Enantioselective C-H bond functionalization triggered by radical trifluoromethylation of unactivated alkene

Article abstract of DOI:10.1002/anie.201405401

An asymmetric unactivated alkene/C-H bond difunctionalization reaction for the concomitant construction of C-CF₃ and C-Obonds was realized by using a Cu/Bronsted acid cooperative catalytic system, thus providing facile access to valuable chiral

Full text of DOI:10.1002/anie.201405401

Angewandte
Chemie
DOI: 10.1002/anie.201405401
À
C H Activation
À
Enantioselective C H Bond Functionalization Triggered by Radical
Trifluoromethylation of Unactivated Alkene**
Peng Yu, Jin-Shun Lin, Lei Li, Sheng-Cai Zheng, Ya-Ping Xiong, Li-Jiao Zhao, Bin Tan,* and
Xin-Yuan Liu*
In memory of Carlos F. Barbas III
À
Abstract: An asymmetric unactivated alkene/C H bond
difunctionalization reaction for the concomitant construction
erable attention as it offers an appealing and mechanistically
[3]
À
complementary pathway in C H activation chemistry.
À
À
of C CF3 and C O bonds was realized by using a Cu/Brønsted
acid cooperative catalytic system, thus providing facile access
to valuable chiral CF3-containing N,O-aminals with excellent
regio-, chemo-, and enantioselectivity. Mechanistic studies
revealed that this reaction may proceed by an unprecedented
1,5-hydride shift involving activation of unactivated alkenes
and a radical trifluoromethylation to initiate subsequent
However, to date, only a few examples dealing with catalytic
and enantioselective processes have been reported.[3] Among
these, the hydride acceptor is limited to electron-deficient
olefins for the stabilization of the carbanion generated by the
hydride shift, a carbanion which undergoes subsequent
intramolecular enantioselective cyclization (Scheme 1a).[3]
À
enantioselective functionalization of C H bonds. Control
experiments also suggested that chiral Brønsted acid plays
multiple roles and not only controls the stereoselectivity but
also increases the reaction rate through activation of Togniꢀs
reagent.
E
nantioselective catalytic carbon–carbon and carbon–het-
À
eroatom bond-forming reactions through C H bond activa-
tion without substrate prefunctionalization have rapidly
emerged as the forefront of current chemical research.[1]
Significant advances have been made in the enantioselective
À
cross-dehydrogenative coupling (CDC) of two C H bonds in
both intra- and intermolecular modes, through the function-
À
Scheme 1. Enantioselective catalytic functionalization of C H bonds
adjacent to heteroatoms based on 1,5-H shift.
À
alization of C H bonds adjacent to heteroatoms in the
presence of hydrogen acceptors, in recent years.[2] Because of
the oxidative nature of these reactions, the use of a stoichio-
metric external oxidant is generally required. As a means of
addressing this problem, redox-neutral processes involving
intramolecular hydride shifts and additional functionalization
of the position a to the nitrogen atom has attracted consid-
In contrast, the incorporation of unactivated alkenes to
À
initiate enantioselective functionalization of C H bonds,
adjacent to heteroatoms, with nucleophiles in an intermolec-
ular mode remains a prominent challenge (Scheme 1b) as the
regio-, chemo-, and enantioselectivity for such transforma-
tions are difficult to control using the existing redox-neutral
processes because of the presence of two unactivated
[*] P. Yu, J.-S. Lin, L. Li, S.-C. Zheng, Y.-P. Xiong, L.-J. Zhao,
Prof. Dr. B. Tan, Prof. Dr. X.-Y. Liu
Department of Chemistry
À
structures including a simple olefin and C H bond in the
current system. Therefore, the discovery of a broadly appli-
cable and mechanistically distinct protocol to realize such
a transformation is highly desired.
