Development of a one-pot sequential Sonogashira coupling for the synthesis of benzofurans

Article abstract of DOI:10.1016/j.tet.2008.05.100

An efficient one-pot protocol was developed for the construction of the benzofuran system from aryl halides and protected iodophenols using carbinol-based acetylene sources. The sequence includes alternating palladium-catalyzed Sonogashira couplings and deprotection steps concluded by a ring closure. The developed one-pot procedure was compared with the stepwise approach and its efficiency was also demonstrated by the total synthesis of vignafuran, a benzofuran natural product.

Full text of DOI:10.1016/j.tet.2008.05.100

Tetrahedron 64 (2008) 8992–8996
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Development of a one-pot sequential Sonogashira coupling for the synthesis
of benzofurans
*
´
´
´
´
´
Marton Csekei, Zoltan Novak, Andras Kotschy
´
´
´
´
Institute of Chemistry, Eo¨tvo¨s Lorand University, Pazmany Peter s. 1/A, H-1117 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot protocol was developed for the construction of the benzofuran system from aryl
halides and protected iodophenols using carbinol-based acetylene sources. The sequence includes al-
ternating palladium-catalyzed Sonogashira couplings and deprotection steps concluded by a ring closure.
The developed one-pot procedure was compared with the stepwise approach and its efficiency was also
demonstrated by the total synthesis of vignafuran, a benzofuran natural product.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 20 February 2008
Received in revised form 4 May 2008
Accepted 22 May 2008
Available online 25 May 2008
Dedicated to Professor Lajos Nova´k on the
occasion of his 70th birthday
1. Introduction
report on their extension to the synthesis of benzofurans. The
present work was aimed at the establishment of an efficient ‘one-
The design and implementation of new economic synthetic
processes is one of the major challenges in modern organic syn-
thesis. The application of cascade,1 domino2 or tandem3 reactions
in a ‘one-pot’ manner offers a straightforward method for the
construction of new bonds simultaneously or in a stepwise manner
without the isolation of the intermediates, making the whole
procedure economically sustainable and environmentally consci-
entious. Among the nearly unlimited combination of organic
transformations in a reaction sequence, palladium-catalyzed car-
bon-carbon bond forming reactions can act as an efficient synthetic
step in a designed multi step reaction.4 A member of this reaction
class is the Sonogashira-Hagihara reaction5 of aryl halides and
terminal alkynes, which is a powerful tool for the construction of
acetylene derivatives. The introduction of a triple bond between
two aryl halide moieties can also be achieved in a ‘one-pot’ multi
step sequence, the domino Sonogashira reaction of aryl halides and
a masked acetylene, in a coupling-deprotection-coupling sequence.
As acetylene source, trimethylsilylacetylene,6 2-metyl-3-butyn-2-
ol7 or 1-ethynyl-cyclohexanol8 can be used with comparable
efficiency.9
pot’ procedure for the preparation of benzofurans from the
appropriate aryl halides and masked acetylenes. Besides comparing
the developed ‘one-pot’ procedure to the stepwise approach,
we planned to test its synthetic utility in the total synthesis of
a benzofuran natural product, vignafuran.13
2. Results and discussion
The first approach tested was the sequential Sonogashira cou-
pling of aryl halides and protected acetylenes to give diarylalkynes
that are capable of cyclizing to benzofurans. To this purpose, a se-
ries of aryl iodides (1a–e) were coupled with 1-ethynyl-cyclo-
hexanol (2) and O-triisopropylsilyl-2-iodophenol (3a) in a one-pot
procedure to give the desired 2-arylethynyl-phenol derivatives
(4a–e) in good yield (Table 1). The coupling conditions were se-
lected on the basis of our previous experience on similar sequential
couplings.8 The use of the analogous acetylene source 2-methyl-3-
butyn-2-ol resulted in decreased yields. The use of ethynyl-
trimethylsilane instead of 2 required the change of the deprotection
agent from KOH to TBAF, which did not allow for the isolation of the
diarylacetylene derivatives, but gave the appropriate benzofurans
directly (vide infra).
To get a feeling for the efficiency of the protocol aryl halides
bearing both electron donating (entries 2 and 4) and electron
withdrawing (entries 3 and 5) groups were tested and found towork
equally well. The placement of the substituents on the aryl halide
had no significant impact on the yield either. The ring closure of the
obtained diarylacetylenes in the presence of TBAF proceeded
smoothly and the expected 2-arylbenzofurans (5a–e) were obtained
in excellent yield. One can envisage that the alkynes (4a–e) might
The use of the Sonogashira coupling is not confined to the
synthesis of acetylene derivatives. This reaction also offers an effi-
cient route for the preparation of condensed heterocycles,10 for
benzofurans11 in particular, which has been demonstrated in the
total synthesis of diverse natural products.12 In spite of the
development of efficient ‘one-pot’ procedures for the preparation
of internal acetylenes, to the best of our knowledge there is no
* Corresponding author. Tel.: þ36 1 372 2910; fax: þ36 1 372 2909.
E-mail address: kotschy@elte.hu (A. Kotschy).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.100

M. Cse´kei et al. / Tetrahedron 64 (2008) 8992–8996
8993
Table 1
Following these studies, we appended the appropriate aryl
moieties of 2-bromo-iodobenzene (entry 5), 3-iodotoluene (entry
6) and 4-nitro-iodobenzene (entry 7) onto the benzofuran core
with good efficiency, using 1-ethynyl-cyclohexanol (2) and O-tri-
isopropylsilyl-2-iodophenol (3a). Again, the electron donating or
withdrawing nature and the placement of the substituents on the
phenyl ring had little effect on the efficiency of the coupling
sequence.
