A Dual-Catalytic Strategy to Direct Asymmetric Radical Aminotrifluoromethylation of Alkenes

Article abstract of DOI:10.1021/jacs.6b04077

A novel asymmetric radical aminotrifluoromethylation of alkenes has been developed for the first time, providing straightforward access to densely functionalized CF₃-containing azaheterocycles bearing an α-tertiary stereocenter with excellent enantioselectivity. The key to success is not only the introduction of a Cu(I)/chiral phosphoric acid dual-catalytic system but also the use of urea with two acidic N-H as both the nucleophile and directing group. The utility of this method is illustrated by facile transformations of the products into other important compounds useful in organic synthesis and medicinal chemistry.

Full text of DOI:10.1021/jacs.6b04077

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Communication
A Dual-Catalytic Strategy to Direct Asymmetric
Radical Aminotrifluoromethylation of Alkenes
Jin-Shun Lin, Xiao-Yang Dong, Tao-Tao Li, Na-Chuan Jiang, Bin Tan, and Xin-Yuan Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b04077 • Publication Date (Web): 14 Jul 2016
Downloaded from http://pubs.acs.org on July 15, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
A Dual-Catalytic Strategy to Direct Asymmetric Radical Aminotri-
fluoromethylation of Alkenes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jin-Shun Lin,†‡ Xiao-Yang Dong,† Tao-Tao Li,† Na-Chuan Jiang,† Bin Tan,† and Xin-Yuan Liu*†
†
Department of Chemistry, South University of Science and Technology of China, Shenzhen, 518055, China
‡
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
Supporting Information Placeholder
ate chiral phosphoric acid (CPA)8,11b might meet the challenge for
ABSTRACT: A novel asymmetric radical aminotrifluorometh-
the asymmetric radical aminotrifluoromethylation of alkenes. It
has been assumed that the inꢀsitu generated α-CF3 alkyl radical
might proceed via either a single-electron oxidation process to
carbocation intermediate A3 with a chiral ion pair through electro-
static interactions (Scheme 1b, Path A)9 or the formation of a
chiral alkylcopper(III) phosphate species B (Path B),5,10 to provide
the desired optically active difunctionalization product 3 with a
superior level of enantiocontrol. If this approach is successful, it
would not only be the first example of such an asymmetric radical
reaction but also open up new avenues for the application of ion-
pair catalysis for the challenging radical reactions. However, the
highly reactive nature of the radical species involved in this strat-
egy makes it a formidable task to the identification of an appro-
priate dual-catalytic system, as well as a suitable amine protecting
group, and hence to achieve a subtle balance among reactivity,
stability, and stereocontrol. Based on our own experience in the
aminotrifluoromethylation6 and asymmetric hydrogen-bonding
and counteranion catalysis,11 we report herein the successful de-
velopment of a dual catalytic system of Cu(I) and CPA, which
enables the first catalytic asymmetric radical aminotrifluoromethꢀ
ylation of alkenes with excellent efficiency and enantioselectivity,
providing straightforward access to diversely functionalized CF3-
containing chiral pyrrolidines with the concomitant creation of an
α-tertiary stereocenter (Scheme 1b),12 an important structural
motif presented in a large number of pharmaceutical and agricul-
tural chemicals.12c
ylation of alkenes is developed for the first time, providing
straightforward access to densely functionalized CF3-containing
azaheterocycles bearing an α-tertiary stereocenter with excellent
enantioselectivity. The key to success is not only the introduction
of a Cu(I)/chiral phosphoric acid dual-catalytic system but also
the use of urea with two acidic N-H as both the nucleophile and
directing group. The utility of this method is illustrated by facile
transformations of the products into other important compounds
useful in organic synthesis and medicinal chemistry.
