Copper-catalyzed trifluoromethylation of aryl boronic acids using a CF 3+ reagent

Article abstract of DOI:10.1039/c1cc10359h

A copper-catalyzed process for trifluoromethylation of aryl, heteroaryl, and vinyl boronic acids has been developed. The reaction is conducted under mild conditions and shows tolerance to moisture and a variety of functional groups.

Full text of DOI:10.1039/c1cc10359h

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COMMUNICATION
Copper-catalyzed trifluoromethylation of aryl boronic acids using
+
a CF reagentw
3
Jun Xu, Dong-Fen Luo, Bin Xiao, Zhao-Jing Liu, Tian-Jun Gong, Yao Fu and Lei Liu*
Received 19th January 2011, Accepted 15th February 2011
DOI: 10.1039/c1cc10359h
À
A copper-catalyzed process for trifluoromethylation of aryl,
heteroaryl, and vinyl boronic acids has been developed. The
reaction is conducted under mild conditions and shows tolerance
to moisture and a variety of functional groups.
copper and CF3 reagents. Thus it is interesting to examine
+
the possibility of using a catalytic amount of Cu and CF3
1
3
reagents to achieve the same goal. In 2009, Amii et al.
developed the first copper-catalyzed trifluoromethylation of
À
aryl iodides at 60 1C by using CF
we want to report the copper-catalyzed trifluoromethylation
3
3
(i.e. Et SiCF
3
). Herein,
Trifluoromethylated aromatic groups are important structural
motifs in many biologically active compounds, such as the
+
of aryl boronic acids at room temperature using a CF
14
reagent.
3
1
anticancer drug celecoxib and the antidepressant fluoxetine.
The incorporation of a CF
3
group into aromatics often
We commenced our study by examining the trifluoromethyl-
enhances their chemical and metabolic stability, hydrophobicity,
1
and binding selectivity. Due to this reason, the introduction
ation reaction of biphenylboronic acid (1a) with (trifluoro-
15
methyl)dibenzothiophenium triflate (2a). At first, a catalytic
of trifluoromethyl groups into aromatic compounds has received
2
considerable attention. Traditional methods for arene trifluoro-
amount of CuI (20 mol%) and a very cheap ligand (i.e. 2,4,6-tri-
methylpyridine, L1) were tested (Table 1, entry 1). Although
4% of the desired product (3a) was detected, the reaction
generated several byproducts, including biphenyl (4), biphenyl
acetate (5), and quaterphenyl (6). Testing of different copper
catalysts (entries 2–6) showed that TcCu and CuOAc can
diminish the protodeboronation process (which produces 4)
and therefore, dramatically increase the yield of 3a to 40% and
45%. To reduce the formation of 5, we decided not to use
NaOAc as the base, but to increase the amount of L1 (which is
also a base) to 2 equiv. (entry 7). This change further increased
the yield of 3a to 58%, but we were disappointed to find that
all of the other related ligands failed to improve the reaction
(entries 8–16). In particular, the often used 1,10-phenanthroline
(L9) and N-heterocyclic carbene (L10) ligands generate 4 as
the major product through protodeboronation (entries 15–16).
Moreover, oxidative homocoupling of 1a to form 6 was
observed with all the ligands. Finally, testing of different
solvents showed that DMAC (dimethylacetamide) provides
the optimal yield (67%, entry 21). When the 1a : 2a ratio was
changed from 1.0 : 1.2 to 1.0 : 1.6, the yield of 3a can be further
increased to 80% (entry 23). Note that the effect of the ligand
has also been examined with DMAC as the solvent. The
results are similar to those obtained for DCE. Moreover,
under the same optimized conditions, the use of (trifluoro-
methyl)dibenzothiophenium tetrafluoroborate (2b, entry 24)
produces 3a in 70% yield. Furthermore, in the absence of
copper we did not observe any trifluoromethylation (entry 25).
With the optimized conditions in hand, we investigated the
scope of the new transformation (Table 2). Both electron-rich
3
methylation include the Swarts reaction and the treatment of
4
benzoic acid derivatives with SF4. These methods usually
require harsh conditions that limit the functional group tolerance.
5
6
The electrophilic and radical trifluoromethylations of
aromatics have also been studied, but these methods are only
compatible with arenes bearing electron-donating substituents
and in some cases, generate mixtures of regioisomers. Recent
breakthroughs in Pd-catalyzed trifluoromethylation by the
7
8
9
Sanford, Yu, and Buchwald groups demonstrate the potential
value of transition metal-catalyzed cross-coupling in solving
the problem. Nonetheless, there are still limitations with the
Pd-based methods (e.g. generality, user friendliness and cost).
Copper-mediated trifluoromethylation is an alternative
approach. The ability to conduct the copper-mediated trifluoro-
methylation reactions under common bench-top conditions
with readily available reagents makes this method of particular
interest to medicinal and academic chemists. Earlier studies
À
