Facile synthesis of trifluoroethyl aryl ethers through copper-catalyzed coupling of CF3CH2OH with aryl- and heteroaryl boronic acids

Article abstract of DOI:10.1016/j.tetlet.2015.06.066

An efficient copper-catalyzed Chan-Lam reaction of trifluoroethanol with a variety of aryl- and heteroaryl boronic acids has been developed. This research provides a practical method to synthesize trifluoroethyl aryl ethers in moderate to good yields under mild conditions.

Full text of DOI:10.1016/j.tetlet.2015.06.066

Tetrahedron Letters 56 (2015) 4815–4818
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of trifluoroethyl aryl ethers through
copper-catalyzed coupling of CF3CH2OH with aryl- and heteroaryl
boronic acids
a
b,d,
Ruixin Wang a, Liang Wang a, Kena Zhang a, Jingya Li b,c, Dapeng Zou a, , Yangjie Wu , Yusheng Wu
⇑
⇑
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450052, PR China
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China
c Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou 450052, PR China
d Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient copper-catalyzed Chan–Lam reaction of trifluoroethanol with a variety of aryl- and heteroaryl
boronic acids has been developed. This research provides a practical method to synthesize trifluoroethyl
aryl ethers in moderate to good yields under mild conditions.
Received 13 May 2015
Revised 21 June 2015
Accepted 22 June 2015
Available online 26 June 2015
Ó 2015 Published by Elsevier Ltd.
Keywords:
Trifluoroethyl aryl ether derivatives
Chan–Lam coupling reaction
Arylboronic acids
Introduction
F3C
F3C
O
O
O
N
HN
S
F
H
N
The inimitable nature of the fluorine atom, such as strong elec-
tronegativity, small size and the low polarizability of the C–F bond,
has remarkably altered the properties of organic molecules.1 Due
to some desirable properties of organo-fluorine compounds, it
has stimulated an enormous amount of research to selectively
and practically incorporate fluorine into complex organic
molecules.2
F
F
N
H
O
CF3
O
Me
Lansoprazole
O
Fluroxene
Flecainide
Figure 1. Examples of drugs with the trifluoroethoxy moiety.
In recent years, trifluoroethoxy compounds have absorbed more
attention as pharmaceuticals and polymer materials. Some studies
have demonstrated that trifluoroethoxy group can bring metabolic
stability and lipophilicity,3 so CF3CH2O-group could be very
important in the design of bioactive molecules.4 The drugs
Fluroxene, Flecainide, and Lansoprazole,5 are some examples
(Fig. 1). Moreover, new studies suggested that some hydrolytically
sensitive polymers serving as potential biomedical materials
contained CF3CH2O-group.6 Trifluoroethoxy-substituted materials
have shown promise as highly ionic conductive and low water
permeation polymers,7 and trifluoroethoxy-coated phthalocya-
nine-fullerene will likely be useful in the construction of novel
electron communication network systems.8
Traditional approaches to obtain 2,2,2-trifluoroethyl aryl ethers
employed the following methods: (1) the reaction of an haloalkyl
fluoride,9 or a fluoroalkyl sulfonate10 with a nucleophilic phenol
or phenoxide; (2) the substitution of activated aryl and heteroaryl
halides or nitroarenes with 2,2,2-trifluoroethoxide anion;11 (3) the
reaction of 2,2,2-trifluorodiazoethane with phenol.12 These
approaches usually need activated substrates, harsh reaction con-
ditions such as elevated temperatures, DMSO, or toxic solvent
HMPA, and have limited applicability. It is worth to notice that
Suzuki and co-workers reported copper-assisted synthesis of
aryl 2,2,2-trifluoroethyl ethers from aryl iodides and sodium
2,2,2-trifluoroethoxide13, soon after Brandsma and co-workers
reported copper-catalyzed alkoxydehalogenation of non-activated
aryl chlorides with 2,2,2-trifluoroethoxide anion.14 More recently,
Vuluga and co-workers have reported copper-catalyzed synthesis
of trifluoroethyl aryl ethers from aryl halides and trifluo-
toethanol.15 For synthesis of alkyl aryl ethers, the copper-mediated
⇑
Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327.
