CuBr/N,N-dimethylglycine-catalyzed coupling reaction of 2-chlorotrifluoroacetanilides with phenols at mild conditions

Article abstract of DOI:10.1002/cjoc.201090279

The ortho-substituent effect directed by the CF3CONH group exists in CuBr/N,N-dimethylglycine-catalyzed diaryl ether formation from o-chlorotrifluoroacetanilides and phenols, leading to this coupling reaction proceeding at 80 °C to afford a wide range of diaryl ethers. The halogen-exchange also plays an important role in this transformation because adding potassium iodide is essential for complete conversion.

Full text of DOI:10.1002/cjoc.201090279

FULL PAPER
CuBr/N,N-Dimethylglycine-Catalyzed Coupling Reaction of
2-Chlorotrifluoroacetanilides with Phenols at Mild Conditions†
Hao, Chaoa(郝超)
Zhang, Yihua*,a(张奕华)
Ma, Dawei*,b(马大为)
Jiang, Yongwenb(蒋咏文)
a Center of Drug Discovery, China Pharmaceutical University, Nanjing, Jiangsu 210009, China
b State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
The ortho-substituent effect directed by the CF3CONH group exists in CuBr/N,N-dimethylglycine-catalyzed di-
aryl ether formation from o-chlorotrifluoroacetanilides and phenols, leading to this coupling reaction proceeding at
80 ℃ to afford a wide range of diaryl ethers. The halogen-exchange also plays an important role in this transfor-
mation because adding potassium iodide is essential for complete conversion.
Keywords copper, Ullmann reaction, cross-coupling, diaryl ether, 2-chlorotrifluoroacetanilide
Introduction
Table 1 Condition screening for the coupling reaction of
2-chlorotrifluoroacetanilides with phenola
During the past decade enormous efforts have been
directed to the development of relatively mild condi-
tions for typical Ullmann reactions by employing some
special ligands.1 Under the promotion of these ligands,
coupling reactions of aryl iodides and bromides with a
wide range of nucleophiles proceed smoothly at tem-
peratures below 90 ℃.2-4 However, for less expensive
aryl chlorides, ligand-effect has been found less effec-
tive and therefore their coupling reactions with nucleo-
philes still required higher temperatures to complete.5-7
For examples, copper-catalyzed coupling of aryl chlo-
rides and phenols only took place at 120—135 ℃ by
using TMHD5 or (2-pyridyl)acetone6 as the ligand.
We have discovered that there is an ortho-substituent
effect directed by amido groups in copper-catalyzed
diaryl ether formation8 and other related coupling reac-
tions.9 In our previous reports, only aryl bromides and
iodides were examined. In order to check if the same
effect could exist in aryl chlorides involved coupling
reactions, we investigated copper-catalyzed coupling of
2-chlorotrifluoroacetanilides with phenols, and were
pleased that this reaction worked well at 80 ℃ to af-
ford a wide range of 2-trifluoroamido substituted diaryl
ethers. Herein we wish to disclose our results.
NHCOCF3
OH
[Cu], N,N-dimethylglycine
+
Cs2CO3, additive, solvent
Cl
2a
1a
NHCOCF3
O
NH2
O
+
3a
4a
Entry [Cu] Additive
Solvent
T/℃ t/h Yield of 3ab/%
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cu2O
—
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
DMF
DMF
100 27
100 11
100 14
100 12
100 10
40c
79
86
80
11
21
46
82
59
40
98
96
DMSO
NMP
Toluene
1,4-Dioxane 100 10
DME
100 18
90 22
90 11
90 11
90 11
80 25
DMSO
DMSO
DMSO
DMSO
DMSO
10 CuCl
11 CuBr
12 CuBr
a
Reaction conditions: 2-chlorotrifluoroacetanilide (0.5 mmol),
phenol (1.5 mmol), [Cu] (0.1 mmol), N,N-dimethylglycine (0.2
Results and discussion
mmol), additive (0.5 mmol), Cs2CO3 (2 mmol), solvent (2 mL);
c
b isolated yield; 4a was isolated in 14% yield and 1a was recov-
As indicated in Table 1, we selected a reaction of
2-chlorotrifluoroacetanilides with phenol as a model to
ered in 21% yield.
