A facile palladium-catalyzed route to 2,5,7-trisubstituted indoles

Article abstract of DOI:10.1016/j.tet.2015.10.002

A facile and general approach to the synthesis of 2,5,7-trisubstituted indoles from readily available 2-bromo-6-iodo-4-substituted and 2-bromo-4-chloro-6-iodoanilines is reported. The assembly of the indole rings is accomplished via a one-pot Sonogashira cross-coupling with terminal alkynes followed by a palladium-catalyzed cyclization step. The functionalization at C7 and at C5 (with indoles bearing a chloro substituent at C5) is carried out by alkynylations, Suzuki-Miyaura cross-couplings, and Buchwald-Hartwig C-N bond forming reactions. One-pot protocols for the synthesis of 2,5,7-trisubstituted indoles from 2-aryl-7-bromo-5-chloroindoles as well as from 2-bromo-4-chloro-6-iodoaniline are also described.

Full text of DOI:10.1016/j.tet.2015.10.002

Tetrahedron 71 (2015) 9346e9356
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A facile palladium-catalyzed route to 2,5,7-trisubstituted indoles
*
Sandro Cacchi, Giancarlo Fabrizi, Antonella Goggiamani , Antonia Iazzetti,
Rosanna Verdiglione
ꢀ
Dipartimento di Chimica e Tecnologie del Farmaco, La Sapienza, Universita di Roma, P.le A. Moro 5, 00185 Rome, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 May 2015
Received in revised form 18 September 2015
Accepted 1 October 2015
Available online 13 October 2015
A facile and general approach to the synthesis of 2,5,7-trisubstituted indoles from readily available 2-
bromo-6-iodo-4-substituted and 2-bromo-4-chloro-6-iodoanilines is reported. The assembly of the in-
dole rings is accomplished via a one-pot Sonogashira cross-coupling with terminal alkynes followed by
a palladium-catalyzed cyclization step. The functionalization at C7 and at C5 (with indoles bearing a chloro
substituent at C5) is carried out by alkynylations, SuzukieMiyaura cross-couplings, and Buchwald-
Hartwig CeN bond forming reactions. One-pot protocols for the synthesis of 2,5,7-trisubstituted in-
doles from 2-aryl-7-bromo-5-chloroindoles as well as from 2-bromo-4-chloro-6-iodoaniline are also
described.
Keywords:
Polysubstituted indoles
One-pot reactions
Palladium
Ó 2015 Elsevier Ltd. All rights reserved.
Cross-coupling
1. Introduction
resultant 2-alkynylanilines and its functionalization at the C7 and
C5 positions via alkynylation, SuzukieMiyaura cross-coupling, and
The indole nucleus is a key structural feature present in several
biologically active natural compounds and in a wide range of
pharmaceuticals.1 Because of this, a great deal of effort has been
devoted to its construction and functionalization. Well established
classical methods include, to name a few of them, Fisher, Gassman,
Madelung, Bischler, BatchoeLeimgruber indole syntheses.2 In the
last 25 years or so, transition metal-catalyzed transformations,
particularly palladium-catalyzed reactions,3 have been widely
employed allowing for the development of a substantial number of
methods for the synthesis of indoles. However, in spite of all known
procedures, efficient and simple protocols for the preparation of
polysubstituted indoles, a subject of great interest for the synthesis
of biologically active compounds, are still an active research field.4
The simplicity and the availability of the requisite starting mate-
rials, the tolerance of functional groups, the selectivity of the sub-
stitution process, and the broad scope of the method are all issues
of particular relevance often difficult to combine in a synthetic
process.
Buchwald-Hartwig CeN bond forming reactions (Scheme 1).
Here we report just such a process providing a ready access to
2,5,7-trisubstituted indoles. Our planning involves the assembly of
the indole ring through a domino Sonogashira cross coupling of 2-
bromo-6-iodo-4-substituted and 2-bromo 4-chloro-6-iodoanilines
with terminal alkynes followed by an endo-dig cyclization of the
Scheme 1. Retrosynthetic representation of the synthesis of 2,5,7-trisubstituted
indoles from 2-bromo-6-iodo-4-substituted- and 2-bromo 4-chloro-6-iodoanilines.
2. Results and discussion
The starting 2-bromo-6-iodo-4-substituted and 2-bromo-4-
chloro-6-iodoanilines 3 were prepared in excellent overall yields
from commercially available 4-substituted anilines 1a and 1b
according to the sequence outlined in Scheme 2.5
* Corresponding author. Tel.: þ39 (06)4991 2798; e-mail address: antonella.
goggiamani@uniroma1.it (A. Goggiamani).
http://dx.doi.org/10.1016/j.tet.2015.10.002
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
9347
trisubstituted indoles bearing an alkynyl substituent at the C7 po-
sition. In spite of the great number of palladium-catalyzed trans-
formations of haloindoles,3d,k little attention has been paid to the
alkynylation of free NH 7-bromoindoles with terminal alkynes. To
the best of our knowledge, no example of this chemistry has been
reported.
We started our study by examining the conversion of 5a to the
corresponding alkynylindole 6a. Taking advantage of the study of
Buchwald and Fu,8 who showed that aryl bromides could readily
undergo the Sonogashira cross-coupling in the presence of
PdCl2(PhCN)2, P(t-Bu)3, CuI, and NH(i-Pr)2 in dioxane at room
temperature, these conditions were initially used substituting HP(t-
Bu)3BF49 for P(t-Bu)3, a remarkably active ligand which, however, is
difficult to handle.10 However, no evidence of alkynylindole for-
mation was observed (Table 1, entry 1), even increasing the reaction
temperature to 80 ꢀC (Table 1, entry 2). After a brief screen of pal-
ladium and copper catalysts, solvents and bases, we found that, as
regards yield and reaction time, excellent results could be obtained
by using Pd2(dba)3, HP(t-Bu)3BF4, and Cs2CO3 in dioxane (Table 1,
entry 8).
Scheme 2. Synthesis of 2-bromo-6-iodo-4-substituted and 2-bromo-4-chloro-6-
iodoanilines.
The assembly of the indole rings from 3a and 3b was readily
accomplished in excellent yields via a one-pot chemoselective
Sonogashira cross-coupling with terminal alkynes followed by
palladium-catalyzed endo-dig cyclization of the resultant 2-
alkynylanilines 4. As shown in Scheme 3, two different palladium
catalysts for the two steps are required, most probably because the
first step is a Pd(0)-catalyzed process6 and the second one is
a Pd(II)-catalyzed process.7 It is conceivable that, under reaction
conditions, Pd(II) species are readily reduced to Pd(0) species, thus
preventing the cyclization of the alkynylation product. Accordingly,
no evidence of indole formation was attained when 3b was reacted
with phenyl acetylene, PdCl2(PPh3)2, CuI in MeCN at room tem-
perature and, after completion of the coupling step, the resulting
reaction mixture was stirred at room temperature for 24 h. The
indole product was also formed in trace amounts, if any, when the
reaction mixture was warmed at 80 ꢀC for 6 h after the coupling
step or when the reaction of 3b with phenyl acetylene in the
presence of the same catalyst system was directly carried out at
80 ꢀC for 6 h. Only the cross-coupling product was isolated in 90 and
91% yield, respectively. Taken together, all these experiments sug-
gest that the first catalyst system is unable to catalyze both the steps
of the transformation. The addition of PdCl2(MeCN)2 after com-
pletion of the coupling step led to the isolation of the desired indole
derivatives in excellent overall yields.
Table 1
The alkynylation of 5a: optimization studiesa
Entry Catalyst system
Base
Solvent
t (h) Yield %
of 6ab
dc,d
1
2
3
4
5
6
7
8
PdCl2(PhCN)2 HP(t-Bu)3BF4 CuI NH(i-Pr)2 Dioxane
6
dd
PdCl2(PhCN)2 HP(t-Bu)3BF4 CuI NH(i-Pr)2 Dioxane 24
PdCl2(PhCN)2 HP(t-Bu)3BF4 CuI K3PO4 Dioxane 24
Dioxane
Dioxane 24
53e
87
PdCl2(PhCN)2 HP(t-Bu)3BF4
Pd2(dba)3 HP(t-Bu)3BF4
Pd2(dba)3 HP(t-Bu)3BF4
Pd2(dba)3 HP(t-Bu)3BF4
Pd2(dba)3 HP(t-Bu)3BF4
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
1
35f
50g
65h
96
Toluene
Toluene
Dioxane
7
5
1
a
Unless otherwise stated, reactions were carried out at 80 ꢀC on a 0.5 mmol scale
in 2 mL of solvent using 1.2 equiv of alkyne, 0.02 equiv of [Pd], 0.02 equiv of CuI
(when used), 0.04 equiv of HP(t-Bu)3BF4, and 2 equiv of base.
b
Yields are given for isolated products.
At room temperature.
5a was recovered in almost quantitative yield.
5a was recovered in 45% yield.
5a was recovered in 62% yield.
5a was recovered in 30% yield.
5a was recovered in 15% yield.
c
d
e
f
g
h
Using the optimized conditions for the model system, we next
explored the scope and generality of the reaction. As shown in
Table 2, treatment of 5a,b,def, with a variety of terminal alkynes
afforded the desired indole derivatives in high to excellent yields.
2.2. Arylation at C7 via SuzukieMiyaura cross-coupling
We next explored the scope and generality of a route to the
arylation of the C7 position of 5 based on the SuzukieMiyaura
cross-coupling. Examples of the Suzuki Miyaura cross-coupling of
7-bromoindoles have been described. However, some of them
suffer from limitations such as the use of harsh and troublesome
reaction conditions (120 ꢀC in a sealed tube)11 or the need of N-
protected indoles.12 In some cases, the reaction has been applied
only to a limited number of examples. Only a couple of arylboronic
acids have been investigated in a comprehensive study dedicated to
the evaluation of some reaction parameters on the SuzukieMiyaura
couplings of 5-, 6-, or 7-substituted indoles.13 A single arylboronic
Scheme 3. Assembly of indole rings from 3a and 3b through a one-pot Sonogashira
cross-coupling/cyclization process.
2.1. Alkynylation at C7
Subsequent studies were initially directed toward the de-
velopment of suitable conditions for the preparation of 2,5,7-

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S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
Table 2
These conditions were then applied when the reaction was ex-
Synthesis of 2,5-disubstituted 7-alkynylindoles 6 from 5a
tended to other arylboronic acids and 7-bromoindoles. As shown by
the results summarized in Table 4, 7-arylated indoles are isolated in
high to excellent yields with a variety of neutral, electron-rich, and
electron-poor arylboronic acids and heteroarylboronic acids.
Entry
5
Alkyne
t (h)
1
Yield % of 6b
(6a) 96
1
2
5a
2
(6b) 85
Table 4
3
3
(6c) 78
Synthesis of 2,5-disubstituted 7-arylindoles 7 from 5a
Entry
5
Arylboronic acid
t (h)
Yield % of 7b
(7a) 100
4
5
6
2.5
7
(6d) 96
(6e) 69
(6f) 87
1
5a
1
2
3
0.5
4
(7b) 91
(7c) 98
1.5
4
2
(7d) 94
5
6
5b
5d
0.5
0.5
(7e) 94
(7f) 95
7
0.6
(6g) 70
7
8
1
(7g) 99
(7h) 93
8
9
5b
5d
1
(6h) 94
(6i) 94
1.5
9
5
2
(7i) 90
(7j) 96
1.5
10
10
11
3
(6j) 73
(6k) 77
(6l) 77
11
5e
5f
1.5
(7k) 99
12
13
1.5
3
(7l) 100
(7m) 88
5e
5f
0.5
8
14
15
a
6
(7n) 76
(7o) 90
12
0.5
a
Reactions were carried out at 80 ꢀC on a 0.5 mmol scale in 2 mL of dioxane using
1.2 equiv of alkyne, 0.02 equiv of Pd2(dba)3, 0.04 equiv of HP(t-Bu)3BF4, and 2 equiv
of Cs2CO3.