The synthesis of TIPS-protected 2-arylethynyl-phenols (4a–e) and their ring closure
to benzofurans 5a–e
1% (PPh3)2PdCl2
HO
1% CuI, DIPA
Ar
1a-e
I
+
Ar
I
2,
4a-e
TBAF
2
TIPSO
TIPSO
3a
In order to introduce a further site for functionalization, we
carried out some experiments using O-triisopropylsilyl-4-bromo-
2-iodophenol (3b) in the second coupling step. Starting either from
4-iodoanisole (entry 8) or from 4-nitro-iodobenzene (entry 9), we
obtained the appropriate 2-aryl-5-bromobenzofurans (5f and 5g)
in high yield. The switch from 3a to 3b (cf. entries 4 and 8, and 7 and
9) had practically no effect on the efficacy of the protocol.
To demonstrate the usefulness of the devised protocol, we se-
lected a natural product, vignafuran, as a benchmark. This com-
pound has been synthesized by different approaches,13b,c,h one of
them utilizing a Sonogashira coupling based route.13f Common to
all strategies is the significant number of reaction steps and puri-
fications encountered on the way. The ‘one-pot’ domino Sonoga-
shira coupling approach could offer a convenient alternative to
these routes.
The appropriate O-methyl-iodoresorcinols were silylated to
provide the necessary aryl halides 6a15 and 6b.16 The coupling of 6a
and 1-ethynyl-cyclohexanol (2) was followed by TLC, and upon its
completion potassium hydroxide, 6b and additional catalyst were
added to the reaction mixture to give rise to the intermediate
diarylacetylene. This compound was converted to vignafuran (7) on
treatment with tetrabutylammonium fluoride (Scheme 1) that was
isolated by column chromatography in 69% yield, nicely demon-
strating the efficacy of the ‘one-pot’ domino Sonogashira coupling
based approach.
3% (PPh3)2PdCl2
3% CuI, KOH
Ar
5a-e
O
Entry
Ar
Phenyl (1a)
4-Anisyl (1b)
2-Bromophenyl (1c)
3-Tolyl (1d)
4a/%
5a/%
1
2
3
4
5
89
80
76
85
69
96
99
90
98
92
4-Nitrophenyl (1e)
a
Yield after purification.
also serve as a starting material for electrophile induced ring clo-
sure14 and lead to the appropriate 2,3-disubstituted benzofuran
derivatives.
The next attempts were directed at combining the five reaction
steps converting the aryl halide, the iodophenol derivative and the
protected acetylene into a benzofuran derivative in a ‘one-pot’
protocol. In the first experiments (Table 2, entries 1–5), we tested
the different acetylene surrogates in the coupling. Iodobenzene (1a)
and O-triisopropylsilyl-2-iodophenol (3a) were coupled with
1-ethynyl-cyclohexanol (entry 1), 2-methyl-3-butyn-2-ol (entry 2)
and ethynyltrimethylsilane (entry 3) to give the desired 2-phenyl-
benzofuran (5a) in good to excellent yield. The highest yield was
obtained by using 1-ethynyl-cyclohexanol, while the lower yield
obtained when using the TMS-protected acetylene is probably due
to the fact that under the deprotection conditions 3a is converted
faster into 2-iodophenol than it undergoes the second coupling.
This is also supported by the fact that on replacing 3a with
2-iodophenol we obtained 2-phenylbenzofuran in 65% yield. These
two acetylene surrogates were also compared in their coupling with
4-iodoanisole, both giving the anisylbenzofuran 5b in good yield,
with 1-ethynyl-cyclohexanol being superior in efficiency again.
I
1, 2, 1%(PPh3)2PdCl2
OMe
1%CuI, DIPA
HO
O
2,
I
OMe
OMe
6a
OMe
OPG
PG=TIPS
6b
PGO
3%(PPh3)2PdCl2
3%CuI, KOH
7, Vignafuran
69%
Table 2
3, TBAF
Scheme 1. The ‘one-pot’ synthesis of vignafuran.
The one-pot synthesis of 2-arylbenzofuran derivatives from aryl halides (1a–e),
O-protected 2-iodophenol derivatives (3a,b) and 1-ethynyl-cyclohexanol (2)
1,2, 1%(PPh3)2PdCl2
X
In summary, we have developed a convenient protocol for the
‘one-pot’ preparation of benzofurans from aryl halides, O-silylated
2-iodophenol derivatives and 1-ethynyl-cyclohexanol. The devised
procedure allows the convenient introduction of different aryl
moieties into the 2-position of the benzofuran core and its ability to
build substituents onto the phenyl moiety of the benzofuran ring
was also demonstrated. The effectiveness of the protocol was
demonstrated by the synthesis of vignafuran.
