p-Toluenesulfonic acid-mediated cyclization of o-(1-alkynyl)anisoles or thioanisoles: synthesis of 2-arylsubstituted benzofurans and benzothiophenes

Article abstract of DOI:10.1016/j.tetlet.2009.03.087

A variety of 2-arylbenzo[b]furans are readily prepared in good to excellent yields from the cyclization of o-(1-alkynyl)anisole derivatives under mild reaction conditions using an alcoholic media, p-toluenesulfonic acid under microwave irradiation. Starti

Full text of DOI:10.1016/j.tetlet.2009.03.087

Tetrahedron Letters 50 (2009) 3588–3592
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
p-Toluenesulfonic acid-mediated cyclization of o-(1-alkynyl)anisoles or
thioanisoles: synthesis of 2-arylsubstituted benzofurans and benzothiophenes
*
Maud Jacubert, Abdallah Hamze, Olivier Provot, Jean-François Peyrat, Jean-Daniel Brion, Mouad Alami
Univ Paris-Sud, BioCIS- UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, rue J.B. Clément Châtenay-Malabry F-92296, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A variety of 2-arylbenzo[b]furans are readily prepared in good to excellent yields from the cyclization of
o-(1-alkynyl)anisole derivatives under mild reaction conditions using an alcoholic media, p-toluenesul-
fonic acid under microwave irradiation. Starting from the corresponding o-(1-alkynyl)thioanisole deriv-
atives, this friendly and environmentally free-metal procedure has been successfully extended to the
synthesis of benzo[b]thiophenes. Relative to the electronic nature of the substituents, the selectivity of
the cyclization reaction from differently o,o0-substituted diarylalkynes is also discussed.
Ó 2009 Published by Elsevier Ltd.
Received 15 January 2009
Revised 5 March 2009
Accepted 10 March 2009
Available online 16 March 2009
Keywords:
Benzofurans
Benzothiophenes
Isocoumarins
Alkynes
Electrophilic cyclization
Microwave irradiation
p-Toluenesulfonic acid
Conversions of alkynes to their corresponding carbonyl com-
pounds are very important and essential in functional group trans-
formation.1 As part of a research program directed toward a
selective functionalization of a carbon–carbon triple bond,2 we
previously reported the hydration of internal alkynes, in water or
alcoholic media under a catalytic amount of p-toluenesulfonic acid
(PTSA).3 Under this environmentally friendly procedure, aliphatic
arylalkynes were regioselectively converted into their correspond-
ing carbonyl compounds according to Markovnikov’s rules. Inter-
estingly, we next demonstrated that under similar conditions,
diarylalkynes bearing in the ortho position of the aromatic nucleus
an electron-withdrawing group such as an ester, an acid, or an
amide group afforded 3-arylsubstituted isocoumarins in high
yields.4 Additionally, under microwave irradiation diarylalkynes
having an ortho electron-donating methoxy group also reacted suc-
cessfully but at higher temperatures (170 °C). However, and con-
trary to our expectations, the reaction did not afford exclusively
the carbonyl product 2 but also allowed the formation of the cy-
clized product 2-arylbenzo[b]furans 3 (Scheme 1).3b One can note
that the electronic nature of the para R substituent on alkyne 1
influences the distribution of compounds 2 and 3, since the major
product is the carbonyl compound 2a when R = H, whereas benzo-
furan 3b predominated when R = Me.
The most common route to heterocycles of type 3 is undoubt-
edly the cyclization of o-(1-alkynyl)phenol compounds through a
transition metal-catalyzed activation of the triple bond.5 In order
to develop a rapid and metal-free access to 2-arylsubstituted ben-
zo[b]furans 3, according to the green chemical philosophy,6 we set
out to carefully examine the transformation of 1 to 3, since benzo-
furans are ubiquitous structural motifs in both natural products
and synthetic pharmaceuticals.7 Additionally, in spite of efficient
procedures for the preparation of benzofurans from internal al-
kynes having an ortho phenolic-free function are well known,5 to
the best of our knowledge there is no report on their synthesis
from the corresponding anisole derivatives. We speculate that,
replacing the R substituent (H or Me) on alkyne 1 by a variety of
strong electron-donating groups would increase the reactivity of
the triple bond and, at least the yields of 3.
