Mild and efficient cyclization reaction of 2-ethynylaniline derivatives to indoles in aqueous medium

Article abstract of DOI:10.1016/j.tet.2005.08.098

Results of the optimized cyclization reaction of 2-ethynylaniline derivatives to indoles catalyzed by copper(II) salts are described. The reactions can be carried out in a mixture of H₂O and MeOH in the presence of 1-ethylpiperidine at room tem

Full text of DOI:10.1016/j.tet.2005.08.098

Tetrahedron 61 (2005) 10958–10964
Mild and efficient cyclization reaction of 2-ethynylaniline
derivatives to indoles in aqueous medium
a,
a
*
Shin Itoh and Takao Sakamoto
a,b
Kou Hiroya,
a
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Tohoku University 21st Century COE Program ‘Comprehensive Research and Education Center for Planning of Drug Development and
Clinical Evaluation’, Sendai 980-8578, Japan
b
Received 10 August 2005; revised 26 August 2005; accepted 26 August 2005
Available online 19 September 2005
Abstract—Results of the optimized cyclization reaction of 2-ethynylaniline derivatives to indoles catalyzed by copper(II) salts are
described. The reactions can be carried out in a mixture of H O and MeOH in the presence of 1-ethylpiperidine at room temperature. These
2
conditions can be applied to a bulky substrate, which is difficult to be cyclized efficiently by existing reaction conditions. Furthermore, this
reaction condition was applied to a catalyst recycling reaction system.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
many applications together with polymer-supported
reactions have also been established.
1
2
Heterocyclic compounds, particularly indoles, occur widely
in nature as partial structures of alkaloids and have unique
Recent interest in indole synthesis from 2-ethynylaniline
derivatives has focused on versatile applicability, con-
venient reagents and conditions, and tandem or sequential
reactions. For such purposes, iodine-promoted cyclization to
1
biological activities. Among the many methods for indole
ring synthesis, the ring closing reactions of 2-ethynylaniline
derivatives are some of the most efficient because methods
for synthesizing a variety of functionalized starting
1
3
yield 3-iodoindoles , sequential cyclization-C3 function-
alization reactions catalyzed by palladium complexes
5
b,11
2
or
materials have already been established (Scheme 1).
Thus far, many kinds of reagents and reaction conditions
have been reported for indole syntheses from 2-ethynyl-
1
4
15
gold(III) salt, and carbazoles synthesis were established.
We have previously developed both copper(II) salt-
catalyzed synthesis of indoles from 2-ethynylaniline
2
c,3
aniline derivatives, including basic conditions,
4
early
transition metal-catalyzed reactions, gold(III), cop-
7
a,c
5
derivatives
and palladium-complex-catalyzed sequential
2
b,6,10a
7
copper(II) salt-catalyzed reactions, and
coupling-cyclization reactions between methyl propiolate
and 2-iodoaniline derivatives, with the latter’s application to
duocarmycin SA synthesis.
per(I),
8
ammonium fluoride-mediated reactions. The most fre-
quently used reagents or catalysts for these ring-closing
1
0d
2
d,3a,5b,9,10,11
reactions are the palladium complexes,
and
Copper(II) salt-catalyzed reactions can be applied to a
variety of 2-ethynylaniline derivatives, including ones with
the following features: (1) electron-donating or electron-
withdrawing groups on the aromatic ring, (2) an alkyl, aryl,
hydroxymethyl, or even methoxycarbonyl group on the
acetylene terminal, and (3) sulfonamide, non-substituted
aniline derivatives and carbamates (depending on the
structure of the substrate). However, problems with
efficiency (low solubility of the catalysts in organic
media) and high temperature requirements (O70 8C) must
be solved for copper(II) salt-catalyzed reactions to be
useful. Herein, we describe solutions to these problems and
improved procedures for copper(II) salt-catalyzed cycliza-
tion reactions of 2-ethynylaniline derivatives.
Scheme 1. Cyclization reaction of 2-ethynylaniline derivatives to indole
derivatives.
Keywords: Indole; Copper(II) salt; 2-Ethynylaniline; Cyclization reaction.