South University of Science and Technology of China
Shenzhen, 518055 (P. R. China)
E-mail: tanb@sustc.edu.cn
Trifluoromethylated compounds have played a profound
role in the realm of medicinal chemistry as it has excellent
metabolic stability, lipophilicity, and electrostatic interactions
with targets.[4,5] In particular, enantiopure CF3-containing
molecules are at the forefront of innovation in modern
organic and medicinal chemistry[4,5a] because the effect of
stereochemistry on biological activity is of great importance
for medicinal application.[6] More recently, copper-catalyzed
trifluoromethylation reactions of unactivated alkenes with
trifluoromethylating reagents involving an a-CF3-alkyl radi-
cal intermediate have emerged as important synthetic tools
liuxy3@sustc.edu.cn
[**] Financial support from the National Natural Science Foundation of
China (Nos. 21302088, 21302087), Shenzhen special funds for the
development of biomedicine, Internet, new energy, and new
material industries (JCYJ20130401144532131,
JCYJ20130401144532137), and South University of Science and
Technology of China (Talent Development Starting Fund from
Shenzhen Government) is greatly appreciated. We thank Prof. Dr.
Tao Wang at Peking University Shenzhen Graduate School for
crystallographic analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405401.
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for the synthesis of new potential pharmaceutical candi-
the reaction of 1a, 2b, and methanol with the molar ratio of
1.0: 1.7: 1.5 in the presence of 15 mol% of CuCN and
10 mol% of the 2,4,6-triisopropylphenyl-derived CPA 4c
[(S)-TRIP] in EtOAc at room temperature (258C); 3a was
obtained in 81% yield with 96% ee (Table 1).
Given the optimal reaction conditions, we next inves-
tigated the scope with respect to N-(2-allylbenzyl)amides,
having various substituents, for the synthesis of enantioen-
riched trifluoromethyl-containing N,O-aminals. As shown in
Table 1, the tandem reaction proceeded smoothly, irrespec-
tive of the electronic nature and position of substituents, to
afford the desired products in moderate to good yields with
excellent enantioselectivities. For example, various N-(2-
allylbenzyl)amides, bearing either electron-donating groups
(X = OMe, Me, Ph) or electron-withdrawing groups (X = Cl,
Br, NO2) on the aryl ring a to the amide group, reacted
dates.[5,7] In contrast, the challenging functionalization of C
À
H bonds by transposition of an inherently high-energy radical
intermediate has become a research focus in synthetic
chemistry,[8,9] as they enable the assembly of functionalized
chemical structures with remarkable precision and excellent
À
functional-group tolerance by controlled activation of C H
bonds. However, although the racemic transformations have
been well documented, to our knowledge, the development of
À
catalyst-controlled enantioselective C H bond functionaliza-
tion by potentially useful radical transposition processes
remains an underdeveloped area. Inspired by these racemic
discoveries and to address the challenge described above, we
envisioned a novel redox-neutral process involving an intra-
À
molecular hydride shift and then an enantioselective C H
functionalization of the position a to the nitrogen atom. Such
a reaction might be realized by using the inherently high
reactivity of an a-CF3-alkyl radical intermediate, derived
from a radical trifluoromethylation of unactivated alkenes,[7]
to give valuable enantioenriched CF3-containing N,O-aminals
using the appropriate cooperative catalytic systems (Sche-
me 1b).[10] Because of their biological and pharmacological
activity,[11] asymmetric N,O-aminal synthesis has been proven
to be an attractive but underexploited strategy.[12] As part of
our continued interest in the area of trifluoromethylation[13]
and asymmetric catalysis,[14] herein, we describe the first
successful example of a highly enantioselective redox-neutral
Table 1: Asymmetric reaction scope for N-(2-allylbenzyl)amides and
alcohols.[a,b,c]
À
À
reaction through a C CF3 formation/1,5-H shift/C H func-
tionalization process in the presence of a copper/Brønsted
acid catalytic system and without the need for an external
oxidant. Notably, the current process provides a convenient
and economical route for facile access to valuable enantioen-
riched CF3-containing N,O-aminal motifs with excellent
regio-, chemo-, and enantioselectivity under mild reaction
conditions.
