Palladium catalyzed suzuki cross-coupling of 3-iodo-2-(methylthio)-benzo[b] furan derivatives: Synthesis of 3-aryl-2-(methylthio)benzo[b]furans

Article abstract of DOI:10.1590/S0103-50532010000900006

A selective and efficient method for the synthesis of 3-aryl-2-(methylthio) benzo[b]furans derivatives by palladium catalyzed cross-coupling reaction with boronic acids has been developed. The reaction proceeded cleanly under mild conditions and was performed with aryl boronic acids bearing electron-withdrawing, electron donating and neutral substituents.

Full text of DOI:10.1590/S0103-50532010000900006

J. Braz. Chem. Soc., Vol. 21, No. 9, 1635-1641, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan
Derivatives: Synthesis of 3-Aryl-2-(methylthio)benzo[b]furans
Rafaela M. Gay, Flávia Manarin, Ricardo Brandão and Gilson Zeni*
Departamento de Química, Centro de Ciências Naturais e Exatas,
Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Neste trabalho desenvolvemos um método seletivo e eficiente para a síntese de derivados de
3-aril-2-(tiometil)-benzo[b]furanos, via reação de acoplamento com ácidos borônicos, catalisada
por paládio. As condições reacionais usadas foram brandas e compatíveis com ácidos borônicos
contendo substituintes retiradores, doadores de elétrons ou neutros.
A selective and efficient method for the synthesis of 3-aryl-2-(methylthio)benzo[b]furans
derivatives by palladium catalyzed cross-coupling reaction with boronic acids has been developed.
The reaction proceeded cleanly under mild conditions and was performed with aryl boronic acids
bearing electron-withdrawing, electron donating and neutral substituents.
Keywords: palladium, Suzuki cross-coupling, benzofuran, boronic acids
Introduction
In addition, the presence of a sulfide group at the
2-position of benzo[b]furan is significant, since it could
be easily oxidized to 2-sulfonylbenzofurans,6 a class of
compounds which has attracted tremendous interest from
the pharmaceutical industry. During the course of our
research program aiming at structure-activity relationship
studies in order to evaluate the pharmacology activity of
heterocycles,7,8 we required the synthesis of benzofurans
having an organochalcogen group at the 2-position and
a substituted aromatic ring at the 3-position. Since the
Suzuki reaction has proven to be successful for the
selective arylation of heterocyles,2 it was of interest to
explore this reaction to obtain 3-aryl-2-(methylthio)
benzo[b]furan derivatives. To our knowledge this
methodology has not been explored and we now wish to
report the application of 3-iodo-2-(methylthio)benzo[b]
furans 1a-c as substrates on the cross-coupling reaction
with boronic acids 2a-k in the presence of a palladium
salt to obtain 3-aryl-2-(methylthio)benzo[b]furans 3a-u
(Scheme 1).
The construction of benzo[b]furans substituted in
the 2,3 positions is of great synthetic interest due to the
presence of this moiety in many complex compounds,
which have potential therapeutic applications.1 In this
context, the preparation of 2,3-disubstituted benzo[b]
furans represents a synthetic challenge and the palladium-
catalyzed Suzuki coupling is one of the most straightforward
methodologies to synthesize 3-arylated-benzofurans.2 The
palladium-catalyzed Suzuki cross-coupling reaction of
aryl halides with organoboron reagents has become a
common and convenient synthetic method in organic
chemistry.3 Many examples of Suzuki coupling reaction
of heterocyclic halides with boronic acids have appeared
in the literature over the past two decades as a promising
synthetic tool.4 More recently, significant advances
have been made in the use of organoboron reagents as
coupling partners in a number of palladium-mediated
carbon–carbon bond formation. Among them, the use
of potassium organotrifluoroborates, as the organoboron
coupling partner, has some of these advantages are higher
nucleophilicity, air-stability and ready access in comparison
to boronic acids and boronic esters.5
The starting materials 1a-c were readily available
by using the electrophilic cyclization protocol9 of
2-(methylthio)alkynylanisoles (Scheme 2). The treatment
of 2-(methylthio)alkynylanisoles with iodine in CH2Cl2, at
room temperature, led to the formation of 1a-c, isolated in
87-95% yield after purification (Scheme 2).10
*e-mail: gzeni@pq.cnpq.br