*
E-mail: madw@mail.sioc.ac.cn; zyhtgd@sohu.com
Received May 5, 2010; revised May 28, 2010; accepted June 1, 2010.
Project supported by the National Natural Science Foundation of China (Nos. 20921091 and 20872156).
† Dedicated to the 60th Anniversary of Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.
Chin. J. Chem. 2010, 28, 1645— 1650
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
1645

Hao et al.
FULL PAPER
optimize the reaction conditions. It was found that this
reaction catalyzed by 20 mol% of CuI and 40 mol%
N,N-dimethylglycine in DMF occurred at 100 ℃ .
However, the desired diaryl ether 3a was isolated in
only 40% yield (Entry 1), mainly because of the forma-
tion of a side product 4a and incomplete conversion.
Adding potassium iodide was helpful for this reaction,
as a better yield was obtained in shorter reaction time
and the side product 4a was not observed (Entry 2).
This effect might result from a copper-catalyzed halo-
gen-exchange as described by Buchwald10 and Taille-
fer.11 Changing the solvent to DMSO gave a slightly
improved result (Entry 3), while other solvents showed
less effective than DMSO (Entries 4—7). At 90 ℃, this
reaction still proceeded, but required prolonging the
reaction time to get complete conversion (Entry 8).
Switching the copper salt from CuI to CuCl and Cu2O
provided worse results (Entries 9 and 10). However,
when CuBr was applied, 98% yield of 3a was observed
after 11 h. This result indicated the anion of the copper
salts may play some roles during the coupling reaction,
although the detailed mechanism is not clear. Further
attempts revealed that the CuBr-catalyzed reaction
could complete even at 80 ℃, although a long reaction
time was needed. Based on these results, we chose the
combination of CuBr, N,N-dimethylglycine, KI and
DMSO for further investigations. Under these optimized
conditions, coupling of chlorobenzene or N-(2-chloro-
phenyl)-acetamide with phenol did not produce any di-
phenyl ether, indicating that the ortho-substituent effect
of the CF3CONH group is essential for this lower tem-
perature reaction.
We next examined the reaction scope and limitations
by varying phenols and o-chlorotrifluoroacetanilides,
and the results are summarized in Table 2. Generally,
both electron-rich and electron-deficient phenols were
compatible with these reaction conditions, delivering
the corresponding diaryl ethers with good to excellent
yields (Entries 1—20). Noteworthy is that some steri-
cally hindered phenols, such as 2-substituted phenols
and 2,4,6-trimethylphenol, also worked well to provide
3k—3n in about 70% yield (Entries 10—13). When less
reactive
3-trifluoromethylphenol,
3-acetylphenol,
3-hydroxypyridine, quinolin-5-ol and isoquinolin-5-ol
were employed, increasing reaction temperature to 100
℃ was required for complete conversion (Entries 16—
20). Additionally, it was found that diaryl ether 3v and
3w could be assembled using substituted o-chlorotri-
fluoroacetanilides as the coupling partners (Entries 21
and 22).
