.
Angewandte
Communications
DOI: 10.1002/anie.201302673
Trifluoromethylation
Copper-Catalyzed Trifluoromethylation-Initiated Radical 1,2-Aryl
Migration in a,a-Diaryl Allylic Alcohols**
Xiaowu Liu, Fei Xiong, Xuanping Huang, Liang Xu, Pengfei Li,* and Xiaoxing Wu*
The trifluoromethyl (CF3) group is an important structural
motif in many pharmaceutically relevant molecules because
of its unique chemical and metabolic stability, lipophilicity,
and binding selectivity.[1] Consequently, much effort has been
directed toward the development of efficient methods for the
introduction of the trifluoromethyl group into small mole-
cules.[2] While a variety of processes have been reported to
2
[3]
À
generate aromatic C(sp ) CF3 bonds, the analogous direct
trifluoromethylation of alkenes and their derivatives has
received less attention. In 2011, the groups of Buchwald, Liu,
and Wang independently reported efficient allylic trifluoro-
methylation of unactivated alkenes with copper catalysts
under mild conditions.[4] The trifluoromethylation of allyl-
silanes,[5] vinyltrifluoroborates,[6] and enamides[7] has since
been disclosed by several groups, allowing the effective
formation of compounds with a CF3 group in an allylic or
vinylic position. Furthermore, oxytrifluoromethylation,[7,8]
carbotrifluoromethylation,[9] and hydrotrifluoromethyla-
tion[10] of alkenes have been achieved with and without
transition-metal catalysis. These reactions provide a valuable
pinacol) rearrangements,[12] whereas electron-poor aryl
groups migrate preferentially in radical (“neophyl”) rear-
rangements.[13,14] Therefore, the structures of the products
from unsymmetrical substrates would provide important
insight into the reaction mechanism.
b-Trifluoromethyl ketones such as 3 are difficult to
prepare. Nucleophilic trifluoromethylating reagents typically
undergo 1,2-addition to enones, affording trifluoromethyl
allylic alcohols rather than b-trifluoromethyl ketones by 1,4-
addition.[15] Only a few cyclic b-trifluoromethyl ketones have
been prepared by 1,4-addition of a nucleophilic CF3 group to
cyclic enones.[16] The use of radical or electrophilic CF3
À
array of highly regioselective C CF3 bond-forming methods
under mild conditions. However, the mechanism of these
copper-catalyzed trifluoromethylation reactions is not fully
understood. Addition of both the trifluoromethyl cation or
radical have been suggested as routes to the observed
products.
Buchwald reported the efficient formation of CF3-con-
taining epoxides from secondary allylic alcohols, possibly via
intermediate A [Eq. (1)].[8b] Thus, we envisioned that the
trifluoromethylation of a,a-diaryl allylic alcohols 2 with the
Togni reagent (1)[11] would lead to the analogous intermedi-
ates B, which could undergo 1,2-aryl migration to provide b-
trifluoromethyl ketones 3 [Eq. (2)]. Importantly, electron-
rich aryl groups migrate preferentially in cationic (semi-
reagents for this challenging task has been rarely described.[17]
3
À
Consequently, we wanted to develop new C(sp ) CF3
bond-forming reactions[18] to prepare b-trifluoromethyl
ketones, and to probe the mechanism of the copper-catalyzed
trifluoromethylation of alkenes as discussed above. We report
herein an unprecedented trifluoromethylation-initiated rad-
ical 1,2-aryl migration(“neophyl rearrangement”)[19] in a,a-
diaryl allylic alcohols utilizing 1, leading to a wide variety of
acyclic b-trifluoromethyl a-aryl ketones 3.
We commenced our study with the reaction of 2a with the
Togni reagent (1) and [(MeCN)4Cu]PF6 as catalyst (Table 1).
To our delight, the reaction in methanol at 508C for 14 h
afforded the desired rearranged product 3a in 27% yield
(entry 1). It also provided 48% of compound 4a, which was
probably derived by trapping of the allylic cation of 2a by
MeOH. Complex product mixtures were obtained when the
reaction was performed in the less nucleophilic alcohols
trifluoroethanol or hexafluoroisopropanol (HFIP; entries 2
and 3, respectively). In acetonitrile and dichloromethane,
mixtures of the desired ketone 3a (22% and 9%, respectively)
and substitution product 4b (23% and 76%, respectively,
entries 4 and 5) were formed. In DMSO, the yield of 3a
increased to 51%, but the conversion was not complete
(entry 6). In DMF, the yield of 3a increased further to 69%
[*] X. Liu, F. Xiong, X. Huang, Prof. Dr. X. Wu
Guangzhou Institutes of Biomedicine and Health, Chinese Acad-
emy of Sciences
190 Kaiyuan Avenue, Guangzhou 510530 (China)
E-mail: wu_xiaoxing@gibh.ac.cn
L. Xu, Prof. Dr. P. Li
Center for Organic Chemistry, Frontier Institute of Science and
Technology (FIST), Xi’an Jiaotong University
99 Yanxiang Road, Xi’an, Shaanxi, 710054 (China)
E-mail: lipengfei@mail.xjtu.edu.cn
[**] We are grateful for financial support of this work by a Start-up Grant
from Guangzhou Institutes of Biomedicine and Health (GIBH), and
by the National Science Foundation of China (grant numbers
21202168 and 21202129).
Supporting information for this article is available on the WWW
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
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