E-mail addresses: zdp@zzu.edu.cn (D. Zou), yusheng.wu@tetranovglobal.com
(Y. Wu).
http://dx.doi.org/10.1016/j.tetlet.2015.06.066
0040-4039/Ó 2015 Published by Elsevier Ltd.

4816
R. Wang et al. / Tetrahedron Letters 56 (2015) 4815–4818
Ullmann ether synthesis is an alternative to palladium-catalyzed
etherification, which typically requires expensive palladium, and
noncommercial and highly oxophilic phosphine ligands.
However, the Ullmann-type coupling reactions also have some
inherent limitations, such as the need for stoichiometric quantities
of the copper salt, high reaction temperatures, and a large amount
of strong alkoxide base.16 During the past few years, chemists have
taken considerable efforts to modify the Ullmann etherification in
order to overcome these drawbacks.17
Since independent reports by the groups of Chan, Evans and
Lam in 1998, Chan–Lam-type reaction has been one of the most
important copper-promoted oxidative coupling reactions18 for
the synthesis alkyl aryl ethers using boronic acids at lower temper-
atures.19 Although Batey and co-worker have reported the coupling
reaction of potassium aryltrifluoroborate with trifluoroethanol,20
long reaction times and an excess of molecular sieves were
required. Thus, the quest for an efficient and practical trifluo-
roethoxylation method is still a worthy objective. Herein, we
report a practical method using copper-catalyzed Chan–Lam reac-
tion to synthesize trifluoroethyl aryl ethers in moderate to good
yields. The etherification processes conducted under mild condi-
tions using 2,2,2-trifluoroethanol as the reactant and solvent, gen-
erally completes within 1 h at or below 40 °C and the products are
easily isolated.
(Table 1, entries 1–3). The results are in accordance with Stahl’s
research21 that Chan–Lam type reaction is a copper-catalyzed aer-
obic oxidative coupling, so the further studies were carried out
under O2 atmosphere. Several organic bases or inorganic bases
such as NEt3, pyridine, t-BuOK, KOAc, NaOH, KF, CsF, Cs2CO3, and
K2CO3, were examined and gave moderate yields (Table 1, entries
3–11). Evans and co-workers18b have speculated the base could
play a dual role as a base and as a participating ligand with a
possible organocopper species in the reaction. Thus, we
attempted to add 2 equiv of DMAP into the reaction system
without other bases. To our delight, the reaction yield has been
significantly improved (Table 1, entry 12). Furthermore,
decreasing or increasing the amount of DMAP, led to slightly
declined yields (Table 1, entries 13 and 14). The combination of
DMAP with other ligands such as
L-proline, glycine, 1,10-
phenanthroline, and 2,20-bipyridine all led to lower yields
(Table 1, entries 15–19). So the use of 2 equiv DMAP was the key
factor for the success of the reaction.
The further goal of our study was to evaluate the effects of dif-
ferent copper sources, temperature, and reaction time. For the
Chan–Lam modifications of the Ullmann condensation reaction,
lots of the researchers selected Cu(OAc)2 as an optimal CuII
source.22 Other copper sources, such as metal Cu, CuI, Cu2O,
CuBr, CuBr2, CuCl2, and Cu(NO3)2 were investigated for the cou-
pling reaction in the presence of DMAP and they all gave only mod-
erate yields (Table 2, entries 1–7). Cu(OAc)2ꢀH2O has been proven
more effective under the same condition (Table 2, entry 8). Next,
the reaction time was optimized as 1 h (Table 2, entries 8–11).
