Convenient synthesis of 2-substituted indoles from 2-ethynylanilines with tetrabutylammonium fluoride

Article abstract of DOI:10.1039/a808842j

The cyclization reaction of various 2-ethynylanilines, which were easily synthesized from 2-haloanilines by the palladium-catalyzed reaction with terminal alkynes, with tetrabutylammonium fluoride (TBAF) to yield 2-substituted indoles proceeded at refluxing or room temperature in THF in excellent yields without affecting the bromo, chloro, cyano, ethoxycarbonyl, and ethynyl groups.

Full text of DOI:10.1039/a808842j

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Convenient synthesis of 2-substituted indoles from 2-ethynyl-
anilines with tetrabutylammonium fluoride
Akito Yasuhara,* Yuichi Kanamori, Masashi Kaneko, Atsushi Numata, Yoshinori Kondo and
Takao Sakamoto*
Faculty of Pharmaceutical Sciences, Tohoku University, Aobaku, Sendai 980-8578, Japan
Received (in Cambridge) 12th November 1998, Accepted 12th January 1999
The cyclization reaction of various 2-ethynylanilines, which were easily synthesized from 2-haloanilines by
the palladium-catalyzed reaction with terminal alkynes, with tetrabutylammonium fluoride (TBAF) to yield
2-substituted indoles proceeded at refluxing or room temperature in THF in excellent yields without affecting
the bromo, chloro, cyano, ethoxycarbonyl, and ethynyl groups.
Table 1 Palladium-catalyzed reactions of iodoanilines with terminal
alkynes
Introduction
The cyclization of 2-ethynylanilines is one of the most useful
methods for the synthesis of 2-substituted indoles, because
2-ethynylanilines can be easily prepared from 2-haloanilines by
the palladium-catalyzed cross-coupling reaction with terminal
alkynes, and many synthetic methods for 2-haloanilines have
been reported. For example, the preparation of 2-haloanilines
is easily achieved by ortho-lithiation with alkyllithium.1
The cyclization of 2-ethynylanilines is promoted in the pres-
ence of metal species such as copper() halides,2 NaAuCl4ؒH2O3
or palladium() species.4 Another method is the cyclization of
2-ethynylphenylcarbamates with alkoxides.5
R2
R3
R4
I
R3
R4
i
R2
NHR1
NHR1
1
Reagents: i, PdCl2(PPh3)2, CuI, Et3N.
Time/ Yield
Compound R1
R2
R3 R4
h
(%)
a
c
d
e
f
H
Ph
Ph
H
H
H
H
H
Br
H
H
H
H
H
H
H
H
H
H
Cl
H
3
95
85
80
90
90
52
80
71
66
94
The cyclization reaction of 2-ethynylanilines is promoted
with copper() chloride or iodide to give 2-unsubstituted and
2-substituted indoles, but the reaction proceeds at relatively
high temperature (100–110 ЊC) in DMF.2 Iritani and co-workers
reported3 the cylization of 2-ethynylanilines to 2-substituted
indoles using NaAuCl4ؒH2O as catalyst. The palladium()
species-promoted cyclization reaction of 2-ethynylanilines,
which was first reported by Taylor et al.,4a was found to have
wide applicability. Namely, N-unsubstituted, N-acyl-, N-alkoxy-
carbonyl-, and N-methylsulfonyl-2-ethynylanilines can be used
as starting materials.
On the other hand, we have reported the cyclization reaction
of 2-ethynylphenylcarbamates to indoles under basic condi-
tions, sodium ethoxide in ethanol, without using a metal
species.3,4a–d The reaction was utilized as a key reaction in the
synthesis of some natural indole derivatives by Ogasawara
et al.5e–g who reported that the cyclization of ethyl 2-dec-1-
ynylphenylcarbamate also proceeded in the presence of lithium
chloride in refluxing DMF,5g although the yield is inferior to
the yield of the reaction using sodium ethoxide. The conditions
of the indole cyclization reaction with alkali metal alkoxides
were improved by using potassium tert-butoxide in tert-butyl
alcohol,5c–d but there is a restriction that the substituents on the
amino group were limited to alkoxycarbonyl groups, namely
that only (2-ethynylaryl)carbamates were used as the starting
materials.
CO2tEt
24
24
24
1.5
24
1
5
3
12
CO2 Bu Ph
COtBu Ph
CHO
Ph
Ph
i
CO2tEt
l
CO2 Bu Hex
m
n
o
CHO
Ac
CO2Et
CH2CH2CO2Et
Ph
Bu
MeO
H
catalyzed reaction of 2-haloanilines with terminal alkynes using
N-ethoxycarbonyl-, N-tert-butoxycarbonyl-, N-pivaloyl-, N-
formyl-, and N-acetyl-2-iodoaniline derivatives as shown in
Table 1. Ethyl 2,4-bis(phenylethynyl)phenylcarbamate (1j) was
prepared from ethyl 4-bromo-2-(phenylethynyl)phenylcarb-
amate (1i) by palladium-catalyzed reaction with ethynylbenz-
ene, and ethyl 4-cyano-2-(phenylethynyl)phenylcarbamate (1k)
was prepared similarly from 4-iodobenzonitrile in 34% overall
yield in 3 steps (Scheme 1).
Ph
X
1i X = Br
(68%) i
1j
X =
C
CPh
NHCOOEt
R1
R
1 = H, R2 = H
Based on the above background concerning the indole cycliz-
ation reaction and the availability of 2-ethynylanilines, we now
report here the synthesis of various indoles from 2-ethynyl-
anilines under mild conditions using TBAF in THF at refluxing
or room temperature.
