Copper-Catalyzed Late-Stage Benzylic C(sp3)–H Trifluoromethylation

Article abstract of DOI:10.1016/j.chempr.2019.02.006

Direct trifluoromethylation of C(sp³)–H bonds, especially in late stages, remains a formidable challenge. Herein, we describe the copper-catalyzed benzylic C(sp³)–H trifluoromethylation. With Cu(I) or Cu(II) as the catalyst, (bpy)Zn(CF₃)₂ (bpy = 2,2′-bipyridine) as the CF₃ source, and NFSI (or Selectfluor) as the oxidant, site-selective benzylic C(sp³)–H trifluoromethylation is successfully implemented in high efficiency under mild conditions. The protocol not only exhibits broad substrate scope and wide functional-group compatibility but also allows efficient late-stage C(sp³)–H trifluoromethylation of natural products or drug derivatives. The introduction of trifluoromethyl groups into organic molecules is of paramount importance in pharmaceuticals and agrochemicals because of their profound effect on properties such as lipophilicity, permeability, and metabolic stability. However, direct C(sp³)–H trifluoromethylation, which is most atom economical, remains a formidable challenge, and only a few examples with limited substrate scope and low to moderate efficiency have been reported to date. In this article, we introduce the copper-catalyzed benzylic C(sp³)–H trifluoromethylation with the easily available (bpy)Zn(CF₃)₂ complex as the CF₃ source. This unprecedented protocol not only exhibits a high efficiency and broad substrate scope but also allows the late-stage trifluoromethylation of bioactive molecules or natural product derivatives. Because the procedure is operationally simple and the conditions are mild, the method should find immediate application in the synthesis of important trifluoromethylated molecules. Trifluoromethylated molecules are of paramount importance in pharmaceuticals and agrochemicals, but methods of making them by direct C(sp³)–H trifluoromethylation are extremely rare. In this issue of Chem, Li and coworkers describe a copper-catalyzed late-stage benzylic C–H trifluoromethylation with broad substrate scope and functional-group tolerance. The reaction may serve the late-stage modification of drug candidates.

Full text of DOI:10.1016/j.chempr.2019.02.006

Article
Copper-Catalyzed Late-Stage Benzylic C(sp3)–
H Trifluoromethylation
Haiwen Xiao, Zhonglin Liu,
Haigen Shen, Benxiang Zhang,
Lin Zhu, Chaozhong Li
zhulin@mail.ustc.edu.cn (L.Z.)
clig@mail.sioc.ac.cn (C.L.)
HIGHLIGHTS
Direct benzylic C–H
trifluoromethylation enabled by
copper catalysis
Broad substrate scope and wide
functional-group compatibility
Late-stage modification of natural
products and drug derivatives
Trifluoromethylated molecules are of paramount importance in pharmaceuticals
and agrochemicals, but methods of making them by direct C(sp3)–H
trifluoromethylation are extremely rare. In this issue of Chem, Li and coworkers
describe a copper-catalyzed late-stage benzylic C–H trifluoromethylation with
broad substrate scope and functional-group tolerance. The reaction may serve the
late-stage modification of drug candidates.
Xiao et al., Chem 5, 1–10
May 9, 2019 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.02.006

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Article
Copper-Catalyzed Late-Stage
Benzylic C(sp3)–H Trifluoromethylation
1,2,3,
Haiwen Xiao,1 Zhonglin Liu,1 Haigen Shen,1 Benxiang Zhang,1 Lin Zhu,1, and Chaozhong Li
*
*
SUMMARY
The Bigger Picture
The introduction of
Direct trifluoromethylation of C(sp3)–H bonds, especially in late stages, remains
a formidable challenge. Herein, we describe the copper-catalyzed benzylic
C(sp3)–H trifluoromethylation. With Cu(I) or Cu(II) as the catalyst, (bpy)
Zn(CF3)2 (bpy = 2,20-bipyridine) as the CF3 source, and NFSI (or Selectfluor) as
the oxidant, site-selective benzylic C(sp3)–H trifluoromethylation is successfully
implemented in high efficiency under mild conditions. The protocol not only ex-
hibits broad substrate scope and wide functional-group compatibility but also
allows efficient late-stage C(sp3)–H trifluoromethylation of natural products or
drug derivatives.