On the basis of our hypothesis, our investigation com-
menced with the reaction of N-(2-allylbenzyl)benzamide (1a)
with MeOH and Togniꢀs reagent[15] (2a) in the presence of
a cooperative catalyst system comprising a copper catalyst
and chiral phosphoric acid (CPA).[16] As such, in the presence
of different copper salts [CuI, CuBr, or CuCl (20 mol%)] and
known CPAs, the reaction gave 3a in good yields with almost
complete regio- and chemoselectivity, albeit with only min-
imal levels of enantioselectivity (not shown). This finding can
be attributed to the fact that 2-iodobenzoic acid, generated by
the reaction system, prevents enantioselective reaction cata-
lyzed by CPAs. Therefore, we surmised that Togniꢀs reagent
(2b) may be a suitable CF3 source for the development of an
enantioselective redox-neutral reaction. As expected, we
were delighted to find that the desired product 3a was
obtained with 77% ee, albeit in only 22% yield, when 1a was
treated with 2b in the presence of 15 mol% of the 9-
anthracenyl-derived CPA 4a and 15 mol% of CuI (see
Table S1 in the Supporting Information). To improve the
product yield and enantioselectivity, various reaction condi-
tions were examined. Upon optimizing the reaction condi-
tions through variation of the copper salt, phosphoric acid,
catalyst loadings, solvent, and the molar ratio of the reactants
(Table S1), we identified the following protocol as optimal:
[a] Reaction conditions: 1 (0.2 mmol), 2b (1.7 equiv), ROH (1.5 equiv),
CuCN (15 mol%), 4c (10 mol%), EtOAc (1.0 mL), 258C, Ar. [b] Yield of
isolated product. [c] The ee value was determined by HPLC analysis
using a chiral stationary phase.
2
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efficiently with methanol to afford the corresponding prod-
ucts 3c–i in 45–74% yield with ee values of 90–96%. The
sterically hindered ortho-methoxy-substituted N-(2-allylben-
zyl)amide (1b) gave the expected product 3b in 75% yield
and 75% ee. Moreover, the reaction of a naphthalene and
thiophene substrate (1j or 1k) was facile under the catalytic
system, thus leading to the corresponding products 3j and 3k
in moderate yields with 81 and 92% ee, respectively. In
addition, an aliphatic amide, as a case study of N-(2-
allylbenzyl)pivalamide (1l) was also a suitable substrate for
this reaction, thus resulting in a product yield of 58% with
good enantioselectivity (68%). Most importantly, substitu-
ents including methyl, chloro, and fluoro groups on the phenyl
ring of the substrates at the different positions were well-
tolerated under the standard reaction conditions, thus giving
the desired products 3m–p in 51–72% yields with excellent
enantioselectivities. It is noteworthy that the geminal-disub-
stituted alkene 1q was also an excellent substrate and gave
the product 3q as a mixture of two diastereomers (1:1 d.r.) in
62% yield with 94 and 93% ee. The absolute configuration of
3k was determined to be S by X-ray crystallographic
analysis[17] (see Figure S1), and those of other trifluoro-
methyl-containing N,O-aminals were determined in reference
to 3k.
Next, we explored the scope with respect to the function-
alized alcohols (see box in Table 1). A range of substrates,
including primary and secondary alcohols, were viable in this
transformation. For instance, the present cooperative catal-
ysis could be applied to primary alcohols, thus giving the
corresponding chiral trifluoromethyl-containing N,O-aminals
3r–y in good yields (57–86%) with excellent enantioselecti-
vites (91–99% ee). Notably, reactive groups, such as benzyl or
methoxy groups, or halo substituents including Cl (3o) and Br
(3h and 3y), were well tolerated. The aryl iodide group
remained intact throughout the reaction and the product 3w
was obtained in 86% yield with 99% ee. These results are
significant as halides, Br and I in particular, are reactive in
many transition-metal-catalyzed reactions and offer oppor-
tunities for further modifications at these positions.[18] More-
over, even the isopropyl group is also applicable without loss
in reaction efficiency and enantiocontrol (3u). This promising
result marks the first example of an enantioselective method
oxazolone 6a with 72% yield with excellent diastereoselec-
tivity and good enantioselectivity. Final hydrolysis of the
easily obtained 6a successfully afforded the optically active
quaternary a,b-diamino acid 7a in 96% yield.[19] Reaction of
3a with 1-benzyl-1H-indole (5b) in the presence of (S)-4b
produced the chiral CF3-containing indole derivative 6b in
68% yield with 87% ee.
To gain some insights into the mechanism of the current
reaction, a series of control experiments were conducted.