NC
ii, iii
34% (3 steps) i
R
1 = I, R2 = CO2Et
NHR2
1k R1
=
, R2 = CO2Et
CPh
C
Scheme 1 Reagents and conditions: i, ethynylbenzene, PdCl2(PPh3)2,
CuI, Et3N; ii, I2, 30% H2O2, MeOH; iii, ClCO2Et, pyridine.
Results and discussion
Preparation of 2-ethynylanilines from 2-haloanilines by
palladium-catalyzed reaction
We have reported that the palladium-catalyzed reaction of
N-(2-iodophenyl)methanesulfonamide with terminal alkynes
gives 2-substituted indoles instead of the corresponding alkynyl
derivatives (1g,h).6 In order to examine the cyclization of 1g
2-Ethynylanilines (1a,c–f,i,l–o) were prepared by the palladium-
J. Chem. Soc., Perkin Trans. 1, 1999, 529–534
529

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Table 2 Cyclization reaction of N-(2-ethynylphenyl)sulfonamides
Ph
i
Ph
Ph
N
N
NHMs
H
Ms
3g
1g
2a
i
Yield (%)
Entry
Solvent
Reagent (equiv.)
Time/h
Temp.
2a
3g
2a ϩ 3g
Recovery
1
2
3
4
5
6
7
8
THF
THF
THF
THF
THF
THF
MeCN
MeCN
TBAF (0.5)
TBAF (1)
TBAF (2)
12
12
12
12
24
24
24
24
reflux
reflux
reflux
rt
reflux
reflux
reflux
reflux
50
81
94
—
—
—
—
—
38
5
88
86
94
—
—
—
75
31
11
5
—
—
—
—
75
31
—
95
75
83
15
54
TBAF (2)
K2CO3 (2)
NaHCO3 (2)
K2CO3 (2)
NaHCO3 (2)
Table 3 Cyclization reaction of various N-substituted 2-phenylethynylanilines with TBAF
R2
i
R2
R2
N
R1
N
NHR1
H
1
2a
3c, d, e
Reagents: i, TBAF, THF.
Yield (%)
TBAF
Entrya
1
R1
R2
Temp.
(equiv.)
Time/h
2a ϩ 3
2a
88
51
43
22
26
96
3
1b
2
3
4
5
6
7
8
b
b
c
d
e
f
Ac
Ac
COOEt
Boc
COt-Bu
CHO
Ms
Ph
Ph
Ph
Ph
Ph
Ph
TMS
TMS
reflux
reflux
reflux
reflux
reflux
reflux
rt
2
1
2
2
2
2
3
3
12
12
12
2
12
2
88
51
100
100
82
96
51
—
— (49)c
57
78
56
—
h
h
24
3
—
51d (46)e
—
Ms
reflux
100
100f
a The cyclization reaction of 2-(2-phenylethynyl)aniline (1a) did not proceed (recovery yield: 92%). b The cyclization reaction with K2CO3 in MeCN
gave 2a in 9% yield. c Values in parentheses are recovery yields of 1. d Product: 1-methylsulfonylindole (3q). e Product: N-(2-ethynylphenyl)-
methanesulfonamide (1p). f Product: indole.
and 1h with TBAF, which were assumed to be intermediates
of the indoles, 1g and 1h were prepared by the palladium-
catalyzed reaction of 2-iodoaniline with terminal alkynes
followed by sulfonylation with methanesulfonyl chloride.
N-(2-Phenylethynyl)ethanamide (1b) was also prepared from
2-phenylethynylaniline (1a) with acetic anhydride.
in THF was refluxed, the cyclization reaction with TBAF gave
2-phenylindole (2a) in 94% yield (Table 2, Entry 3), but the
reaction with K2CO3 or NaHCO3 in THF resulted in the
recovery of 1g in 75 or 83% yield (Table 2, Entries 5, 6). The
cyclization reaction with the same alkali metal carbonates in
acetonitrile gave 3g in 75 and 31% yields, respectively (Table 2,
Entries 7, 8).
The reaction of 1g using 0.5, 1.0, or 2.0 equiv. of TBAF
under reflux gave a mixture of 2a and 1-methylsulfonyl-2-phenyl-
indole (3g) in approximately 90% yields (Table 2, Entries 1–3).
The results suggest that the cyclization reaction can proceed
with a catalytic amount of TBAF. However, because TBAF is
a good desulfonylating reagent for N-sulfonyl nitrogen-hetero-
aromatics and the desulfonylation reaction requires a stoichio-
metric amount of TBAF,7 the amount of TBAF required for
the cyclization reaction was more than 1 equiv.
R2
R2
I
i
ii
NHR1
NH2
NH2
1
b R1 = Ac, R2 = Ph (86%)
g R1 = Ms, R2 = Ph (75%)
h R1 = Ms, R2 = TMS (80%)
Scheme 2 Reagents and conditions: i, ethynylbenzene or ethynyltri-
methylsilane, PdCl2(PPh3)2, CuI, Et3N, 3 h; ii, MsCl or Ac2O, pyridine.
Cyclization reaction of various N-substituted ethynylanilines
Although the cyclization reaction of 1g with 2 equiv. of TBAF
did not proceed at room temperature (Table 2, Entry 4), the
reaction of N-[2-(trimethylsilylethynyl)phenyl]methanesulfon-
amide (1h) with 3 equiv. of TBAF at room temperature gave
1-methylsulfonylindole (3h) in 51% yield (Table 3, Entry 7). And
Reaction conditions for the cyclization into indole
When
a mixture of N-[2-(phenylethynyl)phenyl]methane-
sulfonamide (1g) with 2 equiv. of TBAF, K2CO3, or NaHCO3
530
J. Chem. Soc., Perkin Trans. 1, 1999, 529–534

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Table 4 Synthesis of various indoles substituted at the 2-position and benzene moiety from ethynylanilines with TBAF
R2
R3
R4
NHR1
1
i
R3
R4
R3
R4
R2
R2
N
R1
N
H
2
3
Reagents: i, TBAF, THF.