PTSA, EtOH
R
Microwaves, 170 °C
OMe
1
O
R
R
O
OMe
2
58%
14%
3
39%
63%
a: R = H
b: R = Me
* Corresponding author. Tel.: +33 1 46 83 58 87; fax: +33 1 46 83 58 28.
E-mail address: mouad.alami@u-psud.fr (M. Alami).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.03.087

M. Jacubert et al. / Tetrahedron Letters 50 (2009) 3588–3592
3589
Interestingly, starting from o-(1-alkynyl)thioanisoles this new
and environmentally friendly procedure could also be extended
to the synthesis of 2-aryl-substituted benzo[b]thiophene deriva-
tives8 which are prevalent in many compounds of biological inter-
est.9,7b Herein, we report the results of this study and how the
electronic nature of ortho substituents on diarylalkynes influences
the regiochemical course of this cyclization.
or MeOH under microwave irradiation at 130 °C within 1 h.
Accordingly, the expected benzofuran 3c was obtained in satisfac-
tory yields and no trace of the hydration product was detected
(Table 1, entries 1 and 2). Carrying out the reaction in CD3OD
formed 3d with no signal at 6.88 ppm in 1H NMR spectrum, clearly
indicating a deuteration on the 3-position of the benzofuran ring
(entry 3).
Initially, we studied the reaction with alkyne 1c bearing on aro-
matic rings an ortho and a para methoxy group both useful for the
cyclization and for the activation of the triple bond, respectively.
The best conditions required the use of PTSA (1.0 equiv) in EtOH
The formation of 3d is believed to proceed initially through a
deuterium exchange between CD3OD and PTSA followed by acidic
deuterium activation of the triple bond (Scheme 2). Subsequent
regioselective 5-endo-dig-cyclization with the ortho methoxy sub-
Table 1
Reaction of ortho-substituted arylalkynes 1 with PTSA in EtOH: synthesis of 2-arylbenzo[b]furans and 2-arylbenzo[b]thiophenes
1
1
PTSA (1.0 eq)
Microwaves
R
R
X
XR
1
3
Entry
Alkyne 1
T (°C)
Time (h)
Solvent
Product
Yielda (%)
1
2
130
130
1
1
EtOH
MeOH
76
74
OMe
OMe
O
OMe
1c
3c
D
OMe
3
4
130
130
1
1
CD3OD
EtOH
80
OMe
O
O
OMe
1c
3d
OMe
OMe
62b
OCH2Ph
1d
3c
OMe
OMe
5
6
130
130
1
1
EtOH
EtOH
79
94
O
S
OH
1e
3c
OMe
OMe
SMe
1f
3e
MeO
7
8
9
160
160
160
2
2
2
EtOH
EtOH
EtOH
83
92
93
O
3f
3g
3h
MeO
OMe
OMe
1g
1h
O
S
SMe
1i
O
O
10
160
160
2
2
EtOH
EtOH
44c
OMe
OMe
1j
3i
CO2Et
1k
CO2Et
11
0d
3j
a
Isolated yield.
b
c
Ethylbenzylether was also observed in the crude reaction mixture.
A 32% of hydration product was isolated where the carbonyl function is proximal to the o-methoxyphenyl ring.
A 47% of hydration product was isolated where the carbonyl function is proximal to the o-methoxyphenyl ring. No starting material was left.
d

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M. Jacubert et al. / Tetrahedron Letters 50 (2009) 3588–3592
To support this hypothesis, an attempt was achieved with
D
TsOH (1.0 eq)
CD3OD, MW
alkyne 1d having an ortho benzyloxy substituent. As expected, in
EtOH the reaction provided the benzofuran 3c together with ethyl-
benzylether resulting from the oxonium cleavage (entry 4).10 It
should be noted that 1e with an ortho hydroxyl-free substituent
also underwent the cyclization reaction to afford 3c in a similar
yield as it was observed from 1c (entry 5).