*
Corresponding author. Tel.: C81 795 6867; fax: C81 795 6864;
e-mail: hiroya@mail.tains.tohoku.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.08.098

K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964
10959
2
. Results and discussion
Table 2. Cu(OCOCF
presence of various amines
3
)
2
$xH
2
O-catalyzed cyclization reaction of 1a in the
2
.1. Improvement of the reaction conditions
Copper(II) salt-catalyzed indole formation reactions appear
as suspensions due to low solubility of the salts in organic
solvents such as 1,2-dichloroethane. We have previously
described how the ionic character of the copper–oxygen
bond in copper(II) sulfonate is required for effective catalyst
of the cyclization, which makes suspension in an organic
Entry
Amine (2.0 equiv)
Yield of 2a (%)
a
1
2
3
4
5
1-Ethylpiperidine
Triethylamine
N,N-diisopropylethylamine
N,N-dimethylaniline
Pyridine
14 (85)
10 (88)
7a
a
solvent unavoidable. However, the bulky counter-anion in
copper(II) carbonate (e.g., stearic acid) does not improve
solubility or catalytic activity. Therefore, we changed the
a
17 (83)
No reaction
No reaction
1
6
solvent to H O. The results are summarized in Table 1. It
2
a
The numbers in parentheses are the yields of recovered 1a.
was known that sulfonamides possess the highest reactivity
among 2-ethynylaniline derivatives, so the mesylamide 1a
was selected as the substrate for establishing the new
reaction conditions. Most of the copper(II) salts tested
dissolved into H O except for Cu(OBz) , but the reaction
aliphatic amine slightly accelerated the reaction, but the
yield of 2a was less than the amount of added catalyst and
more than 80% of 1a was recovered (Table 2, entries 1–3).
Addition of a tertiary aromatic amine or pyridine did not
accelerate the reaction (Table 2, entries 4 and 5). The
addition of secondary amines (piperidine or N,N-diiso-
propylamine) or primary amines (butylamine, aniline, or
ethylenediamine) also did not promote the reaction, and the
starting material 1a was completely recovered (data not
shown). Since the reactions in H O appear as a suspension,
2
we speculated that the reason for the reactivity difference
between H O and 1,2-dichloroethane might be the low
solubility of 1a in H O. Therefore, we attempted the
2
reaction in a mixed solvent system, with and without
1-ethylpiperidine (Table 3).
2
2
medium was again a suspension because of the low
solubility of 1a in H O. The copper(II) salts that catalyze
2
the reactions in organic solvent [Cu(OAc) , Cu(OTf) ,
2
2
Cu(OBz) , and Cu(OCHO) $xH O] did not provide satis-
2
2
2
factory results (Table 1, entries 1–4). Surprisingly, only
Cu(OCOCF ) $xH O catalyzed the reaction, even though it
3
2
2
forms a suspension in the reaction mixture (Table 1, entry
). Why only this copper(II) salt works is not yet clear.
However, it is apparent that CF COOH is not a catalyst for
5
2
3
this reaction (Table 1, entry 6). We selected
Cu(OCOCF ) $xH O as the catalyst for further improve-
ment of the reaction conditions.
3
2
2
We wanted to dissolve both the catalyst and the substrate, so
we chose an alcohol as the second solvent. Surprisingly, we
discovered that the efficiency of the reaction is closely
related to the carbon number of employed alcohol: as the
carbon number of the alcohol solvent increased, the yield
decreased (Table 3, entries 1–3). It is apparent from the
above results that the reactivity is controlled by the balance
of the solubility of the catalyst and the substrate. However,
even with the second alcohol solvent, the reaction did not
proceed at room temperature (Table 3, entry 4). The effect
of 1-ethylpiperidine was remarkable, and the amount of
catalyst could be reduced from 20 to 5 mol% (Table 3,
2
Table 1. Copper(II) salt-catalyzed cyclization reactions of 1a in H O
Entry
Catalyst
Time (h)
Yield of 2a (%)
1
2
3
4
5
6
Cu(OAc)
2
23
24
24
24
24
23
Trace
7 (76)
18 (66)
22 (75)
96
No reaction
a
Cu(OTf)
Cu(OBz)
2
a
2
a
Cu(OCHO)
Cu(OCOCF
CF COOH
2
$xH
)
2
O
3
2
$xH
2
O
entries 6 and 7). Note that less expensive Cu(OAc) , which
2
did not show catalytic activities in H O alone (Table 1, entry
2
3
a
1), can be used as the catalyst under optimized reaction
The numbers in parentheses are the yields of recovered 1a.
conditions (Table 3, entry 8). While the reaction could be
promoted with 1-ethylpiperidine in the absence of a
copper(II) salt, the low yield can be disregarded (Table 3,
entry 5).
High temperature is essential for the cyclization reactions of
2
-ehtynylaniline derivatives catalyzed by copper(II) salts
and the substrates can be recovered perfectly at room
temperature. However, we have previously reported that the
rate of copper(II) salt-catalyzed cyclization reactions is
accelerated in the presence of 1-ethylpiperidine and realized
the reaction at room temperature (room temperature for 72 h
2.2. Application to various kinds of substrates
Having established the cyclization reaction in aqueous
solvent at room temperature, we applied it to other
substrates. To avoid too long reaction time, we used same
reaction condition shown in Table 3 entry 6 [20 mol% of
Cu(OCOCF ) $H O] and the results are summarized in
7
a
with 2.0 equiv of 1-ethylpiperidine, 76% yield). We now
apply the Cu(OCOCF ) $xH O-catalyzed cyclization
reaction of 1a with various amines in H O. The results are
3
2
2
2
summarized in Table 2.
