Novel route to 2-trifluoromethylated benzofurans

Article abstract of DOI:10.1080/00397910802431099

A novel route for the synthesis of a variety of 2- trifluoromethylbenzofurans is reported. By selection of solvents, the key intermediates, 2-chloro-3,3,3-trifluoropropenyl phenyl acetates, were cyclized either to give 2-trifluoromethyl-substituted benzof

Full text of DOI:10.1080/00397910802431099

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Novel Route to 2-
Trifluoromethylated
Benzofurans
Hua Zhou a b , Jia-Jia Niu a b , Jing-Wei Xu a & Shao-
Jing Hu c
a Changchun Institute of Applied Chemistry, Chinese
Academy of Sciences, Changchun, China
b Graduate School, Chinese Academy of Sciences,
Beijing, China
c Institute for Diabetes Discovery, Branford,
Connecticut, USA
Published online: 28 Jan 2009.
To cite this article: Hua Zhou , Jia-Jia Niu , Jing-Wei Xu & Shao-Jing Hu (2009)
Novel Route to 2-Trifluoromethylated Benzofurans, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:4,
716-732, DOI: 10.1080/00397910802431099
To link to this article: http://dx.doi.org/10.1080/00397910802431099
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Synthetic Communications1, 39: 716–732, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802431099
Novel Route to 2-Trifluoromethylated
Benzofurans
Hua Zhou,1,2 Jia-Jia Niu,1,2 Jing-Wei Xu,1 and Shao-Jing Hu3
1Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
Changchun, China
2Graduate School, Chinese Academy of Sciences, Beijing, China
3Institute for Diabetes Discovery, Branford, Connecticut, USA
Abstract: A novel route for the synthesis of a variety of 2-trifluoromethylbenzofur-
ans is reported. By selection of solvents, the key intermediates, 2-chloro-3,3,
3-trifluoropropenyl phenyl acetates, were cyclized either to give 2-trifluoromethyl-
substituted benzofurans or to yield trifluoromethyl modified o-alkynylphenols.
The latter intermediates could also be cyclized to give 3-iodo-2-trifluoromethyl-
substituted benzofurans.
Keywords: o-Alkynylphenols, iodocyclization, phenyl acetates, trifluoromethyl-
benzofurans
INTRODUCTION
Trifluoromethylated aromatic compounds have many applications in
pharmaceuticals, dyes, liquid crystals, and polymers.[1] Benzofurans form
the core of numerous natural products, and trifluoromethylated benzofur-
ans have considerable pharmacological potential.[2] Even though the
synthesis of benzofurans are well documented,[3] there are few reports
for the synthesis of 2-trifluoromethyl-substituted benzofurans.[4] In these
methods, the difficult handling of gaseous materials such as 3,3,3-trifluor-
opropyne[4b] and trifluoroiodomethane,[4c] the use of expensive palladium
Received April 24, 2008.
Address correspondence to Jing-Wei Xu, Changchun Institute of Applied
Chemistry, Chinese Academy of Sciences, Changchun 130022, China. E-mail:
jwxu@ciac.jl.cn
716

2-Trifluoromethylated Benzofurans
717
catalyst,[4d,e] the low yields, and poor selectivity have limited their
application. Here we report a novel and convenient way to synthesize 2-tri-
fluoromethylated benzofurans (3a–e) and 3-iodo-2-trifluoromethyl benzo-
furans (6a–e) from 2-chloro-3,3,3-trifluoropropenyl phenyl acetates (2a–e).
RESULTS AND DISCUSSION
In this study, phenyl acetates (2) were prepared by a method similar to
that developed by Fujita et al.[5] Substituted salicylaldehydes (1) were
treated with in situ generated organozinc reagent, 2,2,2-trifluorodichlor-
oethylzinc chloride,[6]and acetic anhydride in N,N-dimethylformamide
(DMF) to give 2 in moderate yield (Table 1). The configuration of 2
1
was studied by H and 19F NMR,[7] and the results indicated that the
major configuration was Z (cis).[5,7]
A set of experiments were carried out using 2a as model substrate.
Under the conditions reported by Meazza and Zanardi,[8] treatment of
2a with 1.2 equivalent of powdered KOH in dimethyl sulphoxide
(DMSO) gave 2-(trifluoromethyl)benzofuran (3a) in 22% yield and
recovered 2a in 50%. The use of 1 equivalent of potassium tert-butoxide
(t-BuOK) in DMF gave 3a and 4a in 26% and 23% yields respectively
Table 1. Synthesis of phenyl acetates (2) from substi-
tuted salicylaldehydes (1)
1
R1
R2
Yield of 2a (%)
1a
1b
1c
1d
1e
H
CH3
Cl
Br
H
H
H
H
H
OCH3
50 (2a) [79=21]b
40 (2b) [89=11]
44 (2c) [93=7]
47 (2d) [95=5]
46 (2e) [81=19]
aIsolated yield.
bThe values in bracket are Z=E ratio of 2.