The increasing importance of chiral CF3-containing heterocycles
in pharmaceuticals and agrochemicals, as well as materials devel-
opment, has spurred vast efforts in the development of new cata-
lytic asymmetric methods for their synthesis.1 In particular, since
the pioneering studies on the Cu(I)-catalyzed deprotonative radi-
cal trifluoromethylation of olefins carried out by the research
groups of Buchwald,2a Liu and Fu,2b and Wang,2c direct radical
difunctionalization of alkenes and alkynes3 has received increas-
ing attention in recent years. Although great endeavors have been
devoted to various racemic versions of radical trifluoromethyla-
tion of alkenes, the development of catalytic asymmetric methods
has proven a formidable challenge largely due to the intrinsic
reactivity of the involved odd-electron species.4 To address this
challenge, Buchwald has more recently championed the copper-
catalyzed enantioselective intramolecular oxytrifluoromethylation
of alkenes with carboxylic acids in the presence of chiral
bis(oxazoline) ligands, providing an efficient access to CF3-
containing lactones with good enantioselectivities (74-83% ee).5
However, difunctionalizationꢀtype radical trifluoromethylation
reactions with other types of nucleophiles, to our best knowledge,
still remain unknown. In the past several years, we and others
have successfully developed the racemic Cu(I)-catalyzed radical
aminotrifluoromethylation of alkenes, offering an efficient way
for the construction of useful trifluoromethyl azaheterocycles
(Scheme 1a).6 Unfortunately, our initial attempts to the use of
Cu(I)/bis(oxazoline)-catalysis, as inspired by Buchwald’s work, to
achieve asymmetric aminotrifluoromethylation of N-alkenyl urea
1a with Togni’s reagent 2a or 2b met with very low yield and
enantioselectivity (Scheme S1 in SI). Clearly, a conceptually dif-
ferent approach is still very desirable to achieve highly efficient
asymmetric radical aminotrifluoromethylation of alkenes.
Scheme 1. Asymmetric Radical Trifluoromethylation of
Alkenes
Our study commenced with the examination of different N-
protecting groups of the alkenyl amines 1 with Togni’s reagent
2a13 in the presence of CuI (10 mol%) and CPA (S)-A1 (15 mol%)
(Scheme 2). Various alkenyl substrates including free amine, and
amide, carbamate or thiourea-protected amines hardly resulted in
any formation of the desired products at room temperature or a
After careful consideration of the reaction mechanism3 and in-
spired by the recent great successes of asymmetric ion-pair cataly-
sis with chiral phosphate counterions,7 we envisioned that a dual-
catalytic system consisting of a copper(I) source and an appropri-
o
higher temperature of 80 C, presumably due to the susceptibility
of free amines to oxidation, and/or the poisoning of the transition-
metal catalyst via strong ligation to the protected amine moieties.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
While a tosyl protecting group afforded the desired product 3A’ in
These results encouraged us to further carry out systematic op-
46% yield, albeit with low enantioselectivity (20% ee) at 80 oC in
EtOAc, we were glad to find that the use of urea substrate 1a
resulted in a remarkable improvement in both yield and enantiose-
lectivity, even at room temperature. Its good performance, as
compared with other protecting groups, might be due to its suita-
ble electron-withdrawing ability to ensure both necessary nucleo-
philicity of the nitrogen and to provide two acidic N-H for coop-
erative multiple hydrogen bonding interactions with CPA for
effective activation and stereocontrol.
timizations of different reaction parameters (Table 1). Evaluation
of various BINOL and SPINOL-based CPAs14 indicated that the
selectivity relies heavily on the substituents at the 3,3’-positions
of the backbone. Among all catalysts screened, good result was
obtained with (S)-A1 with 4-Ph-phenyl groups on the 3,3’-
positions (Table 1, entries 1-8). We next screened different Cu
salts to find out that CuCl was the best in terms of enantioselectiv-
ity (81% ee) (entry 9). Among the solvents screened, ethyl isobu-
tyrate was found to be most efficient to give 85% yield and 91%
ee (entry 15). Further investigation revealed that lowering the
catalyst loading of acid to 10 mol% affected the chemical yield,
but did not lead to a decrease in enantioselectivity (entry 16). It is
noteworthy that changing the CF3 reagent from 2a to 2b resulted
in a remarkable decrease in the enantioselectivity (75% ee) (entry
17), which is largely due to the competitive nonasymmetric back-
ground processes catalyzed by 2-iodobenzoic acid that was gener-
ated in situ in the reaction system (See the detail in Scheme S2, in
SI). Only trace amount of the desired product was obtained either
in the presence of a cationic copper(II) salt or in the absence of
copper(I) catalyst (entries 18 and 19), revealing that copper(I) is
essential as single-electron catalyst to activate Togni’s reagent to
generate CF3 radical.