3
2
2
Table 4.
The rate acceleration effect of the amine in H O was less
2
than in 1,2-dichloroethane. The addition of a tertiary
For the substituents at the alkyne terminal, this condition

10960
K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964
Table 3. Copper(II) salt-catalyzed cyclization reaction of 1a in a mixed solvent system
Entry
Catalyst (mol%)
Amine (2.0 equiv)
Solvent
Temperature
Time (h)
Yield (%)
t
a
1
2
3
4
5
6
7
8
Cu(OCOCF
Cu(OCOCF
Cu(OCOCF
Cu(OCOCF
—
3
3
3
3
)
)
)
)
2
2
2
2
$xH
$xH
$xH
$xH
2
2
2
2
O (20)
O (20)
O (20)
O (20)
—
—
—
—
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O– BuOH (1/1)
O–EtOH (1/1)
O–MeOH (1/1)
O–MeOH (1/1)
O–MeOH (1/1)
O–MeOH (1/1)
O–MeOH (1/1)
O–MeOH (1/1)
w90 8C
w90 8C
w90 8C
Room temperature
Room temperature
Room temperature
Room temperature
Room temperature
24
24
21
23
24
24
24
17
10 (86)
a
85 (7)
93
No reaction
a
14 (85)
1-Ethylpiperidine
1-Ethylpiperidine
1-Ethylpiperidine
1-Ethylpiperidine
Cu(OCOCF
Cu(OCOCF
3
)
)
2
$xH
$xH
2
O (20)
O (5)
92
95
96
3
2
2
2
Cu(OAc) (10)
a
The numbers in parentheses are the yields of recovered 1a.
Table 4. Applications of the copper(II) salt-catalyzed cyclization reaction in aqueous solvent
Entry
Substrate
Time (h)
Yield of 2 and 6 (%)
2b:98
2i:91 (R ZH)
2d:90
2e:85
2f:99
2g:99
2h:99
1
R
2
3
Number
X
R
R
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
3
NMs
NMs
NMs
NMs
NMs
NMs
NMs
NH
Bu
TMS
H
H
H
NO
Br
Me
H
H
H
H
H
H
H
H
H
OMe
H
H
13
14
10
14
72
27
21
24
24
11
2
t
Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
No reaction
No reaction
4
5
NBoc
O
a
10
H
H
6:87 (7)
a
The number in parentheses is the yield of recovered 5.
can be applied not only to the alkyl group (Table 4, entry 1)
and hydrogen (Table 4, entry 2; TMS group eliminated
before cyclization reaction), but also in the presence of a
from 2-ethynylaniline derivatives with a quaternary center
0
7a
at the C-3 position. Substituents on the aromatic ring
generally did not affect the efficiency of the reaction
(Table 4, entries 4–7). Disappointingly, this reaction has the
limitation about the substituents on the nitrogen atom: the
t
bulky Bu group (Table 4, entry 3). To our knowledge, only
5
b
one report had been published for a high yield of an indole
Figure 1. The general form of the catalyst recycling reaction.

K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964
Table 5. The catalyst recycling reaction for 2-ethynylaniline derivatives
10961
Entry
Substrate
Yield of 2 (%)
1
R
2
Number
R
First cycle
Second cycle
Third cycle
1
2
3
1a
1i
1j
Ms
Ms
Ts
Ph
H
CH OH
2
99
73
96
94
84
99
97
89
98
1
are given from TMS (0 ppm) as the internal standard for H
sulfonamides could be cyclized, but not the aniline
derivative or the carbamate (Table 4, entries 8 and 9).
However, this reaction condition could be applied to the
synthesis of the benzofuran derivative 6 (Table 4, entry 10).
1
NMR and CDCl (77.0 ppm) as the internal standard for
3
3
1
3
C NMR. Standard and high-resolution mass spectra were
measured on JEOL JMS-DX303 and MS-AX500 instru-
ments, respectively. IR spectra were recorded on a
Shimadzu FTIR-8400.
2
.3. Catalyst recycling reaction
This reaction, in which the copper(II) salts dissolve into
H O while the indole products dissolve into the organic
4.2. General procedure for the selected entries for
Tables 1, 3, and 4.
2
solvent, allows constructions of a catalyst recycling
reaction, depicted in Figure 1.