First, the model racemic and chiral reactions were performed
in the presence of radical scavengers such as 2,6-di-tert-butyl-
4-methylphenol (BHT) or 2,2,6,6-tetramethyl-1-piperidiny-
loxy (TEMPO) under the standard reaction conditions, and
a significant drop in yield was observed. Notably, for the
reaction in the presence of TEMPO, the TEMPO-CF3 adduct
was formed in 95% (racemic) and 88% (chiral) yield (see
Scheme S1). The results reveal that the CF3 radical is likely
involved as the reactive species under the current reaction
conditions.[7]
With regard to the 1,5-hydride shift, a series of deuterium-
labelling experiments in the racemic version[20] were carried
out (see Scheme S2). The deuterium-substituted [D2]-1a
afforded the corresponding aminal [D2]-( Æ )-3a in 68%
yield, with complete transfer of the deuterium label to the
b-position of the alkene [see Eq. (1) in Scheme S2]. In
addition, a crossover experiment was performed under the
standard reaction conditions using a 1:1 mixture of [D2]-1a
and 1d, and it was found that H/D scrambling between [D2]-
1a and 1d was not observed [see Eq. (2) in Scheme S2]. The
results indicate that the current reaction proceeds with the
intramolecular 1,5-H shift process. The kinetic isotope effect
was also examined through the reaction of [D1]-N-(2-allyl-
benzyl)benzamide ([D1]-1a) under the standard reaction
conditions, and a kH/kD of 4.0 was observed [see Eq. (3) in
À
to generate chiral N,O-aminals by redox-neutral-triggered C
H functionalization of the position a to the nitrogen atom.
It is interesting to note that the asymmetric redox-neutral
protocol could be extended to other aliphatic compounds as
viable substrates for this reaction. Thus, our preliminary result
shows that under the standard reaction conditions the
À
Scheme S2]. This result indicated that the activation of the C
H bond adjacent to the nitrogen atom should be a kinetically
relevant process in this tandem reaction.[21] In addition, the
copper(I)-catalyzed reaction of 1a in the absence of MeOH
under the standard reaction conditions furnished the imine
intermediate N-[2-(4,4,4-trifluorobutyl)benzylidene]benza-
mide 8 [see Eq. (4) in Scheme S2], thus revealing the
formation of an imine intermediate in the current system,
which was easily hydrolyzed to the corresponding aldehyde 2-
(4,4,4-trifluorobutyl)benzaldehyde 9 with 47% yield in the
presence of water.
reaction
of
N-{[1-(but-3-en-1-yl)cyclohexyl]methyl}-4-
methoxybenzamide gave the chiral product 3z in 42% yield
with 90% ee (Table 1). This result indicates that the a-
functionalization of the amide was not severely affected by
switching the nature of the benzylic carbon to the inactive
methylene group.
To demonstrate the synthetic applicability of the com-
pounds derived from this current protocol, we have also
performed additional experiments [Eq. (1)]. For example,
treatment of 3a with 4-benzyl-2-phenyloxazol-5(4H)-one
(5a) in the presence of 4a provided the desired CF3-
Additionally, to acquire a further understanding of the
roles of the phosphoric acid in this enantioselective reaction,
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Scheme 2. Control experiments with phosphoric acid catalyst. n.r. =no
reaction.
Scheme 3. Proposed mechanism for the current reaction system.
several control experiments with the phosphoric acid catalyst
were conducted (Scheme 2). Treatment of 1a with 2b and
MeOH at 258C for 36 hours in the presence of either CuCN
alone or 4c alone gave the corresponding product 3a in only
low yield, thus revealing that both the metal catalyst and
phosphoric acid are needed for the reaction, and activation of
Togniꢀs reagent could be facilitated by the phosphoric acid in
this catalytic system. Notably, the relationship between the
nature of a Brønsted acid and its ability for the activation of
the Togniꢀs reagent has recently been investigated by Togni
and co-workers.[22] This hypothesis is further supported by the
finding that 3a was obtained in 83% yield when 1a was
treated with 2b and MeOH under the same reaction
conditions using the CuCN /achiral 4i combination. Consid-
ering the possibility that a chiral copper phosphate complex
could be generated in situ in the presence of a copper(I)
compound and a chiral phosphoric acid to catalyze the current
reaction,[22] we conducted the same reactions with a catalytic
amount of the isolated 4j alone and the combination of CuCN
and 4j, respectively. The use of such catalytic systems resulted
in the formation of 3a with corresponding ee values of 80 and
85% and yields of only 24 and 40%, and clearly shows that
the present reaction can be catalyzed by the chiral copper
phosphate complex. However, we found that the conversions
in the presence of such catalytic systems were lower than that
in the presence of the CuCN/4c catalyst system. These control
experiments indicate that the use of a chiral phosphoric acid
not only plays a vital role in controlling the stereoselectivity
for the last stage of the asymmetric nucleophilic attack
process, but also acts as an acid to successfully activate Togniꢀs
reagent together with copper catalyst.
