Metal-free synthesis of 3-chalcogen benzo[b]furans via an iodine-mediated electrophilic cyclisation of 2-alkynylanisoles

Article abstract of DOI:10.1016/j.tetlet.2011.10.045

An efficient and metal-free method was developed to synthesize 3-chalcogen benzo[b]furans via the iodine-mediated electrophilic cyclisation of 2-alkynylanisoles with disulfides or diselenides. In the presence of I ₂, various 3-sulfenylbenzofura

Full text of DOI:10.1016/j.tetlet.2011.10.045

Tetrahedron Letters 52 (2011) 6800–6804
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Tetrahedron Letters
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Metal-free synthesis of 3-chalcogen benzo[b]furans via an
iodine-mediated electrophilic cyclisation of 2-alkynylanisoles
Mei Xu a, Xiao-Hong Zhang a, , Ping Zhong a,b,
⇑
⇑
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325035, China
b Oujiang College, Wenzhou University, Wenzhou 325035, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and metal-free method was developed to synthesize 3-chalcogen benzo[b]furans via the
iodine-mediated electrophilic cyclisation of 2-alkynylanisoles with disulfides or diselenides. In the pres-
ence of I2, various 3-sulfenylbenzofurans or 3-selenenylbenzofurans were obtained in moderate to high
yields.
Received 29 July 2011
Revised 6 October 2011
Accepted 8 October 2011
Available online 21 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Metal-free synthesis
3-Chalcogen benzo[b]furans
2-Alkynylanisoles
Introduction
have several inherent limitations, including moisture sensitivity,
costly metal catalysts and environmental toxicity. Therefore, there
Benzofurans are an important class of heterocycles that are
present in many natural products and pharmaceutical intermedi-
ates.1 Many benzo[b]furans are found to exhibit a broad range of
biological activities, including anticancer,2 antimicrobial,3 anti-
inflammatory,4 antiviral5 and antifungal activities.6 Because of
their potential utility, growing interest has recently centred on effi-
ciently constructing the benzo[b]furans scaffold.7 However, to the
best of our knowledge, there is little information available in the
literature about the synthesis of 3-chalcogen benzo[b]furans, such
as sulfenylbenzo[b]furans and selenenylbenzo[b]furans.8 For
example, in 2005, Larock and co-workers reported the synthesis
of a limited number of 3-chalcogen benzo[b]furans through the
electrophilic cyclisation of 2-(phenylethynyl)anisole with 4-
NO2C6H4SCl or PhSeCl (Eq. 1, Scheme 1).9 In 2009, Zeni and co-
workers prepared 2-chalcogen benzo[b]furans via the electrophilic
cyclisation of 2-chalcogen-alkynylanisoles (Eq. 2, Scheme 1) using
I2, ICl, Br2 or PhSeBr as the electrophilic sources.10 Nevertheless,
these two methods are limited to the use of toxic and unstable sul-
fenyl halides as the reaction partners. To avoid using unstable sul-
fenyl halides, Li11 and Zeni12 synthesized chalcogen benzo[b]furans
via palladium-promoted annulation reactions of 2-alkynylphenol
derivatives (Eq. 3, Scheme 1) and FeCl3-promoted cyclisations of
2-alkynylanisoles (Eq. 4, Scheme 1) with disulfides or diselenides,
respectively. However, transition-metal-based protocols usually
is still a need for developing a direct and metal-free method to syn-
thesize chalcogen benzo[b]furans. While studying the reaction of
2-(phenylethynyl) alkynylanisole (1a) with 1,2-diphenyl disulfide
(2a), we serendipitously discovered that the annulation reaction
R1
YAr
CH2Cl2, 25oC
R
+
ArYCl
R1
R
(1)
OCH3
O
Y = S, Se
YR1
E
E+
CH2Cl2, rt
R
R
YR1
(2)
OCH3
O
Y = S, Se E = I2, ICl, PhSeBr, Br2
R1
YR3
R1
PdCl2/I2
MeCN, 80oC
R
+
OR2
R3YYR3
R
(3)
O
Y = S, Se
Ar
YR1
Ar
FeCl3(1equiv)
CH2Cl2, 45oC
R1YYR1
R
R
+
(4)
O
Y = S, Se
OCH3
⇑
Corresponding authors. Tel./fax: +86 0577 86689338.
E-mail addresses: kamenzxh@163.com (X.-H. Zhang), zhongp0512@163.com (P.
Scheme 1. Synthesis of chalcogen benzo[b]furans through different methods.
Zhong).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.045

M. Xu et al. / Tetrahedron Letters 52 (2011) 6800–6804
6801
Table 1
Screening optimal conditionsa
Ph
Ph
S
I2
PhSSPh
2a
OCH3
Solvent
O
1a
3
a
Entry
I2 (equiv)
2a (equiv)
Solvent
Temp (°C)
Conversion (%)
1
2
3
4
5
6
7
8
9
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
CH2Cl2
CH2Cl2
CH2Cl2
CH3OH
CH3CN
DMSO
m-Xylene
Toluene
Toluene
Toluene
45
45
45
45
45
45
45
45
80
23
30
43
12
13
—
68
76
82
93
10
110
a
The conversion of 1a by GC–MS analysis.
can be accomplished in the presence of I2 alone without using
transition-metals, with competitive yields as compared to its
metal-catalysed counterparts.9–12 In this Letter, we describe our
results in detail.
With the optimal reaction conditions, we investigated the scope
of this process with respect to the 2-alkynylanisoles 1b–g (Table 2,
entries 11–20). We found that the optimal conditions were com-
patible with substrates that had aromatic groups at the terminal
of the 1-ethynyl-2-methoxybenzene but inconsistent with alkyl
groups. For example, treatment of substrate 1b bearing an m-Cl
group on the anisole moiety with disulfide 2a, 2b or 2c afforded
the corresponding products, 11, 12 and 13, in 61%, 78% and 63%
yields, respectively (entries 11–13). However, substrate bearing
an alkyl group, such as 1-methoxy-2-(oct-1-ynyl)benzene or 1-
methoxy-2-(t-Bu-1-ethynyl)benzene, gave no desired but the by-
products in 87% or 80% yields (entries 14 and 15). To our delight,
substrate with a 4-MeC6H4 or a 3-ClC6H4 group at the terminal of
1-ethynyl-2-methoxybenzene was well tolerated (entries 17–20).
Unfortunately, the annulation of 1-methoxy-2-(4-nitrophenyle-
thynyl)benzene (1g) to the target product failed under the same
conditions, and 90% by-product-3-iodo-2-phenylbenzofuran was
obtained (entry 20).
Subsequently, we studied the reactions of diselenides 2 with 2-
alkynylanisoles 1 under our previous optimal conditions, and we
found that the reactions could proceed successfully to give the de-
sired 3-selenenylbenzo[b]furans in moderate yields (Table 3). Sub-
strate 1a reacted smoothly with diaryl diselenide 2l or dialkyl
diselenide 2m in the presence of I2 to give the target products 18
and 19 in 67% and 59% yields, respectively (entries 1 and 2). Sim-
ilarly, the substrate 1b, bearing the electron-withdrawing Cl atom,
smoothly underwent the reaction with satisfactory yields (entry 3).
The treatment of substrates 1e or 1f with 1,2-diphenyldiselenide 2l
also afforded the corresponding products in moderate yields (en-
tries 4 and 5).
To explain the formation of the desired product and the by-
product, we hypothesise that the mixture of RSSR, I2 and 2-alkyny-
lanisole results in a competition between the electrophilic cyclisa-
tion of anisole via I2 and RSI. This proposed mechanism is shown in
Scheme 2. According to path a, the reaction of disulfide with I2
would yield RSI (A) in situ. Then, the electrophilic addition of RSI
(A) with 2-alkynylanisoles would afford intermediate B. Annula-
tion of intermediate B gives intermediate C, and then the CH3
group can be removed from intermediate C with the aid of IÀ to af-
ford the target product. However, the direct electrophilic addition
of 2-alkynylanisoles can occur instead with I2 to give intermediate
E. After annulation and the removal of the CH3 group from E, the
by-product of 3-iodo-2-phenylbenzofuran can be produced (path
Results and discussion
As mentioned above, we chose to study the reaction of 2-(phen-
ylethynyl) alkynylanisole (1a) with 1,2-diphenyl disulfide (2a) as a
model system to determine the optimal reaction conditions (Table
1). The amounts of 2a and I2 were first explored using CH2Cl2 as
solvent at 45 °C. It can be seen that the conversion of 1a was in-
creased to 43% by increasing the associated amounts of 2a and I2
to 1 equiv each (entries 1–3). However, more than 50% 1a was
found to be transformed into the by-product 3-iodo-2-phen-
ylbenzofuran, as shown by GC–MS analysis (entries 1–3). To en-
hance the yield of the target product 3, different solvents,
including CH3OH, CH3CN, DMSO, m-xylene and toluene were
investigated. Of these choices, toluene was proved to be the most
effective solvent, leading to a 76% conversion of 1a to 3 (entries
4–8). When the reaction temperature was elevated to 80 °C or
110 °C in toluene, the conversion of 1a was improved, and it
reached 93% when the reaction was carried out at 110 °C (entries
9 and 10). These results indicated that the solvent and temperature
played important roles in the formation of 3.
The application of the above-modified conditions to other 2-
alkynylanisoles and disulfides was studied, and the results are
summarised in Table 2. Initially, a set of disulfides, 2b–k, were
examined by their reaction with 2-(phenylethynyl) alkynylanisole
(1a) (entries 1–10). The results showed that the reaction seemed to
be sensitive to the electronic effects of the substituents in the aro-
matic ring of the disulfide. For example, disulfides with Cl and F
moieties gave lower yields than their methyl and methoxy equiv-
alents (entries 1–5). Moreover, no desired product but only the by-
product, 3-iodo-2-phenylbenzofuran, was obtained in a 45% yield
when the disulfide substituent was NO2, a strong electron-with-
drawing group (entry 6). Gratifyingly, diaryl disulfides, such as
diethyl or dicyclohexyl disulfide, were suitable for the reaction
and gave the desired products in 50% and 55% yields, respectively
(entries 9 and 10). However, the reactions of 1,2-di(pyridin-2-yl)
disulfide (2h) or 1,2-dibenzyl disulfide (2i) with anisole 1a were
unsuccessful, and the by-product 3-iodo-2-phenylbenzofurans
were obtained in 83% and 58%, respectively (entries 7 and 8).

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M. Xu et al. / Tetrahedron Letters 52 (2011) 6800–6804
Table 2
Iodine-mediated electrophilic cyclisation of 2-alkynylanisoles (1) with disulfides (2)a
R3
R2
S
I2, Toluene
110 °C
R2
R3SSR3
R1
O
R1
OCH3
1a-1g
2
Entry
1
Alkynylanisole
R3SSR3
Product (yield%)b
Ph
S
S
4 (96)
S
2b
1a
OMe
F
2
3
1a
1a
5 (80)
6 (87)
S
2c
F
OMe
S
S
2d
MeO
Cl
S
4
5
1a
1a
7 (59)
8 (46)
S
2e
Cl
F
F
S
S
2f
NO2
S
6
7
1a
1a
S
45c
83c
2g
O2N
S
S
N
N
2h
S
8
9
1a
1a
58c
S
S
2i
S
S
9 (50)
10 (55)
2j
S
10
1a
2k
Cl
S
S
Ph
1b
11
12
13
11 (61)
12 (78)
13 (63)
2a
OMe
S
1b
S
2b
F
S
1b
S
2c
F
S
S
S
14
15
87c
80c
1c
2a
OMe
OMe
S
1d
2a

M. Xu et al. / Tetrahedron Letters 52 (2011) 6800–6804
6803
Table 2 (continued)
Entry
Alkynylanisole
R3SSR3
Product (yield%)b
S
S
16
14 (90)
2a
1e
OMe
S
S
17
18
1e
15 (91)
16 (76)
2b
F
S
S
1e
2c
F
S
S
Cl
S
19
17 (35)
2a
1f
OMe
OMe
NO2
S
20
90c
2a
1g
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), I2 (0.2 mmol), and toluene (2 mL) at 110 °C for 10 h.
Yield of isolated products.
The isolated yield of by-product 3-iodo-2-phenylbenzofuran.
b
c
Table 3
Cyclisation reactions of 2-alkynylanisoles (1) with diselenides (2)a
R2
Se R3
R2
I2, Toluene
R3SeSeR3
R1
R1
110oC
O
OCH3
Entry
Alkynylanisole
Diselenides
Product (yield%)b
Ph
Se
1
2
18 (67)
19 (59)
Se
2l
1a
OMe
Se
2m
1a
Se
Cl
Se
Se
Ph
1b
2l
2l
3
4
20 (54)
21 (80)
OMe
OMe
OMe
Se
Se
Se
1e
Se
Cl
2l
5
22 (43)
1f
a
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), I2 (0.2 mmol), and toluene (2 mL) at 110 °C for 10 h.
Yield of isolated products.
b
b). Path a and b appear to be competitive processes. When path a
dominated, target product D was obtained as the main product.
Conversely, when path b dominated, the main product was the
undesired by-product F.
In conclusion, we have developed a convenient and metal
-free protocol for the construction of 3-chalcogen benzo[b]furans
via the iodine-mediated annulation of 2-alkynylanisoles and
disulfides or diselenides. In the presence of I2, a variety of

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M. Xu et al. / Tetrahedron Letters 52 (2011) 6800–6804
RSSR
I2
R
SR
Ph
S
R
S
Ph
RSI (A)
Ph
O
Me
Ph
OMe
O
I
OMe
B
path a
I
D
I
C
I2
path b
I
I
Ph
Ph
Ph
O
O
Me
OMe
I
F
E
Scheme 2. Proposed mechanism.
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3-sulfenylbenzo[b]furans or 3-selenenylbenzo[b]furans were
synthesized from the reaction of 2-alkynylanisoles derivatives
with different disulfides or diselenides in moderate to good yields.
Acknowledgements
The authors thank the National Natural Science Foundation of
China (No. 20972114) and the Zhejiang Provincial Natural Science
Foundation of China (No. Y4100578).
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