Yield (%)
Entry
1
R1
R2
R3
R4
Temp
Time (h)
2 ϩ 3
2
3
1
2
3
4
5
6
7a
8
9
i
CO2Et
CO2Et
CO2Et
CO2 Bu
CHO
Ac
CO2Et
CO2Et
Ms
Ph
Ph
Ph
Hex
Br
H
H
H
Cl
H
MeO
H
H
reflux
reflux
rt
reflux
reflux
reflux
reflux
reflux
reflux
17
21
12
2
3
24
4
98
99
100
100
51
88
100
96
98
99
—
—
—
41
—
—
58
—
—
᎐
j
᎐–Ph
᎐
k
l
m
n
o
o
p
CN
100
59
51
88
42
96
85
t
H
H
H
H
H
H
CH2CH2CO2Et
Ph
Bu
Bu
H
24
17
H
85
a THF–DMF (5:1) was used as a solvent. The cyclization reaction of 1n in THF at refluxing for 48 h gave 2n in 79% yield and the starting material
was recovered in 16% yield.
at refluxing temperature, the cyclization of 1h was faster than
the cyclization of 1g (Table 3, Entry 8). On the basis of the
above results, we next examined the cyclization reaction of
various N-substituted 2-(phenylethynyl)anilines, whose reactiv-
ity toward cyclization was lower than that of 2-(trimethysilyl-
ethynyl)anilines. As shown in Table 3, the cyclization reaction
of N-substituted 2-(phenylethynyl)anilines (1b–f) with 2 equiv.
of TBAF gave the corresponding indoles (2 and 3) in excel-
lent yields. We previously reported5b that the cyclization of
N-acetyl, N-pivaloyl, and N-formyl derivatives of 2-(trimethyl-
silylethynyl)aniline with sodium ethoxide–ethanol proceeded in
low yields (17–34%), because the deacylation of the N-acyl-2-
ethynylanilines occurred before the cyclization to form indoles,
and that the 2-ethynylaniline did not give indole under these
reaction conditions.
from the 2-(trimethylsilylethynyl)aniline (Table 2, Entries 7, 8)
or the 2-ethynylaniline derivative (Table 4, Entry 9).
The cyclization reaction of N-[5-methoxy-2-(phenylethynyl)-
phenyl]ethanamide (1n) with TBAF in THF under reflux for a
long time (48 h) gave the corresponding indole derivatives (2n)
in 79% yield. However, when the reaction was carried out using
THF–DMF (5:1) as a solvent, the yield of 2n was improved to
88% in 24 h (Table 4, Entry 6).
Although ethyl 2-(hex-1-ynyl)phenylcarbamate (1o) was
refluxed for 4 h to give a mixture of 2-butylindole (2o) and
2-butyl-1-ethoxycarbonylindole (3o) (Table 4, Entry 7), the
cyclization reaction of 1o at reflux in THF for 24 h gave only
2o in 96% yield (Table 4, Entry 8). This deethoxycarboxyl-
ation reaction was found in many cases in the cyclization
reaction.
The cyclization of N-[2-(2-phenylethynyl)phenyl]ethanamide
(1b) (Table 3, Entry 2) with 1 equiv. of TBAF gave only
2-phenylindole (2a) in 51% yield. However, the cyclization
reaction of the phenylcarbamates (1c, d) and the 2,2-dimethyl-
propanamide (1e) gave the corresponding 1-acylindoles (3c, d, e)
rather than 2a in good yields.
Although the cyclization reaction of 1g with K2CO3 in
acetonitrile (Table 2, Entry 7) gave 3g in 75% yield, the
cyclization reaction of 1b with K2CO3 gave 2a in only 9%
yield. The reaction of phenylethynylaniline (1a) with TBAF did
not give 2a similarly in the reaction using sodium ethoxide–
ethanol.
It seems that the tendency to promote the cyclization reaction
with TBAF depends on the acidity of the substituted amino
groups. For example, the cyclization reaction of 1k, which
has an electron-withdrawing group on the benzene moiety,
proceeded at room temperature (Table 4, Entry 3).
Conclusion
Because the cyclization reaction of 2-ethynylanilines with
TBAF proceeds under milder conditions to give the corre-
sponding indoles in excellent yields and does not require dry
conditions and complicated operations, the reaction was found
to be a useful synthetic method for indoles. Considering that
many synthetic methods for haloanilines have been reported
and that cyclization reaction with TBAF gave the correspond-
ing indoles without affecting many functional groups, the
synthesis of indoles with functional groups at any position
except for the 3-position seems to be a widely usable method.
Furthermore, the 3-position of indole is the most reactive pos-
ition for electrophiles, and there are many reports that various
functional groups can be introduced to the 3-position of
indole.8 The cyclization reaction of 2-ethynylanilines with
TBAF can be concluded to have a wide usage for the synthesis
of indoles having multi-functional groups.
Synthesis of indoles having various substituents at the 2-position
and the benzene moiety
As shown in Table 4, the cyclization reaction of ethynylanilines
(1i–m) with TBAF gave the corresponding indoles in good
yields without affecting the bromo, chloro, cyano, ethoxycarb-
onyl, and phenylethynyl groups. Synthesis of 2-aryl- (e.g., 2i)
and 2-alkylindoles (e.g., 2l) can be achieved using the corre-
sponding ethynyl derivatives which were prepared by the
palladium-catalyzed reaction with the terminal alkynes. Indoles
without the functional group at the 2-position were synthesized
J. Chem. Soc., Perkin Trans. 1, 1999, 529–534
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N, 3.95. C25H19NO2 requires C, 82.17; H, 5.24; N, 3.83%);
Experimental
νmax(KBr)/cmϪ1 3320 and 1700; δH 1.35 (3 H, t, J 7.1), 4.27 (2 H,
q, J 7.1), 7.32–7.44 (6 H, m), 7.48–7.59 (6 H, m), 7.67 (1 H, d,
J 1.9), 8.21 (1 H, d, J 8.8); m/z 365 (Mϩ, 100%), 319 (15), 293
(32), and 189(7).
