Tetrahedron 61 (2005) 10958–10964

Mild and efficient cyclization reaction of 2-ethynylaniline

derivatives to indoles in aqueous medium
Kou Hiroya,a,* Shin Itoha and Takao Sakamotoa,b
a
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
b
Tohoku University 21st Century COE Program ‘Comprehensive Research and Education Center for Planning of Drug Development and
Clinical Evaluation’, Sendai 980-8578, Japan
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 H2O and MeOH in the presence of 1-ethylpiperidine at room temperature. These
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

reactions12 have also been established.
Heterocyclic compounds, particularly indoles, occur widely
in nature as partial structures of alkaloids and have unique Recent interest in indole synthesis from 2-ethynylaniline
biological activities.1 Among the many methods for indole derivatives has focused on versatile applicability, con-
ring synthesis, the ring closing reactions of 2-ethynylaniline venient reagents and conditions, and tandem or sequential
derivatives are some of the most efficient because methods reactions. For such purposes, iodine-promoted cyclization to
for synthesizing a variety of functionalized starting yield 3-iodoindoles13, sequential cyclization-C3 function-
materials have already been established (Scheme 1).2 alization reactions catalyzed by palladium complexes5b,11 or
Thus far, many kinds of reagents and reaction conditions gold(III) salt,14 and carbazoles synthesis15 were established.
have been reported for indole syntheses from 2-ethynyl- We have previously developed both copper(II) salt-
aniline derivatives, including basic conditions,2c,3 early catalyzed synthesis of indoles from 2-ethynylaniline
transition metal-catalyzed reactions,4 gold(III),5 cop- derivatives7a,c and palladium-complex-catalyzed sequential
per(I),2b,6,10a copper(II) salt-catalyzed reactions,7 and coupling-cyclization reactions between methyl propiolate
ammonium fluoride-mediated reactions.8 The most fre- and 2-iodoaniline derivatives, with the latter’s application to
quently used reagents or catalysts for these ring-closing duocarmycin SA synthesis.10d
reactions are the palladium complexes,2d,3a,5b,9,10,11 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
Scheme 1. Cyclization reaction of 2-ethynylaniline derivatives to indole efficiency (low solubility of the catalysts in organic
derivatives. media) and high temperature requirements (O70 8C) must
be solved for copper(II) salt-catalyzed reactions to be
Keywords: Indole; Copper(II) salt; 2-Ethynylaniline; Cyclization reaction.
useful. Herein, we describe solutions to these problems and
* Corresponding author. Tel.: C81 795 6867; fax: C81 795 6864; improved procedures for copper(II) salt-catalyzed cycliza-
e-mail: hiroya@mail.tains.tohoku.ac.jp tion reactions of 2-ethynylaniline derivatives.

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(OCOCF3)2$xH2O-catalyzed cyclization reaction of 1a in the

presence of various amines

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 Entry Amine (2.0 equiv) Yield of 2a (%)
of the cyclization, which makes suspension in an organic 1 1-Ethylpiperidine 14 (85)a
solvent unavoidable.7a However, the bulky counter-anion in 2 Triethylamine 10 (88)a
3 N,N-diisopropylethylamine 17 (83)a
copper(II) carbonate (e.g., stearic acid) does not improve 4 N,N-dimethylaniline No reaction
solubility or catalytic activity.16 Therefore, we changed the 5 Pyridine No reaction
solvent to H2O. The results are summarized in Table 1. It 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 aliphatic amine slightly accelerated the reaction, but the
reaction conditions. Most of the copper(II) salts tested yield of 2a was less than the amount of added catalyst and
dissolved into H2O except for Cu(OBz)2, but the reaction more than 80% of 1a was recovered (Table 2, entries 1–3).
medium was again a suspension because of the low Addition of a tertiary aromatic amine or pyridine did not
solubility of 1a in H2O. The copper(II) salts that catalyze accelerate the reaction (Table 2, entries 4 and 5). The
the reactions in organic solvent [Cu(OAc)2, Cu(OTf)2, addition of secondary amines (piperidine or N,N-diiso-
Cu(OBz)2, and Cu(OCHO)2$xH2O] did not provide satis- propylamine) or primary amines (butylamine, aniline, or
factory results (Table 1, entries 1–4). Surprisingly, only ethylenediamine) also did not promote the reaction, and the
Cu(OCOCF3)2$xH2O catalyzed the reaction, even though it starting material 1a was completely recovered (data not
forms a suspension in the reaction mixture (Table 1, entry shown). Since the reactions in H2O appear as a suspension,
5). Why only this copper(II) salt works is not yet clear. we speculated that the reason for the reactivity difference
However, it is apparent that CF3COOH is not a catalyst for between H2O and 1,2-dichloroethane might be the low
this reaction (Table 1, entry 6). We selected solubility of 1a in H2O. Therefore, we attempted the
Cu(OCOCF3)2$xH2O as the catalyst for further improve- reaction in a mixed solvent system, with and without
ment of the reaction conditions. 1-ethylpiperidine (Table 3).