OMe
OMe
O
OMe
1c
3d
MeOCD3
TsOD
Me
Keeping in mind our initial goal to extend this reaction to the
synthesis of benzothiophene derivatives, we next examined the
cyclization of thioanisole 1f. We were pleased to observe the for-
mation of the corresponding benzothiophene 3e in excellent yield
(94%, entry 6). By utilizing these experimental conditions, we car-
ried out the cyclization with the symmetrical substrate 1g having
two ortho methoxy groups on aromatic rings. At 130 °C within
1 h, the reaction took place smoothly to provide the desired com-
pound 3f together with starting material 1g. Increasing the tem-
perature to 160 °C, the reaction went to completion and 3f was
isolated in a 83% isolated yield (entry 7). The scope of this reaction
was successfully demonstrated when switching the 2-methoxy-
phenyl by the 1-naphthyl group. In both examples depicted in
D
O
OMe
OMe
O
D
Me
TsO
TsO
CD3OD
Scheme 2. A plausible mechanistic formation of 3d.
stituent would lead to an oxonium species. The latter would be
cleaved by the nucleophilic solvent to form the C3 deuterated ben-
zofuran 3d.
Table 2
Selectivity in heterocycle formation from o,o0-disubstituted diarylalkynes 1a
Entry
Alkyne 1
T (°C)
Product (yield (%))b
Ratio
HO
HO
O
1
160
62:38
O
OMe
OMe
1l
1m
1n
1o
1p
3f (36%)
3k (60%)
HO
TBDMSO
2
3
4
160
160
160
—
O
OMe
HO
3k (61%)
HO
O
85:15
S
SMe
SMe
3m (13%)
3l (71%)
HO
TBDMSO
—
S
SMe
MeO
3l (88%)
MeO
O
5
6
130
160
82:18c
S
SMe
3m
SMe
MeO
3n
MeO
OMe
d
OMe
—
O
OMe
1q
3o (65%)
O
MeO2C
OMe
O
7
130
—
1r
OMe
3p (95%)
(continued on next page)

M. Jacubert et al. / Tetrahedron Letters 50 (2009) 3588–3592
3591
Table 2 (continued)
Entry
Alkyne 1
T (°C)
Product (yield (%))b
Ratio
O
i-PrO2C
O
8
160
—
OMe
1s
1t
OMe
3p (88%)
O
EtO2C
EtO2C
O
9
160
33:67
S
SMe
SMe
3q (21%)
3r (42%)
O
CO2Me
CO2Me
OMe
O
OMe
10
OMe
160
70:30e
O
OMe
1u
OMe
3t (25%)
3s (57%)
a
All reactions were performed according to general procedure; see: Ref. 11.
Isolated yield.
Obtained as an inseparable mixture.
A 26% of hydration product was isolated where the carbonyl function is proximal to the o,p-dimethoxyphenyl ring.
The reaction was performed in MeOH.
b
c
d
e
entries 8 and 9, benzofuran 3g and benzothiophene 3h were
obtained in 92% and 93% isolated yield, respectively. However,
with substrate 1j containing a 2-naphthyl substituent, the reaction
proceeded to give 3i in 44% yield (entry 10) together with a notable
amount of the hydration product (32%) where the carbonyl func-
tion is proximal to the ortho methoxyphenyl ring. These results
clearly suggest that the 1-naphthyl substituent acts as a better
electron-donating group than its 2-isomer for the activation of
the triple bond. Finally, introducing a para ethoxycarbonyl group
on the aromatic nucleus totally deactivates the carbonꢀcarbon
triple bond and, as expected no cyclization occurred. In this case,
the reaction provided exclusively in a moderate yield (47%, entry
11) the hydration product where the carbonyl function is proximal
to the ortho methoxyphenyl ring.