Copper(II) salt was added to a suspension of 2-ethynyl-
aniline derivatives 1a–h or 2-(2-phenylethynyl)phenol 5 in
H O or in mixed solution of H O and alcohol, then the
mixture was stirred under reflux or at room temperature for
the reaction time listed in Tables 1, 3, and 4. The reaction
mixture was extracted with AcOEt (three times). The
combined organic solution was washed with saturated
The reaction was started by adding the 2-ethynylaniline
derivatives to a solution of Cu(OCOCF ) $xH O (20 mol%)
2
2
3
2
2
and 1-ethylpiperidine (2.0 equiv) in H O–MeOH (1/1).
2
After being stirred at room temperature, the mixture was
extracted with Et O. The desired indole derivatives were
2
extracted in essentially pure form from the Et O phase, and
2
aqueous NaCl solution, dried over anhydrous MgSO , and
4
the catalyst-containing H O phase could be recycled after
2
the solvent was evaporated under reduced pressure.
adding more 1-ethylpiperidine (1.0 equiv) and MeOH. The
results of three cycles for three 2-ethynylaniline derivatives
are listed in Table 5. The catalytic activity of
Cu(OCOCF ) $xH O did not change over the three cycles.
4.2.1. 1-Methylsulfonyl-2-phenylindole (2a) (Table 3,
entry 7). A suspension of 1a (89.6 mg, 0.33 mmol),
Cu(OCOCF ) $xH O (4.9 mg, 0.017 mmol) and 1-ethyl-
3
2
2
3 2
2
piperidine (0.090 mL, 0.65 mmol) in mixed solution of H O
2
(5 mL) and MeOH (5 mL) was stirred for 24 h at room
temperature. The residue was chromatographed on silica gel
3
. Conclusion
7
a,8
[
AcOEt–hexane (1/5)] to afford 2a
(85.0 mg, 95%) as a
colorless solid; mp 115–117 8C (colorless needles from
We improved the cyclization reaction of 2-ethynylaniline
derivatives to indoles. While the original conditions require
heating, the optimized reaction can be carried out at room
7
AcOEt–hexane, lit. mp 115–117 8C, lit. mp 115–116 8C);
a
8
K1 1
IR (film, cm ) 1367, 1171; H NMR (400 MHz, CDCl ) d
3
temperature in a mixture of H O and MeOH in the presence
2
2.73 (3H, s), 6.70 (1H, s), 7.34 (1H, td, JZ7.4, 1.5 Hz), 7.37
(1H, td, JZ7.4, 1.5 Hz), 7.40–7.46 (3H, m), 7.52–7.61 (3H,
of 1-ethylpiperidine. Further, the reaction does not require
an argon atmosphere and can be done as open-flask reaction.
This reaction condition was applied to a catalyst recycling
reaction system. Although the substrates for this reaction
condition are limited to sulfonamides, the reaction
conditions will be useful for versatile synthesis of indole
derivatives, especially in large-scale reactions.
1
3
m), 8.12 (1H, d, JZ7.8 Hz); C NMR (100 MHz, CDCl ) d
3
39.5, 113.0, 115.7, 120.9, 124.5, 125.0, 127.6, 128.8, 130.0,
130.2, 131.9, 137.9, 141.8; MS m/z 271 (M , 51), 190
C
(100), 165 (52); HRMS calcd for C H NO S 271.0667,
2
1
5
13
found 271.0673.
4
.2.2. 1-Methylsulfonyl-2-butylindole (2b) (Table 4,
entry 1). A suspension of 1b (102.5 mg, 0.41 mmol),
Cu(OCOCF ) $xH O (21.2 mg, 0.073 mmol), and 1-ethyl-
piperidine (0.113 mL, 0.82 mmol) in mixed solution of H O
4. Experimental
3
2
2
2
4
.1. General
(5.5 mL) and MeOH (5.5 mL) was stirred for 13 h at room
temperature. The residue was chromatographed on silica gel
7
a,8
All melting points were determined with a Yazawa Micro
Melting Point BY-2 and are uncorrected. H NMR spectra
[AcOEt–hexane (1/5)] to afford 2b (100.8 mg, 98%) as a
colorless solid; mp 80–81 8C (colorless needles from
1
1
400 MHz) and C NMR spectra (100 MHz) were recorded
3
7a
AcOEt–hexane, lit. mp 80–81 8C, lit. mp 81–82 8C); IR
8
(
on a JEOL JMN AL-400 spectrometer. Chemical shifts (d)
K1
(film, cm ) 1366, 1171; H NMR (400 MHz, CDCl ) d
1
3

10962
K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964
0
.97 (3H, t, JZ7.5 Hz), 1.46 (2H, sex, JZ7.5 Hz), 1.75
72 h at room temperature. The residue was chromato-
graphed on silica gel [AcOEt–hexane (1/5)] to afford 2f
7
a
(
2H, sex, JZ7.5 Hz), 2.95 (2H, t, JZ7.5 Hz), 3.00 (3H, s),
6
2
.45 (1H, s), 7.21–7.29 (2H, m), 7.48 (1H, dd, JZ7.7,
.7 Hz), 7.99 (1H, dd, JZ7.9, 1.9 Hz); C NMR (100 MHz,
(103.4 mg, 99%) as a colorless solid; mp 186–187 8C
(colorless needles from AcOEt–hexane, lit mp 186–
1
3
7a
K1
187 8C); IR (film, cm ) 1361, 1177; H NMR (400 MHz,
1
CDCl ) d 14.0, 22.5, 28.6, 31.0, 40.3, 108.3, 114.0, 120.1,
3
C
23.5, 123.8, 129.7, 136.7, 142.3; MS m/z 251 (M , 37),
1
2
2
CDCl ) d 2.73 (3H, s), 6.62 (1H, s), 7.40–7.47 (4H, m),
3
09 (40), 130 (100); HRMS calcd for C H NO S
1
7.51–7.56 (2H, m), 7.71 (1H, d, JZ1.7 Hz), 7.98 (1H, d, JZ
3
17
2
1
8.8 Hz); C NMR (100 MHz, CDCl ) d 39.9, 111.8, 117.1,
3
51.0980, found 251.1012.