718
H. Zhou et al.
after 27 h. Further increase of base loading led to an increase of the yield
of 3a (entry 2, Table 2). It was finally noticed that this parameter had a
crucial influence on the outcome of the reaction. Base-induced cyclization
of 2a led to 3a only when more than 2 equivalents of base were used
(entries 3–5, Table 2). t-BuOK appeared to give best results among bases
(NaH, KOH, and 1,8-diazabicyclo[5,4.0]-undec-7-ene [DBU]). Most cur-
ious was the impact of solvent. The effects of solvents such as acetonitrile
(CH3CN), dichloromethane (DCM), ether (Et2O), toluene, tetrahydro-
furan (THF), and tetrachloromethane (CCl4) were investigated and are
presented in Table 2. Dipolar solvents, such as DMF, DMSO, and acet-
onitrile, promoted intramolecular cyclization to form 3a (entries 1, 9, and
10), whereas other solvents, such as DCM, ether, toluene, THF, and
CCl4, favored alkenyl elimination product 2-(3,3,3-trifluoroprop-1-ynyl)-
phenol (5a) even when 3 equivalents of t-BuOK were used.
We could detected 5a when 4a was treated with t-BuOK (Fig. 1). We
found that when 4a was treated with 2 equivalents of t-BuOK, it would
converted to 3a completely.
The process of 2a converting to 3a was presumed as follows
(Scheme 1): when 2a was treated with t-BuOK, firstly it deacetylated to
get 7, with more t-BuOK, then 1 mol HCl was eliminated from 7 to
get 8 which was transformed into 3a by a intramolecular cyclization.
The optimized reaction conditions, 3 equivalents of t-BuOK as alkali
and DMF or Et2O as solvents, were applied to convert 2 into 3 and 5,
respectively. The results are summarized in Table 3. Under these condi-
tions, 2a–e were transformed to 3a–e and 5a–e in good to excellent
yields. No spectacular electronic effects were observed, and a variety of
functional groups was tolerated.
o-Alkynylphenols could be cyclized by a base, such as sodium ethano-
late,[9a] pypridine,[4b] and cesium hydroxide,[9b] to form benzofunans. They
could also be converted into 3-iodobenzofurans by iodocyclization.[10]
Under the standard condition reported by Arcadi (3 equivalents of
sodium bicarbonate, 3 equivalents of iodine in acetonitrile at room tem-
perature), trifluoromethylated o-alkynylphenol 5a was transformed into
expected 3-iodobenzofuran 6a in a low yield of 10%. Other bases (such
as sodium carbonate, potassium carbonate, cesium carbonate, potassium
phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate,
and sodium acetate) and solvents (such as 1,4-dioxane, THF, CH2Cl2,
CHCl3, CCl4, MeOH, and hexane) were investigated. We finally found
5a–d can be converted into 6a–d in moderate yield when sodium carbo-
nate was used as base and the reaction was performed in CCl4 at 70 ꢀC
(Table 4). However, even under this optimized condition, 6e was obtained
in a low yield of 5%. Maybe the electronic effect of substituted groups on
the phenyl ring plays a controlling role in this iodocyclization.

2-Trifluoromethylated Benzofurans
719
Table 2. Cyclization of 2-(2-chloro-3,3,3-trifluoroprop-1-enyl)phenyl acetate 2a
into 2-(trifluoromethyl)benxofuran 3aa
Entry
Base (equivalent)
Solvent
Time (h)
Yieldb (%)
3a=4a=5a
26=23=0
55=44=0
100=0=0
100=0=0
100=0=0
44=44=0
99=0=0
1
2
3
4
5
6
t-BuOK (1.0)
t-BuOK (1.7)
t-BuOK (2.2)
t-BuOK (2.7)
t-BuOK (3.0)
NaH (5.0)
DMF
DMF
DMF
DMF
DMF
DMF
27
27
27
27
1
1
6
7
8
KOH (3.0)
DBU (3.0)
DMF
DMF
1
3
1
27
1
3
3
3
3
75=0=0
100=0=0
24=18=18
99=0=0
100=0=0
99=0=0
19=0=78
0=0=99
10=0=85
17=0=75
0=0=93
9
10
11
12
13
14
15
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
t-BuOK (3.0)
DMSO
CH3CN
DCM
Et2O
Toluene
THF
CCl4
3
3
a
Reaction conditions: 2a (0.5 mmol) dissolved in 2 mL solvent, the base was
added and the reaction was performed at room temperature.
bGC yield.

