Copper-mediated oxidative trifluoromethylation of boronic acids

Article abstract of DOI:10.1021/ol1023135

A copper-mediated oxidative cross-coupling of aryl- and alkenylboronic acids with (trifluoromethyl)trimethylsilane (Me₃SiCF₃) under mild conditions has been developed. This method allows a wide range of functional group tolerant trifluoromethylated arenes and alkenes to be easily prepared. This oxidative trifluoromethylation has the potential to introduce trifluoromethyl groups into advanced, highly functionalized organic molecules.

Full text of DOI:10.1021/ol1023135

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5060-5063
Copper-Mediated Oxidative
Trifluoromethylation of Boronic Acids
Lingling Chu† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China, and College
of Chemistry, Chemical Engineering and Biotechnology, Donghua UniVersity,
2999 North Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received September 26, 2010
ABSTRACT
A copper-mediated oxidative cross-coupling of aryl- and alkenylboronic acids with (trifluoromethyl)trimethylsilane (Me3SiCF3) under mild conditions
has been developed. This method allows a wide range of functional group tolerant trifluoromethylated arenes and alkenes to be easily prepared.
This oxidative trifluoromethylation has the potential to introduce trifluoromethyl groups into advanced, highly functionalized organic molecules.
A large number of biologically active pharmaceuticals and
agrochemicals contain trifluoromethylated aromatic groups,
as the incorporation of a CF3 group into aromatics often
enhances their chemical and metabolic stability, lipophilicity,
and binding selectivity.1 The Swarts reaction (chlorine-
fluorine exchange using reactive SbF5)2 and treatment of
benzoic acid derivatives with SF43 are the traditional methods
for the construction of aryl carbon-CF3 bonds; however, such
harsh reaction conditions are not compatible with a large
number of functional groups. The cross-couplings of aromatic
halides with CuCF3 generated in situ represent the most
popular protocols for the synthesis of trifluoromethylated
aromatics but are mainly limited to aryl iodides and activated
aryl bromides as substrates.4,5 The radical6 and electrophilic7
trifluoromethylation of arenes were also reported, but these
methods were only applied to the trifluoromethylation of
arenes bearing activating substituents such as hydroxy,
methoxy, or amino groups, and in some cases, mixtures of
regioisomers were observed. Recently, palladium-mediated
reactions for the introduction of trifluoromethyl groups onto
aromatic rings have been intensely sought.8,9 Among this
impressive research, the palladium-catalyzed trifluoromethyl-
ation of aryl chlorides developed by Buchwald’s group is
one of the most important breakthroughs in the arena of
(4) For selected Cu-mediated trifluoromethylations, see: (a) Kobayashi,
Y.; Kumadaki, I. Tetrahedron Lett. 1969, 10, 4095. (b) Konderatenko, N. V.;
Vechirko, E. P.; Yagupolskii, L. M. Synthesis 1980, 932. (c) Matsui, K.;
Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981, 1719. (d) Suzuki, H.;
Yoshida, Y.; Osuka, A. Chem. Lett. 1982, 135. (e) Burton, D. J.; Wiemers,
D. M. J. Am. Chem. Soc. 1985, 107, 5014. (f) Umemoto, T.; Ando, A.
Bull. Chem. Soc. Jpn. 1986, 59, 447. (g) Carr, G. E.; Chambers, R. D.;
Holmes, T. F.; Parker, D. G. J. Chem. Soc., Perkin Trans. 1988, 921. (h)
Urata, H.; Fuchikami, T. Tetrahedron Lett. 1991, 32, 91. (i) Long, Z.-Y.;
Duan, J.-X.; Lin, Y.-B.; Guo, C.-Y.; Chen, Q.-Y. J. Fluorine Chem. 1996,
78, 177. (j) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 327. (k)
Xiao, J.-C.; Ye, C.; Shreeve, J. M. Org. Lett. 2005, 7, 1963. (l) Langlois,
B. R.; Roques, N. J. Fluorine Chem. 2007, 128, 1318. (m) Dubinina, G. G.;
Furutachi, H.; Vicic, D. A. J. Am. Chem. Soc. 2008, 130, 8600. (n) Dubinina,
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
(1) (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214.