1%CuI, DIPA
I
3, TBAF
Ar
Ar
1a-e
I
2,
O
3a,b
TIPSO
X
5a-g
3%(PPh3)2PdCl2
3%CuI, KOH
Entry
Ar
X
yielda/%
1
2
3
4
5
6
7
8
9
Phenyl
Phenyl
Phenyl
4-Anisyl
2-Bromophenyl
3-Tolyl
4-Nitrophenyl
4-Anisyl
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
Br (3b)
Br (3b)
87 (5a)
76 (5a)b
65 (5a)c
82 (5b)d
62 (5c)
84 (5d)
68 (5e)
80 (5f)
70 (5g)
3. Experimental part
3.1. General
Unless otherwise indicated, all starting materials were obtained
from commercial suppliers and were used without further purifi-
cation. All coupling reactions were performed under an atmo-
sphere of argon. Analytical thin-layer chromatography (TLC) was
performed on Merck DC pre-coated TLC plates with 0.25 mm Kie-
selgel 60 F254. Visualization was performed with a 254 nm UV lamp.
Silica gel column chromatography was carried out with flash silica
gel (0.040–0.063 mm). The 1H and 13C NMR spectra were recorded
4-Nitrophenyl
a
Yield after purification.
Yield obtained using 2-methyl-3-butyn-2-ol instead of 2.
Yield obtained using ethynyltrimethylsilane instead of 2 and 2-iodophenol in-
b
c
stead of 3. TBAF was added in place of KOH in the second step and step 3 was
omitted.
d
Ethynyltrimethylsilane gave 5b in 76% yield.

8994
M. Cse´kei et al. / Tetrahedron 64 (2008) 8992–8996
at 250 and 62.5 MHz in CDCl3. Chemical shifts are expressed in
parts per million (
). For 1H NMR spectra the residual peak of CHCl3
(% relative intensity, ion): 456 (1, [Mþ]), 454 (1, [Mþ]), 413 (100), 411
(100), 385 (15), 383 (15), 357 (12), 355 (12). Analysis calculated for
d
(7.26 ppm) was used as the internal reference, while for 13C NMR
spectra the central peak of CDCl3 (77.0 ppm) was used as the ref-
erence. Coupling constants (J) are reported in hertz (Hz). Splitting
patterns are designated as s (singlet), br s (broad singlet), d (dou-
blet), t (triplet), m (multiplet), dd (doublet doublet), dt (doublet of
triplets) and td (triplet of doublets). Combination gas chromato-
graphy and low resolution mass spectrometry were obtained on
C15H24BrIOSi: C, 39.57; H, 5.31. Found: C, 39.78; H, 5.20.
3.1.3. 4-Iodo-3-methoxy-O-triisopropylsilylphenol (6a)
4-Iodo-3-methoxyphenol (278 mg, 1.11 mmol) was dissolved in
dichloromethane (3 mL). Triisopropylsilyl chloride (257 mg,
1.33 mmol) was added slowly and then imidazole (189 mg,
2.78 mmol) was added in one portion. The reaction was followed by
TLC and GC–MS. When the protection was complete the reaction
mixture was washed with water (2ꢀ1 mL) and then with brine
(1 mL). The organic phase was dried over magnesium sulfate, fil-
tered and evaporated. The crude product was filtered through a pad
of silica with pure hexane to give 403 mg colourless liquid (6a)
a 30 mꢀ0.25 mm column with 0.25
mm HP-5MS coating using He
carrier gas, and with the following ion source: EIþ, 70 eV, 230 ꢁC;
interface: 300 ꢁC. The purity of the products whose elementary
analysis for carbon differed by more than 0.5% from the calculated
value was above 95% by HPLC in all cases.
(0.99 mmol, 89%). 1H NMR (CDCl3, 250 MHz):
d 7.60 (d, 1H,
3.1.1. O-Triisopropylsilyl-2-iodophenol (3a)
J¼8.7 Hz), 6.45 (d, 1H, J¼2.7 Hz), 6.31 (dd, 1H, J¼8.7, 2.7 Hz), 3.75 (s,
2-Iodophenol (2.20 g, 10 mmol) was dissolved in dichloro-
methane (30 mL). Triisopropylsilyl chloride (2.31 g, 12 mmol) was
added slowly and then imidazole (1.70 g, 25 mmol) was added in
one portion. The reaction was followed by TLC and GC–MS. Upon
completion, the reaction mixture was washed with water
(2ꢀ10 mL) and then with brine (5 mL). The organic phase was dried
over magnesium sulfate, filtered and evaporated. The crude prod-
uct was purified by column chromatography, using pure hexane as
eluent, to give 3.54 g colourless liquid (3a) (9.41 mmol, 94%). 1H
3H), 1.41–1.32 (m, 3H), 1.17–1.14 (m, 18H); 13C NMR (CDCl3,
62.5 MHz): d 160.9,156.1,139.1,107.9,105.2, 79.3, 55.3,18.1,13.0; MS
(EI, 70 eV) m/z (% relative intensity, ion): 406 (4, [Mþ]), 363 (100),
335 (10),180 (12),166 (12),154 (16),151 (26). Analysis calculated for
C16H27IO2Si: C, 47.29; H, 6.70. Found: C, 46.90; H, 6.59.
3.1.4. 2-Iodo-5-methoxy-O-triisopropylsilylphenol (6b)
2-Iodo-5-methoxyphenol (250 mg, 1.00 mmol) was dissolved in
dichloromethane (3 mL). Triisopropylsilyl chloride (231 mg,
1.2 mmol) was added slowlyand then imidazole (170 mg, 2.5 mmol)
was added in one portion. The reactionwas followed by TLC and GC–
MS. When the protection was complete, the reaction mixture was
washed with water (2ꢀ1 mL) and then with brine (1 mL). The or-
ganic phase was dried over magnesium sulfate, filtered and evapo-
rated. The crude product was filtered through a pad of silica with
pure hexane to give 321 mg colourless liquid (6b) (0.79 mmol, 79%).