Finally, decreasing the reaction temperature from 70 to 40 °C led
to higher yields (Table 2, entries 10, 12–14) although when the
reaction was performed at 30 °C the yield dropped (Table 2, entries
15). The combination of Cu(OAc)2ꢀH2O as catalyst and DMAP as the
base and ligand in trifluoroethanol at 40 °C for 1 h under O2 atmo-
sphere was the optimal condition for the trifluoroethoxylation
reaction of arylboronic acids.
Results and discussion
In preliminary studies, the reaction of 2-naphthyl boronic acid
with CF3CH2OH was chosen as a model reaction for optimization
(Table 1). Performing the reaction under an atmosphere of O2 gen-
erally gave higher yields over those obtained under Ar or air
Table 1
Screenings of bases and ligands in the cross-coupling of 2-naphthyl boronic acid with
With the established optimal parameters, we initiated our
study to explore the scope of aryl boronic acids for this reaction
and the results are shown in Table 3. Noteworthily, various aryl
boronic acids containing useful functional groups reacted
2,2,2-trifluoroethanola
OH
O
CF3
Cu(OAc)2·H2O/Ligand
base 70oC O2 6h
B
OH
HO
CF3
+
2
3
1
Table 2
Entry
Base
Ligand
Yieldb (%)
Screening of the other reaction conditions for the cross-coupling of 2-naphthyl
boronic acid with 2,2,2-trifluoroethanola
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Pyridine
t-BuOK
KOAc
NaOH
KF
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
—
19c
43d
56
58
48
54
56
46
37
OH
O
CF3
B
Catalyst/DMAP
Temp O2 Time
OH
HO
CF3
+
2
1
3
Entry
Catalyst
T (°C)
Time (h)
Yieldb (%)
9
CsF
10
11
12
13
14
15
Cs2CO3
K2CO3
DMAP
DMAP
DMAP
Et3N
47
32
71
1
2
3
4
5
6
7
8
Cu
CuI
70
70
70
70
70
70
70
70
70
70
70
60
50
40
30
6
6
6
6
6
6
6
6
3
1
0.5
1
1
1
1
58
49
27
55
62
47
50
71
70
70
63
72
77
78
61
Cu2O
CuBr
CuBr2
CuCl2
Cu(NO3)2
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
Cu(OAc)2ꢀH2O
—
—
54e
66f
Trace
L
-Proline
16
DMAP
43
L
-Proline
17
18
19
DMAP
DMAP
DMAP
Glycine
1,10-Phenanthroline
2,20-Bipyridine
31
19
12
9
10
11
12
13
14
15
a
Reaction conditions: 2-naphthyl boronic acid (0.5 mmol), Cu(OAc)2ꢀH2O
(10 mol %), ligand (20 mol %), base (1 mmol), solvent (CF3CH2OH 3 mL), 70 °C, O2,
6 h.
b
Yield was determined by HPLC using product as standard.
Argon atmosphere.
Air atmosphere.
DMAP (0.5 mmol).
c
d
a
Reaction conditions: 2-naphthyl boronic acid (0.5 mmol), catalyst (10 mol %),
e
DMAP (1 mmol), solvent (CF3CH2OH 3 mL), O2 atmosphere.
f
b
DMAP (1.5 mmol).
Yield was determined by HPLC using product as standard.