All melting points and boiling points are uncorrected. IR spec-
tra were measured on a JASCO IR-810 spectrophotometer.
1H NMR spectra were recorded on a Varian Gemini 2000 (300
MHz). Chemical shifts are expressed in δ (ppm) values with
tetramethylsilane (TMS) as an internal reference, and coupling
constants are expressed in Hz. Mass spectra and high resolution
mass spectra were recorded on JMS-DX303 and JMS-AX500
instruments, respectively.
tert-Butyl
[5-chloro-2-(oct-1-ynyl)phenyl]carbamate
1l.
Yellow viscous oil; νmax(KBr)/cmϪ1 3400 and 1740; δH 0.91 (3 H,
t, J 7.0), 1.31–1.66 (17 H, m), 2.49 (2 H, t, J 7.0 ), 6.89 (d, J 8.3,
1 H), 7.23 (1 H, d, J 8.3), 7.28 (1 H, s), 8.21 (1 H, s); m/z 335
(Mϩ, 23%), 279 (45), and 57 (100) (Found: m/z 335.1642. Calc.
for C19H26ClNO2 335.1651).
General procedure for the palladium-catalyzed cross-coupling
reaction of 2-iodoanilines with terminal alkynes
Ethyl 5-[2-(formylamino)phenyl]pent-4-ynoate 1m. Colour-
less viscous oil; νmax(KBr)/cmϪ1 3330, 1730, and 1700; δH 1.29
(3 H, t, J 7.1), 2.65 (2 H, t, J 7.3), 2.78 (2 H, t, J 7.3), 4.19 (2 H,
q, J 7.1), 7.03 (1 H, t, J 7.8), 7.20–7.43 (4.3 H, m), 8.43
(0.7 H, d, J 8.2), 8.53 (0.7 H, d, J 1.9), 8.57–8.68 (1 H, br), 8.82
(0.3 H, d, J 0.3); m/z 245 (Mϩ, 90%), 227 (8), 217 (14), 200 (34),
and 144 (100) (Found: m/z 245.1031. Calc. for C14H15NO3
245.1051).
A mixture of a 2-iodoaniline (1 mmol), an alkyne (1 mmol),
PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), and Et3N (5 ml) was
refluxed for the time shown in Table 1. After removal of the
solvent, the residue was diluted with H2O and extracted with
AcOEt. The AcOEt extract was dried over MgSO4 and evapor-
ated. The residue was purified by silica gel column chrom-
atography using hexane–AcOEt as an eluent and recrystalliz-
ation or distillation.
N-[5-Methoxy-2-(2-phenylethynyl)phenyl]ethanamide
1n.
2-(2-Phenylethynyl)aniline 1a. Pale yellow prisms from
hexane–acetone; mp 85–86 ЊC (lit.,10 92 ЊC) (Found: C, 86.82;
H, 5.62; N, 7.15. C14H11N requires C, 87.01; H, 5.74; N, 7.25%);
νmax(KBr)/cmϪ1 3500, 2250, and 1620; δH 4.20–4.39 (br, 2 H),
6.79 (2 H, t, J 7.7 ), 7.14 (1 H, dt, J 7.9, 1.4), 7.32–7.39 (4 H, m),
7.51–7.56 (2 H, m); m/z 193 (Mϩ, 100%), and 165 (27).
Colourless needles from hexane–AcOEt; mp 122–123 ЊC
(Found: C, 77.11; H, 5.58; N, 5.34. C17H15NO2 requires C,
76.96; H, 5.70; N, 5.28%); νmax(KBr)/cmϪ1 3280 and 1660;
δH 2.25 (s, 3 H), 3.85 (s, 3 H), 6.63 (1 H, dd, J 8.5, 2.5), 7.36–7.42
(4 H, m), 7.50–7.54 (2 H, m), 7.96–8.05 (1 H, br), 8.13 (1 H, d,
J 2.5); m/z 265 (Mϩ, 100%), 223 (80), and 208 (42).
Ethyl 2-(2-phenylethynyl)phenylcarbamate 1c. Pale yellow
liquid; bp 170 ЊC/3 mmHg (lit.,5a 170–175 ЊC/3 mmHg);
νmax(KBr)/cmϪ1 3400, 1730, and 1240; δH 1.34 (3 H, t, J 7.1),
4.26 (2 H, q, J 7.1), 7.02 (1 H, t, J 7.7), 7.32–7.58 (8 H, m), 8.18
(1 H, d, J 8.5); m/z 265 (Mϩ, 100%), 237 (2), 219 (11), 206 (25),
193 (41), and 165 (37) (Found: m/z 265.1096. Calc. for
C17H15NO2: 265.1103).
