Synthesis of 3-trifluoromethylbenzofurans via palladium-catalyzed tandem elimination/annulation of β-chloro-β-(trifluoromethyl)styrenes with 2-halophenols

Article abstract of DOI:10.1055/s-0033-1338560

A palladium-catalyzed tandem elimination and annulation reaction has been developed. In this way, a variety of 3-trifluoromethybenzofurans were prepared in moderate to good yields via tandem reaction of β-chloro-β- (trifluoromethyl)styrenes with 2-iodophe

Full text of DOI:10.1055/s-0033-1338560

PAPER
▌A
paper
Synthesis of 3-Trifluoromethylbenzofurans via Palladium-Catalyzed
Tandem Elimination/Annulation of β-Chloro-β-(trifluoromethyl)styrenes
with 2-Halophenols
Synthesis of 3-Trifluoromethylbenzofurans
Chong Wang, Lian-Hui Chen,* Chen-Liang Deng, Xing-Guo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325027, P. R. of China
Fax +86(577)86689615; E-mail: lhchen@wzu.edu.cn; E-mail: zxg@wzu.edu.cn
Received: 14.09.2013; Accepted after revision: 25.10.2013
lected as a model reaction to screen the optimal reaction
conditions, and the results are summarized in Table 1. Ini-
tially, various palladium catalysts were tested; the results
demonstrated that Pd(OAc)2/PPh3 was more effective
than others, such as Pd(PPh3)4, Pd2(dba)3, and
Pd(MeCN)2Cl2 (Table 1, entries 1–4). Treatment of sub-
strate 1a with 2a in the presence of 10 mol% of Pd(OAc)2,
20 mol% of PPh3, and 2 equivalents of Cs2CO3 in DMF at
140 °C afforded the desired product 3 in 51% yield (entry
4). The configuration of product 3 was unambiguously
confirmed by X-ray single-crystal diffraction analysis
(Figure 1). Subsequently, a variety of phosphine ligands
were examined with the aim of increasing the reaction
yield (entries 5–8). We were pleased to find that the reac-
tion yield increased to 87% using 20 mol% of X-Phos as
ligand (entry 8). It is well known that base played a key
role during the elimination process, and t-BuONa was
used for the dehydrochlorination of 1a.10 However, only
20% yield of cyclization product was obtained although
all starting materials 1a was consumed when t-BuONa
was used as a base (entry 9). Other inorganic bases, such
as K3PO4 and K2CO3 were also less effective than Cs2CO3
(entries 10 and 11). Finally, a series of other solvents, in-
cluding DMSO, MeCN, NMP, and toluene, were evaluat-
Abstract: A palladium-catalyzed tandem elimination and annula-
tion reaction has been developed. In this way, a variety of 3-trifluo-
romethybenzofurans were prepared in moderate to good yields via
tandem reaction of β-chloro-β-(trifluoromethyl)styrenes with 2-io-
dophenols and 2-bromophenols.
Key words: tandem reaction, trifluoromethyl, benzofuran, X-phos,
palladium acetate, cesium carbonate
Benzofurans are an important class of heterocyclic com-
pounds, which are widely present in a great number of bi-
ologically active compounds1 and isolated natural
products.2 Therefore, considerable efforts have been made
to develop efficient strategies for the construction of ben-
zofuran scaffold.3 However, the synthesis of CF3-contain-
ing benzofurans has been scarcely investigated, despite
the medicinal and pharmaceutical advantages imparted by
trifluoromethyl group.4 Traditionally, the direct trifluoro-
methylation of benzofuran with radical or electrophilic re-
agents provided trifluoromethylated benzofuran in low
yield and poor regioselectivity.5 Alternatively, the trans-
formation of synthons containing a CF3 group at the right
position is an effective method to target trifluoromethyl-
ated compounds.6 For example, Oshima and co-workers
prepared 3-trifluoromethylbenzofurans by extended
Pummerer reactions of trifluoromethylketene dithioacetal
monoxide with phenols.7 Konno and co-workers reported
a palladium-catalyzed annulation of 1-aryl-2,2,2-trifluo-
ropropynes with 2-iodophenol for the synthesis of 3-tri-
fluoromethylbenzofurans.8 Recently, we have developed
β-chloro-β-(trifluoromethyl)styrenes 1 as building blocks
CF3
CF3
HO
X
[Pd]/ligand
base
Ar
R
Ar
R
+
Cl
O
1
2
X = I, Br
for the transformation of CF3-containing aromatics.9 In Scheme 1 Synthesis of 3-trifluoromethylbenzofurans
continuation of our interest in the synthesis of trifluoro-
methylated heterocyclics, we wished to prepare CF3-con-
taining benzofuran derivatives from these building
blocks. Herein, we report a practical and efficient synthe-
sis of 3-trifluoromethylbenzofurans by tandem elimina-
tion and subsequent palladium-catalyzed annulation of β-
chloro-β-(trifluoromethyl)styrenes 1 with 2-iodophenols
and 2-bromophenols (Scheme 1).