attack of nucleophiles to imines catalyzed by chiral Brønsted
acids.[23,24]
In summary, we have presented here the first example of
a highly enantioselective redox-neutral tandem process to
À
À
realize concomitant formation of two new C CF3 and C O
À
bonds by functionalization of a C H bond adjacent to an
amide, and it is triggered by radical trifluoromethylation of
alkenes. The sustainable protocol provides a highly efficient
method for the rapid synthesis of valuable enantioenriched
trifluoromethylated N,O-aminals in good to excellent yields
and with excellent regio-, chemo-, and enantioselectivity as
well as a broad substrate scope using a copper(I)/Brønsted
acid cooperative system. This study led us to discover a 1,5-
hydride transfer which involves activation of unactivated
alkenes triggered by radical trifluoromethylation to initiate
À
subsequent enantioselective functionalization of C H bonds
adjacent to nitrogen atoms by a radical process.
Received: May 19, 2014
Published online: && &&, &&&&
À
Keywords: C H activation · copper · enantioselectivity ·
radical chemistry · reaction mechanisms
.
[1] For recent selected reviews of C-H activation, see: a) K. Godula,
D. Sames, Science 2006, 312, 67; b) K. M. Engle, T.-S. Mei, M.
Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788; c) S. R. Neufeldt,
M. S. Sanford, Acc. Chem. Res. 2012, 45, 936.
On the basis of the above observations and literature
precedence,[7] a mechanism was proposed for the current
system (Scheme 3). First, a CF3 radical is generated from the
reaction of 2 with copper(I) and the phosphoric acid (PA),
and then it adds to the alkene to afford the nascent a-CF3-
alkyl radical intermediate A.[7] Once formed, this inherently
high-energy A abstracts a proximal hydrogen atom[9a,g]
adjacent to the nitrogen atom of the amide to generate
a lower-energy alkyl radical (B),[8] followed by single-electron
oxidation[7] to afford the imine intermediate C. Finally, the
attack of an alcohol nucleophile on the imine via the
zwitterionic transition-state D, which features a two-point
hydrogen-bonding interaction in the presence of a chiral
phosphoric acid, furnishes the final product 3, with excellent
enantioselectivity resulting from the proximity effect, and is
most consistent with a mechanism involving nucleophilic
[2] For a selected review, see: a) C. J. Li, Acc. Chem. Res. 2009, 42,
335. For selected asymmetric CDC reactions, see: b) J. Zhang, B.
Tiwari, C. Xing, X. Chen, Y. R. Chi, Angew. Chem. Int. Ed. 2012,
51, 3649; Angew. Chem. 2012, 124, 3709; c) G. Zhang, Y. Zhang,
R. Wang, Angew. Chem. Int. Ed. 2011, 50, 10429; Angew. Chem.
2011, 123, 10613; d) C. Guo, J. Song, S. W. Luo, L. Z. Gong,
Angew. Chem. Int. Ed. 2010, 49, 5558; Angew. Chem. 2010, 122,
5690; e) A. J. Neel, J. P. Hehn, P. F. Tripet, F. D. Toste, J. Am.
Chem. Soc. 2013, 135, 14044; f) Z. Meng, S. Sun, H. Yuan, H.
Lou, L. Liu, Angew. Chem. Int. Ed. 2014, 53, 543; Angew. Chem.
2014, 126, 553.
[3] For a selected review, see: a) B. Peng, N. Maulide, Chem. Eur. J.