(b) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45, 5432. (c) Ma, J.-A.;
Cahard, D. J. Fluorine Chem. 2007, 128, 975. (d) Mu¨ller, K.; Faeh, C.;
Diederich, F. Science 2007, 317, 1881. (e) Purser, S.; Moore, P. R.; Swallow,
S.; Gouverneur, V. Chem. Soc. ReV. 2008, 37, 320. (f) Hagmann, W. K.
J. Med. Chem. 2008, 51, 4359. (g) Kirk, K. L. Org. Process. Res. DeV.
2008, 12, 305.
G. G.; Ogikubo, J.; Vicic, D. A. Organometallics. 2008, 27, 6233.
(5) For copper-catalyzed trifluoromethylations, see: (a) Chen, Q.-Y.; Wu,
S.-W. Chem. Commun. 1989, 705. (b) Oishi, M.; Kondo, H.; Amii, H. Chem.
Commun. 2009, 1909
.
(6) (a) Wakselman, C.; Tordeux, M. J. Chem. Soc., Chem. Commun.
1987, 1701. (b) Laglois, B. R.; Laurent, E.; Roidot, M. Tetrahedron Lett.
1991, 32, 7525
.
(2) Swarts, F. Bull. Acad. R. Belg. 1892, 24, 309.
(3) Boswell, G. A., Jr.; Ripka, W. C.; Scribner, R. M.; Tullock, C. W.
Org. React 1974, 21, 1.
(7) (a) Mace, Y.; Raymondeau, B.; Pradet, C.; Blazejewski, J. C.;
Magnier, E. Eur. J. Org. Chem. 2009, 1390. (b) Wiehn, M. S.; Vinogradova,
E. V.; Togni, A. J. Fluorine Chem. 2010, 131, 951
.
10.1021/ol1023135  2010 American Chemical Society
Published on Web 10/05/2010

trifluoromethylation chemistry.8a The high reaction temper-
ature (120-140 °C) and the unsuitability for substrates
bearing aldehydes or ketones are current challenges of this
method. Thus, the development of a method of mild reaction
conditions and wide substrate scope for the incorporation of
trifluoromethyl groups into aromatic rings remains a topic
of great current interest. Herein, we report the first copper-
mediated oxidative trifluoromethyaltion of aryl- and alk-
enylboronic acids with nucleophilic (trifluoromethyl)trime-
thylsilane (CF3SiMe3). Advantages of the reported trifluoro-
methylation include mild reaction conditions, high functional
group tolerance, and ready availability of boronic acids.
Arylboronic acid derivatives are compatible with a broad
range of common functional groups, commercially available
and stable to air and moisture.10 Thus, arylboronic acid
derivatives have been widely used in organic synthesis.
Among a wide range of coupling reactions employing
boronic acids as partners, one class with growing importance
is the copper-mediated oxidative coupling of boronic acids
and nucleophiles,11 first developed by Chan and Evans and
separately Evans in 1998.12 A wide range of heteroatom
nucleophiles, including amines, amides, nitrogen hetero-
cycles, alcohols, and phenols, were used in the Chan-
Evans-Lam coupling reactions. However, to the best of our
knowledge, these protocols do not involve carbon (sp3)-
nucleophiles. It was noteworthy that the fluorination of
arylboronic acids was reported,13 but the trifluoromethylation
of arylboronic acids has not been described in the literature.
Very recently, we have successfully developed the first
example of a copper-mediated protocol for Csp-Csp3 aerobic
oxidative trifluoromethylation of terminal alkynes with
nucleophilic (trifluoromethyl)trimethylsilane (Me3SiCF3).14
This reaction provides a general, straighforward, and practi-
cally useful method to prepare trifluoromethylated acetylenes.
Inspired by this work, we envisioned that the oxidative cross-
coupling of in situ generated CuCF3 with arylboronic acid
may be possible and would provide new type of trifluorom-
ethylation protocols for preparation of aryl-CF3 (Scheme 1).