trifluoromethyl groups into
organic molecules is of paramount
importance in pharmaceuticals
and agrochemicals because of
their profound effect on
properties such as lipophilicity,
permeability, and metabolic
stability. However, direct C(sp3)–H
trifluoromethylation, which is
most atom economical, remains a
formidable challenge, and only a
few examples with limited
INTRODUCTION
Trifluoromethyl groups play an increasingly important role in pharmaceuticals and
agrochemicals owing to their profound effect on properties such as lipophilicity,
permeability, and metabolic stability. Thus, the introduction of trifluoromethyl
groups into organic molecules has attracted considerable attention, and significant
progress has been achieved in this field in the past few decades.1–13 However, direct
C(sp3)–H trifluoromethylation, which is most atom economical, remains a formidable
challenge, and only a few examples have been reported to date.14–22 In this context,
allylic C(sp3)–H trifluoromethylation with Umemoto’s reagent23 or Togni’s reagent24
was reported by the groups of Liu14 and Wang,15 and benzylic C(sp3)–H trifluorome-
thylation of phenols and ortho-methyl-substituted phenylketones with Togni’s
reagent was described by Hamashima et al.16,17 These reactions proceed via the
intermediacy of CF3 radicals. Benzylic C(sp3)–H trifluoromethylation of pyridine
and quinoline derivatives with Ruppert-Prakash reagent25–27 was also known, which
takes place via oxidation followed by nucleophilic CF3‒ addition.18–22 The underde-
velopment of C(sp3)–H trifluoromethylation should be largely attributed to the lack
of methods for trifluoromethylation of alkyl radicals.28–30 We recently introduced the
trifluoromethylation of alkyl halides by reaction with (bpy)Cu(CF3)3 (bpy = 2,20-bipyr-
idine), K2S2O8, and Et3SiH in aqueous solution and proposed the mechanism of CF3
transfer to alkyl radicals from Cu(II)–CF3 intermediates.28 The method was then
extended to AgNO3- and K2S2O8-mediated decarboxylative trifluoromethylation
of aliphatic carboxylic acids with (bpy)Cu(CF3)3 and ZnMe2.29 Our strategy was
immediately applied to benzylic C(sp3)–H trifluoromethylation by the Liu group31
(Scheme 1A). Nevertheless, this protocol was applicable only to primary C(sp3)–H
bonds with electron-rich substitution on the aromatic ring. A variant of the method
substrate scope and low to
moderate efficiency have been
reported to date. In this article, we
introduce the copper-catalyzed
benzylic C(sp3)–H
trifluoromethylation with the
easily available (bpy)Zn(CF3)2
complex as the CF3 source. This
unprecedented protocol not only
exhibits a high efficiency and
broad substrate scope but also
allows the late-stage
trifluoromethylation of bioactive
molecules or natural product
derivatives. Because the
procedure is operationally simple
and the conditions are mild, the
method should find immediate
application in the synthesis of
important trifluoromethylated
molecules.
i
with the use of (bpy)Cu(CF3)3, (NH4)2S2O8, and Pr3SiH was published by the Cook
group32 during the preparation of this work (Scheme 1A). However, it requires the
use of UV (365 nm) light and the use of excess (2 equiv) alkylarenes as substrates,
and the yields are based on the copper complex.32 It is certainly highly desirable
to develop efficient and general methods for benzylic C(sp3)–H trifluoromethylation,
Chem 5, 1–10, May 9, 2019 ª 2019 Elsevier Inc.