Ethyl 2-(hex-1-ynyl)phenylcarbamate 1o. Colourless liquid;
bp 160 ЊC/2 mmHg (lit.,5a 170–175 ЊC/3 mmHg); νmax(KBr)/
cmϪ1 3400 and 1740; δH 0.97 (3 H, t, J 7.1), 1.33 (3 H, t, J 7.1),
1.48–1.68 (4 H, m), 2.51 (2 H, t, J 6.87), 4.24 (2 H, q, J 7.1), 6.95
(1 H, t, J 7.3), 7.27 (1 H, t, J 7.3), 7.33 (1 H, d, J 7.3), 7.35–7.45
(1 H, br), 8.12 (1 H, d, J 7.5); m/z 245 (Mϩ, 93%), 216 (20), 156
(28), and 130 (100) (Found: m/z 245.1398. Calc. for C15H19NO2
245.1415).
tert-Butyl 2-(2-phenylethynyl)phenylcarbamate 1d. Colourless
prisms from EtOH; mp 62–65 ЊC (Found: C, 77.71; H, 6.54;
N, 4.84. C19H19NO2 requires C, 77.79; H, 6.53; N, 4.77%);
νmax(KBr)/cmϪ1 3395, 2370, and 1780; δH 1.55 (9 H, s), 7.00
(1 H, t, J 7.9), 7.30–7.57 (8 H, m), 8.16 (1 H, d, J 7.9); m/z 293
(Mϩ, 27%), 237 (100), 220 (10), and 193 (94).
N-[2-(Phenylethynyl)phenyl]methanesulfonamide 1g. A mix-
ture of 2-iodoaniline (20.0g, 91.3 mmol), ethynylbenzene (11.2
g, 0.1 mol), CuI (1.73 g, 9.13 mmol), PdCl2(PPh3)2 (1.9 g, 2.7
mmol), and Et3N (200 ml) was stirred for 1 h at room temper-
ature. The reaction mixture was diluted with H2O, and
extracted with CHCl3. The extract was dried over MgSO4. The
CHCl3 extract was evaporated under reduced pressure. The
residue was dissolved in pyridine–THF (1:2, 150 ml), and
methanesulfonyl chloride (11.4 g, 0.1 mol) was added. The mix-
ture was stirred for 24 h at room temperature. The reaction
mixture was diluted with H2O, extracted with CHCl3 and dried
over MgSO4. The CHCl3 extract was evaporated under reduced
pressure. The residue was purified by silica gel column chrom-
atography using hexane–AcOEt (5:1) as an eluent and
recrystallized from acetone–hexane to give colourless needles.
Yield 16.3 g (75%), mp 128–130 ЊC (lit.,9 mp 128–130 ЊC);
νmax(KBr)/cmϪ1 3340 and 2220; δH 3.03 (3 H, s), 6.80–7.80 (10
H, m); m/z 271 (Mϩ, 70%), 192 (100), and 165 (94).
N-[2-(2-Phenylethynyl)phenyl]-2,2-dimethylpropanamide 1e.
Colourless needles from hexane; mp 59–61 ЊC (Found: C, 82.36;
H, 6.99; N, 5.03. C19H19NO requires C, 82.28; H, 6.90; N,
5.05%); νmax(KBr)/cmϪ1 3400, 2350, and 1680; δH 1.36 (9 H, s),
7.07 (1 H, t, J 7.4), 7.33–3.41 (3 H, m), 7.48–7.56 (2 H, m), 8.48
(1 H, d, J 7.42), 8.42–8.50 (1 H, br); m/z 277 (Mϩ, 100%), 220
(15), and 193 (75).
N-[2-(2-Phenylethynyl)phenyl]methanamide 1f. Colourless
needles from hexane–acetone; mp 97–99 ЊC (Found: C, 81.33;
H, 5.10; N, 6.13. C16H13NO requires C, 81.43; H, 5.01; N,
6.33%); νmax(KBr)/cmϪ1 1690; δH 7.10–7.19 (1 H, m), 7.28–7.51
(4.35 H, m), 7.51–7.58 (3 H, m), 7.89–8.02 (1 H, br), 8.45 (0.65
H, d, J 8.5), 8.52 (0.65 H, s), 8.85 (0.35 H, d, J 11.5); m/z 221
(Mϩ, 100%), 193 (39), 179 (3), and 120 (4).
N-[2-(Phenylethynyl)phenyl]ethanamide 1b. This was pre-
pared according to the procedure for the preparation of 1g,
using acetyl chloride (790 mg, 10 mmol) instead of methane-
sulfonyl chloride. Colourless needles from hexane–acetone;
yield 2.0 g (86%). Mp 119–121 ЊC (lit.,10 mp 122 ЊC); νmax(KBr)/
cmϪ1 3300 and 1660; δH 2.24 (3 H, s), 7.07 (1 H, t, J 7.7), 7.26–
7.56 (7 H, m), 8.41 (1 H, d, J 8.2); m/z 235 (Mϩ, 31%), 193 (100),
and 165 (16).
Ethyl 4-bromo-2-(phenylethynyl)phenylcarbamate 1i. Colour-
less needles from hexane; mp 105–106 ЊC (Found: C, 59.31;
H, 4.11; N, 4.18. C17H14BrNO2 requires C, 59.32; H, 4.10; N,
4.07%); νmax(KBr)/cmϪ1 3350, 2370, and 1700; δH 1.34 (3 H, t,
J 7.1), 4.24 (2 H, d, J 7.1), 7.39–7.46 (4 H, m), 7.54–7.61 (3 H,
m), 8.10 (1 H, d, J 9.3); m/z 345 (98%) 343 (Mϩ, 100), 273 (49),
and 271 (50).
N-[2-(Trimethylsilylethynyl)phenyl]methanesulfonamide 1h.
This was prepared according to the procedure for preparation
of 1g, using trimethylsilylacetylene (2.1 g, 10 mol) instead of
Ethyl 2,4-bis(phenylethynyl)phenylcarbamate 1j. Colourless
needles from hexane; mp 121 ЊC (Found: C, 81.98; H, 5.28;
532
J. Chem. Soc., Perkin Trans. 1, 1999, 529–534

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phenylacetylene to give colourless plates from hexane. Yield
3.1 g (80%), mp 138 ЊC; νmax(KBr)/cmϪ1 3250, 2170, 1330, and
1160; δH 0.28 (9 H, s), 3.00 (3 H, s), 7.09 (1 H, br), 7.13 (1 H, t,
J 8.0), 7.35 (1 H, dt, J 8.0, 1.4), 7.46 (1 H, dd, J 8.0, 1.4), 7.58
(1 H, d, J 8.0); m/z 267 (Mϩ, 67%), 252 (100), 189 (66), and 158
(69) (Found: C, 53.85; H, 6.53; N, 5.13. C12H17NOSSi requires
C, 53.90; H, 6.41; N, 5.24%).