Table 2 CuBr/N,N-dimethylglycine-catalyzed coupling reaction of substituted phenols and o-chlorotrifluoroacetanilidesa
NHCOCF3
O
OH
NHCOCF3
Cl
CuBr, N,N-dimethylglycine
Cs2CO3, KI, DMSO, 80 oC
X
+
Y
Y
X
2
1
3
Entry
1
Product
Yieldb/% Entry
Product
Yieldb/% Entry
Product
Yieldb/%
67c
NHCOCF3
O
NHCOCF3
O
NHCOCF3
Me
O
COCH3
94
9
71
17
Me
3b
3r
3j
Me
NHCOCF3
O
NHCOCF3
O
NHCOCF3
O
2
3
4
87
80
78
10
11
12
73
72
68
18
19
20
70c
78c
71c
Me
3k
OMe
N
3s
3c
NHCOCF3 CH(CH3)2
O
NHCOCF3
O
NHCOCF3
O
N
N
tBu
3l
3d
3t
NHCOCF3
O
NHCOCF3 OMe
O
NHCOCF3
O
SMe
3m
3u
3e
NHCOCF3 Me
O
NHCOCF3
O
NHCOCF3
O
5
91
13
70
21
68
Me
3n
Me
Me
3f
3v
Me
1646
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1645— 1650

Coupling Reaction of 2-Chlorotrifluoroacetanilides with Phenols at Mild Conditions
Continued
Yieldb/%
Entry
6
Product
Yieldb/% Entry
Product
Yieldb/% Entry
Product
NHCOCF3
NHCOCF3
O
NHCOCF3
O
O
Me
85
81
82
14
15
16
70
73
22
76
Cl
F
3g
3o
3w
NHCOCF3
O
NHCOCF3
O
7
F
3p
3h
NHCOCF3
O
NHCOCF3
O
Me
CF3
N
69c
Me
8
3q
3i
a Reaction conditions: 2-chlorotrifluoroacetanilide (0.5 mmol), phenol (1.5 mmol), CuBr (0.1 mmol), N,N-dimethylglycine (0.2 mmol), KI
(0.5 mmol), Cs2CO3 (2 mmol), DMSO (2 mL); b isolated yield; c the reaction was carried out at 100 ℃.
Conclusions
2,2,2-Trifluoro-N-(2-p-tolyloxy-phenyl)-acetamide
(3b) 1H NMR (CDCl3, 300 MHz) δ: 8.63 (s, 1H), 8.39
—8.35 (m, 1H), 7.19 (d, J＝8.1 Hz, 2H), 7.10—7.06 (m,
2H), 6.95 (d, J＝8.7 Hz, 2H), 6.83—6.79 (m, 1H), 2.36
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ: 154.54 (q, J＝
37.3 Hz), 153.07, 147.27, 134.52, 130.61 (2C), 126.44,
126.08, 123.33, 120.93, 119.4 (2C), 116.46, 115.66 (q,
J＝287.1 Hz), 20.69; EI-MS m/z: 295 (M＋); EI-HRMS
calcd for C15H12F3NO3 (M＋) 295.0820, found 295.0816.
2,2,2-Trifluoro-N-[2-(4-methoxy-phenoxy)-phen-
yl]-acetamide (3c) 1H NMR (CDCl3, 300 MHz) δ:
8.66 (s, 1H), 8.39—8.36 (m, 1H), 7.10—7.08 (m, 2H),
7.04—7.01 (m, 2H), 6.95—6.91 (m, 2H), 6.76—6.74
(m, 1H), 3.83 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ:
156.79, 154.53 (q, J＝37.2 Hz), 148.32, 147.87, 126.04,
125.94, 122.93, 121.17 (2C), 120.81, 115.65 (q, J＝
287.2 Hz), 115.48 (2C), 115.12, 55.64; EI-＋MS m/z: 311
(M＋); HRMS calcd for C15H12F3NO3 (M ) 311.0769,
found 311.0765.
N-[2-(4-tert-Butyl-phenoxy)-phenyl]-2,2,2-trifluo-
roacetamide (3d) 1H NMR (CDCl3, 300 MHz) δ:
8.62 (s, 1H), 8.40—8.37 (m, 1H), 7.41 (d, J＝9.0 Hz,
2H), 7.16—7.07 (m, 2H), 7.00 (d, J＝8.7 Hz, 2H), 6.87
—6.84 (m, 1H), 1.34 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ: 154.54 (q, J＝37.3 Hz), 152.96, 147.82, 147.08,
126.97 (2C), 126.49, 126.04, 123.40, 120.89, 118.95
(2C), 116.64, 115.65 (q, J＝287.0 Hz), 34.43, 31.41
(3C); EI-MS m＋/z: 337 (M ＋ ); EI-HRMS calcd for
C18H18F3NO2 (M ) 337.1290, found 337.1288.