720
H. Zhou et al.
Figure 1. (a) 4a treated with 1.2 equivalent of t-BuOK; (b) 4a treated with 2
equivalent of t-BuOK.
In conclusion, a novel and convenient method for the synthesis of
2-trifluoromethylated benzofurans and 3-iodo-2-trifluoromethyl benzo-
furans has been developed. In this method, 1,1,1-trichloro-2,2,2-
trifluoro-ethane was used to introduce the trifluoromethyl group; 2-
chloro-3,3,3-trifluoro-propenyl phenyl acetates were treated with potas-
sium tert-butoxide to give 2-(trifluoromethyl)benzofurans in DMF
and o-alkynylphenols in Et2O respectively with good to excellent yields;
and iodine induced iodocyclization of o-alkynylphenols to give
3-iodo-2-trifluoromethyl benzofurans with moderate yields.
EXPERIMENTAL
Methods
1H NMR and 13C NMR spectra were recorded on Bruker Avance-300,
Bruker Varian-400, and Bruker Varian-600 spectrometers in CDCl3 with

2-Trifluoromethylated Benzofurans
721
Scheme 1. The process of conversion of 2a to 3a.
TMS as an internal standard. 19F NMR spectra were recorded on a
Bruker Avance-300 spectrometer using trifluoroacetic acid as external
standard. All chemical shifts (d) were expressed in parts per million (ppm);
coupling constants (J) were given in hertz. IR spectra were obtained with
a Bruker Vertex 70 FTIR spectrometer. Gas chromatography–mass spec-
tra (GC-MS) were recorded on an Agilent 6890N-5975 spectrometer.
High-resolution mass spectra (HRMS) were done on an IonSpec HiRes.
All reagents were purchased from commercial sources and used without
treatment (purification) unless otherwise indicated. The products were
purified by column chromatography over silica gel.
Typical Procedure for the Synthesis of Substituted 2-(2-Chloro-3,3,
3-trifluoroprop-1-enyl)phenyl Acetates (2)
Five equivalents of zinc powder (washed with 2% HCl, water, 95%
ethanol and ether, then dryed with vacuum) and 3 equivalents of acetic
anhydride were added into a solution of substituted salicylaldehyde
˚
(1, 10 mmol) in DMF (20 mL, dried by 4A molecular sieve) in an argon
atmosphere at room temperature. Then 3 equivalents of 1,1,1-trichloro-2,

722
H. Zhou et al.
Table 3. Solvents selected formation of benzofurans 3 and o-alkynylphenols 5
from phenyl acetates 2
2
R1
R2
Yield of 3a (%)
Yield of 5a (%)
2a
2b
2c
2d
2e
H
CH3
Cl
Br
H
H
H
H
H
OCH3
86 (3a)
82 (3b)
95 (3c)
94 (3d)
94 (3e)
62 (5a)
70 (5b)
72 (5c)
80 (5d)
88 (5e)
aIsolated yield.
Table 4. Iodine cyclization of o-alkynylphenols 5
5
R1
R2
Yield of 6a (%)
5a
5b
5c
5d
5e
H
CH3
Cl
Br
H
H
H
H
H
OCH3
63 (6a)
54 (6b)
80 (6c)
62 (6d)
5 (6e)
aIsolated yield.

2-Trifluoromethylated Benzofurans
723
2,2-trifluoroethane were dripped into this system in 10 min with fierce
stirring using a magnetic bar. The reaction was monitored by thin-layer
chromatography (TLC). After completion, the reaction mixture was trea-
ted with saturated ammonium chloride solution (150 mL) and extracted
with diethyl ether (3 ꢁ 50 mL). The organic phase was dried with magne-
sium sulfate, filtered, and concentrated to get the crude product, which
was purified by column chromatography (hexane–ethyl acetate) over
silica gel to provide phenyl acetates 2.
Compound 2a
This compound was obtained as a mixture of Z–E isomers in a ratio of
79=21 (after purification); light yellow oil. IR (film) (n, cmꢂ1): 1652
1
(C ¼ C), 1772 (C ¼ O). Z isomer: H NMR (CDCl3, 600 MHz): d 2.327
(s, 3H), 7.172 (d, J ¼ 8.4 Hz, 1H), 7.317 (t, J ¼ 7.5 Hz, 2H), 7.446
(t, J ¼ 7.8 Hz, 1H), 7.867 (d, J ¼ 7.8 Hz, 1H). 19F NMR (CDCl3,
282 MHz, CF3COOH as external standard): 8.734 (s). E isomer: 1H
NMR (CDCl3, 600 MHz): d 2.305 (s, 3H), 7.097 (s, 1H), 7.134 (d,
J ¼ 8.4 Hz, 1H), 7.244–7.277 (m, 2H), 7.393 (t, J ¼ 7.5 Hz, 1H). 19F
NMR (CDCl3, 282 MHz, CF3COOH as external standard): 14.171 (s).
13C NMR (CDCl3, 75 MHz) for Z–E mixtures: d 21.01, 119.23 (q,
2
1JC,F ¼ 272.5 Hz), 122.34 (q, JC,F ¼ 37.0 Hz), 122.65, 123.05, 124.92,
3
125.95 (d, JC,F ¼ 4.5 Hz), 126.17, 126.27, 129.98, 130.67, 131.30, 132.09,
148.25, 149.38, 169.04. GC-MS: t ¼ 9.279 min (21%), t ¼ 9.402 min (79%),
m=z 264 (Mþ, 15), 266 (Mþ, 5), 222 (98), 224 (33), 167 (100), 43 (80).
HRMS (ESI) m=z : calcd. for C11H8ClF3O, [M þ Na] 287.00627; found
287.00746.
Compound 2b
This compound was obtained as a mixture of Z–E isomers in a ratio of 89=11
(after purification); light yellow oil. Z isomer: 1H NMR (CDCl3, 400MHz):
d 2.30 (s, 3H), 2.38 (s, 1H), 7.04 (d, J ¼ 8.40Hz, 1H), 7.22 (dd, J¼ 8.40 Hz,
1.20 Hz, 1H), 7.27 (s, 1H), 7.65 (s, 1H). 19F NMR (CDCl3, 282.4MHz,
1
CF3COOH as external standard): d 8.778 (s). E isomer: H NMR: d 2.28
(s, 3H), 2.34 (s, 3H), 6.98 (d, J ¼ 8.00 Hz, 1H), 7.17 (d, J¼ 8.40 Hz, 1H).
19F NMR (CDCl3, 282.4 MHz, CF3COOH as external standard): d 14.067
(s). 13C NMR (CDCl3, 75.48 MHz) for Z–E mixture: d 20.97, 21.24,
1
2
119.26 (q, JCF ¼ 272.46 Hz), 122.08 (q, JCF ¼36.98 Hz), 122.31, 122.71,
3
124.54, 126.12 (d, JCF ¼ 3.77Hz), 130.24, 131.26, 131.95, 132.24, 136.08,
147.19, 169.27. GC-MS: t ¼ 8.211 min (11%), t ¼ 8.284 min (89%), m=z
(%): 278 (Mþ, 11), 280 (Mþ, 4), 236 (98), 238 (31), 181 (100), 43 (67).