3
1
136.5, 143.0; MS m/z 351 (M C2, 66), 349 (M , 65), 272
17.8, 123.5, 127.67, 127.73, 129.1, 130.1, 131.2, 131.8,
C
C
4
.2.3. 1-Methylsulfonylindole (2i) (Table 4, entry 2). A
suspension of 1c (33.5 mg, 0.13 mmol), Cu(OCOCF ) $xH O
(99), 270 (100); HRMS calcd for C15H12BrNO S 348.8772,
2
found 348.9763.
3
2
2
(
0
(
8.0 mg, 0.028 mmol), and 1-ethylpiperidine (0.034 mL,
.25 mmol) in mixed solution of H O (1.5 mL) and MeOH
1.5 mL) was stirred for 14 h at room temperature. The
2
4.2.7. 1-Methylsulfonyl-5-methyl-2-phenylindole (2g)
(Table 4, entry 6). A suspension of 1g (69.0 mg,
0.24 mmol), Cu(OCOCF ) $xH O (12.5 mg, 0.043 mmol),
residue was chromatographed on silica gel [AcOEt–hexane
7
a,8
(1/5)] to afford 2i
(neat, cm ) 1361, 1170; H NMR (400 MHz, CDCl ) d
(22.2 mg, 91%) as a colorless oil; IR
3
2
2
K1
1
and 1-ethylpiperidine (0.067 mL, 0.49 mmol) in mixed
solution of H O (3 mL) and MeOH (3 mL) was stirred for
3
3
7
7
.06 (3H, s), 6.69 (1H, d, JZ3.7 Hz), 7.28 (1H, d, JZ
2
.7 Hz), 7.35 (1H, t, JZ7.7 Hz), 7.42 (1H, d, JZ3.7 Hz),
27 h at room temperature. The residue was chromato-
graphed on silica gel [AcOEt–hexane (1/3)] to afford 2g
1
3
7a
.61 (1H, d, JZ7.7 Hz), 7.90 (1H, d, JZ7.7 Hz); C NMR
(
1
(
100 MHz, CDCl ) d 40.6, 108.7, 112.8, 121.5, 123.4,
(68.4 mg, 99%) as a colorless solid; mp 137–138 8C
(colorless needles from AcOEt–hexane, lit. mp 137–
3
C
24.7, 125.9, 130.5, 134.7; MS m/z 195 (M , 55), 116
7a
K1
138 8C); IR (film, cm ) 1366, 1173; H NMR (400 MHz,
1
100); HRMS calcd for C H NO S 195.0354, found
9
9
2
1
95.0359.
CDCl ) d 2.47 (3H, s), 2.70 (3H, s), 6.65 (1H, s), 7.19 (1H,
3
d, JZ8.5 Hz), 7.37–7.45 (4H, m), 7.53–7.57 (2H, m), 7.98
1
3
4
.2.4. 1-Methylsulfonyl-2-(1,1-dimethylethyl)indole (2d)