In conclusion, we have discovered that copper-
catalyzed coupling reaction of o-chlorotrifluoroacet-
anilides with phenols completed at 80 ℃ to provide
diverse 2-trifluoroamido substituted diaryl ethers. Both
ortho-substituent effect directed by the CF3CONH
group and halogen-exchange play key roles for these
relatively mild conditions. The products described here
should be useful for synthesis of dibenzo[b,f][1,4]-
oxazepin-11(10H)-ones, a class of heterocycles that are
important for pharmaceutical design.12
Expermental
General procedure for CuBr/N,N-dimethylglycine-
catalyzed coupling reaction of 2-chlorotrifluoro-
acetanilide and phenol
A Schlenk tube was charged with 2-chlorotrifluoro-
acetanilide (0.5 mmol), phenol (1.5 mmol), CuBr (0.1
mmol), N,N-dimethylglycine (0.2 mmol), Cs2CO3 (2
mmol), KI (0.5 mmol) and 2 mL of DMSO, evacuated
and backfilled with argon. The reaction mixture was
stirred at 80 ℃ until the conversion was completed
(detected by TLC). The cooled reaction mixture was
partitioned between ethyl acetate and water. The organic
layer was washed with water, brine, and dried over
Na2SO4, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to
provide the desired product.
2,2,2-Trifluoro-N-[2-(4-methylsulfanyl-phenoxy)-
phenyl]-acetamide (3e) 1H NMR (CDCl3, 300 MHz)
δ: 8.49 (s, 1H), 8.30—8.27 (m, 1H), 7.20 (d, J＝8.7 Hz,
2H), 7.05—7.02 (m, 2H), 6.92 (d, J＝8.7 Hz, 2H), 6.76
—6.73 (m, 1H), 2.40 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ: 154.54 (q, J＝39.2 Hz), 153.17, 146.86, 134.54,
128.90 (2C), 126.48, 126.14, 123.72, 121.06, 120.08
(2C), 116.61, 115.59 (q, J＝288.4 Hz), 16.68; EI-MS
m/z: 327 (M＋); EI-HRMS calcd for C15H12F3NO2S (M＋)
327.0541, found 327.0544.
2,2,2-Trifluoro-N-(2-phenoxyphenyl)acetamide
(3a) 1H NMR (CDCl3, 400 MHz) δ: 8.57 (s, 1H), 8.39
(dd, J1＝2.0 Hz, J2＝7.6 Hz, 1H), 7.40 (t, J＝8.0 Hz,
2H), 7,21 (t, J＝7.6 Hz, 1H), 7.17—7.10 (m, 2H), 7.06
(d, J＝8.0 Hz, 2H), 6.86 (dd, J1＝2.0 Hz, J2＝7.6 Hz,
1H); 13C NMR (CDCl3, 100 MHz) δ: 155.53, 154.61 (q,
J＝37.1 Hz), 146.87, 130.21 (2C), 126.71, 126.22,
124.78, 123.77, 121.13, 119.36 (2C), 117.05, 115.68 (q,
J＝287.1 Hz); EI-MS m/z: 281 (M＋).
Chin. J. Chem. 2010, 28, 1645— 1650
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1647

Hao et al.
FULL PAPER
2,2,2-Trifluoro-N-[2-(naphthalen-2-yloxy)-phen-
(M＋) 295.0820, found 295.0817.
2,2,2-Trifluoro-N-[2-(2-isopropyl-phenoxy)-phen-
yl]-acetamide (3l) 1H NMR (CDCl3, 300 MHz) δ:
yl]-acetamide (3f) 1H NMR (CDCl3, 300 MHz) δ:
8.65 (s, 1H), 8.42 (dd, J1＝1.5 Hz, J2＝7.5 Hz, 1H),
7.87 (t, J＝9.0 Hz, 2H), 7.74 (d, J＝7.2 Hz, 1H), 7.52—
8.69 (s, 1H), 8.42—8.39 (m, 1H), 7.42—7.39 (m, 1H),
7.41 (m, 3H), 7.26 (dd, J1＝2.4 Hz, J2＝9.0 Hz, 1H),
7.24—7.20 (m, 2H), 7.12—7.09 (m, 2H), 6.94—6.91
7.22—7.08 (m, 2H), 6.89 (dd, J1＝1.5 Hz, J2＝9.0 Hz,
(m, 1H), 6.73—6.69 (m, 1H), 3.25—3.11 (m, 1H), 1.24
1H); 13C NMR (CDCl3, 100 MHz) δ: 154.63 (q, J＝37.4
Hz), 153.16, 146.81, 134.18, 130.82, 130.48, 127.87,
127.31, 126.99, 126.78, 126.24, 125.52, 123.94, 121.16,
119.54, 117.29, 115.65 (q, J＝287.1 Hz), 115.32; EI-
MS m/z: 331 (M＋); EI-HRMS calcd for C18H12F3NO2
(M＋) 331.0820, found 331.0813.