724
H. Zhou et al.
Compound 2c
This compound was obtained as a mixture of Z–E isomers in a ratio of
93=7 (after purification); light yellow oil. IR (film) (n, cmꢂ1): 1653
1
(C ¼ C), 1771 (C ¼ O). Z isomer: H NMR (CDCl3, 600 MHz): d 2.322
(s, 3H), 7.129 (d, J ¼ 8.40 Hz, 1H), 7.241 (s, 1H), 7.400 (d, J ¼ 9.00 Hz,
1H), 7.837 (s, 1H). 13C NMR (CDCl3, 75.48 MHz): d 20.92, 118.99
1
2
(q, JCF ¼ 272.46 Hz), 123.55(q, JCF ¼ 36.23 Hz), 124.36, 124.89 (d,
3JCF ¼ 4.53 Hz), 126.36, 129.70, 131.15, 131.78, 147.79, 168.75. 19F
NMR (CDCl3, 282.4 MHz, CF3COOH as external standard): d 8.578
(s). E isomer: 1H NMR: d 2.295 (s, 3H), 7.005 (s, 1H), 7.075
(d, J ¼ 9.00 Hz, 1H), 7.348 (d, J ¼ 8.40 Hz, 1H).19F NMR (CDCl3,
282.4 MHz, CF3COOH as external standard): d 13.879 (s). GC-MS:
t ¼ 8.710 min, m=z (%): 298 (Mþ, 5), 300 (Mþ, 3), 256 (68), 258 (45),
260 (6), 201 (56), 203 (19), 43 (100).
Compound 2d
This compound was obtained as a mixture of Z–E isomers in a ratio of
95=5 (after purification); light yellow solid. IR (KBr) (n, cmꢂ1): 1651
1
(C ¼ C), 1765 (C ¼ O). Z isomer: H NMR (CDCl3, 400 MHz): d 2.316
(s, 3H), 7.067 (d, J ¼ 8.40 Hz, 1H), 7.237 (s, 1H), 7.537–7.565 (dd,
J ¼ 8.80, 2.40 Hz, 1H), 7.968 (d, J ¼ 2.00 Hz, 1H). 13C NMR (CDCl3,
1
75.48 MHz): d 20.95, 118.99 (q, JCF ¼ 272.47 Hz), 119.30, 123.55
2
3
(q, JCF ¼ 37.74 Hz), 124.70, 124.84 (d, JCF ¼ 4.53 Hz), 126.75, 132.62,
134.12, 148.32, 168.65. 19F NMR (CDCl3, 282.4 MHz, CF3COOH as
external standard): d 8.606 (s). E isomer: H NMR: d 2.291 (s, 3H),
1
7.005 (s, 1H), 7.014 (d, J ¼ 8.80 Hz, 1H), 7.394 (d, J ¼ 1.60 Hz, 1H),
7.486–7.513 (dd, J ¼ 8.40 Hz, 2.00 Hz, 1H). 19F NMR (CDCl3,
282.4 MHz, CF3COOH as external standard): d 13.899 (s). GC-MS:
t ¼ 9.374 min, m=z (%): 342 (Mþ, 4), 344 (Mþ, 6), 346 (Mþ, 1), 300
(46), 302 (59), 304 (15), 245 (32), 247 (32), 43 (100).
Compound 2e
This compound was obtained as a mixture of Z–E isomers in a ratio of
81=19 (after purification); light yellow solid. Recyclization from n-hexane
gave a colorless sheet crystal. IR (KBr) (n, cmꢂ1): 1653 (C¼ C), 1770
1
(C ¼ O). Z isomer: H NMR (CDCl3, 300 MHz): d 2.3356 (s, 3H), 3.8500
(s, 3H), 7.0138 (d, J ¼ 8.22 Hz, 1H), 7.2398 (d, J¼ 8.10Hz, 1H), 7.2936
(s, 1H), 7.4601 (d, J ¼ 7.89Hz, 1H). 13C NMR (CDCl3, 75.48 MHz): d
1
20.53, 56.37, 114.13, 119.25 (q, JCF ¼ 272.47 Hz), 121.20, 122.39 (q,