Scheme 1. Oxidative Trifluoromethylation of Arylboronic Acids
To test our hypothesis, initially, the oxidation trifluoro-
methylation of phenylboronic acid under the optimal reaction
conditions of the oxidative trifluoromethylation of terminal
alkynes was investigated.14 When phenylboronic acid was
added by using a syringe pump to CuCF3 generated in situ
by combination of KF (5.0 equiv), Me3SiCF3 (5.0 equiv),
and CuI (1.0 equiv) in the presence of 1,10-phenanthroline
(phen, 1.0 equiv) in DMF at 70 °C under air atmosphere,
the products (including the desired product and byproducts)
formed from phenylboronic acid were not observed (Table
1, entry 1). Fortunately, when K3PO4 (3.0 equiv) was added
(8) (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679. (b) Ball, N. D.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 2878. (c) Grushin, V. V.;
Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 12644. (d) Grushin, V. V.;
Marshall, W. J. J. Am. Chem. Soc. 2006, 128, 4632.
Table 1. Evaluation of Reaction Conditions for the
Copper-Mediated Trifluoromethylation of Benzeneboronic Acida
(9) For Pd(II)-catalyzed arene trifluoromethylation reaction via C-H
activation, see : Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 3648.
(10) Boronic Acids: Preparation and Applications in Organic Synthesis
and Medicine; Hall, D. G., Eds.; Wiley-VCH: Weinheim, 2005.
(11) For selected recent examples, see: (a) Chan, D. M. T.; Lam, P. Y. S.
In Boronic Acids: Preparation and Applications in Organic Synthesis and
Medicine; Hall, D. G., Eds.; Wiley-VCH: Weinheim, 2005; pp 205-240.
(b) Singh, B. K.; Appukkutta, P.; Claerhout, S.; Parmar, V. S.; Van der
Eycken, E. Org. Lett. 2006, 8, 1863. (c) Liu, J.; Naruta, Y.; Tani, F.
Chem.sEur. J. 2007, 13, 6365. (d) Tao, C. Z.; Cui, X.; Li, J.; Liu, A. X.;
Liu, L.; Guo, Q. X. Tetrahedron Lett. 2007, 48, 3525. (e) Vogler, T.; Studer,
A. Org. Lett. 2008, 10, 129. (f) Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org.
Lett. 2008, 10, 3005. (g) Benard, S.; Neuville, L.; Zhu, J. J. Org. Chem.
2008, 73, 6441. (h) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem.
Soc. 2009, 131, 5044. (i) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Angew.
Chem., Int. Ed. 2009, 48, 1114. (j) Zhou, C.; Yang, D.; Jia, X.; Zhang, L.;
Cheng, J. Synlett 2009, 3198. (k) Mahoney, M. E.; Oliver, A.; Einarsdottir,
O.; Konopelski, J. P. J. Org. Chem. 2009, 74, 8212. (l) Shade, R. E.; Hyde,
A. M.; Olsen, J. C.; Merlic, C. A. J. Am. Chem. Soc. 2010, 132, 1202. (m)
Zhao, X.; Jing, J.; Lu, K.; Zhang, Y.; Wang, J. Chem. Commun. 2010,
1724. (n) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. AdV. Synth. Catal. 2010,
352, 45. (o) Grimes, K. D.; Gupte, A.; Aldrich, C. C. Synthesis 2010, 1441.
(p) DalZotto, C.; Michaux, J.; Martinand-Lurin, E.; Campagne, J. M. Eur.
J. Org. Chem. 2010, 3811. (q) Liskey, C. W.; Liao, X.; Hartwig, J. F. J. Am.
Chem. Soc. 2010, 132, 11389.