1-Methylsulfonyl-2-phenylindole 3g. Colourless needles from
hexane–Et2O; mp 115–116 ЊC (lit.,6 116–117 ЊC); νmax(KBr)/
cmϪ1 1370; δH 2.74 (3 H, s), 6.73 (1 H, s), 7.35–7.45 (5 H, m),
7.56–7.63 (3 H, m), 8.15 (1 H, d, J 7.1); m/z 271 (Mϩ, 52%), 192
(100), and 165 (50) (Found 271.0662. Calc. for C15H13NO2S:
271.0666).
5-Bromo-2-phenylindole 2i. Colourless scales from hexane;
mp 196–198 ЊC (Found: C, 61.69; H, 3.72; N, 5.14. C14H10BrN
requires C, 61.79; H, 3.70; N, 5.15%); νmax(KBr)/cmϪ1 3430;
δH 6.76 (1 H, s), 7.28 (2 H, s), 7.36 (1 H, d, J 7.4), 7.46 (2 H, t,
J 7.4), 7.66 (2 H, d, J 7.4), 7.75 (1 H, s), 8.32–8.42 (1 H, br).
Ethyl 4-cyano-2-(phenylethynyl)phenylcarbamate 1k. To an
MeOH (30 ml) solution of 30% H2O2 (2.0 ml) and 4-amino-
benzonitrile (2.4 g, 20 mmol), I2 (5.05 g, 12 mmol) in MeOH (50
ml) was added, and the reaction mixture was stirred for 4 h at
room temperature. After addition of 6 M Na2S2O3, the mixture
was extracted with CHCl3 and evaporated under reduced pres-
sure. The residue was dissolved in pyridine (100 ml) and ethyl
chlorocarbonate (2.18 g, 20 mmol) was added. After stirring for
1 h at room temperature, the reaction mixture was diluted with
H2O, extracted with CHCl3, and evaporated under reduced
pressure. Ethynylbenzene (300 mg, 2.97 mmol), CuI (52 mg,
0.27 mmol), PdCl2(PPh3)2, and Et3N (30 ml) were added to
the residue and the mixture was stirred for 1 h at room temper-
ature. The reaction mixture was evaporated under reduced
pressure. The residue was diluted with H2O, and extracted with
CHCl3. The CHCl3 extract was dried over MgSO4 and evapor-
ated under reduced pressure. The residue was purified by silica
gel column chromatography using hexane–AcOEt (10:1) as an
eluent and recrystallized from Et2O–hexane to give colourless
needles. Yield 1.74 g (34%), mp 110 ЊC (Found: C, 74.46; H,
4.87; N, 9.61. C17H14N2O requires C, 74.47; H, 4.86; N, 9.65%);
νmax(KBr)/cmϪ1 3400, 2225, and 1740; δH 1.35 (3 H, t, J 7.14),
4.28 (2 H, q, J 7.14), 7.41–7.61 (7 H, m), 7.75 (1 H, d, J 2.2),
8.34 (1 H, d, J 8.8); m/z 290 (Mϩ, 100%), 262 (5), 245 (10), 231
(30), 218 (51), and 190 (26) (Found: m/z 290.1054. Calc. for
C18H14N2O2 290.1054).
2-Phenyl-5-(2-phenylethynyl)indole 2j. Colourless scales from
hexane–AcOEt; mp 225 ЊC (Found: C, 88.14; H, 5.11; N,
4.70. C22H15Nؒ1/3H2O requires C, 88.27; H, 5.27; N, 4.68%);
νmax(KBr)/cmϪ1 3420 and 2200; δH 6.83 (1 H, d, J 2), 7.25–7.40
(5 H, m), 7.46 (2 H, t, J 7.9), 7.56 (2 H, d, J 7.9), 7.68 (2 H, d,
J 8.1), 7.85 (1 H, s), 8.39–8.44 (1 H, br); m/z 293 (Mϩ, 100%),
265 (5), 189 (8), and 146 (19) (Found: m/z 293.1196. Calc. for
C22H15N: 293.1204).
5-Cyano-2-phenylindole 2k. Colourless needles from hexane;
mp 195 ЊC (Found: C, 82.39; H, 4.81; N, 12.85. C15H10N2
requires C, 82.55; H, 4.62; N, 12.84%); νmax(KBr)/cmϪ1 3320
and 2220; δH 6.88 (s, 1 H), 7.37–7.51 (m, 5 H), 7.68 (1 H, d,
J 7.4), 7.98 (1 H, s), 8.60–8.72 (1 H, br); m/z 218 (Mϩ, 100%)
and 190 (15).
6-Chloro-2-hexylindole 2l. Colourless scales from hexane; mp
178–180 ЊC (Found: C, 71.46; H, 7.75; N, 5.91. C14H18ClN
requires C, 71.33; H, 7.70; N, 5.94%); νmax(KBr)/cmϪ1 1730;
δH 0.94 (3 H, t, J 7.3), 1.31–1.69 (17 H, m), 2.97 (2 H, t, J 8.0),
6.30 (1 H, s), 7.16 (1 H, d, J 8.4), 8.14 (1 H, s); m/z 235 (Mϩ,
40%), 178 (28), and 164 (100).