1
2
3
4
5
6
7
8
Scheme 2. Evaluation of Different Protective Groupsa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
With the optimal conditions established, the generality of the
current dual-catalytic system for the asymmetric radical trifluo-
romethylation were next investigated. First, a wide range of sub-
strates with N-aryl urea groups were surveyed (Table 2). It is
found that both the position and electronic nature of the substitu-
ents (R’) on the aromatic ring have negligible effect on the reac-
tion efficiency and stereoselectivity of the process. For example,
substrates 1 bearing electron-withdrawing (CF3, F, Cl, Br) or elec-
tron-donating groups (Me, OMe) at different positions (para or
meta) of the aryl ring reacted efficiently to afford the correspond-
ing products 3A-3I in 69-88% yield with 91-98% ee (entries 1-9).
Moreover, the sterically hindered ortho-substituted substrates 1j
and 1k (including CF3 and Br) gave the corresponding products
3J and 3K in 50-51% yields with excellent enantioselectivities,
respectively (entries 10 and 11). Particularly noteworthy is that
halo substituents such as F, Cl and Br at different positions were
well-tolerated, which are significant since aryl halides are usually
incompatible with other copper-catalyzed trifluoromethylation
reaction systems,15 while they could offer opportunities for further
useful modifications. The absolute configuration of 3F was de-
termined to be (R) by X-ray crystallographic analysis (Figure S1
in SI), and those of other trifluoromethyl-containing products
were determined in reference to 3F.
Table 1. Screening of Reaction Conditionsa
entry Cu
CPA
solvent
y(%)b ee(%)c
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
(S)-A1 EtOAc
(S)-A2 EtOAc
(S)-A3 EtOAc
(R)-A4 EtOAc
(R)-A5 EtOAc
(R)-A6 EtOAc
(R)-A7 EtOAc
(R)-A8 EtOAc
(S)-A1 EtOAc
(S)-A1 EtOAc
90
91
92
91
85
93
51
90
85
85
60
93
17
55
37
15
8
-10
-36
-24
18
34
81
80
43
78
0
84
91
91
75
77
--h
Table 2. Substrate Scope of Different Urea Groupsa,b,c
9
CuCl
CuOAc
10
11
12
13
14
15d
16d,e
17d,f
18d
19d
Cu(CH3CN)4PF4 (S)-A1 EtOAc
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Cu(OAc)2
--g
(S)-A1 DCM
(S)-A1 CH3CN
(S)-A1 MTBE
(S)-A1 iPrCO2Et 85
(S)-A1 iPrCO2Et 70
(S)-A1 iPrCO2Et 67
entry
R’
3
t
(h) y (%)b
ee (%)c
91
1
2
3,5-(CF3)2C6H3
4-CF3C6H4
3A
3B
72
70
64
64
64
64
64
64
64
64
80
71
70
72
78
83
73
69
88
50
91
3
3-CF3C6H4
4-FC6H4
3C
3D
3E
3F
3G
3H
3I
97
96
97
92
95
98
91
90
(S)-A1 iPrCO2Et
6
4
(S)-A1 iPrCO2Et --h
5
3-ClC6H4
4-BrC6H4
3-BrC6H4
3-MeC6H4
3-MeOC6H4
2-BrC6H4
a Reactions were run on a 0.05 mmol scale. b Yield based on 1H
6
d
or 19F NMR analysis of the crude product. c Ee value on HPLC.