yield of 2a (%)
entry
CuX
oxidant (equiv)
(3a/4a/5a/6a)b
1c
2c
3c
4c
5c
6c
7
CuI
air (no K3PO4)
none
CuI
air
air
air
air
37 (43/5/11/2)d
17 (15/12/34/4)e
8 (6/8/31/12)f
6 (4/43/14/3)g
63 (-/10/21/3)
61 (2/-/-/6)f
73 (-/-/-/3)
46 (2/-/-/5)f
56 (4/-/-/4)f
43 (-/-/-/12)
71 (26/-/-/-)e
CuBr
CuCl
CuCN
[Cu(OTf)]2·C6H6 air
[Cu(OTf)]2·C6H6 DDQ (1.0)
[Cu(OTf)]2·C6H6 BQ (1.0)
8
9
[Cu(OTf)]2·C6H6 Chloranil (1.0)
[Cu(OTf)]2·C6H6 CuCl2 (1.0)
[Cu(OTf)]2·C6H6 TEMPO (1.0)
[Cu(OTf)]2·C6H6 1,2-Dibromo-ethane (1.0)
10
11
12
13
14
15
[Cu(OTf)]2·C6H6 1,2-Dichloro-isobutane (1.0) 63 (7/-/-/3)f
[Cu(OTf)]2·C6H6 Ag2CO3 (1.0)
[Cu(OTf)]2·C6H6 AgOTf (1.0)
85 (-/-/-/3)
61 (-/-/-/2)
87 (-/-/-/4)
93 (-/-/-/2)
16h [Cu(OTf)]2·C6H6 Ag2CO3 (1.0)
17h, i [Cu(OTf)]2·C6H6 Ag2CO3 (1.0)
a Reaction conditions: 1a (0.2 mmol), [Cu(OTf)]2·C6H6 (0.1 mmol), phen
(0.2 mmol), Me3SiCF3 (1.0 mmol), KF (1.0 mmol), K3PO4 (0.6 mmol),
DMF (4 mL), 70 °C, under nitrogen atmosphere. b Yield was determined
by GC using dodecane as an internal standard. c The reaction was conducted
under air atmosphere. CuX (X ) I, Br, Cl, CN, 0.2 mmol). d 3a was PhI.
e 3a was PhBr. f 3a was PhCl. g 3a was PhCN. h [Cu(OTf)]2.C6H6 (0.12
mmol), phen (0.24 mmol). i The reaction was conducted at 45 °C.
(12) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933. (b) Evans, D. A.; Katz, J. L.; West, T. R.
Tetrahedron Lett. 1998, 39, 2937. (c) Lam, P. Y. S.; Clark, C. G.; Saubern,
S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941.
(13) (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed
2008, 47, 5993. (b) Furuya, T.; Ritter, T. Org. Lett. 2009, 11, 2860. (c)
Cazorla, C.; Metay, E.; Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009,
50, 3936.
to the reaction mixture, the desired product PhCF3 was
formed in 37% yield along with byproducts PhI (43% yield),
Org. Lett., Vol. 12, No. 21, 2010
5061

phenol (5% yield), diphenyl ether (11% yield), and biphenyl
(2%) (entry 2). To improve the yield of PhCF3, different Cu
sources were further screened. Switching CuX (X ) I, Br,
Cl, CN) salt to nucleophilic ligand free [Cu(OTf)]2·C6H6, the
desired product 2a was enhanced to 63% yield and the
byproduct Ph-X (3a) formed in the cases of CuX (X ) I,
Br, Cl, CN) was not detected, while byproducts phenol (4a),
PhOPh (5a), and PhPh (6a) were observed (entries 2-6).15
We surmised that the byproducts PhOH and PhOPh arose
from trace water in the air that was used as the oxidant.16
To overcome this hurdle, a suitable oxidizing agent instead
of air, which enables the late oxidation and followed by
reductive elimination and does not inhibit the generation of
CuCF3, was chosen. A series of oxidants were screened
(entries 7-15), and to our delight, silver carbonate (Ag2CO3)
displayed the best result for the Cu-mediated oxidative
trifluoromethylation (entry 14). A higher yield of 2a was
obtained when the [Cu(OTf)]2·C6H6 loading was increased
to 0.6 equiv (entry 16). Interestingly, further investigations
revealed that the reaction was conducted at a lower temper-
ature (45 °C) with the highest yield of 2a (entry 17).
Utimately, optimal reaction conditions were found to be as
follows: 0.6 equiv of [Cu(OTf)]2.C6H5, 1.2 equiv of phen,
5.0 equiv of CF3SiMe3, 5.0 equiv of KF, 3.0 equiv of K3PO4,
and 1.0 equiv of Ag2CO3 in DMF at 45 °C. This afforded a
93% yield of 2a (entry 17).
