Electrophilic cyclization of 2-chalcogenealkynylanisoles: Versatile access to 2-chalcogen-benzo[b]furans

Article abstract of DOI:10.1021/jo802736e

An efficient synthesis of 2-ehalcogen-3-substituted-benzo[b]furan compounds has been accomplished via electrophilic cyclization reaction of 2-chalcogenealkynyl anisoles using I₂, ICl, Br₂, and PhSeBr as electrophile sources. The product distributions were strongly dependent on the nature of substituents in the aromatic ring of anisole and on the chalcogen atom directly bonded to the triple bond. The 2-chalcogen-3-iodo- benzo[b]furans obtained smoothly underwent conversion to more complex structures of benzo-[b]furan derivatives via palladium- or copper-catalyzed cross-coupling reaction with thiols, diphenyl diselenides, and zincates.

Full text of DOI:10.1021/jo802736e

Electrophilic Cyclization of 2-Chalcogenealkynylanisoles:
Versatile Access to 2-Chalcogen-benzo[b]furans
Fla´via Manarin,† Juliano A. Roehrs,† Rafaela Mozzaquatro Gay,† Ricardo Branda˜o,†
Paulo H. Menezes,‡ Cristina W. Nogueira,† and Gilson Zeni*,†
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o Farmacolo´gica e Toxicolo´gica de Organocalcogeˆnios,
CCNE, UFSM, Santa Maria, Rio Grande do Sul, Brazil 97105-900, and Departamento de Qu´ımica
Fundamental, UniVersidade Federal de Pernambuco, CCEN, UFPE, Recife-PE, Brazil 50670-901
gzeni@pq.cnpq.br
ReceiVed December 15, 2008
An efficient synthesis of 2-chalcogen-3-substituted-benzo[b]furan compounds has been accomplished
via electrophilic cyclization reaction of 2-chalcogenealkynyl anisoles using I2, ICl, Br2, and PhSeBr as
electrophile sources. The product distributions were strongly dependent on the nature of substituents in
the aromatic ring of anisole and on the chalcogen atom directly bonded to the triple bond. The 2-chalcogen-
3-iodo-benzo[b]furans obtained smoothly underwent conversion to more complex structures of benzo-
[b]furan derivatives via palladium- or copper-catalyzed cross-coupling reaction with thiols, diphenyl
diselenides, and zincates.
Introduction
Recently, a series of structures containing the benzofuran
nucleus, such as SKF-64346 and SKF-63058, have been
identified as efficient inhibitors of ꢀ-amyloid aggregation,
affording a new class of potential multifunctional drugs for
Alzheimer’s disease (Figure 1).2
In this context, considerable effort has been applied to
development of efficient strategies for the synthesis of ben-
zo[b]furans. During the past years numerous protocols have been
reported in the literature,3 and one of the reliable approaches
for the synthesis of this class of compounds has been based on
electrophilic cyclization of unsatured compounds.4 Important
heterocycles such as indoles,4a,b benzo[b]thiophenes,4c,d
benzo[b]selenophenes,4e thiophenes,4f furans,4g and pyrroles,4h
among others,4i-v have been prepared using this protocol.
The benzo[b]furan moiety is a versatile and useful class of
heterocycles as a result of the prevalence of this structure in a
great number of biologically active compounds and isolated
natural products, including a wide variety of therapeutic
applications such as anti-HIV, anticancer, and antiinflamatory.1
† UFSM.
‡ Universidade Federal de Pernambuco.
(1) (a) Kirilmis, C.; Ahmedzade, M.; Servi, S.; Koca, M.; Kizirgil, A.; Kazaz,
C. Eur. J. Med. Chem. 2008, 43, 300. (b) Schultz, D. M.; Prescher, J. A.; Kidd,
S.; Marona-Lewicka, D.; Nichols, D. E.; Monte, A. Bioorg. Med. Chem. 2008,
16, 6242. (c) Ando, K.; Kawamura, Y.; Akai, Y.; Kunitomo, J.; Yokomizo, T.;
Yamashita, M.; Ohta, S.; Ohishi, T.; Ohishi, Y. Org. Biomol. Chem. 2008, 6,
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Srivastava, A. K.; Kumar, B.; Goel, A. Bioorg. Med. Chem. 2007, 15, 727. (f)
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2008, 51, 2883. (b) Howlett, D. R.; Perry, A. E.; Godfrey, F.; Swatton, J. E.;
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10.1021/jo802736e CCC: $40.75
Published on Web 02/11/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2153–2162 2153

Manarin et al.
SCHEME 1
FIGURE 1. Potential multifunctional drugs for Alzheimer’s disease.
Similar approaches of cyclization reactions containing chal-
cogen atoms, such as sulfur, selenium, and tellurium, have been
scarcely explored in such methodologies, although chalcogenide
compounds have found such wide utility because of their effects
on an extraordinary number of very different reactions, including
many carbon-carbon bond formations,5 under relatively mild
reaction conditions. In addition, they have become attractive
synthetic targets because of their chemo-, regio-, and stereose-
lective reactions,6 use in a wide variety of functional groups,
thus avoiding protection group chemistry, and useful biological
activities.7 The selenium group can be introduced in an organic
substrate via both nucleophile and electrophile reagents. After
being introduced in an organic substrate, the organoselenium
group can easily be removed by selenoxide syn elimination8
and [2,3] sigmatropic rearrangement.9 Conversely, the carbon-
selenium bond can also be replaced by a carbon-hydrogen,10
carbon-halogen,11 carbon-lithium,12 or carbon-carbon bond.13
Among chalcogenides, heterocycles containing a chalcogen
atom play an important role in organic synthesis because of
their excellent electrical properties and environmental stability.