Reaction time was prolonged to 72 h. eCuCl (10 mol%) and (S)-
A1 (10 mol%) were used. f Togni’s reagent 2b was used. g No Cu
catalyst. h Product was not detected.
7
8
9
10
3J
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
likely involved as the reactive species under the current reaction
conditions.17 To further understand the role of phosphoric acid,
treatment of 1a with 2a under otherwise identical conditions in
the presence of either CuCl alone or (S)-A1 alone (see Scheme
S4, eq. 2 in SI and Table 1, entries 19) gave the corresponding
product 3A in only low yield (the detailed kinetic behaviors as
shown in Figure S2 in SI), thus revealing that both the Cu(I) salt
and the phosphoric acid are necessary for the reaction, and the
activation of Togni’s reagent could be facilitated by the phosphor-
ic acid in this dual-catalytic system.11b,18 Furthermore, no desired
product was observed under the standard conditions with methyl-
protected urea derivative 6 as the substrate (Scheme 4a and
Scheme S4, eq. 3, in SI), clearly indicating that the urea with two
acidic N-H at the appropriate position might play a crucial role in
asymmetric induction.
11
2-CF3C6H4
3K
96
51
92
1
2
3
4
5
6
7
8
9
a All the reactions were conducted on 0.2 mmol scale. b Isolated
yields based on 1. c Determined by chiral HPLC analysis.
We next explored the substrate scope with a variety of gem-
disubstituted alkenes bearing different tethering groups (Table 3).
A variety of cyclic N-alkenyl ureas containing three to seven-
membered ring were well tolerated to provide a diverse set of the
enantioenriched trifluoromethylated spiro-products 3L-3P in
moderate to good yields with 87-91% ee. Interestingly, changing
the alkyl groups to ester groups in the tether, such as ethyl (1q)
and t-butyl ester group (1r) had no significant influence on the
reaction to give 3Q and 3R in 60 and 54% yields with 95 and
88% ee, respectively. To further investigate the reaction scope, we
tested the use of other gem-disubstituted alkenes as substrates. A
range of diversely functionalized N-alkenyl ureas with electron-
rich or electron-poor substituents on aromatic ring, were viable in
this transformation to give the corresponding products 3S-3W in
55-82% yields with 90-97% ee. However, non-branched substrate
N-urea-4-pentenylamine 1x gave the desired product 3X with low
yield and ee (Scheme S3 in SI).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Mechanistic Proposal
Table 3. Substrate Scope of Different Tethered Groups
and Alkenyl Parta,b,c
O
O
CF3
R1
R1
R2
R2
CuCl (10 mol%)
(S)-A1 (15 mol%)
R2
R2
I
N
N
H
N
N
O
H
+
H
iPrCO2Et, 25 o
C
R3
On the basis of the above observations and previous stud-
ies,2,3,5,17 two possible reaction pathways for the asymmetric radi-
cal aminotrifluoromethylation are proposed, although further stud-
ies are needed to clarify the details. Initially, the CF3 radical and
chiral Cu(II) phosphate are generated from the reaction of 2a with
Cu(I) and the phosphoric acid, followed by the addition of CF3
radical to alkene to afford the α-CF3 alkyl radical C. Alkyl radical
intermediate and urea could be trapped by Cu(II) to generate a
Cu(III) species D,5,10 wherein chiral phosphate anion could be
coordinated as an anionic ligand (Scheme 4b).7 During this course,
the chiral phosphate could control the facial selectivity of such
reaction via both hydrogen-bonding interactions with N-H bond
adjacent to aryl group and ion-pairing interaction in a concerted
transition state. Finally, reductive elimination of D takes place to
furnish 3 and to regenerate copper(I) and the phosphoric acid.