demonstrated the use of nucleophilic CF
3
sources (e.g. trifluoro-
methylsilanes, trifluoroacetate salts, and methyl fluorosulfonyl-
difluoroacetate) for copper-mediated couplings with aryl
1
0
iodides or activated aryl bromides. Very recently, Qing
11
1
2
and Buchwald’s groups reported a novel strategy for arene
trifluoromethylation through the copper-mediated oxidative
coupling of aryl boronic acids with trifluoromethylsilanes.
Note that all of the above methods use stoichiometric
Department of Chemistry, University of Science and Technology of
China, Hefei 230026, Department of Chemistry, Tsinghua University,
Beijing 100084, China. E-mail: lliu@mail.tsinghua.edu.cn
w Electronic supplementary information (ESI) available: Detailed
procedures and compound characterization. See DOI: 10.1039/c1cc10359h
(
e.g. 3b with two OMe groups) and electron-poor (e.g. 3k with
NO2 substitution) aryl boronic acids can be successfully
trifluoromethylated. This feature compares favorably with
4
300 Chem. Commun., 2011, 47, 4300–4302
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a
Table 1 Optimization of the Cu-catalyzed trifluoromethylation reaction
Byproduct
4/5/6 (%)
Entry
CuX (20 mol%)
Ligand (equiv.)
Base
Solvent
Yield of 3a (%)
1
2
3
CuI
L1 (0.4)
L1 (0.4)
L1 (0.4)
L1 (0.4)
L1 (0.4)
L1 (0.4)
L1 (2.0)
L2 (2.0)
L3 (2.0)
L4 (2.0)
L5 (2.0)
L6 (2.0)
L7 (2.0)
L8 (2.0)
L9 (0.2)
L10 (0.2)
L1 (2.0)
L1 (2.0)
L1 (2.0)
L1 (2.0)
L1 (2.0)
L1 (2.0)
L1 (2.0)
L1 (2.0)
L1 (2.0)
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
—
—
—
—
—
—
—
—
NaOAc
NaOAc
—
—
—
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
4
6
9
40
9
45
58
8
10
20
52
27
45
37
15
19
52
55
55
50
67
43
80
70
trace
24/30/18
20/31/20
28/25/18
4/24/14
42/13/16
2/28/12
0/10/13
78/5/3
56/8/10
46/11/9
3/12/14
32/14/10
16/13/11
38/6/8
36/15/14
58/8/6
5/10/14
2/7/15
3/13/12
9/10/13
0/8/10
10/12/13
1/3/6
2/5/10
CuBr
CuCl
TcCu
b
4
5
6
7
8
9
[Cu(OTf)]
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
—
2
ÁC H
6 6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CH CN
t-AmOH
THF
3
—
—
—
—
—
—
toluene
DMAC
DMSO
DMAC
DMAC
DMAC
c
d
60/0/0
a
Reaction conditions: 1a (0.10 mmol), 2a (0.12 mmol), [Cu] (20 mol%), solvent (0.5 mL), rt, 20 h under Ar atmosphere, GC yields with
b
c
naphthalene as an internal standard. TcCu = (thiophene-2-carbonyloxy)Cu(I). 2a was increased to 0.16 mmol. 2b was used (0.16 mmol).
d
the previously developed Cu-catalyzed trifluoromethylation
reaction of aryl iodides, because good conversions to the desired
products were only observed with electron-deficient aryl
converted in the new reaction, but it gave poor results using
1
the previous methods. Finally, vinyl boronic acids can also
2
be trifluoromethylated (3v).
1
3
+
iodides in Amii’s reaction. Interestingly, the new reaction
can also tolerate the unprotected, acidic OH and NH groups in
the cases of 3e, 3f, 3j, and 3u. This feature compares favorably
Admittedly, the use of CF
3
reagents may increase the
synthetic cost compared to the use of trifluoromethylsilanes.
However, an important advantage of the present reaction is
that the process is not sensitive to moisture. In the trifluoro-
methylation of 1a, intentional addition of 20 mol% water into
the reaction mixture only reduced the yield from 80% to 78%
(see ESIw). Even when 100 mol% water was added, the yield
still remained at 70%. This observation is consistent with our
finding that the reaction can tolerate the unprotected OH and
NH groups.
1
1,12
with Qing and Buchwald’s Chan–Lam-type reaction
because oxidative C–O and C–N cross-coupling may also take
place under the Chan–Lam conditions.
With the traditional methods, carbonyl groups in aryl
iodides readily react with nucleophilic trifluoromethyl agents
1
6
to give the corresponding trifluoromethylated alcohols. In
the new reaction, the ketone group (3m and 3n) does not cause
any problem. Also, although ortho-substituted arenes are
The possible mechanism of the reaction is shown in Fig. 1.
Cu(I) is proposed to undergo transmetallation with the aryl
1
7
usually difficult substrates in Cu-catalyzed cross-coupling,
the present reaction can tolerate substitution at the ortho-position
3c, 3f, and 3t). Note that the chloro group does not interfere
1
8
boronic acid to form an aryl–Cu(I) intermediate. This organo-
copper species can either react with 2a to form a Cu(III)
(or less likely, Cu(II)) species followed by reductive elimination
(
with the transformation (3o), making additional cross-couplings
possible at the halogenated positions. Several five-membered
heteroaryl boronic acids (3r–3u) can also be trifluoromethyl-
ated. In particular, an unprotected indole (3u) was successfully
to give aryl–CF
(or s-bond metathesis) reaction at the CF
aryl–CF . The formation of the aryl–OAc byproduct indicates
3
, or directly initiate an SN2-type substitution
3
center to form
3
This journal is c The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4300–4302 4301