In addition, they are widely studied agents with a diverse array
of biological effects. These include potent antitumor and
antiviral activities, as well as efficacy as a maturation-inducing
agent.14 Halochalcogenophenes are also important derivatives
that provide an useful opportunity for further functionalization.15
In particular, iodo- and bromoselenophenes are useful as
substrates in a variety of C-C,15a,b C-N,15c and C-S15d bond-
forming reactions. However, to the best of our knowledge, there
is no protocol describing the preparation of 2,3-chalcogen
benzo[b]furan using 2-chalcogenealkynylanisoles as substrate
via electrophilic cyclization. Thus, it is necessary to design a
simple, efficient, and versatile method for the construction of
furan rings having two different groups at the 2- and 3-positions.
The applicability of the selectivity of these two functionalities
can constitute a synthetic approach to the preparation of
biologically active furan compounds. Combining the knowledge
that our group has accumulated in the synthesis of the
heterocycles containing a chalcogen16 with the opportunity for
further functionalization in these compounds, herein we suggest
an entirely new approach that focuses on the electrophilic
cyclization of 2-chalcogenealkynylanisoles 4 to obtain 3-iodo-
2-chalcogen-benzo[b]furans 5 (Scheme 1).
(3) For recent advances in the synthesis of benzofurans derivatives, see: (a)
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Results and Discussion
As was mentioned above, using the key starting materials
2-chalcogenealkynylanisoles 4, the cyclization required the
introduction of a terminal alkyne in the aromatic ring and
(10) Sevrin, M.; Vanende, D.; Krief, A. Tetrahedron Lett. 1976, 30, 2643.
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1983, 24, 353. (d) Goldstein, B. M.; Leary, J. F.; Farley, B. A.; Marquez, V. E.;
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Pharmacol. 1982, 31, 2371.
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G. Tetrahedron Lett. 2006, 47, 2179. (b) Prediger, P.; Moro, A. V.; Nogueira,
C. W.; Savegnago, L.; Rocha, J. B. T.; Zeni, G. J. Org. Chem. 2006, 71, 3786.
(c) Barros, O. S. R.; Nogueira, C. W.; Stangherlin, E. C.; Menezes, P. H.; Zeni,
G. J. Org. Chem. 2006, 71, 1552. (d) Zeni, G. Tetrahedron Lett. 2005, 46, 2647.
(e) Panatieri, R. B.; Reis, J. S.; Borges, L. P.; Nogueira, C. W.; Zeni, G. Synlett
2006, 18, 3161.
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2007, 72, 6726. (b) Stein, A. L.; Alves, D.; Rocha, J. T.; Nogueira, C. W.; Zeni,
G. Org. Lett. 2008, 10, 4983.
2154 J. Org. Chem. Vol. 74, No. 5, 2009

Electrophilic Cyclization of 2-Chalcogenealkynylanisoles
SCHEME 2
SCHEME 3
subsequently of a chalcogen group in this terminal alkyne 3.
For the introduction of the terminal alkyne, we chose the
Sonogashira cross-coupling17 followed by retro-Favorskii reac-
tion.18 Thus, the cross-coupling of commercial 2-haloanisoles
with 2-methylbut-3-yn-2-ol using PdCl2(PPh3)2 (2 mol %) as
palladium source, CuI (1 mol %) as co-catalyst and Et3N as
solvent and base, at room temperature for 12 h, gave propargyl
alcohols 2a-e in high yields. With the subunit 2 in hand the
terminal alkynes were easily obtained by retro-Favorskii reaction
using NaOH (3 equiv) in toluene at reflux. For the introduction
of the chalcogen group, we first generated the lithium acetylide
intermediate by reaction of terminal alkynes 3a-e with 1 equiv
of n-BuLi, in THF at -78 °C for 1 h, followed by the reaction
with an electrophilic chalcogen species (Scheme 2). By this way,
we prepared a number of novel 2-chalcogenealkynylanisoles
and applied these new compounds as starting materials in the
electrophilic cyclization reactions (Table 1).
Inspection of Table 1 shows that the reaction worked well
for a variety of substituents in the aromatic ring of anisole. A
closer inspection of the results revealed that the reaction
significantly depends on the electronic effects of substituents
in the aromatic ring bonded at the selenium atom of the
electrophilic-chalcogen species (Table 1, entries 2 and 3). For
example, arylselanyl bromide with an electron-donating sub-
stituent (Table 1, entry 3) in the aromatic ring gave a worse
yield than arylselanyl bromide with an electron-withdrawing
group (Table 1, entry 2). It is noteworthy the electron-donating
groups in the aromatic ring decrease the electrophilicity of
phenylselanyl bromide.