Another pathway via single-electron oxidization of C to the corre-
sponding carbocation A by the Cu(II) through ion pairing
(Scheme 1b, Path A),9 cannot be ruled out at the present stage.19
F3C
2a
R3
3
1
CF3
CF3
O
O
O
RO2
RO2
C
N
N
CF3
N
N
CF3
H
H
C
N
N
CF3
H
F3C
3M, n = 1, 78%, 88% ee (64 h)e
3N, n = 2, 65%, 89% ee (72 h)f
3O, n = 3, 68%, 87% ee (72 h)f
3P, n = 4, 71%, 88% ee (64 h)
F3C
n
F3C
3L, 60%, 91% ee (72 h)d
3Q, R=Et, 60%, 95% ee (120 h)
3R, R=tBu, 54%, 88% ee (120 h)
O
O
N
N
Br
3S, R3 = 3-OMe, 76%, 94% ee (64 h)
3T, R3 = 3-Me, 82%, 96% ee (64 h)
3U, R3 = 3-Ph, 64%, 90% ee (96 h)
3V, R3 = 3-F, 55%, 96% ee (72 h)
N
N
CF3
H
H
R3
F3C
F3C
3W, 60%, 97% ee (96 h)
aAll the reactions were conducted on 0.2 mmol scale. bIsolated yields based on 1. cDetermined by HPLC
analysis. d4 mol% CuCl. e7.5 mol% CuCl. f5 mol% CuCl.
The enantioenriched CF3-containing azaheterocycles from the
current reaction system are both densely and diversely functional-
ized, which would serve as a convenient handle to access other
useful chiral trifluoromethyl molecules (Scheme 3). The selective
In summary, we have developed the first catalytic asymmetric
radical aminotrifluoromethylation of alkenes. The overall process
serves as a novel, efficient, and simple approach for straightfor-
ward access to diversely substituted CF3-containing pyrrolidines
bearing an α-tertiary stereocenter with excellent efficiency, re-
markable enantioselectivity and excellent functional group toler-
ance. Critical to the success of this process is not only the intro-
duction of a Cu(I)/phosphoric acid dual-catalytic system but also
the use of urea with two acidic N-H as both the nucleophile and
directing group. The highly enantioenriched and diversely func-
tionalized products can be easily transformed into other useful
chiral CF3-containing building blocks. Our ongoing efforts in-
clude the expansion with more radical precursors and the devel-
opment of more challenging intermolecular asymmetric version.
.
reduction of 3A by BH3 SMe2 successfully generated the desired
α-tertiary amine 4 in 80% yield. Furthermore, in the presence of
bis(trifluoroacetoxy)iodo]benzene (PIFA), 3A was smoothly cy-
clized to give tricyclic amine 5 bearing an α-tetrasubstituted car-
bon stereocenter in 46% yield without decreasing the ee value.
The tricyclic structure of 5 is the core structure of many biologi-
cally active natural alkaloids such as hinckdentine A.16
Scheme 3. Representative Product Transformations
ASSOCIATED CONTENT
Supporting Information
To obtain some insights into the reaction mechanism, radical
trapping experiments were conducted by employing 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) and 1,4-benzoquinone
(BQ) (Scheme S4, eq. 1 in SI). The reactions were found to be
remarkably inhibited by these reagents, together with the previous
studies of radical trifluoromethylation of alkene with Togni’s
reagent by Cu(I) catalyst,2,3 suggesting that the CF3 radical is
Experimental procedures, characterization of all new compounds,
Schemes S1-4, and Figures S1-2. This information is available
free of charge via the Internet at http://pubs.acs.org.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
Soc. Rev. 2013, 42, 1337. (j) Chen, D.-F.; Han, Z.-Y.; Zhou, X.-L.; Gong,
L.-Z. Acc. Chem. Res. 2014, 47, 2365. (k) Yang, Z.-P.; Zhang, W.; You,
S.-L. J. Org. Chem. 2014, 79, 7785.
AUTHOR INFORMATION
1
Corresponding Author
2
3
4
5
6
7
8
9
(8) For selected examples for Cu/phosphoric acid dual-catalysis, see: (a)
Zhao, B.; Du, H.; Shi, Y. J. Org. Chem. 2009, 74, 8392. (b) Yazaki, R.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 10275. (c)
Rauniyar, V. W.; Wang, Z. J.; Burks, H. E.; Toste, F. D. J. Am. Chem. Soc.