Table 1. Copper(II) salt-catalyzed cyclization reactions of 1a in H2O 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
Entry Catalyst Time (h) Yield of 2a (%)
of the solubility of the catalyst and the substrate. However,
even with the second alcohol solvent, the reaction did not
1 Cu(OAc)2 23 Trace proceed at room temperature (Table 3, entry 4). The effect
2 Cu(OTf)2 24 7 (76)a
3 Cu(OBz)2 24 18 (66)a of 1-ethylpiperidine was remarkable, and the amount of
4 Cu(OCHO)2$xH2O 24 22 (75)a catalyst could be reduced from 20 to 5 mol% (Table 3,
5 Cu(OCOCF3)2$xH2O 24 96 entries 6 and 7). Note that less expensive Cu(OAc)2, which
6 CF3COOH 23 No reaction did not show catalytic activities in H2O alone (Table 1, entry
a
The numbers in parentheses are the yields of recovered 1a. 1), can be used as the catalyst under optimized reaction
conditions (Table 3, entry 8). While the reaction could be
High temperature is essential for the cyclization reactions of promoted with 1-ethylpiperidine in the absence of a
2-ehtynylaniline derivatives catalyzed by copper(II) salts copper(II) salt, the low yield can be disregarded (Table 3,
and the substrates can be recovered perfectly at room entry 5).
temperature. However, we have previously reported that the
rate of copper(II) salt-catalyzed cyclization reactions is 2.2. Application to various kinds of substrates
accelerated in the presence of 1-ethylpiperidine and realized
the reaction at room temperature (room temperature for 72 h Having established the cyclization reaction in aqueous
with 2.0 equiv of 1-ethylpiperidine, 76% yield).7a We now solvent at room temperature, we applied it to other
apply the Cu(OCOCF 3) 2$xH 2O-catalyzed cyclization substrates. To avoid too long reaction time, we used same
reaction of 1a with various amines in H2O. The results are reaction condition shown in Table 3 entry 6 [20 mol% of
summarized in Table 2. Cu(OCOCF3)2$H2O] and the results are summarized in
Table 4.
The rate acceleration effect of the amine in H2O was less
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
1 Cu(OCOCF3)2$xH2O (20) — H2O– BuOH (1/1) w90 8C 24 10 (86)a
2 Cu(OCOCF3)2$xH2O (20) — H2O–EtOH (1/1) w90 8C 24 85 (7)a
3 Cu(OCOCF3)2$xH2O (20) — H2O–MeOH (1/1) w90 8C 21 93
4 Cu(OCOCF3)2$xH2O (20) — H2O–MeOH (1/1) Room temperature 23 No reaction
5 — 1-Ethylpiperidine H2O–MeOH (1/1) Room temperature 24 14 (85)a
6 Cu(OCOCF3)2$xH2O (20) 1-Ethylpiperidine H2O–MeOH (1/1) Room temperature 24 92
7 Cu(OCOCF3)2$xH2O (5) 1-Ethylpiperidine H2O–MeOH (1/1) Room temperature 24 95
8 Cu(OAc)2 (10) 1-Ethylpiperidine H2O–MeOH (1/1) Room temperature 17 96
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 (%)