1636
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
I
Ar
Pd(PPh3)4 (2%), K2CO3/H2O
DMF, 100 oC
SCH3
SCH3
+
ArB(OH)2
O
O
R
R
1a-c
2a-k
3a-u
R = H, Me, F;
Ar = C6H5, p-OMe-C6H4, p-Me-C6H4, o-Me-C6H4, p-Cl-C6H4, p-Br-C6H4, p-Me-COC6H4, m-Me-COC6H4,
m-CF3-C6H4, m-NO2-C6H4, naphtyl
Scheme 1.
I
SMe
R
R
I2, CH2Cl2
30 min., r.t.
SMe
O
OMe
R= H, 1a- 93%
R= Me, 1b- 95%
R= F, 1c- 87%
Scheme 2.
Results and Discussion
(0.4 mL), using DMF (4.0 mL) as solvent, at reflux with
different palladium catalysts was tested (Table 1).As shown
in Table 1, both Pd(0) and Pd(II) catalysts with different
ligands were tested. The best result was obtained using
Pd(PPh3)4 (5 mol%) which gave the desired product 3a in
97% yield (Table 1; entry 1). It is important to note that when
the amount of catalyst was reduced from 5 to 2 mol%, a
small decrease in the yield was observed (Table 1; entry 7).
Our initial studies on Suzuki cross-coupling focused on
the development of an optimum set of reaction conditions.
In this way, 3-iodo-2-(methylthio)benzo[b]furan 1a and
phenylboronic acid 2a were used as standard substrates.
Thus, the reaction of 1a (0.5 mmol), boronic acid 2a
(0.75 mmol), and a solution of K2CO3 (1.0 mmol) in H2O
Table 1. Effects of palladium catalysts on reaction of 1a and 2aa
I
B(OH)2
[Pd], K2CO3 / H2O
SCH3
SCH3
+
DMF, 100 oC
O
O
1a
2a
3a
Entry
Catalysts (mol %)
Yield / (%)b
1
2
3
4
5
6
7
8
Pd(PPh3)4 (5)
Pd(acac)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PhCN)2 (5)
PdCl2 (5)
97
traces
83
traces
nr
Pd(OAc)2 (5)
Pd(PPh3)4 (2)
-
15
93
nr
a Reactions were performed in the presence of 1a (0.5 mmol), 2a (0.75 mmol), K2CO3 (1.0 mmol), H2O (0.4 mL), in DMF (4.0 mL), under 100 oC, during 1h.
bYields are given by GC analysis. nr = no reaction.

Vol. 21, No. 9, 2010
Gay et al.
1637
Our experiments also showed that in the absence of catalyst
the product was not detected, and the starting material was
recovered (Table 1; entry 8).
In order to demonstrate the efficiency of this protocol,
we explored the generality of our method extending the
conditions to other aryl boronic acids and 3-iodo-2-
(methylthio)-benzo[b]furan derivatives and the results are
summarized in Table 3. Inspection of Table 3 shows that
the reaction worked well for a variety of arylboronic acids.
A closer inspection of the results revealed that the reaction
is sensitive to the electronic effect of the aromatic ring
attached in the arylboronic acid. For example, arylboronic
acids bearing an electron-donating group, methyl or
methoxyl, at the para position gave a better yield than
the arylboronic acid bearing an electron-withdrawing
group, halide and acetyl (Table 3; entries 2, 3 versus
4-6). These results are in full agreement with the fact
that electron donating groups increase the nucleophilicity
of boronic acids. We have found that steric effects had
a little influence on the coupling reaction since boronic
acids containing 2-methylphenyl or naphtyl group, gave
similar yields than arylboronic acids with no substituent,
however an increase in the reaction time was required
(Table 3; entries 10, 15, 18 and 21). Differentiation in
the reactivity between halogen and boron atoms can be
seen by coupling showed in the experiments described in
Table 1 (enties 4 and 5), which provide only the Suzuki
product, without any homo-coupling product. To the best
Regarding the influence of solvent, optimal results were
achieved using DMF (Table 2, entry 1). By using dioxane,
CH3CN and THF (Table 2, entries 2, 4 and 6) good yields
were also obtained, while the use of DME (Table 2, entry 5)
did not give the desired product 3a. We also observed that the
nature of the base was critical for the success of the coupling.
When the reaction was carried out with an aqueous solution
of inorganic bases such as K3PO4, Cs2CO3 and Na2CO3 the
coupling product was obtained in good yields (Table 2;
entries 7-9), while the use of NaOH (Table 2, entry 10)
furnished the desired coupling product in low yield. It is
also important to mention that when dry base were used
in place of an aqueous solution, only 54% of product was
obtained (Table 2; entry 11). Careful analysis of the results
revealedthattheoptimumconditionforthiscouplingreaction
was found to be the use of Pd(PPh3)4 (2 mol%), 3-iodo-2-
(methylthio)-benzo[b]furan1a(0.5mmol),phenylboronicacid
(0.75 mmol) in DMF (4.0 mL) and H2O (0.4 mL) at room
temperature.Afterthat, thebaseK3PO4 (1.0mmol)wasadded
andthemixturewasheatedat100oCfor1h.Usingthisreaction
condition we were able to prepare 3-aryl-2-(methylthio)-
benzo[b]furan derivative 3ain excellent yield.12
Table 2. Study of base and solvent effects on cross-coupling reactiona
I
B(OH)2
Pd(PPh3)4 (2%)
SCH3
SCH3
+
base, solvent
O
O
1a
2a
3a
Entry
Base
Solvent
Yield 3a / (%)b
1
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Na2CO3
Cs2CO3
NaOH
K2CO3
DMF
Dioxane
Toluene
CH3CN
DME
93
91
45
90
nr
2
3
4
5
6
THF
70
64
60
73
36
54c
7
DMF
8
DMF
9
DMF
10
11
DMF
DMF
a Reactions wereperformed by using 1a (0.5 mmol), 2a (0.75 mmol), Pd(PPh3)4 (2 mol%), base (1.0 mmol), H2O (0.4 mL) with different solvents (4.0 mL),
under 100 oC. bYields are given by GC analysis. c This reaction was carried out using dry base.