2-Trifluoromethylated Benzofurans
725
2JCF ¼ 35.47Hz), 125.76 (d, 3JCF ¼ 3.77 Hz), 126.22, 126.73 139.07, 151.82,
168.56. 19F NMR (CDCl3, 282.4 MHz, CF3COOH as external standard): d
1
8.755 (s). E isomer: H NMR: d 2.3167 (s, 3H), 3.8351 (s, 3H), 6.863 (d,
J¼ 7.80Hz, 1H), 6.987 (d, J ¼ 7.80Hz, 1H), 7.072 (s, 1H), 7.190 (d,
J¼ 7.80Hz, 1H). 19F NMR (CDCl3, 282.4 MHz, CF3COOH as external
standard): d 14.424 (s). GC-MS: t¼ 9.091min, m=z (%): 294 (Mþ, 3), 252
(100), 232 (9), 216 (11), 197 (45), 145 (11), 43 (53). HRMS (ESI) calcd. for
C12H10ClF3O3, [M þ H] 295.03488, [Mþ Na] 317.01683, 319.01388,
[M þ K] 332.99077, 334.98782; found 295.03459, 317.01538, 319.01273,
332.99004, 334.98717.
Typical Procedure for the Synthesis of Substituted 2-
(Trifluoromethyl)benzofurans (3)
t-BuOK (6 mmol) was added to a solution of 2 (2 mmol) in 4 mL of
DMF. The mixture was stirred at room temperature and monitored by
TLC. After completion, the reaction mixture was treated with saturated
ammonium chloride solution (30 mL) and extracted with diethyl ether
(3 ꢁ 15 mL). The organic layer was dried with magnesium sulfate and fil-
tered. The solvent was distilled, and the residue was purified by column
chromatography and eluted with n-pentane to obtain product 3.
Compound 3a
1
This compound was obtained as colorless volatile oil. H NMR (CDCl3,
300 MHz): d 7.167 (d, J ¼ 0.9 Hz, 1H), 7.328 (t, J ¼ 7.5 Hz, 1H), 7.444 (t,
J ¼ 8.4 Hz, 1H), 7.558 (d, J ¼ 8.4 Hz, 1H), 7.656 (d, J ¼ 7.8 Hz, 1H). 13C
3
NMR (CDCl3, 75 MHz): d 108.50 (d, JC,F ¼ 3.0 Hz), 112.49, 119.75
1
(q, JC,F ¼ 267.9 Hz), 122.88, 124.37, 126.42, 127.32, 143.93 (q,
2JC,F ¼ 41.5 Hz), 155.58. 19F NMR (CDCl3, 282 MHz, CF3COOH as
external standard): 12.885 (s). HRMS (ESI) m=z: calcd. for C9H5F3O,
[M ꢂ H] 185.02142; found 185.02191.
Compound 3b
This compound was obtained as light yellow volatile oil. 1H NMR
(CDCl3, 600 MHz) d 2.455 (s, 3H), 7.080 (s, 1H), 7.232 (m, 1H), 7.429
(s, 1H), 7.442 (d, J ¼ 7.80 Hz, 1H). 13C NMR (CDCl3, 150.92 MHz): d
1
21.15, 107.84, 111.52, 118.56 (q, JCF ¼ 267.13 Hz), 122.06, 126.13,
2
128.31, 133.63, 143.39 (q, JCF ¼ 42.26 Hz), 153.68. 19F NMR (CDCl3,
282.4 MHz, CF3COOH as external standard): d 12.891 (s). GC-MS:

726
H. Zhou et al.
t ¼ 2.362 min, m=z (%): 200 (Mþ, 99), 199 (100), 181 (18), 151 (18), 131
(47), 103 (20), 77 (17), 51(16).
Compound 3c
This compound was obtained as light yellow oil. IR (film) (n, cmꢂ1):
1609, 1585, 1449, 1439, 1359, 1350, 1315, 1278, 1259, 1216, 1181, 1167,
1
1144, 1076, 1063, 934, 873, 806, 733, 698, 587, 480, 438, 419. H NMR
(CDCl3, 300 MHz): d 7.1219 (s, 1H), 7.3851 (dd, J ¼ 8.88, 2.07 Hz, 1H),
7.4867 (d, J ¼ 8.82 Hz, 1H), 7.6428 (d, J ¼ 2.07 Hz, 1H). 13C NMR
1
(CDCl3, 150.92 MHz): d 107.64, 113.19, 118.10 (q, JCF ¼ 267.13 Hz),
2
122.03, 127.31, 127.39, 129.76, 144.74 (q, JCF ¼ 42.26 Hz), 153.50. 19F
NMR (CDCl3, 282.4 MHz, CF3COOH as external standard): d 12.680
(s). GC-MS: t ¼ 11.683 min, m=z (%): 220 (Mþ, 100), 222 (Mþ, 33),
201 (15), 170 (29), 157 (10), 137 (8), 123 (9), 107 (8), 87 (9), 62 (8).
HRMS (ESI) m=z: calcd. for C9H4ClF3O, [M ꢂ H] 218.98245; found
218.98232.
Compound 3d
This compound was obtained as light yellow oil. 1H NMR (CDCl3,
300 MHz): d 7.1223 (s, 1 H), 7.4385 (d, J ¼ 8.88, 1.89 Hz, 1H), 7.8079
(d, J ¼ 1.86 Hz, 1H), 7.6428 (d, J ¼ 2.07 Hz, 1H). 13C NMR (CDCl3,
3
100.58 MHz): d 107.46 (d, JCF ¼ 2.01 Hz), 113.59, 117.11, 117.63 (q,
2
1JCF ¼ 268.54 Hz), 125.12, 127.91, 144.50 (q, JCF ¼ 42.24 Hz), 153.87.
19F NMR (CDCl3, 282.4 MHz, CF3COOH as external standard): d
12.697 (s). GC-MS: t ¼ 3.442 min, m=z (%): 264 (Mþ, 100), 266, (Mþ,
97), 245 (10), 247(10), 214 (17), 216 (17), 185 (13), 157 (24), 137 (22),
87 (15), 62 (15). HRMS (ESI) m=z: calcd. for C9H4BrF3O, [MꢂH]
262.93194, 264.92989; found 262.93200, 264.92996.
Compound 3e
This compound was obtained as light yellow oil. 1H NMR (CDCl3,
300 MHz): d 4.028 (s, 3H), 6.896–6.955 (m, 1H), 7.155 (d, J ¼ 0.90 Hz,
1H), 7.234 (s, 1H), 7.246–7.256 (m, 1H). 13C NMR (CDCl3,
1
150.92 MHz): d 56.02, 108.46, 108.55, 114.28, 118.36 (q, JCF
¼
2
268.64 Hz), 124.75, 127.66, 143.42 (q, JCF ¼ 42.23 Hz), 144.75, 145.79.
19F NMR (CDCl3, 282.4 MHz, CF3COOH as external standard): d
13.128 (s). GC-MS: t ¼ 12.707 min, m=z (%): 216 (Mþ, 100), 201 (33),
197 (11), 186 (8), 173 (41), 145 (37), 125 (10).

2-Trifluoromethylated Benzofurans
727
Procedure for the Synthesis of 2-(2-Chloro-3,3,3-trifluoroprop-1-
enyl)phenol (4a)
t-BuOK (0.336 g, 3 mmol) was added into a solution of 2a (0.528 g,
2 mmol) in 4 mL of DMF. The mixture was stirred at room temperature
for 1 h. Then the reaction mixture was treated with saturated ammonium
chloride solution (30 mL) and extracted with diethyl ether (3 ꢁ 15 mL).
The organic layer was dried with magnesium sulfate and filtered. The sol-
vent was distilled, and the residue was purified by column chromatogra-
phy to obtain 0.112 g of product 4a. It was a mixture of Z–E isomers in a
1
ratio of 79=21 (after purification); light yellow oil. Z isomer: H NMR
(CDCl3, 300 MHz): d 5.112 (s, 1H), 6.808 (d, J ¼ 8.1 Hz, 1H), 7.003 (t,
J ¼ 7.8 Hz, 1H), 7.257 (d, J ¼ 8.7 Hz, 1H), 7.618 (s, 1H), 7.891 (d,
J ¼ 7.8 Hz, 1H). 19F NMR (CDCl3, 282 MHz, CF3COOH as external
1
standard): 9.191 (s). E isomer: H NMR (CDCl3, 300 MHz): d 4.996 (s,
1H), 6.780 (s, 1H), 6.977 (t, J ¼ 8.7 Hz, 1H), 7.187 (d, J ¼ 8.7 Hz, 1H),
7.306 (d, J ¼ 1.5 Hz, 1H). 19F NMR (CDCl3, 282 MHz, CF3COOH as
external standard): 15.149 (s). 13C NMR (CDCl3, 75 MHz) for Z-E mix-
ture: d 115.41, 115.67, 119.04, 119.13, 119.73 (q, 1JC,F ¼ 272.5 Hz), 119.81
2
3
(q, JC,F ¼ 38.4 Hz), 120.22, 125.56 (d, JC,F ¼ 4.5 Hz), 129.79, 130.08,
130.73, 131.32, 132.57, 152.74, 153.95. GC-MS: t ¼ 5.06 min and
5.26 min, m=z 222 (Mþ, 38), 224 (Mþ, 13), 203 (3), 186 (4), 167 (100),
139 (10), 119 (10), 109 (8), 101(8), 89 (13), 63 (10), 39 (7). HRMS (ESI)
m=z: calcd. for C9H6ClF3O, [M ꢂ H] 220.99810, 222.99515; found
220.99824, 222.99531.
Typical Procedure for the Synthesis of Substituted 2-(3,3,3-Trifluoroprop-
1-ynyl)phenols (5)
t-BuOK (30 mmol) was added into a solution of 2 (10 mmol) in 30 mL
of ether. The mixture was stirred at room temperature and monitored
by TLC. After completion, the reaction mixture was treated with sat
aqueous ammonium chloride solution (150 mL) and extracted with diethyl
ether (3 ꢁ 50 mL). The organic layer was dried with magnesium sulfate
and filtered. The solvent was distilled, and the residue was purified by
column chromatography (ether=n-pentane) to give the desired product 5.
Compound 5a
1
This compound was obtained as a light yellow solid. H NMR (CDCl3,
300 MHz): d 5.496 (s, 1H), 6.927–6.988 (m, 2H), 7.361–7.459 (m, 2H).