Number X R1 R2 R3
1 1b NMs Bu H H 13 2b:98
2 1c NMs TMS H H 14 2i:91 (R2ZH)
t
3 1d NMs Bu H H 10 2d:90
4 1e NMs Ph NO2 H 14 2e:85
5 1f NMs Ph Br H 72 2f:99
6 1g NMs Ph Me H 27 2g:99
7 1h NMs Ph H OMe 21 2h:99
8 3 NH Ph H H 24 No reaction
9 4 NBoc Ph H H 24 No reaction
10 5 O Ph H H 11 6:87 (7)a
a
The number in parentheses is the yield of recovered 5.

can be applied not only to the alkyl group (Table 4, entry 1) from 2-ethynylaniline derivatives with a quaternary center
and hydrogen (Table 4, entry 2; TMS group eliminated at the C-3 0 position.7a Substituents on the aromatic ring
before cyclization reaction), but also in the presence of a generally did not affect the efficiency of the reaction
bulky tBu group (Table 4, entry 3). To our knowledge, only (Table 4, entries 4–7). Disappointingly, this reaction has the
one report5b had been published for a high yield of an indole limitation about the substituents on the nitrogen atom: the

Figure 1. The general form of the catalyst recycling reaction.

 K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964 10961

Table 5. The catalyst recycling reaction for 2-ethynylaniline derivatives

Entry Substrate Yield of 2 (%)

Number R1 R2 First cycle Second cycle Third cycle
1 1a Ms Ph 99 94 97
2 1i Ms H 73 84 89
3 1j Ts CH2OH 96 99 98

sulfonamides could be cyclized, but not the aniline are given from TMS (0 ppm) as the internal standard for 1H
derivative or the carbamate (Table 4, entries 8 and 9). NMR and 13CDCl3 (77.0 ppm) as the internal standard for
13
However, this reaction condition could be applied to the C NMR. Standard and high-resolution mass spectra were
synthesis of the benzofuran derivative 6 (Table 4, entry 10). measured on JEOL JMS-DX303 and MS-AX500 instru-
ments, respectively. IR spectra were recorded on a
2.3. Catalyst recycling reaction Shimadzu FTIR-8400.