Reactions were carried out at 100 ꢀC on a 0.5 mmol scale in 2 mL of dioxane
using 1.2 equiv of arylboronic acid, 0.02 equiv of Pd2(dba)3, 0.04 equiv of SPhos, and
2 equiv of Cs2CO3.
b
b
Yields are given for isolated products.
Yields are given for isolated products.
acid was tested in other papers.14 This justifies efforts to develop
a simple and general protocol for the arylation of 7-bromoindoles.
The reaction of 5a with phenylboronic acid was selected as the
model system. A brief optimization study revealed that the cross-
coupling product 7a could be readily obtained in excellent yield
in the presence of Pd2(dba)3, SPhos, and Cs2CO3 in dioxane at 100 ꢀC
(Table 3, entry 5).
2.3. Amination at C7 via Buchwald-Hartwig CeN bond form-
ing reactions
The potential of our strategy to 2,5,7-trisubstituted indoles is
further demonstrated by the ready amination at C7. The palladium-
catalyzed amination of 7-bromoindoles has rarely been reported.
In addition, the described procedures refer to single examples
on N-protected indoles15 or free NH indoles16 with secondary
amines. Therefore, it appeared to us of interest to develop a simple
general CeN bond forming process at the C7 position of free
NH bromoindoles. As the reduction of the starting bromoindole
Table 3
The SuzukieMiyaura cross-coupling of 5a with phenylboronic acid: optimization
studiesa
via a
b-hydride elimination pathway from amidopalladium in-
termediates is known to plague the desired reaction,17 the amina-
tion of 5a with morpholine, an amine that can give rise to this type
of side reaction, was selected as the model system. After an initial
screen, we found that satisfactory results could be obtained in the
presence of Pd2(dba)3, RuPhos, and NaOt-Bu in dioxane at 110 ꢀC
(Table 5, entry 4).
The scope and generality of the process was explored next using
these conditions. As shown in Table 6, good to excellent results
were usually obtained with a variety of 7-bromoindoles and pri-
mary and secondary amines. Neutral, electron-rich and electron-
poor aromatic amines react with 7-bromoindoles to give the cor-
responding amino derivatives in high to excellent yields. Aromatic
amines bearing substituents in the ortho position can also be used
(Table 6, entries 9 and 10). Some limitations appear to arise with
primary aliphatic amines. For example, treatment of butylamine
Entry
Ligand
Base
Solvent
t (h)
Yield % of 7ab
1
2
3
4
5
XPhos
tBuXPhos
SPhos
SPhos
SPhos
K3PO4
K3PO4
K3PO4
K3PO4
Cs2CO3
Toluene
Toluene
Toluene
Dioxane
Dioxane
4
7
2
2.5
0.5
70c
65d
86
90
100
a
Reactions were carried out at 100 ꢀC on a 0.5 mmol scale in 2 mL of solvent using
1.2 equiv of phenylboronic acid, 0.02 equiv of Pd2(dba)3, 0.04 equiv of ligand, and
2 equiv of base.
b
Yields are given for isolated products.
5a was recovered in 10% yield.
5a was recovered in 20% yield.
c
d

S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
9349
Table 5
readily increased by subjecting them to further palladium-
catalyzed CeC bond forming reactions. Given the remarkable ad-
vantages in terms of time, outlays for purification materials, and
often yields of one-pot multistep processes over the corresponding
stepwise processes, we decided to explore this route as a one-pot
protocol starting from 2-substituted 5-chloro-7-bromoindoles,
thus omitting the isolation of 7-functionalized indole in-
termediates. In particular, we investigated the sequential alkyny-
lation, arylation, and amination at C7 of 5d and 5g followed by the
SuzukieMiyaura cross-coupling at C5. The first step was carried out
as usual. Then, the reagents required for the second step were
added to the resulting reaction mixture. Some examples of this
chemistry are shown in Scheme 4. Notably, while SPhos18 could be
successfully used in the SuzukieMiyaura reaction at the C7eBr
bond, the best results were obtained using XPhos when the same
reaction was attempted at the C5eCl bond. For example, 7p was
isolated only in 9% yield when 5-chloro-2,7-diphenylindole, 7g,
was treated with 4-MeOeC6H4B(OH)2, Pd2(dba)3, SPhos, and
Cs2CO3 in dioxane at 100 ꢀC for 24 h (7g was recovered in 90%
yield). Substituting XPhos for SPhos and leaving all the other pa-
rameters the same led to the isolation of 7p in 86% yield. This is in
agreement with the inefficiency of SPhos in the SuzukieMiyaura
cross-coupling of unactivated heteroaryl chlorides observed by
Buchwald et al.19 and with the beneficial effect of XPhos in these
cases. Thus, XPhos was used in the second step when the one-pot
protocol was attempted. However, the addition of XPhos and 4-
MeOeC6H4B(OH)2 to the crude mixture resulting from the reaction
of 5d with PhB(OH)2 produced 7p only in 30% yield, showing that
the first palladium catalyst deactivated, at least in part. The yield
The amination of 5a with morpholine: optimization studiesa
Entry
Ligand
Base
t (h)
Yield %b
8a
9a
1
2
3
4
SPhos
XPhos
XPhos
Ruphos
NaOt-Bu
NaOt-Bu
K3PO4
24
36
38
20
76
30c
62
0.5
0.5
1.5
40d
24
NaOt-Bu
a
Reactions were carried out at 110 ꢀC on a 0.5 mmol scale in 4 mL of dioxane
using 1.2 equiv of amine, 0.05 equiv of Pd2(dba)3, 0.10 equiv of ligand, and 2 equiv of
base.
b
Yields are given for isolated products.
5a was recovered in 27% yield.
5a was recovered in 15% yield.
c
d
Table 6
Synthesis of 2,5-disubstituted 7-aminoindoles 8 from 5a
Entry
5
Amine
t (h)
Yield % of 7b
(8a) 76c
1
5a
0.5
2
3
2
(8b) 66c
(8c) 96c
increased to 54% by adding Pd2(dba)3, XPhos, and 4-MeOeC6H4
-
B(OH)2, suggesting that the amount of base and/or solvent may also
influence the reaction course. Finally, when XPhos was added along
with the whole set of reagents as shown in Scheme 4, 7p was
isolated in 83% overall yield.
0.3
4
5
0.5
0.3
(8d) 70
(8e) 95
Finally, to make this overall approach to 2,5,7-trisubstituted
indoles more attractive from a synthetic standpoint, we also ex-
plored the development of a one-pot protocol starting from 2-
bromo-4-chloro-6-iodoaniline 3b. As an example, 7p was pre-
pared in 73% yield (Scheme 5).
6
5c
2
(8f) 62c
7
8
0.5
2.5
(8g) 92
(8h) 80
9
1
(8i) 78
(8j) 96
(8k) 89
3. Conclusions
10
11
0.5
0.3
In conclusion, we have developed a facile and general approach
to the synthesis of 2,5,7-trisubstituted indoles starting from
readily available 2-bromo-6-iodo-4-substituted and 2-bromo-4-
chloro-6-iodoanilines. Indole rings have been assembled from
them in excellent yields via a one-pot chemoselective Sonogashira
cross-coupling with terminal alkynes followed by a palladium-
catalyzed endo-dig cyclization step. Subsequent functionaliza-
tions at C7 and C5 (with indoles bearing a chloro substituent at the
C5) have been performed by alkynylations, SuzukieMiyaura cross-
couplings, and Buchwald-Hartwig CeN bond forming reactions. In
all these cases, the desired indole derivatives were usually iso-
lated in high to excellent yields. One-pot protocols for the se-
quential functionalization at the C7 and C5 positions have been
12
1
(8l) 64c
13
14
5d
5e
0.5
0.5
(8m) 84
(8n) 87
15
3
(8o) 89c
a
Unless otherwise stated, reactions were carried out at 100 ꢀC on a 0.5 mmol
scale in 4 mL of dioxane using 1.2 equiv of amine, 0.02 equiv of Pd2(dba)3, 0.04 equiv
of Ruphos, and 2 equiv of NaOt-Bu.
b
Yields are given for isolated products.
At 110 ꢀC, 2 mL of dioxane, 1.2 equiv of amine, 0.05 equiv of Pd2(dba)3,
c
0.10 equiv of Ruphos, and 2 equiv of NaOt-Bu.
developed. A one pot-protocol for the synthesis of 2,5,7-
trisubstituted indoles from 2-bromo-4-chloro-6-iodoaniline has
also been described.
and benzylamine with 5d afforded the corresponding indole de-
rivatives only in 8 and 10% yield, respectively.
4. Experimental section
4.1. General comments
2.4. One-pot protocols for the synthesis of 2,5,7-
trisubstituted indoles
Melting points are uncorrected. All of the reagents, catalysts,
and solvents are commercially available and were used as pur-
chased, without further purification. Reaction products were
The molecular complexity of 7-alkynyl-, 7-aryl-, and 7-
aminoindoles bearing a chloro substituent at the C5 can be

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S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
Scheme 4. One-pot preparations of 2,5,7-trisubstituted indoles from 5d.
purified by flash chromatography using SiO2 as stationary phase,
eluting with n-hexane/ethyl acetate mixtures. 1H NMR
(400.13 MHz) and 13C NMR (100.6 MHz) spectra were recorded
with a Bruker Avance 400 spectrometer. Splitting patterns are
designed as s (singlet), d (doublet), t (triplet), q (quartet), sp
(septuplet), m (multiplet), or bs (broad singlet). IR spectra were
recorded with a Jasco FT/IR-430 spectrometer. Mass spectra were
determined with a QP2010 Gas Chromatograph Mass spectrometer
(EI ion source); compounds (6e, 6g, 6k) were derivatized as N-
methyl indoles for obtaining suitable mass data.
4.2. Typical procedures
4.2.1. Typical procedure for the synthesis of 7-bromoindoles (5).
Synthesis of 7-bromo-5-methyl-2-phenyl-1H-indole (5a). In a 50 mL
Carousel Tube Reactor (Radely Discovery Technology) containing
a magnetic stirring bar CuI (1.5 mg, 0.025 mmol) and PdCl2(PPh3)2
(7.0 mg, 0.01 mmol) were dissolved at room temperature with
0.5 mL of anhydrous CH3CN under nitrogen. Then, 2-bromo-6-iodo-
4-methylaniline 3a (156 mg, 0.5 mmol), phenylacetylene (65.8 ml,
0.6 mmol), and 0.5 mL of CH3CN were added. The reaction mixture
was stirred for 12 h at room temperature. After this time
PdCl2(CH3CN)2 (6.5 mg, 0.025 mmol) was added and the reaction
mixture was stirred for 12 h at room temperature. Then, the re-
action mixture was diluted with EtOAc and washed with a satu-
rated NaHCO3 solution. The organic layer was separated, washed
with water, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography (silica gel, n-
hexane/EtOAc 98/2) to afford 138.7 mg (97% yield) of 7-bromo-5-
methyl-2-phenyl-1H-indole 5a as a brown solid. Mp: 130e131 ꢀC;
IR (KBr): 3440, 2910, 839, 756, 730, 681 (cmꢁ1); 1H NMR (CDCl3):
d
8.34 (br s, 1H), 7.68e7.66 (m, 2H), 7.47e7.34 (m, 4H), 7.19 (m, 1H),
6.79 (d, J¼2.0 Hz, 1H), 2.44 (s, 3H); 13C NMR (CDCl3):
d 138.7, 133.9,
131.9, 131.1, 130.5, 129.1, 128.1, 126.0, 125.3, 119.6, 103.9, 100.5, 21.2.
MS m/z (%): 202 (Mþ, 97); 206 (62), 205 (10), 204 (22). Anal. Calcd
Scheme 5. One-pot preparation of 7p from 3b.