1

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A
mediated by copper
(bpy)Cu(CF3)3, (NH4)2S2O8,
ZnMe2
CH3
or
CF3
R
R
(bpy)Cu(CF3)3, (NH4)2S2O8
i-Pr3SiH, CF3CO2H, hv (365 nm)
B catalyzed by copper (this work)
CF3
R1
Cu(I) (cat), (bpy)Zn(CF3)2
R1
NFSI or Selectfluor II
R2
R2
R1 = H, alkyl;
R2 = H, EDG, EWG
catalytic
efficient
broad scope
late-stage
Scheme 1. Benzylic C(sp3)–H Trifluoromethylation
preferably in a catalytic manner. Herein, we report the copper-catalyzed benzylic
C(sp3)–H trifluoromethylation with the novel (bpy)Zn(CF3)2 complex as the CF3
source (Scheme 1B). This unprecedented protocol not only exhibits a high efficiency
and broad substrate scope but also allows the late-stage trifluoromethylation of
bioactive molecules or natural product derivatives.
RESULTS AND DISCUSSION
Our design is shown in Figure 1. Interaction of Cu(I) with trifluoromethyl anion
generates a Cu(I)–CF3 intermediate that undergoes single electron transfer to N-flu-
orobis(benzenesulfonyl)imide (NFSI)33 to give a Cu(II)–CF3 intermediate and
N-centered radical A.34–37 The N-centered radical A abstracts a benzylic hydrogen
atom to generate the corresponding benzyl radical. The benzyl radical is then inter-
cepted by Cu(II)–CF3 either by direct CF3 group transfer28,29 or by the formation of
benzylcopper(III) intermediate followed by reductive elimination,30–32 resulting in
the formation of the corresponding trifluoromethylation product and regeneration
of the Cu(I) catalyst. However, this catalytic cycle is challenging given that the oxida-
‒
tion of CF3 anions to CF3 radicals by Cu(II) is well documented. The choice of
(PhSO2)2N F
CF3
Cu(I)
F3C
1Key Laboratory of Organofluorine Chemistry,
Center for Excellence in Molecular Synthesis,
Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
F- +
(PhSO2)2N
A
F3C Cu(II)
Cu(I)
CF3
(PhSO2)2NH
Ar
2School of Materials and Chemical Engineering,
Ningbo University of Technology, No. 201
Fenghua Road, Ningbo 315211, China
3Lead Contact
R
Ar
R
*Correspondence: zhulin@mail.ustc.edu.cn (L.Z.),
clig@mail.sioc.ac.cn (C.L.)
Ar
R
Figure 1. Design of Catalytic C(sp3)–H Trifluoromethylation
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Method A: CuOAc (cat.), NFSI
(bpy)Zn(CF3)2, PhCF3, 40 oC, 24 h
CH3
CF3
Method B: Cu(OTf)2 (cat.), Selectfluor II
(bpy)Zn(CF3)2, MeCN/DCM, RT, 24 h
R
2a, b
R
1
PhO
CF3
CF3
CF3
tBu
BuO
2b, 80%c
2c, 66%c
2a, 70%c
tBu
CF3
CF3
CF3
2d, 61%c
2e, 88%c
2f, 93%c
CO2Me
tBu
MeO2C
CF3
CF3
CF3
2g, 61%c
MeO2C
2i, 50%d
2h, 50%d
CF3
CF3
CF3
Br
CO2Me
2l, 71%d
CO2Me
2j, 81%d
Cl
CO2Me
2k, 75%d
CF3
CF3
CF3
MeO2C
CO2Me
2o, 67%d
Ac
2m, 74%d
Ac
2n, 47%d
CF3
O
CF3
Cl
Cl
CF3
Ph
2q, 83%d
O
2p, 52%d
2r, 63%c, 54%d
Scheme 2. Benzylic Trifluoromethylation of Primary C(sp3)–H Bonds
aConditions for method A: 1 (0.20 mmol), CuOAc (0.04 mmol), NFSI (0.60 mmol), (bpy)Zn(CF3)2
(0.40 mmol), PhCF3 (4.0 mL), 40ꢀC, 24 h. Conditions for method B: 1 (0.20 mmol), Cu(OTf)2
(0.02 mmol), Selectfluor II (0.60 mmol), (bpy)Zn(CF3)2 (0.40 mmol), MeCN (1.2 mL), DCM (2.8 mL),
room temperature (RT), 24 h.