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Table 2 The scope of the copper-catalyzed trifluoromethylation
reaction with aryl and heteroaryl boronic acids
The reaction also shows good functional group compatibility
with some unprotected OH and NH groups.
a
We thank the support by the national ‘‘973’’ grants from the
Ministry of Science and Technology (No. 2011CB965300). We
also thank the support from The State Key Laboratory of
Elemento-Organic Chemistry, Nankai University.
Notes and references
1
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(
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8
9
a
The reactions were conducted under the optimized conditions.
b
Isolated yield. The reaction was conducted at 0 1C.
1
0 For copper-mediated trifluoromethylation reactions, see:
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095; (b) K. Matsui, E. Tobita, M. Ando and K. Kondo, Chem.
that a Cu(III) intermediate is more likely to be involved,
because the aryl C–O bond would be difficult to form with
(
4
1
9
Cu(I). Note that the mechanism may also explain why
the present reaction is catalytic, because the mechanism does
Lett., 1981, 1719; (c) H. Suzuki, Y. Yoshida and A. Osuka, Chem.
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not require the formation of the Cu(I)CF intermediate.
3
1
3
3
According to Amii’s study, the reaction of Cu(I)CF with
ArI (also presumbly with ArB(OH)
2
under oxidative con-
À
ditions) is much slower than the generation of CF
À
3
. Thus,
most of the CF
3
will decompose unless one equiv. of Cu is
+
1
28, 1318; (j) G. G. Dubinina, H. Furutachi and D. A. Vicic,
used. In the present reaction, a CF
3
reagent is used and it
J. Am. Chem. Soc., 2008, 130, 8600; (k) G. G. Dubinina,
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reacts with aryl–Cu(I) without forming Cu(I)CF
3
.
1
1
In summary, we have developed a Cu-catalyzed method
for the trifluoromethylation of aryl, heteroaryl, and vinyl
+
2 T. D. Senecal, A. T. Parsons and S. L. Buchwald, J. Org. Chem.,
2
011, 76, 1174.
13 M. Oishi, H. Kondo and H. Amii, Chem. Commun., 2009, 1909.
boronic acids using a CF3 reagent. The reaction is carried
1
4 During the prepartion of the manuscript, Xiao et al. reported a
+
out at room temperature or 0 1C and can tolerate moisture.
À
2 3
SCF ] OTf
Cu-mediated method for trifluoromethylation with [Ph
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Fig. 1 A possible mechanism of the catalytic trifluoromethylation
reaction.
4
302 Chem. Commun., 2011, 47, 4300–4302
This journal is c The Royal Society of Chemistry 2011