(d, J＝6.6 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ:
154.52 (q, J＝37.2 Hz), 151.96, 147.40, 140.28, 127.45,
127.24, 126.09, 125.99, 125.51, 123.01, 120.82, 119.98,
115.39, 115.61 (q, J＝287.2 Hz), 27.25, 22.95 (2C);
EI-MS m/z: 323 (M＋); EI-HRMS calcd for C17H16-
F3NO2 (M＋) 323.1133, found 323.1135.
2,2,2-Trifluoro-N-(2-m-tolyloxy-phenyl)-acetamide
2,2,2-Trifluoro-N-[2-(2-methoxy-phenoxy)-phen-
(3g) 1H NMR (CDCl3, 300 MHz) δ: 8.51 (s, 1H), 8.32
yl]-acetamide (3m) 1H NMR (CDCl3, 300 MHz) δ:
—8.28 (m, 1H), 7.19 (t, J＝7.8 Hz, 1H), 7.05—7.02 (m,
8.94 (s, 1H), 8.35 (d, J＝8.4 Hz, 1H), 7.25—6.96 (m,
for C15H12F3NO3 (M ) 311.0769, found 311.0767.
2H), 6.93 (d, J＝7.5 Hz, 1H), 6.7＋9 (m, 2H), 6.76 (s, 1H),
2.27 (s, 3H); EI-MS m/z: 295 (M ); EI-HRMS calcd for
C15H12F3NO2 (M＋) 295.0820, found 295.0822.
6H), 6.82 (d, J＝7.5 Hz, 1H), 3.80 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ: 154.55 (q, J＝37.1 Hz), 151.34,
147.56, 143.87, 126.30, 126.25, 125.86, 123.31, 122.16,
121.15, 120.81, 116.10, 115.71 (q, J ＝ 287.7 Hz),
112.69, 55.71; EI-M＋S m/z: 311 (M＋); EI-HRMS calcd
2,2,2-Trifluoro-N-[2-(3-isopropyl-phenoxy)-phen-
yl]-acetamide (3h)8 1H NMR (CDCl3, 300 MHz) δ:
8.66 (s, 1H), 8.43—8.40 (m, 1H), 7.34 (t, J＝8.1 Hz,
1H), 7.16—7.10 (m, 3H), 7.00 (s, 1H), 6.91—6.88 (m,
2,2,2-Trifluoro-N-[2-(2,4,6-trimethyl-phenoxy)-
2H), 2.99—2.90 (m, 1H), 1.29 (d, J＝6.9 Hz, 6H); 13C
phenyl]-acetamide (3n) 1H NMR (CDCl3, 300 MHz)
NMR (CDCl3, 100 MHz) δ: 155.42, 154.77 (q, J＝37.3
δ: 8.80 (s, 1H), 8.39 (d, J＝9.0 Hz, 1H), 7.03—7.01 (m,
Hz), 151.71, 147.03, 129.93, 126.55, 126.12, 123.48,
2H), 6.94 (s, 2H), 6.42 (d, J＝9.0 Hz, 1H), 2.32 (s, 3H),
122.97, 121.02, 117.56, 116.78, 116.63, 115.65 (q, J＋＝
287.1 Hz), 34.06, 23.81 (2C); EI-MS m＋/z: 323 (M );
EI-HRMS calcd for C17H16F3NO2 (M ) 323.1133,
found 323.1137.
2.07 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ: 154.48 (q,
J＝37.8 Hz), 147.87, 146.53, 135.46, 130.62 (2C),
129.88 (2C), 126.01, 124.65, 121.98, 120.51, 120.05,
115.63 (q, J＝284.4 Hz), 20.78, 16.05 (2C); EI-MS m＋/z:
323 (M＋ ); EI-HRMS calcd for C17H16F3NO2 (M )
323.1133, found 323.1131.