2013, 19, 13274; For selected recent asymmetric redox-neutral
reactions, see: b) S. Murarka, I. Deb, C. Zhang, D. Seidel, J. Am.
Chem. Soc. 2009, 131, 13226; c) Y. K. Kang, S. M. Kim, D. Y.
Kim, J. Am. Chem. Soc. 2010, 132, 11847; d) Z. Jiao, S. Zhang, C.
He, Y. Tu, S. Wang, F. Zhang, Y. Zhang, H. Li, Angew. Chem. Int.
Ed. 2012, 51, 8811; Angew. Chem. 2012, 124, 8941; e) K. Mori, K.
4
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Chemie
Ehara, K. Kurihara, T. Akiyama, J. Am. Chem. Soc. 2011, 133,
6166.
P. Xiong, M.-Y. Wu, X.-Y. Zhang, C.-L. Ma, L. Huang, L.-J.
Zhao, B. Tan, X.-Y. Liu, Org. Lett. 2014, 16, 1000; d) X.-L. Zhu,
J.-H. Xu, D.-J. Cheng, L.-J. Zhao, X.-Y. Liu, B. Tan, Org. Lett.
2014, 16, 2192.
[4] K. Muller, C. Faeh, F. Diederich, Science 2007, 317, 1881.
[5] For selected reviews on trifluoromethylation of organic com-
pounds, see: a) J. Nie, H. C. Guo, D. Cahard, J. A. Ma, Chem.
Rev. 2011, 111, 455; b) T. Furuya, A. S. Kamlet, T. Ritter, Nature
2011, 473, 470.
[14] D.-J. Cheng, L. Yan, S.-K. Tian, M.-Y. Wu, L.-X. Wang, Z.-L.
Fan, S.-C. Zheng, X.-Y. Liu, B. Tan, Angew. Chem. Int. Ed. 2014,
53, 3684; Angew. Chem. 2014, 126, 3758.
[6] A. S. Abu-Surrah, M. Kettunen, Curr. Med. Chem. 2006, 13,
1337.
[15] P. Eisenberger, S. Gischig, A. Togni, Chem. Eur. J. 2006, 12, 2579.
[16] For recent selected reviews on chiral Brønsted acids as organo-
catalysts for asymmetric organic transformations, see: a) T.
Akiyama, Chem. Rev. 2007, 107, 5744; b) A. G. Doyle, E. N.
Jacobsen, Chem. Rev. 2007, 107, 5713.
[17] CCDC 989192 (3k) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[18] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
[19] D. Uraguchi, Y. Ueki, T. Ooi, J. Am. Chem. Soc. 2008, 130, 14088.
[20] It should be noted that Sodeoka and co-workers have described
a racemic version regarding the tandem trifluoromethylation of
[7] For selected recent examples for trifluoromethylation of unac-
tivated alkenes, see: a) A. T. Parsons, S. L. Buchwald, Angew.
Chem. Int. Ed. 2011, 50, 9120; Angew. Chem. 2011, 123, 9286;
b) X. Wang, Y. Ye, S. Zhang, J. Feng, Y. Xu, Y. Zhang, J. Wang, J.
Am. Chem. Soc. 2011, 133, 16410; c) H. Egami, R. Shimizu, S.
Kawamura, M. Sodeoka, Angew. Chem. Int. Ed. 2013, 52, 4000;
Angew. Chem. 2013, 125, 4092; d) X. Wu, L. Chu, F.-L. Qing,
Angew. Chem. Int. Ed. 2013, 52, 2198; Angew. Chem. 2013, 125,
2254; e) P. G. Janson, I. Ghoneim, N. O. Ilchenko, K. J. Szabꢁ,
Org. Lett 2012, 14, 2882.
[8] For a selected review, see: a) A. N. Hancock, C. H. Schiesser,
Chem. Commun. 2013, 49, 9892.
À
alkene/1,5-H shift/C H bond functionalization. Only two spe-
[9] For selected representative examples, see: a) D. P. Curran, A. C.