1638
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Table 3. Coupling products obtained using 3-iodo-2(methylthio)benzo[b]furans 1a-c and boronic acids 2a-ka
I
Ar
Pd(PPh3)4 (2%), K2CO3/H2O
SCH3
ArB(OH)2
+
SCH3
DMF, 100 oC
O
O
R
R
2a-k
1a-c
3a-u
R = H, Me, F
Entry
Substrate
Ar
Yield (%)c / Reaction time
Entry
Substrate
Ar
Yield (%)c / Reaction time
O
1
1a
SCH3
O
7
1a
SCH3
O
O
2a
3a
93/1 hb
2g
3g
90/1 h
OMe
OMe
NO2
NO2
2
3
4
5
1a
1a
1a
1a
SCH3
O
8
1a
SCH3
O
2b
3b
80/1 h
2h
3h
57/12 h
CF3
CF3
9
1a
SCH3
O
SCH3
O
2c
2i
3c
92/2 h
3i
89/2 h
Cl
Cl
10
1a
SCH3
O
SCH3
O
2j
2d
3d
63/1 h
3j
83/6 h
Br
Br
11
1b
2a
SCH3
O
SCH3
O
3k
95/1 h
2e
3e
70/2 h
Cl
O
O
12
1b
2d
6
1a
SCH3
O
SCH3
O
3l
86/2 h
2f
3f
70/3 h

Vol. 21, No. 9, 2010
Gay et al.
1639
Table 3. continuation
Entry
13
Substrate
Ar
Yield (%)c / Reaction time
Entry
Substrate
Ar
Yield (%)c / Reaction time
CF3
1b
2i
SCH3
O
F
18
1c
SCH3
3m
82/1 h
O
2k
3r
O
82/3 h
14
1b
2f
Cl
SCH3
O
3n
60/3 h
F
19
1c
2d
SCH3
O
3s
85/1 h
15
1b
2j
SCH3
O
3o
CF3
92/4 h
F
20
1c
2i
SCH3
O
F
3t
71/2 h
16
1c
2a
SCH3
O
3p
80/1 h
OMe
F
21
1c
2j
SCH3
F
17
1c
2b
O
SCH3
O
3u
82/2 h
3q
90/1 h
a Reactions wereperformed by using 1a-c (0.5 mmol), 2a-k (0.75 mmol), Pd(PPh3)4 (2 mol%), K2CO3 (1.0 mmol), H2O (0.4 mL) in DMF (4.0 mL), under
100 oC. b Yield given by GC analysis. cYields given for isolated products.
of our knowledge, aryl halogen could react with boronic
acids in the presence of palladium catalysts to afford
biaryl products.11 In the example reported in this study,
the halogen substituent was not affected. In an attempt to
broaden the scope of our methodology, the possibility of
performing the reaction with other 3-iodo-2-(methylthio)-
benzofurans was also investigated. Then substrates 1b and
1c, which have methyl and fluoro group in the side chain,
were efficiently cross-coupled. Under these conditions,
both electron-rich and electron-poor arylboronic acids
produced the desired products in good yields (Table 3;
entries 11-21).
Alternatively, under the same conditions described
to boronic acids, we were able to use other organoboron
source, the aryltrifluoroborates (Scheme 3).5 In this way,
3-iodo-2-(methylthio)-benzofuran 1a underwent palladium
cross-coupling with aryltrifluoroborates furnishing the
corresponding 3-aryl-2-(methylthio)benzo[b]furan in
good yields.

1640
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
I
Ar
Pd(PPh3)4 (2%), K2CO3/H2O
DMF, 100 oC
SCH3
SCH3
+
ArBF3K
O
O
1a
Ar = p-OMeC6H4, 3u- 65%
p-MeC6H4, 3v- 70%
o-MeC6H4, 3w- 63%
thienyl, 3x- 60%
Scheme 3.
Conclusions
Ullah, I.; Khera, R. A.; Hussain, M.; Villinger, A.; Langer, P.;
Tetrahedron Lett. 2009, 50, 4651; Dang, T. T.; Rasool, N.; Dang,
T. T.; Reinke, H.; Langer, P.; Tetrahedron Lett. 2007, 48, 845;
Tuan, D. T.; Tung, D. T.; Langer, P.; Synlett 2006, 2812; Bellur,
E.; Langer, P.; Eur. J. Org. Chem. 2005, 22, 4815.
Insummary, wehaveexploredtheSuzukicross-coupling
reaction of arylboronic acids with 3-iodo-2-(methylthio)-
benzofurans using a catalytic amount of Pd(PPh3)4. In
addition, the same procedure used to aryl boronic acids
was efficiently extended to aryltrifluoroborates. The
reaction proceeded cleanly under mild reaction conditions,
short reaction time and was performed with aryl boronic
acids bearing electron withdrawing, electron donating,
and neutral substituents. It is important to point out that
this route permits an easy and efficient access to highly
substituted benzofurans.
3. Miyaura, N.; Suzuki,A.; Chem. Rev. 1995, 95, 2457; Suzuki,A.;
Pure Appl. Chem. 1994, 66, 213; Suzuki,A. In Metal-Catalyzed
Cross-Coupling Reactions; Diederich, F.; Stang, P. J., eds.;
Wiley-VHC: Weinheim, 1998; Lloyd-Williams, P.; Giralt, E.;
Chem. Soc. Rev. 2001, 30, 145.
4. Barancelli, D. A.; Alves, D.; Prediger, P.; Stangherlin, E. C.;
Nogueira, C. W.; Zeni, G.; Synlett 2008, 119; Stanforth, S. P.;
Tetrahedron 1998, 54, 263; Cailly, T.; Fabis, F.; Legay, R.;
Oulyadi, H.; Rault, S.; Tetrahedron 2007, 63, 71; Sicre, C.;
Alonso-Gomez, J. L.; Cid, M. M.; Tetrahedron 2006, 62, 11063;
Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic,
M. D.; Stanetty, P.; Eur. J. Org. Chem. 2006, 15, 3283.
5. Molander, G. A.; Ellis, N.; Acc. Chem. Res. 2007, 40, 275;
Molander, G. A.; Petrillo, D. E.; Landzberg, N. R.; Rohanna, J.
C.; Biolatto, B.; Synlett 2005, 1763; Molander, G.A.; Figueroa,
R.; Aldrichimica Acta 2005, 38, 49; Molander, G. A.; Felix, L.
A.; J. Org. Chem. 2005, 70, 3950; Molander, G. A.; Yun, C.
S.; Ribagorda, M.; Biolatto, B.; J. Org. Chem. 2003, 68, 5534;
Molander, G. A.; Biolatto, B.; J. Org. Chem. 2003, 68, 4302;
Molander, G. A.; Katona, B. W.; Machrouhi, F.; J. Org. Chem.
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2002, 4, 107.
Supplementary Information
Supplementary data (Experimental details and
caracterization of the compounds) are available free of
charge at http://jbcs.sbq.org.br, as PDF file.
Acknowledgments
WearegratefultoConselhoNacionaldeDesenvolvimento
Científico e Tecnológico (CNPq), Coordenação de
Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and
Fundação de Amparo à Pesquisa do Estado do Rio Grande
do Sul (FAPERGS), for the fellowship and financial support.
6. Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.;
Sofia, M. J.; J. Org. Chem. 1996, 61, 8347.
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Vol. 21, No. 9, 2010
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1641
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then heated at 100 oC during 1-4 h, cooled to room temperature,
diluted with dichloromethane (20 mL), and washed with brine
(2 × 20 mL). The organic phase was separated, dried over
MgSO4, and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel using hexane/
ethyl acetate as eluent. Selected spectral and analytical data
for 2-(methylthio)-3-phenylBenzo[b]furan 3a: Yield: 0.111 g
(93%). 1H NMR: CDCl3, 400 MHz, d (ppm): 7.61-7.59 (m, 3H),
7.50-7.46 (m, 3H), 7.37 (t, J 7.3 Hz, 1H), 7.29 (t, J 7.3 Hz, 1H),
7.23 (dd, J 7.5 Hz and J 2.5 Hz, 1H), 2.52 (s, 3H). 13C NMR:
CDCl3, 100 MHz, d (ppm): 155.9, 147.5, 131.8, 129.1, 128.5,
128.3, 127.4, 124.4, 122.9, 122.5, 119.7, 110.8, 16.9. MS (EI,
70 eV) m/z (relative intensity): 238 (26), 222 (17), 194 (100),
163 (23), 151 (10), 76 (8). Anal. (%) Calc. for C15H12OS: C
74.97, H 5.03. Found: C 75.15, H 5.39.
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LeBlond, C. R.;Andrews, A. T.; Sowa, J. R.; Sun,Y.; Org. Lett.
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12. General procedure for the cross-coupling reaction:To a solution
of appropriate 3-iodo-2-(methylthio)Benzo[b]furan (0.5 mmol)
in DMF (4.0 mL) and H2O (0.4 mL) was added to Pd(PPh3)4
(0.011g, 2 mol%) and K2CO3 (1 mmol), under argon. After this
time, boronic acid (0.75 mmol) was added. The mixture was
Submitted: February 4, 2010
Published online: May 11, 2010

J. Braz. Chem. Soc., Vol. 21, No. 9, S1-S14, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan
Derivatives: Synthesis of 3-Aryl-2-(methylthio)benzo[b]furans
Rafaela M. Gay, Flávia Manarin, Ricardo Brandão and Gilson Zeni*
Departamento de Química, Centro de Ciências Naturais e Exatas,
Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil
Experimental
oil bath with an electrically heated coil connected to a
controller.
Proton nuclear magnetic resonance spectra (1H NMR)
were obtained at 400 MHz. Spectra were recorded in CDCl3
solutions. Chemical shifts are reported in ppm, referenced
to the solvent peak of CDCl3 or tetramethylsilane (TMS)
as the external reference. Data are reported as follows:
chemical shift (d), multiplicity, coupling constant (J) in
Hertz and integrated intensity. Carbon-13 nuclear magnetic
resonance spectra (13C NMR) were obtained at 100 MHz.
Spectra were recorded in CDCl3 solutions. Chemical
shifts are reported in ppm, referenced to the solvent peak
of CDCl3. Abbreviations to denote the multiplicity of a
particular signal are s (singlet), d (doublet), t (triplet),
q (quartet), quint (quintet), sex (sextet) and m (multiplet).
High resolution mass spectra were recorded on a double
focusing magnetic sector mass spectrometer using EI at
70 eV. Column chromatography was performed using
silica gel (230-400 mesh) following the methods described
by Still (Still, W.C.; Kahn, M.; Mitra, A.; J. Org. Chem.
1978, 43, 2923). Thin layer chromatography (TLC) was
performed using silica gel GF254, 0.25 mm thickness.
For visualization, TLC plates were either placed under
ultraviolet light, or stained with iodine vapor, or acidic
vanillin. The following solvents were dried and purified
by distillation from the reagents indicated: tetrahydrofuran
from sodium with a benzophenone ketyl indicator.All other
solvents wereACS or HPLC grade unless otherwise noted.
Air- and moisture-sensitive reactions were conducted in
flame-dried or oven dried glassware equipped with tightly
fitted rubber septa and under a positive atmosphere of dry
nitrogen or argon. Reagents and solvents were handled
using standard syringe techniques. Temperatures above
room temperature were maintained by use of a mineral
General procedure for the Suzuki coupling reaction
To a solution of appropriate 3-iodo-2-(methylthio)
benzo[b]furan (0.5 mmol) in DMF (4.0 mL) and H2O
(0.4 mL) was added to Pd(PPh3)4 (0.011g, 2 mol%) and
K2CO3 (1 mmol), under argon.After this time, boronic acid
(0.75 mmol) was added. The mixture was then heated at
100 oC during 1-4 h, cooled to room temperature, diluted
with dichloromethane (20 mL), and washed with brine
(2 × 20 mL). The organic phase was separated, dried over
MgSO4, and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel using hexane/
ethyl acetate as eluent.
2-(Methylthio)-3-phenylbenzofuran (3a)
1
Yield: 0.111 g (93%). H NMR: CDCl3, 400 MHz, d
(ppm): 7.61-7.59 (m, 3H), 7.50-7.46 (m, 3H), 7.37 (t, J
7.3 Hz, 1H), 7.29 (t, J 7.3 Hz, 1H), 7.23 (dd, J 7.5 Hz and
J 2.5 Hz, 1H), 2.52 (s, 3H). 13C NMR: CDCl3, 100 MHz,
d (ppm): 155.9, 147.5, 131.8, 129.1, 128.5, 128.3, 127.4,
124.4, 122.9, 122.5, 119.7, 110.8, 16.9. MS (EI, 70 eV) m/z
(relative intensity): 238 (26), 222 (17), 194 (100), 163 (23),
151 (10), 76 (8). Anal. (%) Calc. for C15H12OS: C 74.97, H
5.03. Found: C 75.15, H 5.39.
3-(4-Methoxyphenyl)-2-(methylthio)benzofuran (3b)
1
Yield: 0.108 g (80%). H NMR: CDCl3, 400 MHz,
d(ppm): 7.59 (d, J 7.6 Hz, 1H), 7.53 (d, J 8.8 Hz, 2H), 7.47
(d, J 8.0 Hz, 1H), 7.30-7.20 (m, 2H), 7.03 (d, J 8.8 Hz, 2H),
13
3.85 (s, 3H), 2.49 (s, 3H). C NMR: CDCl3, 100 MHz,
d (ppm): 159.0, 155.4, 146.8, 130.2, 128.4, 124.4, 124.0,
122.8, 122.4, 119.7, 114.0, 110.8, 55.2, 17.1. MS (EI,
70 eV) m/z (relative intensity): 269 (14), 267 (100), 252
(48), 224 (46), 181 (14), 150 (21).
*e-mail: gzeni@pq.cnpq.br

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Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
2-(Methylthio)-3-p-tolylbenzofuran (3c)
2-(Methylthio)-3-(3-(trifluoromethyl)phenyl)benzofuran
1
Yield: 0.116 g (92%). H NMR: CDCl3, 400 MHz,
(3i)
1
d (ppm): 7.60 (d, J 7.6 Hz, 1H), 7.50 (d, J 7.8 Hz, 2H),
7.44 (d, J 8.0 Hz, 1H), 7.29 (d, J 7.8 Hz, 2H), 7.25-7.17 (m,
1H), 2.50 (s, 3H), 2.40 (s, 3H). 13C NMR: CDCl3, 100 MHz,
d (ppm): 155.4, 147.1, 137.2, 129.2, 128.9, 128.7, 128.3,
124.3, 122.8, 122.6, 119.7, 110.8, 21.2, 16.9. MS (EI,
70 eV) m/z (relative intensity): 254 (3), 251 (100), 236
(24), 208 (58), 176 (13), 150 (19).
Yield: 0.137 g (89%). H NMR: (CDCl3, 400 MHz)
d (ppm): 7.88 (s, 1H), 7.78 (d, J 7.3 Hz, 1H), 7.63-7.55
(m, 3H), 7.49-7.47 (m, 1H), 7.33-7.23 (m, 2H), 2.53 (s,
3H). 13C NMR: (CDCl3, 50 MHz), d (ppm): 155.5, 148.4,
132.8, 132.3, 130.8 (q, J 32 Hz), 129.9, 129.0, 125.7 (q,
J 3.7 Hz), 124.7, 124.0 (q, J 3.6 Hz), 123.8 (q, J 273 Hz),
123.3, 119.3, 111.0, 16.7. MS (EI, 70 eV) m/z (relative
intensity): 305 (100), 289 (8), 262 (95), 221 (15), 150 (13).
3-(4-Bromophenyl)-2-(methylthio)benzofuran (3e)
1
Yield: 0.111 g (70%). H NMR: (CDCl3, 400 MHz)
5-Methyl-2-(methylthio)-3-(naphthalen-1-yl)benzofuran
d (ppm): 7.60 (d, J 8.5 Hz, 2H), 7.54 (d, J 7.6 Hz, 1H),
7.47-7.44 (m, 3H), 7.31-7.21 (m, 2H), 2.51 (s, 3H).
13C NMR: (CDCl3, 50 MHz), d (ppm): 155.4, 147.7, 131.7,
130.7, 130.5, 124.6, 123.1, 121.4, 121.3, 119.4, 110.9, 16.8.
MS (EI, 70 eV) m/z (relative intensity): 318 (10), 221 (100),
193 (11), 161 (14), 150 (33).
(3o)
1
Yield: 0.139 g (92%). H NMR: (CDCl3, 400 MHz)
d (ppm): 7.89 (d, J 8.0 Hz, 2H), 7.73 (d, J 8.5 Hz, 1H),
7.54-7.34 (m, 5H), 7.08 (dd, J 7.1 Hz and J 1.5 Hz, 1H),
6.90 (s, 1H), 2.40 (s, 3H), 2.28 (s, 3H). 13C NMR: (CDCl3,
50 MHz), d (ppm): 153.8, 148.9, 133.7, 132.4, 132.0,
129.9, 129.3, 128.4, 128.3, 128.2, 125.9, 125.8, 125.6,
125.4, 121.4, 119.9, 110.3, 21.1, 16.9. MS (EI, 70 eV) m/z
(relative intensity): 300 (100), 285 (27), 270 (11), 258 (32),
242 (12), 223 (7).
1-(4-(2-(Methylthio)benzofuran-3-yl)phenyl)ethanone (3f)
1
Yield: 0.098 g (70%). H NMR: (CDCl3, 400 MHz)
d (ppm): 8.08 (d, J 8.3 Hz, 2H), 7.70 (d, J 8.3 Hz, 2H), 7.61
(d, J 6.8 Hz, 1H), 7.50 (d, J 7.6 Hz, 1H), 7.34-7.25 (m, 2H),
13
2.65 (s, 3H), 2.56 (s, 3H). C NMR: (CDCl3, 50 MHz),
5-Fluoro-2-(methylthio)-3-phenylbenzofuran (3p)
1
d (ppm): 197.5, 155.5, 148.7, 136.9, 135.8, 129.0, 128.6,
127.8, 124.6, 123.3, 121.1, 119.4, 111.0, 26.6, 16.6. MS