This reaction, in which the copper(II) salts dissolve into 4.2. General procedure for the selected entries for
H2O while the indole products dissolve into the organic Tables 1, 3, and 4.
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
The reaction was started by adding the 2-ethynylaniline H2O or in mixed solution of H2O and alcohol, then the
derivatives to a solution of Cu(OCOCF3)2$xH2O (20 mol%) mixture was stirred under reflux or at room temperature for
and 1-ethylpiperidine (2.0 equiv) in H2O–MeOH (1/1). the reaction time listed in Tables 1, 3, and 4. The reaction
After being stirred at room temperature, the mixture was mixture was extracted with AcOEt (three times). The
extracted with Et2O. The desired indole derivatives were combined organic solution was washed with saturated
extracted in essentially pure form from the Et2O phase, and aqueous NaCl solution, dried over anhydrous MgSO4, and
the catalyst-containing H2O phase could be recycled after the solvent was evaporated under reduced pressure.
adding more 1-ethylpiperidine (1.0 equiv) and MeOH. The
results of three cycles for three 2-ethynylaniline derivatives 4.2.1. 1-Methylsulfonyl-2-phenylindole (2a) (Table 3,
are listed in Table 5. The catalytic activity of entry 7). A suspension of 1a (89.6 mg, 0.33 mmol),
Cu(OCOCF3)2$xH2O did not change over the three cycles. Cu(OCOCF3)2$xH2O (4.9 mg, 0.017 mmol) and 1-ethyl-
piperidine (0.090 mL, 0.65 mmol) in mixed solution of H2O
(5 mL) and MeOH (5 mL) was stirred for 24 h at room
3. Conclusion temperature. The residue was chromatographed on silica gel
[AcOEt–hexane (1/5)] to afford 2a7a,8 (85.0 mg, 95%) as a
We improved the cyclization reaction of 2-ethynylaniline colorless solid; mp 115–117 8C (colorless needles from
derivatives to indoles. While the original conditions require AcOEt–hexane, lit.7a mp 115–117 8C, lit.8 mp 115–116 8C);
heating, the optimized reaction can be carried out at room IR (film, cmK1) 1367, 1171; 1H NMR (400 MHz, CDCl3) d
temperature in a mixture of H2O and MeOH in the presence 2.73 (3H, s), 6.70 (1H, s), 7.34 (1H, td, JZ7.4, 1.5 Hz), 7.37
of 1-ethylpiperidine. Further, the reaction does not require (1H, td, JZ7.4, 1.5 Hz), 7.40–7.46 (3H, m), 7.52–7.61 (3H,
an argon atmosphere and can be done as open-flask reaction. m), 8.12 (1H, d, JZ7.8 Hz); 13C NMR (100 MHz, CDCl3) d
This reaction condition was applied to a catalyst recycling 39.5, 113.0, 115.7, 120.9, 124.5, 125.0, 127.6, 128.8, 130.0,
reaction system. Although the substrates for this reaction 130.2, 131.9, 137.9, 141.8; MS m/z 271 (MC, 51), 190
condition are limited to sulfonamides, the reaction (100), 165 (52); HRMS calcd for C15H13NO2S 271.0667,
conditions will be useful for versatile synthesis of indole found 271.0673.
derivatives, especially in large-scale reactions.
4.2.2. 1-Methylsulfonyl-2-butylindole (2b) (Table 4,
entry 1). A suspension of 1b (102.5 mg, 0.41 mmol),
4. Experimental Cu(OCOCF3)2$xH2O (21.2 mg, 0.073 mmol), and 1-ethyl-
piperidine (0.113 mL, 0.82 mmol) in mixed solution of H2O
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
All melting points were determined with a Yazawa Micro [AcOEt–hexane (1/5)] to afford 2b7a,8 (100.8 mg, 98%) as a