bIsolated yield based on 1.
cMethod A.
dMethod B.
suitable CF3‒ source is thus crucial to the success. Indeed, our extensive study using
Ruppert-Prakash reagent (TMSCF3) as the CF3‒ source failed to initiate the desired
benzylic C(sp3)–H trifluoromethylation. We then tested the trifluoromethylzinc
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CF3
CuCN (cat.), NFSI, (bpy)Zn(CF3)2
R1
R1
Zn(OTf)2, Zn(OAc)2
PhCF3, RT, 24 h
R2
4a, b
CF3
R2
3
CF3
CF3
tBu
AcO
4c, 85%
4b, 75%
AcO
AcO
4a
, 89%
CF3
CF3
CF3
O
Ph
4d, 67%
4e, 59%
4f, 75%
CF3
CF3
O
CF3 O
OBz
OEt
X
4i (X = Cl), 54%
4j (X = Br), 56%
tBu
OR
4g, 65%
4h, 89%
CF3
CF3
CF3
R
4o (R = H), 66%
4p (R = N3), 53%c
4q (R = OAc), 44%
4k (R = Ac), 76%
4l (R = Bz), 74%
4m (R= Ts), 65%
NPhth
4n, 69%
CF3 CO2Et
O
CF3
CF3
Br
N
O
AcO
NPhth
O
4t, 78%
4s, 81%
4r, 71% (64:36)
CF3
CF3
CF3
EtO2C
O
MeO2C
4v, 61%
4u, 50%
4w, 44%
CF3
CF3
CF3
X
N
Ph
MeO
Ar
4y (X = O), 67%c
O
4za, 87%c
O
N
4x, 57%
4z (X = S), 75%c
(Ar = 4-Cl-C6H4)
4
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Scheme 3. Benzylic Trifluoromethylation of Secondary C(sp3)–H Bonds
aConditions for method C: 3 (0.20 mmol), CuCN (0.02 mmol), NFSI (0.60 mmol), (bpy)Zn(CF3)2
(0.40 mmol), Zn(OTf)2 (0.10 mmol), Zn(OAc)2 (0.10 mmol), PhCF3 (4.0 mL), RT, 24 h.
bIsolated yield based on 3.
cCu(MeCN)4BF4 was used in place of CuCN.
reagent (DMPU)2Zn(CF3)2 (DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidi-
none) recently reported by Mikami et al.38 With this zinc reagent as the CF3 source,
we were able to observe the benzylic C(sp3)–H trifluoromethylation but with low ef-
ficiency (<20% yield). In search of more stable CF3‒ salts, we prepared (bpy)Zn(CF3)2
by reacting diethylzinc with CF3I and dimethylformamide in hexane and then adding
bpy (see Supplemental Information). This new complex is more air stable and less
moisture sensitive than (DMPU)2Zn(CF3)2 and can be safely stored at room temper-
ature under argon atmosphere for at least 6 months. When (bpy)Zn(CF3)2 was
employed as the CF3 reagent, we were pleased to find that it had a much better per-
formance than (DMPU)2Zn(CF3)2 in benzylic C–H trifluoromethylation.