NMR (CDCl3, 250 MHz):
d
7.76 (dd, 1H, J¼7.9, 1.6 Hz), 7.19 (td, 1H,
J¼8.2, 1.6 Hz), 6.85 (dd, 1H, J¼8.2, 1.4 Hz), 6.66 (td, 1H, J¼7.9, 1.4 Hz),
1.42–1.28 (m, 3H), 1.17–1.14 (m, 18H); 13C NMR (CDCl3, 62.5 MHz):
d
155.5, 139.5, 129.2, 122.4, 118.1, 90.3, 18.1, 13.1; MS (EI, 70 eV) m/z
(% relative intensity, ion): 376 (1, [Mþ]), 334 (18), 333 (100), 305
(15), 277 (13). Analysis calculated for C15H25IOSi: C, 47.87; H, 6.70.
Found: C, 47.18; H, 6.62.
1H NMR (CDCl3, 250 MHz):
J¼2.5 Hz), 6.31 (dd,1H, J¼8.5, 2.5 Hz), 3.83 (s, 3H),1.29–1.23 (m, 3H),
1.12–1.09 (m, 18H); 13C NMR (CDCl3, 62.5 MHz):
158.7, 157.7, 138.9,
d
7.54 (d, 1H, J¼8.5 Hz), 6.42 (d, 1H,
3.1.2. 4-Bromo-O-triisopropylsilyl-2-iodophenol (3b)
4-Bromophenol (1.73 g, 10 mmol) was dissolved in 25% aqueous
NH3 (40 mL). Potassium iodide (7.97 g, 48 mmol) and iodine (2.54 g,
10 mmol) dissolved in water (20 mL) were added rapidly. The re-
action was followed by TLC and GC–MS. When the iodination was
complete (approximately an hour), the reaction mixture was cooled
and diluted with ice and acidified with concd HCl (40 mL). It was
extracted with ethyl acetate (3ꢀ200 mL). The combined organic
phase was washed with saturated NaHCO3 (40 mL), saturated
Na2S2O3 (40 mL) and brine (20 mL). It was dried over magnesium
sulfate, filtered and evaporated. The crude product was purified by
column chromatography, using hexane–chloroform as eluent, to
give 4-bromo-2-iodophenol (3b0) as a white solid. Yield: 2.14 g
d
113.9, 104.0, 75.0, 56.1, 17.8, 12.6; MS (EI, 70 eV) m/z (% relative in-
tensity, ion): 406 (96, [Mþ]), 363 (93), 335 (52), 307 (62), 293 (18),
277 (12), 236 (20), 221 (39), 208 (16),193 (47),180 (62),166 (67),153
(100),151 (55),135 (29),121 (18), 76 (19), 59 (21). Analysis calculated
for C16H27IO2Si: C, 47.29; H, 6.70. Found: C, 47.81; H, 6.95.
3.2. General procedure for the synthesis of 2-arylethynyl-O-
triisopropylsilylphenols
Aryl halide (1) (1 mmol), 1-ethynyl-cyclohexanol (2) (136 mg,
1.1 mmol), PdCl2(PPh3)2 (7 mg, 0.01 mmol, 1 mol %) and CuI (2 mg,
0.01 mmol, 1 mol %) were placed into a flame-dried Schlenk flask.
Diisopropylamine (7 mL) was added and the mixture was stirred
under argon at 80 ꢁC. The reaction was followed by TLC and GC–MS.
When the first coupling was complete (typically less than 30 min),
2-iodo-O-triisopropylsilylphenol (3a) (376 mg, 1 mmol), KOH
(224 mg, 4 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol, 3 mol %) and
CuI (6 mg, 0.03 mmol, 3 mol %) were added. The mixture was stir-
red under argon at 80 ꢁC until the reaction was complete. After
evaporating the solvent, the product (4) was separated by column
chromatography, using hexane–ethyl acetate mixtures as eluent.
(7.16 mmol, 72%). Mp: 71 ꢁC.17 1H NMR (CDCl3; 250 MHz):
1H, J¼2.2 Hz), 7.34 (dd, 1H, J¼8.7, 2.4 Hz), 6.87 (d, 1H, J¼8.7 Hz),
5.20 (br s, 1H); 13C NMR (CDCl3, 62.5 MHz):
154.2, 139.7, 133.0,
116.2, 113.0, 86.1; MS (EI, 70 eV) m/z (% relative intensity, ion): 300
(100, [Mþ]), 298 (100, [Mþ]),173 (22),171 (22),145 (30),143 (31), 63
(83). Analysis calculated for C6H4BrIO: C, 24.11; H, 1.35. Found: C,
24.04; H, 1.33.
d 7.76 (d,
d
4-Bromo-2-iodophenol (3b0) (2.06 g, 6.88 mmol) was dissolved
in dichloromethane (20 mL). Triisopropylsilyl chloride (1.59 g,
8.26 mmol) was added slowly and then imidazole (1.17 g,
17.2 mmol) was added in one portion. The reaction was followed by
TLC and GC–MS. Upon completion, the reaction mixture was
washed with water (2ꢀ5 mL) and then with brine (5 mL). The
organic phase was dried over magnesium sulfate, filtered and
evaporated. The crude product was purified by column chroma-
tography, using pure hexane as eluent, to give 2.50 g colourless
3.2.1. 2-Phenylethynyl-O-triisopropylsilylphenol (4a)
Yellow oil, 313 mg (0.89 mmol, 89%). 1H NMR (CDCl3, 250 MHz):
d
7.56–7.48 (m, 3H), 7.38–7.32 (m, 3H), 7.21 (td, 1H, J¼7.6, 1.8 Hz),
6.96–6.87 (m, 2H), 1.43–1.31 (m, 3H), 1.19–1.16 (m, 18H); 13C NMR
(CDCl3, 62.5 MHz): 156.7, 133.6, 131.4, 129.4, 128.2, 127.9, 120.8,
d
liquid (3b) (5.49 mmol, 80%). 1H NMR (CDCl3, 250 MHz):
d
7.89 (d,
119.1, 115.4, 111.1, 92.8, 87.0, 18.0, 13.0; MS (EI, 70 eV) m/z (% relative
intensity, ion): 350 (4, [Mþ]), 308 (27), 307 (100), 265 (77), 249 (21),
237 (75), 221 (23), 176 (37), 125 (51). Analysis calculated for
1H, J¼2.2 Hz), 7.31 (dd, 1H, J¼8.6, 2.2 Hz), 6.73 (d, 1H, J¼8.6 Hz),
1.39–1.28 (m, 3H), 1.19–1.16 (m, 18H); 13C NMR (CDCl3, 62.5 MHz):
d
154.9, 141.3, 132.0, 118.9, 113.2, 91.0, 18.0, 13.0; MS (EI, 70 eV) m/z
C23H30OSi: C, 78.80; H, 8.63. Found: C, 78.26; H, 8.93.

M. Cse´kei et al. / Tetrahedron 64 (2008) 8992–8996
8995
3.2.2. 2-(40-Methoxyphenylethynyl)-O-triisopropylsilylphenol (4b)
(4 mL), and the reaction mixture was stirred at 80 ꢁC. The reaction
was followed by TLC and GC–MS. When the deprotection and the
ring closure were complete (typically less than 10 min), the solvent
was evaporated and the product (5) was separated by column
chromatography, using hexane–ethyl acetate mixtures as eluent.
Yellow solid, 305 mg (0.80 mmol, 80%). Mp: 44–46 ꢁC. 1H NMR
(CDCl3, 250 MHz):
6.95–6.87 (m, 4H), 3.83 (s, 3H), 1.40–1.29 (m, 3H), 1.19–1.16 (m,
18H); 13C NMR (CDCl3, 62.5 MHz):
159.3, 156.6, 133.4, 132.8, 129.0,
d
7.49–7.45 (m, 3H), 7.19 (td, 1H, J¼7.9, 1.8 Hz),
d
120.7, 119.0, 116.0, 115.7, 113.9, 92.7, 85.6, 55.2, 18.0, 12.9; MS (EI,
70 eV) m/z (% relative intensity, ion): 380 (18, [Mþ]), 338 (28), 337
(100), 295 (30), 267 (36), 187 (23), 140 (43). Analysis calculated for
3.3.1. 2-Phenylbenzofuran (5a)18
White solid, ‘one-pot’ process yielded 169 mg (0.87 mmol, 87%),
while the ring closure from 4a yielded 93 mg (0.48 mmol, 96%).
C
24H32O2Si: C, 75.74; H, 8.47. Found: C, 75.47; H, 8.69.
Mp: 119–120 ꢁC. 1H NMR (CDCl3, 250 MHz):
d 7.89–7.84 (m, 2H),
3.2.3. 2-(20-Bromophenylethynyl)-O-triisopropylsilylphenol (4c)
7.60–7.19 (m, 7H), 7.02 (d, 1H, J¼0.8 Hz); 13C NMR (CDCl3,
Yellow oil, 327 mg (0.76 mmol, 76%). 1H NMR (CDCl3, 250 MHz):
62.5 MHz): d 155.9, 154.9, 130.5, 129.2, 128.8, 128.5, 124.9, 124.2,
d
7.46–7.36 (m, 3H), 7.13–7.03 (m, 2H), 6.97 (td, 1H, J¼7.7, 1.7 Hz),
6.81–6.72 (m, 2H), 1.28–1.16 (m, 3H), 1.03–1.00 (m, 18H); 13C NMR
(CDCl3, 62.5 MHz): 156.7, 133.9, 132.8, 132.3, 129.8, 128.9, 126.8,
122.9, 120.9, 111.2, 101.3; MS (EI, 70 eV) m/z (% relative intensity,
ion): 194 (100, [Mþ]), 165 (66), 139 (11), 97 (12), 82 (11).
d
125.9, 125.6, 120.8, 119.0, 115.1, 91.8, 91.3, 18.0, 13.0; MS (EI, 70 eV)
m/z (% relative intensity, ion): 430 (3, [Mþ]), 428 (3, [Mþ]), 388 (26),
387 (100), 385 (95), 345 (64), 343 (63), 301 (30), 263 (48), 235 (93),
221 (53), 176 (41), 165 (31), 117 (27). Analysis calculated for
3.3.2. 2-(40-Methoxyphenyl)benzofuran (5b)19
Yellow solid, ‘one-pot’ process yielded 184 mg (0.82 mmol, 82%),
while the ring closure from 4b yielded 111 mg (0.49 mmol, 99%).
Mp: 152–154 ꢁC. 1H NMR (CDCl3, 250 MHz):
d
7.70 (dt, 2H, J¼9.0,
C
23H29BrOSi: C, 64.32; H, 6.81. Found: C, 64.86; H, 6.79.