Melting Point BY-2 and are uncorrected. 1H NMR spectra colorless solid; mp 80–81 8C (colorless needles from
(400 MHz) and 13C NMR spectra (100 MHz) were recorded AcOEt–hexane, lit.7a mp 80–81 8C, lit.8 mp 81–82 8C); IR
on a JEOL JMN AL-400 spectrometer. Chemical shifts (d) (film, cmK1) 1366, 1171; 1H NMR (400 MHz, CDCl3) d
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-
(2H, sex, JZ7.5 Hz), 2.95 (2H, t, JZ7.5 Hz), 3.00 (3H, s), graphed on silica gel [AcOEt–hexane (1/5)] to afford 2f7a
6.45 (1H, s), 7.21–7.29 (2H, m), 7.48 (1H, dd, JZ7.7, (103.4 mg, 99%) as a colorless solid; mp 186–187 8C
2.7 Hz), 7.99 (1H, dd, JZ7.9, 1.9 Hz); 13C NMR (100 MHz, (colorless needles from AcOEt–hexane, lit7a mp 186–
CDCl3) d 14.0, 22.5, 28.6, 31.0, 40.3, 108.3, 114.0, 120.1, 187 8C); IR (film, cmK1) 1361, 1177; 1H NMR (400 MHz,
123.5, 123.8, 129.7, 136.7, 142.3; MS m/z 251 (MC, 37), CDCl3) d 2.73 (3H, s), 6.62 (1H, s), 7.40–7.47 (4H, m),
209 (40), 130 (100); HRMS calcd for C13H17NO2S 7.51–7.56 (2H, m), 7.71 (1H, d, JZ1.7 Hz), 7.98 (1H, d, JZ
251.0980, found 251.1012. 8.8 Hz); 13C NMR (100 MHz, CDCl3) d 39.9, 111.8, 117.1,
117.8, 123.5, 127.67, 127.73, 129.1, 130.1, 131.2, 131.8,
4.2.3. 1-Methylsulfonylindole (2i) (Table 4, entry 2). A 136.5, 143.0; MS m/z 351 (MCC2, 66), 349 (MC, 65), 272
suspension of 1c (33.5 mg, 0.13 mmol), Cu(OCOCF3)2$xH2O (99), 270 (100); HRMS calcd for C15H12BrNO2S 348.8772,
(8.0 mg, 0.028 mmol), and 1-ethylpiperidine (0.034 mL, found 348.9763.
0.25 mmol) in mixed solution of H2O (1.5 mL) and MeOH
(1.5 mL) was stirred for 14 h at room temperature. The 4.2.7. 1-Methylsulfonyl-5-methyl-2-phenylindole (2g)
residue was chromatographed on silica gel [AcOEt–hexane (Table 4, entry 6). A suspension of 1g (69.0 mg,
(1/5)] to afford 2i7a,8 (22.2 mg, 91%) as a colorless oil; IR 0.24 mmol), Cu(OCOCF3)2$xH2O (12.5 mg, 0.043 mmol),
(neat, cmK1) 1361, 1170; 1H NMR (400 MHz, CDCl3) d and 1-ethylpiperidine (0.067 mL, 0.49 mmol) in mixed
3.06 (3H, s), 6.69 (1H, d, JZ3.7 Hz), 7.28 (1H, d, JZ solution of H2O (3 mL) and MeOH (3 mL) was stirred for
7.7 Hz), 7.35 (1H, t, JZ7.7 Hz), 7.42 (1H, d, JZ3.7 Hz), 27 h at room temperature. The residue was chromato-
7.61 (1H, d, JZ7.7 Hz), 7.90 (1H, d, JZ7.7 Hz); 13C NMR graphed on silica gel [AcOEt–hexane (1/3)] to afford 2g7a
(100 MHz, CDCl3) d 40.6, 108.7, 112.8, 121.5, 123.4, (68.4 mg, 99%) as a colorless solid; mp 137–138 8C
124.7, 125.9, 130.5, 134.7; MS m/z 195 (MC, 55), 116 (colorless needles from AcOEt–hexane, lit.7a mp 137–
(100); HRMS calcd for C9H9NO2S 195.0354, found 138 8C); IR (film, cmK1) 1366, 1173; 1H NMR (400 MHz,
195.0359. CDCl3) d 2.47 (3H, s), 2.70 (3H, s), 6.65 (1H, s), 7.19 (1H,
d, JZ8.5 Hz), 7.37–7.45 (4H, m), 7.53–7.57 (2H, m), 7.98
4.2.4. 1-Methylsulfonyl-2-(1,1-dimethylethyl)indole (2d) (1H, d, JZ8.5 Hz); 13C NMR (100 MHz, CDCl3) d 21.3,
(Table 4, entry 3). A suspension of 1d (52.0 mg, 39.0, 113.0, 115.5, 120.9, 126.4, 127.6, 128.7, 130.0, 130.5,
0.21 mmol), Cu(OCOCF3)2$xH2O (12.1 mg, 0.042 mmol), 132.0, 134.2, 136.2, 142.1; MS m/z 285 (MC, 48), 206
and 1-ethylpiperidine (0.057 mL, 0.41 mmol) in mixed (100). Anal. Calcd for C16H15NO2S: C, 67.34; H, 5.30; N,
solution of H2O (2.5 mL) and MeOH (2.5 mL) was stirred 4.91. Found: C, 67.35; H, 5.43; N, 4.52.
for 10 h at room temperature. The residue was chromato-