The reaction of 1-(2-chloro-3,3,3-trifluoroprop-1-en-1-
yl)-4-methylbenzene (1a) with 2-iodophenol (2a) was se-
SYNTHESIS 2013, 45, 000A–000G
Advanced online publication: 21.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
Figure 1 ORTEP diagram of the single-crystal X-ray structure of
compound 3
DOI: 10.1055/s-0033-1338560; Art ID: SS-2013-F0626-OP
© Georg Thieme Verlag Stuttgart · New York

B
C. Wang et al.
PAPER
Table 1 Screening Conditions for the Preparation of 3a
CF3
HO
I
CF3
[Pd], base
ligand
+
Cl
O
1a
2a
3
Entry
Catalyst
Ligand
Base
Solvent
Yield (%)b
1
2
Pd(PPh3)4
Pd2(dba)3
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
t-BuONa
K3PO4
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
MeCN
DMSO
MeCN
NMP
toluene
DMF
38
33
42
51
63
63
31
87
20
10
<5
15
44
<5
13
69
–
3
Pd(MeCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ph3P
4
Ph3P
5
Cy3P
6
dppp
7
S-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
8
9
10
11
12
13
14
15
16c
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Pd] (10 mol%), ligand (20 mol%), and base (2 equiv) in solvent (2 mL) at 140 °C under
N2 atmosphere for 36 h.
b Isolated yield.
c At 120 °C.
ed and found to be less effective than DMF (entries 12– spectively) were conducted smoothly to afford products
15). A lower yield was obtained when the reaction was 10 and 11 in 76% and 45% yield, respectively (entries 7
carried out at 120 °C (entry 16).
and 8). Other aryl olefins, such as biphenyl, naphth-1-yl,
and thiophen-2-yl, were also tolerated well to provide
products in moderate yields (entries 9–11). Subsequently,
the reactions between substrate 1 with cheap 2-bromophe-
nol (2b) were investigated (entries 12–16). The results
demonstrated that both electron-poor and electron-rich
styrenes were also reactive and provide products in mod-
erate to good yields. Methoxy-substituted 1d and 1e, for
instance, reacted with 2-bromophenol (2b) to afford the
corresponding products in 82% and 72% yield, respec-
tively (entries 14 and 15). Substrate 1h bearing trifluoro-
methyl group was converted into product 10 successfully
in 60% yield (entry 16). Finally, various o-bromophenols
bearing different groups were tested. The reaction of sub-
strate 1b with electron-rich 2-bromophenol 2c and 2d
gave products 15 and 16 in 83% and 79% yield, respec-
tively (entries 17 and 18). Substrate 2e and 2f bearing
electron-withdrawing group (CF3 and CN) afforded prod-
ucts 10 and 11 in 52% and 35% yield, respectively (entries
19 and 20).
With the optimized conditions in hand, we next explored
the scope and generality of the annulation. A range of β-
chloro-β-(trifluoromethyl)styrenes and 2-halophenols
were used to investigate the synthesis of 3-trifluorometh-
ylbenzofurans. The results are summarized in Table 2. At
first, the substituents of β-chloro-β-(trifluoromethyl)sty-
renes were investigated. The results indicated that both
electron-deficient and electron-rich styrenes were com-
patible substrates for the tandem reactions and could be
transformed to the corresponding products in moderate to
good yields. For example, (2-chloro-3,3,3-trifluoroprop-
1-en-1-yl)benzene (1b) provided the product in 80% yield
and t-butyl substituted 1c gave a 64% yield (Table 2, en-
tries 1 and 2). Methoxy-substituted 1d and 1e afforded the
corresponding products in 85% and 75% yield, respec-
tively (entries 3 and 4). Substrates bearing a chloro group
provided products 8 and 9 in 78% and 73% yield, respec-
tively (entries 5 and 6). Reactions with substrate 1h and 1i
bearing an electron-withdrawing group (CF3 and CN, re-
Synthesis 2013, 45, A–G
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-Trifluoromethylbenzofurans
C
Table 2 Palladium-Catalyzed Tandem Reaction of β-Chloro-β-(trifluoromethyl)styrenes with 2-Halophenolsa
CF3
Pd(OAc)2 (10 mol%)
HO
CF3
X-Phos (20 mol%)
Ar
R
R
Ar
+
Cs2CO3 (2 equiv)
DMF, 140 °C
Cl
O
X
1
2
Entry
1
Substrate 1
Substrate 2
Product; Yield (%)b
OH
CF3
1b
1c
2a
2a
4; 80
Cl
I
CF3
OH
Cl
2
5; 64
I
CF3
CF3
OH
3
4
5
6
7
8
1d
1e
1f
2a
2a
2a
2a
2a
2a
6; 85
7; 75
Cl
MeO
MeO
I
OH
Cl
CF3
I
OH
8; 78
Cl
Cl
Cl
I
OH
CF3
1g
1h
1i
9; 73
Cl
I
CF3
OH
10; 76
11; 45
Cl
F3C
NC
I
CF3
OH
Cl
I
CF3
OH
Cl
9
1j
2a
2a
12; 50
13; 49
I
CF3
Cl
OH
I
10
1k
CF3
Cl
OH
S
11
12
1l
2a
2b
14; 39
4; 78
I
OH
CF3
1b
Cl
Br
OH
CF3
13
14
1a
1d
2b
2b
3; 82
6; 82
Cl
Br
CF3
OH
Cl
MeO
Br
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–G