N-[2-(3-Dimethylamino-phenoxy)-phenyl]-2,2,2-
trifluoro-acetamide (3i) 1H NMR (CDCl3, 300 MHz)
δ: 8.63 (s, 1H), 8.39—8.36 (m, 1H), 7.22 (t, J＝9.0 Hz,
N-[2-(4-Chloro-phenoxy)-phenyl]-2,2,2-trifluoro-
1H), 7.13—7.09 (m, 2H), 6.91—6.88 (m, 1H ), 6.55 (d,
acetamide (3o) 1H NMR (CDCl3, 300 MHz) δ: 8.54
J＝8.1 Hz, 1H), 6.42 (s, 1H), 6.36 (d, J＝7.8 Hz, 1H),
(s, 1H), 8.38—8.35 (m, 1H), 7.35 (d, J＝8.1 Hz, 2H),
2.96 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ: 156.44,
7.16—7.13 (m, 2H), 7.01 (d, J＝9.0 Hz, 2H), 6.86—
154.54 (q, J＝36.9 Hz), 152.19, 147.04, 130.31, 126.48,
126.02, 123.29, 120.78, 116.89, 115.63 (q, J＝287.2
Hz), 108.82, 106.83, 103.46, 40.40 (2C); EI-MS m/z:
324 (M＋); EI-HRMS calcd for C16H15F3N2O2 (M＋)
324.1086, found 324.1084.
6.83 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ: 154.56 (q,
J＝37.4 Hz), 154.03, 146.46, 130.18 (2C), 129.97,
126.63, 126.25, 124.14, 121.26, 120.59 (2C), 116.＋91,
115.55 (q, J＝287.5 Hz); EI-MS m/z: 315 (M );
EI-HRMS calcd for C14H9ClF3NO2 (M＋ ) 315.0274,
found 315.0278.
N-[2-(3,5-Dimethyl-phenoxy)-phenyl]-2,2,2-trifluo-
roacetamide (3j) 1H NMR (CDCl3, 300 MHz) δ: 8.65
2,2,2-Trifluoro-N-(2-(4-fluorophenoxy)phenyl)-
(s, 1H), 8.43—8.40 (m, 1H), 7.16—7.13 (m, 2H), 6.91
acetamide (3p) 1H NMR (CDCl3, 300 MHz) δ: 8.58
—6.87 (m, 2H), 6.72 (s, 2H), 2.34 (s, 6H); 13C NMR
(CDCl3, 100 MHz) δ: 155.47, 154.53 (q, J＝32.6 Hz),
146.95, 140.13 (2C), 126.66, 126.41, 126.09, 123.48,
120.90, 117.08, 116.93 (2C), 11＋5.65 (q, J＝286.5 Hz),
21.22 (2C); EI-MS m/z: 309 (M ); EI-HRMS calcd for
(s, 1H), 8.40—8.36 (m, 1H), 7.17—7.02 (m, 6H), 6.81
—6.77 (m, 1H); EI-MS m/z: 299 (M＋); EI-HRMS calcd
for C14H9F4NO2 (M＋) 299.0569, found 299.0566.
2,2,2-Trifluoro-N-[2-(3-trifluoromethyl-phenoxy)-
phenyl]-acetamide (3q) 1H NMR (CDCl3, 300 MHz)
C16H14F3NO2 (M＋) 309.0977, found 309.0969.