(EI, 70 eV) m/z (relative intensity): 280 (17), 279 (100),
264 (35), 221 (12), 150 (21), 43 (58).
Yield: 0.103 g (80%). H NMR: (CDCl3, 400 MHz)
d (ppm): 7.55-7.53 (m, 2H), 7.46 (t, J 7.8 Hz, 2H), 7.37-7.33
(m, 2H), 7.24 (dd, J 6.1 Hz and J 2.5 Hz, 1H), 6.97 (td, J
6.3 Hz and J 2.9 Hz, 1H), 2.50 (s, 3H). 13C NMR: (CDCl3,
50 MHz), d (ppm): 160.6, 158.2, 151.6, 149.5, 131.2,
128.7, 128.6, 127.6, 122.1, 111.8 (d, J 26.3 Hz), 111.4 (d,
J 9.5 Hz), 105.3 (d, J 25.6 Hz), 16.5. MS (EI, 70 eV) m/z
(relative intensity): 255 (100), 239 (64), 212 (92), 192 (12),
168 (30), 150 (6).
1-(3-(2-(Methylthio)benzofuran-3-yl)phenyl)ethanone (3g)
1
Yield: 0.126 g (90%). H NMR: (CDCl3, 400 MHz)
d (ppm): 8.02 (t, J 2.0 Hz, 1H), 7.95 (dt, J 7.3 Hz and J
1.2 Hz, 1H), 7.80 (dt, J 7.3 Hz and J 1.2 Hz, 1H), 7.59-
7.54 (m, 2H), 7.49-7.47 (m, 1H), 7.30 (td, J 7.3 Hz and J
1.4 Hz, 1H), 7.25 (td, J 7.5 Hz and J 1.3 Hz, 1H), 2.64 (s,
3H), 2.53 (s, 3H). 13C NMR: (CDCl3, 50 MHz), d (ppm):
197.6, 155.4, 148.0, 137.4, 133.4, 132.3, 128.8, 128.7,
127.8, 127.1, 124.6, 123.1, 121.4, 119.3, 110.9, 26.6, 16.7.
MS (EI, 70 eV) m/z (relative intensity): 280 (17), 278 (100),
264 (7), 150 (19).
5-Fluoro-3-(4-methoxyphenyl)-2-(methylthio)benzofuran
(3q)
1
Yield: 0.130 g (90%). H NMR: (CDCl3, 400 MHz)
d (ppm): 7.50 (d, J 8.5 Hz, 2H), 7.37 (dd, J 4.9 Hz and J
4.1 Hz, 1H), 7.24 (dd, J 6.1 Hz and J 2.7 Hz, 1H), 7.04-6.97
(m, 3H), 3.86 (s, 3H), 2.51 (s, 3H). 13C NMR: (CDCl3, 50
MHz), d (ppm): 160.6, 159.1, 158.2, 151.6, 148.8, 130.0,
123.5, 122.3, 114.2, 111.9 (d, J 24.8 Hz), 111.4 (d, J 9.5
Hz), 105.3 (d, J 24.8 Hz), 55.3, 16.7. MS (EI, 70 eV) m/z
(relative intensity): 285 (100), 269 (73), 242 (49), 226
(14), 155.6 (17).
2-(Methylthio)-3-(3-nitrophenyl)benzofuran (3h)
1
Yield: 0.081 g (57%). H NMR: (CDCl3, 400 MHz)
d (ppm): 8.48 (t, J 2.0 Hz, 1H), 8.20 (dd, J 5.8 Hz and J
2.0 Hz, 1H), 7.94 (d, J 7.6 Hz, 1H), 7.64 (t, J 7.8 Hz, 1H),
7.59 (d, J 8.5 Hz, 1H), 7.50 (d, J 7.8 Hz, 1H), 7.35-7.24 (m,
2H), 2.57 (s, 3H). 13C NMR: (CDCl3, 50 MHz), d (ppm):
155.4, 148.8, 148.4, 134.7, 133.6, 129.4, 127.4, 124.8,
123.5, 123.4, 122.0, 119.9, 119.0, 111.0, 16.5. MS (EI,
70 eV) m/z (relative intensity): 282 (100), 250 (10), 221
(43), 192 (15), 162 (18), 150 (30).
2-(Methylthio)-3-(thiophen-2-yl)benzofuran (3x)
1
Yield: 0.074 g (60%). H NMR: CDCl3, 400 MHz,
d (ppm): 7.82-7.80 (m, 1H), 7.46-7.44 (m, 2H), 7.37 (dd,
J 4.0 Hz and J 1.2 Hz, 1H), 7.32-7.25 (m, 2H), 7.16 (dd, J
4.0 Hz and J 1.4 Hz, 1H), 2.56 (s, 3H).13C NMR: CDCl3,