(1H, d, JZ8.5 Hz); C NMR (100 MHz, CDCl ) d 21.3,
3
(
0
Table 4, entry 3). A suspension of 1d (52.0 mg,
.21 mmol), Cu(OCOCF ) $xH O (12.1 mg, 0.042 mmol),
and 1-ethylpiperidine (0.057 mL, 0.41 mmol) in mixed
39.0, 113.0, 115.5, 120.9, 126.4, 127.6, 128.7, 130.0, 130.5,
132.0, 134.2, 136.2, 142.1; MS m/z 285 (M , 48), 206
(100). Anal. Calcd for C16H15NO S: C, 67.34; H, 5.30; N,
2
C
3
2
2
solution of H O (2.5 mL) and MeOH (2.5 mL) was stirred
2
4.91. Found: C, 67.35; H, 5.43; N, 4.52.
for 10 h at room temperature. The residue was chromato-
graphed on silica gel [AcOEt–hexane (1/5)] to afford 2d
5
b,7a
4.2.8. 1-Methylsulfonyl-6-methoxy-2-phenylindole (2h)
(Table 4, entry 7). A suspension of 1h (71.7 mg,
0.24 mmol), Cu(OCOCF ) $xH O (13.8 mg, 0.048 mmol),
K1
46.9 mg, 90%) as a colorless oil; IR (neat, cm ) 1371,
(
1
1
176; H NMR (400 MHz, CDCl ) d 1.56 (9H, s), 2.93 (3H,
3
3 2
2
s), 6.61 (1H, s), 7.24 (1H, td, JZ7.4, 1.9 Hz), 7.28 (1H, td,
JZ7.4, 1.9 Hz), 7.48 (1H, dd, JZ7.4, 1.9 Hz), 8.07 (1H, br
and 1-ethylpiperidine (0.066 mL, 0.48 mmol) in mixed
solution of H O (3 mL) and MeOH (3 mL) was stirred for
21 h at room temperature. The residue was chromato-
2
1
3
d, JZ7.4 Hz); C NMR (100 MHz, CDCl ) d 30.9, 34.8,
3
7
a
3
MS m/z 251 (M , 42), 236 (51), 172 (100); HRMS calcd for
9.5, 110.1, 115.3, 120.5, 123.8, 124.5, 129.4, 138.5, 151.8;
graphed on silica gel [AcOEt–hexane (1/5)] to afford 2h
(70.7 mg, 99%) as a colorless solid; mp 134–135 8C
(colorless prisms from AcOEt–hexane, lit. mp 134–
C
7
a
C H NO S 251.0980, found 251.0966.
1
3
17
2
K1
1
1
(400 MHz, CDCl ) d 2.68 (3H, s), 3.88 (3H, s), 6.62 (1H, s),
35 8C); IR (film, cm ) 1612, 1367, 1180; H NMR
4
(
0
.2.5. 1-Methylsulfonyl-5-nitro-2-phenylindole (2e)
Table 4, entry 4). A suspension of 1e (56.7 mg,
.18 mmol), Cu(OCOCF ) $xH O (9.1 mg, 0.031 mmol),
3
6.96 (1H, dd, JZ8.5, 2.2 Hz), 7.36–7.40 (3H, m), 7.44 (1H,
d, JZ8.5 Hz), 7.50–7.55 (2H, m), 7.67 (1H, d, JZ2.2 Hz);
3
2
2
1
3
and 1-ethylpiperidine (0.049 mL, 0.35 mmol) in mixed
solution of H O (2.5 mL) and MeOH (2.5 mL) was stirred
C NMR (100 MHz, CDCl ) d 39.0, 55.7, 110.1, 113.0,
113.5, 121.3, 123.9, 127.5, 128.4, 129.8, 132.0, 139.1,
140.6, 158.0; MS m/z 301 (M , 41), 222 (100). Anal. Calcd
3
2
C
for 14 h at room temperature. The residue was chromato-
graphed on silica gel [AcOEt–hexane (1/5)] to afford 2e
for C H NO S: C, 63.77; H, 5.02; N, 4.65. Found: C,
1
6
15
3
(
yellow needles from acetone–hexane); IR (film, cm
48.4 mg, 85%) as a pale yellow solid; mp 187–188 8C (pale
K1
)
518, 1344, 1165; H NMR (400 MHz, CDCl ) d 2.90 (3H,
63.73; H, 4.95; N, 4.60.
1
1
s), 6.81 (1H, s), 7.44–7.50 (3H, m), 7.53–7.58 (2H, m), 7.25
4.2.9. 2-Phenylbenzofuran (6) (Table 4, entry 10). A
suspension of 5 (94.7 mg, 0.49 mmol), Cu(OCOCF ) $xH O
(24.9 mg, 0.086 mmol), and 1-ethylpiperidine (0.135 mL,
3
3
2
2
1
3
(
2H, d, JZ1.5 Hz), 8.51 (1H, t, JZ1.5 Hz); C NMR
(
100 MHz, CDCl ) d 41.4, 112.2, 115.7, 116.9, 119.9,
0.98 mmol) in mixed solution of H O (5 mL) and MeOH
2
3
1
MS m/z 316 (M , 91), 237 (100); HRMS calcd for
C H N O S 316.0518, found 316.0500.