S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
9351
for C15H12BrN, C, 62.96; H, 4.89; N, 13.85; found C, 62.87; H, 4.87; N,
13.86.
afford 110.9 mg (76% yield) of 4-(5-methyl-2-phenyl-1H-indol-7-yl)
morpholine 8a as a brown oil. IR (KBr): 3424, 1611, 1602, 1458
(cmꢁ1); 1H NMR (CDCl3):
d
8.28 (br s,1H), 7.67 (d, J¼7.2 Hz, 2H), 7.45
4.2.2. Typical procedure for the preparation of 2,5-disubstituted-7-
alkynylindoles (6). Synthesis of 5-methyl-2-phenyl-7-(phenyl-
ethynyl)-1H-indole (6a). In a 50 mL Carousel Tube Reactor (Radely
Discovery Technology) containing a magnetic stirring bar HP(t-
Bu)3BF4 (5.8 mg, 0.02 mmol) and Pd2(dba)3 (9.2 mg, 0.01 mmol)
were dissolved at room temperature with 1.0 mL of 1,4-dioxane
under nitrogen. Then, 7-bromo-5-methyl-2-phenyl-1H-indole 5a
(t, J¼7.6 Hz, 2H), 7.32 (t, J¼7.2 Hz, 1H), 7.18 (s, 1H), 6.75 (d, J¼2.4 Hz,
1H), 6.70 (s, 1H), 3.97 (t, J¼4.8 Hz, 4H), 3.14 (t, J¼4.8 Hz, 4H), 2.45 (s,
1H); 13C NMR (DMSO):
d 137.7, 137.5, 132.6, 130.6, 130.2, 129.8,
129.0, 127.6, 125.2, 116.1, 113.1, 100.5, 67.5, 52.2, 21.7. MS m/z (%):
288 (Mþ, 100); 210 (35). Anal. Calcd for C19H20N2O, C, 78.05; H,
6.89; N, 9.58; found C, 78.01; H, 6.88; N, 9.57.
(146.0 mg, 0.5 mmol), phenylacetylene (65.8
m
l, 0.6 mmol), Cs2CO3
4.2.5. Typical procedure for the one-pot alkynylation at the C7 and
arylation at the C5. Synthesis of 5-(4-methoxyphenyl)-2-phenyl-7-(4-
phenylbut-1-ynyl)-1H-indole (6m). In a 50 mL Carousel Tube Re-
actor (Radely Discovery Technology) containing a magnetic stirring
bar HP(t-Bu)3BF4 (5.8 mg, 0.02 mmol) and Pd2(dba)3 (9.2 mg,
0.01 mmol) were dissolved at room temperature with 1.0 mL of 1,4-
dioxane under nitrogen. Then, 7-bromo-5-chloro-2-phenyl-1H-in-
(325.8 mg, 1 mmol), and 1.0 mL of solvent were added. The reaction
mixture was stirred for 0.5 h at 80 ꢀC. After this time, the reaction
mixture was cooled to room temperature, diluted with EtOAc, and
washed with a saturated NaCl solution. The organic layer was
separated, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by chromatography (silica gel, n-
hexane/EtOAc 99/1) to afford 147.4 mg (96% yield) of 5-methyl-2-
phenyl-7-(phenylethynyl)-1H-indole 6a as a brown solid. Mp:
123e125 ꢀC; IR (KBr): 3427, 3123, 2905, 2334, 2374, 1605, 1454,
dole 5d (153.2 mg, 0.5 mmol), phenylacetylene (65.8 ml, 0.6 mmol),
Cs2CO3 (325.8 mg, 1 mmol), and 1.0 mL of 1,4-dioxane were added.
The reaction mixture was stirred for 1 h at 80 ꢀC. After this time,
the reaction mixture was cooled to room temperature, XPhos
(4.8 mg, 0.01 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), 4-
methoxyphenylboronic acid (76.0 mg, 0.5 mmol), Cs2CO3
(325.8 mg, 1 mmol), and 1 mL of 1,4-dioxane were added. The re-
sultant reaction mixture was stirred for 5 h at 100 ꢀC. After this
time, the reaction mixture was diluted with EtOAc, and washed
with a saturated NaCl solution. The organic layer was separated,
dried over Na2SO4, and concentrated under reduced pressure. The
residue was purified by chromatography (silica gel, n-hexane/EtOAc
80/20) to afford 143.6 mg (72% yield) of 5-(4-methoxyphenyl)-2-
phenyl-7-(4-phenylbut-1-ynyl)-1H-indole 6m as an off white
solid. Mp: 190e191 ꢀC; IR (KBr): 3227, 2932, 2814, 1626, 1559
1071 (cmꢁ1); 1H NMR (CDCl3):
d 8.55 (br s, 1H), 7.73e7.67 (m, 4H),
7.50e7.43 (m, 6H), 7.37 (t, J¼7.2 Hz, 1H), 7.30 (s, 1H), 6.81 (d,
J¼2.0 Hz, 1H), 2.56 (s, 3H); 13C NMR (CDCl3):
d 138.3, 135.9, 132.2,
131.7, 129.6, 129.2, 129.1, 128.5,128.4,127.9, 127.1, 125.3,123.4,121.5,
105.6, 100.1, 93.2, 85.8, 21.4; MS m/z (%): 307 (Mþ, 100); 244 (80).
Anal. Calcd for C23H17N, C, 89.87; H, 5.57; N, 4.56; found C, 89.95; H,
5.58; N, 4.57.
4.2.3. Typical procedure for the preparation of 2,5-disubstituted-7-
arylindoles (7). Synthesis of 5-methyl-2,7-diphenyl-1H-indole
(7a). In a 50 mL Carousel Tube Reactor (Radely Discovery Tech-
nology) containing
a magnetic stirring bar SPhos (8.2 mg,
0.02 mmol) and Pd2(dba)3 (9.2 mg, 0.01 mmol) were dissolved at
room temperature with 1.0 mL of 1,4-dioxane. Then, 7-bromo-5-
methyl-2-phenyl-1H-indole 5a (146.0 mg, 0.5 mmol), phenyl-
boronic acid (73.2 mg, 0.6 mmol), Cs2CO3 (325.8 mg, 1 mmol), and
1.0 mL of 1,4-dioxane were added. The mixture was stirred for 1 h at
100 ꢀC. After this time, the reaction mixture was cooled to room
temperature, diluted with EtOAc, and washed with a saturated NaCl
solution. The organic extract was dried over Na2SO4 and concen-
trated under reduced pressure. The residue was purified by chro-
matography (silica gel, n-hexane) to afford 141.5 mg (100% yield) of
5-methyl-2,7-diphenyl-1H-indole 7a as a brown solid. Mp: 160 ꢀC;
IR (KBr): 3422, 2922, 1680, 1605, 1267, 1021, 831, 606, 416, 405
(cmꢁ1); 1H NMR (CDCl3):
d 8.21 (br s, 1H), 7.69 (s, 1H), 7.61e7.56 (m,
5H), 7.46 (t, J¼7.6 Hz, 4H), 7.37e7.25 (m, 2H), 6.97 (d, J¼8.4 Hz, 2H),
6.81 (d, J¼2.4 Hz, 2H), 3.85 (s, 3H), 3.00 (d, J¼6.8 Hz, 2H), 2.88 (d,
J¼6.8 Hz, 2H); 13C NMR (CDCl3):
d 158.7, 140.6, 138.6, 136.9, 134.5,
133.5, 132.0, 129.2, 128.9, 128.7, 128.5, 128.2, 127.9, 126.6, 125.5,
125.3, 124.8, 118.7, 114.1, 106.7, 100.6, 93.5, 55.4, 35.0, 29.7. MS m/z
(%): 427 (Mþ, 100). Anal. Calcd for C31H25NO, C, 87.09; H, 5.89; N,
3.28; found C, 87.01; H, 5.88; N, 3.27.
4.2.6. One-pot synthesis of 5-(4-methoxyphenyl)-2,7-diphenyl-1H-
indole (7p). In a 50 mL Carousel Tube Reactor (Radely Discovery
Technology) containing a magnetic stirring bar CuI (1.5 mg,
0.005 mmol) and PdCl2(PPh3)2 (7.0 mg, 0.01 mmol) were added at
room temperature to 0.5 mL of anhydrous CH3CN under nitrogen.
Then, 2-bromo-6-iodo-4-chloroaniline 3b (166.2 mg, 0.5 mmol),
(cmꢁ1); 1H NMR (CDCl3):
d
8.49 (br s,1H), 7.75 (d, J¼7.2 Hz, 2H), 7.67
(d, J¼7.2 Hz, 2H), 7.60 (t, J¼7.6 Hz, 2H), 7.47 (q, J¼7.6 Hz, 4H), 7.35 (t,
J¼7.6 Hz, 1H), 6.87 (d, J¼2.0 Hz, 1H), 2.58 (s, 3H); 13C NMR (CDCl3):
d
134.5, 138.4, 132.9, 130.3, 130.0, 129.2, 128.2, 127.4, 126.5, 125.3,
phenylacetylene (65.8 ml, 0.6 mmol), and 0.5 mL of 1,4-dioxane
125.0, 124.9, 123.6, 119.4, 114.5, 98.9, 21.5. MS m/z (%): 283 (Mþ,
100); 281 (25), 207 (74). Anal. Calcd for C21H17N, C, 89.01; H, 6.05;
N, 4.94; found C, 89.14; H, 6.04; N, 4.96.
were added. The reaction mixture was stirred for 12 h at room
temperature. After this time PdCl2(CH3CN)2 (6.5 mg, 0.025 mmol)
was added and the reaction mixture was stirred for 12 h at room
temperature. After cooling, the reaction mixture was evaporated
under reduced pressure. Then, 1,4-dioxane (2 mL), SPhos (8.2 mg,
0.02 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), phenylboronic acid
(73.2 mg, 0.6 mmol), and Cs2CO3 (325.8 mg, 1 mmol) were added
and the resultant reaction mixture was stirred at 100 ꢀC for 1 h. The
reaction mixture was then cooled to room temperature and XPhos
(4.76 mg, 0.01 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol), 4-
methoxyphenyl boronic acid (76.0 mg, 0.5 mmol), Cs2CO3
(325.8 mg, 1 mmol), and 4 mL of 1,4-dioxane were added. The re-
action mixture was stirred at 100 ꢀC for 6 h. After this time the
reaction mixture was diluted with EtOAc and washed with a satu-
rated NaCl solution. The organic layer was separated, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by chromatography (silica gel, n-hexane/EtOAc 80/20) to
afford 136.9 mg (73% yield) of 5-(4-methoxyphenyl)-2,7-diphenyl-
4.2.4. Typical procedure for the preparation of 2,5-disubstituted-7-
aminoindoles (8). Synthesis of 4-(5-methyl-2-phenyl-1H-indol-7-yl)
morpholine (8a). In a 50 mL Carousel Tube Reactor (Radely Dis-
covery Technology) containing a magnetic stirring bar RuPhos
(23.3 mg, 0.05 mmol) and Pd2(dba)3 (22.9 mg, 0.025 mmol) were
dissolved at room temperature with 1.0 mL of 1,4-dioxane. Then, 7-
bromo-5-methyl-2-phenyl-1H-indole 5a (146.0 mg, 0.5 mmol),
morpholine (51.7 ml, 0.6 mmol), NaO-t-Bu (96.1 mg, 1 mmol), and
1.0 mL of 1,4-dioxane were added. The reaction mixture was stirred
for 1.5 h at 100 ꢀC. After this time, the reaction mixture was cooled
to room temperature, diluted with EtOAc, and washed with a sat-
urated NaCl solution. The organic layer was separated, dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by chromatography (silica gel, n-hexane/EtOAc 70/30) to

9352
S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
1H-indole 7p as a yellow solid. Mp: 160e161 ꢀC; IR (KBr): 3094,
2962, 2841, 1616, 1539 (cmꢁ1); 1H NMR (DMSO):
11.03 (br s, 1H),
1.56e1.43 (m, 4H), 0.98e0.97 (m, 3H); 13C NMR (CDCl3):
d 138.0,
d
136.2, 132.4, 129.5, 129.0, 129.0, 127.7, 126.9, 125.2, 120.4, 106.5,
100.0, 94.4, 31.3, 28.7, 22.3, 21.3, 19.8, 14.1. MS m/z (%): 301 (Mþ,
100); 246 (20), 244 (33). Anal. Calcd for C22H23N, C, 87.66; H, 7.69;
N, 4.65; found C, 87.60; H, 7.68; N, 4.64.