graphed on silica gel [AcOEt–hexane (1/5)] to afford 2d5b,7a 4.2.8. 1-Methylsulfonyl-6-methoxy-2-phenylindole (2h)
(46.9 mg, 90%) as a colorless oil; IR (neat, cmK1) 1371, (Table 4, entry 7). A suspension of 1h (71.7 mg,
1176; 1H NMR (400 MHz, CDCl3) d 1.56 (9H, s), 2.93 (3H, 0.24 mmol), Cu(OCOCF3)2$xH2O (13.8 mg, 0.048 mmol),
s), 6.61 (1H, s), 7.24 (1H, td, JZ7.4, 1.9 Hz), 7.28 (1H, td, and 1-ethylpiperidine (0.066 mL, 0.48 mmol) in mixed
JZ7.4, 1.9 Hz), 7.48 (1H, dd, JZ7.4, 1.9 Hz), 8.07 (1H, br solution of H2O (3 mL) and MeOH (3 mL) was stirred for
d, JZ7.4 Hz); 13C NMR (100 MHz, CDCl3) d 30.9, 34.8, 21 h at room temperature. The residue was chromato-
39.5, 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 2h7a
MS m/z 251 (MC, 42), 236 (51), 172 (100); HRMS calcd for (70.7 mg, 99%) as a colorless solid; mp 134–135 8C
C13H17NO2S 251.0980, found 251.0966. (colorless prisms from AcOEt–hexane, lit.7a mp 134–
135 8C); IR (film, cmK1) 1612, 1367, 1180; 1H NMR
4.2.5. 1-Methylsulfonyl-5-nitro-2-phenylindole (2e) (400 MHz, CDCl3) d 2.68 (3H, s), 3.88 (3H, s), 6.62 (1H, s),
(Table 4, entry 4). A suspension of 1e (56.7 mg, 6.96 (1H, dd, JZ8.5, 2.2 Hz), 7.36–7.40 (3H, m), 7.44 (1H,
0.18 mmol), Cu(OCOCF3)2$xH2O (9.1 mg, 0.031 mmol), d, JZ8.5 Hz), 7.50–7.55 (2H, m), 7.67 (1H, d, JZ2.2 Hz);
13
and 1-ethylpiperidine (0.049 mL, 0.35 mmol) in mixed C NMR (100 MHz, CDCl3) d 39.0, 55.7, 110.1, 113.0,
solution of H2O (2.5 mL) and MeOH (2.5 mL) was stirred 113.5, 121.3, 123.9, 127.5, 128.4, 129.8, 132.0, 139.1,
for 14 h at room temperature. The residue was chromato- 140.6, 158.0; MS m/z 301 (MC, 41), 222 (100). Anal. Calcd
graphed on silica gel [AcOEt–hexane (1/5)] to afford 2e for C16H15NO3S: C, 63.77; H, 5.02; N, 4.65. Found: C,
(48.4 mg, 85%) as a pale yellow solid; mp 187–188 8C (pale 63.73; H, 4.95; N, 4.60.
yellow needles from acetone–hexane); IR (film, cmK1)
1518, 1344, 1165; 1H NMR (400 MHz, CDCl3) d 2.90 (3H, 4.2.9. 2-Phenylbenzofuran (6) (Table 4, entry 10). A
s), 6.81 (1H, s), 7.44–7.50 (3H, m), 7.53–7.58 (2H, m), 7.25 suspension of 5 (94.7 mg, 0.49 mmol), Cu(OCOCF3)2$xH2O
(2H, d, JZ1.5 Hz), 8.51 (1H, t, JZ1.5 Hz); 13C NMR (24.9 mg, 0.086 mmol), and 1-ethylpiperidine (0.135 mL,
(100 MHz, CDCl3) d 41.4, 112.2, 115.7, 116.9, 119.9, 0.98 mmol) in mixed solution of H2O (5 mL) and MeOH
127.9, 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
MS m/z 316 (MC, 91), 237 (100); HRMS calcd for residue was chromatographed on silica gel [AcOEt–hexane
C15H12N2O4S 316.0518, found 316.0500. (1/20)] to afford 617 (82.4 mg, 87%) as a colorless solid.
From the later fraction, 5 (7.0 mg, 7%) was recovered; 6; mp
4.2.6. 5-Bromo-1-methylsulfonyl-2-phenylindole (2f) 117–118 8C (colorless scales from hexane, lit.17 mp 118–
(Table 4, entry 5). A suspension of 1f (104.0 mg, 120 8C); IR (film, cmK1) 1215, 748; 1H NMR (400 MHz,
0.30 mmol), Cu(OCOCF3)2$xH2O (17.0 mg, 0.059 mmol), CDCl3) d 7.03 (1H, d, JZ0.7 Hz), 7.22 (1H, td, JZ7.5,
and 1-ethylpiperidine (0.082 mL, 0.59 mmol) in mixed 1.3 Hz), 7.28 (1H, td, JZ7.5, 1.3 Hz), 7.35 (1H, t, JZ
solution of H2O (4 mL) and MeOH (4 mL) was stirred for 7.5 Hz), 7.45 (2H, d, JZ7.5 Hz), 7.52 (1H, d, JZ7.5 Hz),
 K. Hiroya et al. / Tetrahedron 61 (2005) 10958–10964 10963