D
C. Wang et al.
PAPER
Table 2 Palladium-Catalyzed Tandem Reaction of β-Chloro-β-(trifluoromethyl)styrenes with 2-Halophenolsa (continued)
CF3
Pd(OAc)2 (10 mol%)
HO
CF3
X-Phos (20 mol%)
Ar
R
R
Ar
+
Cs2CO3 (2 equiv)
DMF, 140 °C
Cl
O
X
1
2
Entry
15
Substrate 1
Substrate 2
Product; Yield (%)b
OH
MeO
CF3
1e
2b
7; 72
Cl
Br
CF3
OH
16
17
1h
1b
2b
2c
10; 60
15; 83
Cl
F3C
Br
OH
CF3
Cl
Cl
MeO
Br
OH
CF3
18
1b
2d
16; 79
Br
OH
CF3
CF3
19
20
1b
1b
2e
2f
17; 52
18; 35
Cl
Cl
F3C
NC
Br
OH
Br
a Reaction conditions: 1 (0.2 mmol), 2 (0.24 mmol), Pd(OAc)2 (10 mol%), X-Phos (20 mol%), and Cs2CO3 (2 equiv) in DMF (2 mL) at 140 °C
under N2 atmosphere for 36 h.
b Isolated yield.
To elucidate the mechanism of the transformation, a con- Based on the present results and the reported mechanism,8
trol reaction of 1f was conducted for 36 hours under stan- a possible mechanism is proposed as outlined in Scheme
dard conditions in the absence of 2-halophenol (Scheme 3. Firstly, the dehydrochlorination of substrate 1 affords
2, equation 1). The dehydrochlorination product 19 was 1-aryltrifluoropropynes, followed by Michael-type addi-
isolated in 21% yield and most of the starting material was tion with 2-halophenol 2 to form vinyl ether A. Subse-
recovered. Compound 19 was consumed completely quently, oxidative addition of palladium(0) with vinyl
when treated with 2-iodophenol (2a) under the standard ether A provides complex B, followed by intramolecular
conditions for 12 hours, and the reaction provided the tar- carbopalladation reaction to form complex C. Finally, re-
get product 8 in 84% yield (Scheme 2, equation 2). These ductive elimination of complex C gives the desired 3-tri-
results indicate that the elimination of β-chloro-β-(trifluo- fluoromethylbenzofurans 3–18 and regenerates the
romethyl)styrene was the rate-determining step in the tan- palladium(0) species.
dem reaction.
Pd(OAc)2 (10 mol%)
Cl
X-Phos (20 mol%)
(1)
(2)
Cl
CF3
CF3
Cs2CO3 (2 equiv)
DMF, 140 °C, 36 h
Cl
+
1f
19 21%
CF3
Pd(OAc)2 (10 mol%)
X-Phos (20 mol%)
HO
Cl
CF3
Cl
Cs2CO3 (2 equiv)
DMF, 140 °C, 12 h
I
O
19
2a
8 84%
Scheme 2 Control experiments
Synthesis 2013, 45, A–G
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-Trifluoromethylbenzofurans
E
X
CF3
CF3
Cs2CO3
2
O
Ar
Ar
CF3
H
Cl
Ar
A
1
R3P
Pd(OAc)2
Pd(0)
CF3
PdX
CF3
CF3
Heck
reaction
O
Ar
Cs2CO3
H
Ar
O
PdX
Ar
O
HX, Pd(0)
C
B
3–18
Scheme 3 Possible mechanism
2-Phenyl-3-(trifluoromethyl)benzofuran (4)7
In summary, we have successfully developed a palladium-
catalyzed tandem reaction for the synthesis of 3-trifluoro-
methylbenzofurans. In the presence of Pd(OAc)2, X-Phos,
and Cs2CO3, a broad range of β-chloro-β-(trifluorometh-
yl)styrenes underwent tandem elimination and subsequent
annulation reaction with 2-iodophenols and 2-bromophe-
nols to give the corresponding 3-trifluoromethylbenzofu-
rans in moderate to good yields. This protocol could be
applied as a new strategy for constructing benzofuran ring
as well as a new synthetic application of trifluoromethyl-
containing building blocks.