Overall, this new process offered an efficient method for the
preparation of benzofuran and benzothiophene derivatives11 from
easily accessible ortho methoxy and thiomethoxy diarylalkynes.12
We continued to demonstrate the high potency of this friendly
methodology, this time in terms of regioselectivity of the cycliza-
tion reaction, when using differently o,o0-disubstituted diarylalky-
nes and the results are summarized in Table 2. Initially, we
examined the reaction with substrates having two o,o0-electron-
donating substituents (Table 2, entries 1–6). Depending on the
nature of substituents on the aromatic rings, a regioisomeric
heterocyclic mixture to a single product, resulting from ortho
and/or ortho0 substituent attack was observed. Alkyne 1l with an
ortho methoxy and ortho0-hydroxyl substituent can undergo cycli-
zation at both the OMe and OH oxygen atoms to give 3k and 3f in
60% and 36% yield, respectively, (3k:3f 62:38, entry 1). However a
total selectivity was observed when replacing the ortho hydroxyl
group with a tert-butyldimethylsilyloxy substituent. Under these
conditions, the cyclization was followed by a deprotection reaction
leading to benzofuran 3k in 61% isolated yield (entry 2). A similar
trend in selectivity was also observed with alkynes 1n and 1o hav-
ing an ortho methylthio substituent as 1o gives exclusively benzo-
thiophene 3l (entry 4) whereas, 1n leads to a mixture of easily
separable 3l (71%) and 3m (13%) (entry 3). This selectivity
(3n:3m 82:18, entry 5) was also observed with alkyne 1p clearly
indicating that the methylthio substituent is a better nucleophile
than the methoxy or the hydroxy one. Interestingly, starting from
o,o0,p-trimethoxyalkyne 1q, a single cyclization product 3o13 (65%,
entry 6) was formed together with a small amount of the hydration
compound (26%) where the carbonyl function is proximal to the
o,p-dimethoxyphenyl nucleus.
Once the selective cyclization with alkynes having two o,o0-
electron-donating substituents was studied, we sought to examine
the reaction with substrates 1r–u bearing both an ortho electron-
donating and an electron-withdrawing substituents (Table 2,
entries 7–10). Using our protocol with alkyne 1r, the 6-endo cycli-
zation proceeded exclusively with the ortho ethoxycarbonyl func-
tion rather than OMe group and provides isocoumarin 3p in an
excellent yield (95%, entry 7). This selectivity for the isocoumarin
3p could not be reversed in favor of the benzofuran skeleton upon
cyclization of substrate 1s containing a bulkier ortho isopropyloxy-
carbonyl substituent (entry 8). When replacing in 1r the ortho
methoxy substituent by a more nucleophilic methylthio one, the
cyclization from 1t was less selective, producing predominantly
the six-membered-ring lactone 3r together with a notable amount
(21%) of the benzothiophene 3q (entry 9). Finally, an attempt was
made with alkyne 1u containing both an ortho electron-donating
and electron-withdrawing substituents on the same nucleus. In
this case the cyclization occurred preferentially at the oxygen atom
of the methoxy rather than the methoxycarbonyl substituent to
give the benzofuran 3s and the isocoumarin 3t in 57% and 25%
yield, respectively, (entry 10).
In conclusion, a useful synthesis of 2-arylbenzo[b]furans and
2-arylbenzo[b]thiophenes has been achieved using in alcoholic med-
ia p-toluenesulfonic acid under microwave irradiation. This metal-
free procedure which proceeds under environmentally friendly
conditions utilizes readily available o-(1-alkynyl)anisole and
o-(1-alkynyl)-thioanisole derivatives. From o,o0-substituted diary-
lalkyne substrates we demonstrated that the cyclization selectivity
is strongly dependent on the electronic nature of the ortho substit-
uents and in some cases it may allow a selective synthesis of the

3592
M. Jacubert et al. / Tetrahedron Letters 50 (2009) 3588–3592
Dingeman, K. M.; Mocharla, V. P.; Pettit, G. P.; Bai, R.; Hamel, E. Bioorg. Med.
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above heterocycles or isocoumarins. Further application of this
process to generate benzofuran or benzothiophene-based chemical
libraries of potential pharmacological interest is currently
underway.
10. Bossharth, B.; Desbordes, P.; Monteiro, N.; Balme, G. Tetrahedron Lett. 2009, 50,
614–616.