Scheme 2
.
Oxidative Trifluoromethylation of Aryl- and
Alkenylboronic Acidsa
The substrate scope of the copper-mediated oxidative
coupling reactions of arylboronic acids with in situ
generated CuCF3 was examined, and the results are
summarized in Scheme 2. The oxidative trifluoromethyl-
ation of arylboronic aicds has substantial scope. Both
electron-donating (1b-f,m) and electron-withdrawing
groups (1g-k) were tolerated. In contrast to traditional
cross-coupling reactions with aryl halides, electron-rich
arylboronic acids afforded slightly higher yields compared
to electron-deficient substrates. Functional groups such as
bromo, alkenyl, ester, and carbonyl groups are compatible
(1g-j). It is particularly noteworthy that the tolerance of
a bromo substituent (1d) provided a complementary
platform for further transformations via conventional
copper mediated cross-coupling reactions. The heterocyclic
arylboronic acids also served as suitable coupling partners
(1n-o). Importantly, the copper-mediated oxidative tri-
fluoromethylations presented herein has also been easily
extended to alkenylboronic acids (1p-q).
a Reaction was conducted in 0.3 mmol of boronic acid under the optimal
condition of entry 17 in Table 1. Isolated yield.
and followed by transmetalation with arylboronic acid
(Scheme 3). The existence of the diamine ligand would
Scheme 3. Plausible Reaction Pathways for Trifluoromethylation
The detailed mechanism remains to be elucidated. On
the basis of the previous work of trifluoromethylation of
terminal alkynes, it was reasonable to assume that the
reaction proceeds by the generation of reactive CuCF3 B
stabilize the reactive Cu-CF3 by chelation and increase
electron density on the copper center by coordination to
promote the oxidation of complex C to Cu(II) or Cu(III)
complex,17 which then undergoes facile reductive elimina-
tion to deliver the desired product. However, the mech-
anism of the formation of Cu(II) or Cu(III) complex from
B is not clear at the moment.
In summary, we have demonstrated the first copper-
mediated oxidative trifluoromethylation of aryl- and alk-
enylboronic acids with Me3SiCF3. The functional group
(14) Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2010, 132, 7262.
(15) The phenols were observed in many metal-catalyzed couplings of
phenylboronic acids in the presence of oxygen: (a) Yoo, K. S.; Yoon, C. H.;
Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384. (b) Chaicharoenwimolkul,
L.; Munmai, A.; Chairam, S.; Tewasekson, U.; Sapudom, S.; Lakliang, Y.;
Somsook, E. Tetrahedron Lett. 2008, 49, 7299. (c) Xu, J.; Wang, X.; Shao,
C.; Su, D.; Cheng, G.; Hu, Y. Org. Lett. 2010, 12, 1964.
(16) 18O-labeling studies have shown that a phenol byproduct arises from
water serving as an oxygen nucleophile: Lam, P. Y. S.; Bonne, D.; Vincent,
G.; Clark, C. G.; Combs, A. P. Tetrahedron Lett. 2003, 44, 1691.
5062
Org. Lett., Vol. 12, No. 21, 2010

tolerance, substrate scope, and mild reaction conditions are
the advantages of this process. We expect this method to
allow the introduction of trifluoromethyl groups into ad-
vanced, highly functionalized organic molecules at the late
stage of synthetic chemistry.
Acknowledgment. The National Natural Science Founda-
tion of China and Shanghai Municipal Scientific Committee
are gratefully acknowledged for funding this work.
Supporting Information Available: Detailed experimen-
tal procedures and spectral data for all new compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) (a) King, A. E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas,
X.; Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068. (b) Huffman, L. M.;
Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196. (c) Snyder, J. Angew. Chem.,
Int. Ed. 1995, 34, 80. (d) Lipshutz, B. H.; Siegmann, K.; Garcia, E.; Kayser,
F. J. Am. Chem. Soc. 1993, 115, 9276. (e) Willert-Porada, D. M.; Burton,
D. J.; Baenziger, N. C. J. Chem. Soc., Chem. Commun. 1989, 1633.
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