After the success in the synthesis of 2-chalcogenealkyny-
lanisoles 4, we next focus our attention on the development of
an optimum set of the electrophilic cyclization conditions. For
this purpose, the reaction of 4a with iodine was chosen as a
model system. We found that the reaction of 4a with I2 in
CH2Cl2 as solvent yielded the desired product 5a in 90% yield,
after 1 h at room temperature (Scheme 3). Encouraged by these
results, we further investigated the reaction behavior with other
solvents, electrophilic sources, and temperature with the aim
to improve the protocol. The outcome of this study and an
investigation of other reaction parameters are depicted in
Table 2.
Regarding the influence of the solvent, better results were
achieved using CH2Cl2, which furnished the desired product 5a
in 90% yield after a short reaction time (Table 2, entry 2). When
THF, Et2O, EtOH, and MeCN were used as solvent, good yields
were also obtained; however, these reactions proceeded more
slowly. The use of another electrophilic source such as ICl, with
the standard reaction condition, failed to produce the electro-
philic cyclization. In this case only a complex nonseparable
mixture of multiple products was observed (Table 2, entry 3).
However, it was gratifying to discover that the simple change
in the temperature to -20 °C had a dramatic effect, giving the
desired product 5a in 93% yield (Table 2, entry 5). It was
pointed out that the amount of electrophilic source also played
an important role in the reaction. The amount of 1.1 equiv was
better than 2 equiv (Table 2, entries 1 and 2). Thus, careful
analysis of the optimized reaction revealed that the optimum
condition for this electrophilic cyclization reaction was the
combination of 1.0 equiv of 2-chalcogenealkynylanisoles, 1.1
equiv of electrophile source, and CH2Cl2 as solvent, at room
temperature. Using this reaction condition we were able to
prepare benzofuran derivative 5a in 90% yield. In order to
demonstrate the efficiency of this reaction, we explored the
generality of our method by extending the conditions to various
2-chalcogenealkynylanisoles 4a-l, as well as other electrophilic
moieties, and the results are summarized in Table 3.
Inspection of Table 3 shows that in general, all of the
reactions proceeded smoothly under mild conditions, ease of
isolation, and high yields. Most importantly, the cyclization
turned out to be general with respect to a diverse array of
functionality and electrophile sources. Satisfactorily, all elec-
trophile sources tested were effective. After the success in the
cyclization reactions using ICl and I2 as eletrophilic source, we
next applied this method to the synthesis of disubstituted 2,3-
bis-chalcogen-benzo[b]furans using PhSeBr as electrophilic
sources. Table 3 shows our results, and in most cases the
corresponding substituted 2-chalcogen-benzofurans were ob-
tained in good yields. Based on the experiments, the reaction
with 2-chalcogenealkynylanisoles 4a-d, having Se-aryl, Se-
aryl-substituted, and Se-alkyl groups attached to the triple bond
(17) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467. (b) Chinchilla, R.; Najera, C. Chem. ReV. 2007, 107, 864.
(18) Dabdoub, M. J.; Dabdoub, V. B.; Lenarda˜o, E. J. Tetrahedron Lett. 2001,
42, 1807.
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Manarin et al.
TABLE 1. Synthesis of 2-Chalcogenealkynylanisoles
TABLE 2. Effect of Reaction Conditions on the Cyclization
Reactiona
entry
E+ (equiv)
solvent
temp, time
rt, 1 h
yield (%)
1
2
3
4
5
6
7
8
9
I2 (2.0)
I2 (1.1)
ICl (2.0)
ICl (1.1)
ICl (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
I2 (1.1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ether
CH3CN
EtOH
THF
81
90
b
54
93
73
87
78
79
rt, 1 h
rt, 10 min
-20 °C, 10 min
-20oC, 1 h
rt, 6 h
rt, 6 h
rt, 6 h
rt, 6 h
a Reactions performed in the presence of 4a (0.25 mmol), I2 (0.275
mmol). b A complex nonseparable mixture of multiple products was
observed.
1-7). In the case of an aromatic ring directly bonded to the
selenium atom, the results revealed that the reaction is not
sensitive to the electronic effects of the substituents. For
example, an aromatic ring having either neutral 4a, electron-
withdrawing 4b, or electron-donating 4c substituents gave the
cyclized products in very similar yields. In the case of
2-chalcogenealkynylanisoles with chalcogen-alkyl groups, our
reaction system was suitable for the cyclization of both short
and long aliphatic chains, giving the desired cyclized products
in good yields. In addition, our reaction system was appropriate
for cyclization of sulfide compounds. Arylsulfide 4e and
alkylsulfide 4f derivatives were efficiently cyclized under the
standard conditions. The introduction of sulfide groups at the
2-position of benzofuran is significant, since it could be easily
oxidized to 2-sulfonylbenzofurans,19 a class of compounds that
has attracted tremendous interest of the pharmaceutical industry.