Acknowledgments
11. Typical procedure: To an Emrys Optimizer 0.5–2 mL pyrex reaction vessel were
added alkyne (0.2 mmol) and PTSA.H2O (38 mg; 0.2 mmol) in EtOH (1 mL). The
reaction vessel was then placed in the Emrys Optimizer and exposed to
microwave irradiation according to the following specifications: temperature,
130 °C or 160 °C (see Table 2); time (1 h); fixed hold time: on; sample
absorption: high; pre-stirring: 60 s. After cooling to room temperature, H2O
(3 mL) was added and the mixture was extracted with CH2Cl2 (3 ꢁ 2 mL).
Organic layers were dried, concentrated, and the crude was purified by column
chromatography on silica gel. Data for all new products are described in entries
2, 3, 6, 9, and 10 in Table 2.
The CNRS is gratefully acknowledged for financial support of
this research and MRES for a doctoral fellowship to M.J. Thanks also
to Estelle Morvan for NMR studies.
References and notes
Entry 2. Compound 3k (61%). Rf 0.22 (cyclohexane:EtOAc, 9:1). 1H NMR (CDCl3,
400 MHz): d 6.72–6.78 (m, 2H), 6.84 (s, 1H), 6.91 (s, 1H), 6.99–7.09 (m, 3H),
7.28 (m, 1H), 7.35 (m, 1H), 7.46 (m, 1H). 13C NMR (CDCl3, 100 MHz): d 103.5,
111.2, 116.2, 117.5, 120.9, 121.1, 123.6, 124.6, 127.3, 128.6, 130.4, 153.5, 154.1,
1. (a) Hintermann, L.; Labonne, A. Synthesis 2007, 1121–1150; (b) Arcadi, A. Chem.
Rev. 2008, 108, 3266–3325. and references cited therein; (c) Marion, N.; Ramón,
R. S.; Nolan, S. J. Am. Chem. Soc. 2009, 131, 448–449; (d) Labonne, A.; Kribber, T.;
Hintermann, L. Org. Lett. 2006, 8, 5853–5856; (e) Ackermann, L.; Kaspar, L. T. J.
Org. Chem. 2007, 72, 6149–6153.
2. (a) Alami, M.; Ferri, F. Synlett 1996, 755–756; (b) Liron, F.; Le Garrec, P.; Alami,
M. Synlett 1999, 246–248; (c) Alami, M.; Liron, F.; Gervais, M.; Peyrat, J.-F.;
Brion, J.-D. Angew. Chem., Int. Ed. 2002, 41, 1578–1580; (d) Hamze, A.; Provot,
O.; Alami, M.; Brion, J.-D. Org. Lett. 2005, 7, 5625–5628; (e) Hamze, A.; Provot,
O.; Brion, J.-D.; Alami, M. Synthesis 2007, 2025–2036; (f) Hamze, A.; Provot, O.;
Brion, J.-D.; Alami, M. J. Org. Chem. 2007, 72, 3868–3874; (g) Giraud, A.; Provot,
O.; Hamze, A.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2008, 49, 1107–1110.
3. (a) Olivi, N.; Thomas, E.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett 2004, 2175–
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Alami, M.; Marsaud, V.; Stella, B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189–
6200.
154.4. IR (m
cmꢀ1): 3451, 3352, 1590, 1446, 1212, 1017, 743. MS (APCI+) m/z
211.0 (M+H)+.
Entry 3. Compound 3l (71%). Rf 0.21 (cyclohexane:EtOAc, 95:5). 1H NMR
(CDCl3, 400 MHz): d 5.63 (s, 1H), 6.99–7.05 (m, 2H), 7.27–7.43 (m, 3H), 7.40
(dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.56 (s, 1H), 7.81–7.89 (m, 2H). 13C NMR (CDCl3,
100 MHz): d 116.5, 121.0, 121.2, 122.3, 123.0, 123.8, 124.7, 124.8, 130.0, 130.4,
139.4, 140.0, 140.4, 152.9. IR (m
cmꢀ1): 3511, 3054, 1481, 1449, 1432, 1333,
1290, 1173, 747. MS (APCI+) m/z 227.0 (M+H)+. Compound 3m (13%). Rf 0.61
(cyclohexane:EtOAc, 9:1). 1H NMR (CDCl3, 400 MHz): d 2.54 (s, 3H), 7.22–7.31
(m, 3H), 7.34–7.36 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.63 (dt, J = 7.6 Hz,
J = 0.7 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H). 13C NMR (CDCl3, 100 MHz): d 16.3, 106.9,
111.2, 121.4, 123.0; 124.7, 125.0, 126.0, 128.9, 129.1, 129.3, 137.1, 153.6,
154.4. IR (
m
cmꢀ1): 2922, 1454, 1260, 1017, 804, 747. MS (APCI+) m/z 241.0
(M+H)+.