7.92 (d, J¼7.2 Hz, 2H), 7.76e7.71 (m, 3H), 7.62 (d, J¼8.8 Hz, 2H), 7.52
(t, J¼8.4 Hz, 2H), 7.43e7.38 (m, 3H), 7.30 (d, J¼5.2 Hz, 2H),
6.99e6.97 (s, 3H), 3.76 (s, 3H); 13C NMR (CDCl3):
d 158.7, 140.2,
139.3, 124.5, 134.4, 128.8, 132.5, 130.9, 129.3, 129.2, 128.9, 128.2,
127.9, 127.7, 126.5, 126.4, 121.9, 117.2, 114.7, 100.8, 55.6. MS m/z (%):
375 (Mþ, 100); 344 (21), 268 (48). Anal. Calcd for C27H21NO2, C,
86.37; H, 5.64; N, 3.73; found C, 86.30; H, 5.63; N, 3. 72.
4.3.7. 3-Methyl-1-(5-methyl-2-phenyl-1H-indol-7-yl)pent-1-yn-3-ol
(6c). Brown wax; IR (neat): 3441, 2931, 2858, 2231, 2207, 1580,
1451, 943, 870, 853, 800, 765, 745 (cmꢁ1); 1H NMR (CDCl3):
d 8.73
(br s, 1H), 7.67 (d, J¼8.0 Hz, 2H), 7.44 (t, J¼7.6 Hz, 2H), 7.37 (s, 1H),
7.32 (t, J¼7.6 Hz, 1H), 7.10 (s, 1H), 6.73 (d, J¼2.0 Hz, 1H), 2.41 (s, 3H),
2.14e2.05 (m, 1H), 1.76 (d, J¼6.4 Hz, 2H). 1.66 (s, 3H), 1.27 (br s, 1H),
4.3. Characterization
4.3.1. 7-Bromo-2-(4-methoxyphenyl)-5-methyl-1H-indole
1.11 (t, J¼6.4 Hz, 6H); 13C NMR (CDCl3):
d 138.4, 136.0, 132.3, 129.4,
(5b). Yellow solid; mp: 110e115 ꢀC; IR (KBr): 3401, 2911, 834, 788,
129.2, 129.0, 127.8, 126.9, 125.3, 121.2, 105.1, 100.0, 83.5, 80.2, 68.9,
52.0, 31.2, 30.6, 25.5, 24.4, 24.2. MS m/z (%): 331 (Mþ, 83); 313 (100),
298 (97). Anal. Calcd for C23H25NO, C, 83.34; H, 7.60; N, 4.23; found
C, 83.25; H, 7.59; N, 4.24.
737 (cmꢁ1); 1H NMR (CDCl3):
d
8.24 (br s, 1H), 7.59 (d, J¼8.8 Hz, 2H),
7.29 (s, 1H), 7.14 (s, 1H), 6.97 (d, J¼8.8 Hz, 2H), 6.67 (d, J¼2.4 Hz, 1H),
3.85 (s, 3H), 2.41 (s, 3H); 13C NMR (CDCl3):
154.9, 134.0, 128.9,
d
126.2, 125.9, 121.9, 120.7, 119.9, 114.6, 109.7, 99.0, 94.6, 50.6,16.5. MS
m/z (%): 316 (Mþ, 99); 315 (100), 301 (53), 299 (55). Anal. Calcd for
4.3.8. 5-Methyl-2-phenyl-7-(4-phenylbut-1-ynyl)-1H-indole
C
16H14BrNO, C, 60.78; H, 4.46; N, 5.06; found C, 60.71; H, 4.45; N,
(6d). Brown solid; mp: 108e109 ꢀC; IR (KBr): 3447, 3025, 2919,
5.06.
2364, 2394, 2334, 2215, 1602, 1450, 1074, 851, 746, 701 (cmꢁ1); 1
H
NMR (CDCl3):
d
8.19 (br s, 1H), 7.63e7.60 (m, 2H), 7.47 (t, J¼7.6 Hz,
4.3.2. 7-Bromo-2-(3-methoxyphenyl)-5-methyl-1H-indole (5c). Off
white solid; mp: 165e167 ꢀC; IR (KBr): 3333, 1609, 1290, 824, 770,
2H), 7.38e7.33 (m, 7H), 7.12 (s, 1H), 6.74 (d, J¼2.4 Hz, 1H), 3.02 (t,
J¼7.6 Hz, 2H), 2.90 (d, J¼7.6 Hz, 2H), 2.45 (s, 3H); 13C NMR (CDCl3):
735 (cmꢁ1); 1H NMR (DMSO):
d
11.20 (br s, 1H), 7.58e7.57 (m, 1H),
d 140.7, 138.1, 136.2, 132.2, 129.4, 129.0, 128.9, 128.7, 127.8, 126.7,
7.50 (d, J¼8.0 Hz, 1H), 7.33e7.27 (m, 2H), 7.13 (d, J¼1.0 Hz, 1H),
126.6, 125.5, 120.6, 106.2, 100.0, 93.3, 78.0, 66.7, 35.1, 21.9, 21.4. MS
m/z (%): 335 (Mþ, 57); 245 (20), 244 (100). Anal. Calcd for C25H21N,
C, 89.51; H, 6.31; N, 4.18; found C, 89.42; H, 6.30; N, 4.19.
6.89e6.86 (m, 2H), 3.83 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO):
d
160.1, 139.8, 134.5, 133.5, 130.9, 130.4, 130.1, 126.2, 119.6, 118.9,
113.9, 111.7, 130.9, 100.8, 55.7, 14.5. MS m/z (%): 316 (Mþ, 99); 315
(100), 301 (53), 299 (55). Anal. Calcd for C16H14BrNO, C, 60.78; H,
4.46; N, 5.06; found C, 60.86; H, 4.46; N, 5.07.
4.3.9. 1-(4-((5-Methyl-2-phenyl-1H-indol-7-yl)ethynyl)phenyl)etha-
none (6e). Brown solid; mp: 171e173 ꢀC; IR (KBr): 3322, 2912, 2847,
2204, 1670, 1600, 848, 765, 743 (cmꢁ1); 1H NMR (DMSO):
d 11.44 (br
4.3.3. 7-Bromo-5-chloro-2-phenyl-1H-indole (5d). Brown solid;
mp: 120e131 ꢀC; IR (KBr): 3852, 3734, 755, 727, 682 (cmꢁ1); 1H
s, 1H), 8.01 (d, J¼8.4 Hz, 2H), 7.92 (d, J¼7.6 Hz, 2H), 7.83 (d, J¼7.6 Hz,
2H), 7.45 (t, J¼7.6 Hz, 3H), 7.32 (t, J¼7.6 Hz, 1H), 7.18 (s, 1H), 6.86 (d,
NMR (CDCl3):
d
8.44 (br s, 1H), 7.69 (d, J¼6.8 Hz, 2H), 7.55e7.48 (m,
J¼1.2 Hz, 1H), 2.59 (s, 3H), 2.36 (s, 3H); 13C NMR (DMSO):
d 197.7,
3H), 7.42e7.35 (m, 2H), 6.83 (s, 1H); 13C NMR (CDCl3):
d
140.0, 134.1,
139.7, 136.4, 136.2, 132.3, 132.2, 129.8, 129.2, 128.9, 128.8, 128.22,
128.21, 127.6, 126.5, 122.1, 105.3, 100.2, 92.6, 90.5, 32.1, 27.2, 21.2. MS
m/z (%) N-methyl derivative: 363 (Mþ, 100); 244 (73). Anal. Calcd for
131.3, 130.6, 129.2, 128.6, 126.0, 125.4, 124.4, 119.3, 104.4, 100.6. MS
m/z (%): 316 (Mþ, 99); 306 (100), 305 (77), 191 (33), 189 (23). Anal.
Calcd for C14H9BrClN, C, 54.85; H, 4.46; N, 5.06; found C, 54.76; H,
4.45; N, 5.05.
C25H19NO, C, 85.93; H, 5.48; N, 4.01; found C, 85.84; H, 5.48; N, 4.00.
4.3.10. 7-((4-Methoxyphenyl)ethynyl)-5-methyl-2-phenyl-1H-indole
(6f). Off-white solid; mp: 147e148 ꢀC; IR (KBr): 3398, 2997, 2937,
2358, 2334, 2203, 1450, 1346, 1020, 860, 832, 765, 745 (cmꢁ1); 1H
4.3.4. 7-Bromo-5-chloro-2-(4-methoxyphenyl)-1H-indole
(5e). Yellow solid; mp: 105e107 ꢀC; IR (KBr): 3401, 2981, 864, 788,
717 (cmꢁ1); 1H NMR (DMSO):
d
11.45 (br s, 1H), 7.88 (d, J¼8.2 Hz,
2H), 7.53 (d, J¼1.6 Hz, 1H), 7.29 (d, J¼2.0 Hz, 1H), 7.00 (d, J¼8.4 Hz,
2H), 6.82 (s, 1H), 3.78 (s, 3H); 13C NMR (DMSO):
159.9, 141.8, 134.7,
NMR (CDCl3):
d
8.56 (br s, 1H), 7.69 (d, J¼7.6 Hz, 2H), 7.56 (d,
J¼8.4 Hz, 2H), 7.47e7.41 (m, 3H), 7.33 (t, J¼7.2 Hz, 1H), 7.24 (s, 1H),
d
6.93 (d, J¼8.4 Hz, 2H), 6.77 (d, J¼2.0 Hz, 1H), 3.84 (s, 3H), 2.46 (s,
131.5, 128.2, 124.6, 124.1, 123.5, 118.7, 114.6, 104.6, 99.5, 55.7. MS m/z
(%): 337 (Mþ, 100); 334 (56), 339 (67), 304 (23), 302 (10). Anal.
Calcd for C15H11BrClNO, C, 53.52; H, 3.29; N, 4.16; found C, 53.64; H,
3.28; N, 4.16.
3H); 13C NMR (CDCl3):
d 159.8, 138.2, 135.9, 132.2, 132.3, 129.6,
129.2, 129.0, 127.8, 126.9, 125.3, 121.1, 115.4, 114.1, 105.9, 100.0, 93.2,
84.3, 55.3, 21.3. MS m/z (%): 337 (Mþ, 100); 322 (32). Anal. Calcd for
C24H19NO, C, 85.43; H, 5.68; N, 4.15; found C, 85.49; H, 5.67; N, 4.14.
4.3.5. 1-(4-(7-Bromo-5-chloro-1H-indol-2-yl)phenyl)ethanone
4.3.11. 7-((7-Methoxynaphthalen-2-yl)ethynyl)-5-methyl-2-phenyl-
1H-indole (6g). Orange solid; mp: 146 ꢀC; IR (KBr): 3460, 3375,
3021, 2927, 2235, 2217, 1602, 1449, 1024, 885, 854, 763, 742 (cmꢁ1);
(5f). Yellow solid; mp: 140e143 ꢀC; IR (KBr): 3401, 2981, 864, 788,
717 (cmꢁ1); 1H NMR (DMSO):
d
11.71 (br s, 1H), 8.11 (d, J¼8.4 Hz,
2H), 8.01 (d, J¼8.4 Hz, 2H), 7.63 (d, J¼2.0 Hz, 1H), 7.39 (d, J¼1.6 Hz,
1H), 7.13 (s, 1H), 2.6 (s, 3H); 13C NMR (DMSO):
197.7, 140.3, 136.4,
1H NMR (CDCl3):
d 8.58 (br s, 1H), 8.06 (s, 1H), 7.76e7.70 (m, 4H),
d
7.62 (d, J¼8.4 Hz, 1H), 7.47e7.42 (m, 3H), 7.34 (d, J¼7.2 Hz, 1H), 7.25
135.7, 135.3, 131.0, 129.1, 126.6, 124.9, 124.8, 119.5, 105.0, 102.7, 27.2.
MS m/z (%): 349 (Mþ, 99); 347 (75), 334 (71), 331 (55). Anal. Calcd
for C16H11BrClNO, C, 55.12; H, 3.18; N, 4.02; found C, 55.10; H, 3.17;
N, 4.01.
