A straightforward synthesis of indole and benzofuran derivatives

Article abstract of DOI:10.1016/j.tet.2007.10.100

A new methodology for the synthesis of indole and benzofuran derivatives has been devised. The starting materials, ortho-substituted aryl diynes, have been easily converted into new unsaturated bis-indolyl and bis-benzofuran derivatives and into 2-ethynylindole and 2-ethynylbenzofuran. Both these products have been further elaborated into more complex unsaturated indole-benzofuran and bis-benzofuran derivatives.

Full text of DOI:10.1016/j.tet.2007.10.100

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 53e60
www.elsevier.com/locate/tet
A straightforward synthesis of indole and benzofuran derivatives
*
Vito Fiandanese , Daniela Bottalico, Giuseppe Marchese, Angela Punzi
Dipartimento di Chimica, Universit a` di Bari, via Orabona 4, 70126 Bari, Italy
Received 29 June 2007; received in revised form 4 October 2007; accepted 26 October 2007
Available online 1 November 2007
Abstract
A new methodology for the synthesis of indole and benzofuran derivatives has been devised. The starting materials, ortho-substituted aryl
diynes, have been easily converted into new unsaturated bis-indolyl and bis-benzofuran derivatives and into 2-ethynylindole and 2-ethynylbenzo-
furan. Both these products have been further elaborated into more complex unsaturated indole-benzofuran and bis-benzofuran derivatives.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Indole; Benzofuran; Aryl diynes; Cyclization
1
. Introduction
unsaturated silylated compounds, and owing to the growing
interest in the synthesis of the heterocyclic systems reported
above, we decided to develop a procedure for the synthesis of
unsaturated molecular frameworks linked to these heterocyclic
systems. Thus, the wide application of the palladium-catalyzed
coupling/cyclization reactions of alkynes with ortho-substituted
aryl halides encouraged us to examine the possibility of prepar-
ing heterocyclic rings starting from ortho-substituted aryl
diynes.
Substituted benzofurans and indoles form the core of numer-
ous natural products and have considerable pharmacological
1
potential. Many synthetic methods for the construction of the
2
indole ring have been reported. Among these, palladium-cata-
lyzed annulation of o-halo anilines and alkynes or of o-alkynyl
anilines has been widely employed for the synthesis of indole
derivatives, due to the versatile nature of this methodology
and increased functional group tolerance. Thus far, many kinds
of reagents have been reported for indole synthesis from 2-ethy-
3
nyl aniline derivatives. Moreover, there has been a growing in-
2
2. Results and discussion
terest in developing general and versatile methods for the
synthesis of benzofuran derivatives, because of their activities
As reported in Scheme 1, starting from 1-trimethylsilyl-1,3-
9
butadiyne 1 and 2-iodoaniline 2a, protected 2-iodophenol 2b
4
as blood coagulation factor Xa inhibitors, as antagonists of
and 2-iodoanisole 2c, we have realized the synthesis of several
ortho-substituted aryl diynes 3, employing, with the appropri-
ate modifications, as reported in Section 3, the Sonogashira
5
angiotensin II receptors and potent calcium blockers. Various
6
7
methods for the preparation of benzofurans are known but
1
4
recent research has focused on the utilization of palladium-cata-
lyzed coupling/cyclization reactions of alkynes with o-hydroxy
protocol.
7
b,f,8
aryl halides.
In connection with our ongoing work
ceeded in synthesizing stereodefined conjugated polyunsatu-
9
e13
in which we suc-
I
Me Si
+
SiMe3
3
Pd(cat.)
1
0e13
rated systems and a series of natural products
using
X
1
X
2
2
2
a X = NH2
b X = OTBDMS
c X = OMe
3a X = NH2 (97%)
3b X = OTBDMS (88%)
3c X = OMe (88%)
*
Corresponding author. Tel./fax: þ39 080 5442075.
E-mail address: fianda@chimica.uniba.it (V. Fiandanese).
Scheme 1.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.100

54
V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
Compounds 3 have been synthesized in excellent yields
88e97%) and we started to investigate on their eventual con-
version into heterocyclic systems. We have found (Scheme 2)
(Scheme 3) by treatment of compound 3b with CuCl in
DMF and to tetrayne derivative 10 (Scheme 4) by reaction
of compound 3c with Cu(OAc) $H O. However, when we per-
(
2
2
1
5
that compound 3a,
Cu(OAc) $H O in pyridine/MeOH as solvent, at room temper-
when subjected to reaction with
formed the reaction of compound 3b with Cu(OAc) $H O, we
2 2
obtained directly the bis-benzofuran derivative 8 with the two
0
2
2
3
m
ature, led easily to tetrayne 4, derived from a dimerization
of compound 3a. However, by employing another copper
rings linked to the positions 2,2 by two triple bonds. (The pyr-
idine/MeOH system probably promotes the deprotection of the
phenolic group and the cyclization reaction, whereas the
dimerization reaction is promoted by the copper salt.)
Moreover, the reaction of compound 3b with a fluoride
1
salt, CuCl in DMF as solvent at 70 C, and performing the
6
ꢀ
reaction in a capped flask, we obtained bis-(1H )-indole 5,
0
with the two indolyl moieties linked to the positions 2,2 by
two triple bonds. (These results are in agreement with the lit-
3
o,8c
ꢀ
source, TBAF
in THF at 55 C, led to the heterocyclic
3
j,16
18
erature data
because it is known that 2-ethynylanilines,
product, 2-ethynylbenzofuran 9 in 70% yield. Thus, these re-
sults confirmed the full versatility of ortho-substituted aryl
diynes 3a and 3b regarding their conversion into the hetero-
cyclic compounds 5, 6, 8 and 9.
without any substituent on the nitrogen atom, in the presence
of copper acetate lead to the cyclized product in very low
3
j
yield, whereas the cyclization is favoured with copper chlo-
1
ride.) Finally, when we performed the reaction of compound
6
In order to evaluate the possibility of synthesizing other and
more complex heterocyclic systems, we decided to employ
compounds 6 and 9 as starting materials in a series of coupling
reactions with different aryl or vinyl halides. Thus (Scheme 5),
we found that when compound 6 was reacted with 2-iodophe-
nol 11, the reaction product 16 was easily cyclized with TBAF
3
a with KH in N-methylpyrrolidone (NMP) as solvent, this
m
3
reaction led directly to the heterocyclic alkyne, 2-ethynylin-
1
dole 6. In an analogous manner, we have subjected also com-
6
1
7
pounds 3b and 3c to similar reactions and for compound 3b
we have found a different selectivity towards the copper salts.