Yield: 41.9 mg (80%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.83–7.81 (m, 2 H), 7.76 (d,
J = 8.5 Hz, 1 H), 7.55 (d, J = 8.0 Hz, 1 H), 7.50–7.49 (m, 3 H),
7.40–7.32 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 155.8 (q, J = 4.6 Hz), 153.6,
130.3, 128.7, 128.6 (q, JC-F = 1.3 Hz), 128.6, 127.1, 125.6, 124.1,
123.6 (q, JC-F = 266.3 Hz), 120.7, 111.5, 107.5 (q, JC-F = 37.5 Hz).
19F NMR (470 MHz, CDCl3): δ = –55.2 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 262 (M+•, 100), 243 (10), 212 (12),
165 (15), 131 (8).
HRMS (ESI): m/z [M + H]+ calcd for C15H10F3O: 263.0678; found:
263.0669.
Chemicals were either purchased or purified by standard tech-
1
niques. H NMR and 13C NMR spectra were measured on a 500
2-[4-(tert-Butyl)phenyl]-3-(trifluoromethyl)benzofuran (5)
Yield: 40.7 mg (64%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, 3 H), 7.54–
7.51 (m, 3 H), 7.38–7.31 (m, 2 H), 1.37 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 156.1 (q, JC-F = 4.5 Hz), 153.7,
153.6, 128.3, 125.9, 125.8, 125.6, 125.4, 124.0, 123.7 (q, JC-F
270.9 Hz), 120.6, 111.4, 107.5 (q, JC-F = 36.8 Hz), 34.9, 31.2.
19F NMR (470 MHz, CDCl3): δ = –55.1 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 303 (100), 318 (M+•, 49), 275 (27),
MHz spectrometer (1H: 500 MHz, 13C: 125 MHz), using CDCl3 as
the solvent with TMS as an internal standard at r.t. Chemical shifts
are given in δ relative to TMS and the coupling constants J are given
in Hz. 19F NMR spectra were recorded on a 500 MHz spectrometer
(19F: 470 MHz) and are reported relative to the CFCl3 as the internal
standard. High-resolution mass spectra were recorded on a ESI-Q-
TOF mass spectrometer. All reactions were conducted under N2 at-
mosphere using standard Schlenk techniques. Column chromatog-
raphy was performed using EM silica gel 60 (300–400 mesh).
=
138 (22), 152 (6).
HRMS (ESI): m/z [M + H]+ calcd for C19H18F3O: 319.1304; found:
319.1309.
3-Trifluoromethylbenzofurans 3–18; General Procedure
A mixture of β-chloro-β-(trifluoromethyl)styrene 1 (0.2 mmol),
Pd(OAc)2 (4.5 mg, 10 mol%), dicyclohexyl(2′,4′,6′-triisopropylbi-
phenyl-2-yl)phosphine (X-Phos; 19.1 mg, 20 mol%), Cs2CO3
(130.4 mg, 0.4 mmol), and 2-halophenol 2 (0.24 mmol) in DMF (2
mL) was stirred at 140 °C under N2 atmosphere for 36 h, or until
complete consumption of starting material as monitored by TLC
(eluent: hexane) or GC-MS analysis. After completion of the reac-
tion, the mixture was poured into EtOAc (10 mL) and evaporated
under vacuum. The residue was purified by flash column chroma-
tography [petroleum ether (bp 60–90 °C)–EtOAc gradients] to af-
ford the desired products 3–18 (Tables 1 and 2).
2-(4-Methoxyphenyl)-3-(trifluoromethyl)benzofuran (6)8
Yield: 49.5 mg (85%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.77 (d, J = 9.0 Hz, 2 H), 7.73 (d,
J = 7.5 Hz, 1 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.37–7.30 (m, 2 H), 7.01
(d, J = 8.5 Hz, 2 H), 3.88 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 161.2, 156.0 (q, JC-F = 4.6 Hz),
153.4, 130.1, 125.8, 125.2, 123.9, 123.8 (q, JC-F = 266.3 Hz), 121.2,
120.5, 114.1, 111.3, 106.3 (q, JC-F = 37.0 Hz), 55.1.
19F NMR (470 MHz, CDCl3): δ = –55.3 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 292 (M+•, 100), 277 (39), 249 (15),
2-p-Tolyl-3-(trifluoromethyl)benzofuran (3)8
Yield: 48.0 mg (87%); white solid; mp 71.1–73.0 °C.
