Angewandte
Chemie
DOI: 10.1002/anie.201206681
Cross-Coupling Reactions
Copper-Promoted Trifluoromethylation of Primary and Secondary
Alkylboronic Acids**
Jun Xu, Bin Xiao, Chuan-Qi Xie, Dong-Fen Luo, Lei Liu, and Yao Fu*
The introduction of a CF3 group to an organic molecule can
significantly modify its biological properties by increasing its
lipophilicity and metabolic stability.[1] Accordingly, the devel-
cross-coupling reactions has been relatively less studied owing
to their poor transmetalation reactivity. Although there has
been some success with Pd catalysts,[16] no cross-coupling of
alkylboronic acids has ever been reported for Cu chemistry.
Thus, the present finding also provides a rare example for the
Cu-promoted cross-coupling reaction of alkylboronic acids.
Our study began by examining the cross-coupling of
a primary alkylboronic acid (1a) with the Ruppert–Prakash
reagent. Initially we tested previous reaction conditions
À
opment of new methods to form the C CF3 bond has
attracted considerable interest in synthetic organic chemis-
try.[2] While earlier studies in this field focused on stoichio-
metric trifluoromethylation methods,[3] recent attention has
been turned to transition-metal-catalyzed trifluoromethyl-
ation reactions, which usually are carried out under milder
conditions and exhibit improved yields, selectivity, and func-
tional-group tolerance.[4] Until now great success has been
achieved with regards to Pd-[5–7] or Cu-mediated[8,9] trifluor-
omethylation of various sp2- and sp-hybridized carbon
centers. In some recent studies breakthroughs have also
been made for the catalytic trifluoromethylation reactions at
allylic sp3-hybridized carbon centers.[10] Nonetheless, it
remains a more difficult challenge to use transition metals
to promote trifluoromethylation at nonactivated sp3-hybrid-
ized carbon centers.
(catalyst = CuOTf·0.5C6H6,
ligand = 1,10-phenanthroline,
oxidant = Ag2CO3) developed for Cu-mediated trifluoro-
methylation of arylboronic acids (Table 1, entry 1).[8c]
Although the desired product (2a) could be detected, its
yield was very low (16%). To improve the reaction, we
examined the effect of using different Cu salts. CuI gives
a similar result to CuOTf·0.5C6H6, whereas the other Cu salts
such as [Cu(MeCN)4]BF4 and CuTc only afford a trace
amount of product (entries 2–4). As CuI is much less
expensive and more air stable than CuOTf·0.5C6H6, we used
CuI in our subsequent investigations. For the ligand, our study
shows that the use of phenanthrolines bearing electron-
donating substituents can increase the yield (entries 5–7). The
often more powerful N-heterocyclic carbene ligand (L5) in
Cu chemistry, however, fails to promote this reaction
(entry 8). In addition, the use of the less-rigid bipyridine
ligand (L6) results in a lower yield (entry 9).
By using the best ligand (L3) identified from the above
experiments, we next examined the effects of using different
oxidants. Most of the Ag salts that we investigated (i.e. Ag2O,
AgOAc, AgOTFA, AgOTf) gave poor results (entries 10–13),
but pleasingly when AgBF4 was used a modest yield of 50%
was achieved (entry 14). Furthermore, the use of other
oxidants including 1,4-benzoquinone and Cu(OAc)2 also
resulted in poor yields (entries 15–16). With AgBF4 as
oxidant, we examined the effect of inorganic bases on the
reaction. The reactions in the presence of K2CO3, Cs2CO3,
and tBuOK gave lower yields than that in the presence of
K3PO4 (entries 17–19), whereas when KF was used the yield
was increased to 68% (entry 20). To further improve the
yield, we increased the loading of CuI to 50 mol% (entry 21)
and obtained a good yield of the desired product (88%).
Finally, we only detected a trace amount of 2a from the
reaction in the absence of CuI (entry 21). This control
experiment confirms the catalytic role of Cu in the trifluor-
omethylation process.
Herein, we report an unprecedented Cu-promoted tri-
fluoromethylation reaction of primary and secondary alkyl-
boronic acids with the Ruppert–Prakash reagent[11]
(TMSCF3). This work was inspired by our recent finding of
a rather general and robust approach for the preparation of
primary and secondary alkylboronic acid derivatives from
aliphatic halides and pseudohalides.[12] Notably, compounds
bearing a CF3 group on their alkyl chains are interesting
candidates in the design of bioactive molecules, but methods
for the incorporation of CF3 into aliphatic skeletons remain
rare.[13–15] It is therefore our goal to extend the scope of the
Cu-promoted reaction to develop a general approach for the
À
construction of Csp3 CF3 bonds. Furthermore, it should be
À
pointed out that the use of alkylboronic acids in catalytic C C
[*] J. Xu, C.-Q. Xie, D.-F. Luo, Prof. Y. Fu
Department of Chemistry
University of Science and Technology of China
Hefei 230026 (China)
E-mail: fuyao@ustc.edu.cn
B. Xiao, Prof. L. Liu
Department of Chemistry, Tsinghua University
Beijing 100084 (China)
and
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics
Chinese Academy of Sciences, Shanghai 200032 (China)
With the optimized reaction conditions established, we
examined the trifluoromethylation of a number of primary
alkylboronic acids to test the scope of the reaction
(Scheme 1). These alkylboronic acids were prepared from
the corresponding alkyl halides or tosylates by using our
[**] This study is supported by the National Basic Research Program of
China (973 program; No.2013CB932800), NSFC (20832004,
20972148), and CAS (KJCX2-EW-J02).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 12551 –12554
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12551
Xu, Jun