728
H. Zhou et al.
2
13C NMR (CDCl3, 100 MHz): d 80.68 (q, JC,F ¼ 53.3 Hz), 82.58 (d,
1
3JC,F ¼ 6.0 Hz), 105.29, 113.53 (q, JC,F ¼ 257.5 Hz), 115.83, 120.61,
132.82, 133.27, 158.07. GC-MS m=z : 186 (Mþ, 100), 166 (59), 158
(50), 138 (70), 107 (18), 89 (26), 69 (17), 63 (26), 39 (16), 28 (7). HRMS
(ESI) m=z: calcd. for C9H5F3O, [M ꢂ H] 185.02142; found 185.02199.
Compound 5b
This compound was obtained as light yellow oil. 1H NMR (CDCl3,
300 MHz): d 2.273 (s, 3H), 5.315 (s, 1H), 6.850 (d, J ¼ 8.40 Hz, 1H),
7.167 (dd, J ¼ 8.40 Hz, 1.80 Hz, 1H), 7.281 (s, 1H). 13C NMR (CDCl3,
2
3
75.48 MHz): d 20.54, 81.47 (q, JCF ¼ 45.29 Hz), 82.77 (d, JCF
¼
1
6.79 Hz), 105.06, 113.47 (q, JCF ¼ 257.39 Hz), 116.07, 130.74, 133.29,
134.35, 156.13.
Compound 5c
This compound was obtained as a dark red oil. 1H NMR (CDCl3, 300 MHz):
d 5.474 (s, 1H), 6.912 (d, J¼ 8.70 Hz, 1H), 7.324 (dd, J¼ 8.70 Hz, 2.70 Hz,
1H), 7.420 (d, J¼ 2.70 Hz, 1H). 13C NMR (CDCl3, 75.48 MHz): d 80.87
3
2
1
(d, JCF ¼ 6.79 Hz), 82.38 (q, JCF ¼ 53.59 Hz), 106.88, 113.21 (q, JCF
¼
258.13 Hz), 117.69, 126.13, 132.57, 133.56, 156.80. GC-MS: t ¼ 5.092 min,
m=z (%): 220 (Mþ, 94), 222 (Mþ, 31), 200 (100), 202 (34), 192 (21), 194
(8), 172 (59), 174 (19), 157 (37), 137 (27), 123 (23), 87 (21).
Compound 5d
1
This compound was obtained as a colorless solid. H NMR (CDCl3,
300 MHz): d 5.5253 (s, 1H), 6.8587 (d, J ¼ 8.79 Hz, 1H), 7.4583 (dd,
J ¼ 8.82 Hz, 2.40 Hz, 1H), 7.5632 (d, J ¼ 2.37 Hz, 1H). 13C NMR (CDCl3,
3
2
75.48 MHz): d 80.73 (d, JCF ¼ 6.04 Hz), 82.53 (q, JCF ¼ 53.59 Hz),
1
107.43, 112.89, 113.20 (q, JCF ¼ 258.13 Hz), 118.05, 135.48, 136.41,
157.24. GC-MS: t ¼ 5.678 min, m=z (%): 264 (Mþ, 100), 266 (Mþ, 100),
244 (82), 246 (82), 236 (16), 238 (16), 216 (39), 218 (37), 179 (7), 181
(7), 167 (7), 169 (7), 157 (41), 137 (70), 107 (16), 87 (37), 69 (16), 62 (18).
Compound 5e
1
This compound was obtained as light yellow powder. H NMR (CDCl3,
300 MHz): d 6.0699 (s, 1H), 6.8159 (t, J ¼ 7.92 Hz, 1H), 6.9299 (dd,

