Copper-mediated trifluoromethylation of arylboronic acids by trifluoromethyl sulfonium salts

Article abstract of DOI:10.1039/c1cc13460d

The ligand-free trifluoromethylation of arylboronic acids with a [Ph ₂SCF₃]⁺[OTf]^-/Cu(0) system has been carefully investigated. Aryl-, alkenyl- and heteroarylboronic acids with a variety of functional groups were suitable substrates for this reaction. It is suggested that a CuCF₃ species is formed under the reaction conditions.

Full text of DOI:10.1039/c1cc13460d

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 9516–9518
www.rsc.org/chemcomm
COMMUNICATION
Copper-mediated trifluoromethylation of arylboronic acids by
trifluoromethyl sulfonium saltsw
Cheng-Pan Zhang,a Ji Cai,a Chang-Bing Zhou,a Xiao-Ping Wang,ab Xing Zheng,b
Yu-Cheng Guc and Ji-Chang Xiao*a
Received 11th June 2011, Accepted 6th July 2011
DOI: 10.1039/c1cc13460d
The ligand-free trifluoromethylation of arylboronic acids with a
[Ph2SCF3]+[OTf]ꢀ/Cu(0) system has been carefully investigated.
Aryl-, alkenyl- and heteroarylboronic acids with a variety of
functional groups were suitable substrates for this reaction. It is
suggested that a CuCF3 species is formed under the reaction
conditions.
to the reaction of aryl iodides and bromides with nucleophilic
trifluoromethylating reagents [e.g. TMSCF3, FSO2CF2CO2Me,
CF3CO2Na(K)].1,4 Chu and Qing have recently developed a
method to trifluoromethylate terminal alkynes using Me3SiCF3
as the reagent,4c and this is a significant advance in the
Cu(I)-mediated trifluoromethylation field. In addition, Chu
and Qing found that Cu(I)-mediated oxidative cross-coupling
takes place between aryl- or alkenylboronic acids and
Me3SiCF3.4d Soon afterwards, Buchwald et al. reported a
Cu-mediated oxidative arene trifluoromethylation, in which
aryl and heteroarylboronic acids are trifluoromethylated by
Me3SiCF3 at room temperature.4e It is clear that copper-
mediated trifluoromethylation using the available reagents
under mild and environment-friendly conditions has drawn
considerable attention from medicinal and materials chemists.
S-(Trifluoromethyl)diarylsulfonium salts, which were first
prepared by Yagupolskii and then developed by Umemoto,
Shreeve and Shibata, have been successfully used for the
electrophilic trifluoromethylation of nucleophiles.5 However,
only a few applications over and above the electrophilic
reactions of these reagents have been reported.3c,4h,i,6 In fact,
reactions using Cu(I) and electrophilic CF+3 as trifluoro-
methylating reagents can achieve the same goal as using
nucleophilic CFꢀ3 reagents.4,6 Although only catalytic amounts
of Cu(I) salts were needed in these reactions, it was found
necessary to use ligands.6 Moreover, cuprous salts have been
carefully investigated but the use of copper powder has never
been reported. Therefore, it was important to examine the
Cu(0)-mediated trifluoromethylation of arylboronic acids
using an S-(trifluoromethyl)diphenylsulfonium salt without
ligands, and this is what we have done. Herein, we report
the details of this work.
Trifluoromethylated compounds have been widely used in the
fields of biochemistry and materials science. Their unique
physical and biological properties, the direct result of the
fluorine substituents, have made them suitable as pharma-
ceuticals, agricultural chemicals, polymers and liquid crystals.1
Trifluoromethylated compounds are often more difficult to
synthesize than their non-fluorinated analogues. Although
there are many approaches, the development of more efficient
methodology to meet the increasing demands for fluorinated
chemicals is a high priority.2
It is known that methods for the direct introduction of
the trifluoromethyl group into common organic compounds
are available through radical, nucleophilic or electrophilic
approaches.1 Recently, notable breakthroughs have been
made in transition metal-catalyzed cross-coupling trifluoro-
methylation.3 For example, Sanford et al. developed the
Pd(II/IV)-catalyzed arene trifluoromethylation reaction, in
which Ar–CF3 species were formed by thermolysis of the
palladium(IV) intermediate.3a,b Furthermore, Buchwald et al.
found that the use of suitable ligands enabled the Pd(II)-
catalyzed trifluoromethylation of a wide variety of aryl chlorides,
allowing the transformation of a wide range of substrates in
excellent yields.3d Although Pd-catalyzed coupling reactions
have achieved remarkable results, Cu-mediated trifluoro-
methylation is still the main approach for the preparation of
trifluoromethylated compounds.4 However, Cu-mediated
trifluoromethylation has, so far, been limited almost entirely
The trifluoromethylation of phenylboronic acid (1a) with
[Ph2SCF3]+[OTf]ꢀ (3) was selected as a model reaction. As
shown in Table 1, copper and base had a major influence on
this trifluoromethylation process. For example, treatment
of 1a with 3 in the absence of Cu and base at 50 1C for 14 h
gave almost no conversion to 2a (entry 1). Furthermore,
the reaction of 1a, 3 and K2CO3 in the absence of Cu
under the same conditions did not produce the desired product
2a either (entry 2). [Ph2SCF3]+[OTf]ꢀ was consumed by
K2CO3 in this reaction and 60% yield of CF3H byproduct
was formed (entry 2).7a This was determined by 19F NMR
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, China.
E-mail: jchxiao@mail.sioc.ac.cn; Fax: +86-21-64166128
b Institute of Pharmacy and Pharmacology, University of South China,
Hengyang, Hunan, China
c Syngenta, Jealott’s Hill International Research Centre, Bracknell,
Berkshire, RG42 6EY, UK
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc13460d
c
9516 Chem. Commun., 2011, 47, 9516–9518
This journal is The Royal Society of Chemistry 2011

View Article Online
Table 1 Trifluoromethylation of phenylboronic acid by [Ph2SCF3]+
-
obtained in lower yield (entries 14–16), and CF3H was generated
in large amounts. Even 2 equiv. of Cu could not inhibit the
formation of CF3H and promote the trifluoromethylation.
2,20-Bipyridine is a useful reagent and can be used not only
as a base but also as a ligand. With 2,20-bipyridine, no CF3H
was formed in this reaction, but the yield of 2a was still very
low (entry 17). Employing NaHCO3 as base, 2a was obtained
in moderate yield (entry 18), and only a trace of CF3H was
observed. Increasing the molar ratio of 3 and Cu to 2 equiv.,
2a was obtained in a very satisfactory 84% yield (entry 19),
and only small quantities of CF3H were formed. This was very
different from the case using K2CO3 and Cs2CO3 as the base
(entries 5, 15 and 19). It seems that bases which are weak or
sterically hindered favor the trifluoromethylation process and
suppress the hydrogenation of S-(trifluoromethyl)diphenyl-
sulfonium salts (entries 2 and 17). Sulfonium salts that are
more reactive than fluoroalkyl halides would be easily hydro-
genated by a strong base.7b On the other hand, the strength or
the nucleophilicity of the base was important for the reaction.
When its nucleophilicity is not strong enough, the [CF3]ꢀ
intermediate decomposes and generates a fluoride ion which
then activates the phenylboronic acid, leading to the formation
of fluorine-containing byproducts with signals around
d = ꢀ149 ppm in the 19F NMR spectrum (see ESIw). Under
these conditions, trifluoromethylation is suppressed, leading
only to a low yield of the desired product. Similar results were
also obtained in the absence of a base (entry 3). Due to the
stability of the B–F bond, reaction between the boron atom in
1a and the fluoride ion is favourable, which leads to the
decomposition of [CF3]ꢀ species. On the basis of these arguments,
we believe that NaHCO3 has the best balance of properties
and is the optimal choice of base for this reaction.
[OTf]ꢀ without a ligand
a Molar ratios. a Determined by 19F NMR analysis of the reaction
mixture, using [OTf]ꢀ as the internal standard. a The conversion of 3,
determined by 19F NMR.
spectra (see ESIw). When our previous trifluoromethylation
conditions were employed to conduct the reaction, 2a was
obtained as expected,4h but the yield was very low (entry 3).
Further investigation indicated that the addition of the base
could improve the yield of 2a (entries 4–8). Byproducts
such as benzene, phenol and biphenyl were also generated
in this reaction, according to the GC-MS analysis of the
reaction mixture. This was the same case as reported in the
literature.4d,e,6
With the optimized conditions in hand (entry 19 in Table 1),
we further investigated the scope of the ligand-free copper-
mediated trifluoromethylation of arylboronic acids. As shown
in Table 2, electron-rich and electron-poor arylboronic acids
could be successfully trifluoromethylated (2b–f). Arylboronic
acids with functional groups such as CN, CHO, NO2, and
OH were all suitable substrates for this reaction (2g–j).
2-Naphthylboronic acid was also converted into the trifluoro-
methyl-substituted product in a reasonable yield (2k). An
alkenylboronic acid reacted with 3 and Cu under the same
conditions, giving 2l in a good yield. Heteroarylboronic acids
could also be trifluoromethylated and some pharmaceutically
important trifluoromethyl-substituted aromatic and hetero-
aromatic compounds were synthesized (2m–q).
A mechanism for this reaction is proposed in Scheme 1.4h,i,8
We suggest that the CuCF3 intermediate is formed via a single
electron transfer process and is then oxidated to a Cu(II)- or
Cu(III)-complex by 3. The Cu(II)- or Cu(III)-complex then
undergoes transmetallation with the arylboronic acid to form
an aryl-Cu(II) or -Cu(III) intermediate, which goes on to
produce the trifluoromethylated product by facile reductive
elimination. This was different in the process proposed by
Liu.6 Evidence for this mechanism was obtained by the
analysis of the 19F NMR and MS spectra of the reaction
mixtures (see entries 10, 12, 14 and 20 of Table 1 and ESIw).
19F NMR detection of the reaction mixture (entry 20
of Table 1) showed that CuCF3 is generated in this reaction
Moreover, the reaction time and the reactant ratio also
influenced the reaction. Prolonging the reaction time from 7 h
to 14 h, little difference was found in the yield of 2a and CF3H
(entries 4 and 7). Increasing the amount of both 3 and Cu to
2 equiv. surprisingly suppressed the required reaction and led
to higher yield of CF3H (entry 5). Reducing the amount of Cu
and K2CO3 to 0.5 equiv. also discouraged the trifluoro-
methylation (entry 6). The yield of 2a was increased (61%)
when 2 equiv. of Cu was used (entry 8). The temperature also
has influence on this reaction. Running the reaction at room
temperature resulted in the formation of only a trace of 2a
(entry 9).
The effect of solvents was also investigated. Treatment of 1a
with 3 in CH3CN gave 2a in only 4% yield and CF3H in 24%
yield (entry 10). Unreacted compound 3 still remained in this
reaction. When DCM was used instead of CH3CN, no reaction
took place (entry 11). Substantial amounts of CF3H were
formed when the reaction was conducted in DMSO (entry 12),
and similar results were also found when THF was used as
solvent (entry 13).
Various bases were employed to improve the trifluoro-
methylation of phenylboronic acid. It was found that the
trifluoromethylation reaction is very sensitive to the choice
of base. Using KF, Cs2CO3, and NaOAc as bases, 2a was
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9516–9518 9517

View Article Online
Table 2 Trifluoromethylation of aryl-, heteroaryl and alkenylboronic
acids by [Ph2SCF3]+[OTf]ꢀa
We thank the Chinese Academy of Sciences, the National
Natural Science Foundation (20972179, 21032006), and the
Syngenta PhD Studentship Award for financial support.
We thank Dr John Clough of Syngenta at Jealott’s Hill
International Research Centre for proofreading of the
manuscript.
Notes and references
1 (a) T. Hiyama, Organofluorine Compounds, Chemistry and
Applications, Springer, Berlin, 2000; (b) P. Kirsch, Modern Fluoro-
organic Chemistry Synthesis, Reactivity, Applications, Wiley-VCH,
Weinheim, 2004; (c) J. P. Begue and D. Bonnet-Delpon, Bioorganic
and Medicinal Chemistry of Fluorine, John Wiley & Sons, Hoboken,
2008.
2 (a) K. Sato, M. Higashinagata, T. Yuki, A. Tarui, M. Omote,
I. Kumadaki and A. Ando, J. Fluorine Chem., 2008, 129, 51;
(b) C.-P. Zhang, H.-P. Cao, Z.-L. Wang, C.-T. Zhang,
Q.-Y. Chen and J.-C. Xiao, Synlett, 2010, 1089; (c) S. Roy,
B. T. Gregg, G. W. Gribble, V.-D. Le and S. Sujata Roy,
Tetrahedron, 2011, 67, 2161.
3 (a) N. D. Ball, J. W. Kampf and M. S. Sanford, J. Am. Chem. Soc.,
2010, 132, 2878; (b) Y. Ye, N. D. Ball, J. W. Kampf and
M. S. Sanford, J. Am. Chem. Soc., 2010, 132, 14682; (c) X. Wang,
L. Truesdale and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 3648;
(d) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson and
S. L. Buchwald, Science, 2010, 328, 1679.
4 (a) G. G. Dubinina, H. Furutachi and D. A. Vicic, J. Am. Chem.
Soc., 2008, 130, 8600; (b) G. G. Dubinina, J. Ogikubo and
D. A. Vicic, Organometallics, 2008, 27, 6233; (c) L. Chu and
F.-L. Qing, J. Am. Chem. Soc., 2010, 132, 7262; (d) L. Chu
and F.-L. Qing, Org. Lett., 2010, 12, 5060; (e) T. D. Senecal,
A. T. Parsons and S. L. Buchwald, J. Org. Chem., 2011, 76, 1174;
(f) Q.-Y. Chen and S.-W. Wu, J. Chem. Soc., Perkin Trans. 1, 1989,
2385; (g) B. R. Langlois, T. Billard and S. Roussel, J. Fluorine
Chem., 2005, 126, 173; (h) M. Oishi, H. Kondo and H. Amii, Chem.
Commun., 2009, 1909; (i) C.-P. Zhang, Z.-L. Wang, Q.-Y. Chen,
C.-T. Zhang, Y.-C. Gu and J.-C. Xiao, Angew. Chem., Int. Ed.,
2011, 50, 1896; (j) C.-P. Zhang, Z.-L. Wang, Q.-Y. Chen,
C.-T. Zhang, Y.-C. Gu and J.-C. Xiao, Chem. Commun., 2011,
47, 6632; (k) H. Kondo, M. Oishi, K. Fujikawa and H. Amii, Adv.
Synth. Catal., 2011, 353, 1247.
a
The molar ratio of 1b–q : 3 : Cu : NaHCO3 was 1 : 2 : 2 : 1. The yield
b
was determined by 19F NMR. Isolated yield.
5 (a) L. M. Yagupolskii, N. V. Kondratenko and G. N. Timofeeva,
Russ. J. Org. Chem. (Transl. of Zh. Org. Khim.), 1984, 20, 103;
(b) T. Umemoto and S. Ishihara, J. Am. Chem. Soc., 1993,
115, 2156; (c) T. Umemoto, Chem. Rev., 1996, 96, 1757;
(d) J.-J. Yang, R. L. Kirchmeier and J. M. Shreeve, J. Org. Chem.,
1998, 63, 2656; (e) E. Magnier, J.-C. Blazejewski, M. Tordeux and
C. Wakselman, Angew. Chem., Int. Ed., 2006, 45, 1279; (f) Y. Mace,
B. Raymondeau, C. Pradet, J.-C. Blazejewski and E. Magnier, Eur.
J. Org. Chem., 2009, 1390; (g) S. Noritake, N. Shibata,
S. Nakamura, T. Toru and M. Shiro, Eur. J. Org. Chem., 2008,
3465; (h) A. Matsnev, S. Noritake, Y. Nomura, E. Tokunaga,
S. Nakamura and N. Shibata, Angew. Chem., Int. Ed., 2010, 49, 572.
6 During the preparation of this manuscript, Liu et al. reported the
Cu(I)-catalyzed trifluoromethylation of arylboronic acids using
Umemoto’s reagent and a suitable ligand (Chem. Commun., 2011,
47, 4300), and Shen et al. reported the Cu(I)-catalyzed trifluoro-
methylation of aryl and vinylboronic acids with Togni’s reagent
(Org. Lett. 2011, 13, 2342).
Scheme 1 Proposed mechanism for the trifluoromethylation of
arylboronic acids with 3.
(d = ꢀ33.0 ppm). ESI-MS analysis further suggested that
CuCF3, Cu(CF3)(OTf), Cu(CF3)(C6H5), and Cu(CF3)(OTf)-
(C6H5) were formed in the reaction (m/z = 131.9, 280.9, 209.0
and 357.9, see ESIw).
In conclusion, the ligand-free trifluoromethylation of a variety
of boronic acids with S-(trifluoromethyl)diphenylsulfonium
triflate and copper powder has been carefully investigated.
Aryl-, alkenyl- and heteroarylboronic acids incorporating a
variety of functional groups are all suitable substrates for this
reaction. The choice of base has an important influence on the
trifluoromethylation process. We assume that a CuCF3 species
takes part in the reaction, and suggest that the mechanism
involves a Cu(II)- or Cu(III)-complex undergoing transmetallation
and reductive elimination.
7 (a) P. Sartori and W. Habel, J. Fluorine Chem., 1980, 16, 265;
(b) C.-P. Zhang, Q.-Y. Chen, J.-C. Xiao and Y.-C. Gu, J. Fluorine
Chem., 2009, 130, 671.
´
8 (a) Y. Mace, C. Pradet, M. Popkin, J.-C. Blazejewski and
E. Magnier, Tetrahedron Lett., 2010, 51, 5388; (b) T. Umemoto,
Chem. Rev., 1996, 96, 1757.
c
9518 Chem. Commun., 2011, 47, 9516–9518
This journal is The Royal Society of Chemistry 2011