Extensive screening on reaction parameters was then carried out for benzylic C–H
trifluoromethylation (see Tables S1–S3). With 4-methyl-1,10-biphenyl as the model
substrate (Table S1), the optimal conditions were to run the reaction in PhCF3 at
40ꢀC by using CuOAc (20 mol %) as the catalyst, NFSI (3.0 equiv) as the oxidant,
and (bpy)Zn(CF3)2 (2.0 equiv) as the CF3 source (method A). This method was then
applied to a number of methylarenes with representative electron-rich substitution,
providing the corresponding benzylic C–H trifluoromethylation products 2a–2g in
good to excellent yields (Scheme 2). However, the extension of the method to the
trifluoromethylation of methylarenes with electron-deficient substitution resulted
in a relatively low efficiency. Given that the substituents on the aromatic ring have
little effect on benzylic C–H bond dissociation energies,39,40 this might be attributed
to a radical polar effect given that N-centered radical A is electrophilic in nature.41
We then switched NFSI to Selectfluor,42–44 a stronger oxidant and powerful reagent
in alkyl C–H functionalization.45 Gratifyingly, our optimization of conditions (Table
S2) showed that when the reaction was carried out in MeCN–DCM solution at
room temperature with Cu(OTf)2 (10 mol %) as the catalyst, Selectfluor II as the
oxidant, and (bpy)Zn(CF3)2 as the CF3 source (method B), the expected trifluorome-
thylation product could be achieved in high efficiency. The generality of the method
was then clearly demonstrated by the synthesis of trifluoromethylated products
2h–2q in satisfactory yields from the corresponding electron-deficient methylarenes
(Scheme 2). Notably, no g-lactone byproducts could be detected in the cases of
2j–2l and 2o, thus providing strong evidence for the radical mechanism of trifluoro-
methylation. Interestingly, both method A and method B were applicable to sub-
strates bearing both electron-donating and electron-withdrawing substituents on
the aromatic ring, as evidenced by the synthesis of 2r from tonalid.
Having established the catalytic protocol for the trifluoromethylation of primary benzylic
C(sp3)–H bonds, we next focused on the trifluoromethylation of secondary benzylic
C(sp3)–H bonds, which is certainly of higher value in organic synthesis. Direct application
of method A or B to the trifluoromethylation of model substrate 4-phenylbutyl acetate
resulted in a low conversion. This phenomenon might be ascribed to the relatively low
concentration of Cu(II)–CF3 species responsible for the trifluoromethylation but much
faster generation of secondary benzyl radicals given that secondary benzylic C(sp3)–H
bonds are weaker than primary ones. A possible solution is to speed up the transmeta-
‒
lation of CF3 from zinc to copper so as to increase the concentration of Cu(II)–CF3
species. We then screened a number of additives based on method A (Table S3).
With a stoichiometric amount of Zn(OTf)2 or Zn(OAc)2 as the additive, the yield of
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O
CF3
CF3
CF3
F
N
O
tBu
OMe
CO2Ph
triclosan analog
celestolide analog
ibuprofen analog
5a, 76%a, b, c
5c, 53%a, b
5b, 51%a, b
CF3
CF3
O
O
O
N
O
OAc
OAc
O
AcO
AcO
OAc
CF3
S
O H
O
salidroside analog
sulbactam analog
5d, 69% (52:48)a, b
5e, 49% (50:50)a, b
CF3
O
O
O
O
O
O
O
O
fenofibric acid analog
camphanic acid analog
5g, 83%a, b
5f, 55%a, b
Cl
CO2Me
CF3
tBu
H
O
MeO2C
F3C
H
retinoic acid receptor
O
O
enoxolone analog
H
agonist analog 5i, 92%a, b
5h, 74% (50:50)a, b
Scheme 4. Late-Stage Benzylic C–H Trifluoromethylation of Natural Products and Drug
Derivatives
a,bSee Scheme 3.
cVia method A.
trifluoromethylation was increased from 10% to 15% or 30%, respectively. Surprisingly,
the combination of Zn(OTf)2 (50 mol %) and Zn(OAc)2 (50 mol %) as additives led to a
much higher yield (55%). Use of CuCN in place of CuOAc further increased the yield
to 76%. The optimal conditions were thus determined as to run the reaction in PhCF3
at room temperature with CuCN (10 mol %) as the catalyst, NFSI (3 equiv) as the oxidant,
(bpy)Zn(CF3)2 (2 equiv) as the CF3 source, and Zn(OTf)2 (0.5 equiv) and Zn(OAc)2
(0.5 equiv) as additives (method C).
Method C was then applied to the trifluoromethylation of a variety of alkylarenes 3, and
the results are summarized in Scheme 3. Substrates with either electron-donating or
6
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F3C
X
F3C
O
CF3
S
CO2Me
CO2Me
Br
N(SO2Ph)2
6a (X = O), 97%a, b
6b (X = S), 99%a, b
6c, 61%a, b, c
6d, 52%a, b
Scheme 5. C(sp3)–H Trifluoromethylation of Alkylheteroarenes
a,b,cSee Scheme 3.
electron-withdrawing substituents on the aromatic ring all underwent benzylic C–H tri-
fluoromethylation smoothly, furnishing the corresponding products in satisfactory
yields. Site-selective trifluoromethylation was observed in the cases of 4d and 4e, which
might be rationalized by radical polar effect given that N-centered radical A is electro-
philic.41,46–48 Amino acid derivatives were also suitable substrates, as exemplified by the
synthesis of trifluoromethylated homophenylalanine ester 4r in 71% yield. The presence
of a wide range of functional groups was tolerated by the process. For example, ethers,
ketones, esters, amides, imides, sulfonates, azides, and aryl halides all proved to be
compatible with the reaction. Interestingly, the vulnerable N–O bond in 4t remained
intact, indicating the mildness of the method. It is worth mentioning that method C
was also applicable to trifluoromethylation of primary benzylic C(sp3)–H bonds. For
example, the trifluoromethylation of tonalid via method C furnished the corresponding
product 2r in 91% yield, compared with 63% via method A and 54% via method B.
The broad substrate scope and wide functional-group compatibility make possible
late-stage benzylic C–H trifluoromethylation. To demonstrate this potential, we
examined a number of well-known natural products or drug derivatives, and the
results are grouped in Scheme 4. Compound 5a as the analog of FabI inhibitor triclo-
san49 was easily achieved in 76% yield by C–H trifluoromethylation via method A.
Note that the literature method49 for the synthesis of 5a required three steps from
the corresponding aryl aldehyde in an overall 29% yield (trifluoromethylation with
TMSCF3 to give the trifluoromethyl carbinol followed by O-tosylation and subse-
quent hydrogenation). Site-selective C–H trifluoromethylation of phenyl ester of
anti-inflammatory drug ibuprofen50 led to 5b. The reaction of O-acetylated salidro-
side, an oxidative stress-induced apoptosis inhibitor,51 provided 5d in 69% yield.
4-Phenylbutyl ester of b-lactamase inhibitor sulbactam52 underwent benzylic C–H
trifluoromethylation to produce 5e. In another case, a trifluoromethylated derivative
of hypolipidemic drug fenofibric acid53 was readily prepared from the parent ester in
83% yield. Esterified enoxolone54 with anti-sodium-dichloroacetate activity was
Cu(MeCN)4BF4 (10 mol %)
NFSI, (bpy)Zn(CF3)2
CF3 N(SO2Ph)2
Zn(OTf)2, Zn(OAc)2
Ph
Ph
(1)
Ph
PhCF3, rt, 24 h
CF3
Ph
7
8, 50%
(55:45)
Ph
Ph
B
Scheme 6. Radical Clock Experiment
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nicely converted to its trifluoromethylated analog 5h in 74% yield via method C.
Finally, a retinoic acid receptor agonist analog55 with a biaryl moiety underwent
benzylic trifluoromethylation to afford 5i in 92% yield. These results demonstrate
the significant potential of the present method for late-stage trifluoromethylation.
The above protocol was also applicable to C(sp3)–H trifluoromethylation of alkyl-
substituted heteroarenes. As shown in Scheme 5, 2-methoxycarbonyl-3-methyl-
substituted benzofuran or benzothiophene underwent smooth trifluoromethylation
via method C, furnishing the corresponding product 6a or 6b in almost quantitative
yield. Trifluoromethylation of secondary C(sp3)–H bonds of alkylheteroarenes was
also accomplished, as evidenced by the synthesis of 6c and 6d. These results further
broadened the scope of application.
The results in Schemes 2, 3, 4, and 5 clearly support the proposed radical mechanism
in Figure 1. To provide more evidence, the following mechanistic experiments were
conducted. The trifluoromethylation of 4-ethylphenyl acetate (3a) was completely
inhibited by a stoichiometric amount of TEMPO (2,2,6,6-tetramethylpiperidine-N-
oxyl radical) or BHT (2,6-di-tert-butyl-4-methylphenol). When the trifluoromethyla-
tion of 3a was carried out in oxygen atmosphere, no 4a could be observed. Instead,
4-acetylphenyl acetate was formed in a 10% yield. In another experiment, C(sp3)–H
trifluoromethylation of 3u in the presence of CCl3Br (3 equiv) as the bromine source
led to the mixture of 4u (28%) and methyl 4-(1-bromoethyl)benzoate (20%) (see Sup-
plemental Information for details). Finally, phenyl-substituted cyclopropane 7 was
employed as the radical probe.56 The trifluoromethylation of 7 via method C fur-
nished the ring-opening product 8 in a 50% isolated yield rather than the expected
product B (Scheme 6). The formation of 8 should be attributed to the (PhSO2)2N
radical (A in Figure 1) addition to intermediate B. Thus, this radical clock experiment
provided unambiguous evidence not only for the benzyl radical intermediacy but
also for the involvement of N-centered radical A. The result also indicated that
CF3 radicals were unlikely to be generated in the transformation given that the addi-
tion of CF3 radicals to styrenes is highly efficient. These mechanistic experiments
further support the proposed radical mechanism depicted in Figure 1.
In conclusion, we have successfully developed a general copper-catalyzed protocol
for benzylic C(sp3)–H trifluoromethylation that allows efficient late-stage functional-
ization of a variety of organic molecules and known drugs. Because the procedure is
operationally simple and the conditions are mild, the method should find immediate
application in the synthesis of important trifluoromethylated molecules. Further-
more, the use of easily available trifluoromethylzinc complex as a CF3 source for tri-
fluoromethylation of alkyl radicals should inspire further development of more new
methods of practical value.
SUPPLEMENTAL INFORMATION
Supplemental Information can be found with this article online at https://doi.org/10.
1016/j.chempr.2019.02.006.
ACKNOWLEDGMENTS
This project was supported by the National Basic Research Program of China (973 Pro-
gram) (grant 2015CB931900), the National Natural Science Foundation of China (grants
21421002, 21472220, 21532008, 21602239, and 21871285), the Strategic Priority
Research Program of the Chinese Academy of Sciences (grant XDB20020000), and
the Shanghai Scientific and Technological Innovation Project (18JC1410600).
8
Chem 5, 1–10, May 9, 2019

Please cite this article in press as: Xiao et al., Copper-Catalyzed Late-Stage Benzylic C(sp3)–H Trifluoromethylation, Chem (2019), https://doi.org/
10.1016/j.chempr.2019.02.006
AUTHOR CONTRIBUTIONS
H.X., Z.L., H.S., B.Z., and L.Z. conducted the experiments; C.L. designed the exper-
iments and wrote the paper.
DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: November 2, 2018
Revised: January 16, 2019
Accepted: February 10, 2019
Published: March 7, 2019
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