δ: 8.50 (s, 1H), 8.40 (dd, J1＝2.1 Hz, J2＝7.5 Hz, 1H),
2,2,2-Trifluoro-N-(2-(o-tolyloxy)phenyl)acetamide
7.56—7.46 (m, 2H), 7.35 (s, 1H), 7.26—7.15 (m, 3H),
(3k) 1H NMR (CDCl3, 300 MHz) δ: 8.69 (s, 1H), 8.41
6.90—6.87 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ:
—8.38 (m, 1H), 7.30 (d, J＝76.9 Hz, 1H), 7.25—7.14
155.87, 154.67 (q, J＝39.2 Hz), 146.00, 132.76 (q, J＝
(m, 2H), 7.12—7.04 (m, 2H), 6.96 (d, J＝7.8 Hz, 1H),
33.4 Hz), 130.83, 126.83, 126.43, 124.62, 123.42 (q,
6.66—6.63 (m, 1H), 2.22 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ: 154.54 (q, J＝37.5 Hz), 152.84, 147.04,
131.87, 130.09, 127.58, 126.08, 125.77, 125.38, 122.93,
120.84, 120.22, 115.67 (q, J＝287.3 Hz), 115.02, 15.96;
EI-MS m/z: 295 (M＋); HRMS calcd for C15H12F3NO2
J＝271.1 Hz), 122.29, 121.54, 121.36 (q, J＝3.8 Hz),
117.32, 116.18 (q, J＋＝4.3 Hz), 115.30 (q, J＝287.2 Hz);
EI-MS m/z: 349 (M ); EI-HRMS calcd for C15H9F6NO2
(M＋) 349.0537, found 349.0533.
N-[2-(3-Acetyl-phenoxy)-phenyl]-2,2,2-trifluoro-
1648
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1645— 1650

Coupling Reaction of 2-Chlorotrifluoroacetanilides with Phenols at Mild Conditions
acetamide (3r) 1H NMR (CDCl3, 300 MHz) δ: 8.65 (s,
154.67 (q, J＝37.5 Hz), 153.42, 142.41 (d, J＝3.4 Hz),
1H), 8.37—8.34 (m, 1H), 7.79 (d, J＝7.8 Hz, 1H), 7.66
134.09, 130.74, 130.61, 127.87, 127.72 (d, J＝12.0 Hz),
(s, 1H), 7.51 (t, J＝7.8 Hz, 1H), 7.30—7.27 (m, 1H),
127.27, 127.08, 125.56, 119.07, 118.58 (d, J＝9.3 Hz),
7.20—7.12 (m, 2H), 6.87—6.84 (m, 1H), 2.60 (s, 3H);
115.39 (q, J＝287.0 Hz), 114.62, 112.51 (d, J＝23.5
13C NMR (CDCl3, 100 MHz) δ: 196.98, 155.91, 154.57
(q, J＝37.0 Hz), 146.42, 139.19, 130.42, 126.69, 126.38,
124.63, 124.24, 123.78, 121.50, 118.60, 117.12, ＋115.56
(q, J＝287.3 Hz), 26.36; EI-MS m/z: 323 (M ); EI-
HRMS calcd for C16H12F3NO3 (M＋) 323.0769, found
323.0768.
Hz), 108.63 (d, J＝29.8 Hz); EI-MS＋m/z: 349 (M＋); EI-
HRMS calcd for C18H11F4NO2 (M ) 349.0726, found
349.0729.
References
1
For Cu-catalyzed coupling reaction reviews, see:
(a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009,
48, 6954.
2,2,2-Trifluoro-N-[2-(pyridin-3-yloxy)-phenyl]-
acetamide (3s) 1H NMR (CDCl3, 300 MHz) δ: 8.75 (s,
1H), 8.47 (s, 2H), 8.34 (d, J＝7.2 Hz, 1H), 7.37—7.38
(m, 2H), 7.23—7.14 (m, 2H), 6.86 (d, J＝7.5 Hz, 1H);
13C NMR (CDCl3, 100 MHz) δ: 154.72 (q, J＝37.5 Hz),
152.27, 146.37, 145.72, 141.66, 126.66, 126.56, 126.36,
124.58, 124.47, 121.95, 116.96, 115.56 (q, J＝287 Hz);
EI-MS m/z: 282 (M＋); EI-HRMS calcd for C13H9F3-
N2O2 (M＋) 282.0605, found 282.0615.
(b) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2008,
47, 3096.