(d, J¼7.2 Hz, 1H), 7.20e7.14 (m, 2H), 6.78 (d, J¼2.0 Hz, 1H), 3.94 (s,
3H), 2.46 (s, 3H); 13C NMR (CDCl3):
d 158.4,138.3,135.9,134.2,132.3,
131.3, 129.6, 129.4, 129.2, 129.0, 128.6, 128.4, 127.8, 127.1, 127.0,
125.3, 121.3, 119.5, 118.2, 105.9,105.8,100.1, 93.8, 85.3, 55.4, 21.3. MS
m/z (%) N-methyl derivative: 401 (Mþ, 100); 357 (20), 244 (81).
Anal. Calcd for C28H21NO, C, 86.79; H, 5.46; N, 3.61; found C, 86.88;
H, 5.47; N, 3.63.
4.3.6. 7-(Hept-1-ynyl)-5-methyl-2-phenyl-1H-indole (6b). Brown
wax; IR (neat): 3441, 2931, 2858, 2231, 2207, 1580, 1451, 943, 870,
853, 800, 765, 745 (cmꢁ1); 1H NMR (CDCl3):
d 8.45 (br s, 1H),
7.70e7.68 (m, 2H), 7.45e7.43 (m, 2H), 7.36e7.33 (m, 2H), 7.13 (s,
1H), 6.75 (s, 1H), 2.56e2.54 (m, 2H), 2.43 (s, 3H). 1.72e1.70 (m, 2H),
4.3.12. 7-(Hept-1-ynyl)-2-(4-methoxyphenyl)-5-methyl-1H-indole
(6h). Orange wax; IR (neat): 3431, 2952, 2250, 1606, 1505, 1433,

S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
9353
850, 832, 786, 750 (cmꢁ1); 1H NMR (CDCl3):
d
8.41 (br s,1H), 7.60 (d,
21.0. MS m/z (%): 443 (Mþ, 100); 381 (23). Anal. Calcd for
C31H25NO2, C, 83.95; H, 5.68; N, 3.16; found C, 83.88; H, 5.68; N,
3.15.
J¼8.8 Hz, 2H), 7.35 (s,1H), 7.13 (s, 1H), 6.97 (d, J¼8.8 Hz, 2H), 6.64 (d,
J¼2.0 Hz, 1H), 3.85 (s, 3H), 2.57 (t, J¼7.2 Hz, 2H), 2.45 (s, 3H), 1.74 (q,
J¼7.2 Hz, 2H), 1.57e1.40 (m, 4H), 1.00 (t, J¼7.2 Hz, 3H); 13C NMR
(CDCl3):
d
159.4, 138.1, 136.1, 129.3, 129.2, 126.5, 126.4, 125.2, 120.2,
4.3.18. 7-(4-Methoxyphenyl)-5-methyl-2-phenyl-1H-indole
114.5, 106.3, 98.9, 94.3, 77.0, 55.4, 31.3, 28.8, 22.4, 21.4, 19.8, 14.1. MS
m/z (%): 331 (Mþ, 100); 316 (11), 274 (18). Anal. Calcd for C24H19NO,
C, 83.34; H, 7.60; N, 4.23; found C, 83.50; H, 7.61; N, 4.22.
(7b). Brown oil; IR (neat): 3436, 3089, 1446, 1398, 1298, 843, 797,
762, 747, 689 (cmꢁ1); 1H NMR (CDCl3):
d 8.45 (br s, 1H), 7.65 (dt,
J1,2¼5.6 Hz, J2,3¼2.0 Hz 4H), 7.45 (t, J¼8.0 Hz, 3H), 7.33 (t, J¼7.4 Hz,
1H), 7.10 (d, J¼8.8 Hz, 2H), 7.05 (d, J¼1.0 Hz, 1H), 6.84 (d, J¼2.0 Hz,
4.3.13. 5-Chloro-7-(hept-1-ynyl)-2-phenyl-1H-indole
wax; IR (neat): 3441, 2931, 2859, 2231, 2207, 1580, 1451, 1390, 870,
853, 800, 765, 745 (cmꢁ1); 1H NMR (CDCl3):
8.57 (br s,1H), 7.68 (d,
(6i). Brown
1H), 3.92 (s, 3H), 2.53 (s, 3H); 13C NMR (CDCl3):
d 159.1, 138.2, 133.3,
132.5, 131.7, 130.0, 129.3, 129.0, 127.7, 127.6, 125.2, 124.9, 123.9,
119.3, 114.7, 100.0, 55.4, 21.6. MS m/z (%): 313 (Mþ, 43); 280 (33),
207 (100). Anal. Calcd for C22H19NO, C, 84.31; H, 6.11; N, 4.47; found
C, 84.18; H, 6.10; N, 4.46.
d
J¼7.6 Hz, 2H), 7.54 (d, J¼1.2 Hz, 1H), 7.48 (t, J¼7.6 Hz, 2H), 7.39 (t,
J¼7.6 Hz, 1H), 7.28e7.27 (m, 1H), 6.76 (d, J¼2.0 Hz, 1H), 2.58 (t,
J¼7.2 Hz, 2H), 1.74 (q, J¼7.6 Hz, 2H), 1.59e1.415 (m, 4H), 1.03 (s, 3H);
13C NMR (CDCl3):
d
139.2, 136.2, 131.7, 129.5, 129.1, 128.2, 125.4,
4.3.19. 1-(4-(5-Methyl-2-phenyl-1H-indol-7-yl)phenyl)ethanone
(7c). Off white solid; mp: 203e204 ꢀC; IR (KBr): 3852, 3273, 1737,
1664, 1559, 1453, 1406, 1306, 960, 542, 803, 770, 754 (cmꢁ1); 1H
125.3, 125.2, 120.0, 108.1, 100.0, 96.0, 75.7, 31.3, 28.5, 22.3, 19.7, 14.2.
MS m/z (%): 321 (Mþ, 100); 264 (28), 244 (20). Anal. Calcd for
C
4.34.
21H20ClN, C, 78.37; H, 6.26; N, 4.35; found C, 78.42; H, 6.26; N,
NMR (CDCl3):
d
8.51 (br s, 1H), 8.10 (d, J¼8.4 Hz, 2H), 7.77 (d,
J¼8.4 Hz, 2H), 7.63 (d, J¼7.2 Hz, 2H), 7.44e7.40 (m, 3H), 7.31 (t,
J¼7.4 Hz, 1H), 7.06 (s, 1H), 6.81 (d, J¼1.0 Hz, 1H), 2.64 (s, 3H), 2.50 (s,
4.3.14. 5-Chloro-2-phenyl-7-(4-phenylbut-1-ynyl)-1H-indole
(6j). Off white wax; IR (neat): 3441, 3021, 2929, 2330, 2230, 2215,
1581, 1489, 1450, 943, 855, 762, 745, 698 (cmꢁ1); 1H NMR (CDCl3):
3H); 13C NMR (CDCl3):
d 197.6, 144.3, 138.6, 136.0, 132.8, 132.2,
130.3, 130.1, 129.3, 129.0, 128.3, 127.8, 125.2, 124.0, 123.9, 120.6,
100.1, 26.6, 21.4. MS m/z (%): 325 (Mþ, 100); 382 (31), 267 (17). Anal.
Calcd for C23H19NO, C, 84.89; H, 5.89; N, 4.30; found C, 84.78; H,
5.88; N, 4.32.
d
8.21 (br s, 1H), 7.56 (d, J¼8.0 Hz, 2H), 7.50e7.44 (m, 3H), 7.39e7.32
(m, 6H), 7.25 (m, 1H), 6.70 (d, J¼2.0 Hz, 1H), 2.99 (t, J¼6.8 Hz, 2H),
2.86 (t, J¼6.8 Hz, 2H); 13C NMR (CDCl3):
d 140.5, 139.3, 136.2, 131.6,
129.5, 129.0, 128.7, 128.5, 128.3, 128.3, 126.6, 125.6, 125.4, 125.0,
120.0, 107.8, 99.9, 94.6, 34.9, 21.8. MS m/z (%): 355 (Mþ, 69); 264
(100), 207 (95). Anal. Calcd for C24H18ClN, C, 81.00; H, 5.10; N, 3.94;
found C, 81.14; H, 5.11; N, 3.95.
4.3.20. 5-Methyl-2-phenyl-7-(thiophen-3-yl)-1H-indole
white solid; mp: 130e132 ꢀC; IR (KBr): 3436, 3089, 1446, 1398,
1298, 843, 797, 762, 747, 689 (cmꢁ1); 1H NMR (CDCl3):
8.43 (br s,
(7d). Off
d
1H), 7.65e7.63 (m, 2H), 7.63e7.51 (m, 2H), 7.46e7.33 (m, 4H), 7.29
(t, J¼7.6 Hz, 1H), 7.09 (s, 1H), 6.80 (d, J¼2.4 Hz,1H), 2.48 (s, 3H); 13
C
4.3.15. 5-Chloro-7-((6-methoxynaphthalen-2-yl)ethynyl)-2-phenyl-
1H-indole (6k). Yellow solid; mp: 190e191 ꢀC; IR (KBr): 3405,
2932, 2832, 2190, 1628, 1251, 1020, 830 (cmꢁ1); 1H NMR (DMSO):
NMR (CDCl3): d 139.9, 138.3, 133.1, 132.4, 130.1, 129.9, 129.0, 127.7,
127.5, 126.8, 125.2, 123.5, 121.3, 120.0, 119.6, 100.1, 21.5. MS m/z (%):
289 (Mþ, 100); 289 (100), 207 (11). Anal. Calcd for C19H15NS, C,
78.86; H, 5.22; N, 4.84; found C, 78.85; H, 5.23; N, 4.84.
d
11.64 (br s, 1H), 8.23 (s, 1H), 7.89 (t, J¼8.4 Hz, 4H), 7.74 (dd,
J1,2¼7.2 Hz, J2,3¼1.2 Hz, 1H), 7.58 (d, J¼1.6 Hz, 1H), 7.36 (d, J¼2.0 Hz,
1H), 7.27 (d, J¼1.6 Hz, 1H), 7.21 (dd, J1,2¼6.8 Hz, J2,3¼2.4 Hz, 2H),
7.02 (d, J¼8.8 Hz, 2H), 6.80 (s, 1H), 3.88 (s, 3H), 3.80 (s, 3H); 13C
4.3.21. 2-(4-Methoxyphenyl)-5-methyl-7-phenyl-1H-indole
(7e). Brown solid; mp: 120e122 ꢀC; IR (KBr): 3456, 1606, 1507,
NMR (DMSO):
d
159.8, 158.7, 141.4, 136.2, 134.6, 131.8, 130.8, 129.9,
1299, 1246, 1185, 832, 796, 768, 701 (cmꢁ1); 1H NMR (CDCl3):
d 8.37
129.4, 128.5, 128.2, 127.5, 124.4, 124.3, 124.2, 120.2, 120.0, 117.8,
114.7, 107.7, 106.6, 99.0, 95.0, 85.4, 55.8, 55.7. MS m/z (%) N-methyl
derivative: 451 (Mþ, 1); 271 (59), 207 (100). Anal. Calcd for
(br s, 1H), 7.70 (d, J¼7.6 Hz, 2H), 7.57e7.53 (m, 4H), 7.45e7.41 (m,
2H), 7.05 (s, 1H), 6.96 (d, J¼8.8 Hz, 2H), 6.71 (d, J¼2.0 Hz, 1H), 3.84
(s, 3H), 2.52 (s, 3H); 13C NMR (CDCl3):
d 159.4, 139.5, 138.9, 132.9,
C
3.22.
28H20ClNO2, C, 76.80; H, 4.60; N, 3.20; found C, 76.71; H, 4.60; N,
130.3, 129.9, 129.2, 128.2, 127.4, 126.5, 125.3, 125.0, 123.6, 119.4,
114.5, 98.9, 55.4, 21.5. MS m/z (%): 313 (Mþ, 100); 298 (43), 281 (20).