15 12 2 4
27.9, 129.62, 129.63, 130.3, 130.6, 140.4, 144.3, 144.7;
(5 mL) was stirred for 11 h at room temperature. The
residue was chromatographed on silica gel [AcOEt–hexane
C
1
7
(1/20)] to afford 6 (82.4 mg, 87%) as a colorless solid.
From the later fraction, 5 (7.0 mg, 7%) was recovered; 6; mp
1
7
4
(
0
.2.6. 5-Bromo-1-methylsulfonyl-2-phenylindole (2f)
Table 4, entry 5). A suspension of 1f (104.0 mg,
.30 mmol), Cu(OCOCF ) $xH O (17.0 mg, 0.059 mmol),
117–118 8C (colorless scales from hexane, lit. mp 118–
1
120 8C); IR (film, cm ) 1215, 748; H NMR (400 MHz,
K1
CDCl ) d 7.03 (1H, d, JZ0.7 Hz), 7.22 (1H, td, JZ7.5,
3
2
2
3
and 1-ethylpiperidine (0.082 mL, 0.59 mmol) in mixed
solution of H O (4 mL) and MeOH (4 mL) was stirred for
1.3 Hz), 7.28 (1H, td, JZ7.5, 1.3 Hz), 7.35 (1H, t, JZ
7.5 Hz), 7.45 (2H, d, JZ7.5 Hz), 7.52 (1H, d, JZ7.5 Hz),
2

K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964
10963
1
3
7
.58 (1H, d, JZ7.5 Hz), 7.86 (2H, d, JZ7.5 Hz); C NMR
Substrate and reagents First cycle
Second cycle
Third cycle
(
1
100 MHz, CDCl ) d 101.3, 111.1, 120.8, 122.9, 124.2,
24.9, 128.5, 128.7, 129.1, 130.4, 154.8, 155.8; MS m/z 194
3
Yield
106.8 mg,
96%
112.7 mg,
99%
114.9 mg,
98%
C
(
M , 100); HRMS calcd for C H O 194.0732, found
14 10
1
94.0727.
.3. General procedure for Table 5
-Ethylpiperidine (2.0 equiv), 2-ethynylaniline derivatives
7
a
Mp 91–92 8C (colorless scales from AcOEt–hexane, lit.
mp 91–92 8C); IR (film, cm ) 3566, 3425, 1367, 1173; H
K1
1
4
NMR (400 MHz, CDCl ) d 2.34 (3H, s), 3.11 (1H, t, JZ
3
7
.4 Hz), 4.90 (2H, d, JZ7.4 Hz), 6.64 (1H, s), 7.20 (2H, d,
JZ8.6 Hz), 7.22 (1H, t, JZ7.7 Hz), 7.29 (1H, t, JZ7.7 Hz),
.48 (1H, d, JZ7.7 Hz), 7.71 (2H, d, JZ8.6 Hz), 8.04 (1H,
1
and Cu(OCOCF )$xH O in mixed solution of H O and
2
MeOH was stirred for 17 h at room temperature. Et O
2
3
2
7
1
3
d, JZ7.7 Hz); C NMR (100 MHz, CDCl ) d 21.6, 58.6,
(
7 mL) was added to the reaction mixture and stirred for
0 min, and then Et O phase were separated. This operation
was repeated again. The combined Et O phase was washed
3
1
1
(
11.2, 114.3, 121.1, 123.7, 124.9, 126.3, 129.0, 129.9,
1
2
C
35.5, 136.9, 140.0, 145.0; MS m/z 301 (M , 68), 129
2
100). Anal. Calcd for C H NO S: C, 63.77; H, 5.02; N,
16 15 3
with saturated aqueous NaCl solution, dried over anhydrous
MgSO , and the solvent was evaporated. The residue was
4.65. Found: C, 63.82; H, 5.02; N, 4.46.
4
purified by silica gel chromatography [AcOEt–hexane (1/5)
for 2b, (1/3) for 2i, and (1/2) for 2j]. For the second and third
cycles, a solution of 1-ethylpiperidine (1.0 equiv) and
2
catalyst solution in H O, and then the mixture was stirred for
-ethynylaniline derivatives in MeOH was added to a
References and notes
2
1
7 hatroomtemperatureandworkedupandpurifiedasabove.
1. (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–103
and reference cited for the previous review. (b) Gribble, G. W.
J. Chem. Soc., Perkin Trans. 1 2000, 1045–1075.
2
. (a) Amemiya, R.; Fujii, A.; Yamaguchi, M. Tetrahedron Lett.
004, 45, 4333–4335. (b) Ezquerra, J.; Pedregal, C.; Lamas,
C.; Barluenga, J.; P e´ rez, M.; Garc ´ı a-Mart ´ı n, M. A.; Gonz a´ lez,
J. M. J. Org. Chem. 1996, 61, 5804–5812. (c) Kondo, Y.;
Kojima, S.; Sakamoto, T. Heterocycles 1996, 43, 2741–2746.