General procedure for the cyclization reaction of 2-ethynyl-
anilines with TBAF
1-tert-Butoxycarbonyl-6-chloro-2-hexylindole 3l. Colourless
plates from hexane; mp 78–79 ЊC (Found: C, 67.78; H, 7.79;
N, 4.06. C19H18ClNO2 requires C, 67.54; H, 7.80; N, 4.17%);
νmax(KBr)/cmϪ1 3400; δH 0.82–1.75 (11 H, m), 2.72 (2 H, t,
J 7.3), 6.20 (1 H, s), 7.02 (1 H, d, J 8.2), 7.27 (1 H, s), 7.40 (1 H,
d, J 8.2), 7.80–7.94 (1 H, br); m/z 335 (Mϩ, 19%), 279 (66), and
57 (100).
A mixture of a 2-ethynylaniline (1 mmol), TBAF (1 M soln. in
THF, 2 or 3 mmol) and THF (5 ml) was refluxed or stirred at
room temperature for the time shown in Tables 2 and 3. After
removal of the THF, the residue was diluted with H2O and
extracted with AcOEt. The AcOEt extract was dried over
MgSO4 and evaporated. The residue was purified by silica gel
column chromatography and/or recrystallization.
Ethyl 3-indol-2-ylpropanoate 2m. Colourless scales from hex-
ane; mp 82 ЊC (Found: C, 71.75; H, 7.03; N, 6.29. C13H15NO2
requires C, 71.87; H, 6.96; N, 6.45%); δH 1.27 (3 H, t, J 7.3), 2.72
(2 H, t, J 6.7), 3.07 (2 H, t, J 6.7), 4.18 (2 H, q, J 7.3), 6.24 (1 H,
s), 7.03–7.14 (2 H, m), 7.31 (1 H, d, J 7.5), 7.51 (1 H, d, J 7.5),
8.44–8.64 (1 H, br); m/z 217 (Mϩ, 80%), 171 (45), and 144 (100).
2-Phenylindole 2a. Colourless scales from hexane–AcOEt;
mp 185–187 ЊC (lit.,11 187–188 ЊC); νmax(KBr)/cmϪ1 3445 and
1655; δH 6.83 (1H, dd, J 1.1, 1.9), 7.12 (1 H, dt, J 7.1, 1.1), 7.20
(1 H, dt, J 8.2, 1.1), 7.22–7.48 (4 H, m), 7.62–7.68 (3 H, m),
8.28–8.42 (1 H, br); m/z 193 (Mϩ, 100%) and 165 (19).
6-Methoxy-2-phenylindole 2n. Colourless scales from
hexane–AcOEt; mp 171–172 ЊC (Found: C, 80.60; H, 5.87; N,
6.21. C15H13NO requires C, 80.69; H, 5.87; N, 6.27%);
νmax(KBr)/cmϪ1 3400; δH 3.87 (3H, s), 6.76 (1 H, d, J 1.5), 6.80
(1 H, dd, J 8.5, 2.1), 6.91 (1 H, d, J 1.5), 7.29 (1 H, t, J 7.1), 7.43
(2 H, t, J 7.1), 7.50 (1 H, d, J 8.5), 7.62 (2 H, d, J 7.14), 8.22–
8.30 (1 H, br); m/z 223 (Mϩ, 100%) and 208 (91).
1-Ethoxycarbonyl-2-phenylindole 3c. Colourless viscous oil;
δH 1.09 (3H, t, J 7.1), 4.24 (2 H, q, J 7.1), 6.60 (1 H, s), 7.24–7.46
(7 H, m), 7.56 (1 H, d, J 7.3), 8.20 (1 H, d, J 8.2); m/z 265 (Mϩ,
100%), 221 (10), 206 (44), 193 (72), and 165 (30) (Found: m/z
265.1087. Calc. for C17H15NO2 265.1102).
1-tert-Butoxycarbonyl-2-phenylindole 3d. Colourless scales
from hexane–Et2O; mp 75–76 ЊC (lit.,12 76–77 ЊC) (Found: C,
77.79; H, 6.50; N, 4.71. C19H19NO requires C, 77.79; H, 6.53; N,
4.77%); νmax(KBr)/cmϪ11720; δH 1.30 (9 H, s), 6.65 (1 H, s),
7.23–7.42 (7 H, m), 7.54 (1 H, d, J 8.2), 8.22 (1 H, d, J 8.2);
m/z 293 (Mϩ, 22%), 237 (44), and 193 (100).
2-Butylindole 2o. Colourless liquid; bp 160 ЊC/3 mmHg (lit.,5a
155–160 ЊC/4 mmHg); νmax(KBr)/cmϪ1 3400; δH 0.95 (3 H, t,
J 7.3), 1.42 (2 H, sextet, J 7.3), 1.71 (2 H, quintet, J 7.3), 2.76
(2 H, t, J 7.3), 6.23 (1 H, s), 7.06 (1 H, t, J 7.2), 7.13 (1 H, t,
J 7.2), 7.31 (1 H, d, J 7.2), 7.53 (1 H, d, J 7.2), 7.80–7.92 (1 H,
br); m/z 173 (Mϩ, 57%) and 130 (100).
1-(2,2-Dimethylpropanoyl)-2-phenylindole 3e. Colourless vis-
cous oil; νmax(KBr)/cmϪ1 1655; δH 1.39 (9 H, s), 6.14 (1 H, s),
7.20–7.26 (3 H, m), 7.29–7.41 (3 H, m), 7.57 (1 H, d, J 7.9), 7.69
(2 H, d, J 7.9); m/z 277 (Mϩ, 100%), 262 (18), 235 (19), 220 (33),
and 193 (34) (Found 277.1445. Calc. for C19H19NO: 277.1466).