Abraham, H. Liu, J. Org. Chem. 1991, 56, 4336; b) V. Snieckus,
J. C. Cuevas, C. P. Sloan, H.-T. Liu, D. P. Curran, J. Am. Chem.
Soc. 1990, 112, 896; c) H. Maja, D. Dolenc, J. Org. Chem. 2007,
72, 7214; d) K. Chen, J. M. Richter, P. S. Baran, J. Am. Chem.
Soc. 2008, 130, 7247; e) K. Chen, P. S. Baran, Nature 2009, 459,
824; f) B. Han, X.-L. Yang, R. Fang, W. Yu, C. Wang, X.-Y. Duan,
S. Liu, Angew. Chem. Int. Ed. 2012, 51, 8816; Angew. Chem.
2012, 124, 8946; g) A.-F. Voica, A. Mendoza, W. R. Gutekunst,
J. O. Fraga, P. S. Baran, Nat. Chem. 2012, 4, 629.
[10] R. J. Phipps, G. L. Hamilton, F. D. Toste, Nat. Chem. 2012, 4, 603.
[11] J. H. Sohn, N. Waizumi, H. M. Zhong, V. H. Rawal, J. Am. Chem.
Soc. 2005, 127, 7290.
[12] a) G. Li, F. R. Fronczek, J. C. Antilla, J. Am. Chem. Soc. 2008,
130, 12216; b) W. Zheng, L. Wojtas, J. C. Antilla, Angew. Chem.
Int. Ed. 2010, 49, 6589; Angew. Chem. 2010, 122, 6739; c) T.
Honjo, R. J. Phipps, V. Rauniyar, F. D. Toste, Angew. Chem. Int.
Ed. 2012, 51, 9684; Angew. Chem. 2012, 124, 9822.
cific examples were utilized as the substrate with fairly good
results, also seen in Ref. [7c].
[21] For a review on the interpretation of deuterium kinetic isotope
À
effects in C H bond functionalization, see: E. M. Simmons, J. F.
Hartwig, Angew. Chem. Int. Ed. 2012, 51, 3066; Angew. Chem.
2012, 124, 3120.
[22] For examples of the activation of Togniꢀs reagent by Brønsted
acids, see: a) R. Koller, Q. Huchet, P. Battaglia, J. M. Welch, A.
Togni, Chem. Commun. 2009, 5993; b) K. Niedermann, N. Frꢂh,
E. Vinogradova, M. S. Wiehn, A. Moreno, A. Togni, Angew.
Chem. Int. Ed. 2011, 50, 1059; Angew. Chem. 2011, 123, 1091.
[23] For selected examples of the reactions using chiral copper(I)/
phosphate complex, see: a) K. Saito, Y. Kajiwara, T. Akiyama,
Angew. Chem. Int. Ed. 2013, 52, 13284; Angew. Chem. 2013, 125,
13526; b) M. Terada, F. Li, Y. Toda, Angew. Chem. Int. Ed. 2014,
53, 235; Angew. Chem. 2014, 126, 239.
[24] For the representative excellent theoretical studies on a related
mechanism, see: a) M. Yamanaka, J. Itoh, K. Fuchibe, T.
Akiyama, J. Am. Chem. Soc. 2007, 129, 6756; b) L. Simꢁn,
J. M. Goodman, J. Am. Chem. Soc. 2008, 130, 8741.
[13] a) J.-S. Lin, Y.-P. Xiong, C.-L. Ma, L.-J. Zhao, B. Tan, X.-Y. Liu,
Chem. Eur. J. 2014, 20, 1332; b) L. Li, M. Deng, S.-C. Zheng, Y.-
P. Xiong, B. Tan, X.-Y. Liu, Org. Lett. 2014, 16, 504; < lit c > Y.-
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C H Activation
P. Yu, J.-S. Lin, L. Li, S.-C. Zheng,
Y.-P. Xiong, L.-J. Zhao, B. Tan,*
X.-Y. Liu*
&&&& — &&&&
À
Enantioselective C H Bond
Functionalization Triggered by Radical
Trifluoromethylation of Unactivated
Alkene
En route: The title redox-neutral reaction
provides a convenient route to valuable
enantioenriched trifluoromethylated N,O-
aminals in good to excellent yields and
with excellent regio-, chemo-, and enan-
tioselectivity. The reaction features a CuI/
Brønsted acid system and broad sub-
strate scope.
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!