2.5 Hz), 7.47–7.38 (m, 2H), 7.20–7.09 (m, 2H), 6.88 (dt, 2H, J¼8.8,
2.5 Hz), 6.78 (d, 1H, J¼0.8 Hz), 3.75 (s, 3H); 13C NMR (CDCl3,
3.2.4. 2-(m-Tolylethynyl)-O-triisopropylsilylphenol (4d)
62.5 MHz): d 159.9, 156.0, 154.6, 129.5, 126.4, 123.7, 123.3, 122.8,
Yellow oil, 310 mg (0.85 mmol, 85%). 1H NMR (CDCl3,
120.5, 114.2, 110.9, 99.6, 55.3; MS (EI, 70 eV) m/z (% relative
250 MHz):
7.12 (m, 3H), 6.96–6.86 (m, 2H), 2.36 (s, 3H), 1.43–1.31 (m, 3H),
1.18–1.15 (m, 18H); 13C NMR (CDCl3, 62.5 MHz):
156.7, 137.8,
d
7.48 (dd, 1H, J¼7.6, 1.4 Hz), 7.36–7.32 (m, 2H), 7.27–
intensity, ion): 224 (100, [Mþ]), 209 (77), 181 (57),152 (37),112 (11).
d
3.3.3. 2-(20-Bromophenyl)benzofuran (5c)20
133.6, 132.1, 129.3, 128.8, 128.4, 128.1, 123.7, 120.8, 119.1, 115.5, 93.0,
86.7, 21.3, 18.0, 13.0; MS (EI, 70 eV) m/z (% relative intensity, ion):
364 (5, [Mþ]), 322 (29), 321 (100), 279 (67), 251 (63), 189 (21), 132
(30). Analysis calculated for C24H32OSi: C, 79.06; H, 8.85; Found: C,
79.77; H, 9.11.
Pale yellow solid, ‘one-pot’ process yielded 169 mg (0.62 mmol,
62%), while the ring closure from 4c yielded 123 mg (0.45 mmol,
90%). Mp: 36–37 ꢁC. 1H NMR (CDCl3, 250 MHz):
d 7.96 (dd, 1H,
J¼7.9, 1.7 Hz), 7.71–7.61 (m, 2H), 7.53–7.50 (m, 2H), 7.40 (td, 1H,
J¼7.6, 1.1 Hz), 7.35–7.14 (m, 3H); 13C NMR (CDCl3, 62.5 MHz):
d
154.3, 153.1, 134.2, 131.0, 129.8, 129.4, 128.8, 127.5, 124.8, 123.0,
3.2.5. 2-(40-Nitrophenylethynyl)-O-triisopropylsilylphenol (4e)
121.4, 120.7, 111.1, 107.0; MS (EI, 70 eV) m/z (% relative intensity,
Orange solid, 273 mg (0.69 mmol, 69%). Mp: 93–95 ꢁC. 1H NMR
ion): 274 (88, [Mþ]), 272 (97, [Mþ]), 165 (100), 137 (21), 82 (36).
(CDCl3, 250 MHz):
d
8.21 (dt, 2H, J¼9.0, 2.1 Hz), 7.63 (dt, 2H, J¼9.0,
2.1 Hz), 7.48 (dd, 1H, J¼7.7, 1.7 Hz), 7.25 (td, 1H, J¼8.2, 1.8 Hz), 6.97–
3.3.4. 2-(m-Tolyl)benzofuran (5d)
6.88 (m, 2H), 1.41–1.27 (m, 3H), 1.17–1.14 (m, 18H); 13C NMR (CDCl3,
White solid, ‘one-pot’ process yielded 175 mg (0.84 mmol, 84%),
while the ring closure from 4d yielded 102 mg (0.49 mmol, 98%).
62.5 MHz):
d 157.1, 146.7, 133.8, 131.9, 130.8, 130.5, 123.6, 120.9,
119.1, 114.2, 92.8, 91.0, 18.0, 12.9; MS (EI, 70 eV) m/z (% relative
intensity, ion): 395 (3, [Mþ]), 353 (27), 352 (100), 310 (73), 282 (82),
249 (23), 236 (25), 221 (22), 176 (26). Analysis calculated for
Mp: 75–76 ꢁC. 1H NMR (CDCl3, 250 MHz):
d
7.68–7.63 (m, 2H), 7.57–
7.49 (m, 2H), 7.34–7.13 (m, 4H), 6.97 (d, 1H, J¼0.8 Hz), 2.40 (s, 3H);
13C NMR (CDCl3, 62.5 MHz):
156.1, 154.8, 138.4, 130.3, 129.3, 129.2,
d
C
3.28.
23H29NO3Si: C, 69.84; H, 7.39; N, 3.54. Found: C, 69.44; H, 7.33; N,
128.7, 125.5,124.1, 122.8,122.1,120.8,111.1,101.1, 21.5; MS (EI, 70 eV)
m/z (% relative intensity, ion): 208 (100, [Mþ]), 178 (18), 165 (28), 89
(10). Analysis calculated for C15H12O: C, 86.51; H, 5.81; Found: C,
86.54; H, 6.10.
3.3. General procedure for the synthesis of 2-arylbenzofurans
One-pot sequential coupling: aryl halide (1) (1 mmol), 1-ethynyl-
cyclohexanol (2) (136 mg, 1.1 mmol), PdCl2(PPh3)2 (7 mg,
0.01 mmol, 1 mol %) and CuI (2 mg, 0.01 mmol, 1 mol %) were
placed into a flame-dried Schlenk flask. Diisopropylamine (7 mL)
was added and the mixture was stirred under argon at 80 ꢁC. The
reaction was followed by TLC and GC–MS. When the first coupling
was complete (typically less than 30 min), KOH (224 mg, 4 mmol),
PdCl2(PPh3)2 (21 mg, 0.03 mmol, 3 mol %), CuI (6 mg, 0.03 mmol,
3 mol %) and 2-iodo-O-triisopropylsilylphenol (3a) (376 mg,
1 mmol) or 4-bromo-2-iodo-O-triisopropylsilylphenol (3b)
(455 mg, 1 mmol) were added. The mixture was stirred under ar-
gon at 80 ꢁC, until the second coupling was complete. Then TBAF
was added in 1 M THF solution (1.1 mL, 1.1 mmol) and the reaction
mixture was stirred under argon at 80 ꢁC until the reaction was
complete. After evaporating the volatiles, the product (5) was
separated by column chromatography using hexane–ethyl acetate
mixtures as eluent.
3.3.5. 2-(40-Nitrophenyl)benzofuran (5e)19
Yellow solid, ‘one-pot’ process yielded 162 mg (0.68 mmol, 68%),
while the ring closure from 4e yielded 110 mg (0.46 mmol, 92%).
Mp: 182–183 ꢁC. 1H NMR (CDCl3, 250 MHz):
d
8.30 (dt, 2H, J¼9.2,
2.2 Hz), 7.99 (dt, 2H, J¼9.0, 2.2 Hz), 7.64 (dt, 1H, J¼7.7, 0.7 Hz), 7.56
(d, 1H, J¼8.2 Hz), 7.37 (td, 1H, J¼7.7, 1.5 Hz), 7.28 (td, 1H, J¼7.4,
1.1 Hz), 7.23 (d, 1H, J¼0.9 Hz); 13C NMR (CDCl3, 62.5 MHz):
d 155.4,
153.2, 147.2, 136.3, 128.6, 125.8, 125.2, 124.3, 123.5, 121.6, 111.5,
105.1; MS (EI, 70 eV) m/z (% relative intensity, ion): 239 (95, [Mþ]),
209 (27), 193 (23), 181 (25), 165 (100), 163 (36), 139 (11).
3.3.6. 5-Bromo-2-(40-methoxyphenyl)benzofuran (5f)21
White solid, ‘one-pot’ process yielded 242 mg (0.80 mmol, 80%).
Mp: 167–169 ꢁC. 1H NMR (CDCl3, 250 MHz):
d
7.77 (d, 2H, J¼8.7 Hz),
7.66 (s, 1H), 7.48–7.35 (m, 2H), 6.97 (d, 2H, J¼8.7 Hz), 6.80 (s, 1H),
3.86 (s, 3H); 13C NMR (CDCl3, 62.5 MHz):
160.3, 157.3, 153.4, 132.9,
d
126.5, 126.5, 123.1, 122.7, 115.8, 114.3, 112.4, 99.0, 55.3; MS
(EI, 70 eV) m/z (% relative intensity, ion): 304 (100, [Mþ]), 302
(100, [Mþ]), 289 (52), 287 (49), 261 (27), 259 (26),180 (25),152 (64),
126 (16).
Deprotection and ring closure of 2-arylethynyl-O-triisopropylsi-
lylphenols: 2-arylethynyl-O-triisopropylsilylphenol (4) (0.50 mmol)
and TBAF$3H2O (173 mg, 0.55 mmol) were dissolved in toluene

8996
M. Cse´kei et al. / Tetrahedron 64 (2008) 8992–8996
3.3.7. 5-Bromo-2-(40-nitrophenyl)benzofuran (5g)21
4. Mu¨ller, T. J. J. Metal Catalyzed Cascade Reactions. Topics in Organometallic
Chemistry; 2006; 19.
Yellow solid, ‘one-pot’ process yielded 222 mg (0.70 mmol,
5. (a) Negishi, E.; de Meijere, A. Handbook of Organopalladium Chemistry for Or-
ganic Synthesis; John Wiley & Sons: New York, NY, 2002; (b) de Meijere, A.;
Diederich, F. Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH, Verlag
GmbH & Co. KGaA: Weinheim, 2004; (c) Tsuji, J. Palladium Reagents and Cata-
lysts: New Perspectives for the 21st Century; Wiley & Sons Ltd: Chichester, UK,
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(e) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834; (f) Chinchilla, R.;
Najera, C. Chem. Rev. 2007, 107, 874; (g) Nova´k, Z.; Szabo´, A.; Re´pa´si, J.; Kotschy,
A. J. Org. Chem. 2003, 68, 3327; (h) Nova´k, Z.; Kotschy, A. Org. Lett. 2003, 5, 3495.
6. (a) Lindstro¨m, S.; Ripa, L.; Hallberg, A. Org. Lett. 2000, 2, 2291; (b) Arcadi, A.;
Cacchi, S.; Di Giuseppe, S.; Fabrizi, G.; Marinelli, F. Synlett 2002, 453; (c) Sor-
ensen, U. S.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697; (d) Yang, C.; Nolan,
S. P. Organometallics 2002, 21, 1020; (e) Kabalka, G. W.; Wang, L.; Pagni, R. M.
Tetrahedron 2001, 57, 8017; (f) Koseki, Y.; Omino, K.; Anzai, S.; Nagasaka, T.