Vol. 21, No. 9, 2010
Gay et al.
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100 MHz, d (ppm): 155.3, 147.6, 133.1, 127.6, 127.2,
126.0, 125.0, 124.6, 123.2, 120.0, 116.4, 110.8, 16.8. MS
(EI, 70 eV) m/z (relative intensity): 243 (100), 228 (75),
200 (64), 169 (15), 114 (20). HRMS calc. for C13H10OS2:
246.0173. Found: 246.0177.
Selected Spectra
Figure S1. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3a; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3a.

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Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Figure S2. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3b; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3b.

Vol. 21, No. 9, 2010
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Figure S3. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3e; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3e.

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Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Figure S4. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3f; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3f.

Vol. 21, No. 9, 2010
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Figure S5. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3g; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3g.

S8
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Figure S6. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3h; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3h.

Vol. 21, No. 9, 2010
Gay et al.
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Figure S7. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3i; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3i.

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Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Figure S8. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3o; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3o.

Vol. 21, No. 9, 2010
Gay et al.
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Figure S9. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3p; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3p.

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Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Figure S10. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3r; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3r.

Vol. 21, No. 9, 2010
Gay et al.
S13
Figure S11. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3u; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3u.

S14
Palladium Catalyzed Suzuki Cross-Coupling of 3-Iodo-2-(methylthio)-benzo[b]furan Derivatives
J. Braz. Chem. Soc.
Figure S12. (up) 1H NMR Spectrum (400 MHz, CDCl3) of compound 3x; (down) 13C NMR Spectrum (100 MHz, CDCl3) of compound 3x.