(c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008,
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2,2,2-Trifluoro-N-[2-(quinolin-5-yloxy)-phenyl]-
acetamide (3t) 1H NMR (CDCl3, 300 MHz) δ: 8.99—
8.98 (m, 1H), 8.76 (s, 1H), 8.43 (t, J＝6.9 Hz, 2H), 7.99
(d, J＝8.4 Hz, 1H), 7.66 (t, J＝8.4 Hz, 1H), 7.46 (dd,
J1＝4.5 Hz, J2＝8.4 Hz, 1H), 7.23—7.06 (m, 3H), 6.79
(d, J＝8.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ:
154.71 (q, J＝37.5 Hz), 151.24, 151.20, 150.87, 149.16,
146.99, 130.12, 129.20, 126.54, 126.43, 126.19, 124.33,
121.58, 121.50, 117.09, 115＋.56 (q, J ＝ 287.1 Hz),
114.53; EI-MS m/z: 332 (M ); EI-HRMS calcd for
C17H11F3N2O2 (M＋) 332.0773, found 332.0776.
2
For selected examples for copper-catalyzed C-N coupling:
(a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793.
(b) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70,
5164.
(c) Cristau, H.-J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.;
Taillefer, M. Eur. J. Org. Chem. 2004, 695.
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2849.
(e) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
8742.
2,2,2-Trifluoro-N-(2-(isoquinolin-5-yloxy)phenyl)-
acetamide (3u) 1H NMR (CDCl3, 300 MHz) δ: 9.35
(s, 1H), 8.78 (s, 1H), 8.59 (s, 1H), 8.42 (d, J＝7.8 Hz,
1H), 7.87—7.84 (m, 2H), 7.58 (t, J＝7.5 Hz, 1H), 7.27
—7.20 (m, 2H), 7.14 (t, J＝7.5 Hz, 1H), 6.80 (d, J＝8.1
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ: 154.74 (q, J＝
37.2 Hz), 152.34, 152.33, 150.47, 146.77, 143.53,
129.21, 129.20, 127.36, 126.57, 124.48, 124.20, 121.75,
118.06, 117.19, 115.54 (q, J＝287.2 Hz), 114.31; EI-
MS m/z: 332 (M＋); EI-HRMS calcd for C17H11F3N2O2
(M＋) 332.0773, found 332.0769.
(f) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007,
72, 672.
3
For selected examples for copper-catalyzed C-O coupling:
(a) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L.
Org. Lett. 2002, 4, 973.
(b) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
(c) Cristau, H.-J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.;
Taillefer, M. Org. Lett. 2004, 6, 913.
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2,2,2-Trifluoro-N-(5-methyl-2-p-tolyloxy-phenyl)-
acetamide (3v) 1H NMR (CDCl3, 300 Hz) δ: 8.52 (s,
1H), 8.23 (d, J＝8.4 Hz, 1H), 7.19 (d, J＝8.1 Hz, 2H),
6.96—6.91 (m, 3H), 6.62 (s, 1H), 2.37 (s, 3H), 2.25 (s,
3H); 13C NMR (CDCl3, 100 MHz) δ: 156.81, 154.52 (q,
J＝37.2 Hz), 148.37, 147.85, 126.02, 126.00, 122.96,
121.11 (2C), 120.82, 115.65 (q, J＝287.2 Hz), 115.＋54,
115.14 (2C), 55.64 (2C); EI-MS ＋m/z: 309 (M );
EI-HRMS calcd for C16H14F3NO2 (M ) 309.0977, found
309.0973.
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(b) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org.
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2,2,2-Trifluoro-N-(5-fluoro-2-(naphthalen-2-yl-
oxy)-phenyl)acetamide (3w) 1H NMR (CDCl3, 300
MHz) δ: 8.63 (s, 1H), 8.27 (dd, J1＝2.4 Hz, J2＝9.6 Hz,
1H), 7.88 (t, J＝9.3 Hz, 2H), 7.74 (d, J＝7.2 Hz, 1H),
7.54—7.45 (m, 2H), 7.36 (d, J＝2.1 Hz, 1H), 7.25 (dd,
J1＝2.4 Hz, J2＝6.3 Hz, 1H), 6.92—6.81 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ: 158.37 (d, J＝241.5 Hz),
7
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Chin. J. Chem. 2010, 28, 1645— 1650
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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FULL PAPER
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1650
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© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2010, 28, 1645— 1650