In fact 2-sulfonylbenzofurans are potent inhibitors of the matrix
metalloproteinase-13 and therefore offer a possible therapy for
osteoarthritis.20
However, there is a limitation in our methodology since
considerable difficulties were found when we attempted to react
2-chalcogenealkynylanisoles having an electron-donating group
at the para position in the aromatic ring of anisole. In this case,
we observed only the triple bond reduction product and
byproduct with no formation of benzofuran product. These
suggest that the presence of an electron-donating group at the
para position increases the electronic density in C-2 at the triple
bond,3k which is stabilized by the selenium atom,21 making this
center susceptive to nucleophilic attack on iodine instead of the
cyclization process, providing exclusively the reduction product
(Scheme 4 and Table 3, entry 20).
Conversely the cyclization of substrates 4g and 4h containing
the tellurium atom did not react in the same way as the substrates
containing selenium or sulfur atoms. Our experiments showed
(19) Kakarla, R.; Dulina, R. G.; Hatzenbuhler, N. T.; Hui, Y. W.; Sofia,
M. J. J. Org. Chem. 1996, 61, 8347.
(20) Hu, Y.; Xiang, J. S.; DiGrandi, M. J.; Du, X.; Ipek, M.; Laakso, L. M.;
Li, J.; Li, W.; Rush, T. S.; Schmid, J.; Skotnicki, J. S.; Tam, S.; Thomason,
J. R.; Wang, Q.; Levin, J. I. Bioorg. Med. Chem. 2005, 13, 6629.
(21) (a) Patai, S.; Rappoport, Z. The Chemistry of Organic Selenium and
Tellurium Compounds; Wiley: New York, 1986; Vol. 1. (b) Liotta, D.
Organoselenium Chemistry; Wiley: New York, 1987. (c) Wirth, T. Organose-
lenium Chemistry-Modern DeVelopments in Organic Synthesis (Topics in
Current Chemistry Vol. 208); Springer-Verlang: Heidelberg, 2000.
a This reaction was carried out using elemental Se or Te and trapped
with bromobutane. b This reaction was performed with diorganoyl
disulfides as electrophilic agent.
has been successfully employed in this electrophilic cyclization,
providing the desired products in high yields (Table 3, entries
2156 J. Org. Chem. Vol. 74, No. 5, 2009

Electrophilic Cyclization of 2-Chalcogenealkynylanisoles
TABLE 3. Synthesis of 2-Chalcogen-3-substituted-benzo[b]furans 5 via Electrophilic Cyclization of 2-Chalcogenealkynylanisoles 4a
J. Org. Chem. Vol. 74, No. 5, 2009 2157

Manarin et al.
TABLE 3. Continued
a Reactions performed in the presence of alkyne (0.25 mmol), E+ (0.27 mmol) in CH2Cl2 (5 mL). b All reactions performed with ICl were carried out at -20 °C.
c Yields of 5a-r are given for isolated products. d The starting material was recovered. e The reduction product was obtained almost exclusively.
2158 J. Org. Chem. Vol. 74, No. 5, 2009

Electrophilic Cyclization of 2-Chalcogenealkynylanisoles
SCHEME 4
SCHEME 5
SCHEME 6
that addition of the electrophilic source consumed the starting
materials; however, the formation of the product was not
detected. After 10 min, we observed the formation of a red
precipitate, and TLC analysis showed a very polar spot, a
common characteristic of tellurium(IV) species, which were
further confirmed and identified by GC/MS. In addition,
treatment of these red precipitates with an excess of sodium
bisulfide regenerated the starting tellurides 4g and 4h,22
confirming that the reaction of these tellurides with iodide does
not allow the cyclized product, even that using an excess of
iodide, reflux, long reaction time, and other electrophiles such
as, BuTeBr, PhSeBr (Scheme 5).
We believe that the mechanism of this cyclization reaction
involves (i) coordination of the carbon-carbon triple bond to
I2 to generate an iodonium intermediate a, which activates the
triple bond toward nucleophilic attack, (ii) anti-nucleophilic
attack of the oxygen atom on the activated iodonium intermedi-
ate to produce the salt b, and (iii) facile removal of the alkyl
group via SN2 displacement by the iodide anion present in the
reaction mixture to generate the 3-iodo-2-chalcogen-benzo-
[b]furan product and one molecule of MeI (Scheme 6).
The benzo[b]furans obtained by electrophilic cyclization
appear highly attractive as intermediates for the preparation
of more highly substituted benzo[b]furans, particularly when
one considers that there are many ways to transform the
resulting halogen and selenium functionalities into other
substituents. Thus, the resulting benzo[b]furan iodides could
be employed as useful intermediates in many transition-metal-
catalyzed processes, such as Sonogashira,17 Suzuki,23 Stille,24
Heck,25 Ullmann, and Negishi27 cross-couplings. In this way,
the potential of 3-iodo-2-chalcogen-benzo[b]furan derivatives
as precursors for increasing molecular complexity via pal-
ladium- and copper-catalyzed reactions has been briefly
investigated (Schemes 7, 8, and 9). For example, compound
5a underwent Ullmann-type coupling with different thiols28
(25) (a) Dieck, H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259. (b)
Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(26) (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. (b) Altman,
R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779. (c) Antilla, J. C.; Baskin, J. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578. (d) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (e) Klapars,
A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727.
(22) Zeni, G.; Chieffi, A.; Cunha, R.; Zukerman-Schpector, J.; Stefani, H. A.;
Comasseto, J. V. Organometallics 1999, 18, 803.