Anal. Calcd for C22H19NO, C, 84.31; H, 6.11; N, 4.47; found C, 84.38;
H, 6.10; N, 4.46.
4.3.16. 1-(4-(5-Chloro-7-(hept-1-ynyl)-1H-indol-2-yl)phenyl)etha-
none (6l). Yellow solid; mp: 138e139 ꢀC; IR (KBr): 3372, 2932,
2230, 2215, 1667, 1603, 851, 836 (cmꢁ1); 1H NMR (DMSO):
d
11.61
4.3.22. 2,7-Bis(4-methoxyphenyl)-5-methyl-1H-indole (7f). Brown
(br s, 1H), 8.08 (d, J¼8.0 Hz, 2H), 8.00 (d, J¼8.0 Hz, 2H), 7.57 (d,
J¼1.2 Hz, 1H), 7.13 (d, J¼1.6 Hz, 1H), 7.05 (s, 1H), 2.58e2.51 (m, 5H),
1.66e1.59 (m, 2H), 1.44e1.28 (m, 4H), 0.90 (s, 3H); 13C NMR
wax; IR (neat): 3456, 1606, 1507, 1299, 1246, 1185, 832, 796, 768,
701 (cmꢁ1); 1H NMR (DMSO):
d
10.64 (br s, 1H), 7.81 (d, J¼8.8 Hz,
2H), 7.56 (d, J¼8.4 Hz, 2H), 7.21 (s, 1H), 7.04 (d, J¼8.4 Hz, 2H), 6.94
(d, J¼8.4 Hz, 2H), 6.80 (s, 1H), 6.70 (s, 1H), 3.80 (s, 3H), 3.76 (s, 3H),
(DMSO):
d 197.7, 139.5, 136.9, 136.3, 136.1, 130.1, 129.1, 126.5, 125.7,
124.4, 120.1, 109.2, 102.1, 96.7, 76.4, 31.2, 28.3, 27.2, 22.2, 19.8, 14.4.
2.36 (s, 3H); 13C NMR (DMSO):
d 159.2, 158.9, 139.5, 133.4, 131.8,
MS m/z (%): 363 (Mþ, 100); 299 (21), 273 (34). Anal. Calcd for
130.6, 130.5, 128.9, 128.8, 127.7, 125.4, 125.0, 123.6, 119.4, 114.5, 98.9,
55.4, 21.6. MS m/z (%): 343 (Mþ, 65); 328 (25), 281 (32), 207 (100).
Anal. Calcd for C23H21NO2, C, 80.44; H, 6.16; N, 4.98; found C, 80.28;
H, 6.15; N, 5.00.
C
23H22ClNO, C, 75.92; H, 6.09; N, 3.85; found C, 76.00; H, 6.08; N,
3.87.
4.3.17. 2-(3-Methoxyphenyl)-7-((4-methoxyphenyl)ethynyl)-5-p-
tolyl-1H-indole (6n). Brown solid; mp: 210e211 ꢀC; IR (KBr): 3184,
4.3.23. 5-Chloro-2,7-diphenyl-1H-indole (7g). Yellow solid; mp:
175e176 ꢀC; IR (neat): 3852, 3419, 3060, 1716, 1578, 1317, 1082, 876,
2962, 2841, 1616, 1539 (cmꢁ1); 1H NMR (CDCl3):
d 8.55 (br s, 1H),
7.78 (s, 1H), 7.66e7.57 (m, 7H), 7.27 (d, J¼7.6 Hz, 2H), 7.00 (d,
860, 761, 748 (cmꢁ1); 1H NMR (CDCl3):
d 8.52 (br s, 1H), 7.70e7.59
J¼8.4 Hz, 2H), 6.94 (d, J¼8.4 Hz, 2H), 6.77 (d, J¼2.0 Hz, 1H), 3.86 (m,
(m, 7H), 7.53e7.45 (m, 3H), 7.38 (t, J¼7.6 Hz, 1H),7.24 (d, J¼2.0 Hz,
6H), 2.42 (s, 3H); 13C NMR (CDCl3):
d
159.8,159.6,139.0,138.8,136.7,
1H), 6.85 (d, J¼2.0 Hz, 1H); 13C NMR (CDCl3):
d 139.5, 137.9, 133.1,
131.8, 130.7, 129.5, 129.1, 128.2, 128.2, 128.0, 126.6, 126.3, 125.4,
136.2, 133.8, 133.2, 129.6, 129.4, 127.1, 126.7, 124.9, 124.8, 124.7,
119.2, 115.34, 115.33, 114.5, 114.1, 106.3, 99.6, 93.3, 84.3, 55.4, 55.37,
122.3, 119.1, 100.0. MS m/z (%): 303 (Mþ, 81); 281 (26), 207 (100).

9354
S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
Anal. Calcd for C20H14ClN, C, 79.07; H, 4.65; N, 4.61; found C, 78.98;
H, 4.66; N, 4.60.
1667, 1606, 1452, 1270, 961, 856, 744 (cmꢁ1); 1H NMR (DMSO):
d
11.40 (br s, 1H), 8.10e7.96 (m, 6H), 7.81 (d, J¼8.0 Hz, 2H), 7.65 (d,
J¼1.2 Hz, 1H), 7.14e7.12 (m, 2H), 2.63 (s, 3H), 2.57 (s, 3H); 13C NMR
4.3.24. 5-Chloro-7-(4-methoxyphenyl)-2-phenyl-1H-indole
(DMSO): d 198.1, 197.7, 142.4, 140.0, 136.5, 136.2, 134.0, 131.2, 129.5,
(7h). Yellow oil; IR (neat): 3434, 1608, 1509, 1462, 1242, 1176, 1031,
129.2, 129.0, 126.8, 126.5, 125.2, 122.9, 119.8, 102.2, 27.3, 27.2. MS m/
z (%): 355 (Mþ, 5); 281 (30), 207 (100). Anal. Calcd for C24H18ClNO2,
C, 74.35; H, 4.68; N, 3.61; found C, 74.35; H, 4.69; N, 3.63.
833, 748, 690 (cmꢁ1); 1H NMR (CDCl3):
d 8.45 (br s,1H), 7.65e7.57 (m,
5H), 7.46 (t, J¼8.0 Hz, 2H), 7.38e7.35 (m, 1H), 7.18 (d, J¼1.6 Hz, 1H),
7.11 (dt, J1,2¼8.8 Hz, J2,3¼1.6 Hz, 2H), 6.82 (d, J¼2.4 Hz, 1H), 3.92 (s,
3H); 13C NMR (CDCl3):
d
159.5, 139.4, 133.2, 131.8, 130.6, 130.3, 129.2,
4.3.31. 1-(4-(5-Chloro-7-(thiophen-3-yl)-1H-indol-2-yl)phenyl)etha-
129.0, 128.1, 126.4, 126.2, 125.3, 122.1, 118.6,114.8,100.0, 55.4. MS m/z
(%): 333 (Mþ, 100); 254 (28), 207 (60). Anal. Calcd for C21H16ClNO, C,
75.56; H, 4.83; N, 4.20; found C, 75.68; H, 4.82; N, 4.22.
none (7o). Yellow solid; mp: 206e207 ꢀC; IR (KBr): 3464, 1671,
1604, 1428, 1282, 830 (cmꢁ1); 1H NMR (DMSO):
d 11.20 (br s, 1H),
8.06 (d, J¼8.4 Hz, 2H), 8.00e7.97 (m, 3H), 7.72e7.70 (m, 1H), 7.56 (d,
J¼8.0 Hz, 2H), 7.22 (d, J¼1.6 Hz, 1H), 7.07 (d, J¼1.6 Hz, 2H), 2.57 (s,
4.3.25. 1-(4-(5-Chloro-2-phenyl-1H-indol-7-yl)phenyl)ethanone
3H); 13C NMR (DMSO):
d 197.7, 139.8, 137.9, 136.3, 136.1, 134.0, 131.2,
(7i). Brown solid; mp: 180e181 ꢀC; IR (KBr): 3337, 2923, 1670,
129.0, 128.4, 127.0, 126.7, 125.1, 124.5, 122.8, 122.3, 119.0, 102.3, 21.2.
1269, 1025, 829, 764 (cmꢁ1); 1H NMR (DMSO):
d
11.24 (br s, 1H),
MS m/z (%): 351 (Mþ, 100); 273 (39), 207 (25). Anal. Calcd for
8.08 (d, J¼8.4 Hz, 2H), 7.88 (d, J¼8.0 Hz, 2H), 7.81 (d, J¼8.4 Hz, 2H),
7.61 (d, J¼1.6 Hz, 1H), 7.41 (t, J¼7.6 Hz, 2H), 7.31 (t, J¼7.2 Hz, 1H),
7.09 (d, J¼2.0 Hz, 1H), 6.94 (d, J¼1.2 Hz, 1H), 2.63 (s, 3H); 13C NMR
C20H14ClNOS, C, 68.27; H, 4.01; N, 3.98; found C, 68.38; H, 4.02; N,
3.99.
(DMSO):
d
198.0, 142.6, 141.5, 136.4, 133.7, 132.0, 131.4, 129.4, 129.2,
4.3.32. 2,7-Bis(4-methoxyphenyl)-5-p-tolyl-1H-indole (7q). Brown
129.0, 128.4, 126.7, 126.6, 124.7, 122.1, 119.5, 100.2, 27.3. MS m/z (%):
345 (Mþ, 100); 302 (24), 267 (45). Anal. Calcd for C22H16ClNO, C,
76.41; H, 4.66; N, 4.05; found C, 76.45; H, 4.67; N, 4.03.
wax; IR (neat): 3427, 3017, 2904, 2823, 1712, 1526, 1462 (cmꢁ1); 1H
NMR (DMSO):
d
10.86 (br s, 1H), 7.84 (d, J¼8.4 Hz, 2H), 7.65 (d,
J¼8.4 Hz, 3H), 7.57 (d, J¼8.0 Hz, 2H), 7.22e7.21 (m, 3H), 7.07 (d,
J¼8.4 Hz, 2H), 6.96 (d, J¼8.6 Hz, 2H), 6.84 (s, 1H), 3.82 (s, 3H), 3.77
4.3.26. 5-Chloro-2-phenyl-7-(thiophen-3-yl)-1H-indole (7j). Brown
solid; mp: 173e174 ꢀC; IR (KBr): 3449, 1450, 1304, 843, 790, 759,
(s, 3H), 2.31 (s, 3H); 13C NMR (CDCl3):
d 159.3, 159.1, 140.2, 139.22,
135.9, 134.5,132.8, 131.7, 130.9, 130.2, 129.8, 127.8, 127.0, 121.2, 116.7,
116.1, 115.0, 114.7, 114.4, 99.6, 55.6, 21.0. MS m/z (%): 419 (Mþ, 100).
Anal. Calcd for C29H25NO2, C, 83.03; H, 6.01; N, 3.34; found C, 83.10;
H, 6.02; N, 3.32.
737 (cmꢁ1); 1H NMR (CDCl3):
d
8.51 (br s, 1H), 7.64 (d, J¼7.6 Hz, 2H),
7.57 (d, J¼4.8 Hz, 3H), 7.49e7.44 (s, 3H), 7.38 (t, J¼7.4 Hz, 1H), 7.27
(d, J¼7.2 Hz, 1H), 7.28e7.26 (m, 1H), 6.81 (d, J¼1.6 Hz, 1H); 13C NMR
(CDCl3):
d 139.5, 138.6, 133.1, 131.7, 130.7, 129.1, 128.2, 127.3, 127.2,
126.3, 125.3, 122.1, 121.8, 121.5, 119.1, 100.1. MS m/z (%): 309 (Mþ,
100); 273 (13). Anal. Calcd for C18H12ClNS, C, 69.78; H, 3.90; N, 4.52;
found C, 69.89; H, 3.89; N, 4.51.
4.3.33. 5-Methyl-2-phenyl-7-(piperidin-1-yl)-1H-indole.