4.3.1. 1-Methylsulfonyl-2-phenylindole (2a) (Table 5,
entry 1).
2
Substrate and reagents First cycle
Second cycle
Third cycle
1
a
98.7 mg,
.36 mmol
21.7 mg,
.075 mmol
0.099 mL,
.72 mmol
96.5 mg,
0.36 mmol
—
94.4 mg,
0.35 mmol
—
(d) Rudisill, D. E.; Stille, J. K. J. Org. Chem. 1989, 54,
5856–5866. For a review about related cyclization reactions,
0
Cu(OCOCF
3
)
2
$xH
2
O
0
see: (e) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev.
2004, 104, 3079–3159. (f) Nakamura, I.; Yamamoto, Y. Chem.
Rev. 2004, 104, 2127–2198.
1
-Ethylpiperidine
0.049 mL,
0.35 mmol
—
0.049 mL,
0.35 mmol
—
0
H
MeOH
Yield
2
O
5 mL
5 mL
97.6 mg, 99% 90.6 mg, 94% 91.4 mg, 97%
3
. (a) Sun, L.-P.; Huang, X.-H.; Dai, W.-M. Tetrahedron 2004,
60, 10983–10992. (b) Koradin, C.; Dohle, W.; Rodriguez,
A. L.; Schmid, B.; Knochel, P. Tetrahedron 2003, 59,
3 mL
3 mL
1
571–1587. (c) Dai, W.-M.; Sun, L.-P.; Guo, D.-S.
Tetrahedron Lett. 2002, 43, 7699–7702. (d) Dai, W.-M.;
Guo, D.-S.; Sun, L.-P. Tetrahedron Lett. 2001, 42, 5275–5278.
4
.3.2. 1-Methylsulfonylindole (2i) (Table 5, entry 2).
(
e) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P.
Substrate and reagents First cycle
Second cycle
Third cycle
Angew. Chem., Int. Ed. 2000, 39, 2488–2490. (f) Arcadi, A.;
Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 2000, 647–649.
1i
71.9 mg,
73.8 mg,
0.38 mmol
—
70.4 mg,
0.36 mmol
—
0
.37 mmol
21.2 mg,
.073 mmol
0.102 mL,
.74 mmol
(
g) Kondo, Y.; Kojima, S.; Sakamoto, T. J. Org. Chem. 1997,
2, 6507–6511. (h) Sakamoto, T.; Kondo, Y.; Iwashita, S.;
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i) Sakamoto, T.; Kondo, Y.; Yamanaka, H. Heterocycles
986, 24, 1845–1847. (j) Sakamoto, T.; Kondo, Y.; Yamanaka,
Cu(OCOCF
3 2 2
) $xH O
6
0
1-Ethylpiperidine
0.051 mL,
0.37 mmol
—
0.050 mL,
0.36 mmol
—
0
(
H
MeOH
Yield
2
O
5 mL
5 mL
52.5 mg, 73% 61.8 mg, 84% 62.8 mg, 89%
1
3 mL
3 mL
H. Heterocycles 1986, 24, 31–32.
. (a) Kusama, H.; Takaya, J.; Iwasawa, N. J. Am. Chem. Soc.
4
2
1
002, 124, 11592–11593. (b) McDonald, F. E. Chem. Eur. J.
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Tetrahedron Lett. 1997, 38, 7687–7690.
. (a) Arcadi, A.; Bianchi, G.; Marinelli, F. Synthesis 2004,
4
(
.3.3. 1-p-Tolylsulfonyl-2-hydroxymethylindole (2j)
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5
610–618. (b) Iritani, K.; Matsubara, S.; Utimoto, K.
Tetrahedron Lett. 1988, 29, 1799–1802.
Substrate and reagents First cycle
Second cycle
Third cycle
1
j
111.1 mg,
113.3 mg,
0.38 mmol
—
116.7 mg,
0.39 mmol
—
6. (a) Kamijo, S.; Sasaki, Y.; Yamamoto, Y. Tetrahedron Lett.
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Est e´ vez, J. C.; Castedo, L.; Est e´ vez, R. J. Synlett 2003,
0
.37 mmol
21.4 mg,
.074 mmol
0.107 mL,
.78 mmol
Cu(OCOCF
3 2 2
) $xH O
0
1
-Ethylpiperidine
0.053 mL,
0.38 mmol
—
0.053 mL,
0.38 mmol
—
1603–1606. (d) Soloducho, J. Tetrahedron Lett. 1999, 40,
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0
H
MeOH
2
O
5 mL
5 mL
3 mL
3 mL

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(
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(
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(
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(
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16. The indole 2a was afforded from the reaction of 1a in the
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(
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