(23) (a) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749. (b) Molander, G. A.;
Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(24) (a) Scott, W. J.; Pen˜a, M. R.; Sward, K.; Stoessel, S. J.; Stille, J. K. J.
Org. Chem. 1985, 50, 2302. (b) Fugami, K., Kosugi, M. In Cross-Coupling
Reactions, A Practical Guide (Topics in Current Chemistry Vol. 219); Springer-
Verlag: Heidelberg, 2002; pp 87-130.
(27) (a) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (b) Negishi,
E.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38, 71.
J. Org. Chem. Vol. 74, No. 5, 2009 2159

Manarin et al.
SCHEME 7
particularly when one considers that there are many ways to
transform the resulting halogen, selenium, and sulfur func-
tionalities13 into a great number of interesting substituted
benzo[b]furans.
Experimental Section
SCHEME 8
General Procedure for the Preparation of 2-Chalcogenealky-
nylanisoles Derivatives 4a-c, 4g, and 4i-l. n-Butyllithium (0.4
mL of a 2.5 M solution in hexane, 1 mmol) was added, under
argon, to a solution of appropriate 2-ethynylanisole (1 mmol)
in THF (2 mL) previously cooled at -78 °C. The resulting
solution was stirred for 30 min at this temperature. After this
time, the mixture was cooled at 0 °C, and the phenylselanyl-
bromide or phenyltellanylbromide desired (1.0 mmol) in THF
(1 mL) was added. The reaction was warmed at room temperature
and stirred for 3 h. After that the mixture was diluted with ethyl
acetate (20 mL) and washed with brine (2 × 20 mL). The organic
phase was separated, dried over MgSO4, and concentrated under
vacuum.
SCHEME 9
((2-Methoxyphenyl)ethynyl)(phenyl)selane (4a). Purified by
flash chromatography and eluted with hexane/ethyl acetate (95:
5). Yield: 0.232 g (81%). 1H NMR (CDCl3, 200 MHz): δ
7.66-7.59 (m, 2H), 7.45 (dd, J ) 7.0 Hz and J ) 2.0 Hz, 1H),
7.36-7.24 (m, 4H), 6.91 (t, J ) 7.0 Hz, 2H), 3.30 (s, 3H). 13C
NMR (CDCl3, 50 MHz): δ 160.2, 133.4, 129.9, 129.4, 129.3,
128.6, 126.8, 120.4, 112.4, 110.6, 99.6, 72.8, 55.7. MS (EI, 70
eV) m/z (relative intensity): 287 (7), 204 (79), 164 (84), 163
(100), 130 (47), 77 (5). Anal. Calcd for C15H12OSe: C 62.73, H
4.21. Found: C 62.91, H 4.51.
((2-Methoxyphenyl)ethynyl)(3-(trifluoromethyl)phenyl)se-
lane (4b). Purified by flash chromatography and eluted with
hexane/ethyl acetate (95:5). Yield: 0.195 g (55%). 1H NMR
(CDCl3, 400 MHz): δ 7.95 (s, 1H), 7.76 (d, J ) 8.0 Hz, 1H),
7.49 (d, J ) 7.8 Hz, 1H), 7.45-7.41 (m, 2H), 7.31 (td, J ) 7.0
Hz and J ) 2.0 Hz, 1H), 6.94-6.89 (m, 2H), 3.90 (s, 3H). 13C
NMR (CDCl3, 100 MHz): δ 160.2, 133.1, 131.7 (q, J ) 32.2
Hz), 131.5, 130.8, 130.1, 129.5, 125.2 (q, J ) 3.7 Hz), 123.6
(q, J ) 3.7 Hz), 122.3 (q, J ) 272 Hz), 120.4, 112.0, 110.6,
101.1, 71.3, 55.7. MS (EI, 70 eV) m/z (relative intensity): 352
(100), 309 (97), 272 (78), 230 (54), 130 (53), 117 (17), 90 (28).
Anal. Calcd for C16H11F3OSe: C 54.10, H 3.12. Found: C 54.29,
H 3.33.
and gave the corresponding 3-(arylthio)-2-(phenylselanyl)-
benzo[b]furans 6a and 6b in 75% and 74% yields, respec-
tively (Scheme 7). To further prove the utility of our
cyclization products, we tested the reactivity of 5f toward
CuI/bipyridine-catalyzed29 cross-coupling with diphenyl dis-
elenides to afford the 2,3-bis(phenylselanyl)benzo[b]furan
products in moderate yields (Scheme 8). In addition, the
substrate 5j has been successfully employed in Negishi cross-
coupling, affording the resultant 3-aryl-2-(methylthio)ben-
zo[b]furan derivatives 6e and 6f in good isolated yields after
short reaction time, under mild conditions (Scheme 9).
Conclusion
In summary, we have demonstrated the electrophilic
cyclization reaction of 2-chalcogenealkynylanisoles with
different electrophilic sources under mild conditions and
established a route to obtain 3-substituted-2-chalcogen-
benzo[b]furans in good to excellent yields. We observed that
the pathway of reaction was sensitive to the nature of
substituents in the aromatic ring of anisole and the chalcogen
atom directly bonded to the triple bond. 2-Seleno- and
2-thioalkynylanisoles provided the corresponding cyclized
products in good yield, under the standard conditions.