In particular (Schemes 3 and 4), both compounds 3b and 3c
have been easily dimerized leading to tetrayne derivative 7
1
9
in THF, leading to the di-heterocyclic compound 21, with
the two rings (the indolyl and the benzofuran rings) linked
Cu(OAc) ·H O
2
2
pyridine-MeOH
r.t.
NH2
N
4
(61%)
(50%)
H N
2
CuCl, DMF
SiMe3
70 °C
N
H
5
NH2
3a
H
KH, NMP
r.t.
N
H
6
(68%)
Scheme 2.
CuCl, DMF
0 °C
7
OTBDMS 7 (50%) TBDMSO
Cu(OAc) ·H O
2
2
SiMe3
pyridine-MeOH
r.t.
O
O
8
(82%)
OTBDMS
3b
TBAF, THF
55 °C
O
(70%)
9
Scheme 3.
Cu(OAc) ·H O
2
2
SiMe3
pyridine-MeOH
r.t.
OMe
3c
OMe
10 (85%)
MeO
Scheme 4.

V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
55
I
1
1OH
TBAF
THF, r.t.
N
N
H
O
H
HO
1
6 (43%)
21 (46%)
I
1
2O
N
O
H 17 (81%)
I
PdCl (PPh )
2
3 2
13
CuI, Et N
N
H
3
N
H 1
THF, r.t.
6
8 (72%)
Me Si
3
Br
SiMe3
14
N
H 1
9 (69%)
Br
15
N
H 20 (79%)
Scheme 5.
by a single bond. Moreover, the reaction of 6 with 2-iodoben-
manner to the procedure reported in Scheme 3, by a dimeriza-
tion reaction of compound 9.
1
8
zofuran 12 led to the di-heterocyclic compound 17 with the
same two rings linked by a triple bond. Also the other reac-
tions of compound 6 with the aryl and vinyl halides 13e15
proceeded very well, leading to the functionalized indole
derivatives 18e20 in good yields.
In summary, our synthetic approach to these heterocyclic
systems compares favourably with other procedures. A special
advantage of our strategy is represented by the possibility of
synthesizing several heterocyclic compounds containing the
benzofuran or the indole-benzofuran rings, starting from the
same intermediates and employing simple coupling and
dimerization reactions. Moreover, the simplicity of the opera-
tions involved, the mild reaction conditions and the ready
availability of the silyl derivative employed are additional
features making the procedure very promising.
In the case of compound 9, we planned to realize a conve-
nient procedure for the synthesis of benzofuran derivatives
containing two benzofuran rings linked directly to the posi-
0
tions 2,2 by a single bond or by one triple bond and also by
two triple bonds. Thus (Scheme 6), we reacted compound 9
with 2-iodophenol 11 and found that this reaction led directly
0
20
to 2,2 -bi-benzofuran 22, by means of a tandem coupling/cy-
2
1
clization reaction. Moreover, to obtain compound 23 it was
sufficient to perform the coupling reaction of 9 with 2-iodo-
benzofuran 12. Finally, as reported in the scheme, the same
dibenzofuran diyne 8 was easily obtained in an alternative
3
. Experimental
3.1. General
MachereyeNagel silica gel (60, particle size 0.040e
.063 mm) for column chromatography and MachereyeNagel
0
I
aluminum sheets with silica gel 60 F254 for TLC were used.
GC analysis was performed on a Varian 3900 gas chromato-
graph equipped with a J & W capillary column (DB-1301,
OH
1
1
PdCl (PPh ) ,CuI
2
3 2
O
2
O
Et N, THF, 50 °C
3
2 (45%)
3
0 mꢁ0.25 mm id). GC/mass-spectrometric analysis was per-
formed on a Shimadzu GCeMS-QP5000 gas chromatograph-
mass spectrometer equipped with a Zebron capillary column
I
12O
1
(methyl polysiloxane, 30 mꢁ0.25 mm id). H NMR spectra
PdCl (PPh ) , CuI
O
2
3 2
O 2
3 (84%)
O
Et N, THF, r.t.
were recorded in deuterochloroform or CD COCD on
3 3
9
3
a Bruker AM 500 spectrometer at 500 MHz or on a Varian In-
3
1
ova at 400 MHz. C NMR spectra were recorded in deutero-
chloroform or CD COCD on a Bruker AM 500 spectrometer
Cu(OAc) ·H O
2
2
3
3
pyridine-MeOH
r.t.
at 125.7 MHz or on a Varian Inova at 100.6 MHz. IR spectra
were recorded on a PerkineElmer FT-IRdSpectrum One
and on a Shimadzu IR Prestige 21 spectrometers. Solvents
O
O
8
(66%)
Scheme 6.

56
V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
were dried before use as follows: tetrahydrofuran was distilled
from sodium and N,N-dimethylformamide and acetonitrile
were distilled over molecular sieves. Commercial NMP was
used as supplied. Melting points (uncorrected) were deter-
mined on a Reichert Microscope. 2-Iodobenzofuran was pre-
(27), 98 (10), 97 (84), 83 (7), 73 (70), 69 (16), 59 (19), 57
(14), 45 (26), 43 (25), 41 (17%).
1
7
3.2.3. 2-(4-Trimethylsilyl-1,3-butadiyn-1-yl)anisole (3c)
To a stirred solution of 1-trimethylsilyl-1,3-butadiyne 1
(1.19 g, 9.74 mmol), 2-iodoanisole 2c (1.14 g, 4.87 mmol),
Pd(PPh ) Cl (0.14 g, 0.20 mmol) and Et N (9.5 mL), under
1
8
pared according to a literature procedure.