2011, 133, 8486. (d) Saito, K.; Kajiwara, Y.; Akiyama, T. Angew. Chem.,
Int. Ed. 2013, 52, 13284.
liuxy3@sustc.edu.cn
Notes
The authors declare no competing financial interest.
(9) (a) Mayer, S.; List, B. Angew. Chem., Int. Ed. 2006, 45, 4193. (b)
Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc. 2011,
133, 3732. (c) Rauniyar, V.; Lackner, A. D.; Hamilton, G. L.; Toste, F. D.
Science 2011, 334, 1681. (d) Lackner, A. D.; Samant, A. V.; Toste, F. D. J.
Am. Chem. Soc. 2013, 135, 14090. (e) Gatzenmeier, T.; van Gemmeren,
M.; Xie, Y.; Höfler D.; Leutzsch, M.; List, B. Science 2016, 351, 949.
(10) For a representative review on high-valent copper in catalysis, see:
(a) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177. For selected
leading references, see: (b) Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J.
C. Science 2012, 338, 647. (c) Kainz, Q. M.; Matier, C. D.; Bartoszewicz,
A.; Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681. (d) Ye,
Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034. (e) Tran, B. L.; Li,
B.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 2555. (f)
Wang, F.; Wang, D.; Mu, X.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014,
136, 10202. (g) Zhang, H.; Yao, B.; Zhao, L.; Wang, D.-X.; Xu, B.-Q.;
Wang, M.-X. J. Am. Chem. Soc. 2014, 136, 6326. (h) Holt, D.; Gaunt, M.
J. Angew. Chem., Int. Ed. 2015, 54, 7857. (i) Cahard, E.; Male, H. P.;
Tissot, M.; Gaunt, M. J. J. Am. Chem. Soc. 2015, 137, 7986. (j)
Walkinshaw, A. J.; Xu, W.; Suero, M. G.; Gaunt, M. J. J. Am. Chem. Soc.
2013, 135, 12532. (k) Wang, Z.-L.; Zhao, L.; Wang, M.-X. Chem. Comꢀ
mun. 2012, 48, 9418.
(11) (a) Liu, X.-Y.; Che, C.-M. Org. Lett. 2009, 11, 4204. (b) Yu, P.;
Lin, J.-S.; Li, L.; Zheng, S.-C.; Xiong, Y.-P.; Zhao, L.-J.; Tan, B.; Liu, X.-
Y. Angew. Chem., Int. Ed. 2014, 53, 11890. (c) Yu, P.; Zheng, S.-C.;
Yang, N.-Y.; Tan, B.; Liu, X.-Y. Angew. Chem., Int. Ed. 2015, 54, 4041.
(d) Lin, J.-S.; Yu, P.; Huang, L.; Zhang, P.; Tan, B.; Liu, X.-Y. Angew.
Chem., Int. Ed. 2015, 54, 7847.
(12) For selected recent reviews on the formation of quaternary stereo-
centers, see: (a) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516, 181.
(b) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Acc. Chem. Res. 2015,
48, 740. (c) Sheikh, N. S.; Leonori, D.; Barker, G.; Firth, J. D.; Campos,
K. R.; Meijer, A. J. H. M.; O’Brien, P.; Coldham, I. J. Am. Chem. Soc.
2012, 134, 5300.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation
of China (Nos. 21572096, 21302088), Shenzhen overseas high
level talents innovation plan of technical innovation project
(KQCX20150331101823702), Shenzhen special funds for the
development of biomedicine, Internet, new energy, and new mate-
rial industries (JCYJ20150430160022517) and the National Key
Basic Research Program of China (973 Program 2013CB834802)
is greatly appreciated.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) For selected recent reviews on enantioselective trifluoromethylation
reactions, see: (a) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (b)
Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011, 473, 470. (c) Nie, J.;
Guo, H.-C.; Cahard, D.; Ma, J.-A. Chem. Rev. 2011, 111, 455. (d) Yang,
X.; Wu, T.; Phipps, R. J.; Toste, F. D. Chem. Rev. 2015, 115, 826.