However, 2-telluroalkynylanisoles gave only the organotel-
lurium(IV) species, even when using an excess of iodide,
reflux, and long reaction time. The halobenzo[b]furans
obtained in the current protocol appear highly promising and
attractive intermediates for the synthesis of more highly
substituted benzo[b]furans. In fact, using the palladium- or
copper-catalyzed cross-coupling reactions with thiols, di-
phenyl diselenides, and zincates, we were able to convert
3-iodo-2-chalcogen-benzo[b]furan to Ullmann- or Negishi-
type products in good yields. We believe that this approach
to halobenzo[b]furans should prove quite useful in synthesis,
General Procedure for Iodocyclization. To a solution of 0.25
mmol of the alkyne and 2 mL of CH2Cl2 was gradually added
1.1 equiv of I2 or ICl dissolved in 3 mL of CH2Cl2. The reaction
mixture was allowed to stir at room temperature (ICl -20 °C)
for the desired time. The excess of I2 or ICl was removed by
washing with satured aqueous Na2S2O3. The mixture was then
extracted (3 × 10 mL). The organic phase was separated, dried
over MgSO4 and concentrated under vacuum.
3-Iodo-2-(phenylselanyl)benzofuran (5a). Purified by flash
chromatography and eluted with hexane. Yield: 0.090 g (91%).
1H NMR (CDCl3, 400 MHz): δ 7.49-7.47 (m, 2H), 7.42-7.36
(m, 2H), 7.34-7.22 (m, 5H). 13C NMR (CDCl3, 100 MHz): δ
156.9, 147.6, 132.0, 131.3, 129.4, 129.0, 127.7, 126.1, 123.6,
121.7, 111.4, 78.8. MS (EI, 70 eV) m/z (relative intensity): 395
(45), 270 (11), 242 (53), 163 (100), 156 (2). Anal. Calcd for
C14H9IOSe: C 42.13, H 2.27. Found: C 42.39, H 2.39.
2-(Butylselanyl)-3-iodobenzofuran (5f). Purified by flash chro-
1
matography and eluted with hexane. Yield: 0.071 g (75%). H
NMR (CDCl3, 400 MHz): δ 7.42-7.40 (m, 1H), 7.33-7.23 (m,
3H), 3.05 (t, J ) 7.5 Hz, 2H), 1.71 (quint, J ) 7.5 Hz, 2H),
1.44 (sext, J ) 7.5 Hz, 2H), 0.90 (t, J ) 7.5 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): δ 156.6, 147.9, 131.4, 125.2, 123.4, 120.9,
110.9, 75.3, 32.6, 28.6, 22.6, 13.5. MS (EI, 70 eV) m/z (relative
intensity): 377 (28), 375 (100), 320 (71), 194 (75), 166 (40).
HRMS calcd for C12H13IOSe: 379.9176, found 379.9171.
(28) Manarin, F.; Roehrs, J. A.; Wilhelm, E. A.; Zeni, G. Eur. J. Org. Chem.
2008, 4460.
(29) (a) Taniguchi, N. J. Org. Chem. 2007, 72, 1241. (b) Taniguchi, N. Synlett
2006, 1351. (c) Taniguchi, N.; Onami, T. J. Org. Chem. 2004, 69, 915. (d) Wang,
L.; Wang, M.; Huang, F. Synlett 2005, 2007. (e) Fukuzawa, S.; Tanihara, D.;
Kikuchi, S. Synlett 2006, 2145. (f) Kumar, S.; Engman, L. J. Org. Chem. 2006,
71, 5400.
2160 J. Org. Chem. Vol. 74, No. 5, 2009

Electrophilic Cyclization of 2-Chalcogenealkynylanisoles
1
General Procedure for PhSeBr Cyclization. To a solution of
0.25 mmol of the alkyne and CH2Cl2 (3 mL) was added 1.1 equiv
of PhSeBr dissolved in 2 mL of CH2Cl2 dropwise. The mixture
was allowed to stir at room temperature for the desired time.
After this time, the mixture was diluted with ethyl acetate (20
mL) and washed with brine (2 × 20 mL). The organic phase
was separated, dried over MgSO4, and concentrated under
vacuum.
0.153 g (74%). H NMR (CDCl3, 400 MHz): δ 7.56-7.54 (m,
2H), 7.49 (d, J ) 8.1 Hz, 1H), 7.39-7.19 (m, 7H), 7.01 (td, J
) 6.4 Hz and J ) 1.2 Hz, 1H), 6.90 (td, J ) 6.6 Hz and J ) 1.4
Hz, 1H), 6.67 (dd, J ) 6.4 Hz and J ) 1.4 Hz, 1H). 13C NMR
(CDCl3, 100 MHz): δ 157.2, 152.1, 135.0, 133.5, 131.2, 129.5,
129.3, 128.9, 128.2, 127.8, 127.1, 127.0, 126.3, 125.4, 123.6,
120.0, 115.1, 111.6. MS (EI, 70 eV) m/z (relative intensity):
414 (15), 269 (100), 242 (72), 221 (71), 194 (26), 150 (48), 76
(27). HRMS calcd for C20H13ClOSSe: 415.9541, found
415.9538.