4. Le Bras, G.; Hamze, A.; Messaoudi, S.; Provot, O.; Le Calvez, P.-B.; Brion, J.-D.;
Alami, M. Synthesis 2008, 1607–1611.
Entry 6. Compound 3o (65%). Rf 0.30 (cyclohexane:EtOAc, 9:1). 1H NMR (CDCl3,
400 MHz): d 3.90 (s, 3H), 4.01 (s, 3H), 6.61–6.68 (m, 2H), 7.22–7.32 (m, 3H),
7.54 (dt, J = 6.6 Hz, J = 1.1 Hz, 1H), 7.62 (m, 1H), 8.03 (d, J = 8,6 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): d 55.6 (2), 98.9, 104.4, 105.0, 110.7, 112.9, 120.8, 122.7,
5. (a) Russo, O.; Messaoudi, S.; Hamze, A.; Olivi, N.; Peyrat, J.-F.; Brion, J.-D.; Sicsic,
S.; Berque-Bestel, I.; Alami, M. Tetrahedron 2007, 63, 10671–10683; (b) Hu, Y.;
Nawoschik, K. J. Org. Chem. 2004, 69, 2235–2239; (c) Hu, Y.; Zhang, Y.; Yang, Z.;
Fathi, R. J. Org. Chem. 2002, 67, 2365–2368; (d) Novák, Z.; Timári, G.; Kotschy, A.
Tetrahedron 2003, 59, 7509–7513; (e) Kabalka, G. W.; Wang, L.; Pagni, R. M.
Tetrahedron 2001, 57, 8017–8028; (f) Droz, A. S.; Neidlein, U.; Anderson, S.;
Seiler, P.; Diederich, F. Helv. Chim. Acta 2001, 84, 2243–2289; (g) Olivi, N.;
Spruyt, P.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2004, 45, 2607–
2610; (h) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett.
2002, 4, 4727–4729; (i) Saejueng, P.; Bates, C.; Venkataraman, D. Synthesis
2005, 1706–1712.
123.7, 128.1, 130.2, 152.6, 153.8, 157.9, 161.1. IR (m
cmꢀ1): 2937, 2836, 1610,
1502, 1252, 1208, 1158, 1029, 796, 740. MS (APCI+) m/z 255.0 (M+H)+.
Entry 9. Compound 3q (21%). Rf 0.27 (cyclohexane:EtOAc, 6:4). 1H NMR (CDCl3,
400 MHz): d 1.04 (t, J = 7.1 Hz, 3H), 4.18 (q, J = 7.1 Hz, 2H), 7.24 (s, 1H), 7.31–
7.39 (m, 2H), 7.45 (dd, J = 7.3, J = 1.6 Hz, 1H), 7.51–7.57 (m, 2H), 7.76–7.81 (m,
2H), 7.84 (d, J = 7,7 Hz, 1H). 13C NMR (CDCl3, 100 MHz): d 13.9, 61.4, 122.2,
123.1, 123.7, 124.4, 124.6, 128.5, 129.7, 131.1, 131.5, 132.5, 134.4, 140.2, 140.5,
142.6, 168.6. IR (m
cmꢀ1): 2982, 1720, 1289, 1257, 1127, 1084, 726. MS (APCI-)
m/z 209.0 (MꢀCO2Et)ꢀ. Compound 3r (42%). Rf 0.12 (cyclohexane:CH2Cl2, 6:4).