Tetrahedron Lett. 2000, 41, 2377; (g) Nishihara, Y.; Ikegashira, K.; Hirabayashi,
K.; Ando, J.; Mori, A.; Hiyama, T. J. Org. Chem. 2000, 65, 1780; (h) Nishihara, Y.;
Ikegashira, K.; Mori, A.; Hiyama, T. Chem. Lett. 1997, 12, 1233.
70%). Mp: 191–192 ꢁC. 1H NMR (CDCl3, 250 MHz):
d
8.31 (d, 2H,
J¼8.8 Hz), 7.98 (d, 2H, J¼8.8 Hz), 7.76 (d, 1H, J¼0.8 Hz), 7.48–7.40
(m, 2H), 7.17 (s, 1H); 13C NMR (CDCl3, 62.5 MHz):
154.5, 154.1,
d
141.1, 135.6, 130.5, 128.7, 125.4, 124.3, 124.2, 116.6, 112.9, 104.2; MS
(EI, 70 eV) m/z (% relative intensity, ion): 319 (75, [Mþ]), 317 (75,
[Mþ]), 289 (53), 287 (47), 192 (52), 180 (25), 164 (55), 163 (100), 152
(24).
3.3.8. Vignafuran (7)13f
4-Iodo-3-methoxy-O-triisopropylsilylphenol (6a) (203 mg,
0.50 mmol), 1-ethynyl-cyclohexanol (2) (68 mg, 0.55 mmol),
PdCl2(PPh3)2 (4 mg, 0.005 mmol, 1 mol %) and CuI (1 mg,
0.005 mmol, 1 mol %) were placed into a flame-dried Schlenk flask.
Diisopropylamine (4 mL) was added and the mixture was stirred
under argon at 80 ꢁC. The reaction was followed by TLC and GC–MS.
When the first coupling was complete 2-iodo-5-methoxy-O-tri-
isopropylsilylphenol (6b) (203 mg, 0.50 mmol), KOH (112 mg,
2 mmol), PdCl2(PPh3)2 (10 mg, 0.015 mmol, 3%) and CuI (3 mg,
0.015 mmol, 3%) were added. The mixture was stirred under argon
at 80 ꢁC, until the second coupling was complete. Then TBAF was
added in 1 M THF solution (1.1 mL, 1.1 mmol). It was stirred under
argon at 80 ꢁC until the cleavage and the ring closure were com-
plete. The reaction mixture was diluted with water (5 mL) and the
pH was set to 5 with 2 M HCl. It was extracted with ethyl acetate
(3ꢀ20 mL). The combined organic layer was washed with brine
(5 mL) and dried over magnesium sulfate. After evaporating the
solvent, the product was purified by column chromatography, using
hexane–ethyl acetate as eluent to give 93 mg brown oil (0.34 mmol,
7. (a) Bleicher, L.; Cosford, N. D. P. Synlett 1995, 1115; (b) Ley, K. D.; Li, Y.; Johnson,
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4917.
8. Cse´kei, M.; Nova´k, Z.; Kotschy, A. Tetrahedron 2008, 64, 975.
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Chem. 2006, 3, 477.
69%). 1H NMR (CDCl3, 250 MHz):
d
7.86 (d, 1H, J¼9.0 Hz), 7.42 (d, 1H,
12. (a) Nova´k, Z.; Tima´ri, G.; Kotschy, A. Tetrahedron 2003, 59, 7509; (b) Beutler, U.;
Mazacek, J.; Penn, G.; Schenkel, B.; Wasmuth, D. Chimia 1996, 50, 154; (c)
J¼8.5 Hz), 7.12 (d, 1H, J¼0.8 Hz), 7.05 (d, 1H, J¼1.4 Hz), 6.85 (dd, 1H,
J¼8.5, 2.3 Hz), 6.54–6.50 (m, 2H), 3.95 (s, 3H), 3.87 (s, 3H); 13C NMR
´
´
´
Csekei, M.; Novak, Z.; Timari, G.; Kotschy, A. Arkivoc 2004, 285; (d) Jinno, S.;
Okita, T.; Inouye, K. Bioorg. Med. Chem. Lett. 1999, 9, 1029; (e) Yao, T.; Yue, D.;
Larock, R. C. J. Org. Chem. 2005, 70, 9985; (f) Aslam, S. N.; Stevenson, P. C.;
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Aoyama, S.; Shioiri, T. Tetrahedron Lett. 1999, 40, 4211.
(CDCl3, 62.5 MHz):
d 157.6, 157.5, 156.5, 154.6, 151.6, 127.6, 123.3,
120.8, 112.9, 111.3, 107.4, 104.0, 99.2, 95.6, 55.7, 55.5; MS (EI, 70 eV)
m/z (% relative intensity, ion): 270 (100, [Mþ]), 255 (92), 227 (15),
212 (19), 135 (25), 128 (14).
13. (a) Preston, N. W.; Chamberlain, K.; Skipp, R. A. Phytochemistry 1975, 14, 1875;
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Heterocycles 2005, 65, 1641.
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Acknowledgements
The authors thank Dr. K. Torkos, Dr. Zs. Eke and Ms. D. Bene-
´
¨
¨
soczki (Eotvos University) for providing the necessary analytical
background. The financial support of the Hungarian Scientific Re-
search Fund (OTKA F047125/2004 and D048657) and KPI (GVOP-
3.2.1.-0358/2004) is gratefully acknowledged.
References and notes
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