2,3-Bis(phenylselanyl)benzofuran (5b). Purified by flash chro-
1
matography and eluted with hexane. Yield: 0.069 g (65%). H
NMR (CDCl3, 400 MHz): δ 7.51-7.49 (m, 2H), 7.45 (d, J )
8.0 Hz, 1H), 7.40 (d, J ) 7.8 Hz, 1H), 7.31-7.27 (m, 3H),
7.25-7.19 (m, 4H), 7.15-7.13 (m, 3H).13C NMR (CDCl3, 100
MHz): δ 157.2, 150.7, 132.8, 130.4, 130.3, 129.4, 129.2, 128.9,
127.8, 126.6, 125.3, 123.4, 120.9, 113.6, 111.4. MS (EI, 70 eV)
m/z (relative intensity): 427 (5), 269 (47), 242 (65), 163 (100),
155 (7), 76 (15). HRMS calcd for C20H14OSe2: 429.9375, found
429.9380.
2-(Butylselanyl)-3-(phenylselanyl)benzofuran (5g). Purified by
flash chromatography and eluted with hexane. Yield: 0.069 g
(68%). 1H NMR (CDCl3, 400 MHz): δ 7.47 (dt, J ) 8.0 Hz and
J ) 1.0 Hz, 1H), 7.39 (dq, J ) 7.0 Hz and J ) 1.0 Hz, 1H),
7.31-7.28 (m, 2H), 7.26-7.13 (m, 5H), 3.08 (t, J ) 7.5 Hz,
2H), 1.72 (quint, J ) 7.5 Hz, 2H), 1.41 (sext, J ) 7.5 Hz, 2H),
0.88 (t, J ) 7.5 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 157.0,
151.9, 131.0, 130.7, 129.8, 129.1, 126.4, 124.3, 123.9, 120.1,
110.8, 32.7, 27.8, 22.7, 13.4. MS (EI, 70 eV) m/z (relative
intensity): 408 (9), 349 (4), 269 (100), 242 (43), 192 (21), 163
(70). HRMS calcd for C18H18OSe2: 409.9688, found
409.9691.
General Procedure for the Cross-Coupling Reaction of
Diaryl Diselenides with 5f. To a round-bottomed flask containing
diaryl diselenide (0.25 mmol), 5f (0.5 mmol), CuI (10 mol %),
and bpy (10 mol %) was added DMSO (2 mL). The reaction
mixture was allowed to stir at reflux for 24 h. After this time, the
solution was cooled to room temperature, diluted with dichlo-
romethane (20 mL), and washed with saturated aqueous NH4Cl (3
× 20 mL). The organic phase was separated, dried over MgSO4,
and concentrated under vacuum.
2-(Butylselanyl)-3-(phenylselanyl)benzofuran (6c). Purified by
flash chromatography and eluted with hexane. Yield: 0.122 g (60%).
1H NMR (CDCl3, 400 MHz): δ 7.47 (dt, J ) 8.0 Hz and J ) 1.0
Hz, 1H), 7.39 (dq, J ) 7.0 Hz and J ) 1.0 Hz, 1H), 7.31-7.28
(m, 2H), 7.26-7.13 (m, 5H), 3.08 (t, J ) 7.5 Hz, 2H), 1.72 (quint,
J ) 7.5 Hz, 2H), 1.41 (sext, J ) 7.5 Hz, 2H), 0.88 (t, J ) 7.5 Hz,
3H). 13C NMR (CDCl3, 100 MHz): δ 157.0, 151.9, 131.0, 130.7,
129.8, 129.1, 126.4, 124.3, 123.9, 120.1, 110.8, 32.7, 27.8, 22.7,
13.4. MS (EI, 70 eV) m/z (relative intensity): 408 (9), 349 (4), 269
(100), 242 (43), 192 (21), 163 (70). HRMS calcd for C18H18OSe2:
409.9688, found 409.9691.
General Procedure for Bromocyclization. To a solution of
0.25 mmol of the alkyne and CH2Cl2 (3 mL) was added 1.1 equiv
of Br2 in benzene dropwise. The mixture was allowed to stir at
room temperature for the desired time. After this time, the
mixture was diluted with ethyl acetate (20 mL) and washed with
brine (2 × 20 mL). The organic phase was separated, dried over
MgSO4, and concentrated under vacuum.
3-Bromo-2-(phenylselanyl)benzofuran (5c). Purified by flash
chromatography and eluted with hexane. Yield: 0.066 g (75%).
1H NMR (CDCl3, 400 MHz): δ 7.52-7.48 (m, 3H), 7.45 (d, J
) 7.6 Hz, 1H), 7.36-7.30 (m, 2H), 7.26-7.24 (m, 3H). 13C
NMR (CDCl3, 100 MHz): δ 156.3, 132.0, 129.5, 128.9, 128.1,
127.8, 126.1, 123.6, 120.0, 111.6, 108.1, 99.9. MS (EI, 70 eV)
m/z (relative intensity): 351 (11), 270 (58), 242 (62), 163 (100),
156 (3), 76 (15). Anal. Calcd for C14H9BrOSe: C 47.76, H 2.58.
Found: C 47.39, H 2.32.