3
2
2
3
3
3
2
.2. Synthesis of 2-substituted aryl diynes 3
nitrogen, at room temperature, after 5 min, CuI (0.019 g,
.10 mmol) was added and stirring was continued at the
same temperature for 12 h. Then, the mixture was quenched
0
15
.2.1. 2-(4-Trimethylsilyl-1,3-butadiyn-1-yl)aniline (3a)
A solution of 1-trimethylsilyl-1,3-butadiyne 1 (3.36 g,
7.54 mmol) in anhydrous CH CN (30 mL) was added at
3
with a saturated aqueous solution of NH Cl (30 mL) and ex-
4
tracted with ethyl acetate (3ꢁ30 mL). The organic extracts
were washed with H O (3ꢁ20 mL), dried over Na SO and
room temperature, under nitrogen, to a stirred mixture of 2-
iodoaniline 2a (3.02 g, 13.77 mmol), Pd(PPh3)4 (0.80 g,
0
2
2
4
concentrated under vacuum. The residue was purified by per-
colation on Florisil column (10% ethyl acetate/petroleum
ether) leading to 0.98 g of compound 3c (88% yield) as
a brown oil. nmax (neat) 2960, 2203, 2102, 1594, 1490,
1463, 1433, 1272, 1248, 1018, 847, 752; dH (400 MHz,
.69 mmol), CuI (0.26 g, 1.37 mmol) and Et N (1.393 g,
3
3.77 mmol) in CH CN (30 mL). After reaction completion
3
1
(6 h), the mixture was quenched with a saturated aqueous so-
lution of NH Cl (50 mL) and extracted with ethyl acetate
4
(
(
3ꢁ50 mL). The organic extracts were washed with H O
CDCl ) 7.44 (dd, J¼7.4, 1.6 Hz, 1H), 7.36e7.29 (m, 1H),
2
3
3ꢁ50 mL), dried over Na SO and concentrated under vac-
6.92e6.85 (m, 2H), 3.89 (s, 3H), 0.23 (s, 9H); dC
(100.6 MHz, CDCl ) 161.7, 134.6, 130.8, 120.5, 110.6, 91.0,
2
4
uum. The residue was purified by column chromatography
on silica gel (10% ethyl ether/petroleum ether) leading to
2
3
88.0, 77.9, 73.3, 55.8, ꢂ0.4 (one coincident peak not ob-
þ
.84 g of compound 3a (97% yield) as a brown oil. nmax
neat) 3480, 3384, 2959, 2195, 2097, 1616, 1489, 1455,
served); MS m/z 228 (M , 37), 214 (21), 213 (100), 198 (7),
183 (21), 161 (8), 139 (8), 106 (21), 85 (11), 73 (9), 53
(10), 43 (19%).
(
1
7
1
316, 1284, 1251, 849, 748, 705; dH (400 MHz, CDCl3)
.29 (dd, J¼6.4, 1.2 Hz, 1H), 7.12 (ddd, J¼6.4, 5.9, 1.2 Hz,
H), 6.66e6.61 (m, 2H), 4.27 (br s, 2H), 0.23 (s, 9H); d
3.3. Synthesis of compounds 4e6
C
(
1
1
100.6 MHz, CDCl ) 149.8, 133.3, 130.7, 117.9, 114.3,
3
þ
0
05.6, 91.7, 87.8, 79.3, 73.9, ꢂ0.4; MS m/z 213 (M , 55),
3.3.1. 2,2 -(Octa-1,3,5,7-tetrayne-1,8-diyl)dianiline (4)
To a solution of Cu(OAc) $H O (1.88 g, 9.40 mmol) in pyr-
99 (18), 198 (100), 182 (7), 170 (6), 168 (8), 158 (9), 144
2
2
(
(
6), 141 (7), 130 (7), 117 (6), 99 (46), 85 (14), 77 (10), 72
13), 53 (21), 44 (15), 43 (35%).
idine (18.5 mL) and methanol (18.5 mL) was added at room
temperature, under nitrogen, 2-(4-trimethylsilyl-1,3-butadiyn-
1-yl)aniline 3a (1.00 g, 4.70 mmol). After reaction completion
(12 h), the mixture was quenched with a saturated aqueous so-
3
.2.2. 2-(4-Trimethylsilyl-1,3-butadiyn-1-yl)-tert-
butyldimethylsilylphenol (3b)
A solution of 2-(tert-butyldimethylsilyloxy)iodobenzene 2b
lution of NH Cl (50 mL) and extracted with ethyl acetate
4
(3ꢁ50 mL). The organic extracts were washed with water
(3ꢁ30 mL), dried over Na SO and concentrated under vac-
(
2
3.83 g, 11.47 mmol), 1-trimethylsilyl-1,3-butadiyne 1 (2.80 g,
2.94 mmol), Pd(PPh3)4 (0.53 g, 0.46 mmol) and Et N
2
4
uum. The residue was purified by column chromatography
on silica gel (30% ethyl acetate/petroleum ether) leading to
0.40 g of compound 4 (61% yield) as a yellow solid
3
(
48.0 mL), under nitrogen, was stirred for 5 min at room tem-
perature, then CuI (0.044 g, 0.23 mmol) was added and stir-
ring was continued for another 2 min. The mixture was
ꢀ
(mp¼130e132 C). [Found: C, 85.74; H, 4.35; N, 9.93.
ꢀ
heated at 50 C for 6 h, then was quenched with a saturated
aqueous solution of NH Cl (50 mL) and extracted with ethyl
C H N requires: C, 85.69; H, 4.31; N, 9.99%.] n
12
2
0
2
max
(KBr) 3307, 3191, 2186, 1609, 1564, 1485, 1449, 1245,
737; dH (500 MHz, CDCl ) 7.32 (ddd, J¼7.6, 1.5, 0.6 Hz,
4
acetate (3ꢁ50 mL). The organic extracts were washed with
H O (3ꢁ50 mL), dried over Na SO and concentrated under
3
2H), 7.16 (ddd, J¼8.2, 7.3, 1.5 Hz, 2H), 6.67e6.63 (m, 4H),
2
2
4
vacuum. The residue was purified by column chromatography
on silica gel (petroleum ether) leading to 3.31 g of compound
4.34 (br s, 4H); d (125.7 MHz, CDCl ) 150.8, 133.7, 131.5,
C
3
118.0, 114.5, 104.4, 79.7, 75.5, 68.7, 64.4.
3
C H OSi requires: C, 69.45; H, 8.59%.] n (neat) 2958,
b (88% yield) as a brown oil. [Found: C, 69.49; H, 8.60.
0
3.3.2. 2,2 -(Buta-1,3-diyne-1,4-diyl)bis(1H-indole) (5)
CuCl (0.19 g, 1.88 mmol) was added to a solution of 3a
1
9
28
2
max
2
1
1
930, 2858, 2205, 2102, 1593, 1485, 1448, 1288, 1252,
019, 910, 843; dH (400 MHz, CDCl ) 7.40 (dd, J¼7.7,
(0.40 g, 1.88 mmol) in DMF (4 mL) and the mixture was
ꢀ
3
.7 Hz, 1H), 7.22 (td like, J¼7.8, 1.7 Hz, 1H), 6.89 (td,
warmed at 70 C in a capped flask. After reaction completion
(5 h), the mixture was quenched with a saturated aqueous so-
J¼7.7, 0.9 Hz, 1H), 6.82 (br d, J¼8.2 Hz, 1H), 1.06 (s, 9H),
0
1
2
.25 (s, 6H), 0.24 (s, 9H); dC (100.6 MHz, CDCl ) 158.3,
3
lution of NH Cl (20 mL) and extracted with ethyl acetate
4
34.1, 130.5, 121.2, 119.8, 114.1, 90.4, 88.2, 77.9, 74.4,
þ
(3ꢁ20 mL). The organic extracts were washed with a saturated
solution of NaCl (3ꢁ20 mL), dried over Na SO and concen-
5.6, 18.2, ꢂ0.4, ꢂ4.4; MS m/z 328 (M , 2), 273 (12), 272
2
4
(
32), 271 (100), 255 (20), 243 (7), 232 (14), 231 (60), 128
trated under vacuum. The residue was purified by percolation

V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
57
0
on silica gel (20% ethyl acetate/petroleum ether) leading to
0
3.4.2. 2,2 -(Buta-1,3-diyne-1,4-diyl)bis(1-benzofuran) (8)
.13 g of compound 5 (50% yield) as a pale yellow solid
ꢀ
Compound 3b (0.30 g, 0.92 mmol) was added, under nitro-
gen, to a solution of Cu(OAc) $H O (0.37 g, 1.84 mmol) in
pyridine (4 mL) and methanol (4 mL), and the reaction was
performed at room temperature. After reaction completion
(12 h), the mixture was quenched with a saturated aqueous so-
(
C H N requires: C, 85.69; H, 4.31; N, 9.99%.] n
mp¼218e220 C). [Found: C, 85.60; H, 4.36; N, 9.95.
2
2
2
0
12
2
max
(
KBr) 3370, 2147, 1606, 1441, 1391, 1342, 1259, 1092,
1
1
0
019, 803, 748, 737, 652, 505; dH (500 MHz, acetone-d6)
0.82 (br s, 2H), 7.59 (br d, J¼7.9 Hz, 2H), 7.42 (dd, J¼8.3,
.7 Hz, 2H), 7.24 (ddd, J¼8.3, 7.1, 1.0 Hz, 2H), 7.09 (ddd,
lution of NH Cl (20 mL) and extracted with ethyl acetate
4
(3ꢁ20 mL). The organic extracts were washed with water
(3ꢁ20 mL), dried over Na SO and concentrated under vac-
J¼7.9, 7.1, 0.7 Hz, 2H), 6.99 (br s, 2H); d (125.7 MHz, ace-
C
2
4
tone-d ) 138.1, 128.3, 125.0, 121.7, 121.3, 117.8, 112.2, 112.2,
uum. The residue was purified by column chromatography
on silica gel (petroleum ether) leading to 0.106 g of compound
6
7
7.3, 76.9.
ꢀ
8 (82% yield) as a yellow solid (mp¼165e168 C). [Found:
C, 85.03; H, 3.60. C H O requires: C, 85.09; H, 3.57%.]
nmax (KBr) 2141, 1439, 1342, 1245, 1176, 940, 883, 810,
2
0 10 2
1
6
3
.3.3. 2-Ethynyl-1H-indole (6)
KH (0.27 g, 6.77 mmol) was dissolved in NMP (5 mL) un-
der nitrogen at room temperature, then a solution of 3a
0.60 g, 2.82 mmol) in NMP (6 mL) was added dropwise
733; dH (400 MHz, CDCl ) 7.57 (ddd, J¼7.8, 1.2, 0.7 Hz,
3
2H), 7.47 (dq like, J¼8.3, 0.9 Hz, 2H), 7.38 (ddd, J¼8.3,
7.2, 1.2 Hz, 2H), 7.26 (ddd, J¼7.8, 7.2, 1 Hz, 2H), 7.15 (d,
J¼0.9 Hz, 2H); d (100.6 MHz, CDCl ) 155.3, 137.3, 127.1,
(
and the mixture was stirred for 1 h at room temperature. The
reaction was quenched with H O (20 mL) and extracted with
C
3
126.7, 123.7, 121.6, 115.4, 111.5, 79.4, 74.6.
2
ethyl acetate (3ꢁ20 mL), dried over Na SO and concentrated
2
4
1
8
under vacuum. The crude product was purified by column
chromatography on silica gel (10% ethyl acetate/petroleum
ether) affording 0.27 g of compound 6 (68% yield) as a yellow
3.4.3. 2-Ethynyl-1-benzofuran (9)
TBAF (1 M in THF, 6.3 mL) was added at room tempera-
ture, under nitrogen, to a solution of 3b (1.60 g, 4.88 mmol)
in THF (27 mL) and the reaction mixture was stirred at
55 C for 5 h. The mixture was quenched with a saturated
aqueous solution of NH Cl (20 mL) and extracted with ethyl
ꢀ
16
ꢀ
solid (mp¼68e70 C, lit. mp¼68e69 C). n
(KBr) 3386,
269, 2104, 1608, 1446, 1397, 1345, 1291, 1213, 1125, 1013,
00, 749, 680, 598, 499; d (400 MHz, acetone-d ) 10.61 (br
max
ꢀ
3
8
H
6
4
s, 1H), 7.55 (br d, J¼8.0 Hz, 1H), 7.38 (dd, J¼8.2, 0.9 Hz,
acetate (3ꢁ30 mL). The organic extracts were washed with
H O (3ꢁ30 mL), dried over Na SO and concentrated under
1
H), 7.18 (ddd, J¼8.2, 7.1, 1.1 Hz, 1H), 7.05 (ddd, J¼8.0,
2
2
4
7
.1, 0.9 Hz, 1H), 6.78 (br s, 1H), 3.95 (s, 1H); d
vacuum. The residue was purified by column chromatography
on silica gel (petroleum ether) leading to 0.485 g of compound
9 (70% yield) as a pale yellow oil. nmax (neat) 3290, 1555,
1447, 1260, 1245, 1183, 943, 813, 747, 684, 607; dH
C
(
1
(
100.6 MHz, acetone-d ) 137.3, 128.3, 124.0, 121.4, 120.9,
6
18.7, 112.0, 109.3, 82.1, 77.2; MS m/z 141 (M , 100), 140
26), 114 (23), 113 (13), 89 (11), 70 (20), 63 (19), 62 (10),
þ
5
5 (7), 52 (7), 51 (7), 50 (7%).
(400 MHz, CDCl ) 7.57 (ddd, J¼7.8, 1.3, 0.7 Hz, 1H), 7.46
3
(
dq like, J¼8.3, 0.9 Hz, 1H), 7.36 (ddd, J¼8.3, 7.2, 1.3 Hz,
1
H), 7.25 (ddd, J¼7.8, 7.2, 1.0 Hz, 1H), 7.01 (dd, J¼0.9,
3
.4. Synthesis of compounds 7e10
0.4 Hz, 1H), 3.50 (d, J¼0.4 Hz, 1H); d (100.6 MHz,
C
CDCl ) 154.8, 137.7, 127.2, 126.0, 123.5, 121.4, 112.6,
3
0
þ
3
.4.1. 2,2 -(Octa-1,3,5,7-tetrayne-1,8-diyl)di-tert-
111.4, 83.4, 74.1; MS m/z 142 (M , 100), 114 (23), 113
(15), 88 (14), 63 (14), 62 (11%).
butyldimethylsilyldiphenol (7)
CuCl (0.15 g, 1.53 mmol) was added to a solution of 3b
(0.5 g, 1.53 mmol) in DMF (10 mL) and the mixture was
ꢀ
warmed at 70 C in a capped flask. After reaction completion
(12 h), the mixture was quenched with a saturated aqueous so-
lution of NH Cl (20 mL) and extracted with ethyl acetate
0
3.4.4. 2,2 -(Octa-1,3,5,7-tetrayne-1,8-diyl)dianisole (10)
Compound 3c (0.30 g, 1.32 mmol) was added at room tem-
perature, under nitrogen, to a solution of Cu(OAc) $H O
2
2
(0.54 g, 2.72 mmol) in pyridine (6 mL) and methanol
(6 mL). After reaction completion (12 h), the mixture was
quenched with a saturated aqueous solution of NH Cl
4
(
3ꢁ20 mL). The organic extracts were washed with a saturated
2 4
solution of NaCl (3ꢁ20 mL), dried over Na SO and concen-
4
trated under vacuum. The residue was purified by column
chromatography on silica gel (petroleum ether) leading to
(20 mL) and extracted with ethyl acetate (3ꢁ30 mL). The
organic extracts were washed with water (3ꢁ20 mL), dried
over Na SO and concentrated under vacuum. The residue
0.195 g of compound 7 (50% yield) as a yellow oil. [Found:
C, 75.33; H, 7.38. C H O Si requires: C, 75.24; H,
2
4
was purified by percolation on a Florisil column (30% ethyl
acetate/petroleum ether) leading to 0.179 g of compound 10
3
2
38
2
2
7
1
.45%.] nmax (neat) 2954, 2930, 2857, 2197, 1593, 1563,
484, 1448, 1289, 1256, 908, 838, 783, 755; dH (400 MHz,
ꢀ
(85% yield) as a pale brown solid (mp¼142e145 C). [Found:
CDCl ) 7.41 (dd, J¼7.6, 1.8 Hz, 2H), 7.23 (ddd, J¼8.3, 7.6,
C, 85.19; H, 4.50. C H O requires: C, 85.14; H, 4.55%.]
22 14 2
3
1
.8 Hz, 2H), 6.88 (td, J¼7.6, 0.9 Hz, 2H), 6.80 (dd, J¼8.3,
nmax (KBr) 2190, 1569, 1482, 1458, 1429, 1268, 1240, 1018,
733; dH (500 MHz, CDCl ) 7.46 (dd, J¼7.6, 1.5 Hz, 2H),
0
CDCl ) 159.1, 134.7, 131.2, 121.3, 119.9, 113.3, 77.9, 75.6,
.9 Hz, 2H), 1.02 (s, 18H), 0.22 (s, 12H); d (100.6 MHz,
C
3
7.34 (ddd, J¼8.4, 7.6, 1.5 Hz, 2H), 6.89 (td, J¼7.6, 0.8 Hz,
2H), 6.86 (br d, J¼8.4 Hz, 2H), 3.87 (s, 6H); dC
3
6
7.5, 64.0, 25.6, 18.2, e4.3.

58
V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
2
2
(
125.7 MHz, CDCl ) 162.4, 135.1, 131.5, 120.6, 110.7, 109.8,
3
3.5.3. 2-(Phenylethynyl)-1H-indole (18)
7
8.2, 74.5, 68.0, 64.1, 55.8.
Product 18 was prepared from 6 (0.22 g, 1.56 mmol) and
iodobenzene 13 (0.27 g, 1.3 mmol) in accordance with the
general procedure. The residue was purified by column chro-
matography on silica gel (10% ethyl acetate/petroleum ether)
leading to 0.20 g (72% yield) of compound 18 as a pale orange
3
1
.5. General procedure for the synthesis of compounds
6e20 and preparation of compound 21
ꢀ
22
ꢀ
solid (mp¼168e170 C, lit. 161e162 C). [Found: C, 88.38;
A THF solution (0.60 M) of 2-ethynyl-1H-indole 6
H, 5.05; N, 6.49. C H N requires: C, 88.45; H, 5.10; N,
1
6 11
(
1.5 equiv) was added at room temperature, under nitrogen,
to a stirred mixture of the halo derivatives 11e15 (1e
.5 equiv), PdCl (PPh ) (2 mol %), CuI (4 mol %) and Et N
6.45%.] nmax (KBr) 3374, 1592, 1530, 1480, 1440, 1394,
1347, 1303, 1104, 1024, 794, 747, 687, 653, 507; dH
1
(400 MHz, acetone-d ) 10.69 (br s, 1H), 7.62e7.49 (m, 3H),
2
3 2
3
6
(
3
1.5 equiv) in THF (0.60 M). After reaction completion (1e
h), the mixture was quenched with a saturated aqueous solu-
tion of NH Cl (20 mL) and extracted with ethyl acetate
7.46e7.35 (m, 4H), 7.21 (t like, J¼7.6 Hz, 1H), 7.08 (t like,
J¼7.3 Hz, 1H), 6.84 (br s, 1H); d (100.6 MHz, acetone-d )
C
6
137.1, 131.4, 128.9, 128.1, 123.4, 122.9, 120.7, 120.3,
118.9, 111.4, 108.3, 91.9, 82.5 (one coincident peak not ob-
4
(
3ꢁ20 mL). The organic extracts were washed with H O
2
þ
(
uum. The residue was purified by column chromatography
3ꢁ20 mL), dried over Na SO and concentrated under vac-
served); MS m/z 217 (M , 100), 216 (33), 189 (14), 109
(26), 94 (18), 83 (6), 81 (7), 63 (7), 51 (6%).
2
4
leading to compounds 16e20.
3.5.4. 2-[(3E )-4-Trimethysilyl-3-buten-1-yn-1-yl]-
3
.5.1. 2-(1H-Indol-2-ylethynyl)phenol (16)
1H-indole (19)
Product 16 was prepared from 6 (0.22 g, 1.56 mmol) and
-iodophenol 11 (0.34 g, 1.56 mmol) in accordance with the
general procedure. Purification by column chromatography
silica gel, 20% ethyl acetate/petroleum ether) afforded
Compound 19 (0.20 g, 69% yield, pale brown oil) was ob-
tained from 6 (0.21 g, 1.46 mmol) and (E )-2-bromovinylsilane
14 (0.22 g, 1.22 mmol) after purification by column chroma-
tography (10% ethyl acetate/petroleum ether). [Found: C,
75.30; H, 7.20; N, 5.89. C H NSi requires: C, 75.26; H,
2
(
0
.156 g of product 16 (43% yield) as a brown solid
ꢀ
1
5 17
(mp¼104e107 C). [Found: C, 82.33; H, 4.80; N, 5.95.
C H NO requires: C, 82.38; H, 4.75; N, 6.00%.] n
7.16; N, 5.85%.] nmax (neat) 3408, 3058, 2954, 2191, 1582,
1569, 1346, 1302, 1248, 972, 863, 840, 792, 748, 736; dH
1
6
11
max
(
(
7
KBr) 3396, 1443, 1406, 1260, 1092, 1020, 798; dH
400 MHz, CDCl ) 8.38 (br s, 1H), 7.60 (d, J¼7.6 Hz, 1H),
(400 MHz, CDCl ) 8.12 (br s, 1H), 7.59 (d, J¼7.6 Hz, 1H),
3
7.29 (d, J¼8.4 Hz, 1H), 7.23 (t like, J¼7.4 Hz, 1H), 7.12
(t like, J¼7.4 Hz, 1H), 6.78 (br s, 1H), 6.59 (d, J¼19.6 Hz,
3
.41 (dd, J¼7.7, 1.5 Hz, 1H), 7.34e7.19 (m, 3H), 7.12
(
t like, J¼7.3 Hz, 1H), 6.97 (d, J¼8.4 Hz, 1H), 6.91 (t like,
1H), 6.20 (d, J¼19.6 Hz, 1H), 0.15 (s, 9H); d (100.6 MHz,
C
J¼7.5 Hz, 1H), 6.85 (br s, 1H); d (100.6 MHz, CDCl )
CDCl ) 146.6, 136.4, 128.0, 123.8, 122.8, 121.1, 120.7,
3
C
3
þ
1
1
2
56.6, 136.2, 131.8, 130.8, 127.6, 123.8, 121.0, 120.6,
20.6, 117.8, 115.0, 110.9, 109.4, 109.1, 88.4, 86.5; MS m/z
119.0, 111.0, 109.2, 93.2, 82.4, ꢂ1.4; MS m/z 239 (M , 64),
238 (12), 224 (48), 199 (18), 198 (100), 180 (10), 174 (12),
154 (7), 146 (6), 141 (5), 130 (5), 112 (7), 105 (7), 99 (38),
85 (12), 73 (11), 59 (22), 53 (10), 45 (25), 43 (26%).
þ
33 (M , 100), 204 (30), 117 (42), 102 (33), 89 (19), 88
(
14), 76 (11), 63 (10%).
3
.5.2. 2-(1-Benzofuran-2-ylethynyl)-1H-indole (17)
Product 17 (0.20 g, 81% yield) was obtained from 6
3.5.5. 2-[(3E )-4-Phenyl-3-buten-1-yn-1-yl]-1H-indole (20)
Product 20 was prepared from 6 (0.25 g, 1.78 mmol) and
(E )-2-bromostyrene 15 (0.27 g, 1.48 mmol). The residue was
purified by column chromatography (silica gel, 10% ethyl ac-
etate/petroleum ether) leading to 0.28 g (79% yield) of 20 as
(
0
0.20 g, 1.43 mmol) and 2-iodobenzofuran 12 (0.23 g,
.95 mmol), in accordance with the general procedure, after
column chromatography (silica gel 10% ethyl acetate/petro-
ꢀ
ꢀ
leum ether) (yellow solid, mp¼182e184 C). [Found: C,
a pale yellow solid (mp¼174e177 C). [Found: C, 88.90; H,
8
4
1
4.09; H, 4.30; N, 5.48. C H NO requires: C, 84.03; H,
11
5.43; N, 5.80. C H N requires: C, 88.86; H, 5.39; N,
18 13
1
8
.31; N, 5.44%.] nmax (KBr) 3374, 2205, 1610, 1582, 1442,
346, 1301, 1252, 1139, 1093, 932, 797, 738, 648, 499; dH
5.76%.] nmax (KBr) 3374, 2189, 1591, 1348, 1300, 1229,
1145, 1043, 1023, 951, 797, 745, 740, 689, 653, 509, 469;
d (400 MHz, CDCl ) 8.14 (br s, 1H), 7.59 (br d, J¼6.8 Hz,
(
500 MHz, CDCl ) 8.27 (br s, 1H), 7.62 (d, J¼7.9 Hz, 1H),
3
H
3
7
.58 (d, J¼7.6 Hz, 1H), 7.49 (d, J¼8.1 Hz, 1H), 7.39e7.32
m, 2H), 7.30e7.23 (m, 2H), 7.15 (t like, J¼7.4 Hz, 1H),
.04 (s, 1H), 6.94 (br d, J¼1.0 Hz, 1H); d (125.7 MHz,
1H), 7.44e7.40 (m, 2H), 7.38e7.26 (m, 4H), 7.25e7.20 (m,
1H), 7.16e7.10 (m, 1H), 7.06 (d, J¼16.2 Hz, 1H), 6.81e
(
7
6.78 (m, 1H), 6.39 (d, J¼16.2 Hz, 1H); d (100.6 MHz,
C
C
CDCl ) 155.0, 138.2, 136.4, 127.6, 127.5, 125.9, 124.2,
CDCl ) 141.8, 136.4, 136.3, 129.1, 129.0, 128.1, 126.6,
3
3
1
1
23.4, 121.3, 121.1, 120.8, 117.3, 112.1, 111.3, 110.9,
þ
123.8, 121.1, 120.8, 119.2, 111.0, 109.1, 107.6, 92.6, 84.3;
þ
10.4, 87.6, 82.9; MS m/z 257 (M , 100), 256 (14), 228
MS m/z 243 (M , 100), 242 (63), 241 (56), 240 (15), 215
(16), 122 (38), 121 (46), 109 (11), 108 (14), 107 (16), 94
(19), 90 (10), 89 (18), 63 (11), 51 (11%).
(
(
13), 227 (10), 201 (6), 200 (6), 129 (37), 114 (27), 101
16), 100 (10), 88 (11), 75 (5), 63 (6%).

V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
59
1
9
3
.5.6. 2-(1-Benzofuran-2-yl)-1H-indole (21)
TBAF (1 M in THF, 1.39 mmol) was added to a solution of
by column chromatography on silica gel (petroleum ether)
leading to 0.38 g of compound 23 (84% yield) as a pale yellow
ꢀ
2
-(1H-indol-2-ylethynyl)phenol 16 (0.25 g, 1.07 mmol) in
solid (mp¼143e145 C). n
(KBr) 1449, 1349, 1295, 1253,
max
1142, 960, 799, 747, 730; dH (400 MHz, CDCl ) 7.60 (ddd,
3
THF (5 mL). The mixture was stirred at room temperature
for 2 h. The mixture was quenched with a saturated aqueous
solution of NH Cl (20 mL) and extracted with ethyl acetate
J¼7.8, 1.3, 0.7 Hz, 2H), 7.50 (br dd, J¼8.3, 0.9 Hz, 2H),
7.37 (ddd, J¼8.3, 7.3, 1.3 Hz, 2H), 7.27 (ddd, J¼7.8, 7.3,
4
(
3ꢁ20 mL). The organic extracts were washed with H O
1.0 Hz, 2H), 7.12 (d, J¼0.9 Hz, 2H); d (100.6 MHz,
2
C
(
uum. The residue was purified by column chromatography
3ꢁ20 mL), dried over Na SO and concentrated under vac-
CDCl ) 155.2, 137.6, 127.4, 126.2, 123.5, 121.4, 113.2,
3
2
4
þ
111.4, 85.2; MS m/z 258 (M , 100), 229 (7), 202 (10), 201
(
10% ethyl acetate/petroleum ether) leading to 0.115 g of
(10), 200 (13), 129 (27), 101 (14), 100 (9), 88 (21), 75 (7),
63 (6%).
compound 21 (46% yield) as a pale yellow solid (mp¼220e
ꢀ
19
22 C, lit. mp¼213e214 C). n
ꢀ
2
1
(KBr) 3422, 1601,
max
0
414, 1261, 1102, 1054, 1021, 979, 749, 731; d (400 MHz,
H
3.6.3. 2,2 -(Buta-1,3-diyne-1,4-diyl)bis(1-benzofuran) (8)
CDCl ) 8.65 (br s, 1H), 7.66 (dd, J¼7.9, 0.8 Hz, 1H), 7.61e
3
2-Ethynyl-1-benzofuran 9 (0.20 g, 1.41 mmol) was added
at room temperature, under nitrogen, to a solution of
Cu(OAc) $H O (0.56 g, 2.82 mmol) in pyridine (5.6 mL)
and methanol (5.6 mL). After reaction completion (12 h), the
mixture was quenched with a saturated aqueous solution of
7
0
1
1
1
.58 (m, 1H), 7.53 (br d, J¼8.1 Hz, 1H), 7.43 (dd, J¼8.1,
.8 Hz, 1H), 7.34e7.22 (m, 3H), 7.16 (ddd, J¼8.0, 7.1,
2
2
.0 Hz, 1H), 7.00e6.97 (m, 2H); dC (100.6 MHz, CDCl )
3
54.4, 149.3, 136.4, 129.0, 128.7, 128.5, 124.4, 123.3,
23.1, 121.0, 120.9, 120.6, 111.1, 111.0, 101.4, 101.2; MS
NH Cl (20 mL) and extracted with ethyl acetate (3ꢁ20 mL).
4
þ
m/z 233 (M , 100), 232 (19), 204 (31), 117 (34), 102 (34),
The organic extracts were washed with water (3ꢁ20 mL),
8
3
3
9 (17), 88 (14), 76 (9), 63 (8), 51 (5%).
dried over Na SO and concentrated under vacuum. The resi-
2
4
due was purified by column chromatography on silica gel (pe-
troleum ether) leading to 0.13 g of compound 8 (66% yield) as
.6. Synthesis of dibenzofuran derivatives 22, 23 and 8
ꢀ
a yellow solid (mp¼165e168 C).
0
20
.6.1. 2,2 -Bi-1-benzofuran (22)
A solution of 2-ethynyl-1-benzofuran 9 (0.30 g, 2.11 mmol)
in THF (2.5 mL) was added at room temperature, under nitro-
Acknowledgements
gen, to a stirred mixture of 2-iodophenol 11 (0.23 g,
1
This work was financially supported by the Ministero
.06 mmol), PdCl (PPh ) (0.037 g, 0.053 mmol), CuI
2 3 2
dell’Universita e della Ricerca (M.U.R.), Rome, and the Uni-
versity of Bari (National Project ‘Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni’).
`
(
0.020 g, 0.106 mmol) and Et N (9 mL) in THF (2.5 mL)
3
ꢀ
and then the reaction mixture was warmed at 50 C. After re-
action completion (6 h), the mixture was quenched with a sat-
urated aqueous solution of NH Cl (20 mL) and extracted with
4
References and notes
ethyl acetate (3ꢁ20 mL). The organic extracts were washed
with H O (3ꢁ20 mL), dried over Na SO and concentrated
2
2
4
1
. (a) Gribble, G. W. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon: Oxford, 1996; Vol.
2, pp 207e257; (b) Muhammad, I.; Li, X.-C.; Jacob, M. R.; Tekwani,
B. L.; Dunbar, D. C.; Ferreira, D. J. Nat. Prod. 2003, 66, 804e809; (c)
Lounasmaa, M.; Tolvanen, A. Nat. Prod. Rep. 2000, 17, 175e191; (d)
Ward, R. S. Nat. Prod. Rep. 1997, 14, 43e74.
under vacuum. The residue was purified by column chroma-
tography on silica gel (petroleum ether) leading to 0.11 g of
compound 22 (45% yield) as a white solid (mp¼176e
ꢀ
20
ꢀ
1
1
78 C, lit. mp¼176 C). n
(KBr) 1439, 1255, 1171,
max
049, 874, 804, 748, 732; dH (400 MHz, CDCl ) 7.61 (dd,
3
2
. For selected reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
J¼7.7, 0.6 Hz, 2H), 7.53 (br d, J¼8.1 Hz, 2H), 7.39e7.20
2
006, 106, 2875e2911; (b) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105,
2873e2920; (c) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285e
309.
(
m, 4H), 7.14 (br s, 2H); dC (100.6 MHz, CDCl ) 155.1,
3
2
1
47.7, 128.5, 125.1, 123.3, 121.4, 111.3, 103.7; MS m/z 234
þ
3. (a) Kurisaki, T.; Naniwa, T.; Yamamoto, H.; Imagawa, H.; Nishizawa, M.
Tetrahedron Lett. 2007, 48, 1871e1874; (b) Nakamura, M.; Ilies, L.;
Otsubo, S.; Nakamura, E. Org. Lett. 2006, 8, 2803e2805; (c) Lu, B. Z.;
Zhao, W.; Wie, H.-X.; Dufour, M.; Farina, V.; Senanayake, C. H. Org.
Lett. 2006, 8, 3271e3274; (d) McLaughlin, M.; Palucki, M.; Davies,
I. W. Org. Lett. 2006, 8, 3307e3310; (e) Shen, Z.; Lu, X. Tetrahedron
(
M , 100), 205 (21), 176 (11), 117 (30), 89 (11), 88 (14),
6 (30), 63 (11%).
7
0
21
.6.2. 2,2 -Ethyne-1,2-diylbis(1-benzofuran) (23)
A solution of 2-ethynyl-1-benzofuran 9 (0.30 g, 2.11 mmol)
3
2
006, 62, 10896e10899; (f) Sakai, N.; Annaka, K.; Konakahara, T. Tetra-
in THF (3.5 mL) was added at room temperature, under nitro-
gen, to a stirred mixture of 2-iodobenzofuran 12 (0.43 g,
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R. J.; Srinivasan, K. V. Tetrahedron 2006, 62, 5109e5115; (h) Hiroya, K.;
Itoh, S.; Sakamoto, T. Tetrahedron 2005, 61, 10958e10964; (i) Li, X.;
Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437e
1
.76 mmol), PdCl (PPh ) (0.025 g, 0.035 mmol), CuI
2 3 2
(0.013 g, 0.070 mmol) and Et N (0.37 mL) in THF (3.5 mL).
3
After reaction completion (3 h), the mixture was quenched
with a saturated aqueous solution of NH Cl (20 mL) and ex-
4
5
1
440; (j) Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69,
126e1136; (k) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037e1040;
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were washed with H O (3ꢁ20 mL), dried over Na SO and
2
2
4
Tetrahedron 2003, 59, 1571e1587; (n) Dai, W.-M.; Guo, D.-S.; Sun,
L.-P. Tetrahedron Lett. 2001, 42, 5275e5278; (o) Yasuhara, A.;
concentrated under vacuum. The crude product was purified

60
V. Fiandanese et al. / Tetrahedron 64 (2008) 53e60
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4
5
. Nagahara, T.; Yokoyama, Y.; Inamura, K.; Katakura, S.; Komoriya, S.;
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7
. (a) De Luca, L.; Giacomelli, G.; Nieddu, G. J. Org. Chem. 2007, 72,
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