1-Ethoxycarbonyl-2-butylindole 3o. White solid; bp 180–
190 ЊC/3 mmHg, mp 35 ЊC (Found: C, 73.22; H, 7.77; N, 5.80.
C15H19NO2 requires C, 73.44; H, 7.81; N, 5.71%); νmax(KBr)/
cmϪ1 1730; δH 0.97 (3 H, t, J 7.4), 1.49–1.51 (5 H, m), 1.64–1.74
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(b) J. Reisch, Chem. Ber., 1964, 97, 2717; (c) C. E. Castro, E. J.
(2 H, m), 3.01 (2 H, t, J 6.8), 4.52 (2 H, q, J 7.4), 6.37 (1 H, s),
7.17–7.24 (2 H, m), 7.44 (1 H, d, J 5.9), 8.11 (1 H, d, J 8.2); m/z
245 (Mϩ, 84%), 203 (100), 174 (29), and 130 (75).
Gaughan and D. C. Owsley, J. Org. Chem., 1966, 31, 4071; (d) C. E.
Castro, R. Havlin, V. K. Honwad, A. Malte and S. Moje, J. Am.
Chem. Soc., 1969, 91, 6464; (e) J. Fujiwara, Y. Fukutani, H. Sano,
K. Maruoka and H. Yamamoto, J. Am. Chem. Soc., 1983, 105, 7177;
( f ) J. Ezquerra, C. Pedregal, C. Lamas, J. Barluenga, M. Perez,
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3 K. Iritani, S. Matsubara and K. Utimoto, Tetrahedron Lett., 1988,
29, 1799.
Indole (Table 3, Entry 8). Colourless scales from EtOH; mp
54 ЊC (lit.,13 53 ЊC); νmax(KBr)/cmϪ1 3030 and 1700; δH 6.57
(1 H, s), 7.10–7.23 (4 H, m), 7.40 (1 H, d, J 8.2), 7.65 (1 H, d,
J 7.7), 8.02–8.30 (1 H, br).
4 (a) E. C. Taylor, A. H. Katz and H. Salgado-Zamora, Tetrahedron
Lett., 1985, 26, 5963; (b) D. E. Rudisill and J. K. Stille, J. Org.
Chem., 1989, 54, 5856; (c) A. Arcadi, S. Cacchi and F. Marinelli,
Tetrahedron Lett., 1989, 30, 2581; (d) N. G. Kundu, J. S. Mahanty,
P. Das and B. Das, Tetrahedron Lett., 1993, 34, 1625; (e) S. Cacchi,
V. Carnicelli and F. Marinelli, J. Organomet. Chem., 1994, 475, 289;
( f ) J. S. Mahanty, M. De, P. Das and N. G. Kundu, Tetrahedron,
1997, 53, 13397.
5 (a) T. Sakamoto, Y. Kondo and H. Yamanaka, Heterocycles, 1986,
24, 31; (b) T. Sakamoto, Y. Kondo, S. Iwashita and H. Yamanaka,
Chem. Pharm. Bull., 1987, 35, 1823; (c) Y. Kondo, S. Kojima and
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and T. Sakamoto, Heterocycles, 1998, 43, 2741; (e) K. Shin and
K. Ogasawara, Chem. Lett., 1995, 289; ( f ) K. Shin and K.
Ogasawara, Synlett, 1995, 859; (g) K. Shin and K. Ogasawara,
Synlett, 1996, 922.
6 T. Sakamoto, Y. Kondo, S. Iwashita, T. Nagano and H. Yamanaka,
Chem. Pharm. Bull., 1988, 36, 1305.
7 A. Yasuhara and T. Sakamoto, Tetrahedron Lett., 1998, 39, 595.
8 A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Comprehensive
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Soc., 1952, 74, 3948.
Reaction of 1h with TBAF at room temperature (Table 3, Entry
8)
According to the general procedure for the cyclization reaction
of 2-ethynylanilines with TBAF, the mixture of 1h (535 mg, 2
mmol) and TBAF (1 M soln in THF, 6 ml, 6 mmol) in THF (30
ml) was stirred at room temperature for 3 h. The reaction mix-
ture was purified by silica gel column chromatography. The first
eluent gave 1-methylsulfonylindole (3q) (200 mg, 51%) and the
second eluent gave N-(2-ethynylphenyl)methanesulfonamide
(1p) (180 mg, 46%). 3q; colourless liquid; bp 170 ЊC/3 mmHg
(lit.,5 140 ЊC/0.5 mmHg); δH 3.10 (3 H, s), 6.73 (1 H, d, J 3.6),
7.31 (1 H, t, J 7.5), 7.38 (1 H, t, J 7.5), 7.38 (1 H, d, J 3.6), 7.92
(1 H, d, J 7.3); m/z 195 (Mϩ, 51%) and 116 (100); 1p; colourless
needles from hexane; mp 105 ЊC (Found: C, 55.47; H, 4.69;
N, 7.09. C9H9NO2S requires C, 55.37; H, 4.65; N, 7.17%);
νmax(KBr)/cmϪ1 3300 and 2250; δH 3.03 (3 H, s), 3.50 (1 H, s),
6.98–7.06 (1 H, br), 7.14 (1 H, t, J 7.7), 7.40 (1 H, t, J 7.7), 7.46
(1 H, d, J 7.7), 7.62 (1 H, d, J 7.7).
Acknowledgements
This research was supported in part by a Fujisawa Pharma-
ceutical Co., Ltd. Award in Synthetic Organic Chemistry,
Japan.
12 T. Sakamoto, Y. Kondo, N. Takazawa and H. Yamanaka, J. Chem.
Soc., Perkin Trans. 1, 1996, 1927.
13 F. T. Tyson, J. Am. Chem. Soc., 1941, 63, 2024.
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