(2) (a) Parsons, A. T.; Buchwald, S. L. Angew. Chem., Int. Ed. 2011, 50,
9120. (b) Xu, J.; Fu, Y.; Luo, D.-F.; Jiang, Y.-Y.; Xiao, B.; Liu, Z.-J.;
Gong, T.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 15300. (c) Wang, X.;
Ye, Y.; Zhang, S.; Feng, J.; Xu, Y.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.
2011, 133, 16410.
(3) For selected recent reviews on trifluoromethylation of alkenes and
alkynes, see: (a) Studer, A. Angew. Chem., Int. Ed. 2012, 51, 8950. (b)
Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem., Int. Ed. 2013, 52,
8214. (c) Chen, P.; Liu, G. Synthesis 2013, 45, 2919. (d) Studer A.; Curran,
D. P. Nat. Chem. 2014, 6, 765. (e) Chu, L.; Qing, F.-L. Acc. Chem. Res.
2014, 47, 1513. (f) Koike, T.; Akita, M. J. Fluorine Chem. 2014, 167, 30.
(g) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598. (h) Xu, J.;
Liu, X.; Fu, Y. Tetrahedron Lett. 2014, 55, 585. (i) Egami, H.; Sodeoka,
M. Angew. Chem., Int. Ed. 2014, 53, 8294. (j) Barata-Vallejo, S.; Lantaño,
B.; Postigo, A. Chem.ꢀEur. J. 2014, 20, 16806. (k) Charpentier, J.; Früh,
N.; Togni, A. Chem. Rev. 2015, 115, 650. (l) Guo, P.; Song, X.-R.; Liu,
X.-Y.; Liang, Y.-M. Chem.ꢀEur. J. 2015, 21, 7648. (m) Zeng, Y.; Ni, C.;
Hu, J. Chem.ꢀEur. J. 2016, 22, 3210.
(13) Synthesis of Togni’s reagent, see: Eisenberger, P.; Gischig, S.;
Togni, A. Chem.ꢀEur. J. 2006, 12, 2579.
(14) For comprehensive reviews on asymmetric Brønsted acid catalysis,
see: (a) Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) You, S.-L.; Cai, Q.;
Zeng, M. Chem. Soc. Rev. 2009, 38, 2190. (c) Yu, J.; Shi, F.; Gong, L. Z.
Acc. Chem. Res. 2011, 44, 1156. (d) Terada, M. Curr. Org. Chem. 2011,
15, 2227. (e) Rueping, M.; Kuenkel, A.; Atodiresei, I. Chem. Soc. Rev.
2011, 40, 4539. (f) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem.
Rev. 2014, 114, 9047. (g) James, T.; van Gemmeren M.; List, B. Chem.
Rev. 2015, 115, 9388.
(15) For selected examples, see: (a) Morimoto, H.; Tsubogo, T.; Litvi-
nas, N. D.; Hartwig, J. F. Angew. Chem., Int. Ed. 2011, 50, 3793. (b)
Kitazume, T.; Nakajima, S. J. Fluorine Chem. 2004, 125, 1447. (c) Krem-
lev, M. M.; Mushta, A. I.; Tyrra, W.; Yagupolskii, Y. L.; Naumann, D.;
Möller, A. J. Fluorine Chem. 2012, 133, 67. (d) Lishchynskyi, A.;
Novikov, M. A.; Martin, E.; Escudero-Adán, E. C.; Novák, P.; Grushin, V.
V. J. Org. Chem. 2013, 78, 11126. (e) Evano, G.; Blanchard, N.; Toumi,
M. Chem. Rev. 2008, 108, 3054. (f) Correa, A.; Bolm, C. Adv. Synth.
Catal. 2007, 349, 2673.
(4) For one selected review on asymmetric radical reactions, see: Sibi,
M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263.
