2
W.-Y. Wang et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Table 1
Table 2
Screening optimal conditionsa
Tandem reaction of 2-alkynylanisoles with iodine and TMSCF3
a
Ph
Ar
CF3
CF3
1) 1 equiv I2, 40 o
C
1) I2
R
Ar
Ph
R
2) TMSCF3/KF/CuI
DMF, 100 oC
2) TMSCF3 2,
[Cu]/KF/Solvent
O
O
OMe
OMe
Me
1a
3
CF3
CF3
CF3
Entry
[Cu]
Solvent
T (°C)
Yieldb (%)
1c
2c
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuOAc
CuI
CH2Cl2
DMF
DMF
DMSO
MeCN
DCE
Toluene
DMF
DMF
DMF
DMF
DMF
50
80
80
80
80
80
80
80
80
0 (53)d
0 (95)e
80
44
56
38
NR
53
45
Me
t-Bu
O
O
O
4, 67%
5, 72%
CF3
6, 67%
CF3
CF3
OMe
F
OMe
O
O
O
7
8
9
, 55%
, 68%
CF3
, 76%
10
11
12f
80
100
100
37
89
49
CF3
CF3
Cl
F
Cl
CuI
O
O
O
a
Reaction conditions: 1a (0.2 mmol) and I2 (0.2 mmol) were stirred at 40 °C for
10
CF3
11
12
, 61%
, 57%
CF3
, 64%
CF3
6 h, followed by addition of 2 (1.0 mmol), KF (2 equiv), [Cu] (0.2 mmol), and solvent
(2 mL), stirred for 16 h.
Me
t-Bu
b
Isolated yield.
Ph
c
Compound 1a, I2, 2, CuI, KF, and solvent were added together.
Isolated yield of iodocyclization product in the parentheses.
The recovered yield of 1a in the parentheses.
0.5 equiv of CuI was used.
O
O
O
d
13
, 57%
4,
15
%
, 74
e
1
81%
f
CF3
CF3
CF3
MeO
MeO
MeO
F
Me
O
O
O
solvents, including DMSO, MeCN, ClCH2CH2Cl, and toluene, were
less effective than DMF. Other copper(I) salts such as CuBr, CuCl,
and CuOAc were investigated (entries 8–10), but lower yields
were observed. During the examination of reaction temperature,
we found the reaction yield increased to 89% when the reaction
was carried out at 100 °C (entry 11). Stoichiometric amount of
copper salt was required to form CuCF3 in situ, only 49% yield
was obtained when the loading of CuI reduced to 0.5 equiv
(entry 12).
F
16, 72%
CF3
17, 70%
18, 51%
CF3
O
CF3
Cl
NC
O
O
O
19, 61%
20, 62%
21b, 49%
b
At 140 °C for 36 h.
a
Reaction conditions: 1 (0.2 mmol) and I2 (0.2 mmol) were stirred at 40 °C for
6 h, followed by addition of CF3Si(Me)3 (1.0 mmol), KF (2 equiv), CuI (0.2 mmol),
and solvent (2 mL), stirred at 100 °C for 16 h.
With the optimal reaction conditions in hand, we examined the
substrate scope of 2-alkynylanisoles for the tandem reaction, and
the results are displayed in Table 2. Firstly, the reaction between
TMSCF3 and various 2-alkynylanisoles bearing different substitu-
ents at the terminal alkyne moiety was investigated under stan-
dard conditions. The results show that 2-alkynylanisole bearing
aromatic groups were suitable substrates and afforded the corre-
sponding products in moderate to excellent yields. For example,
m- or p-tolyl substituted 2-alkynylanisoles gave the products 4
and 5 in 67% and 72% yields, respectively. t-Butylphenyl-substi-
tuted 2-alkynylanisole gave the product 6 in 67% yield. Similar re-
sults were obtained for methoxyphenyl substituted benzofurans 7
and 8. 2-Alkynylanisoles bearing fluoro- or chloro-phenyl groups
provided 55–64% yields (9–12). The reactions of 4-((2-methoxy-
phenyl)ethynyl)biphenyl with TMSCF3 also afforded the desired
product 13 in a 57% yield. However, alkyl groups were not compat-
ible because iodocyclization did not work.4a Subsequently, various
functional groups on the anisole moiety were examined. 2-Alkyny-
lanisoles bearing electron-donating groups (such as 4-methyl, 4-
tert-butyl, and 4-methoxyl) underwent the tandem reaction
smoothly under standard conditions to afford the corresponding
products in 72–81% yields (14–17). 4,6-Difluoro-substituted 2-alk-
ynylanisole was also converted to the corresponding product 18
successfully in 51% yield. 4-Chloro-substituted benzofuran 19
was obtained in 61% yield. It is noteworthy that electron-deficient
2-alkynylanisoles were also tolerated very well. For example, the
Conclusions
In conclusion, we have developed an efficient route for the syn-
thesis of trifluoromethyl substituted benzofurans. In the presence
of I2, CF3SiMe3, CuI, and KF,
a variety of 2-alkynylanisoles
underwent two-step, one-pot tandem iodocyclization and
a
subsequent trifluoromethylation affording the corresponding
3-trifluoromethylbenzofurans in moderate to excellent yields.
The one-pot procedure and the utilization of inexpensive TMSCF3
as trifluoromethyl source are significant advantages for the useful-
ness of the reaction. This method provides a novel and straightfor-
ward way for the preparation of 3-trifluoromethylbenzofurans.
Further investigation is in progress to direct the tandem iodocycli-
zation/trifluoromethylation reaction toward other trifluoromethy-
lated heterocyclics.
Acknowledgements
We thank the National Natural Science Foundation of China
(Nos. 21002070 and 21272177) for financial support.
Supplementary data
reaction
of
methyl
4-methoxy-3-(phenylethynyl)benzoate
proceeded smoothly to provide the product 20 in 62% yield.
4-Cyano-substituted anisole afforded benzofuran 21 in a 49% yield
at 140 °C by prolonging the reaction time.
Supplementary data associated with this article can be found, in