379 (w), 1339 (w), 1317 (w), 1257 (s), 1239 (s), 1168 (m), 1136
(s), 1022 (s), 945 (m), 911 (w), 858 (m), 812 (m), 777 (w), 750 (s),
654 (m), 575 (w), 547 (w). MS (EI, 70 eV): m/z (%)¼348 ([Mþ1]þ,
81Br, 18), 347 ([M]þ, 81Br, 100), 346 ([Mþ1]þ, 79Br, 19), 345 ([M]þ,
79Br, 98), 302 (5), 302 (5), 300 (4), 251 (5), 223 (24),180 (10),152 (7),
102 (5). HRMS (EI) calcd for C17H16Br79NO2 [M]þ is 345.03589,
found 345.035679.
4.2.2. 2-(2,5-Dimethoxyphenyl)-1-methyl-3-phenyl-1H-indole
(5b). Starting with 1 (215 mg, 0.75 mmol), 2k (150 mg, 0.82 mmol),
2d (110 mg, 0.9 mmol), K3PO4 (488 mg, 2.3 mmol), Pd(PPh3)4
(4 mol %) and 1,4-dioxane (4 mL), 5b was isolated as a colourless oil
(177 mg, 69%). 1H NMR (250.13 MHz, CDCl3):
d
¼3.40 (s, 3H, NCH3),
4.1.11. 3-Bromo-2-(2-methoxyphenyl)-1-methyl-1H-indole
(4f). Starting with 1 (289 mg, 1.0 mmol), 2j (167 mg, 1.1 mmol),
K3PO4 (318 mg, 1.5 mmol), Pd(PPh3)4 (3 mol %) and 1,4-dioxane
(4 mL), 4f was isolated as a yellowish oil (224 mg, 71%). 1H NMR
3.44 (s, 3H, OCH3), 3.52 (s, 3H, OCH3), 6.54 (d, J¼3.1 Hz, 1H, ArH),
6.77e6.82 (m, 1H, ArH), 6.87e6.98 (m, 3H, ArH), 7.04e7.18 (m, 5H,
ArH), 7.28 (d, J¼8.3 Hz, 1H, ArH), 7.56 (d, J¼7.8 Hz, 1H, ArH). 13C
NMR (62.9 MHz, CDCl3):
113.3 (CH), 115.7 (C), 115.8, 119.5, 119.8, 120.6 (CH), 122.5 (C), 122.6,
d
¼30.7 (NCH3), 55.9, 56.3 (OCH3), 110.5,
(300.13 MHz, CDCl3):
d¼3.39 (s, 3H, CH3), 3.62 (s, 3H, NCH3), 6.95
(td, J¼7.5, 0.9 Hz, 1H, ArH), 6.98e7.04 (m, 2H, ArH), 7.07e7.12 (m,
1H, ArH), 7.21 (dd, J¼7.6, 1.7 Hz, 1H, ArH), 7.27 (dt, J¼8.1, 0.8 Hz, 1H,
ArH), 7.31e7.37 (m, 2H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
126.2 (CH), 127.7 (C), 129.0, 130.1 (2CH), 135.7, 136.7, 138.1, 153.7,
154.4 (C). IR (ATR, cmꢂ1):
n
¼3051 (w), 2936 (w), 2832 (w), 1736 (w),
~
1712 (w), 1602 (w), 1549 (w), 1502 (m), 1485 (m), 1463 (m), 1366
(m), 1273 (m), 1225 (m), 1210 (m), 1039 (m), 1020 (m), 941 (w), 918
(w), 876 (w), 805 (w), 772 (m), 735 (s), 700 (s), 616 (w), 570 (w), 531
(w). MS (EI, 70 eV): m/z (%)¼345 ([Mþ2]þ, 3), 344 ([Mþ1]þ, 24), 343
([M]þ, 100), 342 (15), 297 (6), 230 (5), 220 (5), 156 (7). HRMS (EI)
calcd for C23H21NO2 [M]þ is 343.15668, found 343.156270.
d
¼31.6 (NCH3), 55.9 (OCH3), 90.3 (C), 110.8, 112.3, 119.4 (CH), 120.1
(C), 120.9, 121.4, 123.3 (CH), 127.9 (C), 132.0, 133.8 (CH), 136.7, 137.5,
158.9 (C). IR (ATR, cmꢂ1):
n
¼3052 (w), 3002 (w), 2929 (m), 2835
~
(m), 2716 (w), 2555 (w),1604 (m),1579 (m),1545 (m),1461 (s),1434
(s),1379 (m),1362 (m),1338 (m),1321 (m),1294 (m),1278 (m),1246
(s), 1232 (s), 1209 (m), 1179 (m), 1154 (m), 1118 (m), 1103 (m), 1054
(m), 1021 (m), 1011 (m), 945 (m), 837 (w), 779 (w), 734 (s), 668 (m),
618 (m), 592 (m), 565 (m). MS (EI, 70 eV): m/z (%)¼318 ([Mþ1]þ,
81Br,18), 317 ([M]þ, 81Br, 98), 316 ([Mþ1]þ, 79Br, 20), 315 ([M]þ, 79Br,
98), 237 (11), 236 (56), 235 (9), 234 (15), 222 (12), 221 (47), 220
(58), 219 (12), 218 (11), 208 (12), 206 (12), 205 (15), 204 (22), 193
(16), 192 (14), 191 (12), 178 (9), 177 (9), 165 (22), 118 (13), 102 (13).
4.2.3. 3-(4-Chlorophenyl)-2-(2,5-dimethoxyphenyl)-1-methyl-1H-
indole (5c). Starting with 1 (215 mg, 0.75 mmol), 2k (150 mg,
0.82 mmol), 2f (141 mg, 0.9 mmol), K3PO4 (488 mg, 2.3 mmol),
Pd(PPh3)4 (4 mol %) and 1,4-dioxane (4 mL), 5c was isolated as
a colourless oil (167 mg, 59%). 1H NMR (300.13 MHz, CDCl3):
(s, 3H, OCH3), 3.65 (s, 3H, NCH3), 3.71 (s, 3H, OCH3), 6.71 (d, J¼3 Hz,
d
¼3.58

M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
7499
1H, ArH), 7.01 (dd, J¼9.0, 3.0 Hz, 1H, ArH), 7.08e7.16 (m, 2H, ArH),
7.22e7.26 (m, 1H, ArH), 7.28e7.32 (m, 4H, ArH), 7.47 (dt, J¼8.0,
1.0 Hz, 1H, ArH), 7.70 (dt, J¼8.0, 1.0 Hz, 1H, ArH). 13C NMR
isolated as colourless crystals (201 mg, 97%), mp 93e95 ꢀC. 1H NMR
(300 MHz, (CD3)2CO):
¼3.77 (s, 3H, NCH3), 6.55 (d, J¼0.8 Hz, 1H,
ArH), 7.05e7.11 (m, 1H, ArH), 7.17e7.23 (m, 1H, ArH), 7.37e7.61 (m,
7H, ArH). 13C NMR ((CD3)2CO, 62.89 MHz):
d
(62.89 MHz, (CD3)2CO):
d
¼30.1 (NCH3), 55.9, 56.3 (OCH3), 110.6,
d¼31.5 (NCH3), 102.2,
113.3 (CH), 114.3 (C), 116.0, 119.4, 119.6, 120.8 (CH), 122.2 (C), 122.7
110.7, 120.5, 121.1, 122.3 (CH), 129.0 (C), 129.5, 130.1 (2CH), 133.8,
139.5, 142.3 (C). IR (ATR, cmꢂ1):
~
n
¼3053 (m), 3026 (m), 2919 (m),
(CH), 127.5 (C), 129.1 (2CH), 131.4 (C), 131.5 (2CH), 135.6,136.0, 138.1,
153.6, 154.4, (C). IR (ATR, cmꢂ1):
2850 (m), 1601 (m), 1539 (w), 1464 (s), 1433 (m), 1382 (m), 1366
(m), 1340 (m), 1319 (m), 1307 (m), 1241 (m), 1233 (m), 1207 (m),
1178 (m), 1168 (m), 1147 (m), 1129 (m), 1119 (m), 1100 (m), 1074 (m),
1035 (w),1007 (m), 996 (w), 988 (w), 975 (w), 924 (m), 893 (w), 842
(m), 796 (m), 765 (s), 747 (s), 731 (s), 700 (s), 672 (m), 659 (m), 616
(m), 582 (m), 576 (m), 532 (s). MS (EI, 70 eV): m/z (%)¼208 ([Mþ1]þ,
16), 207 ([M]þ,100), 206 (44), 204 (10),165 (10). HRMS (EI) calcd for
~
n
¼3047 (w), 2921 (m), 2851 (m),
1732 (w), 1667 (w), 1609 (w), 1544 (w), 1499 (m), 1483 (m), 1463
(m), 1431 (m), 1417 (m), 1366 (m), 1326 (m), 1302 (m), 1274 (m),
1263 (m), 1225 (s), 1209 (s), 1178 (m), 1150 (m), 1133 (m), 1091 (s),
1038 (s), 1013 (s), 934 (m), 912 (m), 879 (m), 866 (m), 835 (m), 810
(s), 761 (m), 732 (s), 719 (m), 712 (m), 699 (m), 675 (m), 649 (m),
630 (m), 603 (m), 585 (m), 571 (m), 551 (m). MS (EI, 70 eV): m/z
(%)¼380 ([Mþ1]þ, 37Cl, 8), 379 ([M]þ, 37Cl, 35), 378 ([Mþ1]þ, 35Cl,
30), 377 ([M]þ, 35Cl, 100), 376 (14), 327 (6), 241 (6), 133 (9), 127 (6).
C
15H13N [M]þ is 207.10425, found 207.103624.
HRMS (EI) calcd for
377.117256.
C
23H20ClNO2 [M]þ is 377.11771, found
4.2.7. 1-Methyl-2-p-tolyl-1H-indole (6b). Starting with 1 (289 mg,
1.0 mmol), 2b (149 mg, 1.1 mmol), K3PO4 (318 mg, 1.5 mmol),
Pd(PPh3)4 (3 mol %), 1,4-dioxane (2 mL) and H2O (2 mL) 6b was
isolated as colourless crystals (203 mg, 92%), mp 88e89 ꢀC. 1H NMR
4.2.4. 3-(4-Fluorophenyl)-2-(2,5-dimethoxyphenyl)-1-methyl-1H-
indole (5d). Starting with 1 (215 mg, 0.75 mmol), 2k (150 mg,
0.82 mmol), 2l (126 mg, 0.9 mmol), K3PO4 (488 mg, 2.3 mmol),
Pd(PPh3)4 (4 mol %) and 1,4-dioxane (4 mL), 5d was isolated as
(250.13 MHz, (CD3)2CO):
d
¼2.39 (s, 3H, ArCH3), 3.74 (s, 3H, NCH3),
6.50 (d, J¼0.8 Hz, 1H, ArH), 7.06 (td, J¼6.9, 1.1 Hz, 1H, ArH), 7.18 (td,
J¼6.9, 1.1 Hz, 1H, ArH), 7.29e7.39 (m, 2H, ArH), 7.42e7.48 (m, 2H,
a yellowish oil (192 mg, 71%). 1H NMR (300 MHz, (CD3)2CO):
d¼3.58
ArH), 7.72e7.80 (m, 3H, ArH), 7.56 (dt, J¼8.0, 0.9 Hz, 1H, ArH). 13
C
(s, 3H, OCH3), 3.63 (s, 3H, OCH3), 3.69 (s, 3H, NCH3), 6.73 (d,
J¼3.0 Hz, 1H, ArH), 6.97e7.08 (m, 4H, ArH), 7.12e7.17 (m, 1H, ArH),
7.26 (td, J¼7.6, 1.0 Hz, 1H, ArH), 7.30e7.38 (m, 2H, ArH), 7.47 (d,
J¼8.3 Hz, 1H, ArH), 7.72 (d, J¼7.7 Hz, 1H, ArH). 13C NMR (62.89 MHz,
NMR (62.89 MHz, (CD3)2CO):
d
¼21.2 (CH3), 31.4 (NCH3),101.9,110.6,
120.4, 121.0, 122.2 (CH), 129.1 (C), 130.0, 130.1 (2CH), 130.9, 138.5,
139.4, 142.4 (C). IR (ATR, cmꢂ1):
n
¼3051 (m), 3018 (m), 2920 (m),
~
2853 (m), 2726 (w), 1925 (w), 1907 (w), 1755 (w), 1607 (w), 1495
(w), 1477 (w), 1462 (m), 1432 (w), 1409 (w), 1382 (m), 1366 (m),
1337 (m), 1317 (m), 1305 (m), 1239 (m), 1219 (m), 1189 (w), 1026
(w), 1006 (m), 955 (m), 918 (m), 895 (w), 826 (m), 773 (s), 749 (s),
734 (s), 716 (m), 666 (m), 636 (m), 623 (w), 581 (m), 556 (s), 526
(m). MS (EI, 70 eV): m/z (%)¼222 ([Mþ1]þ, 18), 221 ([M]þ, 100), 220
(CD3)2CO):
d
¼30.8 (NCH3), 55.9, 56.3 (OCH3),110.6, 113.3 (CH), 114.7
(C), 115.7 (d, JF,C¼21.4 Hz, 2CH), 116.0, 119.5, 119.7, 120.7 (CH), 122.3
(C), 122.7 (CH), 127.7 (C), 131.7 (d, JF,C¼7.8 Hz, 2CH), 132.9 (d,
JF,C¼3.0 Hz, C), 135.7, 138.1, 153.7, 154.4 (C), 161.9 (d, JF,C¼242 Hz, C).
19F NMR (282.40 MHz, CDCl3):
d
¼ꢂ112.53 (ArF). IR (ATR, cmꢂ1):
~
n
¼3046 (w), 2997 (w), 2934 (m), 2832 (m), 1712 (w), 1608 (w), 1589
(38), 205 (10), 204 (14), 178 (6), 110 (8). HRMS (EI) calcd for C16H15
[M]þ is 221.11990, found 221.119448.
N
(w), 1549 (m), 1508 (s), 1487 (s), 1463 (s), 1431 (s), 1417 (m), 1366
(m), 1326 (m), 1301 (m), 1273 (m), 1212 (s), 1179 (m), 1155 (m), 1133
(m), 1089 (m), 1038 (s), 1019 (m), 941 (m), 911 (m), 877 (m), 839
(m), 821 (m), 785 (m), 762 (w), 734 (s), 719 (m), 693 (m), 678 (m),
673 (m), 651 (m), 633 (m), 609 (m), 589 (m), 574 (m), 559 (s). MS
(EI, 70 eV): m/z (%)¼362 ([Mþ1]þ, 26), 361 ([M]þ, 100), 360 (16),
347 (8), 329 (5), 315 (7), 272 (5), 259 (5), 248 (9), 238 (6). HRMS (EI)
calcd for C29H25N [M]þ is 361.14726, found 361.147102.
4.2.8. 2-(4-Ethylphenyl)-1-methyl-1H-indole (6c). Starting with 1
(289 mg, 1.0 mmol), 2c (165 mg, 1.1 mmol), K3PO4 (318 mg,
1.5 mmol), Pd(PPh3)4 (3 mol %), 1,4-dioxane (2 mL) and H2O (2 mL)
6c was isolated as a colourless solid (223 mg, 95%), mp 133e135 ꢀC.
1H NMR (CDCl3, 300 MHz):
d
¼1.19 (t, J¼7.6 Hz, 3H, CH3), 2.61 (q,
J¼7.6 Hz, 2H, CH2), 3.60 (s, 3H, NCH3), 7.00e7.05 (m, 1H, ArH),
7.10e7.24 (m, 4H, ArH), 7.29e7.34 (m, 2H, ArH), 7.31 (dt, J¼8.1,
4.2.5. 3-[4-(Trifluoromethyl)phenyl]-2-(2,5-dimethoxyphenyl)-1-
methyl-1H-indole (5e). Starting with 1 (215 mg, 0.75 mmol), 2k
(150 mg, 0.82 mmol), 2m (171 mg, 0.9 mmol), K3PO4 (488 mg,
2.3 mmol), Pd(PPh3)4 (4 mol %) and 1,4-dioxane (4 mL), 5e was
isolated as a yellowish oil (194 mg, 63%). 1H NMR (300.13 MHz,
1.7 Hz, 1H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
d¼15.6 (CH3),
28.8 (CH2), 31.2 (NCH3), 109.7, 119.9, 120.5, 121.6 (CH), 128.1 (2CH),
128.2 (C), 129.5 (2CH), 130.7, 138.1, 138.4, 141.9, 144.2 (C). IR (ATR,
cmꢂ1):
~
n
¼3045 (w), 3024 (w), 2960 (m), 2922 (m), 2852 (m), 1682
(w), 1598 (m), 1567 (w), 1504 (w), 1495 (w), 1463 (m), 1455 (m),
1432 (m), 1409 (m), 1385 (m), 1362 (m), 1325 (m), 1310 (m), 1250.13
(m),1228 (m),1183 (m),1149 (m),1132 (m),1115 (m),1093 (m),1085
(m), 1053 (m), 1018 (m), 1001 (m), 970 (m), 955 (m), 922 (m), 901
(m), 856 (m), 834 (m), 801 (m), 763 (s), 755 (s), 738 (s), 707 (s), 701
(s), 670 (m), 646 (m), 614 (m), 598 (m), 575 (m), 567 (m), 547 (m).
MS (EI, 70 eV): m/z (%)¼236 ([Mþ1]þ, 19), 235 ([M]þ, 100), 234 (9),
221 (11), 220 (62), 218 (6), 205 (10), 204 (21), 178 (5), 110 (6), 102
CDCl3):
d
¼3.61 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.71 (s, 3H, NCH3),
6.74 (d, J¼3.2 Hz, 1H, ArH), 7.05 (d, J¼3.2 Hz, 1H, ArH), 7.10e7.21 (m,
2H, ArH), 7.29 (ddd, J¼8.1, 7.0, 1.1 Hz, 1H, ArH), 7.50e7.62 (m, 5H,
ArH), 7.79 (d, J¼7.7 Hz, 1H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
d
¼30.8 (NCH3), 55.9, 56.3 (OCH3), 110.8, 113.4 (CH), 114.2 (C), 116.2,
119.3, 119.5, 121.1 (CH), 122.0 (C), 122.9 (CH), 123.5 (C), 125.6 (q,
JF,C¼271 Hz, ArCF3), 125.9 (q, JF,C¼3.8 Hz, 2CH, C), 127.4 (q,
JF,C¼32 Hz, C), 130.2 (2CH), 136.6, 138.2 (C), 141.1 (d, J¼1.4 Hz, C),
(5). HRMS (EI) calcd for
235.135424.
C17H17N
[M]þ is 235.13555, found
153.6, 154.5 (C). 19F NMR (282.40 MHz, acetone):
d
¼ꢂ114.49
(ArCF3). IR (ATR, cmꢂ1):
n
¼3057 (w), 2953 (m), 2921 (m), 2852 (m),
~
1732 (w), 1613 (m), 1574 (w), 1566 (w), 1549 (m), 1494 (w), 1465
(m), 1435 (w), 1415 (w), 1394 (w), 1367 (w), 1320 (s), 1260 (m), 1190
(w), 1166 (m),1106 (s), 1090 (s), 1064 (s), 1014 (m), 961 (m), 941 (m),
930 (m), 863 (m), 851 (m), 833 (m), 802 (m), 768 (m), 748 (m), 734
(s), 695 (m), 674 (m), 650 (m), 631 (m), 597 (m), 574 (m), 557 (m).
4.2.9. 2-(3,5-Dimethylphenyl)-1-methyl-1H-indole (6d). Starting
with 1 (289 mg, 1.0 mmol), 2e (165 mg, 1.1 mmol), K3PO4 (318 mg,
1.5 mmol), Pd(PPh3)4 (3 mol %), 1,4-dioxane (2 mL) and H2O (2 mL)
6d was isolated as a yellowish gel (195 mg, 83%). 1H NMR
(300.13 MHz, CDCl3):
d
¼2.22 (s, 6H, 2CH3), 3.60 (s, 3H, NCH3), 6.35
(d, J¼0.8 Hz, 1H, ArH), 6.89e6.94 (m, 2H, ArH), 7.00e7.06 (m, 3H,
ArH), 7.25 (dd, J¼8.1, 0.8 Hz, 1H, ArH), 7.41 (dt, J¼7.7, 1 Hz, 1H, ArH).
4.2.6. 1-Methyl-2-phenyl-1H-indole (6a). Starting with 1 (289 mg,
1.0 mmol), 2a (134 mg, 1.1 mmol), K3PO4 (318 mg, 1.5 mmol),
Pd(PPh3)4 (3 mol %), 1,4-dioxane (2 mL) and H2O (2 mL) 6a was
13C NMR (62.89 MHz, (CD3)2CO):
d¼21.4 (2ArCH3), 31.5 (NCH3),
102.0, 110.6, 120.4, 121.0, 122.2 (CH), 127.9 (2CH), 129.1 (C), 130.3

7500
M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
(CH), 133.6 (C), 138.8 (2C), 139.5, 142.6 (C). IR (ATR, cmꢂ1):
n
¼3052
J¼7.5 Hz, 2H, CH2), 2.74 (q, J¼7.5 Hz, 2H, CH2), 2.76 (q, J¼7.6 Hz, 2H,
CH2), 3.74 (s, 3H, NCH3), 7.02e7.05 (m, 2H, ArH), 7.12e7.19 (m, 6H,
ArH), 7.21e7.23 (m, 2H, ArH), 7.34 (dd, J¼8.3, 1.5 Hz, 1H, ArH), 7.49
(d, J¼0.9 Hz, 1H, ArH), 7.56 (m, 2H, ArH), 7.74 (d, J¼8.3 Hz, 1H, ArH).
~
(w), 2919 (m), 2853 (m), 2725 (w), 1599 (m), 1537 (m), 1465 (s),
1432 (m), 1376 (m),1362 (m), 1338 (m),1312 (s), 1281 (w), 1262 (w),
1230 (m), 1162 (m), 1146 (m), 1129 (m), 1099 (m), 1074 (m), 1036
(m), 1009 (m), 960 (w), 946 (w), 922 (w), 903 (m), 857 (m), 772 (s),
748 (s), 731 (s), 700 (s), 666 (s), 608 (w), 584 (m), 576 (m), 548 (m),
536 (m). MS (EI, 70 eV): m/z (%)¼236 ([Mþ1]þ, 19), 235 ([M]þ, 100),
234 (30), 220 (8), 219 (8), 218 (11), 217 (5), 205 (6), 204 (14). HRMS
(EI) calcd mass for C17H17N [M]þ is 235.13555, found 235.135292.
13C NMR (62.89 MHz, CDCl3):
d
¼15.3, 15.3, 15.7 (CH3), 28.5, 28.5,
28.7 (CH2), 31.0 (NCH3), 107.9 (CH), 114.8 (C), 119.8 (2CH), 126.3 (C),
127.4, 127.7, 127.9, 128.2 (2CH), 129.2 (C), 129.7, 131.0 (2CH), 132.5,
135.6, 137.8, 138.2, 140.0, 141.2, 142.7, 144.0 (C). IR (ATR, cmꢂ1):
~
n
¼3020 (w), 2962 (m), 2922 (m), 2871 (m), 2852 (m), 1915 (w),
1886 (w), 1800 (w), 1651 (w), 1609 (m), 1566 (w), 1545 (m), 1517
(m), 1464 (m), 1429 (m), 1410 (m), 1393 (m), 1374 (m), 1318 (m),
1278 (m), 1257 (m), 1228 (m), 1206 (w), 1119 (m), 1088 (m), 1060
(m), 1047 (m), 944 (m), 856 (m), 822 (s), 806 (s), 783 (m), 754 (m),
730 (m), 700 (w), 688 (w), 641 (w), 629 (m), 611 (m), 584 (m), 536
(m). MS (EI, 70 eV): m/z (%)¼445 ([Mþ2]þ, 12), 444 ([Mþ1]þ, 43),
443 ([M]þ, 100), 429 (9), 428 (12), 200 (11), 192 (37), 191 (23), 184
(37), 178 (13), 171 (10). HRMS (EI) calcd for C33H33N [M]þ is
443.26075, found 443.260766.
4.2.10. 2-(4-tert-Butylphenyl)-1-methyl-1H-indole
(6e). Starting
with 1 (289 mg, 1.0 mmol), 2f (196 mg, 1.1 mmol), K3PO4 (318 mg,
1.5 mmol), Pd(PPh3)4 (3 mol %), 1,4-dioxane (2 mL) and H2O (2 mL)
6e was isolated as a yellowish solid (213 mg, 81%), mp 108e110 ꢀC.
1H NMR (300.13 MHz, CDCl3):
d
¼1.37 (s, 3H, CH3), 3.76 (s, 3H,
NCH3), 6.51 (s, 1H, ArH), 7.03e7.09 (m, 1H, ArH), 7.14e7.21 (m, 1H,
ArH), 7.48 (dt, J¼8.2, 0.8 Hz, 1H, ArH), 7.49e7.57 (m, 5H, ArH). 13
C
NMR (62.89 MHz, CDCl3):
d
¼31.5 (NCH3), 31.6 (CH3), 35.2 (C), 101.9,
110.6, 120.4, 121.0, 122.2 (CH), 126.3 (2CH), 129.1 (C), 129.8 (2CH),
130.9, 139.5, 142.3, 151.6 (C). IR (ATR, cmꢂ1):
n
¼3049 (w), 2954 (w),
4.3.3. 2,3,6-Tris(4-chlorophenyl)-1-methyl-1H-indole (8c). Starting
with 7 (100 mg, 0.27 mmol), 2d (145 mg, 0.93 mmol), Pd(PPh3)4
(4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL) and H2O
(2 mL), 8c was isolated as white powder (113 mg, 91%), mp
~
2901 (w), 2860 (w), 1613 (w), 1494 (w), 1463 (m), 1454 (m), 1430
(w),1406 (w),1358 (m),1336 (m),1317 (w),1266 (w),1242 (w),1216
(w), 1196 (w), 1165 (w), 1120 (m), 1098 (m), 1023 (w), 1004 (m), 922
(w), 846 (m), 840 (m), 794 (m), 782 (m), 747 (s), 736 (s), 671 (w),
589 (m), 559 (m), 542 (m). MS (EI, 70 eV): m/z (%)¼264 ([Mþ1]þ,
20), 263 ([M]þ, 100), 249 (19), 248 (85), 233 (18), 232 (7), 220 (8),
218 (6), 217 (5), 204 (9), 110 (19), 109 (7), 102 (6). HRMS (EI): calcd
for C19H21N [M]þ is 263.16685, found 263.166607.
198e200 ꢀC. 1H NMR (300.13 MHz, CDCl3):
d
¼3.74 (s, 3H, NCH3),
7.22e7.32 (m, 6H, ArH), 7.35e7.48 (m, 5H, ArH), 7.58 (d, J¼1.1 Hz,1H,
ArH), 7.63e7.67 (m, 2H, ArH), 7.49 (dd, J¼8.3, 0.6 Hz, 1H, ArH). 13
C
NMR (62.89 MHz, CDCl3):
120.2, 126.3 (C), 128.6 (4CH), 128.9, 129.0 (2CH), 129.8 (C), 130.9
d
¼31.1 (NCH3),108.9 (CH),114.4 (C),119.8,
(2CH), 131.7 (C), 132.3 (2CH), 132.9, 133.2, 134.6, 134.9, 137.4, 137.9,
4.3. General procedure for the synthesis of 8aek
140.6 (C). IR (ATR, cmꢂ1):
~
n
¼3078 (w), 3030 (w), 2930 (w),1538 (w),
1496 (m),1463 (m),1427 (m),1396 (m),1370 (m),1334 (m),1315 (m),
1299 (w), 1254 (m), 1234 (m), 1177 (w), 1163 (w), 1089 (s), 1013 (m),
958 (w), 946 (m), 854 (m), 831 (m), 812 (s), 760 (m), 747 (m), 733
(m), 721 (m), 706 (m), 662 (m), 644 (m), 626 (w), 615 (m), 584 (m).
MS (EI, 70 eV): m/z (%)¼465 (30), 464 (25), 463 (100), 465 (30), 461
(99), 376 (5),178 (12),177 (6),170 (6), 69 (5), 44 (6), 43 (5). HRMS (EI)
calcd for C27H18ClN [M]þ is 461.04993, found, 461.049515.
The reaction was carried out in a pressure tube. The mixture of 7,
1,4-dioxane (2 mL), H2O (2 mL), K2CO3, Pd(PPh3)4 and arylboronic
acid 2 was stirred at 110 ꢀC for 8 h. After cooling to 20 ꢀC, a saturated
aqueous solution of NH4Cl was added. The organic and the aqueous
layer were separated and the latter was extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4), filtered and the fil-
trate was concentrated in vacuo. The residue was purified by flash
chromatography (silica gel, heptanes).
4.3.4. 2,3,6-Tris(4-(tert-butyl)phenyl)-1-methyl-1H-indole
(8d). Starting with 7 (100 mg, 0.27 mmol), 2e (166 mg, 0.93 mmol),
Pd(PPh3)4 (4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL)
and H2O (2 mL), 8d was isolated as a white solid (123 mg, 85%), mp
4.3.1. 1-Methyl-2,3,6-tri-p-tolyl-1H-indole (8a). Starting with
7
(100 mg, 0.27 mmol), 2a (126 mg, 0.93 mmol), Pd(PPh3)4 (4 mol %),
K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL) and H2O (2 mL), 8a
was isolated as a white solid (96 mg, 87%), mp 174e177 ꢀC. 1H NMR
116e117 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼1.24 (s, 9H, 3CH3), 1.28 (s,
9H, 3CH3), 1.30 (s, 9H, 3CH3), 3.60 (s, 3H, NCH3), 6.16e7.21 (m, 5H,
ArH), 7.30e7.37 (m, 3H, ArH), 7.39 (d, 3H, J¼3.54 Hz, ArH), 7.49 (d,1H,
J¼1.05 Hz, ArH), 7.57 (d, 2H, J¼8.49 Hz, ArH), 7.76 (d, 1H, J¼8.04 Hz,
(300 MHz, CDCl3):
d
¼2.23 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.31 (s, 3H,
CH3), 3.58 (s, 3H, NCH3), 6.99 (d, 2H, J¼7.86 Hz, ArH), 7.07e7.18 (m,
8H, ArH), 7.32 (dd, 1H, J¼1.53, 8.28 Hz, ArH), 7.46 (d, 1H, J¼1.02 Hz,
ArH). 13C NMR (75.5 MHz, CDCl3):
(CH3), 34.4, 34.5, 34.7 (C), 107.9 (CH), 114.7 (C), 119.8, 119.9, 125.4,
125.5, 125.7 (CH), 126.4 (C), 127.1 (CH), 128.9 (C), 129.3, 130.8 (CH),
132.2, 135.4, 137.8, 138.2, 139.7, 148.0, 149.5, 150.9 (C). IR (KBr):
d
¼31.0 (NCH3), 31.3, 31.4, 31.5
ArH), 7.51 (d, 2H, J¼8.10 Hz, ArH), 7.71 (d, 1H, J¼8.31 Hz, ArH). 13
C
NMR (75.5 MHz, CDCl3):
d
¼21.1, 21.2, 21.4 (CH3), 31.0 (NCH3), 107.9
(CH), 114.8 (C), 119.8, 119.9 (CH), 126.4 (C), 127.3, 129.0, 129.2 (CH),
129.3 (C), 129.5, 129.7, 131.0 (CH), 132.4, 135.0, 135.6, 136.3, 137.8,
n
¼3029(w), 2956(s), 2902, 2865(m),1911,1673,1604,1548,1519 (w),
137.9, 138.3, 139.8 (C). IR (KBr):
n
¼3018, 2917, 2860, 2733, 1610,
1461 (s),1426,1392 (w),1361 (s),1335,1318,1307 (w),1267 (m),1201,
1181, 1166 (w), 1108 (m), 1086, 1047 (w), 1014, 947 (m), 921, 907 (w),
860 (m), 835, 809 (s), 769, 756 (w), 732 (m), 711, 699, 672, 651 (w),
623, 599 (m), 554 (s) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼528 ([MþH]þ,
38), 527 ([M]þ, 100), 513 (11), 512 (26), 471 (12), 249 (9). HRMS (EI,
70 eV): calcd for C39H45N [M]þ: 527.35465, found: 527.35464.
1567, 1548 (w), 1518, 1468 (m),1449, 1428, 1403, 1391 (w), 1373 (m),
1337, 1319, 1304, 1256, 1229, 1212, 1185, 1147, 1112 (w), 1087 (m),
1039, 1015, 971, 962 (w), 944, 852 (m), 840, 820, 810, 801 (s), 777,
755, 726 (m), 698, 689, 642, 633 (w), 612 (m), 577, 567, 539
(w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼402 ([MþH]þ, 33), 401 ([M]þ,
100), 371 (6). HRMS (ESI, 70 eV): calcd for C30H28N [MþH]þ:
402.22163, found: 402.22112.
4.3.5. 1-Methyl-2,3,6-tris(3-(trifluoromethyl)phenyl)-1H-indole
(8e). Starting with 7 (100 mg, 0.27 mmol), 2h (177 mg, 0.93 mmol),
Pd(PPh3)4 (4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL)
and H2O (2 mL), 8e was isolated as a white solid (120 mg, 78%), mp
4.3.2. 2,3,6-Tris(4-ethylphenyl)-1-methyl-1H-indole (8b). Starting
with 7 (100 mg, 0.27 mmol), 2b (139.5 mg, 0.93 mmol), Pd(PPh3)4
(4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL) and H2O
(2 mL), 8b was isolated as colourless crystals (113 mg, 94%), mp
158e160 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.66 (s, 3H, NCH3),
7.28e7.46 (m, 8H, ArH), 7.48e7.58 (m, 4H, ArH), 7.71 (d, 1H,
154e156 ꢀC. 1H NMR (300.13 MHz, CDCl3):
CH3), 1.32 (t, J¼7.5 Hz, 3H, CH3), 1.34 (t, J¼7.5 Hz, 3H, CH3), 2.69 (q,
d
¼1.29 (t, J¼7.5 Hz, 3H,
J¼8.34 Hz, ArH), 7.76e7.78 (m, 1H, ArH), 7.85 (br s, 1H, ArH). 19F
NMR (282.4 MHz, CDCl3):
d
¼ꢂ62.9, ꢂ62.8, ꢂ62.5. 13C NMR

M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
7501
(75.5 MHz, CDCl3):
d
¼30.1 (NCH3), 107.5 (CH), 113.7 (C), 118.9, 119.5
dioxane (2 mL) and H2O (2 mL), 8h was isolated as a white solid
(127 mg, 82%), mp 200e202 ꢀC. 1H NMR (300 MHz, CDCl3):
(s, 3H, NCH3), 7.30 (d, 2H, J¼1.56 Hz, ArH), 7.36e7.42 (m, 3H, ArH),
7.47 (d, 2H, J¼8.13 Hz, ArH), 7.56 (d, 1H, J¼0.84 Hz, ArH), 7.59e7.65
(m, 4H, ArH), 7.71e7.76 (m, 3H, ArH). 19F NMR (282.4 MHz, CDCl3):
(CH), 121.6 (q, JF,C¼3.74 Hz, CH), 122.5 (q, JF,C¼3.75 Hz, CH), 122.7 (q,
JF,C¼272.5 Hz, CF3), 123.0 (q, JF,C¼272.5 Hz, CF3), 123.1 (q,
JF,C¼3.79 Hz, CH), 123.3 (q, JF,C¼272.5 Hz, CF3), 124.2 (q, JF,C¼3.67 Hz,
CH), 125.4 (q, JF,C¼3.76 Hz, CH), 126.7 (q, JF,C¼3.72 Hz, CH), 127.9,
128.2, 128.3, 129.7 (CH), 129.8 (q, JF,C¼25.3 Hz, CeCF3), 130.1 (q,
JF,C¼27.4 Hz, CeCF3), 130.2 (q, JF,C¼30.7 Hz, CeCF3), 130.9 (C), 131.8,
d
¼3.67
d
¼ꢂ62.7, ꢂ62.3, ꢂ62.3. 13C NMR (62.9 MHz, CDCl3):
¼30.2 (NCH3),
d
107.7 (CH), 113.8 (C), 119.0, 119.7 (CH), 122.9 (q, JF,C¼273.3 Hz, CF3),
123.5 (q, JF,C¼272.7 Hz, CF3), 123.7 (q, JF,C¼272.0 Hz, CF3), 124.4 (q,
JF,C¼3.74 Hz, CH), 124.6 (q, JF,C¼3.79 Hz, CH), 124.9 (q, JF,C¼3.56 Hz,
CH), 125.5 (C), 126.6 (CH), 127.0 (q, JF,C¼32.4 Hz, CeCF3), 127.9 (q,
JF,C¼32.4 Hz, CeCF3), 128.8 (CH), 129.6 (q, JF,C¼32.6 Hz, CeCF3),
130.3 (CH), 133.9, 134.0, 136.6, 137.1, 137.3, 144.5 (C). IR (KBr):
133.3 (CH), 134.0, 134.2, 136.4, 137.1, 141.8 (C). IR (KBr):
n
¼3073,
3046, 2960, 2924, 2853, 1610, 1590, 1551, 1494, 1465, 1439, 1424,
1411, 1375 (w), 1334, 1326, 1308 (s), 1270 (w), 1251, 1159, 1112, 1094,
1071 (s), 1049, 1034 (m), 1000, 986, 964 (w), 912 (s), 879, 862, 829,
809 (m), 795 (s), 783 (m), 764 (w), 724 (m), 698 (s), 677 (w), 670 (s),
644, 622, 612, 595, 571, 528 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼
564 ([MþH]þ, 27), 563 ([M]þ, 100), 547 (15), 69 (19). HRMS (ESI,
70 eV): calcd for C30H19F9N [MþH]þ: 564.13683, found: 564.13740.
n
¼3051, 2957, 2923, 2852, 2640 (w), 1613 (m), 1574, 1553, 1520,
1494 (w), 1465 (m), 1431, 1416, 1407, 1397, 1369 (w), 1321 (s), 1257
(m),1187 (w), 1160 (m),1105, 1089, 1163, 1012 (s), 960, 946 (w), 858,
841 (m), 828, 807 (s), 779, 771, 761, 742, 712 (w), 696 (m), 675, 654,
650 (w), 634, 614, 599 (m), 576 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z
(%)¼564 ([MþH]þ, 39), 563 ([M]þ, 100), 97 (10), 84 (13), 71 (18), 69
(27), 57 (28). HRMS (EI, 70 eV): calcd for C30H18F9N [M]þ:
563.12900, found: 563.12941.
4.3.6. 2,3,6-Tris(3,4-dimethoxyphenyl)-1-methyl-1H-indole
(8f). Starting with 7 (100 mg, 0.27 mmol), 2i (154.4 mg, 0.93 mmol),
Pd(PPh3)4 (4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL)
and H2O (2 mL), 8f was isolated as a white powder (120.1 mg, 85%),
mp 176 ꢀC. 1H NMR (300.13 MHz, CDCl3):
d
¼3.72 (s, 3H, NCH3), 3.78
(s, 6H, 2ArOCH3), 3.91 (s, 3H, ArOCH3), 3.96 (s, 3H, ArOCH3), 3.98 (s,
3H, ArOCH3), 4.03 (s, 3H, ArOCH3), 6.86e6.89 (m, 3H, ArH),
6.95e6.98 (m, 3H, ArH), 7.02 (d, J¼8.3 Hz,1H, ArH), 7.27e7.31 (m, 2H,
ArH), 7.44 (dd, J¼8.3,1.5 Hz,1H, ArH), 7.18 (d, J¼0.9 Hz,1H, ArH), 7.85
4.3.9. 2,3,6-Tris(4-methoxyphenyl)-1-methyl-1H-indole (8i). Starting
with 7 (100 mg, 0.27 mmol), 2n (142 mg, 0.93 mmol), Pd(PPh3)4
(4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL) and H2O
(2 mL), 8i was isolated as a white solid (107 mg, 87%), mp
(d, J¼8.3 Hz, 1H, ArH). 13C NMR (62.89 MHz, (CD3)2CO):
d¼30.9
124e126 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.67 (s, 3H, NCH3), 3.72
(NCH3), 55.6, 55.8 (ArOCH3), 55.9, 56.0 (2ArOCH3),107.7,110.9,111.0,
111.1,111.6,113.1,114.2 (CH),114.5 (C),119.58,119.6,119.9,121.8,123.6
(CH), 124.4, 126.0, 127.9, 135.5, 135.6, 137.7, 137.9, 147.0, 148.2, 148.5,
~
(s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 6.68 (d, 1H,
J¼2.94 Hz, ArH), 6.75e6.94 (m, 6H, ArH), 7.14e7.16 (m, 3H, ArH),
7.30 (dd, 1H, J¼1.50, 8.28 Hz, ArH), 7.44 (d, 1H, J¼0.99 Hz, ArH), 7.55
(d, 2H, J¼8.76 Hz, ArH), 7.68 (d, 1H, J¼8.25 Hz, ArH). 13C NMR
148.7, 148.9, 149.1 (C). IR (ATR, cmꢂ1):
n
¼3644 (br), 3068 (w), 2999
(m), 2923 (m), 2839 (m), 1731 (w), 1605 (w), 1585 (m), 1552 (m),
1607 (w),1517 (m),1501 (m),1486 (m),1462 (m),1444 (m),1421 (m),
1403 (m),1387 (m),1369 (m),1333 (m),1315 (m),1301 (m),1274 (s),
1227 (s),1169 (m),1132 (s),1094 (m),1064 (m),1021 (s), 982 (m), 933
(m), 910 (m), 867 (m), 842 (m), 815 (s), 806 (m), 790 (s), 761 (s), 751
(s), 697 (m), 655 (m), 642 (m), 622 (m), 612 (m), 591 (m), 580 (m),
570 (m). MS (EI, 70 eV): m/z (%)¼541 ([Mþ2]þ, 7), 540 ([Mþ1]þ, 34),
539 (Mþ, 100), 270 (3). HRMS (EI) calcd mass for C33H33NO6 [Mþ] is
539.23024, found 539.231334.
(62.9 MHz, CDCl3):
113.8,114.2 (CH), 114.3 (C), 114.8, 116.0,119.6 (CH), 124.2, 126.1, 127.8
(C), 128.4, 130.8, 132.3 (CH), 135.2, 137.6, 137.7, 149.5, 157.5, 158.7,
d
¼30.9 (NCH3), 55.2, 55.3, 55.4 (OCH3), 107.6,
159.3 (C). IR (KBr):
n
¼3053, 3037, 2994, 2961, 2928, 2838, 1607,
1573, 1551 (w), 1515 (m),1478 (w), 1466,1455, 1440 (m), 1426, 1392,
1370, 1338, 1303 (w), 1286 (m), 1239, 1173 (s), 1148, 1107, 1089 (m),
1036, 1026 (s), 961, 944, 932, 856 (w), 838 (m), 820, 809, 795 (s),
755 (m), 729, 721 (w), 688 (m), 646, 640, 628, 625 (w), 611 (s), 586,
576 (m), 556 (w), 537 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 449
([M]þ, 100), 435 (11), 434 (36). HRMS (EI, 70 eV): calcd for
4.3.7. 2,3,6-Tris(4-fluorophenyl)-1-methyl-1H-indole (8g). Starting
with 7 (100 mg, 0.27 mmol), 2l(130mg, 0.93 mmol), Pd(PPh3)4 (4 mol
%), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL) and H2O (2 mL), 8g
was isolated as a white solid (95 mg, 84%), mp 178e180 ꢀC. 1H NMR
C
30H27O3N [M]þ: 449.19855, found: 449.19913.
4.3.10. 2,3,6-Tris(3-chlorophenyl)-1-methyl-1H-indole (8j). Starting
with 7 (100 mg, 0.27 mmol), 2o (145 mg, 0.93 mmol), Pd(PPh3)4
(4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-dioxane (2 mL) and H2O
(2 mL), 8j was isolated as a white solid (101 mg, 80%), mp
(300 MHz, CDCl3):
d
¼3.62 (s, 3H, NCH3), 6.87e6.93 (m, 2H, ArH),
6.98e7.10 (m, 4H, ArH), 7.12e7.24 (m, 4H, ArH), 7.30 (dd, 1H, J¼1.56,
8.28 Hz, ArH), 7.45(d,1H, J¼1.02 Hz, ArH), 7.53e7.59 (m, 2H, ArH), 7.67
120e123 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.63 (s, 3H, NCH3),
(d, 1H, J¼8.28 Hz, ArH). 19F NMR (282.4 MHz, CDCl3):
d¼ꢂ116.8,
6.99e7.02 (m, 1H, ArH), 7.09e7.11 (m, 3H, ArH), 7.21e7.35 (m, 7H,
ArH), 7.46e7.49 (m, 2H, ArH), 7.59e7.60 (m, 1H, ArH), 7.70 (d, 1H,
ꢂ116.6, ꢂ112.7. 13C NMR (75.5 MHz, CDCl3):
¼29.9 (NCH3), 107.0
d
(CH), 113.3 (C), 114.2 (d, JF,C¼21.2 Hz, CH), 114.6 (d, JF,C¼21.4 Hz, CH),
114.7 (d, JF,C¼21.6 Hz, CH), 118.6, 119.1 (CH), 125.2 (C), 126.5 (d,
JF,C¼3.54 Hz, C), 127.9 (d, JF,C¼8.00 Hz, CH), 129.7 (d, JF,C¼3.28 Hz, C),
130.2 (d, JF,C¼7.76 Hz,CH),131.8(d, JF,C¼8.20 Hz,CH),134.1,136.3,136.7
(C), 137.4 (d, JF,C¼3.19 Hz, C), 160.2 (d, JF,C¼245.1 Hz, CeF), 160.7 (d,
J¼8.13 Hz, ArH). 13C NMR (62.9 MHz, CDCl3):
¼30.1 (NCH3), 107.3
d
(CH), 113.4 (C), 118.9, 119.3, 124.5, 125.0 (CH), 125.3 (C), 125.8, 126.4,
126.9, 127.7, 128.3, 128.5, 128.6, 128.9, 129.0, 129.7 (CH), 132.1, 133.1,
133.4, 133.6, 133.8, 135.4, 136.3, 136.8, 143.0 (C). IR (KBr):
n
¼3066,
2917, 2849 (w),1592 (s),1564 (w),1550 (m),1485 (w),1467 (s),1455
(m), 1427, 1410, 1397 (w), 1373 (s), 1334 (m), 1308, 1296 (w), 1256
(m), 1165, 1140 (w), 1099, 1088, 1077 (m), 1050, 1034, 995 (w), 963
(m), 910 (w), 894, 866, 856 (m), 825, 787, 781, 771, 758, 717, 700,
JF,C¼246.1 Hz, CeF), 161.6 (d, JF,C¼248.1 Hz, CeF). IR (KBr): ¼3068,
n
3043, 2961, 2853, 1907, 1891 (w), 1601, 1593, 1556 (m), 1513 (s), 1493
(m),1463 (s),1425,1403 (w),1367,1335 (m),1315,1299 (w),1258 (m),
1219,1156,1087,1014 (s), 946 (m), 907 (w), 860, 837 (m), 819, 811, 800,
794 (s), 762 (w), 730 (m), 724, 686, 643, 628 (w), 608 (s), 576 (w), 566
(m), 538 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%)¼414 ([MþH]þ, 30), 413
([M]þ, 100), 397 (9). HRMS (EI, 70 eV): calcd for C27H18F3N [M]þ:
413.13859, found: 413.13909.
688, 676 (s), 661 (w), 646 (s), 603, 583, 557, 551, 541 (w) cmꢂ1
.
GCeMS (EI, 70 eV): m/z (%): 464 ([(MþH), 35Cl, 35Cl, 37Cl]þ, 29), 463
([M, 35Cl, 35Cl, 37Cl]þ, 98), 462 ([(MþH), 35Cl, 35Cl, 35Cl]þ, 29), 461
([M, 35Cl, 35Cl, 35Cl]þ, 100). HRMS (EI, 70 eV): calcd for C27H18Cl3N
[M, 35Cl, 35Cl, 37Cl]þ: 463.04698, found: 463.04738, calcd for
C
27H18Cl3N [M, 35Cl, 35Cl, 35Cl]þ: 461.04993, found: 461.05006.
4.3.8. 1-Methyl-2,3,6-tris(4-(trifluoromethyl)phenyl)-1H-indole
(8h). Starting with
0.93 mmol), Pd(PPh3)4 (4 mol %), K2CO3 (152 mg, 1.1 mmol), 1,4-
7
(100 mg, 0.27 mmol), 2m (177 mg,
4.3.11. 2,3,6-Tris(2-ethoxyphenyl)-1-methyl-1H-indole (8k). Starting
with 7 (100 mg, 0.27 mmol), 2p (154.4 mg, 0.93 mmol), Pd(PPh3)4

7502
M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
(4 mol %), K2CO3 (152 mg, 1.1 mmol) and 1,4-dioxane (2 mL) and
H2O (2 mL), 8k was isolated as white powder (114 mg, 85%), mp
(5 mL), 9c was isolated as a white solid (94 mg, 80%), mp
173e175 ꢀC. 1H NMR (300 MHz, CDCl3):
¼3.61 (s, 3H, NCH3),
7.31e7.44 (m, 8H, ArH), 7.49e7.58 (m, 3H, ArH). 13C NMR (62.9 MHz,
CDCl3):
¼30.7 (NCH3), 88.5 (C), 107.1, 118.8, 119.4 (CH), 125.8 (C),
127.6, 127.8, 127.9, 130.9 (CH), 131.2, 132.0, 134.0, 134.4, 136.4, 136.5,
139.4 (C). IR (KBr):
¼3069, 3054, 3013, 2961, 2924, 2872, 2851,1598,
d
166 ꢀC. 1H NMR (300.13 MHz, CDCl3):
d
¼1.19 (br s, 3H, CH3), 1.32 (t,
J¼7.0 Hz, 3H, CH3), 1.40 (t, J¼7.0 Hz, 3H, CH3), 3.68 (s, 3H, NCH3),
3.97e4.04 (m, 2H, ArOCH2), 4.10 (q, J¼7.0 Hz, 4H, 2ArOCH2),
6.83e6.91 (m, 3H, ArH), 6.97 (d, J¼7.9 Hz, 1H, ArH), 7.02e7.22 (m,
4H, ArH), 7.28e7.34 (m, 3H, ArH), 7.38 (dd, J¼8.2, 1.4 Hz, 1H, ArH),
7.52 (dd, J¼7.6, 1.7 Hz, 1H, ArH), 7.60 (d, J¼8.3 Hz, 1H, ArH), 7.63 (d,
d
n
1557, 1542, 1498 (w), 1478, 1463 (m), 1426, 1399, 1367, 1340, 1306,
1296 (w), 1258 (m), 1236, 1213, 1180, 1124 (w), 1104 (m), 1089 (s),
1056 (m), 1009 (s), 950, 939 (m), 907, 861 (w), 838 (s), 823, 813 (m),
797 (s), 742, 733 (w), 725 (m), 715, 698, 673, 666, 648, 639, 626 (w),
609 (m), 592, 582, 538 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 431
([(MþH), 81Br, 35Cl]þ, 100), 430 ([M, 81Br, 35Cl]þ, 15), 429 ([(MþH),
79Br, 35Cl]þ, 63), 393 (8), 314 (10),139 (16). HRMS (EI, 70 eV): calcd for
J¼0.8 Hz, 1H, ArH). 13C NMR (262.89 MHz, CDCl3):
¼14.5, 14.7, 14.9
d
(CH3), 30.9 (NCH3), 63.4 (2CH2), 64.1 (CH2), 110.2, 111.5 (2CH), 112.0
(C), 112.9 (2CH), 120.0, 120.2, 120.8, 121.3 (CH), 121.9, 125.0, 126.6
(C), 127.0, 127.7, 129.4 (CH), 131.3 (2CH), 131.8, 132.5, 132.6, 133.2,
~
136.3, 137.1, 156.1 (C). IR (ATR, cmꢂ1):
n
¼3045 (w), 2978 (m), 2922
(m), 2874 (m), 1595 (w), 1577 (m), 1554 (m), 1499 (m), 1467 (m),
1451 (m),1439 (m),1387 (m),1371 (m),1333 (m),1312 (m),1281 (s),
1239 (s), 1158 (m),1117 (s), 1084 (m),1040 (s), 950 (m), 921 (m), 850
(m), 814 (m), 794 (m), 748 (s), 721 (s), 698 (m), 681 (m), 642 (m),
633 (m), 601 (m), 545 (m). MS (EI, 70 eV): m/z (%)¼493 ([Mþ2]þ, 7),
492 ([Mþ1]þ, 37), 491 ([M]þ, 100), 433 (9), 29 (5). HRMS (EI) calcd
for C33H33NO3 [M]þ is 491.24550, found 491.245592.
C
C
21H14BrCl2N [M, 81Br, 35Cl]þ: 430.96607, found: 430.96755, calcd for
21H14BrCl2N [M, 79Br, 35Cl]þ: 428.96812, found: 428.96935.
4.3.15. 3-Bromo-2,6-bis(4-fluorophenyl)-1-methyl-1H-indole
(9d). Starting with 7 (100 mg, 0.27 mmol), 2l (79 mg, 0.57 mmol),
Pd(PPh3)4 (5 mol %), K3PO4 (172 mg, 0.81 mmol) and 1,4-dioxane
(5 mL), 9d was isolated as a white solid (90 mg, 83%), mp
115e117 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.60 (s, 3H, NCH3), 7.06 (t,
4.3.12. 3-Bromo-1-methyl-2,6-di-p-tolyl-1H-indole
(9a). Starting
2H, J¼5.22 Hz, ArH), 7.14 (t, 2H, J¼5.22 Hz, ArH), 7.35 (dd, 1H,
J¼0.87, 4.92 Hz, ArH), 7.39e7.42 (m, 3H, ArH), 7.53e7.57 (m, 3H,
with 7 (100 mg, 0.27 mmol), 2a (77 mg, 0.57 mmol), Pd(PPh3)4
(5 mol %), K3PO4 (172 mg, 0.82 mmol) and 1,4-dioxane (5 mL), 9a
was isolated as a white solid (78 mg, 73%), mp 135e137 ꢀC. 1H NMR
ArH). 19F NMR (282.4 MHz, CDCl3):
d
¼ꢂ116.3, ꢂ111.9. 13C NMR
(62.9 MHz, CDCl3):
d
¼31.7 (NCH3), 90.3 (C), 108.2 (CH), 115.5 (d,
(300 MHz, CDCl3):
d
¼2.30 (s, 3H, CH3), 2.37 (s, 3H, CH3), 3.62 (s, 3H,
JF,C¼6.51 Hz, CH), 117.3 (d, JF,C¼6.83 Hz, CH), 119.7, 120.5 (CH), 126.2,
126.3 (C), 128.9 (d, JF,C¼7.92 Hz, CH), 132.5 (d, JF,C¼8.32 Hz, CH),
135.7, 137.3, 137.7, 138.1 (C), 162.3 (d, JF,C¼245.9 Hz, CeF), 162.9 (d,
NCH3), 7.06e7.11 (m, 1H, ArH), 7.21e7.27 (m, 3H, ArH), 7.33 (d, 2H,
J¼8.24 Hz, ArH), 7.39 (dd, 1H, J¼1.45, 8.24 Hz, ArH), 7.43 (br s, 1H,
ArH), 7.49e7.57 (m, 3H, ArH). 13C NMR (62.9 MHz, CDCl3):
d
¼21.1,
JF,C¼249.2 Hz, CeF). IR (KBr): ¼2925, 2852 (w), 1603, 1591 (m),
n
21.4 (CH3), 31.7 (NCH3), 89.9 (C), 107.9, 119.4, 120.8 (CH), 120.8,
123.1, 126.4 (C), 127.3, 129.2, 129.5, 130.5 (CH), 136.3, 136.6, 137.3,
1574, 1557 (w), 1539 (m), 1515, 1488 (s), 1456 (m), 1424, 1405, 1371,
1339, 1308, 1298 (w), 1229, 1158, 1100 (s), 1022 (w), 1010, 951 (m),
860 (w), 846, 834, 824 (w), 794 (s), 726, 718, 686, 667, 644, 629 (w),
619 (m), 599 (s), 566 (m), 536 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%):
399 ([M, 81Br]þ, 100), 398 ([(MþH), 79Br]þ, 25), 397 ([M, 79Br]þ, 99),
317 (11), 316 (15), 303 (14). HRMS (EI, 70 eV): calcd for C21H14F2BrN
[M, 81Br]þ: 399.02517, found: 399.02549, calcd for C21H14F2BrN [M,
79Br]þ: 397.02722, found: 397.02732.
138.7, 139.3 (C). IR (KBr):
n
¼3022, 2916, 2852, 2729, 1908, 1613,
1556 (w), 1518, 1492 (m), 1455 (s), 1423 (w), 1368, 1341 (m), 1312,
1299, 1253, 1231 (w), 1218 (m), 1183, 1139 (w), 1105 (m), 1059, 1039,
1018, 965 (w), 950 (s), 939 (m), 907, 854 (w), 840, 821 (m), 806 (s),
779 (m), 748 (w), 721 (m), 687, 672, 649, 631 (w), 622, 598 (m), 570,
537 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 392 ([(MþH), 81Br]þ, 24),
391 ([M, 81Br]þ, 100), 390 ([(MþH), 79Br]þ, 31), 389 ([M, 79Br]þ,
100), 295 (11), 294 (14). HRMS (EI, 70 eV): calcd for C23H20BrN [M,
81Br]þ: 391.07532, found: 391.07571, calcd for C23H20BrN [M,
79Br]þ: 389.07736, found: 389.07745.
4.3.16. 3-Bromo-2,6-bis(4-methoxyphenyl)-1-methyl-1H-indole
(9e). Starting with 7 (100 mg, 0.27 mmol), 2n (86 mg, 0.57 mmol),
Pd(PPh3)4 (5 mol %), K3PO4 (172 mg, 0.81 mmol) and 1,4-dioxane
(5 mL), 9e was isolated as a white solid (96 mg, 83%), mp
4.3.13. 3-Bromo-2,6-bis(4-ethylphenyl)-1-methyl-1H-indole
(9b). Starting with 7 (100 mg, 0.27 mmol), 2b (85 mg, 0.57 mmol),
Pd(PPh3)4 (5 mol %), K3PO4 (172 mg, 0.81 mmol) and 1,4-dioxane
(5 mL), 9b was isolated as a white solid (90 mg, 79%), mp
163e165 ꢀC (CH2Cl2/EtOH 1:1). 1H NMR (300 MHz, CDCl3):
d¼3.58
(s, 3H, NCH3), 3.77 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 6.87e6.98 (m,
4H, ArH), 7.31e7.37 (m, 4H, ArH), 7.49e7.54 (m, 3H, ArH). 13C NMR
(62.9 MHz, CDCl3):
112.9, 113.2, 118.3, 119.1 (CH), 121.5, 125.2 (C), 127.4, 130.9 (CH),
133.7, 134.9, 136.2, 137.3, 157.8, 158.8 (C). IR (KBr):
¼3033, 2998,
d
¼30.6 (NCH3), 54.3, 54.4 (OCH3), 88.8 (C),106.7,
119e121 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼1.19e1.26 (m, 6H, 2CH3),
2.59e2.70 (m, 4H, 2CH2), 3.61 (s, 3H, NCH3), 7.24 (q, 4H, J¼8.31 Hz,
ArH), 7.35 (d, 2H, J¼8.25 Hz, ArH), 7.39 (dd,1H, J¼1.47, 8.19 Hz, ArH),
7.43 (d, 1H, J¼0.75 Hz, ArH), 7.50e7.57 (m, 3H, ArH). 13C NMR
n
2961, 2932, 2833 (w), 1606 (m), 1573, 1562, 1542 (w), 1518, 1489,
1461, 1443, 1424 (m), 1372 (w), 1345, 1305, 1288, 1274 (m), 1246,
1175 (s), 1105, 1035 (m), 1019 (s), 950 (m), 864 (w), 845, 832 (m),
815, 804, 781 (s), 747, 732, 704, 687, 668, 643, 629 (w), 621, 600, 576
(m), 556 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 424 ([(MþH), 81Br]þ,
25), 423 ([M, 81Br]þ, 99), 422 ([(MþH), 79Br]þ, 28), 421 ([M, 79Br]þ,
100), 408 (34), 406 (33), 212 (13). HRMS (EI, 70 eV): calcd for
(75.5 MHz, CDCl3):
89.9 (C), 108.1, 119.5, 120.4 (CH), 126.5 (C), 127.4 (CH), 127.6 (C),
127.8, 127.9, 130.6 (CH), 136.4, 137.4, 138.7, 139.6, 143.0, 144.9 (C). IR
d
¼15.3, 15.7 (CH3), 28.6, 28.8 (CH2), 31.7 (NCH3),
(KBr):
n
¼3050, 3019, 2966, 2930, 2872, 2853, 1517, 1492 (w), 1456
(s), 1423, 1410 (w), 1370, 1342 (m), 1309, 1272, 1231 (w), 1216 (m),
1182, 1139, 1115 (w), 1101 (m), 1051, 1017, 964 (w), 949 (s), 908, 858
(w), 844, 835 (m), 812 (s), 771, 763 (m), 750, 732, 685, 676, 647, 631
(w), 619, 603 (m), 562 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 419
([M, 81Br]þ, 99), 418 ([(MþH), 79Br]þ, 28), 417 ([M, 79Br]þ, 100), 404
(27), 402 (26). HRMS (EI, 70 eV): calcd for C25H24BrN [M, 81Br]þ:
419.10662, found: 419.10785, calcd for C25H24BrN [M, 79Br]þ:
417.10866, found: 417.10911.
C
C
23H20BrNO2 [M, 79Br]þ: 421.06719, found: 421.06734, calcd for
23H20BrNO2 [M, 81Br]þ: 421.06515, found: 421.06567.
4.3.17. 3,6-Dibromo-1-methyl-2-(p-tolyl)-1H-indole (10a). Starting
with7 (100 mg, 0.27 mmol), 2a(40mg, 0.29 mmol), Pd(PPh3)4 (3 mol
%), K3PO4 (86 mg, 0.40 mmol) and toluene/1,4-dioxane (4:1) (5 mL),
10a was isolated as a white solid (79 mg, 77%). 1H NMR (300 MHz,
CDCl3):
d
¼2.37(s, 3H,CH3), 3.54(s,3H,NCH3), 7.21e7.32(m, 5H,ArH),
4.3.14. 3-Bromo-2,6-bis(4-chlorophenyl)-1-methyl-1H-indole
(9c). Starting with 7 (100 mg, 0.27 mmol), 2d (89 mg, 0.57 mmol),
Pd(PPh3)4 (5 mol %), K3PO4 (172 mg, 0.81 mmol) and 1,4-dioxane
7.35e7.39 (m, 1H, ArH), 7.42 (d, 1H, J¼1.77 Hz, ArH). 13C NMR
(62.9 MHz, CDCl3):
116.2 (C), 120.5, 123.7 (CH), 126.2, 126.9 (C), 129.3, 130.4 (CH), 137.5,
d¼21.4 (CH3), 31.7 (NCH3), 90.1 (C), 112.7 (CH),

M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
7503
138.8, 139.0 (C). IR (KBr):
n
¼3206, 3070, 3021 (w), 2918 (m), 2866,
408 (23), 406 (45), 404 (23), 378 (8). HRMS (EI, 70 eV): calcd for
C
19H19Br2N [M, 79Br, 81Br]þ: 420.98583, found: 420.98605.
2584, 2550, 2417, 2357, 2326, 2142,1965,1910,1869,1801,1732,1673,
1604,1562(w),1492 (m),1462,1450(s),1419,1370(m),1336(s),1289,
1217, 1182 (m), 1131 (w), 1110, 1054 (m), 1040 (w), 1018 (m), 964 (w),
943 (s), 830, 797 (s), 781 (m), 759, 736 (w), 720 (m), 677, 658, 633 (w),
620, 586 (s), 549 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 381 ([(MþH),
81Br]þ, 49), 380 ([M, 81Br]þ, 19), 379 ([(MþH), 79Br, 81Br]þ, 100), 377
([(MþH), 79Br]þ, 50), 218 (11), 204 (13). HRMS (EI, 70 eV): calcd
for C16H13Br2N [M, 81Br]þ: 380.93683, found: 380.93821, calcd for
4.3.21. 3,6-Bis(4-(tert-butyl)phenyl)-2-(4-fluorophenyl)-1-methyl-
1H-indole (11a). The reaction was carried out in a pressure tube. To
a mixture solvent of toluene/dioxane (4:1) (5 mL) suspension of the
brominated-N-methylindole, Pd(PPh3)4 (5 mol %) and of the
Ar1B(OH)2 (1.1 equiv), K3PO4 (1.5 equiv) was added also. The mix-
ture was heated at the indicated temperature (65 ꢀC) under argon
atmosphere for the indicated period of time (8 h) and cooled to
room temperature. Then Ar2B(OH)2 (2.1 equiv), K2CO3(aq) (2 M,
1 mL) and 1,4-dioxane (3 mL) were added. The reaction mixture
was further heated for 8 h at 110 ꢀC. The reaction mixture was again
cooled to room temperature and diluted with water and extracted
with CH2Cl2 (3ꢁ25 mL). The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by flash chromatography (silica gel, EtOAc/
heptanes). Starting with 7 (100 mg, 0.27 mmol), 2l (41 mg,
0.29 mmol), Pd(PPh3)4 (5 mol %), K3PO4 (86 mg, 0.40 mmol) and
toluene/1,4-dioxane (4:1) (5 mL), 2e (99 mg, 0.57 mmol), K2CO3
(2 M, 1 mL) and 1,4-dioxane (3 mL), 11a was isolated as a yellowish
solid (99 mg, 74%), mp 148e150 ꢀC. 1H NMR (300 MHz, CDCl3):
C
16H13Br2N [M, 79Br, 81Br]þ: 378.93888, found: 378.93905, calcd
for C16H13Br2N [M, 79Br]þ: 376.94093, found: 376.94069.
4.3.18. 3,6-Dibromo-2-(4-ethylphenyl)-1-methyl-1H-indole
(10b). Starting with 7 (100 mg, 0.27 mmol), 2b (44 mg, 0.29 mmol),
Pd(PPh3)4 (3 mol %), K3PO4 (86 mg, 0.40 mmol) and toluene/1,4-
dioxane (4:1) (5 mL), 10b was isolated as a white solid (88 mg,
83%), mp 94e96 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼1.24 (t, 3H, CH3),
2.67 (q, 2H, J¼7.59, CH2), 3.56 (s, 3H, NCH3), 7.20e7.26 (m, 2H, ArH),
7.29 (d, 3H, J¼8.40 Hz, ArH), 7.33e7.39 (m, 1H, ArH), 7.42 (d, 1H,
J¼1.41 Hz, ArH). 13C NMR (62.9 MHz, CDCl3):
¼15.3 (CH3), 28.7
d
(CH2), 31.7 (NCH3), 90.1 (C), 112.7 (CH), 116.2 (C), 120.5, 123.7 (CH),
126.2, 127.1 (C), 128.0, 130.5 (CH), 137.5, 138.8, 145.1 (C). IR (KBr):
n
¼3070, 3022, 2960, 2868 (w), 1492, 1463, 1448 (m), 1414, 1371 (w),
d
¼1.22 (s, 9H, 3CH3), 1.29 (s, 9H, 3CH3), 3.56 (s, 3H, NCH3), 6.97 (t,
1338 (m), 1305, 1289, 1231 (w), 1214 (m), 1183, 1130, 1117 (w), 1109,
1054 (m), 1040, 1015, 966 (w), 943, 934, 843, 837, 829 (s), 811 (w),
800 (s), 765, 734, 677 (w), 659 (m), 632 (w), 617 (m), 587 (s), 560
(w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 395 ([(MþH), 81Br]þ, 49), 394
([M, 81Br]þ, 19), 393 ([(MꢂH), 81Br]þ, 100), 392 ([M, 81Br]þ, 11), 391
([(MþH), 79Br]þ, 51), 378 (32), 376 (16). HRMS (EI, 70 eV): calcd for
2H, J¼8.64 Hz, ArH), 7.10e7.25 (m, 6H, ArH), 7.34 (dd, 1H, J¼1.35,
8.31 Hz, ArH), 7.40 (d, 2H, J¼8.34 Hz, ArH), 7.47 (d, 1H, J¼0.90 Hz,
ArH), 7.56 (d, 2H, J¼8.31 Hz, ArH), 7.75 (d, 1H, J¼8.31 Hz, ArH). 19
F
NMR (282.4 MHz, CDCl3):
d
¼ꢂ113.2. 13C NMR (62.9 MHz, CDCl3):
d
¼30.9 (NCH3), 31.4, 31.5 (CH3), 34.4, 34.5 (C), 107.9 (CH), 115.2 (C),
115.6 (d, JF,C¼21.5 Hz, CH), 120.1, 125.2, 125.7 (CH), 126.3 (C), 127.1
(CH), 128.1 (d, JF,C¼3.49 Hz, CH), 129.3 (CH), 131.9 (C), 132.4 (d,
JF,C¼8.15 Hz, CH), 135.8, 136.9, 137.9, 139.6, 148.4, 149.7 (C), 162.6 (d,
C
C
17H15Br2N [M, 81Br]þ: 394.95248, found: 394.95330, calcd for
17H15Br2N [M, 79Br]þ: 390.95658, found: 390.95765.
JF,C¼247.9 Hz, CeF). IR (KBr): ¼3030 (w), 2957 (m), 2902, 2865,
n
4.3.19. 3,6-Dibromo-2-(4-chlorophenyl)-1-methyl-1H-indole
(10c). Starting with 7 (100 mg, 0.27 mmol), 2d (46 mg, 0.29 mmol),
Pd(PPh3)4 (3 mol %), K3PO4 (86 mg, 0.40 mmol) and toluene/1,4-
dioxane (4:1) (5 mL), 10c was isolated as a white solid (86 mg,
79%), reaction temperature: 65 ꢀC for 8 h.1H NMR (300 MHz, CDCl3):
2244, 1900, 1605, 1593, 1563, 1549 (w), 1516 (m), 1491 (w), 1462 (s),
1426,1404,1392 (w), 1363 (m),1334,1319,1307,1296 (w),1267 (m),
1221 (s), 1202 (w), 1156 (m), 1108, 1093, 1086, 1045, 1014 (w), 947
(m), 906 (s), 860 (m), 836, 823, 810, 802 (s), 761, 750 (w), 729 (s),
694, 672, 649 (w), 624, 604 (m), 561 (s), 538 (w) cmꢂ1. GCeMS (EI,
70 eV): m/z (%): 490 ([MþH]þ, 61), 489 ([M]þ, 100), 474 (38), 444
(8), 229 (23), 215 (36), 201 (96), 189 (16), 183 (15), 134 (14). HRMS
(EI, 70 eV): calcd for C35H36FN [M]þ: 489.28263, found: 489.28253.
d
¼3.54 (s, 3H, NCH3), 7.23e7.26 (m,1H, ArH), 7.32e7.36 (m, 3H, ArH),
7.39e7.44 (m, 3H, ArH). 13C NMR (75.5 MHz, CDCl3):
¼31.8 (NCH3),
90.7 (C),112.8 (CH),116.7 (C),120.8,124.0 (CH),126.1,128.4 (C),128.9,
131.9 (CH),135.2,137.4,137.6 (C). IR (KBr):
¼3079, 3064, 2925, 2854,
d
n
1915, 1872, 1728, 1692, 1599, 1562, 1536, 1503, 1478 (w), 1461, 1454
(m),1418,1400,1361 (w),1336 (m),1288,1268,1232,1212,1179,1129,
1104 (w), 1088 (m), 1051, 1036 (w), 1011 (m), 966 (w), 944, 939 (m),
835 (s), 803 (m), 795 (s), 737 (w), 724 (m), 674, 648, 625 (w), 607 (m),
589 (s), 570 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 399 ([(MþH), 79Br,
81Br, 35Cl]þ,100), 398 ([M, 79Br, 81Br, 35Cl]þ, 8), 397 ([(MþH), 79Br, 79Br,
35Cl]þ, 45), 204 (11). HRMS (EI, 70 eV): calcd for C15H10Br2ClN [M,
79Br, 81Br, 35Cl]þ: 398.88426, found: 398.88410, calcd for
4.3.22. 2-(4-(tert-Butyl)phenyl)-3,6-bis(4-methoxyphenyl)-1-
methyl-1H-indole (11b). The synthesis was carried out following the
procedure given for the synthesis of products 8. Starting with 10d
(71 mg, 0.17 mmol), 2n (53 mg, 0.35 mmol), Pd(PPh3)4 (5 mol %), K2CO3
(2 M, 1 mL) and 1,4-dioxane (3 mL), 11b was isolated as a yellowish
solid (65 mg, 81%), mp 184e186 ꢀC. 1H NMR (300 MHz, CDCl3):
d¼1.27
(s, 9H, 3CH3), 3.62 (s, 3H, NCH3), 3.72 (s, 3H, OCH3), 3.78 (s, 3H, OCH3),
6.76 (d, 2H, J¼8.76 Hz, ArH), 6.92 (d, 2H, J¼8.73 Hz, ArH), 7.16e7.18 (m,
4H, ArH), 7.31 (d, 3H, J¼8.28 Hz, ArH), 7.44 (d,1H, J¼0.84 Hz, ArH), 7.56
(d, 2H, J¼8.70 Hz, ArH), 7.68 (d, 1H, J¼8.22 Hz, ArH). 13C NMR
C
15H10Br2ClN [M, 79Br, 79Br, 35Cl]þ: 396.88630, found: 396.88615.
4.3.20. 3,6-Dibromo-2-(4-(tert-butyl)phenyl)-1-methyl-1H-indole
(10d). Starting with 7 (100 mg, 0.27 mmol), 2e (52 mg, 0.29 mmol),
Pd(PPh3)4 (3 mol %), K3PO4 (86 mg, 0.40 mmol) and toluene/1,4-
dioxane (4:1) (5 mL), 10d was isolated as a white solid (97 mg,
(75.5 MHz, CDCl3):
d¼31.0 (NCH3), 31.3 (CH3), 34.7 (C), 55.2, 55.4
(OCH3), 107.6, 113.7, 114.2 (CH), 114.5 (C), 119.7, 125.3 (CH), 122.1, 127.8
(C), 127.4, 128.7 (CH), 128.9 (C), 130.7, 130.9 (CH), 135.3, 137.8, 138.0,
150.9, 157.6, 158.7 (C). IR (KBr):
n¼3033, 2996, 2953, 2902, 2866, 2832,
84%), mp 156e158 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼1.31 (s, 9H,
3CH3), 3.55 (s, 3H, NCH3), 7.23 (dd, 1H, J¼1.92, 10.11 Hz, ArH),
7.31e7.46 (m, 6H, ArH). 13C NMR (62.9 MHz, CDCl3):
2248, 2059, 1886, 1714, 1650 (w), 1607 (m), 1573, 1548 (w), 1514 (s),
1492 (w),1461 (s),1440 (m),1426,1407,1393 (w),1363 (m),1334,1316,
1302 (w), 1278 (m), 1240, 1174 (s), 1108, 1089 (w), 1035 (s), 946, 906,
858 (m), 832, 807, 794 (s), 783, 760 (w), 727 (s), 688 (m), 648, 624 (w),
607 (s), 582, 558 (w), 531 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 476
([MþH]þ, 36), 475 ([M]þ, 100), 460 (12). HRMS (ESI, 70 eV): calcd for
d
¼31.3 (CH3),
31.8 (NCH3), 33.2, 90.0 (C), 112.7 (CH), 116.2 (C), 120.5, 123.7, 125.5
(CH), 126.2, 126.8 (C), 130.2 (CH), 137.5, 138.8, 151.9 (C). IR (KBr):
n
¼3026 (w), 2959 (m), 2901, 2865, 2707,1920,1868,1731,1681,1599,
1563, 1556 (w), 1491, 1461, 1451, 1416 (m), 1405, 1390 (w), 1360 (m),
1336 (s), 1289, 1267 (w), 1217 (m), 1199, 1131 (w), 1109, 1053, 1014
(m), 968 (w), 945, 842, 800 (s), 738, 723, 689 (w), 654 (m), 628 (w),
615 (s), 589 (m), 576, 553, 543 (w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%):
421 ([(MþH), 79Br, 81Br]þ, 100), 420 ([M, 79Br, 81Br]þ, 11), 419 (52),
C
33H33NO2 [MþH]þ: 476.25841, found: 476.25779.
4.3.23. 2-(4-Chlorophenyl)-3,6-bis(4-methoxyphenyl)-1-methyl-1H-
indole (11c). The synthesis was carried out following the procedure
given for the synthesis of products 8. Starting with 10c (67 mg,

7504
M.F. Ibad et al. / Tetrahedron 69 (2013) 7492e7504
2. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Verber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti,
V. J.; Cerino, D. H.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield,
J. J. Med. Chem. 1988, 31, 2235; (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893 and references therein.
0.17 mmol), 2n (54 mg, 0.35 mmol), Pd(PPh3)4 (5 mol %), K2CO3
(2 M, 1 mL) and 1,4-dioxane (3 mL), 11c was isolated as a yellowish
solid (62 mg, 82%), mp 105e107 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼3.60 (s, 3H, NCH3), 3.72 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 6.77 (d,
3. McAdam, B. F.; Catella-Lawson, F.; Mardini, I. A.; Kapoor, S.; Lawson, J. A.;
FitzGerald, G. A. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 272.
2H, J¼8.79 Hz, ArH), 6.92 (d, 2H, J¼8.79 Hz, ArH), 7.12e7.19 (m, 4H,
ArH), 7.26e7.35 (m, 3H, ArH), 7.44 (br s, 1H, ArH), 7.55 (d, 2H,
J¼8.67 Hz, ArH), 7.67 (d, 1H, J¼8.36 Hz, ArH). 13C NMR (75.5 MHz,
4. (a) Glenn, E. M.; Bowman, B. J.; Kooyers, W.; Koslowske, T.; Myers, M. L. J.
Pharmacol. Exp. Ther. 1967, 155, 157; (b) Kaiser, D. G.; Glenn, E. M.; Johnson, R.
H.; Johnston, R. L. J. Pharmacol. Exp. Ther. 1967, 155, 174; (c) Whitehouse, M. W. J.
Pharm. Pharmacol. 1967, 19, 590; (d) Collier, H. O. J.; James, G. W. L.; Piper, P. J. Br.
J. Pharmacol. 1968, 34, 76; (e) Brune, K.; Graf, P.; Glatt, M. Agents Actions 1976, 6,
159; (f) Podos, S. M.; Becker, B. Invest. Ophthalmol. 1976, 15, 841; (g) Spinelli, H.
M.; Krohn, D. L. Arch. Ophthalmol. 1980, 98, 1106; (h) Klug, R. D.; Krohn, D. L.;
Breitfeller, J. M.; Dieterich, D. Ophthalmic Res. 1981, 13, 122.
CDCl3):
d
¼30.0 (NCH3), 54.2, 54.4 (OCH3), 106.6, 112.8, 113.2, 118.8
(CH), 125.1, 126.1 (C), 127.4, 127.7 (CH), 127.8, 129.4 (C), 129.8, 131.3
(CH), 133.0, 134.0, 134.7, 135.3, 137.0, 156.8, 157.8 (C). IR (KBr):
n
¼3033, 2999, 2958, 2920, 2836 (w), 1606 (m),1572, 1546 (w), 1510,
1462 (s), 1441 (m), 1426, 1395 (w), 1368 (m), 1333, 1316, 1302 (w),
1279 (m),1242,1174,1087, 1033,1013 (s), 945 (m), 907, 887, 873 (w),
856, 826 (m), 815, 804, 794 (s), 760 (w), 725 (m), 698, 684, 649, 637,
618 (w), 603 (s), 578, 568 (w), 534 (m) cmꢂ1. GCeMS (EI, 70 eV): m/z
(%): 454 ([MþH]þ, 27), 453 ([M]þ, 100), 438 (25). HRMS (EI, 70 eV):
calcd for C29H24ClO2N [M]þ: 453.14901, found: 453.14838.
5. (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875; (b) Cacchi, S.;
Fabrizi, G. Chem. Rev. 2005, 105, 2873.
6. For direct C-arylations of indoles with (hetero)aryl halides or pseudohalides,
see: (a) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127, 8050; (b)
Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897; (c) Sezen, B.; Sames, D. J. Am.
Chem. Soc. 2003, 125, 5274; (d) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem.
Soc. 2005, 127, 13148; (e) Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007,
72, 1476; (f) Bellina, F.; Calandri, C.; Cauteruccio, S.; Rossi, R. Tetrahedron 2007,
63, 1970; (g) Zhang, Z.; Hu, Z.; Yu, Z.; Lei, P.; Chi, H.; Wang, Y.; Hen, R. Tetra-
hedron Lett. 2007, 48, 2415; (h) Lebrasseur, N.; Larrosa, I. J. Am. Chem. Soc. 2008,
130, 2926; (i) Bellina, F.; Benelli, F.; Rossi, R. J. Org. Chem. 2008, 73, 5529; (j)
Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673; (k) Ackermann, L.;
Barfuesser, S. Synlett 2009, 808; (l) Boorman, T. C.; Larrosa, I. Prog. Heterocycl.
Chem. 2011, 22, 1; (m) Lebrasseur, N.; Larrosa, I. Adv. Heterocycl. Chem. 2012, 105,
309; (n) Roy, D.; Mom, S.; Royer, S.; Lucas, D.; Hierso, J.-C.; Doucet, H. ACS Catal.
2012, 2, 1033; (o) Dong, H.; Limberakis, C.; Liras, S.; Price, D.; James, K. Chem.
Commun. 2012, 11644 Review: S. Cacchi, G. Fabrizi, Chem. Rev. 111 (2011) 215.
7. Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608 and references
cited therein.
8. For Rh-catalyzed arylation of NH indoles, see: (a) Wang, X.; Lane, B. S.;
Sames, D. J. Am. Chem. Soc. 2005, 127, 4996 For PdII-catalyzed indole alke-
nylation/alkylation, see: (b) Jia, C.; Lu, W.; Kitamura, T. Org. Lett. 1999, 1,
2097; (c) Lu, W.; Jia, C.; Kitamura, T.; Fujiwara, Y. Org. Lett. 2000, 2, 2927;
(d) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578; (e) Liu, C.;
Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250; (f) Grimster, N. P.;
Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed. 2005, 44,
3125; (g) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun. 2005, 1854 For re-
cent examples of Pd-catalyzed intermolecular arylations of nitrogen hetero-
cycles, see: (h) Review: Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211;
(i) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek, A. W.; Gevorgyan, V. Org. Lett.
2004, 6, 1159; (j) Rieth, R. D.; Mankad, N. P.; Calimano, E.; Sadighi, J. P. Org. Lett.
2004, 6, 3981; (k) Gauthier, D. R.; Limanto, J.; Devine, P. N.; Desmond, R. A.;
Szumigala, R. H.; Foster, B. S.; Volante, R. P. J. Org. Chem. 2005, 70, 5938; (l)
Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,127,18020; (m)
Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578; (n) Stuart, D. R.;
Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326; (o) Deprez,
N. R.; Kalyani, D.; Krause, A.; Sanford, M. S. J. Am. Chem. Soc. 2006,128, 4972; (p)
See Ref. 6e. (q) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172.
4.3.24. 2-(4-(tert-Butyl)phenyl)-3,6-bis(2-methoxyphenyl)-1-
methyl-1H-indole (11d). The synthesis was carried out following
the procedure given for the synthesis of products 8. Starting with
10d (71 mg, 0.17 mmol), 2j (54 mg, 0.36 mmol), Pd(PPh3)4 (5 mol %),
K2CO3 (2 M, 1 mL) and 1,4-dioxane (3 mL), 11d was isolated as
a yellowish solid (58 mg, 72%), mp 175e177 ꢀC. 1H NMR (300 MHz,
CDCl3):
d
¼1.24 (s, 9H, 3CH3), 3.38 (s, 3H, NCH3), 3.67 (s, 3H, OCH3),
3.74 (s, 3H, OCH3), 6.77e6.86 (m, 2H, ArH), 6.92e7.00 (m, 2H, ArH),
7.12e7.17 (m, 3H, ArH), 7.19e7.28 (m, 5H, ArH), 7.33e7.36 (m, 1H,
ArH), 7.43e7.46 (m, 2H, ArH). 13C NMR (75.5 MHz, CDCl3):
d¼30.2
(NCH3), 30.3 (CH3), 33.6 (C), 53.8, 54.7 (OCH3), 109.5, 109.9 (CH),
110.1 (C), 110.4 (CH), 118.3, 119.3, 119.8, 120.9 (CH), 123.4 (C), 123.9
(CH), 125.8 (C), 126.4, 126.9 (CH), 128.7 (C), 129.0, 130.0 (CH), 131.2,
131.4 (C), 131.7 (CH), 136.3, 138.0, 149.3, 155.7, 156.2 (C). IR (KBr):
n
¼3050 (w), 2954, 2924 (m), 2854, 1716, 1699, 1683, 1669, 1652,
1635,1615,1597, 1578, 1558,1501 (w), 1457 (s), 1432 (m),1406,1394
(w), 1363 (m), 1333, 1313, 1289 (w), 1252, 1239 (s), 1178, 1160 (w),
1117, 1083, 1050 (m), 1025 (s), 947 (m), 932, 856, 838 (w), 825, 813,
792 (m), 749 (s), 699, 654 (m), 638 (w), 628 (m), 611, 592, 560, 544
(w) cmꢂ1. GCeMS (EI, 70 eV): m/z (%): 476 ([MþH]þ, 36), 475 ([M]þ,
100). HRMS (EI, 70 eV): calcd for C33H33NO2 [M]þ: 475.25058,
found: 475.25047.
9. (a) Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000, 41, 8717; (b) Liu, Y.; Gribble, G.
W. Tetrahedron Lett. 2002, 43, 7135 For Pd(OAc)2-catalyzed regioselective ar-
ylation of indoles with arylsiloxane: (c) Liang, Z.; Yao, B.; Zhang, Y. Org. Lett.
2010, 12, 3185; (d) Regioselective oxidative arylation of indoles: Potqvathri, S.;
Pereira, K. C.; Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc.
2010, 132, 14676; (e) Palladium-catalyzed cross-coupling of 2-
indolylsilanolates: Denmark, S.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008,
73, 1440 For other syntheses of 2,3-diarylindoles, see: (f) Joucla, L.; Batail, N.;
Djakovitch, L. Adv. Synth. Catal. 2010, 352, 2929; (g) Scribner, A.; Moore, J. A., III;
Ouvry, G.; Fisher, M.; Wyvratt, M.; Leavitt, P.; Liberator, P.; Gurnett, A.; Brown,
C.; Mathew, J.; Thompson, D.; Schmatz, D.; Biftu, T. Bioorg. Med. Chem. 2009, 19,
1517; (h) Zhang, H.-C.; Ye, H.; White, K. B.; Maryanoff, B. E. Tetrahedron Lett.
2001, 42, 4751.
10. Ibad, M. F.; Hussain, M.; Abid, O.-U.-R.; Ali, A.; Ullah, I.; Zinad, D. S.; Langer, P.
Synlett 2010, 411.
11. Hussain, M.; Dang, T. T.; Langer, P. Synlett 2009, 1822.
12. CCDC 941362e941366 contains all crystallographic details of this publication
and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or
can be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; Fax: (þ44)1223-336-033; or
deposit@ccdc.cam.ac.uk
References and notes
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K. In Indoles; Houlihan, W. J., Ed.; Wiley-Interscience: New York, NY, 1972;
(f) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry II; Katritzky, A.
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p 119; (g) Gribble, G. W. In Comprehensive Heterocyclic
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