(5) (a) Zhu, R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52,
12655. (b) Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 8069.
(6) (a) Lin, J.-S.; Xiong, Y.-P.; Ma, C.-L.; Zhao, L.-J.; Tan, B.; Liu, X.-
Y. Chem.ꢀEur. J. 2014, 20, 1332. (b) Lin, J.-S.; Liu, X.-G.; Zhu, X.-L.;
Tan, B.; Liu, X.-Y. J. Org. Chem. 2014, 79, 7084. Aminotrifluoromethyla-
tion of alkenes was also reported by other research groups, see: (c)
Fuchikami, T.; Shibata, Y.; Urata, H. Chem. Lett. 1987, 521. (d) Yasu, Y.;
Koike, T.; Akita, M. Org. Lett. 2013, 15, 2136. (e) Kim, E.; Choi, S.; Kim,
H.; Cho, E. J. Chem.ꢀEur. J. 2013, 19, 6209. (f) Egami, H.; Kawamura, S.;
Miyazaki, A.; Sodeoka, M. Angew. Chem., Int. Ed. 2013, 52, 7841. (g)
Kawamura, S.; Egami, H.; Sodeoka, M. J. Am. Chem. Soc. 2015, 137,
4865. (h) Wang, F.; Qi, X.; Liang, Z.; Chen, P.; Liu, G. Angew. Chem., Int.
Ed. 2014, 53, 1881. (i) Carboni, A.; Dagousset, G.; Magnier, E.; Masson,
G. Org. Lett. 2014, 16, 1240. (j) Dagousset, G.; Carboni, A.; Magnier, E.;
Masson, G. Org. Lett. 2014, 16, 4340. (k) Wei, Q.; Chen, J.-R.; Hu, X.-Q.;
Yang, X.-C.; Lu, B.; Xiao, W.-J. Org. Lett. 2015, 17, 4464.
(7) Selected reviews on catalytic processes that involve chiral anions or
anion recognition: (a) Lacour, J.; Hebbe-Viton, V. Chem. Soc. Rev. 2003,
32, 373. (b) Lacour, J.; Moraleda, D. Chem. Commun. 2009, 46, 7073. (c)
Zhang, Z.-G.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187. (d) Phipps,
R. J.; Hamilton, G. L.; Toste, F. D. Nat. Chem. 2012, 4, 603. (e) Parra, A.;
Reboredo, S.; Castro, A. M. M.; Alemán, J. Org. Biomol. Chem. 2012, 10,
5001. (f) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013, 52, 518. (g)
Brak, K.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2013, 52, 534. (h)
Raskatov, J. A.; Thompson, A. L.; Cowley, A. R.; Claridge, T. D.W.;
Brown, J. M. Chem. Sci. 2013, 4, 3140. (i) Du, Z.-T.; Shao, Z.-H. Chem.
(16) Higuchi, K.; Sato, Y.; Tsuchimochi, M.; Sugiura, K.; Hatori, M.;
Kawasaki, T. Org. Lett. 2009, 11, 197.
(17) Ling, L.; Liu, K.; Li, X.; Li, Y. ACS Catal. 2015, 5, 2458.
(18) (a) Koller, R.; Huchet, Q.; Battaglia, P.; Welch, J. M.; Togni, A.
Chem. Commun. 2009, 40, 5993. (b) Niedermann, K.; Früh, N.; Vinogra-
dova, E.; Wiehn, M. S.; Moreno, A.; Togni, A. Angew. Chem., Int. Ed.
2011, 50, 1059.
(19) It should be noted that no reaction of 1a without Togni’s reagent
under the standard conditions was observed (Scheme S4, eq. 4, in SI),
which revealed that a mechanism that involves an aminocupration fol-
lowed by homolysis of the C-Cu bonds and subsequent coupling of a CF3
radical is possibly unlikely; see: Bovino, M. T.; Chemler, S. R. Angew.
Chem., Int. Ed. 2012, 51, 3923.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment