Copper-Catalyzed Carbotrifluoromethylation of Unactivated Alkenes Driven by Trifluoromethylation of Alkyl Radicals

Article abstract of DOI:10.1002/cjoc.201900075

We report herein an unprecedented protocol for radical carbotrifluoromethylation of unactivated alkenes. With Cu(OTf)₂ as the catalyst, the reaction of unactivated alkenes, TMSCF₃ and activated alkyl chlorides at room temperature provides the corresponding carbotrifluoromethylation products in satisfactory yields. Directed by trifluoromethylation of alkyl radicals, the method exhibits an excellent regioselectivity that is opposite to those driven by CF₃ radical addition.

Full text of DOI:10.1002/cjoc.201900075

Accepted Article
Title: Copper-Catalyzed Carbotrifluoromethylation of Unactivated Alkenes Driven
by Trifluoromethylation of Alkyl Radicals
Authors: Zhenzhen Zhang, Lin Zhu, and Chaozhong Li*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2019, 37, 10.1002/cjoc.201900075.
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Copper-Catalyzed Carbotrifluoromethylation of Unactivated Al-
kenes Driven by Trifluoromethylation of Alkyl Radicals
Zhenzhen Zhang,a Lin Zhu,a and Chaozhong Li*, a, b
a Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. China, and b School of Materials and Chemical Engineering,
Ningbo University of Technology, No. 201 Fenghua Road, Ningbo 315211, P. R. China.
Supporting Information Placeholder
CF3 radicals1e and to the lack of methods for trifluoromethylation of
alkyl radicals.
ABSTRACT: We report herein an unprecedented protocol for radical
carbotrifluoromethylation of unactivated alkenes. With Cu(OTf)2 as
the catalyst, the reaction of unactivated alkenes, TMSCF3 and activated
alkyl chlorides at room temperature provides the corresponding car-
botrifluoromethylation products in satisfactory yields. Directed by
trifluoromethylation of alkyl radicals, the method exhibits an excellent
regioselectivity that is opposite to those driven by CF3 radical addition.
Very recently, we introduced (bpy)Cu(CF3)3-mediated (bpy = 2,2’-
bipyridine) radical trifluoromethylation of alkyl halides.4 The method
was then extended to decarboxylative trifluoro-methylation of aliphatic
carboxylic acids5 and to C(sp3)- - H trifluoromethylation of alkylarenes,
carboxamides or sulfonamides.6 In the meantime, the MacMillan group
developed an alternative method for decarboxylative trifluoromethyla-
tion under photoredox conditions.7 These works set the stage for the
exploration of carbotrifluoromethylation of alkenes depicted in
Scheme 1b. However, the realization of this endeavor faces several
challenges: (a) once a carbon-centered radical (C•) is generated, its
addition to an alkene must be much faster than direct trifluoromethyla-
tion of the radical; (b) the generation of CF3 radicals should be strictly
avoided because the addition of CF3 radicals to alkenes is fast and effi-
cient; (c) the trifluoromethylation of adduct radicals A2 should pre-
dominate over any other competing processes (also vide infra); and (d)
to make the carbotrifluoromethylation more practical, it would be ideal
to use cheap CF3 sources and to carry out the reaction in copper-
catalyzed manner.
Trifluoromethylated molecules have found increasingly important
roles in pharmaceuticals and agrochemicals. The introduction of tri-
fluoromethyl groups into pharmaceuticals can make them more lipo-
philic and metabolically stable, and increase the strength of their inter-
actions with target proteins. As a consequence, significant efforts have
been devoted to the development of new trifluoromethylation methods
under mild conditions.1 In this context, trifluoromethylation-involved
difunctionalization of alkenes have received considerable attention.1 Of
particular interest is carbotrifluoromethylation of alkenes that allows
concomitant formations of two new C(sp3)- - C bonds, and is extremely
valuable in the synthesis of fluorinated compounds. These reactions,
without exception, always proceed via CF3 radical addition to alkenes.
The adduct radicals (A1) thus formed can be trapped either intramo-
lecularly2 or intermolecularly3 by radical acceptors such as arenes, al-
kenes, alkynes, nitriles, etc (Scheme 1a). An alternative strategy is the
addition of carbon-centered radicals (C•) other than CF3 radicals to
alkenes to give adduct radicals A2. Subsequent trifluoromethylation of
A2 provides carbotrifluoromethylation products B2 with a regioselec-
tivity opposite to B1 (Scheme 1b). This strategy should significantly
broaden the scope of carbotrifluoromethylation, providing a versatile
tool for the synthesis of trifluoromethylated molecules. Unfortunately,
it remains unexplored to date probably due to the easy generation of
Scheme 1. Carbotrifluoromethylation of Alkenes
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a Conditions: 1a (0.20 mmol), TMSCF3 (0.60 mmol), Cu(OTf)2 (0.04
via CF radical addition
(a)
(b)
(literature works)
3
b
mmol), solvent (4 mL), CsF, [Ag] (if applicable), rt, 24 h. Isolated
C
CF3
C
X
yield based on 1a. c Without Cu(OTf)2.
F
3C
F
3C
R
R
R
A1
B1
The above optimized conditions (entry 4, Table 1) were then ap-
plied to a number of unsaturated trichloroacetamides and the results
are summarized in Scheme 2. Both N-aryl- and N-alkyl-substituted N-
via
of
radicals this work
trifluoromethylation alkyl
(
)
CF3
CF3
C
C
Cu(II)
allyltrichloroacetamides
underwent
efficient
cyclization- -
C
R
R
R
trifluoromethylation, furnishing the corresponding products 3a- - 3g in
high yields. N,N-Diallyltrichloroacetamide also proved to be suitable
substrate and the carbotrifluoromethylation product 3h was obtained
in 65% yield. The result indicated that the reaction is free from CF3
radicals. Similarly, the reaction of N-(2-methylallyl)trichloroacetamide
also proceeded via 5-exo-trig cyclization to provide lactam 3i. Further-
more, 6-exo-trig cyclization- - trifluoromethylation was also successfully
implemented as exemplified by the synthesis of δ-lactam 3j in 76%
yield. These results clearly demonstrate the feasibility of carbotrifluo-
romethylation depicted in Scheme 1b. In the meantime, they also serve
as solid evidence for the proposed radical mechanism.
A2
B2
As a start, we chose N-(4-chlorophenyl)-N-allyltrichloro-acetamide
(1a) as the model substrate, the cheap and easily available Ruppert- -
Prakash reagent (TMSCF3)8 as the CF3 source and Cu(OTf)2 as the
catalyst to test our idea (Table 1). Stirring the mixture of 1a, TMSCF3
(3 equiv), CsF (1.0 equiv), Cu(OTf)2 (20 mol %) and ligand bpy (20
mol %) in acetonitrile at room temperature for 24 hours afforded chlo-
ride 2a in 77% yield while no desired carbotrifluoromethylation prod-
uct 3a could be observed (entry 1, Table 1). Apparently the copper-
assisted chlorine-atom-transfer radical addition (Cl-ATRA) prevailed.9
To inhibit the Cl-ATRA, the commercially available Ag(bpy)2OTf
([Ag]) was introduced as the chloride scavenger,10 and both 2a (25%)
and 3a (23%) was obtained in comparable yields (entry 2, Table 1).
Interestingly, removing the extra ligand bpy from the reaction mixture
resulted in an increased yield (34%) of 3a and decreased yield (12%)
of 2a (entry 3, Table 1). After extensive adjustment of reaction param-
eters (see Tables S1 and S2 in the Supporting Information for details),
we were pleased to find that, with the combination of [Ag] (1.3 equiv)
and CsF (1.7 equiv) in chlorobenzene- - DCM (3:1) solution, the car-
botrifluoromethylation product 3a was achieved in 80% isolated yield
while no Cl-ATRA byproduct 2a could be detected (entry 4, Table 1).
The control experiment indicated that Cu(OTf)2 was required for the
reaction (entry 5, Table 1). Our experiments also showed that 2a could
not be converted to 3a under the above conditions.
Scheme 2. Cyclization- - Trifluoromethylation of Amides
Cl2C
O
CF3
Cl2C
O
CF3
71%a
80%a
73%a
=
3e
3f
t
=
3a
3b
3c
3d
(R -Bu),
N
N
R
(X 4-Cl),
65%a
= c-
H
C6
=
(R
11),
(X 4-F),
76%a
82%a
=
=
3g
(R 4-F-Bn),
CF3
X
(X 4-MeO),
=
68%a
(X H),
CF3
Cl2C
O
CF3
Cl2C
Cl2C
N
N
N
O
O
a
, 65%
76%a
a
3h
,
3i
Bn
, 54%
Bn 3j
a
Conditions: 1 (0.40 mmol), Cu(OTf)2 (0.08 mmol), TMSCF3 (1.2
mmol), CsF (0.68 mmol), Ag(bpy)2OTf (0.52 mmol), PhCl (6.0 mL),
DCM (2.0 mL), rt, 24 h. Isolated yield based on 1.
Table 1. Optimization of Reaction Conditions
Cu(OTf)2 (20 mol%)
CCl3
Cl2C
O
Cl Cl2C
CF3
F
TMSC
3 (3 equiv)
Scheme 3. Carbotrifluoromethylation with CCl3CF3
+
N
O
N
N
O
conditions
=
Ar
Ar
Ar
1a
3a
2a
H4
4-Cl-C6
(Ar
)
yield (%)b
entrya
conditions
bpy (0.2), CsF (1.0), MeCN
2a 3a
77
0
1
2
bpy (0.2), [Ag] (1.0), CsF (1.0), MeCN
[Ag] (1.0), CsF (1.0), MeCN
25 23
12 34
3
[Ag] (1.3), CsF (1.7), PhCl/DCM (3:1)
[Ag] (1.3), CsF (1.7), PhCl/DCM (3:1)
0
0
80
0
4
5c
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L
satisfactory yields, as shown in Scheme 3. The presence of a wide range
of functional groups was well tolerated. For example, ethers, silyl ethers,
ketones, esters, amides, imides, sulfonates, sulfonamides and alkyl or
aryl bromides all proved to be compatible with the reaction. Further-
more, this protocol was also applicable to complex molecules, as exem-
plified by the synthesis of steroid 5v in 62% yield. It is worth noting
that the carbotrifluoromethylation products as gem-dichlorides could
be readily converted to their CH2-derivatives in high yield by reduction
with Zn/HOAc or Bu3SnH (see SI for details), thus providing a con-
venient entry to 1,3-bis(trifluoromethylated) compounds for which no
general synthetic method was available.
Cu(OTf)2 (cat.), (cat.)
F
3CCl2C
CF3
R
TMSCF
AgF,
3
+
CCl3CF3
R
b
5a,
24 h
rt,
MeCN,
4
CCl2CF3
CCl2CF3
CCl2CF3
Ar
OR
Ar
CF3
=
CF3
=
=
CF3
=
=
5c
5d
5e
5f
68%
(Ar 2-naphthyl),
63%
5a
5b
78%
(Ar Ph),
(R Bn),
(Ar Ph),
=
4-CN-C6H
73%
2-Br-
H
C6
(R
4),
(Ar
83%
4),
63%
CCl2CF3
O
CCl2CF3
O
CCl2CF3
CF3
OR
The above copper-catalyzed transformation was also shown to be
compatible with a variety of activated alkyl chlorides, as demonstrated
in Scheme 4. For example, the use of CCl4 in place of CCl3CF3 gave
rise to the corresponding condensation products 6a and 6b in moder-
ate yields under similar conditions. Trichloromethylphosphonate also
participated in the carbotrifluoromethylation, leading to the synthesis
of 6c and 6d. A good yield (62%) of 6c was achieved with
Ar
O
O
CF3
=
CF3
74%
H
4-Cl-C6
70%
H
79%
4),
=
5k
5l
5g
5h
42%
(Ar
(Ar
=
4),
(R Ts),
(R TBDPS),
64%
t
,
=
5j
=
4- Bu-
C6
Br
5i
77%
(Ar 2-naphthyl),
CCl2CF3
CCl2CF3
OPh
CCl2CF3
O
O
OPh
55%
(DMPU)2Zn(CF3)2 (DMPU
=
1,3-dimethyl-3,4,5,6-tetrahydro-
2(1H)-pyrimidinone)11 as the CF3 source without thorough optimiza-
tion of reaction conditions. Trichloromethanesulfonate also proved to
be suitable partner in the transformation, as exemplified by the synthe-
sis of 6e. Trichloroacetate could also be employed for the reaction.
Nevertheless, a low yield of the desired product (6f) was obtained
along with 2,3-dichlorofumarate as the major byproduct apparently
resulting from the dimerization of trichloroacetate.
CF3
O
CF3
CF3
5n
5m
,
, 79%
, 76%
O
5o
, 68%
CCl2CF3
CF3
CCl2CF3
CCl2CF3
Ts
Br
N
NPhth
CF3
CF3
5r
5p
, 65%
, 68%
5q
CCl2CF3
CCl2CF3
NPhth
O
CF3
CF3
5t
, 45%
OMe
Scheme 4. Carbotrifluoromethylation with Activated Alkyl
Chlorides
5s
, 75%
H
H
F
CCl2CF3
CF3
CCl2CF3
CF3
H
L
Cu(OTf)2 (cat.), (cat.)
CCl3
O
E
-Cl
TMSCF
,
AgF,
3
R
5v
R
, 62%
O
5u
(50:50)
, 72%
6a,b
32 h
rt,
MeCN,
CCl3
CF3
CCl
4
a
Conditions: 4 (0.40 mmol), CCl3CF3 (1.0 mmol), TMSCF3 (1.2
CCl3
2P(O)(OEt)2
mmol), AgF (1.2 mmol), Cu(OTf)2 (0.04 mmol), L (0.08 mmol),
OAr
MeCN (4.0 mL), rt, 24 h. b Isolated yield based on 4.
NPhth
NPhth
CF3
CF3
CF3
d
c,
6b
, 46%
6a
, 38%
6c
, 62%
=
H4
4-CN-C6
(Ar
)
We next extended the above protocol to intermolecular three-
component carbotrifluoromethylation. We chose CCl3CF3 as the acti-
vated alkyl chloride as it is very cheap and easily available industrial
material. Direct application of the above optimized conditions to the
condensation of unactivated alkenes, CCl3CF3 and TMSCF3 gave low
yields of the desired products. Gratifyingly, after re-optimization of
reaction conditions (see Tables S3 and S4 in SI), the optimal condition
was determined as follows: 10 mol % of Cu(OTf)2 as the catalyst, 20
mol % of 4,4’-dimethoxy-2,2’-bipyridine (L) as the ligand, three
equivalents of AgF and TMSCF3 as both the CF3 source and the chlo-
ride scavenger, and acetonitrile as the solvent. Thus, a variety of unacti-
vated alkenes 4 underwent smooth carbotrifluoromethylation with
CCl3CF3 and TMSCF3, providing the corresponding products 5 in
CCl2CO2Et
O
O
CCl
O O
S
2P(O)(OEt)2
OAr
Cl2C
OCH2CF3
Ar
CF3
CF3
e
c
6f
, 13%
6d
, 52%
NPhth
t
=
c
4- Bu- H4
C6
)
=
H4
4-CN-C6
CF3
(Ar
(Ar
)
6e
, 51%
a
Conditions: 4 (0.40 mmol), E-Cl (1.0 mmol), TMSCF3 (1.2 mmol),
AgF (1.2 mmol), Cu(OTf)2 (0.04 mmol), L (0.08 mmol), MeCN (4.0
mL), rt, 32 h. Isolated yield based on 4. (DMPU)2Zn(CF3)2 and
b
c
Ag2CO3 were used in place of TMSCF3 and AgF. The reaction was run
d
in 1,2-dichloroethane.
Cu(MeCN)4BF4 was used in place of
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TMSF
TMSCF3
F-
+
e
Cu(OTf)2. A significant amount of diethyl 2,3-dichlorofumarate was
obtained.
disproportionation
F
3C
Cu(II)
Cu(I)
R
Cu(I)
CCl2CF3
L
,
Cu(OTf)2 (cat.) (cat.)
CF3
CCl3CF3
TMSCF
,
AgF,
3
R
(1)
(2)
N
R
24 h
rt,
MeCN,
8
, 74%
Ts
7
N
E
E
Cl
E
E
(85:15)
Ts
CF3
A
L
,
Cu(OTf)2 (cat.) (cat.)
CCl2CF3 CF3
Ph
Ph
CCl3CF3
TMSCF
,
AgF,
3
Cu(II)Cl-
Ag(I)
F
F
3C
Cu(II)
3C
10
, 50%
24 h
rt,
MeCN,
(86:14)
9
AgCl
To gain further insight into the reaction mechanism, the following
mechanistic experiments were conducted. The carbotrifluoromethyla-
tion of alkene 4a with CCl3CF3 was completely inhibited by a stoichi-
ometric amount of TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl
radical) or BHT (2,6-di-tert-butyl-4-methylphenol). Furthermore, the
reaction of diene 7 as a radical probe proceeded via addition- -
cyclization- - trifluoromethylation sequence, furnishing pyrrolidine 8 in
74% yield (Eq. 1). In another case, the reaction of vinylcyclopropane 9
under the above optimized conditions afforded the ring-opening prod-
uct 10 (Eq. 2). These experiments in combination with the results in
Scheme 2 unambiguously demonstrated the radical mechanism of
carbotrifluoromethylation.
Figure 1. Proposed mechanism of carbotrifluoromethylation.
Of particular interest is the remarkable radical polar effect: nucleo-
philic radicals (such as A) rather than electrophilic radicals (such as Eo)
undergo trifluoromethylation. This observation was further supported
by the fact that no dechlorotrifluoromethylation of CCl3CF3 (to give
CF3CCl2CF3) was detected in the absence of unactivated alkenes un-
der conditions otherwise identical to that in Scheme 3. This phenome-
non indicates that Cu(II)- - CF3 is electron demanding rather than elec-
tron providing in trifluoromethylation, which in turn seems to suggest
that alkylcopper(III) intermediates is less likely to be involved in the
trifluoromethylation of alkyl radicals. More mechanistic studies are
certainly required to gain a clear understanding of the mechanism.
In conclusion, we have successfully developed an unprecedented
protocol for the carbotrifluoromethylation of unactivated alkenes.
Driven by trifluoromethylation of alkyl radicals, the reaction exhibits a
regioselectivity opposite to those involving CF3 radical addition. As the
procedure is operationally simple, broad in scope, catalytic in copper,
and utilizes cheap Ruppert- - Prakash reagent as the CF3 source, the
method should find important application in the synthesis of important
trifluoromethylated molecules. Moreover, this finding should inspire
further research towards the development of new methods for trifluo-
romethylation-involved difunctionalization of alkenes with unique
regioselectivity.
A plausible mechanism for the carbotrifluoromethylation is thus
shown in Figure 1. The disproportionation of Cu(II) generates
Cu(I).12 Interaction of Cu(I) with TMSCF3 and fluoride ion leads to
Cu(I)- - CF3 that abstracts a chlorine atom from an activated alkyl chlo-
ride (E- - Cl) to give the electrophilic radical (E•) and Cl- - Cu(II)- - CF3
intermediate. The latter undergoes chloride ion transfer to Ag(I), lead-
ing to the formation of Cu(II)- - CF3 that serves as the active species for
trifluoromethylation. The addition of electrophilic radical Eo to an
unactivated alkene gives the corresponding adduct radical (A). The
radical A is then intercepted by Cu(II)- - CF3 either by direct CF3 group
transfer4, 5a, 6c or by forming alkylcopper(III) intermediate6a, 6b, 7 fol-
lowed by reductive elimination,13 resulting in the formation of the
corresponding carbotrifluoromethylation product and regeneration of
the Cu(I) catalyst.
ASSOCIATED CONTENT
Supporting Information
Full experimental details, characterizations of new compounds, and
copies of 1H, 13C and 19F NMR spectra (PDF). The material is available
free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
*E-mail: clig@mail.sioc.ac.cn
This article is protected by copyright. All rights reserved.

Synth. Catal. 2018, 360, 4084- - 4088. (f) Ye, Q.; Jiang, M.; Deng, Q.-H.;
Liu, J.-T. Copper-catalyzed intramolecular carbotrifluoromethyation of
ene-imines for the construction of 3-(2,2,2-trifluoro)ethylated 4-amino-
chromans. Adv. Synth. Catal. 2018, 360, 1402- - 1406. (g) Li, L.; Li, Z.-L.;
Gu, Q.-S.; Wang, N.; Liu, X.-Y. A remote C- - C bond cleavage- - enabled
skeletal reorganization: Access to medium-/large-sized cyclic alkenes. Sci.
Adv. 2017, 3, e1701487. (h) Yang, N.-Y.; Li, Z.-L.; Ye, L.; Tan, B.; Liu, X.-
Y. Organic base-catalysed solvent-tuned chemoselective carbotrifluoro-
methylation and oxytrifluoromethylation of unactivated alkenes. Chem.
Commun. 2016, 52, 9052- - 9055. (i) Li, L.; Li, Z.-L.; Wang, F.-L.; Guo, Z.;
Cheng, Y.-F.; Wang, N.; Dong, X.-W.; Fang, C.; Liu, J.; Hou, C.; Tan, B.;
Liu, X.-Y. Radical aryl migration enables diversity-oriented synthesis of
structurally diverse medium/macro- or bridged-rings. Nat. Commun.
2016, 7, 13852. (j) Yu, L.-Z.; Xu, Q.; Tan, X.-Y.; Shi, M. Iron- or copper-
catalyzed trifluoromethylation of acrylamide-tethered alkylidenecyclo-
propanes: facile synthesis of CF3-containing polycyclic benzazepine deriv-
atives. ACS Catal. 2016, 6, 526- - 531. (k) Zheng, J.; Deng, Z.; Zhang, Y.;
Cui, S. Copper-catalyzed divergent trifluoromethylation/cycli-zation of
unactivated alkenes. Adv. Synth. Catal. 2016, 358, 746- - 751. (l) Guo, J.-Y.;
Wu, R.-X.; Jin, J.-K.; Tian, S.-K. TfNHNHBoc as a trifluoromethylating
agent for vicinal difunctionalization of terminal alkenes. Org. Lett. 2016,
18, 3850- - 3853. (m) Sahoo, B.; Li, J.-L.; Glorius, F. Visible-light photore-
dox-catalyzed semipinacol-type rearrangement: trifluoromethylation/ring
expansion by a radical- - polar mechanism. Angew. Chem., Int. Ed. 2015, 54,
11577- - 11580. (n) Xu, P.; Hu, K.; Gu, Z.; Cheng, Y.; Zhu, C. Visible light
promoted carbodifluoroalkylation of allylic alcohols via concomitant 1,2-
aryl migration. Chem. Commun. 2015, 51, 7222- - 7225. (o) Zheng, L.;
Yang, C.; Xu, Z.; Gao, F.; Xia, W. Difunctionalization of alkenes via the
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This project was supported by the National Basic Research Program of
China (973 Program) (Grant 2015CB931900), by the National Natu-
ral Science Foundation of China (Grants 21421002, 21472220,
21532008, 21602239 and 21871285), by the Strategic Priority Re-
search Program of the Chinese Academy of Sciences (Grant
XDB20020000), and by the Shanghai Scientific and Technological
Innovation Project (18JC1410600).
REFERENCES
(1) (a) Umemoto, T. Electrophilic perfluoroalkylating agents. Chem. Rev.
1996, 96, 1757- - 1778. (b) Schlosser, M. CF3-bearing aromatic and heter-
ocyclic building blocks. Angew. Chem., Int. Ed. 2006, 45, 5432- - 5446. (c)
Shibata, N.; Matsnev, A.; Cahard, D. Shelf-stable electrophilic trifluoro-
methylating reagents: a brief historical perspective. Beilstein J. Org. Chem.
2010, 6, 65. (d) Nie, J.; Guo, H.-C.; Cahard, D.; Ma, J.-A. Asymmetric
construction of stereogenic carbon centers featuring a trifluoromethyl
group from prochiral trifluoromethylated substrates. Chem. Rev. 2011,
111, 455- - 529. (e) Studer, A. A ‘‘renaissance’’ in radical trifluoromethyla-
tion. Angew. Chem., Int. Ed. 2012, 51, 8950- - 8958. (f) Liang, T.; Neumann,
C. N.; Ritter, T. Introduction of fluorine and fluoro-containing functional
groups. Angew. Chem., Int. Ed. 2013, 52, 8214- - 8264. (g) Merino, E.; Ne-
vado, C. Addition of CF3 across unsaturated moieties: a powerful func-
tionalization tool. Chem. Soc. Rev. 2014, 43, 6598- - 6608. (h) Koike, T.;
Akita, M. Trifluoromethylation by visible-light-driven photoredox cataly-
sis. Top. Catal. 2014, 57, 967- - 974. (i) Egami, H.; Sodeoka, M. Trifluoro-
methylation of alkenes with concomitant introduction of additional func-
tional groups. Angew. Chem., Int. Ed. 2014, 53, 8294- - 8308. (j) Alonso, C.;
de Marigorta, E. M.; Rubiales, G.; Palacios, F. Carbon trifluoromethyla-
tion reactions of hydrocarbon derivatives and heteroarenes. Chem. Rev.
2015, 115, 1847- - 1935. (k) Charpentier, J.; Fruh, N.; Togni, A. Electro-
philic trifluoromethylation by use of hypervalent iodine reagents. Chem.
Rev. 2015, 115, 650- - 682. (l) Koike, T.; Akita, M. Fine design of photore-
dox systems for catalytic fluoromethylation of carbon-carbon multiple
bonds. Acc. Chem. Res. 2016, 49, 1937- - 1945.
(2) For recent selected examples, see: (a) Wang, N.; Wang, J.; Guo, Y.-L.; Li,
L.; Sun, Y.; Li, Z.; Zhang, H.-X.; Guo, Z.; Li, Z.-L.; Liu, X.-Y. Chem. Com-
mun. 2018, 54, 8885- - 8888. (b) Liang, D.; Dong, Q.; Xu, P.; Dong, Y.; Li,
W.; Ma, Y. Synthesis of CF3CH2-containing indulines by transition-metal-
free aryltrifluoromethylation of unactivated alkenes. J. Org. Chem. 2018,
83, 11978- - 11986. (c) Tang, L.; Yang, Z.; Chang, X.; Jiao, J.; Ma, X.; Rao,
W.; Zhou, Q.; Zheng, L. K2S2O8-mediated selective trifluoromethylacyla-
tion and trifluoromethylarylation of alkenes under transition-metal-free
conditions: synthetic scope and mechanistic studies. Org. Lett. 2018, 20,
6520- - 6525. (d) Zhu, M.; Zhou, K.; Zhang, X.; You, S.-L. Visible-light-
promoted cascade alkene trifluoromethylation and dearomatization of in-
dole derivatives via intermolecular charge transfer. Org. Lett. 2018, 20,
4379- - 4383. (e) Cai, S.; Tian, Y.; Zhang, J.; Liu, Z.; Lu, M.; Weng, W.;
Huang, M. Carbotrifluoromethylation of allylic alcohols via 1,2-aryl mi-
gration promoted by visible-light-induced photoredox catalysis. Adv.
visible-light-induced
trifluoromethylarylation/1,4-aryl
shift/desulfonylation cascade reactions. J. Org. Chem. 2015, 80, 5730- -
5736.
(3) (a) Gong, J.; Fuchs, P. L. Alkynylation of C-H bonds via reaction with
acetylenic triflones. J. Am. Chem. Soc. 1996, 118, 4486- - 4487. (b) Carboni,
A.; Dagousset, G.; Magnier, E.; Masson, G. One pot and selective inter-
molecular aryl- and heteroaryl-trifluoromethylation of alkenes by photo-
redox catalysis. Chem. Commun. 2014, 50, 14197- - 14200. (c) Wang, F.;
Wang, D.; Mu, X.; Chen, P.; Liu, G. Copper-catalyzed intermolecular tri-
fluoromethylarylation of alkenes: mutual activation of arylboronic acid
+
and CF3 reagent. J. Am. Chem. Soc. 2014, 136, 10202- - 10205. (d) Yang,
B.; Xu, X.-H.; Qing, F.-L. Copper-mediated radical 1,2-
bis(trifluoromethylation) of alkenes with sodium trifluoromethanesul-
finate. Org. Lett. 2015, 17, 1906- - 1909. (e) Wang, F.; Wang, D.; Wan, X.;
Wu, L.; Chen, P.; Liu, G. Enantioselective copper-catalyzed intermolecu-
lar cyanotrifluoromethylation of alkenes via radical process. J. Am. Chem.
Soc. 2016, 138, 15547- - 15550. (f) Jiang, H.; He, Y.; Cheng, Y.; Yu, S. Rad-
ical alkynyltrifluoromethylation of alkenes initiated by an electron do-
nor−acceptor complex. Org. Lett. 2017, 19, 1240- - 1243. (g) Zhou, S.;
Song, T.; Chen, H.; Liu, Z.; Shen, H.; Li, C. Catalytic radical trifluoro-
methylalkynylation of unactivated alkenes. Org. Lett. 2017, 19, 698- - 701.
(h) He, Y.-T.; Kang, D.; Kim, I.; Hong, S. Metal-free photocatalytic tri-
fluoromethylative pyridylation of unactivated alkenes. Green Chem. 2018,
20, 5209- - 5214. (i) Tu, H.-Y.; Zhu, S.; Qing, F.-L.; Chu, L. A four-
component radical cascade trifluoromethylation reaction of alkenes ena-
bled by an electron-donor-acceptor complex. Chem. Commun. 2018, 54,
12710- - 12713. (j) Chen, D.; Xu, L.; Long, T.; Zhu, S.; Yang, J.; Chu, L.
Metal-free, intermolecular carbopyridylation of alkenes via visible-light-
induced reductive radical coupling. Chem. Sci. 2018, 9, 9012- - 9017. (k)
This article is protected by copyright. All rights reserved.

Wang, Q.; Wang, B.; Deng, H.; Shangguan, Y.; Lin, Y.; Zhang, Y.; Zhang,
Z.; Xiao, Y.; Guo, H.; Zhang, C. Silver-catalyzed three-component difunc-
tionalization of alkenes via radical pathways: access to CF3-functionalized
alkyl-substituted 1,4-naphthoquinone derivatives. J. Org. Chem. 2019, 84,
1006- - 1014.
with well-defined structures undergo reductive elimination to form C-
or C-heteroatom bonds. Chin. J. Chem. 2018, 36, 1213- - 1221.
- C
(4) Shen, H.; Liu, Z.; Zhang, P.; Tan, X.; Zhang, Z.; Li, C. Trifluoromethyla-
tion of alkyl radicals in aqueous solution. J. Am. Chem. Soc. 2017, 139,
9843- - 9846.
(5) (a) Tan, X.; Liu, Z.; Shen, H.; Zhang, P.; Zhang, Z.; Li, C. Silver-catalyzed
decarboxylative trifluoromethylation of aliphatic carboxylic acids. J. Am.
Chem. Soc. 2017, 139, 12430- - 12433. (b) Xu, X.; Chen, H.; He, J.; Xu, H.
Copper-catalyzed decarboxylative trifluoromethylation of ² -ketoacids.
Chin. J. Chem. 2017, 35, 1665- - 1668.
(6) (a) Paeth, M.; Carson, W.; Luo, J.-H.; Tierney, D.; Cao, Z.; Cheng, M.-J.;
Liu, W. Copper-mediated trifluoromethylation of benzylic Csp3- - H bonds.
Chem. - - Eur. J. 2018, 24, 11559- - 11563. (b) Guo, S.; AbuSalim, D. I.;
Cook, S. P. Aqueous benzylic C- - H trifluoromethylation for late-stage
functionalization. J. Am. Chem. Soc. 2018, 140, 12378- - 12382. (c) Liu, Z.;
Xiao, H.; Zhang, B.; Shen, H.; Zhu, L.; Li, C. Copper-catalyzed remote
C(sp3)- - H trifluoromethylation of carboxamides and sulfonamides. Angew.
Chem., Int. Ed. 2019, 58, 2510- - 2513.
(7) Kautzky, J. A.; Wang, T.; Evans, R. W.; MacMillan, D. W. C. Decarboxyla-
tive trifluoromethylation of aliphatic carboxylic acids. J. Am. Chem. Soc.
2018, 140, 6522- - 6526.
(8) (a) Ruppert, I.; Schlich, K.; Volbach, W. Die ersten CF3-substituierten
organyl(chlor)silane. Tetrahedron Lett. 1984, 25, 2195- - 2198. (b) Prakash,
G. K. S.; Krishnamurti, R.; Olah, G. A. Synthetic methods and reactions.
141. Fluoride-induced trifluoromethylation of carbonyl compounds with
trifluoromethyltrimethylsilane (TMS-CF3). A trifluoromethide equivalent.
J. Am. Chem. Soc. 1989, 111, 393- - 395. (c) Shibata, N,; Mizuta, S.; Kawai,
H. Recent advances in enantioselective trifluoromethylation reactions.
Tetrahedron: Asymmetry 2008, 19, 2633- - 2644.
(9) (a) Clark, A. J. Atom transfer radical cyclisation reactions mediated by
copper complexes. Chem. Soc. Rev. 2002, 31, 1- - 11. (b) Severin, K. Ruthe-
nium catalysts for the Kharasch reaction. Curr. Org. Chem. 2006, 10, 217- -
224. (c) Pintauer, T. Catalyst regeneration in transition-metal-mediated
atom-transfer radical addition (ATRA) and cyclization (ATRC) reactions.
Eur. J. Inorg. Chem. 2010, 2010, 2449- - 2460. (d) Li, C. Halogen and chal-
cogen transfer chemistry. In Encyclopedia of Radicals in Chemistry, Biology
and Materials; Chatgilialoglu, C., Studer, A. Eds.; Wiley: Chichester, U.K.,
2012; pp 943- - 964.
(10) Liu, Z.; Chen, H.; Lv, Y.; Tan, X.; Shen, H.; Yu, H.-Z.; Li, C. Radical
carbofluorination of unactivated alkenes with fluoride Ions. J. Am. Chem.
Soc. 2018, 140, 6169- - 617.
(11) (a) Aikawa, K.; Nakamura, Y.; Yokota, Y.; Toya, W.; Mikami, K. Stable
but reactive perfluoroalkylzinc reagents: application in ligand-free copper-
catalyzed perfluoroalkylation of aryl iodides. Chem. - - Eur. J. 2015, 21, 96- -
100. (b) Aikawa, K.; Toya, W.; Nakamura, Y.; Mikami, K. Development of
(trifluoromethyl)zinc reagent as trifluoromethyl anion and difluorocar-
bene sources. Org. Lett. 2015, 17, 4996- - 4999.
(12) Nebra, N.; Grushin, V. V. Distinct mechanism of oxidative trifluorometh-
ylation with a well-defined Cu(II) fluoride promoter: hidden catalysis. J.
Am. Chem. Soc. 2014, 136, 16998- - 17001.
(13) (a) Paeth, M. et al. Csp3- - Csp3 bond-forming reductive elimination from
well-defined copper(III) complexes. J. Am. Chem. Soc. 2019, DOI:
10.1021/jacs.8b12632. (b) Liu, L.; Xi, Z. Organocopper(III) complexes
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SYNOPSIS TOC.
CF3
H
2C CHR
Cu(II)
CF3
E
Cl
E
R
F
R
TMSC
/
AgF
3
unique
regioselectivity
Cu(II) (cat.)
E
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