(8b). Brown wax; IR (neat): 3237, 2924, 2854, 1606, 1555, 916, 862,
833, 806, 771, 753 (cmꢁ1); 1H NMR (DMSO):
d 10.62 (br s, 1H), 7.87
(d, J¼7.2 Hz, 2H), 7.39 (t, J¼7.6 Hz, 2H), 7.26 (t, J¼7.2 Hz, 1H), 6.94 (s,
4.3.27. 5-Chloro-2-(4-methoxyphenyl)-7-(thiophen-3-yl)-1H-indole
1H), 6.70 (d, J¼1.6 Hz, 1H), 6.50 (s, 1H), 3.29 (s, 4H), 2.97 (t, J¼4.8 Hz,
(7k). Yellow wax; IR (neat): 3476, 1606, 1537, 1249, 1216, 1085, 832,
2H), 2.47 (t, J¼1.6 Hz, 4H), 2.30 (s, 3H); 13C NMR (CDCl3):
d 137.7,
796 (cmꢁ1); 1H NMR (DMSO):
d
10.94 (br s,1H), 7.97 (d, J¼1.6 Hz,1H),
137.5, 132.6, 130.6,130.2,129.8,129.8,129.0,127.6, 125.2, 116.1, 113.1,
100.5, 67.5, 52.2, 21.7. MS m/z (%): 314 (Mþ,100); 230 (19), 207. Anal.
Calcd for C22H22N2, C, 82.72; H, 7.64; N, 9.65; found C, 82.81; H,
7.63; N, 9.66.
7.83 (d, J¼8.4 Hz, 2H), 7.69e7.68 (m, 1H), 7.55e7.48 (m, 1H), 7.49 (s,
1H), 7.15 (d, J¼2.0 Hz, 1H), 6.97 (d, J¼8.4 Hz, 3H), 6.77 (d, J¼1.2 Hz,
1H), 3.77 (s, 3H); 13C NMR (DMSO):
d 159.7, 141.4, 138.1, 133.3, 133.0,
131.7, 128.4, 128.2, 126.9, 124.7, 124.2, 122.3, 121.0, 118.2, 114.5, 99.1,
55.7. MS m/z (%): 339 (Mþ, 100); 304 (33), 306 (12). Anal. Calcd for
4.3.34. 5-Methyl-N,2-diphenyl-1H-indol-7-amine (8c). Brown wax;
C
19H14ClNOS, C, 67.15; H, 4.15; N, 4.12; found C, 66.97; H, 4.14; N, 4.10.
IR (neat): 3441, 3372, 3046, 2915, 1588, 1503, 1448, 1292, 851, 798,
749, 691 (cmꢁ1); 1H NMR (CDCl3):
d
8.06 (br s, 1H), 7.55 (d, J¼7.2 Hz,
4.3.28. 1-(4-(5-Chloro-7-phenyl-1H-indol-2-yl)phenyl)ethanone
2H), 7.38 (t, J¼7.6 Hz, 2H), 7.30e7.22 (m, 4H), 6.87 (t, J¼7.2 Hz, 1H),
(7l). Yellow solid mp: 185e186 ꢀC; IR (KBr): 3254, 1667, 1606, 1452,
6.81 (d, J¼8.4 Hz, 3H), 6.76 (d, J¼2.0 Hz, 1H), 5.67 (br s, 1H), 2.43 (s,
1270, 961, 856, 744 (cmꢁ1); 1H NMR (DMSO):
d
11.40 (br s, 1H),
8.09e7.99 (m, 4H), 7.71e7.48 (m, 6H), 7.14e7.10 (m, 2H), 2.6 (s, 3H);
13C NMR (DMSO):
197.2, 139.3, 137.3, 135.8, 135.6, 133.7, 130.6,
3H); 13C NMR (CDCl3):
d 144.9, 138.0, 132.4, 131.0, 130.4, 130.0,
129.4, 129.0, 127.6, 125.9, 125.1, 119.7, 117.9, 116.7, 115.5, 100.0, 21.5.
d
MS m/z (%): 298 (Mþ, 100); 281 (14), 207 (22). Anal. Calcd for
128.9, 128.6, 128.5, 127.8, 127.5, 126.0, 124.7, 122.5, 118.6, 101.7, 26.7.
C21H18N2, C, 84.53; H, 6.08; N, 9.39; found C, 84.41; H, 6.09; N, 9.40.
MS m/z (%): 345 (Mþ, 63); 267 (30), 207 (100). Anal. Calcd for
C
4.32.
22H16ClNO, C, 76.41; H, 4.66; N, 4.05; found C, 76.23; H, 4.62; N,
4.3.35. 2-(3-Methoxyphenyl)-5-methyl-N-phenyl-1H-indol-7-amine
(8d). Brown wax; IR (neat): 3450, 3373, 2914, 1602, 1489, 1451,
1405, 1311, 1255, 834, 763, 740, 714, 687 (cmꢁ1); 1H NMR (CDCl3):
4.3.29. 1-(4-(5-Chloro-7-(4-methoxyphenyl)-1H-indol-2-yl) phenyl)
ethanone (7m). Yellow solid; mp: 206e207 ꢀC; IR (KBr): 3335,1670,
1604, 1510, 1422, 1079, 1031, 958, 832, 795, 758 (cmꢁ1); 1H NMR
d
8.23 (br s, 1H), 7.60 (d, J¼7.6 Hz, 2H), 7.42 (t, J¼8.0 Hz, 2H),
7.34e7.28 (m, 2H), 7.17 (t, J¼8.0 Hz, 1H), 6.87 (s, 1H), 6.80 (d,
J¼2 Hz), 6.496e42 (m, 3H), 5.74 (br s, 1H), 3.76 (s, 3H), 2.47 (s, 3H);
(DMSO):
7.09e7.02 (m, 4H), 3.82 (s, 3H), 2.57 (s, 3H); 13C NMR (DMSO):
198.1, 159.8, 139.5, 136.5, 133.5, 131.8, 130.6, 130.5, 128.9, 128.8,
d
11.28 (br s, 1H), 8.05e7.95 (m, 4H), 7.60e7.54 (m, 3H),
13C NMR (CDCl3):
d 160.9, 146.4, 138.0, 132.4, 131.0, 130.4, 130.2,
130.1, 128.9, 127.6, 125.7, 125.1, 118.0, 116.7, 108.2, 105.0, 101.4, 100.0,
55.2, 21.5. Anal. Calcd for C22H20N2O, C, 80.46; H, 6.14; N, 8.53;
found C, 80.59; H, 6.15; N, 8.52.
d
127.7, 125.4, 125.0, 123.6, 119.4, 114.5, 98.9, 55.4, 21.6. MS m/z (%):
355 (Mþ, 5); 281 (30), 207 (100). Anal. Calcd for C23H18ClNO2, C,
73.50; H, 4.83; N, 3.73; found C, 73.63; H, 4.83; N, 3.72.
4.3.36. N-(3,5-Dimethylphenyl)-5-methyl-2-phenyl-1H-indol-7-
amine (8e). Brown wax; IR (neat): 3436, 3367, 2920, 2854, 1603,
4.3.30. 1,10-(4,40-(5-Chloro-1H-indole-2,7-diyl)bis(4,1-phenylene))
diethanone (7n). Yellow solid; mp: 234e235 ꢀC; IR (KBr): 3254,
1509, 842, 826, 745 (cmꢁ1); 1H NMR (CDCl3):
d
8.17 (br s, 1H), 7.59
(d, J¼8.0 Hz, 2H), 7.41 (t, J¼8.0 Hz, 2H), 7.34e7.28 (m, 2H), 6.81 (d,

S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
9355
J¼2.0 Hz, 2H), 6.62 (s, 1H), 6.58 (s, 2H), 5.52 (br s, 1H), 2.47 (s, 3H),
2.27 (s, 6H); 13C NMR (CDCl3):
145.0, 139.2, 137.9, 132.4, 131.0,
130.4, 130.1, 129.0, 127.6, 126.2, 125.1, 121.7, 118.1, 116.6, 113.5, 100.0,
21.5. MS m/z (%): 326 (Mþ, 100); 310 (10). Anal. Calcd for C23H22N2,
C, 84.63; H, 6.79; N, 8.58; found C, 84.71; H, 6.78; N, 8.59.
(CDCl3): d 160.0, 148.7, 137.8, 133.7, 132.6, 131.0, 130.9, 130.8, 130.0,
d
129.3, 120.0, 118.8, 117.7, 115.5, 113.2, 112.5, 110.8, 100.2, 55.3, 40.2,
21.6. MS m/z (%): 342 (Mþ, 100); 296 (26). Anal. Calcd for
C23H22N2O, C, 80.67; H, 6.48; N, 8.18; found C, 80.76; H, 6.49; N,
8.20.
4.3.37. 2-(3-Methoxyphenyl)-5-methyl-7-(pyrrolidin-1-yl)-1H-in-
4.3.43. 4-(2-(3-Methoxyphenyl)-5-methyl-1H-indol-7-yl)morpho-
dole (8f). Green wax; IR (neat): 3406, 3267, 2910, 2824, 1623, 1509
line (8l). Brown solid; mp: 202e203 ꢀC; IR (KBr): 3371, 2946, 2817,
(cmꢁ1); 1H NMR (CDCl3):
d
8.35 (br s,1H), 7.35 (d, J¼8.0 Hz,1H), 7.25
1586, 959, 848, 800, 760 (cmꢁ1); 1H NMR (CDCl3):
d 8.25 (br s, 1H),
(d, J¼8.0 Hz, 1H), 7.20 (s, 1H), 6.95 (s, 1H), 6.87 (dd, J1,2¼5.6 Hz,
J2,3¼1.6 Hz, 1H), 6.73 (d, J¼2.0 Hz, 1H), 6.36 (s, 1H), 3.89 (s, 3H), 3.54
(t, J¼6.0 Hz, 4H), 2.44 (s, 3H), 2.07 (t, J¼6.0 Hz, 4H); 13C NMR
7.36 (t, J¼8.0 Hz, 1H), 7.25 (d, J¼7.4 Hz, 1H), 7.19 (s, 1H), 7.16 (s, 1H),
6.86 (dd, J1,2¼7.8 Hz, J2,3¼2.0 Hz, 1H), 6.73 (d, J¼2.0 Hz, 1H), 6.68 (s,
1H), 3.95 (t, J¼4.8 Hz, 4H), 3.88 (s, 3H), 3.13 (t, J¼4.4 Hz, 4H), 2.43 (s,
(CDCl3):
d
160.0, 136.9, 131.0, 130.5, 130.1, 130.0, 126.9, 117.8, 117.5,
3H); 13C NMR (CDCl3):
d 160.1, 137.5, 137.4, 134.0, 130.5, 130.2, 130.0,
114.3,112.5,111.0,108.2,100.3, 55.4, 50.3, 25.3, 21.8. MS m/z (%): 306
(Mþ, 100); 244 (70). Anal. Calcd for C20H22N2O, C, 78.40; H, 7.24; N,
9.14; found C, 78.32; H, 7.23; N, 9.16.
129.7, 117.7, 116.0, 113.2, 112.6, 111.3, 100.7, 67.5, 55.4, 52.2, 21.7. MS
m/z (%): 322 (Mþ, 100); 264 (51). Anal. Calcd for C20H22N2O2, C,
74.51; H, 6.88; N, 8.69; found C, 74.40; H, 6.89; N, 8.61.
4.3.38. 2-(3-Methoxyphenyl)-5-methyl-N-phenyl-1H-indol-7-amine
4.3.44. 5-Chloro-N,2-diphenyl-1H-indol-7-amine (8m). Brown wax;
(8g). Yellow oil; IR (neat): 3406, 3267, 2910, 2824, 1623, 1509
IR (neat): 3447, 3382, 3057, 2924, 2853, 1716, 1576, 1465, 907, 850,
(cmꢁ1); 1H NMR (DMSO):
d
8.18 (br s, 1H), 7.32e7.22 (m, 4H),
7.16e7.12 (m, 2H), 6.89e6.76 (m, 5H), 6.76 (s, 1H), 5.71 (br s, 1H),
3.84 (s, 3H), 2.43 (s, 3H); 13C NMR (DMSO):
160.0, 144.9, 137.8,
794, 742 (cmꢁ1); 1H NMR (CDCl3):
d
8.20 (br s, 1H), 7.54 (d, J¼7.6 Hz,
2H), 7.41e7.37 (m, 3H), 7.32e7.24 (m, 3H), 6.95e6.93 (m, 3H), 6.86
(d, J¼7.6 Hz, 2H), 6.74 (d, J¼2.0 Hz, 1H), 5.72 (br s, 1H),13C NMR
d
133.8, 130.9, 130.4, 130.0, 129.8, 129.4, 126.1, 119.7, 117.7, 117.6, 116.4,
115.7, 113.1, 110.9, 100.2, 55.3, 21.5. MS m/z (%): 328 (Mþ, 100); 285
(7). Anal. Calcd for C22H20N2O, C, 80.46; H, 6.14; N, 8.53; found C,
80.53; H, 6.13; N, 8.53.
(CDCl3): d 143.7, 139.0, 131.8, 131.3, 129.5, 129.4, 129.1, 128.1, 127.5,
125.9, 125.3, 120.7, 116.4, 115.6, 115.3, 100.0. MS m/z (%): 322 (Mþ,
100); 282 (34). Anal. Calcd for C20H15ClN2, C, 75.35; H, 4.74; N, 8.79;
found C, 75.42; H, 4.73; N, 8.78.
4.3.39. 4-(2-(3-Methoxyphenyl)-5-methyl-1H-indol-7-yl)benzoni-
4.3.45. 5-Chloro-2-(4-methoxyphenyl)-N-phenyl-1H-indol-7-amine
trile (8h). Brown solid; mp: 165e166 ꢀC; IR (KBr): 3373, 2921, 2359,
(8n). Brown wax; IR (neat): 3429, 3361, 2933, 1736, 1550, 905, 834,
2215, 1518, 1050, 819 (cmꢁ1); 1H NMR (DMSO):
d
11.02 (br s, 1H),
784, 748 (cmꢁ1); 1H NMR (CDCl3):
d
8.51 (br s, 1H), 7.64 (d, J¼7.6 Hz,
1H), 7.39 (m, 2H), 6.90e6.71 (m, 9H), 5.20 (br s,1H), 3.80 (s, 3H); 13
NMR (CDCl3): 159.6, 143.8, 139.1, 131.5, 129.5, 129.3, 127.2, 126.6,
8.45 (s, 1H), 7.55 (d, J¼6.4 Hz, 2H), 7.41e7.30 (m, 2H), 7.09 (s, 1H),
C
6.98 (d, J¼6.8 Hz, 2H), 6.85 (d, J¼8.8 Hz, 3H), 6.58 (d, J¼7.8 Hz, 1H),
d
6.11 (s, 1H), 3.80 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO):
d
160.2,
125.8, 124.5, 120.5, 116.3, 115.5, 115.2, 114.5, 98.8, 55.4. MS m/z (%):
348 (Mþ, 100); 332 (18). Anal. Calcd for C21H17ClN2O, C, 72.31; H,
4.91; N, 8.03; found C, 72.22; H, 4.91; N, 8.02.
150.0,138.3, 134.0,131.0, 130.3, 130.1, 129.1, 125.2, 120.7, 118.2, 116.4,
116.3, 1149, 113.9, 113.3, 111.3, 100.1, 98.8, 55.7, 21.7. MS m/z (%): 353
(Mþ, 100); 232 (37). Anal. Calcd for C23H19N3O, C, 78.16; H, 5.42; N,
11.89; found C, 78.27; H, 5.42; N, 11.88.
4.3.46. 4-(5-Chloro-2-(4-methoxyphenyl)-1H-indol-7-yl)morpholine
(8o). Brown solid; mp: 110e111 ꢀC; IR (KBr): 3237, 2924, 2854,
1606, 1555, 916, 862, 833, 806, 771, 753 (cmꢁ1); 1H NMR (CDCl3):
4.3.40. N-(2-Chlorophenyl)-2-(3-chlorophenyl)-5-methyl-1H-indol-
7-amine (8i). Brown wax; IR (neat): 3371, 3218, 2946, 2817, 1586,
d
8.29 (br s, 1H), 7.57 (d, J¼7.6 Hz, 2H), 7.30 (s, 1H), 6.97 (d, J¼7.2 Hz,
959, 848, 800, 760 (cmꢁ1); 1H NMR (CDCl3):
d
8.10 (br s, 1H), 7.40 (d,
2H), 6.78 (d, J¼0.2 Hz, 1H), 6.62 (d, J¼1.6 Hz, 1H), 3.94 (d, J¼4.4 Hz,
J¼1.6 Hz, 1H), 7.38 (d, J¼7.6 Hz, 3H), 7.31e7.04 (m, 3H), 6.89e6.65
4H), 3.85 (s, 3H), 3.10 (d, J¼4.4 Hz, 4H); 13C NMR (CDCl3):
d 159.7,
(m, 4H), 6.13 (br s, 1H), 3.80 (s, 3H), 2.43 (s, 3H); 13C NMR (CDCl3):
138.9, 138.1, 131.1, 129.6, 126.7, 126.0, 124.7, 115.6, 114.5, 111.9, 99.3,
67.2, 55.4, 52.1. MS m/z (%): 342 (Mþ, 100); 285 (21), 284 (43), 269
(22). Anal. Calcd for C19H19ClN2O2, C, 66.57; H, 5.59; N, 8.17; found
C, 66.48; H, 5.60; N, 8.16.
d
160.1, 141.7, 138.1, 133.6, 131.0, 130.9, 130.5, 130.0, 129.6, 127.8,
127.0, 124.4, 119.9, 119.4, 117.9, 117.7, 114.3, 113.1, 111.0, 100.3, 55.4,
24.3. MS m/z (%): 362 (Mþ, 100); 312 (46). Anal. Calcd for
C
22H19ClN2O, C, 78.82; H, 5.28; N, 7.72; found C, 78.71; H, 5.28; N,
7.71.
4.3.47. 5-(4-Methoxyphenyl)-N-methyl-N,2-diphenyl-1H-indol-7-
amine (8p). Brown solid; mp: 205e206 ꢀC; IR (KBr): 3331, 2926,
4.3.41. N-(2,4-Dimethylphenyl)-2-(3-methoxyphenyl)-5-methyl-1H-
2807, 1576 (cmꢁ1); 1H NMR (CDCl3):
d 7.97 (br s, 1H), 7.68 (s, 1H),
indol-7-amine (8j). Yellow oil; IR (neat): 3367, 3271, 2676, 2897,
7.56e7.51 (m, 4H), 7.39 (t, J¼8.0 Hz, 2H), 7.30e7.24 (m, 6H),
1526 (cmꢁ1); 1H NMR (CDCl3):
d
8.17 (br s,1H), 7.30 (t, J¼8.0 Hz,1H),
6.88e6.85 (m, 3H), 3.51 (s, 3H), 2.42 (s, 3H); 13C NMR (CDCl3):
7.17e7.14 (m, 2H), 7.10 (s, 1H), 7.06 (s, 1H), 6.91 (d, J¼8.0 Hz, 1H),
6.84 (dd, J1,2¼8.0 Hz, J2, 3¼2.4 Hz, 1H), 6.75e6.69 (m, 3H), 5.45 (br s,
1H), 3.84 (s, 3H), 2.43 (s, 3H), 2.32e2.31 (m, 6H); 13C NMR (CDCl3):
d 148.5, 139.3, 138.3, 136.2, 135.0, 132.9, 132.1, 131.9, 131.2, 129.4,
129.3, 128.9, 127.8, 127.2, 125.1, 119.0, 118.0, 115.8, 115.6, 100.6, 40.3,
21.0. MS m/z (%): 404 (Mþ, 100); 298 (41). Anal. Calcd for
d
160.0, 139.9, 137.6, 133.9, 131.6, 130.9, 130.45, 130.1, 130.0, 128.7,
C28H24N2O, C, 83.14; H, 5.98; N, 6.93; found C, 83.06; H, 5.98; N,
127.7, 127.3, 126.4, 117.7, 117.0, 115.7, 115.1, 112.9, 110.9, 100.1, 55.3,
6.92.
21.5, 17.9. MS m/z (%): 356 (Mþ, 100); 282 (36). Anal. Calcd for
C
7.82.
24H24N2O, C, 80.87; H, 6.79; N, 7.86; found C, 80.93; H, 6.79; N,
4.3.48. 2-(3-Methoxyphenyl)-5-(4-methoxyphenyl)-N-phenyl-1H-
indol-7-amine (8q). Brown solid; mp: 130e131 ꢀC; IR (KBr): 3137,
2954, 2814, 1626, 1455 (cmꢁ1); 1H NMR (CDCl3):
d 8.07 (br s, 1H),
4.3.42. 2-(3-Methoxyphenyl)-N,5-dimethyl-N-phenyl-1H-indol-7-
7.58e7.47 (m, 6H), 7.19 (d, J¼1.2 Hz, 1H), 6.98e6.93 (m, 5H), 6.87 (d,
amine (8k). Yellow solid; mp: 120e122 ꢀC; IR (KBr): 3367, 2576,
J¼8.8 Hz, 3H), 6.75 (d, J¼2.0 Hz, 1H), 5.79 (br s, 1H), 3.85e3.84 (m,
2297, 1496 (cmꢁ1); 1H NMR (CDCl3):
d
8.00 (br s, 1H), 7.37e7.25 (m,
6H); 13C NMR (CDCl3):
d 159.4, 158.6, 144.8, 138.5, 134.9, 134.3,
5H), 7.17e7.11 (m, 2H), 6.96e6.88 (m, 3H), 6.82 (d, J¼2.4 Hz, 1H),
131.5, 130.6, 129.5, 128.2, 126.6, 126.5, 126.2, 125.0, 119.7, 115.6,
6.68 (d, J¼7.6 Hz,1H), 3.89 (s, 3H), 3.51 (s, 3H), 2.53 (s, 3H); 13C NMR
115.4, 114.6, 114.4, 99.5, 55.4, 29.7. MS m/z (%): 420 (Mþ, 100); 328

9356
S. Cacchi et al. / Tetrahedron 71 (2015) 9346e9356
47, 4683; (b) Lo, W. F.; Kaiser, H. M.; Spannenberg, A.; Beller, M.; Tse, M. K.
Tetrahedron Lett. 2007, 48, 371; (c) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem. 2007, 72,
9329; (d) Simoneau, A. C.; Strohl, A. L.; Ganem, B. Tetrahedron Lett. 2007, 48,
1809; (e) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J. Org. Chem.
2008, 73, 4160; (f) Nakamura, I.; Nemoto, T.; Shiraiwa, N.; Terada, M. Org. Lett.
2009, 11, 1055; (g) Chen, Z.; Zheng, D.; Wu, J. Org. Lett. 2011, 13, 848; (h) Ali, M.
A.; Punniyamurthy, T. Synlett 2011, 623; (i) Palmieri, A.; Gabrielli, S.; Lanari, D.;
Vaccaro, L.; Ballini, R. Adv. Synth. Catal. 2011, 353, 1425.
(31). Anal. Calcd for C28H24N2O2, C, 79.98; H, 5.75; N, 6.66; found C,
79.08; H, 5.76; N, 6.62.
Acknowledgements
We gratefully acknowledge La Sapienza, University of Rome, for
5. Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 3457.
6. Sonogashira, K. In Organopalladium Chemistry for Organic Synthesis; Negishi, E.,
Ed.; Wiley-Interscience: New York, 2002; Vol. 1, pp 493e529.
7. Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A. Tetrahedron Lett. 1985,
26, 5963.
8. Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.
9. Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
10. Diver, S. T. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
Wiley: New York, 1995; Vol. 7, pp 5014e5016.
financial support.
Supplementary data
Supplementary data (Copies of 1H and 13C NMR spectra for all
products) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2015.10.002.
11. Rathikrishnan, K. R.; Indirapriyadharshini, V. K.; Ramakrishna, R. M. Tetahedron
2011, 67, 4025.
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