2-Trifluoromethylated Benzofurans
729
J ¼ 8.13 Hz, 1.44 Hz, 1H), 7.0322 (dd, J ¼ 7.80 Hz, 1.32 Hz, 1H). 13C
2
NMR (CDCl3, 75.48 MHz): d 56.56, 79.62 (q, JCF ¼ 52.84 Hz), 83.19
3
1
(d, JCF ¼ 6.79 Hz), 105.31, 113.53, 113.66 (q, JCF ¼ 256.63 Hz),
120.40, 125.53, 146.98, 149.00. GC-MS: t ¼ 5.015 min, m=z (%): 216
(Mþ, 100), 197 (21), 186 (6), 173 (9), 167 (17), 153 (9), 145 (76), 138
(17), 125 (29), 119 (17), 99 (18), 91 (11), 75 (17), 69 (12).
Typical Procedure for the Synthesis of Substituted 3-Iodo-2-
(trifluoromethyl)benzofurans (6)
One hundred mg of 5 was dissolved in 1 mL CCl4, then 3 equivalents of
iodine and 3 equivalents of Na2CO3 were added into this solution. It was
flushedwithargon,sealedwithrubber,thenstirredat70ꢀC,andmonitoredby
gas chromatography. When the reactant disappeared, the reaction mixture
was quenched with 2 mL saturated sodium thiosulphate solution, extracted
with ethyl acetate (3ꢁ 3 mL), and filtered through a silica-gel pad. The
filtrate was evaporated and purified by preparative TLC to obtain 6.
Compound 6a
This compound was obtained as a colorless oil. 1H NMR (CDCl3,
300 MHz): d 7.383–7.436 (m, 1H), 7.487–7.565 (m, 3H). 13C NMR (CDCl3,
1
100 MHz): d 66.15, 112.08, 118.08 (q, JC,F ¼ 270.6 Hz), 123.06, 124.57,
2
128.16, 130.08, 142.69 (d, JC,F ¼ 40.2 Hz), 153.89. GC-MS m=z: 312 (Mþ,
100), 293 (8), 262 (8), 185 (11), 157 (28), 137 (23), 107 (11), 87 (8), 62 (7).
Compound 6b
1
This compound was obtained as a colorless solid. H NMR (CDCl3,
400 MHz): d 2.50 (s, 3H), 7.28 (s, 1H), 7.29 (d, J ¼ 8.40Hz, 1H), 7.40
(d, J ¼ 8.40Hz, 1H). 13C NMR (CDCl3, 100.58 MHz): d 21.26, 65.89,
1
111.62, 118.11 (q, JCF ¼ 269.55Hz), 122.58, 129.59, 130.05, 134.47,
2
142.67 (q, JCF ¼ 40.23 Hz), 152.35. GC-MS: t ¼ 7.478 min, m=z (%): 326
(Mþ, 100), 307 (7), 257 (8), 199 (11), 169 (7), 151 (26), 102 (8),75 (6), 51 (5).
Compound 6c
This compound was obtained as a white solid. 1H NMR (CDCl3,
400 MHz): d 7.453–7.482 (m, 2H), 7.502–7.518 (m, 1 H). 13C NMR

730
H. Zhou et al.
1
(CDCl3, 100.58 MHz) d 65.06, 112.91, 117.73 (q, JCF ¼ 270.56 Hz),
2
122.75, 128.63, 130.60, 131.50, 144.05 (q, JCF ¼ 40.23 Hz), 152.28. GC-
MS: t ¼ 8.185 min, m=z (%): 346 (Mþ, 100), 348 (Mþ, 35), 327 (5), 296
(3), 219 (28), 221 (10), 191(20), 193 (7), 173 (5), 156 (32), 141 (5), 105 (5).
Compound 6d
This compound was obtained as a white solid. 1H NMR (CDCl3,
300 MHz): d 7.424 (d, J ¼ 8.70Hz, 1H), 7.591 (dd, J ¼ 8.70 Hz, 1.80 Hz,
1H), 7.672 (d, J ¼ 2.10 Hz, 1H). 13C NMR (CDCl3, 75.48 MHz): d 65.29,
1
114.07, 117.65 (q, JCF ¼ 270.22 Hz), 118.27, 126.27, 131.73, 132.43,
2
144.20 (q, JCF ¼ 40.00 Hz), 153.09. GC-MS: t ¼ 9.017 min, m=z (%): 390
(Mþ, 100), 392 (Mþ, 100), 371 (5), 373 (5), 340 (1), 342 (1), 263 (25), 265
(25), 235 (19), 237 (19), 216 (1), 218 (1), 184 (10), 156 (48), 105 (10), 87 (22).
Compound 6e
This compound was obtained as a white solid. 1H NMR (CDCl3,
300 MHz) d 4.031 (s, 3H), 6.981 (d, J ¼ 7.95Hz, 1H), 7.086 (dd,
J ¼ 8.01 Hz, 0.72 Hz, 1H), 7.3286 (t, J ¼ 8.01 Hz, 1H). 13C NMR (CDCl3,
3
75.48 MHz) d 56.71, 66.66 (d, JCF ¼ 3.02 Hz), 109.96, 115.18, 117.91 (q,
2
1JCF ¼ 270.22 Hz), 125.58, 132.13, 143.16 (q, JCF ¼ 40.76 Hz), 143.93,
145.94. GC-MS: t ¼ 6.019 min, m=z (%): 342 (Mþ, 100), 327 (17), 299
(5), 271 (7), 172 (9), 144 (19), 28 (59).
ACKNOWLEDGMENTS
We thank the National Analytical Research Center of Electrochemistry
and Spectroscopy, Changchun Institute of Applied Chemistry, for
support of this research.
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