1H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 1 H), 7.71 (d,
J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.37–7.31 (m, 2 H), 7.29
(d, J = 8.0 Hz, 2 H), 2.41 (s, 3 H).
199 (20), 146 (8).
2-(3-Methoxyphenyl)-3-(trifluoromethyl)benzofuran (7)
Yield: 43.8 mg (75%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.67 (d, J = 7.5 Hz, 1 H), 7.46 (d,
J = 8.0 Hz, 1 H), 7.32–7.23 (m, 5 H), 6.95–6.94 (m, 1 H), 3.78 (s, 3
13C NMR (125 MHz, CDCl3): δ = 156.1 (q, JC-F = 4.6 Hz), 153.6,
140.6, 129.3, 128.5, 125.9, 125.7, 125.3, 124.0, 123.7 (q, JC-F
=
265.0 Hz), 120.6 (q, JC-F = 2.5 Hz), 111.4, 106.9 (q, JC-F = 37.5 Hz),
21.4.
19F NMR (470 MHz, CDCl3): δ = –55.2 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 276 (M+•, 100), 277 (22), 207 (19),
H).
13C NMR (125 MHz, CDCl3): δ = 159.6, 155.6 (q, JC-F = 4.6 Hz),
153.5, 129.9, 129.6, 125.6, 124.1, 123.6 (q, JC-F = 266.5 Hz), 121.1
179 (8), 138 (8).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–G

F
C. Wang et al.
PAPER
(2 C), 120.7 (q, JC-F = 1.8 Hz), 116.4, 113.8, 111.5, 107.6 (q, JC-F
37.0 Hz), 55.4.
=
HRMS (ESI): m/z [M + H]+ calcd for C16H9F3NO: 288.0631; found:
288.0632.
19F NMR (470 MHz, CDCl3): δ = –55.1 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 292 (M+•, 100), 293 (19), 262 (13),
2-(Biphenyl-4-yl)-3-(trifluoromethyl)benzofuran (12)
Yield: 33.8 mg (50%); white solid; mp 53.4–55.2 °C.
1H NMR (500 MHz, CDCl3): δ = 7.89 (d, J = 8.0 Hz, 2 H), 7.76 (d,
J = 7.5 Hz, 1 H), 7.71 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.0 Hz, 2 H),
7.54 (d, J = 8.0 Hz, 1 H), 7.47–7.44 (m, 2 H), 7.39–7.32 (m, 3 H).
201 (8), 146 (8).
HRMS (ESI): m/z [M + H]+ calcd for C16H12F3O2: 293.0784; found:
293.0801.
13C NMR (125 MHz, CDCl3): δ = 155.6 (q, JC-F = 4.8 Hz), 153.6,
143.0, 140.0, 129.0, 128.9, 127.9, 127.5, 127.2, 127.1, 125.7, 125.6,
124.1, 123.7 (q, JC-F = 266.4 Hz), 120.7, 111.4, 107.5 (q, JC-F = 36.8
Hz).
19F NMR (470 MHz, CDCl3): δ = –55.1 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 338 (M+•, 100), 281 (17), 207 (26),
2-(4-Chlorophenyl)-3-(trifluoromethyl)benzofuran (8)8
Yield: 46.2 mg (78%); white solid; mp 77.6–79.4 °C.
1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 7.0 Hz, 3 H), 7.54 (d,
J = 8.5 Hz, 1 H), 7.48–7.46 (m, 2 H), 7.41–7.33 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 154.5 (q, JC-F = 4.5 Hz), 153.7,
136.6, 129.8 (q, JC-F = 2.1 Hz), 128.9, 127.2, 125.8, 125.5, 124.2,
123.5 (q, JC-F = 266.5 Hz), 120.8 (q, JC-F = 1.7 Hz), 111.5, 107.9 (q,
169 (14), 73 (23).
HRMS (ESI): m/z [M + H]+ calcd for C21H14F3O: 339.0991; found:
JC-F = 37.0 Hz).
339.1006.
19F NMR (470 MHz, CDCl3): δ = –55.3 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 296 (M+•, 100, 35Cl), 298 (32, 37Cl),
246 (6), 183 (6), 148 (9).
2-(Naphthalen-1-yl)-3-(trifluoromethyl)benzofuran(13)
Yield: 30.6 mg (49%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 8.03 (d, J = 8.0 Hz, 1 H), 7.94 (d,
J = 8.5 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.77 (d, J = 8.5 Hz, 1 H),
7.70–7.68 (m, 1 H), 7.61–7.51 (m, 4 H), 7.47–7.40 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 155.6 (q, JC-F = 4.4 Hz), 154.3,
133.5, 132.0, 131.1, 129.5 (q, JC-F = 1.4 Hz), 129.3, 128.4, 127.1,
126.4, 125.8, 125.3, 125.1 (q, JC-F = 275.5 Hz), 124.8, 124.1, 122.1,
120.5, 111.7, 110.8 (q, JC-F = 36.3 Hz).
2-(3-Chlorophenyl)-3-(trifluoromethyl)benzofuran (9)8
Yield: 43.2 mg (73%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.82 (s, 1 H), 7.77 (d, J = 7.5 Hz,
1 H), 7.70 (d, J = 7.5 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.48–7.35
(m, 4 H).
13C NMR (125 MHz, CDCl3): δ = 154.0 (q, JC-F = 4.6 Hz), 153.7,
134.7, 130.4, 130.3, 129.9, 128.5 (q, JC-F = 1.8 Hz), 126.8 (q, JC-F
=
19F NMR (470 MHz, CDCl3): δ = –55.1 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 312 (M+•, 100), 165 (63), 193 (25),
2.3 Hz), 126.0, 125.3, 124.3, 123.4 (q, JC-F = 266.5 Hz), 120.9,
111.6, 108.4 (q, JC-F = 37.6 Hz).
83 (17), 320 (16).
HRMS (ESI): m/z [M + H]+ calcd for C19H12F3O: 313.0835; found:
313.0836.
19F NMR (470 MHz, CDCl3): δ = –55.2 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 296 (M+•, 100, 35Cl), 298 (34, 37Cl),
183 (9), 163 (7), 148 (5), 116 (8).
2-(Thiophen-2-yl)-3-(trifluoromethyl)benzofuran (14)
3-(Trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]benzofuran
(10)
Yield: 20.9 mg (39%); white solid; mp 68.2–70.1 °C.
1H NMR (500 MHz, CDCl3): δ = 7.72 (d, J = 7.5 Hz, 1 H), 7.69–
7.68 (m, 1 H), 7.54–7.51 (m, 2 H), 7.38–7.31 (m, 2 H), 7.18–7.16
(m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 153.2, 150.5 (q, JC-F = 4.6 Hz),
130.0, 129.3 (q, JC-F = 3.4 Hz), 129.1, 128.1, 127.6, 125.6, 124.3,
123.6 (q, JC-F = 266.4 Hz), 120.5 (q, JC-F = 8.0 Hz), 111.3, 106.0 (q,
Yield: 50.2 mg (76%); white solid; mp 52.5–53.4 °C.
1H NMR (500 MHz, CDCl3): δ = 7.96 (d, J = 8.5 Hz, 2 H), 7.81–
7.77 (m, 3 H), 7.59 (d, J = 8.0 Hz, 1 H), 7.46–7.43 (m, 1 H), 7.40–
7.37 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 153.9, 147.8, 146.5, 132.0 (q,
JC-F = 27.1 Hz), 128.9, 126.3, 125.6, 124.4, 123.8 (q, JC-F = 270.8
Hz), 121.2 (q, JC-F = 266.6 Hz), 121.0, 120.5, 111.6, 109.0 (q,
J
C-F = 37.4 Hz).
19F NMR (470 MHz, CDCl3): δ = –55.2 (s, 3 F).
JC-F = 34.8 Hz).
19F NMR (470 MHz, CDCl3): δ = –55.3 (s, 3 F), –63.0 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 268 (M+•, 100), 269 (14), 171 (9), 249
LRMS (EI, 70 eV): m/z (%) = 330 (M+•, 100), 201 (17), 182 (8), 214
(4), 68 (4).
(9), 218 (7), 134 (6).
HRMS (ESI): m/z [M + H]+ calcd for C13H7F3OS: 269.0243; found:
HRMS (ESI): m/z [M + H]+ calcd for C16H9F6O: 331.0552; found:
269.0242.
331.0537.
5-Methoxy-2-phenyl-3-(trifluoromethyl)benzofuran (15)
Yield: 48.5 mg (83%); colorless oil.
4-[3-(Trifluoromethyl)benzofuran-2-yl]benzonitrile (11)
Yield: 25.8 mg (45%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.78–7.77 (m, 2 H), 7.47–7.45 (m,
3 H), 7.39 (d, J = 9.0 Hz, 1 H), 7.15 (s, 1 H), 6.96–6.94 (m, 1 H),
3.84 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 156.8, 156.5 (q, JC-F = 4.5 Hz),
148.7, 130.2, 128.9, 128.5, 127.2, 126.2, 123.7 (q, JC-F = 266.4 Hz),
114.7, 112.0, 107.6 (q, JC-F = 36.9 Hz), 102.7, 55.8.
19F NMR (470 MHz, CDCl3): δ = –55.2 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 292 (M+•, 100), 277 (15), 262 (5), 249
1H NMR (500 MHz, CDCl3): δ = 7.87 (d, J = 8.5 Hz, 2 H), 7.72 (d,
J = 8.5 Hz, 3 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.40–7.36 (m, 1 H),
7.33–7.30 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 153.9, 153.0 (q, JC-F = 4.5 Hz),
132.8, 132.3, 129.0 (q, JC-F = 3.9 Hz), 126.6, 125.2, 124.6, 123.2 (q,
JC-F = 266.9 Hz), 121.1 (q, JC-F = 1.8 Hz), 118.1, 113.8, 111.7, 109.6
(q, JC-F = 37.3 Hz).
19F NMR (470 MHz, CDCl3): δ = –55.2 (s, 3 F).
(33), 201 (15), 152 (15).
LRMS (EI, 70 eV): m/z (%) = 287 (M+•, 100), 268 (8), 208 (7), 190
(9), 143 (5).
HRMS (ESI): m/z [M + H]+ calcd for C16H12F3O2: 293.0784; found:
293.0789.
Synthesis 2013, 45, A–G
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 3-Trifluoromethylbenzofurans
G
5-tert-Butyl-2-phenyl-3-(trifluoromethyl)benzofuran (16)
Supporting Information for this article is available online at
Yield: 50.3 mg (79%); colorless oil.
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
1H NMR (500 MHz, CDCl3): δ = 7.80–7.79 (m, 2 H), 7.74 (s, 1 H),
7.49–7.46 (m, 5 H), 1.40 (s, 9 H).
References
13C NMR (125 MHz, CDCl3): δ = 155.9 (q, JC-F = 4.5 Hz), 152.0,
147.4, 130.1, 129.0, 128.6 (q, JC-F = 1.8 Hz), 128.5, 125.3, 123.8 (q,
JC-F = 266.4 Hz), 123.6, 116.7, 110.8, 107.7 (q, JC-F = 36.6 Hz),
34.9, 31.8.
19F NMR (470 MHz, CDCl3): δ = –55.1 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 303 (100), 318 (M+•, 34), 275 (22),
137 (19), 105 (6).
HRMS (ESI): m/z [M + H]+ calcd for C19H18F3O: 319.1304; found:
319.1307.
(1) (a) Takasaki, M. T.; Komatsu, K.; Tokuda, H.; Nishino, H.
Cancer Lett. 2000, 158, 53. (b) Carter, G. A.; Chamberlain,
K.; Wain, R. L. Ann. Appl. Biol. 1978, 88, 57. (c) Cho, J. Y.;
Kim, A. R.; Yoo, E. S.; Baik, K. U.; Park, M. H. A. J. Pharm.
Pharmacol. 1999, 51, 1267.
(2) (a) Ward, R. S. Nat. Prod. Rep. 1990, 7, 349. (b) Ward, R. S.
Nat. Prod. Rep. 1993, 10, 183. (c) Muhammad, I.; Li, X.-C.;
Jacob, M. R.; Tekwani, B. L.; Dunbar, D. C.; Ferreira, D.
J. Nat. Prod. 2003, 66, 804. (d) Navarro, E.; Alonso, S. J.;
Trujillo, J.; Jorge, E.; Perez, C. J. Nat. Prod. 2001, 64, 134.
(e) Zacchino, S.; Rodriguez, G.; Pezzenati, G.; Orellana, G.;
Enriz, R.; Gonzalez, S. M. J. Nat. Prod. 1997, 60, 659.
(f) Banskota, A.; Tezuka, Y.; Midorikawa, K.; Matsushige,
K.; Kadota, S. J. Nat. Prod. 2000, 63, 1277.
2-Phenyl-3,5-bis(trifluoromethyl)benzofuran (17)
Yield: 34.3 mg (52%); white solid; mp 74.4–74.9 °C.
1H NMR (500 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.85–7.83 (m, 2 H),
7.68–7.64 (m, 2 H), 7.54–7.53 (m, 3 H).
(3) (a) Liang, Y.; Tang, S.; Zhang, X.-D.; Mao, L.-Q.; Xie, Y.-
X.; Li, J.-H. Org. Lett. 2006, 8, 3017. (b) Chen, C.; Dormer,
P. G. J. Org. Chem. 2005, 70, 6964. (c) Okitsu, T.;
Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett. 2008, 10,
4967. (d) Sakai, N.; Uchida, N.; Konakahara, T.
13C NMR (125 MHz, CDCl3): δ = 157.8 (q, JC-F = 4.5 Hz), 154.8,
130.9, 128.7, 128.7 (q, JC-F = 2.0 Hz), 128.0, 127.0 (q, JC-F = 32.6
Hz), 125.8, 124.3 (q, JC-F = 270.6 Hz), 123.2 (q, JC-F = 266.6 Hz),
122.7 (q, JC-F = 3.6 Hz), 118.6 (q, JC-F = 2.0 Hz), 112.0, 107.8 (q,
JC-F = 37.5 Hz).
Tetrahedron Lett. 2008, 49, 3437. (e) De Luca, L.;
Giacomelli, G.; Nieddu, G. J. Org. Chem. 2007, 72, 3955.
(f) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am.
Chem. Soc. 2005, 127, 15022. (g) Fürstner, A.; Davies, P.
W. J. Am. Chem. Soc. 2005, 127, 15024. (h) Huang, X. C.;
Liu, Y. L.; Liang, Y.; Pi, S. F.; Wang, F.; Li, J. H. Org. Lett.
2008, 10, 1525. (i) Bates, C. G.; Saejueng, P.; Murphy, J.
M.; Venkataraman, D. Org. Lett. 2002, 4, 4727.
19F NMR (470 MHz, CDCl3): δ = –55.3 (s, 3 F), –63.1 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 330 (M+•, 100), 311 (11), 280 (7), 183
(5), 165 (5).
HRMS (ESI): m/z [M + H]+ calcd for C16H9F6O: 331.0552; found:
331.0560.
2-Phenyl-3-(trifluoromethyl)benzofuran-5-carbonitrile (18)
Yield: 20.1 mg (35%); white solid; mp 101.3–103.4 °C.
(4) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (b) Hagmann, W. K. J. Med.
Chem. 2008, 51, 4359. (c) Muller, K.; Faeh, C.; Diederich,
F. Science 2007, 317, 1881. (d) Schlosser, M. Angew. Chem.
Int. Ed. 2005, 44, 214.
(5) Mejía, E.; Togni, A. ACS Catal. 2012, 2, 521.
(6) Jiang, Z.-X.; Qing, F.-L. J. Fluorine Chem. 2003, 123, 57.
(7) (a) Kobatake, T.; Fujino, D.; Yoshida, S.; Yorimitsu, H.;
Oshima, K. J. Am. Chem. Soc. 2010, 132, 11840.
1H NMR (500 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.81 (d, J = 8.0 Hz,
2 H), 7.67–7.63 (m, 2 H), 7.52 (d, J = 6.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 158.3 (q, JC-F = 4.0 Hz), 155.0,
131.2, 129.1, 128.8, 128.7 (q, JC-F = 1.8 Hz), 127.5, 126.3, 125.8 (q,
JC-F = 1.9 Hz), 122.9 (q, JC-F = 265.6 Hz), 118.6, 112.8, 108.4, 107.4
(q, JC-F = 44.3 Hz).
19F NMR (470 MHz, CDCl3): δ = –55.3 (s, 3 F).
LRMS (EI, 70 eV): m/z (%) = 287 (M+•, 100), 288 (17), 237 (8), 208
(5), 190 (7).
HRMS (ESI): m/z [M + H]+ calcd for C16H9F3NO: 288.0631; found:
288.0633.
(b) Ookubo, Y.; Wakamiya, A.; Yorimitsu, H.; Osuka, A.
Chem. Eur. J. 2012, 18, 12690.
(8) Konno, T.; Chae, J.; Ishihara, T.; Yamanaka, H. Tetrahedron
2004, 60, 11695.
(9) (a) Dong, S.-X.; Zhang, X.-G.; Liu, Q.; Tang, R.-Y.; Zhong,
P.; Li, J.-H. Synthesis 2010, 1521. (b) Li, C.-L.; Zhang, X.-
G.; Tang, R.-Y.; Zhong, P.; Li, J.-H. J. Org. Chem. 2010, 75,
7037. (c) Sun, L.-L.; Liao, Z.-Y.; Tang, R.-Y.; Deng, C.-L.;
Zhang, X.-G. J. Org. Chem. 2012, 77, 2850. (d) Wang, W.-
Y.; Sun, L.-L.; Deng, C.-L.; Tang, R.-Y.; Zhang, X.-G.
Synthesis 2013, 45, 118. (e) Sun, L.-L.; Hu, B. L.; Tang, R.-
Y.; Deng, C.-L.; Zhang, X.-G. Adv. Synth. Catal. 2013, 355,
377.
1-Chloro-4-(3,3,3-trifluoroprop-1-yn-1-yl)benzene (19)11
Yield: 8.6 mg (21%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.49 (d, J = 8.5 Hz, 2 H), 7.38 (d,
J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 137.4, 133.7, 129.2, 117.0, 114.7
(q, JC-F = 255.9 Hz), 85.3, 76.2 (q, JC-F = 52.6 Hz).
(10) Meazza, G.; Capuzzi, L.; Piccardi, P. Synthesis 1989, 331.
(11) Konno, T.; Chae, J.; Kanda, M.; Nagai, G.; Tamura, K.;
Ishihara, T.; Yamanaka, H. Tetrahedron 2003, 59, 7571.
Acknowledgment
We thank the National Natural Science Foundation of China (No.
21002070 and 21272177) for financial support.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–G