7.58 (1H, d, JZ7.5 Hz), 7.86 (2H, d, JZ7.5 Hz); 13C NMR
(100 MHz, CDCl3) d 101.3, 111.1, 120.8, 122.9, 124.2, Substrate and reagents First cycle Second cycle Third cycle
124.9, 128.5, 128.7, 129.1, 130.4, 154.8, 155.8; MS m/z 194 Yield 106.8 mg, 112.7 mg, 114.9 mg,
(MC, 100); HRMS calcd for C14H10O 194.0732, found 96% 99% 98%
194.0727.
Mp 91–92 8C (colorless scales from AcOEt–hexane, lit.7a
4.3. General procedure for Table 5 mp 91–92 8C); IR (film, cmK1) 3566, 3425, 1367, 1173; 1H
NMR (400 MHz, CDCl3) d 2.34 (3H, s), 3.11 (1H, t, JZ
1-Ethylpiperidine (2.0 equiv), 2-ethynylaniline derivatives 7.4 Hz), 4.90 (2H, d, JZ7.4 Hz), 6.64 (1H, s), 7.20 (2H, d,
and Cu(OCOCF3)$xH2O in mixed solution of H2O and JZ8.6 Hz), 7.22 (1H, t, JZ7.7 Hz), 7.29 (1H, t, JZ7.7 Hz),
MeOH was stirred for 17 h at room temperature. Et2O 7.48 (1H, d, JZ7.7 Hz), 7.71 (2H, d, JZ8.6 Hz), 8.04 (1H,
(7 mL) was added to the reaction mixture and stirred for d, JZ7.7 Hz); 13C NMR (100 MHz, CDCl3) d 21.6, 58.6,
10 min, and then Et2O phase were separated. This operation 111.2, 114.3, 121.1, 123.7, 124.9, 126.3, 129.0, 129.9,
was repeated again. The combined Et2O phase was washed 135.5, 136.9, 140.0, 145.0; MS m/z 301 (MC, 68), 129
with saturated aqueous NaCl solution, dried over anhydrous (100). Anal. Calcd for C16H15NO3S: C, 63.77; H, 5.02; N,
MgSO4, and the solvent was evaporated. The residue was 4.65. Found: C, 63.82; H, 5.02; N, 4.46.
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-ethynylaniline derivatives in MeOH was added to a References and notes
catalyst solution in H2O, and then the mixture was stirred for
17 h at room temperature and worked up and purified as above. 1. (a) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–103
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Yield 97.6 mg, 99% 90.6 mg, 94% 91.4 mg, 97% 60, 10983–10992. (b) Koradin, C.; Dohle, W.; Rodriguez,
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