General Procedure for the Copper-Catalyzed Coupling Reac-
tion of 5a with Thiols. To a Schlenck tube, under argon,
containing a mixture of 3-iodo-2-(phenylselanyl)benzo[b]furan
5a (0.5 mmol) in dry dioxane (3 mL) was added the appropriate
thiol (0.6 mmol). After this Et3N (1 mmol) was added dropwise,
followed by CuI (0.0095 g, 10 mol %), and the reaction mixture
was stirred at reflux temperature for 12 h. After this the solution
was cooled to room temperature, diluted with dichloromethane
(20 mL), and washed with saturated aqueous NH4Cl (3 × 20
mL). The organic phase was separated, dried over MgSO4, and
concentrated under vacuum.
2-(Phenylselanyl)-3-(phenylthio)benzofuran (6a). Purified by
flash chromatography and eluted with hexane. Yield: 0.142 g
(75%). 1H NMR (CDCl3, 400 MHz): δ 7.54-7.52 (m, 1H), 7.45
(d, J ) 8.3 Hz, 1H), 7.37 (d, J ) 7.3 Hz, 1H), 7.28-7.08 (m,
11H). 13C NMR (CDCl3, 100 MHz): δ 157.1, 150.6, 135.5, 133.1,
131.6, 131.5, 130.5, 129.3, 128.9, 128.5, 127.6, 125.9, 125.3,
123.4, 120.2, 111.5. MS (EI, 70 eV) m/z (relative intensity):
380 (27), 269 (85), 242 (68), 194 (72), 163 (100), 150 (55), 76
(31). HRMS calcd for C20H14OSSe: 381.9931, found
381.9935.
2-(Butylselanyl)-3-(3-(trifluoromethyl)phenylselanyl)benzofu-
ran (6d). Purified by flash chromatography and eluted with hexane.
Yield: 0.119 g (50%). 1H NMR (CDCl3, 400 MHz): δ 7.84 (s, 1H),
7.76 (d, J ) 7.8 Hz, 1H), 7.52 (d, J ) 7.8 Hz, 1H), 7.44-7.37 (m,
2H), 7.34-7.27 (m, 3H), 3.06 (t, J ) 7.3 Hz, 2H), 1.73 (quint, J
) 7.3 Hz, 2H), 1.45 (sext, J ) 7.6 Hz, 2H), 0.91 (t, J ) 7.3 Hz,
3H). 13C NMR (CDCl3, 100 MHz): δ 156.7, 147.9, 134.8, 131.5
(q, J ) 32.9 Hz), 131.4, 131.3, 129.6, 128.3 (q, J ) 3.6 Hz), 125.2,
124.9 (q, J ) 3.6 Hz), 123.5, 123.3 (q, J ) 273 HZ), 121.0, 110.9,
99.9, 32.6, 28.6, 22.6, 13.5. MS (EI, 70 eV) m/z (relative intensity):
476 (15), 472 (100), 336 (90), 309 (60), 259 (95), 166 (58). HRMS
calcd for C19H17F3OSe2: 477.9562, found 477.9565.
General Procedure for the Palladium-Catalyzed Negishi
Coupling of 5j with Zincates. A 10 mL Schlenk tube, equipped
with a magnetic bar, rubber septum, and argon, containing the
previously prepared organozinc compound (1.5 mmol), was
charged sequentially with the 3-iodo-2-(methylthio)benzo[b]furan
5j (0.5 mmol) and Pd(PPh3)4 (0.057 g, 10 mol %). The yellow
mixture was stirred at room temperature, and the reaction time
was determined by monitoring the reaction by TLC. After this
the solution was diluted with dichloromethane (20 mL) and
washed with saturated aqueous NH4Cl (3 × 20 mL). The organic
phase was separated, dried over MgSO4, and concentrated under
vacuum.
2-(Methylthio)-3-phenylbenzofuran (6e). Purified by flash
chromatography and eluted with hexane. Yield: 0.091 g (76%).
1H NMR (CDCl3, 200 MHz): δ 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): δ 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. Calcd for C15H12OS: C 74.97,
H 5.03. Found: C 75.15, H 5.39.
2-(Methylthio)-3-(thiophen-2-yl)benzofuran (6f). Purified by
flash chromatography and eluted with hexane. Yield: 0.075 g
(61%). 1H NMR (CDCl3, 400 MHz): δ 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),
3-(2-Chlorophenylthio)-2-(phenylselanyl)benzofuran (6b). Pu-
rified by flash chromatography and eluted with hexane. Yield:
J. Org. Chem. Vol. 74, No. 5, 2009 2161

Manarin et al.
2.56 (s, 3H).13C NMR (CDCl3, 100 MHz): δ 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 calcd for C13H10OS2:
246.0173, found 246.0177.
Supporting Information Available: Experimental proce-
dures, additional experimental details for the preparation of all
compounds, and 1H and 13C NMR spectra for all reaction
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. The authors thank the following agencies
for support: FAPERGS, CNPq, CAPES(SAUX), and UFSM.
CAPES is also acknowledged for a Ph.D. fellowship (F.M.).
G.Z. is the recipient of CNPq fellowship.
JO802736E
2162 J. Org. Chem. Vol. 74, No. 5, 2009