1H NMR (CDCl3, 300 MHz): d 2.48 (s, 3H, SCH3), 6.85 (s, 1H), 7.20–7.26 (m, 1H),
7.32 (dd, J = 8.0 Hz, J = 1.1 Hz, 1H), 7.37–7.43 (m, 1H), 7.48–7.60 (m, 3H), 7.73
(td, J = 7.6 Hz, J = 1.3 Hz, 1H), 8.30 (dt, J = 7.9 Hz, J = 0.6 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): d 16.5, 107.2, 120.7, 124.9, 126.1, 126.2, 128.5, 129.7, 129.8,
6. For recent reports, see: (a) Horvth, I. T.; Anastas, P. T. Chem. Rev. 2007, 107,
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7. (a) Donnelly, D. M. X.; Meegan, M. J.. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Pergamon Press: New York, 1984; Vol. 4, (b) Bakunov, S.;
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Med. Chem. 2008, 51, 6927–6944; (c) Erber, S.; Ringshandl, R.; von Angerer, E.
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8. For recent synthesis of 2-arylbenzothiophenes, see: (a) Takeda, N.; Miyata, O.;
Naito, T. Eur. J. Org. Chem. 2007, 1491–1509; (b) Bíró, A. B.; Kotschy, A. Eur. J.
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130.2, 131.9, 134.9, 137.3, 138.2, 153.1, 162.6. IR (m
cmꢀ1): 2939, 1669, 1596,
1510, 1485, 1251, 1168, 1025, 841, 749. MS (APCI+) m/z 269.0 (M+H)+.
Entry 10. Compound 3s (57%). Rf 0.51 (cyclohexane:CH2Cl2, 6:4). 1H NMR
(CDCl3, 400 MHz): d 3.87 (s, 3H), 4.00 (s, 3H), 7.00 (d, J = 8.7 Hz, 2H), 7.28 (t,
J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.95
(d, J = 7.7 Hz, 1H). 13C NMR (CDCl3, 100 MHz): d 52.1, 55.5, 101.0, 114.5 (2C),
115.4, 122.1, 123.0, 123.1, 125.6, 127.0 (2C), 130.5, 155.3, 158.1, 160.6, 167.3.
IR (m
cmꢀ1): 2952, 1712, 1503, 1247, 1175, 1137, 1042, 751. MS (APCI+) m/z
283.0 (M+H)+. Compound 3t (25%). Rf 0.22 (cyclohexane:CH2Cl2, 6:4). 1H NMR
(CDCl3, 400 MHz): d 3.96 (s, 3H), 7.00 (d, J = 8.3 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H),
7.36–7.40 (m, 2H), 7.45–7.51 (m, 2H), 7.70 (t, J = 8.3 Hz, 1H), 7.97 (dd,
J = 7.9 Hz, J = 1.7 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H). 13C NMR (CDCl3, 100 MHz): d
55.8, 107.1, 111.5, 120.8, 120.9, 121.0, 126.4, 128.1, 129.0, 129.5, 130.9, 134.8,
138.2, 150.6, 157.4, 162.8. IR (m
cmꢀ1): 1724, 1625, 1493, 1225, 1021, 754. MS
(APCI+) m/z 253.0 (M+H)+. Benzofurans and benzothiophenes 3c–i described in
Table 1 are known compounds.
12. (a) Sonogashira, K.; Tokai, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16,
4467–4470; (b) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 1433–1436; (c) Alami, M.; Ferri, F.; Gaslain, Y. Tetrahedron Lett. 1996,
37, 57–58.
9. (a) Jones, C. D.; Jevnikar, M. G.; Pike, A. J.; Peters, M. K.; Black, L. J.; Thompson, A.
R.; Falcone, J. F.; Clemens, J. A. J. Med. Chem. 1984, 27, 1057–1066; (b)
Palkowitz, A. D.; Glasebrook, A. L.; Thrascher, K. J.; Hauser, K. L.; Short, L. L.;
Phillips, D. L.; Muehl, B. S.; Sato, M.; Shetler, P. K.; Cullinan, G. J.; Pell, T. R.;
Bryant, H. U. J. Med. Chem. 1997, 40, 1407–1416; (c) Pinney, K. G.; Bounds, A. D.;
13. The structure of benzofuran 3o was assigned based on NOE experiments.