R. Wang et al. / Tetrahedron Letters 56 (2015) 4815–4818
4817
Table 3
Table 4
Copper-catalyzed cross-coupling of aryl boronic acid with trifluoroethanola,b
Copper-catalyzed cross-coupling of heteroaryl boronic acid or boronic acid with
trifluoroethanola,b
O
CF3
B(OH)2
Cu(OAc)2·H2O/DMAP
40oC O2 1h
R
R
HO
CF3
Cu(OAc)2·H2O/DMAP
+
R
O
B(OH)2
HO
R
CF3
+
CF3
N
80oC O2 3h
N
1r-aa
1a-q
3a-q
2
2
3r-aa
O
CF3
Ph
O
CF3
O
CF3
O
O
CF3
O
CF3
Ph
O
O
CF3
O
Ph
O
O
Ph
N
N
N
3b, 66%
3c, 73%
3a, 43%
3r, 48%
3t,50%
3s,50%
CF3
O
CF3
O
O
CF3
O
CF3
O
O
CF3
TMS
Ph
O
CF3
Ph
S
N
N
N
Ph
Ph
O
O
N
3d, 60%
3e, 79%
3f, 44%
3w, 80% c
3u, 43%
3v, 71% c
O
O
CF3
CF3
O
CF3
O
S
N
CF3
O
O
O
CF3
CF3
O
CF3
O
CF3
CF3
O
O
N
S
3i, 63%
3g, 33%
3h, 68%
N
3z, 39%
3y, 8%
3x, 9%
O
O
CF3
O
S
3l, 70%
3k, 75%
3j, 72%
N
3aa, 41%
O
CF3
O
O
a
Reaction conditions: 1 (0.5 mmol), Cu(OAc)2ꢀH2O (10 mol %), DMAP (1 mmol),
O
CF3
O
CF3
O
solvent (CF3CH2OH 3 mL), 80 °C, 3 h, O2 atmosphere.
O
b
3o, 54%
Isolated yields based on 1.
3m, 53%
3n, 43%
c Boronic acid pinacol esters were used.
O
CF3
yields when the reaction temperature was raised to 80 °C and reac-
tion time extended to 3 h. The results are summarized in Table 4.
O
O
3p, 30%
O
CF3
Conclusion
3q, 34%
a
Reaction conditions: 1 (0.5 mmol), Cu(OAc)2ꢀH2O (10 mol %), DMAP (1 mmol),
In summary, an efficient and practical trifluoroethoxylation
method by the copper-catalyzed coupling of aryl- and heteroaryl
boronic acids with CF3CH2OH has been developed. The etherifica-
tion method could proceed under mild conditions (40 °C, 1 h for
aryl boronic acids, and 80 °C, 3 h for heteroaryl boronic acids).
Moreover, the catalyst and ligand are inexpensive and the sub-
strates are commercially available.
solvent (CF3CH2OH 3 mL), 40 °C, 1 h, O2 atmosphere.
b
Isolated yields based on 1.
smoothly under these conditions and afforded the desired products
in moderate to good yields. The electronic and steric factors of the
substituents have significantly influenced the product’s yield.
Generally, the presence of electron-donating groups in aryl boronic
acids gave better yields than those containing electron-withdraw-
ing groups. 4-(Benzyloxy)phenylboronic acid, [1,10-biphenyl]-3-yl-
boronic acid and 3-methoxyphenylboronic acid reacted smoothly
to provide the corresponding products in good yields (3c, 3e, 3h).
Moreover, the para-substituted or meta-substituted aryl boronic
acids provided the coupling products in higher yields than ortho-
substituted ones (3a vs 3b 3c, 3d vs 3e, 3g vs 3h 3i), indicating
importance of steric hindrance. 2-Methoxyphenylboronic acid
afforded the product in lower yield because of the formation of ani-
sole and 2,2’-oxybis(methoxybenzene) as byproducts under these
reaction conditions (3g). Similarly, due to de-boronation, phenan-
thren-9-trifluoroethyl ether was obtained in only 34% yield (3q).
To further demonstrate the broad applicability of our protocol,
we attempted to check if the heteroaryl boronic acids or esters could
be trifluoroethoxylated in the presence of the same catalyst system.
Unfortunately, only trace amounts of the desired ethers were
obtained under the same conditions for aryl boronic acids.
However, several hetero organoboron compounds were success-
fully transformed to the corresponding ethers in moderate to good
Acknowledgments
We are grateful to the Natural Science Foundation of China
(20772114, 21172200), Research Program of Fundamental and
Advanced Technology of Henan Province (122300413203), and
Technology Research and Development Funds of Zhengzhou
(141PRCYY516) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.
066.
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